Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][C@@H:11]1[C@@H:23]([OH:37])[C@@H:24]([N+:34]([O-])=O)[CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].O>CO.[Ni](Cl)Cl>[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][C@@H:11]1[C@@H:23]([OH:37])[C@@H:24]([NH2:34])[CH2:25][C:26]1[CH:27]=[C:28]([F:33])[CH:29]=[C:30]([F:32])[CH:31]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@@H]1[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Reaction time: 0.33 h
Yield: 94.9 %

Procedure:
Add sodium borohydride (0.242 mg, 6.42 mmol) over 1 minute to a solution of (2R,4R)-4-benzyloxy-2-[(1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-2-nitropropyl]pyrrolidine-1-carboxylic acid tert-butyl ester (0.696 g, 1.41 mmol) and nickel (II) chloride (0.29 g, 2.25 mmol) in methanol (30 mL) at room temperature. Stir 20 minutes, add water (3 mL) and evaporate the methanol. Partition the residue with ethyl acetate and water. Filter through a filtering agent, wash with ethyl acetate (300 mL), separate away the aqueous layer, wash with saturated aqueous sodium chloride, dry (magnesium sulfate), filter and concentrate to give the title compound as a colorless oil (619 mg, 95%).
Reaction SMILES: C(N(CC)CC)C.Cl.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)=[CH:12][CH:11]=1.[C:21](Cl)(=[O:23])[CH3:22]>C1COCC1.O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17]2)=[CH:14][CH:15]=1
Reactant: CC(=O)Cl
Reactant: Brc1ccc(C2CCNC2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1CCC(c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 117.8 %

Procedure:
Triethylamine (192 mg, 1.9 mmol) was added to a suspension of 3-(4-bromophenyl)pyrrolidine hydrochloride (200 mg, 0.76 mmol) in anhydrous THF (5 mL). The mixture was stirred at room temperature for 5 minutes and then treated with acetyl chloride (66 mg, 0.84 mmol). The reaction mixture was stirred for 20 hours at room temperature. The reaction mixture was diluted with water and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give 1-[3-(4-bromophenyl)pyrrolidin-1-yl]ethanone (0.24 g, quantitative yield) as an oil which was used directly in the next step. MS (ES+) 267.9 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:15])([F:14])[CH:11]1[O:13][CH2:12]1>>[C:2]1([CH2:1][N:8]([CH2:12][CH:11]([OH:13])[C:10]([F:15])([F:14])[F:9])[CH2:12][CH:11]([OH:13])[C:10]([F:15])([F:14])[F:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)C1CO1
Reactant: NCc1ccccc1
Product: OC(CN(Cc1ccccc1)CC(O)C(F)(F)F)C(F)(F)F
Temperature: 80 °C
Yield: 57.8 %

Procedure:
Benzylamine (1.5 eq, 2.88 g, 2.94 mL, 26.8 mmol) was combined with 3,3,3-trifluoro-1,2-epoxypropane (2.0 g, 17.86 mmol) in a sealed glass tube and heated at 80° C. for 18 h. Upon cooling to room temperature, the reaction mixture formed a slushy white solid. The solid was collected by filtration and washed with diethyl ether. The mother liquor was concentrated in vacuo to give 1.71 g (43%) of the desired 1,1′-[(phenyl-methyl)imino]bis[3,3,3-trifluoro-2-propanol] product as a colorless oil. FABMS m/z=332 [M+H]+. 1H NMR (CDCl3) δ 2.85-2.96 (m, 4H), 3.94 (s, 2H), 3.94-3.97 (m, 2H), 7.24-7.37 (m, 5H).
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>O>[F:35][C:36]1[CH:41]=[C:40]([C:13]2[C:18]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: OB(O)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(F)c3)c2cc1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonate solution (1 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 3-fluorophenylboronic acid (50 mg) under an argon atmosphere, and the mixture was stirred at 70° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (43 mg, yield 87%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([C:13]1[N:14]=[C:15]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[C:22]=2[Cl:29])[C:16]([NH2:20])=[N:17][C:18]=1[NH2:19])#N.C[OH:31]>C1(C)C=CC=CC=1>[CH:11]([C:13]1[N:14]=[C:15]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[C:22]=2[Cl:29])[C:16]([NH2:20])=[N:17][C:18]=1[NH2:19])=[O:31]
Reactant: N#Cc1nc(-c2cc(Cl)cc(Cl)c2Cl)c(N)nc1N
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: Nc1nc(N)c(-c2cc(Cl)cc(Cl)c2Cl)nc1C=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Diisobutylaluminium hydride (1.5 M in toluene) (2.12 ml, 3.18×10−3 mole) was added dropwise at 0° C. under nitrogen to a suspension of 5-Cyano-2,6-Diamino-3-(2,3,5-trichlorophenyl)pyrazine (0.5 g, 1.59×10−3 mole) in dry toluene (70 ml) and the reaction was stirred at 0° C. for 1 hr. A further one equivalent of diisobutylaluminium hydride was then added and the mixture again stirred at 0° C. for 1 hr. Methanol (1 ml) was added carefully at 0° C. under nitrogen to destroy excess hydride and the reaction was warmed to room temperature. Ethyl acetate (100 ml) was added and the solution was washed with 5% citric acid solution (2×100 ml). The organic layer was separated, washed with brine (100 ml), dried over magnesium sulphate, filtered and the filtrate evaporated in vacuo to give the desired product. Yield 0.340 g (67%), N.m.r. (D6DMSO) δ: 7.53 (1H, d), 7.91 (1H, d), 6.90-7.80 (4H, b), 9.49 (1H, s).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[F:27][C:28]1[CH:43]=[CH:42][C:31]2[N:32]([CH3:41])[C:33]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[N:34][C:30]=2[CH:29]=1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:38]2[CH2:39][CH2:40][N:35]([C:33]3[N:32]([CH3:41])[C:31]4[CH:42]=[CH:43][C:28]([F:27])=[CH:29][C:30]=4[N:34]=3)[CH2:36][CH2:37]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Cn1c(N2CCNCC2)nc2cc(F)ccc21
Product: Cn1c(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc2cc(F)ccc21

Procedure:
Prepared analogously to Example 17 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 5-fluoro-1-methyl-2-piperazin-1-yl-1H-benzimidazole
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][NH2:10].C1COCC1.CCOC(C)=O>CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:10][CH3:9])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CN
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1cc(Cl)ncn1
Reaction time: 18 h
Yield: 62 %

Procedure:
To a solution of 4,6-dichloro-pyrimidine (7.45 g, 50 mmol) in iPrOH (50 mL) was added a solution of methyl amine in THF (2M, 30 mL, 60 mmol) at room temperature. The resulting mixture was stirred for 18 hours. The mixture was concentrated and the residue was purified by flash chromatography on silica eluting with DCM:EtOAc=6:1-1:1 to obtain the title compound (4.4 g, yield: 62%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.96 (d, 3H), 5.22-5.36 (bs, 1H), 6.35 (s, 1H), 8.35 (s, 11H); MS (ESI): 144 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10](Cl)(=[O:12])=[O:11])[S:7][C:6]=2[CH:14]=1.Cl.[NH2:16][C@H:17]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[O:31][C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[C:18]1=[O:32]>>[O:31]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH2:22][N:19]1[CH2:20][CH2:21][C@H:17]([NH:16][S:10]([C:8]2[S:7][C:6]3[CH:14]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[CH:9]=2)(=[O:12])=[O:11])[C:18]1=[O:32]
Reactant: N[C@H]1CCN(Cc2cc3ncccc3o2)C1=O
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Agent: Cl
Product: O=C1[C@@H](NS(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1cc2ncccc2o1

Procedure:
The title compound is prepared as described in EXAMPLE 1, Part K using 6-chloro-benzo[b]thiophene-2-sulfonyl chloride and 3-(S)-amino-1-(furo[3,2-b]pyridin-2-ylmethyl)-pyrrolidin-2-one hydrochloride as starting material. The crude product is purified by column chromatography eluting with a gradient of 25% EtOAc/CH2Cl2 to 90% EtOAc/CH2Cl2 to provide the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[C:19]([NH:27][C:28]2[N:37]=[CH:36][C:35]3[N:34]([CH3:38])[C:33](=[O:39])[CH2:32][N:31]([CH:40]([CH3:42])[CH3:41])[C:30]=3[N:29]=2)[CH:20]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:22]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:15])[NH:16][C:17]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:20]=[C:19]([NH:27][C:28]2[N:37]=[CH:36][C:35]3[N:34]([CH3:38])[C:33](=[O:39])[CH2:32][N:31]([CH:40]([CH3:42])[CH3:41])[C:30]=3[N:29]=2)[CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(N)cc(S(C)(=O)=O)c3)nc21
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(NC(=O)[C@@H]4CCCN4C(=O)OC(C)(C)C)cc(S(C)(=O)=O)c3)nc21
Yield: 25.2 %

Procedure:
The (S)-enantiomer was prepared with the same procedure used for the (R)-enantiomer and described in Scheme 12 starting from (S)pyrrolidine-1,2-dicarboxylic acid tert butyl ester (44 mg; 0.204 mmol) and 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (40 mg; 0.102), 15.2 mg (0.026 mmol; 25.2% yield) of the desired compound were obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[O:22])[CH:15]=3)[C:11]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)=[C:8]2[S:9][CH:10]=1)=O)C.[NH3:40]>CO>[N:37]1[CH:36]=[CH:35][C:34]([C:11]2[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:26][CH:25]=4)=[O:22])[CH:15]=3)=[N:13][N:7]3[C:6]([C:4]([NH2:40])=[O:3])=[CH:10][S:9][C:8]=23)=[CH:39][CH:38]=1
Reactant: CCOC(=O)c1csc2c(-c3ccncc3)c(-c3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)nn12
Reactant: N
Solvent: CO
Product: NC(=O)c1csc2c(-c3ccncc3)c(-c3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)nn12
Temperature: 60 °C
Reaction time: 32 h
Yield: 46 %

Procedure:
7-Pyridin-4-yl-6-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-pyrazolo[5,1-b]-thiazole-3-carboxylic acid ethyl ester (31 mg, 0.056 mmol) was suspended a 7 N ammonia solution in methanol (1.5 mL) in a screw cap Pyrex tube. The mixture was stirred at 60° C. for 32 hours and then allowed to cool slowly to room temperature during the night. The suspended solid was filtered, washed with DCM and dried at 50° C. under high vacuum to give 13 mg of 7-pyridin-4-yl-6-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-pyrazolo[5,1-b]thiazole-3-carboxylic acid amide (46%) as off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].CS([C:42]1[N:47]=[C:46]([CH3:48])[CH:45]=[C:44]([CH3:49])[N:43]=1)(=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][C:42]3[N:47]=[C:46]([CH3:48])[CH:45]=[C:44]([CH3:49])[N:43]=3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: Cc1cc(C)nc(S(C)(=O)=O)n1
Product: COc1ccc(CC2c3cc(Oc4nc(C)cc(C)n4)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 2-methane-sulfonyl-4,6-dimethyl-pyrimidine
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[Cl:30][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][CH2:15][CH2:14][C@@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[C:18]([C:32]3[CH:33]=[C:34]([CH3:39])[CH:35]=[C:36]([CH3:38])[CH:37]=3)[C:19](=[O:31])[NH:20]2)=[CH:25][C:24]=1[N+:27]([O-:29])=[O:28]
Reactant: Cc1cc(C)cc(-c2c(OCC[C@@H]3CCCCN3C(=O)OC(C)(C)C)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1cc(C)cc(-c2c(OCC[C@@H]3CCCCN3)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C

Procedure:
To a solution of (S)-2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-nitro-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (35 mg in 2 mL dry methylene chloride) was added 2 drops of anisole followed by 2 mL of trifluoroacetic acid and the mixture stirred at room temperature. After 30 minutes the solvents were removed in vacuo. The residue was azeotroped in vacuo successively from 2 mL carbon tetrachloride, 2 mL chloroform and 2 mL methylene chloride and the final concentrate purified by preparative tlc on silica gel (chloroform: 10% ammonium hydroxide in methanol, 90:10) to give the title compound, 17 mg.
Reaction SMILES: [CH:1]1([C@@H:4]([NH2:6])[CH3:5])[CH2:3][CH2:2]1.[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14](O)=[O:15])=[N:12][CH:13]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([NH:6][C@H:4]([CH:1]2[CH2:3][CH2:2]2)[CH3:5])=[O:15])=[N:12][CH:13]=1
Reactant: C[C@H](N)C1CC1
Reactant: O=C(O)c1ccc(Br)cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1ccc(Br)cn1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1S)-1-Cyclopropylethanamine (0.50 mL, 5.4 mmol, Alfa Aesar: Cat. #H27499) was added to a mixture of 5-bromopyridine-2-carboxylic acid (1.0 g, 5.0 mmol, Alfa Aesar: Cat. #B25675) in methylene chloride (30.0 mL), followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.4 g, 5.4 mmol) and N,N-diisopropylethylamine (1.7 mL, 9.9 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was worked up with aqueous Na2CO3, and extracted with dichloromethylene (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-15%) to afford the desired product. LCMS (M+H)+: m/z=269.0/271.0.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]([CH2:22][C:23](O)=[O:24])[C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1)[CH3:27]>>[CH2:26]([N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1)[C:23](=[O:24])[CH2:22][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][N:8]=1)(=[O:11])=[O:12])[C:14]1[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH3:27]
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)C)cn2)cn1
Reactant: CCNCc1cccc(C)n1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-(6-methoxy-pyridin-3-yl)-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:11])[C:9]#[N:10].B.C1COCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:11])[CH2:9][NH2:10]
Reactant: CC(C#N)c1ccccc1Cl
Agent: B
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(CN)c1ccccc1Cl
Temperature: 25 °C
Yield: 96.6 %

Procedure:
To a solution of 2-(2-chlorophenyl)propanenitrile (14 g, 84.8 mmol) in toluene at 0° C. was added BH3.THF (127, 255 mmol) and the reaction was warmed to room temperature and heated at reflux for 4 h. The reaction mixture was cooled; quenched with water, concentrated and the residue was purified by column chromatography (silica, ethyl acetate/hexanes gradient) to obtain the desired product (13.9 g, 97%) as a reddish oil: ESI MS m/z 170 [C9H12ClN+H]+.
Reaction SMILES: F[C:2]1[C:3]([F:13])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[Cl:14][CH2:15][CH2:16][CH2:17]I.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[Cl:14][CH2:15][CH2:16][CH2:17][N:7]1[C:6]2[CH:12]=[CH:2][C:3]([F:13])=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11]
Reactant: O=C1COc2cc(F)c(F)cc2N1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C1COc2cc(F)ccc2N1CCCCl
Temperature: 25 °C
Reaction time: 40 h
Yield: 95.3 %

Procedure:
A reaction flask was charged with 6,7-difluoro-4H-benzo[1.4]oxazin-3-one (1.5 g, 8.1 mmol), 1-chloro-3-iodopropane (1.44 g, 8.1 mmol), and Cs2CO3 (4.0 g, 12.2 mmol) in MeCN (10 mL) and stirred at rt for 40 h. The reaction mixture was concentrated, water added, and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiO2; n-heptane/EtOAc 2:1) to give the title compound (1.88 g, 89%). 1H NMR (CDCl3) d 6.99 (dd, J=8.0 Hz, J=5.6 Hz, 1H), 6.79-6.72 (m, 2H), 4.59 (s, 2H), 4.08 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.0 Hz, 2H) 2.18-2.10 (m, 2H); 13C NMR (CDCl3) d 163.9, 159.1 (d, J=244.1 Hz), 146.4 (d, J=11.9 Hz), 124.9 (d, J=3.0 Hz), 115.4 (d, J=9.6 Hz), 109.5 (d, J=22.7 Hz), 105.4 (d, J=26.2 Hz), 67.7, 42.4, 39.2, 30.1.
Reaction SMILES: C[C:2]1[C:11]2[C:10](=[O:12])[CH:9]=[CH:8][C:7](=[O:13])[C:6]=2[NH:5][C:4](=[O:14])[CH:3]=1.CO[C:17]1C=CC(OC)=C[C:18]=1N.CC1(C)OC(=O)C=C(C)O1.S(=O)(=O)(O)O.Br.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>>[CH2:17]([C:3]1[C:4](=[O:14])[NH:5][C:6]2[C:7](=[O:13])[CH:8]=[CH:9][C:10](=[O:12])[C:11]=2[CH:2]=1)[CH3:18]
Reactant: Cc1cc(=O)[nH]c2c1C(=O)C=CC2=O
Reactant: COc1ccc(OC)c(N)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: Br
Agent: CC1=CC(=O)OC(C)(C)O1
Product: CCc1cc2c([nH]c1=O)C(=O)C=CC2=O

Procedure:
Thus, for example the dienophile, 4-methyl-(1H)-quinoline-2,5,8-trione, may be obtained by acetoacetylation of 2,5-dimethoxyaniline with 2,2,6-trimethyl-4H-1,3-dioxin-4-one, followed by Knorr cyclization with sulfuric acid, demethylation with hydrobromic acid and oxidation with potassium dichromate in an acidic medium. The starting dienophile, 3-ethyl-1H-quinoline-2,5,8-trione, may be obtained through Vilsmeier-Haack formylation of 2,5-dimethoxybutyranilide, followed by acidic hydrolysis and oxidative demethylation with cerium ammonium nitrate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:26]([N:29]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:32]([CH2:41][C:42]([NH:44][C@@H:45]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:46](O)=[O:47])=[O:43])[C:31](=[O:56])[CH:30]1[CH:57]([CH3:59])[CH3:58])(=[O:28])[CH3:27]>C(OCC)(=O)C>[C:26]([N:29]1[CH:34]=[C:33]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:32]([CH2:41][C:42]([NH:44][C@@H:45]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:46]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:47])=[O:43])[C:31](=[O:56])[CH:30]1[CH:57]([CH3:59])[CH3:58])(=[O:28])[CH3:27]
Reactant: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(=O)O)C(=O)C1C(C)C
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)C1C(C)C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
4-Nitrophenol (1.39 g) and dicyclohexylcarbodiimide (2.01 g) are added to a solution of (2S)-2-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropionic acid (4.30 g, Compound No. 13-1) in ethyl acetate (100 ml), and the mixture is stirred overnight. The resulting impurity is filtered out, then the filtrate is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (4.52 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:17])[C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[CH2:8][S:9]([CH3:12])(=[O:11])=[O:10].[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[C:29]([CH2:30][NH2:31])=[CH:28][C:27]([C:32]([F:35])([F:34])[F:33])=[N:26]2)[CH:22]=[CH:23][CH:24]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[C:29]([CH2:30][NH:31][C:14](=[O:16])[CH:13]([C:4]3[CH:5]=[CH:6][C:7]([CH2:8][S:9]([CH3:12])(=[O:10])=[O:11])=[C:2]([F:1])[CH:3]=3)[CH3:17])=[CH:28][C:27]([C:32]([F:33])([F:34])[F:35])=[N:26]2)[CH:22]=[CH:23][CH:24]=1
Reactant: CC(C(=O)O)c1ccc(CS(C)(=O)=O)c(F)c1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C(=O)NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)c1ccc(CS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.4 %

Procedure:
To a stirred solution of 2-(3-fluoro-4-(methylsulfonylmethyl)phenyl)propanoic acid (68 mg, 0.231 mmol) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (60 mg, 0.231 mmol) in THF (1.8 mL) were added O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluorborat (73 mg, 0.231 mmol), 1-hydroxybenzotriazole (30 mg, 0.231 mmol) and N-ethyldiisopropylamine (0.078 mL, 0.462 mmol). The reaction mixture was stirred for 48 h at room temperature, concentrated in vacuo and the residue was purified by CC (eluent: ethyl acetate/cyclohexane (3:2)) to give N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methylsulfonyl-methyl)-phenyl]-propionamide (83 mg, 69%).
Reaction SMILES: [C:1]([O:7][C:8]1([CH3:17])[CH2:13][CH2:12][CH:11]([CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]>CO>[OH:4][C@H:3]([CH3:5])[CH2:2][C:1]([O:7][C:8]1([CH3:17])[CH2:9][CH2:10][CH:11]([CH:14]([CH3:15])[CH3:16])[CH2:12][CH2:13]1)=[O:6]
Reactant: CC(=O)CC(=O)OC1(C)CCC(C(C)C)CC1
Solvent: CO
Product: CC(C)C1CCC(C)(OC(=O)C[C@@H](C)O)CC1
Yield: 98.4 %

Procedure:
144.2 g (0.60 mol) of 1-menthyl acetoacetate, 98.8 mg (12.0 μmol) of a catalyst [{RuCl((R)-SEGPHOS)}2(μ-Cl)3][NH2Me2] and 75 ml of methanol were put into a 500 ml capacity autoclave and allowed to undergo the reaction at 70° C. for 5.5 hours under a hydrogen pressure of 4 MPa. The thus obtained reaction solution was subjected to evaporation of the solvent and then distilled under a reduced pressure (121° C./170 Pa) to obtain 143.1 g (yield 98.4%) of the (3R)-1-menthyl 3-hydroxybutyrate of interest as a colorless oily substance.