Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[Cl:16]N1C(=O)CCC1=O.O>CN(C=O)C>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][C:14]=2[Cl:16])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: [N-]=[N+]=Nc1ccc(-c2csc(N)n2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=Nc1ccc(-c2nc(N)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-azidophenyl)thiazol-2-amine (1.18 g, 5.43 mmol) in DMF (18 mL) at 0° C. was added 1-chloropyrrolidine-2,5-dione (0.746 g, 5.59 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was poured into water (100 mL). The precipitate that formed was collected by filtration, washed with water, and dried under high vacuum to give 4-(4-azidophenyl)-5-chlorothiazol-2-amine.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[C:11]([N:21]2[CH2:26][C@H:25]([CH3:27])[O:24][C@H:23]([CH3:28])[CH2:22]2)=[C:12]([CH:17]=[CH:18][C:19]=1[F:20])[C:13]([O:15][CH3:16])=[O:14].CON(C)[C:32](=[O:34])[CH3:33]>C1COCC1>[C:32]([C:18]1[C:19]([F:20])=[C:10]([Cl:9])[C:11]([N:21]2[CH2:22][C@H:23]([CH3:28])[O:24][C@H:25]([CH3:27])[CH2:26]2)=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:34])[CH3:33]
Reactant: CON(C)C(C)=O
Reactant: COC(=O)c1ccc(F)c(Cl)c1N1C[C@@H](C)O[C@@H](C)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(C)=O)c(F)c(Cl)c1N1C[C@@H](C)O[C@@H](C)C1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
To a stirred solution of LDA (3.1 eq) at −50° C. in THF was added methyl 3-chloro-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-4-fluorobenzoate (Intermediate 47, 1.5 g, 4.96 mmol) in anhydrous THF (10 mL) dropwise and the solution was stirred for 1 h at −50° C. N-methoxy-N-methylacetamide (1.66 g, 14.9 mmol) in THF (5 mL) was added dropwise and stirring was continued for additional 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulphate. The solvent was removed under vacuum and the residue was purified over silica gel chromatography column using ethyl acetate-pet. ether gradient to obtain the title compound. Yield: 800 mg, (47%)
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[C:6]([OH:9])=[C:5]([CH:10](O)[C:11]([F:14])([F:13])[F:12])[N:4]([CH3:16])[C:3]=1[CH3:17].[N:18]1[CH:23]=CC=C[CH:19]=1.S(Cl)(Cl)=O.CNC>C(#N)C>[Cl:1][C:2]1[C:7](=[O:8])[C:6]([OH:9])=[C:5]([CH:10]([N:18]([CH3:23])[CH3:19])[C:11]([F:14])([F:13])[F:12])[N:4]([CH3:16])[C:3]=1[CH3:17]
Reactant: Cc1c(Cl)c(=O)c(O)c(C(O)C(F)(F)F)n1C
Reactant: c1ccncc1
Agent: CNC
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: Cc1c(Cl)c(=O)c(O)c(C(N(C)C)C(F)(F)F)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
3-Chloro-5-hydroxy-1,2-dimethyl-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (618 mg, 2.3 mmol) was mixed with pyridine (276 μL, 3.4 mmol) in acetonitrile (10 mL) at room temperature. Thionyl chloride (249 μL, 3.41 mmol) was added dropwise. After being stirred at room temperature for 30 minutes, the reaction mixture was concentrated by rotary evaporation. The residue was dried under vacuum and then mixed with ethanol (20 mL) under ice-water bath. An ethanolic dimethylamine (5.6 M, 4.06 mL, 22.8 mmol) solution was added at about 5° C. and the mixture was stirred for 20 minutes. The reaction mixture was concentrated by rotary evaporation. The residue was mixed with water (10 mL) and the pH of the solution was adjusted to 5.5. The precipitated solid was collected by suction filtration, and washed with water, then triturated with ether/hexanes to give 3-chloro-6-[1-(dimethylamino)-2,2,2-trifluoroethyl]-5-hydroxy-1,2-dimethylpyridin-4(1H)-one (380 mg) as an off-white solid. Yield=56%; 1H NMR (CDCl3, 90 MHz) δ (ppm): 4.88 (q, J=8.6 Hz, 1H), 4.08 (s, 3H), 2.65-2.81 (m, 3H) and 2.39 (s, 6H); MS m/z 299 [M+1]+.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[CH3:12][N:13]1[C:21]2[N:20]=[CH:19][NH:18][C:17]=2[C:16](=[O:22])[NH:15][C:14]1=[O:23].CN(C)C=O>O>[CH2:2]([N:18]1[C:17]2[C:16](=[O:22])[NH:15][C:14](=[O:23])[N:13]([CH3:12])[C:21]=2[N:20]=[CH:19]1)[C:3]#[C:4][CH3:5]
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1cnc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Bromo-2-butyne (55.3 mL) and anhydrous potassium carbonate (84.9 g) were added to a mixture of 3-methylxanthine [CAS No. 1076-22-8] (100 g) and N,N-dimethylformamide (1000 mL), and this reaction solution was stirred at room temperature for 18 hours. After completion of the reaction, water (1000 mL) was added to the reaction solution, this was stirred at room temperature for one hour, and then the white precipitate was collected by filtration. The white solid obtained was washed with water and t-butyl methyl ether to give the title compound (112 g).
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:13](Cl)(=[O:24])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[CH3:8][S:7][C:1]1[CH:6]=[CH:5][C:4]([C:13](=[O:24])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([C:4]2[CH:5]=[CH:6][C:1]([S:7][CH3:8])=[CH:2][CH:3]=2)=[O:22])=[CH:3][CH:2]=1
Reactant: CSc1ccccc1
Reactant: O=C(Cl)CCCCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CSc1ccc(C(=O)CCCCCCCC(=O)c2ccc(SC)cc2)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Thioanisole (23.5 ml, 0.20 mol) is added to a suspension of AlCl3 (27.3 g, 0.205 mol) in 200 ml of CH2Cl2. Azelaoyl chloride (19.7 ml, 0.10 mol) is added dropwise slowly, while the reaction mixture is cooled in an ice bath and the reaction solution is stirred for 19 h at room temperature. Then, the reaction solution is poured into ice-water. The produced white precipitate is filtered off and the crude product is extracted from the filtrate with CH2Cl2, washed with brine, dried over MgSO4, and concentrated. The residue is purified by recrystallization from i-Pr2O—CHCl3. The product is obtained as a white solid. 1H NMR (CDCl3), δ[ppm]: δ1.35-1.43 (m, 6H), 1.72 (t, 4H), 2.52 (s, 6H), 2.91 (t, 4H), 7.26 (d, 4H), 7.87 (d, 4H)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:33])(=[N:27][C:28](=[O:32])[NH:29][CH2:30][CH3:31])=[O:26])=[CH:21][CH:20]=1>>[CH2:30]([NH:29][C:28]([N:27]=[S:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:2]2[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][N:3]=2)=[CH:24][CH:23]=1)([CH3:33])=[O:26])=[O:32])[CH3:31]
Reactant: CCNC(=O)N=S(C)(=O)c1ccc(N)cc1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Product: CCNC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](C)CO)n2)cc1
Yield: 26 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (296.3 mg, 1.1 mmol) with (RS)—S-(4-aminophenyl)-N-(ethylcarbamoyl)-S-methylsulphoximide (241 mg, 1 mmol) according to procedure 5c, the desired product is obtained in 26% yield (133 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: C(O[C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:27])[CH:14]([NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([Cl:25])[CH:19]=1)[CH3:15])=[O:7])(C)(C)C.[O:28]=[C:29]1[O:33][CH:32]([O:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39]C=2)[CH:31]([NH:43]C(C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=O)[CH2:30]1>>[CH:36]1([CH2:35][O:34][CH:32]2[CH:31]([NH:43][C:6]([CH:8]3[CH2:12][CH2:11][CH2:10][N:9]3[C:13](=[O:27])[CH:14]([NH:16][C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([Cl:25])[CH:19]=3)[CH3:15])=[O:7])[CH2:30][C:29](=[O:28])[O:33]2)[CH2:37][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)OC(C)(C)C
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCC1CCCCC1
Yield: 56 %

Procedure:
Prepared from 97a and syn-(2-cyclohexylmethoxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester according to the procedure used to prepare 98a to afford 113 mg (56% yield) of the title compound. 1H-NMR (500 MHz, CDCl3): δ 0.70-1.35 (m, 5H), 1.35-1.90 (m, 8H), 1.90-2.20 (m, 3H), 2.30-2.60 (m, H), 2.80-3.00 (m, H), 3.15-3.80 (m, 4H), 4.28-4.75 (m, 4H), 4.89-4.93 (m, H), 5.42 (d, H), 6.74 (d, H), 6.87 (d, H), 7.30 (d, H), 7.51-7.53 (m, H), 7.74 (d, H); retention time on analytical HPLC: 12.02 min; LC-MS: m/z=535 (M+H+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:14][CH3:15])=[C:7]([C@H:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:8]=1.Br[C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([C:26]([O:28]CC)=[O:27])=[C:19]2[CH:18]=1>>[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:14][CH3:15])=[C:7]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[C:19]3[CH:18]=2)[CH:8]=1
Reactant: CCOC(=O)c1cnn2ccc(Br)cc12
Reactant: COc1ccc(F)cc1[C@H]1CCCN1
Agent: Cl
Product: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2c1

Procedure:
The title compound was prepared by a method substantially similar to that mentioned in step-5 and step-6 of example-3 using (R)-2-(5-Fluoro-2-methoxyphenyl)pyrrolidine hydrochloride (step-1 of example-269) and Ethyl 5-bromo-pyrazolo[1,5-a]pyridine-3-carboxylate to afford the product as white solid. MS (ESI): m/z 356.1 (M+H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].Cl.[NH2:6][C:7]1[C:15]2[S:14][C:13]([Cl:16])=[N:12][C:11]=2[C:10]([Cl:17])=[CH:9][C:8]=1[F:18]>C1(C)C=CC=CC=1>[Cl:16][C:13]1[S:14][C:15]2[C:7]([N:6]=[C:1]=[O:2])=[C:8]([F:18])[CH:9]=[C:10]([Cl:17])[C:11]=2[N:12]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1c(F)cc(Cl)c2nc(Cl)sc12
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1c(F)cc(Cl)c2nc(Cl)sc12
Temperature: 100 °C

Procedure:
31 ml of a 20% solution of phosgene in toluene was added, dropwise, at room temperature to a suspension of 5.1 g 7-amino-2,4-dichloro-6-fluorobenzothiazole hydrochloride in 30 ml abs. toluene. The mixture was heated for 8 hours at 100° C. and the toluene removed in vacuo. The residue was triturated with hexane. Yield: 4.8 g=90% of theory m.p.: 95°-98° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([N:20]3[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]3)[CH:11]=2)=[CH:4][C:3]=1[NH:27][C:28]([N:30]1[C:34]2[N:35]=[CH:36][N:37]=[C:38](Cl)[C:33]=2[CH:32]=[CH:31]1)=[O:29].[NH2:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44]([NH2:46])=[O:45]>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([N:20]3[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]3)[CH:11]=2)=[CH:4][C:3]=1[NH:27][C:28]([N:30]1[C:34]2[N:35]=[CH:36][N:37]=[C:38]([NH:40][C:41]3[CH:49]=[CH:48][CH:47]=[C:43]([C:44](=[O:45])[NH2:46])[CH:42]=3)[C:33]=2[CH:32]=[CH:31]1)=[O:29]
Reactant: NC(=O)c1cccc(N)c1
Reactant: Cc1cn(-c2cc(C(=O)Nc3ccc(C)c(NC(=O)n4ccc5c(Cl)ncnc54)c3)cc(C(F)(F)F)c2)cn1
Solvent: CC(=O)O
Product: Cc1cn(-c2cc(C(=O)Nc3ccc(C)c(NC(=O)n4ccc5c(Nc6cccc(C(N)=O)c6)ncnc54)c3)cc(C(F)(F)F)c2)cn1
Temperature: 80 °C
Reaction time: 24 h
Yield: 72.9 %

Procedure:
4-Chloro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzoylamino]-phenyl}-amide, (50 mg, 0.09 mmol), prepared as in reference 3, in glacial acetic acid (2 mL) is mixed with 3-aminobenzamide (24.5 mg, 0.18 mmol) and shaken at 80° C. for 24 hours. The resulting mixture is directly purified by preparative HPLC-MS to give 4-(3-carbamoyl-phenylamino)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzoylamino]-phenyl}-amide (42.9 mg, yield 73%); 1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 10.65 (s, 1H), 9.96 (s, 1H), 9.68 (s, 1H), 8.59 (d, J=13.1 Hz, 1H), 8.51 (s, 1H), 8.50 (s, 1H), 8.45 (s, 1H), 8.41 (s, 1H), 8.19 (d, J=10.1 Hz, 2H), 8.09 (d, J=7.9 Hz, 1H), 7.94 (s, 1H), 7.83 (d, J=3.9 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.57 (d, J=4.7 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.35 (s, 1H), 7.30 (d, J=8.5 Hz, 1H), 7.08 (d, J=3.9 Hz, 1H), 2.43 (s, 3H), 2.34 (s, 3H); ESIMS m/z 654.1 (M++1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.O[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:23]([C:22]1[CH:25]=[CH:26][C:19]([O:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)=[CH:20][CH:21]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Reactant: O=Cc1ccc(O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C=O)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.2 %

Procedure:
To 0.5 g (2.05 mmol) of tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate, 0.3 g (2.46 mmol) of 4-hydroxybenzaldehyde and 1 g (3.07 mmol) of resin-supported triphenyl-phosphine (3 mmol/g of resin) diluted in 14.5 ml of anhydrous tetrahydrofuran, is added dropwise at 0° C. under argon 0.614 ml (3.07 mmol) of diisopropyldiazene-1,2-dicarboxylate. The reaction mixture is stirred at room temperature for 20 h. The solid is filtered then rinsed in dichloromethane. The filtrate is concentrated and diluted in a sodium hydroxide solution (1M) and the product is extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, and concentrated. The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 4:6 to 100% ethyl acetate) to yield 0.58 g of tert-butyl 4-(3-(4-formylphenoxy)propyl)piperazine-1-carboxylate in the form of a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:6]=1[CH3:19])=[O:4].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:6]=1[CH2:19][Br:20])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(CC)Cn1c(C)c(C(=O)OC)cc(Br)c1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(CC)Cn1c(CBr)c(C(=O)OC)cc(Br)c1=O
Yield: 69.2 %

Procedure:
A mixture of 5-bromo-1-(2-ethyl-butyl)-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (5.72 g, 17.3 mmol), N-bromosuccinimide (3.39 g, 19.1 mmol), and benzoyl peroxide (0.42 g, 1.73 mmol) in CCl4 (170 mL) was refluxed for 16 h. The resulting suspension was filtered, and the filtrate was evaporated in vacuo. The residue was purified by silica gel chromatography (0-20% EtOAc/hexanes) to give 4.9 g of the title compound as a yellow viscous oil. MS: (+) m/z 432.10 (M+Na).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(O)C.[Cl:24][C:25]1[CH:26]=[C:27]([C@@H:32]2[C@H:38]([CH:39]=O)[O:37][CH2:36][CH2:35][N:34]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:33]2)[CH:28]=[CH:29][C:30]=1[Cl:31].C[Si](C=[N+]=[N-])(C)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Cl:24][C:25]1[CH:26]=[C:27]([C@@H:32]2[C@H:38]([CH:39]=[CH2:1])[O:37][CH2:36][CH2:35][N:34]([C:41]([O:43][C:44]([CH3:46])([CH3:47])[CH3:45])=[O:42])[CH2:33]2)[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C=O)[C@@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Rh]
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C=C[C@@H]1OCCN(C(=O)OC(C)(C)C)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.1 %

Procedure:
To a solution of chlorotris(triphenylphosphine)rhodium (I) (52 mg) and triphenylphosphine (620 mg) in tetrahydrofuran (5 mL) was added 2-propanol (0.18 mL), and tert-butyl (6S,7R)-6-(3,4-dichlorophenyl)-7-formyl-1,4-oxazepane-4-carboxylate (800 mg) was added. To the reaction mixture was added trimethylsilyldiazomethane (2 M diethyl ether solution, 2.1 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (224 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:5][C:6]([C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)=[N:7][CH:8]=1.[N:23]#[C:24]Br>C(#N)C.O>[CH3:1][O:2][C:3]1[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]3[NH:15][C:24]([NH2:23])=[N:16][C:11]=3[CH:10]=2)=[N:7][CH:8]=1
Reactant: COc1cnc(-c2ccc(N)c(N)c2)nc1N1CCOCC1
Reactant: N#CBr
Solvent: CC#N
Solvent: O
Product: COc1cnc(-c2ccc3[nH]c(N)nc3c2)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
A mixture of 4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-benzene-1,2-diamine (0.58 g, 1.0 eq.) and ACN/H2O (5 ml/1 ml). In ice bath, cyanogen bromide (0.3 g, 1.5 eq) was added to mixture solution dropwisely. The solution was stirred overnight at room temperature, quenched with a NaHCO3(sat.) solution, and then filtered to give a light brown solid (0.32 g, 51.78%), which was dried in vacuo to give a product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:21]1([C:27]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@H:35]3[C@H:31]([CH2:32][NH:33][CH2:34]3)[C:30](=[O:36])[CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([N:33]1[CH2:32][C@H:31]2[C@H:35]([C:27]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29][C:30]2=[O:36])[CH2:34]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: CC(C)(C)OC(=O)NC[C@@H](C(=O)O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@@H](C(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1)c1ccccc1
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
N,N'-Carbonyldiimidazole (0.5 g) is added to a solution of (S)-3-tert-butoxycarbonylamino-2-phenylpropionic acid (0.79 g) in dry dichloromethane (20 cc), cooled to +5° C. The mixture is stirred for 1 hour 15 minutes at +5° C. and a solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1 g) and triethylamine (0.4 cc) in dichloromethane (25 cc) is then added. The reaction mixture is stirred for 15 minutes at +5° C. and then for 16 hours at 20° C. The reaction mixture is washed with distilled water (3×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.06 mm, diameter 3 cm, height 30 cm), eluting with a mixture of cyclohexane and ethyl acetate (50/50 by volume) and collecting 50 cc fractions. Fractions 2 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa). (3aR,7aR)-2-[(S)-2-tert-butoxycarbonylaminomethyl-2-phenylacetyl]-7,7-diphenyl-4-perhydroisoindolone (1.2 g) is obtained in the form of a white meringue.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-])=O.I[CH2:14][CH3:15]>>[CH2:14]([N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:4]([NH2:1])[C:5]=2[CH:6]=[N:7]1)[CH3:15]
Reactant: CCI
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Product: CCn1ncc2c(N)cccc21

Procedure:
In accordance with Example 68 (Step 2), 4-nitro-1H-indazole was used instead of 4-nitro-1H-indole, and iodoethane was used instead of (S)-tetrahydrofuran-3-yl methanesulfonate to obtain 1-ethyl-1H-indazol-4-amine.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=3)[C:25]2=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: COc1cccc(N=C=O)c1
Product: COc1cccc(-n2c(=O)c3cnc4c(OC)cccc4c3n(C3CCCC3)c2=O)c1
Yield: 76.7 %

Procedure:
1-Cyclopentyl-7-methoxy-3-(3-methoxy-phenyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (32 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-isocyanato-3-methoxy-benzene (0.5 mmol) following general procedure C. LCMS: m/z 418 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.50 (s, 1H), 7.86 (d, 1H), 7.64 (t, 1H), 7.44 (t, 1H), 7.30 (d, 1H), 6.82 (dd, 1H), 6.60 (d, 1H), 6.28 (s, 1H), 5.04 (p, 1H), 4.17 (s, 3H), 3.80 (s, 3H), 2.40 (m, 2H), 2.04-2.20 (m, 4H), 1.24 (m, 2H) ppm.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[OH-].[K+].[I:14]I>CN(C=O)C>[I:14][C:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:1][CH:2]=1
Reactant: O=c1cc[nH]c2ccccc12
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1c(I)c[nH]c2ccccc12

Procedure:
1H-Quinolin-4-one (2.90 g, 20 mmol, 1 equiv) in 5 mL of DMF was treated with 1.12 g of KOH (2 equiv) and 5.30 g of iodine (1.05 equiv) for 2 hours. The reaction was quenched by slow addition of saturated aqueous solution of Na2S2O3. Filtration gave 3-iodo-1H-quinolin-4-one as an off-white solid.
Reaction SMILES: [CH2:1]([C@H:4]([C@H:8]([OH:10])[CH3:9])[C:5]([OH:7])=O)[C:2]#[CH:3].[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][NH2:18].C(Cl)CCl>ClCCl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][NH:18][C:5](=[O:7])[C@H:4]([CH2:1][C:2]#[CH:3])[C@H:8]([OH:10])[CH3:9]
Reactant: C#CC[C@@H](C(=O)O)[C@@H](C)O
Reactant: NOC1CCCCO1
Solvent: ClCCCl
Solvent: ClCCl
Product: C#CC[C@@H](C(=O)NOC1CCCCO1)[C@@H](C)O
Temperature: 23 °C
Reaction time: 4 h
Yield: 37.3 %

Procedure:
To a solution of (2R,3R)-2-(2-propyne-1-yl)-3-hydroxybutanoic acid (3.0 g, 21.13 mmol) in dichloromethane (50 mL) is added 2-tetrahydropyranyloxyamine (3.0 g, 25.35 mmol) and EDC (4.5 g, 23.24 mmol). The resulting solution is stirred at 23° C. for 4 h, then diluted with dichloromethane (100 mL) and washed with 1 M hydrochloric acid. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3R)-2-(2-propyne-1-yl)-3-hydroxybutanoic acid 2-tetrahydropyranyloxyamide as a foam (1.9 g, 37% yield). 1H NMR (400 MHz, CDCl3) δ 8.82 (bs, 1H), 4.96 (m, 1H), 3.94 (m, 2H), 3.62 (m, 1H), 2.64 (m, 1H), 2.56 (m, 1H), 2.23 (m, 1H), 2.04 (m, 1H), 1.82 (m, 2H), 1.61 (m, 4H), 1.23 (d, 3H) ppm. ESI-MS m/z 240.4 (M−H)−.