Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=O)=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[F:26][C:27]([F:38])([F:37])[O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C(O)C.CCCCCC>[CH3:25][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]3[O:21][C:20](=[O:22])/[C:19](=[CH:33]/[C:32]4[CH:35]=[CH:36][C:29]([O:28][C:27]([F:26])([F:37])[F:38])=[CH:30][CH:31]=4)/[N:18]=3)=[CH:23][CH:24]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(CCOc2ccc(C(=O)NCC(=O)O)cc2)cc1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: CN(C)c1ccc(CCOc2ccc(C3=N/C(=C\c4ccc(OC(F)(F)F)cc4)C(=O)O3)cc2)cc1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 69.7 %

Procedure:
A mixture of N-(4-{2-[4-(dimethylamino)phenyl]ethoxy}benzoyl)glycine (241 mg, 0.676 mmol) prepared in Example 23 (23b), 4-(trifluoromethoxy)benzaldehyde (106 μL, 0.742 mmol), sodium acetate (83.9 mg, 1.02 mmol), and acetic anhydride (319 μL, 3.38 mmol) was stirred at 120° C. for 15 minutes and then allowed to cool to room temperature. A saturated sodium hydrogen carbonate aqueous solution, hexane, and ethanol were added to the resulting solidified product which was washed by ultrasonic vibration. The precipitate was collected by filtration and dried by heating under reduced pressure to give 234 mg of the title compound (orange solid, yield: 70%).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([C:11]([OH:13])=O)[S:8][C:9]=1[CH3:10])[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:45]([C:47]1[CH:52]=[C:51]([C:53](=[NH:56])[NH:54]O)[CH:50]=[C:49]([CH3:57])[C:48]=1[CH2:58][CH2:59][C:60]([OH:62])=[O:61])[CH3:46]>C(Cl)Cl>[CH2:45]([C:47]1[CH:52]=[C:51]([C:53]2[N:54]=[C:11]([C:7]3[S:8][C:9]([CH3:10])=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[CH:6]=3)[O:13][N:56]=2)[CH:50]=[C:49]([CH3:57])[C:48]=1[CH2:58][CH2:59][C:60]([OH:62])=[O:61])[CH3:46]
Reactant: Cc1sc(C(=O)O)cc1CC(C)C
Reactant: CCc1cc(C(=N)NO)cc(C)c1CCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(-c2noc(-c3cc(CC(C)C)c(C)s3)n2)cc(C)c1CCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.6 %

Procedure:
To a solution of 4-isobutyl-5-methyl-thiophene-2-carboxylic acid (126 mg, 637 μmol) in DCM (5 mL), DIPEA (249 mg, 1.93 mmol) is added followed TBTU (202 mg, 628 μmol). The mixture is stirred at rt for 30 min before 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid (159 mg, 637 μmol) is added. The mixture is stirred at rt for 16 h before it is diluted with DCM, washed with 1 N aq. HCl solution, dried over Na2SO4, filtered and concentrated. The residue is dissolved in toluene (20 mL) and the reaction mixture is stirred at 110° C. for 18 h. The solvent is evaporated and the crude product is purified by CC on silica gel eluting with DCM containing 5% of methanol to give 3-{2-ethyl-4-[5-(4-isobutyl-5-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionic acid (41 mg) as a beige solid; LC-MS: tR=1.17 min, [M+1]+=413.30; 1H NMR (CDCl3): δ 0.94 (d, J=6.4 Hz, 6H), 1.30 (t, J=7.6 Hz, 3H), 1.84-1.96 (m, 1H), 2.43 (s, 3H), 2.45 (s, 3H), 2.46-2.60 (m, 4H), 2.75 (q, J=7.3 Hz, 2H), 3.02-3.12 (m, 2H), 7.66 (s, 1H), 7.79 (s, 1H), 7.81 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[CH:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[NH4+:18].[OH-]>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:18])=[N:13][CH:12]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: O=S(=O)(c1ccc(Cl)nc1)c1ccc(Br)cn1
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)c2ccc(Br)cn2)cn1
Temperature: 120 °C

Procedure:
5-Bromo-2-((6-chloro-3-pyridinyl)sulfonyl)pyridine (298 mg, 0.89 mmol), NH4OH (aqueous, 3 mL), and EtOH (3 mL) were added to a high-pressure reaction vessel. The vessel was sealed and heated at 120° C. for 2 h. After cooling to room temperature, the solvent was partially removed under vacuum. The white precipitate obtained was filtered, washed with ether, and dried under vacuum to provide 5-((5-bromo-2-pyridinyl)sulfonyl)-2-pyridinamine (280 mg) as a white solid that was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[C@@H:7]([NH2:24])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33]1([S:43](Cl)(=[O:45])=[O:44])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:25])[C@@H:7]([NH:24][S:43]([C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1)(=[O:45])=[O:44])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)cc1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2cccc3ccccc23)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.123 g (0.35 mmol) of (2S)-2-amino-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of dimethylformamide and treated with 0.196 ml (1.4 mmol) of triethylamine and 0.159 g (0.7 mmol) of 1-naphthalenesulfonyl chloride. The solution was stirred for 4 hours at room temperature. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed three times with water. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/1). Yield 47 mg. MS (ES+): m/e=541.3 (M+H+).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]2[S:14][CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[N:8]=[C:9](Cl)[N:10]=1)[CH:2]=[CH2:3].[CH2:21]([NH2:24])[CH:22]=[CH2:23].C(=O)([O-])O.[Na+]>>[CH2:21]([NH:24][C:9]1[N:10]=[C:5]([NH:4][CH2:1][CH:2]=[CH2:3])[C:6]2[S:14][CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[N:8]=1)[CH:22]=[CH2:23]
Reactant: C=CCNc1nc(Cl)nc2c(-c3ccccc3)csc12
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCC=C)c2scc(-c3ccccc3)c2n1
Yield: 85.3 %

Procedure:
168 mg (0.56 mmol) of 4-allylamino-2-chloro-7-phenylthieno[3,2-d]pyrimidine and 508 mg (8.9 mmol) of allylamine were heated in a sealed tube at 140° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (30 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 154 mg (yield: 85.3%) of the title compound.
Reaction SMILES: C([SiH](CC)CC)C.[Br:8][C:9]1[C:27]([C:28]([F:31])([F:30])[F:29])=[C:26]([N+:32]([O-:34])=[O:33])[CH:25]=[C:24]([Br:35])[C:10]=1[O:11][C:12]1[CH:13]=[C:14]([CH:21]([CH3:23])[CH3:22])[C:15]([OH:20])=[C:16]([CH:19]=1)[CH:17]=O.C(O)(C(F)(F)F)=O>>[Br:8][C:9]1[C:27]([C:28]([F:31])([F:30])[F:29])=[C:26]([N+:32]([O-:34])=[O:33])[CH:25]=[C:24]([Br:35])[C:10]=1[O:11][C:12]1[CH:13]=[C:14]([CH:21]([CH3:23])[CH3:22])[C:15]([OH:20])=[C:16]([CH3:17])[CH:19]=1
Reactant: CC(C)c1cc(Oc2c(Br)cc([N+](=O)[O-])c(C(F)(F)F)c2Br)cc(C=O)c1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Oc2c(Br)cc([N+](=O)[O-])c(C(F)(F)F)c2Br)cc(C(C)C)c1O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 99 %

Procedure:
Triethylsilane (115 mg, 0.99 mmol) was added to 5-(2,6-dibromo-4-nitro-3-trifluoromethylphenoxy)-2-hydroxy-3-isopropylbenzaldehyde of Part 11D (130 mg, 0.25 mmol) and stirred at room temperature for two minutes. TFA (6 mL) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and the residue was purified on column (silica gel, gradient elution with n-heptane/EtOAc) to give 133 mg (99%) of 4-(2,6-dibromo-4-nitro-3-trifluoromethylphenoxy)-2-methyl-6-isopropylphenol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:29][C:30](=[O:31])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: O=C(CBr)c1ccccc1
Reactant: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2[nH]c1=O
Product: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2n(CC(=O)c2ccccc2)c1=O

Procedure:
This compound was prepared from 6-fluoro-2-oxo-4-[4-(furan-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (99) and 2-bromoacetophenone according to General Procedure B. Yield 242 mg (31%), MP 293° C.; 1H-NMR (DMSO-d6): δ 3.79 (m, 4H), 3.98 (m, 4H), 5.87 (s, 2H), 6.67 (dd, J=1.6, 3.2 Hz, 1H), 7.10 (d, J=3.6 Hz, 1H) 7.59 (m, 2H), 7.73 (m, 1H), 7.90 (d, J=1.6 Hz, 1H), 8.12 (m, 2H), 8.21 (dd, J=2.8, 9.2 Hz, 1H), 8.70 (d, J=2.8 Hz, 1H); EIMS: 486 (M+1). Anal. (C26H20FN5O4) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[NH:15].[F:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][CH:26]2[CH2:28][O:27]2)=[CH:22][CH:21]=1>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:28][CH:26]([OH:27])[CH2:25][O:24][C:23]2[CH:29]=[CH:30][C:20]([F:19])=[CH:21][CH:22]=2)[C:7]1=[NH:15]
Reactant: N=c1[nH]c2ccccc2n1Cc1cccc(Br)c1
Reactant: Fc1ccc(OCC2CO2)cc1
Solvent: CCO
Product: N=c1n(Cc2cccc(Br)c2)c2ccccc2n1CC(O)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.2 %

Procedure:
To a solution of 1-(3-bromo-benzyl)-1,3-dihydro-benzoimidazol-2-ylideneamine (0.50 g, 1.66 mmol) in EtOH (30 ml) at rt was added 2-(4-fluoro-phenoxymethyl)-oxirane (278 mg, 1.66 mmol). The reaction was heated to reflux where it was maintained for 24 h. After this time, additional 2-(4-fluoro-phenoxymethyl)-oxirane (278 mg, 1.66 mmol) was introduced and the reaction was heated to reflux where it was left for a further 6 h. The mixture was cooled to rt and concentrated under reduced pressure. Purification by column chromatography on silica eluting with MeOH/dichloromethane (2-5% gradient) provided 1-[3-(3-bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-3-(4-fluoro-phenoxy)-propan-2-ol (361 mg, 46%). HPLC-MS 470, 472 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][CH2:15][N:14]([CH3:17])[C:13](=[N:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:28](OC(=O)C)(=[O:30])[CH3:29].O>N1C=CC=CC=1>[C:28]([N:16]1[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:12][C:13](=[N:18][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=2[CH3:27])[N:14]([CH3:17])[CH2:15]1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C2=CC(=Nc3c(C)cc(C)cc3C)N(C)CN2)cc1OC
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C2=CC(=Nc3c(C)cc(C)cc3C)N(C)CN2C(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)-3-methyl-1,2,3,4-tetrahydro-4-(2,4,6-trimethylphenylimino)pyrimidine (0.5 g) in pyridine (5 ml) was added acetic anhydride (1.0 ml), and the mixture was stirred at ambient temperature for 2.5 hours. The mixture was poured into water (150 ml) and extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with chloroform to give 1-acetyl-6-(3,4-dimethoxyphenyl)-3-methyl-1,2,3,4-tetrahydro-4-(2,4,6-trimethylphenylimino)pyrimidine (0.22 g).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:18]3[CH:25]=[CH:26][CH:27]=[CH:28][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[IH:29]>CO>[IH:29].[IH:29].[N:11]1([C:15]2[N:19]([CH2:20][C:21]([F:24])([F:22])[F:23])[C:18]3[CH:25]=[CH:26][CH:27]=[CH:28][C:17]=3[N:16]=2)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CC(F)(F)F)CC1
Agent: I
Solvent: CO
Product: FC(F)(F)Cn1c(N2CCCNCC2)nc2ccccc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Stir a solution of 4-[1-(2,2,2-trifluoro-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.43 g, 1.07 mmol), methanol (10 mL) and 57% hydroiodic acid overnight at room temperature, and then heat for two hours at 50° C. Cool, add 57% hydroiodic acid (1 mL) and heat for two hours. Concentrate in vacuo to remove the solvents, dilute the residue with methanol (150 mL), concentrate in vacuo, and triturate the residual oil with ether (300 mL) to afford a tan solid. Stir the mixture for one hour, collect the solid by vacuum filtration under nitrogen, and dry in vacuo (0.2 Torr) at 82° C. to afford 0.54 g of 2-[1,4]diazepan-1-yl-1-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole dihydroiodide, m.p. >225° C. Elemental Analysis: Calculated for C14H19F3N4.2HI: 30.35%C, 3.46%H, 10.11%N; Found 30.46%C, 3.33%H, 9.79%N.
Reaction SMILES: [CH2:1]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[CH:22]=O>>[CH3:28][O:27][C:25]1[CH:24]=[C:21]([CH:20]=[C:19]([O:18][CH3:17])[CH:26]=1)[CH:22]=[C:9]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]1=2
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: O=C1c2ccccc2CCc2ccccc21
Product: COc1cc(C=C2c3ccccc3CCc3ccccc32)cc(OC)c1
Yield: 40.6 %

Procedure:
Following procedures essentially as described in Preparation 5 and Example 28, above, and using dibenzosuberone (2.00 g, 10.29 mmol) and 3,5-dimethoxybenzaldehyde (1.71 g, 10.29 mmol), affords 1.43 g (41%) of the title compound as a yellow foam. 1H-NMR (CDCl3) δ 2.79-3.64 (br m, 4H), 3.55 (s, 6H), 6.20 (d, 2H), 6.25 (t, 1H), 6.72 (s, 1H), 7.06-7.30 (m, 7H), 7.48 (m, 1H); HPLC shows 99% purity.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH:8]([CH3:33])[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:32])[NH:17][CH:18]1[CH2:22][C:21](=[O:23])[O:20][CH:19]1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:10])(C)(C)C.[NH2:35][C:36]1[CH:44]=[CH:43][C:39](C(O)=O)=[CH:38][C:37]=1[C:45]([F:48])([F:47])[F:46].O=C1OC(OCCC2C=CC=CC=2)C(NC(C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=O)C1>>[CH2:25]([O:24][CH:19]1[CH:18]([NH:17][C:16]([CH:12]2[CH2:13][CH2:14][CH2:15][N:11]2[C:9](=[O:10])[CH:8]([NH:7][C:6](=[O:5])[C:39]2[CH:43]=[CH:44][C:36]([NH2:35])=[C:37]([C:45]([F:46])([F:48])[F:47])[CH:38]=2)[CH3:33])=[O:32])[CH2:22][C:21](=[O:23])[O:20]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Agent: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CC(NC(=O)c1ccc(N)c(C(F)(F)F)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Yield: 48 %

Procedure:
Prepared from {2-[2-(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-pyrrolidin-1-yl]-1-methyl-2-oxo-ethyl}-carbamic acid tert-butyl ester and 4-amino-3-trifluoromethyl-benzoic acid according to the procedure used to prepare 98a to afford 56 mg of title compound (48% yield). 1H-NMR (500 MHz, 1:1 CDCl3:CD3OD) δ 1.20-1.55 (m, 3H), 1.75-2.50 (m, 4H), 2.50-3.10 (m, 2H), 3.50-4.00 (m, 2H), 4.30-5.00 (m, 5H), 5.42 (s, 0.4H), 5.51 (s, 0.2H), 5.62 (d, 0.3H), 5.78 (d, 0.1H), 6.84 (d, 1H), 7.20-8.15 (m, 7H). Analytical HPLC: 14.90, 15.20 min. LC-MS (ES+): m/e=563.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=S)[CH2:6][CH2:5][C:4]=2[C:3]=1[C:13]#[N:14].[C:15]([NH:18][NH2:19])(=O)[CH3:16]>C(O)CCC>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]3[C:15]([CH3:16])=[N:18][N:19]=[C:7]3[CH2:6][CH2:5][C:4]=2[C:3]=1[C:13]#[N:14]
Reactant: CC(=O)NN
Reactant: N#Cc1c(Br)ccc2c1CCC(=S)N2
Solvent: CCCCO
Product: Cc1nnc2n1-c1ccc(Br)c(C#N)c1CC2
Temperature: 120 °C

Procedure:
To a stirred solution of 6-bromo-2-thioxo-1,2,3,4-tetrahydroquinoline-5-carbonitrile (145-3; 0.5 g, 0.00188 mol) in n-butanol (10 mL) was added acetic hydrazide (0.35 g, 0.0047 mol). Reaction mass was heated at 120° C. for 16 h. The reaction mixture was concentrated and directly purified by silica gel column chromatography to obtain title compound. (MS (M+1): 289.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([F:24])[CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1>>[F:24][C:20]1[CH:19]=[C:18]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:31]4[C:26]([F:25])=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:3]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:23]=[CH:22][N:21]=1
Reactant: OB(O)c1cccnc1F
Reactant: NC1=NC(c2cccc(Br)c2)(c2ccnc(F)c2)c2ccccc21
Product: NC1=NC(c2cccc(-c3cccnc3F)c2)(c2ccnc(F)c2)c2ccccc21
Yield: 19 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(2-fluoropyridin-4-yl)-1H-isoindol-3-amine (Example 116) as described in Example 67 Scheme #10, D in 19% yield using 2-fluoropyridine-3-boronic acid. 1H NMR (DMSO-d6) δ 8.26-8.19 (m, 1 H), 8.15 (d, J=5.31 Hz, 1 H), 8.08-7.99 (m, 1 H), 7.95-7.79 (m, 2 H), 7.59-7.38 (m, 7 H), 7.37-7.30 (m, 1 H), 7.18-6.82 (m, 3 H); MS (ESI) m/z 399 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1>C1COCC1.C(Cl)(Cl)Cl>[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH:60][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=3[F:1])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: O=C(O)c1ccc(F)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccc(F)cc3F)nc12

Procedure:
From 2,4-difluorobenzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+19.4° (c=1.00, CHCl3), ES-MS m/e (%): 407 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:12]=[C:11]([CH3:13])[C:9]([NH2:10])=[C:8]([CH3:14])[CH:7]=1)[CH2:2][CH2:3][CH3:4].C(O)(=O)C.[Br:19][CH:20]([CH3:24])[C:21](Br)=[O:22].O.O.O.C([O-])(=O)C.[Na+]>O>[Br:19][CH:20]([CH3:24])[C:21]([NH:10][C:9]1[C:11]([CH3:13])=[CH:12][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][C:8]=1[CH3:14])=[O:22]
Reactant: CC(Br)C(=O)Br
Reactant: CCCCOc1cc(C)c(N)c(C)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCOc1cc(C)c(NC(=O)C(C)Br)c(C)c1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
In a two liter bottle were mixed 4-butoxy-2,6-dimethylaniline (50.7 g, 0.263 mole) and glacial acetic acid (224 ml) and the mixture was cooled to about 10° C. To this was added and mixed rapidly 2-bromopropionyl bromide (62.4 g, 0.289 mole) immediately followed by a precooled (5° C.) solution of sodium acetate trihydrate (87.2 g) in water (362 ml). The whole was vigorously shaken to ensure intimate mixture of the components. After 30 min. of mechanical shaking, the precipitate was filtered off and washed carefully with distilled water. It was thereafter dried. The yield was 68.9 g (72%). Recrystallized from 95% ethanol, it melted at 135.5°-136°. Calcd. for C15H22BrNO2 : C 54.9, H 6.75, Br 24.3. Found: C 55.1, H 6.22, Br 24.7.
Reaction SMILES: N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O.[CH3:17][C:18](=[CH2:22])[CH:19](O)[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][C:43]1[CH:44]=[C:45]([NH:54][C:55]2[N:60]=[C:59]([C:61]([F:64])([F:63])[F:62])[CH:58]=[CH:57][N:56]=2)[CH:46]=[C:47]([C:49]2[CH:50]=[N:51][NH:52][CH:53]=2)[CH:48]=1>C1COCC1>[CH3:42][C:43]1[CH:44]=[C:45]([NH:54][C:55]2[N:60]=[C:59]([C:61]([F:62])([F:64])[F:63])[CH:58]=[CH:57][N:56]=2)[CH:46]=[C:47]([C:49]2[CH:50]=[N:51][N:52]([CH:19]([C:18]([CH3:22])=[CH2:17])[CH3:20])[CH:53]=2)[CH:48]=1
Reactant: C=C(C)C(C)O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cn[nH]c2)c1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(C)C(C)n1cc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(E)-di-tert-butyl diazene-1,2-dicarboxylate (321 mg, 1.39 mmol) was added slowly to a 0° C. well stirred solution of 3-methylbut-3-en-2-ol (100 mg, 1.16 mmol), triphenylphosphine (365 mg, 1.39 mmol) and N-(3-methyl-5-(1H-pyrazol-4-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine (371 mg, 1.16 mmol) in THF (3.5 mL). The reaction was stirred for 10 min and allowed to warm to RT for 18 hours. The reaction was quenched into aqueous potassium hydrogen sulfate (5%, 20 mL) and product extracted with ethyl acetate (2×20 mL). The organic extracts were combined dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10-50% ethyl acetate/hexanes) to afford N-(3-methyl-5-(1-(3-methylbut-3-en-2-yl)-1H-pyrazol-4-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine MS ESI calcd. for C20H21F3N5 [M+H]+ 388. found 388.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]#[C:14][CH2:15][O:16][CH3:17])[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH3:2]
Reactant: CCOC(=O)COc1ccccc1C#CCOC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccccc1CCCOC
Reaction time: 2 h

Procedure:
9.54 g (38.4 mmol) of the above prepared [2-(3-methoxy-prop-1-ynyl)-phenoxy]-acetic acid ethyl ester was hydrogenated at RT in 130 ml of EtOAc over 2.39 g of Pd/C (10%) under 1 atm. of H2-pressure. After 2 h at ambient temperature, the reaction mixture was filtrated over Celite and carefully rinsed with EtOAc. Evaporation of the solvent left finally 9.39 g of the title compound as colorless oil, MS: 252.2 (M)+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:15]=[CH:14][NH:13][N:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O[CH2:17][C@H:18]([NH:21]C(=O)OC(C)(C)C)[CH2:19][CH3:20]>>[NH2:21][C@H:18]([CH2:19][CH3:20])[CH2:17][N:13]1[CH:14]=[CH:15][C:11]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=2[CH3:10])=[N:12]1
Reactant: CC[C@H](CO)NC(=O)OC(C)(C)C
Reactant: Cc1c(-c2cc[nH]n2)ccc(C#N)c1Cl
Product: CC[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2C)n1
Yield: 56.5 %

Procedure:
(R)-4-(1-(2-aminobutyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile was prepared using the method of Example 99 starting from 2-chloro-3-methyl-4-(1H-pyrazol-3-yl)benzonitrile (2.0 g, 9.19 mmol) and (R)-tert-butyl 1-hydroxybutan-2-ylcarbamate (3.48 g, 18.38 mmol). Yield 56.5%. m/z [288.8+1].