Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](F)[CH:25]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.CC(O)=[O:33].O>>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][NH:27][C:26](=[O:33])[CH:25]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:15])([F:16])[F:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: O=C1C(n2cc(-c3ccnc(F)c3)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Solvent: O
Product: O=C1C(n2cc(-c3cc[nH]c(=O)c3)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Temperature: 25 °C

Procedure:
In a sealed tube, 6-fluoro-3-[4-(2-fluoropyridin-4-yl)-1H-1,2,3-triazol-1-yl]-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (100 mg, 0.236 mmol) in 1.2 mL of 5:1 AcOH/H2O was heated at 120° C. overnight. After cooled to ambient temperature and solvent reduced under reduced pressure, the residue was purified by column chromatography on silica gel (0-20% MeOH in EtOAc) to afford 98 mg title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:24](=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CCCCCCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: CCCCCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and heptanoic acid to yield (3aR,4S,7aR)-4-heptanoyloxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+Na]=448; RT=9.098 min; LC-MS Method III
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[C:18](=[O:23])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]#[C:9][CH2:8][NH:7][C:6](=[O:24])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:12]([C:18](=[O:23])[C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:13]=1
Reactant: Fc1cccnc1Br
Reactant: CON(C)C(=O)c1cc(Cl)ccc1C#CCNC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NCC#Cc1ccc(Cl)cc1C(=O)c1ncccc1F
Yield: 45 %

Procedure:
In a manner similar to that described above for compound 3al, 3-(4-chloro-2-(methoxy(methyl)carbamoyl)phenyl)prop-2-ynylcarbamic acid tert-butyl ester and 2-bromo-3-fluoropyridine were converted to 3 am (45% yield): MS m/z=389 (M+H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=2)[C:11]([CH3:20])=[C:10]1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)([OH:3])=[O:2]>Br>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[C:11]([CH3:20])=[C:10]1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)([OH:3])=[O:2]
Reactant: COc1ccc2c(c1)c(C)c(-c1cccnc1)n2CCCCCC(=O)O
Agent: Br
Product: Cc1c(-c2cccnc2)n(CCCCCC(=O)O)c2ccc(O)cc12

Procedure:
A solution of 1.70 g of 1-(5-carboxypentyl)-5-methoxy-3-methyl-2-(3-pyridyl)indole in 85 ml of 48% hydrobromic acid is heated under reflux for 0.5 hour. The reaction mixture is evaporated to dryness, diluted with water and adjusted to pH 6 with dilute sodium hydroxide. The precipitate is collected and recrystallized from acetone-ether to yield 1-(5-carboxypentyl)5-hydroxy-3-methyl-2-(3-pyridyl)indole.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH2:18][CH:19]2[NH2:22])=[CH:14][CH:13]=1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:22][CH:19]1[C:20]2[C:15](=[CH:14][CH:13]=[C:12]([F:11])[CH:21]=2)[CH2:16][CH2:17][CH2:18]1
Reactant: NC1CCCc2ccc(F)cc21
Reactant: Clc1nc2ccccc2[nH]1
Product: Fc1ccc2c(c1)C(Nc1nc3ccccc3[nH]1)CCC2

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 7-fluoro-1,2,3,4-tetrahydro-1-naphthylamine (prepared by Procedure B from 7-fluoro-1 -tetralone) by Procedure A. The product was purified by column chromatography to give the title compound as the free base and as a mixture of enantiomers (white solid, mp 181° C.). MS(ES+) m/z 282 ([M+1]+, 100).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[C:7]([CH3:9])[CH:8]=1.[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([Cl:26])[CH:18]=1.CN1CCOCC1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C(Cl)(Cl)Cl.CO.O>[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:13]2[CH2:12][CH2:11][N:10]([C:4]3[C:3]([CH3:2])=[CH:8][C:7]([CH3:9])=[CH:6][N:5]=3)[CH2:15][CH2:14]2)=[O:22])=[C:19]([Cl:26])[CH:18]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: CN1CCOCC1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3Cl)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A mixture of 1-(3,5-dimethylpyridin-2-yl)piperazine hydrochloride (956 mg) described in Preparation Example 80, 4-bromo-2-chlorobenzoic acid (1 g) and N-methylmorpholine (465 μL) was dissolved in a solution of chloroform (6 mL) and methanol (6 mL), 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (1.7 g) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (1.7 g).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH:5]([NH:18][C:19]([C:21]1([NH:26][C:27](=[O:36])[CH:28]([S:32]C(=O)C)[CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)C.[OH-].[Na+]>CO.O>[SH:32][CH:28]([CH:29]([CH3:31])[CH3:30])[C:27]([NH:26][C:21]1([C:19]([NH:18][CH:5]([CH2:6][C:7]2[S:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[C:4]([OH:37])=[O:3])=[O:20])[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:36]
Reactant: CCOC(=O)C(Cc1ccc(-c2ccccc2)s1)NC(=O)C1(NC(=O)C(SC(C)=O)C(C)C)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C(S)C(=O)NC1(C(=O)NC(Cc2ccc(-c3ccccc3)s2)C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
55 mg (0.101 mmol) of 2-{[1-(2-Acetylthio-3-methyl-butanoylamino)-cyclopentanecarbonyl]-amino}-3-(5-phenyl-thien-2-yl)-propionic acid ethyl ester is dissolved in 2 mL of MeOH. 0.41 mL of 1N NaOH is added, and the solution is stirred at room temperature for 3 h. The reaction mixture is diluted with water, and MeOH is removed in vacuo. The residue is partitioned between water and Et2O. The aqueous phase is extracted twice with Et2O, acidified with 0.41 mL of 1N HCl, and then extracted with EtOAc. The EtOAc phase is concentrated to furnish the product; mp 154-155° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:13])[C:3]=1[F:14].[N+](=[CH2:17])=[N-]>CCOCC>[CH3:17][O:7][C:6](=[O:8])[C:5]1[C:4]([F:13])=[C:3]([F:14])[C:2]([NH2:1])=[C:10]([F:11])[C:9]=1[F:12]
Reactant: C=[N+]=[N-]
Reactant: Nc1c(F)c(F)c(C(=O)O)c(F)c1F
Solvent: CCOCC
Product: COC(=O)c1c(F)c(F)c(N)c(F)c1F
Yield: 75 %

Procedure:
To a solution of 4-amino-2,3,5,6-tetrafluoro-benzoic acid (1.0 g, 4.78 mmol) in ether (75 mL), an ethereal solution of diazomethane gas was added until the starting material is completely consumed. The reaction mixture was then evaporated under reduced pressure. The crude solid obtained was purified by flash column chromatography using 0.5% ethyl acetate in hexane to obtain title compound (0.8 g, 75%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][CH2:21][C@H:18]1[CH2:19]O)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:19][CH:18]2[CH2:21][CH2:22][CH2:23][N:17]2[C:15]([O:14][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:16])=[C:4]([F:9])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Oc1ccc(Br)cc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1COc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.3 %

Procedure:
To a stirred solution of 4-bromo-2-fluorophenol (217 ul, 2.002 mmol), N-tert-butoxycarbonyl prolinol (403 mg, 2.002 mmol), and Ph3P (630 mg, 2.403 mmol) in THF (7 mL) was added DIAD (477 ul, 2.423 mmol) at room temp. The resulting mixture was stirred for 6 hr at room temp and then overnight at 70° C. The mixture was concentrated in vacuo and the residue was chromatographed on silica-gel with n-hexane-EtOAc (5:1, v/v) as eluent to give 549.4 mg (73%) 1-bromo-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3-fluorobenzene as an oil. 1H-NMR (400 MHz, CDCl3) δ1.46 (s, 9H), 1.85 (br m, 1H), 1.90-2.10 (br s, 3H), 3.30-3.47 (m, 2H), 3.85, 4.04 (br s each, 1H), 4.11-4.20 (m, 2H), 6.82-6.98 (m, 1H), 7.13-7.26 (m, 2H); MS (FAB) m/z 374 (M++1).
Reaction SMILES: [CH:1]([N:4]([C:20](=[O:39])/[CH:21]=[CH:22]/[C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:24]=1)[NH:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]([O:17]C)=[O:16])[CH:8]=1)([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:35]([O:34][C:32]([N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](/[CH:22]=[CH:21]/[C:20]([N:4]([CH:1]([CH3:3])[CH3:2])[NH:5][C:6]([C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[O:13][CH2:14][C:15]([OH:17])=[O:16])=[O:19])=[O:39])=[CH:24]1)=[O:33])([CH3:37])([CH3:38])[CH3:36]
Reactant: COC(=O)COc1cccc(C(=O)NN(C(=O)/C=C/c2cn(C(=O)OC(C)(C)C)c3ccccc23)C(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(NC(=O)c1cccc(OCC(=O)O)c1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Reaction time: 0.33 h

Procedure:
(E)-tert-butyl 3-(3-(1-isopropyl-2-(3-(2-methoxy-2-oxoethoxy)benzoyl)hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate (70 mg, 0.13 mmol) was dissolved in THF/H2O (2 ml/1 ml), stirred for 20 min, lithiumhydroxide (10.96 mg, 0.26 mmol) was slowly drop-wise added, and stirred at room temperature for 12 hr. THF was concentrated under reduced pressure, and after titration with 6N HCl at pH=2, the reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4 filtered, and concentrated under reduced pressure so that while solid form of (E)-2-(3-(2-(3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acryloyl)-2-isopropylhydrazinecarbonyl)phenoxy)acetic acid was obtained (68.1 mg, 99%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH:17]=2)[N:3]=1.[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]([CH3:43])[C:40]([NH2:42])=[O:41])#[CH:32].F[B-](F)(F)F.CCN(CC)CC>O1CCOCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:42][C:40](=[O:41])[CH:39]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:31]#[C:32][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH:17]=2)[N:3]=1)[CH3:43]
Reactant: C#Cc1ccccc1C(C)C(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3ncc(C(F)(F)F)c(Cl)n3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C(N)=O)c1ccccc1C#Cc1nc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ncc1C(F)(F)F

Procedure:
A mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate K8 (2.054 g, 4.597 mmol), 2-(2-ethynylphenyl)propanamide K7 (1.027 g, 5.929 mmol), CuI (0.017 g, 0.089 mmol), PdCl2(PPh3)2 (0.062 g, 0.088 mmol) and t-Bu3PH.BF4 (0.025 g, 0.087 mmol) in dioxane (20 mL) and Et3N (2.5 mL, 18 mmol) under a nitrogen atmosphere was heated in the microwave at 110° C. for 40 minutes. The mixture was concentrated under reduced pressure and purified using silica gel column chromatography (50-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A65 (2.121 g, 79%). 1H NMR (400 MHz, d6-DMSO) δ 10.48-10.33 (m, 1H), 8.82-8.73 (m, 1H), 8.09-7.97 (m, 1H), 7.64-7.55 (m, 2H), 7.56-7.44 (m, 2H), 7.41-7.34 (m, 1H), 7.29-7.22 (m, 1H), 7.01 (s, 1H), 4.39-4.29 (m, 1H), 4.18-3.99 (m, 3H), 2.99-2.80 (m, 2H), 2.02-1.94 (m, 2H), 1.83-1.70 (m, 2H), 1.41 (s, 9H), 1.39-1.31 (m, 3H).
Reaction SMILES: FC1C=C(C=CC=1F)CN1C(=[O:16])C2C(=CC=C(I)C=2)N(C)C1=O.C(N(C(C)C)CC)(C)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]#[CH:42])=[CH:36][CH:35]=1.O>CN(C=O)C.[Cu]I>[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]([OH:16])[C:41]#[CH:42])=[CH:36][CH:35]=1
Reactant: C#CCc1ccc(F)cc1
Reactant: Cn1c(=O)n(Cc2ccc(F)c(F)c2)c(=O)c2cc(I)ccc21
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C#CC(O)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To 0.5 g (1.06 mmol) 3-(3,4-Difluoro-benzyl)-6-iodo-1-methyl-1H-quinazoline-2,4-dione and 0.52 g (4.2 mmol) di-isopropyl ethylamine in 15 ml DMF is added bis-triphenylphosphine palladium di-chloride (catalytic) followed by CuI (catalytic). 0.15 g (1.3 mmol) 1-fluoro-4-prop-2-ynyl-benzene is added and the mixture is heated to 70° C. for 6 hours. The mixture is allowed to cool to room temperature and stir overnight. Water is added and the mixture stirred 30 minutes. Filtered and triturated solid in hot EtOAc and filtered. Purified by flash chromatography (EtOAc/hexane eluent).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:27][CH3:28])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([O:25][CH3:26])[CH:17]=2)=[CH:4][CH:3]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.C(#N)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:27][CH3:28])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20]([N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[O:21])=[C:18]([O:25][CH3:26])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: CCc1nccc(-c2ccc(C(=O)O)c(OC)c2)c1C#Cc1ccc(N)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCc1nccc(-c2ccc(C(=O)N3CCN(C)CC3)c(OC)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP5 starting from 70 mg (0.19 mmol) 4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-methoxy-benzoic acid (A-42) using 42 μL (0.38 mmoL) N-methyl piperazine, 71 mg (0.19 mmol) HATU and 35 μL (0.21 mmol) DIPEA in 1.0 mL DMF. After completion of the reaction, the reaction mixture is filtered and the product is isolated from the obtained solution by RP-HPLC using a H2O/ACN-gradient. Yield: 81 mg (95%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CN(C)C=O>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][N:27]1[CH2:28][CH2:29][N:24]([C:20]2[S:19][CH:23]=[CH:22][N:21]=2)[CH2:25][CH2:26]1
Reactant: c1csc(N2CCNCC2)n1
Reactant: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2cc(CN3CCN(c4nccs4)CC3)ccc2c1
Temperature: 150 °C
Yield: 64.6 %

Procedure:
To a solution of 22.1 g (0.1 mole) of 2-bromomethylnaphthalene in 150 ml of dimethylformamide, there were added successively 10.7 g (0.101 mole) of dry potassium carbonate and 17.2 g (0.101 mole) of 1-(2-thiazolyl)-piperazine. The resulting suspension was heated at 150° C. for 10 hours; the salt which had formed was then filtered off and the dimethylformamide was evaporated off under reduced pressure. There was obtained a brown crystalline residue which was washed with water and suction filtered off. The resulting 29 g of crystals were recrystallized in 150 ml of ethanol to give 20 g of 1-(2-naphthylmethyl)-4-(2-thiazolyl)-piperazine as beige crystals melting at 83°-84° C.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].[Cl:8][C:9]1[C:10]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH3:37])[CH:29]=2)=[N:11][C:12]([NH:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19](F)=[CH:18][C:17]=2[O:26][CH3:27])=[N:13][CH:14]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CO>[Cl:8][C:9]1[C:10]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH3:37])[CH:29]=2)=[N:11][C:12]([NH:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([N:5]([CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[CH3:6])=[CH:18][C:17]=2[O:26][CH3:27])=[N:13][CH:14]=1
Reactant: CNCCN(C)C
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Temperature: 140 °C
Yield: 88.7 %

Procedure:
N1,N1,N2-trimethylethane-1,2-diamine (0.189 mL, 1.49 mmol) was added to a suspension 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 87, 700 mg, 1.24 mmol) and DIPEA (0.431 mL, 2.48 mmol) in DMA (5 mL). The mixture was then heated in a microwave at 140° C. for 0.5 h. The mixture was diluted with CH3OH and absorbed onto an SCX column. The column was washed with CH3OH and eluted with ˜1M methanolic ammonia. Appropriate fractions were concentrated and further purification by FCC, eluting with 0-5% methanolic ammonia in CH2Cl2 gave the title compound (561 mg, 89%) as an orange oil; 1H NMR: (CDCl3) 2.26 (6H, s), 2.53-2.58 (2H, m), 2.88 (3H, s), 3.24-3.28 (2H, m), 3.91 (3H, s), 3.98 (3H, s), 6.68 (1H, s), 7.26-7.3 (1H, m), 7.31-7.4 (2H, m), 7.50 (1H, s), 8.23 (1H, s), 8.39 (1H, s), 8.47 (1H, d), 9.07 (1H, s); m/z: ES+ MH+ 510.27.
Reaction SMILES: [CH:1]([C:4]1([CH3:22])[C:8](=[O:9])[NH:7][C:6]([C:10]2[C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=[CH:15][C:11]=2[C:12](O)=[O:13])=[N:5]1)([CH3:3])[CH3:2].C(OC(=O)C)(=O)C>>[CH:1]([C:4]1([CH3:22])[C:8](=[O:9])[N:7]2[C:12](=[O:13])[C:11]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][O:19][C:18]=4[C:10]=3[C:6]2=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)C1(C)N=C(c2c(C(=O)O)ccc3c2OCO3)NC1=O
Solvent: CC(=O)OC(C)=O
Product: CC(C)C1(C)N=C2c3c(ccc4c3OCO4)C(=O)N2C1=O
Reaction time: 8 h

Procedure:
A mixture of 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-3,4-(methylenedioxy) benzoic acid (3.40 g, 11.2 mmol) and acetic anhydride (20 mL, 0.211 mol) is stirred overnight at reflux temperature. Concentration in vacuo and recrystallized from ethyl acetate to yield the title product as a white solid, 1.50 g (46.9%), mp 237°-242° C., identified by NMR spectral analysis.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:13])[CH3:12].[Si:14]([C:21]#[C:22][C:23]([C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=1)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[Si:14]([C:21]1[N:10]([C:11](=[O:13])[CH3:12])[C:3]2[C:2]([C:22]=1[C:23](=[O:24])[C:25]1[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=1)=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[CH:4]=2)([C:17]([CH3:19])([CH3:18])[CH3:20])([CH3:16])[CH3:15]
Reactant: COc1ccc(I)c(NC(C)=O)c1
Reactant: COc1cc(C(=O)C#C[Si](C)(C)C(C)(C)C)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c([Si](C)(C)C(C)(C)C)n(C(C)=O)c2c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 70.5 %

Procedure:
A mixture of N-(2-iodo-5-methoxyphenyl)acetamide (0.45 g; 1.55 mmol), 3-(tert-butyldimethylsilyl)-1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-one (0.5 g; 1.51 mmol), LiCl (0.069 g; 1.6 mmol) and Na2CO3 (0.477 g; 4.5 mmol) in anhydrous DMF (8 ml) was degassed with N2 and temperature was raised to 100° C. with stirring. Pd(OAc)2 (0.15 g) was added and heating was continued for 1.5 h. The solvent was removed in vacuo and the residue was diluted to 100 ml with EtOAc. This was washed with H2O, dried over MgSO4, filtered and the filtrate was evaporated to dryness. The residue was purified by FCC (SiO2) to give the desired product (0.53 g; 69%) as creamy gum. 1H-NMR (CDCl3) 0.12 (s, 6H); 0.98 (s, 9H); 2.84 (s, 3H); 3.77 (s, 3H); 3.86 (s, 6H); 3.93 (s, 3H); 6.8 (dd, 1H, J=2.07, 8.73 Hz), 7.00 (d, 1H, J=8.73 Hz), 7.16 (broad s, 3H).
Reaction SMILES: CC1C=C[C:5]([C:6](NC2C=C(C(F)(F)F)C=C(N3C=C(C)N=C3)C=2)=[O:7])=CC=1NC1N=C(C2C=NC=CC=2)C=CN=1.Cl.Cl.[CH3:42][C:43]1[CH:67]=[CH:66][C:46]([C:47]([NH:49][C:50]2[CH:55]=[C:54]([C:56]([F:59])([F:58])[F:57])[CH:53]=[C:52]([N:60]3[CH:64]=[C:63]([CH3:65])[N:62]=[CH:61]3)[CH:51]=2)=[O:48])=[CH:45][C:44]=1[NH:68][C:69]1[N:74]=[C:73]([C:75]2[CH:76]=[N:77][CH:78]=[CH:79][CH:80]=2)[CH:72]=[CH:71][N:70]=1.[OH2:81].[CH3:82][OH:83]>>[CH2:6]([O:7][CH2:47][OH:48])[CH2:5][O:81][CH2:82][OH:83].[CH3:42][C:43]1[CH:67]=[CH:66][C:46]([C:47]([NH:49][C:50]2[CH:55]=[C:54]([C:56]([F:57])([F:58])[F:59])[CH:53]=[C:52]([N:60]3[CH:64]=[C:63]([CH3:65])[N:62]=[CH:61]3)[CH:51]=2)=[O:48])=[CH:45][C:44]=1[NH:68][C:69]1[N:74]=[C:73]([C:75]2[CH:76]=[N:77][CH:78]=[CH:79][CH:80]=2)[CH:72]=[CH:71][N:70]=1
Reactant: CO
Reactant: O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Agent: Cl
Product: OCOCCOCO
Temperature: 42 °C
Reaction time: 0.25 h

Procedure:
4.0 g 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide free base is dissolved in 60 mL methanol at 50° C. 1.05 equivalent (688.7 μL) of hydrochloric acid is added as a solution in 2 mL of methanol. The solution is let stand for 60 minutes at 50° C. The solution is cooled down to 42° C. and kept at this temperature for 15 minutes. A suspension of 4 mg of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide hydrochloride in methanol (40 mg)/water (0.4 mg) homogenized for 10 seconds in an ultrasonic bath is added. The suspension is let stand for 2.5 hours at 42° C., then cooled down in 7 hours at 20° C. The suspension remains at 20° C. for 56 hours. The suspension is not filtrated before analysis. The dimethanol solvate form SB of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide is obtained.