Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([C:27]4[C:28]([CH3:33])=[N:29][N:30]([CH3:32])[CH:31]=4)=[C:19]([CH:22](OC)[O:23]C)[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].Cl>C1COCC1.O>[C:1]([C:3]1[C:4]([NH:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([C:27]4[C:28]([CH3:33])=[N:29][N:30]([CH3:32])[CH:31]=4)=[C:19]([CH:22]=[O:23])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(-c4cn(C)nc4C)c(C(OC)OC)nc32)ncc1C#N
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COCCNc1cc(NC(=O)N2CCCc3cc(-c4cn(C)nc4C)c(C=O)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 314, 25.6 mg, 0.049 mmol) in THF (250 μL) and water (250 μL) was added 37% aqueous HCl (81 μL, 0.984 mmol) at room temperature. The reaction mixture was stirred for 2 h at room temperature, quenched by the addition of saturated aqueous NaHCO3 and diluted with DCM. Phases were separated and the water phase was extracted with DCM (2×). The combined organic layers were dried using Na2SO4, filtered and solvents were concentrated. The crude product was suspended and sonicated in EtOAc/heptane (1:1). The solid was filtered and dried to yield the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:9])=[N:4][CH:5]=[N:6][C:7]=1I.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[NH2:14].O>CN1CCCC1=O>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:7]2[C:2]([NH2:1])=[C:3]([I:9])[N:4]=[CH:5][N:6]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: Nc1c(I)ncnc1I
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1c(I)ncnc1Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Yield: 81 %

Procedure:
A solution of 5-amino-4,6-diiodopyrimidine (3.83 g) and 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (2.78 g) in 1-methyl-2-pyrrolidone (30 mL) was stirred at 70° C. for 14 hrs. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (eluent, ethyl acetate:hexane=1:4→2:3→1:1) to give the title compound (4.21 g) as brown powder crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:16][CH:9]2[CH2:10][N:11]([CH:13]([CH3:15])[CH3:14])[CH2:12][CH:8]2[CH:7]1[CH2:17][O:18][CH3:19])=[O:4].Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=2)[N:24]=[CH:23][N:22]=1.C(N(CC)CC)C>C(O)C>[CH:13]([N:11]1[CH2:12][CH:8]2[CH:7]([CH2:17][O:18][CH3:19])[CH:6]([NH:5][C:3](=[O:4])[CH2:2][NH:1][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:33])([F:34])[F:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH2:16][CH:9]2[CH2:10]1)([CH3:14])[CH3:15]
Reactant: COCC1C(NC(=O)CN)CC2CN(C(C)C)CC21
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COCC1C(NC(=O)CNc2ncnc3ccc(C(F)(F)F)cc23)CC2CN(C(C)C)CC21

Procedure:
A mixture of 2-amino-N-(2-isopropyl-4-methoxymethyloctahydrocyclopenta[c]pyrrol-5-yl)acetamide, 4-chloro-6-trifluoromethylquinazoline (see Armarego et al., J. Chem. Soc. B, 1967, 449) and triethylamine in ethanol is heated at reflux until the reaction is complete. The solution is concentrated under vacuum yielding a residue. The residue is purified by reverse phase HPLC and lyophilization providing the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=2[CH3:37])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[NH:13][C:12]3=[O:18])[NH:31][C:30]=2[CH3:37])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)NCCN4CCCC4)c2C)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (86 mg, 71%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:13][CH2:14]Br>>[Cl:9][C:10]1[CH:11]=[C:12]([CH2:13][CH2:14][CH:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH3:2])[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: Clc1ccc(CCBr)cc1Cl
Reactant: CCc1ccncc1
Product: CC(CCc1ccc(Cl)c(Cl)c1)c1ccncc1
Yield: 44.7 %

Procedure:
1.0 g (9.35 mmol) of 4-ethylpyridine and 2.37 g (9.35 mmol) of 3,4-dichlorophenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 1.17 g of the desired compound (yield: 44.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:12].[Br:13]Br.CCOCC>C(Cl)Cl>[Br:13][C:4]1[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[CH3:1])[C:7](=[O:12])[NH:6][CH:5]=1
Reactant: BrBr
Reactant: Cc1cccc2c(=O)[nH]ccc12
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cccc2c(=O)[nH]cc(Br)c12
Yield: 66.7 %

Procedure:
To a stirred solution of 5-methylisoquinolin-1(2H)-one (Intermediate-3) (10 g, 63 mmol) in CH2Cl2 (100 mL) was added, Br2 (11.1 g, 69.3 mmol) drop wise and the mixture was stirred at RT (room temperature) overnight. Et2O (200 mL) was added to it, stirred for few min after which, a yellow solid precipitated out. It was filtered, washed with MeOH (10 mL), and dried to give desired intermediate (10 g, 67%) as white solid.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([NH2:21])[CH:15]=[CH:14]2)=[O:10])C1C=CC=CC=1.CC(O)C.[OH-].[K+:27]>O>[K+:27].[NH2:21][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:9]([O-:10])=[O:8])[CH:12]=2)[N:17]=1
Reactant: Nc1ccc2cc(C(=O)OCc3ccccc3)ccc2n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Nc1ccc2cc(C(=O)[O-])ccc2n1
Reaction time: 12 h
Yield: 95 %

Procedure:
A mixture of 2-amino-quinoline-6-carboxylic acid benzyl ester (15.63 g, 0.0562 moles), 2-propanol (235 mL), water (15.6 mL) and potassium hydroxide (6.3 g, 0.112 moles) was heated to reflux, 80° C. to 85° C., for 2 to 4 hours. The reaction mixture was then cooled to 20° C. to 25° C., vacuum concentrated (volume of 160 mL) and granulated at 20° C. to 25° C. for 8 to 16 hours. The product was isolated by filtration (12.08 g, 0.0534 moles, 95% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:13](=[O:22])[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2.I[CH3:24]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:13](=[O:22])[N:14]([CH3:24])[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: CI
Reactant: O=c1[nH]c2ccccc2cc1-c1c(Cl)ccc([N+](=O)[O-])c1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)c(-c2c(Cl)ccc([N+](=O)[O-])c2Cl)cc2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
To a solution of 3-(2,6-dichloro-3-nitro-phenyl)-1H-quinolin-2-one (0.21 g, 0.6266 mmol) in DMF (5.0 mL) is added HNa (30.1 mg, 60%, 0.752 mmol) and IMe (120.1 mg, 0.846 mmol) at 0° C. After the mixture is stirred for two hours at 0° C., the mixture is diluted with EtOAc and washed with saturated K2CO3, brine and water. The organic layer is dried, filtered and concentrated to give crude product, which is purified by flash silica gel column, eluting with CH2Cl2 (100%) gradient to CH2Cl2/MeOH (2N NH3) (95/5), t give the titled intermediate as a solid (78 mg, 35.8%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([C:22]3[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[CH:23]=3)=[O:21])[CH:14]=2)=[CH:9][C:5](C(O)=O)=[CH:4][N:3]=1.[CH3:29][O:30][C:31](=[O:49])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39]([CH3:48])(=[N:41][C:42](=[O:47])C(F)(F)F)=[O:40])[CH:34]=1>>[CH3:29][O:30][C:31](=[O:49])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39]([CH3:48])(=[N:41][C:42]([C:5]2[CH:4]=[N:3][C:2]([NH2:1])=[C:10]([C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([C:22]4[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[CH:23]=4)=[O:21])[CH:14]=3)[CH:9]=2)=[O:47])=[O:40])[CH:34]=1
Reactant: COC(=O)Cc1cccc(S(C)(=O)=NC(=O)C(F)(F)F)c1
Reactant: Cc1cc(C(=O)Nc2cccc(C#Cc3cc(C(=O)O)cnc3N)c2)n(C)n1
Product: COC(=O)Cc1cccc(S(C)(=O)=NC(=O)c2cnc(N)c(C#Cc3cccc(NC(=O)c4cc(C)nn4C)c3)c2)c1

Procedure:
In a manner similar to that described in Example 496 (step 5), 6-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinic acid and methyl{3-[S-methyl-N-(trifluoroacetyl)sulfonimidoyl]phenyl}acetate were reacted to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH2:30][CH3:31]>C(#N)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:29][CH2:30][CH3:31])[C:5]=1[O:21][CH3:22])[CH3:2]
Reactant: CCOc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1c(-c2cccc3c2CCC3=O)ccc(OCC)c1OC
Temperature: 80 °C
Yield: 7.7 %

Procedure:
To a stirring solution of 4-(4-ethoxy-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.268 mmol) in acetonitrile was added potassium carbonate (111 mg, 0.805 mmol) and propyl bromide (99 mg, 0.805 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded title compound as a solid (7 mg, 7.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br.[CH3:10][N:11]1[CH2:17][CH2:16][C:15]2=[CH:18][C:19](=[O:23])[C:20](=[O:22])[CH:21]=[C:14]2[CH2:13][CH2:12]1>CO>[OH:23][C:19]1[C:20]([OH:22])=[CH:21][C:14]2[CH2:13][CH2:12][N:11]([CH3:10])[CH2:17][CH2:16][C:15]=2[C:18]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: CN1CCC2=CC(=O)C(=O)C=C2CC1
Reactant: Fc1ccc(S)cc1
Agent: Br
Solvent: CO
Product: CN1CCc2cc(O)c(O)c(Sc3ccc(F)cc3)c2CC1

Procedure:
To a solution of 1.0 g. (0.0078 mole) of p-fluorothiophenol in 200 ml. of methanol was added portionwise 2 g. (0.0073 mole) of 3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dione hydrobromide (prepared as in Example 2) and the resulting mixture was stirred at room temperature under argon for 1 hour. The methanol was distilled from the reaction mixture in vacuo and the residue was partitioned between ether and water. The aqueous layer was extracted with ether and then made basic with ammonium hydroxide solution. The precipitate was filtered and the dried filtrate was chromatographed on silica using methanol/chloroform. The material eluted from the column was slurried with ether and filtered. Distillation of the ether gave 7,8-dihydroxy-6-(p-fluorophenylthio)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 164°-166° C.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[Br:25][C:26]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:27]=1[NH2:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[Br:25][C:26]1[CH:32]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:30]=[CH:29][C:27]=1[NH:28][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)CCCn1c(Nc2ccc(C(F)(F)F)cc2Br)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 130 °C
Reaction time: 15 h

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 2.24 g, 6.63 mmol), 2-bromo-4-trifluoromethylaniline (3.18 g, 13.25 mmol), p-toluenesulfonic acid monohydrate (1.35 g, 7.09 mmol) and xylene (5.0 mL) was stirred at 130° C. for 15 hr. After cooling, the reaction mixture was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-15% ethyl acetate/n-hexane gradient mixture to give crude ethyl 4-[2-{[2-bromo-4-(trifluoromethyl)phenyl]amino}-4-chloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate. The crude material (MS Calcd.: 573; Found: 574 (M+H)) was subjected for the next step without further purification. To a solution of the crude material in tetrahydrofuran (15.0 mL) was added lithium borohydride (193.0 mg, 8.86 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hr and warmed to 60° C. and stirred for 19 hr. The reaction mixture was quenched with water at 0° C. and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-20% ethyl acetate/n-hexane gradient mixture to give a mixture contained the title compound. The residue was purified by preparative HPLC to give the title compound as the trifluoroacetic acid salt. The salt was washed with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a colorless powder (110.4 mg, 0.207 mmol, 3.1% (2 steps)).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:10]3[S:14][C:13]([NH2:15])=[N:12][C:11]=3[CH:16]=2)[CH:2]=1.C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C1(C)C=CC=CC=1>[CH2:34]([O:33][C:31](=[O:32])[NH:15][C:13]1[S:14][C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:8][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:16][C:11]=2[N:12]=1)[CH3:35]
Reactant: Nc1nc2cc(-c3cccnc3)cc(-c3ccccn3)c2s1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3ccccn3)c2s1
Temperature: 40 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
To a solution of 5-pyridin-3-yl-7-pyridin-2-yl-benzothiazol-2-ylamine (0.10 g, 0.33 mmol) in toluene (5 mL) was added triethylamine (0.10 ml, 0.07 mmol) at room temperature. The reaction mixture was heated to 40° C. followed by the addition of ethyl chloroformate (0.17 g, 0.16 mmol). The resulting reaction mixture was stirred under nitrogen atmosphere at 70° C. for 16 h. After the completion of reaction (TLC monitoring) toluene was evaporated under reduced pressure. The crude solid residue was washed with water and was purified by chromatography over silica gel (230-400 M) using ethyl acetate:hexane (60:40) to provide the title compound as white solid (0.046 g, 38%). M.P. 235° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[NH:20][N:19]=[C:18]([CH:21]4[CH2:23][CH2:22]4)[CH:17]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30]>C(Cl)Cl>[CH:21]1([C:18]2[CH:17]=[C:16]([NH:15][C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:4]4[CH:3]=[C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=5)[CH:7]=[CH:6][CH:5]=4)[N:14]=3)[NH:20][N:19]=2)[CH2:23][CH2:22]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)c1
Solvent: ClCCl
Product: O=C(Nc1cccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)c1)c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
A solution of N2-(3-aminophenyl)-N4-(3-cyclopropyl-1H-pyrazol-5-yl)pyrimidine-2,4-diamine (0.014 g, 0.046 mmol; Shokat Lab: A. Statsyuk) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this 3-(trifluoromethyl)benzoyl chloride (0.007 mL, 0.046 mmol) diluted in CH2Cl2 (5 mL) was added drop wise. The reaction was allowed to warm and was left stirring for 1 hour. The reaction proceeded until completion as judged by TLC and LC-MS. The reaction mixture was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H2O/0.1% TFA (1-100% gradient) to afford AD76. ESI-MS m/z[M+H]+. Found 480.4. Calculated 480.2.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=2[CH:5]=[N:6][CH:7]=1.[CH3:16][N:17]1[C:26]2[C:21](=[CH:22][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:25]=2)[CH2:20][CH2:19][C:18]1=[O:36]>>[CH3:16][N:17]1[C:26]2[C:21](=[CH:22][C:23]([C:2]3[C:3]4[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=4[CH:5]=[N:6][CH:7]=3)=[CH:24][CH:25]=2)[CH2:20][CH2:19][C:18]1=[O:36]
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CCC(=O)NC1CCc2c(Br)cncc21
Product: CCC(=O)NC1CCc2c(-c3ccc4c(c3)CCC(=O)N4C)cncc21
Yield: 87 %

Procedure:
In analogy to the procedure described for the preparation of intermediate A-2 [E], (rac)-N-(4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)propionamide (intermediate A-3) was reacted with 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (intermediate A-1) to give the title compound as an off-white powder in 87% yield. MS: 350.2 (M+H+).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][S:7]([OH:10])(=O)=[O:8])=[N+:2]=[N-:3].[Na].P(Cl)(Cl)(Cl)(Cl)[Cl:13]>C1C=CC=CC=1>[N:1]([CH2:4][CH2:5][CH2:6][S:7]([Cl:13])(=[O:10])=[O:8])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCS(=O)(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na]
Solvent: c1ccccc1
Product: [N-]=[N+]=NCCCS(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Azidopropanesulfonic acid, sodium salt 5 (1.87 g, 10.0 mmol) was suspended in dry benzene (20 mL), and PCl5 (2.3 g, 10.5 mmol) was added to the suspension. The mixture was stirred at room temperature for 30 minutes, then at gentle reflux for about 1 hour. The benzene and P(O)C13 were removed by evaporation under reduced pressure. Benzene was added to the crude mixture and the solvent was removed again under reduced pressure. The residue was dried in vacuo. The dried residue was dissolved in dichloromethane (anhydrous, 15 mL) and cooled at −10° C. using an ice/acetone bath.
Reaction SMILES: I[CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12.C[O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>CN(C)C=O>[CH3:32][Si:3]([CH3:33])([CH2:2][N:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]1=[O:35])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12
Reactant: COc1ccccn1
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CI
Solvent: CN(C)C=O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)Cn1ccccc1=O
Yield: 44 %

Procedure:
A solution of Compound 4 (60 mg) and 2-methoxypyridine (0.11 mL) in N,N-dimethylformamide (1 mL) was heated at 70° C. for 16 hours. The reaction mixture was concentrated under vacuum and the residue was directly eluted on a silica gel column using 4% ethanol in dichloromethane to obtain the required product in 44% yield (25 mg).
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>C(N(CC)CC)C>[C:22]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1)(=[O:25])[CH:23]=[CH2:24]
Reactant: c1ccc(C2CNc3ccccc32)cc1
Reactant: C=CC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CC(c2ccccc2)c2ccccc21
Reaction time: 0.25 h
Yield: 45 %

Procedure:
A mixture comprising 4.0 g of 3-phenylindoline, 40 ml of benzene, 5 ml of triethylamine and 4.0 g of acryloylchloride was stirred at 10°-15° C. for 15 minutes. The mixture was then washed with water, the benzene solution dried and the solvent removed. 4.1 G of resin which was crystallized from ether to give 2.3 g of the desired N-acryloyl-3-phenylindoline which was found to have a melting point of 77°-8° C.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:15][CH2:16][C:17]1[C:18]([F:34])=[C:19]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=2)[C:28]#[N:29])[C:20]([Cl:23])=[CH:21][CH:22]=1.[CH3:35][C:36]([O:39][C:40]([N:42]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:43]1[NH:44][C:45]([C:49](O)=[O:50])=[C:46]([Br:48])[N:47]=1)=[O:41])([CH3:38])[CH3:37].C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:58][C:55]([O:54][C:52]([N:42]([C:43]1[NH:44][C:45]([C:49]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][C:25]3[CH:26]=[C:27]([C:28]#[N:29])[CH:30]=[C:31]([Cl:33])[CH:32]=3)[C:18]=2[F:34])=[O:50])=[C:46]([Br:48])[N:47]=1)[C:40]([O:39][C:36]([CH3:35])([CH3:37])[CH3:38])=[O:41])=[O:53])([CH3:56])[CH3:57]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Br)c(C(=O)O)[nH]1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Br)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
EDC (0.022 g, 0.116 mmol) and HOBT (0.016 g, 0.116 mmol) were added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.033 g, 0.106 mmol) and 2-(bis{[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-bromo-1H-imidazole-5-carboxylic acid (0.043 g, 0.106 mmol) in DMF (2 mL). The mixture was stirred at RT overnight. Saturated sodium bicarbonate was added and the reaction mixture was extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated. Chromatography (MeOH:dichloromethane) gave the desired product (0.030 g, 34%) as a white solid.