Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][CH2:28][C@H:29]([NH2:31])[CH3:30]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][C@@H:29]([CH2:28][CH2:27][O:26][CH3:25])[CH3:30])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: COCC[C@@H](C)N
Product: COCC[C@@H](C)NC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-4-methoxybutan-2-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (d, J=6.82 Hz, 3H) 1.67-1.77 (m, 1H) 1.77-1.89 (m, 1H) 2.44 (s, 3H) 3.39 (t, J=6.57 Hz, 2H) 4.05-4.20 (m, 1H) 7.67 (d, J=8.08 Hz, 1H) 7.74 (s, 1H) 7.78 (br. s., 1H) 8.17 (br. s., 1H) 8.43 (d, J=7.07 Hz, 3H) 8.87-8.95 (m, 1H) 12.98-13.34 (m, 1H); ESI-MS m/z [M+H]+ 406.2.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].Cl.[NH2:46][CH2:47][C:48]([NH2:50])=[O:49].C(N(CC)C(C)C)(C)C>C(#N)C>[NH2:50][C:48](=[O:49])[CH2:47][NH:46][C:21]([N:7]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:18])=[O:19])[C:3]([C:1]#[N:2])=[C:4]([CH3:44])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:6]1=[O:33])=[O:22]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: NCC(N)=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)NCC(N)=O)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
According to the General Procedure 1, 4-nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (197 mg, 0.315 mmol; Example 6A) was reacted with glycinamide hydrochloride (104 mg, 0.945 mmol) and N,N-diisopropylethylamine (122 mg, 0.945 mmol) in acetonitrile (2.5 ml) to give the target compound (72 mg, 39% of theory).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:25])=[C:16]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:17]=1)[N:5]=2.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:25][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:29]([CH:26]4[CH2:28][CH2:27]4)=[O:30])=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:17][C:16]=1[NH:18][C:19](=[O:24])[C:20]([F:22])([F:21])[F:23]
Reactant: O=C(Cl)C1CC1
Reactant: Nc1nc2ccc(Oc3ccc(Cl)c(NC(=O)C(F)(F)F)c3)nc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1nc2ccc(Oc3ccc(Cl)c(NC(=O)C(F)(F)F)c3)nc2s1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
N-{5-[(2-Amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-chlorophenyl}-2,2,2-trifluoroacetamide (5.0 g, 12.9 mmol) was dissolved in pyridine (25 mL), cyclopropanecarbonyl chloride (1.28 ml, 14.2 mmol) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was treated with aqueous sodium hydrogen carbonate solution (100 mL), and diluted with ethyl acetate (100 mL). The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residual solid was crystallized from ethyl acetate (30 mL), collected by filtration, and dried to give the title compound (3.46 g, 59%) as a colorless powder.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[C:21][C:22]4[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=4)[CH:18]=3)[O:13][C:12]([CH3:34])([CH3:33])[CH:11]=2)=[CH:6][CH:5]=1)[CH3:3].[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[C:21][C:22]4[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:31][CH:32]=4)[CH:18]=3)[O:13][C:12]([CH3:34])([CH3:33])[CH:11]=2)=[CH:8][CH:9]=1)[CH3:1]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(C)C)cc2)=CC(C)(C)O3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)c1ccc(C2=CC(C)(C)Oc3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 35 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a solution of ethyl 4-[[4-(4-(1-methylethyl)phenyl)-2,2-dimethyl-(2H)-chromen-6-yl]-ethynyl]-benzoate (Compound 268, 95.0 mg, 0.210 mmol) in 3.0 mL THF and 3.0 mL EtOH was added NaOH (120.0 mg, 3.0 mmol, 3.0 mL of a 1M aqueous solution). The resulting solution was heated to 35° C., cooled to room temperature and stirred overnight. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before the solvent was removed under reduced pressure. The residual solid was recrystallized from CH3CN to give 75.0 mg (84%) the title compound as a colorless solid. 1H NMR (300 MHz, CDCl3) δ: 8.05 (2H, d, J=8.4 Hz), 7.55 (2H, d, J=8.4 Hz), 7.36 (1H, dd, J=2.0, 8.3 Hz), 7.30-7.26 (5H, m), 6.88 (1H, d, J=8.3 Hz), 5.64 (1H, s), 2.98 (1H, hept, J=6.9 Hz), 1.51 (6H, s), 1.31 (6H, d, J=6.9 Hz).
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12](#[N:14])[CH3:13].C[O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]2[O:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]2)=[CH:21][CH:20]=1)=O>O1CCCC1>[C:12]([CH2:13][C:17]([C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]2[O:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]2)=[CH:23][CH:24]=1)=[O:16])#[N:14]
Reactant: COC(=O)c1ccc([C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(C(=O)CC#N)cc2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyllithium 1.6 M in hexane (1.63 ml, 2.61 mmol) was diluted with tetrahydrofuran (2 ml) and cooled to −78° C. Acetonitrile (107 mg, 0.137 ml, 2.61 mmol) was added dropwise and stirring was continuing for 1 hour. (S)-tert-butyl 2-(4-(methoxycarbonyl)phenyl)morpholine-4-carboxylate (420 mg, 1.31 mmol) dissolved in tetrahydrofuran was slowly added to the white slurry over a 10 min period. After 3 hours, the reaction was quenched by addition of saturated ammonium chloride solution (5 ml) and extracted with diethyl ether (10 ml). The organic layer was dried over MgSO4 and evaporated.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2[OH:17].[C:18]([O:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25])(=[O:20])[CH3:19]>N1C=CC=CC=1>[C:18]([O:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2[OH:17])=[O:25])(=[O:20])[CH3:19]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: CCOC(=O)c1nnc2ccc(N)cc2c1O
Solvent: c1ccncc1
Product: CCOC(=O)c1nnc2ccc(NC(=O)c3ccccc3OC(C)=O)cc2c1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 6-amino-4-hydroxycinnolin-3-yl carboxylate (1.0 g.) in dry pyridine (20 ml.) was added o-acetoxybenzoylchloride (0.8 g), and the mixture was stirred at room temperature for 16 hours. The solution was then heated to 100° C. for 1 hr., cooled to 20° C. and poured into a mixture of ice and excess N-HCl. The mixture was filtered and the solid residue crystallised from aqueous ethanol to give ethyl 6-o-acetoxybenzamido-4-hydroxycinnolin-3-yl carboxylate, m.p. 240°-2° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]1([C:17]2[O:18][C:19]3[CH:25]=[C:24]([C:26](=[O:30])[CH2:27][CH2:28][CH3:29])[CH:23]=[CH:22][C:20]=3[N:21]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[O:32][C:33](=[O:36])[CH2:34]Br.Cl>C1(C)C=CC=CC=1.C1COCC1>[CH2:28]([CH:27]([C:26](=[O:30])[C:24]1[CH:23]=[CH:22][C:20]2[N:21]=[C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:18][C:19]=2[CH:25]=1)[CH2:34][C:33]([OH:36])=[O:32])[CH3:29]
Reactant: COC(=O)CBr
Reactant: CCCC(=O)c1ccc2nc(-c3ccccc3)oc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC(CC(=O)O)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
625.00 μl (313 μmol) potassium bis(trimethylsilyl)amide 0.5M in toluene are placed in 15 ml THF and cooled to −78° C. 75.00 mg (283 μmol) 1-(2-phenyl-benzoxazol-6-yl)-butan-1-one, dissolved in 15 ml THF, are added dropwise to this solution and the mixture is stirred for 15 min at −78° C. Then 55 mg (360 μmol) methylbromoacetate, dissolved in 5 ml THF, are also added dropwise and the mixture is stirred for 30 min at −78° C., then 1N hydrochloric acid is added and the mixture is extracted with diethyl ether. The org. phase is dried on magnesium sulphate and the solv. is eliminated i.V.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([N:13]1[C:17]2=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=[C:16]2[NH:15][C:14]1=[O:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].[I-].[CH3:32][N:33]1[C:41]2[C:36](=[C:37]([CH3:42])[CH:38]=[CH:39][CH:40]=2)[C:35]([CH2:43][N+](C)(C)C)=[CH:34]1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([N:13]1[C:17]2=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=[C:16]2[N:15]([CH2:43][C:35]2[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][C:37]=3[CH3:42])[N:33]([CH3:32])[CH:34]=2)[C:14]1=[O:23])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)[nH]c2ccc(C)nc21
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccc(C)nc21
Temperature: 60 °C
Yield: 53.8 %

Procedure:
To a solution of (R)-3-(5-methyl-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-3-phenyl-propionic acid ethyl ester (250 mg, 0.77 mmol) in DMF (5 mL) were added K2CO3 (212 mg, 1.54 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium iodide (397 mg, 1.15 mmol). The reaction mixture was heated to 60° C. for 48 hours. The reaction mixture was then diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 200 mg (54%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1B(O)O>>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: OB(O)c1c(F)cccc1F
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1c(F)cccc1F

Procedure:
The title compound was prepared in analogy to example 58, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2,6-difluorophenyl-boronic acid (CAS RN 162101-25-9) and using preparative HPLC for the chromatographic purification. Off-white solid (16%). MS (ESI): m/z=461.2 [M+H]+.
Reaction SMILES: Br[CH:2]1[C:8]2[CH:9]=[C:10]([I:14])[C:11]([F:13])=[CH:12][C:7]=2[CH:6]2[CH2:15][CH:4]([CH2:5]2)[C:3]1=[O:16].CS(C)=[O:19]>>[F:13][C:11]1[C:10]([I:14])=[CH:9][C:8]2[C:2](=[O:19])[C:3](=[O:16])[CH:4]3[CH2:15][CH:6]([C:7]=2[CH:12]=1)[CH2:5]3
Reactant: O=C1C2CC(C2)c2cc(F)c(I)cc2C1Br
Reactant: CS(C)=O
Product: O=C1C(=O)C2CC(C2)c2cc(F)c(I)cc21

Procedure:
A solution of crude 9-bromo-3-fluoro-2-iodo-6,7-dihydro-5H-5,7-methanobenzo[7]annulen-8(9H)-one (1.400 g at 87% purity LCMS-UV215) in dimethylsulfoxide (15 mL) was warmed to 80° C. for 1 hr under an atmosphere of nitrogen. Evaporation in vacuo furnished the crude title compound (2.855 g) containing residual DMSO as a golden-brown oil which was carried through to the next synthetic step without further purification: 1H NMR (500 MHz, CDCl3) δ 2.25-2.30 (m, 2H), 3.12-3.18 (m, 2H), 3.48-3.51 (m, 1H), 3.61-3.65 (m, 1H), 6.94 (d, J=8.2 Hz, 1H), 8.55 (d, J=6.6 Hz, 1H).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[N+:9]([C:12]1[CH:17]=[C:16]([CH3:18])[C:15](Br)=[CH:14][C:13]=1[CH3:20])([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].Cl>CN(C)C=O.O>[N+:9]([C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([S:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)=[CH:14][C:13]=1[CH3:20])([O-:11])=[O:10]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Br
Reactant: Oc1cccc(S)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Sc1cccc(O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
A mixture of 18.9 g of 3-mercaptophenol (0.150 moles), 32.9 g of 2-nitro-5-bromo-p-xylene (0.143 moles) and K2CO3 (0.143 moles) in 95 ml of N,N-dimethylformamide is stirred at room temperature for 2 hours. A solution of HCl at 10% is added under stirring; the mixture is diluted with H2O and extracted with ethyl acetate. The organic phase is washed again with water, anhydrified on sodium sulfate, filtered and evaporated. 20 g of solid product are obtained, which is used as such for the subsequent reaction.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[CH:9][C:10]([N+:16]([O-:18])=[O:17])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[C:19](=O)([O-])O.[Na+]>CO>[F:6][C:7]1[CH:8]=[CH:9][C:10]([N+:16]([O-:18])=[O:17])=[C:11]([CH:15]=1)[C:12]([O:14][CH3:19])=[O:13]
Reactant: O=C([O-])O
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(F)ccc1[N+](=O)[O-]

Procedure:
2 ml of concentrated sulfuric acid was added to a methanol (200 ml) solution of 10 g of 5-fluoro-2-nitrobenzoic acid, and heated under reflux for 22 hours. 200 ml of aqueous sodium hydrogencarbonate solution was added to it, and the formed solid was taken out through filtration. This was dried under reduced pressure to obtain 10.7 g of the entitled compound as a yellow solid.
Reaction SMILES: Br[C:2]1[C:6]2[C:7]3[N:8]([N:11]=[CH:12][N:13]=3)[CH:9]=[N:10][C:5]=2[S:4][CH:3]=1.[Cu][C:15]#[N:16]>CN(C=O)C>[N:13]1[CH:12]=[N:11][N:8]2[C:7]=1[C:6]1[C:2]([C:15]#[N:16])=[CH:3][S:4][C:5]=1[N:10]=[CH:9]2
Reactant: Brc1csc2ncn3ncnc3c12
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1csc2ncn3ncnc3c12
Temperature: 150 °C

Procedure:
9-Bromothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (1.16 g, 4.55 mmol) was dissolved in DMF (23 mL), and copper(I) cyanide (817 mg, 9.1 mmol) was added. This mixture was heated to 150° C. for 23 h, whereupon the reaction mixture was concentrated under reduced pressure, and the residue purified by flash chromatography. LCMS method [4], retention time=0.890 min; MS (ESI) 202.0 (MH+); 1H NMR (300 MHz, CDCl3) δ 9.36 (s, 1H), 8.57 (s, 1H), 8.32 (s, 1H).
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][C:6](=[O:12])[CH2:7][C:8]([O:10][CH3:11])=[O:9].O>CO.S(=O)(=O)(O)O>[C:1]([CH2:5][C:6](=[O:12])[CH2:7][C:8]([O:10][CH3:11])=[O:9])#[N:2]
Reactant: [C-]#N
Reactant: COC(=O)CC(=O)CCl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)CC(=O)CC#N
Temperature: 40 °C
Yield: 69.2 %

Procedure:
After 0.4 g of potassium cyanide was added at room temperature to a solution of 1 g of Methyl 4-chloro-3-oxobutanoate in 20 ml of methanol, the resulting mixture was warmed to 40° C. and maintained for further 8 hours. Thereafter, reaction solution was cooled and pH of the solution was adjusted to 3 by adding 10 ml of water and a few drops of concentrated sulfuric acid. After the mixture was extracted thrice with diethyl ether, total amount of which was 100 ml, the separated organic layers were combined and concentrated under reduced pressure to give 0.6 g of methyl 4-cyano-3-oxobutanoate (Purity: 71%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.Br[CH2:31][CH:32]1[CH2:34][C:33]1([F:36])[F:35].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:31][CH:32]4[CH2:34][C:33]4([F:36])[F:35])[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: FC1(F)CC1CBr
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CC5CC5(F)F)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 150 °C

Procedure:
A mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (40 mg, 0.096 mmol), 2-(bromomethyl)-1,1-difluorocyclopropane (32.8 mg, 0.19 mmol) and triethylamine (20.2 μL, 0.14 mmol) in 1 mL of DMF was heated at 150° C. in a microwave reactor for 30 min. The crude product was purified by RP-HPLC to afford 5-chloro-N2-(4-(1-((2,2-difluorocyclopropyl)methyl)piperidin-4-yl)-2-fluoro-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; ESMS m/z 506.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CNc2cc(Br)ccc2[N+](=O)[O-])cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (500 mg, 2.27 mmol) in DMF (6 mL) was added (4-methoxyphenyl)methanamine (342 mg, 2.5 mmol) and TEA (345 mg, 3.4 mmol). The reaction mixture was then stirred at 120° C. for 30 min under microwave heating. After cooling, the mixture was diluted with water (40 mL) and the resulting precipitate collected by filtration, washed with water and dried in vacuo to give the desired product (750 mg, crude, 97% yield) which was used in next step without further purification. LCMS (m/z): 338.1 [M+H]+
Reaction SMILES: C[Si](C)(C)[C:3]#[N:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O[CH2:26][C:27]1[NH:28][C:29]([C:33]2[C:34]([CH3:43])=[CH:35][C:36]([CH3:42])=[C:37]([CH:41]=2)[C:38]([OH:40])=[O:39])=[C:30]([CH3:32])[N:31]=1>C(#N)C>[C:3]([CH2:26][C:27]1[NH:28][C:29]([C:33]2[C:34]([CH3:43])=[CH:35][C:36]([CH3:42])=[C:37]([CH:41]=2)[C:38]([OH:40])=[O:39])=[C:30]([CH3:32])[N:31]=1)#[N:4]
Reactant: C[Si](C)(C)C#N
Reactant: Cc1cc(C)c(-c2[nH]c(CO)nc2C)cc1C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: Cc1cc(C)c(-c2[nH]c(CC#N)nc2C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of trimethylsilanecarbonitrile (376 mg, 3.79 mmol) in acetonitrile (20 mL). Tetrabutylammonium fluoride (3.8 mL, 1 M in THF) was added to the reaction. This was followed by the addition of 5-(2-(hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound 222.5, 190 mg, 0.73 mmol), in portions. The reaction mixture was stirred for 1 h at room temperature, then concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:1) as eluent to furnish 190 mg (97%) of the title compound as a yellow solid.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]=1[C:19]1[N:20]=[CH:21][N:22]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[CH:23]=1>>[CH:1]1([NH:6][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([N:22]3[CH:23]=[C:19]([C:9]4[C:10]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)=[N:11][O:12][C:8]=4[CH3:7])[N:20]=[CH:21]3)[CH:25]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(C(=O)O)c2)cn1
Reactant: NC1CCCC1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(C(=O)NC3CCCC3)c2)cn1
Yield: 41 %

Procedure:
As described for Example 71, cyclopentylamine was converted, using 3-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (49 mg, 41%) which was obtained as an off-white solid. MS: m/e=413.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[S:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][C:26]=3[O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:43])[CH2:38][C:39]([O:41]C)=[O:40])=[CH:32][C:31]=3[F:44])[CH:21]=2)=[N:18][CH:19]=1)[CH2:9][CH2:10][O:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[S:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][C:26]=3[O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:43])[CH2:38][C:39]([OH:41])=[O:40])=[CH:32][C:31]=3[F:44])[CH:21]=2)=[N:18][CH:19]=1)[CH2:9][CH2:10][O:11][CH3:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)OC)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)O)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.4 %

Procedure:
To a solution of compound 342 (540 mg, 0.864 mmol) in THF (12 ml) and water (6 ml) was added LiOH monohydrate (363 mg, 8.64 mmol). The mixture was stirred 48 h at room temperature and THF was removed under reduced pressure. The aqueous solution was diluted with water (10 ml) and acidified to pH 4 using 1N HCl. The suspension was filtered and the precipitate was dried under high vacuum to afford compound 343 (485 mg, 0.79 mmol, 92% yield) as a beige solid. MS (m/z): 611.5 (M+H).
Reaction SMILES: [Cl:1][CH:2]([Cl:31])[C:3]([NH:5][C@H:6]([CH2:29][F:30])[C@@H:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:19][C:18]([CH2:20][NH:21]C(=O)OC(C)(C)C)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[OH:8])=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:21][CH2:20][C:18]1[S:19][C:15]([C:12]2[CH:11]=[CH:10][C:9]([C@@H:7]([OH:8])[C@H:6]([NH:5][C:3](=[O:4])[CH:2]([Cl:31])[Cl:1])[CH2:29][F:30])=[CH:14][CH:13]=2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
To a solution of tert-butyl ((5-(4-((1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-hydroxypropyl)phenyl)thiophen-2-yl)methyl)carbamate (140 mg, 0.238 mmol) in CH2Cl2 (10 mL) is added trifluoroacetic acid (1.0 mL) and the reaction mixture stirred at room temperature for 2 hours. The solvent is removed under reduced pressure and the residue washed with diethyl ether, then dissolved in 10% methanol in CH2Cl2 and evaporated to dryness. Washed with n-pentane and dried under vacuum to give the title compound (56 mg): 1HNMR (400 MHz, DMSO-d6) δ: 4.19-4.21 (m, 1H), 4.24-4.26 (m, 2H), 4.29-4.31 (m, 0.5H), 4.39-4.43 (m, 0.5H), 4.55-4.59 (m, 0.5H), 4.67-4.70 (m, 0.5H), 4.87 (bs, 1H), 5.90 (bs, 1H) 6.50 (s, 1H), 7.20 (d, J=3.64 Hz, 1H), 7.39 (d, J=8.24 Hz, 2H), 7.43 (d, J=3.68 Hz, 1H), 7.57 (d, J=8.16 Hz, 2H), 8.20 (bs, 3H), 8.59-8.63 (m, 1H). m/z (Cl) 388 [M−H].