Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 100 °C
Yield: 53.3 %

Procedure:
To a mixture of 2-bromo-5-nitropyridine (0.5 g, 2.46 mmol) and N-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (0.913 g, 2.95 mmol) in toluene (4 mL) and ethanol (1.0 mL) was added potassium carbonate solution (2M, 2 mL) and PdCl2dppf (180 mg, 0.246 mmol). The mixture was degassed with argon and heated to 100° C. in a microwave for 40 minutes with stirring. The solvents were evaporated and the residue was extracted with ethyl acetate. After evaporation of the solvents, the residue was purified using flash chromatography (eluting with ethyl acetate and hexanes) to give 5-nitro-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester as a solid (400 mg). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[OH:24][C:25]([CH3:30])([CH3:29])[C:26](O)=[O:27].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>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:26](=[O:27])[C:25]([OH:24])([CH3:30])[CH3:29])=[C:16]2[N:15]=1
Reactant: CC(C)(O)C(=O)O
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)C(=O)Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a mixture of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol), 2-hydroxy-2-methylpropanoic acid (10 mg, 0.095 mmol), and HATU (36 mg, 0.095 mmol) was added 0.6 mL acetonitrile to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.041 mL, 0.24 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was concentrated, re-dissolved in methanol, and purified by reverse-phase column chromatography, eluting with 5 to 55% acetonitrile/water to yield the final product as an off-white solid (21 mg, 66% yield). MS (apci) m/z=402.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[OH:12].[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:12][C:20]1[CH:21]=[CH:22][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1ccc(Cl)c(O)c1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Product: CS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)ccc2Cl)cc1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of example 1 step (iii) and 4-fluorophenyl methyl sulfone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]3[CH2:16][C@H:15]3[NH:17]C(=O)OC(C)(C)C)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[ClH:25]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]3[CH2:16][C@H:15]3[NH2:17])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[ClH:25]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(-c2cccc(Cl)c2)cc1
Agent: Cl
Solvent: CCOCC
Product: N[C@@H]1C[C@H]1c1ccc(-c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cooled solution of tert-butyl (trans)-2-(3′-chlorobiphenyl-4-yl)cyclopropylcarbamate (3 g) in Et2O (15 mL) at 0° C. was added HCl in Et2O (15 mL), stirred for 16 h at RT. The progress of the reaction was monitored by TLC. After completion, the solvent was evaporated, residue was triturated with. Et2O to get (Trans)-2-(3′-chlorobiphenyl-4-yl)cyclopropanamine as HCl salt (2.3 g, 95.8%) as a white solid. The HCl salt was made free base by using NaHCO3 solution and used in next reaction.
Reaction SMILES: [NH:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[SH:4](=[O:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:3]1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32](Cl)=[O:33])=[CH:28][CH:27]=1>C(Cl)(Cl)Cl>[Cl:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32]([N:1]=[C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[SH:4](=[O:17])([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:3]2)=[O:33])=[CH:28][CH:27]=1
Reactant: N=C1N[SH](=O)(c2ccccc2)c2ccccc21
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(COc1ccc(Cl)cc1)N=C1N[SH](=O)(c2ccccc2)c2ccccc21

Procedure:
24 g. 3-imino-1-phenyl-3H-1,2-benzisothiazole-1-oxide, 13.2 g. triethylamine and 21 g. 4-chlorophenoxyacetyl chloride are heated under reflux for 1 hour in 1 liter chloroform. After working up the reaction mixture in the usual manner, there is obtained 3-(4-chlorophenoxyacetylimino)-1-phenyl-3H-1,2-benzisothiazole-1-oxide which, after recrystallisation from acetonitrile, is obtained in the form of colourless, felted needles melting at 196°C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[N:9]=[CH:8][N:7]=[C:6]([O:15][CH:16]4[CH2:21][CH2:20][C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:22])[CH2:18][CH2:17]4)[C:5]=3[C:4]1=2.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>ClCCl>[CH3:31][S:32]([O:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[N:9]=[CH:8][N:7]=[C:6]([O:15][CH:16]4[CH2:17][CH2:18][C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:22])[CH2:20][CH2:21]4)[C:5]=3[C:4]1=2)(=[O:34])=[O:33]
Reactant: CC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CO)CC4)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](COS(C)(=O)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a solution of tert-butyl N-(4-[[(3S)-3-(hydroxymethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)carbamate (1.0 g, 2.31 mmol, 1.00 equiv) in dichloromethane (20 mL) was added MsCl (632 mg, 5.54 mmol, 2.40 equiv) and triethylamine (839 mg, 8.29 mmol, 3.59 equiv) at 0° C. The resulting solution was stirred for 1 h at room temperature and quenched with water. The resulting solution was extracted with 3×50 mL of DCM and the organic layers were combined, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/3) to yield 1.07 g (91%) of tert-butyl N-(4-[[(3S)-3-[(methanesulfonyloxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)carbamate as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:13]=3[CH:14]=[C:15]([C:21]([OH:23])=O)[NH:16]4)[C:6]=2[CH:24]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][C:29]([CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][C@H:38]([OH:41])[C@@H:37]([CH3:42])[CH2:36]2)([OH:32])[CH2:28][CH2:27]1>>[OH:32][C:29]1([CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][C@H:38]([OH:41])[C@@H:37]([CH3:42])[CH2:36]2)[CH2:30][CH2:31][CH:26]([NH:25][C:21]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[C:12]([O:11][CH2:10][C:7]2[C:6]4[CH:24]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:9][CH:8]=2)[CH:20]=[CH:19][CH:18]=3)=[O:23])[CH2:27][CH2:28]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reactant: O=C(O)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1
Product: C[C@H]1CN(CCC2(O)CCC(NC(=O)c3cc4c(OCc5coc6ccc(Cl)cc56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (synthesis described in WO2005077932A2, cmpd 113) and amine 14.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br>CN(C)C=O>[CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:12])([CH3:13])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[N:3]1[CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=1[C:17]([F:16])([F:26])[F:27]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1ccccc1C(F)(F)F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 31 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 2-trifluoromethyl-benzyl bromide (77 μL, 0.51 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. overnight. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-1,7,8,8-tetramethyl-2-(2-trifluoromethyl-benzyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (55.3 mg, 32%) as a light yellow solid. APCI-MS (M+H) 365.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:13]=[O:14])=[CH:8][CH:7]=1.[CH3:19][NH:20][O:21][CH3:22]>C1C=CC=CC=1>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]([N:20]([CH3:19])[O:21][CH3:22])=[O:14])=[CH:10][CH:11]=1
Reactant: O=C=Nc1ccc(OCc2ccccc2F)cc1
Reactant: CNOC
Solvent: c1ccccc1
Product: CON(C)C(=O)Nc1ccc(OCc2ccccc2F)cc1
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
To a solution of 4-(2-fluorobenzyloxy)phenyl isocyanate (24.3 g) in benzene (150 ml), a solution of N,O-dimethylhydroxylamine (20 g) in benzene (100 ml) is added dropwise at 20° to 30° C., and the resulting mixture is stirred at the same temperature for 30 minutes. The reaction mixture is concentrated in vacuo, and the residual crude crystals are recrystallized from ethanol to give N-[4-(2-fluorobenzyloxy)phenyl]-N'-methyl-N'-methoxyurea (Compound No. 1) (18 g) as white scales. M.P., 99° to 100° C.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C@@H:3]1[CH2:7][N:6]([CH3:8])[C@H:5]([C:9]([OH:11])=O)[CH2:4]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:34][C:35]1[CH:36]=[CH:37][C:38]([NH:41][NH2:42])=[N:39][CH:40]=1>C(Cl)Cl>[F:34][C:35]1[CH:36]=[CH:37][C:38]([NH:41][NH:42][C:9]([C@@H:5]2[CH2:4][C@H:3]([N:2]([CH3:1])[CH3:12])[CH2:7][N:6]2[CH3:8])=[O:11])=[N:39][CH:40]=1
Reactant: NNc1ccc(F)cn1
Reactant: CN(C)[C@H]1C[C@@H](C(=O)O)N(C)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN(C)[C@H]1C[C@@H](C(=O)NNc2ccc(F)cn2)N(C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.1 %

Procedure:
A solution of Intermediate 38a (5.95 g, 34.2 mmol) in DCM (60 mL) was treated with EDCI (7.87 g, 34.2 mmol), HOBt (0.462 g, 41.0 mmol) and (5-fluoro-pyridin-2-yl)-hydrazine (4.35g g, 34.2 mmol) and the solution was stirred at RT for 16 hours. The reaction mixture was partitioned between H2O (50 mL) and DCM (40 mL) and the phases were separated. The organic phase was washed with sat. bicarbonate solution and the brine. The volatiles were concentrated in vacuo and the resultant residue was purified by FCC using 0-10% MeOH in DCM to afford the title compound (1.74 g, 20%). LCMS (Method 3): Rt 0.44 min, m/z 282 [MH+].
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1.[CH3:31][NH:32][CH2:33][CH2:34][OH:35]>C(O)C>[OH:35][CH2:34][CH2:33][N:32]([CH3:31])[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1
Reactant: CNCCO
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Solvent: CCO
Product: CN(CCO)c1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1
Reaction time: 2 h

Procedure:
To a solution of 150 mg (0.337 mmol) of the oxadiazole from Example 23A in 2.25 ml of ethanol were added 507 mg (6.74 mmol) of 2-(methylamino)ethanol, and then the reaction mixture was stirred in the microwave at 80 for 2 h. Another 507 mg (6.74 mmol) of 2-(methylamino)ethanol were added and the mixture was stirred in the microwave at 80 for a further 2 h and then at 100° C. for 30 min. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 53.7 mg (33% of theory)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([NH:31][CH3:32])[C:27]([CH3:34])([CH3:33])[CH2:26]2)=[CH:21][C:20]=1[O:35][CH3:36]>>[Cl:17][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:7][C:2]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH:28]([NH:31][CH3:32])[C:27]([CH3:33])([CH3:34])[CH2:26]3)=[CH:21][C:20]=2[O:35][CH3:36])=[N:3][CH:4]=1
Reactant: CNC1CCN(c2ccc(N)c(OC)c2)CC1(C)C
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Product: CNC1CCN(c2ccc(Nc3ncc(Cl)c(-c4c[nH]c5ccccc45)n3)c(OC)c2)CC1(C)C

Procedure:
Starting materials: 3-(2,5-dichloropyrimidm-4-yl)-1H-indole (INTERMEDIATE 2) and), 1-(4-amino-3-methoxyphenyl)-N,3,3-trimethylpiperidin-4-amine (INTERMEDIATE 44).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(O)(=O)C.CN(C1C=CN=CC=1)C>[C:20]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: Nc1ccc2[nH]c(=O)c(=O)n(C3CCCCC3)c2c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2[nH]c(=O)c(=O)n(C3CCCCC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
18.3 g (70 mmol) of 7-amino-1-cyclohexyl-2,3 (1H,4H)-quinoxalinedione (product e2 from Example 36) were dissolved in 250 ml of acetic acid and, after a spatula tip of 4-(N,N-dimethylamino)pyridine had been added, 7.2 g (70 mmol) of acetic anhydride were added dropwise. The mixture was stirred at room temperature for 30 min and then the precipitate was filtered off with suction and dried to yield 20.8 g (98%) of the product. Melting point 227°-230° C. (decomposition).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[O:9]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:17]=2)[CH:7]=1
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(Nc2cccc(Oc3ccccc3)c2)ncn1
Yield: 57 %

Procedure:
A solution of 4,6-dichloropyrimidine (0.5 g, 3.3 mmol), 3-phenoxyaniline (0.75 g, 4 mmol) and DIPEA (0.65 g, 5 mmol) in n-butanol (5 mL) was subjected to microwave irradiation (110° C., 30 min). The reaction mixture was cooled, concentrated under reduced pressure and the residue was dissolved in EtOAc (10 mL). This solution was washed with water (5 mL) and brine (5 mL), and was dried over Na2SO4. Concentrated under reduced pressure gave a residue that was purified by column chromatography (SiO2, 60-120, hexane/ethylacetate, 8/2) to give 6-chloro-N-(3-phenoxyphenyl)pyrimidine-4-amine (0.56 g, 56%) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:10]=3
Reactant: ClCc1ccccc1
Reactant: O=c1c(Cc2cccnc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Product: O=c1c(Cc2cccnc2)cn2c3c(cc(OCc4ccccc4)cc13)Sc1ccc(Br)cc1-2
Yield: 48 %

Procedure:
According to Example 34, the compound (100 mg) produced in Example 37 was reacted with benzyl chloride (39 μl) to obtain the title compound (58 mg; 48%).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30]([NH:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:10][C@H:1]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]1)[CH:20]=[CH:19]2)=[O:31]
Reactant: O=C=Nc1ccccc1F
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)Nc1ccccc1F

Procedure:
The title compound, MS: m/e=413.7 (M+H+), was prepared in accordance with the general method 4 of example 16 from (R)—N2-indan-1-yl-quinoline-2,6-diamine and 2-fluorophenyl-isocyanate.
Reaction SMILES: Br[CH:2]([CH3:6])[C:3](=O)[CH3:4].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][N:9]=1.CCO>O>[I:14][C:11]1[CH:12]=[CH:13][C:8]2[N:9]([C:2]([CH3:6])=[C:3]([CH3:4])[N:7]=2)[CH:10]=1
Reactant: CC(=O)C(C)Br
Reactant: Nc1ccc(I)cn1
Solvent: CCO
Solvent: O
Product: Cc1nc2ccc(I)cn2c1C
Temperature: 70 °C
Yield: 25.3 %

Procedure:
To a mixture of 3-bromobutan-2-one (1.0 g) and 2-amino-5-iodopyridine (800 mg) was added EtOH (25 ml), and the mixture was heated at 70° C. for 30 h. The reaction mixture was cooled, diluted with water, and extracted with DCM. The DCM layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (250 mg) as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH2:22]([C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C@@H:30]2[CH2:32][O:31]2)=[CH:26][CH:25]=1)[CH3:23]>>[CH2:22]([C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C@@H:30]([OH:31])[CH2:32][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:26][CH:25]=1)[CH3:23]
Reactant: CCc1ccc(OC[C@@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: CCc1ccc(OC[C@@H](O)CN2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)cc1

Procedure:
Compound 207 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-ethylphenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=137-138° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.90 (d, 1H, J=7.8 Hz), 7.82-7.78 (m, 2H), 7.57 (dt, 1H, J=2.0, 6.8 Hz), 7.10 (d, 2H, J=5.6 Hz), 6.85 (d, 2H, J=8.2 Hz), 4.86 (bs, 1H), 4.03-3.80 (m, 3H), 3.07 (s, 2H), 2.88-2.74 (m, 2H), 2.58-2.41 (m, 2H), 2.02-1.94 (m, 2H), 1.88-1.78 (m, 2H), 1.14 (t, J=7.9 Hz, 3H). LCMS: 480 [M+H].
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:15][C@H:16]([C:18]2[N:23]=[C:22]3[CH:24]=[CH:25][N:26]([CH3:27])[C:21]3=[CH:20][C:19]=2[N:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)[CH3:17])=[N:5][C:6](S(C)(=O)=O)=[N:7][C:8]=1[CH2:9][CH3:10])#[N:2].[NH3:41]>O1CCOCC1.CCOC(C)=O>[NH2:41][C:6]1[N:5]=[C:4]([NH:15][C@H:16]([C:18]2[N:23]=[C:22]3[CH:24]=[CH:25][N:26]([CH3:27])[C:21]3=[CH:20][C:19]=2[N:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:30][CH2:29]2)[CH3:17])[C:3]([C:1]#[N:2])=[C:8]([CH2:9][CH3:10])[N:7]=1
Reactant: CCc1nc(S(C)(=O)=O)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCN(C(=O)OC(C)(C)C)CC2)c1C#N
Reactant: N
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCN(C(=O)OC(C)(C)C)CC2)c1C#N
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a 10 mL vial were added tert-butyl (S)-4-(5-(1-((5-cyano-6-ethyl-2-(methylsulfonyl)pyrimidin-4-yl)amino)ethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)piperazine-1-carboxylate (32 mg, 0.056 mmol) in dioxane (2 mL) along with 0.5 M ammonia in dioxane (6.09 μL, 0.281 mmol) to give a yellow solution. The vial was sealed and the reaction mixture was stirred overnight at 75° C. The next day LCMS indicated the reaction was incomplete. Additional NH3 solution (2 eq) was added and the reaction mixture was allowed to stir for 6 hours at 75° C. LCMS showed the reaction was mostly complete. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography (ISCO 4 g, 50-100% EtOAc/hexane gradient) to give the title compound as a yellow oil.
Reaction SMILES: C(OC([N:8]1[C@H:13]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=O)(C)(C)C.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[CH2:17]([O:16][C:14]([C@@H:13]1[CH2:12][C@@H:11]2[C@@H:9]([CH2:10]2)[NH:8]1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H]1C[C@H]2C[C@H]2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 3-benzyl ester 2-tert-butyl ester (3.27 g, 9.79 mmol) in CH2Cl2 (50 mL) was added was added TFA (7.54 mL, 98 mmol). The reaction mixture was stirred overnight at RT and subsequently concentrated under reduced pressure to give the desired material as a yellow oil. MS (UPLC): 218.1 [M+H]+; tR (HPLC conditions b): 1.24 min.
Reaction SMILES: C[Mg]Br.[CH:4]([C:6]1[N:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][CH:7]=1)=[O:5].O.[C:16](OCC)(=O)C>O1CCCC1>[OH:5][CH:4]([C:6]1[N:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][CH:7]=1)[CH3:16]
Reactant: NC(=O)c1cccc(C=O)n1
Reactant: CCOC(C)=O
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1cccc(C(N)=O)n1

Procedure:
An ethereal solution of methyl magnesium bromide (3 mol/l) (546 ml) was added dropwise to a solution of 6-formyl-2-pyridinecarboxamide (61.5 g) in tetrahydrofuran (900 ml) at 0°-13° C. with stirring. After the mixture was stirred at the same temperature for 2 hours and cold water was dropped to the reaction mixture under ice-cooling. To the mixture was added ethyl acetate and adjusted to pH 7 with N-hydrochloric acid. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 6-(1-hydroxyethyl)-2-pyridinecarboxamide (63.2 g) as an oil.