Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19](Br)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH3:38])=[CH:32][N:31]=1>C(O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[N:29]=[C:30]4[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH3:38])=[CH:32][N:31]4[C:19]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: CCOc1ccc(N)nc1
Solvent: CCO
Product: CCOc1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Yield: 26.9 %

Procedure:
A mixture of {1-[4-(2-bromo-2-phenyl-acetyl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester [Int-1-A] (0.87 g, 2.0 mmol), 2-amino-5-ethoxypyridine (0.54 g, 3.9 mmol, 2 equiv) and powdered activated 3A sieves (10 g) in ethanol (7.3 mL) was heated for 5 h at the reflux temperature with monitoring by UPLC-MS. The resulting solution was separated between CH2Cl2 (25 mL) and an saturated aqueous NaHCO3 solution (25 mL). The organic phase was washed with a saturated aqueous NaCl solution (25 mL), dried (Na2SO4 anh), and concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera; 25 g SNAP cartridge: 100% hexane for 1.5 min., gradient to 80% hexane/20% EtOAc over 2.2 min., gradient to 70% hexane/30% EtOAc over 10.6 min., 70% hexane/30% EtOAc for 2.8 min., gradient to 65% hexane/35% EtOAc over 2.2 min., 65% hexane/35% EtOAc for 4.8 min.) to give {1-[4-(6-ethoxy-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (0.26 g, 28%):
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[C:11]([C:13]1[CH:14]=[C:15]([NH:19][CH:20]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:26][CH:25]=2)=[O:22])[CH:16]=[CH:17][CH:18]=1)#[N:12]>CO>[OH:3][NH:2][C:11]([C:13]1[CH:14]=[C:15]([NH:19][CH:20]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[CH:26][CH:25]=2)=[O:22])[CH:16]=[CH:17][CH:18]=1)=[NH:12]
Reactant: NO
Reactant: N#Cc1cccc(NC(C(=O)Nc2ccc(N3CCOCC3)cc2)c2ccccc2)c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: N=C(NO)c1cccc(NC(C(=O)Nc2ccc(N3CCOCC3)cc2)c2ccccc2)c1
Temperature: 70 °C

Procedure:
149 mg (2.15 mmol) of hydroxylamine hydrochloride, 0.30 ml (2.15 mmol) of triethylamine and a few grains of 0.3 nM molecular sieve are added to a solution of 295 mg (0.715 mmol) of 2-(3-cyanophenylamino)-N-(4-morpholin-4-ylphenyl)-2-phenylacetamide in 5 ml of methanol, and the mixture is heated at 70° C. for 18 hours. The reaction mixture is filtered, the filtrate is evaporated, and the residue is taken up in water. The resultant precipitate is filtered off, giving 2-[3-(N-hydroxyamidino)phenylamino]-N-(4-morpholin-4-ylphenyl)-2-phenylacetamide as a colourless solid; ESI 446.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[CH3:25])[NH2:21]>>[F:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)[CH:22]=[CH:23][C:24]=1[CH3:25]
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: Cc1ccc(N)cc1F
Product: Cc1ccc(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1F
Yield: 22.6 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (100 mg, 0.43 mmol) and 3-fluoro-4-methylaniline (0.07 mL, 0.65 mmol) to provide 246 (31 mg, 20% yield) as a brown solid. LC-MS (M+H (parent)=321, obsd.=321).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[NH:31])[NH:7][C:8]1[CH:30]=[CH:29][C:11]2[S:12][CH2:13][CH2:14][N:15]([CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[C:10]=2[CH:9]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>CO>[NH:19]1[CH2:18][CH2:17][CH:16]([N:15]2[CH2:14][CH2:13][S:12][C:11]3[CH:29]=[CH:30][C:8]([NH:7][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[NH:31])=[CH:9][C:10]2=3)[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCSc3ccc(NC(=N)c4cccs4)cc32)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: N=C(Nc1ccc2c(c1)N(C1CCNCC1)CCS2)c1cccs1
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 69.4 %

Procedure:
To a stirred solution of tert-butyl 4-(6-(thiophene-2-carboximidamido)-2H-benzo[b][1,4]thiazin-4(3H)-yl)piperidine-1-carboxylate (398 mg, 0.868 mmol) in MeOH (6 mL) was added aqueous hydrogen chloride, 3M (2.893 mL, 8.68 mmol). The resulting solution was stirred at 90° C. for 45 minutes The mixture was then cooled to room temperature, basified (pH 12) with saturated sodium carbonate, and then extracted with dichloromethane (3×). The combined organics were dried, filtered, concentrated, and then chromatographed in 1:6 (2M NH3 in MeOH):ethyl acetate to give the desired product 29 (216 mg, 69.4%) as a pale yellow foam. 1H NMR (DMSO-d6) δ 7.71 (d, J=2.7 Hz, 1H), 7.59 (d, J=4.8 Hz, 1H), 7.08 (dd, J=5.1, 3.6 Hz, 1H), 6.86 (d, J=8.1 Hz, 1H), 6.37 (brs, 2H), 6.26 (s, 1H), 6.13-6.08 (m, 1H), 3.68-3.52 (m, 1H), 3.43-3.38 (m, 2H), 3.01-2.93 (m, 4H), 2.61-2.51 (m, 2H), 1.64-1.52 (m, 4H); ESI-MS (m/z, %): 359 (MH+, 100); ESI-HRMS calculated for C18H23N4S2 (MH+), calculated: 359.1358, observed: 359.1351; HPLC purity: 97% by area.
Reaction SMILES: N#N.[CH3:3][N:4]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([Cl:16])[C:10]([C:17]([F:20])([F:19])[F:18])=[CH:9][C:8]=1[NH2:21])[CH3:5].[N+]([C:25]1C=C(C(F)(F)F)C=C([N+]([O-])=O)[C:30]=1NN)([O-])=O>[Pd].C(O)C>[N+:13]([C:12]1[C:7]2[N:6]([N:4]([CH3:3])[CH3:5])[C:25]([CH3:30])=[N:21][C:8]=2[CH:9]=[C:10]([C:17]([F:18])([F:20])[F:19])[C:11]=1[Cl:16])([O-:15])=[O:14]
Reactant: NNc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CN(C)Nc1c(N)cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: Cc1nc2cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c2n1N(C)C

Procedure:
A solution of 5.2 g. of N2 -(dimethylamino)-4-chloro-3-nitro-5-trifluoromethyl-1,2-phenylenediamine (prepared by hydrogenation of the corresponding 3,5-dinitro-4-hydrazinobenzotrifluoride in the presence of palladium catalyst) and 7.5 g. of ethyl methylcarboximidate hydrochloride in 60 ml. of ethanol was refluxed for 26 hours. The resultant 7-nitrobenzimidazole was separated by fractionation on a silica gel column, m.p. 160° - 162°C.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:20])([CH3:19])[C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)[C:4](=[O:21])[N:3]1[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:24]=1.[OH-].[K+].Cl>CO.O>[CH3:1][C:2]1([CH3:36])[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:19])([CH3:20])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[C:4](=[O:21])[N:3]1[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:24]=1
Reactant: COC(=O)C(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(Nc4cccnc4)c3)C(C)(C)C2=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C(=O)O)c1ccc(N2C(=O)N(Cc3ccnc(Nc4cccnc4)c3)C(C)(C)C2=O)cc1
Yield: 68.1 %

Procedure:
To a solution of 0.34 g of methyl 2-[4-(4,4-dimethyl-2,5-dioxo-3-{[2-(pyridin-3-ylamino)pyridin-4-yl]methyl}imidazolidin-1-yl)phenyl]-2-methylpropanoate obtained in stage e) below in 20 mL of methanol, at room temperature, are added 7 mL of 1N potassium hydroxide. The reaction medium is heated at reflux for two hours and concentrated under reduced pressure. The residue obtained is taken up in 10 mL of water and then acidified with 2N HCl to pH=5. The white solid formed is filtered off and then dried to give 0.225 g of 2-[4-(4,4-dimethyl-2,5-dioxo-3-{[2-(pyridin-3-ylamino)pyridin-4-yl]methyl}imidazolidin-1-yl)phenyl]-2-methylpropanoic acid, the characteristics of which are as follows:
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.[CH:31]1([NH2:34])[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:31]1([NH:34][C:23](=[O:25])[C:22]2[CH:26]=[CH:27][C:19]([N:16]3[CH2:17][CH2:18][N:13]([CH2:12][C:9]4[CH:10]=[N:11][C:5]5[N:4]6[CH2:28][CH2:29][CH2:30][C@H:3]6[C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)[CH2:14][CH2:15]3)=[CH:20][CH:21]=2)[CH2:33][CH2:32]1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.9 %

Procedure:
(S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (87 mg, 0.214 mmol) and cyclopropanamine (18.29 mg, 0.320 mmol) were suspended in DMF (1 ml) and treated with DIPEA (0.186 ml, 1.068 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (162 mg, 0.427 mmol). The reaction mixture was stirred at room temperature for 3 h and purified using HPLC (25-95% acetonitrile in water, NH4HCO3 buffered) to afford (S)—N-cyclopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (43.0 mg, 0.096 mmol, 45.1% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.46-0.59 (m, 2H) 0.59-0.71 (m, 2H) 1.82-2.02 (m, 3H) 2.10-2.25 (m, 1H) 2.46 (br. s., 4H) 2.74-2.83 (m, 1H) 3.21 (br. s., 4H) 3.34-3.46 (m, 3H) 3.53-3.64 (m, 1H) 3.94-4.02 (m, 1H) 6.91 (d, J=8.84 Hz, 2H) 6.98 (d, J=1.77 Hz, 1H) 7.61 (d, J=1.26 Hz, 1H) 7.68 (d, J=8.84 Hz, 2H) 8.13 (d, J=4.04 Hz, 1H) 10.44 (s, 1H); [M+H] calc'd for C25H30N6O2, 447. found, 447; melting point 265-268° C.
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:19][CH:18]=2)[N:7]=1)C.[OH-].[Na+].O>CCO>[NH2:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:24])(=[O:25])=[O:26])=[CH:19][CH:18]=2)[N:7]=1
Reactant: CCOC(=O)Nc1cc(-c2ccccc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2ccccc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of an ethyl carbamate 5 (0.39 g, 1 mmol) in EtOH (10 mL) was added 10% NaOH solution (3.2 mL) at room temperature. The reaction mixture was refluxed for 5 hours. The reaction mixture was cooled to room temperature and water was added. The resulting white precipitate was filtered and washed with water thoroughly to give the titled compound (0.22 g, 70%) as a white solid. mp 286.3-290.2° C. 1H NMR (DMSO-d6): δ 7.70 (d, J=9 Hz, 2H), 7.43-7.20 (m, 9H), 5.89 (s, 1H), 5.17 (br s, 2H).
Reaction SMILES: [CH:1]1([C@@:4]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)([OH:9])[C:5]([F:8])([F:7])[F:6])[CH2:3][CH2:2]1.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[CH:1]1([C@:4]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:17][CH2:18][N:19]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[CH2:20][CH2:21]3)=[CH:14][CH:15]=2)([OH:9])[C:5]([F:7])([F:6])[F:8])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccccc1)N1CCN(c2ccc([C@@](O)(C3CC3)C(F)(F)F)cc2)CC1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: O=S(=O)(c1ccccc1)N1CCN(c2ccc([C@](O)(C3CC3)C(F)(F)F)cc2)CC1

Procedure:
(1S)-1-cyclopropyl-2,2,2-trifluoro-1-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)ethanol. 1H NMR (400 MHz, CD3OD) δ 7.88-7.78 (m, 2H), 7.74-7.57 (m, 3H), 7.48 (s, 2H), 6.96-6.83 (m, 2H), 3.28-3.23 (m, 4H), 3.18-3.05 (m, 4H), 1.61-1.48 (m, 1H), 0.76-0.63 (m, 1H), 0.58-0.46 (m, 1H), 0.44-0.34 (m, 1H), 0.30-0.20 (m, 1H). m/z (ESI, +ve ion) 441.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=2.62 μM; GK-GKRP EC50 (LC MS/MS)=2.77 μM.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Li]C(C)(C)C.CCCCC.[CH3:19][C:20]1([CH3:32])[CH2:29][C:28](=O)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Br:31])[CH:26]=2)[S:21]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.ClCCl.C(OC(=O)C)C>[CH3:19][C:20]1([CH3:32])[CH:29]=[C:28]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Br:31])[CH:26]=2)[S:21]1
Reactant: CC1(C)CC(=O)c2cc(Br)ccc2S1
Reactant: Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li]C(C)(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1ccc(C2=CC(C)(C)Sc3ccc(Br)cc32)cc1
Temperature: 25 °C

Procedure:
To a cold (-78° C.) solution of 4-bromotoluene (720 mg, 4.2 mmol) in THF (8 mL) was added t-BuLi in pentane (1.7M, 0.5 mL, 0.85 mmol). The mixture was warmed to ambient temperature over 30 minutes with stirring. This mixture was added to a flask containing 2,2-dimethyl-6-bromo-thiochroman-4-one (Compound M, 140 mg, 0.4 mmol) and THF (2 mL). and stirred for 16 hours at ambient temperature. The reaction was quenched by adding aq. NH4Cl, and the resulting mixture was extracted with ethylacetate, washed with brine, dried and the solvent was removed by evaporation. The product was isolated by chromatography on silica gel. The material was dissolved in dichloromethane (5 mL) and pTSA (5 mg) was added and heated to 50° C. for 3 hours. The misture was diluted with ethylacetate (20 mL), washed with 10% NaHCO3 (5 mL), brine (5 mL), dried with MgSO4 and the solvent was removed by evaporation to afford the title compound as an off.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH3:18])[C:7](=[O:17])[N:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[C:3]=1[O:21][CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1.C=O.O.[C:30]([BH3-])#N.[Na+]>O1CCCC1>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH3:18])[C:7](=[O:17])[N:8]([CH2:9][CH2:10][N:11]3[CH2:12][CH2:13][N:14]([CH3:30])[CH2:15][CH2:16]3)[C:4]=2[C:3]=1[O:21][CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1
Reactant: Cn1c(=O)n(CCN2CCNCC2)c2c(OCC3CCC3)c(Br)ccc21
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(CCn2c(=O)n(C)c3ccc(Br)c(OCC4CCC4)c32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
A solution of 5-bromo-4-(cyclobutylmethoxy)-1-methyl-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one (40.0 mg, 0.0945 mmol) in tetrahydrofuran (2.0 mL) was treated with a 1.23M solution of formaldehyde in water (384 μL, 0.474 mmol). The resultant reaction mixture was stirred at RT for 30 min, followed by the addition of sodium cyanoborohydride (17.8 mg, 0.284 mmol). After stirring at RT for 2 h, the reaction mixture was quenched with acetic acid (0.5 mL) and concentrated in vacuo to give the crude product. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (38 mg, 92%). LCMS calculated for C20H30BrN4O2 (M+H)+: m/z=437.2, 439.2. found: 437.1, 439.1.
Reaction SMILES: [CH3:1][C:2]1[C:18](=O)[CH2:17][CH2:16][C@@:15]2([CH3:20])[C:3]=1[CH2:4][CH2:5][C@@H:6]1[C@@H:14]2[CH2:13][CH2:12][C@@:11]2([CH3:21])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[OH:22].[ClH:23].Cl.[NH2:25][CH2:26][CH2:27][O:28][NH2:29]>O1CCOCC1.O.[Cl-].[Na+].O>[ClH:23].[NH2:25][CH2:26][CH2:27][O:28]/[N:29]=[C:18]1/[C:2]([CH3:1])=[C:3]2[C@:15]([CH3:20])([CH2:16][CH2:17]/1)[C@@H:14]1[C@H:6]([C@H:7]3[C@@:11]([CH2:12][CH2:13]1)([CH3:21])[C@@H:10]([OH:22])[CH2:9][CH2:8]3)[CH2:5][CH2:4]2
Reactant: NCCON
Reactant: CC1=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC/C1=N\OCCN
Reaction time: 0.17 h
Yield: 73.9 %

Procedure:
To a stirred solution of 4-methyltestosterone (203 mg) in dioxane (3.7 ml), a solution of 2-aminoethoxyamine dihydrochloride (259 mg) in water (2 ml) was rapidly added dropwise. After 24 h dioxane (20 ml) and brine (10 ml) were added and the mixture was stirred for 10 min. The phases were separated and the aqueous phase was extracted with dioxane (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated to dryness. The residue was triturated with Et2O for 5 h and the precipitate was filtered. The crude product was dissolved in water and freeze-dried to give the title compound (I-aa) as a white solid (197 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[CH2:23][CH2:22]3)[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=O.[CH:29]([NH2:32])([CH3:31])[CH3:30].COC1C(OC)=CC=C(C2C=C3C(=CC=2)C(=O)CC3)C=1OCC(C)(C)C(NC)=O>>[CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[CH2:23][CH2:22]3)[C:4]=1[O:5][CH2:6][C:7]([CH3:11])([CH3:12])[C:8]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:10]
Reactant: CC(C)N
Reactant: COc1ccc(-c2ccc3c(c2)CCC3=O)c(OCC(C)(C)C(=O)O)c1OC
Agent: CNC(=O)C(C)(C)COc1c(-c2ccc3c(c2)CCC3=O)ccc(OC)c1OC
Product: COc1ccc(-c2ccc3c(c2)CCC3=O)c(OCC(C)(C)C(=O)NC(C)C)c1OC

Procedure:
From 3-[2,3-Dimethoxy-6-(1-oxo-indan-5-yl)-phenoxy]-2,2-dimethyl-propionic acid (Compound 205) and isopropylamine following the procedure for preparation of Compound 206. Purification by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) afforded the title compound as a solid.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[CH:8]=[C:9]([Cl:34])[C:10]([C:13]2[CH:14]=[N:15][C:16]([C:19]3[NH:23][C:22]4[CH:24]=[C:25]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH:26]=[CH:27][C:21]=4[N:20]=3)=[CH:17][CH:18]=2)=[N:11][CH:12]=1)=[O:6]>>[Cl:34][C:9]1[C:10]([C:13]2[CH:14]=[N:15][C:16]([C:19]3[NH:23][C:22]4[CH:24]=[C:25]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)[CH:26]=[CH:27][C:21]=4[N:20]=3)=[CH:17][CH:18]=2)=[N:11][CH:12]=[C:7]([C:5]([OH:6])=[O:4])[CH:8]=1
Reactant: COC(=O)c1cnc(-c2ccc(-c3nc4ccc(N5CCOCC5)cc4[nH]3)nc2)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1cnc(-c2ccc(-c3nc4ccc(N5CCOCC5)cc4[nH]3)nc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
4 mL of 2 M lithium hydroxide solution (methanol/water=3/1) was added to 0.55 g of 3-chloro-6′-(6-morpholin-4-yl-1H-benzoimidazol-2-yl)-[2,3]bipyridinyl-5-carboxylic acid methyl ester (71) (1.22 mmol) prepared in Example 58, and stirred at room temperature for 6 hours. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and washed with water. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=5/1) to obtain 0.49 g of yellow crystal, 3-chloro-6′-(6-morpholin-4-yl-1H-benzoimidazol-2-yl)-[2,3]bipyridinyl-5-carboxylic acid (yield 92%).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[N:11]=[C:10]([Cl:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][C:15]=2[F:22])=[C:8]([CH3:23])[N:7]=1>C(Cl)Cl>[Cl:12][C:10]1[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][Cl:3])=[CH:16][C:15]=2[F:22])=[C:8]([CH3:23])[N:7]=[C:6]([NH2:5])[N:11]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(N)nc(Cl)c1Cc1ccc(CO)cc1F
Solvent: ClCCl
Product: Cc1nc(N)nc(Cl)c1Cc1ccc(CCl)cc1F
Temperature: 25 °C

Procedure:
Thionyl chloride (0.078 mL) was added to a stirred solution of the product from step (i) (0.30 g) in DCM (5 mL). The mixture was stirred at rt for Ih and then the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography to give the subtitle compound, 0.13 g.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[NH2:28][C:27]1[CH:29]=[CH:30][C:24]([O:23][C:21]2[CH:22]=[CH:17][N:18]=[C:19]([C:9]3[N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:12]=[CH:11][CH:10]=3)[CH:20]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)n1cccc1-c1cc(Oc2ccc(N)cc2)ccn1
Temperature: 72 °C

Procedure:
To a stirred mixture of N-Boc-pyrrole-2-boronic acid (114 mg, 0.54 mmol) and 4-((2-chloropyridin-4-yl)oxy)aniline (100 mg, 0.45 mmol) in 8 ml of 1,4-dioxane, was added PdCl2(PPh3)2 (10 mg, 0.014 mmol) and 1M Na2CO3 aqueous solution (0.5 ml, 1.0 mmol). The mixture was heated at 72° C. under N2 for one hour, cooled to room temperature and poured into 100 ml of water. The resulting mixture was extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (50 ml), dried over Na2SO4, and evaporated to give a brown oil, which was purified by silica gel chromatography with a gradient of 20˜50% EtOAc/hexanes to give tert-butyl 2-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-1-carboxylate as colorless oil. Yield: 110 mg, 70%.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:28]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:7]([CH:32]1[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Oc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 24.9 %

Procedure:
Phenol (503 mg, 5.34 mmol) and triphenylphosphine (1.40 g, 5.34 mmol) were added to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (500 mg, 2.67 mmol; which may be prepared as described in Step 1) in anhydrous THF (13 mL) under nitrogen. The reaction mixture was cooled to 0° C. and DEAD (775 μL, 4.27 mmol) was added dropwise. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure then diluted with dichloromethane and filtered. The filtrate was washed three times with NaOH 0.2N and brine, dried over Na2SO4 then concentrated. The residue was purified on column chromatography (eluent: pentane EtOAc 9/1) to give the title compound (175 mg, 25%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[S:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[Br:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Br:21])[CH:23]=3)[CH2:33][CH2:32]2)=[S:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(C)nc1NC(=S)Oc1ccccc1
Reactant: Brc1cccc(N2CCNCC2)c1
Product: COc1nc(C)c(C)nc1NC(=S)N1CCN(c2cccc(Br)c2)CC1
Yield: 62.5 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)thiocarbamate and 1-(3-bromophenyl)piperazine were reacted by the same way with the example 28 to obtain the titled compound.