Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][CH:18]([CH:21]4OCCC[O:22]4)[CH2:17][CH2:16]3)=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:16][CH2:17][C@H:18]([CH:21]=[O:22])[CH2:19][CH2:20]3)=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(-c2ccc(C3CCC(C4OCCCO4)CC3)cn2)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=CO
Product: O=C[C@H]1CC[C@H](c2ccc(-c3ccc(F)c(F)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 1.65 g of 2-(3,4-difluorophenyl)-5-[4-(1,3-dioxan-2-yl)cyclohexyl]pyridine, 15 ml of toluene and 10 ml of formic acid is stirred at room temperature for 10 hours and subsequently carefully neutralized to pH 7 with saturated sodium carbonate solution. The aqueous phase is separated and extracted twice with toluene, the organic phases are combined, washed with water, dried over sodium sulphate and evaporated. The residue is dissolved in 15 ml of methanol and added dropwise to 10 ml of 0.1N methanolic potassium hydroxide solution cooled to 0° C. The mixture is stirred at 0° C. for 1 hour, poured on to 40 ml of ice-water and extracted three times with 25 ml of diethyl ether each time. The organic phases are combined, washed neutral with water, dried over sodium sulphate and, after evaporation, give trans-4[2-(3,4-difluorophenyl)-5-pyridyl]-cyclohexanecarboxaldehyde (cis content about 8%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([C:16]([N:18]=[S@:19]([CH2:27][C:28](OCC)=[O:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])=[O:17])[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:33]([CH2:35][NH2:36])[OH:34]>>[OH:34][CH2:33][CH2:35][NH:36][C:28](=[O:29])[CH2:27][S:19](=[O:20])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[N:18][C:16](=[O:17])[C:12]1[CH:11]=[C:10]([C:9]#[C:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[CH:15]=[N:14][CH:13]=1
Reactant: CCOC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Reactant: NCCO
Product: O=C(CS(=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1)NCCO
Yield: 80 %

Procedure:
In a manner similar to that described for Example 471, (S)-Ethyl [N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate (75 mg, 0.17 mmol) and ethanolamine (0.05 mL, 0.84 mmol) were reacted to give the title compound as colorless oil (63 mg, 81%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5](Cl)=O.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:16][CH:15]=[CH:14][CH:13]=2.Cl.N1C=CC=CC=1>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1
Reactant: COCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Product: COCCc1nc2cnc3ccccc3c2n1CCCCNC(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
3-Methoxypropionyl chloride (15.4 g, 126 mmol) was added dropwise over a period of 20 minutes to a chilled (ice bath) solution of tert-butyl N-{4-[(3-aminoquinolin-4-yl)amino]butyl}carbamate (38 g, 115 mmol, U.S. Pat. No. 6,541,485, Example 2, Part B) in pyridine. The reaction mixture was stirred for 4 hours and then allowed to stand at ambient temperature over the weekend. Pyridine hydrochloride (3.9 g, 34 mmol) was added and the reaction mixture was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure and the residue was diluted with dichloromethane (250 mL) and aqueous sodium bicarbonate (250 mL). The layers were separated. The separatory funnel was rinsed with a small amount of methanol to remove a residue coating the walls. The combined organics were concentrated under reduced pressure. The residue was purified by prep HPLC (COMBIFLASH system eluting first with a gradient of 0 to 5% methanol in dichloromethane containing 1% ammonium hydroxide and then with a gradient of 5 to 10% methanol in dichloromethane containing 1% ammonium hydroxide) to provide 18 g of tert-butyl N-{4-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin 1-yl]butyl}carbamate.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20](=[O:22])[CH3:21])[C:15]1[C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=3[S:12][CH2:11][C:10]2=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20](=[O:22])[CH3:21])[C:15]1[C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=3[S:12][CH2:11][C:10]2=1
Reactant: CC(=O)n1c2c(c3cc(O[Si](C)(C)C(C)(C)C)ccc31)CSc1ccccc1-2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)n1c2c(c3cc(O)ccc31)CSc1ccccc1-2
Reaction time: 1 h

Procedure:
1-[8(tert-butyl-dimethyl-silanyloxy)-6H-5-thia-11-aza-benzo[a]fluoren-11-yl]-ethanone (136 mg, 0.332 mmol) in THF (5 mL) was added TBAF (332 μL, 1.0 N in THF, 0.332 mmol, 1.0 eq.). After 1 hour at 25° C., the reaction mixture was partitioned between saturated NaHCO3 aqueous solution and CH2Cl2, the aqueous layer was extracted with CH2Cl2 and the organic layers were dried and concentrated to yield crude product. The crude product was purified by chromatography to yield the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:13]([OH:15])[CH3:14])=[C:8]2[CH2:12][CH2:11][CH2:10][C:9]=12)=[O:4]>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13](=[O:15])[CH3:14])=[C:8]2[CH2:12][CH2:11][CH2:10][C:9]=12)=[O:4]
Reactant: COC(=O)c1sc(C(C)O)c2c1CCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COC(=O)c1sc(C(C)=O)c2c1CCC2
Yield: 95 %

Procedure:
Reflux a mixture of 3-(1-Hydroxy-ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid methyl ester (3.2 g, 0.0141 mol) and manganese dioxide (10.8 g, 0.124 mol) in dichloromethane for 2 hours. Filter the hot reaction mixture solution and concentrate the filtration under vacuum. Purify the residue by silica gel chromatograph (eluting with 2% to 10% ethyl acetate in petroleum ether) to give 3-acetyl-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid methyl ester as white solid (3.0 g, 13.39 mmol, 94.5%). 1H NMR (CDCl3, 400 MHz): δ 3.88 (s, 3H), 2.96 (m, 4H), 2.50 (s, 3H), 2.45 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=O)[CH2:7][CH2:8][CH2:9][S:10][C:4]=2[CH:3]=1.O.NN.[OH-].[K+]>C(O)COCCO>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][S:10][C:4]=2[CH:3]=1
Reactant: O=C1CCCSc2cc(Br)ccc21
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Brc1ccc2c(c1)SCCCC2
Yield: 72.5 %

Procedure:
15.6 g of 8-bromo-3,4-dihydro-1-benzothiepin-5(2H)-one were dissolved in 70 ml of diethylene glycol. The solution was treated with 6.55 ml of hydrazine hydrate and 7.5 g of solid potassium hydroxide and heated to 180°-190° C. under reflux for about 30 hours. After cooling, the mixture was poured on to ice and extracted with ether. The organic phase was washed with water, dried and evaporated. Chromatography on silica gel with petroleum ether yielded 10.7 g of 8-bromo-2,3,4,5-tetrahydro-1-benzothiepine as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH3:48])[C:10]([NH:12][NH:13][C:14]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:18]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)[C:17](=[O:35])[N:16]([CH2:36][C:37]2[C:38]([CH3:47])=[N:39][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:42]=2)[N:15]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:1]([O:8][C@H:9]([C:10]1[N:15]2[N:16]([CH2:36][C:37]3[C:38]([CH3:47])=[N:39][C:40]([C:43]([F:44])([F:45])[F:46])=[CH:41][CH:42]=3)[C:17](=[O:35])[C:18]([C:27]3[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[CH:31][CH:32]=3)=[C:19]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C:14]2=[N:13][N:12]=1)[CH3:48])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc(NNC(=O)[C@H](C)OCc2ccccc2)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccc(C#N)cc2)c(-c2ccc(Cl)cc2)c2nnc([C@H](C)OCc3ccccc3)n21
Temperature: 120 °C
Reaction time: 3 h
Yield: 43.6 %

Procedure:
To a round bottom flask was added (S)-2-(benzyloxy)-N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)propanehydrazide (70 mg, 0.140 mmol) and toluene (3 ml). The reaction was heated to 120° C. Then POCl3(0.3 ml) was added and the reaction was stirred at 120° C. for additional 3 hr. After this time, the solution was cooled to rt and concentrated. The residue was diluted with EtOAc (30 ml) and washed with NaHCO3(sat, 20 ml), water (20 ml) and saturated NaCl (20 ml). The organic solution was dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (4 g silica gel) eluting with a gradient of 20%-50% EtOAc/Hex to give product (S)-4-(3-(1-(benzyloxy)ethyl)-8-(4-chlorophenyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile as a white solid (40 mg, 44% yield).
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:25]([Cl:26])=[CH:24][C:10]3[NH:11][C:12]([C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19](Br)[CH:18]=4)([F:16])[F:15])=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.C([SiH](CC)CC)C.[CH:47]([O:50][P:51]([O-:56])[O:52][CH:53]([CH3:55])[CH3:54])([CH3:49])[CH3:48]>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1>[CH:47]([O:50][P:51]([C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]([C:12]2[NH:11][C:10]3[CH:24]=[C:25]([Cl:26])[C:7]([C:4]4[CH:3]=[CH:2][C:1]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:6][CH:5]=4)=[CH:8][C:9]=3[N:13]=2)([F:16])[F:15])[CH:18]=1)(=[O:56])[O:52][CH:53]([CH3:55])[CH3:54])([CH3:49])[CH3:48]
Reactant: FC(F)(c1cccc(Br)c1)c1nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Reactant: CC(C)OP([O-])OC(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)OP(=O)(OC(C)C)c1cccc(C(F)(F)c2nc3cc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3[nH]2)c1
Reaction time: 0.33 h

Procedure:
To a microwave reactor vial was added compound 15-1 (60 mg, 0.12 mmol), PdCl2(dppf) (19 mg, 0.024 mmol), triethylamine (50 μL, 0.36 mmol), triethylsilane (8 μL, 0.048 mmol), diisopropylphosphite (24 μL, 0.14 mmol) and 3 mL of toluene. The reaction was run in a microwave reactor for 20 min at 140° C. The reaction mixture was then diluted with EtOAc (50 mL) and washed three times with 50 mL portions of saturated aqueous ammonium chloride. The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo, and then purified on ISCO (EtOAc/Hexanes=4/1) to yield the title compound 15-2 as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[C:14](=O)([O-])[O-].[Na+].[Na+].CI.O>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=C([O-])c1cccc([N+](=O)[O-])c1Br
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1Br
Temperature: 60 °C
Yield: 126.2 %

Procedure:
To a stirred solution of 2-bromo-3-nitrobenzoate (3 g, 12.19 mmol) in DMF (33 mL), sodium carbonate (5.16 g, 48.67 mmol) and methyl iodide (6.92 g, 48.67 mmol) were added. Resulting reaction mixture was heated at 60° C. for 4 h. On completion, water was added to the mixture and extraction carried out using DCM. The combined organic layers were dried and concentrated under reduced pressure to obtain crude methyl 2-bromo-3-nitrobenzoate (4 g, crude).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[S:9](=[O:19])(=[O:18])[N:8]([CH2:20][CH2:21][C@H:22]3[CH2:24][O:23]3)[CH2:7][C:6]=2[CH:25]=1.C(O)C.[CH3:29][NH2:30]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[S:9](=[O:18])(=[O:19])[N:8]([CH2:20][CH2:21][C@H:22]([OH:23])[CH2:24][NH:30][CH3:29])[CH2:7][C:6]=2[CH:25]=1
Reactant: O=S1(=O)N(CC[C@H]2CO2)Cc2cc(F)ccc2N1c1ccccc1F
Reactant: CN
Solvent: CCO
Product: CNC[C@@H](O)CCN1Cc2cc(F)ccc2N(c2ccccc2F)S1(=O)=O
Temperature: 100 °C
Yield: 83 %

Procedure:
6-fluoro-1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.12 g, 0.29 mmol) was dissolved in an 8 M solution of methylamine in ethanol (3 mL, 24 mmol) and was heated to 100° C. for 192 sec. in the microwave. The reaction mixture was evaporated and the residue purified by flash chromatography (SiO2, 0-5% 7 M NH3-methanol/dichloromethane). The purified free-base was dissolved in dichloromethane (3 mL) and treated with hydrogen chloride (1.0 mL of a 2 M solution in ethyl ether), resulting in a white precipitate that was evaporated and dried under vacuum to provide (2S)-4-[6-fluoro-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-1-(methylamino)butan-2-ol (0.10 g. 83%) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37]S(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:5]([CH3:14])([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:37][CH2:36][CH2:35][C:33]3[N:34]=[C:30]([CH:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)[O:31][C:32]=3[CH3:48])=[CH:11][CH:12]=2)[C:4]([OH:23])=[O:3])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc(Cl)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(4-chlorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester by the procedure of Example 29. 1H NMR (400 MHz, CDCl3) δ 7.19 (d, 2H, J=8.60 Hz), 7.16 (d, 2H, J=8.60 Hz), 6.83 (d, 2H, J=8.60 Hz), 6.79 (d, 2H, J=8.60 Hz), 4.12 (t, 2H, J=6.26 Hz), 3.21 (d, 1H, J=14.08 Hz), 3.11 (d, 1H, J=14.08 Hz), 2.95 (t, 2H, J=6.26 Hz), 2.89-2.83 (m, 3H), 2.05 (d, 2H, J=11.73 Hz), 1.80 (d, 2H, J=11.73 Hz), 1.55 (q, 2H, J=11.73 Hz), 1.40 (s, 3H), 1.37-1.20 (m, 4H). MS (ES+) m/z mass calcd for C28H33ClNO5 498.21, found 498.2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11](=O)[CH2:12][NH:13][CH3:14])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.S(C)C.CO.C([O-])(O)=O.[Na+]>C1COCC1.Cl.CCOC(C)=O>[NH:1]1[C:9]2[C:4](=[C:5]([N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:12][NH:13][CH3:14])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CNCC(=O)N(c1ccccc1)c1cccc2[nH]ccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CSC
Product: CNCCN(c1ccccc1)c1cccc2[nH]ccc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a room temperature solution of N-(1H-indol-4-yl)-2-methylamino-N-phenyl-acetamide XXIV (122 mg, crude 0.435 mmol) in THF (6 ml) was added BH3.SMe2 (2 M in THF, 653 μl, 1.31 mmol). The mixture was stirred at room temperature for 2 hours, at 50° C. for 2 hours, and at reflux for 2 hours. The resulting mixture was then kept at −18° C. for 5 days. It was then warmed at room temperature and BH3.SMe2 (2M in THF, 653 μl, 1.31 mmol) was added. The mixture was refluxed for 45 minutes, cooled to 0° C., and MeOH (1.5 ml) and HCl (conc., 9 drops) were added. The mixture was stirred at 0° C. for 5 minutes, at room temperature for 1 hour and at 50° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted a saturated solution of NaHCO3 and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (DCM/MeOH/NH4OH). The chromatographed material was dissolved in p-xylene (9 ml) and Pd/C (5%, 14 mg) was added. The reaction mixture was refluxed for 3 hours, cooled to room temperature, and filtered through a celite pad with the aid of hot methanol. The filtrate was concentrated and purified via flash chromatography (DCM/MeOH/NH4OH) affording N-(1H-indol-4yl)-N′-methyl-N-phenyl-ethane-1,2-diamine XXV (8 mg, light brown oil). MS (M+H)=266.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][N:28]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[CH:29]=[N:28][C:27]([O:26][CH2:24][CH3:25])=[N:32][CH:31]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CCOc1ncc(B(O)O)cn1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CCOc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cn1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and 2-ethoxypyrimidine-5-boronic acid (Synthonix, Wake Forest, USA, 22 mg, 0.130 mmol) to give the title compound as a white solid. (HPLC: tR 2.51 min (Method A); M+H=416 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.73-8.67 (m, 2H), 8.16-8.09 (m, 2H), 7.98-7.91 (m, 1H), 7.51-7.46 (m, 1H), 4.39 (q, 2H), 3.89 (s, 3H), 3.57 (s, 3H), 1.96 (s, 3H), 1.35 (t, 3H))
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:7]([N:12]=1)=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:2][CH3:3].[C:13]1([C:19]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:20]2[C:24]([C:25]3[C:30]([C:31]4[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=4)=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:23][N:22]=[N:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>CCOC(C)=O>[CH2:1]([C:4]1[N:12]([CH2:37][C:34]2[CH:33]=[CH:32][C:31]([C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[N:20]([C:19]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:21]=[N:22][N:23]=3)=[CH:36][CH:35]=2)[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[N:5]=1)[CH2:2][CH3:3]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc2ncccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCc1nc2cccnc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
2-propyl-3-(2'-(N-triphenylmethyltetrazol-5-yl)-biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine was prepared according to the procedure described in Example 7, Part A from 2-propylimidazo[4,5-b]pyridine (19 mg, 0.118 mmol), N-triphenylmethyl-5-(4'-bromomethylbiphen-2-yl)tetrazole (60 mg, 0.108 mmol), and NaH (0.236 mmol). Yield: 18 mg (26%) thick oil; Rf: 0.75 (SiO2 tic, 100% EtOAc); 1H NMR (300 MHz, CDCl3) δ 8.27 (dd, 1H, J=6, 1 Hz), 8.01 (dd, 1H, J=9, 1 Hz), 7.85 (dd, 1H, J=9, 1.5 Hz), 7.50-7.42 (m, 2H), 7.38-7.22 (m, 11H), 7.08 (d, 2H J=7 Hz), 6.98-6.88 (m, 7H), 5.40 (s, 2H), 2.66 (t, 2H, J=7.5 Hz), 1.80-1.65 (m, 2H), 0.93 (t, 3H, J=6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-])=O.C1(C)C(C)=CC=CC=1.P.[OH-].[Na+]>Cl[Pd]Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[NH2:12]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: Cl[Pd]Cl
Agent: P
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: Nc1cc(C(F)(F)F)ccc1Cl

Procedure:
A degassed solution of 40 mmol of 2-chloro-5-trifluoromethylnitrobenzene (starting material) and 40 ml of xylene are placed in an autoclave (volume: 200 ml). 3.0 mmol of BINAS (in the form of 17.3 g of an aqueous solution containing 0.173 mol of BINAS/kg of solution) as phosphine and 2.4 g (60 mmol) of NaOH, 23.8 ml of H2O and 1.0 mmol of PdCl2 are added. The pH is from 10.5 to 11.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:21])=[C:4]([C:8]2([OH:20])[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([F:21])=[C:4]([C:8]2([OH:20])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(Cl)c2F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(c2cccc(Cl)c2F)CCNC1
Reaction time: 1 h

Procedure:
Preparation according to Preparation 2: tert-Butyl 3-(3-chloro-2-fluorophenyl)-3-hydroxypyrrolidin-1-carboxylate (4.42 g, 14 mmol), dichloromethane (100 mL), trifluoroacetic acid (10 mL). Stirred for 1 h. Yield: 2.24 g.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:22][CH2:21][N:20](C(OCC)=O)[CH2:19][CH2:18]1.[OH-].[K+].O.NN.O>C(O)CO.ClCCl.CO.CO.C(OCC)(=O)C.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccco2)CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: OCCO
Product: c1coc(Cn2c(NC3CCNCC3)nc3ccccc32)c1
Reaction time: 18 h

Procedure:
Combine (1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)(1-(ethoxycarbonyl)piperidin-4-yl)amine (1.38 g, 3.75 mmol), potassium hydroxide (3.0 g, 56.1 mmol) in ethylene glycol (15 mL). Add hydrazine hydrate (3.09 mL, 63.7 mmol). Heat to reflux. After 18 hours, cool, add water, and extract four times with dichloromethane (200 mL). Combine the organic layers, dry over MgSO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with sequentially with ethyl acetate, 25% methanol/ethyl acetate, 50% methanol/ethyl acetate, 75% methanol/ethyl acetate, and then methanol to give a residue. Dissolve the residue in dichloromethane, extract with water and then brine, dry over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][C:27]=1[N+:35]([O-:37])=[O:36].C(N(CC)CC)C.[C:45]([C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>C(OCC)(=O)C.CN(C=O)C>[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:53][C:52]2[CH:54]=[CH:55][C:49]([C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:50][CH:51]=2)=[O:32])=[CH:28][C:27]=1[N+:35]([O-:37])=[O:36]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(N)c([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To DMF (10 mL) was added HATU (3.61 g, 9.50 mmol), 4-amino-3-nitrobenzoic acid (1.15 g, 6.32 mmol), triethylamine (1.32 mL, 958 mg, 9.47 mmol), and 4-tert-butylaniline (1.0 mL, 945 mg, 6.33 mmol). The mixture was stirred at ambient temperature for 18 h then was poured into ethyl acetate and extracted once with water and five times with brine. The organic phase was dried, filtered, and the solvent removed under reduced pressure. The residue was purified by chromatography using gradient of a 30-70% heptane/ethyl acetate to afford 4-amino-N-(4-tert-butylphenyl)-3-nitrobenzamide. MS (ESI) m/z 314.1 (M+H); retention time 1.50 min (Method 10), which was used directly in the next step.