Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].[Li]C(C)(C)C.CCCCC.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C:21]1([CH2:30][CH2:29][CH:28]([O:31][CH3:32])[CH2:27][CH2:26]1)[C:20]2=[N:33][S:34]([CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])(=[O:36])=[O:35].C(OC=C[Li])C>C1COCC1>[Br:16][C:17]1[CH:18]=[C:19]2[C:23]([CH2:22][C:21]3([CH2:30][CH2:29][CH:28]([O:31][CH3:32])[CH2:27][CH2:26]3)[C:20]2([NH:33][S:34]([CH2:37][CH2:38][Si:39]([CH3:41])([CH3:40])[CH3:42])(=[O:36])=[O:35])[C:1]([O:3][CH2:4][CH3:5])=[CH2:2])=[CH:24][CH:25]=1
Reactant: C=COCC
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=NS(=O)(=O)CC[Si](C)(C)C
Agent: [Li]C(C)(C)C
Agent: [Li]C=COCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: C=C(OCC)C1(NS(=O)(=O)CC[Si](C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Reaction time: 0.17 h

Procedure:
To a solution of ethyl vinyl ether (7 mL, 73 mmol) in THF (10 mL) was added dropwise a solution of 1.7 M t-BuLi in pentane (26 mL, 44 mmol) at −78° C. under nitrogen. After 10 min, the reaction mixture was cooled in an ice bath and stirred for 45 min. To a solution of N-(5′-bromo-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-(trimethylsilyl)ethanesulfonamide (2) (1.3508 g, 2.86 mmol) in THF (20 mL) was added a solution of -ethoxyvinyllithium, obtained as described above, at −78° C. under nitrogen via a cannula. After 2 h, LC-MS indicated the disappearance of starting material. The reaction mixture was quenched with saturated NaHCO3 (5 mL) and saturated brine (20 mL) and then vigorously stirred at room temperature for 1 h. The mixture was extracted three times with EtOAc. The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product 9 (1.7654 g) was directly used in the next step without further purification. LC-MS tR=2.43 min in 3 min chromatography, m/z 544, 546 (MH+), 480, 482.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.O>CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(O)CC1
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCC(OCc2ccc(Cl)cc2)CC1
Reaction time: 3 h
Yield: 84.3 %

Procedure:
1-Acetylpiperidin-4-ol (Preparation 193, 10 g, 70 mmol) in N,N-dimethylformamide (50 ml) was added dropwise to a stirred suspension of sodium hydride (50% wt dispersion in oil, 4.8 g, 0.1 mol) in N,N-dimethylformamide (50 ml) at room temperature under nitrogen. After stirring the reaction mixture for 3 hours, 4-chlorobenzyl chloride (12.8 g, 80 mmol) in N,N-dimethylformamide (50 ml) was added dropwise and the reaction mixture was stirred for a further 4 h. The solution was filtered and the filtrate was evaporated to give an orange oil. Water was added and the mixture was extracted with petroleum ether (3×50 ml) and then with diethyl ether (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated to give the title compound as an orange oil (15.8 g, 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:11][N:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[S:37](Cl)(=[O:39])=[O:38].[Na]>N1C=CC=CC=1>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[C:8]([C:4]3[CH:3]=[C:2]([NH:1][S:37]([C:31]4[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=4[F:29])(=[O:39])=[O:38])[CH:7]=[CH:6][CH:5]=3)=[N:9][N:10]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[CH:11]=2)[CH:18]=[CH:17][N:16]=1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: COc1ccc(Cn2cc(-c3ccnc(N)n3)c(-c3cccc(N)c3)n2)cc1
Agent: [Na]
Solvent: c1ccncc1
Product: COc1ccc(Cn2cc(-c3ccnc(N)n3)c(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3)n2)cc1
Temperature: 25 °C
Yield: 31 %

Procedure:
175 mg (0.47 mmol) of 4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-pyrimidin-2-amine were dissolved with 10 ml of dry pyridine and 63 μl of 2,5-difluorobenzensulfonylchloride were added under stirring. The solution was maintained at room temperature overnight. The reaction mixture was then poured into aqueous sodium hydrogenocarbonate and extracted with dichloromethane. The organic layer was dried over sodium sulphate and evaporated to dryness. The residue was purified by flash-chromatography on a silica gel column (CH2Cl2-CH3COCH3; from 9/1 to 8/2), giving 80 mg (31%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:9].CN[CH2:43][CH3:44]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:37])=[O:38])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH2:9][CH2:43][CH3:44]
Reactant: CCNC
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Solvent: O=C(O)C(F)(F)F
Product: CCCCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Yield: 15.8 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting butyl(methyl)amine (87 mg, 1.0 mmol) for N-methylethanamine to afford 10 mg of the title compound (15.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Li]CCCC.[CH:19]([N:22]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[C:26]([CH3:32])[CH:25]=1)([CH3:21])[CH3:20].OS([O-])(=O)=O.[K+]>C(OCC)C.C1COCC1>[CH:34]1([N:22]([CH:19]([CH3:21])[CH3:20])[C:23](=[O:33])[C:24]2[CH:29]=[CH:28][C:27]([CH:30]([OH:31])[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)=[C:26]([CH3:32])[CH:25]=2)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: COc1cc(Br)cc(OC)c1OC
Reactant: Cc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1C=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(C(O)c2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2C)cc(OC)c1OC
Temperature: -8 °C
Reaction time: 0.17 h

Procedure:
To a stirred, cold (-15° C.) solution Of 3,4,5-trimethoxybromobenzene (965 mg, 3.9 mmol) in ethyl ether (15 ml) is added n-BuLi (3 ml of 1.6 M solution in hexane). The reaction mixture is stirred at -8° C. for 10 min., diluted with THF (5 ml) and warmed to 0° C. After stirring for 5 min., the reaction is cooled to -30° C. and a solution of 4-formyl-3-methylbenzoic acid N-isopropyl-N-cyclohexyl amide (1.12 g, 3.9 mmol) in THF (5 ml) is added. After stirring at -30° C. for 10 min. and warming to room temperature, the reaction is poured onto 0.5 N KHSO4 and extracted with ethyl acetate. The organic layer is washed with saturated NaCl solution and dried (MgSO4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. This is chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]([OH:16])=O)=[CH:12][C:11]([CH3:17])=[N:10]2)=[CH:5][CH:4]=1.[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl.CS(C)=O>[CH:18]1([NH:24][C:14]([C:13]2[N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[N:10]=[C:11]([CH3:17])[CH:12]=2)=[O:16])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1ccc(-n2nc(C)cc2C(=O)O)cc1
Reactant: NC1CCCCC1
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc(-n2nc(C)cc2C(=O)NC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
2-(4-Methoxyphenyl)-5-methyl-2H-pyrazole-3-carboxylic acid (752 mg, 3.24 mmol) was suspended in methylene chloride (25 mL) and DMSO (3 drops) was added. After the reaction was stirred at room temperature for 1 hour, it was concentrated in vacuo. The residue was diluted twice with methylene chloride (60 mL) and concentrated to dryness. The residue was diluted again with methylene chloride (45 mL), cyclohexylamine (650 μL, 5.68 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The reaction was diluted further with methylene chloride, washed with NaOH (10%) and 1 N HCl, then dried over Na2SO4. Concentration gave 630 mg of the title compound, which was used in the next reaction without further purification. LC-MS (C18H23N3O2 calculated 313) m/z 314 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11]([C:13]1[N:14]=[C:15]([CH2:23][NH:24][C:25](OC(C)(C)C)=O)[S:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:12])[CH3:9]>>[CH2:21]([O:20][C:18]([C:17]1[S:16][C:15]2=[CH:23][N:24]=[CH:25][N:14]2[C:13]=1[C:11]([O:10][CH2:8][CH3:9])=[O:12])=[O:19])[CH3:22]
Reactant: CCOC(=O)c1nc(CNC(=O)OC(C)(C)C)sc1C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1sc2cncn2c1C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A 30 ml potion of trifluoroacetic acid was added to 10.24 g 4,5-bis(ethoxycarbonyl)-2-t-butoxycarbonylaminomethylthiazole, and the mixture was then stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and an aqueous saturated sodium hydrogencarbonate solution was then added so as to adjust the pH of the solution to about 8. Further, 150 ml of dichloromethane was added thereto, and a mixture of 27 ml of formic acid and 13.5 ml of acetic anhydride which had been beforehand reacted with each other at 50° C. for 30 minutes was then added at room temperature with vigorous stirring, followed by stirring for additional 1 hour. The organic layer was separated, and the aqueous layer was further extracted with dichloromethane three times. The combined organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under reduced pressure. To the resulting unpurified 4,5-bis(ethoxycarbonyl)-2-(formylamino)methylthiazole, 30 ml of toluene and 13.3 ml of phosphorus oxychloride were added, followed by stirring at 100° C. for 80 minutes. After cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the resulting residue was then diluted with dichloromethane. Afterward, an aqueous potassium carbonate solution was added so as to adjust the pH of the solution to about 8. The organic layer was separated, and it was further extracted four times from the aqueous layer with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by a silica gel column chromatograph to obtain 6.6 g of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[C:14]([O:16]C)=[O:15])[CH2:9]1.[OH-].[Na+].Cl>C(O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[C:14]([OH:16])=[O:15])[CH2:9]1
Reactant: COC(=O)C1C2CC(OC3CCCCO3)CC21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1C2CC(OC3CCCCO3)CC21

Procedure:
A mixture of 5 g. of methyl 3-[(tetrahydropyran-2-yl)oxy]-bicyclo[3.1.0] hexane-6-carboxylate (VIII, syn and anti, from Example 3), ethanol (45 ml.), and sodium hydroxide (10 ml. of a 20% aqueous solution) is refluxed for 20 minutes. Cooling evaporation of the ethanol under reduced pressure, and addition of 100 ml. of water gives a solution which is acidified with dilute hydrochloric acid and extracted with diethyl ether. The diethyl ether extract is dried with anhydrous sodium sulfate and evaporated to give a mixture of exo syn and anti 3-[(tetrahydropyran-2-yl)oxy]bicyclo[3.1.0] hexane-6-carboxylic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[N:9]2)[CH:5]=[CH:4][N:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][C@H:33]([NH2:37])[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].S(C1C=CC(NC2N=CN(C3C=CN=C(N[C@H]4CCCNC4)C=3)N=2)=CC=1)(=O)(=O)N.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CN1C(=O)CCC1.ClCCl>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][C@H:33]([NH:37][C:2]2[CH:7]=[C:6]([N:8]3[CH:12]=[N:11][C:10]([NH:13][C:14]4[CH:19]=[CH:18][C:17]([S:20](=[O:22])(=[O:21])[NH2:23])=[CH:16][CH:15]=4)=[N:9]3)[CH:5]=[CH:4][N:3]=2)[CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: NS(=O)(=O)c1ccc(Nc2ncn(-c3ccnc(Cl)c3)n2)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: NS(=O)(=O)c1ccc(Nc2ncn(-c3ccnc(N[C@H]4CCCNC4)c3)n2)cc1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2cc(-n3cnc(Nc4ccc(S(N)(=O)=O)cc4)n3)ccn2)C1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
A microwave reaction vessel was charged with 50 mg of 4-[1-(2-Chloro-pyridin-4-yl)-1H-[1,2,4]triazol-3-ylamino]-benzenesulfonamide (0.14 mmol, 1 equiv), 110 mg (S)-3-amino-piperidine-1-carboxylic acid tert-butyl ester (0.57 mmol, 4 equiv) and 17.0 mg DMAP (0.014 mmol, 0.1 equiv) in NMP (1.5 mL). The resulting solution was warmed to 130° C. via microwave irradiation for 20 min and then heated at 180° C. for an additional 70 min via microwave irradiation. The reaction mixture was cooled and concentrated in vacuo and the residue purified by preparative HPLC. To a solution of 12.0 mg of this product, 3-(S)-{4-[3-(4-sulfamoyl-phenylamino)-[1,2,4]triazol-1-yl]-pyridin-2-ylamino}-piperidine (0.029 mmol, 1 equiv) in dichloromethane (5 mL), di-tert-butyl dicarbonate (9.5 mg, 0.043 mmol, 1.5 equiv) and 6 μL triethylamine (0.058 mmol, 2 equiv) were added and the resulting solution stirred at rt for 1 h. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with 50% EtOAc: petroleum ether moving to EtOAc (4.2 mg, 29%); MS (ES+) m/e 515.55, (ES−) m/e 513.70
Reaction SMILES: C([Li])CCC.I[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([I:13])[CH:8]=1.F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.O>CCOCC>[I:13][C:9]1[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Fc1ccccn1
Reactant: Ic1cccc(I)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: Ic1cccc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.1 %

Procedure:
n-Butyllithium (2.0 M in cyclohexane, 8 cm3) was added dropwise to a solution of 1,3-diiodobenzene (5.19 g, 16 mmol) in ether (50 cm3), cooled in a salt-ice bath, and the solution was stirred for 10 minutes. 2-Fluoropyridine (1.4 cm3, 16 mmol) was added, at which the pale yellow cloudy solution turned dark brown, and the reaction was allowed to warm to room temperature over 1 hour. Water (50 cm3) and ether (20 cm3) were added, and the layers were separated. The aqueous layer was extracted with ether (3×50 cm3). The combined organic extracts were washed with brine (150 cm3), and dried over magnesium sulfate. The solvent was removed to leave a brown oil. Purification of the crude product by column chromatography over silica using dichloromethane: light petroleum (1:1) as eluent gave (15) as an orange oil (1.04 g, 24%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[S:19][CH:18]=[N:17][CH:16]=3)[CH:10]=2)=[CH:6][CH:5]=[C:4]([N+:20]([O-])=O)[N:3]=1.[NH4+].[Cl-]>C1COCC1.CO.[Zn]>[CH3:1][C:2]1[N:3]=[C:4]([NH2:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[S:19][CH:18]=[N:17][CH:16]=2)[CH:10]=1
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(-c2cncs2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(N)ccc1Oc1ccnc(-c2cncs2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.5 %

Procedure:
A solution of 5-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)thiazole (0.34 g, 1.082 mmol) in THF (10 mL) and MeOH (10 mL) was treated with NH4Cl (2.314 g, 43.3 mmol) followed by zinc powder (1.061 g, 16.23 mmol) and stirred at RT for 24 h. The solids were removed via filtration through diatomaceous earth, washed well with MeOH and the filtrate concentrated to dryness. The residue was treated with water, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness. The material was suspended in 30% EtOAc/Hex, sonicated and the solid collected via filtration and dried to afford 6-methyl-5-((2-(thiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (220 mg, 72%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.12 (s, 1H), 8.58 (s, 1H), 8.37 (d, J=5.8 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.20 (d, J=8.7 Hz, 1H), 6.61 (dd, J=5.8, 2.4 Hz, 1H), 6.35 (d, J=8.7 Hz, 1H), 5.97 (s, 2H), 2.08 (s, 3H); MS (ESI) m/z: 285.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)=[CH:16][C:15]=2[CH:29]=O)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:32]([NH2:34])[CH3:33]>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)=[CH:16][C:15]=2[CH2:29][NH:34][CH2:32][CH3:33])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(OCC)nc3)cc2C=O)c1
Reactant: CCN
Product: CCNCc1cc(-c2ccc(OCC)nc2)ccc1-c1cc(CC(=O)OCC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using the following starting materials: [4′-(6-ethoxy-pridin-3-yl)-2′-formyl-6-methoxy-biphenyl-3-yl]-acetic acid ethyl ester and ethylamine (2M in THF).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:10]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH3:11]>>[CH2:10]([N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:14][CH2:13]1)[CH3:11]
Reactant: CCN1CCNCC1
Reactant: N#Cc1ccccc1F
Product: CCN1CCN(c2ccccc2C#N)CC1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and 4-ethylpiperazine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]3[O:15][CH2:14][CH2:13][C:12]([C:16]([O:18]C)=[O:17])=[CH:11][C:10]=3[CH:20]=2)=[CH:2]1.[OH-].[Na+]>C1COCC1.CO>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]3[O:15][CH2:14][CH2:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=3[CH:20]=2)=[CH:2]1
Reactant: COC(=O)C1=Cc2cc(-c3ccsc3)ccc2OCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1=Cc2cc(-c3ccsc3)ccc2OCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
In THF (24 ml) and methanol (6 ml) was dissolved methyl 7-(3-thienyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (610 mg), and to the mixture was added 1N sodium hydroxide (12 ml). The mixture was stirred at room temperature for 3 hours. Under reduced pressure, the organic solvent was removed, and to the residue was added ethyl acetate. The mixture was extracted with water, and to the aqueous layer was added 6N hydrochloric acid to make the solution pH 4-5, which was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed to give 7-(3-thienyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (500 mg).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:17][CH3:18])[CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([N+:14]([O-])=O)[CH:10]=[CH:11]2)=[N:6]1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:18][O:17][CH:3]([O:2][CH3:1])[CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([NH2:14])[CH:10]=[CH:11]2)=[N:6]1
Reactant: COC(Cn1cc2ccc([N+](=O)[O-])cc2n1)OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(Cn1cc2ccc(N)cc2n1)OC

Procedure:
To a stirred solution of 2-(2,2-dimethoxyethyl)-6-nitro-2H-indazole (1.89 g, 7.52 mmol) and NH4Cl (337 mg, 6.01 mmol) in ethanol/H2O (2:1, 75 mL) at room temperature was added Fe (1.28 g, 23.7 mmol) and the resulting mixture was heated for 2 hours at 70 C. The mixture was allowed to cool and was filtered through celite. The residue was washed with hot Methanol (5×20 mL) and the combined eluent was concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL) and filtered. Concentration of the organic layer under reduced pressure provided 2-(2,2-dimethoxyethyl)-2H-indazol-6-ylamine as an amber oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.25 (m, 6 H), 4.34 (d, J=5.43 Hz, 2 H), 4.81 (t, J=5.59 Hz, 1 H), 5.22 (s, 2 H), 6.52 (m, 2 H), 7.37 (m, 1 H) and 8.02 (s, 1 H); MS (ESI) 222 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[F:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(-c2ccc(F)c(Cl)c2)c(-c2ccccc2)n1
Yield: 29.3 %

Procedure:
6-(3-Chloro-4-fluorophenyl)-5-phenyl-1,2,4-triazin-3-amine (140 mg, 29%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g, 1.59 mmol) and 3-chloro-4-fluorophenylboronic acid (0.33 g, 1.91 mmol) according to the general procedure of Example 1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)[CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH2:11][N:12]([C:22]([C:21]3[CH:25]=[CH:26][C:18]([O:17][CH3:16])=[CH:19][C:20]=3[N:27]3[N:31]=[CH:30][CH:29]=[N:28]3)=[O:23])[CH2:13][CH:14]2[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)O)c(-n2nccn2)c1
Reactant: c1ccc(CN2CC3CNCC3C2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)N2CC3CN(Cc4ccccc4)CC3C2)c(-n2nccn2)c1
Reaction time: 1 h
Yield: 57.9 %

Procedure:
To a mixture of 2-benzyloctahydropyrrolo[3,4-c]pyrrole (282 mg, 1.4 mmol), 4-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (306 mg, 1.4 mmol), and TEA (0.21 mL, 1.5 mmol) in DMF (7.5 mL) was added HATU (583 mg, 1.5 mmol). After 1 h, the reaction mixture was diluted with EtOAc and washed with water. The aqueous layer was then extracted with EtOAc (1×). The combined organics were dried (Na2SO4) and concentrated to give a residue. Purification via Agilent prep system (Basic) gave 327 mg (58%) of the title compound as a clear oil. 1H NMR (CDCl3): 7.79 (s, J=6.5 Hz, 2H), 7.50 (d, J=5.0 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H), 7.34-7.21 (m, 5H), 6.95 (dd, J=8.5, 2.5 Hz, 1H), 3.93 (s, 3H), 3.86-3.72 (m, 1H), 3.65-3.46 (m, 3H), 3.13 (s, 1H), 2.90-2.74 (m, 2H), 2.74-2.59 (m, 2H), 2.57-2.39 (m, 2H), 2.16 (dd, J=9.2, 4.2 Hz, 1H).