Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]([NH:17][C:18]4[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=4)[CH2:21][N:22]4[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]4)[CH:16]=[C:11]3[C:10]([CH3:34])=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:34][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([NH:17][C:18]3[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=3)[CH2:21][N:22]3[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][OH:30])[CH2:26][CH2:27]3)[CH:16]=2)[NH:8][N:9]=1
Reactant: COc1ccc(Cn2nc(C)c3cc(Nc4cccc(CN5CCN(CCO)CC5)c4)cnc32)cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2ncc(Nc3cccc(CN4CCN(CCO)CC4)c3)cc12
Temperature: 60 °C

Procedure:
To a stirred solution of 2-(4-(3-((1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)amino)benzyl)piperazin-1-yl)ethanol (163) (50 mg, 0.103 mmol) in CHCl3 (10 mL) was added trifluoroacetic acid (6 mL) and the reaction mass heated at 60° C. overnight. After completion of the reaction the solvents were completely distilled off and diluted with water and the pH was adjusted to 9 and extracted with chloroform twice. The combined organic layer was washed with brine solution and dried over sodium sulphate and the solvents were removed and the crude material was passed through 100-200 mesh silica gel, eluting with 10% MeOH/CH2Cl2 obtained pure 2-(4-(3-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)amino)benzyl)piperazin-1-yl)ethanol 164 as a pale yellow colored solid (6 mg). MS m/z 353.54 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5](=O)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])(=S)[CH3:2].[NH2:15][C:16]1[C:20]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[C:19]([CH2:26][CH3:27])[NH:18][N:17]=1>O1CCOCC1>[Cl:13][C:7]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=1[C:5]1[N:17]2[N:18]=[C:19]([CH2:26][CH3:27])[C:20]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[C:16]2[N:15]=[C:1]([CH3:2])[N:4]=1
Reactant: CC(=S)NC(=O)c1ccc(Cl)cc1Cl
Reactant: CCc1[nH]nc(N)c1C(CC)CC
Solvent: C1COCCO1
Product: CCc1nn2c(-c3ccc(Cl)cc3Cl)nc(C)nc2c1C(CC)CC
Temperature: 25 °C
Yield: 25.3 %

Procedure:
A mixture of N-(thioacetyl)-2,4-dichlorobenzamide (200 mg, 0.81 mmol) and 3-amino-5-ethyl-4-(3-pentyl)pyrazole (146 mg, 0.81 mmol) in dioxan (1 mL) was stirred at reflux temperature for 16 h. After being cooled to room temperature, the reaction mixture was concentrated in vacuo. Preparative TLC using EtOAc:hexanes::1:1 generated the title product (77.3 mg, 24% yield): mp=91-93° C.; NMR (CDCl3,300 MHz): δ 7.64 (d, 1H, J=8), 7.57 (d, 1H, J=2), 7.44 (dd, 1H, J=8,2), 2.77 (q, 2H, J=8), 2.69 (s, 3H), 2.80-2.60 (m, 1H), 2.00-1.80 (m, 4H), 1.25 (t, 3H, J=8), 0.82 (t, 6H, J=7); CI-HRMS m/z Calcd: 377.1294, Found: 377.1303.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH:26]1([CH2:29][O:30][C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=2[O:40][CH:41]([F:43])[F:42])[C:34](O)=[O:35])[CH2:28][CH2:27]1>>[CH:26]1([CH2:29][O:30][C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=2[O:40][CH:41]([F:42])[F:43])[C:34]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)=[O:35])[CH2:28][CH2:27]1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(O)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc(OC(F)F)c(OCC5CC5)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1.[NH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([OH:20])=[C:15]([Cl:21])[CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[Cl:19][C:17]1[CH:18]=[C:13]([NH2:12])[CH:14]=[C:15]([Cl:21])[C:16]=1[O:20][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1
Reactant: Clc1nc2c(Cl)cccc2s1
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1cc(Cl)c(Oc2nc3c(Cl)cccc3s2)c(Cl)c1
Temperature: 145 °C
Yield: 33.3 %

Procedure:
To solution of 2,4-dichlorobenzothiazole (255, 2.23 g, 11 mmol) and 4-amino-2,6-dichlorophenol (Aldrich, 1.78 g, 10 mmol) in 10 mL of DMSO was add K2CO3 (Aldrich, 4.14 g, 30 mmol). The mixture was heated at 145° C. for 4 h. After cooled to room temperature, the reaction mixture was diluted with EtOAc (300 mL) and filtered through a pad of silica gel and activated carbon followed by washing with EtOAc (500 mL). The filtrate was concentrated and the residue was purified by chromatography (20%-30% EtOAc/Hexanes) to give 1.15 g (33%) of product. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J=8.0 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.34 (t, J=8.0 Hz, 1H), 6.75 (s, 2H), 5.93 (s, 2H). MS (EI): m/z 345 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][CH2:7][CH:8]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][N:12]2[C:11](=O)[CH2:10][O:9]1)[CH3:2].B>O1CCCC1.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][CH2:7][CH:8]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][N:12]2[CH2:11][CH2:10][O:9]1)[CH3:2]
Reactant: CCOc1ccccc1OCC1OCC(=O)N2CCCCC12
Agent: B
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCOc1ccccc1OCC1OCCN2CCCCC12
Temperature: 5 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
In 300 ml of tetrahydrofuran (freshly distilled from lithium aluminum hydride) was dissolved 1-[(2-ethoxyphenoxy)methyl]-6,7,8,9-tetrahydro-1H-pyrido[2,1-c][1,4]oxazin-4(3H)-one (8.12 g, 0.0265 mole). The solution was cooled to 5° C. in an ice bath and 40 ml of 1M borane in tetrahydrofuran was added by syringe to the stirred solution under nitrogen. The solution was stirred at room temperature for 2 hr and then heated at reflux for 2 hr. The reaction mixture was cooled to room temperature and slowly quenched with glacial acetic acid. The solvent was removed in vacuo. The residue was partitioned between 10% sodium hydroxide and diethyl ether. Removal of the diethyl ether gave a yellow oil. This oil was then dissolved in a minimum amount of chloroform and chromatographed on a 500 g. Silica Gel column (gradient elution with chloroform methanol). Fractions from the column were combined which gave a single spot on TLC (methanol-chloroform) at similar Rf. A total of 5.08 g (65.8%) of a light yellow oil was obtained.
Reaction SMILES: C([O:8][C@H:9]1[C@@H:13]2[O:14][CH2:15][C@@:10]1([CH2:25][OH:26])[O:11][C@H:12]2[N:16]1[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]1=[O:18])C1C=CC=CC=1.C([O-])=O.[Na+]>CO.[Pd]>[OH:8][C@H:9]1[C@@H:13]2[O:14][CH2:15][C@@:10]1([CH2:25][OH:26])[O:11][C@H:12]2[N:16]1[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]1=[O:18]
Reactant: Cc1cn([C@@H]2O[C@]3(CO)CO[C@H]2[C@@H]3OCc2ccccc2)c(=O)[nH]c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cn([C@@H]2O[C@]3(CO)CO[C@H]2[C@@H]3O)c(=O)[nH]c1=O
Temperature: 25 °C
Yield: 95.6 %

Procedure:
A mixture of compound 11 (750 mg, 2.09 mmol) and 10% Pd/C (500 mg) was suspended in methanol (20 mL) and sodium formate (700 mg, 11.1 mmol) was added. The reaction was conducted at refluxing for 10 min and cooled to ambient temperature. The catalyst was filtered off and the mixture was concentrated under reduced pressure to give compound 12 (540 mg, 96%) as a white solid material.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]4[CH:35]=[CH:34][C:25]5[C@H:26]([CH2:29][C:30]([O:32]C)=[O:31])[CH2:27][O:28][C:24]=5[CH:23]=4)[CH:15]=3)=[C:9]([CH3:36])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+]>O1CCCC1.CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH3:36])[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]4[CH:35]=[CH:34][C:25]5[C@H:26]([CH2:29][C:30]([OH:32])=[O:31])[CH2:27][O:28][C:24]=5[CH:23]=4)[CH:15]=3)=[C:11]([CH3:13])[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCCC5)cc4C)c3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OC2CCCC2)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Reaction time: 2 h
Yield: 79.4 %

Procedure:
(S)-Methyl 2-(6-((4′-(cyclopentyloxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 10d (40 mg, 0.08 mmol) was dissolved in 7 mL of a mixture of the solvents tetrahydrofuran and methanol (V/V=2:5), followed by addition of 1M aqueous lithium hydroxide solution (0.8 mL, 0.80 mmol). The reaction solution was stirred for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was mixed with 10 mL of water, 1M hydrochloric acid was added dropwise to adjust the pH to 4˜5, and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (S)-2-(6-((4′-(cyclopentyloxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 10 (30 mg, yield 80.0%) as a white solid.
Reaction SMILES: N([O-])=O.[Na+].[F:5][C:6]([F:15])([F:14])[C:7]1[CH:8]=[C:9](N)[CH:10]=[N:11][CH:12]=1.[BrH:16]>O.C(Cl)Cl.[Cu]Br>[Br:16][C:9]1[CH:10]=[N:11][CH:12]=[C:7]([C:6]([F:15])([F:14])[F:5])[CH:8]=1
Reactant: Br
Reactant: Nc1cncc(C(F)(F)F)c1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1cncc(Br)c1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A solution of sodium nitrite (402 mg, 5.83 mmol) in water (6.8 mL) was added slowly to a suspension of 5-(trifluoromethyl)pyridin-3-amine (947 mg, 5.55 mmol) in hydrogen bromide (48% aqueous solution, 1.57 mL) in ice-water bath. After being stirred for 10 min, the resulting orange diazo solution was directly but slowly transferred to a stirring mixture of copper(I) bromide (876 mg, 6.11 mmol) and hydrogen bromide (48% aqueous solution, 0.38 mL). The resulting brown mixture was heated at 60° C. for 1 h. After cooling to room temperature, the mixture was diluted with methylene chloride, washed with 50% NaOH (until pH=11), and water. The aqueous layer was back extracted with methylene chloride. The combined organic extracts were carefully concentrated under vacuum to provide crude product without purification.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][C:5](=O)[CH2:6][C:7]#[N:8].O.[NH2:12][NH2:13]>C(O)C>[CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([NH2:8])[NH:13][N:12]=1
Reactant: CN(C)CCC(=O)CC#N
Reactant: NN
Solvent: O
Solvent: CCO
Product: CN(C)CCc1cc(N)[nH]n1
Temperature: 70 °C
Yield: 70.7 %

Procedure:
To a solution of 5-(dimethylamino)-3-oxopentanenitrile (4.9 g) in ethanol (20 mL) at ambient temperature was added hydrazine monohydrate (1.72 mL, 35.5 mmol) and the reaction mixture was heated to 70° C. for 2 hours. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure to give 3.81 g of 3-(2-(dimethylamino)ethyl)-1H-pyrazol-5-amine (65% over 2 steps) which was carried on without further purification. 1H-NMR (400 MHz, DMSO-d6): δ 12.60 (bs, 1H), 6.52 (bs, 2H), 6.1 (s, 1H), 2.69 (m, 2H), 2.65 (m, 2H), 2.27 (s, 6H).
Reaction SMILES: Br.[Br:2]CCCN.BrC[CH2:9][CH2:10][C:11]1[C:16]2[C:17]([O:23][CH3:24])=[C:18]([C:20]([NH2:22])=[O:21])[S:19][C:15]=2[CH:14]=[CH:13][CH:12]=1>>[Br:2][CH2:9][CH2:10][C:11]1[C:16]2[C:17]([O:23][CH3:24])=[C:18]([C:20]([NH2:22])=[O:21])[S:19][C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: COc1c(C(N)=O)sc2cccc(CCCBr)c12
Reactant: NCCCBr
Agent: Br
Product: COc1c(C(N)=O)sc2cccc(CCBr)c12

Procedure:
Similarly prepared using 3-bromopropylamine hydrobromide was 3-bromopropyl-3-methoxy benzothiophene-2-carboxamide.
Reaction SMILES: [O:1]=[C:2]([NH:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27])[C:3](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:5].C1COCC1.C(=O)([O-])[O-].[Ca+2:42]>O>[Ca+2:42].[O:5]=[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([O-:11])=[O:10])[C:3](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]([NH:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([O-:28])=[O:27])=[O:1]
Reactant: O=C(Nc1ccccc1C(=O)O)C(=Cc1ccccc1)C(=O)Nc1ccccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccccc1C(=O)[O-])C(=Cc1ccccc1)C(=O)Nc1ccccc1C(=O)[O-]

Procedure:
The Compound 11 (430 mg 1 mmol) was treated with THF (20 ml) and water (10 ml), and further with calcium carbonate (100 mg, 1 mmol), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered by suction, and the solvent was removed from the filtrate. The residue was washed with acetone to give the desired calcium salt in pale yellow solid (420 mg, yield, 89.6%). m.p., 300° C. or higher.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[NH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[F:22])[N:15]([CH3:23])[N:14]=1>>[F:22][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:21]=1[C:13]([NH:12][C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5])=[N:14][N:15]2[CH3:23]
Reactant: COC(=O)c1ccncc1Br
Reactant: Cn1nc(N)c2c(F)cccc21
Product: Cn1nc(Nc2cnccc2C(=O)O)c2c(F)cccc21
Yield: 34 %

Procedure:
The title compound was prepared in 34% yield from methyl 3-bromoisonicotinate and 3-amino-4-fluoro-1-methyl-indazole according to the general procedure for Example 6. 1H NMR (400 MHz, DMSO-d6): δ 4.00 (3H, s), 6.84-6.89 (1H, m), 7.39-7.42 (2H, m), 7.80 (1H, d, J=5.0 Hz), 8.21 (1H, d, J=5.0 Hz), 9.90 (1H, s), 10.88 (1H, br s), 14.22 (1H, br s). [M+H] calc'd for C14H11FN4O2, 287; found 287.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1>>[Cl:11][C:12]1[CH:13]=[C:14]([C:2]2[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=2)[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: COc1cc(Cl)cc(B(O)O)c1
Product: COc1cc(Cl)cc(-c2cc(F)c(N)c(F)c2)c1
Yield: 30.1 %

Procedure:
The title compound (39 mg) was prepared from 4-bromo-2,6-difluoroaniline (100 mg, 0.48 mmol) and 3-chloro-5-methoxyphenylboronic acid (116 mg, 0.62 mmol) as a pale-yellow solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.36 (dd, J 2.2, 8.1, 2H), 7.25 (s, 1H), 7.12 (s, 1H), 6.91 (t, J 1.9, 1H), 5.43 (s, 2H), 3.81 (s, 3H).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:24])[NH:15][C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:24])[NH:15][C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(O)c2ccccc2[nH]c1=O
Reactant: NC1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NC1CCCCC1)c1c(O)c2ccccc2[nH]c1=O
Yield: 87.2 %

Procedure:
Cyclohexylamine (13.88 mL, 121.33 mmol) was added to a solution of Compound 112 (9.4 g, 40.44 mmol) in toluene (200 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered. The crude product was recrystallized by ether to yield 10.1 g (87%) of white solids. M.P. 223° C. 1H NMR (DMSO-d6): δ 1.3 (m, 4H), 1.6 (m, 2H), 1.7 (m, 2H), 1.9 (m, 2H), 3.8 (m, 1H), 7.25 (t, J=7.7 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.65 (t, J=7.2 Hz, 1H), 7.95 (d, J=7.7 Hz, 1H), 10.44 (b, 1H); EIMS (neg. mode): 285 (M−H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1)=O)C>C(Cl)Cl>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([CH:14]=[O:13])=[N:17][CH:18]=1)([O-:24])=[O:23]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=Cc1ccc([N+](=O)[O-])cn1
Temperature: 5 °C
Reaction time: 16 h
Yield: 49.8 %

Procedure:
Diisobutylaluminium hydride (1 M in DCM, 44 mL, 44 mmol, 1.3 equiv) was added dropwise to a cold (−78° C.) solution of 5-nitro-pyridine-2-carboxylic acid ethyl ester (step 39.4) (6.56 g, 33.5 mmol) in DCM (130 mL), under an argon atmosphere. The reaction mixture was allowed to warm to 5° C., quenched by addition of an aqueous solution of potassium sodium tartrate, diluted with DCM and H2O, stirred for 16 h at rt, and filtered through a pad of celite. The filtrate was extracted several times with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (EtOAc/Hex, 1:1) to provide 2.54 g of the title compound as a beige solid: ESI-MS: 151.1 [M−H]−.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:8]=3[S:9][C:5]=2[C:4]([NH2:15])=[N:3]1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>O1CCCC1>[CH3:1][N:2]1[C:6]2[C:7]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:8]=3[S:9][C:5]=2[C:4]([NH:15][C:16](=[O:18])[CH3:17])=[N:3]1
Reactant: Cc1ccc2c(c1)sc1c(N)nn(C)c12
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1nn(C)c2c1sc1cc(C)ccc12
Temperature: 20 °C

Procedure:
A solution of 0.1 mole of 1,6-dimethyl-1H-(1)-benzothieno[3,2-c]pyrazol-3-amine and 30.0 g. of acetic anhydride in 180 ml. of tetrahydrofuran was heated under reflux for 1 hour. The reaction mixture was then cooled to 20° C. and the precipitate which formed was collected by filtration. Recrystallization from N,N-dimethyl formamide/water gave N-(1,6-dimethyl-1H-(1)benzothieno-[3,2-c]pyrazol-3-yl)acetamide, m.p. 253°-255° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(Cl)=[S:27]>O1CCCC1>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:9]=2)=[CH:4][CH:3]=1)=[C:26]=[S:27]
Reactant: Nc1ccc(-c2nc(-c3ccccn3)no2)cc1
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: S=C=Nc1ccc(-c2nc(-c3ccccn3)no2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 53.3 %

Procedure:
To a solution of 1.09 g of 5-(4-aminophenyl)-3-(2-pyridyl)-1,2,4-oxadiazole in 200 ml of dry tetrahydrofuran containing 0.42 g of triethylamine, 0.50 g of thiophosgene is added and the mixture stirred at room temperature for 6 hours. After filtration, the solution is evaporated in vacuo to give the crude product. It is crystallized from petroleum ether to give 0.65 g (54%) of the title product, m.p. 145°-146° .
Reaction SMILES: [C:1]([C@@H:3]([NH:22][C:23]([C:25]1([NH:31]C(=O)OC(C)(C)C)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17](=[O:19])[N:16]([CH3:20])[C:15]=3[CH:21]=2)=[CH:7][CH:6]=1)#[N:2]>C(O)=O>[NH2:31][C:25]1([C:23]([NH:22][C@H:3]([C:1]#[N:2])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:12]=[CH:13][C:14]4[O:18][C:17](=[O:19])[N:16]([CH3:20])[C:15]=4[CH:21]=3)=[CH:9][CH:10]=2)=[O:24])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: Cn1c(=O)oc2ccc(-c3ccc(C[C@@H](C#N)NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)cc3)cc21
Solvent: O=CO
Product: Cn1c(=O)oc2ccc(-c3ccc(C[C@@H](C#N)NC(=O)C4(N)CCOCC4)cc3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.1 %

Procedure:
(S)-tert-Butyl 4-(1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 17, step (ii), 145 mg) (crude mixture) was dissolved in formic acid (3 mL) and the mixture stirred at room temperature for 18 h. The mixture was evaporated to dryness, dissolved in methanol (10 mL), re-evaporated to dryness, dissolved in methanol/acetonitrile 50:50 (4 mL) and purified on reversed phase HPLC eluting with methanol in 0.1% aqueous TFA on a Water's SunFire column. The material was converted to free base by evaporating the relevant fractions, dissolving in ethyl acetate (20 mL) and shaking with saturated aqueous sodium bicarbonate solution (20 mL). The sodium bicarbonate was further extracted with ethyl acetate (20 mL). The combined extracts were dried over magnesium sulfate and evaporated to afford the titled compound (47 mg).
Reaction SMILES: [C:1]([O:7]C(C)(C=C)C)(=[O:6])[CH:2]=[C:3]([CH3:5])[CH3:4].CO>O>[C:3]([CH:2]([CH2:1][CH:2]=[C:3]([CH3:5])[CH3:4])[C:1]([OH:7])=[O:6])([CH3:4])=[CH2:5]
Reactant: C=CC(C)(C)OC(=O)C=C(C)C
Solvent: CO
Solvent: O
Product: C=C(C)C(CC=C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 22 h
Yield: 200 %

Procedure:
In a nitrogen atmosphere, a mixture of the 125 mmol of sodium hydride, obtained from 5.00 g of a 60% suspension in mineral oil by removal of mineral oil with n-hexane washing, and 30 ml of toluene was heated to reflux with stirring, and subjected to dropwise addition of 20.0 g of 2-methyl-3-buten-2-yl senecioate having a purity of 96.9% over one hour. After reflux was continued for 22 hours, the reaction mixture was cooled to room temperature, and 10 ml of methanol and 40 ml of water were added dropwise thereto. The organic phase was extracted with water and then discarded. The aqueous phases were combined and then made acidic with 20% hydrochloric acid, followed by extraction with diethyl ether. The diethyl ether solution was subjected to typical work-up including washing, drying and concentration to obtain 20.0 g of the crude product having a purity of 3.6% on basis of stoichiometric amount. The content of each isomer in the crude product was analyzed using capillary GC analysis and GC-MS under the similar conditions as in Example 1. The results are shown in Table 2.
Reaction SMILES: [NH2:1]OS(O)(=O)=O.[OH-].[Na+].[Cl:9][C:10]1[C:11]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[N:14][N:13]([CH3:19])[C:12]=2[S:20]([O-:22])=[O:21].[Li+]>O>[Cl:9][C:10]1[C:11]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[N:14][N:13]([CH3:19])[C:12]=2[S:20]([NH2:1])(=[O:22])=[O:21]
Reactant: Cn1nc2cccc(Cl)c2c1S(=O)[O-]
Reactant: NOS(=O)(=O)O
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1nc2cccc(Cl)c2c1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.8 %

Procedure:
45.2 g (0.4 mol) of hydroxylamine-O-sulfonic acid was gradually added to a solution containing 16 g (0.4 mol) of sodium hydroxide in water (300 ml) under cooling with ice (<10° C.). This solution was added all at once to a solution of the previously prepared crude lithium 4-chloro-2-methyl-2H-indazole-3-sulfinate in water (100 ml). The mixture was stirred at room temperature for 12 hours. Formed crystals were collected by filtration to obtain 17.1 g (yield: 69.8%) of the desired 4-chloro-2-methyl-2H-indazole-3-sulfonamide (slightly yellow granular crystals). Melting point: 173°-175° C.