Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH3:30][O:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:34][C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[O:31][CH3:30])[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: COc1ccccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccccc2OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (300 mg) and 2-methoxybenzaldehyde (517 mg) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (724 mg), and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Then, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to give methyl 7-(4-butoxyethoxyphenyl)-1-(2-methoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (391 mg) as yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[F:8][C:9]([F:31])([F:30])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH:18]([CH3:19])[O:17]2)=[CH:12][CH:11]=1.Cl>CN(C)C=O.O>[F:8][C:9]([F:30])([F:31])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)([OH:17])[CH:18]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH3:19])=[CH:12][CH:11]=1
Reactant: CC1OC1(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Reactant: c1nc[nH]n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(n1cncn1)C(O)(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
1,2,4-1H-triazole was added to a stirred suspension of sodium hydride (0.86 g., 50% dispersion, washed with petroleum ether to remove oil) in dry dimethylformamide (40 cm3). After stirring for 1.5 hours, the oxirane (formed in (b) above) dissolved in dimethylformamide (5 cm3) was added slowly. The mixture was heated at 100° C. for 2 days, then cooled and poured into water, neutralised with dilute hydrochloric acid and the product extracted into ether, which was dried (MgSO1) and concentrated by evaporation of the solvent.
Reaction SMILES: FC1C=CC(CNC)=CC=1.[F:11][CH:12]([F:23])[O:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][NH:19][CH3:20])=[CH:16][CH:15]=1.[F:24][C:25]1[CH:47]=[CH:46][C:28]([CH2:29][NH:30][C:31]([C:33]2[S:37][C:36]([C:38]3[CH:43]=[N:42][CH:41]=[C:40](I)[N:39]=3)=[N:35][C:34]=2[CH3:45])=[O:32])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:47]=[CH:46][C:28]([CH2:29][NH:30][C:31]([C:33]2[S:37][C:36]([C:38]3[CH:43]=[N:42][CH:41]=[C:40]([N:19]([CH2:18][C:17]4[CH:16]=[CH:15][C:14]([O:13][CH:12]([F:11])[F:23])=[CH:22][CH:21]=4)[CH3:20])[N:39]=3)=[N:35][C:34]=2[CH3:45])=[O:32])=[CH:27][CH:26]=1
Reactant: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccc(F)cc1
Reactant: CNCc1ccc(OC(F)F)cc1
Agent: CNCc1ccc(F)cc1
Product: Cc1nc(-c2cncc(N(C)Cc3ccc(OC(F)F)cc3)n2)sc1C(=O)NCc1ccc(F)cc1
Yield: 80 %

Procedure:
Following the procedure described in Example 14, making variations as required to replace 4-fluoro-N-methyl-benzylamine with (4-difluoromethoxy-benzyl)-methyl-amine to react with 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide, the title compound was obtained in 80% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.58 (s, 1H), 8.07 (s, 1H), 7.26-7.37 (m, 4H), 7.00-7.11 (m, 4H), 6.51 (bt, J=76, 64 Hz, 1H, CH—F signal), 6.16 (bs, 1H), 4.82 (s, 2H), 4.54 (d, J=8.0 Hz, 2H), 3.14 (s, 3H), 2.70 (s, 3H); MS (ES+) m/z 514.2 (M+1), Rt=1.63 min.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[CH2:26]([O:28][C:29]1[C:36]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:35][CH:34]=[CH:33][C:30]=1[CH:31]=[O:32])[CH3:27].O>O1CCCC1>[CH2:38]([O:37][C:36]1[C:29]([O:28][CH2:26][CH3:27])=[C:30]([CH:31]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=2)[OH:32])[CH:33]=[CH:34][CH:35]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CCOc1c(C=O)cccc1OCc1ccccc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOc1c(OCc2ccccc2)cccc1C(O)c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 13.9 %

Procedure:
To a solution of 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (635, 1.306 g, 3.26 mmol) in tetrahydrofuran (42 mL) at −20° C. under nitrogen was added isopropylmagnesium chloride (1.70 mL, 2.0 M solution in tetrahydrofuran, 3.40 mmol). The reaction mixture was stirred at −20° C. for 1.5 hours. It was allowed to warm to 5° C. and then kept at 5° C. for 1 hour. The reaction mixture was then cooled down to −20° C. To this solution was slowly added a solution of 2-ethoxy-3-benzyloxybenzaldehyde (663, 0.698 g, 2.72 mmol, prepared by protocol of Example 43, Steps 1-3 of Scheme 71, using benzyl bromide in place of 4-chloro-benzyl bromide in Step 1) in tetrahydrofuran (42 mL). The reaction mixture was stirred at −20° C. for 2.5 hrs, and was allowed to warm to 5° C. for 2.5 hours. The reaction mixture was poured into iced water, extracted with ethyl acetate, washed with saturated ammonium chloride and brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as light-yellow oil (664, 200 mg, 13.9%).
Reaction SMILES: C(O[C:4]1[C:9]([C:10]([NH2:12])=[O:11])=[CH:8][N:7]=[C:6]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:5]=12)C.O.[NH2:19][NH2:20]>CO>[CH2:16]([N:13]1[C:6]2=[N:7][CH:8]=[C:9]([C:10]([NH2:12])=[O:11])[C:4]([NH:19][NH2:20])=[C:5]2[CH:15]=[N:14]1)[CH3:17]
Reactant: CCOc1c(C(N)=O)cnc2c1cnn2CC
Reactant: NN
Solvent: O
Solvent: CO
Product: CCn1ncc2c(NN)c(C(N)=O)cnc21
Reaction time: 72 h

Procedure:
To 3.6 g. of 4-ethoxy-1-ethyl-1H-pyrazolo-[3,4-b]pyridine-5-carboxamide [J. Het. Chem. 9, 235 (1972)] (0.0154 mol.), dissolved in 100 ml. of hot methanol, are added 0.83g. of hydrazine hydrate (98%). On allowing the reaction mixture to stand for 3 days, 2.15g. of 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxamide crystallize out. Work up of the mother liquor gives another 0.9g., total yield 3.05g. (90%). The product is recrystallized from ethanol, m.p. 201°-202° (dec.).
Reaction SMILES: CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[C:20]([O:24][C:25]([NH:27][CH2:28][C@H:29]1[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:31]([C:41]([OH:43])=O)[CH2:30]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].Cl.[Cl:45][C:46]1[C:47]([CH3:58])=[C:48]([N:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)[CH:49]=[CH:50][CH:51]=1.ON1C2C=CC=CC=2N=N1>O1CCCC1.CN(C)C=O>[C:37]([O:36][C:34]([NH:32][CH2:33][C@H:29]1[CH2:28][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[C@H:31]([C:41]([N:55]2[CH2:54][CH2:53][N:52]([C:48]3[CH:49]=[CH:50][CH:51]=[C:46]([Cl:45])[C:47]=3[CH3:58])[CH2:57][CH2:56]2)=[O:43])[CH2:30]1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: Cc1c(Cl)cccc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1N1CCN(C(=O)[C@@H]2C[C@@H](CNC(=O)OC(C)(C)C)CN2C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-Methylmorpholine (60 μL) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (94 mg) were added to a solution of trans-4-(N-tert-butoxycarbonylaminomethyl)-N-tert-butoxycarbonyl-L-proline (Compound 109 (D), 120 mg), 1-(3-chloro-2-methylphenyl)piperazine hydrochloride (A, 128 mg) and 1-hydroxybenzotriazole (70 mg) in tetrahydrofuran (6 mL) and N,N-dimethylformamide (2 mL) at room temperature. After stirring at room temperature for 16 hr, the reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic layer was washed with saturated sodium hydrogen carbonate and brine. After drying over anhydrous sodium sulfate, the organic layer was concentrated in vacuo. The residue was washed with hexane to give the titled compound (98 mg) as a white powder: 1H NMR (400 MHz, ) δ 1.42-1.59 (18H), 1.80-2.00 (br s, 2H), 2.36 (s, 3H), 2.86 (br s, 4H), 2.98 (br s, 0.5H), 3.23 (br s, 2.5H), 3.60-3.80 (6 H), 4.68 (m, 1H), 6.89 (br m, 1H), and 7.11 (m, 2H); mass spectrum (EI+) m/e 511 (M).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:10][OH:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[Bi].[OH-].[Na+].OO>[Pt]>[CH2:1]([C:5]1[NH:6][C:7]([CH:10]=[O:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CO)[nH]1
Agent: [Pt]
Agent: OO
Agent: [Bi]
Product: CCCCc1ncc(C=O)[nH]1
Yield: 98.2 %

Procedure:
4.0 g of 2-n-butyl-5-hydroxymethylimidazole, 0.6 g of 5 percent platinum and 5 percent bismuth on activated carbon (comprising 61.3 percent water), and 25.6 ml of 1N NaOH solution were heated to about 60° C. with stirring. At 60° to 64° C., 6.8 g of 15 percent strength aqueous H2O2 solution was added dropwise over the course of 45 min. The reaction mixture was then allowed to react for 15 min and then filtered off. The pH of the filtrate was adjusted from 13.2 to 9.0 using 20 percent H2SO4, as a result of which a yellow suspension formed. This was cooled, and the crude product was able to be filtered off and/or extracted with methylene chloride. The reaction was monitored by GC analysis. The reaction yield was 98.2 percent (1.8 percent of starting material).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])[NH2:6].[C:15](O)(=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C(N(CC)CC)C>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])[NH:6][C:15](=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: COC(=O)[C@@H](N)CCCNC(=N)N
Reactant: CC(C)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCCNC(=N)N)NC(=O)CC(C)C

Procedure:
A 2.0 g (8.9 mMol) portion of arginine methyl ester hydrochloride was contacted with isovaleric acid (755 mg), HOBT (1 g), triethylamine (747 mg) and DCC (1.52 g) in DMF (150 ml) under the conditions described in Example 30 to give N-isovaleryl-arginine methyl ester as a crystalline solid (1.71 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[C:11](=[O:20])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:32][C:33]([N:35]([CH3:46])[C:36]1[CH:45]=[CH:44][C:39]2[N:40]=[C:41]([CH3:43])[O:42][C:38]=2[CH:37]=1)=[O:34]>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[C:11](=[O:20])[N:10]([CH2:32][C:33]([N:35]([CH3:46])[C:36]3[CH:45]=[CH:44][C:39]4[N:40]=[C:41]([CH3:43])[O:42][C:38]=4[CH:37]=3)=[O:34])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(-c3cccc(F)c3)n[nH]c(=O)c2c1
Reactant: Cc1nc2ccc(N(C)C(=O)CBr)cc2o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(-c3cccc(F)c3)nn(CC(=O)N(C)c3ccc4nc(C)oc4c3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
A 0° C. solution of 4-(3-fluorophenyl)-7-methoxyphthalazin-1(2H)-one (7.0 g, 25.9 mmol) in THF (160 mL) was treated with LiHMDS (1M in THF) (38 mL, 38 mmol) and stirred for 30 min. 2-Bromo-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (7.33 g, 25.9 mmol) in THF (40 mL) was added dropwise and stirring was maintained at rt for 16 h. The reaction mixture was diluted with water (200 mL) and the product extracted with EtOAc (3×150 mL). The organics were washed with brine (100 mL), dried over Na2SO4, and concentrated. The crude was triturated with MeOH (250 mL) to yield 2-(4-(3-fluorophenyl)-7-methoxy-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (9.1 g, 74%). (472.87 [M+H]) 1H NMR: (400 MHz, DMSO) δ: 2.62 (s, 3H), 3.33 (s, 3H), 4.95 (s, 3H), 4.73 (s, 2H), 7.37-7.43 (m, 4H), 7.48-7.51 (d, J=2.4, 8.8, 1H), 7.58-7.73 (m, 4H), 7.90 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:25])([C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])C(O)=O.[Br:26]Br.FF.Cl>>[F:1][C:2]([Br:26])([F:25])[C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12]
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: BrBr
Agent: Cl
Agent: FF
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Br
Yield: 450 %

Procedure:
Perfluorooctanoic acid 286 g (0.691 mole), bromine 55.3 g (0.345 mole) and Freon 113 (200 ml) were treated with fluorine (40 cc/min) at 30°-37° C. When approximately 0.42 mole of fluorine was used, the solution turned from dark red to orange. Perfluorooctanoic acid 500 g (1.208 mole) and bromine 112 g (0.700 mole) were added to the reaction mixture. The mixture was again treated with fluorine until the color of bromine disappeared (about 0.83 mole of additional fluorine was used). The reaction mixture was poured into dilute hydrochloric acid and the precipitated solid comprising unreacted perfluorooctanoic acid (about 115 grams) was recovered. The organic phase was then separated, washed with water containing some sodium thiosulfite, and dried over magnesium sulfate. Fractional distillation of the precipitate produced 697 g of perfluoroheptyl bromide (96% yield based on the amount of acid reacted), having a boiling point of 118° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13]C(C)(C)C)=O)[CH2:10][CH:5]2[CH:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:3]1.FC(F)(F)C(O)=O.O1CCCC1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]=C=O)=[CH:39][CH:38]=1>ClCCl>[F:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:11]([N:9]2[CH2:8][CH2:7][N:6]3[C:2](=[O:1])[O:3][CH:4]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:5]3[CH2:10]2)=[O:13])=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)OC(c3ccccc3)C2C1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)N1CCN2C(=O)OC(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.8 %

Procedure:
To a solution of 1,1-dimethylethyl tetrahydro-3-oxo-1-phenyl-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxylate (94 mg, 0.30 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.5 mL), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated, and then ethyl acetate was added to the residue. The resulting mixture was washed with a 0.5 M aqueous sodium hydrogen carbonate solution (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue were added tetrahydrofuran (5 mL) and 4-fluorophenyl isocyanate (0.10 g, 0.73 mmol), and the mixture was stirred at 50° C. for 1 hour. The reaction solution was concentrated, and then the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1 to ethyl acetate) to obtain the title compound (20 mg, yield 19%) as a diastereomer mixture. Diastereomer ratio (α:β=3:1).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].CN(C)C=O.S(Cl)([Cl:26])=O>C1(C)C=CC=CC=1>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:26])=[O:15])=[CH:12][CH:11]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCOc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCOc1ccc(C(=O)Cl)cc1

Procedure:
62.56 g of 4-methacryloyloxyethyloxybenzoic acid was charged to a flask with 0.5 g dimethyl formamide , and 54.38 ml of thionyl chloride was added dropwise under stirring. The reaction was exothermic. The reaction mixture was stirred overnight to give a clear brownish solution. The excess thionyl chloride was drawn off under vacuum. The residue was digested once with 20 ml of distilled toluene, and the toluene drawn off under vacuum. The residue was directly usable.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[N:10][CH:9]=[CH:8]2.C(=O)([O-])[O-].[K+].[K+]>CO.CCOC(C)=O.O>[C:4]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[N:10][CH:9]=[CH:8]2)#[CH:3]
Reactant: C[Si](C)(C)C#Cc1ccc2cnccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1ccc2cnccc2c1
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of 6-(2-(trimethylsilyl)ethynyl)isoquinoline (2.2 g, 9.8 mmol) in 45 mL of MeOH was added potassium carbonate (2.7 g, 20 mmol). After 1 hour, the reaction mixture was diluted with 100 mL of EtOAc and 50 mL of water. The mixture was partitioned and the aqueous portion was extracted three times with 50 mL of EtOAc. The combined organic layers were washed with 100 mL of brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (5% to 30% EtOAc/hexanes) afforded 6-ethynylisoquinoline (1.3 g, 87% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ pp 9.25 (s, 1H), 8.56 (d, J=5.7 Hz, 1H), 7.99 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.65 (dd, J=1.2 Hz, 8.6 Hz, 1H), 7.62 (d, J=5.8 Hz, 1H), 3.26 (s, 1H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]=2[C:8]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])=[N:7]1.C([O-])(O)=O.[Na+].[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>O.C(OCC)(=O)C>[CH:33]1([C:36]([N:11]2[CH2:12][CH2:13][C:14]3[N:6]([CH2:5][C:4]4[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:3]=4[F:2])[N:7]=[C:8]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[C:18]#[N:19])[C:9]=3[CH2:10]2)=[O:37])[CH2:35][CH2:34]1
Reactant: N#Cc1cccc(-c2nn(Cc3ccc(F)cc3F)c3c2CNCC3)c1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(-c2nn(Cc3ccc(F)cc3F)c3c2CN(C(=O)C2CC2)CC3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.9 %

Procedure:
To a 0° C. cold mixture of 3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile, hydrochloride salt (7c) (0.050 g, 0.129 mmol), NaHCO3 (44 mg, 0.517 mmol), water (2 ml) and ethyl acetate (2 ml) was added cyclopropanecarbonyl chloride (13.5 mg, 0.129 mmol) and the mixture was stirred at 25° C. for 16 h. Water was added, the solution was extracted 2 times with ethyl acetate, the combined organic layers were washed once with brine, dried over MgSO4, filtrated and purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 21 mg of 3-[5-Cyclopropanecarbonyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (8c).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18]([O:20]CC)=[O:19])=[C:9]1[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CCO.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18]([OH:20])=[O:19])=[C:9]1[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)n(Cc2ccccc2)c2ccc(O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)c2cc(O)ccc2n1Cc1ccccc1

Procedure:
General Procedure 2 A solution of ethyl 1-benzyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate (Compound 1, 873 mg, 2.83 mmol) and NaOH (2.2 g, 56 mmol) in EtOH (10 ml) and H2O (10 ml) was heated to 90° C. for 16 h. The reaction was quenched with 6M HCl (10 ml), extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (30% EtOAc-hexanes to 20% MeOH-EtOAc) to yield 1-benzyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (Compound 2) as a reddish brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:9]([S:16]([CH:19]2[CH2:21][CH2:20]2)(=[O:18])=[O:17])S(C2CC2)(=O)=O)[C:5]([Cl:8])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].[C:70](=[NH:83])([C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[Cl:8][C:5]1[C:4]([NH:9][S:16]([CH:19]2[CH2:20][CH2:21]2)(=[O:17])=[O:18])=[CH:3][C:2]([N:83]=[C:70]([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)=[CH:7][N:6]=1
Reactant: O=S(=O)(C1CC1)N(c1cc(Br)cnc1Cl)S(=O)(=O)C1CC1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1cc(N=C(c2ccccc2)c2ccccc2)cnc1Cl)C1CC1
Temperature: 130 °C

Procedure:
To a 20 mL microwave vial was added N-(5-bromo-2-chloropyridin-3-yl)-N-(cyclopropylsulfonyl)cyclopropanesulfonamide (0.880 g, 2.117 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Acros) (0.122 g, 0.212 mmol), tris(dibenzylideneacetone)dipalladium (0) (Strem) (0.097 g, 0.106 mmol), sodium tert-butoxide (Fluka) (0.814 g, 8.47 mmol), DMF (10 mL), and benzophenone imine (Aldrich) (0.426 mL, 2.54 mmol). The resulting mixture was degassed by bubbling N2 for 5 min. It was sealed off and microwave heated at 130° C. for 20 min. The resulting mixture was partitioned between EtOAc and sat. NH4Cl (25 mL). The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (80 g, 10% to 20% acetone in hexanes) to afford the desired product as a yellow foam-like solid (300 mg). MS (ESI pos. ion) m/z: 412.0. 1H NMR (300 MHz, CDCl3) δ ppm 0.89 (d, J=7.02 Hz, 2H) 1.03 (d, J=3.07 Hz, 2H) 6.60 (br. s., 1H) 7.14 (d, J=3.65 Hz, 2H) 7.34 (d, J=6.28 Hz, 4H) 7.39-7.48 (m, 2H) 7.49-7.56 (m, 1H) 7.68-7.80 (m, 3H).