Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]1([NH:9][C:10]([CH:12]([CH:45]([CH3:47])[CH3:46])[CH2:13][CH:14]([OH:44])[CH:15]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:16][CH:17]([CH2:21][C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[CH:27][N:28]3[CH2:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:24][CH:23]=2)[CH:18]([CH3:20])[CH3:19])=[O:11])[C:3]2([CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:2]1.ClS([N:52]=[C:53]=O)(=O)=O.CN(C)C=O>ClCCl>[C:53]([C:26]1[C:25]2[C:29](=[CH:30][C:22]([CH2:21][CH:17]([CH:18]([CH3:19])[CH3:20])[CH2:16][CH:15]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:40])([CH3:42])[CH3:41])[CH:14]([OH:44])[CH2:13][CH:12]([C:10](=[O:11])[NH:9][C@H:1]3[C:3]4([CH2:4][CH2:5][O:6][CH2:7][CH2:8]4)[CH2:2]3)[CH:45]([CH3:47])[CH3:46])=[CH:23][CH:24]=2)[N:28]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[CH:27]=1)#[N:52]
Reactant: COCCCn1ccc2ccc(CC(CC(NC(=O)OC(C)(C)C)C(O)CC(C(=O)N[C@@H]3CC34CCOCC4)C(C)C)C(C)C)cc21
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCCn1cc(C#N)c2ccc(CC(CC(NC(=O)OC(C)(C)C)C(O)CC(C(=O)N[C@@H]3CC34CCOCC4)C(C)C)C(C)C)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1 mmol of tert-butyl (4-((R)-(6-oxaspiro[2.5]-oct-1-yl)carbamoyl)-2-hydroxy-1-(2-[1-(3-methoxypropyl)-1H-indol-6-ylmethyl]-3-methylbutyl)-5-methylhexyl)carbamate in 15 ml of dichloromethane is mixed with 1.5 mmol of chlorosulphonyl isocyanate and stirred at room temperature for 16 hours. 2 ml of N,N-dimethylformamide are added, and the reaction mixture is again stirred for 2 hours. It is quenched with water, and the suspension is vigorously stirred for 10 minutes. It is poured into 1M sodium bicarbonate solution and extracted with ethyl acetate (3×). The combined organic phases are washed with brine, dried with sodium sulphate and evaporated. The title compound is identified by means of the Rf from the residue by flash chromatography (SiO2 60 F).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:14])[S:11][C:7]=2[C:6]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:5][CH:4]=1.[C:27](Cl)(=[O:29])[CH3:28].N1C=CC=CC=1>CN(C=O)C>[C:27]([N:24]1[CH2:23][CH2:22][N:21]([C:6]2[C:7]3[S:11][C:10]([NH:12][C:13]([C:15]4[S:16][C:17]([CH3:20])=[CH:18][CH:19]=4)=[O:14])=[N:9][C:8]=3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:26][CH2:25]1)(=[O:29])[CH3:28]
Reactant: COc1ccc(N2CCNCC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(C(C)=O)CC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 55 %

Procedure:
5-Methyl-thiophene-2-carboxylic acid (4-methoxy-7-piperazin-1-yl-benzothiazol-2-yl)-amide (100 mg, 0.26 mmol) were suspended in DMF (2 ml) and treated with acetyl chloride (22 μl, 0.30 mmol) and pyridine (27 μl, 0.34 mmol) and the mixture stirred for 5 h at ambient temperature. Workup and purification as described in the general procedure C afforded the product as a white solid (55%), MS: m/e=431(M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O.[NH4+].[Cl-]>CCO.[Fe]>[NH2:20][C:17]1[CH:18]=[CH:19][C:10]2[N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[CH2:14][C:13](=[O:15])[NH:12][C:11]=2[CH:16]=1
Reactant: O=C1CC(c2cccc(Br)c2)=Nc2ccc([N+](=O)[O-])cc2N1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)NC(=O)CC(c1cccc(Br)c1)=N2
Temperature: 90 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
To a stirred solution of compound 3 (0.1 g, 0.27 mmol) in EtOH:H2O (10 mL, 6:3) was added Fe-powder (0.076 g, 1.39 mmol) followed by NH4Cl (0.037 g, 0.70 mmol) at RT. The resulting reaction mixture was heated to 90° C. and stirred for 1 h; progress of the reaction was monitored by TLC. The reaction mixture was then cooled to RT; the reaction mixture was filtered and the obtained filtrate was concentrated under reduced pressure. The residue was diluted with water (10 mL) and then extracted with EtOAc (2×10 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 4 (35 mg, 38%) as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.32 (bs, 1H), 8.15-8.13 (m, 1H), 7.97 (d, J=7.6 Hz, 1H), 7.69 (d, J=7.2 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H), 6.52 (d, J=8.4 Hz, 1H), 6.32 (s, 1H), 5.48 (bs, 2H), 3.42 (s, 2H). Mass: m/z 331 [M+1]+
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[C:5](=O)[CH2:6][C:7]#[N:8].O.[NH2:11][NH2:12]>C(O)C>[CH3:1][C@@H:2]1[CH2:4][C@H:3]1[C:5]1[NH:12][N:11]=[C:7]([NH2:8])[CH:6]=1
Reactant: CC1CC1C(=O)CC#N
Reactant: NN
Solvent: O
Solvent: CCO
Product: C[C@@H]1C[C@H]1c1cc(N)n[nH]1
Yield: 79 %

Procedure:
The crude 3-(2-methylcyclopropyl)-3-oxopropanenitrile was dissolved in ethanol (50 mL) and hydrazine hydrate (0.83 mL, 17 mmol) was added. The solution was maintained at reflux for 10 hours and then the solvent evaporated under vacuum. The residue was redissolved in methylene chloride and washed several times with brine. The organic layer was dried over anhydrous sodium sulfate and the solvent evaporated to give compound trans 5-(−2-methylcyclopropyl)-1H-pyrazol-3-amine (1 g, 79%, three step).
Reaction SMILES: C(OC([N:8]1[C@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][C@H:12]([CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[CH2:11][OH:10]
Reactant: CC(C)(C)OC(=O)N1[C@H](CCc2ccc(F)cc2)COC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](CO)CCc1ccc(F)cc1
Reaction time: 16 h
Yield: 72.5 %

Procedure:
To a stirred solution of (R)-4-[2-(4-fluoro-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (190 mg) at r.t. in dioxane (3.5 ml) under an argon atmosphere was added 4 M HCl solution in dioxane (1.47 ml). The mixture was stirred for 16 h. The mixture was concentrated. The crude product was purified by column chromatography (SiO2; gradient: CH2Cl2->CH2Cl2/MeOH 9:1) to give (R)-2-amino-4-(4-fluoro-phenyl)-butan-1-ol (78 mg) as off-white solid. MS (ISP): 184.1 ([M+H]+))
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:8]=2)[N:3]1[CH2:22][C:23]([O:25]C(C)(C)C)=[O:24].Cl.O1CCOCC1>>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:16][CH:17]=3)[CH:8]=2)[N:3]1[CH2:22][C:23]([OH:25])=[O:24]
Reactant: CC(C)(C)OC(=O)CN1C(=O)CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CN1C(=O)CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
To tert-butyl 2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetate (202 mg, 0.50 mmol) in a 50 mL round-bottom flask was added 4N hydrochloric acid in 1,4-dioxane (6.0 mL, 24.0 mmol). The reaction mixture was stirred at room temperature for 4 hours, and the solvent removed under reduced pressure. A second portion of 4N HCl in 1,4-dioxane (6.0 mL, 24.0 mmol) was added with stirring for another 13 hours, and again the solvent was removed under reduced pressure, to afford 2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetic acid as a solid (162 mg, 0.46 mmol, 92%). LCMS mz 350.0 (M+H), 372.0 (M+Na), anal HPLC>97% in purity, 1H NMR (400 MHz; CDCl3) δ 7.67 (m, 4H); 7.40-7.50 (m, 2H); 6.92 (d, J=8.6 Hz, 1H); 4.76 (s, 2H); 3.04 (m, 2H); 2.79 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[C:23]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:22][CH:21]=[CH:20][N:19]=2)[CH2:13][CH2:12]1)=[O:10].[OH-].[Na+].C(OCC)(=O)C.[CH3:37][N:38](C)C=O>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:25]([O:24][C:23]1[C:18]([CH2:17][N:14]2[CH2:15][CH2:16][CH:11]([C:9](=[O:10])[CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:37]#[N:38])[CH2:12][CH2:13]2)=[N:19][CH:20]=[CH:21][N:22]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)Oc1nccnc1CN1CCC(C(=O)Cc2ccccc2Br)CC1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1nccnc1CN1CCC(C(=O)Cc2ccccc2C#N)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
After dissolving 298 mg of 2-(2-bromophenyl)-1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]ethanone in 2 ml of N,N-dimethylformamide, 235 mg of zinc cyanide and 77 mg of tetrakis(triphenylphosphine) palladium(0) were added and the mixture was stirred overnight at 100° C. A 1N sodium hydroxide solution was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (90 mg, 34% yield).
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[S:17][C:16]([S:18][CH2:19][C:20](O)=[O:21])=[N:15][N:14]=2)=[C:6]([CH2:25][CH2:26][CH3:27])[C:5]=1[OH:28])(=[O:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[OH:44][N:45]1[C:49]2C=CC=CC=2N=N1.Cl.CNO>C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C.O1CCCC1>[C:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[S:17][C:16]([S:18][CH2:19][C:20]([N:45]([OH:44])[CH3:49])=[O:21])=[N:15][N:14]=2)=[C:6]([CH2:25][CH2:26][CH3:27])[C:5]=1[OH:28])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSc2nnc(SCC(=O)O)s2)ccc(C(C)=O)c1O
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CNO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1c(OCCCSc2nnc(SCC(=O)N(C)O)s2)ccc(C(C)=O)c1O
Yield: 36.8 %

Procedure:
To a mixture of 0.5 g of [[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1,3,4-thiadiazol-2-yl]thio]acetic acid obtained in example 22, 0.23 g of dicyclohexylcarbodiimide, 0.14 g of 1-hydroxybenzotriazole, and 50 ml of tetrahydrofuran was added a mixture of 0.27 g of N-methylhydroxylamine.hydrochloride, 0.3 g of triethylamine, and 5 ml of N,N-dimethylformamide and the resultant mixture was stirred overnight at room temperature. Then, insoluble matters were filtered off and the filtrate thus formed was concentrated under reduced pressure. To the residue thus formed was added 100 ml of ethyl acetate and the mixture was washed with water, washed with a diluted aqueous solution of sodium hydrogencarbonate, and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue thus obtained was added ethyl acetate, then insoluble materials were filtered off and the filtrate formed was concentrated. The residue thus obtained was recrystallized from a mixture of toluene and n-hexane to provide 0.18 g of 2-[[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1,3,4-thiadiazol-2-yl]thio]-N-hydroxy-N-methylacetamide.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15]C(OC(C)(C)C)=O>FC(F)(F)C(O)=O>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]
Reactant: CC(C)(C)OC(=O)NCCCCNc1nc2ccccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Product: NCCCCNc1nc2ccccc2[nH]1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
198 mg (0.65 mmol) of 4-(benzimidazol-2-ylamino)-1-(tert-butyloxycarbonylamino)butane (Example 23c) were dissolved in 20 ml of 95% strength trifluoroacetic acid at 0° C. and stirred at 0° C. for 2 h, then concentrated at RT during the course of 30 min. The residue was coevaporated three times with toluene, then stirred with ether and washed with pentane and dried in vacuo. Yield: 100%. MS (ES+): m/e=205.2 ( (M+H)+, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[Li]CCCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.C(=O)=O.CC(C)=O>>[Cl:9][C:4]1[CH:3]=[C:2]([B:15]([OH:20])[OH:16])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: Oc1ccc(Br)cc1Cl
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Product: OB(O)c1ccc(O)c(Cl)c1
Temperature: -78 °C

Procedure:
A dry 250 ml r.b. flask was loaded with 4-bromo-2-chlorophenol (5.00 g, 24.1 mmol) and purged with N2(g). Anhydrous THF (100 mL) added with stirring and the vessel cooled to −78° C. (dry ice/acetone bath). After 30 mins n-BuLi, 2.3 M in hexanes, (12.9 mL, 28.9 mmol) was added dropwise over 20 min. The reaction was left to stir for 1 h. Triisopropyl borate (6.65 mL, 28.9 mmol) was added dropwise with the reaction still at −78° C. After 15 min of stirring at this temperature the dry ice/acetone bath was removed. At about 0° C. 2 M HCl(aq) (5 mL) was added and the reaction left to stir for a further 15 min. THF removed under vacuum and residues taken up in ethyl acetate (50 mL). Distilled H2O (50 mL) was added and the organic layer separated. The aqueous layer was extracted with ethyl acetate (50 mL×2). The organic portions were combined and washed with sat. Na2CO3 (aq). The aqueous layer was separated and treated with 2M HCl (aq) until the pH was about 4. This was then extracted with ethyl acetate (50 mL×2). The organic portions were then dried over MgSO4 and solvent removed. The resultant off white residues were taken up in a minimum of ethyl acetate (2-3 mL) and added to dropwise to hexane (50 mL) with stirring. The white ppt was filtered to give the title compound as an off white solid (0.490 g, 12%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH:17]=[O:18])[CH:9]=1)=[O:4].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C=O)nn1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2CO)nn1C
Yield: 70.6 %

Procedure:
A solution of 5-[3-(4-fluoro-phenyl)-5-formyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (720 mg, 2.0 mmol) and sodium borohydride (158 mg, 4.0 mmol) in methanol (36 mL) were stirred for 1 h at room temperature. Addition of 10% aqueous citric acid (100 mL) was followed by extraction with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica, heptane:ethyl acetate=4:1 to 1:1) afforded the title compound (510 mg, 70%) as a white solid. MS: m/e=420.3 [M+OAc]−.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:7][C:6]=1[S:17]([NH:20][CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28]([OH:30])=O)[CH2:24][CH2:23]1)(=[O:19])=[O:18].C([N:35](CC)CC)C.ClC(OCC)=O.N>C1COCC1>[F:32][C:2]([F:31])([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:14])[F:15])=[CH:7][C:6]=1[S:17]([NH:20][CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28]([NH2:35])=[O:30])[CH2:24][CH2:23]1)(=[O:18])=[O:19]
Reactant: O=C(O)[C@H]1CC[C@H](CNS(=O)(=O)c2cc(OCC(F)(F)F)ccc2OCC(F)(F)F)CC1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)[C@H]1CC[C@H](CNS(=O)(=O)c2cc(OCC(F)(F)F)ccc2OCC(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of trans-4-{[2,5-bis-(2,2,2-trifluoro-ethoxy)-benzenesulfonylamino]-methyl}-cyclohexanecarboxylic acid (2.78 g, 5.63 mmol) and triethylamine (1.9 mL, 13.6 mmol) in THF (25 mL) was cooled to 0° C. To the mixture was added ethyl chloroformate (0.586 mL, 6.2 mmol) in THF (5 mL) over 10 min. After stirring at 0° C. for 15 min, 25% aqueous ammonia (10 mL) was added dropwise. The mixture was stirred at ambient temperature for 2 hr. The resulting mixture was concentrated under reduced pressure and the concentrate was diluted with water to give a solid. The solid was filtered and washed with water and hexanes to give trans-4-{[2,5-bis-(2,2,2-trifluoro-ethoxy)-benzenesulfonylamino]-methyl}-cyclohexanecarboxylic acid amide as a white solid (2.7 g, 98%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:5])=[O:4].C[Al](C)C.[Cl:10][C:11]1[CH:21]=[C:20](/[CH:22]=[CH:23]/[CH:24]([C:29]2[CH:34]=[C:33]([Cl:35])[C:32]([Cl:36])=[C:31]([Cl:37])[CH:30]=2)[C:25]([F:28])([F:27])[F:26])[CH:19]=[CH:18][C:12]=1[C:13](OCC)=[O:14]>C(Cl)Cl>[Cl:10][C:11]1[CH:21]=[C:20](/[CH:22]=[CH:23]/[CH:24]([C:29]2[CH:30]=[C:31]([Cl:37])[C:32]([Cl:36])=[C:33]([Cl:35])[CH:34]=2)[C:25]([F:26])([F:27])[F:28])[CH:19]=[CH:18][C:12]=1[C:13]([NH:1][CH2:2][C:3](=[O:4])[NH:5][CH2:24][C:25]([F:28])([F:27])[F:26])=[O:14]
Reactant: NCC(N)=O
Reactant: CCOC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Agent: C[Al](C)C
Solvent: ClCCl
Product: O=C(CNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl)NCC(F)(F)F
Temperature: 28 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
To a stirred solution of glycine amide (0.15 g, 0.58 mmol) in CH2Cl2 (5 mL) was added trimethylaluminum (2 M solution in toluene; 1.45 mL, 2.91 mmol) dropwise, and the reaction mixture was stirred at 28° C. for 30 min. A solution of (E)-ethyl 2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoate (0.3 g, 0.58 mmol) in CH2Cl2 (5 mL) was added drop wise to the reaction mixture at 28° C. The reaction mixture was stirred at reflux for 18 h, cooled to 25° C., quenched with 1N HCl solution (50 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 40% EtOAc in n-hexane) to afford the title compound as yellow solid (0.15 g, 50%): mp 83-85° C.; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.40 (s, 2H), 7.36 (d, J=6.8 Hz, 1H), 7.05 (t, J=5.2 Hz, 1H), 6.70 (t, J=5.2 Hz, 1H), 6.57 (d, J=15.6 Hz, 1H), 6.44 (dd, J=15.6, 8.0 Hz, 1H), 4.23 (d, J=5.6 Hz, 2H), 4.15 (m, 1H), 4.01 (m, 2H); ESIMS m/z 580.72 ([M−H]−).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH:15]=2)=[CH:7][C:6]=1[N+]([O-])=O>CO.[Pd]>[NH:2]1[C:6]2[C:5](=[N:10][CH:9]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:18][CH2:17]4)[CH:15]=3)[CH:7]=2)[CH:4]=[CH:3]1
Reactant: CN(C)/C=C/c1ncc(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4cc[nH]c4c3)cn2)CC1
Yield: 93.2 %

Procedure:
To a solution of tert-butyl 4-(4-{6-[(E)-2-(dimethylamino)ethenyl]-5-nitropyridin-3-yl}-1H-pyrazol-1-yl)piperidine-1-carboxylate (prepared in example 18: 4.0 g, 9.05 mmol) in MeOH (50 mL) was added Pd—C (10%, wet, 2.0 g) and the reaction mixture was hydrogenated under a hydrogen balloon at room temperature for 2 h. The catalyst was filtered off and solvent was evaporated. The residue was washed with ethyl acetate to give a solid (3.1 g, yield 93%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([C:13]3[C:21]([O:22][CH3:23])=[CH:20][C:19]([CH3:24])=[C:18]4[C:14]=3[CH:15]=[CH:16][N:17]4[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=O)=[N:8][C:7]=2[CH:32]=1)#[N:2].[CH3:33][C:34]([S:37]([NH2:39])=[O:38])([CH3:36])[CH3:35]>C1(C)C=CC=CC=1.CCOC(C)=O.[Cl-].[Na+].O>[C:34]([S:37]([N:39]=[C:11]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:32][C:7]=2[N:8]=1)[C:13]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([CH3:24])=[C:18]2[C:14]=1[CH:15]=[CH:16][N:17]2[C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])=[O:38])([CH3:36])([CH3:35])[CH3:33]
Reactant: CC(C)(C)S(N)=O
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(=O)c1nc2cc(C#N)ccc2o1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(=NS(=O)C(C)(C)C)c1nc2cc(C#N)ccc2o1

Procedure:
To a solution of tert-butyl 4-(5-cyanobenzo[d]oxazole-2-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 126-A) (711 mg, 1.648 mmol) and 2-methyl-2-propanesulfinamide (599 mg, 4.94 mmol) in toluene (16.5 mL), Zr(O-t-Bu)4 (4.33 mL, 8.24 mmol) was added at room temperature. After 2 hours the reaction mixture was diluted with EtOAc and brine. The resulting mixture was filtered through Celite® and the organic layer of the filtrate was dried over MgSO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (0-80% EtOAc:Heptanes) to provide the title compound. MS (ESI+) m/z 535.2 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=[CH:6]2)#[N:2].Cl.[NH2:20][OH:21].C([O-])([O-])=O.[Na+].[Na+]>CCO>[OH:21][NH:20][C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=[CH:6]2)=[NH:2]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(C#N)ccc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)n1ccc2cc(C(=N)NO)ccc21
Temperature: 75 °C
Reaction time: 8 h

Procedure:
Prepared using General Procedure 1. To a flask containing tert-butyl 5-cyano-1H-indole-1-carboxylate INT-65 (200 mg, 0.73 mmol) was added EtOH (6 mL), hydroxylamine hydrochloride (177 mg, 2.54 mmol) and Na2CO3 (154 mg, 1.45 mmol). The mixture was stirred at 75° C. overnight then concentrated, re-dissolved in DCM and washed with NaHCO3. The combined organic layers were dried over Na2SO4 and concentrated to provide 222 mg of crude tert-butyl 5-(N-hydroxycarbamimidoyl)-1H-indole-1-carboxylate INT-66 as a white solid which was used directly in the next experiment. LCMS-ESI (m/z) calculated for C14H17N3O3: 275.3; found 276.1 [M+H]+, tR=2.25 min.