Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[CH:16]=[C:17]([CH3:19])[N:18]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:25][C:26]([OH:43])([CH3:42])[CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1>>[CH:20]([N:15]1[CH:16]=[C:17]([CH3:19])[N:18]=[C:14]1[C:12]1[N:13]=[C:6]2[C:5]3[CH:23]=[CH:24][C:2]([C:31]4[CH:30]=[N:29][N:28]([CH2:27][C:26]([CH3:42])([OH:43])[CH3:25])[CH:32]=4)=[CH:3][C:4]=3[O:10][CH2:9][CH2:8][N:7]2[CH:11]=1)([CH3:22])[CH3:21]
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cn(C(C)C)c(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n1
Product: Cc1cn(C(C)C)c(-c2cn3c(n2)-c2ccc(-c4cnn(CC(C)(C)O)c4)cc2OCC3)n1
Yield: 22 %

Procedure:
Following the procedure in Example 182, 9-bromo-2-(1-isopropyl-4-methyl-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine was coupled with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol to give 195. Yield 22%. MS (ESI+): 447.1. 1H NMR (400 MHz, DMSO) δ 8.34 (d, J=8.4, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 7.63 (s, 1H), 7.36 (dd, J=8.4, 1.7, 1H), 7.25 (d, J=1.7, 1H), 7.00 (d, J=0.6, 1H), 5.68-5.57 (m, 1H), 4.72 (s, 1H), 4.48 (s, 4H), 4.03 (s, 2H), 2.10 (s, 3H), 2.07 (s, 1H), 1.42 (d, J=6.7, 6H), 1.09 (s, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([N:12]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[CH:14]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:13]2)=[O:11])[CH:3]=[CH:2]1.[CH2:35]1OCCOCCOCCOCCOCCOC1.CC([O-])(C)C.[K+].CI>CCOCC>[CH3:35][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([N:12]2[CH2:16][CH:15]([C:17]([F:19])([F:20])[F:18])[CH:14]([CH2:21][N:22]3[CH2:23][CH2:24][CH:25]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH2:26][CH2:27]3)[CH2:13]2)=[O:11])[CH:3]=[CH:2]1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: O=C(c1cccc2cc[nH]c12)N1CC(CN2CCC(c3ccc(F)cc3)CC2)C(C(F)(F)F)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CI
Product: Cn1ccc2cccc(C(=O)N3CC(CN4CCC(c5ccc(F)cc5)CC4)C(C(F)(F)F)C3)c21
Reaction time: 0.08 h

Procedure:
To a solution of 0.033 g (0.07 mmol) of 1-(7-indolecarbonyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(trifluoromethyl)pyrrolidine and 0.022 g (0.084 mmol) of 18-Crown-6 ether in 2 mL of ether at rt was added 0.084 mL of KOt-Bu (1M in t-BuOH). After stirring for 5 min, 0.006 mL (0.098 mmol) of MeI was added and the reaction was stirred for 1 h. The reaction mixture was concentrated and the residue was purified by chromatography (silica, acetone:hexanes, 1:3) to give the title compound.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][CH:4]1[N:9]=[C:8]([Cl:10])[N:7]=[C:6](F)[N:5]1[O:12][CH:13]([F:15])[F:14]>C(OCC)C>[NH2:3][CH:4]1[N:9]=[C:8]([Cl:10])[N:7]=[C:6]([NH:2][CH3:1])[N:5]1[O:12][CH:13]([F:15])[F:14]
Reactant: NC1N=C(Cl)N=C(F)N1OC(F)F
Reactant: CN
Solvent: CCOCC
Product: CNC1=NC(Cl)=NC(N)N1OC(F)F
Reaction time: 8 h

Procedure:
2.9 g (0.093 mol) of gaseous methylamine were passed into a solution of 10 g (0.047 mol) of 2-amino-4-chlorodifluoromethoxy-6-fluoro-1,3,5-triazine in 150 ml of diethyl ether at 0° C. in the course of 20 minutes, while stirring. Stirring was continued for one hour at 0° C. and overnight at 22° C. Washing with water, drying and evaporating down gave 9.4 g (89.5% of theory) of the title compound of melting point 143° C. (decomposition).
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4](Cl)=[O:5].[CH2:13]([O:20][N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][CH:24]=[N:25][C:26]=2[NH2:30])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:13]([O:20][N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][CH:24]=[N:25][C:26]=2[N:30]1[C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]2[C:1]1=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ncnc2c1ncn2OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1c1ncnc2c1ncn2OCc1ccccc1
Yield: 49 %

Procedure:
Phthaloyl dichloride (13.35 g; 92.2 mmol) was added to a cooled solution of 9-benzyloxyadenine (14.9 g, 61.5 mmol), 4-dimethylaminopyridine (1.5 g, 12.3 mmol) and triethylamine (25.7 ml, 184.4 mmol) in tetrahydrofuran (200 ml). After 1 hour at room temperature the solvent was removed under reduced pressure and the residue partitioned between chloroform (500 ml) and saturated potassium bicarbonate (300 ml). The organic phase was separated, washed with water (200 ml), brine (200 ml), dried (MgSO4) and evaporated to dryness. Column chromatography on silica gel eluting with chloroformmethanol (100:1) afforded the title compound (11.20 g, 49%). IR: νmax (KBr) 3070, 1800, 1740, 1730, 1605, 1585, 1450 and 1410 cm-1 ; 1H NMR δH [(CD3)2SO] 5.70(2H, s, CH2Ph), 7.55(5H, s, CH2Ph), 8.20(4H, s, Ar), 8.95(1H, s, H-2), 9.25(1H, s, H-8). Found: C, 64.71; H, 3.78; N, 18.85%; m/z 371.1025. C20H13N5O3 requires: C, 64.68; H, 3.54; N, 18.86%; m/e 371.1018.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[C:8](/[C:12]2[N:13]=[CH:14][N:15]([S:17]([N:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH:16]=2)=[CH:9]/[O:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30].Cl>ClCCl>[CH2:29]([S:31]([NH:1][C:2]1[CH:3]=[C:4](/[C:8](/[C:12]2[N:13]=[CH:14][N:15]([S:17]([N:20]([CH3:22])[CH3:21])(=[O:18])=[O:19])[CH:16]=2)=[CH:9]/[O:10][CH3:11])[CH:5]=[CH:6][CH:7]=1)(=[O:33])=[O:32])[CH3:30]
Reactant: CO/C=C(/c1cccc(N)c1)c1cn(S(=O)(=O)N(C)C)cn1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cccc(/C(=C/OC)c2cn(S(=O)(=O)N(C)C)cn2)c1
Reaction time: 5 h

Procedure:
A solution of Example 46B (0.32 g, 0.99 mmol) in dichloromethane (5 mL) was treated with pyridine (0.24 mL, 3.0 mmol), treated with ethanesulfonyl chloride (0.10 mL, 1.1 mmol), stirred for 5 hours, treated with 1M HCl and extracted with dichloromethane (3×). The combined dichloromethane extractions were dried (Na2SO4) and concentrated to provide the title compound.
Reaction SMILES: [N+](C1C=CC(COC(C2N3[C@H](SC=2)C(C(OC(=O)C)[C:21]2[N:22]=[C:23]4[CH2:28][N:27]([CH3:29])[C:26](=[O:30])[CH2:25][N:24]4[CH:31]=2)(Br)C3=O)=O)=CC=1)([O-])=O.P([O-])([O-])([O-])=O.[C:44](OCC)(=[O:46])C>C1COCC1.C(#N)C.[Zn]>[CH3:29][N:27]1[C:26](=[O:30])[CH2:25][N:24]2[C:31]([CH:44]=[O:46])=[CH:21][N:22]=[C:23]2[CH2:28]1
Reactant: CCOC(C)=O
Reactant: CC(=O)OC(c1cn2c(n1)CN(C)C(=O)C2)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Agent: O=P([O-])([O-])[O-]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC#N
Product: CN1Cc2ncc(C=O)n2CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(5R,6RS)-6-[Acetoxy-(7-methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (481 mg) was dissolved in THF (6.7 mL) and acetonitrile (3.1 mL). Freshly activated Zn dust (1.92 g) and 0.5 M phosphate buffer (pH 6.5, 9.9 mL) were added to the mixture. The reaction vessel was covered with foil to exclude light. The reaction mixture was vigorously stirred for 2 h at room temperature. The reaction solution was mixed with ethyl acetate and filtered through a pad of Celite. The pad was washed with water and the aqueous layer was separated. The aqueous layer was cooled to 3° C. and 1 M NaOH was added to adjust pH to 8.0. The mixture was concentrated under high vacuum at 35° C. and lyophilized. The residue was separated by the preparative HPLC (Inertsil ODS-2, GL Science Inc., 10×250 mm, 0.05 mol/L phosphate buffer (pH 7.1): CH3CN=93:7, 4.0 mL/min.). The separated fractions of (5R),(6Z)-6-(7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt and (5R),(6E)-6-(7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt were cooled to 3° C. and 1 M NaOH was added to adjust pH to 8.0 respectively. Each solution was concentrated under high vacuum at 35° C. Each concentrate was applied to Diaion HP-21 (60 mL, Mitsubishi Kasei Co. Ltd.) resin column chromatography. After adsorbing, the column was eluted with water and then with 5% acetonitrile-water. The combined fractions were concentrated under high vacuum at 35° C. and lyophilized to give the title compound (5R),(6Z)-6-(7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt as a yellow amorphous solid (125 mg, 44.4%, Mp 115-117° C. (dec)) and compound (5R),(6E)-6-(7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt as yellow amorphous solid (19 mg, 6.7%) respectively.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:27]=1>ClCCl.C(N(CC)CC)C>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([S:32]([N:21]2[C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=[C:17]2[S:15]([CH2:14][C:3]2[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=2)=[O:16])(=[O:34])=[O:33])[CH:27]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1cccnc1
Reaction time: 5 h
Yield: 68 %

Procedure:
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (370 mg) was dissolved in 20 ml of dichloromethane and 1 ml of triethylamine. Pyridine-3-sulfonyl chloride (195 mg) was added and stirred in ice-bath for 5 hr. Dichloromethane layer was washed with an aqueous solution composed of 0.1M NaCl and 0.1M sodium bicarbonate. Dichloromethane layer was dried over anhydrous magnesium sulfate. Solvent was removed under reduced pressure. Residual material was precipitated by dichloromethane-ethyl ether-heptane to provide 348 mg of 1-(pyridine-3-sulfonyl)-2-[(3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.Cl>N1C=CC=CC=1>[CH:1]1([O:6][S:13]([C:10]2[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=2)(=[O:15])=[O:14])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: OC1CC=CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CC=CC2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 78.8 %

Procedure:
Cyclopent-3-ene-1-ol (200 mg, 2.38 mmol) was dissolved in pyridine (2.5 ml) and p-toluenesulfonyl chloride (558 mg, 2.92 mmol) was added portionwise at 0° C. After the addition was completed the reaction mixture was stirred at 0° C. for 3 h and then kept in the fridge overnight. Then it was poured into to a mixture of ice and diluted HCl (pH ˜5). The solid was filtered off, washed with diluted HCl and dried to obtain the title compound as off-white solid (447 mg, 79%). MS (EI): 256.2 (M+NH4)+.
Reaction SMILES: [C:1](OCC)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH:9][C@@H:10]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:26]2[C:25](=[O:31])[CH2:24][C@@:23]2([CH3:32])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C:20](=[O:22])[CH3:21])[CH2:11]1.[H-].[Na+].CO>CS(C)=O>[C:1]([CH2:21][C:20](=[O:22])[C@@H:19]1[C@:23]2([CH3:32])[C@H:16]([C@H:15]3[C@H:26]([C:25](=[O:31])[CH2:24]2)[C@:27]2([CH3:30])[C@H:12]([CH2:11][C@H:10]([OH:9])[CH2:29][CH2:28]2)[CH2:13][CH2:14]3)[CH2:17][CH2:18]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OCC
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: CCCC(=O)CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 4 h

Procedure:
Ethyl butyrate (0.84 ml) was added to a mixture of 3α-hydroxy-5α-pregnane-11,20-dione (665 mg) and sodium hydride (150 mg.) in dry dimethyl sulphoxide (10 ml.). The mixture was stirred, under N2, for 13/4 hrs. The reaction mixture was treated with methyl alcohol to destroy excess sodium hydride, then poured into 2N-hydrochloric acid. The product was extracted with ethyl acetate and the combined extracts were washed with water, dried and evaporated. Preparative t.l.c. of the residue (859 mg.) gave two fractions. The more polar fraction was title compound (244 mg.) [α]D + 74.0°, λmax. 278 nm (ε 12,980).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][N:4]=1)#[CH:2].[N:13]([C:16]1[CH:29]=[CH:28][C:19]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1)=[N+:14]=[N-:15].Cl>CN(C=O)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][N:4]=[C:3]2[C:1]1[N:15]=[N:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[O:21])=[CH:28][CH:29]=2)[CH:2]=1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: C#Cc1n[nH]c2ccc(C)cc12
Agent: [Cu+2]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2[nH]nc(-c3cn(-c4ccc(C(=O)N5CCOCC5)cc4)nn3)c2c1
Temperature: 80 °C
Yield: 83.6 %

Procedure:
Copper sulfate pentahydrate (70 mg; 0.28 mmol; 0.07 eq.) was added to a solution of 3-ethynyl-5-methyl-1H-indazole (665 mg; 4.26 mmol; 1.00 eq.), 4-(4-azidobenzoyl)morpholine (987 mg; 4.25 mmol; 1.0 eq.) and D-(−)-isoascorbic acid sodium salt (283 mg; 1.43 mmol; 0.34 eq.) in DMF (15 mL) and water (0.5 mL). The reaction suspension was heated in MW at 80° C. for 40 min then poured into HCl solution (1N) and extracted with EtOAc (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give a yellow solid (1.38 g, 83%). 1H NMR (300 Mz, DMSO-d6) δ: 13.25 (s, 1H), 9.36 (s, 1H), 8.20-8.10 (m, 3H), 7.68 (d, J=108.7 Hz, 2H), 7.51 (d, J=8.6 Hz, 1H), 7.28 (dd, J=1.4, 8.6 Hz, 1H), 3.74-3.36 (m, 8H), 2.48 (s, 3H). HPLC (Condition A): Rt 3.21 min (purity 98.6%). MS (ESI+): 389.2, MS (ESI−): 387.2.
Reaction SMILES: Cl[CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[I-:12].[Na+]>C(N(CC)CC)C.C(C(C)=O)C>[I:12][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: O[C@@H](CCCl)c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: O[C@@H](CCI)c1ccccc1
Yield: 74.9 %

Procedure:
Commercially available (S)-3-chloro-1-phenyl-1-propanol (6 g) was heated with excess sodium iodide (4 equiv., 18 g) and a few drops of triethylamine in 30 mL of methyl ethyl ketone at 100° C. for 20 h. A sample was taken and monitored by NMR to determine the extent of conversion. The solvent was removed in vacuo and the residue was taken up in dichloromethane and filtered to remove the salts and the iodoalcohol was purified by flash chromatography to yield 6.9 g of product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[CH2:13][C:14]#[N:15])([O-:3])=[O:2].O>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[CH2:13][CH2:14][NH2:15])([O-:3])=[O:2]
Reactant: N#CCc1c[nH]c2c([N+](=O)[O-])cccc12
Solvent: O
Solvent: C1CCOC1
Product: NCCc1c[nH]c2c([N+](=O)[O-])cccc12
Reaction time: 20 h

Procedure:
Dissolve in a 500 mL round bottom flask equipped with magnetic stirring, and a nitrogen inlet, (7-nitro-1H-indol-3-yl)-acetonitrile (5.27 g, 26 mmol) in dry tetrahydrofuran (150 mL). Treat the solution with 1M BH3:THF (55 mL, 55 mmol) and stir at room temperature. After 20 hours, quench the reaction by the cautious dropwise addition of water (9 mL) and stir until foaming and gas evolution has stopped. Concentrate the mixture to dryness in vacuo, redissolve in 1 N HCl (300 ml) and extracte with ethyl acetate. Basify the aqueous phase 5 N NaOH and extract with ethyl acetate. Pool the ethyl acetate extracts and dry over sodium sulfate and concentrate in vacuo to give the title compound as an orange-brown solid: 1H NMR (400 MHz, dmso-d6): 11.66 (br s, 1H) 8.07 (t, 2H, J=7.6 Hz), 7.32 (s, 1H), 7.20 (t, 1H, J=8.0 Hz) 2.79-2.83 (m, 4H), MS (APCI): m/e 189.0 (M−NH2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[N+](N[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:27]=[N:28][C:29]([CH3:33])=[CH:30][C:31]=2[CH3:32])=[CH:20][N:19]=1)([O-])=O>C1(OC)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:18]2[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]3[CH:27]=[N:28][C:29]([CH3:33])=[CH:30][C:31]=3[CH3:32])=[CH:20][N:19]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1CCCCN
Reactant: Cc1cc(C)c(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Solvent: COc1ccccc1
Product: Cc1cc(C)c(Cc2cnc(NCCCCc3ncc(Br)cc3C)[nH]c2=O)cn1
Yield: 60.3 %

Procedure:
A mixture of 5-bromo-2-(4-aminobutyl)-3-methyl pyridine, (0.68 g) and 2-nitroamino-5-(4,6-dimethyl-3-pyridylmethyl)-4-pyrimidone (0.83 g) in anisole (25 ml) were refluxed for 4 hrs. Petroleum ether was added to precipitate the product which was then chromatographed on a silica gel column eluting with chloroform. The product was crystallised from ethyl acetate to give 2-[4-(5-bromo-3-methylpyrid-2-yl)-butylamino]-5-(4,6-dimethyl-3-pyridylmethyl)-4-pyrimidone (0.77 g) m.p. 110°-112° C.
Reaction SMILES: [CH3:1][N:2]([CH3:39])[C:3]1[CH:38]=[CH:37][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([C:21]3[C:29]4[C:24](=[CH:25][C:26]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)=[CH:27][CH:28]=4)[NH:23][CH:22]=3)[CH2:17][N+:18]([O-])=O)[C:11]=2[F:36])=[O:8])=[CH:5][CH:4]=1.[H][H]>CO.[Ni]>[NH2:18][CH2:17][CH:16]([C:12]1[C:11]([F:36])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:39])=[CH:38][CH:37]=2)[CH:15]=[CH:14][CH:13]=1)[C:21]1[C:29]2[C:24](=[CH:25][C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:27][CH:28]=2)[NH:23][CH:22]=1
Reactant: CN(C)c1ccc(C(=O)Nc2cccc(C(C[N+](=O)[O-])c3c[nH]c4cc(N5CCOCC5)ccc34)c2F)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CN(C)c1ccc(C(=O)Nc2cccc(C(CN)c3c[nH]c4cc(N5CCOCC5)ccc34)c2F)cc1
Yield: 82.1 %

Procedure:
A mixture of 4-(dimethylamino)-N-(2-fluoro-3-(1-(6-morpholino-1H-indol-3-yl)-2-nitroethyl)phenyl)benzamide (0.388 g, 0.730 mmol) and Raney Ni (a small amount) in MeOH (35 mL) was treated with hydrogen at 55 psi a Parr shaker apparatus for 3 hr. The catalyst was removed by suction filtration. The filtrate was concentrated under vacuum, diluted with CH2Cl2 (100 mL), washed with brine (25 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (0.321 g, 0.599 mmol, 82% yield) as an off-white solid.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][NH:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[CH2:5][CH2:4]1.Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(OCC)C>CN(C=O)C>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:7]([CH2:6][CH:3]2[CH2:5][CH2:4]2)[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:9][C:10]=1[C:16]([F:17])([F:18])[F:19])#[N:13]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1ccc(NCC2CC2)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 7.5 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
Sodium hydride (60%, 2.0 g, 50 mmol) was added to a stirred solution of 4-[(cyclopropylmethyl)amino]-2-(trifluoromethyl)benzonitrile (6.0 g, 25 mmol), and tert-butyl bromoacetate (6.82 g, 35 mmol) in 20 mL of DMF at 0° C. over 20 minutes. The mixture was then stirred at 5-10° C. for 30 minutes. Diethyl ether (200 mL) was added to the mixture and the resulting slurry was extracted with water (3×50 mL). The organic phase was dried (MgSO4), filtered, and then concentrated under reduced pressure. The residue was purified with silica gel chromatography (eluent: hexane-EtOAc; 3:1) to obtain 6.55 g (74%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J=8.8 Hz, 1H), 6.92 (d, J=2.6 Hz, 1H), 6.77 (dd, J=8.8, 2.7 Hz, 1H), 4.10 (s, 2H), 3.33 (d, J=6.6 Hz, 2H), 1.43 (s, 9H), 1.05 (m, 1H), 0.62 (m, 2H), 0.26 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([NH:20][C:21](=[O:31])[CH2:22][NH:23]C(=O)OC(C)(C)C)[N:19]=[C:6]2[N:5]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)[C:4]=1[CH3:42])#[N:2].[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>ClCCl>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([NH:20][C:21](=[O:31])[CH2:22][NH2:23])[N:19]=[C:6]2[N:5]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:40])([F:41])[F:39])[CH:33]=2)[C:4]=1[CH3:42])#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)CNC(=O)OC(C)(C)C)nc2N1c1cccc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)CN)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 0.67 h

Procedure:
Under an atmosphere of argon protective gas, tert-butyl [2-((7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-ylamino)-2-oxoethyl]carbamate (6.4 mg, 11 μmol) was dissolved in dry dichloromethane (5 ml). At room temperature, trifluoroacetic acid (1 ml) was added, and the mixture was stirred for 40 min. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (˜6 mg, quant.).
Reaction SMILES: C(OC(=O)[C:5]([NH:16][C:17](=[O:19])[CH3:18])([C:11]([CH:13]1[CH2:15][CH2:14]1)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.O>CS(C)=O>[CH2:9]([O:8][C:6]([C:5]1[N:16]=[C:17]([CH3:18])[O:19][C:11]=1[CH:13]1[CH2:14][CH2:15]1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(NC(C)=O)(C(=O)OCC)C(=O)C1CC1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1nc(C)oc1C1CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 34 %

Procedure:
2-Acetylamino-2-cyclopropanecarbonyl-malonic acid diethyl ester in DMSO was treated with 2 eq H2O and stirred at room temperature for 6 h then extracted with Et2O to give after concentration the title compound in 34% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([NH2:9])=[N:6][C:7]=1Cl.C(N(CC)CC)C.[NH2:20][CH2:21][CH2:22][OH:23]>C(O)(C)C>[NH2:9][C:5]1[N:6]=[C:7]([NH:20][CH2:21][CH2:22][OH:23])[C:2]([Cl:1])=[N:3][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: NCCO
Reactant: Nc1nc(Cl)c(Cl)nc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Nc1nc(NCCO)c(Cl)nc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
To 1.0 g of 5,6-dichloro-3-nitropyrazinamine in 20 ml isopropanol is added 0.5 ml triethylamine and then 0.3 ml 2-aminoethanol. The reaction mixture is stirred for 3 hours and then concentrated in vacuo to solids. The solids are triturated with hot chloroform and recrystallized from acetonitrile to afford 0.6 g of 2[(6-Amino-3-chloro-5-nitropyrazin-2-yl)amino]ethanol, m.p. 196°-197° C.