Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:6][N:5](C(OC(C)(C)C)=O)[C@@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.C(Cl)Cl.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[O-][Mn](=O)(=O)=O.[K+]>CCOC(C)=O>[OH:26][C:24]([C:23]([F:28])([F:27])[F:22])=[O:25].[CH3:17][O:16][C:14]([C@@H:4]1[CH2:3][C:2]([F:18])([F:1])[CH2:6][NH:5]1)=[O:15]
Reactant: COC(=O)[C@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CC(F)(F)CN1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A round-bottom flask was charged with (R)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate (675 mg, 2545 μmol), 10.2 mL DCM and trifluoroacetic acid (980 μl, 12724 μmol). The mixture was stirred at RT. After 6 h, TLC (50% hex/EtOAc, KMnO4 stain) indicated complete conversion. The mixture was concentrated, and the crude (5)-methyl-4,4-difluoropyrrolidine-2-carboxylate TFA salt was use as is.
Reaction SMILES: [C:1]([BH3-])#N.[Na+].C1COCC1.[CH:10]1([C:16]2[C:17]3[CH:18]=[CH:19][C:20]([C:49]([NH:51][S:52]([CH:55]4[CH2:57][CH2:56]4)(=[O:54])=[O:53])=[O:50])=[CH:21][C:22]=3[N:23]3[CH2:29][C:28]([C:30]([N:32]4[CH2:39][C:38]56[CH2:40][NH:41][CH2:42][C:34]5([CH2:35][O:36][CH2:37]6)[CH2:33]4)=[O:31])=[CH:27][C:26]4[CH:43]=[C:44]([O:47][CH3:48])[CH:45]=[CH:46][C:25]=4[C:24]=23)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C=O>CO>[CH:10]1([C:16]2[C:17]3[CH:18]=[CH:19][C:20]([C:49]([NH:51][S:52]([CH:55]4[CH2:57][CH2:56]4)(=[O:53])=[O:54])=[O:50])=[CH:21][C:22]=3[N:23]3[CH2:29][C:28]([C:30]([N:32]4[CH2:39][C:38]56[CH2:40][N:41]([CH3:1])[CH2:42][C:34]5([CH2:35][O:36][CH2:37]6)[CH2:33]4)=[O:31])=[CH:27][C:26]4[CH:43]=[C:44]([O:47][CH3:48])[CH:45]=[CH:46][C:25]=4[C:24]=23)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: [BH3-]C#N
Reactant: COc1ccc2c(c1)C=C(C(=O)N1CC34CNCC3(COC4)C1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C=C(C(=O)N1CC34COCC3(CN(C)C4)C1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
A 1M solution of sodium cyanoborohydride in THF (0.15 mL, 0.15 mmol) was added to a solution of 13-cyclohexyl-N-(cyclopropylsulfonyl)-3-methoxy-6-(3-oxa-7,10-diazatricyclo[3.3.3.01,5]undec-7-ylcarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (Example 22) (10 mg, 0.015 mmol) and formaldehyde (37 wt. % in water) (0.01 mL, 0.1 mmol) in MeOH (1 mL) and the mixture was stirred at rt for 16 h. The reaction was concentrated, dissolved into MeOH, filtered and purified by preparative HPLC (H2O-MeOH with 0.1% TFA buffer) to yield 13-cyclohexyl-N-(cyclopropylsulfonyl)-3-methoxy-6-((10-methyl-3-oxa-7,10-diazatricyclo[3.3.3.01,5]undec-7-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (7.9 mg, 9.4 μmol, 63% yield) as a bright yellow solid. LCMS: m/e 685 (M+H)+. LCMS retention time: 1.92 min. (Column: SunFire C18 5u 4.6×50 mm. Solvent A=90% Water/10% Acetonitrile/0.1% TFA. Solvent B=10% Water/90% Acetonitrile/0.1% TFA. Start % B=0. Final % B=100. Gradient Time=3 min. Flow Rate=4 mL/min.) 1H NMR (400 MHz, MeOD) δ ppm 8.09 (br s, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.54 (br d, J=8.5 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.14 (dd, J=8.5, 2.5 Hz, 1H), 7.10 (d, J=2.5 Hz, 1H), 7.07 (s, 1H), 5.22 (br d, J=14.8 Hz, 1H), 4.13-3.12 (m, 10H), 4.23 (br d, J=14.8 Hz, 1H), 3.90 (s, 3H), 2.97-2.76 (m, 5H), 2.15-1.67 (m, 6H), 1.52-1.07 (m, 8H).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20]CC)=[O:19])=[CH:16][C:3]1=2.CO>O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:3]1=2
Reactant: CCOC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CN2
Solvent: O
Solvent: CO
Product: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CN2
Yield: 68.4 %

Procedure:
A mixture of ethyl 5,6-dihydro-11-oxodibenz[b,e]azepine-2-acetate (0.333 g), methanol (20 ml) sodium hydroxide (1 g) and water (20 ml) was heated under refluxing for 3 hours. After removal of the solvent by distillation, water was added to the mixture, and then, 5% sulfuric acid was added. The precipitated crystals were collected by filtration, washed in water, and dried to obtain 5,6-dihydro-11-oxodibenz[b,e]azepine-2-acetic acid (0.206 g). m.p.: 135°-145° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:7][C:5]=2[N:6]=1.[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(-c3ccccc3)ccc2o1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nc2cc(-c3ccccc3)ccc2o1
Yield: 32.3 %

Procedure:
2-Methyl-5-phenyl-benzoxazole 48 (1.05 g, 5.0 mmol), N-bromosuccinimide (89 mg, 5.0 mmol) and azodiisobutyronitrile (AIBN) (41 mg, 0.25 mmol) in 10 ml of CCl4 was heated to reflux. After 5 hrs an additional 50 mg AIBN were added and the mixture was refluxed overnight. The mixture was diluted, washed with water, dried and concentrated. The crude product was chromatographed to give about 465 mg 2-bromomethyl-5-phenyl-benzoxazole 49.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.C(N(CC)CC)C.[P:16](Cl)([Cl:19])([Cl:18])=[O:17]>CCOCC>[P:16]([Cl:19])([Cl:18])(=[O:17])[O:7][C:6]1[CH:5]=[CH:4][C:3]([Br:8])=[CH:2][CH:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=P(Cl)(Cl)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following the procedure described by McGuigan et al.,1993, Supra, a solution of p-bromophenol (13.20 g; 76.30 mmol) and distilled triethylamine (10.65 mL) in anhydrous Et2O (165 mL) was added dropwise into a vigorously stirred solution of phosphoryl chloride (8.5 mL; 91.2 mmol) in anhydrous Et2O (83 mL) at 0° C. over a period of three hours under nitrogen atmosphere. Subsequently, the resultant mixture was gradually warmed up to room temperature, stirred efficiently overnight at room temperature and then heated to reflux for two hours. The reaction mixture was cooled to room temperature and filtered under aspirator pressure. The precipitate was washed with anhydrous Et2O (2×50 mL). The combined Et2O layers were evaporated to dryness on rotary evaporator to yield crude 4c as a pale yellow oil which was then subjected to vacuum distillation to give pure 4c (14.05 g; 63.5 % yield) as a colorless viscous oil (bp. 110-115° C./2 mm Hg). IR (Neat) 3095, 1481, 1303, 1187, 948, 829 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.50 (2H, d, J=9.0 Hz), 7.15 (2H, d, J=9.0 Hz). GC/MS (m/e) 290 (M+), 254 (M+−Cl), 173 (M+−POCl2, 81Br), 171 (M+−POCl2, 79Br), 156 (M+−PO2Cl2, 81Br), 154 (M+−PO2Cl2, 79Br).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:31])[NH:23][C:24]2[S:25][C:26]([S:29][CH3:30])=[CH:27][N:28]=2)[CH:17]=1)(=[O:14])[CH3:13]>ClCCl>[C:12]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:31])[NH:23][C:24]2[S:25][C:26]([S:29]([CH3:30])=[O:9])=[CH:27][N:28]=2)[CH:17]=1)(=[O:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cnc(NC(=O)c2cccc(OC(C)=O)c2)s1
Solvent: ClCCl
Product: CC(=O)Oc1cccc(C(=O)Nc2ncc(S(C)=O)s2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 106.4 %

Procedure:
A solution of m-chloroperbenzoic acid (0.458 g, 2.04 mmol, maximum 77%) is dissolved in dichloromethane (8.0 mL) and added dropwise over 15 minutes to a solution of 516 (0.630 g, 2.04 mmol) dissolved in dichloromethane (25.0 mL). The reaction is stirred at room temperature for 6 hours. The reaction is then partitioned between dichloromethane and saturated aqueous sodium thiosulfate. The organic layer is washed again with a saturated aqueous sodium thiosulfate, twice with saturated aqueous sodium bicarbonate and once with brine. The dichloromethane layer is dried over magnesium sulfate and concentrated in vacuo to give crude 8 (0.704 g, >100%), which is contaminated with traces of residual 3-chlorobenzoic acid. The crude product is re-dissolved in ethyl acetate and washed three times with a saturated aq. sodium bicarbonate, dried using magnesium sulfate and concentrated in vacuo to give a tan solid. The residue is dissolved in THF, and the light brown solution was filtered through a plug of Magnesol. The filter pad is washed well with THF, and the colorless filtrate is concentrated in vacuo to give 8 as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH2:8][N:9]([CH2:27][CH2:28][NH:29][C:30]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:10]([NH:19]C(OC(C)(C)C)=O)=[N:11]C(OC(C)(C)C)=O.[C:49]1([C:55](Cl)([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:7][N:6]1[C:2]([NH:1][C:55]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[C:3]([CH2:8][N:9]([CH2:27][CH2:28][NH:29][C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:10]([NH2:19])=[NH:11])[CH:4]=[N:5]1
Reactant: Cn1ncc(CN(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cn1ncc(CN(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=N)N)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
To a solution of N-[(5-amino-1-methyl-1H-pyrazol-4-yl)methyl]-N′,N″-bis(tert-butoxycarbonyl)-N-[2-(tritylamino)ethyl]guanidine (1.84 g) in pyridine (10 ml) was added triphenylmethyl chloride (0.94 g), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added chloroform (50 ml). The mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 3% methanol/chloroform to give N′,N″-bis(tert-butoxycarbonyl{-N-([1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]methyl}-N-[2-(tritylamino)ethyl]guanidine (1.60 g) as a solid.
Reaction SMILES: [CH:1]([N-:3][CH:4]=[O:5])=[O:2].[Na+].C(#N)C.CN(C)C=O.Cl[CH2:16]/[C:17](=[CH:27]/[F:28])/[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1>O>[F:28]/[CH:27]=[C:17](\[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)/[CH2:16][N:3]([CH:4]=[O:5])[CH:1]=[O:2]
Reactant: O=C[N-]C=O
Reactant: F/C=C(/CCl)CCc1ccc(F)cc1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=CN(C=O)C/C(=C/F)CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Combine sodium diformylamide (28.8 g, 0.31 mol), acetonitrile (360 g), and N,N-dimethylformamide (48 g). Add (E)-1-chloro-2-(fluoromethylene)-4-(p-fluorophenyl)butane (50.6 g, 0.23 mol). Heat to reflux. After 5 hours, cool to ambient temperature. Add water (466 g) and stir for 15 minutes. After 30 minutes, the aqueous layer is removed. Evaporate the organic layer in vacuo to give the title compound. 1H NMR (CDCl3, 300 MHz) δ 2.28 (m, 2H), 2.72 (m, 2H), 4.07 (d, J=3 Hz, 2H), 6.74 (d, J=81 Hz, 1H), 6.94 (m, 2H), 7.13 (m, 2H), 8.73 (s, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[N:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:29]([CH:37]=O)[NH:28][C:27]=2[CH3:39])=[O:25])=[CH:19][CH:18]=1>>[N:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:30]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:29]([CH:37]=[C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[CH:15][C:7]=4[C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[NH:11][C:10]3=[O:16])[NH:28][C:27]=2[CH3:39])=[O:25])=[CH:19][CH:18]=1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: Cc1[nH]c(C=O)c(-c2ccccc2)c1C(=O)Nc1ccncc1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)c(-c2ccccc2)c1C(=O)Nc1ccncc1

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid pyridin-4-ylamide to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][NH:20][CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:8][C:9]([N:20]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[CH3:19])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CNCc1c[nH]c2ccccc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 73.2 %

Procedure:
N-(Benzyloxycarbonyloxy)succinimide (8.9 g, 35.7 mmole) was added to a solution of 3-(methylaminomethyl)-1H-indole (5.2 g, 32.5 mmole) and triethylamine (5.0 mL, 65.7 mmole) in DMF (100 mL) at RT. The reaction was stirred overnight then was concentrated in vacuo. The residue was diluted with water and the mixture was extracted with ethyl acetate. The combined extracts were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (33% ethyl acetate/hexanes) gave the title compound (7.0 g, 74%) as an off-white solid: MS (ES) m/e 295 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])([CH3:4])([CH3:3])[CH3:2].[CH3:29][C:30]1[O:34][C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:32][C:31]=1[CH2:41][CH2:42]OS(C1C=CC(C)=CC=1)(=O)=O.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:28])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:42][CH2:41][C:31]2[N:32]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:34][C:30]=2[CH3:29])=[CH:11][C:10]=1[CH2:16][N:17]1[C:18](=[O:27])[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]1=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1CN1C(=O)c2ccccc2C1=O
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CN2C(=O)c3ccccc3C2=O)c1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A 2 L 3-neck flask was charged with 3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-hydroxy-phenyl]-propionic acid tert-butyl ester (67.9 g, 0.178 mol), toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester (76.6 g, 0.214 mol) and DMF (680 mL). Cesium carbonate (75.4 g, 0.231 mol) was added, and the reaction mixture was heated at 55° C. for 18 h. After cooling, ethyl acetate (890 mL) and DI water (1200 mL) were added, the mixture was agitated, and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (740 mL). The organic layers were combined and washed with 1N NaOH (375 mL) then saturated NaCl solution (2×375 mL). The organic solution was dried (Na2SO4), filtered, and concentrated to an oil (107 g). The crude oil was dissolved in toluene (50 mL), and heptane was added (˜100 mL) until cloudiness remained even with agitation. The mixture was warmed to 50° C. on a rotary evaporator to yield a solution. Seed crystals were added, and rotation was continued at ambient temperature overnight. The product slurry was placed in the freezer overnight and filtered. The title compound was dried in a vacuum oven at 35° C. (71.4 g, 70.8%).
Reaction SMILES: ClC1C(Cl)=NC2C(=CC=C([N+]([O-])=O)C=2)N=1.Cl[C:17]1[C:26](Cl)=[N:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:28][CH3:29])[CH:23]=2)[N:18]=1.[K][S:31][C:32](=[C:35]([C:38]#[N:39])[C:36]#[N:37])[S:33][K]>>[CH3:29][O:28][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]1[S:31][C:32](=[C:35]([C:38]#[N:39])[C:36]#[N:37])[S:33][C:26]1=[N:25]2
Reactant: COc1ccc2nc(Cl)c(Cl)nc2c1
Reactant: N#CC(C#N)=C(S[K])S[K]
Agent: O=[N+]([O-])c1ccc2nc(Cl)c(Cl)nc2c1
Product: COc1ccc2nc3c(nc2c1)SC(=C(C#N)C#N)S3
Yield: 79 %

Procedure:
The process of Example 13 is followed except that the 2,3-dichloro-6-nitroquinoxaline is replaced by 0.75 g of 2,3-dichloro-6-methoxyquinoxaline and 0.90 g of the di(potassiomercapto)methylenemalononitrile is used. The recovered material is a dark yellow powder weighing 0.78 g with a calculated overall yield of 79 percent.
Reaction SMILES: [CH3:1][CH:2](O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:11]=[C:12]([N:15]([C:22]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:13][CH3:14].[C:33](=[O:36])([O-:35])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[C:28]([OH:30])(=[O:29])[C:33]([OH:35])=[O:36].[CH3:1][CH:2]([N:25]1[CH2:26][CH2:27][C:22]([N:15]([C:12](=[O:11])[CH2:13][CH3:14])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23][CH2:24]1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1(N(C(=O)CC)c2ccccc2)CCNCC1
Reactant: O=C([O-])[O-]
Reactant: CC(O)Cc1ccccc1
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)C1(N(C(=O)CC)c2ccccc2)CCN(C(C)Cc2ccccc2)CC1
Product: O=C(O)C(=O)O

Procedure:
A mixture of 3.54 parts of α-methylphenethyl alcohol, methanesulfonate ester, 4.6 parts of ethyl 4-[N-(1-oxopropyl)-N-phenylamino]-4-piperidinecarboxylate, 3.97 parts of sodium carbonate and 160 parts of 4-methyl-2-pentanone is stirred and refluxed for 16 hours. The reaction mixture is cooled and filtered. The filtrate is washed twice with 200 parts of water, dried, filtered and evaporated. The residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and 5% of methanol as eluent. The first fraction is collected and the eluent is evaporated. The residue is converted into the ethanedioate salt in 2-propanol. The whole is evaporated and the residual salt is crystallized from 80 parts of 4-methyl-2-pentanone. The product is filtered off and dried in vacuo at 120° C., yielding ethyl 1-(1-methyl-2-phenylethyl)-4-[N-(1-oxopropyl)-N-phenylamino]-4-piperidinecarboxylate ethanedioate; mp. 201.8° C.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[S:8])[NH:6][NH2:7])[CH:2]=[CH2:3].[Cl:9][CH2:10][C:11](=O)[C:12]([CH3:15])([CH3:14])[CH3:13]>>[ClH:9].[C:12]([C:11]1[N:4]([CH2:1][CH:2]=[CH2:3])[C:5](=[N:6][NH2:7])[S:8][CH:10]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)C(=O)CCl
Reactant: C=CCNC(=S)NN
Product: C=CCn1c(C(C)(C)C)csc1=NN
Product: Cl

Procedure:
From 4-(2-propenyl)-3-thiosemicarbazide and 1-chloro-3,3-dimethyl-2-butanone.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[C:8]([Cl:12])=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[CH3:13].[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>CN1C(=O)CCC1.O>[C:14]([NH:18][C:2]1[N:7]=[C:6]2[C:8]([Cl:12])=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[CH3:13])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)N
Reactant: Cc1nc2ccnc(Cl)c2nc1Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nc2ccnc(Cl)c2nc1NC(C)(C)C
Temperature: 60 °C
Yield: 11.8 %

Procedure:
A glass microwave reaction vessel was charged with 3,5-dichloro-2-methylpyrido[3,4-b]pyrazine (110 mg, 0.51 mmol) and tert-butylamine (0.16 mL, 1.54 mmol) (Sigma Aldich) in NMP (1.0 mL). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 60° C. for 2 h. The mixture was diluted with water and extracted with DCM (30 mL×3). The combined organic layers was washed with water (30 mL×3) and dried (MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography (10-30% EtOAc in Hexanes) to give N-(tert-butyl)-5-chloro-2-methylpyrido[3,4-b]pyrazin-3-amine (15 mg, 0.060 mmol, 11% yield). MS (ESI, pos. ion) m/z: 251.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[N:10])[CH2:4][CH2:3]1.[NH2:11][OH:12]>C(O)C>[OH:12][NH:11][C:9](=[NH:10])[CH2:8][N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCN(CC#N)CC1
Reactant: NO
Solvent: CCO
Product: CN1CCN(CC(=N)NO)CC1

Procedure:
A mixture (4-methylpiperazin-1-yl)acetonitrile (400 mg), hydroxylamine (50% aqueous solution, 2.0 mL) and ethanol (10.0 mL), was stirred at room temperature for 18 hours. The reaction mixture was evaporated to dryness to give a crystalline solid that was washed with hexane and dried under vacuum to give N-hydroxy-2-(4-methylpiperazin-1-yl)ethanimidamide (405 mg). 1H-NMR (400 MHz; CDCl3): 5.19 (br s, 3H), 3.00 (s, 2H), 2.75-2.28 (br m, 8H), 2.70 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:3]=1.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:7][C:8]([N:30]2[CH2:31][CH2:32][N:27]([C:25]3[S:24][N:23]=[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:26]=3)[CH2:28][CH2:29]2)=[O:15])[CH:3]=1
Reactant: Cc1cc(NC(=O)OCC(Cl)(Cl)Cl)no1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)no1
Temperature: 70 °C
Reaction time: 3 h
Yield: 43.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl (5-methylisoxazol-3-yl)carbamate (200 mg, 0.731 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.141 ml, 0.812 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to obtain the desired product (119 mg, 44.0%) as a solid.
Reaction SMILES: C([BH3-])#N.[Na+].C(#N)C.[C:8]([C:10]1[CH:26]=[CH:25][C:13]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[CH:18][CH:17]=2)=O)=[CH:12][CH:11]=1)#[N:9].C(OCC)(=O)C>CCCCCC>[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH2:14][C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[CH:18][CH:17]=2)=[CH:25][CH:26]=1)#[N:9]
Reactant: N#Cc1ccc(C(=O)c2ccc3ccccn23)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC#N
Product: N#Cc1ccc(Cc2ccc3ccccn23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.4 %

Procedure:
Sodium cyanoborohydride (0.32 grams, 5.06 mmol) was added in portions to an acetonitrile (15 mL) solution of 3-(4-cyanobenzoyl)indolizine (13) (0.19 grams, 0.84 mmol) and chlorotrimethylsilanen (0.65 mL, 5.06 mmol) cooled in an ice-bath. The reaction mixture was stirred at room temperature for 4 hours. It was then quenched with aqueous sodium bicarbonate solution, extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with water, dried over sodium sulfate and concentrated in vacuo to give an oily residue, which was applied to the flash column chromatography using 10% ethyl acetate in hexane (Rf 0.3) to afford 3-(4-cyanobenzyl)indolizine (14) (0.11 grams, 56% yield). 1H NMR (CDCl3) δ 4.09 (s, 2H), 6.36 (m, 2H), 6.56 (m, 2H), 7.15 (d, J=8.4, 2H), 7.32 (d, J=9.3, 1H), 7.45 (m, 3H). ESMS calcd (C16H12N2): 232.1. found: 233.1 (M+H)+.