Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[CH:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH:6]1[NH:15][C:16]([C:18]1[C:19](Cl)=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=1)=[O:17])[CH2:12]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[CH:5]12[CH2:12][CH:11]3[CH2:10][CH:9]([CH2:8][CH:7]([CH2:13]3)[CH:6]1[NH:15][C:16]([C:18]1[C:19]([S:4][CH2:1][CH2:2][CH3:3])=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=1)=[O:17])[CH2:14]2
Reactant: CCCS
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCSc1nc(Cl)ccc1C(=O)NC1C2CC3CC(C2)CC1C3
Temperature: 60 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
Propanethiol (1.45 mL, 16 mmol) was added to N-(2-adamantyl)-2,6-dichloro-pyridine-3-carboxamide (5.2 g, 16 mmol), and sodium carbonate (5.09 g, 48 mmol) in DMF (50 mL) at 20° C. under nitrogen. The resulting suspension was stirred at 60° C. for 3 hours. The reaction mixture was diluted with EtOAc (400 mL) and washed with water (3×50 mL), and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product which was recrystallised from 15% ethyl acetate/hexane to give N-(2-adamantyl)-6-chloro-2-propylsulfanyl-pyridine-3-carboxamide (4.9 g, 84%)
Reaction SMILES: C([Li])CCC.[Cl-].[Cl:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C@H:35]2[CH2:41][C@H:40]3[N:42]([CH3:43])[C@H:37]([CH2:38][CH2:39]3)[C@H:36]2[CH:44]=O)=[CH:31][CH:30]=1.O>CCOCC>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C@H:35]2[CH2:41][C@H:40]3[N:42]([CH3:43])[C@H:37]([CH2:38][CH2:39]3)[C@H:36]2/[CH:44]=[CH:8]/[Cl:7])=[CH:31][CH:30]=1
Reactant: CN1[C@H]2CC[C@@H]1[C@@H](C=O)[C@@H](c1ccc(Cl)cc1)C2
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CN1[C@H]2CC[C@@H]1[C@@H](/C=C/Cl)[C@@H](c1ccc(Cl)cc1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.5 %

Procedure:
A solution of butyllithium (0.32 mL, 2.5M in hexane, 0.68 mmol) was added to a stirred solution of chloromethyltriphenylphosphonium chloride (237 mg, 0.68 mmol) in dry EtzO (5 mL) at room temperature under N2 atmosphere. The resulting orange mixture was stirred for 30 min at that temperature, and then crude 3β-(4-chlorophenyl)-2β-formyltropane (60 mg, 0.23 mmol) in dry ether (4 mL) was added dropwise. The mixture was stirred at room temperature for 2 hr, cooled at 0° C., mixed with water (2 mL), and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude product was purified by flash column chromatography on silica gel saturated with NH3 eluting with hexane:ethyl acetate=1:1. Removal of the solvent gave 2d (14 mg, 20%); [α]D22 =-124° (c=0.52, CHCl3); IR (thin film) 3061, 2930, 2798, 1618, 1492, 941, 925 cm-1 ; 1H NMR (CDCl3, 300 MHz) δ 7.23 (d, 2H, J=8.5 Hz), 7 (d, 2H, J=8.5 Hz), 6.14 (dd, 1H, J=13.4, 10 Hz), 5.47 (d, 1H, J=13.4 Hz), 3.27 (s, 1H), 3.03 (m, 2H), 2.28 (m, 1H), 2.22 (s, 3H), 2.18-1.64 (m, 6H); 13C NMR (CDCl3, 75.46 MHz) 141.14, 133.88, 131.75, 129.34, 128.17, 117.55, 67.29, 61.99, 49.64, 41.96, 36.61, 34.50, 26.44, 24.98; mass spectrum, m/z 297 (M+, 37Cl), 195 (M+, 35Cl), 260, 218, 141, 97, 82.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:9][CH:8]2[CH:10]=[CH:11][S:12][CH:7]2[CH:6]=1)=[O:4].[C:13]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CC#N>C(N(CC)CC)C>[S:9]1[C:5]([C:3](=[O:4])[CH2:2][O:24][C:22]([CH:21]2[CH2:25][CH2:26][CH2:27][N:20]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:23])=[CH:6][CH:7]2[S:12][CH:11]=[CH:10][CH:8]12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(CBr)C1=CC2SC=CC2S1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)OCC(=O)C1=CC2SC=CC2S1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
Crude 2-Bromo-1-(3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl)-ethanone (2.48 mmol assuming complete conversion from starting material) was treated with Boc-proline and MeCN (25 mL). Triethylamine was added and the solution was stirred at RT for 1 h then concentrated. The crude residue was purified by silica column chromatography (14% to 35% EtOAc/Hex) to afford the title compound (595 mg, 61%).
Reaction SMILES: [NH:1]1[CH2:7][CH:6]([CH2:8][OH:9])[CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:10]([N:17]1[C:25]2[C:24](=[O:26])[N:23]([CH3:27])[C:22](=[O:28])[N:21]([CH3:29])[C:20]=2[N:19]=[C:18]1Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:10]([N:17]1[C:25]2[C:24](=[O:26])[N:23]([CH3:27])[C:22](=[O:28])[N:21]([CH3:29])[C:20]=2[N:19]=[C:18]1[N:1]1[CH2:7][CH:6]([CH2:8][OH:9])[CH2:5][NH:4][CH2:3][CH2:2]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCC1CNCCNC1
Reactant: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2)n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(N3CCNCC(CO)C3)n2Cc2ccccc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 1 %

Procedure:
([1,4]Diazepan-6-yl)methanol (1C) including potassium carbonate salts (ca 1 mmol) was suspended in dry DMF (200 ml) and 7-benzyl-8-chloro-1,3-dimethyl-3,7-dihydro-purine-2,6-dione (199.9 mg, 0.656 mmol) and potassium carbonate (453 mg, 3.28 mmol) were added. The reaction mixture was stirred at room temperature for 24 hours, heated to 60° C. for 3 hours, heated to 95° C. for 5 hours and heated to 120° C. for 2 hours. The suspension was allowed to cool to room temperature and white salts were filtered off. The filtrate was evaporated and purified by chromatography on silica, using 5% methanol in dichloromethane as the eluent. Fractions containing the product were evaporated and purified by preparative HPLC (method A2; Rt=2.52 min.) to afford 8 mg of the title compound as an yellow oil in 1% yield.
Reaction SMILES: BrC(Br)C.[CH:5]1[C:10]([CH2:11]Br)=[CH:9][CH:8]=[C:7]([C:13]#[N:14])[CH:6]=1.I[C:16]1[N:17]=[CH:18][N:19]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1>C1COCC1.[Zn]>[C:21]([N:19]1[CH:20]=[C:16]([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([C:13]#[N:14])=[CH:6][CH:5]=2)[N:17]=[CH:18]1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#Cc1ccc(CBr)cc1
Agent: CC(Br)Br
Agent: [Zn]
Solvent: C1CCOC1
Product: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 20 °C

Procedure:
To a suspension of activated zinc dust (3.57 g, 54.98 mmol) in THF (50 mL) was added dibromoethane (0.315 mL, 3.60 mmol) and the reaction stirred under argon at 20° C. The suspension was cooled to 0° C. and a-bromo-p-tolunitrile (9.33 g, 47.6 mmol) in THF (100 mL) was added dropwise over a period of 10 minutes. The reaction was then allowed to stir at 20° C. for 6 hours and bis(triphenylphosphine)Nickel II chloride (2.4 g, 3.64 mmol) and 4-iodo-1-tritylimidazole (15.95 g, 36.6 mmol, S. V. Ley, et al., J. Org. Chem. 56, 5739 (1991)) were added in one portion. The resulting mixture was stirred 16 hours at 20° C. and then quenched by addition of sat. aq. NH4Cl solution (100 mL) and the mixture stirred for 2 hours. Saturated aq. NaHCO3 solution was added to give a pH of 8 and the solution was extracted with EtOAc (2×250 mL), dried, (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 0-20% EtOAc in CH2Cl2 to afford the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:26]([O:33][CH2:34][N:35]1[C:39](=[O:40])[CH:38]([CH3:41])[NH:37][C:36]1=[O:42])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([O:33][CH2:34][N:35]1[C:39](=[O:40])[CH:38]([CH3:41])[N:37]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH:23]5[CH2:25][CH2:24]5)=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[C:36]1=[O:42])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC1NC(=O)N(COCc2ccccc2)C1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)N(COCc4ccccc4)C(=O)C3C)cc2)CC1
Yield: 64.6 %

Procedure:
Using (4-bromophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (320 mg) described in Preparation Example 185 and 3-benzyloxymethyl-5-methylimidazolidine-2,4-dione (225 mg) described in Preparation Example 206 and by the reaction and treatment in the same manner as in Example 536, the title compound (286 mg) was obtained.
Reaction SMILES: [CH2:1]([CH:3]1[C:12]2[C:7](=[N:8][C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=2)[NH:6][CH2:5][CH2:4]1)[CH3:2].O=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([CH:3]1[C:12]2[C:7](=[N:8][C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:11]=2)[N:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1CCNc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Reactant: CCOC(=O)CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)CCCCCCN1CCC(CC)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C

Procedure:
To a solution of rac-8-ethyl-2,3-diphenyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate HC)(13 mg, 0.041 mmol) in DCE (2 ml) was added ethyl 7-oxoheptanoate (24.84 mg, 0.144 mmol) followed by sodium triacetoxyborohydride (69.9 mg, 0.330 mmol). The reaction mixture was left to stir at room temperature under an atmosphere of nitrogen. Water (10 ml) was added and the resulting mixture was extracted with EtOAc (3×10 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The crude product was passed through a pre-conditioned Isolute SCX-2 SPE column loading with MeOH and eluting with 1M ammonia in MeOH (10 ml) to afford the title product;
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[N:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]=1[CH3:32])=[O:7])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[OH:4][CH2:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[N:13]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:12]=1[CH3:32])=[O:7]
Reactant: CC(=O)OCC(=O)NCCc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccccc2)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1c(CCNC(=O)CO)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccccc1
Temperature: 50 °C
Yield: 98 %

Procedure:
A solution of 2-(acetoxy)-N-[2-(1-phenyl-2-methyl-5-(4-methylsulphonylphenyl)-1H-pyrrol-3-yl)-ethyl]acetamide (0.95 g, 0.210 mmol) in methanol (10 mL) is treated with K2CO3 (0.58 g, 0.421 mmol) in water (10 mL). The reaction mixture is heated at 50° C. for 2 h, then it is concentrated and the residue is extracted with CH2Cl2. It is dried and concentrated, obtaining the product at yield of 98%. 1H NMR 400 MHz, CDCl3: δ 2.05 (s, 3H), 2.41 (s, 1H), 2.74 (t, J=4.00 Hz, 2H), 3.00 (s, 3H), 3.56-3.58 (m, 2H), 4.13 (s, 2H), 6.44 (s, 1H), 6.56 (s, 1H), 7.14-7.16 (m, 4H), 7.39-7.44 (m, 3H), 7.65 (d, J=8.00 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[C:4]=1[N+:20]([O-:22])=[O:21].[CH:23](O)=O>C=O>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][N:9]([CH3:23])[CH2:10][CH2:11][C:5]=2[C:4]=1[N+:20]([O-:22])=[O:21]
Reactant: COc1ccc2c(c1[N+](=O)[O-])CCNCC2c1ccccc1
Reactant: O=CO
Agent: C=O
Product: COc1ccc2c(c1[N+](=O)[O-])CCN(C)CC2c1ccccc1

Procedure:
0.40 g (0.00134 mol) 7-methoxy-6-nitro-1 -phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine was dissolved in a mixture of 5 ml formic acid and 4 ml 35% aqueous formaldehyde. The mixture was heated to reflux for 2.5 hours and then evaporated in vacuo. The residue was partitioned between dichloromethane and saturated NaHCO3-solution, the organic layer was washed twice with water and once with brine, dried with NaSO4 and concentrated in vacuo, yielding the compound as a light yellow oil.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([NH:25][CH3:26])[CH2:21][CH2:20]4)[CH:14]=3)[C:9]2=[O:27])=CC=1.CO>C(O)(C(F)(F)F)=O>[CH3:26][NH:25][C@H:22]1[CH2:23][CH2:24][C@H:19]([O:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:27])[NH:8][CH:17]=[CH:16]3)[CH2:20][CH2:21]1
Reactant: CNC1CCC(Oc2ccc3c(=O)n(Cc4ccc(OC)cc4)ccc3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CN[C@H]1CC[C@H](Oc2ccc3c(=O)[nH]ccc3c2)CC1
Temperature: 150 °C

Procedure:
2.46 g of 2-(4-methoxy-benzyl)-6-(4-methylamino-cyclohexyloxy)-2H-isoquinolin-1-one (151) were dissolved in 15 mL of TFA and heated in a microwave oven at 150° C. for 2 h. Methanol was added and the reaction mixture was evaporated. The solution was taken up in 1N HCl and extracted three times with dichloromethane. The combined dichloromethane layers were extracted with 1N HCl twice and the combined HCl layers were lyophilized, the residue was taken up in water and lyophilized again to yield 1.31 g of 6-(4-methylamino-cyclohexyloxy)-2H-isoquinolin-1-one (152) as hydrochloride. Rt=0.81 min (Method B). Detected mass: 273.2 (M+H+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9](=[O:22])[NH:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2.N1C=CC=CC=1.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>ClCCl>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9]([O:22][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCCC3C)nc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCCC3C)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-(2-methylpiperidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (520 mg, 1.73 mmol) in dichloromethane (60 ml) was added pyridine (690 mg, 8.72 mmol) followed by the addition of Tf2O (1.22 g, 4.32 mmol), and the resulting solution was stirred overnight at room temperature. The reaction was quenched by the addition of ice-water (200 ml) and extracted with dichloromethane (2×30 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford methyl 3-(2-methylpiperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (880 mg, crude).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22].CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1NCc1ccccc1
Reactant: COC(=O)CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC(=O)N(Cc1ccccc1)c1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of N-benzyl-2-nitroaniline (1.62 g, 7.1 mmol) and methyl 3-chloro-3-oxopropanoate (1.17 mg, 8.5 mmol), Et3N (1.8 g, 17.8 mmol) in 50 mL of CH2Cl2 was stirred at 80° C. for 2 days. The solvent was evaporated, and the residue was purified by combi-flash to give methyl 3-(benzyl(2-nitrophenyl)amino)-3-oxopropanoate as a yellow solid. LRMS (M+H)+: 328 m/z.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]([CH2:24][O:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C[CH2:33][N:34](CC)CC.N#CBr>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:15]([CH2:24][O:25][CH:26]3[CH2:27][CH2:28][N:29]([C:33]#[N:34])[CH2:30][CH2:31]3)=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(COC2CCNCC2)n1-c1ccc(F)cc1
Reactant: CCN(CC)CC
Agent: N#CBr
Solvent: ClCCl
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(COC2CCN(C#N)CC2)n1-c1ccc(F)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)methoxy)piperidine (prepared above) in anhyd DCM (2 mL) was added Et3N (37 uL, 0.27 mmol), followed by cyanic bromide (20 mg, 0.18 mmol). After stirring overnight, the reaction was diluted with DCM, washed with brine, dried over Na2SO4, and concentrated in vacuo to give 4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)methoxy)piperidine-1-carbonitrile as a white solid that was used directly for the next step.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[C:26]1([CH2:25][N:12]([C:10]2[O:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)[CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1cccc2ccccc12
Reactant: c1ccc(-c2cc(NCCCN3CCCCC3)on2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(-c2cc(N(CCCN3CCCCC3)Cc3cccc4ccccc34)on2)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 3-phenyl-isoxazol-5-yl-(3-piperidin-1-yl-propyl)amine (142.5 mg, 0.0005 m) in DMF (6 ml) was added 25 mg 60% sodium hydride in oil. The reaction foamed and turned yellow. After stirring for 5 minutes, 110.5 mg 1-(bromomethyl)naphthalene in DMF (3 ml) was added. The reaction turned from yellow to brown in color. The DMF was removed under reduced pressure. The oil was flash chromatographed using a 50 mm×6″ silica gel column with methylene chloride 95-methanol 5-ammonium hydroxide 0.5 as the solvent system. The product fractions were collected and concentrated to an oil. Add hexane/ether and remove under reduced pressure (2×s). Ethanol was added followed by 1M HCl in ether (1 ml). Remove the solvent. Add hexane/ether (2×s) to yield “title” as a foam. Dry under high vac. HPLC 95.43% at 215. Mass Spectra cal'd. 425.57; found 426.4. H NMR (CDCl3) 11.95-11.75(br,s,1H), 8.1-7.3(m, 12H), 5.6-5.4(s,1H), 5.2-4.8(s,2H), 3.6-3.4(br,2H)3.35-3.15(br,2H), 2.7-2.5(br, 2H),2.3-2.0(br,6H.)
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.Cl[C:16]1[N:21]=[C:20]([Cl:22])[CH:19]=[C:18]([O:23][CH3:24])[N:17]=1>C(OCC)C.CCCCCC>[Cl:22][C:20]1[CH:19]=[C:18]([O:23][CH3:24])[N:17]=[C:16]([C:5]2[S:4][C:3]([C:2]([F:9])([F:8])[F:1])=[CH:7][CH:6]=2)[N:21]=1
Reactant: FC(F)(F)c1cccs1
Reactant: COc1cc(Cl)nc(Cl)n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cc(Cl)nc(-c2ccc(C(F)(F)F)s2)n1
Temperature: -40 °C

Procedure:
2.05 g 2-Trifluoromethylthiophene in 20 mL diethylether are treated with 8.2 mL of a 1.6 M solution of n-butyllithium in hexane at -70° C. After 30 minutes the mixture is warmed to -40° C. and added dropwise to a solution of 2,4-dichloro-6-methoxypyrimidine in 20 mL of ether, which is kept at 0° C. The mixture is allowed to reach room temperature, is washed with water and 0.24 g of the product are isolated as an oil after flash chromatography.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:16]=[CH:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N:12]([C:21](=[O:25])[CH:22](Br)[CH3:23])[C:11]=2[CH:26]=1)([O:3][CH2:4][CH3:5])=[O:2].[CH3:27][NH2:28]>C(O)C>[C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:16]=[CH:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N:12]([C:21](=[O:25])[CH:22]([NH:28][CH3:27])[CH3:23])[C:11]=2[CH:26]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CN
Reactant: CCOC(=O)Nc1ccc2c(c1)N(C(=O)C(C)Br)c1ccccc1C=C2
Solvent: CCO
Product: CCOC(=O)Nc1ccc2c(c1)N(C(=O)C(C)NC)c1ccccc1C=C2
Temperature: 4 °C

Procedure:
3-Carbethoxyamino-5-(α-bromopropionyl)-5H-dibenz[b,f]-azepine (10 g) is mixed with 15 ml of approximately 35% aqueous methylamine solution and 75 ml of ethanol and heated in a laboratory autoclave for 12 hours at 90° to 95° C. After cooling to 4° C., the formed precipitate is filtered off with suction, mixed with 50 ml of acetone and then, again filtered off with suction and dried. 3-Carbethoxyamino-5-(α-methylaminopropionyl)-5H-dibenz[b,f]azepine (7 g) is obtained, which can be purified by being dissolved in dilute hydrochloric acid and precipitated with concentrated ammonia solution. The purified compounds melts at 217° to 219° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:7](=[O:14])[N:8]([CH2:9][C:10](OC)=[O:11])[C:4]=2[C:3]=1[N+:22]([O-])=O>CC(O)=O.O.[Fe]>[Cl:1][C:2]1[C:3]2[NH:22][C:10](=[O:11])[CH2:9][N:8]3[C:7](=[O:14])[N:6]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:5]([C:4]=23)=[CH:20][CH:21]=1
Reactant: COC(=O)Cn1c(=O)n(CC(=O)OC)c2c([N+](=O)[O-])c(Cl)ccc21
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)Cn1c(=O)n2c3c(c(Cl)ccc31)NC(=O)C2
Temperature: 70 °C

Procedure:
To a solution of dimethyl 2,2′-(5-chloro-4-nitro-2-oxo-1H-benzimidazole-1,3-diyl)diacetate (100 mg, 0.28 mmol) from Step D in AcOH (1.0 mL) and water (0.1 mL) was added fine granular iron (78 mg, 1.4 mmol) and the slurry was heated at 70° C. for 1 h. The reaction was cooled, filtered, concentrated and dissolved in DMF (4 mL). The DMF solution was added dropwise to H2O (30 mL) with stirring and the precipitate was isolated by filtration to give the title compound. MS: m/z=296 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]([CH2:12][CH:13]=[CH:14][OH:15])=[C:10]([Cl:16])[N:9]=[C:8]2[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1.[C:23]1(=[O:33])[O:28][C:26](=[O:27])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12>C(Cl)(Cl)Cl.CCOCC>[C:26]([C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]([CH2:12][CH:13]=[CH:14][OH:15])=[C:10]([Cl:16])[N:9]=[C:8]2[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:21][CH:22]=1)=[O:33])([OH:28])=[O:27]
Reactant: CCCCc1nc(Cl)c(CC=CO)n1Cc1ccc(N)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCCCc1nc(Cl)c(CC=CO)n1Cc1ccc(NC(=O)c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 95 mg of 3-[1-(4-aminobenzyl)-2-butyl-4-chloroimidazol-5-yl]propen-1-ol in 2 mL of CHCl3 was added 45 mg of phthalic anhydride and the mixture was stirred at room temperature for 1 hour. During this period of time the initially clear solution because turbid and produced solid. The reaction mixture was diluted with 2 mL of ether and the solid was collected by filtration and washed with ether. The desired product was obtained as a tan solid, 115 mg, m.p. 150°-151°; NMR (10% DMSO-d6CDCl3); δ 9.94 (s, 1h); 7.71 and 6.93 (d, 4H, J=8.3 Hz); 6.36 (m, 2H); 5.1 (s, 2H); 4.18 (d, 2H, J=3.9 Hz); 2.6 (t, 3H, J=7.4 Hz); 1.68 (m, 2H); 1.34 (m, 2H); 0.89 (t, 3H, J=7.4 Hz).