Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:33][CH2:34][O:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:33][CH2:34][O:35][CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1
Reactant: Oc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1ccc(-c2nn3c(c2-c2ccnc4cc(OCCOC5CCCCO5)ccc24)CCC3)nc1
Yield: 81 %

Procedure:
Heat 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol (376 mg, 1.146 mmol), cesium carbonate (826 mg, 2.54 mmol), and 2-(2-bromoethoxy)tetrahydro-2H-pyran (380 μL, 2.52 mmol) in DMF (5 mL) at 120° C. for 4 hours. Quench the reaction with saturated sodium chloride and then extract with chloroform. Dry the organic layer over sodium sulfate and concentrate in vacuo. Purify the reaction mixture on a silica gel column eluting with dichloromethane to 10% methanol in dichloromethane to give the desired subtitled intermediate as a yellow oil (424 mg, 81%). MS ES+m/e 457.0 (M+1).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>COCCOC>[Cl:3][C:2]1[N:1]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:4]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C1COCCN1
Solvent: COCCOC
Product: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
Cyanuric chloride (3.63 g, 19.7 mmol) was dissolved in ethylene glycol dimethyl ether (50 ml), cooled to -10° C.-0° C. and gradually added dropwise with morpholine (7.00 ml, 80.3 mmol) dissolved in ethylene glycol dimethyl ether (27 ml). This reaction mixture was stirred at the same temperature for 30 minutes and then stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure. The residue was added with dichloromethane and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography, using dichloromethane and ethyl acetate (8:2) as eluant, to obtain 5.13 g (yield: 91.2%) of 2-chloro-4,6-dimorpholino-1,3,5-triazine as colorless crystals having melting point of 173.5° C.-174° C.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:54](=[O:55])[N:6]2[C:7]([C:41]([O:43]CC3C=CC([N+]([O-])=O)=CC=3)=[O:42])=[C:8]([S:11][C@@H:12]3[CH2:16][N:15](C(OCC4C=CC([N+]([O-])=O)=CC=4)=O)[C@H:14]([C:30]([N:32]4[CH2:35][CH:34]([N:36]5[CH:40]=[CH:39][N:38]=[CH:37]5)[CH2:33]4)=[O:31])[CH2:13]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[H][H]>O1CCCC1.O.[Pd]>[OH:1][C@@H:2]([C@H:4]1[C:54](=[O:55])[N:6]2[C:7]([C:41]([OH:43])=[O:42])=[C:8]([S:11][C@@H:12]3[CH2:16][NH:15][C@H:14]([C:30]([N:32]4[CH2:33][CH:34]([N:36]5[CH:40]=[CH:39][N:38]=[CH:37]5)[CH2:35]4)=[O:31])[CH2:13]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC(n5ccnc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CC(n5ccnc5)C4)C3)[C@H](C)[C@H]12

Procedure:
0.25 g of 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(2S,4S)-2-[3-(1-imidazolyl)azetidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (1) above] was dissolved in a mixture of 7.5 ml of tetrahydrofuran and 7.5 ml of water, and 0.25 g of a 10% w/w palladium-on-carbon catalyst was added to the resulting solution, after which the mixture was hydrogenated at room temperture for 1.5 hours in an atmosphere of hydrogen. At the end of this time, the catalyst was removed by filtration and the filtrate was washed with diethyl ether. The resulting aqueous layer was then concentrated by evaporation under reduced pressure, and the residue was subjected to reverse phase column chromatography (Cosmosil 75C18 -prep, 30 g, manufactured by Nacalai Tesque). Of the fractions obtained by elution with 7% by volume aqueous acetonitrile, the fraction containing the title compound was concentrated by evaporation under reduced pressure and freeze-dried, to obtain 70 mg of the title compound as a powder.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:30]=[CH:29][C:7]([CH2:8][CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[Li]CCCC.[C:36]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH:47]([CH3:50])[CH:48]=O)=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]>>[C:36]([C:40]1[CH:41]=[CH:42][C:43]([CH2:46][CH:47]([CH3:50])[CH:48]=[CH:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:30][CH:29]=2)=[CH:44][CH:45]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Reactant: COc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: COc1ccc(CC=CC(C)Cc2ccc(C(C)(C)C)cc2)cc1
Yield: 51.1 %

Procedure:
Starting from p-methoxyphenethyltriphenylphosphonium bromide (3.10 g, 6.49 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 4.1 mL, 6.49 mmol, 1.0 equiv.) and 3-(4-tert-butylphenyl)-2-methylpropanal (1.99 g, 9.74 mmol, 1.5 equiv.), 1.07 g (44%) of the title compound as a light yellow oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][CH:3]=1.[Br:13]Br>C(Cl)(Cl)Cl>[Br:13][C:3]1[N:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:6][C:2]=1[Br:1]
Reactant: BrBr
Reactant: Brc1cnc(-c2ccccc2)s1
Solvent: ClC(Cl)Cl
Product: Brc1nc(-c2ccccc2)sc1Br
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
Compound 18 (5.0 g, 21 mmol) was dissolved in CHCl3 (250 mL). Br2 (16.7 g, 105 mmol) was dissolved in CHCl3 (50 mL) and added to the solution of 18 via addition funnel over 10 minutes. The reaction mixture stirred at room temperature for 5.5 hours; then was transferred to a 1 L separatory funnel and washed with Na2S2O3 (3×100 mL) followed by brine (2×150 mL). The organic fractions were dried over MgSO4 and concentrated. The crude product was purified by column (2:1 hexanes/CHCl3). 1H NMR (600 MHz, CDCl3) δ 7.85 (d, J=7.3, 2H), 7.50-7.40 (m, 3H).
Reaction SMILES: C[N:2]1[C:7]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:6]=2[C:5](=[O:15])O[C:3]1=O.C(O)C.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.C(N(CC)CC)C>[CH3:3][NH:2][C:7]1[S:8][C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:6]=1[C:5]([NH:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23])=[O:15]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: Cn1c(=O)oc(=O)c2c3c(sc21)CCCC3
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CNc1sc2c(c1C(=O)N[C@@H](C)c1ccc(C(=O)OC)cc1)CCCC2
Temperature: 25 °C

Procedure:
To 1-methyl-5,6,7,8-tetrahydro-2H-[1]benzothieno[2,3-d][1,3]oxazine-2,4(1H)-dione (0.50 g) was added ethanol (20 mL), and triethylamine (0.44 mL) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride were sequentially added, followed by heating with reflux for 18 hours. The reaction mixture was cooled to room temperature, and a 10% aqueous citric acid solution (15 mL) was added thereto. To a mixture was added ethyl acetate, followed by washing with water, and the obtained organic layer was dried over anhydrous sodium sulfate. After filtering and concentrating under reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate: 90/10-75/25) to obtain methyl 4-[(1S)-1-({[2-(methylamino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)ethyl]benzoate (0.42 g).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH3:19])[C:4]=1[S:20][CH:21]([CH3:23])[CH3:22].C1C=C(Cl)C=C(C(OO)=[O:33])C=1.C1C=C(Cl)C=C(C(O)=O)C=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH3:19])[C:4]=1[S:20]([CH:21]([CH3:22])[CH3:23])=[O:33]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(SC(C)C)c1CC
Agent: O=C(O)c1cccc(Cl)c1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(S(=O)C(C)C)c1CC

Procedure:
Prepared from product of Example 11 (5.89 g, 15.86 mmol) and MCPBA (3.22 g of an 85% mixture with MCBA, 15.86 mmol) as described above. Recrystallization (ether/petroleum ether) afforded the product as a white solid (6.2 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:12]=[C:13]([NH:27][C@H:28]([CH3:31])[CH2:29][OH:30])[C:14]2[S:19][C:18](=[O:20])[N:17](C3CCCCO3)[C:15]=2[N:16]=1.Cl>C(#N)C.O.O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:12]=[C:13]([NH:27][C@H:28]([CH3:31])[CH2:29][OH:30])[C:14]2[S:19][C:18](=[O:20])[NH:17][C:15]=2[N:16]=1
Reactant: C[C@H](CO)Nc1nc(SCc2cccc(F)c2F)nc2c1sc(=O)n2C1CCCCO1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: C[C@H](CO)Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(=O)sc12
Temperature: 25 °C
Yield: 94.9 %

Procedure:
To a stirred solution of 5-[[(2,3-difluorophenyl)methyl]thio]-7-[[(1R)-2-hydroxy-1-methylethyl]amino]-3-(tetrahydro-2H-pyran-2-yl)thiazolo[4,5-d]pyrimidin-2-(3H)-one (10.0 g) in acetonitrile (200 ml), water (36 ml) and tetrahydrofuran (30 ml) at 65° C. was added 1M hydrochloric acid (23.25 ml) over 3 hours. The product crystallised during the addition time. The mixture was cooled to 25° C. and the product collected by filtration, washing firstly with water (30 ml) then acetonitrile (30 ml), to afford the title compound as an off-white solid (7.79 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:10][CH:11]1[CH2:17][C:16]2[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:15]=2[CH2:14][CH2:13][CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23][CH2:24][CH2:25]Br.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:3]([NH:10][CH:11]1[CH2:12][CH2:13][CH2:14][C:15]2[CH:21]=[CH:20][C:19]([O:22][CH:24]([CH3:25])[CH3:23])=[CH:18][C:16]=2[CH2:17]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCBr
Reactant: Oc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Reaction time: 0.5 h

Procedure:
Under nitrogen, to a suspension of sodium hydride (60% in oil, 47 mg) in N,N-dimethylformamide (3 ml) was dropwise added 8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (300 mg) in N,N-dimethylformamide (2 ml) at 5° C., and the mixture was stirred at the same temperature for 30 minutes. To this one was added n-propyl bromide (0.10 ml), and the mixture was stirred at the same temperature for 3 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate =50:1 to 30:1) to give N-benzyl-(3-isopropoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (278 mg)
Reaction SMILES: [O:1]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][CH2:16][C:17](Cl)=[O:18].C(N(CC)C(=O)COC1C=CC(C(=O)CCl)=CC=1)C>>[Cl:15][CH2:16][C:17]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][CH:4]=1)=[O:18]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)C(C)Oc1ccccc1
Agent: CCN(CC)C(=O)COc1ccc(C(=O)CCl)cc1
Product: CCOC(=O)C(C)Oc1ccc(C(=O)CCl)cc1

Procedure:
Ethyl 2-phenoxypropionate was reacted with chloroacetyl chloride as described for N,N-diethyl-4-(chloroacetyl)phenoxyacetamide, used as a starting material for Example 7, to give ethyl 2-[4-(chloroacetyl)phenoxy]-propionate as a white solid, having a satisfactory analysis (found: C, 57.7, H, 5.5, N, 13.0; required: C, 57.7; H, 5.6; N, 13.1).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:55][CH2:56][N:57]1[CH:61]=[CH:60][N:59]=[C:58]1[CH3:62]>C(Cl)Cl.CCOCC>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:55][CH2:56][N:57]4[CH:61]=[CH:60][N:59]=[C:58]4[CH3:62])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: Cc1nccn1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCn1ccnc1C
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 155.1 %

Procedure:
Diethyl azodicarboxylate (261 mg, 1.5 mmol) was added dropwise to a suspension of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5 mmol), (prepared as described for the starting material in Example 24), triphenylphosphine (393 mg, 1.5 mmol) and 1-(2-hydroxyethyl)-2-methylimidazole (88 mg, 0.7 mmol), (Chem.Abs. 1964, 60, 2949), in methylene chloride (8 ml) and the mixture stirred for 2 hours at ambient temperature. The mixture was diluted with ether (8 ml) and the solid product was collected by filtration. The solid was dissolved in methylene chloride/methanol and a solution of 3M ethereal hydrogen chloride (0.5 ml)was added. The resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-methylimidazol-1-yl)ethoxy)quinazoline hydrochloride (180 mg, 72%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH2:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:10]([CH3:12])[CH3:11].[S:19](=[O:23])(=[O:22])([OH:21])[OH:20].[NH4+].[NH4+].[O-]S(OOS([O-])(=O)=O)(=O)=O>O>[S:19]([O-:23])([OH:22])(=[O:21])=[O:20].[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([I+:1][C:16]2[CH:17]=[CH:18][C:13]([CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:14][CH:15]=2)=[CH:3][CH:4]=1
Reactant: CC(C)Cc1ccccc1
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(I)cc1
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: Cc1ccc([I+]c2ccc(CC(C)C)cc2)cc1
Product: O=S(=O)([O-])O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.9 g (54.8 mmol) of 4-iodotoluene and 9.2 g (68.5 mmol) of isobutylbenzene are added dropwise to a solution of 35 ml of conc. sulfuric acid and 22 ml of water under cooling by an ice bath. 25 g of ammonium peroxodisulfate are added by portions to the solution under cooling by an ice-salt bath, keeping the temperature below 0° C. for 1 hour. The reaction mixture is stirred overnight and the temperature is gradually raised to room temperature during the course of the reaction. After cooling the reaction mixture by ice an bath, 118 ml of water are added. The product is extracted with methylene chloride, and the organic layer is washed with water, dried over MgSO4, and concentrated, yielding (4-methylphenyl)(4′-isobutylphenyl)iodonium hydrogensulfate as a brown solid. The crude (4-methylphenyl)(4′-isobutylphenyl)iodonium hydrogensulfate is used in the next step without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([Cl:18])=[N:10][N:9]=1.[C:19]([O:23][C:24](=[O:33])[N:25]([CH3:32])[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].O>CN1CCCC1>[Cl:18][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([N:29]2[CH2:28][CH2:27][CH:26]([N:25]([CH3:32])[C:24](=[O:33])[O:23][C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:31][CH2:30]2)=[N:9][N:10]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2nnc(Cl)c3ccccc23)CC1
Yield: 36.6 %

Procedure:
Heat a mixture of potassium carbonate (21.23 g, 153 6 mmol), 1,4-dichlorophthalazine (26 g, 128 mmol) and methyl-piperidin-4-yl carbamic acid tert-butyl ester (30.01 g, 134.4 mmol) in N-methylpyrrolidine (200 mL) at 80° C. overnight. Pour the reaction mixture into water, extract with dichloromethane, dry over Na2SO4, and concentrate under reduced pressure. Add diethylether and filter off the resulting solid (4-chlorophethalazin-1-ol from starting material impurity). Concentrate the filtrate. Purify the resulting residue by flash silica gel chromatography (hexane:ethyl acetate=2:1) to provide the title compound as a white solid (17.66 g, 37%). ES/MS m/z (37Cl) 377.0 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]#[N:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.Cl.[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].C(N(CC)CC)C>CCO>[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][C:2]1[N:7]=[C:6]([S:8][C:9]#[N:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1
Reactant: NCc1ccccc1Br
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#CSc1nc(NCc2ccccc2Br)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
2-Chloro-5-nitro-4-thiocyanatopyrimidine (100 mg, 0.46 mmol) was suspended in 1 mL absolute EtOH. o-Bromobenzylamine hydrochloride (103 mg, 0.46 mmol) was dissolved in 1 mL absolute EtOH and added to the reaction quickly at ambient temperature. Then triethylamine (129 μL, 0.92 mmol) was added dropwise via syringe. The reaction was stirred 16 h at ambient temperature. The resulting precipitate was filtered providing 136 mg of the desired (2-bromo-benzyl)-(5-nitro-4-thiocyanato-pyrimidin-2-yl)-amine as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C@@H:7]([OH:10])[CH2:8][OH:9])[CH2:3][CH2:2]1.N1C(C)=CC=CC=1C.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].[NH4+].[Cl-]>C(Cl)Cl>[Si:19]([O:9][CH2:8][C@@H:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[OH:10])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: OC[C@H](O)C1CCOCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H](O)C1CCOCC1
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of (1R)-1-tetrahydro-2H-pyran-4-ylethane-1,2-diol (2.40 g, 16.2 mmol) in 60 mL of CH2Cl2 was cooled to 0° C. under N2. 2,6-Lutidine (3.77 mL, 32.4 mmol) and tert-butyldimethylsilyl chloride (2.57 g, 17.0 mmol) were added and the reaction mixture was stirred and allowed to warm to ambient temperature overnight. The reaction mixture was treated with saturated aqueous NH4Cl solution and the layers were separated. The organic portion was washed successively with aqueous 3.5% NaH2PO4 solution (2×), H2O and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 20% ethyl acetate/hexanes) gave 3.29 g of (1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-tetrahydro-2H-pyran-4-ylethanol as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:15]([OH:17])[CH3:16]>CN(C)C=O>[CH2:15]([O:17][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1)[CH3:16]
Reactant: CCO
Reactant: CNc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc([N+](=O)[O-])c(NC)n1

Procedure:
A procedure similar to that described in Preparation 88 was repeated, except that 6.00 g of 6-chloro-2-methylamino-3-nitropyridine (prepared as described in Preparation 66), 1.54 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 2.1 ml of ethanol and 150 ml of dimethylformamide were used. After working up the product as described in Preparation 88, the resulting crude product was crystallized by trituration with ethanol, to give 5.10 g of the title compound, melting at 101° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:58][S:59](Cl)(=[O:61])=[O:60]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH2:16][O:17][S:59]([CH3:58])(=[O:61])=[O:60])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CO)c4)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(COS(C)(=O)=O)c4)c4ccccc43)cn12
Reaction time: 3 h
Yield: 100 %

Procedure:
To an ice-bath cooled solution of Intermediate 167a (316 mg, 0.49 mmol) in DCM (5.0 mL) was added DIPEA (339 μL, 1.95 mmol) followed by methanesulfonyl chloride (76 μL, 0.97 mmol). The reaction mixture was stirred for 3 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative, assumed 0.49 mmol). The isolated product was used in the following step without further purification. LCMS (Method 4): Rt 3.61 min, m/z 727 [MH+].
Reaction SMILES: [ClH:1].[CH2:2]([NH:4][CH:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)[CH3:3].C(O)C.[OH-].[K+].Cl>CCOCC>[ClH:1].[ClH:1].[NH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][CH:5]([NH:4][CH2:2][CH3:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCNC(Cc1ccccc1[N+](=O)[O-])c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CCNC(Cc1ccccc1N)c1ccccc1
Reaction time: 3 h

Procedure:
3.00 g of N-Ethyl-2-nitro-α-phenylphenethylamine hydrochloride is treated with 100 ml of hot 95% ethanol containing 1.10 g of potassium hydroxide for 15 minutes, after which the mixture is filtered and placed in a Paar flask. 0.15 g of 10% palladium on charcoal is added and the mixture is hydrogenated at room temperature and 50 psia for 3 hours, after which the catalyst is removed. The ethanol is evaporated from the filtrate and the resulting yellow oil is poured onto 100 ml of water. The biphasic aqueous mixture is extracted with methylene chloride (2×100 ml). The combined methylene chloride extracts are dried over anhydrous magnesium sulfate and the methylene chloride evaporated to afford a colorless oil. The oil is dissolved in 50 ml of ether. Ethereal hydrogen chloride (100 ml) is added precipitating the hydrochloride acid salt as an oil. The ethanol is evaporated and the oil is dissolved in 20 ml of i-propanol with heating. Upon cooling, white crystals, mp >248° C. dec, fell from solution providing 2-amino-N-ethyl α-phenylphenethylamine dihydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:19])=CC=1>O1CCCC1>[NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[S:19])[NH2:9]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1sccc1N
Solvent: C1CCOC1
Product: NC(=S)c1sccc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.1 %

Procedure:
A solution of 3-aminothiophene-2-carboxamide (4.5 g, 31 mmol) in tetrahydrofuran was treated with Lawesson's Reagent (7.7 g, 190 mmol) and the solution was stirred at room temperature for 18 h. The solvent was removed and the residue purified by chromatography on silica gel using dichloromethane as eluent. The product was obtained as a yellow powder (2.8 g, 56%), m.p. 98-99° C.