Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH3:8][C:9]1([CH3:37])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](O)=[O:20])[CH:17]=2)[NH:12][CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=[O:36])[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:23]=2)[CH2:10]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:3][S:4]([NH:7][C:19]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[C:28]([NH:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:36])[CH2:10][C:9]2([CH3:37])[CH3:8])=[O:20])(=[O:6])=[O:5]
Reactant: CS(N)(=O)=O
Reactant: CC1(C)CC(c2cccc(C(=O)Nc3ccccc3)c2)Nc2ccc(C(=O)O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2cccc(C(=O)Nc3ccccc3)c2)Nc2ccc(C(=O)NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.3 %

Procedure:
To a suspension of 60% sodium hydride (198 mg, 4.95 mmol) in N,N-dimethylformamide (2 mL) was added methanesulfonamide (475 mg, 5 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A20. A solution of 4,4-dimethyl-2-(3-phenylcarbamoyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (400 mg, 1 mmol) and 1,1′-carbonyldiimidazole (324 mg, 2 mmol) in N,N-dimethylformamide (2 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B20. Solution B20 was added to Solution A20 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3-(6-methanesulfonylaminocarbonyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-N-phenyl-benzamide (35 mg, 7%) as a white solid: MS (ESI) M+1=478.2.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=O)[N:9]3[CH2:21][CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3C(O)=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH2:23]>CN(C)C=O>[Br:1][C:2]1[C:7]2[CH2:8][N:9]3[CH2:21][CH2:20][CH2:19][C@H:10]3[CH:11]3[C:15](=[O:23])[N:14]=[CH:13][N:12]3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: O=C(O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Solvent: CN(C)C=O
Product: O=C1N=CN2c3cccc(Br)c3CN3CCC[C@H]3C12
Reaction time: 0.5 h

Procedure:
109.03 g (300 mmol) of (S)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid was decarboxylated at 290°. The melt was dissolved in about 400 ml of N,N-dimethylformamide and the solution was poured into 2.5 l of water. After stirring for 30 minutes the precipitated product was filtered off, rinsed with water and dried. There was obtained (S)-8-bromo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-one of melting point 232°-233°.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:8]1[O:12][CH:11]([N:13]2[CH:18]=[CH:17][C:16]([N:19]=[CH:20][N:21]([CH3:23])[CH3:22])=[N:15][C:14]2=[O:24])[C:10]([OH:26])([CH3:25])[CH:9]1[OH:27])([CH3:4])([CH3:3])[CH3:2].[C:40]([NH:47][C@H:48]([C:52](O)=[O:53])[CH:49]([CH3:51])[CH3:50])([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[C:1]([SiH2:5][O:6][C:7]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH:8]1[CH:9]([O:27][C:52](=[O:53])[CH:48]([NH:47][C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[CH:49]([CH3:51])[CH3:50])[C:10]([OH:26])([CH3:25])[CH:11]([N:13]2[CH:18]=[CH:17][C:16]([N:19]=[CH:20][N:21]([CH3:22])[CH3:23])=[N:15][C:14]2=[O:24])[O:12]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=Nc1ccn(C2OC(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)C(O)C2(C)O)c(=O)n1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OC1C(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2ccc(N=CN(C)C)nc2=O)C1(C)O

Procedure:
In another method to synthesize the compounds of the invention, shown in FIG. 1b, benzoylcytosine, BSA and SnCl4/acetonitrile are reacted with 1,2,3,5-tetra-O-benzoyl-2-C-methyl-β-D-ribofuranose (1) to form 4-benzoylamino-1-(3,4-dibenzoyloxy-5-benzoyloxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (2a); reacting (2a) with NH3 in methanol and chromatographically separating the product, 4-amino-1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (3), also known as β-D-2′-C-methyl-cytidine; reacting (3) with Me2NCH(OMe)2 in DMF at room temperature for 1.5 hours to form N-[1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine (4); reacting (4) with TBDPSCl and pyridine at room temperature for 6 hours to provide N′-{1-[5-(tert-butyl-diphenyl-silanyloxymethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2yl]-2-oxo-1,2-dihydro-pyrimidin-4-yl}-N,N-dimethyl-formamidine (5); reacting (5) with N-Boc-L-valine, DEC and DMAP in THF/DMF at room temperature for 2 days and subjecting the product formed from this reaction to HPLC in order to provide 2-tert-butoxycarbonylamino-3-methyl-butyric acid 2-(tert-butyl-diphenyl-silanyloxy-methyl)-5-[4-(dimethylaminomethyleneamino)-2-oxo-2H-pyrimidin-1-yl]-4-hydroxy-4-methyl-tetrahydro-furan-3-yl ester (6); refluxing (6) with NH4F in MeOH for about 3 hours to remove the silyl and amino-protecting groups, and subjecting the product to chromatographic purification to provide 2-tert-butoxycarbonylamino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester (7); and finally reacting (7) with HCl in EtOAc at room temperature to provide 2-amino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester, dihydrochloride salt (8) as a final product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15](Br)=[CH:16][CH:17]=2)[C:12]([CH3:20])=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C.C([Li])CCC>C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([B:21]([OH:26])[OH:22])=[CH:16][CH:17]=2)[C:12]([CH3:20])=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1nn(COCc2ccccc2)c2ccc(Br)cc12
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nn(COCc2ccccc2)c2ccc(B(O)O)cc12
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 72.8 %

Procedure:
To a −78° C. stirred solution of the compound from step A (0.72 g, 2.18 mmol) in anhydrous toluene/THF (5 mL/3 mL) under nitrogen was added triisopropyl borate (0.53 g, 2.83 mmol) and then butyl lithium (2.5 M in hexanes, 1.22 mL, 3.05 mmol) slowly over about 10 min. After 10 min the dry ice bath was removed and stirring was continued for 20 min. The mixture was cooled at −78° C. and triisopropyl borate (0.32 g, 1.71 mmol) and butyl lithium (2.5 M in hexanes, 0.85 mL, 2.14 mmol) were added. The dry ice bath was removed and the mixture was allowed to warm to ambient temperature and was stirred for additional 20 min before quenching with a saturated solution of sodium bicarbonate (30 mL). The mixture was extracted with ethyl acetate (50 mL×2). The extracts were dried and contracted to give a solid. The solid was triturated with ethyl acetate/hexane (1:1) and dried to give the title compound (0.47 g, 81%).
Reaction SMILES: Br[C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:32])[CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:18]([F:33])[CH:17]=2)=[C:4]([O:34][CH3:35])[CH:3]=1.[CH3:36]B1OB(C)OB(C)O1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[F:33][C:18]1[CH:17]=[C:16]([C:5]2[C:6]3[C:7]4[CH:15]=[CH:14][S:13][C:8]=4[C:9](=[O:12])[NH:10][C:11]=3[C:2]([CH3:36])=[CH:3][C:4]=2[O:34][CH3:35])[CH:21]=[CH:20][C:19]=1[CH:22]([CH3:32])[CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28]
Reactant: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CNC(=O)OC(C)(C)C)c(F)c1
Reactant: CB1OB(C)OB(C)O1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CNC(=O)OC(C)(C)C)c(F)c1
Yield: 52.4 %

Procedure:
Following General Procedure I, tert-butyl 2-(4-(6-bromo-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)-2-fluorophenyl)propylcarbamate (282 mg, 0.50 mmol) was reacted with trimethylboroxine (170 mg, 1.35 mmol) and Pd(pph3)4 (50 mg, 0.04 mmol) to afford the desired product (130 mg, 52%) as a yellow solid. ESI MS m/z 497 [C27H29FN2O4S+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][C:11]=1[Cl:18].ClC1C=CC(C(C2C=CC(OC)=CC=2)O)=CC=1>>[Cl:18][C:11]1[CH:12]=[C:13]([CH:14]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[OH:15])[CH:16]=[CH:17][C:10]=1[F:9]
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: Clc1ccc(Br)cc1
Agent: COc1ccc(C(O)c2ccc(Cl)cc2)cc1
Product: OC(c1ccc(Cl)cc1)c1ccc(F)c(Cl)c1

Procedure:
The title compound was prepared starting from 5.00 g (26.12 mmol) of 4-chlorobromobenzene and 4.97 g (31.34 mmol) of 4-fluoro-3-chlorobenzaldehyde in analogy to the synthesis of the compound from Example 175A. 5.57 g (77% of theory) of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14].[C:16](=O)([O:18]CC)[NH2:17]>CC(C)=O.[Cl-].[Zn+2].[Cl-]>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[C:6]2[CH:5]=[CH:4][S:3][C:2]=2[NH:1][C:16](=[O:18])[N:17]=1
Reactant: Nc1sccc1C(=O)c1ccccc1F
Reactant: CCOC(N)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)=O
Product: O=c1nc(-c2ccccc2F)c2ccsc2[nH]1
Temperature: 200 °C

Procedure:
A mixture of 500 mg of 2-amino-3-(o-fluorobenzoyl)thiophene, 760 mg of ethyl carbamate and 46 mg of zinc chloride is heated at 200°C for 1 hour. After cooling, the reaction mixture is washed with chloroform and filtered to give crystals, which are disolved in acetone and filtered. The filtrate is condensed under reduced pressure to give 4-(o-fluorophenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-2-one as crystals having a melting point of 254° - 256°C. Recrystallization from acetone gives crystals having a melting point of 278° - 279°C (decomp.)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5](C#N)=[C:4](/[CH:10]=[CH:11]/[N:12]([CH3:14])C)[CH:3]=1.C(O)(=[O:17])C>Br.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:8][CH:9]=1)[C:14](=[O:17])[NH:12][CH:11]=[CH:10]2
Reactant: CC(=O)O
Reactant: CN(C)/C=C/c1cc(Br)ccc1C#N
Agent: Br
Solvent: O
Product: O=c1[nH]ccc2cc(Br)ccc12

Procedure:
A solution of 4-bromo-2-[(E)-2-(dimethylamino)ethenyl]benzonitrile (Example 1a, 1.0 g) in 33% Hydrobromic acid in acetic acid (10 mL) under nitrogen was stirred at 80° C. for 4 h. The reaction mixture was diluted with water (250 mL), and the brown solid was filtered off, washed with diethyl ether and dried to afford the subtitle compound (0.70 g) as a solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH:22]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]([O:29][C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:23]2=[O:49])(=[O:21])=[O:20])=[CH:15][CH:14]=1>ClCCl>[O:49]=[C:23]1[CH:22]([S:19]([C:16]2[CH:15]=[CH:14][C:13]([CH:12]=[O:11])=[CH:18][CH:17]=2)(=[O:21])=[O:20])[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[O:29][C:30]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C1C(S(=O)(=O)c2ccc(CO)cc2)CCCCN1OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=Cc1ccc(S(=O)(=O)C2CCCCN(OC(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (0.12 ml, 2.0 M in dichloromethane) in dichloromethane (5.0 ml) was added DMSO (0.05 ml) at −78 degree C. dropwise. The mixture was stirred for 15 minutes, at which time, 3-(4-hydroxymethyl-benzenesulfonyl)-1-trityloxy-azepan-2-one (60.5 mg in 2 ml of dichloromethane) from step F was added dropwise. The resulting solution was stirred for 30 minutes and then TEA (0.9 ml) was added in one portion. The reaction mixture was stirred and warmed to 0 degree C. for a period of 15 minutes, at which time, the reaction mixture was diluted with dichloromethane and washed sequentially with water and saturated NaCl solution. The organic phase was then dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude material, which was then purified by a column chromatography (0˜30% EtOAc in hexane). MS: 562.1 (M+Na)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([NH:15][CH3:16])=[O:14].C(N(CC)C(C)C)(C)C>CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([NH:15][CH3:16])=[O:14])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CNC(=O)c1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CNC(=O)c1cccc(Nc2cc(Cl)ncn2)c1
Temperature: 80 °C
Yield: 92.4 %

Procedure:
To 4,6-dichloropyrimidine (500.0 mg, 3.36 mmol) and 3-amino-N-methylbenzamide (504 mg, 3.36 mmol) in 2-propanol (5.00 mL) at RT was added N,N-diisopropylethylamine (0.877 mL, 5.03 mmol). The resulting reaction mixture was heated at 80° C. for 3 days, cooled to RT, concentrated, purified using MPLC (25 g cartridge, 40 g column, 0 to 100% EtOAc-hexanes then 30-100% 90:10 CH2Cl2-MeOH in CH2Cl2). Fractions with product were combined and concentrated giving 3-(6-chloropyrimidin-4-ylamino)-N-methylbenzamide (815.2 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]([C:12]1([CH2:25][CH2:26][CH2:27]Br)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11])[CH3:8].O>O1CCCC1>[CH2:7]([O:9][C:10]([C:12]1([CH2:25][CH2:26][CH2:27][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11])[CH3:8]
Reactant: CCOC(=O)C1(CCCBr)CCN(C(=O)OC(C)(C)C)CC1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1(CCCN2CCCCC2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 62.5 °C

Procedure:
Piperidine (0.13 mL, 0.00132 mol) is added to a solution of 4-(3-bromopropyl)piperidine-1,4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester (0.1 gm, 0.00026 mol) in tetrahydrofuran (5 mL). The reaction mixture is heated at 60-65° C. for 3 hours. It is then cooled to room temperature, treated with demineralized water (12 mL) and extracted with ethyl acetate (2×20 mL). Combined extract is dried over sodium sulphate and concentrated under reduced pressure to get a crude residue which is purified by column chromatography (silica gel 230-400 mesh, methanol:dichloromethane, 1:9) to yield 4-(3-piperidin-1-yl propyl)piperidine-1,4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester.
Reaction SMILES: O[CH:2]([C:17]1[N:18]=[CH:19][N:20](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:21]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:20]1[CH:21]=[C:17]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:18]=[CH:19]1
Reactant: N#Cc1ccc(-c2ccccc2C(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccccc2Cc2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2′-[Hydroxy-(1-trityl-1H-imidazol-4-yl)-methyl]-biphenyl-4-carbonitrile (Intermediate D2) (2.4 g, 4.6 mmol) in CH2Cl2 (100 mL) was cooled to 0° C. and treated with triethyl silane, Et3SiH (7.4 mL, 46 mmol) (commercially available from Aldrich) followed by trifluoroacetic acid, TFA (10.7 mL, 140 mmol) dropwise. After several minutes the cooling bath was removed and the mixture was stirred at rt for an additional 12 h. The reaction was quenched with solid NaHCO3 followed by aqueous workup. The layers were separated and the organic layers were combined and dried over Na2SO4. The mixture was filtered and concentrated to dryness. The residue was purified by chromatography on silica gel with 3% NH3-MeOH: CH2Cl2 to give the product 2′-(1H-imidazol-4-ylmethyl)-biphenyl-4-carbonitrile (Intermediate D3), 0.74 mg, 62% yield.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[CH2:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:17]1[C:11]2[CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:5][CH2:6]3)=[N:13][C:12]=2[CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc2c(c1)Cc1ccccc1C(N1CCNCC1)=N2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(C2=Nc3ccccc3Cc3ccccc32)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
A mixture of 2.77 g of 6-(1-piperazinyl)-11H-dibenz[b,e]azepine, 2.00 g of ethyl bromoacetate and 1.38 g of potassium carbonate in 14 ml of N,N-dimethylformamide was stirred at 70° C. for 3 hrs. After cooling, water was added to the reaction mixture and extracted with ether. The etheral layer was washed with water, dried and concentrated. The residue was chromatographed on silica gel using a mixture of n-hexane and ethyl acetate (2:1 and 1:1) as eluents to give 2.91 g of colorless crystals, which were recrystallized from isopropyl ether to give colorless prisms, mp 107°-108° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH2:4]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>O.C(Cl)Cl.[OH-].[Na+]>[C:15]([NH:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH2:4]1)(=[O:17])[CH3:16]
Reactant: COc1ccc2c(c1)CCC(N)C2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(c1)CCC(NC(C)=O)C2
Temperature: 15 °C

Procedure:
2-Amino-6-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride is dissolved in a mixture of water and methylene chloride, and 10 N sodium hydroxide solution is added thereto until the pH is 12. 1.5 equivalents of acetic anhydride are then added, the pH being kept between 10 and 12 with 10 N sodium hydroxide solution, and the mixture being cooled to about 15° C. The pH is then brought to between 7 and 8 and the organic phase is separated off, dried and evaporated. When recrystallised from petroleum ether, the residue melts at 175° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24].O>C1COCC1>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[C:11]3[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:18][C:17]=1[C:23]([F:24])([F:25])[F:26]
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc2c(Nc3ccc(F)c(C(F)(F)F)c3)ncnc12
Yield: 74.7 %

Procedure:
A solution of 4-chloro-8-nitroquinazoline (Intermediate-7, step-2, 200 mg, 0.95 mmol) and 4-fluoro-3-(trifluoromethyl)aniline (510 mg, 2.85 mmol) in THF (4 mL) was stirred at rt for 2 h. Then water was added to the reaction mixture and it was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 250 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 10.47 (s, 1H), 8.83-8.80 (d, J=8.4 Hz, 1H), 8.72 (s, 1H), 8.42-8.39 (d, J=7.8 Hz, 1H), 8.31-8.25 (m, 2H), 7.86-7.81 (t, J=7.8 Hz, 1H), 7.64-7.58 (t, J=9.6 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][C:11](=O)[CH3:12])[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[S:24][C:11]([CH3:12])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)CCC(=O)c1cccc(Br)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cccc(Br)c2)s1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
To a stirring solution of 1-(3-bromo-phenyl)-pentane-1,4-dione (18.32 mmol) in toluene (90 mL) was added Lawesson's Reagent (19.24 mmol, 1.05 eq.) and the mixture was heated to reflux for 20 min. The reaction mixture was then cooled to room temperature and diluted with 1:1 hexanes/ether (90 mL) resulting in a precipitate. The mixture was filtered through a small pad of celite and the filtrate was concentrated to a light yellow solid that was purified by recrystallization from hexanes to give the final product as a white solid (12.17 mmol, 66%). MS (ESI) m/z 254.3.
Reaction SMILES: [C:1](=[O:27])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.Cl.Cl.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[CH:42][CH:41]=1>CN(C=O)C>[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([N:46]2[CH2:51][CH2:50][N:49]([C:1]([O:2][CH2:3][CH:4]3[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]3)=[O:27])[CH2:48][CH2:47]2)=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(OCC1CCNCC1)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.8 %

Procedure:
(1-(tert-Butoxycarbonyl)piperidin-4-yl)methyl 4-nitrophenyl carbonate (Intermediate 2; 10.0 g, 26.3 mmol), was dissolved in DMF (50 mL). DIPEA (16.0 mL, 92.0 mmol) and 4-(4-chlorophenyl)piperazine dihydrochloride (7.09 g, 26.3 mmol) were added and the reaction mixture was stirred at room temperature for 24 hours, and the reaction mixture was then concentrated in vacuo. The resulting residue was dissolved in EtOAc (300 mL) and washed with a 1 M aq Na2CO3 solution (6×200 mL), 10% citric acid solution (50 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in a mixture of DCM (100 mL) and TFA (20 mL), stirred for 4 hours and then concentrated in vacuo. The residue was dissolved in 1 M aq Na2CO3 solution (220 mL), and extracted with DCM (3×200 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was recrystallised from EtOAc to give (1-piperidin-4-yl)methyl 4-(4-chlorophenyl)piperazine-1-carboxylate (4.07 g, 45.7%) as a cream solid.