Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1NC(=O)c1ccccc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(N)ccc1NC(=O)c1ccccc1
Temperature: 70 °C
Yield: 97.2 %

Procedure:
A suspension of N-(2-methyl-4-nitrophenyl)benzamide (0.256 g, 1.0 mmol) and tin(II) chloride dihydrate (0.89 g, 3.96 mmol) in ethyl acetate (6 mL) was heated at 70° C. for 19 hr. The reaction mixture was then chilled, poured onto 50 mL ice, basified with 5% NaHCO3 (20 mL), extracted into EtOAc, washed with brine, dried and concentrated in vacuo to give N-(4-amino-2-methylphenyl)-benzamide (0.22 g, 97%). ES-MS (M+H)+=227, (M+Na)+=249.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C@H:11]3[NH:22][CH2:21][CH2:20][C@@:17]4([C:18]=2[CH:19]=1)[C@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16]4.Cl.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C@H:11]3[N:22]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:21][CH2:20][C@@:17]4([C:18]=2[CH:19]=1)[C@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16]4
Reactant: ClCCCOc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OCCCCl)cc13
Temperature: 25 °C
Yield: 88 %

Procedure:
To a stirred solution of 3-(3-chloropropyloxy)morphinan.HCl 54 (3 mg, 0.008 mmol) and triethylamine (7 μL, 0.050 mmol) in dry dichloromethane (0.3 mL) was added methanesulfonylchloride (2 μL, 0.025 mmol) and the mixture was stirred at room temperature. After starting material disappeared on TLC, solvent was removed and column chromatography gave 3 mg (88%) of title compound: 1H NMR (300 MHz, CDCl3) δ7.01 (1H, m); 6.85 (1H, d); 6.70 (1H, d.d); 4.05 (3H, m); 3.78 (2H, t); 3.56 (1H, d.d.); 3.15 (1H, d.d.); 2.90 (3H, s); 2.83 (2H, m); 2.32 (1H, m); 2.20 (2H, m); 1.00˜1.90 (10H, m).
Reaction SMILES: [CH3:1][N:2]([CH2:12][C:13]1[CH:14]=[C:15]([C:19]2[S:23][C:22]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)[C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>CO.[Pd]>[CH3:1][N:2]([CH2:12][C:13]1[CH:14]=[C:15]([C:19]2[S:23][C:22]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)[C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCC(=O)N(C)Cc1cccc(-c2ccc(C=CC(=O)O)s2)c1
Agent: [Pd]
Solvent: CO
Product: CCCCCCCC(=O)N(C)Cc1cccc(-c2ccc(CCC(=O)O)s2)c1
Yield: 88.4 %

Procedure:
A solution of 80 mg (0.20 mmol, 1 eq) of 3-(5-{3-[(methyloctanoylamino)methyl]phenyl}thiophen-2-yl)acrylic acid (prepared as in 1 h) in 2 mL of methanol is stirred for 2 hours at room temperature in the presence of 50 mg of 10% Pd/C under a hydrogen atmosphere. The palladium is filtered off and the solvents are then evaporated off. The residue is crystallized from pentane/dichloromethane. 71 mg of 3-(5-{3-[(methyloctanoylamino)methyl]phenyl}thiophen-2-yl)propanoic acid are obtained. Yield=89%. m.p.=67-68° C.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].N1CCCCC1.[C:13]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])/[CH:14]=[CH:15]/[CH3:16]>>[CH3:6][O:5][C:1](=[O:4])[CH2:2][S:3][CH:15]([CH3:16])[CH2:14][C:13]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: C/C=C/C(=O)OC(C)(C)C
Reactant: COC(=O)CS
Solvent: C1CCNCC1
Product: COC(=O)CSC(C)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.1 %

Procedure:
A mixture of methyl thioglycolate (0.8 mL, 8.9 mmol), piperidine (0.12 mL, 1.2 mmol) and 2 g (14 mmol) of t-butyl crotonate was stirred at room temperature for 12 hours, followed by distillation under reduced pressure. The reaction solution was purified by column chromatography to give 2.05 g (8.2 mmol) of the title compound in a yield of 92%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:16]=[CH:15][N:14]=1.Cl>O1CCOCC1>[S:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH:1][C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[CH:16]=[CH:15][N:14]=1)(=[O:9])(=[O:10])[NH2:11]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: Clc1nccc(Nc2ccccc2N2CCOCC2)n1
Agent: Cl
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cccc(Nc2nccc(Nc3ccccc3N3CCOCC3)n2)c1
Temperature: 100 °C
Yield: 84.2 %

Procedure:
To 3-aminobenzenesulphonamide (172 mg, 1.0 m.mol) in 1,4-dioxane (8 ml) was added 2-Chloro-4-[(2-Morpholino)anilino]pyrimidine (290 mgs, 1 m.mol) and hydrogen chloride (4.0M solution in 1,4-dioxane, 50 μl). The mixture was heated at 100° C. for 60 hrs. The reaction mixture was cooled, the resulting solid filtered, washed with 1,4-dixane and dried (in vacuo at 48° C.) to give pale brown solid (358 mg). Rt 5.88; MS (M+H)+: 427.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH:15]([C:19]([NH2:21])=[O:20])[CH2:14]2)=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:31]=[C:32]([CH2:42][NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH:33]=[C:34]([Cl:41])[C:35]=1[NH:36][C:37](=[O:40])[CH2:38]Cl.C(N(CC)CC)C>CN(C)C=O>[NH2:21][C:19]([CH:15]1[CH2:14][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH:8]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:18][CH2:17][N:16]1[CH2:38][C:37]([NH:36][C:35]1[C:34]([Cl:41])=[CH:33][C:32]([CH2:42][NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[CH:31][C:30]=1[Cl:29])=[O:40])=[O:20]
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)c(NC(=O)CCl)c(Cl)c1
Reactant: NC(=O)C1CN(CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cc(Cl)c(NC(=O)CN2CCN(CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2C(N)=O)c(Cl)c1
Temperature: 70 °C
Yield: 80.7 %

Procedure:
A mixture of 7 parts of 4-[5,5-bis(4-fluorophenyl)pentyl]-2-piperazinecarboxamide, 6.6 parts of (1,1-dimethylethyl) [[3,5-dichloro-4-[(2-chloroacetyl)amino]phenyl]methyl]carbamate, 2.8 parts of N,N-diethylethanamine and 94 parts of N,N-dimethylformamide was stirred over weekend at 70° C. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The desired fractions were collected and the eluent was evaporated, yielding 8.7 parts (80.7%) of (1,1-dimethylethyl) [[4-[[2-[2-(aminocarbonyl)-4-[5,5-bis(4-fluorophenyl)pentyl]-1-piperazinyl]acetyl]amino]-3,5-dichlorophenyl]methyl]carbamate as a residue (int. 102).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:34]=[CH:33][C:8]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[NH:18][C:19](=[O:32])[CH2:20][NH:21]C(=O)OCC2C=CC=CC=2)=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CCOCC.[BrH:40].CC(O)=O>>[BrH:40].[NH2:21][CH2:20][C:19]([NH:18][C@H:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C@H:12]1[NH:11][C:9](=[O:10])[C:8]1[CH:7]=[CH:6][C:5]([S:2]([NH2:1])(=[O:4])=[O:3])=[CH:34][CH:33]=1)=[O:32]
Reactant: NS(=O)(=O)c1ccc(C(=O)N[C@H]2CCCC[C@H]2NC(=O)CNC(=O)OCc2ccccc2)cc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: NCC(=O)N[C@H]1CCCC[C@H]1NC(=O)c1ccc(S(N)(=O)=O)cc1
Reaction time: 1 h

Procedure:
The material from above benzyl (cis)-2-[(2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethylcarbamate (217 mg) was dissolved in 30% HBr/AcOH (5 mL) at rt. After 1 h, Et2O was added and the solid was collected to give N-(cis)-{2-[(aminoacetyl)amino]cyclohexyl}-4-(aminosulfonyl)benzamide hydrogen bromide. MS found: (M+H)+=355.2.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[NH3:10]>C1COCC1.COCCOCCOC>[NH2:10][C:2]1[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: N
Solvent: C1CCOC1
Solvent: COCCOCCOC
Product: Nc1nc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 300 g (1.63 mol) of cyanuric chloride in 1 liter THF and 0.24 liter diglyme was cooled to 0° C. and 81.6 mL (3.36 mol) of liquid ammonia added dropwise over 90 min. keeping the temperature between 10°-15°. The mixture was stirred for one hour at -10° to 0° and then allowed to warm to ambient temperature over one hour. The resulting suspension was filtered, the solid washed with THF, the filtrate reduced to 1/2 its original volume, and poured over 1 liter of ice water to give a white solid which was collected, washed with water, and dried in vacuo to give 244.3 g of 2-amino-4,6-dichloro-1,3,5-triazine with m.p. 221°-223.5° (dec).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16]2[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[C:18]([CH3:24])[N:17]=2)=[CH:10]3)=[CH:4][C:3]=1[OH:25].[C:26]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16]2[N:20]([CH:21]([CH3:22])[CH3:23])[N:19]=[C:18]([CH3:24])[N:17]=2)=[CH:10]3)=[CH:4][C:3]=1[O:25][CH3:26]
Reactant: O=C([O-])[O-]
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)c(O)cc2OCC3)n(C(C)C)n1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc2c(cc1Br)-c1nc(-c3nc(C)nn3C(C)C)cn1CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
To a solution of 13-bromo-4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-12-ol (5.5 g) in acetone (30 mL) was added K2CO3 (3.03 g, 22.0 mmol) and methyl iodide (1.87 g, 13.1 mmol). The mixture was stirred at room temperature for 16 h. The mixture was concentrated and diluted with ethyl acetate (50 mL). After removal of the solvent, the residue was purified by silica gel chromatography using 1-10% MeOH in DCM as eluant to afford the desired product (3.0 g, 65% yield for two steps). LCMS m/z [M+H]+ 418.1.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[Cl:9][CH2:10][CH2:11][O:12][CH2:13][Mg]Cl.[Cl-].[NH4+].Cl.C(=O)([O-])O.[Na+]>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([CH:7]([OH:8])[CH2:13][O:12][CH2:11][CH2:10][Cl:9])[S:5][CH:6]=1
Reactant: Cc1csc(C=O)n1
Reactant: ClCCOC[Mg]Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1csc(C(O)COCCCl)n1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
1.6 g of 4-methyl-2-formylthiazole was dissolved in 30 ml of tetrahydrofuran. The solution was cooled to -30° C. Thereto was dropwise added, in 10 minutes, 10 ml of a tetrahydrofuran solution containing 1.6M of 2-chloroethoxymethylmagnesium chloride. The mixture was stirred for 1 hour with ice cooling. The reaction mixture was added to a mixture of 50 ml of ice water, 50 ml of ethyl acetate and 2 g of ammonium chloride. The resulting mixture was adjusted to pH 2 with 6N hydrochloric acid and stirred at the same temperature for 5 minutes. The reaction mixture was adjusted to pH 6 with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distallation under reduced pressure. The residue thus obtained was pruned by column chromatography (eluant: toluene/ethyl acetate=4/1) to obtain 1.3 g of oily 1-(4-methyl-2-thiazolyl)-2-(2-chloroethoxy)ethanol.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:38])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([NH:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:42]=O.S([O-])([O-])(=O)=O.[Mg+2]>O>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]([CH3:39])([CH3:38])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH:33]([CH2:36][OH:37])[CH2:34][O:35][CH2:42]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:40])[F:41])[CH:8]=1
Reactant: C=O
Reactant: Cc1cc(F)ccc1-c1cc(NC(CO)CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Product: Cc1cc(F)ccc1-c1cc(N2COCC2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 85 °C
Yield: 58.9 %

Procedure:
A mixture of 0.10 g (0.17 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-1-hydroxymethyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide (Example 142), 12 mg (0.39 mmol) paraformaldehyde and 61 mg (0.51 mmol) magnesium sulfate in 2 ml 1,2-dichloromethane was heated at 85° C. until complete consumption of starting material. After cooling to room temperature the reaction mixture was diluted with water and extracted with 3 portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 60 mg (59%) of the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:19])[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:20]([C:23]1[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=1[CH:25]([OH:29])[C:26](Cl)=[O:27])(=[O:22])[CH3:21]>N1C=CC=CC=1>[CH2:1]([NH:9][C:10](=[O:19])[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:12][C:26](=[O:27])[CH:25]([C:24]1[CH:30]=[CH:31][CH:32]=[CH:33][C:23]=1[C:20](=[O:22])[CH3:21])[OH:29])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(NCCc1ccccc1)C(O)c1ccccc1
Reactant: CC(=O)c1ccccc1C(O)C(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)c1ccccc1C(O)C(=O)OC(C(=O)NCCc1ccccc1)c1ccccc1
Reaction time: 5 h

Procedure:
N-phenethyl mandelic amide 51 g is dissolved in 150 ml of pyridine, and o-acetylmandelic acid chloride 60 ml is added with stirring. Exothermic acylation takes place immediately and the stirring is continued for 5 hours. The reaction mixture is mixed with 1 liter of cold 0.2N HCL. The sticky solid thus formed is extracted with 300 ml of chloroform, washed with 400 ml of 5% sodium bicarbonate and is dried over anhydrous sodium sulfate. On evaporation of chloroform a syrupy product 98 g is obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[C:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:19]2[CH2:20][CH2:21][N:16]([C:13](=[O:15])[CH3:14])[CH2:17][CH2:18]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(C)=O)CC2)ccc1[N+](=O)[O-]

Procedure:
The compound obtained in Step 1 above (300 mg), N-acetylpiperazine (300 mg), and potassium carbonate (500 mg) were dissolved in dimethylformamide (3 mL) and reacted at 80° C. overnight. The dimethylformamide of the reaction mixture was removed under reduced pressure, and added with water to form a solid. The solid was filtered to obtain a target compound as a yellow solid.
Reaction SMILES: C1([NH2+]C2CCCCC2)CCCCC1.[CH2:14]([O:21][C:22]([NH:24][C@@H:25]([C@H:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:30])[C:26]([O-])=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.ClC(OCC(C)C)=O.CN1CCOCC1>C1COCC1>[CH2:14]([O:21][C:22](=[O:23])[NH:24][C@@H:25]([C@H:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:30])[CH2:26][OH:27])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)[O-]
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C[C@@H](OC(C)(C)C)[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
A solution of (2S,3R)-2-(((benzyloxy)carbonyl)amino)-3-(tert-butoxy)butanoic acid dicyclohexylammonium salt (500 mg, 1.0 mmol) in 10 ml of THF and isobutyl chloroformate (167 mg, 1.2 mmol, 1.2 equiv) at −25° C. was added N-methylmorpholine (124 mg, 1.2 mmol, 1.2 equiv), the mixture was stirred at same temperature for 10 min and filtered. The filtrate was cooled to −20° C. and to it was added NaBH4, followed by 2 ml of water immediately afterwards. The reaction mixture was stirred at same temperature for 5 min. then gradually warmed to room temperature for 25 min, poured into water (10 ml) and extracted with ethyl acetate (2×20 ml). The combined organic phases were washed with water, brine and dried over Na2SO4. The solvent was removed to yield benzyl((2R)-(3R)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate as a clear oil. No further purification was required for next step. 1H NMR (400 MHz, CDCl3) δ 7.37-7.16 (m, 5H), 5.25 (d, J=8.0 Hz, 1H), 5.02 (s, 1H), 4.04 (ddd, J=12.0, 8.9, 2.8 Hz, 1H), 3.92-3.75 (m, 1H), 3.59 (dddd, J=32.3, 14.6, 8.2, 4.3 Hz, 2H), 1.10 (s, 9H), 1.09-1.06 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:10][CH2:11][C:12]([N:14]([CH3:15])[CH3:16])=[O:13])=[C:2]([NH:1][S:25]([C:19]2[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=2[F:17])(=[O:27])=[O:26])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: CN(C)C(=O)CCSc1ccc(Cl)cc1N
Solvent: c1ccncc1
Product: CN(C)C(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(F)cc1F
Yield: 71.7 %

Procedure:
Following General Procedure B, the title compound (364 mg, 72%) was prepared from 3-((2-amino-4-chlorophenyl)thio)-N,N-dimethylpropanamide (300 mg, 1.167 mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (248 mg, 1.167 mmol) in pyridine (5 ml).
Reaction SMILES: [F-].[K+].[CH3:3][O:4][C:5]1[C:18]2[C:9](=[N:10][C:11]3[C:16]([C:17]=2[C:19]#[C:20][Si](C)(C)C)=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([O:25][CH3:26])=[CH:7][CH:6]=1>CO>[CH3:3][O:4][C:5]1[C:18]2[C:9](=[N:10][C:11]3[C:16]([C:17]=2[C:19]#[CH:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([O:25][CH3:26])=[CH:7][CH:6]=1
Reactant: COc1ccc(OC)c2c(C#C[Si](C)(C)C)c3ccccc3nc12
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: C#Cc1c2ccccc2nc2c(OC)ccc(OC)c12
Yield: 96.7 %

Procedure:
Potassium fluoride (0.5 g, 9.0 mmol) was added to a solution of 1,4-dimethoxy-9-trimethylsilylethynylacridine (prepared as described in Preparation 2 above) (1 g, 3.0 mmol) in methanol (30 ml) and the mixture was stirred at reflux for 30 min. The solvent was evaporated and the residue was dissolved in CH2Cl2. The organic solution was washed with H2O, dried and evaporated to give the title compound (764 mg, 97%) as a brown solid; m.p. 155-157° C. (Et2O). IR (KBr): ν/cm−1=2100 (w, C≡C), 1625 (m, Ar), 1460 (m, Ar); 1H NMR (200 MHz, CDCl3): δH/ppm=3.98 (s, 3H, OCH3), 4.10 (s, 3H, OCH3), 4.20 (s, 1H, ≡CH), 6.75 (d, J=8.4 Hz, 1H, H-2), 6.92 (d, J=8.4 Hz, 1H, H-3), 7.62 (dd, J=8.4 and 7.4 Hz, 1H, H-7), 7.78 (dd, J=8.6 and 7.4 Hz, 1H, H-6), 8.36 (d, J=8.6 Hz, 1H, H-5), 8.66 (d, J=8.4 Hz, 1H, H-8); 13C NMR (75.4 MHz, CDCl3): δC/ppm=56.0 (q, OCH3), 56.1 (q, OCH3), 85.6 (s, ≡C), 92.7 (d, ≡C), 104.1 (d, C-2), 105.8 (d, C-3), 121.0 (s, C-9a), 124.2 (s, C-9), 126.2 (d, C-6), 127.1 (d, C-7), 127.8 (s, C-8a), 130.0 (d, C-8), 130.4 (d, C-5), 141.3 (s, C-4a), 147.5 (s, C-1), 149.3 (s, C-10a), 149.5 (s, C-4); MS (EI); m/z (%)=264 [M+1] (7), 263 [M+] (35), 248 (100); HRMS: calcd. for C17H13NO2 263.0946; found 263.0940.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:41]=[CH:40][C:25]([CH2:26][N:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.Cl>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:41]=[CH:40][C:25]([CH2:26][N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:24][CH:23]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)CC1
Agent: Cl
Solvent: CC#N
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccc(CN3CCNCC3)cc1)C2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The mixture of tert-butyl 4-(4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzyl)piperazine-1-carboxylate (70 mg, 0.12 mmol) in a solution of HCl (g) in acetonitrile (sat. 10 mL) was stirred for 3 hr at room temperature. Then the mixture was filtered to give the crude product. The crude product was purified by flash chromatography to give the title compound as a hydrochloride salt (35 mg, yield 60%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.63-2.64 (m, 4H), 3.19-3.21 (m, 4H), 3.54 (s, 2H), 4.29-4.31 (d, J=8.0 Hz, 1H), 4.69-4.71 (d, J=8.4 Hz, 1H), 6.89-6.93 (m, 2H), 7.07-7.10 (m, 2H), 7.19-7.26 (m, 5H), 7.54-7.56 (m, 1H), 7.61-7.65 (m, 1H). LC-MS (ESI) m/z: 456 (M+1)+.
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:9])=[CH:6][CH:5]=1)(=O)[CH3:2].[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[CH2:11]([NH:10][C:8](=[O:9])[C:7]1[CH:23]=[CH:24][C:4]([CH:1]([NH:32][CH2:31][C:30]2[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:35])[F:36])=[CH:34][CH:33]=2)[CH3:2])=[CH:5][CH:6]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(C(C)=O)cc1
Product: CCCCCCCCCCCCNC(=O)c1ccc(C(C)NCc2ccc(C(F)(F)F)cc2)cc1
Yield: 71 %

Procedure:
The same procedure as employed in the preparation of Example 223 (step b) but using 4-acetyl-N-dodecylbenzamide and 4-(trifluoromethyl)benzylamine gave the title compound as a colorless oil (71%). M−(LC/MS(ESI)): 489.1; M+(LC/MS(ESI)): 491.5. HPLC (Condition A), Rt: 5.51 min (HPLC purity: 50.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.O1CCOCC1.[Cl:18][C:19]1[C:31](I)=[CH:30][C:22]2[NH:23][C:24]([C:26]([F:29])([F:28])[F:27])=[N:25][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:18][C:19]1[C:31]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:30][C:22]2[NH:23][C:24]([C:26]([F:28])([F:29])[F:27])=[N:25][C:21]=2[CH:20]=1
Reactant: FC(F)(F)c1nc2cc(Cl)c(I)cc2[nH]1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1nc2cc(Cl)c(-c3ccc(Cl)cc3Cl)cc2[nH]1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Compound number 260 (i.e., 6-chloro-5-(2,4-dichlorophenyl)-2-trifluoromethylbenzimidazole) was prepared as follows. A 100-mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen. (2,4-dichlorophenyl)boronic acid (229 mg, 1.20 mmol, 2.00 equiv), dioxane (30 mL), 5-chloro-6-iodo-2-(trifluoromethyl)-1H-1,3-benzodiazole (200 mg, 0.58 mmol, 1.00 equiv), sodium carbonate (191 mg), water (8 mL) and Pd(PPh3)4 (34.7 mg) was placed in the flask. The resulting solution was stirred overnight at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4). This resulted in 87.8 mg (42%) of 6-chloro-5-(2,4-dichlorophenyl)-2-trifluoromethylbenzimidazole as a white solid.