Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([CH:8](F)F)/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:19][C:20]1[O:24][N:23]=[C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[N:21]=1>ClCCl.CN(C=O)C>[F:11][C:2]([F:1])([CH3:8])/[CH:3]=[CH:4]/[C:5]([N:28]1[CH2:29][CH2:30][N:25]([C:22]2[N:21]=[C:20]([CH3:19])[O:24][N:23]=2)[CH2:26][CH2:27]1)=[O:7]
Reactant: O=C(O)/C=C/C(F)(F)C(F)F
Reactant: Cc1nc(N2CCNCC2)no1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(C(=O)/C=C/C(C)(F)F)CC2)no1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
(E)-4,4,5,5-Tetrafluoropent-2-enoic acid (31 mg, 0.23 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (20 μl, 0.23 mol) and one drop of DMF were added and the resulting solution was stirred at room temperature for 15 minutes. This solution was added to a solution of 5-methyl-3-piperazin-1-yl-1,2,4-oxadiazole hydrochloride (25 mg, 0.122 mmol) in dichloromethane (2 ml) and the resulting mixture was stirred at room temperature for three hours. The solvent was removed under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 24.3 mg of a solid (0.083 mmol, 69%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]C(=O)C)=[C:15]([O:23]C(=O)C)[CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(N(CC)CC)C>[CH2:1]([O:8][C:9](=[O:27])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:23])[CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Oc1ccc(C[C@H](N)C(=O)OCc2ccccc2)cc1OC(C)=O
Solvent: CCN(CC)CC
Product: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)OCc1ccccc1

Procedure:
First, carbobenzozyglycyl-3,4-diacetyloxy-L-phenylalanine-benzyl ester was obtained in the manner which follows. Dichloromethane (100 ml) solution containing 0.95 g. (9.4 millimole) of triethylamine was permitted to react with 3.64 g (8.92 millimole) of 3,4-diacetyloxy-L-phenylalanine-benzyl ester hydrochloride for 0.3 hours at room temperature. The solution was then concentrated in vacuo at room temperature to dryness. The residue obtained was filtered and washed with ether to give 1.54 g of triethylamine hydrochloride, contaminated with 3,4-diacetyloxy-L-phenylalanine-benzyl ester in various stages of deprotection. For instance, 3,4-dihydroxy-L-phenylalanine-benzyl ester was obtained quantitatively if a large excess of triethylamine was employed to neutralize the hydrochloride. The ether filtrate was concentrated in vacuo at room temperature. The resulting residue was analyzed by nmr and found to be consistent with the proposed structure, 3,4-diacetyloxy-L-phenylalanine-benzyl ester.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Br:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1>C(Cl)Cl>[Br:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: Nc1ccccn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Br
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.2 %

Procedure:
A solution of triphenylphosphine (168 mg, 0.64 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (114 mg, 0.64 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 72, 200 mg, 0.53 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 25 min. The reaction mixture was then treated with 2-aminopyridine (110 mg, 1.17 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide (175 mg, 73%) as a white foam: mp 99-101° C.; FAB-HRMS m/e calcd for C20H23BrN2O3S (M+H)+451.0692, found 451.0689.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]([O:16]CC)=O)[C:9]([O:11]CC)=O)=[CH:4][CH:3]=1.Cl.[C:20]([NH2:25])(=[NH:24])[CH2:21][CH2:22][CH3:23].C[O-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([OH:11])=[N:24][C:20]([CH2:21][CH2:22][CH3:23])=[N:25][C:14]=2[OH:16])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C)cc1
Reactant: CCCC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCc1nc(O)c(-c2ccc(C)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a solution of diethyl (4-methylphenyl)malonate (9.45 g) and butyramidine hydrochloride (5.00 g) in methanol (25 ml) is added 28% sodium methoxide (19.67 g) under ice-cooling, and the mixture is stirred at room temperature overnight. After the reaction is complete, the reaction solution is concentrated to the half volume thereof, and the resultant is diluted with water. The mixture is acidified with 10% hydrochloric acid, and the precipitated crystals are collected by filtration, washed, and dried to give 5-(4-methylphenyl)-4,6-dihydroxy-2-n-propylpyrimidine (5.17 g) as crystalline powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2[SH:18])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]1([C:32](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2[S:18][C:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:6][CH:7]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cnc(S)n1-c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 1-(4-fluorophenyl)-2-mercapto-1H-imidazole-5-carboxylate (3) (4.09 g, 15.34 mmol) in THF (70 mL) was added triethyl amine (4.50 mL, 32.29) and triphenylmethyl chloride (4.67 g, 16.76 mmol) and the solution was stirred for 1 hour at room temperature. The reaction was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (10%-40% EtOAc in hexanes) to give ethyl 1-(4-fluorophenyl)-2-(tritylthio)-1H-imidazole-5-carboxylate. A solution of ethyl 1-(4-fluorophenyl)-2-(tritylthio)-1H-imidazole-5-carboxylate (6.34 g, 12.47 mmol), sodium hydroxide (0.74 g, 18.39 mmol), methanol (10 mL), THF (20 mL), and water (10 mL) was stirred at room temperature for 16 hour and was then concentrated in vacuo. The aqueous was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to yield 1-(4-fluorophenyl)-2-(tritylthio)-1H-imidazole-5-carboxylic acid (6).
Reaction SMILES: C[O:2]C1C=CC(S(C(C)(CC2C=CC(OCCN3CCCCC3)=CC=2)C(O)=O)(=O)=O)=CC=1.O[CH:34]([C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH2:59][N:60]2[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]2)=[CH:53][CH:52]=1)[C:35]([S:40]([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)(=[O:42])=[O:41])([CH3:39])[C:36]([NH2:38])=[O:37]>>[OH:2][NH:38][C:36](=[O:37])[C:35]([S:40]([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)(=[O:42])=[O:41])([CH3:39])[CH2:34][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH2:59][N:60]2[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]2)=[CH:53][CH:52]=1
Reactant: COc1ccc(S(=O)(=O)C(C)(C(N)=O)C(O)c2ccc(OCCN3CCCCC3)cc2)cc1
Reactant: COc1ccc(S(=O)(=O)C(C)(Cc2ccc(OCCN3CCCCC3)cc2)C(=O)O)cc1
Product: COc1ccc(S(=O)(=O)C(C)(Cc2ccc(OCCN3CCCCC3)cc2)C(=O)NO)cc1

Procedure:
Starting from 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[4-(2-piperidin-1-yl-ethoxy) phenyl]-propionic acid (2.0 g, 4.2 mmol) and following the procedure as outlined in example 1, -1 g of 1N-hydroxy- 2-(4-methoxy-benzenesulfonyl)2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)phenyl]-propionamide was isolated as colorless solid. Yield: 1 g, 48%; mp 98° C.; MS: 477 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 1.2 (s, 3H), 3.5-1.5 (m, 16 H), 3.9 (s, 3H), 4.4 (m, 1H), 6.5-7.8 (m, 8H), 10.8 (bs, 1H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[C:13]([Cl:24])=[N:14][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][CH:17]=1>C1(C)C(C)=CC=CC=1>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:11][C:12]1[C:13]([Cl:24])=[N:14][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][CH:17]=1
Reactant: Clc1nc2ccccc2o1
Reactant: CCOC(=O)Cc1ccc(N)c(Cl)n1
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cc1ccc(Nc2nc3ccccc3o2)c(Cl)n1
Temperature: 25 °C
Yield: 53.5 %

Procedure:
In xylene (100 ml), 2-chlorobenzoxazole (326 μl, 2.86 mmol) and ethyl (3-amino-2-chloro-6-pyridyl)acetate (557 mg, 2.59 mmol) were heated under reflux for 4 hours under stirring. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (3:1, v/v) eluate fractions, ethyl (3-(2-benzoxazolyl)amino-2-chloro-6-pyridyl)acetate (460 mg, 53%) was obtained as a colorless gum.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[F:24][CH:25]([F:27])[OH:26]>>[F:24][CH:25]([F:27])[O:26][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: OC(F)F
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(OC(F)F)cc1OCC2

Procedure:
Following the procedures of the Examples herein, 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 194 and difluoromethanol were reacted to give 492. LC/MS (ESI+): m/z 362.1 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[CH3:14])=[O:4]>C1COCC1>[OH:10][CH2:9][C:8]1[CH:12]=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:6]([CH3:14])[CH:7]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CO)cc1C
Temperature: 25 °C

Procedure:
410 mg of dimethyl 2-methylterephthalate was hydrolyzed via Procedure M and purified by ISCO Combi-Flash to afford 4-(methoxycarbonyl)-3-methylbenzoic acid. 255 mg of 4-(methoxycarbonyl)-3-methylbenzoic acid was cooled to 0° C. in 2 mL of THF before a solution of 2.6 mL of 1M BH3-THF complex in THF was added dropwise. The ice bath was subsequently removed and the reaction was stirred at room temperature until reaction stalled out at −50% complete by TLC. The reaction was re-cooled to 0° C. and another 2.6 mL of BH3-THF was added dropwise before the ice bath was removed. Upon completion, the reaction was re-cooled to 0° C. and quenched with 3N HCl dropwise. The aqueous layer was extracted 2 times with Ethyl Acetate and the organic layer was then extracted once with bicarbonate solution and brine, dried over Magnesium Sulfate, filtered and concentrated to give methyl 4-(hydroxymethyl)-2-methylbenzoate.
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]([F:20])([F:19])[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[C:6]=1Cl.ClCl.O>CO>[F:3][C:4]([F:20])([F:19])[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[C:6]=1[OH:1]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1Cl
Agent: ClCl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1O

Procedure:
To a solution of 168 g (4 moles +5% excess) of sodium hydroxide in 1000 ml methanol there were added portionwise, at 50°-65°C internal temperature, 586 g (2 moles) 2,4-bis-trifluoromethyl-6-nitrochlorobenzene; the reaction mixture, after completion of addition (about 1 hour) of the reactive chlorine compound, was boiled under reflux for one hour. After cooling, 700 ml of water were added to the mixture and unreacted starting materials were extracted once with 400 ml methylene chloride. The aquous phase was separated off, distinct acidification was effected with 20%-strength sulfuric acid; the 2,4-bis-trifluoromethyl-6-nitrophenol which separated was taken up in methylene chloride. The organic phase was dried over sodium sulfate. The 2,4-bis-trifluoromethyl-6-nitro-phenol remaining behind after methylene chloride had been distilled off was subjected to vacuum distillation. 480 g (87%) of the boiling pont 105°-106°C/20 mm Hg were obtained; refractive index nD20 : 1.4580.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[Cl:18][C:19]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(Cl)cc4Cl)nc23)CC1
Yield: 72.6 %

Procedure:
Beginning with 0.085 gm (0.369 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.108 mL (0.776 mMol) 2,4-dichlorobenzoyl chloride, 0.108 gm (72.7%) of the title compound was recovered as an amorphous solid by the procedure described in Example 16.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[N:8][C:9]([C:15]2[NH:16][C:17](=[O:24])[C:18]([CH:21]([CH3:23])[CH3:22])([CH3:20])[N:19]=2)=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12].C(=O)(O)[O-].[Na+:29].O>O1CCCC1>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:7]=[N:8][C:9]([C:15]2[NH:16][C:17](=[O:24])[C:18]([CH:21]([CH3:22])[CH3:23])([CH3:20])[N:19]=2)=[C:10]([CH:14]=1)[C:11]([O-:13])=[O:12].[Na+:29]
Reactant: CC(C)C1(C)N=C(c2ncc(C3OCCO3)cc2C(=O)O)NC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C1(C)N=C(c2ncc(C3OCCO3)cc2C(=O)[O-])NC1=O
Yield: 76.8 %

Procedure:
5-(1,3-Dioxolan-2-yl)-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinic acid (0.507 g, 0.00152 mol), sodium bicarbonate (0.12 g, 0.00143 mol), water and tetrahydrofuran is heated at reflux temperature for 1 hour. Concentration in vacuo yields a solid which is triturated with ether to give the title compound as an orange solid (0.39 g, 72%), mp 209°-210° C., identified by IR and NMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1.[CH2:21]([Mg]Br)[CH3:22]>O1CCCC1>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH2:21][CH3:22])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)c1ccc(Cl)cc1Nc1ccccc1
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(Cl)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
A solution of 4-chloro-N-methoxy-N-methyl-2-phenylamino-benzamide (5.0 g, 17.2 mmol) in tetrahydrofuran (60 mL) was treated dropwise with ethylmagnesium bromide (1M solution in tetrahydrofuran, 70 mL, 70 mmol). Upon completion of addition, the mixture was allowed to slowly warm to 25° C. where it was stirred for 2 h. At this time, the reaction was cooled to 0° C., was quenched with a 1N aqueous hydrochloric acid solution (50 mL) and was then extracted with ethyl acetate (2×300 mL). The combined organics were washed with water (100 mL) and a saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (silica gel; 100-200 mesh, ethyl acetate/hexanes 10-25%) afforded 1-(4-chloro-2-phenylamino-phenyl)-propan-1-one (4.15 g, 92.9%) as a yellow oil. 1H NMR (DMSO-d6) δ ppm 10.53 (s, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.34-7.51 (m, 2H), 7.28 (d, J=7.7 Hz, 2H), 7.13-7.23 (m, 1H), 7.07 (d, J=1.8 Hz, 1H), 6.82 (dd, J=8.6, 1.9 Hz, 1H), 3.07 (q, J=7.2 Hz, 2H), 1.09 (t, J=7.3 Hz, 3H).
Reaction SMILES: C1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)C=CC=CC=1.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1>>[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=C1NCCc2c(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for preparation of Compound 12, the tricyclic bromide (300 mg, 1,13 mmol) and 3,5-bis-trifluoromethylphenylboronic acid (202 mg, 1.24 mmol) were coupled to yield 2-(3,5-bis-trifluoromethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 70 mg (16%), as a pale-yellow solid. mp 230° C. (dec.); 1H NMR (300 MHz, d6-DMSO) δ 3.11 (m, 2H), 3.42 (m, 2H), 7.31 (app t, 1H, J=7.8 Hz), 7.64 (d, 1H, J=8.1 Hz), 7.73 (d, 1H, J=7.5 Hz), 8.13 (br s, 1H), 8.16 (br t, 1H), 8.28 (br s, 2H), 11.95 (br s, 1H); MS (FAB, MH+) 399; Anal. (C19H12F6N2O.0.2 hexanes) C, H, N.
Reaction SMILES: [Na].[C:2]([O:10]CC)(=[O:9])[CH2:3][C:4]([O:6]CC)=[O:5].Br[CH:14](Br)[C:15]1[C:16]([CH3:21])=[CH:17][CH:18]=[CH:19][CH:20]=1>C(O)C.C(OCC)C>[CH2:21]1[C:16]2[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][C:3]1([C:4]([OH:6])=[O:5])[C:2]([OH:10])=[O:9]
Reactant: Cc1ccccc1C(Br)Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: O=C(O)C1(C(=O)O)Cc2ccccc2C1

Procedure:
Sodium (3.7 g) was dissolved in 80 ml of ethyl alcohol, followed by the addition of 150 ml of diethyl ether. Diethyl malonate (12.5 ml) was added followed by 20 g of α, α-dibromo-o-xylene in 150 ml of diethyl ether with overhead stirring. The reaction was heated to reflux for 5 hours. The reaction was cooled, filtered, and the solvent was removed under vacuum. The residue was treated with a potassium hydroxide solution (20 g in 125 ml of water) and heated to reflux for 15 hours. The reaction was then cooled and rinsed with 200 ml of diethyl ether. The aqueous phase was acidified with 30% hydrochloric acid. The precipitate was collected and dried under vacuum over Drieruite for 5 hours to yield 8.86 g of indan-2,2-dicarboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16]O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.S(Cl)([Cl:20])=O>>[Cl:20][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[CH:13]1
Reactant: Nc1nc2ccccc2c2c1ncn2CCO
Reactant: O=S(Cl)Cl
Product: Nc1nc2ccccc2c2c1ncn2CCCl
Temperature: 80 °C
Yield: 86 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, 2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (8.46 g, 37.06 mmol), and thionyl chloride (68.99 g, 57.99 mmol) under a nitrogen atmosphere. The reaction mixture was heated to 80° C. to give a heterogeneous reaction mixture that was maintained at 80° C. for 2 hours at which time the starting material was completely consumed. The solution was cooled and quenched by the addition of water (400 mL). To the stirred solution was added solid sodium carbonate until the pH reached 10 at which time a solid precipitated out of solution. The solid was collected by filtration to afford 1-(2-chloroethyl)-1H-imidazo[4,5-c]quinolin-4-amine (7.86 g, 31.86 mmol) as an off-white solid. The material was used without further purification.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:32]([CH3:33])=[CH:31][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][NH:27][C@H:26]([CH3:30])[CH2:25]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:41](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C=O>CN(C=O)C>[C:1]([O:5][C@@H:6]([C:11]1[C:32]([CH3:33])=[CH:31][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][N:27]([CH3:41])[C@H:26]([CH3:30])[CH2:25]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN[C@H](C)C4)n3)sc2c1-c1ccc(Cl)cc1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C)[C@H](C)C4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
To crude (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-((R)-3-methylpiperazin-1-yl)pyrimidin-4-yl)benzo[d]thiazol-6-yl)acetate (45.8 mg, 0.079 mmol) and sodium triacetoxyborohydride (83.7 mg, 0.395 mmol) in DMF (1 mL) was added acetic acid (23.7 mg, 22.6 μL, 0.395 mmol). The reaction mixture was heated to 60° C., then 37% w/w aq. formaldehyde (9.48 mg, 23.5 μL, 0.316 mmol) was added dropwise over 1 min. The reaction mixture was heated at 60° C. for 2 h. Upon completion of the reaction, the reaction mixture was filtered through Celite (ethyl acetate eluent) and concentrated. Purification by flash column chromatography on silica gel using 100:5:1 EtOAc/MeOH/NH4OH (0 to 100%) in EtOAc provided the product. LCMS-ESI+ calc'd for C31H37ClN5O3S (M+H+): 594.2; Found: 593.7 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:12][C:7]=2[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)=[N:5][CH2:4][C:3]1=[O:28]>CO.C(Cl)Cl.[Pd]>[NH2:25][C:21]1[CH:20]=[C:19]([C:6]2[C:7]3[CH:12]=[C:11]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:10]=[CH:9][C:8]=3[N:2]([CH3:1])[C:3](=[O:28])[CH2:4][N:5]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CN1C(=O)CN=C(c2cccc([N+](=O)[O-])c2)c2cc(-c3ccccc3)ccc21
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CN1C(=O)CN=C(c2cccc(N)c2)c2cc(-c3ccccc3)ccc21
Yield: 16 %

Procedure:
1-Methyl-5-(3-nitro-phenyl)-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one Example 65 (40 mg, 0.11 mmole)was dissolved in Methanol/CH2Cl2 then Pd/C (10 mg) was added and the flask was stirred over hydrogene atmosphere. The solution was filtered over celite, and the solvent was evaporated. The crude material was chromatographied: eluant: AcOEt/Hexane: 1/1. The title compound (6 mg) was obtained as a beige solid, (yield=16%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[S:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([S-:20])=[S:19])[CH2:14][CH2:13]1.[Na+].[CH3:22]I>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[S:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([S:20][CH3:22])=[S:19])[CH2:14][CH2:13]1
Reactant: S=C([S-])N1CCC(Sc2c[nH]c3ccc(Br)cc23)CC1
Reactant: CI
Agent: [Na+]
Solvent: CCO
Product: CSC(=S)N1CCC(Sc2c[nH]c3ccc(Br)cc23)CC1

Procedure:
A solution of sodium 4-[(5-bromo-1H-indol-3-yl)thio]piperidine-1-carbodithioate (3 g, prepared in the previous Example) and methyl iodide (0.5 ml) in 95% ethanol (15 ml) is refluxed for one hour. The orange reaction mixture is concentrated, taken up with ether and washed with water. The organic phase is dried over sodium sulfate and concentrated. After chromatography on silica gel (eluent: cyclohexane/AcOEt 70/30), methyl 4-[(5-bromo-1H-indol-3-yl)thio]piperidine-1-carbodithioate (13 g) is obtained in the form of an oil, which is taken up with pentene to give a white solid.