Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[C:9]1([P:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(#N)C>C1C=CC=CC=1>[Br-:1].[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][P+:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([OH:8])=[O:7]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)CCCCBr
Solvent: c1ccccc1
Solvent: CC#N
Product: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
A mixture of 103 g. of 5-bromovaleric acid and 152 g. of triphenylphosphine in 400 ml. of acetonitrile is refluxed for 48 hours, cooled, diluted with 100 ml. of benzene and allowed to crystallize. The crystals are filtered, washed with benzene and ether, to yield colorless material, m.p. 207°-209° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C1N=C[N:15](C(N2C=NC=C2)=O)C=1.C(=O)([O-])[O-].[NH4+].[NH4+].O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To a solution of 2-bromo-5-methoxybenzoic acid (21.6 mmol) in DMF (20 mL) was added N,N-carbonyldiimidazole (54.1 mmol). The reaction mixture was allowed to stir at rt for 30 min and then ammonium carbonate (97.4 mmol) was added in portions over several minutes. The reaction mixture was allowed to stir until for 5 days and then poured into water. A white precipitate formed. The mixture was extracted with EtOAc. The organic solutions were combined, washed sequentially with water, 1N HCl, sat. aq. NaHCO3 and brine, dried over Na2SO4 filtered and concentrated to give 2-bromo-5-methoxybenzamide (18.5 mmol, 85%), which was used without further purification.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([O:15]CC)=O)=[CH:4]2.ON1C(=O)CCC1=O.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:39][CH2:40][CH2:41][N:42]1[C:47](=[O:48])[CH2:46][N:45]([CH2:49][CH2:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:44][C:43]1=[O:58].C(N(CC)CC)C>C(#N)C.C(Cl)(Cl)Cl>[O:58]=[C:43]1[CH2:44][N:45]([CH2:49][CH2:50][CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:46][C:47](=[O:48])[N:42]1[CH2:41][CH2:40][NH:39][C:13]([C:5]1[S:6][C:7]2[N:12]3[C:3](=[CH:2][N:1]=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH:4]=1)=[O:15]
Reactant: NCCN1C(=O)CN(CCCc2ccccc2)CC1=O
Reactant: CCOC(=O)C1=Cc2cnc3cccc(n23)S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: O=C(NCCN1C(=O)CN(CCCc2ccccc2)CC1=O)C1=Cc2cnc3cccc(n23)S1
Reaction time: 2 h

Procedure:
To a suspension of 0.8 g (3.67 mmol.) of ethyl 5-thia-1,8b-diazaacenaphthylene-4-carboxylate and 0.84 g (7.30 mmol.) of N-hydroxysuccinimide in acetonitrile (10 ml) was added, at room temperature, 1.41 g (7.36 mmol.) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodiimide. The mixture was stirred for 2 hours. To the reaction system was added a solution of 1.66 g (4.77 mmol.) of 1-(2-aminoethan-1-yl)-2,6-dioxo-4-(3-phenylpropan-1-yl)piperazine.dihydrochloride and 2.7 ml (19.4 mmol.) of triethylamine in chloroform (5 ml). The mixture was stirred for further one hour. The solvent was distilled off under reduced pressure. To the residue was added water, and the mixture was subjected to extraction with chloroform. The organic layer was washed with a saturated aqueous saline solution, which was dried over magnesium sulfate. The concentrate was purified by means of a column chromatography (methanol/ethyl acetate 20%) to afford the object compound as a reddish amorphous product. The yield was 1.56 g (89%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[C:12]1[C:17]([CH:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]([CH3:29])[N:15]=[C:14]2[S:30][C:31]3[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=3[C:13]=12)C=C.CN1C(=O)CC(=O)N(C)C1=O>ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:25]([O:24][CH:18]([C:17]1[C:12]([C:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=2[OH:4])=[C:13]2[C:32]3[CH2:33][CH2:34][CH2:35][CH2:36][C:31]=3[S:30][C:14]2=[N:15][C:16]=1[CH3:29])[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:26])[CH3:27]
Reactant: C=CCOc1cc(C)ccc1-c1c(C(OC(C)(C)C)C(=O)OCC)c(C)nc2sc3c(c12)CCCC3
Agent: [Pd]
Agent: CN1C(=O)CC(=O)N(C)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1O)CCCC3
Yield: 63 %

Procedure:
To a stirred solution of ethyl {4-[2-(allyloxy)-4-methylphenyl]-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl}(tert-butoxy)acetate (Step 8, 370 mg, 729 μmol) in dichloromethane (10 mL) was added 1,3-dimethylbarbituric acid (569 mg, 3.64 mmol), and the reaction was evacuated and filed with nitrogen. Palladium tetrakis(triphenylphosphine) (17 mg, 15 μmol) was added and the reaction was heated to reflux for 16 hours. Further palladium tetrakis(triphenylphosphine) (17 mg, 15 μmol) was added and the reaction was heated to reflux for a further 4 hours. The reaction was concentrated in vacuo and preabsorbed onto silica. The residue was purified using ISCO Companion with a Redisep silica gel 12 g cartridge and a gradient of heptane and ethyl acetate (0% to 20%). Product containing fractions were concentrated in vacuo to give the title compound as a pair of diastereoisomers as a colourless oil, 214 mg, in a 63% yield. The other pair of minor diastereoisomers co-eluted with unreacted starting material and were not isolated. LC-MS (12 min acidic) 6.89 mins 100% pure by UV, ES+/APCI+ 468, ES−/APCI− 466 1H NMR (400 MHz, CDCl3) δ ppm 1.01 (s, 9 H) 1.20 (t, 3 H) 1.62-1.85 (m, 4 H) 2.02-2.14 (m, 2 H) 2.41 (s, 3 H) 2.74 (s, 3 H) 2.78-2.85 (m, 2 H) 4.08-4.18 (m, 2 H) 5.14 (s, 1 H) 6.78 (s, 1 H) 6.82 (d, 1 H) 7.17 (d, 1 H).
Reaction SMILES: [F:1][CH:2](F)[CH:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([C:17]([O:19][CH3:20])=[O:18])=[C:5]([C:21]([F:24])([F:23])[F:22])[NH:4]1.FC(F)C1NC(C(F)(F)F)C(C(OC)=O)=C(CC(C)C)C=1C(OC)=O.C1CCN2C(=NCCC2)CC1>CCOCC>[F:1][CH2:2][C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([C:17]([O:19][CH3:20])=[O:18])=[C:5]([C:21]([F:24])([F:22])[F:23])[N:4]=1
Reactant: COC(=O)C1=C(C(F)(F)F)NC(C(F)F)C(C(=O)OC)=C1CC(C)C
Agent: COC(=O)C1=C(C(F)F)NC(C(F)(F)F)C(C(=O)OC)=C1CC(C)C
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1c(CF)nc(C(F)(F)F)c(C(=O)OC)c1CC(C)C
Yield: 19 %

Procedure:
To a solution of 50.3 g (0.136 mole) of product of example 14 in 200 ml of DMF is added 21.3 g (0.563 mole) of sodium borohydride. The reaction mixture becomes exothermic and the temperature of the reaction mixture rises to 65° C. and subsides to 40° C. after 40 min. of stirring. To the reaction mixture is added 15 ml of water. The exothermic reaction mixture is cooled by an ice-water bath to 40° C. The cooling bath is removed and the reaction mixture is stirred for 20 min. before being poured into 1 L of water. The organic is extracted into 500 ml of methylene chloride. The methylene chloride extract is dried over magnesium sulfate and concentrated. The residual oil (44.5 g) is purified by HPLC using 5% ethyl acetate in cyclohexane as eluent. The first 2.8 L of eluate gives 7.6 g of an oil which contains 56% of the desired product, 22% of the starting material, and 22% of an unidentified material. The second 2.5 L of eluate gives 24.6 g of an oil which contains a mixture of dimethyl 2-(difluoromethyl)-1,2-dihydro-4-isobutyl-6-(trifluoromethyl)-3,5-pyridinedicarboxylate (E) and dimethyl 6-(difluoromethyl)-1,2-dihydro-4-isobutyl-2-(trifluoromethyl)-3,5-pyridinedicarboxylate (F) and other unidentified products. This oil is crystallized from ether-hexane to give 7.4 g (15%) of a solid, mp 82°-85° C., which is a 4.6:1 mixture of above mentioned (E) and (F). The mother liquor is concentrated to an oil (15.6 g) which contains (E), (F), and other unidentified products. A solution of above oil, 9.0 g (0.0568 mole) of DBU and 100 ml of ether is stirred for 18 hours and washed with 100 ml of 3N hydrochloric acid. The ether solution is dried over magnesium sulfate and concentrated. The residual oil (14.5 g) is purified by HPLC using 5% ethyl acetate in cyclohexane as eluent. The first 2.0 L of eluate gives 8.8 g (19%) of the desired product as an oil, n25D 1.4567.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH:5]([C:7]([O:9]C)=[O:8])[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1.O.[OH-].[Li+]>C1COCC1.O>[C:14]([O:13][C:11]([N:4]1[CH:5]([C:7]([OH:9])=[O:8])[CH2:6][S:2](=[O:1])(=[O:18])[CH2:3]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C1CS(=O)(=O)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CS(=O)(=O)CC1C(=O)O
Yield: 92 %

Procedure:
A solution of O3-tert-butyl O4-methyl 1,1-dioxo-1,3-thiazolidine-3,4-dicarboxylate (Example 127 a, 0.35 g, 1.25 mmol) and lithium hydroxide hydrate (63.1 mg, 1.5 mmol) in THF (3.5 mL) and water (1.05 mL) was stirred for 20 h at ambient temperature. The reaction mixture was poured onto ice/0.1N HCl (25 mL) and extracted with EtOAc (2×25 mL). The combined extracts were washed with ice/brine (1×25 mL), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to give the title compound (306 mg, 92%) as colorless foam, MS (ESI) m/e=264.05 [M−H−].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][CH:11]=[C:10]3[N:14]([CH3:18])[N:15]=[C:16]([NH2:17])[C:9]=23)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[N:30]=[C:31]=[O:32].FC1C=CC(C)=CC=1N=C=O>>[NH2:17][C:16]1[C:9]2[C:10](=[CH:11][N:12]=[CH:13][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:31]([NH:30][C:21]3[CH:22]=[C:23]([C:26]([F:27])([F:29])[F:28])[CH:24]=[CH:25][C:20]=3[F:19])=[O:32])=[CH:7][CH:6]=2)[N:14]([CH3:18])[N:15]=1
Reactant: Cn1nc(N)c2c(-c3ccc(N)cc3)cncc21
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Agent: Cc1ccc(F)c(N=C=O)c1
Product: Cn1nc(N)c2c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)cncc21

Procedure:
The title compound was prepared using the procedure described in Example 1E using the product from Example 6A and 1-fluoro-2-isocyanato-4-trifluoromethyl-benzene instead of the product from Example 1D and 1-fluoro-2-isocyanato-4-methyl-benzene. MS (ESI(+)) m/e 445 (M+H)+; 1H NMR (500 MHz, DMSO-D6) δ ppm 3.92 (s, 3H) 4.66 (s, 2H) 7.36-7.45 (m, 1H) 7.46-7.55 (m, 1H) 7.50 (d, J=8.73 Hz, 2H) 7.65 (d, J=8.42 Hz, 2H) 7.95 (s, 1H) 8.64 (dd, J=7.33, 2.03 Hz, 1H) 8.87 (s, 1H) 8.95 (d, J=2.81 Hz, 1H) 9.35 (s, 1H).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:16]([O:18]C)=O)[CH:9]=[C:10]([CH:15]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:20]([O:23][CH3:24])(=[O:22])[CH3:21].C[O-].[Na+].Cl>CN(C)C=O.O>[CH3:14][O:13][C:11]([C:10]1[CH:9]=[C:8]([C:16](=[O:18])[CH2:21][C:20]([O:23][CH3:24])=[O:22])[CH:7]=[C:6]([N:1]2[CH:2]=[CH:3][CH:4]=[CH:5]2)[CH:15]=1)=[O:12]
Reactant: COC(=O)c1cc(C(=O)OC)cc(-n2cccc2)c1
Reactant: COC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)c1cc(C(=O)OC)cc(-n2cccc2)c1
Temperature: 55 °C
Yield: 8.9 %

Procedure:
A mixture of dimethyl 5-(pyrrol-1-yl)isophthalate (3.0 g), methyl acetate (0.86 g) and sodium methoxide (0.81 g) in N,N-dimethylformamide (21 ml) was heated at 55° C. for 3 hours. After being cooled to room temperature, the reaction mixture was poured into water (100 ml) and the whole was adjusted to pH 3 with 10% hydrochloric acid. The resulting precipitate was collected and washed with water. This crude product was purified by column chromatography on silica gel (150 ml) with benzene-ethyl acetate (30:1) as an eluent. The fractions containing the object product were collected and evaporated in vacuo. The residue was recrystallized from methanol to afford methyl 3-[3-methoxycarbonyl-5-(pyrrol-1-yl)phenyl]-3-oxopropionate (0.31 g).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3].Br[C:20]1[O:24][C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][N:32]3[CH:35]=[CH:36][N:37]=[C:31]3[CH:30]=2)=[O:26])=[CH:22][CH:21]=1.BrC1C=CC(N)=CC=1>>[N:37]1[CH:36]=[CH:35][N:32]2[CH:33]=[CH:34][C:29]([CH2:28][NH:27][C:25]([C:23]3[O:24][C:20]([C:9]4[N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[N:6]=[CH:7][CH:8]=4)=[CH:21][CH:22]=3)=[O:26])=[CH:30][C:31]=12
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(Br)o1
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Nc1ccc(Br)cc1
Product: CC(C)Cn1nccc1-c1ccc(C(=O)NCc2ccn3ccnc3c2)o1

Procedure:
The title compound was prepared as described in Example 51A, substituting 1-isobutyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5-bromo-N-(imidazo[1,2-a]pyridin-7-ylmethyl)furan-2-carboxamide for 4-bromoaniline. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.03 (t, J=6.1 Hz, 1H), 8.49 (dd, J=7.0, 0.7 Hz, 1H), 7.89 (s, 1H), 7.54-7.51 (m, 2H), 7.41 (s, 1H), 7.30 (d, J=3.6 Hz, 1H), 6.96 (d, J=3.6 Hz, 1H), 6.85 (dd, J=7.0, 1.6 Hz, 1H), 6.76 (d, J=1.9 Hz, 1H), 4.50 (d, J=6.0 Hz, 2H), 4.22 (d, J=7.3 Hz, 2H), 2.04 (dp, J=13.8, 6.8 Hz, 1H), 0.81 (d, J=6.7 Hz, 6H); MS (ESI(+)) m/e 364 (M+H)+.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[NH:33]1[CH2:38][CH2:37][CH:36]([N:39]2[C:43]3[CH:44]=[CH:45][C:46]([F:48])=[CH:47][C:42]=3[N:41]=[CH:40]2)[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CN(C=O)C>[F:48][C:46]1[CH:45]=[CH:44][C:43]2[N:39]([CH:36]3[CH2:35][CH2:34][N:33]([CH2:1][C@@H:3]4[C@@H:7]([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)[CH2:6][N:5]([C@H:14]([CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)[C:15]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=5)=[O:16])[CH2:4]4)[CH2:38][CH2:37]3)[CH:40]=[N:41][C:42]=2[CH:47]=1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: Fc1ccc2c(c1)ncn2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(n4cnc5cc(F)ccc54)CC3)[C@@H](c3ccccc3)C2)cc1
Yield: 73.3 %

Procedure:
The title compound was prepared from 40 mg of α-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxy-benzyl ester (prepared above as Aldehyde 5), 40 mg 1-piperidin-4-yl-5-fluoro-1-H-benzoimidazole (from Step C ) and 60 mg of sodium triacetoxyborohydride in 4 mL of THF and 1 mL of DMF, using a procedure analogous to that described in Example 95, Step D to provide 43 mg of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH3:7])=[C:4]([C:8]([OH:10])=O)[CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:17]1([O:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([CH3:7])=[C:4]([C:8]([C:20]2[CH:21]=[CH:22][C:17]([O:23][CH3:24])=[CH:18][CH:19]=2)=[O:10])[CH:3]=1
Reactant: Cc1sc(Br)cc1C(=O)O
Reactant: COc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cc(Br)sc2C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of acid 8 (10 g, 45.2 mmol) in CH2Cl2 (200 mL) were added oxalyl chloride (4.8 mL, 54.3 mmol) and catalytic amounts of DMF at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and dried under high vacuum. The crude acid chloride was dissolved with CH2Cl2 (200 mL) and cooled to 0° C. To the mixture was added anisole (5.0 mL, 45.2 mmol) at 0° C. and stirred at 0° C. for 5 min. To the reaction mixture was added AlCl3 (6.0 g, 45.2 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 2 hours, warmed up to room temperature and stirred at room temperature for 15 hours. The mixture was poured into ice-water and extracted with CH2Cl2 (100 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was tritulated with MeOH (100 mL) and stirred at 0° C. for 1 hour. The precipitated solid was filtered and washed with MeOH (50 mL). The solid was dried under high vacuum and used without further purification (11.7 g, 83%).
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)[CH2:3][CH2:4][Cl:5].[CH3:17][C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C1(C)C(C)=CC=CC=1>[ClH:5].[O:1]=[C:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)[CH2:3][CH2:4][N:28]1[CH2:29][CH2:30][N:25]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:18]=2[CH3:17])[CH2:26][CH2:27]1
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: O=C1CCc2cc(C(=O)CCCl)ccc2N1
Solvent: Cc1ccccc1C
Product: Cc1cccc(N2CCN(CCC(=O)c3ccc4c(c3)CCC(=O)N4)CC2)c1C
Product: Cl

Procedure:
2.4 Grams of 6-(1-oxo-3-chloropropyl)-3,4-dihydrocarbostyril and 4.5 g of 4-(2,3-dimethylphenyl)-piperazine were mixed with 80 ml of xylene and the mixture was refluxed by heating for 24 hours. Then the reaction mixture was concentrated under a reduced pressure to dryness. Thus obtained solid matter was dissolved in 100 ml of chloroform, the chloroform layer was washed with 5%-sodium hydrogencarbonate aqueous solution twice and washed with water twice then dried with anhydrous sodium sulfate, and chloroform was removed by distillation to obtain the residue. To the residue thus obtained was added ether-hexane and the insoluble matters were collected by filtration and recrystallized from concentrated hydrochloric acid-ethanol-water to obtain 2.6 g of 6-{1-oxo-3-[4-(2,3-dimethylphenyl)-1-piperazinyl]-propyl}-3,4-dihydrocarbostyril monohydrochloride in cololress needle-like crystals.
Reaction SMILES: [CH2:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:10][CH2:11]O)[C:4]1=[O:13])[CH3:2].CCN(CC)CC.CS(Cl)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>C(Cl)Cl.CN(C=O)C>[N:34]([CH2:11][CH2:10][N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C:3]([CH2:1][CH3:2])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[C:4]1=[O:13])=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC1(c2cccc(OC)c2)CCCCN(CCO)C1=O
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC1(c2cccc(OC)c2)CCCCN(CCN=[N+]=[N-])C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-ethyl-1-(2-hydroxy-ethyl)-3-(3-methoxyphenyl)-azepan-2-one (as described above in Step A) (0.6 g, 2.05 mmol) in CH2Cl2 (15 mL) at 0° C. was added NEt3 (0.85 mL, 6.15 mmol) and methanesulfonyl chloride (0.19 mL, 2.45 mmol). The mixture was stirred for 30 min at 25° C. then NaN3 (0.27 g, 4.1 mmol) in DMF (3 mL) was added. The reaction was stirred for 18 hr then partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was washed with brine and dried (MgSO4) Filtration and concentration to dryness gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH3:16])[CH:5]=[CH:4][N:3]=1.[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:22](Cl)=[O:23]>>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH3:16])[C:22](=[O:23])[C:21]2[CH:20]=[C:19]([C:18]([F:33])([F:32])[F:17])[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccnc(Cl)c1F
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccnc(Cl)c1F

Procedure:
The title compound was prepared in analogy to example 55, from (2′-chloro-3′-fluoro-[4,4]bipyridinyl-3-yl)-methyl-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using preparative HPLC for the chromatographic purification. Off-white solid (12%). MS (ESI): m/z=478.0 [M+H]+.
Reaction SMILES: [CH:1]1([CH:6]2[CH2:14][C:13]3[C:8](=[C:9]([Cl:18])[C:10]([Cl:17])=[C:11]([S:15][CH3:16])[CH:12]=3)[C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:22]I>COCCOC>[CH:1]1([C:6]2([CH3:22])[CH2:14][C:13]3[C:8](=[C:9]([Cl:18])[C:10]([Cl:17])=[C:11]([S:15][CH3:16])[CH:12]=3)[C:7]2=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CSc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2

Procedure:
2-Cyclopentyl-2-methyl-5-methylthio-6,7-dichloro-1-indanone is prepared following substantially the same procedure described in Example 10, Step D, using the following substances: 2-cyclopentyl-5-methylthio-6,7-dichloro-1-indanone (7.9 g., 0.025 mole), 1,2-dimethoxyethane (200 ml.), sodium hydride (660 mg., 0.0275 mole) and methyl iodide (7.5 ml.).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([O:27]C)=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[C:8]([S:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].ClC1C=C(C=CC=1)C(OO)=[O:45]>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([OH:27])=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[C:8]([S:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[O:45])=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(SCc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(OC(C(=O)OC)c2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCc1nnc(S(=O)Cc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(OC(C(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-butyl-4-[[4-[1-(carbomethoxy)-1-phenylmethoxy]phenyl]methyl]-5-(4-nitrobenzylthio)-4H-1,2,4-triazole (from Example 1, Step F) in dry CH2Cl2 is treated with m-chloroperoxybenzoic acid (1 equivalent), and the resulting mixture is stirred at room temperature for about 30 minutes or until TLC indicates complete reaction. At this point the mixture is partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase is washed repeatedly with saturated NaHCO3, then dried over MgSO4, filtered, and concentrated. The residue may be purified by chromatography on silica gel to give the title compound.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].CS(CCO)(=O)=[O:22].[H-].[Na+]>CN(C=O)C>[OH:22][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)CCO
Reactant: O=C(O)c1ccc(F)c(S(=O)(=O)N2CCOCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(O)c(S(=O)(=O)N2CCOCC2)c1
Reaction time: 0.08 h
Yield: 73.3 %

Procedure:
4-Fluoro-3-(morpholine-4-sulfonyl)-benzoic acid (Example 6, 5.36 g, 19 mmol) was dissolved in DMF and commercially available 2-methylsulfonyl ethanol (4.8 g, 39 mmol) was added. After five minutes of stirring, sodium hydride (2.4 g of 60% dispersion in mineral oil, 61 mmol) was added. The solution immediately turned black. After 15 min, the reaction was complete. The DMF solution was partitioned between ethyl acetate (150 mL) and brine/HCl (200 mL). The brine solution was discarded, and this was repeated two additional times. All ethyl acetate was dried with magnesium sulfate, and removed under reduced pressure to provide the title compound as a white solid (4.0 g, 74%): 1HNMR (DMSO-d6) δ8.23 (d, J=2 Hz, 1H), 8.02 (dd , J=9 Hz, 2 Hz, 1H), 7.09 (d, J=9 Hz, 1H), 3.62 (m, 4H), 3.12 (m, 4H); MS (−APCI):[M−H]−286; Anal.Calc. for C11H13NO6S: C, 44.99; H, 4.56; N, 4.88. Found: C, 45.45; H, 4.41; N, 4.74.