Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([OH:13])=O)=[CH:7][CH:8]=2)[NH:3]1.[NH2:14][C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:19][CH:20]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:22]([NH:21][C:17]1[CH:16]=[C:15]([NH:14][C:11]([C:6]2[CH:5]=[C:4]3[C:9]([CH2:10][C:2](=[O:1])[NH:3]3)=[CH:8][CH:7]=2)=[O:13])[CH:20]=[CH:19][CH:18]=1)(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1Cc2ccc(C(=O)O)cc2N1
Reactant: Nc1cccc(NC(=O)c2ccccc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1Cc2ccc(C(=O)Nc3cccc(NC(=O)c4ccccc4)c3)cc2N1
Reaction time: 20 h

Procedure:
To a solution of 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid (0.20 g, 1.1 mmol) in DMF (1 ml) is added N-(3-amino-phenyl)-benzamide (0.26 g, 1.2 mmol), N,N-diisopropylethylamine (0.44 g, 3.4 mmol) and HATU (0.47 g, 1.24 mmol). The reaction is stirred for 20 hours and concentrated. The residue is purified by HPLC (C18 column, eluted with CH3CN—H2O containing 0.05% TFA) to give 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid (3-benzoylamino-phenyl)-amide as off-white solid. This amide (15 mg, 0.04 mmol) is then heated with 1H-pyrrole-2-carbaldehyde (6.0 mg, 0.06 mmol) in ethanol (2 ml) in the presence of 2 drops of piperidine at 80° C. for 20 hours. The mixture is concentrated and the desired compound is obtained after HPLC purification: 1H NMR (DMSO-d6) δ 6.41 (s, 1H), 6.93 (s, 1H), 7.31 (t, 1H, J=7.8 Hz), 7.44 (s, 1H), 7.48-7.51 (m, 3H), 7.54 (t, 2H, J=7.2 Hz), 7.59 (d, 1H, J=6.6 Hz), 7.70 (d, 1H, J=8.4 Hz), 7.78 (d, 1H, J=8.4 Hz), 7.92 (s, 1H), 7.98 (d, 2H, J=7.2 Hz), 8.33 (s, 1H), 10.27 (s, 1H), 10.31 (s, 1H), 11.13 (s, 1H), 13.38 (s, 1H); LC-MS: 449.1 (MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[C:16]([O:22][CH2:23][CH2:24][O:25][C:26]4[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=4)=[N:17][N:18]([CH3:21])[C:19]=3[NH2:20])=[CH:14][C:9]=2[O:8][CH2:7]1.CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[C:16]([O:22][CH2:23][CH2:24][O:25][C:26]4[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=4)=[N:17][N:18]([CH3:21])[C:19]=3[N:20]([S:2]([CH3:1])(=[O:4])=[O:3])[S:2]([CH3:1])(=[O:4])=[O:3])=[CH:14][C:9]=2[O:8][CH2:7]1
Reactant: Cn1nc(OCCOc2ncc(Cl)cn2)c(-c2ccc3c(c2)OCO3)c1N
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: Cn1nc(OCCOc2ncc(Cl)cn2)c(-c2ccc3c(c2)OCO3)c1N(S(C)(=O)=O)S(C)(=O)=O
Reaction time: 24 h

Procedure:
Methanesulfonyl chloride (20 ul) was added at room temperature under an atmosphere of nitrogen to a mixture of 4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-ylamine (50 mg) (Preparation 48), dimethylaminopyridine (16 mg) in anhydrous pyridine (2.4 ml) and the reaction was stirred for 24 h. The mixture was concentrated under reduced pressure, then a saturated solution of ammonium chloride (6 ml), ethyl acetate (6 ml), and brine (6 ml) were sequentially added to the residue. The aqueous phase was extracted with ethyl acetate (2×8 ml) and the combined organic fractions were washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The oil was purified by preparative TLC (silica) eluted with dichloromethane:methanol (95:5) to yield the title compound as a pale yellow oil (71 mg).
Reaction SMILES: CN(C=[N:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[C:26](C=O)=[C:25]([Cl:29])[N:24]=[C:23]3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])C.Cl.C(O)C>O>[Cl:29][C:25]1[N:24]=[C:23]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:22]([CH2:21][C:18]2[CH:17]=[CH:16][C:15]([C:10]3[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:20][CH:19]=2)[CH:26]=1
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(Cn2c(-c3ccccc3)nc(Cl)c2C=O)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)c1ccccc1-c1ccc(Cn2cc(Cl)nc2-c2ccccc2)cc1
Yield: 0 %

Procedure:
9.2 g of 4′-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonic acid dimethylaminomethylenamide (Example 11a), 95 ml of a saturated aqueous HCl solution and 95 ml of ethanol are refluxed for 2 h. After cooling, the mixture is diluted with 500 ml of water and extracted twice using 500 ml of EA each time and the organic phase is washed twice using 100 ml of a saturated aqueous NaCl solution each time. The extract is dried over Na2SO4 and the solvent is removed in vacuo. The product mixture is recrystallized from 200 ml of EA and 6.2 g of 4′-(4-chloro-5-formyl-2-phenyl-imidazol-1-ylmethyl)biphenyl-2-sulfonamide (compare Example 11b) are obtained. The solvent of the mother liquor is removed in vacuo and the residue is chromatographed on silica gel using MTB/DIP 1:1.40 mg of a colorless oil are obtained.
Reaction SMILES: [CH3:1][CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[Li]CCCC.[CH2:20]1[O:22][CH2:21]1>C1COCC1>[CH3:1][C:2]1([CH2:20][CH2:21][OH:22])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: C1CO1
Reactant: CC1c2ccccc2-c2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(CCO)c2ccccc2-c2ccccc21
Temperature: -20 °C

Procedure:
To a solution of 9-methylfluorene (10.0 g, 55.5 mmol) in 100 mL of THF was added n-BuLi (61.0 mmol) at -10° C., then a solution of ethylene oxide (61.0 mmol) in THF was added in one portion. The reaction mixture was stirred at -20° C., then allowed to warm to room temperature, quenched with NH4Cl solution and evaporated to a residue. This was then partitioned between ethyl acetate and water, the organic layer was washed with brine, dried with MgSO4 and evaporated to get the product which was purified by chromatography using 10% ethyl acetate/hexane mixture to provide a pure sample of 9-methylfluorene-9-ethanol, m.p. 84°-85° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=3)[N:12]=2)[CH2:5][C@@H:4]([CH3:20])[O:3]1.Cl.Cl.[NH2:23][C@H:24]1[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1>>[N:26]12[CH2:25][C@@H:24]([NH:23][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:10]4[O:9][C:8]([N:6]5[CH2:5][C@@H:4]([CH3:20])[O:3][C@@H:2]([CH3:1])[CH2:7]5)=[N:12][C:11]=34)=[O:19])[CH:29]([CH2:30][CH2:31]1)[CH2:28][CH2:27]2
Reactant: C[C@@H]1CN(c2nc3c(C(=O)O)cccc3o2)C[C@H](C)O1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: Cl
Product: C[C@@H]1CN(c2nc3c(C(=O)N[C@@H]4CN5CCC4CC5)cccc3o2)C[C@H](C)O1

Procedure:
Following general procedure GP-C1, a mixture of 2-[(2S,6R)-2,6-dimethylmorpholino]benzoxazole-4-carboxylic acid and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to provide (S)—N-(quinuclidine-8-yl)-2-((2S,6R)-2,6-dimethylmorpholino)benzoxazole-4-carboxamide, which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:16]1[C:17]2[C:22]([N:23]=[C:24]3[C:29]=1[CH:28]=[CH:27][CH:26]=[CH:25]3)=[CH:21][CH:20]=[CH:19][CH:18]=2>CN(C=O)C>[CH:18]1[C:17]2[C:22](=[N:23][C:24]3[C:29]([C:16]=2[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:21]=[CH:20][CH:19]=1
Reactant: Clc1c2ccccc2nc2ccccc12
Reactant: COC(=O)Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc(Cl)cc1)c1c2ccccc2nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
After a mixture of DMF (250 ml), methyl p-chlorophenylacetate (25.9 g, 140 mmol) and NaH (211 mmol) was stirred at room temperature for 1 hour, 9-chloroacridine (15.0 g, 70.2 mmol) dissolved in 250 ml of DMF was added slowly. The resultant reaction mixture was stirred at room temperature for 18 hours. This reaction mixture was then poured onto 1.5 l. of an ice/H2O mixture and extracted with CHCl3 (500 ml). The CHCl3 extract was washed with H2O (3×500 ml) and dried over MgSO4. Evaporation of the CHCl3 extract gave a crude residual solid which was recrystallized from cyclohexane; yield, 20.2 g (79.4%), mp 192°-193°.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[NH2:18][OH:19].[OH-].[K+]>C(O)C>[CH3:1][O:2][C:3]1([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[N:18][OH:19])[CH2:5][CH2:4]1
Reactant: NO
Reactant: COC1(c2ccc(C)cc2)CCC(=O)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC1(c2ccc(C)cc2)CCC(=NO)CC1

Procedure:
A mixture of 3.73 g. (0.17 mole) of 4-methoxy-4-(p-methylphenyl)cyclohexanone (prepared as in Example 28), 3.75 g. of hydroxylamine hydrochloride and 7.5 ml. of aqueous 50% potassium hydroxide solution in 70 ml. of ethanol is heated at reflux for about 4 hours. The solvent is removed under vacuum and the residue dissolved in water and ether. The organic layer is washed with water and brine and evaporated to dryness to give 4.04 g. (99%) of product. A sample recrystallized from aqueous methanol gives pure 4-methoxy-4-(p-methylphenyl)cyclohexanone oxime, having a melting point of 114° to 115.5° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[Na].[CH3:11][C:12]1[N:17]2[N:18]=[CH:19][C:20]([C:21](OCC)=[O:22])=[C:16]2[CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[CH3:11][C:12]1[N:17]2[N:18]=[CH:19][C:20]([C:21]([O:9][CH:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[O:22])=[C:16]2[CH:15]=[CH:14][CH:13]=1
Reactant: OC1CN2CCC1CC2
Reactant: CCOC(=O)c1cnn2c(C)cccc12
Agent: [Na]
Solvent: c1ccccc1
Product: Cc1cccc2c(C(=O)OC3CN4CCC3CC4)cnn12
Reaction time: 2.5 h
Yield: 85.7 %

Procedure:
After a suspension of 370 mg (2.9 mmol) of 3-quinuclidinol (product of Aldrich Chemical Co., Inc.) in 30 ml of benzene was refluxed for 1.5 hours by using a Dean-Stark apparatus, 0.1 g of metal sodium was added and the resultant mixture was refluxed under stirring for further 2.5 hours. Unreacted sodium was removed and 200 mg (0.98 mmol) of ethyl 7-methylpyrazolo[1,5-a]pyridine-3-carboxylate were added, followed by heating under reflux for 24 hours. The solvent of the reaction mixture was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column (chloroform: methanol=10:1), whereby 240 mg (0.84 mmol) of the title compound were obtained as white crystals (yield: 86%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:44]=[C:35]5[CH2:36][N:37]([CH2:40][CH:41]([F:43])[F:42])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:45])[N:27]([CH3:46])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.ClCCl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:44]=[C:35]5[CH2:36][N:37]([CH2:40][CH:41]([F:43])[F:42])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:45])[N:27]([CH3:46])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2C=O)cc(Nc2cc3n(n2)CCN(CC(F)F)C3)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2cc3n(n2)CCN(CC(F)F)C3)c1=O
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a solution of 135e (100 mg, 0.158 mmol) in methanol/dichloromethane (4/4 mL) was added NaBH4 (18 mg, 0.475 mmol) at room temperature. After the reaction was stirred for 1 h, LCMS indicated the reaction was complete. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 135 (60 mg, 60%) as a white solid. MS-ESI: [M+H]+ 635.3. 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J=5.0 Hz, 1H), 8.35 (d, J=2.5 Hz, 1H), 8.00 (d, J=2.5 Hz, 1H), 7.59-7.58 (m, 1H), 7.56-7.55 (m, 1H), 7.53-7.52 (m, 2H), 7.45 (s, 1H), 6.07-5.83 (m, 1H), 5.72 (s, 1H), 4.51-4.49 (m, 2H), 4.11-4.08 (m, 2H), 4.05-4.03 (m, 1H), 3.94 (s, 2H), 3.73 (s, 3H), 3.13-3.10 (m, 2H), 3.00-2.94 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([S:10]([NH2:13])(=[O:12])=[O:11])[C:4]=2[CH2:3][S:2]1(=O)=O.C[Al](C)C.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([NH:30][C:31](=O)[O:32]C)[N:23]=1.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:29][O:28][C:26]1[CH:27]=[C:22]([O:21][CH3:20])[N:23]=[C:24]([NH:30][C:31]([NH:13][S:10]([C:9]2[C:4]3[CH2:3][S:2][CH2:1][C:5]=3[CH:6]=[CH:7][CH:8]=2)(=[O:12])=[O:11])=[O:32])[N:25]=1
Reactant: NS(=O)(=O)c1cccc2c1CS(=O)(=O)C2
Reactant: COC(=O)Nc1nc(OC)cc(OC)n1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cccc3c2CSC3)n1
Temperature: 25 °C
Yield: 26.1 %

Procedure:
A suspension of 0.74 g of the sulfonamide prepared in Example 13 in 50 ml of methylene chloride was cooled to 10° to 15° under nitrogen, and 1.7 ml of a 2M solution of trimethylaluminum in toluene was added slowly. The suspension was allowed to warm to room temperature, 0.67 g of methyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate was added, and the reaction mixture was heated at reflux overnight. The turbid solution was cooled to 0°-5° and 50 ml of 5% hydrochloric acid was added dropwise. The two-phase suspension was allowed to warm to ambient temperature, then filtered. The solid was washed with 1-chlorobutane and dried giving 0.31 g of 1,3-dihydro-N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]benzo[c]thiophene-4-sulfonamide, 2,2-dioxide, m.p. 170°-173°(d).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]Br)[CH:20]=1>>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:25][C:21]3[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=3)[C:18]([OH:27])=[O:17])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2ccc(O)cc2)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Product: COc1ccc(-c2ccc(OCc3cccc(C(=O)O)c3)cc2)cc1

Procedure:
3-(4′-Methoxy-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure A from 4-hydroxy-4′-methoxybiphenyl (available from TCI America, Portland, Oreg.) and 3-(bromomethyl)benzoic acid methyl ester (available from Lancaster Synthesis Ltd., Morcambe, Lancashire, UK). Yield: 73 mg. Mass spectrum (ES) MH+=335.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.[CH3:14][N:15](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[NH2:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[CH2:7][C:6]=2[C:5]([C:14]#[N:15])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CN1Cc2c(Br)ccc(N)c2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CN1Cc2c(C#N)ccc(N)c2C1=O
Temperature: 150 °C
Yield: 64.4 %

Procedure:
A mixture of 7-Amino-4-bromo-2-methyl-2,3-dihydro-1H-isoindol-1-one (100.0 mg, 0.4148 mmol), zinc cyanide (48.71 mg, 0.4148 mmol) and Pd(PPh3)4 (71.90 mg, 0.06222 mmol) in DMF (1.5 mL, 19 mmol) was evacuated and purged with N2 three times. The mixture was heated in microwave at 150° C. for 5 minutes. The crude mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was evaporated and purified on an ISCO Combiflash unit to isolate the title compound (50.0 mg, 64% yield). MS (ES+): m/z 188.14 (100) [MH+]; HPLC: tR=1.00 min (UPLC, analytical).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[F:1][C:2]1[CH:10]=[C:6]([C:7]([NH:20][C@H:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH3:22])=[O:9])[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[N:4][CH:3]=1
Reactant: O=C(O)c1cc(F)cnc1Oc1cccc(F)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(F)cnc2Oc2cccc(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-fluoro-2-(3-fluorophenoxy)nicotinic acid (step 1) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.33 (1H, dd, J=8.2, 3.1 Hz), 8.12–7.98 (4H, m), 7.47–7.38 (3H, m), 7.05–6.89 (3H, m), 5.36 (1H, m), 3.90 (3H, s), 1.60 (3H, d, J=6.9 Hz).
Reaction SMILES: N[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:3]=1[C:20]#[N:21].[I:22]CI.N(OCCC(C)C)=O>C(#N)C>[C:20]([C:3]1[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:6][C:2]=1[I:22])#[N:21]
Reactant: ICI
Reactant: CCOC(=O)c1sc(N)c(C#N)c1-c1ccc(Cl)cc1Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CCOC(=O)c1sc(I)c(C#N)c1-c1ccc(Cl)cc1Cl
Temperature: 38 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
To a suspension of ethyl 5-amino-4-cyano-3-(2,4-dichlorophenyl)thiophene-2-carboxylate (2.92 g, 0.00856 mol) in acetonitrile (10 mL) was added diiodomethane (2.41 mL, 0.0300 mol) under an atmosphere of argon and was heated at 38° C. Isoamyl nitrite (2.61 g, 0.0214 mol) was added dropwise and the reaction mixture was cooled to room temperature and stirred for one hour. The reaction was concentrated in vacuo and column chromatography was performed to yield the title compound (1.44 g, 37%) as an orange solid. 1H NMR (400 MHz, d1-chloroform) δ: 7.53 (d, 1H, J=2.00 Hz), 7.38-7.34 (m, 1H), 7.21 (d, 1H, J=8.28 Hz), 4.25-4.15 (m, 2H), 1.21-1.16 (m, 3H).
Reaction SMILES: C(O)[CH:2]([OH:8])[CH2:3][CH2:4][CH2:5]CC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C:21]1([CH3:39])[CH:26]=[CH:25][C:24]([S:27]([O:30][CH2:31][CH:32]([OH:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1>[C:2]([O:38][CH:32]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:31][O:30][S:27]([C:24]1[CH:23]=[CH:22][C:21]([CH3:39])=[CH:26][CH:25]=1)(=[O:28])=[O:29])(=[O:8])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC(O)CO
Reactant: CCCCCC(O)COS(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCCCC(COS(=O)(=O)c1ccc(C)cc1)OC(=O)CCC

Procedure:
Using 1,2-heptanediol, pyridine and p-toluenesulfonyl chloride, (RS)-1-p-toluenesulfonyloxy-2-heptanol 2c ##STR26## was prepared in the same manner as Example 1 of Production.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[O:8])[NH:5][CH:6]=1.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[C:2]1[CH:3]=[C:4]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[O:8])[NH:5][CH:6]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Br)c[nH]2)CC1
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: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(Cl)cc3Cl)c[nH]2)CC1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
A mixture of tert-butyl 4-(4-bromo-1H-pyrrole-2-carbonyl)piperazine-1-carboxylate (350 mg, 0.98 mmol), (2,4-dichlorophenyl) boronic acid (280 mg, 1.47 mmol), Pd(PPh3)4 (116 mg, 0.1 mmol), Na2CO3 (312 mg, 2.94 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at reflux under argon for 16 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=30:1) to afford the desired product (273 mg, 59% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14](O)=[O:15])[C:11]3[C:17]([CH:24]=[O:25])=[C:18]([C:20]([O:22][CH3:23])=[O:21])[S:19][C:10]=3[C:9]=2[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:65]([N:68]1[CH2:72][CH2:71][CH:70]([NH:73][CH3:74])[CH2:69]1)([CH3:67])[CH3:66]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:13][C:14]([N:73]([CH:70]3[CH2:71][CH2:72][N:68]([CH:65]([CH3:67])[CH3:66])[CH2:69]3)[CH3:74])=[O:15])[C:11]3[C:17]([CH:24]=[O:25])=[C:18]([C:20]([O:22][CH3:23])=[O:21])[S:19][C:10]=3[C:9]=2[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:6][CH:7]=1
Reactant: CNC1CCN(C(C)C)C1
Reactant: COC(=O)c1sc2c(C3CCCCC3)c(-c3ccc(Cl)cc3)n(CC(=O)O)c2c1C=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1sc2c(C3CCCCC3)c(-c3ccc(Cl)cc3)n(CC(=O)N(C)C3CCN(C(C)C)C3)c2c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
A solution (0.13 M) of [5-(4-chlorophenyl)-6-cyclohexyl-3-formyl-2-(methoxycarbonyl)-4H-thieno[3,2-b]pyrrol-4-yl]acetic acid in DMF was treated with DIEA (3 eq.), HATU (1.5 eq.) and a solution (0.5 M) of 1-isopropyl-N-methylpyrrolidin-3-amine (1.5 eq.) in DMF. The reaction mixture was stirred at RT for 3 h. The reaction was quenched with aqueous NaHCO3 (saturated solution) and extracted with AcOEt. The combined organic phase was washed with brine and dried. Evaporation under reduced pressure gave a residue that was purified by flash chromatography on silica gel (1:49 Et3N/AcOEt) to afford the title compound (62%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])[CH:11]=NO)[CH:5]=[CH:6][C:7]=1[F:8].S(=O)(=O)(O)[OH:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:11](=[O:16])[C:10](=[O:14])[NH:9]2)=[CH:6][C:7]=1[F:8]
Reactant: O=C(C=NO)Nc1ccc(F)c(Br)c1
Reactant: O=S(=O)(O)O
Product: O=C1Nc2cc(Br)c(F)cc2C1=O
Temperature: 90 °C
Yield: 80 %

Procedure:
To the concentrated sulfuric acid (40 mL) at 50° C. was added N-(3-bromo-4-fluoro-phenyl)-2-hydroxyimino-acetamide (4 g, 0.0152 mol). The temperature was raised to 90° C. and maintained for 3 h. The reaction mixture was added to ice cold water to get the precipitate. The precipitate was filtered and dried to get the title compound (3.0 g, 80%). LC-MS (ESI): Calculated mass: 243.0; Observed mass: 242.1 [M−H]+ (RT: 0.47 min).