Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][NH:15]C2N=C(N(C)C)C3C(=CC=CC=3)N=2)[CH2:10][CH2:9]1)(C)(C)C.Cl.[CH3:31][CH2:32][O:33][C:34](C)=[O:35]>>[CH2:32]([O:33][C:34](=[O:35])[NH:15][CH2:14][C@H:11]1[CH2:12][CH2:13][C@@H:8]([NH2:7])[CH2:9][CH2:10]1)[C:31]1[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1
Reactant: CN(C)c1nc(NC[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)nc2ccccc12
Reactant: CCOC(C)=O
Agent: Cl
Product: N[C@H]1CC[C@@H](CNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of cis-[4-(benzyloxycarbonylamino-methyl)-cyclohexyl]-carbamic acid tert-butyl ester obtained in step C of example 23 (12.9 g, 35.6 mmol) in EtOAc (129 mL) was added 4 M hydrogen chloride in EtOAc (129 mL). The reaction mixture was stirred at ambient temperature for 3 hr, filtered, washed with EtOAc, and dried under reduced pressure. The solid was dissolved in saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 (five times), dried over MgSO4, filtered and concentrated, and dried under reduced pressure to give cis-(4-amino-cyclohexylmethyl)-carbamic acid benzyl ester (8.88 g, 95%) as a colorless oil.
Reaction SMILES: C[O-:2].[Na+].[CH3:4][C:5]1[O:6][CH:7]=[CH:8][C:9]=1[SH:10].Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18]Cl.O>CO.CCCCCC>[CH3:4][C:5]1[O:6][CH:7]=[CH:8][C:9]=1[S:10][CH:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)[OH:2]
Reactant: Cc1occc1S
Reactant: C[O-]
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Solvent: O
Product: Cc1occc1SC(O)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 25 ml 3 neck round bottom flask equipped with magnetic stirrer, pot thermometer, Y tube, nitrogen inlet tube, reflux condenser and heating mantle is placed a solution of 0.54 g (0.01 moles) of sodium methoxide dissolved in 3 ml absolute methanol. The reaction mass is maintained at 25°-30° C and a solution of 0.57 g (0.005 moles) of 2-methyl-3-furan thiol in 3 ml absolute methanol is added to the reaction mass. While maintaining the reaction mass at 25° C, picolyl chloride hydrochloride (0.82 g; 0.005 moles) dissolved in 2 ml absolute methanol is added to the reaction mass. The reaction being exothermic, the reaction mass warms up to 42° C and a white solid precipitate forms. The reaction mass is then allowed to cool to 25° C (with stirring) over a period of 30 minutes. The reaction is then heated to reflux (60° - 65° C) under nitrogen and reflux is continued for a period of 1 hour. The reaction mass is cooled to 25° C. After remaining at room temperature for a period of 12 hours, 10 ml of water is added to the reaction mass with stirring, causing the reaction mass to now exist in two phases; an aqueous phase and an organic phase. The pH of the reaction mixture is 5. 7 ml of n-hexane is then added to the reaction mass with stirring and transferred to a separatory funnel. The aqueous layer is separated from the organic phase and extracted with 8 ml n-hexane after first diluting the aqueous phase with another 10 ml of water. The hexane extracts are combined, washed with 7 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, gravity filtered, then concentrated on a rotary evaporator using water-aspirator vacuum.
Reaction SMILES: F[C:2]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:14])[C:8]=2[CH:7]=[N:6]1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][N:25]2[C:28]([C:31](O)=[O:32])=[CH:29][N:30]=[C:24]2[CH:23]=1.C(N1C2C=CC=C(N)C=2C=N1)C1C=CC=CC=1>>[CH2:4]([N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:31]([C:28]3[N:25]4[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][C:24]4=[N:30][CH:29]=3)=[O:32])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)[C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:2]=1
Reactant: Nc1cccc2c1cnn2Cc1ccc(F)cc1F
Reactant: COc1ccn2c(C(=O)O)cnc2c1
Agent: Nc1cccc2c1cnn2Cc1ccccc1
Product: COc1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3ccccc3)cnc2c1

Procedure:
Prepared according to the method of Example 109, replacing 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid and 1-(2,4-difluorobenzyl)-1H-indazol-4-amine with 7-methoxyimidazo[1,2-a]pyridine-3-carboxylic acid and 1-benzyl-1H-indazol-4-amine, respectively. MS (APCI) m/z=398 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6].[C:12](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(F)cc(Cl)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(Cl)cc(F)cc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.3 %

Procedure:
3-Chloro-5-fluoro-2-hydroxybenzaldehyde (2.5 g., 0.014 mole) was taken into 25 ml. of acetone. Potassium carbonate (2.48 g., 0.018 mole) and methyl iodide (2.55 g., 0.018 mole) were added in sequence and the mixture stirred for 16 hours at room temperature. The reaction mixture was filtered and the filtrate concentrated to an oil. The oil was partitioned between methylene chloride and water. The organic layer was washed in sequence with fresh water, 1 N sodium hydroxide and brine, dried over anhydrous magnesium sulfate, and concentrated to yield 3-chloro-5-fluoro-2-methoxybenzaldehyde (1.83 g., 69%; m.p. 59°-62° C.).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][O-:13].[Na+]>CN(C)C=O.CO>[CH3:12][O:13][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(N)c1
Temperature: 80 °C
Yield: 99 %

Procedure:
To a solution of 5-chloro-2-nitroaniline (5.0 g) in dimethylformamide (25 ml) was added 24% sodium methoxide in methanol (11 ml) and the mixture was heated at 80° C. for 4 hours. At the end of this time, the reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The extract was washed with 20% aqueous sodium chloride solution and insoluble material was filtered off. The filtrate was concentrated in vacuo to give the desired compound (4.8 g, yield 99%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([C:28]([OH:30])=O)[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.Cl.[F:33][C:34]([F:45])([F:44])[C:35]1[N:40]=[CH:39][C:38]([C@H:41]([NH2:43])[CH3:42])=[CH:37][N:36]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl>CN(C)C=O>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[C:18]1[CH:19]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:15]=[C:16]([C:28]([NH:43][C@@H:41]([C:38]2[CH:37]=[N:36][C:35]([C:34]([F:45])([F:44])[F:33])=[N:40][CH:39]=2)[CH3:42])=[O:30])[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(C(=O)O)cc(-c3ccc(F)cc3F)c2)CC1
Reactant: C[C@@H](N)c1cnc(C(F)(F)F)nc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C[C@@H](NC(=O)c1cc(-c2ccc(F)cc2F)cc(N2CCNCC2)c1)c1cnc(C(F)(F)F)nc1
Reaction time: 16 h
Yield: 80.3 %

Procedure:
To a solution of 5-[4-(tert-butoxycarbonyl)piperazin-1-yl]-2′,4′-difluorobiphenyl-3-carboxylic acid (30.0 mg, 0.072 mmol), in N,N-dimethylformamide (1.0 mL) was added (1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethanamine dihydrochloride (22.7 mg, 0.086 mmol), EDC (17.8 mg, 0.093 mmol), HOBT (11.0 mg, 0.072 mmol) and diisopropylethylamine (0.038 mL, 0.215 mmol). After 16 h, the mixture was acidified with hydrochloric acid gas. After 15 min, the mixture was concentrated and purified by reverse phase HPLC (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid) to give the title compound (28.4 mg). HRMS 492.1833 (M+1). 1H NMR (500 MHz, CD3OD): δ 9.00 (s, 2H); 7.57-7.50 (m, 1H); 7.47-7.43 (m, 2H); 7.24 (q, J=1.7 Hz, 1H); 7.09-7.03 (m, 2H); 5.33 (q, J=7.1 Hz, 1H); 3.25 (t, J=4.9 Hz, 4H); 3.00 (t, J=4.7 Hz, 4H); 1.68 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([C:15]2[S:19][C:18]([C:20]([OH:22])=[O:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:7][CH:6]=1)=[O:4].C(Cl)CCl.[Cl:28][C:29]1[CH:30]=[N+:31]([O-:54])[CH:32]=[C:33]([Cl:53])[C:34]=1[CH2:35][C@@H:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH:45]([F:47])[F:46])=[C:40]([O:48][CH2:49][CH:50]2[CH2:52][CH2:51]2)[CH:39]=1)O>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Cl:28][C:29]1[CH:30]=[N+:31]([O-:54])[CH:32]=[C:33]([Cl:53])[C:34]=1[CH2:35][C@@H:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH:45]([F:47])[F:46])=[C:40]([O:48][CH2:49][CH:50]2[CH2:52][CH2:51]2)[CH:39]=1)[O:21][C:20]([C:18]1[S:19][C:15]([S:12](=[O:14])(=[O:13])[NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:3](=[O:4])[N:2]([CH3:23])[CH3:1])=[CH:6][CH:7]=2)=[CH:16][CH:17]=1)=[O:22]
Reactant: CN(C)C(=O)c1ccc(NS(=O)(=O)c2ccc(C(=O)O)s2)cc1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1ccc(NS(=O)(=O)c2ccc(C(=O)O[C@@H](Cc3c(Cl)c[n+]([O-])cc3Cl)c3ccc(OC(F)F)c(OCC4CC4)c3)s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13 %

Procedure:
5-(N-(4-(dimethylcarbamoyl)phenyl)sulfamoyl)thiophene-2-carboxylic acid (Int. 76) (54 mg, 0.152 mmol), DMAP (6.20 mg, 0.051 mmol), and EDC (38.9 mg, 0.203 mmol) were dissolved in DMF. (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (42.7 mg, 0.102 mmol) was added. The reaction was stirred at RT for 4 hours. The reaction mixture was diluted with water and extracted with AcOEt. The organic phase was dried over Na2SO4 and concentrated under vacuum to give a crude product which was purified by preparative HPLC-Method 2 to give 10 mg of the desired product (Compound 77).
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:35][C:30]4[CH2:31][NH:32][CH2:33][CH2:34][C:29]=4[N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:36])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:37](OC(OC)=O)(OC)=O.CCN(C(C)C)C(C)C>CN(C)C=O>[CH:1]1([C:5]2[C:26]([C:27]3[NH:35][C:30]4[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:29]=4[N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH3:36])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1cc(C2CCC2)c(-c2nc3c([nH]2)CNCC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: COC(=O)OC(=O)OC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C2CCC2)c(-c2nc3c([nH]2)CN(C)CC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
To a solution of 4-(1-(4-cyclobutyl-2-methyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile (406.3, 180 mg, 0.300 mmol, 1.00 equiv, 80%) in N,N-dimethylformamide (5 mL) were added dimethyl dicarbonate (176 mg, 1.31 mmol, 5.00 equiv) and DIEA (169 mg, 1.31 mmol, 5.00 equiv). The resulting solution was stirred overnight at 25° C. and then quenched with 20 mL of methanol. The resulting mixture was concentrated under reduced pressure and the crude product was purified by Prep-HPLC using the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (28% CH3CN up to 43% in 8 min, up to 100% in 3 min, down to 28% in 2 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 29.9 mg (19%) of the title compound as a white solid. m/z (ES+) 538 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 7.70 (m, 2H), 7.50-7.35 (m, 4H), 4.90 (m, 1H), 4.70 (s, 2H), 4.00 (m, 2H), 3.80 (m, 4H), 3.60 (m, 1H), 3.25 (m, 1H), 3.05 (m, 2H), 2.85 (m, 2H), 2.50 and 2.40 (2 singlets, amide rotamers, ArCH3, 3H), 2.16-2.00 (m, 6H), 1.86-1.64 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C@:10]3([C@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH2:26]Cl)[C@@H:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1.[CH3:32]OC([Si](C)(C)C)C.[N:40]1([C:46](=[O:48])[CH3:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.FC(F)(F)C(O)=O>>[CH3:25][CH2:24][N:12]([CH:11]([CH3:10])[CH3:28])[CH:13]([CH3:14])[CH3:32].[C:46]([N:40]1[CH2:45][CH2:44][N:43]([CH2:26][CH2:25][CH2:24][N:12]2[C:13](=[O:23])[CH2:14][CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:31])[CH:11]2[C:28]([CH3:30])=[CH2:29])[CH2:42][CH2:41]1)(=[O:48])[CH3:47]
Reactant: C=C(C)[C@H]1N(CCCCl)C(=O)C[C@@H](c2cccc(Cl)c2)[C@]12C(=O)Nc1cc(Cl)ccc12
Reactant: CC(=O)N1CCNCC1
Reactant: COC(C)[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)C1N(CCCN2CCN(C(C)=O)CC2)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Product: CCN(C(C)C)C(C)C
Yield: 166.8 %

Procedure:
In a manner similar to the method described in example 60b, (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-1′-(3-chloro-propyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane prepared in example 123a (0.2 g, 0.20 mmol) was reacted with 1-piperazin-1-yl-ethanone (0.51 g, 4 mmol), trifluoroacetic acid (2 mL) and then N,N′-diisopropylethylamine (2 mL) to give racemic (2′R,3R,4′S)-1′-[3-(4-acetyl-piperazin-1-yl)-propyl]-6-chloro-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′ piperidine]-2,6′(1H)-dione as a yellow solid (Yield: 95 mg, 50.8%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[N:6]([CH2:20][C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22])[C:5]2=[O:27].[C:28]([N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[CH2:41][CH2:42]O)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>ClCCl.CN(C=O)C>[C:31]([O:30][C:28]([N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[CH2:41][CH2:42][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[N:6]([CH2:20][C:21](=[O:22])[NH:23][CH:24]([CH3:25])[CH3:26])[C:5]2=[O:27])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCO
Reactant: COc1cccc(-c2nc3ccc(O)cc3c(=O)n2CC(=O)NC(C)C)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(-c2nc3ccc(OCCC4CCCCN4C(=O)OC(C)(C)C)cc3c(=O)n2CC(=O)NC(C)C)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
A mixture of 2-[6-hydroxy-2-(3-methoxy-phenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropyl-acetamide (INTERMEDIATE IV.4) (200 mg, 0.55 mmol), N-Boc-2-piperidine ethanol (250 mg, 1.09 mmol) and resin-bound triphenylphosphine (˜3 mmol/g, 543 mg, 1.63 mmol) in dichloromethane (4.5 mL) and DMF (0.5 mL) was cooled to 0° C. and diisopropylazodicarboxylate (DIAD) (0.21 mL, 1.09 mmol) was added dropwise with stirring. The reaction mixture was allowed to warm to room temperature and stirring was continued for 16 h. The mixture was then filtered and concentrated in vacuo. The crude residue was dissolved in dichloromethane (100 mL) and washed with 1 N NaOH (aq.) and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. Purification by chromatography on silica gel with ethyl acetate:hexane (2:1, v/v) afforded 2-{2-[3-(isopropylcarbamoylmethyl)-2-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yloxy]ethyl}piperidine-1-carboxylic acid tert-butyl ester (65 mg, 0.11 mmol, 20%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])(=O)=O.[NH2:17][C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1.C(O)C>CN(C)P(N(C)C)(N(C)C)=O.C(O)C.O>[CH2:6]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][CH:28]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16]
Reactant: C=CCCCCCCCCCOS(C)(=O)=O
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCO
Product: C=CCCCCCCCCCNc1ccc(C(=O)OCC)cc1

Procedure:
A solution of 14.0 g. of 1-methanesulfonyloxy-10-undecene and 19.8 g. of ethyl p-aminobenzoate in hexamethylphosphoramide is heated at 120° C. for 20 hours. After cooling the reaction mixture is diluted with ethanol:water (1:1) (30 ml.) and chilled. More ethanol is added and the solid material is collected. This solid is recrystallized from ethanol to yield ethyl 4-(10-undecenylamino)benzoate as a white solid.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH3:14])[CH:8]=1)C.CC1C2C=CSC=2C=CC=1Cl>>[Cl:13][C:10]1[C:9]([CH3:14])=[CH:8][C:7]2[S:6][CH:5]=[CH:4][C:12]=2[CH:11]=1
Reactant: CCOC(CSc1ccc(Cl)c(C)c1)OCC
Agent: Cc1c(Cl)ccc2sccc12
Product: Cc1cc2sccc2cc1Cl

Procedure:
The title compound was prepared by adding (3-methyl-4-chlorophenylthio)acetaldehyde diethyl acetal to polyphosphoric acid under reduced pressure (1.5 mm Hg).* This gave 1.8 g of a mixture of the title compound (D27) and 4-methyl-5-chlorobenzo[b]thiophene in a 60:40 ratio.
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.CCCCCC[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].CO[C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[CH2:41][CH2:40][CH2:39][CH2:38]2.O(C(C)C)C(C)C.C1(C)C(C2C(C)=CC=CC=2)=CC=CC=1.CC1C=C(O)C=CC=1>CC(OC)(C)C>[CH3:32][C:31]1[CH:26]=[CH:27][C:28]([C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:29][CH:30]=1
Reactant: COc1ccc2c(c1)CCCC2
Reactant: CCCCCCCCCCCCC
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: Cc1ccccc1-c1ccccc1C
Solvent: CC(C)OC(C)C
Solvent: Cc1cccc(O)c1
Solvent: COC(C)(C)C
Product: Cc1ccc(-c2ccc3c(c2)CCCC3)cc1
Temperature: 25 °C
Yield: 75 %

Procedure:
In a reaction flask was placed NiCl2(PCy3)2 (49.0 mg, 0.0710 mmol), PCy3 (44.0 mg, 0.157 mmol), tridecane (333 mg, 1.806 mmol, as an internal standard), and 6-methoxy-1,2,3,4-tetrahydronaphthalene (222 mg, 1.368 mmol). The solvent in the Grignard reagent (1 M in ether, 3.70 mmol) was exchanged with i-Pr2O (8.0 mL) and MTBE (2.0 mL) and this solution added to the above catalyst mixture under a nitrogen atmosphere at room temperature. The resulting solution was stirred for several minutes at room temperature and then warmed to 80° C. for 15 hours. A sample was withdrawn and quenched with an aqueous sodium citrate solution (1 M). The resulting aqueous solution was extracted with ethyl acetate. GC analysis of the organic phase showed the presence of 6-(4-methylphenyl)-1,2,3,4-tetrahydronaphthalene (1.030 mmol, 75% yield) and 6-methoxy-1,2,3,4-tetrahydronaphthalene (0.131 mmol) and bitoluene (0.376 mmol) and m-methylphenol (0.220 mmol) in the reaction mixture.
Reaction SMILES: [CH2:1]([S:7][CH:8]=[CH:9][CH2:10]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(C(C)C)CC)(C)C.[CH3:21][OH:22]>CCCCCC>[CH3:21][O:22][CH2:10][CH:9]=[CH:8][S:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCSC=CCCl
Reactant: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Product: CCCCCCSC=CCOC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Hexylthio-2-propenyl chloride is added to a solution of diisopropyl ethyl amine (3.68 g, 28.5 mmol) in 20 ml of methanol. The mixture is stirred overnight at RT. It is then diluted with hexane, washed with water and with brine and is stripped. The crude product is purified by prep. TLC to give 3-methoxy-1-hexylthio-1-propene.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(O[N:61]1[C:66](=[O:67])[CH2:65][CH2:64][C:62]1=[O:63])=[N+](C)C)C>C1COCC1>[O:63]=[C:62]1[CH2:64][CH2:65][C:66](=[O:67])[N:61]1[O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[C:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:38])[CH:8]=1
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1C(=O)OC(C)(C)C
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCOc1ccc(C(=O)ON2C(=O)CCC2=O)cc1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.8 %

Procedure:
4-(14-tert-Butoxycarbonyl tetradecyloxy) isophthalic acid 3-tert-butyl ester (0.15 g, 0.28 mmol) was dissolved in THF (2 ml). DIEA (58 μl, 0.34 mmol) was added, and the solution was cooled to 0° C. TSTU (0.10 g, 0.28 mmol) was added. The reaction was stirred at 0° C. for 30 min and then at rt for 16 h. The sample was concentrated under vacuum to near dryness. AcOEt (20 ml) was added and the solution was washed with 0.2 N HCl and sat. NaHCO3 (3×5 ml each), dried over MgSO4 and concentrated to yield a residue (0.18 g). The residue was purified by flash chromatography (silica: AcOEt/heptane 3:7 (0.5 l), 1:1 (0.2 l)) yielding an oil with white solids (55 mg, 31%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.[B:18](OCCCC)([O:24]CCCC)[O:19]CCCC>CCOCC>[C:9]([CH:8]([C:4]1[CH:3]=[C:2]([B:18]([OH:24])[OH:19])[CH:7]=[CH:6][CH:5]=1)[CH3:12])([OH:11])=[O:10]
Reactant: CC(C(=O)O)c1cccc(Br)c1
Reactant: CCCCOB(OCCCC)OCCCC
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC(C(=O)O)c1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(3-bromo-phenyl)-propionic acid [500 mg, 2.18 mmol, Intermediate (69)] in anhydrous ether (20 mL) is added tert-butyl lithium (1.7 M in pentane, 5.4 mL, 9.16 mmol) dropwise at −78° C. and this mixture is stirred for 30 minutes treated with tributyl borate (2.34 mL, 8.72 mmol). The reaction mixture is allowed to warm up to room temperature, stirred for 15 hours, diluted with ether, and quenched with 1 M H3PO4. After stirring for 30 minutes the ether layer is separated and extracted three times with 2 N sodium hydroxide (20 mL). The combined sodium hydroxide extracts are acidified with 6 N hydrochloric acid to pH=1 and extracted three times with ether (50 mL). The combined organic extracts are washed with brine, dried over sodium sulfate and concentrated to obtain 3-(1-carboxy-ethyl)-phenyl boronic acid [Intermediate (70)] as a solid, which is used without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:13]2[N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:8]=2[C:7]([C:18](Cl)=O)=[CH:6][CH:5]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([NH2:30])[CH:24]=1>>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:18]2[NH:29][C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][C:25]=3[N:30]=2)=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:10]=[CH:9]2
Reactant: COc1ccc(C(=O)Cl)c2ccc(C(F)(F)F)nc12
Reactant: COc1ccc(N)c(N)c1
Agent: Cl
Product: COc1ccc2[nH]c(-c3ccc(OC)c4nc(C(F)(F)F)ccc34)nc2c1

Procedure:
Prepared from 8-methoxy-2-trifluoromethylquinoline-5-carbonyl choride, hydrochloride (Intermediate 35 of PCT/GB97/01359) and 4-methoxy-1,2-phenylenediamine; purification by column chromatography eluting with 50%-70% ethyl acetate in hexane afforded the title compound as a pale yellow solid (1.32 g).