Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][C@@H:8]2[C@H:12]([OH:13])[C@@H:11]([OH:14])[CH2:10][NH:9]2)=[CH:5][CH:4]=1.[C:17]([O:21][C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>C(Cl)Cl>[OH:13][C@@H:12]1[C@@H:11]([OH:14])[CH2:10][N:9]([C:26](=[O:27])[CH2:25][NH:24][C:22](=[O:23])[O:21][C:17]([CH3:18])([CH3:19])[CH3:20])[C@@H:8]1[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COc1ccc(C[C@H]2NC[C@H](O)[C@H]2O)cc1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc(C[C@@H]2[C@H](O)[C@@H](O)CN2C(=O)CNC(=O)OC(C)(C)C)cc1
Yield: 96.3 %

Procedure:
Following the procedure as described in Example 24, except using the material from Example 39 (432 mg, 1.935 mmol), 2-(tert-butoxycarbonylamino)acetic acid (486.1 mg, 2.77 mmol), 1-hydroxy-7-azabenzotriazole (134.0 mg, 0.984 mmol), CH2Cl2 (20 mL), N-methylmorpholine (1.1 mL, 10.01 mmol), and EDC (560.5 mg, 2.92 mmol), 709.1 mg (96%) of the title compound is obtained as a white solid. Purification is done by BIOTAGE® Silica gel chromatography on a 25 g Thompson Single Step silica cartridge using a linear gradient from 100% CH2Cl2 to 100% EtOAc/Hexanes over 12 column volumes. LC/MS (Condition A): ret. T=3.07 min, (M+Na) 403.20.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:36])[CH2:10][C:11]2[S:15][C:14]([NH:16]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[N:13][CH:12]=2)=[CH:4][C:3]=1[Cl:37]>C(O)(C(F)(F)F)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:36])[CH2:10][C:11]2[S:15][C:14]([NH2:16])=[N:13][CH:12]=2)=[CH:4][C:3]=1[Cl:37]
Reactant: O=C(Cc1cnc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)s1)Nc1ccc(F)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1ncc(CC(=O)Nc2ccc(F)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
N-(4-fluoro-3-chlorophenyl)-2-(2-tritylamino-1,3-thiazole-5-yl)acetamide (12.28 g, 23 mmol) was dissolved in TFA (100 ml) and water (10 ml). The mixture was stirred at room temperature for 45 minutes. Water (300 ml) was added to the reaction mixture, a solid was recovered by filtration, washed with water and ether. The solid was dissolved in MeOH, and the solution treated with ammonia (pH 8), MeOH was then partially evaporated, water (300 ml) was added and a precipitate of title compound recovered, dried (5.37 g, 81%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][C:37]1[C:38]([N:46]2[CH2:51][CH2:50][CH:49]([N:52]3[CH2:57][CH2:56][N:55]([S:58]([CH3:61])(=[O:60])=[O:59])[CH2:54][CH2:53]3)[CH2:48][CH2:47]2)=[CH:39][C:40]([O:44][CH3:45])=[C:41]([CH:43]=1)[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[C:37]([CH3:36])[C:38]([N:46]4[CH2:51][CH2:50][CH:49]([N:52]5[CH2:53][CH2:54][N:55]([S:58]([CH3:61])(=[O:60])=[O:59])[CH2:56][CH2:57]5)[CH2:48][CH2:47]4)=[CH:39][C:40]=3[O:44][CH3:45])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(C)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(C)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 175 °C
Yield: 30.2 %

Procedure:
A mixture of 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (0.075 g, 0.15 mmol), 5-methyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (0.058 g, 0.15 mmol) and para-toluenesulfonic acid (0.070 g, 0.37 mmol) in i-PrOH (5 mL) was heated in a microwave at 175° C. for 25 min. The reaction mixture was concentrated onto silica gel and purified by flash chromatography. Recrystallization from DCM and diethyl ether afforded N-(2,6-difluorophenyl)-5-(3-{2-[(5-methyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamide (0.038 g, 30%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.80 (s, 1H), 9.33-9.43 (m, 1H), 8.47 (s, 1H), 8.25 (d, J=5.2 Hz, 1H), 8.08-8.14 (m, 1H), 7.76-7.84 (m, 1H), 7.71 (d, J=9.0 Hz, 1H), 7.34-7.55 (m, 3H), 7.30 (d, J=8.7 Hz, 1H), 7.15-7.25 (m, 2H), 6.97 (t, J=6.8 Hz, 1H), 6.76 (s, 1H), 6.57 (d, J=5.1 Hz, 1H), 4.00 (s, 3H), 3.80 (s, 3H), 3.06-3.19 (m, 6H), 2.88 (s, 3H), 2.59-2.72 (m, 6H), 2.38-2.44 (m, 1H), 2.16 (s, 3H), 1.80-1.91 (m, 2H), 1.50-1.71 (m, 2H). MS (M+2H, ES+) 839.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:29]([O:31][C:32](=[O:47])[CH2:33][CH:34]1[CH2:39][CH2:38][N:37]([C:40](N2C=CN=C2)=[O:41])[CH2:36][CH2:35]1)[CH3:30]>C(Cl)Cl>[CH2:29]([O:31][C:32](=[O:47])[CH2:33][CH:34]1[CH2:35][CH2:36][N:37]([C:40]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:41])[CH2:38][CH2:39]1)[CH3:30]
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CCOC(=O)CC1CCN(C(=O)n2ccnc2)CC1
Solvent: ClCCl
Product: CCOC(=O)CC1CCN(C(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)CC1
Reaction time: 1 h
Yield: 53.4 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (51.6 mg, 0.122 mmol) and [1-(imidazole-1-carbonyl)-piperidin-4-yl]-acetic acid ethyl ester (293.3 mg, 1.10 mmol) in CH2Cl2 (8 mL) was stirred at reflux for 16 hrs then 1 h at 140° C. in a microwave tube and finally at 160° C. for 1 hr. The reaction mixture was then purified by flash column to give rac-{1-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-piperidin-4-yl}-acetic acid ethyl ester (40.4 mg, 53.4%). HRMS (ES+) m/z Calcd for C32H37Cl2F2N3O3+H [(M+H)+]: 620.2253; Found: 620.2254.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:12]=1)[C:7]([O:9]CC)=[O:8].O.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:6]([CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1cc(Cl)ccc1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(Cl)ccc1-c1ccccc1
Yield: 79.8 %

Procedure:
Ethyl 5-chloro-2-phenylbenzoate (0.473 g, 1.81 mmol) was hydrolyzed with lithium hydroxide monohydrate to provide 5-chloro-2-phenylbenzoic acid (0.336 g, 80% yield). MS (ESI) m/z: 233.0 (M+H+)
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][CH:5]([CH2:7][C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4](=[O:18])[O:3]1.Cl>C1(C)C=CC=CC=1>[OH:6][CH:5]([CH2:7][C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[C:4]([O:3][CH:2]([CH3:19])[CH3:1])=[O:18]
Reactant: CC(C)(C)OC(=O)CC(=O)CC1OC(C)(C)OC1=O
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)C(O)CC(=O)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
In a solution of tert.-butyl 4-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)-3-oxobutanoate (13.62 g, 50.00 mmol) in toluene (100.0 ml), the above yellow solution was dropwise added and stirred at 0° C. for 30 minutes. After dropwise adding 1N hydrochloric acid (160.0 ml), the mixture was stirred at 0° C. for 10 minutes. After evaporating off the most of the organic solvent under reduced pressure, the mixture was extracted with ethyl acetate and washed with a saturated saline and a phosphate buffer (pH 7.0). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: acetone=2:1) to give pure 1-isopropyl 6-tert.-butyl 2-hydroxy-4-oxoadipate (11.07 g, 40.35 mmol). Yield, 80.7%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[C:21]2[N:20]=[C:19]([CH2:22][N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]([CH:32]([CH3:34])[CH3:33])[C:24]3=[O:35])[N:18]([CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[C:17]=2[CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH:32]([N:25]1[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:23]([CH2:22][C:19]2[N:18]([CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([CH:12]=[O:11])[C:21]=3[N:20]=2)[C:24]1=[O:35])([CH3:33])[CH3:34]
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2c(CO)cccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2c(C=O)cccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a cooled (−45° C.) solution of oxalyl chloride (0.4 mL 2M in dichloromethane, 0.8 mmol) in DCM (5 mL) was added DMSO (115 μL, 1.62 mmol) under a nitrogen atmosphere. After stirring for 3 min. a solution of 1-[4-hydroxymethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one (300 mg, 0.738 mmol) in DCM (4 mL) was cannulated and stirring was continued for 15 min. at the same temperature. Then diisopropylethyl amine (643 μL, 3.69 mmol) was added, and the mixture was allowed to warm to room temperature after 5 min. Stirring was continued for 4 hrs, the mixture was quenched with satd. ammonium chloride and the layers separated. The aqueous phase was extracted with DCM, and the combined organic phases washed with water, brine and dried (MgSO4) to afford 2-(3-Isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-4-carbaldehyde as a pale yellow solid (quantitative recovery), that was sufficiently pure for the next steps:
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(N[S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[N:43][C:42]=2[C:52]2[C:53]([F:60])=[C:54]([CH:56]=[CH:57][C:58]=2[F:59])[NH2:55])[CH:38]=[CH:37][N:36]=1.FC1C=CC=C(F)C=1S(Cl)(=O)=O>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)=[N:43][C:42]=2[C:52]2[C:53]([F:60])=[C:54]([NH:55][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:56]=[CH:57][C:58]=2[F:59])[CH:38]=[CH:37][N:36]=1
Reactant: Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Agent: O=S(=O)(Cl)c1c(F)cccc1F
Product: O=S(=O)(Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluoroaniline (900 mg, 2.196 mmol) and 2,6-difluorobenzenesulfonyl chloride (0.357 mL, 2.64 mmol) the title compound of Step A was obtained as a light yellow solid (857 mg, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.89 (s, 1H), 8.40 (d, J=5.5 Hz, 1H), 7.64-7.72 (m, 1H), 7.49-7.56 (m, 1H), 7.21-7.32 (m, 3H), 6.55 (d, J=5.3 Hz, 1H), 3.70-3.74 (m, 4H), 3.52-3.55 (m, 4H). MS (ESI): 585 [M+H]+.
Reaction SMILES: [O-]CC.[Na+].[C:5]([NH:8][CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:7])[CH3:6].[I-].[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>[Na].O>[C:5]([NH:8][C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])(=[O:7])[CH3:6]
Reactant: CCOC(=O)CCCCCCBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCCCCCC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C

Procedure:
In a dried flask was dissolved 23.0 g (1.0 g atom) of sodium and 600 ml. of ethanol dried by the method of R. H. Manski, J. Am. Chem. Soc., 53, 1106 (1931). To the solution of sodium ethoxide, under nitrogen, was added 217 g (1.0 mole) of dry diethyl acetamidomalonate and 1.0 g of dry sodium iodide. The resulting solution was heated at reflux while 249 g (1.05 mole) of ethyl 7-bromoheptanoate was added dropwise over a period of 1.5-2 hrs. After addition was completed, the reaction mixture was heated at reflux for 20-24 hrs. By the end of this time a drop of the reaction mixture applied to moist pH paper indicated pH 6-7. The reaction mixture was cooled to room temperature, mixed with 2 liters of water and extracted with ether twice. The combined organic layers were washed with water twice and then with saturated sodium chloride, dried over MgSO4 and evaporated under reduced pressure. The final stage of the evaporation was carried out at 70°-80° to remove last traces of solvent. The remaining oil, which weighed about 363 g, was distilled through a wiped-film molecular still (Rota-Film Molecular Still, All-Starr Scientific Equipment Supply Co., Pompano Beach, Fla.). A foreshot (about 45 g) was collected at about 100°/.01-.005 mm and discarded. Pure triethyl-1-acetamido-1,1,7-heptanetricarboxylate, about 316 g (85%), was then collected at 240°-250°/.005 mm. For other samples prepared similarly: HRMS Calcd for C18H31NO7 m/e 373.2099, measured 373.2078; pmr (CDCl3, TMS) δ1.25 (t, 9H, ethyl CH CH3 's), 2.03 (s, 3H, COCH3), 4.2 (q, 6H, OCH2), 6.95 (s, 1H, NH); ir (neat) 3480 (NH), 1735 (--CO2 --), 1680 (CONH), 1500, 1470, 11450, 1375, 1210 (OC2H5) cm-1.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[NH:4][C:5](=[O:14])[N:6]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]=1[NH2:8].[CH2:16](O)C>C(N)=O>[CH3:13][C:10]([CH3:11])([CH3:12])[CH2:9][N:6]1[C:7]2[N:8]=[CH:16][NH:1][C:2]=2[C:3](=[O:15])[NH:4][C:5]1=[O:14]
Reactant: CC(C)(C)Cn1c(N)c(N)c(=O)[nH]c1=O
Reactant: CCO
Solvent: NC=O
Product: CC(C)(C)Cn1c(=O)[nH]c(=O)c2[nH]cnc21

Procedure:
4.0 g of XXVIII was refluxed in 20 ml of formamide for 30 minutes. After cooling 30 ml of ethanol was added and the yellow crystals were filtered off and recrystallized from 15 ml of DMF. Yield 2.0 g (XXIX) NMR (see Table I).
Reaction SMILES: [Cl:1][C:2]1[S:13][C:5]2=[N:6][C:7]([Cl:12])=[C:8]([CH:10]=[O:11])[CH:9]=[C:4]2[CH:3]=1.[CH3:14][Mg]Cl>C1COCC1>[Cl:1][C:2]1[S:13][C:5]2=[N:6][C:7]([Cl:12])=[C:8]([CH:10]([OH:11])[CH3:14])[CH:9]=[C:4]2[CH:3]=1
Reactant: C[Mg]Cl
Reactant: O=Cc1cc2cc(Cl)sc2nc1Cl
Solvent: C1CCOC1
Product: CC(O)c1cc2cc(Cl)sc2nc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a reaction flask containing 2,6-dichlorothieno[2,3-b]pyridine-5-carbaldehyde (5.1 g, 21.97 mmol) in 300 mL of THF at −20° C. was added methylmagnesium chloride, 3.0M solution in tetrahydrofuran (7.69 mL, 23.07 mmol) dropwise. After 1 h, an additional charge of 0.7 mL of MeMgCl was added. After 15 min, the reaction was quenched by the addition of 50 mL sat. NH4Cl and 50 mL water. After warming to rt, ethyl acetate was added and the organic layer was separated and washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated to afford 1-(2,6-dichlorothieno[2,3-b]pyridin-5-yl)-ethanol. 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J=0.8 Hz, 1H), 7.14 (s, 1H), 5.32 (qdd, J=6.3, 3.5, 0.8 Hz, 1H), 2.07 (J=3.5 Hz, 1H), 1.56 (d, J=6.6 Hz, 3H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C@@H:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([OH:17])=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[CH:28]1(O)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([O:16][C:15](=[O:17])[C@@H:14]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:12])=[O:11])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: OC1CCCC1
Reactant: O=C(O)[C@@H](NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(OC1CCCC1)[C@@H](NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Temperature: 70 °C
Yield: 70 %

Procedure:
To a solution of stage 1 acid (4.32 g, 12.8 mmol) in cyclopentanol (60 ml) at 0° C. was added slowly thionyl chloride (9.3 ml, 128 mmol). The reaction mixture was stirred and heated under reflux at 70° C. for 2 hours. The excess thionyl chloride was removed by evaporation in vacuo, the reaction mixture was extracted into EtOAc and washed with saturated NaHCO3 solution and dried over Na2SO4, filtered and evaporated to dryness. Flash column chromatography purification with DCM gave the required product (3.6 g, 70% yield). LCMS purity of 100%, (molecular ion not observed).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][CH2:19][OH:20])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][CH2:19][O:20][S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(CCO)ccc2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)cc1

Procedure:
6-[2-(Toluene-4-sulfonyloxy)-ethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester is prepared as example 7d from 1.60 g (5.77 mmol) 6-(2-hydroxy-ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 10b) and 1.21 g (6.35 mmol) 4-methyl-benzenesulfonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:48])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[C:31]([OH:38])[C:30]=1[CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.[CH3:49]O>>[CH3:1][O:2][C:3](=[O:48])[CH2:4][CH2:5][C:6]1[C:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]3[C:35](=[O:37])[CH:36]=[CH:49][O:38][C:31]=3[C:30]=2[CH2:39][CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:8][CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: CO
Reactant: COC(=O)CCCCCOc1cccc(CCCCCCOc2ccc(C(C)=O)c(O)c2CCCc2ccccc2)c1CCC(=O)OC
Product: COC(=O)CCCCCOc1cccc(CCCCCCOc2ccc3c(=O)ccoc3c2CCCc2ccccc2)c1CCC(=O)OC
Yield: 57.4 %

Procedure:
Using the procedure of example 1 with the modification that methanol was used in place of ethanol, 2-[6-[4-acetyl-3-hydroxy-2-(3-phenylpropyl)phenoxy]hexyl]-6-[(6-methoxy-6-oxohexyl)oxy]benzenepropanoic acid methyl ester from the preceding example was converted into the title compound, a pale-yellow oil purified by flash-chromatography on silica gel (eluting with 3:1 toluene-ethyl acetate), in 57.4% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[C@@H:14]([CH3:32])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C.[Co](Cl)Cl>[NH2:30][CH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([N:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:12]([N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:9](=[O:11])[CH3:10])[CH2:13][C@@H:14]2[CH3:32])=[O:31])=[CH:28][CH:27]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(C#N)cc2)c2ccccc21
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(CN)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
N-{(2S,4R)-1-[4-(aminomethyl)benzoyl]-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl}-N-(4-chlorophenyl)acetamide was made following general procedure H, substituting 4-cyanobenzoyl chloride for 6-trifluoromethyl nicotinyl chloride. The rest of the procedure is followed as indicated in general procedure H to yield the corresponding nitrile, N-(4-chloro-phenyl)-N-[(2S,4R)-1-(4-cyano-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide. N-(4-Chloro-phenyl)-N-[(2S,4R)-1-(4-cyano-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (225 mg, 0.51 mmol) was dissolved in ethanol (7 mL) and cobalt dichloride (0.079 g, 0.61 mmol) and NaBH4 (0.059 g, 1.57 mmol) were added and the mixture was stirred at room temperature for 2 h. The slurry was filtered, concentrated, and subjected to flash chromatography (1% NH4OH, 15% MeOH, EtOAc) to yield the title compound (188 mg, 83%) as a white solid. 1H-NMR (CDCl3) δ: 1.00-1.20 (m, 1H), 1.14 (s, 3H), 1.48 (bs, 2H), 2.02 (s, 3H), 2.20-2.36 (m, 1H), 3.79 (s, 2H), 4.73-4.83 (m, 1H), 5.35-5.70 (m, 1H), 6.49 (d, 1H), 6.89 (t, 1H), 7.11-7.29 (m, 8H), 7.37 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.S(=O)(=O)(O)[OH:11].CC1C=C(C)C=C(O)C=1O>>[CH3:8][C:6]1[CH:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[C:7]=1[OH:11]
Reactant: Cc1cc(C)cc(O)c1
Reactant: O=S(=O)(O)O
Agent: Cc1cc(C)c(O)c(O)c1
Product: Cc1cc(O)cc(C)c1O
Reaction time: 0.33 h

Procedure:
In a vessel used in Example 55, 100 g. (819 m.moles) of 3,5-dimethylphenol, 5.68 g. (P=42.11) of 4-methyl-2-pentanone peroxide and 0.01 g. of 98% sulfuric acid were placed and the reaction was carried out at 100° C. for 20 minutes in the same manner as in Example 55 and analyzed. 3.67 g. (26.6 m.moles) of 3,5-dimethylcatechol and 1.52 g. (11.0 m.moles) of 2,6-dimethylhydroquinone were obtained. The yield of dihydric alkylphenols was 89.3%.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:10]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[N+:23]([O-])([O-:25])=[O:24].[K+]>S(=O)(=O)(O)O>[C:1]([NH:8][C:9]1[CH:10]=[C:11]([C:19]([F:20])([F:21])[F:22])[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[C:14]=1[N+:23]([O-:25])=[O:24])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 9 %

Procedure:
To a solution of 4.3 g (13 mmol) N-ethoxalyl-3,5-bistrifluoromethylaniline in 15 ml concentrated sulfuric acid was added at 0° C. 1.5 g (15 mmol) potassium nitrate. Stirring was continued at 0° C. for 90 min., and then at 25° C. for 120 min. The reaction mixture was poured into 100 ml ice-water and the precipitate was filtered off. The crude product was purified by column chromatography on silica gel with toluene/ethylacetate 5:1 as eluent, to give 0.44 g (9%) of N-ethoxalyl-3,5-bistrifluoromethyl-2-nitroaniline. M.p. 115.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[Br:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:13][CH2:14][CH2:15][CH2:16][O:12][C:5]1[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: BrCCCBr
Reactant: COc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OCCCBr)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3-methoxy-4-nitrophenol (Intermediate 18 in EP-A-494623) (2.4 g), 1,3-dibromopropane (7.5 ml) and potassium carbonate (2.2 g) in DMF (30 ml) was stirred at room temperature for 24 h. The mixture was filtered and the filtrate was evaporated to dryness. The residue was treated with water and extracted with dichloromethane. The organic extract was then washed with 5% sodium hydroxide solution and brine, dried and concentrated in vacuo to give the title compound (3.5 g) as an oil.