Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1>O1CCCC1.CCCCCC>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH:14]([OH:23])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: COc1cccc(C=O)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(C(O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
A solution of 35.0 g (183 mmole) of 4-bromchlorobenzene in 300 ml of dry tetrahydrofuran was cooled to -78° C. under nitrogen and 115 ml (183 mmole) of 1.59M n-butyllithium in hexane was added dropwise at a rate to maintain temperature below -60° C. After stirring an additional 15 minutes, 23.0 ml (183 mmole) of m-anisaldehyde was added dropwise and the reaction was stirred for 15 minutes. The reaction was quenched at -78° C. with saturated aqueous ammonium chloride and allowed to warm to room temperature. The reaction solution was diluted with 300 ml of diethyl ether and washed with three 150 ml portions of 1.0M sodium bisulfite, followed by 100 ml of 1.0M sodium hydroxide, 100 ml of water, and 50 ml of saturated sodium chloride. After drying over magnesium sulfate, the solvent was removed to give 45.2 g (99%) of crude 4-chloro-α-(3-methoxyphenyl)benzyl alcohol as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:5]([Cl:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][OH:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:18][C:5]1[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[N:7][C:2]([NH:19][C:20]2[CH:21]=[C:22]([CH2:23][OH:24])[CH:25]=[CH:26][CH:27]=2)=[N:3][CH:4]=1
Reactant: COc1cccc(CNc2nc(Cl)ncc2Cl)c1
Reactant: Nc1cccc(CO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(CNc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Temperature: 105 °C
Yield: 97.6 %

Procedure:
Into the reaction flask was added 2,5-dichloro-N-(3-methoxybenzyl)pyrimidin-4-amine (0.82 g, 2.9 mmol), 1,4-dioxane (20 mL), 3-aminobenzyl alcohol (0.53 g, 4.3 mmol), and p-toluenesulfonic acid monohydrate (0.22 g, 1.2 mmol). The mixture was heated at 105° C. for 3 hours and then was heated at 70° C. overnight. The reaction was quenched with NaHCO3 (saturated). The organic solvent was removed under vacuum, followed by the addition of water and EtOAc. The aqueous layer was extracted with EtOAc twice. The organic layers were combined, dried over Na2SO4 and concentrated under vacuum to give the desired product as a brown powder (1.05 g, 98%). LCMS for C19H20N4O2 (M+H)+: m/z=371.1, 373.0. 1H NMR (400 MHz, DMSO-d6): δ 9.54 (s, 1H), 8.28 (s, 1H), 8.03 (s, 1H), 7.54 (s, 1H), 7.40 (d, J=8.3 Hz, 1H), 7.20 (t, J=8.3 Hz, 1H), 7.14 (t, J=7.9 Hz, 1H), 6.89 (m, 1H), 6.77 (ddd, J=8.3, 2.2, 1.4 Hz, 1H), 4.59 (d, J=6.2 Hz, 2H), 4.38 (s, 2H), 3.64 (s, 3H).
Reaction SMILES: O=[C:2]1[CH2:11][N:10]2[C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C:13]=3[C:8]3[C:9]2=C([CH:5]=[CH:6][CH:7]=3)N1.[H-].[Na+].CI.[CH3:27][N:28]([CH:30]=[O:31])[CH3:29]>O>[CH3:2][CH:11]1[N:10]2[C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C:13]=3[C:8]3[C:9]2=[C:27]([CH:5]=[CH:6][CH:7]=3)[N:28]([CH3:29])[C:30]1=[O:31]
Reactant: CN(C)C=O
Reactant: CCOC(=O)N1CCc2c(c3cccc4c3n2CC(=O)N4)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCOC(=O)N1CCc2c(c3cccc4c3n2C(C)C(=O)N4C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a solution of ethyl 2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (from Example 211, StepA) (500 mg, 1.6 mmol) in DMF (20 mL) at rt was added NaH (147 mg, 3.6 mmol), MeI (0.25 mL, 4.0 mmol) and stirred at 25° C. for 3 hours. The solution was diluted with water (30 mL) and extracted with EtOAc (2×30 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford ethyl 1,3-dimethyl-2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (350 mg, 64%) as an oil. MS [M+H]+328. 1H NMR (CDCl3, 300 MHz): δ 7.18 (d, 1H, J=7.7 Hz), 7.01 (t, 1H, J=7.7 Hz), 6.63 (d, 1H, J=7.7 Hz), 4.90 (m, 1H), 4.51 (m 1H), 3.20 (m, 5H), 3.49 (m, 1H), 3.42 (s, 3H), 2.91 (m, 1H), 2.80 (m, 1H), 1.61 (d, 3H, J=7.0), 1.28 (t, 3H, J=7.3 Hz) ppm.
Reaction SMILES: [Cl-].[CH3:2][Al+:3][CH3:4].[CH3:5][N:6]([CH3:15])[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][Li]>CCCCCC>[CH3:5][N:6]([CH3:15])[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][Al:3]([CH3:4])[CH3:2]
Reactant: C[Al+]C
Reactant: [Li]Cc1ccccc1N(C)C
Agent: [Cl-]
Solvent: CCCCCC
Product: CN(C)c1ccccc1C[Al](C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 58 %

Procedure:
10.0 ml (107.8 mmol) of dimethylaluminium chloride were added dropwise to a suspension, cooled to −30° C., of 15.21 g (107.8 mmol) of [2-(dimethylamino)benzyl]lithium in 250 ml of hexane in an inert nitrogen atmosphere. After slow warming to room temperature, the mixture was stirred for 14 hours in order to complete the reaction. Filtration through a D4 frit and removal of the solvent by distillation gave 11.95 g of [2-(dimethyl-amino)benzyl]dimethylaluminium (62.5 mmol/58%) as a colourless liquid by slow fractional distillation from the residue.
Reaction SMILES: C([NH:8][CH:9]([CH:29]([CH3:32])[CH2:30][CH3:31])[C:10]([NH:12][CH:13]([C:18]1([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:21][CH2:20][CH2:19]1)[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])(OC(C)(C)C)=O>C(O)(C(F)(F)F)=O>[NH2:8][CH:9]([CH:29]([CH3:32])[CH2:30][CH3:31])[C:10]([NH:12][CH:13]([C:18]1([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH2:21][CH2:20][CH2:19]1)[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11]
Reactant: CCC(C)C(NC(=O)OC(C)(C)C)C(=O)NC(CC(C)C)C1(c2ccc(Cl)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)C(N)C(=O)NC(CC(C)C)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(Boc-amino)-N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-3-methylvaleramide (Example 2) was dissolved in CF3COOH. This solution was stirred at room temperature for 3 hours, and then evaporated under vacuum to remove CF3COOH. The produced white solid was collected, dissolved in anhydrous ethyl ether, and washed repeatedly with saturated sodium bicarbonate until pH of the eluate was neutral. This solution of ethyl ether was then washed with saturated sodium chloride for 2-3 times, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography to give 2-amino-N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-3-methylvaleramide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH2:12][OH:13].Cl.C([O-])(O)=O.[Na+]>CO>[OH:13][NH:12][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[CH:3]2)=[NH:11]
Reactant: NO
Reactant: N#Cc1ccc2[nH]ncc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N=C(NO)c1ccc2[nH]ncc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
5-cyano indazole (D1) (500 mg), hydroxylamine.HCl (485 mg) and NaHCO3 (1.47 g) were dissolved/suspended in MeOH (18 ml), heated to 50° C. and stirred for 19 hours and overnight. The reaction mixture was then filtered, washed with MeOH and evaporated to give the title compound (584 mg) as a white solid. MS (ES): C8H8N4O requires 176; found 177 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3scc(C)c23)cc1Cl
Reactant: c1nc[nH]n1
Product: COc1ccc(CNc2nc(-n3cncn3)nc3scc(C)c23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.O.O[N:15]1[C:19]2C=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=N1.[CH2:24]([NH:26][C:27](=[O:45])[NH:28][C:29]1[N:34]=[C:33]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:32]([C:42]([OH:44])=O)=[CH:31][N:30]=1)[CH3:25].NC1C=NC=CC=1>CN(C)C=O.O>[CH2:24]([NH:26][C:27](=[O:45])[NH:28][C:29]1[N:34]=[C:33]([NH:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:32]([C:42]([NH:17][C:18]2[CH:19]=[N:15][CH:21]=[CH:22][CH:23]=2)=[O:44])=[CH:31][N:30]=1)[CH3:25]
Reactant: CCNC(=O)Nc1ncc(C(=O)O)c(Nc2ccccc2)n1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1cccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ncc(C(=O)Nc2cccnc2)c(Nc2ccccc2)n1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 48.2 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.096 g, 0.500 mmol) and 1-hydroxybenzotriazole monohydrate (0.077 g, 0.500 mmol) were added to a stirred solution of 2-(3-ethylureido)-4-(phenylamino)pyrimidine-5-carboxylic acid (v) (0.100 g, 0.330 mmol) in dimethylformamide (3 mL) at room temperature. After 15 min, 3-aminopyridine (0.047 g, 0.500 mmol) was added and the reaction mixture stirred at 40° C. for 24 h. The mixture was cooled to room temperature, treated with water (2 mL) and the resulting off-white precipitate filtered, washed with water, air-dried and triturated with hot EtOH to give Compound 6 (0.060 g, 0.159 mmol, 48%) as a colourless powder. 1H NMR (300 MHz, DMSO-d6): δ 10.67 (1H, br s), 10.52 (1H, br s), 9.89 (1H, br s), 8.91-8.84 (3H, m), 8.35 (1H, dd, J 1.0 and 4.6), 8.12 (1H, dt, J 2.0 and 8.7), 7.67 (2H, d, J 8.2), 7.46-7.38 (3H, m), 7.20 (1H, t, J 7.2), 3.10 (2H, dq, J 5.6 and 7.2), 0.93 (3H, t, J 7.2); [M+H]+ m/z=378.2.
Reaction SMILES: [Na].Cl[C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([CH:9]=1)[NH2:8].[CH2:13]([OH:15])[CH3:14]>>[CH2:13]([O:15][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([CH:9]=1)[NH2:8])[CH3:14]
Reactant: CCO
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Na]
Product: CCOc1ccc([N+](=O)[O-])c(N)c1
Temperature: 80 °C
Yield: 94 %

Procedure:
A mixture of sodium metal (1.86 g, 80.9 mmol) and ethanol (65 mL) was stirred at ambient temperature until all of the sodium metal had been consumed. 5-Chloro-2-nitroaniline (4.64 g, 26.9 mmol) was added and the mixture was heated at 80° C. for 48 hours, cooled to room temperature, quenched with water, concentrated under vacuum, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel with 7:3 hexane/ethyl acetate to provide 4.6 g (94%) of the desired product. MS (ESI) m/e 183 (M+H)+; 1H NMR (300 MHz, DMSO-d6) □ 7.90 (d, J=9.5 Hz, 1H), 7.46 (br s, 2H), 6.43 (d, J=2.7 Hz, 1H), 6.23 (dd, J=2.7, 9.5 Hz, 1H), 4.04 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[CH3:37])[CH2:5][N:6]1[CH2:10][CH:9]([CH2:11][CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)[N:8]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:7]1=[O:33].[CH2:38]([O:40][C:41](=[O:53])[C:42]([O:45][C:46]1[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=1)([CH3:44])[CH3:43])[CH3:39].N#N>CN(C=O)C>[CH2:38]([O:40][C:41](=[O:53])[C:42]([O:45][C:46]1[CH:47]=[CH:48][C:49]([O:52][CH2:12][CH2:11][CH:9]2[CH2:10][N:6]([CH2:5][C:4]3[CH:34]=[CH:35][C:36]([CH3:37])=[C:2]([CH3:1])[CH:3]=3)[C:7](=[O:33])[N:8]2[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[CH:50][CH:51]=1)([CH3:44])[CH3:43])[CH3:39]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: COc1ccc(CN2C(=O)N(Cc3ccc(C)c(C)c3)CC2CCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CN(Cc3ccc(C)c(C)c3)C(=O)N2Cc2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 108.9 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-[1-(3,4-dimethyl-benzyl)-3-(4-methoxy-benzyl)-2-oxo-imidazolidin-4-yl]-ethyl ester (2.54 g, 4.86 mmol), 2-(4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester (0.99 g, 4.01 mmol) and CS2CO3 (1.73 g, 5.31 mmol) in DMF (60 mL) was heated at 55° C. for under N2 for 16 h. The reaction mixture was cooled to room temperature, quenched with aqueous 1 N HCl (25 mL), and worked up extractively with EtOAc and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 4:1 hexanes:acetone to afford 2.51 g (99%) 2-(4-{2-[1-(3,4-dimethyl-benzyl)-3-(4-methoxy-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester. MS (ES+) Calc'd for C34H43N2O6 (M+1) 575. Found m/z 575 (100%). 1H NMR.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20](C)([O-])C.[K+].ICC>C(O)(C)(C)C.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH2:19][CH3:20])([C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)(C)O
Solvent: CCI
Product: CCC1(C(=O)OC)CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A solution of 26 gm (101 mMol) methyl 1-tert-butoxycarbonyl-4-oxo-3-piperidinecarboxylate and 11.9 gm (106 mMol) potassium tert-butoxide in 300 mL tert-butanol was heated to 70° C. under nitrogen. To this solution were then added 23.6 gm (152 mMol) iodoethane over 20 minutes, and the reaction mixture was heated at reflux for about 16 hours. The reaction mixture was then cooled to room temperature and was diluted with diethyl ether. The organics were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to provide 28.7 gm (99%) of the desired compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[CH3:16])=[O:5].C1CCCCC=1.C(O)C>[Pd].O>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=2[F:1])=[C:8]([CH3:16])[CH:9]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1NC(=O)c1ccccc1F
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Solvent: O
Product: Cc1cc(N)ccc1NC(=O)c1ccccc1F
Temperature: 4 °C

Procedure:
A mixture of 2-fluoro-N-(2-methyl-4-nitrophenyl)benzamide (4.55 g), cyclohexene (30 mL), ethanol (70 mL), water (30 mL) and 10% palladium on charcoal (3 g) is heated at reflux for 30 minutes. The mixture is filtered through diatomaceous earth and concentrated under reduced pressure. The resulting oil is dissolved in 50 mL of ethyl acetate and cooled at 4° C. for 12 hours. Filtration provides the product as a tan solid.
Reaction SMILES: [C:1]1([CH3:27])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][CH2:11][O:12][C:13](=[O:26])[CH2:14][O:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH:23]([CH3:25])[CH3:24])[CH:17]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:28][S:29](O)(=[O:31])=[O:30]>C(Cl)Cl>[C:1]1([CH3:27])[CH:2]=[CH:3][C:4]([S:7]([CH2:10][CH2:11][O:12][C:13](=[O:26])[CH2:14][O:15][C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([S:29]([Cl:28])(=[O:31])=[O:30])=[C:18]([CH:23]([CH3:24])[CH3:25])[CH:17]=2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)CCOC(=O)COc2cc(C)cc(C(C)C)c2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CCOC(=O)COc2cc(C)c(S(=O)(=O)Cl)c(C(C)C)c2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
To a mixture of 3-isopropyl-5-methylphenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 64, 5.5 g, 14.0 mmol) and 4 mL of CH2Cl2 was added dropwise chlorosulfonic acid (8.2 g, 70.0 mmol, 5.0 eq) with ice-bath cooling. The mixture was stirred at 0° C. for 3 h. The resulting thick oil was poured onto crushed ice with vigorous stirring. The mixture was extracted with EtOAc. The organic layer was washed with 1 N NaHCO3 solution, dried over MgSO4, and concentrated by evaporation to give crude product 4-chlorosulfonyl-3-isopropyl-5-methylphenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 65, 6.0 g, 87%) as light brown thick oil, which was purified by silica gel column chromatography.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[CH:19][CH:18]=2)=[CH:12][C:11]=1[CH3:33].C(N(CC)CC)C.O>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][S:2]([O:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([CH3:33])=[CH:12][C:13]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])=[CH:19][CH:18]=2)=[CH:14][C:15]=1[CH3:16])(=[O:4])=[O:3]
Reactant: Cc1cc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc(C)c1OCCO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc(C)c1OCCOS(C)(=O)=O
Temperature: 0 °C

Procedure:
Methanesulfonyl chloride (0.10 mL) was added to an ice-cooled mixture of benzyl 4′-(2-hydroxy-ethoxy)-3′,5′-dimethylbiphenyl-4-carboxylate (0.38 g) and triethylamine (0.21 mL) in methylene chloride (5 mL) with stirring, and the mixture was stirred at room temperature for 1 hr. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford benzyl 4′-(2-methanesulfonyloxy-ethoxy)-3′5′-dimethylbiphenyl-4-carboxylate (0.45 g).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][N:8]([CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:9]2=[O:12])=[CH:5][CH:4]=1>Br>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][N:8]([CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:9]2=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)N(Cc1cccnc1)C2
Agent: Br
Product: O=C1c2cc(O)ccc2CN1Cc1cccnc1

Procedure:
The titled compound was prepared in the same manner as in Example 10 (1) b) by refluxing 2,3-dihydro-6-methoxy-2-(3-pyridylmethyl)-1H-isoindole-1-one in 47% hydrogen bromide under heating.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.Cl[C:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1>COCCO.O>[CH3:11][CH:9]([CH3:10])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:14]2[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:7][CH:6]=1)=[O:12]
Reactant: COC(=O)c1cccnc1Cl
Reactant: CC(C)C(=O)c1ccc(N)cc1
Solvent: O
Solvent: COCCO
Product: COC(=O)c1cccnc1Nc1ccc(C(=O)C(C)C)cc1
Yield: 118.9 %

Procedure:
A mixture of 1-(4-aminophenyl)-2-methyl-1-propanone (0.0637 mol) and methyl 2-chloro-3-pyridinecarboxylate (0.0637 mol) in 2-methoxyethanol (200 ml) was stirred and refluxed for 90 hours. The mixture was taken up in water and EtOAc and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 22.6 g of methyl 2-[[4-(2-methyl-1-oxopropyl)phenyl]amino]-3-pyridinecarboxylate (interm. 20).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.C(N(CC)CC)C.Cl>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(#N)C>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:3]#[C:2][CH2:1][OH:4]
Reactant: Brc1ccccn1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: OCC#Cc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
2-Propynyl alcohol (35 ml) was added dropwise to a stirred mixture of 2-bromopyridine (23.7 g), bis(triphenylphosphine)palladium chloride (1.54 g), triethylamine (21 ml), cuprous iodide (1.5 g) and acetonitrile (150 ml) and the mixture was stirred at ambient temperature for 30 minutes and then heated to 60° C. for 2 hours. The mixture was cooled to ambient temperature, poured into water (200 ml) and neutralised by adding dilute aqueous hydrochloric acid. The mixture was extracted with methylene chloride (2×500 ml) and the combined extracts were washed with water (500 ml), dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with a 1:1 v/v mixture of methylene chloride and ethyl acetate to give 3-(2-pyridyl)prop-2-yn-1-yl alcohol (14 g, 70%), m.p. 78°-80° C. (recrystallised from a mixture of hexane and ethyl acetate).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[C:16]([CH3:17])=[C:15]([CH3:18])[N:14]([CH3:19])[C:13]=1[C:20]([O-:22])=[O:21].[K+:23].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH3:19][N:14]1[C:15]([CH3:18])=[C:16]([CH3:17])[C:12]([NH:11][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[C:13]1[C:20]([O-:22])=[O:21].[K+:23]
Reactant: Cc1c(N)c(C(=O)[O-])n(C)c1C
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1c(Nc2ccccc2[N+](=O)[O-])c(C(=O)[O-])n(C)c1C
Reaction time: 12 h

Procedure:
38 g of 1-chloro-2-nitrobenzene, 38.8 g of potassium 3-amino-1,4,5-trimethyl-1H-pyrrole-2-carboxylate (crude product from Example 2) and 36 g of ground potassium carbonate (particle size: 0.07 mm) are stirred in 120 ml of 1-methyl-2-pyrrolidone under nitrogen at an internal temperature of 140° C. After 12 hours, a further 3.3 g of 1-chloro-2-nitrobenzene are added. For working up, the mixture is filtered hot, and the residue on the filter is rinsed 3 times with 10 ml of hot (100° C.) 1-methyl-2-pyrrolidone each time. The combined filtrates are further processed without purification.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]([N:10]([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([OH:9])=[O:8])[C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2.[N:22]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[C@@H:24](O)[CH2:23]2.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[S:1]1[CH:5]=[C:4]([CH:6]([N:10]([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([O:9][C@@H:24]2[CH:25]3[CH2:28][CH2:29][N:22]([CH2:27][CH2:26]3)[CH2:23]2)=[O:8])[C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2
Reactant: CN(c1ccccc1)C(C(=O)O)c1csc2ccccc12
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN(c1ccccc1)C(C(=O)O[C@H]1CN2CCC1CC2)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
A mixture of 2-(benzo[b]thiophen-3-yl)-2-(methyl(phenyl)amino)acetic acid (I34) (351 mg, 1.18 mmol), (R)-quinuclidin-3-ol (180 mg, 1.42 mmol), DCC (292 mg, 1.42 mmol), and HOBT (217 mg, 1.42 mmol) in dry THF (20 ml) was stirred at room temperature overnight. The solvent was evaporated, and the crude product was portioned between EtOAc and 2M K2CO3. The organic phase was washed with 2M K2CO3 and brine, dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by flash chromatography (MeCN/MeOH=8/2+0.2% NH4OH) to obtain (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-3-yl)-2-(methyl(phenyl)amino)acetate (224 mg, 46.7% yield).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[C:4]([CH:12]=O)=[C:3]1Cl.C([O-])([O-])=O.[K+].[K+].[SH:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]>>[CH3:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3]1[S:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:12][C:4]2=1
Reactant: COC(=O)CS
Reactant: Cc1ccc2c(c1)c(C=O)c(Cl)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc2c3cc(C)ccc3n(C)c2s1
Yield: 14.4 %

Procedure:
Prepared from (46) (0.80 g), K2CO3 (1.5 g) and methyl 2-mercaptoacetate (0.60 ml) yielding (52) 0.144 g (14.4%). M.p. 152°-155° C.