Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C:12]1[NH:13][C:14](=[O:36])[C:15]2[N:16]=[CH:17][N:18]([C:34]=2[N:35]=1)[C@@H:19]1[O:33][C@H:30]([CH2:31][OH:32])[C@@H:28]([OH:29])[C@H:20]1[O:21][CH2:22][O:23][CH2:24][CH2:25][C:26]#[N:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:43][O:44][C:45]1[CH:66]=[CH:65][C:48]([C:49](Cl)([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)=[CH:47][CH:46]=1>CO>[O:1]([CH2:8][C:9]([NH:11][C:12]1[NH:13][C:14](=[O:36])[C:15]2[N:16]=[CH:17][N:18]([C:34]=2[N:35]=1)[C@@H:19]1[O:33][C@H:30]([CH2:31][O:32][C:49]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)[C:48]2[CH:47]=[CH:46][C:45]([O:44][CH3:43])=[CH:66][CH:65]=2)[C@@H:28]([OH:29])[C@H:20]1[O:21][CH2:22][O:23][CH2:24][CH2:25][C:26]#[N:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCOCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(NC(=O)COc3ccccc3)nc21
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)COc5ccccc5)nc43)[C@H](OCOCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
N2-Phenoxyacetyl-2′-O-(2-cyanoethoxymethyl)guanosine (660 mg, 1.32 mmol) was subjected to azeotropic distillation with pyridine, and then was dried with a vacuum pump for 30 minutes. The residue was dissolved in 9 mL of THF, and 2.1 g of pyridine (26.4 mmol) and 600 mg of molecular sieve 4 A were added under an argon atmosphere, and the reaction solution was stirred for 10 minutes. To the solution was added 540 mg of 4,4′-dimethoxytritylchloride (1.58 mmol) by 3 portions every 1 hour, and the reaction solution was further stirred for 1 hour. After 2 mL of methanol was added and the reaction solution was stirred for 2 minutes, the reaction solution was filtrated with a celite, and was washed with ethyl acetate. After concentrating the filtrate with evaporation, the residue was dissolved in ethyl acetate, and was separated with a saturated aqueous sodium bicarbonate solution. After the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, the solvent was distilled off. The obtained residue was purified by silica gel chromatography to obtain the objective compound (800 mg, yield 75%).
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2C=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N)CCC.C1(=O)CCCCC1>C(OC(=O)C)C>[CH2:21]([N:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:8](=[O:20])[NH:9][C:10]1[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=1)[CH2:22][CH2:23][CH3:24]
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Solvent: O=C1CCCCC1
Solvent: CCCCN
Solvent: CCOC(C)=O
Product: CCCCN(C(=O)Nc1ncc(SCC(=O)O)s1)C1CCCCC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from n-butylamine, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH2:20][N:21]2[C:26]3[CH:27]=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][C:25]=3[O:24][CH2:23][C:22]2=[O:33])[CH:14]([C:34]([O:36]C)=[O:35])[CH2:13]1.[OH-].[Na+].Cl>CO.O>[C:31]([C:28]1[CH:29]=[CH:30][C:25]2[O:24][CH2:23][C:22](=[O:33])[N:21]([CH2:20][CH2:19][CH2:18][CH:15]3[CH2:16][CH2:17][N:12]([CH2:11]/[CH:10]=[CH:9]/[C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])[CH2:13][CH:14]3[C:34]([OH:36])=[O:35])[C:26]=2[CH:27]=1)#[N:32]
Reactant: COC(=O)C1CN(C/C=C/c2cc(F)ccc2F)CCC1CCCN1C(=O)COc2ccc(C#N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc2c(c1)N(CCCC1CCN(C/C=C/c3cc(F)ccc3F)CC1C(=O)O)C(=O)CO2
Reaction time: 64 h

Procedure:
A solution of methyl 1-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]-4-[3-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate (Example 64) (73 mg, 0.143 mmol) in methanol (12 mL) and water (5 mL) was treated with sodium hydroxide solution (1N, 1 mL). After 64 hours, the pH was adjusted to 6 with 1N HCl. The mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over magnesium sulfate and concentrated at reduced pressure. Chromatography on silica gel using methanol in dichloromethane (0-10%) and trituration with diethyl ether gave the title compound as a colorless solid, mixture of diastereomers, 10 mg (14%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:13]1[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=1)(=[O:12])=[O:11].[F:24][C:25]([F:36])([F:35])[CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][OH:34])[CH2:29][CH2:28]1.[H-].[Na+]>CS(C)=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([O:34][CH2:33][CH:30]2[CH2:31][CH2:32][N:27]([CH2:26][C:25]([F:24])([F:35])[F:36])[CH2:28][CH2:29]2)=[CH:17][CH:18]=1)(=[O:12])=[O:11]
Reactant: OCC1CCN(CC(F)(F)F)CC1
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(F)cc2)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCN(CC(F)(F)F)CC3)cc2)c(C)c1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a solution of N-(2,4-dimethylphenyl)-4-fluoro-N-isobutylbenzenesulfonamide (25 mg, 0.075 mmol) and (1-(2,2,2-trifluoroethyl)piperidin-4-yl)methanol (14.70 mg, 0.075 mmol) in dimethyl sulfoxide (DMSO) (0.5 mL) stirred in air at 20° C., was added sodium hydride (approximately 2.98 mg, 0.075 mmol, 60% dispersed in oil) in one charge. The reaction mixture was stirred at 20° C. for 16 hours. The reaction was carefully quenched with methanol (0.5 mL) and water (0.5 mL). The solvent was concentrated in vacuo (Biotage V10) to give the crude product in DMSO (0.5 mL). The residue was taken up in additional DMSO (0.5 mL) and methanol (1 mL) then purified by mass directed autoprep (formic acid modifier). The appropriate fractions were evaporated under a stream of nitrogen to give the required product, 11.5 mg. LCMS [LCMS1] Rt 1.51 min, m/z (ES+) 513 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([OH:12])=[CH:7]2.IC.O.[C:16](OCC)(=O)C>CN(C=O)C.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([O:12][CH3:16])=[CH:7]2
Reactant: Oc1cc2cccc(Br)c2cn1
Reactant: CCOC(C)=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc2cccc(Br)c2cn1
Temperature: 50 °C
Reaction time: 24 h
Yield: 22 %

Procedure:
To a suspension of 8-bromoisoquinolin-3-ol (Description 53; 7.3 g, 0.03 mol) and silver carbonate (13.6 g, 0.05 mol) in dry DMF (380 ml) under nitrogen was added iodomethane (2.25 ml, 0.04 mol). The mixture was stirred at 50° C. for 24 hours. Further iodomethane (1 ml, 0.015 mol) was added and the mixture heated for 64 hours at 50° C. The mixture was cooled, water (300 ml) and ethyl acetate (300 ml) were added and shaken well. The mixture was filtered through Celite™, the layers separated and the aqueous layer was extracted with ethyl acetate (3×50 ml). The organic layers were combined, evaporated to ˜150 ml, washed twice with water and then brine. The organic extract was then evaporated to give the title compound (1.7 g, 22%).
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][N:49]([S:52]([CH3:55])(=[O:54])=[O:53])[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.C(O)C(F)(F)F.N>CO.C(Cl)Cl>[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][N:49]([S:52]([CH3:55])(=[O:54])=[O:53])[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(N2CCN(S(C)(=O)=O)CC2)c(C)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: CO
Solvent: OCC(F)(F)F
Solvent: ClCCl
Product: COc1cc(N2CCN(S(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 100 °C
Yield: 36.7 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 5-methyl-2-(methyloxy)-4-[4-(methylsulfonyl)-1-piperazinyl]aniline (53 mg, 0.18 mmol), and p-toluenesulfonicacid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 1 mL of trifluoroethanol was added and the mixture was heated to 100° C. for 72 h. 2 mL of 2 N ammonia in MeOH was added. The solvent was rotovaped down. The residue was taken up in 3 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-absorbed solids were purified by flash chromatography to give the title compound (50 mg, 0.066 mmol, 37%). 1H NMR (400 MHz, DMSO-d6) d ppm 9.78 (s, 1H), 9.38 (d, J=6.97 Hz, 1H), 8.49 (s, 1H), 8.24 (d, J=5.13 Hz, 1H), 8.10 (d, J=2.20 Hz, 1H), 7.78 (dd, J=8.80, 2.20 Hz, 1H), 7.70 (d, J=8.80 Hz, 1H), 7.54 (s, 1H), 7.42-7.48 (m, 1H), 7.34-7.42 (m, 1H), 7.28 (d, J=8.80 Hz, 1H), 7.18 (t, J=8.07 Hz, 2H), 6.92-7.01 (m, 1H), 6.83 (s, 1H), 6.57 (d, J=5.13 Hz, 1H), 3.98 (s, 3H), 3.81 (s, 3H), 3.24-3.30 (m, 4H), 2.95-2.99 (m, 4H), 2.94 (s, 3H), 2.17 (s, 3H); MS (ESI): 755 [M+H]+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:24](=[O:25])[N:20]3[CH2:21][CH2:22][CH2:23][N:19]3[C:18]=2[C:26]2[CH:31]=[CH:30][N:29]=[C:28](S(C)(=O)=O)[N:27]=2)=[CH:13][CH:12]=1>C1COCC1.C([O-])(O)=O.[Na+]>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:24](=[O:25])[N:20]3[CH2:21][CH2:22][CH2:23][N:19]3[C:18]=2[C:26]2[CH:31]=[CH:30][N:29]=[C:28]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:27]=2)=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)c(=O)n3n2CCC3)n1
Reactant: Oc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c(-c2ccc(F)cc2)c(-c2ccnc(Oc3ccccc3)n2)n2n1CCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
To a solution of phenol (0.66 g, 7.08 mmol) in THF (5 mL) is added NaH (0.24 g, 5.91 mmol) followed by a solution of the crude 2-(4-fluorophenyl)-3-(2-methanesulfonyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 5, prepared herein above (0.25 g, 0.67 mmol) in THF (2 mL). The reaction mixture is stirred for 1.5 hours at room temperature, diluted with aqueous NaHCO3 and extracted with twice with ethyl acetate. The organic layers are combined, dried over MgSO4, and concentrated in vacuo to afford the crude product which is purified over silica (100% EtOAc, followed by 10% MeOH/EtOAc) to provide 0.35 g (38% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.47 (d, J=5.1 Hz, 1H), 7.49 (dd, J=7.8, 7.8 Hz, 2H), 7.40 (ddd, J=5.4, 5.4 Hz, 2H), 7.35-7.22 (m, 3H), 7.10 (dd, J=8.4, 8.4 Hz, 2H), 6.90 (d, J=6.8 Hz, 1H), 4.05 (t, J=7.2 Hz, 2H), 3.86 (t, J=7.2 Hz, 2H), 2.59 (dt, J=7.2, 7.2 Hz, 2H); HRMS calcd for C22H18FN4O2 (M+H)+389.1414. found 389.1407. This compound corresponds to analog 1 from Table I.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH2:17][S:18]([CH2:21][CH2:22][CH3:23])(=O)=O)[CH:14]=2)[CH2:9][CH2:8][CH:7]1[NH:24][C:25](=[O:29])[O:26][CH2:27][CH3:28].C([O-])=O.[NH4+]>CO.[Pd]>[CH2:27]([O:26][C:25](=[O:29])[NH:24][CH:7]1[CH2:8][CH2:9][C:10]2[C:15](=[CH:14][C:13]([CH2:16][CH2:17][S:18][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=2)[CH:6]1[CH2:5][C:4]1[CH:3]=[CH:2][CH:32]=[CH:31][CH:30]=1)[CH3:28]
Reactant: CCCS(=O)(=O)CCc1ccc2c(c1)C(Cc1cccc(Cl)c1)C(NC(=O)OCC)CC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCSCCc1ccc2c(c1)C(Cc1ccccc1)C(NC(=O)OCC)CC2
Temperature: 80 °C
Reaction time: 4 h
Yield: 54.1 %

Procedure:
Ethyl 1-(3-chlorobenzyl)-7-(2-(propylsulfonyl)ethyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (27.1 mg, 0.057 mmol) and ammonium formiate (71.5 mg, 1.134 mmol) were dissolved in 5 ml MeOH. Pd/C (0.845 mg, 7.94 μmol) was added and stirred at 80° C. for 4 h. The mixture was filtered, the solvent evaporated, the residue re-dissolved in ethyl acetate, which was subsequently washed with water, NaHCO3 and brine, dried, filtered. Solvent was evaporated to obtain white solid which was purified by chromatography affording 12.7 mg of product as a white solid.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([OH:17])[C:8]([CH3:16])([CH3:15])[CH2:9]OS(C)(=O)=O)(=O)=O.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH2:18]([N:25]1[CH2:9][C:8]([CH3:16])([CH3:15])[C@H:7]([OH:17])[CH2:6]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(COS(C)(=O)=O)[C@H](O)COS(C)(=O)=O
Reactant: NCc1ccccc1
Solvent: CCO
Product: CC1(C)CN(Cc2ccccc2)C[C@H]1O
Temperature: 25 °C
Yield: 89.6 %

Procedure:
A solution of 21.7 g (75 mmol) of (2S)-2-hydroxy-3,3-dimethyl-4-[(methylsulfonyl)oxy]butyl methanesulfonate and 24.4 mL (228 mmol) of benzylamine in 200 mL of ethanol was heated at 120° C. for 18 h in a 400 mL capacity bomb. The reaction mixture was allowed to cool to room temperature, the bomb was vented, and the reaction mixture was concentrated under reduced pressure to 100 mL. The reaction was diluted with 50 mL of water and made acidic with concentrated hydrochloric acid. The aqueous phase was then washed with ether, made basic with 5M aqueous sodium hydroxide, and extracted with ether. The ether extract was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 0.25:9.75 2M ammonia in methanol:ethyl acetate to afford 13.8 g (90%) of (3S)-1-benzyl-4,4-dimethyl-3-pyrrolidinol. 1H NMR (300 MHz, CDCl3) δ 7.30-7.36 (m, 5H), 3.77 (br s, 1H), 3.65 (s, 2H), 2.93-2.99 (m, 1H), 2.55-2.64 (m, 2H), 2.31 (d, J=9 Hz, 1H), 1.76 (d, J=7 Hz, 1H), 1.09 (d, J=1 Hz, 6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]([CH3:14])[CH:8]=1.Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([C:25]([OH:27])=[O:26])=[CH:18][C:17]=1[S:28]([NH2:31])(=[O:30])=[O:29].Cl>O>[N+:22]([C:21]1[CH:20]=[C:19]([CH:18]=[C:17]([S:28](=[O:30])(=[O:29])[NH2:31])[C:16]=1[O:13][C:12]1[CH:7]=[CH:8][C:9]([CH3:14])=[CH:10][CH:11]=1)[C:25]([OH:27])=[O:26])([O-:24])=[O:23]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(Oc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)cc1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
124 g (0.9 mol) of potassium carbonate are dissolved in 800 ml of water. To this solution, there are added portionwise 1.6 mols of p-cresol and subsequently 112 g (0.4 mol) of 2-chloro-3-nitro-5-carboxy-benzenesulphonamide and the solution is heated to 85° C. The whole is stirred for 16 hours at this temperature, cooled to 25°-30° C. and acidified with concentrated hydrochloric acid to pH 1. The oil which thereupon separates is isolated from the aqueous phase and subjected to steam distillation. Alternatively, it is also possible to adjust a pH-value of 8-9, to extract the excess phenol with ethyl acetate and then to acidify the aqueous phase. After having separated in this manner the excess p-cresol, the product crystallises upon cooling. By recrystallisation from acetone/H2O, the 3-nitro-4-(4'-methylphenoxy)-5-sulphamoylbenzoic acid melting at 236° C. is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].[H-].[Na+].[C:12]1([C:18]2[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.[I-].[K+]>[C:18]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:19]=[CH:20][C:21]([CH2:22][O:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])=[CH:24][CH:25]=1
Reactant: N#Cc1cccc(O)c1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: N#Cc1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Temperature: 0 °C
Yield: 97.6 %

Procedure:
To a solution of 3-cyanophenol (5.0 g, 40.72 mmol) in dry N,N-dimethylformamide (100 mL) kept under an atmosphere of nitrogen, sodium hydride (2 g, 48.86 mmol, 60% dispersion in oil) was added in portions and the reaction mixture was stirred until gas evolution ceased. p-Phenylbenzyl chloride (9.26 g, 44.79 mmol) and potassium iodide (0.2 g, 1.21 mmol) were added and the reaction mixture was stirred at room temperature for 60 hours. The reaction mixture was poured on to a mixture of saturated sodium carbonate (100 mL) and ice water (300 mL). The precipitate was filtered of and washed with water (3×100 mL), n-hexane (2×80 mL) and dried in vacuo at 50° C. for 18 hours affording 11.34 g (98%) of 3-(biphenyl-4-ylmethoxy)-benzonitrile as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[C:18]([CH3:29])=[C:19]([CH:25]=[CH:26][C:27]=1[CH3:28])[O:20][CH2:21][C:22]([OH:24])=[O:23].O=S(Cl)Cl.[CH3:34][CH:35](O)[CH3:36]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[C:18]([CH3:29])=[C:19]([CH:25]=[CH:26][C:27]=1[CH3:28])[O:20][CH2:21][C:22]([O:24][CH:35]([CH3:36])[CH3:34])=[O:23]
Reactant: CC(C)O
Reactant: Cc1ccc(OCC(=O)O)c(C)c1NCc1cc(-c2cccc(F)c2)ccc1F
Solvent: O=S(Cl)Cl
Product: Cc1ccc(OCC(=O)OC(C)C)c(C)c1NCc1cc(-c2cccc(F)c2)ccc1F
Yield: 90 %

Procedure:
A solution of 2-[3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]-2,4-dimethyl-phenoxy]acetic acid (I(j)) (120 mg, 0.3 mmol, 1 eq) and SOCl2 (1 mL) in i-PrOH (4 mL) was heated at reflux for 2 h. The solvent was evaporated in vacuo and the residue was taken up in water and basified to pH 8 by addition of aqueous NaHCO3. The mixture was extracted with EtOAc and the organic extract was dried (Na2SO4) filtered and evaporated in vacuo. The residue obtained was purified by column chromatography to give the title compound as an oil (120 mg, 90%).
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.Br[C:27]1C=CC(N)=C(C)C=1.P(Cl)(Cl)(Cl)=O.N>O>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][C:15]=4[CH3:27])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1cc(Br)ccc1N
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc(Br)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Temperature: 105 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(4-(1H-pyrazol-1-yl)benzyl)malonic acid (20.0 g, 71.5 mmol, Intermediate 3: step b) and 4-bromo-2-methylaniline (13.3 g, 71.5 mmol) in phosphorus oxychloride (66.8 mL, 712 mmol) was heated at 105° C. After 5 hours, the mixture was cooled to 23° C. and added to water (600 mL) with cooling so that the internal temperature did not exceed 35° C. The pH of the mixture was adjusted to 8-9 by the slow addition of saturated aqueous ammonia solution such that the internal temperature did not exceed 35° C. After 30 minutes of stirring at room temperature, the mixture was filtered and the solid material was suspended in acetonitrile (200 mL), sonicated and filtered. The solid material was collected and suspended in DCM (80 mL), sonicated, filtered and washed with ether (40 mL). The filtrate was concentrated, suspended in DCM (40 mL), sonicated and filtered to provide more of the title compound. To 5 g of the isolated solid, DCM (300 mL) and saturated aqueous NaHCO3 (100 mL) were added and the mixture was transferred to a separatory funnel, and the layers were separated. The DCM layer was further washed with brine (100 mL), dried (MgSO4), filtered and the solvents were removed under reduced pressure. The crude material was purified using flash-column chromatography on silica gel eluting with DCM to provide the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]=1[O:13][CH2:14][O:15][CH3:16])[CH2:8][NH2:9])([CH3:4])[CH3:3].[C:21]1([NH:27][C:28](N)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH2:8][NH:9][C:28]([NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])[CH:10]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]=1[O:13][CH2:14][O:15][CH3:16])([CH3:1])[CH3:3]
Reactant: COCOc1c(C(C)(C)C)cc(CN)cc1C(C)(C)C
Reactant: NC(=O)Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COCOc1c(C(C)(C)C)cc(CNC(=O)Nc2ccccc2)cc1C(C)(C)C
Yield: 9148 %

Procedure:
The above-titled compound was prepared substantially in accordance with the procedure described in Example 6A using 5.4 g (19.2 mmol) of 3,5-Bis(1,1-dimethylethyl)-4-(methoxymethoxy) benzylamine (prepared substantially in accordance with the procedures described in Example 1), 2.61 g (19.2 mmol) of N-phenylurea, 0.96 g (16 mmol) of acetic acid and 160 ml of toluene. Such reaction provided 700 g of N-[[3,5-bis-(1,1-dimethylethyl)-4-(methoxymethoxy)phenyl]methyl]-N'-phenylurea. (m.p. 168°-170° C.). The methoxymethyl hydroxy protecting group was then removed, substantially in accordance with the procedure described in Example 6B, to provide 600 mg of the above-titled compound. m.p. 199°-202° C.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][C:6]2[CH:8]=[CH:9][S:10][C:5]=2[C:4](=[O:11])[CH2:3]1.N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19].C(O)C>ClCCl>[C:18]([N:7]1[CH:2]([CH3:1])[CH2:3][C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]1=2)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CC1CC(=O)c2sccc2N1
Solvent: CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2ccsc2C(=O)CC1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
[Step 4] 123 mg (0.74 mmol) of the 5-methyl-5,6-dihydrothieno[3,2-b]pyridin-7(4H)-one were dissolved in 4 mL of anhydrous dichloromethane followed by sequentially adding 0.12 mL (1.5 mmol) of anhydrous pyridine and 0.078 mL (1.1 mmol) of acetyl chloride and stirring for 1 hour at room temperature. Following completion of the reaction, ethanol was added, the solution was concentrated under reduced pressure and then additionally boiled with toluene. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain 111 mg of 4-acetyl-5-methyl-5,6-dihydrothieno[3,2-b]pyridin-7(4H)-one in the form of a pale brown oil (72%).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][OH:21].C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.CC(O)C>[CH2:9]([NH:16][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][OH:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: OCc1ccccc1I
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: OCc1ccccc1NCc1ccccc1
Yield: 95.2 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (10 mg, 0.5 mmol), K3PO4 (425 mg, 2.00 mmol), benzylamine (131 μL, 1.20 mmol), 2-iodobenzylalcohol (234 mg, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL). Column chromatography using a solvent mixture (hexane/ethyl acetate=4/1, Rf=0.3) afforded 2-(N-benzyl)aminobenzylalcohol (203 mg, 95% isolated yield) as off-white solid. The spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity. See Coppola, G. A. J Herterocyl. Chem. 1986, 23, 223-224.