Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:8][C:9]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])=[CH:10][CH:11]=2)[N:6]=1.[Br:17]Br>C(O)(=O)C>[BrH:17].[NH2:1][C:2]1[S:3][C:4]([Br:17])=[C:5]([C:7]2[S:8][C:9]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])=[CH:10][CH:11]=2)[N:6]=1
Reactant: CC(=O)NCc1ccc(-c2csc(N)n2)s1
Reactant: BrBr
Solvent: CC(=O)O
Product: Br
Product: CC(=O)NCc1ccc(-c2nc(N)sc2Br)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2.0 g of 2-amino-4-(5-acetylaminomethyl-2-thienyl]thiazole in 50 ml of acetic acid is added dropwise a solution of 1.44 g of bromine in 10 ml of acetic acid with stirring at room temperature for 15 minutes. After the whole mixture is stirred for an hour, the precipitated crystals are collected by filtration and washed with ether to give 2-amino-4-(5-acetylaminomethyl-2-thienyl)-5-bromothiazole hydrobromide, melting at 185° C.-186° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[CH:14]=[N:13][NH:12][C:10]3=2)[N:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1>C(O)C>[ClH:1].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]4[CH:14]=[N:13][NH:12][C:10]4=3)[N:5]=[CH:4][CH:3]=2)[CH:18]=1
Reactant: COc1cccc(N)c1
Reactant: Clc1ccnc2ccc3cn[nH]c3c12
Solvent: CCO
Product: COc1cccc(Nc2ccnc3ccc4cn[nH]c4c23)c1
Product: Cl
Yield: 58.9 %

Procedure:
To a suspension of 9-chloro-1H-pyrazolo[3,4-f]quinoline (1.10 g, 5.4 mmol) in absolute ethanol (50 ml) was added m-anisidine (0.79 ml, 7.1 mmol) and the reaction mixture heated at reflux for 48 hours. The solvent was removed by rotary evaporation and the residue was dissolved in boiling methanol, treated with decolorizing carbon and filtered to give a light yellow solution. The solvent was removed by rotary evaporation and the residue was recrystallized from methanol/ether to give 9-(m-anisidino)-1H-pyrazolo[3,4-f]quinoline hydrochloride (1.04 g, 59%) as off-white crystals.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([O:9][C:10]2[C:24]([CH:25]3[CH2:29][CH2:28][CH2:27][NH:26]3)=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CCCCCC.[CH3:38][CH:39]([OH:41])C.C(NCC)C>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[C:24]([CH:25]3[CH2:29][CH2:28][CH2:27][N:26]3[C:39](=[O:41])[CH3:38])=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:30][CH:31]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cc1
Reactant: CC(C)O
Solvent: CCNCC
Solvent: CCCCCC
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1

Procedure:
230 mg of 5-(4-methanesulfonyl-phenoxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole obtained in Example 162 (step 7) was optically resolved, using an optical resolution column (CHIRALPAK AD 2 cmφ×25 cmL (by Daicel Chemical), mobile phase: hexane/2-propanol/diethylamine=20/80/0.1, flow rate: 10 ml/min), into an enantiomer A (retention time: 19.0 min) and an enantiomer B (retention time: 32.2 min) each as a yellow oily substance.
Reaction SMILES: [OH:1][C:2]1([C:16]([O:18][CH3:19])=[O:17])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([O:14][CH3:15])[CH:6]=[CH:7][C:8]=2[O:12][CH3:13])[CH2:3]1.[C:20](OC(=O)C)(=[O:22])[CH3:21].O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:20]([O:1][C:2]1([C:16]([O:18][CH3:19])=[O:17])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([O:14][CH3:15])[CH:6]=[CH:7][C:8]=2[O:12][CH3:13])[CH2:3]1)(=[O:22])[CH3:21]
Reactant: COC(=O)C1(O)CCc2c(OC)ccc(OC)c2C1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)C1(OC(C)=O)CCc2c(OC)ccc(OC)c2C1
Temperature: 0 °C
Reaction time: 24 h
Yield: 96.5 %

Procedure:
5.0 g of methyl rac-1,2,3,4-tetrahydro-2-hydroxy-5,8-dimethoxynaphthalene-2-carboxylate were dissolved in 50 ml of pyridine. The solution was cooled to 0° C. and 10 ml of acetic anhydride and 150 mg of 4-dimethylaminopyridine were added. After standing at 0° C. for 24 hours, the mixture was poured into 250 ml of water. The mixture obtained was extracted with three 100 ml portions of ethyl acetate and the combined ethyl acetate extracts were washed with 2-N hydrochloric acid until the washings were acidic, then with 200 ml of water, 200 ml of dilute aqueous potassium hydrogen carbonate and 200 ml of brine. After drying, the solvent was evaporated to give a white crystalline residue. Recrystallisation from diethyl ether gave 5.6 g (96.5%) of methyl rac-2-acetoxy-1,2,3,4-tetrahydro-5,8-dimethoxynaphthalene-2-carboxylate in the form of colourless crystals of melting point 155.5°-156° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:17][CH:16]3[N:12]([C:13](=[O:18])[CH2:14][CH2:15]3)[C:11]([CH3:20])([CH3:19])[CH2:10]2)[C:5]([F:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[C:24]([F:39])=[CH:25][C:26]([CH:36]2[CH2:38][CH2:37]2)=[C:27]([N:29]2[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]2)[CH:28]=1>C(O)(C(F)(F)F)=O.C(O)(C)C>[F:21][C:5]1[C:6]([NH:8][CH:9]2[CH2:17][CH:16]3[N:12]([C:13](=[O:18])[CH2:14][CH2:15]3)[C:11]([CH3:20])([CH3:19])[CH2:10]2)=[N:7][C:2]([NH:22][C:23]2[C:24]([F:39])=[CH:25][C:26]([CH:36]3[CH2:38][CH2:37]3)=[C:27]([N:29]3[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]3)[CH:28]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2F)CC2CCC(=O)N21
Reactant: Cn1nnn(-c2cc(N)c(F)cc2C2CC2)c1=O
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Cn1nnn(-c2cc(Nc3ncc(F)c(NC4CC5CCC(=O)N5C(C)(C)C4)n3)c(F)cc2C2CC2)c1=O
Temperature: 100 °C

Procedure:
A mixture of 7-(2-chloro-5-fluoropyrimidin-4-ylamino)-hexahydro-5,5-dimethylindolizin-3(5H)-one isomer B (trans) (100 mg), 1-(5-amino-2-cyclopropyl-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one (100 mg) and TFA (5 drops) in isopropanol (1 ml) was heated at 100° C. overnight in a sealed vial. After allowing to cool to room temperature, the solvent was removed in vacuo and the residue was purified by Combiflash chromatography (2.0 M ammonia methanol in dichloromethane=0-30%) to give product as racemic mixture.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([NH:10][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][N:14]=2)[CH3:12])=[O:9])=[CH:3][CH:2]=1.Br[CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8]([NH:10][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:27][CH2:28][CH3:29])=[CH:15][N:14]=2)[CH3:12])=[O:9])=[CH:5][CH:6]=1
Reactant: C[C@@H](NC(=O)Cc1ccc(-c2ccccc2)cc1)c1ccc(O)cn1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc([C@@H](C)NC(=O)Cc2ccc(-c3ccccc3)cc2)nc1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To a mixture of 2-(1,1′-biphenyl-4-yl)-N-[(1R)-1-(5-hydroxypyridin-2-yl)ethyl]acetamide (30 mg, 0.09 mmol) (Example 8), 1-bromopropane (0.02 ml, 0.22 mmol) in DMF (1.2 ml) was added potassium carbonate (37 mg, 0.27 mmol). The reaction was stirred at 40° C. for 18 hours and then filtered through a cotton plug to remove any precipitates, washing with DMSO (2 ml). The collected filtrate was purified using reverse phase prep HPLC chromatography to afford the mono-trifluoroacetate salt of 2-(1,1′-biphenyl-4-yl)-N-[(1R)-1-(5-propoxypyridin-2-yl)ethyl]acetamide as an oil. 1H NMR (CD3OD, 400 MHz) δ 8.34 (s, 1H); 7.97 (dd, J=2.80 and 9.20 Hz, 1H); 7.74 (d, J=8.80 Hz, 1H); 7.56 (m, 4H); 7.40 (m, 2H); 7.33 (m, 3H); 5.07 (m, 1H); 4.11 (t, J=6.40 Hz, 2H); 3.61 (s, 2H); 1.84 (m, 2H); 1.57 (d, J=7.20 Hz, 3H); 1.05 (t, J=7.60 Hz, 3H). HRMS (ES) exact mass calcd for C24H26N2O2: 375.2067, Found: 375.2078.
Reaction SMILES: [NH3:1].[CH2:2]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]=[C:8](Cl)[N:7]=1)[CH:3]=[CH2:4].O>C(O)C.C1COCC1>[CH2:2]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]=[C:8]([NH2:1])[N:7]=1)[CH:3]=[CH2:4]
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: N
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: C=CCNc1nc(N)nc2ccc([N+](=O)[O-])cc12
Temperature: 70 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
After 10 ml of ammonia gas was dissolved in 50 ml of ethanol at −78° C., 15 ml of a solution of 2.40 g (9.07 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline in THF was added thereto, followed by stirring overnight in a sealed tube at 70° C. 150 ml of water was added to the reaction solution, and then crystals thus precipitated were filtered out, followed by recrystallization from ethyl acetate-hexane to give 1.88 g (84.6%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C@H:11]([OH:24])[CH2:12][C@@H:13]([NH:17][S@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH:14]([CH3:16])[CH3:15])[S:9][CH:10]=1)=[O:5])[CH3:2].[CH2:25]=O>C1(C)C=CC=CC=1>[CH3:2][CH2:1][O:3][C:4]([C:6]1[N:7]=[C:8]([C@@H:11]2[O:24][CH2:25][N:17]([S:18]([C:20]([CH3:21])([CH3:22])[CH3:23])=[O:19])[CH:13]([CH:14]([CH3:15])[CH3:16])[CH2:12]2)[S:9][CH:10]=1)=[O:5]
Reactant: C=O
Reactant: CCOC(=O)c1csc([C@H](O)C[C@@H](N[S@@](=O)C(C)(C)C)C(C)C)n1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1csc([C@H]2CC(C(C)C)N(S(=O)C(C)(C)C)CO2)n1
Temperature: 25 °C
Reaction time: 50 h
Yield: 87.1 %

Procedure:
A 0.1 M solution of N-sulfinyl amino alcohol 32 (0.575 g, 1.53 mmol) in toluene (15.3 mL) with paraformaldehyde (0.917 g, 30.5 mmol) was heated in a sealed vessel at 70° C. with stirring for 50 h. After cooling to rt, the mixture was filtered through Celite, washing the filter cake thoroughly with toluene. The solution was concentrated and purified via HPFC (88:12 to 30:70 CH2Cl2:EtOAc) to afford 0.518 g of tetrahydrooxazine 33 (87%) as a foamy yellow solid. [α]25D=+108.4 (c=1.0, CHCl3). IR (film): 1011, 1076, 1087, 1163, 1195, 1474, 1729, 2957, 2979 cm−1. 1H NMR (500 MHz, CDCl3): δ 1.01 (d, 3H, J=6.8 Hz), 1.02 (d, 3H, J=6.8 Hz), 1.17 (s, 9H), 1.35 (t, 3H, J=7.1 Hz), 2.08-2.16 (m, 1H), 2.28-2.40 (m, 1H), 2.31 (d, 1H, J=14.3 Hz), 3.02 (dd, 1H, J=4.7, 10.1 Hz), 4.37 (q, 2H, J=7.1 Hz), 4.72 (d, 1H, J=11.6 Hz), 5.14 (d, 1H, J=11.6 Hz), 5.20 (dd, 1H, J=2.5, 11.5 Hz), 8.11 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 14.3, 20.5, 20.7, 22.8, 27.5, 32.6, 59.2, 61.3, 62.7, 71.4, 71.6, 127.8, 146.5, 161.3, 173.3. HRMS (FAB) calcd. for C17H29N2O4S2 (M+H): 389.1569. Found 389.1566.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[OH2:27].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][N:10]=[C:11]([N:19]3[CH2:20][CH2:21][N:22]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:23][CH2:24]3)[C:12]=2[C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2n[nH]c(N3CCNCC3)c2-c2ccncc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CS(=O)(=O)N1CCN(c2n[nH]c(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Product: O
Temperature: 25 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
A solution of 3-(4-chlorophenyl)-4-(4-pyridyl)-5-(4-piperazinyl)pyrazole (200 mg; 0.54 mmol; prepared as set forth in Example A-169), methanesulfonyl chloride (75 mg) and 4-dimethylaminopyridine (5 mg) in pyridine was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue was treated with water. The resultant crystalline solid was filtered, air dried and recrystallized from methanol and water to give 118 mg (37%) of 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-(methylsulfonyl)piperazine, monohydrate, m.p. 245-248° C. Anal. Calc'd. for C19H20ClN5SO2.H2O: C, 52.35; H, 5.09; N, 16.07. Found: C, 52.18; H, 5.31; N, 16.00.
Reaction SMILES: O=[C:2]([CH3:21])[CH2:3][O:4][C:5]([CH:7]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:8]1)=O.C([NH2:25])(=O)C.B(F)(F)F.CCOCC>C1(C)C(C)=CC=CC=1>[CH2:14]([O:13][C:11]([N:9]1[CH2:10][CH:7]([C:5]2[O:4][CH:3]=[C:2]([CH3:21])[N:25]=2)[CH2:8]1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(N)=O
Reactant: CC(=O)COC(=O)C1CN(C(=O)OCc2ccccc2)C1
Agent: FB(F)F
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: Cc1coc(C2CN(C(=O)OCc3ccccc3)C2)n1
Temperature: 130 °C

Procedure:
To 130 mg (0.45 mmol) azetidine-1,3-dicarboxylic acid 1-benzyl ester 3-(2-oxo-propyl)ester in 4 mL xylene were added 132 mg (2.25 mmol) acetamide, 39 μL (0.31 mmol) boron trifluoride etherate and the mixture was heated at 130° C. for 24 hours. After cooling to room temperature and evaporation of the solvent the product was purified by chromatography (silica, hexane-EtOAc 6:4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2O)cc1
Reactant: ClCc1ccccc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2OCc2ccccc2)cc1
Temperature: 60 °C
Yield: 73.4 %

Procedure:
To a stirred solution of 2-(3-chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 332) (0.100 g, 0.28 mmol) in DMF (2.8 mL) was added benzyl chloride (0.32 mL, 0.28 mmol). The resulting solution was stirred with heating to 60° C. overnight. The solvent was removed in vacuo and the resulting residue partitioned between ethyl acetate and 10% citric acid. After extracting with ethyl acetate, the combined organics were dried over MgSO4 and concentrated in vacuo. The crude product was purified using flash chromatography (SiO2, 1:1 ethyl acetate:hexanes) to provide the desired product (yield: 0.096 g, 76%). mp 110-113° C. 1H NMR (300 MHz, DMSO d6) δ 3.39 (s, 3H), 5.48 (s, 2H), 7.29 (m, 4H), 7.59-7.71 (m, 3H), 7.76 (m, 3H), 8.00 (m, 2H), 8.21 (s, 1H). MS (DCI/NH3) m/z 467 (M+H)+, 484 (M+NH4)+. Anal. calc. for C24H19ClN2O4S: C, 61.73; H, 4.10; N, 6.00. Found: C, 62.00; H, 4.18; N, 5.93.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([O:10][CH3:11])[CH:6]=[CH:7][C:8]=1Br.[Mg].II.[C:17](=[O:19])=[O:18].Cl>O1CCCC1>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([O:10][CH3:11])[CH:6]=[CH:7][C:8]=1[C:17]([OH:19])=[O:18]
Reactant: COc1ccc(Br)c(C(F)(F)F)c1
Reactant: O=C=O
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)c(C(F)(F)F)c1
Reaction time: 2 h
Yield: 39.5 %

Procedure:
Dry tetrahydrofuran (10 ml) was added to 3-trifluoromethyl-4-bromo-1-methoxybenzene (compound III) (4.4 g) and metallic magnesium (0.41 g) and thereto was further added a catalytic amount of iodine, followed by refluxing for 1.5 hours with stirring. After the temperature was returned to room temperature, to the mixture was slowly added dropwise a solution prepared by adding dry ice (30 g) to dry tetrahydrofuran (10 ml) at -40° C. or lower. The temperature was returned to room temperature and then the reaction was allowed to proceed for further 2 hours. Then, the reaction mixture was added to 1N hydrochloric acid (50 ml) to stop the reaction and repeatedly extracted with ethyl acetate. The ethyl acetate layer was sufficiently washed with water and dried by adding anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and then, the resulting solid was recrystallized from methylene chloride to obtain 2-trifluoromethyl-4-methoxybenzoic acid (compound IV, 1.5 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6](N)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.N(OCCCCC)=O.[CH:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: c1ccccc1
Reactant: CSc1ccc(N)c([N+](=O)[O-])c1
Agent: CCCCCON=O
Product: CSc1ccc(-c2ccccc2)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-methylthio-2-nitroaniline (27.6 g), amyl nitrite (22.5 ml) and cupric chloride (4.5 g) in dry benzene (250 ml) was heated under reflux for 9 hours to give 4-methylthio-2-nitrobiphenyl (m.p. 51°-52° C.).
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[C:4]([S:7]([NH2:10])(=[O:9])=[O:8])[CH:3]=1.Cl[C:12](OC1C=CC=CC=1)=[O:13].C(N(CC)CC)C.[CH2:28]([C:30]1[S:34][C:33]([NH2:35])=[N:32][C:31]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:29]>C(#N)C>[CH2:28]([C:30]1[S:34][C:33]([NH:35][C:12]([NH:10][S:7]([C:4]2[CH:3]=[C:2]([CH3:1])[S:6][CH:5]=2)(=[O:9])=[O:8])=[O:13])=[N:32][C:31]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:29]
Reactant: Cc1cc(S(N)(=O)=O)cs1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCc1sc(N)nc1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1sc(NC(=O)NS(=O)(=O)c2csc(C)c2)nc1-c1ccccc1
Temperature: 57.5 °C
Yield: 44.7 %

Procedure:
5-Methyl-thiophene-3-sulfonic acid amide (0.0789 g, 0.445 mmol) was dissolved in 4 mL of abs. acetonitrile and treated successively with phenyl chloroformate (0.0697 g, 1.00 eq.) and triethylamine (0.154 mL, 2.5 eq.), and the mixture kept at ambient temperature for 1. h. The above prepared 5-ethyl-4-phenyl-thiazol-2-ylamine (0.0910 g, 1.00 eq.), dissolved in a tiny amount of acetonitrile, was then added, and the mixture heated to 55-60° C. over night. Cooling, pouring onto crashed ice/NH4Cl, twofold extraction with ethyl acetate, washing with brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/ethyl acetate=1/1), yielded 0.081 g of the title compound as off-white crystals.
Reaction SMILES: [CH3:1][S:2][C:3]1C=CC(C#N)=[CH:5][CH:4]=1.[CH3:11][Li].[CH2:13]1[CH2:17][O:16][CH2:15][CH2:14]1>>[CH3:11][C:15]([C:14]1[CH:13]=[CH:17][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1)=[O:16]
Reactant: CSc1ccc(C#N)cc1
Reactant: [Li]C
Reactant: C1CCOC1
Product: CSc1ccc(C(C)=O)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-(methylthio)benzonitrile (50 g, 340 mmol) in THF (2 L) at −78° C., was added methyllithium (282 ml, 1.4 M in diethyl ether, 390 mmol) over a period of ten minutes. The solution was stirred at −78° C. for one hour and then the dry ice bath was removed. After five hours, 100 ml of water followed by 200 ml of 3N HCl were added to the reaction mixture and it was stirred overnight. Concentration in vacuo gave a residue which was partitioned between ethyl acetate and water. The water layer was extracted with three portions of ethyl acetate and the combined ethyl acetate layers were dried (MgSO4). Concentration in vacuo gave 58 g of crude 4-(methylthio)acetophenone as a yellow solid: 1H NMR (CDCl3) δ 2.52 (s, 3H), 2.57 (s, 3H), 7.26 (d, J=8.7 Hz, 2H), 7.87 (d, J=8.7 Hz, 2H). The sample was used without further purification.
Reaction SMILES: [CH2:1]([CH:10]1[C:15](=O)[CH2:14][CH2:13][S:12][CH2:11]1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[CH3:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21][NH2:22].C(O)C.[ClH:27]>Cl.CCOCC>[ClH:27].[CH3:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21][N:22]1[C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:1][C:10]2[CH2:11][S:12][CH2:13][CH2:14][C:15]1=2
Reactant: CN(C)CCCN
Reactant: O=C(CC1CSCCC1=O)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CN(C)CCCn1c(-c2ccccc2)cc2c1CCSC2
Temperature: 25 °C

Procedure:
A solution of 3.0 g (0.013 mole) of 3-phenacyl-2,3,5,6-tetrahydrothiopyran-4-one, 1.33 g of 3-dimethylaminopropylamine, 20 ml. of ethanol, and one drop of concentrated hydrochloric acid is heated under reflux under nitrogen for 1.5 hours, and then cooled to ambient temperature. The reaction mixture is treated with 4 ml. of saturated ethereal hydrogen chloride and diluted to the cloud point with ether. The solid which separates is collected and recrystallized from ethanol to provide colorless crystals of 1-(3-dimethylaminopropyl)-2-phenyl-1,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrole hydrochloride, m.p. 225° to 227° C. dec.
Reaction SMILES: [NH2:1][C:2]([C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][NH:5]1)=[O:3].[CH2:10]=O.[H][H]>C(O)(=O)C.O.[Pt]=O>[CH3:10][N:5]1[CH2:6][C@H:7]([OH:9])[CH2:8][C@H:4]1[C:2]([NH2:1])=[O:3]
Reactant: C=O
Reactant: [H][H]
Reactant: NC(=O)[C@@H]1C[C@@H](O)CN1
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: O
Product: CN1C[C@H](O)C[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4R)-2-aminocarbonyl4-hydroxypyrrolidine (1.40 g) in acetic acid (12.4 ml) and water (6.8 ml), 37% aqueous formaldehyde solution (1.09 g) and platinum oxide (33 mg) were added, and the mixture was vigorously stirred at room temperature for 16 hours under an atmospheric pressure of hydrogen. The reaction mixture was filtered, followed by removal of the solvent. The residue was dissolved in isopropanol, and magnesium sulfate and potassium carbonate were added thereto. The resultant mixture was stirred at room temperature for 1 hour and filtered. After removal of the solvent, the residue was purified by silica gel column chromatography to give (2S,4R)-1-methyl-2-aminocarbonyl-4-hydroxypyrrolidine.
Reaction SMILES: [NH2:1][C:2]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:5].[BrH:18].OO>>[NH2:1][C:2]1[C:16]([CH3:17])=[CH:15][C:14]([Br:18])=[CH:13][C:3]=1[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:5]
Reactant: CCCCCCOC(=O)c1cccc(C)c1N
Reactant: Br
Agent: OO
Product: CCCCCCOC(=O)c1cc(Br)cc(C)c1N
Yield: 795.6 %

Procedure:
The above-described method (Example 1) was repeated to react hexyl 2-amino-3-methylbenzoate (2.50 g, 10 mmol) with hydrogen bromide (2.21 g, 13 1 mmol, 48% in water) and hydrogen peroxide (1.72 g, 15.0 mmol, 30% in water). Following working up similar to Example 1 and additional column chromatography, hexyl 2-amino-5-bromo-3-methylbenzoate (2.5 g, 78.8% of theory, >99 area % LC) was obtained as a brown oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[C:4]([NH:6][CH3:7])=[O:5])[CH3:2].[Cl:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>O1CCOCC1>[ClH:10].[CH2:1]([N:3]([CH2:8][CH3:9])[C:4]([N:6]([CH3:7])[CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)NC
Reactant: ClCCCN1CCOCC1
Solvent: C1COCCO1
Product: CCN(CC)C(=O)N(C)CCCN1CCOCC1
Product: Cl

Procedure:
13 g (0.1 mole) of N,N-diethyl-N'methyl urea are dissolved in 100 cc. of anhydrous dioxane. 3.9 g (0.1 mole) of NaNH2 are added thereto and the reaction mixture is heated one hour at reflux. After cooling, 16.4 g (0.1 mole) of N-(3-chloropropyl)morpholine dissolved in 50 cc. of anhydrous dioxane are added thereto dropwise and the reaction mixture is refluxed for 6 hours. After cooling, the precipitated NaCl is filtered off with suction, the filtrate is evaporated and the remaining residue is subjected to fractionated distillation.