Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2)=[O:4].C([O-])([O-])=O.[K+].[K+].Cl.[CH2:25]([NH2:27])[CH3:26]>C(#N)C>[CH2:25]([NH:27][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2)=[O:4])[CH3:26]
Reactant: CCN
Reactant: O=C(CCl)N1CCOc2cc([N+](=O)[O-])ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCNCC(=O)N1CCOc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 75.5 %

Procedure:
A solution of 2-chloro-1-(7-nitro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanone (9.9 g, 38.6 mmol) in anhydrous acetonitrile (250 mL) under positive argon pressure was treated with K2CO3 (42.7 g, 309 mmol) to give a yellow suspension. The mixture was cooled to 0° C. and treated with ethanamine hydrochloride (15.7 g, 193 mmol). The reaction was brought to room temperature and stirred for 2.5 hours. The mixture was then filtered through a pad of Celite, washed with CH2Cl2 (500 mL), and concentrated. The residue was subjected to flash chromatography on silica gel using EtOAc, followed by 2.5:97.5 (2M NH3 in MeOH):CH2Cl2 to give a yellow solid (7.73 g, 76%). 1H-NMR (DMSO-d6) δ 8.29 (d, J=9.0 Hz, 1H), 7.80 (dd, J=2.7, 9.3 Hz, 1H), 7.71 (d, J=2.7 Hz, 1H), 4.36 (t, J=4.2 Hz, 2H), 3.93 (t, J=4.8 Hz, 2H), 3.71 (s, 2H), 2.62 (q, J=7.2 Hz, 2H), 1.05 (t, J=7.2 Hz, 3H). ESI-MS (m/z, %): 266.1 (MH+, 100).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.C(=O)(OC(C)(C)C)[O:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>C1COCC1>[CH3:16][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(NCCN(C)C)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N(CCN(C)C)C(=O)OC(C)(C)C)cc1
Yield: 73.8 %

Procedure:
Methyl 4-(2-[dimethylamino]ethylamino)benzoate (1.00 g, 4.50 mmol) was dissolved in THF (30 ml). (2-Methylpropan-2-yl)oxycarbonyl tert-butyl carbonate (1.035 g, 4.72 mmol) was added and the solution was refluxed for 3 h. The solvent was then evaporated, the residue was dissolved in DCM, washed with sat. aq. ammonium chloride solution, dried over sodium sulphate, filtered and evaporated to give methyl 4-[2-dimethylaminoethyl-[tert-butoxycarbonyl]amino]benzoate (1.07 g, 74%) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]=[C:10]([C:16]([O:18]CC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=[C:4]([CH3:21])[N:3]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([CH3:21])[CH:5]=[C:6]2[C:7]=1[NH:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]2=[O:18]
Reactant: CCOC(=O)C(=CNc1ccc(C)nc1Cl)C(=O)OCC
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2c(Cl)nc(C)cc2c1=O
Temperature: 25 °C

Procedure:
A mixture of diethyl 2-(((2-chloro-6-methyl-3-pyridinyl)amino)methylene)malonate (Preparation 42, 0.59 g) is added to diphenyl ether (15 mL) and the mixture is degassed by alternately bubbling in nitrogen then subjecting to high vacuum. The mixture is heated rapidly to reflux and after 30 minutes cooled to room temperature. Diphenyl ether is distilled away under high vacuum and the residue taken up in CH2Cl2 (40 mL). The solid is collected by filtration and washed with CH2Cl2 with a second crop obtained by reducing the solvent volume of CH2Cl2 filtrate and collecting more solid. The title compound is obtained as a pale green powder, 0.24 g (47%). Physical characteristics: MS (ESI+) m/z 267 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:28][CH:27]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C3CCCCO3)[CH:14]=2)(=[O:10])=[O:9])=[C:4]([O:40][C:41]([F:44])([F:43])[F:42])[CH:3]=1.Cl>C(O)C.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]3[CH2:36][CH2:37][CH2:38][CH2:39]3)=[CH:28][CH:27]=2)(=[O:9])=[O:10])=[C:4]([O:40][C:41]([F:42])([F:44])[F:43])[CH:3]=1
Reactant: O=S(=O)(c1ccc(Br)cc1OC(F)(F)F)N(Cc1cccc(OC2CCCCO2)c1)c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(c1ccc(Br)cc1OC(F)(F)F)N(Cc1cccc(O)c1)c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 32.5 %

Procedure:
To a solution of 4-bromo-N-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-N-[3-(tetrahydro-pyran-2-yloxy)-benzyl]-2-trifluoromethoxy-benzenesulfonamide (0.106 g, 0.15 mmol) in 4 mL ethanol was added 0.8 mL of 1.2N HCl. The reaction mixture was stirred at room temperature for 6 days and was diluted with 10 mL saturated aqueous sodium bicarbonate. The aqueous solution was washed with methylene chloride (2×10 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by preparative TLC (1.0 mm silica gel layer, eluting with 10% methanol/ethyl acetate) to afford 0.030 g (29%) of 4-bromo-N-(3-hydroxy-benzyl)-N-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-2-trifluoromethoxy-benzenesulfonamide. MS 617.3 (M+1)+
Reaction SMILES: [O:1]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][C:14]=1[O:21][CH3:22])[C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[K].[C:24]([C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37](=[O:38])[CH2:36][S:35][C:34]2=[S:39])=[CH:29][CH:28]=1)([OH:26])=[O:25]>C(O)C.N1CCCCC1>[C:24]([C:27]1[CH:28]=[CH:29][C:30]([N:33]2[C:37](=[O:38])[C:36](=[CH:19][C:16]3[CH:17]=[CH:18][C:13]([O:1][C@@H:2]4[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]4[OH:4])=[C:14]([O:21][CH3:22])[CH:15]=3)[S:35][C:34]2=[S:39])=[CH:31][CH:32]=1)([OH:26])=[O:25]
Reactant: COc1cc(C=O)ccc1O[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=C(O)c1ccc(N2C(=O)CSC2=S)cc1
Agent: [K]
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(C=C2SC(=S)N(c3ccc(C(=O)O)cc3)C2=O)ccc1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 24.3 %

Procedure:
To a stirred suspension of 4-formyl-2-=methoxyphenyl β-D-galactopyranoside (1c)(0.47 g, 1.5 mmol) in absolute ethanol (25 ml) containing piperidine (1 drop), was added the potassium salt of 3-(4-carboxyphenyl)-2-thioxothiazolidin-4-one (0.44 g, 1.5 mmol) and the suspension was heated under gentle reflux for 2 h. A yellow solid separated which was filtered hot and washed with small portions of boiling methanol and ethyl acetate followed by ether to give the product (0.2 g, 22%) as the potassium salt, m.p. decomp.>230° C.
Reaction SMILES: O[C:2]1([C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>>[C:2]1([C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1
Reactant: OC1(c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: Fc1ccc(-c2nc(C3=CCCCC3)[nH]c2-c2ccncc2)cc1

Procedure:
The product of Example 7, 2-((1-hydroxy)cyclohexyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole (50 mg 0.15 mmol) is dissolved in toulene (100 ml) and refluxed with pTsOH (100 mg) for 15 min. The reaction mixture is poured on saturated NaHCO3 and extracted 3× with ethyl acetate. The combined organic phases are dried over Na2SO4, evaporated to dryness and chromatographed (SiO2 acetone/hexane 4/6) to render the title compound as white crystals (38 mg 81%),
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(CN2CCN(c3ccncc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 3 h
Yield: 52.9 %

Procedure:
To a solution of the product of step (a) (849 mg) in methanol (15 ml) was added 2N sodium hydroxide (6.8 ml) and the resulting mixture was stirred for 3 hours. The mixture was evaporated to dryness. The resulting gum was dissolved in water (7 ml) and acidified with acetic acid. The mixture was filtered to give 4-(4-(4-pyridyl)piperazin-1-ylmethyl)benzoic acid (429 mg);
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.[Cl-]>N1C=CC=CC=1.C(Cl)Cl>[S:34]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])([C:31]1[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=1)(=[O:36])=[O:35]
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCCCCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 94.7 %

Procedure:
In a mixed solvent of 15 ml pyridine and 120 ml methylene chloride was dissolved methyl 22-hydroxydocosanoate (1.70 g, 4.59 mmoles) . P-toluenesulfonyl chloride (1.75 g, 9.18 mmoles) was gradually added to the obtained solution under ice-cooled condition, over a period of 1 hour, and the mixture was stirred for 14 hours in a refrigerator. Then, ptoluenesulfonyl chloride (1.75 g, 9.18 mmoles) was added to the reaction mixture, and reaction was effected for 24 hours. After the completion of reaction, the reaction mixture was treated in the same manner as in Reference Example 1, to give methyl 22-tosyloxydocosanoate (2.28 g, 75%) having the following properties.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH2:13]1[O:23][C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14]1>CCOCC.C1COCC1>[CH2:14]1[O:15][C:16]2([CH2:21][CH2:20][C:19]([OH:22])([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[CH2:18][CH2:17]2)[O:23][CH2:13]1
Reactant: Brc1cccnc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1(c2cccnc2)CCC2(CC1)OCCO2
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
To a solution of n-BuLi (2.5 M in hexanes, 88.4 mL, 221.0 mmol) in Et2O (250 mL) at −78° C. was added a chilled solution (−78° C.) of 3-bromopyridine (35 g, 221.0 mmol) in Et2O (125 mL) via cannula. After being stirred for 10 min, a solution of 1,4-cyclohexanedione monoethylene ketal (34.5 g, 221.0 mmol) in THF (125 mL) was added via cannula The reaction mixture was stirred for 1 h at −78° C., then slowly warmed to −20° C. over 1 h. The reaction was quenched by pouring into saturated aqueous NH4Cl, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (100 mL×3) and the combined organic layers were washed with brine (200 mL), dried with MgSO4 and concentrated in vacuo. The crude product was triturated with Et2O to afford 4-hydroxy-4-(3-pyridyl)cyclohexanone ethylene ketal as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4](Cl)[C:3]=1[Cl:11].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCOCC1>[CH2:12]([NH:19][C:4]1[C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=[C:2]([Cl:1])[C:3]=1[Cl:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Reactant: NCc1ccccc1
Solvent: C1COCCO1
Product: Clc1nc(Cl)c(Cl)c(NCc2ccccc2)c1Cl
Temperature: 25 °C
Yield: 129.2 %

Procedure:
Pentachloropyridine (80 g, 320 mmol) is treated with benzyl amine (104 mL, 96 mmol), dissolved in dioxane (1 L) and refluxed for 16 hours. The reaction mixture is cooled to ambient temperature and the precipitated white solid is removed by filtration. The filtrate is concentrated to a brown residue and triturated with 4% ethyl acetate in hexane (3×250 mL) to give 4-benzylamino-2,3,5,6-tetrachloropyridine as an off-white solid (40 g, 124 mmol). This material is dissolved in chloroform (400 mL), cooled in an ice bath and treated with trifluoroacetic acid (500 mL) and 30% hydrogen peroxide (100 mL). The reaction mixture is warmed to room temperature overnight and treated with additional trifluoroacetic acid (500 mL) and 30% hydrogen peroxide (100 mL). After stirring 24 hours the reaction is treated with water (1 L). The lower organic layer is separated and the aqueous layer is extracted with chloroform. The combined organic layers are concentrated to a solid residue and redissolved in ethyl acetate/hexane (30 mL). The suspended orange solid is removed and the filtrate is loaded on a silica flash column. The column is eluted with hexane and the title compound is collected as a white solid (15.6 g, 60 mmol). EI MS m/z 260, 262, 264 [M+].
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:18]=[N:19][C:20]([O:23]C)=[CH:21][CH:22]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1>C(O)C.Cl>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:22]=[CH:21][C:20](=[O:23])[NH:19][CH:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Agent: Cl
Solvent: CCO
Product: O=c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)c[nH]1

Procedure:
3-Cyclobutyl-7-{[6-(methyloxy)-3-pyridinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine (E213a) (69 mg, 0.21 mmol) was dissolved in a solution of ethanol saturated with hydrogen chloride (5 ml). The reaction mixture was stirred at reflux for 18 hours, cooled and concentrated in vacuo. Purification of the resulting residue by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (1:9:90) afforded the title compound (E213). MS (ES+) m/e 311 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9](I)=[CH:10]3)[C:6]=2[CH:16]=1.[CH3:17][C:18]1[C:19]([Sn](CCCC)(CCCC)CCCC)=[N:20][CH:21]=[CH:22][CH:23]=1>CN(C=O)C.[Cu](I)I>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:19]4[C:18]([CH3:17])=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:10]3)[C:6]=2[CH:16]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccc1C
Reactant: Brc1ccc2c(c1)-c1nc(I)cn1CCO2
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: Cc1cccnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Temperature: 100 °C
Yield: 74 %

Procedure:
A mixture of 9-bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (200 mg, 0.512 mmol), 3-methyl-2-tributylstannanylpyridine (235 mg, 0.614 mmol), Pd2(PPh3)2Cl2 (36 mg, 0.051 mmol) and copper iodide (29 mg, 0.153 mmol) in DMF (4 mL) was purged with nitrogen and then heated at 100° C. for 1 h using microwave irradiation. The reaction mixture was diluted with MeOH (30 mL) and then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient 0-5% MeOH in EtOAc) affording the title compound as a white solid (135 mg, 74%). LCMS: RT 3.22 min [M+H]+ 355.9/357.9
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[CH2:17]([NH:24][C:25]([C:27]1[S:31][C:30]([NH2:32])=[N:29][C:28]=1[CH3:33])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([NH:24][C:25]([C:27]1[S:31][C:30]([NH:32][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([N:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]3=[O:1])=[CH:16][CH:15]=2)=[N:29][C:28]=1[CH3:33])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(O)c1ccc(-n2ccccc2=O)cc1
Product: Cc1nc(NC(=O)c2ccc(-n3ccccc3=O)cc2)sc1C(=O)NCc1ccccc1
Yield: 58 %

Procedure:
Following the procedure as described in Example 11, making variations only as required to use 4-(2-oxopyridin-1-yl)-benzoic acid in place of 5-phenylpentanoic acid to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 58% yield; 1H NMR (CDCl3, 300 MHz) δ 12.96 (s, 1H), 8.63 (t, J=5.9 Hz, 1H), 8.18 (d, J=8.6 Hz, 2H), 7.66 (dd, J=1.7, 6.9 Hz, 1H), 7.57 (d, J=8.6 Hz, 2H), 7.50 (ddd, J=2.0, 6.8, 9.0 Hz, 1H), 7.35-7.20 (m, 5H), 6.48 (d, J=9.0 Hz, 1H), 6.32 (dt, J=1.1, 6.8 Hz, 1H), 4.38 (d, J=5.9 Hz, 2H), 2.52 (s, 3H); MS (ES+) m/z 445.4 (M+1).
Reaction SMILES: C([O:8][C:9]1[C:10]([C:40]([O:42]C(C)(C)C)=[O:41])=[N:11][C:12]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][N:30]=4)=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[N:13][C:14]=1[CH3:15])C1C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH2:38]([O:37][C:35]([C:32]1[CH:33]=[CH:34][C:29]([C:26]2[CH:25]=[CH:24][C:23]([N:20]3[CH2:21][CH2:22][CH:17]([CH2:16][C:12]4[N:11]=[C:10]([C:40]([OH:42])=[O:41])[C:9]([OH:8])=[C:14]([CH3:15])[N:13]=4)[CH2:18][CH2:19]3)=[CH:28][CH:27]=2)=[N:30][CH:31]=1)=[O:36])[CH3:39]
Reactant: CCOC(=O)c1ccc(-c2ccc(N3CCC(Cc4nc(C)c(OCc5ccccc5)c(C(=O)OC(C)(C)C)n4)CC3)cc2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(-c2ccc(N3CCC(Cc4nc(C)c(O)c(C(=O)O)n4)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
tert-Butyl 5-(benzyloxy)-2-[(1-{4-[5-(ethoxycarbonyl)pyridin-2-yl]phenyl}piperidin-4-yl)methyl]-6-methylpyrimidine-4-carboxylate (0.25 g, 0.40 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (10 mL) was added, followed by stirring at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added, followed by extraction with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to afford 2-[(1-{4-[5-(ethoxycarbonyl)pyridin-2-yl]phenyl}piperidin-4-yl)methyl]-5-hydroxy-6-methylpyrimidine-4-carboxylic acid.
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH:13]([NH:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH3:14])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[O-:23][C:24]#[N:25].[K+].Cl>O>[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:25][C:24](=[O:23])[N:15]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:13]=2[CH3:14])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ccc(C(=O)C(C)NC2CCCCC2)cc1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCCCc1ccc(-c2[nH]c(=O)n(C3CCCCC3)c2C)cc1

Procedure:
4'-n-Butyl-2-cyclohexylaminopropiophenone hydrochloride (1768 mg, 5.5 mmol) was suspended in water (30 ml), and potassium cyanate (914 mg, 11.3 mmol) in water (10 ml) was added thereto. The aqueous mixture was heated under reflux for one hour under nitrogen atomosphere, added with conc. hydrochloride (2 ml), and heated under reflux an additional one hour. The reaction mixture was extracted with dichloromethane, and the extract was washed with 10% hydrochloride, and dried over anhydrous magnesium sulfate. Evaporation of the solvent under vacuum and recrystalization from ethyl acetate gave the title compound. Yield: 155 mg (9%), m.p. 236° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[OH-].[K+:34]>C(O)(C)C.O>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([O-:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[K+:34]
Reactant: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c([O-])c(=O)n2C)o1
Temperature: 27.5 °C
Reaction time: 17 h
Yield: 88.4 %

Procedure:
Raltegravir (50 gm) was suspended in isopropyl alcohol (500 ml) and then added a solution of potassium hydroxide (8 gm) in water (10 ml) at 25 to 30° C. The reaction mass was stirred for 17 hours at 25 to 30° C. and filtered. The solid obtained was dried under vacuum at 60° C. for 9 hours to obtain 48 gm of raltegravir potassium crystalline form H1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([N:15]=[C:16]=[S:17])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH3:18]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]([NH2:18])=[S:17])=[CH:7][CH:8]=1
Reactant: N
Reactant: COc1ccc(-c2ccccc2N=C=S)cc1
Solvent: CCO
Product: COc1ccc(-c2ccccc2NC(N)=S)cc1

Procedure:
Reaction of 4'-methoxy-2-biphenylylisothiocyanate (12.7 g) in ethanol (30 ml) with 28% aqueous ammonia (20 ml) at 0° C. for 2 hours gave N-(4'-methoxy-2-biphenylyl)thiourea (m.p. 158°-159° C.).
Reaction SMILES: O(Cl)[Cl:2].[P+5].[CH:5]1([C:10]2[NH:15][C:14](=O)[CH:13]=[C:12]([CH2:17][CH3:18])[N:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1>[OH-].[Na+]>[Cl:2][C:14]1[CH:13]=[C:12]([CH2:17][CH3:18])[N:11]=[C:10]([CH:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)[N:15]=1
Reactant: CCc1cc(=O)[nH]c(C2CCCC2)n1
Reactant: ClOCl
Agent: [Na+]
Agent: [OH-]
Agent: [P+5]
Product: CCc1cc(Cl)nc(C2CCCC2)n1
Temperature: 100 °C
Yield: 24.6 %

Procedure:
Phosphorus(V) oxychloride (150 g, 99.0 mmol) was slowly added to 2-cyclopentyl-6-ethylpyrimidin-4(3H)-one (18.9 g, 98.3 mmol) at 0° C. Then, the reaction mixture was warmed to 100° C. for 3 h. After this time, the mixture was cooled, diluted with sodium hydroxide, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/dichloromethane) to afford the title compound (5.1 g, 57%) as yellow oil. MW=210.70. 1H NMR (CDCl3, 300 MHz) δ 7.01 (s, 1H), 3.36-3.20 (m, 1H), 2.74 (q, J=7.5 Hz, 2H), 2.14-1.99 (m, 2H), 1.98-1.76 (m, 4H), 1.75-1.63 (m, 2H), 1.29 (t, J=7.5 Hz, 3H); APCI MS m/z 211 [M+H]+.
Reaction SMILES: C(N1CCC2C=CC(S([Cl:18])(=O)=O)=CC=2CC1)(=O)C.C(N1CCC2C=CC(SC)=CC=2CC1)(=O)C.C([N:38]1[CH2:44][CH2:43][C:42]2[CH:45]=[CH:46][C:47]([S:49]([CH3:51])=[O:50])=[CH:48][C:41]=2[CH2:40][CH2:39]1)(=O)C.Cl>>[ClH:18].[CH3:51][S:49]([C:47]1[CH:46]=[CH:45][C:42]2[CH2:43][CH2:44][NH:38][CH2:39][CH2:40][C:41]=2[CH:48]=1)=[O:50]
Reactant: CC(=O)N1CCc2ccc(S(C)=O)cc2CC1
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2CC1
Agent: CSc1ccc2c(c1)CCN(C(C)=O)CC2
Agent: Cl
Product: CS(=O)c1ccc2c(c1)CCNCC2

Procedure:
Following the procedure of Examples 4 and 5, 3-acetyl-7-chlorosulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine is converted to 3-acetyl-7-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine and then to 3-acetyl-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine which is hydrolyzed with dilute hydrochloric acid to give 7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.