Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][C:17]=1[C:25](=[O:36])[NH:26][C:27]1[CH:28]=[C:29]2[CH:35]=[CH:34][NH:33][C:30]2=[N:31][CH:32]=1>C(Cl)Cl>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:14][C:11]2[CH:12]=[N:13][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)=[O:21])=[CH:18][C:17]=1[C:25]([NH:26][C:27]1[CH:28]=[C:29]2[CH:35]=[CH:34][NH:33][C:30]2=[N:31][CH:32]=1)=[O:36]
Reactant: Nc1ccc(Oc2ccccc2)nc1
Reactant: O=C(Cl)c1ccc(Cl)c(C(=O)Nc2cnc3[nH]ccc3c2)c1
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccccc2)nc1)c1ccc(Cl)c(C(=O)Nc2cnc3[nH]ccc3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
6-Phenoxy-pyridin-3-ylamine (0.078 g, 0.42 mmol) was added to a solution of 4-chloro-3-(1H-pyrrolo[2,3-b]pyridin-5-ylcarbamoyl)-benzoyl chloride in DCM (5 ml) and the reaction stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the crude product triturated with acetonitrile:water (1:1, 10 ml). The solid was filtered to afford 4-Chloro-N1-(6-phenoxy-pyridin-3-yl)-N3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-isophthalamide as the hydrochloride salt, 0.086 g, (37% yield) over two steps.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([OH:22])=[CH:16][C:15]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:31])=O)=[CH:25][C:24]=1[O:32][CH3:33])[CH:8]1[CH2:34][C:35]3[C:40]([CH:7]21)=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[NH:3])[NH2:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:68]([NH2:72])[CH:69]([CH3:71])[CH3:70]>CN(C=O)C>[CH2:68]([NH:72][C:29]([C:26]1[CH:27]=[CH:28][C:23]([C:15]2[CH:16]=[C:17]([OH:22])[C:18]([O:20][CH3:21])=[CH:19][C:14]=2[CH:9]2[CH:8]3[CH2:34][C:35]4[C:40]([CH:7]3[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([C:1](=[NH:3])[NH2:2])[CH:5]=3)[NH:10]2)=[CH:39][CH:38]=[CH:37][CH:36]=4)=[C:24]([O:32][CH3:33])[CH:25]=1)=[O:31])[CH:69]([CH3:71])[CH3:70]
Reactant: CC(C)CN
Reactant: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)O)cc2OC)cc1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)NCC(C)C)cc2OC)cc1O

Procedure:
A mixture of 2′-(2-Carbamimidoyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-5′-hydroxy-2,4′-dimethoxy-biphenyl-4-carboxylic acid (10.7 mg, 0.02 mmol), BOP, (0.04 mmol), diidopropylethylamine (10.3 mg, 0.08 mmol) and isobutylamine (4.4 mg, 0.06 mmol) in DMF was allowed to react at room temperature. Example 235 was purified by HPLC. Mass Spectrum: 591 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:5]2[C:16](=[O:30])[CH:17]([NH:18][C:19](=[O:29])[C:20](=[N:27][OH:28])[C:21]3[N:22]=[C:23]([NH2:26])[S:24][CH:25]=3)[C@H:4]2[S:3]1.[N+](=[CH2:33])=[N-]>O1CCOCC1.C(OCC)C>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][C:12]([Cl:13])([Cl:15])[Cl:14])=[O:9])[N:5]2[C:16](=[O:30])[CH:17]([NH:18][C:19](=[O:29])[C:20](=[N:27][O:28][CH3:33])[C:21]3[N:22]=[C:23]([NH2:26])[S:24][CH:25]=3)[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2S1
Reactant: C=[N+]=[N-]
Agent: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(=NO)c3csc(=N)[nH]3)[C@H]2S1
Solvent: C1COCCO1
Solvent: CCOCC
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CC(C)S[C@H]12)c1csc(N)n1

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-7-[2-hydroxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), which can be represented as 2,2,2-trichloroethyl 2-methyl-7-[2-hydroxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), (125 mg.) in dioxane (5 ml.) was added dropwise 0.1 M solution of diazomethane in diethyl ether till the starting compound disappeared. After the reaction mixture was concentrated, the residue was pulverized in diethyl ether, collected by filtration and then dried to give brown powder of 2,2,2-trichloroethyl 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), which can be represented as 2,2,2-trichloroethyl 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), (110 mg.), mp 128° to 149° C. (dec.).
Reaction SMILES: [CH2:1]([C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C:21]3[CH:22]=[C:23]([C:31](OC)=[O:32])[C:24](=[CH:29][CH:30]=3)[C:25](OC)=[O:26])[CH:14]=2)=[C:9]([CH3:35])[CH:8]=1)([OH:6])[CH2:4][CH3:5])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C:21]3[CH:30]=[CH:29][C:24]([CH2:25][OH:26])=[C:23]([CH2:31][OH:32])[CH:22]=3)[CH:14]=2)=[C:9]([CH3:35])[CH:8]=1)([OH:6])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(O)(CC)c1ccc(-c2cccc(COc3ccc(C(=O)OC)c(C(=O)OC)c3)c2)c(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCC(O)(CC)c1ccc(-c2cccc(COc3ccc(CO)c(CO)c3)c2)c(C)c1

Procedure:
In a manner similar to that of Example 20(e), by reaction of 1.5 g (3.15 mmol) of dimethyl 4-[4′(1-ethyl-1-hydroxypropyl)-2′-methylbiphenyl-3-ylmethoxy)-phthalate with 480 mg (12.6 mmol) of lithium aluminium hydride, the desired product is obtained in the form of a white solid (m.p.=87° C.; m=1.03 g; Y=78%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[C:17]([OH:19])=[O:18])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.O1CCCC1>[OH-].[OH-].[Pd+2].C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[C:17]([OH:19])=[O:18])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)[C@H]1CCCC[C@H]1C(=O)c1cc(F)cc(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CCCC[C@@H]1Cc1cc(F)cc(F)c1
Reaction time: 96 h

Procedure:
A mixture of (1S, 2R)-2-(3,5-difluorophenylcarbonyl)cyclohexanecarboxylic acid (1 g, 3.7 mmol), 10% Pd(OH)2 on carbon (1 g), tetrahydrofuran (10 mL) and acetic acid (0.5 mL) was shaken under hydrogen atmosphere at 50 psi for 96 h. The reaction mixture was filtered through CeliteR, and filtrate and evaporated to give (1S, 2R)-2-(3,5-difluorophenylmethyl)cyclohexanecarboxylic acid, as a white solid (0.9 g, 95%).
Reaction SMILES: [CH2:1]([C:17]1([CH3:75])[CH2:26][CH2:25][C:24]2[C:19](=[C:20]([CH3:74])[C:21]([CH3:73])=[C:22]([O:28][CH2:29][CH2:30][O:31][C:32](=[O:72])[NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([N:41]3[CH2:45][CH:44]([OH:46])[CH2:43][CH:42]3[CH:47]([C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[O:48][CH:49]([C:58]3[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=3)[C:50]3[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=3)=[O:40])[C:23]=2[CH3:27])[O:18]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][CH3:16].[C:76]1(=[O:82])[O:81][C:79](=[O:80])[CH2:78][CH2:77]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:57][O:56][C:53]1[CH:54]=[CH:55][C:50]([CH:49]([C:58]2[CH:59]=[CH:60][C:61]([O:64][CH3:65])=[CH:62][CH:63]=2)[O:48][CH:47]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[CH:42]2[N:41]([C:39](=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][NH:33][C:32]([O:31][CH2:30][CH2:29][O:28][C:22]3[C:23]([CH3:27])=[C:24]4[C:19](=[C:20]([CH3:74])[C:21]=3[CH3:73])[O:18][C:17]([CH2:1][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][CH3:16])([CH3:75])[CH2:26][CH2:25]4)=[O:72])[CH2:45][CH:44]([O:46][C:76](=[O:82])[CH2:77][CH2:78][C:79]([OH:81])=[O:80])[CH2:43]2)=[CH:51][CH:52]=1
Reactant: CCCCCCCCCCCCCCCCC1(C)CCc2c(C)c(OCCOC(=O)NCCCCCC(=O)N3CC(O)CC3C(OC(c3ccc(OC)cc3)c3ccc(OC)cc3)c3ccccc3)c(C)c(C)c2O1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCC1(C)CCc2c(C)c(OCCOC(=O)NCCCCCC(=O)N3CC(OC(=O)CCC(=O)O)CC3C(OC(c3ccc(OC)cc3)c3ccc(OC)cc3)c3ccccc3)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
Referring to scheme 7, Compound 19 (5.1 g, 5 mmol) was mixed with succinic anhydride (0.75 g, 7.5 mmol) and DMAP (0.062 g, 0.5 mmol) and dried in a vacuum at 40° C. overnight. The mixture was dissolved in anhydrous dichloromethane (25 mL), triethylamine (1.52 g, 2 mL, 15 mmol) was added and the solution was stirred at room temperature under argon atmosphere for 16 h. It was then diluted with dichloromethane (50 mL) and washed with ice cold aqueous citric acid (5% wt., 50 mL) and water (2×50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The crude product was purified by column chromatography to afford compound 21 as white foamy solid (2.85 g, 51% yield; Rf=0.65 in 10% MeOH/CHCl3).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][C:8]1[CH:12]=[C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH3:18])[O:10][N:9]=1>C(OCC)C>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][C:8]1[CH:12]=[C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH3:18])[O:10][N:9]=1
Reactant: Cc1cc(C2CCCN2C)on1
Agent: O=C(O)C(=O)O
Solvent: CCOCC
Product: Cc1cc([C@@H]2CCCN2C)on1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of oxalic acid (51 mg, 0.57 mmol) in diethyl ether was added dropwise to a stirring solution of 3-methyl-5-(1-methyl-2-pyrrolidinyl)-isoxazole (62.8 mg, 0.38 mmol), from Example 2a, in diethyl ether. After 0.5 hour of stirring at ambient temperature, the reaction flask became coated with a glass-like clear colorless solid. The diethyl ether was evaporated and the solid was triturated several times with diethyl ether to give, after evaporation of the solvent in vacuo, 102 mg of the title compound (2b). MS (DCl/NH3) m/e 167 (M+H)+, 184 (M+NH4)+. 1H NMR (D2O) δ: 2.11-2.33 (m, 3H), 2.31 (s, 3H), 2.49-2.60 (m, 1H), 2.48 (dd, 2H), 4.92 (t, 1H), 6.52 (s, 1H). Anal. calcd. for C10H13NO5.0.2H2O.0.2C2H2O 2 : C, 48.65; H, 6.16; N, 9.95. Found: C, 48.80; H, 5.90; N, 9.77.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[CH:8]=2)=[CH:5][N:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=[CH:22][C:15]=23)[N:3]=1.CO.[BH4-].[Na+]>[Pd]>[CH3:1][C:2]1[C:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH:9]([OH:13])[CH2:8]2)=[CH:5][N:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[CH:21]=[CH:22][C:15]=23)[N:3]=1
Reactant: Cc1nn(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cc1C1=CC(=O)CCC1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nn(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cc1C1CCCC(O)C1
Reaction time: 8 h
Yield: 26 %

Procedure:
A mixture of 3-[3-methyl-1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]cyclohex-2-en-1-one (0.019 g, 0.000045 mol) and palladium on carbon (Pd/C) (0.018 g, 0.000017 mol) in methanol (2 mL, 0.05 mol) was degassed and was stirred under a hydrogen atmosphere overnight. An additional 48 mg of 10% Pd/C was added and stirred under a hydrogen atmosphere for 8 h. The palladium was filtered and the filtrate was stirred with sodium tetrahydroborate (0.032 g, 0.00084 mol) for 5 h. The reaction was purified by prep-HPLC to give 5 mg of the desired product. MS (M+H)+: 426.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:24]2[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=2)=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=2)[C:10]2[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:34][CH2:35][C:36]#[N:37]>C1COCC1>[C:36]([CH2:35][CH2:34][S:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:24]2[CH:25]=[CH:26][C:27]([S:30][CH2:34][CH2:35][C:36]#[N:37])=[CH:28][CH:29]=2)=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH2:34][CH2:35][C:36]#[N:37])=[CH:19][CH:18]=2)[C:10]2[CH:11]=[CH:12][C:13]([S:16][CH2:34][CH2:35][C:36]#[N:37])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1)#[N:37]
Reactant: N#CCCBr
Reactant: Sc1ccc(C(=C(c2ccc(S)cc2)c2ccc(S)cc2)c2ccc(S)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCCSc1ccc(C(=C(c2ccc(SCCC#N)cc2)c2ccc(SCCC#N)cc2)c2ccc(SCCC#N)cc2)cc1
Temperature: 85 °C

Procedure:
1,1,2,2-tetrakis(4-mercaptophenyl) ethylene (0.5 mmol) made in Example 2 was added to 30 ml of THF, and 160 mg (4.0 mmol) of sodium hydride and 0.35 mL (4.0 mmol) of 3-bromopropionitrile were added with stirring in an ice-cooled bath followed by being refluxed at 85° C. for 24 hours. After solvent was evaporated, ice-cooled water was added to the residue, the mixture was acidified with hydrochloric acid, and then was extracted with dichloromethane. The extract was dehydrated with anhydrous magnesium sulfate. Subsequently, it was subjected to a silica gel column chromatography (φ40 mm, height=50 mm, developing solvent: ethyl acetate: chloroform=1:15), and was recrystallized from chloroform and carbon tetrachloride to afford the target compound.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[CH2:5]([OH:16])[C@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14]O)[OH:13])[OH:11])[OH:9])[OH:7].[CH2:17](O)[C@H:18]([C@H:20]([C@@H]([C@@H](CO)O)O)O)O>[Cl-].[Zn+2].[Cl-].CC(C)=O>[CH3:1][C:2]1([CH3:4])[O:13][C@@H:12]([C@@H:10]([OH:11])[C@H:8]([OH:9])[C@@H:6]2[O:7][C:18]([CH3:20])([CH3:17])[O:16][CH2:5]2)[CH2:14][O:3]1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: CC1(C)OC[C@H]([C@@H](O)[C@H](O)[C@H]2COC(C)(C)O2)O1

Procedure:
In the preparation of the diketonide deriving from D-mannitol acetone is the ketone which is preferentially used. Then, the 1,2,5,6-diacetone D-mannitol is prepared by reacting acetone, to which solid zinc chloride has been added, with D-mannitol with stirring within a temperature range of from 0° C. to +50° 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.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: O
Solvent: CCO
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: 16 h
Yield: 95.8 %

Procedure:
Raltegravir (50 gm) was suspended in ethanol (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 16 hours at 25 to 30° C. and filtered. The solid obtained was dried under vacuum at 60° C. for 9 hours to obtain 52 gm of raltegravir potassium crystalline form H1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:28])=O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]([Cl:28])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Cl)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
3,4-dibenzyloxybenzoic acid (3.1 g. 9.3 mmol) was combined with pyridine (5 drops, catalytic) and thionyl chloride (15 ml, 205 mmol). The solution was heated at reflux for 4 h, cooled, and excess thionyl chloride removed under reduced pressure. The crude product was dissolved in benzene (50 ml), and stripped of solvent under vacuum. The benzoyl chloride (theoretical yield 3.4 g) was then dissolved in dichloromethane and used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH:44]1[CH:48]=[C:47]([C:49]2[CH:50]=[C:51]3[C:56](=[CH:57][CH:58]=2)[CH:55]=[N:54][C:53]([NH2:59])=[CH:52]3)[CH:46]=[N:45]1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:59][C:53]2[N:54]=[CH:55][C:56]3[C:51]([CH:52]=2)=[CH:50][C:49]([C:47]2[CH:46]=[N:45][NH:44][CH:48]=2)=[CH:58][CH:57]=3)=[O:12])=[CH:7][CH:8]=1
Reactant: Nc1cc2cc(-c3cn[nH]c3)ccc2cn1
Reactant: COc1ccc(CC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COc1ccc(CC(=O)Nc2cc3cc(-c4cn[nH]c4)ccc3cn2)cc1
Temperature: 75 °C
Reaction time: 24 h

Procedure:
Activation of (4-Methoxy-phenyl)-acetic acid (315.6 mg, 1.9 mmol) is accomplished by treatment of the carboxylic acid in DMA (5 mL) with HATU (802.6 mg, 2.1 mmol) and triethylamine (388.2 mg, 3.8 mmol) at room temperature for 1 hour. The 6-(1H-Pyrazol-4-yl)-isoquinolin-3-ylamine (200.0 mg, 0.9 mmol) was added and the mixture was stirred at 75° C. for 24 hours. The reaction was monitored by LC/MS. Evaporation of DMA gave a residue that was washed with NaHCO3 to remove the by-products from HATU. The crude residue then was dissolved in MeOH (10 mL) and was treated with K2CO3 (26.0 mg, 0.5 mmol) at 75° C. for 18 hrs. The solvent was evaporated and the product extracted with CH2Cl2 (20 mL). The extracts were washed with water (3×10 mL) and evaporated. The crude product was purified by ISCO (with petroleum ether:ethyl acetate 50:50) to give the title compound as a light yellow crystalline solid product (143.3 mg, 41.4%). 1H NMR (DMSO-d6, 400 MHz): δ 3.68 (2H, s), 3.73 (3H, s), 6.79-6.98 (2H, m), 7.31 (2H, d, J=8.8 Hz,), 7.81 (1H, dd, J=8.6, 1.5 Hz,), 8.00 (1H, d, J=8.6 Hz), 8.08 (1H, s), 8.14 (1H, s), 8.41 (2H, d, J=8.3 Hz), 9.03 (1H, s), 10.69 (1H, s), 13.09 (1H, s). 13CNMR (DMSO-d6, 100 MHz): δ 42.18, 55.01, 106.30, 113.76, 120.44, 120.56, 124.11, 124.39, 126.71, 127.87, 128.06, 130.13, 135.26, 136.96, 137.87, 147.51, 150.75, 158.14, 170.14. HRMS: m/z 359.1489, calc. 359.1503. MS m/z, (APCI); 359.2 [(M+1)+100].
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15][CH2:16][CH2:17]Cl)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15][CH:16]=[CH2:17])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CSCCCl)cc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: C=CSCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
A mixture of 4-chloro-4'-(2-chloroethylmercaptomethyl)benzophenone (4.9 g) and 1,8-diaza-bicyclo[5.4.0]undec-7-ene (4.3 g) in 100 ml of toluene was stirred for 3 hours at 80° C. After that, the mixture was washed with aqueous 2N hydrochloric acid solution and water, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4-chloro-4'-vinylmercaptomethylbenzophenone (4.3 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9](O)(=[O:14])[CH2:10][CH2:11][C:12]#[CH:13].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:9](=[O:14])[CH2:10][CH2:11][C:12]#[CH:13]
Reactant: CNc1ccccc1
Reactant: C#CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: C#CCCC(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of N-methylbenzenamine (110 mg, 1.02 mmol) in DCM (3 mL) was successively added at R.T. 4-pentynoic acid (100 mg, 1.02 mmol), HOBT (171 mg, 1.12 mmol) and EDCI.HCl (293 mg, 1.53 mmol). The reaction was stirred at R.T. overnight. The reaction was quenched with water. The organic layer was separated and washed with 1M NaHCO3 and water. The solvent was removed under reduced pressure to afford 150 mg N-methyl-N-phenylpent-4-ynamide (Yield: 78%) as an orange oil which can be used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[C:14](=[O:15])[CH:13]=[CH:12]O[CH:10]=2)=[CH:5][CH:4]=1.[NH3:18].O>>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[C:14](=[O:15])[CH:13]=[CH:12][NH:18][CH:10]=2)=[CH:5][CH:4]=1
Reactant: N
Reactant: COc1ccc(COc2coccc2=O)cc1
Solvent: O
Product: COc1ccc(COc2c[nH]ccc2=O)cc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A suspension of 3-[(4-methoxybenzyl)oxy]-4H-pyran-4-one (6.2 g, 26.7 mmol) and 120 mL of NH3.H2O was sealed in a glass tube, and the mixture was stirred at 100° C. After 18 h, the reaction mixture was filtered and the collected solid was washed with MeOH to give 3-[(4-methoxybenzyl)oxy]pyridin-4(1H)-one. 1H-NMR (DMSO, 400 MHz) δ 11.27 (s, 1H), 7.50 (s, 1H), 7.41 (s, 1H), 7.30 (dd, J=8.4, 2.8 Hz, 2H), 6.90 (m, 2H), 6.13 (s, 1H), 4.8(s, 2H), 3.72 (s, 3H). MS (M+H)+ 232.0.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1>CCO>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][N:10]2[CH2:11][CH2:12][CH:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:26][CH:25]=3)[CH2:8][CH2:9]2)=[CH:21][CH:20]=1
Reactant: Cc1ccc(CC2CCN(CCOc3ccc([N+](=O)[O-])cc3)CC2)cc1
Solvent: CCO
Product: Cc1ccc(CC2CCN(CCOc3ccc(N)cc3)CC2)cc1
Yield: 84 %

Procedure:
From a mixture of 4-(4-methylbenzyl)-1-[2-(4-nitrophenoxy)ethyl]piperidine (1.80 g, 5.2 mmol), stannous chloride dihydrate (7.40 g, 32.8 mmol) in EtOH (50 mL) was obtained 1.43 g (84%) of the title compound as a viscous oil. 1H NMR (CDCl3): 1.25-1.38 (m, 2H), 1.36-1.56 (m, 1H), 1.61-1.65 (m, 2H), 1.98-2.05 (m, 2H), 2.315 (s, 3H), 2.490 (d, 2H, J=7), 2.726 (t, 2H, J=6), 2.94-2.98 (m, 2H), 3.316 (bs, 2H), 4.015 (t, 2H, J=6), 6.681 (AB, 2H, J=9), 7.056 (AB, 4H, J=9).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C@:8]23[CH2:16][O:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]3)[CH:7]=1.[F:27][C:28]1[CH:29]=[CH:30][C:31]([C:34](O)=[O:35])=[N:32][CH:33]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH-].[Na+]>ClCCl.CN(C=O)C>[C:18]([NH:17][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][O:15][CH2:16][C@:8]2([C:6]2[CH:7]=[C:2]([NH:1][C:34](=[O:35])[C:31]3[CH:30]=[CH:29][C:28]([F:27])=[CH:33][N:32]=3)[CH:3]=[CH:4][C:5]=2[F:26])[N:9]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(F)cn1
Reactant: Nc1ccc(F)c([C@]23COC[C@H]2CSC(NC(=O)c2ccccc2)=N3)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1=N[C@@]2(c3cc(NC(=O)c4ccc(F)cn4)ccc3F)COC[C@H]2CS1)c1ccccc1
Temperature: 22 °C
Reaction time: 1.33 h
Yield: 92.9 %

Procedure:
A mixture of N-((4aS,7aS)-7a-(5-amino-2-fluorophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (20.4 g, 51.8 mmol), 5-fluoropicolinic acid (8.77 g, 62.2 mmol), 1-hydroxybenzotriazole hydrate (10.3 g, 67.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.2 g, 67.4 mmol) in a mixture of dichloromethane (345 mL) and DMF (6.5 mL) is stirred at 22° C. for 80 min. A solution of 2 M sodium hydroxide (129.5 mL, 259 mmol) is added and the stirring is continued for 10 min. The mixture is separated and the aqueous phase is extracted with twice with dichloromethane (2×100 mL). The organic layer is concentrated under reduced pressure and the residue is diluted with ethyl acetate (200 mL). The organic layer is washed with cooled water (2×50 mL), brine (50 mL) and filtered through a short pad of silica using 100% ethyl acetate to give title compound (23.8 g, 79%). ES/MS m/e: 495 (M+1).