Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:7])([O-:6])[O:2][CH:3](Cl)[CH3:4].[CH3:8][CH2:9][O:10][C:11]1[N:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:32]([C:33]4[N:37]([C:38]([C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)[C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[N:36]=[N:35][N:34]=4)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[C:57]([OH:59])=[O:58])[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CS(C)=O.O.C1(C)C=CC=CC=1>[CH3:8][CH2:9][O:10][C:11]1[N:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[C:32]([C:33]4[N:37]([C:38]([C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=5)([C:51]5[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=5)[C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[N:36]=[N:35][N:34]=4)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:25][CH:26]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[C:57]([O:59][CH:3]([O:2][C:1]([O:6][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:7])[CH3:4])=[O:58])[N:12]=1
Reactant: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(Cl)OC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 62.5 °C

Procedure:
Carbohexyl 1-chloroethyl carbonate (36 g) is added to a suspension of trityl candesartan (100 g), potassium carbonate (24 g) and potassium iodide (12 g) in DMSO (500 ml) at temperature of 60-65° C. over 30 min. Reaction mass is maintained at 60-65° C. for 2 hrs, added toluene (300 ml) and water (300 ml). Reaction mass is mixed for 15 min., allowed to settle, the layers are separated at 60-65° C. and aqueous layer is extracted with toluene (200 ml). Water (200 ml) washings are given to the combined organic layer and toluene extractions twice at temperature of 60-65° C. Toluene is distilled off from water washed organic layer at temperature below 60° C. under vacuum, ethanol (100 ml) is added, mixed for about 30 min and distilled off solvents under vacuum at temperature below 60° C. under vacuum. Residue is cooled to 30-35° C., ethanol (300 ml) is added, mixed for 2 hrs at 25-30° C. and filtered the product. Wet cake is washed with ethanol (100 ml) and suck dried. Wet weight of Cilexetil trityl candesartan is 180 g
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9][C:8]=1[O:25]CCCCCCCCCC)C.[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(=O)[C:42](Cl)=[O:43].Cl>C(Cl)Cl>[CH2:23]([O:22][C:20]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[O:13][C:10]1[CH:9]=[C:8]([OH:25])[C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:36])=[CH:12][C:11]=1[C:42]2=[O:43])=[O:21])[CH3:24]
Reactant: CCCCCCCCCCOc1cc(Oc2ccccc2C(=O)OCC)ccc1CCC(=O)OCC
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)c1cccc2c(=O)c3cc(CCC(=O)O)c(O)cc3oc12
Reaction time: 1 h

Procedure:
To a solution of 0.7 g of 2-(decyloxy)-4-[2-(ethoxycarbonyl)phenoxy]benzenepropanoic acid ethyl ester in methylene chloride at room temperature were added 0.187 g of aluminum chloride followed by 0.122 ml of oxalyl chloride. After stirring for approximately 1 hour, the mixture was poured into a combination of ice and hydrochloric acid. After stirring for approximately 1 hour, the layers were separated and the organic layer was dried and concentrated in vacuo. The material was used without further purification in the subsequent reaction.
Reaction SMILES: [C@:1]12([CH2:11][S:12]([OH:15])(=[O:14])=[O:13])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=[O:3].[Cl:16][C:17]1[CH:18]=[C:19]([C:24]2([CH2:30][CH2:31][CH2:32]O)[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]2)[CH:20]=[CH:21][C:22]=1[Cl:23]>CC(O)C>[CH3:9][C:8]1([CH3:10])[CH:5]2[CH2:6][CH2:7][C@@:1]1([CH2:11][S:12]([O:15][CH2:32][CH2:31][CH2:30][C@@:24]1([C:19]3[CH:20]=[CH:21][C:22]([Cl:23])=[C:17]([Cl:16])[CH:18]=3)[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1)(=[O:13])=[O:14])[C:2](=[O:3])[CH2:4]2
Reactant: OCCCC1(c2ccc(Cl)c(Cl)c2)CCCNC1
Reactant: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CC1(C)C2CC[C@@]1(CS(=O)(=O)OCCC[C@@]1(c3ccc(Cl)c(Cl)c3)CCCNC1)C(=O)C2
Yield: 104.9 %

Procedure:
A solution of (S)-(+)-camphorsulfonic acid (10.3 g, 44.41 mmol) in iPrOH (10 mL) was added to a solution of hydroxy piperidine (8) (12.8 g, 44.41 mmol) in iPrOH. The mixture was heated to reflux for 15 minutes. The solvent was removed to give glassy solid 23.4 g, which solid was then recrystallized in iPrOH two times to give white crystals (5.5 g, 23.8%, 95% ee), mp 188-189° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br)=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH2:24][C:25]#[N:26])(=[O:23])=[O:22])=[CH:17][CH:16]=1.N12CCCN=C1CCCCC2>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:24]([S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[C:25]#[N:26])=[CH:4][CH:3]=1
Reactant: Clc1ccc(CCCCCBr)cc1
Reactant: Cc1ccc(S(=O)(=O)CC#N)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)C(C#N)CCCCCc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 4.5 g (17.2 mmol) of 5-(4-chlorophenyl)pentyl bromide, 3.36 g (17.2 mmol) of (4-methylphenyl)sulfonylacetonitrile, 2.26 g (17.2 mmol) of 1,8-diazabicyclo(5,4,0)undec-7-ene and 30 ml of benzene is stirred at room temperature for 6 hours. Then the reaction mixture is washed with water; the organic phase is dried, and concentrated. The concentrate is chromatographed with a mixture of toluene and dioxane (10:1) on silica gel. Yield: 4.2 g (65% of theory) of the title compound, a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5](CCl)[CH2:6][C:7]1[N:16]=[C:15](O)[C:14]2[C:9](=[CH:10][C:11]([C:18]3[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:12][CH:13]=2)[N:8]=1)[CH3:2].O=P(Cl)(Cl)[Cl:33].N1C(C)=CC=CC=1C>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][C:7]1[N:16]=[C:15]([Cl:33])[C:14]2[C:9](=[CH:10][C:11]([C:18]3[C:23]([C:24]([F:25])([F:27])[F:26])=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:12][CH:13]=2)[N:8]=1)[CH3:2]
Reactant: CCOC(=O)C(CCl)Cc1nc(O)c2ccc(-c3ncccc3C(F)(F)F)cc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)CCc1nc(Cl)c2ccc(-c3ncccc3C(F)(F)F)cc2n1

Procedure:
Reflux a mixture of 2-chloromethyl-3-[4-hydroxy-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-propionic acid ethyl ester (600 mg, 1.6 mmol), POCl3 (445 μl, 4.77 mmol), and 2,6-lutidine (596 μl, 4.77 mmol) in CHCl3 (20 ml) for 60 hours. Cool the mixture and concentrate under reduced pressure. Partition the residue between EtOAc and saturated NaHCO3 solution. Wash the EtOAc portion with additional NaHCO3 and then dry (Na2SO4) and concentrate under reduced pressure. Filter the brown residue through 2 inches of silica gel (1:1 EtOAc/hexanes eluent) and concentrate under reduced pressure to give 3-[4-chloro-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-propionic acid ethyl ester.
Reaction SMILES: C([S:4][CH:5]([CH3:12])[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])(=O)C.CN(C)C=O.[C:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])#[N:19]>CC(=O)OCC>[NH2:19][C:18]1[S:4][CH:5]([CH3:12])[C:6]([OH:11])([C:7]([F:10])([F:9])[F:8])[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CC(=O)SC(C)C(=O)C(F)(F)F
Reactant: CCOC(=O)CC#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(N)SC(C)C1(O)C(F)(F)F
Temperature: 0 °C

Procedure:
Into a 100-mL round-bottom flask, was placed 3-(acetylsulfanyl)-1,1,1-trifluorobutan-2-one (5.8 g, 28.97 mmol, 1.00 equiv), N,N-dimethylformamide (10 mL). This was followed by the addition of TEA (3 g, 29.65 mmol, 1.02 equiv) and ethyl 2-cyanoacetate (3.27 g, 28.91 mmol, 1.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred overnight at 25° C. Then it was diluted with 20 mL of EA. The organic phase was separated and washed with 3×20 mL of H2O. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (30/70). The collected fractions were combined and concentrated under vacuum. This resulted in 6.5 g (79%) of ethyl 2-amino-4-hydroxy-5-methyl-4-(trifluoromethyl)-4,5-dihydrothiophene-3-carboxylate as a dark red liquid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:4]=2[C:3]=1[Br:12].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH2:15]([O:11][C:8]1[CH:9]=[CH:10][C:4]2[C:3]([Br:12])=[C:2]([Br:1])[S:6][C:5]=2[CH:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc2c(Br)c(Br)sc2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Brc1sc2cc(OCc3ccccc3)ccc2c1Br
Reaction time: 0.33 h
Yield: 92 %

Procedure:
Add a solution of 2,3-dibromo-benzo[b]thiophen-6-ol (43.9 g, 143 mmol) in DMF (1000 mL), dropwise, to a suspension of sodium hydride in DMF (1.5 L) at 0° C. Stir for 20 minutes, add benzyl bromide (17 mL, 143 mmol). Remove ice bath, and stir at room temperature for 2 hours. Pour reaction mixture into water (8 L) and ethyl acetate (4 L) and stir overnight. Separate layers and wash organic layer with water (3×800 mL) and brine (800 mL). Dry with sodium sulfate, filter, and concentrate in vacuo to give 52.4 g of 6-benzyloxy-2,3-dibromo-benzo[b]thiophene (92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:14](#[N:18])/[CH:15]=[CH:16]/[CH3:17]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH:16]([CH3:17])[CH2:15][C:14]#[N:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: C/C=C/C#N
Product: COc1ccc(CCNC(C)CC#N)cc1OC
Temperature: 100 °C
Reaction time: 30 h

Procedure:
A mixture of 10.0 g of 2-(3,4-dimethoxyphenyl)ethylamine with 14 ml of crotononitrile was stirred at 100° C. for 30 h.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:35](=[O:36])[C:34]([C:37](O)=[O:38])=[N:33][N:32]([CH:40]([CH3:42])[CH3:41])[C:31]2=[O:43])=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[NH:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:37]([C:34]2[C:35](=[O:36])[N:30]([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=3)[C:31](=[O:43])[N:32]([CH:40]([CH3:42])[CH3:41])[N:33]=2)=[O:38])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Nc3ccc(N)cc3)c2cc1OC
Reactant: CC(C)n1nc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: COc1cc2nccc(Nc3ccc(NC(=O)c4nn(C(C)C)c(=O)n(-c5ccc(F)cc5)c4=O)cc3)c2cc1OC

Procedure:
This compound was synthesized using N-(6,7-dimethoxyquinolin-4-yl)-benzene-1,4-diamine and 4-(4-fluorophenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carboxylic acid by the method for example 134. mp=152-155° C.; LCMS m/z=571 (M+1); 1H NMR (DMSO-d6) δ: 8.67 (s, 1H), 7.68 (d, 2H, J=8.87 Hz), 7.54 (d, 2H, J=8.68 Hz), 7.20-7.34 (m, 12H), 7.10 (brs, 1H), 6.99 (s, 1H), 6.60 (d, 2H, J=8.6 Hz), 4.04 (d, 7H, J=2.2 Hz), 3.79 (brs, 2H), 1.21 (t, 1H, J=7.0 Hz), 0.81-0.91 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])[CH3:2].C(O[CH2:19][CH3:20])(OCC)(OCC)C.[C:21](O)(=O)[CH3:22]>>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:6][C:5](=[N:6][C:21]2[CH:22]=[CH:9][CH:3]=[C:1]([CH2:19][CH3:20])[CH:2]=2)[CH3:4])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCc1cccc(N)c1
Reactant: CCOC(C)(OCC)OCC
Reactant: CC(=O)O
Product: CCc1cccc(N=C(C)Nc2cccc(CC)c2)c1
Temperature: 132.5 °C
Yield: 875.9 %

Procedure:
A mixture of 3-ethylaniline (1.0 g, 8.25 mmol), triethyl orthoacetate (0.670 g, 4.13 mmol) and glacial acetic acid (0.019 ml, 0.33 mmol) was heated to reflux in an oil bath at 125-140° C. for 3 hr. It was purified by flash chromatography on silica gel and the product was then crystallized from pet-ether-dichloromethane to give the title compound (0.770 g, 72%) as an off-white soft crystal. Mp 86°-87° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH2:12][S:11][C:10]2=[S:15])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:16]([O:19][C:20](=O)[CH3:21])(=O)[CH3:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[C:16]([O:19][CH2:20][CH3:21])[CH2:17][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[S:11][C:10]2=[S:15])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CSC(=S)N1c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Product: CCOC(Cc1ccccc1)=C1SC(=S)N(c2ccc(Cl)c(Cl)c2)C1=O

Procedure:
The rhodanine is reacted as described in Examples 1 and 3 with triethylorthophenylacetate in acetic anhydride to yield 3-(3',4'-dichlorophenyl)-5-(1'-ethoxy-2'-phenylethylidene)-rhodanine which is similarly hydrolyzed to 3-(3',4'-dichlorophenyl)-5-(1'-hydroxy-2'-phenylethylidene)-rhodanine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:9]=1)[C:7]#[N:8].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](OB(O)O)[CH:12]=1>C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Br)ccc1I
Reactant: OB(O)Oc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1cc(Br)ccc1-c1cccnc1
Temperature: 100 °C

Procedure:
5-Bromo-2-iodobenzonitrile and 3-pyridylboric acid were dissolved in a mixture solution of aqueous 2 M sodium carbonate solution and toluene, then tetrakis(triphenylphosphine)palladium was added thereto, and the mixture was heated, stirred with heating in an argon atmosphere at 100° C. for 3 days to obtain 5-bromo-2-pyridin-3-ylbenzonitrile. EI: 258, 260.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[N:11]#[C:12][S-:13].[N:14]1([CH:19]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH:20]([CH3:22])[CH3:21])[CH:18]=[CH:17][N:16]=[CH:15]1>CC(=O)C>[C:1]([NH:11][C:12]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([CH:19]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[CH:20]([CH3:22])[CH3:21])=[CH:24][CH:25]=1)=[S:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(c1ccc(N)cc1)n1ccnc1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: CC(C)C(c1ccc(NC(=S)NC(=O)c2ccccc2)cc1)n1ccnc1
Temperature: 80 °C

Procedure:
Benzoylchloride (0.067 mol) was added to a solution of NH4SCN (5.09 g) in 2-propanone (150 ml) and the mixture was stirred and refluxed for 20 minutes. A solution of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]benzenamine (0.0557 mol) in 2-propanone (150 ml) was added and the mixture was stirred and refluxed at 80° C. overnight. The mixture was cooled, filtered through celite and the filtrate was evaporated. The residue was taken up in CH2Cl2. The organic layer was dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 98/2/0.1). The pure fractions were collected and evaporated. The residue was recrystallized from 2-propanone and DIPE, yielding (±)—N-benzoyl-N′-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]thiourea (compound 698).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][C@H:23]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:24][OH:25]>>[OH:25][CH2:24][C@H:23]([NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: N[C@@H](CO)Cc1ccccc1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N[C@@H](CO)Cc3ccccc3)cc2c1=O
Yield: 65 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with (R)-2-amino-3-phenyl-propan-1-ol according to the GPA affording 22.2 mg (65%) of a purple powder. Rt=4.40 min.
Reaction SMILES: COC([CH:5]1[CH:11]([CH3:12])[C:10](=[O:13])[NH:9][C:8]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:7]=2[C:6]1=[O:19])=O.O>CN(C=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:7]2[C:6](=[O:19])[CH2:5][CH:11]([CH3:12])[C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1
Reactant: COC(=O)C1C(=O)c2ccc(Cl)cc2NC(=O)C1C
Solvent: O
Solvent: CN(C)C=O
Product: CC1CC(=O)c2ccc(Cl)cc2NC1=O
Temperature: 230 °C

Procedure:
To a solution of 8-chloro-3-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester (iii-i) (0.2 g, 0.7 mmol) in DMF (2 mL) was added H2O (0.3 mL) and the reaction mixture heated to 230° C. in a microwave reactor for 5 minutes. H2O (20 mL) was added to the reaction mixture and the resulting precipitate was filtered and washed with H2O. The solid was dried under reduced pressure at 40° C. for 16 h to afford iv-i (0.12 g, 77%) as a white solid: MS m/z=224 (M+H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=O)[CH2:14][CH2:15]C1SCCS1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:23](C)=[O:24]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH:23]=[O:24])[CH2:14][CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: O=C(CCCCOCc1ccccc1)CCC1SCCS1
Product: CCC(C=O)CCCCOCc1ccccc1

Procedure:
0.135 mole = 44 g of 7-benzyloxy-1-(1,3-dithia-2-cyclopentyl)-heptane-3-one were heated for 1 hour under nitrogen and under reflux in 1 liter of acetone with [0.275 mole] = 47 g of CuCl2. 2 H2O and [0.57 mole] = 44 g of CuO, the copper salts were filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in ether, washed twice with 2N- HCl and thrice with water, dried and the solvent was removed by distillation under reduced pressure. The residue was distilled under reduced pressure. B.p.0.5 mm 185°-192° C.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:15][CH:14]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: O=C1NCc2ccccc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(CN2Cc3ccccc3C2=O)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 42.1 %

Procedure:
A mixture of 2,3-dihydro-isoindol-1-one (0.133 g, 1 mmol), 1-bromomethyl-4-methyl-benzene (0.222 g, 1.2 mmol), Cs2CO3 (0.816 g, 2.5 mmol), and 18-crown-6 (0.026 g, 0.1 mmol) in acetone (5 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(4-methyl-benzyl)-2,3-dihydro-isoindol-1-one (0.100 g, 84%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.36 (s, 3H), 4.24 (s, 2H), 4.76 (s, 2H), 7.15-7.54 (m, 7H), 7.90 (d, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH:26]([CH3:29])[CH2:27][OH:28])=[O:24])[C:5]1=[O:30].[N:31]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH:26]([CH3:29])[CH2:27][OH:28])=[O:24])[C:5](=[O:30])[N:4]3[CH2:3][CH2:2][NH:1][C:37]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:38])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Product: CC(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNC(=O)N2CCOCC2)c1=O

Procedure:
This compound was prepared from 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxy-1-methylethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide and 4-morpholinecarbonyl chloride employing methods similar to those described in Example 450 and was obtained as an orange solid: ES+ MS: 528 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][O:15][CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:10][C@H:9]1[CH2:14][O:15][CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-methoxymethylpyrrolidine (2.8 g) and methanesulfonyl chloride (1.12 ml) in dichloromethane (30 ml) was added dropwise triethylamine (2.38 ml) at 0° C. After 30 minutes, the reaction mixture was washed in turn with 1N-hydrochloric acid, water and brine. The organic layer was dried over magnesium sulfate and evaporated to give an oil, which was chromatographed on silica gel (300 ml) eluting with a mixture of hexane and ethyl acetate (1:1, V/V) to give (2S,4R)-1-(tert-butoxycarbonyl)-4-methanesulfonyloxy-2-methoxymethylpyrrolidine (3.61 g).
Reaction SMILES: [CH2:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)[CH:2]=[CH2:3].[Cl:9][SiH:10]([Cl:12])[Cl:11]>[Pt].C1(C)C=CC=CC=1>[Cl:9][Si:10]([Cl:12])([Cl:11])[CH2:3][CH2:2][CH2:1][C:4]1[S:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: C=CCc1cccs1
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cl[Si](Cl)(Cl)CCCc1cccs1
Temperature: 60 °C

Procedure:
2-Allylthiophene (25 g), 13 g of anhydrous toluene (13 g), and 250 mg of Platinum Catalyst were combined under nitrogen in a three-neck flask equipped with a reflux condenser and a dropping funnel. Then, 30 g of trichlorosilane was added drop-wise to the mixture. Upon completion of the addition, the mixture was heated to 60° C. and maintained at that temperature for 2 h. Then, the mixture was distilled at 150° C. and 0.02 ton to give 2-(3-trichlorosilylpropyl)thiophene as a colorless liquid: 1H NMR (CDCl3) δ 7.16 (dd, 1H, J=5.1, 0.9 Hz); 6.95 (dd, 1H, J=4.8, 3.3 Hz); 6.83 (m, 1H); 2.96 (t, 2H, J=7.2 Hz); 1.98 (m, 2H); 1.46 (m, 2H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([N:19]1[C:31]2[C:30]([S:32][CH3:33])=[C:29]([CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])[CH:28]=[C:27]([CH3:41])[C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[CH2:12]([N:19]1[C:31]2[C:30]([S:32]([CH3:33])=[O:9])=[C:29]([CH2:34][C:35]([O:37][CH:38]([CH3:39])[CH3:40])=[O:36])[CH:28]=[C:27]([CH3:41])[C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1c(CC(=O)OC(C)C)cc(C)c2c3ccccc3n(Cc3ccccc3)c12
Solvent: O
Product: Cc1cc(CC(=O)OC(C)C)c(S(C)=O)c2c1c1ccccc1n2Cc1ccccc1

Procedure:
750 mg of 80% v/v m-chloroperbenzoic acid in water was added gradually to 40 ml of a solution of isopropyl (9-benzyl-1-methylthio-4-methylcarbazol-2-yl)acetate (1.00 g), obtained in a manner similar to that of the title compound of Example 115, in methylene chloride, and the reaction mixture was stirred for 1 hour, with ice-cooling. After this time, the reaction mixture was diluted with an excess of ethyl acetate and washed with a saturated aqueous solution of sodium hydrogen-carbonate. The resulting organic layer was dried over anhydrous sodium sulfate and then the solvent was removed by evaporation under reduced pressure. The residue was subjected to column chromatography (eluent: a 50-60% v/v solution of ethyl acetate in hexane) to yield 719 mg of the title compound as a solid.