Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:18](C)[C:19]2[CH:24]=[CH:23][CH:22]=[C:21](N)[CH:20]=2)([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].[CH:38]([N:41](C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:38][NH:41][C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[CH:20]=2)([C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(C(C)c2cccc(N)c2)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1(Cc2cccc(CNC(=O)OCc3ccccc3)c2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
A mixture of methyl N-tert-butoxycarbonyl-4-(3-amino-methylbenzyl)piperidine-4-carboxylate (1.67 mmol), benzyl chloroformate (0.48 mL, 3.36 mmol), and diisopropylethylamine (1 mL, 5.74 mmol) in dichloromethane was stirred at room temp. The resultant solution was diluted with dichloromethane, washed with aqueous sodium bicarbonate, and then brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 40% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound as clear colorless gum.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([N:22]([C:32]4[CH:36]=[CH:35][O:34][N:33]=4)[CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:37])=[C:4]([OH:38])[CH:3]=1.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[C:44]([F:46])[CH:45]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C.O>[O:34]1[CH:35]=[CH:36][C:32]([N:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[S:19]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[N:9]([C:5]2[C:4]([OH:38])=[CH:3][C:2]([C:42]4[CH:41]=[C:40]([F:39])[CH:45]=[C:44]([F:46])[CH:43]=4)=[C:7]([F:8])[CH:6]=2)[C:10](=[O:37])[CH:11]=[CH:12]3)(=[O:21])=[O:20])=[N:33]1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(F)c(Br)cc3O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(F)c(-c4cc(F)cc(F)c4)cc3O)c2)cc1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
To a solution of 1-(4-bromo-5-fluoro-2-hydroxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.037 g, 0.062 mmol) and (3,5-difluorophenyl)boronic acid (0.015 g, 0.092 mmol) in DMF (0.246 ml) and water (0.062 ml) was added potassium carbonate (0.026 g, 0.185 mmol) followed by PdCl2dppf, DCM adduct (2.255 mg, 3.08 μmol). The resulting mixture was heated to 50° C. and stirred for 2.5 hours. The solution was then cooled to room temperature and transferred to a sep. funnel containing water. The aqueous layer was washed 2× with DCM. The aqueous layer was subsequently neutralized and washed 3× with DCM. The organic layers were combined, dried with MgSO4, filtered and concentrated to an oil. The crude product was used without further purification assuming quantitative yield. m/z (ESI) 634.2 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:6]([CH2:7][CH:8]([OH:26])[CH2:9][CH2:10][CH2:11][CH2:12]CCC/C=C\C/C=C\CCCCC)[O:5][C:4]1=[O:27])[CH3:2].[CH:28]([N:30](C)[C@H:31]([C:36]([OH:38])=O)[CH2:32][CH:33]([CH3:35])[CH3:34])=[O:29]>>[CH2:1]([C@@H:3]1[C:4](=[O:27])[O:5][C@H:6]1[CH2:7][C@@H:8]([O:26][C:36](=[O:38])[C@H:31]([CH2:32][CH:33]([CH3:34])[CH3:35])[NH:30][CH:28]=[O:29])[CH2:9][CH2:10][CH:11]=[CH2:12])[CH2:2][CH2:2][CH2:1][CH2:3][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(O)CC1OC(=O)C1CC
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C=O
Product: C=CCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCCCCCC)OC(=O)[C@H](CC(C)C)NC=O

Procedure:
by esterifying 3-ethyl-4-[(10Z,13Z)-2-hydroxy-10,13-nonadecadienyl)-2-oxetanone with N-formyl-N-methyl-L-leucine there was obtained
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[N:11]=[N:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]=1[OH:24])([O-])=O.C(N)CCC.[H][H]>[Pt].C1(C)C(C)=CC=CC=1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]2=[N:1][N:12]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]=3[OH:24])[N:11]=[C:5]2[CH:6]=1
Reactant: [H][H]
Reactant: Cc1cc(N=Nc2cc(Cl)ccc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Agent: [Pt]
Solvent: CCCCN
Solvent: Cc1ccccc1C
Product: Cc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Reaction time: 1.5 h

Procedure:
60 g of 2-nitro-5-chloro-2'-hydroxy-3'-tert-butyl-5'-methylazobenzene (purity 86%), 40 g of xylene, 60 g of n-butylamine and 1 g of 1% Pt on activated carbon are put into a 300 ml hydrogenation reactor at room temperature under argon. Argon is then replaced by hydrogen. After the injection of 10 bar hydrogen, the hydrogenation is carried out at 35°-37° C. with intensive stirring. The heat released is removed by cooling. The end of the hydrogenation reaction is easily detectable by the hydrogen absorption ceasing after 2 mol equivalents of hydrogen, relative to the azobenzene starting product. The total hydrogenation time is about 1.5 hours.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.[CH3:10][S-:11].[Na+].C(OCC)(=O)C.O>C1COCC1>[C:8]([C:4]1[CH:3]=[C:2]([S:11][CH3:10])[CH:7]=[CH:6][N:5]=1)#[N:9]
Reactant: N#Cc1cc(Cl)ccn1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ccnc(C#N)c1
Yield: 100.1 %

Procedure:
4-Chloro-2-cyanopyridine (2.18 g, 15.7 mmol) and sodium thiomethoxide (2.20 g, 31.4 mmol) were dissolved in THF (100 ml), and the mixture was refluxed for 2 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (2.36 g, 99%) as pale yellow crystals.
Reaction SMILES: C(OC([NH:8][O:9][S:10]([C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21])(=[O:12])=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>O>[O:9]([S:10]([C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21])(=[O:11])=[O:12])[NH2:8]
Reactant: Cc1cc(C)c(S(=O)(=O)ONC(=O)OC(C)(C)C)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reaction time: 0.5 h

Procedure:
To the solid product N-(tert.-butoxycarbonyl)-O-(mesitylsulfonyl)-hydroxylamine (2.1 g, 6.6 mmol) is added trifluoroacetic acid (20 mL) slowly at 0° C. under a nitrogen atmosphere. The reaction mixture is stirred for 30 minutes followed slowly by water (60 mL). The reaction is left at 0° C. for 15 minutes. The solid precipitated is filtered and washed several times with water until the pH of the filtrate was neutral. The white solid (1.4 g, 98%) is dried in the Buchner funnel and used immediately for the next reaction; 1H NMR (400 MHz, DMSO-d6): δ6.73 (s, 2H), 2.48 (s, 6H), 2.15 (s, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH:20]=[O:21])[CH2:16][C:15]1=[O:22])=[O:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].O>C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:9][C@H:8]1[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH:20]=[O:21])[CH2:16][C:15]1=[O:22])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1CN1CCN(C=O)CC1=O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1CCN(C=O)CC1=O

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-2-(4-formyl-2-oxopiperazin-1-yl) methyl-4-hydroxypyrrolidine (11.38 g) in ethyl acetate (110 ml) were added triethylamine (5.6 ml) and methanesulfonyl chloride (3.11 ml) under ice-cooling with stirring, and the mixture was stirred at the same temperature for 1 hour. To the mixture was added water and the mixture was evaporated in vacuo. To the residue was added tetrahydrofuran, and the mixture was stirred at 50° C. for 20 minutes. The mixture was filtered and the filtrate was dried over anhydrous magnesium sulfate, and evaporated in vacuo to give (2S,4R)-1-allyloxycarbonyl-2-(4-formyl-2-oxopiperazin-1-yl) methyl-4-(methanesulfonyloxy)pyrrolidine (14.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH2:9][CH2:8]1>ClCCl.CO>[Cl:1][C:2]1[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][CH:10]([CH3:13])[CH2:11][CH2:12]1
Reactant: CC1CCN(CCOc2ccc([N+](=O)[O-])cc2Cl)CC1
Solvent: ClCCl
Solvent: CO
Product: CC1CCN(CCOc2ccc(N)cc2Cl)CC1

Procedure:
Prepared analogously to Example 3.1.b. from 1-[2-(2-chloro-4-nitrophenoxy)ethyl]4-methylpiperidine. Yield: 3.66 g (59% of theory); C14H21ClN2O (M=268.78); calc.: molecular ion peak (M+H)+: 269/271; found: molecular ion peak (M+H)+: 269/271; Rf value: 0.52 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [Se](=O)=O.[OH:4]O.[CH2:6]([S:9][C:10]1[N:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)[C:7]#[CH:8].[Na+].[Cl-]>O.CO>[CH2:6]([S:9]([C:10]1[N:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:4])[C:7]#[CH:8]
Reactant: C#CCSc1ncc(Cl)cn1
Reactant: OO
Agent: O=[Se]=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C#CCS(=O)c1ncc(Cl)cn1
Yield: 63 %

Procedure:
A mixture of selenium dioxide (4 mmol) and 35% H2O2 (4 mmol) in water (2.5 ml) was added to a solution of 2-propargylthio-5-chloropyrimidine in methanol (10 ml). The mixture was stirred at room temperature for 18 h before water (50 ml), saturated with NaCl, was added and the mixture extracted with chloroform (3×20 ml). The dried (MgSO4) chloroform solution was evaporated and the residue recrystallized from chloroform: pet. ether; yield 63%, m.p. 92° C. 1H NMR (CDCl3): δ2.28 (HC≡t, J 2 Hz), 3.87 and 4.09 (CH2J 15 Hz), 8.85 (H-4, H-6), IR (KBr): 3235 (CH≡), 2110 and 2100 (--C≡C--). MS [70 eV; m/e (% rel. int)]: 200 (13, M) 199 (19), 173 (33), 171 (100), 146 (25), 114 (30), 113 (31), 111 (47).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][SiH:10]([CH3:12])[Cl:11]>[Pt].C1(C)C=CC=CC=1>[CH2:1]([Si:10]([CH3:12])([CH3:9])[Cl:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: C[SiH](C)Cl
Agent: [Pt]
Solvent: Cc1ccccc1
Product: C[Si](C)(Cl)CCc1ccccc1
Yield: 8.4 %

Procedure:
Reaction between styrene and dimethylchlorosilane with platinum catalyst in the presence of trimethylsilyl-N,N-dimethyl carbamate. 526 mg Styrene and 480 mg dimethylchlorosilane were introduced into a glass tube, and 41 mg of trimethylsilyl-N,N-dimethyl carbamate were added using a microsyringe. 0.65 mg Of a toluene solution of a 0-valent platinum complex of divinylsiloxane (0.4 wt % platinum content) was added. The tube was sealed with Teflon tape and a rubber septum and placed in a 100° C. oil bath where it was heated for 20 hours. After cooling, the tube contents were analyzed by gas chromatography revealing a styrene conversion of 38% and a phenethyl dimethylchlorosilane yield of 8.4%. The ratio between the phenethyl dimethylchlorosilane and the (α-methylbenzene) dimethylchlorosilane was 44:1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH3:9])[C:3]=1[F:10].C([Mg]Cl)(C)C.C(O[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)(C)C>O1CCCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)=[C:3]([F:10])[C:4]=1[CH3:9]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(Cl)ccc(Br)c1F
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1c(Cl)ccc(B2OC(C)(C)C(C)(C)O2)c1F
Temperature: -10 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a stirred solution of 1-bromo-4-chloro-2-fluoro-3-methylbenzene (1.70 g, 7.61 mmol) in tetrahydrofuran (45 mL) cooled to −10° C. was added isopropylmagnesium chloride (2.9 M in THF) (3.0 mL, 8.75 mmol) dropwise. The reaction mixture was stirred at −10° C. for 1 h then allowed to warm to 0° C. and stirred for 1 h. The reaction mixture was cooled to −10° C. followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.785 mL, 8.75 mmol) dropwise. The reaction was allowed to warm to room temperature and stirred for 14 h. The reaction mixture was quenched with 1 N aqueous sodium hydroxide solution and stirred for 10 min. The pH of the reaction was adjusted to 3 with concentrated HCl and the solution was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulphate, and concentrated under reduced pressure to afford 2-(4-chloro-2-fluoro-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.75 g, 6.47 mmol, 85% yield) which was taken to the next step without purification. 1H NMR (400 MHz, CDCl3) δ 7.47 (m, 1H), 7.14 (d, J=8 Hz, 1H), 2.29 (d, J=2 Hz, 3H), 1.36 (s, 12H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.C[N:7](C)[C:8]1C=C[CH:11]=[CH:10][CH:9]=1.C([C:19]1[N:24]2[N:25]=[C:26]([CH3:37])[C:27]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=3[CH3:36])=[C:23]2[N:22]=[C:21]([CH3:38])[C:20]=1[CH2:39][CH2:40][CH2:41][CH2:42]O)CCC.C(=O)([O-])[O-].[K+].[K+]>>[CH2:8]([NH:7][C:20]1([CH2:39][CH2:40][CH2:41][CH2:42][Cl:3])[CH2:19][N:24]2[N:25]=[C:26]([CH3:37])[C:27]([C:28]3[C:29]([CH3:36])=[CH:30][C:31]([CH3:35])=[CH:32][C:33]=3[CH3:34])=[C:23]2[N:22]=[C:21]1[CH3:38])[CH2:9][CH2:10][CH3:11]
Reactant: CN(C)c1ccccc1
Reactant: CCCCc1c(CCCCO)c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCNC1(CCCCCl)Cn2nc(C)c(-c3c(C)cc(C)cc3C)c2N=C1C
Temperature: 0 °C

Procedure:
Phosphorus oxychloride (11.3 g) and N,N-dimethylaniline (3 droplets) were added to 4-(7-(butyl)-3-mesityl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)-1-butanol (320 mg, 0.78 mmol), followed by heating under reflux for 0.5 hour. After the reaction, the mixture was treated with ice-water, neutralized with potassium carbonate, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (10-15% ethyl acetate/hexane), to give the title compound (254 mg) as a pale yellow oil.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]=1[OH:27])[CH:22]=O)[CH3:17].[NH2:31][C:32]([NH2:34])=[O:33].Cl>CCO.CO.CCOC(C)=O>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:22]2[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:34][C:32](=[O:33])[NH:31]2)[CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]=1[OH:27])[CH3:17]
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 48.3 %

Procedure:
To a mixture of compound 1,2-diphenylethanone (557 mg, 2.8 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (500 mg, 2.4 mmol), and urea (427 mg, 7.1 mmol) in EtOH (50 mL) was added concentrated HCl (0.24 mL), and the reaction mixture was heated at reflux for three days. TLC (EtOAc:MeOH=10:1) showed that the starting materials were consumed. The reaction mixture was concentrated and purified by column chromatography (EtOAc:MeOH=30:1) to afford Compound 1 as a yellow solid (500 mg, yield: 49.0%). 1H NMR (DMSO-d6 400 MHz): δ 10.25 (s, 1H), 8.70 (s, 1H), 7.50 (s, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.15-7.25 (m, 6H), 6.95-7.05 (m, 3H), 6.80 (d, J=6.4 Hz, 2H), 5.15 (d, J=2.8 Hz, 1H), 4.05 (m, 2H), 1.30 (t, J=6.8 Hz, 3H); MS (ESI): m/z 432.2 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9](O)=[O:10])[CH:7]=1.[NH2:26][C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([NH:26][C:27]2[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:29][CH:28]=2)=[O:10])[CH:7]=1
Reactant: CC(C)CC(C(=O)O)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CC(C)CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
87 mg (0.23 mmol) of 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methylpentanoic acid (racemate) and 49 mg (0.25 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 45 mg (35% of theory)
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.Cl[S:8]([OH:11])(=O)=[O:9].[OH-].[NH4+:13]>>[CH3:1][C:2]1[S:3][C:4]([S:8]([NH2:13])(=[O:11])=[O:9])=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1cccs1
Agent: [OH-]
Product: Cc1ccc(S(N)(=O)=O)s1

Procedure:
The procedure of Example 3 was followed using 2-methylthiophene (8.0 g, 81.6 mmole), chlorosulfonic acid (28.4 g, 245 mmole) and 200 ml concentrated ammonium hydroxide to produce 5-methyl-2-thiophenesulfonamide which was contacted with 3,4-dichlorophenyl isocyanate (2.61 g, 13.8 mmole) and 1N NaOH (14.5 ml) in 10 ml acetone to provide 3.5 g of the named product as a solid.
Reaction SMILES: [OH:1][C:2]([CH2:34][CH2:35][CH3:36])([CH2:31][CH2:32][CH3:33])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C@@H:11]([O:26][Si](C)(C)C)[C@@H:12]([CH3:25])[CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH:8]=[CH:9][CH:10]=1.FC(F)(F)C(O)=O>CCO>[OH:26][C@H:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][CH2:3][C:2]([OH:1])([CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32][CH3:33])[CH:6]=1)[C@@H:12]([CH3:25])[CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24]
Reactant: CCCC(O)(CCC)CCc1cccc([C@@H](O[Si](C)(C)C)[C@@H](C)CN2C(=O)c3ccccc3C2=O)c1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCCC(O)(CCC)CCc1cccc([C@@H](O)[C@@H](C)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C

Procedure:
To a solution of 2-((2S,3S)-3-(3-(3-hydroxy-3-propylhexyl)phenyl)-2-methyl-3-(trimethylsilyloxy)propyl)isoindoline-1,3-dione in EtOH is added trifluoroacetic acid. The reaction mixture is stirred at room temperature then concentrated under reduced pressure, re-evaporated with EtOAc then with hexane to give 2-((2S,3S)-3-hydroxy-3-(3-(3-hydroxy-3-propylhexyl)phenyl)-2-methylpropyl)isoindoline-1,3-dione.
Reaction SMILES: [CH3:1][O:2][C:3]([O:7][CH3:8])([O:5][CH3:6])[CH3:4].[Cl:9]Cl>>[Cl:9][CH2:4][C:3]([O:7][CH3:8])([O:5][CH3:6])[O:2][CH3:1]
Reactant: ClCl
Reactant: COC(C)(OC)OC
Product: COC(CCl)(OC)OC
Reaction time: 4 h
Yield: 85.1 %

Procedure:
A 1000 ml flask equipped with a stirrer and gas inlet tube was initially charged at 10° C. with 480 g (4 mol) of 1,1,1-trimethoxyethane. Within 4 hours, 220 g (3.14 mol) of chlorine were introduced into the flask in gaseous form, and the internal temperature of the flask did not rise above 15° C. Once the entire amount of chlorine had been introduced into the flask, the mixture was worked-up by distillation. A distillation apparatus having approx. 5 theoretical plates was used to remove low boilers such as methanol and methyl acetate in the first stages at a reflux ratio of 5:1. In the main fraction, 413 g of 2-chloro-1,1,1-trimethoxyethane in a purity of >99.0% were obtained at a reflux ratio of 2:1. This amount of product corresponds to a yield of approx. 67%.
Reaction SMILES: [C:1]([C@:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].S(OC)(O[CH3:22])(=O)=O.[OH-].[Na+].[OH-].[NH4+]>CC(C)=O>[C:1]([C@:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([O:15][CH3:22])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2]
Reactant: COS(=O)(=O)OC
Reactant: C#C[C@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C#C[C@]1(C)CCc2c(C)c(OC)c(C)c(C)c2O1
Yield: 47 %

Procedure:
A solution of (S)-(+)-2-ethynyl-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol (354 mg, 1.54 mmol) in acetone (9 mL) was treated with dimethyl sulfate (0.8 mL), and 50% NaOH (1.2 mL) for 2 h at 25° C. with stirring. Ammonium hydroxide solution (1.0N, 50 mL) was added, and it was extracted with ether (3×50 mL). The extracts were combined, washed with 1.0 N HCl, water, and dried over MgSO4. It was filtered and concentrated in vacuo to give 400 mg of solid, which or crystallization from ether-hexane (1:12) afforded 141 mg (47%) of (S)-(+)-2-ethynyl-3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran as white prisms : mp 94°-97° C., [α]D25 +53.86°, (C 0.4233, CHCl3).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14].Cl.[NH:18]1[CH2:21][CH:20]([OH:22])[CH2:19]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:18]2[CH2:21][CH:20]([OH:22])[CH2:19]2)=[O:8])=[CH:4][C:3]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: OC1CNC1
Reactant: O=C(O)c1ccc(Br)c(OCC(F)(F)F)c1
Agent: Cl
Product: O=C(c1ccc(Br)c(OCC(F)(F)F)c1)N1CC(O)C1

Procedure:
Starting with 4-bromo-3-(2,2,2-trifluoroethoxy)benzoic acid and azetidin-3-ol hydrochloride, Int06.05 was prepared analogously to the procedure for the preparation of Int02.03.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[O:15][CH2:14]2)[NH:21][C:20]([CH2:25][CH3:26])=[CH:19]4)(=O)=O)=CC=1.[NH:28]1[CH2:33][CH:32]=[C:31]([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:36][CH:35]=2)[CH2:30][CH2:29]1>CS(C)=O.C(OCC)(=O)C>[CH2:25]([C:20]1[NH:21][C:22]2[C:18]([CH:19]=1)=[C:17]1[O:27][CH:13]([CH2:12][N:28]3[CH2:29][CH:30]=[C:31]([C:34]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[NH:36][CH:35]=4)[CH2:32][CH2:33]3)[CH2:14][O:15][C:16]1=[CH:24][CH:23]=2)[CH3:26]
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: CCc1cc2c3c(ccc2[nH]1)OC[C@H](COS(=O)(=O)c1ccc(C)cc1)O3
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCc1cc2c3c(ccc2[nH]1)OCC(CN1CC=C(c2c[nH]c4ccccc24)CC1)O3

Procedure:
A solution of 0.52 g (1.3 mmole) of [(2R)-8-ethyl-2,3-dihydro-7H-[1,4]-dioxino[2,3-e]indol-2-yl]methyl 4-methylbenzenesulfonate and 0.80 g (4.1 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 20 mL of DMSO was heated at 65° C. for 3 hours. The mixture was diluted with 300 mL of ethyl acetate, washed with 200 ml portions of saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 0-2% methanol in methylene chloride as eluant. The product fractions were combined and concentrated in vacuum, and the residue triturated with ether/hexane (1:1) to give 0.11 g of the (S)-enantiomer of the title compound as a yellow solid hydrate, m.p. 175-177° C.