Azzindani/Open_Reaction_Data huggingface dataset:
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]=[C:8]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[N:7]=[C:6]2[C:27](O)=[O:28].Cl.[CH3:31][O:32][C:33]1[CH:42]=[CH:41][CH:40]=[C:39]2[C:34]=1[CH2:35][CH2:36][NH:37][CH2:38]2>>[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]=[C:8]([C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1)[N:7]=[C:6]2[C:27]([N:37]1[CH2:36][CH2:35][C:34]2[C:39](=[CH:40][CH:41]=[CH:42][C:33]=2[O:32][CH3:31])[CH2:38]1)=[O:28]
Reactant: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(C(=O)O)c2cc1OC
Reactant: COc1cccc2c1CCNC2
Agent: Cl
Product: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(C(=O)N3CCc4c(cccc4OC)C3)c2cc1OC
Yield: 41.6 %

Procedure:
Reaction of 6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 5-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 116 (41.6% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.84 and 2.90 (2t, 2H), 3.52-4.09 (m, 20H), 4.45 and 4.96 (2s, 2H), 6.45-7.26 (m, 4H), 7.45 and 7.49 (2s, 1H), 7.76 and 7.82 (2s, 2H); MS (ESI) m/z 546 ([M+H]+).
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[CH2:4][CH2:5][C:6]2([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]=1[C:13]1[C:8](=[CH:9][C:10]([O:15][CH3:16])=[CH:11][CH:12]=1)[CH2:7]2.[Cu][C:23]#[N:24]>CN1CCCC1=O>[CH2:17]([C:6]12[CH2:5][CH2:4][C:3](=[O:21])[C:2]([C:23]#[N:24])=[C:14]1[C:13]1[C:8](=[CH:9][C:10]([O:15][CH3:16])=[CH:11][CH:12]=1)[CH2:7]2)[CH2:18][CH2:19][CH3:20]
Reactant: N#C[Cu]
Reactant: CCCCC12CCC(=O)C(Br)=C1c1ccc(OC)cc1C2
Solvent: CN1CCCC1=O
Product: CCCCC12CCC(=O)C(C#N)=C1c1ccc(OC)cc1C2
Temperature: 160 °C
Yield: 81 %

Procedure:
A solution of 4-bromo-9a-butyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (50 mg, 0.138 mmol) in anhydrous 1-methyl-2-pyrrolidinone (0.276 mL) was treated with copper(I) cyanide (25 mg, 0.275 mmol). The resulting mixture was stirred under a nitrogen atmosphere and heated in an oil bath at 160° C. for 40 minutes. The mixture was partitioned between EtOAc (20 mL) and water (20 ml). The organic phase was washed with water (2×20 mL) and brine (10 mL), dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate, developing with 5% EtOAc in CH2Cl2, to afford 9a-butyl-4-cyano-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (33 mg) as an oil.
Reaction SMILES: [C:1]1(=[O:8])O[C:5](=[O:6])[CH:4]=[C:2]1[CH3:3].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1>C1(C)C=CC=CC=1>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[C:5](=[O:6])[CH:4]=[C:2]([CH3:3])[C:1]2=[O:8])=[N:11][CH:12]=1
Reactant: CC1=CC(=O)OC1=O
Reactant: Nc1ccc(Br)cn1
Solvent: Cc1ccccc1
Product: CC1=CC(=O)N(c2ccc(Br)cn2)C1=O
Yield: 70.8 %

Procedure:
A mixture of citraconic anhydride (1.00 mL, 11.1 mmol) and 2-amino-5-bromopyridine (1.93 g, 11.2 mmol) in toluene (60 mL) was heated to reflux overnight. The solution was cooled down, filtered. The filtrate was concentrated in vacuo to give a solid (2.10 g, yield: 71%). MS 267 and 269 (M+H).
Reaction SMILES: C([Li])CCC.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]#[CH:8].[O:13]=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(O)(=O)C>O1CCCC1>[CH2:11]([O:10][C:6](=[O:9])[C:7]#[C:8][C:14]1([OH:13])[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]1)[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C#CC(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C#CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 105.6 %

Procedure:
n-Butyllithium (175 ml, 0.28 mol) was added dropwise over 45 minutes to a stirred, cooled (−70° C.) solution of ethyl propiolate (32 ml, 0.32 mol) in tetrahydrofuran (250 ml). The mixture was stirred at −70° C. for 10 minutes, then a solution of 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (18.6 g, 0.093 mol) in tetrahydrofuran (250 ml) was added dropwise over 1 hour maintaining the internal temperature below −70° C. The mixture was stirred at −70° C. for 1 hour and then acetic acid (21 ml) in tetrahydrofuran (50 ml) was added. The mixture was warmed to room temperature and the solvent was evaporated under reduced pressure. Saturated aqueous sodium hydrogen carbonate (300 ml) and ethyl acetate (650 ml) were added and the layers were separated. The aqueous fraction was extracted with ethyl acetate (2×650 ml) and the combined organic fractions were washed with brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a short silica gel column, eluting with 1:1 isohexane:ethyl acetate, to give the title compound (29.2 g, contains trace impurity).
Reaction SMILES: [CH:1]([SiH:4]([CH:14]([CH3:16])[CH3:15])[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].OS(O)(=O)=O.[CH3:22]O>C(Cl)(Cl)Cl>[CH3:22][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([SiH:4]([CH:1]([CH3:3])[CH3:2])[CH:14]([CH3:16])[CH3:15])=[CH:6][CH:7]=1
Reactant: CC(C)[SiH](c1ccc(C(=O)O)cc1)C(C)C
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc([SiH](C(C)C)C(C)C)cc1
Yield: 93 %

Procedure:
4-diisopropylsilanylbenzoic acid (9 g, 38 mmol)was dissolved in methanol (300 mL), and conc. H2SO4 (15 mL) was added dropwise to the solution cooled on ice. After being heated to reflux for 2 hours, the reaction solution was dissolved in chloroform (500 mL). The solution was then extracted two times with water (300 mL) and three times with 5 wt % aqueous solution (300 ml) of sodium hydrogen carbonate. An organic layer was collected and dehydrated with anhydrous sodium sulfate and filtered so that the resulting solvent was distilled out under a reduced pressure. The resulting crude product was then purified by silica gel column chromatography. After eluted with hexane having 0-5% ethyl acetate gradient, the solvent was distilled out to give a desired product (8.8 g, 93%). Its NMR data are as follows:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([C:15]([OH:17])=[O:16])[NH:8][CH2:7][CH2:6][C:5]2=1.S(Cl)([Cl:20])=O.[CH3:22]O>>[ClH:20].[F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([C:15]([O:17][CH3:22])=[O:16])[NH:8][CH2:7][CH2:6][C:5]2=1
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1NCCc2c1[nH]c1ccc(F)cc21
Product: COC(=O)C1NCCc2c1[nH]c1ccc(F)cc21
Product: Cl
Temperature: 0 °C
Reaction time: 24 h

Procedure:
The title compound was prepared by mixing 6-fluoro-1,2,3,4-tetrahydro-β-carboline-1-carboxylic acid (2 g; 0.0085 mole) with 60 ml of methanol. After cooling at 0° C., thionyl chloride (2 ml., 0.028 mole) was added dropwise and the mixture stirred at room temperature for 24 hours whereupon the solvent was removed in vacuo. The residue was partitioned in ethylacetate/6% K2CO3 solution whereupon the organic phase was dried over MgSO4, filtered and treated with 4 N HCl in dioxane to pH 5. A white solid product was collected. Yield: 1.2 g (38%) MP 219°-220° C.
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:8].[K+].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C1(C)C=CC=CC=1.O>[CH2:10]([O:8][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:6])=[O:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [OH-]
Reactant: ClCc1ccccc1
Reactant: O=C1CCCCO1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)CCCCOCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 100 g of δ-valerolactone, 50 ml of water, 350 ml of toluene, 280g of potassium hydroxide pellets and 300 ml of benzyl chloride is refluxed overnight with mechanical stirring and azeotroping the water with the use of a Dean-Stark apparatus. The thick white mass is cooled to room temperature and dissolved in 1 l of cold water. The organic layer is separated and the aqueous layer is condensed to 1/3 by heating over a period of 5 h. The mixture is cooled to room temperature, acidified with concentrated hydrochloric acid and extracted with ethyl acetate (2×300 ml). The combined extracts are washed with brine, dried (MgSO4) and evaporated to dryness to give 5-benzyloxypentanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[S:10][C:11]=2/[CH:12]=[N:13]/[S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.C1(C)C=CC(S([CH2:37][N+:38]#[C-:39])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)[S:10][C:11]=2[C:12]2[N:13]([S:14]([N:17]([CH3:18])[CH3:19])(=[O:16])=[O:15])[CH:39]=[N:38][CH:37]=2)=[CH:26][CH:27]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CN(C)S(=O)(=O)/N=C/c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)n1cncc1-c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Yield: 30.9 %

Procedure:
A solution of N′-{(1E)-[4-(4-chlorobenzyl)-2-pyridin-4-yl-1,3-thiazol-5-yl]methylene}-N,N-dimethylsulfamide (148 mg, 0.352 mmol), p-tolylsulfonylmethyl isocyanide (75.5 mg, 0.387 mmol) and potassium carbonate (146 mg, 1.05 mmol) in DME (2.50 mL) was heated at 78° C. for 2 hours. The reaction was diluted with DCM (10 mL) and water (5 mL). The layers were separated and the aqueous layer was extracted with DCM (5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (methanol/DCM=0/100→15/85) to give 50 mg of 5-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide. LC/MS (FA) ES+ 460. (Some of the deprotected product, 4-(4-chlorobenzyl)-5-(1H-imidazol-5-yl)-2-(pyridin-4-yl)thiazole, was also obtained (19 mg). This material was combined with the material obtained in the following deprotection step.)
Reaction SMILES: [C:1]1([N:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:8]([O:10][CH2:11][C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:13]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=[O:37])C.[OH2:41]>C(#N)C>[OH:41][CH:13]1[C:14]2[C:19](=[C:18]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][C:12]1([OH:37])[CH2:11][O:10][C:8](=[O:9])[N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O
Reactant: CCOC(C)=O
Reactant: CCOC(=O)COc1cccc2c1CCC(COC(=O)N(c1ccccc1)c1ccccc1)=C2
Solvent: CC#N
Product: CCOC(=O)COc1cccc2c1CCC(O)(COC(=O)N(c1ccccc1)c1ccccc1)C2O
Reaction time: 4 h

Procedure:
To a solution of 2-(N,N-diphenylcarbamoyloxymethyl)-5-ethoxycarbonylmethyloxy-3,4-dihydronaphthalene (270 mg) in a mixture of acetonitrile (10 ml) and water (5 ml) were added 4-methylmorphorine N-oxide (0.34 ml) and OSO4 (1 ml, 2.5% in t-butyl alcohol) at 0° C. After being stirred for 4 hours, the solution was diluted into ethyl acetate. The mixture was washed with 1N-HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1,2-dihydroxy-2-(N,N-diphenylcarbamoyloxymethyl)-5-ethoxycarbonylmethyloxy-1,2,3,4-tetrahydronaphthalene.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[C:10](=[CH:11][N:12]=[C:13]([S:16][CH3:17])[N:14]=3)[CH:9]=[CH:8][S:7]2(=[O:19])=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:27])C=CC=CC=1>ClCCl.CO>[CH:1]1([N:6]2[C:15]3[C:10](=[CH:11][N:12]=[C:13]([S:16]([CH3:17])=[O:27])[N:14]=3)[CH:9]=[CH:8][S:7]2(=[O:18])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1ncc2c(n1)N(C1CCCC1)S(=O)(=O)C=C2
Solvent: ClCCl
Solvent: CO
Product: CS(=O)c1ncc2c(n1)N(C1CCCC1)S(=O)(=O)C=C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
1-Cyclopentyl-7-methylsulfanyl-2-thia-1,6,8-triaza-naphthalene 2,2-dioxide (6.0 g, 20 mmol) prepared as in Example 1 and 2-benzenesulfonyl-3-phenyl-oxaziridine (6.3 g, 24 mmol) were dissolved in 50% dichloromethane in methanol (75 ml) and stirred overnight at room temperature. Following evaporation of the solvent, the crude product was purified by recrystallization in diethyl ether/methanol to yield 5.22 g (83% yield) 1-Cyclopentyl-7-methylsulfinyl-1H-thia-1,6,8-triaza-naphthalene 2,2-dioxide as a white solid MS: APCI: M+1: 314.1 (M: 314.3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13]O)[N:10]=[CH:9]2)=[CH:4][C:3]=1[CH3:15].S(Cl)(Cl)=O.[H-].[Na+].[N:22]1[C:26]2[CH2:27][CH2:28][CH2:29][CH2:30][C:25]=2[NH:24][CH:23]=1>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][N:22]3[C:26]4[CH2:27][CH2:28][CH2:29][CH2:30][C:25]=4[N:24]=[CH:23]3)[N:10]=[CH:9]2)=[CH:4][C:3]=1[CH3:15]
Reactant: c1nc2c([nH]1)CCCC2
Reactant: Cc1cc(-n2cnc(CO)c2)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: Cc1cc(-n2cnc(Cn3cnc4c3CCCC4)c2)ccc1Cl
Product: Cl

Procedure:
[1-(4-Chloro-3-methyl-phenyl)-1H-imidazol-4-yl]-methanol was treated first with thionylchloride, then with the reaction mixture of sodium hydride and 4,5,6,7-tetrahydro-benzimidazole. After extractive workup and chromatography the title compound was obtained as the free base. It was converted into its white hydrochloride salt. Mp. >250° C. (MeOH/Et2O), MS: m/e=326 (M+).
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-].[Na+].OO.CC(O)=[O:32]>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:8])([F:9])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]([C:17]([NH2:18])=[O:32])=[N:15][CH:16]=1
Reactant: CC(=O)O
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccccc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(phenylamino)pyrazine-2-carbonitrile (47 mg, 0.136 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (31 mg). MS 363.3 (M+H); UV 203.6, 248.7, 301.5 nm; t 0.477 min.
Reaction SMILES: O.[Na+].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:32]([O-:34])=[O:33].Cl.C([OH:38])C>O>[OH2:15].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:32]([OH:34])=[O:33].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:32]([OH:34])=[O:33].[OH2:38].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:32]([OH:34])=[O:33]
Reactant: CCO
Reactant: Cn1c(C(=O)[O-])cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cn1c(C(=O)O)cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Reaction time: 8 h

Procedure:
1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylic acid sodium salt hydrate (0.629), from the previous alternative, and aqueous hydrochloric acid (2 molar) were combined in refluxing ethanol (13 mL) and water (1.3 mL). The mixture was cooled, granulating overnight, chilled in ice and the resulting slurry was filtered. The product solids were dried, yielding the title compound, 1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylic acid hydrate (0.5 g, 83%, containing 2% water by weight). Anhydrous Mot wt (calc) 438.41, MS: 439.35 (MH+), 437.20 (M−). 1H NMR (DMSO-d6): δ 3.97 (s, 3H), 7.13 (s, 1H), 7.30-7.75 (complex, 10H), 7.92 (s, 1H), 10.21 (s, 1H).; HPLC retention time 9.29 minutes.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][C:13]2=[O:16])=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[S:2]([O:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][C:13]2=[O:16])=[CH:9][CH:8]=1)([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCc2ccc(O)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc2c(c1)C(=O)CC2
Yield: 99 %

Procedure:
12.6 ml of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 12.0 g of 6-hydroxy-1-indanone and 45.2 ml of triethylamine in 350 ml of dichloro-methane and the solution was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 200 ml of dichloromethane, washed twice with 150 ml of saturated sodium hydrogen carbonate solution each time an the combined aqueous phases were extracted once with 100 ml of dichloromethane. The combined organic phases were washed with 200 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. 18.3 g (99%) of 6-mesyloxy-1-indanone were obtained as a brown solid which was used directly in the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][C:11](=[O:13])[NH:10][CH2:9]2)=[N:6][CH:7]=1.[H-].[Na+].[CH:16](Br)([CH3:18])[CH3:17].BrC1C=CC(C2OC(=O)N(C)C2)=NC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH:16]([CH3:18])[CH3:17])[CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C1NCC(c2ccc(Br)cn2)O1
Reactant: CC(C)Br
Agent: CN1CC(c2ccc(Br)cn2)OC1=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CC(c2ccc(Br)cn2)OC1=O
Yield: 46.1 %

Procedure:
Compound 14b (125 mg, 0.51 mmol), NaH (51 mg, 1.28 mmol) and isopropyl bromide (125 mg, 1.02 mmol) reacted following the synthetic method of compound 14c to afford 67 mg colorless liquid, yield 46%.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH2:4][OH:5].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br.Cl[C:21]([N:23]1[C@H:28]([CH3:29])[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][C@@H:24]1[CH3:37])=[O:22]>>[CH3:37][C@H:24]1[CH2:25][NH:26][CH2:27][C@@H:28]([CH3:29])[N:23]1[C:21]([O:5][CH2:4][C:3]1[CH:6]=[C:7]([O:10][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([F:11])[CH:13]=2)[CH:8]=[CH:9][C:2]=1[F:1])=[O:22]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Reactant: Fc1cccc(CBr)c1
Reactant: OCc1cc(O)ccc1F
Product: C[C@@H]1CNC[C@H](C)N1C(=O)OCc1cc(OCc2cccc(F)c2)ccc1F

Procedure:
2-Fluoro-5-(3-fluorobenzyl)oxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate was prepared from 2-fluoro-5-hydroxybenzyl alcohol, 3-fluorobenzyl bromide and 1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazine according to the procedures described for Examples 121 and 54 to give the product as a yellow oil: δH (400 MHz, DMSO-d6) 1.28 (6H, d, J 6.9 Hz), 2.77–2.90 (4H, m), 4.10 (2H, br), 5.03 (2H, s), 5.17 (2H, s), 6.85 (1H, m), 6.95–7.10 (3H, m), 7.15 (2H, m) and 7.35 (1H, m), NH not observed; HPLC (XTERRA, 50/80%, 220 nm) 85% (4.83 min).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.[CH3:26]CCCCC.[C:32]([C:34]1[CH:35]=[C:36](/[CH:40]=[CH:41]/[C:42]([O:44]CC)=O)[CH:37]=[CH:38][CH:39]=1)#[N:33]>ClCCl>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:42](=[O:44])/[CH:41]=[C:40](/[C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([C:32]#[N:33])[CH:35]=2)\[CH3:26])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCC
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)cc1
Reactant: CCOC(=O)/C=C/c1cccc(C#N)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: C/C(=C\C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a solution of 2′-tert-butylaminosulfonyl-4-amino-[1,1′]-biphenyl (79 mg, 0.26 mmol) in 4 ml anhydrous dichloromethane was added a solution of 2M trimethylaluminum in hexane (0.39 ml, 0.78 mmol). Reaction was stirred at room temperature for 20 minutes to which a solution of ethyl (E) 3-(3-cyanophenyl)-2-propenoate (56 mg, 0.26 mmol) in 1 ml anhydrous dichloromethane was added. Reaction was stirred at room temperature overnight. Reaction was quenched with 5 ml 1N HCl after which an additional 10 ml dichloromethane was added. Organic layer was washed with 2×20 ml water, dried over magnesium sulfate, filtered and concentrated to give the (2E)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)but-2-enamide (90 mg, 72%) as an off-white powder which was sufficiently pure to be used without further purification.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:14][C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16]>C(O)C.O.[OH-].[Na+]>[CH3:18][C:17]([CH3:20])([CH3:19])[C:15](=[O:16])[CH:14]=[CH:10][C:9]1[CH:12]=[CH:13][C:6]([CH:2]2[O:3][CH2:4][CH2:5][O:1]2)=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(C2OCCO2)cc1
Reactant: CC(=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)C(=O)C=Cc1ccc(C2OCCO2)cc1
Reaction time: 1 h
Yield: 38.8 %

Procedure:
100 g (0.5612 mol) of 4-(1,3-dioxolan-2-yl)-benzaldehyde and 56.1 g (0.56 mol) of pinacoline are dissolved in a mixture of 280 ml of ethanol and 56 ml of water, and 17 ml of 10% strength sodium hydroxide solution are added at room temperature. The mixture is subsequently stirred for 1 hour, 0.56 g of solid sodium hydroxide are added and the mixture is subsequently stirred for 2 days. Thereafter, the precipitate is filtered off with suction, washed with 200 ml of ethanol/water (1:1) and then with water, dried and recrystallized twice from ethanol. 56.5 g (39% of theory) of 4,4-dimethyl-1-[4-(1,3-dioxolan-2-yl)-phenyl]-1-penten-3-one of melting point 79°-81° C. are obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]=[O:6].[OH:7][CH2:8][CH:9]([CH3:12])[CH:10]=[O:11]>[Pd].O1CCCC1>[CH2:5]([OH:6])[CH2:4][CH2:3][CH2:2][OH:1].[CH3:12][CH:9]([CH2:10][OH:11])[CH2:8][OH:7]
Reactant: CC(C=O)CO
Reactant: O=CCCCO
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(CO)CO
Product: OCCCCO

Procedure:
hydrogenating an aqueous solution containing 4-hydroxybutanal and 3-hydroxy-2-methylpropanal in the presence of a palladium compound supported on a zeolite-type catalyst support to produce tetrahydrofuran as the major product, and 1,4-butanediol and 2-methyl-1,3-propanediol as the minor products.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14].[O-:16][C:17]#[N:18].[K+].CO>Cl.O>[CH3:15][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:17]([NH2:18])=[O:16]
Reactant: CN(C)CCCCCCCCCCCN
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(C)CCCCCCCCCCCNC(N)=O
Yield: 21.7 %

Procedure:
A solution of this amine (4.6 g) in dilute hydrochloric acid (40 ml) and concentrated hydrochloric acid (12 ml) was treated with potassium cyanate (7.0 g) in water (10 ml). The mixture was refluxed for 18 hours and the solvent removed leaving a white solid. To this methanol (10 ml) was added and the mixture filtered. The solvent was evaporated from the filtrate which was then chromatographed on a basic alumina column eluting with 10% methanol in chloroform, to give a yellow solid which was washed with ether to give N,N-dimethyl-N-(11-ureidoundecyl)amine as a white solid (1.2g).