Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][C:21]2[CH:35]=[CH:34][C:24]([O:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:42][C:39]1[CH:38]=[CH:37][C:36]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][C:21]2[CH:35]=[CH:34][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:23][CH:22]=2)=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Nc2cc(=O)[nH]c3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(Nc2cc(=O)[nH]c3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 100-mL round-bottom flask, was placed tert-butyl 2-[4-([6-[bis(4-chlorophenyl)methyl]-2-oxo-1,2-dihydroquinolin-4-yl]amino)phenoxy]acetate (200 mg, 0.33 mmol, 1.00 equip, 98%), trifluoroacetic acid (379 mg, 3.32 mmol, 10.00 equip), and dichloromethane (20 mL). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The resulting residue was purified by re-crystallization from methanol to yield 2-[4-([6-[bis(4-chlorophenyl)methyl]-2-oxo-1,2-dihydroquinolin-4-yl]amino)phenoxy]acetic acid as an off-white solid.
Reaction SMILES: C(S[C:4]1[S:5][C:6](=[CH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][C:22]=2[C:31]([F:34])([F:33])[F:32])[N:15]=[CH:14]3)[C:7](=[O:9])[N:8]=1)C.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][C@@H:43]1[CH2:48][OH:49])=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:4]2[S:5][C:6](=[CH:10][C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][C:22]=3[C:31]([F:33])([F:32])[F:34])[N:15]=[CH:14]4)[C:7](=[O:9])[N:8]=2)[CH2:44][C@@H:43]1[CH2:48][OH:49])=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(C)(C)O)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CO
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(C)(C)O)cc4C(F)(F)F)c3)S2)C[C@@H]1CO

Procedure:
(2R)-2-Hydroxymethyl-4-(5-{1-[4-(1-hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-4-oxo-4,5-dihydro-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester was prepared from 2-Ethylsulfanyl-5-{1-[4-(1-hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-thiazol-4-one and (2R)2-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[N:30]=2)=[C:25]([CH:28]=1)[CH:26]=O.OOS([O-])=O.[K+]>CN(C=O)C.O>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:26]1[C:25]1[CH:28]=[C:21]([Cl:20])[CH:22]=[CH:23][C:24]=1[C:29]1[O:33][N:32]=[C:31]([CH3:34])[N:30]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: Cc1noc(-c2ccc(Cl)cc2C=O)n1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(Cl)cc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.2 %

Procedure:
To a mixture of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (25 mg, 0.10 mmol) and 5-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)-benzaldehyde (27 mg, 0.12 mmol) in DMF (5.0 mL) is added oxone (60 mg, 0.10 mmol) in H2O (2.0 mL). The reaction mixture is stirred at room temperature for 1.5 hours and then quenched with saturated sodium thiosulfate aq. (25 mL). The quenched reaction mixture is extracted with EtOAc (25 mL×2) and the combined organic layers are washed with H2O (50 mL×2) and dried with Na2SO4. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel flash column chromatography with 5% MeOH in CH2Cl2 as the eluent to afford the title compound (30 mg, 45%) as a white solid. LCMS (ESMS): m/z 460.20 (M++1)
Reaction SMILES: CC1C=CC(C(C)C)=CC=1.[S].[CH3:12][CH:13]1[CH2:22][C:21]2[N:20]([CH:23]([CH3:25])[CH3:24])[C:19](=[O:26])[N:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:16]=2[CH2:15][CH2:14]1>>[CH3:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:18][C:19](=[O:26])[N:20]2[CH:23]([CH3:25])[CH3:24])=[CH:15][CH:14]=1
Reactant: CC1CCc2c(-c3ccccc3)nc(=O)n(C(C)C)c2C1
Agent: [S]
Solvent: Cc1ccc(C(C)C)cc1
Product: Cc1ccc2c(-c3ccccc3)nc(=O)n(C(C)C)c2c1
Temperature: 175 °C
Reaction time: 0.67 h

Procedure:
A mixture of 200 ml. of p-cymene, 40 g. of ferric oxide and 7 g. of sulfur is heated to reflux (ca. 175° C.), and there is then added thereto dropwise over a period of 40 minutes a hot (130° C.) solution of 28.2 g. of 7-methyl-1-isopropyl-4-phenyl-5,6,7,8-tetrahydro-2(1H)-quinazolinone in 200 mls. of p-cymene. The resulting solution is refluxed for 3.5 hours during which time 1.8 mls. of water are collected in a Dean Stark separator. The reaction solution is then cooled to 28° C. and filtered through a celite pad which is then washed 4 times each with 25 mls. of toluene. The toluene washings are extracted with 50 mls. of 4 N. hydrochloric acid and the p-cymene filtrate is extracted with 350 mls. of 4 N. hydrochloric acid. The acid extracts are combined and extracted with 100 mls. of toluene, and such toluene extracts discarded. The acid solution remaining after such toluene extraction is treated by addition of 350 mls. of toluene and 100 g. of 50% aqueous sodium hydroxide solution. The phases are separated and the toluene phase washed twice each with 100 mls. of water, followed by drying over sodium sulfate, filtering and evaporation in vacuo. The solid residue is crystallized from ethyl acetate to obtain 7-methyl-1-isopropyl-4-phenyl-quinazolin-2(1H)-one, m.p. 139°-141° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[F:11].[CH3:12][S:13]([C:16]1[CH:42]=[CH:41][C:19]([CH2:20][NH:21][C:22]([C:24]2[C:29](=[O:30])[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]([F:39])[F:38])[CH:32]=3)=[C:27]([CH3:40])[NH:26][CH:25]=2)=[O:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[CH3:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][C:22]([C:24]2[C:29](=[O:30])[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]([F:38])[F:39])[CH:32]=3)=[C:27]([CH3:40])[N:26]([CH2:2][C:3]3[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=3[F:11])[CH:25]=2)=[O:23])=[CH:41][CH:42]=1)(=[O:15])=[O:14]
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: Cc1[nH]cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)c1-c1cccc(C(F)F)c1
Product: Cc1c(-c2cccc(C(F)F)c2)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cn1Cc1ccc(C#N)cc1F

Procedure:
Example 41 is prepared as described for example 2.1, substituting benzyl bromide with 4-bromomethyl-3-fluoro-benzonitrile and substituting preparation 5 with preparation 39a. ESI mass spectrum: [M+H]+=580; Retention time HPLC: 1.02 min (Z018_S04).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23][NH2:24].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CC(C)=O.O.CC(C)=O.O>[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23][NH:24][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:3]=1[N:2]([CH3:1])[CH3:15]
Reactant: COC(CN)OC
Reactant: CN(C)c1ccc([N+](=O)[O-])cc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: COC(CNC(=O)c1cc([N+](=O)[O-])ccc1N(C)C)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-dimethylamino-5-nitro benzoic acid (300 mg, 1.42 mmol) and thionyl chloride (0.41 ml 5.7 mmol) in dry chloroform (5 ml) was heated to reflux for 3 hr. The excess thionyl chloride was evaporated to give a residue, which was then dissolved in acetone (2 ml). This was then added drop-wise to a mixture of 2,2-dimethoxy-ethylamine (0.15 ml, 1.44 mmol) and sodium bicarbonate (120 mg, 1.44 mmol) in 2:1 acetone-water (12 ml) at 0° C. and stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and then brine, dried and concentrated to yield of N-(2,2-dimethoxyethyl)-2-dimethylamino-5-nitro benzamide (313 mg, 79%) as solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[C:16]2[N:15]=[CH:14][N:13]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]=2[C:11](=[O:36])[NH:10][C:9]1=[O:37].[Cl:38][C:39]1[CH:49]=[CH:48][C:42]([CH2:43][O:44][CH2:45][CH2:46]Cl)=[CH:41][CH:40]=1.O>CN1CCCC1=O>[Cl:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:43][O:44][CH2:45][CH2:46][N:10]2[C:11](=[O:36])[C:12]3[N:13]([C:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:14]=[N:15][C:16]=3[N:8]([CH3:7])[C:9]2=[O:37])=[CH:48][CH:49]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClCCOCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cn1c(=O)n(CCOCc2ccc(Cl)cc2)c(=O)c2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
1.3 g (9.44 mmol) of potassium carbonate were added at 60° C. to a solution of 2.4 g (5.9 mmol) of 3-methyl-7-tritylxanthine (prepared according to Example 17a) in 50 ml of N-methylpyrrolidone and the mixture was stirred at this temperature for one hour. 1.57 g (7.67 mmol) of 2-(4-chlorobenzyloxy)ethyl chloride were then added dropwise and the mixture was stirred at 80° C. for one hour. A further 1.0 g (4.9 mmol) of 2-(4-chlorobenzyloxy)ethyl chloride was then added and the mixture was stirred again for one hour. 50 ml of water were then added, the mixture was extracted three times using 60 ml of methyl tert-butyl ether each time, and the combined organic phases were washed twice with 30 ml of water each time, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, heptane/ethyl acetate (3/2).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:15]([OH:17])=O)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:6]=1.C1C=[CH:20][C:21]2N(O)N=[N:24][C:22]=2C=1.Cl.CN(C)CCCN=C=NCC.C(N)C=C>ClCCl.O>[CH2:22]([NH:24][C:15]([C:4]1[S:3][C:2]([Br:1])=[N:6][C:5]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=[O:17])[CH:21]=[CH2:20]
Reactant: O=C(O)c1sc(Br)nc1-c1ccc(Cl)cc1Cl
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C=CCN
Solvent: ClCCl
Product: C=CCNC(=O)c1sc(Br)nc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
To a solution of 2-Bromo-4-(2,4-dichlorophenyl)-1,3-thiazole-5-carboxylic acid (3.42 g, 9.69 mmol) in dichloromethane (59 mL) was added HOBT.H2O (1.48 g, 9.69 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.97 g, 15.5 mmol) followed by 2-propen-1-amine (2.91 mL, 38.8 mmol) and the solution was stirred at room temperature for 16 hours. The solution was then diluted with water and the layers were separated. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (3.11 g, 82%). LCMS: (AA) ES+, 393. 1H NMR (400 MHz, d1-chloroform) δ: 7.57-7.56 (m, 1H), 7.46-7.39 (m, 2H), 5.75-5.65 (m, 1H), 5.43 (br s, 1H), 5.10-5.06 (m, 1H), 5.00-4.94 (m, 1H), 3.88-3.84 (m, 2H).
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([C:11](OC)(OC)[CH2:12][CH2:13][C:14]2(C2C=CC=CC=2OC)O)[CH2:9]1)C1C=CC=CC=1.C(N(CC)CC)C.FC(F)(F)C(O)=[O:40].[OH-].[Na+]>ClCCl>[C:9]1(=[O:40])[CH:10]2[CH:15]([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:16][NH:8]1
Reactant: COc1ccccc1C1(O)CCC(OC)(OC)C2CN(Cc3ccccc3)CC21
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1NCC2CCCCC12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7 g of (3aRS,4RS,7aSR)-2-benzyl-7,7-dimethoxy -4-(2-methoxyphenyl)-4-perhydroisoindolol in 70 cm3 of dry dichloromethane are added 6.5 cm3 of triethylamine and 6.5 cm3 of trifluoroacetic acid. After stirring for 3 hours at room temperature, the reaction mixture, cooled to +5° C., is basified with 50 cm3 of 1N sodium hydroxide. The organic phase is separated out, washed with water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is crystallized in diisopropyl ether. The solid, washed with petroleum ether, is then drained and dried under reduced pressure at 40° C. 3.4 g of (3aRS,7RS,7aSR)-2-benzyl-7-hydroxy -7-(2-methoxyphenyl)-4)-perhydroisoindolone are obtained, in the form of a cream-coloured solid. M.p.=96C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7](=[O:9])[CH3:8].[Li+].[BH4-]>C1COCC1>[CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[CH:7]([OH:9])[CH3:8]
Reactant: CC(=O)c1cc(-c2ccccc2)sc1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1sc(-c2ccccc2)cc1C(C)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(2-Methyl-5-phenyl-thiophen-3-yl)-ethanone (1.08 g, 5.0.0 mmole) in THF (20 mL), is added to LiBH4 (0.327 g, 15.0 mmole) in one portion at 0° C. The reaction is kept at 0° C. for 30 minutes and warmed up to room temperature for 2 hours. The reaction is quenched using NH4Cl(aq) (50 mL) at 0° C. The THF is removed on rota vapor, the aqueous solution is then extracted with ethyl acetate (3×50 mL). The combined organic solution is dried over Na2SO4 and concentrated to provide the titled compound as white solid, which is used for the next step without further purification.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][S:16]([O-:19])(=[O:18])=[O:17].[Na+]>O>[S:16]([CH2:15][CH2:14][N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)([OH:19])(=[O:18])=[O:17]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=S(=O)([O-])CCBr
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)CCN1CCN(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
A 3.25 g quantity (20 mmols) of 1-phenylpiperazine is dissolved in 10 ml of water, and a solution of 4.3 g (20 mmols) of sodium 2-bromoethanesulfonate in 10 ml of water is added dropwise thereto at room temperature with stirring. The mixture is subjected to reaction at room temperature for 1 hour and then at 70° C. overnight, and cooled. The crystals precipitated are collected by filtration and recrystallized from water-acetone.
Reaction SMILES: [N:1]1([CH2:7][C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([NH:20][C:21](=[O:42])[CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)(=[O:31])=[O:30])[CH2:15][CH2:14][CH2:13]3)=[CH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCO>[CH3:9][C@@H:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C@H:16]([NH:20][C:21](=[O:42])[CH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:40])([F:41])[F:39])[CH:33]=1)(=[O:31])=[O:30])[CH2:15][CH2:14][CH2:13]2)[CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C(CN1CCCCC1)c1ccc2c(c1)CCCC2NC(=O)CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Solvent: CCO
Product: C[C@H](CN1CCCCC1)c1ccc2c(c1)CCC[C@H]2NC(=O)C[C@@H]1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
A mixture of N-[6-(1-piperidin-1-ylmethyl-vinyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[1-(3-trifluoromethyl-benzenesulfonyl)-piperidin-2-yl]-acetamide (34 mg, 0.05 mmol), EtOH (2 mL), Pd/Al2O3 (Johnson Matthey, 12 mg, 0.1 eq) was purged with H2 and connected to a H2 balloon for 30 min at RT. The catalyst was filtered through Celite and washed with MeOH. The filtrate was concentrated in vacuo. The crude was purified by silica gel chromatography (7%–10% MeOH—CH2Cl2) to afford the title compound as a mixture of two diastereomers. MS (ESI): 606 (M+H)+. Calc'd for C32H42F3N3O3S—605.29.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)C(O)=O)C.[OH-].[K+].Cl>O.C(O)C>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:5][C:4]([OH:21])=[O:3])=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(CCCCCc1ccc(Cl)cc1)C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCCCc1ccc(Cl)cc1

Procedure:
80 g of 5-(4-chlorophenyl)pentylmalonic acid ethyl ester are boiled under reflux with 45 g of potassium hydroxide in 230 ml of water and 100 ml of ethanol for 5 hours; after cooling, the mixture is adjusted to pH 1-2 with concentrated hydrochloric acid and is extracted 3 times with diethyl ether. The combined organic solutions are concentrated and the residue [5-(4-chlorophenyl)pentylmalonic acid] is heated to 160° for 3.5 hours. The residue consists of 51 g of 7-(4-chlorophenyl)heptanoic acid of m.p. 75° to 78°.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.[OH-].[Na+]>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH:6][S:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=1)(=[O:26])=[O:25]
Reactant: COC(=O)[C@H](C)N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](C)NS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C

Procedure:
Alanine methyl ester hydrochloride (7.0 g, 50.0 mmol) is dissolved in methylene chloride (100.0 mL) and triethylamine (20.0 mL, 143.0 mmol). To this solution is added 4-methoxybenzenesulfonyl chloride (10.3 g, 50.0 mmol), and the reaction is stirred at room temperature briefly. The reaction is made basic with 1N sodium hydroxide, and washed with methylene chloride. The combined organic layers are dried (Na2SO4), and the solvent is evaporated. Hexane is added to the residue and the precipitate is collected to give N-[4-methoxybenzenesulfonyl]-alanine methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[O:8])=[CH:5][CH:4]=1.B.[Na].O.Cl.[CH2:24](O)[CH3:25]>>[CH2:24]([O:8][CH:7]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=1)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH3:25]
Reactant: CCOC(=O)CCCCC(=O)c1ccc(OC)cc1
Reactant: CCO
Agent: B
Agent: Cl
Agent: [Na]
Solvent: O
Product: CCOC(CCCCC(=O)O)c1ccc(OC)cc1
Reaction time: 1 h

Procedure:
A solution of ethyl 5-(4-methoxybenzoyl)pentanoate (50 g, 0.19 mole) in ethanol (500 ml) was cooled with ice, and sodium boron hydride (10 g) was added gradually to the solution. After the reaction was allowed to proceed for 1 hour, water (200 ml) and 2N hydrochloric acid (50 ml) were added to the reaction solution, followed by concentration under reduced pressure. The resulting residue was dissolved in ethyl acetate, and the organic layer was washed with water, dried and concentrated under reduced pressure. Methanol (300 ml), water (100 ml) and sodium hydroxide (40 g) were added to the resulting residue, followed by stirring for 2 hours, and the methanol was removed under reduced pressure. The water layer was washed with isopropyl ether and then adjusted to pH 4.0 with hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure, and the residue was chromatographed on a silica gel column, followed by elution with isopropyl ether-ethyl acetate (1:1) to give firstly 6-ethoxy-6-(4-methoxyphenyl)hexanoic acid (21 g) and then 6-hydroxy-6-(4-methoxyphenyl)hexanoic acid (20 g).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[S:23][C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:25][C:5]=2[C:4](=[O:31])[NH:3]1.Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[F:43])=[O:35].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[F:43][C:37]1[CH:38]=[C:39]([F:42])[CH:40]=[CH:41][C:36]=1[C:34](=[O:35])[CH2:33][N:3]1[C:4](=[O:31])[C:5]2[CH:25]=[C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])[S:23][C:6]=2[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[C:2]1=[O:1]
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(=O)[nH]c(=O)c3cc(CC(F)(F)F)sc32)cc1
Reactant: O=C(CBr)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CC(=O)c3ccc(F)cc3F)c(=O)c3cc(CC(F)(F)F)sc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a mixture of 4′-{[2,4-dioxo-6-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (1.5 g), 2-bromo-1-(2,4-difluorophenyl)ethanone (0.88 g) and N,N-dimethylformamide (30 mL) was added 60% sodium hydride (0.16 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.98 g, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:25])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH:5]=[CH:6][C:7]=1[CH2:8]Cl.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:25])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[Cl:24])[CH:5]=[CH:6][C:7]=1[CH2:8][N:28]([CH2:29][CH3:30])[CH2:26][CH3:27]
Reactant: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(CCl)c(Cl)c1
Reactant: CCNCC
Product: CCN(CC)Cc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl

Procedure:
Prepared analogously to Example 170 starting from N-(3-chloro-4-chloromethyl-phenyl)-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z32b) and diethylamine. The crude product was recrystallised from petroleum ether.