Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]([O-])(=O)(=O)=O.[C:6]([CH2:8][CH2:9][CH:10]1[C:19]2[C:18]3[NH:20][C:21]4[C:26]([C:17]=3[CH2:16][CH2:15][N+:14]=2[CH2:13][CH2:12][CH2:11]1)=[CH:25][CH:24]=[CH:23][CH:22]=4)#[N:7]>CO.[Pd]>[ClH:1].[C:6]([CH2:8][CH2:9][CH:10]1[CH:19]2[N:14]([CH2:15][CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][C:18]=32)[CH2:13][CH2:12][CH2:11]1)#[N:7]
Reactant: [O-][Cl+3]([O-])([O-])[O-]
Reactant: N#CCCC1CCC[N+]2=C1c1[nH]c3ccccc3c1CC2
Agent: [Pd]
Solvent: CO
Product: Cl
Product: N#CCCC1CCCN2CCc3c([nH]c4ccccc34)C12

Procedure:
2.50 g (6.6) mmoles) of the product of Example 8 are hydrogenated in 120 ml of methanol in the presence of 2.0 g of palladium-on-charcoal. After the uptake of the calculated amount of hydrogen (about 25 minutes) the catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is admixed with 30 ml of water, the mixture is rendered alkaline with aqueous sodium carbonate solution, and extracted with dichloromethane. The dichloromethane solutions are combined, dried, filtered, and the filtrate is evaporated. The oily residue is dissolved in 10 ml of methanol, and the solution is acidified to pH 6 with methanolic hydrochloric acid. The separated substance is filtered off, washed with ether and dried.
Reaction SMILES: [CH:1](=[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:18]1([C:29](=[O:30])[C:28]2[N:27]([CH2:31][C:32]([OH:34])=[O:33])[CH:26]=[N:25][C:24]=2[N:22]([CH3:23])[C:20]1=[O:21])[CH3:19]>C(O)CC>[CH:1](=[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][NH2+:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[N:18]1([C:29](=[O:30])[C:28]2[N:27]([CH2:31][C:32]([O-:34])=[O:33])[CH:26]=[N:25][C:24]=2[N:22]([CH3:23])[C:20]1=[O:21])[CH3:19]
Reactant: C(=C1NCCc2ccccc21)c1ccccc1
Reactant: Cn1c(=O)c2c(ncn2CC(=O)O)n(C)c1=O
Solvent: CCCO
Product: C(=C1[NH2+]CCc2ccccc21)c1ccccc1
Product: Cn1c(=O)c2c(ncn2CC(=O)[O-])n(C)c1=O
Yield: 48 %

Procedure:
2.21 g. (0.01 mole) of 1-benzal-1,2,3,4-tetrahydroisoquinoline and 2.38 g. (0.01 mole) of theophylline-7-acetic acid are dissolved under boiling in 25 ml. of n-propanol. The undissolved substances is filtered from the hot solution. The clear filtrate is crystallized while the mixture is cooled. The precipitated crystals are filtered out, covered with n-propanol and dried at room temperature. Thus 2.2 g. of 1-benzal-1,2,3,4-tetrahydroisoquinolinium-theophylline-7-acetate yield 48%) are obtained. Mp.: 168°-173° C. After recrystallization from a twofold amount of n-propanol the melting point was 195°-198° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.[I:25]I>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[C:5]([I:25])=[CH:4][CH:3]=1
Reactant: II
Reactant: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)C(=O)Nc1nc(Cl)ccc1I
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.5 %

Procedure:
To a solution of N-(6-chloropyridin-2-yl)pivalamide (15.8 g, 74.2 mmol) in anhydrous THF (150 mL) at −78° C. under a nitrogen atmosphere, is added 1.7 M t-butyllithium in pentane (96 mL, 163 mmol, 2.2 eq.) dropwise (dropping funnel) over 0.5 h. The reaction mixture is then stirred at −78° C. for 3 h before iodine (22.6 g, 89 mmol, 1.2 eq.) in THF (60 mL) is slowly added in one portion. After 10 min., the cooling bath is removed and the reaction is allowed to warm to rt and stirred for 2 h. Hydrochloric acid (1 M, 75 mL) is then added to the reaction mixture. The reaction mixture is concentrated in vacuo (rotary evaporator) to remove the THF, the resulting mixture is extracted with ethyl acetate (800 mL). The phases are separated and the organic layer is washed with aqueous 1 M Na2S2O3 (100 mL), brine (300 mL×2), water (300 mL), dried over MgSO4, and evaporated. The crude product is recrystallized from DCM/hexanes (1:4) and the solid that forms collected by filtration to provide N-(6-chloro-3-iodopyridin-2-yl)pivalamide as a white crystalline solid (17.2 g). The filtrate is evaporated and the residue chromatographed on a silica gel column (hexanes/EtOAc, 9/1) to provide an additional product (2.5 g). Overall 19.7 g (78% yield) of N-(6-chloro-3-iodopyridin-2-yl)pivalamide is obtained. 1H NMR (300 MHz, DMSO-d6), δ 9.86 (s, 1H), 8.30 (d, J=8.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 1.23 (s, 9H). LCMS-ESI (m/z): calcd for C10H12Cl1N2O 337.9; [M+H]+ found 339.0.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([CH2:14][N:15]([CH3:35])[CH2:16][CH2:17][C:18](N1CCC3C=C(OC)C(OC)=CC=3CC1)=[O:19])[CH2:7]2.[CH3:36][O:37][C:38]1[CH:39]=[C:40]2[C:43](=[CH:44][C:45]=1[O:46][CH3:47])[CH:42]([CH2:48][NH:49][CH3:50])[CH2:41]2.[CH3:51]OC1C=C2C(=CC=1OC)CC(CNC)C2>>[ClH:1].[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:6](=[CH:5][C:4]=1[O:3][CH3:2])[CH2:7][CH:8]([CH2:14][N:15]([CH3:35])[CH2:16][CH2:17][C:18]([N:49]1[CH2:50][CH2:41][C:40]3[CH:39]=[C:38]([O:37][CH3:36])[C:45]([O:46][CH3:47])=[CH:44][C:43]=3[CH2:42][CH2:48]1)=[O:19])[CH2:51]2
Reactant: COc1cc2c(cc1OC)CCN(C(=O)CCN(C)CC1Cc3cc(OC)c(OC)cc31)CC2
Reactant: CNCC1Cc2cc(OC)c(OC)cc21
Reactant: CNCC1Cc2cc(OC)c(OC)cc2C1
Agent: Cl
Product: COc1cc2c(cc1OC)CCN(C(=O)CCN(C)CC1Cc3cc(OC)c(OC)cc3C1)CC2

Procedure:
Obtained in the same manner as the product of Example 1, but with replacement of the [(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl]methylamine in Step 4 by [(5,6-dimethoxy-2,3-dihydro-1H-inden-2-yl)methyl]methylamine.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]1([C:14]2([CH2:24][NH:25][CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=3)[CH2:23][CH2:22][C:17]3([O:21][CH2:20][CH2:19][O:18]3)[CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[C:8]1([C:14]2([CH2:24][N:25]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[C:29]([C:37]([F:39])([F:40])[F:38])[CH:28]=3)[C:1](=[O:3])[CH3:2])[CH2:23][CH2:22][C:17]3([O:21][CH2:20][CH2:19][O:18]3)[CH2:16][CH2:15]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: FC(F)(F)c1cc(CNCC2(c3ccccc3)CCC3(CC2)OCCO3)cc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC1(c2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Acetic anhydride (2 mL) was added to a solution of N-[(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)methyl]-3,5-bis(trifluoromethyl)benzenemethanamine (Example 19, 291 mg, 0.61 mmol) in pyridine (5 mL) and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (25 mL). The mixture was washed with aqueous copper sulphate (5%, 2×25 mL) and brine (25 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (316 mg, 100%). m/z (ES+) 516 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Yield: 98 %

Procedure:
In this synthesis the new (4-amino or substituted amino-3-hydroxyphenyl)-alkylnitriles of Formula (1), of this invention, where R2 is H, can be prepared by reaction of a 3-hydroxy-4-nitrobenzaldehyde of Formula (2) with a benzyl halide, such as benzyl bromide, in the presence of an inorganic base such as potassium carbonate in dimethylformamide (DMF) at room temperature for about 18 hours to produce the 3-benzyloxy-4-nitro-benzaldehyde compound of Formula (3) in about 98% yield; then reacting the compound of Formula (3) with diethyl cyanoalkylphosphonate of Formula (4) in a suspension of sodium hydride in anhydrous THF at room temperature for about 2 hours to produce 3-(3-benzyloxy-4-nitro-phenyl)-acrylonitrile of Formula (5) in about 100% yield; catalytically hydrogenating the compound of Formula (5) with 10% Pd on carbon at about 60 psi hydrogen at room temperature for about 4 hours to provide a compound of Formula (1) where R2 is H in about 100% yield.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:12]1)#N.S(=O)(=O)(O)[OH:29].[OH2:33]>>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:12]1)([OH:29])=[O:33]
Reactant: O=S(=O)(O)O
Reactant: O
Reactant: N#CCCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)n1
Product: O=C(O)CCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)n1
Yield: 75 %

Procedure:
2-(8-Cyanooctyl)-4,5-diphenyltriazole (3.0 g) was treated with sulphuric acid (50 ml) and water (50 ml) and the mixture heated at reflux temperature for 4 hours. Water (200 ml) was added and the cooled mixture was extracted with ethyl acetate (3×75 ml), and the organic extracts combined and evaporated to give a solid. Recrystallisation from ethanol and water gave 2-(8-carboxyoctyl)-4,5-diphenyltriazole (2.37 g, 75%) as a white solid m.p. 84-85° C. Found: C, 72.92; H, 7.20; N, 11.07%;
Reaction SMILES: BrC1C=C(C(C)(C)CC2(C(F)(F)F)COC(C)(C)O2)C2OCCC=2C=1.C[N:27](C)[S:28]([C:31]1[CH:32]=[C:33]([C:40]([CH3:51])([CH3:50])[CH2:41][C:42]([OH:49])([CH2:47][OH:48])[C:43]([F:46])([F:45])[F:44])[C:34]2[O:38][CH2:37][CH2:36][C:35]=2[CH:39]=1)(=[O:30])=[O:29]>>[F:46][C:43]([F:44])([F:45])[C:42]([OH:49])([CH2:47][OH:48])[CH2:41][C:40]([C:33]1[C:34]2[O:38][CH2:37][CH2:36][C:35]=2[CH:39]=[C:31]([S:28]([NH2:27])(=[O:30])=[O:29])[CH:32]=1)([CH3:51])[CH3:50]
Reactant: CN(C)S(=O)(=O)c1cc2c(c(C(C)(C)CC(O)(CO)C(F)(F)F)c1)OCC2
Agent: CC1(C)OCC(CC(C)(C)c2cc(Br)cc3c2OCC3)(C(F)(F)F)O1
Product: CC(C)(CC(O)(CO)C(F)(F)F)c1cc(S(N)(=O)=O)cc2c1OCC2

Procedure:
7-(4,4,4-Trifluoro-3-hydroxy-3-hydroxymethyl-1,1-dimethylbutyl)-2,3-dihydrobenzofuran-5-sulfonic acid amide was prepared from 5-bromo-7-[2-(2,2-dimethyl-4-trifluoromethyl-[1,3]dioxolan-4-yl)-1,1-dimethylethyl]-2,3-dihydrobenzofuran in the same manner as in the preparation of 7-(4,4,4-trifluoro-3-hydroxy-3-hydroxymethyl-1,1-dimethylbutyl)-2,3-dihydrobenzofuran-5-sulfonic acid dimethylamide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:14]2[CH:15]=[C:16]([CH2:24][CH3:25])[C:17]3[O:21][CH:20]=[C:19]([CH3:22])[C:18]=3[CH:23]=2)[C:11](O)=[O:12])=[CH:5][CH:4]=1)#[N:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[S:38]([NH2:42])([NH2:41])(=[O:40])=[O:39].CCCCCCC=CCCC>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]([C:14]2[CH:15]=[C:16]([CH2:24][CH3:25])[C:17]3[O:21][CH:20]=[C:19]([CH3:22])[C:18]=3[CH:23]=2)[C:11]([NH:41][S:38]([NH2:42])(=[O:40])=[O:39])=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: NS(N)(=O)=O
Reactant: CCc1cc(C(Nc2ccc(C#N)cc2)C(=O)O)cc2c(C)coc12
Agent: CCCC=CCCCCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCc1cc(C(Nc2ccc(C#N)cc2)C(=O)NS(N)(=O)=O)cc2c(C)coc12
Reaction time: 1 h
Yield: 69.5 %

Procedure:
2-(4-Cyanophenylamino)-2-(7-ethyl-3-methylbenzofuran-5-yl)acetic acid 6 (5.45 g, 16.4 mmoles), carbonyldiimidazole (CDI, 5.28 g 32.6 mmoles) were combined under a nitrogen atmosphere and THF (50 ml) added. The reaction was stirred for 1 h. Sulfamide (4.7 g, 49 mmoles) was added to the reaction followed by drop wise addition of 1,8-diazabiocyclo[5.4.0]undec-7-ene (DBU, 7.3 ml, 49 mmoles). The reaction was then stirred an additional 2 hours at room temperature and the solvent removed in vacuo. The residue was taken up in ethyl acetate (ca. 150 ml) and washed with aqueous 2 N HCl. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to a yellow foam. The crude product was then purified on a silica flash column eluted with 40% ethyl acetate/60% hexane to provide 2-(4-cyanophenylamino)-2-(7-ethyl-3-methylbenzofuran-5-yl)acetylsulfamide 7 (4.7 g).
Reaction SMILES: C[C:2]1[C:3](Cl)=[C:4]([Cl:20])C(C(O)=O)=[N:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1.[N-:22]=[N+]=[N-].[Na+].[BH4-].[Na+].[C:28]([O:31][CH2:32]C)(=[O:30])[CH3:29]>CN(C=O)C.O>[NH2:22][C:3]1[CH:2]=[C:7]([O:8][C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=2)[N:6]=[C:29]([C:28]([O:31][CH3:32])=[O:30])[C:4]=1[Cl:20]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(Oc2cc(Cl)cc(Cl)c2)nc(C(=O)O)c(Cl)c1Cl
Reactant: CCOC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Oc2cc(Cl)cc(Cl)c2)cc(N)c1Cl
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Methyl 3,4-dichloro-6-(3,5-dichlorophenoxy)pyridine-2-carboxylic acid (1.93 g, 5.26 mmol) was dissolved in a minimum amount of DMF and to it was carefully added NaN3 (0.444 g, 6.84 mmol) and water to form a homogeneous mixture which was heated to 70° C. and stirred overnight. The reaction mixture was poured into a water-ice mixture and the product was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with pet ether/water (200 mL), dried (MgSO4) and concentrated to dryness in vacuo. The resulting oil was dissolved in methanol and to it was added NaBH4 (0.200 g, 5.26 mmol) and stirred at RT for 1.5 hr. Ethyl acetate and water was added and the aqueous phase was extracted with ethyl acetate (2×100 mL). The combined extracts were dried (MgSO4) and concentrated to dryness. Purification by column chromatography (silica gel) using an eluent of 20% diethyl ether/hexane-50% diethyl ether/hexane to give 0.900 g of clear solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5]P(CC(OCC)=O)(OCC)=O)[CH3:4].[O:17]=[C:18]1[C:24]2[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=2[N:22]([C:30](=[O:48])[C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:46])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH3:45])=[CH:33][C:32]=2[CH3:47])[CH2:21][CH2:20][CH2:19]1.O1CC[CH2:51][CH2:50]1>>[CH2:50]([O:17][CH:18]1[C:24]2[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=2[N:22]([C:30](=[O:48])[C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:46])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH3:45])=[CH:33][C:32]=2[CH3:47])[C:21](=[C:4]=[C:3]=[O:5])[CH2:20][CH2:19]1)[CH3:51]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)c(C)c1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCOC1CCC(=C=C=O)N(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2C)c2ccc(Cl)cc21
Temperature: 0 °C

Procedure:
0.85 g of 60% sodium hydride was added to 200 ml of tetrahydrofuran. Thereto was dropwise added 4.68 ml of ethyl diethylphosphonoacetate with ice-cooling and stirring. The mixture was stirred for 10 minutes with ice-cooling. To the reaction mixture was added 2.10 g of 5-oxo-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)-benzoyl]-2,3,4,5-tetra-hydro-1H-benzoazepine. The mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into 200 ml of ice water. The resulting mixture was subjected to extraction with 300 ml of ethyl acetate. The extract was washed with 300 ml of an aqueous sodium chloride solution, then dried over magnesium sulfate, and subjected to distillation to remove the solvent. The residue was purified by silica gel column chromatography (elutant: ethyl acetate/n-hexane =1/2) to obtain 2.22 g of 5-ethoxy-carbonylmethylidene-7-chloro-1-[2-methyl-4-(2-methylbenzoyl-amino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine as a mixture of the E form and the Z form.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:19]O>[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([O:10][CH3:19])=[O:9])=[CH:13][CH:14]=1
Reactant: CO
Reactant: CC(C)(Oc1ccc(Br)cc1)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)C(C)(C)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
2-(4-Bromophenoxy)-2-methylpropionic acid (1 g) was dissolved in methanol (5 mL), a catalytic amount of thionyl chloride was added, and the mixture was stirred at room temperature for 7 hrs. Saturated brine was added to the reaction mixture, and the mixture was extracted with a mixed solvent of chloroform-methanol. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (920 mg) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:9]3[CH:10]=[C:11]([C:15]#[N:16])[CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]=1.[CH3:25][Si:26]([CH3:33])([CH3:32])[CH2:27][CH2:28][O:29][CH2:30]Cl>CN(C=O)C.C(N(CC)C(C)C)(C)C>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:9]3[CH:10]=[C:11]([C:15]#[N:16])[CH:12]=[CH:13][C:14]=3[C:5]=2[N:4]([CH2:30][O:29][CH2:28][CH2:27][Si:26]([CH3:33])([CH3:32])[CH3:25])[N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: N#Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(Br)n[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(Br)c2nc(-c3c(F)cccc3F)c3cc(C#N)ccc3c21
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A 250 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 3.3 g of 3-bromo-5-(2,6-difluorophenyl)-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile in 85 ml of DMF, 10.6 ml of N,N-diisopropylethylamine and 3.2 ml of 2-(trimethylsilyl)ethoxymethyl chloride. After 5 h at RT, the mixture is poured into 8 volumes of ice-water. The aqueous phase is extracted with 3 times 200 ml of AcOEt, and the organic extracts are combined, washed with saturated NaCl solution, dried over MgSO4 and concentrated under RP. Purification is carried out by flash chromatography on silica gel (40-63 μm), eluting with a mixture of DCM and methanol (99.5/0.5 by vol.), to give on one hand 2.1 g of 3-bromo-5-(2,6-difluorophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile in the form of a white solid. MS (E/I): m/z=515 (M+); 1H NMR: −0.12 (s, 9H); 0.87 (t, J=8.0 Hz, 2H); 3.65 (t, J=8.0 Hz, 2H); 6.17 (s, 2H); 7.40 (t, J=8.0 Hz, 2H); 7.77 (m, 1H); 8.41 (broad s, 1H); 8.47 (dd, J=1.5 and 8.5 Hz, 1H); 8.77 (d, J=8.5 Hz, 1H). And, on the other hand, 1.2 g of 3-bromo-5-(2,6-difluorophenyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile (white solid). MS (E/I): m/z=515 (M+); 1H NMR: −0.05 (s, 9H); 0.90 (t, J=8.0 Hz, 2H); 3.73 (t, J=8.0 Hz, 2H); 5.92 (s, 2H); 7.38 (t, J=8.0 Hz, 2H); 7.76 (m, 1H); 8.24 (broad s, 1H); 8.34 (dd, J=1.5 and 8.5 Hz, 1H); 8.69 (d, J=8.5 Hz, 1H).
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:18]=[CH:17][C:12]([NH:13][CH:14]([CH3:16])[CH3:15])=[CH:11][CH:10]=1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>N1C=CC=CC=1>[Cl:19][CH2:20][C:21]([N:13]([CH:14]([CH3:16])[CH3:15])[C:12]1[CH:17]=[CH:18][C:9]([F:8])=[CH:10][CH:11]=1)=[O:22]
Reactant: CC(C)Nc1ccc(F)cc1
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)N(C(=O)CCl)c1ccc(F)cc1
Yield: 97 %

Procedure:
To 100 ml dry toluene 15.3 g (0.1 m) 4-fluoro-N-isopropylaniline and 8.7 ml (0.11 m) pyridine were added and stirred. To this solution 12.4 g (0.11 m) chloroacetyl chloride was added dropwise below 25° C. It was allowed to stir overnight at room temperature and the mixture was washed with 2×100 ml water. The organic layer was dried on anhydrous magnesium sulfate and evaporated to give 22.2 g pale yellow liquid, yield 97%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:29](I)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(O)cc3)CC2)CC1
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc([C@H]2CC[C@H]([C@H]3CC[C@H](CCC)CC3)CC2)cc1

Procedure:
A mixture of 30 g of trans-1-p-hydroxyphenyl-4-(trans-4-propylcyclohexyl)-cyclohexane, 6.9 g of K2CO3, 25 g of hexyl iodide and 250 ml of DMF is heated to 80° for 16 hours, while stirring, and is then cooled and worked up in the customary manner. Trans-1-p-hexoxyphenyl-4-(trans-4-propylcyclohexyl)-cyclohexane is obtained.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[S:10]([C:13]1[S:17][C:16]([NH:18][C:19]([N:21]([CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[O:20])=[N:15][CH:14]=1)(=[O:12])=[O:11])=[O:4].C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(S(C)(=O)=O)=CC=2)CCCC1.COC([C@@H]1CCCN1S(C1SC(N)=NC=1)(=O)=O)=O>>[CH:33]1([CH2:32][N:21]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=2)[C:19](=[O:20])[NH:18][C:16]2[S:17][C:13]([S:10]([N:6]3[CH2:7][CH2:8][CH2:9][C@H:5]3[C:3]([OH:4])=[O:2])(=[O:12])=[O:11])=[CH:14][N:15]=2)[CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc(NC(=O)N(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1
Agent: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: CS(=O)(=O)c1ccc(NCC2CCCC2)cc1
Product: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2ncc(S(=O)(=O)N3CCC[C@H]3C(=O)O)s2)cc1

Procedure:
The title compound was prepared via (S)-1-{2-[3-cyclopentylmethyl-3-(4-methanesulfonylphenyl)-ureido]-thiazole-5-sulfonyl}-pyrrolidine-2-carboxylic acid methyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonylphenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-methanesulfonyl-phenyl)amine and (S)-1-(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([C:15]#N)[CH:9]=2)=[CH:4][CH:3]=1.O.[C:18](O)(=[O:20])[CH3:19].C([OH:24])C>[OH-].[K+]>[CH2:18]([O:20][C:15]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([CH3:14])[N:11]=1)=[O:24])[CH3:19]
Reactant: CC(=O)O
Reactant: Cc1cc(-c2ccc(F)cc2)cc(C#N)n1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)cc(C)n1
Temperature: 100 °C
Yield: 63 %

Procedure:
A suspension of 0.55 g (2.6 mmol) 4-(4-Fluoro-phenyl)-6-methyl-pyridine-2-carbonitrile in 11 ml of 25% potassium hydroxide solution was heated to 100° C. for 14 h. Water (5 ml) was added and the pH adjusted to 6 by addition of acetic acid, then 10 ml of ethanol was added and the mixture was evaporated to dryness. The crude material was suspended in 30 ml of ethanol. Concentrated sulfuric acid (2 ml) were added and the suspension was refluxed for 35 h. The solution was concentrated, taken up in 20 ml of water, neutralized (pH=7-8) by addition of 5% sodium bicarbonate solution, and extracted twice with 50 ml of ethyl acetate. The combined organic phases were washed with 20 ml of water, 20 ml of brine, dried over magnesium sulfate, and concentrated in vaccuo to yield 0.42 g (1.63 mmol, 63%) of a light yellow oil which is sufficiently pure for further use in the next step, MS (ISP): m/e=260.1 (M+H)+.