Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:15])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[CH:19][C:18]=1O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]([O:15][C:18]1[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:17]=1[Cl:16])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CCCCCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCCCC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Yield: 95.9 %

Procedure:
A solution of n-tridecanoic acid (Sigma Chemical Co.) (12.5 g), 2,4,5-trichlorophenol (11.5 g), and N,N'-dicyclohexylcarbodiimide (12.0 g) in methylene chloride (650 ml) is stirred at room temperature for 16 hours. The reaction mixture is then filtered and dried in vacuo to give 2,4,5-trichlorophenyl n-tridecanoate (22 g). The material is purified by column chromatography over silica gel (Woelm) using toluene as the eluent. Fractions are monitored by TLC using a shortwave UV light for detection. Fractions containing the purified product are pooled and concentrated in vacuo to dryness.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19]([C@H:21]([NH:24]C(=O)OC(C)(C)C)[CH2:22][CH3:23])=[O:20])=[CH:14][N:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:24][C@H:21]([CH2:22][CH3:23])[C:19]([NH:18][C:15]1[CH:14]=[N:13][C:12]([O:11][C:7]2[C:6]3[C:2]([CH3:1])([CH3:32])[CH2:3][O:4][C:5]=3[CH:10]=[CH:9][CH:8]=2)=[N:17][CH:16]=1)=[O:20]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cnc(Oc2cccc3c2C(C)(C)CO3)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](N)C(=O)Nc1cnc(Oc2cccc3c2C(C)(C)CO3)nc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88.1 %

Procedure:
To a solution of 1,1-dimethylethyl {(1R)-1-[({2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}amino)carbonyl]propyl}carbamate (Intermediate 66, 4.4 mg) in dichloromethane (1 ml) cooled to 0° C. TFA (0.019 ml, 0.249 mmol) was added dropwise. The mixture reaction was stirred at 0° C. for 1.5 hours. The solvent and the TFA were evaporated. The mixture was diluted with dichloromethane (5 ml) and neutralized with an aqueous saturated solution of NaHCO3 (5 ml). The organic layer was separated, dried over sodium sulphate, filtered end evaporated to afford the title compound (3 mg) which was directly used in the next step
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])=[N:3][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(F)cn1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(F)cn2)cc1
Temperature: 80 °C

Procedure:
2-Amino-5-fluoropyridine (4.0 g, 0.036 mol) was dissolved in pyridine (40 mL) and p-toluenesulfonyl chloride (7.5 g, 0.039 mol) was added. The reaction was heated at 80° C. for 24 hours then cooled and the pyridine was removed under vacuum. The residue was partioned between water (100 mL) and ethyl acetate (100 mL). The layers were separated and the organic layer was washed (3×100 mL) with water then dried and solvent stripped to give clean N-(5-fluoropyridin-2-yl)-4-methylbenzenesulfonamide 1 Rf 0.42, 50% E/H; MS m/z 267 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: Cc1ccc(N=C=O)cc1C(F)(F)F
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Product: Cc1ccc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4ncccc34)cc2)cc1C(F)(F)F

Procedure:
47.1 mg of solid white 3-{4-[3-(4-methyl-3-trifluoromethylphenyl)ureido]-phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 4-methyl-3-trifluoromethylphenyl isocyanate.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(=O)([O-])[O-].[Na+].[Na+].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>COCCOCCOC.O.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34]([CH2:2][C:3]2[N:4]=[C:5]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[S:6][C:7]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOCCOC
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1Cc1ccc(C(F)(F)F)cc1
Temperature: 110 °C
Yield: 31.1 %

Procedure:
To a solution of ethyl 4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate (0.25 g, 0.63 mmol) in 4 ml of 2-methoxyethyl ether was added tetrakis(triphenylphosphine)palladium(0), (0.02 g, 0.019 mmol) and then sodium carbonate (0.13 g, 1.2 mmol) in 0.5 ml water. After brief stirring, 4-(trifluoromethyl)phenyl boronic acid (0.13 g, 0.7 mmol) in 1 ml ethanol was added. After heating at 110° C. for 15 hours, the reaction was complete by HPLC and was treated with water (5 ml) and extracted with tert-butyl methyl ether (2×30 ml). The organic layers were dried with magnesium sulfate and immediately loaded onto silica to give a crude residue which was purified on a Biotage FlashElute with a 40M silica cartridge, eluting with 10% ethyl acetate in hexanes to yield ethyl 4-[4-(trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate as a white solid (0.09 g, 35%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13]CC(=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:18].[O:19]1[CH2:23][CH2:22][CH2:21]C1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:23](=[O:19])[C:22]([CH3:21])([CH3:18])[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CI
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (16 g, 80 mmol) in tetrahydrofuran (400 mL) at 0° C. was added sodium hydride (4.1 g, 2.1 equiv) in 4 portions. To this was added iodomethane (12.5 mL, 2.5 equiv) dropwise. The reaction was allowed to gradually warm to room temperature and stirred overnight. The reaction was concentrated, dissolved in diethyl ether, washed with brine, dried over magnesium sulfate, and concentrated. The product was crystallized from hot pentane (2×) to give 5.9 g (32%). 1H-NMR (CDCl3, 500 MHz) δ 1.09 (s, 6H), 1.47 (s, 9H), 2.47 (dd, J=6.4, 6.4, 2H), 3.41 (m, 2H), 3.70 (m, 2H). Mass spec.: 250.12 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[CH2:9](O)[CH2:10][OH:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1
Reactant: OCCO
Reactant: Cc1ccsc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccsc1C1OCCO1

Procedure:
A mixture of 3-methylthiophene carboxaldehyde (6.8 g), ethylene glycol (10 ml) and p-toluenesulfonic acid (0.30 g) in toluene (125 ml) was heated at reflux for 18 hours. The reaction mixture was cooled; extracted with 2M aqueous sodium carbonate and then dried with brine and over magnesium sulfate. Analysis of the crude product indicated that the reaction was incomplete so the crude material was re-subjected to the ketalisation conditions as outlined above. The crude material isolated after reprocessing was distilled under reduced pressure (1 mmHg) to give the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[O:6][CH2:7][CH2:8][N:9]1[CH2:17][CH2:16][CH:15]2[NH:18][CH:11]([CH2:12][CH2:13][CH2:14]2)[C:10]1=[O:19].CCN(C(C)C)C(C)C.[S:34]1[C:38]2[CH:39]=[C:40]([S:43](Cl)(=[O:45])=[O:44])[CH:41]=[CH:42][C:37]=2[N:36]=[CH:35]1>C(Cl)Cl>[S:34]1[C:38]2[CH:39]=[C:40]([S:43]([N:18]3[CH:15]4[CH2:14][CH2:13][CH2:12][CH:11]3[C:10](=[O:19])[N:9]([CH2:8][CH2:7][O:6][C:5]3[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:17][CH2:16]4)(=[O:44])=[O:45])[CH:41]=[CH:42][C:37]=2[N:36]=[CH:35]1
Reactant: COc1ccc(OCCN2CCC3CCCC(N3)C2=O)cc1OC
Reactant: O=S(=O)(Cl)c1ccc2ncsc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(OCCN2CCC3CCCC(C2=O)N3S(=O)(=O)c2ccc3ncsc3c2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(2-(3,4-Dimethoxyphenoxy)ethyl)-3,10-diazabicyclo[4.3.1]decan-2-one (24 mg, 0.07 mmol) in 3 ml DCM was treated with DIPEA (11 mg, 0.09 mmol) and stirred for 30 min at room temperature followed by addition of 1,3-benzothiazole-6-sulfonyl chloride (20 mg, 0.09 mmol). After stirring overnight at room temperature, the reaction was quenched with saturated NH4Cl solution (5 ml), extracted with DCM (4×10 ml). The organic layers were dried over MgSO4 and concentrated in vacuo. The mixture was purified with Preparative-TLC in 10% MeOH in CHCl3.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[C:4]([F:11])[CH:3]=1.[I:12]N1C(=O)CCC1=O.FC(F)(F)C(O)=O.OS([O-])=O.[Na+].[Na+].[Cl-]>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[C:4]([F:11])[C:3]=1[I:12]
Reactant: Fc1cc(F)c2c(c1)OCO2
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Fc1cc2c(c(F)c1I)OCO2
Reaction time: 20 h
Yield: 76 %

Procedure:
4,6-Difluorobenzo[d][1,3]dioxole (300 mg, 1.9 mmol) and N-iodosuccinimide (640 mg, 2.9 mmol) were combined in dry acetonitrile (5 mL), treated with trifluoroacetic acid (430 mg, 3.8 mmol) and stirred for 20 h. The mixture was stirred with a solution of NaHSO3 (100 mg in 2 mL water) and then shaken with ethyl acetate (30 mL) and saturated NaCl (5 mL). The organic phase was washed with saturated NaCl (5 mL), dried (Na2SO4) and evaporated. The material was purified by chromatography on silica with a 0-5% ethyl acetate-hexane gradient to give the title compound as a white solid (410 mg, 76%): mp 65-66° C. 1H NMR (400 MHz, CDCl3) δ 6.54 (dd, J=6.9, 1.6 Hz, 1H), 6.07 (s, 2H); 19F NMR (376 MHz, CDCl3) δ −99.31, −117.98; EIMS m/z 284.
Reaction SMILES: C([O:3][C:4](=[O:21])/[CH:5]=[CH:6]\[CH:7]=[C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.[OH-].[K+]>CO>[C:9]1([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7]/[CH:6]=[CH:5]\[C:4]([OH:21])=[O:3])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)/C=C\C=C(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C\C=C(c1ccccc1)c1ccccc1
Yield: 96.9 %

Procedure:
A solution of (Z)-5,5-diphenyl-2,4-pentadieneoic acid ethyl ester (3.5 g) in methanol (20 mL) was treated with a 4N potassium hydroxide solution (5 mL) and the mixture was stirred at reflux for 30 minutes. Most of the methanol was removed under reduced pressure, then the residual solution was poured over ice containing 3N hydrochloric acid (10 mL). The resulting solid was collected by filtration, washed with water, dried and crystallized from dichloromethane-hexane to furnish 3.05 g of (Z)-5,5-diphenyl-2,4-pentadienoic acid mp 175°-176.5° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH:9]([C:17]1([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]1=[O:30])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH:9]([C:17]1([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]1=[O:30])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CC1(C(CCO)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC1(C(CCOS(C)(=O)=O)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Reaction time: 2 h
Yield: 75.2 %

Procedure:
Methanesulfonyl chloride (0.29 mL, 3.7 mmol) is added to a solution of tert-butyl α-(2-hydroxyethyl)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (EXAMPLE 4, step 2; 1.36 g, 3.37 mmol), triethylamine (0.52 mL, 3.7 mmol) and CH2Cl2 (8 mL) at 0° C. The mixture is stirred for 2 hours, washed with saturated NaHCO3 (2×10 mL), water (10 mL), dried (MgSO4), filtered, and concentrated to give 1.22 g (75%) of the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[CH:22]=[CH:21][C:10]2[C@:11]3([CH3:20])[C@@H:16]([CH2:17][CH2:18][C:9]=2[CH:8]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3.[C:23](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:23][N:15]1[C@H:16]2[C@@:11]([CH3:20])([C:10]3[CH:21]=[CH:22][C:7]([C:6]4[CH:5]=[CH:4][S:3][C:2]=4[CH3:1])=[CH:8][C:9]=3[CH2:18][CH2:17]2)[CH2:12][CH2:13][C:14]1=[O:19]
Reactant: CC(C)(C)O
Reactant: Cc1sccc1-c1ccc2c(c1)CC[C@H]1NC(=O)CC[C@]21C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: Cc1sccc1-c1ccc2c(c1)CC[C@H]1N(C)C(=O)CC[C@]21C
Temperature: 25 °C
Reaction time: 4 h
Yield: 26 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(2-methylthiophenyl)-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (55 mg, 0.16 mmol), 0.4 mL of t-butanol, and potassium t-butoxide (55 mg, 0.48 mmol). Methyl iodide (0.031 mL, 0.48 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 15 mg (26%) of the title compound as an oil. FDMS: m/e=351.
Reaction SMILES: [OH:1][CH:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:44])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[OH:1][CH:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N+:31]=1[O-:44])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:7][CH:8]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)cc2)CCO3)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
To a solution of N-[4-[hydroxy(2-pyridyl)methyl]phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (351.3 mg) in tetrahydrofuran (20 ml) was added 3-chloroperbenzoic acid (70%, 0.28 g) at 0° C., and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added sodium thiosulfate solution, and the mixture was stirred for a few minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethanol-diethylether=1:1), and recrystallized from ethanol to give N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 167) (184 mg) as colorless crystals.
Reaction SMILES: [N:1]1([CH:7](O)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.OO>C1COCC1.C(OCC)C>[N:1]1([CH2:7][CH2:8][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(O)N1CCCCC1
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: OO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1ccc(OCCN2CCCCC2)cc1
Reaction time: 0.83 h
Yield: 34.3 %

Procedure:
A 1 L 3-neck round bottom flask was charged with anhydrous THF (200 mL), 1-piperidinylethanol (14.9 g, 15.27 mL, 0.115 mol), 4-hydroxybenzaldehyde (14.16 g, 0.116 mol), and triphenylphosphine (31,21 g, 0.119 mol) under a nitrogen atmosphere. The above mixture was stirred and diethylazodicarboxylate (DEAD; 22.6 g, 20.4 mL, 0.130 mol) in anhydrous THF (25 mL) was added dropwise over 15 min during which time the temperature was carefully monitored and not allowed to exceed 60° C. The reaction was stirred overnight at ambient temperature and then worked up by the addition of 10 mL 30% hydrogen peroxide and extraction of by ethyl ether. The organic layer was washed eight times with water, dried over anhydrous sodium sulfate, and concentrated to an oil. The oil was purified by chromatography over silica gel using a Waters LC2000 instrument. The elution solvent employed a gradient system beginning with 100% methylene chloride and ramping to 9:1 methylene chloride:methanol over 50 min at a flow rate of 150 mL/min. Concentration of appropriate fractions provided 9.2 g (35%) of the desired product as a pale brown oil.
Reaction SMILES: CC([O-])(C)C.[K+].Cl.[NH2:8][C@@H:9]([CH2:14][CH2:15][CH2:16]C)[C:10]([O:12][CH3:13])=[O:11].C(N(CC)CC)C.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]Br)=[CH:28][N:27]=1>COCCOC.CN(C=O)C>[Br:25][C:26]1[N:27]=[CH:28][C:29]([CH2:32][NH:8][C@H:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:14][CH2:15][CH3:16])=[CH:30][CH:31]=1
Reactant: BrCc1ccc(Br)nc1
Reactant: CCCC[C@H](N)C(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: COCCOC
Solvent: CN(C)C=O
Product: CCC[C@H](NCc1ccc(Br)nc1)C(=O)OC
Temperature: 20 °C
Reaction time: 1 h

Procedure:
1.48 g (13.2 mmol) of potassium tert-butylate are added to a solution of 2.18 g (12 mmol) of methyl (S)-2-aminohexanoate hydrochloride and 1.66 ml of triethylamine in 20 ml of DME and 15 ml of DMF under argon. After stirring at 20° C. for 1 h, a solution of 3.01 g (12 mmol) of 2-bromo-5-bromomethylpyridine in 15 ml of DMF is injected and the mixture is stirred for 16 h. Subsequently, the solvent is distilled off in vacuo and the residue is taken up in dichloromethane/water; the organic phase is then dried over sodium sulphate and, after concentrating, purified on silica gel using petroleum ether/ethyl acetate (4:1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.O=[CH:13][C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>[Cl-].[Zn+2].[Cl-]>[C:23]([O:20][C:19]1[CH:21]=[CH:22][C:14](/[CH:13]=[C:6]2\[CH2:7][CH2:8][CH2:9][C:10]3[CH:11]=[C:2]([CH3:1])[CH:3]=[N:4][C:5]\2=3)=[CH:15][C:16]=1[O:17][CH3:18])(=[O:25])[CH3:24]
Reactant: COc1cc(C=O)ccc1O
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: COc1cc(/C=C2\CCCc3cc(C)cnc32)ccc1OC(C)=O

Procedure:
A mixture of 5,6,7,8-tetrahydro-3-methylquinoline (20 ml), vanillin (25 g), acetic anhydride (50 ml), and zinc chloride (1 g) was heated at reflux for 30 hours. The solvent was removed by evaporation and the residue was dissolved in ethyl acetate. This solution was shaken with 2N HCl and a crystalline solid was deposited. This was removed by filtration, washed with diethyl ether and propan-2-ol/diethyl ether. The product was then dried to give the title compound as the hydrochloride salt (34 g) m.p. 223°-5° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.O=S(Cl)Cl.[N:15]1([CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[S:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[CH:30]=3)=[CH:25][CH:24]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1.C([O-])(O)=O.[Na+]>ClCCCl.CN(C=O)C.Cl[Ti](Cl)(Cl)Cl>[N:15]1([CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[S:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[C:30]=3[C:6]([C:5]3[CH:4]=[CH:3][C:2]([I:1])=[CH:10][CH:9]=3)=[O:8])=[CH:25][CH:24]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: c1ccc2sc(-c3ccc(OCCN4CCCC4)cc3)cc2c1
Reactant: O=C(O)c1ccc(I)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(c1ccc(I)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Temperature: 0 °C
Reaction time: 5.5 h

Procedure:
A slurry of 4-iodobenzoic acid (7.67 g, 30.9 mmol) in 300 mL of 1,2-dichloroethane and 2 drops of DMF was treated with SOCl2 (11.3 mL, 154.6 mmol). The resulting mixture was heated at reflux overnight. The clear solution was evaporated in vacuo, then the solid residue was resuspended in 1,2-dichloroethane and reconcentrated. The crude acid chloride was dissolved in 300 mL of 1,2-dichloroethane, and 2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (5.0 g, 15.5 mmol) was added. The solution was cooled to 0° C. and treated with TiCl4 (8.5 mL, 77.3 mmol). After 5.5 h, the reaction mixture was carefully poured into 600 mL of saturated aqueous NaHCO3. The layers were separated, and the aqueous phase was extracted with CHCl3 (3×300 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by PrepLC (SiO2; 1% MeOH in CHCl3, saturated with NH4OH) afforded 6.79 g (12.3 mmol; 79%) of the title product as a yellow foam.
Reaction SMILES: N1(C2C=CC=CC=2C(N[C@H]2CCC[C@@H]2NC2C=NC(C(F)(F)F)=CN=2)=O)C=CC=N1.Cl.[F:32][C:33]([F:48])([F:47])[C:34]1[N:35]=[CH:36][C:37]([NH:40][C@H:41]2[CH2:45][CH2:44][CH2:43][C@@H:42]2[NH2:46])=[N:38][CH:39]=1.[F:49][C:50]1[CH:51]=[CH:52][C:53]([N:59]2[N:63]=[CH:62][CH:61]=[N:60]2)=[C:54]([CH:58]=1)[C:55](O)=[O:56]>>[F:49][C:50]1[CH:51]=[CH:52][C:53]([N:59]2[N:63]=[CH:62][CH:61]=[N:60]2)=[C:54]([CH:58]=1)[C:55]([NH:46][C@H:42]1[CH2:43][CH2:44][CH2:45][C@@H:41]1[NH:40][C:37]1[CH:36]=[N:35][C:34]([C:33]([F:32])([F:47])[F:48])=[CH:39][N:38]=1)=[O:56]
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Agent: Cl
Agent: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ccccc1-n1cccn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1cc(F)ccc1-n1nccn1

Procedure:
Prepared according to the procedure for 2-(1H-pyrazol-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 31) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14, 213 mg, 0.75 mmol) and 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 8; 172 mg, 0.83 mmol) except this was then purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.