Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH3:3].[F:13][C:14]1[CH:15]=[CH:16][C:17]2=[C:18]([CH:34]=1)[O:19][CH2:20][C:21]1[CH:31]=[C:30]([CH:32]=O)[CH:29]=[CH:28][C:22]=1/[C:23]/2=[C:24](/[CH3:27])\[C:25]#[N:26]>>[F:13][C:14]1[CH:15]=[CH:16][C:17]2=[C:18]([CH:34]=1)[O:19][CH2:20][C:21]1[CH:31]=[C:30]([CH2:32][C:12]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:5][C:4]=3[CH2:1][CH2:2][CH3:3])[CH:29]=[CH:28][C:22]=1/[C:23]/2=[C:24](/[CH3:27])\[C:25]#[N:26]
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Reactant: CCCc1cc2ccccc2[nH]1
Product: CCCc1[nH]c2ccccc2c1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 55.1 %

Procedure:
[step 5] Using 2-propyl-1H-indole (100 mg, 0.64 mmol) obtained in step 4 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (153 mg, 0.52 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 13A, the target compound (125 mg, 55%) was obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])=[O:11])=[C:8]([O:23][CH3:24])[CH:7]=1.N1C=CC=CC=1>C1C=CC=CC=1>[F:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([Cl:3])=[O:15])=[O:11])=[C:8]([O:23][CH3:24])[CH:7]=1
Reactant: COc1cc(F)ccc1C(=O)c1ccccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COc1cc(F)ccc1C(=O)c1ccccc1C(=O)Cl

Procedure:
Thionyl chloride (1.5 ml) was added to a solution of 2-(4-fluoro-2-methoxybenzoyl)benzoic acid (mp 119°-120° C.) (3.66 g) and pyridine (0.03 ml) in benzene (50 ml), followed by refluxing for an hour. The solvent was distilled off to give 2-(4-fluoro-2-methoxybenzoyl)benzoyl chloride (IRνmaxNujol : 1795 cm-1). A solution of this product in methylene chloride (40 ml) was added to a solution of ethyl 4-isopropylaminocrotonate (Reference Example I) (3.6 g) and triethylamine (3.0 ml) in methylene chloride (40 ml), followed by stirring at room temperature for 16 hours. After removing the solvent, ethyl acetate was added to the residue. The mixture was washed with water, dil. hydrochloric acid, water, sodium hydrogen carbonate solution and water in turn. The ethyl acetate layer was dried over anhydrous sodium sulfate and distilled to give the title compound (5.50 g) as pale brown oily substance.
Reaction SMILES: Cl[C:2]1[C:3]([C:12]#[N:13])=[N:4][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:20]=1[Cl:21].CC([O-])(C)C.[K+]>CS(C)=O.C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:22][C:2]1[C:3]([C:12]#[N:13])=[N:4][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1
Reactant: CCCSc1ccc(Cl)c(C#N)n1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCCSc1ccc(Oc2ccc(Cl)c(Cl)c2)c(C#N)n1

Procedure:
3-Chloro-6-propylthio-2-pyridinecarbonitrile (6.2 g) was mixed with 5.7 g of 3,4-dichlorophenol and 3.9 g of t-BuOK in 30 ml of DMSO and 30 ml THF. The desired, 3-(3,4-dichlorophenoxy)-6-propylthio-2-pyridinecarbonitrile was recovered, b.p. 203° C. (at 0.2 mm Hg).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[CH:9][CH:10]=[C:11]3[CH2:15][CH2:14][O:13][C:12]=23)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][CH:30]=O)[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>ClCCl.CO>[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([CH2:29][CH2:30][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[N:8]=[CH:9][CH:10]=[C:11]4[CH2:15][CH2:14][O:13][C:12]=34)[CH2:6][CH2:5]2)[CH2:27][CH2:28]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: c1cc2c(c(N3CCNCC3)n1)OCC2
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-(piperazin-1-yl)-2,3-dihydro-furo[2,3-c]pyridine (0.96 g, 4.68 mmol) in dichloromethane (30 ml) and MeOH (0.8 ml) was added at room temperature commercially available trans-tert-butyl-4-(2-oxoethyl)-cyclohexylcarbamate (1.71 mg, 6.02 mmol) and triethylamine (1.02 g, 1.4 ml, 10 mmol) and the solution was allowed to stir for 30 min. Sodium triacetoxyboron hydride (1.91 g, 9.03 mmol) was added step wise and the mixture was allowed to stir for 4 h at room temperature. The solution was added to ice/2N sodium carbonate solution (50 ml), extracted with dichloromethane (2×30 ml). The combined organic layers were dried (MgSO4) and evaporated. The crude material (2.53 g) was purified by flash chromatography on silica gel (20% to 100% dichloromethane/dichloromethane-MeOH 9:1) to yield trans-(4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester as off-white solid (1.3 g, 65%), MS (ISP) m/z=431.5 [(M+H)+], mp 141° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[C:13]([CH3:14])=[N:12][CH:11]=[N:10]1.[Cu][C:16]#[N:17]>CN1CCCC1=O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]#[N:17])=[C:3]([N:9]2[C:13]([CH3:14])=[N:12][CH:11]=[N:10]2)[CH:4]=1
Reactant: N#C[Cu]
Reactant: Cc1ncnn1-c1cc(F)ccc1Br
Solvent: CN1CCCC1=O
Product: Cc1ncnn1-c1cc(F)ccc1C#N
Temperature: 145 °C

Procedure:
To a solution of 1-(2-bromo-5-fluorophenyl)-5-methyl-1H-1,2,4-triazole (4.1 g, 16 mmol) in N-methylpyrrolidone (NMP, 30 mL) was added copper (I) cyanide, CuCN (1.72 g, 19.2 mmol; Aldrich) and the mixture was stirred in an oil bath heated at 140-150° C. under a nitrogen atmosphere for 3 h. After cooling, the solvent was removed in vacuo and the residue mixed with CH2Cl2 (50 mL), water (50 mL), and conc-NH4OH (50 mL). The mixture was stirred for 30 min, and the insoluble material was filtered through Celite®. The aqueous filtrate was extracted again with CH2Cl2. The combined CH2Cl2 filtrate and extracts were washed again with dilute NH4OH, dried (MgSO4), filtered and concentrated to a dark solid which was triturated with diethyl ether to give 1.6 g of the title compound as an off-white solid. An additional amount (750 mg) of the title compound was obtained from the mother liquor by column chromatography (SiO2, 5% Et2O—CH2Cl2) followed by trituration with Et2O. Total yield, 2.35 g (11.6 mmol, 73% yield); HPLC: 1.29 min (AP 99% at 254 nm); LC/MS m/z 203 (M+H); 1H NMR (CDCl3, 500 MHz) δ ppm 2.50 (3H, s, 10-Me), 7.25 (1H, dd, J=8, 2.5 Hz, 3-CH), 7.30-7.36 (1H, m, 5-CH), 7.85 (1H, dd, J=8.8, 5.5 Hz, 6-CH), 8.00 (1H, s, 9-CH); 13C NMR (CDCl3, 125.8 Hz) δ ppm 12.7 (10-Me), 107.2 (d, J=Hz, 1-C), 114.6 (7-CN), 116.2, (d, J=25 Hz, 3-CH), 117.9 (d, J=23 Hz, 5-CH), 136.1 (d, J=10 Hz, 6-CH), 141.5 (d, J=l 1 Hz, 2-C), 152.3 (9-CH), 153.9 (8-C), 164.9 (d, J=261 Hz, 4-CF).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=[N:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CN2CCC(=Nc3cccnc3)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(CN2CCC(Nc3cccnc3)CC2)cc1
Temperature: 50 °C

Procedure:
To a stirred solution of 27 parts of N-[1-(phenylmethyl)-4-piperidinylidene]-3-pyridinamine in 40 parts of ethanol are added portionwise 3.8 parts of sodium borohydride. After the addition is complete, the whole is heated to 50° C. The solvent is evaporated. The oily residue is dissolved in 150 parts of hydrochloric acid 1 N and filtered. The filtrate is rendered alkaline with ammonium hydroxide and extracted with methylbenzene. The organic layer is dried over magnesium sulfate, filtered and evaporated. The solid residue is washed with 2,2'-oxybispropane and dried, yielding 14 parts of N-[1-(phenylmethyl)-4-piperidinyl]-3-pyridinamine; mp. 131°-133° C.; beige, amorphous powder.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].O=[C:14]([CH2:20][CH3:21])[CH2:15][C:16]([O:18][CH3:19])=[O:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:20]([C:14]1[O:4][C:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)=[CH:2][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[CH3:21]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCC(=O)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1oc(-c2ccc(OC)cc2)cc1C(=O)OC
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
To a solution of 2-bromo-4′-methoxyacetophenone (13.7 g) and methyl 3-oxopentanoate (7.8 g) in toluene (100 mL) was added dropwise 1,8-azabicyclo[5.4.0]-7-undecene (9.1 mL) over 30 min or more under ice-cooling. After the completion of the dropwise addition, the mixture was stirred for 30 min under ice-cooling, and then at room temperature for 2 hr. The resulting precipitate was filtered, and washed with toluene. The obtained toluene solution was passed through silica gel, and the silica gel was washed with ethyl acetate-hexane (1:1). The collected solutions were concentrated under reduced pressure to remove ethyl acetate-hexane to give a toluene solution. To this toluene solution was added 4-toluenesulfonic acid monohydrate (2.3 g), and the mixture was stirred at 100° C. for 2 hr. The reaction mixture was washed with aqueous sodium hydrogen carbonate solution, and the aqueous layer was extracted with ethyl acetate. The organic layers were collected, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 5% ethyl acetate/hexane) to give the title compound (9.2 g, 59%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[OH:9])=[CH:4][C:3]=1[S:17]([NH2:20])(=[O:19])=[O:18].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:9])[C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[CH:4][C:3]=1[S:17]([NH2:20])(=[O:18])=[O:19]
Reactant: NS(=O)(=O)c1cc(C(O)c2ccc(F)cc2)ccc1Cl
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: NS(=O)(=O)c1cc(C(=O)c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
A solution of 65 mg of 2-chloro-5-((4-fluoro-phenyl)-hydroxy-methyl)-benzenesulfonamide in 1 mL of acetone is stirred at room temperature as 0.2 mL of 3 M Jones' reagent is added. The reaction mixture is stirred at room temperature for 30 minutes then diluted with ethyl acetate, filtered through celite, the filtrate is concentrated in vacuo. The crude product is purified by silica gel chromatography to give 48 mg of the title compound as white foam. 1H NMR (CDCl3): 5.15 (br, 2H), 7.12-7.30 (m, 3H), 7.70 (d, J=8 Hz, 1H), 7.80-7.90 (m, 2H), 7.90-8.0 (dd, 1H), 8.5 (d, J=2 Hz, 1H). MS (m/z): 312 (M−1).
Reaction SMILES: [CH2:1]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9](O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.C(O)(=O)[CH2:18][C:19]([OH:21])=[O:20]>>[CH:4]1[C:3]2[CH2:2][CH2:1][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:9]([CH2:18][C:19]([OH:21])=[O:20])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)CC(=O)O
Reactant: OC1c2ccccc2CCc2ccccc21
Product: O=C(O)CC1c2ccccc2CCc2ccccc21
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
A round-bottom flask, equipped with a distillation apparatus, is charged with dibenzosuberol (25.0 g, 0.119 mol) and malonic acid (61.9 g, 0,595 mol). The mixture is heated in an 160° C. oil bath. The solids melt. Gas bubbles form and water and acetic acid are distilled through the condenser. After 30 minutes, the mixture is cooled to room temperature and dissolved in ethyl acetate. The organic solution is washed with brine and dried (magnesium sulfate). The solvent is removed in vacuo to give an off-white solid, which is recrystallized from hexane-ethyl acetate/1:1 to yield the title compound as white crystals, 28.8 g; mp 164°-165° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:9]([C:14]2[N:18]([CH2:19][CH3:20])[N:17]=[N:16][N:15]=2)[CH:10]=[CH:11][CH:12]=[O:13])=[CH:4][CH:3]=1.[C:28]([O:34][CH2:35][CH3:36])(=[O:33])[CH2:29][C:30]([CH3:32])=[O:31]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:9]([C:14]2[N:18]([CH2:19][CH3:20])[N:17]=[N:16][N:15]=2)[CH:10]=[CH:11][CH:12]([OH:13])[CH2:32][C:30](=[O:31])[CH2:29][C:28]([O:34][CH2:35][CH3:36])=[O:33])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CCn1nnnc1C(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1CC
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.5 g (1.4 mmoles) of 5,5-bis(4-fluorophenyl)-4-(1-ethyl-1H-tetrazol-5-yl)2,4-pentadienal in tetrahydrofuran at -50° C., was added 1.75 mL of 0.8M (1.4 mmoles) of a freshly prepared solution of ethyl acetoacetate dianion [described in Example 10]. The solution was stirred for 30 minutes at -50° C. and then allowed to warm to -10° C. during the next 30 minutes. The solution was quenched with 1N HCl and extracted with methylene chloride. The organic extracts were dried and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with chloroform to give 0.4 g of the title compound as an oil. MS (CI): m/e=497 for (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:9][C:10]([OH:12])=[O:11])[C:3]1=[O:13].[OH-].[Na+].O.[C:17]1([CH2:23][C:24](=O)[C:25]([O-:27])=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na+].C([BH3-])#N.[Na+]>O>[C:10]([CH2:9][N:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:2]([NH:1][CH:24]([C:25]([OH:27])=[O:26])[CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:3]1=[O:13])([OH:12])=[O:11]
Reactant: N[C@H]1CCCCN(CC(=O)O)C1=O
Reactant: O=C([O-])C(=O)Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN1CCCC[C@H](NC(Cc2ccccc2)C(=O)O)C1=O

Procedure:
Prepare an aqueous solution of 500 mg 3-(S)-amino-1-carboxymethylperhydroazepin-2-one in 5 ml water. Adjust the pH to 6 with 1N sodium hydroxide solution and add 15 ml water. React this amine with 2.24 g sodium phenylpyruvate monohydrate and 400 mg sodium cyanoborohydride as described in Example 1. Purify 370 mg of the crude product on an LH-20 column and isoalte 240 mg of 1-carboxymethyl-3-(S)-[(1-carboxy-2-phenylethyl)amino]perhydroazepin-2-one.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: O=C(CCl)N1CCCC1
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCCC2)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 28 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (8.0 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.2 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[CH:5]=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2cccc(C)c12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc2cccc(CBr)c12
Temperature: 25 °C

Procedure:
1,8-Dimethyl-naphthalene (1.30 g, 8.32 mmol) was dissolved in dry carbon tetrachloride (80 mL). To the reaction mixture was added N-bromosuccinimide (1.39 g, 7.82 mmol), dibenzoyl peroxide (6 mg, catalyst) and the reaction mixture was refluxing for 6 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature, a precipitate formed on cooling and the precipitate was separated by filtration. The filtrate was evaporated in vacuo to yield the title compound as a solid which was used in further steps without additional purification.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[Cl:11][C:12]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:13]=1[O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:13]=1[O:14][CH:15]1[CH2:16][CH2:17][N:18]([C:2]2[C:3](=[O:10])[NH:4][C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)[CH2:19][CH2:20]1
Reactant: Fc1ccc(Cl)c(OC2CCNCC2)c1
Reactant: Cn1nc(Br)c(=O)[nH]c1=O
Solvent: Cc1ccccc1
Product: Cn1nc(N2CCC(Oc3cc(F)ccc3Cl)CC2)c(=O)[nH]c1=O

Procedure:
The compound 90 (white powder) is prepared from the triazine 2e and from the intermediate 8b according to the synthesis method 1 in toluene.
Reaction SMILES: [I:1]I.N1C=CC=CC=1.[Si:9]([O:16][C@@H:17]1[CH2:21][C:20](=[O:22])[CH:19]=[CH:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].Cl>C(Cl)Cl>[Si:9]([O:16][C@@H:17]1[CH2:21][C:20](=[O:22])[C:19]([I:1])=[CH:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=CC(=O)C1
Reactant: II
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C=C(I)C(=O)C1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
The procedure described in Johnson, C. R., Braun, M. P. J. Am. Chem Soc. 1993, 115, 11014 was followed with modification. A solution of I2 (6.55 g, 25.8 mmol) and pyridine (12 mL) in CH2Cl2 (12 mL) was cannula transferred to a 0° C. solution of (R)-4-((tert-butyldimethylsilyl)oxy)cyclopent-2-enone (3.17 g, 14.9 mmol) and pyridine (5.4 mL) in CH2Cl2 (5.4 mL). The reaction was allowed to warm to room temperature and after 2 h, 100 mL 1 M HCl was added. The resulting mixture was extracted with CH2Cl2 (3×60 mL) and the combined organic solution was washed with 100 mL saturated NaHSO3 solution and 50 mL brine and then was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (ethyl acetate/hexanes) gave the title compound (4.997 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH2:32]O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:32][C:31]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Reactant: CCOC(=O)CO
Product: CCOC(=O)COC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and ethyl glycolate according to Method E. 1H NMR (400 MHz, CDCl3) δ ppm 1.32 (t, J=7.12 Hz, 4H), 1.40-1.67 (m, 6H) 1.72-1.83 (m, 1H), 1.96 (ddd, J=26.25, 13.09, 4.16 Hz, 1H), 2.06-2.20 (m, 1H), 2.25-2.36 (m, 1H), 2.84-2.99 (m, 1H), 3.12 (ddd, J=16.18, 3.36, 3.02 Hz, 1H), 3.49 (ddd, J=13.76, 9.33, 4.83 Hz, 1H), 4.28 (q, J=7.25 Hz, 2H), 4.64 (dd, J=9.67, 5.37 Hz, 1H), 4.87 (s, 2H), 7.03 (dd, J=8.73, 2.01 Hz, 1H), 7.31 (d, J=2.15 Hz, 1H), 7.46 (d, J=8.59 Hz, 1H), 7.93-8.02 (m, 2H), 8.17 (d, J=8.86 Hz, 1H). ES-MS m/z 506 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14].[H-].[Na+].[C:24]([O:28][CH3:29])(=[O:27])[C:25]#[CH:26].Cl>CN(C)C=O.C(OCC)(=O)C.O>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11]/[CH:26]=[CH:25]/[C:24]([O:28][CH3:29])=[O:27])=[CH:7][C:6]=1[NH:12][S:13]([CH3:16])(=[O:14])=[O:15]
Reactant: CS(=O)(=O)Nc1cc(O)ccc1Oc1ccc(F)cc1F
Reactant: C#CC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/Oc1ccc(Oc2ccc(F)cc2F)c(NS(C)(=O)=O)c1
Temperature: 22.5 °C
Reaction time: 0.33 h
Yield: 31.6 %

Procedure:
3 g of 4-(2,4-difluorophenoxy)-3-methylsulfonylaminophenol was dissolved in 15 ml of N,N-dimethylformamide. 420 mg of sodium hydride (purity: 60%) was added. The mixture was stirred for 20 minutes at 20-25° C. Then, 0.88 g of methyl propiolate was added dropwise in about 5 minutes so that the reaction temperature was maintained below 40° C. The mixture was stirred for 30 minutes at 30°-40° C. After the completion of the reaction, 50 ml of water and 50 ml of ethyl acetate were added thereto. The resulting mixture was adjusted to pH 4 with 4N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by a column chromatography (eluant: a 20:1 mixture of toluene and ethyl acetate) to obtain 1.2 g (yield: 31.6%) of methyl trans-3-[4-(2,4-difluorophenoxy)-3-methylsulfonylaminophenoxy]acrylate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=1)=[CH:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[CH:16][CH:17]=1)[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)C(=CC1CCCC1)c1ccc(S(=O)(=O)CC)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(CC1CCCC1)c1ccc(S(=O)(=O)CC)cc1
Reaction time: 44 h
Yield: 71.2 %

Procedure:
A solution of 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-acrylic acid ethyl ester [4.89 g, 14.53 mmol, (E):(Z)=3:1] in ethanol (36 mL) was slowly treated with 10% palladium on activated carbon (244.5 mg). The reaction mixture was stirred under a positive pressure of hydrogen gas (balloon) at 25° C. and atmospheric pressure for 44 h. The catalyst was then filtered off through a pad of celite, and the celite pad was washed well with ethyl acetate. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionic acid ethyl ester (3.50 g, 71%) as a colorless viscous oil: FAB-LRMS m/e calcd for C18H26O4S (M+H)+ integer mass 338, found 339.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:13]>>[Br:13][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCc1ccccc1
Reactant: Br
Product: BrCCCCCc1ccccc1

Procedure:
A mixture of 20 g of 5-phenylpentan-1-ol and 30 ml of 47% hydrobromic acid was refluxed for 6 hours. The reaction mixture was cooled and extracted with n-hexane The extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:n-hexane-ethyl acetate=100:1) to give 16.87 g of 1-bromo-5-phenylpentane.