Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:11]2[CH2:12][CH2:13]O[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=2[NH:3]1.[CH2:20]([C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24])[CH3:21]>C(O)COCCO.[Cl-].[Na+].O>[CH2:20]([C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[N:24]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=3[N:3]=[C:2]([NH:3][CH2:4][CH2:5][OH:15])[C:11]=2[CH2:12][CH2:13]1)[CH3:21]
Reactant: O=c1[nH]c2c(OC(F)(F)F)cccc2c2c1CCO2
Reactant: CCc1ccccc1N
Agent: [Cl-]
Agent: [Na+]
Solvent: OCCOCCO
Solvent: O
Product: CCc1ccccc1N1CCc2c(NCCO)nc3c(OC(F)(F)F)cccc3c21
Temperature: 250 °C
Yield: 94.7 %

Procedure:
4-Oxo-6-trifluoromethoxy-2,3,4,5-tetrahydrofuro[3,2-c]quinoline(7.0 g, 25.8 mmol) was dissolved in diethylene glycol(30 ml) and 2-ethylaniline(6.7 g, 51 mmol) was added under nitrogen. The reaction mixture was refluxed at 250° C. for 15 hours. The reaction mixture was diluted in brine(20 ml), then the aqueous layer was extracted with dichloromethane(15 ml) for 3 times. The organic layer was washed with water(15 ml) for 3 times, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate as eluent to obtain 5.1 g of desired compound as solid in 53% of yield.
Reaction SMILES: [CH2:1]([C:8]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11][CH2:10][CH:9]1[OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[CH2:1]([C:8]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11][CH2:10][CH:9]1[O:13][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1(Cc2ccccc2)CCCC1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1(Cc2ccccc2)CCCC1OC(=O)c1ccccc1
Reaction time: 12 h

Procedure:
12.4 grams of 2-benzyl-2-ethoxycarbonyl-cyclopentanol obtained from Example 14 were diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, 6.108 ml of pyridine was slowly added, then 8.876 ml of benzoyl chloride was dropwise added Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, and then using 10% aqueous solution of sodium carbonate for three times. The organic layer was dried, and removing solvent gave 19.71 g of yellow liquid. MS: m/e 353(M++1), 352(M+), 351(M+−1), 279(M+—CO2CH2CH3), 261(M+—CH2C6H5), 247(M+—C6H5CO), 231(M+—C6H5CO2), 201, 184, 156, 139, 105 (base), 91, 77.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([NH2:16])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:14][NH2:16])([CH3:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C(N)=O)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(CN)CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A THF (30 ml) solution of 1-benzyl-4-methylpiperidine-4-carboxamide (2.85 g) was added dropwise over 30 minutes to an ice-cooled suspension of LAH (1.40 g) in THF (50 ml) under a flow of argon gas. After beating the reaction to room temperature and stirring for 1 hour, heating and stirring were performed at 50° C. for 1 hour. The reaction liquid was ice-cooled, and a 90% THF aqueous solution (14 mL), a 15% sodium hydroxide aqueous solution (1.4 mL), and water (4.2 mL) were sequentially added. After stirring the reaction liquid at room temperature for 1 hour, Celite filtration was performed, and the filtrate was concentrated under reduced pressure to obtain 1-(1-benzyl-4-methylpiperidin-4-yl)methanamine (2.68 g).
Reaction SMILES: O1CCCC1.[AlH4-].[Li+].[C:8]1([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][C:23](OCC)=[O:24])[CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>O>[C:8]1([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH2:23][OH:24])[CH2:17][CH2:16]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CCC1CCN(Cc2ccccc2)CC1
Agent: [AlH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCCCC1CCN(Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 100 %

Procedure:
270 Parts of tetrahydrofuran were added carefully to 10 parts of lithium tetrahydroaluminate. A solution of 66 parts of ethyl 1-(phenylmethyl)-4-piperidinepropanoate in 180 parts of tetrahydrofuran was added dropwise to the thus obtained mixture (exothermic reaction, the temperature rose to about 45° C.). The whole was stirred overnight at reflux temperature. The mixture was cooled in an ice salt bath and decomposed at 0° C. with successively 10.5 parts of water, 7.8 parts of a sodium hydroxide solution 20% and 33.8 parts of water. The mixture was filtered over diatomaceous earth and the filtrate was evaporated, yielding 56 parts (100% of 1-(phenylmethyl)-4-piperidinepropanol as a residue (int. 40).
Reaction SMILES: [CH3:1][C:2]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:3][CH2:4][NH:5][C:6](=[O:12])[C:7]([O:9]CC)=O.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][NH2:27]>C(O)C>[CH2:4]([NH:5][C:6](=[O:12])[C:7]([NH:27][CH2:26][CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=1)=[O:9])/[CH:3]=[C:2](/[CH2:13][CH2:14][CH:15]=[C:16]([CH3:17])[CH3:18])\[CH3:1]
Reactant: NCCc1ccccn1
Reactant: CCOC(=O)C(=O)NCC=C(C)CCC=C(C)C
Solvent: CCO
Product: CC(C)=CCC/C(C)=C/CNC(=O)C(=O)NCCc1ccccn1
Yield: 66.7 %

Procedure:
The ethyl 2-(3,7-dimethylocta-2,6-dienylamino)-2-oxoacetate (1.5 g, 5.92 mmol) was mixed with 2-(pyridin-2-yl)ethanamine (1 g, 8.19 mmol) in ethanol (20 ml) to give a yellow solution. The reaction mixture was stirred at reflux for 1.5 hour. Then the solvent was removed by evaporation. The remaining residual solid was washed with ethanol/pentane to provide the target compound as white crystals (1.3 g; 65% yield). The product is ca. 97% pure according to NMR analysis.
Reaction SMILES: [OH-].[Na+].[CH:3]1([NH:9][C:10](=[O:33])[N:11]([C:13]2[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22](/[CH:25]=[C:26](\[O:31][CH3:32])/[C:27]([O:29]C)=[O:28])=[CH:21][CH:20]=3)[CH:16]=[CH:17][CH:18]=2)[CH3:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(O)(=O)C>O1CCCC1>[CH:3]1([NH:9][C:10](=[O:33])[N:11]([C:13]2[CH:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22](/[CH:25]=[C:26](\[O:31][CH3:32])/[C:27]([OH:29])=[O:28])=[CH:23][CH:24]=3)[CH:16]=[CH:17][CH:18]=2)[CH3:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)NC3CCCCC3)c2)cc1)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CO/C(=C\c1ccc(-c2cccc(N(C)C(=O)NC3CCCCC3)c2)cc1)C(=O)O
Temperature: 68 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
2.2 mL (2.2 mmol) of aqueous 1 N sodium hydroxide solution are added to a solution of 0.6 g (1.5 mmol) of methyl (Z)-3-[3′-(3-cyclohexyl-1-methylureido)biphenyl-4-yl]-2-methoxyacrylate in 12 mL of tetrahydrofuran. The reaction medium is heated at 68° C. and stirred for 4 hours. The reaction medium is acidified with 2.4 mL of 1 N acetic acid solution and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is recrystallized from hot ethyl acetate. 500 mg (82%) of (Z)-3-[3′-(3-cyclohexyl-1-methylureido)biphenyl-4-yl]-2-methoxyacrylic acid are obtained in the form of a white solid with a melting point of 192° C.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[C:18]4[N:19]([CH:28]=[CH:29][N:30]=4)[C:20]([C:23]4[CH:24]=[N:25][NH:26][CH:27]=4)=[CH:21][N:22]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(C)C.Br[CH2:32][C:33]([NH2:35])=[O:34]>>[NH:25]1[CH:24]=[C:23]([C:20]2[N:19]3[CH:28]=[CH:29][N:30]=[C:18]3[C:17]([NH:16][C:13]3[CH:12]=[CH:11][C:10]([CH:7]4[CH2:8][CH2:9][N:4]([CH2:32][C:33]([NH2:35])=[O:34])[CH2:5][CH2:6]4)=[CH:15][CH:14]=3)=[N:22][CH:21]=2)[CH:27]=[N:26]1
Reactant: CC(C)N1CCC(c2ccc(Nc3ncc(-c4cn[nH]c4)n4ccnc34)cc2)CC1
Reactant: NC(=O)CBr
Product: NC(=O)CN1CCC(c2ccc(Nc3ncc(-c4cn[nH]c4)n4ccnc34)cc2)CC1

Procedure:
This compound may be prepared using the methods described for Compound 202, using 2-bromoacetamide in Step 1. LCMS: Rt=0.73 min (100%), m/z (ESI) 417 (M+H)+.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][CH2:31][CH:30]([C:34](O)=[O:35])[CH2:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34]([CH:30]5[CH2:31][CH2:32][CH2:33][O:28][CH2:29]5)=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C1CCCOC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)C1CCCOC1

Procedure:
The title compound, white solid (91 mg, 82%), MS (ISP) m/z=443.5 [(M+H)+], mp 216° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and rac-tetrahydro-pyran-3-carboxylic acid.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:9]([F:10])=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)[N:7]=[C:6]([C:18]([O:20]C)=[O:19])[C:5]=1[Cl:22].Cl>CO>[NH2:3][C:4]1[C:9]([F:10])=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([I:17])=[CH:15][CH:16]=2)[N:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]=1[Cl:22]
Reactant: COC(=O)c1nc(-c2ccc(I)cc2)c(F)c(N)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1c(F)c(-c2ccc(I)cc2)nc(C(=O)O)c1Cl
Temperature: 23 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
A 2 M solution of sodium hydroxide (740 μL, 1.5 mmol, 4.0 equiv) was added to a stirred solution of methyl 4-amino-6-(4-iodophenyl)-3-chloro-5-fluoropicolinate (150 mg, 0.37 mmol, 1.0 equiv) in methanol (3.7 mL) at 23° C. The resulting pink solution was stirred at 23° C. for 3 h. The reaction mixture adjusted to pH 3, using concentrated hydrochloric acid, and concentrated by rotary evaporation. The residue was slurried in water and vacuum filtered to afford the title compound as a pale pink powder (110 mg, 79%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:11].[C:12](Cl)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([C:12]2[O:11][C:3]3[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=[CH:10][C:2]=3[N:1]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cccc(C(=O)O)c1O
Reactant: O=C(Cl)c1ccccc1
Product: O=C(O)c1cccc2nc(-c3ccccc3)oc12
Yield: 86 %

Procedure:
2-Phenylbenzoxazole-7-carboxylic acid was prepared from 3-aminosalicyclic acid and benzoyl chloride using a procedure identical to that described in Step A of Example 1. This material was obtained in 86% yield as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 8.30 (dd, J=7.2, 2.1 Hz, 2H), 7.98 (dd, J=12.9, 7.8 Hz, 2H), 7.60 (m, 3H), 7.48 (t, J=7.8 Hz, 1H); MS (APCI) m/z 240 [M+H]+
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH3:8][O:9][CH:10]([O:18][CH3:19])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=1>CN(C)C=O.O.[Cu]>[CH3:19][O:18][CH:10]([O:9][CH3:8])[C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:16]=1
Reactant: COC(OC)c1cccc(Br)c1
Reactant: c1c[nH]cn1
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(OC)c1cccc(-n2ccnc2)c1
Temperature: 155 °C
Reaction time: 36 h
Yield: 79.4 %

Procedure:
A solution of 296 mg of imidazole and 131 mg of sodium hydride (80% dispersion in mineral oil) in 2 ml of anhydrous dimethylformamide was stirred at room temperature for 1 hour under nitrogen. 1.0 g of 3-bromobenzaldehyde dimethyl acetal and 30 mg copper powder were then added and the mixture was stirred at 150-160° C. under nitrogen for 36 hours. The cooled mixture was diluted with 20 ml of water and extracted with four 25 ml portions of dichloromethane. The combined extracts were washed with two 25 ml portions of 25% aqueous ammonia, followed by two 25 ml portions of brine and then dried over anhydrous magnesium sulphate. The solution was concentrated under reduced pressure to give 0.75 g of 3-(1-imidazolyl)-benzaldehyde dimethyl acetal as a clear viscous oil.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[N:3]=1.C(NC(C)C)(C)C.[CH3:21][C:22]1[CH:26]=[C:25]([NH2:27])[NH:24][N:23]=1>C1COCC1.C(OCC)(=O)C.O>[Cl:9][C:6]1[N:5]=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[N:3]=[C:2]([NH:27][C:25]2[NH:24][N:23]=[C:22]([CH3:21])[CH:26]=2)[C:7]=1[F:8]
Reactant: CS(=O)(=O)c1nc(Cl)c(F)c(Cl)n1
Reactant: Cc1cc(N)[nH]n1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: Cc1cc(Nc2nc(S(C)(=O)=O)nc(Cl)c2F)[nH]n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4,6-dichloro-5-fluoro-2-(methylsulfonyl)pyrimidine in THF (25 ml) was added diisopropylamine (1.32 g, 10.20 mmol, 1.82 ml) and 3-methyl-1H-pyrazol-5-amine (1.04 g, 10.71 mmol) and the mixture stirred at room temperature for 30 mins. The reaction was diluted with ethyl acetate (100 ml) and water (100 ml), the organic layer was washed with brine (50 ml), dried (Na2SO4), and partially concentrated until a solid started to precipitate. The suspension was cooled in an ice bath for 1 hr and filtered to give the title compound as a pale yellow solid. A second crop was obtained by leaving the filtrate to stand overnight (total 1.55 g, 50%). 1H NMR (DMSO, 400 MHz) 2.26 (3H, s), 3.32 (3H, s), 6.48 (1H, s), 11.03 (1H, s), 12.35 (1H, s) ES+306.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([P:11]([CH:21](Br)[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]1([Mg]Cl)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:1]([O:5][C:6]([NH:8][CH:9]([P:11]([CH:21]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(Br)P(=O)(OCc1ccccc1)C(Br)NC(=O)OC(C)(C)C
Reactant: Cl[Mg]c1ccccc1
Product: CC(C)(C)OC(=O)NC(c1ccccc1)P(=O)(OCc1ccccc1)C(NC(=O)OC(C)(C)C)c1ccccc1
Yield: 32 %

Procedure:
In analogy to Example 11, the benzyl phosphinate 12 is prepared from the bis-substituted benzyl bromophosphinate 8 and a 2.0N phenylmagnesium chloride solution in a yield of 32%.
Reaction SMILES: C1(O[C:8](=[O:20])[NH:9][CH2:10][C:11]2[CH:19]=[CH:18][C:17]3[O:16][CH2:15][O:14][C:13]=3[CH:12]=2)C=CC=CC=1.Cl.[NH2:22][CH2:23][CH2:24][SH:25].[OH-].[Na+]>N1C=CC=CC=1>[SH:25][CH2:24][CH2:23][NH:22][C:8]([NH:9][CH2:10][C:11]1[CH:19]=[CH:18][C:17]2[O:16][CH2:15][O:14][C:13]=2[CH:12]=1)=[O:20]
Reactant: NCCS
Reactant: O=C(NCc1ccc2c(c1)OCO2)Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=C(NCCS)NCc1ccc2c(c1)OCO2

Procedure:
6 g (0.022 mol) of phenylpiperonylcarbamate, prepared as in example 2A, are placed in pyridine and a heterogenous suspension is obtained. Separately a solution made in a nitrogen stream of 2.75 g (0.024 mol) of cysteamine hydrochloride and of NaOH (0.96 g, 0.024 mol) is prepared. The cysteamine solution thus obtained is added to the phenylpiperonylcarbamate solution and heated while stirring for 8 hours.
Reaction SMILES: [C:1]([CH:3]([NH:9][CH:10]=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[C:12](#[N:15])[CH:13]=[CH2:14].FC(F)(F)C(O)=O>ClCCCl>[NH2:2][C:1]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N:9][CH:10]=[CH:14][C:13]=1[C:12]#[N:15]
Reactant: CCOC(=O)C(C#N)NC=O
Reactant: C=CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCOC(=O)c1nccc(C#N)c1N
Yield: 20.9 %

Procedure:
A stirred solution of ethyl 2-cyano-2-(formylamino)acetate (J. Org. Chem., 1979, 44, 3835; 0.47 g, 0.003 mol), acrylonitrile (1.2 ml, 0.018 mol) and tri-fluoroacetic acid (0.02 ml, 0.0003 mol) in 1,2-dichloroethane (4 ml) was heated under reflux for 3 days. The solvent was removed by evaporation under vacuum, the residue dissolved in dichloromethane (30 ml) and the resulting solution washed with saturated aqueous sodium bicarbonate solution (30 ml). The aqueous phase was washed with dichloromethane (30 ml) and the organic solutions then combined, dried (MgSO4) and evaporated under vacuum. Chromatography of the residue on silica gel (12 g), eluting with dichloromethane:methanol (100:1), followed by crystallization from acetone:hexane, gave the title compound as a colourless solid (0.12 g, 21%), m.p. 114-116° C.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10]([NH2:12])=[S:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:23])[CH:20]=2)[C:15]1=[O:24]>CC(C)=O>[CH2:1]([S:8][CH2:9][C:10]1[S:11][CH:14]2[CH2:22][C:21]3[CH:20]=[C:19]([Cl:23])[CH:18]=[CH:17][C:16]=3[C:15]2([OH:24])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Reactant: NC(=S)CSCc1ccccc1
Solvent: CC(C)=O
Product: OC12N=C(CSCc3ccccc3)SC1Cc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
At room temperature, 0.54 g of 2-benzylsulfanyl-thioacetamide were dissolved in 10 ml of dry acetone and mixed with 0.67 g of 2-bromo-5-chlorindan-1-on, and the mixture was stirred at room temperature for 4 h. The resulting precipitate was filtered off with suction, washed with acetone, taken up in ethyl acetate, mixed with saturated sodium bicarbonate solution and extracted twice. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. This synthesis yielded 2-benzylsulfanylmethyl-6-chloro-8,8a-dihydroindeno[1,2-d]thiazol-3a-ol having a melting point of 102-104° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:10][CH2:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][O:16][CH:17]([CH3:19])[CH3:18].[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([OH:30])=[CH:24][C:23]=2[O:22]1>CC(C)=O>[CH:17]([O:16][CH2:15][CH2:14][C:13]([CH3:20])=[CH:12][CH2:11][CH2:10][O:30][C:25]1[CH:26]=[CH:27][C:28]2[O:29][CH2:21][O:22][C:23]=2[CH:24]=1)([CH3:19])[CH3:18]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CC(=CCCBr)CCOC(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=CCCOc1ccc2c(c1)OCO2)CCOC(C)C

Procedure:
2.35 g (0.017 mol) of potassium carbonate and 50 mg of potassium iodide are added to a solution of 4.0 g (0.017 mol) of 1-bromo-6-isopropoxy-4-methyl-3-hexene and 2.35 g (0.017 mol) of 3,4-methylendioxy-phenol in 120 cc of acetone. The suspension is boiled under reflux during the course of 20 hours, is then filtered and liberated from acetone in a vacuum. The residue is taken up in ether, washed with water and saturated salt solution, dried over sodium sulphate and evaporated. The residue is chromatographed on silica gel with hexane/ethyl acetate 9:1. Thus the cis/trans isomeric mixture of the 5-(6-isopropoxy-4-methyl methyl-3-hexenyloxy)-1,3-benzodioxol is obtained as colourless oil. nD20 = 1.5111.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:19])[CH2:4][C:5]1[CH:6]=[C:7]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1.CC([O-])C.CC([O-])C.CC([O-])C.[Al+3].CC(C)=O>C(O)(C)C>[Cl:1][CH2:2][CH:3]([OH:19])[CH2:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CCl)Cc1cccc(C(=O)c2ccccc2)c1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)O
Solvent: CC(C)=O
Product: OC(CCl)Cc1cccc(C(O)c2ccccc2)c1
Temperature: 50 °C
Yield: 105 %

Procedure:
A solution of 11.23 g of 3'(3'-chloro-2'-oxo-propyl)-benzophenone in 112 ml of isopropanol was added to 50 ml of isopropanol and 17 g of aluminum isopropylate heated to 50° C and the mixture was refluxed for 2 hours while slowly distilling isopropanol and the acetone formed while keeping the volume constant by adding 30 ml of isopropanol. The mixture was concentrated to 50 ml and after returning to room temperature, the mixture was added with stirring to a mixture of ice-water-hydrochloride acide. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness to obtain 11.97 g of 3-(3'-chloro-2'-hydroxypropyl)-benzhydrol which was used as is for the next step.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]([C:26]2[N:30](COCC[Si](C)(C)C)[C:29]3[CH:39]=[CH:40][C:41]([C:43]#[N:44])=[CH:42][C:28]=3[N:27]=2)([O:24][CH3:25])[CH3:23])=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7](S(C1C=CC(C)=CC=1)(=O)=O)[CH:6]=[CH:5]2.CC1C(C(C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)(OC)C)=C2C(=C(C)C=1)N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2>>[CH3:1][C:2]1[C:3]([C:22]([C:26]2[NH:30][C:29]3[CH:39]=[CH:40][C:41]([C:43]#[N:44])=[CH:42][C:28]=3[N:27]=2)([O:24][CH3:25])[CH3:23])=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: COC(C)(c1c(C)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: COC(C)(c1c(C)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Product: COC(C)(c1nc2cc(C#N)ccc2[nH]1)c1c(C)cc(C)c2[nH]ccc12

Procedure:
The title compound was synthesized from a mixture of (±)-2-(1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)-1-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)-1-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile analogously to Example 64-B and 64-C. 1H NMR (TFA salt, 400 MHz, DMSO-d6) δ ppm 10.89 (s, 1H) 8.07 (s, 1H) 7.55-7.64 (m, 2H) 7.12 (t, J=2.78 Hz, 1H) 6.67 (s, 1H) 6.08 (dd, J=3.03, 2.02 Hz, 1H) 3.05 (s, 3H) 2.39 (s, 3H) 2.05 (s, 3H) 2.03 (s, 3H). HRMS calcd. for C21H20N4O (M+H)+ 345.1710. found 345.1715.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=2[CH3:21])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc([N+](=O)[O-])cc1-c1ccc(F)cc1
Yield: 90 %

Procedure:
4-Fluorophenylboronic acid (6.72 g; 0.048 mol) was added to a suspension of 2-bromo-4-nitrotoluene (6.9 g; 0.032 mol) and tetrakis(triphenylphosphine) palladium (1.5 g; 1.4 mmol) in DME (90 ml). After addition of aqueous sodium carbonate solution 2M (120 ml), the mixture was refluxed overnight. After extraction with ether and evaporation, the residue was purified by flash chromatography (ethyl acetate/petroleum ether 95/5 to give 2-(4-fluorophenyl)-4-nitrotoluene (6.66 g; 90%).