Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([CH3:21])=[C:14]([CH:19]=[O:20])[CH2:15][O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CC1C=C(C)C(C)=C(C)C=1C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([CH3:21])=[C:14]([CH:19]=[O:20])[CH2:15][O:16]2)=[CH:11][CH:10]=1
Reactant: CC1=C(C=O)COc2cc(OCc3ccccc3)ccc21
Agent: Cc1cc(C)c(C)c(C)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(C=O)COc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To 7-(benzyloxy)-4-methyl-2H-chromene-3-carbaldehyde (230 mg) and 1,2,3,4,5-pentamethylbenzene (608 mg) was added TFA (3 mL), followed by stirring at room temperature overnight. The reaction liquid was poured into an aqueous NaHCO3 solution, followed by extraction with EtOAc three times. The organic layer was combined, washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=80:20 to 20:80) to obtain 7-hydroxy-4-methyl-2H-chromene-3-carbaldehyde (130 mg) as a pale yellow powder.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:7][CH2:6][CH2:5][CH2:4]1>CCOC(C)=O.[Pd]>[CH3:1][O:2][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1
Reactant: COC1CCCC=C1c1c[nH]c2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC1CCCCC1c1c[nH]c2ccccc12
Yield: 63 %

Procedure:
Treat 3-(6-methoxy-cyclohex-1-enyl)-1H-indole (200 mg, 0.879 mmol) with 10% Pd/C (40 mg) in EtOAc under atmospheric hydrogenation conditions for 1.5 hours. Filter resulting solution over Celite to remove catalyst. Concentrate crude on rotovap and purify on silica gel chromatography to give 3-(2-Methoxy-cyclohexyl)-1H-indole (127 mg, 63% yield). Mass Spectrum (m/e): 230.03 (MH+), 228.14 (M−).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH:7]([C:9]1[C:10](=[O:22])[N:11]([CH3:21])[C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=2)[NH2:8].C(N(CC)CC)C>O1CCOCC1>[CH3:21][N:11]1[C:12]2[C:17](=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=2)[N:18]=[C:9]([NH:7][NH:8][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])[C:10]1=[O:22]
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc2c(c1)nc(NN)c(=O)n2C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc2c(c1)nc(NNC(=O)C1CC1)c(=O)n2C

Procedure:
Cyclopropylcarboxylic acid chloride (6.60 g., 6.32 mmol) is added dropwise to a solution of 3-hydrazino-1-methyl-6-methoxy-1H-quinoxalin-2-one (52.6 mmol) and triethylamine (6.38 g., 63.2 mmol) in 500 ml. of dioxane and the mixture stirred at room temperature for 20 hours. The dioxane is then removed under vacuum and the residue washed with water, filtered, and dried under vacuum to give a crude yield of 12.8 g. (95%). A 4.8 g. sample of this material is recrystallized from 100 ml. of acetonitrile to obtain purified product.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[CH:6]([N:9]=[C:10]=[N:11][CH:12]([CH3:14])[CH3:13])([CH3:8])[CH3:7]>>[CH2:1]([NH:5][C:10]([NH:11][CH:12]([CH3:14])[CH3:13])=[N:9][CH:6]([CH3:8])[CH3:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)N=C=NC(C)C
Reactant: CCCCN
Product: CCCCNC(=NC(C)C)NC(C)C
Yield: 96.7 %

Procedure:
A mixture of 33 g of N-butylamine (0.45 mol) and 19 g of diisopropylcarbodiimide (0.15 mol) is heated at reflux for 3 hours 30 minutes. GC analysis then shows a conversion of more than 99.5% of the diisopropylcarbodiimide. The final mixture, which is colorless, is concentrated at 60° C. under 20 mbar for 2 hours, to give 29 g of a colorless and virtually odorless liquid of low viscosity, which corresponds to the expected guanidine (96.7% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH2:21]([N:25]([CH3:36])[S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Cl)(=[O:28])=[O:27])[CH2:22][CH2:23][CH3:24]>C(N(C(C)C)C(C)C)C>[CH2:21]([N:25]([CH3:36])[S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)(=[O:28])=[O:27])[CH2:22][CH2:23][CH3:24]
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CCCCN(C)S(=O)(=O)CCCCCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(C)S(=O)(=O)CCCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Yield: 91.4 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and N-n-butyl-N-methyl-6-chlorohexanesulfonamide (539.7 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (50:1), to give N-n-butyl-N-methyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfonamide (951.0 mg) as a pale brown oil (yield: 91.4%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([CH3:12])=[CH:5][C:3]=1[NH2:4].Cl.CO[CH2:16][CH2:17][C:18](OC)(OC)[CH3:19].[OH-].[Na+]>[Cl-].[Zn+2].[Cl-].C(O)C>[N+:9]([C:7]1[C:6]([CH3:12])=[C:5]2[C:3](=[C:2]([CH3:1])[CH:8]=1)[N:4]=[CH:16][CH:17]=[C:18]2[CH3:19])([O-:11])=[O:10]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1N
Reactant: COCCC(C)(OC)OC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc([N+](=O)[O-])c(C)c2c(C)ccnc12
Temperature: 60 °C

Procedure:
A mixture of 2,5-dimethyl-4-nitroaniline (0.96 g), ferric chloride hexahydrate (2.50 g), zinc chloride (0.094 g), concentrated hydrochloric acid (0.481 mL), and ethanol (8 mL) is heated to 60° C. 1,3,3-trimethoxybutane (0.73 mL) is added dropwise while the reaction mixture is kept at 60° C. The reaction mixture is heated at reflux overnight and cooled to room temperature. A solution of 10% aqueous sodium hydroxide is added, and the mixture is extracted three times with methylene chloride. The combined organic layers are dried over sodium sulfate, filtered and evaporated to afford a crude product. The crude product is purified by flash chromatography using 25% ethyl acetate in hexane as eluent, providing 6-nitro-4,5,8-trimethylquinoline.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[Cl:30][C:31]1[N:36]=[CH:35][N:34]=[C:33]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:32]=1.C(N(CC)CC)C>O1CCCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:12]([N:40]2[CH2:41][CH2:42][N:37]([C:33]3[CH:32]=[C:31]([Cl:30])[N:36]=[CH:35][N:34]=3)[CH2:38][CH2:39]2)=[O:14])[CH2:15][CH2:16]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Clc1cc(N2CCNCC2)ncn1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(c3cc(Cl)ncn3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-tert-butoxycarbonyl isonipecotic acid (12.93 g) in tetrahydrofuran (250 ml) at 0° C. was added a solution of carbonyldiimidazole (8.32 g) in tetrahydrofuran (70 ml). The resulting solution was stirred at ambient temperature for 2 hours. This solution was cooled to 0° C. and a solution of (6-chloro-pyrimidin-4-yl)piperazine hydrochloride (13.25 g) and triethylamine (23.57 ml) in dichloromethane (200 ml) added dropwise over 20 minutes. The suspension obtained was stirred at ambient temperature for 18 hours. The mixture was diluted with dichloromethane and washed with water, 2M aqueous citric acid solution, saturated aqueous sodium bicarbonate solution, dried (Na2SO4) and evaporated to give 1-(tert-butoxycarbonyl)-4-[4-(6-chloro-pyrimidin-4-yl)piperazin-1-ylcarbonyl]piperidine (17.45 G) as a cream solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][C:13]([OH:15])=O)[CH2:9][CH2:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]12([NH2:26])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl>[C:16]12([NH:26][C:13](=[O:15])[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10][CH3:11])[CH2:23][CH:22]3[CH2:21][CH:20]([CH2:19][CH:18]([CH2:24]3)[CH2:17]1)[CH2:25]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CCCN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CC(=O)NC12CC3CC(CC(C3)C1)C2)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Next, methylene chloride (208 ml) was added to a mixture of 2-[N-(t-butoxycarbonyl)-N-propylamino]acetic acid (4.52 g, 20.8 mmol) and 1-adamantaneamine (3.46 g, 22.9 mmol), and the whole was stirred at room temperature. N,N-Diisopropylethylamine (7.25 ml, 41.6 mmol) and then O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (8.71 g, 22.9 mmol) were added thereto, and the whole was stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 7.88 g (quantitatively) of 2-[N′-(t-butoxycarbonyl)-N′-propylamino]acetic acid N-(1-adamantyl)amide as a colorless oily matter. The obtained oily matter solidified at room temperature.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.Br[CH2:14][CH2:15][CH:16]=[CH2:17].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:17]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=1)[CH2:16][CH:15]=[CH2:14]
Reactant: C=CCCBr
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C=CCCNc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 6.2 %

Procedure:
4-Trifluoromethoxy-phenylamine (2.5 g, 14 mmol), 4-bromobut-1-ene (2.0 g, 14 mmol) and Cs2CO3 (1.4 g, 4.2 mmol) were mixed together, and the mixture was stirred at ambient temperature for 7 days. The title compound (0.2 g, 6.1%) was obtained by silica gel column chromatography (eluting with petroleum ether/ethyl acetate=10/1). 1H NMR (300 MHz, CDCl3): δ 7.12-7.02 (m, 2H), 6.58-6.53 (m, 2H), 5.80-5.46 (m, 1H), 5.20-5.11 (m, 2H), 3.17 (t, 2H, J=6.6 Hz), 2.43-2.35 (m, 2H). LC-MS: [M+1]+ 232.2.
Reaction SMILES: CN(C)C=[N:4][C:5]1[S:9][N:8]=[C:7]([C:10]#[N:11])[C:6]=1[C:12]#[N:13].C(O)C.Cl>O>[NH2:4][C:5]1[S:9][N:8]=[C:7]([C:10]#[N:11])[C:6]=1[C:12]#[N:13]
Reactant: CN(C)C=Nc1snc(C#N)c1C#N
Agent: Cl
Solvent: O
Solvent: CCO
Product: N#Cc1nsc(N)c1C#N
Yield: 87 %

Procedure:
A mixture of 45.3 parts of N,N-dimethyl-N'-(3,4-dicyanoisothiazol-5-yl)-formamidine, 400 parts of ethanol and 60 parts of concentrated hydrochloric acid is heated at the boil for 2.5 hours, after which it is introduced into 400 parts of water. The colorless precipitate is filtered off under suction, washed with water and dried to give 28.6 parts (87% of theory) of 5-aminoisothiazole-3,4-dicarbonitrile.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC3OCCOC=3C=2)[C:31](F)=[CH:30][N:29]=1.NC1C=C2C(=CC=1)NC=C2>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:21]=[C:22]5[C:23](=[CH:24][CH:25]=4)[NH:29][CH:30]=[CH:31]5)[N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Nc1ccc2[nH]ccc2c1
Product: Fc1cnc(Nc2ccc3[nH]ccc3c2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 5-aminoindole were reacted to yield N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[(1H)-indol-5-yl]-2,4-pyrimidinediamine. LCMS: ret. time: 20.37 min.; purity: 97%; MS (m/e): 378 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH3:27].O>CN(C=O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)([O:3][CH2:26][CH3:27])=[O:2]
Reactant: O=C(O)c1ccc(-c2nc3ccccc3s2)cc1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2nc3ccccc3s2)cc1
Reaction time: 48 h
Yield: 81 %

Procedure:
To a slurry of 2-(4-carboxyphenyl)benzothiazole (4.5 g, 17 mmol.) in DMF (38 mL), potassium carbonate (5.39 g, 39 mmol) was added and the mixture was cooled in an ice bath. Bromoethane (7.2 mL, 102 mmol) was added in portions, and the mixture was allowed to come to room temperature. After 48 hours, the mixture was poured into water and the separated solids (4.51 g) were collected. A solution of the crude product was passed through a column of silica gel. The product residue (4.19 g), left after evaporation of the solvent, was recrystallized from ethanol; 3.96 g (81% yield), m.p. 132-133.6° C. Mass spec: m/z 283 (M+). Anal. Calcd for C16H13NO2S: C, 67.83; H, 4.62; N, 4.94; S, 11.31%. Found, C, 67.86; H, 4.62; N, 4.89; S, 11.45%. FT-IR (KBr; cm−1): 3100 (sp2C—H), 2989 (sp3C—H), 1710 (C═O), 1522 (asym NO2), 1341 (sym NO2), 1279 (C—O—C), 1108, 773, 753, 696. 1H NMR (CDCl3; δ in ppm): 1.45 (t, 3H, methyl), 4.45 (q, 2H, OCH2), 7.4-7.55 (m, 2 ArH), 7.9 (d, 1 ArH), 8.05-8.20 (m, 5 ArH). 13C NMR (CDCl3; δ in ppm): 14.76, 61.72 (sp3 C), 122.12, 123.99, 126.09, 126.99, 127.78, 130.61, 132.79, 135.67, 137.67, 137.74, 154.51, 166.32 (sp2C).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=2)[NH:6][CH:5]=1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>[OH-].[Na+]>[C:21]1([CH2:20][O:19][C:17]([NH:1][CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=3)[NH:6][CH:5]=2)=[O:18])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCc1c[nH]c2ccc(C(=O)O)cc12
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCc1c[nH]c2ccc(C(=O)O)cc12)OCc1ccccc1
Reaction time: 1.25 h

Procedure:
A vigorously stirred solution of 3-(2-amino-ethyl)-1H-indole-5-carboxylic acid (50 g) in aqueous sodium hydroxide (1 M, 450 ml) was cooled in an icebath and benzyl chloroformate (60 ml) and aqueous sodium hydroxide (1 M, 430 ml) were added simultaneously dropwise over a period of 1 hour so as to maintain the pH >10. The reaction mixture was stirred at ca 5° C. for 1.25 hour then a further portion of aqueous sodium hydroxide (1 M, 130 ml) was added. After a further 2 hour. the reaction mixture was extracted with ether (2×500 l ml) and the aqueous layer treated with sodium chloride (200 g), acidified to pH 1 with concentrated hydrochloric acid (80 ml) and extracted with ethyl acetate (3×500 ml). The combined extracts were washed with aqueous sodium chloride (10%, 2×500 ml) dried (MgSO4) and evaporated to dryness to give the title compound as a white solid (61.8 g) mp 186.5°-188°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].FC(F)(F)S(O[CH2:16][C:17]([F:20])([F:19])[F:18])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C.CCOC(C)=O>[F:18][C:17]([F:20])([F:19])[CH2:16][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1cccc(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of commercially available 3-hydroxybenzaldehyde (2.000 g; 16.40 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.561 g; 19.70 mmol), and Cs2CO3 (8.004 g; 24.60 mmol) in anh. DMF (30 ml) was stirred at rt, under nitrogen, for 1 h. Water and AcOEt were added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 3-(2,2,2-trifluoroethoxy)benzaldehyde as a colorless oil. LC-MS (conditions A): tR=0.75 min.; no ionisation.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2>>[C:1]1([S:7]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([O:12][CH3:11])=[CH:21][CH:20]=3)[CH:16]=[CH:17]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Yield: 67 %

Procedure:
The title compound was prepared from benzene sulfonyl chloride and 5-methoxy-1H-indole, according to Method A, described above. Yield 67%; mp 73-75° C.; 1H NMR (CDCl3) δ 7.55-7.82 (m, 3H), 7.41-7.48 (m, 2H), 7.31-7.37 (m, 2H), 6.83-6.90 (m, 2), 6.51-6.52 (dd, J=4 Hz, 1H); 13C NMR (CDCl3) δ 156.9, 138.6, 134.2, 132.2, 129.9, 129.6, 127.5, 127.1, 114.8, 114.2, 109.8, 104.1, 56.0; MS (ES+) m/z 287.99 (M++1).
Reaction SMILES: [Na].[CH3:2][C:3]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[CH2:5][C:4]2=[N:12][OH:13].[CH2:14](Br)[CH:15]=[CH2:16]>CO>[CH2:16]([O:13][N:12]=[C:4]1[CH2:5][CH:6]2[C:9]([CH3:10])([CH3:11])[C:3]1([CH3:2])[CH2:8][CH2:7]2)[CH:15]=[CH2:14]
Reactant: CC12CCC(CC1=NO)C2(C)C
Reactant: C=CCBr
Agent: [Na]
Solvent: CO
Product: C=CCON=C1CC2CCC1(C)C2(C)C
Reaction time: 1 h

Procedure:
4.6 g (0.2 moles) of metallic sodium are dissolved in 200 ml of methanol, and 33.4 g (0.2 moles) of (±)-1,7,7-trimethyl-bicyclo(2.2.1)heptane-2-one-oxime are added to the solution. After one hour of boiling 24.0 g (0.2 moles) of allyl bromide are introduced, and the mixture is boiled for 3 hours. The suspension is cooled, the separated sodium bromide is filtered off, the filtrate is concentrated, and the concentrate is subjected to fractional distillation in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[NH:14][C:15](=[O:26])[NH:16][C:17]1[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=1)=[O:6].[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[NH:14][C:15](=[O:26])[NH:16][C:17]1[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:35][CH2:34][CH2:33][O:32][CH3:31])=[O:25])[N:21]=1)=[O:6]
Reactant: COCCN
Reactant: COc1ccccc1C(=O)c1ccc(C)cc1NC(=O)Nc1nc(CC(=O)O)cs1
Product: COCCNC(=O)Cc1csc(NC(=O)Nc2cc(C)ccc2C(=O)c2ccccc2OC)n1
Yield: 70 %

Procedure:
2-(2-{3-[2-(2-Methoxy-benzoyl)-5-methyl-phenyl]-ureido}-thiazol-4-yl)-N-(methoxy-ethyl)-acetamide (169 mg, 70%) was prepared from (2-{3-[2-(2-methoxy-benzoyl)-5-methyl-phenyl]-ureido}-thiazol-4-yl)-acetic acid (213 mg, 0.5 mmol) and 2-methoxyethylamine (38 mg, 0.5 mmol) following the general procedure K.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[N:18][O:19][CH2:20][C:21]([O:23]CC)=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[OH-].[K+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[N:18][O:19][CH2:20][C:21]([OH:23])=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CON=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=NOCC(=O)O)c2ccc(OC)cc2)cc1
Reaction time: 16 h
Yield: 55 %

Procedure:
A solution of ethyl di-(4-methoxyphenyl)methyleneamino-oxyacetate (1.0 g.) in ethanol (20 ml.) and water (5 ml.) containing potassium hydroxide (1.0 g.) was left at ambient temperature for 16 hours. The solution was evaporated and the residue partitioned between ether and water. The aqueous layer was separated and acidified with concentrated hydrochloric acid. The mixture was extracted with ether, the extract dried (MgSO4) and evaporated to give di-(4-methoxyphenyl)methyleneamino-oxyacetic acid as a solid (0.5 g.), m.p. 105°-107° C. (55% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-:10].[Na+]>O.[Ni].[Pd]>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([C:7]([OH:10])=[O:8])[CH2:4][O:3]1
Reactant: [OH-]
Reactant: CC1(C)OCC(CO)O1
Agent: [Ni]
Agent: [Pd]
Agent: [Na+]
Solvent: O
Product: CC1(C)OCC(C(=O)O)O1
Reaction time: 2 h
Yield: 86 %

Procedure:
40.7 g (308 mmoles) of a glycerin ketal mixture containing 97.5% by weight of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane and 12.2 g (305 mmoles) of sodium hydroxide were dissolved in 366 ml of water. After transferring the mixture to a nickel shaker-type autoclave, the solution was heated to about 80° C. under a pressure of 25 bar in the presence of 4 g of an activated carbon containing 5% by weight of palladium with agitation for about 2 hours. The pressure in the autoclave rose briefly to 30 bar, subsequently fell back to 25 bar and, after another hour, increased to 63 bar. After 2 hours, the pressure remained constant at 53 bar. The autoclave was then vented. The pH of the solution was adjusted, the water in the solution was distilled off, and the remaining residue was hot extracted in the same manner as described in Example 2. The 2,2-dimethyl-1,3-dioxolane-4-carboxylic acid, Na salt was isolated in a yield of 86% of the theoretical. The melting point of the salt was 243°-246° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]=2[CH3:15])[O:4][N:3]=1.[H][H]>C(O)C.[Pt]=O>[CH3:15][C:8]1[CH2:9][CH2:10][CH2:11][C:12]([CH3:13])([CH3:14])[C:7]=1[C:5](=[O:4])[CH:6]=[C:2]([NH2:3])[CH3:1]
Reactant: [H][H]
Reactant: CC1=C(c2cc(C)no2)C(C)(C)CCC1
Agent: O=[Pt]
Solvent: CCO
Product: CC(N)=CC(=O)C1=C(C)CCCC1(C)C
Yield: 99.4 %

Procedure:
30.75 g (0.15 mole) of 3-methyl-5-[2,6,6-trimethylcyclohex-1-en-1-yl]-isoxazole were dissolved in 50 ml of dry ethanol and the solution was added to 1.396 g of a mixture of 82.9 % of platinum oxide in 600 ml of ethanol, the said mixture having previously been subjected to a hydrogenation. The alcoholic solution was then subjected to a hydrogenation at ordinary temperature and pressure and, after absorption of one equivalent of hydrogen, was filtered through a Celite carrier. After having been concentrated under reduced pressure, the residual mixture was recrystallized from hexene containing traces of ethanol to yield 30.91 g (yield 100 %) of 2,6,6-trimethyl-1-[3-amino-but-2-enoyl]-cyclohex-1-ene which exists in two interconvertible crystalline structures: m.p. 124.5° - 125.0° and 135°-136°.
Reaction SMILES: C([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])=[O:12])=[O:7])(C)(C)C.Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[S:42]([NH:45][CH2:46][CH3:47])(=[O:44])=[O:43])=[CH:32][CH:31]=1>>[CH2:19]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[S:42]([NH:45][CH2:46][CH3:47])(=[O:44])=[O:43])=[CH:32][CH:31]=2)[C:15]1=[O:25])=[O:12])=[O:7])[C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:17]=1
Reactant: CCNS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Product: CCNS(=O)(=O)c1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]butanamide (prepared by the method of Fisher, et al; U.S. Pat. No. 5,206,235) and 4-bromomethyl-2'-(ethylaminosulfonyl)-1,1'-biphenyl by the procedure described in Example 1, Step E. 1H NMR (400 MHz, CDCl3): δ 0.77 (t, 7Hz, 3H), 1.33 (s, 6H), 1.40 (s, 9H), 1.47 (s, 3H), 1.87 (m, 1H), 2.35-2.6 (m, 7H), 3.12 (t, 7Hz, 1H), 4.52 (m, 1H), 4.83 (d, 15 Hz, 1H), 5.17 (br s, 1H), 5.38 (d, 15 Hz, 1H), 6.66 (d, 7Hz, 1H), 7.1-7.3 (m, 7H), 7.35 (d, 8 Hz, 2H), 7.46 (m, 1H), 7.55 (m, 1H), 8.10 (d, 8 Hz, 1H). FAB-MS: calculated for C35H44N4O6S 648; found 649 (M+H, 42%).