Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][C:19]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([NH2:38])[N:33]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:48](Cl)(=[O:50])[CH3:49]>C1COCC1.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[NH:18][C:19]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([NH:38][C:48](=[O:50])[CH3:49])[N:33]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=3)[N:21]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nccc(-c2[nH]c(C3CCN(C(=O)OCc4ccccc4)CC3)nc2-c2cccc(C(F)(F)F)c2)n1
Reactant: CC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nccc(-c2[nH]c(C3CCN(C(=O)OCc4ccccc4)CC3)nc2-c2cccc(C(F)(F)F)c2)n1
Temperature: 20 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
To a stirred solution of 4-[5-(2-aminopyrimidin-4-yl)-4-(3-trifluoromethylphenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid benzyl ester (Example 12) (0.220 g, 0.421 mmole) in THF (4 mL) under argon at 0° C. was added diisopropylethylamine (0.22 mL, 1.26 mmole) followed by acetyl chloride (0.036 mL, 0.50 mmole). The reaction was stirred at 20° C. for 1 hour, diluted with water (10 mL) and product extracted with ethyl acetate (2×50 mL). The ethyl acetate extracts were dried over anhydrous sodium sulfate, filtered, concentrated and chromatographed on silica using 5% methanol/methylene chloride to give the product (0.170 g) as an oil.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[C:39]1(B(O)O)[CH2:43][CH2:42][CH2:41][CH:40]=1>>[NH2:30][C:29]1[S:28][C:27]([C:39]2[CH2:43][CH2:42][CH2:41][CH:40]=2)=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1)=[O:24]
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Reactant: OB(O)C1=CCCC1
Product: Cn1ncc(NC(=O)c2nc(C3=CCCC3)sc2N)c1N1CCC(CN)CC1
Yield: 29 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and cyclopent-1-ene-1-boronic acid gave 256 as an off-white solid (23 mg, 29% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.60 (s, 1H), 7.46 (s, 1H), 7.36 (s, 2H), 6.21 (t, J=2.4 Hz, 1H), 3.66 (s, 3H), 3.12-2.97 (m, 4H), 2.75 (t, J=7.3 Hz, 2H), 2.54 (s, 2H), 2.48 (d, J=5.9 Hz, 2H), 2.03-1.93 (m, 2H), 1.84-1.74 (m, 4H), 1.33-1.16 (m, 3H). LCMS (ES+) m/z 402 (M+1)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[NH:14][C:13](=O)[C:12]=2[CH2:11][CH2:10]1.[CH2:29]([N:31](CC)CC)C.CS(Cl)(=O)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:25])([F:26])[F:27])[C:15]=3[N:14]=[C:13]([NH:31][CH3:29])[C:12]=2[CH2:11][CH2:10]1
Reactant: Cc1cc(O)ccc1N1CCc2c1c1cccc(OCC(F)(F)F)c1[nH]c2=O
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CNc1nc2c(OCC(F)(F)F)cccc2c2c1CCN2c1ccc(O)cc1C
Temperature: -10 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
1-(2-Methyl-4-hydroxyphenyl)-4-oxo-6-β,β,β-trifluoroethoxy-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline (2.5 g, 6.4 mmol) was dissolved in dichloromethane, triethylamine(2.2 ml, 16.0 mmol), and methanesulfonyl chloride(1.1 ml, 13.5 mmol) was added at -78° C. The reaction mixture was stirred for 3 hours, then slowly warmed up to -10° C., and stirred for 1 hours. The reaction mixture was extracted with dichloromethane, and the organic layer was washed with water for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized in dichloromethane/hexane to obtain 2.3 g of desired compound as solid in 75% of yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:12][N:11]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[N:31]=[C:32]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[O:33][C:34]=4[CH3:35])=[CH:24][CH:23]=3)[N:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:11]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[N:31]=[C:32]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[O:33][C:34]=4[CH3:35])=[CH:24][CH:23]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(-c2nn(Cc3ccc(OCc4nc(-c5ccccc5)oc4C)cc3)cc2CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
A mixture of ethyl 3-[3-(4-methoxyphenyl)-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (450 mg), 1N aqueous sodium hydroxide solution (2 ml), ethanol (3 ml), and tetrahydrofuran (3 ml) was stirred at room temperature for 1 hour. The reaction mixture was acidified with 1N hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[3-(4-methoxyphenyl)-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (350 mg, yield: 81%). This was recrystallized from ethyl acetate-hexane. Melting point: 137–138° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][NH2:41])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][NH:41][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A67) and 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.[CH2:26]([N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40])[CH2:27][CH:28]=[CH2:29].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[CH2:24]([O:23][CH2:22][C:13]1[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[C:6]2[C:5]3[CH:4]=[CH:3][C:2](/[CH:29]=[CH:28]/[CH2:27][CH2:26][N:30]4[C:38](=[O:39])[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[C:31]4=[O:40])=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:12]=1)[CH3:25]
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCOC(C)C
Reactant: C=CCCN1C(=O)c2ccccc2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOCc1nc2cnc3cc(/C=C/CCN4C(=O)c5ccccc5C4=O)ccc3c2n1CCCOC(C)C
Temperature: 140 °C
Yield: 77.1 %

Procedure:
7-Bromo-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinoline (1.9 g, 4.68 mmol), 2-but-3-enyl-1H-isoindole-1,3(2H)-dione (1.04 g, 5.15 mmol), cesium carbonate (3.05 g, 9.36 mmol), triphenylphosphine (0.246 g, 0.94 mmol), palladium(II) acetate (0.105 g, 0.47 mmol), and N,N-dimethylformamide (DMF) (28 mL) were added to a pressure tube. The vessel was sealed with a TEFLON cap and heated at 140° C. for 2.5 hours. The reaction was cooled to ambient temperature. The reaction was diluted with ethyl acetate and washed multiple times with water. The initial water wash was extracted with ethyl acetate. The organic fractions were combined and washed with water once again. The organic fractions were concentrated under reduced pressure and the residue was purified using a HORIZON HPFC system (silica cartridge, eluting with a linear gradient of 2-20% CMA in chloroform) to yield 1.9 g of 2-{(3E)-4-[2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinolin-7-yl]but-3-enyl}-1H-isoindole-1,3(2H)-dione as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[C@@:19]2([CH3:23])[C:20]([CH3:22])([CH3:21])[C@H:16]([CH2:17][CH2:18]2)[CH2:15][N:14]2[C:24](=[O:34])[C:25]([OH:33])=[C:26]([C:28](OCC)=[O:29])[N:27]=[C:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][NH2:43])=[CH:38][CH:37]=1.CCN(CC)CC>CCO.CCOCC>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@@H:12]1[C@@:19]2([CH3:23])[C:20]([CH3:22])([CH3:21])[C@H:16]([CH2:17][CH2:18]2)[CH2:15][N:14]2[C:24](=[O:34])[C:25]([OH:33])=[C:26]([C:28](=[O:29])[NH:43][CH2:42][C:39]3[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=3)[N:27]=[C:13]12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)C[C@H]1CC[C@@](C)(C2NC(=O)OCc2ccccc2)C1(C)C
Solvent: CCOCC
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(C)[C@@H]2CC[C@@]1(C)[C@@H](NC(=O)OCc1ccccc1)c1nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n1C2
Yield: 21.5 %

Procedure:
A solution of ethyl (7S,10R)-11-(((benzyloxy)carbonyl)amino)-3-hydroxy-10,12,12-trimethyl-4-oxo-6,7,8,9,10,11-hexahydro-4H-7,10-methanopyrimido[1,2-a]azocine-2-carboxylate (1.4595 g, 3.11 mmol), (4-fluorophenyl)methanamine (1.143 mL, 10.00 mmol) and Et3N (1.394 mL, 10 mmol) in EtOH (25 mL) was heated at reflux for 14 h. the reaction mixture was then cooled, diluted with Et2O (100 mL), washed with 1N aq. HCl (1×25 mL), water (2×25 mL) followed by brine (25 mL), then dried (Na2SO4), filtered and concentrated to give a brown paste. The product was purified by preparative HPLC using a C18-column and 40-90% methanol/water (0.1 trifluoroacetic acid) to afford the title compound (0.367 g, 0.669 mmol, 22% yield) as a light brown solid. 1H NMR (500 MHz, CDCl3) δ: 12.21 (0.3 H, brs), 12.08 (0.7 H, s), 8.24 (0.3 H, brs), 7.71 (0.7 H, t, J=6.1 Hz), 7.18-7.38 (8 H, m), 6.92-7.05 (2 H, m), 4.98-5.21 (4 H, m), 4.52-4.58 (1H, m), 4.41-4.47 (1 H, m), 3.67 (0.7 H, d, J=15.6 Hz), 3.56 (0.3 H, d, J=15.6 Hz), 2.08 (0.7 H, t, J=8.1 Hz), 2.01-2.06 (0.3 H, m), 1.73-1.87 (2 H, m), 1.40-1.49 (1H, m), 1.37 (2 H, s), 1.28-1.35 (1 H, m), 1.25 (1 H, s), 1.00 (2 H, s), 0.99 (2 H, s), 0.95 (1 H, s), 0.92 (1 H, s). LCMS (M+H) calcd for C30H34FN4O5: 549.25; found: 549.28. Purity: >96%.
Reaction SMILES: [CH2:1]([N:6]([CH2:12]Cl)[C:7](=[O:11])[CH:8]([Cl:10])[Cl:9])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:14]([O:16][CH2:17][CH2:18][OH:19])[CH3:15].C(N(CC)CC)C.O>C1C=CC=CC=1>[CH2:1]([N:6]([CH2:12][O:19][CH2:18][CH2:17][O:16][CH2:14][CH3:15])[C:7](=[O:11])[CH:8]([Cl:10])[Cl:9])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CCOCCO
Reactant: CC(C)CCN(CCl)C(=O)C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccccc1
Product: CCOCCOCN(CCC(C)C)C(=O)C(Cl)Cl

Procedure:
The solution of N-isopentyl-N-chloromethyldichloroacetamide (24.7 g., 0.1 mole) and 2-ethoxyethanol (9.9 g., 10.7 ml., 0.11 mole) in dry benzene (70 ml) is weighed in a four-necked, round-bottom flask of 250 ml, equipped with a calcium chloride tube, reflux condenser, mechanical stirrer, dropping funnel and thermometer. Triethylamine (10.1 g., 13.9 ml., 0.1 mole) is added to this solution under stirring and cooling by water in such a rate that the temperature is maintained below 40° C. After the addition is complete, the mixture is stirred for an additional 2 hours at room temperature. The mixture is washed with water (2×100 ml.) to remove triethylamine hydrochloride and the possible hydrophilic side-product, the benzene solution is dried over anhydrous sodium sulfate after distillation of the solvent and the residue is evaporated to dry under reduced pressure to give 27.9 g. (93%) of the named product as a pale yellow oil which is of 96% purity according to analysis by gas chromatography and is directly useful for practical purposes without any purification; nD25 =1.4649.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:13][NH:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:21][C:22]([NH:24][C:25](=[NH:28])OC)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:11][N:12]([C:25](=[NH:28])[NH:24][C:22]([O:21][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:23])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CNC1
Reactant: COC(=N)NC(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCC1CN(C(=N)NC(=O)OCc2ccccc2)C1
Temperature: 70 °C
Reaction time: 72 h
Yield: 38.5 %

Procedure:
0.9 g (4.8 mmol) of 3-(N-tert-butyloxycarbonylaminomethyl) azetidine and 1.3 g (6.3 mmol) of N-benzyloxycarbonyl-O-methylisourea was mixed in 6.5 mL toluene and heated to 70° C. for 72 h and then left at roomtemperature for another 72 h. Evaporation followed by flash chromatography using EtOAc followed by MeOH (saturated with NH3(g))/CH2Cl21 1/9, as eluent gave 0.67 g (38%) of the title compound as a white powder.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:23]=[CH:22][C:12]([O:13][CH2:14][CH:15]([OH:21])[CH2:16][N:17]=C(C)C)=[CH:11][CH:10]=1)([CH3:3])[CH3:2].C(OCCOCC1C=CC(OCC2OC2)=CC=1)(C)C.N>>[CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH:15]([OH:21])[CH2:16][NH2:17])=[CH:22][CH:23]=1)([CH3:3])[CH3:2]
Reactant: CC(C)=NCC(O)COc1ccc(COCCOC(C)C)cc1
Agent: CC(C)OCCOCc1ccc(OCC2CO2)cc1
Agent: N
Product: CC(C)OCCOCc1ccc(OCC(O)CN)cc1

Procedure:
A solution of 10 g. of 1-(p-2-isopropoxyethoxymethylphenoxy)-3-isopropylideneamino-propan-2-ol [obtainable by reacting 1-(p-2-isopropoxyethoxymethylphenoxy)-2,3-epoxypropane with ammonia to give 1-(p-2-isopropoxyethoxymethylphenoxy)-3-amino-propan-2-ol and subsequently reacting this with acetone] in 250 ml. of ethanol was hydrogenated on 0.5 g. of Raney nickel at 25° under 1 atmosphere of pressure until 1 equivalent of H2 had been absorbed. The mixture was filtered and the filtrate evaporated to give 1-(p-2-isopropoxyethoxymethyl-phenoxy)-3-isopropylamino-propan-2-ol, fumarate, m.p. 100°.
Reaction SMILES: Br.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[C:13]([OH:24])=[CH:14][C:15]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17][C:16]=3[CH:23]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:25]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:30]=CC=C[CH:26]=1.C(O)(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.CO.ClCCl>[F:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:12]2[C:13]([O:24][CH:25]([CH3:30])[CH3:26])=[CH:14][C:15]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17][C:16]=3[CH:23]=2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CN1CCc2cc(O)c(S(=O)(=O)c3ccc(F)cc3)cc2CC1
Agent: Br
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CC(C)Oc1cc2c(cc1S(=O)(=O)c1ccc(F)cc1)CCN(C)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The phenol (D6) (1.1 g), triphenylphosphine (1.7 g) and isopropanol (0.5 ml) were dissolved in tetrahydrofuran and cooled to 0° C., Diisopropyl azodicarboxylate (1.3 ml) was added dropwise and the mixture stirred at room temperature for 1 h. The mixture was passed through an SCX column and then chromatography on silica eluting with 4% methanol/dichloromethane afforded the titled compound D29 (870 mg) MH+ 365
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([CH:19]=[O:20])[CH2:15][O:16]3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+].CCOC(C)=O.[CH3:38][N:39](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[CH:19]([C:14]1[CH2:15][O:16][C:17]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:8][CH2:7][C:5]1[S:6][C:2]([C:38]#[N:39])=[C:3]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:4]=1)[CH:18]=2)=[O:20]
Reactant: CN(C)C=O
Reactant: O=CC1=Cc2ccc(OCc3cc(-c4ccccc4)c(Br)s3)cc2OC1
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: [C-]#N
Solvent: CCOC(C)=O
Product: N#Cc1sc(COc2ccc3c(c2)OCC(C=O)=C3)cc1-c1ccccc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
7-[(5-Bromo-4-phenyl-2-thienyl)methoxy]-2H-chromene-3-carbaldehyde (120 mg) was dissolved in DMF (2.4 mL). To this reaction liquid were added Zn(CN)2 (65 mL) and Pd(PPh3)4 (65 mg) at room temperature. The reaction mixture was stirred at 100° C. for 5 hours and then poured into 1:1 a mixed vehicle of aqueous NaHCO3 and EtOAc, followed by stirring for 1 hour. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure, followed by purification by silica gel column chromatography (hexane:EtOAc=100:0 to 70:30) to obtain 5-{[(3-formyl-2H-chromen-7-yl)oxy]methyl}-3-phenylthiophene-2-carbonitrile (83 mg) as a pale yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[C:3]1=[N:9]O.C(=O)([O-])[O-:12].[Na+].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[NH:9][C:3]1=[O:12]
Reactant: O=C([O-])[O-]
Reactant: C[C@@H]1CCC[C@H](C)C1=NO
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: C[C@@H]1CCC[C@H](C)C(=O)N1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
Into 40 ml of xylene were added 3.1 g of cis-2,6-dimethylcyclohexanone oxime and 12 g of polyphosphoric acid, the mixture was stirred for 10 hours at 100° C. The reaction mixture was cooled to near room temperature, poured into ice-water. Sodium carbonate was added to the mixture, and the mixture was extracted with ethyl acetate three times. The organic layers was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 2.5 g of cis-3,7-dimethylhexahydro-1H-azepine-2-one.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].I[CH:21]([CH3:23])[CH3:22]>[Cu]>[CH:21]([NH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[C:4]#[N:5])([CH3:23])[CH3:22]
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: CC(C)I
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(C#N)c(NC(C)C)cc1OC
Temperature: 90 °C
Reaction time: 120 h

Procedure:
A suspension of 4.52 g (25.4 mmol) 2-amino-4,5-dimethoxy-benzonitrile, 4.38 g (31.7 mmol) potassium carbonate and 100 mg copper powder in 15 ml 2-iodo-propane is stirred at 90° C. for 5 days. Extractive work-up with ethyl acetate/water and concentration i.V. affords a dark oil, which is purified by flash chromatography (ethyl acetate/hexane). yield: 4.15 g (74%) yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Li]C(C)(C)C.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[O:34][C:33]([C:35]([O:37]C)=O)=[N:32][N:31]=1>C1COCC1>[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[O:34][C:33]([C:35](=[O:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N:32][N:31]=1
Reactant: COC(=O)c1nnc(-c2ccccn2)o1
Reactant: CCCCCCCC/C=C\CCCCCCCBr
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCCCCCCC=CCCCCCCCC(=O)c1nnc(-c2ccccn2)o1
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
A solution of cis-1-bromo-heptadec-8-ene (60 mg, 0.2 mmol) in THF (1 mL) was treated with t-BuLi (1.5 M in pentane, 270 μL, 0.4 mmol) at −40° C. After stirring for 30 min, the resulting alkyl lithium reagent was added to a solution of methyl 5-(pyridin-2-yl)-[1,3,4]-oxadiazole-2-carboxylate (20 mg, 0.1 mmol) in THF (2 mL) at −40° C. The reaction mixture was stirred for 4 h before it was quenched with the addition of brine. The mixture was extracted with EtOAc, concentrated, and purified by flash chromatography (SiO2, 1×3 cm, 30% EtOAc-hexanes) to provide the title compound (8.5 mg, 23%) as white solid. 1H NMR (400 MHz, CDCl3) 8.85 (dd, J=5, 1.2 Hz, 1H), 8.30 (dd, J=7.9, 1.2 Hz, 1H), 7.94 (td, J=7.6, 1.5 Hz, 1H), 7.54 (ddd, J=7.6, 4.7, 1.2 Hz, 1H), 5.34-5.37 (m, 2H), 3.22 (t, J=7.3 Hz, 2H), 2.02 (m, 4H), 1.82 (m, 2H), 1.27-1.41 (m, 20H), 0.88 (t, J=6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) 187.2, 165.1, 161.2, 150.8, 142.6, 150.8, 142.6, 137.3, 130.0, 129.7, 126.7, 124.0, 40.1, 31.9, 29.8, 29.7, 29.5, 29.3, 29.2, 29.1, 29.0, 27.2, 27.1, 23.6, 22.7, 14.1; MALDI-FTMS m/z 412.2955 (C25H37N3O2+H+ requires 412.2958).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]2[C:15]3([CH2:38][O:39][C:11]=2[CH:10]=1)[C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:17](C(C1C=CC=CC=1)C1C=CC=CC=1)[C:16]3=[O:37])C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]2[C:15]3([CH2:38][O:39][C:11]=2[CH:10]=1)[C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:17][C:16]3=[O:37]
Reactant: [H][H]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(OCc3ccccc3)ccc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1Nc2ccccc2C12COc1cc(O)ccc12
Yield: 82.3 %

Procedure:
A suspension of 6-(benzyloxy)-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.60 g, 1.2 mmol) in methanol (20 mL) was degassed by bubbling through nitrogen for 1 h before palladium hydroxide on carbon (20%, 0.08 g, 0.12 mmol) was added. The mixture was stirred under 120 psi of hydrogen at 60° C. for 16 h. The mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The obtained residue was recrystallized with ethyl acetate and hexane to afford 6-hydroxy-2H-spiro[benzofuran-3,3′-indolin]-2′-one (0.25 g, 83%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 10.86-9.35 (br, 2H), 7.19 (td, J=7.6, 1.2 Hz, 1H), 7.03 (d, J=7.3 Hz, 1H), 6.96-6.84 (m, 2H), 6.42 (d, J=8.2 Hz, 1H), 6.29 (d, J=2.1 Hz, 1H), 6.17 (dd, J=8.2, 2.1 Hz, 1H), 4.72 (d, J=9.2 Hz, 1H), 4.59 (d, J=9.2 Hz, 1H); MS (ES+) m/z 254.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1>[Rh].C(O)C>[F:1][C:2]([F:14])([F:15])[CH:3]1[CH2:4][CH2:5][CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:12][CH2:13]1
Reactant: CCOC(=O)c1ccc(C(F)(F)F)cc1
Agent: [Rh]
Solvent: CCO
Product: CCOC(=O)C1CCC(C(F)(F)F)CC1
Reaction time: 5 h

Procedure:
A mixture of 0.47 mol of ethyl 4-trifluoromethylbenzoate (prepared from 4-trifluoromethylbenzoyl chloride, ethanol and pyridine), 1000 ml of ethanol and 20 g of rhodium/activated charcoal (5%) is hydrogenated for 5 hours under a pressure of 5 bar and at a temperature of 60° C. The ethyl 4-trifluoromethylcyclohexanecarboxylate (cis/trans =87%/13%) obtained after removal of the catalyst by filtration and removal of the solvent is, without prior purification, suspended in 300 ml of water and treated with 70 g of 30% sodium hydroxide solution, and the mixture is briefly heated to boiling and stirred at room temperature for 18 hours. Acidification using hydrochloric acid gives the carboxylic acid as a cis/trans mixture.