Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:58])[C:5]([S:52]([CH:55]([CH3:57])[CH3:56])(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][C:34]=2[F:35])[C:31]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:30][CH:29]=[CH:28]3)[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:59](Cl)(Cl)=[O:60]>C(#N)C.ClCCl>[C:39]([O:38][C:37]([N:36]([C:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[C:4]([F:58])[C:5]=4[S:52]([CH:55]([CH3:57])[CH3:56])(=[O:53])=[O:54])[NH:1][C:59](=[O:60])[O:21][CH2:20][C@H:19]([CH3:22])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:23])=[C:34]([F:35])[CH:33]=2)[CH:28]=[CH:29][N:30]=1)[C:44](=[O:45])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:43])([CH3:42])([CH3:40])[CH3:41]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(C(Nc2cc3ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3cc2F)C(=O)N(C)Cc2cc(N)cc(F)c2S(=O)(=O)C(C)C)ccc1[C@@H](C)CO
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1cc(F)c(S(=O)(=O)C(C)C)c(c1)CN(C)C(=O)[C@@H]2Nc1cc2ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2cc1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 21.8 %

Procedure:
A solution of 34A (170 mg, 0.206 mmol) in acetonitrile (3 mL) and dichloromethane (6 mL) was cooled to 0° C. To this solution, was added phosgene (20% in toluene, 0.112 mL, 0.226 mmol). The mixture was stirred at 0° C. for 5 min, and rt for 1 h. The mixture was bubbled with Ar for 10 min to remove excess phosgene. The resulting solution was added dropwise over 3 h via syringe pump into a solution of TEA (0.287 mL, 2.058 mmol) in CH2Cl2 (260 mL). The solution was stirred for 16 h, and then concentrated and purified by flash chromatography to give a mixture of diastereoisomers (98 mg, 0.115 mmol, 55.9% yield). The diastereomers were separated by a prep chiral HPLC equipped with a OD column to give 34B (38 mg, 0.045 mmol, 38.8% yield). MS (ESI) m/z: 852.3 [M+1]+. 1H NMR (500 MHz, methanol-d4) δ ppm 8.10 (1H, d, J=5.8 Hz), 7.78 (1H, dd, J=7.8, 1.5 Hz), 7.55 (1H, d, J=5.8 Hz), 7.51 (1H, d, J=8.0 Hz), 7.41 (1H, d, J=12.1 Hz), 7.06 (1H, d, J=8.3 Hz), 7.04 (1H, d, J=1.7 Hz), 6.61 (1H, dd, J=12.0, 2.1 Hz), 6.27 (1H, d, J=1.1 Hz), 5.67-5.78 (2H, m), 4.63 (1H, t, J=11.0 Hz), 4.24 (1H, d, J=17.9 Hz), 3.98 (1H, dd, J=10.7, 4.4 Hz), 3.45-3.57 (2H, m), 3.34-3.41 (3H, m), 2.28 (3H, s), 1.38 (3H, d, J=6.9 Hz), 1.35 (3H, d, J=6.9 Hz), 1.33 (3H, d, J=6.9 Hz), 1.28 (18H, s).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:13]=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.C(=O)([O-])[O-].[K+].[K+].[N+:20]([C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH2:29][CH2:30]I)=[CH:25][CH:24]=1)([O-:22])=[O:21]>C(#N)C.C(O)C>[N+:20]([C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH2:29][CH2:30][N:2]([CH2:3][C:4]2[CH:13]=[N:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH3:1])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: CNCc1cnc2ccccc2n1
Reactant: O=[N+]([O-])c1ccc(OCCCI)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: CN(CCCOc1ccc([N+](=O)[O-])cc1)Cc1cnc2ccccc2n1
Temperature: 85 °C
Yield: 83.1 %

Procedure:
To a stirred suspension of 2-(methylaminomethyl)quinoxaline (1.10 g, 6.35 mmol) and potassium carbonate (0.88 g, 6.35 mmol) in 2:1 acetonitrile/ethanol (40 mL) was added 1-(4-nitrophenoxy)-3-iodopropane (1.95 g, 6.35 mmol). The resulting mixture was heated at 85° C. overnight, concentrated, and partitioned between ethyl acetate and 10% aqueous potassium carbonate. The organic phase was dried (MgSO4), decolorized (charcoal), and concentrated to afford 1.86 g (83%) of product as a yellow semi-solid which was of sufficient purity to use in the next step.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH2:14][CH:15]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:17][CH2:16]1>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][CH2:14][CH:15]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:17][CH2:16]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OCCC1COc2ccccc2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.2 %

Procedure:
6.29 g (33 mmol) of p-toluenesulphonyl chloride are added while stirring at room temperature to a solution of 5.35 g (30 mmol) of 3-(2-hydroxyethyl)chroman in 30 ml of absolute pyridine, the slightly exothermic reaction being maintained at room temperature by means of an ice bath. After stirring for a further three hours at room temperature, the reaction mixture is poured onto ice-water. The crystals formed are filtered off with suction, washed with water and dried in vacuo. 5.9 g (59.2%) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman, which melts at 91°-93°, are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:14]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])([CH3:16])[CH3:15].N1C=CN=C1.O>CN(C)C=O>[C:14]([Si:18]([CH3:20])([CH3:19])[O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102 %

Procedure:
To a solution of ethyl 3-hydroxyphenylacetate (6 g) and tertbutyldimethylsilyl chloride (6 g) in 80 ml of anhydrous dimethylformamide are added 5.66 g of imidazole and the mixture is stirred at room temperature for 1 hour 30 minutes. The reaction mixture is then poured into water and extracted twice with ethyl acetate. The pooled organic extracts are dried over sodium sulfate and concentrated to dryness to give 10 g of the product as a yellow oil.
Reaction SMILES: CS(C)=O.Cl[C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]#[C:15][CH3:16])[N:9]=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([NH:26][CH2:27][CH2:28][CH3:29])[CH2:24][CH3:25]>C(OCC)(=O)C>[CH2:13]([O:12][C:10]1[CH:11]=[C:6]([N:26]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24][CH3:25])[N:7]=[CH:8][N:9]=1)[C:14]#[C:15][CH3:16]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: CCCNCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC#CCOc1cc(N(CCC)CCC)ncn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To 2 ml of dimethylsulfoxide were added 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate, and 152 mg of dipropylamine, followed by stirring at 80° C. for 8 hours. The reaction mixture was then left for cooling to room temperature, diluted with ethyl acetate, and washed twice with an aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel thin layer chromatography to give 179 mg of 4-(2-butynyloxy)-6-(dipropylamino)pyrimidine (the present compound (113)).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:35])[O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1>N1C=CC=CC=1>[C:24](=[O:35])([O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)[CH2:4][CH2:3]1)[O:25][C:26]1[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=1
Reactant: O=c1ccc(N2CCC(O)CC2)n[nH]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCN(c2ccc(=O)[nH]n2)CC1
Temperature: 30 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
To a solution of 6-(4-hydroxypiperidin-1-yl)pyridazin-3(2H)-one (3.9 g, 20 mmol) in pyridine (10 mL) was added DIPEA (3.87 g, 30.0 mmol) and 4-nitrophenyl carbonochloridate (6.03 g, 30 mmol) and the resulting mixture was stirred at 30° C. for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (DCM to DCM/MeOH=20/1) to afford the title compound (3.3 g, 46%) as a white solid. [LCMS: Rt=1.47 min, m/z 361.1 (M+H)]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][C:6]2[C:7](=[O:19])[CH2:8][CH2:9][CH2:10][N:11]([C:16]([NH2:18])=[O:17])[C:12](=[O:15])[CH2:13][CH2:14][C:5]=2[CH:4]=1.[CH2:22]([OH:24])[CH3:23]>>[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([C:7](=[O:19])[CH2:8][CH2:9][CH2:10][NH:11][C:16]([NH2:18])=[O:17])=[C:5]([CH:4]=1)[CH2:14][CH2:13][C:12]([O:24][CH2:22][CH3:23])=[O:15]
Reactant: CCO
Reactant: NC(=O)N1CCCC(=O)c2ccc(Cl)cc2CCC1=O
Agent: Cl
Product: CCOC(=O)CCc1cc(Cl)ccc1C(=O)CCCNC(N)=O
Temperature: 25 °C
Reaction time: 312 h

Procedure:
7 ml of concentrated hydrochloric acid are added to a solution of 6.80 g (0.023 mol) of 11-chloro-2,3,5,6,7,8-hexahydro-3,8-dioxo-4-benzazecine-4(1H)-carboxamide in 5 l of ethanol and the mixture is stirred at room temperature for 13 days. The solution is concentrated, extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatography on silica gel with methylene chloride/methanol (97:3) and crystallization from ethyl acetate/hexane gives ethyl 5-chloro-2-(4-ureidobutyryl)hydrocinnamate as white crystals with melting point 127°-129°.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[N:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=1[C:9]([OH:11])=O.C(N(CC)CC)C.[NH2:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([OH:34])[CH2:29]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:16][C:13]1[CH:14]=[N:15][C:7]([O:6][C:5]2[CH:17]=[CH:18][CH:19]=[C:3]([S:2][CH3:1])[CH:4]=2)=[C:8]([CH:12]=1)[C:9]([NH:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([OH:34])[CH2:29]1)=[O:11]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Reactant: N[C@@H]1CCC[C@@H](O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@@H]2CCC[C@@H](O)C2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.6 %

Procedure:
2-[3-(Methylsulfanyl)phenoxy]-5-fluoronicotinic acid (345 mg, 1.26 mmol) was dissolved in dimethylformamide (10 ml) and triethylamine (865 μl, 11.8 mmol) was added followed by (1R,3R)-3-aminocyclohexanol hydroformate (200 mg, 1.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (715 mg, 3.73 mmol) and 1-hydroxybenzotriazole (185 mg, 1.37 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between 10% aq. citric acid solution (50 ml) and diethyl ether (50 ml). The organic was washed with sat. sodium bicarbonate solution (50 ml), water (25 ml) and brine (10 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (10:90 to 70:30) as eluant to give 5-fluoro-N-[(1R,3R)-3-hydroxycyclohexyl]-2-[3-(methylsulfanyl)phenoxy]nicotinamide (171 mg) as a colourless gum.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19](=[S:21])[NH2:20])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:22]([O:24][C:25](=[O:32])[C:26](=O)[CH:27](Cl)[CH2:28][CH3:29])[CH3:23]>CN(C)C=O>[CH2:22]([O:24][C:25]([C:26]1[N:20]=[C:19]([C:10]2[C:11]3[C:16](=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:9]=2)[S:21][C:27]=1[CH2:28][CH3:29])=[O:32])[CH3:23]
Reactant: COc1cccc2c(C(N)=S)cn(CC3CCCCC3)c12
Reactant: CCOC(=O)C(=O)C(Cl)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(-c2cn(CC3CCCCC3)c3c(OC)cccc23)sc1CC
Yield: 152.3 %

Procedure:
A mixture of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbothioic acid amide (0.227 g, 0.754 mmol) and crude 3-chloro-2-oxo-pentanoic acid ethyl ester (1.34 g, 7.52 mmol) in dimethylformamide (4 ml) was subjected to microwave irradiation for 25 min at 140° C. The reaction mixture was concentrated in vacuo and the obtained reside was purified by silica gel column chromatography eluting with 25% acetone in heptane to afford crude 2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-5-ethyl-thiazole-4-carboxylic acid ethyl ester (0.490 g). This material was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[O:10][C:9]([C:11]2[C:18]([O:19][CH2:20][O:21][CH3:22])=[CH:17][C:16]([O:23][CH2:24][O:25][CH3:26])=[CH:15][C:12]=2[CH:13]=[O:14])=[CH:8][CH:7]=1.[CH2:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(OCC)C.C1([Li])C=CC=CC=1.O>C(OCC)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[O:10][C:9]([C:11]2[C:18]([O:19][CH2:20][O:21][CH3:22])=[CH:17][C:16]([O:23][CH2:24][O:25][CH3:26])=[CH:15][C:12]=2[CH:13]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[OH:14])=[CH:8][CH:7]=1
Reactant: COCOc1cc(C=O)c(-c2ccc(C3OCCO3)o2)c(OCOC)c1
Reactant: C1CCCCC1
Agent: [Li]c1ccccc1
Solvent: CCOCC
Solvent: O
Product: COCOc1cc(OCOC)c(-c2ccc(C3OCCO3)o2)c(C(O)c2ccccc2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
2-[5-(1,3-Dioxolan-2-yl)furan-2-yl]-3,5-bis(methoxymethoxy)benzaldehyde (135 mg, 0.374 mmol) was dissolved in diethyl ether (10 mL), and the solution was cooled to −78° C., and then cyclohexane/diethyl ether solution of 1.06 mol/L phenyllithium (0.54 mL, 0.57 mmol) was added thereto and stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and extracted with diethyl ether. The organic layer was washed with aqueous saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent was extracted out under reduced pressure. The resulting residue was purified through preparative thin-layer chromatography (chloroform/methanol=50/1) to obtain 1-{2-[5-(1,3-dioxolan-2-yl)furan-2-yl]-3,5-bis(methoxymethoxy)phenyl}-1-phenylmethanol (93.9 mg, 57%).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@:6]12[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:24])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]1=[CH:10][C:9](=[O:25])[CH2:8][CH2:7]2)(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[C:1]([O:4][CH2:5][C@@:6]12[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([OH:24])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]1=[CH:10][C:9](=[O:25])[CH2:8][CH2:7]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reaction time: 2 h

Procedure:
To a solution of 25.6 g of 19-acetoxyandrost-4-ene-3,17 -dione in 4 liters of methanol cooled to 0° C is added 3.1 g of sodium borohydride, and the mixture is stirred at 0° C for 1 hour after which 30 ml of acetic acid is added and the methanol removed under reduced pressure. The resulting residue is taken up in ethyl acetate and washed with water. The organic layer is dried over magnesium sulfate, filtered and the solvent removed. The solid residue is dissolved in 2 liters of chloroform treated with 125 g of manganese dioxide and stirred for 2 hours. The reaction mixture is filtered, and the solvent removed under reduced pressure. The residue is chromatagraphed on alumina using benzene-ether (1:1) as the eluant. The product is recrystallized from acetone-hexane to give 19- acetoxy-17β-hydroxyandrost-4-en-3-one, M.P. 125°-127° C.
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:13])=O.[CH3:15]COCC>CO>[ClH:13].[NH2:1][C:2]1([C:8]([O:10][CH3:15])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: CCOCC
Reactant: NC1(C(=O)O)CCCCC1
Solvent: CO
Product: COC(=O)C1(N)CCCCC1
Product: Cl

Procedure:
To a suspension of 2 g (14 mmol) of 1-aminocyclohexanecarboxylic acid in 20 mL of methanol is sparged hydrogen chloride for 2 minutes. 1.2 mL (16.8 mmol) of thionyl chloride are added to the solution obtained and the reaction medium is refluxed for 6 hours. After cooling, the mixture is concentrated under reduced pressure and the residue obtained is taken up in 5 mL of methanol. 50 mL of ether are added so as to precipitate 2.3 g of methyl 1-aminocyclohexanecarboxylate hydrochloride in the form of a white powder.
Reaction SMILES: [F:1][C:2]1[C:3](SC)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:15]1C=CC=C(C(OO)=O)C=1.[S:25](S([O-])=O)([O-:28])(=O)=[O:26].[Na+].[Na+]>ClCCl>[F:1][C:2]1[C:3]([S:25]([CH3:15])(=[O:28])=[O:26])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: COC(=O)c1cccc(F)c1SC
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cccc(F)c1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of methyl 3-fluoro-2-methylsulphenylbenzoate (14.0 g) and 3-chloroperbenzoic acid (50-60%, 55.0 g) in dichloromethane was stirred at 25° C. for 1.5 hours. 1M Sodium metabisulphite was added and the organic phase washed with sodium bicarbonate and brine, dried over sodium sulphate, filtered and evaporated. The product was recrystallised from ethyl acetate to give 8.6 g of methyl 3-fluoro-2-methylsulphonylbenzoate as white crystals, m.p. 116.2° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH2:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].COC1C=CC2N=[C:26]([NH:28][C:29](=O)[CH2:30][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)SC=2C=1.C(=O)([O-])[O-].[K+].[K+]>CO>[OH2:3].[CH2:16]([O:15][P:11]([CH:9]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH2:10][CH:30]([C:29]1[CH:31]=[CH:30][CH:29]=[CH:26][N:28]=1)[C:31](=[O:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)(=[O:18])[O:12][CH2:13][CH3:14])[CH3:17].[O:38]=[C:31]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH:30]([C:29]1[CH:37]=[CH:32][CH:33]=[CH:26][N:28]=1)[CH2:10][CH:9]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[P:11](=[O:18])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17]
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reactant: COc1ccc2nc(NC(=O)CC(=O)c3ccccc3)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCOP(=O)(OCC)C(CC(C(=O)c1ccccc1)c1ccccn1)P(=O)(OCC)OCC
Product: O

Procedure:
Ethenylidenebisphosphonic acid tetraethyl ester (I, 3.00 g), 1-phenyl-2-(2-pyridinyl)ethanone (II, 2.17 g) and potassium carbonate (2.07 g) are stirred in methanol (20 ml) overnight. The reaction is concentrated under reduced pressure, taken up in ethyl acetate, washed with sodium chloride, dried with magnesium sulfate, and concentrated under reduced pressure. The product is chromatographed eluting with ethyl acetate. The appropriate fractions are pooled and concentrated to give the title compound, MS (m/e) 497, 452, 392, 302 and 288; IR (neat) 2983, 1683, 1597, 1580, 1470, 1448 and 1253 cm-1 ; NMR (CDCl3) 8.52, 8.02, 7.60, 7.49, 7.37, 7.11, 5.46, 4.12, 2.75, 2.55, 1.36, 1.25 and 1.16 δ.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][CH3:13])=[CH:8][C:7]([N+:14]([O-:16])=[O:15])=[CH:6][CH:5]=2.[BH4-].[Na+].O.[F:20][C:21]([F:26])([F:25])[C:22](O)=O>>[CH3:1][CH:2]1[CH:10]([CH2:11][CH2:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=2)[N:3]1[CH2:22][C:21]([F:26])([F:25])[F:20]
Reactant: CCCc1c(C)[nH]c2ccc([N+](=O)[O-])cc12
Reactant: O=C(O)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCCC1c2cc([N+](=O)[O-])ccc2N(CC(F)(F)F)C1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 200 ml 2-neck round bottom flask, equipped with a magnetic stirrer and a cold water condenser, 4-nitrophenylhydrazine was dissolved in 75 mL concentrated hydrochloric acid and stirred at room temperature for 15 minutes. A solution of 2-hexanone (5 mL) in ethanol (25 mL) was added slowly and the reaction flask was heated in an oil bath at 105° C. for 18 h. The mixture was cooled to room temperature and water (100 mL) was added. The mixture was extracted with EtOAc. The organic layer washed with saturated sodium bicarbonate solution, water, and brine solutions and evaporated to dryness. The oily residue was absorbed on silica gel and purified by silica gel chromatography with 20% EtOAc in Hexane solution to give 2-methyl-5-nitro-3-propyl-1H-indole. This indole product was dissolved in trifluoroacetic acid (10 mL) and 1 pellet sodium borohydride (0.7 g) was added and the reaction was stirred at room temperature for 18 h. Water (10 mL) was carefully added and the reaction mixture was extracted twice with EtOAc (15 mL) The organic layer washed with brine and dried over MgSO4, and purified by flash column chromatography on silica gel eluted with 20% EtOAc in hexanes to give 280 mg of 2-methyl-5-nitro-3-propyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-indole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][C:3]=1[F:11].[C:12]1(O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:9])=[CH:4][C:3]=1[F:11]
Reactant: Oc1ccccc1
Reactant: CC(O)c1ccc(Br)c(F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1ccccc1)c1ccc(Br)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
A solution of 1-(4-bromo-3-fluorophenyl)ethanol (1 g, 4.58 mmol), phenol (474 mg, 4.58 mmol), and triphenyl phosphine (2.4 g, 6.88 mmol) was stirred in dry tetrahydrofuran (40 mL) under nitrogen atmosphere. After 1 h, the mixture was cooled to 0° C. Diisopropyl azodicarboxylate (2.3 g, 6.88 mmol) was added with drop-wise method and the reaction was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was purified by column chromatography (silica gel, petroleum ether) to get 1-bromo-2-fluoro-4-(1-phenoxyethyl)benzene (900 mg, 89%).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:8])[CH3:7].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1>CCOCC>[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:8][CH:6]([CH3:7])[CH2:5][CH2:4][CH2:3][C:2]#[CH:1]
Reactant: C1=COCCC1
Reactant: C#CCCCC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: C#CCCCC(C)OC1CCCCO1
Reaction time: 18 h
Yield: 96 %

Procedure:
Alcohol 5 (7.7 g, 68.75 mmol) was dissolved in 75 mL dry ether and cooled to 0°. A few crystals of p-toluenesulphonic acid were added, followed by dropwise addition of 6.35 g (75.6 mmol) of dihydropyran. The solution was warmed to 20°, stirred for 18 hr, and then extracted with saturated aqueous NaHCO3 (25 mL) and brine (25 mL). The solution was dried (MgSO4), concentrated in vacuo, and distilled, yielding 12.96 g of 6 (96% yield).
Reaction SMILES: [Si]([O:18][C:19]1[CH:59]=[CH:58][C:22]([O:23][CH2:24][C@@H:25]([OH:57])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:56]=[CH:55][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH3:52])[C:46]=4[O:53][CH3:54])=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH3:54][O:53][C:46]1[C:47]([O:51][CH3:52])=[CH:48][CH:49]=[CH:50][C:45]=1[CH2:44][NH:43][C:41]([N:38]1[CH2:37][CH2:36][CH:35]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:57])[CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([OH:18])=[CH:59][CH:58]=3)=[CH:56][CH:55]=2)[CH2:40][CH2:39]1)=[O:42]
Reactant: COc1cccc(CNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)c1OC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cccc(CNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)c1OC

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-N-(2,3-dimethoxybenzyl)-1-piperidinecarboxamide ((0.163 g, 0.20 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.035 g, 0.06 mmol)