Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[CH:12][CH3:13])[CH:6]=1.C([O-])(O)=O.[Na+].[H][H]>[Pd].CCOC(C)=O.CCO>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH3:13])[CH:6]=1
Reactant: [H][H]
Reactant: CC=Cc1cccc(OCOC)c1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCc1cccc(OCOC)c1
Yield: 100.3 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (11.0 g, 90.1 mmol) in DMF (110 mL) at 0° C. was added methoxymethyl chloride (7.5 mL, 99.1 mmol) followed by NaH (99.1 mmol, 3.96 g, 60% dispersion in oil) in three portions (violent deprotonationl). The mixture was stirred at 0° C. for 15 min and then at room temperature for 15 h. The reaction was quenched with water and more water was added until all the precipitate dissolved. The solution was extracted in ether (2×150 mL) with water (50 mL), then with saturated Na2CO3 (100 mL), and finally with water (100 mL). The crude product was used in the next reaction. To a suspension of (ethyl)triphenylphosphonium bromide (36.8 g, 99.1 mmol, dried at 90° C. under high vacuum overnight) in THF (250 mL) at 0° C. was added n-BuLi (39.6 mL, 99.1 mmol, 2.5 M in hexanes) over five min. The resulting pretty dark burgundy mixture was stirred at 0° C. for 10 min and then at room temperature for 30 min. It was re-cooled to 0° C. and a solution of the above crude 3-methoxymethoxybenzaldehyde in THF (15 mL) was added slowly. The resulting medium brown mixture was stirred at 0° C. for 2 h and then at room temperature for 2 h. The mixture was quenched by exposing it to air for several min. Because filtering the mixture for this particular Wittig reaction would result in a sticky precipitate clogging the sintered-glass filter, the THF was removed in vacuo and the crude material was dissolved in DMF (100 mL). Extraction in hexanes (4×100 mL) with 50% saturated brine (100 mL) eliminated triphenylphosphonium oxide into the aqueous layer. Flash chromatography with silica gel (gradient to 6% ether/hexanes) produced 1-(methoxymethoxy)-3-(1-propenyl)benzene [(E)/(Z)˜1:1] as a colorless liquid (13.2 g, 82% yield for two steps). A suspension of 3 produced 1-(methoxymethoxy)-3-(1-propenyl)benzene (13.2 g, 74.1 mmol), NaHCO3 (1.24 g, 14.8 mmol), and 10% palladium on carbon (3.3 g) in EtOAc (75 mL) and EtOH (19 mL) was stirred at room temperature for 20 h with a hydrogen balloon attached. The round-bottom flask was purged with nitrogen, the mixture was filtered through Celite, and the Celite was washed well with EtOAc to furnish 1-(methoxymethoxy)-3-propylbenzene as a colorless liquid (13.4 g, 100% yield): 1H NMR (300 MHz, CDCl3) δ 0.94 (t, 3H, J=7.4 Hz), 1.64 (m, 2H), 2.56 (t, 2H, J=7.7 Hz), 3.48 (s, 3H), 5.17 (s, 2H), 6.80-6.90 (three overlapping peaks, 3H), 7.19 (m, 1H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[NH:7])[CH3:6])[CH2:3][CH2:2]1.Br[C:9](=[CH:13]OC)[C:10](=[O:12])[CH3:11].C(N(CC)CC)C.S(=O)(=O)(O)O>C(O)(C)C>[C:10]([C:9]1[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]([CH3:6])=[N:7][CH:13]=1)(=[O:12])[CH3:11]
Reactant: CC(=N)NC1CC1
Reactant: COC=C(Br)C(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(=O)c1cnc(C)n1C1CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
In a 300 mL-volume glass vessel equipped with a stirrer, a thermometer and a dropping funnel, the isopropyl alcohol solution containing 15.9 g (0.162 mol) of N-cyclopropylacetamidine (which was prepared in the above-mentioned Reference Example 4), 19.3 g (0.108 mol) of 3-bromo-4-methoxy-3-buten-2-one and 16.4 g (0.162 mol) of triethylamine were placed. The mixture was heated to 80° C. under stirring for 8 hours for carrying out reaction. After the reaction was complete, 80 mL of sulfuric acid (2 mol/L) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The concentrate was washed with methyl isobutyl ketone, and the aqueous portion was taken out. The aqueous portion was made basic by adding an aqueous 48% sodium hydroxide, while the mixture was kept at a temperature of not higher than 40° C. The aqueous basic portion was subjected to extraction with methyl isobutyl ketone, and the extracted portion was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=2/1) to give 11.8 g (yield: 67%) of 5-acetyl-1-cyclopropyl-2-methylimidazole as pale yellow liquid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[C:16]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:21]([OH:23])=O)#[N:17]>>[C:16]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:21]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:23])#[N:17]
Reactant: N#Cc1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C#N)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-cyano-5-trifluoromethyl-benzoic acid after a reaction time of 94 hours. The product was purified by silica gel chromatography using a 10 g column eluting with EtOAc followed by a second chromatography on a 5 g column eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Colorless solid (2%). MS (ESI): m/z=396.13 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10](=[O:12])(=[O:11])[NH:9][C:8](=[O:13])[C:7]=2[CH:14]=1.CN1C([C:22](NC2SC(C)=CN=2)=[O:23])=C(O)C2C=C(C)C=CC=2S1(=O)=O.[OH-].[Na+:40].Cl[CH2:42][C:43]([O:45][CH3:46])=[O:44]>C1(C)C=CC=CC=1.C(O)(C)(C)C>[OH:13][C:8]1[C:7]2[CH:14]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[S:10](=[O:12])(=[O:11])[NH:9][C:42]=1[C:43]([O:45][CH3:46])=[O:44].[CH3:22][O-:23].[Na+:40]
Reactant: COC(=O)CCl
Reactant: Cc1ccc2c(c1)C(O)=C(C(=O)Nc1ncc(C)s1)N(C)S2(=O)=O
Reactant: COc1ccc2c(c1)C(=O)NS2(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: COC(=O)C1=C(O)c2cc(OC)ccc2S(=O)(=O)N1
Product: C[O-]

Procedure:
The starting compound was prepared by conversion of 5-methoxy-benzisothiazole-3(2H)-one-1,1-dioxide, analogous to 5-methyl-benzisothiazole-3(2H)-one-1,1-dioxide (see Example 8), with sodium hydroxide and methyl chloroacetate into methyl 5-methoxy-3-oxo-benzisothiazolo-2(3H)-acetate-1,1-dioxide. Methyl 4-hydroxy-6-methoxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide (m.p. 183° C., from ethyl acetate/cyclohexane) was obtained by subsequent rearrangement with sodium methylate in toluene/tert. butanol, and methyl 4-hydroxy-6-methoxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide was obtained by subsequent methylation.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:13][C:14]([NH2:16])=[O:15].[CH:17]([O-])([O-])OCC>C1(C)C(C)=CC=CC=1>[OH:15][C:14]1[N:16]=[C:3]([C:2]([F:12])([F:11])[F:1])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:17][N:13]=1
Reactant: NC(N)=O
Reactant: CCOC([O-])[O-]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cnc(O)nc1C(F)(F)F
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 68.5 %

Procedure:
A mixture of ethyl 4,4,4-trifluoroacetoacetate (23.1 g), urea (7.54 g) and ethyl orthoformate (18.6 g) is stirred at 130° C. under argon gas atmosphere for 1.5 hours. To the reaction mixture is added xylene (100 mL) and the mixture is stirred at 140° C. for 17 hours. The reaction mixture is evaporated to remove solvent and the residue is diluted with methanol. The solution is treated with an activated carbon powder, concentrated in vacuo, and triturated in diisopropylether to give ethyl 2-hydroxy-4-trifluoromethyl-5-pyrimidinecarboxylate (20.3 g, yield; 69%) as crystals. MS (ESI) m/z; 235 [M−H]−
Reaction SMILES: OCCC#C[C:6]1[CH:7]=[C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[S:9][CH:10]=1.[C:16]([O:19][C:20](=[O:22])[CH3:21])(=O)[CH3:17].O.N1C=CC=[CH:26][CH:25]=1>>[C:20]([O:19][CH2:16][CH2:17][C:25]#[C:26][C:13]1[S:12][C:11]([C:8]2[S:9][CH:10]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1)(=[O:22])[CH3:21]
Reactant: OCCC#Cc1csc(-c2cccs2)c1
Reactant: c1ccncc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)OCCC#Cc1ccc(-c2cccs2)s1
Reaction time: 8 h

Procedure:
4-(Hydroxy-1-butynyl)-2,2'-bithiophene (1.23 g) was dissolved in pyridine (6 ml ). Acetic anhydride (1 ml ) was added at room temperature, stirred for few minutes and further kept overnight. Water (20 ml) was added oily product was then extracted with 30 ml of ethyl acetate. The extract was washed with 10 ml of HCl (1N) for 3 times, 10 ml of water once and 10 ml of diluted KHCO3 solution once. Ethyl acetate was then removed under reduced pressure. The residual solid was purified by silica gel column chromatography, eluted with ethyl acetate/n-hexane (1/19). Light yellowish oily product (1.7 g) was obtained after removal of the solvent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16]3)(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH2:23]([N:25]([CH2:40][CH3:41])[CH2:26][CH2:27][NH:28][C:29]([C:31]1[C:35]([CH3:36])=[C:34]([CH:37]=O)[NH:33][C:32]=1[CH3:39])=[O:30])[CH3:24].N1CCCCC1>C(O)C>[CH2:40]([N:25]([CH2:23][CH3:24])[CH2:26][CH2:27][NH:28][C:29]([C:31]1[C:35]([CH3:36])=[C:34](/[CH:37]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:11])=[O:12])=[CH:21][CH:20]=3)[NH:33][C:32]=1[CH3:39])=[O:30])[CH3:41]
Reactant: COc1cccc(CS(=O)(=O)c2ccc3c(c2)CC(=O)N3)c1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(OC)c4)cc32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.2 %

Procedure:
To a solution of 5-(3-methoxy-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (100 mg, 0.32 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (84 mg, 0.32 mmol) in ethanol (4 mL) was added piperidine (0.1 mL). The reaction mixture was stirred at 25° C. for three days. The solvent was evaporated and the residue was purified on a silica gel column eluting with MeOH—CH2Cl2 1:9 to provide 125 mg (69%) of 5-[5-(3-methoxy-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a pale orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][C:4]=1[CH3:12].Br[CH2:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=O>C(Cl)(Cl)Cl>[CH3:12][C:4]1[CH:5]=[C:6]([C:7]2[NH:9][CH:14]=[C:15]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[N:8]=2)[CH:10]=[CH:11][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C(=N)N)cc1C
Reactant: O=C(CBr)c1cccs1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2nc(-c3cccs3)c[nH]2)cc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.3 %

Procedure:
A slurry of 22 (21.6 g, 0.132 mol) in CHCl2 (300 ml) was treated dropwise over 15 minutes with 2-(bromoacetyl)-thiophene (10.84, 0.0476 mol, 92% pure) in CHCl3 (55 ml). The reaction mixture was stirred at room temperature for 24 hours, and then filtered to remove 10.2 g of the hydrobromide of 22. The mother liquors were concentrated to a semisolid which was swirled with 75 ml of methylene chloride and refrigerated overnight. The resultant gray solid was washed with CH2Cl2 and dried to give 10.2 grams (79%) of 23; m.p. 110°-114°. The analytical sample was dried in vacuo at 85°, m.p. 115°-117°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:26])[CH:13]1[CH2:18][CH2:17][C:16]([C:19]2[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=2)=[CH:15][CH2:14]1>N1C=CC=CC=1>[ClH:8].[CH3:11][N:12]([CH3:26])[CH:13]1[CH2:18][CH2:17][C:16]([C:19]2[CH:20]=[C:21]([NH:25][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[CH:22]=[CH:23][CH:24]=2)=[CH:15][CH2:14]1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN(C)C1CC=C(c2cccc(N)c2)CC1
Solvent: c1ccncc1
Product: CN(C)C1CC=C(c2cccc(NC(=O)c3ccc(F)cc3)c2)CC1
Product: Cl
Temperature: 55 °C
Yield: 66.5 %

Procedure:
Add 4-fluorobenzoyl chloride (155 mg, 0.976 mmol) to a solution of 3-(4-dimethylamino-cyclohex-1-enyl)-phenylamine (preparation 2, 176 mg, 0.814 mmol) in pyridine (8 mL) and heat at 55° C. overnight. Remove the volatile under reduced pressure, dissolve the residue in DCM, wash with 0.1N NaOH, dry over sodium sulfate, filter and concentrate to give a residue. Purify the residue by chromatography (silica gel, 8% 2M NH3/MeOH in DCM) to provide the free base of the title compound (203 mg, 74%): MS (ES): m/z=339.2 (M+H)+; 1H NMR (CDCl3): δ 7.92 (m, 3H), 7.70 (s, 1H), 7.52 (d, 1H), 7.32 (t, 1H), 7.18 (m, 3H), 6.12 (m, 1H), 2.50 (m, 4H), 2.37 (s, 6H), 2.13 (m, 2H), 1.57 (m, 1H).
Reaction SMILES: [Cl-].C(CC[N+:7]1[CH:12]=[CH:11][C:10](C#N)=[CH:9][CH:8]=1)(=O)N.[OH:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[OH-].[Na+]>O>[OH:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:10]2[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=2)[CH2:21][CH2:20]1
Reactant: N#Cc1cc[n+](CCC(N)=O)cc1
Reactant: OCCCC1CCNCC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCCC1CCN(c2ccncc2)CC1
Reaction time: 1 h
Yield: 40.3 %

Procedure:
A solution of N-(2-carbamoylethyl)-4-cyanopyridinium chloride (2.1 g) in water (5 ml) was added dropwise to a stirred mixture of 4-hydroxypropylpiperidine (2.4 g), water (10 ml) and 2.5M sodium hydroxide solution (4.6 ml) cooled in an ice-bath. The mixture was stirred at 0°-5° C. for 1 hour. 2.5M sodium hydroxide solution (7 ml) was added and the mixture heated at reflux for 3 hours. The mixture was cooled in an ice-bath and gummy solid separated out. The aqueous layer was decanted off and the gummy solid dissolved in dichloromethane (75 ml). The solution was washed with saturated sodium chloride solution (10 ml) and dried (MgSO4). The solvent was removed by evaporation to give a gummy solid (880 mg) which on trituration with ether gave a solid; NMR(d6 DMSO): 1.0-1.35(m,4H), 1.35-1.6(m,3H), 1.7(dd,2H), 2.70-2.88(dt,2H), 3.38(t,2H), 3.89(brd,2H), 4.35(brs,1H), 6.78(d,2H), 8.1(d,2H); mass spectrum(CI+): 221(M+H)+.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].N[C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][C:20]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=3[N:22]=2)=[CH:14][CH:13]=1)=[O:10].[CH2:32]=O>CC(O)=O>[CH3:32][N:2]([CH3:1])[C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][C:20]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=3[N:22]=2)=[CH:14][CH:13]=1)=[O:10]
Reactant: COc1ccc2nc(-c3ccc(NC(=O)c4cccc(N)c4)cc3)sc2c1
Reactant: [BH3-]C#N
Reactant: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc2nc(-c3ccc(NC(=O)c4cccc(N(C)C)c4)cc3)sc2c1

Procedure:
Prepared as described in the Amination section using sodium cyanoborohydride (67 mg, 1.06 mmol), 3-amino-N-[4-(6-methoxybenzothiazol-2-yl)-phenyl]-benzamide (80 mg, 0.213 mmol) and paraformaldehyde (64 mg, 2.13 mmol) in AcOH (2 ml) to give the title compound as colourless plates (53 mg, 62%) after recrystallisation from EtOH.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH:11]([C:15](O)=[O:16])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]([C:26]1[CH:40]=[CH:39][C:29]([CH2:30][N:31]2[C:35]([CH2:36][CH2:37][NH2:38])=[CH:34][N:33]=[CH:32]2)=[CH:28][CH:27]=1)#[N:25].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>CN(C=O)C>[C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH:11]([C:15](=[O:16])[NH:38][CH2:37][CH2:36][C:35]3[N:31]([CH2:30][C:29]4[CH:39]=[CH:40][C:26]([C:24]#[N:25])=[CH:27][CH:28]=4)[CH:32]=[N:33][CH:34]=3)[CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ccc(Cn2cncc2CCN)cc1
Reactant: O=C(O)C1CCCN(CC(c2ccccc2)c2ccccc2)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Cn2cncc2CCNC(=O)C2CCCN(CC(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2,2-Diphenylethyl)-3-carboxy piperidine(472 mg, 1,52 mmol),3-(4-cyanobenzyl) histamine (456 mg, 1.52 mmol) (EXAMPLE 1, Step E) HOBT (216 mg, 1.60 mmol), EDC (307 mg, 1.60 mmol), and Et3N (637 uL, 4.57 mmol) were dissolved in DMF (10 mL) and was stirred overnight at ambient temperature. The solution was concentrated under reduced pressure and chromatographed (silica gel, 0.5-2% MeOH/CH2Cl2 with NH4OH) to give the title compound 1H NMR (CDCl3) δ7.96 (br s, 1H), 7.60 d, 2H, J=8 Hz), 7.46 (s, 1H), 7.09-7.37 (m, 12H), 6,74 (s, 1H), 5.20 (s, 2H), 4.26 (t, 1H, J=8 Hz), 3.05-3.17 (m, 2H), 2.93-3.04 (m,1H), 2.78-2.91 (m,2H), 2.49-2,61 (m 1H), 22.40-2.47 (m, 1H), 2.15-2.30 (m, 2H), 1.95-2.14 (m, 2H), 1.86 (d, 1H, J=12 Hz), 1.29-1.55 (m, 3H). FAB MS 518 (M+1)
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([OH:10])[CH2:5]1)[CH:2]=[CH2:3].[Si:11](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CN=C1.CN(C1C=CC=CN=1)C>CN(C)C=O>[CH2:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C=CC[C@@H]1CCC[C@H](O)C1
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CC[C@@H]1CCC[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
6.8 g of cis-3-allylcyclohexanol and 15 ml of tert-butyldiphenylsilyl chloride, 5 g of imidazole and 200 mg of dimethylaminopyridine are dissolved in 100 ml of dimethylformamide and stirred at room temperature for 12 hours. 400 ml of methyl tert-buthyl ether are added to the reaction mixture, and the mixture is washed three times with water. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 20.5 g of (cis-3-allylcyclohexyloxy)tert-butyl-diphenylsilane as an oil. C25H34OSi (378.64), MS(ESI): 379 (M+H+), Rf(n-heptane:ethyl acetate=2:1)=0.93.
Reaction SMILES: [NH2:1][CH:2]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]([NH:1][CH:2]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH:3]([OH:4])[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][CH:6]=2)=[O:35])=[CH:26][CH:25]=1
Reactant: NC(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (274 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (358 mg, 1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Recrystallization from ethyl acetate-hexane gave the title compound (430 mg, 62%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CN(C)C=O.[C:12]([O:16][C:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=C2)=[O:18])([CH3:15])([CH3:14])[CH3:13].O1CCCC1>ClCCl>[C:12]([O:16][C:17]([C:19]1[CH:27]=[C:26]2[C:25](=[CH:21][CH:20]=1)[NH:24][CH:23]=[C:2]2[CH:1]=[O:5])=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)c1ccc2[nH]ccc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc2[nH]cc(C=O)c2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
0.4 ml (4.87 mmol) oxalylchloride are dissolved in a three-neck flask under nitrogen in 15 ml absolute dichloromethane and cooled to 0° C. Thereafter, 0.4 ml absolute dimethylformamide dissolved in 15 ml absolute dichloromethane is added. The mixture is stirred on ice cooling for 20 minutes, gas generation and the formation of a colorless precipitate being observed. Then, 1.00 g (4.64 mmol) tert-butylindole-5-carboxylate is added and the reaction mixture is allowed to heat to room temperature. Stirring is continued for another 20 min, the suspension is transferred using tetrahydrofurane to a round flask and concentrated on a rotary evaporator. The residue is taken up in 40 ml tetrahydrofurane, mixed with 50 ml 20% sodium acetate solution and heated under reflux for 30 minutes. After cooling down, 30 ml 5% sodium hydrogen carbonate solution are added, extracted three times using ethyl acetate, the volume of the combined organic phases is concentrated to about 150 ml and washed with saturated NaCl solution. The organic phase is dried on sodium sulfate and the solvent is removed on the rotary evaporator. Recrystallization of the crude product from n-hexane/ethyl acetate supplies the product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N+:13]([O-:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:26]([CH2:32][CH2:33][CH:34]=[O:35])([CH:29]([CH3:31])[CH3:30])[C:27]#[N:28])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].[F-].[K+]>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:13]([O-:15])=[O:14])[CH:34]([OH:35])[CH2:33][CH2:32][C:26]([C:27]#[N:28])([CH:29]([CH3:30])[CH3:31])[C:20]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(C#N)(CCC=O)C(C)C)cc1OC
Reactant: COc1ccc(CC[N+](=O)[O-])cc1OC
Agent: [F-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1ccc(CC(C(O)CCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)[N+](=O)[O-])cc1OC
Temperature: 25 °C
Yield: 73.9 %

Procedure:
A mixture of 2-(3,4-dimethoxyphenyl)-1-nitroethane (4, 135 g, 0.64 mol), 2-(3,4-dimethoxyphenyl)-2-(3-oxopropyl)-2-isopropylacetonitrile (7, 156 g, 0.57 mol) and KF (19.3 g, anhydrous, Aldrich) in 2-propanol (2.0 L) was heated to 50°-55° C. for about 40 hours. The mixture was then cooled to room temperature and the isopropanol removed in vacuo. The residue was dissolved in CH2Cl2 (1.6 L) and filtered through Celite (50 g). The filtrate was extracted with saturated aqueous NaHCO3 (2×500 mL), the organic layer evaporated, and the product recrystallized from ethyl acetate-hexane (1:1) to yield 1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexan-3-ol (8, 205 g, m.p. 171°-173° C., MS m/e 486 (M+)).