Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@H:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.Br[CH2:12][C:13]([C:15]1[CH:26]=[CH:25][C:18]2[O:19][C:20]([CH3:24])([CH3:23])[O:21][CH2:22][C:17]=2[CH:16]=1)=[O:14].C(N(CC)C(C)C)(C)C.C(#N)C>C1COCC1>[CH3:23][C:20]1([CH3:24])[O:19][C:18]2[CH:25]=[CH:26][C:15]([C:13](=[O:14])[CH2:12][NH:10][C@@H:7]([C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)[CH2:8][OH:9])=[CH:16][C:17]=2[CH2:22][O:21]1
Reactant: CC1(C)OCc2cc(C(=O)CBr)ccc2O1
Reactant: N[C@H](CO)c1ccccc1
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OCc2cc(C(=O)CN[C@H](CO)c3ccccc3)ccc2O1

Procedure:
(S)-Phenylglycinol (28.9 g) was added in two portions to a solution of 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone (40g) and N,N-di-iso-propylethylamine (48.9 ml) in THF (500 ml) under nitrogen. After 4h the resulting white precipitate was removed by filtration and the mother liquor concentrated in vacuo to give an orange oil. Acetonitrile (40 ml) was added and then removed in vacuo to give a light orange solid which was pulverised and triturated with cold acetonitrile (50 ml). The resulting solid was collected by filtration and washed with acetonitrile (2×30 ml) to give the title compound (38.5 g) as a white solid.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:17]12([C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=3[O:36][CH3:37])[C:30](Cl)=[O:31])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>ClCCl>[C:17]12([C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=3[O:36][CH3:37])[C:30]([S:1][C:2]3[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=3)=[O:31])[CH2:18][CH:19]3[CH2:25][CH:23]([CH2:22][CH:21]([CH2:20]3)[CH2:26]1)[CH2:24]2
Reactant: COc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1ccc(S)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(=O)Sc2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
In a round bottom flask, there are introduced 1.7 g (11 mmoles) of 4-mercaptobenzoic acid and 20 ml of pyridine. There is then slowly added a solution of 3.4 g (11.17 mmoles) of 3-(1-adamantyl)-4-methoxybenzoic acid chloride in 50 ml of dichloromethane. The reaction mixture is stirred at ambient temperature for 8 hours, evaporated to dryness, taken up in 100 ml of water and acidified to pH 5 with 1N HCl. The solid is filtered, washed with water and dried at 60° C. under a vacuum, then recrystallized in dioxan. 3.3 g (75% yield) of 4-[3-(1-adamantyl)-4-methoxybenzoylthio]benzoic acid having a melting point of 264° C. are obtained.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].O>O1CCCC1>[CH2:14]([C:12]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCC
Reactant: CCCCCCBr
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCC1(CCCCCC)c2ccccc2-c2ccccc21
Reaction time: 1 h
Yield: 95 %

Procedure:
In the stream of dry nitrogen, 5.0 g (30 mmol) of fluorene was dissolved in dry tetrahydrofuran. To this solution, 22 m l (35 mmol) of a 1.6 M hexane solution of n-butylithium was added dropwise at −78° C., and the mixture was stirred at the temperature for 1 hour. To this was then added dropwise 4.9 ml (35 mmol) of n-hexyl bromide, and the mixture was stirred at −78° C. for 1 hour, and then at room temperature for 1 hour. To the resultant, 22 ml (35 mmol) of a 1.6 M hexane solution of n-butylithium was further added dropwise at −78° C., and the mixture was stirred at the temperature for 1 hour. To this was then added dropwise 4.9 ml (35 mmol) of n-hexyl bromide, and the mixture was stirred at −78° C. for 1 hour, and then at room temperature for 1 hour. Water was added dropwise to this mixture with ice-cooling, and the resultant was then subjected to extraction with ethyl acetate. The extract was dehydrated and dried over magnesium sulfate, and the solvent was then distilled off. The residue was subjected to recrystallization from hexane to obtain 9.5 g (95%) of 9,9-dihexylfluorene.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]([NH:12][C:13]1[NH:14][C:15]2[C:20]([C:21]=1[C:22]([NH2:24])=[O:23])=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11]>CN(C)C=O>[NH2:9][C:10]([NH:12][C:13]1[NH:14][C:15]2[C:20]([C:21]=1[C:22]([NH2:24])=[O:23])=[CH:19][CH:18]=[C:17]([Br:1])[CH:16]=2)=[O:11]
Reactant: NC(=O)Nc1[nH]c2ccccc2c1C(N)=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: NC(=O)Nc1[nH]c2cc(Br)ccc2c1C(N)=O
Temperature: 50 °C
Reaction time: 6 h
Yield: 67.3 %

Procedure:
N-Bromosuccinimide (4.8 g, 27 mmol) was added to a solution of 2-aminocarbonylaminoindole-3-carboxamide (Compound 2-10, 5.9 g, 27 mmol) in anhydrous N,N-dimethylformamide (180 mL) under ice-cooling, and the mixture was stirred at 50° C. for 6 hours. The reaction mixture was poured into ice-water (400 mL) and the whole was extracted with ethyl acetate (500 mL). The organic layer was washed with saturated sodium hydrogen carbonate aqueous solution (200 mL×2), 2 N sodium thiosulfate aqueous solution (200 mL×2), brine (150 mL), and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resultant solid was washed with chloroform (40 mL) and dried under reduced pressure to give the title compound (5.4 g) as a slightly brown solid (yield 67%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[NH:15]1[CH:19]=[CH:18][CH:17]=[N:16]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu-]=O>[N+:8]([C:6]1[CH:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=[C:2]([N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)[CH:7]=1)([O-:10])=[O:9]
Reactant: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Reactant: c1cn[nH]c1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(-n2cccn2)cc([N+](=O)[O-])c1
Temperature: 120 °C
Yield: 86 %

Procedure:
To a solution of N-(3-bromo-5-nitrophenyl)acetamide of Example 1(c) (10 g, 38.6 mmol) in DMF (100 ml) were added pyrazole (5.26 g, 77.2 mmol, 2.0 eq.), copper(I) oxide (1.104 g, 7.72 mmol, 0.2 eq.) and cesium carbonate (25.15 g, 77.2 mmol, 2.0 eq.) and the mixture was heated at 120° C. for 16 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off and the residue was purified by column chromatography over silica gel (30% ethyl acetate in hexane) to afford the compound in 86% yield (8.2 g). 1H NMR (300 MHz, DMSO-d6): δ 10.62 (s, 1H), 8.7 (d, 1H), 8.5-8.48 (m, 2H), 8.32 (t, 1H), 7.84 (d, 1H), 6.62 (t, 1H), 2.08 (s, 3H); LC-MS (ESI): Calculated mass: 246.22; Observed mass: 247.1 [M+H]+ (rt: 0.6 min).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH:4]([CH3:9])[C:5]([O:7]C)=O.[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[O:25][C:24]=2[CH:23]=[CH:22][C:21]=1[CH:33]=O>>[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[O:25][C:24]=2[CH:23]=[CH:22][C:21]=1[CH2:33][N:1]1[CH:2]([C:10]2[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:3][CH:4]([CH3:9])[C:5]1=[O:7]
Reactant: O=Cc1ccc2oc3ccccc3c2c1
Reactant: COC(=O)C(C)CC(N)c1c(OC)ccnc1OC
Product: COc1ccnc(OC)c1C1CC(C)C(=O)N1Cc1ccc2oc3ccccc3c2c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,4-dimethoxypyridin-3-yl)-2-methylbutanoate with commercially available dibenzo[b,d]furan-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.85 min.; [M+H]+: 416.90 g/mol.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.C1(C)C=CC=CC=1.[OH-].[Na+].S([NH:34][N:35]=[CH:36][CH:37](Cl)Cl)(C1C=CC(C)=CC=1)(=O)=O>O.CO>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][N:2]2[CH:37]=[CH:36][N:35]=[N:34]2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)NN=CC(Cl)Cl)cc1
Reactant: COc1ccc(CCCCN)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(CCCCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
1-(4-Aminobutyl)-4-methoxybenzene hydrochloride (1.0 g, 4.64 mmol) was dissolved in water. Toluene (10 ml) and 2N-sodium hydroxide (10 ml) were added and the mixture was partitioned. The organic layer was washed with 20% brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in methanol (8 ml), and a suspension of 2,2-dichloroacetaldehyde tosylhydrazone (2.61 g, 9.28 mmol) in methanol (12 ml) was added dropwise at 15-20° C. The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. To the residue was added ethyl acetate (50 ml) and then was added saturated aqueous sodium hydrogen carbonate (50 ml). The mixture was stirred for 10 min and partitioned, which was followed by washing with saturated brine and concentration under reduced pressure. Purification by silica gel column gave 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole (1.1 g, yield 100%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:14](=[O:35])[C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20](=[O:34])[C@H:21]([NH:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH3:40][CH:41](O)[CH3:42]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:14](=[O:35])[C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20](=[O:34])[C@H:21]([NH:29][CH2:30][C:31]([O:33][CH:41]([CH3:42])[CH3:40])=[O:32])[CH2:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)O
Reactant: Nc1nccc2cc(CNC(=O)[C@@H]3CCCN3C(=O)[C@@H](CC3CCCCC3)NCC(=O)O)ccc12
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)CN[C@H](CC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1

Procedure:
To a stirred solution of 96 mg of N-(1-amino-isoquinolin-6-ylmethyl) 1-(2-hydroxycarbonylmethylamino-2(R)-cyclohexylmethyl-acetyl)-prolinamide in 6 mL of 2-propanol was added 0.03 mL of thionyl chloride and the reaction mixture was heated at reflux temperature for two days. After this period the reaction mixture was concentrated, ethyl acetate added, washed with aqueous 5% sodium hydrogencarbonate and brine, dried over sodium sulphate and concentrated. The residue was dissolved in a t-butanol/water 1/1 (v/v) mixture lyophilisation yielded 56 mg of the title compound. MS ESI+: 524 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH:14]1[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15]1.CCN(C(C)C)C(C)C>C(O)CCC>[N+:8]([C:7]1[C:2]([N:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:15]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3ccsc23)C1
Temperature: 110 °C
Reaction time: 12 h
Yield: 92.6 %

Procedure:
To a vial containing 7-chloro-6-nitrothieno[3,2-b]pyridine (128.7 mg, 0.5996 mmol) and tert-butyl (3S)-piperidin-3-ylcarbamate (Combi-Blocks, 297.6 mg, 1.486 mmol), 1-butanol (3.00 mL) was added, followed by DIPEA (179.9 mg, 1.392 mmol). The mixture was stirred at 110° C. for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-30% EtOAc in hexanes) to give the sub-title compound as a yellow solid (210.1 mg, 93%). LCMS calc. for C17H23N4O4S (M+H)+: m/z=379.1. found 379.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:21]1[C:25]([NH2:26])=[CH:24][NH:23][N:22]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CS(C)=O.O>[NH:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:12]=[C:13]1[C:21]1[C:25]([NH:26][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:24][NH:23][N:22]=1
Reactant: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Reactant: COc1cccc(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Solvent: ClCCCl
Solvent: O
Product: COc1cccc(C(=O)Nc2c[nH]nc2-c2nc3ccccc3[nH]2)c1
Yield: 12.6 %

Procedure:
A mixture of 3-methoxybenzoic acid (84 mg, 0.55 mmol), 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (100 mg, 0.50 mmol), EDC (116 mg, 0.60 mmol) and HOBt (81 mg, 0.60 mmol) was stirred at ambient temperature in DMSO (3 ml) for 20 h. The reaction mixture was poured into water (30 ml) and the resultant solid was collected by filtration and purified by flash column chromatography [SiO2, (dichloromethane 120 ml, methanol 15, acetic acid 3 ml, water 2 ml (DMAW 120)] to yield N-[3-(1H-Benzimidazol-2-yl)-1H-pyrazol-4-yl]-3-methoxy-benzamide as a pale pink-gray solid (21 mg, 13%). (LC/MS: Rt 3.81, [M+H]+ 334.03).
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[CH3:5])[CH:2]=[CH2:3].F[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1>>[CH2:1]([N:4]([CH3:5])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[CH:15]=[CH:14]2)[CH:2]=[CH2:3]
Reactant: C=CCN(C)CCCCCc1ccc2[nH]ccc2c1
Reactant: Fc1ccc(C(F)(F)F)cc1
Product: C=CCN(C)CCCCCc1ccc2c(ccn2-c2ccc(C(F)(F)F)cc2)c1

Procedure:
In analogy to example 4.6, Allyl-[5-(1H-indol-5-yl)-pentyl]-methyl-amine and 1-fluoro-4-trifluoromethyl-benzene were converted to yield Allyl-methyl-{5-[1-(4-trifluoromethyl-phenyl)-1H-indol-5-yl]-pentyl}-amine as light brown oil, MS: 401 (MH+).
Reaction SMILES: C([SiH](C(C)C)C(C)C)(C)C.FC(F)(F)C(O)=O.[Cl:18][C:19]1[CH:20]=[C:21]([N:26]2[C:30](=[O:31])[O:29][N:28]=[C:27]2[C:32]2[C:36]([NH:37][CH2:38][CH2:39][NH:40]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[N:35][O:34][N:33]=2)[CH:22]=[CH:23][C:24]=1[F:25]>>[ClH:18].[NH2:40][CH2:39][CH2:38][NH:37][C:36]1[C:32]([C:27]2[N:26]([C:21]3[CH:22]=[CH:23][C:24]([F:25])=[C:19]([Cl:18])[CH:20]=3)[C:30](=[O:31])[O:29][N:28]=2)=[N:33][O:34][N:35]=1
Reactant: O=c1onc(-c2nonc2NCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)n1-c1ccc(F)c(Cl)c1
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 197.7 %

Procedure:
A premixed solution of triisopropylsilane (3.4 mL, 17 mmol) and trifluoroacetic acid (44 mL, 570 mmol) was added to 4-(3-chloro-4-fluorophenyl)-3-(4-{[2-(tritylamino)ethyl]amino}-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (6.5 g, 11 mmol) and the resulting suspension was stirred at 25° C. for 30 min. The reaction mixture was filtered and washed with trifluoroacetic acid. The filtrate was concentrated to an oil which was diluted with methanol (25 mL), cooled to 0° C., treated with 4 M HCl in 1,4-dioxane (14 mL), and stirred at 25° C. for 15 min. The mixture was concentrated to a solid that was treated with diethyl ether (50 mL) and filtered. The solid was washed with diethyl ether (50 mL) and dried to give the desired product (4.1 g, 98%) as a white solid. LCMS for C12H11ClFN6O3 (M+H)+: m/z=341.1. 1H NMR (300 MHz, DMSO-d6): δ 8.05-8.00 (m, 4 H), 7.75-7.69 (m, 1 H), 7.64 (dd, J=9.1, 8.8 Hz, 1 H), 6.77 (dd, J=5.9, 5.9 Hz, 1 H), 3.54-3.47 (m, 2 H), 3.04-2.99 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:15][CH2:16][NH:17][CH3:18])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:19]=O>C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CNCCC1(c2cccc(OC)c2)C=CCCC1
Reactant: C=O
Solvent: O=CO
Product: COc1cccc(C2(CCN(C)C)C=CCCC2)c1
Reaction time: 2 h

Procedure:
5.0 g of 1-(m-methoxyphenyl)-N-methyl-2-cyclohexene-1-ethylamine are treated with a mixture of 1.5 liters of 35% aqueous formaldehyde solution and 2.0 ml of 90% formic acid, and the resulting mixture is held at 100° C. for 2 hours. After distillation of the solvent, the residue is treated with 1 N hydrochloric acid solution. The neutral portion is taken up in ether, the aqueous phase is made alkaline by the addition of 3 N sodium hydroxide and the rac. 1-(m-methoxyphenyl)-N,N-dimethyl-2-cycloexene-1-ethylamine is taken up in methylene chloride. After distillation of the solvent, the oil obtained is purified on a 10-fold amount of aluminium oxide. The fractions eluted with toluene are combined and evaporated, and pure rac. 1-(m-methoxyphenyl)-N,N-dimethyl-2-cyclohexene-1-ethylamine remains as the residue. The hydrochloride of this compound melts at 161°-162° C. (after recrystallization from ethyl acetate/ethanol).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH3:25][O:26][CH:27]1[CH:31]([CH:32]=O)[CH2:30][CH:29]([O:34][CH3:35])[O:28]1>C(Cl)Cl.[Zn]>[Br:21][C:20]([Br:24])=[CH:32][CH:31]1[CH2:30][CH:29]([O:34][CH3:35])[O:28][CH:27]1[O:26][CH3:25]
Reactant: BrC(Br)(Br)Br
Reactant: COC1CC(C=O)C(OC)O1
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC1CC(C=C(Br)Br)C(OC)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.2 %

Procedure:
A mixture of Zn powder (1.65 g, 25.0 mmol), triphenylphosphine (6.54 g, 25.0 mmol), and CBr4 (8.30 g, 25.0 mmol) in dry CH2Cl2 (40 mL) was stirred at ambient temperature. After 24 hours, 2,5-dimethoxy-tetrahydrofuran-3-carboxaldehyde (2.00 g, 12.5 mmol) was added and an exothermic reaction ensued. After 30 minutes, pet ether (100 mL) was added and the resultant upper layer separated. The lower layer was twice diluted with CH2Cl2 (50 mL) and pet ether (50 mL), and the upper layer reserved. The combined upper layers were combined, passed through a pad of SiO2, and concentrated under reduced pressure at 30° C. or below to give 2.18 g (55%) of 3-(2,2-dibromoethenyl)-2,5-dimethoxy-tetrahydrofuran as a volatile colorless oil, which was a mixture of diastreomers by 1H NMR and used immediately without further purification.
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:36][C:37]1[N:42]=[CH:41][C:40]([CH2:43]O)=[CH:39][CH:38]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:36][C:37]1[N:42]=[CH:41][C:40]([CH2:43][O:18][C:15]2[CH:16]=[CH:17][C:10]3[O:9][C:8]([CH:7]([NH:19][C:20]4[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:24][CH:25]=4)[CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[C:12]([CH3:13])[C:11]=3[CH:14]=2)=[CH:39][CH:38]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(O)cc3c2C)C2CCCCC2)cc1
Reactant: OCc1ccc(Cl)nc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(OCc4ccc(Cl)nc4)cc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.2 %

Procedure:
Ethyl 3-{[(4-{[cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl]amino}propanoate (0.35 g) synthesized in Example A167(1) was dissolved in tetrahydrofuran (5 mL), and 6-chloro-3-pyridinemethanol (0.13 g), tributylphosphine (0.33 mL) and 1,1′-(azodicarbonyl)dipiperidine (0.33 g) were added to the solution under ice-cooling. The ice bath was removed, the reaction mixture was stirred at room temperature for 12 hr then hexane (5 mL) was added to the mixture, and the precipitate was filtered off through celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (0.31 g, 65%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[CH2:12][CH2:13][CH2:14][CH2:15][O:16]C=C)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[CH2:12][CH2:13][CH2:14][CH2:15][OH:16])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C=COCCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCCCO)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In methanol (30 ml) was dissolved 2-[1-[(4-chlorophenyl)sulfonyl]-5-vinyloxypentyl]-1,4-difluorobenzene (0.90 g, 2.3 mmol). After addition of p-toluenesulfonic acid monohydrate (20 mg, 0.11 mmol), the resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=3:2) to yield a white solid. The resulting white solid was washed with diisopropyl ether, whereby the title compound (0.73 g, 85%) was obtained as a white powder.
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[N:4]=[C:5]([CH2:8][OH:9])[S:6][CH:7]=1.[CH2:11]([C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[C:20]([N:23]3[CH:28]=[CH:27][C:26](O)=[CH:25][C:24]3=[O:30])[CH:21]=[CH:22][C:15]=2[N:14]=1)[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>O.C1COCC1>[F:1][CH:2]([F:10])[C:3]1[N:4]=[C:5]([CH2:8][O:9][C:26]2[CH:27]=[CH:28][N:23]([C:20]3[CH:21]=[CH:22][C:15]4[N:14]=[C:13]([CH2:11][CH3:12])[N:17]([CH3:18])[C:16]=4[CH:19]=3)[C:24](=[O:30])[CH:25]=2)[S:6][CH:7]=1
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Reactant: OCc1nc(C(F)F)cs1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2ccc(-n3ccc(OCc4nc(C(F)F)cs4)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.1 %

Procedure:
A mixture of (4-(difluoromethyl)-1,3-thiazol-2-yl)methanol (61.3 mg), 1-(2-ethyl-1-methyl-1H-benzo[d]imidazol-6-yl)-4-hydroxypyridin-2(1H)-one (50 mg), triphenylphosphine (146 mg), bis(2-methoxyethyl) azodicarboxylate (130 mg) and THF (3 ml) was stirred at room temperature for 3 h. The mixture was diluted with water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated in vacuo and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (10.1 mg) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:23]>>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3][CH2:2][N:34]2[CH2:35][CH2:36][CH:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[NH:24][C:22](=[O:23])[CH:21]([CH3:20])[CH3:37])[CH2:32][CH2:33]2)=[CH:7][CH:8]=1
Reactant: CC(C)C(=O)Nc1ccccc1C1CCNCC1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Product: CC(C)C(=O)Nc1ccccc1C1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
Prepared by Procedure G and Scheme AI using 1-[4-chloro-1-(4-fluorophenyl)butyl]-4-fluorobenzene and 2-methyl-N-[2-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 490.9 (M+H)+.