Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH2:2]([CH:4]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:5]Br)[CH3:3].[S:11]1[CH:15]=[CH:14][C:13]2[C:16](=O)[C:17]3[S:18][CH:19]=[CH:20][C:21]=3[C:22](=O)[C:12]1=2.Cl[Sn]Cl>[Cl-].[Na+].O.C1COCC1>[CH2:2]([CH:4]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:5][C:16]1[C:17]2[S:18][CH:19]=[CH:20][C:21]=2[C:22]([CH2:5][CH:4]([CH2:2][CH3:3])[CH2:7][CH2:8][CH2:9][CH3:10])=[C:12]2[S:11][CH:15]=[CH:14][C:13]=12)[CH3:3]
Reactant: CCCCC(CC)CBr
Reactant: O=C1c2ccsc2C(=O)c2ccsc21
Agent: Cl[Sn]Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(CC)Cc1c2ccsc2c(CC(CC)CCCC)c2ccsc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
To a 100 mL flask under nitrogen was added magnesium (656 mg, 27 mmol) and anhydrous THF (10 mL). The mixture was heated under reflux and 2-ethylhexyl bromide (5.6 mL, 30 mmol) was added dropwise. The reaction mixture was kept at refluxing temperatures until all magnesium was consumed. After cooling down, 4,8-dihydrobenzo[1,2-b:4,5-b′]dithiophene-4,8-dione (1.1 g, 5.0 mmol) was added in one portion. After refluxing for 1 hour more, it was cooled down again to room temperature. SnCl2 solution (7.5 g in 19 mL 10% HCl) was slowly added dropwise and then the mixture was kept at 60° C. for 1 hour. After cooling down, brine (11 mL) was added. The organic phase was separated and dried over Na2SO4. The residue after vacuum evaporation was purified by column chromatography with hexane as eluent and gave a pale yellow oil (910 mg, yield 43%). 1H NMR (CDCl3, 500 MHz) δ=7.47 (d, J=6.0 Hz, 2H), 7.45 (d, J=6.0 Hz, 2H), 3.08-3.20 (m, 4H), 1.92-2.04 (m, 2H), 1.13-1.49 (m, 16H), 0.91 (t, J=7.0 Hz, 6H), 0.85 (t, J=7.0 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[CH3:27][C@H:28]1[O:33][CH2:32][CH2:31][NH:30][C@@H:29]1[C:34]([OH:36])=[O:35].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:30]2[CH2:31][CH2:32][O:33][C@H:28]([CH3:27])[C@H:29]2[C:34]([OH:36])=[O:35])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: C[C@H]1OCCN[C@@H]1C(=O)O
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C1=C(CN2CCO[C@H](C)[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.5 %

Procedure:
A mixture of ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.96 g, 1.9 mmol), (2R,3S)-2-methylmorpholine-3-carboxylic acid (0.28 g, 1.9 mmol) and potassium carbonate (0.53 g, 3.8 mmol) in anhydrous ethanol (35 mL) was stirred at 25° C. for 12 hours under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=15/1) to give the title compound as a yellow solid (0.48 g, 45%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[C:4]([O:14][CH3:15])[CH:3]=1.[B-](F)(F)(F)[O+](C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([O:14][CH3:15])[CH:3]=1)[S:8][CH2:9][CH2:10][C:11]2=[O:13]
Reactant: COc1cc(Cl)ccc1SCCC(=O)O
Agent: C[O+](C)[B-](F)(F)F
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc(Cl)cc2c1SCCC2=O

Procedure:
To a solution/suspension of 3-(4-chloro-2-methoxyphenylthio)propanoic acid (1.46 g, 5.92 mmol; see step (ii) above) in dichloromethane (50 mL) under N2(g) was added boron trifluoride dimethyl etherate (1.4 mL, 15 mmol) and trifluoroacetic anhydride (2.1 mL, 15 mmol). After 2.5 h at rt the reaction was quenched with water (2 mL), then washed with more water. The deep green colour disappeared when it was further washed with sat. aq. sodium hydrogencarbonate. Drying (MgSO4) and removal of the solvent in vacuo afforded the sub-title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]([NH2:28])=[N:15][CH:16]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:18]=1)[CH3:11].I[C:30]1[CH:31]=[N:32][N:33]([CH:35]2[CH2:38][C:37]3([CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]3)[CH2:36]2)[CH:34]=1.N#N.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.O1CCOCC1>[NH2:28][C:14]1[N:15]=[CH:16][C:17]([C:30]2[CH:31]=[N:32][N:33]([CH:35]3[CH2:36][C:37]4([CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]4)[CH2:38]3)[CH:34]=2)=[CH:18][C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(n1cc(I)cn1)C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](Oc1cc(-c2cnn(C3CC4(CCN(C(=O)OC(C)(C)C)CC4)C3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 80 °C
Reaction time: 24 h
Yield: 72.9 %

Procedure:
(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (104 mg, 0.244 mmol, 1.0 equiv), tert-butyl 2-(4-iodo-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (112 mg, 0.268 mmol, 1.1 equiv) were added to a RBF (25 mL). It was vacuumed and refilled with N2 (3 times). Dioxane (1.0 mL) and a solution of Na2CO3 (2.0 M, 0.4 mL) were added sequentially. It was vacuumed again and refilled with N2 (3 times). Pd(PPh3)2Cl2 catalyst (9 mg, 5 mol %) was added last. It was vacuumed and refilled with N2 (3 times). The mixture was then heated to 80° C. (oil bath) and stirred at this temperature under N2 for 24 hrs. The mixture was cooled to room temperature, and concentrated to give black residue which was treated with H2O (30 mL). The aqueous phase was extracted with EtOAc (4×30 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, concentrated to give black green residue which was purified by CombiFlash (12 g silica gel column; EtOAc/Hexane: 0-100%) to afford 105 mg (yield 73%) of (R)-tert-butyl 2-(4-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate as a pale yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]1[C:31]2[CH:30]=[C:29]([CH:32]=O)[N:28]=[CH:27][C:26]=2[O:25][CH2:24][CH2:23]1.C([BH3-])#N.[Na+]>>[O:22]1[C:31]2[CH:30]=[C:29]([CH2:32][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]4[C:15]5[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=5[O:13][CH2:12][C:11]4=[O:21])[CH2:4][CH2:3]3)[N:28]=[CH:27][C:26]=2[O:25][CH2:24][CH2:23]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: Cc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: Cc1ccc2c(c1)N(CCN1CCC(NCc3cc4c(cn3)OCCO4)CC1)C(=O)CO2

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-methyl-2H-1,4-benzoxazin-3(4H)-one (Intermediate 91), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described for Example 21 to give the product as an oil, 4.7 mg (2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:12]1(NN)[CH:17]=CC=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:17]=[CH:12][C:13]([CH3:14])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NNc1ccc(Cl)c(Cl)c1
Reactant: NNc1ccccc1
Agent: Cl
Product: Cc1ccn(-c2ccc(Cl)c(Cl)c2)n1

Procedure:
This compound was prepared by the same methodology described for EXAMPLE 1 with 3,4-dichlorophenyl hydrazine.HCl substituted for phenyl hydrazine. There was obtained the title compound; HRMS (M+H)+: calc. 501.055493; found 501.053920.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:37]=[CH:38][C:39]=1[CH2:40][O:41][Si](C(C)(C)C)(C)C)[CH2:13][O:14][C:15]1[CH:16]=[C:17](/[C:21](/[CH2:35][CH3:36])=[CH:22]/[CH:23]=[CH:24]/[C:25]([C:31]([F:34])([F:33])[F:32])([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:18]=[CH:19][CH:20]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:37]=[CH:38][C:39]=1[CH2:40][OH:41])[CH2:13][O:14][C:15]1[CH:16]=[C:17](/[C:21](/[CH2:35][CH3:36])=[CH:22]/[CH:23]=[CH:24]/[C:25]([C:26]([F:27])([F:28])[F:29])([OH:30])[C:31]([F:33])([F:34])[F:32])[CH:18]=[CH:19][CH:20]=1
Reactant: CC/C(=C\C=C\C(O)(C(F)(F)F)C(F)(F)F)c1cccc(OCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC/C(=C\C=C\C(O)(C(F)(F)F)C(F)(F)F)c1cccc(OCc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner analogous to example 2m, by reaction of 640 mg (0.89 mmol) of (3E,5E)-6-{3-[3,4-bis(tert-butyldimethylsilanyloxymethyl)benzyloxy]-phenyl}1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol with 2.1 ml (2.1 mmol) of a 1.0 M solution of tetrabutylammonium fluoride. A colorless oil is obtained (m=260 mg; Y=60%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>N1C=CC=CC=1>[N+:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:7]=1)([O-:10])=[O:9]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccnc(N2CCNCC2)c1
Yield: 18.8 %

Procedure:
A solution of 2-chloro-4-nitropyridine (4.89 g), and piperazine (7.90 g) in pyridine (90 ml) was heated under reflux for 5 hours and then evaporated. The residue was dissolved in water and the solution was basified with sodium bicarbonate (to pH 8-9) and then continuously extracted with dichloromethane. The extract was dried (Na2SO4) and evaporated to give an oil which was chromatographed on silica gel. Elution with dichloromethane/methanol/concentrated aqueous ammonia (98:2:1) first gave a solid that was crystallised from ethyl acetate/hexane to give 1-[4-nitro-2-pyridinyl]piperazine (1.21 g), m.p. 92°-93° C.
Reaction SMILES: Br[C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].[C:86]([N:89]1[CH2:94][CH2:93][NH:92][CH2:91][CH2:90]1)(=[O:88])[CH3:87]>C1(C)C=CC=CC=1.[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O.C(OCC)(=O)C>[C:86]([N:89]1[CH2:94][CH2:93][N:92]([C:2]2[CH:33]=[CH:32][C:5]([CH2:6][CH:7]3[C:16]4[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[CH:14][CH:15]=4)[CH2:10][CH2:9][N:8]3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:4][CH:3]=2)[CH2:91][CH2:90]1)(=[O:88])[CH3:87]
Reactant: CC(=O)N1CCNCC1
Reactant: Fc1ccc(N2CCc3cc(OCc4ccccc4)ccc3C2Cc2ccc(Br)cc2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)N1CCN(c2ccc(CC3c4ccc(OCc5ccccc5)cc4CCN3c3ccc(F)cc3)cc2)CC1
Temperature: 80 °C
Yield: 41.1 %

Procedure:
A mixture of 1-(4-bromobenzyl)-6-phenylmethoxy-2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (1.0 g, 1.99 mmol), dibenzylideneacetone palladium (36 mg, 0.04 mmol), BINAP (74 mg, 0.12 mmol), sodium tert-butoxide (0.29 g, 3.0 mmol) and N-acetylpiperazine (0.38 g, 3.0 mmol) in 2 ml of toluene were added to a sealed tube under an argon atmosphere and heated at 80° C. for 16 h. The sealed tube was cooled to room temperature and the contents of the tube transferred to a separatory funnel. Ethyl acetate and water were added and the organic layer was separated. The combined organic layers were dried over MgSO4, concentrated, and purified by column chromatography (SiO2, chloroform/methanol, 99:1) to provide the title compound (0.45 g, 41% yield): ES-MS (m/z) 550 [M+H]+.
Reaction SMILES: C([C@@H]1C(OC)=[N:8][C@@H:7]([C@@H:12]([O:23][CH3:24])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[C:6]([O:25][CH3:26])=N1)(C)C.Cl.C1C[O:31]CC1>CC#N>[NH2:8][C@@H:7]([C@@H:12]([O:23][CH3:24])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[C:6]([O:25][CH3:26])=[O:31]
Reactant: C1CCOC1
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1[C@@H](OC)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CC#N
Product: COC(=O)[C@@H](N)[C@@H](OC)c1ccc(C(F)(F)F)cc1
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of (2R,5S)-2-isopropyl-3,6-dimethoxy-5-((S)-methoxy(4-(trifluoromethyl)phenyl)methyl)-2,5-dihydropyrazine (3.40 g, 9.1 mmol) in THF (25 mL) and CH3CN (50 mL) was added 0.25 N hydrochloric acid (73 mL, 18 mmol) at room temperature. The mixture was stirred overnight and the solvent was removed in vacuo. The residue was neutralized with saturated NaHCO3 and extracted with ether. The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (30%-50% EtOAc-hexane) to provide the product as a colorless oil (1.1 g, 43%). LCMS (API-ES) m/z (%): 278 (M+H).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:10]=1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: COc1ccc(N)cc1
Product: COc1ccc(Nc2cc(Cl)ccc2C(=O)O)cc1
Yield: 60 %

Procedure:
4-Chloro-2-(4-methoxyphenylamino)benzoic acid [VII; R=4--Cl, R"=H, OR°=4--OCH3 ] was prepared from 2,4-dichlorobenzoic acid and 4-methoxyaniline according to the procedure of Example 1, part (a), and was obtained in about 60% yield as a green-grey solid.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:18])[CH2:6]1)C.Cl.[C:20]([NH2:25])(=[NH:24])[CH2:21][CH2:22][CH3:23]>>[CH3:17][C:14]1[CH:15]=[CH:16][C:9]2[NH:8][C:7](=[O:18])[CH2:6][C:5]3[CH:4]=[N:24][C:20]([CH2:21][CH2:22][CH3:23])=[N:25][C:11]=3[C:10]=2[CH:13]=1
Reactant: CCCC(=N)N
Reactant: Cc1ccc2c(c1)C(=O)C(=CN(C)C)CC(=O)N2
Agent: Cl
Product: CCCc1ncc2c(n1)-c1cc(C)ccc1NC(=O)C2
Yield: 90 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-3,4-dihydro-7-methyl-1H-benzazepine-2,5-dione and butyramidine hydrochloride. Yield: 90%.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][C:14](=[O:37])[C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C:16]=3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]1([CH3:39])[CH3:38])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:40]#[N:41].C([Al+]CC)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH:14]([OH:37])[C@@H:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@@:16]3([C:40]#[N:41])[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]1([CH3:39])[CH3:38])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2=C3C(=O)C[C@H]4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: CC[Al+]CC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@@]2(C#N)[C@@H]3C(O)C[C@H]4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
A solution of 3β-benzoyloxy-4,4-dimethyl-5α-cholest-8(14)-en-7-one (5 g, 9.4 mmole) in toluene (75 mL) at 0° C. under an argon atmosphere was treated with a solution of diethyl aluminum cyanide (1.4 M in toluene, 12.7 mL, 17 mmole). The reaction mixture was stirred at 0° C. for 0.5 hours, poured into 1N sodium hydroxide solution and extracted with methylene chloride. The organic phase was washed with water, dried and concentrated to one half the volume. An equal volume of methanol was added, the mixture was placed in a cold water bath and sodium borohydride (0.75 g) was added in portions. The mixture was stirred for 0.5 hours at ambient temperature, poured into brine, the layers separated and the organic layer was dried and concentrated to give 4.5 g (85%) of 3β-benzoyloxy-14α-cyano-4,4-dimethyl-5α-cholestan-7-ol; mp 270°-271° C. (from CH2Cl2 ).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[N:12]([CH2:19][CH3:20])[C:11]3=[O:21])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C([O-])([O-])=O.[Cs+].[Cs+].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:19]([N:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[N:1]([C:23]2[S:24][CH:25]=[CH:26][N:27]=2)[CH:2]=[CH:3]3)[C:11]1=[O:21])[CH3:20]
Reactant: CCn1c(=O)n(-c2ccc3c(c2)CCN3)c2ncccc21
Reactant: Clc1nccs1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc3c(ccn3-c3nccs3)c2)c2ncccc21
Temperature: 100 °C
Reaction time: 72 h
Yield: 27.9 %

Procedure:
A mixture of 3-(2,3-dihydro-1H-indol-5-yl)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (75 mg), 2-chlorothiazole (48.0 mg) and Cs2CO3 (174 mg) in DMF (3 mL) was stirred at 100° C. for 3 days, treated with saturated NaHCO3 solution, and extracted with AcOEt. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified by prep. HPLC and crystallized from AcOEt/Hexane to give the title compound as white crystals (27.0 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][N:22]=3)[CH2:17][CH2:16]2)=[O:14])=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.[C:29]([N:32]1[CH2:36][CH2:35][NH:34][C:33]1=[O:37])(=[O:31])[CH3:30]>>[C:29]([N:32]1[CH2:36][CH2:35][N:34]([C:2]2[CH:3]=[CH:4][C:5]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][N:22]=4)[CH2:17][CH2:16]3)=[O:14])=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=2)[C:33]1=[O:37])(=[O:31])[CH3:30]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3NS(C)(=O)=O)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)c(NS(C)(=O)=O)c2)C1=O
Yield: 13 %

Procedure:
Using N-{5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}methanesulfonamide (806 mg) described in Preparation Example 226 and 1-acetylimidazolidin-2-one (221 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (115 mg) was obtained.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@H:14]([OH:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=1>C(#N)C>[C:33]1([CH3:37])[CH:34]=[CH:35][CH:36]=[C:31]([NH:30][CH2:12][CH2:13][C@@H:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[OH:21])[CH:32]=1
Reactant: Cc1cccc(N)c1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@H](O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(NCC[C@H](O)c2ccccc2)c1
Yield: 56.5 %

Procedure:
To a solution of the (S)-3-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate (100 mg, 0.33 mmol) in anhydrous acetonitrile (2 mL) were added K2CO3 (91 mg, 0.66 mmol), NaI (12 mg, 0.0825 mmol) and m-toluidine (42 mg, 0.39 mmol). The mixture was refluxed overnight. The mixture was filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated to give the crude product, which was purified by preparative TLC (3:1 Petroleum ether/EtOAc) to give (S)-3-(m-tolylamino)-1-phenylpropan-1-ol (45 mg, 57%). 1H NMR (400 MHz, CDCl3): δ=2.05 (m, 2H), 2.25 (s, 3H), 3.25 (m, 2H), 3.40 (s, 2H), 4.90 (m, 1H), 6.50 (m, 4H), 7.05 (m, 1H), 7.30 (m, 1H), 7.40 (d, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[C:11]([CH3:19])[C:10]=2[CH:20]=1.[BH4-].[Na+]>O1CCCC1.CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH:14]([OH:18])[CH:15]([CH3:16])[CH3:17])=[C:11]([CH3:19])[C:10]=2[CH:20]=1
Reactant: COCCOc1ccc2oc(C(=O)C(C)C)c(C)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COCCOc1ccc2oc(C(O)C(C)C)c(C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
1-[5-(2-Methoxyethoxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropan-1-one (0.71 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (5 mL) and methanol (0.5 mL), and sodium borohydride (90%, 0.21 g) was added to the solution under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (1 mL) and 1N hydrochloric acid (5 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a crude product (0.70 g, quantitative) of the title object compound as a pale-yellow oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]C>ClCCl>[CH2:20]([Br:24])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A series of n-alkyl bromides (CnH2n+1Br) were purchased from TCI (n=3, 6, 9, 12, 15, and 18) and Aldrich (n=22), and used as received. 1-Tetracosyl bromide (n-C24H49Br) was prepared from the corresponding alcohol (Aldrich) according to the following procedure. Triphenylphosphine (95 mg, 0.36 mmol) and carbontetrabromide (120 mg, 0.36 mmol) were sequentially introduced into a dichloromethane solution (50 ml) dissolved with 1-tetracosanol (60 mg, 0.17 mmol), and the mixture was stirred at room temperature for 12 hr. The solvent was then removed by evacuation, and the produced 1-tetracosyl bromide was isolated from the reaction mixture by column chromatography. 4-[4-(Dimethylamino)styryl]pyridin (Aldrich), tetraethylorthosilicate (TEOS, Acros), sodium aluminate (NaAlO2, Kanto) and tetrapropylammonium hydroxide (TPAOH, Aldrich) were purchased, and used as received. n-Octadecane and n-heptadecane were purchased from PolyScience Corporation and used as such. 4-Nitroaniline was purchased from Aldrich, and used as such.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[C:16]([CH2:19][O:20][C:21]1[CH:31]=[CH:30][C:24]([CH:25](O)[C:26](O)=[O:27])=[CH:23][CH:22]=1)([OH:18])=[O:17].CS(O)(=O)=O>C(O)(=O)C>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]2[O:15][C:26](=[O:27])[CH:25]([C:24]3[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:16]([OH:18])=[O:17])=[CH:31][CH:30]=3)[C:7]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)COc1ccc(C(O)C(=O)O)cc1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccc(OCC(=O)O)cc1
Yield: 78.2 %

Procedure:
A mixture of 20.6 g (0.10 mol) of 2,4-di-tert-butylphenol, 22.6 g (0.10 mol) of 4-carboxymethoxymandelic acid and 1 g (10 mmol) of methanesulfonic acid in 50 ml of acetic acid is refluxed for 15 hours. The acetic acid is then distilled off. The residue is dissolved in 100 ml of dichloromethane, and the solution is washed three times with water. The organic phases are combined, dried over magnesium sulfate and concentrated on a vacuum rotary evaporator. Crystallisation of the residue from ligroin gives 31.0 g (78%) of 5,7-di-tert-butyl-3-(4-carboxymethoxyphenyl)benzofuran-2-one, melting point 158°-162° C. (Compound (116), Table 1).