Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[F:13][CH:14]([F:29])[C:15]1[CH:28]=[CH:27][C:18]([CH2:19][N:20]2[CH2:24][CH2:23][C@H:22]([OH:25])[C:21]2=[O:26])=[CH:17][CH:16]=1>ClCCl.O>[CH3:8][S:9]([O:25][C@H:22]1[CH2:23][CH2:24][N:20]([CH2:19][C:18]2[CH:17]=[CH:16][C:15]([CH:14]([F:13])[F:29])=[CH:28][CH:27]=2)[C:21]1=[O:26])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1[C@@H](O)CCN1Cc1ccc(C(F)F)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCN(Cc2ccc(C(F)F)cc2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
Triethylamine (0.319 mL, 2.29 mmol) and methansulfonyl chloride (0.131 mL, 1.68 mmol) was added to a stirred solution of (S)-1-(4-(difluoromethyl)benzyl)-3-hydroxypyrrolidin-2-one (368 mg, 1.53 mmol, intermediate L) in dichloromethane (7.63 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The resulting mixture was diluted with water and the aqueous mixture was extracted with dichloromethane. The combined organic layers were washed with 10% sodium bicarbonate solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified using silica gel column chromatography (0-100% EtOAc). The pure fractions were combined and concentrated in vacuo to afford the desired product (322 mg, 66% yield) as a white solid: LC-MS (M+H)+ 320.1; 1H NMR (500 MHz, chloroform-d) δ 7.53 (d, J=7.9 Hz, 2H), 7.38-7.33 (m, 2H), 6.67 (br. t, J=1.0 Hz, 1H), 5.27 (dd, J=8.2, 7.5 Hz, 1H), 4.60-4.49 (m, 2H), 3.41-3.35 (m, 1H), 3.33 (s, 3H), 3.27 (dt, J=9.9, 7.3 Hz, 1H), 2.64-2.55 (m, 1H), 2.27 (ddt, J=13.9, 8.9, 7.1 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[N:32][CH:33]=1.N1C=C(CCCCCCO)C=NC=1>>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[N:32][CH:31]=[N:30][CH:29]=3)[CH2:13][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C(=C(c1ccccc1)c1ccccc1)C1CCNCC1
Reactant: ClCCCCCCc1cncnc1
Agent: OCCCCCCc1cncnc1
Product: C(=C(c1ccccc1)c1ccccc1)C1CCN(CCCCCCc2cncnc2)CC1
Yield: 49.3 %

Procedure:
The title compound was prepared in a manner similar to that employed for the compound of Example 23 starting with 7.4 g of 4-(2,2-diphenylethenyl)piperidine and 5.9 g of 5-(6-chlorohexyl)pyrimidine, from 5-pyrimidinehexanol. Chromatography provided 5.9 g (50%) of crude 5-[6-[4-(2,2-diphenylethenyl)-1-piperidinyl]hexyl]pyrimidine. Crystallization from hexane provided the analytically pure 5-[6-[4-(2,2-diphenylethenyl)-1-piperidinyl]hexyl]pyrimidine, mp 88°-90° C. Analysis Calculated for C29H35N3 : C, 81.84; H, 8.29; N, 9.87. Found: C, 81.90; H, 8.31; N, 9.78.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:7]=[CH:8][C:9]=1[NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)([O-:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]>CN(C)C=O>[CH3:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][N:13]1[CH2:14][CH2:15][C@@H:11]([NH:10][C:9]2[CH:8]=[CH:7][C:6]([S:16]([NH2:19])(=[O:17])=[O:18])=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:12]1
Reactant: COCCOCCBr
Reactant: NS(=O)(=O)c1ccc(N[C@@H]2CCNC2)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCCN1CC[C@@H](Nc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])C1
Temperature: 60 °C

Procedure:
To a solution of (R)-3-nitro-4-(pyrrolidin-3-ylamino)benzenesulfonamide (440 mg) in N,N-dimethylformamide (10 mL) was added sodium carbonate (132 mg) and 1-bromo-2-(2-methoxyethoxy)ethane (0.155 mL). The reaction mixture was heated at 60° C. for 18 hours and after an aqueous workup, the crude product was purified on silica gel with a 2.5-10% methanol in methylene chloride gradient to provide the title compound.
Reaction SMILES: [C:1]([C:4]1[CH2:9][C:8]([C:23]#[N:24])([C:10]2[CH:15]=[CH:14][C:13](OC)=[C:12]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[CH:11]=2)[CH2:7][CH2:6][C:5]=1[O:25][CH2:26][O:27][CH3:28])([OH:3])=O.C[N:30]1CCOCC1.ClC(OCC(C)C)=O.[OH-].[NH4+]>COCCOC>[NH2:30][C:1]([C:4]1[CH2:9][C:8]([C:23]#[N:24])([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:18][CH2:19][CH:20]3[CH2:21][CH2:22]3)[CH:11]=2)[CH2:7][CH2:6][C:5]=1[O:25][CH2:26][O:27][CH3:28])=[O:3]
Reactant: CN1CCOCC1
Reactant: COCOC1=C(C(=O)O)CC(C#N)(c2ccc(OC)c(OCC3CC3)c2)CC1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: COCCOC
Product: COCOC1=C(C(N)=O)CC(C#N)(c2cccc(OCC3CC3)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.1 %

Procedure:
A mixture of 2-carboxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-(methoxymethyloxy)cyclohex-1-ene (0.26 g. 0.67 mmol), N-methyl morpholine (0.09 ml, 0.8 mmol) and isobutyl chloroformate (0.1 mL, 0.77 mmol) in dry 1,2-dimethoxyethane (7 mL) was stirred under an argon atmosphere at room temperature for 10 min. Ammonium hydroxide (0.07 mL, 1.0 mmol) was added and stirring was continued for 0.5 h. The mixture was partitioned between methylene chloride and 5% aqueous sodium carbonate, was extracted three times, the organic layer was dried (potassium carbonate) and the solvent was removed in vacuo to provide a white solid (0.22 g, 85%): m.p. 120°-122° C.
Reaction SMILES: [CH:1]([C:3]1[S:36][C:6]2[N:7]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)[C:8](=[O:20])[N:9]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)=[O:2].O1CCCC1.[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[S:36][C:6]2[N:7]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][CH:27]=3)[C:8](=[O:20])[N:9]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CCc3ccccc3)c(=O)c3cc(C=O)sc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CCc3ccccc3)c(=O)c3cc(CO)sc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a mixture of 4′-{[6-formyl-2,4-dioxo-3-(2-phenylethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.5 g), tetrahydrofuran (20 mL) and methanol (20 mL) was added sodium borohydride (0.088 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the residue was extracted with chloroform and saturated aqueous ammonium chloride solution. The chloroform layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.45 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])/[C:8]([OH:10])=[O:9])[N:6]=1.[Cl:21]N1C(=O)CCC1=O>CCCCCC>[NH2:1][C:2]1[S:3][C:4]([Cl:21])=[C:5](/[C:7](=[N:11]/[O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1csc(N)n1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1nc(N)sc1Cl
Yield: 97.2 %

Procedure:
Six grams of 2-(2-aminothiazol-4-yl)-2(Z)-(tert-butoxycarbonylmethoxyimino)acetic acid and 3.2 g of N-chlorosuccinimide are reacted in the manner of Reference Example 35 and the product obtained is solidified by treating hexane to give 6.5 g of the above-identified compound as a powder.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Br:23][C:24]1[N:28]([CH3:29])[N:27]=[CH:26][C:25]=1[CH:30]([C:32]1[C:33]([Cl:39])=[N:34][CH:35]=[N:36][C:37]=1[Cl:38])[OH:31]>C(Cl)(Cl)Cl>[Br:23][C:24]1[N:28]([CH3:29])[N:27]=[CH:26][C:25]=1[C:30]([C:32]1[C:33]([Cl:39])=[N:34][CH:35]=[N:36][C:37]=1[Cl:38])=[O:31]
Reactant: Cn1ncc(C(O)c2c(Cl)ncnc2Cl)c1Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Product: Cn1ncc(C(=O)c2c(Cl)ncnc2Cl)c1Br
Reaction time: 2 h

Procedure:
Dess-Martin periodinane (2.26 g, 5.33 mmol) was added in portions to a solution of (5-bromo-1-methyl-1H-pyrazol-4-yl)(4,6-dichloropyrimidin-5-yl)methanol (C25) (1.20 g, 3.55 mmol) in chloroform (30 mL), and the mixture was stirred for 2 hours. After filtration, the filtrate was concentrated in vacuo, diluted with ethyl acetate (300 mL), washed with saturated aqueous sodium hydrogen sulfite solution (3×150 mL), and washed with saturated aqueous sodium carbonate solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification using silica gel chromatography (Eluent: 5:1 heptane/ethyl acetate) provided the product. Yield: 1.16 g, 3.45 mmol, 97%. LCMS m/z 337.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 3.97 (s, 3H), 7.92 (s, 1H), 8.90 (s, 1H).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[F:6][C:7]1[CH:8]=[C:9]([NH2:25])[CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:15]=[N:16][C:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])=[CH:18][CH:19]=1>FC(F)(F)C(O)=O>[F:6][C:7]1[C:12]([O:13][C:14]2[CH:15]=[N:16][C:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])=[CH:18][CH:19]=2)=[CH:11][C:10]([N+:1]([O-:4])=[O:2])=[C:9]([NH2:25])[CH:8]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2ccc(N)cc2F)cn1
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)c1ccc(Oc2cc([N+](=O)[O-])c(N)cc2F)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.8 g of potassium nitrate was added to a trifluoroacetic acid (100 ml) solution of 10.5 g of 3-fluoro-4-(6-ethanesulfonyl-pyridin-3-yloxy)-phenylamine, and the reaction liquid was stirred for 1 hour at room temperature, and the solvent was evaporated away under reduced pressure. The residue was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/2) to obtain the entitled compound.
Reaction SMILES: [CH3:1]/[C:2](/[CH:8]=[CH:9]/[C:10](/[F:23])=[C:11](\[CH3:22])/[CH:12]=[CH:13]/[C:14]1[C:18]([CH3:19])=[C:17]([CH3:20])[S:16][C:15]=1[CH3:21])=[CH:3]\[C:4](OC)=[O:5].[H-].C([Al+]CC(C)C)C(C)C.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH3:1]/[C:2](/[CH:8]=[CH:9]/[C:10](/[F:23])=[C:11](\[CH3:22])/[CH:12]=[CH:13]/[C:14]1[C:18]([CH3:19])=[C:17]([CH3:20])[S:16][C:15]=1[CH3:21])=[CH:3]\[CH2:4][OH:5]
Reactant: COC(=O)/C=C(C)/C=C/C(F)=C(C)/C=C/c1c(C)sc(C)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: ClCCl
Product: CC(/C=C/c1c(C)sc(C)c1C)=C(F)\C=C\C(C)=C\CO
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A solution of 1.05 g. (31.4 mmole) of methyl 2E,4E,6Z,8E-3,7-dimethyl-6-fluoro-9-(2,4,5-trimethyl-3-thienyl)-2,4,6,8-nonatetraenoate in 100 ml. of methylene chloride was cooled to -60° C. under argon and 5.2 ml. (69 mmole) of diisobutylaluminium hydride were added dropwise thereto. The temperature was raised to -10° C. for 10 minutes and 4 ml. of a saturated solution of magnesium sulfate were added thereto. This mixture was stirred at 25° C. for 2 hours, filtered through celite and evaporated to give a light yellow solid which was crystallized from hexane-ether (4:1 parts by volume) to give 700 mg. (73% yield) of 2E,4E,6Z,8E-3,7-dimethyl-6-fluoro-9-(2,4,5-trimethyl-3-thienyl)-2,4,6,8-nonatetraen-1-ol, m.p. 106°-107.5° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]([Si](C)(C)C)([F:18])[F:17]>CN(C)C=O>[Cl:1][C:2]1[S:3][C:4]([CH:7]([OH:8])[C:16]([F:18])([F:17])[F:15])=[CH:5][N:6]=1
Reactant: O=Cc1cnc(Cl)s1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(c1cnc(Cl)s1)C(F)(F)F

Procedure:
According to Reference Example 8-2, by use of 2-chlorothiazole-5-carbaldehyde (300 mg, 2.03 mmol) dissolved in N,N-dimethylformamide (4 mL), potassium carbonate (56 mg, 0.41 mmol) and (trifluoromethyl)trimethylsilane (0.360 mL, 2.44 mmol), the mixture was stirred and reacted at room temperature for 1.3 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=15/1) was performed to give
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][OH:10])=[CH:7][C:6]=1[O:14][CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(C(=O)O)ccc1C(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.4 %

Procedure:
step a—To a solution of 4-tert-butyl-3-methoxybenzoic acid (3.00 g, 14.40 mmol, CASRN 79822-46-1) in THF (60 mL) cooled to 5° C. was added dropwise a solution of BH3-Me2S (2.0M in THF, 16.60 mL, 33.10 mmol). The reaction was allowed to stir for 24 h at RT then cooled to −50° C. and quenched by dropwise addition of MeOH (20 mL). The reaction mixture was warmed to RT and concentrated in vacuo. The residue was taken up in MeOH (3×20 mL) and concentrated in vacuo. The final residue partitioned between EtOAc and sat'd. aq. NaHCO3. The organic layer was washed with water, brine, dried (MgSO4), filtered and concentrated to afford 2.64 g (95%) of (4-tert-Butyl-3-methoxy-phenyl)-methanol (345) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][CH2:10][O:11][N:12]=[C:13]([C:44]1[N:45]=[C:46]([NH:49]C=O)[S:47][CH:48]=1)[C:14]([NH:16][CH:17]1[C:42](=[O:43])[N:19]2[C:20]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:21]([CH:24]=[CH2:25])[CH2:22][S:23][C@H:18]12)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)(O)[O-].[Na+].C(OC(C)C)(C)C>C(OCC)(=O)C.O1CCCC1.CO>[C:1]([O:5][C:6]([CH2:8][CH2:9][CH2:10][O:11][N:12]=[C:13]([C:44]1[N:45]=[C:46]([NH2:49])[S:47][CH:48]=1)[C:14]([NH:16][CH:17]1[C:42](=[O:43])[N:19]2[C:20]([C:26]([O:28][CH:29]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:27])=[C:21]([CH:24]=[CH2:25])[CH2:22][S:23][C@H:18]12)=[O:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCCCC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CO
Solvent: C1CCOC1
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCCCC(=O)OC(C)(C)C)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.9 %

Procedure:
A mixture of benzhydryl 7-[2-(3-tert-butoxycarbonylpropoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (3.5 g), conc. hydrochloric acid (1.0 g), methanol (30 ml) and tetrahydrofuran (15.0 ml) was stirred at ambient temperature for 2.5 hours. To the reaction mixture was added ethyl acetate, followed by adjusting to pH 7.5 with a saturated aqueous sodium bicarbonate. The separated organic layer was washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave a residue, which was pulverized with diisopropyl ether to obtain benzhydryl 7-[2-(3-tert-butoxycarbonylpropoxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (3.33 g).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Br[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1>CN(C=O)C>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[N:10][CH:11]=1
Reactant: OCC1CC1
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(OCC2CC2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.4 %

Procedure:
To a solution of cyclopropylmethanol (0.890 mL, 11.0 mmol) in DMF (30 mL) was added sodium hydride (oil, 60%, 440 mg, 11.0 mmol), and the mixture was stirred at room temperature for 10 min. To this solution was added 2,5-dibromopyridine (2.00 g, 8.46 mmol) and the mixture was stirred at 70° C. for 1 hr. The reaction was quenched with water, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=49:1 to 17:3) to give the title compound (1.88 g, yield 97%) as an oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:11]1([NH:17][CH3:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(O)(C)(C)C.Cl>O>[CH:11]1([N:17]([CH3:18])[C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CNC1CCCCC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl
Solvent: CC(C)(C)O
Solvent: O
Product: CN(c1ncnc2[nH]ccc12)C1CCCCC1
Yield: 87.8 %

Procedure:
A mixture of 200 mg (1.30 mmol) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (prepared by the method of Davoll, J. Am. Chem. Soc., (1960), 82, 131), the product from Method A (589 mg/5.21 mmol) and 3 mL of tert-butanol was stirred in a sealed tube at 100° C. for 24 h. The reaction mixture was added to water, acidified to pH 1 with 1 N HCl (aq), washed twice with diethylether (ether) and basified to pH 14 with 1 N sodium hydroxide (NaOH). The resulting precipitate was filtered and dried in vacuo to obtain 263 mg (88%) of the title compound, mp 177-180° C. 1H NMR (400 MHz, CDCl3): δ 1.11-1.22 (m, 1H), 1.43-1.63 (m, 4H), 1.73 (br d, 1H, J=13.3 Hz), 1.83-1.90 (m, 4H), 3.23 (s, 3H), 4.69 (br, 1H), 6.53 (d, 1H, J=3.5 Hz), 7.03 (d, 1H, J=3.5 Hz), 8.30 (s, 1H), 10.6 (br, 1H). LRMS: 231 (M+1).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccc(Br)cc1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc(Br)cc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-bromobenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-bromophenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: C(OC([N:7]1[C@:11]2([C@@H:16]([F:17])[CH2:15][C@@H:14]3[C@H:12]2[C@H:13]3[C:18]([OH:20])=[O:19])[C:10](=[O:21])[O:9]C1)=O)C=C.[CH3:22][C:23]12[CH2:33][CH:27]3[CH2:28][C:29]([CH3:32])([CH2:31][C:25]([C:34]([O:36][CH:37](Cl)[CH3:38])=[O:35])([CH2:26]3)[CH2:24]1)[CH2:30]2>>[NH2:7][C@@:11]1([C:10]([OH:9])=[O:21])[C@@H:16]([F:17])[CH2:15][C@@H:14]2[C@H:12]1[C@H:13]2[C:18]([O:20][CH2:38][CH2:37][O:36][C:34]([C:25]12[CH2:31][C:29]3([CH3:32])[CH2:28][CH:27]([CH2:33][C:23]([CH3:22])([CH2:30]3)[CH2:24]1)[CH2:26]2)=[O:35])=[O:19]
Reactant: C=CCOC(=O)N1COC(=O)[C@]12[C@H]1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O
Reactant: CC(Cl)OC(=O)C12CC3CC(C)(CC(C)(C3)C1)C2
Product: CC12CC3CC(C)(C1)CC(C(=O)OCCOC(=O)[C@H]1[C@@H]4C[C@H](F)[C@@](N)(C(=O)O)[C@@H]41)(C3)C2
Yield: 9.6 %

Procedure:
(1S,2S,3S,5R,6S)-3′-((Allyloxy)carbonyl)-3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-6-carboxylic acid (A-1-2, 500 mg) and 1-chloroethyl 3,5-dimethyladamantane-1-carboxylate (A-5-1, 1.13 g) were treated in the same manner as in Example A-1 (3) and (4) to give the title compound (A-5, 70 mg) as a colorless solid.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][CH:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[BrH:13]>>[BrH:13].[Br:13][CH2:2][CH2:3][NH:4][CH:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(NCCO)c1ccccc1
Agent: Br
Product: CC(NCCBr)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.23 %

Procedure:
100 g (605.32 mmole) of N-(2-hydroxyethyl)-α-methylbenzylamine produced in Example 5(1) above was suspended in 515 ml of 48% aqueous hydrobromic acid solution and the resulting suspension was reacted at 126° C. for 30 minutes under refluxing. The reaction solution was then distilled for 2 hours under normal pressure at constant temperature and 465 ml of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 550 ml of acetone, and 500 ml of ethyl acetate and 670 ml of ether were added thereto. The reaction solution was stirred for 30 minutes, cooled to 0° C. and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 400 ml of ethyl acetate and then dried to obtain 97 g of the first crop of the title compound. The filtrate was then concentrated. The residue was dissolved in 450 ml of acetone, diluted with 680 ml of ether and then allowed to stand at 0° C. for 12 hours. The resulting solid product was filtered, collected, and washed with 450 ml of ethyl acetate to obtain 32.5 g of the second crop of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH2:16][OH:17])[CH:15]=1>C1COCC1.C(Cl)Cl.O=[Mn]=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:15]=1)[CH:16]=[O:17]
Reactant: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1CO
Agent: O=[Mn]=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1C=O
Temperature: 25 °C
Yield: 90.6 %

Procedure:
To a solution of [5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]methanol (Ex-57C, 5.8 g, 20 mmol) in 250 ml of THF and 250 ml of CH2Cl2, was added MnO2 (1.8 g, 20 mmol). The mixture was heated to reflux. The reaction was pushed to completion by adding two more portions of MnO2 (1.8 g each ) within 48 h. The mixture was then cooled to room temperature and filtered. The filtrate was concentrated and the residue was recrystallized from EtOAc/Hexane to give 5.1 g (88%) of 5-(1H-indol-2-yl)-2,4-dimethoxybenzaldehyde. 1H-NMR (300 MHz, DMSO-d6) δ 11.29 (br s, 1H), 10 24 (s, 1H), 8.10 (s, 1H), 7.47 (d, J=8 Hz, 1H), 7.37 (d, J=7 Hz, 1H), 7.01–7.05 (m, 1H), 6.91–6.95 (m, 1H), 6.85–6.86 (m, 2H), 4.06 (s, 3H), 3.99 (s, 3H). HRMS (EI) Calcd. for C17H15NO3: 281.1052 (M+); Found: 281.1046.
Reaction SMILES: [CH:1]([C:3]1([C:6]2([CH3:11])[O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1)=[CH2:2].B.[O:13]1CCCC1.[OH-].[Na+].OO.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.O>[CH3:11][C:6]1([C:3]2([CH2:1][CH2:2][OH:13])[CH2:4][CH2:5]2)[O:7][CH2:8][CH2:9][O:10]1
Reactant: C1CCOC1
Reactant: C=CC1(C2(C)OCCO2)CC1
Agent: B
Agent: O=S([O-])([O-])=S
Agent: OO
Solvent: O
Product: CC1(C2(CCO)CC2)OCCO1

Procedure:
5.4 g of 8 is dissolved in 200 ml of tetrahydrofuran (THF), and 14 ml of borane-THF solution (1.0 M in THF) is added in drops at 0° C. under nitrogen. The reaction mixture is then allowed to reach room temperature, and it is stirred for 2 more hours. After cooling was again performed at 0° C., 17 ml of water, 17 ml of aqueous sodium hydroxide solution (25%) and 2 ml of hydrogen peroxide (30%) are added in succession and stirred for 1 more hour. Then, sodium thiosulfate solution is added, extracted with ethyl acetate, washed with sodium chloride solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 3.9 g of title compound 9 is obtained as a colorless oil.