Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH2:14]O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BrH:16].S(=O)(=O)(O)O.O>CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH2:14][Br:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OC[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCCCCC
Product: Clc1ccc([C@H]2CC[C@H](CBr)CC2)cc1

Procedure:
To a stirred suspension of trans-(4-(4-chlorophenyl)cyclohexane)carboxylic acid (47.74 g) in dry ether (250 ml), under nitrogen, was added dropwise borane-methyl sulphide complex (8 ml; ca.10M solution--Aldrich). After 30 min the mixture was heated to reflux and further borane-methyl sulphide complex (16 ml) added. After 1 hr the mixture was cooled to room temperature and poured into methanol (500 ml). The solvent was evaporated in vacuo and the residue treated again with methanol (100 ml) followed by concentration in vacuo, to give trans-(4-(4-chlorophenyl)cyclohexyl) methanol (44 g), m.p. 60°-63°. A portion of this alcohol (41 g) was added to 48% hydrobromic acid (61 g) and conc. sulphuric acid (20 g). The mixture was stirred and heated at 140° for 5.5 hr, cooled and poured into iced water. The precipitate was filtered, dissolved in ether, washed with satd. aq. sodium bicarbonate and brine, dried over magnesium sulphate and the solvent evaporated in vacuo to leave a brown oil. Trituration with cold hexane gave trans-(4-(4-chlorophenyl)cyclohexyl)methyl bromide (44 g), m.p. 36°-38°. To magnesium turnings (33.06 g) in dry ether (70 ml) under nitrogen was added a crystal of iodine followed by a solution of the bromide (19.7 g) in ether (20 ml). The mixture was heated at reflux for a further 30 min, cooled to room temperature and then added dropwise to vigorously stirred acetic anhydride in dry ether (70 ml) at -78°, such that the temperature did not exceed -70°. The mixture was stirred at -78° for a further 1 hr, then allowed to warm to 0° and poured into satd. aq. ammonium chloride (200 ml). The mixture was stirred for 30 min then the organic phase was separated and washed with satd. aq. sodium bicarbonate and brine, dried over magnesium sulphate and concentrated in vacuo, to leave a white solid , which was recrystallised from hexane to afford the title compound (9.3 g), m.p. 58°-60°, NMR δH (CDCl3) 7.3-7.0 (4H, m), 2.55-2.3 (1H, m), 2.4-2.3 (2H, m), 2.15 (3H, s), 2-1.75 (5H, m), 1.6-1.45 (2H, m), 1.25-1.0 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[C:14]([CH3:17])(O)[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.C(Cl)Cl.C(N(S(F)(F)F)CC)C.C([O-])(O)=O.[Na+].[OH-].[Na+]>CCOCC>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:12][CH:11]([C:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)=[C:14]([CH3:17])[CH3:15])[CH2:10]2)=[CH:31][CH:30]=1
Reactant: CC(C)(O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)=C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 47 mg (0.099 mmol) of 1-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-1-(3,5-difluorophenyl)-2-methylpropan-2-ol in 0.5 mL of CH2Cl2 52 uL (0.395 mmol) of DAST (diethylaminosulfur trifluoride) was added and the solution was stirred for 2 h at −78° C. Then to the reaction mixture was added 10 mL of ether and 3 mL of ag NaHCO3. The pH was adjusted to 8-9 with 2N NaOH. The water layer was extracted with CH2Cl2 (3×10 mL). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound as a white solid; 1H NMR (CDCl3) δ 1.51 (s, 3H), 1.71 (s, 3H), 2.60 (t, J=7.8 Hz, 2H), 3.36 (t, J=7.6 Hz, 2H), 3.70 (m, 1H), 4.06 (s, 1H), 6.56 (m, 2H), 6.73 (m, 1H), 7.24 (m, 8H); Mass Spectrum: m/e=458 (M+1 35Cl, 35Cl) and 460 (M+1 35Cl, 37Cl).
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[C:8]2[CH:9]=[CH:10][C:11](F)=[CH:12][C:7]=2[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]([OH:20])[C:4]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:21][CH3:22])[CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:34]([O:38]CC)(=[O:37])[CH2:35][SH:36].O>CN(C=O)C>[O:1]=[S:2]1(=[O:27])[C:8]2[CH:9]=[CH:10][C:11]([S:36][CH2:35][C:34]([OH:38])=[O:37])=[CH:12][C:7]=2[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]([OH:20])[C:4]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:21][CH3:22])[CH2:3]1
Reactant: CCCCC1(CC)CS(=O)(=O)c2ccc(F)cc2C(c2ccccc2)C1O
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC1(CC)CS(=O)(=O)c2ccc(SCC(=O)O)cc2C(c2ccccc2)C1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 48.3 %

Procedure:
1,1-Dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7-fluoro-2,3,4,5-tetrahydrobenzothiepine (prepared according to WO 98/40375; 300 mg, 0.77 mmol) was dissolved in DMF (3 ml) and caesium carbonate (540 mg, 1.66 mmol) was added followed by ethyl thioglycolate (0.17 ml, 1.54 mmol) and the reaction mixture was subjected to microwave irradiation in a Smith Synthesiser at 100° C. for 5 min. The reaction mixture was added to water (25 ml), extracted with DCM (5×5 ml) and concentrated. The crude ethyl ester was dissolved in THF (4 ml) and water (2 ml) and NaOH (1 M, 4 ml) was added. The reaction mixture was stirred at ambient temperature for 6 hours, quenched with HCl (1 M), diluted with water (25 ml) and extracted with DCM (4×5 ml). The combined organic layers were purified with preparative HPLC using MeCN/ammonium acetate buffer as the eluent (50:50) to give the title compound (172 mg, 48%). NMR (400 MHz, DMSO-d6): 0.74 (t, 3H), 0.84 (t, 3H), 1.01 (m, 1), 1.18-1.46 (m, 5H), 1.60 (m, 1H), 2.02 (m, 1H), 3.07/3.12 (ABq, 2H), 3.33/3.39 (ABq, 2H), 3.95 (s, 1H), 5.23 (s, 1H), 6.38 (d, 1H), 7.19 (dd, 1H), 7.34 (m, 1H), 7.42 (m, 4H), 7.73 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[CH3:30][C@H:31]1[NH:36][C@@H:35]([CH3:37])[CH2:34][N:33]([C:38]2[O:39][C:40]3[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=3[N:42]=2)[CH2:32]1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:36]3[C@H:35]([CH3:37])[CH2:34][N:33]([C:38]4[O:39][C:40]5[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=5[N:42]=4)[CH2:32][C@@H:31]3[CH3:30])[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN(c2nc3ccccc3o2)C[C@H](C)N1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: C[C@@H]1CN(c2nc3ccccc3o2)C[C@H](C)N1CCCCC1(C(=O)NCc2ccc(F)cc2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-benzoxazole.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[CH:14]=[N:13][C:12]([C:17]([F:20])([F:19])[F:18])=[N:11][C:10]=2[CH2:9]1)=O)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>ClCCl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[F:20][C:17]([F:18])([F:19])[C:12]1[N:13]=[CH:14][C:15]2[CH2:16][NH:8][CH2:9][C:10]=2[N:11]=1
Reactant: CC(C)(C)OC(=O)N1Cc2cnc(C(F)(F)F)nc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ncc2c(n1)CNC2
Yield: 100 %

Procedure:
3.4 mmol of 2-Trifluoromethyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester was dissolved in a mixture of 20 ml dichloromethane and 3 g trifluoroacetic acid. The mixture was hold at 45° C. for 3 hours and concentrated to give the title compound as a waxy solid. Yield=100%. MS (m/e): 190.3 ([M+H]+, 100%).
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([CH2:11][N:12]([CH2:19][C:20]1[CH:25]=[C:24]([C:26](OCC)=[O:27])[CH:23]=[CH:22][N:21]=1)C(=O)C(F)(F)F)=[O:10])[CH3:2].[BH4-].[Na+]>>[CH2:31]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:10])[CH2:11][NH:12][CH2:19][C:20]1[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[CH:22][N:21]=1)[CH3:32]
Reactant: CCOC(=O)c1ccnc(CN(CC(=O)NCCCCN(CC)CC)C(=O)C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: CCN(CC)CCCCNC(=O)CNCc1cc(CO)ccn1

Procedure:
Prepared by General Procedure U from ethyl 2-{[N-({[4-(diethylamino)butyl]carbamoyl}methyl)-2,2,2-trifluoroacetamido]methyl}pyridine-4-carboxylate, using 5 equivalents of NaBH4. Purification by column chromatography with (10% MeOH and 1% NH4OH in DCM) gave the title product as light yellow oil. 1H NMR (300 MHz, methanol-d4): δ ppm 8.45 (d, 1H), 7.47 (s, 1H), 7.31 (d, 1H), 4.68 (s, 2H), 3.88 (s, 2H), 3.28 (m, 4H), 2.59 (q, 4H), 2.51 (m, 2H), 1.52 (m, 4H), 1.05 (t, 6H).
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.Cl[CH2:15][CH2:16][N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][C:18]1=[O:26].C(=O)([O-])[O-].[Na+].[Na+].N#N>C(C(C)=O)C(C)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][N:2]1[CH2:15][CH2:16][N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][C:18]1=[O:26])=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: O=c1[nH]c2ccccc2n1CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccccc2n1CCN1CCc2c([nH]c3ccccc23)C1

Procedure:
1,2,3,4-Tetrahydro-9H-pyrido[3,4-b]indole (1.50 g, 8.7 mmol) was suspended in methyl isobutyl ketone (50 ml). 1-(2-Chloroethyl)-1,3-dihydro-2H-benzimidazol-2-one (1.958 g, 9.58 mmol) was added to the mixture along with sodium carbonate (1.110 g, 10.45 mmol) and tetrabutyl ammonium iodide (10 mg). The suspension was heated to 90° C. for 2 days, under an inert (N2) atmosphere. The mixture was concentrated in vacuo to dryness. Water (70 ml) was added, followed by addition of 2N HCl to pH1. The mixture was extracted with CHCl3 (2×70 ml), basified to pH10 using 5N NaOH, and again extracted with CHCl3 (3×70 ml). The organics were combined and washed with brine, separated and dried over MgSO4. The resulting solid was purified by chromatography (CHCl3, MeOH (2%)) to yield a yellow solid, m.p. 214°-216° C.
Reaction SMILES: [CH3:1][C:2]1([NH:21][C:22]2C=N[C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[N:19]=[CH:18][CH:17]=[N:16]1.Cl.[NH2:33][C:34]1(C)CCCC1NC(=O)C1C=CC=CC=1N1N=CC=N1.ClC1N=CC(C(F)(F)F)=CN=1>>[CH3:1][C:2]1([NH:21][C:22]2[N:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:34][N:33]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[N:16]=[CH:17][CH:18]=[N:19]1
Reactant: CC1(N)CCCC1NC(=O)c1ccccc1-n1nccn1
Reactant: CC1(Nc2cnc(C(F)(F)F)cn2)CCCC1NC(=O)c1ccccc1-n1nccn1
Agent: Cl
Agent: FC(F)(F)c1cnc(Cl)nc1
Product: CC1(Nc2ncc(C(F)(F)F)cn2)CCCC1NC(=O)c1ccccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-(2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 82) from N-(2-amino-2-methylcyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 26; 200 mg, 0.70 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (CAS number 69034-12-4; 141 mg, 0.77 mmol) except this was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) followed by reverse phase chromatography (C18 silica, 0-100% water (with 0.05% ammonia)/acetonitrile) to afford the title compound.
Reaction SMILES: N1(O)CCOCC1.[CH3:8][CH:9](NC(C)(C)C)[C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:18])[CH:17]=1)=[O:11].Cl.ClC1C=C(C(=O)CC)C=CC=1.[Br-:36].[Br-].O1CCOCC1>O1CCOCC1.O>[Br:36][CH:9]([CH3:8])[C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:18])[CH:17]=1)=[O:11]
Reactant: [Br-]
Reactant: CC(NC(C)(C)C)C(=O)c1cccc(Cl)c1
Agent: CCC(=O)c1cccc(Cl)c1
Agent: Cl
Agent: ON1CCOCC1
Solvent: C1COCCO1
Solvent: O
Product: CC(Br)C(=O)c1cccc(Cl)c1
Yield: 85 %

Procedure:
The racemate of the morpholinol metabolite of bupropion hydrochloride ((+/−)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol hydrochloride) may be synthesized by the following process. To 3′-chloropropiophenone (10.0 g, 0.06 mol) in dioxane (50 mL) was added a solution of dioxane dibromide (14.9 g, 0.06 mol) in dioxane (50 mL). The reaction mixture was stirred for 2h at ambient temperature and poured into a mixture of ice and water (500 mL). The mixture was extracted several times with methylene chloride. The combined extracts were dried (Na2SO4) and concentrated in vacuo to give 14.8 g (85%) of 2-bromo-3′-chloropropiophenone as a pale yellow oil. This was used without further purification. NMR (300 Mhz, CDCl3); δ 7.99 (m, 1H), 7.90 (d, 1H), 7.57 (d, 1H), 7.44 (t, 1H), 5.22 (q, 1H), 1.91 (t, 3H).
Reaction SMILES: [CH2:1]([NH:4][S:5]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-])=O)[C:9]=1[OH:18])(=[O:7])=[O:6])[CH:2]=[CH2:3].O.O.[Sn](Cl)Cl>C(O)C>[CH2:1]([NH:4][S:5]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([NH2:15])[C:9]=1[OH:18])(=[O:7])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: C=CCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Yield: 84.6 %

Procedure:
A solution of N-allyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (25 mg, 0.09 mmol) and tin (II) chloride dihydrate (101 mg, 0.44mmol) in 5 mL of ethanol was stirred at room temperature. The mixture was concentrated, the residue was diluted with ethyl acetate and 10% aq. NaHCO3. The organic layer was dried over Na2SO4 and concentrated to give the crude product (20 mg) which was carried on to the next step without purification. EI-MS (m/z) 263.1, 265.2 (M−).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]>[Pd].CO>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: NC(=O)Nc1[nH]c(-c2cccc([N+](=O)[O-])c2)cc1C(N)=O
Agent: [Pd]
Solvent: CO
Product: NC(=O)Nc1[nH]c(-c2cccc(N)c2)cc1C(N)=O
Yield: 53 %

Procedure:
5% Palladium on activated carbon (30 mg) was added to a solution of 2-aminocarbonylamino-5-(3-nitrophenyl)pyrrole-3-carboxamide (Compound No. 1-6, 0.15 g, 0.52 mmol) in methanol (10 mL) and the mixture was stirred at room temperature for 6.5 hours under hydrogen gas atmosphere. After the insoluble solid was filtered out, the solvent was removed under reduced pressure. The obtained solid was washed with a mixed solvent (6 mL) which consists of chloroform and methanol (5:1), and dried under reduced pressure to give the target compound (0.072 g) as a pale yellow solid (Yield 53%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[C:11]2[CH:19]([F:21])[F:20])[CH:3]=1.CN(C)C(=O)C.[OH:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32][CH2:31]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[F:20][CH:19]([F:21])[C:11]1[N:10]([C:4]2[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32][CH2:31]3)[CH:3]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: CC(C)(C)OC(=O)NN1CCC(CO)CC1
Reactant: CSc1nc(Cl)cc(-n2c(C(F)F)nc3ccccc32)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CSc1nc(OCC2CCN(NC(=O)OC(C)(C)C)CC2)cc(-n2c(C(F)F)nc3ccccc32)n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 42.7 %

Procedure:
To a mixture of 1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-2-(difluoromethyl)-1H-benzimidazole (1 g) and N,N-dimethylacetamide (10 mL) were added tert-butyl 4-(hydroxymethyl)piperidine-1-carbamate (1 g) and cesium carbonate (3 g), and the mixture was stirred at 120° C. for 3 hours. The reaction mixture was poured into water, followed by extraction with hexane-ethyl acetate (1:1). The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain tert-butyl 4-[({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(methylsulfanyl)pyrimidin-4-yl}oxy)methyl]piperidine-1-carbamate (680 mg) as a white amorphous substance.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[CH:10]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:26]([O:28][CH:29]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:39])[CH2:35][CH:36]([CH3:38])[CH3:37])[CH3:30])=[O:27].N1C=CC=CC=1>C1COCC1.CCOCC>[CH2:1]([O:8][C:9](=[O:24])[CH:10]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[CH2:11][O:12][C:26]([O:28][CH:29]([CH3:30])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:39])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CC(C)CCCC(C)OC(=O)Cl
Reactant: O=C(NC(CO)C(=O)OCc1ccccc1)OCc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)CC(C)CCCC(C)OC(=O)OCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 25 h
Yield: 89.3 %

Procedure:
To a mixture of 10 g 2-benzyloxycarbonylamino-3-hydroxy-propionic acid benzyl ester [C. G. Skinner, T. J. McCord, J. M. Ravel, W. Shive, J. Am. Chem. Soc., 78, 1956, 2412] and 10 g 6,8-dimethyl-non-2-yl chloroformate in 80 ml of THF was added a solution of 3.4 ml of pyridine in 40 ml THF at 0° C. The reaction mixture was stirred for 25 h at rt, diluted with ether and washed with 2N hydrochloric acid, saturated sodium bicarbonate and brine. The organic phase was dried and evaporated to dryness. The resulting oil was purified by chromatography on silica gel to yield 14.3 g of a colorless liquid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13][C:14]1[N:26]=[CH:25][C:17]2=[CH:18][C:19]3[C:24]([N:16]2[N:15]=1)=[CH:23][CH:22]=[CH:21][CH:20]=3.C([O-])(O)=O.[Na+]>ClCCl.O>[CH3:12][S:13]([C:14]1[N:26]=[CH:25][C:17]2=[CH:18][C:19]3[C:24]([N:16]2[N:15]=1)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:9]
Reactant: CSc1ncc2cc3ccccc3n2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CS(=O)c1ncc2cc3ccccc3n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
261 g) Into a round-bottom flask, m-chloroperbenzoic acid (77% by weight in benzoic acid, 853 mg, 3.80 mmol) was added to a solution of 2-methylsulfanyl-[1,2,4]triazino[1,6-a]indole (780 mg, 3.60 mmol) in dichloromethane (20 mL), at 0° C. The reaction was stirred for 1 hour at room temperature. Saturated NaHCO3 in water was added and the reaction mixture was stirred for 30 minutes. The organic phase was separated, washed with brine, and dried over magnesium sulfate, then filtered. The solvent was removed under vacuum to afford 2-methanesulfinyl-[1,2,4]triazino[1,6-a]indole (820 mg, 98%) as an orange solid, which was used without further purification. 1H-NMR (CDCl3) δ 9.28 (s, 1H), 8.34 (d, J=8.5 Hz, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.60 (m, 1H), 7.52 (m, 1H), 7.21 (s, 1H), 3.06 (s, 3H); LC/MS (ESI+): 254.5 (M+Na).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=O.[NH2:13][C:14]1[S:15][CH2:16][CH2:17][N:18]=1.Cl.N>C(#N)C.CO>[S:15]1[CH2:16][CH2:17][N:18]2[C:3]([C:5]3[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=3)=[CH:2][N:13]=[C:14]12
Reactant: NC1=NCCS1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: Cl
Agent: N
Solvent: CC#N
Solvent: CO
Product: N#Cc1ccc(-c2cnc3n2CCS3)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
3.00 g (12.72 mmol) of 4-bromoacetylbenzonitrile is dissolved in 40 mL acetonitrile, and combined with 2.65 g (25.42 mmol) of 2-amino-4,5-dihydrothiazole and 2.00 g of molecular sieve 4 Å. Then the mixture is stirred for 2.5 days at ambient temperature. Then the solvent is eliminated in vacuo, and the residue is taken up with 100 mL of 1 molar hydrochloric acid solution and the insoluble matter is taken up with a little methanol and concentrated ammonia solution. After filtration, the filtrate is concentrated in vacuo and purified by chromatography on silica gel (gradient: initially ethyl acetate/ethanol=100:0 □40:60+0.5% ammonia, then dichloromethane/methanol=6:4+2% triethylamine). Yield: 2.4 g; Rf value: 0.65 (silica gel; ethyl acetate/ethanol=8:2+1% ammonia); C12H9N3S (227.29); mass spectrum: (M+H)+=228
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([CH2:13]O)=[CH:10][CH:9]=[CH:8]2)[CH3:2].C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:16][CH2:13][C:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:1][CH3:2])[CH:8]=[CH:9][CH:10]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCc1cccc2cccc(CO)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1cccc2cccc(CBr)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
A solution of (8-ethyl-naphthalen-1-yl)-methanol (760 mg) in dichloromethane (15 ml) was cooled to 0° C. and treated with carbon tetrabromide (2.03 g). A solution of triphenylphosphine (1.28 g) in dichloromethane (15 ml) was added dropwise. The reaction mixture was stirred at r.t. overnight, then concentrated. The crude product was purified by column chromatography (silica gel; cyclohexane→cyclohexane/EtOAc 4:1) to give 1-bromomethyl-8-ethyl-naphthalene (670 mg) as light yellow liquid.
Reaction SMILES: BrC1C=C(C2C=CC=CC=2)C=CC=1.[O:14]1CCOCC1.[CH:20]1([P:26]([CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:34]=2[O:41][CH3:42])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O.NN>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(OCC)(=O)C.CO>[CH:43]1([P:26]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:34]=2[O:41][CH3:42])=[O:14])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: C1COCCO1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: Brc1cccc(-c2ccccc2)c1
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(OC)c1-c1ccccc1P(=O)(C1CCCCC1)C1CCCCC1
Temperature: 94 °C
Reaction time: 8 h

Procedure:
To the mixture of 3-bromobiphenyl (0.020 ml, 0.12 mmol) and 1,4-dioxane (1.5 nil), water (0.15 ml), potassium phosphate tribasic n-hydrate (170 mg, 0.72 mmol), sodium 1,3-dioxo-1,3-dihydro-isoindole-2-ylmethyl trifluoroborate (60 mg, 0.24 mmol), palladium(II) acetate (2.7 mg, 0.012 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (9.9 mg, 0.024 mmol) were added, and then the obtained reaction mixture was stirred at 94° C. (an outer temperature) overnight. The reaction mixture was cooled to room temperature, and then hydrazine hydrate (48 mg, 0.96 mmol) and methanol (2 ml) were added thereto, followed by heating to reflux for 40 min. The reaction mixture was cooled to room temperature, and then ethyl acetate and water were added to the reaction mixture, followed by filtration with celite. The organic layer of the filtrate was separated and washed with saline. The solvents were evaporated under reduced pressure from the organic layer, and then the obtained residue was purified with NH-silica gel column chromatography (ethyl acetate), thereby obtaining the entitled compound (11 mg, 51%) as the mixture with 2′-(dicyclohexyl-phosphinoyl)-2,6-dimethoxy-biphenyl (6.2 mg).