Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:23][N:24](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:23]([C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)#[N:24]
Reactant: COC(=O)CCc1nc(-c2cc(Br)cc(C(F)(F)F)c2)co1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1nc(-c2cc(C#N)cc(C(F)(F)F)c2)co1
Temperature: 100 °C
Yield: 75 %

Procedure:
A suspension of methyl 3-(4-(3-bromo-5-(trifluoromethyl)phenyl)oxazol-2-yl)-propanoate (Reference Example 44, 0.645 g, 1.71 mmol) and zinc cyanide (0.120 g, 1.02 mmol) in DMF (15.0 mL) was evacuated and purged with nitrogen. To this reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (0.197 g, 0.170 mmol) and the resulting reaction mixture was heated at 100° C. for 8 h. After this time, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate 4:1) to provide methyl 3-(4-(3-cyano-5-(trifluoromethyl)phenyl)-oxazol-2-yl)propanoate (0.417 g, 75%) as a white solid.
Reaction SMILES: [NH3:1].CC(O)C.Cl[C:7]([C:34]1[CH:39]=[CH:38][C:37]([I:40])=[CH:36][CH:35]=1)([C:28]1[N:32]([CH3:33])[CH:31]=[N:30][N:29]=1)[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]1[N:18]=[N:19][N:20]=[C:13]1[N:12]=[C:11]2[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1>C1COCC1>[Cl:27][C:23]1[CH:22]=[C:21]([C:11]2[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([C:7]([C:34]4[CH:35]=[CH:36][C:37]([I:40])=[CH:38][CH:39]=4)([C:28]4[N:32]([CH3:33])[CH:31]=[N:30][N:29]=4)[NH2:1])[CH:9]=3)[N:14]3[N:18]=[N:19][N:20]=[C:13]3[N:12]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Cn1cnnc1C(Cl)(c1ccc(I)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Reactant: N
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cn1cnnc1C(N)(c1ccc(I)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Temperature: 60 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
NH3/iPrOH (45 ml) was added dropwise at 5° C. to a mixture of 7-[chloro(4-iodophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-5-(3-chlorophenyl)-tetrazolo[1,5-a]quinazoline (0.0076 mol) in THF (45 ml). The mixture was brought to room temperature, poured out into a pressure vessel, stirred at 60° C. for 6 hours, cooled and poured out into ice water. The precipitate was filtered off and dried under a vacuum, yielding 1.6 g of a first batch of 5-(3-chlorophenyl)-α-(4-iodophenyl)-α-(4-methyl-4H-1,2,4-triazol-3-yl)-tetrazolo[1,5-a]quinazoline-7-methanamine (35%) The aqueous layer was extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (1.7 g) was purified by column chromatography over silica gel (eluent: toluene/iPrOH/NH4OH 84/15/1; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 1.03 g (23%) of a second batch of 5-(3-chlorophenyl)-α-(4-iodophenyl)-α-(4-methyl-4H-1,2,4-triazol-3-yl)-tetrazolo[1,5-a]quinazoline-7-methanamine. A sample (0.23 g) was crystallized from CH3CN, the precipitate was filtrated and dried yielding 0.09 g of 5-(3-chlorophenyl)-α-(4-iodophenyl)-α-(4-methyl-4H-1,2,4-triazol-3-yl)-tetrazolo[1,5-a]quinazoline-7-methanamine, mp. 238° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:11][C:10]=1[F:21])C1C=CC=CC=1>CO.[Pd]>[F:21][C:10]1[CH:11]=[C:12]([CH2:15][CH2:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: CS(=O)(=O)CCc1ccc(OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)CCc1ccc(O)c(F)c1
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a solution of 1-benzyloxy-2-fluoro-4-(2-methylsulfonyl-ethyl)-benzene (1.5 g, 4.87 mmol) in MeOH (25 mL) was added Pd/C (50 mg). The reaction was stirred under H2 (1 atm) for 3 hours. The solid material was filtrated off and the filtrate was concentrated under vacuum to afford the desired compound (981 mg, 92.4%) as a yellowish solid. The crude compound was used for the next step without further purification. 1H NMR (400 Mz, DMSO-d6) δ 9.73 (s, 1H), 7.14˜7.11 (m, 1H), 6.94˜6.87 (m, 2H), 3.43˜3.37 (m, 2H), 2.98 (s, 3H), 2.95˜2.91 (m, 2H). LCMS 228.2 [MH+].
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][C@@H:8]([S:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][NH:6]1)=[N+]=[N-].Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:34]([O:33][C:31]([N:6]1[CH2:7][C@H:8]([S:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][C@H:5]1[CH2:4][NH2:1])=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: [N-]=[N+]=NC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccccc1

Procedure:
(2S,4R)-2-azidomethyl-4-tritylsulfanyl-pyrrolidine and benzyl chloroformate/N-ethyldiisopropylamine in CH2Cl2 (see cabamate synthesis, Method A)—followed by Staudinger reduction gave (2S,4R)-2-aminomethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid benzyl ester as white foam, MS: 509 (MH+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=3)[N:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)n2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cnc(N)nc3)n2)n1

Procedure:
The title compound was prepared from 6′-bromo-6-methyl-4-(4-trifluoromethylphenyl)-[2,2′]bipyridinyl (example E.26) (0.150 g, 0.38 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.092 g, 0.42 mmol) according to the general procedure VI. Obtained as a white solid (0.080 g, 57%). MS (ISP) 407.3 [(M+H)+]; mp 219-222° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O.[Cl:13][C:14]1[CH:32]=[CH:31][C:17]2[O:18][C:19]3[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=3[CH2:21][N:22]([C:23]([NH:25][NH2:26])=[O:24])[C:16]=2[CH:15]=1>>[O:12]=[C:10]([NH:26][NH:25][C:23]([N:22]1[CH2:21][C:20]2[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=2[O:18][C:17]2[CH:31]=[CH:32][C:14]([Cl:13])=[CH:15][C:16]1=2)=[O:24])[CH2:9][CH2:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: O=C(O)CCCCc1cccs1
Product: O=C(CCCCc1cccs1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-5-(2-thienyl)pentyl]hydrazide (59) was prepared in the manner described in Example 7 on a 7.6 mmol scale from 5-(2-thienyl)pentanoic acid (58), prepared as described above in Example 58, and 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared as described above in Example 1. Analysis calculated for C23H22N3O3SCl (M.W. 455.95): C, 60.58; H, 4.86; N, 9.22; Cl, 7.78; S, 7.03. Found: C, 60.72; H, 4.94; N, 9.22; Cl, 7.97; S, 7.08.
Reaction SMILES: [CH2:1]([N:8]([CH3:30])[C:9](=[O:29])[C@@H:10]([N:18]([CH2:26][CH:27]=[O:28])[C:19]([O:21][C:22]([CH3:25])(C)[CH3:23])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[CH2:33](O)C>C(OCC)(=O)C>[CH2:1]([N:8]([CH3:30])[C:9](=[O:29])[C@@H:10]([N:18]([CH2:26][CH2:27][OH:28])[C:19]([O:21][CH:22]([CH2:25][CH3:33])[CH3:23])=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)N(CC=O)C(=O)OC(C)(C)C
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCC(C)OC(=O)N(CCO)[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1
Reaction time: 16 h

Procedure:
Combine (S)-N-benzyl-N-methyl-2-[N-(t-butoxycarbonyl)-2-oxo-ethylamino]-3-phenyl-propionamide (5.0 mmol) and sodium borohydride (5.0 mmol) in ethanol (20 mL). Stir for 16 hours. Concentrate in vacuo to obtain a residue. Dilute the residue with ethyl acetate and extract with 0.5M hydrochloric acid solution and water. Separate the layers, dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[C:9]([NH2:19])=[N:10][N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][N:23]=1>N1C=CC=CC=1.C(Cl)Cl>[Cl:21][C:22]1[N:23]=[CH:24][C:25]([C:26]([NH:19][C:9]2[C:8]([NH:7][C:6](=[O:20])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:12][N:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:10]=2)=[O:27])=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)Nc1cn(-c2ccccc2)nc1N
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cn(-c2ccccc2)nc1NC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of t-butyl(3-amino-1-phenyl-1H-pyrazol-4-yl)carbamate (100 mg, 0.364 mmol) in pyridine (500 μL) was added 6-chloronicotinoyl chloride (53 mg, 0.304 mmol) in CH2Cl2 (2 mL). After 6 hours of stirring at room temperature, the reaction mixture was filtered and the solvent concentrated. Formation of t-butyl(3-([(6-chloropyridin-3-yl)carbonyl]amino)-1-phenyl-1H-pyrazol-4-yl)carbamate (J) was confirmed by MS (ESI+): cal'd [M+H]+ 414.1, obs'd 414.1.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=[CH2:8])[CH:2]1[O:4][CH2:3]1.[CH3:9][O:10][SiH:11]([O:14][CH3:15])[O:12][CH3:13]>CC(C)=O>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][Si:11]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:9])[CH:2]1[O:4][CH2:3]1
Reactant: CO[SiH](OC)OC
Reactant: C=CCOCC1CO1
Solvent: CC(C)=O
Product: CO[Si](CCCOCC1CO1)(OC)OC
Reaction time: 0.33 h
Yield: 91.5 %

Procedure:
In a 10-liter flask provided with stirrer, reflux condenser, internal thermometer and 2 dropping funnels, one filled with 2.85 kg of allyl glycidyl ether and the other with 3.05 kg of trimethoxysilane, 500 ml of allyl glycidyl ether or gamm-glycidyloxypropyltrimethoxysilane was heated to 130°C. Then 1 ml of an 0.01 molar solution of the mesityl oxide-platinum dichloride complex in acetone was added and the reaction was allowed to take place with rapid stirring and the simultaneous feeding in of the two reactants, within about 20 minutes. The internal temperature was kept between 130°C and 140°C by slight external cooling and by regulating the feed. This was followed by vacuum distillation producing 5.4 kg of γ-glycidyloxypropyltrimethoxysilane boiling at BP0.05 81°C (nD20 : 1.4290, d420 : 1.073).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH:12]1[CH2:15][NH:14][CH2:13]1.Cl.[O:17]=[C:18]1[NH:27][C:26]2[N:25]=[CH:24][C:23](/[CH:28]=[CH:29]/[C:30](O)=[O:31])=[CH:22][C:21]=2[CH2:20][CH2:19]1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH:12]1[CH2:13][N:14]([C:30](=[O:31])/[CH:29]=[CH:28]/[C:23]2[CH:22]=[C:21]3[C:26](=[N:25][CH:24]=2)[NH:27][C:18](=[O:17])[CH2:19][CH2:20]3)[CH2:15]1
Reactant: Cc1c(C2CNC2)oc2ccccc12
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C2CN(C(=O)/C=C/c3cnc4c(c3)CCC(=O)N4)C2)oc2ccccc12
Temperature: 25 °C
Reaction time: 21 h
Yield: 58.3 %

Procedure:
To a solution of 3-(3-methylbenzofuran-2-yl)azetidine hydrochloride (19.9 mg, 0.089 mmol) in DMF (2 mL) were added (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (15.8 mg, 0.062 mmol), EDCI.HCl (19.9 mg, 0.104 mmol), HOAt (14.0 mg, 0.103 mmol) and N,N-diisopropylethylamine (58 μL, 0.339 mmol). The reaction was stirred at rt for 21 h, after which the mixture was partitioned between EtOAc and H2O. The layers were separated and the aqueous layer extracted with EtOAc. The combined organic layers were washed with brine (3×), dried with Na2SO4 and concentrated. The residue was triturated twice with Et2O and the dried to yield (the title compound (14.0 mg, 58%) as a pale orange solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>C(Cl)Cl>[CH3:8][S:9]([O:1][CH:2]1[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1)(=[O:11])=[O:10]
Reactant: OC1CCSCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCSCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 300 ml methylene chloride solution of 14.6 g (0.12 mol) of 4-hydroxytetrahydrothiopyran, 11.5 ml (0.15 mol) of methanesulfonyl chloride and 25.8 ml (0.19 mol) of triethylamine were added at 0° C. and stirred at room temperature for 1 hour. The reaction mixture was diluted with methylene chloride (100 ml) and successively washing with water (100 ml) and saturated saline (100 ml), followed by drying over anhydrous sodium sulfate. The solvent was then distilled off under vacuum to obtain 24.5 g (quant.) of the above-identified compound as a slightly brown crystal.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])(=O)=O.[C:45]([C@@H:48]1[CH2:52][CH2:51][CH2:50][NH:49]1)(=[O:47])[NH2:46]>CN(C)C=O>[C:45]([C@@H:48]1[CH2:52][CH2:51][CH2:50][N:49]1[CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])(=[O:47])[NH2:46]
Reactant: CS(=O)(=O)OC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Product: NC(=O)[C@@H]1CCCN1C[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 25.3 %

Procedure:
To a solution of (2S,4S)-2-(methanesulfonyloxy)methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (3.0 g) in dimethylformamide (30 ml) was added (2S)-2-carbamoylpyrrolidine (10.76 g) and the mixture was stirred at 100°-110° C. for 5 hours. The reaction mixture was poured into ice-water (100 ml). The resulting precipitates were collected by filtration and washed with water (100 ml). The precipitates were dissolved in ethyl acetate (80 ml) and the solution was washed with aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S ,4S )-2-[(2S)-2-carbamoylpyrrolidin-1-yl]methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (0.78 g).
Reaction SMILES: [I:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([S:9]([CH3:12])(=[O:11])=[O:10])[N:3]=1.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH:15]1([CH2:14][O:8][C:7]2[C:2]([I:1])=[N:3][C:4]([S:9]([CH3:12])(=[O:10])=[O:11])=[CH:5][CH:6]=2)[CH2:17][CH2:16]1
Reactant: BrCC1CC1
Reactant: CS(=O)(=O)c1ccc(O)c(I)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CS(=O)(=O)c1ccc(OCC2CC2)c(I)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 84.8 %

Procedure:
A mixture of 2-iodo-6-methylsulfonylpyridin-3-ol (500.0 mg, 1.67 mmol), bromomethylcyclopropane (248.4 mg, 1.84 mmol) and K2CO3 (461.3 mg, 33.4 mmol) in ACN (15 mL) was stirred at 80° C. for 4 hrs. Water (30 mL) was added and the mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give the title compound (500.0 mg, 84.8%). 1H NMR (CDCl3, 400 MHz) δ 7.96 (d, J=8.8 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 4.09 (d, J=6.8 Hz, 2H), 3.22 (s, 3H), 1.36-1.22 (m, 1H), 0.69-0.57 (m, 2H), 0.43-0.37 (m, 2H). LCMS: 354.0 (M+1)+
Reaction SMILES: [CH3:1][CH:2]([C:4]12[CH2:10][CH:9]1[C:7](=[O:8])[CH2:6][CH2:5]2)[CH3:3].[CH:11](C1CCC(=O)C=1)(C)C>>[CH3:1][CH:2]([C:4]12[CH2:10][CH:9]1[C:7]([OH:8])([CH3:11])[CH2:6][CH2:5]2)[CH3:3]
Reactant: CC(C)C12CCC(=O)C1C2
Reactant: CC(C)C1=CC(=O)CC1
Product: CC(C)C12CCC(C)(O)C1C2
Yield: 57 %

Procedure:
In the process, however, a relatively greater number of steps have to be pursued up to the course of synthesis of sabina ketone (6). In addition, since sabine ketone is obtainable from the starting material 3-isopropyl-2-cyclopenten-1-one only in about 57% yield, the total yield of sabinene hydrate results in lower value. Moreover, according to the process, operations and works are complicated and laborious, as it requires isolation procedures for each intermediate. Further, it is necessary to use valuable reagents and chromate compound hazardous in handling. Therefore, sabinene hydrates cannot be produced efficiently or economically, in particular, in large scale. Furthermore, by the process, cis-sabinene hydrate (formula 8) is produced preferentially and trans-sabinene hydrate (formula 7) appears only in a considerably minor amount. That is to say, a ratio of formation of trans-compound to cis-compound is 1:8.5, so that the process does not suit an industrial synthesis of trans-sabinene hydrate. Also, yield of trans- and cis-sabinene hydrates from sabina ketone is about 11%, and yield from 3-isopropyl-2-cyclopenten-1-one is about 6.3%.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:11][C@H:10]2[CH2:12][OH:13])=[CH:5][CH:4]=1.Cl([O-])(=O)(=O)=O.[Li+].[N-:22]=[N+:23]=[N-:24].[Na+]>C(#N)C>[N:22]([C@H:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:4][CH:5]=1)[C@@H:10]([OH:11])[CH2:12][OH:13])=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: OC[C@@H]1O[C@H]1c1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: [N-]=[N+]=N[C@H](c1ccc(C(F)(F)F)cc1)[C@@H](O)CO
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
To a mixture of ((2S,3S)-3-(4-(trifluoromethyl)phenyl)oxiran-2-yl)methanol (15.00 g, 68.8 mmol) in 400 mL ACN was added lithium perchlorate (75.3 mL, 1719 mmol). The reaction mixture was a suspension. After stirring for 15 minutes, sodium azide (12.1 mL, 344 mmol) was added, and the mixture was heated at 65° C. for 24 hours under nitrogen. The reaction mixture was then cooled, and the solvent was evaporated under reduced pressure. Distilled water (500 mL) was added, and the resulting mixture was extracted 3 times (3×400 mL) with diethyl ether. The combined ether layers were directly dried over MgSO4. After removing the solvent, a colorless oil was obtained as the desired product (14.5 g, yield=81%). 1H NMR (400 MHz, CD3OD) δ ppm 3.50-3.56 (m, 1H) 3.58-3.63 (m, 1H) 3.84-3.90 (m, 1H) 4.78 (d, J=6.53 Hz, 1H) 7.62 (d, J=8.03 Hz, 2H) 7.67-7.73 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=2[O:6][C:7]=1[CH3:8])=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=2[O:6][C:7]=1[CH3:8]
Reactant: Cc1oc2c([N+](=O)[O-])cccc2c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1oc2c([N+](=O)[O-])cccc2c1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A mixture of 3-formyl-2-methyl-7-nitrobenzo[b]furan (1.83 g) and sodium borohydride (200 mg) in methanol (40 ml) was stirred at ambient temperature for 2 hours. The reaction mixture was poured into cold water. The separated oil was extracted with dichloromethane. The extract was washed with brine, dried and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give 3-hydroxymethyl-2-methyl-7-nitrobenzo[b]furan (1.38 g) as a solid.
Reaction SMILES: [O:1]1[C:5]2[C:6]([CH2:10][OH:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.CS(C)=O.C(Cl)(=O)C(Cl)=O>C(N(CC)CC)C>[O:1]1[C:5]2[C:6]([CH:10]=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: OCc1cccc2c1OCC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1cccc2c1OCC2
Yield: 95.4 %

Procedure:
A solution of 2,3-dihydro-benzofuran-7-methanol (8.13 g, 54.5 mmol) was oxidized using DMSO, oxalyl chloride, and triethyl amine similar to the above procedures to give the product as an oil (7.7 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[C:13]([NH2:19])[N:12]=3)[N:9]=[C:8]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:5]2=[N:6][CH:7]=1.Cl[C:29]([O:31][CH3:32])=[O:30]>N1C=CC=CC=1>[NH2:19][C:13]1[C:14]([NH:18][C:29](=[O:30])[O:31][CH3:32])=[C:15]([NH2:17])[N:16]=[C:11]([N:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[C:8]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])=[N:9]2)[N:12]=1
Reactant: Nc1nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc(N)c1N
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)Nc1c(N)nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc1N
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Under argon, 1.00 g (2.72 mmol) of the compound from example 6A was initially charged in pyridine (55 ml), the mixture was cooled to 0° C. and 228 μl (2.72 mmol) of methyl chloroformate (solution in 10 ml of dichloromethane) were then added dropwise. The reaction mixture was stirred further at RT overnight and then concentrated. The residue was triturated with ethanol and the solid was filtered off and dried at 50° C. under high vacuum. This gave 873 mg (75% of theory) of the title compound as a beige solid. The filtrate was re-concentrated, and purification by preparative RP-HPLC (acetonitrile:water (+0.1% formic acid)−gradient) of the residue gave a further 180 mg (16% of theory) of the title compound.