Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([CH2:9][NH2:10])=[O:8].C(=O)(O)[O-].[Na+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([NH:10][CH2:9][C:7]([C:3]1[O:2][CH:6]=[CH:5][CH:4]=1)=[O:8])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCC(=O)c1ccco1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(NCC(=O)c1ccco1)c1ccccc1
Yield: 82.9 %

Procedure:
3.4 g of (2-furylcarbonyl)methylamine hydrochloride, 4.4 g of sodium bicarbonate and 3.3 g of benzoyl chloride are treated in the same manner as described in Preparation 1-(1). 4.0 g of N-benzoyl-(2-furylcarbonyl)methylamine are thereby obtained. Yield: 83.3%
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C=O.[C:11](O)(=O)[CH2:12][C:13]([OH:15])=[O:14].S(=O)(=O)(O)O>N1C=CC=CC=1>[CH3:1][CH:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:11]=[CH:12][C:13]([OH:15])=[O:14]
Reactant: CC(C)CCCCCC=O
Reactant: O=C(O)CC(=O)O
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Product: CC(C)CCCCCC=CC(=O)O
Reaction time: 3 h

Procedure:
In a similar reaction as in 1 above, 100 ml toluene, sodium (39.5 g, 1.72 mole), 7-methyl-octanoate (52 g, 0.29 mole), and 260 ml anhydrous methanol reacted to yield 7-methyl-1-octanol (44.3 g, yield rate 85%); 7-methyl-1-octanol (44.3 g, 0.31 mole) reacted with chloro-chromic pyridine (100 g, 0.465 mole) to yield 7-methyl-octanaldehyde (31 g, yield rate 70%); and finally, 7-methyl-octanaldehyde (20 g, 0.14 mole), malonic acid (15 g, 0.14 mole), and 15 ml pyridine were added together and refluxed with heating for 3 hours. After cooling down 15 ml 30% sulfuric acid was added and the reaction mixture was stirred for 3 hours under ice bath and then extracted by diethyl ether. Diethyl ether was removed by evaporation and product was subject to vacuum fractional distillation and 122° C./1.5 mmHg fraction was collected as 9-methyl-2-decenoic acid (16 g, yield rate 80%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[O:25])[O:23][C:21](=[O:22])[C:20]2=[CH:26][CH:27]=1.ClCCl.[Cl-].[Al+3].[Cl-].[Cl-]>O>[Br:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([C:5]2[CH:6]=[CH:7][C:8]3[C:9]4[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:2]([CH3:15])([CH3:1])[C:3]=3[CH:4]=2)=[O:22])=[C:19]([CH:18]=1)[C:24]([OH:25])=[O:23]
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: CC1(C)c2ccccc2-c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)c2ccccc2-c2ccc(C(=O)c3ccc(Br)cc3C(=O)O)cc21
Temperature: 25 °C
Yield: 49.8 %

Procedure:
9,9-dimethyl-9H-fluorene (27.78 g, 0.143 mol) and 4-Bromo Phthalic anhydride (48.69 g, 0.214 mol) were placed in a reaction vessel, and added with Dichloromethane (700 ml). At 0° C., aluminum chloride (28.7 g, 0.214 mol) was gradually added thereto, and the temperature was raised up to room temperature. Then, the resultant mixture was stirred for 12 hours. After the reaction was completed, the resultant product was gradually added with distilled water. The resultant product was extracted with an excess of dichloromethane, and washed several times with distilled water. After solvent removal, the produced solid was placed in a Hexane 2 l-containing vessel, washed, filtered, and dried, 5-bromo-2-(9,9-dimethyl-9H-fluorene-2-carbonyl)benzoic acid (30 g, yield 50%) was obtained.
Reaction SMILES: FC1C=CC(C(C2C=CC=C3C=2C=CC=C3[C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26](C(N5CCN(C)CC5)=O)=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:40]([NH2:42])=[O:41])=[CH:20][CH:19]=2)=O)=CC=1.[BH4-].[Na+]>C(O)C.Cl>[C:21]1([C:40]([NH2:42])=[O:41])[C:22]2[NH:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]=2[CH:18]=[CH:19][CH:20]=1
Reactant: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(-c4cccc5c(C(=O)c6ccc(F)cc6)cccc45)c23)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cccc2c1[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-(5-(4-fluorobenzoyl)naphthalen-1-yl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide (Example 3-96, 30 mg, 0.051 mmol) in ethanol (0.5 mL) was treated with a couple granules of sodium borohydride and stirred at rt. After 90 min, the mixture was treated with 2 drops of 1 M hydrochloric acid and purified by preparative HPLC to provide two diastereomers of 4-(5-((4-fluorophenyl)(hydroxy)methyl)naphthalen-1-yl)-7-(4-methyl)piperazine-1-carbonyl)-9H-carbazole-1-carboxamide. Diastereomer 1 (Example 13-1) was isolated as a white powder (10.4 mg, 31%). 1H NMR (400 MHz, methanol-d4) δ 8.23 (1H, d, J=8.6 Hz), 7.99 (1H, d, J=7.7 Hz), 7.48-7.61 (3H, m), 7.36-7.46 (3H, m), 7.31 (1H, d, J=8.4 Hz), 7.19 (1H, dd, J=8.4, 7.0 Hz), 7.12 (1H, d, J=7.7 Hz), 7.02 (2H, t, J=8.8 Hz), 6.59 (1H, dd, J=8.1, 1.5 Hz), 6.51 (1H, s), 6.31 (1H, d, J=8.1 Hz), 3.68 (2H, br. s.), 3.35 (2H, br. s.), 2.43 (2H, br. s.), 2.28 (2H, br. s.), 2.23 (3H, s). Mass spectrum m/z 587.4 (M+H)+. Diastereomer 2 (Example 13-2) was isolated as a white powder (8 mg, 23%). 1H NMR (400 MHz, methanol-d4) δ 8.19 (1H, d, J=8.6 Hz), 7.99 (1H, d, J=7.9 Hz), 7.61 (1H, d, J=6.8 Hz), 7.59 (1H, s), 7.49-7.56 (1H, m), 7.43 (1H, dd, J=6.8, 0.7 Hz), 7.38 (2H, dd, J=8.5, 5.4 Hz), 7.26-7.32 (1H, m), 7.16-7.24 (1H, m), 7.11 (1H, d, J=7.7 Hz), 7.00 (2H, t, J=8.8 Hz), 6.61 (1H, dd, J=8.1, 1.3 Hz), 6.58 (1H, s), 6.36 (1H, d, J=8.1 Hz), 3.68 (2H, br. s.), 3.35 (2H, br. s.), 2.43 (2H, br. s.), 2.28 (2H, br. s.), 2.22 (3H, s). Mass spectrum m/z 587.4 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:17]=[C:16]([NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)[CH3:2].[CH3:27][N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[CH:37]=O)[CH:30]=[CH:29]1.[BH3-]C#N.[Na+]>CO.[Cl-].[Cl-].[Zn+2]>[CH2:25]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:17]=[C:16]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:37][C:35]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:36]=3[N:28]([CH3:27])[CH:29]=[CH:30]4)[CH2:21][CH2:20]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)[CH3:26]
Reactant: CCN(CC)CCCNc1nc(NC2CCNCC2)c2ccccc2n1
Reactant: Cn1ccc2cccc(C=O)c21
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCN(CC)CCCNc1nc(NC2CCN(Cc3cccc4ccn(C)c34)CC2)c2ccccc2n1

Procedure:
A solution of N2-(3-(diethylamino)propyl)-N4-(piperidin-4-yl)quinazoline-2,4-diamine (56 mg, 0.157 mmol), 1-methyl-1H-indole-7-carbaldehyde (27 mg, 0.157 mmol), NaCNBH3 (10 mg, 0.160 mmol) and ZnCl2 (11 mg, 0.08 mmol) in MeOH (1 ml) was stirred at room temperature overnight to obtain the target compound.
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@H:7]1[CH2:11][CH2:10][C@@H:9](O)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:60]=[N+:61]=[N-:62])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:60]([C@H:9]1[CH2:10][CH2:11][C@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:14])[CH3:13])[CH2:8]1)=[N+:61]=[N-:62]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](O)C1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 0.04 h

Procedure:
To a 0° C. solution of (+)-(1R,3S)-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentanol (745 mg, 3.44 mmol) (from Example 29b supra) and triphenyl phosphine (1.17 g, 4.47 mmol) (Aldrich) in anhydrous tetrahydrofuran (60 mL) was added dropwise diethyl azodicarboxylate (710 μL, 780 mg, 4.47 mmol) (Aldrich). After 2 to 3 minutes followed a dropwise addition of diphenylphosphoryl azide (950 μL, 1.23 g, 4.47 mmol) (Aldrich). The mixture was allowed to warm up slowly to room temperature stirred overnight and then partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered, concentrated and the resulting residue was chromatographed on a silica gel column with a 0–20% diethyl ether in hexanes gradient to give (+)-(1S,3S)-(3-azido-cyclopentyloxy)-tert-butyl-dimethyl-silane as a colorless liquid. (Yield 589 mg, 70%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][OH:19])[CH2:12][CH2:11]1)[CH3:8])([CH3:4])([CH3:3])C.Cl.ClC(OC1C=[CH:30][C:29]([Cl:32])=[CH:28]C=1)=O>CO.O>[Cl:32][C:29]1[CH:30]=[CH:3][C:1]([O:5][C:6](=[O:20])[N:7]([CH2:9][C@H:10]2[CH2:11][CH2:12][C@H:13]([CH2:16][CH2:17][CH2:18][OH:19])[CH2:14][CH2:15]2)[CH3:8])=[CH:4][CH:28]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CN(C[C@H]1CC[C@H](CCCO)CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: CO
Product: CN(C[C@H]1CC[C@H](CCCO)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the sequence described in examples 1.5 and 1.6, trans-[4-(3-hydroxy-propyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester was treated with hydrogen chloride solution in methanol/water followed by acylation with 4-chlorophenyl chloroformate [Org. Lett. (2000), 2(8), 1049-1051] to yield trans-[4-(3-hydroxy-propyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 340 (MH+, 1Cl).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:9]([O:22][CH3:23])=[CH:10][C:11]2[O:16][C:15](=[O:17])[C:14]3[CH2:18][CH2:19][CH2:20][C:13]=3[C:12]=2[CH:21]=1.[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(C)C.C([O-])(=O)/C=C/C([O-])=O>CC(OC)(C)C>[CH3:23][O:22][C:9]1[C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:33]2[CH2:34][CH2:35][N:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:31][CH2:32]2)=[CH:21][C:12]2[C:13]3[CH2:20][CH2:19][CH2:18][C:14]=3[C:15](=[O:17])[O:16][C:11]=2[CH:10]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCCBr)CCC3
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: COC(C)(C)C
Solvent: CC(C)O
Product: COc1cc2oc(=O)c3c(c2cc1OCCCCCN1CCN(c2ccccc2)CC1)CCC3
Yield: 97 %

Procedure:
Method B (10 h at 80° C.); starting materials: 8-(5-bromopentyloxy)-2,3-dihydro-7-methoxycyclopenta[c][1]benzopyran-4(1H)-one (example 85) and 1-phenylpiperazine; yield 97%; fusion point 118°-120° C. (from isopropanol). Fumarate (x 0.5 C4H4O4): method E; yield 93%; fusion point 153°-155° C. (from isopropanol and TBME).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH:6]([CH:8]=O)[CH2:5][C@H:4]([CH3:10])[O:3]1.[Br:11][C:12]1[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl.C(OCC)(=O)C>[Br:11][C:12]1[N:17]=[C:16]([NH:18][CH2:8][CH:6]2[CH2:7][C@H:2]([CH3:1])[O:3][C@H:4]([CH3:10])[CH2:5]2)[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cccc(Br)n1
Reactant: C[C@@H]1CC(C=O)C[C@H](C)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C[C@@H]1CC(CNc2cccc(Br)n2)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 43.8 %

Procedure:
The mixture of (2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-carbaldehyde (120 mg, 0.84 mmol) and 6-bromo-2-aminopyridine (219 mg, 1.26 mmol) in 5 ml DCM was stirred at ambient temperature for about 40 min. To this solution was added sodium triacetoxy borohydride (268 mg, 1.26 mmol), followed by the addition of 0.01 ml acetic acid. The resulting solution was stirred at ambient temperature for about 40 hours. The reaction mixture was concentrated in vacuo to yield a residue was diluted with ethyl acetate, washed with sodium bicarbonate, brine, dried, concentrated. The resulting residue was purified by ISCO eluting with 10% to 20% ethyl acetate in heptane to yield 110 mg of the desired product as colorless oil. LCMS (m/z): 299/301 (MH+), retention time=1.01 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[NH:11][C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1.[N+:22]([O-])([OH:24])=[O:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[NH:11][C:10]2=[O:20])=[C:6]([N+:22]([O-:24])=[O:23])[C:7]=1[OH:8]
Reactant: O=[N+]([O-])O
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(O)c(Cl)cc1F
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1c(F)cc(Cl)c(O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-(4-chloro-2-fluoro-5-hydroxyphenyl)6-trifluoromethyl-2,4(1H,3H)-pyrmidinedione (2.5 g) was added to an ice cooled con. nitric acid (50 ml). After stirring for 1 hr, the reaction mixture was poured into ice-cold water. The yellow crystals were collected by filtration to afford the title compound (0.9 g). The filtrate was extracted by ethyl acetate (200 ml) and washed with brine. The organic phase was dried over anhydrous sodium sulfate. After removal of the solvent, 0.6 g of title compound was obtained as yellow crystal.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([O:16][CH3:17])=[C:8]2[C:18](O)=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OCC)=O.[CH2:27]([N:29]([CH2:32][CH:33]([OH:36])[CH2:34][NH2:35])[CH2:30][CH3:31])[CH3:28].Cl>C(Cl)Cl.O.C(N(CC)CC)C>[CH2:27]([N:29]([CH2:32][CH:33]([OH:36])[CH2:34][NH:35][C:18]([C:8]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:15]2[C:10]([C:9]=1[O:16][CH3:17])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:19])[CH2:30][CH3:31])[CH3:28]
Reactant: CCN(CC)CC(O)CN
Reactant: COc1c(C(=O)O)n(-c2ccccc2)c2ccccc12
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)CC(O)CNC(=O)c1c(OC)c2ccccc2n1-c1ccccc1

Procedure:
6.6 g of N-phenyl-3-methoxyindole-2-carboxylic acid and 7 ml of triethylamine in 75 ml of methylene chloride are added dropwise to 7 g of ethyl chloroformate in 25 ml of methylene chloride at -30° C. The temperature is allowed to rise slowly to 5° C., whilst stirring, and 3.7 g of 3-(N,N-diethylamino)-2-hydroxypropylamine are added. The reaction solution is subsequently stirred at room temperature, poured into water and worked up as described in Example 8. Yield: 4.5 g of the hydrochloride of the title compound, melting point: 148°-150° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Br)([CH3:7])[CH3:6])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:16]([O:20][C:21]([N:23]1[CH2:28][C@@H:27]2[CH2:29][C@H:24]1[CH2:25][NH:26]2)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(#N)C>[C:16]([O:20][C:21]([N:23]1[CH2:28][C@@H:27]2[CH2:29][C@H:24]1[CH2:25][N:26]2[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:9])([CH3:7])[CH3:6])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)N1C[C@@H]2C[C@H]1CN2C(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
2-Bromo-2-methylpropionic acid ethyl ester (155 μL, 1.06 mmol) was added to a solution of potassium carbonate (145 mg, 1.05 mmol) and (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (200 mg, 1.01 mmol) in anhydrous acetonitrile (1 mL) The resulting mixture was heated at 80° C. for 48 h, then cooled to ambient temperature and partitioned between EtOAc and water. The organic layer was separated, washed with brine, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; 100:0 to 98:2) to give (1S,4S)-5-(1-ethoxycarbonyl-1-methylethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a pale brown oil. To a solution of (1S,4S)-5-(1-ethoxycarbonyl-1-methylethyl)-2,5-diazabicyclo[2.2.1]-heptane-2-carboxylic acid tert-butyl ester (1 mmol) in anhydrous THF (5 mL) at 0° C., a solution of LiAlH4 (1 M in THF, 3.2 mL, 3.2 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g), washed with MeOH before the desired product was eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a brown oil (168 mg, 99%). 1H NMR (CDCl3, 400 MHz) δ 3.37 (bs, 1H); 3.31 (d, J=10.2 Hz, 1H); 3.21 (d, J=10.2 Hz, 1H); 3.15-3.00 (m, 2H); 2.81-2.61 (m, 2H); 2.45 (s, 2H); 1.76 (d, J=10.0 Hz, 1H); 1.56 (d, J=10.0 Hz, 1H); 1.46 (t, J=5.02 Hz, 1H); 1.03 (s, 3H) and 1.00 (s, 2H).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH3:6])(=[O:5])=[O:4].[CH3:7][C:8]1([CH3:27])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:17]1[C:18](S(C)(=O)=O)=[N:19][CH:20]=[N:21][CH:22]=1.[H-].[Na+]>CN(C)C=O>[CH3:7][C:8]1([CH3:27])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:17]1[C:18]([N:2]([S:3]([CH3:6])(=[O:5])=[O:4])[CH3:1])=[N:19][CH:20]=[N:21][CH:22]=1
Reactant: CNS(C)(=O)=O
Reactant: CC1(C)Cc2ccccc2C1c1cncnc1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ncncc1C1c2ccccc2CC1(C)C)S(C)(=O)=O
Temperature: 80 °C
Yield: 10.1 %

Procedure:
N-Methylmethanesulfonamide (1.9 g) and then 1.2 g (17 mmol) of 5-(2,2-dimethylindan-1-yl)-4-methanesulfonylpyrimidine were added to a slurry of 0.40 g (17 mmol) of sodium hydride in 50 mL of dry N,N-dimethylformamide with stirring and the resulting mixture was heated at 80° C. for 1 hour. The mixture was then cooled and partitioned between ether and water. The organic phase was recovered, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel and 0.57 g of the title compound was obtained as a tan solid melting at 107°-109° C.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:26])[C@H:17]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH3:18])=[CH:12][CH:11]=1.O>CS(C)=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([C@H:17]([O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[CH3:18])[CH2:2][O:26]2)=[CH:14][CH:15]=1
Reactant: C[S+](C)(C)=O
Reactant: C[C@@H](OC1CCCCO1)C(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@@H](OC1CCCCO1)C1(c2ccc(Cl)cc2)CO1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 102.6 %

Procedure:
Trimethylsulfoxonium iodide (67.8 g) was added portionwise to an ice-cooled dispersion of 60% sodium hydride in oil (11.8 g) in dimethyl sulfoxide (450 ml) under nitrogen atmosphere. After stirring for 45 minutes at room temperature, the mixture was again cooled in an ice-water bath. To the mixture was added dropwise a solution of (2R)-4'-chloro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (69 g) in dimethylsulfoxide (100 ml) over the period of 45 minutes, followed by stirring for 2 hours at room temperature. Cold water (600 ml) was added to the reaction mixture, which was then extracted three times with ethyl acetate (400 ml, 300 ml and 300 ml). The combined extracts were washed twice with water (100 ml) and once a saturated aqueous saline solution (100 ml), dried over anhydrous magnesium sulfate and distilled under reduced pressure, thereby affording a crude product of 2-(4-chlorophenyl)-2-[(1R)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl]oxirane (74.5 g) as a pale yellow oily substance.
Reaction SMILES: O=O.[CH3:3]/[C:4](=[CH:7]\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[CH2:5][OH:6]>C1(C)C=CC=CC=1>[CH3:3][C@@H:4]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][OH:6]
Reactant: C/C(=C\c1ccccc1)CO
Agent: O=O
Solvent: Cc1ccccc1
Product: C[C@H](CO)Cc1ccccc1

Procedure:
In a glove box (O2 content<1 ppm), a catalyst solution is prepared by dissolving 9.15 mg (0.0186 mmol) of dichloro-bis(1,5-cyclooctadiene)dirhodium and 25.18 mg (0.0371 mmol) of (R)-p-TolBINAP in 50 ml of toluene. This catalyst solution is then added to a solution of 5.5 g (37.1 mmol) of (E)-2-methyl-3-phenyl-2-propen-1-ol in 35 ml of toluene in a 500 ml autoclave. The hydrogenation is carried out at 100° C. under a constant pressure of 60 bar and with efficient stirring. The conversion is 100% after 22 hours. The pale yellow hydrogenation solution is worked up as described in Example 2, giving (S)-2-methyl-3-phenylpropan-1-ol in an enantiomeric purity of 89.1% e.e.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:15]([Mg]Br)=[CH2:16].O>ClCCl>[CH:15]([C:2]1([OH:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)=[CH2:16]
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: ClCCl
Solvent: O
Product: C=CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.00 g, 5.02 mmol) in 20 mL of dichloromethane at 0° C. under an atmosphere of nitrogen was added vinylmagnesium bromide (0.7 M dichloromethane solution, 9.32 mL, 6.52 mmol) dropwise. After 1 hr, the mixture was treated with water and extracted 3× with ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-60% ethyl acetate in hexanes, to provide tert-butyl 4-ethenyl-4-hydroxypiperidine-1-carboxylate that gave a proton NMR spectra consistent with theory.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:31]4[CH2:32][CH2:33][CH:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:29][CH2:30]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(c2ccccc2)CC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-phenylpiperidine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=447.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][C:3]=1[CH:10]1[S:14](=[O:16])(=[O:15])[NH:13][C:12](=[O:17])[CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>O1CCOCC1.C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][Br:38])[CH:5]=[CH:4][C:3]=1[CH:10]1[S:14](=[O:16])(=[O:15])[NH:13][C:12](=[O:17])[CH2:11]1
Reactant: BrC(Br)(Br)Br
Reactant: O=C1CC(c2ccc(CO)cc2Br)S(=O)(=O)N1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CC#N
Product: O=C1CC(c2ccc(CBr)cc2Br)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-[2-bromo-4-(hydroxymethyl)phenyl]isothiazolidin-3-one 1,1-dioxide (54.0 mg, 0.169 mmol) in 1,4-dioxane (5 mL) was added triphenylphosphine (49 mg, 0.18 mmol) and carbon tetrabromide (62 mg, 0.18 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was diluted with acetonitrile and purified by preparative LCMS to give the product as a white solid.