Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Clc1ncccc1I
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccnc2Cl)CC1
Yield: 54 %

Procedure:
Dissolve 2-chloro-3-iodopyridine (4.00 g, 16.74 mmol) in anhydrous toluene (25 mL). Add piperazine-1-carboxylic acid t-butyl ester (2.96 g, 15.90 mmol), followed by palladium acetate (0.113 g, 0.50 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.313 g, 0.502 mmol), triethylamine (0.034 g, 0.047 mL, 0.335 mmol) and cesium carbonate (27.3 g, 83.7 mmol). Heat at reflux for 18 hr. Concentrate and partition the residue between DCM and a saturated solution of sodium bicarbonate. Extract the aqueous phase twice with DCM and once with ethyl acetate. Dry the combined organic extracts (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 5:95 to 20:80 ethyl acetate:hexanes), to give 4-(2-Chloropyridin-3-yl)-piperazine-1-carboxylic acid t-butyl ester (54%). MS (ES): m/z=298 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[C:15]([CH3:26])=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[C:5]2[CH:27]=[O:28].[BH4-].[Na+].Cl>CO.CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[C:15]([CH3:26])=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[C:5]2[CH2:27][OH:28]
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1cc(C=O)c2cc(F)ccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1cc(CO)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
A solution of 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-3-formyl-indol-1-yl)-amide (230 mg, 0.614 mmol) in MeOH (10 mL) is treated with NaBH4 (233 mg, 6.14 mmol) and stirred at rt for 1 h. The mixture is diluted with EtOAc (50 mL) and H2O, neutralized with HCl (conc.), and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by preparative reverse-phase HPLC eluting with 20%-100% MeCN in H2O to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-3-hydroxymethyl-indol-1-yl)-amide (90 mg, 8%). MS: 378 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 11.92 (s, NH, 1H), 9.27 (s, 1H), 8.81 (d, 1H), 8.47 (d, 1H), 8.05 (m, 1H), 7.61 (m, 1H), 7.44 (m, 3H), 7.10 (m, 1H), 5.00 (t, OH, 1H), 4.66 (d, 2H), 2.78 (s, 3H).
Reaction SMILES: C(OC(N1CCCC1C=CC(OCC)=O)=O)C1C=CC=CC=1.C([O:25][C:26](=O)[CH:27]=[CH:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])C.[H-].C([Al+]CC(C)C)C(C)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:38]([O:37][C:35]([N:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH:29]1[CH:28]=[CH:27][CH2:26][OH:25])=[O:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCOC(=O)C=CC1CCCCN1C(=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: CCOC(=O)C=CC1CCCN1C(=O)OCc1ccccc1
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCCCC1C=CCO
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of either ethyl 3-(N-benzyloxycarbonylpyrrolidin-2-yl)-2-propenoate or ethyl-3-(N-benzyloxycarbonylpiperid-2-yl)-2-propenoate (R, or S, or racemate, 10.00 mmol) in anhydrous tetrahydrofuran (75 mL) at -78° C. under nitrogen was added dropwise a solution of diisobutylaluminium hydride (1.0M in hexanes, 12.0 mL, 22.0 mmol, 2.2 eq). The resulting solution was stirred at -78° C. under nitrogen for 30 minutes. The reaction solution was then allowed to warmed to room temperature over the course of 2 hours. A saturated solution of sodium hydrogen carbonate (50 mL) was added, and the aqueous mixture was extracted with ethyl acetate (3×50 mL). The extracts were combined, dried (MgSO4), and evaporated under reduced pressure. Column chromatography of the residue with diethyl ether/hexanes [1:1] afforded either 1-(N-benzyloxycarbonylpyrrolidin-2-yl)-3-hydropropene or 1-(N-benzyloxycarbonyl-piperid-2-yl)-3-hydroxypropene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])=[N:15]3)=O)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C(=O)([O-])[O-].[Na+].[Na+].O>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])=[N:15]3)=[N:31][OH:32])=[CH:4][CH:3]=1
Reactant: NO
Reactant: COc1ccccc1CNc1ccc2c(C(=O)c3ccc(F)cc3)cccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccccc1CNc1ccc2c(C(=NO)c3ccc(F)cc3)cccc2n1
Yield: 64.3 %

Procedure:
A stirred suspension of (4-fluoro-phenyl)-[2-(2-methoxy-benzylamino)-quinolin-5-yl]-methanone (example 137) (60 mg, 0.155 mmol), hydroxylamine hydrochloride (32 mg, 0.46 mmol) and sodium carbonate (49 mg, 0.46 mmol) in EtOH (2 ml) was heated under reflux conditions for 28 h, the reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/ethyl acetate) to yield the title compound as white foam (40 mg, 64%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[C:18]1([CH:24]2[CH2:26][O:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[OH:25][CH:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:26][N:15]1[CH2:16][CH2:17][CH:12]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[N:8]([CH3:11])[N:7]=2)[CH2:13][CH2:14]1
Reactant: c1ccc(C2CO2)cc1
Reactant: Cn1nc(C2CCNCC2)c2ccc(F)cc21
Solvent: CC#N
Product: Cn1nc(C2CCN(CC(O)c3ccccc3)CC2)c2ccc(F)cc21
Yield: 32.9 %

Procedure:
A mixture of 4-(6-fluoro-1-methyl-1H-indazol-3-yl)piperidine (1 g; 4.3 mmol) and phenyloxirane (0.6 g; 5 mmol) in 10 ml acetonitrile was refluxed for 16 h. The cooled reaction mixture was concentrated in vacuo and purified by chromatography on silica gel 60 with ethyl acetate: methanol (9:1, v/v) as eluent. Concentration of the appropriate fractions gave 500 mg (33%) of 1-(2-hydroxy-2-phenyl-ethyl)-4-(6-fluoro-1-methyl-1H -indazol-3-yl)-piperidine.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[Na].OC1C(C(OCC)=O)=CN=C(N2C=CC=N2)N=1.[CH2:36](Cl)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN(CC)CC>CN(C=O)C.O>[CH2:36]([O:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)c1cnc(-n2cccn2)nc1O
Reactant: ClCc1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(-n2cccn2)nc1OCc1ccccc1
Temperature: 60 °C
Yield: 42 %

Procedure:
To a solution of ethyl 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylate, 11-a, (0.62 g, 2.7 mmol) in DMF (7 ml) were added benzyl chloride (0.5 g, 3.99 mmol) and Et3N (0.8 g, 7.97 mmol). The resulting mixture was then heated at 60° C. for 12 hours. Then it was cooled to room temperature and diluted with water followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel column with the eluent of ethyl acetate/petroleum ether=1/1 (Rf=0.7) to afford the product, 11-b, (0.36 g, 42%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10]2)=[N:7][CH:8]=1.C(N(CC)CC)C.[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[C:25]([F:31])[CH:24]=1.[BH4-].[Na+]>CO.ClCCl>[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:14][C@H:11]2[CH2:12][CH2:13][N:9]([C:6]3[N:7]=[CH:8][C:3]([Br:2])=[CH:4][N:5]=3)[CH2:10]2)=[C:25]([F:31])[CH:24]=1
Reactant: NC1CCN(c2ncc(Br)cn2)C1
Reactant: O=Cc1ccc(Br)cc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1cc(Br)ccc1CN[C@H]1CCN(c2ncc(Br)cn2)C1

Procedure:
Dissolve 1-(5-bromopyrimidin-2-yl)-pyrrolidin-3-ylamine hydrochloride (60 mg, 0.22 mmol) in methanol (10 mL) and dichloromethane (1 mL). Add triethylamine (100 μL, 0.72 mmol) and 4-bromo-2-fluorobenzaldehyde (87 mg, 0.43 mmol) and stir overnight at room temperature. Add sodium borohydride (25 mg, 0.66 mmol) and stir 1 h. Dilute the mixture with methanol and pour onto a column of Dowex® 50wx4-200. Wash with methanol, then elute with 10% triethylamine in methanol. Concentrate and chromatograph on silica gel, eluting with 20:80 to 1:1 ethyl acetate:hexanes to give the title compound as a residue. Dissolve the residue in methanol and add 1 N HCl in methanol (0.75 mL). Concentrate and dry in a vacuum oven at 60° C. overnight to give the title compound as its hydrochloride salt, as a white solid (80 mg, 80%). 1H NMR (400 MHz, MeOH-d4) 8.45 (s, 2H), 7.57-7.52 (m, 3H), 4.42-4.34 (m, 2H), 4.15-4.09 (m, 1H), 4.04-3.99 (m, 1H), 3.87-3.77 (m, 2H), 3.69-3.62 (m, 1H), 2.63-2.54 (m, 1H), 2.36-2.27 (m, 1H), MS (ES): m/z=429 [M+H].
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([C:17](OCC)=[O:18])[C:11]=2[O:10][CH2:9][CH2:8]1.O.[OH-].[Na+]>C(OCC)C>[OH:18][CH2:17][C:16]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1cccc2c1OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCc1cccc2c1OCCO2
Temperature: 0 °C
Yield: 88496.9 %

Procedure:
To a suspension of lithium aluminum hydride (7.0 g, 0.18 mmol) in dry diethyl ether (100 mL) was added a solution of ethyl 1,4-benzodioxan-5-carboxylate (35 g, 0.17 mmol) in diethyl ether (100 mL). After boiling under reflux for 2 h, the reaction mixture was cooled to 0° C. and carefully treated with water (35 mL) and 4N aqueous sodium hydroxide (35 mL). The resulting mixture was filtered and dried (Na2SO4). Evaporation of the solvents afforded 25 g (88%) crystalline title compound: mp 51-53° C.; 1H NMR (CDCl3) δ 2.50 (s, 1H), 4.20-4.3 (m, 4H), 4.60 (s, 2H), 6.75-6.90 (m, 3H).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:10][CH:11]=[C:12]([CH2:14][N:15]3[N:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[N:16]3)[N:13]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[S:10][CH:11]=[C:12]([CH2:14][N:15]3[N:19]=[C:18]([NH2:20])[CH:17]=[N:16]3)[N:13]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2nc(Cn3ncc([N+](=O)[O-])n3)cs2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC1(c2nc(Cn3ncc(N)n3)cs2)OCCO1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 2-[2-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-4-ylmethyl]-4-nitro-2H-[1,2,3]triazole (86 mg, 0.29 mmol), iron powder (49 mg, 0.87 mmol) and NH4Cl (78 mg, 1.45 mmol) in a mixture of EtOH (1.0 mL) and water (0.5 mL) was stirred at 75° C. for 60 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (10 mL) was added followed by 1N NaOH (10 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as an oil. LC-MS-conditions 02: tR=0.68 min; [M+H]+=268.25.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.Cl.CN.[CH2:15]([N:17](CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:17][CH3:15])=[S:10])[CH:7]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(Cl)cc1N=C=S
Agent: CN
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CNC(=S)Nc1cc(Cl)ccc1C
Temperature: 25 °C
Yield: 96.9 %

Procedure:
5-Chloro-2-methylphenyl isothiocyanate (36.6 g; 0.2 mol) was added to the solution of methylamine hydrochloride (26.8 g; 0.4 mol) in chloroform (300 mL). Triethylamine (65 mL; 0.47 mol) was added dropwise while stirring at ambient temperature. The mixture was stirred for 18 hours. The solvent was evaporated. The residue was treated with ethyl acetate (800 mL) and water (400 mL). The organic phase was separated, washed with water (2×300 mL), dried over magnesium sulfate and evaporated to dryness to give 41.6 g of N-(5-chloro-2-methylphenyl)-N′-methylthiourea, m.p. 139–140° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C@H:5]([NH:13][C:14]([C@@H:16]([N:18]([CH3:27])[C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])[CH3:17])=[O:15])[CH2:6][CH:7]([CH3:12])[CH2:8][CH2:9][CH:10]=[CH2:11])=[O:4].[BH4-].[Na+]>C(O)C>[Cl:1][CH2:2][CH:3]([C@H:5]([NH:13][C:14]([C@@H:16]([N:18]([CH3:27])[C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])[CH3:17])=[O:15])[CH2:6][CH:7]([CH3:12])[CH2:8][CH2:9][CH:10]=[CH2:11])[OH:4]
Reactant: C=CCCCCC(=O)N(C)[C@@H](C)C(=O)N[C@H](CC(C)CCC=C)C(=O)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C=CCCCCC(=O)N(C)[C@@H](C)C(=O)N[C@H](CC(C)CCC=C)C(O)CCl
Temperature: 25 °C

Procedure:
A solution of 3.15 g (5 mmol) hept-6-enoic acid {(S)-1-[(R)-1-(2-chloro-acetyl)-3-methyl-hept-6-enylcarbamoyl]-ethyl}methyl-amide in 110 ml ethanol is added to a suspension of 378 mg (10 mmol) sodium borohydride in 30 ml ethanol at −78° C. The temperature is kept below −75° C. during the addition and the mixture is stirred for an additional hour. The reaction is quenched with 25 ml 1 M HCl at −78° C. and the mixture is allowed to warm to rt. After evaporation of the ethanol and addition of 50 ml 1 M HCl the mixture is extracted with EtOAc. The organic layer is washed with 1 M HCl and a half-saturated aqueous sodium chloride solution, dried with sodium sulfate and evaporated. Purification by chromatography on silica gel (cyclohexane/EtOAc 70/30 to 50/50) gives the desired product as a brown oil (mixture of diastereomers).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:11]=1.[NH2:32][CH2:33][C@H:34]([OH:37])[CH2:35][OH:36].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[OH:37][C@H:34]([CH2:35][OH:36])[CH2:33][NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][Si:13]([CH:14]([CH3:16])[CH3:15])([CH:17]([CH3:19])[CH3:18])[CH:20]([CH3:22])[CH3:21])[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:29]
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: NC[C@H](O)CO
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)NC[C@H](O)CO)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (9.32 g, 20.8 mmol) synthesized in Example (106c) was dissolved in methanol (200 mL), and (S)-(−)-3-amino-1,2-propanediol (5.01 g, 55.0 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n hydrate (10.13 g, 32.3 mmol) were added, followed by stirring at room temperature overnight under nitrogen atmosphere. The solvent was distilled off under reduced pressure, water (300 mL) and ethyl acetate (200 mL) were added to the resulting residue, and the solution was separated. The organic layer was washed with saturated brine, subsequently dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=70%-100%) to afford the desired product (9.32 g, yield 86%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[N:18][C:13]3[O:14][CH2:15][CH2:16][NH:17][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1.[Br:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([Br:34])[C:31]=1[O:32][CH3:33])[C:26](Cl)=[O:27].C(N(CC)CC)C>ClCCl>[Br:22][C:23]1[CH:24]=[C:25]([C:26]([N:17]2[CH2:16][CH2:15][O:14][C:13]3[N:18]=[CH:19][C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=4)=[CH:11][C:12]2=3)=[O:27])[CH:29]=[C:30]([Br:34])[C:31]=1[O:32][CH3:33]
Reactant: FC(F)(F)Oc1ccc(-c2cnc3c(c2)NCCO3)cc1
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4ccc(OC(F)(F)F)cc4)cc32)cc1Br
Yield: 69.8 %

Procedure:
By the same method as in the step c) of Example 45, 7-(4-trifluoromethoxy-phenyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (83 mg, 0.28 mmol), 3,5-dibromo-4-methoxy-benzoyl chloride (138 mg, 0.42 mmol) and triethylamine (78 μl, 0.56 mmol) were dissolved in dichloromethane (3 ml) and reacted at room temperature for 3 hours to obtain (3,5-dibromo-4-methoxy-phenyl)-[7-(4-trifluoromethoxy-phenyl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone as white solid (115 mg, 69.8%).
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[NH:5][C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:21][O:20]1>CN(C=O)C>[CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[N:5]([CH2:18][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)([OH:20])[CH3:21])[C:4]=2[CH2:3]1
Reactant: CC1(c2ccncc2)CO1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccncc2)CN(C)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 20.9 %

Procedure:
2,6-Dimethyl-2,3,4,9-tetrahydro-1H-β-carboline (500 mg, 2.5 mmol) was dissolved in 10 mL DMF and stirred for 10 min at 0° C. Sodium hydride (300 mg, 7.5 mmol) was added portionwise at RT and stirred for 10 min. 4-(2-Methyl-oxiranyl)-pyridine (472 mg, 3.5 mmol) was added dropwise at the same temperature and stirred for 4 h at RT. The reaction was monitored by TLC & LCMS. After consumption of starting material, the reaction mixture was quenched with ice water and extracted with EtOAc (2×60 mL). The combined organic layer was washed with water (5×75 mL), dried over anhydrous sodium sulfate and concentrated and the residue was crystallized in EtOH and hexane to obtain 175 mg of 1-(2,6-dimethyl-1,2,3,4-tetrahydro-β-carbolin-9-yl)-2-pyridin-4-yl-propan-2-ol. 1H NMR (CDCl3, Free base) δ (ppm): 8.58 (d, 2H), 7.40 (d, 2H), 7.25 (s, 1H), 7.16 (d, 1H), 6.92 (d, 1H), 4.18-4.0 (dd, 2H), 3.50-3.38 (dd, 2H), 2.80 (m, 2H), 2.70 (m, 2H), 2.44 (s, 3H), 2.42 (s, 3H), 1.58 (s, 3H). Separation by chiral HPLC provided enantiomers 19a and 19b. Optical rotations: Compound 19a, (+)22.35 (c 0.58, Chloroform, 98.36% HPLC purity); Compound 19b, (−)22.43 (c 0.55, Chloroform, 99.09% HPLC purity).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[S:16][C:17]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=3)=[CH:18][N:19]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>CO>[ClH:1].[CH3:26][C:22]1[CH:21]=[C:20]([C:17]2[S:16][C:15]([N:12]3[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]3)=[N:19][CH:18]=2)[CH:25]=[CH:24][N:23]=1
Reactant: Cc1cc(-c2cnc(N3CCN(C(=O)OC(C)(C)C)CC3)s2)ccn1
Agent: Cl
Solvent: CO
Product: Cc1cc(-c2cnc(N3CCNCC3)s2)ccn1
Reaction time: 0.17 h

Procedure:
A saturated solution of hydrochloride in methanol (12 ml) was added to 1-(t-butoxycarbonyl)-4-[5-(2-methylpyridin-4-yl)thiazol-2-yl]piperazine (400 mg) at room temperature. After stirring for 10 minutes, the reaction mixture was concentrated under reduced pressure, whereby 1-[5-(2-methylpyridin-4-yl)thiazol-2-yl]piperazine hydrochloride was obtained as a white solid. In a solution of the resulting hydrochloride in methylene chloride (12 ml) was dissolved 5-chloro-1-phenylsulfonylindol-2-sulfonyl chloride (522 mg), followed by the addition of diisopropylethylamine (538 μl) at room temperature. After stirring for 3 hours, a saturated aqueous solution (50 ml) of sodium bicarbonate was added to the reaction. mixture to separate it into layers. The water layer was extracted with methylene chloride (2×15 ml). The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride:acetone=7:1), whereby the title compound (240 mg) was obtained as a foam.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:16][CH2:17][CH3:18])[CH:5]=[CH:6]B1OC(C)(C)C(C)(C)O1)[CH3:2].Br[C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][C:21]=1[F:29].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:17]([O:16][CH:4]([O:3][CH2:1][CH3:2])/[CH:5]=[CH:6]/[C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][C:21]=1[F:29])[CH3:18]
Reactant: O=[N+]([O-])c1cccc(F)c1Br
Reactant: CCOC(C=CB1OC(C)(C)C(C)(C)O1)OCC
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: C1COCCO1
Solvent: O
Product: CCOC(/C=C/c1c(F)cccc1[N+](=O)[O-])OCC
Temperature: 120 °C
Yield: 61 %

Procedure:
A glass microwave reaction vessel was charged with 3,3-diethoxy-1-propenylboronic acid pinacol ester (0.154 mL, 0.600 mmol, Frontier Scientific), 2-bromo-1-fluoro-3-nitrobenzene (110 mg, 0.500 mmol, Aldrich), dichloro 1,1′-bis(diphenylphosphino)ferrocene palladium (II) (40.8 mg, 0.050 mmol, Strem) and cesium carbonate (326 mg, 1.00 mmol, Aldrich) in dioxane (3 mL) and water (0.5 mL). The reaction mixture was stirred and heated in an Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 20 min. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material. The crude product was purified by silica gel chromatography eluting with 10% EtOAc/hexanes to give (E)-2-(3,3-diethoxyprop-1-enyl)-1-fluoro-3-nitrobenzene (82 mg, 0.305 mmol, 60.9% yield). 1H NMR (300 MHz, CDCl3) δ 1.26 (t, J=7.02 Hz, 6H) 3.45-3.81 (m, 4H) 5.09 (d, J=4.09 Hz, 1H) 6.16-6.37 (m, 1H) 6.76 (d, J=17.25 Hz, 1H) 7.29-7.53 (m, 2H) 7.57-7.75 (m, 1H). m/z (ESI, +ve ion) 270 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([C-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)[CH3:3].[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14].B(F)(F)F.CCOCC.[Li]CCCC.[CH3:29][Si:30](Cl)([CH3:32])[CH3:31]>C1COCC1>[CH3:29][Si:30]([CH3:32])([CH3:31])[C:5]1[C-:4]([N:2]([CH3:3])[CH3:1])[CH:8]=[CH:7][CH:6]=1.[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14]
Reactant: C[Si](C)(C)Cl
Reactant: CN(C)[c-]1cccc1
Agent: [Fe+2]
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)[c-]1cccc1[Si](C)(C)C
Yield: 92.6 %

Procedure:
A solution of 11 (229 mg, 1.0 mmol) in THF (10 mL) was sequentially treated with BF3.OEt2 (0.13 mL, 1.05 mmol), n-BuLi (0.48 mL, 2.30 M, 1.10 mmol) and TMSCl (0.15 mL, 1.20 mmol). Standard workup followed by column chromatography (silica gel, 7:3 hexanes/Et2O, Rf=0.68) gave 12a (279 mg, 93%) as an orange oil; IR (KBr, neat) max 3096, 2952, 2818, 2774, 1247 cm−1; 1H NMR (300 MHz, CDCl3) 4.16 (s, 5H), 4.13 (t, 1H, J=2.7 Hz), 4.10 (m, 1H), 3.86 (m, 1H), 2.57 (s, 6H), 0.33 (s, 9H) ppm; 13C NMR (75.5 MHz, CDCl3) 120.1, 70.6, 68.5, 66.2, 65.9, 58.0, 46.1, 0.5 ppm; EIMS [m/z(%)] 301 (M+, 100); HRMS (EI) calcd for C15H23N28Si56Fe: 301.0949. Found 301.0945.