Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].CS(C)=O.C(N(C(C)C)CC)(C)C>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[O:11]
Reactant: OCCCCCCCCCBr
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=CCCCCCCCCBr
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
9-Bromononan-1-ol (3 g. 13.4 mmol) was dissolved in dichloromethane (70 mL, 0.2M) and to this solution were added dimethyl sulfoxide (2.9 mL, 40.3 mmol) and diisopropylethylamine (7.0 mL, 40.3 mmol). The flask was then sealed under nitrogen and cooled to −15° C. Pyridine sulfur trioxide complex (6.4 g, 40.3 mmol) was added in two equal portions over 2 minutes and the resulting mixture was stirred at temperature between −10° C. and −20° C. for 30 minutes. The reaction was then quenched by adding water and the layers were separated. The organic layer was washed with aqueous sodium bisulfate (1M×3) and brine (×1), and then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as an amber oil (2.4 g 81% yield). 1H NMR (CDCl3, δ): 9.78 (s, 1H), 3.40 (t, 2H), 2.43 (t, 2H), 1.85 (m, 2H), 1.63 (m, 2H), 1.5-1.25 (m, 8H).
Reaction SMILES: [Mg].[CH2:2](Br)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].Br[C:12]1[CH:13]=[C:14]([F:33])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:20][CH:19]=2)=[N:16][CH:17]=1>O1CCCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[F:33][C:14]1[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:20][CH:19]=2)=[N:16][CH:17]=[C:12]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:13]=1
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCOc1ccc(-c2ncc(Br)cc2F)cc1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ncc(CCCCCCCC)cc2F)cc1
Temperature: -10 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
0.30 g (12.30 mmol) of magnesium and 2.16 g (11.18 mmol) of octyl bromide in 10 ml of tetrahydrofuran are used to prepare, at 50° C. for 2 hours, the solution of the Grignard compound, which is added dropwise to a solution, cooled to -10° C. of 2.13 g (5.59 mmol) of 5-bromo-3-fluoro-2-(4-octyloxyphenyl)pyridine and 0.03 g (0.06 mmol) of [1,3-bis(diphenylphosphino)propane]nickel(II) chloride in 60 ml of tetrahydrofuran, and the mixture is stirred at -10° C. for 3 hours. The mixture is subsequently partitioned between ether and aqueous ammonium chloride solution, and the organic phase is washed twice with aqueous sodium chloride solution, dried over sodium sulfate and evaporated to dryness. Chromatographic purification (silica gel/dichloromethane:hexane 7:3) gives 1.89 g of 3-fluoro-5-octyl-2-(4-octyloxyphenyl)pyridine. ##STR16## The compound has the phase sequence: X 25.5 (5) N 35 I.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N+:16]#[C-:17])#[C-:9].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]=O>Cl(O)(=O)(=O)=O>[N+:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=[N:1][C:24]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=1)#[C-:9]
Reactant: Nc1ccccn1
Reactant: O=Cc1ccccn1
Reactant: [C-]#[N+]CCCCCC[N+]#[C-]
Agent: [O-][Cl+3]([O-])([O-])O
Product: [C-]#[N+]CCCCCCNc1c(-c2ccccn2)nc2ccccn12

Procedure:
Compound (1) was prepared in accordance with general instructions 1 from 1.0 ml 2-aminopyridine solution (0.1 M, MC), 0.575 ml 1,6-diisocyanohexane solution (0.2 M, MC), 0.500 ml pyridine-2-carbaldehyde solution (0.3 M, MC), and 10 μl perchloric acid (w=20%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C[Al](C)C.C[O:14][C:15]([C:17]1[N:18]=[C:19]([CH3:23])[S:20][C:21]=1[Br:22])=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15]([C:17]2[N:18]=[C:19]([CH3:23])[S:20][C:21]=2[Br:22])=[O:14])=[N:3][CH:4]=1
Reactant: Nc1ccc(F)cn1
Reactant: COC(=O)c1nc(C)sc1Br
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(C(=O)Nc2ccc(F)cn2)c(Br)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
A solution of 2-amino-5-fluoropyridine (6.0 g, 53 mmol) in 40 ml dry dioxane was treated at 0° C. with trimethylaluminium (2M in hexane, 26.8 ml, 53 mmol). The mixture was stirred at room temperature for 1 h. A solution of 5-bromo-2-methyl-thiazole-4-carboxylic acid methyl ester (4.2 g, 18 mmol) in 40 mL dry dioxane was added and the reaction mixture was refluxed for 4 h. 10 ml water and 10 g sodium sulfate were sequentially added and filtered. The filtrate was evaporated and the residue purified by flash chromatography (hetane, ethyl acetate) to yield 5-bromo-2-methyl-thiazole-4-carboxylic acid (5-fluoro-pyridin-2-yl)-amide (3.0 g, 53%) as a white solid, MS (ISP): m/e=318.0 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:21]I.O>O1CCCC1.C(OCC)(=O)C>[CH3:21][C:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12]
Reactant: CI
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)(C(=O)OC)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
640 mg of compound 229.1 were dissolved in 12 ml of dry tetrahydrofuran and admixed with 138 mg of sodium hydride (60% in mineral oil). The mixture was stirred at room temperature for one hour, then a solution of 393 μl of methyl iodide in 5 ml of dry tetrahydrofuran was added dropwise and the resulting mixture was stirred at room temperature overnight. For workup, the reaction mixture was admixed cautiously with water and ethyl acetate. The organic phase was removed, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel; n-heptane/0-10% ethyl acetate). Dimethyl 2-methyl-2-(4-nitrophenyl)malonate (231.1) was obtained; 1H NMR: 8.22, d, 2H, 7.61, d, 2H, 3.71, s, 6H, 1.82, s, 3H.
Reaction SMILES: [H-].[Li+].[C:3]([NH:9][CH2:10][C:11]1([CH2:28][CH3:29])[CH:20]2[N:15]([CH2:16][CH2:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:19]=32)[CH2:14][CH2:13][CH2:12]1)(=O)[CH2:4][CH2:5][CH2:6][CH3:7].O.ClCCl>C(OCC)C>[CH2:3]([NH:9][CH2:10][C:11]1([CH2:28][CH3:29])[CH:20]2[N:15]([CH2:16][CH2:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:19]=32)[CH2:14][CH2:13][CH2:12]1)[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(=O)NCC1(CC)CCCN2CCc3c([nH]c4ccccc34)C21
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCNCC1(CC)CCCN2CCc3c([nH]c4ccccc34)C21
Reaction time: 0.25 h
Yield: 98.3 %

Procedure:
In a 500 ml three-necked flask of having a stirrer, a reflux condenser, a thermometer, and a dropping funnel there were placed 100 ml of anhydrous ethyl ether. When this had been cooled on an ice bath there were added 4 g of lithium hydride, and the contents of the flask were stirred for 15 minutes. There was then added very slowly a solution of 7.4 g of the product of Example 7 in 50 ml of anhydrous ethyl ether. The mixture was then heated under reflux for 2 hours and stirred for a further 15 hours at room temperature. It was then cooled on an ice bath and there were added dropwise 20 ml of water followed by 150 ml of dichloromethane. The mixture was then filtered over Celite, dried over sodium sulphate and concentrated by evaporation. There were obtained 7 g of an oil which could be crystallized to a product melting at 80° C.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([C:15]2[C:16](=[O:31])[NH:17][C:18](=[O:30])[C:19]=2[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:28]=2[N:27]([CH3:29])[CH:26]=[CH:25]3)=[CH:5]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:52]>C(Cl)Cl.C1COCC1.CCOC(C)=O>[Br:52][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([C:15]2[C:16](=[O:31])[NH:17][C:18](=[O:30])[C:19]=2[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:28]=2[N:27]([CH3:29])[CH:26]=[CH:25]3)=[CH:5]1
Reactant: COc1ccc2c(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)cn(CCO)c2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc2c(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)cn(CCBr)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a solution of 3-[1-(2-hydroxyethyl)-6-methoxy-1H-indol-3-yl]-4-(1-methyl-1H-indol-7-yl)pyrrole-2,5-dione (7.3 g, 17.7 mmol) in a mixture of CH2Cl2 (360 mL) and THF (240 mL) was added PPh3 (4.6 g, 17.7 mmol) and CBr4 (5.8 g, 17.7 mmol). The reaction mixture was stirred at room temperature and under nitrogen for 1 h. Another equivalent of PPh3 (4.6 g, 17.7 mmol) was added followed by an equivalent of CBr4 (5.8 g, 17.7 mmol). This operation was repeated one more time after 1 h. The reaction was monitored by TLC and was completed after 1 h. The reaction mixture was diluted with EtOAc (300 mL) and washed with saturated aqueous NaHCO3 (500 mL), and brine (500 mL). The organic solution was dried (MgSO4), filtered and concentrated. Flash chromatography (SiO2, 50% EtOAc/hexanes) gave the title compound (6.5 g, 77%) as a red solid. 1H NMR (300 MHz, DMSO-d6) 11.08 (s, 1H), 7.95 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.23 (d, J=3.1 Hz, 1H), 7.03–6.96 (m, 3H), 6.88 (d, J=6.2 Hz, 1H), 6.47 (d, J=3.1 Hz, 1H), 6.13 (s, 1H), 4.60 (t, J=6.0 Hz, 2H), 3.81 (t, J=6.0 Hz, 2H), 3.69 (s, 3H), 3.65 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[I-].[K+].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: C1CCNCC1
Reactant: Fc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CN3CCCCC3)n1-2

Procedure:
In the manner given in Preparation 48, 8-fluoro-1 -(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide, and piperidine in tetrahydrofuran are reacted to give 8-fluoro-1-(piperidinomethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][Cl:24].[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[ClH:24].[OH:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6](=[O:18])[CH:7]=[C:8]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[O:9][C:10]=3[CH:11]=2)[CH2:28][CH2:27]1
Reactant: ClCCCCBr
Reactant: OC1CCNCC1
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Product: Cl
Product: O=c1cc(-c2ccccc2)oc2cc(OCCCCN3CCC(O)CC3)ccc12

Procedure:
The compound was prepared by the method of Example 1 from 7-hydroxyflavone, 1-bromo-4-chlorobutane, and 4-hydroxypiperidine: mp 207°-209° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=O.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1>CN(C=O)C.CCCCCC.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=1)[C:8](=[O:11])[CH2:7]2
Reactant: O=C1Nc2c(Br)cccc2C1=O
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C1Cc2cccc(Br)c2N1Cc1ccc(C(F)(F)F)cc1
Temperature: 55 °C
Reaction time: 6 h
Yield: 70.6 %

Procedure:
A mixture of 7-bromo-1H-indole-2,3-dione (4.5 g), Cs2CO3 (10 g) and 1-bromomethyl-4-trifluoromethylbenzene (5 g) in 50 ml of DMF was stirred at 55° C. for 6 h. The reaction mixture was cooled to r.t., diluted with 100 ml of 1:1 hexane/EtOAc and filtered through a pad of silica gel. The filtrate was concentrated under vacuum and the crude product was dissolved in 100 ml of ethanol and 10 ml of 50% aqueous solution of hydrazine. The resulting mixture was heated to reflux for 10 h and diluted with 50 ml of water. After cooling to r.t., solid was collected by filtration and air-dried to give the title compound as a white solid (5.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10]([CH3:12])[CH3:11])[N:4]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][O:25][CH3:26].[Li]CCCC>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][O:25][CH3:26])[N:6]=[C:5]([N:10]([CH3:12])[CH3:11])[N:4]=1
Reactant: COCOCCCCCCCCCBr
Reactant: COc1cc(C)nc(N(C)C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOCCCCCCCCCCc1cc(OC)nc(N(C)C)n1
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution containing 933 mg (5.58 mmol) of 4-methoxy-N,N,6-trimethylpyrimidin-2-amine and 1.5 g (5.58 mmol) of 1-Bromo-9-(methoxymethoxy)nonane in 20 mL of anhydrous THF were added 5.23 mL (8.37 mmol) of 1.6 M n-BuLi in hexanes. The reaction mixture was stirred at 23° C. for 20 min. The reaction mixture was quenched with saturated aqueous ammonium chloride and poured into 100 mL of water. The compound was extracted with two 80-mL portions of ethyl acetate. The combined organic layer was washed with one 80-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (15×5 cm). Elution with 9:1 hexanes-ethyl acetate afforded the expected product as colorless oil: yield 1.41 g (71%); silica gel TLC Rf 0.45 (9:1 hexanes-ethyl acetate); 1H-NMR (CDCl3) δ 1.24-1.32 (br m, 10H), 1.82 (m, 4H), 2.48 (dd, 2H, J=8.0, 8.0 Hz), 3.14 (s, 6H), 3.33 (s, 3H), 3.48 (t, 2H, J=6.8 Hz), 3.85 (s, 3H), 4.59 (s, 2H) and 5.76 (s, 1H); 13C NMR (CDCl3) δ 26.18, 28.46, 28.66, 29.29, 29.39, 29.45, 29.54, 29.72, 36.77, 37.81, 37.81, 52.74, 55.04, 67.85, 93.03, 96.35, 162.35, 170.25 and 172.03; mass spectrum (APCI+), m/z 354.2766 (M+H) (C19H36N3O3 requires 254.2757).
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[N:11]([CH2:12][C@H:13](O)[C:14]2[C:15]([CH3:24])=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[O:18][CH2:17]3)[CH2:10][CH2:9][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:7]1)(=[O:3])[CH3:2].S(Cl)([Cl:35])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([S:4][CH2:5][C@H:6]1[N:11]([CH2:12][CH:13]([Cl:35])[C:14]2[C:15]([CH3:24])=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[O:18][CH2:17]3)[CH2:10][CH2:9][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:7]1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)SC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C[C@H](O)c1ccc2c(c1C)COC2=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)SC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CC(Cl)c1ccc2c(c1C)COC2=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a cooled with an ice bath solution of (S)-tert-butyl 3-(acetylthiomethyl)-4-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazine-1-carboxylate (573 mg, 1.23 mmol) in anhydrous toluene (12.3 mL) was added thionyl chloride (0.268 mL, 3.70 mmol). Then, anhydrous pyridine (0.399 mL, 4.93 mmol) was added dropwise. The reaction mixture was kept at 0° C. for 20 min, then warmed to room temperature and stirred for 3 hours. TLC showed the consumption of the starting material. The reaction was concentrated under reduced pressure and dried on high vacuum overnight. Used directly in the next step.
Reaction SMILES: S=C1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][CH3:22])[CH:12]=2)=[O:8])[CH2:5][CH2:4]S1.[CH3:23][C:24](C)([CH3:28])[CH2:25]CN.C1COCC1>C(Cl)Cl>[C:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:7](=[O:8])[NH:6][CH2:5][CH2:4][C:24]([CH3:28])([CH3:25])[CH3:23])=[CH:12][C:13]=1[O:21][CH3:22])(=[O:20])[CH3:19]
Reactant: CC(C)(C)CCN
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(COC(=O)NCCC(C)(C)C)ccc1OC(C)=O
Reaction time: 2 h

Procedure:
This compound was prepared from VII (288.5 mg, 0.845 mmol), 3,3-dimethylbutylamine (85.5 mg, 114 μL, 0.845 mmol) and anhydrous THF (4.2 mL) as described for 13. The reaction was complete within 2 hours. The reaction solution was diluted with CH2Cl2 and extracted with in 1N HCl and saturated NaCl. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The crude material was purified by column chromatography on silica gel eluting with hexanes/ethyl acetate (7:3, v/v) to render 95.8 mg (35%) of 16 as an oil; 1HNMR (CDCl3) δ 6.99 (d, 3J=7.95 Hz, 1H), 6.95 (s, 1H), 6.92 (d, 3J=7.95 Hz, 1H), 5.04 (s, 2H), 4.60 (bs, 1H), 3.82 (s, 3H), 3.21-3.17 (m, 2H), 2.29 (s, 3H), 1.42-1.38 (m, 2H) and 0.91-0.90 (m, 9H). Exact mass (ESI) calculated for C17H26NO5 [M+H]=324.1805. found 324.1814.
Reaction SMILES: [CH:1]([N:3]([CH:12]1[CH:17]([CH2:18][CH3:19])[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:20][CH3:21])[C:4](=[CH:10]O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=O.Cl.C([NH2:25])=O>>[CH2:20]([CH:13]1[CH2:14][CH2:15][CH2:16][CH:17]([CH2:18][CH3:19])[CH:12]1[N:3]1[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:10][N:25]=[CH:1]1)[CH3:21]
Reactant: NC=O
Reactant: CCOC(=O)C(=CO)N(C=O)C1C(CC)CCCC1CC
Agent: Cl
Product: CCOC(=O)c1cncn1C1C(CC)CCCC1CC
Yield: 55 %

Procedure:
39.7 g (0.13 mol) of ethyl 2-(N-formyl-2,6-diethylcyclohexylamino)-3-hydroxy-acrylate, together with 240 ml of formamide and 24 ml of concentrated hydrochloric acid, were heated at 150° C. for 6 hours. After cooling, the mixture was extracted twice with diisopropyl ether, the organic phase was washed twice with water, dried over sodium sulfate and evaporated, and the residue was chromatographed over a silica gel column (mobile phase 7:3 petroleum ether (low-boiling)/ethyl acetate). 20.5 g (55% of theory) of ethyl 1-(2,6-diethylcyclohexyl)-imidazole-5-carboxylate was obtained as a colorless oil. Identification was effected by means of NMR spectroscopy.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](O)=O)[CH:12]2[CH2:17][CH2:18][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:34][C:35]1[CH:39]=[C:38]([Br:40])[S:37][C:36]=1[C:41]([NH2:43])=[O:42]>O1CCCC1.O>[Br:40][C:38]1[S:37][C:36]2[C:41](=[O:42])[NH:43][C:14]([C@@H:13]3[CH:12]4[CH2:17][CH2:18][CH:9]([CH2:10][CH2:11]4)[N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:34][C:35]=2[CH:39]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC(CC2)[C@H]1C(=O)O
Reactant: NC(=O)c1sc(Br)cc1N
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C2CCC(CC2)[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Temperature: 60 °C
Yield: 43.8 %

Procedure:
To a solution of (3S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.2]octane-3-carboxylic acid (0.511 g) and triethylamine (0.348 mL) in tetrahydrofuran (5 mL) was added isobutyl chloroformate (0.26 mL) while stirring under ice-cooling. After stirring at room temperature for 30 min, a solution of 3-amino-5-bromothiophene-2-carboxamide (0.221 g) produced in Example 1, step D, in tetrahydrofuran (1 mL) was added. The reaction system was stirred with heating at 60° C. for 4 days. Water was poured into the reaction system, and the mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. 2M Aqueous sodium hydroxide solution (3.0 mL) and 1,2-dimethoxyethane (6.0 mL) were added to the residue, and the mixture was stirred with heating in a microwave reactor at 150° C. for 1 hr. Insoluble material was removed by filtration, and the mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane) to give the title compound (193 mg) as a colorless solid. The optical purity was 70% ee. The analysis was performed by high performance liquid chromatography (column: CHIRALPAK AD-H (4.6 mm i.d.×250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (800/200), flow rate: 1.0 mL/min, column temperature: 30° C., detection 220 nm).
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([O:13]CC)=O)=[O:6])[CH:2]=[CH2:3].[Cl:19][C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1>[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>[Cl:19][C:20]1[N:25]=[C:24]([CH2:26][C:11]([C:10]2[CH:9]=[C:8]([NH:7][C:5](=[O:6])[O:4][CH2:1][CH:2]=[CH2:3])[CH:18]=[CH:17][CH:16]=2)=[O:13])[CH:23]=[CH:22][N:21]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)OCC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
Ethyl 3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (20.0 g, 80.24 mmol) was dissolved in 1 M LiHMDS in THF (260 mL) and cooled to 0° C. A solution containing 2-chloro-4-methylpyrimidine (10.32 g, 80.24 mmol) in 20 mL dry THF was added to the reaction mixture. The reaction was stirred at 0° C. for 2 h, quenched with MeOH (100 mL), dried directly onto silica, and purified via flash chromatography EtOAc/CH2Cl2 0-100% gradient run over 60 min. The desired fractions were combined and the solvent was removed to give the title compound (13.6 g, 51% yield); ES-LCMS m/z 332 (M+H).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.O.C(O)(=O)C>[CH2:7]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(N)CO
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: CC(C)(CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
Acetic acid (5.4 ml) was added to a solution of 2-amino-2-methyl-1-propanol (8.4 g) and benzaldehyde (10 g) in 1,2-dichloroethane (140 ml) under ice-cooling. After 30 minutes of stirring at the same temperature, sodium triacetoxyborohydride (26 g) was added by small portions to the solution over 10 minutes. After 2 hours of stirring at room temperature, the mixture was poured into a solution of sodium hydrogen carbonate (48 g) in water (300 ml). The aqueous layer was separated and adjusted to pH 12 with 24% sodium hydroxide aqueous solution. The alkaline solution was extracted with ethyl acetate (2 times). The extract was dried over sodium sulfate and evaporated under reduced pressure to give colorless crystals of 2-benzylamino-2-methyl-1-propanol (13.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](SC)[CH:6]=[CH:7][CH:8]=1.O[O:12][S:13]([O-:15])=O.[K+].[CH3:17]C(C)=O>O>[CH3:17][S:13]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1)(=[O:15])=[O:12]
Reactant: CC(C)=O
Reactant: COc1cccc(SC)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: COc1cccc(S(C)(=O)=O)c1
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 3-methoxythioanisole (3.084 g, 20 mmol) in 300 mL acetone was added a solution of oxone (30.74 g, 50 mmol) in 125 mL water, resulting in the formation of a white precipitate. Stirring continued overnight, and the solid was filtered off and washed with acetone. Filtrate was concentrated to remove acetone. Aqueous layer was extracted with EtOAc (2×200 mL) and dried over Na2SO4. The solvent was removed to give 1-methanesulfonyl-3-methoxy benzene (3.68 g, 98%) as oil.