Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:4]=1[NH2:5].Br[C:20]1[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(OCC)(=O)C.[Cl-].[Na+].O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([C:20]2[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=2)[CH:7]=[CH:6][C:4]=1[NH2:5]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: Cn1cc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(-c2cnn(C)c2)ccc1N
Temperature: 60 °C
Yield: 70.4 %

Procedure:
A solution of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (5 g, 24.03 mmol), 4-bromo-1-methyl-1H-pyrazole (3.53 g, 17.47 mmol), Pd(dppf)Cl2.DCM (0.38 g, 0.465 mmol) and 2M sodium carbonate (20 ml0 in THF (60 ml) was stirred and heated to 60° C. for 24 hours. The reaction was diluted with ethyl acetate and brine. The organic solution was collected, dried (MgSO4) and concentrated in vacuum. The residue was purified using Biotage silica gel column chromatography eluting with a gradient of 0 to 70% ethyl acetate in cyclohexane to afford the title compound as a white powder (2.5 g, 70%). 1H NMR (500 MHz, CDCl3) δ 3.8 (s, br, 2H), 3.9 (s, 3H), 3.94 (s, 3H), 6.71 (d, J=7.9 Hz, 1H), 6.9 (m, 2H), 7.52 (s, 1H), 7.68 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:9][CH2:10][CH2:11][C:5]2=[N:4][C:3]=1[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1.BrC1N=[C:33]2[CH2:41][CH2:40][CH2:39][N:38](CCCCCCC(OCC)=O)[C:34]2=NC=1Cl.CC1(C)C(C)(C)OB(C2C=CN=CC=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[N:38]1[CH:39]=[CH:40][C:41]([C:2]2[N:7]=[C:6]3[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:9][CH2:10][CH2:11][C:5]3=[N:4][C:3]=2[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)=[CH:33][CH:34]=1
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(Br)c(Cl)nc21
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(C)cc3)c(Cl)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccncc3)nc21

Procedure:
A (3:1) mixture of ethyl 7-(3-chloro-2-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (Example 13.2, step 1) (30 mg, 0.072 mmol) and ethyl 7-(2-bromo-3-chloro-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (Example 13.1, step 2)(10 mg, 0.025 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (39.4 mg, 0.192 mmol) and potassium carbonate (39.9 mg, 0.288 mmol) in dioxane (2 ml) was degassed by bubbling nitrogen through (×3). Pd(Ph3P)4 (22.22 mg, 0.019 mmol) was added and the mixture was degassed by bubbling nitrogen through (×3). The reaction mixture was heated using microwave radiation at 150° C. for 2 hours. The mixture was diluted with water and extracted with EtOAc (×2). The combined extracts were washed with brine, dried (MgSO4) and evaporated under vacuum. The crude material was purified by ion exchange [Isolute SCX-2 washing with MeOH and eluting with 2M NH3 in MeOH] to give a brown residue. The crude residue was purified by chromatography on silica eluting with 0-100% EtOAc in iso-hexane followed by 10% MeOH/DCM to afford the title compound;
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:8])=[CH:5][CH:4]=1.C(OC)(OC)OC.[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.[BH4-].[Na+]>CO.O>[CH2:18]([N:14]([CH2:15][CH2:16][CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:21]=[CH:22][C:3]([CH2:2][NH:1][CH2:36][C:32]2[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=2)=[CH:4][CH:5]=1)[CH2:19][CH3:20]
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCNC(=O)c1ccc(CN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: O
Solvent: CO
Product: CCCN(CCC)CCCCNC(=O)c1ccc(CNCc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 111.1 %

Procedure:
The compound (538 mg) obtained in Example 20-2 was dissolved in anhydrous methanol (10 ml), added with trimethyl orthoformate (600 μl) at room temperature under a nitrogen atmosphere, and then added with a methanol solution (2.0 ml) containing 1-methyl-2-imidazole carboxaldehyde (240 mg). The whole was stirred at room temperature for 36 hours and then added with sodium borohydride (140 mg) under ice-cooling. The whole was warmed to room temperature and stirred for 1 hour. After completion of the reaction, the resultant was added with water under ice-cooling while the whole was stirred. The solvent was distilled off under reduced pressure and the residue was dissolved in chloroform and added with water, followed by extraction of the aqueous layer with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (782 mg) as a yellow oily substance.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]1([O:14][CH2:13][CH2:12][O:11]1)[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:15](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.Cl.[Cl-].[Na+]>C(OCC)(=O)C.O>[CH3:15][O:1][N:2]=[C:3]([C:9]1([O:11][CH2:12][CH2:13][O:14]1)[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(=NO)C1(C)OCCO1
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(=NOC)C1(C)OCCO1
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-hydroxyimino-3,3-ethylenedioxybutyrate (syn isomer, 5 g) in dried ethyl acetate (20 ml) was added potassium carbonate (5.78 g), and dimethyl sulfate (3.96 ml) was added dropwise thereto at ambient temperature with stirring, and then the mixture was stirred for 2 hours at 43°-45° C. To the reaction mixture were added water (10 ml) and ethyl acetate (5 ml), and the mixture was stirred for 40 minutes at ambient temperature. The mixture was adjusted to pH 7.2 with 6 N hydrochloric acid and saturated with sodium chloride, and then ethyl acetate layer was separated. The remaining aqueous layer was further extracted with ethyl acetate (10 ml). The ethyl acetate layer and extract were combined together, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then filtered. The filtrate was evaporated to give ethyl 2-methoxyimino-3,3-ethylenedioxybutyrate (syn isomer), quantitatively.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:10]=2[NH2:23])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:24]([O-])=O.[Na+].CO.[Sn](Cl)Cl>Cl.O.C1COCC1>[C:1]1([C:7]2[C:9]3[C:10](=[CH:11][CH:12]=[C:13]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:14]=3)[NH:23][N:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1C(=O)c1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(COc2ccc3[nH]nc(-c4ccccc4)c3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a solution of 2-amino-5-(phenylmethoxy)phenyl phenyl ketone (2.6 g, 8.0 mmol) in 6N HCl (70 mL) at 0° C. was added a solution of sodium nitrite (NaNO2) (650 mg, 9.4 mmol) in water (2 mL). To this solution was added methanol and THF to keep it homogeneous. A solution of tin (II) chloride (SnCl2) (5.3 g, 23.6 mmol) in concentrated HCl (20 mL) was then added. The solution was stirred at room temperature overnight. The solid was then filtered and the solution concentrated and chromatographed on silica gel eluting with 20% ethyl acetate in hexane to give the title compound (1.15 g, 48% yield). 1H NMR (DMSO-d6) δ 13.1 (s, 1H), 7.95 (d, 2H), 7.56-7.48 (m, 6H), 7.44-7.3 (m, 4H), 7.14 (d, 1H), 5.12 (s, 2H); ES-MS (m/z) 301 [M+1]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C@H:10]1[O:15][C@@H:14]([CH3:16])[CH2:13][N:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:27]=[CH:26][O:25][C:24]=3[CH3:28])[N:18]=2)[CH2:11]1>C(Cl)(Cl)Cl>[Br:1][C:20]1[CH:21]=[CH:22][C:17]([N:12]2[CH2:11][C@H:10]([CH3:9])[O:15][C@H:14]([CH3:16])[CH2:13]2)=[N:18][C:19]=1[C:23]1[CH:27]=[CH:26][O:25][C:24]=1[CH3:28]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1occc1-c1cccc(N2C[C@@H](C)O[C@@H](C)C2)n1
Solvent: ClC(Cl)Cl
Product: Cc1occc1-c1nc(N2C[C@@H](C)O[C@@H](C)C2)ccc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-Bromosuccinimide (137 mg, 0.771 mmol) was added portionwise to a solution of cis-2,6-dimethyl-4-[6-(2-methyl-3-furanyl)-2-pyridinyl]morpholine (210 mg, 0.771 mmol) in chloroform (7 mL) at 0° C. The reaction was stirred at 0° C. for 1 hour. Crude LC/MS showed desired product can be seen and no starting material left, so the reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (10 mL), brine (10 mL), water (10 mL) and brine (10 mL). The organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane (˜10 ml) and purified on silica by a Biotage SP4 chromatographic system (40+S cartridge, eluted with 0-100% ethyl acetate in isohexanes). Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound as a colourless oil (280 mg, 0.678 mmol, 88% yield). LC/MS [M+H]+=351/353.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([NH2:11])=[CH:5][N:4]=1.C1N=CN([C:17](N2C=NC=C2)=[S:18])C=1.CCCCCC.C(OCC)(=O)C>O1CCCC1>[N:11]([C:6]1[C:7]([O:9][CH3:10])=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=1)=[C:17]=[S:18]
Reactant: COc1ncc(N)c(OC)n1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ncc(N=C=S)c(OC)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84 %

Procedure:
To a solution of 2,4-dimethoxypyrimidin-5-amine (prepared by the method described in U.S. Pat. No. 6,342,503B1) (4.68 g, 30.0 mmol) in tetrahydrofuran (60 mL) was added 1,1-thiocarbonyldiimidazole (6.41 g, 36.0 mmol) portionwise at 0° C. The mixture was warmed to room temperature and stirred for 20 hr. The mixture was concentrated in vacuo to give a residue which was passed through a pad of silica gel eluting with n-hexane/ethyl acetate. The filtrate was concentrated in vacuo to give the title compound (5.0 g, 84%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:13][C@H:12]([OH:14])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:18]>O1CCCC1>[CH3:18][O:14][C@H:12]1[CH2:13][C@@H:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11]1
Reactant: CI
Reactant: O[C@H]1C[C@@H](COCc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H]1C[C@@H](COCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of cis-3-benzyloxymethylcyclobutanol (Albany Molecular Research Institute, 1.0 g, 5.2 mmol) in 10 mL of tetrahydrofuran at 0° C. was added NaH (0.62 g, 15.6 mmol). The mixture stirred for 15 minutes and iodomethane (0.49 mL, 7.8 mmol) was added and the mixture was allowed to warm to ambient temperature and stirred for 16 hours. Some starting material remained by TLC so additional NaH (0.21, 5.2 mmol) and iodomethane (0.32 mL, 5.2 mmol) were added and the mixture stirred for an additional 2 hours. The mixture was quenched with 10 mL of NH4Cl and diluted with 10 mL of ethyl acetate. The layers were separated and the aqueous layer was extracted twice with 5 mL portions of ethyl acetate. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 75% hexanes in ethyl acetate) afforded the title compound. MS (DCI/NH3) m/z 207 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:25])[CH:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>O1CCOCC1.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>[CH:9]1([C:7]2[O:8][C:4]3[C:5](=[C:12]([C:15]#[N:16])[C:13]([CH3:14])=[C:2]([C:21]4[CH:20]=[C:19]([F:18])[CH:24]=[C:23]([F:25])[CH:22]=4)[C:3]=3[F:17])[N:6]=2)[CH2:11][CH2:10]1
Reactant: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: Cc1c(-c2cc(F)cc(F)c2)c(F)c2oc(C3CC3)nc2c1C#N
Temperature: 95 °C
Reaction time: 60 h

Procedure:
6-Bromo-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-77) (200 mg, 0.68 mmol), 3,5-difluorophenylboronic acid (428 mg, 2.71 mmol) and tripotassium phosphate (288 mg, 1.36 mmol) were dissolved in 1,4-dioxane (8 ml), then at room temperature, tetrakis(triphenylphosphine)palladium(0) (157 mg, 0.14 mmol) was added. The solution was stirred under nitrogen atmosphere at 95° C. for 60 hours. After cooling to room temperature, aqueous saturated ammonium chloride solution was added to the reaction liquid, followed by stirring at room temperature for 5 minutes. This was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, hexane:ethyl acetate=8:1) to obtain the entitled compound (240.5 mg containing impurities (reference)) as a white solid. Since the impurities were difficult to separate, they are separated in the next step.
Reaction SMILES: I[C:2]1[C:7]2[C:8](=[O:15])[N:9]([CH3:14])[CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu][C:17]#[N:18].CN(C)C=O>O>[C:17]([C:2]1[C:7]2[C:8](=[O:15])[N:9]([CH3:14])[CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:18]
Reactant: N#C[Cu]
Reactant: CN1CC(=O)Nc2cccc(I)c2C1=O
Solvent: O
Solvent: CN(C)C=O
Product: CN1CC(=O)Nc2cccc(C#N)c2C1=O

Procedure:
A mixture of 5.7 g (0.018 mol) of 3,4-dihydro-6-iodo-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione, 2.4 g (0.026 mol) of copper (I) cyanide and 60 ml of dimethylformamide is heated to 50° for 45 minutes. After cooling, the mixture is diluted with water and extracted several times with chloroform/isopropanol (4:1). The combined organic extracts are dried over magnesium sulphate and evaporated. The yellow-brown crude product is recrystallized from methanol, there being obtained 6-cyano-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione of melting point 253°-256° (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.C([BH3-])#N.[Na+].Cl>C1(C)C=CC=CC=1.CO.C(O)(=O)C.O>[ClH:10].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(N)cc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(NCc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-methoxyaniline (75.0 g; 609 mmol) and 4-chlorobenzaldehyde (86.5 g; 615 mmol) in 1000 mL toluene was heated at reflux overnight with removal of water. The solvent was evaporated under reduced pressure, and the resulting light gray solid was taken up in 1500 mL tetrahydrofuran (THF). A solution of sodium cyanoborohydride (38.3 g; 609 mmol) in 180 mL methanol was added. Upon complete addition the reaction was acidified by the slow addition of acetic acid (36 mL). The reaction was stirred at ambient temperature overnight. The mixture was cooled to 0° C. and excess aqueous 6N HCl was added. The resultant precipitate was collected and washed well with diethyl ether to give N-(4-chlorobenzyl)-4-methoxyaniline hydrochloride salt as an off white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)cccc21
Temperature: 0 °C
Yield: 90.4 %

Procedure:
Under a nitrogen atmosphere, a solution of 4-bromo-1H-indole (200 g) in tetrahydrofuran (2.0 L) was ice-cooled to 0° C., and sodium hydride (49 g) was added thereto, followed by stirring under ice-cooling for 1 hour. Benzenesulfonyl chloride (200 g) was added dropwise under ice-cooling to the reaction mixture, and the ice bath was removed, followed by stirring at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by ethyl acetate extraction. The organic layer was washed with brine and dried over magnesium sulfate, followed by filteration. The resulting residue was washed with isopropylether-hexane (1:1, 1.0 L), and then dried to obtain the title compound (310 g) having the following physical properties.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[C:10](B3OC(C)(C)C(C)(C)O3)[C:9]([CH3:21])=[C:8]([F:22])[CH:7]=2)[CH2:3][CH2:2]1.Br[C:25]1[CH:40]=[CH:39][C:28]2[N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[N:30]=[N:31][C:27]=2[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>O1CCOCC1.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>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[N:29]1[C:28]2[CH:39]=[CH:40][C:25]([C:10]3[CH:11]=[C:6]([CH:7]=[C:8]([F:22])[C:9]=3[CH3:21])[C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[O:23])=[CH:26][C:27]=2[N:31]=[N:30]1
Reactant: Clc1ccccc1-n1nnc2cc(Br)ccc21
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(c1)nnn2-c1ccccc1Cl
Temperature: 125 °C

Procedure:
To a mixture of N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (100 mg, 0.31 mmol), 5-bromo-1-(2-chlorophenyl)-1H-benzo[d][1,2,3]triazole (110 mg, 0.34 mmol), tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.016 mmol) in dioxane (3 mL) was added 1.3 mL of 2 N sodium carbonate solution. The reaction mixture was heated at 125° C. in a microwave for 30 min. The mixture was then treated with 2 mL of 1 N NaOH and extracted with 2×15 mL of EtOAc. The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography on silical gel (30-70% of EtOAc in Hexanes) to give the title compound as an off white crystalline solid. MS (ESI, pos. ion) m/z: 421.0 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH:15]2[CH:21]([C:22]([O-:24])=[O:23])[NH:20][CH2:19][CH2:18][CH2:17][S:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH:15]2[CH:21]([C:22]([OH:24])=[O:23])[NH:20][CH2:19][CH2:18][CH2:17][S:16]2)(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2SCCCNC2C(=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)C2SCCCNC2C(=O)O)cc1

Procedure:
Following the procedure of Step 3 of Example 173, tert-butyl (3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-thiazepane-3-carboxylate (800 mg, 1.88 mmol), trifluoroacetic acid (6 mL) in methylene chloride (15 mL) provide 650 mg (94%) of (3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-thiazepane-3-carboxylic acid; 1H NMR (300 MHz, acetone-d6): δ 1.74 (m, 3H), 1.90 (m, 2H), 2.59 (m, 2H), 2.90 (m, 1H), 3.18 (m, 1H), 3.26 (m, 1H), 3.70 (m, 1H), 4.70 (m, 3H), 7.03 (d, 2H, J=8.7 Hz), 7.77 (d, 2H, J=8.7 Hz); HRMS (C16H19NO5S2)(M+H);
Reaction SMILES: C1(S(O)(=O)=O)C=CC=CC=1.[CH2:11]([O:13][C:14]([C:16]12[CH2:23][CH2:22][C:19]([NH:24][CH2:25][C:26]([N:28]3[CH2:32][C@@H:31]([F:33])[CH2:30][C@H:29]3[C:34]([NH2:36])=O)=[O:27])([CH2:20][CH2:21]1)[CH2:18][CH2:17]2)=[O:15])[CH3:12].FC(F)(F)C(OC(=O)C(F)(F)F)=O.O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:11]([O:13][C:14]([C:16]12[CH2:23][CH2:22][C:19]([NH:24][CH2:25][C:26]([N:28]3[CH2:32][C@@H:31]([F:33])[CH2:30][C@H:29]3[C:34]#[N:36])=[O:27])([CH2:20][CH2:21]1)[CH2:18][CH2:17]2)=[O:15])[CH3:12]
Reactant: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C(N)=O)(CC1)CC2
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Yield: 83.7 %

Procedure:
(2S,4S)-1-[2-[(4-Ethoxycarbonylbicyclo[2.2.2]-oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide benzenesulfonate (791 mg) was suspended in N,N-dimethylformamide (2.8 mL), and trifluoroacetic acid anhydride (0.22 mL) was added thereto, followed by stirring under ice-cooling for 1 hour. After adding water (14 mL), potassium carbonate (644 mg) was added thereto at a bath temperature of 40° C., followed by ice-cooling and 1 hour of stirring. The precipitate were collected by filtration, washed with water (3 mL) and then blast-dried at 60° C., thereby obtaining a white powder of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (441 mg, 84%).
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:26]I)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na].[CH3:31][SH:32]>CN(C)C=O.O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:26][S:32][CH3:31])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O[C@@H]1C[C@@H](CI)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Reactant: CS
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CSC[C@@H]1C[C@@H](OC(=O)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
(2S,4R)-1-p-Nitrobenzyloxycarbonyl-2-iodomethyl-4-benzoyloxypyrrolidine (1.05 g) was dissolved in 10 ml of dimethylformamide, and a solution of 1.40 g of 15% methylmercaptan sodium salt in water was added thereto, followed by stirring at room temparature for 30 minutes under a nitrogen stream. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel thin layer chromatography to obtain (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-methylthiomethyl-4-benzoyloxypyrrolidine.