Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[CH2:11]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCc2ccccc2)c(F)c1
Yield: 80.9 %

Procedure:
A mixture of 3-fluoro-4-hydroxybenzaldehyde (4.264 g, 30.0 mmol), benzyl bromide (5.986 g, 35.0 mmol, 4.16 mL) and K2CO3 (820 g, 59.0 mmol) in DMF (50 mL) was stirred for 48 hours at room temperature before EtOAc (100 mL) and water (50 mL) were added. The organic layer was separated, washed with water (2×50 mL), brine (30 mL) and dried (Na2SO4). Concentration in vacuo gave a white solid residue. Recrystallization from CH2Cl2/n-hexane afforded CAB06038 as colorless needles (5.59 g, 81%). Mp. 94-95° C.; 1H NMR (400 MHz, CDCl3) δ 524 (s, 2H), 7.12 (dd, J=8.2, 8.2 Hz, 1H), 734-7.48 (m, 5H), 7.59-7.66 (m, 2H), 9.85 (d, J=2.0 Hz, 1H); LRMS (ES+): m/z 231.1 (100%, [M+H]+).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[O:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:32])[CH2:30]Cl)[CH2:25][CH2:24]1>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:30][C:29]([N:26]2[CH2:27][CH2:28][O:23][CH2:24][CH2:25]2)=[O:32])[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=C(CCl)N1CCOCC1
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3ccccc32)cc1
Product: CC(C)c1ccc(N(CC(=O)N2CCOCC2)C(=O)C2CCCc3ccccc32)cc1
Yield: 60 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g) and 2-morpholino-2-oxoethyl chloride (0.33 g) as starting materials, N-(4-isopropylphenyl)-N-(2-morpholino-2-oxoethyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.43 g) was obtained. melting point: 180° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:7]=2[O:6]1)#[N:2].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])O.[Na+]>>[C:1]([CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH:15][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=[CH:14][C:7]=2[O:6]1)#[N:2]
Reactant: N#CCCC1CCc2cc(N)ccc2O1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)Nc1ccc2c(c1)CCC(CCC#N)O2

Procedure:
By a process analogous to that of step 6 of Example 1, starting from 2.4 g (12 mmol) of 2-cyanoethyl-6-amino-3,4-dihydro-2H-1-benzopyran, 1.24 ml (13.0 mmol) of ethyl chloroformate and 1.5 g (18 mmol) of sodium hydrogencarbonate, 2.0 g of product are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:15]1[CH2:18][CH2:17][CH2:16]1>COCCOC>[N:15]1([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[Br:1])[CH2:18][CH2:17][CH2:16]1
Reactant: C1CNC1
Reactant: Clc1ccncc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: Brc1cnccc1N1CCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
To a 16×100 mm reaction tube under N2 was added, 3-bromo-4-chloropyridine (320 mg, 1.663 mmol), cesium carbonate (1.65 g, 5.06 mmol), and 1,2-dimethoxyethane (3 mL). The reaction mixture was flushed with nitrogen and then treated with azetidine (210 μL, 3.12 mmol). The reaction mixture was securely capped, stirred at room temperature for 5 min, then heated at 90° C. for 18 h. The reaction mixture was filtered through a small Celite plug by gravity, washed with dichloromethane (30 mL) and the volatiles were evaporated in vacuo to give 350 mg (99%) of the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([C:16](O)=[O:17])=[C:13]([C:19]3[CH:24]=[CH:23][C:22]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:21][CH:20]=3)[C:12]=2[CH3:29])=[CH:7][CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([C:16]([N:2]([CH3:3])[CH3:1])=[O:17])=[C:13]([C:19]3[CH:24]=[CH:23][C:22]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:21][CH:20]=3)[C:12]=2[CH3:29])=[CH:7][CH:6]=1
Reactant: CNC
Reactant: Cc1c(-c2ccc(Cl)cc2)sc(C(=O)O)c1-c1ccc(S(N)(=O)=O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccc(Cl)cc2)sc(C(=O)N(C)C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 10 °C
Yield: 22.6 %

Procedure:
Dimethyl amine (0.055 g, 0.61 ml 2M solution in THF, 1.22 mmol) was added drop wise to a solution of 5-(4-chlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid (compound 1c, 0.25 g, 0.61 mmol) in dry THF (15 ml) under a nitrogen atmosphere at 0° C. To the reaction mixture HATU (0.26 g, 0.67 mmol) and DIPEA (0.16 g, 0.21 ml, 1.24 mmol) were added at 0° C. with stirring. The mixture was then allowed to warm to 10° C. and stirred for 2 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The concentrated mass so obtained was diluted with ethyl acetate (30 ml) and washed with saturated sodium bicarbonate solution (2×15 ml) and brine (1×15 ml). The organic layer obtained was then dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 25% ethyl acetate in hexanes as an eluent to obtain the title compound (0.06 g, 22.50%).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C(=O)=O.CC(C)=O.[CH:15]1([C:18](=[O:29])[C@@H:19]([NH:21][C:22](=[O:28])OC(C)(C)C)[CH3:20])[CH2:17][CH2:16]1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH:15]1([C@@:18]2([OH:29])[C@H:19]([CH3:20])[NH:21][C:22](=[O:28])[CH2:1]2)[CH2:16][CH2:17]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)C1CC1
Reactant: CC(C)NC(C)C
Agent: O=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: C[C@@H]1NC(=O)C[C@@]1(O)C1CC1
Reaction time: 0.33 h
Yield: 62.1 %

Procedure:
A solution of diisopropylamine (4.06 g) in tetrahydrofuran (40 mL) was ice-cooled under a nitrogen atmosphere, and 1.6 mol/L n-butyllithium-hexane solution (24.6 mL) was added. The mixture was stirred at the same temperature for 20 min, and the reaction solution was cooled with dry ice/acetone. Ethyl acetate (3.88 ml) was added to the reaction solution, the mixture was stirred at the same temperature for 30 min, and a solution of tert-butyl [(1S)-2-cyclopropyl-1-methyl-2-oxoethyl]carbamate (3.65 g) in tetrahydrofuran (10 mL) was added. The mixture was stirred at the same temperature for 7 hr, saturated aqueous ammonium chloride solution (100 mL) was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0→30%), the obtained oil was dissolved in 4 mol/L hydrogen chloride-ethyl acetate solution (30 mL), and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (80 mL), and diisopropylethylamine (8.09 mL) was added. The reaction solution was refluxed under heating for 4 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol/ethyl acetate=0→5%), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound as colorless crystals (yield: 1.65 g, 71%).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[NH:17]([C:19]1[CH:20]=[CH:21][C:22]2[S:26][CH:25]=[CH:24][C:23]=2[CH:27]=1)N.[C:28]([O-:33])(=[O:32])[CH:29]([CH3:31])[OH:30]>>[C:28]([OH:33])(=[O:32])[CH:29]([CH3:31])[OH:30].[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2[NH:17][C:19]3[C:27]([C:11]=2[CH2:10]1)=[C:23]1[CH:24]=[CH:25][S:26][C:22]1=[CH:21][CH:20]=3)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: NNc1ccc2sccc2c1
Reactant: CC(O)C(=O)[O-]
Agent: Cl
Product: CC(O)C(=O)O
Product: c1ccc(CN2CCc3[nH]c4ccc5sccc5c4c3C2)cc1

Procedure:
The compound is formed analogously to that described in Example 2, from 9.5 g of 1-benzyl-4-piperidone hydrochloride and 10.0 g of 5-hydrazinobenzothiophene hydrochloride. The unstable base is converted into the lactate. Melting point: 183° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[C:17]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:26]3[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=3)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=2)=[CH:9][CH:10]=1)([CH3:16])[CH3:15]
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: CC(C)c1ccc(-c2ccnc(Cl)c2)cc1
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: CC#N
Solvent: O
Product: CCOC(=O)c1cccc(-c2cc(-c3ccc(C(C)C)cc3)ccn2)c1
Yield: 70 %

Procedure:
Part D. A solution of 2-chloro-4-(4-isopropyl-phenyl)-pyridine (110 mg, 0.48 mmol) in acetonitrile-water (1 mL/0.5 mL) is treated with 3-carboethoxybenzeneboronic acid (186 mg, 0.96 mmol), sodium carbonate (153 mg, 1.44 mmol) and tetrakis(triphenylphosphine)palladium (cat. amount). The mixture is heated to reflux for 12 h., then cooled and partitioned between water and ethyl acetate. The organic phase is washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue is separated by column chromatography to afford ethyl 3-[4-(4-isopropyl-phenyl)-pyridin-2-yl]-benzoate (116 mg, 70%).
Reaction SMILES: C[O:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][C:8]2[C:9]([CH3:26])=[CH:10][C:11]([NH:17][C:18](=[O:25])[CH2:19][C:20]([O:22]CC)=[O:21])=[C:12]3[C:16]=2[CH2:15][CH2:14][CH2:13]3)=[CH:5][C:4]=1[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37]C)=[CH:33][CH:32]=1.B(Br)(Br)Br.CO.Cl>ClCCl>[OH:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][C:8]2[C:9]([CH3:26])=[CH:10][C:11]([NH:17][C:18](=[O:25])[CH2:19][C:20]([OH:22])=[O:21])=[C:12]3[C:16]=2[CH2:15][CH2:14][CH2:13]3)=[CH:5][C:4]=1[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1
Reactant: CCOC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(OC)c(CCc3ccc(OC)cc3)c2)c2c1CCC2
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(NC(=O)CC(=O)O)c2c(c1Oc1ccc(O)c(CCc3ccc(O)cc3)c1)CCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.1 %

Procedure:
Ethyl N-(7-{4-methoxy-3-[2-(4-methoxyphenyl)ethyl]phenoxy}-6-methylindan-4-yl)malonamate (40 mg) was dissolved in dichloromethane (5 mL). Adding dropwise a 1 mol/L solution of boron tribromide in dichloromethane (1 mL) under dry ice/acetone-cooling, the solution was stirred at room temperature for 24 hours. To the reaction mixture was added dropwise methanol (5 mL) under ice-cooling with stirring. Adding diluted hydrochloric acid, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. To the residue were added methanol (5 mL) and a 1 mol/L aqueous solution of sodium hydroxide (5 mL), and the mixture was stirred under an argon atmosphere at 50° C. for 30 min. The reaction mixture was evaporated under reduced pressure to dryness and water (10 mL) was added thereto. The mixture was washed with diethyl ether (10 mL) twice. To the aqueous layer were added 1 mol/L hydrochloric acid (20 mL) and brine (10 mL), and the aqueous layer was extracted with ethyl acetate (10 mL) twice. The organic layer was dried over anhydrous magnesium sulfate and evaporated-under reduced pressure to dryness to give the title compound (20 mg).
Reaction SMILES: [OH:1][C@H:2]([CH2:35][OH:36])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[N:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=3)[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].C(N(CC)CC)C.[CH:44]([Si:47](Cl)([CH:51]([CH3:53])[CH3:52])[CH:48]([CH3:50])[CH3:49])([CH3:46])[CH3:45]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[OH:1][C@H:2]([CH2:35][O:36][Si:47]([CH:51]([CH3:53])[CH3:52])([CH:48]([CH3:50])[CH3:49])[CH:44]([CH3:46])[CH3:45])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[N:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=3)[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6]
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C(=O)NC[C@H](O)CO)[nH]2)c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C(=O)NC[C@H](O)CO[Si](C(C)C)(C(C)C)C(C)C)[nH]2)c1
Reaction time: 14 h
Yield: 64.4 %

Procedure:
N-[(2S)-2,3-Dihydroxypropyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[5-(methylsulfonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrole-2-carboxamide (666 mg, 1.28 mmol) synthesized in Example (101a) was dissolved in methylene chloride (20 mL), and triethylamine (0.89 mL, 6.40 mmol), triisopropylsilyl chloride (410 μL, 1.92 mmol) and 4-dimethylaminopyridine (234 mg, 1.92 mmol) were added, followed by stirring for 14 hours under nitrogen atmosphere. The reaction solution was diluted with methylene chloride (50 mL), washed with water and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-60%) to afford the desired product (558 mg, 64%) as a white solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([OH:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)C.[Li+].[BH4-].O>C1COCC1>[OH:18][C:6]1([CH2:5][CH2:4][OH:3])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7]1
Reactant: CCOC(=O)CC1(O)CCN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(CCO)C1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
To a solution of tert-butyl 3-(2-ethoxy-2-oxoethyl)-3-hydroxypyrrolidine-1-carboxylate (6.35 g) in THF (100 mL) was added LiBH4 (1.01 g), followed by heating under reflux for 4 hours. The reaction mixture was cooled to room temperature, then added with water, and extracted with EtOAc. The organic layer was washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure to obtain tert-butyl 3-hydroxy-3-(2-hydroxyethyl)pyrrolidine-1-carboxylate (4.72 g) as a colorless oily substance.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14](=[NH:17])OC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(O)C>[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:14](=[NH:17])[CH2:13][CH2:12][S:11][CH2:10][C:8]2[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=2)(=[O:26])=[O:27])=[CH:21][CH:20]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: COC(=N)CCSCc1csc(NC(=N)N)n1
Solvent: CCO
Product: N=C(N)Nc1nc(CSCCC(=N)NS(=O)(=O)c2ccc(N)cc2)cs1
Yield: 79.3 %

Procedure:
In 10 ml of ethanol were dissolved 1 g of methyl 3-[(2-guanidinothiazol-4-yl)methylthio]propionimidate and 0.69 g p-aminobenzenesulfonamide and after causing reaction for 48 hours at room temperature, the solvent was distilled off under reduced pressure. Then, the residue formed was purified by a silica gel column chromatography using a mixture of chloroform and methanol (20:1→10:1) to provide 1.2 g N-(p-aminobenzenesulfonyl)-3-[(2-guanidinothiazol-4-yl)methylthio]propionamidine as an amorphous solid. The product shows the following physicochemical properties.
Reaction SMILES: [C-:1]#[N:2].[Na+].[O:4]([C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:19](Cl)[CH2:20][CH2:21][CH3:22].[OH-].[Na+]>O.CS(C)=O>[O:4]([C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]([CH2:19][CH2:20][CH2:21][CH3:22])[C:1]#[N:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: CCCCCl
Reactant: ClCc1ccccc1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCC(C#N)c1ccccc1Oc1ccccc1
Reaction time: 2 h
Yield: 92.8 %

Procedure:
Into a three-necked 300 ml round-bottom flask are charged 7.4 g (0.15 mole) of sodium cyanide and 80 ml of dimethyl sulfoxide. To this slurry is added 30 g (0.13 mole) of 2-phenoxybenzyl chloride dropwise. Reaction temperature increases from 24° to 44° C. The reaction mixture is stirred for an additional 11/2 hours. To this reaction mixture is added 13.7 g (0.13 mole) of butyl chloride followed by dropwise addition of 34 g (0.4 mole) of 50% sodium hydroxide solution. After stirring for an additional 1/2 hour, reaction mixture is poured into 150 ml of water and extracted with hexane. The combined hexane extracts are washed with water and dried over MgSO4. Solvent is evaporated to give 32 g of crude product. Material can be further purified by vacuum distillation (bp 149-60/0.25 mm).
Reaction SMILES: [C:1]1(=[O:14])[N:5]([CH2:6][CH2:7][OH:8])[C:4](=[O:9])[C:3]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:2]12.[H-].[Na+].[CH2:17](Br)[C:18]#[CH:19].CO>CN(C)C=O>[C:4]1(=[O:9])[N:5]([CH2:6][CH2:7][O:8][CH2:19][C:18]#[CH:17])[C:1](=[O:14])[C:2]2=[CH:13][CH:12]=[CH:11][CH:10]=[C:3]12
Reactant: C#CCBr
Reactant: O=C1c2ccccc2C(=O)N1CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: C#CCOCCN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
To a stirred solution of compound 3 (1.14 g, 5.96 mmol) in N,N-dimethylformamide (20 mL) was added NaH (0.36 g, 80%) dropwise. After complete NaH addition, stirring was continued for 0.5 h at room temperature, and then the reaction was cooled to 0° C. Propargyl bromide 4 (1.5 mL, 13.47 mmol) was added, and the stirring was continued for an additional 0.5 h at 0° C., then, at room temperature for 2 h. After careful addition of methanol to decompose excess NaH, the solvent was evaporated and the crude product was purified by flash column chromatography (3:2 to 1:1 to 2:3 hexane-ethyl acetate) to give compound 5 as a solid (495 mg, 36.2%) having an RF of 0.22 (3:2 hexane-ethyl acetate). See FIG. 5.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:18]([NH2:20])=[O:19])[C:13]=3[C:14]([NH:16][CH3:17])=[O:15])[C:4]=2[CH:3]=1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C@:29]([OH:33])([C:31]#[CH:32])[CH3:30])[CH:25]=1>>[OH:33][C@:29]([C:26]1[CH:25]=[C:24]([CH3:23])[O:28][N:27]=1)([CH3:30])[C:31]#[C:32][C:2]1[CH:22]=[CH:21][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:18]([NH2:20])=[O:19])[C:13]=3[C:14]([NH:16][CH3:17])=[O:15])[C:4]=2[CH:3]=1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: CNC(=O)c1c(C(N)=O)nn2c1CCOc1ccc(Br)cc1-2
Product: CNC(=O)c1c(C(N)=O)nn2c1CCOc1ccc(C#C[C@@](C)(O)c3cc(C)on3)cc1-2
Yield: 26 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-N3-methyl-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2,3-dicarboxamide was reacted with (R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol to give the titled compound as an off-white solid (37 mg, 26%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:36](Br)[CH:37]=[CH2:38]>O1CCCC1>[CH2:38]([C@H:11]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:10][C@@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:37]=[CH2:36]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 719 mg (2.00 mmol) di-tert-butyl N-(tert-butoxycarbonyl)-L-glutamate in tetrahydrofuran (12 mL) at −78° C., lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (1.0 M in tetrahydrofuran, 4.40 mL) was added dropwise. The solution was stirred for 30 min, then allyl bromide (0.52 mL, 6.00 mmol) was added dropwise. The reaction was stirred at −78° C. overnight and then quenched at −10° C. by the addition of 10 mL of 2 N aqueous hydrogen chloride. The mixture was warmed to room temperature poured into 10 mL 1 N aqueous hydrogen chloride and extracted with dichloromethane (3×30 mL). The organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified on silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: [Cl:1]C1C=CC(OC)=C([C@@]2(F)C3C(=CC(C(F)(F)F)=CC=3)N(C([NH:23][C@@H:24]([CH3:32])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=O)C2=O)C=1.C(N(CC)CC)C>>[ClH:1].[C:28]([O:27][C:25](=[O:26])[C@H:24]([CH3:32])[NH2:23])([CH3:31])([CH3:30])[CH3:29]
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)N[C@@H](C)C(=O)OC(C)(C)C)c2cc(C(F)(F)F)ccc21
Solvent: CCN(CC)CC
Product: C[C@H](N)C(=O)OC(C)(C)C
Product: Cl

Procedure:
(S)-tert-butyl 2-((S)-3-(5-chloro-2-methoxyphenyl)-3-fluoro-2-oxo-6-(trifluoromethyl)indoline-1-carboxamido)propanoate (XVIII1): Following general procedure (F), after forming the intermediate, (L)-Alanine-t-butyl ester hydrochloride (0.252 g, 1.39 mmol) and triethylamine (0.39 mL, 2.78 mmol) were added. After work-up and purification, 0.38 g of the title compound was obtained as a white foam solid (52% yield). mp: 62–64° C. MS: 531 (MH+). Anal. Calcd. for C24H23ClF4N2O5: C, 54.30; H, 4.37; N, 5.28. Found: C, 54.37; H, 4.38; N, 5.16. 1H NMR (CDCl3): δ 1.51 (s, 9H), 1.56 (d, J=6.9 Hz, 3H), 3.54 (s, 3H), 4.52 (m, 1H), 6.77 (dd, J=8.8 Hz, 1.4 Hz, 1H), 7.25 (m, 1H), 7.36 (dd, J=8.7 Hz, 2.6 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.80 (dd, J=2.5 Hz, 0.9 Hz, 1H), 8.6 (m, 1H), 8.76 (d, J=6.8 Hz, 1H). IR (KBr, cm−1): 3338, 2983, 1765, 1737, 1716, 1520, 1490, 1439, 1319, 1262, 1172, 1130.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]1>>[CH3:8][C:7]1[CH:9]=[CH:10][C:4]([S:1]([O:19][CH2:18][CH:15]2[CH2:16][CH2:17][N:12]([S:1]([C:4]3[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=3)(=[O:3])=[O:2])[CH2:13][CH2:14]2)(=[O:3])=[O:2])=[CH:5][CH:6]=1
Reactant: OCC1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCC2CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1

Procedure:
Reaction of tosyl chloride and piperidin-4-yl-methanol as described in Preparation 1 gave the desired compound, (1-tosylpiperidin-4-yl)methyl 4-methylbenzenesulfonate, which was used without further purification.