Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(=O)(O)[O-].[Na+]>CCOCC>[CH2:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:3]1[NH:2][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)NC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49435.4 %

Procedure:
A mixture of 2-aminoindan hydrochloride (13.3 g, 78 mmol), acetic anhydride (6 g, 0.157 mmol) and saturated sodium bicarbonate (100 mL) in ether (100 mL) was stirred at room temperature for 1 h. The organic phase was separated, and the aqueous layer back washed with ether. The combined organic layer was washed with saturated chloride solution, dried over magnesium sulfate, filtered and evaporated to give the acetamide (13.6 g) in quantitative yield.
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[O:20][C:19]=2[CH3:31])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37]>>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[O:20][C:19]=2[CH3:31])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([N:33]([CH3:32])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1oc(-c2ccc(F)cc2F)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Product: Cc1oc(-c2ccc(F)cc2F)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 94.7 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-{cyclohexyl[5-(2,4-difluorophenyl)-2-methyl-3-furyl]methoxy}benzoic acid (235 mg) as well as ethyl 3-(methylamino)propanoate (86 mg) to give the title compound (267 mg, 95%) as an amorphous compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)C(=O)[O:9][N:8]=2)=[N:4][O:5][N:6]=1.[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:7](=[N:8][OH:9])[C:3]2[C:2]([NH:1][C:27](=[O:28])[CH2:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:6][O:5][N:4]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1nonc1-c1noc(=O)n1-c1cccc(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1)Nc1nonc1C(=NO)Nc1cccc(Cl)c1
Reaction time: 4 h
Yield: 45.2 %

Procedure:
A solution of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one (30.0 mg, 0.107 mmol) and 4-dimethylaminopyridine (2.6 mg, 0.021 mmol) in pyridine (0.50 mL) was treated with benzeneacetyl chloride (42.6 μL, 0.322 mmol) and stirred for 4 h. The reaction mixture was concentrated and rediluted with ethanol (1.0 mL) and 2 M of sodium hydroxide in water (0.30 mL) stirred for 45 min. Purification of the crude reaction mixture by preparative HPLC gave the desired product (18 mg, 45%). LCMS for C17H15ClN5O3 (M+H)+: m/z=371.9.
Reaction SMILES: [CH3:1][N:2]([Si](C)(C)C)[C:3](=[O:5])[CH3:4].[CH:10]([S:13]([N:16]1[C:20]2[CH:21]=[C:22]([C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[NH2:33])(=[O:15])=[O:14])([CH3:12])[CH3:11].C([Li])CCC>>[CH:10]([S:13]([N:16]1[C:20]2[CH:21]=[C:22]([C:25]([OH:32])([CH2:4][C:3]([NH:2][CH3:1])=[O:5])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[NH2:33])(=[O:14])=[O:15])([CH3:12])[CH3:11]
Reactant: CC(=O)N(C)[Si](C)(C)C
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(=O)c3ccccc3)cc21
Agent: [Li]CCCC
Product: CNC(=O)CC(O)(c1ccccc1)c1ccc2nc(N)n(S(=O)(=O)C(C)C)c2c1

Procedure:
Following the general procedure of Example 23, N-methyl-N-trimethylsilylacetamide was reacted with 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole in the presence of n-butyl lithium to provide 1-isopropylsulfonyl-2-amino-6-(α-hydroxy-α-methylaminocarbonylmethylbenzyl)benzimidazole. M.P. 92°-95° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([O-:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Na+].Br[C:14]1[CH:22]=[CH:21][C:20]2[N:19]([CH3:23])[C:18]3[CH2:24][CH:25]4[NH:29][CH:28]([C:17]=3[C:16]=2[C:15]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]4>>[C:1]([C:3]1[CH:4]=[C:5]([S:9]([C:14]2[CH:22]=[CH:21][C:20]3[N:19]([CH3:23])[C:18]4[CH2:24][CH:25]5[NH:29][CH:28]([C:17]=4[C:16]=3[C:15]=2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]5)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Reactant: N#Cc1cccc(S(=O)[O-])c1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cccc(C#N)c4)ccc31)C1CCC(C2)N1
Yield: 35 %

Procedure:
Intermediate 5 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude material was purified by flash column chromatography (SiO2, 7.5:2.5 hexane/ethyl acetate) to give tert-butyl 2-(3-cyanophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (106 mg, 35%) as a yellow solid: 1H NMR (CDCl3, 300 MHz): δ 8.13-8.24 (m, 3H), 7.76 (td, J=7.8, 1.2 Hz, 1H), 7.66 (dd, J=8.7, 1.5 Hz, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.34 (d, J=8.7 Hz, 1H), 5.20-5.37 (m, 1H), 4.58-4.82 (m, 1H), 3.62 (s, 3H), 3.25-3.50 (m, 1H), 2.52 (d, J=16.2 Hz, 1H), 2.13-2.42 (m, 2H), 1.88-2.00 (m, 1H), 1.55-1.68 (m, 1H), 1.38 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[C:28]1([C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][O:30]1)=O.Cl>C1COCC1.O>[C:28]1(=[C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:8][C:7]2=[O:12])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][O:30]1
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: O=C1OCc2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=C1OCc3ccccc31)C(=O)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.6 %

Procedure:
To a stirred solution of 5-methoxyoxindole (100 mg, 0.61 mmol) in anhydrous THF (5 ml) under nitrogen was added 1.0M LiHMDS/THF solution (1.3 ml, 1.3 mmol). The mixture was stirred at room temperature for 10 minutes, and phthalide (74 mg, 0.55 mmol) was added. The mixture was stirred at room temperature for 5 hours and was then poured into a mixture of THF (10 ml) and 2M HCl (10 ml). The mixture was heated at 45° C. for 30 minutes, cooled to room temperature, and poured into water (125 ml). The resulting solid was separated, washed with water and dried under vacuum to give 3-(3H-Isobenzofuran-1-ylidene)-5-methoxy-1,3-dihydro-indol-2-one (70 mg, 46%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.I[CH:13]([CH3:15])[CH3:14]>>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][N:8]([CH:13]([CH3:15])[CH3:14])[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: CC(C)I
Product: CC(C)n1ccc2c(Cl)nc(Cl)nc21

Procedure:
Following the procedure of Example 15b, 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (0.5 g, 2.67 mmol) was reacted with 2-iodopropane. The crude residue was purified by silica gel chromatography (15 to 25% ethyl acetate in hexane eluant) to afford the title compound as a solid. MS m/z 230.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:31]=[C:30]([C:32](=[O:36])[NH:33][CH2:34][CH3:35])[CH:29]=[CH:28][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][C:17]=1[O:26][CH3:27])(=[O:11])=[O:10].[NH2:37]C(N)=O.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[C:23]([CH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:14]2[CH:28]=[CH:29][C:30]([C:32]([NH:33][CH2:34][CH3:35])=[O:36])=[CH:31][C:13]=2[NH:12][S:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:11])=[C:17]([O:26][CH3:27])[CH:18]=1)(=[O:24])[NH2:37]
Reactant: NC(N)=O
Reactant: CCNC(=O)c1ccc(Oc2ccc(CC(=O)O)cc2OC)c(NS(=O)(=O)c2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCNC(=O)c1ccc(Oc2ccc(CC(N)=O)cc2OC)c(NS(=O)(=O)c2ccc(Cl)cc2Cl)c1
Temperature: 175 °C
Yield: 67.5 %

Procedure:
A mixture of acid 12 (70 mg, 0.126 mmol) and urea (1.0 g, 16.6 mmol) was heated to 170-180° C. and maintained at this temperature for 4 h, and the mixture was allowed to cool. As soon as the temperature dropped to 110-120° C. 2 mL of 5% sodium carbonate aqueous solution was added, and the mixture was shaken vigorously. After mixture was cooled to room temperature, 20 mL of 3N HCl aqueous solution was added and the resulting mixture was extracted with ethyl acetate (4×20 mL). The combined extracts were washed with water and brine, dried and concentrated. The residue was purified by silica gel chromatography using EtOAc and 10% CH3OH/EtOAc sequentially as the eluents to give 47 mg of product. 1H NMR (Acetone-d6): δ 8.77 (s, 1H), 8.04 (d, J=2.13 Hz, 1H), 7.96 (d, J=8.57 Hz, 1H), 7.70 (, br s, 1H), 7.63 (d, J=2.13 Hz, 1H), 7.56 (dd, J=8.53, 2.13 Hz, 1H), 7.51 (dd, J=8.53, 2.13 Hz, 1H), 7.11 (d, J=1.86 Hz, 1H), 6.88 (dd, J=8.13, 1.87 Hz, 1H), 6.85 (br s, 1H), 6.75 (d, J=8.13 Hz, 1H), 6.659 (d, J=8.67 Hz, 1H), 3.67 (s, 3H), 3.51 (s, 2H), 3.38 (m, 2H), 1.17 (dd, J=7.20, 7.20 Hz, 3H). LCMS (ESI−) 551 (M−1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1.O>CN1CCCC1=O>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Solvent: CN1CCCC1=O
Solvent: O
Product: FC(F)(F)c1ccc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
Piperazine (12.9 g) was suspended in N-methyl-2-pyrrolidone (130 mL), and a solution of 2-chloro-5-trifluoromethylpyridine (9.08 g) in N-methyl-2-pyrrolidone (30 mL) was added dropwise. The mixture was stirred at room temperature for 18 hr. The reaction mixture was added to water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure to give 1-(5-trifluoromethyl-2-pyridyl)piperazine (11.5 g) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[O:1]1[CH2:2][CH2:3][CH:4]([O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(OC2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(OC2CCOCC2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
To a solution of methyl 4-((tetrahydro-2H-pyran-4-yl)oxy)benzoate (400 mg, 1.6 mmol) in MeOH (10 ml) was added a solution of NaOH (128 mg, 3.2 mmol) in H2O (4 mL) at 22° C. The mixture was stirred at 50° C. for 4 h. The mixture was concentrated and the residue was treated with water and extracted with EA. The water layer was treated with 2N HCl to pH=3. The water layer was then extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give the title product which was used in next step without further purification (350 mg, Yield 98.6%). 1H NMR (CDCl3, 400 MHz): δ 8.08 (d, J=8.9 Hz, 2H), 6.98 (d, J=8.9 Hz, 2H), 4.64 (tt, J=7.7, 3.8 Hz, 1H), 3.95-4.09 (m, 2H), 3.64 (ddd, J=11.6, 8.2, 3.3 Hz, 2H), 2.01-2.13 (m, 2H), 1.78-1.93 (m, 2H).
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:12][C:13]1([CH2:19][C:20](O)=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH3:12][C:13]1([CH2:19][C:20]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][CH:2]=[N:1]3)=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Nc1cccc2ncccc12
Reactant: CC1(CC(=O)O)CCCCC1
Product: CC1(CC(=O)Nc2cccc3ncccc23)CCCCC1
Yield: 17.8 %

Procedure:
Prepared according to the method of example 18, using 5-quinolinamine (230 mg) and 1-methyl-cyclohexaneacetic acid (250 mg). Purification (SiO2, methanol:dichloromethane 1:9 as eluant) followed by recrystallisation from methanol/ethyl acetate gave the title compound as a colourless solid (80 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[CH:16]([Mg]Br)=[CH2:17]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[CH:16]=[CH2:17])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: C=C[Mg]Br
Product: C=CC(O)c1c(C)noc1-c1ccc(Br)cc1

Procedure:
Prepared according to the procedure described in Example 114, Step 3, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and vinylmagnesium bromide.
Reaction SMILES: O[C:2]([CH3:13])([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(N(S(F)(F)[F:20])CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[F:20][C:2]([CH3:13])([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(O)CNC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(F)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
A solution of tert-butyl 2-hydroxy-2-methylpropylcarbamate (19.2 g, 101 mmol) in dichloromethane (500 mL) was stirred at −78° C. under a nitrogen atmosphere, and (diethylamino)sulfur trifluoride (DAST) (18.0 g, 112 mmol) was added dropwise. The solution was allowed to warm to room temperature and stirred overnight. Saturated aqueous sodium bicarbonate (150 mL) was added. The organic layer was then separated and washed sequentially with saturated aqueous sodium bicarbonate (150 mL), water (150 mL), and brine (150 mL); dried over magnesium sulfate; filtered; and concentrated under reduced pressure. The resulting oil was purified by automated flash chromatography (FLASH 65I cartridge, eluting with 10% ethyl acetate in hexane) to provide 13.7 g of tert-butyl 2-fluoro-2-methylpropylcarbamate as a light yellow oil that crystallized overnight.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[NH2:9][C:10]1[N:15]=[C:14]([CH2:16][O:17][CH2:18][CH3:19])[NH:13][C:12](=[O:20])[C:11]=1[N:21]=O.[CH:23]([CH:25]=O)=O>O>[CH2:18]([O:17][CH2:16][C:14]1[NH:13][C:12](=[O:20])[C:11]2[C:10](=[N:9][CH:23]=[CH:25][N:21]=2)[N:15]=1)[CH3:19]
Reactant: O=CC=O
Reactant: CCOCc1nc(N)c(N=O)c(=O)[nH]1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOCc1nc2nccnc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 19.1 g (0.11 mole) of sodium dithionite in 88 ml of water is added dropwise to a suspension, maintained at 20° C., of 10.0 g (0.050 mole) of 6-amino-2-(ethoxymethyl)-5-nitroso-4(3H)-pyrimidinone in 50 ml of water. After being stirred for 30 minutes at room temperature, the reaction mixture, still maintained at 20° C., is treated with 47.9 g (0.33 mole) of a 40% aqueous solution of glyoxal. Stirring is continued for 20 hours at room temperature. The solution obtained is then extracted with dichloromethane. These organic extracts are dried over sodium sulphate and concentrated to dryness under reduced pressure. The solid residue is recrystallized from methanol in the presence of Norit. Yld: 6.5 g (63%), m.p. 168°-169° C. The product is identical to that obtained in Example 1.
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)C.[CH3:13][NH2:14]>CO>[CH3:13][NH:14][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)Cc1ccncc1
Reactant: CN
Solvent: CO
Product: CNCCc1ccncc1

Procedure:
Ethyl-4-pyridylacetate (2 g) was allowed to stand in methanol (50 ml), saturated with methylamine gas, for 3 days. The solution was evaporated under reduced pressure and the residue heated under reflux for 16 hours in toluene (20 ml) with boranedimethylsulphide complex (1.26 ml). The solution was cooled then treated with methanol (1.5 ml) for 1 hour. Hydrogen chloride gas was bubbled through the solution until the pH was less than 2. The solution was heated under reflux for 1 hour then cooled and concentrated. Aqueous sodium hydroxide was added and the mixture extracted with ethyl acetate. The ethyl acetate solution was dried (Na2SO4) and evaporated under reduced pressure to give the title compound as a yellow oil.
Reaction SMILES: C(OC([NH:8][C:9]([CH3:44])([C:11]([O:13][C@@H:14]([CH3:43])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[C:27](/[N:29]=[C:30]1\[S:31][C:32]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[N:38]\1[CH2:39][CH2:40][CH2:41][CH3:42])=[O:28])=[O:12])[CH3:10])=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:44][C:9]([C:11]([O:13][C@@H:14]([CH3:43])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[C:27](/[N:29]=[C:30]1\[S:31][C:32]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[N:38]\1[CH2:39][CH2:40][CH2:41][CH3:42])=[O:28])=[O:12])([CH3:10])[NH2:8]
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OC[C@H](C)OC(=O)C(C)(C)NC(=O)OC(C)(C)C)sc2ccncc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OC[C@H](C)OC(=O)C(C)(C)N)sc2ccncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of Example 2A (265 mg, 0.415 mmol) in anhydrous dichloromethane (4 mL) was added trifluoroacetic acid (Aldrich, 0.320 mL, 4.15 mmol). The solution was stirred at room temperature overnight, then saturated sodium bicarbonate solution was added to adjust the pH to 9. The mixture was extracted with dichloromethane (3×15 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporator. Purification by flash chromatography (silica gel: 50-100% ethyl acetate in hexanes) afforded 202 mg (90%) of the title compound. 1H NMR (DMSO-d6) δ 0.94 (t, J=7.3 Hz, 3H), 1.08 (s, 3H), 1.10 (s, 3H), 1.30 (d, J=6.8 Hz, 3H), 1.34-1.46 (m, 3H), 1.77-1.87 (m, 3H), 4.19-4.32 (m, 2H), 4.53 (t, J=7.3 Hz, 2H), 5.08-5.18 (m, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.84 (dd, J=8.6, 2.2 Hz, 1H), 8.03 (d, J=4.4 Hz, 1H), 8.23 (d, J=2.0 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H), 9.03 (s, 1H). MS (ESI+) m/z 539 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].[N:21]1[CH2:24][CH:23]([OH:25])[CH:22]=1>>[OH:25][CH:23]1[CH2:24][N:21]([C:10]([C:9]2[CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=2[O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[O:12])[CH2:22]1
Reactant: OC1C=NC1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CC(O)C1)C(F)(F)F
Yield: 43 %

Procedure:
Prepared in analogy to Example 1 from 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A2(c)) and azetin-3-ol. The crude material was purified by flash chromatography (ethyl acetate/n-heptane) to yield the title compound as a white crystalline solid (yield 43%). MS (m/e): 367.9 (M+H+, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15]([CH3:16])=[C:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=2)[C:13]([O:28][C@@H:29]2[O:37][C@H:36]([CH2:38][OH:39])[C@@H:34]([OH:35])[C@H:32]([OH:33])[C@H:30]2[OH:31])=[N:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:41]([O:43][CH2:44][CH3:45])=[O:42].O.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC1C=C(C)C=C(C)N=1>[CH2:1]([O:8][C:9]([N:11]1[C:15]([CH3:16])=[C:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:23]=2)[C:13]([O:28][C@@H:29]2[O:37][C@H:36]([CH2:38][O:39][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C@@H:34]([OH:35])[C@H:32]([OH:33])[C@H:30]2[OH:31])=[N:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cc2ccc(OC(C)C)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1C(=O)OCc1ccccc1
Reactant: CCOC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)OC[C@H]1O[C@@H](Oc2nn(C(=O)OCc3ccccc3)c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1-(benzyloxycarbonyl)-3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methylpyrazole (0.20 g) in 2,4,6-trimethylpyridine (4 mL) was added ethyl chloroformate (0.092 mL), and the mixture was stirred at room temperature for 1 day. To the reaction mixture were added water and citric acid monohydrate, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 1-(benzyloxycarbonyl)-3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methylpyrazole (0.17 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[OH:17].[C:18](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.Cl>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][CH:5]=[CH:6][C:7]=1[B:8]1[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]1
Reactant: CC1(C)OB(c2cccc(O)c2Cl)OC1(C)C
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COc1cccc(B2OC(C)(C)C(C)(C)O2)c1Cl
Reaction time: 0.17 h
Yield: 85.3 %

Procedure:
To a stirred solution of 2-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (830 g, 3.26 mol) in dry DMF (4.15 L) was added potassium carbonate (1126.4 g, 8.15 mol) under an inert atmosphere. Me2SO4 (402 mL, 4.24 mol) was added slowly to control the resulting exotherm (addition over 30 minutes gave a temperature rise from 28° C. to 55° C.) and after complete addition the reaction was stirred for 10 minutes. The reaction mixture was added to stirring HCl (5.98 L, 2 N, aq.) very slowly to control effervescence and the resulting precipitate stirred for 2 hours. The solids were filtered and washed with water (1 L) and dried in a vacuum oven over drying agent for 4 days to give 2-(2-chloro-3-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane 7a as a white powder (746.7 g, 2.78 mol, 85%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[CH:7]=[CH:8][CH2:9]Cl)([O-:3])=[O:2].[NH2:14][C:15]1[S:16][C:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][C:23]=2[N:24]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:14][C:15]1[S:16][C:17]2[CH2:18][CH2:19][N:20]([CH2:9][CH:8]=[CH:7][C:6]3[CH:11]=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:21][CH2:22][C:23]=2[N:24]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: O=[N+]([O-])c1cccc(C=CCCl)c1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(s1)CCN(CC=Cc1cccc([N+](=O)[O-])c1)CC2
Yield: 56 %

Procedure:
Prepared from 3-nitro-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine in chloroform. Yield: 56% of theory, Melting point: 165°-168° C. (ether).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1.[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[C:19]([NH:27][C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1)=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: CC(=O)Nc1nc(CCc2ccc(NC(=S)NC(=O)c3ccccc3)cc2)cs1
Temperature: 0 °C
Yield: 73.8 %

Procedure:
To an ice-cold solution of N-(4-(2-(4-aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide (300 mg) prepared in a similar manner according to Step 6 of Production Example 1 in acetone (5 ml) was added benzoyl isothiocyanate (187 mg) and the mixture was refluxed for 2 hours. The reaction mixture was cooled to 0° C. The precipitated crystals were filtered and washed with ice-cold acetone to give N-{4-[2-(4-{[(benzoylamino)carbonothioyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide (359 mg).