Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Li].[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14]([OH:16])=O)=[CH:9][CH:8]=[CH:7]2>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14](=[O:16])[CH3:1])=[CH:9][CH:8]=[CH:7]2
Reactant: O=C(O)c1cccc2cc(F)ccc12
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(=O)c1cccc2cc(F)ccc12
Reaction time: 2 h

Procedure:
Methyl lithium (1.59M solution in ether; 4.2 ml) was added dropwise to a stirred solution of 6-fluoro-1-naphthalene carboxylic acid (640 mg) in dry THF (10 ml) at -78° under nitrogen. The solution was stirred at -78° for 2 h and was slowly allowed to warm to -15°. The solution was quenched with saturated aqueous ammonium chloride (1 ml) and partitioned between 2N sodium hydroxide (25 ml) and ethyl acetate (25 ml). The organic phase was dried and evaporated to give the title compound (404 mg) as an oil, t.l.c. (System B, 1:6) Rf 0.2.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([F:40])=[C:6]([CH:37]=[CH:38][CH:39]=1)[NH:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:35][CH3:36])=[C:15]([O:18][C@H:19]3[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31]([O:33]C)=[O:32])[CH2:20]3)[CH:16]=2)[N:11]=[CH:10][N:9]=1.Cl>CO.C1COCC1.O>[Cl:3][C:4]1[C:5]([F:40])=[C:6]([CH:37]=[CH:38][CH:39]=1)[NH:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:35][CH3:36])=[C:15]([O:18][C@H:19]3[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31]([OH:33])=[O:32])[CH2:20]3)[CH:16]=2)[N:11]=[CH:10][N:9]=1
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Aqueous sodium hydroxide solution (2M, 1.0 ml) was added to a stirred solution of 4-(3-chloro-2-fluoroanilino)-6-[(2S,4R)-1-(tert-butoxycarbonyl)-2-(methoxycarbonyl)pyrrolidin-4-yloxy]-7-methoxyquinazoline (prepared as described in Example 46; preparation of starting materials) in methanol (8 ml) and THF (3 ml) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then reduced under vacuum and the residue dissolved in water and adjusted to pH 6 by the addition of hydrochloric acid (2N). The product was extracted with ethylacetate/n-propanol and the organic layer was washed with brine, dried over MgSO4 and the solvent removed under vacuum to give 4-(3-chloro-2-fluoroanilino)-6-[(2S,4R)-1-(tert-butoxycarbonyl)-2-carboxypyrrolidin-4-yloxy]-7-methoxyquinazoline as a white powder solid (0.42 g); Mass Spectrum: (M+H)+ 532.98
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:7]([CH2:10][C:11]([OH:13])=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH3:46][O:47][C:48](=[O:51])[CH2:49][NH2:50].C(N(CC)CC)C>C(Cl)Cl>[CH3:46][O:47][C:48](=[O:51])[CH2:49][NH:50][C:11]([CH2:10][C:7]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][CH:8]=1)=[O:13]
Reactant: CCCCc1ncc(CC(=O)O)n1Cc1ccccc1Cl
Reactant: COC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1ncc(CC(=O)NCC(=O)OC)n1Cc1ccccc1Cl
Yield: 53.6 %

Procedure:
The procedure of Example 1-(iii) was followed using 0.5 g (1.63 mmol) of 2-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]acetic acid, 0.21 g (1.79 mmol) of N-hydroxysuccinimide, 0.37 g (1.79 mmol) of dicyclohexylcarbodiimide, 0.27 g (2.12 mmol) of glycine methyl ester hydrochloride, triethylamine (0.3 mL, 2.12 mmol) and methylene chloride (15 mL), there was obtained 0.33 g (53%) of N-[{2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl}methylcarbonyl]glycine methyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([O:4][C:5]([NH:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][C:9]=1[CH3:16])=[O:6])[CH3:3]>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:3][C:2]([CH3:17])([O:4][C:5]([NH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][C:9]=1[CH3:16])=[O:6])[CH3:1]
Reactant: Cc1cc(CO)ccc1NC(=O)OC(C)(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1cc(C=O)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 76 h
Yield: 77.5 %

Procedure:
To a solution of 4-[(1,1-dimethylethoxy)carbonyl]amino-3-methylbenzyl alcohol (42.9 mmol, 10.18 g) in dichloromethane (85 mL) was added manganese dioxide (138 mmol, 12 g) and 4A molecular sieves (6 g) at room temperature. The reaction mixture was stirred for 76 h at room temperature and was filtered through a pad of celite washing with dichloromethane. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a Biotage (40m) column to obtain 7.82 g (77% yield) of 4-[[(1,1-dimethylethoxy)carbonyl]amino]-3-methylbenzaldehyde as a white solid: mp 109-111° C. EI-HRMS m/e calcd for C13H17NO3 (M+) 235.1208, found 235.1207.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[H][H]>C(O)C.O.[Pt]=O>[F:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccccc1F
Agent: O=[Pt]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCc1ccccc1F
Yield: 85.1 %

Procedure:
A mixture of ethyl 2-fluorocinnamate (29.25 g, 0.176 mol) and platinum oxide hydrate (0.25, EM Scientific) in 95% ethanol (150 mL) was placed on a Parr hydrogenation apparatus and shaken under 2-4 atm at hydrogen pressure. After the appropriate amount of hydrogen was consumed, the catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give 29.39 g (99%) of crude ethyl 3-(2-fluorophenyl)propionate. This material was used without further purification.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N:11]([O-])=[O:12].[Na+].CCOC(C)=O>CC(O)=O.O>[N:11]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:12]
Reactant: O=N[O-]
Reactant: c1ccc2c(c1)CCCN2
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=NN1CCCc2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
1,2,3,4-Tetrahydroquinoline (2.12 g, 15.9 mmol) was dissolved in AcOH (30 mL) and water (10 mL). The solution was cooled to 0° C. An aqueous solution of NaNO2 (1.20 g, 17.5 mmol in 3 mL water) was added dropwise. The reaction was warmed to RT and stirred 2 hrs. Water (20 mL) and EtOAc (20 mL) were added. The layers were separated and the aqueous phase was extracted (2×20 mL) with EtOAc. The combined organic layers were washed with brine, dried, and concentrated to afford a crude orange oil (2.62 g). The product was purified by column chromatography (20–40% EtOAc/hexane) to afford 1-nitroso-1,2,3,4-tetrahydroquinoline (2.48 g, 96%) as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ 8.07 (d, 1H, J=8.1 Hz), 7.21–7.34 (m, 3H), 3.91 (t, 2H, J=6.2 Hz), 3.81 (t, 2H, J=6.2 Hz), 1.97–2.05 (m, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:19]([C:21]3[N:25]([CH3:26])[C:24]([CH3:27])=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1>[O-2].[O-2].[Mn+4].O1CCOCC1>[Cl:1][C:2]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:21]3[N:25]([CH3:26])[C:24]([CH3:27])=[N:23][CH:22]=3)=[O:20])[CH:8]=2)[N:3]=1
Reactant: Cc1ncc(C(O)c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)n1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: Cc1ncc(C(=O)c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)n1C

Procedure:
To a flask containing (2,4-dichloro-3-phenylquinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanol (520 mg, 1.31 mmol, Intermediate 18: step a) was added 1,4-dioxane (12 mL) followed by manganese dioxide (475 mg, 5.46 mmol). The mixture was heated to reflux for 3.25 hours and then the contents were filtered through a Celite® pad, while still warm, and the Celite® pad was rinsed with warm THF. The effluent was concentrated under reduced pressure to provide the title compound as an off white foam.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:31]([C:33]1[N:37]([CH3:38])[C:36]([C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])=[N:35][CH:34]=1)#[CH:32]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:4]([N:1]3[CH:32]=[C:31]([C:33]4[N:37]([CH3:38])[C:36]([C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])=[N:35][CH:34]=4)[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: C#Cc1cnc(C(=O)C(C)(C)C)n1C
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cnc(C(=O)C(C)(C)C)n4C)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 30 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide and 1-(5-ethynyl-1-methyl-1H-imidazol-2-yl)-2,2-dimethyl-propan-1-one in the same manner as Example 15. ESI MS m/z 622 [C31H39N7O5S+H]+.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[F:9][C:10]1[CH:11]=[C:12]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>CO.C(Cl)Cl>[F:9][C:10]1[CH:11]=[C:12]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][C:19](=[N:7][OH:8])[CH2:18][CH2:17]1
Reactant: NO
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=NO)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Sodium acetate (517 mg) and hydroxylamine hydrochloride (219 mg) are successively added to a methanol-methylene chloride solution (10--10 ml) of 1.00 g of the product of Step 2, and the mixture is stirred at room temperature for 2 days. The solvent is evaporated and the residue is dissolved in methanol, followed by addition of a silica gel (8 g). Methanol is evaporated and the residue is purified by silica gel column chromatography (solvent: chloroform/methanol=50/1-25/1) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][Si](Cl)(C)C>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)Cc1ccccc1F
Solvent: CO
Product: COC(=O)Cc1ccccc1F

Procedure:
A solution of 2-(2-fluorophenyl)acetic acid (9.6 g) in methanol (200 mL) was treated with trimethylsilyl chloride (10 mL) and the mixture heated at reflux for 2 hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution, the organic layer was dried over sodium sulphate, filtered and the solvent removed under reduced pressure to afford the subtitled compound. Yield 9.7 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1)=O.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(Cc2ccc3c(c2)NC(=O)C3)c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A 2 L, 3-necked round bottomed flask equipped with a condenser, heating mantle, overhead stirrer and a thermocouple was charged with 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (47 g, 0.19 mol) then trifluouroacetic acid (TFA, 294 mL). The initial reaction was exothermic raising the reaction temperature from 20° C. to 32° C. Triethylsilane (148 mL) was added and the reaction mixture was heated at 55° C. for 3 d. During this period, additional triethylsilane (518 mL total, by 2.5 equivalents at a time) was added until the reaction was complete by thin layer chromatographic analysis (ethylacetate/Hexanes 8:2). The thin layer chromatography plate was viewed with short wavelength UV and 12 stain. The reaction mixture was concentrated to remove the TFA and the remaining solids were washed with methyl t-butyl ether (500 mL) and THF (1 L). The solids were then suspended in water (500 mL) and saturated sodium bicarbonate (500 mL) and allowed to stir overnight. The suspension was then filtered and the solids collected were washed with water (300 mL). Subsequently the solids were dried in the vacuum oven at 40° C. to afford pure 6-(3-Amino-benzyl)-1,3-dihydro-indol-2-one in 75% yield (33.4 g, 0.14 mol).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([Br:13])[CH:11]=2)[C:6](=[O:15])[C:5]1([CH3:17])[CH3:16])(=O)C.[OH-].[Na+]>C(O)C>[Br:13][C:10]1[CH:11]=[C:12]2[C:7]([C:6](=[O:15])[C:5]([CH3:16])([CH3:17])[NH:4]2)=[CH:8][C:9]=1[F:14]
Reactant: CC(=O)N1c2cc(Br)c(F)cc2C(=O)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)Nc2cc(Br)c(F)cc2C1=O
Temperature: 90 °C
Yield: 95.5 %

Procedure:
To a mixture of 1-acetyl-6-bromo-5-fluoro-2,2-dimethylindolin-3-one (D89) (297 mg, 0.990 mmol) in ethanol (3 mL) was added 2M aqueous sodium hydroxide (0.594 mL, 1.188 mmol) and the mixture was heated at 90° C. for 1 h. After cooling to RT, ethanol was evaporated in vacuo. Aqueous residue was poured into water (10 mL) and extracted with ethyl acetate (10 mL×3). The organic layers were combined, washed with brine (10 mL), dried over MgSO4, filtered and evaporated in vacuo. The crude residue was purified by chromatography on silica, eluting with a gradient of 0-40% ethyl acetate in cyclohexane to give title compound (244.1 mg). LCMS (A): m/z (M+H)+ 258/260, C10H9BrFNO requires 257/259 (acidic).
Reaction SMILES: [CH3:1][C:2]1[N:6](COCC[Si](C)(C)C)[CH:5]=[N:4][C:3]=1[C:15]([OH:17])=O.[NH2:18][CH2:19][C:20]1[C:21]([F:37])=[C:22]([O:27][C:28]2[CH:29]=[C:30]([CH:33]=[C:34]([Cl:36])[CH:35]=2)[C:31]#[N:32])[C:23]([Cl:26])=[CH:24][CH:25]=1>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][NH:18][C:15]([C:3]2[NH:4][CH:5]=[N:6][C:2]=2[CH3:1])=[O:17])=[C:21]([F:37])[C:22]=1[O:27][C:28]1[CH:29]=[C:30]([C:31]#[N:32])[CH:33]=[C:34]([Cl:36])[CH:35]=1
Reactant: Cc1c(C(=O)O)ncn1COCC[Si](C)(C)C
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Product: Cc1nc[nH]c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Yield: 254.4 %

Procedure:
The procedure and process are similar to that described herein except that 5-methyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-4-carboxylic acid (0.077 g, 0.30 mmol) and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.093 g, 0.30 mmol) were employed to provide the title compound (0.32 g, 25% overall) as a white solid after deprotection and purification by Reverse-Phase HPLC (water:acetonitrile with 0.1% NH4OH. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.29 (br. s., 1H), 8.43 (t, J=5.84 Hz, 1H), 7.82 (s, 1H), 7.57 (s, 1H), 7.44-7.54 (m, 3H), 7.32 (t, J=7.83 Hz, 1H), 4.45 (d, J=6.04 Hz, 2H), 2.43 (s, 3H). ES-LCMS: m/z 419.0, 421.0 (M+1).
Reaction SMILES: [CH3:1][C:2]([S:7]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)(=[O:9])=[O:8])([CH3:6])[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.[C:22]([C:26]1[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1)([CH3:25])([CH3:24])[CH3:23].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl>[C:22]([C:26]1[CH:30]=[C:29]([CH2:31][NH:32][C:3](=[O:5])[C:2]([CH3:1])([S:7]([CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH3:6])[O:28][N:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1cc(CN)on1
Reactant: CC(C)(C(=O)O)S(=O)(=O)C1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1cc(CNC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Yield: 43.9 %

Procedure:
Activation of 51 mg (0.22 mmol) of 2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionic acid as the corresponding acid chloride is achieved by treatment with oxalyl chloride (0.04 mL) and DMF (1 drop) in DCM (2 mL) at room temperature for 1 h. The reaction is concentrated under reduced pressure. The crude acid chloride is dissolved in DCM (1 mL) and added dropwise to a solution of (3-tert-butyl-1,2-oxazol-5-yl)methanamine (42 mg, 80%, 0.22 mmol) and N,N-diisopropylethylamine (114 μL, 0.66 mmol) in DCM (2 mL). The reaction is concentrated under reduced pressure. The residue is purified twice by column chromatography (silica, eluent: heptanes, 0-50% ethyl acetate then DCM, 20% ethyl acetate), followed by preparative HPLC (neutral method) to give 36 mg of N-(3-tert-butyl-isoxazol-5-ylmethyl)-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide. Yield: 44%; ES-MS: m/z 373 [M+H]. Compounds in Table 4 amide method D are made according to this procedure.
Reaction SMILES: [Cl:1][C:2]1[C:10](Cl)=[CH:9][C:8]([Cl:12])=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[C:13]([OH:15])=[O:14].[OH-].[Na+]>O.[Zn]>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:12])=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1c(Cl)cc(Cl)c(Cl)c1C(=O)O
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Product: O=C(O)c1c(Cl)ccc(Cl)c1C(=O)O
Temperature: 90 °C
Yield: 97367 %

Procedure:
This compound was prepared by modifications to the literature method of J. Het. Chem., 1995, 32, 907. Zinc dust (165 g, 2.52 mmol) was added portionwise (over 15 min) to a homogenous mixture of 20 (118 g, 0.437 mmol) and NaOH (120 g) in water (1200 mL) stirred at 90° C. (bath) under a nitrogen atmosphere. The resulting heterogeneous mixture was further stirred at 95-100° C. for 5 h, then cooled to room temperature and filtered through a bed of Celite. The filter and residue was washed with water (3×100 mL), and the combined filtrate was acidified with conc. HCl (250 mL) and extracted with EtOAc (2×300 mL). The combined EtOAc solution was dried (Na2SO4), filtered and evaporated under reduced pressure to give crude 3,6-dichlorophthalic acid (100 g). Toluene (1000 mL) was added to this solid, and the mixture was distilled until the distillate was clear (after about 600 mL had been collected). The hot concentrate was gravity-filtered, and the residue was washed with hot toluene (3×50 mL). The combined filtrate was seeded and chilled to give 3,6-dichlorophthalic anhydride (21) as a colourless solid (67.0 g, 72%), m.p. 187-190° C. (lit. m.p. 188-191° C.). 1H NMR identical to literature.
Reaction SMILES: [N:1]1([C:6]2[CH:28]=[CH:27][C:9]([CH2:10][N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=S)[C:13]([C:22]([O:24]CC)=O)=[N:12]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH2:29][NH2:30]>C(O)C>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][N:11]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:14]4=[N:29][NH:30][C:22](=[O:24])[C:13]4=[N:12]3)=[CH:27][CH:28]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2ccccc2c1=S
Reactant: NN
Solvent: CCO
Product: O=c1[nH]nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)nc1-2
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
Ethyl 1-[4-(1H-pyrazol-1-yl)benzyl]-4-thioxo-1,4-dihydrocinnoline-3-carboxylate [(Example 31, Step 4) 449 mg, 1.15 mmol] was dissolved in ethanol (12.0 mL) and treated with hydrazine (0.61 mL, 19.57 mmol, 17 equiv). The mixture was stirred at 70° C. for 30 minutes then cooled to ambient temperature and concentrated in vacuo. The residue was suspended in ethyl acetate and filtered. The resulting solid was washed with dichloromethane and dried under in vacuo to afford the titled compound as a dark red powder.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[CH2:49]([N:52]([CH2:59][CH2:60][CH3:61])[CH2:53][C:54]([CH3:58])([CH3:57])[CH2:55][NH2:56])[CH2:50][CH3:51]>CN(C=O)C>[NH:13]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:8][N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:56][CH2:55][C:54]([CH3:57])([CH3:58])[CH2:53][N:52]([CH2:49][CH2:50][CH3:51])[CH2:59][CH2:60][CH3:61])=[O:20])=[CH:22][CH:23]=1)[CH2:6][C:2]1[NH:1][CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: CCCN(CCC)CC(C)(C)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCN(CCC)CC(C)(C)CNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (100 mg) obtained in Example 2-2 was dissolved in DMF (2.0 ml) and then added with DCC (55.4 mg), HOBt (36.3 mg), and the compound (50.0 mg) obtained in Example 23-3, followed by stirring overnight at room temperature. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform. Then, the solution was added with 1 mol/l hydrochloric acid to separate the solution into layers. After the aqueous layer was added with a 1 mol/l sodium hydroxide aqueous solution to make the solution basic, the solution was subjected to extraction with chloroform and the extract was then washed with saturated saline solution. Subsequently, the organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. After that, the residue was subjected to purification through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (17.5 mg) of the subject compound as a white solid.
Reaction SMILES: [CH:1]1([N:4]=[C:5]=[S:6])[CH2:3][CH2:2]1.[C:7]([O:11][C:12](=[O:25])[N:13]([C@@H:15]([CH2:23][NH2:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:14])([CH3:10])([CH3:9])[CH3:8]>ClCCl>[C:7]([O:11][C:12](=[O:25])[N:13]([C@H:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:23][NH:24][C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[S:6])[CH3:14])([CH3:10])([CH3:8])[CH3:9]
Reactant: S=C=NC1CC1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CN)Cc1ccccc1
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@@H](CNC(=S)NC1CC1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
At 0° C., cyclopropylisothiocyanate (0.32 ml) was added to a solution of N-((1R)-1-aminomethyl-2-phenylethyl)-N-methylcarbamic acid tert-butylester (410 mg, 1.6 mmol) in dichloromethane (4 ml). The reaction mixture was first stirred at 0° C. for 10 min, and successively for 2.5 h at room temperature. The solvent were removed in vacuo. The crude product was purified by flash chromatography on silica (50 g) using ethyl acetate/heptane as eluent to give 492 mg of N-((1R)1-benzyl-2-(3-cyclopropylthioureido)ethyl)-N-methylcarbamic acid tert-butylester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([OH:12])[CH:8]=[N+:7]2[O-].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([OH:12])[CH:8]=[N:7]2
Reactant: Cc1cc(Br)c2nc(O)c[n+]([O-])c2c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(Br)c2nc(O)cnc2c1
Reaction time: 1 h
Yield: 65.3 %

Procedure:
The title compound of Step C (25 g, 98 mmol) and sodium dithionite (38 g, 220 mmol) were suspended in a mixture of ethanol (1000 mL) and water (200 mL) at room temperature. After 1 h, most of the solvent was removed under reduced pressure. The residue was diluted with water and acidified with hydrochloric acid. Insolubles were removed by filtration. The filtrate was extracted twice with methylene chloride. The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure to afford the title compound of Step D as a tan/yellow solid (15.29 g, 65%). 1H NMR (CDCl3): δ2.37 (s,3H), 7.5 (d,2H), 8.15 (s, 1H), 9.8 (br s, 1H).