Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])O.[Na+].[CH:6]1([N:12]([CH3:19])[CH2:13][CH2:14][C:15]([CH3:18])([NH2:17])[CH3:16])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C1COCC1.[C:25](ON1C(=O)CCC1=O)([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>O>[CH:6]1([N:12]([CH3:19])[CH2:13][CH2:14][C:15]([NH:17][C:25](=[O:26])[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH3:16])[CH3:18])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CN(CCC(C)(C)N)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(CCC(C)(C)NC(=O)OCc1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.9 %

Procedure:
Sodium hydrogen carbonate (15.0 g, 0.18 mol) dissolved in water (200 mL) was added to reaction containing crude N1-cyclohexyl-N1,3-dimethylbutane-1,3-diamine (14.0 g, 46.1 mmol) was dissolved into THF (200 mL). CbzOSu (11.0 g, 1 equiv, 44.2 mmol) was added in one portion to the reaction and left to stir at room temperature for 16 h. The organic solvent was removed and the aqueous residue was extracted with DCM (3×150 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil (12.7 g). The crude oil was purified on an ISCO purification system with gradient elution from 20-100% ethyl acetate then1-10% methanol in ethyl acetate. The desired fraction was collected and concentrated to give a colorless oil (5.27 g, yield: 34.4%). 1H NMR (CDCl3, 400 MHz): δ 1.0-1.49 (m, 5H), 1.37 (s, 6H), 1.55 (t, 2H), 1.6-1.64 (m, 1H), 1.76 (bs, 4H), 2.21 (s, 3H), 2.32-2.4 (m, 1H), 2.60 (t, 2H), 5.03 (s, 2H), 7.2-7.4 (m, 5H), 7.96 (s, 1H). LRMS (ESI+) for C20H32N2O2 (332.3); Found: 333 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13](/[CH:14]=[C:15]2/[C:16](=[O:21])[NH:17][C:18](=[O:20])[S:19]/2)=[CH:12][N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28]N(C)C=O.[H-].[Na+].CI>O>[CH2:1]([O:8][C:9]1[C:13](/[CH:14]=[C:15]2/[C:16](=[O:21])[N:17]([CH3:28])[C:18](=[O:20])[S:19]/2)=[CH:12][N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)/C(=C/c2cn(-c3ccccc3)nc2OCc2ccccc2)S1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN1C(=O)S/C(=C\c2cn(-c3ccccc3)nc2OCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a mixture of (5Z)-5-[(3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)methylene]-1,3-thiazolidine-2,4-dione (1.30 g) and N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 0.15 g) at 0° C. After stirring the reaction mixture at 0° C. for 30 min, methyl iodide (0.58 g) was added to the reaction mixture, and the mixture was further stirred at room temperature for 4 hrs. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration to give (5Z)-5-[(3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)methylene]-3-methyl-1,3-thiazolidine-2,4-dione as yellow crystals (1.30 g, yield 98%). Recrystallization from tetrahydrofuran-hexane gave yellow prism crystals. melting point: 226-227° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[F:11].[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH2:2][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])=[C:4]([F:11])[CH:5]=1)#[N:8]
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(C#N)cc1F)OCC
Temperature: 150 °C
Yield: 103.8 %

Procedure:
A mixture of 1.5 g (7.0 mmol) of 4-(bromomethyl)-3-fluorobenzonitrile [ref. J.Med.Chem., 40, 2064 (1997)] and 1.4 g (8.4 mmol) of triethyl phosphite was heated at 150° C. for 2 hours. At the end of this time, the reaction mixture was concentrated under reduced pressure. Volatile materials in the residue thus obtained were removed by heating said residue at 100° C. in vacuo for 1 hour to afford 1.97 g (quantitative yield) of the title compound as an oil which solidified in the freezer. This oily product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[F:9][C:10]([F:46])([F:45])[C:11]1[CH:12]=[C:13]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:14][N:15]([C:32]1[N:33]=[N:34][N:35]([CH3:37])[N:36]=1)[C@H:16]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]2[CH:23]=[C:24]([C:28]([F:31])([F:30])[F:29])[C:25]([CH3:27])=[CH:26][C:17]1=2.N1C=CC=CC=1>C(Cl)Cl>[F:45][C:10]([F:9])([F:46])[C:11]1[CH:12]=[C:13]([CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=1)[CH2:14][N:15]([C:32]1[N:33]=[N:34][N:35]([CH3:37])[N:36]=1)[C@H:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:4](=[O:5])[CH:3]([CH2:7][CH3:8])[CH2:1][CH3:2])[C:18]2[CH:23]=[C:24]([C:28]([F:29])([F:30])[F:31])[C:25]([CH3:27])=[CH:26][C:17]1=2
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: CCC(CC)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(CC)C(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc(C)c(C(F)(F)F)cc21
Reaction time: 1 h
Yield: 106.7 %

Procedure:
Add 2-ethyl-butyryl chloride (0.014 g, 0.108 mmol) dropwise under an atmosphere of nitrogen to a 0° C. cooled solution of (S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine (Example 3, Step 18) (0.060 g, 0.108 mmol) and pyridine (0.010 g, 0.108 mmol) in methylene chloride (5 mL). After stirring for 1 h, wash the reaction with saturated aqueous sodium bicarbonate solution (10 mL), 2N aqueous hydrogen chloride solution (10 mL), and brine (10 mL). Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to afford the title compound as a colorless gum (0.075 g, 98%). 1H NMR (CDCl3, 300 MHz) δ 0.71-2.16 (m, 16H), 2.34-2.43 (m, 1H), 2.43 (s, 3H), 2.50-2.41 (m, 1H), 4.14 (s, 3H), 4.25-4.67 (m, 2H), 6.89 (bs, 1H), 7.43 (s, 1H), 7.75 (s, 2H), 7.85 (s, 1H); ESI MS m/z 651 [C29H31F9N6O+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[C:9]([I:16])=[CH:8][C:3]=1[C:4](=[NH:7])[NH:5][OH:6].[CH2:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=O)=[CH:22][CH:21]=1)[CH2:18][CH3:19].ONC(=N)C1C=CC(OC(C)C)=C(I)C=1.ClC1C=C(C=CC=1OCCC)C(O)=O>>[Cl:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:14])[CH3:15])[C:9]([I:16])=[CH:8][C:3]=1[C:4]1[N:7]=[C:24]([C:23]2[CH:27]=[CH:28][C:20]([CH2:17][CH2:18][CH3:19])=[CH:21][CH:22]=2)[O:6][N:5]=1
Reactant: CCCc1ccc(C(=O)O)cc1
Reactant: CC(C)Oc1cc(Cl)c(C(=N)NO)cc1I
Agent: CC(C)Oc1ccc(C(=N)NO)cc1I
Agent: CCCOc1ccc(C(=O)O)cc1Cl
Product: CCCc1ccc(-c2nc(-c3cc(I)c(OC(C)C)cc3Cl)no2)cc1
Yield: 20 %

Procedure:
When the product of Step A and 4-propylbenzoic acid were substituted for N-hydroxy-3-iodo-4-isopropoxybenzimidamide and 3-chloro-4-propoxybenzoic acid in Example 36, Step B, the similar procedure afforded the title compound in 20% yield, as white solid. 1H NMR (CDCl3) 8.46 (s, 1H); 8.10 (d, 2H, J=8.25 Hz); 7.34 (d, 2H, J=8.28 Hz); 6.92 (s, 1H); 7.67-7.59 (m, 1H); 2.67 (t, 2H, J=7.35 Hz); 1.72-1.65 (m, 2H); 1.43 (d, 6H, J=6.06 Hz); 0.96 (t, 3H, J=7.32 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].C[CH2:15][N:16](C(C)C)[CH:17](C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CNC>CN(C=O)C.O>[CH3:15][N:16]([CH3:17])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([CH3:1])[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N(C)C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.1 %

Procedure:
To a solution of 3-methyl-4-nitrobenzoic acid (0.5 g, 2.76 mmol) in DMF (5 mL) was added DIPEA (1.06 g, 8.28 mmol), followed by HATU (1.57 g, 4.14 mmol) and dimethylamine (0.24 g, 5.52 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with water and extracted with EtOAc. The organic layer was washed with brine, then concentrated to provide crude material which was further purified by column chromatography (silica:100-200 mesh, MeOH:DCM 8-10%), to afford the title compound (0.42 g, 73.17%). LCMS (ES+) 209 (M+H)+, RT 1.92 minutes (method 3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[O:13]=[S:14]1(=[O:31])[CH2:19][CH2:18][N:17]2[CH2:20][CH2:21][CH2:22][C@@H:23]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C:16]2=[N:15]1.N1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.C(O[Cu]OC(=O)C)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:9])[C:7]=1[F:8])[O:30][C:27]1[CH:26]=[CH:25][C:24]([C@H:23]2[C:16]3=[N:15][S:14](=[O:31])(=[O:13])[CH2:19][CH2:18][N:17]3[CH2:20][CH2:21][CH2:22]2)=[CH:29][CH:28]=1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Agent: CC(=O)O[Cu]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: c1ccncc1
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(Oc4cc(F)c(F)c(F)c4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.4 %

Procedure:
A mixture of (3,4,5-trifluorophenyl)boronic acid (1882 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (1000 mg), pyridine (7.21 mL), cesium carbonate (1162 mg), diacetoxycopper (1296 mg) and powdered 4A MS (10.0 g) in MeCN (36 mL) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) then recrystallized from EtOAc to give the title compound (196 mg) as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][N:6]=[CH:7][C:8]([CH3:14])([S:10]([CH3:13])(=O)=O)[CH3:9])=[O:4].CC(SC)(C)C=NO.CN=C=O>>[CH3:1][NH:2][C:3]([O:5][N:6]=[CH:7][C:8]([CH3:14])([S:10][CH3:13])[CH3:9])=[O:4]
Reactant: CNC(=O)ON=CC(C)(C)S(C)(=O)=O
Agent: CN=C=O
Agent: CSC(C)(C)C=NO
Product: CNC(=O)ON=CC(C)(C)SC

Procedure:
This invention relates to a process for preparing 2-methyl-2-(methylsulfonyl) propionaldehyde O-(methylcarbamoyl) oxime (aldoxycarb) as an agueous wet cake by reacting 2-methyl-2-(methylthio) propionaldehyde oxime (aldicarb oxime) with methyl isocyanate in an aqueous medium to give 2-methyl-2-(methylthio) propionaldehyde O-(methylcarbamoyl) oxime (aldicarb) which is then oxidized in an agueous medium to give 2-methyl-2-(methylsulfonyl) propionaldehyde O-(methylcarbamoyl) oxime. This invention also relates to an agueous wet cake composition containing 2-methyl-2-(methylsulfonyl) propionaldehyde O-(methylcarbamoyl) oxime.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].C(N(CC)CC)C>C(O)CCC>[NH2:1][C:2]1[C:3]([NH:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[F:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: NCc1ccccc1F
Reactant: Nc1cnc(Cl)nc1Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Nc1cnc(Cl)nc1NCc1ccccc1F
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g (3.1 mmol) of 5-amino-2,4-dichloropyrimidine [D. T. Hurst, Heterocycl. 22, 79 (1984)], 0.35 ml (3.1 mmol) of 2-fluorobenzylamine and 0.46 ml (3.4 mmol) of triethylamine in 8 ml of 1-butanol is heated under reflux for 24 hours. The reaction mixture is then cooled to 0°. The resulting beige-coloured suspension is filtered with suction and the filter cake is washed with cyclohexane and suspended in water for 30 minutes at room temperature with stirring. The suspension is again filtered with suction and the filter cake is dried under a high vacuum at 100° over tetraphosphorus decaoxide. In this manner 5-amino-2-chloro-4-[N-(2-fluorobenzyl)amino]-pyrimidine is obtained in the form of beige-coloured crystals having a melting range of from 224° to 225°.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:5][CH3:6].[CH3:16]I.Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([C:7]1[N:8]([CH3:16])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:5][CH3:6]
Reactant: CI
Reactant: CCCCc1cc2ccccc2[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 105.3 %

Procedure:
Sodium hydride (60% oil disperson; 1.52 g, 38.0 mmol) was added under nitrogen in portions over 5 minutes to a solution of 2-butyl-1H-indole (5.00 g, 28.9 mmol) in 150 mL of anhydrous DMF at room temperature. After the addition the reaction was stirred at room temperature for 1.25 h. Methyl iodide (3.60 mL, 57.8 mmol) was then added and the reaction stirred at room temperature for 3.5 h. 1 N HCl was added to the reaction until the evolution of gas ceased. The reaction was diluted with ethyl acetate, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 2-butyl-1-methyl-1H-indole (5.70 g, 100%) as a yellow oil, MS m/z: 188 [M+H]+.
Reaction SMILES: [ClH:1].NC1NC2C=C(N3C(=O)C=CC3=O)C=CC=2N=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[N:27]=[C:26]([N:28](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[N:25](C(OC(C)(C)C)=O)[C:24]=2[CH:50]=1.[CH3:51][C:52]1([CH3:60])[CH2:57][C:56](=[O:58])[O:55][C:54](=O)[CH2:53]1>>[ClH:1].[NH2:28][C:26]1[NH:25][C:24]2[CH:50]=[C:20]([N:19]3[C:54](=[O:55])[CH2:53][C:52]([CH3:60])([CH3:51])[CH2:57][C:56]3=[O:58])[CH:21]=[CH:22][C:23]=2[N:27]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2ccc(N)cc2n1C(=O)OC(C)(C)C
Reactant: CC1(C)CC(=O)OC(=O)C1
Agent: Cl
Agent: Nc1nc2ccc(N3C(=O)C=CC3=O)cc2[nH]1
Product: CC1(C)CC(=O)N(c2ccc3nc(N)[nH]c3c2)C(=O)C1
Yield: 98 %

Procedure:
Following the same procedure to synthesize 1-(2-amino-1H-benzo[d]imidazol-6-yl)-1H-pyrrole-2,5-dione hydrochloride, tert-butyl 6-amino-2-(bis(tert-butoxycarbonyl)amino)-1H-benzo[d]imidazole-1-carboxylate (0.300 g, 0.669 mmol) was reacted with 4,4-dimethyldihydro-2H-pyran-2,6(3H)-dione (0.095 g, 0.669 mmol) to give the title product (0.202 g, 98% yield) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.86 (s, 1H), δ 7.28 (s, 2H), δ 2.49 (s, 2H), δ 2.39 (s, 2H), δ 1.15 (s, 6H) ppm; 13C NMR (75 MHz, CD3OD) 174.8, 171.7, 151.2, 134.9, 129.8, 126.1, 116.4, 111.3, 103.8, 45.4, 33.1, 27.2 ppm; HRMS (ESI) Calcd for C14H16N4O2 (M+) 272.1273. Found 272.1282.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22]([OH:27])[CH2:23][CH2:24][C:25]\3=[CH2:26])/[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].C(N(CC)C(C)C)(C)C.Cl[CH2:39][O:40][CH3:41].[Cl-].[NH4+]>ClCCl>[CH3:39][O:40][CH2:41][O:27][CH:22]1[CH2:23][CH2:24][C@@:25]2([CH3:26])[C:20](=[CH:19][CH:18]=[C:17]3[C@@H:16]2[CH2:15][CH2:14][C@@:13]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8])[CH2:21]1
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]12
Reactant: COCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOC1CC[C@@]2(C)C(=CC=C3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.2 %

Procedure:
In dichloromethane (45 mL), 7-dehydrocholesterol (2.0 g, 5.2 mmol) was dissolved, then N,N-diisopropylethylamine (2.70 mL, 15.6 mmol) and chloromethylmethylether (1.00 mL, 13.2 mmol) were sequentially added under ice-cooling, followed by stirring at room temperature for 20 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate (100 mL×2). The organic layer was washed with dilute aqueous hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated to yied a residue. To the residue, methanol was added to triturate to obtain the title compound (1.9 g, 83%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH3:14])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])(C)(C)C.[C:16]([OH:22])([C:18]([F:21])([F:20])[F:19])=[O:17]>C(Cl)Cl>[F:19][C:18]([F:21])([F:20])[C:16]([OH:22])=[O:17].[CH3:14][C@@H:8]([NH2:7])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: C[C@H](CC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)CC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ((R)-1,3,3-trimethyl-butyl)-carbamic acid tert-butyl ester (35 mg, 0.163 mmol) in CH2Cl2 (1 mL) was added TFA (0.125 mL, 1.625 mmol). The reaction mixture was stirred at RT for 2 h and concentrated to give the desired material which was used without further purification in the next step. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.66 (bs, 3H), 3.25 (m, 1H), 1.50 (dd, 1H), 1.38 (dd, 1H), 1.23 (d, 3H), 0.93 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:43][O:44][NH:45][CH3:46]>CN(C=O)C>[CH3:43][O:44][N:45]([CH3:46])[C:8]([C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: Nc1nccnc1C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1nccnc1N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-aminopyrazine-2-carboxylic acid (1 g, 7.2 mmol) in DMF (15 ml) is added EDC hydrochloride (1.7 g, 8.6 mmol), HOBt (1.16 g, 8.6 mmol), diisopropylethylamine (3.08 ml, 18 mmol) and N-methoxy-N-methylamine hydrochloride (0.84 g, 8.6 mmol), and the resulting solution is stirred at room temperature for 15 hours. The reaction is concentrated in vacuo, and sat. aq. NaHCO3 (50 ml) is added to the residue. The product is extracted into EtOAc (3×60 ml), washed with sat. aq. NaCl (2×50 ml), dried (MgSO4) and concentrated in vacuo to afford a yellow residue. Purification by flash chromatography (SiO2, 0-5% MeOH in DCM) yields 3-amino-pyrazine-2-carboxylic acid methoxy-methylamide as a yellow solid.
Reaction SMILES: [N:1]1([C:6]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:22]([O:24][C:25]([O:27][C:28]1[CH:38]=[CH:37][C:31]([CH:32]=[CH:33][C:34](Cl)=[O:35])=[CH:30][CH:29]=1)=[O:26])[CH3:23]>C(Cl)(Cl)Cl>[CH2:22]([O:24][C:25]([O:27][C:28]1[CH:29]=[CH:30][C:31]([CH:32]=[CH:33][C:34]([N:12]2[CH2:11][CH2:10][N:9]([CH2:8][C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[O:7])[CH2:14][CH2:13]2)=[O:35])=[CH:37][CH:38]=1)=[O:26])[CH3:23]
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: CCOC(=O)Oc1ccc(C=CC(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Oc1ccc(C=CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cc1
Yield: 54 %

Procedure:
In 140 ml of chloroform were dissolved 17.7 g of 1-(pyrrolidinocarbonylmethyl)piperazine and 8.4 ml of triethylamine. To the solution was added 15.2 g of 4-(ethoxycarbonyloxy)cinnamoylchloride with ice-cooling, followed by stirring the resultant mixture overnight at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and dissolved in ethyl acetate. Any insoluble matter was removed by filtration, and the filtrate was extracted with 140 ml of 1N-hydrochloric acid. The extract was washed with ethyl acetate, neutralized with sodium bicarbonate and then extracted with chloroform. The chloroform layer was successively washed with water and then with brine. The layer was then dried and subjected to distillation to remove the solvent. The resultant crystals were recrystallized from ethyl acetate, thereby obtaining 13.4 g (yield: 54.0%) of 1-[4-(ethoxycarbonyloxy)cinnamoyl]-4-(pyrrolidinocarbonylmethyl)piperazine as crystals having a melting point of 128°-130° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N+:16]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([O-:18])=[O:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>COCC(O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[NH:23][C:22]1[CH:24]=[CH:25][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCC(C)O
Product: COc1cc2nccc(Nc3ccc([N+](=O)[O-])cc3)c2cc1OC
Temperature: 25 °C
Yield: 73 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (0.40 g, 1.79 mmol, p-nitroaniline (0.414 g, 2.68 mmol) and p-toluenesulfonic acid (0.154 g, 0.894 mmol) in 1-methoxy-2-propanol (5 mL) were heated to 120° C. for 8 h. The mixture was cooled to rt, triturated with ether and filtered to yield (6,7-dimethoxyquinolin-4-yl)-(4-nitrophenyl)amine (0.43 g, 73%). LCMS m/z=326 (M+1); 1H NMR (DMSO) δ: 14.37 (s, 1H), 10.72 (s, 1H), 8.54 (d, 1H, J=6.80 Hz), 8.39 (d, 2H, J=9.08 Hz), 8.05 (s, 1H), 7.74 (d, 2H, J=9.09 Hz), 7.47 (d, 1H, 8.13 Hz), 7.43 (s, 1H), 7.19 (d, 1H, J=6.85), 7.10 (d, 1H, J=7.84), 4.02 (d, 7H, J=5.48), 2.28, (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[N:14]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:17]1[CH:18]=[CH:13][N:14]=[C:15]([NH:19][CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[N:16]=1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: Fc1cc(F)c2[nH]ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4c(F)cc(F)cc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared as described in Example 215, starting from SEM-protected 5,7-difluoro-1H-indole and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by cleavage of the SEM-protecting group with TBAF. Yield: 260 mg (63%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[CH2:15]([O:12][C:11]1[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cnc(Cl)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(Cl)c(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
To a solution of methyl 6-chloro-5-hydroxynicotinate (10.5 g) in DMF (80 mL) was added 60% sodium hydride (2.80 g) at 0° C., and the mixture was stirred at 0° C. for 0.5 hr. Benzyl bromide (10.5 g) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was poured into water, and the precipitate was collected by filtration. The crude crystals were purified by silica gel column chromatography (petroleum ether/THF) to give the title compound (6.00 g) as a white solid.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)=O)C.[CH3:27][NH:28][NH:29][CH3:30]>C1(C)C=CC=CC=1.O>[CH3:17][S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:29]([CH3:30])[N:28]([CH3:27])[C:4](=[O:3])[C:5]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: CCOC(=O)C(C(=O)c1ccc(S(C)(=O)=O)cc1)c1ccc(OC)cc1
Reactant: CNNC
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2c(-c3ccc(S(C)(=O)=O)cc3)n(C)n(C)c2=O)cc1
Temperature: 120 °C
Yield: 53 %

Procedure:
3-(4-methanesulfonylphenyl)-2-(4-methoxyphenyl)-3-oxo-propionic acid ethyl ester was dissoved in 20 ml of toluene and then 0.24 g of dimethyl hydrazine was added to the solution. The apparatus containing the mixture was heated and refluxed at 120° C. for 24 hours in the Dean-Stark trap apparatus. The reaction mixture was cooled, diluted with water, and extracted with ethyl acetate. The obtained organic layer was dried on anhydrous magnesium sulfate and concentrated under reduced pressure. The resultant was recrystalized with n-hexane to give 160 mg of the title compound as a yellow solid(yield 53%).