Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Br:23])[N:10]=[C:9]([C:24](=O)[NH2:25])[C:8]=1[S:27]([CH3:30])(=[O:29])=[O:28]>O>[NH2:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:21])([F:22])[F:20])=[CH:14][C:13]=2[Br:23])[N:10]=[C:9]([C:24]#[N:25])[C:8]=1[S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)c1c(C(N)=O)nn(-c2c(Cl)cc(C(F)(F)F)cc2Br)c1N
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CS(=O)(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Br)c1N
Reaction time: 8 h

Procedure:
Phosphorus oxychloride (20 ml) was added to 5-amino-1-(2-bromo-6-chloro-4-trifluoromethylphenyl)-3-carbamoyl-4-methanesulphonylpyrazole (4.0 g) and the solution heated at 50°-60° C. for 3.25 hours, and left at room temperature overnight. The mixture was cautiously added to vigorously stirred water (200 ml), and the precipitated solid collected and dried in vacuo. Recrystallisation from toluene/ethanol gave 5-amino-1-(2-bromo-6-chloro-4-trifluoromethylphenyl)-3-cyano-4-methanesulphonylpyrazole as buff crystals, m.p. 235°-238° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:13]=[CH:14][C:15]([C:30]([F:33])([F:32])[F:31])([OH:29])[CH2:16][C:17]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[O:27][CH3:28])([CH3:19])[CH3:18])[N:4]=1)[CH3:2].[BH4-].[Na+].O>CO>[CH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:13][CH2:14][C:15]([C:30]([F:31])([F:32])[F:33])([OH:29])[CH2:16][C:17]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[O:27][CH3:28])([CH3:19])[CH3:18])[N:4]=1)[CH3:2]
Reactant: CCc1ccc2c(N=CC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCc1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Reaction time: 2 h

Procedure:
600 mg (1.3 mmol) of 1-(2-ethylquinolin-5-ylimino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol in 5.0 ml of methanol is mixed at 0° C. with 197 mg (5.2 mmol) of sodium borohydride. After 2 hours at room temperature, water is added, and methanol is removed in a vacuum. The aqueous phase is extracted with dichloromethane, the combined organic phases are dried on sodium sulfate, and the solvent is removed in a vacuum. After purification on silica gel with hexane-ethyl acetate (0-100%), 400 mg (66% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[CH2:8]([NH:15][C:16]([C:18]1[S:22][C:21]([NH2:23])=[N:20][C:19]=1[CH3:24])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([NH:15][C:16]([C:18]1[S:22][C:21]([NH:23][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[N:20][C:19]=1[CH3:24])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)C(C)(C)C)sc1C(=O)NCc1ccccc1
Yield: 23 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 2,2-dimethylpropionyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 23% yield; 1H NMR (CDCl3, 300 MHz) δ 8.85 (s, br, 1H), 7.36-7.25 (m, 5H), 5.91 (s, br, 1H), 4.56 (d, J=5.8 Hz, 2H), 2.60 (s, 3H), 1.27 (s, 9H); MS (ES+) m/z 332.0 (M+1).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.O=[C:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:31])[C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)=[CH:22][CH:21]=2)[CH2:15][CH2:14]1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH2:41])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH:41][CH:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:31])[C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH:30]=[N:29][CH:28]=[N:27]4)=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:35][CH:34]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: O=C1CCN(C(=O)c2ccc(-n3cncn3)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-n2cncn2)cc1)N1CCC(NCCc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A catalytic amount of p-toluenesulfonic acid was added to a solution of 0.45 g of 4-oxo-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine and 0.39 g of 2-(4-chlorophenyl)ethylamine in 10 ml of toluene. The mixture was refluxed by heating, for 5 hours while removing the generated water using a Dean-Stark trap. The reaction mixture was concentrated under reduced pressure. To the residue was added 10 ml of ethanol. Thereto was added 70 mg of sodium borohydride at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was made acidic with cocentrated hydrochloric acid and then concentrated under reduced pressure. To the residue was added ice water. The mixture was made basic with an aqueous sodium hydroxide solution and extracted with two 30-ml portions of ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution in this order, dried with sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluant: methylene chloride/methanol=25/1) and then recrystallized from ethyl acetate to obtain 4-[2-(4-chlorophenyl)ethylamino]-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine as a white powder.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:22][CH:23]([OH:25])[CH3:24])=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[NH:5][CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1C=CN=C1.[C:31]([Si:35]([CH3:38])([CH3:37])Cl)([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[F:1][C:2]1[C:3]([CH2:22][CH:23]([O:25][Si:35]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:38])[CH3:37])[CH3:24])=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[NH:5][CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C(=CNc1ccc(F)c(F)c1CC(C)O)C(=O)OCC
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCOC(=O)C(=CNc1ccc(F)c(F)c1CC(C)O[Si](C)(C)C(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76 %

Procedure:
14.2 g (40 mmol) of the compound (151) and 3.27 g (48 mmol) of imidazole were added to 100 ml of methylene chloride, and 20 ml of methylene chloride containing 7.23 g (48 mmol) of t-butyldimethylchlorosilane was dropped to the solution through 30 minutes. After the solution was stirred for 2.5 hours at room temperature, it was heated at reflux for 2 hours. 3.27 g of imidazole and 7.23 g of t-butyldimethylehlorosilane were supplemented to the solution, and the solution was heated at reflux for 11 hours. The solution was washed 100 ml of water, 50 ml of aqueous 5% citric acid solution and 50 ml of saturated aqueous sodium hydrogen carbonate solution in this order, and after drying over magnesium sulfate, the solvent was removed by distillation. The solid matter was separated by column chromatography (silica gel 600 g, eluent solvent; chloroform:n-hexane=1:1) to obtain 14.2 g of an oily subject compound (152) in a 76% yield.
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9](=[O:14])[CH2:10][CH2:11][O:12][CH3:13])([CH3:7])[CH2:3][C:4](=O)[CH3:5].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.Cl([O-])(=O)(=O)=O.C[NH2+]C>[Pt]=O>[CH3:1][C:2]([NH:8][C:9](=[O:14])[CH2:10][CH2:11][O:12][CH3:13])([CH3:7])[CH2:3][CH:4]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH3:5]
Reactant: COCCC(=O)NC(C)(C)CC(C)=O
Reactant: C1CCNCC1
Agent: O=[Pt]
Agent: C[NH2+]C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: COCCC(=O)NC(C)(C)CC(C)N1CCCCC1

Procedure:
Following the procedure of Example 4, a mixture of 201 parts (1 mole) of N-(1,1-dimethyl-3-oxobutyl)-3-methoxypropionamide, 170 parts (2 moles) of piperidine, 0.5 part of platinum oxide and 1 part of dimethylammonium perchlorate is hydrogenated in the Parr apparatus, starting at a pressure of 70 psi. and recharging when the pressure has reached 39 psi. After workup as described in Example 4, the desired product, N-(1,1-dimethyl-3-piperidinobutyl)-3-methoxypropionamide, is obtained boiling at 112°-115° C./0.25 mm.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19].Cl>C(Cl)Cl>[Cl:10][C:11]1[C:12]([CH3:19])=[CH:13][C:14]([O:17][CH3:18])=[C:15]([C:5](=[O:8])[CH2:6][CH3:7])[CH:16]=1
Reactant: COc1ccc(Cl)c(C)c1
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1cc(Cl)c(C)cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 54.1 %

Procedure:
A suspension of 2.55 g of AlCl3 in 30 ml of DCM is cooled to 0° C. under a nitrogen atmosphere, and a solution of 1.77 g of propionyl chloride in 15 ml of DCM is added dropwise. A solution of 3 g of 2-chloro-5-methoxytoluene in 15 ml of DCM is then added dropwise, and the reaction mixture is left stirring for 2 hours. It is poured into a mixture of concentrated HCl and ice, the organic phase is extracted with DCM and dried over magnesium sulphate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica, eluting with a DCM/heptane (70:30; v/v) mixture. 2.2 g of the expected product, m.p.=79° C., are obtained.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][C@@H:20]1[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.O1CCCC1.O>[C:11]([O:15][C:16]([NH:18][C@@H:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][C@@H:20]1[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(O)CC[C@H]1NC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC(=O)CC[C@H]1NC(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
Dimethylsulfoxide (6.8 ml) was added to a solution of oxalyl chloride (8.2 ml) in dichloromethane (100 ml) at −60° C., and a solution of (1R*,2S*)-N1,N2-bis(tert-butoxycarbonyl)-4-hydroxy-1,2-cyclohexanediamine (mixture of stereoisomers) (6.32 g) in tetrahydrofuran (80 ml) was added at a time, and the mixture was stirred for 1 hour. The temperature of the mixture was raised to −40° C., and triethylamine (21 ml) was added. The mixture was heated to room temperature. After 3 hours, the reaction mixture was poured into water and extracted with dichloromethane. The resultant organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1) to obtain the title compound (3.8 g) as a pale yellow solid.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[C:18]([NH2:22])(=[O:21])[CH:19]=[CH2:20]>O>[S:1]=[C:2]1[N:6]([CH2:20][CH2:19][C:18]([NH2:22])=[O:21])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3]1
Reactant: C=CC(N)=O
Reactant: Sc1nc2ccccc2s1
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=O)CCn1c(=S)sc2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
To a stirred solution at 50° C. containing 86 g (0.5 mol) of 2-mercaptobenzothiazole, 60.8 g (0.6 mol) of triethylamine and 500 ml of water, 43 g (0.6 mol) of acrylamide was added in one portion. After stirring at 60°-70° C. for 24 hours, the stirred reaction mixture was cooled to 25° C., the solid collected by filtration, washed with water until neutral and air-dried at 50° C. The product, 2-thioxo-3(2H)-benzothiazolepropanamide, mp 226°-227° C. was obtained in 77% yield.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[CH:20][C:15]4=[N:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:24]([O:31][NH2:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31]/[N:32]=[C:21](/[C:18]1[CH:19]=[CH:20][C:15]2[N:16]([C:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[N:13][N:14]=2)[N:17]=1)\[CH3:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Reactant: NOCc1ccccc1
Product: C/C(=N\OCc1ccccc1)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1

Procedure:
The title compound was prepared from 1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (41.2) and O-benzylhydroxylamine (intermediate H) using the same procedure described in the synthesis of example 41. 1H-NMR (400 MHz, CHCl3-d1) δ ppm 8.87 (d, 1H), 8.06 (m, 2H), 7.95 (d, 1H), 7.84 (s, 1H), 7.80 (m, 2H), 7.38 (m, 6H), 5.30 (s, 2H), 4.77 (s, 2H), 2.32 (s, 3H). LC-MS (method J): [MH]+=409.1, tR=2.42 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH3:16][O:17][C:18]1[CH:62]=[C:61]([O:63][CH3:64])[CH:60]=[C:59]([O:65][CH3:66])[C:19]=1[CH:20]=[CH:21][CH:22]([S:32]([CH:35]([CH:45]=[CH:46][C:47]1[C:52]([O:53][CH3:54])=[CH:51][C:50]([O:55][CH3:56])=[CH:49][C:48]=1[O:57][CH3:58])[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([NH2:44])[CH:37]=1)(=[O:34])=[O:33])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([NH2:31])[CH:24]=1>O1CCCC1>[CH3:66][O:65][C:59]1[CH:60]=[C:61]([O:63][CH3:64])[CH:62]=[C:18]([O:17][CH3:16])[C:19]=1/[CH:20]=[CH:21]/[CH:22]([S:32]([CH:35](/[CH:45]=[CH:46]/[C:47]1[C:48]([O:57][CH3:58])=[CH:49][C:50]([O:55][CH3:56])=[CH:51][C:52]=1[O:53][CH3:54])[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([NH:44][C:7](=[O:8])[C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=2)[CH:37]=1)(=[O:34])=[O:33])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([NH:31][C:7](=[O:8])[C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=2)[CH:24]=1
Reactant: COc1cc(OC)c(C=CC(c2ccc(OC)c(N)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)c2)c(OC)c1
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 3,5-dinitrobenzoyl chloride (10 mmol) in tetrahydrofuran (40 mL) was added drop wise a solution of 2,4,6-trimethoxystyryl-3-amino-4-methoxybenzylsulfone (10 mmol) in tetrahydrofuran. The solution was stirred overnight and the completion of the reaction was monitored by TLC. The solvent was removed and the residue was taken up in dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated to give (E)-2,4,6-trimethoxystyryl-3-(3,5-dinitrobenzamido)-4-methoxybenzylsulfone in 80% yield (m.p. 277-279° C.). NMR (DMSO-d6) δ 3.80 (s, 3H), 3.82(s, 6H), 3.86(s, 3H), 4.35(s, 2H), 6.3(s, 2H), 7.15-9.1(m, aromatic+vinylic), 9.8(s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.[H-].[Na+].I[CH2:13][CH2:14][CH2:15][CH3:16]>CN(C=O)C>[CH2:13]([N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]1=[O:9])[CH2:14][CH2:15][CH3:16]
Reactant: COc1ccc[nH]c1=O
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1cccc(OC)c1=O
Reaction time: 0.33 h
Yield: 92.5 %

Procedure:
To a solution of 3-methoxy-2(1H)-pyridone (2-034-01) (5.0 g) in DMF (40 mL) was added sodium hydride (60% wt, 2.2 g) at room temperature. After the reaction mixture was stirred for 20 min, 1-iodobutane (15.5 g) was added to the reaction mixture, and the reaction mixture was stirred for 40 min. After the reaction was quenched with water, the solvent was removed. To the residue were added a saturated aqueous solution of ammonium chloride and ethyl acetate, and the organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed water and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (toluene/acetone=4/1) to give 1-butyl-3-methoxy-2-pyridone (2-034-02) (6.7 g, 93%) as an oil.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[NH:10][C:9](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH3:25])[C:4]1=[O:5])[CH3:2].[C:26](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:26])[C:9](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH3:25])[C:4]1=[O:5])[CH3:2]
Reactant: CCn1c(=O)c2[nH]c(/C=C/c3cccc(OC)c3)nc2n(CC)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCn1c(=O)c2c(nc(/C=C/c3cccc(OC)c3)n2C)n(CC)c1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
Compound r (1.70 g, 5.0 mmol) obtained in Reference Example 17 was dissolved in 40 ml of dimethylformamide. To the solution were added 1.73 g (12.5 mmol) of potassium carbonate and subsequently 0.62 ml (10.0 mmol) of methyl iodide, and the resulting mixture was stirred at 50° C. for 30 minutes. After cooling, insoluble matters were filtered off, and 100 ml of water was added to the filtrate. The mixture was extracted three times with 50 ml of chloroform. The extract was washed twice with water and once with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The obtained crude crystals were purified by silica gel column chromatography (eluent: 40% ethyl acetate/hexane), followed by recrystallization from cyclohexane/toluene to give 1.10 g (yield 62%) of Compound s as pale yellow needles.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][N:7]([CH3:13])[C:6]=2[CH:14]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:33][CH2:34][C@@H:35]1[CH2:39][CH2:38][CH2:37][N:36]1[CH2:40][CH2:41][CH2:42][CH3:43]>O1CCCC1.CN(C)C=O>[CH2:40]([N:36]1[CH2:37][CH2:38][CH2:39][C@H:35]1[CH2:34][NH:33][C:15]([C:4]1[C:5]2[O:10][C:9]([CH3:11])([CH3:12])[CH2:8][N:7]([CH3:13])[C:6]=2[CH:14]=[C:2]([Cl:1])[CH:3]=1)=[O:17])[CH2:41][CH2:42][CH3:43]
Reactant: CCCCN1CCC[C@H]1CN
Reactant: CN1CC(C)(C)Oc2c(C(=O)O)cc(Cl)cc21
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCCN1CCC[C@H]1CNC(=O)c1cc(Cl)cc2c1OC(C)(C)CN2C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1.03 g of 6-chloro-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid in a mixed solvent of 5 ml of dimethylformamide and 10 ml of tetrahydrofuran was added 0.6 g N-methylmorpholine, and 0.55 g of isobutyl chloroformate was added dropwise thereto at -10° to -5° C. under ice-cooling. After stirring for 20 minutes at the same temperature, 0.63 g of (S)-(-)-2-aminomethyl-1-butylpyrrolidine was added at -10° to -5° C. and the mixture was stirred at room temperature for three hours. The resultant mixture was concentrated under reduced pressure, and to the residue were added an aqueous potassium carbonate solution and ethyl acetate. The organic layer was separated and washed with water and then dried over magnesium sulfate. The solvent was distilled off and the residue was recrystallized from isopropyl ether to give (S)-N-[(1-butyl-2-pyrrolidinyl)methyl]-6-chloro-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide as white crystals, melting at 110° to 112° C. [α]D =-61.7° (c=1, methanol)
Reaction SMILES: [CH2:1]([OH:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H-].[Na+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](F)[N:11]=1>CS(C)=O>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[N:11]=1
Reactant: Fc1cccc(F)n1
Reactant: CC(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)COc1cccc(F)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.8 %

Procedure:
A solution of neopentyl alcohol (1.065 mL, 9.81 mmol) in DMSO (82 mL) was cooled to 0° C. NaH (60% in mineral oil; 0.490 g, 12.26 mmol) were added in one portion, the reaction mixture was warmed to rt and stirred for 20 minutes. 2,6-Difluoropyridine (0.941 mL, 8.175 mmol) was added and the reaction mixture was stirred at overnight. The reaction mixture was quenched with aqueous, saturated ammonium chloride solution, diluted with water and EtOAc. The organic layer was separated, washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford 2-fluoro-6-(neopentyloxy)pyridine (1.48 g, 8.08 mmol) as a colorless liquid.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:13](OC(C)C)=[O:14])[C:7]=2[CH:6]=[CH:5]1)([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>[O-2].[O-2].[Mn+4]>[CH:1]([N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([CH:13]=[O:14])[C:7]=2[CH:6]=[CH:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1cccc2c1ccn2C(C)C
Agent: [Mn+4]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CC(C)n1ccc2c(C=O)cccc21

Procedure:
Isopropyl 1-isopropylindole-4-carboxylate (2.6 g) was reduced by diisobutyl aluminum hydride, followed by oxidation with manganese dioxide, whereby the title compound was obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@@H:40]2[NH:49][CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33].[C:52]([O:56][C:57](=[O:66])[CH2:58][C@@H:59]1[CH2:62][C@H:61]([C:63](O)=[O:64])[CH2:60]1)([CH3:55])([CH3:54])[CH3:53].CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:36][C:30]1[CH:29]=[C:28]([NH:37][C:38]([C@@H:40]2[N:49]([C:63]([C@@H:61]3[CH2:60][C@H:59]([CH2:58][C:57]([O:56][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:66])[CH2:62]3)=[O:64])[CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:27]=[C:26]([F:25])[C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: COc1ccc2c(n1)CCN[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HATU (107 mg, 0.28 mmol) was added to a solution of (R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide (100 mg, 0.26 mmol), cis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (60.2 mg, 0.28 mmol) and DIEA (0.050 mL, 0.28 mmol) in DMF (2 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give tert-butyl 2-(cis-3-((R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclobutyl)acetate (100 mg, 0.170 mmol, 66.6%) as a colorless oil.