Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2](Cl)[C:3](=[O:22])[C:4]([NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][CH:11]=1)([CH2:6][CH3:7])[CH3:5].C(O)C.C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Pd]>[Cl:1][CH2:2][C:3](=[O:22])[C:4]([NH:8][C:9](=[O:21])[C:10]1[CH:11]=[CH:12][C:13]([N:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[CH:14][CH:15]=1)([CH2:6][CH3:7])[CH3:5]
Reactant: CCN(CC)c1ccc(C(=O)NC(C)(CC)C(=O)C(Cl)Cl)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCN(CC)c1ccc(C(=O)NC(C)(CC)C(=O)CCl)cc1
Reaction time: 3 h
Yield: 76.6 %

Procedure:
The N-(3,3-dichloro-1-ethyl-1-methyl-2-oxopropyl)-4-diethylaminobenzamide (390 mg) prepared in the previous step, 50 mL of ethanol and 75 mg of 5% palladium over charcoal were placed in a hydrogenation bottle and hydrogenated in a Parr apparatus (50 psia, room temperature) for 3 hours. The reaction mixture was filtered through celite and the solvent eliminated under reduced pressure, to yield a crude product. The crude product was dissolved in ethyl acetate and then shaken with saturated aqueous sodium bicarbonate. The phases were separated and the organic layer was dried over anhydrous magnesium sulfate. The solvent was then eliminated using a rotary evaporator, yielding 270 mg N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-diethylamino-benzamide.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][N:13]=[C:12]2[O:21][C:22]1[C:23]([F:31])=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[CH:25]2)C1C=CC=CC=1.C([O-])=O.[NH4+].O>[Pd].CN(C=O)C>[F:31][C:23]1[C:22]([O:21][C:12]2[C:11]3[C:16](=[CH:17][C:18]([O:19][CH3:20])=[C:9]([OH:8])[CH:10]=3)[N:15]=[CH:14][N:13]=2)=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][NH:27]2
Reactant: COc1cc2ncnc(Oc3ccc4[nH]ccc4c3F)c2cc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3ccc4[nH]ccc4c3F)c2cc1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 80.4 %

Procedure:
6-Benzyloxy-4-(4-fluoroindol-5-yloxy)-7-methoxyquinazoline (0.75 g, 1.8 mmol), ammonium formate (1.14 g, 18 mmol) and 10% palladium on carbon (115 mg) in DMF (8 ml) containing water (1.5 ml) was stirred at ambient temperature for 2.5 hours. The mixture was filtered over diatomaceous earth and the filtrate was evaporated. The residue was triturated under diethyl ether, filtered, washed with water, followed by diethyl ether and dried overnight over P2O5 to give 4-(4-fluoroindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (0.471 g, 80%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:13][O:12][C:11](=[O:14])[C:10]2[C:15]([CH3:35])=[C:16]([O:27][Si](C(C)(C)C)(C)C)[CH:17]=[C:18]([O:19][Si](C(C)(C)C)(C)C)[C:9]=2[CH2:8][S:7][CH2:6][C@@H:5]([C:36]([O:38][CH3:39])=[O:37])[NH:4][C:3]1=[O:40].[C:41]([O:45][C:46]([NH:48][C@H:49]([C:52](O)=[O:53])[CH2:50][OH:51])=[O:47])([CH3:44])([CH3:43])[CH3:42].Cl.CN(CCCN=C=NCC)C>C(#N)C.C(OCC)(=O)C>[C:41]([O:45][C:46]([NH:48][C@@H:49]([CH2:52][OH:53])[C:50]([NH:1][C@H:2]1[CH2:13][O:12][C:11](=[O:14])[C:10]2[C:15]([CH3:35])=[C:16]([OH:27])[CH:17]=[C:18]([OH:19])[C:9]=2[CH2:8][S:7][CH2:6][C@@H:5]([C:36]([O:38][CH3:39])=[O:37])[NH:4][C:3]1=[O:40])=[O:51])=[O:47])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c(C)c2C(=O)OC[C@H](N)C(=O)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)[C@@H]1CSCc2c(O)cc(O)c(C)c2C(=O)OC[C@H](NC(=O)[C@H](CO)NC(=O)OC(C)(C)C)C(=O)N1
Temperature: 0 °C
Reaction time: 4 h
Yield: 38.7 %

Procedure:
To a solution of 61 mg of methyl (4R, 7S)-7-amino-12,14-bis(tert-butyldimethylsilyloxy)-1,3,4,5,6,7,8,10-octahydro-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-4-carboxylate and 21 mg N-(tert-butoxycarbonyl)-L-serine in 2 ml of acetonitrile, cooled to 0° C., were added 20 mg of N-(dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride. The mixture was stirred at 0° C. for 4 hours, then diluted with 30 ml of ethyl acetate, and washed successively with 0.5N hydrochloric acid, water, 5% sodium bicarbonate solution, and with brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in 2 ml of methanol, 20 mg of ammonium fluoride were added, and the mixture was stirred for 30 minutes at room temperature. The mixture was diluted with 40 ml of ethyl acetate and washed with 30 ml of water. The organic layer was dried over sodium sulfate, and the solvent was evaporated in vacuo. The solid residue was triturated with 2 ml of ether, then hexane was added, and the white solid was isolated by filtration to give 22 mg of methyl (4R, 7S)-7-[(S)-2-(1-tert-butoxyformamido)-3-hydroxypropionylamino]-1,3,4,5,6,7,8,10-octahydro-12,14-dihydroxy-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-4-carboxylate.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C>CS(C)=O.C(OCC)(=O)C>[C:25]([O:24][C:23]([NH:22][C:20]1[N:21]=[C:16]([NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)[CH:17]=[CH:18][C:19]=1[C:30](=[O:35])[C:31]([F:32])([F:33])[F:34])=[O:29])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: CC(C)(C)OC(=O)Nc1nc(Cl)ccc1C(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1nc(NC2CCCN(C(=O)OC(C)(C)C)C2)ccc1C(=O)C(F)(F)F
Temperature: 90 °C

Procedure:
561 mg (2.8 mmol) of tert-butyl 3-aminopiperidine-1-carboxylate, 700 mg (2.16 mmol) of tert-butyl [6-chloro-3-(trifluoroacetyl)pyridin-2-yl]carbamate (Example 32A) and 0.56 ml (3.23 mmol) of diisopropylethylamine were suspended in 14 ml of DMSO and heated in a microwave reactor at 90° C. for 45 min. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous ammonium chloride solution (three times 40 ml) and then saturated aqueous sodium bicarbonate solution (40 ml). The organic phase was dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate 5:1 to 1:1). This gave 670 mg (63% of theory) of the product.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccncc1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Product: O=C(Nc1ccncc1)c1cc(N(CC2CC2)C2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidine-4-carboxylic acid (Intermediate 13) and 4-aminopyridine (Tyger), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH3:1]OC(=O)[O-].C[N+:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:13]([OH:20])(=[O:19])/[CH:14]=[CH:15]\[C:16]([OH:18])=[O:17]>>[C:13]([O-:20])(=[O:19])/[CH:14]=[CH:15]\[C:16]([O-:18])=[O:17].[CH3:1][C:10]1[CH:9]=[CH:8][NH+:7]=[CH:12][CH:11]=1.[CH3:13][C:10]1[CH:9]=[CH:8][NH+:7]=[CH:12][CH:11]=1
Reactant: C[n+]1ccccc1
Reactant: O=C(O)/C=C\C(=O)O
Reactant: COC(=O)[O-]
Product: Cc1cc[nH+]cc1
Product: O=C([O-])/C=C\C(=O)[O-]
Yield: 75.4 %

Procedure:
By following the same procedure as Example 6 except that a mixture of N-methylpyridinium methyl carbonate obtained in the 1st step of Example 4 and an equimolar amount of maleic acid were used, 4-methylpyridinium maleate was synthesized. By recrystallization, the desired product was obtained at 96.0% of the theoretical yield (yield of 75.4% to pyridine).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]2C(=O)C3=CC=CC=C3C2=O)=[CH:4][CH:3]=1.O.NN.Cl>C(O)C.ClCCl>[Br:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCOc1ccc(Br)cc1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: NCCCCOc1ccc(Br)cc1
Temperature: 80 °C
Yield: 74.5 %

Procedure:
N(4-(4-bromophenoxy)butyl)phthalimide (6.01 g, 16.1 mmol) is dissolved in ethanol (200 mL) under nitrogen, followed by the addition of hydrazine monohydrate (7.8 mL, 161 mmol). The reaction was refluxed at 80° C. for 2 hours. Once reaction completed (solids formed at the top layer), cooled reaction to room temperature and neutralized with 1M HCl (50 mL). The mixture is allowed to stir until all solids are completely dissolved and diluted with dichloromethane (150 mL). The solution was extracted with two portions of saturated NaHCO3 (2×). The organic layers were combined, washed with brine and water, then dried over MgSO4, and filtered. Removal of solvent yields a yellow oil (2.93 g, 75%).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1)=[O:27]>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][S:14]([C:11]2[CH:12]=[CH:13][C:8]([C:2]3([CH3:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]3)=[CH:9][CH:10]=2)(=[O:16])=[O:15])=[C:20]([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)=[O:27])[CH:21]=1
Reactant: Cc1cccc(C(=O)c2cc(Cl)ccc2N)n1
Reactant: CC1(c2ccc(S(=O)(=O)Cl)cc2)CCOCC1
Product: Cc1cccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C3(C)CCOCC3)cc2)n1

Procedure:
The title compound was prepared by the reacting 4-(4-methyl-tetrahydro-pyran-4-yl)-benzenesulfonyl chloride with (2-amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)-methanone according to the general procedure described for the preparation of (N-aryl-benzenesulfonamides. MS: m/z 486 (M++1).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)(=O)=O.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)=[CH:11][CH:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)OCCCCc1ccc(OCc2ccccc2)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COc2ccc(CCCCn3ccnc3)cc2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
A mixture of 4-(4-benzyloxyphenyl)butyl methane sulfonate (25.0 g), imidazole (11.2 g), potassium carbonate (15.5 g) and N,N-dimethylformamide (200 ml) was stirred for 16 hours at 80° C. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate-methanol (20:1, v/v), 1-[4-(4-benzyloxyphenyl)butyl]imidazole (14.0 g, 61%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 97-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: Nc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(S(=O)(=O)Nc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
4-Chloro-3-nitrobenzenesulfonyl chloride (460 mg, 1.8 mmol) was added to a colorless solution of aniline (250 mg, 2.7 mmol) in CH2Cl2 (10 mL) followed by pyridine (0.80 mL, 10.0 mmol). The resulting orange solution was stirred at room temperature for 30 minutes, after which time the mixture was concentrated under vacuum. Acidification with 2M aq. HCl followed by extraction using EtOAc and drying with Na2SO4 followed by filtration through a plug of silica, gave 500 mg (62%) of 4-chloro-3-nitro-N-phenylbenzenesulfonamide. 1H NMR (CDCl3) δ 8.30 (d, 1H), 7.80 (dd, 2H), 7.55 (d, 1H), 7.20 (m, 5H). MS (negESI) m/z=311(M−H+). 1-Methylhomopiperazine (258 mg, 2.3 mmol) was added to a solution of 4-chloro-3-nitro-N-phenylbenzenesulfonamide obtained as above (500 mg, 1.6 mmol) in CH2Cl2 (20 mL) followed by addition of K2CO3 (310 mg, 2.3 mmol). The reaction mixture was heated to reflux. After 2.5 h, the solution was concentrated under vacuum. After adjusting to pH=6, the product was extracted using EtOAc to give, after drying with Na2SO4 and concentration, 450 mg (72%) of 4-(4-methyl-1,4-diazepan-1-yl)-3-nitro-N-phenylbenzenesulfonamide as an orange oil. 1H NMR (CDCl3) δ 8.15 (d, 1H), 7.60 (dd, 1H), 7.15 (m), 6.95 (d, 1H), 3.45 (m, 2H), 3.30 (m, 2H), 2.75 (m, 2H), 2.60 (m, 2H), 2.35 (s, 3H), 1.95 (m, 2H). MS (posESI) m/z=391(M+H+). To a solution of 4-(4-methyl-1,4-diazepan-1-yl)-3-nitro-N-phenylbenzenesulfonamide (225 mg, 0.58 mmol) in EtOH/THF (4/1, 25 mL) activated Raney-Ni (slurry in EtOH) and hydrazine monohydrate (142 μL, 2.9 mmol) were added. After stirring for 30 minutes at room temperature, the mixture was filtered and the yellow solution concentrated to give yellow oil. The oil was dissolved in a mixture diethyl ether/EtOAc followed by addition of excess of HCl/ether. The resulting precipitate was filtered and washed with ether to give, after drying under vacuum at 40° C., 88 mg (38%) of 3-amino-4-(4-methyl-1,4-diazepan-1-yl)-N-phenylbenzenesulfonamide as a beige solid. Mp 84-85° C. MS (posESI) m/z=361 (M+H+). 1H NMR (MeOH-d3) δ 7.85 (d, 2H), 7.60 (d, 1H), 7.15 (m, 5H), 3.50 (m, 7H), 3.15 (m, 2H), 3.00 (s, 3H), 2.30 (m, 1H), 2.20 (m, 1H). Anal. (C18H24N4SO2.2HCl) C, H, N, S.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH2:4][S:5][CH3:6].[N:9]1([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:26][C:25](=[O:27])[C:24]4([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[N:23]=3)=[CH:18][CH:17]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.O>CN(C)C=O>[N:9]1([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([NH:23][C:24]3([C:25]([NH:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:27])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)=[O:26])=[CH:20][CH:21]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: CSCC[C@H](N)CO
Reactant: O=C1OC(c2ccc(CN3CCOCC3)cc2)=NC12CCCCC2
Solvent: O
Solvent: CN(C)C=O
Product: CSCC[C@@H](CO)NC(=O)C1(NC(=O)c2ccc(CN3CCOCC3)cc2)CCCCC1
Reaction time: 8 h
Yield: 48.3 %

Procedure:
43 mg (0.32 mmol) of L-methioninol was added to a solution of 100 mg (0.29 mmol) of 2-[4-(4-morpholinylmethyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in 3 ml of N,N-dimethylformamide, the mixture was stirred overnight. Water was slowly added, and the precipitated crystal was collected by filtration. The obtained crystal was dried under reduced pressure to obtain 65 mg (49%) of the title compound.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].O.[C:6]([C:8]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[CH:9][C:10](Cl)=[O:11])#[N:7]>O1CCOCC1>[C:6]([C:8]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[CH:9][C:10]([N:1]=[N+:2]=[N-:3])=[O:11])#[N:7]
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC(=CC(=O)Cl)c1cccs1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#CC(=CC(=O)N=[N+]=[N-])c1cccs1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
To a vigorously stirring suspension of NaN3 (55 g, 0.85 mol) in 1:1; dioxane:H2O (200 mL) cooled to 0° C. was added dropwise over 20 min a solution of 3-cyano-3-thiophen-2-yl-acryloyl chloride 22 (84.3 g, 0.428 mol) in dioxane (150 mL). After stirring at 0° C. for 20 min, the reaction was warmed to room temperature and stirred for 1 h. To the reaction solution was added 600 mL H2O, thus producing a precipitate which was filtered, washed with H2O and dried under vacuum to provide pure 85 g of 23.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[C:5]([OH:18])=[CH:4][CH:3]=1.[C:19]([O-])([O-])=O.[Cs+].[Cs+].ClCI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH2:19][N:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]([F:17])[C:15]=4[CH:16]=[C:8]3[C:6]=2[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Agent: ClCI
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cccc2c1cc1n2COc2ccc(Cl)nc2-1
Yield: 86.2 %

Procedure:
A solution of 6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-ol (2 g, 7.6 mmol) and Cs2CO3 (7.46 g, 22.89 mmol) in DMF (100 mL) was stirred at 100° C. (internal temperature) for 15 min, and then chloroiodomethane (2.85 g, 15.3 mmol) in DMF (2 mL) was added dropwise. After the reaction was completed, the mixture was filtered and concentrated in vacuo. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether:EA=10:1) to provide 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (1.8 g, yield: 86.1%). 1H-NMR (DMSO-d6, 400 MHz) δ 7.64 (d, J=8.8 Hz, 1H), 7.39˜7.46 (m, 2H), 7.21˜7.25 (m, 1H), 7.06 (s, 1H), 6.88˜6.92 (m, 1H), 6.18 (s, 2H). MS (M+H)+: 275/277.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1.C(=O)(O)[O-].[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C1COCC1.O>[CH2:19]([O:18][C:16]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
A solution of (R)-piperidine-3-carboxylic acid (XXVII) (5.0 g, 39 mmol) in a mixture of 50 ml of THF and 20 ml of water was cooled to 0° C. and sodium bicarbonate (6.5 g, 77.4 mmol) and benzyl chloroformate (8.0 g, 46.4 mmol) were added simultaneously. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for 3 hours and concentrated under reduced pressure. The remaining aqueous phase was extracted with ethyl ether to remove excess of benzyl chloroformate, then it was acidified with 1 M HCl solution to pH 6 followed by extraction with ethyl acetate. The organic layer was separated, dried over sodium sulfate and evaporated to provide (R)-piperidine-1,3-dicarboxylic acid 1-benzyl ester (XXVIII) (3.7 g, 36%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CN(C)C=O>[C:1]1([C:7]2[N:8]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cn2c(-c3ccccc3)cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.8 %

Procedure:
A solution of 2-phenylindole (4.2 g, 21.7 mmol) and sodium hydride (60% in oil, 0.96 g, 24 mmol) in tetrahydrofuran (90 mL) and N,N-dimethylformamide (10 mL) was stirred under ice-cooling for 20 min. To the reaction mixture was added methyl 4-bromomethylbenzoate (5.0 g, 21.8 mmol), and the mixture was stirred at room temperature for 18 hr. An aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:10-1:5-1:2) to give the title compound (2.8 g, yield 38%) as a pale-yellow oil.
Reaction SMILES: Cl[CH:2]([Cl:4])C.[F:5][C:6]([F:18])([F:17])[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12].[O:19]1CCCOO1>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4].O>[F:5][C:6]([F:18])([F:17])[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([O:19][CH2:2][Cl:4])=[O:12]
Reactant: CC(Cl)Cl
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Reactant: C1COOOC1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: O
Product: O=C(OCCl)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 10 ml of dichloroethane were added 0.93 g of zirconium tetrachloride and 1 g of 3-trifluoromethoxybenzoyl chloride, and the mixture was stirred at room temperature for 20 minutes. At 10° C., 0.15 g of trioxane was added, and the mixture was stirred for 30 minutes, and further stirred at room temperature for 1 hour. Water was added slowly under ice-cooling, the resultant solution was extracted with chloroform three times, and the organic layers were combined, washed with an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated to obtain 1 g of chloromethyl 3-trifluoromethoxybenzoate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][CH:7]([C:11](=[O:13])[CH3:12])[C:8](=[O:10])[CH3:9])[CH3:2].[CH2:15]([O:17][C:18](=[O:26])/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:16].N12CCCN=C1CCCCC2.C(O)(=O)C>N12CCCN=C1CCCCC2.C(OCC)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]([C:8](=[O:10])[CH3:9])([C:11](=[O:13])[CH3:12])[CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:26])[CH3:2]
Reactant: CCOC(=O)CCC(C(C)=O)C(C)=O
Reactant: CCOC(=O)/C=C/C(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)CCC(C(C)=O)(C(C)=O)C(CC(=O)OCC)C(=O)OCC
Reaction time: 24 h
Yield: 53.6 %

Procedure:
25.7 g of 4-acetyl-5-oxohexanoic acid ethyl ester and 0.3 g of 1,8-diazabicyclo-[5.4.0]-undec-7-ene were mixed, and 35 g of fumaric acid diethyl ester was added at room temperature over 40 minutes. After stirring for 24 hours, the amount of 1,8-diazabicyclo-[5.4.0]-undec-7-ene was doubled and stirring continued until conversion was complete. 0.5 g of acetic acid and 50 ml of diethyl ether were added, and the solution was extracted with an aqueous potassium carbonate solution and water. Fractional distillation of the dry organic layer yielded 25.6 g of 4,4-diacetyl-5-(ethoxycarbonyl)-heptanedioic acid diethyl ester (boiling point: 170° C./0.002 mbar; purity: 93%; colorless). Content of the active structural element C3O2: 18%.