Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].[CH3:25][NH:26][C:27]([C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32])=[O:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:20])[NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[C:29]([C:27](=[O:28])[NH:26][CH3:25])[CH:30]=3)=[CH:16][CH:17]=2)=[O:10])=[CH:4][C:3]=1[C:21]([F:23])([F:24])[F:22]
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNC(=O)c1cccc(N)c1
Product: CNC(=O)c1cccc(NC(=O)c2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)c1

Procedure:
Entry 67: N-(4-Chloro-3-(trifluoromethyl)phenyl-N′-(4-ethoxycarbonylphenyl)urea was synthesized according to Method C1e. N-(4-Chloro-3-(trifluoromethyl)phenyl-N′-(4-ethoxycarbonylphenyl)urea was saponified according to Method D3 to give N-(4-chloro-3-(trifluoromethyl)phenyl-N′-(4-carboxyphenyl)urea. N-(4-Chloro-3-(trifluoromethyl)phenyl-N′-(4-carboxyphenyl)urea was coupled with 3-methylcarbamoylaniline according to Method D1b to give N-(4-chloro-3-(trifluoromethyl)phenyl-N′-(4-(3-methylcarbamoylphenyl)carbamoylphenyl)urea.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7](=S)[NH:8][C@@H:9]([CH3:14])[C:10]([F:13])([F:12])[F:11])[S:5][CH:6]=1.O.[NH2:17][NH2:18]>>[Br:1][C:2]1[N:3]=[C:4]([C:7](=[N:17][NH2:18])[NH:8][C@@H:9]([CH3:14])[C:10]([F:13])([F:12])[F:11])[S:5][CH:6]=1
Reactant: NN
Reactant: C[C@H](NC(=S)c1nc(Br)cs1)C(F)(F)F
Solvent: O
Product: C[C@H](NC(=NN)c1nc(Br)cs1)C(F)(F)F

Procedure:
To a solution of (S)-4-bromo-N-(1,1,1-trifluoropropan-2-yl)thiazole-2-carbothioamide (46 g, 1.0 eq.) was added hydrazine hydrate (15 g, 2.0 eq.). It was refluxed overnight. TLC and LCMS showed the reaction was complete. It was concentrated and the residue was purified by a flash column to obtain (S)-4-bromo-N-(1,1,1-trifluoropropan-2-yl)thiazole-2-carbohydrazonamide.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:15]=3[CH:16]([C:17]3[C:18](=O)[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:10]=2[N:9]=[C:8]1[CH3:31])(=[O:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>>[C:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:15]=3[CH:16]([C:17]3[C:18](=[S:41])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:10]=2[N:9]=[C:8]1[CH3:31])(=[O:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)OCCn1c(C)nc2c1C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=O
Product: CC(=O)OCCn1c(C)nc2c1C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=S

Procedure:
The title compound was prepared from the product of step (iv) (0.3 g) and Lawesson's reagent (1.376 g) according to the method of example 34 step (iv). Purification was by biotage chromatography on silica eluting with 3% methanol in dichloromethane with 1% 0.880 ammonia present to give a yellow glass.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([O:12][C:13](=[O:15])[NH2:14])[CH2:7][C:8]([N:10]=[O:11])=[O:9].[N+:16]([O-])([OH:18])=[O:17]>C(OC(=O)C)(=O)C.C(O)(=O)C>[N+:16]([C:5]1[S:1][C:2]([CH:6]([O:12][C:13](=[O:15])[NH2:14])[CH2:7][C:8]([N:10]=[O:11])=[O:9])=[CH:3][CH:4]=1)([O-:18])=[O:17]
Reactant: NC(=O)OC(CC(=O)N=O)c1cccs1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: NC(=O)OC(CC(=O)N=O)c1ccc([N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 11.7 %

Procedure:
In 4 ml of acetic anhydride there was suspended (2-(2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide (0.50 g) and the resulting mixture was cooled to 0°. A mixture of nitric acid (60% in water 0.37 g) in 4 ml of acetic acid was added dropwise and the mixture was stirred at room temperature for 1.5 hours, poured into 100 ml of ice water, extracted with ethyl acetate and washed with saturated brine. The extracts were dried over sodium sulfate, filtered, concentrated and purified by recrystallization from ether to yield the title compound as a yellow solid (0.07 g, yield 12%). M.p. 145-1847 (from ether).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([CH3:16])[CH:14]=[O:15])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[OH-].[Ca+2].[OH-].[H][H]>[Pd]>[C:1]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH:13]([CH3:16])[CH:14]=[O:15])=[CH:10][CH:11]=1)([CH2:4][CH3:5])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CCC(C)(C)c1ccc(C=C(C)C=O)cc1
Agent: [Pd]
Agent: [Ca+2]
Agent: [OH-]
Product: CCC(C)(C)c1ccc(CC(C)C=O)cc1

Procedure:
A mixture of 110 g of 3-(p-tert.amyl-phenyl)-2-methyl-acrolein, 4.75 g of 5% palladium/carbon and 0.390 g of calcium hydroxide is flushed with nitrogen and a solution of 7.6 ml of water in 285 ml of methanol is added. The mixture is hydrogenated at room temperature until 1 mol of hydrogen has been taken up. The catalyst is filtered the filtrate is evaporated and the residue is distilled. There is obtained pure 3-(p-tert.amyl-phenyl)-2-methyl-propionaldehyde of boiling point 109°-111° C./0.06 Torr.
Reaction SMILES: C([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:28])C=1>O>[OH:28][C:3]1[CH:16]=[CH:15][C:6]([O:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)C(C)Oc1ccc(C=O)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(C)Oc1ccc(O)cc1
Yield: 52.9 %

Procedure:
A mixture of 2.2 g of (+)-ethyl 2-(4-formylphenoxy)propionate ([α]D25 =+51.3° optical purity: 93%), 10 ml of methylene chloride and 2.6 g of m-chloroperbenzoic acid, was reacted for 2 hours under reflux, and after an addition of 0.5 g of water, further refluxed for 1 hour. After cooling, the reaction mixture was washed twice with 20 g of a 5% sodium hydrogen carbonate aqueous solution, then with 10 g of a 5% sodium hydrogen sulfite aqueous solution and further with 10 g of water. Then, the reaction mixture was concentrated by distilling off methylene chloride and then subjected to distillation under reduced pressure, whereby 1.1 g of ethyl 2-(4-hydroxyphenoxy)propionate was obtained as a colorless transparent liquid. The boiling point was from 130° to 140° C./1 mmHg. [α]D25 =+40.6°, optical punity: 90%
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[CH:13]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[CH:13]1([N:18]2[C:9](=[O:10])[C:4]3[C:5](=[CH:11][CH:12]=[C:2]([OH:1])[CH:3]=3)[C:6]2=[O:8])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1OC(=O)c2cc(O)ccc21
Reactant: NC1CCCC1
Solvent: Cc1ccccc1
Product: O=C1c2ccc(O)cc2C(=O)N1C1CCCC1
Yield: 80.2 %

Procedure:
4-Hydroxy-phthalic anhydride (5.4 g, 32.9 mmol), cyclopentyl amine (4.9 mL, 49.6 mmol) and 4 Å molecular sieves in toluene (136 mL) were stirred at reflux overnight. The reaction mixture was filtered and the solvent was evaporated in vacuo to obtain the product (6.1 g, 80%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 7.60 (d, J=7.8 Hz, 1H), 7.05-7.01 (m, 2H), 4.50-4.40 (m, 1H), 1.97-1.52 (m, 8H).
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[C:4](/[CH:7]=[C:8](/[C@H:10]2[O:28][C:26](=[O:27])[CH2:25][C@H:24]([OH:29])[C:23]([CH3:31])([CH3:30])[C:21](=[O:22])[C@H:20]([CH3:32])[C@@H:19]([OH:33])[C@@H:18]([CH3:34])[CH2:17][CH2:16][CH2:15][C@H:13]3[O:14][C@H:12]3[CH2:11]2)\[CH3:9])[N:3]=1.C[OH:36]>>[CH3:34][C@@H:18]1[C@H:19]([OH:33])[C@@H:20]([CH3:32])[C:21](=[O:22])[C:23]([CH3:31])([CH3:30])[C@@H:24]([OH:29])[CH2:25][C:26](=[O:27])[O:28][C@H:10](/[C:8](/[CH3:9])=[CH:7]/[C:4]2[N:3]=[C:2]([CH2:1][OH:36])[S:6][CH:5]=2)[CH2:11][C@@H:12]2[O:14][C@@H:13]2[CH2:15][CH2:16][CH2:17]1
Reactant: CO
Reactant: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2O[C@@H]2CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Product: C/C(=C\c1csc(CO)n1)[C@@H]1C[C@@H]2O[C@@H]2CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Reaction time: 21.5 h

Procedure:
The concentrated culture is transferred to a 4 liter bioreactor and a methanolic solution of 1 g of epothilone A in 10 ml of methanol is added. The culture is then cultured further for a period of time of 21.5 h. The temperature is 32° C., the stirrer speed is 455 rpm and the introduction of air takes place at 6 l/min. At the time of harvesting, 100 ml of XAD is added and the mixture is incubated further for 1 h. The XAD is separated from the cells by screening and exhaustively eluted with methanol. The concentrated eluate is analysed by means of HPLC.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]([CH3:11])[CH2:9][OH:10])=[N:6][CH:7]=1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]([CH3:11])[CH2:9][OH:10])=[N:6][C:7]=1[Br:19]
Reactant: CC(CO)c1cnc(N)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(CO)c1cnc(N)c(Br)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(5-aminopyrazin-2-yl)propan-1-ol (30 mg, 0.196 mmol) in DCM (653 μL) was added NBS (31.4 mg, 0.176 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 min. After quenched with sat NaHCO3, the reaction mixture was extracted with EtOAc 3 times. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate. Filtered and concentrated in vacuo. The crude product was used in next step reaction without purification. LCMS (m/z): 234.0 (MH+), 0.40 min.
Reaction SMILES: Br[C:2]1[C:3]([Cl:18])=[C:4]([C:16]#[N:17])[C:5](=[O:15])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[CH:7]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:18][C:3]1[C:2]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:7][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[C:5](=[O:15])[C:4]=1[C:16]#[N:17]
Reactant: Cc1ccccc1-n1cc(Br)c(Cl)c(C#N)c1=O
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccccc1-n1cc(-c2ccccc2)c(Cl)c(C#N)c1=O
Temperature: 90 °C
Yield: 64.3 %

Procedure:
A mixture of 5-bromo-4-chloro-1-(2-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step A (400 mg), phenylboronic acid (211 mg), tetrakis(triphenylphosphine)palladium(0) (143 mg), aqueous sodium carbonate solution (2 M, 1.24 mL) and 1,2-dimethoxyethane (4.0 mL) was heated with microwave irradiation at 90° C. for 1 hr. The reaction mixture was cooled to room temperature, and water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (255 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=O.[CH3:24][N:25]([CH3:35])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]([CH3:34])[CH3:33])[CH:27]=1.C(OC(=O)C)(=O)C.[OH-].[Na+]>Cl>[CH3:33][N:32]([CH3:34])[C:28]1[CH:27]=[C:26]([N:25]([CH3:35])[CH3:24])[CH:31]=[CH:30][C:29]=1[C:4]1([C:3]2[CH:15]=[CH:16][C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:18][C:2]=2[CH3:1])[C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[O:10]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccccc32)c(C)c1
Temperature: 95 °C

Procedure:
A mixture of 2-(2-methyl-4-(diethylamino)benzoyl)-benzoic acid (25 g.), N,N,N',N'-tetramethyl-m-phenylenediamine (13.2 g.) and acetic anhydride (75 g.) was heated (to 95° C.) during 1 hour, then refluxed with dilute hydrochloric acid (32 g. concentrated hydrochloric acid plus 160 ml. water) during one and one-half hours. The resulting mixture was poured onto ice and the pH was adjusted to 6 with sodium hydroxide. Recrystallization of the resulting product afforded 3-(2,4-bis(dimethylamino)-phenyl)-3-(2-methyl-4-(diethylamino)phenyl)phthalide (I: X = (CH3)2N, Y2 = CH3, Y4 = (CH3CH2)2N, Z4 = Z5 = Z6 = Z7 = H) in a first crop from toluene (m.p. 204°-206° C.) and in a second crop from a mixture of toluene and hexane (m.p. 191°-195° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:11])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(=O)C.C([BH3-])#N.[Na+].[CH:20]1([CH:23]=O)[CH2:22][CH2:21]1>C(O)C>[Cl:1][C:2]1[C:3]([NH:11][CH2:23][CH:20]2[CH2:22][CH2:21]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c(Cl)cnc2[nH]ccc12
Reactant: O=CC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: Clc1cnc2[nH]ccc2c1NCC1CC1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
In a round bottom flask, 5-chloro-1H-pyrrolo[2,3-b]pyridin-4-ylamine (22, 0.21 g, 1.25 mmol) is combined with 3.5 mL of ethanol, acetic acid (0.38 g, 6.25 mmol), silica bound sodium cyanoborohydride (1.1 g, 1.02 mmol), and cyclopropanecarbaldehyde (23, 0.26 g, 4 mmol). The reaction mixture was stirred over night at room temperature, heated up to 145° C. until the reaction was complete, filtered, concentrated, and purified by flash chromatography to provide compound as a solid (24, 0.191 g; yield=69%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([OH:3])=O.C(N(CC)CC)C.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:36]1([NH:35][C:1]([C:4]2[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]3[N:18]=[C:17]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[CH:20]4)[CH:16]=[CH:15][N:14]=3)[CH3:11])[CH:7]=[CH:8][CH:9]=2)=[O:3])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (32.2 mg) was dissolved in CH2Cl2 (2 mL), then triethylamine (62 μL), aniline (25 μL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (62.7 mg) and 4-dimethylaminopyridine (˜1 mg) were added in that order. Mixture stirred 16 h at room temperature then 2 mL more CH2Cl2 added (reaction had gone dry overnight) and thin layer chromatography showed complete conversion of starting material. Concentrated under reduced pressure then purified by silica gel chromatography (98:2 CH2Cl2:MeOH) to yield 16.9 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.48 (br s, 1H); 8.48 (br s, 1H); 8.41 (d, J=5.5 Hz, 1H); 8.00 (s, 1H); 7.75-7.84 (m, 3H); 7.61-7.66 (m, 3H); 7.51 (t, J=7.8 Hz, 1H); 7.33-7.41 (m, 4H); 7.17 (t, J=7.5 Hz, 1H); 6.81 (d, J=5.5 Hz, 1H); 5.73 (br s, 1H); 5.28 (br s, 1H); 1.68 (d, J=6.8 Hz, 3H). Mass Spectrum (ESI): m/e 435.1 (M+1).
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([CH3:19])([CH2:14][C:15]([O:17]C)=[O:16])[CH2:4]1.Cl>>[ClH:1].[NH2:2][CH:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([CH3:19])([CH2:14][C:15]([OH:17])=[O:16])[CH2:4]1
Reactant: COC(=O)CC1(C)CC(N)c2ccc(OC)cc21
Agent: Cl
Product: COc1ccc2c(c1)C(C)(CC(=O)O)CC2N
Reaction time: 3 h
Yield: 97.3 %

Procedure:
4 g of the title compound of Example 2 in 2 normal hydrochloric acid was heated to reflux, stirred at that temperature for 3 hours and evaporated to give 3.7 g of white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Cl.[NH:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:21])[C:14]=2[CH:13]=[CH:12]1>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:21])[C:14]=2[CH:13]=[CH:12]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: Fc1cccc(F)c1CCl
Product: O=Cc1cccc2c1ccn2Cc1c(F)cccc1F
Yield: 100.1 %

Procedure:
The same procedures used in Example 1 were repeated except for using 2.35 g of 2,6-difluorobenzyl chloride and 2.00 g of indole-4-carbaldehyde as a starting material to give 3.74 g of 1-(2,6-difluorobenzyl)indole-4-carbaldehyde as pale yellow crystals. The yield thereof was found to be 100%.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](C1C2N=NNC=2C=CC=1)=[O:4].[CH2:16]([CH:20]1[CH2:25][CH2:24][CH:23]([CH:26]2[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]2)[CH2:22][CH2:21]1)[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH2:16]([CH:20]1[CH2:25][CH2:24][CH:23]([CH:26]2[CH2:27][CH2:28][CH:29]([O:32][C:3](=[O:4])[C:2]([F:15])([F:14])[F:1])[CH2:30][CH2:31]2)[CH2:22][CH2:21]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCC1CCC(C2CCC(O)CC2)CC1
Reactant: O=C(c1cccc2[nH]nnc12)C(F)(F)F
Solvent: C1CCOC1
Product: CCCCC1CCC(C2CCC(OC(=O)C(F)(F)F)CC2)CC1

Procedure:
Trifluoroacetylbenzotriazole in an amount of 7.5 g (35 mmol) was dissolved in 75 ml of THF, 4.6 g (19 mmol) of 4-(4-butyl-cyclohexyl)cyclohexanol was added thereto, they were refluxed for 1 hour, and then the solvent was distilled off. After the residue was purified by column chromatography on silica gel (eluent: heptane/ethyl acetate=5/1), the solvent was distilled off, the residue was subjected twice to recrystallization by using heptane to give 1.5 g (4.5 mmol) of trifluoroacetic acid 4-(4-butylcyclohexyl)cyclohexyl ester. Yield of this compound based on 4-(4-butylcyclohexyl)cyclohexanol was 24%.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([C:32](=O)[CH2:33][CH2:34][CH2:35][CH3:36])[C:23](=NOC)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.Cl.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][C:41]=1[NH:49][NH2:50].C(O)(=O)C>COCCO>[CH2:33]([C:32]1[C:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:16][CH:17]=2)=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:49]([C:41]2[CH:42]=[C:43]([N+:46]([O-:48])=[O:47])[CH:44]=[CH:45][C:40]=2[Cl:39])[N:50]=1)[CH2:34][CH2:35][CH3:36]
Reactant: NNc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=NOC)C(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Solvent: COCCO
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C(=O)OCC)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Temperature: 105 °C
Reaction time: 20 h
Yield: 49.5 %

Procedure:
A mixture of 3.07 g (5.79 mmol) of ethyl 3-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-2-methoxyimino-4-oxooctanoate (from Step F), 5.00 g (22.3 mmol) of 2-chloro-5-nitrophenylhydrazine hydrochloride [prepared from 2-chloro-5-nitroaniline according to H. Stroh and G. Westphal, Chem. Ber., 96, 184 (1963)], 55 mL of glacial acetic acid, and 25 mL of 2-methoxyethanol was stirred under N2 at 105° C. for 20 hours. The cooled mixture was concentrated in vacuo and the residue was partitioned between 200 mL of 0.2N HCl and 200 mL of ethyl acetate. The organic layer was washed with H2O (200 mL), dried over Na2SO4, filtered, and concentrated. Flash chromatography of the residue twice on silica gel (first column eluted with 2% MeOH in CH2Cl2, second column eluted with 1% MeOH in CH2Cl2) to provide 1.71 g (47%) of the title compound as a viscous, orange oil; homogeneous by TLC in 98:2 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 598 (M+1)+. 400 MHz 1H NMR (CDCl3) δ0.87 (t, J=7.3 Hz, 3H), 1.06 (t, J=7.1 Hz, 3H), 1.34 (m, 2H), 1.59 (m, 2H, partially obscured by H2O peak), 2.62 (t, J=7.8 Hz, 2H), 4.10 (s, 2H), overlapping 4.14 (q, J=7.0 Hz, 2H), 4.24 (s, 2H), 7.26 (d, J=8.2 Hz, 2H), 7.32 (dd, J=7.5, 1.3 Hz, 1H), 7.41 (d, J=8.2 Hz, 2H), 7.49 (m, 1H), 7.58 (m, 1H), 7.66 (d, J=8.8 Hz, 1 H), 8.14 (dd, J=7.9, 1.3 Hz, 1H), 8.26 (dd, J=8.8, 2.7 Hz, 1H), 8.36 (d, J=2.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:26][C:27]([CH3:31])([CH3:30])[CH2:28][OH:29]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:26][C:27]([CH3:31])([CH3:30])[CH2:28][OH:29])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Solvent: CN(C)C=O
Product: CC(C)(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-amino-2-methyl-1-propanol employing methods similar to those described in Example 2 and using N,N-dimethylformamide as the reaction solvent. The product was obtained as an off-white solid: 1H NMR (d6-DMSO) tautomers are observed δ 11.95 (1H, br s), 10.95 (1H, br s), 10.01 (1H, br s), 8.17 (0.70H, s), 8.13 (0.30H, s), 7.34-7.25 (3H, m), 7.15-7.09 (2H, m), 4.86 (1H, br s), 3.98 (2H, s), 3.50-3.41 (2H, m), 1.29 (3H, s), 1.24 (3H, s); HRMS calcd for C20H20FN3O4+H+: 386.1516. Found 386.1521.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Br[C:36]1[C:37]([N:56]2[CH2:60][CH2:59][O:58][C:57]2=[O:61])=[CH:38][C:39]2[O:43][C:42]([C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)=[C:41]([C:51]([NH:53][CH3:54])=[O:52])[C:40]=2[CH:55]=1.[F:62][C:63]1[C:64]2[CH:65]=[C:66]3[C:75]4[N:76]=[C:77]([Sn](C)(C)C)[CH:78]=[CH:79][C:74]=4[O:73][CH2:72][N:67]3[C:68]=2[CH:69]=[CH:70][CH:71]=1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:62][C:63]1[C:64]2[CH:65]=[C:66]3[C:75]4[N:76]=[C:77]([C:36]5[C:37]([N:56]6[CH2:60][CH2:59][O:58][C:57]6=[O:61])=[CH:38][C:39]6[O:43][C:42]([C:44]7[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=7)=[C:41]([C:51]([NH:53][CH3:54])=[O:52])[C:40]=6[CH:55]=5)[CH:78]=[CH:79][C:74]=4[O:73][CH2:72][N:67]3[C:68]=2[CH:69]=[CH:70][CH:71]=1
Reactant: C[Sn](C)(C)c1ccc2c(n1)-c1cc3c(F)cccc3n1CO2
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N3CCOC3=O)c(Br)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N3CCOC3=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 100 °C
Yield: 23.5 %

Procedure:
Pd2(dba)3 (10 mg, 0.01 mmol) and X-Phos (11 mg, 0.02 mmol) was added to the mixture of 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(2-oxooxazolidin-3-yl)benzofuran-3-carboxamide (100 mg, 0.23 mmol), 11-fluoro-2-(trimethylstannyl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (140 mg, 0.35 mmol) in dioxane/H2O (4 mL/0.2 mL) under N2. Then the reaction mixture was heated to 100° C. for 1 hour and filtered. The resulting residue was extracted with EtOAc. The combined organic phase was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether:EtOAc=1:2) to provide 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(2-oxooxazolidin-3-yl)benzofuran-3-carboxamide (32 mg, yield: 24%). 1H-NMR (CDCl3, 400 MHz) δ 8.01 (s, 1H), 7.94˜7.98 (m, 2H), 7.58 (s, 1H), 7.51 (m, 2H), 7.19˜7.23 (m, 4H), 7.11˜7.13 (d, J=8.0 Hz, 1H), 6.83˜6.88 (m, 1H), 6.12 (s, 1H), 6.00 (s, 2H), 4.37˜7.41 (m, 2H), 4.12˜4.14 (m, 2H), 3.00 (d, J=4.8 Hz, 3H). MS (M+H)+: 593.