Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:12]([NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[O:13].ClS(O)(=O)=O.N.[OH-].[Na+].[CH:35]1([N:41]=[C:42]=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>CC(C)=O.O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:12]([NH:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([S:23]([NH:26][C:42]([NH:41][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:43])(=[O:24])=[O:25])=[CH:21][CH:22]=1)=[O:13]
Reactant: O=C=NC1CCCCC1
Reactant: NS(=O)(=O)c1ccc(CCNC(=O)N2CCc3ccccc3C2=O)cc1
Agent: N
Agent: O=S(=O)(O)Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC1CCCCC1)NS(=O)(=O)c1ccc(CCNC(=O)N2CCc3ccccc3C2=O)cc1
Temperature: 25 °C

Procedure:
5.5 g of 4-(2-[1-oxo-1,2,3,4-tetrahydroisoquinoline-2-carboxamido]-ethyl)-benzenesulfonamide (melting point 197°-198° C., prepared from 1-oxo-1,2,3,4-tetrahydroisoquinoline-2-(N-2-phenylethyl)-carboxamide [melting point 98°-99° C., prepared from 1-oxo-1,2,3,4-tetrahydro-isoquinoline and 2-phenylethyl isocyanate] and chlorosulfonic acid, with subsequent reaction of the sulfochloride with ammonia) are suspended in 75 ml of acetone and 7.5 ml of 2 N sodium hydroxide solution and the mixture is cooled to 0°-5° C. 2.15 g of cyclohexyl isocyanate in 10 ml of acetone are added dropwise, whilst stirring, and the mixture is then stirred for one hour whilst cooling with ice and for three hours at room temperature. The precipitate is dissolved by adding water. After removing the acetone in vacuo, the aqueous solution which remains is acidified with dilute hydrochloric acid. The N-(4-[2-(1-oxo-1,2,3,4-tetrahydro-isoquinoline-2-carboxamido)-ethyl]-benzenesulfonyl)-N'-cyclohexyl-urea which has precipitated is filtered off with suction, reprecipitated once from dilute ammonia solution by means of dilute hydrochloride acid, filtered off with suction, dried and recrystallized from ethanol. The product thus obtained melts at 197°-199° C.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[N:36]1([C:40]2[N:45]=[CH:44][C:43](Br)=[CH:42][N:41]=2)[CH2:39][CH2:38][CH2:37]1>>[N:36]1([C:40]2[N:45]=[CH:44][C:43]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:42][N:41]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: Brc1cnc(N2CCC2)nc1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cnc(N3CCC3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared following a procedure analogous to Example 31 using (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one and 2-(azetidin-1-yl)-5-bromopyrimidine. LC (method 5): tR=1.48 min; Mass spectrum (ESI+): m/z=487 [M+H]+; 1H NMR (CD3OD) δ 0.95 (s, 3H), 1.23 (s, 3H), 1.55 (d, 3H), 2.14 (s, 2H), 2.20 (m, 1H), 2.40-2.60 (m, 4H), 3.04 (m, 1H), 4.33 (m, 4H), 5.57 (q, 1H), 7.08 (d, 2H), 7.25-7.40 (m, 7H), 8.62 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:12]([F:13])=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][C:8]=2[F:17])=[CH:4][CH:3]=1>[Pd].CCOC(C)=O>[F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:12]([F:13])=[CH:11][C:10]([NH2:14])=[CH:9][C:8]=2[F:17])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)c(Oc2ccc(F)cc2)c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(F)c(Oc2ccc(F)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
A mixture of 4-(4-fluorophenoxy)-3,5-difluoronitrobenzene (30.4 g, 113 mmol), EtOAc (300 ml), 10% Pd/C (2.6 g) was stirred under an atmosphere of H2 at room temperature and pressure for approximately 6 hrs. The reaction mixture was filtered through Celite and concentrated in vacuo to give 4-(4-fluorophenoxy)-3,5-difluoroaniline (26.5 g, 98%) which was used in the next step without further purification. 1H NMR (CDCl3): δ 3.82 (s, 2H), 6.26 (d, 2H, J=8.4 Hz), 6.88 (m, 2H), 6.93 (m, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1.[CH2:26]([NH2:28])[CH3:27]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:28][CH2:26][CH3:27])=[C:3]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][C:14]=3[N:15]=2)[CH:4]=1)([O-:10])=[O:9]
Reactant: CCN
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Product: CCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg, 0.60 mmol), and ethylamine (3 ml) the subtitle compound was obtained (217 mg, 100%). MS 360 m/z (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20](O)(=[O:26])/[CH:21]=[CH:22]\[C:23](O)=[O:24].C(N=C=NC(C)C)(C)C.C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3[C:23](=[O:24])[CH:22]=[CH:21][C:20]3=[O:26])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN)OC2
Reactant: O=C(O)/C=C\C(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN1C(=O)C=CC1=O)OC2
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a solution of 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.53 g, 1.86 mmol, prepared as described in Example 17) in tetrahydrofuran (10 ml) was added, maleic acid (0.24 g, 2.05 mmol) and diisopropylcarbodiimide (0.58 ml, 3.72 mmol). The reaction mixture was heated to reflux for 3 hours and then allowed to cool to room temperature over an 18 hour period. The solvent was stripped off in vacuo and the residue diluted into ethyl acetate (50 ml). The organic phase was washed with saturated sodium bicarbonate (2×50 ml), 1% hydrochloric acid (2×20 ml), brine (3×50 ml), dried (MgSO4), filtered, and the solvent evaporated in vacuo affording an oil which was subjected to flash chromatography using a mixture of ethyl acetate/hexanes (6:4) as eluant. Pure fractions (Rf=0.25) were collected and the solvent evaporated in vacuo to give 0.60 g (90%) of 2-amino-5-(2,5-dioxo-2,5-dihydro-pyrrol-1-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: FC1C=CC=CC=1C1([C@H](OC2CCCCO2)C)CO1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1([C@H:30]([OH:32])[CH3:31])[CH2:29][O:28]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:52]([C:55]1[CH:56]=[C:57]([CH:61]=[C:62]([N+:64]([O-:66])=[O:65])[CH:63]=1)[C:58](O)=[O:59])([O-:54])=[O:53].N(C(OCC)=O)=NC(OCC)=O.C(OC(C)C)(C)C>O1CCCC1.O.C(OCC)(=O)C>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C@:27]1([C@@H:30]([O:32][C:58](=[O:59])[C:57]2[CH:56]=[C:55]([N+:52]([O-:54])=[O:53])[CH:63]=[C:62]([N+:64]([O-:66])=[O:65])[CH:61]=2)[CH3:31])[CH2:29][O:28]1
Reactant: C[C@@H](O)C1(c2ccccc2F)CO1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: C[C@@H](OC1CCCCO1)C1(c2ccccc2F)CO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](OC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)[C@@]1(c2ccccc2F)CO1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
In the same manner as in Reference Example 1, starting from 2-(2-fluorophenyl)-2-[(1R)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxyethyl]oxirane (synthesized by the method described in EP 0548553A), (1R)-1-[2-(2-fluorophenyl)-2-oxiranyl]ethanol was obtained. To a solution of this product (34.77 g) in tetrahydrofuran (600 ml) were added, with ice cooling, 127.21 g of triphenyl phosphine, 102.88 g of 3,5-dinitrobenzoic acid and 84.47 g of diethyl azodicarboxylate, and the resulting mixture was stirred at room temperature for 7 hours under an atmosphere of argon. To the reaction solution were added 600 ml of ethyl acetate, 100 ml of diisopropyl ether and 800 ml of water to fractionate and the aqueous layer was extracted with ethyl acetate (600 ml, 400 ml). The organic layers were combined, washed with water and a saturated aqueous solution of sodium chloride successively, then dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=5/1) to give 23.15 g of [(1S)-1-[(2R)-2-(2-fluorophenyl)-2-oxiranyl)ethyl]3,5-dinitrobenzoate as colorless needles.
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22](OC)=[O:23])[CH:17]=3)=[C:11]([CH3:26])[CH:10]=2)[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[O:1]=[S:2]1(=[O:27])[CH2:3][CH2:4][CH:5]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[CH:17]=3)=[C:11]([CH3:26])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: COC(=O)c1cccc(-c2c(C)cc(OC3CCS(=O)(=O)CC3)cc2C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OC2CCS(=O)(=O)CC2)cc(C)c1-c1cccc(CO)c1
Reaction time: 1.5 h
Yield: 93.3 %

Procedure:
To a solution of methyl 4′-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-2′,6′-dimethylbiphenyl-3-carboxylate (0.128 g, 0.33 mmol) in tetrahydrofuran (2 mL) was added lithium aluminum hydride (80%, 15.7 mg, 0.33 mmol) by small portions under ice-cooling, and the mixture was stirred at the same temperature for 1.5 hr. Sodium sulfate 10 hydrate (0.106 g, 0.33 mmol) was added by small portions to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The insoluble substance was filtered off through celite, and the filtrate was concentrated under reduced pressure to give the title compound (0.111 g, yield 93%) as a colorless amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][N:6]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:26])[CH2:24][CH3:25].C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:23]([NH:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)=[CH:5][N:6]=1)(=[O:26])[CH2:24][CH3:25]
Reactant: CCC(=O)Cl
Reactant: Nc1ncc(Sc2ccc([N+](=O)[O-])cc2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCC(=O)Nc1ncc(Sc2ccc([N+](=O)[O-])cc2)s1
Temperature: 0 °C
Yield: 78.7 %

Procedure:
To a mixture of 2-amino-5-(4-nitrophenylthio)thiazole (2.6 g) and pyridine (1 g) in N,N-dimethylformamide (30 ml) was added dropwise the propionylchloride (1.1 g) at 5° C. under ice cooling with stirring. The mixture was stirred at 5° C. for 3.5 hours. The reaction mixture was poured into ice water and the mixture was adjusted to pH 8 using aqueous sodium bicarbonate. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-propionylamino-5-(4-nitrophenylthio)thiazole (2.5 g, yield: 78.7%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[C:9]1([CH3:17])[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1.O>[C:9]1([CH3:17])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[NH2:16]
Reactant: Cc1ccccc1C#N
Reactant: Cc1ccccc1I
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1C(N)c1ccccc1C
Temperature: 23 °C
Yield: 95.5 %

Procedure:
The following procedure was adapted from Zhang et al. (Org. Lett. 2008, 10, 5429-5432). To Mg turnings (1.53 g, 63.0 mmol, 1.50 equiv) in THF (50 mL) in an oven-dried round-bottom flask fitted with a reflux condenser was added 2-methyliodobenzene (11.0 g, 6.40 mL, 1.20 equiv) dropwise. The reaction mixture was heated to reflux for 1 h. To the reaction mixture was added o-tolunitrile (4.94 g, 5.00 mL, 42.2 mmol, 1.00 equiv) and the reaction mixture was heated to reflux for 22 h. The reaction mixture was cooled to 23° C. and a suspension of LiAlH4 (1.97 g, 51.9 mmol, 1.23 equiv) in THF (50 mL) was added and the reaction mixture was heated to reflux for 25 h. The reaction mixture was cooled to 23° C. and H2O (2 mL) was added dropwise. A solution of NaOH (2 mL, 1 M in H2O) was added slowly and 8 mL H2O was added. The reaction mixture was filtered through a celite pad, eluting with EtOAc, and concentrated. The residue was purified by Kugelrohr distillation (240 mTorr, 200° C.) to give di-o-tolylmethanamine as a yellow oil (8.52 g, 96% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH:15]1([N:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[C:19]2=[O:34])[CH2:17][CH2:16]1.[H-].[Na+]>CN(C=O)C.CO>[CH:15]1([N:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:3]4[N:2]([CH3:1])[C:6]5=[N:7][CH:8]=[CH:9][CH:10]=[C:5]5[N:4]=4)=[CH:29][CH:28]=3)[C:19]2=[O:34])[CH2:17][CH2:16]1
Reactant: O=c1n(-c2ccc(O)cc2)c2ncccc2n1C1CC1
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1c(Oc2ccc(-n3c(=O)n(C4CC4)c4cccnc43)cc2)nc2cccnc21
Temperature: 180 °C
Yield: 53.7 %

Procedure:
3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (79 mg) was added to a solution of 1-cyclopropyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) and NaH (17.96 mg) in DMF (2 ml) at 100° C. The mixture was heated at 180° C. for 1 h under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-cyclopropyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (80 mg) as white crystals.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.C(N(CC)CC)C.[C:13]([C:15]1[CH:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:16]=1)#[N:14].Cl>CN(C=O)C>[C:25]1([C:17]2[CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:20]=[C:15]([C:13]3[NH:14][N:3]=[N:2][N:1]=3)[N:16]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)c1cc(C#N)nc(-c2ccccc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccccc2)nc(-c2nnn[nH]2)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Sodium azide (1.7 g) and triethylamine hydrochloride (3.5 g) were added to a DMF (80 mL) solution of methyl 2-cyano-6-phenylpyridine-4-carboxylate (2 g), and stirred overnight at 100° C. With cooling with ice, diluted hydrochloric acid was added to it, and extracted with a mixed solution of chloroform/methanol=10/1. The organic layer was washed with water and saturated saline water, dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated away to obtain the title compound as a brown solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[N:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=3[CH:15]=[C:7]2[C:6]2[N:17]=[C:18]([C:21]3[C:22]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])=[CH:23][C:24]4[O:28][C:27]([C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=5)=[C:26]([C:36]([NH:38][CH3:39])=[O:37])[C:25]=4[CH:40]=3)[CH:19]=[CH:20][C:5]=2[O:4]1.O=[CH:48][C:49]([O:51][CH2:52][CH3:53])=[O:50].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:16][C:13]1[C:14]2[CH:15]=[C:7]3[C:6]4[N:17]=[C:18]([C:21]5[C:22]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:43])=[O:44])=[CH:23][C:24]6[O:28][C:27]([C:29]7[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=7)=[C:26]([C:36](=[O:37])[NH:38][CH3:39])[C:25]=6[CH:40]=5)[CH:19]=[CH:20][C:5]=4[O:4][CH:3]([CH2:2][NH:1][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[N:8]3[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)C=O
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CN)O4)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)CNCC1Oc2ccc(-c3cc4c(C(=O)NC)c(-c5ccc(F)cc5)oc4cc3N(C)S(C)(=O)=O)nc2-c2cc3c(F)cccc3n21
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
To a solution of 5-(6-(aminomethyl)-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (200 mg, 0.31 mmol) and ethyl 2-oxoacetate (64 mg, 0.62 mmol) in CH2Cl2 (4 mL) was added acetic acid (4 mg, 0.06 mmol). The mixture was stirred at room temperature for 1 hour, and then NaBH(AcO)3 (144 mg, 0.68 mmol) added to the mixture. After stirring overnight, the mixture diluted with CH2Cl2, washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-HPLC give the product of ethyl 2-(((11-fluoro-2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)methyl)amino)acetate (45 mg, yield: 20%). 1H-NMR (CDCl3, 400 MHz) δ 8.01 (s, 1H), 7.96 (dd, J=8.4, 5.2 Hz, 2H), 7.67 (s, 1H), 7.50 (s, 2H), 7.13˜7.25 (m, 5H), 6.84 (dd, J=9.2, 8.0 Hz, 1H), 6.50 (dd, J=7.6, 3.6 Hz, 1H), 5.99 (br s, 1H), 4.12 (q, J=7.2 Hz, 2H), 3.29˜3.44 (m, 5H), 3.20 (dd, J=12.8, 8.4 Hz, 1H), 3.00 (d, J=4.8 Hz, 3H), 2.86˜2.96 (m, 1H), 2.67 (s, 3H), 1.22 (t, J=7.2 Hz, 3H). MS (M+H)+: 730.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=1)[CH2:15][CH:12]1[CH2:14][CH2:13]1)=[O:6]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: NCC(CC1CC1)c1cnc(C(F)(F)F)nc1
Product: O=C(NCC(CC1CC1)c1cnc(C(F)(F)F)nc1)c1c(Cl)cccc1Cl

Procedure:
From 2,6-dichlorobenzoic acid and 3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine. LCMS (MH+): m/z=418.1, tR (minutes, Method G)=2.62
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18](O)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:24]=4[O:23][CH3:22])[CH2:29]3)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccccc12
Reactant: COc1ccc2c(c1OC)CCNC2
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3ccc(F)cc3)nc3ccccc13)C2
Yield: 10 %

Procedure:
Reaction of 2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 3 (10% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.72 and 2.98 (2t, 2H), 3.49 and 4.03 (2t, 2H), 3.68 and 3.75 (2s, 3H), 3.76 and 3.81 (2s, 3H), 4.42 and 4.93 (2s, 2H), 6.63 and 7.01 (2d, 1H), 6.81 and 7.08 (2d, 1H), 7.37-7.44 (m, 2H), 7.76-7.79 (m, 1H), 7.89-7.99 (2d, 1H), 8.07-8.15 (m, 2H), 8.53-8.62 (m, 2H); MS (ESI) m/z 444 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([S:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:3]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[S:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1Sc1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2Sc2ccncc2)cc1

Procedure:
4-Mercaptopyridine (1.1 1 g, 10 mmol) and K2CO3 (1.38 g, 10 mmol) were suspended in DMF (10 mL) and stirred at room temperature for 15 min. The mixture was treated with 4-chloro-2-fluoro-1-nitro-benzene (1.75 g, 10 mmol) and heated at 50° C. for 16 h. After cooling to room temperature, water (50 mL) was added and the mixture extracted 3 times with ethyl acetate. The organic layer was combined the ethyl acetate and then reduced in vacuo. The residue was dissolved in DMF (30 mL) and treated with SnCl2.2H2O. The mixture was heated at 50° C. for 16 hr. The DMF was distilled off under vacuum and the reduction product was purified by flash chromatography on silica gel column (50-100% EtOAc/hexane) to afford 4-chloro-2-(pyridin-4-ylsulfanyl)-phenylamine as light yellow solid. The title sulfonamide compound was prepared according to the general procedure using 118 mg of 4-chloro-2-(pyridin-4-ylsulfanyl)-phenylamine prepared above and 116 mg of 4-tert-Butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.33 (s, 9H), 7.06 (d, 2H, J=6.8 Hz), 7.45 (d, 2H, J=8.4 Hz), 7.51 (m, 2H), 7.66 (d, 2H, 8.4 Hz), 7.71 (d, 1H, J=9.2 Hz), 8.43 (d, 2H, J=6.4 Hz). MS: m/z 433.9 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:24])[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]4[CH2:23][O:22]4)=[CH:15][CH:14]=3)=[CH:9][O:10]2)=[CH:5][CH:4]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(O)C>[OH:22][CH:21]([CH2:23][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]2[C:7](=[O:24])[C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[O:10][CH:9]=2)=[CH:14][CH:15]=1
Reactant: C1COCCN1
Reactant: COc1ccc2c(=O)c(-c3ccc(OCC4CO4)cc3)coc2c1
Solvent: CCO
Product: COc1ccc2c(=O)c(-c3ccc(OCC(O)CN4CCOCC4)cc3)coc2c1
Yield: 68.1 %

Procedure:
A mixture of compound 3 (obtained from example 1) (0.32 g, 1 mmol), morpholine (0.43 g, 5 mmol), and ethanol (30 mL) was refluxed for 4 hrs (TLC monitoring). After removal of solvent in vacuo, the residue was treated with H2O (50 mL). The resulting precipitate was collected and purified by column chromatography (MeOH/CH2Cl2=1:20) to give the title compound 5a (0.28 g, 68% yield). M.p.: 117-118° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[C:7](F)=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10]>CC(N(C)C)=O.O.CCOCC>[N:1]([C:11]1[CH:12]=[CH:13][C:6]([F:5])=[CH:7][C:8]=1[C:9]#[N:10])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(F)c1F
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1cc(F)ccc1N=[N+]=[N-]
Temperature: 100 °C
Yield: 102.8 %

Procedure:
A mixture of NaN3 (1.17 g, 1.8 mmol) and difluorobenzonitrile (0.5 g, 3.6 mmol) in DMA (60 mL) was heated at 100° C. for 30 minutes. The mixture was next diluted with water (300 mL) and ether (300 mL). The organic layer was washed three times with water and brine. The organic layer was dried (MgSO4) and concentrated. The crude product was purified by flash column chromatography using ether:hexane (1:5) as eluent to give the desired product (1q) as white crystals (0.3 g, 53% isolated yield). 1H NMR (400 MHz, CDCl3) δ 7.38-7.31 (m, 2H), 7.27-7.18 (m, 1H).
Reaction SMILES: [OH-].[Na+].[O:3]=[CH:4][C:5]1[CH:13]=[CH:12][C:10]([OH:11])=[C:7]([O:8][CH3:9])[CH:6]=1.Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:15]([O:11][C:10]1[CH:12]=[CH:13][C:5]([CH:4]=[O:3])=[CH:6][C:7]=1[O:8][CH3:9])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C=O)ccc1OCc1ccccc1

Procedure:
Sodium hydroxide (2.4 g) is dissolved in water (50 mL) by stirring. Vanillin (7.60 g, 0.05 mol) and α-chloro-toluene (7.60 g, 0.06 mol) are added and the reaction mixture is heated at reflux with stirring for 16 hours. The product is extracted from the aqueous mixture using methylene chloride (10 mL). When the solvent is removed under vacuum an oil results which crystallizes when treated with isopropyl alcohol and stirred. Mass spectrometry supports the following structure: ##STR17##