Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][O:3][CH2:4][C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6].[CH:11]1[C:20]2[N:21]3[C:25]([C:26](=O)[C:18]4[C:19]=2[C:14]([CH:15]=[CH:16][N:17]=4)=[CH:13][CH:12]=1)=[CH:24][CH:23]=[CH:22]3>O.C(O)C.N1C=CC=CC=1>[CH:8]([O:7][C:5]([CH2:4][O:3][N:2]=[C:26]1[C:18]2[C:19]3[C:14]([CH:15]=[CH:16][N:17]=2)=[CH:13][CH:12]=[CH:11][C:20]=3[N:21]2[C:25]1=[CH:24][CH:23]=[CH:22]2)=[O:6])([CH3:10])[CH3:9]
Reactant: O=c1c2nccc3cccc(c32)n2cccc12
Reactant: CC(C)OC(=O)CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: CC(C)OC(=O)CON=c1c2nccc3cccc(c32)n2cccc12
Yield: 74.3 %

Procedure:
A solution of isopropyl aminooxyacetate hydrochloride (23.4 g.) in water (128 cc.) is added to a stirred boiling suspension of 7H-indolizino[5,6,7-ij]isoquinolin-7-one (16.0 g.) in ethanol (320 cc.) and pyridine (11.05 g.). Boiling is maintained for 2 hours 45 minutes. After cooling to a temperature of about 20° C., water (960 cc.) is added with stirring. After stirring for 16 hours, the brown amorphous product which has precipitated is filtered off, then washed with distilled water and dissolved in ethyl acetate (500 cc.). The resulting organic solution is washed with water (3 × 200 cc.) and then dried over calcined magnesium sulphate. After evaporation of the solvent under reduced pressure, crude 7-isopropoxycarbonylmethoxyimino-7H-indolizino[5,6,7-ij]isoquinoline (18.1 g.) is obtained and is recrystallised from a mixture of ethyl acetate (115 cc.) and cyclohexane (460 cc.). 7-Isopropoxycarbonylmethoxyimino-7H-indolizino[5,6,7-ij]isoquinoline, solvated by ethyl acetate, (12.49 g.), melting at 70° C., is thus obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=O)[CH2:7]Cl)#[N:2].[C:13]([NH:16][C:17]([NH2:19])=[S:18])(=[NH:15])[NH2:14]>CCO>[NH:16]([C:17]1[S:18][CH:7]=[C:6]([C:5]2[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=2)[C:1]#[N:2])[N:19]=1)[C:13]([NH2:15])=[NH:14]
Reactant: N#Cc1cccc(C(=O)CCl)c1
Reactant: N=C(N)NC(N)=S
Solvent: CCO
Product: N#Cc1cccc(-c2csc(NC(=N)N)n2)c1

Procedure:
A mixture of 3-cyanophenacyl chloride (1.78 g.) and amidinothiourea (1.2 g.) in EtOH (40 ml.) was heated under reflux for 1 hour. The solid precipitate was filtered off, dissolved in hot water (100 ml.) and the solution basified with sodium bicarbonate. The precipitated solid was filtered off and dried to give 3-[2-guanidinothiazol-4-yl]benzonitrile which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH:10]2[C:18]#[N:19])[CH:8]=1)(=[O:3])[NH2:2].[CH2:28](Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CO>[C:1]([C:4]1[C:5]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:28])=[O:16])[CH2:11][CH:10]2[C:18]#[N:19])[CH:8]=1)(=[O:3])[NH2:2]
Reactant: N#CC1CC(C(=O)O)CCC1n1cc(C(N)=O)c(Nc2ccc(Cl)cc2)n1
Reactant: ClCCCl
Agent: On1nnc2ccccc21
Solvent: CO
Product: COC(=O)C1CCC(n2cc(C(N)=O)c(Nc3ccc(Cl)cc3)n2)C(C#N)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the crude acid (1S,3S,4S and 1R,3R,4R)-4-[4-carbamoyl-3-[(4-chlorophenyl)amino]-1H-pyrazol-1-yl]-3-cyanocyclohexane-1-carboxylic acid (Example #35-1 Step C, 500 mg, 1.3 mmol) in MeOH (5 mL) were sequentially added EDC (324 mg, 1.7 mmol) and HOBt (210 mg, 1.6 mmol). The resulting solution was stirred at ambient temperature overnight before it was concentrated in vacuo. The crude residue was partitioned between DCM (20 mL) and water (5 mL). The organic solution was washed with saturated aqueous NaHCO3 (2×5 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by MPLC on Silica gel (eluting with 2-4% MeOH/DCM) to afford the title compound. 1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.24 (d, J=9.2 Hz, 2H), 4.35-4.28 (m, 1H), 3.74 (s, 3H), 3.52-3.34 (m, 1H), 2.68-2.62 (m, 1H), 2.55-2.52 (m, 1H), 2.24-2.16 (m, 3H), 2.00-1.90 (m, 1H), 1.73-1.70 (m, 1H). MS ESI: [M+H]+ m/z 401.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][C:7]3[NH:12][C:11]4[N:13]=[CH:14][CH:15]=[CH:16][C:10]=4[C:8]=32)[CH2:3][CH2:2]1.[OH-].[K+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1>CN1C(=O)CCC1.O>[F:30][C:20]([F:19])([F:29])[C:21]1[N:22]=[CH:23][C:24]([CH2:27][CH2:28][N:12]2[C:7]3[CH2:6][CH2:5][N:4]4[CH:9]([C:8]=3[C:10]3[CH:16]=[CH:15][CH:14]=[N:13][C:11]2=3)[CH2:1][CH2:2][CH2:3]4)=[CH:25][CH:26]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: c1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccc(CCn2c3c(c4cccnc42)C2CCCN2CC3)cn1
Reaction time: 24 h

Procedure:
A solution of 2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine (120 mg, 0.565 mmol) and powdered KOH (221.5 mg, 3.955 mmol) in NMP (2 mL) was stirred at RT for 10 min. 2-(Trifluoromethyl)-5-vinylpyridine (195.5 mg, 1.13 mmol) was added into the reaction mixture and stiffing continued for 24 h at RT. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel flash chromatography to yield 7-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine;
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH2:16]([O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[CH2:26]Br)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[CH2:26][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1)[CH3:17]
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: CCOC(=O)c1cccnc1CBr
Product: CCOC(=O)c1cccnc1CN1CCC(c2c[nH]c3ccccc23)CC1
Yield: 92.4 %

Procedure:
This compound was prepared following the procedure described in example 1 (part D) starting with 0.5 g (2.5 mmol) of 3-piperidin-4-yl-1H-indole and 0.65 g (3.25 mmol) of 2-bromomethyl-nicotinic acid ethyl ester. After the standard purification, 0.84 g (92% of yield) of 2-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-nicotinic acid ethyl ester were obtained.
Reaction SMILES: [CH2:1]1[C@H:5]([N:6]2[C:11](=[O:12])[N:10]=[C:9]([NH2:13])[CH:8]=[CH:7]2)[O:4][C@H:3]([CH2:14][O:15][P:16]([OH:19])([OH:18])=[O:17])[C@H:2]1[O:20][P:21]([O:24][CH2:25][C@H:26]1[O:30][C@@H:29]([N:31]2[C:35]3[N:36]=[CH:37][N:38]=[C:39]([NH2:40])[C:34]=3[N:33]=[CH:32]2)[C@H:28]([OH:41])[C@@H:27]1[OH:42])([OH:23])=[O:22].[C:43]([O:47][C:48]([NH:50][C@@H:51]([CH2:58][S:59][S:60][C:61]([CH3:64])([CH3:63])[CH3:62])[C:52](OCC#N)=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44]>O.C1COCC1>[C:43]([O:47][C:48]([NH:50][C@@H:51]([CH2:58][S:59][S:60][C:61]([CH3:64])([CH3:63])[CH3:62])[C:52]([O:42][C@H:27]1[C@@H:28]([OH:41])[C@H:29]([N:31]2[CH:32]=[N:33][C:34]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[NH2:40])[O:30][C@@H:26]1[CH2:25][O:24][P:21]([O:20][C@H:2]1[CH2:1][C@H:5]([N:6]2[CH:7]=[CH:8][C:9]([NH2:13])=[N:10][C:11]2=[O:12])[O:4][C@@H:3]1[CH2:14][O:15][P:16]([OH:18])([OH:19])=[O:17])([OH:23])=[O:22])=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (200 mg, 0.314 mmol) in water (6.25 ml) and a solution of (R)-cyanomethyl 2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanoate (Compound 21-A) (454 mg, 1.26 mmol) in THF (3.15 ml) were added to buffer A (113 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then lyophilized. The resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution=100/0→60/40) to afford (2R)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanoate (Compound 2m-A) (129 mg, 46%).
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[OH-].[K+].[CH3:7][N:8]1[C:12](Cl)=[C:11]([Cl:14])[C:10]([Cl:15])=[N:9]1.O>CS(C)=O>[CH3:7][N:8]1[C:12]([S:4][CH2:1][CH2:2][CH3:3])=[C:11]([Cl:14])[C:10]([Cl:15])=[N:9]1
Reactant: Cn1nc(Cl)c(Cl)c1Cl
Reactant: CCCS
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCSc1c(Cl)c(Cl)nn1C
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A stirred mixture of 4.9 g (0.064 moles) propanthiol and 3 g (0.054 moles) potassium hydroxide in 50 ml dimethylsulfoxide was heated (at about 120° C.) for thirty minutes. Then 10 g (0.054 moles) 1-methyl-3,4,5-trichloropyrazole was added in one portion. Heating (at about 120° C.) of the stirred reaction mixture was continued for about 6 hours. The reaction mixture was allowed to cool. The reaction mixture was added to water (about 50 ml); the resulting mixture was extracted with ether. The etheral phase was separated, washed with water twice, and dried over magnesium sulfate. The solvent was then stripped. The product was distilled out at 124° C. under high vacuum and heat.
Reaction SMILES: [N:1]12[CH2:8][C:5]([C:9]([O:11]CC)=O)([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.Cl.S(Cl)(Cl)=O.[NH3:19].ClCCl.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[N:1]12[CH2:8][C:5]([C:9]([NH2:19])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2
Reactant: N
Reactant: CCOC(=O)C12CCCN(CC1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: NC(=O)C12CCCN(CC1)C2
Yield: 76 %

Procedure:
Ethyl 1-azabicyclo[3.2.1]oct-5-ylcarboxylate (E7, Example 7 hereinafter, 9.6 g, 0.053 mole) was treated with 8M hydrochloric acid (130 ml) and heated under reflux for 18h. The solution was concentrated in vacuo to give a white solid, which was treated with thionyl chloride (80 ml) and heated under reflux for 6h. The reaction mixture was concentrated in vacuo to leave a red semi-solid, which was suspended in dichloromethane (120 ml), cooled in an ice bath and treated with an excess of ammonia/dichloromethane solution. The mixture was stirred at room temperature for 1h, then treated with saturated potassium carbonate solution. The organic layer was separated and the aqueous was extracted with chloroform (3×70 ml). All the organics were combined, then dried (Na2SO4) and concentrated in vacuo to give the title compound (D20) as a brown solid (6.2 g, 76%), which was used without further purification.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:30])=[CH:6][C:7]([F:29])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([CH3:24])=[C:17](F)[C:18]=3[N+:20]([O-:22])=[O:21])[C:13](=[O:25])[C:12]([C:26]([OH:28])=[O:27])=[CH:11]2)[CH:9]=1>CS(C)=O.N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:30])=[CH:6][C:7]([F:29])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([CH3:24])=[C:17]([NH:2][CH3:1])[C:18]=3[N+:20]([O-:22])=[O:21])[C:13](=[O:25])[C:12]([C:26]([OH:28])=[O:27])=[CH:11]2)[CH:9]=1
Reactant: Cc1cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c([N+](=O)[O-])c1F
Reactant: CN
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: CNc1c(C)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Pyridine (500 mg) and a 40% aqueous solution (300 mg) of methylamine were added to 1-(5-amino-2,4-difluorophenyl)-7-fluoro-6-methyl-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (70 mg), and the mixture was heated and stirred overnight at 40° C. Dimethyl sulfoxide (10 drops) was added to the reaction mixture, followed by stirring at 40° C. for 5 hours. The solvent and the like were distilled off under reduced pressure, and ethanol (0.5 ml) was added to the residue. Solids deposited were collected by filtration aid washed with ethanol and diethyl ether to obtain the title compound (53 mg) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.ONN1C=CN=N1.C(N(CC)C(C)C)(C)C.[Cl:49][C:50]1[CH:51]=[CH:52][C:53]2[N:54]([CH:56]=[C:57]([C:59](O)=[O:60])[N:58]=2)[CH:55]=1>CN(C)C=O.C(=O)([O-])O.[Na+]>[Cl:49][C:50]1[CH:51]=[CH:52][C:53]2[N:54]([CH:56]=[C:57]([C:59]([NH:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[Cl:1])=[O:60])[N:58]=2)[CH:55]=1
Reactant: Nc1ccccc1Cl
Reactant: O=C(O)c1cn2cc(Cl)ccc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1Cl)c1cn2cc(Cl)ccc2n1
Temperature: 70 °C

Procedure:
54 μl of 2-chloroaniline, 211 mg of HATU, 75 mg of 1-hydroxyaminotriazole and 237 μl of N,N-diisopropylethylamine are added to a solution of 100 mg of 6-chloroimidazo[1,2-a]pyridine-2-carboxylic acid in 1 ml of N,N-dimethylformamide. The reaction mixture is heated at 70° C. for 16 hours, diluted with a saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The combined organic phases are dried and concentrated under reduced pressure. The residue is purified by flash chromatography on silica, elution being carried out with a hexane/ethyl acetate 70/30 mixture to give 62 mg of 6-chloro-N-(2-chlorophenyl)imidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][C:4]([CH:6]1[C:11](=[O:12])OC(C)(C)OC1=O)=[O:5].[C:17]12([CH2:27][NH2:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>O1CCOCC1>[C:17]12([CH2:27][NH:28][C:11](=[O:12])[CH2:6][C:4](=[O:5])[CH2:3][CH:2]([CH3:1])[CH3:16])[CH2:24][CH:23]3[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]3)[CH2:18]1)[CH2:26]2
Reactant: CC(C)CC(=O)C1C(=O)OC(C)(C)OC1=O
Reactant: NCC12CC3CC(CC(C3)C1)C2
Solvent: C1COCCO1
Product: CC(C)CC(=O)CC(=O)NCC12CC3CC(CC(C3)C1)C2
Yield: 54.3 %

Procedure:
A solution of 5-(3-methylbutanoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.76 g, 12 mmol) and (1-adamantylmethyl)amine (2 g, 12 mmol) in anhydrous 1,4-dioxane (10 mL) was heated under reflux for 2 h. Solvent was removed in vacuo. The residue was diluted with EtOAc (50 mL), washed with water, aq K2CO3 and brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by chromatography on a silica gel column eluted with 20:1 PE/EtOAc to give the N-(1-adamantylmethyl)-5-methyl-3-oxohexanamide (1.90 g, 54.4%). 1H NMR: (400 MHz, CDCl3): δ=0.92 (s, 3H), 0.96 (s, 3H), 1.54 (s, 7H), 1.62-1.73 (m, 9H), 1.98 (s, 4H), 2.12(m, 1H), 2.45(d, 2H), 2.95(d, 2H), 3.65(s, 2H).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.C(N(C(C)C)CC)(C)C.[N:26]1([C:31](=N)[NH2:32])C=CC=N1>C(#N)C>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:31]([NH2:32])=[NH:26])[CH2:15][CH2:16]2)=[CH:9][CH:10]=1
Reactant: N=C(N)n1cccn1
Reactant: FCCOc1ccc(N2CCNCC2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)N1CCN(c2ccc(OCCF)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of 1-(4-(2-fluoroethoxy)phenyl)piperazine (50 mg, 0.15 mmol) and diisopropylethylamine (59 μL, 0.34 mmol) in ACN (1 mL) was added 1H-pyrazole-1-carboximidamide (25 mg, 0.17 mmol). The reaction stirred at room temperature for 1 h, monitored by LC-MS. The precipitate was then filtered and washed with ACN to obtain the desired product as a white solid (33.8 mg, 58% yield). 1H NMR (300 MHz, DMSO-d6): δ 7.55 (br s, 3H), 6.95-6.86 (m, 4H), 4.78 (m, 1H), 4.62 (m, 1H), 4.21 (m, 1H), 4.11 (m, 1H), 3.57 (dd, 4H, J=5.2, 4.9 Hz), 3.09 (dd, 4H, J=5.1, 5.0 Hz); 19F NMR (DMSO-d6): δ−222.037 (m, 1F); 13C NMR (75.5 MHz, DMSO-d6): δ 156.0, 152.2, 144.9, 119.2, 115.1, 82.2 (81.1), 67.4 (67.2), 48.9, 44.9; HRMS calcd. for C12H17FN2O: 267.16157 found 267.16146.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.C(N(CC)CC)C.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17]>O1CCOCC1>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:1][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=2)=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: O=c1cc(O)cc[nH]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(Oc1cc[nH]c(=O)c1)c1ccc([N+](=O)[O-])cc1
Yield: 73.4 %

Procedure:
To a suspension of 1.00 g of 4-hydroxy-2-pyridone in 50 ml of dried dioxane were added 3.78 ml of triethylamine and a solution of 2.17 g of 4-nitrobenzoyl chloride in 30 ml of dried dioxane, and the mixture was refluxed for 6 hours. After the dioxane was distilled off, the residue was washed with water and then with a 1:1 mixture of methanol-acetone to obtain the title compound in an amount of 1.72 g (yield: 73.4%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([S:18]([N:21]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:20])=[O:19])[CH:16]=[CH:17][C:9]1=2.Br[CH2:37][C:38]#[N:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:38]([CH2:37][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([S:18]([N:21]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:19])=[O:20])[CH:16]=[CH:17][C:9]1=2)#[N:39]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2O)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2OCC#N)cc1
Temperature: 80 °C
Yield: 33.8 %

Procedure:
To a solution of 4-(2-hydroxyphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (From Example 256, Step 3; 550 mg, 1.080 mmol) and 2-bromoacetonitrile (194 mg, 1.62 mmol) in DMF (10 mL) was added potassium carbonate (447 mg, 3.24 mmol). The reaction mixture was heated at 80° C. for 12 h. After completion, the reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with water (3×50 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by combiflash column chromatography (column size: 12 g; elution: 0-30% ethyl acetate in hexane) to yield 4-(2-(cyanomethoxy)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (200 mg, 33.8%). MS (ESI, positive ion) m/z; 549.1 (M+1)
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[CH:23]=[CH:22][C:11]3[CH2:12][CH2:13][CH2:14][CH:15]([C:18]([O:20][CH3:21])=[O:19])[C:16](=O)[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].C(N(CC)CC)C.CS(Cl)(=O)=O.C1CCN2C(=NCCC2)CC1>ClCCl.CO.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:23]=[CH:22][C:11]3[CH2:12][CH2:13][CH2:14][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:10]=3[CH:9]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)C1CCCc2ccc(OCc3ccc(C)cc3)cc2C1=O
Agent: CS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: COC(=O)C1=Cc2cc(OCc3ccc(C)cc3)ccc2CCC1
Temperature: -40 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To methyl 3-(4-methylbenzyloxy)-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylate (2.77 g, 8.19 mmol) dissolved in a mixed solvent of dichloromethane (40 ml) and methanol (10 ml) was added at −40° C. (inner temperature) sodium borohydride (465 mg, 12.3 mmol), and the resulting mixture was stirred at −20° C. to −10° C. for 2 hours. The reaction mixture was cooled to −40° C., was mixed with water (20 ml) and extracted with dichloromethane (40 ml, 10 ml×2). The combined organic layers were dried with anhydrous magnesium sulfate and were then concentrated under reduced pressure. To the residue dissolved in THF (30 ml) were added at 0° C. triethylamine (5.70 ml, 40.9 mmol) and methanesulfonyl chloride (0.95 ml, 12.3 mmol), and the resulting mixture was stirred at room temperature for 12 hours. In order to complete the reaction, DBU (3.67 ml, 24.5 mmol) and dichloromethane (30 ml) were added, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, was mixed with water (30 ml) and was extracted with ethyl acetate (30 ml×3). The combined organic layers were washed with 1 N hydrochloric acid (5 ml×3), were dried with anhydrous magnesium sulfate and were then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel: 60 g, ethyl acetate/hexane=1/30→1/9). The objective fractions were concentrated under reduced pressure to obtain methyl 2-(4-methylbenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (2.40 g, 7.44 mmol, 91%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[NH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(N(CC)CC)C>>[N:19]1([CH2:18][CH2:17][NH:16][S:12]([C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[Cl:1])(=[O:14])=[O:13])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: NCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCCN2CCOCC2)c1Cl
Yield: 74.6 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (600 mg, 2.07 mmol), 4-(2-aminoethyl) morpholine (269 mg, 2.07 mmol) and triethylamine (0.58mL, 4.13 mmol) were reacted to form the desired product (593 mg, 75%). LC-MS (m/z) 384.0 (M+).
Reaction SMILES: Cl.[CH:2](=[NH:6])OCC.[CH3:7][C:8]1[N:9]([NH2:26])[CH:10]=[C:11]([C:13]2[CH:14]=[N:15][N:16]([CH3:25])[C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[N:12]=1>C(O)C>[CH3:7][C:8]1[N:9]([NH:26][CH:2]=[NH:6])[CH:10]=[C:11]([C:13]2[CH:14]=[N:15][N:16]([CH3:25])[C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[N:12]=1
Reactant: CCOC=N
Reactant: Cc1ccc(-c2c(-c3cn(N)c(C)n3)cnn2C)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(-c2c(-c3cn(NC=N)c(C)n3)cnn2C)cc1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
Ethyl imidoformate hydrochloride (608 mg, 5.55 mmol) was added to a solution of 2-methyl-4-[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]-1H-imidazol-1-amine (148 mg, 0.554 mmol) in ethanol (5 mL), and the reaction mixture was heated at 75° C. for 66 hours. Additional ethyl imidoformate hydrochloride (300 mg, 2.74 mmol) was added, and heating was continued for 8 hours. A final charge of ethyl imidoformate hydrochloride (300 mg, 2.74 mmol) was followed by maintaining the reaction at 75° C. for an additional 18 hours. The reaction mixture was cooled, concentrated in vacuo and diluted with ethyl acetate. This organic layer was washed with saturated aqueous sodium bicarbonate solution, washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. Filtration and removal of solvent under reduced pressure, followed by purification using silica gel chromatography (Eluant: 10% methanol in dichloromethane) provided the product as a yellow solid. Yield: 70 mg, 0.24 mmol, 43%. LCMS m/z 295.5 (M+1). 1H NMR (400 MHz, CD3OD), presumed to be a mixture of rotamers or tautomers: δ 2.20 and 2.25 (2 s, 3H), 2.43 (br s, 3H), 3.68 (s, 3H), 6.14 and 6.30 (2 s, 1H), 7.26-7.30 (m, 3H), 7.35 (br d, J=8 Hz, 2H), 7.84 and 7.81 (2 s, 1H).