Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18](OC)=[O:19].[NH2:22][C:23]1[S:24][CH:25]=[C:26]([CH3:28])[N:27]=1>>[OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18]([NH:22][C:23]1[S:24][CH:25]=[C:26]([CH3:28])[N:27]=1)=[O:19]
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Reactant: Cc1csc(N)n1
Product: Cc1csc(NC(=O)C2=C(O)c3sc4ccccc4c3S(=O)(=O)N2C)n1
Yield: 66 %

Procedure:
Prepared analogous to Example 1 from methyl 4-hydroxy-2-methyl-2H-[1]benzothieno[2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-amino-4-methyl-thiazole with a yield of 66% of theory.
Reaction SMILES: [Cl:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:8]=2)[C:3]1=O.[CH3:18][NH:19][C:20]([NH2:22])=[S:21].CC(C)=O>CO>[ClH:1].[CH3:18][NH:19][C:20]1[S:21][C:2]2[CH2:10][C:9]3[CH:8]=[C:7]([C:11]4[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=4)[CH:6]=[CH:5][C:4]=3[C:3]=2[N:22]=1
Reactant: O=C1c2ccc(-c3cccnc3)cc2CC1Cl
Reactant: CNC(N)=S
Solvent: CO
Solvent: CC(C)=O
Product: CNc1nc2c(s1)Cc1cc(-c3cccnc3)ccc1-2
Product: Cl

Procedure:
366 mg of 2-chloro-5-pyridin-3-yl-1-indanone are dissolved with 203 mg of N-methylthiourea in 5 ml of methanol and heated to reflux for 7 h. The reaction mixture is cooled and, after addition of 20 ml of acetone, the precipitate is filtered off with suction, washed with acetone and dried in vacuo. Methyl(6-pyridin-3-yl-8H-indeno[1,2-d]thiazol-2-yl)amine hydrochloride is obtained with a melting point of 225° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:29]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15](=[O:28])[NH:16][CH:17]3[CH:24]4[CH2:25][C:20]5(F)[CH2:21][CH:22]([CH2:26][CH:18]3[CH2:19]5)[CH2:23]4)[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:30][C:31]([O:33]CC)=O.CC[N:38]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:38][C:31](=[O:33])[CH2:30][CH:7]1[C:6]2[C:29](=[CH:2][CH:3]=[CH:4][CH:5]=2)[C:9]2([CH2:10][CH2:11][N:12]([C:15]([NH:16][CH:17]3[CH:18]4[CH2:26][CH:22]5[CH2:21][CH:20]([CH2:25][CH:24]3[CH2:23]5)[CH2:19]4)=[O:28])[CH2:13][CH2:14]2)[CH2:8]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(=O)CC1CC2(CCN(C(=O)NC3C4CC5CC3CC(F)(C5)C4)CC2)c2c(Br)cccc21
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC(=O)CC1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Reaction time: 8 h
Yield: 55.5 %

Procedure:
To a solution of the compound 1 (200 mg, 0.47 mmol) in CH2Cl2 (5 mL), EDCI (187 mg, 0.95 mmol), HOBt (128 mg, 0.95 mmol), DIEA (303 mg, 2.35 mmol) were added under NH3 at 0° C., and then stirred overnight. The solvent was removed under reduced pressure to give crude product, which was purified by preparative TLC to afford (±)-3-(2-amino-2-oxoethyl)-N-(2-adamantyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide (110 mg, 56%). 1H NMR (CDCl3): δ=1.52-1.61 (m, 4H), 1.62-1.66 (m, 2H), 1.68-1.70 (m, 2H), 1.75-1.76 (m, 2H), 1.78-1.80 (m, 1H), 1.82-1.85 (m, 6H), 1.90-1.98 (m, 2H), 2.11-2.21 (m, 1H), 2.30-2.40 (m, 1H), 2.60-2.70 (m, 1H), 2.80-2.88 (m, 1H), 2.95-3.15 (m, 2H), 3.65-3.75 (m, 2H), 3.76-3.88 (m, 1H), 4.00 (s, 2H), 5.40-5.55 (d, 2H), 7.15-7.25 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4]([Cl:11])[N:3]=1.S(Cl)([Cl:15])(=O)=O>ClC(Cl)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]([C:9]([Cl:15])=[O:10])=[C:6]([Cl:8])[N:7]=1
Reactant: O=Cc1c(Cl)nc(Cl)nc1Cl
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(Cl)Cl
Product: O=C(Cl)c1c(Cl)nc(Cl)nc1Cl
Temperature: 60 °C

Procedure:
To the subtitle product of step i) (5.0 g) in dichloroethane (25 ml) was added aza-bis-isobutyronitrile (25 mg) and the mixture heated to 60° C. Sulfuryl chloride (3.67 g) was then added and the reaction heated at 75° C. for 4 h. The same amount of aza-bis-isobutyronitrile (4×25 mg) and sulfuryl chloride (4×3.36 g) was added for 4 days on each day interval. The solvent was evaporated to give a yellow oil which was distilled under reduced pressure to yield the subtitle compound as a yellow oil. Yield 5.8 g.
Reaction SMILES: O.[NH2:2][NH2:3].C[O:5][C:6](=O)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=[O:8]>C(O)C>[NH:2]([C:6](=[O:5])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=[O:8])[NH2:3]
Reactant: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)OC)cc2)CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Hydrazine hydrate (229 mg, 4.57 mmol) was added in one portion to a stirred solution of trans-ethyl 2-[4-(4-{[methoxy(oxo)acetyl]amino}phenyl)cyclohexyl]propanoate (1.3 g, 3.6 mmol) in ethanol (25 mL) and the reaction mixture was stirred at room temperature for 18 h. The mixture was filtered to leave a solid, which was washed with ethanol (10 mL) to give the title compound (Intermediate 99) (1.2 g, 92%) as a solid; 1H NMR δ 1.07 (3H, d), 1.1-1.3 (2H, m), 1.2 (3H, t), 1.36-1.5 (2H, m), 1.5-1.63 (1H, m), 1.65-1.72 (1H, m), 1.75-1.88 (3H, m), 2.2-2.32 (1H, m), 2.35-2.49 (1H, m), 4.0-4.17 (2H, m), 4.6 (2H, s), 7.19 (2H, d), 7.7 (2H, d), 10.44 (1H, s); MS m/e MH+ 362.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=[O:5])=[O:4].C([Li])CCC.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].[CH:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1.CCCCCC>[CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[C:9]([CH:25]([OH:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]=[C:7]1[Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1ccnc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(C(O)c2ccccc2)nc1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.9 %

Procedure:
To a solution of 0.30 g (1.71 mmol) 1-(dimethylsulfamoyl)-imidazole in 10 ml tetrahydrofuran were added 1.2 ml (1.88 mmol) of a 1.6M butyl lithium solution in hexane at −75° C. After stirring for 15 min 0.30 g (2 mmol) tert-butyldimethylsilyl chloride was added at −75° C. and the mixture was stirred at ambient temperature for 2 h. The mixture was cooled down again to −75° C. and 1.2 ml (1.88 mmol) of a 1.6M butyl lithium solution in hexane were added. After stirring for 30 min 0.22 ml (2.14 mmol) benzaldehyde was added at −75° C. and the mixture was allowed to reach room temperature overnight. The mixture was partitioned between water and dichloromethane, re-extracted with dichloromethane and the combined organic layers are dried over MgSO4, filtered and evaporated to yield 0.73 g of an yellow oil, that was used directly in the next step, MS (EI): 338.1 ((M-tBu)+.).
Reaction SMILES: CC(O)C.O.NN.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:27][CH2:28][C:29]2[O:33][N:32]=[C:31]([CH3:34])[CH:30]=2)=[C:13]([CH:26]=1)[CH2:14][N:15]1C(=O)C2C(=CC=CC=2)C1=O>C1COCC1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:27][CH2:28][C:29]2[O:33][N:32]=[C:31]([CH3:34])[CH:30]=2)=[C:13]([CH:26]=1)[CH2:14][NH2:15]
Reactant: Cc1cc(COc2ccc(Cl)cc2CN2C(=O)c3ccccc3C2=O)on1
Agent: NN
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(COc2ccc(Cl)cc2CN)on1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a flask containing anhydrous 2-propanol (40 mL), hydrazine hydrate (4 mL, and anhydrous THF (60 mL), at room temperature, was added 2-{5-chloro-2-(3-methylisoxazol-5-ylmethoxy)benzyl]isoindole-1,3-dione (5 g, 13 mmol). The reaction was stirred at 50° C. for 3 h. The solids were filtered and washed with THF. The filtrate was concentrated, dissolved in ether (100 ml) and washed with 1N NaOH (1×) and brine, dried (MgSO4), filtered and concentrated to afford the title product as a solid.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].[CH2:7]([Li])CCC.[CH3:12][C:13](=[O:16])[CH2:14]C>O1CCCC1>[CH3:12][C:13]([OH:16])([C:5]#[C:4][C:2]([CH3:3])([OH:6])[CH2:1][CH3:7])[CH3:14]
Reactant: [Li]CCCC
Reactant: CCC(C)=O
Reactant: C#CC(C)(C)O
Solvent: C1CCOC1
Product: CCC(C)(O)C#CC(C)(C)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A solution of 2-methyl-3-butyne-2-ol (15 g, 0.178 mol) in tetrahydrofuran (150 ml) is cooled to −78° C. under a nitrogen atmosphere and n-butyl lithium (1.6 molar solution in hexanes, 244 ml, 0.39 mol) is added slowly over 1.5-2.0 hours. The reaction mixture is stirred for 1 hour at −78° C. and to this mixture a solution of 2-butanone (24 ml, 0.266 mol) in tetrahydrofuran (24 ml) is added. The reaction mixture is stirred at −78° C. for one hour and allowed to come to ambient temperature and stirred at ambient temperature for 2-3 hours. The reaction mixture is cooled to 10° C., quenched with ice cold water. The aqueous phase is extracted with dichloromethane (3×150 ml). The organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 2,5-dimethylhept-3-yne-2,5-diol (15 g) as colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:21]=[CH:20][C:7]([CH:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH3:2].C[Si]([C:26]#[N:27])(C)C>>[CH2:1]([O:3][C:4]1[CH:21]=[CH:20][C:7]([CH:8]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=2)[C:26]#[N:27])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1
Reactant: C[Si](C)(C)C#N
Product: CCOc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(4-ethoxybenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a slightly yellow powder (yield 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[NH:26][C:27]4[CH:37]=[CH:36][C:35]5[C:30](=[C:31]([OH:42])[CH:32]=[C:33]([S:38](Cl)(=[O:40])=[O:39])[CH:34]=5)[C:28]=4[N:29]=3)[CH:20]=2)[CH:15]=[CH:16][C:17]=1[CH3:18].Cl>C1COCC1.O>[CH3:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[NH:26][C:27]4[CH:37]=[CH:36][C:35]5[C:30](=[C:31]([OH:42])[CH:32]=[C:33]([S:38]([NH:1][C:2]6[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=6)[C:5]([OH:7])=[O:6])(=[O:40])=[O:39])[CH:34]=5)[C:28]=4[N:29]=3)[CH:20]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: Cc1ccc(-c2cccc(-c3nc4c(ccc5cc(S(=O)(=O)Cl)cc(O)c54)[nH]3)c2)cc1C
Reactant: Nc1cccc(C(=O)O)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(-c3nc4c(ccc5cc(S(=O)(=O)Nc6cccc(C(=O)O)c6)cc(O)c54)[nH]3)c2)cc1C
Reaction time: 0.5 h
Yield: 4.9 %

Procedure:
To an agitated suspension of 3-aminobenzoic acid (0.028 g, 0.2 mmol) in THF (1 mL) was added 2-(3′,4′-dimethylbiphenyl-3-yl)-9-hydroxyl-3H-naphtho[1,2-d]imidazole-7-sulfonyl chloride (0.083 g, 0.18 mmol) and sodium hydroxy (0.018 g, 0.4 mmol) in water (0.5 mL). After agitated for 30 minutes, the reaction mixture was added 6N hydrochloride (2 ml) and concentrated under reduced pressure. The residue was subjected to HPLC (ODS-A, gradient 10-90% CH3CN/water 0.1% TFA) to provide the title compound (0.005 g, 4%) MS(ES) m/z 564 [M+H].
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]1[CH2:22][CH2:23][CH2:24][CH:25]([NH2:26])[C:17]1=[C:16]2[CH3:27].O>O1CCCC1>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]1[CH2:22][CH2:23][CH2:24][CH:25]([NH:26][CH:1]=[O:3])[C:17]1=[C:16]2[CH3:27]
Reactant: COc1ccc2c(c1)c(C)c1n2CCCC1N
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)c(C)c1n2CCCC1NC=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of formic acid (6 mL) and acetic anhydride (12 mL) was heated at 60° C. for 4 hours. A solution of 6,7,8,9-tetrahydro-2-methoxy-10-methylpyrido[1,2-a]indol-9-amine (5.8 g, 25.2 mmol) in dry tetrahydrofuran (60 mL) was added upon cooling to the resultant mixed anhydride. The reaction mixture was stirred at 25° C. overnight, poured into water (100 mL), and extracted with ether (3×70 mL). The combined extracts were washed successively with 5% hydrochloric acid (80 mL), 5% aqueous sodium bicarbonate (100 mL), and water (100 mL). The ethereal solution was dried over MgSO4, filtered, and evaporated. The solid residue was crystallized from ether-hexane to give 5.4 g (83%) of the title formamide, m.p. 130°-132° C. as a beige solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].[C:12]([O:17][CH2:18][CH2:19][N:20]=[C:21]=[O:22])(=[O:16])[C:13]([CH3:15])=[CH2:14].[N-]=C=O>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C1(C)C=CC=CC=1>[CH3:15][C:13](=[CH2:14])[C:12]([O:17][CH2:18][CH2:19][NH:20][C:21]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])=[O:22])=[O:16]
Reactant: O=[N+]([O-])c1ccccc1CO
Reactant: C=C(C)C(=O)OCCN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: [N-]=C=O
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCCNC(=O)OCc1ccccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A composition was prepared by mixing 14.4 g (94 mmol) of 2-nitrobenzyl alcohol (Alfa Aesar; Ward Hill, Mass.), 14.6 g (94 mmol) of isocyanatoethyl methacrylate (Aldrich; Milwaukee, Wis.) and 1 drop of dibutyltin dilaurate (Alfa Aesar) in a 4 ounce glass jar. The jar was sealed and placed in an oven set at 70° C. for 2 hours. Analysis of the reaction mixture by infrared (IR) spectroscopy (Nexus 670 FT-IR E.S.P., Thermo Nicolet Corp.; Madison, Wis.) showed no absorbance at 2250 cm−1, indicating substantially no remaining isocyanate functionality. To the cooled reaction mixture were added 40 mL of toluene and the jar was placed in a refrigerator overnight. The next day, white crystals that had formed were filtered off and dried to provide 26.9 g of 2-({[(2-nitrobenzyl)oxy]carbonyl}amino)ethyl 2-methylacrylate (NBMA). The structure of the product was confirmed by NMR and IR spectroscopy analyses.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[CH2:23]([O:25][C:26](=[O:36])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]=[C:34]=[O:35])[CH:28]=1)[CH3:24].O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:34]([NH:33][C:29]5[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=5)[C:26]([O:25][CH2:23][CH3:24])=[O:36])=[O:35])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Reactant: CCOC(=O)c1cccc(N=C=O)c1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cccc(NC(=O)N2CCc3c(cnc4c3cnn4Cc3ccc(OC)cc3)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
To a solution of 3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.208 g, 0.707 mmol) in anhydrous dichloromethane (10 mL) was added 3-isocyanato-benzoic acid ethyl ester (0.135 g, 0.707 mmol). The reaction was then shaken at room temperature for 30 minutes. On completion of the reaction water (10 mL) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (20 mL). The organic extracts were combined, washed with brine (2×20 mL), dried using sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified using flash column chromatography (SiO2, gradient from 50% EtOAc in hexanes to 66% EtOAc in hexane) to give the pure desired product, ethyl 3-(3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamido)benzoate (0.265 g, 77%) as a white solid. M.p.=>80° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.97 (s, 1H), 8.41 (s, 1H), 8.2 (s, 1H), 8.14-8.1 (m, 1H), 7.85-7.8 (m, 1H), 7.57-7.53 (m, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.21-7.16 (m, 2H), 6.88-6.82 (m, 2H), 5.59 (s, 2H), 4.81 (s, 2H), 4.31 (q, J=7.2 Hz, 2H), 3.84 (t, J=6 Hz, 2H), 3.69 (s, 3H), 3.15 (t, J=6 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H); LCMS [M+H]: 486.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[C:27]([NH2:30])(=[O:29])[CH3:28]>>[C:27]([NH:30][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1)(=[O:29])[CH3:28]
Reactant: CC(N)=O
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(Br)ccc1OC2)c1ccc(F)cc1F
Product: CC(=O)Nc1ccc2c(c1)-c1sc(C(=O)N(C)c3ccc(F)cc3F)cc1CO2

Procedure:
Following Example 70 and General Procedure D, 8-bromo-N-(2,4-difluorophenyl)-N-methyl-4H-thieno[3,2-c]chromene-2-carboxamide 160bp and acetamide were reacted to give 121bp. 1H NMR (400 MHz, CDCl3) δ 6.84-7.31 (m, 6H), 6.76 (s, 1H), 5.05 (s, 2H), 3.40 (s, 3H), 2.16 (s, 3H). LCMS (ESI) m/z: 414.9
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1)[NH2:2].[N:13]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[C:14]=[S:15]>C(#N)C.CCOCC>[OH:12][C:9]([C:6]1[CH:5]=[CH:4][C:3]([NH:1][NH:2][C:14](=[S:15])[NH:13][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:8][CH:7]=1)([CH3:10])[CH3:11]
Reactant: CC(C)(O)c1ccc(NN)nc1
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)(O)c1ccc(NNC(=S)Nc2ccc([N+](=O)[O-])cc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
A mixture of 2-(6-hydrazinylpyridin-3-yl)propan-2-ol (250 mg, 1.495 mmol) and 1-isothiocyanato-4-nitrobenzene (269 mg, 1.495 mmol) in ACN (Volume: 2.0 mL) was stirred at room temperature for 1 hr. The reaction was diluted with Et2O (Volume: 5.0 mL), and the resulting solid was filtered. Minimal product was present in the solid. On standing for 1 hr, the filtrate had formed a precipitate. This was filtered to provide 2-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)-N-(4-nitrophenyl)hydrazinecarbothioamide (175 mg, 0.504 mmol, 33.7% yield) as an orange solid. A solution of 2-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)-N-(4-nitrophenyl)hydrazinecarbothioamide (275 mg, 0.792 mmol) in DME (Volume: 2.0 mL) was heated in a microwave on high absorbance for 3 hr at 110° C. The reaction was stripped to dryness onto silica gel via rotary evaporation and purified compound by MPLC with DCM:MeOH (98:2) to provide 2-(3-mercapto-[1,2,4]triazolo[4,3-a]pyridin-6-yl)propan-2-ol.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:16]([N:19]([CH:30]([CH3:32])[CH3:31])[CH2:20][CH2:21][NH:22][C:23](N1C=CN=C1)=[O:24])([CH3:18])[CH3:17].C(N(CC)CC)C>ClCCl>[CH:30]([N:19]([CH:16]([CH3:18])[CH3:17])[CH2:20][CH2:21][NH:22][C:23]([NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:24])([CH3:32])[CH3:31]
Reactant: NCCNC(=O)OCc1ccccc1
Reactant: CC(C)N(CCNC(=O)n1ccnc1)C(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(CCNC(=O)NCCNC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Yield: 109.6 %

Procedure:
A solution of benzyl 2-aminoethylcarbamate hydrochloride (4.33 g, 18.8 mmol), N-[2-(diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (Preparation 19) (3.73 g, 15.64 mmol) and triethylamine (2.62 ml, 18.8 mmol) in dichloromethane (100 ml) was heated under reflux for 14 hours. The solution was allowed to cool to room temperature and then washed with water (20 ml). The aqueous layer was separated and extracted with more dichloromethane (20 ml). The combined organic layers were dried over anhydrous magnesium sulfate and solvent evaporated under reduced pressure to give the title compound as a yellow oil (6.25 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.Cl.[C:12]([S:16][CH2:17][C:18](=O)[CH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])([CH3:15])([CH3:14])[CH3:13]>CC(O)(C)C>[C:12]([S:16][C:17]1[C:7]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[NH:9][C:18]=1[CH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])([CH3:15])([CH3:14])[CH3:13]
Reactant: COc1ccc(NN)cc1
Reactant: COC(=O)C(C)(C)CC(=O)CSC(C)(C)C
Agent: Cl
Solvent: CC(C)(C)O
Product: COC(=O)C(C)(C)Cc1[nH]c2ccc(OC)cc2c1SC(C)(C)C
Temperature: 25 °C
Yield: 39.3 %

Procedure:
A mixture containing 4-methoxyphenyl hydrazine . HCl (70.66 g, 0.405 mol) and methyl 5-(t-butylthio)-2,2-dimethyl-4-oxopentanoate (99.54 g, 0.405 mol) in tBuOH (400 ml) was heated at a gentle reflux for 48 hours. The mixture was allowed to cool to RT and the precipitated NH4Cl was removed by filtration. The residue was concentrated and fractionated on a plug of silica using EtOAc/hexane (1:3) as eluent. Evaporation of the appropriate fraction gave an orange-brown solid which was crystallized from EtOH (100 ml). Yield from two crops afforded 55.6g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([CH2:14][NH2:15])[CH:8]=2)[CH:4]=[CH:5][N:6]=1.Cl.[C:17](=N)(OC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N)(=N)C1C=CC=CC=1>CO.O=[Mn]=O>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:9]3[C:10](=[CH:12][CH:13]=2)[N:11]=[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]=[CH:14]3)[CH:4]=[CH:5][N:6]=1
Reactant: COC(=N)c1ccccc1
Reactant: Cc1nccn1-c1ccc(N)c(CN)c1
Agent: O=[Mn]=O
Agent: Cl
Agent: N=C(N)c1ccccc1
Solvent: CO
Product: Cc1nccn1-c1ccc2nc(-c3ccccc3)ncc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
4-(2-methyl-1H-imidazol-1-yl)-2-aminomethylaniline (2.0 g, 10 mmol) and methyl benzimidate hydrochloride (3.5 g, 20 mmol; RN: 5873-90-5, Aldrich) were dissolved in methanol (50 mL), the resulting mixture was heated at reflux for 2 hours, during this time the aminomethyl-derivative was converted into the corresponding benzamidine. After that, the methanol was evaporated and the residue taken up with glacial acetic acid (50 mL), the reaction mixture was heated at reflux for 1.5 hours. After cooling at r.t. the reaction mixture was diluted with toluene (50 mL) and evaporated. The residue was taken up with AcOEt (400 mL), washed with aq. ammonia, with water, then dried and concentrated. The obtained oily residue was dissolved in DCM (400 mL) and MnO2 (6.0 g, 70 mmol) was added at r.t., in three portions, over 2 hours. The resulting suspension was stirred at r.t. for 24 hrs, then filtered over celite and the cake was rinsed with DCM. The combined filtrate and washings were concentrated and the residue chromatographed over silica gel (DCM/MeOH/NH3, 85:25.2) the appropriate combined fractions were evaporated and the residue taken up with ethyl ether, heated at reflux for 5 minutes then cooled at 25° C. to crystallize the titled product as slightly brown powder (2.0 g; yield: 74%). C18H14N4, MW: 286.34; MS: m/z 287 (M+H); 1H-NMR (200 MHz, d6-DMSO) ppm: 2.40 (s, 1H), 7.0 (s, 1H), 7.40 (s, 1H), 7.60 (m, 3H), 8.10-8.30 (m, 3H), 8.60 (m, 2H), 9.80 (s, 1H).