Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C@@H:5]1[NH:10][CH2:9][CH2:8][N:7]([C:11]2[C:20]3[N:19]=[C:18]([CH:21]([CH3:23])[CH3:22])[S:17][C:16]=3[NH:15][C:14]3[CH:24]=[CH:25][CH:26]=[CH:27][C:13]=3[N:12]=2)[CH2:6]1.C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][CH2:3][CH2:4][C@@H:5]1[N:10]([CH3:30])[CH2:9][CH2:8][N:7]([C:11]2[C:20]3[N:19]=[C:18]([CH:21]([CH3:23])[CH3:22])[S:17][C:16]=3[NH:15][C:14]3[CH:24]=[CH:25][CH:26]=[CH:27][C:13]=3[N:12]=2)[CH2:6]1
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(C)C)nc32)CCN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(C)C)nc32)CCN1C
Yield: 89.6 %

Procedure:
Combine (S)-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.181 g, 0.469 mmol), formaldehyde (50 μL, 0.610 mmol, 37%), and sodium triacetoxyborohydride (0.149 g, 0.704 mmol) in dichloroethane (12 mL) and stir at room temperature for 2 hours. Dilute the mixture with saturated sodium bicarbonate and extract three times with methylene chloride. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure to give the crude product. Purification by flash chromatography, eluting with a step gradient starting with dichloromethane going to 5% 2N ammonia-methanol in dichloromethane gives (S)-10-[3-(2-methoxy-ethyl)-4-methyl-piperazin-1-yl]-2 isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.168 g, 0.420 mmol, 90%) as a yellow oil: mass spectrum (APCI): m/z=400.3 (M+1). Isolate clean product as the corresponding dihydrochloride in the following manner: dissolve the yellow foam in ethanol (5 mL) and add a solution of about 5 equivalents of HCl in ethanol (5 mL). Evaporate the mixture to obtain the title compound as a brown foam. Exact Mass, Calc: 400.2171; Found: 400.2171.
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[C:7]([N+:16]([O-:18])=[O:17])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cc([N+](=O)[O-])cc2c1OC(C)(C)C2
Reaction time: 1 h

Procedure:
2,3-Dihydro-2,2-dimethyl-7-benzofuranol (16.4 g, 0.1 mol) was dissolved in 100 ml of an aqueous solution of sodium hydroxide (6.0 g, 0.15 mol), and 12.8 g of acetic anhydride was dumped into the solution and thoroughly mixed, whereby a white solid substance was precipitated. This substance was collected by filtration and dried, whereby 19.5 g of 7-acetoxy-2,3-dihydro-2,2-dimethylbenzofuran was obtained. The melting point of this product was 48.5°-49.5° C. This phenol acetate was dissolved in 400 ml of chloroform, and 60 ml of 70% nitric acid was dropwise added at -5° C. Then, the stirring was continued at 10° C. for one hour. The reaction solution was washed with water, then dried over anhydrous sodium sulfate and concentrated. The solid substance thereby obtained was recrystallized from benzene-cyclohexane, whereby 19.6 g of 7-acetoxy-2,3-dihydro-2,2-dimethyl-5-nitrobenzofuran was obtained. The melting point of this product was 141°-142° C. The structure was confirmed by 1H-NMR spectrum and IR spectrum. Then, the product was added to a solution containing 35 g of sodium hydroxide in 200 ml of water and 50 ml of methanol, and heated at 40° C. for 15 minutes to complete hydrolysis. The reaction solution was neutralized by concentrated hydrochloric acid, and then extracted with ether. The extracted solution was washed with water, then dried over anhydrous sodium sulfate and concentrated, whereby 13.0 g of substantially pure 2,3-dihydro-2,2-dimethyl-5-nitro-7-benzofuranol was obtained. The melting point of this product was 97°-97.5° C. The phenol thus obtained, was reacted with O-ethyl-S-n-propyl-thiophosphoryl chloride in the same manner as in Example 1, whereby the compound (No. 4) identified in Table 1 was obtained as oily substance.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([OH:12])=O)[C:7]([NH:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[CH3:20][NH:21][C:22]([C:24]1[N:25]([CH3:30])[N:26]=[CH:27][C:28]=1[NH2:29])=[O:23]>>[CH3:30][N:25]1[C:24]([C:22](=[O:23])[NH:21][CH3:20])=[C:28]([NH:29][C:10]([C:8]2[C:7]([NH:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[N:9]=2)=[O:12])[CH:27]=[N:26]1
Reactant: O=C(O)c1nc(C2CC2)cnc1Nc1cccnc1
Reactant: CNC(=O)c1c(N)cnn1C
Product: CNC(=O)c1c(NC(=O)c2nc(C3CC3)cnc2Nc2cccnc2)cnn1C

Procedure:
The product was obtained starting from 6-cyclopropyl-3-(pyridin-3-ylamino)pyrazine-2-carboxylic acid (30 mg, 0.12 mmol) and 4-amino-2-methyl-2H-pyrazole-3-carboxylic acid methylamide (23 mg, 0.15 mmol) according to the method described in example 64, step 6 as yellow solid (30 mg, 64%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:41])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH2:39]C)[CH:33]=2)[CH:27]=1)=O)(C)(C)C.[C:43](O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:19])([F:20])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:41])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH2:39][CH3:43])[CH:33]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(CC)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)nc(CC)c3)c1)=N2

Procedure:
The title compound was prepared from (5-ethoxy-2-{3-[3-(2-ethyl-6-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M230) (282 mg, 0.48 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (205 mg, 91%).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:17])[N:6]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:7]=[CH:8][C:9]=1[N:10](C)C)(=O)[CH3:2].[NH2:18]N>C(O)C>[C:13]([N:6]1[C:5](=[O:17])[C:4]2[C:1]([CH3:2])=[N:18][NH:10][C:9]=2[CH:8]=[N:7]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(=O)c1c(N(C)C)cnn(C(C)(C)C)c1=O
Reactant: NN
Solvent: CCO
Product: Cc1n[nH]c2cnn(C(C)(C)C)c(=O)c12

Procedure:
4-Acetyl-2-t-butyl-5-dimethylamino-3(2H)-pyridazinone (2.5 g) was added to hydrazine (3.2 g)/ethanol (30 ml) and the mixture was refluxed for 6 hours. After the ethanol-hydrazine was distilled off, the residue was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated to dryness. The residue was washed with n-hexane and diethyl ether and dried. White powder, 1.7 g. 1H-NMR (CDCl3) 6: 1.70(9H,s), 2.74(3H,s), 8.10(1H,s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16](C(O)=O)[CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.O=C1C2C(=CC([C:35]([OH:37])=[O:36])=CC=2)C=CN1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([C:35]([OH:37])=[O:36])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccc2c(=O)[nH]ccc2c1
Reactant: COc1ccc(CNc2nccc3ccc(C(=O)O)cc23)cc1
Product: COc1ccc(CNc2nccc3cc(C(=O)O)ccc23)cc1

Procedure:
The title compound was prepared by a method analogous to that described in Steps 2-5 of Intermediate 27, using 1-oxo-1,2-dihydroisoquinoline-6-carboxylic acid. +ESI (M+H) 309.2; 1H NMR (400 MHz, CD3OD, δ): 8.37 (d, J=1.56 Hz, 1H), 8.34 (d, J=8.78 Hz, 1H), 8.12 (dd, J=8.68, 1.66 Hz, 1H), 7.67 (d, J=6.44 Hz, 1H), 7.29-7.36 (m, 2H), 7.15 (d, J=6.24 Hz, 1H), 6.86-6.93 (m, 2H), 4.73 (s, 2H), 3.76 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:14][CH:15]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=4)[CH2:22][CH2:21]3)[CH2:16][CH2:17][CH2:18][NH-:19])[S:12][CH:13]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>ClCCl.C(Cl)(Cl)Cl>[ClH:33].[C:42]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:14][CH:15]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=4)[CH2:22][CH2:21]3)[CH2:16][CH2:17][CH2:18][NH-:19])[S:12][CH:13]=2)=[CH:5][CH:4]=1)(=[O:44])[CH3:43]
Reactant: CC(=O)Cl
Reactant: [NH-]CCCC(Sc1nc(-c2ccc(N)cc2)cs1)C1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-c2csc(SC(CCC[NH-])C3CCN(Cc4ccc(Cl)c(Cl)c4)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The product (106 mg) of Example 5 was dissolved in dichloromethane (80 mL), and triethylamine (30 μL) and acetyl chloride (15 μL) were added to the solution. The mixture was stirred at room temperature for 12 hrs. The reaction mixture was diluted with chloroform, washed with 0.1 mol/L sodium hydroxide and then saturated brine, and dried. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in ethanol (10 mL). 1 mol/L Hydrogen chloride diethyl ether solution (2 mL) was added, which was followed by filtration to give the title compound (62 mg) as a white amorphous solid.
Reaction SMILES: C([O:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:22]2[O:23][C:24]([CH3:27])=[N:25][N:26]=2)=[O:21])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:22]2[O:23][C:24]([CH3:27])=[N:25][N:26]=2)=[O:21])=[CH:11][CH:10]=1
Reactant: Cc1nnc(C(=O)CCCCCCOc2ccc(OCc3ccccc3)cc2)o1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1nnc(C(=O)CCCCCCOc2ccc(O)cc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a solution of 65.2 (30 mg, 0.076 mmol) in AcOEt (5 mL) was added 10% Pd/C (6 mg, 20% w/w) and the resulting suspension was stirred vigorously under hydrogen atmosphere, overnight at room temperature. The catalyst was removed by filtration through Celite, and the filtrate was evaporated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (60% ethyl acetate-hexane) to give pure compound 66 (0.016 g, 71% yield) as a white solid (m p 134-135° C.).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[CH3:32]>>[CH3:32][C:31]1[CH:30]=[CH:29][C:28]([C:2]2[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:27][C:26]=1[NH2:25]
Reactant: CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: Cc1ccc(B(O)O)cc1N
Product: Cc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C)CC4)cc3n2)cc1N

Procedure:
2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 3-amino-4-methylbenzeneboronic acid in general procedure A. Purification by flash chromatography on silica yielded 2-Methyl-5-[6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-phenylamine. To a solution of 2-Methyl-5-[6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-phenylamine (154 mg) in chloroform (10 ml) and acetic acid (2 ml) was added isoamyl nitrite (55 μL). The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with chloroform and washed with a 50/50 mixture of saturated sodium bicarbonate solution and brine, dried (MgSO4) and the solvents were removed in vacuo to give a crude residue. This was purified by flash chromatography to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)[N:12]([C@@H:21]([CH2:29][CH3:30])[CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:11](=[O:31])[C@:10]([CH2:33][CH:34]=[O:35])([CH3:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CC(=CC)C.Cl([O-])=[O:42].[Na+].O.O.P([O-])(O)(O)=O.[Na+]>CC(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)[N:12]([C@@H:21]([CH2:29][CH3:30])[CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:11](=[O:31])[C@:10]([CH2:33][C:34]([OH:42])=[O:35])([CH3:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CN1CCOCC1)N1C(=O)[C@@](C)(CC=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cn1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC[C@@H](CN1CCOCC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 16 mg (0.03 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetaldehyde (Example 121, Step O) and 1.0 mL (9.4 mmol) of 2-methyl-2-butene in t-BuOH (3 mL) was added a solution of 28 mg (0.31 mmol) of sodium chlorite and 4.6 mg (0.03 mmol) of sodium dihydrogenphosphate dihydrate in water (1.6 mL). The resulting mixture was stirred at room temperature for 2 h, and then was quenched with 1 M HCl and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by reversed phase prep. HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 35% MeCN in water to 60% MeCN in water over a 35 min period, where both solvents contain 0.1% TFA provided the title compound as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[CH:14]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>O1CCOCC1>[C:21]1([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:27]2[CH2:28][CH2:29][N:30]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=3)[CH2:31][CH2:32]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.8 %

Procedure:
A 200 ml eggplant-shaped flask was charged with 5.38 g of methyl 4-bromomethylphenylacetate, 6.06 g of 1-benzhydrylpiperazine, 6.1 ml of triethylamine, and 100 ml of dioxane and the mixture was stirred at room temperature for 5 hours. The solvent was then distilled off and the residue was extracted with ethyl acetate. The extract was washed with water, the solvent was distilled off, and the residue was recrystallized from methanol to provide 8.33 g of methyl 4-[(4-diphenylmethyl-1-piperazinyl)methyl]phenylacetate melting at 124° C.-125° C.
Reaction SMILES: N[C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.[CH3:11][O:12][CH2:13][O:14][CH2:15][C:16]([NH2:18])=[NH:17].[CH3:19][OH:20]>>[NH2:10][C:9]1[C:3]2[C:2](=[N:7][C:6]([O:20][CH3:19])=[CH:5][N:4]=2)[N:18]=[C:16]([CH2:15][O:14][CH2:13][O:12][CH3:11])[N:17]=1
Reactant: CO
Reactant: COCOCC(=N)N
Reactant: N#Cc1ncc(Cl)nc1N
Product: COCOCc1nc(N)c2ncc(OC)nc2n1

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 11.2 g (0.0725 mole) of 3-amino-5-chloro-2-pyrazinecarbonitrile[prepared according to E. C. Taylor et al. 1975, 40, 2341] and the above solution of 2-(methoxymethoxy)acetamidine in methanol. Refluxing time: 5 hours. Yld: 13.2 g (72%), m.p. 193°-195° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:24][CH3:25])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2NC1C=CC(C)=C(O)C=1)=[O:5])[CH3:2].[NH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[N:31][CH:32]=1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:24][CH3:25])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:26][C:27]1[CH:32]=[N:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(N)cn1
Reactant: CCOC(=O)c1cn2ncnc(Nc3ccc(C)c(O)c3)c2c1OC
Solvent: CC#N
Product: CCOC(=O)c1cn2ncnc(Nc3ccc(OC)nc3)c2c1OC
Yield: 36.4 %

Procedure:
Compound G of Example 96 (0.1 mmol) and 5-amino-2-methoxypyridine (62 mg, 0.5 mmol) in CH3CN (0.5 mL) was stirred for 2 hrs. The crude mixture was purified by preparative HPLC. The desired material was collected, concentrated, and neutralized with aqueous NaHCO3. The solid was collected, washed with water, and dried to provide 12.5 mg (36%) of red solid. MS: [M+H]+=344; 1H NMR (CDCl3): δ 8.30 (s, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.78 (d, J=7.9 Hz, 2H), 6.77 (d, J=8.8 Hz, 1H), 4.30 (q, J=7.0 Hz, 2H), 4.11 (s, 3H), 3.89 (s, 3H), 1.33 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3][C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.C(=O)C1C=CC=CC=1.C1(N)C=CC=CC=1N>C(O)C>[F:16][C:2]([F:1])([F:17])[S:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:14][CH:15]=1
Reactant: N#CC(C#N)=Cc1ccc(SC(F)(F)F)cc1
Agent: Nc1ccccc1N
Solvent: O=Cc1ccccc1
Solvent: CCO
Product: N#CC(C#N)Cc1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Yield: 77.1 %

Procedure:
Then, 8.00 g of (4-(trifluoromethylthio)benzylidene)malononitrile and 3.35 g of benzaldehyde were dissolved in 320 ml of ethanol, and while stirring at room temperature, 3.41 g of phenylenediamine was slowly added, and the mixture was stirred at room temperature for 5 hours. Then, the reaction mixture was concentrated, 300 ml of t-butyl methyl ether was added, and insoluble matters were filtered. The filtrate was concentrated and the resulting residue was subjected to silica gel chromatography to give 6.22 g of (4-(trifluoromethylthio)benzyl)malononitrile (the intermediate (14)).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]2[O:6][CH2:7][O:8][CH2:9][C:4]=2[CH:3]=1>CO.[Ni]>[O:6]1[C:5]2[CH:10]=[C:11]([NH2:12])[C:2]([NH2:1])=[CH:3][C:4]=2[CH2:9][O:8][CH2:7]1
Reactant: Nc1cc2c(cc1[N+](=O)[O-])OCOC2
Agent: [Ni]
Solvent: CO
Product: Nc1cc2c(cc1N)OCOC2
Yield: 84.4 %

Procedure:
14.4 g of 6-amino-7-nitro-1,3-benzodioxane were hydrogenated in 1 l of methanol with Raney-nickel. After completion of the H2 -uptake, the catalyst was separated, the solvent was removed by evaporation in vacuo, and the residue was recrystallized from isopropanol. 10.3 g (84.4% of theory) of 1,3-benzodioxane-6,7-diamine of melting point 156°-158° C. were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:7][CH2:8][C:9]2(C)[CH3:12])=[CH:4][CH:3]=1.BrC1C=C2C(=CC=1)C(=O)CC2(C)C>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[CH:7][C:9]2([CH3:8])[CH3:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C2=CCC(C)(C)c3cc(Br)ccc32)cc1
Agent: CC1(C)CC(=O)c2ccc(Br)cc21
Product: Cc1ccc(C2=CC(C)(C)c3cc(Br)ccc32)cc1
Yield: 75 %

Procedure:
Following a procedure similar to that for the preparation of 7-bromo-1,1-dimethyl-4-p-tolyl-1,2-dihydro-naphthalene (Compound 4) while using 5-bromo-3,3-dimethyl-indan-1-one (Compound 12, 1.00 g, 4.2 mmol) as the starting material yielded the title compound (981 mg, 75% yield) as a colorless oil:
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[C:15]2[S:14](=[O:17])(=[O:16])[N:13]=[C:12]([CH2:18][C:19]([OH:21])=O)[NH:11][C:10]=2[S:9][CH:8]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1([O:38][C:39](N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.C(OC(=O)[CH:57]([CH2:62][NH:63][CH2:64][C:65]1[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=1)[CH2:58][CH:59]([CH3:61])[CH3:60])C.[O-]CC.[Na+].C(O)C>CN(C)C=O>[F:71][C:68]1[CH:67]=[CH:66][C:65]([CH2:64][N:63]2[CH2:62][CH:57]([CH2:58][CH:59]([CH3:60])[CH3:61])[C:19]([OH:21])=[C:18]([C:12]3[NH:11][C:10]4[S:9][CH:8]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:15]=4[S:14](=[O:16])(=[O:17])[N:13]=3)[C:39]2=[O:38])=[CH:70][CH:69]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C(CNCc1ccc(F)cc1)CC(C)C
Agent: CC[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CN1CCOCC1
Product: CC(C)CC1CN(Cc2ccc(F)cc2)C(=O)C(C2=NS(=O)(=O)c3c(CNS(C)(=O)=O)csc3N2)=C1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.2 %

Procedure:
[7-(Methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid (prepared as described in Example 2c; 0.133 g, 0.376 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.157 g, 0.413 mmol) and 4-methylmorpholine (0.083 mL, 0.755 mmol) were added sequentially to a solution of rac-2-[(4-fluoro-benzylamino)-methyl]-4-methyl-pentanoic acid ethyl ester (0.106 g, 0.377 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 18 h, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was dissolved in ethanol (10 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (0.732 mL, 2.26 mmol) was added and the reaction mixture was heated to 70° C. for 22 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography (Teledyne Isco RediSep column; 50-100% ethyl acetate in hexanes) to afford (after trituration with diethylether) rac-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-5-isobutyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.097 g, 0.170 mmol, 45%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.73 (3H, d, J=5.5 Hz), 0.77 (3H, d, J=5.5 Hz), 1.17-1.21 (1H, m), 1.31-1.33 (2H, m), 2.60 (1H, bs), 2.95 (3H, s), 3.16 (1H, d, J=13.3 Hz), 3.58 (1H, dd, J1=4.8 Hz, J2=12.5 Hz), 4.24 (2H, d, J=5.4 Hz), 4.34 (1H, d, J=15.0 Hz), 4.85 (1H, d, J=14.6 Hz), 7.15-7.19 (2H, m), 7.25 (1H, s), 7.37-7.40 (2H, m), 7.64 (1H, t, J=5.9 Hz). LC-MS (ESI) calculated for C23H27FN4O6S3 570.11. found 571.2 [M+H+].
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[CH:33]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][CH2:34]1>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:37]([CH:33]3[CH2:36][CH2:35][CH2:34]3)=[O:38])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: O=C(Cl)C1CCC1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)C3CCC3)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 μmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, cyclobutanecarbonyl chloride (23 mg, 193 μmol, 3 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (21.9 mg, 68% of theory).