Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.CC(C)([O-])C.[K+].C1COCC1.C[O:27][C:28](=O)[C:29]([C:31]1[C:39]2[C:34](=[CH:35][C:36]([Br:40])=[CH:37][CH:38]=2)[NH:33][CH:32]=1)=O>CN(C=O)C>[Br:40][C:36]1[CH:35]=[C:34]2[C:39]([C:31]([C:29]3[C:28](=[O:27])[NH:14][C:12](=[O:13])[C:11]=3[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:2]([CH3:1])[CH:3]=[CH:4]4)=[CH:32][NH:33]2)=[CH:38][CH:37]=1
Reactant: COC(=O)C(=O)c1c[nH]c2cc(Br)ccc12
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5cc(Br)ccc45)C(=O)NC3=O)c21
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 73.4 %

Procedure:
To solution of 2-(1-methyl-1H-indol-7-yl)-acetamide (0.300 g, 1.59 mmol) in DMF (15 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (1.59 mL, 1.59 mmol), followed after 5 minutes by (6-bromo-1H-indol-3-yl)-oxo-acetic acid methyl ester (0.235 g, 0.83 mmol) in DMF (1.25 mL). After another 5 minutes additional potassium tert-butoxide (1.59 mL) was introduced followed by the additional (6-bromo-1H-indol-3-yl)-oxo-acetic acid methyl ester (0.235 g, 0.83 mmol) in DMF (1.25 mL). The reaction was stirred for 5 minutes and an additional potassium tert-butoxide (1.59 mL) was introduced. After heating at 50° C. over night, then deep red solution and was cooled to room temperature, quenched with 1N HCl and poured in EtOAc. The two layers were separated and the organic layer was washed with H2O, saturated aq NaHCO3, and brine (×3), dried (MgSO4), filtered, and concentrated. Flash chromatography (80% EtOAc/hexane) gave the title compound (0.256 g, 38%) as a red solid. 1H NMR (400 MHz, DMSO-d6) 3.64 (s, 3H), 6.26 (d, J=4.4 Hz, 1H), 6.47 (d, J=2.8 Hz, 1H), 6.60 (dd, J=2, 8.8 Hz, 1H), 6.88 (d, J=7.2 Hz, 1H), 6.98 (dd, J=7.2, 7.2 Hz, 1H), 7.24 (d, J=3.6 Hz, 1H), 7.61 (dd, J=1.2, 8 Hz, 1H), 7.87 (d, J=2.8 Hz, 1H), 11.18 (s, 1H), 11.91 (s, 1H). MS (electrospray, m/z) 420/418 (M−−1).
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:18]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25](O)=[O:26])[CH:19]([CH3:21])[CH3:20].C(OCC)(=O)C>C(#N)C>[CH2:18]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25]([N:5]1[CH2:4][CH2:3][N:2]([C:8]2[CH:9]=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][CH2:6]1)=[O:26])[CH:19]([CH3:21])[CH3:20]
Reactant: c1ccc2ncc(N3CCNCC3)cc2c1
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2cnc3ccccc3c2)CC1

Procedure:
Prepared in analogy to example 1.1 (b) from 3-piperazin-1-yl-quinoline hydrochloride and 2-isobutoxy-5-methanesulfonyl-benzoic acid (example 2.4) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](F)=[N:6][CH:7]=1.[CH:10]1([C:13]#[N:14])[CH2:12][CH2:11]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH4+].[Cl-]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([C:10]2([C:13]#[N:14])[CH2:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: Fc1cc(Br)cnc1F
Reactant: N#CC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#CC1(c2ncc(Br)cc2F)CC1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Under an atmosphere of argon, 5-bromo-2,3-difluoropyridine (5 g, 25.8 mmol, Eq: 1.00) and cyclopropanecarbonitrile (1.78 g, 2.00 ml, 25.8 mmol, Eq: 1.00) were combined with toluene (50.0 ml) to give a colorless solution. The reaction mixture was cooled to −5° C. Potassium bis(trimethylsilyl)amide (0.5 M, 51.6 ml, 25.8 mmol, Eq: 1.00) was added dropwise at −5° C. The reaction mixture was stirred 1 hr at −5° C., and over the weekend at RT. The reaction mixture was then poured into NH4Cl solution (satd., 50 ml). The aqueous layer was extracted with ethyl acetate (3×60 ml). The organic layers were combined and dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 70 g, 0% to 50% ethyl acetate in heptane as eluent) to yield the title compound as a light brown waxy solid (0.49 g, 7.89%, MS (m/e)=248.1 [M+H+]).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[N:7][C:6]([OH:9])=[N:5]1)([CH3:3])[CH3:2].[Cl:10]Cl>C(N(CC)CC)C>[CH:1]([N:4]1[C:8]([Cl:10])=[N:7][C:6]([OH:9])=[N:5]1)([CH3:3])[CH3:2]
Reactant: ClCl
Reactant: CC(C)n1cnc(O)n1
Solvent: CCN(CC)CC
Product: CC(C)n1nc(O)nc1Cl

Procedure:
127 g of 1-isopropyl-3-hydroxy-1,2,4-triazole and 276 ml of triethylamine are dissolved in 1200 ml of absolute alcohol. The solution turns cloudy yellow. While cooling (26° to 30°C), 106.5 g of chlorine (dried by concentrated sulphuric acid) are passed in within 30 minutes. In the process, the yellow solution initially becomes clear. Subsequently triethylamine hydrochloride precipitates as crystalline product, which is filtered off after stirring for 1 further hour. The filtrate is concentrated to dryness in a rotary evaporator. The brown residue is dissolved in 1 liter of water and 1 liter of ether. The mixture is extracted and separated in a separating funnel. The aqueous phase is extracted three times with 500 ml of ether on each occasion. The combined ether phases are dried over sodium sulphate, the drying agent is filtered off and the filtrate is concentrated to dryness. The light brown residue is dissolved in 500 ml of carbon tetrachloride containing activated charcoal, whereupon the mother liquor is concentrated to 1/3 of its volume and then cooled. The active substance crystallises out and is dried in vacuo for 15 hours at 60°C/15 mm Hg. Yield: 96.3 g (60 % of theory); m.p. : 103°-105°C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([SH:12])=[C:4]([CH:13]([CH3:15])[CH3:14])[CH:3]=1.Br[C:17]1C(C(C)C)=CC(S)=C(C(C)C)C=1>>[CH3:17][S:12][C:5]1[CH:6]=[C:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:2]([Cl:1])=[CH:3][C:4]=1[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)Cc1cc(S)c(C(C)C)cc1Cl
Reactant: CC(C)c1cc(Br)c(C(C)C)cc1S
Product: CSc1cc(CC(C)C)c(Cl)cc1C(C)C

Procedure:
4-Chloro-2-isopropyl-5-isobutylphenyl methyl sulfide was prepared using the procedure of Example 1C except that 4-chloro-2-isopropyl-5-isobutylbenzenethiol was substituted for the 4-bromo-2,5-diisopropylbenzenethiol. The resulting product had a boiling point of 89°C at 0.08 mm Hg.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[C:27]1([C:38](=[NH:40])[NH2:39])[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]([F:37])([F:36])[F:35])[CH2:28]1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:40]=[C:38]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]([F:35])([F:36])[F:37])[CH:28]=4)[N:39]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: N=C(N)C1(O)C=CC=C(OC(F)(F)F)C1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4cccc(OC(F)(F)F)c4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 48 mg (0.22 mmol, 1.1 eq.) of 1-hydroxy-3-(trifluoromethoxy)benzenecarboximidamide were reacted according to the General Method 1. Yield: 68 mg (64% of theory)
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([NH2:22])[S:20][CH:21]=2)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:18]=[C:19]([NH:22][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=3)[S:20][CH:21]=2)=[CH:15][CH:16]=1
Reactant: Nc1nc(-c2ccc(Cl)cc2)cs1
Reactant: O=C(Cl)c1cccnc1
Product: O=C(Nc1nc(-c2ccc(Cl)cc2)cs1)c1cccnc1

Procedure:
In a manner similar to that described in Example 5 but using nicotinoyl chloride and 4-parachlorophenyl 2-amino thiazole, there is obtained a product of the formula: ##STR11##
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[CH2:9][C:10]([O:12]C)=O)[CH:6]=[N:5][CH:4]=1)=O.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:22]([N:29]1[C:10](=[O:12])[CH2:9][CH:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[N:7]2[CH:6]=[N:5][CH:4]=[C:3]2[CH2:1]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)CC(c1ccc(C#N)cc1)n1cncc1C=O
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: N#Cc1ccc(C2CC(=O)N(Cc3ccccc3)Cc3cncn32)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the title C compound, methyl 3-[5-formyl-imidazol-1-yl]-3-(4-cyano-phenyl)-propionate (0.22 g, 0.78 mmol) in DCE (5 mL) is added benzylamine (0.100 mL, 0.92 mmol) followed by sodium triacetoxyborohydride (0.49 g, 2.3 mmol). The reaction mixture is stirred at RT for 16 h, then partitioned between EtOAc and saturated aqueous sodium bicarbonate, and the organic solution is washed with brine, dried (anhydrous sodium sulfate) and concentrated. The residue is subjected to flash chromatography (silica) eluting with EtOAc:MeOH:NH4OH (90:10:1) to give 4-(8-benzyl-7-oxo-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-5-yl)-benzonitrile: m.p. 65° C.; e/z (ES) 343 (M+1, 100%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([F:15])([F:14])[F:13])[C:9]([C:16]([OH:18])=[O:17])=[CH:8][C:7]=2[CH:19]=1)=[O:2].[BH4-].[Na+]>C1COCC1.C(O)C>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([F:14])([F:15])[F:13])[C:9]([C:16]([OH:18])=[O:17])=[CH:8][C:7]=2[CH:19]=1
Reactant: O=Cc1ccc2c(c1)C=C(C(=O)O)C(C(F)(F)F)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(CO)ccc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.3 %

Procedure:
To a chilled (ice bath), stirred solution of 6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (Example 75, Step 2) (0.133 g, 0.489 mmol) in THF (1 mL) and ethanol (1 mL) in a 10 mL round bottom flask was added NaBH4 (0.020 g, 0.528 mmol) in two portions. The reaction was allowed to warm to room temperature and more NaBH4 (0.050 g, 1.322 mmol) was added. The total reaction time was 3 hours. The reaction was quenched with aqueous HCl (1 N solution) and was extracted with chloroform. The organic phase was dried over MgSO4, filtered and concentrated in vacuo yielding a foam. This crude product was purified by flash chromatography (silica gel 60, eluant 1:1, hexane-ethyl Acetate with 2% acetic acid). The product collected from the chromatography was recrystallized from hexanes and ethyl acetate, and collected by vacuum filtration yielding the title compound (0.042 g, 31%) as a very pale yellow powder: mp 177.5–180.8° C. 1H NMR (acetone-d6/300 MHz) 7.89 (s, 1H), 7.44 (s, 1H), 7.41 (d, 1H, J=8.3 Hz), 6.99 (d, 1H, J=8.3 Hz), 5.80 (q, 1H, J=7.3 Hz), 4.59 (s, 2H). FABLRMS m/z 275 (M+H). EIHRMS m/z 274.0417 (M+, Calc'd 274.0453). Anal. Calc'd for C12H9F3O4: C, 52.57; H, 3.31. Found: C, 52.43; H, 3.34.
Reaction SMILES: [CH:1]1([N:4]2[C:11](=[O:12])[CH2:10][CH2:9][NH:8][C:7]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:6]=3[CH2:5]2)[CH2:3][CH2:2]1.C(O)(=O)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31]=O)=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][N:8]2[CH2:9][CH2:10][C:11](=[O:12])[N:4]([CH:1]3[CH2:2][CH2:3]3)[CH2:5][C:6]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:7]2=3)=[CH:26][CH:25]=1
Reactant: COc1ccc2c(c1)CN(C1CC1)C(=O)CCN2
Reactant: O=CCc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1ccc2c(c1)CN(C1CC1)C(=O)CCN2CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a solution of 5-cyclopropyl-8-methoxy-2,3,5,6-tetrahydrobenzo[b][1,5]diazocin-4(1H)-one (50.0 mg, 0.203 mmol) from Example 1 in dichloroethane (2 ml) at 0° C. was added acetic acid (0.035 ml, 0.609 mmol), 2-(4-chlorophenyl)acetaldehyde (47.0 mg, 0.304 mmol) prepared as above and sodium triacetoxyborohydride (129.0 mg, 0.609 mmol). The mixture was stirred overnight at room temperature and then sodium bicarbonate was added followed by extraction with dichloromethane. The organic phases were dried over sodium sulfate, filtered and concentrated. Preparative thin layer chromatography (pentane/ethyl acetate: 1/1) of the obtained residue gave the desired compound as a yellow oil (59 mg, 76%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+].[OH-].[Na+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: Brc1ccc2c(c1)CNCC2
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: O=[N+]([O-])c1cc2c(cc1Br)CNCC2
Temperature: -5 °C

Procedure:
In a 5 liter three neck round bottom flask, 173 9 (0.813 mol) of 7-bromo-1,2,3,4-tetrahydroisoquinoline was dissolved carefully into 950 ml of concentrated sulfuric acid. The resulting solution was cooled to -5° C. and a solution of 82.7 g (0.816 mol) of potassium nitrate in 1 liter of concentrated sulfuric acid was added dropwise. After addition, the reaction was maintained at -5° C. for 15 minutes and poured onto 3 liters of ice. The resulting mixture was basffied to pH 14 with 50% sodium hydroxide solution. The basic solution was extracted three times with 1 liter of dichloromethane. The combined organic layers were washed with 1 liter each of water and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to yield 201 g of an oil. The oil preadsorbed onto silica gel was charged onto a column of 4 kg of silica gel and eluted with a gradient of 1-5% methanol/dichloromethane. The fractions containing product were combined and concentrated to yield 115 g of a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-])=O>CO.[Pd]>[NH:9]1[C:10]2[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=2)[CH:7]=[N:8]1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2[nH]ncc2c1
Yield: 96.9 %

Procedure:
A mixture of 5-nitro-1H-indazole (50 g, 0.31 mol) and 10% Pd/C (5.0 g) in MeOH (400 mL) was heated under H2 (30 psi) atmosphere overnight. After the mixture was filtered, the filtrate was concentrated to give 1H-indazol-5-ylamine as a yellow solid (40 g, 97% yield). 1H NMR (300 MHz, DMSO-d6) δ 12.50 (br s, 1H), 7.70 (s, 1H), 7.22 (d, J=6.6 Hz, 1H), 6.77 (d, J=6.6 Hz, 1H), 6.74 (s, 1H), 4.72 (br s, 1H); MS (ESI) m/z: 134.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:29][CH2:28][C:27]3[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Reactant: COc1ccc(CN)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2ncc3c(C)c(Br)c(=O)n(C4CCCC4)c3n2)cc1
Yield: 86.9 %

Procedure:
A suspension of 6-bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.00 g, 2.70 mmol) and 4-methoxybenzylamine (0.39 mL, 4.0 mmol) in toluene (15 mL) was heated under reflux for 2 hours. The solution was cooled, and the resulting solid was collected by filtration to give 6-bromo-8-cyclopentyl-2-(4-methoxy-benzylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.04 g, 86.4%). 1H NMR δ(400 MHz, CDCl3) 1.6 (m, 2H), 1.8 (m, 2H), 2.0 (m, 2H), 2.2 (m, 2H), 2.53 (s, 3H), 3.79 (s, 3H), 4.59 (m, 2H), 5.96 (m, 1H), 6.1 (m, 1H), 6.86 (d, J=8.3 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 8.5 (br s, 1H). MS (APCl) (C21H23Br1N4O2): Calc for M+H, 443. 1; Found, 443.1
Reaction SMILES: NC1C=C(Cl)C(OC)=CC=1C(C1C=CC=CC=1Cl)=O.NC1C(C)=NN(CC=C)C=1Cl.[Cl:31][C:32]1[C:56]([O:57][CH3:58])=[CH:55][C:35]2[C:36]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[Cl:54])=[N:37][C:38]3[C:39]([N:41](CC=C)[NH:42][C:43]=3[CH3:44])=[N:40][C:34]=2[CH:33]=1.[H-].C([Al+]CC(C)C)C(C)C>>[Cl:31][C:32]1[C:56]([O:57][CH3:58])=[CH:55][C:35]2[C:36]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[Cl:54])=[N:37][C:38]3[C:39]([NH:41][NH:42][C:43]=3[CH3:44])=[N:40][C:34]=2[CH:33]=1
Reactant: C=CCN1NC(C)=C2N=C(c3ccccc3Cl)c3cc(OC)c(Cl)cc3N=C21
Agent: C=CCn1nc(C)c(N)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: COc1cc(C(=O)c2ccccc2Cl)c(N)cc1Cl
Product: COc1cc2c(cc1Cl)N=C1NNC(C)=C1N=C2c1ccccc1Cl

Procedure:
8-chloro-5-(2-chlorophenyl)-1,2-dihydro-7-methoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVy) was prepared by reacting 0.0012 moles of (2-amino-4-chloro-5-methoxyphenyl)(2-chlorophenyl)-methanone (Xy) with 4-amino-5-chloro-3-methyl-1-(2-propenyl)-1H-pyrazole (XIII), and subsequent dealkylation of the intermediate, 8-chloro-5-(2-chlorophenyl)-1,2-dihydro-7-methoxy-3-methyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine (XIVy) with diisobutylaluminum hydride in a manner analogous to Example 72. MH+/Z=373.
Reaction SMILES: Br[Si](C)(C)C.C([O:8][P:9]([C:14]1[C:15](=[O:29])[NH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][C:20]([S:24](=[O:27])(=[O:26])[NH2:25])=[C:19]([Cl:28])[CH:18]=2)(=[O:13])[O:10]CC)C>C(#N)C>[Cl:28][C:19]1[CH:18]=[C:17]2[C:22]([CH:23]=[C:14]([P:9](=[O:8])([OH:13])[OH:10])[C:15](=[O:29])[NH:16]2)=[CH:21][C:20]=1[S:24](=[O:26])(=[O:27])[NH2:25]
Reactant: CCOP(=O)(OCC)c1cc2cc(S(N)(=O)=O)c(Cl)cc2[nH]c1=O
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: NS(=O)(=O)c1cc2cc(P(=O)(O)O)c(=O)[nH]c2cc1Cl

Procedure:
3.33 ml (25.3 mmol) of bromotrimethylsilane are added to a suspension of the compound obtained in Step F (1.0 g, 2.53 mmol) in 30 ml of anhydrous acetonitrile. The batch is stirred at reflux for 1 hour and evaporated to dryness. The residue is dried in vacuo and is taken up in methanol. The suspension is stirred for 30 minutes, becoming thicker and thicker. After filtering off the white precipitate and rinsing with a little methanol and then ether, the title product is obtained.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:9])=[CH:5][C:6]=1[CH:7]=[O:8].P([O-])(O)(O)=[O:11].[Na+].[OH-].[Na+]>C(#N)C.O.OO>[CH3:1][C:2]1[S:3][C:4]([CH3:9])=[CH:5][C:6]=1[C:7]([OH:11])=[O:8]
Reactant: Cc1cc(C=O)c(C)s1
Reactant: O=P([O-])(O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cc1cc(C(=O)O)c(C)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 261.8 %

Procedure:
Phosphorus oxychloride (10 ml) was slowly added dropwise to dimethylformamide (30 g) under ice-cooling, and 2,5-dimethylthiophene (11.2 g) was added. The mixture was stirred at 100° C. for 15 hours, poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2,5-dimethyl-3-thiophenecarbaldehyde (1.41 g). 2,5-Dimethyl-3-thiophenecarbaldehyde (3.89 g) synthesized in this manner was dissolved in acetonitrile (30 ml), and sodium dihydrogen phosphate (1.2 g) in water (15 ml) and 30% aqueous hydrogen peroxide (3.5 ml) were added dropwise. The mixture was stirred at room temperature for 2 hours, alkalified with 1N aqueous sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2,5-dimethyl-3-thiophenecarboxylic acid (4.09 g) as crystals.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C@@H:11]2[C@H:15]([OH:16])[C@@H:14]([CH2:17][OH:18])[O:13][C@H:12]2[N:19]2[C:29]3[N:28]=[C:26]([NH2:27])[NH:25][C:23](=[O:24])[C:22]=3[N:21]=[CH:20]2)[CH:5]=[CH:4][N:3]=[CH:2]1.C[Si](Cl)(C)C.[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37]>N1C=CC=CC=1>[C:35]([NH:27][C:26]1[NH:25][C:23](=[O:24])[C:22]2[N:21]=[CH:20][N:19]([C:29]=2[N:28]=1)[C@@H:12]1[O:13][C@H:14]([CH2:17][OH:18])[C@@H:15]([OH:16])[C@H:11]1[O:10][CH2:9][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:39])[CH:36]([CH3:38])[CH3:37]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCCn2ccnc2)c(=O)[nH]1
Reactant: CC(C)C(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCCn2ccnc2)c(=O)[nH]1

Procedure:
2'-O-(imidazol-1-yl)butylguanosine in pyridine will be treated with trimethylsilyl chloride (5 eq) and isobutyryl chloride (5 eq) as per the procedure of Example 4 to yield the product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([NH:10][C@H:11]([C@H:26]([OH:28])[CH3:27])[C:12]([NH:14][NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].S(Cl)(C1C=CC(C)=CC=1)(=O)=O.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([NH:10][C@@H:11]([C:12]2[O:25][C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=3)=[N:15][N:14]=2)[C@H:26]([OH:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@@H](C)O)ccc(C#N)c1Cl
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.6 %

Procedure:
To a 250 mL, round-bottomed flask equipped with a magnetic stir bar and septum was added N′-((2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-cyanobenzohydrazide (0.6871 g, 2.4 mmol) followed by addition of anhydrous THF (200 mL) under an atmosphere of nitrogen. To this was then added tosyl chloride (318 mg, 1.7 mmol) followed by addition of polystyrene bound (2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (PS-BEMP) (2.2 mmol/g loading, 2.29 g, 5.0 mmol). This mixture was allowed to stir at room temperature for a period of 16 h. The solids were then filtered off and washed with additional THF (100 mL). The filtrate was then concentrated under reduced pressure to reveal a yellow solid. This was purified via silica gel chromatography eluted with 50% EtOAc/hexanes to provide product as a white solid (138 mg, 21%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 8.19 (AA′XX′, J=8.4 Hz, 2H), 7.98 (AA′XX′, J=8.5 Hz, 2H), 7.48 (d, J=8.6 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 5.89 (d, J=8.8 Hz, 1H), 5.11 (dd, J=5.6, 8.8 Hz, 1H), 4.71 (d, J=5.9 Hz, 1H), 4.55 (m, 1H), 2.36 (s, 3H), 1.43 (d, J=6.3 Hz, 3H).