Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:11][O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:20]([N:19]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][C@H:9]([OH:10])[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CO
Product: O[C@H](COc1ccccc1)CN(Cc1ccccc1)Cc1ccccc1
Yield: 88 %

Procedure:
A reaction mixture containing (2S)-2-(phenoxymethyl)oxirane (Example 15, 20.6 mmol, 1.0 eq.) and dibenzylamine (22.7 mmol, 1.1 eq.) in MeOH (100 mL) was heated at reflux overnight. The resulting solution was concentrated in vacuo and the crude product was purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexanes:EtOAc=10:1). The product was obtained as a colorless oil in 88% yield. MH+=348.3, Rf=0.42 (hexanes:EtOAc 6:1), retention time (LC-MS)=2.22 min.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[N:4]([C@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][CH2:20][CH2:19]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:21]2[C:22]3[C:18](=[CH:17][C:16]([Cl:15])=[CH:24][C:23]=3[Cl:25])[CH2:19][CH2:20]2)[C:3](=[O:14])[N:4]([C@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:5]=1
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Reactant: COC[C@@H](C)n1cc(Cl)nc(Cl)c1=O
Product: COC[C@@H](C)n1cc(Cl)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-2-methoxy-1-methylethyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 93-95° C.; 1H NMR (300 MHz, CDCl3): δ 7.18 (s, 1 H), 7.11 (s, 1 H), 7.06 (s, 1 H), 4.35 (t, J=7.9 Hz, 2 H), 3.62-3.56 (m, 3 H), 3.36 (s, 3 H), 3.12 (t, J=8.1 Hz, 2 H), 0.90-0.86 (m, 3 H); HRMS (ESI) calcd for C16H17N3O2Cl3 (M+H)+: 388.0386; found m/z 388.0358.
Reaction SMILES: [CH2:1]([N:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].ClCCl.O>C(O)C>[CH2:1]([NH:8][CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc2c(c1)C(=NCc1ccccc1)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: Fc1ccc2c(c1)C(NCc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
Dissolve benzyl-(6-fluoroindan-1-ylidene)-amine (23.22 g, 97.03 mmol) in ethanol (1200 mL). Cool the mixture to 0° C. under nitrogen. Add sodium borohydride (11.01 g, 291.10 mmol) to the mixture. After one hour, add dichloromethane (150 mL) and water (150 mL). Stir for 14 hours under nitrogen and concentrate in vacuo to remove ethanol. Extract the residue with dichloromethane and saturated aqueous sodium chloride. Dry the resulting organics with magnesium sulfate, filter, and concentrate in vacuo to give the title compound as a red oil (22.12 g, 94%). MS (ES) m/z=242 [M+1].
Reaction SMILES: [O:1]1[CH2:5][CH2:4]/[C:3](=[CH:6]/[C:7]([O:9][CH2:10][CH3:11])=[O:8])/[CH2:2]1.[NH3:12]>O1CCOCC1.CO>[NH2:12][C:3]1([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][O:1][CH2:2]1
Reactant: N
Reactant: CCOC(=O)/C=C1/CCOC1
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)CC1(N)CCOC1
Temperature: 150 °C

Procedure:
Ethyl (2Z)-dihydrofuran-3(2H)-ylideneacetate (Preparation 36, 1.29 g, 8.25 mmol) was stirred in 1,4-dioxane (7 mL) in a microwave vial. A solution of 7M ammonia in methanol (5 mL) was added and the reaction heated for 4 hours at 150° C. in a Biotage Initiator™ microwave. The reaction was concentrated in vacuo, but later deemed not to have reached completion. A solution of 7M ammonia in methanol (7 mL) was added and the reaction heated again for 3 hours at 150° C. in the microwave. A further portion of 7M ammonia in methanol (3 mL) was added and the reaction heated for a further 2 hours. The reaction was concentrated in vacuo to afford the title compound along with the methyl ester where trans-esterification had occurred. The material was used without further purification in the next step.
Reaction SMILES: S1(CCCC1)(=O)=O.C[C:9]([O:11][CH2:12][C:13]1[CH2:22][S:21][C@@H:16]2[C@H:17]([NH2:20])[C:18](=[O:19])[N:15]2[C:14]=1[C:23]([OH:25])=[O:24])=O.B(F)(F)F.CCOCC>CO>[NH2:20][CH:17]1[C:18](=[O:19])[N:15]2[C:14]([C:23]([OH:25])=[O:24])=[C:13]([CH2:12][O:11][CH3:9])[CH2:22][S:21][C@H:16]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CO
Solvent: O=S1(=O)CCCC1
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 50 °C

Procedure:
To 10 ml of sulfolane were added 1.41 g of 7-ACA, 5.8 ml of boron trifluoride ethyl ether and 0.84 ml of methanol. The mixture was heated at 50° C. for 1.25 hours to advance a reaction. After completion of the reaction, substantially the same procedure dure as in Example 1 was repeated, to thereby obtain the desired product, namely 7-amino-3-methoxy methyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.23 g. The yield of the desired product was 18%.
Reaction SMILES: C([N:4]1[CH2:12][C@@H:11]2[C@@:6]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[CH:23]=3)([N:7]=[C:8]([NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:9][CH2:10]2)[CH2:5]1)C=C>C(Cl)(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:28][C:24]1[CH:23]=[C:22]([C@:6]23[CH2:5][NH:4][CH2:12][C@H:11]2[CH2:10][S:9][C:8]([NH:13][C:14](=[O:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:7]3)[CH:27]=[CH:26][CH:25]=1
Reactant: C=CCN1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cccc(Br)c2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: O=C(NC1=N[C@@]2(c3cccc(Br)c3)CNC[C@H]2CS1)c1ccccc1
Reaction time: 2 h

Procedure:
In a separate flask, a mixture of N-[(4aR,7aS)-6-allyl-7a-(3-bromophenyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (22.2 g, 48.6 mmol) and N,N-dimethylbarbituric acid (19.28 g, 121.6 mmol) in chloroform (486 mL) is degassed by bubbling nitrogen through the resulting slurry at RT for 5 min. The mixture is treated with tetrakis(triphenylphosphine)palladium (5.79 g, 4.86 mmol) and is stirred for 2 hours under nitrogen.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=1>CO.[OH-].[Na+]>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:16])=[O:2])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1cccc(-c2ccco2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1cccc(-c2ccco2)c1
Reaction time: 8 h

Procedure:
To a solution of the methyl 3-(2-furanyl)phenylacetate from step (b) in 5 ml of methanol was added 10 ml of 1N NaOH aqueous solution, the resulting solution was stirred overnight before diluting with 40 of ml 1N NaOH aqueous solution and washing with 2×30 ml CH2Cl2. The aqueous solution was then acidified with 2N HCl, and extracted with 3×30 ml of CH2Cl2. The organic extracts were combined and were dried with MgSO4, filtered, and evaporated to give 0.32 g of the product as a golden-colored solid.
Reaction SMILES: Cl[C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1.[C:14]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([N:20]2[CH2:25][CH2:24][N:23]([C:2]3[N:12]4[C:13]5[C:8]([CH2:9][CH2:10][CH2:11]4)=[CH:7][CH:6]=[CH:5][C:4]=5[N:3]=3)[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Clc1nc2cccc3c2n1CCC3
Product: c1ccc(N2CCN(c3nc4cccc5c4n3CCC5)CC2)cc1
Yield: 45 %

Procedure:
A solution of 2-chloro-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline (3.00 g) in 1-phenylpiperazine (10 ml) was stirred at 100° C., under nitrogen, for five hrs. The reaction mixture was quenched with saturated sodium bicarbonate solution (200 ml) and extracted with chloroform. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by high performance liquid chromatography (silica gel; 4:1 dichloromethane-ethyl acetate). The appropriate fractions were collected and evaporated. The residue was recrystallized from ethyl acetate to give 2.2 g (45%) of product, mp 168°-169° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:9][CH:8]=[C:7]([F:18])[C:3]=1[C:4]([OH:6])=O.[CH3:19][O:20][C:21]1[C:29]2[C:24](=[N:25][CH:26]=[C:27]([NH2:30])[CH:28]=2)[NH:23][N:22]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:9][CH:8]=[C:7]([F:18])[C:3]=1[C:4]([NH:30][C:27]1[CH:28]=[C:29]2[C:21]([O:20][CH3:19])=[N:22][NH:23][C:24]2=[N:25][CH:26]=1)=[O:6]
Reactant: COc1n[nH]c2ncc(N)cc12
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(OC)c3c2)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 15.9 %

Procedure:
2-Chloro-6-fluoro-3-(propylsulfonamido)benzoic acid (75.7 mg, 0.256 mmol) in N,N-dimethylformamide (2.5 mL) was sequentially treated with 3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-amine (46.2 mg, 0.282 mmol), EDCI (54.0 mg, 0.282 mmol), and HOBt (38.0 mg, 0.282 mmol). The reaction mixture was allowed to stir at ambient temperature for 24 hours. The mixture was then diluted with ethyl acetate and washed with water (4×), sodium bicarbonate (2×), and brine, dried over sodium sulfate and concentrated. The crude product was triturated with DCM to afford 2-chloro-6-fluoro-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (18.0 mg, 0.0407 mmol, 15.9% yield) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 12.62-12.56 (s, 1H), 11.08-11.03 (s, 1H), 9.78-9.65 (s, 1H), 8.61-8.56 (s, 1H), 8.50-8.45 (s, 1H), 7.63-7.55 (m, 1H), 7.44-7.35 (m, 1H), 4.03-3.99 (s, 3H), 3.14-3.07 (m, 2H), 1.83-1.73 (m, 2H), 1.04-0.95 (t, 3H); MS (APCI-neg) m/z=440.1 (M−H).
Reaction SMILES: [O-]O.[B].[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].C([O:16]O)(C)(C)C>B#[W]>[CH2:11]1[O:16][CH:10]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4]
Reactant: C=CCCCCCC
Reactant: CC(C)(C)OO
Agent: B#[W]
Agent: [B]
Agent: [O-]O
Product: CCCCCCC1CO1
Temperature: 90 °C
Yield: 36 %

Procedure:
In this example, the liquid phase epoxidation of an olefinic compound with an organic hydroperoxide was carried out in the presence of a catalytic amount of a boron containing substance in accordance with the instant invention. A 250 ml. flask equipped with a stirrer, thermometer, reflux condenser and dropping funnel was charged with 84 g. octene-1 and 1 g. tungsten boride (WB). The charged mixture was heated to 90° C. and 90% tertiary butyl hydroperoxide was added dropwise until a total of 25 g. has been added. The reaction mixture was then heated at reflux (108°-110° C.) for 220 minutes with stirring. The heated mixture was allowed to cool and then the crude reaction product was analyzed. The analysis indicated a 36% yield of octene oxide based on the amount of charged hydroperoxide. The crude reaction product was filtered by conventional methods and the resulting filtrate was analyzed for metal content by atomic absorption analysis. No metals were detected in the filtrate.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:25])[C:7]([C:20]([O:22]CC)=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:4][C:3]=1[F:26]>Cl.O>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:25])[C:7]([C:20]([OH:22])=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:4][C:3]=1[F:26]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Agent: Cl
Solvent: O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Yield: 97.1 %

Procedure:
In 10 ml of conc. hydrochloric acid was suspended 500 mg of ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, and the resulting suspension was subjected to reaction under reflux for 1 hour. The reaction mixture was diluted with 10 ml of water, and the crystals thus deposited were collected by filtration, and then washed with 2 ml of water to obtain 450 mg (yield 97.1%) of 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid having a melting point of 238°-242° C.
Reaction SMILES: C(P(=O)(OCC)OCC)#[N:2].FC(F)(F)[C:13]1[CH:14]=[C:15]2C=C(C(O)=O)[N:19]([CH2:25][C:26]3[CH:31]=CC=C(F)C=3)[C:16]2=[N:17][CH:18]=1>>[NH2:2][C:13]1[CH:18]=[N:17][C:16]([N:19]2[CH2:25][CH2:26][CH2:31]2)=[CH:15][CH:14]=1
Reactant: CCOP(=O)(C#N)OCC
Reactant: O=C(O)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1
Product: Nc1ccc(N2CCC2)nc1
Yield: 120 %

Procedure:
Add, dropwise, 4.26 g (24.83 mmol) of diethyl cyanophosphonate to a solution, stirred at 20° C. under a nitrogen atmosphere, of 7 g (20.69 mmol) of 5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid as obtained in Stage 1.3 and 3.7 g (24.83 mmol) of 3-amino-6-(azetidin-1-yl)-pyridine prepared in the preceding stage in 140 mL of dimethylformamide. Then add, dropwise, 4.6 mL (45.53 mmol) of triethylamine, then stir the reaction mixture for 70 hours at 20° C. After this time, the mixture is concentrated at reduced pressure and then taken up in 700 mL of ethyl acetate and 300 mL of water. The aqueous phase is separated and then extracted with 200 mL of ethyl acetate. The organic phases are combined, washed three times with 200 mL of a saturated sodium bicarbonate solution, then dried over sodium sulfate and concentrated at reduced pressure. The product thus obtained is purified in a silica column, eluting with a mixture of dichloromethane and ethyl acetate, then recrystallized from a mixture of ethanol and methanol. In this way we isolate 5.7 g of the expected product in the form of white crystals.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH:3]=[CH:2]1.[C:12]([C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([NH:11][C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: Nc1ccc2c(c1)OC=CO2
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(Nc2ccc3c(c2)OCCO3)cc1
Temperature: 25 °C
Yield: 55 %

Procedure:
To a flask equipped with a magnetic stirrer, reflux condensor, and nitrogen inlet was added 1,4-benzodioxin-6-amine (5.26 grams, 34.8 mmoles), 4-tert-butyl bromobenzene (6.83 grams, 32.1 mmoles), tris(dibenzylideneacetone)dipalladium (0) (0.58 grams, 0.6 mmoles), rac-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (0.79 grams, 1.2 mmoles), sodium tert-butoxide (6.08 grams, 63.0 mmoles) and anhydrous toluene (70 mL). The contents of the flask were refluxed for three days; cooled to room temperature; and filtered through a pad of silica gel. The silica gel pad was then eluted with dichloromethane (300 mL). The combined organic layers were concentrated in vacuo to yield a dark solid. The solid was chromatographed on silica gel, eluting with a hexane/ethyl acetate gradient to afford 5 grams of the desired product as a white solid. 1H NMR (CDCl3) δ 7.25 (d, 2H), 6.9 (d, 2H), 6.75 (d, 1H), 6.5-6.7 (m, 2H), 5.4 (bs, 1H), 4.2 (s, 4H), 1.3 (s, 9H).
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([Br:17])[CH:16]=1)CBr>CN.CO.CN(C)C=O>[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([Br:17])[CH:16]=1)[CH2:7][CH2:6][NH2:3]
Reactant: BrCc1cc(Br)cc(Br)c1
Reactant: CCN(CC)CC
Agent: CN
Solvent: CO
Solvent: CN(C)C=O
Product: NCCc1cc(Br)cc(Br)c1
Temperature: 25 °C
Yield: 77.7 %

Procedure:
Triethylamine (5.28 g; 52.2 mmol) was dissolved in 40% methylamine in methanol (100 ml). While the mixture was stirred at room temperature, 3,5-dibromobenzyl bromide (17.2 g; 52.2 mmol) in N,N-dimethylformamide (20 ml) was added dropwise. The mixture was stirred overnight at room temperature, and the solvent was evaporated under reduced pressure. The residue was taken up in 2N hydrochloric acid (150 ml), and the mixture was extracted with diethyl ether (150 ml), to thereby exclude impurities. The aqueous layer was alkalinized with aqueous sodium hydroxide solution, and extracted with chloroform (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, to thereby yield 11.3 g of the target compound as orange oily matter (yield: 77.7%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([O:28][CH3:29])[C:23]([O:26][CH3:27])=[CH:24][CH:25]=1.O>CN1CCCC1=O>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2nc(Cl)n(Cc3ccccc3)c2c1
Reactant: COc1ccc(N)cc1OC
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(Nc2nc3ccc(O)cc3n2Cc2ccccc2)cc1OC
Temperature: 150 °C
Yield: 38.9 %

Procedure:
A mixture of 3-benzyl-2-chloro-3H-benzoimidazol-5-ol (250 mg) and 4-amino veratrole (296 mg) in N-methylpyrrolidinone (3 ml) was heated at 150° C. in a sealed tube for 4 hours then allowed to cool. The reaction mixture was then poured into water (30 ml) and extracted three times with ethyl acetate (30 ml). The combined extracts were dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (95:5, v/v) to give 3-benzyl-2-(3,4-dimethoxy-phenylamino)-3H-benzoimidazol-5-ol (141 mg) as a yellow solid. Mass spectrum: 376 [M+H]+ retention time: 3.44 minutes.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(S)C.[CH3:8][N:9]([CH3:33])[CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:18]3[C:22]4[CH:28]=[C:27]([O:29]C)[CH:26]=[CH:25][C:23]=4[S:24][C:17]=3[C:16]([CH3:31])=[CH:15][C:14]=2[C:13]1=[O:32]>C(Cl)Cl>[CH3:33][N:9]([CH3:8])[CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:18]3[C:22]4[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:23]=4[S:24][C:17]=3[C:16]([CH3:31])=[CH:15][C:14]=2[C:13]1=[O:32]
Reactant: COc1ccc2sc3c(C)cc4c(c3c2c1)C(=O)N(CCN(C)C)C4=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: Cc1cc2c(c3c1sc1ccc(O)cc13)C(=O)N(CCN(C)C)C2=O
Reaction time: 0.5 h
Yield: 93 %

Procedure:
690 mg of anhydrous aluminum chloride was suspended in 100 ml of methylene chloride. To the suspension was added 1.1 ml of ethanethiol at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Thereto was dropwise added, in 1 minute, a solution of 380 mg of 2-(2-dimethylaminoethyl)-9-methoxy-5-methyl-1H-[1]benzothieno[3,2-e]isoindole-1,3(2H)-dione dissolved in 100 ml of methylene chloride. The mixture was stirred at room temperature overnight. The solvent was removed by distillation under reduced pressure. The residue was mixed with 100 ml of ethyl acetate and 50 ml of an aqueous saturated sodium hydrogencarbonate solution. The mixture was stirred for 30 minutes. The resulting insoluble material was removed by filtration. The separated insoluble material was washed with 50 ml of ethyl acetate. The filtrate and the washings were combined. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from n-propanol to obtain 340 mg (yield: 93%) of 2-(2-dimethylaminoethyl)-9-hydroxy-5-methyl-1H-[1]benzothieno[3,2-e]isoindole-1,3(2H)-dione as yellow crystals.
Reaction SMILES: [NH2:1][C:2]([N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[C:3]([C:7]#[N:8])[C:4](=[S:6])[NH2:5].OO>>[NH2:5][C:4]1[S:6][N:1]=[C:2]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:3]=1[C:7]#[N:8]
Reactant: N#CC(C(N)=S)=C(N)N1CCCC1
Agent: OO
Product: N#Cc1c(N2CCCC2)nsc1N
Yield: 88.1 %

Procedure:
Using the procedure of Example I, part F, 81.7 g of 3-amino-2-cyano-3-(1-pyrrolidinyl)propenethioamide were oxidized with 48 ml of 30% hydrogen peroxide to give 71.2 g of 5-amino-4-cyano-3-(1-pyrrolidinyl)isothiazole, m.p. 198°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].C(N(CC)CC)C.[CH3:16][N:17]([C@@H:27]1[C@H:32]([CH3:33])[CH2:31][CH2:30][NH:29][CH2:28]1)[C:18]1[C:19]2[CH:26]=[CH:25][NH:24][C:20]=2[N:21]=[CH:22][N:23]=1>C1(C)C=CC=CC=1>[CH3:33][C@@H:32]1[CH2:31][CH2:30][N:29]([C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH2:28][C@@H:27]1[N:17]([CH3:16])[C:18]1[C:19]2[CH:26]=[CH:25][NH:24][C:20]=2[N:21]=[CH:22][N:23]=1
Reactant: C[C@@H]1CCNC[C@@H]1N(C)c1ncnc2[nH]ccc12
Reactant: CCOC(=O)CC#N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)c1ncnc2[nH]ccc12
Temperature: 110 °C
Reaction time: 16 h
Yield: 55.6 %

Procedure:
Ethyl 2-cyanoacetate (140 mg, 1.23 mmol, 6.00 equiv.) and triethylamine (40 mg, 0.39 mmol, 2.00 equiv.) were added to a solution of N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 12 (50 mg, 0.19 mmol, 1.00 equiv.) in toluene (10 mL). The resulting solution was stirred at about 110° C. for about 16 hours and then was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol (50:1)) to give the title product as a light yellow solid (33 mg; yield=52%). 1H NMR (300 MHz, CD3OD) δ: 8.10 (s, 1H), 7.10 (d, J=4.0 Hz, 1H), 6.65 (d, J=4.0 Hz, 1H), 5.00-5.10 (m, 1H), 3.80-4.00 (m, 2H), 3.55-3.75 (m, 1H), 3.40-3.55 (m, 1H), 3.30-3.40 (m, 5H), 2.40-2.55 (m, 1H), 1.82-2.00 (m, 1H), 1.60-1.80 (m, 1H), 1.05-1.20 (m, 3H). LC-MS: m/z=313 (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1.[CH2:16]=[O:17]>>[OH:17][CH2:16][NH:1][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1
Reactant: C=O
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(N)S1
Product: Cn1c([N+](=O)[O-])cnc1C1=CNN(NCO)S1

Procedure:
A suspension of 5 g. of 2-(2-amino-5-thiadiazolyl)-1-methyl-5-nitroimidazole in 200 ml. of 36% aqueous formaldehyde solution is stirred for 20 hours at room temperature. The suspension is cooled in ice, and the insoluble solid is collected by filtration and washed with acetone. The yield of the title compound is 6.15 g., melting point 177° C. with decomposition (rapid heating).