Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:3](N1CC(C2C=CC3C4N=C(C5N(C(C)C)N=CN=5)SC=4CCOC=3C=2)C1)(=[O:5])=[O:4])=[CH2:2].Cl.[F:33][C:34]1([F:38])[CH2:37][NH:36][CH2:35]1>C(Cl)Cl>[CH:1]([S:3]([N:36]1[CH2:37][C:34]([F:38])([F:33])[CH2:35]1)(=[O:5])=[O:4])=[CH2:2]
Reactant: FC1(F)CNC1
Reactant: C=CS(=O)(=O)N1CC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)C1
Agent: Cl
Solvent: ClCCl
Product: C=CS(=O)(=O)N1CC(F)(F)C1

Procedure:
The title compound was prepared by a similar procedure to 8-(1-ethenesulfonyl-azetidin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene using 3,3-difluoroazetidine hydrochloride salt. 1-Ethenesulfonyl-3,3-difluoro-azetidine was isolated as a light brown oil after flash chromatography (SiO2, DCM) (171 mg, 61%). 1H NMR δ (ppm) (CDCl3): 6.56 (1 H, dd, J=16.56, 9.83 Hz), 6.40 (1H, d, J=16.59 Hz), 6.20 (1 H, d, J=9.83 Hz), 4.32-4.17 (4 H, m)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:21][C:22]1[C:23]([F:29])=[N:24][CH:25]=[C:26]([OH:28])[CH:27]=1>>[Cl:21][C:22]1[CH:27]=[C:26]([O:28][C:8]2[CH:7]=[CH:6][C:5]([S:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=3)(=[O:12])=[O:11])=[CH:4][C:3]=2[C:1]#[N:2])[CH:25]=[N:24][C:23]=1[F:29]
Reactant: N#Cc1cc(S(=O)(=O)Nc2ccc(F)cn2)ccc1F
Reactant: Oc1cnc(F)c(Cl)c1
Product: N#Cc1cc(S(=O)(=O)Nc2ccc(F)cn2)ccc1Oc1cnc(F)c(Cl)c1

Procedure:
The title compound was prepared according to the method described for Method Variation 1 using 3-cyano-4-fluoro-N-(5-fluoropyridin-2-yl)benzenesulfonamide (Preparation 2) and 3-chloro-2-fluoro-5-hydroxypyridine and then purified using silica gel column chromatography eluting with 30-35% EtOAc in heptanes.
Reaction SMILES: C([CH:4]1[CH2:7][CH:6]([CH2:8][CH3:9])[CH2:5]1)(=O)C.ClC1C=CC=[C:13]([C:17]([O:19]O)=[O:18])C=1>C(Cl)(Cl)Cl>[C:17]([O:19][CH:4]1[CH2:5][CH:6]([CH2:8][CH3:9])[CH2:7]1)(=[O:18])[CH3:13]
Reactant: CCC1CC(C(C)=O)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCC1CC(OC(C)=O)C1
Reaction time: 120 h
Yield: 57.3 %

Procedure:
A solution of 5.5 g of the 1-acetyl-3-ethylcyclobutane, and 10.7 g of m-chloroperbenzoic acid in 107 ml chloroform was allowed to stand for five days in the dark. The reaction mixture was cooled via external ice cooling and filtered. The filtrate was diluted with CHCl3 and washed with 10 percent aqueous sodium thiosulfate, 10 percent aqueous sodium carbonate and brine, dried over Na2SO4, and filtered. The solution was subjected to distillation (aspirator vacuum) to afford 3.55 g of 1-acetoxy-3-ethylcyclobutane, as a clear oil (bp 65°-67°). The material had the following spectral chracteristics: nmr (CDCl3) δ 0.82 (3H, t, J=7.0 Hz) 1.10 and 1.12, (same side product noted in the 1-acetyl compound spectra), 1.0-2.5 (7H, m), 2.01 (3H, s) and 4.9 (1H, m); ir (CHCl3) 950, 1040, 1085, 1205, 1250, 1375, 1460, 1720, 2870, 2925 and 2960 cm-1 along with trace of 3200-3600 (broad) and 3600 cm-1 for the same side product noted in the 1-acetyl the compound spectra.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[O:16][C:15]([NH:18][C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=4)=[N:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[CH3:26][O:25][C:23]1[CH:24]=[C:19]([NH:18][C:15]2[O:16][C:17]3[C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][NH:1][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:4][CH:5]=4)=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=2)[CH:20]=[C:21]([O:29][CH3:30])[C:22]=1[O:27][CH3:28]
Reactant: COc1cc(Nc2nc3cccc(-c4ccc(CN)cc4)c3o2)cc(OC)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(Nc2nc3cccc(-c4ccc(CNS(C)(=O)=O)cc4)c3o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 0.10 g (0.247 mmol) [7-(4-aminomethyl-phenyl)-benzooxazol-2-yl]-(3,4,5-trimethoxy-phenyl)-amine (example 29) and 0.037 g (0.32 mmol) methanesulfonyl chloride in 4 ml pyridine is stirred for 1.5 h at room temperature. Then the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with 0.1N NaOH solution and water, dried over MgSO4, filtered and the filtrate is concentrated in vacuo and co-evaporated twice with toluene. The residue is purified by crystallisation from dichloromethane to afford the title compound as off-white crystals. Rt=2.20 min (Waters Symmetry C8, 2.1×50 mm, detection 210-250 nM, 5% to 100% CH3CN in H2O in 2 min+0.05% TFA, flow rate 1.0 ml/min); MS: 474 (M+1)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([F:11])[CH:5]=1)(=[O:3])[CH3:2].FC(F)(F)OC1C=CC(C(=O)C[Br:21])=CC=1>>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH2:2][Br:21])=[CH:5][C:6]=1[F:11]
Reactant: CC(=O)c1ccc(Cl)c(F)c1
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Product: O=C(CBr)c1ccc(Cl)c(F)c1

Procedure:
The title compound was prepared from 4-acetyl-1-chloro-2-fluorobenzene according to the procedure for preparing 4-(trifluoromethoxy)phenacyl bromide described in Example 189.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[CH3:17][C:18](=[O:21])[C:19]#[CH:20].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:3][CH:20]=[C:19]([C:18](=[O:21])[CH3:17])[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C#CC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C1=CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
To a solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (9.76 g, 0.041 mol) in CH2Cl2 (40 mL) at 0° C., was added dropwise over a 5 minutes period but-3-yn-2-one (2.0 g, 0.029 mol) followed by trifluoroacetic acid (0.22 mL, 0.003 mol) (very exothermic reaction). The ice bath was removed after 30 minutes, and the solution was stirred at 25° C. for an additional 2 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/Heptane 1:1) afforded 2.90 g (49%) of the title compound as a yellow oil. ES-MS m/e: 202.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[O:9]1[CH2:11][CH:10]1[CH2:12][N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1>CCO>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:11][CH:10]([OH:9])[CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc2c(c1)CCN(CC1CO1)C2
Reactant: Nc1cccc(Br)c1
Solvent: CCO
Product: OC(CNc1cccc(Br)c1)CN1CCc2ccccc2C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
To a stirred mixture of 3-bromoaniline (300 mg, 1.75 mmol) in EtOH (10 mL) was added 2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (331 mg, 1.75 mmol). The mixture was stirred at 80° C. for 16 hours. The reaction mixture was concentrated. The residue was purified by prep-TLC to afford the desired compound (120 mg). LCMS (m/z): 361.1/362.1 [M+H]+/[M+2H]+
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:31])C=1>ClCCl>[CH2:16]([O:15][C:5]1[C:6]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][CH:2]1[CH2:3][O:31]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1cccc(C2CCCC2)c1OCc1ccccc1
Solvent: ClCCl
Product: c1ccc(COc2c(CC3CO3)cccc2C2CCCC2)cc1
Reaction time: 2.5 h
Yield: 113.3 %

Procedure:
20 g (0.0684 mol) of 1-allyl-2-benzyloxy-3-cyclopentylbenzene are dissolved in 200 ml of dichloromethane. While stirring and cooling in an ice bath, 14 g (0.081 mol) of m-chloroperbenzoic acid are added in portions. The mixture is allowed to reach room temperature and, after 2.5 h, a further 5 g of m-chloroperbenzoic acid are added. The mixture is further stirred at room temperature overnight, and then the precipitated m-chlorobenzoic acid is removed by filtration and the filtrate is concentrated in vacuo. The oily residue is thoroughly stirred with n-pentane and filtered, and the filtrate is washed three times with 2N sodium hydroxide solution and then once with saturated brine. Drying over sodium sulfate is followed by removal of the solvent by distillation in vacuo. 23.9 g of (2-benzyloxy-3-cyclopentylbenzyl)oxirane are obtained as an oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[Cl:16][CH2:17][C:18](Cl)=[O:19]>>[Cl:16][CH2:17][C:18]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: O=C(Cl)CCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)CCl)CC1

Procedure:
The title compound 604 mg (89%) was obtained in a manner similar to the Manufacturing Example 3 by use of tert-butyl trans-4-aminocyclohexylcarbamate and chloroacetyl chloride, instead of the compound obtained in the Manufacturing Example 2 and acetyl chloride, respectively.
Reaction SMILES: [CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][C:5](=[O:14])[N:4]([CH3:15])[C:3]1=[O:16].[O:17]([CH2:24][CH2:25]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)C>[CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:25][CH2:24][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:14])[N:4]([CH3:15])[C:3]1=[O:16]
Reactant: Cn1c(N2CCNCC2)cc(=O)n(C)c1=O
Reactant: BrCCOc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cn1c(N2CCN(CCOc3ccccc3)CC2)cc(=O)n(C)c1=O
Yield: 64 %

Procedure:
1.12 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)pyrimidinedione and 1.4 g of phenoxyethyl bromide were dissolved in 5 ml of ethanol, and 1.0 g of triethylamine was then added, followed by heating under reflux for 1 hour. Furthermore, 0.6 g of phenoxyethyl bromide was added, and the solution was heated under reflux for 2 hours. The precipitated crystals were collected by filtration, washed with water, dried and then recrystallized from hexane/ethanol to obtain 1.1 g (yield: 63%) of 1,3-dimethyl-6-[4-(2-phenoxyethyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[N:30]=[C:31]([C:33]([OH:36])([CH3:35])[CH3:34])[N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[N:30]=[C:31]([C:33]([OH:36])([CH3:34])[CH3:35])[N:32]=[C:20]4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(C(C)(C)O)nn4cc3-c3ccccc3)cc2)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)c1nc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
To the solution of 8-5 (50 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated by evaporation and the residue was purified by prep.HPLC to give the product 8-6 (37 mg, yield 92.5%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:2]([O:1][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:3]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
REFERENCE: J. Med Chem. 1997, 40, 105-111. To an acetone solution (500 mL) of methyl 3-hydroxy-4-nitrobenzoate (25.0 g, 126.8 mmol) was added cesium carbonate (61.9 g, 190.2 mmol) followed by benzyl bromide (15.0 mL, 126.8 mmol). The reaction was heated to reflux and monitored by TLC. The reaction was judged complete in approximately 7 h. The reaction was then cooled to room temperature and concentrated under reduced pressure to approximately 20 mL. The residue was diluted with ethyl acetate (700 mL) and washed in succession with 1N hydrochloric acid, 1N sodium hydroxide, 1N hydrochloric acid and finally with saturated aqueous sodium chloride. The organic layer was then dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 3-benzyloxy-4-nitro-benzoic acid methyl ester as a solid. 1H NMR (CDCl3) 7.83(m,2H), 7.70(dd, 1H), 7.50-7.30(m,5H), 5.28(s,2H), 3.96(s,3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]#[N:22])[CH:16]=[CH:17][CH:18]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[CH:20][C:21]#[N:22])[CH:14]=1)=[O:9]
Reactant: N#CC=Cc1cccc(N)c1
Reactant: O=C(O)c1cc(Br)ccc1F
Product: N#CC=Cc1cccc(NC(=O)c2cc(Br)ccc2F)c1

Procedure:
5-Bromo-2-fluoro-benzoic acid (380 mg, 1.74 mmol) was coupled to aniline (88) (250 mg, 1.74 mmol) using Method C. The residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]=[C:23]1[CH2:28][S:27][C:26]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[N:32][C:25]=2[NH:24]1.C([BH3-])#N.[Na+]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]2[O:13][CH2:12][C:11](=[O:21])[N:10]([CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][CH:2]([NH:1][CH2:33][C:31]4[CH:30]=[CH:29][C:26]5[S:27][CH2:28][C:23](=[O:22])[NH:24][C:25]=5[N:32]=4)[CH2:7][CH2:6]3)[C:15]=2[CH:16]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: NC1CCN(CCN2C(=O)COc3ccc(F)cc32)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C1CSc2ccc(CNC3CCN(CCN4C(=O)COc5ccc(F)cc54)CC3)nc2N1
Yield: 23 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-fluoro-2H-1,4-benzoxazin-3(4H)-one (Intermediate 54) (0.7 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (WO 2004/058144) (160 mg, 0.82 mmol) and sodium cyanoborohydride (90 mg, 1.4 mmol) were reacted as described under Example 21, (but the reaction mixture was refluxed overnight before reduction with sodium cyanoborohydride at room temperature for 2 hours) to give 76 mg (23%) of product.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3]1.[BH4-].[Na+]>CCO>[CH3:1][CH:2]1[CH2:7][CH:6]([OH:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3]1
Reactant: CC1CC(=O)C=C(c2ccncc2[N+](=O)[O-])C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1CC(c2ccncc2[N+](=O)[O-])=CC(O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of 5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enone (1.0 equiv.) was added EtOH (1.1M) and CeCl3-7H2O (1.3 equiv.). The reaction was cooled to 0° C., then NaBH4 (1.3 equiv.) was added in portions. Stirred for 2 h at 0° C., then quenched by adding water, concentrated to remove the EtOH, added EtOAc, extracted the organics, dried with brine, then Na2SO4, and concentrated to yield 5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enol (91%). LC/MS=235.2 (M+H), LC=2.62 min.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]C)=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:15]([O:17]C)=O.[CH3:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].[H-].[Na+].Cl>O1CCCC1>[CH3:22][C:21]([CH3:24])([CH3:23])[C:20](=[O:25])[CH2:19][C:11]([C:7]1[CH:8]=[CH:9][C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:15](=[O:17])[CH2:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:1]=2)[CH:6]=1)=[O:13]
Reactant: CC(=O)C(C)(C)C
Reactant: COC(=O)c1ccc2cc(C(=O)OC)ccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CC(=O)c1ccc2cc(C(=O)CC(=O)C(C)(C)C)ccc2c1
Yield: 67.4 %

Procedure:
To 2.0 gm of dimethyl 2,6-naphthalene dicarboxylate and 2.8 gm of pinacolone, which had been dissolved in 25 ml of anhydrous tetrahydrofuran, 1.1 gm of 60% sodium hydride was added. The mixture was reacted at 60° C. for 4 hours while stirring. The reaction mixture was poured into ice-cooled 2N hydrochloric acid. Organic substances were extracted using chloroform and, after evaporating the solvent, recrystallized in a mixed solvent of chloroform-methanol to obtain 2.1 gm of the target compound as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH:14]=O.[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19]>>[Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH2:14][N:30]1[CH2:31][CH2:32][CH:27]([C:23]2[CH:22]=[C:21]([NH:20][C:18](=[O:19])[CH:17]([CH3:16])[CH3:33])[CH:26]=[CH:25][CH:24]=2)[CH2:28][CH2:29]1
Reactant: Cc1nn(-c2ccccc2)c(Cl)c1C=O
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: Cc1nn(-c2ccccc2)c(Cl)c1CN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure F and Scheme R using 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 451.2 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:11]2[N:12]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13](=[O:15])[NH:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].N(C(C)(C)C#N)=NC(C)(C)C#N.[Cl:34]N1C(=O)CCC1=O>ClC1C=CC=CC=1>[Cl:34][C:9]1[C:10]2[NH:14][C:13](=[O:15])[N:12]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:11]=2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)Cn1c(=O)[nH]c2cccc(C(CC)CC)c21
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: CCOC(=O)Cn1c(=O)[nH]c2c(Cl)ccc(C(CC)CC)c21
Temperature: 70 °C
Reaction time: 48 h
Yield: 63.2 %

Procedure:
To a solution of ethyl [7-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate (3.91 g, 13.5 mmol) and 2,2′-azobisisobutyronitrile (222 mg, 1.35 mmol) in chlorobenzene (40 mL) was added portionwise N-chlorosuccinimide (1.80 g, 13.5 mmol) at 65° C., and the mixture was stirred at 70° C. for 2 days. After cooling, the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate. The aqueous layer was separated and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 15-50% ethyl acetate/n-hexane gradient mixture, and the fractions containing the title compound were concentrated in vacuo. The mixture was suspended in diisopropyl ether, and the suspension was stirred at 60° C. for 2 hr. After cooling, the resulting solid was collected by filtration and washed with n-hexane to give the title compound (2.77 g, 8.53 mmol, 63%) as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]#[N:11])[CH:5]=1)([O-:3])=[O:2].Cl[Si](C)(C)C.[OH2:17]>CCOC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([NH2:11])=[O:17])[CH:5]=1)([O-:3])=[O:2]
Reactant: N#Cc1cc([N+](=O)[O-])ccn1
Reactant: O
Agent: C[Si](C)(C)Cl
Solvent: CCOC(C)=O
Product: NC(=O)c1cc([N+](=O)[O-])ccn1
Yield: 119.7 %

Procedure:
4-Nitropicolinonitrile (100 mg, 0.67 mmol), chlorotrimethylsilane (0.17 mL, 1.4 mmol) and H2O (0.024 mL, 1.4 mmol) was sonicated in a sonicator at rt for 1.0 h. It was diluted with EtOAc, washed with NaHCO3, brine and dried over Na2SO4. After removal of solvent, 99A (134 mg, 100% yield) was obtained as a solid. 1H NMR (400 MHz, Methanol-d4) δ ppm 8.29 (dd, J=5.27, 2.20 Hz, 1H) 8.74 (d, J=2.20 Hz, 1H) 8.98 (d, J=5.27 Hz, 1H).
Reaction SMILES: [NH2:1][CH:2]([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[OH:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].N1C=CN=C1.C1CCC(N=C=NC2CCCCC2)CC1>CCOC(C)=O>[OH:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH:1][CH:2]([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:17]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(N)CNC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: CC(CNC(=O)OC(C)(C)C)NC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.6 %

Procedure:
To a solution of tert-butyl 2-aminopropylcarbamate (3.6 g, 20.6 mmol), 2-hydroxybenzoic acid (2.79 g, 20.6 mmol) and imidazole (1.41 g, 20.6 mmol) in EtOAc (100 mL) at 0° C. was slowly added a solution of DCC (4.26 g, 20.6 mmol) in EtOAc (50 mL). The reaction mixture was stirred (RT, 16 h), filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, EtOAc/PE (0-20%) to afford tert-butyl 2-(2-hydroxybenzamido)propylcarbamate (2.4 g, 40%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14].C(N(CC)CC)C>CN(C)C=O>[C:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:16]([NH:15][CH2:13][CH3:14])=[O:17])[S:3][C:4]=2[CH:10]=1)#[N:12]
Reactant: N#Cc1ccc2nc(N)sc2c1
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2ccc(C#N)cc2s1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
0.2 grams of 2-amino-1,3-benzothiazole-6-carbonitrile is dissolved in about 5 ml dimethylformamide. About 0.2 ml of ethylisocyanate is added followed by about 0.3 ml triethylamine and the solution is heated to about 80° C. under good agitation. The solution is allowed to stir for about 4 hours then cooled to RT. The solvent is removed in vacuo and the solids are washed well with ether. The product is further purified by column chromatography and after drying in vacuo, about 0.14 grams is isolated.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][N:5]=[C:4]2[S:15][CH:16]=[CH:17][C:3]=12.[Cl:18][C:19]1[CH:20]=[C:21]([C:26]2([C:29](Cl)=[O:30])[CH2:28][CH2:27]2)[CH:22]=[CH:23][C:24]=1[Cl:25]>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:29]([C:26]3([C:21]4[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=4)[CH2:28][CH2:27]3)=[O:30])=[CH:12][CH:13]=2)[CH2:6][N:5]=[C:4]2[S:15][CH:16]=[CH:17][C:3]=12
Reactant: NC1=c2ccsc2=NCN1c1ccc(N)cc1
Reactant: O=C(Cl)C1(c2ccc(Cl)c(Cl)c2)CC1
Solvent: c1ccncc1
Product: NC1=c2ccsc2=NCN1c1ccc(NC(=O)C2(c3ccc(Cl)c(Cl)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-Amino-3-(4-aminophenyl)thieno[2,3-d]pyrimidine (0.3 mL of a 0.324 M solution, 0.1 mmol) 1-(3,4-Dichloro-phenyl)-cyclopropanecarbonyl chloride (0.2 mL of a 1 M solution in pyridine, 0.2 mmol) was added in one portion. After the mixture was stirred at room temperature for 3 d, the reaction was purified by hplc to afford the title compound as a beige solid. MS(ES) m/e 455 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[CH3:11].C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[O:2][CH3:1])[C:7]#[N:8]
Reactant: COc1ccc(C#N)cc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C#N)cc1CBr
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To 9.8 g of 4-methoxy-3-methylbenzonitrile, were added 150 ml of carbon tetrachloride, 10 g of NBS, and 0.4 g of BPO. The mixture was heated under reflux for 2.5 hours. The reaction mixture was cooled in ice, filtered from insolubles and concentrated under reduced pressure. The residue was admixed with n-hexane, stirred for 30 minutes, and collected by filtration to yield 9 g of 3-bromomethyl-4-methoxybenzonitrile; m.p. 102°-103° C.