Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([NH:14][NH:15][C:16](=O)[C:17]([OH:23])([CH3:22])[C:18]([F:21])([F:20])[F:19])=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1(C)C=CC=CC=1.O>[NH2:1][C:2]1[C:3]([C:12]2[S:34][C:16]([C:17]([OH:23])([CH3:22])[C:18]([F:21])([F:20])[F:19])=[N:15][N:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(O)(C(=O)NNC(=O)c1ncc(C(F)(F)F)cc1N)C(F)(F)F
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O)(c1nnc(-c2ncc(C(F)(F)F)cc2N)s1)C(F)(F)F

Procedure:
A mixture comprising 3-amino-N′-(3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-5-(trifluoromethyl) picolinohydrazide (184 mg, 0.511 mmol) in toluene (5.108 ml) was treated with Lawesson reagent (310 mg, 0.766 mmol) and heated at reflux for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed saturated sodium bicarbonate solution, brine, dried (phase separator) and concentrated in vacuo. Purification by chromatography on silica eluting with 0-30% EtOAc in iso-hexane afforded an orange gum. Further purification was carried out by preparative reverse phase HPLC eluting with 30-70% MeCN in water (0.1% TFA) to afford the title compound; 1H NMR (400 MHz, DMSO-d6) δ 8.2 (1H, s), 8.0 (1H, s), 7.6 (1H, s), 7.4 (2H, s), 1.9 (3H, s). LC-MS Rt=4.03 min [M+H]+ 359.4 Method 10minLC_v003.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.C(OC([CH:17]([C:27](=[O:30])[CH2:28][CH3:29])[C:18]([C:20]1[C:21]([CH3:26])=[N:22][CH:23]=[N:24][CH:25]=1)=[O:19])=O)C=C>C1COCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:26][C:21]1[C:20]([C:18](=[O:19])[CH2:17][C:27](=[O:30])[CH2:28][CH3:29])=[CH:25][N:24]=[CH:23][N:22]=1
Reactant: C=CCOC(=O)C(C(=O)CC)C(=O)c1cncnc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: C1CCOC1
Product: CCC(=O)CC(=O)c1cncnc1C
Yield: 101.7 %

Procedure:
To a suspension of 6.6 mg of palladium diacetate (Pd(OAc)2), triethylamine (226 mg), and formic acid (204 mg) in 2 ml THF was added 410 mg of 2-(allyloxycarbonyl)-1-(4-methylpyrimidin-5-yl)pentan-1,3-dione. The mixture was refluxed for 3.5 hours, cooled and partitioned between ethyl acetate and water. The organic layer was dried with magnesium sulfate, filtered and evaporated to yield 290 mg of 1-(4-methylpyrimidin-5-yl)pentan-1,3-dione as an amber liquid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)=[CH:26][CH:25]=1.O>CN(C=O)C>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:17]2[N:18]=[CH:19][N:20]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([N:30]4[CH:34]=[N:33][CH:32]=[N:31]4)=[CH:28][CH:29]=3)[CH:21]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1
Reactant: BrCc1ccc(-n2cncn2)cc1
Reactant: CCOC(=O)C(Cc1ccc(N)nc1)c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1ccc(N)nc1)c1cn(Cc2ccc(-n3cncn3)cc2)cn1
Reaction time: 1 h

Procedure:
11 mg (0.23 mmol, 50%) of sodium hydride were added to a solution of 60 mg (0.23 mmol) of ethyl 3-(6-aminopyridin-3-yl)-2-(1H-imidazol-4-yl)propionate (example 1g) in 0.5 ml of DMF at RT, and stirred for 1 h. Then 55 mg (0.23 mmol) of 1-[4-(bromomethyl)phenyl]-1H-1,2,4-triazole were added, and the mixture was stirred at RT for 3 h. After this, 1 ml of water was added, the mixture was extracted with EA, and the organic phase was dried over Na2SO4, filtered and concentrated. Chromatography on silica gel afforded ethyl 3-(6-aminopyridin-3-yl)-2-[1-(4-[1,2,4]triazol-1-ylbenzyl)-1H-imidazol-4-yl]propionate. The product obtained in this way was taken up in 0.4 ml of 50% concentrated hydrochloric acid and treated in the microwave at 180° C. for 3 min. Freeze-drying after cooling of the reaction mixture afforded 5 mg of the title compound as bishydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([NH:14][C:15]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:20][CH:19]=3)=S)[N:8]=[C:7]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:40])[C:6]=2[CH:41]=1.[NH3:42]>ClCCl.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([NH:14][C:15]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:20][CH:19]=3)=[NH:42])[N:8]=[C:7]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:40])[C:6]=2[CH:41]=1
Reactant: CN1C(=O)C(NC(=S)Nc2ccc(N3CCOCC3)c3ccccc23)N=C(c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: N
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)C(NC(=N)Nc2ccc(N3CCOCC3)c3ccccc23)N=C(c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
As illustrated in the scheme above, to a solution of N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[4-(4-morpholinyl)-1-naphthalenyl]-thiourea (EXAMPLE 11) (0.029 g, 0.05 mmol) and silver triflate (0.038 g, 0.15 mmol) in dichloromethane (2 ml) was added a solution of ammonia (0.25 ml, 2M in methanol). The reaction mixture was stirred at room temperature for 3 h, diluted with dichloromethane (10 ml) and washed with brine (2×5 ml). The organic layer was dried with MgSO4 filtered, concentrated in vacuo. The residue was triturated with ether to give the title compound (0.008 g, 28%) as a pale yellow solid. 1H-NMR (CDCl3): δ 8.22 (d, J=9.2 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.75 (br.s, 1H), 7.50-7.41 (m, 7H), 7.31 (d, J=8.8 Hz, 1H), 7.04 (m, 2H), 5.8 (br.s, 1H), 3.96 (t, J=9.2 Hz, 4H) 3.51 (s, 3H) and 3.05 (br.s, 4H).). (ESI) (M+H)+=587.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C@H:6]2[CH2:11][CH2:10][C@H:9]([CH2:12][NH:13][C:14]3[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=[C:16]([NH:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][C:32]([F:35])([F:34])[F:33])[N:15]=3)[CH2:8][CH2:7]2)[CH2:3]1.[C:36](O)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.N=C=N.C1N=CN(C(N2C=NC=C2)=O)C=1.C(N(CC)CC)C>C1COCC1>[N+:20]([C:19]1[C:14]([NH:13][CH2:12][C@H:9]2[CH2:10][CH2:11][C@H:6]([N:4]3[CH2:5][CH:2]([NH:1][C:36](=[O:43])[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:3]3)[CH2:7][CH2:8]2)=[N:15][C:16]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][C:32]([F:34])([F:35])[F:33])=[N:17][CH:18]=1)([O-:22])=[O:21]
Reactant: NC1CN([C@H]2CC[C@H](CNc3nc(NCc4ccccc4OC(F)(F)F)ncc3[N+](=O)[O-])CC2)C1
Reactant: O=C(O)c1ccccc1
Agent: N=C=N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1CN([C@H]2CC[C@H](CNc3nc(NCc4ccccc4OC(F)(F)F)ncc3[N+](=O)[O-])CC2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N4-{[Trans-4-(3-aminoazetidin-1-yl)cyclohexyl]methyl}-5-nitro-N2-[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine (20 mg, 0.04 mmol) was dissolved in THF (1.0 mL). To this solution was added benzoic acid (7.3 mg, 0.06 mmol), Polystyrene-linked Carbodiimide (PS-CDI) (47 mg, 0.06 mmol) followed by triethylamine (0.084 mL, 0.06 mmol). The reaction was allowed to stir at 25° C. for 18 h. The reaction was filtered to remove the PS-CDI and the volatiles were removed in vacuo. The crude was redissolved in CH2Cl2 and extracted with 10% aqueous NaHCO3. The aqueous phase was separated and extracted two more times with CH2Cl2. The organic layers were combined, dried (Na2SO4), decanted and concentrated. The resultant residue was purified via flash chromatography (SiO2, 10-30% (2:18:80, NH4OH:CH3OH:CH2Cl2)—CH2Cl2) to afford 18 mg (74%) of the target compound, m/z 600.34 (M+1)+.
Reaction SMILES: [CH3:1][S:2][CH:3]([O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([CH3:17])=[C:12]([CH3:18])[CH:11]=1)[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>C1COCC1.O>[CH3:1][S:2][CH:3]([O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([CH3:17])=[C:12]([CH3:18])[CH:11]=1)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(Oc1cc(C)c(C)c(C)c1)SC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSC(Oc1cc(C)c(C)c(C)c1)C(=O)O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
The product from Step 2 (2.0 g) in THF (10 ml) and water (3 ml) containing sodium hydroxide (0.4 g) were stirred at 60° C. for 2 hours then cooled to ambient temperature, evaporated under reduced pressure, diluted with water and washed with diethyl ether. The aqueous fraction was acidified with dilute hydrochloric acid and extracted with ethyl acetate (three times). The extracts were combined, washed with brine, dried over magnesium sulphate, then evaporated to give 2-methylthio-2-(3,4,5-trimethylphenoxy)acetic acid, 1.05 g, as a yellow gum. A portion of the gum was fractionated by chromatography (silica; ethyl acetate then methanol) to provided an analytical sample and the remainder used in the next stage without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][CH:8]([C:36](=[O:40])[N:37]([CH3:39])[CH3:38])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH2:24][C:25](=[O:35])[NH:26][O:27]CC2C=CC=CC=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:41])[NH:7][CH:8]([C:36](=[O:40])[N:37]([CH3:39])[CH3:38])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH2:24][C:25](=[O:35])[NH:26][OH:27])=[CH:14][CH:15]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CN(C)C(=O)C(Cc1ccc(Oc2ccccc2CCC(=O)NOCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)C(Cc1ccc(Oc2ccccc2CCC(=O)NO)cc1)NC(=O)OC(C)(C)C
Yield: 119.1 %

Procedure:
Palladium on BaSO4 (5%, 0.24 g) was added to a degassed solution of the benzyl hydroxamate 63 (0.7 g) in MeOH (20.0 mL) and the suspension was treated with hydrogen at atmospheric pressure for 6 h. The suspension was filtered over a Celite® bed and concentrated to yield the desired hydroxamate 64 (0.7 g, 97%). 1H NMR (DMSO-d6): 10.37 (s, 1H), 7.28 (d, J=7.6 Hz, 1H), 7.23-7.16 (m, 3H), 7.06 (t, J=8.4 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 6.76 (d, J=7.6 Hz, 1H), 4.53 (m, 1H), 2.80 (s, 3H), 2.79-2.75 (m, 7H), 2.23 (t, J=2.0 Hz, 2H), 1.30 (s, 9H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH2:9]1[C:20]2=[C:21]3[C:16](=[CH:17][CH:18]=[CH:19]2)[CH2:15][CH2:14][CH2:13][CH:12]3[CH2:11][CH2:10]1>C(=S)=S>[C:19]1([C:5](=[O:7])[CH3:6])[C:20]2=[C:21]3[CH:12]([CH2:11][CH2:10][CH2:9]2)[CH2:13][CH2:14][CH2:15][C:16]3=[CH:17][CH:18]=1
Reactant: c1cc2c3c(c1)CCCC3CCC2
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c3c1CCCC3CCC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45 %

Procedure:
A suspension of aluminum chloride (0.250 g) in carbon disulfide (3 ml) was added with acetyl chloride (0.16 ml). The mixture was stirred at room temperature for 5 minutes, and then slowly added with 2,3,3a,4,5,6-hexahydro-1H-phenalene (0.250 g) dissolved in carbon disulfide (2 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and at room temperature for 1 hour, and then poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:500) to obtain (±)-1-(5,6,6a,7,8,9-hexahydro-4H-1-phenalenyl)ethanone (0.139 g, yield: 45%) and the title compound (0.135 g, yield: 43%).
Reaction SMILES: O.NN.C([NH:12][C:13](=[S:47])[N:14]([C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH2:23][CH2:24][S:25]([N:28]2[CH2:45][CH2:44][C:31]3([N:35]=[C:34]([CH:36]4[CH2:41][CH2:40][CH:39]([CH3:42])[CH2:38][CH2:37]4)[NH:33][C:32]3=[O:43])[CH2:30][CH2:29]2)(=[O:27])=[O:26])=[C:18]([CH3:46])[CH:17]=1)[CH3:15])(=O)C1C=CC=CC=1>C(O)C>[CH3:46][C:18]1[CH:17]=[C:16]([N:14]([CH3:15])[C:13]([NH2:12])=[S:47])[CH:21]=[C:20]([CH3:22])[C:19]=1[CH2:23][CH2:24][S:25]([N:28]1[CH2:45][CH2:44][C:31]2([N:35]=[C:34]([CH:36]3[CH2:37][CH2:38][CH:39]([CH3:42])[CH2:40][CH2:41]3)[NH:33][C:32]2=[O:43])[CH2:30][CH2:29]1)(=[O:26])=[O:27]
Reactant: Cc1cc(N(C)C(=S)NC(=O)c2ccccc2)cc(C)c1CCS(=O)(=O)N1CCC2(CC1)N=C(C1CCC(C)CC1)NC2=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(N(C)C(N)=S)cc(C)c1CCS(=O)(=O)N1CCC2(CC1)N=C(C1CCC(C)CC1)NC2=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 101.3 %

Procedure:
Hydrazine monohydrate (55 mg, 1.1 mmol) was added to a solution of 3-benzoyl-1-(3,5-dimethyl-4-{2-[2-(4-methyl-cyclohexyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-phenyl)-1-methyl-thiourea (140 mg, 0.22 mmol) in ethanol (7 ml). The mixture was stirred at room temperature for 15 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to give 1-(3,5-dimethyl-4-{2-[2-(4-methyl-cyclohexyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-phenyl)-1-methyl-thiourea (119 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])[C:11]([CH3:28])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[Cl:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][C:45]=1[Cl:46])[C:40](Cl)=[O:41]>C(Cl)Cl>[Cl:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][C:45]=1[Cl:46])[C:40]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)[CH2:19][CH2:18]3)=[O:16])[C:11]([CH3:28])=[N:10]2)[CH:4]=1)=[O:41]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Cc1nn(-c2cccc(N)c2)c(C)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nn(-c2cccc(NC(=O)c3ccc(Cl)c(Cl)c3)c2)c(C)c1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 25 °C

Procedure:
A solution of 0.080 g (0.20 mmol) of [1-(3-amino-phenyl)-3,5-dimethyl-1H-pyrazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone hydrochloride and 0.11 ml (0.79 mmol, 4 eq) of triethylamine in 3 ml of CH2Cl2 was treated at 0° C. with 0.050 g (0.24 mmol, 1.2 eq) of 3,4-dichlorobenzoyl chloride. The reaction was stirred over night at RT, then partitioned three times between EtOAc and aqueous saturated NaHCO3, dried over Na2SO4 and evaporated to give 0.115 g (quant.) of the title compound as light yellow solid. MS: 540.4 (MH+, 2 Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=O)[CH2:7][Br:8])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[CH3:18][O:19][NH2:20].C(OCC)(=O)C>C(O)(=O)C>[CH3:18][O:19][N:20]=[C:6]([C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:7][Br:8]
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CON=C(CBr)c1ccc(Cl)cc1

Procedure:
50.3 g of 4-chlorophenacyl bromide in 300 ml of glacial acetic acid are stirred with 23 g of sodium acetate and 21.6 g O-methylhydroxylamine hydrochloride for 2 hours at 70° C. 150 ml of ethyl acetate are added to the mixture, which is then extracted by washing several times with water and saturated sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated by evaporation in vacuo. Crystallisation from hexane yields 4-chlorophenacyl bromide O-methyloxime having a melting point of 57 to 60° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:17])[C:5]1[C:10]([S:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][CH:8]=[CH:7][C:6]=1[F:16])[CH3:2].[OH:18]OS([O-])=O.[K+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CO.O>[CH3:14][C:12]([S:11]([C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([F:16])[C:5]=1[C:4]([NH:3][CH2:1][CH3:2])=[O:17])=[O:18])([CH3:13])[CH3:15]
Reactant: O=S([O-])OO
Reactant: CCNC(=O)c1c(F)cccc1SC(C)(C)C
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCNC(=O)c1c(F)cccc1S(=O)C(C)(C)C
Reaction time: 0.03 h
Yield: 60 %

Procedure:
A 0° C. solution of N-ethyl-2-fluoro-6-(1,1-dimethylethylthio)benzamide (3.45 g, 13.51 mmol) in methanol (100 mL) was combined with a 0° C. solution of OXONE® (8.31 g, 13.51 mmol) in water (100 mL). This mixture was stirred for 2 min, then was poured into 25% aq sodium metabisulfite (100 mL) and extracted with ether (3×100 mL). The combined organics were washed with brine followed with water, then was dried (MgSO4), concentrated, and recrystallized from ethyl acetate--hexanes to afford 2.2 g of the title compound as a white solid, a 60% yield. m.p. 114°-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([O:29]C)=[O:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CO>O>[C:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:19][C:3]2[C:4]3[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=3[CH:17]=[CH:18][C:2]=2[Cl:1])=[CH:26][CH:25]=1)([OH:29])=[O:28]
Reactant: COC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(CNc2c(Cl)ccc3c2CCNCC3)cc1

Procedure:
Combine 7-chloro-6-(4-methoxycarbonyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (70 mg, 0.16 mmol), potassium carbonate (0.87 g, 6.3 mmol), methanol (2 mL), water (2 mL) and heat at 50° C. for 3 h. Purify by SCX chromatography to obtain 6-(4-carboxy-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH2:25][CH2:24]1>C(Cl)Cl>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([N:13]([CH3:14])[C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]([CH2:2][NH:1][C:23](=[O:29])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])[N:12]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(N(C)c2nc(CN)nc3ccccc23)cc1
Reactant: O=C1CCC(=O)O1
Solvent: ClCCl
Product: COc1ccc(N(C)c2nc(CNC(=O)CCC(=O)O)nc3ccccc23)cc1

Procedure:
A solution of (2-aminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (76 mg, 0.25 mmol) and succinic anhydride (25 mg, 0.25 mmol) was stirred overnight in CH2Cl2 (1 mL). Solvent removal yielded the title compound. 1H NMR (CDCl3) δ 7.80-7.75 (m, 1H), 7.61 (ddd, 1H), 7.23-7.17 (m, 2H), 7.08-6.98 (m, 4H), 4.57 (s, 2H), 3.84 (s, 3H), 3.64 (s, 3H), 2.68-2.62 (m, 4H); HRMS (ES) m/z calcd for C21H23N4O4 395.1714, found 395.1737.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][NH:5][C:6]=1Cl.[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]O)=[CH:11][CH:10]=1.[I:17][CH3:18]>>[I-:17].[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:5]2[CH:6]=[CH:2][N+:3]([CH3:18])=[CH:4]2)=[CH:11][CH:10]=1
Reactant: CI
Reactant: Clc1nc[nH]c1Cl
Reactant: OCc1ccc(O)cc1
Product: C[n+]1ccn(Cc2ccc(O)cc2)c1
Product: [I-]
Temperature: 155 °C

Procedure:
4,5-Dichloroimidazole (0.1 mol) and 4-hydroxybenzyl alcohol (0.1 mol) were combined and heated to 155° C. The crude product was washed with cold ethanol and recrystallized in an EtOH/DMF mixture. This powder (3-(4-hydroxybenzyl)-4,5-dichloroimidazole, 8.23 mmol) was then was dissolved in DMF (3 mL). Iodomethane (72.3 mmol) was added to the reaction mixture and refluxed for 24 hours at 80° C. The solvent was evaporated and remaining oil was washed using ethyl ether to yield a brown precipitate. Yield: 1.28 g, 61%. 1H NMR (300 MHz, DMSO-d6) 3.81 (3H, s, CH3N), 5.34 (2H, CH2), 6.82 (2H, d, Ar), 7.26 (2H, d, Ar), 9.32 (1H, s, NCHN), 9.70 (1H, s, OH).
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[C:6]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[N:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=O.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[N:16]1([C:6]2[C:5]3[N:10]([CH:1]=[N:3][CH:4]=3)[C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][N:7]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccs3)nc2CNC=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1csc(-c2cnc(N3CCNCC3)c3cncn23)c1
Temperature: 90 °C
Yield: 87.6 %

Procedure:
A 50 mL round bottom flask was charged with tert-butyl 4-(3-(formamidomethyl)-5-(thiophen-2-yl)pyrazin-2-yl)piperazine-1-carboxylate (0.40 g, 1.0 mmol) and toluene (20 mL). To the above mixture was added dropwise POCl3 (0.76 g, 5.0 mmol). The resulting mixture was heated at 90° C. for 1 h. Work-up: the reaction mixture was poured into saturated aqueous NaHCO3 and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 5% MeOH in dichloromethane, to afford 0.25 g (85%) of the product. 1H NMR (300 MHz, CDCl3) δ: 8.41 (s, 1H), 7.74 (s, 1H), 7.46 (dd, J=5.1, 1.2 Hz, 1H), 7.37 (dd, J=3.6, 1.2 Hz, 1H), 7.25 (s, 1H), 7.19 (dd, J=5.1, 3.6 Hz, 1H), 3.89 (t, J=5.1 Hz, 4H), 3.08 (t, J=5.1 Hz, 4H). MS m/z: 286 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:3]=1.Br[CH2:14][CH2:15]Br>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([S:9]([CH3:12])(=[O:10])=[O:11])[CH2:15][CH2:14]2)[CH:3]=1
Reactant: CS(=O)(=O)Cc1cc(Br)ccn1
Reactant: BrCCBr
Product: CS(=O)(=O)C1(c2cc(Br)ccn2)CC1
Yield: 20 %

Procedure:
The title compound was prepared from 4-bromo-2-methanesulfonylmethyl-pyridine and 1,2-dibromoethane following a procedure analogous to that described in Step 3 for Intermediate 4. Yield: 20% of theory; Mass spectrum (ESI+): m/z=276/278 (Br) [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9](B3OC(C)(C)C(C)(C)O3)[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1.Br[C:28]1[N:32]([CH3:33])[N:31]=[CH:30][C:29]=1[C:34]#[N:35].C(Cl)Cl.C1CCN2C(=NCCC2)CC1.CS(C)=[O:52].O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:28]3[N:32]([CH3:33])[N:31]=[CH:30][C:29]=3[C:34]([NH2:35])=[O:52])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1cc(B2OC(C)(C)C(C)(C)O2)c2[nH]c(=O)[nH]c2c1
Reactant: CS(C)=O
Reactant: Cn1ncc(C#N)c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1noc(C)c1-c1cc(-c2c(C(N)=O)cnn2C)c2[nH]c(=O)[nH]c2c1
Temperature: 120 °C

Procedure:
To a microwave vial containing 6-(3,5-dimethylisoxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (100 mg, 0.28 mmol, 1 equiv.) was added 5-bromo-1-methyl-1H-pyrazole-4-carbonitrile (130 mg, 0.30 mmol, 2.5 equiv.), Pd(dppf)Cl2.CH2Cl2 (23 mg, 0.03 mmol, 0.1 equiv.) and DBU (253 μL, 1.69 mmol, 6 equiv.) and dissolved in DMSO-H2O (4 mL, 0.2 M, 2/1, v/v). The mixture was heated to 120° C. for 30 min in microwave. The reaction was concentrated in vacuo and purification was then carried out by reverse phase HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20]C=1>CCO.CCO.CCO.CCO.[Ti]>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([N:11]1[CH:12]=[CH:13][CH:14]=[CH:15]1)[C:4]([O:3][CH2:1][C:2]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:18]=1)=[O:16])[C:10]1[CH:18]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C(=O)OCC)n1cccc1
Reactant: OCc1ccccc1
Agent: [Ti]
Solvent: CCO
Product: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)n1cccc1
Temperature: 110 °C
Reaction time: 15 h
Yield: 87.3 %

Procedure:
To a solution of 2-(pyrrol-1-yl)malonic acid diethyl ester (75.7 g) in benzyl alcohol (200 ml) was added tetraethyl titanate (3.0 g), and the resulting mixture was stirred at 110° C. for 15 hours. After removal of the benzyl alcohol under reduced pressure, the residue was chromatographed on silica gel using n-hexane/ethyl acetate (10:1) as the eluent. Fractions containing the title compound were pooled and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (102.5 g, 87.3%) as colorless crystals, mp 48.5°-49° C.