Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:4]([CH3:6])=[O:5].[N+:14]([O:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22])([O-:16])=[O:15]>C1COCC1>[N+:14]([O:17][CH2:18][CH2:19][CH2:20][C:21]([O:13][C:10]1[CH:11]=[CH:12][C:7]([NH:3][C:4](=[O:5])[CH3:6])=[CH:8][CH:9]=1)=[O:22])([O-:16])=[O:15]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=C(Cl)CCCO[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(OC(=O)CCCO[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 40 %

Procedure:
Sodium hydride (270 mg of 60% NaH, 6.8 mmol) was added under argon and under magnetic stirring to a solution of 4-acetaminophenol (840 mg, 5.6 mmol) in dry THF (20 ml) kept at 0° C. The reaction mixture was stirred at 0° C. for 40 minutes. A solution of crude 4-(nitrooxy)butanoyl chloride in dry THF (10 ml), was then added dropwise to the reaction mixture kept at 0° C. The reaction temperature was allowed to rise to r.t. and the mixture was stirred for 18 hours. The unreacted 4-acetaminophenol was removed by washing the solution with 2M NaOH solution (75 ml). The resulting mixture was extracted with CH2Cl2 (3×75 ml). The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. Purification of the residue by silica gel column chromathography by using petroleum ether/ethyl acetate=30/70 mixture as eluent provided 300 mg (1.1 mmol, 40% yield on converted paracetamol) of pure 4-(acetylamino)phenyl 4-(nitrooxy)butanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3=[CH:13][S:14][CH:15]=[C:9]3[C:8](SC)=[N:7][C:6]=2[CH:18]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[Cl:26]([OH:30])(=[O:29])(=[O:28])=[O:27]>C(O)(=O)C.O>[Cl:26]([OH:30])(=[O:29])(=[O:28])=[O:27].[Cl:26]([OH:30])(=[O:29])(=[O:28])=[O:27].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3=[CH:13][S:14][CH:15]=[C:9]3[C:8]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)=[N:7][C:6]=2[CH:18]=1
Reactant: CN1CCNCC1
Reactant: CSC1=Nc2cc(Cl)ccc2N(C)c2cscc21
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CN1CCN(C2=Nc3cc(Cl)ccc3N(C)c3cscc32)CC1

Procedure:
A solution of 0.7 g. of 7-chloro-4-methyl-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in 3.5 ml. of N-methylpiperazine is treated with 1-2 drops of glacial acetic acid and heated under reflux for 4 days. The solution is concentrated to dryness and the residue is warmed with dilute acetic acid. The acidic solution is filtered, cooled and made alkaline with concentrated ammonium hydroxide. The sticky precipitate is collected and dissolved in chloroform. The dried chloroform solution is concentrated under reduced pressure to give an oil. An ethanolic solution of the oil is treated with 70% perchloric acid and is diluted with water. The precipitate is collected and recrystallized from ethanol to give a white solid, m.p. 212°-215° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].CS(O[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CCCCCCCCCCCCCCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCN1CCN(C(=O)OCC)CC1

Procedure:
25.0 Grams of 1-ethoxycarbonylpiperazine, 43.0 grams of pentadecyl methylsulfonate, 250 ml. of ethanol, and 9.53 grams of sodium carbonate are combined and heated to gentle reflux. After refluxing for 6 hours, the mixture is filtered, and the solvents removed under reduced pressure. The residue is dissolved in a mixture of water and ethyl ether. The organic layer is separated, washed once with water, and dried over anhydrous magnesium sulfate and anhydrous sodium sulfate. The solvent is removed under reduced pressure to give 1-ethoxycarbonyl-4-pentadecylpiperazine.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([NH:11][NH:12][C:13](=O)[CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[CH2:18][CH2:17]2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>[OH-].[Na+]>[CH:1]1([CH2:7][N:8]2[C:13]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=4)[CH2:18][CH2:17]3)=[N:12][NH:11][C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCN1CCN(c2cccc([N+](=O)[O-])c2)CC1)NNC(=O)NCC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]nc(CCN2CCN(c3cccc([N+](=O)[O-])c3)CC2)n1CC1CCCCC1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
A suspension of N-(cyclohexylmethyl)-2-{3-[4-(3-nitrophenyl)piperazin-1-yl]propanoyl}hydrazine carboxamide D8 (0.70 g, 1.62 mmol) in 2M NaOH aqueous solution (10 mL) was heated at reflux for 5 hrs, then cooled to room temperature and brought to pH 8 by the drop-wise addition of HCl 28%. The resulting precipitate was filtered, washed with water and diethyl ether to afford 0.60 g (89%) 4-(cyclohexylmethyl)-5-{2-[4-(3-nitrophenyl)piperazin-1-yl]ethyl}-2,4-dihydro-3H-1,2,4-triazol-3-one D9 as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.N1(C(N2C=CN=C2)=O)C=CN=C1.C(N(C(C)C)C(C)C)C.[C:33]1([NH:39][NH2:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:40][NH:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:6]
Reactant: NNc1ccccc1
Reactant: Nc1cc(Br)ccc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(Br)ccc1C(=O)NNc1ccccc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-amino-4-bromobenzoic acid (10 g, 46.30 mmol, 1.00 equiv) in tetrahydrofuran (300 mL). To the resulting mixture was then added di(1H-imidazol-1-yl)methanone (9 g, 55.56 mmol, 1.20 equiv) dropwise, with stirring at 0-5° C. The resulting mixture was warmed and stirred at 20° C. for 2 hours. To the resulting mixture was then added N-ethyl-N-isopropylpropan-2-amine (7.2 g, 55.81 mmol, 1.20 equiv) dropwise with stirring at room temperature. To the mixture was then added 1-phenylhydrazine (5 g, 46.30 mmol, 1.00 equiv) in several batches at room temperature. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 1N hydrogen chloride/H2O. The pH value of the solution was adjusted to about pH1 with 1N HCl. The resulting mixture was then neutralized to pH=7 with 50% NaOH. The resulting solution was extracted with ethyl acetate (2×250 mL) and the organic layers combined. The resulting mixture was washed with water (2×500 mL), sodium bicarbonate (2×500 mL) and saturated brine (2×500 mL). The resulting solution was concentrated under reduced pressure to yield 2-amino-4-bromo-N′-phenylbenzohydrazide as a red solid. MS: 306 (MH+)
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[NH:3]1.[H-].[Na+].[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=1>CN(C=O)C>[C:11]([O:10][C:8](=[O:9])[CH2:7][N:6]1[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]([C:26]2[CH:27]=[C:22]([Cl:21])[N:23]=[CH:24][N:25]=2)[C:2]1=[O:1])([CH3:14])([CH3:13])[CH3:12]
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c(=O)n(-c2cc(Cl)ncn2)c2ccccc21
Temperature: 140 °C
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl (2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate (130 mg, 0.52 mmol, described in Intermediate 7) in DMF (0.7 mL) was added sodium hydride (15 mg of a 60% dispersion in mineral oil, 0.38 mmol). The mixture was stirred for 5 min, then 4,6-dichloropyrimidine (234 mg, 1.57 mmol) was added and argon was bubbled through the mixture for 5 min. The reaction mixture was heated at 140° C. for 10 min in a microwave reactor. The cooled mixture was partitioned between CHCl3 (10 mL) and saturated aqueous NaHCO3 (5 mL). The aqueous phase was extracted further with CHCd3 (10 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-95:5 to 75:25, to give the title compound. MS: m/z=361 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Br)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[C:15]([CH3:20])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](C([Sn])=C(CCCC)CCCC)[CH2:23]CC>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:22]=[CH2:23])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[C:15]([CH3:20])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(Br)ccc(OCc3ccccc3)c2[nH]c1=O
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(OCc2ccccc2)c2[nH]c(=O)c(C)cc12
Temperature: 100 °C

Procedure:
Palladium tetrakis(triphenylphosphine) (30 mg) is added to a solution of 8-benzyloxy-5-bromo-3-methyl-1H-quinolin-2-one (239 mg) and tributylvinyltin (203 μL) in toluene (7 mL) at room temperature. The reaction mixture is heated for 2 hours at 100° C., cooled to room temperature, evaporated and the product purified by flash column chromatography on silica gel, eluting with 2% ethyl acetate in dichloromethane.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].N1C=CC=CC=1.[CH2:12]([C:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O:19][CH3:20])[C:16](Cl)=[O:17])[CH:13]=[CH2:14]>C1C=CC=CC=1>[CH2:12]([C:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O:19][CH3:20])[C:16]([O:5][CH2:1][CH2:2][C:3]#[CH:4])=[O:17])[CH:13]=[CH2:14]
Reactant: C=CCC(OC)(C(=O)Cl)c1ccccc1
Reactant: C#CCCO
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: C#CCCOC(=O)C(CC=C)(OC)c1ccccc1
Yield: 89.2 %

Procedure:
Into a solution of 1.4 g of 3-butyn-1-ol and 20 g of pyridine in 20 cc of benzene, was added a solution of 4.5 g of α-allyl-α-methoxyphenyl acetic chloride in 10 cc of benzene while being cooled with ice, whereby white precipitates were deposited immediately. The reaction mixture was washed with a diluted hydrochloric acid, 5% aqueous solution of sodium carbonate and an aqueous solution saturated with sodium chloride, and dried over anhydrous sodium sulfate. Evaporation of benzene gave 4.6 g of oily 3-butynyl α-allyl-α -methoxyphenylacetate, nD25 1.5137.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2.[CH:29]([NH2:32])([CH3:31])[CH3:30]>C1COCC1>[OH:16][C@H:15]([CH2:17][NH:32][CH:29]([CH3:31])[CH3:30])[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:28])=[CH:22]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@H]1CO1
Reactant: CC(C)N
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@H](O)CNC(C)C
Temperature: 75 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
A mixture of (2R)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (250 mg, 0.66 mmol), (prepared as described for the starting material in Example 269), and isopropylamine (1.5 ml) in THF (10 ml) was stirred at 75° C. for 18 hours under an atmosphere of nitrogen and then allowed to cool to ambient temperature. The mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by silica gel chromatography using gradient elution with dichloromethane/methanolic ammonia (7M) (100/0 to 90/10) to give (2R)-7-(2-hydroxy-3-(isopropylamino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (243 mg, 84%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)=[C:12]([CH3:23])[NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:30](I)([CH3:32])[CH3:31]>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[C:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH3:22])=[CH:19][CH:20]=2)=[C:12]([CH3:23])[N:11]([CH:30]([CH3:32])[CH3:31])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(Cc2c(OCc3ccccc3)n[nH]c2C)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(Cc2c(OCc3ccccc3)nn(C(C)C)c2C)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 79 %

Procedure:
To a suspension of the thus obtained 3-benzyloxy-4-(4-ethylbenzyl)-5-methyl-1H-pyrazole (200 mg, 0.65 mmol) and cesium carbonate (1.06 g, 3.25 mmol) in N,N-dimethylformamide (4 mL), isopropyl iodide (350 mg, 2.06 mmol) was added dropwise at room temperature. After stirring at room temperature for 13 hours, additional cesium carbonate (1.06 g, 3.25 mmol) and isopropyl iodide (350 mg, 2.06 mmol) were added. After stirring at room temperature for an additional 3 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 3-benzyloxy-4-(4-ethylbenzyl)-1-isopropyl-5-methyl-1H-pyrazole (179 mg, 79%) as a light-brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[CH:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]1=[O:21])=[O:5])[CH3:2].CN(C)C=O.Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>O>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[C:8]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]1=[O:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(=O)N(C(=O)OCC)c2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1C(=O)C(CC(=O)OC(C)(C)C)(C(=O)OCC)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl-5-chloro-2-oxoindoline-1,3-dicarboxylate, intermediate 50, (5.0 g, 16.04 mmol) in anhydrous N,N-dimethylformamide (80 ml) 1,8-diazabicyclo[5.4.0]undec-7-ene (2.63 ml, 17.64 mmol) was added dropwise at ambient temperature at such a rate that the internal temperature remained below 30° C. After continuous stirring at ambient temperature for one hour the solution was treated with tert-butyl bromoacetate (2.73 ml, 18.45 mmol) and stirring was allowed to continue for 72 h. Water (100 ml) was added, the product was extracted with tert-butyl methyl ether (2×50 ml), the combined extracts were washed with brine (50 ml) and dried (MgSO4) to give a red solid (7.11 g). Purification by flash chromatography (n-heptane/ethyl acetate=15%; increased up to 20%) yielded the title compound (4.00 g, 59%) as colorless solid (HPLC purity: 99%).MS (ESI+): 426.3
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])/[C:6](=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)/[CH2:5]2>CO.[Pt]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]([F:24])([F:23])[F:25])=[CH:17][CH:16]=1)[CH2:5]2
Reactant: COc1cc2c(cc1Cl)C/C(=C\c1ccc(SC(F)(F)F)cc1)C2=O
Agent: [Pt]
Solvent: CO
Product: COc1cc2c(cc1Cl)CC(Cc1ccc(SC(F)(F)F)cc1)C2=O

Procedure:
The compound 171 (85 mg, 0.195 mmol) was dissolved in methanol 25 mL and Pt/C (40 mg) and the reaction stirred under H2 balloon for 6 h. The reaction was filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude. The crude was purified by flash chromatography using 100-200 mesh silica gel. The compound was eluted at 25% ethylacetate in hexane as half white coloured solid 172. 1H NMR (400 MHz, CDCl3) δ ppm 7.57 (d, 2H), 7.43 (s, 1H), 7.27 (d, 2H), 7.25 (s, 1H), 3.94 (s, 3H), 3.37 (dd, 1H), 3.11 (m, 1H), 2.99 (m, 1H), 2.72 (m, 2H); MS-ES+386.8.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].[CH3:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH2:24]Cl>CC(C)=O>[CH3:11][C:9]1[N:10]=[C:3]2[C:2]([NH:1][CH2:24][C:23]3[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:22]=3[CH3:21])=[CH:7][CH:6]=[CH:5][N:4]2[C:8]=1[CH3:12]
Reactant: Cc1nc2c(N)cccn2c1C
Reactant: Cc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cccc(C)c1CNc1cccn2c(C)c(C)nc12
Reaction time: 8 h
Yield: 57.7 %

Procedure:
A mixture of 8-amino-2,3-dimethylimidazo[1,2-a]pyridine (0.7 g, 4.34 mmol), sodium carbonate (2.0 g), sodium iodide (0.3 g), 2,6-dimethylbenzylchloride (0.671 g, 4.34 mmol) and acetone (30 ml) was stirred overnight. The reaction mixture was filtered and the solvent was removed in vacuo. The residue was dissolved in methylene chloride and washed with aqueous NaHCO3. The organic layer was separated and the solvent was evaporated. The crude product was purified by flash chromatography eluting with CH2Cl2/MeOH to give 0.7 g of the title compound.
Reaction SMILES: N[N:2]1[C:7](=[O:8])[C:6]([CH:9]([NH:24][C:25]([CH:27]2[CH2:30][CH2:29][CH2:28]2)=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]=2)=[N:5][N:4]=[CH:3]1.Cl.N([O-])=O.[Na+]>CCO.O>[CH2:17]([O:16][C:12]1[CH:11]=[C:10]([CH:9]([NH:24][C:25]([CH:27]2[CH2:28][CH2:29][CH2:30]2)=[O:26])[C:6]2[C:7](=[O:8])[NH:2][CH:3]=[N:4][N:5]=2)[CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nn1cnnc(C(NC(=O)C2CCC2)c2cccc(OCc3ccccc3)c2)c1=O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(NC(c1cccc(OCc2ccccc2)c1)c1nnc[nH]c1=O)C1CCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of cyclobutanecarboxylic acid [(4-amino-5-oxo-4,5-dihydro-[1,2,4]triazin-6-yl)-(3-benzyloxy-phenyl)-methyl]-amide (315 mg, 0.777 mmol) and concentrated HCl (344 μL) in anhydrous EtOH (16 mL) was dropwise added a solution of sodium nitrite (120 mg, 1.72 mmol) in H2O (4 mL) at 0° C. and stirred for 30 min and warmed to rt for an additional 1.5 h. The reaction mixture was concentrated in vacuo and the crude material was chromatographed on silica gel [eluting with 3% MeOH in CHCl3] to obtain the title compound as an off-white foam solid. 1H NMR (CDCl3, 400 MHz) δ 1.78-1.93 (m, 1H), 1.93-2.04 (m, 1H), 2.12-2.2.36 (m, 4H), 3.13 (quint, J=8.4 Hz, 1H), 4.97 (s, 2H), 6.35 (d, J=8.8 Hz, 1H), 6.85 (dd, J=2.4, 8.4 Hz, 1H), 6.96-7.05 (m, 2H), 7.20 (t, J=8.0 Hz, 1H), 7.27-7.41 (m, 4H), 7.61 (brs, 1H), 8.46 (s, 1H); MS (ES+): m/z 391.04 (100) [MH+]; HPLC: tR=2.87 min (MicromassZQ, polar—5 min).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[C:20]1([CH3:34])[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[S:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:21]=1>>[C:20]1([CH3:34])[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[S:30][CH:29]=[N:28][C:27]=2[C:31]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:32])[CH:21]=1
Reactant: Cc1cccc(-c2scnc2C(=O)O)c1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1cccc(-c2scnc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 5-m-Tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.29 min; [M+H]+=478.1.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:11].[CH3:12][C:13]([S@@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5](/[CH:6]=[N:18]/[S@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C=O)cc(C)c1Cl
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(/C=N/[S@@](=O)C(C)(C)C)cc(C)c1Cl
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of 4-chloro-3,5-dimethyl-benzaldehyde (2 g, 11.86 mmol) and (S)-2-methylpropane-2-sulfinamide (1.58 g, 13.05 mmol) in toluene (35 mL) was treated with titanium(IV) isopropoxide (5.27 mL, 17.79 mmol). The mixture was stirred at 50° C. for 24 hours. It was then quenched with 10% sodium bicarbonate solution (50 mL) and extracted twice with EtOAc. The organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude was purified by chromatography on silica gel (cyclohexane/EtOAc).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[S:18](Cl)(=[O:20])=[O:19].O>ClCCl>[F:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[S:18]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:19])=[O:20]
Reactant: C1CCNCC1
Reactant: COc1cc(F)c(S(=O)(=O)Cl)cc1OC
Solvent: O
Solvent: ClCCl
Product: COc1cc(F)c(S(=O)(=O)N2CCCCC2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Piperidine (4.15 ml, 42.02 mmol) was slowly added to a cooled (ice-bath) solution of 2-fluoro-4,5-dimethoxy-benzenesulfonyl chloride (5 g, 19.63 mmol) in dichloromethane (110 mL). The mixture was stirred overnight at room temperature, diluted with dichloromethane and poured into water. The aqueous phase was extracted with dichloromethane and the combined organic phases washed with brine, dried over magnesium sulfate and evaporated. The crude product was used without further purification.
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH3:22])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:19]([O-:21])=[O:20])=[C:9]([CH:18]=1)[C:10]([O:12]CC(O)(C)C)=[O:11].[OH-].[Na+].Cl>CO>[OH:1][C:2]([CH3:23])([CH3:22])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:19]([O-:21])=[O:20])=[C:9]([CH:18]=1)[C:10]([OH:12])=[O:11]
Reactant: CC(C)(O)COC(=O)c1cc(OCC(C)(C)O)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(O)COc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a solution of 2-hydroxy-2-methylpropyl 5-(2-hydroxy-2-methylpropoxy)-2-nitrobenzoate (0.24 g, 733 μmol) in MeOH (10 ml) at r.t was added NaOH 1 N (2.2 ml, 2.2 mmol). The solution was stirred at r.t overnight. 2.2 ml 1 N HCl were added. The solvents were evaporated. The residue was dissolved in methylenechloride/MeOH 9:1 (100 ml), washed with 10 ml H2O, dried over MgSO4, filtered and evaporated to give the title compound (149 mg, 80%) as off-white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]([O:13]CC1C=CC=CC=1)=[O:12])[CH2:6][CH2:7][O:8][CH3:9]>CO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][CH2:7][O:8][CH3:9]
Reactant: COCCN(CCOC)CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COCCN(CCOC)CC(=O)O

Procedure:
A solution of Example 81A (19.4 g; 69 mmol) and 10% Pd/C (3.5 g) in methanol (150 mL) at room temperature was stirred under 4 atm of H2 for 17 hours, filtered through diatomaceous earth (Celite®), and concentrated to provide the desired product.