Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]3[NH:21][C:20](=[O:22])[O:19][N:18]=3)=[N:9]2)=[N:6][CH:7]=1.[CH3:23]CN(C(C)C)C(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:14])([F:16])[F:15])=[CH:11][C:10]([C:17]3[N:21]([CH3:23])[C:20](=[O:22])[O:19][N:18]=3)=[N:9]2)=[N:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=c1[nH]c(-c2cc(C(F)(F)F)n(-c3ccc(Br)cn3)n2)no1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cn1c(-c2cc(C(F)(F)F)n(-c3ccc(Br)cn3)n2)noc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
Step-4: 3-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazol-5(4H)-one: To a stirred and (0° C.) cooled solution of step-3 intermediate (106 mg, 0.303 mmol) and DIPEA (0.106 mL, 0.606 mmol) in DCM (15 mL) was added drop-wise a solution of triphosgene (35 mg, 0.121 mmol) in DCM (3 mL). The reaction was stirred at room temperature for 1 h before quenching with ice water (5 mL). Water (10 mL) was added to the above mixture followed by DCM (25 mL). The layers were separated and the aqueous layer was extracted with DCM (2×15 mL). The combined organic layers were washed with brine (15 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated to afford 100 mg (88%) of the title compound as brown solid. ESI-MS (m/z) 376, 378 [(MH)+, Br79,81].
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[C:16]([Br:27])[CH:15]=2)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:35][C:36]([N:38]1[CH2:42][CH2:41][CH2:40][C@@H:39]1[CH:43]=[CH:44][CH2:45]O)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36]([N:38]1[CH2:42][CH2:41][CH2:40][C@@H:39]1[CH:43]=[CH:44][CH2:45][N:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:11]2[O:10][N:9]=[C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:12]=2)=[CH:15][C:16]=1[Br:27])[C:21](=[O:26])[C:22]([F:25])([F:23])[F:24])=[O:37])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCO
Reactant: O=C(Nc1ccc(Cc2nc(Cc3ccccc3)no2)cc1Br)C(F)(F)F
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCN(C(=O)C(F)(F)F)c1ccc(Cc2nc(Cc3ccccc3)no2)cc1Br
Yield: 90 %

Procedure:
4-(3-Benzyl-1,2,4-oxadiazol-5-ylmethyl)-2-bromo-1-trifluoroacetylaminobenzene and (R)-1-(N-benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene were used. Chromatography using elution with 5% either in methylene chloride afforded the title compound (90%) as a thick yellow oil: R1 =0.75 (CHCl3 --CH3OH 20:1); LRMS (m/z, relative intensity) 683 (M+,18).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.Br[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:17]([O:16][C:14]([CH2:13][N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C1CCN(CC(=O)OCc2ccccc2)CC1

Procedure:
Ethyl isonipecotate was reacted with benzyl bromoacetate in acetonitrile in the presence of cesium carbonate, and then the reaction mixture was worked up and purified in a usual manner to obtain ethyl 1-(benzyloxycarbonylmethyl)isonipecotate as a colorless oily substance. MS: 306.
Reaction SMILES: COC([O:5][C@@H:6]1[C@H:10]([O:11]C(OC)=O)[C@@H:9]([CH3:16])[O:8][C@H:7]1[N:17]1[CH:32]=[C:31]([F:33])[C:21]([NH:22][C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:24])=[N:20][C:18]1=[O:19])=O.CO.[OH-].[Na+].Cl>O>[F:33][C:31]1[C:21]([NH:22][C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:24])=[N:20][C:18](=[O:19])[N:17]([CH:32]=1)[C@@H:7]1[O:8][C@H:9]([CH3:16])[C@@H:10]([OH:11])[C@H:6]1[OH:5]
Reactant: CCCCCOC(=O)Nc1nc(=O)n([C@@H]2O[C@H](C)[C@@H](OC(=O)OC)[C@H]2OC(=O)OC)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCOC(=O)Nc1nc(=O)n([C@@H]2O[C@H](C)[C@@H](O)[C@H]2O)cc1F
Temperature: -2.5 °C
Yield: 88.2 %

Procedure:
42.9 g of the compound obtained in Example 3 was added to 215 ml of methanol, and the mixture was stirred and cooled to −5 to 0° C. 10.8 g of NaOH was dissolved in 107 ml of water, and NaOH solution was added thereto while maintaining the reaction mixture temperature at less than 0° C. The resulting mixture was stirred for 30 min, and 48 ml of 6 N HCl was added dropwise thereto until the pH of the reaction mixture became 5.3. The resulting mixture was successively washed twice with 215 ml of dichloromethane and once with 108 ml of dichloromethane, and the combined organic layer was washed with 215 ml of water, dried over anhydrous sodium sulfate, filtered and concentrated under a reduced pressure. After adding 129 ml of ethylacetate thereto, the residue was mixed with 97 ml of ethylacetate by stirring to be crystallized. 97 ml of hexane was added dropwise thereto to allow the crystal to be matured, and the resulting mixture was stirred for 1 hr, cooled to 0° C. and again stirred for 1 hr. The resulting solid was filtered, washed with 86 ml of a solid mixture of ethylacetate and hexane (1:1 (v/v)) cooled to 0° C., and dried in a 35° C. vacuum oven overnight, to obtain 28.6 g of the title compound as a light white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]#[CH:13])[CH:7]=[C:6]([F:14])[C:3]=1[CH2:4][OH:5].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28](Cl)=[O:29])[C@H:24]([CH2:31][CH3:32])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]#[CH:13])[CH:7]=[C:6]([F:14])[C:3]=1[CH2:4][O:5][C:28]([N:25]1[CH2:26][CH2:27][N:22]([C:20]([O:19][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:21])[CH2:23][C@H:24]1[CH2:31][CH3:32])=[O:29]
Reactant: C#CCOc1cc(F)c(CO)c(F)c1
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Product: C#CCOc1cc(F)c(COC(=O)N2CCN(C(=O)OC(C)(C)C)C[C@H]2CC)c(F)c1
Yield: 67 %

Procedure:
This compound was prepared from 2,6-difluoro-4-prop-2-ynyloxy-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (336 mg; 67%); MS (ISP): 456.5 (M+NH4)+.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([NH:25][CH2:26][CH2:27][CH3:28])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:29](O)([C:31]([F:34])(F)F)=O>C(Cl)Cl>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([NH:11][C:14]4[CH:23]=[CH:29][C:31]([F:34])=[CH:16][CH:15]=4)=[O:5])[CH2:9][CH2:10]3)=[CH:15][C:16]([NH:25][CH2:26][CH2:27][CH3:28])=[N:17]2)=[CH:22][CH:21]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CCCNc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1
Solvent: ClCCl
Product: CCCNc1cc(N2CCN(C(=O)Nc3ccc(F)cc3)CC2)c2ccc(Cl)cc2n1

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloro-2-(n-propylamino)quinoline (25 mg, 0.06 mmol) is deprotected with TFA in CH2Cl2 and transformed into the title product according to method C using 4-fluorophenyl isocyanate (10 μL, 0.09 mmol) and triethylamine (60 μL, 0.43 mmol) to give a colorless solid.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[NH:13][CH:12]=[N:11][CH:10]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].C1C=CC(OC(Cl)=[S:27])=CC=1>C1COCC1.O>[C:1]1([CH:7]([C:9]2[NH:13][C:12](=[S:27])[NH:11][CH:10]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(c1ccccc1)c1cnc[nH]1
Reactant: S=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccccc1)c1c[nH]c(=S)[nH]1
Reaction time: 3 h

Procedure:
A solution of 5-(1-phenyl-ethyl)-1H-imidazole (Intermediate C2) (0.20 g, 1.16 mmol) in THF (6 mL) and water (6 mL) was treated with NaHCO3 (0.98 g) at rt for 10 sm. Phenyl chlorothionoformate (0.40 mL, ˜3.0 mmol) was added and stirring was continued for 3 h. The mixture was diluted with water (10 mL) and extracted with ether (3×15 mL). The organic portions were combined, dried over MgSO4, filtered and freed of solvent. The residue was dissolved in MeOH (8 mL) and treated with NEt3 (1 mL) for 16 h. The solvent was removed under vacuum and the product was washed on a glass frit with 50% CH2Cl2:hexanes to give 4-(1-phenyl-ethyl)-1,3-dihydro-imidazole-2-thione (Compound 4)
Reaction SMILES: N[C:2]1[NH:7][C:6](=[O:8])[C:5]2=[C:9]([I:21])[N:10]=[C:11]([CH:12]3[CH2:17][CH2:16][CH:15]([C:18]([O-:20])=[O:19])[CH2:14][CH2:13]3)[N:4]2[N:3]=1.[CH3:22]N(C=O)C.N(OC(C)(C)C)=O>C1COCC1>[I:21][C:9]1[N:10]=[C:11]([C@H:12]2[CH2:13][CH2:14][C@H:15]([C:18]([O:20][CH3:22])=[O:19])[CH2:16][CH2:17]2)[N:4]2[C:5]=1[C:6](=[O:8])[NH:7][CH:2]=[N:3]2
Reactant: CN(C)C=O
Reactant: Nc1nn2c(C3CCC(C(=O)[O-])CC3)nc(I)c2c(=O)[nH]1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](c2nc(I)c3c(=O)[nH]cnn32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl ir ans-4-(2-amino-5-iodo-4-oxo-3,4-dihydroimidazo[5,1-f] [1,2,4]triazin-7-yl)cyclohexanecarboxylate (0.880 g, 0.00211 mol) in anhydrous THF (74 mL) and DMF (13.2 mL) was charged with tert-butyl nitrite (1.2 mL, 0.010 mol) and stirred at rt for 2 h. The reaction was concentrated in vacuo and was purified by chromatography over silica gel [eluting with 5% MeOH in CHCl3] resulting in 570 mg, (67% yield) of the title compound as a pale orange solid. (1H NMR (400 MHz, DMSO-d6) δ ppm 1.40-1.54 (m, 2H), 1.56-1.69 (m, 2H), 1.92-2.06 (m, 4H), 2.36-2.46 (m, 1H), 3.02-3.14 (m, 1H), 3.61 (s, 3H), 7.89 (d, J=3.28 Hz, 1 H) and 11.79 (br. s., 1H); MS (ES+): m/z 402.86 [MH+].
Reaction SMILES: [CH2:1](Cl)[CH2:2][CH2:3][CH2:4][C:5]#[C:6]/[CH:7]=[CH:8]\[CH2:9][CH3:10].[C:12]([O-:15])(=[O:14])[CH3:13].[Na+].CN(C)C(=O)C>[I-].[Na+].O>[C:12]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6]/[CH:7]=[CH:8]\[CH2:9][CH3:10])(=[O:14])[CH3:13]
Reactant: CC(=O)[O-]
Reactant: CC/C=C\C#CCCCCCl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC/C=C\C#CCCCCOC(C)=O
Temperature: 122.5 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
In a reactor equipped with a stirrer, a cooling condenser, a dropping funnel and a thermometer were placed Z-7-decen-5-yn-yl chloride (170.7 g: 1.0 mol), sodium acetate (98.4 g: 1.2 mol), sodium iodide (8.9 g: 0.06 mol) and N,N-dimethylacetamide (113.2 g), and stirred at from 120 to 125° C. for 6 hours. After the completion of the reaction was confirmed by gas chromatography, water (350.0 g) was added to the reaction mixture. The organic phase separated from the aqueous phase was washed with an aqueous 1.0% by weight sodium bicarbonate solution (250.0 g). The organic phase was subjected to removal of solvent under reduced pressure, followed by dehydration. The residue was then distilled under reduced pressure to obtain Z-7-decen-5-yn-yl acetate [bp: from 75 to 79° C./0.13 KPa, 181.4 g, 0.93 mol]. [Yield: 93.4%]
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[CH:19][CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[CH:21][CH:22]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2C=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.5 %

Procedure:
A mixture of {1-benzyl-3-[(4{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazol-4-yl}methanol (0.38 g), activated manganese dioxide (1.20 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 20 hrs. Manganese dioxide was removed by filtration, and the filtrate was concentrated. The obtained crystals were collected by filtration to give 1-benzyl-3-[(4{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carbaldehyde (0.35 g, yield 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 118-119° C.
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].C[N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[NH:11][C:10]2[N:20]=[CH:21][CH:22]=[CH:23][C:9]1=2>O1CCOCC1>[Cl:1][CH:2]([CH3:6])[C:3]([N:11]1[C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[C:14](=[O:15])[NH:8][C:9]2[CH:23]=[CH:22][CH:21]=[N:20][C:10]1=2)=[O:4]
Reactant: CN1C(=O)c2ccccc2Nc2ncccc21
Reactant: CC(Cl)C(=O)Cl
Solvent: C1COCCO1
Product: CC(Cl)C(=O)N1c2ccccc2C(=O)Nc2cccnc21

Procedure:
A solution of 2-chloropropionyl chloride and 5-methyl-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one in dioxane was reacted to obtain 11-(2-chloropropionyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one which after crystallization from acetonitrile melted at 210°-212° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9]([C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1)#[N:10].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:9]([C:11]1[CH:16]=[C:15]([C:2]2[CH:7]=[N:6][NH:5][C:4](=[O:8])[CH:3]=2)[CH:14]=[CH:13][CH:12]=1)#[N:10]
Reactant: O=c1cc(Cl)cn[nH]1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1cccc(-c2cn[nH]c(=O)c2)c1
Yield: 59.7 %

Procedure:
To a mixture of 5-chloropyridazin-3(2H)-one (2.0 g, 15.3 mmol) and 3-cyanophenyl boronic acid (2.71 g, 18.4 mmol) in anhydrous toluene (20 ml) was added dichloro-(1,4-bis(diphenylphosphino)-butane)palladium (0.1 g, 0.16 mmol), and saturated aqueous sodium carbonate solution (5.0 ml) and the mixture was irradiated in a Milestone microwave reactor at 120° C. for 15 minutes. The resulting suspension was filtered and the solid was washed with isopropanol (20 ml) and dried on the sinter to give 5-(3-cyanophenyl)pyridazin-3-one (1.8 g, 50%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].[Cl:14][C:15]1[N:16]=[N:17][C:18]([Cl:22])=[C:19](Cl)[N:20]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:14][C:15]1[N:16]=[N:17][C:18]([Cl:22])=[C:19]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[N:20]=1
Reactant: Clc1nnc(Cl)c(Cl)n1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Temperature: 25 °C

Procedure:
To a solution of 1-Amino-2-(isopropylsulphonyl)benzene (350 mg, 1.6 mmol) and 3,5,6-trichloro-1,2,4-triazine (1.6 mmol) in CH2Cl2, is added triethylamine (2 mmol). The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])=[N:15]3)=O)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C(=O)([O-])[O-].[Na+].[Na+].O>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])=[N:15]3)=[N:31][OH:32])=[CH:4][CH:3]=1
Reactant: COc1ccccc1CNc1ccc2c(C(=O)c3ccc(F)cc3)cccc2n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccccc1CNc1ccc2c(C(=NO)c3ccc(F)cc3)cccc2n1
Yield: 64.3 %

Procedure:
A stirred suspension of (4-fluoro-phenyl)-[2-(2-methoxy-benzylamino)-quinolin-5-yl]-methanone (example 137) (60 mg, 0.155 mmol), hydroxylamine hydrochloride (32 mg, 0.46 mmol) and sodium carbonate (49 mg, 0.46 mmol) in EtOH (2 ml) was heated under reflux conditions for 28 h, the reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/ethyl acetate) to yield the title compound as white foam (40 mg, 64%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH:28]([OH:33])[C:29]([F:32])([F:31])[F:30])[N:23]=1>>[F:20][C:11]1[CH:12]=[C:13]([C:16]([OH:19])([CH3:17])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:26]2[CH:27]=[CH:22][N:23]=[C:24]([CH:28]([OH:33])[C:29]([F:32])([F:30])[F:31])[N:25]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: OC(c1nccc(Cl)n1)C(F)(F)F
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3ccnc(C(O)C(F)(F)F)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (68 mg, 0.23 mmol) and 1-(4-chloropyrimidin-2-yl)-2,2,2-trifluoroethanol (49 mg, 0.23 mmol) as starting materials.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:7]=1.[C:20]([C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])#[CH:21]>>[Cl:19][C:5]1[CH:4]=[CH:3][C:2]([C:21]#[C:20][C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])=[CH:7][C:6]=1[CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14]
Reactant: C#CC(O)(CCC)CCC
Reactant: O=C(NCCC(O)c1cc(Br)ccc1Cl)C(F)(F)F
Product: CCCC(O)(C#Cc1ccc(Cl)c(C(O)CCNC(=O)C(F)(F)F)c1)CCC

Procedure:
N-(3-(5-bromo-2-chlorophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide was coupled with alkynol 20 to give N-(3-(2-chloro-5-(3-hydroxy-3-propylhex-1-ynyl)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide as a pale yellow oil. Yield (1.03 g, 68%): 1H NMR (400 MHz, DMSO-d6) δ 9.42 (t, J=5.6 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.23 (dd, J=8.0 Hz, 2.0, 1H), 5.57 (d, J=4.0 Hz, 1H), 5.17 (s, 1H), 4.87-4.82 (m, 1H), 3.33-3.28 (m, 2H), 1.87-1.79 (m, 1H), 1.66-1.39 (m, 9H), 0.89 (t, J=7.2 Hz, 6H).
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=2)=[S:11])=[CH:5][CH:4]=[C:3](Cl)[CH:2]=1.[CH3:21][OH:22]>>[CH3:21][O:22][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=2)=[S:11])=[CH:1][CH:2]=1
Reactant: CO
Reactant: S=C(NCCc1ccc(Cl)cc1)Nc1ccc(Br)cn1
Product: COc1ccc(CCNC(=S)Nc2ccc(Br)cn2)cc1

Procedure:
N-[2-(4-chlorophenethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (II-9) yield: 71%; mp 180-183° C.; UV (MeOH) λmax: 206, 209, 219, 256, 275 and 305 nm; IR(KBr) ν 3221, 3153, 3086, 3022, 2931, 1674, 1593, 1562, 1533, 1473, 1406, 1340, 1304, 1265, 1227, 1169, 1138, 1092, 1016, 820, 752, 714 cm−1; 1H NMR (CDCl3) δ 11.40 (br s, 1H), 9.34 (br s, 1H), 8.15-8.14 (d, 1H), 7.84-7.80 (dd, 1H), 7.46-7.30 (m, 4H), 6.92-6.89 (d, 1H), 4.10-4.07 (q, 2H), 3.13-3.08 (t, 2H); 13C NMR (CDCl3) δ 179.2, 151.6, 146.3, 141.3, 137.1, 130.2, 128.6, 113.5, 112.8, 46.8 and 34.2; Maldi Tof found: 372.0 (M+1), calculated: 371.0; Anal. (C14H13BrClN3S) C, H, N, S.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[C:10]([OH:12])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:46][C:47]1[S:48][CH:49]=[C:50]([C:52]2[CH:63]=[CH:62][C:55]([C:56]([NH:58][CH:59]3[CH2:61][CH2:60]3)=[O:57])=[CH:54][CH:53]=2)[N:51]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[C:10](=[O:12])[NH:46][C:47]1[S:48][CH:49]=[C:50]([C:52]2[CH:53]=[CH:54][C:55]([C:56](=[O:57])[NH:58][CH:59]3[CH2:61][CH2:60]3)=[CH:62][CH:63]=2)[N:51]=1)=[O:4]
Reactant: COC(=O)[C@@H]1CCC[C@@H]1C(=O)O
Reactant: Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCC[C@@H]1C(=O)Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Reaction time: 0.25 h

Procedure:
Rac-cis-cyclopentane-1,2-dicarboxylic acid monomethyl ester (172 mg) was dissolved in DMF (5 mL) and treated with HATU (1.1 eq. 470 mg) and DIEA (3 eq, 500 μL) and stirred for 15 minutes. Then 4-(2-amino-thiazol-4-yl)-N-cyclopropyl-benzamide (1 eq, 260 mg) was added and the mixture stirred at ambient temperature overnight. The reaction was cooled, filtered and the solvents removed. The resulting mixture was redissolved in 5 ml of 90% DMF, 10% water with 0.1% TFA and purified by reverse phase HPLC to give the product. MS: 414.5.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[CH:7]=[C:8]([C:16]2[N:20]([CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:19]([CH3:28])=[C:18]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:17]=2)[CH:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1)([CH3:5])[CH3:4].[CH3:33][C:34](OC(C)=O)=[O:35]>C(Cl)Cl>[C:12]([C:10]1[CH:11]=[C:6]([C:3]([CH3:4])([CH3:5])[CH2:2][NH:1][C:34](=[O:35])[CH3:33])[CH:7]=[C:8]([C:16]2[N:20]([CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:19]([CH3:28])=[C:18]([S:29](=[O:31])(=[O:30])[NH2:32])[CH:17]=2)[CH:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)CN)c2)n1CC1CCCCC1
Solvent: ClCCl
Product: CC(=O)NCC(C)(C)c1cc(-c2cc(S(N)(=O)=O)c(C)n2CC2CCCCC2)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a solution of compound 48 (100 mg, 0.22 mmol) in dry DCM (5 mL) was added Ac2O (25 mg, 0.24 mmol) at 0° C. and then the solution was stirred overnight at rt, concentrated and purified by prep-TLC to afford compound 49 (60 mg, 54%) as a white solid. 1H-NMR (DMSO-d6, 400 MHz) δ: 0.64-0.67 (2H, m), 0.93-0.95 (3H, m), 1.26-1.30 (20H, m), 1.46 (3H, d, J=6.8 Hz), 1.77 (3H, s), 2.43 (3H, s), 3.28 (2H, d, J=5.6 Hz), 3.76 (3H, d, J=7.2 Hz), 6.28 (1H, s), 6.91 (2H, s), 7.09 (1H, s), 7.16 (1H, s), 7.35 (1H, s), 7.67 (1H, m). MS Calcd.: 501; MS Found: 502 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:10]Br>C(=S)=S.C(OCC)C>[Br:10][C:3]1[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=1[OH:9]
Reactant: BrBr
Reactant: Oc1cc(F)cc(F)c1
Solvent: CCOCC
Solvent: S=C=S
Product: Oc1cc(F)cc(F)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
A solution of 2.6 gm (20 mMol) 3,5-difluorophenol in 20 mL carbon disulfide was cooled to 0° C. and then a solution of 1.02 mL (20 mMol) bromine in 10 mL carbon disulfide was added dropwise over 30 minutes. After stirring for an additional 30 minutes, the reaction mixture was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was diluted with 200 mL diethyl ether and was washed sequentially with aqueous sodium metabisulfite and saturated aqueous sodium chloride. The organic phase was then dried over sodium sulfate and concentrated under reduced pressure. The residue was vacuum distilled to provide 2.5 gm (60%) of 2-bromo-3,5-difluorophenol (b.p.=65° C. (5 mm Hg)).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=1[O:15][CH3:16].[CH2:17](I)[CH3:18]>>[CH2:17]([O:1][C:2]1[CH:14]=[CH:13][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=1[O:15][CH3:16])[CH3:18]
Reactant: CCI
Reactant: CCOC(=O)/C=C/c1ccc(O)c(OC)c1
Product: CCOC(=O)/C=C/c1ccc(OCC)c(OC)c1
Yield: 84.5 %

Procedure:
Following a procedure similar to that described in Preparation 116, but using 5.83 g of ethyl (E)-4-hydroxy-3-methoxycinnamate and 5.61 g of ethyl iodide, 5.55 g of the title compound were obtained as a solid material.