Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[Si](C)(C)C.Br[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[F:15][C:16]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19]>C1COCC1.[Zn]>[F:15][C:16]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]([OH:19])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1cccc(C=O)c1F
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: COc1cccc(C(O)CC(=O)OC(C)(C)C)c1F
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 58.1 %

Procedure:
To a suspension of zinc (0.848 g, 12.98 mmol) in dry THF (10 mL), was added chlorotrimethylsilane (0.829 mL, 6.49 mmol). After 10 min, tert-butyl 2-bromoacetate (0.959 mL, 6.49 mmol) was added and the reaction mixture was heated at 50° C. for 10 min. The reaction mixture was then cooled to 0° C. under argon. To the cooled solution was then added 2-fluoro-3-methoxybenzaldehyde (1 g, 6.49 mmol) in THF (3 mL) and the reaction was allowed to warm to rt overnight. The reaction mixture after overnight stirring was quenched with 5% NaHCO3 solution, filtered off the solids and rinsed with EtOAc. The organic layer was washed with water followed by brine and dried over MgSO4 to yield the crude product. The crude product was then purified using silica gel chromatography to yield the desired product (1.02 g, 58%) as clear oil. MS (ESI) m/z: 215.1 (M-tBu)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[O:8][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[CH2:10][C:3]=12.C(=O)([O-])[O-].[Na+].[Na+].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[C:25]1([CH2:24][NH:31][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[O:8][C:9]4([CH:15]5[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]5)[CH2:11]4)[CH2:10][C:3]=23)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: Clc1ccnc2c1CC1(CN3CCC1CC3)O2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: c1ccc(CNc2ccnc3c2CC2(CN4CCC2CC4)O3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34 %

Procedure:
A solution of 97 mg (0.387 mmol) of 4′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] in 5 mL of benzylamine was heated to reflux under a nitrogen atmosphere and stirred for 18 hours. Upon cooling to ambient temperature, the diluted with 40 mL of water, basicified with 2 mL of saturated aqueous sodium carbonate and extracted with chloroform (3×25 mL). The combined organic extract was dried over anhydrous magnesium sulfate, concentrated in vacuo, and flash chromatographed on neutral silica gel using a 9:1 mixture of ammoniated chloroform/methanol to provide 42 mg (34%) of the title compound as a white solid: electrospray MS (m/z, relative intensity) 322 ([MH]+).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16](Cl)(=[O:18])[CH3:17].Cl>C(Cl)Cl>[CH3:5][O:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1
Reactant: CC(=O)Cl
Reactant: COCCCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COCCCc1ccc(C(C)=O)cc1

Procedure:
Next, 195 g of AlCl3 and 100 g of 3-methoxypropylbenzene were poured into 1.5 liters of CH2Cl2, and the resulting mixture was cooled with ice under stirring. Thereto was gradually added dropwise 79 g of acetyl chloride (CH3COCl), and the thus obtained mixture was stirred under ice-cooling continuously for 6 hours. After the termination of the evolution of hydrogen chloride (HCl) gas was ascertained, the reaction solution was poured into 1 liter of dilute hydrochloric acid, and the CH2Cl2 layer was separated, after which the CH2Cl2 was distilled off, and the residue was distilled under reduced pressure to obtain p-(3-methoxypropyl)acetophenone. The boiling point of this compound was 94-95° C./0.3 mmHg.
Reaction SMILES: [CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.Br[C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:23][C:22]1[C:17]([N:3]2[CH2:4][CH:5]3[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:1]([CH2:7][CH2:6]3)[CH2:2]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: Clc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1ncccc1Cl)C2
Temperature: 120 °C
Reaction time: 48 h

Procedure:
tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (435 mg, 2.26 mmol), 2-bromo-3-chloropyridine (400 mg, 1.88 mmol), and potassium carbonate (390 mg, 2.83 mmol) were combined in dry dimethylformamide (10 mL) and stirred at 120° C. for 48 hours. The mixture was allowed to cool room temperature, diluted with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (85:15 hexanes:ethyl acetate) to provide the title compound.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[F:30][C:31]1([F:41])[CH2:34][N:33]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:41][C:31]1([F:30])[CH2:34][N:33]([CH:35]2[CH2:36][CH2:37][N:38]([CH2:18][C:13]3[N:14]([CH3:17])[C:15]4[C:11]([N:12]=3)=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=[C:8]([N:7]3[C:6]5[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=5[N:4]=[C:3]3[CH2:1][CH3:2])[N:16]=4)[CH2:39][CH2:40]2)[CH2:32]1
Reactant: FC1(F)CN(C2CCNCC2)C1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(N4CC(F)(F)C4)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.4 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.139 g, 0.36 mmol), 4-(3,3-difluoroazetidin-1-yl)piperidine (0.075 g, 0.43 mmol) and 4 Å molecular sieves (0.4 g) in DCE (5 mL). The reaction mixture was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.15 g, 0.71 mmol) was added and the reaction mixture was stirred for 72 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 12:88) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 576 as an off-white solid (0.104 g, 53%). LCMS (Method I): RT=2.61 min, [M+H]+ 552.2 1H NMR (400 MHz, DMSO-d6): δ 8.03-7.99 (m, 1 H), 7.65-7.61 (m, 1 H), 7.27-7.20 (m, 2 H), 4.60-3.95 (s, 4 H), 3.81 (s, 3 H), 3.80-3.74 (m, 6 H), 3.52 (t, J=12.3 Hz, 4 H), 3.27 (q, J=7.4 Hz, 2 H), 2.79-2.70 (m, 2 H), 2.20-2.10 (m, 3 H), 1.68-1.59 (m, 2 H), 1.34 (t, J=7.4 Hz, 3 H), 1.30-1.17 (m, 2 H)
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[O:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15](O)=[O:16])[CH:11]=[CH:12][CH:13]=1)[CH3:3].S(Cl)([Cl:24])=O>>[CH3:1][N:2]([CH2:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[O:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]([Cl:24])=[O:16])[CH:11]=[CH:12][CH:13]=1)[CH3:3]
Reactant: CN(C)Cc1ccccc1Oc1cccc(CC(=O)O)c1
Reactant: O=S(Cl)Cl
Product: CN(C)Cc1ccccc1Oc1cccc(CC(=O)Cl)c1

Procedure:
2 g of 3-(2-dimethylaminomethylphenoxy)-phenylacetic acid are treated with 20 ml of thionyl chloride and heated with stirring and under reflux for 1/2 an hour. The solvent is then removed. The residue is taken up with toluene and the solvent is again distilled off.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[CH:10]=[CH:9][C:8]=1[F:30].Cl.Cl.[NH2:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:33][CH:34]1[CH2:37][N:36]([C:20]2[C:21]([Br:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[CH:10]=[CH:9][C:8]([F:30])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:35]1
Reactant: NC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)ccc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Br)c32)ccc1F
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
To 250 mg of N,N-dimethylformamide were added 80 mg of 1-(6-amino-5-fluoropyridine-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 55 mg of 3-aminoazetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 10 minutes. After adding 0.3 ml of ethanol, the solution was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 68 mg of the title compound as-a colorless powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][N:6]([C:26]([S:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:7][P:8]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:9])[CH3:2].ClC1C=CC=C(C(OO)=[O:45])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][N:6]([C:26]([S:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:45])=[O:27])[CH2:7][P:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[O:9])[CH3:2]
Reactant: CCOC(=O)CN(CP(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1)C(=O)SCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)CN(CP(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1)C(=O)S(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl-N-[(benzylthio)carbonyl]-N-[bis(4-chlorophenoxy)phosphinylmethyl]-glycinate (3 g.; 0.0053 mol.) dissolved in 25 ml. of methylene chloride at 0° C. was added metachloroperbenzoic acid (1.1 g.; 0.0053 mol.). The reaction mixture was stirred for one hour at 0° C. The mixture was washed with 5% sodium hydroxide, dried and concentrated in vacuo to yield ethyl-N-[(benzylsulfinyl)carbonyl]-N-[bis(4-chlorophenoxy)phosphinylmethyl]-glycinate as a solid having a melting point of 121°-125° C. and the following analysis:
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH:16][CH2:17][C:18]([OH:36])([C:32]([F:35])([F:34])[F:33])[CH2:19][C:20]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[O:30]C)([CH3:22])[CH3:21])[N:7]=1)=[O:5])[CH3:2].B(Br)(Br)Br.O>ClCCl>[CH2:37]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH:16][CH2:17][C:18]([OH:36])([C:32]([F:34])([F:33])[F:35])[CH2:19][C:20]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[OH:30])([CH3:21])[CH3:22])[N:7]=1)=[O:5])[CH3:38]
Reactant: CCN(CC)C(=O)c1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCN(CC)C(=O)c1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3O)C(F)(F)F)cccc2n1
Reaction time: 20 h
Yield: 27.5 %

Procedure:
210 mg (0.39 mmol) of 5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylamino]quinoline-2-carboxylic acid diethylamide is mixed with 7.8 ml (7.8 mmol) of a 1 M boron tribromide solution in dichloromethane. After 20 hours at room temperature, the reaction is halted by adding water. It is extracted with ethyl acetate, the combined organic phases are washed with saturated sodium bicarbonate solution, and it is dried on sodium sulfate. After the solvent is removed and after purification on silica gel with hexane-ethyl acetate (0–100%), 56 mg (28%) of the product is obtained.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:3].[I:11]Cl.O.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[I:11][C:6]1[CH:5]=[C:4]([CH:2]([CH3:3])[CH3:1])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: ClI
Reactant: CC(C)c1ccc(O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1ccc(O)c(I)c1
Yield: 49.6 %

Procedure:
4-(1-Methylethyl)phenol (27.2 g., 0.20 moles) is dissolved in acetic acid (100 ml.). Iodine monochloride (32.5 g., 0.20 mole) in acetic acid (50 ml.) is then added slowly. The dark mixture is refluxed for 6 hours, cooled and poured into cold water (1 l.) containing a little sodium bisulfite. The black oil that separates is extracted with ether and the extract is washed with water and saturated brine and dried over magnesium sulfate. The ether is evaporated and the residue is purified by distillation to obtain 2-iodo-4-(1-methylethyl)phenol (26 g.), b.p. 137°-140° C. (15 mm.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[CH3:15][N:16]=[C:17]=[O:18]>>[CH3:15][NH:16][C:17]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]=1)=[O:18]
Reactant: NCCSCc1nc2ccccc2[nH]1
Reactant: CN=C=O
Product: CNC(=O)NCCSCc1nc2ccccc2[nH]1

Procedure:
By the procedure of Example 24, 2-[(2-aminoethyl)thiomethyl]benzimidazole is reacted with methyl isocyanate to give the title compound.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:27])[C@H:12]([CH:24]([CH3:26])[CH3:25])[NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=CC=1)([O-])=O.[NH2:28][C@H:29]([C@H:37]([OH:49])[C@@H:38]([OH:48])[C@@H:39]([NH2:47])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:14]([NH:13][C@H:12]([C:11]([NH:28][C@H:29]([C@H:37]([OH:49])[C@@H:38]([OH:48])[C@@H:39]([NH:47][C:11](=[O:27])[C@H:12]([CH:24]([CH3:25])[CH3:26])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH:24]([CH3:26])[CH3:25])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)[C@@H](O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Yield: 5 %

Procedure:
Cbz-valine p-nitrophenyl ester was coupled to (2S,3S,4S,5S)-2,5-diamino-3,4-dihydroxy-1,6-diphenylhexane using the procedure of Example 172B to provide the desired compound (Rf 0.42, 5% methanol in chloroform) as a white solid, m.p. 239°-242° C. in 86% yield.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1/[C:16](=[N:18]/[S@@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])/[CH3:17]>C1COCC1.[Zn].[Cu]Cl>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][C@@:16]([C:10]1[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:9]=1[F:8])([NH:18][S@@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])[CH3:17])[CH3:7]
Reactant: C/C(=N\[S@](=O)C(C)(C)C)c1cc(Br)ccc1F
Reactant: CCOC(=O)CBr
Agent: Cl[Cu]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@](C)(N[S@](=O)C(C)(C)C)c1cc(Br)ccc1F
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
A dried four-necked 750 ml round-bottom flask equipped with mechanical stirrer, reflux condenser, internal thermometer and septum was charged with activated zinc powder (30.6 g, 468 mmol) and copper(I) chloride (4.64 g, 47 mmol), the two solids were mixed under a slow stream of nitrogen while the flask was dried with a heat gun. After cooling to 23° C., dry THF (90 ml) was added to produce a dark slurry, heated to reflux and stirred vigorously for 30 min. The heating bath was removed and a solution of ethyl bromoacetate (12.95 ml, 117 mmol) in dry THF (50 ml) was added at such rate that reflux was reinitiated and a controllable reflux was maintained. Once addition was complete, the mixture was stirred for 30 min at 50° C. Cooled to 5° C., a solution of (R)-2-methyl-propane-2-sulfinic acid [1-(2-fluoro-5-bromo-phenyl)-(E)-ethylidene]-amide (intermediate A2B) (15.0 g, 47 mmol) in dry THF (60 ml) was added dropwise and the mixture was stirred at 0° C. for 1 h. The reaction mixture was filtered through dicalite, washed with TBME, the filtrate was washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried over Na2SO4. Removal of the solvent in vacuum left the crude title compound as an orange oil (20.3 g, 106%), which was used in the next step without further purification. MS (ISP): m/z=408.0 [(M+H)+] and 410.1 [(M+2+H)+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[CH2:12]([NH:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]([CH2:20][CH2:21][CH2:22][CH3:23])[C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(N=C=O)c(C)c1
Reactant: CCCCNCc1ccccc1
Product: CCCCN(Cc1ccccc1)C(=O)Nc1ccc(C)cc1C

Procedure:
Many of the novel ureas and thioureas of this invention are prepared by reacting arylisocyanates and arylisothiocyanates with secondary amines. These reactions may be performed in aprotic solvents such as hexane, diethyl ether, toluene, tetrahydrofuran, and the like at temperatures from room temperature or below up to the boiling point of the solvent used. The ureas and thioureas are isolated by filtration or by evaporation of the solvent, and they may be purified by recrystallization, absorption chromatography, or distillation under reduced pressure Examples of this process are the reaction of 2,4-dimethylphenylisocyanate with N-benzyl-N-(n-butyl)amine to yield 1-benzyl-1-(n-butyl)-3-(2,4-dimethylphenyl)urea and the reaction of 6-[[(4-butylphenyl)methyl]amino]-1-hexanol with 2,4-dimethylphenyl isocyanate in hexane at room temperature to yield 1-[(4-butylphenyl)methyl]-3-(2,4-dimethylphenyl)-1-(6-hydroxyhexyl)urea.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=1)=[O:5].[N:31]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[O:34]1[CH2:35][CH2:36][N:31]([C:37]([O:1][C:2]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][C:3]=2[C:4]([NH:6][C:7]2[CH:8]=[C:9]([C:17]([F:18])([F:19])[F:20])[CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=2)=[O:5])=[O:38])[CH2:32][CH2:33]1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(-c2ccccc2)ccc1O
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(-c2ccccc2)ccc1OC(=O)N1CCOCC1
Yield: 91.4 %

Procedure:
Using 2-hydroxy-5-phenyl-N-[3,5-bis(trifluoromethyl)phenyl]benzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:6]([NH:8][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH2:25]([N:32]=[C:33]=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO.C(Cl)(Cl)Cl.[Pd]>[C:26]1([CH2:25][NH:32][C:33]([NH:1][C@H:2]([C:6]([NH:8][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C=NCc1ccccc1
Reactant: COC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)NCc1ccccc1)C(C)C
Reaction time: 1 h
Yield: 59 %

Procedure:
CBZValAlaOCH3 (1.35 g, 4.00 mmole) was hydrogenated at 3 arm. over 10% Pd on carbon (150 mg) in CH3OH (40 mL) at room temperature. After 1 hour, the catalyst was removed by filtration through a nylon filter. The filtrate was evaporated in vacuo giving a white solid which was slurried in CHCl3 (40 mL) and treated with benzyl isocyanate (586 mg, 4.4 mmole). After 1 hour at room temperature, the reaction mixture was washed three times with 1N HCl, dried over MgSO4, filtered and concentrated in vacuo giving 791 mg (61%) of the desired product as a white powder. Recrystallization of a portion from ethyl acetate/CH3OH gave an analytical sample: mp 227°-228° C.; 1H NMR (DMSO-d6) δ 0.80 (d, J=6.8 Hz, 3H), 0.86 (d, J=6.7 Hz, 3H), 1.26 (d, J=7.3 Hz, 3H), 1.85-1.95 (m, 1H), 3.59 (s, 3H), 4.10 (dd, J=5.9, 9.2 Hz, 1H), 4.15-4.3 (m, 3H), 6.08 (d, J=9.3 Hz, 1H), 6.53 (t, J=6.0 Hz, 1H), 7.15-7.35 (m, 5H), 8.39 (d, J=6.7 Hz, 1H); MS (LSIMS) m/e 336 (100, M+ +1), 233 (62), 203 (76); [α]D20 +6.1° (c=1.0, DMF); Analysis calculated for C17H25N3O4 ; C, 60.88; H, 7.51; N, 12.53; found: C, 60.98; H, 7.30; N, 12.34.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:27][C:28]([C:30]2[C:31](=[O:43])[N:32]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:33]([CH3:36])[C:34]=2[CH3:35])=[O:29])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH2:22][C:23]3([OH:26])[CH2:25][CH2:24]3)=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[C:44]([NH:51][CH2:52][C:53](O)=[O:54])([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[C:47]([O:46][C:44]([NH:51][CH2:52][C:53]([O:26][C:23]1([CH2:22][CH2:21][CH2:20][O:19][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([NH:27][C:28]([C:30]5[C:31](=[O:43])[N:32]([C:37]6[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=6)[N:33]([CH3:36])[C:34]=5[CH3:35])=[O:29])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][CH:16]=2)[CH2:25][CH2:24]1)=[O:54])=[O:45])([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCCC5(O)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCCC5(OC(=O)CNC(=O)OC(C)(C)C)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
To a mixture of N-(3-fluoro-4-(7-(3-(1-hydroxycyclopropyl)propoxy)-quinolin-4-yl-oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (218 mg, 0.374 mmol), N-Boc-glycine (133.4 mg, 0.768 mmol, Alfa), and DMAP (7.03 mg, 0.058 mmol, Aladdin) in 10 mL of dichloromethane was added DCC solid (323.4 mg, 1.54 mmol, Aldrich) slowly at 0° C. The reaction was then warmed up to rt and continued to stir at rt overnight. The mixture was filtered and the solid was washed with CH2Cl2 (10 mL×2). The combined organic phases were washed with 15 mL of saturated NaHCO3 solution followed by 15 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on a silica gel column (PE:EtOAc=1:6) to give the desired compound as a yellow solid (160 mg, 60%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([CH3:9])[CH:8]=1)=[O:2].[F-].[Cs+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH2:15]([C:5]1[CH:4]=[C:3]([CH:8]=[C:7]([CH3:9])[CH:6]=1)[CH:1]=[O:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(C=O)cc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: Cc1cc(C=O)cc(Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
To a DME solution (0.1 M) of (3-formyl-5-methylphenyl)boronic acid (1 eq.) was added cesium fluoride (3 eq.), tetrakis(triphenylphosphine)palladium (0.1 eq.) and benzyl bromide (1.2 eq.). The mixture was refluxed for 3 h, cooled down to RT and quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate. The combined organic extracts were then washed with brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→7:3 (v/v) Hex:EtOAc) afforded the title compound.