Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]#[C:5][CH2:6][OH:7])[CH2:3][CH2:2]1.[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:15][C:14]1[CH:16]=[CH:17][C:11]([S:8]([O:7][CH2:6][C:5]#[C:4][CH:1]2[CH2:3][CH2:2]2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: OCC#CC1CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC#CC2CC2)cc1
Reaction time: 3 h

Procedure:
To a stirred solution of crude 3-cyclopropylprop-2-yn-1-ol (intermediate AT) (0.55 mg) in 10 mL of CH2Cl2 was added TsCl (1.33 g, 6.87 mmol) and DMAP (0.035 g, 0.2865 mmol) at 0° C. Triethylamine (0.96 mL, 6.87 mmol) was added dropwise to the mixture and the reaction temperature was held so as not to exceed 0° C. After stirring for 3 h, the mixture was quenched with 10 mL of water. The aqueous layer was extracted twice with 20 mL each of CH2Cl2. The organic layer was washed with 20% HCl and water prior to drying over anhydrous Na2SO4. The organic phase was concentrated and the crude product was purified by gel column chromatography to obtain intermediate AU (0.4 g).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][C:22]#[CH:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].I[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][C:22]#[C:23][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: Ic1ccccc1
Reactant: C#CCOCCn1c(COCC)nc2cnc3ccccc3c21
Product: CCOCc1nc2cnc3ccccc3c2n1CCOCC#Cc1ccccc1
Reaction time: 0.83 h
Yield: 78.5 %

Procedure:
Using the general method of Example 12 Part A, 2-(ethoxymethyl)-1-[2(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline (1.5 g, 4.13 mmol) was reacted with iodobenzene (0.51 mL, 4.54 mmol) at 40° C. After 50 minutes the reaction was judged complete. The volatiles were removed under reduced pressure and the resulting oil was partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The aqueous layer was extracted with dichioromethane. The organic fractions were combined, washed with brine, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure to leave a brown oil. The oil was purified by chromatography over silica gel (98/2 dichloromethane/methanol) to provide 1.25 g of 2-(ethoxymethyl)-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline as a brown glassy solid.
Reaction SMILES: C(Cl)(=O)C.[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([N:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)=[O:23])=[CH:17][CH:16]=1)=[O:14].NC1C=C2C(=CC=1)CN(C(N[C:46]1[CH:51]=[CH:50][C:49]([C:52](=[O:57])NCCC)=[CH:48][CH:47]=1)=O)C2>>[C:52]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([N:24]2[CH2:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:32]2)=[O:23])=[CH:17][CH:16]=1)=[O:14])(=[O:57])[C:49]1[CH:50]=[CH:51][CH:46]=[CH:47][CH:48]=1
Reactant: NCCCCCCNC(=O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CC(=O)Cl
Product: O=C(NCCCCCCNC(=O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1)c1ccccc1

Procedure:
The title compound was prepared as described in Example 278, substituting benzoyl chloride for acetyl chloride and N-{4-[(6-aminohexyl)carbamoyl]phenyl}-1,3-dihydro-2H-isoindole-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.57 (s, 1H), 8.43 (t, J=5.6 Hz, 1H), 8.25 (t, J=5.6 Hz, 1H), 7.81-7.86 (m, 2H), 7.74-7.78 (m, 2H), 7.63-7.67 (m, 2H), 7.41-7.54 (m, 3H), 7.29-7.39 (m, 4H), 4.78-4.79 (bs, 4H), 3.15-3.27 (m, 4H), 1.44-1.64 (m, 4H), 1.19-1.39 (m, 4H); MS (ESI(+)) m/e 485 (M+H)+.
Reaction SMILES: O1C=CC=C1B(O)O.Br[C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13].C(=O)([O-])[O-].[Na+].[Na+].[C:24]1(C)[C:25]([CH2:30][CH2:31][OH:32])=[CH:26][CH:27]=[CH:28][CH:29]=1>C(Cl)Cl.[Pd].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>[O:32]1[C:31]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=[O:13])=[CH:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]1=2
Reactant: O=Cc1ccccc1Br
Reactant: Cc1ccccc1CCO
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccco1
Solvent: ClCCl
Product: O=Cc1ccccc1-c1cc2ccccc2o1
Temperature: 100 °C

Procedure:
A mixture of 3 g of benzolb]furan-2-boronic acid, 3.14 g 2-bromobenzaldehyde, 0.56 g tetrakis(triphenylphosphine)-palladium (0), and 17 ml of 2N aqueous sodium carbonate in 50 ml of a 9:1 mixture of toluene-ethanol, under a nitrogen atmosphere, was heated to 100° C. for 10 h. The mixture was cooled to room temperature, diluted with 100 ml of methylene chloride and washed with 50 ml of 5% sodium bicarbonate containing 5 ml of 0.880 ammonia. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give 2-(benzo[b]furan-2-yl)benzaldehyde as a brown gum, GC-M.S. (E.I.) (M/Z): 222 [M+].
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][C:9](C3C(=O)C4C(=CC=CC=4)C3=O)=[N:10][C:4]2=[CH:3][CH:2]=1.[OH-].[Na+].Cl>O>[N:10]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1c2ccccc2C(=O)C1c1ccc2ccccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc2ncccc2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
45 parts of C.I. Pigment Yellow 138 (manufactured by BASF “Paliotol Yellow D0960”) was added gradually to 450 parts of 101% sulfuric acid prepared from fuming sulfuric acid (25% SO3) and sulfuric acid, and the mixture was stirred at 80° C. for 3 hours, allowing a sulfonation reaction to proceed. The reaction solution was poured into 5,000 parts of ice water, and the precipitate was filtered, washed with 2,000 parts of 0.1% hydrochloric acid, and additionally with 2,000 parts of purified water, to give a paste of the sulfonated compound of quinophthalone. The water-wet paste was redispersed in 5,000 parts of water, and the dispersion was adjusted to a pH of 11.5 by addition of an aqueous sodium hydroxide solution. The solution was stirred additionally for one hour while the pH of the solution was adjusted by addition of an aqueous sodium hydroxide solution. The reaction solution changed from an yellow suspension to a red solution. The reaction solution was then heated to 60° C. at pH 11.5 and stirred for 3 hours. The solution was then adjusted to a pH of 1 or less by addition of hydrochloric acid and stirred at 90° C. for 2 hours. Precipitate formed was filtered, washed and dried, to give a quinoline derivative [D].
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].C(=O)([O-])[O-].[K+].[K+].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:27][N:26]=[C:25]([C:28]3[O:29][CH:30]=[CH:31][CH:32]=3)[N:24]=2)=[C:19]([Cl:33])[CH:18]=1>O1CCOCC1>[Cl:33][C:19]1[CH:18]=[C:17]([NH:16][C:2](=[O:3])[O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])[CH:22]=[CH:21][C:20]=1[C:23]1[O:27][N:26]=[C:25]([C:28]2[O:29][CH:30]=[CH:31][CH:32]=2)[N:24]=1
Reactant: Nc1ccc(-c2nc(-c3ccco3)no2)c(Cl)c1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(Nc1ccc(-c2nc(-c3ccco3)no2)c(Cl)c1)OCC(Cl)(Cl)Cl
Yield: 55.3 %

Procedure:
2,2,2-Trichloroethyl chloroformate (1.56 g) is added to a mixture of 1.05 g of potassium carbonate and 1.3 g of 5-(4-amino-2-chlorophenyl)-3-(2-furanyl)-1,2,4-oxadiazole in 30 ml of dioxane. The mixture is heated at reflux for 2 hours and concentrated to dryness. The residue is partitioned between water and chloroform and the aqueous layer is extracted twice with chloroform. The combined chloroform extract is dried, filtered and concentrated to yield the crude product. Recrystallization from benzene/dioxane yields 1.2 g of the title compound, melting point 219°-220°C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:7][C:8]1[C:14]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:13][C:11]([NH2:12])=[C:10]([F:19])[CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:7][C:8]1[C:14]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:13][C:11]([NH:12][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[C:10]([F:19])[CH:9]=1
Reactant: CCOC(=O)Cl
Reactant: CC(C)Oc1cc(N)c(F)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cc(OC(C)C)c(Cl)cc1F

Procedure:
12.8 g of ethyl chloroformate are added while stirring to a solution of 20 g of 4-chloro-2-fluoro-5-isopropoxyaniline in 100 ml of methylene chloride at room temperature. 9.4 g of pyridine are subsequently added dropwise during 20 minutes at 20° C. while stirring and cooling. The reaction mixture is stirred for 20 minutes, washed three times with in each case 200 ml of a solution of 20 ml of 2N hydrochloric acid in 200 ml of water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. There is obtained ethyl N-(4-chloro-2-fluoro-5-isopropoxyphenyl)-carbamate, m.p. 89°-91° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH3:18][O:19][C:20](=[O:30])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:22]>>[CH3:18][O:19][C:20](=[O:30])[C@@H:21]([NH:22][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]2)=[CH:16][CH:15]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-oxo-piperidine-1-yl)-benzoic acid (which was obtained in Example 151) and L-phenylalanine methyl ester hydrochloride according to the procedure of Example 154 as a pale yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 2.41 (t, J=6.0 Hz, 4H), 3.05-3.20 (m, 2H), 3.71 (t, J=6.0 Hz, 4H), 4.55-4.65 (m, 1H), 6.97 (d, J=8.9 Hz, 2H), 7.10-7.45 (m, 5H), 7.73 (d, J=8.9 Hz, 2H), 8.52 (d, J=7.8 Hz, 1H); MS (ES) m/z: 381.3 (MH+); HRMS Calcd. for C22H25N2O4 (MH+): 381.1809. Found: 380.1807.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-])=O.[H][H]>[Pd].C1COCC1>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cccc2[nH]ccc12

Procedure:
A round-bottom flask was charged with 4-nitroindole (4.8 g, 30 mmol), Palladium on carbon (10%, 480 mg), and THF (50 mL), and the mixture was stirred under one hydrogen atmosphere overnight. TLC showed the reaction was complete. The catalyst was filtered off and the filtrate was concentrated to afford 4-amino-1H-indole, which was used directly in the next step without purification.
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH3:19])[CH2:8][CH2:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[NH2:17])=[CH:5][CH2:4]1)[CH3:2].Cl.Cl[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]Cl>ClC1C=CC=CC=1Cl>[CH2:18]([C:3]1([CH2:1][CH3:2])[CH2:8][CH2:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:5][CH2:4]1)[CH3:19]
Reactant: ClCCNCCCl
Reactant: CCC1(CC)CC=C(c2ccc(OC)cc2N)CC1
Agent: Cl
Solvent: Clc1ccccc1Cl
Product: CCC1(CC)CC=C(c2ccc(OC)cc2N2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
A solution of 2-(4,4-diethylcyclohex-1-enyl)-5-methoxyphenylamine (2.6 g, 10 mmol) prepared in Example (6e) and bis(2-chloroethyl)amine hydrochloride (2.2 g, 12 mmol) in 1,2-dichlorobenzene (10 mL) was stirred at an external temperature of 210° C. Nitrogen gas was blown into the reactor several times during the reaction to remove the excess hydrogen chloride gas in the reactor. After 1 hour, the reaction mixture was cooled to room temperature, and then saturated aqueous sodium hydrogencarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 1.4 g of the title compound as a yellow oil.
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:10][CH3:11])([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.[H-].[Na+].Cl[CH2:22][C:23]([CH3:25])=[CH2:24]>CN(C=O)C>[CH3:11][O:10][C:7]1([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3][CH:2]1[O:1][CH2:24][C:23]([CH3:25])=[CH2:22]
Reactant: C=C(C)CCl
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)COC1CN(C(=O)OC(C)(C)C)CCC1(OC)OC
Yield: 76.9 %

Procedure:
The same operation as in Example (90a) was performed using tert-butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate (5.2 g, 20 mmol), sodium hydride (55% content, 1.31 g, 30 mmol), 3-chloro-2-methyl-1-propene (3.63 g, 40 mmol) and DMF (50 mL). The residue was purified by column chromatography (elution solvent: hexane/ethyl acetate=10/1, 4/1, 2/1) to obtain 4.85 g of the title compound as a colorless oily substance (77%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH2:15][C@@H:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][O:29][CH2:30][CH2:31][CH2:32][C:33]([CH2:44][CH3:45])([O:36][Si:37]([CH2:42][CH3:43])([CH2:40][CH3:41])[CH2:38][CH3:39])[CH2:34][CH3:35])[CH2:12][C@@H:11]([O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[C:74]1([N:80]2[C:84](=[O:85])[N:83]=[N:82][C:81]2=[O:86])[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1>CCCCCC>[C:74]1([N:80]2[C:81](=[O:86])[N:82]=[N:83][C:84]2=[O:85])[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=1.[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][O:29][CH2:30][CH2:31][CH2:32][C:33]([CH2:44][CH3:45])([O:36][Si:37]([CH2:38][CH3:39])([CH2:42][CH3:43])[CH2:40][CH3:41])[CH2:34][CH3:35])[CH2:12][C@@H:11]([O:46][Si:47]([C:50]([CH3:51])([CH3:52])[CH3:53])([CH3:48])[CH3:49])[CH2:10]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCC(CC)(CCCOC[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)O[Si](CC)(CC)CC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Agent: O=C1N=NC(=O)N1c1ccccc1
Solvent: CCCCCC
Product: CCC(CC)(CCCOC[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)O[Si](CC)(CC)CC

Procedure:
To 1α,3β-bis(tert-butyldimethylsilyloxy)-17β-{4-ethyl-4-(triethylsilyloxy)hexyloxymethyl}androst-5-ene (1.0 g), were added hexane (15 ml), N-bromosuccinimide (336.4 mg) and then 2,2′-azobis isobutyronitrile (77.6 mg), followed by reaction under reflux for 30 min. After cooling with ice, the mixture was filtered to remove insoluble material and the filtrate was evaporated under reduced pressure to remove the solvent. To the resulting residue, were added toluene (10 ml) and γ-collidine (534.4 mg), followed by reflux for 2 hours. The mixture was filtered to remove insoluble material and the filtrate was diluted with hexane. The organic layer was washed with IM hydrochloric acid, a saturated aqueous sodium bicarbonate solution and then saturated brine and evaporated to remove the solvent under reduced pressure. The resulting residue was purified by column chromatography (hexane:ethyl acetate 40:1), dissolved in dichloromethane (20 ml) and subjected to reaction for 1 hour by adding 4-phenyl-1,2,4-triazoline-3,5-dione. The reaction mixture was evaporated to remove the solvent under reduced pressure and the resulting residue was purified by column chromatography (hexane:ethyl acetate=7:1) to give the titled compound (0.45 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:12][C:13]([NH2:15])=[S:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH:17]([CH:23]([CH3:25])[CH3:24])[C:18](OCC)=[O:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:12][C:13]3[S:14][CH:17]([CH:23]([CH3:25])[CH3:24])[C:18](=[O:19])[N:15]=3)[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: NC(=S)NC1(c2ccc(Cl)cc2)CCC1
Reactant: CCOC(=O)C(Br)C(C)C
Product: CC(C)C1SC(NC2(c3ccc(Cl)cc3)CCC2)=NC1=O

Procedure:
Synthesis was performed from N-[1-(4-chlorophenyl)cyclobutyl]thiourea and ethyl 2-bromo-3-methylbutanoate according to Method D.
Reaction SMILES: C([O:5][C:6](=[O:24])[CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH:20]=[CH:21][CH2:22][Br:23])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:23][CH2:22][CH:21]=[CH:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][C:6]([OH:24])=[O:5]
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCC=CCBr
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCOCCOCCOCCOCC=CCBr
Yield: 98.8 %

Procedure:
At RT, a solution of 1 g of 3-(2-{2-[2-(4-bromo-but-2-enyloxy)-ethoxy]-ethoxy}-ethoxy)-propionic acid tert-butyl ester (commercially available), 6 ml of TFA and 3 ml of DCM is stirred during 3 hrs, and then concentrated to dryness under RP. The oily residue is diluted with toluene and concentrated to dryness under RP affording 853 mg of 3-(2-{2-[2-(4-bromo-but-2-enyloxy)-ethoxy]-ethoxy}-ethoxy)-propionic acid in the form of a brown oil.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:31])[C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1.CN(C=O)C>C(OCC)(=O)C>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:31])[C:23](=[O:30])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:16]=3)=[CH:13][CH:14]=2)[S:3]1
Reactant: CN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)c1ccccc1

Procedure:
1.4 g (3.3 mmol) of N-[4′-(2,4-dioxo-thiazolidin-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-methylbenzamide, 30 ml of DMF and 25 ml of ethyl acetate are introduced into a three-necked flask. The reaction medium is degassed, 1.4 g of palladium-on-charcoal (10%) are introduced and the mixture is hydrogenated under atmospheric pressure at 60° C. The reaction medium is filtered and evaporated, and the residue obtained is purified by chromatography on a column of silica eluded with a mixture of dichloromethane and methanol (99/1). After evaporation of the solvents, 300 mg (21%) of N-[4′-(2,4-dioxo-thiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbenzamide with a melting point of 70-71° C., are collected.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([O:22]CC(=O)C)[CH:16]=[CH:17][CH:18]=2)[N:13]=1>>[CH3:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([O:22][CH2:2][C:3](=[O:4])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: CC(=O)COc1cccc2ccc(C)nc12
Reactant: O=C(CBr)c1ccccc1
Product: Cc1ccc2cccc(OCC(=O)c3ccccc3)c2n1
Yield: 72 %

Procedure:
2-Methyl-8-(2-oxo-2-phenylethoxy)quinoline (11a) was prepared from 2-bromoacetophenone by the same procedure as 10a in 72% yield. mp: 70°-71° C.; 1H-NMR (CDCl3): δ2.77 (s, 3H, 2-CH3), 5.63 (s, 2H, OCH2), 6.94-8.10 (m, 8H, Ar--H), 7.29 (d, 1H, 3-H), 7.99 (d, 1H, 4-H).
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([N:3]2[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
To a solution of 4-piperidone monohydrate hydrochloride (7.68 g, 50 mmol) in methylene chloride (50 ml) were added sequentially p-toluenesulfonyl chloride (10.50 g, 55.07 mmol) and triethylamine (21 ml). The mixture was stirred at room temperature for 16 h before being quenched with water (100 ml). The organic layer was washed with 1 M HCl (100 ml) and brine (100 ml), and dried over sodium sulfate. Evaporation of the solvent gave the desired ketone (8.60 g, 68%) as a colorless solid. mp 130-132° C.; 1H NMR (500 MHz, CDCl3) δ2.40 (s, 3H), 2.58 (t, J=6.4 Hz, 4H), 3.38 (t, J=6.4 Hz, 4H), 7.35 (d, J=7.8 Hz, 2H), 7.68 (d, J=8.3 Hz, 2H).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH3:19])[CH2:14][CH2:13]3)[CH2:9]2)C=CC=CC=1>[OH-].[Pd+2].[OH-].[C].CO>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH3:19])[CH2:14][CH2:13]2)[CH2:9]1
Reactant: CCN1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCN1CCN(C2CNC2)CC1

Procedure:
To a mixed solution of 1-(1-(diphenylmethyl)azetidin-3-yl)-4-ethylpiperazine (12.7 g, 37.9 mmol) described in Production Example 1-3-1 and methanol (50 mL) was added palladium hydroxide-carbon (5.00 g) at room temperature. The resultant mixture was stirred under a hydrogen atmosphere at room temperature and at 0.35 MPa to 0.40 MPa for 10 hours. The reaction mixture was purged with a nitrogen atmosphere and was then filtrated using Celite. A filtrate was concentrated under a reduced pressure to give the title compound in the form of a mixture (12.4 g) with benzylbenzene. The product was used in the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[C:26]([CH3:27])=[N:25][C:18]3[N:19]=[C:20](SC)[N:21]=[CH:22][C:17]=3[CH:16]=2)[C:12]([CH3:28])=[CH:11][C:10]=1[F:29])=[O:7].C1C=C(Cl)C=C(C(OO)=O)C=1.[NH3:43]>C(Cl)Cl>[NH2:43][C:20]1[N:21]=[CH:22][C:17]2[CH:16]=[C:15]([C:13]3[C:12]([CH3:28])=[CH:11][C:10]([F:29])=[C:9]([NH:8][C:6]([NH:5][CH2:4][CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])=[O:7])[CH:14]=3)[C:26]([CH3:27])=[N:25][C:18]=2[N:19]=1
Reactant: CSc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)C)c(F)cc3C)c(C)nc2n1
Reactant: N
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(F)c(NC(=O)NCCC(C)(C)C)cc1-c1cc2cnc(N)nc2nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.7 %

Procedure:
Treat a suspension of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.248 g, 0.562 mmol) in DCM (20 mL) with 70 wt % mCPBA (0.208 g, 0.842 mmol) and stir the mixture at RT for 2 h. Add ammonia (0.5N in dioxane, 8.99 mL, 4.49 mmol) and stir the mixture at RT overnight. Add additional ammonia (7N in MeOH, 5 mL, 35 mmol) and stir at RT overnight. Concentrate the mixture to dryness, treat with saturated. Na2CO3 and extract with DCM (4×). Dry the combined organics over MgSO4, concentrate to dryness and purify via silica gel chromatography (50-100% EtOAc/Hex, then 0-10% MeOH/EtOAc) to afford the title compound as an off-white solid (57 mg, 24%). MS (m/z): 411.2 (M+1).