Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C1C=C(NC(N[C@@H]2CCCC[C@H]2N(C)C)=S)C=C(C(F)(F)F)C=1.[Cl:36][C:37]1[CH:38]=[C:39](/[C:44](/[C:62]([F:65])([F:64])[F:63])=[CH:45]\[C:46]([C:48]2[CH:60]=[CH:59][C:51]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])=[C:50]([CH3:61])[CH:49]=2)=[O:47])[CH:40]=[C:41]([Cl:43])[CH:42]=1>C1(C)C=CC=CC=1>[CH2:1]([S:8][C:44]([C:39]1[CH:40]=[C:41]([Cl:43])[CH:42]=[C:37]([Cl:36])[CH:38]=1)([C:62]([F:63])([F:64])[F:65])[CH2:45][C:46]([C:48]1[CH:60]=[CH:59][C:51]([C:52]([O:54][C:55]([CH3:57])([CH3:58])[CH3:56])=[O:53])=[C:50]([CH3:61])[CH:49]=1)=[O:47])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Agent: CN(C)[C@@H]1CCCC[C@H]1NC(=S)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)CC(SCc2ccccc2)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 6 h

Procedure:
Benzylmercaptan (1.5 eq.) and 1-[3,5-bis(trifluoromethyl)phenyl]-3-[(1R,2R)-2-(dimethylamino)cyclohexyl]thiourea (0.01 eq.) were added to a solution of tert-butyl 4-[(E)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoate (200 mg) in toluene (1.5 mL) at −40° C. The solution was stirred at −40° C. for 6 hours then at room temperature for 17 hours. The reaction was quenched by the addition of a saturated solution of sodium chloride, and then extracted with ethylacetate. The collected organic phases were dried over magnesium sulfate, filtered and the filtrate was evaporated under vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate) to give tert-butyl 4-[3-benzylsulfanyl-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-butanoyl]-2-methyl-benzoate (205 mg) as a mixture of two enantiomers.
Reaction SMILES: [Si](C=[N+]=[N-])(C)(C)[CH3:2].[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]([CH3:22])[CH2:18][C:19]([OH:21])=[O:20])=[CH:9]1>CO>[CH3:2][O:20][C:19](=[O:21])[CH2:18][C@H:17]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][CH:9]=1)[CH3:22]
Reactant: CC(CC(=O)O)c1c[nH]c2ccccc12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)C[C@@H](C)c1c[nH]c2ccccc12

Procedure:
3-(1H-Indol-3-yl)-butanal (130 mg, 0.690 mmol) was dissolved in tert-butyl alcohol (27 mL) and 2-methyl-2-butene (4.7 mL) and subsequently was stirred for 10 min. To this solution was added an aqueous solution (4.7 mL) of NaClO2 (75 mg, 0.83 mmol) and NaH2PO4 (115 mg, 0.830 mmol) in one portion. The reaction mixture was stirred at room temperature for 12 h. The organics were removed by concentrating in vacuo. The residue was diluted with 10 mL of H2O, and adjusted to a neutral pH with 1M HCl. Extraction with EtOAc (3×10 mL), drying over Na2SO4, and concentration in vacuo provided 3-(1H-indol-3-yl)-butanoic acid. TMS-diazomethane was added dropwise to a solution of the crude 3-(1H-indol-3-yl)-butanoic acid in methanol (7 mL) until a yellow color persisted. The residual TMS-diazomethane was quenched by the dropwise addition of acetic acid until the yellow color disappeared. The reaction was then treated with an excess of saturated aqueous sodium bicarbonate, extracted with Et2O (3×20 ml), dried over Na2SO4 and purified by silica gel chromatography (20:80 EtOAc/hexanes to provide (R)-3-(1H-indol-3-yl)-butyric acid methyl ester. [α]D=−7.6 (c=1.0 benzene); reported rotation for (S)-3-(1H-indol-3-yl)-butyric acid methyl ester [α]D=+10.9 (c=2.12, benzene).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[F:16].[F:17][C:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[CH:20][N:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(O)CC>C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:17][C:18]1[CH:23]=[C:22]([C:2]2[C:3]([F:16])=[CH:4][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:6][N:7]=2)[CH:21]=[CH:20][N:19]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: CC(C)(C)OC(=O)Cc1cnc(Cl)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCC(C)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cc1cnc(-c2ccnc(F)c2)c(F)c1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
To a flask containing tert-butyl 2-(6-chloro-5-fluoropyridin-3-yl)acetate 205-3 (370 mg, 1.5 mmol), 2-fluoropyridin-4-ylboronic acid 205-4 (318 mg, 2.25 mmol), Pd(OAc)2 (17 mg, 0.075 mmoL), 2-dicyclohexylphosphino-2′,6′-dimethoxyybiphenyl (62 mg, 0.15 mmol), K3PO4 (800 mg, 9 mmol) under argon was added 2-butanol (1.5 mL). The reaction mixture was stirred at 100° C. for 10 hours. After cooled to room temperature, the mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation. The crude was purified by silica gel flash chromatography, eluted with 20% ethyl acetate in dichloromethane to give tert-butyl 2-(2′,3-difluoro-2,4′-bipyridin-5-yl)acetate 205-5 as a yellow oil. MS m/z 307.1 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.[NH2:36][C@H:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:38][OH:39]>CN(C=O)C.O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:36][C@H:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:38][OH:39])=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: O=C(O)CCCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCCCc1ccccc1)N[C@@H](CO)c1ccccc1
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a solution of 5-phenylpentanoic acid (1.25 g) and hydroxybenzotriazole (1.18 g) in N,N′-dimethylformamide (25 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.74 g) at 0° C. and the mixture was stirred for 1 hour. To the mixture was added (2R)-2-amino-2-phenylethanol (960 mg) and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water (150 ml) and then extracted with ethyl acetate. The organic layer was washed with 2N hydrochloric acid, 2N aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystal was washed with diethy ether to give the title compound (1.09 g) having the following physical data.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[S:20][C:19]4[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:18]=4[CH:17]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:26][C:27]1([CH3:34])[CH2:32][C:31](=[O:33])[O:30][C:28]1=[O:29]>C(Cl)Cl>[Cl:25][C:24]1[C:18]2[CH:17]=[C:16]([C:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([N:1]4[CH2:6][CH2:5][N:4]([C:31](=[O:33])[CH2:32][C:27]([CH3:34])([CH3:26])[C:28]([OH:30])=[O:29])[CH2:3][CH2:2]4)=[N:12][CH:11]=3)=[O:15])[S:20][C:19]=2[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Nc1ccc(N2CCNCC2)nc1)c1cc2c(Cl)cccc2s1
Reactant: CC1(C)CC(=O)OC1=O
Solvent: ClCCl
Product: CC(C)(CC(=O)N1CCN(c2ccc(NC(=O)c3cc4c(Cl)cccc4s3)cn2)CC1)C(=O)O
Temperature: 25 °C
Yield: 89.1 %

Procedure:
A mixture of 4-chloro-benzo[b]thiophene-2-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide (50 mg, 0.13 mmol), CH2Cl2 (5 mL), and TEA (40 mg, 0.39 mmol) was stirred at room temperature. 2,2-Dimethylsuccinic anhydride (36 mg, 0.28 mmol) was added slowly. The reaction was stirred at room temperature for 0.5 hr then concentrated and the residue was taken up into 50 mL of EtOAc and washed with 50 mL of saturated ammonium chloride, brine and dried over anhydrous sodium sulfate. The solvent was removed and the product was triturated with diethyl ether and hexanes followed by filtration, to afford the product 4-(4-{5-[(4-chloro-benzo[b]thiophene-2-carbonyl)-amino]-pyridin-2-yl}-piperazin-1-yl)-2,2-dimethyl-4-oxo-butyric acid (58 mg, 89% yield). LCMS for C24H25ClN4O4S calcd. (m/e) 500, observed 499 (M−H).
Reaction SMILES: O.[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=O)[C:6]2=[O:14].Cl.[C:16]1([NH:22][C:23](=[O:26])[NH:24][NH2:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=[N:25][NH:24][C:23]([NH:22][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:26])[C:6]2=[O:14]
Reactant: O=c1c(=O)c2ccc(O)cc2c1=O
Reactant: NNC(=O)Nc1ccccc1
Agent: Cl
Solvent: O
Product: O=C(NN=c1c(=O)c2ccc(O)cc2c1=O)Nc1ccccc1

Procedure:
5-hydroxyindan-1,2,3-trione, monohydrate, 4-phenyl semicarbazide hydrochloride; reflux for 4 hours
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=[CH:9][CH:10]=[C:11]([C:17]1C=CC=CC=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[S:5].F[B-](F)(F)F.CN(C)C(C(OCC)=O)=CC=[N+](C)C.CC[O-].[Na+].CSCC(OCC)=O>C(O)C>[CH3:23][N:2]([CH3:1])[C:3](=[CH:9][CH:10]=[C:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[S:5]
Reactant: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Agent: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: CCOC(=O)CSC
Agent: CC[O-]
Solvent: CCO
Product: CCOC(=O)C(C)=CC=C(C(=S)OCC)N(C)C

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (28.6 g), a 2M ethanolic solution of sodium ethylate (50 cc) and ethyl (methylthio)acetate (13.4 g) in ethanol (180 cc). Diethyl 2-dimethylamino-5-methylthio-2,4-hexadienedioate (21.9 g) is thereby obtained in the form of a brown oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]=O)=[CH:23][CH:24]=2)[N:19]=[C:18]([CH3:28])[CH:17]=1.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1.C(O)(=O)C>ClCCCl>[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][NH:29][C:30]3[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=3)=[CH:23][CH:24]=2)[N:19]=[C:18]([CH3:28])[CH:17]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(Cl)c2ccc(C=O)cc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1cc(Cl)c2ccc(CNc3ccc(C#N)cc3)cc2n1
Yield: 65 %

Procedure:
Sodium triacetoxyborohydride (74 mg, 0.34 mmol) was added to a solution of 4-chloro-2-methyl-quinoline-7-carbaldehyde (example 13a, 50 mg, 0.24 mmol), 4-aminobenzonitrile (29 mg, 0.24 mmol), and acetic acid (88 mg, 1.5 mmol) in 1,2-dichloroethane (0.5 mL), then after 16 h the reaction mixture was partitioned between ethyl acetate and 2 M aq. sodium hydroxide solution. The organic layer was washed with brine, dried (MgSO4), and evaporated. Flash chromatography (SiO2, hexane/ethyl acetate 1:1) afforded the title compound (48 mg, 64%). White solid, ISP-MS: m/e=308.2 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[N+:10]([C:4]1[C:5]([C:8]#[N:9])=[N:6][CH:7]=[C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1)([O-:12])=[O:11]
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1ncc(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 3 h

Procedure:
5-bromo-3-nitropicolinonitrile (1 eq) and phenylboronic acid (1.5 eq) was mixed with 15 mL of 1,4-dioxane and 5 mL of 2 M Na2CO3 aqueous solution in a glass pressure tube. The reaction mixture was degassed by anhydrous N2 stream for 5 min followed by the addition of Pd(dppf)Cl2-DCM (0.1 eq). The reaction mixture was stirred at 100° C. for 3 hours. Then the mixture was diluted with 100 mL of ethyl acetate and washed with water, brine, then dried over MgSO4, filtered, and evaporated under reduced pressure to give crude product, which was triturated by DCM, ether, hexanes to give the pure titled compound. LC/MS (m/z): 226.1 (MH+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C:15]1=[O:23].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[C:24]([OH:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15]1=[O:23]
Reactant: CN1C(=O)Cc2ccccc21
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CN1C(=O)C(=C(O)c2ccccc2)c2ccccc21
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
4.15 g (41 mmol) of diisopropylamine are placed in 50 ml of THF, cooled to −70° C. and combined with a solution of 14.4 ml of (36 mmol) of n-butyl lithium solution (2.5 mol in toluene) and stirred for 10 minutes. Then a solution of 5.0 g (34 mmol) of 1-methyl-2-indolinone in 30 ml of THF is added dropwise and stirred for 45 minutes at −70° C. Then 5.8 g (0.041 mol) of benzoylchloride are added dropwise. The reaction solution is left to heat up slowly within 14 hours. It is then poured onto sodium chloride solution and extracted with ethyl acetate. The combined organic extracts are dried and concentrated by evaporation. The residue is chromatographed on silica gel (dichloromethane/methanol/ammonia=200:8:1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:11][CH2:12][C@@H:13]([C:15]([OH:17])=[O:16])[N:14]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+].[S:20](Cl)(Cl)(=[O:22])=[O:21].Cl>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:4]1([S:20]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]4[S:11][CH2:12][CH:13]([C:15]([OH:17])=[O:16])[N:14]=4)=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:22])=[O:21])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)[C@@H]1CSC(c2ccc3[nH]ccc3c2)=N1
Reactant: O=S(=O)(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Product: O=C(O)C1CSC(c2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2)=N1

Procedure:
(R)-2-(1H-Indol-5-yl)-4,5-dihydrothiazole-4-carboxylic acid 63a was synthesized from 1H-indole-5-carbonitrile using the same method as used for 42a of U.S. application Ser. No. 12/981,233 (now US2011/0257196) and U.S. application Ser. No. 1/216,927 (now US2012/0071524), incorporated herein by reference in their entirety. Briefly, benzonitrile (40 mmol) was combined with L-cysteine (45 mmol) in 100 mL of 1:1 MeOH/pH 6.4 phosphate buffer solution. The reaction was stirred at 40° C. for 3 days. The precipitate was removed by filtration, and MeOH was removed using rotary evaporation. To the remaining solution was added 1 M HCl to adjust to pH=2 under 0° C. The resulting precipitate was filtered to yield a white solid 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid 42a, which was used directly to next step without purification. To a vigorously stirring solution of 63a (1 mmol) and tetrabutylammonium hydrogen sulfate (0.15 mmol) in toluene (10 mL) at 0° C. was added 50% aqueous sodium hydroxide (10 mL) and sulfonyl chloride (2 mmol). The resultant solution was stirred at RT for 6 h. Then 1 N HCl was added to acidify the mixture to pH=2 and extracted with CH2Cl2, the organic layer was separated and dried (MgSO4); then evaporated to dryness to yield 64a, which were used in subsequent steps without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH2:12])[N:3]=1.[CH:19]([Mg]Br)=[CH2:20].[NH4+].[Cl-].C(OCC)(=O)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([OH:10])[CH:19]=[CH2:20])=[C:4]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH2:12])[N:3]=1
Reactant: C=C[Mg]Br
Reactant: C=C(c1ccccc1)c1nc(Cl)nc(Cl)c1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC(O)c1c(Cl)nc(Cl)nc1C(=C)c1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2,4-dichloro-6-(1-phenylvinyl)pyrimidine-5-carbaldehyde (200 mg) in THF (3.6 mL) at −78 C was added vinylmagnesium bromide (0.79 mL, 1M solution in THF) dropwise, and the reaction mixture was stirred at −78° C. for 20 min. Saturated NH4Cl was added followed by ethyl acetate, the aqueous layer was extracted with ethyl acetate (×3), and the combined organic layers were dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to give the title compound (156 mg) as a colorless oil. The crude product was used directly for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=4)(O)[C:19]4[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=4)[CH:16]=3)[N:11]([CH3:33])[C:10](=[O:34])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CO.C(Cl)(Cl)Cl.[NH4+:41].[OH-]>S(Cl)(Cl)=O>[NH2:41][C:18]([C:26]1[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=1)([C:19]1[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=1)[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:33])[C:10](=[O:34])[CH:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: [NH4+]
Reactant: Cn1cncc1C(O)(c1ccc(Cl)nc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Agent: [OH-]
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cn1cncc1C(N)(c1ccc(Cl)nc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
4-(3-Chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-1H-quinolin-2-one (2 g, 4.08 mmol) was dissolved in 25 ml of thionyl chloride (SOCl2) and stirred at room temperature under an atmosphere of dry N2 for 2 hours. Thiony chloride was removed under reduced pressure. The crude chloride was taken up in toluene and concentrated under vacuum. The resulting solid was dissolved in THF (20 mL) and to this solution was bubbled ammonia gas (NH3) for 30 minutes. The reaction mixture was stirred at ambient temperature under an atmosphere of NH3 for 15 hours. After removal of THF, the product mixture was partitioned between CHCl3 and water. The organic layer was washed, dried over MgSO4 and concentrated under vacuum to give a brown solid. This was chromatographed on silica gel with CHCl3 then MeOH-CHCl3—NH4OH (1:99:0.1) as eluents to afford the titled compound as a white solid (1.065 g, 2.02 mmol, 50% yield).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH:13]([C:15]([F:18])([F:17])[F:16])[NH:12][C:11]3=[O:19])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.I[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[CH3:27].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH:13]([C:15]([F:17])([F:18])[F:16])[N:12]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:26]=4[CH3:27])[C:11]3=[O:19])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Cc1ccncc1I
Reactant: O=C1NC(C(F)(F)F)CN1c1ccc2ncsc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1ccncc1N1C(=O)N(c2ccc3ncsc3c2)CC1C(F)(F)F
Yield: 7.6 %

Procedure:
1-Benzothiazol-6-yl-4-trifluoromethyl-imidazolidin-2-one (I-170b: 100 mg, 0.348 mmol) was reacted with 3-iodo-4-methyl-pyridine (83.9 mg, 0.383 mmol), Pd2(dba)3 (15.9 mg, 0.0174 mmol), Xantphos (30.2 mg, 0.0528 mmol), cesium carbonate (170 mg, 0.152 mmol) and 1,4-dioxane (10 mL) to afford the crude product. Purification by column chromatography on silica gel (2% methanol in chloroform) followed by preparative HPLC afforded 10 mg of the product (7.5% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[CH2:8][CH2:9][CH2:10][CH3:11]>C(OCC)C>[CH2:8]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCI
Reactant: C1CCNCC1
Solvent: CCOCC
Product: CCCCN1CCCCC1

Procedure:
45.0 g piperidine (0.53 mol) was added to 150 g ethyl ether. 48.6 g iodobutane (0.26 mol) was then added drop wise. After 3 days the resulting piperidine hydroiodide salt was removed by filtration and the N-butylpiperidine was recovered from the ether solution.
Reaction SMILES: [SH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[C:11]([OH:16])(=[O:15])[C:12]#[C:13][CH3:14]>>[NH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([S:1]/[C:13](/[CH3:14])=[CH:12]\[C:11]([OH:16])=[O:15])=[CH:3]1
Reactant: Sc1c[nH]c2ccccc12
Reactant: CC#CC(=O)O
Product: C/C(=C/C(=O)O)Sc1c[nH]c2ccccc12

Procedure:
-- By the same method as described in Example 1, 0.2 mole each of 3-mercaptoindole and tetrolic acid gives 10.2 g of product after recrystallization from acetonitrile, mp 201°-202° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:20][C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:10]2[CH2:15][CH2:14][N:13]([C:16]([NH:18][OH:19])=[NH:17])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:28]([O-])([O-])OCC>O1CCOCC1>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:20][C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:10]2[CH2:11][CH2:12][N:13]([C:16]3[N:17]=[CH:28][O:19][N:18]=3)[CH2:14][CH2:15]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=N)NO)CC1
Reactant: CCOC([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(c2ncon2)CC1
Temperature: 100 °C
Yield: 69 %

Procedure:
A mixture of 4-[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-N-hydroxy-piperidine-1-carboxamidine (50 mg, 0.13 mmol), dioxane (2 ml) and ethyl orthoformate (2 ml) were heated for 17 hours at 100° C. The volatiles were removed in vacuo, and the residue was purified using radial chromatography on silica gel (20:1:1 CH2Cl2:MeOH:NH4OH) to provide COMPOUND 335 as a yellow oil (34.2 mg, 69%). 1H NMR (CHCl3) δ 1.70-1.82 (m, 5H), 1.96-2.00 (m, 2H), 2.10 (s, 6H), 2.68-2.86 (m, 3H), 3.83 (s, 4H), 4.08-4.13 (m, 2H), 7.09 (dd, 2H, J=5.7, 8.4 Hz), 7.37 (d, 2H, J=8.4 Hz), 8.29 (s, 1H), 8.34 (d, 2H, J=5.7 Hz); 13C NMR (CHCl3) δ 18.4, 26.7, 46.9, 55.0, 57.6, 122.8, 133.8, 138.4, 146.3, 157.6, 164.3, 169.9; ES-MS m/z 401 (M+Na). Anal. Calcd. for C21H26N6.0.2H2O.0.4CH2Cl2: C, 61.78; H, 6.59; N, 20.20. Found: C, 61.77; H, 6.59; N, 19.93.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[F:17][C:18]([F:26])([F:25])[CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:22]2[CH2:23][CH2:24][CH:19]([C:18]([F:26])([F:25])[F:17])[CH2:20][CH2:21]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: FC(F)(F)C1CCNCC1
Agent: Cl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(C(F)(F)F)CC2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 4-(trifluoromethyl)piperidine hydrochloride (9.2 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (8.5 mg). Calcd for C17H17F3N2O2: 338.1242, found 338.1238.