Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([OH:25])[CH:21]=2)[C:16]=1[C:26](=O)[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:29][CH:28]=1)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.[BH4-].[Na+].C([BH3-])#N.[Na+]>ClCCl>[F:14][C:12]1[CH:11]=[CH:10][C:9]2[C:15]3[CH:24]=[CH:23][C:22]4[CH:21]=[C:20]([OH:25])[CH:19]=[CH:18][C:17]=4[C:16]=3[CH:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]4[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]4)=[CH:29][CH:28]=3)[NH:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)ccc1-c1ccc2cc(O)ccc2c1C(=O)c1ccc(OCCN2CCCCC2)cc1
Agent: [BH3-]C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: Oc1ccc2c3c(ccc2c1)-c1ccc(F)cc1NC3c1ccc(OCCN2CCCCC2)cc1
Yield: 35.2 %

Procedure:
To a round bottom flask add (5-fluoro-2-{6-hydroxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl}-phenyl)-carbamic acid tert-butyl ester (0.060 g, 0.103 mmol), dichloromethane (1.25 mL), anisole (0.15 mL, 1.39 mmol) and trifluoroacetic acid (0.25 mL). Stir the reaction for 1.5 hour at ambient temperature. Add trifluoroacetic acid (2.0 mL) and sodium borohydride (0.024 g, 0.62 mmol) and stir the reaction at ambient temperature for 1.5 hours. Add more sodium borohydride (0.024 g, 0.62 mmol) and stir the reaction at ambient temperature an additional 2 hours. After aqueous work-up and purification LC/MS showed significant amounts of the (M-2) intermediate, so take this material up in acetic acid (3.0 mL) and to it add sodium cyanoborohydride (0.032 g, 0.51 mmol). Stir this mixture for 1.5 hours at ambient temperature. Add more sodium cyanoborohydride (0.032 g, 0.51 mmol) and stir an additional 1.5 hours at ambient temperature. Quench the reaction with saturated aqueous sodium bicarbonate. Extract the resulting aqueous mixture into ethyl acetate. Wash the combined extracts with saturated aqueous sodium bicarbonate, H2O and brine; then dry (sodium sulfate) and evaporate the filtrate in vacuo. Purify the resulting residue by radial chromatography over silica (5%-10% methanol gradient in dichloromethane) to provide 17 mg (35%) of the title compound: mass spectrum (ion spray) m/z=469 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=2)[N:6]=1.[CH2:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)[CH2:18][CH3:19]>>[CH2:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:12]=3)[N:6]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1)[CH2:18][CH3:19]
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)Nc1ccc(-c2csc(N)n2)cc1
Product: CCCc1ccc(S(=O)(=O)Nc2nc(-c3ccc(NC(C)=O)cc3)cs2)cc1

Procedure:
The title compound was prepared from N-[4-(2-amino-1,3-thiazol-4-yl)phenyl]acetamide and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (1.0 mg) with purity >80%. MS (pos) m/z 416.2.
Reaction SMILES: [Cl:1][C:2]1[C:20]([N:21]([CH2:36]C(OCC)=O)[C:22](=[O:35])[CH2:23][N:24]2C(=O)C3=CC=CC=C3[C:25]2=[O:34])=[CH:19][CH:18]=[C:17]([Cl:42])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.CN>ClCCl.CO>[Cl:1][C:2]1[C:20]([N:21]2[CH2:36][C:25](=[O:34])[NH:24][CH2:23][C:22]2=[O:35])=[CH:19][CH:18]=[C:17]([Cl:42])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: CCOC(=O)CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Agent: CN
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N4CC(=O)NCC4=O)c3Cl)c2n1
Reaction time: 24 h
Yield: 50 %

Procedure:
To the solution of 8-[2,6-dichloro-3-[N-ethoxycarbonylmethyl-N-(phthalimidoacetyl)amino]benzyloxy]-2-methylquinoline (527 mg) in dichloromethane (5.3 ml) was added 30% solution of methylamine in methanol (2 ml) at ambient temperature. After stirring for 24 hours, the reaction mixture was evaporated in vacuo. The residue was purified by flash column chromatography (silica gel 50 ml) eluting with dichloromethane/methanol (20/1, V/V) and by crystallizing from isopropyl ether to give 8-[2,6-dichloro-3-(2,5-dioxopiperazin-1-yl)benzyloxy]-2-methylquinoline (187 mg) as colorless crystals.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)(=[O:4])=[O:3].[CH:15]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)([CH3:17])[CH3:16]>>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[C:21]1[CH2:22][CH2:23][N:18]([CH:15]([CH3:17])[CH3:16])[CH2:19][CH:20]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1ccc2[nH]ccc2c1
Reactant: CC(C)N1CCC(=O)CC1
Product: CC(C)N1CC=C(c2c[nH]c3ccc(NS(C)(=O)=O)cc23)CC1
Yield: 64.3 %

Procedure:
Beginning with 1.0 gm (4.76 mMol) 5-methanesulfonylamino-1H-indole and 0.873 gm (6.2 mMol) 1-isopropyl-4-piperidone, 1.02 gm (64.2%) of the title compound were recovered as a tan powder.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].N1C=CN=C1.Cl[Si:13]([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl.O>[CH3:14][Si:13]([CH3:16])([CH3:15])[O:6][CH2:1][CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C#CCCCO
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: C#CCCCO[Si](C)(C)C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a solution of 4-pentyn-1-ol (25.0 g, 0.30 mole) in dry CH2Cl2 (250 ml) at 0° C., was added imidazole (40.46 g, 0.60 mole) and chlorotrimethylsilane (56.6 ml, 0.45 moles) and stirred for 2 h. The reaction mixture was diluted with water and extracted with CH2Cl2 (3×100 ml). Combined organic extracts were washed with water, brine, dried (Na2SO4) and the solvent was evaporated. Purification of the crude product by vacuum distillation afforded the pure ether 13 (44.1 g, 95%).
Reaction SMILES: CCN(C(C)C)C(C)C.[Li]CCCC.[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[F:33]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O>C1COCC1.CCOC(C)=O>[CH2:15]([N:22]1[CH2:27][CH2:26][C:25]([F:33])([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(F)CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
A flask was charged with DIEA (8.64 mL, 60.6 mmol) and THF (100 mL). The mixture was cooled to about −78° C. followed by the addition of n-BuLi (24.3 mL, 60.6 mmol) over about 5 min. The mixture was warmed to about 0° C. and stirred for about 30 min and then cooled to about −40° C. To the mixture was added a solution of ethyl 1-benzylpiperidine-4-carboxylate (10.0 g, 40.4 mmol, Oakwood) in THF (75 mL) over about 10 min such that the solution is kept between −40 to −30° C. The mixture was stirred for about 1 h at about −10° C. before being cooled to about −78° C. A solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (14.0 g, 44.5 mmol) in THF (75 mL) was added over about 20 min while keeping the mixture between about −65 and −78° C. The mixture was then stirred for about 1 h at about −78° C. The mixture was poured into a separatory funnel containing ice water (30 mL) and EtOAc (30 mL) was added. The aqueous layer was extracted with EtOAc (3×25 mL) and the combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting mixture was adsorbed onto silica gel and purified by flash silica gel chromatography eluting with hexanes/EtOAc (10:1) to afford ethyl 1-benzyl-4-fluoropiperidine-4-carboxylate (7.13 g, 66%): LC/MS (Table 2, Method h) Rt=2.21 min; MS m/z: 266 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:20])[CH:7](OC(=O)C)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>>[CH2:1]([O:5][C:6](=[O:20])[CH:7]([NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:21][CH:22]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Reactant: c1ccc2[nH]ccc2c1
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1c[nH]c2ccccc12

Procedure:
A solution of 20.2 g. (0.070 mol.) of N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester and 8.8 g. (0.075 mol.) of indole in 300 ml. of toluene was slowly distilled over a 30 minutes interval with periodic replacement of the toluene with fresh solvent. After an additional 45 minutes the reaction mixture was cooled and the solvent was evaporated in vacuo. The residue was triturated with hexane to give α-(N-t-butoxycarbonylamino)indole-3-acetic acid n-butyl ester, m.p. 127°-128° (ether-hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:10]=2[C:11]([OH:13])=O)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)[F:42].C(N(C(C)C)C(C)C)C.F[C:56]1[CH:57]=[C:58]([CH:61]=[CH:62][C:63]=1[N:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1)[C:59]#[N:60]>CN(C)C=O.C1COCC1>[C:59]([C:58]1[CH:61]=[CH:62][C:63]([N:64]2[CH2:69][CH2:68][N:67]([C:11]([C:10]3[CH:14]=[C:15]([S:18]([NH2:19])(=[O:21])=[O:20])[CH:16]=[CH:17][C:9]=3[O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=3)=[O:13])[CH2:66][CH2:65]2)=[CH:56][C:57]=1[F:42])#[N:60]
Reactant: N#Cc1ccc(N2CCNCC2)c(F)c1
Reactant: F[B-](F)(F)F
Reactant: COc1ccc(COc2ccc(S(N)(=O)=O)cc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COc2ccc(S(N)(=O)=O)cc2C(=O)N2CCN(c3ccc(C#N)c(F)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.5 mmol 2-(4-methoxy-benzyloxy)-5-sulfamoyl-benzoic acid in 4 ml dimethylformamide and 12 ml THF were added 5.3 mmol TBTU, 17.5 mmol N-ethyldiisopropylamine and 3.5 mmol 3-fluoro-4-piperazin-1-yl-benzonitrile (WO9625414). The reaction was then stirred at RT for 1 h, concentrated in vacuo, and purified by chromatography on silica gel (eluant: ethyl acetate/heptane gradient) to afford the title compound. MS (m/e): 525.1 (M+H+)
Reaction SMILES: C[C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[C:4]([NH2:10])[C:3]=1[Br:11].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16].[C:20]1(C)C=CC=CC=1>>[Br:11][C:3]1[C:4]([N:10]=[CH:14][N:15]([CH3:17])[CH3:16])=[C:5]([C:7]([O:9][CH3:20])=[O:8])[S:6][CH:2]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1ccccc1
Reactant: Cc1sc(C(=O)O)c(N)c1Br
Product: COC(=O)c1scc(Br)c1N=CN(C)C

Procedure:
A solution of methyl 3-amino-4-bromo-2-thenoic acid (for preparator, see J. Gen. Chem. USSR, (1964), 34, 961) (5 g) and N,N-dimethylformamide dimethyl acetal (5 g) in toluene (30 ml) were heated under reflux for 8 hours. On cooling the solvent was removed and the residue purified by silica gel chromatography eluting with ethyl acetate: light petroleum (b.p. 60-80° C.) (1:3) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH2:5].[C:10](Cl)(Cl)=[S:11].C([N:16](CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:9])[C@:4]([N:16]=[C:10]=[S:11])([CH:6]([CH3:8])[CH3:7])[NH2:5]
Reactant: CCN(CC)CC
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@](N)(N=C=S)C(C)C
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A suspension of 1.0 g (5.96 mmol) of (L)-valine methyl ester in 10 ml of chloroform was cooled to -20° C. and treated with a solution of 0.48 ml of thiophosgene in 5 ml of chloroform. The resulting solution was treated dropwise with 2.49 ml (17.9 mmol) of triethylamine, stirred at -20° C. for 15 min, then quenched with 10 ml of 0.1M HCl. The chloroform layer was separated, washed with four 5 ml portions of water, dried over MgSO4, and concentrated in vacuo to provide 1.01 g of the α-isothiocyanato-(L)-valine methyl ester as an oil. The crude oil (1.01 g) was taken up in 10 ml of dichloromethane and added to a mixture of 0.81 g (4.15 mmol) of the resultant compound of Example 3C and 1.14 ml (10.4 mmol) of 4-methylmorpholine in 40 ml of dichloromethane. The resulting mixture was stirred at ambient temperature for 16 h, washed with three 15 ml portions of water, dried over MgSO4, and concentrated in vacuo. Silica gel chromatography of the residue using 15% ethyl acetate in dichloromethane provided 1.23 g (100%) of the desired compound as an oil. 1H NMR (CDCl3) δ 1.02 (d, J=7 Hz, 3 H), 1.06 (d, J=7 Hz, 3 H), 2.33 (m, 1 H), 3.40 (s, 3 H), 3.74 (s, 3 H), 4.83 (AA', 2 H), 5.10 (dd, J=8, 5 Hz, 1 H), 7.27 (dd, J=8, 5 Hz, 1 H), 7.33 (d, J=8 Hz, 1 H), 7.73 (br t, J=8 Hz, 1 H), 8.56 (dd, J=5, 1 Hz, 1 H). Mass spectrum: (M+H)+ =296.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[S:52][C:18]2[N:19]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]4[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=4)=[CH:40][CH:39]=3)[C:20](=[O:36])[N:21]([CH:24]([CH3:35])[C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]>C(Cl)(Cl)Cl>[CH2:13]([C:15]1[S:52][C:18]2[N:19]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[C:50]4[NH:3][C:4](=[O:7])[O:5][N:51]=4)=[CH:42][CH:43]=3)[C:20](=[O:36])[N:21]([CH:24]([CH3:35])[C:25]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: CCc1cc2c(=O)n(C(C)C(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: CCc1cc2c(=O)n(C(C)C(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
A mixture of hydroxylammonium chloride (0.54 g), sodium hydrogencarbonate (0.82 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[6-ethyl-3-[2-(4-methoxyphenyl)-1-methyl-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.27 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in methylene chloride (20 ml). N,N′-Carbonyldiimidazole (0.079 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.067 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.2 g, 65%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.[CH2:54]([O:56][CH2:57][CH2:58][NH2:59])[CH3:55]>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:59][CH2:58][CH2:57][O:56][CH2:54][CH3:55])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Reactant: CCOCCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Combined 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (100 mg, 0.327 mmol), EDCI (94.0 mg, 0.490 mmol), and HOBT (66.2 mg, 0.490 mmol) in DMF (2.5 mL) and added N,N-diisopropyl ethylamine (227 μL, 1.306 mmol). Then 2-ethoxyethanamine (43.7 mg, 0.490 mmol) was added and the reaction allowed to stir at room temperature for 16 hours. The reaction mixture was then diluted with water (3.5 mL) and acidified to an approximate pH=4 to give a solid which was collected by filtration, washed with water, MeOH, and diethyl ether to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 1.04 (t, J=6.95 Hz, 3H) 3.33-3.41 (m, 4H) 3.41-3.48 (m, 2H) 7.70 (d, J=8.34 Hz, 2H) 8.06 (d, J=7.07 Hz, 2H) 8.26-8.49 (m, 2H) 8.58 (br. s., 1H) 8.71 (t, J=5.18 Hz, 1H) 8.77-8.93 (m, 1H) 12.95-13.90 (m, 1H). MS m/z [M+H]+ 378.1.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=[O:27])[CH2:15][C@H:16]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[C:17]([OH:19])=[O:18].C(N1C=CN=C1)(N1C=CN=C1)=O.N12CCCN=C1CCCCC2.[C:51](O)([CH3:54])([CH3:53])[CH3:52]>CCOCC.CN(C=O)C>[C:51]([O:18][C:17](=[O:19])[C@@H:16]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH2:15][C:14]([C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=1)=[O:27])([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)(C)O
Reactant: O=C(C[C@H](NC(=O)C(F)(F)F)C(=O)O)c1ccc2oc3ccccc3c2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CC(=O)c1ccc2oc3ccccc3c2c1)NC(=O)C(F)(F)F
Temperature: 24 °C
Reaction time: 1 h

Procedure:
To a DMF solution (10 mL) of (S)-4-dibenzofuran-2-yl-4-oxo-2-(2,2,2-trifluoroacetylamino)-butyric acid (0.3 g, 0.00079 mol) at 40° C. was added carbonyldimidazole (0.13 g, 0.00079 mol). This mixture was stirred for 1 hour and then 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU, 0.12 mL, 0.00079 mol) and t-butanol (0.15 mL, 0.00158 mol) were added. The reaction mixture was stirred for 24 hours at 40° C., cooled to 24° C., and then diluted with ether (20 mL). The solution was washed with water (2×10 mL), brine (2×10 mL), and dried over anhydrous magnesium sulfate. The mixture was filtered and the filtrate was concentrated to an oil by evaporation of the solvent in vacuo. The oil was flash chromatographed on silica gel eluting with 20% ethyl acetate/hexane (v/v) to yield the title compound; mp 92-94° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH2:15])[CH:6]=[C:7]([O:12][CH3:13])[C:8]=1[CH2:9][CH2:10][CH3:11].Br[C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([OH:22])=[O:21].COC1C=C(C=CC2C=CC(C(O)=O)=CC=2)C=C(OC)C=1CCC>>[CH3:13][O:12][C:7]1[CH:6]=[C:5]([CH:14]=[CH:15][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=2)[C:20]([OH:22])=[O:21])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[CH2:9][CH2:10][CH3:11]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: C=Cc1cc(OC)c(CCC)c(OC)c1
Agent: CCCc1c(OC)cc(C=Cc2ccc(C(=O)O)cc2)cc1OC
Product: CCCc1c(OC)cc(C=Cc2cccc(C(=O)O)c2)cc1OC
Yield: 77 %

Procedure:
This compound was synthesized from (3,5-dimethoxy-4-1-propylphenyl)-ethene and 3-bromobenzoic acid in 77% yield in the same way as described in preparation of 1B. 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.1 Hz, 6H), 3.63 (qint, J=7.1 Hz, 1H), 3.90 (s, 6H), 6.76 (s, 6H), 7.08 (d, J=17 Hz, 1H), 7.25 (d, J=17 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 8.04 (d, J=7.7 Hz, 1H), 8.31 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:13]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:13][C:9]1[C:10]([I:12])=[CH:11][C:2]([OH:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(I)cc1O
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)c(I)cc1O
Temperature: 100 °C
Yield: 61.9 %

Procedure:
A solution of methyl 2-hydroxy-4-iodobenzoate (50 g, 0.18 mol) [Aldrich, 652636] in acetic acid (360 mL) was treated with N-chlorosuccinimide (29 g, 0.22 mol) and heated at 100° C. for 1 hour. The reaction mixture was cooled until the internal temperature was 19° C. and then the solid that precipitated was filtered, washed with cold acetic acid, and air dried. The solid was diluted with toluene and concentrated (2×200 mL) to remove residual acetic acid to give 34.8 g of the desired product. The filtrate was concentrated, and the residue was purified by flash column chromatography using ethyl acetate in hexanes (0%-20%) to give an additional 8.6 g of desired product (total yield=43 g, 77%). LCMS for C8H7ClIO3 (M+H)+: m/z=312.9; Found: 313.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:13]([C:15]([C:21]#[N:22])=[C:16](SC)[NH:17][CH3:18])#[N:14]>C(#N)C>[C:13]([C:15]([C:21]#[N:22])=[C:16]([NH:17][CH3:18])[NH:12][CH2:11][CH2:10][CH2:9][CH2:8][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:14]
Reactant: NCCCCc1ncccc1Cl
Reactant: CNC(SC)=C(C#N)C#N
Solvent: CC#N
Product: CNC(NCCCCc1ncccc1Cl)=C(C#N)C#N

Procedure:
Reaction of 3-chloro-2-(4-aminobutyl)pyridine with 1,1-dicyano-2-methylthio-2-methylaminoethylene in acetonitrile at room temperature for one hour yields the title product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.Cl[CH2:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15].CN(C)[CH:20]=[O:21].Cl>CN(C)P(N(C)C)(N(C)C)=O.O1CCCC1>[CH3:15][C:14]([CH3:17])([CH3:16])[CH2:13][CH2:12][C:5]1[S:1][C:2]([CH:20]=[O:21])=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: c1ccsc1
Reactant: CC(C)(C)CCCl
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)CCc1ccc(C=O)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 18.5 %

Procedure:
To a solution of thiophene (300 mg, 3.57 mmol) in anhydrous 10% hexamethylphosphoramide in tetrahydrofuran (33 mL) under argon at −78° C. was added n-butyllithium (1.57 mL, 2.5 M in hexanes) dropwise. After stirring at −78° C. for 1 hour, 1-chloro-3,3-dimethylbutane (430 mg, 3.57 mmol) was added dropwise and the resulting solution allowed to warm to room temperature over 3 hours. The reaction mixture was re-cooled to −78° C., a second portion of n-butyllithium (1.78 mL, 4.46 mmol) was added dropwise over 5 minutes and the mixture was stirred for 1 hour at −78° C. before anhydrous dimethylformamide (1.38 mL, 17.8 mmol) was added dropwise and the resulting mixture allowed to warm to room temperature. The reaction mixture was poured into 1 N hydrochloric acid (150 mL) and organics were extracted with ether (3×100 mL), dried with magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel with gradient elution (5%→20% ethyl acetate in hexanes) to give 5-(3,3-dimethylbutyl)thiophene-2-carbaldehyde (130 mg, 19%). Used without further characterization.