Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16]C)=O)(C)C.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[Pb](SC#N)[S:30][C:31]#[N:32]>ClCCl>[C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([N:32]=[C:31]=[S:30])=[O:16])#[CH:5]
Reactant: COC(=O)Cc1ccccc1C#C[Si](C)(C)C
Reactant: N#CS[Pb]SC#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C#Cc1ccccc1CC(=O)N=C=S
Reaction time: 1 h

Procedure:
To acid 319 (0.34 g, 2.1 mmol) in dry dichloromethane (25 mL) was added oxalyl chloride (0.39 mL, 0.57 g, 4.5 mmol) and dry DMF (0.05 mL). The mixture was stirred for 1 h, then concentrated under reduced pressure. The residue was re-dissolved in toluene (40 mL) and lead thiocyanate (0.75 g, 2.3 mmol) was added. The resulting suspension was heated to reflux with vigorous stirring for 3 h, then cooled, filtered through celite, and concentrated to afford crude 317 which was used without further purification.
Reaction SMILES: C(O[C:4](=[O:20])[C:5](=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C(O)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4](=[O:20])[C:14]2[C:13](=[CH:18][CH:17]=[C:16]([I:19])[CH:15]=2)[NH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccc(I)cc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1c[nH]c2ccc(I)cc2c1=O
Temperature: 240 °C
Yield: 81.9 %

Procedure:
A mixture of 2-[(4-iodo-phenylamino)-methylene]-malonic acid diethyl ester (81 g, 0.21 mol) in diphenylether (60 mL) was refluxed at 240° C. for 14 h. After cooling, ethanol was added and the mixture was heated to reflux for 3 h. After cooling, the solid was collected by filtration, washed with hexane and dried to obtain 6-iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (59 g, 83%) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=2[CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34]O)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][O:13][C:10]3[CH:11]=[CH:12][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[C:8]([CH3:14])[CH:9]=3)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)CC1
Reactant: Cc1cc(O)ccc1-c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 4-phenyl-3-methyl-phenol (1 eq), 4-(4-hydroxymethyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (1 eq) and PPh3 (1.5 eq) in dry THF (3 mL) is added 1,1′-(azodicarbonyl)-dipipperidine (1.5 eq) in THF (1 mL). The mixture is stirred at room temperature for 12 hours. After concentration, the residue is purified by silica gel chromatography (10% EtOAc in hexanes) to give 4-[4-(4-phenyl-3-methyl-phenoxymethyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([NH:4][C@:5]1([C@@H:23]([CH2:25][CH3:26])[CH3:24])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11](O)=[O:12])[C:6]1=[O:22])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:60][O:61][C:62]1[CH:91]=[CH:90][C:65]([CH2:66][N:67]2[C@@H:76]([C@@H:77]([OH:89])[C@@H:78]([NH2:88])[CH2:79][C:80]3[CH:85]=[C:84]([F:86])[CH:83]=[C:82]([F:87])[CH:81]=3)[CH2:75][C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[CH2:68]2)=[CH:64][CH:63]=1>ClCCl>[CH3:60][O:61][C:62]1[CH:63]=[CH:64][C:65]([CH2:66][N:67]2[C@@H:76]([C@@H:77]([OH:89])[C@@H:78]([NH:88][C:11](=[O:12])[C@@H:10]([N:7]3[CH2:8][CH2:9][C@:5]([NH:4][C:1](=[O:3])[CH3:2])([C@@H:23]([CH2:25][CH3:26])[CH3:24])[C:6]3=[O:22])[CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:79][C:80]3[CH:85]=[C:84]([F:86])[CH:83]=[C:82]([F:87])[CH:81]=3)[CH2:75][C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[CH2:68]2)=[CH:90][CH:91]=1
Reactant: COc1ccc(CN2Cc3ccccc3C[C@@H]2[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)cc1
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)O)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2Cc3ccccc3CN2Cc2ccc(OC)cc2)C1=O
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-4-phenylbutanoic acid (Preparation B, 25 mg, 0.069 mmol) in dichloromethane (1 mL) was added Hunig's base (27 mg, 0.21 mmol) to make a clear solution and HATU (34 mg, 0.090 mmol) was then added. After stirring for 1 h, to the reaction mixture was added (1S,2S)-1-((R)-2-(4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)-2-amino-3-(3,5-difluorophenyl)propan-1-ol (Preparation A, 33.5 mg, 0.076 mmol) and the reaction mixture was stirred at rt overnight. Solvent was removed and the crude mixture was purified by silica gel Flash Chromatography to give 50 mg of the title compound: 1H NMR (CD3OD, 500 MHz) δ 0.68 (3H, d, J=5 Hz), 0.94-1.08 (4H, m), 1.61-1.66 (2H, m), 1.94 (3H, s), 2.01-2.20 (4H, m), 2.46 (1H, m), 2.60-2.69 (2H, m), 2.76-2.94 (2H, m), 3.00 (1H, m), 3.07 (1H, dd, J=5, 15 Hz), 3.22 (1H, m), 3.46 (1H, dt, J=5, 10 Hz), 3.62-3.69 (3H, m), 3.74 (3H, s), 3.82 (1H, m), 4.02 (1H, d, J=15 Hz), 4.14 (1H, dd, J=5, 10 Hz), 4.72 (1H, m), 6.70 (1H, m), 6.81 (2H, d, J=10 Hz), 6.87 (2H, d, J=10 Hz), 6.96 (1H, d, J=5 Hz), 7.08-7.13 (6H, m), 7.17-7.20 (2H, m), 7.24 (2H, d, J=5 Hz). MS (ESI)(M+H)+ 781.39.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:18]([CH3:19])=[N:17][N:16]([CH3:20])[C:10]=2[N:11]=[C:12](S)[CH2:13][N:14]=1.O1CCCC1.[CH2:26]([NH2:29])[C:27]#[CH:28]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:18]([CH3:19])=[N:17][N:16]([CH3:20])[C:10]=2[N:11]=[C:12]([NH:29][CH2:26][C:27]#[CH:28])[CH2:13][N:14]=1
Reactant: C#CCN
Reactant: Cc1nn(C)c2c1C(c1ccccc1Cl)=NCC(S)=N2
Solvent: CO
Solvent: C1CCOC1
Product: C#CCNC1=Nc2c(c(C)nn2C)C(c2ccccc2Cl)=NC1

Procedure:
A mixture of 4.65 g. of 4-(2-chlorophenyl)-1,6-dihydro-1,3-dimethylpyrazolo[3,4-e][1,4]diazepine-7-thiol (prepared as disclosed in U.S. Pat. No. 3,770,762), 250 ml. of tetrahydrofuran, 3.0 g. of 2-propynylamine and 20 ml. of methanol is allowed to stand at room temperature (20°-30° C.) for 3 days, then evaporated at reduced pressure to give a residue of 4-(2-chlorophenyl-1,6-dihydro-1,3-dimethyl-7-(2-propynylamino)pyrazolo[3,4-e][1,4]diazepine; m.p. 165°-167° C. after crystallization from acetonitrile. For further purification, the product is dissolved in 9:1 tolueneacetonitrile and chromatographed on a column of neutral alumina. The column is eluted with 9:1 methanol-acetonitrile and the eluate is evaporated at reduced pressure to give a residue of m.p. 176°-178° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)=[C:4]([NH:18][C:19]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:20])[CH:3]=1.[CH3:27][NH2:28].C1COCC1>>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([NH:28][CH3:27])=[O:11])=[C:4]([NH:18][C:19]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:20])[CH:3]=1
Reactant: O=C(Nc1nccs1)Nc1cc(F)ccc1Oc1ccccc1C(=O)O
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1Oc1ccc(F)cc1NC(=O)Nc1nccs1

Procedure:
2-[4-Fluoro-2-(3-thiazol-2-yl-ureido)-phenoxy]-N-methyl-benzamide was prepared from 2-[4-fluoro-2-(3-thiazol-2-yl-ureido)-phenoxy]-benzoic acid and 1N solution of methyl amine in THF (0.5 mL, 0.5 mmol) following the general procedure K.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]([CH3:22])([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[O:12][C:13]([CH3:22])([CH3:21])[C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCN)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-[3-(3-phthalimidopropyl)phenoxy]-2-methylpropionate (1.87 g, 4.41 mmol) was dissolved in ethanol (10.0 mL) Subsequently, hydrazine monohydrate (184 mg, 5.74 mmol) was added dropwise, and the mixture was stirred overnight at 80° C. Thereafter, the temperature of the mixture was returned to room temperature, and the mixture was subjected to filtration. The resultant filtrate was subjected to drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol (saturated with ammonia)=20/1), whereby the target compound was obtained (560 mg, 43%).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:7][S:8](=[S:11])([O-:10])=[O:9].[Na+].O>CN(C=O)C>[CH3:7][S:8](=[S:11])([O:10][CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5])=[O:9]
Reactant: CS(=O)([O-])=S
Reactant: CC(C)CCBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCOS(C)(=O)=S
Temperature: 50 °C
Yield: 69.9 %

Procedure:
The reaction mixture of 1-bromo-3-methylbutane (1.7520 g, 0.0116 mol) and sodium methanethiosulfonate (1.554 g, 0.0116 mol) in dry DMF (5 mL) was heated at 50° C. for 2 hr. At room temperature, water (15 mL) was added and the mixture was extracted with ether (3×30 mL). The combined extracts were washed with brine, dried, concentrated. The residue was subjected to flash column chromatography on silica gel with EtOAc-hexanes (1:4). The product was obtained as a colorless liquid (1.4777 g, 70%). IR (film): 3030 (w), 3011 (w), 2958 (st), 2932 (st), 2873 (st), 1468 (m), 1410 (w), 1388 (w), 1367 (w), 1319 (st), 1136 (st), 955 (st), 748 cm−1 (st); 1H NMR (200 MHz, CDCl3): δ 3.33 (s, 3H, CH3SO2S); 3.19 (t, J=7.1 Hz, 2H, SCH2CH2), 1.70-1.58 (m, 3H, SCH2CH2CHMe2), 0.95 (d, J=5.3 Hz, 6H, CHMe2); 13C NMR (50 MHz, CDCl3): δ 50.60, 38.19, 34.59, 27.40, 22.06.
Reaction SMILES: O1CCCC1.COP([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(OC)=O.[H-].[Na+].[CH:22]([C:26]1[CH2:27][C@@H:28]2[C@H:31]([CH:32]=1)[C:30](=O)[CH2:29]2)([CH2:24][CH3:25])[CH3:23]>O>[CH:22]([C:26]1[CH2:32][C@@H:31]2[C@H:28]([CH:27]=1)[C:29](=[CH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:30]2)([CH2:24][CH3:25])[CH3:23]
Reactant: CCC(C)C1=C[C@@H]2C(=O)C[C@@H]2C1
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)C1=C[C@@H]2C(=CC(=O)OC(C)(C)C)C[C@@H]2C1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A tetrahydrofuran (15 mL) solution of tert-butyl dimethylphosphonoacetate (3.70 g, 16.5 mmol) was added dropwise at 0° C. over 20 minutes to a tetrahydrofuran (15 mL) suspension of sodium hydride (0.68 g, 63%, 18.0 mmol), and the mixture was stirred at 0° C. for 20 minutes. To this solution, a tetrahydrofuran (15 mL) solution of (±)-(1S,5R)-3-sec-butylbicyclo[3.2.0]hept-3-en-6-one (2.48 g, 15.1 mmol) was added dropwise at 0° C. over 15 minutes, and the mixture was stirred at room temperature for 2 hours. The mixture was treated with water, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a yellow oil substance (3.10 g, 78%).
Reaction SMILES: C1(COC2C(C3N(CC4C=CC(CCC(O)=O)=CC=4)C4C=C(F)C(F)=CC=4N=3)=CC=CN=2)CC1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:46]([CH2:47][CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)[C:45]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:44]=3[N:43]=2)=[C:38]([O:60][CH2:61]C2C=CC=CC=2Cl)[CH:37]=1.[CH3:69][O:70][C:71](=[O:82])[CH2:72][CH2:73]C1C=CC(CBr)=CC=1>>[CH3:69][O:70][C:71](=[O:82])[CH2:72][CH2:73][C:51]1[CH:52]=[CH:53][C:48]([CH2:47][N:46]2[C:45]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:44]=3[N:43]=[C:42]2[C:39]2[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][C:38]=2[O:60][CH3:61])=[CH:49][CH:50]=1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3OCc3ccccc3Cl)n(CC3CCCCC3)c2cc1F
Reactant: COC(=O)CCc1ccc(CBr)cc1
Agent: O=C(O)CCc1ccc(Cn2c(-c3cccnc3OCC3CC3)nc3cc(F)c(F)cc32)cc1
Product: COC(=O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OC)nc3cc(F)c(F)cc32)cc1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and 3-(4-bromomethyl-phenyl)-propionic acid methyl ester (CAS Reg. No. 56607-18-2). Brown sticky solid (75%). MS (Turbo Spray): m/z=471.0 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=3)[C:8]=2[CH2:7][CH2:6][N:5]1[C:19](=[O:21])[CH3:20].CN(C=[O:26])C>>[C:19]([N:5]1[CH2:6][C:7]2[C:8](=[O:26])[C:9]3[CH:10]=[C:11]([O:17][CH3:18])[CH:12]=[CH:13][C:14]=3[NH:15][C:16]=2[CH:4]1[CH3:3])(=[O:21])[CH3:20]
Reactant: CN(C)C=O
Reactant: COc1ccc2[nH]c3c(c2c1)CCN(C(C)=O)C3C
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2[nH]c3c(c(=O)c2c1)CN(C(C)=O)C3C
Reaction time: 48 h
Yield: 45 %

Procedure:
NaH (1.2 eq; 60% suspension in oil) is added to a solution of 1-methyl-2-acetyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline (1.56 g; 6.0 mmol) in DMF (20 ml). The mixture is stirred under an oxygen atmosphere for 48 hours, further NaH (1.1 eq) is then added and stirring is continued overnight. The DMF is then distilled off under reduced pressure. The crude product is taken up in water and then filtered. Saturated NH4Cl solution is added to the aqueous phase. The mixture is stirred for 30 minutes. The precipitate is filtered off and then washed successively with water, an MeOH/CH2Cl mixture (10/90), acetone and then ethyl acetate. After drying, 2-acetyl-7-methoxy-3-methyl-9-oxo-1,3,4,9-tetrahydropyrrolo[3,4-b]quinoline is obtained (yield=45%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([CH3:17])[S:8][C:6]=2[N:7]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>ClCCl.C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][N:21]([C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)=[O:34])[CH2:22][CH2:23]2)[C:5]2[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:9]([CH3:17])[S:8][C:6]=2[N:7]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: Cc1sc2nc(N)nc(N3CCNCC3)c2c1-c1ccccc1
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc(NC(=O)N2CCN(c3nc(N)nc4sc(C)c(-c5ccccc5)c34)CC2)cc1
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a solution of Example 11 (50 mg, 0.16 mmol) in dichloromethane (2 mL) and acetonitrile (1 mL) was added 4-methoxyphenyl isocyanate (22 μL, 0.17 mmol). The reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo and the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 1% to 2% methanol in dichloromethane), yielding the title compound (49 mg) as a white powder. 13C NMR δ (75 MHz, acetone-d6) 169.83, 161.99, 159.36, 155.05, 154.65, 135.58, 133.58, 130.55, 130.10 (2C), 127.84 (2C), 127.00, 126.13, 121.29 (2C), 113.26 (2C), 110.65, 64.94, 54.72 (2C), 49.33 (2C), 13.54. MS (m/z) 475 [M+H]+.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6]CC.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(#N)C1C=CC=CC=1>>[C:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[C:16][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C#Cc1ccccc1
Reactant: C#CCCCCCC
Solvent: N#Cc1ccccc1
Product: CCCCCCC#Cc1ccccc1
Reaction time: 18 h
Yield: 80 %

Procedure:
The procedure was identical to Example 1, with the exception that 1-octyne (0.590 ml; 0.441 g; 4.00 mmol) was used as a substrate instead of phenylacetylene. GC analysis of the organic phase of the hydrolyzed reaction sample after 18 h at 65° C. showed the presence of 1.59 mmol (80% yield) of 1-octynylbenzene, and 0.03 mmol of benzonitrile remaining in the reaction mixture.
Reaction SMILES: C([N:8]([C@H:16]([C@@H:24]([OH:30])[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)CC1C=CC=CC=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.O.[C].[Pd]>[NH2:8][C@H:16]([C@@H:24]([OH:30])[CH2:25][CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)CC[C@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC(C)CC[C@H](O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.6 %

Procedure:
2(S)-(N,N-Dibenzylamino)-1-phenyl-3(S)-hydroxy- 6-methylheptane (25 g) was dissolved in methanol (250 ml), and 10% palladium-carbon (1.25 g) suspended in water (10 ml) was added thereto. Then, ammonium formate (15.70 g) was added thereto, and the mixture was stirred at ambient temperature for 5 hours, followed by concentration under reduced pressure. The residue was dissolved in methylene chloride and washed with water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 14.0 g of 2(S)-amino-1-phenyl-3(S)-hydroxy-6-methylheptane.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:18][C:19]1[CH:38]=[CH:37][C:22]([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][N:32]=[CH:31]3)=[O:27])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[N:33]([C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][C:3]=2[C:1]#[N:2])[N:32]=[CH:31]3)=[O:27])=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(-n2ncc3cc(C(=O)NCCc4ccc(Cl)cc4)ccc32)c(C#N)c1
Temperature: 90 °C
Yield: 22 %

Procedure:
To a stirred solution of tert-butyl 2-(3-cyano-4-fluorophenyl)acetate (110 mg, 0.468 mmol) and N-(4-chlorophenethyl)-1H-indazole-5-carboxamide (168 mg, 0.561 mmol) in DMSO (2 ml) was added K2CO3 (77.5 mg, 0.561 mmol). The reaction was heated to 90° C. overnight via an oil bath. The reaction was diluted with EtOAc and 10% aqueous sodium carbonate. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with brine, dried over MgSO4, and concentrated. The crude product was purified over silica gel on a Biotage Horizon high-performance FLASH chromatography system (25+M silica gel cartridge) eluting with a gradient of 5% ethyl acetate/hexanes to 70% ethyl acetate/hexanes to provide tert-butyl 2-(4-(5-((4-chlorophenethyl)carbamoyl)-1H-indazol-1-yl)-3-cyanophenyl)acetate (0.241 g, 0.103 mmol, 22%).
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1.[Cl:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[Cl:12][CH2:13][CH2:14][CH2:15][C:16]([C:2]1[S:1][C:5]2[C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1)=[O:17]
Reactant: O=C(Cl)CCCCl
Reactant: O=C1NCCCc2ccsc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(CCCCl)c1cc2c(s1)C(=O)NCCC2
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
To a solution of 2 g of 4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one and 2.5 g of 4-chlorobutyryl chloride in 25 ml of dichloromethane was added 4.8 g of aluminum chloride under cooling. The mixture was stirred for 30 minutes, refluxed under heating and poured into water, and then extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated. The residue was crystallized from ethyl acetate-isopropyl ether to give 1.2 g of 2-(4-chlorobutyryl)-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one as white crystals, m.p. 163°-165° C.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7](Cl)=[O:8])[CH:2]=1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[C:11]1([O:17][C:7](=[O:8])[C:3]2[CH:4]=[CH:5][CH:6]=[C:1]([CH3:10])[CH:2]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C(=O)Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 23.19 g (0.15 mol) of m-toluoyl chloride in 70 mL of methylene chloride was added dropwise to a solution containing 14.12 g (0.15 mol) of phenol and 16.7 g (0.165 mol) of triethylamine in 70 mL of methylene chloride at ice bath temperature. A precipitate formed upon addition. The reaction mixture was stirred overnight at room temperature and was then filtered. The filtrate was washed successively by water (100 mL) and then by brine (75 mL) The organic layer was removed and dried over magnesium sulfate, filtered and evaporated in a rotary evaporator. The clear liquid product amounted to 29.91 g.
Reaction SMILES: [H-].[Na+].C(O[C:6](=O)[CH2:7][C:8]([O:10][C:11]([CH3:14])(C)C)=[O:9])C.ClC1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1>C1COCC1.CCOC(C)=O>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][C:6]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1)[CH3:14]
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.9 %

Procedure:
To a suspension of NaH (60% dispersion, 0.900 g, 22.5 mmol) in 40 mL of THF was added malonic acid tert-butyl ester ethyl ester (4.00 mL, 21.1 mmol) and the mixture stirred for 15 min at RT. To this mixture was then added 2-chloro-5-nitro-pyridine (2.56 g, 16.0 mmol) and the reaction stirred for 10 h at RT. The mixture was diluted with 100 mL of EtOAc and washed with NH4Cl (2×100 mL) and brine (100 mL) and dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in DCM (20 mL), TFA (10 mL) was added and the mixture stirred for 2 h at RT. The mixture was concentrated, the residue dissolved in 100 mL of EtOAc and washed with NaHCO3 (2×100 mL) and brine (100 mL) and again dried over Na2SO4 and concentrated in vacuo. The title compound was purified by flash chromatography eluting with 30% EtOAc/hexanes to give 2.35 g (70%) of a light yellow solid. 1H-NMR (CDCl3, 400 MHz): δ 9.38 (d, J=2.6 Hz, 1H), 8.46 (dd, J=8.6, 2.6 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 3.99 (s, 2H), 1.28 (t, J=7.1 Hz, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]([F:36])([F:35])[CH:30]([OH:34])[C:31](O)=[O:32]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:31](=[O:32])[CH:30]([OH:34])[C:29]([F:36])([F:35])[F:28])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: O=C(O)C(O)C(F)(F)F
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)C(O)C(F)(F)F)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F2) and rac-3,3,3-trifluoro-2-hydroxy-propionic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=405.4 [M+H]+.