Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[F:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+].Br[CH:29]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:30]([N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[O:31]>CC(OC)(C)C>[CH2:35]([N:32]([CH2:33][CH3:34])[C:30](=[O:31])[CH:29]([N:19]1[CH2:20][CH2:21][N:16]([C:8]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:7]=2[F:6])[CH2:17][CH2:18]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:36]
Reactant: CCN(CC)C(=O)C(Br)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 500 mL, round-bottomed flask under a positive pressure of nitrogen was equipped with a magnetic stirrer and charged with anhydrous DMF (100 mL), 1-(2-fluoro-4-nitro-phenyl)-piperazine (4.0 g, 17.8 mmol), anhydrous K2CO3 (4.9 g, 35.5 mmol) and 2-bromo-N,N-diethyl-2-phenyl-acetamide (6.2 g, 23.0 mmol). The pale yellow reaction mixture was stirred at ambient temperature for 4 h, following which the solvent was removed on the rotary evaporator to yield a yellow colored semi-solid. MTBE (250 mL) was added and the resulting suspension was stirred at ambient temperature for 0.5 h and then filtered. The filtrate was extracted with 1.5N HCl (1×200 mL, then 1×100 mL). The aqueous layers were pooled, cooled to ˜0° C. in an ice bath and then basified with 2N NaOH (to pH ca. 13). The basified reaction mixture was extracted with MTBE (4×125 mL). The organic layers were pooled, dried over anhydrous sodium sulfate, filtered and concentrated to yield a brown colored oil. The oil was purified by silica gel chromatography (solvent: EtOAc/Hexane) to yield the title compound as a reddish-brown oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:8]([CH3:18])[N:7]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[N:8]([CH3:18])[N:7]=[C:6]([CH2:4][OH:3])[CH:10]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cn1nc(CO)cc1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for example 1 a], 5-(4-chloro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester was reduced with lithium aluminium hydride to give [5-(4-chloro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanol as white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH:11][C:12]2[C:21]3[CH:20]=[CH:19][NH:18][C:17](=[O:22])[C:16]=3[C:15]3[CH:23]=[C:24](B4OC(C)(C)C(C)(C)O4)[CH:25]=[CH:26][C:14]=3[N:13]=2)=[C:6]([Cl:36])[CH:5]=1)(=[O:3])[CH3:2].Br[C:38]1[N:39]=[C:40]([C:43]([OH:46])([CH3:45])[CH3:44])[S:41][CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH:11][C:12]2[C:21]3[CH:20]=[CH:19][NH:18][C:17](=[O:22])[C:16]=3[C:15]3[CH:23]=[C:24]([C:38]4[N:39]=[C:40]([C:43]([OH:46])([CH3:45])[CH3:44])[S:41][CH:42]=4)[CH:25]=[CH:26][C:14]=3[N:13]=2)=[C:6]([Cl:36])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Cl)c(Nc2nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3c3c(=O)[nH]ccc23)c(Cl)c1
Reactant: CC(C)(O)c1nc(Br)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(Cl)c(Nc2nc3ccc(-c4csc(C(C)(C)O)n4)cc3c3c(=O)[nH]ccc23)c(Cl)c1
Temperature: 80 °C

Procedure:
To a solution of 5-[(4-acetyl-2,6-dichlorophenyl)amino]-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c]-2,6-naphthyridin-1(2H)-one (135 mg, 0.26 mmol) in THF (4 mL) was added 2-(4-bromo-1,3-thiazol-2-yl)propan-2-ol (114 mg, 0.52 mmol), Pd(Ph3P)4 (60 mg, 0.05 mmol) and sodium carbonate (0.129 mL, 0.26 mmol, 2M in water). The reaction was heated to 80° C. for 16 h. The reaction was diluted with ethyl acetate and extracted with water. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8](=[NH:20])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])N=1.CS(O)(=O)=O.[NH2:26]C1C=NC=CC=1>>[NH2:20][C:8]([NH:4][C:5]1[CH:7]=[N:26][CH:1]=[CH:2][CH:6]=1)=[N:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: Nc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)n2nc(C)cc2C)cc1
Agent: CS(=O)(=O)O
Product: Cc1ccc(S(=O)(=O)N=C(N)Nc2cccnc2)cc1

Procedure:
The compound of Example 24 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of 3-aminopyridine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 290.34; found mol. wt. (M+H) 291.1; 580.9 (Dimer)
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])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][C:27]1([CH3:33])[CH3:32]>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[C:27]([CH3:33])([CH3:32])[CH2:28]3)=[O:20])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN1CCNCC1(C)C
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN(C)C(C)(C)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1,2,2-trimethylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95 (br. s., 6H) 2.20 (s, 3H) 2.35 (s, 3H) 2.60 (t, J=5.05 Hz, 2H) 2.97-3.72 (m, 4H) 7.53 (dd, J=8.08, 1.52 Hz, 1H) 7.59 (d, J=1.01 Hz, 1H) 7.85 (d, J=8.08 Hz, 1H) 7.93 (d, J=7.33 Hz, 1H) 7.98 (s, 1H) 8.36 (d, J=8.59 Hz, 1H) 8.43 (br. s., 1H); ESI-MS m/z [M+H]+ 431.3.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34].C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C(C)C.[I-].[Na+]>[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:9][CH2:10][N:11]([CH2:21][CH2:22][CH2:23][N:24]3[C:28](=[O:29])[C:27]4=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]4[C:25]3=[O:34])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=C1c2ccccc2C(=O)N1CCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
A mixture of 1.8 g of 4-diphenylmethylpiperidine, 1.92 g of N-(3-bromopropyl)phthalimide, 3.0 g of sodium carbonate and 20 mg of sodium iodide in 70 ml of methyl isobutyl ketone was heated under reflux for 5 hours. At the end of this time, the mixture was cooled to room temperature and filtered. The filtrate was concentrated by evaporation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.0 g (yield 95%) of the title compound as crystals, melting at 104°-106° C.
Reaction SMILES: [OH:1][C:2]1[C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:25][C:5]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OCC3C=CC=CC=3)=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[C:31]([CH3:34])([CH3:33])[CH3:32].[H][H]>[Pd].C(O)(=O)C>[OH:1][C:2]1[C:3]([C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:4][C:5]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:25][C:26]=1[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(C(=O)N2CCCN(C(=O)OCc3ccccc3)CC2)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C(=O)N2CCCNCC2)cc(C(C)(C)C)c1O
Reaction time: 7 h

Procedure:
A mixture of 46.6 g (0.1 mol) of 1-(4-hydroxy-3,5-di-tert.-butylbenzoyl)-4-benzyloxycarbonylhomopiperazine (Example 1), 350 ml of glacial acetic acid and 2.3 g of palladium black is treated with hydrogen while stirring at 70°-80° C. for about 7 hours. The catalyst is then filtered off, and the solvent is removed by distillation under reduced pressure. The residue is dissolved in methylene chloride, and the solution is extracted by shaking with dilute sodium hydroxide solution and separated off. The organic phase is washed several times with water and then dried over anhydrous sodium sulfate. The residue left after the solvent has been removed in vacuo is recrystallized from acetonitrile with the addition of active charcoal.
Reaction SMILES: C([Mg]Cl)(C)C.[CH2:6]([O:8][C:9](=[O:14])[CH2:10][C:11]([OH:13])=O)[CH3:7].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]C(Cl)=O)=[CH:18][CH:17]=1.Cl>O1CCCC1>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:11](=[O:13])[CH2:10][C:9]([O:8][CH2:6][CH3:7])=[O:14])=[CH:18][CH:17]=1
Reactant: CCOC(=O)CC(=O)O
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)Cc1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
1 l (2 mol) of a 2M solution of isopropylmagnesium chloride in tetrahydrofuran is added dropwise to a solution of 125 g (0.95 mol) of malonic acid monoethyl ester in 1 l of tetrahydrofuran at 0° C. and the mixture is stirred at 20° C. for 1 hour. 146 g (0.63 mol) of 4-bromophenylacetyl chloride are then added dropwise at 20° C., and the reaction mixture is stirred at this temperature for 2 hours and brought to pH=3 with 1N hydrochloric acid. It is stirred overnight, the phases are separated, the aqueous phase is washed with diethyl ether, the combined organic phases are washed with water and aqueous sodium bicarbonate solution, the solvent is distilled off, the residue is dissolved in methylene chloride, the solution is dried with sodium sulphate and filtered over silica gel using methylene chloride and the solvent is removed on a rotary evaporator.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([Si](C)(C)C)#[CH:17].[OH-].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(NCC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:16]#[CH:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccc(OCc2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCNCC
Product: C#Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-benzyloxy iodobenzene (193 g, 0.625 mol), ethynyl-trimethyl-silane (75 g, 0.76 mol), Cul (2 g, 10.5 mmol) and Pd(PPh3)2Cl2 (1 g, 1.0 mmol) were added to diethylamine (880 mL) at 0° C. The reaction mixture was warmed to 25° C. and then stirred for 6 h. The reaction mixture was concentrated and partitioned in H2O/ethyl acetate (100 mL/100 mL). The reaction mixture was further extracted with ethyl acetate (300 mL×2). The combined organic layers were washed by water (300 mL), dried over MgSO4 and concentrated in vacuo. The crude product was dissolved in methanol (400 mL) and was stirred with KOH (28 g, 0.5 mol) for 1 h at 25° C. Concentration and purification by silica gel column chromatograph (5% ethyl acetate/Hexane) yielded 4-benzyloxy phenyl acetylene as liquid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:28])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)=O)C.[BH4-].[Na+]>O1CCCC1>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([CH2:4][OH:3])[N:7]=2)=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1nc(CO)cs1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 25 %

Procedure:
A solution of 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-4-carboxylic acid ethyl ester (prepared as in Example 1(B)(f), 200 mg, 0.45 mmol) in tetrahydrofuran (3 mL) at 25° C. was slowly treated with sodium borohydride (26.0 mg, 0.68 mmol). The reaction mixture was heated under reflux for 48 h. The reaction mixture was allowed to cool to 25° C. and then slowly quenched by the dropwise addition of water. The resulting reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-hydroxymethyl-thiazol-2-yl)-propionamide (44.9 mg, 25%) as a white solid: mp 88-90° C.; EI-HRMS m/e calcd for C18H20Cl2N2O2S (M+) 398.0623, found 398.0631.
Reaction SMILES: C([O:8][C:9]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:12]2[N:13]([CH2:25][O:26]S(C)(=O)=O)[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]=2[CH:10]=1)C1C=CC=CC=1>[Pd]>[C:21]([O:20][C:18]([CH:17]1[CH2:16][CH2:15][CH2:14][N:13]([CH2:25][OH:26])[C:12]2[C:31]3[C:36]([C:9]([OH:8])=[CH:10][C:11]1=2)=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)C1CCCN(COS(C)(=O)=O)c2c1cc(OCc1ccccc1)c1ccccc21
Agent: [Pd]
Product: CC(C)(C)OC(=O)C1CCCN(CO)c2c1cc(O)c1ccccc21

Procedure:
Following the general procedure detailed for 86, 84 (0.015 g, 0.035 mmol, 1 equiv) was treated with 10% Pd—C (0.001 g, 0.3 equiv) followed by aqueous HCO2NH4 (0.2 mL, 25% w/v, 23 equiv). Filtration and concentration gave 101 as an analytically pure colorless oil in quantitative yield (0.012 g, 0.012 g theoretical) which crystallized upon storage: mp 202-203° C.; 1H NMR 400 MHz, CDCl3) major rotamer δ 9.19 (s, 1H), 8.07-8.05 (m, 1H), 7.26-7.22 (m, 1H), 6.81-6.75 (m, 2H), 6.50 (s, 1H), 4.28-4.24 (m, 1H), 4.18-4.08 (m, 2H), 3.89-3.86 (m, 1H), 2.85-2.79 (m, 1H), 2.11-2.07 (m, 1H), 1.94-1.91 (m, 1H), 1.70-1.67 (m, 2H), 1.62 (s, 9H); 1H NMR 400 MHz, acetone-d6) major rotamer 9.03 (s, 1H), 8.26 (d, J=8.2 Hz, 1H), 8.07 (d, J=8.6 Hz, 1H), 7.55-7.51 (m, 1H), 7.46-7.43 (m, 1H), 6.74 (s, 1H), 4.37-4.33 (m, 1H), 4.03-3.99 (m, 1H), 3.91-3.80 (m, 1H), 3.61-3.52 (m, 2H), 2.73-2.66 (m, 1H), 2.36-2.32 (m, 1H), 2.20-2.10 (m, 1H), 1.60-1.55 (m, 1H), 1.33 (s, 9H); IR (film) νmax 3272, 2976, 2925, 1662, 1621, 1596 cm−1; FABHRMS (NBA-NaI) m/z 344.1855 (M+H+, C20H25NO4 requires 344.1862).
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:17])([CH3:16])[C@H:3]1[OH:18].[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[OH:18][C@H:3]1[C@H:2]([NH:1][C:26]([NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:27])[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=[CH:11][C:6]=2[O:5][C:4]1([CH3:16])[CH3:17]
Reactant: O=C=Nc1ccccc1
Reactant: CC1(C)Oc2ccc(C(F)(F)F)cc2[C@@H](N)[C@@H]1O
Solvent: CCO
Product: CC1(C)Oc2ccc(C(F)(F)F)cc2[C@@H](NC(=O)Nc2ccccc2)[C@@H]1O
Yield: 69.2 %

Procedure:
A suspension of (trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-trifluoromethyl-2H-1-benzopyran (0.5 g, 1.9 mmol) (prepared according to D. R. Buckle et al., J. Med. Chem., 1990, 33, p. 3028) in ethanol (5 ml) under argon was treated with phenylisocyanate (0.23 g, 1.9 mmol) and the reaction was heated at reflux temperature for 4 hours. The product precipitated out of the reaction. The reaction was then concentrated in vacuo and the residue was triturated with isopropyl ether and hexanes to give the title compound as a colorless solid (0.5 g), m.p. 174-175° C.: 1H NMR (CDCl3) δ 7.4 (s, 1 H), 7.32 (d, J=9.8 Hz, 1 H), 7.17 (m, 5 H), 7.0 (m, 1 H), 6.77 (d, J=8.2 Hz, 1 H), 5.22 (br d, 1H), 4.80 (br t, 1 H), 3.45 (d, J=9.4 Hz, 1 H), 1.37 (s, 3 H), 1.12 (s, 3 H); 13C NMR (CDCl3) 157.0, 156.5, 139.1, 137.3, 129.4, 126.5, 125.0, 124.7, 122.0, 121.7, 118.0, 79.6, 76.4, 51.4, 26.3, 18.2; IR (KBr) 1118.5, 1264.8, 1332.1, 1443.4, 1500.9, 1558.3, 1598.8, 1647.8, 2981.4, 3391.3 cm-1.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C[O:11][C:12]([C:14]1[O:18][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:16][C:15]=1[CH3:25])=O>C1(C)C=CC=CC=1.C1COCC1>[CH3:25][C:15]1[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:18][C:14]=1[CH2:12][OH:11]
Reactant: COC(=O)c1oc(-c2ccccc2)nc1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)oc1CO
Temperature: -78 °C
Reaction time: 8 h

Procedure:
19.0 mL of 1.0M DIBAL-H solution in toluene is added slowly to a solution of 1.63 g (7.5 mmol) of 4-methyl-2-phenyl-oxazole-5-carboxylic acid methyl ester (J. Chem. Soc., Chem. Comm. 1995, 22, 2335) in 30 mL of THF at −78° C. The cooling bath is removed, and the reaction mixture is stirred overnight. The reaction mixture is cooled to −78° C. and quenched with 9 mL of MeOH. The cooling bath is removed, and 9 mL of brine and 6.5 g of Na2SO4 are added, and the reaction mixture is stirred vigorously for 2 h, and then filtered off, and concentrated in vacuo to produce (4-methyl-2-phenyl-oxazol-5-yl)-methanol as a solid; 1H NMR (250 MHz, CDCl3) δ7.93-8.01 (m, 2H), 7.37-7.43 (m, 3H), 4.65 (s, 2H), 2.61 (br s, 1H), 2.18 (s, 3H).
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:17][C:16]=2[CH2:28][NH:29][CH3:30])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](Cl)(=[O:33])[CH3:32]>>[C:31]([N:8]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[CH:17][C:16]=2[CH2:28][NH:29][CH3:30])[CH2:11][CH2:10]1)[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](NCc2ccccc2)CC1
Product: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](N(Cc2ccccc2)C(C)=O)CC1

Procedure:
from trans-N-benzyl-4-(4-tert.butoxycarbonyl-methylaminomethylphenyl)cyclohexylamine and acetylchloride. Oil. Rf value: 0.66 (alumina, ethyl acetate/petroleum ether= 1:3, v:v).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([C:10]([O-:12])=O)=[CH:7][CH:6]=1)=[O:4].[K+].CN(C)C=O.S(Cl)([Cl:21])=O>ClCCCl>[Cl:21][C:10]([C:8]1[S:9][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1)=[O:12]
Reactant: COC(=O)c1ccc(C(=O)[O-])s1
Reactant: O=S(Cl)Cl
Agent: [K+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)Cl)s1
Temperature: 90 °C
Yield: 371.2 %

Procedure:
150 g (749 mmol) of dimethyl thiophene-2,5-dicarboxylate in 1350 mL of toluene was azeotropically distilled at 130° C. to evaporate 150 mL of it. The reaction solution was cooled to an inner temperature of 70° C., then stirred with 300 mL of 2.5 M potassium hydroxide/methanol for 40 minutes and cooled to room temperature, and the precipitated solid was washed with ethyl acetate by filtration and dried under reduced pressure to obtain 160 g of potassium 5-(methoxycarbonyl)-thiophene-2-carboxylate. 100 g (446 mmol) of potassium 5-(methoxycarbonyl)-thiophene-2-carboxylate in 700 mL of 1,2-dichloroethane was mixed with 1.73 mL of N,N-dimethylformamide and heated to 90° C., and 68.9 g (119 mmol) of thionyl chloride was added dropwise. The reaction solution was refluxed for 1 hour and then cooled to room temperature, and the resulting crystals were filtered off with 300 mL of 1,2-dichloroethane. The filtrate was concentrated to dryness to obtain 90.4 g (yield 99%) of methyl 5-(chlorocarbonyl)thiophene-2-carboxylate (TEC).
Reaction SMILES: O1CCCC1.[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])=[CH:20][CH:19]=1.[OH-].[Na+]>C(OCC)(=O)C>[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:29]2[CH2:30][CH2:31][CH:26]([C:24](=[O:25])[C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=3)[CH2:27][CH2:28]2)=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To tetrahydrofuran (120 mL) were added 4-bromobenzoyl chloride (25 g), (4-chlorophenyl)piperidin-4-ylmethanone hydrochloride (30 g) and 1N aqueous sodium hydroxide solution (250 mL), and the mixture was stirred at room temperature for 3 hr. Ethyl acetate was added for partitioning, the organic layer was washed with saturated brine, and the solvent was evaporated. The residue was recrystallized to give the title compound (46 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].[CH3:12][S:13]SC.Cl>CCCCCC.O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([S:13][CH3:12])[C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Cl)c(F)c1
Reactant: CSSC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1c(C(=O)O)ccc(Cl)c1F
Temperature: -40 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
n-Butylithium (2.5M in hexane, 180 ml) was added dropwise to a stirred, cooled solution of 4-chloro-3-fluorobenzoic acid (37.5 g) in tetrahydrofuran while maintaining the temperature below -40° C. The mixture was stirred at -40° C. for 3 hours. Dimethyl disulphide (60.5 g) in tetrahydrofuran was added dropwise and the mixture was stirred at -40° C. for half an hour and at room temperature overnight. Hydrochloric acid (2M) was added and the layers were separated. The aqueous layer was extracted with ether and the combined organic layers were extracted with aqueous sodium hydroxide (2M). The aqueous extract was acidified to pH1 and extracted with ether. washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with n-hexane and filtered to give 4-chloro-3-fluoro-2-(methylsulphenyl)benzoic acid (32.84 g) as a white solid m.p. 149.5°-150.50° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][C@@H:12]1[C:20]2[C:15](=[C:16]([C:21]3[S:25][C:24]([C:26]4[CH:27]=[CH:28][C:29]([O:34][CH:35]([CH3:37])[CH3:36])=[C:30]([CH:33]=4)[C:31]#[N:32])=[N:23][CH:22]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)(C(C)(C)C)(C)C.Cl>CCOCC>[OH:8][CH2:9][CH2:10][NH:11][C@@H:12]1[C:20]2[C:15](=[C:16]([C:21]3[S:25][C:24]([C:26]4[CH:27]=[CH:28][C:29]([O:34][CH:35]([CH3:37])[CH3:36])=[C:30]([CH:33]=4)[C:31]#[N:32])=[N:23][CH:22]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CC[C@@H]4NCCO[Si](C)(C)C(C)(C)C)s2)cc1C#N
Agent: Cl
Solvent: CCOCC
Product: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CC[C@@H]4NCCO)s2)cc1C#N
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.5 %

Procedure:
To a solution of (S)-5-(5-(1-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile (10 mg, 0.018 mmol) in ether (1 mL) was added 2N HCl in ether (0.1 mL). The mixture was stirred at room temperature for 12 h and solvent was evaporated. The crude material was purified by a preparative HPLC to afford 6 mg (80%) of (S)-5-(5-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile 92. LCMS-ESI (m/z) calculated for: C24H25N3O2S: 419.2; found 420.2 [M+H]+, tR=2.43 min.