Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].O[CH2:7][CH:8]1[CH2:13][O:12][CH2:11][CH:10]([CH3:14])[O:9]1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][S:2]([CH2:7][CH:8]1[CH2:13][O:12][CH2:11][CH:10]([CH3:14])[O:9]1)(=[O:4])=[O:3]
Reactant: CC1COCC(CO)O1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1COCC(CS(C)(=O)=O)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
13.7 ml of methanesulphonic acid chloride are added dropwise, over a period of approximately 30 minutes, while stirring at 0° to 5° C., to a solution of 21.1 g of 2-hydroxymethyl-6-methyl-1,4-dioxan, 15.2 g of pyridine and 0.6 g of 4-dimethylaminopyridine in 80 ml of dichloromethane. After stirring for a further 18 hours at room temperature, the reaction mixture is extracted repeatedly with 1N hydrochloric acid and then washed with water until neutral. After the organic phase, which has been separated off, has been dried over sodium sulphate and the solvent has been distilled off completely, the title compound of formula ##STR55## is obtained. The 1H-proton resonance spectrum corresponds to this structure; nD22 =1.4607.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4SC(C5C=CC=CC=5)=C[N:30]=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5].NC1C=CC([C:46]2[CH:54]=[C:53]3[C:49](C[N:51]([C@@H](C(C)C)C(OC)=O)[C:52]3=[O:55])=[CH:48][CH:47]=2)=CC=1.C1(C2OC(C(OCC)=O)=NN=2)C=CC=CC=1>>[CH3:1][CH:2]([CH3:38])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]([C:26]4[O:55][C:52]([C:53]5[CH:54]=[CH:46][CH:47]=[CH:48][CH:49]=5)=[N:51][N:30]=4)=[O:25])=[CH:21][CH:22]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: CCOC(=O)c1nnc(-c2ccccc2)o1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4nnc(-c5ccccc5)o4)cc3)cc2C1=O
Yield: 44 %

Procedure:
The compound of example 625 was prepared analogous to the compound of example 611 by reaction of compound of example 6 with commercially available ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (Enamine Ltd, Ukraine, Europe).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH2:12])=[O:11])#[CH:2].Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:27][CH:26]=2)[N:15]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cu]I>[NH2:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:18]1[C:19]([C:20]([F:21])([F:22])[F:23])=[CH:14][N:15]=[C:16]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:29][CH:30]=2)[N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reactant: C#Cc1ccccc1CC(N)=O
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3CC(N)=O)n2)cc1
Temperature: 120 °C
Yield: 74 %

Procedure:
To a nitrogen de-gassed solution of 2-(2-ethynylphenyl)acetamide (I39) (0.054 g, 0.788 mmol) and tert-butyl 2-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I37) in dry DMF (4 mL) were added triethylamine (0.159 mL, 1.138 mmol), triphenylphosphine (0.011 g, 0.043 mmol), trans-dichlorobis(triphenylphosphine) palladium(II) (0.020 g, 0.028 mmol) and CuI (0.008 g, 0.04 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes. The reaction was concentrated to dryness in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-5% methanol in EtOAc) to give the title compound (I40) (0.122 g, 74% yield) as a yellow glassy solid; 1H NMR (400 MHz, d6-DMSO) δ 10.48 (s, 1H), 8.82 (s, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.65-7.55 (m, 1H), 7.55-7.47 (m, 1H), 7.47-7.33 (m, 3H), 7.16 (d, J=8.5 Hz, 2H), 7.01 (s, 1H), 5.29-5.22 (m, 1H), 3.92 (d, J=13.1 Hz, 1H), 3.70 (s, 2H), 2.71 (t, J=13.3 Hz, 1H), 2.34-2.24 (m, 1H), 1.82-1.68 (m, 1H), 1.54 (d, J=11.3 Hz, 2H), 1.45-1.22 (m, 11H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]>C(O)(=O)C>[F:5][C:6]1[CH:13]=[C:12]([OH:14])[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(O)cc1F
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: N#Cc1cc([N+](=O)[O-])c(O)cc1F
Temperature: 40 °C
Yield: 30.2 %

Procedure:
Nitric acid (0.326 mL, 7.29 mmol) 70% was added dropwise to a stirred solution of 2-fluoro-4-hydroxybenzonitrile (1 g, 7.29 mmol) in acetic acid (20 mL). The resulting solution was warmed to 40° C. for 24 hr. Solvent removed under reduced pressure to afford a yellow solid. Recrystallisation from EtOH (˜15 mL) afforded 2-fluoro-4-hydroxy-5-nitrobenzonitrile (401 mg, 2.202 mmol, 30.2% yield) as a yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[C:9]2[S:21][CH:20]=[CH:19][C:10]=2[N:11]=[C:12]([C:14]([O:16][CH2:17]C)=[O:15])[N:13]=1)=[O:7]>CO.O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[C:9]2[S:21][CH:20]=[CH:19][C:10]=2[N:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[N:13]=1)=[O:7]
Reactant: CCOC(=O)c1nc(C(=O)c2cccs2)c2sccc2n1
Solvent: CO
Solvent: O
Product: COC(=O)c1nc(C(=O)c2cccs2)c2sccc2n1
Yield: 77.4 %

Procedure:
A solution of ethyl 4-(2-thienylcarbonyl)thieno[3,2-d]pyrimidine-2-carboxylate (100 mg, 0.31 mmol) in MeOH (5 mL) was refluxed for 2 h, cooled, diluted with water and filtered to give the title compound (73 mg, 74%) as a cream solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:9][C:10]1[C:15]([CH3:16])=[C:14]([O:17][CH3:18])[C:13]([F:19])=[CH:12][N:11]=1.FC(F)(F)C(O)=O.[NH2:27][C:28]1[C:29]2[C:30]3[C:31](=[N:43][NH:44][N:45]=2)[CH:32]=[C:33]([CH2:38][C:39]([NH:41][CH3:42])=[O:40])[C:34]=3[CH2:35][S:36][N:37]=1>CN(C)C=O>[NH2:27][C:28]1[C:29]2[C:30]3[C:31](=[N:43][N:44]([CH2:9][C:10]4[C:15]([CH3:16])=[C:14]([O:17][CH3:18])[C:13]([F:19])=[CH:12][N:11]=4)[N:45]=2)[CH:32]=[C:33]([CH2:38][C:39]([NH:41][CH3:42])=[O:40])[C:34]=3[CH2:35][S:36][N:37]=1
Reactant: COc1c(F)cnc(CCl)c1C
Reactant: CNC(=O)Cc1cc2n[nH]nc3c-2c1CSN=C3N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)Cc1cc2nn(Cc3ncc(F)c(OC)c3C)nc3c-2c1CSN=C3N
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 45.4 %

Procedure:
Potassium carbonate (85 mg) and 2-(chloromethyl)-5-fluoro-4-methoxy-3-methylpyridine hydrochloride (52 mg) were added to an N,N-dimethylformamide (5 ml) solution of 2-(4-amino-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl)-N-methylacetamide trifluoroacetate (60 mg). The resulting mixture was stirred at 50° C. for 3.5 hours. Thereafter, insoluble matter was removed by filtration, and the filtrate was then concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol), so as to obtain the title compound (30 mg) as a solid.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[F:6][CH:7]([F:17])[O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O.C(O)C>O>[F:6][CH:7]([F:17])[O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[N:2][OH:3]
Reactant: NO
Reactant: O=Cc1cccc(OC(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1cccc(OC(F)F)c1

Procedure:
A 2.0 g portion of hydroxylamine hydrochloride was dissolved in 12 ml of water and 8 ml of 5N sodium hydroxide was added. A 1.0 g portion of 3-(difluoromethoxy)benzaldehyde was added followed by enough ethanol to give a solution. After 10 minutes of reflux, the reaction mixture was concentrated in vacuo and the residue taken up in 10 ml of water. The pH was adjusted to 4 with hydrochloric acid, then the mixture was extracted with chloroform. The organic phase was dried over sodium sulfate and concentrated, giving the desired compound as an oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[C:53]([CH3:58])=[N:54][CH:55]=[CH:56][CH:57]=2)[C:47]1=[O:59])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[C:53]([CH3:58])=[N:54][CH:55]=[CH:56][CH:57]=2)[C:47]1=[O:59])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: Cc1ncccc1CN1CCN([C@H](C(=O)O)C(C)(C)C)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccnc2C)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.3 %

Procedure:
A solution containing the product from Example 2C (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 82A (0.025 g, 0.082 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.033 mL, 0.189 mmol) and the mixture was stirred at 25° C. for 16 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed brine, dried over MgSO4, filtered and concentrated to give the title compound (0.016 g, 52% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.83 (s, 9 H), 0.89 (s, 9 H), 1.26 (m, 2 H), 1.54 (m, 2 H), 2.32 (m, 1 H), 2.61 (m, 4 H), 2.81 (m, 2 H), 2.96 (q, J=8.95 Hz, 1 H), 3.21 (m, 1 H), 3.50 (s, 3 H), 3.66 (m, 1 H), 3.85 (d, J=9.93 Hz, 1 H), 4.08 (s, 1 H), 4.21 (m, 3 H), 4.42 (m, 1 H), 4.55 (d, J=7.72 Hz, 1 H), 6.65 (d, J=9.93 Hz, 1 H), 7.00 (m, 3 H), 7.10 (m, 2 H), 7.24 (m, 3 H), 7.31 (m, 1 H), 7.54 (m, 2 H), 7.87 (m, 5 H), 8.38 (dd, J=4.78, 1.47 Hz, 1 H), 8.64 (d, J=4.41 Hz, 1 H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18](O)=[O:19])=[CH:12]2>C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][C:18]([C:13]1[NH:14][C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([Cl:8])=[CH:17][CH:16]=2)=[O:19]
Reactant: COC(=O)CN
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
Glycine methyl ester hydrochloride (50 mmol) and 5-chloro-1H-indole-2-carboxylic acid (50 mmol) were coupled according to procedure A, substituting the following workup: the reaction mixture was stirred in ethyl acetate (250 mL), hexanes (50 mL) and 1N NaOH (50 mL) and the suspension was filtered. The solid was washed with 1N NaOH, 1N HCl, with water, ethyl acetate, and dried: Yield 11.5 g, 86%; mp 252-254° C. with decomposition;
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:4][C:5]3[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]4[CH2:20]CCC[CH2:16]4)[C:11](O)=[O:12])[C:7](=[O:21])[C:6]=3[O:22][C:23]=2[CH:24]=[CH:25][CH:26]=1.C(Cl)(=O)C(Cl)=O.[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1>C(Cl)Cl.O>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([NH:40][C:11](=[O:12])[C@@H:10]([N:8]2[CH2:9][C:5]3[CH2:4][C:3]4[C:2]([Cl:1])=[CH:26][CH:25]=[CH:24][C:23]=4[O:22][C:6]=3[C:7]2=[O:21])[CH2:14][CH:15]([CH3:16])[CH3:20])=[N:38][CH:39]=1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Reactant: Nc1ccc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1ccc(Cl)cn1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
A solution of (S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (200 mg, 2.1 mmol) (from Example 3, Step 1c), in methylene chloride (10 mL) was treated with oxalyl chloride (0.12 mL, 1.07 mmol) at 0° C. The mixture was warmed to 25° C. and stirred for additional 2 hours. Then, the reaction mixture was cooled to 0° C., and N,N′-diisopropylethyl amine (0.61 mL, 3.57 mmol) and commercially available 5-chloro-pyridin-2-ylamine (137 mg, 1.07 mmol), were added. The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradiant elution, afforded (S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (5-chloro-pyridin-2-yl)-amide (145 mg, 36.3%), as a white solid. 1H NMR (DMSO-d6) δ: 11.11 (s, 1H), 8.40 (d, J=2.4 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.90 (dd, J=8.8, 2.4 Hz, 1H), 7.21-7.38 (m, 2H), 7.09 (dd, J=7.1, 2.2 Hz, 1H), 5.06 (dd, J=10.5, 4.6 Hz, 1H), 4.42 (d, J=18.6 Hz, 1H), 4.07 (d, J=19.1 Hz, 1H), 3.75 (s, 2H), 1.77-1.89 (m, 1H), 1.61-1.73 (m, 1H), 1.46 (br. s., 1H), 0.93 (t, J=6.4 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:15][CH2:14][CH:13]2[C:9]1(O)[CH2:10][CH2:11][CH2:12]2.[CH3:19][O:20]C(CC)CCCCC1CCC2C1CC(O)C2.[I-].[Na+].CI>O1CCCC1>[CH3:19][O:20][CH:11]1[CH2:10][CH:9]2[CH:13]([CH2:14][CH2:15][CH:8]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:17][CH3:18])[CH2:12]1
Reactant: CCC(CCCCC1CCC2CCCC12O)OC
Reactant: CCC(CCCCC1CCC2CC(O)CC12)OC
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCC(CCCCC1CCC2CC(OC)CC12)OC
Temperature: 50 °C

Procedure:
The starting material, 2-(5-methoxyhept-1-yl)bicyclo[3.3.0]octanol {octahydro-4-(5-methoxyheptyl)-2-pentalenol} (1.0 g, 3.9 mmoles) is added to a reaction vessel containing sodium iodide (0.12 g, 4.9 mmoles) and tetrahydrofuran (12 ml). The solution is stirred while methyl iodide (0.84 g, 5.9 mmoles) is rapidly added. The reaction is heated in a 50° C. water bath for 4 hours. The water bath is removed and the reaction neutralized with the addition of water (5 ml). The organic phase is separated and the aqueous phase extracted with ether (2×50 ml). The ether extracts are combined and washed with brine (50 ml). The solution is dried over anhydrous magnesium sulfate and the solvent removed under vacuum leaving a clear yellow oil. The product is then kugelrohred under reduced pressure leaving a pale yellow oil (0.8 g, 3.1 mmoles).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[CH3:14][C:15]([OH:19])([C:17]#[CH:18])[CH3:16]>COCCOC.[Cu]I.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>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:18]#[C:17][C:15]([CH3:16])([OH:19])[CH3:14]
Reactant: C#CC(C)(C)O
Reactant: Brc1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CC(C)(O)C#Cc1nccs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Bromo-1,3-thiazole (6.0 g, 37 mmol) and CuI (1.3 g, 7.3 mmol) were combined in DME (150 mL) and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (25 mL, 180 mmol) and PdCl2(PPh3)2 (2.5 g, 3.7 mmol) were added and 2-methyl-3-butyne-2-ol (4.6 g, 55 mmol) was added dropwise. After stirring at ambient temperature for 16 h, GC/MS showed the reaction was not complete. The reaction was heated to reflux for 2 h. The mixture was filtered through Celite.™., the filter pad was washed thoroughly with ethyl acetate, and the combined filtrates were concentrated in vacuo. The residue was dissolved in ethyl acetate (600 mL), washed with water (600 mL), brine (600 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with hexane then 7:3 hexane:ethyl acetate to afford 4-(2-thiazolyl)-2-methyl-3-butyn-2-ol contaminated with 2,7-dimethyl-but-3,5-diyne-2,7-diol. (The dimer of 2-methyl-3-butyne-2-ol) The product was crystallized from boiling hexane to afford 2-methyl-4-(1,3-thiazol-2-yl)-3-butyn-2-ol (2.18 g, 36% yield) as off white crystals that were contaminated with a small amount of 2,7-dimethyl-but-3,5-diyne-2,7-diol. M.p. 69-70° C. 1H NMR (CDCl3, 300 MHz) Δ7.80 (d, J=3.0 Hz, 1H), 7.34 (d, J=3.0 Hz, 1H), 4.40 (s, 1H), 1.65 (s, 6H). MS (ESI) 168.1 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][C:21]=1[N+:29]([O-:31])=[O:30]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[S:28])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])=[CH:22][C:21]=1[N+:29]([O-:31])=[O:30]
Reactant: O=[N+]([O-])c1cc(N=C=S)ccc1Cl
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1ccc(Cl)c([N+](=O)[O-])c1
Yield: 70.9 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.973 g, 4.00 mmol) and 4-chloro-3-nitrophenyl isothiocyanate (0.859 g, 4.00 mmol) to afford the product (1.296 g); m.p. 174-175° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:9]([CH2:17][CH2:18][CH:19]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[CH:26][C:27]=1[Cl:28].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][N:32]([CH2:19][CH2:18][CH2:17][C:9]3[CH:10]=[C:11]([C:12]4[S:13][CH:14]=[CH:15][CH:16]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:31][CH2:30]2)[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: O=CCCc1cc(-c2cccs2)n(-c2ccccc2)n1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(N2CCN(CCCc3cc(-c4cccs4)n(-c4ccccc4)n3)CC2)cc1Cl

Procedure:
51 mg (68%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0,142 mmol), 1-(3,4-dichlorophenyl)piperazine (33 mg, 0.142 mmol), DIPEA (0.040 mL, 0.213 mmol) and NaBH(OAc)3 (90 mg, 0.573 mmol).
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32].[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>CN(C=O)C>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:33])=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1Cl)n1ccc2c3c(ccc21)OCCNC3
Reaction time: 0.17 h

Procedure:
DMF (1 mL) was added to a mixture of tert-butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 10.0 mg, 0.035 mmol) and 60% NaH (5.56 mg, 0.139 mmol). The reaction mixture was stirred for 10 minutes at room temperature before 2-chlorophenylsulfonyl chloride (11 mg, 0.052 mmol) was added all in one portion. After 30 minutes TFA (1 mL) was added and the mixture was stirred for 10 minutes and evaporated. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound as a white solid (9.6 mg) in the form of the trifluoroacetate salt. MS m/z 363 [M+H]+.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.[Cl:12][C:13]1[CH:26]=[CH:25][C:16]([CH:17]([NH2:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][CH:14]=1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:24][CH:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:16]1[CH:25]=[CH:26][C:13]([Cl:12])=[CH:14][CH:15]=1
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: Clc1nc2ccccc2[nH]1
Agent: Cl
Product: Clc1ccc(C(Nc2nc3ccccc3[nH]2)c2ccccc2)cc1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 4-chlorobenzhydrylamine HCl by Procedure A. The product was isolated by preparative LCMS to give the title compound as the free base (white solid, mp 180-184° C.). MS(ES+)m/z 334 ([M+1]+, 100). 1NMR (DMSO-d6) δ 6.18 (d, 1H), 6.80-6.90 (m, 2H), 7.08-7.14 (m, 2H), 7.20-7.40 (m, 9H), 7.66 (d, 1 H), 10.6 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH2:25].[CH2:26]([N:28]=[C:29]=[S:30])[CH3:27]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH:25][C:29]([NH:28][CH2:26][CH3:27])=[S:30]
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Reactant: CCN=C=S
Solvent: ClCCl
Product: CCNC(=S)NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and ethyl isothiocyanate (0.053 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.14 g, 60%): mp 88-91° C.; 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J=8 Hz, 1H), 7.41 (d, J=7.2 Hz, 2H), 7.26 (m, 2H), 6.50 (d, J=16 Hz, 1H), 6.35 (dd, J=16.0, 8.0 Hz, 1H), 6.0 (br s, 1H), 5.73 (br s, 1H), 4.80 (br s, 2H), 4.09 (m, 1H), 1.23 (m, 3H); ESIMS m/z 515.01 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.Cl.[CH:11]1([NH:16][C:17](=[O:20])[CH2:18][NH2:19])[CH2:15][CH2:14][CH2:13][CH2:12]1>>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:19][CH2:18][C:17]([NH:16][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:20])[CH:5]=[CH:4][CH:3]=1
Reactant: NCC(=O)NC1CCCC1
Reactant: O=Cc1cccc(Br)n1
Agent: Cl
Product: O=C(CNCc1cccc(Br)n1)NC1CCCC1

Procedure:
The title compound was prepared by using the procedure listed in Example 47, Step 7 with 6-bromopyridine-2-carbaldehyde (1.0 g, 5.38 mmol) and N-cyclopentylglycinamide hydrochloride (0.96 g, 5.38 mmol) as the starting materials.