Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=2[O:7][N:6]=1.[C:15]([N:19]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:18])[CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[ClH:1].[F:14][C:12]1[CH:11]=[CH:10][C:9]2[C:5]([CH2:4][CH2:3][CH2:2][N:29]3[CH2:28][CH2:27][CH:26]([N:19]([C:15](=[O:18])[CH2:16][CH3:17])[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:31][CH2:30]3)=[N:6][O:7][C:8]=2[CH:13]=1
Reactant: CCC(=O)N(c1ccccc1)C1CCNCC1
Reactant: Fc1ccc2c(CCCCl)noc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(=O)N(c1ccccc1)C1CCN(CCCc2noc3cc(F)ccc23)CC1
Product: Cl
Yield: 52.1 %

Procedure:
A mixture of 9.8 g of 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole, 10 g of 4-(N-propionylanilino)piperidine, 7.1 g potassium carbonate, and a few crystals potassium iodide in 125 ml of dimethylformamide was stirred at 75° C. for three hrs. The reaction mixture was cooled, filtered and concentrated to an oil. The oil was stirred with water and extracted with ether. The organic extracts were washed with water (2×), saturated sodium chloride solution and dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was treated with ethereal hydrogen chloride to give 10 g (55%) of product, mp 155°-160° C.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][C:4](=O)[CH3:5].[N:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[NH:14][NH2:15]>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:5])[N:14]([C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:8]=2)[N:15]=1
Reactant: CC(=O)CC(C)=O
Reactant: NNc1ncccn1
Solvent: CC(=O)O
Product: Cc1cc(C)n(-c2ncccn2)n1
Reaction time: 69 h
Yield: 97.5 %

Procedure:
Dissolve 2,4-pentanedione (0.81 mL, 7.85 mmol) and pyrimidin-2-yl-hydrazine (1.037 g, 9.42 mmol) in acetic acid (10 mL). Stir the mixture for 69 hr. at room temperature then concentrate. Dilute the residue with saturated aqueous sodium bicarbonate, extract 3 times with DCM, dry (sodium sulfate), filter and concentrate to give 2-(3,5-dimethylpyrazol-1-yl)-pyrimidine as a white solid (1.333 g, 97%). MS (ES): m/z=175 [M+H]+.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][NH:31][CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:20][CH2:19]1)[C:12]#[N:13].C=O.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:19][CH2:20][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][N:31]([CH3:2])[CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:22][CH2:23]1)[C:12]#[N:13].[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CNCC2
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CN(C)CC2
Temperature: 23 °C
Reaction time: 2 h

Procedure:
To a solution of 3-fluoro-4-((1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrile TFA salt (20.7 mg, 0.039 mmol) and formaldehyde (3.2 μL, 0.043 mmol) in MeOH (0.5 mL) was added DIPEA (0.014 mL, 0.079 mmol) and sodium triacetoxyborohydride (16.7 mg, 0.079 mmol) at 23° C. The mixture was stirred at 23° C. for 2 hr and then concentrated via rotary evaporation. The crude material was diluted with DMSO, filtered, rinsed with DMSO, and purified by with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used, using a 30% to 40% ACN gradient to give the title compound as a TFA salt (5.3 mg, 25%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.16-1.24 (m, 6H), 1.87-1.96 (m, 2H), 2.08-2.16 (m, 2H), 2.74-2.85 (m, 0.9H), 2.85-2.92 (m, 1.1H), 2.95 (br s, 1.3H), 2.96 br s, 1.7H), 2.97-3.00 (m, 1H), 3.25-3.42 (m, 3H), 3.65-3.71 (m, 1H), 4.12-4.19 (m, 2H), 4.25-4.31 (m, 1H), 4.82-4.88 (m, 1H), 5.89 (d, J=8.3 Hz, 1H), 7.50 (t, J=8.6 Hz, 1H), 7.66-7.71 (m, 1H), 7.87 (dd, J=11.4, 2.0 Hz, 1H), 9.96 (br s, 1H); ESI-MS m/z [M+H]+ 425.5.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:10]#[N:11])[S:8][CH:9]=1)=O.[OH:12][CH2:13][C:14]([NH:17][C:18]([NH2:20])=[S:19])([CH3:16])[CH3:15]>C(O)C>[ClH:1].[OH:12][CH2:13][C:14]([NH:17][C:18]1[S:19][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([C:10]#[N:11])[S:8][CH:9]=2)[N:20]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(CO)NC(N)=S
Reactant: N#Cc1cc(C(=O)CCl)cs1
Solvent: CCO
Product: CC(C)(CO)Nc1nc(-c2csc(C#N)c2)cs1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
A mixture of 4-(chloroacetyl)thiophene-2-carbonitrile (500.5 mg, 2.73 mmol), prepared in step 1 of Example 59, and N-(2-hydroxy-1,1-dimethylethyl)thiourea (399.4 mg, 2.69 mmol), prepared in step 2 of Example 52, in 20 mL of ethanol was stirred under nitrogen at room temperature overnight. The solid was collected by filtration and dried under reduced pressure to give 4-{2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}thiophene-2-carbonitrile hydrochloride (738.1 mg, 86%) as a light tan solid, mp 197-201° C.; MS (ES) m/z 277.9 [M−H]−.
Reaction SMILES: [CH2:1]([S:5][CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]#[CH:4].[C:10]([C:14]1([CH2:18]O)[CH2:17][O:16][CH2:15]1)([CH3:13])([CH3:12])[CH3:11].C(C12COC(C(SCCC#C)C)(OC1)OC2)CCC>>[C:10]([C:14]12[CH2:15][O:16][C:7]([CH2:6][S:5][CH2:1][CH2:2][C:3]#[CH:4])([O:9][CH2:18]1)[O:8][CH2:17]2)([CH3:13])([CH3:12])[CH3:11]
Reactant: C#CCCSCC(=O)O
Reactant: CC(C)(C)C1(CO)COC1
Agent: C#CCCSC(C)C12OCC(CCCC)(CO1)CO2
Product: C#CCCSCC12OCC(C(C)(C)C)(CO1)CO2

Procedure:
4-t-Butyl-1-(but-3-ynylthiomethyl)-2,6,7-trioxabicyclo[2.2.2]octane was prepared from 2-(but-3-ynylthio)acetic acid and 3-t-butyl-3-hydroxymethyloxetane using the methodology described in Example I. A small amount of 4-butyl-1-[1-(but-3-yn-1-ylthio)ethyl]-2,6,7-trioxabicyclo[2.2.2]octane was also present.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12](Cl)[CH:13]=1)[C:8]([OH:10])=[O:9].Cl>CN1C(=O)N(C)CCC1>[Cl:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:2][CH3:1])[CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: C[O-]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: COc1cc(Cl)cc(C(=O)O)c1
Temperature: 170 °C

Procedure:
Sodium methoxide (25% wt., 7 ml) was added to a stirred solution of 3,5-dichlorobenzoic acid (2 g) in DMPU (10 ml) and heated at 170° C. for 5 days. The reaction was poured onto 1M HCl (50 ml). The resulting solid formed was filtered and washed with water, then dried in vacuo to give the subtitle compound (0.8 g).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:38][CH3:39])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]4([OH:36])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[C:24]([CH3:37])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:40])=[CH:9][CH:8]=1>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:41])=[O:4])=[CH:8][CH:9]=2)=[C:14]([CH3:40])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]2([OH:36])[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[C:24]([CH3:37])[CH:23]=1)[CH2:38][CH3:39])[CH3:21]
Reactant: CCC(CC)(c1ccc(/C=C/C2(O)CCOCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCOCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.157 mL, 0.157 mmol) was added to a solution of [4′-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-pyran-4-yl)-vinyl]-3-methyl-phenyl}-propyl)-2′-methyl-biphenyl-4-yl]-acetic acid methyl ester (Example 131-(4); 27.6 mg, 0.052 mmol) in methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred at room temperature overnight. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:methanol=5:1) to give the target compound as a colorless oil (24.4 mg, 92%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][C:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])[CH2:22][C:23](O)=[O:24]>>[CH2:12]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:19])[N:2]([NH:1][C:23](=[O:24])[CH2:22][C:21]([CH3:20])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[N:11]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nn1nc(Cc2ccccc2)c2ccccc2c1=O
Reactant: CC(C)(CC(=O)O)c1ccccc1
Product: CC(C)(CC(=O)Nn1nc(Cc2ccccc2)c2ccccc2c1=O)c1ccccc1

Procedure:
The product of Example 139A and 3-methyl-3-phenylbutanoic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.31 (s, 1H), 8.31 (dd, J=7.8, 1.4 Hz, 1H), 7.96-8.01 (m, 1H), 7.90 (ddd, J=8.0, 7.2, 1.5 Hz, 1H), 7.85 (ddd, J=7.8, 7.2, 1.4 Hz, 1H), 7.44-7.47 (m, 2H), 7.25-7.35 (m, 6H), 7.17-7.23 (m, 2H), 4.30-4.30 (bs, 2H), 2.61 (s, 2H), 1.48 (s, 6H); LC/MS (APCI) M/Z 412 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].[C:30]([C:34]1[C:39](Cl)=[N:38][N:37]2[N:41]=[CH:42][N:43]=[C:36]2[CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>O1CCCC1>[C:30]([C:34]1[C:39]([O:17][CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:10][CH2:11]2)=[N:38][N:37]2[N:41]=[CH:42][N:43]=[C:36]2[CH:35]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1cc2ncnn2nc1Cl
Reactant: OCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2ncnn2nc1OCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Yield: 32.9 %

Procedure:
4-(Diphenylmethoxy)-1-piperidineethanol (740 mg) was dissolved in dried tetrahydrofurane (18 ml), followed by addition of sodium t-butoxide (251 mg). The mixture was refluxed under heating for 25 minutes. After the mixture was cooled, 7-tert-butyl-6-chloro[1,2,4]triazolo[1,5-b]pyridazine (501 mg) was added thereto. The mixture was refluxed under heating for 2 hours. After the mixture was cooled, ice-water was added thereto, followed by extraction with ethyl acetate. The extract was washed with an aqueous sodium chloride saturated solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica-gel column chromatography and eluted with ethyl acetate. Fractions containing the objective compound were collected and recrystalized from ethyl acetate to yield the title compound (380 mg).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=S)=[CH:5][CH:4]=1.[F:14][C:15]([F:38])([F:37])[C:16]1[NH:20][C:19]([C:21]2[CH:26]=[C:25]([O:27][C:28]3[CH:29]=[C:30]([NH2:36])[C:31]([NH:34][CH3:35])=[CH:32][CH:33]=3)[CH:24]=[CH:23][N:22]=2)=[N:18][CH:17]=1.NC(N)=S>C(#N)C.O=P(Cl)(Cl)Cl>[CH3:35][N:34]1[C:31]2[CH:32]=[CH:33][C:28]([O:27][C:25]3[CH:24]=[CH:23][N:22]=[C:21]([C:19]4[NH:20][C:16]([C:15]([F:37])([F:14])[F:38])=[CH:17][N:18]=4)[CH:26]=3)=[CH:29][C:30]=2[N:36]=[C:10]1[NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Reactant: CNc1ccc(Oc2ccnc(-c3ncc(C(F)(F)F)[nH]3)c2)cc1N
Agent: NC(N)=S
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(Nc2ccc(C(F)(F)F)cc2)nc2cc(Oc3ccnc(-c4ncc(C(F)(F)F)[nH]4)c3)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-Trifluoromethylphenyl isothiocyanate (200 mg, 1 mmol) was added to a mixture of 4-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N1-methylbenzene-1,2-diamine (350 mg, 1 mmol) in 3 mL of acetonitrile. After stirring for 20 min at ambient temperature, HPLC analysis showed complete conversion. A mixture of thiourea (553 mg, 1 mmol) in POCl3 (3 mL) was stirred at ambient temperature. After 4 h, the mixture was heated to approximately 50° C. After heating for 2 h, HPLC analysis indicated completion of reaction:
Reaction SMILES: [O-]CC.[Na+].C(O)C.[C:8]([O:11][CH2:12][CH3:13])(=[O:10])[CH3:9].C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=O)C>C1(C)C=CC=CC=1>[CH2:12]([O:11][C:8](=[O:10])[CH2:9][C:17](=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH3:13]
Reactant: CCOC(=O)c1ccccn1
Reactant: CCOC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)c1ccccn1
Temperature: 90 °C
Yield: 91 %

Procedure:
Stir a mixture of sodium ethoxide (360 g, 5.29 mol), toluene (4 L), ethanol (18 mL, 0.265 mol), and ethyl acetate (1.04 L, 10.6 mol) in a 22 L flask equipped with a reflux condenser, nitrogen inlet, and mechanical stirrer. Stir for 1 h as the mixture warms to 26° C. Add pyridine-2-carboxylic acid ethyl ester (Fluka; 400 g, 2.65 mol) and heat the mixture to reflux (90° C.) for 18 h. Cool the mixture to room temperature, dilute with toluene (8 L), wash with water (6 L), and separate the layers. Acidify the aqueous layer to pH 5 with glacial acetic acid. Extract with ethyl acetate (2×4 L), dry the combined organic layers (sodium sulfate), filter, and concentrate in vacuo to yield 466 g (91%) the subtitled compound as a dark oil in 93% purity by HPLC analysis. MS ES+ m/e 194 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:12]([Mg]Cl)[CH3:13].Cl>C1COCC1.Cl[Ni]Cl.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH2:12][CH3:13])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: CC[Mg]Cl
Agent: Cl[Ni]Cl
Agent: Cl
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ncc(C(=O)O)cc1Cl
Temperature: 55 °C

Procedure:
To solution of 5,6-dichloronicotinic acid (21.46 g, 112 mmol) and 1,2-bis(diphenylphosphino)ethane dichloronickel(II) ((Ni(dppe)Cl2) (2.00 g, 3.6 mmol) in THF (60 mL, 1.9 M) is cooled to 0° C. and treated with ethyl magnesium chloride (2.8 M, 107 mL, 300 mmol) slowly via syringe with stirring under nitrogen. The reaction mixture is warmed to 55° C. for 3 h, cooled to 0° C. and acidified to pH 5 with 2 M HCl (100 mL). After concentrating in vacuo, the solution is reconstituted and extracted with ethyl acetate (2×200 mL), dried over Na2SO4, filtered and concentrated. The solvent removed in vacuo to provide crude 5-chloro-6-ethyl-nicotinic acid as a light brown glass (ESI-LCMS m/z calcd for C8H8ClNO2: 185.0; found 186.0 (M+1)+, which is used without further purification.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[CH3:10][O:11][C:12]1[CH:23]=[CH:22][C:15]([C:16]([NH:18][C:19](=[O:21])[CH3:20])=S)=[CH:14][CH:13]=1.Cl.Cl.[NH2:26][CH:27]([CH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[C:28]([NH:30][C:31]1([C:38]#[N:39])[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1)=[O:29].C(N(CC)C(C)C)(C)C>ClCCl>[C:19]([N:18]=[C:16]([NH:26][CH:27]([CH2:40][CH:41]1[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]1)[C:28]([NH:30][C:31]1([C:38]#[N:39])[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]1)=[O:29])[C:15]1[CH:22]=[CH:23][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)(=[O:21])[CH3:20]
Reactant: COc1ccc(C(=S)NC(C)=O)cc1
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=NC(C)=O)NC(CC2CCCCC2)C(=O)NC2(C#N)CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Chloro-N-methylpyridinium iodide (660 mg, 2.58 mmol), was added to a solution of N-(4-methoxy-thiobenzoyl)acetamide (420 mg, 2.01 mmol), 2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide bis hydrochloride salt (730 mg, 2.00 mmol), and N,N-diisopropylethylamine (1.05 mL, 6.02 mmol) in dichloromethane (8.0 mL). The reaction mixture was stirred at room temperature for 2 h, then diluted with dichloromethane (100 mL)and washed with 2×150 mL of saturated sodium bicarbonate. The organic phase was dried (MgSO4) and concentrated. The resulting residue was chromatographed over 100 g of flash silica first using EtOAc, then dichloromethane/methanol 9:1 as the eluant to provide the desired product as an off white solid (377 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ 0.70-0.90 (m, 2H), 1.00-1.30 (m, 4H), 1.35-1.65 (m, 8H), 1.72 (s, 3H), 1.85-2.20 (m, 6H), 2.48-2.60 (m, 1H), 3.78 (s, 3H), 4.20-4.35 (m, 1H), 6.95-6.99 (m, 2H), 7.33 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H). MS, m/z 468=M+1.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[CH:29]1([NH:32][C:33](=[O:50])[C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:35]=2)[CH2:31][CH2:30]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH:29]1([NH:32][C:33](=[O:50])[C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([C:2]3[CH:10]=[C:9]4[C:5]([C:6]([S:19]([C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=5)(=[O:21])=[O:20])=[N:7][N:8]4[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:16])[CH3:17])=[CH:4][CH:3]=3)[CH:35]=2)[CH2:30][CH2:31]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: C[Si](C)(C)CCOCn1nc(S(=O)(=O)c2ccc(F)cc2)c2ccc(Br)cc21
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: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(S(=O)(=O)c3ccc(F)cc3)nn(COCC[Si](C)(C)C)c2c1
Yield: 69.8 %

Procedure:
A mixture of 6-bromo-3-[(4-fluorophenyl)sulfonyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-indazole (Intermediate 70) (0.06 g) N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 5) (0.04 g) aqueous sodium carbonate (1M, 0.66 ml) and tetrakis(triphenylphosphine)palladium(0) (0.015 g) in 1,2-dimethoxyethane (4 ml) was stirred at reflux under nitrogen for 18 h. The mixture was concentrated under vacuum and the residue was purified on a Varian Bond-Elut SPE cartridge, eluting with cyclohexane:ethyl acetate (100:0 to 50:50) to give the title compound (0.05 g).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[OH:9][C:10]1[CH:17]=[CH:16][C:15]([N:18]2[N:22]=[N:21][CH:20]=[N:19]2)=[CH:14][C:11]=1[CH:12]=[O:13]>CN(C)C=O.O>[CH3:1][O:9][C:10]1[CH:17]=[CH:16][C:15]([N:18]2[N:22]=[N:21][CH:20]=[N:19]2)=[CH:14][C:11]=1[CH:12]=[O:13]
Reactant: O=Cc1cc(-n2ncnn2)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-n2ncnn2)cc1C=O
Reaction time: 2 h
Yield: 42.4 %

Procedure:
Potassium carbonate (1.06 g) and methyl iodide (0.5 ml) were added to a solution of 2-hydroxy-5-tetrazol-2-yl-benzaldehyde (930 mg) in dimethylformamide (6 ml) at room temperature. The mixture was stirred for 2 h then evaporated to give an orange solid. This was dissolved in water (40 ml), extracted with dichloromethane (3×30 ml), dried (Na2 SO4) and evaporated. The residue was purified by FCC (dichloromethane) to give the title compound as a yellow solid (423 mg). T.l.c. (Ethyl acetate/cyclohexane(1:1)), Rf 0.44.
Reaction SMILES: Cl[SiH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:4][CH2:3]1.[Cl-].[CH2:25]([Zn+])[CH2:26][CH2:27][CH:28]=[CH2:29].Cl[SiH]1CCC(CC[C@H]2CC[C@H](C3C=CC(F)=CC=3)CC2)CC1.[Cl-].C([Zn+])CCCC>>[F:23][C:18]1[CH:17]=[C:16]([C@H:13]2[CH2:14][CH2:15][C@H:10]([CH2:9][CH2:8][C@H:5]3[CH2:6][CH2:7][Si@H:2]([CH2:29][CH2:28][CH2:27][CH:26]=[CH2:25])[CH2:3][CH2:4]3)[CH2:11][CH2:12]2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: Fc1ccc([C@H]2CC[C@H](CCC3CC[SiH](Cl)CC3)CC2)cc1F
Reactant: C=CCCC[Zn+]
Agent: CCCCC[Zn+]
Agent: Fc1ccc([C@H]2CC[C@H](CCC3CC[SiH](Cl)CC3)CC2)cc1
Agent: [Cl-]
Product: C=CCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(F)c(F)c3)CC2)CC1

Procedure:
The preparation was conducted in the same manner as in Example 6, except that 7.5 g (21 mmol) of 1-chloro-4-(2-(trans-4-(3,4-difluorophenyl)cyclohexyl)ethyl)-1-silacyclohexane and 4-pentenylzinc chloride were used instead of 7.0 g (21 mmol) of 1-chloro-4-(2-(trans-4-(p-fluorophenyl)cyclohexyl) ethyl)-1-silacyclohexane and n-pentylzinc chloride.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:7][N:6]=1)=[O:4].COC([C:22]1[CH:27]=[N:26][C:25](C=O)=[CH:24][N:23]=1)=O.N1CC[CH2:33][CH2:32][CH2:31]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH:32]([N:23]1[CH2:22][CH2:27][N:26]([C:3]([C:5]2[CH:10]=[N:9][C:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:7][N:6]=2)=[O:4])[CH2:25][CH2:24]1)([CH3:33])[CH3:31]
Reactant: C1CCNCC1
Reactant: COC(=O)c1cnc(C=O)cn1
Reactant: COC(=O)c1cnc(CN2CCCCC2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2cnc(CN3CCCCC3)cn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23 %

Procedure:
5-Piperidin-1-ylmethyl-pyrazine-2-carboxylic acid methyl ester. A mixture of 5-formyl-pyrazine-2-carboxylic acid methyl ester (0.400 g, 2.40 mmol), piperidine (0.204 g, 2.40 mmol), and NaB(OAc)3H (1.40 g, 3.60 mmol) in DCM (10 mL) was stirred for 18 h at rt. The reaction was quenched by the addition of 10% aq. NaOH (10 mL) and the mixture was stirred for 30 min. The mixture was extracted with DCM (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to yield the title compound (0.130 g, 23%).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1)[OH:4].I[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Cl>CN(C)C=O.O1CCCC1>[CH2:27]([O:4][C:3]1[CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCCCCI
Reactant: Oc1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 28.99 g of 60% sodium hydride in 350 ml of N,N-dimethylformamide, cooled to 0° C. and under argon is added 60 g of hydroquinone in 450 ml of N,N-dimethylformamide with stirring over 40 minutes. After an additional 30 minutes, 450 ml of tetrahydrofuran is added followed by 192 g of 1-iodohexadecane over one hour. The mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into dilute hydrochloric acid and extracted with chloroform. The organic layer is washed with water, dried and evaporated to give the desired product as an oil.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: C1CCNC1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCCC4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-Dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3-methyl-cyclohexyl methyl)-amide and pyrrolidine. 1H NMR (400 MHz, DMSO-d6): δ 8.50 (t, J=6.01 Hz, 1H), 7.80 (d, J=9.21 Hz, 1H), 7.47-7.54 (m, 2H), 6.96 (d, J=9.22 Hz, 1H), 4.16 (s, 1H), 3.51-3.53 (m, 4H), 3.26-3.28 (m, 2H), 1.97-1.98 (m, 4H), 1.71-1.73 (m, 1H), 1.45-1.61 (m, 6H), 1.00-1.07 (m, 1H), 0.83-0.84 (m, 3H), 0.73-0.74 (m, 1H). m/z: 402.2 [M+H]+