Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(O)C>CS(C)=O>[CH3:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[CH:25]1[CH2:30][CH2:29][N:28]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)[CH2:27][CH2:26]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Cc1cccc2c(C3CCNCC3)c[nH]c12
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1cccc2c(C3CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)c[nH]c12

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.280 g, 1.48 mmol) and 7-methyl-3-(piperidin-4-yl)-1H-indole (0.290 g, 1.39 mmol) using ethanol as reaction solvent. Yield 0.320 g (57%) as a tan foam. FDMS m/e=404 (M+ of free base). α[D]589 =11.6 (c=0.98, dimethylsulfoxide).
Reaction SMILES: [CH:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([OH:22])[C:8]([O:10][C:11]([CH3:21])([CH3:20])[C:12]#[C:13][CH2:14]N(CC)CC)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N#C[Br:31].O.Cl>C(OCC)C>[CH:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([OH:22])[C:8]([O:10][C:11]([CH3:21])([CH3:20])[C:12]#[C:13][CH2:14][Br:31])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CBr
Reactant: CCN(CC)CC#CC(C)(C)OC(=O)C(O)(c1ccccc1)C1CCCCC1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CC(C)(C#CCBr)OC(=O)C(O)(c1ccccc1)C1CCCCC1
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of 9.5 g 4-diethylamino-1,1-dimethyl-2-butynyl α-cyclohexyl-α-phenylglycolate in diethyl ether, was added dropwise an etheral solution of 3.2 g cyanogen bromide, and the mixture was stirred for one hour under ice cooling and then for 18 hours under cooling with water. 2N-HCl (14 ml) was added to the reaction mixture under ice cooling, and the separated etheral layer was collected, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue left was purified by silica gel column chromatography (Wako Gel C-200; 1:15 mixture of ethyl acetate and n-hexane), giving 6.0 g of the objective compound as colorless oil.
Reaction SMILES: [S:1]=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:6]2[S:5][C:4](=[O:7])[NH:3][C:2]2=[S:1])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: O=C1NC(=S)CS1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: C1CCNCC1
Product: O=C1NC(=S)C(=Cc2cc(O)c(O)c([N+](=O)[O-])c2)S1
Temperature: 100 °C

Procedure:
A solution containing 0.67 g (0.005 mol) of 4-thioxothiazolidin-2-one, 0.92 g (0.005 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.05 ml of piperidine in 10 ml of acetic was heated for 8 h at 100° C. The product was filtered and washed with 2-propanol. Yield 1.14 g (76.5%), mp >350° C. (decomp.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:21]1[N:22]=[CH:23][N:24]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:25]=1)[CH2:6][C:7]1[CH:8]=[N:9][C:10]([NH:13]C(OC(C)(C)C)=O)=[CH:11][CH:12]=1)[CH3:2].Cl>C(O)C>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:21]1[N:22]=[CH:23][N:24]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[CH:25]=1)[CH2:6][C:7]1[CH:8]=[N:9][C:10]([NH2:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)c1cn(C2CCCCC2)cn1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(N)nc1)c1cn(C2CCCCC2)cn1
Yield: 99.4 %

Procedure:
39.0 g (88.1 mmol) 3-(6-tert-Butoxycarbonylamino-pyridin-3-yl)-2-(1-cyclohexyl-1H-imidazol-4-yl)-propionic acid ethyl ester as prepared in Example 2 were suspended in 200 ml Ethanol (EtOH) at RT. The mixture was saturated with HCl and was then refluxed for 2 h. The mixture was concentrated and the residue was treated with saturated aqueous K2CO3 (pH 9.0). The aqueous layer was extracted with AcOEt (3×200 ml). The combined organic layers were washed with brine (100 ml), dried with MgSO4 and concentrated to yield the title compound (30 g, 87.6 mmol, 99%) as brown oil.
Reaction SMILES: Cl.Cl.[CH:3]1([O:8][C:9]2[CH:10]=[C:11]([N:17]3[CH2:22][CH2:21][NH:20][C@@H:19]([CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:18]3)[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:3]1([O:8][C:9]2[CH:10]=[C:11]([N:17]3[CH2:22][CH2:21][N:20]([C:36](=[O:38])[CH3:37])[C@@H:19]([CH2:23][N:24]4[CH2:25][CH2:26][CH2:27][CH2:28]4)[CH2:18]3)[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COc1ccc(N2CCN[C@@H](CN3CCCC3)C2)cc1OC1CCCC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCN(C(C)=O)[C@@H](CN3CCCC3)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.8 %

Procedure:
A solution of (S)-1-(3-(cyclopentyloxy)-4-methoxyphenyl)-3-(pyrrolidin-1-ylmethyl)piperazine, dihydrochloride (Example 40, Compound 128) (108 mg, 0.25 mmol) in CH2Cl2 (5 mL) at 0-5 C was treated with triethylamine (105 uL, 0.75 mmol) followed by acetic anhydride (51 uL, 0.50 mmol). The reaction mixture was allowed to warm to room temperature and stir 16 h. After this time the reaction mixture was treated with a saturated aqueous solution of NaHCO3 (2 mL). The organic portion was then dried over MgSO4, filtered, and evaporated to afford quenched with evaporated and the residue purified by silica gel flash chromatography with 100% EtOAc then 10% MeOH/EtOAc as eluant to afford product as an oil (65 mg, 65%). LC/MS (Method B) 2.22 min, [M+1]+ 402. Potency class C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2([CH2:15][OH:16])[CH2:14][CH2:13]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:30]#[C:31][CH3:32])[CH2:25][C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:9]=[C:8]([CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[O:10][CH2:11][C:12]1([CH2:15][O:16][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([C:30]#[C:31][CH3:32])[CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)[CH2:13][CH2:14]1
Reactant: N#Cc1ccc(OCC2(CO)CC2)cc1Cl
Reactant: CC#CC(CC(=O)OC)c1ccc(O)cc1
Product: CC#CC(CC(=O)O)c1ccc(OCC2(COc3ccc(C#N)c(Cl)c3)CC2)cc1

Procedure:
Analogously to example 1, 2-chloro-4-(1-hydroxymethylcyclopropylmethoxy)benzonitrile and methyl 3-(4-hydroxyphenyl)hex-4-ynoate were used to obtain 3-{4-[1-(3-chloro-4-cyanophenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoic acid.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH3:7][S:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][NH:16][C:17](=O)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][CH:10]=1.C1(O)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:7][S:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][N:16]=[C:17]([Cl:2])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][CH:10]=1
Reactant: CSc1ccc(NNC(=O)c2ccccc2)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: Oc1ccccc1
Product: CSc1ccc(NN=C(Cl)c2ccccc2)cc1

Procedure:
A mixture consisting of 7.9 g. (0.038 mole) phosphorus pentachloride, 100 ml. carbon tetrachloride, and 9.05 g. (0.035 mole) benzoic acid 2-[p-(methylthio)phenyl]hydrazide (prepared in Part A above) was heated at the reflux temperature until evolution of gas ceased. The reaction mixture was chilled in ice, and a suspension of 11.3 g. (0.12 mole) phenol in 50 ml. carbon tetrachloride was added. After removing the carbon tetrachloride by evaporation under reduced pressure, the resulting triphenylphosphate solution of the desired product was poured through a column of silica gel. The column was eluted with a mixture of 1 part benzene and 1 part Skellysolve B. After removing the solvents from the eluate by evaporation under reduced pressure, the residue was recrystallized two times from cyclohexane to give benzoyl chloride [p-(methylthio)phenyl]hydrazone having a melting point at 94° to 95°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6]Cl.C[O-].[Na+].[CH2:12]([SH:15])[CH:13]=[CH2:14]>O>[CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6][S:15][CH2:12][CH:13]=[CH2:14]
Reactant: C=CCS
Reactant: COC(=O)CCCCl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: C=CCSCCCC(=O)OC

Procedure:
Into a 1 liter flask equipped with cooling bath, thermometer, reflux condenser and additional funnel as well as electric stirrer is placed 68.2 grams of methyl-4-chlorobutyrate. The methyl-4-chlorobutyrate is cooled to 20° C. The mixture of sodium methoxide and allyl mercaptan is added to the addition funnel. Over a period of 0.5 hours while maintaining the pot temperature at 20°-30° C., the mixture of allyl mercaptan and sodium methoxide is added slowly to the methyl-4-chlorobutyrate with stirring. The reaction is exothermic and requires slight cooling. At the end of the addition of the mixture of allyl mercaptan and sodium methoxide, the reaction mass is stirred for 1 hour and the temperature of the reaction mass is permitted to rise to 38° C. 500 ml water are then added to the reaction mass and the reaction mass is transferred to a separatory funnel. The reaction mass is then extracted with three 50 ml portions of methylene dichloride and dried over anhydrous sodium sulfate and filtered. The reaction mass is then distilled on a micro Vigreux column yielding the following fractions:
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.CN(C)C(=O)C.Cl.Cl[CH2:19][C:20]1[N:21]=[C:22]([CH3:25])[S:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:1][C:2]1[N:6]([CH2:19][C:20]2[N:21]=[C:22]([CH3:25])[S:23][CH:24]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Cc1nc(CCl)cs1
Reactant: Clc1nc2ccccc2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1nc(Cn2c(Cl)nc3ccccc32)cs1
Temperature: 75 °C
Reaction time: 18 h
Yield: 42.8 %

Procedure:
To a mixture of 15.5 pans of 2-chloro-1H-benzimidazole and 235 parts of N,N-dimethylacetamide there were added 22 pans of 4-(chloromethyl)-2-methylthiazole monohydrochloride and 25.4 pans of sodium carbonate. The whole was stirred for 18 hours at 75° C. and was then poured into water. The product was extracted with 4-methyl-2-pentanone and the extract was washed with water, dried, filtered and evaporated. The residue was crystallized from 2,2'-oxybispropane, yielding 11.3 parts (42.8%) of 2-chloro-1-[(2-methyl-4-thiazolyl)methyl]-1H-benzimidazole (interm. 1). In a similar manner there was also prepared 2-chloro-1-[(6-methyl-2-pyridinyl)methyl]1H-benzimidazole (interm. 2).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C@@H:11]([CH2:28][N:29]2[CH:34]3[CH2:35][C:36](=[O:38])[CH2:37][CH:30]2[CH2:31][O:32][CH2:33]3)[CH2:10]1)(=[O:8])=[O:7].[CH3:39][Mg]Br>C1COCC1>[CH3:39][C:36]1([OH:38])[CH2:35][C@H:34]2[N:29]([CH2:28][C@H:11]3[CH2:10][N:9]([S:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)(=[O:7])=[O:8])[CH2:14][CH2:13][N:12]3[C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[C@H:30]([CH2:31][O:32][CH2:33]2)[CH2:37]1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2C3COCC2CC(=O)C3)cc1)C(F)(F)F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)C[C@H]2COC[C@@H](C1)N2C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 0 °C

Procedure:
A 25-mL round-bottomed flask was cooled to 0° C. and charged with 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (50 mg, 0.087 mmol, Example 106) and THF (5 mL). Methylmagnesium bromide was added (3.0M in THF, 0.15 mL, 0.44 mmol, Sigma-Aldrich, St. Louis, Mo.) and after 20 min another 0.5 equivalent of methylmagnesium bromide was added. The reaction was then quenched with MeOH (50 mL), concentrated onto silica gel, and purified via column chromatography (12 g silica gel, 0 to 100% hexanes in EtOAc). The material was purified further via reverse-phase preparative HPLC using a Phenomenex Gemini C18 column (30×150 mm, 10 μm) eluting with 0.1% TFA in CH3CN/H2O (5% to 100% over 15 min) to give (1R,5S)-7-methyl-9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) (10 mg) as a mixture of two isomers.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1>C1COCC1>[CH:4]1[C:5]2[CH:6]([CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[OH:29])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][C:14]=2[CH:1]=[CH:2][CH:3]=1
Reactant: COc1cccc(C=O)c1
Reactant: c1ccc2c(c1)Cc1ccccc1C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(C(O)C2c3ccccc3Cc3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cool a THF (50 mL) solution of 9,10-dihydroanthracene (5.10 g, 28 mmol) to 0° C. and add 1.6M n-BuLi (19 mL, 30 mmol) slowly. After 30 minutes, add m-anisaldehyde (3.4 mL, 28 mmol) to the dark brown solution. Allow the reaction to slowly warm to ambient temperature and then carefully quench with aqueous saturated NH4Cl. Shake the entire reaction with water/EtOAc and dry the organic layer (MgSO4). Concentrate under reduced pressure to give 9.4 g light tan oil. Purify by column chromatography using 25% EtOAc/hexane to give 4.7 g (53%) as a colorless oil that rapidly crystallized, mp 105.9° C. HPLC shows 94% purity.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35]>>[CH3:35][C:34]([CH3:36])=[CH:33][CH2:32][CH2:31][O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=CCCBr
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: CC(C)=CCCOc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 5-Bromo-2-methyl-pent-2-ene following the procedure of Example 478: MS (ESI) m/z 476.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].CCN(CC)CC.Cl[C:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24]([O:31][CH3:32])[N:23]=1>CCO>[CH3:32][O:31][C:24]1[N:23]=[C:22]([NH:1][C@@H:2]([CH2:5][O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3][OH:4])[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: N[C@H](CO)COCc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc([N+](=O)[O-])c(N[C@H](CO)COCc2ccccc2)n1
Temperature: 78 °C
Yield: 115.5 %

Procedure:
To a solution of (R)-2-amino-3-benzyloxy-1-propanol (698.4 g, 3.931 mol) in EtOH (3.6 L) was added Et3N (1.27 L, 9.11 mol) in portions over 10 min. Then a solution of 2-chloro-6-methoxy-3-nitropyridine (672.7 g, 3.567 mol) in EtOH (0.6 L) was added in portions over 10 min. The mixture was heated at 78° C. for 2 h. The reaction mixture was cooled to room temperature and added to stirred ice/H2O (8.4 L). The mixture was extracted with EtOAc (9+6+3 L). The extracts were washed with brine (6 L), dried over MgSO4 (˜900 g), filtered and evaporated to give (2R)-2-{[6-(methyloxy)-3-nitro-2-pyridinyl]amino}-3-[(phenylmethyl)oxy]-1-propanol (1373.1 g, 115%) as an orange oil.
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[O:19])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.Br[CH2:31][C:32]1[S:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[C:33]=1[Cl:41]>C1COCC1>[C:1]([Si:5]([CH3:21])([CH3:20])[O:6][C@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([CH2:31][C:32]3[S:36][C:35]4[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=4[C:33]=3[Cl:41])[C:14]2=[O:19])[CH2:11][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1c(CBr)sc2ccccc12
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N2CCCCC2=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N2CCCC(Cc3sc4ccccc4c3Cl)C2=O)CC1
Reaction time: 0.08 h

Procedure:
Place trans-1-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyl]-piperidin-2-one, (300 mg, 0.96 mmol) in 7.0 mL of THF, cool to −78° C. and treat with 2.0 M LDA (0.72 mL, 1.5 mmol). Stir for 5.0 minutes, treat with 2-bromomethyl-3-chloro-benzo[b]thiophene (375 mg, 1.5 mmol) and stir overnight at room temperature. Quench reaction with ammonium chloride, extract with dichloromethane, dry over sodium sulfate and purify via silica chromatography (ethyl acetate/hexanes 0-25%) affords 310 mg (65
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:8][NH2:9].[CH3:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH:17]=[CH:18][C:19]2[C:27]3[C:22](=[CH:23][C:24]([NH:28][C:29]4[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=4[C:31](O)=[O:32])=[CH:25][CH:26]=3)[N:21]([CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)[N:20]=2)[CH:12]=1>C(Cl)Cl>[CH3:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:8][NH:9][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=1[NH:28][C:24]1[CH:23]=[C:22]2[C:27]([C:19]([CH:18]=[CH:17][C:13]3[CH:12]=[C:11]([CH3:10])[CH:16]=[CH:15][N:14]=3)=[N:20][N:21]2[CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)=[CH:26][CH:25]=1
Reactant: Cc1ccnc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)O)ccc23)c1
Reactant: Cn1ccnc1CN
Agent: Cl
Solvent: ClCCl
Product: Cc1ccnc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)NCc4nccn4C)ccc23)c1

Procedure:
Prepared in a similar manner to that described for Example 6 above except using C-(1-Methyl-1H-imidazol-2-yl)-methylamine hydrochloride and 2-[3-[2-(4-Methyl-pyridin-2-yl) -vinyl]-1-(tetrahydro-pyran-2-yl)-1H-indazol-6-ylamino]-benzoic acid. 1H NMR (DMSO-d6) δ 9.83 (1H, s 9.03 (1H, t, J=5.5 Hz), 8.45 (1H, d, J=4.7 Hz), 8.09 (1H, d, J=8.5 Hz), 7.85 (1H, d , J=16.5 Hz), 8.67 (1H, d , J=7.3 Hz), 7.53–7.39 (4H, m), 7.11 (3H, m), 6.90 (1H, d, J=6.9 Hz), 6.86 (1H, s), 5.79 (1H, d , J=8.9 Hz), 5.75 (1H, s), 4.54 (1H, d , J=5.5 Hz), 3.85–3.70 (2H, m), 3.66 (3H, s), 2.35 (3H, s), 2.10 (2H, m), 1.70 (2H, m), 1.60 (3H, m). Anal. Calcd for C32H33N7O2.0.8 CH2Cl2: C, 63.99; H, 5.672; N, 15.93. Found: C, 63.95; H, 5.72; N, 16.01.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[CH3:13][O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH:20]([C:23](=[NH:26])[NH:24][OH:25])[CH2:19][CH2:18]1)=[O:16]>O1CCOCC1>[CH3:13][O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[NH:26][C:6](=[O:7])[O:25][N:24]=2)[CH2:19][CH2:18]1)=[O:16]
Reactant: COC(=O)C1CCC(C(=N)NO)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: COC(=O)C1CCC(c2noc(=O)[nH]2)CC1
Temperature: 100 °C
Yield: 66.6 %

Procedure:
A mixture of carbodiimidazole (624 mg, 3.85 mmol) and 4-(N-hydroxycarbamimidoyl)-cyclohexanecarboxylic acid methyl ester (770 mg, 3.85 mmol) in anhydrous 1,4 dioxane (15 mL) was heated in a sealed vial in an oil bath at 100° C. for 30 min. The reaction was concentrated, diluted with ethyl acetate (200 mL) washed with aqueous ammonium chloride (sat'd, 200 mL) and brine (200 mL), dried over sodium sulfate, and concentrated to give 4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-cyclohexanecarboxylic acid methyl ester (580 mg 67%) as a clear light yellow oil. LCMS calcd for C10H14N2O4 (m/e) 226, obsd 225 (M−H).
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[C:8](I)=[C:9]2[CH:15]=[CH:14][N:13]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[C:10]2=[N:11][CH:12]=1.[CH2:27]([N:34]1[CH2:39][CH2:38][CH:37]([CH:40]=[O:41])[CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:27]([N:34]1[CH2:39][CH2:38][CH:37]([CH:40]([C:8]2[C:7]([Cl:6])=[CH:12][N:11]=[C:10]3[N:13]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:15][C:9]=23)[OH:41])[CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(I)c(Cl)cnc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(O)C3CCN(Cc4ccccc4)CC3)c(Cl)cnc21
Reaction time: 0.67 h
Yield: 99.9 %

Procedure:
n-BuLi (1.6 M in hexanes, 5.17 mL, 8.28 mmol) was added dropwise to a solution of 5-chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3.0 g, 6.9 mmol, Adesis) in THF (120 mL) at about −78° C., keeping the internal temperature of the reaction below about −70° C. during the addition. After stirring for about 40 min, 1-benzylpiperidine-4-carbaldehyde (2.1 g, 10.3 mmol) was added dropwise and the resulting mixture was stirred at about −75° C. for about 1 h. The reaction was quenched by the dropwise addition of saturated aqueous ammonium chloride (60 mL). The mixture was concentrated under reduced pressure and the remaining aqueous portion was extracted with EtOAc (125 mL). The organic layer was washed with brine (80 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure to afford crude (1-benzylpiperidin-4-yl)(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-4-yl)methanol (3.53 g, quantitative) as a yellow oil: LC/MS (Table 2, Method n) Rt=1.82 min; MS m/z: 512 and 514 (M+H)+. The crude material was used directly in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22]>CN(C)C(=O)C.O.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]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:26]3[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2ccc(C#N)cc2)CC1
Yield: 88.3 %

Procedure:
Dissolve 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (9.19 g, 30.8 mmol) and 4-cyanobenzeneboronic acid (5.18 g, 35.2 mmol) in N,N-dimethylacetamide (90 mL) and water (35 mL), purge with nitrogen for 0.5 hr. and then add tetrakis(triphenylphosphine)palladium(0) (0.170 g, 0.15 mmol). Heat for 3 hr. at 110° C., allow to cool about 1.5 hr. to room temperature, filter and then dry the solid in an oven overnight to give 3′-(4-cyanophenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester as a white solid (9.94 g, 88%). MS (ES): m/z=366 [M+H]+. Add 4 M HCl in 1,4-dioxane (10 mL) to 3′-(4-cyanophenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (3.29 g, 9.0 mmol). Add more 4 M HCl in 1,4-dioxane (10 mL) to the reaction mixture and heat at 40° C. for 3 hr. Filter off the solid and wash with a mixture of 1,4-dioxane/isohexane to give the dihydrochloride salt as a yellow solid (4.2 g). MS (ES): m/z=266 [M+H]+. Dissolve the dihydrochloride in water (20 mL), add 2 N sodium hydroxide (10 mL), extract with DCM and concentrate the DCM extract to give the title preparation as a yellow solid (1.8 g). MS (ES): m/z=266 [M+H]+.