Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:5]2[CH:4]=[C:3]([CH2:2][N:21]3[CH2:26][CH2:25][N:24]([CH2:2][C:3]4[CH:8]=[CH:7][N:6]=[C:5]([C:9]5[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=5)[CH:4]=4)[CH2:23][CH2:22]3)[CH:8]=[CH:7][N:6]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: C1CNCCN1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)ccn2)cc(OC)c1OC

Procedure:
4-Chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (100 mg) and piperazine (15 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([NH2:6])[CH2:2]1.S=[C:8]1[CH2:12][S:11][C:10](=[O:13])[NH:9]1>C(O)C>[O:1]1[CH2:5][CH2:4][CH:3]([NH:6][C:8]2[CH2:12][S:11][C:10](=[O:13])[N:9]=2)[CH2:2]1
Reactant: O=C1NC(=S)CS1
Reactant: NC1CCOC1
Solvent: CCO
Product: O=C1N=C(NC2CCOC2)CS1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a solution of tetrahydrofuran-3-amine (2.94 g) in ethanol (20 mL) was added 4-thioxo-1,3-thiazolidin-2-one (3.0 g), and the mixture was stirred at room temperature for 1 hr. The precipitate was collected by filtration and washed with ethanol to give the title compound (2.41 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:34]=[N:33][C:32]([Br:35])=[CH:31][N:30]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[Br:35][C:32]1[N:33]=[CH:34][C:29]([NH:28][C:13](=[O:15])[CH:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:30][CH:31]=1
Reactant: Nc1cnc(Br)cn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (1.00 g, 3.023 mmol) in methylene chloride (16 mL) was cooled to 0° C. The reaction mixture was then treated with oxalyl chloride (1.15 mL, 13.18 mmol) followed by N,N-dimethylformamide (2 drops). The reaction mixture was stirred at 0° C. for 20 min and then at 25° C. for 2 h. The solution was then concentrated in vacuo. The residue was dissolved in methylene chloride (16 mL) and cooled to 0° C. To this solution was added a solution of 2-amino-5-bromopyrazine (530.0 mg, 3.046 mmol) and 2,6-lutidine (420 μL, 3.606 mmol) in tetrahydrofuran (16 mL) over 1 min. The reaction mixture was stirred at 0° C. for 30 min and then at 25° C. for 3 h. The reaction material was then diluted with ethyl acetate and washed with a 1N aqueous hydrochloric acid solution. The aqueous layer was back-extracted with a 1N aqueous hydrochloric acid solution. The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 1/3 ethyl acetate/hexanes) afforded N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (1.00 g, 68%) as a white foam: (ES)+-HRMS m/e calcd for C19H21BrClN3O3S (M+H)+ 486.0249, found 486.0254.
Reaction SMILES: [C:1]1([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][NH:13][C:8]=1[CH:7]=[CH:6]2.CN(C)C=O.[H-].[Na+].Cl.Br[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>C(O)(=O)C>[N:28]1[CH:29]=[CH:30][C:25]([N:13]2[C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[C:1]([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=4)[C:9]=3[CH:11]=[CH:12]2)=[CH:26][CH:27]=1
Reactant: Brc1ccncc1
Reactant: Nc1nc(N)c2c(ccc3[nH]ccc32)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Nc1nc(N)c2c(ccc3c2ccn3-c2ccncc2)n1
Temperature: 110 °C

Procedure:
A solution of 7.97 g. of 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 500 ml. of dry dimethylformamide is stirred, under nitrogen, with 4.61 g. ca. 50% sodium hydride-mineral oil dispersion for 1.5 hours. Addition of 8.95 g. of p-bromopyridine hydrochloride is followed by heating of the reaction mixture at 110° C. for 5 hours. Glacial acetic acid (10 ml) is added and the solvent is removed in vacuo. The residue is stirred thoroughly with a mixture of excess aqueous potassium carbonate solution and 100 ml. of 1 N sodium hydroxide solution, collected, washed with water and dried. Three crystallizations from methanol and one from dimethylformamide and drying afford 0.61 g. of the title product, m.p. 328.5°-329.5° C., NMR (dDMSO): δ 7.16 (doublet, J=8 Hz, 5H), 7.22 (doublet, J=3 Hz, 9H), 7.88 (doublet, J=3 Hz, 8H), 7.96 (doublet, J=8 cps, 6H) p.p.m λmax95%EtOH 255 mμ (22,900) and 297 mμ (22,100).
Reaction SMILES: C(OC([NH:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH3:19])[CH2:14][C:13]=2[C:12]([C:20]([OH:22])=[O:21])=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[NH2:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH3:19])[CH2:14][C:13]=2[C:12]([C:20]([OH:22])=[O:21])=[CH:11][CH:10]=1
Reactant: CN1Cc2c(C(=O)O)ccc(NC(=O)OC(C)(C)C)c2C1=O
Solvent: O=C(O)C(F)(F)F
Product: CN1Cc2c(C(=O)O)ccc(N)c2C1=O

Procedure:
The title compound was prepared by deprotecting Compound 116C with TFA. The crude product was taken on to the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]2=[CH:8][CH:9]=[CH:10][C:11]([C:12]([O:14][C@H:15]3[C@H:27]([O:28][C@H:29]4[O:34][C@H:33]([CH3:35])[C@H:32]([OH:36])[C@H:31]([OH:37])[C@H:30]4[NH:38][CH3:39])[C:26]4=[CH:25][C:24]#[C:23][C@H:21]5[O:22][C@@:20]5([C@@H:40]5[O:45][C:43](=[O:44])[O:42][CH2:41]5)[C:19]#[C:18][C:17]4=[CH:16]3)=[O:13])=[C:6]2[CH:5]=[C:4]([O:46][CH3:47])[CH:3]=1.Cl.C[OH:50]>>[CH3:35][C@H:33]1[O:34][C@H:29]([O:28][C@H:27]2[C@H:15]([O:14][C:12]([C:11]3[C:6]4[C:7](=[C:2]([CH3:1])[CH:3]=[C:4]([O:46][CH3:47])[CH:5]=4)[CH:8]=[CH:9][C:10]=3[OH:50])=[O:13])[CH:16]=[C:17]3[C:18]#[C:19][C@:20]4([CH:40]5[O:45][C:43](=[O:44])[O:42][CH2:41]5)[O:22][C@@H:21]4[C:23]#[C:24][CH:25]=[C:26]23)[C@H:30]([NH:38][CH3:39])[C@@H:31]([OH:37])[C@H:32]1[OH:36]
Reactant: CN[C@H]1[C@@H](O[C@@H]2C3=CC#C[C@H]4O[C@@]4([C@H]4COC(=O)O4)C#CC3=C[C@H]2OC(=O)c2cccc3c(C)cc(OC)cc23)O[C@H](C)[C@H](O)[C@@H]1O
Reactant: CO
Agent: CN[C@H]1[C@@H](O[C@@H]2/C3=C/C#C[C@H]4O[C@@]4(C4COC(=O)O4)C#CC3=C[C@H]2OC(=O)c2c(O)ccc3c(C)cc(OC)cc23)O[C@H](C)[C@H](O)[C@@H]1O
Agent: CN[C@H]1[C@@H](O[C@@H]2/C3=C/C#C[C@H]4O[C@@]4([C@H]4COC(=O)O4)C#CC3=C[C@H]2OC(=O)c2cccc3c(C)cc(OC)cc23)O[C@H](C)[C@H](O)[C@@H]1O
Agent: Cl
Product: CN[C@H]1[C@@H](O[C@@H]2C3=CC#C[C@H]4O[C@@]4(C4COC(=O)O4)C#CC3=C[C@H]2OC(=O)c2c(O)ccc3c(C)cc(OC)cc23)O[C@H](C)[C@H](O)[C@@H]1O
Reaction time: 2 h

Procedure:
Into 1.5 l of a 95% methanol solution was suspended 16 g of neocarzinostatin powder. After adjusting the pH of the suspension with 1 N hydrochloric acid to pH 2.0, the suspension was stirred for 2 hours and then subjected to centrifugal separation. The supernatant was then concentrated and dried to 920 mg of crude powder of the NCS-C substance. The crude powder was subjected to Sephadex LH-20 chromatography in the same manner as in Example 3. The NCS-C substance was obtained in a powder form (yield: 105 mg).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2Cl)=[CH:16][CH:15]=[CH:14][C:13]=3[O:20][CH3:21])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>O1CCOCC1.NC1C(C)=CC=CC=1>[CH:1]1([C:7]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[O:20][CH3:21])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc2c(Cl)c(C(=O)C3CCCCC3)cnc12
Solvent: Cc1ccccc1N
Solvent: C1COCCO1
Product: COc1cccc2c(Nc3ccccc3C)c(C(=O)C3CCCCC3)cnc12
Yield: 18.2 %

Procedure:
3-cyclohexylcarbonyl-4-chloro-8-methoxyquinoline (5.0 g, 0.017 mol) was heated under reflux in a mixture of 1,4-dioxan (50 ml) and o-toluidine (2.0 ml) for 2 hours. The reaction mixture was evaporated and the residue dissolved in dichloromethane, washed with sodium hydrogen carbonate solution and brine. The organic solution was dried, evaporated and chromatographed (silica gel, dichloromethane) to affort an oil, which on trituration with hexane-ether gave 3-cyclohexylcarbonyl-4-(2-methylphenylamino)-8-methoxyquinoline as yellow crystals (0.58 g, 9.4%) m.p. 115°-7° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][O:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:19][CH2:18]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[N-:32]=[N+]=[N-].[Na+]>CN1C(=O)CCC1.C(Cl)Cl>[C:11]1([C:10]2[C:5]3[C:4]([N:17]4[CH2:22][CH2:21][CH:20]([CH2:23][O:24][CH2:25][CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[CH2:19][CH2:18]4)=[N:3][C:2]([NH2:32])=[N:7][C:6]=3[S:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1nc(N2CCC(COCCN3CCCC3)CC2)c2c(-c3ccccc3)csc2n1
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Nc1nc(N2CCC(COCCN3CCCC3)CC2)c2c(-c3ccccc3)csc2n1
Temperature: 150 °C
Yield: 20.6 %

Procedure:
2-Chloro-5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidine (0.4 g, 0.9 mmol) was dissolved in NMP (2 mL). Sodium azide (0.3 g, 4 mmol) was added and the reaction heated to 150° C. in the microwave for 30 minutes. The reaction mixture was diluted with DCM, washed with water, dried over Na2SO4 and concentrated at reduced pressure. The resulting residue was purified by basic prep HPLC (method 6) to afford 5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidin-2-amine as a brown gum (81 mg). LCMS RT=2.8 min. M+1=438.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:14][CH2:15][S:16][C:3]1=2.[N-:17]=[N+:18]=[N-:19].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]3[NH:19][N:18]=[N:17][N:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:14][CH2:15][S:16][C:3]1=2
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2nc3c(c(=O)n2c1)SCC3
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=c1c2c(nc3ccc(-c4nnn[nH]4)cn13)CCS2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3.2-d]pyrimidine-7-carbonitrile (0.8 g., 0.003 mol), sodium azide (0.8 g., 0.012 mol) and ammonium chloride (0.07 g., 0.013 mol) in dimethylformamide (100 ml) is heated under nitrogen at 100° C. for 18 hours. The reaction mixture is cooled, poured into ice-water (750 ml), acidified with concentrated hydrochloric acid and stirred for one hour. The precipitate is filtered, washed with water and with acetone. Recrystallization from dimethylformamide gives a crystalline product (0.63 g.), mp 297° C. (dec).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].Cl.Cl[CH2:24][CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][N:27]1[CH3:31]>CC(N(C)C)=O>[CH3:31][N:27]1[CH2:28][CH2:29][CH2:30][CH:26]1[CH2:25][CH2:24][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccccc1CCc1ccccc1
Reactant: CN1CCCC1CCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CN1CCCC1CCOc1ccccc1CCc1ccccc1
Yield: 34.2 %

Procedure:
Following a procedure similar to that described in Example 35(a), 900 mg of 2-(2-phenylethyl)phenol (prepared as described in Preparation 19), 1.02 g of potassium t-butoxide and 836 mg of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride were reacted in 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 35(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 480 mg of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C([Li])CCC.[CH2:33]1[O:36][C@@H:34]1[CH3:35].B(F)(F)F.CCOCC>C1COCC1.CCCCCC>[CH2:24]([C:21]1[CH:20]=[N:19][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([C@H:10]3[CH2:11][C@H:9]3[CH2:8][O:7][CH2:6][C:5]3[CH:26]=[CH:27][C:2]([CH2:33][C@H:34]([OH:36])[CH3:35])=[CH:3][CH:4]=3)[CH2:13][CH2:14]2)=[N:23][CH:22]=1)[CH3:25]
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(Br)cc3)CC2)nc1
Reactant: C[C@@H]1CO1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(C[C@@H](C)O)cc3)CC2)nc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
The product of example 54 (step A) (100 mg, 0.2 mmol), was dissolved in THF (2.3 mL), and the solution was cooled to −78° C. under N2. n-Butyl lithium (0.1 mL of a 2.5 M solution in hexane, 0.25 mmol) was added dropwise at 78° C. The solution was stirred at −78° C. for 20 minutes. (R)-propylene oxide (16 mg, 0.028 mmol) and BF3.Et2O (33 mg, 0.23 mmol) were then added. The solution was stirred at −78° C. for 30 minutes, and then at RT for 1 h. The solution was partitioned between water and DCM. The aqueous layer was extracted with DCM. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography (2/1 hexanes/EtOAc) to provide the title compound. MS (ESI) m/z 410 [M+H]+. GPR119 Human EC50: 11 nM
Reaction SMILES: [C@@H:1]12[N:8]([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]=[C:2]2[C:10]([O:12]CC)=O.[Si](Cl)(C)(C)[CH3:16].[Li]C>C1COCC1>[CH3:9][N:8]1[CH:5]2[CH2:6][CH2:7][CH:1]1[C:2]([C:10](=[O:12])[CH3:16])=[CH:3][CH2:4]2
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)C1=CC[C@@H]2CC[C@H]1N2C
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)C1=CCC2CCC1N2C
Temperature: -100 °C
Reaction time: 16 h

Procedure:
To a mixture of ethyl trop-2-ene-2-carboxylate (3.43 g, 0.019 mol) and Me3SiCl (10.32 g, 0.095 mol) in THF (70 mL) cooled to -100° C., MeLi (1.4 M, 17.07 n%L, 0.0239 mol) was added dropwise. After warming up to room temperature, the reaction mixture was stirred for 16 hours. Excess Me3SiCl and THF was evaporated off and the resulting residue was stirred with EtOH (6 mL) followed by water (6 mL). The mixture was then made acidic (6N HCl )and extracted with ether. The aqueous layer was made basic (solid K2CO3)and extracted with chloroform, dried (K2CO3) and concentrated to give
Reaction SMILES: Br.Br[CH:3]([C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(=[O:20])C.[K+].O>C(OC(=O)C)(=O)C>[OH:20][CH:3]([C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)[O-]
Reactant: O=C(c1cccnc1)C(Br)c1ccccc1
Agent: Br
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C(c1cccnc1)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
Alternatively, a mixture of 20.0 g (56.0 mmoles) of 3-pyridyl α-bromobenzyl ketone hydrobromide and 24.0 g (0.24 mole) of potassium acetate in 100 ml of acetic anhydride was stirred overnight at room temperature. The reaction mixture was poured into water and the product extracted into ether. The combined ether layers were washed with water and then 10% aqueous sodium bicarbonate solution. The ether layer was dried over potassium carbonate and evaporated. A solution of the residue in 140 ml of 1 N aqueous hydrochloric acid was heated at reflux for 30 minutes and after cooling made basic with solid sodium carbonate. The product was extracted into ether and the combined ether extracts evaporated, after drying over anhydrous potassium carbonate, to give 8.15 g of 3-pyridyl α-hydroxybenzyl ketone.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=[O:5].C[Si]([C:12]#[N:13])(C)C>[I-].[Zn+2].[I-].CO>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]([OH:5])[C:12]#[N:13]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)CC=O
Agent: [I-]
Agent: [Zn+2]
Solvent: CO
Product: CC(C)(C)CC(O)C#N

Procedure:
Tert-butylacetic acid (b) is reduced with a hydride reducing agent, preferably lithium aluminum hydride, to provide 3,3-dimethyl-1-butanol (c). Oxidation of alcohol (c) with 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (TEMPO), provides 3,3-dimethylbutyraldehyde (d), which is isolated by co-distillation with tetrachloroethane. Aldehyde (d) is treated sequentially with trimethylsilyl cyanide and a catalytic amount of zinc iodide, followed by methanol to afford (±)-4,4-dimethyl-2-hydroxypentanenitrile (e). This nitrile is hydrolyzed first with hydrochloric acid, followed by 50% NaOH to provide racemic pentanoic acid (f). Sequential treatment of racemate (f) with neat acetyl chloride, followed by either oxalyl chloride or thionyl chloride and N,N-dimethylformamide, provides 4,4-dimethyl-2-acetoxypentanoyl chloride (g), which is then coupled with (R)-(−)-4-phenyl-2-oxazolidinone in the presence of 4-dimethylaminopyridine and N,N-diisopropylethylamine in dichloromethane to give a mixture of the acetoxy diastereomers. This diastereomeric mixture of acetates is separated by column chromatography to provide the single diastereomeric acetate (h). The acetate (h) is treated with sodium hydroxide in a solution of tetrahydrofuran/methanol/water to give the desired (2S)-(−)-4,4-dimethyl-2-hydroxypentanoic acid IV. The crude pentanoic acid IV is converted to an ester, preferably the allyl ester, and is then purified by chromatography to provide allyl (2S)-(−)-4,4-dimethyl-2-hydroxypentanoate (i).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C(CO)=CC=CC=1.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>[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: Cc1cccc(C)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1CO
Agent: O=C([O-])[O-]
Solvent: O
Product: Cc1cccc(C)c1-c1ccc(CO)cc1
Yield: 65.4 %

Procedure:
(4-Bromophenyl)methanol (5.00 g, 32 mmol), (2,6-dimethylphenyl)boronic acid (5.77 g, 39 mmol) and sodium carbonate (10.2 g, 96 mmol) were dissolved in toluene-methanol-water (5:1:1, 210 mL) and, after argon substitution, tetrakistriphenylphosphinepalladium (1.85 g, 1.6 mmol) was added. The reaction mixture was heated under reflux overnight under an argon atmosphere. The reaction mixture was cooled, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7:3) to give the title compound (4.44 g, yield 65%) as a white powder.
Reaction SMILES: [K+].[Cl:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[C:12](=[O:16])[C:13]([O-:15])=O.[C:17]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([N:25]1[CH2:30][CH2:29][N:28]([C:13](=[O:15])[C:12]([C:8]2[C:7]3[C:11](=[C:3]([Cl:2])[N:4]=[CH:5][CH:6]=3)[NH:10][CH:9]=2)=[O:16])[CH2:27][CH2:26]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C([O-])C(=O)c1c[nH]c2c(Cl)nccc12
Reactant: O=C(c1ccccc1)N1CCNCC1
Agent: [K+]
Product: O=C(C(=O)N1CCN(C(=O)c2ccccc2)CC1)c1c[nH]c2c(Cl)nccc12

Procedure:
Precursor 5k, 1-benzoyl-4-[(7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a, starting from (7-chloro-6-azaindol-3-yl)-oxoacetic acid potassium salt, Precursor 4a, and 1-benzoylpiperazine. MS m/z: (M+H)+ calcd for C20H18ClN4O3: 397.11; found 396.97. HPLC retention time: 2.37 minutes (column F, gradient time=3 min, flow rate=4 ml/min).
Reaction SMILES: CC(S([NH:7][C@@H:8]([C:10]1[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=1)[CH3:9])=O)(C)C.Cl>CO>[F:18][C:16]([F:17])([F:19])[C:13]1[N:12]=[CH:11][C:10]([C@H:8]([NH2:7])[CH3:9])=[CH:15][CH:14]=1
Reactant: C[C@@H](NS(=O)C(C)(C)C)c1ccc(C(F)(F)F)nc1
Agent: Cl
Solvent: CO
Product: C[C@@H](N)c1ccc(C(F)(F)F)nc1
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
To a solution of 2-methyl-N-{(1R)-1-[6-(trifluoromethyl)-3-pyridinyl]ethyl}-2-propanesulfinamide (41.6 g, 141 mmol) in methyl alcohol (470 mL) at 0° C. was added hydrogen chloride (4.0 M in dioxane; 106 mL, 424 mmol). After 30 min, the mixture was concentrated to dryness. The residue was recrystallized using ethyl alcohol (15 mL) and ether (40 mL). The white solid was filtered and dried under reduced pressure to give the hydrochloride salt of the title compound (26.3 g). MS 191.2 (M+1). 1H NMR (500 MHz, CD3 OD): δ 8.83 (d, J=2.2 Hz, 1 H); 8.17 (d, J=8.2 Hz, 1 H); 7.93 (d, J=8.2 Hz, 1 H); 4.69 (q, J=6.9 Hz, 1 H); 1.70 (d, J=6.9 Hz, 3 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([OH:15])=O)[CH:7]=[CH:6]2)#[N:2].S(Cl)([Cl:18])=O.S([O-])([O-])(=O)=O.[Ca+2]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([Cl:18])=[O:15])[CH:7]=[CH:6]2)#[N:2]
Reactant: N#Cc1ccc2cc(C(=O)O)ccc2c1
Reactant: O=S(Cl)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: N#Cc1ccc2cc(C(=O)Cl)ccc2c1

Procedure:
A mixture of 6-cyano-naphthalene-2-carboxylic acid (250.00 mg, 1.27 mmol), thionyl chloride (15 mL), and a few drops of DMF was refluxed for two hours under a condenser equipped with a drying tube containing anhydrous calcium sulfate. The thionyl chloride was then removed by high vacuum distillation, yielding a quantitative yield of a yellow solid. This material was not characterized, and was carried on without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([C:30](=[O:36])[CH:31]=[CH:32][N:33](C)C)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.NO.Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[O:36][N:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C=CC(=O)c1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: NO
Solvent: CO
Product: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(-c3ccno3)cc2)n1-c1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
To a slurry of 5-(4-chloro-phenyl)-6-[4-(3-dimethylamino-acryloyl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (8.0 mg, 0.016 mmol) in MeOH (0.5 mL) is added NH2OH.HCl (1.5 mg, 0.022 mmol). The mixture is heated to 80° C. for 2 h and cooled down to room temperature. After concentration under vacuum, the residue is purified by preparative LC/MS to provide the titled compound 5-(4-Chloro-phenyl)-6-(4-isoxazol-5-yl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one as white solid.