Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH2:11][C@H:10]([OH:12])[C@@H:9]2[CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[CH3:28][S:29]([O:12][C@H:10]1[CH2:11][N:8]([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@H:9]1[CH2:13][CH3:14])(=[O:31])=[O:30]
Reactant: CC[C@H]1[C@@H](O)CN1C(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CC[C@H]1[C@@H](OS(C)(=O)=O)CN1C(c1ccccc1)c1ccccc1
Yield: 32.3 %

Procedure:
The same operation as in Example (234c) was performed using cis(±)-1-(diphenylmethyl)-2-ethylazetidin-3-ol obtained in Example (235b) (769 mg, 2.88 mmol), triethylamine (0.60 mL, 4.32 mmol) and methanesulfonyl chloride (0.29 mL, 3.74 mmol), to obtain 321 mg of the title compound as a pale yellow oily substance (32%).
Reaction SMILES: [Na].C(O)(=[S:4])C.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23].[OH-].[Na+].Cl>CO>[SH:4][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: CC(O)=S
Reactant: O=C(O)CCCCCCCCCCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: O=C(O)CCCCCCCCCCCCCCCS
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
Under inert atmosphere 2.0 gr of sodium metal suspension (40% in mineral oil) were slowly added to 100 ml of dry methanol at 0° C. At the end of the addition reaction mixture was stirred for 10 min at RT and 1.75 ml (21.58 mmole) of thioacetic acid were added. After additional 10 min of stirring, 30 ml degassed methanolic solution of 6.1 gr (18.19 mmole) of 16-bromohexadecanoic acid were added. The resulted mixture was refluxed for 15 hrs, after which, allowed to cool to RT and 50 ml of degassed 1.0 M NaOH aqueous solution were injected. Additional refluxing for 3 hrs required for reaction completion. Resulted reaction mixture was cooled with ice bath and poured, with stirring, into a vessel containing 200 ml of ice water. This mixture was titrated to pH=7 by 1.0 M HCl and extracted with 300 ml of ether. The organic layer was separated, washed with 3×150 ml of water, 150 ml of saturated NaCl aqueous solution and dried over sodium sulfate. After removal of ether material was purified by recrystalization from n-hexane, filtering out and drying over high vacuum. 5.1 gr (97% yield) of the desired product was obtained.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([O:27][C:28](=[O:43])[CH2:29][NH:30][C:31]([C:33]1[N:34]=[C:35]2[CH:40]=[CH:39][C:38](Cl)=[N:37][N:36]2[CH:42]=1)=[O:32])[CH3:26].C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH2:25]([O:27][C:28](=[O:43])[CH2:29][NH:30][C:31]([C:33]1[N:34]=[C:35]2[CH:40]=[CH:39][C:38]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)=[N:37][N:36]2[CH:42]=1)=[O:32])[CH3:26]
Reactant: CCOC(=O)CNC(=O)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 95 °C
Reaction time: 24 h
Yield: 45.9 %

Procedure:
1.90 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.38 g of N-(6-chloroimidazo[1,2-b]pyridazine-2-carbonyl)glycine ethyl ester were dissolved in 15 ml of 1-methyl-2-pyrrolidone; 0.841 ml of N-ethyldiisopropylamine was added, followed by stirring in an oil bath (90-100° C.) for 24 hours. After cooling, ice water were added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (95:5:1). The desired fraction was collected and recrystallized from ethyl acetate to yield 1.28 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1O[C:4]([CH3:19])=[C:5]([CH3:18])[C:6](=[O:17])[C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].[CH:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH2:28])=[CH:22][CH:21]=1.C1(C)C=CC=CC=1.[OH-].[Na+]>CO.CCOCC.O>[CH3:1][C:2]1[N:28]([CH2:27][CH2:26][C:23]2[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=2)[C:4]([CH3:19])=[C:5]([CH3:18])[C:6](=[O:17])[C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9]
Reactant: NCCc1ccccc1
Reactant: Cc1oc(C)c(C(=O)Nc2ccccc2)c(=O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(C)n(CCc2ccccc2)c(C)c(C(=O)Nc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
To a mixture of 1 g (3.89 mmol) of 2,5,6-trimethyl -4-oxo-N-phenyl-4H-pyran-3-carboxamide, 0.71 g (5.83 mmol) of β-phenethylamine and 5 ml of toluene, 0.4 ml of 1N solution of sodium hydroxide in methanol were added and stirred overnight at room temperature. After addition of about 10 ml of water and about 10 ml of ether, the mixture was shaken and allowed to stand. The crystals precipitated were separated by filtration and dried in vacuo to afford 1.16 g of the title compound having m.p. 191°-193° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[C:6]([CH:12]([OH:14])[CH3:13])[CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:3]=1.N12CCCN=C1CCCCC2.[Cl:34][C:35]([Cl:39])([Cl:38])[C:36]#[N:37]>C(Cl)Cl>[Cl:34][C:35]([Cl:39])([Cl:38])[C:36](=[NH:37])[O:14][CH:12]([C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[C:10]2[C:5]=1[N:4]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:21])([CH3:20])[CH3:22])[N:3]=[C:2]2[Br:1])[CH3:13]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(O)c1cc(Cl)cc2c(Br)nn(COCC[Si](C)(C)C)c12
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Cl)cc2c(Br)nn(COCC[Si](C)(C)C)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(±)-1-(3-Bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)ethanol (1.29 g, 3.18 mmol) was dissolved in methylene chloride (10 mL), cooled to 0° C. and treated with 1,8-diazabicyclo(5.4.0)undec-7-ene (96 μL, 0.64 mmol). The reaction was stirred for 10 min and treated with trichloroacetonitrile (3.19 mL, 31.8 mmol) dropwise over 10 min. The ice bath was removed and the reaction stirred at room temperature for 1 h and concentrated. Flash chromatography on silica gel (5% ethyl acetate/hexanes) gave 1.69 g (77%) as an oil. 1H-NMR (CDCl3, 300 MHz) δ 8.27 (s, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.53 (d, J=1.8 Hz, 1H), 6.58 (q, J=6.6 Hz, 1H), 6.19 (qAB, JAB=11.4 Hz, 2H), 3.50-3.56 (m, 2H), 1.74 (m, 3H), 0.80-0.84 (m, 2H), 0.06 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:16]=2)[C:11]([OH:13])=O)=[N:6][CH:7]=1.[CH3:23][C:24]1[N:29]=[CH:28][C:27]([C@H:30]([NH2:32])[CH3:31])=[CH:26][N:25]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:16]=2)[C:11]([NH:32][C@@H:30]([C:27]2[CH:26]=[N:25][C:24]([CH3:23])=[N:29][CH:28]=2)[CH3:31])=[O:13])=[N:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)O)c2)nc1
Reactant: Cc1ncc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)N[C@H](C)c3cnc(C)nc3)c2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(5-methylpyridin-2-yl)-5-(thiazol-2-yloxy)benzoic acid (40 mg, 0.13 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(2-methylpyrimidin-5-yl)ethanamine (40 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol), and N,N-diisopropylethylamine (120 μL, 0.69 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the product as a light color solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH:21]=[CH:22][CH3:23])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH2:21][CH2:22][CH3:23])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC=Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Solvent: CCO
Product: CCCc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (6.7 g), bis(tricyclohexylphosphine)palladium (II) dichloride (148 mg), tripotassium phosphate (13 g) and cis-1-propene-1-boronic acid (2.6 g) were added toluene (60 mL) and water (3 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-[3-methyl-5-propenylpyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (6 g). 4-[3-Methyl-5-propenylpyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (6 g) was dissolved in ethanol (40 mL), 5% palladium carbon-ethylenediamine complex (1.2 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. After celite filtration, the solvent in the filtrate was evaporated to give 4-[3-methyl-5-propylpyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (6 g). 4-[3-Methyl-5-propylpyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (6 g) was dissolved in chloroform (10 mL), 4N hydrogen chloride/ethyl acetate (10 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N aqueous sodium hydroxide solution (40 mL), and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give the title compound (2.9 g).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:19])=[C:6]([CH:15]=[CH:16][C:17]=1[CH3:18])[CH2:7][NH:8]C(=O)C(F)(F)F)([O-:3])=[O:2].[OH-].[Na+]>CO>[N+:1]([C:4]1[C:5]([CH3:19])=[C:6]([CH:15]=[CH:16][C:17]=1[CH3:18])[CH2:7][NH2:8])([O-:3])=[O:2]
Reactant: Cc1ccc(CNC(=O)C(F)(F)F)c(C)c1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(CN)c(C)c1[N+](=O)[O-]

Procedure:
A mixture of N-(3-nitro-2,4-dimethyl-benzyl)-2,2,2-trifluoroacetamide (1.53 g, 5.54 mmol), 4M NaOH-solution (6.9 mL, 28 mmol) and MeOH (30 mL) is refluxed for 2 h. Then the mixture is concentrated, diluted with water and extracted with EtOAc. The organic phase is dried with Na2SO4, filtered and concentrated.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:20])[C:14]([C:15]([O:17]CC)=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:21])[CH:7]=1.[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:20])[C:14]([C:15]([OH:17])=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:21])[CH:7]=1
Reactant: CCOC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)O)c2c1
Temperature: 90 °C
Reaction time: 36 h
Yield: 61.2 %

Procedure:
A solution of 0.440 g (1.22 mmol, 1 eq.) of ethyl 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate from Example 3A in 12.7 ml of dioxane was admixed with 4.9 ml (4.88 mmol, 4.0 eq.) of 1 N aqueous sodium hydroxide solution and the mixture was stirred at 90° C. for 36 h. Subsequently, the reaction mixture was concentrated and the precipitated solids were filtered off. The filtrate was acidified with 6 N aqueous hydrochloric acid and stirred briefly, and the precipitated solids were filtered off, washed with water and dried. 248 mg of the title compound were obtained (61% of theory, 60% purity), which was converted further without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[C:5]([N+:12]([O-])=O)=[CH:4][N:3]=1.[C:15]([OH:20])(=O)[CH2:16][CH2:17][CH3:18]>>[CH3:11][C:6]1[C:5]([NH:12][C:15](=[O:20])[CH2:16][CH2:17][CH3:18])=[CH:4][N:3]=[C:2]2[NH:1][C:4]([CH2:5][CH2:6][CH3:7])=[N:8][C:7]=12
Reactant: Cc1c([N+](=O)[O-])cnc(N)c1[N+](=O)[O-]
Reactant: CCCC(=O)O
Product: CCCC(=O)Nc1cnc2[nH]c(CCC)nc2c1C

Procedure:
The title compound was prepared from 2-amino-4-methyl-3,5-dinitropyridine according to method described in Example 1, Step 2 using butyric acid in the place of valeric acid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=O)=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[NH3:31]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH2:31])=[O:16])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: N
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](Nc2cccc(N3CCOCC3)c2)C[C@@H]1C
Product: CC(=O)N1c2ccc(C(N)=O)cc2[C@H](Nc2cccc(N3CCOCC3)c2)C[C@@H]1C
Yield: 80 %

Procedure:
Reactions and treatments were carried out in the same manner as in Example 110, using 25 mg of (2S,4R)-1-acetyl-2-methyl-4-[(3-morpholinophenyl)amino]-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (compound 179) and aqueous ammonia. Thus, 20 mg (80%) of the title compound was obtained as a light yellow oily substance.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:31])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[N:9]=3)[CH2:2]1.[CH3:32][S:33]([CH:36]=[CH2:37])(=[O:35])=[O:34]>>[CH3:31][N:7]1[C:6]([CH2:5][CH:3]2[CH2:2][N:1]([CH2:37][CH2:36][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:4]2)=[N:14][C:13]2[C:8]1=[N:9][C:10]([N:21]1[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[C:22]1[CH3:30])=[N:11][C:12]=2[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C=CS(C)(=O)=O
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(CCS(C)(=O)=O)C3)n(C)c2n1

Procedure:
Following General Procedure C, 4-(8-(azetidin-3-ylmethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and methylvinylsulfone were reacted to give 543. LCMS m/z: 525.3 (MH+)
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[S:30][C:29]5[C:24](=[N:25][CH:26]=[CH:27][C:28]=5Cl)[CH:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(C1CN(C(=O)[C@H](N[C:53](C2C3C(=NC=C(C4SC5C(=NC=CC=5Cl)C=4)N=3)N(COCC[Si](C)(C)C)C=2)=[O:54])C2CC2)C1)#N>>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[S:30][C:29]5[C:24](=[N:25][CH:26]=[CH:27][C:28]=5[O:54][CH3:53])[CH:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(-c3cc4nccc(Cl)c4s3)cnc21
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cc4nccc(Cl)c4s3)nc12)C(=O)N1CC(C#N)C1
Product: COc1ccnc2cc(-c3cnc4[nH]cc(C(=O)N[C@H](C)C(=O)N5CC(C#N)C5)c4n3)sc12

Procedure:
Prepared according to the procedure outlined in Example 157 substituting 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide for 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide in step 1. MS: (M+H)+=462.
Reaction SMILES: [N:1]1([CH2:6]/[CH:7]=[C:8](/[C:16]2[N:21]=[C:20](/[CH:22]=[CH:23]/[CH2:24][OH:25])[CH:19]=[CH:18][CH:17]=2)\[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[N:1]1([CH2:6]/[CH:7]=[C:8](/[C:16]2[N:21]=[C:20](/[CH:22]=[CH:23]/[CH:24]=[O:25])[CH:19]=[CH:18][CH:17]=2)\[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(/C(=C\CN2CCCC2)c2cccc(/C=C/CO)n2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1ccc(/C(=C\CN2CCCC2)c2cccc(/C=C/C=O)n2)cc1
Reaction time: 3 h
Yield: 93 %

Procedure:
A solution of 3-(6-[3-pyrrolidino-1-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-prop-2E-en-1-ol (1.00 g, 2.99 mmol) in DCM (20 ml) was treated portionwise with manganese dioxide (4 g, 46 mmol). The reaction mixture was stirred vigorously for 3 hours before filtration through a glass fiber pad. The filtrate was concentrated under reduced pressure to yield 3-(6-[3-pyrrolidino-1-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-prop-2E-enal as a brown solid (0.924 g, 93%). 1H-NMR; δ (CDCl3), 9.87 (1H, d, J=9.5 Hz), 7.55 (1H, t, J=7.5 Hz), 7.50 (1H, d, J=15.5 Hz), 7.33 (1H, d, J=8.0 Hz), 7.21 (2H, d, J=8.5 Hz), 7.18-7.13 (2H, m), 7.08 (2H, d, J=8.5 Hz), 6.92 (1H, d, J=9.5 Hz), 3.27 (2H, d, J=9.5 Hz), 2.62-2.27 (4H, m), 2.39 (3H, s) and 1.81-1.77 (4H, m).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[C:8]([CH:26]=1)[C:9]([NH:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)=[O:10])(=[O:3])[CH3:2].[BH4-].[Na+].Cl>C(O)C>[F:19][C:18]([F:20])([F:21])[C:16]1[CH:17]=[C:12]([NH:11][C:9](=[O:10])[C:8]2[CH:26]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=[CH:6][C:7]=2[OH:27])[CH:13]=[C:14]([C:22]([F:24])([F:25])[F:23])[CH:15]=1
Reactant: CC(=O)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.7 %

Procedure:
5-Acetyl-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide (50.5 mg, 0.13 mmol) was suspended in ethanol (2 mL). Sodium borohydride (23.6 mg, 0.62 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was washed with isopropyl ether/n-hexane under suspension to give the title compound (39.7 mg, 78.3%) as white powder.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C(NC(C)C)(C)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][OH:28])=[CH:21][CH:20]=1.[Cl-].[NH4+]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:19]1([CH3:29])[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][O:28][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])=[CH:23][CH:24]=1
Reactant: Cc1ccc(CCCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: Cc1ccc(CCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 6 h
Yield: 66.1 %

Procedure:
2.46 g of tosyl chloride (13 mM), 3.4 ml of diisopropylamine (19.4 mM) and 158 mg of 4-(dimethylamino)pyridine (1.29 mM) were added to reaction solution (6.46 mM) dissolving 971 mg of 3-p-tolyl-propane-1-ol (40ac) prepared by above step 3 in methylene chloride at 0° C. under Ar atmosphere with stirring for 6 hrs, and the reaction mixture was stirred for 12 hrs at room temperature. After the reaction mixture was neutralized with ammonium chloride, the mixture was extracted with ethyl acetate, washed with saturated NaCl solution, dried over MgSO4, filtered, and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:7) as an eluant to give 1.3 g of toluene-4-sulfonate-3-p-tolyl-propyl ester (40ad) (yield: 70%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.Cl.[CH3:12][NH:13][CH3:14].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[CH3:12][N:13]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][C:4]=1[CH3:10])[CH3:14]
Reactant: Cc1cc(O)ccc1C=O
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(O)ccc1CN(C)C
Temperature: 25 °C
Yield: 94.9 %

Procedure:
To a mixture of 4-hydroxy-2-methylbenzaldehyde (5.0 g, 37 mmol) and dimethylamine hydrochloride (12 g, 147 mmol) in DCM (200 mL), triethylamine (10 mL, 73 mmol) was added. Sodium triacetoxyborohydride (9.3 g, 44 mmol) was added in portions and the reaction mixture was stirred at rt over night. Water (20 mL) was added and the solution was concentrated by evaporation. THF (100 mL) and aqueous NaHCO3 (sat., 30 mL) was added and the two phases were separated. NaCl (3-4 g) was added to the aqueous phase and it was extracted twice with THF (50 mL). The combined solutions were evaporated. EtOAc (150 mL) was added to the residue and the two phases were separated. The organic phase was dried (Na2SO4) and evaporated to dryness. There was obtained 5.8 g (96%) of 20A as an oil. 1H NMR (600 MHz, DMSO-d6): δ 2.08 (s, 6H), 2.21 (s, 3H), 3.19 (s, 2H), 6.49 (d, 1H), 6.54 (s, 1H), 6.92 (d, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:18][NH:19][CH2:20][CH2:21][OH:22].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH3:18][NH:19][CH2:20][CH2:21][O:22][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccc1OCCOC1CCCCO1
Reactant: CNCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CNCCOc1ncccc1OCCO
Reaction time: 48 h
Yield: 14.4 %

Procedure:
A solution of 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (from Example 4; 100 mg, 0.39 mmol), 2-(methylamino)ethanol (47 μl, 0.58 mmol) and 1.0 M potassium tert-butoxide in tert-butanol (0.8 mL, 0.80 mmol) in 4 mL of toluene was heated at 100° C. for 1 day. The organic phase was washed with 3×2 mL of 1.0 M NaOH and 1 mL of brine. The organic phase was shaken with 4 mL of 2.0 M acetic acid for 2 days. The aqueous phase was washed with 3×3 mL of ethyl acetate, made basic by addition of potassium hydroxide, saturated with sodium chloride and extracted with 3×2 mL of chloroform. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 12 mg (0.056 mmol, 14%) of the title compound as a colorless oil. LC-UV purity 90%. MS m/z 213 (M+1)+, calc. 213 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:30]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][Br:30])[CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cncc(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cncc(Br)c1
Temperature: 0 °C

Procedure:
(5-bromopyridin-3-yl)methanol (475 mg, 2.5 mmol) and triphenylphosphine (1.3 g, 5 mmol) were combined in methylene chloride (20 mL) and cooled to 0° C. carbon tetrabromide (927 mg, 2.8 mmol) was introduced in portions and the reaction was maintained at 0° C. for 1 h. The reaction was concentrated and purified by column chromatography on silica gel (0 to 50% ethyl acetate/hexanes) to produce 254 mg (41%) as a white solid. 1H-NMR (D6DMSO, 400 MHz) δ 8.65 (s, br, 2H), 8.18 (s, 1H), 4.73 (s, 2H). Mass spec.: 249.89 (MH)+.