Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C(O)=O.[C:7]([O:11][C:12]([N:14]1[CH2:20][C:16]2([CH2:19][NH:18][CH2:17]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[CH2:36][N:37]=[C:38]=[O:39]>ClCCl>[C:7]([O:11][C:12]([N:14]1[CH2:15][C:16]2([CH2:17][N:18]([C:38](=[O:39])[NH:37][CH2:36][C:30]3[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:29]=3[Cl:28])[CH2:19]2)[CH2:20]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC2(CNC2)C1
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2(CN(C(=O)NCc3ccc(Cl)cc3Cl)C2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a stirred solution of 6-(tert-butoxycarbonyl)-2,6-diaza-spiro[3.3]heptane oxalate (200 mg, 1.01 mmol) in dichloromethane (10 mL) was added triethylamine (141 μl, 1.01 mmol) followed by 2,4-dichloro-1-(isocyanatomethyl)benzene (204 mg, 1.01 mmol). The reaction mixture was stirred at ambient temperature for 1 h. The crude reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2; methanol:dichloromethane 0:1 to 1:9) to give the title compound (344 mg, 85%) as a white solid. MS (EI) m/e: 400.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:14](=[O:15])[NH:13][C:12]([CH3:16])=[N:11][C:10]=1[CH2:17][CH2:18][CH3:19].[CH3:28][C:29]1([CH3:42])[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34](B(O)O)[CH:35]=2)[O:30]1.N1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:28][C:29]1([CH3:42])[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([N:13]3[C:14](=[O:15])[C:9]([CH2:8][C:7]4[CH:6]=[CH:5][C:4]([C:20]5[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=5)=[CH:3][C:2]=4[F:1])=[C:10]([CH2:17][CH2:18][CH3:19])[N:11]=[C:12]3[CH3:16])[CH:35]=2)[O:30]1
Reactant: CC1(C)CCc2cc(B(O)O)ccc2O1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCCc1nc(C)n(-c2ccc3c(c2)CCC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reaction time: 16 h
Yield: 70.2 %

Procedure:
A mixture of 3′-fluoro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.72 g), (2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)boronic acid (0.82 g), copper(II) acetate (0.73 g), pyridine (0.81 mL), triethylamine (1.4 mL), molecular sieves 4 A (1.5 g) and dichloromethane (10 mL) was stirred for 16 hr. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.73 g, 70%) as a pale-yellow liquid.
Reaction SMILES: Cl.[F:2][C:3]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>ClCCl>[C:27]([N:9]1[CH2:10][CH2:11][CH:6]([O:5][C:4]2[C:12]([F:19])=[C:13]([F:18])[C:14]([F:17])=[C:15]([F:16])[C:3]=2[F:2])[CH2:7][CH2:8]1)(=[O:29])[CH3:28]
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirring solution of 4.76 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine hydrochloride in 100 ml of dichloromethane was treated with 4.46 ml of triethyl amine followed by a solution of 1.413 g of acetyl chloride in 60 ml of dichloromethane (dropwise). After stirring at ambient temperature for 18 hours, the reaction mixture was washed with water followed by a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. Filtration, followed by evaporation of the solvents afforded an oil which was purified by means of high pressure liquid chromatography (silica gel; elution with 10% ethyl acetate/dichloromethane). The resultant oil solidified upon standing and this material was sublimed to 3.2 g (64.7%) of 1-acetyl-4-(2,3,4,5,6-pentafluorophenoxy)piperidine, m.p. 60°-65° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8](=[O:34])[C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-])=O)=[CH:18][C:17]=2[CH3:26])[CH:12]=[CH:11][C:10]=1[O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]>[Pd].CCOC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8](=[O:34])[C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:17]([CH3:26])=[CH:18][C:19]([NH2:23])=[CH:20][C:21]=2[CH3:22])[CH:12]=[CH:11][C:10]=1[O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]
Reactant: COCCOCOC(=O)c1cc(Oc2c(C)cc([N+](=O)[O-])cc2C)ccc1OCOCCOC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCOCOC(=O)c1cc(Oc2c(C)cc(N)cc2C)ccc1OCOCCOC
Reaction time: 3 h

Procedure:
A mixture of the title A compound, 5-(2,6-dimethyl-4-nitrophenoxy)-2-(2-methoxy-ethoxymethoxy)benzoic acid 2-methoxyethoxymethyl ester (3.2 g, 6.68 mmol) and palladium on activated carbon (10 wt. %; 320 mg) in 50 mL of EtOAc is stirred under hydrogen atmosphere (H2, 1 atm) for 3 h. The catalyst is removed by vacuum filtration through celite, washed with EtOAc, and the combined filtrate and washings are concentrated and dried under vacuum to give 5-(4-amino-2,6-dimethylphenoxy)-2-(2-methoxyethoxymethoxy)benzoic acid 2-methoxy-ethoxymethyl ester: NMR (CDCl3) 2.07 (s, 6H), 3.37 (s, 3H), 3.40 (s, 3H), 3.52-3.62 (m, 4H), 3.83-3.92 (m, 4H), 5.26 (s, 2H), 5.52 (s, 2H), 6.60 (s, 2H), 6.80 (dd, 1H, J=8.3, 3), 7.13 (d, 1H, J=8.3)7.24 (d, 1H, J=3).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH3:22]I>>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]=[C:7]2[N:12]([CH3:22])[C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[N:17][C:9]=3[S:8]2)=[CH:4][CH:3]=1
Reactant: O=c1nc(Nc2ccc(Br)cc2)sc2ncccc12
Reactant: CI
Agent: [H-]
Agent: [Li+]
Product: Cn1c(=Nc2ccc(Br)cc2)sc2ncccc2c1=O
Yield: 85.7 %

Procedure:
The reaction procedure of Example 11 was followed except that 900 mg (2.69 mmol) of 2-(4-bromoanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 24 mg of lithium hydride and =420 mg of methyl iodide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 803 mg of 2-[(4-bromophenyl)imino]-2,3-dihydro-3-methyl-4H-pyrido[3,2-e]-1,3-thiazin-4-one (86%, recrystallized from a mixture of ether and hexane) as a low polarity substance and 107 mg of 2-[N-(4-bromophenyl)-N-methylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (recrystallized from ether) as a high polarity substance.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]([CH2:26][CH3:27])[N:19]=[C:20]3[CH:25]=[CH:24][CH:23]=[N:22][C:21]=23)=[CH:13][CH:12]=1.IC.[C:30](=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[CH2:26]([N:18]1[C:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][C:2]3[N:1]([CH3:30])[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[CH:12][CH:13]=2)=[C:21]2[N:22]=[CH:23][CH:24]=[CH:25][C:20]2=[N:19]1)[CH3:27]
Reactant: O=C([O-])[O-]
Reactant: CCn1nc2cccnc2c1-c1ccc(Oc2nc3ccccc3[nH]2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCn1nc2cccnc2c1-c1ccc(Oc2nc3ccccc3n2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
A mixture of 3-[4-(1H-benzimidazol-2-yloxy)phenyl]-2-ethyl-2H-pyrazolo[4,3-b]pyridine (25 mg) obtained in Example 3, iodomethane (5.72 μl), cesium carbonate (34.4 mg) and DMF (1 ml) was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized from ethyl acetate/hexane to give the title compound (24.0 mg).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2[C:13]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][CH:15]=[C:16]([Cl:17])[C:4]=2[N:3]=1.[Cl:23][C:24]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:25]=1[NH2:26].C(=O)([O-])O.[Na+]>CN1CCCC1=O>[Cl:17][C:16]1[C:4]2[N:3]=[C:2]([NH:26][C:25]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:24]=3[Cl:23])[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]=2[C:13]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][CH:15]=1
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)Cn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)Cn1c(Nc2ccc(Cl)cc2Cl)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 100 °C
Reaction time: 84 h
Yield: 11.9 %

Procedure:
A mixture of ethyl [2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]acetate (708 mg, 2.06 mmol), 2,4-dichloroaniline (1.00 g, 6.19 mmol) and N-methyl-2-pyrrolidinone (0.5 mL) was stirred at 100° C. for 3.5 days. After cooling, the reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by basic silica gel column chromatography eluting with a 3-15% ethyl acetate/n-hexane gradient mixture. The resulting solid was washed with n-hexane to give the title compound (115 mg, 0.245 mmol, 12%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][N:18]([CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:12]2=[N:11][C:10]=1[C:28]([OH:30])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:32][CH2:33][C:34](=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>C1COCC1>[F:42][C:39]1[CH:38]=[CH:37][C:36]([CH2:35][C:34](=[O:43])[CH2:33][NH:32][C:28]([C:10]2[N:11]=[C:12]3[N:18]([CH2:19][C:20](=[O:27])[N:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)[CH:17]=[CH:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:30])=[CH:41][CH:40]=1
Reactant: O=C(O)c1nc2n(CC(=O)N3CCCCC3)ccn2c(=O)c1OCc1ccccc1
Reactant: NCC(=O)Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: O=C(CNC(=O)c1nc2n(CC(=O)N3CCCCC3)ccn2c(=O)c1OCc1ccccc1)Cc1ccc(F)cc1
Reaction time: 8 h
Yield: 40.2 %

Procedure:
To a solution of the product of example 4 (1.0 g, 2.4 mmol) in THF (10 ml) was added compound 1-amino-3-(4-fluoro-phenyl)-propan-2-one hydrochloride (1.0 g, 4.9 mmol), EDCI.HCl (560 mg, 2.9 mmol), HOBt (400 mg, 2.9 mmol) and TEA (1 g, 9.9 mmol) successively at room temperature. The mixture was stirred overnight, after which saturated sodium bicarbonate was added and then extracted with ethyl acetate. The extracts were combined, washed with brine, and then dried over sodium sulfate. The product was purified by column chromatography (CH2Cl2/MeOH=100/1) to give the desired product (540 mg, 40% yield).
Reaction SMILES: [C:1]([C@@:3]1([CH2:32][CH3:33])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:27]=[CH:26][C:18]([C:19]([O:21]C(C)(C)C)=[O:20])=[C:17]([O:28][CH2:29][CH3:30])[CH:16]=3)[N:9]=2)[C:4]1=[O:31])#[N:2].[ClH:34]>C(OCC)(=O)C>[ClH:34].[C:1]([C@@:3]1([CH2:32][CH3:33])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:27]=[CH:26][C:18]([C:19]([OH:21])=[O:20])=[C:17]([O:28][CH2:29][CH3:30])[CH:16]=3)[N:9]=2)[C:4]1=[O:31])#[N:2]
Reactant: CCOc1cc(Nc2nccc(N3CC[C@@](C#N)(CC)C3=O)n2)ccc1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOc1cc(Nc2nccc(N3CC[C@@](C#N)(CC)C3=O)n2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 4-((4-((3R)-3-cyano-3-ethyl-2-oxopyrrolidin-1-yl)pyrimidin-2-yl)amino)-2-ethoxybenzoate (120 mg) obtained in Step A of Example 250 was added a solution of 4 M hydrogen chloride in ethyl acetate (6.0 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (90 mg).
Reaction SMILES: [CH2:1]([C:3]([OH:18])([CH2:6][CH2:7]/[CH:8]=[C:9](/[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1)\[CH3:10])[CH2:4][CH3:5])[CH3:2].Br[CH2:20][C:21]1[CH:22]=[C:23]([C:31](OC)=[O:32])[C:24](=[CH:29][CH:30]=1)[C:25](OC)=[O:26]>>[OH:32][CH2:31][C:23]1[CH:22]=[C:21]([CH:30]=[CH:29][C:24]=1[CH2:25][OH:26])[CH2:20][O:17][C:13]1[CH:12]=[C:11](/[C:9](/[CH3:10])=[CH:8]/[CH2:7][CH2:6][C:3]([CH2:4][CH3:5])([OH:18])[CH2:1][CH3:2])[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(CBr)cc1C(=O)OC
Reactant: CCC(O)(CC)CC/C=C(\C)c1cccc(O)c1
Product: CCC(O)(CC)CC/C=C(\C)c1cccc(OCc2ccc(CO)c(CO)c2)c1
Yield: 84.3 %

Procedure:
In a manner similar to Example 64(d), by reacting 112 mg (0.39 mmol) of (E)-3-ethyl-7-(3-hydroxyphenyl)oct-6-en-3-ol with 145 mg (0.51 mmol) of dimethyl 4-bromomethylphthalate, 131 mg (74%) of expected product are obtained in the form of an oil.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH:7]([C:10]1[CH:32]=[CH:31][C:13]([CH2:14][NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([CH3:9])[CH3:8].[N-:33]=[N+:34]=[N-:35].[Na+]>O>[C:24]([O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]2[N:15]([CH2:14][C:13]3[CH:31]=[CH:32][C:10]([CH:7]([CH3:9])[CH3:8])=[CH:11][CH:12]=3)[N:35]=[N:34][N:33]=2)=[CH:18][CH:19]=1)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)c1ccc(CNC(=O)c2ccc(OC(=O)C(C)(C)C)cc2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: CC(C)c1ccc(Cn2nnnc2-c2ccc(OC(=O)C(C)(C)C)cc2)cc1
Reaction time: 2 h
Yield: 52.9 %

Procedure:
Phosphorus pentachloride (0,249 g) was added to a solution of N-(4-isopropylbenzyl)-4-pivaloyloxybenzamide (0.353 g) in dichloeomethane (5 ml) under ice cooling, and stirring was continued for 2 h. This reaction mixture was added dropwise to a solution of sodium azide (0.78 g) in H2O (10 ml) at room temperature, and stirring was continued for 1 h. The mixture was extracted with chloroform, and the extract was washed with water, dried and evaporated to dryness. The residue was purified by column chromatography on silica gel with ethyl acetate-benzene (5/100) as an eluate and crystallization from hexane gave 0.2 g of the title compound.
Reaction SMILES: O[C:2]1[C:3](=[O:22])[N:4]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[N:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH3:23]>>[NH2:23][C:2]1[C:3](=[O:22])[N:4]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[N:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: N
Reactant: O=c1c(O)c([N+](=O)[O-])cnn1Cc1cccc2ccccc12
Product: Nc1c([N+](=O)[O-])cnn(Cc2cccc3ccccc23)c1=O
Temperature: 130 °C

Procedure:
9.4 g (31.6 mmol) of 4-hydroxy-2-naphthalen-1-ylmethyl-5-nitro-2H-pyridazin-3-one were combined with 150 ml saturated methanolic ammonia solution and heated to 130° C. for 24 hours in a Roth bomb. The mixture was concentrated down to a volume of about 40 ml using the rotary evaporator, the product precipitated was suction filtered and recrystallised from tetrahydrofuran.
Reaction SMILES: Br[CH2:2][CH2:3][O:4]C1CCCCO1.[ClH:11].[CH3:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[NH:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:16]=[N:15][CH:14]=1>>[ClH:11].[OH:4][CH2:3][CH2:2][N:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:21]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:22]=2[C:13]([CH3:12])=[CH:14][N:15]=[CH:16]3)[CH2:25][CH2:26]1
Reactant: BrCCOC1CCCCO1
Reactant: Cc1cncc2cccc(NC3CCNCC3)c12
Agent: Cl
Product: Cc1cncc2cccc(NC3CCN(CCO)CC3)c12

Procedure:
According to the method of Example 144, an alkylation reaction with 2-(2-bromoethoxy)tetrahydro-2H-pyran and a deprotection reaction were performed by using the compound of Example 106 to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([CH3:7])[CH:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:4][C:3]1=[O:17]>CO.[Pd]>[CH3:1][N:2]1[CH:6]([CH3:7])[CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][C:3]1=[O:17]
Reactant: CC1C(c2ccc([N+](=O)[O-])cc2)CC(=O)N1C
Agent: [Pd]
Solvent: CO
Product: CC1C(c2ccc(N)cc2)CC(=O)N1C
Yield: 100 %

Procedure:
A solution of 4.89 g (20.9 mmoles) of Ir in 50 ml of methanol and 0.49 g of 10% palladium on charcoal are placed into a 250 ml hydrogenation flask and hydrogenated at room temperature for 30 hr. The catalyst is filtered off and the methanol evaporated in vacuo. The resulting 1,5-dimethyl-4-(4'-aminophenyl)-pyrrolidin-2-one (Is), isolated in 100% yield, is dissolved in 12 ml of 18% hydrochloric acid in a 250 ml beaker and dropwise treated with 5.23 ml of 4 N sodium nitrite solution at 0°-5° C. After 5 min at 0° C. the excess nitrite was destroyed with urea. After 10 min at 0°-5° C. the diazonium solution was added dropwise to a freshly prepared solution of CuCl (20.9 mmoles) in 8 ml of 37% hydrochloric acid at 0° C. A brown precipitate forms immediately which is warmed to 60° C. for 1 hr. Extraction with chloroform and washing with water gave 4.30 g of crude reaction product after evaporation. After filtration through 130 g of silicagel 3.80 g (81%) of It were recovered as a gum.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]=O)=[CH:4][N:3]=1.[NH3:11].CO>O[Mo](O)(=O)=O>[CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][NH2:11])=[CH:4][N:3]=1
Reactant: N
Reactant: Cc1ncc(C=O)c(N)n1
Agent: O=[Mo](=O)(O)O
Solvent: CO
Product: Cc1ncc(CN)c(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
Into an Erlenmeyer's flask of 100 ml, 2.00 g (14.6 millimole) of 2-methyl-4-amino-5-formylpyrimidine, 40 g of 20 wt. % ammonia-methanol solution and 2.0 mg of molybdic acid (H2MoO4.H2O) were added, and the mixture was stirred for 2 hours under room temperature, with the flask being closely stoppered. Following subsequently the same procedure as in Example 1, 2-methyl-4-amino-5-aminomethylpyrimidine was obtained at a yield of 93.5%.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]1([C:17]2[C:25]([CH:26]=[CH:27][C:28]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][C@@H:31]3[CH2:36][CH2:37][OH:38])=[O:29])=[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]3[N:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>C(Cl)Cl.C(N(CC)CC)C>[C:11]1([C:17]2[C:25]([CH:26]=[CH:27][C:28]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][C@@H:31]3[CH2:36][CH:37]=[O:38])=[O:29])=[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]3[N:18]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(C=Cc1c(-c2ccccc2)nn2ccccc12)N1CCCC[C@@H]1CCO
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CC[C@H]1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Temperature: -45 °C
Reaction time: 0.17 h
Yield: 38.4 %

Procedure:
A solution of dimethyl sulfoxide (202 mg) in methylene chloride (1.0 ml) was added dropwise to a solution of oxalyl dichloride (247 mg) in methylene chloride (10 ml) over 5 minutes at -78° C. After 10 minutes, a solution of (2R)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-hydroxyethyl)piperidine (trans isomer) (364 mg) in methylene chloride (3.4 mg) was added dropwise over 10 minutes at -78° C. The solution was stirred at -78° C. for 20 minutes and at -45° C. for 1 hour. Triethylamine (986 μl) was added to the solution and the mixture was stirred at -20°~0° C. for 20 minutes. Saturated ammonium chloride solution (20 ml) was added to the reaction mixture was the mixture was extracted with methylene chloride (10 ml×2). The combined extracts were washed with brine (10 ml), dried over magnesium sulfate and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (10 g) with a mixture of methylene chloride and ethyl acetate (10:1) as an eluent to give (2R)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(formylmethyl)piperidine (trans isomer) (139.0 mg) as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:31][CH2:32][CH2:33][CH3:34])[N:8]=[C:9]([CH2:27][CH2:28][CH2:29][CH3:30])[C:10]=1[CH2:11][C:12]1[S:13][C:14]([C:17]2([C:22]([O:24]CC)=[O:23])[CH2:21][CH:20]=[CH:19][CH2:18]2)=[CH:15][CH:16]=1)=[O:5])C.[OH-].[Na+]>CO>[CH2:31]([N:7]1[C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH2:11][C:12]2[S:13][C:14]([C:17]3([C:22]([OH:24])=[O:23])[CH2:21][CH:20]=[CH:19][CH2:18]3)=[CH:15][CH:16]=2)[C:9]([CH2:27][CH2:28][CH2:29][CH3:30])=[N:8]1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCc1nn(CCCC)c(C(=O)OCC)c1Cc1ccc(C2(C(=O)OCC)CC=CC2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nn(CCCC)c(C(=O)O)c1Cc1ccc(C2(C(=O)O)CC=CC2)s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The product of Step 2, above (86) (40 mg), was dissolved in 1.0 ml of methanol and an excess of 2N NaOH (0.5 ml) was added. The reaction mixture was stirred at room temperature for 5 hours, evaporated to dryness and the residue taken up into water. The aqueous solution was extracted with ethyl acetate to remove unreacted starting material, then was acidified with acetic acid and extracted again with ethyl acetate. The EtOAc extract was dried and concentrated using heptane to azeotrope off any residual acetic acid. The resulting solid was precipitated from EtOAc/hexanes, filtered and dried under vacuum to yield the title compound (87).
Reaction SMILES: [OH:1][CH:2]([C:19]1[CH:20]=[C:21]([Si:24]([CH3:27])([CH3:26])[CH3:25])[O:22][CH:23]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[C:28](OC(=O)C)(=[O:30])[CH3:29].N1C=CC=CC=1>>[C:28]([O:1][CH:2]([C:19]1[CH:20]=[C:21]([Si:24]([CH3:26])([CH3:25])[CH3:27])[O:22][CH:23]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Solvent: c1ccncc1
Product: CC(=O)OC(CCCCCCCCO[Si](C)(C)C(C)(C)C)c1coc([Si](C)(C)C)c1

Procedure:
A solution of 4-(1-hydroxy-9-t-butyldimethylsiloxynonyl)-2-trimethylsilylfuran (0.892 g, 2.17 mmol), acetic anhydride (5 ml) and pyridine (0.729 g, 8.66 mmol) was stirred at room temperature until no starting material was visible by TLC. The reaction mixture was concentrated and the residue was taken up in ethyl ether, washed with 10% hydrochloric acid, saturated sodium bicarbonate, aqueous 5% cupric sulfate solution, water, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give the title compound which was carried on without further purification.
Reaction SMILES: CS/[C:3](=[N:9]\[C:10](=O)[CH:11]=[C:12]([CH3:14])[CH3:13])/[N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:16][NH:17][NH2:18]>>[CH3:16][N:17]1[C:10]([CH:11]=[C:12]([CH3:14])[CH3:13])=[N:9][C:3]([N:4]2[CH2:8][CH2:7][CH2:6][CH2:5]2)=[N:18]1
Reactant: CNN
Reactant: CS/C(=N\C(=O)C=C(C)C)N1CCCC1
Product: CC(C)=Cc1nc(N2CCCC2)nn1C
Yield: 106 %

Procedure:
Was prepared in the same manner as described in General procedure 1d, using 3-Methyl-but-2-enoic acid 1-methylsulfanyl-1-pyrrolidin-1-yl-meth-(Z)-ylideneamide and methylhydrazine as starting materials. Extraction and evaporation of the solvents afforded 1-Methyl-5-(2-methyl-propenyl)-3-pyrrolidin-1-yl-1H-[1,2,4]triazole (261 mg/106%) as yellow oil. MS: m/z=207.1 (M+H+)