Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8].[CH3:30][N:31]=[C:32]=[S:33]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21]([NH:22][C:32]([NH:31][CH3:30])=[S:33])(=[O:23])=[O:24])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NCC1CCOc2cc(OC)c(S(N)(=O)=O)cc21
Reactant: CN=C=S
Solvent: CN(C)C=O
Product: CNC(=S)NS(=O)(=O)c1cc2c(cc1OC)OCCC2CNC(=O)c1cc(Cl)ccc1OC

Procedure:
(+)-4-(5-Chloro-2-methoxy-benzamidomethyl)-6-(methylaminothiocarbonyl-aminosulfonyl)-7-methoxychroman ##STR59## (+)-4-(5-Chloro-2-methoxy-benzamidomethyl)-6-(methylaminothiocarbonylaminosulfonyl)-7-methoxychroman is prepared as described in Example 4 from optically active 4-(5-chloro-2-methoxy-benzamidomethyl)-6-sulfamoyl-7-methoxychroman and methyl isothiocyanate. Melting point: 201° C.; [α]D20 : +47.2° (c=1, DMF); HPLC: ee 88.1%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:30]([O:34][C:35]([N:37]1[CH:42]([C:43]2[NH:44][C:45]([C:48]3[CH:53]=[CH:52][C:51](Br)=[CH:50][CH:49]=3)=[CH:46][N:47]=2)[CH:41]2[CH2:55][CH:38]1[CH2:39][CH2:40]2)=[O:36])([CH3:33])([CH3:32])[CH3:31].C(N(CC)CC)C.N#N>CN(C=O)C.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.[Cu]I.CO.CCOC(C)=O>[C:30]([O:34][C:35]([N:37]1[CH:42]([C:43]2[NH:44][C:45]([C:48]3[CH:53]=[CH:52][C:51]([C:28]#[C:27][C:24]4[CH:25]=[CH:26][C:21]([C:18]5[NH:17][C:16]([CH:12]6[CH2:13][CH2:14][CH2:15][N:11]6[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:29])[CH:6]([CH3:8])[CH3:7])=[N:20][CH:19]=5)=[CH:22][CH:23]=4)=[CH:50][CH:49]=3)=[CH:46][N:47]=2)[CH:41]2[CH2:55][CH:38]1[CH2:39][CH2:40]2)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: C#Cc1ccc(-c2cnc(C3CCCN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(C#Cc3ccc(-c4cnc(C5C6CCC(C6)N5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Yield: 53.5 %

Procedure:
A solution of (1-{2-[5-(4-Ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (500 mg, 1.27 mmol), 3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (530 mg, 1.27 mmol), and triethylamine (531 □L, 3.81 mmol) in DMF (6.4 mL) was degassed with N2 gas for 20 minutes. To the degassed solution was added Pd(PPh3)4 (150 mg, 0.13 mmol) and CuI (25 mg, 0.13 mmol). The pressure flask was sealed then heated at 80° C. overnight. After cooling to room temperature, the reaction was quenched with AcOH then purified by reverse phase preparative HPLC (10-70% MeCN—H2O; 0.1% formic acid modifier) then silica gel chromatography (0-10% MeOH-EtOAc gradient) to afford 3-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl ethynyl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (500 mg, 0.68 mmol, 54% yield). LCMS-ESI+: calc'd for C42H50N7O5: 732.4 (M+H+). Found: 732.2 (M+H+).
Reaction SMILES: FC1C=C([C@@H]2CCCC(=O)N2[C:16]([O:18]C(C)(C)C)=[O:17])C=C(F)C=1.[F:23][C:24]1[CH:25]=[C:26]([C@H:31]2[N:36]([C:37](OC(C)(C)C)=O)[C:35](=[O:44])[C@H:34]([CH3:45])[CH2:33][CH2:32]2)[CH:27]=[C:28]([F:30])[CH:29]=1>>[F:30][C:28]1[CH:27]=[C:26]([C@H:31]2[N:36]([CH2:37][C:16]([OH:18])=[O:17])[C:35](=[O:44])[C@H:34]([CH3:45])[CH2:33][CH2:32]2)[CH:25]=[C:24]([F:23])[CH:29]=1
Reactant: C[C@@H]1CC[C@@H](c2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1=O
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC[C@H]1c1cc(F)cc(F)c1
Product: C[C@@H]1CC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C1=O

Procedure:
Essentially following the procedures described for Intermediate 26, but using tert-butyl (3R,6S)-6-(3,5-difluorophenyl)-3-methylpiperidin-2-one-1-carboxylate in place of tert-butyl (6S)-6-(3,5-difluorophenyl)-3,3-diethylpiperidin-2-one-1-carboxylate, the title compound was prepared. MS: m/z=284 (M+1).
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[K+].ClC1[N:12]=[N:11][C:10]([NH:13][C@@H:14]2[C:19]3[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:18]=3[O:17][C:16]([CH2:29][O:30][CH3:31])([CH2:26][O:27][CH3:28])[C@H:15]2[OH:32])=[CH:9]C=1>C(O)(=O)C>[C:24]([C:21]1[CH:22]=[CH:23][C:18]2[O:17][C:16]([CH2:26][O:27][CH3:28])([CH2:29][O:30][CH3:31])[C@@H:15]([OH:32])[C@H:14]([NH:13][C:10]3[CH:9]=[CH:2][C:1](=[O:4])[NH:12][N:11]=3)[C:19]=2[CH:20]=1)#[N:25]
Reactant: CC(=O)[O-]
Reactant: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2ccc(Cl)nn2)[C@@H]1O
Agent: [K+]
Solvent: CC(=O)O
Product: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2ccc(=O)[nH]n2)[C@@H]1O
Reaction time: 5 h
Yield: 70 %

Procedure:
Potassium acetate (380 mg) and acetic acid (6 ml) were added to (-)-(3S,4R)-4-[(6-chloro-3-pyridazinyl)amino]-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1benzopyran-3-ol (750 mg) obtained in Example 5, and the mixture was refluxed with stirring for 5 hours. The reaction mixture was filtered and the residue was washed with acetic acid. The residue obtained by removing the solvent from the filtrate under reduced pressure was purified by silica gel column chromatography (ethyl acetate:ethanol=95:5), whereby (-)-(3S,4R)-4-[(6-acetyloxy-3-pyridazinyl)amino]-6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol (180 mg, 22.6%) and (-)-(3S,4R)-6-cyano-3,4-dihydro-4-[(1,6-dihydro-6-oxo-3-pyridazinyl)amino]-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol (500 mg, 69.9%) were obtained in the order of elution.
Reaction SMILES: [CH:1]([Si:3]([CH:8]=[CH2:9])([CH:6]=[CH2:7])[CH:4]=[CH2:5])=[CH2:2].[C:10]1([PH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:17]1([P:16]([CH2:2][CH2:1][Si:3]([CH2:8][CH2:9][P:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([CH2:6][CH2:7][P:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:4][CH2:5][P:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=C[Si](C=C)(C=C)C=C
Reactant: c1ccc(Pc2ccccc2)cc1
Product: c1ccc(P(CC[Si](CCP(c2ccccc2)c2ccccc2)(CCP(c2ccccc2)c2ccccc2)CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 39.2 %

Procedure:
A mixture of 27.2 g (0.2 mole) of tetravinyl silane and 149.5 g (0.804 mole) diphenylphosphine was reacted in a quartz pressure tube at 200° C. with u.v. light initiation until most of the diphenyl phosphine was converted. The hot, molten reaction mixture was added to 720 g of hot tuluene with stirring. The tetraadduct product precipitated from the solution as a white crystalline solid. The mixture was allowed to cool to ambient temperature and then filtered with suction. After washing with toluene and drying in vacuo, 84 g (47.7%) of crude product was obtained. This was recrystallized from 1200 ml of xylene to obtain 69 g of pure tetrakis-(diphenylphosphinoethyl) silane of mp. 198°-199° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1([F:23])[O:13][C:12]2[CH:14]=[CH:15][C:16]([C:18](O)=[O:19])=[CH:17][C:11]=2[O:10][C:9]1([F:22])[F:21].[OH-].[Na+]>O1CCCC1>[F:23][C:8]1([F:7])[O:13][C:12]2[CH:14]=[CH:15][C:16]([CH2:18][OH:19])=[CH:17][C:11]=2[O:10][C:9]1([F:21])[F:22]
Reactant: O=C(O)c1ccc2c(c1)OC(F)(F)C(F)(F)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of lithium aluminum hydride (1.40 g, 36.89 mmol) in tetrahydrofuran (30 ml) was gradually added 2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxine-6-carboxylic acid (4.65 g, 18.44 mmol) at 0° C. After the reaction solution was stirred at 0° C. for 10 min., 1N aqueous sodium hydroxide solution was added. Insoluble material was filtered off with celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the objective substance (3.54 g, 81%).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[O:32]1[C:41]2[C:36](=[CH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:32]1[C:41]2[C:36](=[CH:37][C:38]([C:2]3[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:3]=3)=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: CC1(C)OB(c2ccc3c(c2)CCCO3)OC1(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)CCCO2
Yield: 90.3 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.08 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 mg; 0.025 mmol), N,N-diisopropylethylamine (0.173 mL; 1 mmol) and 2-(chroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.131 g; 0.5 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.094 g (86%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:31]=[C:30]4[C:25]([C:26]([C:36]([O:38]C)=[O:37])=[CH:27][C:28]([C:32]([O:34]C)=[O:33])=[N:29]4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[C:12]([CH:40]([CH3:42])[CH3:41])[O:11][N:10]=1.CCO.O.[OH-].[Na+]>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:31]=[C:30]4[C:25]([C:26]([C:36]([OH:38])=[O:37])=[CH:27][C:28]([C:32]([OH:34])=[O:33])=[N:29]4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[C:12]([CH:40]([CH3:42])[CH3:41])[O:11][N:10]=1
Reactant: COC(=O)c1cc(C(=O)OC)c2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(=O)O)cc(C(=O)O)nc3c2)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 62.3 %

Procedure:
To a solution of 60 mg (0.10 mmol) of dimethyl 7-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2,4-quinolinedicarboxylate in a mixture of 1 mL THF, 3 mL EtOH, and 1 mL H2O was added 40 mg (0.99 mmol) of NaOH. The mixture was stirred at 60° C. for 16 hr. H2O (1.5 mL) was added to dissolve some solids then the solution was concentrated to ⅓ volume and added dropwise to 10 mL of 0.5 N HCl (aq). After sitting for 5 min, the resulting solids were collected by suction filtration, washed with H2O and dried to yield 36 mg (63%) of 7-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2,4-quinolinedicarboxylic acid as an orange solid. 1H NMR (400 MHz, DMSO-d6): δ 8.82 (d, J=9 Hz, 1H), 8.41 (s, 1H), 8.38 (s, 1H), 8.14 (dd, JA=2 Hz, JB=9 Hz, 1H), 7.79 (d, J=9 Hz, 2H), 7.61 (d, J=8 Hz, 2H), 7.55-7.51 (m, 1H), 6.94 (d, J=9 Hz, 2H), 4.88 (s, 2H), 3.45 (septet, J=7 Hz, 1H), 1.34 (d, J=7, 6H). ESI-LCMS m/z 578 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:19]([O:21]C)=[O:20])[C:16]([CH3:18])=[CH:17][C:12]=2[S:11][CH:10]([CH3:23])[C:9]1=[O:24])=[O:4].O1CCC[CH2:26]1.C(O)C>[OH-].[Na+]>[CH3:1][O:2][C:3]([NH:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:19]([OH:21])=[O:20])[C:16]([CH3:18])=[CH:17][C:12]=2[S:11][C:10]([CH3:23])([CH3:26])[C:9]1=[O:24])=[O:4]
Reactant: C1CCOC1
Reactant: COC(=O)NCCN1C(=O)C(C)Sc2cc(C)c(C(=O)OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)NCCN1C(=O)C(C)(C)Sc2cc(C)c(C(=O)O)cc21
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Methyl 4-{2-[(methoxycarbonyl)amino]ethyl}-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (210 mg) was dissolved in 1M aqueous sodium hydroxide solution/tetrahydrofuran/ethanol=(2:1:1), and the mixture was stirred at 80° C. for one hour. The reaction solution was concentrated under reduced pressure to remove ethanol. To the concentrated residue was added 2N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 4-{2-[(methoxycarbonyl)amino]-ethyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylic acid (200 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=O)[CH:7]([CH3:9])[CH3:8])=[O:4].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH2:41]([NH:48][NH2:49])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CCN(CC)CC>>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:10]([NH:49][NH:48][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:12])[CH:7]([CH3:9])[CH3:8]
Reactant: NNCc1ccccc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H](C(=O)NNCc1ccccc1)C(C)C
Yield: 65 %

Procedure:
The general procedure for the preparation of hydrazides described above was followed using N-(methoxycarbonyl)-(L)-valine (J. Med. Chem., 39, 3203-3216, 1996) (2.11 g, 12.0 mmol), EDAC (2.41 g, 12.6 mmol), HOBT (1.70 g, 12.6 mmol), NMM (1.38 mL, 12.6 mmol), benzylhydrazine×2HCl (2.45 g, 12.6 mmol) and Et3N (3.52 mL, 25.0 mmol), which gave the title compound (2.08 g, 65%) as a light yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].CN(C)C=O.[CH3:11][O:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:2][CH2:3][CH2:4][OH:5])=[CH:16][CH:15]=1
Reactant: OCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCO)cc1
Reaction time: 12 h
Yield: 29.7 %

Procedure:
To a 250 mL flask was added 3-bromo-1-propanol (4.17 g, 0.03 mol), anhydrous dimethylformamide (40 mL), methyl-4-hydroxybenzoate (3.0 g, 0.02 mol) and potassium carbonate (4.15 g, 0.03 mol). The flask was placed in a 50° C. oil bath and stirred for 12 hours. After cooling the reaction was diluted with ethyl acetate, transferred to separatory funnel, washed with aqueous 0.1 N hydrochloric acid, water then brine. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure to give 5.14 g of crude oil. Column chromatography [silica gel; eluent hexanes-ethyl acetate (1.68:1)] provided the desired product (1.25 g, 30%) as a white powder. 1H (CDCl3) δ(ppm): 2.04-2.08 (m, 2H); 3.86-3.88 (m, 5H); 4.17 (t, 2H); 6.91 (d, 2H); 7.98 (d, 2H); 13C (CDCl3) δ(ppm): 31.89, 51.81, 59.88, 65.50, 114.06, 122.67, 131.57, 162.60, 166.84.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Cl[CH2:17][C:18]#[C:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:7][CH:6]=1
Reactant: ClCC#Cc1ccccc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCC#Cc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 67.6 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with (3-chloro-l-propynyl)benzene (0.754 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The crude dichloromethane extract was purified by HPLC (dichloromethane-hexane; 4: 1) and the resulting solids were crystallized from diethyl ether-hexane to give 0.8 g of alpha-oxo-4-[(3-phenyl-2-propynyl)oxy]benzeneacetic acid methyl ester mp 57°-59° C.
Reaction SMILES: [I:1][C:2]1[C:6]([CH:7]=O)=[CH:5][N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:3]=1.[CH3:15][NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[I:1][C:2]1[C:6]([CH2:7][N:16]([CH3:15])[CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[CH:5][N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:3]=1
Reactant: O=Cc1cn(C2CCCCO2)nc1I
Reactant: CNCCNC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CN(CCNC(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
A mixture of 3-iodo-1-(oxan-2-yl)-1H-pyrazole-4-carbaldehyde (3.2 g, 10.45 mmol, 1.00 equiv), tert-butyl N-[2-(methylamino)ethyl]carbamate (2.2 g, 12.63 mmol, 1.21 equiv) and NaBH(OAc)3 (6.65 g, 31.38 mmol, 3.00 equiv) in dichloroethane (30 mL) was stirred for 2 h at room temperature. The reaction was quenched with 50 mL of saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with 3×200 mL of dichloromethane. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 30-100% ethyl acetate in petroleum ether to give 4.05 g (83%) of tert-butyl (2-(((3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)(methyl)amino)ethyl)carbamate as a light yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.48 (s, 1H), 5.35-5.30 (m, 1H), 4.13-4.03 (m, 1H), 3.71-3.63 (m, 1H), 3.36 (s, 2H), 3.26-3.25 (m, 2H), 2.52-2.49 (m, 2H), 2.21 (s, 3H), 2.09-2.01 (m, 3H), 1.68-1.58 (m, 3H), 1.44 (s, 9H) ppm. LCMS (method C, ESI): RT=0.58 min, m/z=465.0 [M+H]+.
Reaction SMILES: C[NH2:2].CCO.CO[C:8]([C:10]1[C:11]2[N:12]([CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:18]=2)[CH:13]=[CH:14][N:15]=1)=O>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:18]=[C:11]3[C:10]([CH2:8][NH2:2])=[N:15][CH:14]=[CH:13][N:12]3[CH:16]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1nccn2cc(-c3ccc(F)cc3)nc12
Reactant: CN
Solvent: CCO
Product: NCc1nccn2cc(-c3ccc(F)cc3)nc12
Temperature: 100 °C
Yield: 91 %

Procedure:
In a sealed tube vessel was added 8M methylamine in EtOH (10 mL, 80 mmol) and 8-chloro-2-(4-fluorophenyl)-imidazo[1,2-a]pyrazine (prepared from general procedure B using 3-chloropyrazin-2-ylamine and 2-bromo-1-(4-fluorophenyl)-ethanone; 2.30 g, 9.3 mmol). The mixture was heated at about 100° C. for about 1 h. The mixture was cooled to ambient temperature and the reaction mixture was partitioned between water and dichloromethane. The layers were separated. The organic layer was washed with brine, dried over Na2SO4, and filtered prior to concentrating under reduced pressure. The product was purified by silica gel chromatography using EtOAc/heptane (1:1) to give the title compound as a beige solid (2.05 g, 91%): LC/MS (Table 1, Method a) Rt=1.70 min; MS m/z: 243.3 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4([CH2:36][CH3:37])[CH2:33][CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[C:28]4=[O:35])[CH:22]=3)[CH:13]=2)[C:9]([CH3:38])=[N:8][CH:7]=1.C(N(CC)CC)C.[C:46](Cl)(=[O:48])[CH3:47]>C(Cl)Cl>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([CH2:11][N:10]2[C:6]([CH2:5][CH2:4][NH:3][C:46](=[O:48])[CH3:47])=[CH:7][N:8]=[C:9]2[CH3:38])=[CH:13][C:14]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2([CH2:36][CH3:37])[CH2:33][CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[C:28]2=[O:35])[CH:22]=1)#[N:17]
Reactant: CCC1(c2cccc(Oc3cc(Cn4c(CCN)cnc4C)ccc3C#N)c2)CCCCN(C)C1=O
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1(c2cccc(Oc3cc(Cn4c(CCNC(C)=O)cnc4C)ccc3C#N)c2)CCCCN(C)C1=O
Reaction time: 2 h

Procedure:
To a solution of 4-[5-(2-amino-ethyl)-2-methyl-imidazol-1-ylmethyl]-2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-benzonitrile dihydrochloride (as described in Example 11) (0.06 g, 0.108 mmol) in CH2Cl2 (3.0 mL) was added triethylamine (0.06 mL, 0.43 mmol) and acetyl chloride (0.010 mL, 0.14 mmol). After stirring for 2 hr, the solvents were removed in vacuo and the residue was partitioned with EtOAc and saturated NaHCO3. The EtOAc was dried with brine and MgSO4 and evaporated in vacuo to obtain the title compound.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:19][CH:20]([C:29]([CH3:36])([CH3:35])[CH2:30][O:31][C:32](=[O:34])[CH3:33])[C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])(=[O:18])[CH3:17].[CH:37]1[C:42]([N+:43]([O-:45])=[O:44])=[CH:41][CH:40]=[C:39](O)[CH:38]=1>O1CCCC1>[C:16]([O:19][CH:20]([C:29]([CH3:36])([CH3:35])[CH2:30][O:31][C:32](=[O:34])[CH3:33])[C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][C:39]1[CH:38]=[CH:37][C:42]([N+:43]([O-:45])=[O:44])=[CH:41][CH:40]=1)=[O:27])=[O:22])(=[O:18])[CH3:17]
Reactant: CC(=O)OCC(C)(C)C(OC(C)=O)C(=O)NCCC(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(=O)OCC(C)(C)C(OC(C)=O)C(=O)NCCC(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 32.3 %

Procedure:
Dicyclohexylcarbodiimide (15.5 g) was added to a solution of 22.6 g of 3-[N-(2,4-diacetoxy-3,3-dimethyl-1-oxobutyl)amino]propionic acid and 10.4 g of p-nitrophenol in 500 ml of tetrahydrofuran, and the mixture was stired for one night. After completion of the reaction, insoluble matter was removed and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate. The resulting solution was washed with saturated aqueous sodium bicarbonate solution, with water and then with saturated saline, and dried over anhydrous sodium sulfate. After removing the solvent by evaporation, 10.2 g of the objectived compound was obtained as a residue (yield: 32%).