Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:21])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27].C(N(CC)CC)C>C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:21][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:27]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nccc1-c1cc(NC(=O)c2cccc(Cl)c2)ccc1OCCN1CCCC1
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of 3-(1-methyl-1H-pyrazol-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (0.029 g, 0.10 mmol) in CH2Cl2 (1.5 mL) was added 3-chlorobenzoyl chloride (0.015 mL, 0.12 mmol) and triethylamine (0.018 mL, 0.13 mmol). The reaction was stirred for 1 h, and concentrated and purified by RP-HPLC. Lyophilization afforded a TFA salt as a brown oil (0.037 g, 87%). LCMS m/z (%)=425 (M+H35Cl, 100), 427 (M+H37Cl, 42). 1H NMR (400 MHz, DMSO-d6) δ: 10.40 (s, 1H), 8.01-8.00 (m, 1H), 7.94-7.87 (m, 2H), 7.72 (d, J=2.6 Hz, 1H), 7.70-7.67 (m, 1H), 7.60-7.55 (m, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.25 (d, J=9.0 Hz, 1H), 6.31 (d, J=1.8 Hz, 1H), 4.32-4.28 (m, 2H), 3.69 (s, 3H), 3.58-3.52 (m, 2H), 3.35-3.25 (m, 2H), 2.95-2.82 (m, 2H), 1.95-1.85 (m, 2H), 1.78-1.68 (m, 2H).
Reaction SMILES: CI.CN([CH:6]=[O:7])C.[Br:8][C:9]1[C:18]([O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Br:8][C:9]1[C:18]([O:19][S:20]([C:23]([F:26])([F:24])[F:25])(=[O:21])=[O:22])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[O:7][CH3:6]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(O)c(Br)c(OS(=O)(=O)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC)c(Br)c(OS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 1-liter egg plant-type flask, methyl iodide (6.67 mL, 105 mmol) was added to a DMF (200 mL) solution of methyl 4-bromo-3-hydroxy-5-{[(trifluoromethyl)sulfonyl]oxy}benzoate (19.9 g) and potassium carbonate (14.5 g, 105 mmol), and stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline water, dried with sodium sulfate, filtered, and concentrated to obtain a crude product. This was purified through silica gel column chromatography (Biotage [SiO2, 40+M]) with a hexane/ethyl acetate developer system to obtain the title compound as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:9]([C:15]2[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[N:17][N:16]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.O1CCCC1.CO.[Li+].[OH-]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:9]([C:15]2[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[N:17][N:16]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1C(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)n1nnnc1C(C(=O)O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a chilled (0° C.) solution of ethyl 3,3-bis(4- fluorophenyl)-2-[1-(1-methylethyl)-1H-tetrazol-5-yl]-2-propenoate (0.95 g, 2.39 mmoles) in 20 mL of 1:1 (v/v) mixture of tetrahydrofuran and methanol was added an aqueous solution of LiOH (4.0 mL, 3 Molar) in one single portion. The reaction mixture was stirred at 0° C. for 15 minutes followed by warming up to ambient temperature. Saponification was allowed to proceed at room temperature for four hours forming a very pale clear solution. The crude reaction mixture was diluted with 12 mL of 2M H2SO4 and the product was extracted into diethyl ether (40 mL×2). The organic layers were combined, dried over MgSO4, concentrated under reduced pressure and then vigorously dried under high vacuum (0.01 mmHg) at room temperature for 24 hours to yield the title compound. The propenoic acid was then utilized in the next step without further purification.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH:72]1[CH2:77][CH2:76][NH:75][CH2:74][C:73]1=[O:78].C(N(CC)CC)C>ClCCl>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([N:75]4[CH2:76][CH2:77][NH:72][C:73](=[O:78])[CH2:74]4)=[O:43])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:3])[CH3:5]
Reactant: O=C1CNCCN1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCNC(=O)C2)CC1
Reaction time: 2 h
Yield: 23.1 %

Procedure:
{4-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride salt (31.5 mg, 0.47 mmol, example 99), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 19.7 mg, 0.052 mmol, Advchemtech), piperazin-2-one (12 mg, ) and triethylamine (0.05 mL) was mixed in dichloromethane (2 ml) and stirred for 2 h. The mixture was diluted with dichloromethane (5 mL) and was washed with sodium hydroxide (0.1 N solution), saturated sodium chloride solution and water. Dichloromethane solution was dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by preparative HPLC (reversed phase, eluting with acetonitrile and water) gave the title compound (20.7 mg). HR-MS (ES, m/z) calculated for C39H48Cl2N7O4 [(M+H)+] 748.314, observed 748.3138.
Reaction SMILES: [F:1][C:2]([F:25])([C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3]([NH2:5])=[O:4].[CH3:26][Si:27]([CH3:30])([CH3:29])Cl.CCCCCCCCCCCCCCCC>CCCCCC>[CH3:26][Si:27]([CH3:30])([CH3:29])[N:5]([Si:27]([CH3:30])([CH3:29])[CH3:26])[C:3](=[O:4])[C:2]([F:25])([F:1])[C:6]([F:23])([F:24])[C:7]([F:21])([F:22])[C:8]([F:19])([F:20])[C:9]([F:17])([F:18])[C:10]([F:15])([F:16])[C:11]([F:14])([F:13])[F:12]
Reactant: C[Si](C)(C)Cl
Reactant: NC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCCCCCCCCCCCCCCC
Solvent: CCCCCC
Product: C[Si](C)(C)N(C(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)[Si](C)(C)C

Procedure:
First, perfluorooctaneamide (CF3(CF2)7CONH2) (46 g) was dissolved in n-hexane (300 ml). Thereafter, trimethylchlorosilane (15 ml) was dropped gradually into the solution obtained above, in a dry nitrogen atmosphere. Then this was allowed to react for two hours while being stirred. After the reaction was completed, hexadecane contained in the reaction solution was removed with the evaporator. Thus, N,N-bis(trimethylsilyl)perfluorooctaneamide was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:20]([CH3:23])([O-:22])=[O:21]>>[CH2:11]([N:10]([C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[CH:23][N+:20]([O-:22])=[O:21])=[CH:3][C:2]=1[Cl:1])[CH2:13][CH3:14])[CH3:12]
Reactant: CCN(CC)c1ccc(C=O)cc1Cl
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CCN(CC)c1ccc(C=C[N+](=O)[O-])cc1Cl
Temperature: 100 °C
Yield: 39 %

Procedure:
A solution was prepared by dissolving 34 grams (0.16 mol) of 3-chloro-4-(N,N-diethyl)aminobenzaldehyde in 150 ml of nitromethane, and added with 5 grams of ammonium acetate. The mixture was heated at 100° C. for 5 hours under agitation. The reaction solution was then cooled on a dry ice-acetone bath until crystallization had been completed. The separated solid (crystal) was filtered off and dried in vacuum. The obtained product was recrystallized from acetonitrile for two times. An amount of 16 grams of red crystals was obtained. The yield was 39%.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:12][CH2:13][CH2:14][NH:15][C:16]1[N:25]=[C:24]([NH2:26])[C:23]2[C:18](=[CH:19][C:20]([O:29][CH3:30])=[C:21]([O:27][CH3:28])[CH:22]=2)[N:17]=1.CN(C)C=O>O>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:12][CH2:13][CH2:14][NH:15][C:16]1[N:25]=[C:24]([NH2:26])[C:23]2[C:18](=[CH:19][C:20]([O:29][CH3:30])=[C:21]([O:27][CH3:28])[CH:22]=2)[N:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: COc1cc2nc(NCCN)nc(N)c2cc1OC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nc(NCCNCC(O)COc3ccccc3)nc(N)c2cc1OC
Reaction time: 48 h

Procedure:
3.8 g. Phenyl glycidyl ether and 10 g. 2-(2-aminoethylamino)-4-amino-6,7-dimethoxyquinazoline are dissolved in 5 ml. dimethylformamide and left to stand for 48 hours at ambient temperature. The reaction mixture is then poured into water, filtered with suction and purified chromatographically on a silica gel column in the manner described in Example 24. There are obtained 2.5 g. (24% of theory) of the desired product in the form of colorless crystals; m.p. 122°-124° C., after recrystallization from isopropyl alcohol.
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]1C=C[CH:13]=[CH:12][CH:11]=1>>[NH:10]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH:1]=[CH:13][CH:12]=[CH:11]1
Reactant: c1ccncc1
Reactant: O=C(Cl)c1ccccc1
Product: C1=CNc2ccccc2C=C1

Procedure:
As described for Example 1, 5 mmol of 4- (2-chlorobenzoyl)amino!benzoyl chloride is reacted with 5 mmol of 5,6-dihydro-7H-pyrimido 5,4-d! 1!benzazepine in pyridine to give the product as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:20])[CH3:1])=[CH:24][CH:23]=1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC1(C)CC(=O)c2ccc(-c3ccc(Cl)cc3)cc21
Temperature: 25 °C

Procedure:
To a stirred solution of trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester (0.25 g, 0.81 mmol) in glyme (7 mL) was added 4-chlorophenyl boronic acid (0.19 g, 1.22 mmol), a solution of sodium carbonate (0.26 g, 2.43 mmol) in water (1.5 mL), and tetrakis(triphenylphosphine)palladium (0) (0.05 g, 0.04 mmol). The resulting solution was heated to reflux for 2 hours. The mixture was cooled to room temperature, concentrated, taken up in ethyl acetate and filtered through a pad of the Celite® reagent. The filtrate was concentrated and the residue was purified by Gilson high performance liquid chromatography (HPLC—10 to 100 acetonitrile in water) to afford 5-(4-chlorophenyl)-3,3-dimethylindan-1-one as a white solid. (0.11 g, 50%). MS (ES) m/z 271.0; HRMS: calcd for C17H15ClO+H+, 271.0884; found (ESI, [M+H]+), 271.0877.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][O:25]2)[N:3]=1
Reactant: C1=COCCC1
Reactant: N#Cc1ccc2[nH]nc(Br)c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Yield: 76.1 %

Procedure:
To a solution of 13.67 g (61.56 mmol) of 3-bromo-1H-indazole-5-carbonitrile and 2.06 g (10.8 mmol, 0.175 equiv.) of p-toluenesulfonic acid monohydrate in 247 mL of anhydrous tetrahydrofuran (THF) was added 11.2 mL (123 mmol, 2.00 equiv.) of 3,4-dihydro-2H-pyran. The mixture was refluxed under a nitrogen atmosphere for 14 h. The reaction was quenched with saturated aqueous sodium bicarbonate (sat. aq. NaHCO3). The mixture was extracted twice with EtOAc. The combined organics were washed with 2×sat. aq. NaHCO3, 1×sat. aq. NaCl, and dried over Na2SO4. Chromatography of the crude material on 200 g of silica gel using 30% EtOAc in hexanes afforded the title compound (14.34 g, 76% yield): ES-MS (m/z) 306 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:33][CH2:32][CH:31]([NH:34][CH3:35])[CH2:30][CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.CCN(C(C)C)C(C)C.Br[CH2:50][C:51]1[CH2:55][O:54][C:53](=[O:56])[CH:52]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:38])[F:39])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:29][CH2:30][CH:31]([N:34]([CH3:35])[CH2:50][C:51]4[CH2:55][O:54][C:53](=[O:56])[CH:52]=4)[CH2:32][CH2:33]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C1C=C(CBr)CO1
Reactant: CNC1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC1=CC(=O)OC1)C1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(methylamino)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.18 mmol) in DMF (4 mL) was added DIEA (46 mg, 0.36 mmol), 4-(bromomethyl)-2,5-dihydrofuran-2-one (63 mg, 0.36 mmol). The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (40.0% up to 48.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 40.0% in 2 min); Detector, UV 254/220 nm. This resulted in 15.5 mg (13%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(4-[methyl[(5-oxo-2,5-dihydrofuran-3-yl)methyl]amino]piperidin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (Method 20) [M+H]+=655.2, RT=1.91 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=9.2 Hz), 7.28 (dd, 1H, J=4.4, 7.2 Hz), 7.09 (t, 1H, J=73.2 Hz), 6.04 (s, 1H), 5.24-5.22 (m, 2H), 4.86 (d, 2H, J=1.2 Hz), 4.39-3.37 (m, 1H), 4.01-3.93 (m, 1H), 3.47 (s, 2H), 3.10-3.01 (m, 1H), 2.67-2.62 (m, 2H), 2.20 (s, 3H), 1.76-1.73 (m, 2H), 1.56-1.42 (m, 1H), 1.40-1.29 (m, 1H).
Reaction SMILES: C(O[K])(C)(C)C.[CH3:7][C:8]1[NH:9][CH:10]=[CH:11][N:12]=1.[OH:13][CH:14]([CH2:17][OH:18])[CH2:15]Br.Cl>C(O)(C)(C)C.O1CCCC1>[OH:13][CH:14]([CH2:17][OH:18])[CH2:15][N:9]1[CH:10]=[CH:11][N:12]=[C:8]1[CH3:7]
Reactant: OCC(O)CBr
Reactant: Cc1ncc[nH]1
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: Cc1nccn1CC(O)CO
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
A200 ml flask was charged with 2.0 g of t-butoxypotassium, 70 ml of tetrahydrofuran, 1.23 g of 2-methylimidazole. After stirring for 30 minutes, a solution of 2.5 g of 2,3-dihydroxyl-n-propyl bromide in 5 ml of t-butanol was added. After refluxing for one hour, 5 ml of 1 N HCl solution was added and the mixture was allowed to stand over night. The solvent was evaporated under reduced pressure. The residue was extracted with dichloromethane, washed with saturated aqueous solution of sodium hydrogencarbonate, and dried over anhydrous magnesium sulfate. After removing anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography (development solvent: methyl acetate/methanol=90/10) to obtain 1.9 g of 1-(2′,3′-dihydroxylpropyl)-2-methylimidazole (compound (A-1)). 1H-NMR spectrum of the resulting compound is shown in FIG. 1.
Reaction SMILES: [OH:1][C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH:14]2[O:16][CH2:15]2)[N:3]=1.[NH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]([CH3:34])[CH2:29][C:30](=[O:33])[NH:31][N:32]=2)=[CH:23][CH:22]=1>>[OH:1][C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:28]([CH3:34])[CH2:29][C:30](=[O:33])[NH:31][N:32]=3)=[CH:25][CH:26]=2)[N:3]=1
Reactant: CC1CC(=O)NN=C1c1ccc(OCCN)cc1
Reactant: OC1=Nc2cccc(OCC3CO3)c2CC1
Product: CC1CC(=O)NN=C1c1ccc(OCCNCC(O)COc2cccc3c2CCC(O)=N3)cc1

Procedure:
Prepared analogously to Example 1 from 1-(3,4-dihydro-2-hydroxy-quinolin-5-yloxy)-2,3-epoxypropane and 6-[4-(2-aminoethoxy)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([C:12]([NH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@@H:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[CH3:19][O:18][C:16](=[O:17])[CH2:15][NH:14][C:12](=[O:13])[C:11]1[CH:20]=[CH:21][C:8]([N:5]2[CH2:6][CH2:7][CH:2]([NH:22][CH2:23][C@H:24]([OH:25])[C:26]3[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=3)[CH2:3][CH2:4]2)=[CH:9][CH:10]=1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: COC(=O)CNC(=O)c1ccc(N2CCC(=O)CC2)cc1
Product: COC(=O)CNC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from methyl {[4-(4-oxo-1-piperidineyl)benzoyl]amino}acetate (which was obtained in Example 162) and N-[5-((1R)-2-amino-1-hydroxy- ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as a white solid; mp >75° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.35 (m, 2H), 1.75-1.90 (m, 2H), 2.50-2.90 (m, 5H), 2.91 (s, 3H), 3.63 (s, 3H), 3.70-3.85 (m, 2H), 3.95 (d, J=5.7 Hz, 2H), 4.49 (dd, J=8.0, 4.3 Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.96 (d, J=8.9 Hz, 2H), 7.00 (dd, J=8.2, 2.0 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 7.71 (d, J=8.9 Hz, 2H), 8.60 (t, J=5.8 Hz, 1H); MS (ES) m/z: 521.3 (MH+); HRMS Calcd. for C25H37N4O7S(M+): 520.2064. Found: 520.2054.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:14][CH:15]=[CH2:16])([CH3:13])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:18].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OO)(C)(C)C>C1C=CC=CC=1>[CH2:14]([C:4]1([CH3:13])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11](=[O:18])[CH:12]=[C:3]1[O:2][CH3:1])[CH:15]=[CH2:16]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: C=CCC1(C)C(OC)=CCc2ccccc21
Agent: CC(C)(C)OO
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: C=CCC1(C)C(OC)=CC(=O)c2ccccc21
Yield: 24.9 %

Procedure:
To a solution of Example 123B (7.72 g, 36.1 mmol) in benzene (400 mL) was added celite (15 g), pyridinium dichromate (54.3 g, 144.3 mmol) and tert-butylhydroperoxide (70% in water) (19.9 mL, 144.3 mmol). The resultant solution was stirred at room temperature for 1.25 hours, followed by filtering the solution through a plug of celite (20 g) which was rinsed with benzene (100 mL). The combined filtrate was concentrated in vacuo, and the resultant residue was purified by column chromatography employing 70-230 mesh silica gel eluting with a mixture of 20% ethyl acetate in hexane followed by 50% ethyl acetate in hexane to provide the title compound as a light yellow oil (2.05 g, 25%). 1H NMR (300 MHz, DMSO-d6): δ 1.53 (s, 3 H), 2.77 m, 2 H), 3.82 (s, 3 H), 4.75 m, 2 H), 5.02 (m, 1H), 5.84 (s, 1 H), 7.42 m, 1 H), 7.65 (dt, J=8.1, 1.5 Hz, 1 H), 7.76 (d, J=8.1 Hz, 1 H), 7.96 (dd, J=7.7, 1.5 Hz, 1 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:7])[CH3:6].[H-].[Na+].Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[Cl:21])[CH:14]=[C:13]([C@@H:22]([NH:24][C:25]2[N:33]=[CH:32][N:31]=[C:30]3[C:26]=2[N:27]=[CH:28][N:29]3C(OC(C)(C)C)=O)[CH3:23])[N:12]=1.O>C1COCC1>[N:33]1[C:25]([NH:24][C@H:22]([C:13]2[N:12]=[C:11]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:7])[CH3:6])[C:20]3[C:15]([CH:14]=2)=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:21])[CH3:23])=[C:26]2[C:30]([NH:29][CH:28]=[N:27]2)=[N:31][CH:32]=1
Reactant: C[C@H](Nc1ncnc2c1ncn2C(=O)OC(C)(C)C)c1cc2cccc(Cl)c2c(Cl)n1
Reactant: CC(=O)NCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NCCOc1nc([C@H](C)Nc2ncnc3[nH]cnc23)cc2cccc(Cl)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred mixture of N-(2-hydroxyethyl)acetamide (110 mg, 1.07 mmol, 2.43 eq) in THF (20 mL) at 0° C., NaH (60% in mineral oil, 110 mg, 2.75 mmol, 6.25 eq) was added and the resulting mixture was stirred for 15 min. To this mixture, (S)-tert-butyl 6-(1-(1,8-dichloroisoquinolin-3-yl)ethylamino)-9H-purine-9-carboxylate 39 (200 mg, 0.44 mmol, 1.0 eq) was added. The resulting mixture was stirred at reflux for 2 h, cooled to RT and then poured into water (30 mL). The mixture was extracted with DCM (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (3% MeOH-DCM) to afford the product (S)—N-(2-(3-(1-(9H-purin-6-ylamino)ethyl)-8-chloroisoquinolin-1-yloxy)ethyl)acetamide 40. ESI-MS m/z: 426.0 [M+H]+.
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([OH:32])[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:35]([O:37][CH3:38])=[O:36].C(N(CC)CC)C>O1CCCC1>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([O:32][C:35]([O:37][CH3:38])=[O:36])[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cl
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)OC(C)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a stirred solution of p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate (500 mg) in tetrahydrofuran (20 ml) are added dropwise methyl chloroformate (200 mg) and triethylamine (216 mg) under ice cooling. After 1 hour, the reaction mixture is poured into ice water, and is extracted with ethyl acetate. The extract solution is washed with water, dried, and evaporated to give p-nitrobenzyl α-[3-penoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methoxycarbonyloxyethylidene)acetate (546 mg). Foam. Yield: 97%.