Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[OH:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][N:14]3[C:21](=[O:22])[C:20]([C:23]([OH:25])=[O:24])=[CH:19][N:18]=[C:15]32)=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][N:14]3[C:21](=[O:22])[C:20]([C:23]([OH:25])=[O:24])=[CH:19][N:18]=[C:15]32)=[CH:10][CH:9]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: O=C(O)c1cnc2n(c1=O)CCc1ccc(O)cc1-2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)Oc1ccc2c(c1)-c1ncc(C(=O)O)c(=O)n1CC2
Temperature: 0 °C
Yield: 63.7 %

Procedure:
Isobutyryl chloride (455 mg., 4.26 mmoles) was added to a stirred, cooled (ice-water) mixture of 6,7-dihydro-10-hydroxy-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylic acid (1.03 g., 3.87 mmoles) and triethylamine (785 mg., 7.75 mmoles) in methylene chloride (20 ml.). The mixture was concentrated to dryness and the residue was triturated with cold 1N HCl, and then crystallized from benzene to give the title compound 0.81 g. (64% yield). The product was recrystallized successively from ethyl acetate and methanol to give the analytical sample, m.p. 183°-185°.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:31]1[C:43]2[CH:42]([CH2:44][O:45][C:46]([NH:48][C@H:49]([C:57](O)=[O:58])[CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:47])[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]=2[CH:34]=[CH:33][CH:32]=1>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)[CH:14]=1)[C:57](=[O:58])[C@H:49]([CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[NH:48][C:46]([O:45][CH2:44][CH:42]1[C:43]2[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=2[C:36]2[C:41]1=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:47])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1cc(-c2cc(CNCCO[Si](C)(C)C(C)(C)C)ccn2)cc(OC)c1OC
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Product: COc1cc(-c2cc(CN(CCO[Si](C)(C)C(C)(C)C)C(=O)[C@H](Cc3ccccc3)NC(=O)OCC3c4ccccc4-c4ccccc43)ccn2)cc(OC)c1OC

Procedure:
N-[2-(tert-Butyldimethylsilyloxy)ethyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amine (973 mg) and N-(9-fluorenylmethoxycarbonyl)-L-phenylalanine (871 mg) were treated in the same manner as in Preparation Example 9 to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:9][CH:8]([O:10]CC2C=CC=CC=2)[CH2:7]1)=[O:5])[CH3:2].C(OCC)(=O)C.[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:7][CH:8]([OH:10])[CH2:9]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1(NC(=O)OC(C)(C)C)CC(OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(NC(=O)OC(C)(C)C)CC(O)C1
Temperature: 25 °C

Procedure:
The 1-(N-(t-butoxycarbonyl)amino)-3-benzyloxy-cyclobutane-1-carboxylic acid ethyl ester synthesized as above is dissolved in an alcohol solvent such as ethanol or an acetate ester solvent such as ethyl acetate ester, and palladium-on-activated carbon (amount: 10 w/w % or more relative to the substrate) is added to the solution in an atmosphere of hydrogen to allow them to react under stirring at room temperature. The reaction solution is then filtered through Celite, and the filtrate is concentrated and purified to yield 1-(N-(t-butoxycarbonyl)amino)-3-hydroxy-cyclobutane-1-carboxylic acid ethyl ester (Step 4).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:7])=[N:5][N:6]=1.[S:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([NH:7][CH:11]2[CH2:12][CH2:13][S:8][CH2:9][CH2:10]2)=[N:5][N:6]=1
Reactant: Cc1nnc(N)[nH]1
Reactant: O=C1CCSCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nnc(NC2CCSCC2)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.5 %

Procedure:
To a solution (50 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (2.5 g) and tetrahydro-4H-thiopyran-4-one (3.6 g) in acetic acid was added sodium cyanoborohydride (8.1 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (2.4 g, 48%).
Reaction SMILES: [CH2:1]([C:4]1[C:5](=[O:19])[C:6]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:7]=2[NH:8][C:9](=[O:13])[C:10]=1[O:11]C)[CH:2]=[CH2:3].B(Br)(Br)Br>ClCCl>[CH2:1]([C:4]1[C:5](=[O:19])[C:6]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:7]=2[NH:8][C:9](=[O:13])[C:10]=1[OH:11])[CH:2]=[CH2:3]
Reactant: C=CCc1c(OC)c(=O)[nH]c2cc(Cl)ccc2c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C=CCc1c(O)c(=O)[nH]c2cc(Cl)ccc2c1=O
Reaction time: 1.5 h
Yield: 49 %

Procedure:
To a solution of 4-allyl-8-chloro-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.159 g) in dichloromethane (10 mL) was added boron tribromide (1M in dichloromethane, 1.8 mL). After 1.5 hours, the reaction mixture was quenched with 50 mL of saturated aqueous sodium bicarbonate. Dichloromethane (30 mL) was added and the mixture was adjusted to pH 3 using 2.4N hydrochloric acid. The organic portion was separated, washed (water, brine), dried and evaporated. The resulting yellowish solid was triturated with hexanes to afford the title compound (0.074 g); mp 172°-174° C.; NMR: 11.73 (s,1), 10.39 (s,1), 7.93 (d,1, J=8.6), 7.48 (s,1), 7.30 (dd,1, J=8.8, 2.1), 5.86-5.73 (m,1), 5.01-4.91 (m,2), 3.35 (m,2). Analysis for C13H10ClNO3.0.25 H2 O: Calculated: C, 58.22; H, 3.95; N, 5.22; Found: C, 58.18; H, 3.91; N, 5.13.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:21]=[N:20][C:19]=1[O:30][CH3:31].[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:31][O:30][C:19]1[N:20]=[N:21][C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:23][C:18]=1[C:3]1[NH:4][C:5]2[C:10]([C:2]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:9][CH:8]=[C:7]([CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:6]=2
Reactant: COc1nnc(-c2ccncc2)cc1-c1[nH]c2cc(CN3CCCCC3)ccc2c1I
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1nnc(-c2ccncc2)cc1-c1[nH]c2cc(CN3CCCCC3)ccc2c1-c1ccccc1
Temperature: 90 °C
Yield: 100.7 %

Procedure:
68 mg 3-Iodo-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-6-piperidin-1-ylmethyl-1H-indole, 17 mg phenylboronic acid, 86 mg potassium phosphate tribasic n-hydrate, and 12 mg tetrakis(triphenylphosphine)palladium(0) are dissolved in a mixture of 2.0 mL toluene and 72 μL water. Argon is bubbled through the solution for 5 minutes. The mixture is heated to 90° C. for 2.5 hours. Concentration in vacuo affords 62 mg crude product.
Reaction SMILES: [CH2:1]([CH:8]([CH:14]([OH:16])[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[CH2:1]([CH:8]([CH:14]([O:16][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccccc1)C(C)OC(=O)c1ccccc1
Yield: 85 %

Procedure:
A mixture of 0.04 mol of ethyl 2-benzyl-3-hydroxybutyrate, 0.045 mol of pyridine, 0.05 mol of benzoyl chloride and 40 ml of dried tetrahydrofuran (THF) was refluxed by heating for 8 hrs, and then was allowed to react at room temperature for further 12 hrs. Upon the completion of the reaction, the reaction mixture was filtered, and the solid component was wished with diethyl ether for three times. The organic phases were combined, wished well with saturated saline, and then dried over anhydrous sodium sulfate. After removing the solvent, residue was subjected to column chromatography to give a colorless liquid. Yield 85%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1)[N:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Brc1ccc2c(cnn2C2CCCCO2)c1
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a suspension of 5-bromo-1H-indazole (2.5 g, 12.69 mmol, 1.0 eq) in DCM (10 ml) was added dihydropyran (3.2 g, 38 mmol, 3.0 eq) and a catalytic amount of PTSA (12% in AcOH, 1.8 ml, 0.1 eq). The mixture was stirred overnight and neutralized by addition of sodium bicarbonate. Then the organic layer was sequentially washed with 10% citric acid and brine, dried on Na2SO4 and concentrated under vacuum. The resulting residue was purified by chromatography on silica gel, eluting with DCM to give the expected compound as a colorless liquid (3.57 g, 82%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][CH:16]2[O:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].[NH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=2)=[CH:27][CH:26]=1>>[CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][CH:16]([OH:18])[CH2:17][NH:21][CH2:22][CH2:23][O:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:29][CH:30]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOCc1ccc(OCC2CO2)cc1
Reactant: NCCOc1ccc(C2=NNC(=O)CC2)cc1
Product: CCCCOCCOCc1ccc(OCC(O)CNCCOc2ccc(C3=NNC(=O)CC3)cc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-n-butyloxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)phenyl]-4,5-dihydro-3-(2H)-pyridazinone.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]2[C:24]3[CH:23]=[CH:22][C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[NH:14][S:13](=[O:26])(=[O:25])[N:12]2[CH3:27])=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:50][N:51]([CH3:55])[CH2:52][CH2:53][NH2:54].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:50][N:51]([CH3:55])[CH2:52][CH2:53][NH:54][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([CH:11]2[C:24]3[CH:23]=[CH:22][C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[NH:14][S:13](=[O:26])(=[O:25])[N:12]2[CH3:27])[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: CN1C(c2ccc(F)c(C(=O)O)c2)c2ccc3cccnc3c2NS1(=O)=O
Reactant: CN(C)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CCNC(=O)c1cc(C2c3ccc4cccnc4c3NS(=O)(=O)N2C)ccc1F
Yield: 14.6 %

Procedure:
In a similar fashion, using route 37 general procedure 90, 2-fluoro-5-(2-methyl-3,3-dioxo-1,2,3,4-tetrahydro-3λ*6*-thia-2,4,5-triaza-phenanthren-1-yl)-benzoic acid 424 (60 mg, 0.15 mmol), TBTU (50 mg, 0.15 mmol), N,N-dimethylethane-1,2-diamine (16.9 μl, 0.15 mmol) and DIPEA (25.6 μl, 0.15 mmol) in DCM (1 ml) gave the title compound (10 mg, 14%) after purification by preparative HPLC (acidic conditions 1).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[Si:14]([O:21][C@@H:22]1[C@@H:26]([CH2:27][OH:28])[O:25][C@@H:24]([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl.N1C=CC=CC=1>[Si:14]([O:21][C@@H:22]1[C@@H:26]([CH2:27][O:28][C:2]([O:4][C:5]2[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)=[O:3])[O:25][C@@H:24]([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:23]1)([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:15])[CH3:16]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](COC(=O)Oc3ccc([N+](=O)[O-])cc3)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
p-Nitrophenyl chloroformate (252 mg, 1.25 mmol) in anhydrous methylene chloride was added to a stirred solution of 3'-O-(t-butyldimethylsilyl)thymidine (356 mg, 10 mmol, Wang et al. Nucleosides Nucleotides 1998, 17, 1033-1051) in anhydrous methylene chloride (4 mL) and pyridine (0.5 mL). The resulting solution was stirred at room temperature overnight, then cooled with ice, quenched with water (2 mL), stirred at 0° C. for 30 min, diluted with methylene chloride, washed with dilute acetic acid, water, then 5% sodium bicarbonate, dried over sodium sulfate, and concentrated to dryness. Chromatography on silica with ethyl acetate-hexanes (1:1 to 3:2) gave 505 mg of the titled compound as a colorless foam.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10](=[N:12][OH:13])[CH3:11].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:13][N:12]=[C:10]([C:3]1[C:4]([OH:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[OH:1])[CH3:11])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=NO)c1c(O)cc(C)cc1O
Product: CC(=O)ON=C(C)c1c(O)cc(C)cc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1-(2,6-dihydroxy-4-methylphenyl)ethanone oxime (Intermediate 17, 829 mg), acetic anhydride (2.6 ml, 27.5 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. After the removal of the volatiles, the residue was washed with water, filtered and dried. This afforded 1.0 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[C:12]=2[C:11]2[C:19]3[CH:25]=[C:24]([OH:26])[CH:23]=[C:22]([CH:27]=[CH2:28])[C:20]=3[O:21][C:10]=2[CH:9]=1.CO.[H][H]>[Ni].O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[C:12]=2[C:11]2[C:19]3[CH:25]=[C:24]([OH:26])[CH:23]=[C:22]([CH2:27][CH3:28])[C:20]=3[O:21][C:10]=2[CH:9]=1
Reactant: [H][H]
Reactant: C=Cc1cc(O)cc2c1oc1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(O)cc2c1oc1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Yield: 48.9 %

Procedure:
A solution of (863) (0.054 g, 0.167 mmol) prepared as described in example 444 in a methanol:tetrahydrofuran mixture (1:1, 4 mL) was hydrogenated over Raney nickel (100 mg) and hydrogen. The product was purified by column chromatography using a gradient of 0–100% ethyl acetate in dichloromethane to give (864) (0.032 g, 59%). 1H NMR δ [(CD3)2SO] 9.65 (s, 1H), 7.92 (m, 1H), 7.56 (d, J=3.0 Hz, 1H), 7.43 (m, 3H), 6.96 (d, J=2.5 Hz, 1H), 2.90 (q, 2H), 1.5 (t, 3H). MH−:392, 390.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:11][CH3:12])[CH2:7][CH:6](OC)[NH:5][C:4]1=[O:10].[C:13]([O:16][C@@H:17]1[C@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@@H:20]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[O:19][C@H:18]1[N:31]1[C:40]2[N:39]=[CH:38][N:37]=[C:35]([NH2:36])[C:34]=2[N:33]=[CH:32]1)(=[O:15])[CH3:14]>C1C=CC=CC=1.CC(C)=O>[C:13]([O:16][C@@H:17]1[C@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@@H:20]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[O:19][C@H:18]1[N:31]1[C:40]2[N:39]=[CH:38][N:37]=[C:35]([NH:36][CH:6]3[NH:5][C:4](=[O:10])[C:3]([O:2][CH3:1])([O:11][CH3:12])[CH2:7]3)[C:34]=2[N:33]=[CH:32]1)(=[O:15])[CH3:14]
Reactant: COC1CC(OC)(OC)C(=O)N1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: COC1(OC)CC(Nc2ncnc3c2ncn3[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)NC1=O
Temperature: 160 °C
Yield: 73.4 %

Procedure:
3,3,5-Trimethoxy-2-pyrrolidinone (445 mg) was evenly admixed with adenosine 2',3',5'-triacetate (1 g) and the mixture was melted and reacted by heating at 160° C. for 2 hours. The reaction mixture was then allowed to cool and subjected to silica gel column chromatography using benzene-acetone (2:1) as the eluent to give N6 -(3,3-dimethoxy-2-oxo-5-pyrrolidinyl)adenosine 2',3',5'-triacetate (1 g). This product was dissolved in ammonia-saturated methanol (30 ml) and left standing at 5° C. for 17 hours, after which time it was concentrated under reduced pressure. The residue was washed with benzene and the insolubles were subjected to silica gel column chromatography using chloroform-methanol (10:1) as the eluent. The active fractions were pooled and concentrated under reduced pressure to give crystals. Recrystallization from methanol-acetone yielded N6 -(3,3-dimethoxy-2-oxo-5-pyrrolidinyl)adenosine as colorless crystals (680 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[C:3]=1[CH3:14].[CH3:15][NH2:16].O>C(#N)C>[Cl:13][C:4]1[C:3]([CH3:14])=[C:2]([NH:16][CH3:15])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(Cl)c(C)c1Cl
Reactant: CN
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cnc(Cl)c(C)c1NC
Temperature: 50 °C
Reaction time: 72 h
Yield: 81 %

Procedure:
To a solution of ethyl 4,6-dichloro-5-methylnicotinate (2.6 g, 11.1 mmol) in acetonitrile (60 mL) was added dropwise 40% methylamine in water (689 mg, 22.2 mmol, 60 mL), and the mixture was stirred at 50° C. for 72 h. LCMS monitored the reaction was completed. The reaction mixture was concentrated and extracted with ethyl acetate (100 mL). The organic layer was separated, combined, washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column (petroleum ether:ethyl acetate=2:1) to get the title compound (2.05 g, 81%) as a colorless oil. MS (ES+) C10H13ClN2O2 requires: 228, 230. found: 229, 231 [M+H]+.
Reaction SMILES: [CH3:1][C@@:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][NH:3]1.[C:10](Cl)(=[O:12])[CH3:11].C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[C:10]([N:3]1[CH2:4][CH2:5][CH2:6][C@@:2]1([CH3:1])[C:7]([OH:9])=[O:8])(=[O:12])[CH3:11]
Reactant: CC(=O)Cl
Reactant: C[C@@]1(C(=O)O)CCCN1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC[C@@]1(C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
To a solution of (S)-2-methyl-pyrrolidine-2-carboxylic acid (50.0 mg, 0.387 mmol) dissolved in N,N-dimethylacetamide (1.5 mL, 16 mmol) was added a solution of acetyl chloride (31.9 mg, 0.406 mmol) dissolved in N,N-dimethylacetamide (0.5 mL), and then N,N-diisopropylethylamine (1 mL, 6 mmol) was added and the reaction mixture stirred at room temperature for 30 minutes. The reaction mixture was concentrated to produce the title compound as a light brown oil (30 mg, 40% yield). (m/z): [M+H]+ calcd for C8H11NO3 172.10 found 172.2.
Reaction SMILES: Br.[CH3:2][C:3]1[N:4]=[C:5]([NH2:20])[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:9]=1.C(N(C(C)C)C(C)C)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[CH3:2][C:3]1[N:4]=[C:5]([NH:20][C:30](=[O:32])[CH3:31])[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(N)sc1-c1ccnc(N2CCOCC2)c1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(C)c(-c2ccnc(N3CCOCC3)c2)s1
Temperature: 75 °C

Procedure:
A stirred suspension of 4-methyl-5-(2-morpholin-4-yl-pyridin-4-yl)-thiazol-2-ylamine hydrobromide (13b) (0.035 g, 0.098 mmol) and ethyldiisopropylamine (0.034 ml, 0.196 mmol) in acetic anhydride (2 ml) is heated to 75° C. for 2 hours. The reaction mixture is cooled to room temperature and the solvent is removed in vacuo. Ethyl acetate is added and a white solid by-product is filtered off. The filtrate is concentrated in vacuo to afford the titled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[N:10]=[C:9]2[CH:20]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:22]1([CH2:27][C:28]2[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])[CH2:26][CH2:25][CH2:24][CH2:23]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[N:10]=[C:9]2[CH2:20][NH:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:28]([CH2:27][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[CH:29]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(CN2CCCC2)c1
Reactant: O=Cc1nc2ccc(F)cc2c(=O)n1-c1cccnc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: O=c1c2cc(F)ccc2nc(CNc2cccc(CN3CCCC3)c2)n1-c1cccnc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(2-chloro-pyridin-3-yl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (0.150 g, 0.49 mmol), 3-pyrrolidin-1-ylmethylaniline (0.044 g, 0.25 mmol), and acetic acid (0.14 mL, 2.45 mmol) in dichloroethane (10 mL) was chilled to 0° C. and sodium triacetoxyborohydride (0.312 g, 1.47 mmol) was added. The reaction was stirred for 1 hour at 0° C. and then allowed to warm to ambient temperature. The reaction was quenched by addition of saturated aqueous bicarbonate and continued stirring for 30 minutes. The phases were separated and the aqueous layer was extracted with methylene chloride. The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (45 g) with elution proceeding as follows: 10% methanol/0.5% ammonium hydroxide/chloroform (200 mL), nil; (50 mL), unweighed impurity; (25 mL), nil; (75 mL), unweighed mixed fraction; (200 mL), 0.010 g (8%) of 3-(2-chloro-pyridin-3-yl)-6-fluoro-2-[(3-pyrrolidin-1-ylmethyl-phenylamino)-methyl]-3H-quinazolin-4-one as a pale yellow solid which had: 1H NMR δ 8.60 (d, J=5 Hz, 1 H), 7.80 (t, J=5 Hz, 1 H), 7.76 (d, J=9 Hz, 1 H), 7.71 (dd, J=3, 9 Hz, 1 H), 7.58-7.50 (m, 2 H), 7.35 (dd, J=5, 8 Hz, 1 H), 7.14-7.08 (m, 2 H), 6.80 (dd, J=4, 9 Hz, 1 H), 4.44 (s, 1 H), 3.90-3.65 (m, 4 H), 2.79 (br s, 4 H), 1.90 (br s, 4 H); APCI MS m/z=464 (P+1).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]#[N:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1([CH3:24])[C:15]2[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:14]=2[NH:13][C:12](=[O:23])[O:11]1>>[CH3:9][C:10]1([CH3:24])[O:11][C:12](=[O:23])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:2]3[S:6][C:5]([C:7]#[N:8])=[CH:4][CH:3]=3)=[CH:16][C:15]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: N#Cc1ccc(Br)s1
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)s3)cc21

Procedure:
Prepared according to Procedure B from 5-bromo-2-thiophenecarbonitrile and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. Off-white solid: mp 264-266° C. 1H-NMR (DMSO-d6) δ10.3 (s, 1H), 7.97 (d, 1H, J=7.9 Hz), 7.60-7.66 (m, 3H). 6.96 (d, 1H, J=8.1 Hz), 1.65 (s, 6H). MS (APCI) m/z 285 (M+H)+, 302 (M+NH4)+. Anal. Calc. For C15H12N202S: C, 63.36; H, 4.25; N, 9.8 Found: C, 63.01; H, 4.36; N, 9.39.