Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)[CH:10]([C:18]3[C:19]([OH:27])=[CH:20][C:21]4[O:25][CH2:24][CH2:23][C:22]=4[CH:26]=3)[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:29]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)[C:10]3([CH2:35][O:27][C:19]4[CH:20]=[C:21]5[C:22](=[CH:26][C:18]3=4)[CH2:23][CH2:24][O:25]5)[C:9]2=[O:28])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2ccc(F)cc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2cc(F)ccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-6-fluoro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-6′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (87%) as a colorless solid: mp 194-196° C. (methanol); 1H NMR (300 MHz, CDCl3) δ7.42-7.25 (m, 10H), 7.10-7.04 (m, 2H), 6.67-6.61 (m, 1H), 6.40-6.39 (m, 2H), 6.23-6.19 (m, 1H), 4.81 (ABq, 2H), 4.53 (t, J=9.0 Hz, 2H), 2.99 (t, J=9.0 Hz, 2H); MS (ES+) m/z 463.8 (M+1).
Reaction SMILES: [C:1]([CH:4]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[CH:5]([CH3:13])[CH:6](C)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2].N1C=CC(CC(=O)C)=CC=1.CC(=CC)C(OCC)=O>>[C:1]([CH:4]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[CH:5]([CH3:13])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(C)C(C)C(C(C)=O)c1ccncc1
Agent: CC(=O)Cc1ccncc1
Agent: CC=C(C)C(=O)OCC
Product: CCOC(=O)CC(C)C(C(C)=O)c1ccncc1

Procedure:
B-4. Ethyl 4-Acetyl-2,3-dimethyl-4-(4-pyridinyl)butanoate, using 1-(4-pyridinyl)-2-propanone and ethyl α,β-dimethylacrylate.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([NH:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.Br[CH2:19][C:20]([O:22]C(C)(C)C)=[O:21].[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>CN(C=O)C.O>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([N:6]([CH2:7][C:8]([F:11])([F:10])[F:9])[CH2:19][C:20]([OH:22])=[O:21])=[C:4]([C:14]([F:15])([F:16])[F:17])[CH:3]=1
Reactant: FC(F)(F)CNc1ccc(Br)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC[SiH](CC)CC
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)CN(CC(F)(F)F)c1ccc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64.4 %

Procedure:
To a slurry of hexanes-washed NaH (0.492 g of a 60% w/w suspension in mineral oil, 12.3 mmol) in dry DMF (10 mL) at 0° C. was added a solution of 4-bromo-N-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)aniline (1.96 g, 6.13 mmol) in DMF (2 mL), dropwise over 5 min. The mixture was stirred 15 min and tert-butyl bromoacetate (1.82 mL, 12.3 mmol) was added dropwise over 1 min. The mixture was stirred overnight, slowly warming to rt. The mixture was poured into water and the whole was extracted with Et2O (×3). Combined organic portions were washed (water, brine), dried over Na2SO4, filtered and concentrated. The residue was dissolved in CH2Cl2 (20 mL) and to this solution was added Et3SiH (4.9 mL, 31 mmol) and TFA (20 mL). The mixture was stirred 1.5 h at rt and concentrated in vacuo. The residue was partitioned between water/Et2O and the layers were separated. The organic layer was concentrated in vacuo. The residue was purified by filtration through a pad of silica gel (10% EtOAc/hexanes, then EtOAc to elute carboxylic acid) affording 1.50 g of the title compound as a pale yellow solid: MS (APCI) m/z 380 ([M−H]−, 81Br), 378 ([M−H]−, 79Br).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:26])([F:25])[C:7]1[C:16]([C:17](O)=[O:18])=[C:15]([OH:20])[C:14]2[C:9](=[CH:10][C:11]([C:21]([F:24])([F:23])[F:22])=[CH:12][CH:13]=2)[N:8]=1>C1C=CC=CC=1>[F:5][C:6]([F:26])([F:25])[C:7]1[C:16]([C:17]([Cl:3])=[O:18])=[C:15]([OH:20])[C:14]2[C:9](=[CH:10][C:11]([C:21]([F:24])([F:23])[F:22])=[CH:12][CH:13]=2)[N:8]=1
Reactant: O=C(O)c1c(C(F)(F)F)nc2cc(C(F)(F)F)ccc2c1O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1c(C(F)(F)F)nc2cc(C(F)(F)F)ccc2c1O
Yield: 102.2 %

Procedure:
31.89 g of thionyl chloride were added to a suspension of 17.246 g of the product of Step E in 535 ml of anhydrous benzene and the mixture was refluxed for 105 minutes and was then evaporated to dryness under reduced pressure at 40° C. The residue was taken up in benzene and the solution was evaporated to dryness under the same conditions to obtain 18.62 g of 2,7-bis-(trifluoromethyl)-4-hydroxy-3-quinolinecarboxylic acid chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][C:18](N=[N+]=[N-])=[O:19])=[CH:12][C:11]([Br:23])=[CH:10][CH:9]=2)=[O:5])[CH3:2].S(O)(C1C=CC(C)=CC=1)(=O)=O.O.[CH2:36]([OH:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][C:18]([O:43][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:19])=[CH:12][C:11]([Br:23])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1CCCC(=O)N=[N+]=[N-]
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)c1[nH]c2ccc(Br)cc2c1CCCC(=O)OCc1ccccc1
Yield: 86.1 %

Procedure:
3-(3-Azidocarbonyl-propyl)-5-bromo-1H-indole-2-carboxylic acid ethyl ester (1.28 g, 3.4 mmol, 1.0 equiv), TsOH hydrate (65 mg, 0.34 mmol, 0.1 equiv), and benzyl alcohol (0.74 mL, 6.8 mmol, 2.0 equiv) were refluxed in 30 mL of benzene for 16 h. The solution was then poured into saturated aqueous sodium bicarbonate (50 mL) and extracted with 2×50 mL of diethyl ether. The pooled organic fractions were dried (Na2SO4), filtered, and evaporated. The residue was purified by flash chromatography on silica gel using 0% EtOAc in hexanes graded to 20% EtOAc in hexanes to provide 5-bromo-3-[3-benzyloxycarbonyl-propyl]-1H-indole-2-carboxylic acid ethyl ester (1.3 g, 75%). This material was used without further manipulation.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([N:29]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]3=[O:38])[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:41][N:40]=[N:39][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([N:29]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]3=[O:38])[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc2c(C)cc(N3Cc4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(N3Cc4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-propyl-4-methyl-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH3:32][CH:33]([SH:35])[CH3:34]>O>[CH:33]([S:35][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)([CH3:34])[CH3:32]
Reactant: CC(C)S
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Sc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 60 °C
Yield: 77.4 %

Procedure:
To a mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.50 g of potassium carbonate and 2 ml of DMF, a mixture of 0.15 g of 2-propanethiol and 0.5 ml of DMF was added. The reaction mixture was stirred while heating at 60° C. for two hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with 5% aqueous solution of potassium carbonate and a saturated sodium chloride solution, sequentially, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.26 g of 2-(3-isopropylthiopyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 43”).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)[CH:5]=[CH:4]1.[CH3:27][O:28][CH2:29][C:30](O)=[O:31]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH2:29][O:28][CH3:27])[CH2:24][CH2:25]2)[CH:5]=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1
Reactant: COCC(=O)O
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1

Procedure:
The title compound, off-white solid (96 mg, 84%), MS (ISP) m/z=399.4 [(M+H)+], mp 124° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-4-yl-piperidin-1-yl)-ethyl]-cyclohexyl-amine dihydrochloride (intermediate A) (115 mg, 0.29 mmol) and methoxy-acetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[F:12][C:13]([F:25])([F:24])[C:14]1[N:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:20]([C:17]2[CH:18]=[N:19][C:14]([C:13]([F:25])([F:12])[F:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)nc1
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1ccc(C(F)(F)F)nc1
Yield: 56.6 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (200 mg, 1.38 mmol), 6-(trifluoromethyl)pyridine-3-sulfonyl chloride (0.31 g, 1.25 mmol) and DMAP (cat) gave the title compound (250 mg, 58%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[NH:20][C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1.Cl.Cl[CH2:33][CH2:34][N:35]([CH3:37])[CH3:36]>>[CH3:36][N:35]([CH3:37])[CH2:34][CH2:33][N:20]1[C:19](=[O:24])/[C:18](=[CH:17]/[C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:6]2[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[C:27]([F:30])([F:29])[F:28])[N:9]=[CH:10]3)/[S:22][C:21]1=[O:23]
Reactant: CN(C)CCCl
Reactant: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)NC4=O)ccc32)c(C(F)(F)F)c1
Agent: Cl
Product: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)N(CCN(C)C)C4=O)ccc32)c(C(F)(F)F)c1

Procedure:
(5Z)-3-[2-(Dimethylamino)ethyl]-5-[(1-{[4-(methyloxy)-2-(trifluoromethyl)phenyl]methyl}-1H-indazol-5-yl)methylidene]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 8) and 2-chloro-N,N-dimethylethylamine hydrochloride following General Procedure H.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[O:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][C@@H:10]1[CH2:19][N:20]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]2[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=2[S:36]1(=[O:46])=[O:45])[C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCCl>[C:5]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[O:9][C@@H:10]([CH2:19][N:20]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]3[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=3[S:36]1(=[O:46])=[O:45])[C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:11][CH2:12]2)(=[O:7])[CH3:6]
Reactant: O=C(OCc1ccccc1)N(CCCCN1C(=O)c2ccccc2S1(=O)=O)C[C@H]1CCc2ccccc2O1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc2c(c1)CC[C@H](CN(CCCCN1C(=O)c3ccccc3S1(=O)=O)C(=O)OCc1ccccc1)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
12.7 g (95 mmol) of anhydrous aluminum chloride are suspended in 10 ml of 1,2-dichloroethane. At 0° C., initially 5.9 ml (82 mmol) of acetyl chloride are added. At 0° C., a solution of 34 g (63 mmol) of benzyl (2R)-3,4-dihydro-2H-chromen-2-ylmethyl[4-(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)butyl]carbamate in 100 ml of 1,2-dichloroethane is slowly added dropwise to this mixture. The reaction is stirred at room temperature overnight. The mixture is poured into ice-water and the organic phase is then separated off and the aqueous phase is repeatedly extracted with dichloromethane. The combined organic extracts are dried over magnesium sulfate and concentrated. The resulting crude product is purified by chromatography (silica gel, mobile phase toluene/ethyl acetate 3:1). This gives 9.6 g (26.5% of theory) of benzyl [(2R)-6-acetyl-3,4-dihydro-2H-chromen-2-yl]methyl[4-(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)butyl]carbamate.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:4].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([OH:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1>CC(C)=O>[CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:4].[S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)([O-:31])(=[O:30])=[O:29]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
Clopidogrel base was dissolved in acetone to obtain a clear solution. To it was added p-toluene sulfonic acid at room temperature. The reaction mixture was heated to reflux temperature for 2 to 10 hrs. The solvent was evaporated to dryness under reduced pressure to obtain amorphous Clopidogrel tosylate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH2:18][CH2:19][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:21][CH:22]=3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:27]([O:30][CH2:31][C:32]1[C:33]([N:47]2[CH2:59][CH2:58][N:50]3[C:51]4[CH2:52][CH2:53][CH2:54][CH2:55][C:56]=4[CH:57]=[C:49]3[C:48]2=[O:60])=[N:34][CH:35]=[CH:36][C:37]=1B1OC(C)(C)C(C)(C)O1)(=[O:29])[CH3:28].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:27]([O:30][CH2:31][C:32]1[C:33]([N:47]2[CH2:59][CH2:58][N:50]3[C:51]4[CH2:52][CH2:53][CH2:54][CH2:55][C:56]=4[CH:57]=[C:49]3[C:48]2=[O:60])=[N:34][CH:35]=[CH:36][C:37]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH2:18][CH2:19][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:21][CH:22]=3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:29])[CH3:28]
Reactant: Cn1cc(Br)cc(Nc2ccc(C3=CCN(C4COC4)CC3)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4=CCN(C5COC5)CC4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 80 °C
Yield: 66.6 %

Procedure:
A round-bottomed flask equipped with a reflux condenser was charged with 200e (300 mg, 0.72 mmol), 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (414 mg, 1.08 mmol), PdCl2(dppf) (57 mg, 0.070 mmol), K3PO4 3H2O (560 mg, 2.16 mmol), sodium acetate (177 mg, 2.16 mmol), acetonitrile (10 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 80° C. for 3 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified with silica-gel column chromatography eluting with 1:20 methanol/dichloromethane to afford 200f as a red solid (324 mg, 68%). MS-ESI: [M+H]+ 676.2
Reaction SMILES: [N:1]1([C:7]2[N:12]3[CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:15]=[C:11]3[CH:10]=[C:9]([NH2:22])[N:8]=2)[CH2:6][CH2:5]O[CH2:3][CH2:2]1.N1(C2N=C(N)C=C(N)N=2)CCCC[CH2:24]1>>[C:16]1([C:14]2[N:15]=[C:11]3[CH:10]=[C:9]([NH2:22])[N:8]=[C:7]([N:1]4[CH2:6][CH2:5][CH2:24][CH2:3][CH2:2]4)[N:12]3[CH:13]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cc(N)nc(N2CCCCC2)n1
Reactant: Nc1cc2nc(-c3ccccc3)cn2c(N2CCOCC2)n1
Product: Nc1cc2nc(-c3ccccc3)cn2c(N2CCCCC2)n1

Procedure:
The title compound was prepared in analogy to 5-morpholin-4-yl-2-phenyl-imidazo[1,2-c]pyrimidin-7-ylamine (Example 63, Step 1) from 2-piperidin-1-yl-pyrimidine-4,6-diamine. MS (m/e)=294.2 [M+H+].
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[C:10]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[O:11].[C:21]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])([CH3:23])[CH3:22].N1C=CN=C1>O>[O:6]([C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[C:10]([O:12][CH2:13][C:14]([F:15])([F:16])[F:17])=[O:11])[Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(OCC(F)(F)F)c1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)OCC(F)(F)F)c1
Reaction time: 10 h

Procedure:
Into a 250 mL round bottom flask was added 30 mL of dry dimethyl formamide and 4.0 parts of ester (47) and 3.5 parts of tert-butyldimethyl silyl chloride were added to the reaction flask with stirring. Three parts of Imidazole was added in portions and stirring was continued for 10 hours. The reaction mixture was diluted with 80 mL of water and the product was extracted with ethyl acetate. The organic layer was washed with water and dried on anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give an oil, yield 5.65 parts. The structure was confirmed on the basis of 1H NMR. The reaction proceeded as follows:
Reaction SMILES: [N:1]([C:4](=[CH:10][C:11]1[C:12]2[N:13]([CH:17]=[C:18]([CH3:20])[N:19]=2)[CH:14]=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-].[K+].[Br-]>>[CH3:20][C:18]1[CH2:17][N:13]2[CH:14]=[CH:15][C:16]3[C:11]([CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:1]=3)=[C:12]2[N:19]=1
Reactant: CCOC(=O)C(=Cc1cccn2cc(C)nc12)N=[N+]=[N-]
Agent: [Br-]
Agent: [K+]
Product: CCOC(=O)c1cc2c3n(ccc-2n1)CC(C)=N3

Procedure:
From 6b (yield: 52%); mp 201-203° C., IR (KBr) 3280, 1680, 1250 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.39 (t, 1H, J=7 Hz), 2.48 (s, 3H), 4.40 (q, 2H, J=7 Hz), 6.86 (d, 1H, J=7 Hz), 7.23 (s, 1H), 7.62 (s, 1H), 7.80 (d, 1H, J=7 Hz), 10.01 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ 14.1, 14.3, 61.1, 100.6, 107.9, 109.7, 114.4, 123.2, 126.3, 132.6, 140.6, 141.1, 161.6; MS m/z 243 (M+, 44), 197 (100), 169 (22), 168 (21), 143 (27). Anal. Calcd for C13H13N3O2: C, 64.19; H, 5.39; N, 17.27. Found: C, 64.44; H, 5.58; N, 17.34.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:22][CH2:21][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[CH:20]=[C:12]3[C:11]2=[O:23])[N:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][C@H:48]3[CH3:57])=[CH:43][N:42]=2)[C:26]1=[O:58].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[CH3:24][N:25]1[C:26](=[O:58])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:54][O:55][CH2:56]4)[CH2:49][C@H:48]3[CH3:57])=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([N:10]3[CH:22]=[CH:21][N:13]4[C:14]5[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=5[CH:20]=[C:12]4[C:11]3=[O:23])[N:5]=[CH:4][CH:3]=2)=[CH:30]1
Reactant: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ccn5c6c(cc5c4=O)CCCC6)c3C=O)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 30.6 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 4-chloro-2-(1-oxo-6,7,8,9-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde 103b (150 mg, 0.45 mmol), 151f (331 mg, 0.69 mmol), PdCl2(dppf) (37 mg, 0.045 mmol), K3PO4 (190 mg, 0.90 mmol), sodium acetate (74 mg, 0.90 mmol), acetonitrile (15 mL), and water (1.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified with silica-gel column chromatography eluting with 1:20 methanol/dichloromethane to afford 151g as a red solid (89 mg, 30%). MS-ESI: [M+H]+ 647
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20](S(C)(=O)=O)[C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.C[N:28]1C(C2SC3N=CN=C(S(C)(=O)=O)C=3C=2)=C(C2C=CC=CC=2)N=C1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:28])[C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cnc(-c2cccc(Br)c2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Product: Cn1cnc(-c2cccc(Br)c2)c1-c1cc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Example 8 but using 6-[4-(3-Bromophenyl)-1-methyl-1H-imidazol-5-yl]-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (Intermediate 59) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (intermediate 17). Solid (357 mg, 58%);
Reaction SMILES: [N:1]1([C:6]([C:8]2[S:12][C:11]([C:13]3(O)[CH2:22][CH2:21][C:16]4([O:20][CH2:19][CH2:18][O:17]4)[CH2:15][CH2:14]3)=[N:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:26])=O>N1C=CC=CC=1>[Cl:26][C:13]1([C:11]2[S:12][C:8]([C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])=[CH:9][N:10]=2)[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1
Reactant: O=C(c1cnc(C2(O)CCC3(CC2)OCCO3)s1)N1CCCC1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(c1cnc(C2(Cl)CCC3(CC2)OCCO3)s1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.4 %

Procedure:
To a mixture of 8-[5-(pyrrolidin-1-ylcarbonyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5]decan-8-ol (0.2 g, 3.32 mmol) in pyridine (3 mL) at 0° C. was added thionyl chloride (0.5 mL, 6.86 mmol) under N2. The mixture was warmed to room temperature and stirred overnight. After the reaction solution was concentrated, water and EtOAc were added. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with saturated NaCl, dried (MgSO4), concentrated and flash chromatographed (50% EtOAc/hexane to EtOAc) to give 0.10 g of the title compound in 53% yield. MS (EI) calcd: (M+1)+=356.1. Found: 357.0.
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:18][N:19]([CH3:23])[C:20](Cl)=[O:21]>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:18][N:19]([CH3:23])[C:20]([NH:10][O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:21]
Reactant: NOCc1ccccc1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)NOCc1ccccc1
Yield: 42 %

Procedure:
To a stirred slurry of benzyloxyamine hydrochloride (3.19 g, 20 mmol) in the THF (40 ml) at room temperature under nitrogen was added triethylamine (6.13 ml). This slurry was stirred, and dimethylcarbamyl chloride (1.84 ml) was added rapidly. 4-(N,N-dimethylamino)pyridine (1.0 g, 0.4 equiv.) was added, and the mixture was stirred for 20 hours. The mixture was filtered, and the filtrate evaporated. Purification by chromatography on silica provided N,N-dimethyl-N'benzyloxyurea as a colorless oil (1.62 g, 42% yield).