Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=2)=[N:9]1)=O)(C)(C)C.C[O-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH2:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8][N:9]=2)=[CH:23][CH:22]=1)[CH3:25]
Reactant: CCc1ccc(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)cc1
Agent: C[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CO
Product: CCc1ccc(Cc2n[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A mixture of zinc powder (712 mg) and dibromoethane (0.04 ml) in N,N-dimethylformamide (2.5 ml) were stirred under heating at 70° C. for 10 minutes under argon atmosphere. The reaction mixture was cooled to room temperature, and chlorotrimethylsilane (0.04 ml) was added thereto, and the mixture was stirred at room temperature for 30 minutes. To the activated zinc solution was added dropwise a solution of 4-ethylbenzyl bromide (1.74 g) in N,N-dimethylformamide (10 ml) at 0° C. over a period of 2 hours. Subsequently, the mixture was stirred at 0° C. for 2 hours, to prepare a solution of 4-ethylbenzylzinc bromide in N,N-dimethylformamide, which was used in the subsequent step without further purification. (2) A solution of tris(dibenzylideneacetone)dipalladium (0) (167 mg) and tri(2-furyl)phosphine (135 mg) in tetrahydrofuran (20 ml) was stirred at room temperature for 5 minutes under argon atmosphere. Thereto were added 1-t-butoxycarbonyl-3-iodo-1H-indazole (2.0 g) and the above 4-ethylbenzylzinc bromide (N,N-dimethylformamide solution) at 0° C., and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The extract was washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-92:8) to give 1-t-butoxycarbonyl-3-(4-ethylphenylmethyl)-1H-indazole (1.37 g) as colorless oil. APCI-Mass m/Z 337 (M+H). (3) The above 1-t-butoxycarbonyl-3-(4-ethylphenylmethyl)-1H-indazole (1.35 g) was dissolved in methanol (15 ml), and added thereto was 28% sodium methoxide solution (methanol solution, 1.0 ml), and the mixture was stirred at room temperature for one hour. Added thereto was an aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from hexane to give the desired 3-(4-ethylphenylmethyl)-1H-indazole (800 mg) as colorless crystals. APCI-Mass m/Z 237 (M+H).
Reaction SMILES: N1C2C(=NC=CC=2)N(O[C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=[O:12])N=1.Cl.[F:44][CH2:45][CH2:46][NH2:47]>CC(N(C)C)=O>[F:44][CH2:45][CH2:46][NH:47][C:11]([C:13]1[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]2\[C:21](=[O:41])[NH:22][C:23]3[C:28]\2=[CH:27][C:26]([S:29]([CH2:32][C:33]2[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:40])(=[O:30])=[O:31])=[CH:25][CH:24]=3)[NH:15][C:14]=1[CH3:42])=[O:12]
Reactant: NCCF
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)On1nnc2cccnc21
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCF
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (100 mg, 0.162 mmol) in DMA (2 mL) was added 2-fluoro-ethylamine hydrochloride salt (32 mg, 2 eq.). The mixture was stirred at rt for 2 hours. The reaction was concentrated, diluted with DCM, washed with sat. NaHCO3 and water, concentrated and triturated with methanol to give the titled compound as a yellow solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][C:15]([C:16]#[N:17])([C:12]1[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:14][CH:13]=1)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC#N)cc1
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(O[Si](C)(C)C(C)(C)C)cc1

Procedure:
Prepare by the method of example 1.1.2 using 4-(tert-butyldimethylsilyloxy)-phenyl-acetonitrile (0.161 mol) and ethyl bromoacetate (0.325 mol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]1>>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:27]4[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]4)=[CH:4][CH:5]=3)[C:12](=[O:26])[CH:13]=2)=[N:20][CH:21]=1
Reactant: O=c1cc(OCc2ccc(Br)cn2)ccn1CCc1ccc(CBr)cc1
Reactant: CC(=O)NC1CCNCC1
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(OCc4ccc(Br)cn4)cc3=O)cc2)CC1

Procedure:
N-[1-(4-{2-[4-(5-Bromo-pyridin-2-ylmethoxy)-2-oxo-2H-pyridin-1-yl]-ethyl}-benzyl)-piperidin-4-yl]-acetamide is prepared as example 12.1c from 75 mg (0.16 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(5-bromo-pyridin-2-ylmethoxy)-1H-pyridin-2-one (example 12.1b) and 89 mg (0.63 mmol) N-piperidin-4-yl-acetamide.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17]Cl>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH2:17][O:16][CH2:15][CH2:14][Si:13]([CH3:20])([CH3:19])[CH3:12])[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1[nH]nc(Cl)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(Cl)cc(Br)c1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
A 500-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with anhydrous DMF (150 mL) and 4-bromo-6-chloropyridazin-3(2H)-one (10.0 g, 47.8 mmol). The reaction mixture was cooled to 0° C. and sodium hydride was added. The reaction was stirred at 0° C. for 20 min. After this time, 2-(trimethylsilyl)ethoxymethyl chloride (11.9 g, 71.6 mmol) was added and the cooling bath was removed, and the reaction was stirred at room temperature for 3 h. The reaction was then quenched with saturated aqueous sodium bicarbonate (30 mL). The mixture was extracted with ethyl acetate (2×300 mL). The extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 110a in a 56% yield (9.00 g) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.02 (s, 1H), 5.42 (s, 2H), 3.79 (t, 2H, J=5.4 Hz), 0.96 (t, 2H, J=5.4 Hz), 0.01 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][C:4]([C:6]1[C:7]([C:22](OC)=[O:23])=[CH:8][N:9]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[CH:10]=1)=O.[CH3:27][NH:28][NH2:29].Cl>C(O)C>[CH3:27][N:28]1[C:22](=[O:23])[C:7]2=[CH:8][N:9]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[CH:10]=[C:6]2[C:4]([CH2:3][CH:2]([CH3:26])[CH3:1])=[N:29]1
Reactant: CNN
Reactant: COC(=O)c1cn(Cc2cccc3ccccc23)cc1C(=O)CC(C)C
Agent: Cl
Solvent: CCO
Product: CC(C)Cc1nn(C)c(=O)c2cn(Cc3cccc4ccccc34)cc12

Procedure:
Methyl 4-(3-methyl-1-oxobutyl)-1-(1-naphthalenylmethyl)-1H-pyrrole-3-carboxylate (0.35 g) prepared as described in c) above and methylhydrazine (0.10 ml) in ethanol (15 ml) were heated to reflux for 16 hours. The mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate, which was washed with brine, dried, and evaporated to a gum. The gum was chromatographed with ethyl acetate-isohexane (1:1) to afford a solid which was recrystallised from cyclohexane to give 2,6-dihydro-2-methyl-4-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyridazin-1-one (0.16 g).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH3:19])[S:6]([C:9]2[CH:10]=[N:11][C:12]([Sn](C)(C)C)=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:3][CH2:2]1.[NH2:20][C:21]1[C:26]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[C:33](=[O:37])[NH:32][CH2:31][CH2:30]3)=[CH:25][C:24](Br)=[CH:23][N:22]=1>>[NH2:20][C:21]1[N:22]=[CH:23][C:24]([C:12]2[CH:13]=[CH:14][C:9]([S:6]([N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH3:19])(=[O:8])=[O:7])=[CH:10][N:11]=2)=[CH:25][C:26]=1[C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[NH:32][CH2:31][CH2:30]2
Reactant: Nc1ncc(Br)cc1-c1ccc2c(c1)CCNC2=O
Reactant: CN(CC1CC1)S(=O)(=O)c1ccc([Sn](C)(C)C)nc1
Product: CN(CC1CC1)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc4c(c3)CCNC4=O)c2)nc1
Yield: 45 %

Procedure:
General method D was applied to N-(cyclopropylmethyl)-N-methyl-6-(trimethylstannyl)pyridine-3-sulfonamide (233 mg, 0.6 mmol) and 6-(2-amino-5-bromopyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (190 mg, 0.6 mmol) to give 6′-amino-N-(cyclopropylmethyl)-N-methyl-5′-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-[2,3′-bipyridine]-5-sulfonamide as a yellow solid (127 mg, 0.27 mmol, 46% yield) after purification by reverse phase preparatory HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.87 (d, J=1.5 Hz, 1H), 8.84 (d, J=2.3 Hz, 1H), 8.05-8.19 (m, 3H), 7.90-7.98 (m, 2H), 7.43-7.50 (m, 2H), 6.34 (s, 2H), 3.38-3.45 (m, 2H), 2.97 (t, J=1.0 Hz, 2H), 2.91 (d, J=6.8 Hz, 2H), 2.80 (s, 3H), 0.85-0.96 (m, 1H), 0.43-0.51 (m, 2H), 0.16-0.21 (m, 2H); MS (EI) m/z=464.5 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[S:29])[CH:23]=[CH:24][C:25]=1[Cl:26]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28](=[S:29])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1ccc(Cl)c(Cl)c1
Yield: 78.4 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.00 mmol) and 3,4-dichlorophenyl isothiocyanate (0.82 g, 4.02 mmol) to afford the product (1.40 g) in two crops; m.p. 174-175° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]([C:15](CC)=[O:16])[CH3:14])[CH:5]=[CH:6][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[NH2:19][C@H:20]([CH2:28][OH:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[CH2:21]([C@H:20]([NH:19][C:15](=[O:16])[C@H:13]([C:4]1[CH:5]=[CH:6][C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[C:2]([F:1])[CH:3]=1)[CH3:14])[CH2:28][OH:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCC(=O)C(C)c1ccc(NS(C)(=O)=O)c(F)c1
Reactant: N[C@H](CO)Cc1ccccc1
Solvent: ClCCl
Product: C[C@H](C(=O)N[C@H](CO)Cc1ccccc1)c1ccc(NS(C)(=O)=O)c(F)c1

Procedure:
A mixture of 2-[3-fluoro-4-(methylsulfonylamino)phenyl]propion acid (100 mg, 0.234 mmol) and L-phenyl alaninol (71 mg, 0.468 mmol) in CH2Cl2 (3 mL) was refluxed for 3 h and concentrated in vacuo. The residue was dissolved in MeOH (2 mL) and purified by flash column chromatography on silica gel using EtOAc:hexanes (2:1) to EtOAc:MeOH (20:1) as eluant to afford N-[(1S)-1-Benzyl-2-hydroxyethyl]-(2S)-2-[3-fluoro-4-(methylsulfonylamino)phenyl]propionamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:28][CH:29]([CH3:31])[CH3:30])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:15][C:14]=1[OH:27])(=[O:12])=[O:11].[CH2:32](O)[CH3:33].C(P(CCCC)(CCCC)=CC#N)CCC>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:28][CH:29]([CH3:31])[CH3:30])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[CH:15][C:14]=1[O:27][CH2:32][CH3:33])(=[O:11])=[O:12]
Reactant: CCO
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)cc2O)c(C)c1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOc1cc(OCC2CCOCC2)ccc1S(=O)(=O)N(CC(C)C)c1ccc(C)cc1C
Temperature: 20 °C
Reaction time: 24 h

Procedure:
To a solution of N-(2,4-dimethylphenyl)-2-hydroxy-N-isobutyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide (15.7 mg, 0.035 mmol) and ethanol (4.8 mg, 0.105 mmol) in toluene (1.5 mL) stirred in air at 20° C., was added a solution of 2-(tributylphosphoranylidene)acetonitrile (8.47 mg, 0.035 mmol) in toluene (0.5 mL) over 1 minute. The reaction mixture was stirred at 20° C. for 24 hours. Additional 2-(tributylphosphoranylidene)acetonitrile (8.47 mg, 0.035 mmol) was then added and the reaction stirred for a further 2 hours. The solvent was evaporated in vacuo and the residue purified by pre-packed silica cartridge eluting with ethyl acetate-cyclohexane (0-50%). The relevant fractions were evaporated to give the title product, 8.7 mg. LCMS [LCMS1] Rt 1.48 min, m/z (ES+) 476 (M+H).
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])[CH:18]=[CH:19][C:20]=1[CH:21]=[O:22])[CH3:13].O>CN(C=O)C>[Br:1][C:18]1[CH:19]=[C:20]([CH:21]=[O:22])[C:15]([O:14][CH2:12][CH3:13])=[CH:16][C:17]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30]
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Reactant: CCOc1cc(-c2ccc(F)cc2F)ccc1C=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(-c2ccc(F)cc2F)c(Br)cc1C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 148.8 %

Procedure:
Dibromoisocyanuric acid (3.39 g) was added to a solution of 3-ethoxy-2′,4′-difluorobiphenyl-4-carbaldehyde (5.16 g) in DMF (30 mL) at room temperature. The mixture was stirred at room temperature for 4 hours. Water (6 mL) was added to the mixture. Then the crystalline seed was added to the mixture. The mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration, washed with DMF-water (8 mL-2 mL), and dried at 70° C. to give the title compound (6.00 g).
Reaction SMILES: [O:1]=[C:2]([C:14]1[CH:19]=[CH:18][C:17]([S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[CH2:3][N+:4]12CN3CN(CN(C3)C1)C2.[Br-].[ClH:28]>C(O)C>[ClH:28].[NH2:4][CH2:3][C:2]([C:14]1[CH:19]=[CH:18][C:17]([S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)=[O:1]
Reactant: O=C(C[N+]12CN3CN(CN(C3)C1)C2)c1ccc(Sc2ccccc2)cc1
Agent: Cl
Agent: [Br-]
Solvent: CCO
Product: NCC(=O)c1ccc(Sc2ccccc2)cc1
Reaction time: 17 h

Procedure:
To a suspension of 3.53 g of 1-[2-oxo-2-[4(phenylthio)phenyl]ethyl]-3,5,7-triaza-1-azoniatricyclo[3.3.1.13,7 ]decane, bromide in 35 ml of ethanol was added 6 ml of concentrated hydrochloric acid. This mixture was stirred for 17 hours, then the solid was collected and washed with ethanol and ether. This solid was stirred with 15 ml of water at 0° C. for 50 minutes, then the solid was collected, washed with 20 ml of ice cold water and dried, giving 1.38 g of the desired compound as a white solid, mp 222°-224° C. (dec.).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@H:26]4[CH2:28][O:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:29])[NH:6]2.[C:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])[CH3:31]>>[C:30]([N:33]1[CH2:38][CH2:37][N:36]([CH2:28][C@@H:26]([OH:27])[CH2:25][O:24][C:18]2[CH:17]=[C:16]3[C:21]([C:12]([O:11][C:10]4[C:2]([F:1])=[C:3]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([CH3:29])=[CH:4]5)=[N:13][CH:14]=[N:15]3)=[CH:20][C:19]=2[O:22][CH3:23])[CH2:35][CH2:34]1)(=[O:32])[CH3:31]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@H]1CO1
Reactant: CC(=O)N1CCNCC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@H](O)CN1CCN(C(C)=O)CC1
Yield: 66.1 %

Procedure:
Using an analogous procedure to that described for the preparation of Example 51, 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2R)-oxiran-2-ylmethoxy]quinazoline (200 mg, 0.506 mmol), (prepared as described for the starting material in Example 48), was reacted with 1-acetylpiperazine (195 mg, 1.51 mmol) to give 7-{(2R)-3-[4-acetylpiperazin-1-yl]-2-hydroxypropoxy}-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (175 mg, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([C:8](O)=[O:9])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[S:5][N:4]=1.B.C1COCC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:7]([CH2:8][OH:9])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[S:5][N:4]=1
Reactant: COc1ccc(-c2snc(OC)c2C(=O)O)cc1
Agent: B
Solvent: C1CCOC1
Product: COc1ccc(-c2snc(OC)c2CO)cc1
Temperature: 0 °C

Procedure:
Into a 25-mL round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed 3-methoxy-5-(4-methoxyphenyl)-1,2-thiazole-4-carboxylic acid (160 mg, 0.60 mmol, 1.00 equiv), tetrahydrofuran (4.0 mL). This was followed by the addition of BH3.THF(1 M) (1.83 mL) dropwise with stirring at 0° C. The resulting solution was stirred overnight at 45° C. in an oil bath. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:2). The reaction was then quenched by the addition of 5.0 mL of water. The resulting solution was extracted with 3×10.0 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a TLC-Plate with ethyl acetate/petroleum ether (1:2). This resulted in 63 mg (42%) of [3-methoxy-5-(4-methoxyphenyl)-1,2-thiazol-4-yl]methanol as a white solid. Mass spectrum (ESI, m/z): Calcd. for C12H13NO3S, 252.1 (M+H). found 252.1.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([CH2:18][O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[O:12]1.[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=[CH:9][N:10]=2)[C@@H:11]2[O:12][C@H:13]([CH2:18][O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[C@@H:14]([OH:17])[C@H:15]2[OH:16])=[CH:28][CH:27]=1
Reactant: Nc1ccc(F)cc1
Reactant: O[C@@H]1[C@H](O)[C@@H](COCC(F)(F)F)O[C@H]1n1cnc2c(Cl)ncnc21
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1[C@H](O)[C@@H](COCC(F)(F)F)O[C@H]1n1cnc2c(Nc3ccc(F)cc3)ncnc21
Temperature: 22 °C
Yield: 46.6 %

Procedure:
(2R,3R,4S,5R)-2-(6-Chloro-purin-9-yl)-5-(2,2,2-trifluoroethoxymethyl)-tetrahydro-furan-3,4-diol (125 mg) in isopropanol (5 ml) under nitrogen was treated with 4-fluoroaniline (0.08 ml, 90 mg) and diisopropylethylamine (0.28 ml, 210 mg), and the mixture was heated under reflux for 24 h. After cooling to 22° C. the mixture was filtered, the filter cake washed with isopropanol (2 ml) and ether (15 ml) and the solid dried in vacuo to give the title compound as a white solid (70 mg), m.p. 214-5°.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O[CH:19](N(C)C)[N:20]([CH3:22])[CH3:21])(C)(C)C>>[CH3:19][N:20]([CH3:22])[CH:21]=[C:9]1[CH2:10][CH2:11][CH2:12][CH:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[C:8]1=[O:13]
Reactant: O=C1CCCCC1N1CCOCC1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C1CCCC(N2CCOCC2)C1=O

Procedure:
2-Morpholin-4-yl-cyclohexanone (183 mg, 1.0 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (260 mg) as a yellow oil which was used directly in the next step.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@H:12]2[C@@H:16]([OH:17])[CH2:15]N(C(OCC3C=CC=CC=3)=O)[CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].N[C@H]1C[O:32]C[C@H]1O>>[CH2:1]([C:3]1[C:4]([NH:11][C@H:12]2[CH2:13][O:32][CH2:15][C@H:16]2[OH:17])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2O)n1
Reactant: N[C@H]1COC[C@H]1O
Product: CCc1cnc(CC)c(N[C@H]2COC[C@H]2O)n1

Procedure:
Following the procedure for the preparation of benzyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate but substituting cis-(+/−)-4-aminotetrahydrofuran-3-ol and making non-critical variations provided the title compound as a light yellow amorphous solid. IR (diffuse reflectance) 3399, 3259, 3223, 3218, 3212, 2969, 2867, 2847, 1582, 1546, 1493, 1465, 1160, 1066, 920 cm−1; MS (EI) m/z 237 (M+); HRMS (FAB) calcd for C12H19N3O2+H1 238.1555, found 238.1558.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10](=[O:11])[C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C@@H:3]1[CH2:2][NH:1][C:26]1[N:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: N#Cc1cnc(Cl)nc1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C#N)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone and 2-chloropyrimidine-5-carbonitrile. ESI-MS (m/z): 427 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([NH2:11])=[C:5]([NH2:12])[CH:4]=1.[CH3:13][O:14][C:15]1[CH:23]=[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:20][C:16]=1[C:17](O)=O>>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[N:12]=[C:17]([C:16]3[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:15]=3[O:14][CH3:13])[NH:11][C:6]=2[CH:7]=1
Reactant: COc1cc(N)c(N)cc1OC
Reactant: COc1cc(NS(C)(=O)=O)ccc1C(=O)O
Product: COc1cc2nc(-c3ccc(NS(C)(=O)=O)cc3OC)[nH]c2cc1OC

Procedure:
Prepared analogously to Example 14 from 4,5-dimethoxy-1,2-phenylenediamine and 2-methoxy-4-methanesulfonylamino-benzoic acid.
Reaction SMILES: [CH3:1][C:2]1[S:24][C:5]2[NH:6][C:7]3[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:32][O:33][C:34](=[O:47])[CH2:35][CH2:36][C:37](ON1C(=O)CCC1=O)=[O:38]>ClCCl>[CH3:32][O:33][C:34](=[O:47])[CH2:35][CH2:36][C:37]([NH:23][CH2:22][C:19]1[CH:20]=[CH:21][C:7]2[NH:6][C:5]3[S:24][C:2]([CH3:1])=[CH:3][C:4]=3[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[N:9][C:8]=2[CH:18]=1)=[O:38]
Reactant: COC(=O)CCC(=O)ON1C(=O)CCC1=O
Reactant: Cc1cc2c(s1)Nc1ccc(CN)cc1N=C2N1CCN(C)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)NCc1ccc2c(c1)N=C(N1CCN(C)CC1)c1cc(C)sc1N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepin-7-yl)methanamine, prepared as described in Example 3, (40 mg, 0.12 mmol) in dichloromethane (2 mL) was added triethylamine (0.030 mL, 0.22 mmol) and succinic acid 2,5-dioxo-pyrrolidin-1-yl ester methyl ester, prepared as described in the previous step, (31 mg, 0.13 mmol). The solution was stirred at room temperature for 1 hour and concentrated. The crude was loaded onto a silica column, eluted with 3-5% methanol/dichloromethane containing ammonium hydroxide to give the title compound as a yellow solid. LC-MS: m/z 456 (M+1).