Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:22]1[N:23]=[C:24]([NH2:40])[C:25]2[N:26]=[CH:27][N:28]([C:38]=2[N:39]=1)[C@@H:29]1[O:37][C@H:34]([CH2:35][OH:36])[C@@H:32]([OH:33])[C@H:30]1[OH:31]>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][C:10]([N:7]1[CH2:8][CH2:9][CH:4]([CH2:1][C:2]#[C:3][C:22]2[N:23]=[C:24]([NH2:40])[C:25]3[N:26]=[CH:27][N:28]([C:38]=3[N:39]=2)[C@@H:29]2[O:37][C@H:34]([CH2:35][OH:36])[C@@H:32]([OH:33])[C@H:30]2[OH:31])[CH2:5][CH2:6]1)=[O:11]
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CCC1CCN(C(=O)Oc2ccccc2OC)CC1
Product: COc1ccccc1OC(=O)N1CCC(CC#Cc2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)CC1

Procedure:
2-Methoxyphenyl 4-(prop-2-ynyl)piperidine-1-carboxylate (0.565 g, 2.067 mmol) was added to a solution of 2-iodoadenosine (0.650 g, 1.653 mmol) according to general procedure 2: yield 775 mg, 87%. 1H NMR (CD3OD) δ 8.30 (s, 1H), 7.24-7.17, 7.09-7.04, 6.97-6.91 (3×m, 4H), 5.96 (d, 1H, J=6.5 Hz), 4.74 (dd, 1H, J=5.1, J=6.4 Hz), 4.43-4.32 (m, 2H), 4.25-4.16 (m, 2H), 3.96-3.89, 3.82 (s, 3H), 3.80-3.74, (2×m, 2H), 3.07, 2.92 (2×br t, 2H), 2.51 (d, 2H, J=6.0 Hz), 2.03-1.85, 1.60-1.35 (2×m, 5H). 13C NMR (CD3OD) δ 157.3, 155.5, 153.1, 150.2, 147.5, 142.6, 141.9, 127.6, 124.1, 121.7, 120.4, 113.7, 91.3, 88.3, 86.7, 82.2, 75.5, 72.6, 64.7, 63.5, 56.4, 45.8, 36.6, 32.5, 26.5, 25.2. LRMS ESI (M+H+) 539.1. HPLC rt=5.1 min.
Reaction SMILES: [C@:1]12([CH2:11][S:12]([OH:15])(=[O:14])=[O:13])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=[O:3].[Cl:16][C:17]1[CH:18]=[C:19]([C:24]2([CH2:30][CH2:31][CH2:32]O)[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]2)[CH:20]=[CH:21][C:22]=1[Cl:23]>CC(O)C>[CH3:9][C:8]1([CH3:10])[CH:5]2[CH2:6][CH2:7][C@@:1]1([CH2:11][S:12]([O:15][CH2:32][CH2:31][CH2:30][C@@:24]1([C:19]3[CH:20]=[CH:21][C:22]([Cl:23])=[C:17]([Cl:16])[CH:18]=3)[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1)(=[O:13])=[O:14])[C:2](=[O:3])[CH2:4]2
Reactant: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Reactant: OCCCC1(c2ccc(Cl)c(Cl)c2)CCCNC1
Solvent: CC(C)O
Product: CC1(C)C2CC[C@@]1(CS(=O)(=O)OCCC[C@@]1(c3ccc(Cl)c(Cl)c3)CCCNC1)C(=O)C2
Yield: 104.9 %

Procedure:
A solution of (S)-(+)-camphorsulfonic acid (10.3 g, 44.41 mmol) in iPrOH (10 mL) was added to a solution of hydroxy piperidine (8) (12.8 g, 44.41 mmol) in iPrOH. The mixture was heated to reflux for 15 minutes. The solvent was removed to give glassy solid 23.4 g, which solid was then recrystallized in iPrOH two times to give white crystals (5.5 g, 23.8%, 95% ee), mp 188-189° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH3:23]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:12][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCCCCBr
Reactant: Cc1cc(O)c2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOc1cc(C)cc2ccccc12
Temperature: 90 °C
Reaction time: 3 h
Yield: 12 %

Procedure:
The crude product of 3-methylnaphthalen-1-ol, dimethylformamide (DMF, 20 ml), potassium carbonate (3 g, 21.7 mmol) and pentyl bromide (4.0 ml, 32.3 mmol) were mixed in a reaction vessel replaced with argon, and this solution was stirred at 90° C. for 3 hours. DMF was evaporated under reduced pressure, and water (20 ml) was added. The aqueous layer was extracted with ethyl acetate (20 ml) 3 times. The organic layer was washed with saturated brine (20 m1l) and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=100/0-50/1) to give 3-methyl-1-pentyloxynaphthalene (827 mg, 12% in 3 steps) as a colorless oil.
Reaction SMILES: Br[CH:2]([CH:8](Br)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:11][N:10]=1)[C:3](OCC)=[O:4].Cl.[OH:32][NH2:33].[OH-].[Na+].CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[O:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[O:32][N:33]=[C:3]([OH:4])[CH:2]=2)=[N:10][CH:11]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NO
Reactant: CCOC(=O)C(Br)C(Br)c1ccc(OCc2ccccc2Oc2ccccc2)cn1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Oc1cc(-c2ccc(OCc3ccccc3Oc3ccccc3)cn2)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2,3-dibromo-3-(5-((2-phenoxybenzyl)oxy)-2-pyridinyl)propanoate (159.3 mg) in tetrahydrofuran (1 ml), 32 mg of hydroxyamine hydrochloride, 0.6 ml of 2.5N sodium hydroxide/methanol solution and 0.078 ml of water were added, and the reaction solution was stirred at room temperature for 2 hours and then heated to reflux overnight. The reaction solution was cooled, then diluted with water, acidified with 10% aqueous citric acid, then extracted with chloroform, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified through reversed phase medium pressure liquid chromatography (ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid). The solvent of the resultant fraction was distilled off under reduced pressure, and then purification by preparative thin layer chromatography (Kieselgel™ 60 F254, Art5744, made by Merck & Co., chloroform/methanol (9:1)) was carried out to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:23])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[CH:18])[CH:15]=2)[N:10]([C:19](=[O:21])[CH3:20])[C@@H:9]([CH3:22])[CH2:8]1)[CH3:3].[N:24]([CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[N+:25]=[N-:26]>CN(C)C=O.CO.[Cu]I>[CH3:3][CH:2]([O:4][C:5](=[O:23])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[N:26]=[N:25][N:24]([CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:37])[CH:18]=3)[CH:15]=2)[N:10]([C:19](=[O:21])[CH3:20])[C@@H:9]([CH3:22])[CH2:8]1)[CH3:1]
Reactant: C#Cc1ccc2c(c1)[C@H](NC(=O)OC(C)C)C[C@H](C)N2C(C)=O
Reactant: CC(C)(C)OC(=O)NCCCN=[N+]=[N-]
Agent: [Cu]I
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3cn(CCCNC(=O)OC(C)(C)C)nn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Reaction time: 2 h
Yield: 126 %

Procedure:
To a solution of 1-methylethyl[(2S,4R)-1-acetyl-6-ethynyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Intermediate 58) (250 mg, 0.795 mmol) in a mixture of N,N-dimethylformamide (DMF) (4.5 mL) and methanol (0.500 mL) were successively added 1,1-dimethylethyl (3-azidopropyl)carbamate (for a preparation, see Intermediate 74) (318 mg, 1.590 mmol) and copper(I) iodide (7.57 mg, 0.040 mmol). The resulting mixture was stirred at 100° C. under microwave irradiation for 2 h, and then cooled to room temperature and partitioned between EtOAc and brine. The two layers were separated and the aqueous phase was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over a Na2SO4 cartridge and concentrated in vacuo. Purification of the residue by SP4 column using a 10 G silica cartridge (gradient: 2 to 10% MeOH in DCM) gave 1-methylethyl((2S,4R)-1-acetyl-6-{1-[3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propyl]-1H-1,2,3-triazol-4-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (514 mg, 0.999 mmol, 126%) as a viscous yellow oil which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:36])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:35])[N:25]([CH3:34])[C:26]([CH3:33])=[CH:27][C:28]=2[C:29]([F:32])([F:31])[F:30])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7].[OH-].[Na+]>C(O)C>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:36])=[O:2])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:24](=[O:35])[N:25]([CH3:34])[C:26]([CH3:33])=[CH:27][C:28]=2[C:29]([F:32])([F:31])[F:30])=[CH:21][CH:22]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)C(=O)O
Temperature: 42.5 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
To a suspension of N-[(2-chloro-6-methylphenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester (91 mg, 0.174 mmol) in ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (4 mL) at room temperature. The resulting solution was heated to 40-45° C. and stirred for 4 h. Then, the ethanol was removed under vacuum and the residue was diluted with water (25 mL). The aqueous solution was washed with diethyl ether (25 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N HCl and was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine solution (50 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the filtrate afforded 71 mg (80% yield) of N-[(2-chloro-6-methylphenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine as a white solid: mp 220-223° C. ES-HRMS m/e calcd for C25H22ClF3N2O4 (M+Na) 529.1111. found 529.1119.
Reaction SMILES: Br[CH:2]([C:4]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](=[O:21])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:3].[CH3:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>C(N(CC)CC)C>[CH3:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][CH:2]([C:4]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12](=[O:21])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH3:3])=[CH:26][CH:25]=1
Reactant: CC(Br)c1nc2ccccc2c(=O)n1Cc1ccccc1
Reactant: COc1ccc(N)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(NC(C)c2nc3ccccc3c(=O)n2Cc2ccccc2)cc1

Procedure:
2-Ethyl-3-benzyl-quinazolin-4-one is prepared following the procedure set forth in part (A) above, but substituting N-benzyl-2-(propanoylamino)-benzamide for N-(1-benzoylethyl)-2-(formylamino)-benzamide (“Compound E”). Compound E is brominated by heating in acetic acid with bromine to provide 2-(1-bromoethyl)-3-benzyl-quinazolin-4-one (“Compound F”). Compound F is treated with 4-methoxy-aniline in triethylamine to provide 2-(1-(4-methoxyphenylamino)ethyl)-3-benzyl-quinazolin-4-one (“Compound G”). Compound G is then acylated with benzoyl chloride to provide 2-(1-(N-benzoyl-N-(4-methoxyphenyl)-aminoethyl)-3-benzyl-quinazolin-4-one.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.[Pd]>[CH3:17][N:16]([CH3:18])[C:14]([CH:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1)=[O:15]
Reactant: CN(C)C(=O)C1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CN(C)C(=O)C1CNCCO1
Temperature: 50 °C
Yield: 99 %

Procedure:
A mixture of 4-benzyl-N,N-dimethylmorpholine-2-carboxamide (803 mg, 3.23 mmol), ammonium formate (2.15 g, 32.3 mmol) and 10% Pd/C (400 mg) in EtOH (20 mL) was heated at 50° C. for 1 hour. After cooling to room temperature, the catalyst was filtered off, washed with EtOH. The combined filtrate and washings were concentrated, and the residue was dissolved in EtOH (20 mL). Ammonium formate (2.15 g, 32.3 mmol) and 10% Pd/C (400 mg) were added to the mixture. The mixture was heated at 50° C. for 1 hour. After cooling to room temperature, the catalyst was filtered off, washed with EtOH. The combined filtrate and washings were concentrated to afford desired product (506 mg, 98.9%) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].C(OC([N:35]1[CH2:39][CH2:38]OS1(=O)=O)=O)(C)(C)C.Cl>CN(C=O)C.O>[NH2:35][CH2:39][CH2:38][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:15][CH2:14]2)=[O:12])=[CH:7]1
Reactant: CC(C)(C)OC(=O)N1CCOS1(=O)=O
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCN(c2ccccc2F)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NCCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone in dry DMF under argon at 0° C. was added (1.1 eq) NaH. The reaction mixture was stirred for 1 h at 0° C. 2,2-Dioxo-2λ6-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (1.1 eq) (described in WO 2003037327) was added, and the reaction mixture was stirred for 2 h at RT. After evaporation of DMF, redissolution in dioxan, addition of 5 eq. of HCl (4.0M solution in dioxane) and a few drops of water, the reaction mixture was stirred for 2 h at 50° C.; LC-MS showed complete conversion to the crude product.
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])=[CH:9][CH:8]=1.C([Cu])#N.[Li+].[Cl-].[Br:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38]Br)[CH:32]=1.[Cl-].[NH4+].N>O1CCCC1.O>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH:32]=1)[CH2:38][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])=[CH:9][CH:8]=1
Reactant: CC(C)[Si](C#Cc1ccc(I)cc1)(C(C)C)C(C)C
Reactant: Clc1ccc(Br)cc1CBr
Agent: N#C[Cu]
Agent: CC(C)[Mg]Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C#Cc1ccc(Cc2cc(Br)ccc2Cl)cc1)(C(C)C)C(C)C
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
Under argon 0.66 ml of a 2 M solution of isopropylmagnesium chloride in tetrahydrofuran are added dropwise to a solution of 0.50 g (4-iodo-phenylethynyl)-triisopropyl-silane in 2.2 ml dry tetrahydrofuran chilled to −25° C. The solution is stirred for 30 min at −25° C. and then combined with 0.26 ml of a 1 M solution of CuCN*2 LiCl in tetrahydrofuran (prepared by dissolving CuCN and LiCl in the ratio 1:2). Shortly afterwards, 0.35 g 4-bromo-2-bromomethyl-1-chlorbenzene are added and the reaction mixture is brought up to −5° C. in the cooling bath. After 6 h stirring at −5° C. the solution is heated to ambient temperature and stirred overnight. Then a mixture of saturated ammonium chloride solution and 25% ammonia solution (9:1) is added and the resulting mixture is added to water. The organic phase is separated off and the aqueous phase is extracted with ethyl acetate, the combined organic phases are dried over sodium sulphate, and the solvent is removed. The residue is purified through silica gel (cyclohexane).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([NH2:12])=[O:11])=[CH:8][S:7][C:6]=2[CH:13]=1.NC1C=CC2SC=C(C(N)=O)C=2C=1.[Cl:27][C:28]1[CH:29]=[C:30]([S:35](NC2C=CC3SC=C(C(N)=O)C=3C=2)(=[O:37])=[O:36])[CH:31]=[C:32]([Cl:34])[CH:33]=1>C(OCC)(=O)C>[Cl:34][C:32]1[CH:31]=[C:30]([S:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:9]([C:10]([NH2:12])=[O:11])=[CH:8][S:7][C:6]=3[CH:13]=2)(=[O:36])=[O:37])[CH:29]=[C:28]([Cl:27])[CH:33]=1
Reactant: NC(=O)c1csc2ccc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)cc12
Reactant: NC(=O)c1csc2cc(N)ccc12
Agent: NC(=O)c1csc2ccc(N)cc12
Solvent: CCOC(C)=O
Product: NC(=O)c1csc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc12

Procedure:
Obtained from the reaction of a mixture of 6-amino-benzo[b]thiophene-3-carboxylic acid-amide and 5-amino-benzo[b]thiophene-3-carboxylic acid-amide (Example XII (30)). The crude product is dissolved in hot ethyl acetate. After cooling to ambient temperature the precipitated solid (5-(3,5-dichloro-phenylsulphonylamino)-benzo[b]thiophene-3-carboxylic acid-amide) is filtered off. The mother liquor is freed from the solvents in vacuo and the residue is chromatographed on silica gel, to obtain 6-(3,5-dichloro-phenylsulphonylamino)-benzo[b]thiophene-3-carboxylic acid-amide.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH2:18]([NH2:21])[CH:19]=[CH2:20]>CN(C=O)C>[CH2:18]([NH:21][C:4]1[C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[CH:19]=[CH2:20]
Reactant: C=CCN
Reactant: Clc1nc(Cl)c2scc(-c3ccccc3)c2n1
Solvent: CN(C)C=O
Product: C=CCNc1nc(Cl)nc2c(-c3ccccc3)csc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 88.4 %

Procedure:
In 1 ml of DMF, 176 mg (0.63 mmol) of 2,4-dichloro-7-phenylthieno[3,2-d]pyrimidine was dissolved, and then 79 mg (1.4 mmol) of allylamine was added dropwise thereto under ice cooling over 5 minutes. The reaction solution was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for further 1 hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (30 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 168 mg (yield: 88.9%) of the title compound.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:21][C:22]1[CH:23]=[C:24]([NH:28]N)[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:25]=[CH:26][CH:27]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Reactant: NNc1cccc(Cl)c1
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1cccc(Cl)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 3-chloro-phenylhydrazine according to the method described for example 1. MS: M=349.2 (M+H)+
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:7](C(=O)C(F)(F)F)=[CH:6][N:5]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=2[F:31])[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+]>CO.C([O-])(O)=O.[Na+]>[O:32]=[S:2]1(=[O:1])[CH:3]=[CH:4][N:5]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=2[F:31])[CH2:6][CH2:7]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3C=C(C(=O)C(F)(F)F)S(=O)(=O)CC3)c(F)c2)C(=O)O1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1

Procedure:
The product of Step 2 (0.670 g, 1.39 mmol) is suspended in 28 mL of methanol, and the solution heated to reflux. Dry K2CO3 (0.386 g, 2.8 mmol) is added, and the mixture is stirred at reflux for 1 h. Upon cooling, the solution is diluted with 2.5% aq. NaHCO3 (20 mL) and the methanol removed by rotary evaporation. The resulting aqueous phase is extracted with EtOAc (5×30 mL), and the combined organic layers are dried (MgSO4). Solvent is evaporated under vacuum, and the crude material purified by silica gel column chromatography (gradient 0–4% MeOH-DCM) to afford the title compound as a white solid. Yiled 0.309 g (58%). Rf=0.13 (5% MeOH-DCM). M.p. 193°–194° C.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:17]=[C:18]([CH3:30])[C:19]3[CH:23]([CH2:24][C:25]([OH:27])=[O:26])[O:22][B:21]([OH:28])[C:20]=3[CH:29]=2)=[N:13][CH:14]=1)=O)(C)(C)C.Cl.O1CCOCC1>>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:17]=[C:18]([CH3:30])[C:19]3[CH:23]([CH2:24][C:25]([OH:27])=[O:26])[O:22][B:21]([OH:28])[C:20]=3[CH:29]=2)=[N:13][CH:14]=1
Reactant: Cc1cc(Oc2ccc(NC(=O)OC(C)(C)C)cn2)cc2c1C(CC(=O)O)OB2O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Oc2ccc(N)cn2)cc2c1C(CC(=O)O)OB2O
Yield: 81.2 %

Procedure:
[6-(5-tert-Butoxycarbonylamino-pyridin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (26 mg) was treated with HCl/dioxane (0.5 mL) at room temperature for 2 h. The reaction was concentrated to dryness. The residue was purified by preparative HPLC to give the title compound (16 mg). 1H NMR (300 MHz, CD3OD) δ 7.66 (s, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.00 (s, 1H), 6.96 (s, 1H), 6.78 (d, J=7.8 Hz, 1H), 5.68-5.64 (m, 1H), 3.20-3.14 (m, 1H), 2.36 (s, 3H), 2.34-2.26 (m, 1H). MS calcd for (C15H15BN2O5+H)+: 315.1. MS found: (M+H)+=315.1.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:17](=O)[CH3:18])=[CH:4][S:5][C:6]=1[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1.[NH:20]([C:22]([C:24]1[S:28][C:27]([C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39](=[O:44])[NH:40][CH2:41][CH2:42][OH:43])=[CH:35][CH:34]=2)=[O:30])=[CH:26][CH:25]=1)=[O:23])[NH2:21]>>[OH:1][C:2]1[C:3]([C:17](=[N:21][NH:20][C:22]([C:24]2[S:28][C:27]([C:29]([NH:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([C:39](=[O:44])[NH:40][CH2:41][CH2:42][OH:43])=[CH:35][CH:34]=3)=[O:30])=[CH:26][CH:25]=2)=[O:23])[CH3:18])=[CH:4][S:5][C:6]=1[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1
Reactant: NNC(=O)c1ccc(C(=O)NCc2ccc(C(=O)NCCO)cc2)s1
Reactant: CC(=O)c1csc(-c2ccc3c(c2)CCCC3)c1O
Product: CC(=NNC(=O)c1ccc(C(=O)NCc2ccc(C(=O)NCCO)cc2)s1)c1csc(-c2ccc3c(c2)CCCC3)c1O
Yield: 64.9 %

Procedure:
Synthesis was carried out in the same manner as in Synthetic Example 1 by using 24.4 mg (0.0895 mmol) of 1-[4-hydroxy-5-(5,6,7,8-tetrahydronaphthalen-2-yl)thiophen-3-yl]ethanone and 32.6 mg (0.0900 mmol) of 5-(hydrazinecarbonyl)-N-[4-(2-hydroxyethylcarbamoyl)benzyl]thiophene-2-carboxamide to obtain the desired product (35.8 mg, yield 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH2:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:27]1[N:32]=[C:31]([CH3:33])[N:30]=[C:29]([C:34]#[N:35])[CH:28]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:27]3[N:32]=[C:31]([CH3:33])[N:30]=[C:29]([C:34]#[N:35])[CH:28]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: NCC[C@@H]1C[C@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: Cc1nc(Cl)cc(C#N)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(C#N)cc(NCC[C@@H]2C[C@H]2C2CCN(c3ncc(Cl)cn3)CC2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanamine from Example 60 Step 1 (50 mg, 0.178 mmol) was in 0.5 mL DMF. Cs2CO3 (290 mg, 0.890 mmol) was added. Reaction mixture was stirred at room temperature for 10 min before cooled to 0° C. in ice bath. 6-chloro-2-methylpyrimidine-4-carbonitrile from Example 5 step 4 (30.1 mg, 0.196 mmol) in 0.3 mL DMF was added via syringe. Reaction was stirred at 0° C. in ice bath for 2 hours. The mixture was quenched with ice water and aqueous phase was further extracted with ethyl acetate for 3 times. The combined organic layers were washed with water and brine, then dried over Na2SO4 and concentrated. The residue was purified by column chromatography eluting with 30% Ethyl acetate/hexane with 0.5% 2M NH3-MeOH to give the titled compound.