Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:18][NH2:19])[CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH2:18][NH:19][C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:15][CH2:16][OH:17])=[CH:12][CH:13]=1
Reactant: NCC(CCO)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCC(CCO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
Ethyl chloroformate (4.7 mL, 49.5 mmol) was added dropwise to a stirred cooled (−40° C.) solution of 3-(4-chlorophenyl)-4-amino-1-butanol (9.0 g, 45 mmol) and triethylamine (7.2 mL, 51.8 mmol) in DCM (125 mL). The solution was stirred at room temperature for 30 min and poured into 1N HCl (60 mL). The organic layer was washed with 1N HCl (70 mL), saturated sodium bicarbonate (70 mL) and saturated sodium chloride; dried (MgSO4), filtered and the solvent removed to provide the title compound (11.4 g, 93%) as a yellow oil. 1H-NMR (CDCl3): δ 1.18-1.23 (t, 3H CH) 1.75-1.84 (m, 1H, CH) 1.90-1.99 (m, 1H, CH) 2.94-2.99 (m, 1H, CH) 3.21-3.30 (m, 1H, CH) 3.47-3.65 (m, 3H, CH) 4.04-4.11 (q, 2H, CH) 4.58 (s, 1H, OH or NH) 7.12-7.15 (d, 2R, ArH) 7.26-7.37 (m, 2H, ArH); MS m/z 272 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]1[CH:35]=[C:34]([OH:36])[CH:33]=[CH:32][C:31]=1[S:37]([N:40]1[C:48]2[C:43](=[C:44]([OH:52])[CH:45]=[C:46](B(O)O)[CH:47]=2)[CH:42]=[CH:41]1)(=[O:39])=[O:38].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:46]1[CH:47]=[C:48]2[C:43]([CH:42]=[CH:41][N:40]2[S:37]([C:31]2[CH:32]=[CH:33][C:34]([OH:36])=[CH:35][C:30]=2[F:29])(=[O:38])=[O:39])=[C:44]([OH:52])[CH:45]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: O=S(=O)(c1ccc(O)cc1F)n1ccc2c(O)cc(B(O)O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)c4ccn(S(=O)(=O)c5ccc(O)cc5F)c4c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 19 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (28 mg, 0.06 mmol) were added (1-((2-fluoro-4-hydroxyphenyl)sulfonyl)-4-hydroxy-1H-indol-6-yl)boronic acid (22 mg, 0.06 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (5 mg, 0.01 mmol) and 63 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by reverse phase using SP1® Purification System to give 8 mg (19% yield) as a white solid. Purity 99%.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[CH:9][N:8]=1)=[O:5].[CH2:33]([N:35]([CH2:50][CH3:51])[CH2:36][CH2:37][N:38]([CH2:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44](O)=[O:45])[CH3:39])[CH3:34].CCN=C=NCCCN(C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH2:50]([N:35]([CH2:33][CH3:34])[CH2:36][CH2:37][N:38]([CH2:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44]([NH:1][C:2]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:14]=2)=[CH:9][N:8]=1)=[O:5])=[O:45])[CH3:39])[CH3:51]
Reactant: CCN(CC)CCN(C)Cc1cccc(C(=O)O)c1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ncc(-c2cccc(C(F)(F)F)c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCN(CC)CCN(C)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ncc(-c3cccc(C(F)(F)F)c3)cn2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 10.4 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 2-amino-5-(piperidin-1-yl)-N-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)benzamide (200 mg, 0.45 mmol, 1.00 equiv) in dichloromethane (5 mL), 3-(((2-(diethylamino)ethyl)(methyl)amino)methyl)benzoic acid (120 mg, 0.45 mmol, 1.00 equiv), EDCI (130 mg, 0.68 mmol, 1.50 equiv), and 4-dimethylaminopyridine (83 mg, 0.68 mmol, 1.50 equiv). The resulting solution was stirred for 10 h at 25° C. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 32.2 mg (9%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 11.45 (s, 1H), 11.29 (s, 1H), 9.18 (s, 2H), 8.12-8.21 (m, 3H), 8.03 (s, 1H), 7.89-7.91 (d, J=6.6 Hz, 1H), 7.75-7.84 (m, 2H), 7.62-7.66 (m, 2H), 7.51 (s, 1H), 7.28-7.31 (d, J=8.1 Hz, 1H), 3.37 (s, 2H), 3.26 (s, 4H), 3.10-3.18 (m, 4H), 1.58-1.68 (m, 6H), 1.15-1.20 (m, 6H). MS (ES, m/z): 688.00 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:45])[CH2:29][C:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([O:42]C)(OC)[CH2:38][Br:39])[CH:32]=1)(C)(C)C>C1(C)C=CC=CC=1>[Br:39][CH2:38][C:37]([C:33]1[CH:32]=[C:31]([C:30]2[CH2:29][C:28](=[O:45])[NH:21][C:9]3[CH:10]=[C:11]([C:17]([F:18])([F:19])[F:20])[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]=3[N:7]=2)[CH:36]=[CH:35][CH:34]=1)=[O:42]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: COC(CBr)(OC)c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Solvent: Cc1ccccc1
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(C(=O)CBr)c1)=N2
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 46.9 %

Procedure:
A solution of (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J6) (0.32 g) and 3-oxo-3-[3-(2-bromo-1,1-dimethoxy-ethyl)-phenyl]-propionic acid tert-butyl ester (0.43 g) (Example K28) in toluene (3 mL) was heated to 100° C. for 2 h. The solvent was evaporated in vacuum and the crude product was purified by chromatography on silica gel using AcOEt/Hexan(1:3) as eluent. A solution of the purified material (0.57 g) in CH2Cl2/TFA (1:1, 7 mL) was stirred at 20° C. for 15 min and then evaporated. The residual oil was dissolved in AcOEt and the solution was washed with IN HCl and with brine, dried and evaporated to give crude 4-(3-bromoacetyl-phenyl)-7-dimethylamino-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (0.22 g) as light-brown solid.
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:5]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:4][N:3]=1.[C:23](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:23][S:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:5]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:4][N:3]=1
Reactant: COc1ccc(-c2nc(S)ncc2-c2ccc(Cl)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(-c2nc(SC)ncc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-mercapto-4-(4-methoxyphenyl)-5-(4-chlorophenyl)pyrimidine* (7 g) and potassium carbonate (8 g) in 200 ml acetone was treated with methyl iodide (4.8 ml) and stirred 5 hours at room temperature. The reaction mixture was filtered and concentrated on the rotary evaporator. Chromatography on silica gel and crystallization from ethanol gave the title compound (3.4 g), m.p. 127°-130°. Infrared and H-NMR spectra were consistent with the assigned structure. MS 342 (M+).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1.[O:30]1CCC[CH2:31]1>CO.F[B-](F)(F)F.[Ag+]>[CH3:2][C:3]1([O:30][CH3:31])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:14])([Cl:15])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4][CH2:29]1
Reactant: C1CCOC1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CO
Product: COC1(C)CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reaction time: 1 h

Procedure:
2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.55 g) was dissolved in a mixture of tetrahydrofuran (5 ml) and methanol (5 ml). To this solution was added silver fluoroborate (0.24 g) under cooling and then the mixture was stirred for 1 hour. The reaction mixture was concentrated and the obtained residue was dissolved in chloroform. This solution was washed with a saturated sodium bicarbonate aqueous solution and with water and dried over magnesium sulfate. The residue obtained by distilling off the solvent was subjected to chromatography on silica gel using chloroform as developing solvent. The obtained crystals were recrystallized from carbon tetrachloride to give 2,2,2-trichloroethyl 3-methyl-3-methoxy-7-(2-phenylacetamido)-cepham-4-carboxylate (0.27 g), mp. 132° to 133° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[N:11]1([C:17](=[O:19])[CH3:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C>CS(C)=O>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:14]2[CH2:15][CH2:16][N:11]([C:17](=[O:19])[CH3:18])[CH2:12][CH2:13]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a sealed tube was added 5-bromo-2-nitropyridine 111-1 (2.3 g, 11.4 mmol), 1-(piperazin-1-yl)ethanone 111-2 (1.6 g, 12.8 mmol), triethylamine (4.8 mL, 34.2 mmol) and DMSO (5 mL). The reaction was heated to 120° C. and stirred for 16 hours. The reaction was cooled to room temperature. Triethylamine was removed by rotary evaporation. The residue was triturated in 15 mL ethyl acetate. The solid was collected by filtration and washed with small amount of ethyl acetate to give 1-(4-(6-nitropyridin-3-yl)piperazin-1-yl)ethanone 111-3 as a light yellow solid. MS m/z 251.1 (M+1).
Reaction SMILES: [F:1][CH:2]([F:25])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]3[O:20][N:19]=[C:18]([CH2:21][CH2:22][O:23][CH3:24])[N:17]=3)[CH2:13][NH:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=1)=[O:35]>ClCCl>[F:25][CH:2]([F:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]3[O:20][N:19]=[C:18]([CH2:21][CH2:22][O:23][CH3:24])[N:17]=3)[CH2:13][N:12]([C:34]([O:36][C:37]3[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=3)=[O:35])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COCCc1noc(C2CNCC(c3ccc(CC(F)F)cc3)C2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCc1noc(C2CC(c3ccc(CC(F)F)cc3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 36.3 mg (0.061 mmol, purity 70%) of the compound from Example 61A in dichloromethane (2.0 ml) was admixed with 0.03 ml (21.6 mg, 0.21 mmol) of triethylamine and then 12.3 mg (0.061 mmol) of 4-nitrophenyl chloroformate were added at RT. The mixture was stirred at RT for 2 h and then the reaction solution was washed with saturated aqueous sodium hydrogencarbonate solution and water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 56.2 mg (91% of theory, purity 60%)
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.S(O[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1
Reactant: COc1ccc(CCCOS(C)(=O)=O)cc1
Reactant: OC[C@H]1CCCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CCCN2CCCC[C@@H]2CO)cc1
Temperature: 90 °C

Procedure:
(R)-2-hydroxymethylpiperidine (288 mg, 2.50 mmol), 3-(4-methoxyphenyl)propyl mesylate (915 mg, 3.75 mmol), sodium carbonate (398 mg, 3.75 mmol) and sodium iodide (30 mg, 0.20 mmol) were added to acetonitrile (25 ml), and they were heated under reflux at 90° C. for 6 hours. The solvent was evaporated under reduced pressure. The residue was distributed in ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with water and dried over magnesium sulfate. Then the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane as the eluent and then with dichloromethane and methanol (20:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-2-hydroxymethyl-1-[3-(4-methoxy-phenyl) propyl]piperidine in the form of a light yellow oil (422 mg, 64%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)=[C:6](C=1)[C:7]([NH:9][C@H:10]1[CH2:14][CH2:13][CH2:12][C@@H:11]1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=1)=[O:8].Cl.FC(F)(F)C1C=CC(N[C@H]2CCC[C@@H]2N)=[N:39]C=1.N1N(C2C(C(O)=O)=NC=CC=2)N=CC=1>>[N:28]1[N:27]([C:5]2[C:6]([C:7]([NH:9][C@H:10]3[CH2:14][CH2:13][CH2:12][C@@H:11]3[NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][N:17]=3)=[O:8])=[N:39][CH:2]=[CH:3][CH:4]=2)[N:31]=[CH:30][CH:29]=1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1cc(Cl)ccc1-n1nccn1
Reactant: N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Agent: Cl
Agent: O=C(O)c1ncccc1-n1nccn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1ncccc1-n1nccn1

Procedure:
Prepared according to the procedure for 5-chloro-2-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide (Example 97) from (1S,2S)-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 1; 50 mg, 0.20 mmol) and 3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid (CAS number 1252907-86-0; 39 mg, 0.20 mmol) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:9][CH:10]=2)[C:5]([OH:16])=[C:4]([C:17]([OH:19])=O)[N:3]=1.Cl.C[O:22][C:23](=[O:28])[C:24]([NH2:27])([CH3:26])[CH3:25]>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH:13]([CH3:14])[CH3:15])=[CH:9][CH:10]=2)[C:5]([OH:16])=[C:4]([C:17]([NH:27][C:24]([CH3:26])([CH3:25])[C:23]([OH:28])=[O:22])=[O:19])[N:3]=1
Reactant: COC(=O)C(C)(C)N
Reactant: CC(C)Oc1ccc2c(Cl)nc(C(=O)O)c(O)c2c1
Agent: Cl
Product: CC(C)Oc1ccc2c(Cl)nc(C(=O)NC(C)(C)C(=O)O)c(O)c2c1

Procedure:
Prepared in analogy to Example A-1 a) and b) from 1-chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid (can be obtained according to U.S. Pat. No. 6,093,730, October 1998, Weidmann et al.) and 2-amino-2-methyl-propionic acid methyl ester hydrochloride; MS-(+)-ion: M+1=367.0 amu.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CS(O[C:9]([N:12]1[C:25]2[CH:24]=[C:23]([C:26]#[N:27])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)([CH3:11])[CH3:10])(=O)=O>C1(C)C=CC=CC=1>[CH2:1]([NH:3][CH2:11][CH:9]([N:12]1[C:25]2[CH:24]=[C:23]([C:26]#[N:27])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:10])[CH3:2]
Reactant: CCN
Reactant: CC(C)(OS(C)(=O)=O)N1c2ccccc2Sc2ccc(C#N)cc21
Solvent: Cc1ccccc1
Product: CCNCC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Reaction time: 24 h

Procedure:
Ethylamine (18.75 cc) is added to a solution of 2-(2-cyano-10-phenothiazinyl)-2-propyl methanesulphonate, D series (10 g) in toluene (100 cc), and this mixture is brought to a temperature in the region of 105° C. for 24 hours. After being cooled, the reaction mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up with ethyl ether (250 cc) and extracted successively with N aqueous hydrochloric acid solution (2×100 cc). The combined aqueous phases are alkalinized with caustic soda (d=1.33) to pH 13 and extracted with ethyl ether (2 x 200 cc). The combined organic phases are washed successively with distilled water (50 cc) and with saturated aqueous sodium chloride solution (50 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40.° C. 10-(1-Ethylamino-2-propyl)- 2-phenothiazinecarbonitrile D series (5 g) is thereby obtained in the form of an orange oil. This product is dissolved at a temperature in the region of 60° C. in ethanol (17 cc) and this solution is poured into a solution of fumaric acid (1.9 g) in ethanol (17 cc) at the same temperature, crystallization is then primed and the mixture is left for 16 hours at a temperature in the region of 20° C. The solid is drained, washed with ethanol (2×2 cc) and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 40° C. 10-(1-Ethylamino-2-propyl)-2-phenothiazinecarbonitrile acid fumarate, D series (4 g) is thereby obtained in the form of a yellow solid, m.p. 208° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH2:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].C(N(C(C)C)CC)(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH:30][S:42]([CH3:41])(=[O:44])=[O:43])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(F)ccc1-c1nc(NCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1nc(NCCNS(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 0.25 h

Procedure:
A solution of the product of Example 157 (250 mg, 0.58 mmol), di-isopropylethylamine (111 uL, 0.64 mmol) and CH2Cl2 (10 mL) was cooled to −5° and methanesulfonyl chloride (50 uL, 0.64 mmol) was added and the resulting soln was warmed to 23°, stirred 15 min, diluted with CH2Cl2 (75 mL) and washed with 10% aq NaOH (2×20 mL) and satd aq NaCl, dried (Na2SO4), and concentrated to afford a brown solid. Chromatotron chromatography (CH2Cl2/CH3OH) and crystallization from Et2O afforded a pink solid. mp=105-115° (dec); LC MS (m/e)=504.2 (MH+). Rt=1.94 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH:19]=[CH2:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26](COCC[Si](C)(C)C)[C:27]=1[C:28](O)=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([CH:19]=[CH2:20])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:21])=[O:29]
Reactant: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 37.1 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-ethenylbenzonitrile (0.076 g, 0.251 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.069 g, 0.251 mmol) and DIPEA (0.088 mL, 0.502 mmol) were combined in THF (2 mL) and treated with HATU (0.105 g, 0.276 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in DCM (2.5 mL) and treated with TFA (2.5 mL) at 25° C. for 3 days. The reaction mixture was concentrated to dryness and partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified on an XTerra™ C-18 column eluted with 5 to 90% CH3CN/H2O (0.2% NH4OH buffer). Appropriate fractions were combined, concentrated to dryness, chased twice with ethanol and twice with toluene to remove residual water to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethenyl phenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.040 g, 0.093 mmol, 36.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.2 (br. s., 1H), 8.31 (br. s., 1H), 7.80 (s, 1H), 7.77 (s, 1H), 7.26-7.53 (m, 4H), 6.75 (dd, 1H), 6.04 (d, 1H), 5.44 (d, 1H), 4.53 (d, 2H). LC-MS (ES−) m/z 429.08, 431.11, 433.00 [M−1]. LC-MS (ES+) m/z 430.97, 432.95, 434.95 [M+H].
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.[CH3:31][Mg]Br>O1CCCC1.C(OCC)C>[CH3:31][C:2]1([OH:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(C)(O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Oxo-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.50 g) is suspended in tetrahydrofuran (20 ml), and thereto is added dropwise a 3.0 M solution of methyl magnesium bromide in diethyl ether (1.5 ml) at room temperature. The mixture is stirred at room temperature for 1 hour. The reaction solution is poured into ice-water (20 ml), and extracted with ethyl acetate. The extract is dried over magnesium sulfate, and the solvent is distilled off. The resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=2:3→1:1), and recrystallized from ethyl acetate/n-hexane to give 5-methyl-5-hydroxy-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.23 g) as white powder, m.p. 204-205° C.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([OH:9])[CH:4]=1)[NH2:2].N(C1NC=NC(=O)C=1)N.[CH3:19][CH2:20][C:21](=O)[CH2:22][CH3:23]>C(O)C>[CH3:19][CH2:20][C:21](=[N:2][NH:1][C:3]1[N:8]=[CH:7][N:6]=[C:5]([OH:9])[CH:4]=1)[CH2:22][CH3:23]
Reactant: NNc1cc(O)ncn1
Reactant: CCC(=O)CC
Agent: NNc1cc(=O)nc[nH]1
Solvent: CCO
Product: CCC(CC)=NNc1cc(O)ncn1
Temperature: 3 °C
Yield: 75.7 %

Procedure:
A mixture comprising 5.0 g (39.6 mmol) 6-hydrazinopyrimidin-4-ol/6-hydrazinopyrimidin-4(1H)-one (CAS-No: 29939-37-5), 5.12 g pentan-3-one and 80.8 mL ethanol was heated under reflux for 2 hours. After cooling to 3° C., the precipitated solid was filtered off and washed with diethyl ether to give 5.82 g (72%) of the title compound.