Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[O:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][C:8]([Cl:13])=[C:7]([OH:14])[CH:6]=2.[OH-:16].[Na+]>>[Cl:13][C:8]1[C:7]([OH:14])=[CH:6][C:5]2[O:4][C:2]([C:3]([OH:15])=[O:16])=[C:11]([CH3:12])[C:10]=2[CH:9]=1
Reactant: Cc1c(Cl)c(=O)oc2cc(O)c(Cl)cc12
Reactant: [OH-]
Agent: [Na+]
Product: Cc1c(C(=O)O)oc2cc(O)c(Cl)cc12
Yield: 54 %

Procedure:
3-Chloro-4-methyl-6-chloro-7-hydroxycoumarin was refluxed with NaOH (30 ml, 1N) for 1 hour. The mixture was washed with three 50 ml portions of ethyl acetate. Then acidification (HCl, 3N) of the aqueous phase followed by filtration of the solid that precipitated gave 0.5 g (54% yield) of the desired acid, m.p. 279°-280° C. In the ethyl acetate extract 0.2 g of decarboxylate product was recovered as a by product,
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]=[C:12]([S:14][CH3:15])[NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[CH2:1]([S:8][C:9]1[N:13]=[C:12]([S:14][CH3:15])[N:11]([C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nc(SCc2ccccc2)n[nH]1
Reactant: Clc1ncccn1
Product: CSc1nc(SCc2ccccc2)nn1-c1ncccn1

Procedure:
The product of stage (a) (50 g) was treated with 2-chloropyrimidine (24.4 g) in a method analogous to that of Example F, to give, after chromatographic separation of two products, 23.6 g of the desired product.
Reaction SMILES: [C:1]([C:4]1[N:5]=[N:6][N:7]([C:9]2[CH:10]=[C:11]([CH:24]=[C:25]([N:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:28][CH2:29][CH3:30])[CH:26]=2)[C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH3:16])=[O:13])[CH:8]=1)(=O)[CH3:2].[CH3:35][C:36]([S:39]([NH2:41])=[O:40])([CH3:38])[CH3:37].CCOC(C)=O>C1COCC1.[Cl-].[Na+].O>[C:36]([S:39](/[N:41]=[C:1](/[C:4]1[N:5]=[N:6][N:7]([C:9]2[CH:10]=[C:11]([CH:24]=[C:25]([N:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:28][CH2:29][CH3:30])[CH:26]=2)[C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH3:16])=[O:13])[CH:8]=1)\[CH3:2])=[O:40])([CH3:38])([CH3:37])[CH3:35]
Reactant: CC(C)(C)S(N)=O
Reactant: CCCN(c1cc(C(=O)N[C@H](C)c2ccc(F)cc2)cc(-n2cc(C(C)=O)nn2)c1)S(C)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCN(c1cc(C(=O)N[C@H](C)c2ccc(F)cc2)cc(-n2cc(/C(C)=N/S(=O)C(C)(C)C)nn2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
To a solution of 0.135 g (0.28 mmol) 3-(4-acetyl-1H-1,2,3-triazol-1-yl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[(methylsulfonyl)(propyl)amino]benzamide in 1 mL THF was added 0.18 mL (0.83 mmol) Ti(OEt)4 and 0.04 g (0.33 mmol) 2-methyl-2-propanesulfinamide. The mixture was stirred at rt for 1 hr then heated to reflux for 7 hours whereupon 40 mg more racemic 2-methyl-2-propanesulfinamide and 0.15 mL Ti(OEt)4 and were added and the mixture heated 2 more hr before cooling in an ice bath. To this was added 1 mL brine and 10 mL EtOAc and the mixture was stirred vigorously, breaking up clumps with a spatula. The mixture was filtered through celite and rinsed w. 50 mL EtOAc. The filtrate washed with 50 mL brine, dried over MgSO4, filtered, and concentrated to give 0.07 g 3-{4-[(1E)-N-(tert-butylsulfinyl)ethanimidoyl]-1H-1,2,3-triazol-1-yl}-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[(methylsulfonyl)(propyl)amino]benzamide as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.14 (s, 1H), 7.96 (s, 1H), 7.87 (s, 1H), 7.39 (m, 2H) 7.07 (m, 2H), 6.51 (br d, J=7.33 Hz, 1H), 5.31 (quint, J=7.14 Hz, 1H), 3.74 (t, J=6.78 Hz, 2H), 2.94 (s, 3H), 2.92 (s, 3H), 1.65 (d, J=6.96 Hz, 3H), 1.54 (m, 2H), 1.33 (s, 9H), 0.93 (t, J=7.32 Hz, 3H). LCMS [M+H]+=591.2
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][O:4][CH2:5][C:6]1[CH:17]=[CH:16][C:9]([C:10](N(OC)C)=[O:11])=[CH:8][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[O:11])=[CH:16][CH:17]=1
Reactant: CON(C)C(=O)c1ccc(COCC(C)(C)C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)COCc1ccc(C=O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a solution in tetrahydrofuran (5.93 mL) of the compound (472 mg) obtained in step (2) above, diisobutylaluminum hydride (about 1.0 mol/L, solution in n-hexane, 2.64 mL) was added at −78° C. After stirring the mixture at −78° C. for 30 minutes, 1 mol/L hydrochloric acid (5.00 mL) was added at that temperature. After being stirred at room temperature for an hour, the reaction mixture was poured into 1 mol/L hydrochloric acid (20.0 mL). After three extractions with ethyl acetate, the combined organic layers were washed with saturated brine. The washed organic layers were passed through a phase separator and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-90:10) to give the titled compound as a colorless oil (302 mg).
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([N+:32]([O-])=O)[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][N:21]4[C:25](=[O:26])[CH2:24][CH2:23][C:22]4=[O:27])=[CH:16][CH:15]=3)[S:13][C:6]=12.[NH4+].[Cl-]>CO.O.[Zn]>[NH2:32][C:30]1[CH:29]=[CH:28][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[N:19]=[CH:18][C:17]([CH2:20][N:21]5[C:22](=[O:27])[CH2:23][CH2:24][C:25]5=[O:26])=[CH:16][CH:15]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:31]=1
Reactant: O=C1CCC(=O)N1Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5C(=O)CCC5=O)cn4)sc23)c(F)c1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
To a suspension of 138 (100 mg, 0.209 mmol) in MeOH (10 mL) was added zinc (109 mg, 1.672 mmol) and NH4Cl (44.7 mg, 0.836 mmol) in water (1 mL) and the reaction mixture was heated to reflux for 48 hrs, cooled to RT and concentrated. The crude product was dissolved in MeOH/DCM and washed with water. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated to afford title compound 139 (80 mg, 85% yield) that was used without additional purification. MS (m/z)=448.47 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][OH:9])[N:3]=1.[H-].[Na+].I[CH3:13].O>CN(C)C=O>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][O:9][CH3:13])[N:3]=1
Reactant: CI
Reactant: OCCn1ccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCn1ccc(Br)n1

Procedure:
To a solution of 2-(3-bromo-1H-pyrazol-1-yl)ethanol obtained in Step D of Example 6 (300 mg) in N,N-dimethylformamide (16 mL) were added sodium hydride (55%, 137 mg) and iodomethane (196 μL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 2 hr, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (150 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3](C(=O)N)[N:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)=[CH:9][CH:8]=2)=[CH:5][NH:4][N:3]=1
Reactant: NC(=O)n1ncc(-c2ccc(Cc3ccc4c(c3)OCO4)cc2)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1n[nH]cc1-c1ccc(Cc2ccc3c(c2)OCO3)cc1
Yield: 74.5 %

Procedure:
To a suspension of 3-amino-2-carbamoyl-4-[4-(3,4-methylenedioxyphenylmethyl)phenyl]pyrazole (2.0 g) in methanol (20 ml) was added 5N sodium hydroxide solution (2.0 ml), and the mixture was refluxed for 1 hour. The solvent was distilled away under reduced pressure, and thereto was added water (50 ml) under ice-cooling. The mixture was neutralized (pH 7 to 8) with 10% hydrochloric acid, and the precipitate was separated by filtration, washed with chloroformdiethyl ether to give the title compound (1.3 g, 74.0%).
Reaction SMILES: CI.[O:3]=[C:4]1[N:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:8]2[CH2:20][CH2:21][C:22](=[O:23])[C:7]=2[CH:6]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[S:32]([CH3:35])(=[O:34])=[O:33])[NH:5]1.[C:36](=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:36][N:5]1[CH:6]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[S:32]([CH3:35])(=[O:33])=[O:34])[C:7]2[C:22](=[O:23])[CH2:21][CH2:20][C:8]=2[N:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([F:17])([F:19])[F:18])[CH:11]=2)[C:4]1=[O:3]
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2ccnc(C(F)(F)F)c2)C2=C1C(=O)CC2
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN1C(=O)N(c2ccnc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 25 °C

Procedure:
Methyl iodide (2 M in tert-butyl methyl ether, 63 μL, 0.13 mmol) is added to a solution of 4-(2,5-dioxo-1-(2-(trifluoromethyl)pyridin-4-yl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile (example 15.6, 50 mg, 0.11 mmol) and cesium carbonate (68 mg, 0.21 mmol) in N,N-dimethylformamide (2.0 mL), and the mixture is stirred at room temperature over night. Water is added and the mixture is purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 39 mg; ESI mass spectrum [M+H]+=491; Retention time HPLC: 0.97 min (Z018_S04).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(N(CC)CC)C.[N:13]1[C:18]2[NH:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[NH:22][C:23](=[O:24])[C:17]=2[CH:16]=[N:15][CH:14]=1>O1CCOCC1>[Cl:1][CH2:2][C:3]([N:19]1[C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[NH:22][C:23](=[O:24])[C:17]2[CH:16]=[N:15][CH:14]=[N:13][C:18]1=2)=[O:4]
Reactant: O=C1Nc2ccccc2Nc2ncncc21
Reactant: O=C(Cl)CCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1Nc2ccccc2N(C(=O)CCl)c2ncncc21

Procedure:
A solution of 3.16 g (0.028 mol) of chloroacetyl chloride in 8 ml of absolute dioxan and a solution of 2.82 g (0.028 mol) of dry triethylamine in 6 ml of absolute dioxan are added dropwise, simultaneously and as uniformly as possible, in the course of 20 minutes, at 60° to 70° C., to a suspension of 4.24 g (0.02 mol) of 5,6-dihydropyrimido[4,5-b][1,5]benzodiazepin-5-one in 60 ml of absolute dioxan, while stirring. The mixture is heated under reflux for a further 4 hours; precipitated triethylamine hydrochloride is filtered off, and the filtrate is concentrated in vacuo. The residue is chromatographed on neutral silica gel, using chloroform; the eluate is evaporated and the residue therefrom is stirred with ether and, after filtration, recrystallized from ethanol; yield: 3.9 g, m.p. 196° C. (dec.), from isopropanol.
Reaction SMILES: [ClH:1].[CH3:2][N:3](C(OC(C)(C)C)=O)[CH:4]([CH3:43])[CH2:5][CH2:6][N:7](C(OC(C)(C)C)=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH2:17][CH:18]([CH3:28])[N:19](C)[C:20](OC(C)(C)C)=O>CO>[ClH:1].[ClH:1].[ClH:1].[ClH:1].[CH3:20][NH:19][CH:18]([CH3:28])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][CH:4]([NH:3][CH3:2])[CH3:43]
Reactant: CC(CCN(CCCCCCCN(CCC(C)N(C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CNC(C)CCNCCCCCCCNCCC(C)NC
Reaction time: 8 h

Procedure:
Add 1N HCl in methanol (50 ml) to 1,2,16,17-tetramethyl-1,5,13,17-tetra(t-butoxycarbonyl)-1,5,13,17-tetraazaheptadecane (3.8 g, 0.0054 mol) and stir overnight. Remove the solvent in vacuo and recrystallize the residue two times from methanol/acetonitrile (40/60, v/v) to yield 0.74 g of the title compound as a white solid (mp 238°-9 ° C.). Rf is 0.31 for TLC on silica gel developed with 40% conc. ammonia in methanol.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5](N)=[C:4]([CH3:10])[CH:3]=1.Cl.N([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].[Cu](C#N)[C:23]#[N:24].[C-]#N.[K+]>O>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([C:23]#[N:24])=[C:4]([CH3:10])[CH:3]=1
Reactant: N#C[Cu]C#N
Reactant: Cc1cc(Br)cc(C)c1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: Cc1cc(Br)cc(C)c1C#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-2,6dimethylaniline (4.49 g, 22.4 mmol) was taken up in water (25 ml) and concentrated hydrochloric acid (8.0 ml) was added. The mixture was sonicated to form a fine suspension and then cooled to 0° C. A solution of sodium nitrite (1.67 g, 24.2 mmol) in water (5 ml) was then added dropwise so as to maintain the temperature of the reaction between 0–5° C. The mixture was stirred at 0–5° C. for ½ h and then neutralised by addition of solid sodium carbonate. The resulting solution was then added portionwise to a solution of copper cyanide (2.42 g, 27.0 mmol) and potassium cyanide (3.65 g, 56.1 mmol) in water (25 ml) at 70° C. The mixture was stirred at 70° C. for ½ h, allowed to cool and then extracted with toluene (2 times). The combined extracts were washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 5:95) to give an orange solid; yield 3.2 g (68%).
Reaction SMILES: [C:1]([O:11][C:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15](=[O:23])(=[O:22])[N:14]([CH3:24])[C:13]=1[C:25]([OH:27])=O)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(Cl)Cl.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>C(OCC)C>[C:1]([O:11][C:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15](=[O:23])(=[O:22])[N:14]([CH3:24])[C:13]=1[C:25]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)=[O:27])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN1C(C(=O)O)=C(OC(=O)C=Cc2ccccc2)c2ccccc2S1(=O)=O
Reactant: Nc1ccccn1
Solvent: CCOCC
Solvent: ClCCl
Product: CN1C(C(=O)Nc2ccccn2)=C(OC(=O)C=Cc2ccccc2)c2ccccc2S1(=O)=O

Procedure:
The cinnamoyl anhydride and the other mixed anhydrides of 4-cinnamoyloxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide prepared respectively according to Example 12 or Example 13 are directly reacted, without previous purification or recovery from their methylene chloride solution, with 2-2.5 molar equivalents of 2-aminopyridine with stirring and external cooling. After dilution with 3 volumes of diethyl ether the reaction mixture is stirred at 15° C. for 3 hours, then the procedure of Example 16 is repeated obtaining the desired 4-cinnamoyloxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]4[C:32]([C:37](O)=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:27][CH:26]=2)[C:19]([CH3:40])=[C:18]3[CH3:41])=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[CH3:42][S:43]([NH2:46])(=[O:45])=[O:44].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37](=[O:38])[NH:46][S:43]([CH3:42])(=[O:45])=[O:44])=[CH:29][CH:30]=2)[C:19]([CH3:40])=[C:18]3[CH3:41])=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CS(N)(=O)=O
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)NS(C)(=O)=O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The mixture of (S)-4′-((5-((1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (30 mg, 0.055 mmol), methanesulfonamide (15 mg, 0.16 mmol), EDAC (25 mg, 0.13 mmol) and DMAP (26 mg, 0.21 mmol) in DMF (3 mL) was stirred at rt for 15 h. The solvent was removed and the residue was purified by reverse phase prep-HPLC (MeOH/Acetonitrile/water) to obtain the title compound. ESI-MS (m/z): 622 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:4]2[NH:11][CH:10]=[N:9][C:5]=2[CH:6]=[N:7][CH:8]=1)#[CH:2].I[C:13]1[CH:14]=[C:15]([CH:37]=[CH:38][C:39]=1[CH3:40])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[C:21]([C:33]([F:36])([F:35])[F:34])[CH:20]=1)=[O:17]>>[NH:11]1[C:4]2[C:3]([CH2:1][CH2:2][C:38]3[CH:37]=[C:15]([CH:14]=[CH:13][C:39]=3[CH3:40])[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[C:21]([C:33]([F:36])([F:35])[F:34])[CH:20]=3)=[O:17])=[CH:8][N:7]=[CH:6][C:5]=2[N:9]=[CH:10]1
Reactant: C#Cc1cncc2nc[nH]c12
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1CCc1cncc2nc[nH]c12

Procedure:
The title compound can be synthesized from 7-ethynyl-1H-imidazo[4,5-c]pyridine and 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl) benzamide in a manner similar to that described for Example 1. 7-ethynyl-1H-imidazo[4,5-c]pyridine is prepared from 7-bromo-1H-Imidazo[4,5-c]pyridine and ethynyltrimethylsilane according to the 2 steps procedure described in Example 1.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20]CC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[H][H]>[Pd].CN(C)C(=O)C>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Nc1nc(N)c2c(Oc3ccc(OCc4ccccc4)cc3)cccc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2c(Oc3ccc(O)cc3)cccc2n1
Yield: 85.7 %

Procedure:
2,4-Diamino-5-(4-benzyloxyphenoxy)quinazoline (3.6 g, 10 mmol) was heated at 50-60° C. under 4 atmospheres of hydrogen gas in the presence of 0.36 g of 10% palladium on carbon in 80 mL of N,N-dimethylacetamide. After 4 hours the reaction mixture was filtered through silica gel in a fritted glass funnel, concentrated, dissolved in 50 mL of 2-propanol and allowed to crystallize at 4° C. The precipitate was collected by vacuum filtration, washed with 2-propanol and dried at 50° C. under vacuum to give 2.3 g (85.2% yield) of 2,4-diamino-5(4-hydroxyphenoxy)quinazoline, mp 330-341° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[O:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=O>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:3]3[N:4]=[CH:5][C:6]([C:7]([C:9]4[S:10][CH:11]=[CH:12][N:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)[CH:21]=1
Reactant: Nc1n[nH]cc1C(=O)c1nccs1
Reactant: CN(C)C=CC(=O)c1cccnc1
Product: O=C(c1nccs1)c1cnn2c(-c3cccnc3)ccnc12

Procedure:
As described for Example 1, (3-amino-1H-pyrazol-4-yl)-2-thiazolyl-methanone was reacted with 3-dimethylamino-1-(3-pyridinyl)-2-propen-1-one to give the product as colorless crystals, mp 262°-264° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]2[CH2:18][CH2:17]2)[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]2[CH2:17][CH2:18]2)[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:34]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: CN(c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F)C1CC1
Product: CN(c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F)C1CC1

Procedure:
The title compound was prepared from [2-amino-5-(cyclopropyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J15) (259 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (393 mg).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([NH:18][C@H:19]([C@H:27]1[O:31][C:30](=[O:32])[C@H:29]([CH3:33])[CH2:28]1)[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=O)(C)(C)C.Cl.[CH2:35]([C@H:42]([CH2:46][C:47]([N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1)=[O:48])[C:43]([OH:45])=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCOCC1>[CH2:35]([C@H:42]([CH2:46][C:47]([N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1)=[O:48])[C:43]([NH:8][C@H:9]([C:16]([NH:18][C@H:19]([C@H:27]1[O:31][C:30](=[O:32])[C@H:29]([CH3:33])[CH2:28]1)[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:45])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)[C@H](Cc2cscn2)NC(=O)OC(C)(C)C)OC1=O
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)[C@H](Cc2cscn2)NC(=O)[C@@H](CC(=O)N2CCOCC2)Cc2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
A mixture of 1.7 g (3.64 mmole) of (3R, 5S)-5-{(1S)-1-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl ]amino-2-cyclohexylethyl}-3-methyldihydrofuran-2(3H)-one (prepared as described in Preparation 25) and 20 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 60 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure. Diethyl ether was added to the residue, and the resulting mixture was concentrated by evaporation under reduced pressure. This operation was repeated three times, in total. After the final residue had been dried under reduced pressure for 8 hours, the dried materials were suspended in 30 ml of anhydrous tetrahydrofuran. 1.11 g (4.0 mmole) of 2(R)-benzyl-3-(morpholinocarbonyl)propionic acid were then added to the suspension, after which 0.71 ml (4.37 mmole) of 95% diethyl cyanophosphonate and 2.0 ml (14.56 mmole) of triethylamine were added to the resulting mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred at room temperature for 15 hours, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by medium pressure column chromatography through silica gel (using ethyl acetate as the eluent), to afford 1.43 g of the title compound as a colourless amorphous product.
Reaction SMILES: [C:1]([C:3]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:16][CH:15]=2)=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[C:5]([CH:25]=[CH2:26])[C:4]=1[CH3:27])#[N:2].O.[OH-].[Li+].CO>C1COCC1.O>[C:1]([C:3]1[C:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:18][CH:19]=2)=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH:25]=[CH2:26])[C:4]=1[CH3:27])#[N:2]
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(-n3cccn3)cc2)c(C#N)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=Cc1c(C(=O)O)cc(Cc2ccc(-n3cccn3)cc2)c(C#N)c1C
Temperature: 10 °C
Reaction time: 16 h
Yield: 89.2 %

Procedure:
To a solution of methyl 4-cyano-2-ethenyl-3-methyl-5-[4-(1H-pyrazol-1-yl)benzyl]benzoate (0.70 g) in THF (5.00 mL)-water (5.00 mL) were added lithium hydroxide monohydrate (0.25 g) and methanol (1.00 mL), and the mixture was stirred at 10° C. for 16 hr. The reaction mixture was diluted with water, and the mixture was extracted with tert-butyl methyl ether. The aqueous layer was acidified with 2N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.60 g).