Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:16])=[C:11]([NH2:15])[CH:12]=2)[CH2:7][N:6]1[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[O:4].O.C(=O)(O)[O-].[Na+].Cl[CH:30]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=2)=[CH:36][CH:35]=1)[C:31](Cl)=[O:32]>CCOC(C)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[C:10]([O:16][C@@H:30]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]5[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=5)=[CH:36][CH:35]=4)[C:31](=[O:32])[NH:15]3)=[CH:9][C:8]=2[CH2:7][N:6]1[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[O:4]
Reactant: COC(=O)[C@@H]1Cc2cc(N)c(O)cc2CN1C(=O)OC(C)C
Reactant: O=C(Cl)C(Cl)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(S)-6-amino-7-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-isopropyl ester 3-methyl ester (1.8 g) was dissolved in 10 mL EtOAc, 20 mL water and 5.0 g sodium bicarbonate added. 2-Chloro-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-acetyl chloride in 10 mL of EtOAc was added and the mixture stirred at rt for 1.5 h. The organic layer was washed with brine, dried and evaporated. The residue was dissolved in 15 mL DMF and potassium carbonate (4.1 g) added. The mixture stirred at rt for 3 h and was poured onto water and EtOAc. The organic was washed with 1N HCl, dried and evaporated. The residue was purified over silica (hexanes-EtOAc-2M ammonia in MeOH) to provide (S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-isopropyl ester 7-methyl ester (2.0 g). LC-MS (m/z) 600.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:49])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C@@H:33]([N:41]3[CH2:46][C@@H:45]([CH3:47])[NH:44][CH2:43][C@@H:42]3[CH3:48])[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=3)[CH:28]=2)[CH2:22][CH2:21]1)=[O:19])[CH3:16].[F:50][C:51]1[CH:52]=[C:53]([CH:56]=[CH:57][CH:58]=1)[CH:54]=O.C(O)(=O)C>CN(C)C=O>[CH2:15]([O:17][C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:49])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C@@H:33]([N:41]3[CH2:46][C@@H:45]([CH3:47])[N:44]([CH2:54][C:53]4[CH:56]=[CH:57][CH:58]=[C:51]([F:50])[CH:52]=4)[CH2:43][C@@H:42]3[CH3:48])[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=3)[CH:28]=2)[CH2:22][CH2:21]1)=[O:19])[CH3:16]
Reactant: O=Cc1cccc(F)c1
Reactant: CCOC(=O)C1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)NC[C@@H]3C)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(Cc4cccc(F)c4)C[C@@H]3C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (1.012 g) was added to a mixture of 1-{3-[(R)-((2S,5R)-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperidine-4-carboxylic acid ethyl ester (916 mg, Example 121), 3-fluorobenzaldehyde (474 mg) and acetic acid (229.4 mg) in dimethylformamide (15 mL). The reaction was stirred under nitrogen at room temperature for 2 hours. The reaction was quenched by the addition of saturated NH4Cl solution (2 mL), followed by the addition of H2O (10 mL). The resulting solution was diluted with 120 mL of H2O to precipitate product. The solution was neutralized with saturated NaHCO3 solution to pH=7 to produce additional precipitate. The mixture was filtered thru a celite pad. The collected solid was rinsed by water (35 mL×2). The solid was dissolved in EtOAc (50 mL) and then eluted from the celite pad. The filtrate (EtOAc solution) was washed with H2O (15 mL×2) and brine (15 mL×1), dried over Na2SO4 and concentrated to give crude product, which was purified by silica gel chromatography conducted on CombiFlash™ Sq 16×(gradient: 100% CH2Cl2 to 10% MeOH in CH2Cl2) to give 1-{3-[(R)-[(2S,5R)-4-(3-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperidine-4-carboxylic acid ethyl ester as light pink solid (675 mg; 60%). 1H NMR (300 MHz, CDCl3) δ 7.47 (m, 2H), 7.25 (m, 3H), 7.06 (m, 3H), 6.90 (m, 1H), 6.64 (m, 3H), 5.03 (s, 1H), 4.50 (m, 1H), 4.15 (q, J=7.0 Hz, 2H), 3.91 (d, J=13.5 Hz, 1H), 3.70 (m, 1H), 3.18 (d, J=13.5 Hz, 1H), 3.02 (m, 2H), 2.60 (m, 5H), 2.01 (m, 3H), 1.72 (m, 3H), 1.26 (t, J=7.0 Hz, 3H), 1.05 (m, 6H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:13][C:12]=2[CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:36]([O:40][C:41](=[O:44])[CH:42]=[CH2:43])([CH3:39])([CH3:38])[CH3:37]>CO>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH2:22][N:21]([CH2:43][CH2:42][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:44])[CH2:20][CH2:19]4)=[CH:13][C:12]=2[CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: c1ccc(Cc2ccc3oc(-c4ccc5c(c4)CCNC5)cc3c2)cc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCN1CCc2cc(-c3cc4cc(Cc5ccccc5)ccc4o3)ccc2C1
Reaction time: 0.5 h

Procedure:
6-(5-benzylbenzofuran-2-yl)-1,2,3,4-tetrahydroisoquinoline (67 mg, 0.2 mmol) was dissolved in methanol (2 mL). DIEA (0.35 mL) and acrylic acid tert-butyl ester (51 mg, 0.4 mmol) were added. The mixture was headed to 90° C. for 30 minutes using microwave irradiation. All the solvents was evaporated and the crude product of tert-butyl 3-(6-(5-benzylbenzofuran-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propanoate was used in the next step without further purification. MS (ESI) m/z: Calculated: 467.25; Observed: 468.30 (M++1).
Reaction SMILES: N#N.[N:3]([CH2:6][C:7]1[N:12]=[N:11][CH:10]=[N:9][C:8]=1[O:13][CH3:14])=[N+]=[N-]>[Pd].CO>[CH3:14][O:13][C:8]1[N:9]=[CH:10][N:11]=[N:12][C:7]=1[CH2:6][NH2:3]
Reactant: COc1ncnnc1CN=[N+]=[N-]
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: COc1ncnnc1CN
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A flask filled with N2 was charged with 6-(azidomethyl)-5-methoxy-1,2,4-triazine (15.0 g, 0.0903 mol) and Pd/C (10%) (3.20 g) followed by MeOH (480 mL). The suspension was purged with N2. The reaction was then stirred under H2 (1 atm) at rt for 5 h. The inorganics were filtered off, the solvent was removed under reduced pressure to give 1-(5-methoxy-[1,2,4]triazin-6-yl)-methylamine which was used for next step without any further purification.
Reaction SMILES: C(O[C:4](=[O:11])[CH2:5][C:6]([O:8]CC)=O)C.[C:12]1([N:18](C)[C:19]([NH2:21])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:23][O-].[Na+]>CO>[C:12]1([N:18]2[C:4](=[O:11])[CH2:5][C:6](=[O:8])[N:21]([CH3:23])[C:19]2=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[O-]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CN(C(N)=O)c1ccccc1
Agent: [Na+]
Solvent: CO
Product: CN1C(=O)CC(=O)N(c2ccccc2)C1=O

Procedure:
1-Phenyl-3-methyl-barbituric acid was prepared by condensation of malonic acid diethyl ester with phenyl-methylurea in methanol, with addition of sodium methylate. It melts at about 124°C after recrystallization from toluene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C([N-]C(C)C)(C)C.[Li+].[Br:19]C(Cl)(Cl)C(Cl)(Cl)Br.O>C1COCC1>[Br:19][C:10]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=[CH:3][C:2]=1[Br:1]
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: O=C(O)c1cncc(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cncc(Br)c1Br
Temperature: -55 °C
Reaction time: 2.5 h
Yield: 57 %

Procedure:
A cooled (−70° C.) solution of 5-bromonicotinic acid (12.6 g, 62.5 mmol) in THF under nitrogen was treated with 2 M lithium diisopropylamide (72 mL, 144 mmol) dropwise over 1 h. The solution stirred for 2.5 h at −55° C. The mixture was then cooled to −70° C. and treated with 1,2-dibromotetrachloroethane (25 g, 77.2 mmol) in portions over 30 min. After 1 h, the reaction mixture was allowed to warm to −20° C. over 2 h and then water (75 mL) was added slowly. The organic layer was then evaporated in vacuo and the aqueous residue was diluted with water (250 mL), then washed with ethyl acetate. The aqueous layer was then acidified to pH 3 by addition of concentrated hydrochloric acid. The precipitated solid was collected by filtration and dried at 60° C. in vacuo to afford 10 g (57%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.75 (s, 1H), 3.2 (br. s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C@H:12]([O:14]S(C)(=O)=O)[CH2:11][CH2:10][N:9]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:4][CH:3]=1.[C:26]([O-])(=[O:28])[CH3:27].[Na+]>CS(C)=O.C(OCC)(=O)C>[C:26]([O:14][C@@H:12]1[CH2:11][CH2:10][N:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:13]1)(=[O:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C[C@H]1c1ccc(F)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(=O)O[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(F)cc2)C1
Yield: 55.6 %

Procedure:
A solution of (±)-(2S,4R)-tert-butyl 2-(4-fluorophenyl)-4-(methylsulfonyloxy)piperidine-1-carboxylate (0.30 g, 0.80 mmol) and sodium acetate (0.33 g, 4.0 mmol) in dimethylsulfoxide (15 mL) was heated to 90° C. for 2.5 hours. After cooling, the reaction mixture was diluted with ethyl acetate (40 mL), and washed with water (25 mL) and brine (25 mL). The organic layer was dried over anhydrous sodium sulfate then filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexanes 1:10) to give (±)-(2R,4R)-tert-butyl 4-acetoxy-2-(4-fluorophenyl)piperidine-1-carboxylate (150 mg, 49% yield). 1H NMR (400 MHz, d6-DMSO): 7.24 (m, 4H), 5.14 (br s, 1H), 4.63 (m, 1H), 4.00 (br d, 1H), 2.72 (m, 1H), 2.56 (br d, 1H), 1.88 (s, 3H), 1.84 (br d 1H), 1.78 (m, 1H), 1.44 (m, 1H), 1.39 (s, 9H).
Reaction SMILES: [CH2:1]([N:5](C(OC(C)(C)C)=O)[CH2:6][CH2:7][CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][CH2:20][CH2:21][N:22]([CH2:30][CH:31]=[C:32]=[CH2:33])C(OC(C)(C)C)=O)[CH:2]=[C:3]=[CH2:4].Cl>CCO.CCOCC>[CH2:30]([NH:22][CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:1][CH:2]=[C:3]=[CH2:4])[CH:31]=[C:32]=[CH2:33]
Reactant: C=C=CCN(CCCN(CCCCCCCCN(CCCN(CC=C=C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: C=C=CCNCCCNCCCCCCCCNCCCNCC=C=C
Yield: 92.6 %

Procedure:
Dissolve 0.5 gm of the product of Step H in 2 ml of EtOH and while stirring treat the mixture with 10 ml of 2N HCl in Et2O. Stir the resulting mixture overnight, filter and dry the solids (in vacuo) to obtain 0.22 gm of the desired product, mp 283°-284° C. dec. Using the abbreviated form for naming the compounds embraced by formula I, it is to be noted that the following specific compounds are readily prepared by applying the foregoing described techniques and procedures and by applying known prior art principles to achieve the necessary modifications:
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]CCCC)=O.[NH2:22][C:23]1[CH:28]=[N:27][CH:26]=[C:25]([Cl:29])[N:24]=1>>[Cl:29][C:25]1[N:24]=[C:23]([NH:22][C:15]([C:3]2[N:4]([CH3:14])[S:5](=[O:12])(=[O:13])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:17])[CH:28]=[N:27][CH:26]=1
Reactant: CCCCOC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reactant: Nc1cncc(Cl)n1
Product: CN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O

Procedure:
This compound was prepared from butyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2-amino-6-chloro-pyrazine analogous to Example 1.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[CH2:29]([O:36][C:37]([NH:39][C:40]1[C:41]([C:52](O)=[O:53])=[N:42][C:43]2[C:48]([CH:49]=1)=[CH:47][CH:46]=[C:45]([CH2:50][CH3:51])[CH:44]=2)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:52]([C:41]3[C:40]([NH:39][C:37]([O:36][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:38])=[CH:49][C:48]4[C:43](=[CH:44][C:45]([CH2:50][CH3:51])=[CH:46][CH:47]=4)[N:42]=3)=[O:53])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)O)nc2c1
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)Nc3cnc4c(c3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)CCC4OC(C)=O)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
A mixture of 3-amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (6.15 mg, 0.0158 mmol), 3-{[(benzyloxy)carbonyl]amino}-7-ethylquinoline-2-carboxylic acid (4.6 mg, 0.013 mmol), HATU (12.5 mg, 0.0328 mmol), DMF (0.0305 mL) and DIPEA (5.09 mg, 0.0394 mmol) was stirred at room temperature for 1 h. The reaction mixture was filtered, concentrated under reduced pressure and purified by preparative LC MS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with NH4OH) to give pure sub-title compound as a colorless gum (4 mg, 40%). LCMS calc. for C40H47N6O7 (M+H)+: m/z=723.4. Found: 723.3.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:25]=1)[NH:22][C:21]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:20]2.C(N(CC)CC)C>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:25]=4)[NH:22][C:21]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:20]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)c1cc(N)cc2cc(C(C)(C)C)[nH]c12
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc2cc(C(C)(C)C)[nH]c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.20 mmol) and methyl 5-amino-2-tert-butyl-1H-indole-7-carboxylate (49.3 mg, 0.200 mmol) were dissolved in N,N-dimethylformamide (2 mL) containing a magnetic stir bar and triethylamine (0.084 mL, 0.60 mmol). The resulting solution was allowed to stir for 10 minutes at room temperature. The crude product was then purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield methyl 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-butyl-1H-indole-7-carboxylate. ESI-MS m/z calc. 434.2, found 435.5. (M+1)+. Retention time of 2.12 minutes.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:11][CH:12]([OH:17])[C:13]([CH3:15])([CH3:14])[CH3:16])=[CH:8][CH:9]=1
Reactant: CC(C)(C)C(=O)CSc1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C(O)CSc1ccc(Cl)cc1
Yield: 98 %

Procedure:
A 0.4 g quantity of sodium borohydride was added in small portions to a solution of 2.43 g of 1-(p-chlorophenylthio)-3,3-dimethyl-2-butanone in 50 ml of methanol at a temperature of up to 10° C. with stirring. After the completion of addition, the mixture was stirred at room temperature for 30 minutes and then distilled in a vacuum to remove the methanol. The residue was subjected to extraction with ether. The extract was washed with water, then dried over anhydrous magnesium sulfate and distilled to remove the solvent, affording 2.4 g of the above-identified desired compound in the form of a colorless oil.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([CH2:13][CH2:14][C:15]3[N:16]=[C:17]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[O:18][C:19]=3[CH:20]([CH3:22])[CH3:21])[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:31])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>CC(C)=O>[CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([CH2:13][CH2:14][C:15]3[N:16]=[C:17]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[O:18][C:19]=3[CH:20]([CH3:22])[CH3:21])[C:8]=2[CH:7]=[CH:6][C:5]=1[O:31][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)ccc2c(CCc3nc(-c4ccc(Cl)cc4Cl)oc3C(C)C)noc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCc1c(OCC(=O)OCC)ccc2c(CCc3nc(-c4ccc(Cl)cc4Cl)oc3C(C)C)noc12
Reaction time: 20 h
Yield: 80.7 %

Procedure:
The obtained 7-allyl-6-hydroxy-3-[2-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]ethyl]-1,2-benzisoxazole (45 mg, 0.098 mmol) and potassium carbonate (20 mg, 0.147 mmol) was suspended in acetone (5.0 mL). An acetone solution of ethyl bromoacetate (25 mg, 0.147 mmol) was added to the suspension while cooling with ice. The mixture was allowed to room temperature, and stirred for 20 hours. After insoluble was filtered off, the filter cake was washed with acetone. The filtrate and washings were combined, and concentrated. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (4/1) to give the desired compound (43 mg) as colorless oil (yield 80%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH2:11])[N:2]=1.N1([C:17]([N:19]2[CH:23]=[CH:22][N:21]=C2)=[S:18])C=CN=C1.[CH3:24][O:25][C:26](=[O:35])[C:27]1C=C[CH:30]=[C:29](N)[C:28]=1N>C1COCC1.CCN(C(C)C)C(C)C>[CH3:24][O:25][C:26](=[O:35])[C:27]1[CH:28]=[CH:29][CH:30]=[C:23]([NH:19][C:17]([NH:11][C:3]2[N:2]=[CH:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[S:18])[C:22]=1[NH2:21]
Reactant: COC(=O)c1cccc(N)c1N
Reactant: Nc1cc2ccccc2cn1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(NC(=S)Nc2cc3ccccc3cn2)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 0.86 g (6.0 mmol) of isoquinolin-3-ylamine in dry THF (30 mL) was added 1.25 g (7.0 mmol) of di-imidazol-1-yl-methanethione. The reaction mixture was refluxed for 30 min. After cooling to room temperature, a solution of 1.7 g (10 mmol) of 2,3-diamino-benzoic acid methyl ester (for synthesis see example 1) in THF (40 mL) and DIEA (2 mL) was added subsequently. The reaction mixture was stirred at room temperature for 1 h and diluted with hexanes (40 mL). The resulting precipitate was filtered. The solid was washed with water and ether and dried under vacuum to give 2-amino-3-(3-isoquinolin-3-yl-thioureido)-benzoic acid methyl ester as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[C:10]([F:23])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1>>[F:23][C:10]1[C:9]2[O:8][C:5]3[C:4]([C@@:15]4([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]4)[C:14]=2[CH:13]=[C:12]([C:36]2[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=2)[N:11]=1)=[CH:3][C:2]([C:30]1[C:25]([F:24])=[N:26][CH:27]=[CH:28][CH:29]=1)=[CH:7][CH:6]=3
Reactant: OB(O)c1cccnc1
Reactant: NC1=N[C@@]2(CCO1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Reactant: OB(O)c1cccnc1F
Product: NC1=N[C@@]2(CCO1)c1cc(-c3cccnc3F)ccc1Oc1c2cc(-c2cccnc2)nc1F

Procedure:
The title compound was synthesized by steps analogous to those described in method A1 above, but using intermediate 15B, 2-fluoropyridin-3-ylboronic acid and 3-pyridylboronic acid. MS m/z=458.0 [M+H]+. Calculated for C25H17F2N5O2: 457.14
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33]>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)=[O:33]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (20 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (2.0 g) and triethylamine (2.0 ml), and 3-chlorobenzoyl chloride (2.0 g) was gradually added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [OH-].[K+].COC([C:7]1([C:20]2[C:29]3[C:24](=[CH:25][C:26](Cl)=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=O.[OH:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>O>[NH:10]1[CH2:9][CH2:8][CH:7]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:12][CH2:11]1
Reactant: OCCCN1CCCCC1
Reactant: COC(=O)C1(c2ncnc3cc(Cl)ccc23)CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: c1nc(C2CCNCC2)c2ccc(OCCCN3CCCCC3)cc2n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Solid KOH (112 mg, 2 mmol) was added to a mixture of 4-(7-chloro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (3a; 82 mg, 0.2 mmol), prepared as described in Example 3, and 3-hydroxypropylpiperidine (0.25 mL). The mixture was stirred at 100° C. for 3 h. It was then cooled to rt and diluted with water. The mixture was extracted with DCM and the organic layer was drawn off and washed with water thrice, with brine once, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. To this was added 3 ML of 3M HCl/MeOH and the mixture was stirred at rt for 2 h and then concentrated in vacuo to afford crude 4-piperidin-4-yl-7-(3-piperidin-1-yl-propoxy)-quinazoline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][N:5]=[N+:6]=[N-:7].[F:9][C:10]1[C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O.C[O-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:8])[C:4]([N:5]=[N+:6]=[N-:7])=[CH:12][C:11]1[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:10]=1[F:9]
Reactant: O=Cc1cccc(OCc2ccccc2)c1F
Reactant: COC(=O)CN=[N+]=[N-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=Cc1cccc(OCc2ccccc2)c1F)N=[N+]=[N-]
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
A mixture of methylazidoacetate (36.64 g) and 2-Fluoro-3-benzyloxy benzaldehyde (18.32 g) in methanol (250 ml) was added dropwise, with stirring, over 1 hour to a mixture of sodium methoxide (17.20 g) in methanol (100 ml) at −25° C. under a stream of argon. Mixture was left to stir for 20 minutes, allowed to warm to 5° C. and stirred overnight.