Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[N:22]=[CH:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:20])[NH:14][C:13]=2[CH:12]=[C:11]([N+:31]([O-])=O)[CH:10]=1)=[O:8]>CN(C=O)C.C(O)(=O)C.[Pd]>[NH2:31][C:11]1[CH:10]=[C:9]([C:7](=[O:8])[NH:6][C:2]2[NH:3][CH:4]=[CH:5][N:1]=2)[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[N:22]=[CH:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:20])[NH:14][C:13]=2[CH:12]=1
Reactant: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cc([N+](=O)[O-])cc2[nH]1)c1cc2ccccc2cn1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Nc1cc(C(=O)Nc2ncc[nH]2)c2nc(NC(=O)c3cc4ccccc4cn3)[nH]c2c1
Reaction time: 3 h
Yield: 103.1 %

Procedure:
0.1 g (0.2 mmol) of isoquinoline-3-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-6-nitro-1H-benzoimidazol-2-yl]-amide (Example 129) was suspended in a mixture of 2 mL of DMF and 5 mL of acetic acid. To this stirring solution, ˜20 mg of 10% Pd on carbon was added, and the resulting mixture was hydrogenated at 42 psi of H2 at room temperature for 3.0 h. The reaction mixture was filtered, and the solid was washed with 5 mL of DMF. The filtrate and washings were combined and evaporated to reduce the volume to 10 mL, then diluted with saturated NaHCO3 (10 mL), and extracted with ethyl acetate. The organic layer was washed with water and brine and evaporated to provide 85 mg (91%) of isoquinoline-3-carboxylic acid [6-amino-4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 413 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][CH:11]=1.[CH3:19][N:20]([CH:31]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32]1)[C:21]1[S:22][C:23]2[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:24]=2[N:25]=1>>[CH3:19][N:20]([CH:31]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32]1)[C:21]1[S:22][C:23]2[CH:29]=[C:28]([NH:30][C:16]([C:13]3[CH:12]=[CH:11][C:10]([C:3]4[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=4[Cl:1])=[CH:15][CH:14]=3)=[O:18])[CH:27]=[CH:26][C:24]=2[N:25]=1
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)c(Cl)c1
Reactant: CN1CCC(N(C)c2nc3ccc(N)cc3s2)C1
Product: COc1ccc(-c2ccc(C(=O)Nc3ccc4nc(N(C)C5CCN(C)C5)sc4c3)cc2)c(Cl)c1

Procedure:
The title compound is prepared by following Method A, using 2′-chloro-4′-methoxy-biphenyl-4-carboxylic acid (0.26 g, 0.99 mmol), and isomer-1 of N*2*-Methyl-N*2*-(1-methyl-pyrrolidin-3-yl)-benzothiazole-2,6-diamine (0.20 g, 0.76 mmol) to afford the product (0.125 g, 32%). LC/MS: Retention time=5.27 min; (m/z): calcd for C27H27ClN4O2S. m/e: 507.1; found: 507.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:20]([NH2:21])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)=[O:10].[Cl:22][CH2:23][C:24](Cl)=O>C(O)(=O)C>[Cl:22][CH2:23][C:24]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9](=[O:10])[C:11]2[C:20](=[CH:19][C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:12]=2)[N:21]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cc2ccccc2cc1C(=O)Nc1ccccc1Cl
Solvent: CC(=O)O
Product: O=c1c2cc3ccccc3cc2nc(CCl)n1-c1ccccc1Cl
Yield: 38.9 %

Procedure:
Prepared according to Procedure B with 1n (500 mg, 1.68 mmol) and chloroacetyl chloride (0.40 mL, 5.05 mmol) in acetic acid (10 mL). Purified by chromatography in CH2Cl2 followed by recrystallization from isopropanol to afford 232 mg of a light-brown solid (39%). 1H NMR (CDCl3) δ: 8.92 (s, 1H); 8.29 (s, 1H); 8.81 (d, J=8.3, 1H); 8.32 (d, J=8.3 Hz, 1H); 7.51-7.69 (m, 4H); 7.55 (d, J=5.2 Hz, 1H); 7.53 (d, J=3.8 Hz, 1H); 4.43 (d, J=12 Hz, 1H), 4.12 (d, J=12 Hz, 1H). MS (ES): m/z 355.0 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9](/[CH:13]=[C:14](\[CH3:18])/[C:15]([NH2:17])=[O:16])[CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH:3]=1>CO.[Pd]>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH2:13][CH:14]([CH3:18])[C:15]([NH2:17])=[O:16])[CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH:3]=1
Reactant: C/C(=C\c1cccc(-n2nc(-c3ccccc3F)cc2N)c1)C(N)=O
Agent: [Pd]
Solvent: CO
Product: CC(Cc1cccc(-n2nc(-c3ccccc3F)cc2N)c1)C(N)=O
Yield: 57.9 %

Procedure:
(E)-3-(3-(5-amino-3-(2-fluorophenyl)-1H-pyrazol-1-yl)phenyl)-2-methylacrylamide (0.4192 g, 1.25 mmol, 1.00 eq) was hydrogenated (3.5 atm) over 10% Pd/C (0.0838 g, 0.0394 mmol, 0.0316 eq) in MeOH (5 ml) at RT for 36 h. Filtration through Celite® and evaporation yielded 0.245 g (58%) of crude 3-(3-(5-amino-3-(2-fluorophenyl)-1H-pyrazol-1-yl)phenyl)-2-methylpropanamide which was used as is in the next reaction. MS (ESI) m/z: 339.2 (M+H+).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:54])[O:5][C:6]1[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[C:8]([CH2:17][N:18]([C:22](=[O:53])[CH:23]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][O:43][C:44]3[C:49]([Cl:50])=[CH:48][C:47]([CH3:51])=[CH:46][C:45]=3[Cl:52])=[CH:36][CH:35]=2)[CH2:24][NH:25]C(OC(C)(C)C)=O)[CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)[CH3:2].Cl>C(Cl)Cl>[CH2:1]([NH:3][C:4](=[O:54])[O:5][C:6]1[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[C:8]([CH2:17][N:18]([C:22](=[O:53])[CH:23]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([O:40][CH2:41][CH2:42][O:43][C:44]3[C:45]([Cl:52])=[CH:46][C:47]([CH3:51])=[CH:48][C:49]=3[Cl:50])=[CH:38][CH:39]=2)[CH2:24][NH2:25])[CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Oc1cc(CCCOC)cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Agent: Cl
Solvent: ClCCl
Product: CCNC(=O)Oc1cc(CCCOC)cc(CN(C(=O)C(CN)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a CH2Cl2 solution (0.07 M) of 3-{[(3-[(tert-butoxycarbonyl)amino]-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}propanoyl)(cyclopropyl)amino]methyl}-5-(3-methoxypropyl)phenyl ethylcarbamate from the previous step (1 eq.) was added HCl (4.0 M dioxane solution, 35 eq.). The resulting solution was stirred at RT for 3 h. Following the removal of the volatiles in vacuo, the resulting residue was directly subjected to column chromatography (SiO2, 94:6 (v/v) CH2Cl2:2.0 M NH3 in MeOH) to afford the title compound. MS (ESI+): 686.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:18]=[CH:17][CH:16]=[N:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:7]=1.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[C:23]2[NH2:29]>>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([NH:29][C:23]2[C:22]3[C:26](=[CH:27][CH:28]=[C:20]([F:19])[CH:21]=3)[NH:25][N:24]=2)[C:3]2[CH:18]=[CH:17][CH:16]=[N:15][C:4]=2[N:5]=1
Reactant: Nc1n[nH]c2ccc(F)cc12
Reactant: Clc1ccccc1-c1nc(Cl)c2cccnc2n1
Product: Fc1ccc2[nH]nc(Nc3nc(-c4ccccc4Cl)nc4ncccc34)c2c1

Procedure:
Prepared from 4-Chloro-2-(2-chloro-phenyl)-pyrido[2,3-d]pyrimidine (100 mg, 0.36 mmol) and 5-Fluoro-1H-indazol-3-ylamine (108 mg, 0.72 mmol). Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt (45 mg, 22% yield). HPLC-Method A, Rt 3.00 min; 1H NMR (DMSO, 500 MHz): δ 13.0 (1H, s), 10.90 (1H, bs), 9.15-9.05 (2H, m), 7.70 (1H, m), 7.60-7.30 (6H, m), 7.20 (1H, m); MS (m/z), MH+ 391.1.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][NH2:36])[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]>C(#N)C>[CH2:20]([N:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][NH:36][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CCCN(CCC)CC1CCCCN1CCN
Solvent: CC#N
Product: CCCN(CCC)CC1CCCCN1CCNC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 88 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[(dipropylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 88% of theory. Colourless crystals, m.p. 165° C. (acetonitrile).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[N:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:24]=[N:25][N:26]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(O)(C)C>[CH3:33][Si:32]([CH3:35])([CH3:34])[CH2:31][CH2:30][O:29][CH2:28][N:26]1[CH:27]=[C:23]([C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[N:3]=2)[CH:24]=[N:25]1
Reactant: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Reactant: COC(=O)c1cc2nccn2c(Cl)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1cc2nccn2c(-c2cnn(COCC[Si](C)(C)C)c2)n1
Temperature: 80 °C
Yield: 27.1 %

Procedure:
Methyl 5-chloroimidazo[1,2-c]pyrimidine-7-carboxylate (1.00 g, 4.73 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (Preparation E; 1.53 g, 4.73 mmol), K3PO4 (2.01 g, 9.45 mmol), Pd2dba3 (0.433 g, 0.473 mmol), and XPHOS (0.563 g, 1.18 mmol) were combined dry. To this was added isopropanol (20 mL) and water (0.34 mL, 19 mmol). After de-gassing for 10 minutes, the flask was sealed and heated to 80° C. for 15 hours. The reaction mixture was diluted in EtOAc and undissolved solid was removed by filtration. The filtrate was concentrated down and purified by silica chromatography using 50-100% EtOAc/Hexanes gradient to afford methyl 5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-7-carboxylate (0.477 g, 1.28 mmol, 27.0% yield) as an orange brown solid. MS (apci) m/z=374.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([OH:17])=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[Br:18][C:19]1[CH:20]=[N:21][C:22]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)=[N:23][CH:24]=1>>[Br:18][C:19]1[CH:20]=[N:21][C:22]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[O:17])[CH2:27]2)=[N:23][CH:24]=1
Reactant: COc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: Brc1cnc(N[C@@H]2CCCNC2)nc1
Product: COc1ccc(-c2ccccc2C(=O)N2CCC[C@@H](Nc3ncc(Br)cn3)C2)cc1

Procedure:
prepared by reaction of 4′-methoxy-biphenyl-2-carboxylic acid with (R)-(5-bromo-pyrimidin-2-yl)-piperidine-3-yl-amine.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[NH2:7]
Reactant: CC(C)(C)OC(=O)Nc1cnccc1-c1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cnccc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
An ice-cold solution of [4-(2-chloro-phenyl)-pyridin-3-yl]-carbamic acid tert-butyl ester (1.08 g, 3.54 mmol) in CH2Cl2 (11 mL) was treated with TFA (4.04 g, 2.73 mL) and stirred at room temperature for 3.5 hours. The volatiles were removed at a rotary evaporator and the residue taken up in CH2Cl2 and saturated aqueous NaHCO3 solution and the layers were separated. The aqueous layer was extracted twice with CH2Cl2 and the organic layers were washed with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless solid (0.658 g, 90%). MS (ESI): m/z=205.05 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[N:12]([C:15]([F:18])([F:17])[F:16])[C:11](=[O:19])[O:10]2)=[CH:5][CH:4]=1.[OH:20]O>CC(C)=O>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[N:12]([C:15]([F:18])([F:17])[F:16])[C:11](=[O:19])[O:10]2)=[CH:5][CH:4]=1)=[O:20]
Reactant: CSc1ccc(-n2oc(=O)n(C(F)(F)F)c2=O)cc1
Reactant: OO
Solvent: CC(C)=O
Product: CS(=O)c1ccc(-n2oc(=O)n(C(F)(F)F)c2=O)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 2-(4'-methylthiophenyl)-4-trifluoromethyl-1,2,4-oxadiazolidine-3,5-dione (29.2 grams; 0.10 mol) in acetone (200 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. Hydrogen peroxide (16 grams; 0.14 mol) is then slowly added, with stirring, at room temperature. Stirring is continued for a period of about 72 hours after the addition is completed. After this time the solvent is removed from the reaction mixture by evaporation resulting in a solid product. The product is washed, recrystallized, and dried to yield 2-(4'-methylsulfinylphenyl)-4-trifluoromethyl-1,2,4-oxadiazolidine-3,5-dione.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([CH2:16][OH:17])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([O-])([O-])([O-])=[O:19].[Na+].[Na+].[Na+].Cl([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O.CC1(C)N([O])C(C)(C)CCC1>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:13])[F:14])=[C:10]([C:16]([OH:19])=[O:17])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1onc(-c2ccccc2)c1C(F)(F)F
Reactant: O=P([O-])([O-])[O-]
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 35 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A mixture of (3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)methanol (2.1 g, 8.64 mmol), TEMPO (0.094 g, 0.604 mmol), and a sodium phosphate buffer (0.67M) (32.2 mL, 21.59 mmol) in acetonitrile (30 mL) was heated to 35° C. A fresh solution of sodium phosphate buffer (40 mL, pH ˜6.5) consisting of a 1:1 solution of NaH2PO4 (20 mL, 0.67M) and Na2HPO4 (20 mL, 0.67M) was prepared and used. Solutions of sodium chlorite (3.91 g, 34.5 mmol) in water (4.5 mL) and bleach (4.3 mL, 6% wt.) were added simultaneously over 40 min. The reaction was monitored by HPLC, and after 2 h, ˜30% of the starting material remained. After 6 h, 10% remained. Additional bleach (100 μL) was added, and the reaction mixture was left at room temperature overnight. Additional bleach (100 μL) was added. The resulting mixture was allowed to stir at 35° C. for additional 2 h. HPLC indicated complete conversion. The reaction was quenched by the slow addition of a solution of sodium sulfite (2.07 mL, 43.2 mmol) in water (90 mL) at 0° C., resulting in the disappearance of the brown reaction color. The solvent was removed under reduced pressure, and the remaining aqueous residue was extracted with ethyl acetate (3×40 mL). The organic layers were combined, washed with water (8 mL), washed with brine (8 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (2.2 g, 8.55 mmol, 99% yield) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:4]=1[C:5]([O:7]CC)=[O:6].CO.[OH-].[Na+].Cl>O>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:4]=1[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)c1c(C)cccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(C)c1C(=O)O

Procedure:
A mixture of ethyl 2-methoxy-6-methylbenzoate (5.0 g, 25 mmol), water (10 ml), methanol (40 ml) and sodium hydroxide (2.1 g, 50 mmol) is heated under reflux with stirring. The reaction mixture is diluted with water (150 ml) and acidified with concentrated hydrochloric acid. The solid material is collected by filtration, washed with water and dried yielding dark yellow crystals, 2.1 g, mp 136° C.
Reaction SMILES: N(CC=C)CC(O)=O.CCN=C=NCCCN(C)C.[CH2:20]([NH:28][C:29]([C@@H:31]1[CH2:35][CH2:34][C@H:33]([CH2:36][CH:37]=[CH2:38])[NH:32]1)=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:39]([N:43]1[CH2:50][CH2:49][CH2:48][C@H:44]1[C:45](N)=[O:46])CC=C>ClCCl.CN(C1C=CN=CC=1)C>[CH2:20]([NH:28][C:29]([C@@H:31]1[CH2:35][CH2:34][C@H:33]([CH2:36][CH:37]=[CH2:38])[N:32]1[C:45](=[O:46])[C@@H:44]([NH:43][CH3:39])[CH2:48][CH:49]=[CH2:50])=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C=CCCN1CCC[C@H]1C(N)=O
Reactant: C=CC[C@H]1CC[C@@H](C(=O)NCCc2ccccc2)N1
Agent: C=CCNCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC[C@H]1CC[C@@H](C(=O)NCCc2ccccc2)N1C(=O)[C@H](CC=C)NC
Reaction time: 8 h

Procedure:
AllylGlyOH (10.5 g, 26.4 mmol) is suspended in dichloromethane (200 mL) and EDCI (5.1 g, 26.4 mmol) and DMAP (3.2 g, 26.4 mmol) are added to obtain a clear solution. 11E homoallylproline amide in dichloromethane (50 mL) is added and stirred overnight. The product is quenched with saturated bicarb and extracted with dichloromethane, followed by washing with brine, drying over anhydrous magnesium sulfate, filtering and concentrating. The crude is used in following deprotection. LCMS characterization ES+456.1 (m+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([N:18](COCC[Si](C)(C)C)[C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21]([OH:23])=[O:22])=[CH:15][CH:16]=2)[NH:11][N:10]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.C(N)CN.C(O)(=O)C>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21]([OH:23])=[O:22])=[CH:15][CH:16]=2)[NH:11][N:10]=1
Reactant: C[Si](C)(C)CCOCN(c1ccc2c(C#Cc3ccccn3)n[nH]c2c1)c1ccccc1C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: NCCN
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1Nc1ccc2c(C#Cc3ccccn3)n[nH]c2c1
Reaction time: 6 h
Yield: 73.4 %

Procedure:
A solution of 2-[3-Pyridin-2-ylethynyl- -(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-ylamino]-benzoic acid (231 mg, 0.477), 1M tetrabutylammonium fluoride in THF (3.8 mL, 3.816 mmol), and ethylenediamine (127 μL, 1.908 mmol), were stirred in an oil bath at 80 deg C. for 6 h. The reaction was quenched with acetic acid (218 μL, 3.816 mmol), diluted with water, and extracted with EtOAc (10×50 mL). The combined organics were washed with brine and dried over MgSO4. After concentrating a solid forms which was triturated with CH2Cl2, giving the product as a yellow powder (124 mg, 73%). ESIMS M−H−): 353.0.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:7])[CH2:5][OH:6].Cl[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([F:30])[CH:24]=3)=[O:22])[CH2:17][CH2:16]2)[CH:10]=1>CN(C=O)C>[F:30][C:25]1[CH:24]=[C:23]([C:21]([N:18]2[CH2:19][CH2:20][N:15]([C:11]3[CH:10]=[C:9]([O:6][CH2:5][CH:4]([CH3:7])[CH3:3])[N:14]=[CH:13][N:12]=3)[CH2:16][CH2:17]2)=[O:22])[CH:28]=[CH:27][C:26]=1[CH3:29]
Reactant: CC(C)CO
Reactant: Cc1ccc(C(=O)N2CCN(c3cc(Cl)ncn3)CC2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCN(c3cc(OCC(C)C)ncn3)CC2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 20 mg, 0.52 mmol) in DMF was added 2-methylpropan-1-ol (39 mg, 0.52 mmol) at rt. After stirring at rt for 15 min, (4-(6-chloropyrimidin-4-yl)piperazin-1-yl)(3-fluoro-4-methylphenyl)methanone (35 mg, 0.11 mmol) was added to the mixture. After stirring at rt for 12 h, the mixture was poured onto water (5 mL), and the aqueous phase was extracted with dichloromethane (three times). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative LC-MS to give 14.4 mg (37% yields) of the title compound.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)[CH:12]([N:15]([CH3:17])[CH3:16])[CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1.Cl>ClCCCl.CCCCO>[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:2]2[S:3][C:4]3[CH:10]=[C:9]([CH:11]([N:18]4[CH:22]=[CH:21][N:20]=[CH:19]4)[CH:12]([N:15]([CH3:17])[CH3:16])[CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCC(C(c1ccc2nc(Br)sc2c1)n1ccnc1)N(C)C
Agent: Cl
Solvent: CCCCO
Solvent: ClCCCl
Product: CCC(C(c1ccc2nc(Nc3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C

Procedure:
A solution of 1-(2-bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethyl-butan-2-amine (30 mg, 0.079 mmol), methyl-4-aminobenzoate (24 mg, 0.16 mmol) in 300 μL DCE and 300 μL n-BuOH was treated with 4N HCl (40 μL, 0.16 mmol) and refluxed overnight. The mixture was then partitioned between DCM and saturated NaHCO3 and the aqueous phase was extracted with DCM. The combined organic extracts were dried over Na2SO4, decanted and concentrated in vacuo. The residue was purified by PTLC using two 1 mm silica plates eluting with 5% MeOH (2N NH3)/DCM to provide methyl-4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)benzoate. MS (ESI+) m/z 450.19 [M+H]
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([CH:13]([CH3:15])[CH3:14])[C:7]2=[O:16].[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18].O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:21][C:17]([CH3:20])([CH3:19])[CH3:18])[N:8]([CH:13]([CH3:15])[CH3:14])[C:7]2=[O:16]
Reactant: CC(C)n1c(Cl)nc2c(Br)cccc2c1=O
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: O
Product: CC(C)n1c(NC(C)(C)C)nc2c(Br)cccc2c1=O
Yield: 86.7 %

Procedure:
A slurry of 8-bromo-2-chloro-3-isopropylquinazolin-4(3H)-one (406c, 0.40 g, 1.326 mmol) and tert-butylamine (4.18 mL, 39.8 mmol) was heated in a sealed tube at 80° C. overnight. The reaction was treated with ice, water, and DCM. The cloudy aq. layer was extracted 4×DCM and 1× EtOAc. The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (24 g column) using 0-40% EtOAc/hexanes. The product-containing fractions were concentrated to afford 8-bromo-2-(tert-butylamino)-3-isopropylquinazolin-4(3H)-one (0.39 g, 1.15 mmol, 87% yield) as an oil which slowly solidified. 1H NMR (400 MHz, CDCl3) δ ppm 8.05 (1H, dd, J=7.9, 1.5 Hz), 7.83 (1H, dd, J=7.6, 1.4 Hz), 6.97 (1H, t, J=7.7 Hz), 5.55 (1H, br. s.), 4.68 (1H, br. s.), 1.63 (9H, s), 1.55 (6H, d, J=7.2 Hz). m/z (ESI, +ve) 338.0/340.0 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11]C)[CH2:6][NH2:7].[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1.Br>CC(=O)CC>[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH2:6][NH:7][CH2:14][CH2:13][CH2:19][S:16]([OH:18])(=[O:17])=[O:15]
Reactant: O=S1(=O)CCCO1
Reactant: COc1ccc(CN)cc1OC
Agent: Br
Solvent: CCC(C)=O
Product: O=S(=O)(O)CCCNCc1ccc(O)c(O)c1
Temperature: 25 °C

Procedure:
To a solution of 3,4-dimethoxybenzylamine (2.2 mL, 15.0 mmol) in 2-butanone (20 mL) was added 1,3-propane sultone (1.98 g, 15.8 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. The crude product was suspended in 75% Acetone/MeOH (75 mL). The suspension was stirred at reflux for 30 sec.; the solid material was collected by filtration, washed with acetone (2×25 mL), and dried in vacuo. The solid (1.94 g, 6.7 mmol) was dissolved hydrobromic acid (48%, 27 mL). The solution was stirred at 100° C. for 4 h. The solvent was removed under reduced pressure. The residue was dissolved in water (20 mL). The aqueous phase was washed with CH2Cl2 (3×20 mL), and evaporated under educed pressure. The solid residue was suspended in hot MeOH (75 mL). The suspension was stirred at reflux for 30 sec.; the solid was collected by filtration, washed with 50% MeOH/acetone, and dried in vacuo. This allowed the isolation of compound S, 1.22 g (70%).