Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[N:7]=[C:8]([CH2:12][C:13]#[N:14])[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>O1CCOCC1>[CH:3]1[C:2]([Cl:1])=[CH:11][C:10]2[NH:9]/[C:8](/[NH:7][C:6](=[O:15])[C:5]=2[CH:4]=1)=[C:12](/[C:26]([C:25]1[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:24]=1[Cl:23])=[O:27])\[C:13]#[N:14]
Reactant: N#CCc1nc(=O)c2ccc(Cl)cc2[nH]1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N#C/C(C(=O)c1ccc(Cl)cc1Cl)=C1/NC(=O)c2ccc(Cl)cc2N1
Yield: 25.7 %

Procedure:
To solution of 2-(7-chloro-4-oxo-1,4-dihydroquinazolin-2-yl)acetonitrile (24.9 mg, 113 μmol) and triethylamine (17.4 μL, 125 μmol) in dioxane (4 mL) was added 2,4-dichlorobenzoyl chloride (15.9 μL, 113 μmol), and the resulting mixture was refluxed overnight with stirring. A solid precipitate formed upon cooling of the reaction mixture, which was recovered by vacuum filtration and washed sequentially with methanol, water, methanol, and dichloromethane. The solid was then dried to yield ciliobrevin D (5) (11.4 mg, 26%). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.47-7.52 (m, 2H), 7.56 (dd, J1=8.2 Hz, J2=1.8 Hz, 1H), 7.77 (d, J1=1.8 Hz, 1H), 7.90 (br s, 1H), 8.04 (d, J=8.5 Hz, 1H). 13C NMR (500 MHz, DMSO-d6) δ ppm 72.44, 116.56, 118.79, 118.85, 125.74, 127.65, 128.66, 129.2, 129.65, 130.49, 134.81, 138.21, 140.03, 155.62, 157.98, 188.6. HRMS (m/z): [M+Na]+ calc. for C17H8N3O2Cl3Na, 413.9580; observed, 413.9583.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[C:10]([F:19])=[C:11]([C:15]([F:18])=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.[C:28]([Cu])#[N:29].Cl>N1C=CC=CC=1>[C:28]([C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[C:10]([F:19])=[C:11]([C:15]([F:18])=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)#[N:29]
Reactant: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2Br)cc1
Reactant: N#C[Cu]
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2C#N)cc1
Temperature: 150 °C
Yield: 11.6 %

Procedure:
To a solution of 3-[5-bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.20 g, 0.43 mmol) in pyridine (4.0 mL) was added CuCN (0.19 g, 2.19 mmol). The reaction mixture was heated to 150° C. in microwave for 2 h. After the completion of the reaction, pH was adjusted to 3-4 with 1N HCl solution and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (60-120 M, 45% EtOAc-Hexane) to get the desired product (0.02 g, 11%) as a brown solid. 1H NMR (DMSO-d6, 400 MHz): δ 3.79 (s, 3H), 5.67 (s, 2H), 7.16 (m, 3H), 7.42 (m, 1H), 7.88 (br s, 1H), 8.03 (d, J=8.80 Hz, 2H) and 8.19 (br s, 1H). MS ES+ (402.07), HPLC (method I) Rt=16.60 min.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([O:3]C(C)(C)C)=O.Cl.C(N(CC)CC)C.[Cl:28][C:29]1[CH:37]=[C:36]([N+:38]([O-:40])=[O:39])[C:35]([N+:41]([O-:43])=[O:42])=[CH:34][C:30]=1C(O)=O.C1CCC(N=C=NC2CCCCC2)CC1>O1CCOCC1.CN(C1C=CN=CC=1)C.O>[Cl:28][C:29]1[CH:37]=[C:36]([N+:38]([O-:40])=[O:39])[C:35]([N+:41]([O-:43])=[O:42])=[CH:34][C:30]=1[C:1]([NH:8][CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])=[O:3]
Reactant: O=C(O)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc1Cl
Reactant: CC(C)(C)OC(=O)NCC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc1Cl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
A mixture of benzyl N-Bocglycinate (3 g, 11.3 mmol) and HCl in dioxane (20 mL) was stirred at rt for 2 h. Solvents were evaporated under reduced pressure and was diluted with dioxane (20 mL) and triethylamine (2.24 mL, 16.24 mmol). Then 2-chloro-4,5-dinitrobenzoic acid (2 g, 8.1 mmol) was added and cooled to 5° C. A solution of DCC (5.8 g, 28.1 mmol) in dioxane (20 mL) was added followed by catalytic amount of DMAP. The reaction mixture was stirred at rt for 5 h. Few drops of water was added to the reaction mixture and again stirred for 15 min. Reaction mixture was cooled to 0° C. and filtered. The solid was washed with ether (50 mL) and EtOAc (50 mL). The filtrate was poured into water and the organic layer was separated. The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organic layer was washed with brine and dried over anhyd Na2SO4. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform:acetone (90:10) as eluents to give the product as a pale yellow color solid (2.5 g, 75%), mp 122-124° C. 1H NMR (400 MHz, CDCl3): δ 8.30 (1H, s), 7.96 (1H, s), 7.39 (5H, s), 6.94 (1H, br s), 5.25 (2H, s), 4.32 (2H, d, J=4.8 Hz); LC-MS (negative ion mode): m/z 392 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][OH:19])[C:13]([O-:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].[CH3:32]S(OCCCCC([O-])=O)(=O)=O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][O:19][S:28]([CH3:27])(=[O:30])=[O:29])[C:13]([O:15][CH3:32])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](CCCO)C(=O)[O-])OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)OCCCCC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCCOS(C)(=O)=O)NC(=O)OCc1ccccc1
Reaction time: 0.58 h

Procedure:
To a solution of methyl ((2S)-2-[N-(benzyloxycarbonyl)amino]-5-hydroxy-pentanoate (1.84 g, 6.98 mmol) in dichloromethane (27 ml) cooled to -10° C. under argon was added triethylamine (1.057 g, 10.47 mmol) and then methanesulphonyl chloride (0.99 g, 8.72 mmol) over a 2 minute period. Stirring was continued for 35 minutes while the temperature was maintained below 0° C. The reaction mixture was then diluted with dichloromethane (200 ml) and washed with water (100 ml), 10% aqueous citric acid (2×100 ml), saturated aqueous sodium bicarbonate (100 ml) and dilute brine (100 ml), dried (Na2SO4) and concentrated in vacuo to a yellow oil residue. Purification by column chromatography, on elution with 1:1 v/v ethyl acetate/hexanes, afforded methyl (2S)-2-{N-(benzyloxycarbonyl)amino!-5-(methylsulphonyloxy)-pentanoate as a colourless viscous oil (2.40 g, 96%);
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[CH:17]2>>[ClH:1].[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][N:18]=[CH:17]4)=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Fc1ccc2c(Cl)ncnc2c1
Reactant: Nc1ccc2[nH]ncc2c1
Product: Cl
Product: Fc1ccc2c(Nc3ccc4[nH]ncc4c3)ncnc2c1
Yield: 70 %

Procedure:
Using an analogous procedure to that described in Example 5, 4-chloro-7-fluoroquinazoline was reacted with 5-amino-1H-indazole to give 7-fluoro-4-(1H-indazol-5-ylamino)quinazoline hydrochloride in 70% yield, m.p. >300° C.;
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]([CH3:36])([CH3:35])[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[C:17]([C:22]2[O:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)=[N:25][N:26]=2)[CH:16]=3)=[C:8]([CH3:34])[CH:7]=1.[OH-].[Na+].C1COCC1.Cl>CO.O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[O:23][C:22]([C:17]3[CH:16]=[C:15]4[C:20]([CH:21]=[C:13]([C:9]5[C:8]([CH3:34])=[CH:7][C:6]([CH2:5][C:4]([CH3:35])([CH3:36])[C:3]([OH:37])=[O:2])=[CH:11][C:10]=5[CH3:12])[NH:14]4)=[CH:19][CH:18]=3)=[N:26][N:25]=2)=[CH:28][CH:29]=1
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(-c2cc3ccc(-c4nnc(-c5ccc(Cl)cc5)o4)cc3[nH]2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CC(C)(C)C(=O)O)cc(C)c1-c1cc2ccc(-c3nnc(-c4ccc(Cl)cc4)o3)cc2[nH]1
Temperature: 50 °C

Procedure:
Suspend 3-(4-{6-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-1H-indol-2-yl}-3,5-dimethyl-phenyl)-2,2-dimethyl-propionic acid methyl ester (262 mg, 0.510 mmol) in MeOH (2.6 mL)/1 N NaOH (2.6 mL) and heat to 50° C. for 3 h. Add THF (2.6 mL) and heat to 50° C. for 15 h. Add 1 N NaOH (2.6 mL), THF (2.6 mL), and NaOH (225 mg, 5.63 mmol) in water (1 mL). Heat the reaction at 50° C. until the ester is not observed by LC/MS. Concentrate the reaction under reduced pressure. Adjust the pH to 2 with 1 N HCl. Collect the resulting precipitate by filtration and rinse the solid with Et2O to afford a light yellow solid: (M+H)+ 500.2.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[N:13][N:14]([C:16]2[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][N:17]=2)[CH:15]=1)(C(C)(C)C)(C)C.Cl.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>C1COCC1.O>[OH:8][CH2:9][CH2:10][C:11]1[CH:12]=[N:13][N:14]([C:16]2[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][N:17]=2)[CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cnn(-c2cc(C#N)ccn2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccnc(-n2cc(CCO)cn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of 2-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrazol-1-yl]pyridine-4-carbonitrile (1.2 g, 3.6 mmol) in THF (15 mL) at 0° C. was added 3N HCl (5 mL). The reaction mixture was then stirred for 2 hours at room temperature. Cool to 0° C., added ethyl acetate, water and acidified with NaHCO3 to pH=8. The mixture was then extracted with ethylacetate, concentrated to afford the title compound (700 mg, 91%). [M+H] Calc'd for C11H10N4O, 215; Found, 215.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.Cl.CN.[CH:31]([N:34](C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1>[CH3:31][NH:34][C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:17]=[C:11]2[CH:10]=1)=[O:24])=[O:26]
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CCCP(=O)=O
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 66.6 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), methanamine hydrochloride (186 mg, 2.76 mmol), diisopropylethylamine (627 μl, 3.59 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7.00 ml) is stirred for 4 hours at 70° C. and then over the weekend at 25° C. under nitrogen atmosphere. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording N4,1-dimethyl-N5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (69 mg, 66.6%) as a white solid. mp.: >250° C. MS: m/z=376.2 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.CCN(C(C)C)C(C)C.Cl.[CH2:22]([C:24]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25]1)[CH3:23].O>CS(C)=O>[CH2:22]([C:24]1([NH:29][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1)[CH3:23]
Reactant: CCC1(N)CCCC1
Reactant: CSc1ncc(C#N)c(Cl)n1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCC1(Nc2nc(SC)ncc2C#N)CCCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
To a stirring solution of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (984 mg, 5.3 mmol) in DMSO (10 mL) was added DIEA (2.1 g, 15.9 mmol) and 1-ethylcyclopentanamine hydrochloride (900 mg crude). The resulting mixture was stirred at 60° C. for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford the crude product. The crude product was purified by silica gel column chromatography (5% ethyl acetate in petroleum ether) to get the desired product as a yellow oil (830 mg, 3.2 mmol, 53.5% yield). MS (ESI) m/z=263.2 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:24])[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:8][C:7]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[N:6][CH:5]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40]Br>O1CCCC1>[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40][N:2]([CH3:1])[C:3](=[O:24])[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:8][C:7]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[N:6][CH:5]=1
Reactant: CNC(=O)c1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of 750 mg (2.32 mmol) N-methyl-6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide in 16 ml tetrahydrofuran, 3 ml of a 1 M solution (3 mmol) of potassium hexamethyldisilazide in tetrahydrofuran was added at room temperature. After 1 h, 0.43 ml (2.3 mmol) 3,5-bis(trifluoromethyl)benzyl bromide was added dropwise to the resulting suspension. The reaction was quenched with water after 1 h and the mixture was extracted with three 20 ml portions of ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried with sodium sulfate and concentrated. Column chromatography gave 950 mg (74%) N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide. The white foam was dissolved in a small amount of diethyl ether and treated with 2 ml 3 N hydrochloric acid solution in diethyl ether. Concentration afforded 1.02 g (74%) of the title compound as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:6]=[CH:7][CH:8]=1)=O.[CH2:38]([NH2:40])[CH3:39].C1COCC1.[BH4-].[Na+]>CO.C(Cl)Cl>[CH2:38]([NH:40][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:6]=[CH:7][CH:8]=1)[CH3:39]
Reactant: CCN
Reactant: NC(=O)c1cc(-c2cccc(C=O)c2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)c[nH]c12
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CCNCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CCCN5CCCC5)CC4)c3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a solution of 5-(3-formylphenyl)-3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (25 mg, 0.048 mmol) in MeOH/CH2Cl2 (1 mL/1 mL) was added 2M ethyl amine in THF (0.144 mL, 0.288 mmol). The reaction mixture was stirred at room temperature for 2 hours before NaBH4 (12 mg, 0.3 mmol) was added. The reaction mixture was stirred at room temperature overnight and evaporated all the solvent. The residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (11 mg, 52%)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7]([NH2:9])=[N:8][C:4]=2[CH:3]=1.F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br-]>O.CN(C)C(=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:4]=2[CH:3]=1
Reactant: Fc1ccccn1
Reactant: Nc1nc2cc(Br)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1nc2ccc(Br)cc2n1-c1ccccn1
Temperature: 150 °C
Yield: 26 %

Procedure:
To two 10-20 mL microwave vials was added 5-bromo-1H-benzo[d]imidazol-2-amine (3.00 g, 14.1 mmol, Carbocore, The Woodlands, Tex.), N,N-dimethylacetamide (20 mL), 2-fluoropyridine (1.46 mL, 17.0 mmol, Aldrich, St. Louis, Mo.) and cesium carbonate (7.84 g, 24.1 mmol). (One-half of the material in each vial, ie 1.5 g of the bromide in each vial.) The mixture was heated at 150° C. for 140 min in the microwave. After cooling to rt, the combined reaction mixtures were poured into water (400 mL) and then extracted with EtOAc/hexane (80:20) (3×150 mL). The combined extracts were washed with water (3×100 mL) and brine (100 mL) and then dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (0.5 to 3.8% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound (1.06 g, 26%). MS (ESI, positive ion) m/z: 289 (M(79Br)+1).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]=O.C(N(CC)CC)C.[ClH:21].[NH2:22][CH:23]([CH3:32])[CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25].[BH4-].[Na+]>CO.O>[ClH:21].[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][NH:22][CH:23]([CH3:32])[CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25]
Reactant: O=Cc1ccc2ccccc2c1Br
Reactant: CC(N)C(O)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: CC(NCc1ccc2ccccc2c1Br)C(O)c1ccccc1
Yield: 89.3 %

Procedure:
A mixture of 38.4 g (0.164 mole) 1-bromo-2-naphthaldehyde, 16.4g (0.164 mole) triethylamine, and 30.6 g (0.164 mole) of 2-amino-1-phenyl-1-propanol hydrochloride in 500 ml CH3OH was stirred and refluxed for 60 minutes, then cooled to 10°-20° while 6.23 g (0.164 mole) of sodium borohydride was added over 5 minutes. The reaction mixture was stirred at ambient temperature (15°-21°) for 60 minutes and diluted with 500 ml H2O. The mixture was stirred for 15 minutes and extracted with 2 × 350 ml CHCl3. The combined extracts were dried (MgSO4) and concentrated to dryness in vacuo to give 59.6 g (99%) of the free base.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:19]=[C:18]([N:20]2[C:24]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=3)=[N:23][N:22]=[N:21]2)[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.[CH3:34][O:35][C:36](=[O:57])[C@H:37]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47]([C:49]2[C:54]([Cl:55])=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:56])=[O:48])=[CH:42][CH:41]=1)[NH2:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:34][O:35][C:36](=[O:57])[C@H:37]([CH2:39][C:40]1[CH:41]=[CH:42][C:43]([NH:46][C:47]([C:49]2[C:54]([Cl:55])=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:56])=[O:48])=[CH:44][CH:45]=1)[NH:38][C:13]([C:12]1[CH:16]=[CH:17][C:18]([N:20]2[C:24]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=3)=[N:23][N:22]=[N:21]2)=[CH:19][C:11]=1[Cl:10])=[O:15]
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reactant: O=C(O)c1ccc(-n2nnnc2NCc2cccc(O)c2)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccc(-n2nnnc2NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 75.8 %

Procedure:
In an argon atmosphere, DIPEA (0.102 mL; 0.585 mmol) was added to a stirred solution of 2-chloro-4-[5-[[(3-hydroxyphenyl)methyl]amino]-1H-tetrazol-1-yl]benzoic acid (51 mg; 0.15 mmol), 4-[[(2,6-dichlorophenyl]carbonyl]amino]-L-phenylalanine methyl ester (60 mg; 0.15 mmol) and HBTU (59 mg; 0.1555 mmol) in dimethylformamide (3 mL). The reaction mixture was stirred for 17 hr at room temperature, then was concentrated under reduced pressure. The residual oil was taken up in dichloromethane (25 mL) and washed in turn with 0.5 N HCl (10 mL) and water (10 mL). The aqueous layers were backwashed in turn with dichloromethane. The combined organic layers were dried (Na2SO4) and evaporated to give 85 mg of crude product. This material was crystallized from dichloromethane-diethyl ether to furnish 79 mg of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[2-chloro-4-[5-[[(3-hydroxyphenyl)methyl]amino]-1H-tetrazol-1-yl]phenyl]carbonyl]-L-phenylalanine methyl ester as a colorless solid, mp 155-158° C. FAB HRMS: (C32H26Cl3N7O5) Obs. Mass 694.1158 Calcd. Mass 694.1139 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:27][CH2:26][CH2:25][C@H:24]3[C:28]([F:31])([F:30])[F:29])=[N:21][CH:22]=2)O1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[F:31][C:28]([F:29])([F:30])[C@@H:24]1[CH2:25][CH2:26][CH2:27][N:23]1[C:20]1[N:19]=[CH:18][C:17]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=2)=[CH:22][N:21]=1
Reactant: Nc1cncc(Cl)n1
Reactant: CC1(C)OB(c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cncc(-c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)n1
Reaction time: 8 h
Yield: 68.3 %

Procedure:
A round bottom flask was charged with 6-chloropyrazin-2-amine (0.401 g, 3.09 mmol), (S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidine (1.062 g, 3.09 mmol), Pd(PPh3)4 (0.358 g, 0.309 mmol) and 1,4-Dioxane (Volume: 7.74 ml). The reaction mixture was purged with nitrogen for several minutes before an aqueous 2M sodium carbonate (3.09 ml, 6.19 mmol) was added. The reaction mixture was purged for another 10 minutes under nitrogen before it was placed in a 90° C. oil bath and allowed to stir overnight. 1,4-Dioxane was removed in vacuo and the crude mixture was diluted with EtOAc. The product was wash with water (3×) and brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified on silica gel using normal phase flash chromatography, eluting with CH2Cl2:MeOH to yield 0.655 g (2.11 mmol, 68.2%) of the title product; 1H NMR (300 MHz, DMSO-d6) δ 9.01 (s, 2H), 8.26 (s, 1H), 7.83 (s, 1H), 6.55 (s, 2H), 5.16-5.02 (m, 1H), 3.77-3.60 (m, 2H), 2.29-2.01 (m, 4H); m/z [M+H]+=311.12
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.F[B-](F)(F)F.[N:20]1(OC(N(C)C)=[N+](C)C)[C:24]2C=[CH:26][CH:27]=[CH:28][C:23]=2N=N1.C(N(C(C)C)C(C)C)C.N1CCCCC1>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:20]1[CH2:26][CH2:27][CH2:28][CH2:23][CH2:24]1)=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Product: O=C(c1ccc2cc(O)ccc2c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.5 g (0.003 mol) 6-hydroxy-2-naphtoic acid, 1.2 g (0.003 mol) 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate, 2.3 ml (0.013 mol) N-ethyldiisopropylamine and 0.29 ml (0.030 mol) piperidine in 10 ml DMF was stirred for 16 h at room temperature. The mixture was concentrated to dryness and 50 ml ethyl acetate, 30 ml water and 20 ml NaHCO3 aq. (10%) was added. The aqueous phase was extracted with 50 ml ethyl acetate and the combined organic layers were purified with column chromatography on silica. The product fractions were concentrated to dryness and titurated twice with 20 ml diethyl ether/heptane 1/1. The residue was dried under vacuum at 50° C. to yield 0.58 g (0.0227 mmol; 85%) of the title compound as light brown solid. MS (m/e): 254.3 (MH−, 100%)