Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[N:7]3[CH2:16][CH2:15][CH:14](O)[CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.CCN(S(F)(F)[F:25])CC>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[N:7]3[CH2:16][CH2:15][CH:14]([F:25])[CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1c2ccc(Br)cc2nc2n1CCC(O)CC2
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=c1c2ccc(Br)cc2nc2n1CCC(F)CC2
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3-bromo-8-hydroxy-7,8,9,10-tetrahydroazepino[2,1-b]-quinazolin-12(6H)-one (200 mg, 0.64 mmol, 1 equiv) in DCM was added excess DAST under N2 at −78° C. After that, the resulting mixture was stirred at −78° C. for 3 h. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extract was dried over Na2SO4. After filtration and concentration, the crude product was purified by silica gel chromatography to give 200 mg of the desired product. MS (ESI): 311, 313 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:15][S:16]([CH2:19][C:20](O)=[O:21])(=[O:18])=[O:17]>C(O)(=O)C>[Cl:26][C:25]1[CH:24]=[CH:23][C:14]([CH2:15][S:16]([C:19]2[C:20](=[O:21])[O:10][C:5]3[C:6]([CH:7]=2)=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:18])=[O:17])=[CH:13][C:12]=1[NH2:11]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: Nc1cc(CS(=O)(=O)CC(=O)O)ccc1Cl
Solvent: CC(=O)O
Product: Nc1cc(CS(=O)(=O)c2cc3cc(Cl)ccc3oc2=O)ccc1Cl
Yield: 91 %

Procedure:
A solution of 5-chlorosalicylaldehyde (1 mmol) and 2-(3-amino-4-chlorobenzylsulfonyl)acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 2, Method A to generate a 91% yield of the title compound.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH2:18][CH2:17]2)=[O:15])=[C:9]([CH3:27])[CH:8]=1>C1COCC1.O>[CH:23]1([CH2:22][N:19]2[CH2:18][CH2:17][N:16]([C:14](=[O:15])[CH2:13][C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:28])=[O:5])=[CH:8][C:9]=3[CH3:27])[CH2:21][CH2:20]2)[CH2:26][CH2:25][CH2:24]1
Reactant: COC(=O)c1ccc(CC(=O)N2CCN(CC3CCC3)CC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1CC(=O)N1CCN(CC2CCC2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 63 %

Procedure:
Lithium hydroxide monohydrate (122 mg, 2.9 mmol) was added to a solution of 4-[2-(4-cyclobutylmethyl-piperazin-1-yl)-2-oxo-ethyl]-3-methyl-benzoic acid methyl ester from Example E85.1 (500 mg, 1.4 mmol) in THF (10 ml) and water (5 ml). The mixture was stirred for 20 h at room temperature and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 3% acetic acid:7% methanol:90% chloroform) to yield the title compound (300 mg, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:26][CH3:27])[C@@H:22]([O:24][CH3:25])[CH3:23])[C:11](=[O:28])[C@:10]([CH2:30][C:31]([O:33]C)=[O:32])([CH3:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:26][CH3:27])[C@@H:22]([O:24][CH3:25])[CH3:23])[C:11](=[O:28])[C@:10]([CH2:30][C:31]([OH:33])=[O:32])([CH3:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H]([C@H](C)OC)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC[C@@H]([C@H](C)OC)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-methoxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetate (34 mg, 0.067 mmol; Example 153, Step B) in THF/MeOH/H2O (1/1/1, 0.48 mL) was added 2 M lithium hydroxide (67 uL, 0.134 mmol) at rt. After being stirred at rt for 4 h, the reaction was quenched saturated aqueous NH4Cl and extracted (2×DCM) and the combined organic layers were washed (1×sat. aq. NaCl solution) and concentrated under the reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 70 to 100% EtOAc/hexanes) provided the title compound.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8](B(O)O)[CH:7]=[CH:6][C:5]=12.I[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[N:3]1[O:2][N:1]=[C:5]2[CH:6]=[CH:7][C:8]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[N:20][C:21]=4[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=3)=[CH:9][C:4]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: OB(O)c1ccc2nonc2c1
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: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2ccc3nonc3c2)c2c(N)ncnc21
Temperature: 80 °C

Procedure:
A solution of Benzo[c][1,2,5]oxadiazole-5-boronic acid (18 mg, 0.11 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA44. ESI-MS (M+H)+ m/z calcd 296.1, found 296.1.
Reaction SMILES: [Cl:1][C:2]1[C:9]([NH2:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH2:11].[CH2:12]([O:14][CH2:15][C:16](Cl)=[O:17])[CH3:13]>N1C=CC=CC=1>[CH2:12]([O:14][CH2:15][C:16]([NH:11][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([NH:10][C:16](=[O:17])[CH2:15][O:14][CH2:12][CH3:13])[C:2]=1[Cl:1])[C:6]#[N:7])=[O:17])[CH3:13]
Reactant: N#Cc1cc(N)c(Cl)c(N)c1
Reactant: CCOCC(=O)Cl
Solvent: c1ccncc1
Product: CCOCC(=O)Nc1cc(C#N)cc(NC(=O)COCC)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-chloro-3,5-diaminobenzonitrile (3.3 g) in pyridine (80 ml) is added dropwise ethoxyacetyl chloride (4.8 ml) at room temperature. The mixture is stirred at room temperature for 3 hours, and thereafter, pyridine is distilled off under reduced pressure. To the residue is added water, and the resulting solid substance is separated by filtration and washed with water. The resulting crude crystals are recrystallized from ethanol to give the title compound (4.0 g) having the following physical properties.
Reaction SMILES: NCC(N)C.[CH3:6][CH:7]([CH3:13])[CH2:8][C@H:9]([NH2:12])[CH2:10][NH2:11].[C:14]([NH:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][N:31]=1)[C:26](O)=O)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:8]([CH:9]1[CH2:10][NH:11][C:26]([C:25]2[CH:29]=[CH:30][N:31]=[C:23]([NH:22][C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:24]=2)=[N:12]1)[CH:7]([CH3:13])[CH3:6]
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Reactant: CC(C)C[C@H](N)CN
Agent: CC(N)CN
Product: CC(C)CC1CNC(c2ccnc(NC(=O)c3ccccc3)c2)=N1
Yield: 23 %

Procedure:
Following the procedure as described in Example 9, making variations as required to replace 1,2-diaminopropane with (S)-4-methylpentane-1,2-diamine to react with 2-benzamidoisonicotinic acid, N-(4-(4-isobutyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-2-yl)benzamide was obtained in 23% yield: MS (ES+) m/z 323.2 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8](=[O:19])[C:7]=1[CH2:20][N:21]([CH2:32][C:33]([O:35][CH3:36])=[O:34])S(C1C=CC(C)=CC=1)(=O)=O)=O)C.C[O-].[Na+].Cl>CO.[Cl-].[Na+].O>[CH3:36][O:35][C:33]([C:32]1[N:21]=[CH:20][C:7]2[C:8](=[O:19])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[CH:11][C:6]=2[C:4]=1[OH:3])=[O:34]
Reactant: CCOC(=O)c1ccn(Cc2ccccc2)c(=O)c1CN(CC(=O)OC)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Reaction time: 8 h
Yield: 85.2 %

Procedure:
1-Benzyl-3-{[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid ethyl ester (232 mg, 0.45 mmol) was dissolved in MeOH (10 mL). NaOMe solution (0.32 mL, 1.36 mmol, 25 wt % in MeOH) was added, and the mixture was stirred overnight. Brine (20 mL) was added, followed by 1M HCl until pH was about 4. The resulting suspension was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The residue was chromatographed (5-60% EtOAc/hexanes+2% AcOH) to give 119 mg of the title compound as a yellow solid. MS: (+) m/z 311.13 (M+1).
Reaction SMILES: CN(C)CCCN=C=NCC.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([OH:19])=O.[NH2:20][C@@H:21]([CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[C:22]([NH:24][C@H:25]1[CH2:31][CH2:30][C@@H:29]([CH3:32])[N:28]([CH2:33][CH2:34][CH3:35])[CH2:27][C@@H:26]1[OH:36])=[O:23].CN1CCOCC1.OC1C2N=NNC=2C=CC=1>CN(C=O)C.CCOC(C)=O>[CH:38]1([CH2:37][C@H:21]([NH:20][C:17]([C:13]2[O:12][CH:16]=[CH:15][CH:14]=2)=[O:19])[C:22](=[O:23])[NH:24][C@H:25]2[CH2:31][CH2:30][C@@H:29]([CH3:32])[N:28]([CH2:33][CH2:34][CH3:35])[CH2:27][C@@H:26]2[OH:36])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=C(O)c1ccco1
Reactant: CCCN1C[C@H](O)[C@@H](NC(=O)[C@@H](N)CC2CCCCC2)CC[C@H]1C
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN1C[C@H](O)[C@@H](NC(=O)[C@H](CC2CCCCC2)NC(=O)c2ccco2)CC[C@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.10 g, 0.53 mmol) was added to a solution of furan-2-carboxylic acid (0.059 g, 0.53 mmol), (S)-2-Amino-3-cyclohexyl-N-((3S,4S,7R)-3-hydroxy-7-methyl-1-propyl-azepan-4-yl)-propionamide (0.15 g, 0.36 mmol), 4-methylmorpholine (0.14 g, 0.16 ml, 1.44 mmol), hydroxybenztriazole (0.071 g, 0.53 mmol) in DMF (2.0 ml) and was stirred at RT overnight. The reaction mixture was then warmed to RT and was stirred overnight. The reaction mixture was diluted with EtOAc (30 ml), washed with H2O, brine, dried with magnesium sulfate, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 2.5% MeOH/CH2Cl2) to yield the title compound (0.12 g, 76%): Electrospray mass spec: M+H+=434.2.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]([CH:19]=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:1]1([CH2:7][N:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]([CH2:19][N:30]3[CH2:31][CH2:32][CH:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:28][CH2:29]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: c1ccc(CN2CC(CN3CCC(c4ccccc4)CC3)C(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A solution of 680 mg (2.6 mmol) of 1-phenylmethyl -3-(RS)-formyl -4-(SR)-phenylpyrrolidine (from Example 9, Step B) and 420 mg (2.6 mmol) of (4-phenyl)piperidine in 25 mL of dichloroethane at 0° C. was treated with 635 mg (3.0 mmol) of sodium triacetoxy-borohydride. The cooling bath was removed and the resulting mixture was stirred at rt for 2h. The reaction mixture was partitioned between 100 mL of EtOAc and 50 mL of sat'd NaHCO3 and the layers were separated. The organic layer was washed with 50 mL of sat'd NaCl, dried over MgSO4 and concentrated in vacuo. Flash chromatography on 50 g of silica gel using 10:1 v/v hexanes/EtOAc+1% TEA as the eluant afforded 1.01 g of the title compound as an oil. 1H NMR (500 MHz, CDCl3): δ1.65-2.02 (6H.), 2.42-3.03 (11H), 3.72 (AB q, J=35.4, 2H), 7.20-7.43 (m, 15H). Mass Spectrum (NH3 -CI): 411 (M+1).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH2:24]([NH:27][C:28]1[CH2:32][S:31][C:30](=[O:33])[N:29]=1)[C:25]#[CH:26].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:32]2/[C:28]([NH:27][CH2:24][C:25]#[CH:26])=[N:29][C:30](=[O:33])[S:31]/2)[CH2:8][CH2:7]1
Reactant: C#CCNC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 58.9 %

Procedure:
To a suspension of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (35.0 g) and 4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one (23.9 g) in 2-propanol (400 mL) was added piperidinium acetate (15.0 g) at room temperature. The reaction mixture was stirred at 80° C. for 4 hr and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the precipitate was removed by filtration. Water and ethyl acetate were added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with diisopropyl ether to give a solid. The obtained solid was recrystallized from ethyl acetate/heptane/diisopropyl ether to give the title compound (28.9 g).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]2[O:8][CH:9]=[N:10][C:4]=2[C:3]1=[O:11].C1C(=O)N([Br:19])C(=O)C1>CC#N>[Br:19][C:6]1[C:5]2[O:8][CH:9]=[N:10][C:4]=2[C:3](=[O:11])[N:2]([CH3:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1ccc2ocnc2c1=O
Solvent: CC#N
Product: Cn1cc(Br)c2ocnc2c1=O
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To the title compound of step 4 (100 mg, 0.7 mmol) in CH3CN (5 mL) was added NBS (154 mg, 0.8 mmol) at 20° C. After 2 h, the mixture was concentrated in vacuum at 45° C. Purification by silica gel chromatography (PE: EA=5:1˜2:1) to gave the title compound (70 mg, yield: 45%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.04 (s, 1H), 7.52 (s, 1H), 3.69 (s, 3H).
Reaction SMILES: O.[NH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14])([O-:10])=[O:9]>O1CCCC1.O>[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1)=[O:14])([O-:10])=[O:9]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1nnn[nH]1
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1nnn[nH]1)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of 10.3 g of 5-aminotetrazole monohydrate in 300 ml of tetrahydrofuran and 15 ml of water was added 9.3 g of 2-nitrobenzoyl chloride. The solution was allowed to stand for 30 minutes before it was diluted with 200 ml of water and stored in a refrigerator for 72 hours. The solid which formed was separated by filtration to give 2-nitro-N-(1H-tetrazol-5-yl)benzamide melting at about 272°-273° C. with decomposition.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:12]1([CH3:27])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1C1C=CC=CC=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.COCCOC>[CH3:27][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccccc1-c1ccccc1B(O)O
Reactant: Clc1ccc2ccccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccc2ccccc2n1
Yield: 88.3 %

Procedure:
To a 500 mL round bottom flask was added, 2-chloroquinoline (4.7 g, 31 mmol), o-tolylphenyl boronic acid (4.7 g, 36 mmol) into 100 mL of ethylene glycol dimethyl ether. Sodium carbonate (8.9 g, 84 mmol) was dissolved into 50 mL of distilled water and added to the reaction mixture. After the addition of 0.1 mole % of triphenylphosphine (0.8 g) followed by 0.025 mol % of palladium(II) acetate (0.2 g). the reaction was heated under a nitrogen atmosphere for 4 hours. After cooling, additional ethyl acetate was added and the aqueous layer discarded. The organic layer was washed with a saturated solution of brine. The organic layer was dried over magnesium sulfate, filtered and the solvent removed by a rotary evaporator. The crude yellow oil was purified by column chromatography using a silica gel column and 20% ethyl acetate/hexanes as the eluants. The pure product was collected, combined and concentrated to give 2-(2-methylphenyl)quinoline (6.0 g, 75% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:42]=[CH:41][S:40][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:26][C:27]4[CH:39]=[CH:38][C:30]([C:31]([O:33]C(C)(C)C)=[O:32])=[CH:29][CH:28]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:42]=[CH:41][S:40][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:26][C:27]4[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:38][CH:39]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)C3)nc3scnc23)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)Nc4ccc(C(=O)O)cc4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.8 %

Procedure:
To a stirred solution of tert-butyl 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxamido)benzoate (75 mg, 0.127 mmol) in 5 mL of DCM was added TFA (2 mL) dropwise at room temperature. Then the reaction mixture was stirred at room temperature for 24 hours. The solvent was evaporated at 40° C. at reduced pressure and the residue was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 30% acetonitrile/70% water (0.1% TFA V/V) initially, and then proceed to 55% acetonitrile/45% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxamido)benzoic acid (25 mg, 36.8%) as a white solid. 1H NMR (300 MHz, CD3OD): δ 8.71 (s, 1H), 7.99-7.96 (m, 2H), 7.68-7.65 (m, 2H), 7.51 (s, 1H), 7.27-7.23 (m, 1H), 6.86 (d, 1H, J=8.4 Hz), 3.79 (s, 3H), 3.70 (s, 3H), 2.67 (brs, 3H), 2.19-1.87 (m, 6H). LC-MS: 535 [M+H]+; 533 [M−H]−, tR=1.47 min. HPLC: 96.74% at 214 nm, 97.85% at 254 nm, tR=5.46 min.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1.O>ClCCl>[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]=3)=[CH:22][CH:23]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: CCOC(=O)Cn1nc(Cc2ccc(N)cc2)c2ccccc21
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)Cn1nc(Cc2ccc(NC(=O)c3ccc(Cl)cc3)cc2)c2ccccc21
Yield: 31.4 %

Procedure:
220 mg (0.711 mmol) ethyl 2-[3-(4-aminobenzyl)-1H-indazol-1-yl]acetate was dissolved in 20 mL dichloromethane, and triethylamine 0.15 mL (1.08 mmol) was added. The system was placed in an ice bath, and 137 mg (0.78 mmol) p-chlorobenzoyl chloride was added slowly. Upon completion of addition, the reaction was monitored to be complete by TLC. Water was added, extracted with ethyl acetate, and separated by a preparative chromatography to obtain 100 mg a white solid, at a yield of 31.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14]CC)=O)[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:14])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1
Reactant: C1CCNCC1
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Solvent: O=C(O)C(F)(F)F
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)N2CCCCC2)C1
Temperature: 120 °C

Procedure:
A mixture of ethyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate (200 mg) and piperidine (2 ml) was heated at 120° C. for 8 h to obtain 5 mg of 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(piperidin-1-yl)ethanone as TFA salt after purification on silica gel (230-400 mesh) chromatography eluting with methanol-dichloromethane gradient followed by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:38])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([NH:29][C@@H:30]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:31](O)=[O:32])=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]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.[CH2:72]([O:74][C:75]([N:77]1[CH2:82][CH2:81][NH:80][CH2:79][CH2:78]1)=[O:76])[CH3:73]>CN(C=O)C>[CH2:72]([O:74][C:75]([N:77]1[CH2:78][CH2:79][N:80]([C:31](=[O:32])[C@@H:30]([NH:29][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:38])[N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:19]=2)=[O:28])[CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:81][CH2:82]1)=[O:76])[CH3:73]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)C[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
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: CCOC(=O)N1CCN(C(=O)[C@H](CC(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a mixture of 116 mg (S)-2-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-4-methyl-pentanoic acid in 2.5 ml DMF were added 84 mg HATU, 116 l DIPEA and 32 l 1-ethoxycarbonylpiperazine. After stirring for 12 h it was concentrated and the crude product thus obtained was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound. Yield: 70 mg MS (ES+): m/e=666.