Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]3[B:11]([OH:14])[O:12][CH2:13][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[OH:14][B:11]1[C:10]2[CH:15]=[CH:16][C:7]([O:6][C:5]3[CH:17]=[CH:18][C:2]([NH:1][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:3][CH:4]=3)=[CH:8][C:9]=2[CH2:13][O:12]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Oc2ccc3c(c2)COB3O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 20 mL scintillation vial containing 5-(4-amino-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (50 mg, 0.21 mmol, 1.0 eq.) in DCM (3.0 mL) was added Et3N (35 μL, 0.25 mmol, 1.2 eq.), followed by methanesulfonyl chloride (18 μL, 0.31 mmol, 1.1 eq.). The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give N-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenyl]-methanesulfonamide as a white solid. LCMS (m/z) 342 (M+23); 1H NMR (DMSO-d6) δ: 9.72 (s, 1H), 7.65-7.79 (m, 1H), 7.21-7.26 (m, 2H), 7.01-7.05 (m, 2H), 6.91-6.94 (m, 1H), 6.89-6.91 (m, 1H), 4.88 (s, 2H), 2.94 (s, 3H).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16]([NH:18][C:19]2[S:20][CH:21]=[C:22]([CH2:24][CH:25]=O)[N:23]=2)=[O:17])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16]([NH:18][C:19]2[S:20][CH:21]=[C:22]([CH2:24][CH2:25][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:23]=2)=[O:17])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: Cc1ccc(NC(=O)Nc2nc(CC=O)cs2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2nc(CCN3CCOCC3)cs2)c(C(=O)C2CCCC2)c1
Yield: 30.8 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[4-(2-morpholin-4-yl-ethyl)-thiazol-2-yl]-urea (15 mg, 31%) was prepared from 1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[4-(2-oxo-ethyl)-thiazol-2-yl]-urea (0.04 g, 0.11 mmol) and morpholine (0.009 g, 0.11 mmol) following the general procedure O.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].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.[NH2:39][CH2:40][CH2:41][NH:42][C:43]1[N:48]=[C:47]([C:49]2[S:53][C:52]([C:54]([CH3:57])([CH3:56])[CH3:55])=[N:51][C:50]=2[C:58]2[C:59]([F:76])=[C:60]([NH:64][S:65]([C:68]3[CH:73]=[C:72]([F:74])[CH:71]=[CH:70][C:69]=3[F:75])(=[O:67])=[O:66])[CH:61]=[CH:62][CH:63]=2)[CH:46]=[CH:45][N:44]=1>CN(C=O)C.CCOC(C)=O>[F:75][C:69]1[CH:70]=[CH:71][C:72]([F:74])=[CH:73][C:68]=1[S:65]([NH:64][C:60]1[C:59]([F:76])=[C:58]([C:50]2[N:51]=[C:52]([C:54]([CH3:56])([CH3:55])[CH3:57])[S:53][C:49]=2[C:47]2[CH:46]=[CH:45][N:44]=[C:43]([NH:42][CH2:41][CH2:40][NH:39][C:1](=[O:5])[CH2:2][OH:3])[N:48]=2)[CH:63]=[CH:62][CH:61]=1)(=[O:67])=[O:66]
Reactant: O=C(O)CO
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(NCCN)n2)s1
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
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(NCCNC(=O)CO)n2)s1
Reaction time: 1 h
Yield: 46.4 %

Procedure:
A mixture of glycolic acid (0.040 g, 0.50 mmol), HATU (0.19 g, 0.50 mmol) and DIEA (0.09 ml, 0.50 mmol) in DMF (1 mL) was added to a stirring solution of N-{3-[5-{2-[(2-aminoethyl)amino]-4-pyrimidinyl}-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.15 g, 0.25 mmol) and DIEA (0.09 ml, 0.50 mmol) in DMF (1 mL). The reaction was stirred for 1 h. LCMS analysis indicated approximately 50% conversion to product. An additional 2.0 equivalents of activated glycolic acid was added and the reaction was allowed to stir for an additional 1 h. LCMS analysis indicated the starting material was still not completely consumed so an additional 2.0 equivalents of activated glycolic acid was added and the reaction was stirred for an addition 1 h. The reaction was diluted with EtOAc, washed with water (×5) and a saturated aqueous brine solution (×2). The organic layer was dried over MgSO4, filtered and the filtrate was concentrated onto silica gel and purified by flash chromatography to afford the title compound (0.072 g, 44% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.75 (br. s., 1H), 8.04 (d, J=5.1 Hz, 1H), 7.77-7.98 (m, 1H), 7.15-7.65 (m, 7H), 5.81-6.01 (m, 1H), 5.49 (t, J=5.2 Hz, 1H), 3.80 (d, J=5.3 Hz, 2H), 3.29 (br. s., 2H), 1.40 (s, 9H). MS (ES+): 621 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
0.072 mol (12.6 g) of 4-chloro-2-nitrophenol, 40 ml of acetone and 9.72 g of potassium carbonate are introduced into a 250 ml three-necked flask equipped with a stirring system, a thermometer and a condenser. The mixture is brought to 40° C. and 9.72 g of dimethyl sulphate are then added drop by drop; the mixture is heated under reflux for 5 hours; the potassium sulphate is separated; the acetone solution is concentrated under reduced pressure and the 4-chloro-2-nitroanisole is precipitated. It is separated and then crystallized in a water/acetone mixture.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:18][CH2:19]N)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][O:10]1.[CH2:30]=O.[C:32]([BH3-])#[N:33].[Na+]>C(#N)C>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:18][CH2:19][N:33]([CH3:32])[CH3:30])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][O:10]1
Reactant: [BH3-]C#N
Reactant: NCCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCc2ccccc21
Reactant: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)CCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCc2ccccc21
Reaction time: 1 h

Procedure:
To a solution of 2-(1-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-1,3-dihydroisobenzofuran-1-yl)ethanamine (40 mg, 95.4 μmol) in acetonitrile (2 mL) at 0° C. was added formalin (0.250 mL) and then sodium cyanoborohydride (30 mg, 0.48 mmol). The ice bath was removed and stirring continued for 1 h, occasionally treating with a drop of acetic acid to keep the pH slightly less than 7. The reaction was concentrated, diluted with ether, washed with 1 M sodium hydroxide, then brine, dried over sodium sulfate, and concentrated. Column chromatography (4% MeOH/DCM) gave 28.5 mg (67%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz) δ 7.75 (s, 1H), 7.64 (s, 2H), 7.30 (m, 2H), 7.15-7.25 (m, 2H), 5.11 (qAB, JAB=120.5 Hz, 2H), 4.62 (qAB, JAB=13.4 Hz, 2H), 3.67 (qAB, JAB=10.1 Hz, 2H), 2.41 (ddd, J=11.3, 11.3, 5.5 Hz, 1H), 2.20 (s, 6H), 2.19 (m, 1H), 1.98-2.14 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 141.3, 141.2, 139.9, 131.7 (q, J=33.6 Hz), 128.2, 127.6, 126.1, 123.4 (q, J=273 Hz), 121.6, 121.4, 121.1, 89.5, 76.8, 72.9, 72.0, 54.3, 45.4, 34.4. Mass spec.: 448.22 (MH)+. Accurate mass spec.: m/z 448.1711 [MH]+, Δ=0.6 ppm.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)=[N:15][N:16]4[CH:21]=[C:20]([NH:22]C(=O)OC(C)(C)C)[CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-:37]>ClCCl.CCOCC>[ClH:37].[ClH:37].[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)=[N:15][N:16]4[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [Cl-]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1
Solvent: ClCCl
Solvent: CCOCC
Product: Cl
Product: Nc1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.1 %

Procedure:
To a solution of tert-butyl 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-ylcarbamate (35 mg, 0.072 mmol) in dichloromethane was addedhydrogen chloride (144 μL, 4 N in dioxane, 0.58 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ether and the precipitated solids were collected on a filter to provide 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-amine dihydrochloride (9 mg, 27%) as a brownish yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.25 (br, 1H), 7.97–7.91 (m, 2H), 7.53 (m, 2H), 7.26 (t, 2H), 7.06 (d, 1H), 6.15 (br, 1H), 4.14–3.85 (br, 1H), 1.85 (br, 2H), 1.65 (br, 2H), 1.48 (br, 4H); MS m/z 389 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:13][C:14]1[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([CH3:23])[C:15]=1[CH:16]=O>CS(C)=O.O>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[N:12]=[C:16]([C:15]3[C:14]([CH3:13])=[CH:21][C:20]([OH:22])=[CH:19][C:18]=3[CH3:23])[NH:1][C:2]=2[CH:3]=1)=[O:6]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: Cc1cc(O)cc(C)c1C=O
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2nc(-c3c(C)cc(O)cc3C)[nH]c2c1
Reaction time: 120 h

Procedure:
3.65 g of methyl 3,4-diaminobenzoate and 3.3 g of 2,6-dimethyl-4-hydroxybenzaldehyde were stirred in 25 ml of DMSO at room temperature. A solution of 170 mg of FeCl3 in 5 ml of DMSO was added by pipet and the reaction was stirred at the same temperature for 5 days. The reaction was then diluted with water and the resulting precipitates were collected by filtration. The filter cake was washed with water and heptane, and dried by air in the suction funnel to afford the title compound. LCMS retention T=1.01 min. (M+H)+=297.01, Method 10.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8])([O-:3])=[O:2].Br[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:10]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1c[nH]c2ccccc12
Reactant: CCOC(=O)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(C(=O)c2cccc([N+](=O)[O-])c2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
A mixture of 3-(3-nitrobenzoyl)indole (2.09 g), ethyl 4-bromobutyrate (1.614 g) and potassium carbonate (3.118 g) in N,N-dimethylformamide (20 ml) was stirred at 25° C. overnight. The reaction mixture was poured into a mixture of ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of solvent, the crystalline residue was recrystallized from a mixture of ethyl acetate and hexane to give ethyl 4-[3-(3-nitrobenzoyl)indol-1-yl]butyrate (2.71 g) as colorless crystals.
Reaction SMILES: [OH:1]/[N:2]=[C:3]1\[CH2:4][C@@H:5]2[C@@H:14]([C@:15]3([CH3:22])[CH:20]\1[CH2:19][C:18](=O)[CH2:17][CH2:16]3)[CH2:13][CH2:12][C@@:10]1([CH3:11])[C@H:6]2[CH2:7][CH2:8][C:9]1=[O:23].[ClH:24].Cl.[NH2:26][C@@H:27]([CH3:31])[CH2:28][O:29][NH2:30]>>[NH2:26][C@@H:27]([CH3:31])[CH2:28][O:29][N:30]=[C:18]1[CH2:19][CH2:20][C@@:15]2([CH3:22])[CH:16]([CH2:3][CH2:4][C@@H:5]3[C@@H:14]2[CH2:13][CH2:12][C@@:10]2([CH3:11])[C@H:6]3[CH2:7][CH2:8][CH2:9]2)[CH2:17]1.[ClH:24].[OH:1]/[N:2]=[C:3]1\[CH2:4][C@@H:5]2[C@@H:14]([C@:15]3([CH3:22])[CH:20]\1[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:13][CH2:12][C@@:10]1([CH3:11])[C@H:6]2[CH2:7][CH2:8][C:9]1=[O:23]
Reactant: C[C@H](N)CON
Reactant: C[C@]12CCC(=O)CC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Product: C[C@H](N)CON=C1CC[C@@]2(C)C(CC[C@H]3[C@@H]4CCC[C@@]4(C)CC[C@@H]32)C1
Product: C[C@]12CCCCC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 93 %

Procedure:
Prepared as described in Example 1 starting from 6-(E)-hydroxyiminoandrostane-3,17-dione (II-at, Prepn. 20, 500 mg) and (S)-2-aminopropoxyamine dihydrochloride (Prepn. 92, 257 mg). The crude product was crystallized from MeOH/EtOAc to give the title compound as a white solid (503 mg, 75%). NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.50 (1H, s), 7.98 (3H, m), 3.97 (2H, m), 3.40 (1H, m), 3.11 (0.5H, m), 3.05 (0.5H, m), 2.54-1.15 (22H, m), 0.79 (3H, s), 0.78 (3H, s)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[N:3]1.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2[O:27][C:26]([CH2:28][CH2:29][NH2:30])=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2[O:27][C:26]([CH2:28][CH2:29][NH:30][C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:2]([CH3:1])[N:3]=3)=[O:13])=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Reactant: Cn1nc(C(=O)O)c2ccccc21
Agent: Cl
Product: Cn1nc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)c2ccccc21

Procedure:
The title compound was prepared as in Example 12 starting from N-methyl-indazole-3-carboxylic acid and 2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylamine hydrochloride. The crude product was purified by flash chromatography using heptane/EtOAc as a gradient eluent (9:1-8:2). 1H NMR (400 MHz, DMSO-d6): 3.00 (2H, t), 3.64 (2H, m), 4.12 (3H, s), 6.36 (1H, d), 7.01 (1H, d), 7.26 (1H, m), 7.46 (1H, m), 7.600 (1H, s), 7.602 (1H, s), 7.72 (1H, d), 7.83 (1H, s), 8.16 (1H, d), 8.48 (1H, t).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].Cl[C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O.O>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc(Nc2ncccn2)c1
Temperature: 170 °C
Yield: 21 %

Procedure:
A mixture of 3-nitroaniline (6.14 g), 2-chloropyrimidine (4.85 g) and potassium carbonate (6.15 g) in dimethylsulfoxide (50 ml) was heated at 170° C. for 5 hours. The mixture was cooled and poured into a mixture of ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The resulting solid was collected and washed with isopropyl ether to give 2-(3-nitrophenylamino)pyrimidine (1.92 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]3)[CH:19]=[C:18]([F:31])[CH:17]=1)[C:10]([CH3:33])([CH3:32])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[F:31][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:32])([CH3:33])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[C:20]([N:22]2[CH2:23][CH2:24][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:26][CH2:27]2)[CH:19]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(N3CCN(C(C)C)CC3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N1CCN(c2cc(F)cc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 34.9 %

Procedure:
A mixture of 2-[3-fluoro-5-(4-isopropyl-piperazin-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.27 g, 0.60 mmol), lithium hydroxide hydrate (0.25 g, 6.0 mmol), water (2 mL) in methanol (3 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-fluoro-5-(4-isopropyl-piperazin-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (89 mg, 35%) as a white solid: LC/MS mrn/e calcd for C25H32FN3O2 (M+H)+: 426.6, observed: 426.3.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][S:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:4]1.P(Br)(Br)[Br:15].C([O-])(O)=O.[Na+]>CCOCC>[Br:15][CH2:2][CH:3]1[CH2:7][S:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:4]1
Reactant: OCC1CSC(c2ccccc2)S1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: BrCC1CSC(c2ccccc2)S1
Temperature: 0 °C
Yield: 99 %

Procedure:
4-Hydroxymethyl 2-phenyl 1,3-dithiolane (30 g., 0.14 mole) was suspended in 150 ml of ether and cooled to 0°C. Phosphorus tribromide (15 g., 0.053 mole) were added over a 1.5 hour period and the mixture was stirred at ambient temperature with 5% aqueous NaHCO3 until neutral (ph = 7). After drying over MgSO4 the solvent was removed under vacuum to yield 38 g. (99%) of desired product.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:28][C:29]3[C:30]([F:40])=[C:31]([CH:37]=[CH:38][CH:39]=3)[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:7]([CH:25]3[CH2:27][CH2:26]3)[N:8]2[C:12]2[CH:13]=[N:14][N:15](COCC[Si](C)(C)C)[CH:16]=2)=[CH:4][CH:3]=1.Cl.CCN(CC)CC.CCCCC>CCO>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:28][C:29]3[C:30]([F:40])=[C:31]([CH:37]=[CH:38][CH:39]=3)[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:7]([CH:25]3[CH2:26][CH2:27]3)[N:8]2[C:12]2[CH:13]=[N:14][NH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(COCC[Si](C)(C)C)c3)c3c(F)c(Cl)ccc23)c1F
Agent: Cl
Solvent: CCCCC
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cn[nH]c3)c3c(F)c(Cl)ccc23)c1F
Yield: 82.6 %

Procedure:
To a stirred solution of compound 3 (140 mg, 0.23 mmol) in EtOH (17 mL) was added 3 N HCl (4 mL) at RT and heated to reflux for 3 h. After completion of the reaction (TLC), the pH of the mixture was neutralized with Et3N (2 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the crude. The crude was titurated with n-pentane, dried under reduced pressure to afford 4 (90 mg, 90%) as a pale brown solid. 1H NMR (500 MHz, DMSO-d6): 13.21 (br s, 1H), 8.24 (s, 1H), 7.84 (s, 1H), 7.60 (t, J=6.5 Hz, 1H), 7.21-7.11 (m, 3H), 6.84 (t, J=6.5 Hz, 1H), 4.34 (q, 2H), 1.81-1.76 (m, 1H), 1.32 (t, J=8.0 Hz, 3H), 0.93-0.90 (m, 2H), 0.84-0.79 (m, 2H); LC-MS (ESI): m/z 474.9 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([CH2:21][N:22]=[N+]=[N-])[CH:18]=[CH:17][N:16]4[C:25]=3[CH3:26])[CH:8]=[CH:7][C:5]=2[N:6]=1.[H][H]>[Pd].CO>[NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([CH2:21][NH2:22])[CH:18]=[CH:17][N:16]4[C:25]=3[CH3:26])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1c(CCc2ccc3nc(N)oc3c2)nc2cc(CN=[N+]=[N-])ccn12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1c(CCc2ccc3nc(N)oc3c2)nc2cc(CN)ccn12
Yield: 44.3 %

Procedure:
10% Palladium on carbon (0.3 g) was added to a solution of 2-amino-6-[2-(7-azidomethyl-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (1.0 g) in methanol (100 ml) and the mixture was subjected to catalytic reduction at ambient temperature under atmospheric pressure of hydrogen gas. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was purified by alumina column chromatography eluting with a solution of chloroform and methanol (4:1, V/V). The fractions containing object compound was evaporated to give 2-amino-6-[2-(7-aminomethyl-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.41 g).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:21]=[CH:20][C:8]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:7][CH:6]=1)#[N:4].S(OCC)(O[CH2:26][CH3:27])(=O)=O.O>CN(C=O)C>[C:3]([C:5]1[CH:21]=[CH:20][C:8]([N:9]([CH2:26][CH3:27])[S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:7][CH:6]=1)#[N:4]
Reactant: CCOS(=O)(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C#N)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(c1ccc(C#N)cc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
To a suspension of sodium hydride (65%, 3.39 g (91.8 mmol)) in DMF (60.0 ml), 4′-cyano-p-toluenesulfonanilide (10.0 g (36.7 mmol)) was added with stirring at room temperature. To the resulting mixture, after stirring for an hour at room temperature, diethyl sulfate (12.0 ml (91.8 mmol)) was added dropwise, and the resulting mixture was heated with stirring at 75° C. for 4 hours. Then, the reaction mixture was allowed to cool to room temperature, poured into water and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with chloroform as eluent, to give 9.8 g (89%) of the title compound as white crystals.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].C(Cl)Cl.[CH2:31]([NH2:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[C:33]1([CH2:32][CH2:31][NH:39][C:1]([C:4]2[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]3[N:18]=[C:17]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[CH:20]4)[CH:16]=[CH:15][N:14]=3)[CH3:11])[CH:7]=[CH:8][CH:9]=2)=[O:2])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCCc1ccccc1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)NCCc2ccccc2)c1
Reaction time: 18 h

Procedure:
Made in the same manner as EXAMPLE 62 using 2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (37.2 mg), CH2Cl2 (2 mL), triethylamine (72 μL), phenethylamine (39 μL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58 mg) and 4-dimethylaminopyridine (˜1 mg). Run for 18 h then concentrated under reduced pressure and purified by silica gel chromatography (98:2 CH2Cl2:MeOH) to yield 21.6 mg of the title compound. 1H NMR (500 MHz, CDCl3 partial): δ 8.48 (br s, 1H); 8.40 (d, J=5.5 Hz, 1H); 7.84 (m, 2H); 7.56 (m, 2H); 7.42 (t, J=7.7 Hz, 1H); 6.80 (d, J=5.5 Hz,1H); 6.10 )br s, 1H); 5.69 (br s, 1H); 5.23 (br s, 1H); 3.72 (m, 2H); 2.94 (t, J=7.0 Hz, 2H); 1.65 (d, J=6.9 Hz, 3H). Mass Spectrum (ESI): m/e 463.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][CH2:12][CH2:13][N:14]2[CH:18]=[C:17]([NH:19][C:20]([C:22]3[N:23]=[CH:24][O:25][C:26]=3[C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)=[O:21])[CH:16]=[N:15]2)[N:4]=1.[H-].[Na+].Br[CH2:37][CH3:38].O>CN(C=O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([N:11]([CH2:37][CH3:38])[CH2:12][CH2:13][N:14]2[CH:18]=[C:17]([NH:19][C:20]([C:22]3[N:23]=[CH:24][O:25][C:26]=3[C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)=[O:21])[CH:16]=[N:15]2)[N:6]=1
Reactant: CCBr
Reactant: COc1cc(OC)nc(NCCn2cc(NC(=O)c3ncoc3-c3cccc(C)c3)cn2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CCn1cc(NC(=O)c2ncoc2-c2cccc(C)c2)cn1)c1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To an ice-cooled solution of N-(1-(2-((4,6-dimethoxypyrimidin-2-yl)amino)ethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide (80 mg, 0.178 mmol) in DMF (1 mL) was added NaH (12 mg, 0.27 mmol). The icebath was removed and the mixture was stirred for 40 min at rt, then 1-bromo ethane (20 uL, 0.25 mmol) was added and stirred for 18 h at rt. To the reaction mixture was added few drops of water and directly purified by prep. HPLC. LC-MS conditions D: tR=1.19 min, [M+H]+=478.3