Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[C:14]1[N:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][N:15]=1.CC(C)([O-])C.[K+].[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1.CCOC(C)=O.O.C1OCCOCCOCCOCCOCCOC1>[C:30]1([S:36]([N:12]2[C:13]3[CH2:1][N:2]([C:14]4[N:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:19]=4)[CH2:3][CH2:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1cnc(N2CCc3c([nH]c4ccccc34)C2)nc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cnc(N2CCc3c(n(S(=O)(=O)c4ccccc4)c4ccccc34)C2)nc1
Temperature: 0 °C
Reaction time: 0.21 h
Yield: 27.5 %

Procedure:
To a stirred solution of Example 8 (150 mg, 0.487 mmol) in THF (15 mL) was added potassium t-butoxide (81 mg, 0.720 mmol) and 18-crown-6 (2 mg) at 0° C. The suspension was stirred for 10-15 min at 0° C. and then benzenesulfonyl chlorde (0.86 mg, 0.486 mmol) was added. The reaction mixture was further stirred at 0° C. for 30 min. and then stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography using EtOAc in hexanes (50%) to obtain methyl 2-[9-(phenylsulfonyl)-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl]pyrimidine-5-carboxylate (60 mg). 1HNMR (200 MHz, DMSO-d6) ppm: 8.8 (s, 2H), 8.14-7.25 (m, 9H), 5.42 (s, 2H), 4.26 (t, 2H, J=5.4 Hz), 3.91 (s, 3H), 2.81 (2H, t, J=5.4 Hz); m/e=449 (M+1).
Reaction SMILES: C(N(CCC)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)CC.[CH3:31][C:32]1[N:33]=[CH:34][C:35]([CH:38]=O)=[N:36][CH:37]=1.[C:40]([BH3-])#[N:41].[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH2:6]([N:41]([CH2:40][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:20]([CH2:21][C:22]3[NH:26][CH:25]=[CH:24][N:23]=3)[CH2:38][C:35]3[CH:34]=[N:33][C:32]([CH3:31])=[CH:37][N:36]=3)=[CH:17][CH:18]=2)=[CH:9][CH:10]=1)[CH2:7][CH2:8][CH3:9])[CH2:5][CH3:10]
Reactant: CCCN(CCC)c1ccc(NC(=O)c2ccc(CNCc3ncc[nH]3)cc2)cc1
Reactant: Cc1cnc(C=O)cn1
Reactant: [BH3-]C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3cnc(C)cn3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The compound (82.2 mg) obtained in Example 47-3 was dissolved in methanol (5.0 ml) and added with the compound (35.9 mg) obtained in Example 73-1, followed by the addition of sodium cyanoborohydride (36.9 mg). Then, the reaction solution was adjusted to about pH 5 with acetic acid, followed by stirring at room temperature for 16 hours. The reaction solution was added with a saturated aqueous sodium bicarbonate solution and then extracted with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off. The resulting crude product was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (84.0 mg) of the subject compound as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[NH:11][CH2:12][C:13]1[S:17][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:15][CH:14]=1.[CH:25]1([CH2:28][NH2:29])[CH2:27][CH2:26]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH:25]1([CH2:28][NH:29][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]([NH:11][CH2:12][C:13]3[S:17][C:16]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[N:15][CH:14]=3)[CH:4]=2)[CH2:27][CH2:26]1
Reactant: NCC1CC1
Reactant: O=C(O)c1ccc(F)c(NCc2cnc(Nc3ccccn3)s2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCC1CC1)c1ccc(F)c(NCc2cnc(Nc3ccccn3)s2)c1
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 4-fluoro-3-{[2-(pyridin-2-ylamino)-thiazol-5-ylmethyl]-amino}-benzoic acid (35 mg, 0.10 mmol) in DMF (1 mL) at RT, cyclopropylmethyl amine (14 mg 0.20 mmol) was added followed by the addition of BOP reagent (53 mg, 0.12 mmol). The above reaction mixture was stirred for 2 h, diluted with EtOAc (10 mL), washed with 10% NaHCO3 (3×5 mL), and 10% LiCl (5 mL). The organic layer was dried over Na2SO4, concentrated and the residue was purified by preparative HPLC to give the title compound as a off-white solid (33 mg, 83%). (M+H)+=398.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12][C:13]1[CH:29]=[CH:28][C:16]([O:17][CH2:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.C(=O)([O-])O.[K+]>ClC(Cl)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12]([C:13]1[CH:29]=[CH:28][C:16]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=2)=[CH:15][CH:14]=1)=[O:38]
Reactant: O=C(O)c1ccc(COc2ccc(SCc3ccc4ccccc4n3)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(Cl)Cl
Product: O=C(O)c1ccc(COc2ccc(S(=O)Cc3ccc4ccccc4n3)cc2)cc1

Procedure:
4-(4-(2-quinolinylmethylthio)phenoxymethyl)benzoic acid (4 mmol) in dichloroethane (50 ml) is stirred with m-chloroperbenzoic acid (4 mmol) and solid potassium hydrogen carbonate (1.0 g). The reaction is assayed by TLC and upon consumption of the starting thio compound, the mixture is filtered, washed with dilute aqueous sodium bisulfate, dried and evaporated to give 4-(4-(2-quinolinylmethylsulfinyl)phenoxymethyl)benzoic acid.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][CH:9]([F:48])[O:10][CH2:11][C@@H:12]([O:14][C:15]1[CH:16]=[C:17]([CH:33]=[C:34]([O:36][C:37]2[CH:42]=[N:41][C:40]([C:43](=[O:47])[N:44]([CH3:46])[CH3:45])=[CH:39][N:38]=2)[CH:35]=1)[C:18]([NH:20][C:21]1[CH:25]=[CH:24][N:23](C(OC(C)(C)C)=O)[N:22]=1)=[O:19])[CH3:13]>C(Cl)Cl>[F:48][CH:9]([F:8])[O:10][CH2:11][C@@H:12]([O:14][C:15]1[CH:35]=[C:34]([CH:33]=[C:17]([C:18](=[O:19])[NH:20][C:21]2[CH:25]=[CH:24][NH:23][N:22]=2)[CH:16]=1)[O:36][C:37]1[N:38]=[CH:39][C:40]([C:43]([N:44]([CH3:46])[CH3:45])=[O:47])=[N:41][CH:42]=1)[CH3:13]
Reactant: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(C(=O)Nc2cc[nH]n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl 3-[[3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-benzoyl]amino]pyrazole-1-carboxylate (150 mg, 0.26 mmol) in DCM (16 mL) and stirred at RT for 2 hours. The solvent was removed in vacuo, DCM (20 mL) added and the mixture washed with water (20 mL), saturated sodium bicarbonate solution (20 mL), brine (20 mL), dried (MgSO4) and reduced in vacuo to give the desired compound (94 mg).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](=[O:21])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[CH2:22]([O:24][C:25]([CH:27]1[CH2:32][NH:31][C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[O:28]1)=[O:26])[CH3:23]>ClCCl>[CH2:14]([O:13][C:11]([CH2:10][C:9]([N:31]1[C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[O:28][CH:27]([C:25]([O:24][CH2:22][CH3:23])=[O:26])[CH2:32]1)=[O:21])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)CC(=O)OCc1ccccc1
Reactant: CCOC(=O)C1CNc2ccccc2O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CN(C(=O)CC(=O)OCc2ccccc2)c2ccccc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
54.6 mmol (7.6 ml) of triethylamine and 35.9 mmol (7.64 g) of benzyl 3-chloro-3-oxopropanoate are added to 17.1 mmol (3.53 g) of 2-ethoxycarbonyl-3,4-dihydro-2H-1,4-benzoxazine (described in J. Heterocyclic Chem., 1985, 22, 177) in 35 ml of dichloromethane. The reaction mixture is stirred at room temperature for 1 hour. After hydrolysis and extraction with dichloromethane, the organic phase is concentrated and purified by chromatography on silica gel using an ethyl acetate/petroleum ether mixture (2/8) as eluant to yield the expected compound.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[C:8]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:9][N:10]([C:15]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=3[Cl:24])[C:11]=2[C:12]([NH2:14])=O)=[C:4]([F:31])[CH:3]=1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)=O>C(Cl)Cl>[Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[C:8]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:9][N:10]([C:15]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=3[Cl:24])[C:11]=2[C:12]#[N:14])=[C:4]([F:31])[CH:3]=1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C(N)=O)c1Cc1ccc(Br)cc1F
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C#N)c1Cc1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
A mixture of 600 mg (1.18 mmol) of 4-(4-bromo-2-fluorobenzyl)-3-n-butyl-1-(2-chloro-5-nitrophenyl)-1H-pyrazole-5-carboxamide (from Step E), 330 μL (238 mg, 2.35 mmol) of triethylamine, and 7 mL of methylene chloride was cooled to 0° C. and treated with 145 μL of trichloroacetyl chloride. The mixture was stirred under N2 and allowed to warm to room temperature. After 3 hours, the mixture was concentrated to dryness. The orange residue was triturated with ether. The insoluble material was removed by filtration. The filtrate was washed with 0.2N HCl followed by 0.25N NaOH. The organic layer, after being dried over Na2SO4, was filtered and concentrated. The orange residual oil was flash chromatographed on silica gel (elution with 4:1 and then 3:1 hexane-EtOAc) to give 399 mg (69%) of the title compound as a yellow oil; nearly homogeneous by TLC in 3:1 hexane-EtOAc; mass spectrum (FAB) m/e 491, 493 (M+1)+. 200 MHz 1H NMR (CDCl3) δ0.91 (t, J=7.1 Hz, 3H), 1.36 (m, 2H), 1.61 (m, 2H, partially obscured by H2O peak), 2.61 (t, J=7.7 Hz, 2H), 3.97 (s, 2H), 7.07 (dd, J=8, 8 Hz, 1H), 7.26-7.31 (m, 2H), 7.78 (d, J=8.8 Hz, 1H), 8.31-8.39 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[N:12]2)[CH:5]=1.CO.NN>C(OCC)(=O)C.[Ni].O>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[CH:5]=1
Reactant: COC(=O)c1cccc(Cn2ccc([N+](=O)[O-])n2)c1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cccc(Cn2ccc(N)n2)c1
Yield: 69.1 %

Procedure:
The 3-(3-nitro-pyrazol-1-ylmethyl)-benzoic acid methyl ester (1.78 g, 6.82 mmol) was dissolved in ethyl acetate (5 mL) and methanol (5 mL) was added. While stirring, a 50% slurry of raney nickel in water (1 mL) was added followed by hydrazine (1.5 mL). Immediate effervescence was observed. The reaction continued to stir and bubble for 30 min. The reaction was passed through a plug of celite and concentrated in vacuo to give a yellow oil. The oil was taken up in ethyl acetate (100 mL), washed with water (2×20 mL), saturated aqueous brine solution (20 mL), dried over magnesium sulfate and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 120 g; 15% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded 3-(3-amino-pyrazol-1-ylmethyl)-benzoic acid methyl ester (1.09 g, 69%) as a beige solid: H1-NMR (400 MHz, DMSO-d6) δ 3.83 (3H, s), 4.57 (2H, bs), 5.09 (2H, s), 5.41 (1H, d, J=2.0 Hz), 7.44-7.46 (3H, m), 7.76 (1H, bs), 7.82-7.84 (1H, m).
Reaction SMILES: C1COCC1.Br[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[F:12][C:13]1[N:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1.Cl>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[CH:17][N:18]=1
Reactant: Fc1ccc([Mg]Br)cn1
Reactant: Brc1cccs1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1ccc(-c2cccs2)cn1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
In a separate reaction vessel, under a nitrogen atmosphere were added NiCl2(dppp) (0.02 equiv, 0.60 g) and THF (50 ml). 2-Bromothiophene (8.1 g, 4.81 ml, 50 mmol, 1 equiv.) was added and the resulting solution stirred for 2 min. To the resulting mixture was then added the mixture prepared in STEP A above, over about 30 min at 0° C., then allowed to warm to room temperature, with stirring. To the resulting mixture was then added diethylether, then cooled to 0° C. and treated with 1N HCl. The resulting mixture was extracted with diethylether (3×), the layers separated, the organic layer dried over MgSO4, then filtered and the filtrate evaporated to yield 2-fluoro-5-(thiophen-2-yl)pyridine as a liquid residue.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([C:6]1[C:13](=[O:14])[N:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:7]=1[C:15]1[CH:20]=[CH:19][N:18]=[C:17](SC)[N:16]=1)=[O:5].O[O:28][S:29]([O-:31])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+].[C:41]([O-])(O)=O.[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([C:6]1[C:13](=[O:14])[N:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:7]=1[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:29]([CH3:41])(=[O:31])=[O:28])[N:16]=1)=[O:5]
Reactant: O=C([O-])O
Reactant: CSc1nccc(-c2c(C(=O)c3ccccc3Cl)c(=O)n3n2CCC3)n1
Reactant: O=S([O-])OO
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1nccc(-c2c(C(=O)c3ccccc3Cl)c(=O)n3n2CCC3)n1

Procedure:
To a solution of 2-(2-chloro-benzoyl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 23, (0.15 g, 0.39 mmol)) in THF/MeOH (3 mL of 1:1 mixture) is added dropwise a solution of Oxone® (potassium peroxymonosulfate) (0.72 g, 1.16 mmol) in H2O (3 mL). After stirring the reaction for 1.5 hour at room temperature, the solution is poured into aqueous saturated NaHCO3. The aqueous phase is extracted three times with CHCl3 and the combined organic phases are dried (MgSO4), filtered and concentrated in vacuo. The crude product is used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[C:11]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]4[N:25]([CH3:33])[C:26]5[C:31]([CH:32]=4)=[CH:30][CH:29]=[CH:28][CH:27]=5)=[O:23])=[C:17]([O:34][CH3:35])[CH:16]=3)=[CH:13][S:14][C:10]=2[C:9]([N:36]=C(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][N:7]=1)[CH3:3].Cl>O1CCCC1.CO.ClCCl>[NH2:36][C:9]1[C:10]2[S:14][CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]4[N:25]([CH3:33])[C:26]5[C:31]([CH:32]=4)=[CH:30][CH:29]=[CH:28][CH:27]=5)=[O:23])=[C:17]([O:34][CH3:35])[CH:16]=3)[C:11]=2[C:6]([N:5]=[CH:4][N:2]([CH3:3])[CH3:1])=[N:7][CH:8]=1
Reactant: COc1cc(-c2csc3c(N=C(c4ccccc4)c4ccccc4)cnc(N=CN(C)C)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(-c2csc3c(N)cnc(N=CN(C)C)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
N-(4-{4-{[(dimethylamino)methylene]amino}-7-[(diphenylmethylene)amino]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.117 g, 0.177 mmol) was dissolved in tetrahydrofuran (5 mL), and aqueous hydrochloric acid (1 M, 0.24 mL) was added, and the mixture was stirred at ambient temperature for 12 h. The mixture was diluted with methanol/dichloromethane (1:19, 50 mL) the resulting solution was extracted with aqueous sodium bicarbonate (1 M, 10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. Purification of the residue by flash column chromatography on silica gel which had been deactivated with triethylamine (10% by volume of silica gel used) using methanol/dichloromethane (1:19) as the mobile phase afforded the title compound (0.085 g, 0.17 mmol) as a tan powder: 1H NMR (DMSO-d6, 400 MHz) δ 9.40 (s, 1H), 8.13 (s, 1H), 7.79 (d, 1H), 7.70 (d, 1H), 7.58 (d, 1H), 7.56 (s, 1H), 7.49 (s, 1H), 7.33 (m, 2H), 7.15 (t, 1H), 7.06 (m, 1H), 7.01 (d, 1H), 5.07 (br, 2H), 4.04 (s, 3H), 3.88 (s, 3H), 2.94 (s, 3H), 2.47 (s, 3H); MS: (MH)+ 499.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11](=[O:45])[NH:12][CH:13]([C:23](=[O:44])[N:24]([CH2:27][C:28]1[C:29]([CH3:43])([CH3:42])[NH:30][S:31](=[O:41])(=[O:40])[C:32]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[CH2:25][CH3:26])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:10])[CH3:9])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[ClH:39].[NH2:7][C:8]([CH3:9])([CH3:10])[C:11]([NH:12][CH:13]([C:23](=[O:44])[N:24]([CH2:27][C:28]1[C:29]([CH3:43])([CH3:42])[NH:30][S:31](=[O:41])(=[O:40])[C:32]=1[C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)[CH2:25][CH3:26])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:45]
Reactant: CCN(CC1=C(c2ccc(Cl)cc2)S(=O)(=O)NC1(C)C)C(=O)C(COCc1ccccc1)NC(=O)C(C)(C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC1=C(c2ccc(Cl)cc2)S(=O)(=O)NC1(C)C)C(=O)C(COCc1ccccc1)NC(=O)C(C)(C)N
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound from above, [1-(2-benzyloxy-1-{[5-(4-chloro-phenyl)-3,3-dimethyl-1,1-dioxo-2,3-dihydro-1H-1λ6-isothiazol-4-ylmethyl]-ethyl-carbamoyl}-ethylcarbamoyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (1.00 g, 1.48 mmol) was dissolved in dichloromethane (30 mL) and trifluoroacetic acid added (5 mL) and the mixture stirred for 2 hours at room temperature. The mixture was concentrated in vacuo and the residue treated with saturated aqueous sodium bicarbonate followed by extraction with ethyl acetate. The combined extracts were dried over sodium sulfate. Concentration left a residue which was chromatographed over silica (methanol/chloroform) to give the amine. This amine was dissolved in minimal ethyl acetate and treated with excess ether/hydrochloric acid. Concentration and drying netted 0.37 g (41%) of the desired hydrochloride salt as a white solid. Anal. Calc'd for C28H3ClN4O5S.1.1HCl: C, 54.49; H, 6.22; N, 9.38. Found: C, 54.17; H, 6.16; N, 9.38. m.p. 107–113° C. MS(ES): (M+1)+ 579.4 m/z.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]([C@@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:7]([C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[C:21]([OH:23])=[O:22])=[O:8].[Cl:37][C:38]1[CH:39]=[CH:40][C:41]([O:47][CH3:48])=[C:42](B(O)O)[CH:43]=1>>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([O:47][CH3:48])=[C:40]([C:2]2[CH:36]=[CH:35][CH:34]=[C:4]([CH2:5][N:6]([C@@H:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)[C:7]([C:9]3[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=3[C:21]([OH:23])=[O:22])=[O:8])[CH:3]=2)[CH:39]=1
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Br)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Reactant: COc1ccc(Cl)cc1B(O)O
Product: COc1ccc(Cl)cc1-c1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1

Procedure:
The product from Example 15B (165 mg, 0.3 mmol) and 5-chloro-2-methoxyphenylboronic acid were processed as described in Example 85 to provide the title compound.
Reaction SMILES: [CH2:1]([O:5][CH:6]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:7][NH:8][CH2:9][CH:10]1[O:14][CH:13]([CH3:15])[CH:12]([CH3:16])[O:11]1)[CH2:2][CH2:3][CH3:4].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:34][CH2:35][C:36](Cl)=[O:37]>O>[CH2:18]([O:17][CH:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:7][N:8]([CH2:9][CH:10]1[O:14][CH:13]([CH3:15])[CH:12]([CH3:16])[O:11]1)[C:36](=[O:37])[CH2:35][Cl:34])[CH2:19][CH2:20][CH3:21]
Reactant: O=C(Cl)CCl
Reactant: CCCCOC(CNCC1OC(C)C(C)O1)OCCCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCCCOC(CN(CC1OC(C)C(C)O1)C(=O)CCl)OCCCC

Procedure:
N-(2,2-Dibutoxyethyl)-N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)amine (0.05 mole), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of from 5° to 10° C and chloroacetyl chloride (0.05 mole) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture has reached room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,2-dibutoxyethyl)-N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as the residue.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=O)[NH:8]2)=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[N:22]2)=[CH:17][CH:16]=1>>[N:22]1[C:23]2[C:18](=[CH:17][CH:16]=[C:15]([NH:14][C:11]([C:7]3[NH:8][C:9]4[C:5]([CH:6]=3)=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=4)=[O:13])[CH:24]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1cc2ccc(Br)cc2[nH]1
Reactant: Nc1ccc2cccnc2c1
Product: O=C(Nc1ccc2cccnc2c1)c1cc2ccc(Br)cc2[nH]1

Procedure:
This material was prepared analogous to the procedure described for Example 6(b). 6-Bromo-1H-indole-2-carboxylic acid (208 mg, 0.87 mmol, Asymchem) reacted with 7-amino-quinoline (125 mg, 0.87 mmol, prepared according to the procedure described in WO03099284) to give the title compound as a light-brown amorphous solid. MS (ESI, pos. ion) m/z: 366 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37].[CH3:38][CH:39]([NH:41][CH2:42][CH2:43][NH2:44])[CH3:40]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:44][CH2:43][CH2:42][NH:41][CH:39]([CH3:40])[CH3:38])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37]
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CC(C)NCCN
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(NCCNC(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared from 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide and N-(1-methylethyl)-1,2-ethanediamine by following the procedures in Example 79c. LC-MS m/z 576 (M+H)+; 1H-NMR (MeOD) 1.02 (d, J=6.0 Hz, 6H), 2.31 (m, 3H), 2.72 (m, 3H), 3.23 (m, 1H), 3.55 (m, 1H), 6.36 (d, J=8.8 Hz, 1H), 7.13 (m, 1H), 7.24 (m, 2H), 7.47 (m, 2H), 7.56 (m, 2H), 8.00 (s, 1H), 8.10 (d, J=7.6 Hz, 1H).
Reaction SMILES: [F:1][CH:2]([F:17])[CH:3]1[CH2:8][CH:7]([C:9]([O:11]C)=[O:10])[CH2:6][CH2:5][N:4]1[C:13]([O:15][CH3:16])=[O:14].[OH-].[Li+].Cl.C(Cl)Cl>C1COCC1.O>[F:17][CH:2]([F:1])[CH:3]1[CH2:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][CH2:5][N:4]1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C1CCN(C(=O)OC)C(C(F)F)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N1CCC(C(=O)O)CC1C(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
Dimethyl 2-(difluoromethyl)piperidine-1,4-dicarboxylate (2.35 g, 9.35 mmol) was dissolved in THF (35 mL) and 1 M lithium hydroxide (12.16 mL, 12.16 mmol) in water was added. The mixture was stirred at room temperature for 3 h, then 1 M HCl and DCM were added and the phases were separated. The aqueous phase was extracted with DCM and the combined organic layers were dried by filtration through a phase separator and evaporated. 2-(Difluoromethyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (2.2 g, 99%) was isolated. MS m/z 275 (M−H)−