Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][N:5]1[C:15]2[C:10](=[C:11]([O:16][CH2:17][CH:18]3[O:20][CH2:19]3)[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:6]1=[O:7].[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>CC(C)=O>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][N:5]1[C:15]2[C:10](=[C:11]([O:16][CH2:17][CH:18]([OH:20])[CH2:19][N:31]3[CH2:32][CH2:33][N:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:29][CH2:30]3)[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:6]1=[O:7]
Reactant: CC(C)CCN1C(=O)CCc2c(OCC3CO3)cccc21
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CC(C)=O
Product: CC(C)CCN1C(=O)CCc2c(OCC(O)CN3CCN(c4ccccc4)CC3)cccc21
Yield: 38.7 %

Procedure:
2.9 grams of 1-(3-methylbutyl)-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril and 1.7 g of 4-phenylpiperazine are mixed with 50 ml of methanol and reacted at 50°-60° C. for 3 hours. The reaction mixture is concentrated under reduced pressure and the residue thus obtained is dissolved in 50 ml of acetone. Into this solution, 20 ml of an acetone solution containing 1.1 g of oxalic acid are added, then the precipitate thus formed is collected by filtration, washed with acetone and dried. Recrystallization from ethanol-ether to obtain 2.1 g of 1-(3-methylbutyl)-5-[2-hydroxy-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril monooxalate in the form of colorless crystals. This product is confirmed as a single compound by a silica-gel thin layer chromatography-(developing solvent; chloroform:methanol=9:1).
Reaction SMILES: FC(F)(F)C(O)=O.CC(OC([N:15]1[CH2:20][CH2:19][C:18]2[O:21][C:22]([CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:23][C:17]=2[CH2:16]1)=O)(C)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[O:25]([CH2:24][C:22]1[O:21][C:18]2[CH2:19][CH2:20][NH:15][CH2:16][C:17]=2[N:23]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc(COc3ccccc3)nc2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(OCc2nc3c(o2)CCNC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
Trifluoroacetic acid (1.0 mL, 13.0 mmol) was added to a solution of 6,7-dihydro-2-(phenoxymethyl)-oxazolo[4,5-c]pyridine-5(4H)-carboxylic acid 1,1-dimethylethyl ester (0.11 g, 0.35 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 30 minutes and basified with a saturated solution of Na2CO3. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield 4,5,6,7-tetrahydro-2-(phenoxymethyl)-oxazolo[4,5-c]pyridine (80 mg, 100% yield, 30% pure) that was used in the next step without further purification. C13H14N2O2 LCMS: Rt 0.65, m/z 231 [M+H]+ (using method, LC-MS Method 7).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[CH2:33]([N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3][C:2]1=[O:1])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of benzyl 3-oxopiperazine-1-carboxylate (4.7 g, 20 mmol) in DMF (75 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (24 mL, 24 mmol) was added and stirred at the temperature for 30 min. The resultant solution was treated with benzyl bromide (2.9 mL, 24 mmol), and stirred at room temperature overnight. The product mixture was concentrated under vacuum, and the residue partitioned between aqueous HCl and ethyl acetate. The organic extracted was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 50-50 mixture of ethyl acetate and hexane. Collection and concentration of appropriate fractions provided the benzylated product.
Reaction SMILES: C([O:3][C:4](=[O:40])[C@@H:5]([NH:9][C:10](=[O:39])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([NH:23][CH2:24][C@H:25]([OH:38])[C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:27]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH:6]([CH3:8])[CH3:7])C.[OH-].[Na+]>>[OH:38][C@H:25]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([NH:33][S:34]([CH3:37])(=[O:35])=[O:36])[CH:27]=1)[CH2:24][NH:23][CH:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:10]([NH:9][C@@H:5]([CH:6]([CH3:8])[CH3:7])[C:4]([OH:40])=[O:3])=[O:39])=[CH:12][CH:13]=2)[CH2:18][CH2:19]1
Reactant: CCOC(=O)[C@@H](NC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Product: CC(C)[C@H](NC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-2-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-3-methyl-butyric acid ethyl ester (which was obtained in Example 202) by sodium hydroxide hydrolysis as a pale yellowish solid; mp>135° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 0.90 (d, J=2.3 Hz, 3 H), 0.92 (d, J=2.3 Hz, 3 H), 1.45–1.55 (m, 2 H), 1.90–2.05 (m, 2 H), 2.05–2.20 (m, 1 H), 2.60–2.94 (m, 5 H), 2.94 (s, 3 H), 3.70–3.85 (m, 2 H), 4.11 (t, J=6.0 Hz, 1 H), 4.65–4.75 (m, 1 H), 6.86 (d, J=8.3 Hz, 1 H), 6.91 (d, J=8.9 Hz, 2 H), 7.06 (dd, J=8.3, 2.0 Hz, 1 H), 7.22 (d, J=2.0 Hz, 1 H), 7.65–7.75 (m, 3 H); MS (ES) m/z: 549.3 (MH+); HRMS Calcd. for C26H35N4O7S (M−H)−: 547.2231. Found: 547.2229.
Reaction SMILES: C(N(CC)CC)C.F[C:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[C:17]([NH:22][C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH:18]=[CH:19][C:20]=2[CH3:21])[CH:12]=[C:11]([F:35])[N:10]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CO>[F:35][C:11]1[CH:12]=[C:13]([C:15]2[CH:16]=[C:17]([NH:22][C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH:18]=[CH:19][C:20]=2[CH3:21])[CH:14]=[C:9]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[N:10]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(F)nc(F)c1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(F)nc(N2CCOCC2)c1
Temperature: 55 °C

Procedure:
To a solution of triethylamine (3.0 equiv.) and N-(3-(2,6-difluoropyridin-4-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (1.0 equiv.) at RT in MeOH (0.12 M) was added morpholine (2.0 equiv) in one portion, the resulting mixture was then heated at 55° C. for 8 hours. LCMS analysis indicated 90% conversion to the desired product (M+H=460.1, Rt=0.43 min/non-polar). Water was then added, and the mixture was extracted with ethyl acetate, and the combined extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated to yield N-(3-(2-fluoro-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide as a light brown solid (>100%). LCMS (m/z) (M+H)=460.1, Rt=0.43 min/non-polar.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([CH2:13][O:14][C:15]2[N:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH:22]3[O:34][CH2:35][C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=3)=[CH:17][N:16]=2)[O:10][N:9]=1>[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([CH2:13][O:14][C:15]2[N:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH:22]3[O:34][CH2:35][C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=3)=[CH:17][N:16]=2)[O:10][N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cnc(OCc3nc(-c4ccccc4Cl)no3)nc2)C(OCc2ccc3ccccc3c2)C1
Agent: [Br-]
Agent: [Zn+2]
Product: Clc1ccccc1-c1noc(COc2ncc(C3CCNCC3OCc3ccc4ccccc4c3)cn2)n1

Procedure:
In an analogous manner to that described in Example 125(h), from tert-butyl (3RS,4RS)-4-[2-[3-(2-chlorophenyl)-[1,2,4]oxadiazol-5-ylmethoxy]-pyrimidin-5-yl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate by cleavage of the BOC group by means of anhydrous zinc bromide there was obtained 2-[3-(2-chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethoxy]-5-[(3RS,4RS)-3-(naphthalen-2-ylmethoxy)-piperidin-4-yl]-pyrimidine in the form of an amorphous yellowish solid; MS: 528 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH3:22][C:23]1[CH:24]=[C:25]([SH:29])[CH:26]=[CH:27][CH:28]=1.N1CCCCC1>ClCCl.[OH-].[Na+]>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH3:22])[CH:24]=1
Reactant: Cc1cccc(S)c1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Cc1cccc(SC2=C(O)CC(c3ccccc3)(c3ccccc3)OC2=O)c1

Procedure:
The title compound was prepared as described in General Method 6 from 1.3 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 1.4 mmol of 3-methylbenzenethiol, and 1.4 mmol of piperidine in 25 mL of dichloromethane. The product was triturated with hexane:ether (1:1) to afford a solid which was dissolved in 2 N NaOH, washed with ether, acidified to pH 2, and extracted with ethyl acetate. The extract was washed with water, dried over MgSO4, and concentrated to give a solid (m.p. 58-60° C.). 1H NMR (DMSO-d6) δ 2.07 (s, 3 H), 3.77 (s, 2 H), 6.06 (m, 1 H), 6.45 (s, 1 H), 6.78 (m, 2 H), 7.25-7.47 (m, 10 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][SH:8])=[CH:5][CH:4]=1.[H-].[Na+].CS(O[CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)(=O)=O.[Cl-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][S:8][CH:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CS)cc1
Reactant: CN1CCC(OS(C)(=O)=O)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CSC2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10.9 ml of 4-methoxybenzyl mercaptan were dissolved in 55 ml of dry dimethylformamide, and 3.4 g of sodium hydride (as a 55% w/w suspension in mineral oil) were added to the solution, whilst ice-cooling. The mixture was then stirred at room temperature for 30 minutes. At the end of this time, a solution of 12.6 g of 4-methanesulfonyloxy-1-methylpiperidine in 63 ml of dry dimethylformamide was added to the mixture, which was then allowed to stand overnight at room temperature. The reaction mixture was then poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract as washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel (eluted with a 1:4 by volume mixture of ethyl acetate and methanol) to afford 9.01 g of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH:20]=[CH2:21].F[C:23](F)(F)S(OC1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(C)C=C2)(=O)=O>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[C:3]([CH:20]=[CH2:21])=[C:2]([CH3:23])[CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([CH3:12])=[N:9]3)=[CH:14][CH:15]=1
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c(OS(=O)(=O)C(F)(F)F)c(C)cc2n1
Reactant: C=Cc1c(Cl)cc2nc(C)ccc2c1-c1ccc(Cl)cc1
Product: C=Cc1c(C)cc2nc(C)ccc2c1-c1ccc(Cl)cc1

Procedure:
Compound 2F was prepared following the procedure used to prepare compound 1G of Example 1, except that 5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl trifluoromethanesulfonate (2E) was used instead of compound 1F. LCMS-ESI+ (m/z): 294.3, 296.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].C(Cl)(=O)C1C=CC=CC=1.[CH3:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([CH3:36])[CH:35]=1)[C:30](Cl)=[O:31]>>[CH2:10]([N:5]1[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:30](=[O:31])[C:29]2[CH:33]=[C:34]([CH3:36])[CH:35]=[C:27]([CH3:26])[CH:28]=2)[N:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Solvent: O=C(Cl)c1ccccc1
Product: Cc1cc(C)cc(C(=O)Nc2ncn(Cc3ccccc3)c2C(N)=O)c1
Yield: 91 %

Procedure:
An amidation reaction and post-treatment were carried out according to the conditions of Example 1, using 6.54 g (30.2 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide prepared in Reference Example 2 and, instead of benzoyl chloride, 3,5-dimethylbenzoyl chloride which was separately prepared by a conventional method, to obtain 9.62 g of 1-benzyl-4-(3,5-dimethylbenzoylamino)-5-imidazolecarboxamide (yield 91%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[I-].[Na+].Cl[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>O1CCCC1>[C:3]([CH:2]([CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][CH:20]([C:23](=[O:31])[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH2:21][CH2:22]1)[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCl)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(C)=O
Temperature: 20 °C

Procedure:
A solution of 5.45 g of ethyl acetoacetate in 20 ml of tetrahydrofuran is added at 0° C. to a suspension of 1.68 g of sodium hydride at a concentration of 60% in oil in 100 ml of anhydrous tetrahydrofuran. The medium is maintained at 20° C. for 1 hour 30 minutes. 6.3 g of sodium iodide are added, followed by the addition at 0° C. of 11.3 g of 1-(2-chloroethyl)-4-(4-fluorobenzoyl)piperidine in 100 ml of tetrahydrofuran. The reaction mixture is brought to reflux for 15 hours. It is concentrated under vacuum. The residue is taken up in water and the product is extracted with dichloromethane.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][NH2:14])[CH:7]=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21].[C:24](OCC)(OCC)(OCC)[CH3:25]>C1(C)C(C)=CC=CC=1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[C:24]([CH3:25])=[N:14][N:13]=[C:8]1[CH:7]=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21]
Reactant: CCOC(C)(OCC)OCC
Reactant: NNc1cc(-c2ccccc2Cl)c2cc(C(F)(F)F)ccc2n1
Solvent: Cc1ccccc1C
Product: Cc1nnc2cc(-c3ccccc3Cl)c3cc(C(F)(F)F)ccc3n12

Procedure:
In the manner given in Example 2, 6-(trifluoromethyl)-4-(o-chlorophenyl)-2-hydrazinoquinoline and triethyl orthoacetate are refluxed in xylene to give 7-(trifluoromethyl)-1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2([NH:17][C:18]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[S:19])[CH2:13][CH:12]([OH:14])[CH2:11][CH:10]2[CH2:15]O)[CH:5]=[CH:6][C:7]=1[F:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:13][CH:12]([OH:14])[CH2:11][CH:10]2[CH2:15][S:19][C:18]([NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:17]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(NC(=S)NC1(c2ccc(F)c(Br)c2)CC(O)CC1CO)c1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NC1=NC2(c3ccc(F)c(Br)c3)CC(O)CC2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of racemic N-((1SR,2RS,4RS)-1-(3-bromo-4-fluorophenyl)-4-hydroxy-2-(hydroxymethyl)cyclopentylcarbamothioyl)benzamide (1.21 g, 2.02 mmol) and triphenylphosphine (0.690 mg, 2.63 mmol) in anhydrous THF (18 mL) is added to a separate solution of di-tert-butyl azodicarboxylate (0.606 g, 2.63 mmol) in THF (36 mL) at room temperature. The reaction mixture is stirred at room temperature for 1 hr and concentrated under reduced pressure to give a residue that is purified by silica gel chromatography eluting with a linear gradient of 0% to 40% ethyl acetate in dichloromethane over 15 minutes to give the title compound as racemic mixture (0.557 g, 61%). ES/MS m/e (79Br/81Br) 449, 451 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH3:8][C:9]1([CH3:34])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19](O)=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:8][C:9]1([CH3:34])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CCNCC2)c1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cccc(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
To a suspension of 60% sodium hydride (196 mg, 4.9 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (475 mg, 5 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-(3-piperazin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (180 mg, 0.5 mmol) and 1,1′-carbonyldiimidazole (162 mg, 1.0 mmol) in N,N-dimethylformamide (1.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. 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% ammonium hydroxide in water) afforded N-[3,3-dimethyl-2-(3-piperazin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (66 mg, 30%) as a white solid: LC/MS m/e calcd for C23H30N4O3S (M+H)+: 443.58, observed: 442.9.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH:34]=O)=[CH:4][N:3]=1.[CH3:36][C:37]1([CH3:44])[NH:42][C:41](=[O:43])[CH2:40][NH:39][CH2:38]1>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][N:39]2[CH2:40][C:41](=[O:43])[NH:42][C:37]([CH3:44])([CH3:36])[CH2:38]2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CC1(C)CNCC(=O)N1
Product: COc1cc(-c2csc3c(/C=C/CN4CC(=O)NC(C)(C)C4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
N-(4-{4-Amino-7-[(1E)-3-oxoprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (60.0 mg, 0.125 mmol) and 6,6-dimethyl-piperazin-2-one (75.7 mg, 0.498 mmol) were reacted according to General Procedure B. The product was purified via flash chromatography to furnish the title compound as a yellow powder. (5.0 mg, 0.0084 mmol): LCMS (Conditions a): MH+=595.0, Rt=3.58 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.52 (s, 1H), 7.98 (m, 2H), 7.80 (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.35 (m, 1H), 7.31 (m, 1H), 7.20 (m, 1H), 7.15 (t, J=7.8 Hz, 1H), 7.09 (dd, J=8.2, 1.56 Hz, 1H), 6.74 (d, J=16.0 Hz, 1H), 6.23 (m, 1H), 5.66 (br, 2H), 4.04 (s, 3H), 3.91 (s, 3H), 3.24 (m, 2H), 2.95 (s, 2H), 2.42 (s, 2H), 1.20 (s, 6H).
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH:10]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:17])[CH3:16])[CH2:11]2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:25].[OH-].[Na+]>>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH:10]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:17])[CH3:16])[CH2:11]2)[C:8]([NH2:9])=[O:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: CC(C)N1CCC(C(C#N)(c2ccccc2)c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)N1CCC(C(C(N)=O)(c2ccccc2)c2ccccc2)C1

Procedure:
A solution of 29.0 g. of α,α-diphenyl-α-(1-isopropyl-3-pyrrolidinyl)acetonitrile in 100 ml. of conc. sulfuric acid was heated at 80° C. for 18 hours. The reaction mixture was poured onto ice, the resulting cold acidic solution made basic using sodium hydroxide and the basic solution extracted with chloroform. The dried chloroform extract was concentrated and the residue crystallized from isooctane. The solid was recrystallized from isopropyl ether to give 13.2 g. (43%) of product which melted at 110.5°-112.5° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[N:25]=[CH:24][N:23](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:22]=4)[CH:19]=3)[N:14](C3CCCCO3)[N:13]=2)[CH:7]=1)(=[O:4])=[O:3]>O1CCOCC1.Cl>[NH:23]1[CH:24]=[N:25][C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[C:8]2[CH:7]=[C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:11]=[CH:10][CH:9]=2)=[N:22]1
Reactant: CS(=O)(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Reaction time: 18 h
Yield: 71 %

Procedure:
Hydrolysis was performed by stirring (methylsulfonyl)(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)amine (0.140 g, 0.205 mmol) in 4 mL of 4.0 N commercial solution of HCl in dioxane and 2 mL of 6.0 N aqueous HCl, at room temperature for 18 hours. The title compound was purified by preparative HPLC (15-80% acetonitrile in water) (0.052 g, 71% yield): 1H NMR (DMSO-d6) δ 13.5 (br s, 1H), 10.0 (s, 1H), 8.7 (s, 1H), 8.4 (br s, 1H), 8.1 (d, 1H), 7.9 (s, 1H), 7.7 (dd, 2H), 7.5 (dd, 1H), 7.3 (d, 1H), 3.06 (s, 3H); ES-MS (m/z) 355 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[S:16]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[C:5]([Cl:24])=[CH:4][N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:28][CH2:27]1>C(Cl)Cl.CO>[Cl:24][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[S:16]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])=[N:7][C:2]([NH:37][C:36]2[CH:35]=[CH:34][C:33]([CH2:32][N:29]3[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]3)=[CH:39][CH:38]=2)=[N:3][CH:4]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: O=S(=O)(c1cc(F)ccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(Nc3ncc(Cl)c(Nc4ccc(F)cc4S(=O)(=O)N4CCCC4)n3)cc2)CC1
Yield: 78 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2,5-dichloro-N-(4-fluoro-2-(pyrrolidin-1-ylsulfonyl)phenyl)pyrimidin-4-amine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 78% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 9.30 (s, 1H), 8.49 (dd, 1H, J=9.2, 4.8 Hz), 7.60 (dd, 1H, J=8.0, 2.9 Hz), 7.41 (d, 2H, J=8.2 Hz), 7.23 (d, 2H, J=8.2 Hz), 7.19 (m, 1H), 3.48 (s, 2H), 3.23 (m, 4H), 2.50 (bs, 8H), 2.31 (s, 3H), 1.78 (m, 4H); MS (ESI): 560.3 [M+H]+.