Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH2:16][CH3:17].Cl>CN(C=O)C>[CH2:15]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH2:16][CH3:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(C(=O)OCC)C(=O)OCC
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 107.3 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 12.6 g, 315 mmol, 1.05 equiv) in DMF (300 mL) at 23° C. was added a solution of diethyl malonate (45.5 mL, 300 mmol, 1 equiv) in DMF (100 mL) via cannula over the course of 10 min. The addition caused a mild exotherm and H2 gas evolution was observed, cooling was not necessary. Following the addition, the reaction was stirred for 45 min at 23° C. then treated with 1-bromopropane (27.3 mL, 300 mmol, 1 equiv). The reaction was stirred at 23° C. for 25 min, then heated to 65° C. for 3 h, then stirred at 23° C. overnight. The reaction mixture was added to 1.0 N HCl (1 L) then extracted with diethyl ether (700 mL). The ether extracts were washed with H2O (400 mL), brine (200 mL), dried (MgSO4), filtered and concentrated to give 65.1 g of product as a clear oil. 13C NMR revealed approximately 4:1 mono to bis-alkylated product ratio. The product diethyl n-propylmalonate was used without further purification: 1H NMR (300 MHz, CDCl3) 4.18 (q, J=6.9 Hz, 4H), 3.32 (t, J=7.8 Hz, 1H), 1.91-1.79 (m, 2H), 1.41-1.25 (m, 2H), 1.25 (t, J=6.9 Hz, 6H), 0.92 (t, J=7.5 Hz, 3H); 13C NMR (300 MHz, CDCl3) (*denotes signal due to minor product of bis-alkylation) 169.6, 61.2, 60.9*, 51.8, 34.4*, 30.7, 20.5, 17.3*, 14.4*, 14.0, 13.7.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[S:21](Cl)(=[O:23])=[O:22]>>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[S:21]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:23])=[O:22]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cccc(Cl)c2Cl)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2,3-dichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (25.0 mg) with purity >90%. MS (pos) m/z 395.1, 397.1.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][OH:25])=[O:18])([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>ClCCl>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][O:25][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
At a temperature of 0° C., p-toluenesulfonylchloride (6.0 g, 30.4 mol) was added portionwise to a stirred solution of (S)-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (4.9 g, 24.3 mmol) and pyridine (14.6 ml, 181 mmol) in dichloromethane (50 ml). The reaction mixture was stirred for 30 minutes at 0° C. and then allowed to stand for 15 hours at ambient temperature. Then dichloromethane (50 ml) was added. The solution was washed with water (4×50 ml) and saturated NaCl (50 ml) and then dried over Na2SO4. After evaporation of the solvent, the crude product (9.83 g in the form of an oil) was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 1:1) to afford 8.07 g (83.4% of theory) of (S)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a colorless oil. 1H NMR (400 MHz, DMSO): δ 1.29 and 1.35 (s, 9H), 1.72 (m, 3H), 1.92 (m, 1H), 2.43 (s, 3H), 3.18 (m, 2H), 3.83 (m, 1H), 4.03 (m, 2H), 7.49 (d, 2H), 7.78 (d, 2H). MS [M+H]+ 256. [α]23D=−39.1 (c 5.98, CHCl3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:23]12[CH2:30][CH2:29][CH:26]([CH2:27][CH2:28]1)[C@@H:25](O)[CH2:24]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[C:10]([O:12][C@@H:25]1[CH:26]2[CH2:29][CH2:30][N:23]([CH2:28][CH2:27]2)[CH2:24]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O[C@H]1CN2CCC1CC2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)O[C@H]1CN2CCC1CC2
Yield: 69.6 %

Procedure:
A solution of 2-(tert-butoxycarbonylamino)-3-(1H-indol-3-yl)propanoic acid (100 mg, 0.33 mmol), (R)-quinuclidin-3-ol (50.1 mg, 0.39 mmol), HOBT (53.3 mg, 0.39 mmol) and EDC (76 mg, 0.39 mmol) in DMF (2 ml) was heated at 90° C. for 1.5 hours under microwave irradiation. The solvent was evaporated. The residue was taken up with EtOAc and washed with 1N Na2CO3, water and brine. The organic phase was dried over Na2SO4, filtered and evaporated to obtain (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-3-(1H-indol-3-yl)propanoate (95 mg, 69.9% yield), which was used as such in the next step.
Reaction SMILES: [CH:1]1([PH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14]C(Cl)(Cl)C(Cl)(Cl)Cl.Cl>>[CH:8]1([P:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[Cl:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: C1CCC(PC2CCCCC2)CC1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: Cl
Product: ClP(C1CCCCC1)C1CCCCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 58.9 %

Procedure:
19.8 g (0.1 mol) dicyclohexylphosphane was added dropwise at room temperature to 26.1 g (0.11 mol) hexachloroethane. After the exothermal reaction which took place with evolution of HCl was terminated, the reaction mixture was stirred for 3 hours at 100° C. The yields (31 -P-NMR) were as follows: δ P=125.2 ((C6H11)2PCl, 94 wgt %); δ P=194.4 (C6H11PCl2, 2 wgt %); δ P=76.7 ((C6H11)2P(O)Cl, 4 wgt %). The crude product was distilled and 13.7 g (59 wgt %) dicyclohexylchlorophosphane (bp.: 136°-138° C./4 millibars) was obtained.
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+].Br[CH2:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1>O.C(#N)C>[Na+:5].[N+:20]([C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:12]2[CH:23]=[CH:24][C:9]([CH2:8][S:1]([O-:4])(=[O:3])=[O:2])=[CH:10][CH:11]=2)=[CH:19][CH:18]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(CBr)cc2)cc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Cc2ccc(CS(=O)(=O)[O-])cc2)cc1
Yield: 124.2 %

Procedure:
A solution of sodium sulfite (0.73 g, 7 mmol) dissolved in water (10 mL) was added to a solution of 4-(4-bromomethylbenzyl)-nitrobenzene (1.41 g, 5.6 mmol) in acetonitrile (10 mL). The mixture was stirred and heated under reflux for 2 hours. Solvents were evaporated and dried to give the 4-(4-nitrobenzyl)-phenylmethanesulfonic acid sodium salt as a white powder (2.29 g).
Reaction SMILES: [S:1]1[C:5]([C@:6]([C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)([OH:13])[CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:4][C:3]2[CH:27]=[CH:28][CH:29]=[CH:30][C:2]1=2.[OH-].[Na+]>Cl.C(#N)C>[S:1]1[C:5]([C@:6]([C@@H:14]2[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)([OH:13])[CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:4][C:3]2[CH:27]=[CH:28][CH:29]=[CH:30][C:2]1=2
Reactant: COCCCC[C@@](O)(c1cc2ccccc2s1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: COCCCC[C@@](O)(c1cc2ccccc2s1)[C@@H]1CCCNC1
Yield: 82.7 %

Procedure:
(R)-tert-butyl 3-((S)-1-(benzo[b]thiophen-2-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (160 mg, 0.37 mmol) was dissolved in 1:1 2 N aq HCl solution/acetonitrile (50 mL). The mixture was stirred overnight at rt and neutralized with 5% aq NaOH. The acetonitrile was removed by evaporation. The aqueous residue was extracted by CH2Cl2 (2×40 mL). The combined organic layers were concentrated to afford (S)-1-(benzo[b]thiophen-2-yl)-5-methoxy-1-((R)piperidin-3-yl)pentan-1-ol (102 mg, 83%) which was used without purification.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][C:6]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH2:5]1)#[N:2].[NH:20]1[CH:24]=[C:23]([C:25]2[C:26]3[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:27]=3[N:28]=[CH:29][N:30]=2)[CH:22]=[N:21]1.N12CCCN=C1CCCCC2>C(#N)C>[C:1]([CH2:3][C:4]1([N:20]2[CH:24]=[C:23]([C:25]3[C:26]4[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:27]=4[N:28]=[CH:29][N:30]=3)[CH:22]=[N:21]2)[CH2:5][C:6]([C:8]([O:10][CH:11]([CH3:12])[CH3:13])=[O:9])([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[CH2:7]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: CC(C)OC(=O)C1(C(=O)OC(C)C)CC(=CC#N)C1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)OC(=O)C1(C(=O)OC(C)C)CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 50 °C
Yield: 17.2 %

Procedure:
Diisopropyl 3-(cyanomethylene)cyclobutane-1,1-dicarboxylate (2.65 g, 0.00999 mol) was combined with 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (1 g, 0.003 mol) in acetonitrile (10 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.5 mL, 0.003 mol) was added under N2. The mixture was heated at 50° C. overnight. The reaction was concentrated and purified with Combiflash (silica gel, 0-50% EtOAc/Hex) to give the desired product (0.3 g) as colorless oil. LCMS calculated for C29H41N6O5Si(M+H): 581.3; Found: 581.4.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[N:19]=[C:18]([CH2:29][OH:30])[CH:17]=2)[CH:12]=[CH:13][C:14]=1[Cl:15].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C1COCC1.C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[N:20]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[N:19]=[C:18]([CH2:29][O:30][S:32]([CH3:31])(=[O:34])=[O:33])[CH:17]=2)[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: COc1ccc(-n2nc(CO)cc2-c2ccc(Cl)c(Cl)c2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(COS(C)(=O)=O)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
Triethylamine (3.25 L, 23.3 mol) was added to a solution containing [5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-methanol (Example 516, 5.18 kg, 14.8 mol) in THF (25.2 L) and toluene (6.3 L) at rt under N2. The reaction mixture was heated to 35° C. and methanesulfonyl chloride (1.82 L, 23.5 mol) was added slowly maintaining the temperature between 35-45° C. The reaction mixture was stirred for an additional 2 h at 45° C. When HPLC analysis indicated the disappearance of the starting material, the reaction mixture was cooled to rt and quenched with 10% aq. NaCl (6.3 L). The organic layer was washed with brine (5.0 L) and the desired mesylate was used in solution in the next synthetic step without isolation. Data compared favorably with that obtained for Example 1, Step D.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:17][C:16]3[C:18]4[CH2:19][CH2:20][CH2:21][C:22]=4[CH:23]=[C:24]([Cl:25])[C:15]=3[CH2:14]2)(=O)=O)=CC=1.[N-:26]=[N+:27]=[N-:28].[Na+]>>[Cl:25][C:24]1[C:15]2[CH2:14][CH:13]([CH2:12][N:26]=[N+:27]=[N-:28])[O:17][C:16]=2[C:18]2[CH2:19][CH2:20][CH2:21][C:22]=2[CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(Cl)cc4c(c3O2)CCC4)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2c(Cl)cc3c(c2O1)CCC3

Procedure:
Treatment of (±)-(4-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methyl 4-methylbenzenesulfonate (4.0 g, 10.6 mmol) with sodium azide (2.75 g, 42.2 mmol) generally according to the procedure described for Intermediate 24 gave (±)-(4-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methyl azide. Treatment of the azide with sulfided platinum on carbon (5 wt. %, 0.63 g) followed by hydrogen chloride (3 mL, 4 M in isopropanol) generally according to the procedure described for Example 2 provided 2.1 g (76%) of (±)-1-(4-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methanamine as a white solid, hydrochloride salt. mp 251-254° C.; Anal. calcd. for C12H14ClNOHCl: C, 55.40; H, 5.81; N, 5.38. Found: C, 55.10; H, 5.68; N, 5.29.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:10]=3)[C@:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1.[C:27](=[O:30])([O-])[O-].[Na+].[Na+].[CH:33]1([NH2:36])[CH2:35][CH2:34]1.O1CCOCC1>CCOC(C)=O.O.C(O[Pd]CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C)(=O)C>[NH2:26][C:23]1[O:24][CH2:25][C@:5]2([N:22]=1)[C:4]1[CH:3]=[C:2]([C:27]([NH:36][CH:33]3[CH2:35][CH2:34]3)=[O:30])[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([O:16][CH2:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:9][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)ccc1O2
Reactant: NC1CC1
Agent: CC(=O)O[Pd]Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(C(=O)NC3CC3)ccc1O2
Temperature: 170 °C
Reaction time: 0.43 h

Procedure:
A 0.5-2 mL microwave vial charged with (R)-2′-bromo-7′-(neopentyloxy)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (0.1000 g, 0.240 mmol), Mo(CO)6 (0.063 g, 0.240 mmol), acetoxy(2-(dio-tolylphosphino)benzyl)palladium (0.011 g, 0.012 mmol), sodium carbonate (0.025 g, 0.240 mmol), cyclopropylamine (0.025 mL, 0.359 mmol), and 1,4-dioxane (0.443 mL, 5.03 mmol) was sealed and heated to 170° C. for 30 minutes. The mixture was diluted with EtOAc and water and filtered through celite. The celite was washed with EtOAc and MeOH. The aqueous phase was extracted with EtOAc three times. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude was purified by silica gel chromatography (2-10% MeOH—CH2Cl2, then 10% MeOH—CH2Cl2). The product was purified again by reverse phase prep HPLC: 10-55% CH3CN (0.1% TFA)-water (0.1% TFA) in 26 min. The fractions were combined and neutralized with solid Na2CO3, extracted three times with DCM. The organic layer was concentrated to provide (S)-2-amino-N-cyclopropyl-7′-(neopentyloxy)-5H-spiro[oxazole-4,9′-xanthene]-2′-carboxamide.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([Cl:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[ClH:34].[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([S:31]([N:18]2[C:19]3[C:15](=[C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:22]=[CH:21][CH:20]=3)[CH:16]=[CH:17]2)(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]ccc23)CC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)n2ccc3c(N4CCNCC4)cccc32)cc1
Product: Cl

Procedure:
The title compound was prepared from 4-(4-boc-piperazinyl)-indole and 4-methoxyphenylsulfonyl chloride according to Method 3: 1H NMR (270 MHz, DMSO-d6) δ 9.07 (br, 1 H), 7.90 (d, J=8 Hz, 2 H), 7.78 (d, J=5 Hz, 1 H), 7.61 (d, J=8 Hz, 1 H), 7.25 (t, J=8 Hz, 1 H), 7.09 (d, J=8 Hz, 2 H), 6.92 (d, J=5 Hz, 1 H), 6.68 (d, J=8 Hz, 1 H), 3.79 (s, 3 H), 3.24 (m, 8 H); MS (ESI+) for m/z 371 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[C:19]([C:27]5[CH:28]=[C:29]([NH:33][C:34](=O)[C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[CH:30]=[CH:31][CH:32]=5)=[N:20][N:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=45)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:51])=CC=1>O1CCOCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[C:19]([C:27]5[CH:28]=[C:29]([NH:33][C:34](=[S:51])[C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[CH:30]=[CH:31][CH:32]=5)=[N:20][N:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=45)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)OCCO4)n2)c1)c1ccccc1
Solvent: C1COCCO1
Product: S=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)OCCO4)n2)c1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of N-(3-{3-[2-(2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-pyrimidin-4-yl]-pyrazolo[1,5-a]pyridin-2-yl}-phenyl)-benzamide (43 mg, 0.08 mmol) and excess of Lawesson's Reagent in 1,4-dioxane (1 mL) was heated at 100° C. in a sealed tube. When LC/MS showed the starting material to be consumed, the mixture was cooled to ambient temperature and diluted with DCM. The organic phase was washed with water, dried over MgSO4 and concentrated. The crude material was purified through silica gel to give the title compound as a yellow solid. 1H NMR (400 MHz, d6-DMSO): δ 11.85 (s, 1H), 9.34 (s, 1H), 8.82 (d, J=6.8 Hz, 1H), 8.49 (d, J=8.4 Hz, 1H), 8.20 (d, J=5.6 Hz, 1H), 8.14 (s, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.80 (d, J=7.2 Hz, 1H), 7.57-7.42 (m, 6H), 7.35 (m, 1H), 7.13-7.10 (m, 2H), 6.73 (d, J=8.8 Hz, 1H), 6.49 (d, J=5.2 Hz, 1H), 4.19 (m, 4H). MS (ESI) m/z=557 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][NH:27][CH:28]([CH3:30])[CH3:29])=[CH:8][CH:7]=1)([OH:5])[CH3:4].[C:33](Cl)(=[O:35])[CH3:34].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:30][CH:28]([N:27]([CH2:26][C@H:13]1[CH2:14][N:15]([S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])[CH2:16][CH2:17][N:12]1[C:9]1[CH:8]=[CH:7][C:6]([C:3]([OH:5])([CH3:4])[C:2]([F:1])([F:31])[F:32])=[CH:11][CH:10]=1)[C:33](=[O:35])[CH3:34])[CH3:29]
Reactant: CC(C)NC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N(C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1,1,1-trifluoro-2-(4-((2S)-2-(((1-methylethyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.150 g, 0.305 mmol, Example 195, Step 1) in CH2Cl2 (5.0 mL) was added 4-dimethylaminopyridine (7.46 mg, 0.061 mmol), acetyl chloride (0.043 mL, 0.610 mmol), Hünig's base (0.159 mL, 0.915 mmol). The resulting mixture was stirred at room temperature. After 20 min, the solvent was concentrated and the crude product was purified by column chromatography (24 g of silica, 10 to 40% acetone in hexanes) to afford N-(1-methylethyl)-N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)acetamide as a mixture of two isomers.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][Cl:26]>C(O)C>[Cl:26][CH2:25][CH2:24][CH2:23][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1
Reactant: ClCCCBr
Reactant: c1ccc2c(c1)ccn2C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: ClCCCN1CCC(n2ccc3ccccc32)CC1
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of 1-(piperidin-4-yl)-indole (100 mg, 0.5 mmol) in absolute ethanol (2 mL) was added anhydrous potassium carbonate (70 mg, 0.5 mmol) and 1-bromo-3-chloropropane (150 mg, 1 mmol). After stirring overnight additional 1-bromo-3-chloropropane (150 mg) was added and stirring continued for 2 hours. The mixture was evaporated; and the residue dissolved in methylene chloride and shaken with water. The organic solution was dried over anhydrous potassium carbonate and evaporated. The residue was chromatographed on silica gel with methylene chloride/ethanol (95:5) to give the title compound (90 mg, 65% yield).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:24][CH2:23][C@:12]34[C:13]5[C:14]6[O:22][C@H:11]3[C:10](=[O:25])[CH2:9][CH2:8][C@@:7]4([CH2:26][CH3:27])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[O:20]C)[CH2:3][CH2:2]1.Cl.N1C=CC=CC=1.N>O>[CH:1]1([CH2:4][N:5]2[CH2:24][CH2:23][C@:12]34[C:13]5[C:14]6[O:22][C@H:11]3[C:10](=[O:25])[CH2:9][CH2:8][C@@:7]4([CH2:26][CH3:27])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[OH:20])[CH2:2][CH2:3]1
Reactant: CC[C@@]12CCC(=O)[C@@H]3Oc4c(OC)ccc5c4[C@@]31CCN(CC1CC1)[C@@H]2C5
Agent: Cl
Agent: N
Solvent: c1ccncc1
Solvent: O
Product: CC[C@@]12CCC(=O)[C@@H]3Oc4c(O)ccc5c4[C@@]31CCN(CC1CC1)[C@@H]2C5

Procedure:
3.25 g (8.9 mMol) of the compound of example 1 and 10 g of pyridine hydrochloride are heated for 3 hours to 190° C., then taken up in water after cooling, rendered basic with conc. ammonia, and extracted three times with methylene chloride. Flash-chromatography with ethyl acetate/hexane 1:5 yields the title compound as colorless crystals. Recrystallization from ether/pentane yields an analysis-pure product: M.p.: 157°-158° C.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][C:10](=[O:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][C:15]#[N:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]1([C:7]2[CH:11]=[C:10]([O:12][CH2:14][C:15]#[N:16])[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCBr
Reactant: O=C1CC(c2ccccc2)=NN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-phenyl-1H-pyrazol-5(4H)-one (1.00 g, 6.24 mmol) in DMF (5.0 mL) was added 2-bromoacetonitrile (0.520 mL, 7.80 mmol) and K2CO3 (0.863 g, 6.24 mmol). The reaction was stirred at 25° C. for 12 h, quenched with water (40.0 mL), extracted with EtOAc (3×50.0 mL) and washed with brine. The combined organics were dried over MgSO4, filtered, and concentrated to give the title compound as a yellow oil. This yellow oil was purified by silica gel flash chromatography to give the title compound as a clear oil (0.990 g). LCMS m/z=200.3 [M+H]+.
Reaction SMILES: S([O-])(O)=O.[Na+].C([O:8][C:9]([C:11]1[NH:12][C:13]([CH3:19])=[C:14]([CH:17]=O)[C:15]=1[CH3:16])=[O:10])C.[NH2:20][C:21]1[CH:22]=[C:23]([CH:32]=[CH:33][C:34]=1[NH2:35])[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[C:24]([C:23]1[CH:32]=[CH:33][C:34]2[N:35]=[C:17]([C:14]3[C:15]([CH3:16])=[C:11]([C:9]([OH:8])=[O:10])[NH:12][C:13]=3[CH3:19])[NH:20][C:21]=2[CH:22]=1)(=[O:25])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Reactant: CCOC(=O)c1[nH]c(C)c(C=O)c1C
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1[nH]c(C(=O)O)c(C)c1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Temperature: 120 °C
Reaction time: 10 h
Yield: 84.9 %

Procedure:
Sodium hydrogensulfite (1.0 g) and 3,5-dimethyl-4-formylpyrrole-2-carboxylic acid ethyl ester (1.5 g) were added to an N,N-dimethylacetamide (20 ml) solution of 3,4-diaminobenzophenone (1.6 g), and the mixture was heated to 120° C. and stirred for 10 hours. After the mixture was allowed to cool to room temperature, a 5% sodium carbonate (60 g) was added and stirred at room temperature, and the precipitate was collected by filtration and washed with water. The obtained solid was dissolved in ethanol (15 ml) and tetrahydrofuran (15 ml), and a 4 N sodium hydroxide aqueous solution (20 ml) was added and heated under reflux for 12 hours. After the starting material was disappeared, the reaction mixture was allowed to cool to room temperature, and neutralized with a 1 N hydrochloric acid solution. The precipitate was collected by filtration to afford 4-(5-benzoylbenzimidazol-2-yl)-dimethylpyrrole-2-carboxylic acid (2.3 g, 90%) as a light yellow solid.