Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24](O)=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:41][O:42][C:43](=[O:48])[C@H:44]([CH2:46][OH:47])[NH2:45].CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:41][O:42][C:43](=[O:48])[C@H:44]([CH2:46][OH:47])[NH:45][C:24](=[O:25])[C@@H:23]1[CH2:27][CH2:28][CH2:29][N:22]1[C:20](=[O:21])[C@H:18]([CH3:19])[NH:17][P:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9]
Reactant: COC(=O)[C@@H](N)CO
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NP(=O)(Cc1ccccc1)Cc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
Dibenzylphosphoryl-L-alanyl-L-proline (1.2 g, 2.5 m mole) as shown in the Japanese patent first publication No. 104863/1981, HOBt (338 mg, 2.5 m mole) and L-serine methylester hydrochloride (467 mg, 3 m mole) were suspended in DMF (10 ml), and WSC (0.5 ml) was added dropwise thereto while cooling to -15° C. and stirring. The reaction was carried out for 3 hours under cooling and next overnight at a room temperature. Ethyl acetate (100 ml) was added to the reaction solution, washed 1N hydrochloric acid and water in order, and dried with anhydrous sodium sulfate. The thus obtained solution was distilled under reduced pressure to give an oily dibenzylphosphoryl-L-alanyl-L-prolyl-L-serine methyl ester (1.3 g). The oily product gave a single spot with Rf 0.46 by thin layer chromatography (developing solvent; chloroform:methanol:acetic acid=95:5:3, colour forming method: spraying of 25% hydrobromic acid and 0.1% ninhydrine and heating). The oily material was dissolved in a mixture (20 ml) of acetone and methanol (1:1) and 1N sodium hydroxide (5 ml) was added thereto under cooling with ice. The mixture was stirred for 1.5 hours at room temperature and neutralized with 1N hydrochloric acid. The solution was distilled under reduced pressure to eliminate the organic solvent, and the residue was dissolved in ethyl acetate, washed with 1N hydrochloric acid and water in order, and dried with anhydrous sodium sulfate. The thus obtained solution was distilled under reduced pressure to give oily dibenzylphosphoryl-L-alanyl-L-prolyl-L-serine (1.2 g). The oily material gave a single spot with Rf 0.18 by thin layer chromatography (developing solvent: chloroform:methanol:acetic acid=95:5:3, colour forming method; spraying of 25% hydrobromic acid and 0.1% ninhydrine, and heating).
Reaction SMILES: Cl.[Cl:2]C1C=CC(NN)=CC=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22](=O)[C:21]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:20]=3[NH:19]2)=[CH:14][CH:13]=1.N1C=CC(=O)N=1.P(Cl)(Cl)(Cl)=O>>[Cl:2][C:22]1[N:18]([C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)[N:19]=[C:20]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:21]=12
Reactant: O=c1c2c([nH]n1-c1ccc(Cl)cc1)CCCCC2
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Agent: O=C1C=CN=N1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc(-n2nc3c(c2Cl)CCCCC3)cc1

Procedure:
By substituting 2-carbethoxycycloheptanone [prepared by the method of G. Stork, et al., J. Am. Chem. Soc., 85, 207 (1963)] and p-chlorophenylhydrazine hydrochloride (available from Aldrich Chemical Company) in the procedure of Example 1(c), 2-(4-chlorophenyl)-1,4,5,6,7,8-hexahydrocycloheptapyrazol-3(2H)-one (m.p. 224°-225°) was prepared. By reacting this pyrazolone with phosphorous oxychloride according to the procedure of Example 1(d), 3-chloro-2-(4-chlorophenyl)-2,4,5,6,7,8-hexahydrocycloheptapyrazole (m.p. 59°-61°) was obtained.
Reaction SMILES: [CH2:1]([C:3]1([CH2:22][CH3:23])[C:8]2[CH:9]=[C:10]([C:13]3[N:17]([CH3:18])[C:16]([C:19]#[N:20])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=O)[O:4]1)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH2:22][CH3:23])[C:8]2[CH:9]=[C:10]([C:13]3[N:17]([CH3:18])[C:16]([C:19]#[N:20])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[S:33])[O:4]1)[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCC1(CC)OC(=O)Nc2ccc(-c3ccc(C#N)n3C)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC1(CC)OC(=S)Nc2ccc(-c3ccc(C#N)n3C)cc21
Yield: 15.2 %

Procedure:
5-(4,4-diethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile (0.5 g, 1.6 mmol) and Lawesson's Reagent (0.33 g, 0.81 mmol) were heated to 100° C. in toluene (20 mL). Upon completion by TLC, the reaction was poured into saturated sodium carbonate (100 mL) and extracted with ethyl acetate (50 mL), dried over magnesium sulfate, and concentrated. The purification with column gave 5-(4,4-diethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile (0.040 g, 8%) as a tan solid. 1H NMR (DMSO-d6): δ 12.15 (s, 1H), 7.44 (d, 1H, J=8.3, 1.8 Hz), 7.37 (d, 1H, J=1.8 Hz), 7.12 (d, 1H, J=8.3 Hz), 7.04 (d, 1H, J=4.03 Hz), 6.35 (d, 1H, J=4.2 Hz), 3.7 (s, 3H), 2.07 (m, 2H, J=7.4 Hz), 1.95 (m, 2H, J=7.4 Hz), 0.79 (t, 6H, J=7.4 Hz). MS (ESI) m/z 326 ([M+H]+); MS (ESI) m/z 324 ([M−H]−). HRMS: calcd for C18H19N3OS, 325.1249; found (ESI_FT), 326.13187.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12]C)=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6]
Reactant: COc1ccc(C=O)c(OC)c1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1ccc(C=O)c(O)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 72.0 g. (0.359 mol) of (13h) in 450 ml. of CH2Cl2 at -50° C. under N2 was added dropwise 90.0 g. (0.359 mol) of BBr3. After the addition was complete, the reaction mixture was warmed to 0° C. and stirred for 1 hour. The reaction mixture was then poured into 500 ml. of ice-water and extracted with EtOAc. The organic solution was washed with aqueous NaCl and dried over Na2SO4. Evaporation of the EtOAc gave a residue that was rapidly passed through a silica gel column eluting with an EtOAc/CH2Cl2 mixture. This afforded 49.5 g. of (14h), m.p. 114°-117° C. Analysis (C8H7ClO3) C,H.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH3:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]1>CS(C)=O.CCOC(C)=O>[CH3:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: C[C@@H]1CCCCN1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[C@@H]1CCCCN1c1ccc(C#N)cc1C(F)(F)F
Temperature: 100 °C

Procedure:
A mixture of 4-fluoro-3-(trifluoromethyl)benzonitrile (1.0 g, 5.29 mmol) and (R)-(−)-2-methylpiperidine (3.1 mL, 26.4 mmol) was prepared in DMSO (10 mL) and heated at 100° C. under nitrogen for 12 hours. The reaction mixture was diluted with EtOAc, and then washed with water, a saturated aqueous solutions of NaHCO3 and a saturated aqueous solution of NH4Cl. The organic layer was dried (MgSO4) and concentrated under vacuum to give the title compound as a yellow oil, which was used without further purification in the next step. HPLC (Method A) Rt 5.65 min (82.6%). LC/MS (Method B): 269.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH2:12].[CH2:13]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18])[C:14]#[CH:15].C(NC(C)C)(C)C>C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[NH2:12][C:3]1[C:4]2[O:8][CH2:7][O:6][C:5]=2[C:9]([C:15]#[C:14][CH2:13][NH:16][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])=[CH:10][C:2]=1[Cl:1]
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Reactant: C#CCNC(=O)N1CCOCC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: Nc1c(Cl)cc(C#CCNC(=O)N2CCOCC2)c2c1OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.5 %

Procedure:
5-Chloro-7-iodo-1,3-benzodioxol-4-amine (600 mg, 2.02 mmol) and N-prop-2-yn-1-ylmorpholine-4-carboxamide (406 mg, 2.42 mmol) in ethyl acetate (10 ml) were cooled in ice-methanol, under an atmosphere of nitrogen, and then treated with bis(triphenylphosphine) palladium(II) dichloride (140 mg, 10 mol %) followed by copper(I) iodide (38 mg, 10 mol %) and diisopropylamine (407 mg, 4.03 mmol). The reaction was allowed to warm to room temperature and stirred for 3 hours and then filtered through Celite. The filtrate was purified by column chromatography on silica using ethyl acetate as eluent to give N-[3-(7-amino-6-chloro-1,3-benzodioxol-4-yl)prop-2-yn-1-yl]morpholine-4-carboxamide (529 mg, 78%) as a pale brown solid; NMR Spectrum:(DMSOd6) 3.28 (m, 4H), 3.54 (m, 4H), 4.05 (d, 2H), 5.47 (s, 2H), 6.05 (s, 2H), 6.78 (s, 1H), 7.01 (t, 1H); Mass Spectrum: M+H+ 338/340.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:40]1([CH2:46][CH2:47][NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:43]3[CH2:44][CH2:45][N:40]([CH2:46][CH2:47][NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH2:41][CH2:42]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:31])[CH3:32])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)NCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)O)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with N-(2-piperazin-1-yl-ethyl)-methanesulfonamide dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C36H45N5O5SCl2 [(M+H)+] 730.2591, observed 730.2585.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1>C(O)CO>[F:11][C:8]1[CH:9]=[N:10][C:2]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[C:3]([CH:7]=1)[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1cc(F)cnc1Cl
Reactant: COc1ccc(CN)cc1
Solvent: OCCO
Product: COc1ccc(CNc2ncc(F)cc2C(N)=O)cc1
Yield: 50 %

Procedure:
A solution of 2-chloro-5-fluoro-nicotinamide (70 mg, 0.40 mmol) and 4-methoxybenzylamine (550 mg, 4.01 mmol) in ethyleneglycol (1 ml) was microwaved for 50 min at 140° C. A white solid was filtered off and the filtrate evaporated. The residue was dissolved in EtOAc, washed with water and brine, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by column chromatography (silica gel, EtOAc/heptane, 1/1) to obtain 5-fluoro-2-(4-methoxy-benzylamino)-nicotinamide (56 mg, 0.2 mmol; 51%) as white solid. MS (m/e): 276.3 [M+H+].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F-].[Cs+].[Cl:9][C:10]1[NH:11][CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[N:14]=1.[CH3:18][C:19]1([CH2:22][CH2:23]OS(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:21][O:20]1>O.CN(C=O)C>[Cl:9][C:10]1[N:11]([CH2:23][CH2:22][C:19]2([CH3:18])[CH2:21][O:20]2)[CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[N:14]=1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: CC1(CCOS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(CCn2cc([N+](=O)[O-])nc2Cl)CO1
Temperature: 60 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
Potassium carbonate (1.16 g) and cesium fluoride (196 mg) were added to a DMF solution (20 ml) of 2-chloro-4-nitro-1H-imidazole (953 mg) and 4-nitrobenzene sulfonic acid 2-(2-methyloxiranyl)ethyl ester (1.856 g), and the mixture was stirred at 60° C. overnight. Thereafter the reaction mixture was cooled to room temperature. Water was added to the reaction solution, and the reaction mixture was then extracted repeatedly with ethyl acetate. The combined organic layer was washed with water and a saturated sodium chloride aqueous solution, and then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to afford the title compound as a yellow oil (1.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[N:11][CH:10]=2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:31][C:32]1[C:33](F)=[CH:34][C:35]([F:58])=[C:36]([S:38]([N:41]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=2[O:56][CH3:57])[C:42]2[S:43][CH:44]=[N:45][N:46]=2)(=[O:40])=[O:39])[CH:37]=1>CS(C)=O>[Cl:31][C:32]1[C:33]([O:8][C:6]2[C:5]([C:9]3[CH:14]=[CH:13][N:12]=[N:11][CH:10]=3)=[CH:4][C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:16]=3)=[C:2]([Cl:1])[CH:7]=2)=[CH:34][C:35]([F:58])=[C:36]([S:38]([N:41]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=2[O:56][CH3:57])[C:42]2[S:43][CH:44]=[N:45][N:46]=2)(=[O:39])=[O:40])[CH:37]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: Oc1cc(Cl)c(-c2cccc(C(F)(F)F)c2)cc1-c1ccnnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(Cl)c(-c4cccc(C(F)(F)F)c4)cc3-c3ccnnc3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
2-Chloro-5-(pyridazin-4-yl)-3′-(trifluoromethyl)biphenyl-4-ol (Preparation 52, 140 mg, 0.4 mmol) was dissolved in DMSO (1 mL) and potassium carbonate (110 mg, 0.8 mmol) was added followed by 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 16, 203 mg, 0.44 mmol). The reaction was stirred at room temperature for 18 hours and then partitioned between ethyl acetate (50 mL) and water (40 mL). The ethyl acetate was separated and dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica eluting with a gradient of heptane:ethyl acetate 80:20 to 20:80 to give the title compound (231 mg, 0.30 mmol, 73%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:10][CH:9]1[CH2:14][O:15][S:24]([CH3:23])(=[O:26])=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(O)CC1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)CC1COS(C)(=O)=O
Temperature: 25 °C

Procedure:
To a stirred solution of the diol (344) (12.7 g, 58.5 mmol) and triethylamine (5 equiv., 41 mL) in CH2Cl2 (200 mL) at 0° C. was added methanesulfonyl chloride (NsCl) (2.4 equiv., 10.9 mL). The resulting suspension was removed from the ice bath and allowed to warm to room temperature with stirring at which point TLC analysis indicated complete consumption of the starting material and conversion to a single spot of higher Rf (5% MeOH/CHCl3, stained with K2MnO4). The reaction was quenched by the addition of water (20 mL) with vigorous stirring. NaHCO3 (sat., aqueous, 200 mL) was added and the organic layer was separated, washed with brine, dried (MgSO4) and purified by flash chromatography (1–10% MeOH/CHCl3) to yield the desired compound (345) as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.CCN(CC)CC.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[NH4+].[Cl-].[Li+].[OH-].Cl>C(Cl)Cl>[C:22]1([S:28]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][CH2:4][C:3]([OH:2])=[O:14])=[CH:8][CH:9]=2)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)CCCc1ccc(N)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CCCc1ccc(NS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
To a solution of 40 (500 mg, 2.59 mmol) in CH2Cl2 at room temperature were added Et3N (901 μL, 6.48 mmol) followed by benzenesulfonyl chloride (661 μL, 5.18 mmol). The mixture was stirred overnight at room temperature then treated with a saturated aqueous solution of NH4Cl. The phases were separated and the organic layer was extracted several times with CH2Cl2. The combined organic extracts were dried over (MgSO4) then evaporated under reduced pressure. The residue was dissolved in a solvent mixture of THF (25 mL) and water (25 mL) then LiOH (1.08 g, 25.9 mmol) was added. The mixture was heated at 50° C. for 1 h then treated with HCl (1N) until pH2. The phases were separated and the aqueous layer was extracted several times with AcOEt. The combined organic extracts were dried over (MgSO4) then evaporated. The crude was purified by flash chromatography using CH2Cl2/MeOH (95:5) as solvent mixture yielding 41 (800 mg, 96%) as a white solid
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:6]2[N:5]=[CH:4][C:3]=1C(O)=O.NC1C=CC=CC=1.O.Cl>CO>[OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:6]2[N:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc2c(-c3ccc(Sc4ccccc4)cc3)cnn2c1O
Agent: Cl
Solvent: CO
Solvent: O
Solvent: Nc1ccccc1
Product: Oc1ccnc2c(-c3ccc(Sc4ccccc4)cc3)cnn12
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A mixture of 9.32 g of 7-hydroxy-6-carboxy-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine and 68 ml of aniline was heated and stirred at 80° C. for 1.5 hours to react. To the reaction mixture, 300 ml of water was added, and while ice-cooling, hydrochloric acid was added to adjust the pH to 1 to 2. Adding 100 ml of methanol, the mixture was stirred for 30 minutes while ice-cooling, and the precipitate was filtered, washed in cold water-methanol (3:1), and dried, and the title compound was obtained (8.17 g).
Reaction SMILES: [C:1]([CH2:3][O:4][NH:5][C:6]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]2[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:9]1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[Cl:37])=[O:7])#[N:2].[NH2:38][OH:39]>CO>[NH2:2][C:1](=[N:38][OH:39])[CH2:3][O:4][NH:5][C:6]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]2[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:9]1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[Cl:37])=[O:7]
Reactant: NO
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCC#N)C1c1ccc(Cl)cc1Cl
Solvent: CO
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCC(N)=NO)C1c1ccc(Cl)cc1Cl
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of 128 mg of (3RS,4RS)—N-(cyanomethoxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 1.92 ml of methanol was added 0.018 ml of a hydroxylamine solution at room temperature, followed by warming to 40° C. and stirring overnight. The reaction solution was cooled to room temperature and the precipitated crystal was then collected by filtration to obtain 26 mg of (3RS,4RS)—N-[2-amino-2-(hydroxyimino)ethoxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[CH2:17][C@H:16]3[NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:11][CH:10]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O1[CH2:37][CH2:36]OCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:16]1[N:18]=[CH:37][C:36]([C:9]2[CH:10]=[CH:11][C:12]([C@@H:15]3[CH2:17][C@H:16]3[NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])=[CH:13][CH:14]=2)=[CH:12][CH:15]=1
Reactant: C1COCCO1
Reactant: CC(C)S(=O)(=O)N[C@@H]1C[C@H]1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(-c2ccc([C@@H]3C[C@H]3NS(=O)(=O)C(C)C)cc2)cn1
Temperature: 90 °C
Reaction time: 3.5 h

Procedure:
In an 8 ml vial (PLS apparatus) the bromoaryl reagent (3-bromo-6-methylpyridine for Example 2) (0.328 mmol) was placed together with a solution of trans-N-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl}-2-propanesulfonamide (Intermediate 8) (60 mg, 0.164 mmol) in dry 1,4-dioxane (1.0 ml). Polymer supported Tetrakis catalyst (Pol-Pd(PPh3)4) (15 mg, 0.00164 mmol), and Na2CO3 2M (0.205 ml, 0.41 mmol) were added. The reaction mixture was shaken at 90° C. for 3-4 h (if reaction not complete by LC/MS analysis then heated for an additional 3 h) then left at room temperature overnight. The resin was filtered off (by Alltech filter tube) and washed with dichloromethane, water, methanol and dichloromethane. The liquid phase was evaporated until dryness under reduced pressure and the residue was taken up in dichloromethane (2 ml) and washed with HCl 1M (1 ml) then the acidic solution was basified with K2CO3 2M and extracted with dichloromethane (2×1 ml). The combined organic extracts were concentrated under reduced pressure to give a crude oil which was purified by reverse phase HPLC to give the title compound. The HPLC conditions were as given in “Preparative Chromatography” above.
Reaction SMILES: [CH3:1][Si:2]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17](C(O)=O)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)[CH2:4][CH2:3]1.Cl>ClCCl.O1CCOCC1>[CH3:1][Si:2]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH2:16][CH2:15]3)=[N:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: C[Si]1(c2ccccc2)CCN(c2ccc(N3CCN(C(=O)O)c4ccccc43)nc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[Si]1(c2ccccc2)CCN(c2ccc(N3CCNc4ccccc43)nc2)CC1
Reaction time: 16 h

Procedure:
0.43 g of tert-butyl ester of 4-[5-(4-methyl-4-phenyl-[1,4]azasilinan-1-yl)-pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid is put in 50 mL of dichloromethane and after cooling on an ice bath, 3.5 mL of a 4N solution of hydrochloric acid in dioxane is added. The reaction mixture is stirred for 16 h. After concentration, the mixture is taken up in dichloromethane, and neutralized by adding a saturated solution of sodium bicarbonate. After decanting, the aqueous phase is extracted with dichloromethane. The dichloromethane phases are combined and dried over sodium sulfate. After concentration under vacuum, 0.338 g of 1-[5-(4-methyl-4-phenyl[1,4]azasilinan-1-yl)-pyridin-2-yl]-1,2,3,4-tetrahydroquinoxaline is obtained.