Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]([C:25]#[N:26])([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[CH2:13][CH2:12]1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])([C:25]#[N:26])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NCCCN1CCC(C#N)(c2ccc(Cl)cc2Cl)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1(c2ccc(Cl)cc2Cl)CCN(CCCN)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To 3-[4-cyano-4-(2,4-dichlorophenyl)-piperidin-1-yl]-propyl-carbamic acid tert-butyl ester (0.589, 1.42 mmol) in dichloromethane (5 mL), trifluoroacetic acid (1 mL) is was added and the solution stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10% KOH solution and extracted into 25 mL of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.423 g (93%) of 1-(3-aminopropyl)-4-(2,4-dichlorophenyl)-piperidine-4-carbonitrile which was used as such for the subsequent step.
Reaction SMILES: C(F)(OC(F)(F)C(F)(F)C(F)(F)F)=C(F)F.[C:17]([O:27][CH:28]([C:30]([O:32]C)=[O:31])[F:29])([C:20]([C:23]([F:26])([F:25])[F:24])([F:22])[F:21])([F:19])[F:18].[NH3:34]>>[C:17]([O:27][CH:28]([C:30]([O-:32])=[O:31])[F:29])([C:20]([C:23]([F:24])([F:25])[F:26])([F:22])[F:21])([F:19])[F:18].[NH4+:34]
Reactant: COC(=O)C(F)OC(F)(F)C(F)(F)C(F)(F)F
Reactant: N
Agent: FC(F)=C(F)OC(F)(F)C(F)(F)C(F)(F)F
Product: O=C([O-])C(F)OC(F)(F)C(F)(F)C(F)(F)F
Product: [NH4+]

Procedure:
The calculated yield was 59% based on total PPVE used; 70% based on converted PPVE. The ester is converted to the ammonium salt by reaction with aqueous ammonia. Methanol is removed by fractionated distillation. The resulting aqueous solution is used as an emulsifier in the polymerization of fluorinated olefins.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Cl[C:25]1[N:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[N:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)nn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. ESI-MS (m/z): 461 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9](=[O:10])[CH2:8][CH2:7][C@@H:6]1[C:11]([NH:13][CH:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:15]([OH:19])[C:16](O)=[O:17])=[O:12].[CH3:31][O:32][NH2:33]>>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9](=[O:10])[CH2:8][CH2:7][C@@H:6]1[C:11]([NH:13][CH:14]([CH:15]([OH:19])[C:16]([NH:33][O:32][CH3:31])=[O:17])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:12]
Reactant: CON
Reactant: O=C(O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1F
Product: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1F

Procedure:
The reaction can be carried out in analogy to reaction step 20.3 by reacting 3-((R)-1-(2-fluorobenzyl)-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenylbutanoic acid with O-methylhydroxylamine.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].Cl[CH:14]([OH:16])[CH3:15]>CO>[OH:16][CH2:14][CH2:15][S:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(S)cc1
Reactant: CC(O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(SCCO)cc1
Yield: 62566.4 %

Procedure:
To a stirred solution of 4-mercapto benzoic acid (10 g, 0.0645 mmol) in methanol (100 mL) was added KOH (10.8 g, 0.1935 mol) at 25-30° C. Chloroethanol (10.3 g, 0.1290 mol) was then added to it. Reaction mixture was refluxed for 4 hr. Excess methanol was evaporated and then quenched in dil.HCl. Product obtained was filtered. Drying afforded 8 g of titled compound in 62% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:50]([CH3:51])=[CH:49][C:39]([O:40][CH2:41][CH2:42][N:43]2[CH2:47][CH2:46][CH2:45][C:44]2=[O:48])=[CH:38][C:37]=1[CH3:52]>>[CH3:52][C:37]1[CH:38]=[C:39]([O:40][CH2:41][CH2:42][N:43]2[CH2:47][CH2:46][CH2:45][C:44]2=[O:48])[CH:49]=[C:50]([CH3:51])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: Cc1cc(OCCN2CCCC2=O)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCCN6CCCC6=O)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 1-(2-(4-bromo-3,5-dimethylphenoxy)ethyl)pyrrolidin-2-one following a procedure analogous to that described in Step 5 of Intermediate 1. The product is purified by HPLC on reversed phase. LC (method 8): tR=0.68 min; Mass spectrum (ESI+): m/z=574 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.Cl[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH2:23][CH:24]2[CH2:26][CH2:25]2)=[C:16]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:15]=1.[CH3:33][NH:34][C:35]1[N:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1>C(OCC)(=O)C.O>[CH:24]1([CH2:23][N:20]2[CH:19]=[N:18][C:17]3[C:21]2=[N:22][C:14]([C:38]2[CH:37]=[N:36][C:35]([NH:34][CH3:33])=[N:40][CH:39]=2)=[N:15][C:16]=3[N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH2:26][CH2:25]1
Reactant: Clc1nc(N2CCOCC2)c2ncn(CC3CC3)c2n1
Reactant: CNc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1ncc(-c2nc(N3CCOCC3)c3ncn(CC4CC4)c3n2)cn1
Yield: 60.6 %

Procedure:
Sodium carbonate (2.40 g, 22.7 mmol) and tetrakis triphenylphosphine palladium (0.44 g, 0.38 mmol) were added to a 1,4-dioxane (44.0 ml)-water (22.0 ml) mixture solution of 2-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purine (2.22 g, 7.56 mmol) and 2-methylaminopyrimidine-5-boronic acid pinacol ester (2.31 g, 9.82 mmol) at room temperature and the resulting mixture was heated to reflux for 3.5 hours in an argon atmosphere. The reaction mixture was left standing to cool and then poured into water and ethyl acetate was added to separate the layers. The solid precipitated in the aqueous layer was collected by filtration, washed with water, and then dried at 50° C. under reduced pressure. Meanwhile, the organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, then the filtrate was concentrated under reduced pressure, and the resulting solid was washed with dichloromethane and collected by filtration. These solids were combined to give the title compound (1.68 g, 61%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[N:14][O:15][CH2:16][CH2:17][OH:18])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:20]1[CH:52]=[CH:51][C:23]([CH2:24][CH:25]2[S:29][C:28](=[O:30])[N:27]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]2=[O:50])=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[N:14][O:15][CH2:16][CH2:17][O:18][C:20]3[CH:52]=[CH:51][C:23]([CH2:24][CH:25]4[S:29][C:28](=[O:30])[N:27]([C:31]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:26]4=[O:50])=[CH:22][CH:21]=3)=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCON=Cc1ccc(-c2ccccc2)nc1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1SC(Cc2ccc(OCCON=Cc3ccc(-c4ccccc4)nc3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 78.6 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 390 mg of 2-(2-phenyl-5-pyridylmethyleneaminooxy)ethanol (prepared as described in Preparation 10), 576 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 422 mg of triphenylphosphine and 280 mg of diethyl azodicarboxylate, 671 mg of the title compound were obtained as a crystalline powder, melting at 146-148° C.
Reaction SMILES: CC([N:5]([CH2:9][C@@H:10]([NH:18][C:19]([C:21]1[S:22][C:23]([Cl:32])=[C:24]([C:26]2[N:30]([CH3:31])[N:29]=[N:28][CH:27]=2)[CH:25]=1)=[O:20])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)C(=O)[O-])(C)C.C1C(=O)N([Br:40])C(=O)C1>CN(C=O)C>[NH2:5][CH2:9][C@@H:10]([NH:18][C:19]([C:21]1[S:22][C:23]([Cl:32])=[C:24]([C:26]2[N:30]([CH3:31])[N:29]=[N:28][C:27]=2[Br:40])[CH:25]=1)=[O:20])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cn1nncc1-c1cc(C(=O)N[C@@H](CC2CCCCC2)CN(C(=O)[O-])C(C)(C)C)sc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cn1nnc(Br)c1-c1cc(C(=O)N[C@H](CN)CC2CCCCC2)sc1Cl
Yield: 10.6 %

Procedure:
A solution of 1,1-dimethylethyl[(2S)-2-({[5-chloro-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-cyclohexylpropyl]carbamate (140 mg, 0.29 mmol, prepared in Example 280) and NBS (103 mg, 0.58 mmol) in 2 mL of DMF was heated at 100° C. for 2 hours. The reaction mixture was purified by reverse phase HPLC (5-65% acetonitrile in H2O with 1% TFA) to give the title compound 14.1 mg (8%) as a white solid. LCMS (ES) m/z 462.0 (M+H)+, 1H NMR (400 MHz, METHANOL-d4) ppm 7.75 (s, 1H), 4.43 (m, 1H), 4.05 (s, 3H), 3.17 (m 1H), 3.05 (m, 1H), 2.00-0.90 (m, 13H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][N:8]([C:17](=[O:25])[C:18]3[CH:23]=[CH:22][C:21](N)=[CH:20][CH:19]=3)[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1.C([N:28](CC)CC)C.[CH3:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][N:8]([C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:41]3[CH:40]=[CH:39][C:35]([C:36]([NH2:28])=[O:37])=[C:34]([CH3:33])[CH:42]=3)=[O:25])[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1
Reactant: CCN(CC)CC
Reactant: Cc1ncc2c(n1)-c1ccccc1N(C(=O)c1ccc(N)cc1)CC2
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Product: Cc1ncc2c(n1)-c1ccccc1N(C(=O)c1ccccc1-c1ccc(C(N)=O)c(C)c1)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 0.216 mg of 6,7-dihydro-2-methyl-7-(4-aminobenzoyl)-5H-pyrimido[5,4-d][1]benzazepine in 6 ml of methylene chloride under argon is added 100 μl of triethylamine followed by a solution of 94 μl of 2-methylbenzoyl chloride in 1.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours, washed with water, saturated NaHCO3 and the separated organic layer treated with activated carbon and filtered through MgSO4. The filtrate is evaporated to a residue which is dissolved in ethyl acetate and evaporated in vacuo to give 300 mg of the desired product as a pale yellow foam. HR FABMS: Exact Mass (M+H):449.1974.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[P:18]([NH:26][NH2:27])(=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>C(Cl)Cl>[CH:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[N:27][NH:26][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOP(=O)(NN)OCC
Reactant: O=C1CCC(C2CCCCC2)CC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOP(=O)(NN=C1CCC(C2CCCCC2)CC1)OCC
Temperature: 25 °C
Reaction time: 27 h

Procedure:
To a solution of 4-cyclohexylcyclohexanone (27.04 g) and acetic acid (3 ml) in CH2Cl2 (400 ml) was added a solution of diethyl phosphorohydrazidate (28.91 g) in CH2Cl2 (100 ml). The reaction was stirred at room temperature for 27 hours and then was concentrated under reduced pressure. Toluene was added (2×) and removed under reduced pressure in order to aid in the removal of acetic acid by co-distillation. The residual yellow liquid was the product and was used without further purification. TLC Rf=0.52 (20% acetone in CH2Cl2, silica gel).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:18]=[C:17]([NH2:19])[CH:16]=[C:6]([C:7]([N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.CCN(CC)CC.[Cl:28][CH2:29][CH2:30][CH2:31][C:32](Cl)=[O:33]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:18]=[C:17]([NH:19][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][Cl:28])[CH:16]=[C:6]([C:7]([N:9]([CH2:10][CH2:11][CH3:12])[CH2:13][CH2:14][CH3:15])=[O:8])[CH:5]=1
Reactant: O=C(Cl)CCCCl
Reactant: CCCN(CCC)C(=O)c1cc(N)cc(C(=O)OC)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)c1cc(NC(=O)CCCCl)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.3 %

Procedure:
A solution of 5-amino-N,N-dipropyl-isophthalamic acid methyl ester (D88) (1.2 g, 4.3 mmol, 1 equiv) in CH2Cl2 (10 ml) was treated with NEt3 (525 mg, 5.2 mmol, 1.2 equiv). The solution was cooled to 0° C. and 4-chlorobutyryl chloride (733 mg, 5.0 mmol, 1.2 equiv) was added dropwise. The reaction mixture was then allowed to warm to room temperature and stirred for 1 h. The solution was washed with 2N aqueous HCl solution (20 ml), dried over MgSO4 and concentrated in vacuo to give 5-(4-chloro-butanoylamino)-N,N-dipropyl-isophthalamic acid methyl ester (D89) (1.7 g, 104%) as a colourless oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([CH2:11]O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1C=CC(P([N:27]=[N+:28]=[N-:29])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.Cl.C(OCC)(=O)C>[N:27]([CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:1]2)=[N+:28]=[N-:29]
Reactant: OCc1cccc2ncccc12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCc1cccc2ncccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.3 %

Procedure:
To a solution of quinolin-5-yl-methanol (96 mg, 0.60 mmol) and DPPA (202 μL, 0.91 mmol) in toluene (2 mL) was added DBU (166 μL, 1.09 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with 3M HCl (1.7 mL) and ethyl acetate (5 mL). The organic phase was separated and the aqueous phase was re-extracted with ethyl acetate (×2). The combined organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 49 mg of 5-azidomethyl-quinoline as light brown oil (44%).
Reaction SMILES: [OH:1][C:2]([CH2:7][F:8])([CH3:6])[C:3](O)=[O:4].S(Cl)(Cl)=O.[C:13]1([S:19]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:18]=[CH:17]C=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+].C.CC([N:38](C)C)=O>>[N:38]1[CH:17]=[CH:18][C:13]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([NH:26][C:3](=[O:4])[C:2]([OH:1])([CH3:6])[CH2:7][F:8])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:14][CH:15]=1
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Reactant: CC(=O)N(C)C
Reactant: CC(O)(CF)C(=O)O
Agent: C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CC(O)(CF)C(=O)Nc1ccc(S(=O)(=O)c2ccncc2)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 2-hydroxy-2-fluoromethylpropionic acid (0.53 g, 4.33 mmol) in dry dimethylacetamide (12 ml) was stirred under a nitrogen atmosphere at -10° C. Thionyl chloride (0.52 g, 4.33 mmol) was added and the resulting mixture was allowed to stir at -10° C. for 1 hour. 4-Phenylsulfonylaniline (0.68 g, 2.89 mmol) was then added and the reaction mixture was stirred at -10° C. for a further 15 mins. The solution was then allowed to warm to room temperature where it was stirred overnight. The reaction mixture was poured onto water and the pH adjusted to pH 8.0 with sodium bicarbonate solution. The aqueous solution was extracted with ethyl acetate, and the combined ethyl acetate portions were washed with water, and brine. After drying (Na2SO4) the ethyl acetate was removed by evaporation to give a yellow-orange solid. The solid was washed with ether/methylene chloride to yield the title tertiary carbinol (0.32 g, 32%) as a pale yellow solid; mp=209°-211° C. 1H-NMR (300 MHz, d6 -DMSO): 1.31 (s, 3H, CH3), 4.38 (dd, J=72 and 9.4 Hz, 1H, CH2F), 4.58 (dd, J=72 and 9.3 Hz, 1H, CH2F), 6.31 (s, 1H, OH), 7.87 (d, J=6 Hz, 2H, PyH), 7.96 (d, J=8.9 Hz, 2H, PhH), 8.06 (d, J=8.9 Hz, 2H, PhH), 8.86 (d, J=6 Hz, 2H, PyH), 10.22 (s, 1H, NH). MS (CI, CH4): 339(M+1, 100).
Reaction SMILES: CS[CH2:3][C@@H:4](C(O)=O)[NH:5][C:6](=O)[CH3:7].C(N)C.[CH2:15]([S:17][CH2:18][C@@H:19]([C:24]([OH:26])=O)[NH:20][C:21](=[O:23])[CH3:22])[CH3:16].N1CCCC1>>[C:21]([NH:20][C@H:19]([C:24]([N:5]1[CH2:4][CH2:3][CH2:7][CH2:6]1)=[O:26])[CH2:18][S:17][CH2:15][CH3:16])(=[O:23])[CH3:22]
Reactant: CCSC[C@H](NC(C)=O)C(=O)O
Reactant: CSC[C@H](NC(C)=O)C(=O)O
Agent: CCN
Solvent: C1CCNC1
Product: CCSC[C@H](NC(C)=O)C(=O)N1CCCC1

Procedure:
N-(N-Acetyl-S-ethyl-L-cysteinyl)pyrrolidine was synthesized in exactly the same manner as described in Example 14 except that the S-methyl-N-acetyl-L-cysteine and aqueous 70% ethylamine solution used in that example were replaced by S-ethyl-N-acetyl-L-cysteine and pyrrolidine, respectively.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11](Cl)[CH3:12].[SH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=1[O-:21].[Na]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=1[O-:21])[CH3:12]
Reactant: CC(Cl)c1ccc2ccccc2c1
Reactant: [O-][n+]1ccccc1S
Agent: [Na]
Product: CC(Sc1cccc[n+]1[O-])c1ccc2ccccc2c1

Procedure:
The intermediate 2-(1-[2-naphthyl]ethylthio)-pyridine N-oxide is prepared from 1-(2-naphthyl)ethyl chloride and 2mercapto pyridine N-oxide, sodium salt by the procedure described in Example 2. Melting point 112° - 115°C. Structure confirmed by IR and NMR.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:21])[N:7]=[C:8]([NH:10]C(OCC2C=CC=CC=2)=O)[CH:9]=1)=[O:4]>[Pd].CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:21])[N:7]=[C:8]([NH2:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(NC(=O)OCc2ccccc2)nn1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)nn1C
Reaction time: 3 h
Yield: 101.8 %

Procedure:
5-Benzyloxycarbonylamino-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (643, 2.2 g, 7.6 mmol) was combined with methanol (50 mL) and 10% palladium on carbon (500 mg). The mixture was stirred under an atmosphere of hydrogen for three hours. The mixture was filtered through Celite and the solvent was removed under reduced pressure to give the desired compound (644, 1.2 g, 98%). (ESI) [M+H+]+=156.1.
Reaction SMILES: CO.[CH3:3][N:4]([CH:6]=O)C.C([O-])([O-])=O.[K+].[K+].Cl[CH2:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C:20]2[N:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[N:25]=[CH:26][C:19]1=2)=[O:17]>C1COCC1.CCOC(C)=O>[F:33][C:30]1[CH:31]=[CH:32][C:27]([N:24]2[C:20]3[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][N:25]4[C:3]5=[N:4][CH:6]=[CH:23][CH:22]=[C:21]5[CH:20]=[N:24]4)[C:19]=3[CH:26]=[N:25]2)=[CH:28][CH:29]=1
Reactant: CN(C)C=O
Reactant: O=C(CCl)N1CCCc2c1cnn2-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Cn1ncc2cccnc21)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 75 °C
Yield: 43 %

Procedure:
The carbinol obtained above (69 mg, 0.4 mmol) was diluted in 1.2 mL of THF and 500 μL of DMF and treated with K2CO3 (111 mg, 0.8 mmol) and 2-chloro-1-(1-(4-fluorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-b]pyridin-4(5H)-yl)ethanone (118 mg, 0.4 mmol). The slurry was heated to 75° C. The reaction slurry was diluted with EtOAc and washed with brine, dried on MgSO4, filtered, and concentrated. The residue was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to provide 69 mg of the desired product (43%) as a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.37 (s, 0.8H), 7.63 (s, 0.2H), 7.42-7.46 (m, 2H), 7.13-7.19 (m, 2H), 5.14 (s, 0.4H), 5.03 (s, 1.6H), 3.90 (m, 0.4H), 3.87 (m, 1.6H), 2.86 (m, 2H), 2.28 (s, 2.4H), 2.25 (s, 0.6H), 2.05-2.13 (m, 2H), 1.62 (s, 6H); MS: (ES) m/z calculated for C21H24ClFN5O2 [M+H]+ 432.2, found 432.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:23])[C:11]([OH:22])([CH3:21])[CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:5][C:4]=1[C:24]([F:27])([F:26])[F:25])#[N:2].C(=O)([O-])[O-:29].[K+].[K+].OO.[OH2:36]>C(#N)C.CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:23])[C:11]([OH:22])([CH3:21])[CH2:12][S:13]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)(=[O:29])=[O:36])=[CH:5][C:4]=1[C:24]([F:27])([F:26])[F:25])#[N:2]
Reactant: CC(O)(CSc1ccc(F)cc1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Reactant: O
Agent: OO
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: CC(O)(CS(=O)(=O)c1ccc(F)cc1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
To a solution of 2 g (2.51 mmol) of N-[4-cyano-3-trifluoromethyl-phenyl]-3-[4-fluorophenyl-thio]-2-hydroxy-2-methyl-propionamide in 10 ml of acetonitrile, 20 ml of methanol and 0.6 ml of water 0.38 g (2.75 mmol) of potassium carbonate was added. The mixture was cooled to 5° C. and 10 ml of 30% aqueous hydrogen peroxide solution was added dropwise. The mixture was stirred at 25° C. overnight, then diluted with 100 ml of water and extracted twice with 100 ml of dichloromethane. The organic layer was washed with 50 ml of brine, dried over sodium sulfate and concentrated under diminished pressure. The residue was recrystallized from a 1:4 mixture of ethyl acetate/petroleum ether, which has a boiling range of 40–70° C. The yield was 1.53 g (70.83%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]=[C:8]([C:13]3[CH:14]=[C:15]([S:23]([N:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]4)(=[O:25])=[O:24])[CH:16]=[CH:17][C:18]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:7][C:6]=2[C:5]2=[CH:34][N:35](CC3C=CC(OC)=CC=3)[N:36]=[C:4]2[N:3]=1.C(O)(C(F)(F)F)=[O:47]>>[OH:47][C:2]1[C:11]2[C:10](=[O:12])[N:9]=[C:8]([C:13]3[CH:14]=[C:15]([S:23]([N:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]4)(=[O:24])=[O:25])[CH:16]=[CH:17][C:18]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:7][C:6]=2[C:5]2=[CH:34][NH:35][N:36]=[C:4]2[N:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CCCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc(=O)c2c(Cl)nc3nn(Cc4ccc(OC)cc4)cc3c2[nH]1
Product: CCCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc(=O)c2c(O)nc3n[nH]cc3c2[nH]1
Temperature: 25 °C

Procedure:
A solution of 1-[[3-[5-Chloro-4,8-dihydro-8-[(4-methoxyphenyl)methyl]-4-oxo-1H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-yl]-4-propoxyphenyl]sulfonyl]-4-ethylpiperazine (20 mg) in TFA (8 mL) was heated at 70° C. under nitrogen for 2 h. After cooling to rt, the mixture was subjected to preparative HPLC to give the titled compound (15 mg). LC:2.65′ (Gradient 1); MH+: 514.