Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])[CH:14]=3)=[CH:11][C:10]([NH2:27])=[N:9]2)=[CH:4][CH:3]=1.[O:28]=[C:29]1[NH:33][CH2:32][C@@H:31]([C:34](O)=[O:35])[CH2:30]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:24])([F:23])[F:25])[CH:14]=3)=[CH:11][C:10]([NH:27][C:34]([C@H:31]3[CH2:30][C:29](=[O:28])[NH:33][CH2:32]3)=[O:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](OCc1cccc(-c2cc(N)nn2-c2ccc(F)cc2)c1)C(F)(F)F
Reactant: O=C1C[C@H](C(=O)O)CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: C[C@@H](OCc1cccc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccc(F)cc2)c1)C(F)(F)F
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (52 mg) in N,N-dimethylacetamide (0.5 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (20 mg) prepared according to the same procedures as Preparation 5 and WSC.HCl (40 mg) at room temperature, and the mixture was stirred for 0.5 hours. To this reaction mixture was added water, and then the precipitated solid was collected by filtration. This solid was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected by filtration from this suspension, and dried under reduced pressure to give the titled compound (37 mg).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][S:11](Cl)(=[O:13])=[O:12].[OH:15][CH2:16][CH2:17][S:18][S:19][CH2:20][CH2:21][OH:22]>ClCCl>[CH3:10][S:11]([O:15][CH2:16][CH2:17][S:18][S:19][CH2:20][CH2:21][O:22][S:11]([CH3:10])(=[O:13])=[O:12])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: OCCSSCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCSSCCOS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
N,N-Diisopropylethylamine (4.35 ml) and 1.70 ml of methanesulfonyl chloride were added to a suspension of 1.22 ml of 2-hydroxyethyl disulfide in 30 ml of dichloromethane at −40° C. under an argon atmosphere. The mixture was stirred at that temperature for 30 min. The reaction solution was then diluted with dichloromethane, and the diluted solution was washed with an dilute aqueous hydrochloric acid solution, an aqueous sodium hydrogencarbonate solution, and water in that order, and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure to prepare 3.08 g of 2-methanesulfonyloxyethyl disulfide.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:6]=[CH:7][C:8]=1OC.[Br:20]C1C=CC(CC(O)=O)=CC=1>>[Br:20][C:8]1[CH:7]=[CH:6][C:5]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: COc1ccc(CC(=O)c2ccccc2)cc1OC
Product: O=C(Cc1ccc(Br)cc1)c1ccccc1

Procedure:
Prepared by the same two step synthesis described in the synthesis of Intermediate 7, starting from 2-(4-bromophenyl)acetic acid.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([CH2:26][Cl:27])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:6]=1[NH2:25].[N:28]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.Cl.O>[Cl:27][CH2:26][CH:3]([CH2:2][Cl:1])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[NH:25][N:28]=[C:11]2[S:12]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: O=N[O-]
Reactant: Nc1c(CS(=O)(=O)c2cccc3ccccc23)cccc1OC(CCl)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OC(CCl)CCl)cccc12
Temperature: 3 °C

Procedure:
A mixture of 2-(2-chloro-1-chloromethyl-ethoxy)-6-(naphthalene-1-sulfonylmethyl)-phenylamine (4) (2 g, 4.77 mmoles) in THF and 4M HCl (15 ml) was stirred, under nitrogen, at 3° C., treated dropwise with a solution of sodium nitrite (0.34 g, 5 mmoles) in H2O (2 ml). The reaction mixture was poured into a cold solution of saturated sodium bicarbonate and extracted with EtOAc. The extracts were combined, dried over Na2SO4 and concentrated under vacuum to afford the title compound as an off white solid (1.76 g, 4.05 mmoles), identified by HNMR analysis.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2]2.Br[C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:23][C:22]1[C:17]([N:8]2[CH:5]3[CH2:6][CH2:7][CH:1]2[CH2:2][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]3)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2
Reactant: Clc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ncccc1Cl
Temperature: 120 °C
Reaction time: 48 h

Procedure:
tert-Butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (454 mg, 2.36 mmol) and 2-bromo-3-chloropyridine (418 mg, 1.97 mmol) were combined in dry N,N-dimethylformamide (10 mL) and treated with potassium carbonate (408 mg, 2.95 mmol). After stirring at 120° C. for 48 hours, the mixture was allowed to cool to room temperature, diluted with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (4:1, hexanes:ethyl acetate) to provide the title compound. MS (ESI) m/z: 324 (M+H)+; 1H NMR (CDCl3) δ 1.47 (s, 9H), 1.77 (m, 2H), 1.93 (m, 2H), 3.22 (d, 1H), 3.31 (d, 1H), 3.76 (d, 1H), 3.90 (d, 1H), 4.53 (d, 2H), 6.76 (dd, 1H), 7.56 (dd, 1H), 8.09 (dd, 1H).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[F:23][C:24]([F:47])([F:46])[C@H:25]([CH3:45])[O:26][C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:44])[CH3:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1.Br[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[Cl:56]>>[Cl:56][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[CH2:49][N:34]1[N:33]=[C:31]2[N:32]=[C:27]([O:26][C@@H:25]([CH3:45])[C:24]([F:23])([F:46])[F:47])[N:28]=[C:29]([N:36]3[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:44])[CH3:43])[CH2:37]3)[C:30]2=[N:35]1
Reactant: CC(=O)N[C@H]1CCN(c2nc(O[C@@H](C)C(F)(F)F)nc3[nH]nnc23)C1
Reactant: Clc1ccccc1CBr
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: CC(=O)N[C@H]1CCN(c2nc(O[C@@H](C)C(F)(F)F)nc3nn(Cc4ccccc4Cl)nc23)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from N—{(S)-1-[5-((S)-2,2,2-Trifluoro-1-methyl-ethoxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-yl}-acetamide and 1-(bromomethyl)-2-chlorobenzene. MS (m/e): 484.4 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[C:44]([Si:48]([O:51][CH2:52][CH2:53][CH2:54]I)([CH3:50])[CH3:49])([CH3:47])([CH3:46])[CH3:45].C[SiH2]C>CN(C)C=O>[CH2:1]([O:8][C:9]([C:11]1([N:16]([CH2:54][CH2:53][CH2:52][O:51][Si:48]([C:44]([CH3:45])([CH3:47])[CH3:46])([CH3:49])[CH3:50])[S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCCC1
Reactant: CC(C)(C)[Si](C)(C)OCCCI
Agent: C[SiH2]C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCN(C1(C(=O)OCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.7 %

Procedure:
To a solution of 1-[4-(4-fluorophenoxy)benzenesulfonylamino]-cyclopentanecarboxylic acid benzyl ester (199 grams, 0.42 mole) in dry N,N-dimethylformamide (2.5 L) at room temperature was added potassium hexamethyldisilazide (100 grams, 0.50 mole) and, after 3 hours, tert-butyl-(3-iodopropoxy)dimethylsilane (150 grams, 0.50 mole). The resulting mixture was stirred at room temperature for 16 hours. Additional tert-butyl-3-iodopropoxy)-dimethylsilane (20 grams, 0.067 mole) was then added. Stirring at room temperature was continued for a further 3.5 hours. The mixture was quenched by addition of saturated ammonium chloride solution. The N,N-dimethylformamide was removed by evaporation under vacuum. The residue was taken up in diethyl ether and washed with water and brine. After drying over magnesium sulfate, the diethyl ether was evaporated to afford crude 1-{[3-(tert-butyl-dimethylsilanyloxy)-propyl]-[4-(4-fluorophenoxy)benzenesulfonyl]-amino}cyclopentanecarboxylic acid benzyl ester as an amber oil (279.6 grams).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C@@H:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:29])[CH2:15][O:16][C:17]3[C:18]([CH2:24][CH2:25][C:26](O)=[O:27])=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[C@H:9]([CH3:30])[CH2:8]2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C@@H:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:29])[CH2:15][O:16][C:17]3[C:18]([CH2:24][CH2:25][C:26]([NH:49][S:46]([CH3:45])(=[O:48])=[O:47])=[O:27])=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[C@H:9]([CH3:30])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(OCC(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)c(CCC(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(OCC(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)c(CCC(=O)NS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.6 %

Procedure:
To a solution of 3-(3-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-6-methyl-pyridin-2-yl)-propionic acid (0.10 g, 0.23 mmol) in methylene chloride (2 mL) was added 4-dimethylaminopyridine (0.032 g, 0.27 mmol), (3-(dimethylamino)propyl)ethyl carbodiimide hydrochloride (0.051 g, 0.27 mmol), methanesulfonamide (0.025 g, 0.27 mmol) and triethylamine (0.037 mL, 0.27 mmol). The reaction was stirred at ambient temperature for 18 hours. The reaction mixture was then diluted with dichloromethane and washed with 0.2 M hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel to give the title compound (0.051 g, LRMS: 521.5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11](=[O:16])[CH:10]=2)=[CH:5][CH:4]=1.C1C(=O)N([Br:24])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:24][C:10]1[C:11](=[O:16])[C:12]([CH3:14])([CH3:15])[O:13][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COc1ccc(C2=CC(=O)C(C)(C)O2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C2=C(Br)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
To a stirred solution of 5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (5.5 g, 0.025 mol) in CHCl3 (100 mL) was added NBS (6.733 g, 0.038 mol) portion wise at RT. The reaction mixture was stirred for 2 h at RT. The reaction mixture was diluted with DCM (100 mL), washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered and then concentrated in vacuo to obtain the crude product. The crude material was purified via by flash column chromatography using 25% ethyl acetate in hexane and silica gel (230-400 Mesh) to afford 4-bromo-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (4.6 g, 65%) as a solid.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([OH:11])[CH:10]=1)[CH:6]=[CH2:7].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]1[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)[CH:10]=1)[CH:6]=[CH2:7]
Reactant: C=Cc1cc(O)cc(O)c1
Reactant: C1=COCCC1
Agent: Cl
Product: C=Cc1cc(OC2CCCCO2)cc(OC2CCCCO2)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
0.5 ml of concentrated hydrochloric acid is added to 80 g (587 mmol) of 3,5-dihydroxystyrene in 300 g of dihydropyran and the reaction mixture is stirred for 2 h at 40° C. The mixture is then poured into ice-water and extracted twice with ether. The organic phase is washed three times at 0° C. with 1N NaOH, dried, and concentrated by evaporation. The residue is purified by column chromatography (silica gel, hexane/ethyl acetate 4:1), giving 110 g (62%) of a viscous liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10][C:9]2=[O:16])=[CH:4][C:3]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1.[Br:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[CH2:30]Br>>[Br:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[CH2:30][N:10]1[C:11]([CH3:15])([CH3:14])[C:12](=[O:13])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:4]=2)[C:9]1=[O:16]
Reactant: CC1(C)NC(=O)N(c2ccc(F)c(-c3cccs3)c2)C1=O
Reactant: Fc1ccc(CBr)c(Br)c1
Product: CC1(C)C(=O)N(c2ccc(F)c(-c3cccs3)c2)C(=O)N1Cc1ccc(F)cc1Br

Procedure:
Under conditions as described for the preparation of 1.2, compound 267.2 was reacted with 2-bromo-1-bromomethyl-4-fluorobenzene and afforded 267.1. Molecular weight 490.01 (C22H17BrF2N2O2S); retention time Rt=3.05 min. [E]; MS (ESI): 493.08 (MH+)
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:1]([O:16][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][C:10]([NH2:9])=[N:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(C(=O)OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.5 %

Procedure:
Benzyl bromide (0.86 ml, 7.9 mmol) was added to a mixture of 6-aminonicotinic acid (1.0 g, 7.2 mmol) and potassium carbonate (1.5 g, 10.8 mmol) in DMF (4 mL). The mixture was stirred at room temperature for 16 hr and diluted with water (50 mL). The aqueous mixture was extracted with ethyl acetate (1×). The EtOAc layer was washed with brine, dried over MgSO4 and concentrated to provide crude solid product. Recrystallization from diethyl ether provided the title compound as a pale yellow solid (0.88 g, 53%).
Reaction SMILES: COS([O-])(=O)=O.[N:7]1([C:12]2[CH:13]=[C:14]3[C:20]([CH2:21][N+](C)(C)C)=[CH:19][NH:18][C:15]3=[CH:16][N:17]=2)[CH:11]=[N:10][CH:9]=[N:8]1.[C-:26]#[N:27].[K+]>O>[N:7]1([C:12]2[CH:13]=[C:14]3[C:20]([CH2:21][C:26]#[N:27])=[CH:19][NH:18][C:15]3=[CH:16][N:17]=2)[CH:11]=[N:10][CH:9]=[N:8]1
Reactant: C[N+](C)(C)Cc1c[nH]c2cnc(-n3cncn3)cc12
Reactant: [C-]#N
Agent: COS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: N#CCc1c[nH]c2cnc(-n3cncn3)cc12
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 63.9 %

Procedure:
To a solution of N-([5-(1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]methyl-N,N,N-trimethylammonium methylsulphate (0.56 g, 1.5 mmol) in water (4ml) was added a solution of potassium cyanide (0.239 g, 3.7 mmol) in water (2ml). This mixture was heated at 70° C. for 1 h. Further potassium cyanide (80mg, 1.2 mmol) was added and the mixture heated for another hour at 70° C. Further potassium cyanide (80mg, 1.2 mmol) was added and the mixture heated at 70° C. for 1 hour and then at 100° C. for 20 min. The mixture was then cooled in ice for 30 min. The precipitate was collected by filtration and washed with water. The solid was chromatographed on silica eluting with 5% MeOH in DCM to afford the title compound (0.215 g, 63%) as a colourless solid; mp 218°-220° C. 1H NMR (250 MHz, d6 -DMSO) δ 4.19 (2H, s), 7.78 (1H, s), 8.12 (1H, s), 8.26 (1H, s), 8.71 (1H, s), 9.29 (1H, s), 11.93 (1H, br s).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH:10]1[C:19]2[CH:18]=[C:17]([C:20]([O:22]C)=[O:21])[CH:16]=[CH:15][C:14]=2[CH2:13][CH2:12][CH2:11]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].C(NCC1(C(O)=O)C=CC2CCCCC=2C1)(OC(C)(C)C)=O>C(O)C.O>[C:1]([NH:8][CH2:9][CH:10]1[C:19]2[CH:18]=[C:17]([C:20]([OH:22])=[O:21])[CH:16]=[CH:15][C:14]=2[CH2:13][CH2:12][CH2:11]1)([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: COC(=O)c1ccc2c(c1)C(CNC(=O)OC(C)(C)C)CCC2
Agent: CC(C)(C)OC(=O)NCC1(C(=O)O)C=CC2=C(CCCC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC1CCCc2ccc(C(=O)O)cc21

Procedure:
Part E--To a solution of methyl N-(BOC)-8-aminomethyl-5,6,7,8-tetrahydro-2-naphthoate (0.50 g, 0.0016 mol) in ethanol (12.5 mL) was added, dropwise, a solution of sodium hydroxide (0.50 g) in water (12.5 mL). All was stirred a reflux over 4 hours. The reaction mixture was concentrated to half volume and then acidified to a pH equal to 1.0 using hydrochloric acid (1N). The residue was purified by flash chromatography using a gradient of hexane:ethyl acetate::1:1 to ethyl acetate to ethyl acetate: methanol::9:1 to give the racemic mixture of the title compound, N-(BOC)-2-aminomethyl-5,6,7,8-tetrahydro-2-naphthoic acid (0.19 g, 0.00062 mol, 39%) as a white solid. mp=172-176° C.; 1H NMR (DMSO) d 7.8 (s, 1H), 7.65 (d, 1H, J=8.1 Hz), 7.15 (d, 1H, J=8.1 Hz), 7.1-7.0 (m, 1H), 3.2-3.1 (m, 2H), 3.0-2.7 (m, 4H), 1.8-1.6 (m, 4H), 1.4 (s, 9H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=23)[S:5]1(=[O:17])=[O:16].C(N(CC)CC)C.[F:25][C:26]1[CH:39]=[CH:38][C:29]([C:30]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:31])=[CH:28][CH:27]=1.[I-].[Na+]>CN(C)C=O>[F:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([CH:32]2[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[C:12]5[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=45)[S:5]3(=[O:17])=[O:16])[CH2:34][CH2:33]2)=[O:31])=[CH:38][CH:39]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)C1CCN(CCN2c3cccc4cccc(c34)S2(=O)=O)CC1
Temperature: 20 °C
Yield: 26.4 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (6.7 g), triethylamine (3.5 cc), 4-(4-fluorobenzoyl)piperidine (5.2 g) and sodium iodide (3.7 g) in dimethylformamide (100 cc). The mixture is heated for 6 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under current of argon at medium pressure (0.5-1.5 bar) with dichloromethane as eluant, and recrystallization from boiling acetonitrile (8 cc), 2-{2-[4-(4-fluorobenzoyl)piperidino}ethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.9 g) is obtained, m.p. 145° C.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:25][CH:24]=2)[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>C1COCC1>[C:32]([O:31][C:29]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][O:21][CH:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[C:17]([O:19][CH3:20])=[O:18])=[CH:28][CH:27]=1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)C(Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)OCc1ccc(C(=O)OC(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C(Cc1ccc(O)cc1)OCc1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 0.25 h
Yield: 108.6 %

Procedure:
A solution of methyl 3-(4-tert-butyldimethylsilyloxyphenyl)-2-[(4-tert-butoxycarbonylphenyl)methoxy]propionate (310 mg, 0.61 mmol) in THF (5 ml) at −20° C. was treated with tetrabutylammonium fluoride-acetic acid (1.0M in THF, 0.76 ml, 0.76 mmol). The mixture was stirred at this temperature for 15 minutes, quenched with saturated aqueous sodium bicarbonate and extracted with diethyl ether. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the title material (256 mg, 100%) as a pale yellow oil.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][Cl:22])=[N:19][C:18]([C:23](O)=[O:24])=[N:17]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:39]([CH2:41][NH2:42])[OH:40]>O1CCCC1>[C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][Cl:22])=[N:19][C:18]([C:23]([NH:42][CH2:41][CH2:39][OH:40])=[O:24])=[N:17]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Reactant: NCCO
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCO)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Reaction time: 0.08 h

Procedure:
To a stirred solution of 3.76 parts of 1-(2-benzoyl-4-chlorophenyl)-5-chloromethyl-1H-1,2,4-triazole-3-carboxylic acid and 1.4 volume part of triethylamine in 60 volume parts of dry tetrahydrofuran, 1.0 volume part of ethyl chlorocarbonate is added dropwise under cooling with ice-salt. After 5 minutes, a solution of 1.2 volume part of ethanolamine in 10 volume parts of dry tetrahydrofuran is added dropwise to the mixture. After evaporation of the solvent below 40°C under reduced pressure, the residue is diluted with water. This procedure yields 1-(2-benzoyl-4-chlorophenyl)-5-chloromethyl-N-(2-hydroxyethyl)-1H-1,2,4-triazole-3-carboxamide as crystals. Recrystallization from ethanol gives colorless prisms melting at 170°-171°C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.CC1C=CC(S(O[CH2:28][P:29]([O:34][CH2:35][CH3:36])([O:31][CH2:32][CH3:33])=[O:30])(=O)=O)=CC=1>>[CH2:32]([O:31][P:29]([CH2:28][O:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)(=[O:30])[O:34][CH2:35][CH3:36])[CH3:33]
Reactant: CCOP(=O)(COS(=O)(=O)c1ccc(C)cc1)OCC
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Product: CCOP(=O)(COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)OCC
Yield: 23 %

Procedure:
Using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (313 mg, 1.42 mmol) and (diethoxyphosphoryl)methyl 4-methylbenzenesulfonate (550 mg, 1.71 mmol), the desired title compound (121 mg, yield 23%) was obtained by the same method as in Reference Example 2 (2a).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:13][N:12]=[C:11]([NH:27][C@H:28]3[CH2:33][CH2:32][C@@H:31]([CH3:34])[CH2:30][CH2:29]3)[N:10]=2)[CH2:3][CH2:2]1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[CH3:35][S:36]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:13][N:12]=[C:11]([NH:27][C@H:28]3[CH2:29][CH2:30][C@@H:31]([CH3:34])[CH2:32][CH2:33]3)[N:10]=2)[CH2:5][CH2:6]1)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1CC[C@@H](Nc2ncc(-c3ccc(N4CCOCC4)cc3)c(OCC3CCNCC3)n2)CC1
Product: CS(=O)(=O)N1CCC(COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2-c2ccc(N3CCOCC3)cc2)CC1

Procedure:
Using the procedure of Example 1 Step 5, 4-((piperidin-4-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-amine was reacted with methanesulfonyl chloride to provide the title compound at 86% yield. 1H NMR (CDCl3, 400 MHz) 8.07 (s, 1H), 7.36 (d, 2H), 6.93 (d, 2 h), 5.20 (s, 1H), 4.23 (d, 2H), 4.07 (m, 1H), 3.89-3.83 (m, 6H), 3.21-3.18 (m, 4H), 2.76 (s, 3H), 2.67 (m, 2H), 1.90-1.24 (m, 14H), 0.94 (d, 3H); MS (ESI) m/z: Calc: 543.3 (M+). Found. 544.3 (M+1).
Reaction SMILES: [CH2:1]([S:5][S:6]Cl)[CH2:2][CH2:3][CH3:4].[CH3:8][NH:9][C:10]([F:12])=[O:11]>>[CH3:8][N:9]([S:6][S:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:10]([F:12])=[O:11]
Reactant: CCCCSSCl
Reactant: CNC(=O)F
Product: CCCCSSN(C)C(=O)F

Procedure:
Prepared by the procedure of Example II by reacting n-butylthiosulfenyl chloride with methylcarbamoyl fluoride b.p. 68°-70° C/0.15 Torr