Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:6]=[CH:5][CH:4]=1.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:35]=[N+:36]=[N-:37].[Na+]>CN(C=O)C>[N:35]([CH2:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:6]=[CH:5][CH:4]=1)=[N+:36]=[N-:37]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCCN1c1cccc(CBr)n1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cccc(N2CCCC2=O)n1
Reaction time: 18 h

Procedure:
A solution of 1-(6-bromomethylpyridin-2-yl)pyrrolidin-2-one (10.19 g, 39.94 mop containing triphenylphosphine oxide impurity in DMF (80 mL) was treated with sodium azide (2.60 g, 39.94 mmol), stirred for 18 h and partitioned between EtOAc and water. The organic phase was separated and the aqueous phase re-extracted with EtOAc (×2). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow oil, contaminated with triphenylphosphine oxide; used in the next step without further purification; LC-MS retention time 2.19 min, (M+H)+ 218.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([C:7]2[C:11]([C:12]([O:14]C)=[O:13])=[CH:10][O:9][N:8]=2)=[CH:3][CH:2]=1.[OH-].[Li+].Cl>C1COCC1>[C:1]1([CH3:16])[CH:2]=[CH:3][C:4]([C:7]2[C:11]([C:12]([OH:14])=[O:13])=[CH:10][O:9][N:8]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1conc1-c1ccc(C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2nocc2C(=O)O)cc1
Reaction time: 4 h
Yield: 100 %

Procedure:
Methyl 3-p-tolyl-isoxazole-4-carboxylate (3.1 g, 14.3 mmol) was dissolved in THF (50 ml), 2N aqueous lithium hydroxide solution (50 ml) was added, and the mixture was stirred for 4 hours. Then, 1N hydrochloric acid (150 ml) was added at 0° C., and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (2.89 g, 14.3 mmol, 100%).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([CH3:23])[CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[C:19]([Si:16]([CH3:18])([CH3:17])[O:15][CH2:14][C@@H:13]([CH3:23])[CH2:12][CH2:11][CH2:10][CH2:9][OH:8])([CH3:21])([CH3:22])[CH3:20]
Reactant: C[C@@H](CCCCOCc1ccccc1)CO[Si](C)(C)C(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](CCCCO)CO[Si](C)(C)C(C)(C)C
Yield: 100.2 %

Procedure:
A solution of 64.0 g (0.19 mol) of the benzylether VIII in 500 ml of THF was hydrogenated (3.5 bar) over 7.0 g of 20% Pd(OH)2/C for 30 min at ambient temperature. The catalyst was removed by filtration and the filtrate was concentrated to afford alcohol IX as colorless oil (46.9 g, 100%). Rf=0.33 (SiO2, 1:1 heptane-TBME).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=O.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[Cl:1][CH2:2][CH2:3][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2
Reactant: O=C1Cc2cc(C(=O)CCl)ccc2N1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2cc(CCCl)ccc2N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 100 ml round-bottomed flask equipped with condenser and nitrogen inlet were added 5.0 grams (23.9 mmol) of 5-chloroacetyl oxindole and 18.5 ml triflouroacetic acid. To the stirring solution was added 8.77 ml (54.9 mmol) of triethylsilane while cooling to prevent exotherm, and the reaction stirred 16 hours at room temperature. The reaction was then poured into ice water, stirred and the beige solid filtered, washed with water and hexane, and dried to give 5-(2-chloroethyl)oxindole, m.p. 168°-170° C., 3.0 grams (64%).
Reaction SMILES: COC(=O)O[CH2:5][C:6]1[C:7]([F:21])=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[CH:33][C:34]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:35][CH:36]=2)O1.C1(P(C(P(C2C=CC=CC=2)C2C=CC=CC=2)(CC)CC)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].CN(C)C=O>[Cl:20][C:16]1[CH:15]=[C:14]([C:8]2[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:31]3[CH:32]=[CH:33][C:34]([N:37]4[CH2:38][CH2:39][NH:40][CH2:41][CH2:42]4)=[N:35][CH:36]=3)[C:7]=2[F:21])[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)OCc1ccc(OC)c(-c2cccc(Cl)c2)c1F
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)nc2)OC1(C)C
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: CCC(CC)(P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(Cc2ccc(N3CCNCC3)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 85 °C
Reaction time: 18 h
Yield: 18 %

Procedure:
To carbonic acid 3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl ester methyl ester (0.2 g, 0.62 mmol), 1-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-piperazine (0.2 g, 0.68 mmol), bis-diphenylphosphinopentane (0.08 g, 0.18 mmol), potassium carbonate (0.26 g, 1.85 mmol) and allyl palladium (II) chloride dimer (0.034 g, 0.09 mmol) was added dimethyl formamide (6 mL). The reaction was degassed with an argon stream for 10 min. The reaction was stirred at 85° C. for 18 h. The reaction was cooled to room temperature, poured onto crushed ice-water (150 mL), filtered, washed with water, dried over sodium sulfate, filtered, and the solvent removed under vacuum. The residue was purified by silica gel column chromatography using 10% methanol in dichloromethane to afford P-423 (0.05 g, 18% yield) as light brown gummy solid. 1H NMR (400 MHz, DMSO-d6): 3.20 (br s, 3H) 3.55-3.99 (m, 10H), 6.95 (d, J=8.59 Hz, 1H), 7.11 (br s, 1H), 7.23-7.39 (m, 3H), 7.39-7.55 (m, 2H), 7.69 (br s, 1H), 8.02 (s, 1H), 9.33 (br s, 2H) ppm. Calc. 411.9; APCI+ (M+1): 412.1, 97%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH:6]([C:12]([O:14][CH3:15])=[O:13])[CH2:5]2.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH2:16]([N:7]1[CH:6]([C:12]([O:14][CH3:15])=[O:13])[CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[CH2:8]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)C1Cc2cc(F)ccc2CN1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C1Cc2cc(F)ccc2CN1Cc1ccccc1
Yield: 45.8 %

Procedure:
702 mg of methyl 6-fluoro-1,2,3,4-tetrahydroisoquinoline-3-carboxylate, 425 mg of benzyl chloride, and 425 mg of potassium carbonate were dissolved in 5 mL of acetonitrile, followed by stirring under reflux for 3 hours. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was then washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using silica gel chromatography (acetone:n-hexane=1:20) to obtain 460 mg (yield 46%) of a title compound as a pale yellow oily substance.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[CH:12][C:11]3=[O:26])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:31][C@H:32]1[O:34][CH2:33]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[O:34]1[CH2:33][C@H:32]1[CH2:31][N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=4)=[CH:12][C:11]3=[O:26])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@@H]2CO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A mixture of 1-(1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (1.1 g, 3.1 mmol), (S)-(+)-glycidyl nosylate (0.96 g, 3.7 mmol) and cesium carbonate (1.5 g, 4.6 mmol) in methyl sulfoxide (10 mL) was stirred at ambient temperature overnight. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure. Purification by column chromatography (silica gel, ethyl acetate) gave the title compound (510 mg, 40%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.08 (s, 1H), 7.76-7.73 (m, 5H), 7.64 (d, J=9.0 Hz, 1H), 7.51 (d, J=7.0 Hz, 1H), 7.47 (dd, J=9.0, 2.0 Hz, 1H), 6.92 (d, J=2.0 Hz, 1H), 6.52 (dd, J=7.5, 2.0 Hz, 1H), 4.78 (dd, J=15.5, 3.5 Hz, 1H), 4.48 (dd, J=15.0, 5.5 Hz, 1H), 3.41-3.38 (m, 1H), 2.88 (app t, J=4.5 Hz, 1H), 2.60 (dd, J=5.0, 3.0 Hz, 1H).
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]=[C:6]([CH3:17])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])C.CO.[OH-].[Na+].Cl>C1COCC1.O>[Cl:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[CH:8]=[CH:7][C:6]([CH3:17])=[CH:5][C:4]([OH:18])=[O:3]
Reactant: CCOC(=O)C=C(C)C=Cc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C=Cc1ccc(Cl)cc1Cl)=CC(=O)O
Reaction time: 6 h
Yield: 89.6 %

Procedure:
5-(2,4-Dichlorophenyl)-3-methylpenta-2,4-dienoic acid ethyl ester (5 g, 0.0184 mol) was dissolved in THF (125 mL). Water (50 mL), MeOH (50 mL), and NaOH (18.44 mL of a 2M solution in water, 2 eq) were then added. After 6 hours, TLC analysis showed complete conversion of the starting materials and the mixture was acidified to pH 1 by addition of 6N HCl. The resulting solid was collected to give 4.24 g of 5-(2,4-dichlorophenyl)-3-methylpenta-2,4-dienoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([Cl:17])=[CH:4][C:3]=1[OH:18].CC(C)([O-])C.[K+].FC(F)(F)S(O[CH2:31][CH2:32][O:33][C:34]([F:37])([F:36])[F:35])(=O)=O.[NH4+].[Cl-]>CC#N>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([Cl:17])=[CH:4][C:3]=1[O:18][CH2:31][CH2:32][O:33][C:34]([F:37])([F:36])[F:35]
Reactant: O=S(=O)(OCCOC(F)(F)F)C(F)(F)F
Reactant: CCc1ccc(Cc2cc(Br)c(O)cc2Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Product: CCc1ccc(Cc2cc(Br)c(OCCOC(F)(F)F)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-bromo-5-chloro-4-(4-ethylbenzyl)phenol (AT) (0.12 g, 0.38 mmol) in anhydrous CH3CN (4 mL), was added potassium tert-butoxide [1.0 M solution in tert-butanol] (380 μL, 0.38 mmol) followed by 2-(trifluoromethoxy)ethyl trifluoromethanesulfonate (0.10 g, 0.38 mmol) [prepared as described in the Journal of Organic Chemistry, 2001, 66, 1061-1063]. The reaction mixture was stirred for 15 h at room temperature, after which saturated NH4Cl was added and the mixture was partitioned between EtOAc and brine. The organic layer was dried with anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative TLC to give intermediate BP (0.06 g, 36%). 1H-NMR (CDCl3, 300 MHz) δ 7.31 (s, 1H), 7.10 (m, 4H), 6.89 (s, 1H), 4.31 (m, 2H), 4.20 (m, 2H), 3.96 (s, 2H), 2.61 (q, J=7.5 Hz, 2H), 1.22 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O)[CH:2]([CH3:4])[CH3:3].Cl.[F:20][C:21]([F:34])([F:33])[C:22]1[S:26][C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:24][CH:23]=1>>[CH2:1]([S:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([N:30]1[CH2:31][CH2:32][N:27]([C:25]2[S:26][C:22]([C:21]([F:34])([F:20])[F:33])=[CH:23][N:24]=2)[CH2:28][CH2:29]1)=[O:10])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)CSc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CC(C)CSc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1
Yield: 88 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isobutylsulfanyl-5-methanesulfonyl-benzoic acid (Example A25) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a light yellow solid (yield 88%). MS (m/e): 508.3 (M+H+, 100%).
Reaction SMILES: CS(O[CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([CH2:16]OS(C)(=O)=O)[O:8]1)(=O)=O.[NH4+:22].[OH-].Cl>C(#N)C>[CH:9]12[O:8][CH:7]([CH2:6][NH:22][CH2:16]1)[C:15]1[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)OCC1OC(COS(C)(=O)=O)c2ccccc21
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CC#N
Product: c1ccc2c(c1)C1CNCC2O1
Temperature: 100 °C

Procedure:
Methanesulfonic acid 3-methanesulfonyloxymethyl-1,3-dihydro-isobenzofuran-1-ylmethyl ester (12.1 g, 36 mmol) and conc. NH4OH (50 mL) was dissolved in acetonitrile (100 mL) and heated at 100° C. in a sealed vessel for 2 h. The reaction was then cooled, adjusted to pH 5-6 with 1 N HCl and extracted with diethyl ether (100 mL). The aqueous layer was then basified with 10 N NaOH and extracted with diethyl ether (2×100 mL). The later organic layer was dried over MgSO4, filtered, concentrated and purified with silica gel chromatography (0-15% MeOH in CH2Cl2) to obtain 12-Oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene as a brown, viscous oil (5.1 g, 88%). MS (m/e) 162 (M+1); HPLC (93%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15](=[N:24][NH2:25])[NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[Cl:23])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.C1N=CN([C:32](N2C=NC=C2)=[O:33])C=1>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:16]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=5[Cl:23])[C:32](=[O:33])[NH:25][N:24]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1
Reactant: NN=C(Nc1ccccc1Cl)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]nc(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)n1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
A solution of 8-bromo-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbohydrazonamide (200 mg, 0.45 mmol) in anhydrous THF (8 mL) was treated with CDI (145 mg, 0.89 mmol) and stirred at room temperature overnight, diluted with water. The solid was washed with water and dried in vacuum to give 3-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-4-(2-chlorophenyl)-1H-1,2,4-triazol-5(4H)-one (195 mg, yield: 92%). ESI-MS: 473.96
Reaction SMILES: I[C:2]1[C:10]2[O:9][C:8](=[O:11])[N:7]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[CH:5]=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.[C:23]([C:25]1[CH:26]=[C:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:28]=[CH:29][CH:30]=1)#[CH:24]>>[N+:20]([C:4]1[CH:3]=[C:2]([C:24]#[C:23][C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH:28]=[CH:29][CH:30]=2)[C:10]2[O:9][C:8](=[O:11])[N:7]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[CH:5]=1)([O-:22])=[O:21]
Reactant: C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Reactant: C[Si](C)(C)CCOCn1c(=O)oc2c(I)cc([N+](=O)[O-])cc21
Product: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cc([N+](=O)[O-])cc3c2oc(=O)n3COCC[Si](C)(C)C)c1

Procedure:
The desired compound was prepared according to the procedure of Example B5, step C, using 7-iodo-5-nitro-3-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-benzoxazol-2(3H)-on and tert-butyl (3-ethynylphenyl)carbamate as the starting materials in quantitative yield. LCMS for C26H31N3O7SiNa (M+Na)+: m/z=548.0.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[SH:19][C:20]1C=C(NC2C=CC=CC=2)C=CC=1.N1C=CC=CC=1C=O>>[CH3:20][S:19][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1cccc(Nc2ccccc2)c1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Agent: O=Cc1ccccn1
Product: CSc1cccc(-n2nnc(-c3ccccn3)n2)c1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3-mercaptophenylaniline (41.8 mg, 0.3 mmol) and 2-pyridinecarboxaldehyde (32.1 mg, 0.3 mmol) were employed to obtain 2-[2-(3-Methylmercaptophenyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=O)[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]([C:23]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)=[S:24])[NH2:22].CN(C)C=O>Cl.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:22][NH:21][C:23]([NH:25][C:26]3[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)=[S:24])[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Yield: 48.8 %

Procedure:
1-[5-(4-tert-Butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (0.163 mmol, 44.4 mg) synthesized in Synthetic Example 3 and 4-hydrazinocarbonothioylaminobenzoic acid (0.163 mmol, 34.4 mg) were stirred with dimethylformamide (3 mL) and two drops of concentrated hydrochloric acid at room temperature for 20 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a yellow solid (37 mg, yield 48%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][CH2:6]1)(=[O:4])=[O:3].C(O)C.[H][H]>[Pd]>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: [H][H]
Reactant: CS(=O)(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl 1-piperazinecarboxylate (2.03 g, 9.22 mmol) was dissolved in pyridine (23.0 mL, 9.22 mmol) and cooled to 0° C. before methanesulfonyl chloride (2.85 mL, 36.9 mmol) was added. The reaction mixture was stirred at 0° C. for 30 minutes and warmed to RT for 2 h. The reaction mixture was diluted with 75 mL of ethyl acetate, added to a separation funnel, partitioned with 3 N HCl (aqueous), washed 3× with 50 mL of 3 N HCl (aqueous), and separated, before the aqueous layer was extracted 3× with chloroform/isopropanol, then dried over sodium sulfate, and concentrated in vacuo to give the title compound. Benzyl 4-(methylsulfonyl)piperazine-1-carboxylate (2.80 g, 9.4 mmol) was dissolved in ethanol (0.43 g, 9.4 mmol) before palladium, 10 wt. % on activated carbon (2.0 g) was added and a hydrogen balloon attached. The reaction mixture was stirred at RT for 2 h before it was filtered through a pad of Celite®, washed with methanol, and concentrated in vacuo to give the title compound. MS (ES+): 165 (M+H)+.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=[NH:4].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[C:20]([C:28](O)=O)[N:19]=2)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[N:21]=[C:20]([C:28]3[O:1][N:2]=[C:3]([C:5]4[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=4)[N:4]=3)[N:19]=2)=[CH:16][CH:17]=1
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1
Reactant: N=C(NO)c1ccncc1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2nc(-c3ccncc3)no2)n1

Procedure:
The title compound was prepared from commercially available N-hydroxy-4-pyridinecarboxamidine [CAS-No. 1594-57-6] (0.103 g, 0.75 mmol) and 4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.1) (0.15 g, 0.5 mmol) according to the general procedure V. Obtained as a light yellow solid (0.088 g, 44%). MS (ISP) 404.1 [(M+H)+]; mp 187.5° C.
Reaction SMILES: C([NH:8][C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][C@@H:10]1[CH3:19])C1C=CC=CC=1>CO.[H][H].[Pd]>[NH2:8][C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][C@@H:10]1[CH3:19]
Reactant: [H][H]
Reactant: COC(=O)N1CC[C@@H](NCc2ccccc2)[C@@H](C)C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)N1CC[C@@H](N)[C@@H](C)C1
Yield: 101.6 %

Procedure:
Methyl (3S,4R)-4-(benzylamino)-3-methylpiperidine-1-carboxylate (8.0 g, 0.02 mol) was dissolved in methanol (200 mL) and hydrogenated at room temperature, under 50 psi of hydrogen pressure, in the presence of palladium (2.5 g) on carbon for 2 h. The solution was then filtered and concentrated under reduced pressure to yield 3.5 g (92%) Methyl (3S,4R)-4-amino-3-methylpiperidine-1-carboxylate as liquid.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([C:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:27])[C:15]([CH3:26])([S:17]([CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])(=[O:19])=[O:18])[CH3:16])[O:10][N:9]=1)([CH3:7])[CH3:6].Br[CH2:29][CH2:30][O:31][CH3:32]>C1COCC1.O>[CH3:32][O:31][CH2:30][CH2:29][O:3][CH2:4][C:5]([C:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:27])[C:15]([CH3:16])([S:17]([CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])(=[O:19])=[O:18])[CH3:26])[O:10][N:9]=1)([CH3:7])[CH3:6]
Reactant: CC(C)(CO)c1cc(NC(=O)C(C)(C)S(=O)(=O)CCC(F)(F)F)on1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOCC(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)CCC(F)(F)F)on1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14 %

Procedure:
To a solution of NaH (60% in mineral oil; 11.0 mg; 0.284 mmol) in anhydrous THF (2.0 mL) is added N-[3-(2-Hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-methyl-2-(3,3,3-trifluoro-propane-1-sulfonyl)-propionamide (50.0 mg; 0.129 mmol). The reaction is stirred at room temperature for 15 minutes and then 1-bromo-2-methoxy-ethane (0.037 mL, 0.387 mmol) is added. The reaction is stirred at 50° C. for 6 h and monitored by LC MS. Additional NaH (60% in mineral oil; 0.011 g; 0.284 mmol) and 1-bromo-2-methoxy-ethane (0.037 mL; 0.387 mmol) is added and the reaction is stirred overnight at room temperature. The crude mixture is diluted with water and extracted with ethyl acetate. The combined organics are dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound is obtained after purification by prep HPLC to afford 8 mg. Yield 14%. ESI m/z 445[M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[C:12](=[O:15])[CH2:13][Cl:14].[BH4-].[Na+].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[CH:12]([OH:15])[CH2:13][Cl:14]
Reactant: O=C1Cc2cc(C(=O)CCl)c(Cl)cc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1Cc2cc(C(O)CCl)c(Cl)cc2N1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A reactor is loaded with 200 g (0.82 mol) of 6-chloro-5-(2-chloro-acetyl)-1,3-dihydro-indol-2-one, in 1 L of ethanol. The reaction mixture is added with 15.5 g (0.41 mol) of sodium borohydride in portions, under strong stirring, at room temperature. The temperature is kept at 15-20° C. during the addition, after that the mixture is left under stirring for about 15 h at room temperature. The mixture is then added with 250 ml of glacial acetic acid and refluxed (approx. 85° C.) for 1 hr 30 min, then 200 ml of acetic acid are added and the mixture is refluxed a further 30 min, then cooled to 20° C. The suspension is filtered and washed with ethanol and heptane. The solid product is dried under vacuum at a temperature of 60° C., to obtain 177 g (88% molar yield).