Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[S:7]([CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:8].CN1C=NN=C1S(CC1C=CC(C(O)=O)=CC=1)(=O)=O.[Cl:38][C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][C:40]=1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1>>[Cl:38][C:39]1[CH:45]=[CH:44][C:42]([NH:43][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([CH2:9][S:7]([C:3]3[N:2]([CH3:1])[CH:6]=[N:5][N:4]=3)=[O:8])=[CH:18][CH:17]=2)=[CH:41][C:40]=1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: Cn1cnnc1S(=O)Cc1ccc(C(=O)O)cc1
Agent: Cn1cnnc1S(=O)(=O)Cc1ccc(C(=O)O)cc1
Product: Cn1cnnc1S(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
500 mg of methyl 4-(bromomethyl)benzoate was reacted with 4-methyl-4H-1,2,4-triazole-3-thiol via Procedure Q. 804 mg of methyl 4-((4-methyl-4H-1,2,4-triazol-3-ylthio)methyl)benzoate was subsequently reacted via Procedure R to give an approximate 1:9 mixture of methyl 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoate and methyl 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoate. The mixture of 740 mg was hydrolyzed via Procedure M to give 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoic acid and 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid. 114 mg of the mixture of 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoic acid and 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid was coupled to 75 mg of 4-chloro-3-(pyridin-2-yl)aniline via Procedure G. The mixture was separated on reverse phase HPLC to give N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4-methyl-4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzamide. MS (Q1) 452.3 (M)+.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:27][C:28](=[O:43])[C:29]1[CH:34]=[CH:33][C:32]([C:35]([N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:36])=[C:31]([CH3:42])[CH:30]=1)[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:19]=2[N:18]=1)=O)C1C=CC=CC=1.I[Si](C)(C)C.CO>ClCCl>[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:27][C:28](=[O:43])[C:29]1[CH:34]=[CH:33][C:32]([C:35]([N:37]2[CH2:38][CH2:39][CH2:40][CH2:41]2)=[O:36])=[C:31]([CH3:42])[CH:30]=1)[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:19]=2[N:18]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C(=O)N[C@@H](CCCCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.3 g (0.49 mmol) of N-[(1S)-5-(benzyloxycarbonylamino)-1-(5-chloro-1H-benzimidazol-2-yl)pentyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide is dissolved in 15 mL of dichloromethane and, after the addition of 0.25 mL (0.76 mmol) of iodotrimethylsilane, stirred for 3 hours at ambient temperature. Then 10 mL of methanol is added and the mixture is stirred for a further 30 minutes. The solvent is distilled off and the residue is chromatographed on silica gel, eluting with dichloromethane/methanol (80:20). Yield: 0.22 g (96%); Rf value: 0.15 (silica gel; dichloromethane/methanol=9:1); C25H30ClN5O2 (468.00); mass spectrum: (M+H)+=468/470 (chlorine isotope).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH:10]([CH3:12])[CH3:11])[CH:3]=1.Cl.Cl[C:15]1[C:16]2[C:23]([CH3:24])=[C:22]([S:25]([NH:28][CH2:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])(=[O:27])=[O:26])[S:21][C:17]=2[N:18]=[CH:19][N:20]=1.O.[OH-].[NH4+]>O1CCOCC1.O>[CH3:34][N:32]([CH3:33])[CH2:31][CH2:30][CH2:29][NH:28][S:25]([C:22]1[S:21][C:17]2[N:18]=[CH:19][N:20]=[C:15]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=3[O:9][CH:10]([CH3:12])[CH3:11])[C:16]=2[C:23]=1[CH3:24])(=[O:27])=[O:26]
Reactant: Cc1c(S(=O)(=O)NCCCN(C)C)sc2ncnc(Cl)c12
Reactant: CC(C)Oc1cc(F)ccc1N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(S(=O)(=O)NCCCN(C)C)sc2ncnc(Nc3ccc(F)cc3OC(C)C)c12
Temperature: 25 °C
Yield: 28.9 %

Procedure:
4-Fluoro-2-iso-propoxyaniline (0.049 g, 0.28 mmol) and 4-chloro-N-(3-(dimethylamino)propyl)-5-methylthieno[2,3-d]pyrimidine-6-sulfonamide hydrochloride salt (0.1 g, 0.28 mmol) were heated at 70° C. in anhydrous 1,4-dioxane (1.5 mL) for 4 hours. The solution was cooled to ambient temperature and diluted with water (2.0 mL) and adjusted to pH 9 (4:1 water/ammonium hydroxide solution). The precipitate was collected, washed with water and diethyl ether to yield the title compound as beige solid (0.039 g, 28%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][C:13]1[N:17](C(OC(C)(C)C)=O)[N:16]=[C:15]([O:25][CH2:26][C:27]2[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=2)[CH:14]=1>C1COCC1>[CH3:34][O:33][C:31]1[CH:32]=[C:27]([CH2:26][O:25][C:15]2[CH:14]=[C:13]([NH:12][C:7](=[O:8])[C:6]3[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:17][N:16]=2)[CH:28]=[C:29]([O:35][CH3:36])[CH:30]=1
Reactant: COc1cc(COc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2cc(OCc3cc(OC)cc(OC)c3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.1 %

Procedure:
4-Methoxybenzoyl chloride (54 mg, 0.315 mmol, 1.1 eq) in THF (2 ml) was added dropwise to a solution of tert-butyl 5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (100 mg, 0.286 mmol, 1 eq) in THF (3 ml) under nitrogen and the solution was heated at reflux for a total of 14 h, then stirred at room temperature for 16 h. The solvent was evaporated and the residue was purified by prep. HPLC, using a gradient of 55-75% MeCN in H2O (containing 1% ammonium hydroxide). The product fractions were evaporated to dryness and taken up in DCM (4 ml). 4M HCl in dioxane (1 ml) was added and the mixture stirred at room temperature for 1 h, then evaporated to dryness. The residue was partitioned between ethyl acetate (6 ml) and aqueous NaHCO3 (6 ml), the layers were separated and the aqueous layer was re-extracted with ethyl acetate (3×6 ml). The combined organic extracts were dried over Na2SO4, filtered and evaporated to afford the title compound as an off-white solid (22 mg, 20% yield); 1H NMR (400.132 MHz, DMSO) δ 3.74 (s, 6H), 3.82 (s, 3H), 5.06 (s, 2H), 5.59 (s, 1H), 6.43 (t, 1H), 6.59 (d, 2H), 7.00 (d, 2H), 7.96 (d, 2H) MS: m/z 384 (MH+)
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O=S(Cl)[Cl:19]>C1C=CC=CC=1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([Cl:19])=[O:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)OCCCCCC(=O)O
Solvent: c1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCCCCC(=O)Cl
Yield: 91.9 %

Procedure:
A solution of 0.5 g (2.03 mmol) of 6-[(tert-butyldimethylsilyl)oxy]-hexanoic acid in 4 ml of benzene is mixed with 362 mg (3.04 mmol, 1.5 equivalents) of SOCl2 and heated under reflux for 2 hours. It is allowed to cool, and the solvent is distilled off in a rotary evaporator. To remove excess SOCl2 from the reaction mixture, the residue is mixed again with benzene and again distilled off. 494 mg (1.865 mmol, 92%) of the 6-[(tert-butyldimethylsilyl)oxy]-hexanoyl chloride is obtained. This crude product is further reacted without purification and characterization.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[N:7]=[C:6]([OH:13])[N:5]=1)([CH3:3])[CH3:2].S(=O)(=O)(O)O.[N+:19]([O-])([OH:21])=[O:20].[OH-].[Na+]>C(Cl)(Cl)Cl>[CH:10]([C:8]1[C:9]([N+:19]([O-:21])=[O:20])=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([OH:13])[N:7]=1)([CH3:12])[CH3:11]
Reactant: CC(C)c1cc(C(C)C)nc(O)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)c1nc(O)nc(C(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 49 %

Procedure:
Compound 4 (20 mg) was suspended in a mixture of concentrated sulfuric acid (1 mL) and chloroform (1 mL). To the resulting mixture, fuming nitric acid (166 μL: d=1.50) was added while being stirred and cooled with ice at 5° C. or below. The resulting mixture was allowed to slowly warm to room temperature (20-30° C.), and subsequently kept stirred at room temperature (20-30° C.) overnight. The reaction mixture was poured into ice and neutralized with a 10N aqueous sodium hydroxide solution to a pH of approx. 5 (at 20° C. or below). The mixture was extracted twice with chloroform and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methylene chloride:methanol=50:1 to 10:1) to give 17.8 mg (49% yield) of the desired product as a brown amorphous.
Reaction SMILES: C1(OC(=O)[CH2:9][CH2:10][C@@H:11]([CH2:27][O:28]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:12][C@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[N:14]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])CCCCC1.C[Mg]Br.[CH2:43]1[CH2:47]OC[CH2:44]1>>[CH3:44][C:43]1([CH3:47])[O:28][CH2:27][C@@H:11]([CH2:12][C@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[N:14]2[C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:10][CH2:9]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CCC(=O)OC2CCCCC2)C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Reactant: C1CCOC1
Agent: C[Mg+]
Agent: C[Mg]Br
Agent: [Br-]
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@H]2CCC(C)(C)OC2)COC1(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
The (S)-tert-butyl 4-((R)-5-(cyclohexyloxy)-5-oxo-2-(tosyloxymethyl)pentyl)-2,2-dimethyloxazolidine-3-carboxylate (309 mg, 0.545 mmol, 1.0 equiv) was dissolved in 17 mL of THF and the solution cooled to 0° C. Methylmagnesiumbromide (3.0 M in THF, 1.64 mL, 3.0 equiv) was added via syringe. LC/MS analysis showed ca 15% conversion to the mono-tosylate. An additional 0.55 mL of MeMgBr solution was added and the mixture warmed to ambient and stirred overnight. LC/MS analysis showed complete conversion to the mono-tosylate. The mixture was heated to reflux for 24 hr. After this time, complete conversion to the cyclised product was observed. The mixture was cooled to ambient and quenched with water. The layers were separated and the organic layer washed with brine, dried over Na2SO4, filtered and evaporated. The pyran derivative was purified by flash chromatography on silica, (12 g), eluting with 0-41% EtOAc in hexanes. This afforded 138 g (78% yield) of (S)-tert-butyl 4-(((R)-6,6-dimethyl-tetrahydro-2H-pyran-3-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate as a clear syrup. MS ESI +ve m/z 350 (M+Na).
Reaction SMILES: [CH3:1][C:2]([OH:10])([CH3:9])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6].N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>CO>[C:17]([O:6][CH2:5][CH2:4][C:3]([F:8])([F:7])[C:2]([CH3:9])([OH:10])[CH3:1])(=[O:19])[CH3:18]
Reactant: CC(C)(O)C(F)(F)CCO
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)OCCC(F)(F)C(C)(C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 6.92 g (0.045 mol) of 4-methyl-3,3-difluoro-1,4-pentanediol and 28 mL of pyridine at 0° C. was added 16 mL of acetic anhydride and the mixture was stirred at 0° C. for 1 hr and at 25° C. for 1 hr. The mixture was added to 15 mL of methanol and the solution was evaporated to dryness to yield oily 4-methyl-3,3-difluoro-1,4-pentanediol 1-acetate. NMR (CDCl3) δ4.40 (triplet, 2, J=7 Hz), 2.30 (multiplet, 2), 2.06 (singlet, 3) and 1.33 ppm (triplet, 6, J=1 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[C:15]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)[N:14]=1>>[CH3:24][O:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[C:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1)=[N:14][C:15]([NH:25][C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=1)=[CH:16]2
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(Oc3ccc(NC(C)=O)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from N-(4-hydroxy-phenyl)-acetamide and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give N-{4-[6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-phenyl}-acetamide. LC-MS m/e 404(MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([CH:21](O)[C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[C:19]([CH:33]([CH3:35])[CH3:34])[CH:18]=[C:17]3[C:9]=2[C:10](=[O:36])[CH2:11][C:12]2([O:16]3)[CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:43])CC)C.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:20]([CH:21]([F:43])[C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:27]=3)=[C:19]([CH:33]([CH3:34])[CH3:35])[CH:18]=[C:17]3[C:9]=2[C:10](=[O:36])[CH2:11][C:12]2([O:16]3)[CH2:13][CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(C(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under argon, 180 mg (0.32 mmol) of 5-(4-fluorophenyl)-6-{hydroxy[4-(trifluoromethyl)phenyl]-methyl}-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 52A) are dissolved in 3.2 ml of toluene, 52 μl (0.39 mmol) of diethylaminosulfur trifluoride are slowly added at −78° C. and the mixture is stirred at −78° C. for 1 h. The temperature is then slowly increased to −60° C. After 2 h, water is added and the mixture is extracted twice with ethyl acetate. The combined organic phases are washed once with saturated sodium bicarbonate solution and once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is purified on a silica gel column (mobile phase: cyclohexane/ethyl acetate 12:1). This gives 107 mg (66% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:9]1[S:10][C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([CH:14]=[O:15])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:28]([Mg]Br)[CH3:29]>C(OCC)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([N:8]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[C:9]1[S:10][C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([CH:14]([OH:15])[CH2:28][CH3:29])[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC[Mg]Br
Reactant: CCOC(=O)c1sc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOCC
Product: CCOC(=O)c1sc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1C(O)CC
Temperature: -78 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
Ethyl 2-[bis(tert-butoxycarbonyl)amino]-4-formyl-1,3-thiazole-5-carboxylate obtained in Example (62d) (915.5 mg, 2.29 mmol) was dissolved in diethyl ether (30 mL), followed by cooling to −78° C. Then, tetrabutylammonium bromide (890 mg, 2.76 mmol) and ethylmagnesium bromide (1 M solution in THF, 2.8 mL) were added, and the mixture was stirred for one hour. Diethyl ether was added to the reaction solution, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=91/9, 85/15) to obtain 327.2 mg of the title compound (33%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([CH:43]3[CH2:45][CH2:44]3)[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([CH:43]3[CH2:44][CH2:45]3)[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C2CC2)n1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cc(C2CC2)n1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(2-cyclopropyl-6-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K36) (264 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (309 mg, 73%).
Reaction SMILES: [P:1]([O:13][CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C@@H:21]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](=[O:69])(=[O:68])[NH:38][C:39](=[O:67])[C:40]2[CH:45]=[CH:44][C:43]([N:46]3[CH2:51][CH2:50][CH:49]([C@H:52]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=4[C:60]4[CH:65]=[CH:64][C:63]([Cl:66])=[CH:62][CH:61]=4)[OH:53])[CH2:48][CH2:47]3)=[CH:42][CH:41]=2)=[CH:33][C:32]=1[S:70]([C:73]([F:76])([F:75])[F:74])(=[O:72])=[O:71])[CH2:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:17][CH3:18])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].Cl>C(Cl)Cl.CO>[ClH:66].[P:1]([OH:8])([OH:3])([O:13][CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C@@H:21]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](=[O:69])(=[O:68])[NH:38][C:39](=[O:67])[C:40]2[CH:41]=[CH:42][C:43]([N:46]3[CH2:51][CH2:50][CH:49]([C@H:52]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=4[C:60]4[CH:61]=[CH:62][C:63]([Cl:66])=[CH:64][CH:65]=4)[OH:53])[CH2:48][CH2:47]3)=[CH:44][CH:45]=2)=[CH:33][C:32]=1[S:70]([C:73]([F:74])([F:76])[F:75])(=[O:71])=[O:72])[CH2:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:17][CH3:18])=[O:2]
Reactant: CCN(CCOP(=O)(OC(C)(C)C)OC(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCN(CCOP(=O)(O)O)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Yield: 143.4 %

Procedure:
A solution of di-tert-butyl 2-(((R)-3-(4-(N-(4-(4-((R)-(4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoyl)sulfamoyl)-2-(trifluoromethylsulfonyl)phenylamino)-4-(phenylthio)butyl)(ethyl)amino)ethyl phosphate (INTERMEDIATE 55, 147 mg, 0.14 mmol) in DCM (3.17 ml) was treated with a solution of HCl (4M in dioxane, 0.60 ml). When the addition was completed, a white precipitate was observed. The mixture was diluted with MeOH after an hour and the volatiles were evaporated under reduced pressure to give a gummy residue. The material was dissolved in MeOH, and diluted with ˜20 ml DCM, resulting in a white precipitate. The mixture was concentrated under reduced pressure to provide a white solid. The material was triturated in 10-15 ml CH2Cl2, and dried under high vacuum to provide the title compound (108 mg, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([S:12][CH:13]1[N:16](/[C:17](=[C:21](\[O:23][CH3:24])/[CH3:22])/[C:18](O)=[O:19])[C:15](=[O:25])[CH:14]1[NH:26][C:27](=[O:36])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:11])=[O:10].C(Cl)(=O)C([Cl:40])=O>CN(C)C=O.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([S:12][CH:13]1[N:16](/[C:17](=[C:21](\[O:23][CH3:24])/[CH3:22])/[C:18]([Cl:40])=[O:19])[C:15](=[O:25])[CH:14]1[NH:26][C:27](=[O:36])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:11])=[O:10]
Reactant: CO/C(C)=C(/C(=O)O)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CO/C(C)=C(/C(=O)Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
One drop of dimethylformamide in dioxane is added to a soltuion of 54 mg (0.1 mM) of 2-[4-(o-methoxybenzensulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonic acid in 0.5 ml of a 10% strength solution of oxalyl chloride in dioxane, whereupon an evolution of gas occurs immediately. The mixture is stirred for 2 hours at room temperature and the solvent and the excess oxalyl chloride are evaporated off in vacuo. The residue is dried in a high vacuum and gives 2-[4-(o-methoxybenzenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1yl]-3-methoxy-isocrotonic acid chloride in the form of a slightly orange-coloured foam, IR spectrum (CH2Cl2): 5.60, 5.90 and 8.70 μ.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[C:22]([C:23]([OH:25])=O)=[C:21]([NH:26][CH2:27][CH:28]3[CH2:36][CH2:35][C:31]4([CH2:34][CH2:33][CH2:32]4)[CH2:30][CH2:29]3)[N:20]=[C:19]([C:37]#[N:38])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN.C[CH2:42][N:43]=C=NCCCN(C)C.Cl>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[C:22]([C:23](=[O:25])[NH:43][CH3:42])=[C:21]([NH:26][CH2:27][CH:28]3[CH2:36][CH2:35][C:31]4([CH2:32][CH2:33][CH2:34]4)[CH2:30][CH2:29]3)[N:20]=[C:19]([C:37]#[N:38])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2nc(C#N)nc(NCC3CCC4(CCC4)CC3)c2C(=O)O)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1c(NCC2CCC3(CCC3)CC2)nc(C#N)nc1OCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4[2-(1-tert-butoxycarbonylpiperidin-4-yl)ethoxy]-2-cyano-6-[(spiro[3.5]non-7-ylmethyl)amino]pyrimidine-5-carboxylic acid (0.23 mmol, step 75.4) and 2 M methyl amine solution (0.30 mmol) in DMF (1 mL) are added EDCI-HCl (0.34 mmol) and HoAt (0.34 mmol) at 0° C. The reaction mixture is stirred at room temperature for 1 h. After dilution with AcOEt, the mixture is washed with H2O and brine. The organic layer is dried over MgSO4, filtered, and concentrated. The residue is purified by silicagel column chromatography to give 4-(2-{2-cyano-5-methylcarbamoyl-6-[(spiro[3.5]non-7-ylmethyl)amino]-pyrimidin-4-yloxy}ethyl)piperidine-1-carboxylic acid tert-butyl ester as a white solid; 1H-NMR (CDCl3), δ: 0.98-1.07 (2H, m), 1.14-1.85 (2H, m), 1.46 (9H, s), 2.70 (2H, t), 2.93 (3H, d), 3.33 (2H, t), 4.05-4.15 (2H, m), 4.54 (2H, t), 7.80-7.85 (1H, m), 10.10-10.15 (1H, m).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[N:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[N:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+]>CO.O>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:4]2[N:3]3[N:29]=[N:30][N:31]=[C:2]3[N:7]([CH3:8])[C:6](=[N:9][C:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[CH3:18])[CH:5]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(Cl)n2)cc1OC
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c3nnnn23)cc1OC
Yield: 78.9 %

Procedure:
To a suspension of 2-chloro-3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (1.0 g) in a mixture of methanol (9 ml) and water (1.5 ml) was added sodium azide (0.163 g). The mixture was stirred at 50° to 55° C. for an hour. After removal of the solvent, the residue was washed with water and collected by filtration to give 4,5-dihydro-7-(3,4-dimethoxyphenyl)-4-methyl-5-(2,4,6-trimethylphenylimino)tetrazolo[1,5-a]pyrimidine (0.80 g).