Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][NH:21][CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[CH3:32])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:35]([N:21]1[CH2:22][C@H:18]2[C@H:17]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[CH3:32])[C@@H:16]([O:15][C@@H:13]([C:5]3[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:4]=3)[CH3:14])[O:24][CH2:23][C@@H:19]2[CH2:20]1)(=[O:37])[CH3:36]
Reactant: Cc1cc(F)ccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CNC[C@H]21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)N1C[C@H]2CO[C@H](O[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)[C@@H]2C1

Procedure:
A solution of (3aS,6R,7R,7aR)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluoro-2-methylphenyl)octahydropyrano[3,4-c]pyrrole (29 mg, 0.059 mmol), DMAP (1 mg) and acetic anhydride (0.028 mL, 0.30 mmol) in 2 mL of pyridine was stirred at rt for 4 hr. Volatiles were removed and the crude was purified by reverse phase HPLC to afford the title compound. MS: (MH)+534.
Reaction SMILES: [C:1]1([CH:7]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C@H:8]([NH:46][C:47](=[O:61])[C@H:48]([CH3:60])[NH:49][C:50]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:51])[CH:9]=[CH:10][S:11]([CH:14]=[CH:15][C@@H:16]([NH:30][C:31](=[O:45])[C@H:32]([CH3:44])[NH:33][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C(OO)(C)(C)C.C1(C(C2C=CC=CC=2)[C@H](NC(=O)[C@H](CC(C)C)NC(OCC2C=CC=CC=2)=O)C=CS(C=C[C@@H](NC(=O)[C@H](CC(C)C)NC(OCC2C=CC=CC=2)=O)C(C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[C:18]1([CH:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:16]([NH:30][C:31](=[O:45])[C@H:32]([CH3:44])[NH:33][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])=[CH:15][CH2:14][S:11]([CH2:10][CH:9]=[C:8]([NH:46][C:47](=[O:61])[C@H:48]([CH3:60])[NH:49][C:50]([O:52][CH2:53][C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)=[O:51])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)(=[O:12])=[O:13])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C=CS(=O)(=O)C=C[C@@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)OO
Agent: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C=CS(=O)(=O)C=C[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)NC(=CCS(=O)(=O)CC=C(NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Yield: 93 %

Procedure:
Cbz-Ala-Phe-VS-Ph was treated with butyllithium and tert-butylhydroperoxide in freshly distilled THF, as described with Cbz-Leu-Phe-VS-Ph above, to give Cbz-Ala-Phe-AS-Ph as a white powder, yield 93%. 1H-NMR (CDCl3) δ 1.21 (d, 3H, Ala-CH3), 3.80 (m, 4H, CH2-Phe and CH2—SO2), 4.12 (q, 1H, α-H), 4.88 (t, 1H, CH═), 5.11 (m, 3H, NH and Cbz), 7.30 (m, 10H, 2×Ph), 7.50 (t, 2H, SO2-Ph), 7.64 (t, 1H, SO2-Ph), 7.83 (d, 2H, SO2-Ph), 8.40 (b, 1H, NH). 13C NMR (400 MHz, CDCl3) δ 172.1, 156.3, 144.4, 140.8, 135.7, 134.2, 133.6, 131.2, 129.5, 129.4×2, 129.3, 128.8×2, 128.7, 128.6, 128.4, 128.3, 127.8, 127.3, 126.9, 107.2, 67.6, 51.7, 51.6, 40.2, 19.4. MS (FAB+) m/z 493 (M+1, 100%). HRMS calcd. for C27H29N2O5S: 493.17972. Obsd. 493.17663. Anal. calcd. for C27H28N2O5S: C, 65.83; H, 5.73; N, 5.69. Found: C, 65.73; H, 5.82; N, 5.68.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[N:17]=3)=[N:12][C:11]([N:24]([CH2:26][CH3:27])[CH3:25])=[N:10][C:9]=2[C:8]([C:28]([O:30]C)=[O:29])=[N:7]1)[CH3:2].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[N:17]=3)=[N:12][C:11]([N:24]([CH2:26][CH3:27])[CH3:25])=[N:10][C:9]=2[C:8]([C:28]([OH:30])=[O:29])=[N:7]1)[CH3:2]
Reactant: CCOCCn1nc(C(=O)OC)c2nc(N(C)CC)nc(Nc3cccc(CC)n3)c21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOCCn1nc(C(=O)O)c2nc(N(C)CC)nc(Nc3cccc(CC)n3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
The ester of step 8 (13.57 g, 32.83 mmol) and a 1M aqueous solution of sodium hydroxide (90 mL) were dissolved in methanol (10 mL) and the reaction mixture stirred at 85 C for 1 hour. The reaction mixture was cooled to room temperature and acidified with 10% aqueous citric acid (90 mL). The aqueous layer was extracted twice with dichloromethane (36 mL and 24 mL). The aqueous layer was further acidified with 10% aqueous citric acid (20 mL) and extracted with dichloromethane (24 mL). The combined dichloromethane extracts were combined and ethanol (13 mL) was added. The solution was distilled at ambient pressure and the distilled dichloromethane replaced with ethanol (52 mL). Water (12 mL) was added and the mixture was cooled to 5 C and stirred for 1 hour. The slurry was filtered and washed with water (24 mL) and dried in vacuo at 55 C to give a yellow solid (8.858 g, 22.2 mmol, 68%)
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N+]([C:11]1[CH:12]=[C:13]([C:19]#[N:20])[C:14](=[CH:17][CH:18]=1)[C:15]#[N:16])([O-])=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:1][C:11]1[CH:12]=[C:13]([C:19]#[N:20])[C:14](=[CH:17][CH:18]=1)[C:15]#[N:16]
Reactant: Sc1ccccn1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(Sc2ccccn2)cc1C#N

Procedure:
10 g of 2-mercaptopyridine, 14.2 g of 4-nitrophthalonitrile, and 22.6 g of potassium carbonate were suspended in 250 ml of acetone and heated at reflux temperature for 4 hours. The solution was filtered through a pad of celite and a course glass filter to remove residual solids. The solution was concentrated to a crude residue and purified by column chromatography on silica gel eluting the product with a gradient of 0-10% ethyl acetate in dichloromethane. 6.4 g of product was recovered; 1H NMR (200 Mz, CDCl3) δ=8.49-8.53 (m, 1H), 7.84-7.83 (dd, 1H), 7.76-7.71 (m, 2H), 7.68-7.64 (dd, 1H), 7.40-7.36 (dt, 1H), 7.27-7.20 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=O)[NH:8][C:7](=[O:12])[C:6]=2[CH:13]=1.C([O:16][C:17](=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]CBr)C>CC(N(C)C)=O>[Cl:1][C:2]1[CH:13]=[C:6]([C:7]([NH:8][CH2:9][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:17]([OH:26])=[O:16])=[O:12])[C:5]([OH:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCCCCCBr
Reactant: O=c1[nH]c(=O)c2cc(Cl)ccc2o1
Solvent: CC(=O)N(C)C
Product: O=C(O)CCCCCCCNC(=O)c1cc(Cl)ccc1O
Temperature: 70 °C

Procedure:
222 L of dry dimethylacetamide was charged to a dry 200 gallon glass-lined reactor. The reactor agitator was set to 100-125 rpm. Cooling was applied to the condenser and valve reactor overheads were set for distillation. 41.6 kg of dry anhydrous sodium carbonate was charged to the reactor and the reactor charging port was closed. Caution was used due to some off-gassing and a slight exothermic reaction. 77.5 kg of dry 6-chloro-2H-1,3-benzoxazine-2,4(3H)-dione was charged to the reactor. Quickly, 88 kg of dry ethyl-8-bromooctanoate was charged to the reactor. The reaction was evacuated to 22-24 inches of vacuum and the reactor temperature was raised to 65-75° C. The reactor temperature was maintained and the contents were watched for foaming. The reactor mixture was sampled and monitored for conversion by monitoring for the disappearance of the bromo ester in the reaction mixture by gas chromatography. The reaction was complete (0.6% bromo ester was found) after 7 hours. The vacuum was broken and the reactor contents cooled to 45-50° C. The contents were centrifuged and the filtrate sent into a second 200 gallon glass-lined reactor. 119 L of ethanol (200 proof denatured with 0.5% toluene) was charged to the first 200 gallon reactor, wanned to about 45° C. and the filter cake washed with warm ethanol and this wash was charged to the reaction mixture in the second 200 gallon reactor.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([N:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:9])=[N:4][NH:5][C:6]=1[CH3:7].F[C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][C:21]=1[C:31]([N:33]1[CH2:42][CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]1)=[O:32]>>[Br:1][C:2]1[C:3]([C:8](=[O:9])[N:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:15][CH2:16][CH2:17][CH3:18])=[N:4][N:5]([C:20]2[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][C:21]=2[C:31]([N:33]2[CH2:42][CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34]2)=[O:32])[C:6]=1[CH3:7]
Reactant: CCCCN(CCCC)C(=O)c1n[nH]c(C)c1Br
Reactant: CCOC(=O)c1ccc(F)c(C(=O)N2CCc3ccccc3C2)c1
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)OCC)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Br
Yield: 51.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1E, 4-bromo-N,N-dibutyl-5-methyl-1H-pyrazole-3-carboxamide (646 mg, 2.04 mmol) and ethyl 4-fluoro-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (Intermediate 1D, 1.07 g, 3.27 mmol) were converted to the title compound (660 mg, 48%). 1H NMR (CDCl3, 2:1 mixture of amide rotamers) δ 8.24-8.19 (m, 1H), 8.14-8.10 (m, 1H), 7.45-7.39 (m, 1H), 7.25-7.09 (m, 3.5H), 6.88 (d, J=7.3 Hz, 0.5H), 4.78 (d, J=8.8 Hz, 1H), 4.49-4.36 (m, 3H), 3.71-2.69 (m, 8H), 2.32 (s, 2H), 2.28 (s, 1H), 1.54-1.27 (m, 8.5H), 1.11 (d, J=7.7 Hz, 2H), 0.92 (q, J=7.2 Hz, 3.5H), 0.79 (t, J=8.0 Hz, 3H); MS(ESI+) m/z 625.3 (M+H)+.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1COS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][C@H:2]1[CH2:3][O:1]1
Reactant: COc1ccccc1O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccccc1O[C@H]1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
A mixture of (2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (777 mg, 3.0 mmol), 2-methoxyphenol (372.5 mg, 3.0 mmol) and Cs2CO3 (1.3 g, 4.0 mmol) in DMF was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-30% ethyl acetate in petroleum spirit 40-60) to give subtitled compound (425 mg).
Reaction SMILES: [C:1]([CH:3]([NH:5]/[C:6](=[C:9](\[NH2:12])/[C:10]#[N:11])/[C:7]#[N:8])[CH3:4])#N.[O:13]=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(O)C>[C:10]([C:9]1[NH:12][C:4](=[O:13])[CH:3]([CH3:1])[NH:5][C:6]=1[C:7]#[N:8])#[N:11]
Reactant: CC(C#N)N/C(C#N)=C(\N)C#N
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCO
Product: CC1NC(C#N)=C(C#N)NC1=O
Yield: 420.2 %

Procedure:
A mixture of 1.0 g of α-cyanoethyldiaminomaleonitrile obtained as described in Example 4 and 0.3 g of phosphorus pentoxide was heated under refluxing for 19 hours in 30 ml of ethanol. Thereafter, the solvent was distilled off, and the resulting residue was treated with ice-water to obtain brown-colored fine crystals. The crystals thus obtained were recrystallized from a mixture of tetrahydrofuran, methanol and water (2:2:1 by volume) to obtain 0.72 g (72% yield) of 5,6-dicyano-2-methyl-1,2,3,4-tetrahydropyrazin-3-one having a melting point of 243°-245° C as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][S:9](=[O:12])(=[O:11])[CH:8]=[CH:7][C:6]=2[CH:13]=1.[Cl:14][S:15](O)(=[O:17])=[O:16]>>[Br:1][C:2]1[CH:3]=[C:4]([S:15]([Cl:14])(=[O:17])=[O:16])[C:5]2[O:10][S:9](=[O:11])(=[O:12])[CH:8]=[CH:7][C:6]=2[CH:13]=1
Reactant: O=S1(=O)C=Cc2cc(Br)ccc2O1
Reactant: O=S(=O)(O)Cl
Product: O=S1(=O)C=Cc2cc(Br)cc(S(=O)(=O)Cl)c2O1
Temperature: 0 °C

Procedure:
6.0 g of 6-bromo-2,2-dioxo-1,2-benzoxathiine and 22.0 g of chlorosulfonic acid are heated for 1 hour to 60° C. The mixture is then poured into ice-water. The precipitated 6-bromo-8-chlorosulfonyl-2,2-dioxo-1,2-benzoxathiine is isolated, washed with water and dried.
Reaction SMILES: [C:1]([C:6]1[N:7]([CH3:19])[S:8](=[O:18])(=[O:17])[C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]=1[OH:12])([O:3]CC)=O.[NH2:20][C:21]1[CH:25]=[CH:24][O:23][N:22]=1>C1(C)C(C)=CC=CC=1>[OH:12][C:11]1[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[S:8](=[O:17])(=[O:18])[N:7]([CH3:19])[C:6]=1[C:1](=[O:3])[NH:20][C:21]1[CH:25]=[CH:24][O:23][N:22]=1
Reactant: Nc1ccon1
Reactant: CCOC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2ccon2)=C(O)c2ccccc2S1(=O)=O

Procedure:
A mixture of 4.15 g. (0.0155 mole) of 3-carbethoxy-4-hydroxy-2-methyl-2H-1,2-benzothiazine 1,1-dioxide, 1.3 g. (0.0155 mole) of 3-aminoisoxazole, and 500 ml. of xylene was refluxed for 24 hr. in a Soxhlet apparatus, the thimble of which contained 10 g. of Linde 4A molecular sieve. The mixture was cooled to 25° and the resulting crystalline precipitate was collected and washed with ether to give 3.2 g. of product, m.p. 235-240° dec. Recrystallization from 175 ml. of ethyl acetate gave 1.6 g. of material, m.p. 237-240° dec.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:11][CH2:12][CH2:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH3:22])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=O.[H-].[Na+].CO.[Sn]>C1COCC1.C(Cl)Cl.C(OCC)(=O)C>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([N:14]2[CH2:13][CH2:12][CH2:11][C:5]3([CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)[C:3]2=[O:2])=[C:16]([CH3:22])[CH:17]=1
Reactant: COC(=O)C1(CCCNc2ccc(Br)cc2C)CCOCC1
Agent: [H-]
Agent: [Na+]
Agent: [Sn]
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(Br)ccc1N1CCCC2(CCOCC2)C1=O
Temperature: 50 °C
Yield: 104.1 %

Procedure:
To a clear solution of 4-[3-(4-bromo-2-methyl-phenylamino)-propyl]-tetrahydro-pyran-4-carboxylic acid methyl ester (0.85 g, 2.3 mmol) in THF (25 mL) was added NaH (60% in mineral oil, ˜100 mg) and the reaction temperature was raised to 50° C. (external) for 2 h. TLC (2.5% MeOH in DCM for SM, 5% MeOH in DCM for product) showed the reaction was complete. LC/MS detected the product peak. The reaction was cooled tin an ice-water bath, diluted with 25 mL of ethyl acetate, quenched with 10 mL of water. The two layers were separated. The aqueous layer was extracted with EtOAc (2×10 mL). The combined EtOAc extracts were washed with brine, and concentrated on rotavap to yield a crude product as a slightly yellow solid. This material was loaded onto a 25-g of silica gel column, eluted with DCM and 5% MeOH in DCM to get 0.81 g (95% yield) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].O=S(Cl)Cl.[OH:29][CH:30]([CH:33]1[CH2:37][O:36][C:35]([CH3:39])([CH3:38])[O:34]1)[CH2:31][NH2:32]>C(OCC)(=O)C>[OH:29][CH:30]([CH:33]1[CH2:37][O:36][C:35]([CH3:39])([CH3:38])[O:34]1)[CH2:31][NH:32][C:16](=[O:17])[C:15]1[CH:14]=[CH:13][C:12]([S:9](=[O:11])(=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:21]([F:22])([F:23])[F:24])[CH:4]=2)=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccc(F)c(C(F)(F)F)c2)cc1
Reactant: CC1(C)OCC(C(O)CN)O1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CC1(C)OCC(C(O)CNC(=O)c2ccc(S(=O)(=O)Nc3ccc(F)c(C(F)(F)F)c3)cc2)O1

Procedure:
Analogously to Example 11(a), 3.63 g (10 mmol) of 4-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl)benzoic acid in ethyl acetate with SOCl2 is converted into the acid chloride and the latter is reacted with 1.93 g (12 mmol) of 2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamine and the crude product is purified by chromatography. 4.2 g=82.9% of the theoretical yield of the compound is obtained as an amorphous solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][CH:11]1[O:16][CH:15]([CH3:17])[CH2:14][NH:13][CH2:12]1>>[CH3:17][CH:15]1[O:16][CH:11]([CH3:10])[CH2:12][N:13]([C:2]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=2)[CH2:14]1
Reactant: CC1CNCC(C)O1
Reactant: N#Cc1ccc(F)cc1
Product: CC1CN(c2ccc(CN)cc2)CC(C)O1

Procedure:
4-Fluorobenzonitrile and 2,6-dimethylmorpholine were processed as described in Examples 66A and 66B to provide the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]1[CH2:23][CH2:24][N+]([O-])=O)=[O:9])([CH3:6])([CH3:5])[CH3:4].[Mn]([O-])(=O)(=O)=[O:29].[K+].B(O)(O)O.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+].S(=O)(=O)(O)O>C(O)(C)(C)C.O.CCCCCCC>[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@H:11]1[CH2:23][CH:24]=[O:29])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1CC[N+](=O)[O-]
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: O=S([O-])([O-])=S
Agent: OB(O)O
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CC=O
Reaction time: 0.33 h
Yield: 63.7 %

Procedure:
To 60% sodium hydride (2.56 g, 64 mmol), tert-butylalcohol (50 ml) was added in a nitrogen stream at room temperature and the mixture was stirred for 20 minutes. To this mixture, a solution of (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(2-nitroethyl)pyrrolidine (11.8 g, 32 mmol) in tert-butylalcohol (30 ml) was added at room temperature. After stirring for 20 minutes, the mixture was added to precooled heptane (1 l) in an ice-bath and further stirred for to minutes at 0° C.. To the reaction mixture, a solution of potassium permanganate (5.06 g, 32 mmol) in water (100 ml) and a solution of boric acid (3.94 g, 64 mmol) in water (50 ml) were added, and the mixture stirred for minutes. To the reaction mixture, a solution of sodium thiosulfate pentahydrate (15.88 g, 64 mmol) in water ml) and 1 N sulfuric acid (64 ml) were added. After stirring for 10 minutes, the reaction mixture was filtered with celite and washed with heptane (200 ml). The filtrate and washings were combined, and the organic layer was washed sequentially with a saturated sodium hydrogencarbonate aqueous solution (200 ml) and a saturated sodium chloride aqueous solution (200 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained oily residue was subjected to silica gel column chromatography (Wakogel™ C-300, heptane-ethyl acetate 5:1) to obtain (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(formylmethyl)pyrrolidine (7.0 g, yield: 66%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH2:12][CH3:13])[C@H:3]([OH:10])[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([C:24]([N:26]3[CH2:30][C@H:29]([S:31]([C:34]4[CH:39]=[CH:38][C:37]([O:40][C@@H:41]([CH3:46])[C:42]([F:45])([F:44])[F:43])=[CH:36][C:35]=4[Cl:47])(=[O:33])=[O:32])[CH2:28][C@H:27]3[C:48](O)=[O:49])=[O:25])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1>>[Cl:47][C:35]1[CH:36]=[C:37]([O:40][C@@H:41]([CH3:46])[C:42]([F:45])([F:44])[F:43])[CH:38]=[CH:39][C:34]=1[S:31]([C@H:29]1[CH2:30][N:26]([C:24]([C:21]2([C:18]3[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=3)[CH2:22][CH2:23]2)=[O:25])[C@H:27]([C:48]([NH:1][C@@H:2]([CH2:11][CH2:12][CH3:13])[C:3](=[O:10])[C:4]([NH:6][CH:7]2[CH2:8][CH2:9]2)=[O:5])=[O:49])[CH2:28]1)(=[O:32])=[O:33]
Reactant: C[C@H](Oc1ccc(S(=O)(=O)[C@@H]2C[C@@H](C(=O)O)N(C(=O)C3(c4ccc(Cl)cc4)CC3)C2)c(Cl)c1)C(F)(F)F
Reactant: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(O[C@@H](C)C(F)(F)F)cc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1)C(=O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide and (2S,4R)-1-[1-(4-chloro-phenyl)-cyclopropanecarbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid in step 1. MS (m/e)=746.17 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13]S(C)(=O)=O)[C@H:9]1[C:18]([N:20]1[CH2:26][CH2:25][CH2:24][N:23]([CH:27]2[CH2:30][CH2:29][CH2:28]2)[CH2:22][CH2:21]1)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:33]=[C:34](O)[CH:35]=[CH:36][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=2)[C@H:9]1[C:18]([N:20]1[CH2:26][CH2:25][CH2:24][N:23]([CH:27]2[CH2:30][CH2:29][CH2:28]2)[CH2:22][CH2:21]1)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)[C@H]1C(=O)N1CCCN(C2CCC2)CC1
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cccc(F)c2)[C@H]1C(=O)N1CCCN(C2CCC2)CC1
Temperature: 90 °C
Yield: 15.3 %

Procedure:
A vial containing a mixture of (2S,3S)-2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-3-methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester (106.0 mg, 0.24 mmol), 3-fluorophenol (29.3 mg, 0.26 mmol), and K2CO3 (39.5 mg) in DMF (2.5 mL) was capped and heated for 60 h at 90° C. The mixture was cooled to rt and filtered. The filtrate was concentrated and the residue was purified by FCC to afford the title compound (17 mg, 15%). MS (ESI): mass calcd. for C25H36FN3O4, 461.57; m/z found, 462.3 [M+H]+. 1H NMR (CDCl3): 7.25-7.19 (m, 1H), 6.74-6.64 (m, 2H), 6.64-6.57 (m, 1H), 5.09-4.70 (m, 2H), 3.81-3.49 (m, 6H), 2.90-2.76 (m, 1H), 2.59-2.29 (m, 5H), 2.15-1.72 (m, 7H), 1.64-1.53 (m, 2H), 1.49-1.41 (m, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](Cl)[C:5]2[C:6]([N:19]=1)=[C:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[N:8]=[N:9][CH:10]=2.[C:21]1([CH3:31])[CH:26]=CC(S(O)(=O)=O)=CC=1>C(NCCC)CC>[CH3:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:26][CH2:21][CH3:31])[CH2:7][CH2:6][CH3:5])[C:5]2[C:6]([N:19]=1)=[C:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[N:8]=[N:9][CH:10]=2
Reactant: Cc1cc(Cl)c2cnnc(-c3ccc(Cl)c(Cl)c3)c2n1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCNCCC
Product: CCCN(CCC)c1cc(C)nc2c(-c3ccc(Cl)c(Cl)c3)nncc12
Temperature: 25 °C

Procedure:
Heat a mixture of 2-methyl-4-chloro-8-(3,4-dichlorophenyl)pyrido[2,3-d]pyridazine (4) (2.0 g, 6.2 mmol) and p-toluenesulfonic acid (3.2 g) in 10 mL of di-n-propylamine in a sealed tube at 180° C. for 48 hours. Cool the reaction mixture to ambient temperature and partition the reaction mixture between ethyl acetate and water. Wash the organic layer with water and dry over MgSO4. Evaporate the dried solution and purify the product 5 by flash chromatography.