Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@H:9]1[C@H:13]([F:14])[CH2:12][C@H:11]([CH2:15][C@H:16]2[C:21]([O:22][CH3:23])=N[C@H](C(C)C)C(OC)=[N:17]2)[CH2:10]1)(C(C)(C)C)(C)C.C([O-])([O-])=[O:30].[K+].[K+].[C:35]([O:45]N1C(=O)CCC1=O)([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=O>Cl.C(#N)C.O>[CH2:38]([O:37][C:35]([NH:17][C@@H:16]([CH2:15][C@@H:11]1[CH2:10][C@@H:9]([OH:8])[C@H:13]([F:14])[CH2:12]1)[C:21]([O:22][CH3:23])=[O:30])=[O:45])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1C[C@H]1C[C@@H](F)[C@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)[C@H](C[C@@H]1C[C@@H](O)[C@H](F)C1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
(2S,5R)-2-(((1r*,3R*,4R*)-3-(tert-butyldimethylsilyloxy)-4-fluorocyclopentyl)methyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (500 mg, 1.21 mmol) was dissolved in 1:1 mixture of 1 N HCl solution and acetonitrile (50 mL). The mixture was stirred 3 h at rt, then concentrated. K2CO3 (840 mg, 5 equiv.) and CbzOSu (903 mg, 3 equiv.) were added to the residue, The mixture was dissolved in 1:1 water and acetonitrile (50 mL), stirred overnight at rt. The acetonitrile was removed by evaporation under reduced pressure. The aqueous residue was extracted by EtOAc (3×20 mL). The combined organic layers were washed by brine (20 mL), dried over Na2SO4. After filtration and concentration, the residue was purified by ISCO (40 g column) to afford 274 mg (67% yield) of (s)-methyl 2-(benzyloxycarbonylamino)-3-((1r*,3R*,4R*)-3-fluoro-4-hydroxycyclopentyl)propanoate. MS ESI +ve m/z 362 (M+Na). 1H NMR (CDCl3) δ 7.35 (m, 5H), 5.34 (s, 1H), 5.10 (s, 2H), 4.82 (d, 1H), 4.39-4.19 (m, 2H), 3.73 (s, 3H), 2.43-2.24 (m, 2H), 2.09-1.38 (m, 6H). 19F NMR (CDCl3) δ −175.92.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[C:15]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)(=[O:19])=[O:18])=[CH:14][C:13]([Cl:31])=[CH:12][N:11]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[C:32]([NH:39][CH2:40][C:41](O)=[O:42])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].C(N(C(C)C)CC)(C)C.CCCP(=O)=O>C(Cl)Cl.CCOC(C)=O>[C:35]([O:34][C:32](=[O:33])[NH:39][CH2:40][C:41](=[O:42])[NH:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[C:15]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)(=[O:19])=[O:18])=[CH:14][C:13]([Cl:31])=[CH:12][N:11]=2)=[O:9])[CH:5]=[CH:4][N:3]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccnc(N)c2)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCCP(=O)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccnc(NC(=O)CNC(=O)OC(C)(C)C)c2)cc1C(F)(F)F
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a mixture of N-[2-(2-amino-pyridine-4-carbonyl)-5-chloro-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide (800 mg, 1.69 mmol), Boc-glycine (742 mg, 4.24 mmol), diisopropylethylamine (1.9 mL, 10.14 mmol) in methylene chloride (4 mL) was added propylphosphonic anhydride (2.68 mL, 50% solution in EtOAc, 4.24 mmol) was added slowly. The resultant heterogeneous solution was allowed to stir overnight at 45° C. The following day, the reaction was diluted with EtOAc, the organics were washed with saturated sodium bicarbonate, aqueous saturated NH4Cl and dried with sodium sulfate, concentrated in vacuo, and purified via automated silica gel chromatography to provide ({4-[5-chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine -2-carbonyl]-pyridin-2-ylcarbamoyl}-methyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[CH:8]=O.[C:10]1([C:16]2[O:17][C:18]3[C:19]([N:28]=2)=[C:20]2[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.Cl>N1CCCCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1/[CH:8]=[C:21]1\[C:22](=[O:27])[NH:23][C:24]2[CH:25]=[CH:26][C:18]3[O:17][C:16]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[N:28][C:19]=3[C:20]\1=2
Reactant: O=C1Cc2c(ccc3oc(-c4ccccc4)nc23)N1
Reactant: COc1cc[nH]c1C=O
Agent: Cl
Solvent: O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc3oc(-c4ccccc4)nc3c21
Temperature: 90 °C
Reaction time: 1 h

Procedure:
3-Methoxypyrrole-2-carboxaldehyde (15 mg, 0.12 mmol) (prepared according to F. Bellamy et. al., J. Chem. Research (S) (1979), 18-19; J. Chem Research (M) (1979) 0101-0116), piperidine (3 drops)(Aldrich), and 2-phenyl-6,8-dihydro-oxazolo[4,5-e]indol-7-one (25 mg, 0.10 mmol)(from Example 2) were dissolved in DMF (1 mL). The mixture was heated to 90° C. and stirred at that temperature for 1 h. The mixture was cooled, poured into water, and acidified with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate, and the combined organic extracts were washed with water, brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the crude product was purified by reverse phase HPLC with acetonitrile—water mixture as solvent. (Yield 3.6 mg, 8.4%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O.C(OCC)(=O)C>[CH:36]([C:33]1[CH:34]=[CH:35][C:27]2[C:26]([NH:25][C:17]3[CH:18]=[C:19]([C:20]([N:39]4[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]4)=[O:22])[CH:23]=[CH:24][C:16]=3[S:15][C:12]3[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:10][CH:11]=3)=[N:31][CH:30]=[N:29][C:28]=2[N:32]=1)([CH3:38])[CH3:37]
Reactant: C1CNCCN1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N4CCNCC4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Temperature: 25 °C
Yield: 133 %

Procedure:
To a solution of the product from Example 1E (100 mg, 0.188 mmol) in DMSO (2.0 mL) were added piperazine (16 mg, 0.188 mmol), HATU (79 mg, 0.207 mmol) and Hunigs base (100 μL, 0.564 mmol) and the mixture was stirred at room temperature until the starting material was consumed. Additional product from Example 1E (100 mg, 0.188 mmol), HATU (79 mg, 0.212 mmol), and Hunigs base (100 μL, 0.564 mmol), were added and the reaction was stirred for 2 hours. The reaction was diluted with ethyl acetate and washed water. Dried over Na2SO4, filtered and evaporated. Purification by chromatography on silica gel eluting with (10% methanol in dichloromethane) gave the title compound (150 mg) as a yellow solid.
Reaction SMILES: Cl.C([N:6]([N:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[N+:25]([O-:27])=[O:26])[C:17]1=[O:28])[C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][C:10](=[O:12])[NH2:11])(C)(C)C.CCOCC>C(Cl)Cl>[O:28]=[C:17]1[C:18]2[C:23](=[C:22]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:20][CH:19]=2)[CH2:24][N:16]1[NH:6][C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][C:10](=[O:12])[NH2:11]
Reactant: CC(C)(C)N([C@@H](CCC(N)=O)C(=O)O)N1Cc2c(cccc2[N+](=O)[O-])C1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: NC(=O)CC[C@H](NN1Cc2c(cccc2[N+](=O)[O-])C1=O)C(=O)O
Temperature: 25 °C
Yield: 103.4 %

Procedure:
Hydrogen chloride gas as bubbled into a stirred 5° C. solution of t-butyl N-(1-oxo-4-nitro-isoindolin-2-yl)-L-glutamine (3.6 g, 9.9 mmol) in methylene chloride (60 mL) for 1 hour. The mixture was then stirred at room temperature for another hour. Ether (40 mL) was added and the resulting mixture was stirred for 30 minutes. The slurry was filtered, washed with ether and dried to afford 3.3 g of the product: 1H NMR (DMSO-d6) δ 8.45(d, J=8.1 Hz, 1H), 8.15(d, J=7.5 Hz, 1H), 7.83(t, J=7.9 H 1H), 7.24(s, 1H), 6.76(s, 1H), 4.93(s, 2H), 4.84–4.78(dd, J=4.8amd 10.4 Hz 2.34–2.10(m, 4H); 13C NMR (DMSO-d6) δ 173.03, 171.88, 165.96, 143.35, 137.49, 134.77, 130.10, 129.61, 126.95, 53.65, 48.13. 31.50, 24.69; Anal. Calcd for C13H13N3O6: C, 50.82; H, 4.26; N, 13.68. Found: C, 50.53; H, 4.37; N, 13.22,
Reaction SMILES: [CH2:1](OC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)C1C=CC=CC=1>O>[C:22]1([N:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(COc2ccccc2)cc1
Reactant: c1ccc(Nc2ccccc2)cc1
Solvent: ClCc1ccccc1
Solvent: O
Product: c1ccc(CN(c2ccccc2)c2ccccc2)cc1

Procedure:
N-phenylbanzaldimine (1.81 g, 0.010 mol) and benzylphenyl ether (1.84 g, 0.010 mol) were heated at 75° C. in Na/DMF solution (2.0 g; 50 mL) for 30 minutes. The solution was then poured in 200 mL of water, the precipitate was filtered washed with water and dried. Recrystallization from methanol, 70 mL, gave white needles (73% isolated) mp 88°-90° C. (lit mp 86°-7°C8, 88°-9°C9). No depression in melting point occurred when this material was admixed with an authentic sample prepared from diphenylamine and benzyl chloride.
Reaction SMILES: O=[C:2]1[CH2:20][CH2:19][N:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]2[CH2:3]1.C1C=CC=CC=1.[C:27](#[N:29])[CH3:28]>>[C:27]([CH:28]=[C:2]1[CH2:20][CH2:19][N:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]2[CH2:3]1)#[N:29]
Reactant: CC#N
Reactant: O=C1CCN2c3ccccc3Cc3ccccc3C2C1
Solvent: c1ccccc1
Product: N#CC=C1CCN2c3ccccc3Cc3ccccc3C2C1

Procedure:
1 of 2-keto-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f]-azepine is mixed with 1 ml of benzene, 0.5 ml of acetonitril and 0.5 g. of molecular sieve (4 A). 50 mg of sodium-ethoxyde are added and the mixture is heated for 3 hours (90°-100° C). After cooling the mixture the molecular sieve is filtered off and the filtrate evaporated. The precipitate is recrystallized from ethanol.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=[O:8])=CC=1.[C:12]1([N:18]2[C:26]3[CH2:25][CH2:24][CH2:23][C:22](=[CH:27][CH2:28][N+:29]4[CH:34]=[CH:33]C=[CH:31][CH:30]=4)[C:21]=3[CH:20]=[N:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CCOCC1>C(#N)C.C(OCC)(=O)C>[N:29]1([CH2:28]/[CH:27]=[C:22]2/[C:21]3[CH:20]=[N:19][N:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:26]=3[CH2:25][CH2:24][CH2:23]/2)[CH2:34][CH2:33][O:8][CH2:31][CH2:30]1
Reactant: C(C[n+]1ccccc1)=C1CCCc2c1cnn2-c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: C1COCCN1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C(\CN1CCOCC1)=C1\CCCc2c1cnn2-c1ccccc1
Yield: 57.1 %

Procedure:
A mixture of 1-[2-(1-phenyl-1,5,6,7-tetrahydro-indazol-4-ylidene)-ethyl]-pyridinium toluene-4-sulfonate (290 mg, 0.63 mmol) and morpholin (180 mg, 1.5 mmol) in 15 mL of acetonitrile is refluxed during 4 hours, following the reaction by TLC. The solvent is next evaporated, the crude is diluted in ethyl acetate and washed three times with water. Then the organic phase is evaporated under reduced pressure. The crude thus obtained is purified by silica gel cgromatography giving (E)-4,5,6,7-tetrahydro-4-(2-(morpholin-4-yl)ethylidene)-1-phenyl-1H-indazole (110 mg, 0.36 mmol, 57%, beige solid, m.p=114-116° C.).
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:15]1[CH2:38][CH:37]([C:39]2[O:43][N:42]=[C:41]([CH3:44])[N:40]=2)[O:36][C:17]2([CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([CH3:35])[CH:26]=3)=[O:24])[CH2:19][CH2:18]2)[CH2:16]1)C1C=CC=CC=1>ClCCCl>[ClH:1].[CH:32]([O:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]([N:20]2[CH2:21][CH2:22][C:17]3([O:36][CH:37]([C:39]4[O:43][N:42]=[C:41]([CH3:44])[N:40]=4)[CH2:38][NH:15][CH2:16]3)[CH2:18][CH2:19]2)=[O:24])=[CH:26][C:27]=1[CH3:35])([CH3:34])[CH3:33]
Reactant: Cc1noc(C2CN(Cc3ccccc3)CC3(CCN(C(=O)c4ccc(OC(C)C)c(C)c4)CC3)O2)n1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: Cc1noc(C2CNCC3(CCN(C(=O)c4ccc(OC(C)C)c(C)c4)CC3)O2)n1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
A solution of 1-chloroethyl chloroformate (89 μL, 0.80 mmol) in DCE (0.1 mL) was added to a stirred solution of [8-benzyl-10-(3-methyl-1,2,4-oxadiazol-5-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (67 mg, 0.13 mmol) in DCE (488 μL) under an atmosphere of nitrogen and the reaction mixture was heated to reflux. After 1 hour, an additional aliquot of 1-chloroethyl chloroformate (89 μL, 0.80 mmol) was added and the reaction mixture was heated to reflux for a further 8 hours. After 8 hours, an additional 1-chloroethyl chloroformate (89 μL, 0.80 mmol) was added and the reaction mixture was heated to reflux for a further 15 hours. The excess solvent was removed under reduced pressure and the carbamate intermediate was dissolved in MeOH (2 mL) and heated at reflux for 1 hour. The reaction mixture was cooled to room temperature, filtered and purified by Waters mass directed LC/MS-HPLC: (10-99% ACN/H2O (5 mM HCl)) to afford (4-isopropoxy-3-methyl-phenyl)-[10-(3-methyl-1,2,4-oxadiazol-5-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanone hydrochloride salt (28 mg, 47%). ESI-MS m/z calc. 414.2. found 415.7 (M+1)+; Retention time: 1.54 minutes (3 min run).
Reaction SMILES: [CH2:1]([C:8]([N:26]([CH3:28])[CH3:27])([CH2:24][CH3:25])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20]O)=[C:13]([O:22][CH3:23])[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:49]>C(Cl)Cl>[CH2:1]([C:8]([N:26]([CH3:28])[CH3:27])([CH2:24][CH3:25])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][Br:49])=[C:13]([O:22][CH3:23])[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(OCCCO)c(OC)c1)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(OCCCBr)c(OC)c1)N(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
14.3 g (37.1 mmol) of 2-benzyl-2-dimethylamino-1-[4-(3-hydroxy-propoxy)-3-methoxy-phenyl]-butan-1-one are dissolved in 200 ml of methylene chloride, and 10.7 g (40.8 mmol) of triphenylphosphine and 13.5 g (40.8 mmol) of carbon tetrabromide are added at 0° C. successively. The solution is stirred at 0° C. for 0.5 h. Then the solution is concentrated to give the crude product, which is purified by column chromatography on silica gel with ethyl acetate-hexane (20:80) as an eluent. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 0.69 (t, 3H), 1.83-1.92 (m, 1H), 2.03-2.13 (m, 1H), 2.38 (s, 6H), 2.38-2.45 (m, 2H), 3.17-3.25 (m, 2H), 3.64 (t, 2H), 3.88 (s, 3H), 4.22 (t, 2H), 6.86 (d, 1H), 7.15-7.28 (m, 5H), 7.93 (d, 1H), 8.20 (dd, 1H).
Reaction SMILES: [N:1]1([CH2:7][C:8]#[C:9][C:10](=O)[CH3:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br.[CH2:14]([S:20][C:21](=[NH:23])[NH2:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:14]([S:20][C:21]1[N:23]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:9]=[C:10]([CH3:11])[N:22]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCSC(=N)N
Reactant: CC(=O)C#CCN1CCOCC1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCSc1nc(C)cc(CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-Morpholin-4-yl-pent-3-yn-2-one (1 g, 6 mmol) and 2-hexyl-isothiourea hydrobromide (1.06 g, 7 mmol) were dissolved under nitrogen in DMF (10 mL), then N,N-diisopropyl ethylamine (4.1 mL, 24 mmol) was added and stirring at the room temperature continued for 18 hours.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])=O.[S:13]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=2[N:15]=[C:14]1[CH2:22][C:23]([CH3:25])=O.[NH2:26]/[C:27](/[CH3:31])=[CH:28]\[C:29]#[N:30]>C(O)(C)C>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH:1]2[C:22]([C:14]3[S:13][C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=4[N:15]=3)=[C:23]([CH3:25])[NH:26][C:27]([CH3:31])=[C:28]2[C:29]#[N:30])=[C:4]([O:11][CH3:12])[CH:5]=1)#[N:8]
Reactant: C/C(N)=C/C#N
Reactant: COc1cc(C#N)ccc1C=O
Reactant: CC(=O)Cc1nc2c(s1)CCCC2
Solvent: CC(C)O
Product: COc1cc(C#N)ccc1C1C(C#N)=C(C)NC(C)=C1c1nc2c(s1)CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.931 mmol) of the compound from example 3A, 181 mg (0.931 mmol) of the compound from example 19A and 76 mg (0.931 mmol) of 3-aminocrotononitrile are dissolved in 4 ml of isopropanol and stirred at the reflux temperature overnight. After cooling to room temperature, the volatile components are removed in a rotary evaporator, and the crude product is taken up in 3 ml of ethyl acetate. The crystallizing solid is removed by filtration. The precipitate obtained in this way is washed with hot acetonitrile and dried under high vacuum. 131 mg (35% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6])#[N:2].[Cl:14][C:15]([Cl:21])([S:19]Cl)[CH:16]([Cl:18])[Cl:17].C(N(CC)CC)C>C(Cl)Cl>[C:1]([CH2:3][N:4]([S:19][C:15]([Cl:21])([Cl:14])[CH:16]([Cl:18])[Cl:17])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])=[O:7])#[N:2]
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Reactant: N#CCNS(=O)(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCN(SC(Cl)(Cl)C(Cl)Cl)S(=O)(=O)c1ccccc1
Reaction time: 0.33 h
Yield: 65 %

Procedure:
To a stirred solution of 5.0 g (0.025 mole) N-cyanomethyl phenylsulfonamide (the product of Example 6) and 6.0 g (0.026 mole) 1,1,2,2-tetrachloroethylsulfenyl chloride in 125 ml methylene chloride, 3.2 g (0.032 mole) triethylamine in 25 ml methylene chloride were dropped in over 35 minutes. The reaction mixture was stirred 20 minutes. The reaction mixture was washed three times with 75 ml portions of water, dried over magnesium sulfate and stripped to give 6.4 g of a brown oil. The oil crystallized when hexane was added to it and the resulting mixture was cooled in an ice bath. The solids were taken up with 25 ml toluene, treated with charcoal and filtered, Hexane, 25 ml, was added to the toluene filtrate, and the resulting mixture was cooled in an ice bath to give 2.3 g of yellow crystals, melting point 89°-101° C. The crystals were recrystallized from a mixture of 25 ml hexane and 5 ml toluene. The filtrate was cooled in an ice bath to give 0.8 g of the above-identified product as a white solid, melting point 106° C.-108° C.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].C(=O)([O-])[O-].[K+].[K+].[NH2:11][C:12]1[C:16]([C:17]#[N:18])=[C:15]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20]2)[N:14]([CH2:33][C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[Cl:41])[C:13]=1[C:42]([O:44]CC)=O.C1(C)C=CC=CC=1>N1C=CC=CC=1>[Cl:41][C:35]1[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:34]=1[CH2:33][N:14]1[C:13]2[C:42](=[O:44])[N:2]([CH3:1])[C:3](=[S:4])[NH:11][C:12]=2[C:16]([C:17]#[N:18])=[C:15]1[N:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:27])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:20]1
Reactant: CN=C=S
Reactant: CCOC(=O)c1c(N)c(C#N)c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n1Cc1cc(F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cn1c(=S)[nH]c2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3cc(F)ccc3Cl)c2c1=O
Temperature: 130 °C

Procedure:
Methyl isothiocyanate (7.36 ml) and potassium carbonate (14.86 g) were added to a solution (200 ml) of ethyl 3-amino-5-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-1-(2-chloro-5-fluorobenzyl)-4-cyano-1H-pyrrole-2-carboxylate (27.96 g) in pyridine, and the resulting mixture was stirred with heating at 130° C. for 13 hours. After the reaction solution was cooled to 25° C., toluene (50 ml) was added thereto and the resulting mixture was concentrated under reduced pressure. This procedure was repeated three times. The resulting residue was adjusted to pH 2 with an aqueous potassium hydrogensulfate solution and the solid precipitated was collected by filtration and washed with water and then hexane. The solid thus obtained was dried at 45° C. under reduced pressure to obtain the title compound (28.56 g).
Reaction SMILES: N#N.C(OC([C@@:13]1([C:30]([NH2:32])=[O:31])[CH2:17][C@@H:16]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][N:14]1[C:26]([CH3:29])([CH3:28])[CH3:27])=O)C1C=CC=CC=1>C(O)C.[Pd]>[C:22]([O:21][C:19]([NH:18][C@H:16]1[CH2:15][N:14]([C:26]([CH3:29])([CH3:28])[CH3:27])[C@H:13]([C:30]([NH2:32])=[O:31])[CH2:17]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(C(C)(C)C)[C@@](C(N)=O)(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(N)=O)N(C(C)(C)C)C1
Yield: 106.6 %

Procedure:
0.25 g of N2 -(benzyloxycarbonyl)-4(R)-(tert.butoxyformamido)-N1 -tert.butyl-L-prolinamide was dissolved in ethanol and hydrogenated over 0.1 g of 10% palladium-on-carbon at room temperature and under atmospheric pressure for 4 hours. The catalyst was filtered off and the filtrate was evaporated to give 0.17 g of 4(R)-(tert.butoxyformamido)-N1 -tert.butyl-L-prolinamide as a glass which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[Br:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>C(OCC)(=O)C>[Br:23][CH2:24][CH2:25][CH2:26][C:27]([N:12]1[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[S:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:13]1)=[O:28]
Reactant: Clc1ccc(C2CNc3ccccc3S2)cc1
Reactant: O=C(Cl)CCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CCCBr)N1CC(c2ccc(Cl)cc2)Sc2ccccc21
Yield: 93.2 %

Procedure:
To a mixture of 2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (1.08 g), ethyl acetate (20 ml) and aqueous sodium hydrogen carbonate solution (20 ml) is added dropwise a solution of 4-bromobutyryl chloride (0.97 g) in ethyl acetate (5 ml) with stirring under ice cooling. The ethyl acetate layer is washed, dried and distilled to remove the solvent. The residue is recrystallized from ethyl acetate-n-hexane to give 4-(4-bromobutyryl)-2-(4-chlorophenyl)-3,4-dihyro-2H-1,4-benzothiazine (1.58 g, yield 93%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:13][C:12]2[S:11][C:10]3[C:9](=[O:14])[NH:8][N:7]=[CH:6][C:5]=3[C:4]=2[CH2:3]1.[Br:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21](Br)[C:18]=1[CH:19]=[O:20].N(CC(O)=O)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[Br:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([N:8]2[N:7]=[CH:6][C:5]3[C:4]4[CH2:3][C:2]([CH3:15])([CH3:1])[CH2:13][C:12]=4[S:11][C:10]=3[C:9]2=[O:14])[C:18]=1[CH:19]=[O:20]
Reactant: O=Cc1c(Br)cc(F)cc1Br
Reactant: CC1(C)Cc2sc3c(=O)[nH]ncc3c2C1
Agent: CNCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC1(C)Cc2sc3c(=O)n(-c4cc(F)cc(Br)c4C=O)ncc3c2C1
Temperature: 95 °C

Procedure:
A 100-mL round bottom flask equipped with a magnetic stirrer and a reflux condenser was charged with 131h (330 mg, 1.5 mmol), 2,6-dibromo-4-fluorobenzaldehyde (1.26 g, 4.5 mmol), CuBr (113 mg, 0.8 mmol), sarcosine (142 mg, 1.6 mmol), K2CO3 (420 mg, 3.0 mmol), and dioxane (20 mL). See FIG. 15. After three cycles of vacuum/argon flush, the mixture was heated at 95° C. for 15 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography 5:1 eluting with petroleum ether/ethyl acetate to 131i as a white solid (380 mg, 60%). MS-ESI: [M+H]+ 420.6