Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:10]2[N:11](C3C=C[C:19]([S:22](=O)(=O)N)=CC=3)[CH:12]=[C:13](C)[CH:14]=2)[CH:5]=[CH:6][C:7]=1OC.C[O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]2[C:40]2[CH:45]=[CH:44][C:43]([S:46](=[O:49])(=[O:48])[NH2:47])=[CH:42][CH:41]=2)=[CH:30][CH:29]=1>>[CH2:14]([CH2:13][C:12]#[N:11])[C:10]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1)=[O:27].[CH3:39][C:37]1[CH:36]=[C:35]([C:40]2[CH:45]=[CH:44][C:43]([S:46](=[O:49])(=[O:48])[NH2:47])=[CH:42][CH:41]=2)[N:34]([C:31]2[CH:32]=[CH:33][C:28]([S:22][CH3:19])=[CH:29][CH:30]=2)[CH:38]=1
Reactant: COc1ccc(-n2cc(C)cc2-c2ccc(S(N)(=O)=O)cc2)cc1
Reactant: COc1ccc(-c2cc(C)cn2-c2ccc(S(N)(=O)=O)cc2)cc1Cl
Product: CSc1ccc(-n2cc(C)cc2-c2ccc(S(N)(=O)=O)cc2)cc1
Product: N#CCCC(=O)c1ccccc1

Procedure:
In this Step, a phenacyl acetonitrile compound of formula (17) is prepared by alkylating the cyano compound of formula (16) with a phenacyl halide compound of formula (7). This reaction is essentially the same as and may be carried out in the same manner as and using the same reagents and reaction conditions as Step B3 of Method B.
Reaction SMILES: [C:1]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[SH:19][CH2:20][C:21]([OH:23])=[O:22]>>[C:21]([CH2:20][S:19][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[O:12])([OH:23])=[O:22]
Reactant: O=C(O)CS
Reactant: C=CCCCCCCCCC(=O)N1CCOCC1
Product: O=C(O)CSCCCCCCCCCCC(=O)N1CCOCC1
Temperature: 60 °C

Procedure:
5 g (.02 mole) of 10-undecenoylmorpholine and 2.3 g (.025 mole) of mercaptoacetic acid were placed in a flask equipped with stirring bar. The temperature was raised to 60° C and maintained there for two hours with stirring. The excess mercaptoacetic acid was removed by distillation at reduced pressure and water washings.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:8]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH2:23][CH3:24])[CH:17]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.O[N:26]1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[Cl-].[NH4+].C(N(CC)CC)C>CN(C)C=O.O>[NH2:1][C:2]1[N:10]=[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:8]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH2:23][CH3:24])[CH:17]=2)=[CH:7][C:3]=1[C:4]([NH2:26])=[O:6]
Reactant: On1nnc2ccccc21
Reactant: CCn1cc(-c2cc(C(=O)O)c(N)nc2-c2ccco2)ccc1=O
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1cc(-c2cc(C(N)=O)c(N)nc2-c2ccco2)ccc1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.1 %

Procedure:
2-Amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinic acid (20 mg, 61.5 μmol), 1-hydroxybenzotriazole (28 mg, 183 μmol), 3-(3′-dimethylaminopropyl)-1-ethyl carbodiimide (29 mg, 187 μmol), ammonium chloride (16 mg, 299 μmol), and a suspension of triethylamine (43 μL, 309 μmol) in N,N-dimethylformamide (1.0 mL) was stirred at room temperature for 18 hours. After diluting the reaction solution with water, the resulting solid was collected by filtration and washed with water, to give the title compound (9 mg, 45%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@H:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:23][C:22]4[C:17](=[CH:18][C:19]([Cl:24])=[CH:20][CH:21]=4)[C:16]3=[O:25])=[CH:11][CH:10]=2)[N:6]=1>CO>[ClH:24].[NH2:1][C:2]1[O:3][CH2:4][C@H:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]3=[O:25])=[CH:11][CH:10]=2)[N:6]=1
Reactant: NC1=N[C@@H](CCc2ccc(N3Cc4ccc(Cl)cc4C3=O)cc2)CO1
Solvent: CO
Product: Cl
Product: NC1=N[C@@H](CCc2ccc(N3Cc4ccccc4C3=O)cc2)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a stirred solution of 2-{4-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-6-chloro-2,3-dihydro-isoindol-1-one (9 mg) in methanol (3 ml) was added 10% paladium on charcoal (2.7 mg) and the mixture was then stirred under an atmosphere of hydrogen at room temperature for 2 hours. The mixture was then filtered through celite and the filtrate was concentrated in vacuo to afford (S)-2-(4-(2-(2-amino-4,5-dihydrooxazol-4-yl)ethyl)phenyl)isoindolin-1-one hydrochloride (9 mg, 55%) as a white solid. MS (ISP): 322.2 ([M+H]+)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C@H:10]3[CH2:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][CH2:15][C@@H:9]3[C:8]([CH3:20])([CH3:19])[O:7][C:6]=2[CH:5]=[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.O[N:42]1[C:46](=[O:47])[CH2:45][CH2:44][C:43]1=[O:48]>C1COCC1>[OH:1][C:2]1[C:11]2[C@H:10]3[CH2:12][C:13]([C:16]([O:18][N:42]4[C:46](=[O:47])[CH2:45][CH2:44][C:43]4=[O:48])=[O:17])=[CH:14][CH2:15][C@@H:9]3[C:8]([CH3:19])([CH3:20])[O:7][C:6]=2[CH:5]=[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:3]=1
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@H]1CC=C(C(=O)O)C[C@H]21
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@H]1CC=C(C(=O)ON3C(=O)CCC3=O)C[C@H]21
Reaction time: 43 h

Procedure:
With reference to scheme 3, to a solution of (XVIII) (6 mg, 0.017 mmol) in dry THF (2 mL), under argon, was added dicyclohexylcarbodiimide (Aldrich; 13 mg, 0.063 mmol) and N-hydroxysuccinimide (Aldrich; 11 mg, 0.096 mmol). The resulting reaction mixture was stirred for 43 h, filtered from dicyclohexylurea, and the filtrate evaporated in vacuo to afford white solids. This material was digested with a small volume of THF and the insoluble part (urea) was filtered off. The filtrate was evaporated in vacuo to dryness and the process repeated to give a foam which was subjected to preparative TLC on silica, eluting with EtOAc-hexanes (1:1), to give 5 mg, 67%, of the NHS ester as an off-white foam.
Reaction SMILES: [N:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[P:6]([O-:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.P(C1CCCN1)(=O)=O.N1CCC[C@H]1C(O)=O.C[C@H](NC([C@H]1N(C([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](N)CC(O)=O)=O)CCCNC(N)=N)=O)C(C)C)=O)CC2C=CC(O)=CC=2)=O)C(C)C)=O)CC2NC=NC=2)=O)CCC1)=O)C(O)=O>>[NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[P:6]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:21])[O:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C1=NCCC1
Reactant: [O-]P(Oc1ccccc1)Oc1ccccc1
Agent: CC(C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CC(=O)O)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)O)C(C)C
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P(=O)C1CCCN1
Product: O=P(Oc1ccccc1)(Oc1ccccc1)C1CCCN1
Temperature: 85 °C
Yield: 49 %

Procedure:
This compound was synthesized from 1-pyrroline trimer (Nomura, Y., Ogawa, K., Takeuchi, Y., Tomoda, S., One Step Synthesis and Structural Confirmation with 1-Pyrroline Trimer, Chem. Lett. 1977, 693-696) and diphenyl phosphite using the procedure previously described for the synthesis of the diethyl ester (Petrillo, E. W., Spitzmiller, E. R., Synthesis of 2-Phosphopyrrolidine and Its Substitution for Proline in an Inhibitor of Angiotensin-Converting Enzyme, Tet. Lett. 1979, 51, 4929). A mixture of 1-pyrroline trimer (17 mmol, 3.5 g) and diphenyl phosphite (50 mmol, 11.7 g) was heated at 85° C. for 1.5 h under argon to give crude diphenyl pyrrolidine-2-phosphonate which was dissolved in 100 ml of dry diethyl ether, filtered and saturated with dry gaseous HCl. The precipitated hydrochloride 1 was collected by filtration, washed with ether and recrystallized from acetone, to give the pure product as a white solid in 49% yield: mp 146°-148° C.; 1H-NMR (D2O) δ(ppm): 2.0-2.5 (m, 4H), 3.40 (m, 2H), 4.25 (m, 1H), 6.90-7.30 (m, 10H); MS (FAB) m/e 304 (M-Cl)30. Anal. (C16H19NO3PCl): C, H, N, Cl.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[C:23]([N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH:35]3[CH2:37][CH2:36]3)[CH2:27][CH2:26]2)=[O:24])[C:13]([Cl:38])=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9](O)=[O:10])=[O:5].[NH2:39]CCC(N)=O>>[C:9]([CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:12]=[C:13]([Cl:38])[C:14]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[C:23]([N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH:35]3[CH2:36][CH2:37]3)[CH2:27][CH2:26]2)=[O:24])=[CH:15][C:2]=1[Cl:1])(=[O:10])[NH2:39]
Reactant: NCCC(N)=O
Reactant: O=C(O)CCNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Product: NC(=O)CCNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl

Procedure:
The title compound was prepared in analogy to Example 52, from 3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-propionic acid (Example 34) and 3-amino-propionamide (commercially available, CAS RN 4726-85-6). Light brown foam (74%). MS (ESI): m/z=554.136 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:21]=2[F:22])[N:18]([CH3:23])[C:17](=[O:24])[CH2:16][CH2:15]3)[CH:9]=[N:10][CH:11]=1.[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26]>>[F:22][C:21]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][C:17](=[O:24])[N:18]2[CH3:23])=[CH:13][C:12]=1[C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH2:3][NH:2][S:27]([CH2:25][CH3:26])(=[O:29])=[O:28])[CH:11]=[N:10][CH:9]=1
Reactant: CN1C(=O)CCc2cc(-c3cncc(OCCN)c3)c(F)cc21
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Product: CCS(=O)(=O)NCCOc1cncc(-c2cc3c(cc2F)N(C)C(=O)CC3)c1

Procedure:
In analogy to the procedure described for the preparation of example 38, 6-[5-(2-amino-ethoxy)-pyridin-3-yl]-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 238) and ethanesulfonyl chloride gave the title compound as an orange amorphous solid. MS: 408.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[O:15])[C:11]3[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.Cl.C([NH+](CC)CC)C.[N-:45]=[N+:46]=[N-:47].[Na+].Cl>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[NH:47][N:46]=[N:45][N:24]=4)=[CH:21][CH:22]=3)=[O:15])[C:11]3[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccc(-c2nnn[nH]2)cc1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 145 °C
Reaction time: 2.5 h
Yield: 68 %

Procedure:
The suspension of 0.13 g (0.25 mmol) 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-N-(4-cyano-phenyl)-2-cyclohexyl-acetamide, 0.17 g (1.26 mmol) triethylammonium hydrochloride and 82 mg (1.26 mmol) sodium azide in 3 mL ortho-xylene was stirred at 145° C. for 2.5 hrs. The brown suspension was poured on 1M aqueous hydrochloric acid solution and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness. The residue was dissolved in acetonitrile and a few drops of water were added upon which precipitation started. The formed suspension was filtered and the solid was washed with acetonitrile containing a few drops of water to give the desired compound as a white solid (68%). MS (ES+): 548.3 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[NH2:5].CC(S(N)=O)(C)C.Cl[C:31]1[N:36]=[CH:35][C:34]([C:37]([O:39][CH3:40])=[O:38])=[CH:33][N:32]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:1][CH:2]([CH3:22])[CH2:3][CH:4]([NH:5][C:31]1[N:36]=[CH:35][C:34]([C:37]([O:39][CH3:40])=[O:38])=[CH:33][N:32]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)c1cnc(Cl)nc1
Reactant: CC(C)CC(N)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CC(C)(C)S(N)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)c1cnc(NC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Temperature: 100 °C
Yield: 112.7 %

Procedure:
A solution of 3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butan-1-amine (307 mg, 1 mmol), prepared as in example 1.1 using racemic 2-methylpropane-2-sulfinamide, methyl 2-chloropyrimidine-5-carboxylate (186 mg, 1 mmol) and diisopropylethylamine (516 mg, 4 mmol) in 2-propanol (3 mL) was heated to 100° C. for 3 hours. The mixture was concentrated under reduced pressure and the crude residue was purified by column chromatography to give methyl 2-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)pyrimidine-5-carboxylate (500 mg, 87.3%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([OH:11])=[CH:9][N:8]([CH3:12])[C:7]=1[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2].[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([C:9]2[N:8]([CH3:12])[C:7]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:10]=2[OH:11])=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(O)cn1C
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Cc1c(C(=O)OCC)c(O)c(C(=O)c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
Ethyl 3-ethoxycarbonyl-4-hydroxy-1-methylpyrrole-2-acetate (255 mg, 1.0 mmol) is mixed with p-chlorobenzoyl chloride (385 μl, 3.0 mmol) under nitrogen, and 2.0 ml anhydrous trifluoromethanesulfonic acid is added. The reaction mixture is stirred at room temperature for one hour followed by dilution with methylene chloride (50 ml). Solid sodium bicarbonate is slowly added until the acid is neutralized. The solids are filtered off and washed with an additional 50 ml methylene chloride. The combined methylene chloride solutions are washed with water (20 ml) and saturated brine (50 ml). Subsequently, the washed layers are dried with sodium sulfate and the solvent is removed in vacuo to give a red solid which is recrystallized from ethanol to give 275 mg (70%) of ethyl 5-(p-chlorobenzoyl)-3-ethoxycarbonyl-4-hydroxy-1-methylpyrrole-2-acetate, m.p. 145°-147° C.
Reaction SMILES: C1(O)C=CC=CC=1.C(O)C/C=C/CCCCCC.CCOC(/N=N/C(OCC)=O)=O.[CH3:31][O:32][C:33](=[O:59])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]CCCCCCCC)=[CH:36][CH:35]=1>CCOCC>[CH3:31][O:32][C:33](=[O:59])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42]/[CH:43]=[CH:44]/[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:36][CH:35]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: CCCCCC/C=C/CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: Oc1ccccc1
Solvent: CCOCC
Product: CCCCCC/C=C/CCOc1ccc(C(=O)OC)cc1
Yield: 85 %

Procedure:
Ester 34 (500 mg, 3.29 mmol), 3-decenol 26h (514 mg, 3.29 mmol), TPP (992 mg, 3.78 mmol), DEAD (658 mg, 3.78 mmol), and 33 ml ether were reacted according to the procedure for compound 35a. The crude product was purified via flash chromatography over silica gel with gradual elutions from 95/5-90/10 (v/v, Hex/EtOAc). Evaporation of solvent yielded 810 mg (85%) of colorless liquid which was not quite pure. The product was used without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[CH:13][CH:14]=2)[N:9]([CH3:20])[CH:8]=1.C(N(CC)CC)C.O>ClCCl>[CH3:1][S:2]([O:6][C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[CH:13][CH:14]=2)[N:9]([CH3:20])[CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(=O)c(O)cn(C)c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(=O)c(OS(C)(=O)=O)cn(C)c2c1

Procedure:
Methanesulphonyl chloride (0.88 ml) was added to a stirred suspension of 3-hydroxy-7-methoxy-1-methyl-4quinolone (0.7 g) and triethylamine (2.4 ml) in dry dichloromethane (100 ml) at ambient temperature and the resultant solution stirred for 3 hours. Water (50 ml) was added and the layers separated. The dichloromethane layer was dried over magnesium sulphate and the solvent evaporated. The residue was purified by flash chromatography on a silica gel column eluted with dichloromethane:methanol (19:1) followed by crystallisation from acetonitrile:methanol (20:1, 10 ml) to give the novel compound 7-methoxy-1-methyl-4-oxo-1,4-dihydroquinol-3-yl methanesulphonate, m.p. 163°.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[C:11](O)(=[O:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[O:2]1[C:6]2[CH2:7][N:8]([C:11](=[O:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1
Reactant: CCCCCCCCCC(=O)O
Reactant: c1cc2c(o1)CNCC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)N1CCc2ccoc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.19 g (1.1 mmol) of n-decanoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel chromatography (hexane/ethyl acetate=10/1) to yield the desired product.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:6]([Se:19][C:20]2[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=2)=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1.[I-:31].[Na+].O.C(OCC)C>CCC(C)=O>[I:31][CH2:2][CH2:3][O:4][C:5]1[C:6]([Se:19][C:20]2[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=2)=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1
Reactant: [I-]
Reactant: CCOC(=O)c1ccc([Se]c2cc3c(cc2OCCCl)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc([Se]c2cc3c(cc2OCCI)C(C)(C)CCC3(C)C)cc1
Yield: 67.9 %

Procedure:
A mixture of 200 mg (0.4 mmol) of ethyl 4-[3-(2-chloroethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanyl]benzoate with 607 mg (4 mmol) of sodium iodide in MEK (4 ml) is refluxed for 12 h. The reaction medium is treated with water and ethyl ether. The organic phase is washed with water, dried over magnesium sulphate and concentrated on a rotary evaporator. The oil obtained is reacted under the same conditions. 159 mg (68%) of a yellow solid are obtained. m.p.=87° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][OH:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:20]2[S:33][CH:32]=[CH:31][C:21]=2[N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[N:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O.C(OCC)(=O)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:20]2[S:33][CH:32]=[CH:31][C:21]=2[N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[N:23]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(CO)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
To a solution of 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester [373 mg, 0.794 mmol Intermediate (10)] in Dichloromethane (20 mL) is added Dess-Martin Periodinane (407 mg, 0.959 mmol). Stirred at room temperature for 30 minutes. Water (10 mL) is added and stirred for 30 minutes at room temperature. The reaction mixture is dissolved with ethyl acetate (30 mL) and washed twice with a mixture of 10% Na2S2O3/saturated NaHCO3 (4 mL) solution. The ethyl acetate phase is washed with water, NaHCO3, brine and dried over sodium sulfate. The residue is chromatographed on 10 g silica gel cartridge eluting with 30 to 40% ethyl acetate gradient in heptane to afford 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-formyl-indole-1-carboxylic acid tert-butyl ester [300 mg, 81%, Intermediate (11)] as a white solid; 1H NMR [(CD3)2SO)]: δ 10.079 (1H, s, CHO), 8.323 (1H, s), 8.318 (1H, d), 8.017 (1H, s), 7.978 (1H, d), 7.391 (1H, d), 7.345 (1H, s), 1.660 (9H, s), 1.341 (9H, s); TLC data Rf=0.37 (30% ethyl acetate in heptane).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([Cl:19])=[CH:15][C:16]=3[CH3:18])[C:11](=O)[C:10]2=[O:21])=[O:8])[N:4]([C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[N:3]=1.[CH3:29][NH2:30].[C:31](#[N:33])C>>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:9][C:17]2[C:12](/[C:11](=[N:33]\[CH3:31])/[C:10]([NH:30][CH3:29])=[O:21])=[CH:13][C:14]([Cl:19])=[CH:15][C:16]=2[CH3:18])=[O:8])[N:4]([C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[N:3]=1
Reactant: CN
Reactant: Cc1cc(Cl)cc2c1N(C(=O)c1cc(Br)nn1-c1ncccc1Cl)C(=O)C2=O
Reactant: CC#N
Product: C/N=C(/C(=O)NC)c1cc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A suspension of 1-[[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]carbonyl]-5-chloro-7-methyl-1H-indole-2,3-dione (i.e. the crude product of Example 5) (4.80 g, 10 mmol) in acetonitrile (15 mL) was cooled to −10° C., and liquefied methylamine (0.35 g, 11 mmol) was added. The mixture was stirred for 1 hour at −10° C., then warmed to 0° C., and three more portions of liquefied methylamine (each 0.35 g, 11 mmol) were added periodically. Finally the reaction mass was filtered, and the solids were washed with acetonitrile (3×2 mL) and dried under nitrogen to afford the title product, a compound of the present invention, as off-white solids, 1.09 g. Almost immediately, more solids began to precipitate from the filtrate. These were filtered, washed with acetonitrile (3×2 mL), and dried under nitrogen to afford a second crop of the title product as light yellow crystals, 2.91 g, m.p. 230-234° C. (decomp.). The total isolated yield from both crops was 4.00 g (76.3%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]3=[N:16][S:17](=[O:21])(=[O:20])[CH2:18][CH2:19][N:14]3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1>C1COCC1.C(O)C.[C].[Rh]>[F:23][C:2]([F:1])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:15]3=[N:16][S:17](=[O:21])(=[O:20])[CH2:18][CH2:19][N:14]3[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(OC(F)(F)F)cc3)C2=N1
Agent: [Rh]
Solvent: CCO
Solvent: C1CCOC1
Product: O=S1(=O)CCN2CCCC(c3ccc(OC(F)(F)F)cc3)C2=N1
Temperature: 25 °C
Reaction time: 7 h
Yield: 100.8 %

Procedure:
A mixture of 5% rhodium-carbon (50% wet, 15 mg) and 9-[4-(trifluoromethoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (150 mg) in THF (30 mL) and ethanol (30 mL) was stirred under a hydrogen atmosphere at room temperature for 7 hr. The reaction mixture was filtered, the filtrate was concentrated to give the title compound (153 mg) as a gray white solid. The obtained solid was crystallized from THF and diisopropyl ether to give a gray white solid.