Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][CH3:10])[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=1.[CH3:23][O:24][CH:25]1[CH2:28][NH:27][CH2:26]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[CH2:9]([S:8][C:6]1[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=[C:2]([N:27]2[CH2:28][CH:25]([O:24][CH3:23])[CH2:26]2)[N:7]=1)[CH3:10]
Reactant: CCSc1nc(Cl)cc(C)c1C(=O)NCc1cccc(F)c1
Reactant: COC1CNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCSc1nc(N2CC(OC)C2)cc(C)c1C(=O)NCc1cccc(F)c1
Yield: 31 %

Procedure:
A solution of 410 mg (1.2 mmol) 6-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section b) of example 2), 125 mg (1.0 mmol) 3-methoxy-azetidine and 824 mg (2.53 mmol) Cs2CO3 in 1,4-dioxane (7 ml) was heated at 110° C. for 24 h. Subsequently the RM was concentrated in vacuo. The residue obtained was partitioned between water and EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:1) provided 122 mg (0.31 mmol, 31%) 2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-(3-methoxy-azetidin-1-yl)-4-methyl-pyridine-3-carboxylic acid amide (example 6). [M+H]+ 390.2.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:20]([O:24][C:25]([N:27]1[CH2:32][C@@H:31]2[CH2:33][C@H:28]1[CH2:29][N:30]2[C:34]([C:36]1[CH:37]=[N:38][C:39]([NH2:42])=[CH:40][CH:41]=1)=[O:35])=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH2:32][C@@H:31]2[CH2:33][C@H:28]1[CH2:29][N:30]2[C:34]([C:36]1[CH:37]=[N:38][C:39]([NH:42][C:10]2[N:11]=[CH:12][C:7]3[CH:6]=[C:5]([C:3](=[O:4])[NH:2][CH3:1])[N:14]([CH:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)[C:8]=3[N:9]=2)=[CH:40][CH:41]=1)=[O:35])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1ccc(N)nc1
Reactant: CNC(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CNC(=O)c1cc2cnc(Nc3ccc(C(=O)N4C[C@@H]5C[C@H]4CN5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methylamide, see WO 2010020675, (0.120 g, 0.431 mmol) was combined with (1S,4S)-5-(6-amino-pyridine-3-carbonyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.144 g, 0.452 g, 1.05 eq), which gave (1S,4S)-5-[6-(7-Cyclopentyl-6-methylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a yellow solid. This material was used directly in the following step 3. MS m/z 561.5 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[Na]>CN(C)C=O>[N:17]1([CH2:2][CH:3]=[CH:4][CH2:5][N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: O=C1c2ccccc2C(=O)N1CC=CCCl
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC=CCn1ccnc1

Procedure:
A mixture of 23.5 g. of N-(4-chloro-2-butenyl)-isoindole-1,3(2H)-dione, 11.0 g. of sodium imidazol and 200 ml. of dimethyl formamide was heated on the steam bath for 18 hours and concentrated to remove the solvent; the residue was taken up in methylene chloride, washed with water, dried with magnesium sulfate and again concentrated. The residue was dissolved in hot ethylacetate and allowed to cool and N-[4-(1H-imidazol-1-yl)-2-butenyl]isoindole-1,3-(2H)-dione, m.p. 106°-108° C., was obtained.
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:7])[C:4](=[NH:6])[NH2:5].[H-].[Na+].[C:10]([C:12](=[C:17](SC)[S:18][CH3:19])[C:13](OC)=[O:14])#[N:11].O>CN(C)C=O>[CH3:2][CH:3]([C:4]1[NH:6][C:17]([S:18][CH3:19])=[C:12]([C:10]#[N:11])[C:13](=[O:14])[N:5]=1)[CH3:7]
Reactant: CC(C)C(=N)N
Reactant: COC(=O)C(C#N)=C(SC)SC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1[nH]c(C(C)C)nc(=O)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A solution of 2-methylpropanimidamide hydrochloride (7.0 g, described in Example 7) in dimethylformamide (15 mL) was added dropwise to a suspension of sodium hydride (3.0 g, 50% in mineral oil, prewashed with hexane) in dimethylformamide (15 mL) and the whole mixture was left at 25° C. for 1 hr. 2-Cyano-3,3-bis(methylthio)-2-propenoic acid, methyl ester (6.5 g) in dimethylformamide (15 mL) was then added dropwise, and the reaction mixture was stirred for an additional 4 hr at 25° C. Water (25 mL) was then added, and acidification with concentrated hydrochloric acid (10 mL) precipitated the product. The precipitate was collected and air dried to give the title compound (6.0 g): mp>260° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)[N:7]=[C:6]2[CH2:25][C:26](O)=[O:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:48][C:49]1[C:50]([CH3:61])=[C:51]([N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH:52]=[CH:53][CH:54]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)[N:7]=[C:6]2[CH2:25][C:26]([N:58]1[CH2:59][CH2:60][N:55]([C:51]2[CH:52]=[CH:53][CH:54]=[C:49]([Cl:48])[C:50]=2[CH3:61])[CH2:56][CH2:57]1)=[O:27]
Reactant: COc1ccc(Cn2nc(CC(=O)O)c3cc(OC)c(OC)cc32)cc1OC
Reactant: Cc1c(Cl)cccc1N1CCNCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(Cn2nc(CC(=O)N3CCN(c4cccc(Cl)c4C)CC3)c3cc(OC)c(OC)cc32)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
5,6-dimethoxy-1-(3,4-dimethoxybenzyl)-1H-indazole-3-acetic acid (41.0 g) was suspended in dichloromethane (500 ml). Then 2,2-dipyridyl disulfide (24.5 g) and triphenylphosphine (30.0 g) were added thereto and the mixture was stirred at room temperature. Next, (3-chloro-2-methyl-phenyl)piperazine (23.5 g) dissolved in dichloromethane (200 ml) was dropped thereinto within 5 minutes and the mixture was stirred at room temperature for 30 minutes. Then dichloromethane (1000 ml) was added to the reaction mixture. After washing with water, the organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue thus obtained was purified by using a silica gel column (ethyl acetate/hexane=2/1, silica gel 2 kg) to give 61.5 g of a colorless solid. This solid product was used in the subsequent reaction without purification. A small amount of this product was taken and recrystallized from ethanol. Thus colorless prism crystals (m.p.: 165°-169° C.) were obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([SH:8])=[N:6][N:7]=1.[CH3:9][N:10]=[C:11]=[O:12]>O1CCOCC1.C(N(CC)CC)C>[CH3:9][NH:10][C:11]([N:2]([CH3:1])[C:3]1[S:4][C:5]([SH:8])=[N:6][N:7]=1)=[O:12]
Reactant: CNc1nnc(S)s1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CNC(=O)N(C)c1nnc(S)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
To a stirred slurry of 126 g of 2-methylamino-5-mercapto-1,3,4-thiadiazole in 525 ml of dioxane containing a few drops of triethylamine is added 49 g of methyl isocyanate. After stirring two hours at room temperature, the solid is collected by filtration and washed with hexane giving 165 g, melting at 162°-3°. This product is heated on the steam bath 11/2 -2 hours with 250 ml of triethylamine, during which time the initial solid is converted to a heavy amber oil. The supernatent liquid is decanted and the oil is dissolved in water and neutralized with dilute hydrochloric acid to pH 2-3. The precipitated solid is collected and washed with water and air dried, giving 132 g of N,N'-dimethyl-N'-(5-mercapto-1,3,4-thiadiazol-2-yl)urea, m.p. 230° (dec.).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=O)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)=[CH:20][CH:19]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: O=C(O)c1ccc(F)cc1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(F)cc2)o1
Yield: 40 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (5.00 g, 23.0 mmol) was converted using 4-fluorobenzoic acid instead of o-toluic acid to the title compound (recrystallisation from tert-butylmethylether, 2.98 g, 40%) which was obtained as an off-white solid. MS: m/e=322.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[S:7](=[O:9])(=[O:8])[N:6]([CH:13]([S:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]2=[O:26].[C:27](Cl)(=[O:29])[CH3:28]>C(#N)C>[C:27]([NH:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[S:7](=[O:9])(=[O:8])[N:6]([CH:13]([S:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:5]2=[O:26])(=[O:29])[CH3:28]
Reactant: Nc1ccc2c(c1)C(=O)N(C(Sc1nnn[nH]1)c1ccccc1)S2(=O)=O
Reactant: CC(=O)Cl
Solvent: CC#N
Product: CC(=O)Nc1ccc2c(c1)C(=O)N(C(Sc1nnn[nH]1)c1ccccc1)S2(=O)=O
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
A suspension of 0.4 g of 5-amino-2-(1-phenyl-1H-tetrazol-5-ylthiomethyl)saccharin in 25 ml of acetonitrile was treated with 0.08 g (0.001 mol) of acetyl chloride, the mixture was heated under reflux for 30 minutes, treated with an additional drop of acetyl chloride and refluxing continued for another 30 minutes. Evaporation of the mixture to dryness afforded a white foam which was chromatographed on silica gel with 95:5 MDC:ethyl acetate to give 200 mg (43%) of 5-acetylamino-2-(1-phenyl-1H-tetrazol-5-ylthiomethyl)saccharin.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][C@@H:11]([C:16]([OH:18])=[O:17])[C:12]([SH:15])([CH3:14])[CH3:13]>CO>[CH3:13][C:12]1([CH3:14])[S:15][CH:6]([C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)[NH:10][C@H:11]1[C:16]([OH:18])=[O:17]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Solvent: CO
Product: CC1(C)SC(c2ccc(O)cc2)N[C@H]1C(=O)O
Reaction time: 20 h

Procedure:
1.26 g (10 mmoles) of 4-hydroxybenzaldehyde dissolved in 20 ml of 30% aqueous methanol are added to a solution containing 1.49 g (10 mmoles) of D-penicillamine in 30 ml of 30% methanol. After stirring for 20 hours and recrystallization from ethanol containing water, the title acid is obtained in a yield of 2.4 g (94.8%), m.p.: 207°-209° C., [α]D =+91.3° (c=0.2, dimethylformamide).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH2:12][C:13]2[CH:14]=[C:15]([CH:40]=[CH:41][CH:42]=2)[C:16]([NH:18][CH2:19][C:20]2[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]3[CH:30]=[N:29][N:28]([CH2:31][CH3:32])[C:23]3=[N:24][C:25]=2[CH2:26][CH3:27])=[O:17])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:43][C:44]([O:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([CH2:56][C:57]2[CH:58]=[C:59](B(O)O)[CH:60]=[CH:61][CH:62]=2)[CH2:52][CH2:51]1)=[O:49])([CH3:46])[CH3:45].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:31]([N:28]1[C:23]2=[N:24][C:25]([CH2:26][CH3:27])=[C:20]([CH2:19][NH:18][C:16]([C:15]3[CH:14]=[C:13]([CH2:12][N:10]([CH2:9][C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:59]5[CH:60]=[CH:61][CH:62]=[C:57]([CH2:56][N:53]6[CH2:54][CH2:55][N:50]([C:48]([O:47][C:44]([CH3:46])([CH3:45])[CH3:43])=[O:49])[CH2:51][CH2:52]6)[CH:58]=5)[CH:3]=4)[CH3:11])[CH:42]=[CH:41][CH:40]=3)=[O:17])[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]2[CH:30]=[N:29]1)[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(B(O)O)c2)CC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CN(C)Cc2ccc(F)c(Br)c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CN(C)Cc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1
Temperature: 150 °C
Yield: 82 %

Procedure:
To a solution of 3-{[[(3-bromo-4-fluorophenyl)methyl](methyl)amino]methyl}-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (0.37 g, 0.58 mmol) in p-dioxane/H2O (4.5/1.5 mL) was added {3-[(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-piperazinyl)methyl]phenyl}boronic acid (0.279 g, 0.87 mmol), Pd(PPh3)4 (33.6 mg, 0.029 mmol), and K2CO3 (0.32 g, 2.32 mmol). The mixture was heated with a microwave at 150° C. for 15 min. The organic layer was separated and concentrated. The residue was redissolved in EtOAc, washed with H2O, brine, dried over Na2SO4, filtered, concentrated and the concentrate purified by CombiFlash chromatograph to afford the title compound 0.396 g (82%). LC-MS m/z 833 (M+H)+.
Reaction SMILES: [CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:20]([CH:21]4[CH2:23][CH2:22]4)[C:19](Br)=[N:18][C:17]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:32])(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH3:33][Si:34]([C:37]#[CH:38])([CH3:36])[CH3:35].C(N(CC)CC)C>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:20]([CH:21]4[CH2:23][CH2:22]4)[C:19]([C:38]#[C:37][Si:34]([CH3:36])([CH3:35])[CH3:33])=[N:18][C:17]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:32])(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3c(-c4ccccc4F)nc(Br)n3C3CC3)cc21
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3c(-c4ccccc4F)nc(C#C[Si](C)(C)C)n3C3CC3)cc21
Temperature: 25 °C
Yield: 86 %

Procedure:
Combine 1-isopropylsulfonyl-2-amino-6-(1-(cyclopropyl)-2-(bromo)-4-(2-fluorophenyl)-imidazol-5-yl)-benzimidazole (0.332 g, 0.64 mmol), trimethylsilylacetylene (0.36 mL, 2.56 mmol), tetrakis(triphenylphosphine)-palladium (0.150 g, 0.128 mmol), triethylamine (2 mL) and dimethylformamide (4 mL) and heat to 70° C. for 18 hours. Cool to ambient temperature and remove solvents under reduced pressure. Purify the residue on silica gel eluting with acetonitrile/dichloromethane mixtures to provide the title compound (0.295 g). MS(ES+): m/z=536.2 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][OH:21])=[C:14]([OH:22])[CH:13]=1)[CH3:2].[CH2:24](I)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][OH:21])=[C:14]([O:22][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:13]=1)[CH3:2]
Reactant: CCCCCCCCCCI
Reactant: CCOC(=O)c1ccccc1Oc1ccc(CCCO)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCOc1cc(Oc2ccccc2C(=O)OCC)ccc1CCCO
Temperature: 25 °C

Procedure:
A mixture of 600 mg of 2-[3-hydroxy-4-(3-hydroxypropyl)phenoxy]benzoic acid ethyl ester, 0.4 ml of decyl iodide, and 0.26 g of potassium carbonate in 50 ml of methyl ethyl ketone was stirred at reflux overnight. After cooling to room temperature, the mixture was filtered and the filtrate concentrated in vacuo. Purification of the residue by column chromatography over silica gel eluting with 20% ethyl acetate in hexane provided 510 mg of the desired subtitled intermediate as an oil, MS, IR, NMR.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([OH:13])=O)[NH:3]1.[C:14]1([C:20]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:24]3[CH2:25][NH:26][CH2:27][CH2:28][N:23]3[C:22](=[O:29])[O:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(N(CC)CC)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([N:26]2[CH2:27][CH2:28][N:23]3[C:22](=[O:29])[O:21][C:20]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:24]3[CH2:25]2)=[O:13])[NH:3]1
Reactant: O=C1NC(C(=O)O)c2ccccc21
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Solvent: CCN(CC)CC
Product: O=C1NC(C(=O)N2CCN3C(=O)OC(c4ccccc4)(c4ccccc4)C3C2)c2ccccc21
Yield: 14 %

Procedure:
In the same manner as in Reference Example 19, the reaction was performed using 2,3-dihydro-3-oxo-1H-isoindole-1-carboxylic acid instead of 1,4-bis(phenylmethyl)-2-piperazine carboxylic acid, and using hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one instead of N,O-dimethylhydroxylamine hydrochloride and triethylamine. The reaction solution was extracted with ethyl acetate, washed with a 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added hexane-ethyl acetate. Then, the obtained crystals were collected by filtration and washed with hexane to obtain the title compound. Yield 14%.
Reaction SMILES: S(=O)(=O)(O)[OH:2].N[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][C:16]#[N:17].N>>[NH2:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:8]2[C:9]=1[CH2:10][CH2:11][CH2:12][C:7]2=[O:2]
Reactant: O=S(=O)(O)O
Reactant: N#CCCCc1ccccc1N
Agent: N
Product: Nc1cccc2c1CCCC2=O
Temperature: 100 °C

Procedure:
In a 20 ml Schlenk vessel, 1 g of 96% sulfuric acid (9.79 mmol) is added to 100 mg of 4-(2-aminophenyl)butyronitrile (0.62 mmol) under argon. The mixture is heated to 100° C. for 66 h, stirring. After cooling, it is neutralised with aqueous ammonia solution (ice cooling), and the product is then extracted with chloroform and identified using GC.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:35]=[CH:34][C:12]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27](=[O:30])(=[O:29])[NH2:28])=[O:19])=[CH:11][CH:10]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([NH:28][C:1](=[O:3])[CH3:2])(=[O:30])=[O:29])=[O:19])=[CH:34][CH:35]=1
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(Cl)cc2)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
In a stream of nitrogen and at 0° C., 0.12 ml (1.30 mmol) of acetic anhydride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 500 mg (1.20 mmol) of 3-(4-chlorobenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 4 and 293 mg (2.40 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was recrystallized from an ethyl acetate-diethyl ether mixed solvent to obtain 290 mg (yield: 52.7%) of the title compound.
Reaction SMILES: N(=C([C:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([C:20](=[O:24])[CH2:21]2)[C@:17]2([CH3:18])[C@H:12]([CH2:13][CH:14]=[CH:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH:6]=1)C)O.P(Cl)(Cl)(Cl)=[O:26].Cl>N1C=CC=CC=1.O>[CH3:23][C@:22]12[CH2:21][C:20](=[O:24])[C@H:19]3[C@@H:9]([CH2:10][CH2:11][C@@H:16]4[C@:17]3([CH3:18])[CH2:12][CH:13]=[CH:14][CH2:15]4)[C@@H:5]1[CH2:6][CH2:7][C:8]2=[O:26]
Reactant: CC(=NO)C1=CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: C[C@]12CC=CC[C@@H]1CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 60 h

Procedure:
A solution of 20-oximino-5α-pregna-2,16-diene-11-one (60 g) in anhydrous pyridine (250 ml) was treated with 225 ml of a solution prepared from phosphorus oxychloride (55 ml) in anhydrous pyridine (250 ml) whilst maintaining the reaction temperature at `5° during addition of the reagent. The reaction mixture was then added to a solution of concentrated HCl (350 ml) in water (3 l). This mixture was stirred for 60 hours before collecting the precipitate by filtration. The precipitate was washed with water, dissolved in hot industrial methylated spirits and treated with 2 N HCl (50 ml) at room temperature. After one hour, the reaction mixture was diluted with water and the precipitate obtained was collected by filtration, washed with water and dried. (38.4 g). Crystallisation from methanol afforded the title compound, m.p. 188°-192°, [α]D +207°.
Reaction SMILES: C([O:5][C:6](=[O:36])[C@H:7]([CH3:35])[NH:8][C@H:9]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:16][CH2:15]1)(C)(C)C.C(OCC)(=O)C.[ClH:43]>>[ClH:43].[CH2:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][CH:14]([CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([NH:8][C@H:7]([C:6]([OH:36])=[O:5])[CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:15][CH2:16]1)=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)O
Reaction time: 5 h

Procedure:
In 30 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 1.5 g of N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanine tert-butyl ester, and the solution is allowed to stand at room temperature for 5 hours. The reaction solution is concentrated to dryness under reduced pressure, and the residue is rinsed with ethyl ether and dried under reduced pressure to give 1.15 g of N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanine.hydrochloride as a colorless gum.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[O:7]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:24]1[C:29]2=[N:30][S:31](=[O:35])(=[O:34])[CH2:32][CH2:33][N:28]2[CH:27]=[CH:26][CH:25]=1>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:7]([C:14]1[CH:19]=[CH:18][C:17]([C:24]2[C:29]3=[N:30][S:31](=[O:35])(=[O:34])[CH2:32][CH2:33][N:28]3[CH:27]=[CH:26][CH:25]=2)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S1(=O)CCN2C=CC=C(Br)C2=N1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccccc4)cc3)C2=N1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A mixture of sodium carbonate (121 mg), tetrakis(triphenylphosphine)palladium(0) (13.18 mg), (4-phenoxyphenyl)boronic acid (98 mg) and 9-bromo-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (100 mg) in DMF (dry) (10 mL) and water (2 mL) was stirred at 80° C. under N2 overnight. NH silica gel was added and the mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give 9-(4-phenoxyphenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (116 mg) as a white solid. The solid was crystallized from DMSO (1.5 mL)-EtOH (3 mL) to give the title compound (90.7 mg) as a white solid.