Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][N:8]=2)[CH2:3][CH2:2]1.CC([O-])(C)C.[K+].C1(P(O[NH2:39])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.CCOC(C)=O>[NH2:39][N:9]1[N:8]=[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:17]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: O=c1[nH]nc(N2CCOCC2)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 39.5 %

Procedure:
To a mixture of the product from Example 1A (0.300 g, 1.30 mmol) in THF (3.5 mL) was added a 1 M solution of potassium 2-methylpropan-2-olate in THF (1.7 mL, 1.7 mmol). The mix was stirred at room temperature for 90 minutes, and O-(diphenylphosphoryl)hydroxylamine (0.395 g, 1.70 mmol) was added and stirred overnight. The mixture was diluted with EtOAc, washed with 0.5N NaOH and water, concentrated, and chromatographed (40% EtOAc/DCM) to give 126.4 mg of product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.31-8.25 (m, 1H), 8.03-7.98 (m, 1H), 7.94-7.80 (m, 2H), 6.20 (s, 2H), 3.87-3.78 (m, 4H), 3.15-3.07 (m, 4H).
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[CH3:19][CH:20]([CH3:32])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[CH:24][CH:23]=1.[CH3:33][Si:34]([CH3:37])([CH3:36])Cl>O1CCCC1>[CH3:19][CH:20]([CH3:32])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[C:29]([O:31][Si:34]([CH3:37])([CH3:36])[CH3:33])[O:30][Si:34]([CH3:37])([CH3:36])[CH3:33])=[CH:24][CH:23]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)Cc1ccc(CC(=O)O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC(C)Cc1ccc(C=C(O[Si](C)(C)C)O[Si](C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
Butyllithium in hexane (175 ml of 1.6 M solution, 0.28 mol) was added to a solution of 30 g (0.3 mol) of diisopropylamine in 200 ml of tetrahydrofuran at 25° C. The reaction mixture was cooled to 0° C. and a solution of 26.0 g (0.135 mol) of 4-(2-methylpropyl)benzeneacetic acid in 200 ml of tetrahydrofuran was added dropwise near 0° C. The mixture was stirred for 1 hour at 0° C. and then 70 ml (0.55 mol) of trimethylchlorosilane were added. The reaction mixture was warmed to room temperature and stirred for 2 hours. The solid that formed was filtered off; the filtrate was concentrated under reduced pressure and then mixed with 100 ml of diethyl ether. The resultant mixture was filtered and the filtrate was concentrated. Distillation of the residue gave 31.92 g (70% yield) of 4-(2-methylpropyl)-β,β-bis(trimethylsiloxy)styrene as a colorless liquid: bp 128° -130° C. (0.4 mm); ir (liquid) 6.07μ (C=C). Anal. Calcd. for C18H32O2Si2 : C, 64.22; H, 9.58; Found: C, 64.34; H, 9.95.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([OH:36])(=[O:35])[CH2:31][C:32]([OH:34])=[O:33]>CO.ClCCl>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([O-:36])(=[O:35])[CH2:31][C:32]([O-:34])=[O:33]
Reactant: O=C(O)CC(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CO
Solvent: ClCCl
Product: O=C([O-])CC(=O)[O-]
Temperature: 27.5 °C
Reaction time: 15 h

Procedure:
Sunitinib (2.0 g) was suspended in 10% methanol in dichloromethane (30 mL) at 25° C., followed by addition of malonic acid (0.29 g) .The reaction mass was maintained under stirring at 25-30° C. for 15 hrs. The solids obtained were filtered, suck dried and dried under vacuum for a period of 10 hrs at 60° C. to obtain sunitinib malonate. (2.0 g; yield: 80%)
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](OC2C=CC=CC=2)=[O:29])[CH:4]=[N:3]1.C(N(CC)CC)C.[NH2:44][CH2:45][CH2:46][NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51].O>CN(C)C=O>[C:50]([O:49][C:48]([NH:47][CH2:46][CH2:45][NH:44][C:28]([NH:27][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[NH:7][C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:29])=[O:54])([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Cn1ncc(NC(=O)Oc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1ncc(NC(=O)NCCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
To a suspension of 1-methyl-4-phenoxycarbonylamino-5-triphenylmethylaminopyrazole (253.6 g) in N,N-dimethylformamide (1.5 L) were added triethylamine (59.5 g) and tert-butyl N-(2-aminoethyl)carbamate (94.2 g) in N,N-dimethylformamide (254 ml). The mixture was stirred for 5 hours and poured into water (10.6 L). The slurry was stirred for 1 hour. The precipitated solid was collected by filtration and dried to give a crude product. The crude product was suspended in N,N-dimethylformamide, and the suspension was heated under reflux for 20 minutes. The suspension was cooled to ambient temperature over 4 hours. The solid was collected by filtration, washed with acetonitrile and dried to give 4-[N-(2-tert-butoxycarbonylaminoethyl)carbamoylamino]-1-methyl-5-triphenylmethylaminopyrazole (261.2 g).
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:25]([F:26])=[CH:24][C:10]3[NH:11][C:12]([O:14][CH:15]4[CH2:18][CH:17]([C:19]([O:21]CC)=[O:20])[CH2:16]4)=[N:13][C:9]=3[C:8]=2[F:27])=[CH:3][CH:2]=1.O([Si](C)(C)C)[K]>C1COCC1.CCOC(C)=O>[C:1]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:25]([F:26])=[CH:24][C:10]3[NH:11][C:12]([O:14][CH:15]4[CH2:18][CH:17]([C:19]([OH:21])=[O:20])[CH2:16]4)=[N:13][C:9]=3[C:8]=2[F:27])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3[nH]2)C1
Agent: C[Si](C)(C)O[K]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)C1CC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3[nH]2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 3-{[5-(biphenyl-4-yl)-4,6-difluoro-1H-benzimidazol-2-yl]oxy}cyclobutane carboxylate (0.046 g, 0.102 mmol) was dissolved in 1 mL of THF and treated with KOTMS (0.039 g, 0.308 mmol). The reaction mixture was stirred at ambient temperature overnight, and then diluted with EtOAc and washed with 2 N HCl. The aqueous layer was further extracted with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound. LCMS: calculated for C24H18F2N2O3 420.41, observed m/e 420.9 (M+H)+ (Rt 2.07/4 min). 1H NMR (500 MHz, d6-DMSO): δ7.77 (d, 2H), 7.73, (d, 2H), 7.55-7.47 (m, 4H), 7.39 (m, 1H), 7.15 (br, 1H), 5.23 (m, 1H), 2.82-2.70 (m, 2H), 2.32-2.25 (m, 2H), 1.98 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:20]#[N:21])=[CH:8][N:9]2[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:4][C:3]=1[N+:23]([O-:25])=[O:24].[NH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(#N)C>[N:29]1([CH2:28][CH2:27][NH:26][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:22])[C:7]([C:20]#[N:21])=[CH:8][N:9]3[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:4][C:3]=2[N+:23]([O-:25])=[O:24])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: NCCN1CCOCC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c(=O)c2cc([N+](=O)[O-])c(Cl)cc21
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1cc(C#N)c(=O)c2cc([N+](=O)[O-])c(NCCN3CCOCC3)cc21
Yield: 62 %

Procedure:
A mixture of 1.25 g (3.29 mmol) of 7-chloro-6-nitro-4-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydro-3-quinolinecarbonitrile and 1.07 g (8.2 mmol) of 4-(2-aminoethyl)-morpholine in 21 mL of acetonitrile is heated at reflux temperature for 17 hours. After cooling, the mixture is concentrated under reduced pressure and the residue is partitioned between methylene chloride and brine. The separated organic layer is dried over sodium sulfate and filtered. Removal of the solvent yields a residue which is flash chromatographed (elution with methylene chloride, then a gradient of 99:1 to 98:2 methylene chloride/methanol), giving 966 mg (61.9%) of the product as a yellow solid, mp 294-216° C.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:11]=[CH:10][S:9][CH:8]=1.[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[NH4+].[Cl-]>C1COCC1>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[OH:18])=[CH:15][CH:14]=1
Reactant: Brc1ccsc1
Reactant: O=Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccc(Br)cc1)c1ccsc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.5M BuLi in hexanes (3.5 mL, 5.25 mmol) in THF (6.5 mL) cooled to −78° C. was added 3-bromothiophene dropwise (469 μL, 5.0 mmol). The mixture was stirred for 30 minutes and a 1.0M solution of 4-bromobenzaldehyde in THF was slowly added (5.5 mL, 5.5 mmol). The reaction was warmed to 0° C. and aged for 1 hour. The mixture was then poured into a saturated aqueous solution of NH4Cl. The resulting mixture was extracted 3 times with ethyl acetate and the organic layers were washed with brine, dried and evaporated. The crude residue was chromatographed on silica gel using a gradient of 10-25% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: O1CCCC1.[CH:6]([Mg]Br)=[CH2:7].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[N+:18]([O-])=O.[Cl-].[NH4+]>C(OCC)(=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:6]([CH3:7])=[C:13]2[C:12]=1[NH:18][CH:17]=[CH:14]2
Reactant: C=C[Mg]Br
Reactant: Cc1ccc(Br)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(Br)c2[nH]ccc12
Reaction time: 1 h

Procedure:
1 l (1 mol) of a tetrahydrofuran solution containing 1.0 M vinylmagnesium bromide was added to a tetrahydrofuran solution (300 ml) containing 65.0 g (301 mmol) of 2-bromo-5-methylnitrobenzene at −60° C. under stirring for one hour in nitrogen atmosphere. An aqueous saturated ammonium chloride and ethyl acetate were added to the reaction mixture solution, and the insoluble matters were filtered off. The filtrate was dried over magnesium sulfate and concentrated. Then, the residue was purified by silica gel column chromatography, to give 35.5 g of the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][N:6]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2[NH:14][C:15]([CH:18]=O)=[C:16]([CH3:17])[C:8]=2[C:7]1=[O:20])[CH3:2].[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2.N1CCCCC1>C(O)C>[CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][N:6]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2[NH:14][C:15](/[CH:18]=[C:27]3\[C:28](=[O:33])[NH:29][C:30]4[C:26]\3=[CH:25][C:24]([F:23])=[CH:32][CH:31]=4)=[C:16]([CH3:17])[C:8]=2[C:7]1=[O:20])[CH3:2]
Reactant: CCN(CC)CCN1CCCCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCN1CCCCc2[nH]c(/C=C3\C(=O)Nc4ccc(F)cc43)c(C)c2C1=O
Temperature: 25 °C
Yield: 48.4 %

Procedure:
5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7,8,9-hexahydro-1H-1,5-diaz a-cyclopentacyclooctene-2-carbaldehyde 60e (20 mg, 0.066 mmol) was dissolved in 1 ml of ethanol under stirring, and added with 5-fluoro-1,3-dihydro-indol-2-one (9.9 mg, 0.066 mmol) to the solution at room temperature. The reaction mixture was stirred in dark until dissolved, added with 0.1 ml of piperidine, and heated to reflux for 2 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled down to room temperature, filtered to obtain the title compound (Z)-5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-6,7,8,9-tetrahydro-1H,5H-1,5-diaza-cyclopentacycloocten-4-one 60 (14 mg, yield 48.8%) as a yellow solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C:7]1[C:8]([NH:29][CH2:30][C@@H:31]([C:43]([OH:45])=[O:44])[NH:32][C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])=[N:9][CH:10]=[N:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[N:28]=[C:27]3[C:22]([CH2:23][CH2:24][CH2:25][NH:26]3)=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)[CH3:6].[CH2:46](O)[CH3:47]>>[ClH:3].[ClH:3].[CH2:5]([C:7]1[C:8]([NH:29][CH2:30][C@@H:31]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:32][C:33]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])=[N:9][CH:10]=[N:11][C:12]=1[N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[N:28]=[C:27]3[C:22]([CH2:23][CH2:24][CH2:25][NH:26]3)=[CH:21][CH:20]=2)[CH2:17][CH2:18]1)[CH3:6]
Reactant: CCO
Reactant: CCc1c(NC[C@H](NC(=O)OCc2ccccc2)C(=O)O)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Reactant: O=S(Cl)Cl
Product: CCOC(=O)[C@H](CNc1ncnc(N2CCC(c3ccc4c(n3)NCCC4)CC2)c1CC)NC(=O)OCc1ccccc1
Product: Cl
Temperature: -12 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
160 μl (2.19 mmoles) of thionyl chloride is added to 5 ml of ethanol cooled down to −12° C. under a nitrogen atmosphere and the mixture is stirred for 30 minutes. Then a solution of 354 mg (0.45 mmoles) of 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine, bis(trifluoroacetate) in 13 ml of ethanol is added. The mixture is stirred for 30 minutes at −12° C. then left to return to ambient temperature and finally heated at 40° C. for 4 hours under nitrogen. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue crystallizes from a mixture of diisopropyl ether and pentane and the solid is filtered. 284 mg (Yield=95%) of expected product is obtained in the form of an amorphous beige solid.
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1.C(N1C=CN=C1)([N:15]1C=CN=C1)=O.C([N-]C(C)C)(C)C>C1COCC1.CN(C=O)C>[C:1]([NH2:15])(=[O:12])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cccc(C(=O)O)c1
Agent: CC(C)[N-]C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(C(=O)O)c1
Temperature: 20 °C
Reaction time: 13.5 h
Yield: 80 %

Procedure:
These compounds are preferably prepared as set forth as follows. An ester, preferably the monomethyl ester of isophthalic acid or methyl 5-methyl-1,3-isophthalate is dissolved in a THF/DMF mixture. 1,1′-Carbonyldiimidazole is added at 20-25 degrees C. The diisopropyl amide is added. After 3-24 hr of stirring at 20 degrees C. to the reflux temperature of the solvent, the reaction mixture is partitioned between saturated aqueous ammonium chloride and a water immiscible organic solvent such as ethyl acetate. The aqueous layer is separated and extracted twice more with the organic solvent (ethyl acetate). The solvent removed and the residue thus obtained is basified to yield the isophthalic amide (IIa) in 80% yield.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:24])[CH2:12][CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=2[CH3:23])[CH2:7][CH2:6]1.C(N(CC)CC)C.[CH3:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[NH:41][CH2:40][CH2:39][CH2:38]2>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C:11](=[O:24])[CH2:12][CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([N:41]3[C:42]4[C:37](=[CH:36][C:35]([CH3:34])=[CH:44][CH:43]=4)[CH2:38][CH2:39][CH2:40]3)=[O:19])=[CH:16][C:15]=2[CH3:23])[CH2:9][CH2:10]1
Reactant: Cc1cc(C(=O)O)ccc1CCC(=O)N1CCN(CCC(C)(C)C)CC1
Reactant: Cc1ccc2c(c1)CCCN2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)CCCN2C(=O)c1ccc(CCC(=O)N2CCN(CCC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 6 %

Procedure:
DMAP (51 mg, 0.42 mmol) and WSCD (161 mg, 0.84 mmol) were added to a solution of 4-{3-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-3-oxo-propyl}-3-methyl-benzoic acid from Example E44 (150 mg, 0.42 mmol) in dichloromethane (10 ml) and triethylamine (0.176 ml, 1.26 mmol) and the mixture was stirred for 30 min at room temperature. 6-Methyl-1,2,3,4-tetrahydro-quinoline (67 mg, 0.46 mmol) was added and the mixture was stirred for 20 h at room temperature then solvents were removed in vacuo. The residue was redissolved in EtOAC, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as the title compound (12 mg, 6%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:1]([CH2:2][C:3]2[CH:4]=[CH:5][C:6]([C:9]([OH:11])=[O:10])=[CH:7][CH:8]=2)[S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=2)(=[O:21])=[O:20])=[CH:26][CH:25]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-11 from 4-(aminomethyl)phenylcarboxylic acid, 4-methylbenzene-1-sulfonylchloride and 4-fluorobenzyl bromide. 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.11 (s, 3H), 4.21 (s, 2H), 4.24 (s, 2H), 6.94-7.08 (m, 6H), 7.40-7.42 (d, 2H, J=8 Hz), 7.63 (d, 2H, J=8 Hz). 7.73 (d, 2H, J=8 Hz)
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C:17]3([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.C(N(CC)CC)C.[C:30](O)(=[O:37])[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C:17]3([NH:22][C:30](=[O:37])[C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1
Reactant: O=C(O)c1ccncc1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OCC3(N)CCCC3)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC1=NS(=O)(=O)Nc2cccc(OCC3(NC(=O)c4ccncc4)CCCC3)c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
To a stirred suspension of 4-amino-5-((1-aminocyclopentyl)methoxy)-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide hydrochloride (346.83 mg, 1 mmol) in DMF (6 mL) was added triethylamine (0.278 mL, 2 mmol). After being stirred at room temperature for 10 min., a mixture of isonicotinic acid (123.11 mg, 1.1 mmol), EDCI (211 mg, 1.1 mmol) and HOBt (149 mg, 1.1 mmol) in 4 ml of DMF was added and the reaction mixture was then stirred at room temperature overnight. The resulting solution was purified by reverse phase HPLC, and then the product was re-crystallized from ethanol/water, after dry to give the title compound as a white solid (300 mg) in 72% yield. M.p.: >250° C. 1H NMR (400 MHz, DMSO-d6) δ 1.65-1.67 (m, 2H), 1.75-1.78 (m, 2H), 1.83-1.88 (m, 2H), 2.19-2.24 (m, 2H), 4.43 (s, 2H), 6.59 (d, J=8.0 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.66 (d, J=8.0 Hz, 2H), 7.85 (s, 1H), 8.43 (s, 1H), 8.56 (s, 1H), 8.66 (d, J=8 Hz, 2H), 10.96 (s, 1H). MS 416 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[CH2:3][CH2:4][N:5]([CH2:17][C:18]1[CH:37]=[CH:36][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34]C)=[O:33])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1.O.Cl>CO.O1CCCC1.[OH-].[Na+]>[CH3:1][CH:2]([CH3:38])[CH2:3][CH2:4][N:5]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:28][CH:29]=2)=[CH:36][CH:37]=1)[C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:10]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CN(CCC(C)C)c3nc(-c4ccccc4)cs3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)CCN(Cc1ccc(COc2ccc(CCC(=O)O)cc2)cc1)c1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Methyl 3-{4-[(4-{[(3-methylbutyl)(4-phenyl-1,3-thiazol-2-yl)amino]methyl}benzyl)oxy]phenyl}propanoate (240 mg) was dissolved in a mixed solvent of methanol (2 mL) and tetrahydrofuran (2 mL), and 2N aqueous sodium hydroxide solution (2 mL) was added. The mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, acidified with 1N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The ethyl acetate layer was dried using Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated to give the title compound (220 mg, yield 90%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.C=O.[C:18](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:8][C@H:6]1[N:7]([CH3:18])[C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:5]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 1,1-dimethylethyl (3R,5S)-3,5-dimethyl-1-piperazinecarboxylate (2.04 g, 9.5 mmol) in dichloromethane (25 mL) at 0° C. was added formaldehyde (1.075 mL, 37% water solution, 14.3 mmol) followed by sodium triacetoxyborohydride (2.628 g, 12.4 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h before being diluted with dichloromethane and washed with 1N NaOH solution. The organics were then washed with brine, dried (MgSO4) and evaporated to yield 1,1-dimethylethyl (3R,5S)-3,4,5-trimethyl-1-piperazinecarboxylate (2.06 g, 95%). LCMS: (M+H)+: 229.2.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([OH:15])(=[O:14])[CH2:10]C(O)=O.C([O-])(=O)C.[NH4+:20]>C(O)C>[CH:5]1[CH:6]=[CH:7][C:2]([CH:1]([NH2:20])[CH2:10][C:9]([OH:15])=[O:14])=[CH:3][CH:4]=1
Reactant: [NH4+]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC(CC(=O)O)c1ccccc1
Reaction time: 8 h

Procedure:
A suspension of 100 g of benzaldehyde, 94 g of malonic acid, 109 g of ammonium acetate in 300 cm3 of ethanol, is brought to boiling point in a nitrogen atmosphere, under vigorous stirring. The suspension is mantained under the above conditions for about eight hours.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:9][C:10]1([CH3:18])[O:17][C:15](=[O:16])[CH2:14][C:12](=[O:13])[O:11]1.N1CCC[C@H]1C(O)=O>C(#N)C>[CH3:9][C:10]1([CH3:18])[O:17][C:15](=[O:16])[C:14](=[CH:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[C:12](=[O:13])[O:11]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1ccncc1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CC#N
Product: CC1(C)OC(=O)C(=Cc2ccncc2)C(=O)O1
Yield: 84.7 %

Procedure:
Pyridine-4-carboxaldehyde (2.04 g) was mixed with Meldrum's acid (2,2-Dimethyl-[1,3]dioxane-4,6-dione, 2.7 g) and proline (0.20 g) in acetonitrile (40 ml) with stirring under a nitrogen atmosphere. Almost immediately product began to precipitate. The mixture was stirred overnight, filtered and washed with ether, affording 3.7 g of 2,2-dimethyl-5-pyridin-4-ylmethylene-[1,3]dioxane-4,6-dione which was used with no further purification in the next step.