Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:33])/[C:11](/[CH2:21][O:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[CH:5]=[CH:4][N:3]=[CH:2]1.O.[OH-].[Li+].O1CCCC1>O>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:33])/[C:11](/[CH2:21][O:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)CCCC/C=C(\COc1cccc2ccccc12)C(=O)NCCCn1ccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCC/C=C(\COc1cccc2ccccc12)C(=O)NCCCn1ccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 103.2 %

Procedure:
Methyl (E)-8-(3-(1H-imidazol-1-yl)propylamino)-7-((naphthalen-1-yloxy)-methyl)-8-oxo-6-octenoate (350 mg, 0.77 mM) obtained in Example (2-1-1) was dissolved in water (1 ml), and lithium hydroxide monohydrate (LiOH.H2O) (96 mg, 2.31 mM) and tetrahydrofuran (4 ml) were added thereto. The resulting mixture was stirred at room temperature for 10 mins, followed by stirring at 50° C. for 3 hrs. After the completion of reaction, the reaction mixture was cooled to room temperature, followed by adding ice water thereto. Then, the solvent was removed under reduced pressure, and the residue was cooled to 5° C. again and acidified (pH 4) with 2N hydrochloric acid. The resultant was filtered and dried over anhydrous magnesium sulfate to obtain the 350 mg of the title compound as a white solid (yield 85%).
Reaction SMILES: [N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:24])[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][N:12]3[CH2:15][CH2:16][C:17]#[N:18])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[Br:25]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)(Cl)Cl>[N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:24])[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][N:12]3[CH2:15][CH2:16][C:17]#[N:18])=[CH:7][C:6]=2[Br:25])[CH2:2][CH2:3][CH2:4]1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC3)ccc2c1=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC3)c(Br)cc2c1=O

Procedure:
A solution of EXAMPLE 81C (0.50 g) and 1,3-dibromo-5,5-dimethylhydantoin (0.26 g) in chloroform (100 mL) was refluxed for 10 minutes then cooled, diluted with chloroform, washed with 10% sodium bisulfate and brine, dried (MgSO4), filtered, and concentrated; and the concentrate was crystallized from dichloromethane/ethyl acetate/hexanes.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH3:12])[N:3]=1.Cl[C:14]1N=C(Cl)C(C#N)=C(NC)[N:15]=1.CN>>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:15][CH3:14])[N:3]=[C:4]([NH:11][CH3:12])[N:5]=1
Reactant: CNc1nc(Cl)c(C#N)c(Cl)n1
Reactant: CNc1nc(Cl)nc(Cl)c1C#N
Agent: CN
Product: CNc1nc(Cl)c(C#N)c(NC)n1

Procedure:
The crude reaction product of Example IX, approximately 19% 4,6-dichloro-2-methylamino-5-pyrimidinecarbonitrile and 72% 2,4-dichloro-6-methylamino-5-pyrimidinecarbonitrile, was treated with aqueous 40% methylamine in the manner of Example V, to give 4-chloro-2,6-bis(methylamino)-5-pyrimidinecarbonitrile; mp, 281°-284° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].S([CH2:22][N+:23]#[C-:24])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[O:9][CH:24]=[N:23][CH:22]=2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2cnco2)cc1
Yield: 95.3 %

Procedure:
A mixture of 4-nitro benzaldehyde (500 mg, 3.31 mmol), tosylmethyl isocyanide (640 mg, 3.31 mmol) and potassium carbonate (1.37 g, 9.9 mmol) were heated to reflux in methanol (10 ml) for 2 hr. Evaporation of the solvent yielded a residue, which was diluted with water and extracted into ethyl acetate. The organic layer was washed with water and brine, dried and concentrated under reduced pressure to yield 5-(4-nitro-phenyl)-oxazole (600 mg, 95%) as solid.
Reaction SMILES: OCCS(C1C([N+]([O-])=O)=C(C=CC=1)C(O)=O)(=O)=O.[OH:19][CH2:20][CH2:21][S:22]([C:25]1[C:33]([N+:34]([O-])=O)=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28])(=[O:24])=[O:23]>>[OH:19][CH2:20][CH2:21][S:22]([C:25]1[C:33]([NH2:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28])(=[O:24])=[O:23]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1S(=O)(=O)CCO
Agent: O=C(O)c1cccc(S(=O)(=O)CCO)c1[N+](=O)[O-]
Product: Nc1cccc(C(=O)O)c1S(=O)(=O)CCO

Procedure:
The procedure of previous Example 15 is repeated, except that the 3-hydroxyethylsulfonyl-2-nitrobenzoic acid is replaced by 2-hydroxyethylsulfonyl-3-nitrobenzoic acid and, after the clarifying filtration to remove iron sludge, a pH of 6.5 to 7.0 is established to give 64 parts of 2-hydroxyethylsulfonyl-3-aminobenzoic acid of the formula ##STR16## of melting point 75° to 77° C. and a purity (by diazotization) of 99.1%. Elemental analysis confirms the above structure.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][CH2:23][OH:24])[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[OH:24][CH2:23][CH2:22][CH2:21][C:17]1[CH:16]=[C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: OCCCc1cccc(-c2cccc(OCc3ccccc3)c2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: OCCCc1cccc(-c2cccc(O)c2)c1

Procedure:
7.8 g (23.7 mmol) of 3-(3′-benzyloxybiphenyl-3-yl)propanol are hydrogenated to completion in THF on a palladium/activated carbon catalyst. The catalyst is filtered off, the filtrate is evaporated, and the residue is chromatographed on silica gel with toluene/ethyl acetate (2:1), giving 3′-(3-hydroxypropyl)biphenyl-3-ol as a colourless oil.
Reaction SMILES: [C:1]([C:3](=[CH:12]OCC)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2].[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:1]([C:3](=[CH:12][NH:23][NH:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2]
Reactant: NNc1ccccc1
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Product: CCOC(=O)NC(=O)C(C#N)=CNNc1ccccc1

Procedure:
Following the procedure of Example 1, α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide is reacted with phenylhydrazine to give α-cyano-β-phenylhydrazino-N-ethoxycarbonylacrylamide, which in turn is cyclized by heating in tetralin, yielding 5-cyano-1-anilino-2,4-pyrimidinedione. The foregoing compound has been reported by G. Shaw, J. Chem. Soc., 1955, 1834-1840.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH:10]=O)=[CH:4][CH:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][NH2:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH2:10][NH:27][CH2:26][CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)=[CH:4][CH:3]=1
Reactant: NCCc1ccccn1
Reactant: O=CCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Fc1ccc(C(CCNCCc2ccccn2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 3,3-bis(4-fluorophenyl)propanal (0.967 g, 3.93 mmol) in DCE (15 mL) at room temperature was added 2-(pyridin-2-yl)ethanamine (1.73 g, 14.2 mmol) and NaBH(OAc)3 (1.08 g, 5.10 mmol). The reaction mixture was stirred at room temperature for 17 h, diluted with EtOAc, washed with 5 M NaOH (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 2% to 8% MeOH (2M NH3) in DCM) followed by purification by flash column chromatography on silica gel (eluted with 50% to 100% EtOAc (10% 2M NH3 in MeOH) in hexanes) gave 3,3-bis(4-fluorophenyl)-N-(2-(pyridin-2-yl)ethyl)propan-1-amine.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[N:8][C:9]([NH2:10])=[C:4]2[CH:3]=[N:2]1.IN1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:39][C:40]1[CH:53]=[C:52](B2OC(C)(C)C(C)(C)O2)[CH:51]=[CH:50][C:41]=1[O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1>C(#N)C.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:39][C:40]1[CH:53]=[C:52]([C:3]2[C:4]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:10])[NH:1][N:2]=2)[CH:51]=[CH:50][C:41]=1[O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1
Reactant: Nc1ncnc2[nH]ncc12
Reactant: CC1(C)OB(c2ccc(OCc3ccccn3)c(F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC#N
Solvent: CN(C)C=O
Product: Nc1ncnc2[nH]nc(-c3ccc(OCc4ccccn4)c(F)c3)c12
Temperature: 80 °C

Procedure:
1H-pyrazolo[3,4-d]pyrimidin-4-amine (1 equivalent), N-iodosuccinimide (1.25 equivalents) and AIBN (0.1 equivalents) are heated in acetonitrile for 10 h. The reaction is filtered and the filtered material (1 equivalent) is placed in DMF. Pd(dppf)Cl2 (0.6 equivalents), KI (0.1 equivalents), K3PO4 (3 equivalents) and 2-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyridine (1 equivalent) are added and the mixture is heated at 80° C. overnight. The reaction is partitioned between EtOAc and water, the organic layer is separated, washed with water, brine, dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[O:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[C@@H:9]([C:15](OCC)=[O:16])[C@H:10]([CH2:11][N+:12]([O-:14])=[O:13])[C:4]=2[CH:3]=1.O1CCCC1.[BH4-].[Na+].CC(C)=O>CO.C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[O:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[C@@H:9]([CH2:15][OH:16])[C@H:10]([CH2:11][N+:12]([O-:14])=[O:13])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)[C@@H]1c2ccccc2Oc2ccc(Cl)cc2[C@H]1C[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])C[C@@H]1c2cc(Cl)ccc2Oc2ccccc2[C@H]1CO
Reaction time: 2 h

Procedure:
A 180.9 g portion of the ethyl trans-2-chloro-11-(nitromethyl)-10,11-dihydrodibenzo[b,f]oxepin-10-carboxylate obtained in Reference Example 6 (mixture of the initially obtained whitish crystals and subsequently obtained light yellow crystals, 0.5 mol, trans/cis=99.3/0.7) was added to and mixed with a mixture of 904 mL of tetrahydrofuran and 24.6 g of sodium borohydride (0.65 mol, powdered). Next, 134.1 g (45.5 wt %, 0.90 mol) of a boron trifluoride/tetrahydrofuran complex was added dropwise to the obtained mixture under a nitrogen atmosphere, over a period of about 1 hour and 30 minutes. The internal temperature of the mixture during the dropwise addition was 20-26° C. The obtained mixture was stirred at the same temperature for approximately 2 hours, and then stirred at 40° C. for approximately 3 hours. After cooling the reaction mixture with an ice water bath, 58 g of acetone and 452 mL of water were added dropwise in that order, at an internal temperature of 5-10° C. To the obtained mixture there were added 542 mL of toluene and 180 mL of methanol, the mixture was stirred, and liquid separation was performed. The obtained organic layer was washed twice with 250 mL of a methanol/water=1/10 (v/v) mixed solution and once with 300 mL of 10 wt % brine in that order, and then the organic layer was subjected to dehydration treatment with anhydrous magnesium sulfate and concentrated to obtain 158.1 g of crude trans-[2-chloro-11-(nitromethyl)-10,11-dihydrodibenzo[b,f]oxepin-10-yl]methanol as a highly viscous fluid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.Br[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.CCCCCC.C(OCC)(=O)C>[CH:14]1([CH2:13][O:11][C:4]2[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1cnc([N+](=O)[O-])c(O)c1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: Cc1cnc([N+](=O)[O-])c(OCC2CCCCC2)c1
Temperature: 78 °C
Reaction time: 12 h

Procedure:
A suspension of 1 g of 5-methyl-2-nitropyridin-3-ol, 1.35 ml of (bromomethyl)cyclohexane, and 1.79 g of potassium carbonate in 10 ml of DMF was stirred at 78° C. for 12 hours. After leaving to be cooled at room temperature, to the reaction mixture were added water and hexane/ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 1.8 g of 3-(cyclohexylmethoxy)-5-methyl-2-nitropyridine.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[CH:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]1>CCCCO>[Br:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[CH:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Cc1cc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)no1
Solvent: CCCCO
Product: Cc1cc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)no1
Temperature: 150 °C
Reaction time: 24 h
Yield: 13.1 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylisoxazole-3-carboxamide (200 mg, 0.590 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (591 mg, 2.95 mmol) in n-BuOH (5 mL) was stirred at 150° C. for 24 hours in a sealed tube. The reaction mixture was then concentrated in vacuo, and the liquid residue was purified by C-18 reverse phase flash chromatography (Biotage C-18 Flash 25M+) on Biotage SP4 unit eluting with 10-80% CH3CN/water gradient (24 CV). The product isolated was crystallized from MeOH/CH3CN to provide (R)-tert-butyl 1-(5-bromo-3-(5-methylisoxazole-3-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (40 mg, 13% yield) as a solid. LCMS (APCI+) m/z 519, 521 (M+H)+, Retention time=4.08 minutes (Method 2).
Reaction SMILES: [ClH:1].[CH:2]1([C:5]2[O:9]C=[N:7][C:6]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4][CH2:3]1>C(O)C>[ClH:1].[NH2:7][CH:6]([C:5](=[O:9])[CH:2]1[CH2:4][CH2:3]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1ncoc1C1CC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(N)C(=O)C1CC1
Temperature: 50 °C

Procedure:
Concentrated hydrochloric acid (21.5 ml) was added to a solution of the product of step (a) (9.3 g) in ethanol (65 ml). The mixture was heated at 50° C. for 1 h, cooled and the solvent was evaporated. Toluene (3×50 ml) was added to the residue and was evaporated after each addition. The residue was triturated with diisopropyl ether (80 ml) to give the title compound (Intermediate 12) as a pale brown powder (6.8 g) m.p. 158°-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=O)[N:12]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:11]1=[O:27].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[S:37])[N:12]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:11]1=[O:27]
Reactant: CCOC(=O)Cn1c(=O)c2ccccc2n(Cc2ccc(Cl)cc2Cl)c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)Cn1c(=S)c2ccccc2n(Cc2ccc(Cl)cc2Cl)c1=O
Yield: 70.9 %

Procedure:
Into 100 ml of toluene was dissolved 3.80 g of ethyl 1-(2,4-dichlorophenyl)methyl-1,4-dihydro-2,4-dioxo-3(2H)-quinazolineacetate, and 5.70 g of Lawesson's reagent were added. After refluxed for 7 hours and 30 minutes, 1.90 g of Lawesson's reagent were further added and, after refluxed for 5 hours, solvent was distilled off. To the residue were added 10 ml of ethanol for washing, then it was further recrystallized from ethanol to obtain 2.80 g of title compound. m.p. 138°-139° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH:32]([C:35]1[C:40](=[O:41])[NH:39][C:38](=[O:42])[NH:37][C:36]=1[O:43][C:44]1[CH:45]=[C:46]([CH:51]=[CH:52][C:53]#[N:54])[CH:47]=[C:48]([CH3:50])[CH:49]=1)([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+]>C(Cl)(Cl)Cl.ClCCl.CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:37]2[C:36]([O:43][C:44]3[CH:45]=[C:46]([CH:51]=[CH:52][C:53]#[N:54])[CH:47]=[C:48]([CH3:50])[CH:49]=3)=[C:35]([CH:32]([CH3:34])[CH3:33])[C:40](=[O:41])[NH:39][C:38]2=[O:42])[CH:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1
Reactant: Cc1cc(C=CC#N)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: COc1ccc(CNc2cc(CO)cc(F)n2)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CNc2cc(Cn3c(Oc4cc(C)cc(C=CC#N)c4)c(C(C)C)c(=O)[nH]c3=O)cc(F)n2)cc1
Reaction time: 1.5 h
Yield: 45.9 %

Procedure:
To a stirred solution of 2-fluoro-6-(p-methoxybenzylamino)-4-pyridinemethanol (262 mg, 1 mmol) in chloroform (10 ml) at 0° C. (ice bath), was added triethylamine (210 μl, 1.5 mmol) and methanesulfonyl chloride (90 μl, 1.2 mmol). After stirring for 1.5 hr., the mixture was diluted with dichloromethane, washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was further dried in high vacuo and mixed with 3-[3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yloxy)-5-methyl-phenyl]-acrylonitrile (123) (311 mg, 1 mmol), anhydrous powdered potassium carbonate (138 mg, 1 mmol), lithium iodide (134 mg, 1 mmol). Anhydrous DMF (5 ml) was then added into the mixture and stirred for overnight at room temperature. The mixture was evaporated in vacuo. The residue was dissolved in methanol-dichloromethane (1:9), filtered through celite pad, and the filtrate was evaporated in vacuo to give a pale yellow foam. The crude product was purified by silica gel column chromatography (eluent, EA:hexanes (1:2); The fraction of Rf=0.19 was collected.) to afford 255 mg (46%) of a white foam. 1H NMR (300 MHz, CDCl3) δ 1.10 (6H, d, J=6.9 Hz), 2.32 (3H, s), 2.68 (1H, m), 3.79 (3H, s), 4.31 (2H, d, J=5.5 Hz), 4.73 (2H, s), 5.02 (1H, t, J=5.5 Hz), 5.81 (1H, d, J=16.6 Hz), 5.85 (1H, s), 5.98 (1H, s), 6.64 (2H, s), 6.86-6.89 (2H, m), 6.98 (1H, s), 7.20-7.24 (3H, m), 8.98 (1H, s).
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH2:23].[OH-].[Na+].Cl>C(OCC)C.C(O)C>[ClH:2].[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8]([N:23]=[CH:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([C:18]([F:17])([F:27])[F:28])[CH:20]=1)=[NH:11]
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: I
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: N=C(N=Cc1cccc(C(F)(F)F)c1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 4.88 g. of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydroiodide (U.S. Pat. No. 3,657,337) and 4.37 g. of m-(trifluoromethyl)benzylamine [F. N. Freidfelder and Y. H. Ng, J. Pharm. Sci., 54, 1204 (1965)] in 270 ml. of absolute ethanol is heated at reflux for 18 hours. The solution is cooled, made basic with 2N NaOH and the solvent is removed under reduced pressure. The yellow residue is triturated with dichloromethane and the triturate is evaporated under reduced pressure to give a yellow oil. A diethyl ether solution of this oil is treated with ethanolic hydrogen chloride. Filtration gives colorless crystals which are recrystallized from ethanol-diethyl ether, giving the desired product as colorless crystals, m.p. 165°-167° C.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:15]=1[CH2:16][CH:17]1[CH2:22][NH:21][CH2:20][CH2:19][NH:18]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl.O>[CH2:1]([O:8][C:9]([N:21]1[CH2:20][CH2:19][NH:18][CH:17]([CH2:16][C:15]2[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:14]=2[O:13][CH3:12])[CH2:22]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1cccc(CC2CNCCN2)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(CC2CN(C(=O)OCc3ccccc3)CCN2)c1OC
Reaction time: 0.25 h
Yield: 53.1 %

Procedure:
A solution of benzyloxycarbonyl chloride (0.59 g) in dichloromethane (3.0 ml) was added dropwise to a solution of 2-(2,3-dimethoxybenzyl)piperazine (0.91 g) and triethylamine (0.64 ml) in dichloromethane (18 ml) below 5° C. over 5 minutes under ice-cooling, and the reaction mixture was stirred at the same temperature for 15 minutes. After 2 hours of stirring at room temperature, the mixture was poured into a mixed solvent of water (40 ml) and dichloromethane (25 ml) and the whole was adjusted to pH 9 with aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (20 g) using a mixed solvent of dichloromethane and methanol (40:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give colorless oil of 1-(benzyloxycarbonyl)-3-(2,3-dimethoxybenzyl)piperazine (0.68 g).
Reaction SMILES: [C:1]1([CH:7]2[N:15]3[C:10]([S:11][CH2:12][CH2:13][CH2:14]3)=[N:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)=[O:17]>[OH-].[Na+]>[SH:11][CH2:12][CH2:13][CH2:14][N:15]1[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][NH:9][C:10]1=[O:17]
Reactant: c1ccc(C2CN=C3SCCCN32)cc1
Reactant: O=C=O
Agent: [Na+]
Agent: [OH-]
Product: O=C1NCC(c2ccccc2)N1CCCS

Procedure:
A mixture of 55.0 g of 3-phenyl-2,3,6,7-tetrahydro-5H-imidazo[2,1-b][1,3]thiazine and 540 ml of 0.5N sodium hydroxide solution is stirred and refluxed under nitrogen for thirty hours. The solution is cooled, neutralized to pH 8 with carbon dioxide and extracted with methylene chloride. The organic extracts are dried over magnesium sulfate, filtered and concentrated in vacuo to yield a colorless solid. Recrystallization from isopropyl acetate yields the product of this example, 53.8 g, m.p. 97°-99° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][O:23][C:24]1[C:25]([NH2:43])=[CH:26][C:27]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH2:30][CH2:29][C:28]=2[CH:42]=1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:43][C:25]2[C:24]([O:23][CH3:22])=[CH:42][C:28]3[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[CH2:32][CH2:33][C:27]=3[CH:26]=2)=[N:3][CH:4]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CCN1CCOCC1)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(CCN1CCOCC1)CC2
Yield: 28 %

Procedure:
In an analogous manner to Example 1513, the product was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide and 8-Methoxy-3-(2-morpholin-4-yl-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine. Product isolated as a white foam (30 mg, 28%). MS (ESI+): 616 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.35 (s, 1H), 8.55 (d, J=8 Hz, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.57 (t, 1H), 7.50 (s, 1H), 7.26 (m, 1H), 6.66 (s, 1H), 3.89 (s, 3H), 3.74 (s, 4H), 2.88 (s, 2H), 2.76-7.70 (m, 14H), 2.69-2.52 (m, 6H).