Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:10][CH3:11])=[N:4][CH:5]=[C:6]([CH2:8]Cl)[CH:7]=1.[C-:12]#[N:13].[K+]>CN(C)C=O.O.[Na+].[Cl-]>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:12]#[N:13])[CH:5]=[N:4][C:3]=1[CH2:10][CH3:11]
Reactant: CCc1ncc(CCl)cc1Cl
Reactant: [C-]#N
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ncc(CC#N)cc1Cl
Reaction time: 4 h
Yield: 90.2 %

Procedure:
A solution of 3-chloro-5-chloromethyl-2-ethyl-pyridine (4.03 g, 21 mmol) in dimethylformamide (26 mL, 0.8 M) is cooled to 0° C. and treated with a solution of potassium cyanide (1.48 g, 22.7 mmol) in water (10 mL). After 4 h, the solution is diluted with 50% aq NaCl and extracted with ethyl acetate. The organic extracts are washed with sat'd aq lithium chloride and purified by MPLC (30-90% ethyl acetate in heptane) to give 5-chloro-6-ethyl-pyridin-3-yl-acetonitrile as a light brown oil (3.42 g, 90%): Rf 0.29 (30% ethyl acetate in n-heptane), 1H NMR (CDCl3, 300 MHz) δ 8.38 (br s, 1 H), 7.67 (br s, 1 H), 3.74 (s, 2 H), 2.97 (q, J=7.5 Hz, 2 H), 1.30 (t, J=7.5 Hz, 3 H) ESI-LCMS m/z calcd for C9H9ClN2: 180.0; found 181.0 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[CH3:21][NH2:22]>C1COCC1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:22][CH3:21])=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: CN
Reactant: O=C(Cl)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Yield: 49.8 %

Procedure:
The product from Example 126c (225 mg, 0.72 mmol) was reacted with methylamine (1.0 mL, 2.0 mmol) in THF (20 mL) at room temperature. The THF was removed under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes/ethyl acetate (30:70) to give the title compound (110 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8](Cl)(Cl)=[S:9]>C1COCC1>[N:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[C:8]=[S:9]
Reactant: Nc1ccccn1
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Product: S=C=Nc1ccccn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 62.6 %

Procedure:
A solution of 2-aminopyridine (0.94 g, 9.99 mmol, Sigma Aldrich) and TEA (3.06 mL, 21.97 mmol) in THF (40.0 mL) was set stirring at 0° C. under nitrogen. A solution of thiophosgene (0.804 mL, 10.49 mmol, Fluka) in 2 mL THF was added dropwise over 5 minutes, and the reaction was stirred for 3 h at 0° C. Silica was added, and the reaction mixture was adsorbed under reduced pressure. It was purified on 16 g SiO2 (eluent: 0-100% EtOAc/hexanes over 30 min, RediSep Gold). The product fractions containing the product by TLC (50% EtOAc/hexanes) were combined and concentrated under reduced pressure to give 2-isothiocyanatopyridine (852 mg, 63%). m/z (ESI, +ve) 137.0 (M+H)+.
Reaction SMILES: N1C=CN=C1.[I:6]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:27][C@@H:28]([CH2:38]O)[CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>C(Cl)Cl>[F:27][C@@H:28]([CH2:38][I:6])[CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: II
Reactant: CC(C)(C)OC(=O)NC[C@@H](F)CO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@@H](F)CI
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.9 %

Procedure:
Imidazole (26.6 g, 0.39 mol) was dissolved in methylene chloride (400 mL) at room temperature. Iodine (102.5 g, 0.39 mol) was added and the reaction mixture was stirred for 10 min at room temperature and then cooled to 0° C. Triphenylphosphine (102.5 g, 0.39 mol) was added portionwise over 10 min such that the internal temperature remained below 10° C. A solution of tert-butyl (2R)-2-fluoro-3-hydroxypropylcarbamate (60.4 g, 0.31 mol) in methylene chloride (100 mL) was added dropwise. On completion of addition of tert-butyl (2R)-2-fluoro-3-hydroxypropylcarbamate, additional methylene chloride (200 mL) was added. The reaction mixture was allowed to warm to room temperature and stirring was continued for 17 h. The reaction mixture was filtered through a pad of Celite® (50 g) and washed with additional methylene chloride. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with methylene chloride. This procedure afforded tert-butyl (2R)-2-fluoro-3-iodopropylcarbamate as a white solid (64.7 g, 68%).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:7]([CH3:8])[NH:6][CH2:5][CH2:4][NH:3]1.CS(O)(=O)=O.C([O-])(=O)C.[K+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O.C(O)C>[CH3:1][C@H:2]1[C@@H:7]([CH3:8])[NH:6][CH2:5][CH2:4][N:3]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]
Reactant: C[C@@H]1NCCN[C@@H]1C
Reactant: O=C(Cl)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C[C@H]1NCCN(C(=O)OCc2ccccc2)[C@H]1C
Temperature: 20 °C
Yield: 48.2 %

Procedure:
A 100 mL, three-necked round-bottom flask was charged with cis-2,3-dimethylpiperazine (Helvetica Chimica Acta, 1994, 77, 1057-64) (1.781 g, 15.6 mmol). The flask was cooled in an ice bath, and a solution of methanesulfonic acid (2.02 mL, 31.2 mmol) in 1.4 mL of water was added slowly, maintaining the temperature below 40° C. The solution was cooled to 20° C., and 2 mL of ethanol was added. The pH was adjusted to 4 with 60% aqueous potassium acetate, and then benzyl chloroformate (2.08 mL, 14.8 mmol in 1 mL of THF) and potassium acetate solutions were simultaneously added dropwise with adjustment of the rate to maintain the reaction solution at pH 4, with cooling to maintain the temperature at 25° C. After the mixture was stirred an additional hour, the organic solvents were removed and the remaining aqueous solution was washed with ethyl acetate. The ethyl acetate wash was extracted with 1 M HCl twice to recover the desired product. The acid extracts were combined with the original aqueous solution, and the pH was adjusted to 11 by the addition of 6 N NaOH, with cooling to maintain temperature below 40° C. The aqueous solution was extracted with ethyl acetate, and the combined extracts were dried over magnesium sulfate and concentrated in vacuo to provide phenylmethyl cis-2,3-dimethyl-1-piperazinecarboxylate (enantiomeric mixture) as a yellow oil (1.77 g, 46%). LCMS: (M+H)+: 249.1.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:18][Mg]Br.O1CCCC1.Cl>CCOCC>[N:1]1([CH:6]([C:10]2[CH:11]=[CH:12][C:13]([CH:14]([OH:15])[CH3:18])=[CH:16][CH:17]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCC(c1ccc(CO)cc1)n1ccnc1
Reactant: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC(c1ccc(C(C)O)cc1)n1ccnc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
460 mg of the aldehyde of example 5 in 8 ml of ether is mixed with 1.5 ml of a 3M methyl magnesium bromide solution in ether with ice cooling and is stirred for 20 hours at room temperature; 10 ml of tetrahydrofuran is added and heated to 60° C. in 6 hours. It is added to 1M of hydrochloric acid, extracted with ether, then the water phase is alkalized with potassium carbonate and extracted with ether. After drying and concentration by evaporation of this ether phase, the residue is chromatographed on silica gel (methylene chloride/methanol (95:5)). 300 mg of the title compound is obtained.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:25][C:26]([F:29])([F:28])[F:27])[CH2:12][CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=2)=[CH:7][C:6]=1[C:30]([F:33])([F:32])[F:31])#[N:4].I[CH3:35]>CN(C=O)C>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:25][C:26]([F:29])([F:27])[F:28])[CH2:12][CH2:13][S:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]([CH3:35])[C:22](=[O:24])[CH3:23])=[CH:19][CH:20]=2)=[CH:7][C:6]=1[C:30]([F:31])([F:33])[F:32])#[N:4]
Reactant: CC(=O)Nc1ccc(SCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc(SCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 0.1 %

Procedure:
NaH (60% in oil, 0.003 g, 0.075 mmol) was added to a solution of N-[4-({2-[[4-cyano-3-(trifluoromethyl)phenyl](2,2,2-trifluoroethyl)amino]ethyl}thio)phenyl]acetamide (0.026 g, 0.056 mmol) in DMF (2 mL) under N2. After 5 min, iodomethane (0.009 g, 0.063 mmol) was added and stirred at rt for 30 min. The mixture was partitioned between Et2O and water. The organic phase was washed with water and brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel chromatography (5-80% EtOAc/hexanes gradient) to give the title compound (0.018 mg, 66% yield): MS (ES) m/z 476 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(NC3C=CC(CC)=CC=3)=O)=[CH:11][CH:10]=2)[CH:3]=1.[C:27]([C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:38]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([C:27]([CH3:30])([CH3:28])[CH3:29])=[CH:32][CH:33]=3)=[O:39])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: CCc1ccc(NC(=O)Nc2ccc(Cc3cc(N)ncn3)cc2)cc1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(NC(=O)Nc2ccc(Cc3cc(N)ncn3)cc2)cc1
Reaction time: 3 h

Procedure:
The title compound is prepared as described in Example 102 but using 6-(4-aminobenzyl)-pyrimidin-4-ylamine (see Example 157), 4-tert-butyl-phenyl-isocyanate, and DMF as the solvent. The reaction mixture is stirred for 3 h. The title compound is obtained as a white solid: ES-MS: 348.0 [M+H]+; single peak at tR=6.94 min (System 2).
Reaction SMILES: [ClH:1].[C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][N:12](CC3C=CC=CC=3)[CH2:11][C:10]2=[O:22])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[ClH:1].[C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]2=[O:22])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C1CNCCN1Cc1ccccc1

Procedure:
A mixture of 1,4-bis(phenylmethyl)piperazinone hydrochloride (XIII, Example 39, 15.0 g.) and 10% palladium charcoal (5.0 g.) in ethanol (200 ml.) is hdyrogenated (50 lb. initial hydrogen pressure) until uptake of hydrogen ceased. The solution is filtered, the ethanol is removed under reduced pressure and the residual solid is recrystallized from methanol-isopropanol to give the title compound, m.p. 160°-161°.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15](Cl)(=[O:24])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClC(Cl)C>[C:18]1([CH2:17][CH2:16][C:15]([NH:14][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC1CCc2oc3ccccc3c2C1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CC(Cl)Cl
Product: O=C(CCc1ccccc1)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 50.9 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.15 g, 0.80 mmol), hydrocinnamoyl chloride (0.12 mL, 0.80 mmol), and poly(vinylpyridine) (0.5 g) in dichloroethane (8 mL) provided 3-phenyl-N-(6,7,8,9-tetrahydrodibenzo[b,d]furan-2-yl)propanamide (0.13 g) after flash column chromatography (elution with 35% ethyl acetate-hexanes). MS (ESI) m/z 320.
Reaction SMILES: C(OC([N:6]=[S:7]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[N:27]=[C:26]([NH:28][C@@H:29]([CH2:32][OH:33])[CH2:30][CH3:31])[C:25]([C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)=[CH:24][N:23]=2)=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])=O)C.CC[O-].[Na+]>>[OH:33][CH2:32][C@H:29]([NH:28][C:26]1[C:25]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)=[CH:24][N:23]=[C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([S:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)(=[NH:6])=[O:8])=[CH:16][CH:17]=2)[N:27]=1)[CH2:30][CH3:31]
Reactant: CCOC(=O)N=S(=O)(c1ccccc1)c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](CC)CO)n2)cc1
Agent: CC[O-]
Agent: [Na+]
Product: CC[C@H](CO)Nc1nc(Nc2ccc(S(=N)(=O)c3ccccc3)cc2)ncc1-c1cccs1
Yield: 35 %

Procedure:
In the reaction of (RS)—N-(ethoxycarbonyl)-S-(4-{[4-{[(R)-1-(hydroxymethyl)-propyl]amino}-5-(2-thienyl)pyrimidine-2-yl]amino}phenyl)-S-phenylsulfoximide with sodium ethylate according to procedure 14, the desired product is obtained in 35% yield after chromatographic purification (silica gel, dichloromethane/ethanol (0-10% ethanol)).
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[N:15]([CH3:17])[CH:14]=[C:13]2[S:18]([NH:21][C:22](=[O:31])[NH:23][C:24]1[S:25][C:26]([O:29][CH3:30])=[CH:27][N:28]=1)(=[O:20])=[O:19])(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C1COCC1>[OH:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[N:15]([CH3:17])[CH:14]=[C:13]2[S:18]([NH:21][C:22](=[O:31])[NH:23][C:24]1[S:25][C:26]([O:29][CH3:30])=[CH:27][N:28]=1)(=[O:19])=[O:20]
Reactant: COc1cnc(NC(=O)NS(=O)(=O)c2cn(C)c3c(OCCOC(C)=O)cccc23)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cnc(NC(=O)NS(=O)(=O)c2cn(C)c3c(OCCO)cccc23)s1
Temperature: 25 °C
Reaction time: 60 h
Yield: 93 %

Procedure:
A solution of 2-{[3-({[(5-methoxy-1,3-thiazol-2-yl)carbamoyl]amino}sulfonyl)-1-methyl-1H-indol-7-yl]oxy}ethyl acetate (0.065 g) in THF (10 mL) was treated with 2N sodium carbonate (2 mL) and 2N sodium hydroxide (2 mL). The reaction mixture was stirred at rt for 60 h and acidified to about pH 4. The organic solvent were slowly evaporated, leaving back a solid, which was filtered, washed and dried to obtain the title compound (0.055 g) as a brownish solid. MS (ISN): m/e 425.3 (M−H)−
Reaction SMILES: F[C:2]1[C:22]([F:23])=[CH:21][C:5]2[C:6]3[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]([CH3:14])[C:11]=3[CH:12]=[N:13][C:4]=2[CH:3]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C)C=O>[F:23][C:22]1[C:2]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:3][C:4]2[N:13]=[CH:12][C:11]3[N:10]([CH3:14])[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7](=[O:20])[C:6]=3[C:5]=2[CH:21]=1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cn(C)c2cnc3cc(F)c(F)cc3c2c1=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2cnc3cc(N4CCCC4)c(F)cc3c2c1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
A suspension of 2 g of ethyl 8,9-difluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate and 1.1 g of pyrrolidine in 40 cm3 of dimethylformamide was heated, with stirring, at a temperature of 70° C. for 8 hours. After cooling to 20° C., the mixture was poured into 150 cm3 of ice-cold water. The insoluble material was dewatered, washed 3 times with 30 cm3 of water, and dissolved in 300 cm3 of dichloromethane; the residual water was decanted off. The organic extracts were dried over sodium sulphate; after filtration and concentration under reduced pressure (5.2 kPa), the compound obtained was purified by chromatography on 180 g of silica gel (0.06-0.20 mm). Elution was carried out with 3.6 liters of a dichloromethane-ethanol mixture (97-3 by volume) and with 6 liters of a dichloromethane-ethanol mixture (94-6 by volume), 150 cm3 fractions were collected. The fractions obtained from the latter mixture were concentrated to dryness under reduced pressure. 0.85 g of ethyl 9-fluoro-4-methyl-1-oxo-8-pyrrolidinyl-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate was obtained in the form of a yellow compound, which melted at 270° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:4][CH:3]=1.C(O[CH:20](N(C)C)[N:21]([CH3:23])[CH3:22])(C)(C)C>>[CH3:20][N:21]([CH3:23])[CH:22]=[C:10]1[C:9](=[O:14])[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: O=C1CCCCC1c1ccc(F)cc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C1CCCC(c2ccc(F)cc2)C1=O

Procedure:
2-(4-Fluoro-phenyl)-cyclohexanone (102 mg, 0.53 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (143 mg) as a red oil which was used directly in the next step. MS ISP (m/e): 248.1 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C@H:14]2[CH2:19][O:18][C:16](=[O:17])[CH2:15]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH:25]=O.[H-].[Na+].CO.Cl>C1(C)C=CC=CC=1>[CH3:33][O:32][C:28]1[CH:27]=[C:24]([CH:23]=[C:22]([O:21][CH3:20])[C:29]=1[O:30][CH3:31])/[CH:25]=[C:15]1/[C:16]([O:18][CH2:19][C@@H:14]/1[CH2:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:17]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COc1cc(C[C@H]2COC(=O)C2)cc(OC)c1OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cc(/C=C2/C(=O)OC[C@@H]2Cc2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 45 h
Yield: 32.1 %

Procedure:
A solution of (R)-3-[1-(3,4,5-trimethoxyphenyl)-methyl]butanolide [10.52 g, 0.04 mol; K. Lalami, D. Dhai, and E. Brown, Heterocycles, 27, 1131 (1988)] and 3,4,5-trimethoxybenzaldehyde (11.4 g, 0.058 mol) in toluene (150 ml) was cooled to 0° C. under an argon stream. The solution was added with 4.0 g of sodium hydride (60%, 0.1 mol) and 0.15 ml (0.0037 mol) of methanol, followed by stirring at room temperature for 45 hours. The reaction mixture was ice-cooled and then added with 100 ml of 2N-HCl. After the removal of the water layer, the organic layer was washed successively with water, saturated NaHCO3 and saturated NaCl and then dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue thus obtained (20 g) was purified by column chromatography on a silica gel column (silica gel: "MERCK #9385", 500 g, eluent: 1:2 mixed solvent of ethyl acetate and hexane), whereby 5.71 g of the title compound were obtained as pale yellow oil (yield: 33%). [α]27D : -75.64° (C=0.55, CHCl3)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13]3=[C:14]([C:16](=[O:26])[C:17]([CH2:19][C:20]4[CH:21]=N[CH:23]=[CH:24][CH:25]=4)=[CH:18][N:12]3[C:11]3[CH:10]=[CH:9][C:8]([Cl:27])=[CH:7][C:6]=3[O:5]2)[CH:15]=1.[CH:28](=O)C1C=CC=CC=1>>[Cl:27][C:8]1[CH:7]=[C:6]2[C:11]3=[C:10]([C:16](=[O:26])[C:17]([CH2:19][C:20]4[CH:21]=[CH:28][CH:23]=[CH:24][CH:25]=4)=[CH:18][N:12]3[C:13]3[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][C:4]=3[O:5]2)[CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: O=c1c(Cc2cccnc2)cn2c3c(cc(Cl)cc13)Oc1cc(Cl)ccc1-2
Product: O=c1c(Cc2ccccc2)cn2c3c(cc(Cl)cc13)Oc1cc(Cl)ccc1-2
Yield: 81 %

Procedure:
According to Example 1<step 4>, the compound (500 mg) produced in Example 1<step 3> was reacted with benzaldehyde (260 μl) to obtain the title compound (508 mg; 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CO.CC#N>[CH2:31]([NH:38][C:39]([NH:30][C:29]1[C:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:10][C:11]2[CH:16]=[N:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[N:13][C:12]=2[N:28]=1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C=NCc1ccccc1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Solvent: CO
Solvent: CC#N
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(NC(=O)NCc4ccccc4)nc3n2)CC1
Yield: 63.4 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.08 g) from Example 36 was reacted with 0.298 g of benzyl isocyanate according to the general procedure of Example 37 to give 0.822 g of 1-benzyl-3-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=579; mp 144-148.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][CH:9]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:24]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:10][CH:9]=1)[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCBr
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2ccccc2O)cc1
Product: CCCCCOc1ccccc1-c1ccc(CNC(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 20 using tert-butyl N-(2′-hydroxybiphenyl-4-ylmethyl)carbamate instead of tert-butyl N-(3′-hydroxybiphenyl-4-ylmethyl)carbamate and 1-bromopentane instead of 1-bromopropane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([N:20]3[CH2:24][C:23](=[O:25])[NH:22][S:21]3(=[O:27])=[O:26])=[C:14]([OH:19])[CH:15]=2)[CH:10]=1)[CH3:2].[CH3:29]C([O-])(C)C.[K+]>CC(O)C>[CH:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([N:20]3[CH2:24][C:23](=[O:25])[NH:22][S:21]3(=[O:26])=[O:27])=[C:14]([OH:19])[CH:15]=2)[CH:10]=1)([CH3:29])[CH3:2]
Reactant: CCOC(=O)CCCCc1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)cc2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)OC(=O)CCCCc1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)cc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of 5-[6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-naphthalen-2-yl]-pentanoic acid ethyl ester (0.003 g, 0.007 mmol) in iPrOH (1 mL) is added t-BuOK (1M in THF, 0.044 mL). The mixture is stirred for 18 h at room temperature. The reaction is quenched with 1 N HCl (1.5 mL) and extracted with EtOAc (3×10 mL). The organic layers are dried and concentrated. The residue is passed through a short column of reverse phase silica gel eluting with 40% MeOH/H2O to afford 5-[6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-naphthalen-2-yl]-pentanoic acid isopropyl ester: Retention time=1.17 min (Method A); (M−H)−=419.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12]O)=[CH:9][CH2:8][CH:7]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)=[O:16])[C:6]1=[O:27].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:28])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:9][CH2:8][CH:7]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)=[O:16])[C:6]1=[O:27]
Reactant: COC(=O)CN1CC(CO)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN1CC(CS(C)(=O)=O)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of {6-hydroxymethyl-3-[(isoquinoline-1-carbonyl)-amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl}-acetic acid methyl ester, 19, (1.35 g, 3.52 mmol) in 10 mL CH2Cl2is treated with triethyl amine (1.3 mL, 8.81 mmol) and methanesulfonyl chloride (0.61 mL, 7.93 mmol) at −78° C. After stirring at −78° C. for 2 hours, the reaction mixture is poured into a CH2Cl2/saturated NaCl solution. The organic layer is collected and washed with saturated NaHCO3, saturated NaCl, dried (Na2SO4) and concentrated in vacuo to afford the desired product which is used without further purification.