Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][O:15]C(=O)C)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC[C@@H]1CN(Cc2ccccc2)CCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OC[C@@H]1CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.6 %

Procedure:
5 g of (S)-4-benzyl-2-acetoxymethylmorpholine was dissolved in 10 ml of ethanol. To the solution was added a solution of 1 9 of sodium hydroxide dissolved in 5 ml of water with ice cooling. The mixture was stirred at room temperature for 10 minutes. The reaction mixture was added to 50 ml of ice water and extracted with 50 ml of chloroform. The organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/ethanol=30/1) to obtain 3.6 g of oily (S)-4-benzyl-2-hydroxymethylmorpholine.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1.CCOC(C)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Br)n1
Reactant: Fc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Fc1ccc(CNc2cccc(Br)n2)cc1
Temperature: 100 °C
Yield: 62.3 %

Procedure:
To a suspension of 6-bromopyridin-2-amine (500 mg, 2.89 mmol), sodium tert-butoxide (695 mg, 7.24 mmol) in anhydrous toluene (20 ml) was added 4-fluorobenzylchloride (415 mg, 2.90 mmol) at room temperature. The reaction mixture was heated at 100° C. overnight. EtOAc was added and the mixture was washed with brine and was concentrated. Flash chromatography (10-14% EtOAc in hexanes) gave the title compound (506 mg, 63%). 1H NMR (CDCl3) δ 4.40 (m, 2H), 4.95 (br s, 1H), 6.20 (m, 1H), 6.73 (m, 1H), 7.00 (m, 2H), 7.25 (m, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4]([C:12]([C:14]2[CH:15]=[N:16][N:17]([CH3:20])[C:18]=2[OH:19])=[O:13])[C:3]1=[O:21].N1C=CC=CC=1.C(Cl)(Cl)Cl.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>O>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[C:4]([C:12]([C:14]2[CH:15]=[N:16][N:17]([CH3:20])[C:18]=2[O:19][S:38]([C:35]2[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=2)(=[O:40])=[O:39])=[O:13])[C:3]1=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1ncc(C(=O)c2ccc(C(F)(F)F)n(C)c2=O)c1O
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Oc2c(C(=O)c3ccc(C(F)(F)F)n(C)c3=O)cnn2C)cc1
Yield: 90.6 %

Procedure:
To a mixed solution of 4-[1,2-dihydro-1-methyl-2-oxo-6-(trifluoromethyl)pyridine-3-carbonyl]-5-hydroxy-1-methyl-1H-pyrazole (0.25 g, 0.80 mmol), pyridine (0.13 g, 1.6 mmol) and chloroform (5 mL), p-toluenesulfonyl chloride (0.23 g, 1.2 mmol) was added little at a time. After the stirring for a day at room temperature, the reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. After separating the inorganic substance by filtration, the solvent was distilled off under reduced pressure, and thus obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/1.5), to obtain 0.33 g of a subject compound (yield: 92%).
Reaction SMILES: [C:1]1([C:7]2[C:8](=[N:13][NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]([NH2:12])=[N:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([C:7]2[C:8](=[N:13][NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:9]([NH:12][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=3)=[N:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: NC1=NN=C(c2ccccc2)C1=NNc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1=NN=C(c2ccccc2)C1=NNc1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.9 %

Procedure:
5-Phenyl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine (66 mg, 0.25 mmol) was dissolved in 5 mL of anhydrous methylene chloride. Nicotinoylchloride hydrochloride (50 mg, 0.28 mmol) and triethylamine (78 μL, 0.56 mmol) were added to the solution. Slight fuming of the reaction was noted and the solution became red. The reaction was stirred at ambient temperature for 48 hours. The reaction was filtered to remove a small amount of white solid. To the filtrate was added 30 mL of methylene chloride. The solution was washed with 20 mL of a 5% HCl solution. The aqueous layer was washed with methylene chloride and the combined methylene chloride fractions were washed with water and saturated NaHCO3 solution. The methylene chloride solution was dried over MgSO4, filtered, and evaporated to afford a solid. The material was purified by flash chromatography (CH2Cl2:MeOH=15:1) to yield 34 mg (36%) of the title compound as a yellow solid. 1H NMR (ppm, 200 MHz, CDCl3) δ 7.30-7.55 (m, 8H), 7.75 (d, 2H), 8.20-8.30 (m, 2H), 8.55 (d, 1H), 8.81 (d, 1H), 9.45 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17]C)=O)[C:5]([CH2:11]Cl)=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:24]([CH2:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[C:15](=[O:17])[C@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:13][C:4]=2[CH:3]=1
Reactant: NCc1ccncc1
Reactant: COC(=O)C[C@H](Cc1cc(Cl)c2[nH]ncc2c1CCl)C(=O)OC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 48 %

Procedure:
(S)-Dimethyl 2-((7-chloro-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate (120 mg, 0.33 mmol) was dissolved in DMF (1.0 mL). 4-Aminomethylpyridine (100 μL, 1.0 mmol) was added to the mixture. Reaction stirred at room temperature for 24 hours. Mixture was diluted with ethyl acetate. Mixture was washed twice with water and once with brine. Organic was dried (magnesium sulfate), filtered and concentrated in vacuo. Residue was dissolved in toluene (4 mL). Acetic acid (1 mL) was added to the mixture. Reaction was heated at reflux for 3.5 hours. Mixture was cooled to room temperature then diluted with ethyl acetate. Material was washed once with water and twice with aqueous sodium bicarbonate. Aqueous was made basic with sodium bicarbonate. Back extracted from the aqueous twice with ethyl acetate. Combined organics were dried (magnesium sulfate), filtered and concentrated in vacuo. Residue was purified with silica gel chromatography eluting dichloromethane and 2N ammonia in methanol. Title compound was obtained as yellow solid in 48% yield. MS m/e (M+H)+=399.2.
Reaction SMILES: [N:1]1[C:10]2[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][CH:9]2[C:10]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7][CH2:8]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C1CCCc2cccnc21
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC2CCCc3cccnc32)CC1

Procedure:
Using General Procedure B: Reaction of 6,7-Dihydro-5H-quinolin-8-one and 4-Amino-piperidine-1-carboxylic acid tert-butyl ester with NaBH(OAc)3 in CH2Cl2 gave 4-(5,6,7,8-Tetrahydro-quinolin-8-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][CH:13]=C)[C:5]([O:7][CH3:8])=[O:6].[CH3:16][OH:17]>>[CH3:15][C:3]1[C:2]2[O:1][CH:13]([O:17][CH3:16])[CH2:12][C:11]=2[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CO
Reactant: C=CCc1ccc(C(=O)OC)c(C)c1O
Product: COC(=O)c1ccc2c(c1C)OC(OC)C2
Temperature: -78 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
A solution of methyl 3-hydroxy-2-methyl-4-prop-2-en-1-ylbenzoate (1.64 g, 8.0 mmol) in methanol (20 mL) was cooled to −78° C. While maintaining the reaction temperature at −78° C., ozone was bubbled into the reaction mixture for 30 minutes, followed by the addition of dimethyl sulfide (5 mL). The reaction mixture was allowed to warm to room temperature and was then stirred for an additional 15 hours. The reaction mixture was concentrated in vacuo and diluted with diethyl ether. The organic portion was washed with water, brine, dried over sodium sulfate and concentrated to afford (1.59 g, 90%) of methyl 7-methyl-2-(methyloxy)-2,3-dihydro-1-benzofuran-6-carboxylate as a yellow oil. MS (EI) for C12H14O4: 223 (MH+).
Reaction SMILES: [C:1](=[O:20])([O:18][CH3:19])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([Cl:12])=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[BH4-].[Na+]>CO.Cl[Ni]Cl>[C:1](=[O:20])([O:18][CH3:19])[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([Cl:12])=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(Cl)cc1C1CCCC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Oc1cc(N)c(Cl)cc1C1CCCC1
Yield: 51 %

Procedure:
To a solution of 4-chloro-2-cyclopentyl-5-nitrophenyl methyl carbonate (870 mg, 2.90 mmol) and NiCl2 (376 mg, 2.90 mmol) in methanol (10 mL) at 0° C. was added NaBH4 (330 mg, 8.71 mmol) portion-wise. After 10 min the reaction was quenched with NaHCO3 and diluted with ethyl acetate. The reaction mixture was filtered through a pad of Celite and the layers were separated. The aqueous layer was re-extracted with ethyl acetate (3×100 mL) and the combined organic extracts dried over MgSO4. The solution was filtered and concentrated in vacuo to provide 5-amino-4-chloro-2-cyclopentylphenyl methyl carbonate which was used for the next step without further purification (400 mg, 51% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.11 (s, 1H), 6.57 (d, J=11.4 Hz, 1H), 5.38 (s, 1H), 3.85-3.80 (m, 3H), 2.89-2.80 (m, 2H), 1.88-1.81 (m, 2H), 1.75-1.56 (m, 2H), 1.52 (s, 2H), 1.46-1.37 (m, 2H).
Reaction SMILES: [H-].[Na+].CS(C)=O.[PH4+].FC([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O)(F)F>C(OCC)(=O)C>[C:13]1([CH:14]=[CH:14][C:13]2[CH:12]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Agent: [PH4+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C(=Cc1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 208.2 %

Procedure:
In a nitrogen atmosphere, 8.7 g of 55% sodium hydride dispersion are added to 100 ml of absolute dimethylsulphoxide and stirred at 80° C. for 45 minutes. After cooling to ambient temperature, a suspension of 98 g (0.2 mol) of phosphonium salt 4 is added dropwise and the reaction mixture is stirred for a further 10 minutes. Then 34.8 g of trifluoromethylbenzaldehyde are added dropwise and the mixture is stirred for 2 hours at ambient temperature. The mixture is then diluted with 400 ml of ethyl acetate and washed twice with water. The organic phase is dried and the residue is chromatographed (SiO2 column, eluant: dichloromethane). The main fraction is evaporated down in vacuo and the residue is recrystallised from isopropylether. 37.5 g (61% of theory) of stilbene of the type 8 are obtained in the form of crystals, m.p. 157°-158° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:4][CH2:3]1.[CH:28]1[CH:33]=[C:32]([OH:34])[CH:31]=[C:30]([CH:35]([OH:38])[CH2:36][NH2:37])[CH:29]=1>>[OH:38][CH:35]([C:30]1[CH:29]=[CH:28][CH:33]=[C:32]([OH:34])[CH:31]=1)[CH2:36][NH:37][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:4][CH2:3]1
Reactant: NCC(O)c1cccc(O)c1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2N2CCC(=O)CC2)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2N2CCC(NCC(O)c3cccc(O)c3)CC2)cc1

Procedure:
The title compound was prepared from N-{4-[2-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 222) and DL-norphenylephrine according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.70-1.90 (m, 2H), 1.90-2.10 (m, 2H), 2.06 (s, 3H), 2.50-3.20 (m, 7H), 4.75-4.95 (m, 1H), 6.10 (brs, 1H), 6.50-7.40 (m, 8H), 7.65-7.80 (m, 4H), 9.48 (s, 1H), 10.42 (s, 1H); MS (ES) m/z: 525.6 (MH+); HRMS Calcd. for C27H33N4O5S(MH+): 525.2172. Found: 525.2164.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:11]([O:16][CH3:17])(=[O:15])[C:12]([CH3:14])=O.Cl>CO.[Pd]>[F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH:4][CH:12]([CH3:14])[C:11]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)C(C)=O
Reactant: Nc1ccc(F)c(F)c1F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)C(C)Nc1ccc(F)c(F)c1F
Temperature: 40 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
2,3,4-Trifluoroaniline (0.83 g) and methyl pyruvate (0.87 g) were dissolved in methanol (8 ml). After adding 5% Pd—C (0.11 g) and conc. hydrochloric acid (0.03 g), the mixture was stirred at 40° C. under a hydrogen gas pressure of 2.94 MPa for 2 hours. After filtering off Pd—C, the obtained filtrate was concentrated under reduced pressure. Thus the title compound (1.26 g) was obtained as slightly yellowish crystals. Various spectral data of this product was identical with those obtained in Example 5.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.CN1CCOCC1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([CH3:36])[CH:27]=1>ClCCl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:34])=[O:33])=[C:28]([CH3:36])[CH:27]=1
Reactant: Cc1cc(Br)ccc1S(=O)(=O)Cl
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (1.20 g, 5.1 mmol) in dichloromethane (35 ml) was treated with morpholinomethyl-polystyrene HL resin (2.43 g, 4.2 mmol/g loading, 10.2 mmol) followed by 4-bromo-2-methylbenzenesulfonyl chloride (2.75 g, 10.2 mmol). The resulting solution was stirred at room temperature overnight, the resin filtered off, the solvent evaporated in vacuo and the residue passed through an SCX column eluting first with methanol and then 2M ammonia in methanol. The basic fractions were combined and solvent evaporated in vacuo to afford a crude product which was purified further by chromatography on silica gel using a Flashmaster and an elution gradient of 0 to 10% methanol in dichloromethane. The relevant fractions were combined and the solvent evaporated in vacuo to afford the title compound (E102). MS (ES+) m/e 468/470 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[CH:14]=[N:15][OH:16])[N:4]=1.[CH2:21](Br)[C:22]#[CH:23].O>CN(C)C=O.C(=O)([O-])[O-]>[CH2:23]([C:12]1([O:11][C:5]2[N:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:13]1[CH:14]=[N:15][OH:16])[C:22]#[CH:21]
Reactant: COc1cc(OC)nc(Oc2ccccc2C=NO)n1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCC1(Oc2nc(OC)cc(OC)n2)C=CC=CC1C=NO
Temperature: 100 °C
Reaction time: 4 h
Yield: 76.2 %

Procedure:
5.5 g of 2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime and 7.1 g of propargyl bromide were dissolved in 100 ml of N,N-dimethylformamide containing 1.4 g of potassisum carbonate, and the solution was stirred at 100° C. for 4 hours. After the reaction mixture was allowed to cool down, it was poured into water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (developer: n-hexane:ethyl acetate=10:1) to obtain 4.8 g of 0-(2-propynyl)-2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime as an oily substance.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:9][C:10]=2[N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:5]=[CH:4][N:3]=1.[Cl:26][C:27]1[C:32]([NH2:33])=[C:31]2[O:34][CH2:35][O:36][C:30]2=[CH:29][CH:28]=1>C(O)(C)C>[Cl:26][C:27]1[C:32]([NH:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:18][CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:9][C:10]=3[N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:5]=[CH:4][N:3]=2)=[C:31]2[O:34][CH2:35][O:36][C:30]2=[CH:29][CH:28]=1
Reactant: Nc1c(Cl)ccc2c1OCO2
Reactant: Clc1ncnc2cc(OCCN3CCCC3)cc(N3CCOCC3)c12
Solvent: CC(C)O
Product: Clc1ccc2c(c1Nc1ncnc3cc(OCCN4CCCC4)cc(N4CCOCC4)c13)OCO2
Temperature: 80 °C
Yield: 9.4 %

Procedure:
A mixture of 4-chloro-5-morpholino-7-(2-pyrrolidin-1-ylethoxy)quinazoline (0.27 g), 6-chloro-2,3-methylenedioxyaniline (0.14 g) and isopropanol (4 ml) was stirred and heated to 80° C. for 1 hour. The mixture was evaporated and the residue was dissolved in a 49:1 mixture of methylene chloride and a saturated methanolic ammonia solution. The mixture was filtered and the filtrate was poured onto a column of silica and eluted with a 97:3 mixture of methylene chloride and a saturated methanolic ammonia solution. The material so obtained was triturated under diethyl ether. The resultant solid was isolated, washed with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.035 g); NMR Spectrum: (CDCl3) 1.85 (br s, 4H), 2.65 (br s, 4H), 3.0 (m, 2H), 3.08 (m, 2H), 3.18 (d, 2H), 3.82 (m, 2H), 4.05 (m, 2H), 4.25 (m, 2H), 6.05 (s, 2H), 6.75 (d, 1H), 6.95-7.1 (m, 3H), 8.52 (s, 1H); Mass Spectrum: M+H+ 498 and 500.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[CH:5]=[C:4]([CH3:12])[N:3]=1.[I:13]N1C(=O)CCC1=O.S([O-])(O)=O.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([I:13])=[C:4]([CH3:12])[N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCCNc1cc(C)nc(Cl)n1
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCNc1nc(Cl)nc(C)c1I
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To a suspension of 2-chloro-6-methyl-N-propylpyrimidin-4-amine (T1, 200 mg) in acetic acid (4 mL), N-iodosuccinimide (485 mg) was added at room temperature, and the mixture was stirred at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature, and then saturated aqueous sodium hydrogensulfite, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 90-75% hexane in ethyl acetate) to obtain 2-chloro-5-iodo-6-methyl-N-propylpyrimidin-4-amine (T2, 252 mg).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH:7]=[C:6]2[C:14]2[N:18]([CH3:19])[C:17]3[C:20](OC)=[CH:21][C:22]([C:24]([OH:26])=[O:25])=[CH:23][C:16]=3[N:15]=2)[CH2:3][CH2:2]1.C1(CN2C3=NC=CC=C3C=C2C2N(C)C3C=CC(C(OC)=O)=CC=3N=2)CC1>>[CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH:7]=[C:6]2[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][C:22]([C:24]([OH:26])=[O:25])=[CH:23][C:16]=3[N:15]=2)[CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)cc2nc(-c3cc4cccnc4n3CC3CC3)n(C)c12
Agent: COC(=O)c1ccc2c(c1)nc(-c1cc3cccnc3n1CC1CC1)n2C
Product: Cn1c(-c2cc3cccnc3n2CC2CC2)nc2cc(C(=O)O)ccc21

Procedure:
Prepared in a similar manner to Intermediate 46 from methyl 2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxylate (111 mg, 0.308 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:11]=2[O:10][C@@H:9]1[CH3:21])([CH3:4])([CH3:3])[CH3:2].O([CH2:31][C:32]([F:35])([F:34])[F:33])S(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:12]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:11]=2[O:10][C@@H:9]1[CH3:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: C[C@H]1Oc2ccc(F)cc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@H]1Oc2ccc(F)cc2N(CC(F)(F)F)C(=O)[C@H]1NC(=O)OC(C)(C)C
Yield: 96.6 %

Procedure:
A solution of 3.00 g (10.0 mmol) ((6R,7S)-2-fluoro-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester and 3.37 g (15.0 mmol) 2,2,2-trifluoroethyl triflate in 30 ml dimethylformamide were treated with 4.73 g (15.0 mmol) cesium carbonate for 6 hours. The solvent was distilled off at low pressure and the residue was extracted with water/ethylacetate. Chromatography on silicagel with heptane/ethylacetate 100:0 to 0:100 yielded 3.79 g (99%) [(6R,7S)-2-fluoro-6-methyl-8-oxo-9-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-carbamic acid tert-butyl ester, MS m/e (%): 393.3 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:20]=1.IC.[CH3:23]N(C)C=O.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:23])[C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:20]=1
Reactant: CN(C)C=O
Reactant: CC1CN(C2CCCCC2)c2nc(Cl)ncc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC1CN(C2CCCCC2)c2nc(Cl)ncc2N(C)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice cooled solution of 0.48 g (0.0016 mole) of (rac)-2-chloro-9-cyclohexyl-7-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-18), 0.2 mL (0.0032 mole) of iodomethane and 5 mL of dimethylformamide was added 0.13 g (0.0032 mole) of 60% oil dispersion of sodium hydride. The mixture was stirred at room temperature for 1 hour, then 100 mL of water was added and the mixture was extracted with twice with 100 mL of ethyl acetate. The organic layers were washed with 100 mL of brine, combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-ethyl acetate (85:15), followed by recrystallization from dichloromethane-hexanes to give 0.41 g of (rac)-2-chloro-9-cyclohexyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-19) as white needles.