Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Cl.[Cl:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CS(C)=O.O>[ClH:21].[N:24]1([CH2:23][CH2:22][O:1][CH2:2][C:3]2[C:11]3[O:10][C:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:8][C:7]=3[CH:6]=[CH:5][CH:4]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: ClCCN1CCCCC1
Reactant: OCc1cccc2cc(-c3ccccc3)oc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(-c2cc3cccc(COCCN4CCCCC4)c3o2)cc1
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
7-Hydroxymethyl-2-phenylbenzofuran (1.57 g) is dissolved in dimethylsulfoxide (10 ml), and sodium hydride (60% oil dispersion) (0.57 g) is added thereto. After the mixture is stirred for 10 minutes, N-(2-chloroethyl)piperidine hydrochloride (1.35 g) is added to the mixture and the mixture is stirred at room temperature for 4 hours. The mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried and concentrated under reduced pressure to remove solvent. The residue is converted to its hydrochloride and recrystallized from ethyl acetate, whereby 7-[(2-piperidinoethoxy)methyl]-2-phenylbenzofuran hydrochloride (1.32 g) is obtained. Yield: 51%.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](O)=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.P(Cl)(Cl)([Cl:18])=O>CN(C)C=O>[Cl:18][C:6]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]([S:2][CH3:1])=[CH:4][C:5]=1[N+:13]([O-:15])=[O:14]
Reactant: CSc1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CSc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
A mixture of 4-(methylthio)-2,6-dinitrophenol (1 g.), phosphorus oxychloride (7.5 ml.), and dimethylformamide (1 ml.) is heated at 90°-100° C. for four hours. The cooled reaction mixture is poured into ice-water. The resulting product is collected by filtration.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=1.C(N(CC)CC)C.[OH-].[Na+]>C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][N:25]([C:7](=[O:8])[C:6]3[CH:10]=[CH:11][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][CH:5]=3)[CH2:26][CH2:27]2)=[CH:16][CH:15]=1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5.1 g of 4-dimethylaminobenzoyl chloride in 130 ml of methylene chloride is added dropwise, over a period of 10 minutes, to a solution, stirred at room temperature, of 6.08 g of 1-[2-(4-chlorophenyl)-ethyl]-piperazine and 2.74 g of triethylamine in 150 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature, diluted with methylene chloride, rendered alkaline with 2N NaOH and washed with water, dried over sodium sulphate and concentrated to dryness by evaporation. The residue is recrystallised from ethanol. 1-[2-(4-chlorophenyl)-ethyl]-4-(4-dimethylaminobenzoyl)piperazine having a melting point of 133°-134° is thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:3]=1[C:4]([OH:6])=O.[C:16]([O:20][C:21]([N:23]1[CH2:30][CH:29]2[CH:25]([CH2:26][NH:27][CH2:28]2)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH:25]2[CH:29]([CH2:28][N:27]([C:4](=[O:6])[C:3]3[C:7]([N:11]4[N:15]=[CH:14][CH:13]=[N:12]4)=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[CH2:26]2)[CH2:30]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3c(F)cccc3-n3nccn3)CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
2-Fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (0.97 g, 4.71 mmol), hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (Intermediate 15, 1.0 g, 4.71 mmol), HATU (2.68 g, 7.06 mmol), in DMF (18.8 mL) was added DIEA (2.43 mL, 14.13 mmol). The mixture was stirred at rt for 1 hr. The mixture was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, the organic layers were combined, dried (Na2SO4), filtered and concentrated to provide the crude product. Purification (FCC) (5-50% of a solution 10% MeOH, 0.1% NH4OH in DCM/EtOAc over 25 minutes, and 50-100% from 25-35 minutes) provided 5-(2-fluoro-6-[1,2,3]triazol-2-yl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (0.376 g, 19.5%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1.CCN(C(C)C)C(C)C>C(O)(C)C.C(Cl)Cl>[N:17]1[CH:18]=[CH:19][CH:20]=[N:21][C:16]=1[NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1ncccn1
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncccn2)CC1
Yield: 36.7 %

Procedure:
4-Amino-1-t-butoxycarbonylpiperidine from Step A, (1.9 g, 9.5 mmol), 2-chloropyrimidine (1.1 g, 9.5 mmol) and DIPEA (3.3 mL, 19 mmol) were combined in isopropanol (10 mL) and the mixture was refluxed for 24 h. The mixture was cooled, diluted with methylene chloride (100 mL) and washed with water and brine. The organic phase was dried over sodium sulfate and concentrated. FC (60 g silica, 1/1 hexanes/ethyl acetate) afforded the title compound (0.97 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][CH:23]=1>>[ClH:1].[OH:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=[C:2]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][CH:23]=3)[N:7]=2)[CH2:9][CH2:10]1
Reactant: OC1CCN(c2cc(-c3ccccc3)nc(Cl)n2)CC1
Reactant: CC(=O)c1ccc(N)cc1
Product: CC(=O)c1ccc(Nc2nc(-c3ccccc3)cc(N3CCC(O)CC3)n2)cc1
Product: Cl

Procedure:
A sample of 1-{4-[4-(4-hydroxy-piperidin-1-yl)-6-phenyl-pyrimidin-2-ylamino]-phenyl}-ethanone hydrochloride was prepared from compound 1-(2-chloro-6-phenyl-pyrimidin-4-yl)-piperidin-4-ol (0.3 g, 1.04 mmol) and 1-(4-amino-phenyl)-ethanone (0.14 g, 1.04 mmol) according to a procedure analogous to that described above in Example 48.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@H:13]([OH:16])[CH2:14]C)=[CH:7][C:5]=2[N:6]=1.[N:17]1(C(OC(C)(C)C)=O)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.FC(F)(F)C(O)=O.C(Cl)Cl>CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@H:13]([OH:16])[CH2:14][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:7][C:5]=2[N:6]=1
Reactant: CC[C@@H](O)COc1ccc2sc(C)nc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (2R)-1-(2-methylbenzothiazol-5-yloxy)butan-2-ol, tert butyl piperazinecarboxylate, a compound of formula (5) (2.0 g, 4.9 mmol), and 25% trifluoroacetic acid/methylene chloride (20 ml) was allowed to stir at room temperature overnight. The solvent was evaporated (in vacuo) to yield an oil. The oil was diluted with acetone (20 ml) and solid potassium carbonate was added until the foaming stopped. The resulting mixture was allowed to stir overnight. The solution was filtered through Celite 512, and the filtrate was evaporated (in vacuo), to yield an oil. The oil was placed under high vacuum overnight, to yield (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-ol, as a clear viscous oil (3.4 g. 6.3 mmol).
Reaction SMILES: [CH3:1][O:2][CH2:3][I:4].[CH2:5]([O:8][C:9]([N:11]1[C@H:15]([CH2:16][C:17]2[S:21][C:20]3=[CH:22][N:23]=[C:24]([CH3:25])[N:19]3[CH:18]=2)[CH2:14][C@H:13]([S:26][C:27]2[C@H:28]([CH3:44])[C@@H:29]3[C@@H:39]([C@H:40]([OH:42])[CH3:41])[C:38](=[O:43])[N:30]3[C:31]=2[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[CH2:12]1)=[O:10])[CH:6]=[CH2:7]>CC(C)=O>[I-:4].[CH2:5]([O:8][C:9]([N:11]1[C@H:15]([CH2:16][C:17]2[S:21][C:20]3=[CH:22][N:23]([CH2:1][O:2][CH3:3])[C:24]([CH3:25])=[N+:19]3[CH:18]=2)[CH2:14][C@H:13]([S:26][C:27]2[C@H:28]([CH3:44])[C@@H:29]3[C@@H:39]([C@H:40]([OH:42])[CH3:41])[C:38](=[O:43])[N:30]3[C:31]=2[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[CH2:12]1)=[O:10])[CH:6]=[CH2:7]
Reactant: COCI
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3cn4c(C)ncc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Solvent: CC(C)=O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3c[n+]4c(C)n(COC)cc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [I-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Iodomethyl methyl ether (0.01 ml) is added to a solution of 34.0 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(5-methylimidazo[5,1-b]thiazol-2-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate, described in Example 31-a), in 0.5 ml of dry acetone, and the mixture is stirred in an argon atmosphere at room temperature for 10 min. The solvent is removed by evaporation under reduced pressure. The residue is purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1) to give 42.3 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[6-methoxymethyl-5-methylimidazo[5,1-b]thiazolium-2-yl]methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate iodide as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:23]=[CH:22][C:12]([O:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[C:11]([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][C@@H:27]([CH2:31][CH3:32])[CH2:26]2)[CH:10]=1.C(=O)(O)[O-].[Na+].[C:38]1([S:44](Cl)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl.O>[Cl:8][C:9]1[CH:23]=[CH:22][C:12]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:11]([CH2:24][N:25]2[CH2:30][CH2:29][N:28]([S:44]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:46])=[O:45])[C@@H:27]([CH2:31][CH3:32])[CH2:26]2)[CH:10]=1
Reactant: CC[C@H]1CN(Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)CCN1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H]1CN(Cc2cc(Cl)ccc2OCC(=O)O)CCN1S(=O)(=O)c1ccccc1
Reaction time: 16 h

Procedure:
To a vigorously stirred solution/suspension of the product from example 69 part f) (0.393 g) and solid sodium bicarbonate (0.342 g) in DCM (3 ml) and water (3 ml) was added benzenesulfonyl chloride (0.21 ml) dropwise. The mixture was stirred for 16 h. The organic layer and 1 further DCM extract were combined and purified by passage through SCX resin eluting with MeCN, MeOH followed by 7M NH3 in MeOH. The basic fractions were concentrated in vacuo, dissolved in DCM (3 ml) and treated with TFA (20 ml) for 16 h. Concentration in vacuo and purification by RPHPLC gave the title product as a white foam (45 mg).
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.O=S(Cl)[Cl:10].[CH3:12][OH:13]>>[CH3:12][O:13][C:1](=[O:7])[CH:2]=[CH:3][C:4]([Cl:10])=[O:5]
Reactant: O=C1C=CC(=O)O1
Reactant: O=S(Cl)Cl
Reactant: CO
Product: COC(=O)C=CC(=O)Cl
Temperature: 25 °C

Procedure:
5.0 g (51.0 mmol) of maleic anhydride were heated to 100° C. in 2.2 ml of MeOH for 1 hour [J. Chem. Soc., 1964, 526-528]. The reaction mixture was cooled to room temperature and 37 ml (50.7 mmol) of SOCl2 were added dropwise. The reaction was refluxed for 1.5 hours and then distilled collecting the fraction boiling at 42-44° C./2 mbar to obtain 5.3 g of the title compound, possibly as a mixture of E and Z diastereoisomers. This compound was used without further purification in the subsequent reaction to prepare Examples 18 and 19.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4C=[CH:24][CH:23]=[CH:22][C:21]=4C(F)(F)F)=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:30](N(CC)C(C)C)(C)C.IC.Cl[CH2:42][Cl:43]>C(#N)C>[CH3:30][N:12]1[CH2:11][CH2:10][N:9]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:42]=3[Cl:43])=[CH:18][CH:19]=2)[CH2:8][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1ccccc1-c1ccc(CN2CCNC(c3ccccc3)C2)cc1
Reactant: ClCCl
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: CC#N
Product: CN1CCN(Cc2ccc(-c3ccccc3Cl)cc2)CC1c1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
This compound could be made the following manner: 100 mg of 3-phenyl-1-(2′-trifluoromethyl-biphenyl-4-ylmethyl)-piperazine would be dissolved in acetonitrile, 3 equiv. of N,N-diisopropylethylamine would be added followed by 1.1 equiv. of iodomethane. The reaction would be stirred at 80° C. overnight. The reaction would be diluted with dichloromethane and washed with 1N aqueous NaOH solution. The organic layer would be dried over Na2SO4, filtered and concentrated in vacuo. The crude residue would be purified by column chromatography to afford 1-methyl-2-phenyl-4-(2′-chloro-biphenyl-4-ylmethyl)-piperazine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[N:10]=[CH:11][S:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].C(O[C:18](=O)[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26](=[O:31])N(OC)C)[CH2:22][CH2:21]1)(C)(C)C.[O:33]1[C:38]2[CH:39]=[CH:40][C:41](C=O)=[CH:42][C:37]=2[O:36][CH2:35][CH2:34]1>>[O:33]1[C:38]2[CH:39]=[CH:40][C:41]([CH2:18][NH:19][C@H:20]3[CH2:21][CH2:22][C@H:23]([C:26]([C:11]4[S:12][C:8]5[CH:7]=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]=5[N:10]=4)=[O:31])[CH2:24][CH2:25]3)=[CH:42][C:37]=2[O:36][CH2:35][CH2:34]1
Reactant: CCOc1cccc2scnc12
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Product: CCOc1cccc2sc(C(=O)[C@H]3CC[C@H](NCc4ccc5c(c4)OCCO5)CC3)nc12

Procedure:
Using 4-ethoxy-benzothiazole (5 mmol), [trans-4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (2.5 mmol) and 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (0.3 mmol) according to the same protocol as that described for example 1, steps 1.a to 1.c, the title compound was obtained as an off-white solid (6 mg).
Reaction SMILES: CO[CH:3]([O:14][CH3:15])[CH2:4][O:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.C1(C)C=C[C:20]([S:23](O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:6]([O:5][CH2:4][CH:3]1[S:23][CH2:20][CH2:15][O:14]1)(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(COC(=O)c1ccccc1)OC
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(OCC1OCCS1)c1ccccc1
Temperature: 25 °C
Yield: 5173.6 %

Procedure:
Aliquots of 2-benzoyloxyacetaldehyde dimethyl acetal (50.0 g) prepared according to Example 1,2-mercaptoethanol (20.4 g), p-toluenesulfonic acid monohydrate (0.90 g) and toluene (250 mL) were placed in a three-neck flask, followed by heating. By-produced methanol was distilled off with the solvent. After distilling off about 150 mL, the reaction mixture was cooled to room temperature, was washed with a saturated aqueous sodium hydrogen carbonate solution and water and was dried over anhydrous sodium carbonate. After filtration and vacuum distillation at 144-147° C. and at 0.60 mmHg, the target compound (54.9 g) was obtained in a yield of 100%.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[C:16]([Cl:24])[C:17]([N:19]([CH3:23])[CH:20]([CH3:22])[CH3:21])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>C1(C)C=CC=CC=1>[ClH:24].[Cl:24][C:16]1[C:17]([N:19]([CH3:23])[CH:20]([CH3:21])[CH3:22])=[N:18][C:12]2[O:11][CH2:10][CH2:9][NH:8][CH2:14][C:13]=2[N:15]=1
Reactant: CC(C)N(C)c1nc2c(nc1Cl)CN(Cc1ccccc1)CCO2
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Product: CC(C)N(C)c1nc2c(nc1Cl)CNCCO2
Product: Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 120.7 %

Procedure:
To a solution of 8-benzyl-2-chloro-N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (200 mg) in toluene (3 mL) was added 1-chloroethyl chloroformate (0.075 mL), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled to room temperature, and concentrated. To the obtained residue was added methanol (3 mL) and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was cooled to room temperature, and concentrated. The obtained residue was purified by recrystallization (methanol-diisopropyl ether) to give the title compound (102 mg, 60%) as pale-yellow crystals.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O)(=[O:9])[CH3:8].[NH2:20][C:21]1[CH:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[C:7]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:20][C:21]1[CH:33]=[C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:15])(=[O:9])[CH3:8]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccccc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
2.0 mL of methylene chloride, 3.9 μL of N,N-dimethylformamide and 0.094 mL of oxalyl chloride were added to 180 mg of 2-acetoxybenzoic acid at room temperature sequentially and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 81 mg of tert-butyl 2-amino-4-phenylbenzoate, 3.0 mL of methylene chloride and 0.67 mL triethylamine, and stirred at room temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(2-acetoxybenzamido)-4-phenylbenzoate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[C:16](B(O)O)=[CH:15][CH:14]=[CH:13][N:12]=1.COCCOC.C([O-])(O)=O.[Na+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:16]2[C:11]([Cl:10])=[N:12][CH:13]=[CH:14][CH:15]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: OB(O)c1cccnc1Cl
Reactant: Fc1cnc(Cl)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Fc1cnc(Cl)nc1-c1cccnc1Cl
Temperature: 80 °C

Procedure:
To 2,4-dichloro-5-fluoropyrimidine (500 mg, 2.99 mmol), 2-chloropyridine-3-boronic acid (707 mg, 4.49 mmol), Pd(PPh3)4 (346 mg, 0.30 mmol) was added DME (9.0 mL) and 1 M NaHCO3 (3.0 mL). The mixture was heated overnight in a sealed tube at 80° C., cooled to RT, diluted with EtOAc, and washed with water and saturated Na2CO3. The organic layer was dried over Na2SO4, filtered, concentrated and purified by reverse-phase HPLC to provide 2-chloro-4-(2-chloro-pyridin-3-yl)-5-fluoro-pyrimidine. MS m/z=244, 246 [M]+ and [M+2]+. Calc'd for C9H4Cl2FN3: 244.06.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[O:32]1[C:41]2[C:36](=[CH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:32]1[C:41]2[C:36](=[CH:37][C:38]([C:2]3[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:3]=3)=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: CC1(C)OB(c2ccc3c(c2)CCCO3)OC1(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)CCCO2
Yield: 90.3 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.08 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 mg; 0.025 mmol), N,N-diisopropylethylamine (0.173 mL; 1 mmol) and 2-(chroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.131 g; 0.5 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.094 g (86%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:34]1([CH2:40][CH2:41]O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:41][CH2:40][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(Nc2ccccc2)n1
Reactant: OCCC1CCCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1nccc(N(CCC2CCCCC2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
2-Chloro-4-anilinopyrimidine (Reference Example A-9, 700 mg, 3.4 mmol) was dissolved in DCM (70 ml), triphenyl phosphine (1.07 g, 4.1 mmol) and 2-cyclohexyl ethanol (0.57 ml, 4.1 mmol) were added followed by dropwise addition of DEAD (0.646 ml, 4.1 mmol). After 1 hour additional triphenyl phosphine (0.5 g, 2 mmol), 2-cyclohexyl ethanol (0.28 ml, 2 mmol) and DEAD (0.320 ml, 2 mmol) were added and the reaction mixture was stirred overnight at ambient temperature. The solvent was evaporated off and the residue was purified by flash chromatography using EtOAc/petroleum ether (15/85, then 20/80) as the eluent. The solvent was evaporated to give the title product as a colourless oil (368 mg, 37%). NMR (400 MHz, 353K): 0.90 (m, 2H), 1.20 (m, 3H), 1.30 (m, 1H), 1.65 (m, 7H), 3.90 (t, 2H), 4.05 (m, 1H), 6.10 (d, 1H), 7.34 (d, 2H), 7.43 (t, 1H), 7.54 (t, 2H), 7.95 (d, 1H); m/z (ES+) 316 and 318 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([F:19])[C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[OH:20].C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1>CN(C=O)C.CCOCC>[Cl:1][C:2]1[CH:18]=[C:17]([F:19])[C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:20][CH2:32][C:31]1[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C(N1CCc2c(F)cc(Cl)c(O)c2CC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(N1CCc2c(F)cc(Cl)c(OCc3ccc(F)cc3)c2CC1)C(F)(F)F
Reaction time: 14 h

Procedure:
Dissolve 7-chloro-9-fluoro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.25 g, 0.8 mmol) in DMF (8 mL), add potassium carbonate (0.56 g, 4.0 mmol) and 4-fluorobenzyl bromide (0.46 mL, 2.4 mmol). After 14 h at 90° C., dilute with ether and wash with brine. Dry the organic layer over Na2SO4 and evaporate onto silica gel. Purify by chromatography on silica gel eluting with EtOAc/hexane (0:1 to 1:0) to obtain 7-chloro-9-fluoro-6-(4-fluorobenzyloxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.