Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C@H:14]3[C@H:9]([CH2:10][CH2:11][NH:12][CH2:13]3)[CH2:8][C:7](=[O:15])[C:6]=2[CH:16]=1.Br[CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C@H:14]3[C@H:9]([CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH3:20])[CH2:13]3)[CH2:8][C:7](=[O:15])[C:6]=2[CH:16]=1
Reactant: CCCBr
Reactant: O=C1C[C@H]2CCNC[C@H]2c2ccc(F)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1CC[C@@H]2CC(=O)c3cc(F)ccc3[C@@H]2C1
Temperature: 125 °C
Yield: 63.8 %

Procedure:
A mixture of 0.29 g (1.32 mmol) of cis-8-fluoro-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one, 0.12 ml (1.39 mmol) of bromopropane, 0.2 g (1.45 mmol) of potassium carbonate and 20 ml of anhydrous DMF was heated to 125° C. for 1 hour. Subsequently, the mixture was poured into 3 ml of water and extracted once with 50 ml of ethyl acetate. The organic phase was washed once with 40 ml of saturated sodium chloride solution, dried (MgSO4) and concentrated in a vacuum. The crude product obtained was purified by column chromatography on silica gel (methylene chloride/methanol/NH4OH 9:1:0.2). There were obtained 220 mg (63%) of cis-8-fluoro-2-propyl-1,3,4,4a, 5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one as a yellow oil, which was converted with MeOH/HCl into the hydrochloride with m.p. >220°.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=2[O:19][CH3:20])[C:12]([C:23]([N:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])=[CH:11][N:10]=1)(C)(C)C.[ClH:35]>CCOC(C)=O>[ClH:35].[NH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=2[O:19][CH3:20])[C:12]([C:23]([N:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])=[CH:11][N:10]=1
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)N3Cc4ccccc4C3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc(OC)c2c(CN)ncc(C(=O)N3Cc4ccccc4C3)c2c1
Yield: 100 %

Procedure:
As described in example 1, 61 mg of [4-(1,3-dihydro-isoindole-2-carbonyl)-6,8-dimethoxy-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester was treated with HCl in EtOAc to give 59 mg (>100%) of (1-aminomethyl-6,8-dimethoxy-isoquinolin-4-yl)-(1,3-dihydro-isoindol-2-yl)-methanone hydrochloride. H1-NMR (DMSO): δ, 8.49 (s, 1H), 8.43 (br s, 3H), 7.42-7.15 (m, 4H), 6.85 (s, 1H), 6.74 (s, 1H), 4.97 (s, 2H), 4.70 (d, J=4.7 Hz, 2H), 4.49 (s, 2H), 3.99 (s, 3H), 3.82 (s, 3H); MS: APCI (M+H) calc'd for C21H21N3O3+H 364.4; found 364.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([O:13][C:14](=[S:18])[N:15]([CH3:17])[CH3:16])=[C:6]([F:19])[C:5]=1F.Cl.[NH2:23][C:24]1[C:25]([CH3:30])=[CH:26][CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([O:13][C:14](=[S:18])[N:15]([CH3:17])[CH3:16])=[C:6]([F:19])[C:5]=1[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]
Reactant: Cc1ccccc1N
Reactant: COC(=O)c1cc([N+](=O)[O-])c(OC(=S)N(C)C)c(F)c1F
Agent: Cl
Product: COC(=O)c1cc([N+](=O)[O-])c(OC(=S)N(C)C)c(F)c1Nc1ccccc1C
Reaction time: 1 h

Procedure:
The compound 4-dimethylthiocarbamoyloxy-2,3-difluoro-5-nitro-benzoic acid methyl ester is dissolved in excess o-toluidine. The stirring mixture is brought to 200° C. for one hour. The mixture is then poured into 5% aqueous hydrochloric acid. The aqueous mixture is extracted with diethyl ether. The organic phase is washed with water and brine, is dried over magnesium sulfate, and is concentrated in vacuo. The crude product is purified by ordinary methods such as chromatography or crystallization from an appropriate solvent.
Reaction SMILES: [CH3:1][O:2][C:3]([O:19][CH3:20])([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)[CH:4]([OH:6])[CH3:5].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH3:21][S:22]([O:6][CH:4]([CH3:5])[C:3]([O:19][CH3:20])([O:2][CH3:1])[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2cc(C(OC)(OC)C(C)O)ccc2c1
Solvent: c1ccncc1
Product: COc1ccc2cc(C(OC)(OC)C(C)OS(C)(=O)=O)ccc2c1
Reaction time: 3 h

Procedure:
1.2 G of 1,1-dimethoxy-1-(6 methoxy-2-naphthyl)-propan 2-ol is dissolved in 10 ml of pyridine and 1.1 g of methanesulfonyl chloride is added to that solution in one portion. The mixture is allowed to stand for about three hours and the separation of pyridine hydrochloride crystals is observed. The reaction mixture is poured into 100 ml of water and extracted with 50 ml of ether. The ethereal extract is washed several times with water and dried over magnesium sulfate. The ethereal layer is evaporated under reduced pressure to afford 1,1-dimethoxy-1-(6-methoxy-2-naphthyl)prop-2-yl methanesulfonate as an oil. The compound displays a characteristic NMR spectra in the deuterochloroform of τ=9.0 (doublet, J=2), 6.85, 6.70, 6.61, 6.07, 4.89 (quartet, J=2), 1.99-2.88 (multiplet).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]4)[CH2:12][CH2:11]2)[CH:7]=1.[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30]>>[F:27][C:5]1[CH:4]=[CH:3][C:2]([NH:32][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:7][C:6]=1[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]3)[CH2:12][CH2:11]1
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc2c(N3CCN(CCc4cc(Br)ccc4F)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cc(NS(C)(=O)=O)ccc4F)CC3)cccc2n1
Yield: 69 %

Procedure:
The title compound was prepared in 69% yield according to the general procedure for the preparation of amides, ureas and carbamates (Method A) starting from 5-{4-[2-(5-bromo-2-fluorophenyl)ethyl]-1-piperazinyl}-2-methylquinoline and methanesulfonamide.
Reaction SMILES: [CH:1]1([N:4]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=3)[O:9][N:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:26][C:27]1([CH3:30])[O:29][CH2:28]1>>[CH:1]1([N:4]([CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]([OH:29])([CH3:30])[CH3:28])[CH2:22][CH2:21]2)[C:5]([C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=3)[O:9][N:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(-c2cc(C(=O)N(C3CCNCC3)C3CC3)no2)cc1
Reactant: CC1(C)CO1
Product: CC(C)(O)CN1CCC(N(C(=O)c2cc(-c3ccc(C#N)cc3)on2)C2CC2)CC1

Procedure:
The title compound is prepared from 5-(4-cyano-phenyl)-isoxazole-3-carboxylic acid cyclopropyl-piperidin-4-yl-amide and 1,1-dimethyloxirane following a procedure analogous to that described for Intermediate 2. LC (method 4): tR=1.17 min; Mass spectrum (ESI+): m/z=409 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2>>[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:20]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Br)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Yield: 70.4 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c obtained from step 3 of Example 28 and 5-bromo-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 46 (61 mg, yield 70.4%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[C:21]([C:25]#[N:26])[CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:27]([F:30])([F:29])[F:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[NH4+:32]>O1CCCC1>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:14][C:15]3[C:16]([C:17]([NH2:32])=[O:19])=[CH:20][C:21]([C:25]#[N:26])=[CH:22][C:23]=3[CH3:24])=[O:18])=[CH:11][C:10]([C:27]([F:29])([F:30])[F:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C#N)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C(N)=O)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the cyanobenzoxazinone product of Step E) (200 mg, 0.46 mmol) in tetrahydrofuran (5 mL) was added dropwise ammonium hydroxide (0.5 mL, 12.8 mmol) at room temperature. The reaction mixture was then stirred for five minutes, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford 620 mg of the title compound, a compound of the present invention, as a solid melting at 200-202° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[N:11]=[C:10]3[CH:13]=[C:14](F)[C:15]([F:17])=[CH:16][C:9]3=[CH:8][C:7]=2[C:6](=[O:19])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1)[CH3:2].[F:23][C:24]1[CH:25]=[C:26]([CH:30]2[CH2:35][NH:34][CH2:33][CH2:32][NH:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH2:1]([N:3]1[C:12]2[N:11]=[C:10]3[CH:13]=[C:14]([N:34]4[CH2:33][CH2:32][NH:31][CH:30]([C:26]5[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=5)[CH2:35]4)[C:15]([F:17])=[CH:16][C:9]3=[CH:8][C:7]=2[C:6](=[O:19])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1)[CH3:2]
Reactant: Fc1cccc(C2CNCCN2)c1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(c5cccc(F)c5)C4)cc3nc21
Yield: 87.3 %

Procedure:
Working under the conditions of Example 16, but starting with 1-ethyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.5 g) and (RS)-2-(3-fluorophenyl)piperazine (1.98 g), (RS)-1-ethyl-7-fluoro-8-[3-(3-fluorophenyl)-1-piperazinyl]-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid (2 g) is obtained in the form of a yellow solid, m.p. 284° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][O:5][C:6]([C:8]12[CH2:13][CH:12]1[CH2:11][CH2:10][C:9]2=[O:14])=[O:7]>CS(C)=O>[CH3:4][O:5][C:6]([CH:8]1[CH:12]([CH2:13][C:1]#[N:2])[CH2:11][CH2:10][C:9]1=[O:14])=[O:7]
Reactant: COC(=O)C12CC1CCC2=O
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1C(=O)CCC1CC#N
Temperature: 25 °C
Yield: 60.3 %

Procedure:
In argon atmosphere, sodium cyanide (200 mg, 4 mmol) and 2-oxo-bicyclo [3.1.0] hexane-1-carboxylic acid methyl ester (462 mg, 3 mmol) were added to dimethyl sulfoxide (2ml). The mixture was stirred at the room temperature for one night and was treated in accordance with the process of Preparation 4 to obtain 328 mg of 5-cyanomethyl-2-oxo-cyclopentanecarboxylic acid methyl ester. Yield: 60%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[NH:17]1[C:21]([C:22]2[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=2)[NH2:25])=[N:20][N:19]=[N:18]1>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:22]([C:21]3[NH:20][N:19]=[N:18][N:17]=3)[CH:23]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: Oc1cccc(Nc2nc(Nc3cccc(-c4nnn[nH]4)c3)ncc2F)c1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 3-(tetrazol-5-yl)aniline gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(tetrazol-5-yl)phenyl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.05 (bs, 1H), 9.80 (bs, 1H), 8.27 (s, 1H), 8.23 (d, 1H, J=3.3 Hz), 7.86 (d, 1H, J=8.1 Hz) 7.65 (d, 1H, J=6.9 Hz), 7.44 (t, 1H, J=7.5 Hz), 7.19 (m, 2H), 6.93 (t, 1H, J=7.5 Hz), 6.49 (dd, 1H, J=2.4 and 8.1 Hz); LCMS: purity: 89%; MS (m/e): 364 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]#[C:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[C:4]([CH2:8][O:9][C:10](=[O:16])[C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])[CH:5]=[CH:6][CH:7]=1>CO.[Pd]>[O:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH:21]1[O:20][CH2:19][CH2:18][CH2:17][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:8][O:9][C:10](=[O:16])[C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13]
Reactant: CCC(C)(C)C(=O)OCc1cccc(C)c1C#CCOC1CCCCO1
Agent: [Pd]
Solvent: CO
Product: CCC(C)(C)C(=O)OCc1cccc(C)c1CCCOC1CCCCO1
Reaction time: 1.5 h
Yield: 98.9 %

Procedure:
A solution of rac-2,2-dimethylbutanoic acid[3-methyl-2-[3-(2-tetrahydropyranyloxy)-1-propynyl]phenyl]methyl ester (1.2 g) in methanol (50 mL) was hydrogenated over 10% palladium on carbon (0.2 g) at room temperature and ambient pressure for 90 minutes. After the catalyst was removed by filtration through Celite, the methanol was removed in vacuo to give 1.2 g of rac-2,2-dimethylbutanoic acid [2-[3-(2-tetrahydropyranyloxy)-1-propyl]-3-methylphenyl]methyl ester as an oil. A solution of the oil (1.2 g) and pyridinium p-toluenesulfonate (0.1 g) in ethanol (25 mL) was stirred and heated in an oil bath maintained at 55° C. After 6 hours, the solvent was evaporated and the residue was partitioned between diethyl ether and water. The aqueous phase was extracted with diethyl ether, then the combined organic extracts were dried (Na2SO4) and evaporated to furnish 1 g of an oil. The material was purified by HPLC (diethyl ether-hexane; 1:9) to give 0.72 g of 2,2-dimethylbutanoic acid [2-(3-hydroxy-1-propyl)-3-methylphenyl]methyl ester.
Reaction SMILES: [C:1]1([N:11]2[C:15]([C:16]3[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=3[O:24][CH3:25])=[CH:14][C:13]([C:26]([NH:28][C:29]3([C:39]([OH:41])=[O:40])[CH:36]4[CH2:37][CH:32]5[CH2:33][CH:34]([CH2:38][CH:30]3[CH2:31]5)[CH2:35]4)=[O:27])=[N:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.[C:43](=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.CN(C)C=O>[C:1]1([N:11]2[C:15]([C:16]3[C:17]([O:24][CH3:25])=[CH:18][CH:19]=[CH:20][C:21]=3[O:22][CH3:23])=[CH:14][C:13]([C:26]([NH:28][C:29]3([C:39]([O:41][CH3:43])=[O:40])[CH:36]4[CH2:35][CH:34]5[CH2:33][CH:32]([CH2:31][CH:30]3[CH2:38]5)[CH2:37]4)=[O:27])=[N:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COc1cccc(OC)c1-c1cc(C(=O)NC2(C(=O)O)C3CC4CC(C3)CC2C4)nn1-c1cccc2ccccc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(NC(=O)c2cc(-c3c(OC)cccc3OC)n(-c3cccc4ccccc34)n2)C2CC3CC(C2)CC1C3
Reaction time: 1 h

Procedure:
0.5 g of the compound prepared in Example 11 is dissolved in 34.6 ml of anhydrous tetrahydrofuran and 4 ml of dimethylformamide. 3.5 ml of water and 0.208 g of caesium carbonate are added and the reaction mixture is left at room temperature for 1 hour. It is concentrated under vacuum and treated azeotropically with toluene. The residue is taken up in 5 ml of tetrahydrofuran. 0.6 ml of methyl iodide is added and the reaction mixtureis left for 1 hour at room temperature. It is concentrated under vacuum, the residue is taken up in water, the mixture is stirred and the precipitate is separated by filtration. The precipitate is washed with water and with pentane.
Reaction SMILES: C([O:4][CH:5]([C:7](=[CH2:12])[C:8]([O:10][CH3:11])=[O:9])[CH3:6])(=O)C>P([O-])([O-])([O-])=O>[OH:4][C@@H:5]([C:7](=[CH2:12])[C:8]([O:10][CH3:11])=[O:9])[CH3:6]
Reactant: C=C(C(=O)OC)C(C)OC(C)=O
Agent: O=P([O-])([O-])[O-]
Product: C=C(C(=O)OC)[C@@H](C)O
Temperature: 25 °C
Reaction time: 55 h
Yield: 17 %

Procedure:
A mixture of methyl 2-(1-acetoxyethyl)acrylate (5 g) and "Lipase P" (Trademark; origin : Pseudomonas sp.; maker : Amano Pharmaceutical Co.) (1.25 g) in phosphate buffer solution (0.1M) pH 7.0 (400 ml) was stirred at room temperature for 55 hours. The whole mixture was extracted with ethyl acetate three times and the combined extracts were dried. After removal at the solvent in vacuo, the crude product was purified by column chromatography on silica gel (eluent : a mixture of hexane and ethyl acetate, 2:1). The resultant oily residue (840 mg) was distilled in vacuo to give methyl 2-[(1R)-1-hydroxyethyl]acrylate (644 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1.[C:20]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1)([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:23][O:22][C:20](=[O:21])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:8][C:6]2[CH:5]=[CH:4][C:3]([S:9][C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=3)=[C:2]([NH2:1])[CH:7]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(=O)Nc1ccc(Sc2ccc(O)cc2N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2ccc(Sc3ccc(NC(C)=O)cc3)c(N)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.5 %

Procedure:
A mixture of the product from Example 232b (28 mg, 0.085 mmol), 4-carbomethoxybenzyl bromide (22 mg, 0.096 mmol) and potassium carbonate (13 mg, 0.09 mmol) in DMF (1 mL) was stirred at room temperature 15 hr. The next day, the reaction mixture was poured onto ice and the solid collected by filtration providing the title compound (35 mg, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]C=O.[CH:11](OC)([O:14][CH3:15])[O:12][CH3:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+].[Cl-].[Na+].O>CO.C(OCC)C>[CH3:13][O:12][CH:11]([O:14][CH3:15])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: O=CCc1ccccc1Br
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: COC(Cc1ccccc1Br)OC

Procedure:
To a solution of 10.0 grams (0.05 mole) of 2-(2-bromophenyl)acetaldehyde (from the above preparation and another similar preparation) in 50 milliliters of dry methanol, was added 50 milliliters of trimethyl orthoformate and 0.25 gram of p-toluenesulfonic acid monohydrate and the resulting mixture was heated at reflux temperature for 3.5 hours. At the end of this period, the reaction mixture was cooled and 100 milliliters of diethyl ether and 50 milliliters of a 1:1 solution of 50 percent aqueous sodium hydroxide/brine were added. The ether solution was mechanically separated, washed, dried and stripped on the rotary evaporator to obtain 2-(2-bromophenyl)acetaldehyde dimethylacetal intermediate as a yellow oil. The latter was distilled to obtain 10.5 grams (85 percent yield) of purified product as a clear oil, b.p. 65°-67° /0.2 mm.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[O:19][CH2:20][C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:22]=2)[CH:13]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:23]1([C@@H:21]2[CH2:20][O:19][C:18]([C:14]3[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=3)[O:11][CH2:10][CH2:9][OH:8])=[N:22]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1cccc(C2=N[C@H](c3ccccc3)CO2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCCOc1cccc(C2=N[C@H](c3ccccc3)CO2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 89.8 %

Procedure:
To a solution of 1-(tert-butyldimethylsilyloxy)-2-[3-(4,5-dihydro-4(R)-phenyloxazol-2-yl)phenoxy]ethane (4.4 g, 11 mmol) in THF (35 ml) was added dropwise tetrabutylammonium fluoride (1M in THF, 14 ml). The reaction mixture was stirred at room temperature for 45 min., solvent removed by evaporation and the resulting residue was purified by column chromatography on silica gel eluting with ethyl acetate/n-hexane (=1:2) to afford 2-[3-(4,5-dihydro-4(R)-phenyl-oxazol-2-yl)phenoxy]ethan-1-ol (2.8 g, 91%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][CH3:7].[C:8](#[N:11])[CH2:9]O.CCN(CC)CC>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:9][C:8]#[N:11])[CH3:7]
Reactant: N#CCO
Reactant: CNCCCOC
Solvent: CCN(CC)CC
Product: COCCCN(C)CC#N
Yield: 73 %

Procedure:
A solution of amine hydrochloride 272 (2.6 g, 18.7 mmol), aqueous glycolonitrile (55%, 2.4 mL, 24.7 mmol) and Et3N (4.0 mL, 28.1 mmol) was stirred at 50° C. for 3 h. The solution was cooled and partitioned between water (50 mL) and Et2O (50 mL). The organic fraction was washed with water (2×50 mL) and brine (50 mL), dried and the solvent evaporated to give nitrile 273 (1.94 g, 73%) as a colourless oil; 1H NMR δ 3.53 (s, 2H, CH2CN), 3.42 (t, J=6.3 Hz, 2H, CH2N), 3.33 (s, 3H, OCH3), 2.54 (t, J=7.1 Hz, 2H, CH2), 2.36 (s, 3H, NCH3), 1.73 (tt, J=7.1, 6.3 Hz, 2H, CH2); MS (APCI) m/z 143 (MH+, 100%).
Reaction SMILES: Cl[C:2](=[O:16])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1.CC1C=CC=C(C)N=1.[H][H]>[Pd].O1CCCC1>[O:16]=[CH:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: CCOC(=O)N1CCC(CCC(=O)Cl)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)N1CCC(CCC=O)CC1
Yield: 81 %

Procedure:
A mixture of 102 parts of ethyl 4-(3-chloro-3-oxopropyl)-1-piperidinecarboxylate, 45 parts of 2,6-dimethylpyridine and 630 parts of tetrahydrofuran was hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in 650 parts of dichloromethane. The solution was washed twice with 100 parts of a hydrochloric acid solution 5% and twice with 100 parts of water, dried, filtered and evaporated. The residue was distilled, yielding 71.1 parts (81%) of ethyl 4-(3-oxopropyl)-1-piperidinecarboxylate; bp. 130°-135° C. at 133 Pa (int. 46).
Reaction SMILES: [F-:1].C([N+](CCCC)(CCCC)CCCC)CCC.CS(F)(=O)=O.O[CH2:25]/[CH:26]=[CH:27]\[C:28]1[CH:33]=[CH:32][C:31]([C@H:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C@H:37]3[CH2:44][CH2:45][CH2:46][N:36]3[CH2:35]2)=[CH:30][CH:29]=1.CO>C1COCC1.C(Cl)Cl.CCN(CC)CC>[F:1][CH2:25]/[CH:26]=[CH:27]\[C:28]1[CH:33]=[CH:32][C:31]([C@H:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C@H:37]3[CH2:44][CH2:45][CH2:46][N:36]3[CH2:35]2)=[CH:30][CH:29]=1
Reactant: [F-]
Reactant: OC/C=C\c1ccc([C@@H]2CN3CCC[C@@H]3c3ccccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)F
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FC/C=C\c1ccc([C@@H]2CN3CCC[C@@H]3c3ccccc32)cc1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
To a stirred solution of 1.0 M tetrabutylamonium fluoride (0.45 mL, 0.45 mmol) in 2.0 mL of THF in the presence of molecular sieves (4 Å, 1.0 g) was added a mixture of methylsufonyl fluoride (21 μL, 0.30 mmol) and trans-1,2,3,5,6,10b-Hexahydro-6-[4'-(3-hydroxy-1(Z)-propenyl)phenyl]pyrrolo[2,1-a]isoquinoline (18) (23 mg, 0.075 mmol) in 5 mL of THF at room temperature. The reaction mixture was heated at reflux for 16 h, cooled to room temperature, filtered through a sintered glass funnel with aid of a small amount of methylene chloride (10 mL) and ethyl acetate (10 mL). The filtrate was concentrated to afford a crude product. Flash chromatography with 2.3% MeOH, 0.046% Et3N in methylene chloride gave 10 mg of thick colorless oil (43% yield). 1H NMR (CDCl3) δ 1.73-2.05 (m, 3H, C2H2 & C1H), 2.30-2.2.44 (m, 1H, C1H), 2.579 (dt, 1H, J=9.0, 8.7 Hz, C3H), 2.869 (dd, 1H, J=5.1, 11.1 Hz, C5H), 2.90-3.03 (m, 2H, C3H & C5H), 3.480 (dd, 1H, J=7.2, 9.0 Hz, C10bH), 4.125 (t, 1H, J=4.8 Hz, C6H), 6.865 (d, 1H, J=7.5 Hz, aryl), 6.995 (d, 2H, J=8.1 Hz, C6 phenyl aryl), 7.04-7.20 (m, 3H, aryl), 7.575 (d, 2H, J=8.1 Hz, C6 phenyl aryl) (aromatic), 126.30, 129.30, 130.97, 137.23.