Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[C:7]1[N:13]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:14]3[CH:15]=[CH:16][C:17]([N+:20]([O-])=O)=[CH:18][C:19]=3[C:6]1=[N:5]2.[H][H].C(Cl)Cl>CC(N(C)C)=O.[Pd]>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]2[N:13]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:7]3[C:6]([C:19]=2[CH:18]=1)=[N:5][C:4]1[C:9](=[CH:10][C:11]([CH3:12])=[C:2]([CH3:1])[CH:3]=1)[N:8]=3
Reactant: [H][H]
Reactant: Cc1cc2nc3c4cc([N+](=O)[O-])ccc4n(CCN(C)C)c3nc2cc1C
Agent: [Pd]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: Cc1cc2nc3c4cc(N)ccc4n(CCN(C)C)c3nc2cc1C
Yield: 84 %

Procedure:
A suspension of 3.63 g (10 mmol) of (2d) and 0.36 g 10% Pd/C in 160 ml DMA was left under 2.7 atm hydrogen pressure for 24 h. The product was soluble in DMA. Pd/C was filtered away with celite. The filtrate was poured onto ice-water and pH was increased to basic with 20% KOH, which resulted in a brown precipitate. The precipitate was chromatographied in 20% MeoH/CH2Cl2, which resulted in 2.80 g of the product (3d).
Reaction SMILES: [CH2:1]([N:13]1[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]1[C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O[C@@H:27]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH2:1]([N:13]1[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]1[C:19]1[CH:24]=[CH:23][C:22]([O:25][C@H:27]([CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCn1c(C)ccc1-c1ccc(O)cc1
Reactant: CCOC(=O)[C@@H](O)Cc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCn1c(C)ccc1-c1ccc(O[C@H](Cc2ccccc2)C(=O)OCC)cc1
Yield: 33 %

Procedure:
To a solution of 4-(1-dodecyl-5-methyl-1H-pyrrol-2-yl)phenol (2.97 g, 8.70 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (1.86 g, 9.58 mmol) and triphenylphosphine (2.51 g, 9.57 mmol) in toluene (120 ml) was added diethyl azodicarboxylate (1.67 g, 9.57 mmol) and the mixture was refluxed for 20 hours under heating. The insoluble matter was filtered out and the filtrate was diluted with ethyl acetate. The obtained solution was washed with water and dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to give the object compound as an oily substance. 1.49 g (yield: 33%)
Reaction SMILES: [SH:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.C[O-].[Na+].[NH2:10][C:11]1[N:16]=[C:15]([CH2:17]Cl)[CH:14]=[C:13]([O:19][CH3:20])[N:12]=1>CO.O>[NH2:10][C:11]1[N:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([CH2:17][S:1][C:2]2[S:3][CH2:4][CH2:5][N:6]=2)[N:16]=1
Reactant: SC1=NCCS1
Reactant: COc1cc(CCl)nc(N)n1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(CSC2=NCCS2)nc(N)n1
Reaction time: 1 h

Procedure:
11.9 g of 4,5-dihydro-2-mercapto-thiazole are suspended in 100 ml of methanol, and to the suspension are added 18.0 g of 30% methanolic sodium methylate solution. To the formed clear solution are subsequently added 17.4 g of 2-amino-4-chloromethyl-6-methoxy-pyrimidine, and refluxing is carried out for 1 hour. After the solution has cooled, it is diluted with about 1 liter of water, and the product which precipitates is separated and dried. The yield is 22.5 g (88% of theory) of 2-amino-4-methoxy-6-(4,5-dihydrothiazol-2-yl-thiomethyl)-pyrimidine, m.p. 122°-124° C.
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:8][C:9]([C:11]([C:13]2[C:23]([F:24])=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([F:25])[C:14]=2[F:26])=[CH2:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:35])=[N-].C(OCC)C.CN(N=O)C(N)=O>C(OCC)C.C1(C)C=CC=CC=1>[C:27]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][C:9]([C:11]([C:13]2[C:23]([F:24])=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([F:25])[C:14]=2[F:26])=[CH:12][CH3:35])=[O:10])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C=[N+]=[N-]
Reactant: C=C(C(=O)OC(c1ccccc1)c1ccccc1)c1c(F)cc(C(=O)OCC)c(F)c1F
Agent: CN(N=O)C(N)=O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC=C(C(=O)OC(c1ccccc1)c1ccccc1)c1c(F)cc(C(=O)OCC)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.2 %

Procedure:
In 30 ml of diethyl ether was dissolved 3.08 g of ethyl 4-(1-diphenylmethoxycarbonylvinyl)-2,3,5-trifluorobenzoate. To the resulting solution was added, with ice-cooling, a diazomethane-diethyl ether solution prepared from 2.00 g of N-methyl-N-nitrosourea. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in 30 ml of toluene. The resulting solution was stirred at 60° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue obtained was purified by a column chromatography (eluant: toluene) to obtain 2.90 g (yield: 91.2%) of ethyl 4-(1-diphenylmethoxycarbonyl-2-methylvinyl)-2,3,5-trifluorobenzoate.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:22]=[CH:21][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18]CC)=O)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[NH2:25][NH2:26]>C(O)C>[F:1][C:2]([F:23])([F:24])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH:25][NH2:26])=[O:18])[CH2:13][CH2:14]2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)CN1CCN(Cc2ccc(OC(F)(F)F)cc2)CC1
Reactant: NN
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2ccc(OC(F)(F)F)cc2)CC1

Procedure:
Synthesized according to General Procedure C: 6{17} (5.57 g, 16.1 mmol, 1 equiv.), anhydrous hydrazine (1.5 mL, 48.3 mmol, 3 equiv.), ethanol (32.4 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{17} (4.67 g, 87%) as a beige solid. 1H-NMR (500 MHz, CDCl3): δ 8.15 (br s, 1H), 7.28 (d, 2H, J=8.0 Hz), 7.11 (d, 2H, J=8.0 Hz), 3.83 (br s, 2H), 3.45 (s, 2H), 3.03 (s, 2H), 2.49 (br s, 4H), 2.41 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 170.3, 148.1, 136.7, 130.1, 120.5, 120.3 (q, JC-F=255.5 Hz), 61.8, 60.4, 53.5, 52.9. 19F-NMR (470 MHz, CDCl3): −58.3.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9]C(C#N)=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:15].[Na+].[CH2:17]([OH:19])[CH3:18]>O>[C:1]1([C:7]2[CH:8]=[CH:9][C:18]([C:17]([OH:15])=[O:19])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(-c2ccccc2)cn1
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(-c2ccccc2)cn1
Reaction time: 8 h
Yield: 75 %

Procedure:
A mixture of toluene (20 mL) and water (5 mL) was degassed with argon for 5 minutes. Sodium carbonate (1.53 g, 0.01444 mole) was then added and the mixture was degassed with argon for a further 5 minutes. Phenyl boronic acid (1.126 g, 0.00866 mole) and 5-chloro-pyridine-2-carbonitrile (1 g, 0.00722 mole) were added and the resulting mixture was degassed with argon for a further 5 minutes. tetrakis(triphenylphosphine)palladium(0) (1.67 g, 0.00144 mole) was added and the resulting mixture was degassed with argon for a further 5 minutes. The reaction mixture was then heated to reflux for 3 hours. The reaction mixture was diluted with ethyl acetate. The ethyl acetate layer was washed with water followed by brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (4% ethyl acetate in hexane) to afford 0.9 g (69%) of 5-phenyl-pyridine-2-carbonitrile. LCMS: 181.07 (M+1)+, 28.90%, 1H NMR (DMSO-d6): δ 9.1 (s, 1H), 8.4-8.3 (m, 1H), 8.2-8.1 (m, 1H), 7.9-7.78 (m, 2H), 7.6-7.4 (m, 3H). To a stirred solution of 5-phenyl-pyridine-2-carbonitrile (0.9 g, 0.005 mol) in a mixture of ethanol (10 mL) and water (5 mL) was added NaOH (1 g, 0.025 mol) and the resulting mixture was stirring overnight. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in water, washed with ether and the aqueous layer was acidified with citric acid. The acidified aqueous solution was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 0.75 g (75%) of 5-phenyl-pyridine-2-carboxylic acid. LCMS: 200.06 (M+1)+, 97.53%, 1H NMR (DMSO-d6): δ 13 (bs, 1H), 9.1-9.0 (d, 1H), 8.3-8.2 (dd, 1H), 8.2-8.1 (d, 1H), 7.8 (d, 1H), 7.6-7.4 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[O:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH:45]([OH:49])[CH2:46][CH2:47][CH3:48])[CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:49][CH:45]([CH2:44][CH2:43][N:40]2[CH2:41][CH2:42][O:37][CH2:38][CH2:39]2)[CH2:46][CH2:47][CH3:48])=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: CCCC(O)CCN1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCC(CCN1CCOCC1)OC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C
Yield: 89.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-morpholino-3-hexanol (43 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (74 mg, yield 81%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].[C:15]([N:22]1[CH2:28][CH2:27][CH2:26][C@H:23]1[CH2:24]O)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:14][O:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[O:1][CH2:24][C@@H:23]1[CH2:26][CH2:27][CH2:28][N:22]1[C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c(OC)c1
Temperature: 25 °C

Procedure:
To a stirred solution of ethyl 4-hydroxy-3-methoxybenzoate (3.00 g, 15.29 mmol), (S)-N-Boc-prolinol (3.08 g, 15.30 mmol), Ph3P (4.81 g, 18.34 mmol) in THF (50 mL) was added DIAD (3.61 mL, 18.33 mmol) at 0° C. The resulting mixture was heated under reflux 6.5 hr. After cooling to room temp, the mixture was evaporated and purified by column chromatography on silica-gel with CHCl3-MeOH (50:1, v/v) as eluent to give ethyl (S)-3-methoxy-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl methoxy]benzoate as a gum. The above ethyl (S)-3-methoxy-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinylmethoxy]benzoate was dissolved in CH2Cl2 (50 mL) and TFA (45 mL). The mixture was stirred for 2 days at room temp. The resulting mixture was concentrated in vacuo and made basic with sat. NaHCO3. The mixture was extracted with CH2Cl2, washed with brine, and dried over MgSO4. The solvent was evaporated and the residue was purified by column chromatography on silica-gel with CHCl3-MeOH (20:1, v/v) as eluent to give 3.27 g (77% for 2 steps) ethyl (S)-3-methoxy-4-(2-pyrrolidinylmethoxy) benzoate as a yellow oil. 1H-NMR (CDCl3) δ 1.39 (t, 3 H, J=7.1 Hz), 1.52–1.59 (m, 1 H), 1.76–1.88 (m, 2 H), 1.92–2.01 (m, 1H), 2.92–3.06 (m, 2 H), 3.56–3.63 (m, 1 H), 3.90 (s, 3 H), 3.91–4.02 (m, 2 H), 4.35 (q, 2 H, J=7.1 Hz), 6.89 (d, 1 H, J=8.3 Hz), 7.54 (d, 1 H, J=2.0 Hz), 7.65 (dd, 1 H, J=2.0, 8.3 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])O[C:5]2=[O:12].[N:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:19](=[C:16]1[CH:17]=[CH:18][NH:13][CH:14]=[CH:15]1)[C:5]2=[O:12]
Reactant: Cc1ccncc1
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Solvent: CCO
Product: O=C1C(=C2C=CNC=C2)C(=O)c2cc(Br)ccc21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Under N2 atmosphere, a mixture of 30 g (132 mmol) 5-bromoisobenzofuran-1,3-dione (≡4-bromophthalic acid anhydride; Apin, GB) and 12.87 ml (132 mmol) 4-picoline is heated for 15 h to 180° C. The resulting black mass is cooled to 100° C., mixed with 160 ml ethanol, boiled for 2 hours, and filtered off. The dried residue is triturated in a mortar, boiled further for 1 h in 180 ml ethanol, filtered, and washed with ethanol. The residue is dissolved at 140° C. in 90 ml DMEU, cooled, mixed with 250 ml ethyl acetate and filtered (→residue is washed out with ethyl acetate and discarded). The ethyl acetate from the filtrate is evaporated off and the residue then diluted with 260 ml acetonitrile, the title compound crystallizing out in the process: HPLC: tRet(Grad20-100)=10.4; MS (M)+=301/303.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[N:8]([CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:6]=2[N:7]=1.[I:28]N1C(C)(C)C(=O)N(I)C1=O.C([O-])(O)=O.[Na+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([I:28])=[C:9]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[N:8]([CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C:6]=2[N:7]=1
Reactant: CCOC(OCC)c1cc2cnc(Cl)nc2n1CCNC(=O)OC(C)(C)C
Reactant: CC1(C)C(=O)N(I)C(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(OCC)c1c(I)c2cnc(Cl)nc2n1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.9 %

Procedure:
To 0.1 g (0.00025 mole) of tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate in acetonitrile (2 mL) was added 1,3-Diiodo-5,5-dimethylhydantoin (95 mg, 1 eq), and solid NaHCO3 (63 mg, 3 eq). Stir at room temperature for 16 hrs. Filter, concentrate and then column with hexane/ethylacetate (0-50%) to afford tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate as a pale yellow solid 0.03 g. LCMS (ESI) 525 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13](Cl)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([Br:18])=[C:9]1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl>C(N)C1C=CC=CC=1>[CH2:1]([N:8]1[C:12]2=[C:13]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([Br:18])=[C:9]1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Br)c2cnnc(Cl)c2n1Cc1ccccc1
Agent: Cl
Solvent: NCc1ccccc1
Solvent: O
Product: Cc1c(Br)c2cnnc(NCc3ccccc3)c2n1Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 1.0 g (2.97 retool) of 1-benzyl-3 -bromo-7-chloro-2-methylpyrrolo [2,3-d]pyridazine in 5 ml of benzylamine is heated to 150° C. for 5 h and subsequently cooled to room temperature. The solution is then treated with 50 ml of water, adjusted to pH 6 with 2 N hydrochloric acid and extracted with 2×50 ml of dichloromethane. The organic extracts are dried over magnesium sulfate and concentrated. The residue which remains is chromatographed on silica gel (eluent: toluene/dioxane=2:1). After concentration of the fractions of Rf=0.25 and crystallization from diisopropyl ether, 1.01 g (84%) of the title compound are isolated. M.p.: 185°-188° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[CH:7]=[C:6]1[C:11]([O:13][CH3:14])=[O:12])=[O:4].[BH4-].[Na+]>CO>[CH3:14][O:13][C:11]([CH:6]1[CH2:7][CH:8]([OH:10])[CH:9]=[C:5]1[C:3]([O:2][CH3:1])=[O:4])=[O:12]
Reactant: COC(=O)C1=CC(=O)CC1C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1=CC(O)CC1C(=O)OC
Yield: 93.1 %

Procedure:
To a cold solution (−30° C.) of compound 61 (3.18 g, 16.1 mmol) dissolved in MeOH (23 mL), NaBH4 (0.66 g, 17.5 mmol) was added. After nine minutes the excess of NaBH4 was destroyed by adding brine (80 mL). The mixture was concentrated and extracted with ethyl acetate (4×80 mL). The organic phases were dried, filtrated and concentrated which gave the title compound (3.0 g, 92%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:35])[C:15]([OH:34])=[C:16]2[C:31](=[O:32])[N:20]3[C@@H:21]([CH3:30])[CH2:22][CH2:23][N:24]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C@@H:19]3[CH2:18][N:17]2[CH:33]=1)=[O:12].N[C@@H](C)CCN[CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44].[C:47](O)(=O)[CH3:48].[Cl:51]CCl>>[ClH:51].[ClH:51].[NH2:20][C@@H:21]([CH3:30])[CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:35])[C:15]([OH:34])=[C:16]2[C:31](=[O:32])[N:20]3[C@@H:21]([CH3:30])[CH2:22][CH2:23][N:24]([CH2:25][CH2:26][CH:27]([CH3:28])[CH3:29])[C@@H:19]3[CH2:18][N:17]2[CH:33]=1)=[O:12].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:35])[C:15]([O:34][CH2:45][C:43]2[CH:42]=[CH:41][CH:48]=[CH:47][CH:44]=2)=[C:16]2[C:31](=[O:32])[N:20]3[C@@H:21]([CH3:30])[CH2:22][CH2:23][N:24]([CH2:25][CH2:26][CH:27]([CH3:28])[CH3:29])[C@@H:19]3[CH2:18][N:17]2[CH:33]=1)=[O:12]
Reactant: CC(=O)O
Reactant: ClCCl
Agent: CC(C)CCN1CC[C@H](C)N2C(=O)c3c(O)c(=O)c(C(=O)NCc4ccc(F)cc4F)cn3C[C@@H]12
Agent: CC(C)CCNCC[C@H](C)N
Product: CC(C)CCN1CC[C@H](C)N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4F)cn3C[C@@H]12
Product: Cl
Yield: 72 %

Procedure:
[(3S)-3-Aminobutyl](3-methylbutyl)amine dihydrochloride was prepared in a similar manner as described in example Z-32, 1H NMR (400 MHz, CDCl3/CD3OD) δ 0.86 (d, J=5.6 Hz, 6H), 1.27 (d, J=6.0 Hz, 3H), 1.58 (m, 3H), 2.03-2.14 (m, 2H), 2.87-2.09 (m, 4H), 3.38 (m, 1H), 8.1.5 (br, <1H), 8.87 (br, <1H), b) (4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(3-methylbutyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide. The title compound was made in two steps using a similar process to that described in example Z-2, 16a (0.100 g, 0.21 mmol) and free based [(3S)-3-aminobutyl](3-methylbutyl)amine (0.104 g, 0.66 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4S,12aS)—N-[(2,4-difluorophenyl)methyl]-4-methyl-1-(3-methylbutyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (88 mg, 72%) as a film. This material was hydrogenated in a second step as described in example Z-2 to give (4S,12aS)—N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(3-methylbutyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (55 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 0.84 (a, J=6.4 Hz, 3H), 0.85 (d, J=6.4 Hz, 3H), 1.24-1.37 (m, 5H), 1.45-1.53 (m, 2H), 2.02-2.11 (m, 1H), 2.37-2.44 (m, 1H), 2.56-2.63 (m, 1H), 2.80-2.92 (m, 2H), 4.22-4.29 (m, 2H), 4.45 (s, 1H), 4.62-4.63 (m, 2H), 4.97-5.00 (m, 1H), 6.75-6.82 (m, 2H), 7.31-7.37 (m, 1H), 8.37 (s, 1H), 10.48 (m, 1H), 12.53 (br, 1H); ES+ MS: 489 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20].N1C=CC=CC=1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][CH2:16][O:17][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#CCO)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C#CCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.4 %

Procedure:
A solution of 3.34 g (13.96 mmol) of 4-(3-Hydroxy-prop-1-ynyl)-piperidine-1-carboxylic acid tert-butyl ester in 100 ml CH2Cl2 was treated at 0° C. with 1.2 ml (15.4 mmol) of methanesulfonylchloride, 1.7 ml (20.93 mmol) of pyridine and 1.71 g (13.96 mmol) of DMAP. The reaction mixture was warmed up to RT for 3 h, treated with water (10 ml) and stirred for 5 min. After extraction with aqueous 10% KHSO4/Et2O (3×), the organic phases were washed with aqueous saturated NaHCO3 (2×), aqueous 10% NaCl, dried over Na2SO4 and evaporated to give 4.05 g (90%) of 4-(3-Methanesulfonyloxy-prop-1-ynyl)-piperidine-1-carboxylic acid tert-butyl ester, MS: 317 (M).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][CH:4]=1.[CH3:12][C:13]([N:16]1[C:20]([C:21](Cl)=[O:22])=[CH:19][C:18]([CH3:24])=[N:17]1)([CH3:15])[CH3:14].C(N(CC)CC)C>CN(C=O)C>[CH3:15][C:13]([N:16]1[C:20]([C:21]([NH:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([B:9]([OH:11])[OH:10])=[CH:7][CH:8]=2)=[O:22])=[CH:19][C:18]([CH3:24])=[N:17]1)([CH3:12])[CH3:14]
Reactant: Cc1cc(C(=O)Cl)n(C(C)(C)C)n1
Reactant: NCc1ccc(B(O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)NCc2ccc(B(O)O)cc2)n(C(C)(C)C)n1
Reaction time: 2 h

Procedure:
To a solution of [4-(aminomethyl)phenyl]boronic acid (145 mg, 0.966 mmol) in DMF (2 mL) was added 1-(1,1-dimethylethyl)-3-methyl-1H-pyrazole-5-carbonyl chloride (290 mg, 1.45 mmol) and triethylamine (403 μL, 2.90 mmol). The reaction was stirred for 2 h. It was then quenched and partitioned between EtOAc and H2O and the organic layer was concentrated to give {4-[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}boronic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:10]=1[Cl:11])[C:7](O)=[O:8].C(Cl)(=O)C([Cl:17])=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:10]=1[Cl:11])[C:7]([Cl:17])=[O:8]
Reactant: COc1ccc(Br)c(Cl)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(Br)c(Cl)c1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4B (1.2 g, 4.6 mmol), dichloromethane (15 ml) and oxalyl chloride (1 ml) is stirred at room temperature for 2 hours. The mixture is concentrated and the resulting benzoylchloride is used without further purification.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].CO>P([O-])([O-])([O-])=O>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2].[CH2:1]([O:3][C@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Product: CCOC(=O)[C@@H](Cc1ccc(O)cc1)OCC
Product: CCO[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
Ethyl (2RS) (+/−) 2-ethoxy-3-(4-hydroxyphenyl)propanoate (0.5 g) was shaken with 60 mg of the lyophilised hydrolytic enzyme mixture from Aspergillus oryzae in 1 ml 1M phosphate buffer (pH=7) with organic co-solvents (according to the table below) at 27° C. The reaction mixture was poured into 20 ml MeOH after 4 h to stop the enzymatic reactions followed by analysis by the chiral CCE method 2.