Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:25](=[O:26])[N:5]2[C:6]([C:22]([O-:24])=[O:23])=[C:7]([CH:10]=[CH:11][CH2:12][N+:13]3[CH:18]=[CH:17][C:16]([C:19](=[O:21])[NH2:20])=[CH:15][CH:14]=3)[CH2:8][S:9][C@H:4]12.Cl.[CH2:28]([O:30][N:31]=[C:32]([C:36]1[N:40]=[C:39]([NH2:41])[S:38][N:37]=1)[C:33](Cl)=[O:34])[CH3:29].C([O-])([O-])=O.[Na+].[Na+].Cl>CC(C)=O>[NH2:41][C:39]1[S:38][N:37]=[C:36]([C:32](=[N:31][O:30][CH2:28][CH3:29])[C:33]([NH:2][CH:3]2[C:25](=[O:26])[N:5]3[C:6]([C:22]([O-:24])=[O:23])=[C:7]([CH:10]=[CH:11][CH2:12][N+:13]4[CH:14]=[CH:15][C:16]([C:19](=[O:21])[NH2:20])=[CH:17][CH:18]=4)[CH2:8][S:9][C@H:4]23)=[O:34])[N:40]=1
Reactant: NC(=O)c1cc[n+](CC=CC2=C(C(=O)[O-])N3C(=O)C(N)[C@H]3SC2)cc1
Reactant: CCON=C(C(=O)Cl)c1nsc(N)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[n+]3ccc(C(N)=O)cc3)CS[C@H]12)c1nsc(N)n1
Temperature: 10 °C
Yield: 93.4 %

Procedure:
To a solution of 200 mg of 7-amino-3-[3-(4-carbamoylpyridinio)-1-propen-1-yl]-3-cephem-4-carboxylate hydrochloride (E isomer) in 5 ml of 50% aqueous acetone was added portionwise 190 mg of 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetyl chloride hydrochloride [prepared according to the procedure described in published Japan patent application (Kokai) No. 57-24389 (2/8/82)], and the mixture was adjusted to pH 6.5-7.0 with 2N Na2CO3 (about 1 ml). The reaction mixture was stirred at 10° C. for an hour, acidified to pH 2 with 1N HCl and evaporated in vacuo. The residue was filtered and the filtrate was chromatographed on a column of HP-20, which was eluted with 500 ml of water and 25% aqueous isopropanol, successively. Fractions containing the desired product were combined and evaporated under reduced pressure. The oily residue was treated with isopropanol (20 ml) to give 263 mg (93%) of the title compound (I-2H). M.p. 170° C. (dec.).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][C:9]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11][C:10]=3[CH:23]=[C:6]2[O:5][CH2:4][C:3]1=[O:24].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[C:7]2=[CH:8][C:9]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C:10]=3[CH:23]=[C:6]2[O:5][CH2:4][C:3]1=[O:24]
Reactant: CN1C(=O)COc2cc3c(cc21)CCN(C(=O)OC(C)(C)C)CC3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)COc2cc3c(cc21)CCNCC3

Procedure:
1,1-Dimethylethyl 4-methyl-3-oxo-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate (0.16 g) was treated with TFA (2 ml) in DCM (4 ml) for 3 h at 25° C. After elimination of volatiles under reduced pressure the residue was partitioned between aqueous NaHCO3 and DCM. The organic layer was collected and the aqueous phase extracted twice with DCM. The combined DCM layers were dried (Na2CO3), filtered and concentrated to give the title compound as a colourless solid which was used without further analysis (0.11 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C@H:14]([C:19]([OH:21])=O)[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:12].[C:22]([CH:24]([NH2:35])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)#[N:23].C(C(NC(C(NC(C1C=CC2C(=CC=CC=2)C=1)=O)CC(C)C)=O)CC(C)C)#N>>[C:22]([CH:24]([NH:35][C:19]([CH:14]([NH:13][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:12])[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:21])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)#[N:23]
Reactant: N#CC(N)Cc1c[nH]c2ccccc12
Reactant: CC(C)C[C@H](NC(=O)c1ccc2ccccc2c1)C(=O)O
Agent: CC(C)CC(C#N)NC(=O)C(CC(C)C)NC(=O)c1ccc2ccccc2c1
Product: CC(C)CC(NC(=O)c1ccc2ccccc2c1)C(=O)NC(C#N)Cc1c[nH]c2ccccc12
Yield: 36 %

Procedure:
The title compound is prepared analogously to the compound of Example 22. N-(Naphthalene-2-carbonyl)-leucine and 1-cyano-2-(1H-indol-3-yl)-ethylamine (CAS 169545-97-5) are reacted by the same procedure as for Naphthalene-2-carboxylic acid [1-(1-cyano-3-methyl-butylcarbamoyl)-3-methyl-butyl]-amide, to give the product in 36% yield after chromatography on silica gel (hexane/ethyl acetate 1/1) (mixture of epimers).
Reaction SMILES: O[CH2:2][CH:3]([CH2:14][O:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:4][CH2:5][N:6]1[CH:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]1=[O:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:55].C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:55][CH2:2][CH:3]([CH2:14][O:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:4][CH2:5][N:6]1[CH:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]1=[O:13]
Reactant: O=c1ccn(CCC(CO)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=c1ccn(CCC(CBr)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of compound 36 (33 g, 0.073 mol) in dry DMF (200 mL) was added triphenylphosphine (29 g, 0.11 mol) with vigorous stirring at RT. The reaction mixture was cooled to 0° C., added CBr4 (36 g, 0.11 mol) portion wise over a period of 30 min and allowed to stir at RT for 24 h. The reaction mixture was cooled to 0° C., added saturated NaHCO3 solution (100 mL) and extracted with ethyl acetate (4×150 mL). The combined organic layer was dried, concentrated under vacuum and the crude product was purified by column chromatography on silica gel (50% ethyl acetate in hexane) to give the title compound (22 g, 57%). TLC: 100% EtOAc, Rf=0.7
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[CH3:16]O>C(OCC)(=O)C.CCCCCC>[OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CO)c2ccccc12
Reactant: CO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1ccc(CO)c2ccccc12
Yield: 35 %

Procedure:
A mixture of 4-hydroxymethylnaphthoic acid (10 g, 50 mmol), methanol (300 mL), and conc. H2 SO4 (2 mL) was refluxed overnight. The insolubles were filtered off and the filtrate was concentrated. The residue was taken up in ethyl acetate and washed with aqueous NaHCO3 (2×), brine, dried over MgSO4, and concentrated to give a yellow oil. Silica gel column chromatography using ethyl acetate/hexane (1/3) gave the desired product as a yellow oil (3.3 g, 35%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[C:16](O)(=[O:19])[CH:17]=[CH2:18].C1(C=CC(O)=CC=1)O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC(Cl)(Cl)C>[C:16]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)(=[O:19])[CH:17]=[CH2:18]
Reactant: O=C(O)c1ccc(OCCCCO)cc1
Reactant: C=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: CC(Cl)(Cl)Cl
Product: C=CC(=O)OCCCCOc1ccc(C(=O)O)cc1

Procedure:
A solution of (1) (282 g; 1.34 mol), freshly distilled acrylic acid (230 ml; 3.35 mol), hydroquinone (1.9 g) and p-toluenesulfonic acid (23.7 g) in 1,1,1-trichloroethane (1.1 l) is refluxed for 10 hours. The reaction mixture is cooled to from 60° to 70° C. and stirred into 2.5 l of petroleum ether, and the precipitate is filtered off, washed with petroleum ether and dried at room temperature under reduced pressure for 24 hours.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:12]([O:13]C(C)C)=[CH:11][C:10]([N:17]2[C:25](=[O:26])[N:20]3[CH2:21][CH2:22][CH2:23][CH2:24][N:19]3[C:18]2=[S:27])=[C:9]([F:28])[CH:8]=1>C(Cl)Cl>[Cl:6][C:7]1[C:12]([OH:13])=[CH:11][C:10]([N:17]2[C:25](=[O:26])[N:20]3[CH2:21][CH2:22][CH2:23][CH2:24][N:19]3[C:18]2=[S:27])=[C:9]([F:28])[CH:8]=1
Reactant: CC(C)Oc1cc(-n2c(=O)n3n(c2=S)CCCC3)c(F)cc1Cl
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=c1n(-c2cc(O)c(Cl)cc2F)c(=S)n2n1CCCC2
Temperature: 0 °C
Yield: 95.5 %

Procedure:
Conc. sulfuric acid (22 ml) was added dropwise to a solution of 2-[4-chloro-2-fluoro-5-(isopropyloxy)phenyl]hexahydro-3-thioxo-1H-[1,2,4]triazolo[1,2-a]pyridazin-1-one (17.2 g) in methylene chloride (120 ml) stirred at 0° C. The mixture was stirred at room temperature for 1 hour and ice-water (200 g) added. The aqueous phase was extracted with methylene chloride and the organic phases combined, dried over sodium sulfate and chromatographed (silica gel, ethyl acetate) to give the product (14.5 g, 96%). 1H NMR (CDCl3, TMS): 1.84(4H, m), 3.82(4H, m), 7.06(1H, d, J=6.5 Hz), 7.58(1H, d, J=8.8 Hz), 10.6(1H, s).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:19])=[C:14]([C:17]#[N:18])[C:15]#[N:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20](OC)(OC)OC>>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:19][CH3:20])=[C:14]([C:15]#[N:16])[C:17]#[N:18])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)OC
Reactant: N#CC(C#N)=C(O)c1cnn(Cc2ccccc2)c1
Product: COC(=C(C#N)C#N)c1cnn(Cc2ccccc2)c1
Yield: 51.8 %

Procedure:
A solution of 2-((1-benzyl-1H-pyrazol-4-yl)(hydroxy)methylene)malononitrile (26.5 g, 106 mmol) in CH(OMe)3 (250 mL) was heated to 75° C. for 16 hr. Then the solution was concentrated. The residue was washed with MeOH (50 mL) to give 14.5 g (51.8%) of 2-((1-benzyl-1H-pyrazol-4-yl)(methoxy)methylene)malononitrile as an off-white solid. 1H NMR (DMSO-d6) δ 8.71 (s, 1H), 8.08 (s, 1H), 7.42-7.24 (m, 5H), 5.46 (s, 2H), 4.12 (s, 3H). MS (ESI) m/e [M+1]+ 264.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][C:43](=[O:47])[C:44]([CH3:46])=[CH2:45])[CH2:10]2)=[CH:5][CH:4]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][C:43](=[O:47])[CH:44]([CH3:45])[CH3:46])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: C=C(C)C(=O)C[C@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1S(=O)(=O)c1ccc(C)cc1
Agent: [Pd]
Solvent: CCO
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)C(C)C)C[C@@H]3c3ccc(OC)cc3)cc21
Reaction time: 0.5 h

Procedure:
A mixture of 0.19 g of 1-[(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-3-methyl-but-3-en-2-one and 0.044 g of 10% Pd/C in 5 ml of ethanol is hydrogenated at room temperature for 30 minutes. The reaction mixture is clarified by filtration and concentrated to afford the crude title compound as a light brown oil which is used in the next step without any further purification. Rf=0.30 (EtOAc-heptane 1:1); Rt=5.54.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH2:5]([S:8](Cl)(=[O:10])=[O:9])[CH2:6][CH3:7]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]1([NH:4][S:8]([CH2:5][CH2:6][CH3:7])(=[O:10])=[O:9])[CH2:3][CH2:2]1
Reactant: CCCS(=O)(=O)Cl
Reactant: NC1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCS(=O)(=O)NC1CC1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a solution of cyclopropylamine (1.2 ml, 17.5 mmol) in 100 ml CH2Cl2 and DMAP (2.4 g, 17.5 mmol) was added dropwise a solution of propane-1-sulfonyl chloride (2.3 ml, 19.2 mmol) in 50 ml CH2Cl2. The resulting mixture was stirred at room temperature over night and diluted with 50 ml of CH2Cl2. The mixture was extracted subsequently with water, 1 M HCl, and brine, tried over Na2SO4, filtered and the solvent evaporated to obtain 2.8 g of product (oil) which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:18]=1[CH2:19][OH:20])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(Cl)c3C=O)ncc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(Cl)c3CO)ncc2c1
Temperature: 25 °C
Yield: 76.2 %

Procedure:
2-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-chloro-benzaldehyde 101i (519 mg, 1.4 mmol) was dissolved in DCM (2 mL) with stirring at room temperature, and then 1 mL of iPA was added to the solution. The resulting solution was cooled to 4° C., and NaBH4 (27 mg, 0.7 mmol) was added in one portion. After 30 min stirring, the reaction was quenched by adding H2O (2 mL). The aqueous layer was extracted with CH2Cl2 (2×5 mL), washed with brine and dried over MgSO4. The filtrate was concentrated to give a residue which was purified by silica gel chromatography eluting with 0-20% EtOAc/CH2Cl2 to furnish 101j as a white solid (385 mg, 72%). MS: [M+H]+: 361
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1.FC1C=CC([CH:18]=[O:19])=C(C)C=1>Cl>[F:5][C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][C:11]=1[CH:18]=[O:19]
Reactant: Cc1cc(F)ccc1C=O
Reactant: Cc1cccc(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C=O)c(F)c1
Temperature: 60 °C
Yield: 76.2 %

Procedure:
100.89 g of aluminum chloride (mol. Wt. 133.34; 756.6 mmol) and about 503.54 g of 3-fluorotoluene (mol. Wt. 110.13; 4,572 mmol) were charged to a 2 liter Parry -brand 4522 stainless steel reaction vessel. To this mixture was added 5 drops of concentrated HCl. The vessel was sealed, heated to 60° C., and purged three times with carbon monoxide with the pressure of the vessel increased to 200 psi for each purging. After the third purge, the vessel was vented and a final introduction of CO was made at a pressure of about 200 psi, the pressure at which the reaction was maintained for the total reaction time of about 17 hours (the reaction temperature was maintained at 60° C. for the duration as well). Once the reaction was complete, the resultant mixture (exhibiting a dark orange color) was poured into about 500 mL of ice water (which turned the solution a yellow color), to which was added 500 mL of cyclohexane. The top, organic layer was removed and washed three times with water using a separatory funnel and dried over magnesium sulfate. The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 3-fluorotoluene, and left about 79.65 g of a benzaldehyde mixture consisting of 4-fluoro-2-methylbenzaldehyde (88.4%) and 2-fluoro-4-methylbenzaldehyde (11.6%) (mol. Wt. 138.14; 576.6 mmol; yield of approximately 76.2%).
Reaction SMILES: [C:1](=O)([O:33]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3]([CH3:32])[C:4](=[C:13]1[CH2:16][N:15]([CH:17]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:14]1)[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1.[CH:44]([NH2:47])([CH3:46])[CH3:45]>C(Cl)Cl>[CH:44]([NH:47][C:1](=[O:33])[O:2][CH:3]([CH3:32])[C:4](=[C:13]1[CH2:14][N:15]([CH:17]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:16]1)[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1)([CH3:46])[CH3:45]
Reactant: CC(C)N
Reactant: CC(OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Solvent: ClCCl
Product: CC(C)NC(=O)OC(C)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 45 mg (0.073 mmol) of 2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-2-(3,5-difluorophenyl)-1-methylethyl 4-nitrophenyl carbonate (Example 37) in 3 mL of methylene chloride was added 0.3 mL of isopropylamine, followed by stirring for 4 h at rt. The reaction mixture was concentrated and the residue was purified by silica gel chromatography with hexanes/ethyl acetate=4:1 to afford the title compound; Mass Spectrum: m/e=545 (M+1 35Cl, 35Cl) and 547 (M+1 35Cl, 37Cl).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][C:12](O)=[O:13])=[CH:4][C:3]=2[O:2]1.B.O1CCCC1>CCOCC>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(O)CCc1ccc2c(c1)OCO2
Agent: B
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCCc1ccc2c(c1)OCO2

Procedure:
To a solution of 3-(3,4-methylenedioxyphenyl)propionic acid (1.0 g, 5.2 mmoles) in ether (100 ml) at 0° C. was added borane-tetrahydrofuran (1.0 M, 6.2 ml, 6.2 mmoles). The cooling bath was removed and 15 minutes later methanol (5 ml) was slowly added. One hour later the reaction was washed with H2O (200 ml), and then the organic layer was dried (MgSO4), filtered and concentrated to collect 0.91 g (98%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:7])=[N:5][N:6]=1.[O:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([NH:7][CH:11]2[CH2:12][CH2:13][O:8][CH2:9][CH2:10]2)=[N:5][N:6]=1
Reactant: O=C1CCOCC1
Reactant: Cc1nnc(N)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nnc(NC2CCOCC2)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.2 %

Procedure:
To a solution (40 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (3 g) and tetrahydro-4H-pyran-4-one (3.7 g) in acetic acid was added sodium cyanoborohydride (9.7 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (0.79 g, 14%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:22][CH3:23])[C:18]=1[CH:19]([CH3:21])[CH3:20])[C:12](OC)=[O:13]>CCOCC>[CH3:23][O:22][C:17]1[CH:16]=[C:11]([CH:10]=[C:9]([O:8][CH3:7])[C:18]=1[CH:19]([CH3:21])[CH3:20])[CH2:12][OH:13]
Reactant: COC(=O)c1cc(OC)c(C(C)C)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1cc(CO)cc(OC)c1C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To a suspension of LiAlH4 (95%) (5.00 g, 125 mmol) in dry ether (100 mL) at 0° C. was added a solution of methyl 3,5-dimethoxy-4-i-propylbenzoate (17.67 g, 90.1 mmol), obtained in example 1(b) in ether (300 mL) under N2. The suspension was stirred at 0° C. for one hour then for an additional hour at room temperature. The reaction was quenched by slow addition of a saturated Na2SO4 aqueous solution (10 mL) at 0° C. The mixture was stirred overnight. The solid was filtered off and the filtrate was evaporated to dryness to give 3,5-dimethoxy-4-i-propylbenzyl alcohol (13.76 g, 88.3% yield) as white crystals. 1HNMR (CDCl3, ppm): δ 1.34 (d, J=7.2 Hz, 6H), 3.65 (hept., J=7.2 Hz, 1H), 3.88 (s, 6H), 4.70 (s, 2H), 6.62 (s, 2H).
Reaction SMILES: [ClH:1].N[C:3]1[N:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[N:4]=1.N([O-])=O.[Na+].[OH-].[Na+]>O>[Cl:1][C:3]1[N:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[N:4]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(OC)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,260 ml of 36% hydrochloric acid were charged in a 5-l four-necked flask and then cooled to 0° C. After 180 g (1.16 moles) of 2-amino-4,6-dimethoxypyrimidine were added in small portions into the flask, the resulting mixture was stirred for about 1 hour until the reaction mixture changed into a syrupy form. After the reaction mixture was cooled to -15° C., 260 ml of 159 g (2.3 moles) of NaNO2 in H2O were added dropwise over about 1 hour under vigorous stirring. After completion of the dropwise addition, the resulting mixture was stirred at -15° to -10° C. for additional 1 hour so that the reaction was brought to completion. While the reaction mixture was retained at -5° C., 1.5 l of a 30% aqueous solution of NaOH were charged dropwise so that the reaction mixture was neutralized to pH 7. By filtration under reduced pressure, a clay-like material of a purple color was collected. The target compound was extracted from the clay-like material using 3 l of ethyl acetate. Through the procedure of washing with water, drying over anhydrous sodium sulfate and removal of the solvent, 63 g of bluish crude crystals were obtained. They were crystallized further by silica get chromatography to obtain 60.8 g of white crystals (yield: 29.9%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]([C:32]3[C:40]4[C:35](=[CH:36][C:37]([C:41](OC)=[O:42])=[CH:38][CH:39]=4)[N:34]([CH3:45])[CH:33]=3)[C:17]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=3[O:30][CH3:31])(=[O:22])=[O:21])=[O:18])=[CH:15][C:10]=2[O:9][CH2:8]1.C(OCC)(=O)C>O1CCCC1>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]([C:32]3[C:40]4[C:35](=[CH:36][C:37]([CH2:41][OH:42])=[CH:38][CH:39]=4)[N:34]([CH3:45])[CH:33]=3)[C:17]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=3[O:30][CH3:31])(=[O:22])=[O:21])=[O:18])=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: COC(=O)c1ccc2c(C(C(=O)NS(=O)(=O)c3ccc(C)cc3OC)c3ccc4c(c3)OCO4)cn(C)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(CO)ccc12
Temperature: 25 °C
Yield: 62.2 %

Procedure:
Lithium aluminium hydride (15 mg, 0.2 mmol) was added slowly to a stirred solution of methyl 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxo-ethyl}-1-methyl-1H-6-indolecarboxyate (from step (a), 200 mg, 0.4 mmol) in tetrahydrofuran at 0° C. under a nitrogen atmosphere. After 2 h a further 1 equivalent (30 mg) of lithium aluminium hydride was added and the mixture was warmed to room temperature. After 1 h ethyl acetate (10 ml) was carefully added and the product extracted from 1N hydrochloric acid with ethyl acetate (2×50 ml). The combined organic layers were dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography (elution with 95% dichloromethane /5% methanol) gave the product as a white solid (130 mg).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][NH:5][CH:4]2[CH2:8][CH2:9][CH2:10][CH:3]12.Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(N(CC)CC)C>ClCCl>[O:2]1[CH2:7][CH2:6][N:5]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH:4]2[CH2:8][CH2:9][CH2:10][CH:3]12
Reactant: C1CC2NCCOC2C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCOC2CCCC21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To octahydrocyclopenta[b][1,4]oxazine hydrochloride (purchased from Enamine) (300 mg, 1.83 mmol) dissolved in dichloromethane (2.4 mL) was added benzyl chloroformate (0.44 mL, 2.57 mmol). Triethylamine (0.72 mL, 5.13 mmol) was added slowly to the reaction mixture, and the reaction was stirred for 16 hours at room temperature. The mixture was quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient), and then purified by chiral supercritical fluid chromatography (Chiralpak AZ-H, 21×250 mm, 10% methanol in CO2) to afford the trans stereoisomers of benzyl hexahydrocyclopenta[b][1,4]oxazine-4(4aH)-carboxylate. (4aS,7aS)-Benzyl hexahydrocyclopenta[b][1,4]oxazine-4(4aH)-carboxylate (faster eluting enantiomer): MS ESI calc'd. for C15H19NO3 [M+H]+ 262. found 262; (4aR,7aR)-Benzyl hexahydrocyclopenta[b][1,4]oxazine-4(4aH)-carboxylate (slower eluting enantiomer): MS ESI calc'd. for C15H19NO3 [M+H]+ 262. found 262.