Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[CH3:8][NH:9][C:10](=[S:13])[NH:11][NH2:12]>N1C=CC=CC=1>[CH2:1]([O:3][CH2:4][CH:5]1[N:9]([CH3:8])[C:10](=[S:13])[N:11]=[N:12]1)[CH3:2]
Reactant: CCOCC(=O)Cl
Reactant: CNC(=S)NN
Solvent: c1ccncc1
Product: CCOCC1N=NC(=S)N1C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
Ethoxyacetyl chloride (57 g.) was added slowly to a stirred solution of 4-methylthiosemicarbazide (53.5 g.) in dry pyridine (500 ml.) at 0°-5°. The mixture was allowed to attain room temperature and stirring was continued for 18 hours. Following concentration under reduced pressure the residue was treated with a solution of sodium (21.4 g.) in ethanol (500 ml.) and the mixture was heated under reflux for 24 hours. Following concentration and acidification with hydrochloric acid a solid was obtained. After partial concentration the solid was collected and recrystallised from ethyl acetate to give 3-ethoxymethyl-4-methyl-1,2,4-triazoline-5-thione (53 g.), m.p. 137°-138°. The thione (44 g.) was desulphurised by slow addition to a solution prepared from nitric acid (75 ml.) water (150 ml.) and sodium nitrite (1.5 g.) at 15°-20°. Following subsequent basification with sodium carbonate and concentration the residue was extracted with ethanol-ether 1:1 and distilled to afford 3-ethoxymethyl-4-methyl-1,2,4-triazole (30 g.) b.p. 154°-156°/0.05 mm. The above compound (15 g.) dissolved in 48% aqueous hydrobromic acid (150 ml.) was heated under reflux for 24 hours and concentrated to dryness to give 3-hydroxymethyl-4-methyl-1,2,4-triazole.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].CO>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:27][CH2:28][CH:23]([C:19]4[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:29])[F:30])[CH:18]=4)[CH2:24][CH2:25]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: FC(F)(F)c1cccc(C2CCNCC2)c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2cccc(C(F)(F)F)c2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(3-trifluoromethylphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 50% overall yield. FDMS m/e=419 (M+ of free base). α[D]589 =-11.62 (c=0.45, methanol).
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[CH2:23]>O1CCOCC1>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:23][CH2:22][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Reactant: C=Cc1ccccn1
Solvent: C1COCCO1
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCc2ccccn2)C1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (1.0 g-see Preparation 8), 2-vinylpyridine (0.5 g) and 1,4-dioxane (10 ml) was heated under reflux for 20 hours. On cooling to room temperature the mixture was filtered and the filtrate was diluted with water (100 ml) then extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a brown oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (2% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield, 0.31 g.
Reaction SMILES: BrC1C=CC(C(N)=O)=CC=1.O=CC(Cl)(Cl)[Cl:14].[Br:17][C:18]1[CH:32]=[CH:31][C:21]([C:22]([NH:24][CH:25](O)[C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23])=[CH:20][CH:19]=1.P(Cl)(Cl)(Cl)(Cl)Cl>C1COCC1.C(Cl)(Cl)Cl>[Br:17][C:18]1[CH:32]=[CH:31][C:21]([C:22]([NH:24][CH:25]([Cl:14])[C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23])=[CH:20][CH:19]=1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1ccc(Br)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: NC(=O)c1ccc(Br)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C(NC(Cl)C(Cl)(Cl)Cl)c1ccc(Br)cc1

Procedure:
A mixture of 4-bromoaniline 118 (5.0 g, 24.2 mmol) and chloral (4.7 mL, 48.2 mmol) in THF (4 mL) was heated for 30 minutes. Solvent was removed under vacuum. 4-Bromo-N-(2,2,2-trichloro-1-hydroxyethyl)benzamide 121 (1.26 g, 3.62 mmol) in chloroform (15 mL) and PCl5 (0.8 g, 3.65 mmol) was heated at 50° C. for 30 minutes. The product was isolated from a standard aqueous work-up and extraction to produce 4-bromo-N-(1,2,2,2-tetrachloroethyl)benzamide. 4-Bromo-N-(1,2,2,2-tetrachloroethyl)benzamide (1.21 mmol) in ether (50 mL) was reacted with 6-chloropyridin-3-amine (0.32 g, 2.44 mmol) at room temperature for 18 hours. The mixture was subjected to a standard aqueous work-up and extraction. Chromatography on silica gel (7:3 hexanes:CH2Cl2) gave 4-bromo-N-(2,2,2-trichloro-1-(6-chloropyridin-3-ylamino)ethyl)benzamide (Compound-42, 0.36 g, 65%). 1H NMR (300 MHz, d4-methanol): δ=7.99 (dd, J=3.0, 0.6 Hz, 1H), 7.74 (d, J=9.0 Hz, 2H), 7.65 (d, J=9.0 Hz, 2H), 7.36 (dd, J=9.0, 3.3 Hz, 1H), 7.26 (dd, J=8.7, 0.6 Hz, 1H), 6.36 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=3)=[N:10][CH2:11][C:12]3[N:13]([C:14]([CH:17](Br)[CH3:18])=[N:15][N:16]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[C:27]#[N:28])#[N:2].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30].[I-].[Na+]>>[C:1]([C:3]1[C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=3)=[N:10][CH2:11][C:12]3[N:13]([C:14]([CH:17]([N:31]([CH2:32][CH3:33])[CH2:29][CH3:30])[CH3:18])=[N:15][N:16]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[C:27]#[N:28])#[N:2]
Reactant: CC(Br)c1nnc2n1-c1ccc(C#N)c(C#N)c1C(c1ccc(Br)cc1)=NC2
Reactant: CCNCC
Agent: [I-]
Agent: [Na+]
Product: CCN(CC)C(C)c1nnc2n1-c1ccc(C#N)c(C#N)c1C(c1ccc(Br)cc1)=NC2

Procedure:
In the manner given in Example 1, 7,8-dicyano-1-(α-bromoethyl)-6-(p-bromophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine was reacted with diethylamine in the presence of sodium iodide to give 7,8-dicyano-1-[α-(diethylamino)ethyl]-6-(p-bromophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH2:13][CH:12]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[C:28]([C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O)#[N:29].C(N1C2C(=CC(Cl)=CC=2)CC(NC(=O)OC(C)(C)C)C1)C1C=CC=CC=1>>[C:28]([C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][N:14]1[C:15]2[C:10](=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:17][CH:16]=2)[CH2:11][CH:12]([NH:18][S:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:20])=[O:21])[CH2:13]1)#[N:29]
Reactant: O=S(=O)(NC1CNc2ccc(-c3ccc(F)cc3)cc2C1)c1ccccc1
Reactant: N#Cc1cccc(C=O)c1
Agent: CC(C)(C)OC(=O)NC1Cc2cc(Cl)ccc2N(Cc2ccccc2)C1
Product: N#Cc1cccc(CN2CC(NS(=O)(=O)c3ccccc3)Cc3cc(-c4ccc(F)cc4)ccc32)c1

Procedure:
Compound 113B was prepared from 113A and 3-cyanobenzaldehyde by procedures analogous to those described in 22A. HPLC: 96% at 6.25 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 498 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]1[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([C:21]([O:23][CH3:24])=[O:22])#[C:16][C:17]([O:19][CH3:20])=[O:18]>>[CH3:20][O:19][C:17]([C:16]1[C:12]2([CH3:13])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]([CH3:14])([C:15]=1[C:21]([O:23][CH3:24])=[O:22])[CH:10]=[CH:11]2)=[O:18]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Cc1ccc(C)n1C(=O)OC(C)(C)C
Product: COC(=O)C1=C(C(=O)OC)C2(C)C=CC1(C)N2C(=O)OC(C)(C)C
Yield: 50 %

Procedure:
A mixture of crude 2,5-dimethyl-pyrrole-1-carboxylic acid tert-butyl ester (prepared according to a literature (Haiser, H.-P.; et al. J. Org. Chem. 1984 49(22) 4203-4209); 500 mg) and dimethyl acetylenedicarboxylate (0.5 mL, ca 4 eq) was stirred at 120° C. under argon for 2 h. Purification by silica gel flash chomatography on SiO2 eluting with EtOAc/heptane (gradient from 1:20 to 1:2 ratio) gave compound 780A (166 mg, 50% yield) as a colorless liquid. HPLC: 90% at 3.67 min (retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.[C:9]1(=[O:15])[NH:13][C:12](=[O:14])[CH2:11][CH2:10]1.[Na].C1(=O)NC(=O)CC1.[H-].[Na+]>O.CN(C=O)C>[CH:2]1([N:13]2[C:9](=[O:15])[CH2:10][CH2:11][C:12]2=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: BrC1C=CCCCC1
Reactant: O=C1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCC(=O)N1C1C=CCCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Bromocycloheptene (1.75 g) was added dropwise at room temperature to a DMF suspension (10 ml) of sodium succinimide prepared from succinimide (0.99 g) and 60% sodium hydride (0.40 g). This mixture was stirred at room temperature for 24 hours, poured into water (10 ml) and extracted with ether. The oily product obtained by concentration was purified by chromatography on silica gel to obtain 0.09 g of N-(2-cycloheptenyl)succinimide [Compound (214)].
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5][CH2:4]1.[H-].[Na+].I[CH2:24][CH2:25][OH:26]>O1CCCC1>[CH3:1][N:2]([CH3:20])[CH:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH2:24][CH2:25][OH:26])[C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:5][CH2:4]1
Reactant: OCCI
Reactant: CN(C)C1CCC(NC(=O)OCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C1CCC(N(CCO)C(=O)OCc2ccccc2)CC1
Temperature: 2.5 °C
Yield: 150.9 %

Procedure:
To a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added a solution of benzyl N-[4-(dimethylamino)cyclohexyl]carbamate (2 g, 7.24 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). This was followed by the addition of a solution of sodium hydride (320 mg 60% W/W, 7.971 mmol, 1.1 equiv) in tetrahydrofuran (10 mL) dropwise with stirring at 0-5° C. The resulting solution was stirred for 2 h at room temperature. To this was added 2-iodoethan-1-ol (2.5 g, 14.54 mmol, 2.01 equiv) dropwise with stirring at 0-5° C. The resulting solution was allowed to react, with stirring, for an additional 4 days at room temperature. The reaction was then quenched by the addition of 10 mL of water and concentrated under vacuum. The residue was washed with a solution of dichloromethane/methanol (10:1, 20 mL×4) and the organic layers combined, dried and concentrated to give 3.5 g (crude) of benzyl N-[4-(dimethylamino)cyclohexyl]-N-(2-hydroxyethyl)carbamate as a yellow oil. MS: m/z 321 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][CH3:14])[C@H:10]([C:15]#[N:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[OH:19]>C(Cl)(Cl)Cl.CC(O)=O.O=[Pt]=O>[C:11]([OH:13])(=[O:19])[CH3:12].[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][CH3:14])[C@H:10]([CH2:15][NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C#N
Reactant: CCO
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN
Reaction time: 16 h

Procedure:
80.3 A suspension of (3S,4S)-3-cyano-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg) in 15 ml of EtOH, 0.3 ml of chloroform, 0.38 ml of AcOH and 8 mg of PtO2 was hydrogenated at 22° C. and atmospheric pressure for 16 h. The suspension was filtered and the filtrate evaporated to give 188 mg of (3R,4S)-3-aminomethyl-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester acetate. Colorless semisolid. MS 231.3 ([M+H]+)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[S:6]1(=[O:23])=[O:22].[CH3:24][NH2:25].Cl>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:25][CH3:24])[S:6]1(=[O:23])=[O:22]
Reactant: O=S1(=O)N(CCCBr)Cc2ccccc2N1c1ccccc1F
Reactant: CN
Agent: Cl
Product: CNCCCN1Cc2ccccc2N(c2ccccc2F)S1(=O)=O

Procedure:
In an analogous manner to Example 11 step 5, 3-(3-bromopropyl)-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.1 g, 0.23 mmol) was reacted to methylamine and then treated with HCl to provide 3-[1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine as a white solid:
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([OH:21])[CH3:20])[C:10](=[O:22])[N:9]([CH3:23])[C:8]=2[N:7]=[C:6]1[SH:24])[CH3:2].Br[CH2:26][CH2:27][Cl:28]>C(#N)C>[CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([OH:21])[CH3:20])[C:10](=[O:22])[N:9]([CH3:23])[C:8]=2[N:7]=[C:6]1[S:24][CH2:26][CH2:27][Cl:28])[CH3:2]
Reactant: ClCCBr
Reactant: CCOCn1c(S)nc2c1c(=O)n(CCCC[C@@H](C)O)c(=O)n2C
Solvent: CC#N
Product: CCOCn1c(SCCCl)nc2c1c(=O)n(CCCC[C@@H](C)O)c(=O)n2C
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 67.2 %

Procedure:
A mixture of (R)-7-ethoxymethyl-1-(5-hydroxyhexyl)-8-mercapto-3-methylxanthine (0.19 g, 0.533 mmol) potassium carbonate (0.15 g, 10.7 mmol) and 1-bromo-2-chloroethane (114 mg, 0.80 mmol) in acetonitrile (10 ml) was stirred at 65° C. for 1.5 hours. After concentrating under reduced pressure, the residue was purified by column chromatography on silica gel eluting with ethyl acetate-hexane (1:1) to provide (R)-7-ethoxymethyl-8-(2-chloroethylsulfanyl)-1-(5-hydroxyhexyl)-3-methylxanthine (150 mg, 67% yield) as a white powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[C:15]([OH:17])=[O:16])[CH2:3][CH2:2]1.C[O-].[Na+].[CH3:21][O:22]C(OC)N(C)C>CO>[C:15]([C:11]1[N:10]([CH2:9][CH2:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([CH:21]=[O:22])[CH2:2][CH2:3]2)[CH:14]=[CH:13][N:12]=1)([OH:17])=[O:16]
Reactant: O=C(O)c1nccn1CCCC1CCNCC1
Reactant: COC(OC)N(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=CN1CCC(CCCn2ccnc2C(=O)O)CC1
Temperature: 80 °C

Procedure:
A mixture of 1-[3-(4-piperidinyl)propyl]-1H-imidazole-2-carboxylic acid 1.75 molar hydrochloride 0.65 molar hydrate (1.3 g, 0.0047M) and sodium methoxide (0.005M) in methanol (23 ml) was added to dimethylformamide dimethylacetal (15 ml) and heated at 80° C. for 8 hrs. The reaction mixture was filtered and stripped to dryness to give 4-[3-(2-carboxy-1H-imidazol-1-yl)propyl]-1-piperidine carboxaldehyde. The solution of the above piperidine carboxaldehyde dimethylacetal in methanol (5 ml) was then added to a mixture of 6-aminopenicillanic acid (0.81 g, 0.0037M) and diisopropylethylamine (0.4 ml) in chloroform (30 ml) at 0° C. The reaction was stirred at 0° C. 2 hrs and room temperature for 2 hrs. The solvent was removed and water (15 ml) was added. After being washed with ether, the aqueous solution, acidified to pH 3 to about 3.5, was purified on Sephadex LH 20 columns to give [2S-(2alpha,5alpha,6beta]-6-[[[1-[(3-(2-carboxy-1H-imidazol-1-yl)propyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrate (0.38 g, 17% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[CH2:11][NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]2[C:26]3[CH:27]=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][C:25]=3[O:24][CH2:23][C:22]2=[O:33])[CH2:15][CH2:14]1.[N+](=[CH:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N-]>ClCCl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:31]([C:28]1[CH:29]=[CH:30][C:25]2[O:24][CH2:23][C:22](=[O:33])[N:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][CH:13]([N:12]([CH2:11]/[CH:10]=[CH:9]/[C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:14][CH2:15]3)[C:26]=2[CH:27]=1)#[N:32]
Reactant: N#Cc1ccc2c(c1)N(CCN1CCC(NC/C=C/c3cc(F)ccc3F)CC1)C(=O)CO2
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)CN(C/C=C/c1cc(F)ccc1F)C1CCN(CCN2C(=O)COc3ccc(C#N)cc32)CC1
Reaction time: 72 h
Yield: 5 %

Procedure:
To a mixture of 4-[2-(4-{[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]amino}piperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Example 37) (120 mg, 0.265 mmol) and ethyl diazoacetate (0.09 mL) in dichloromethane (5 ml) was added rhodium(II) acetate (4 mg, 0.009 mmol) at room temperature. After 72 hrs, the product was concentrated and purified by preparative TLC to give 6.7 mg of product (5%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:18])=[C:10](S(CC)(=O)=O)[N:11]=2)[C:6](=[O:19])[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4]1)[CH3:2].[C:25]([CH2:28][NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)(=[O:27])[CH3:26]>C(#N)C>[C:25]([CH2:28][NH:29][CH:30]1[CH2:34][CH2:33][N:32]([C:10]2[N:11]=[C:12]3[C:7]([C:6](=[O:19])[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:18])[CH2:31]1)(=[O:27])[CH3:26]
Reactant: CCOC(=O)c1cn(CC)c2nc(S(=O)(=O)CC)c(F)cc2c1=O
Reactant: CC(=O)CNC1CCNC1
Solvent: CC#N
Product: CCOC(=O)c1cn(CC)c2nc(N3CCC(NCC(C)=O)C3)c(F)cc2c1=O
Yield: 78.2 %

Procedure:
A mixture containing ethyl 1-ethyl-7-ethylsulfonyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (1.78 g), 3-(N-acetylmethylamino)pyrrolidine (2.13 g), and acetonitrile (70 ml) was heated under reflux for 3 hours. After cooling the mixture, the resulting precipitate was collected and recrystallized from acetonitrile to yield 1.58 g of ethyl 7-[3-(N-acetylmethylamino)-1-pyrrolidinyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, m.p. 212°-213° C.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][N:25]=1)[C:20]([NH2:22])=[O:21].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([NH:16][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][N:25]=2)[C:20]([NH2:22])=[O:21])=[O:13])=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Reactant: NC(=O)c1ccnc(N)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(OCC(=O)Nc2cc(C(N)=O)ccn2)cc1
Yield: 56.5 %

Procedure:
A solution of 4-tert-butylphenoxy acetic acid (60.1 mg, 0.29 mmol), 2-amino isonicotinamide (60.3 mg, 0.44 mmol), DIPEA (0.1 ml, 0.58 mmol) and PyBOP (301.8 mg, 0.58 mmol) in DMF 4.0 mL was stirred, then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous MgSO4, and concentrated. The residue was purified by Prep-TLC (n-Hexane:EtoAc:MeOH=6:3:1) to give 2-[2-(4-tert-butyl-phenoxy)-acetylamino]-isonicotinamide as a white solid (53.6 mg, 56.5% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[C:14]([CH3:21])=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[C:23]1([CH:29]2[CH2:34][C:33](=O)[O:32][C:30]2=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1.C(OC(=O)C)(=O)C>[CH3:1][C:2]1([CH3:22])[CH:6]([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[C:5]2[C:14]([CH3:21])=[C:15]([N:20]3[C:33](=[O:32])[CH2:34][CH:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:30]3=[O:31])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1
Reactant: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Reactant: O=C1CC(c2ccccc2)C(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(C2c3c(C)c(N4C(=O)CC(c5ccccc5)C4=O)c(C)c(C)c3OC2(C)C)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A solution of 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine (2.95 g, 10 mmol) and phenylsuccinic anhydride (1.94 g, 11 mmol) in toluene was refluxed for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. A mixture of the residue and sodium acetate (0.86 g, 10.5 mmol) in acetic anhydride (60 ml) was stirred at 90° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and removed under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate−4/1) to obtain 2.27 g (yield 50%) of the title compound. mp. 130–131° C. low polarity product, 1H-NMR (CDCl3) δ: 1.00 (3H, s)=1.52 (3H, s), 1.64 (3H, s), 2.02 (3H, s), 2.16 (3H, s), 2.30 (3H, s), 3.00 (1H, dd, J=4.7, 18.5 Hz), 3.36 (1H, dd, J=9.5, 18.5 Hz), 4.15–4.25 (2H, m), 6.85 (2H, br), 7.06 (2H, brd, J=6.6 Hz), 7.30–7.47 (5H, m).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH:12]([NH2:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1CCCCC1>[CH2:10]([O:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:25][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:11]
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCCCCBr
Solvent: C1CCCCC1
Product: CCOC(=O)CCCCCNC(c1ccccc1)c1ccccc1
Yield: 69.2 %

Procedure:
22.3 g of ethyl 6-bromocaproate, 55 g of benzhydrylamine and 30 ml of cyclohexane are stirred at room temperature for 20 days. Preparation analogously to Example 19 yields 22.5 g (69% of theory) of ethyl-6-benzhydrylaminocaproate [B.P. 162° to 167° (0.02 mm Hg)].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:27]([O:28][CH3:29])=[CH:26][C:6]2[S:7][C:8](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:5]=2[CH:4]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[C:27]([O:28][CH3:29])=[CH:26][C:6]2[S:7][C:8]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:5]=2[CH:4]=1
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1sc2cc(OC)c(OC)cc2c1Oc1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1sc2cc(OC)c(OC)cc2c1Oc1ccc(OC)cc1

Procedure:
A solution containing 0.8 mmol of the product obtained in Example 9 in 20 ml of methanol, and 0.2 g of 10% Pd/C is maintained at 40° C. for 24 hours under a stream of hydrogen. Filtration and concentration under reduced pressure and chromatography over silica gel (cyclohexane/ethyl acetate: 80/20) enable the expected product to be isolated.