Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O:14][CH2:15][CH:16]([CH2:21]Br)[C:17]([CH3:20])([CH3:19])[CH3:18])(=O)C.O>CN(C)C=O>[CH2:3]([S:10][CH2:21][CH:16]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:15][OH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)OCC(CBr)C(C)(C)C
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(CO)CSCc1ccccc1
Yield: 33.7 %

Procedure:
Sodium hydride (2 g; 80%) was added to a stirred solution of benzyl mercaptan (9.4 g) in dry dimethylformamide (100 ml) at room temperature under a nitrogen atmosphere. The resulting mixture was heated at reflux for 1 hour when a solution of 2-bromomethyl -3,3-dimethylbutyl acetate (13.3 g) in DMF (10 ml) was added. After a further hour at reflux, the mixture was allowed to cool and then poured into water (300 ml). The aqueous mixture was extracted with ether and then the combined ethereal extracts were washed with water before drying over anhydrous magnesium sulphate and evaporation in vacuo. The resulting residue was taken up in a mixture of 10% aqueous potassium hydroxide and ethanol (1:1, 50 ml) and heated to reflux for 1 hour. After cooling, the aqueous solution was exhaustively extracted with ether. The combined ethereal extracts were dried over anhydrous magnesium sulphate and then evaporated in vacuo. The residue was purified by column chromatography on silica. Gradient elution with hexane/diethylether mixtures gave 2-benzylthiomethyl-3,3-dimethylbutanol as an oil (4.5 g).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH:15]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:16][O:17][CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=2)[CH2:11][CH2:10]1)C.C(O)C.[OH-].[Na+].Cl>O>[F:28][C:25]([F:26])([F:27])[C:23]1[CH:24]=[C:19]([CH:20]=[C:21]([C:29]([F:30])([F:31])[F:32])[CH:22]=1)[CH2:18][O:17][CH2:16][CH:15]([N:12]1[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:39])=[O:3])[CH2:14][CH2:13]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)CCCCN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 75.1 %

Procedure:
In a round-bottomed flask fitted with a reflux condenser and a thermometer 2.48 g (4 mmoles) of 5-{4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazin-1-yl}-pentanoic acid ethyl ester (compound 140 prepared at example 1.4.1 above), 45 ml of ethyl alcohol, 4 ml of water, and 6.6 ml of a 1N solution of sodium hydroxide in water were introduced. The mixture was stirred at room temperature for 22 hours, and 6.6 ml of a 1N solution of hydrochloric acid in water was added. The volatile substances were removed under reduced pressure, water and methylene chloride were added, the aqueous layer was extracted with methylene chloride, and the combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 35 ml of methylene chloride, 3.96 ml of a 1.96 N solution of hydrochloric acid in diethyl ether were added, and the volatile substances were removed under reduced pressure. The residue was recristallized from acetonitrile, affording 1.6 g of 5-{4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazin-1-yl}-pentanoic acid (compound 233) as a solid. Yield: 61%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10]([S:12][CH3:13])[N:9]=[C:8]([NH2:14])[N:7]=1.[I:15]N1C(=O)CCC1=O>C(O)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:15])=[C:10]([S:12][CH3:13])[N:9]=[C:8]([NH2:14])[N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CSc1cc(-c2ccco2)nc(N)n1
Solvent: CC(=O)O
Product: CSc1nc(N)nc(-c2ccco2)c1I

Procedure:
From 4-furan-2-yl-6-methylsulfanyl-pyrimidin-2-ylamine and N-iodosuccinimide in acetic acid. EI-MS m/e (%): 333 (M+, 66), 206 ([M—I]+, 100), 118 (44).
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[CH:20])[C:11](Cl)=[O:12].[CH:21]1([CH2:27][NH2:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(N(CC)CC)C>[CH:21]1([CH2:27][NH:28][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]#[CH:20])=[C:8]([O:7][CH3:6])[CH:9]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NCC1CCCCC1
Reactant: C#CCOc1ccc(C(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCOc1ccc(C(=O)NCC2CCCCC2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a mixture of 10 ml of THF and 0.20 g of 3-methoxy-4-(2-propynyloxy)benzoyl chloride were added dropwise 0.22 g of cyclohexylmethylamine and 0.20 g of triethylamine in order under ice cooling The mixture obtained was stirred at room temperature for 4 hours. Then, the reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.22 g of N-cyclohexylmethyl-4-(2-propynyloxy)-3-methoxybenzamide (hereinafter, described as the compound 17 of the present invention) represented by the formula:
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[CH2:7]([O:9][CH:10]([O:13][CH2:14][CH3:15])[CH2:11]Br)[CH3:8].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[CH2:7]([O:9][CH:10]([O:13][CH2:14][CH3:15])[CH2:11][N:5]1[CH:6]=[C:2]([I:1])[N:3]=[CH:4]1)[CH3:8]
Reactant: CCOC(CBr)OCC
Reactant: Ic1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(Cn1cnc(I)c1)OCC
Temperature: 110 °C
Yield: 71 %

Procedure:
To a stirred solution of 4-iodoimidazole (10 g, 51.6 mmol) and bromoacetaldehyde diethyl acetal (9.31 mL) in DMSO (30 mL) was added K2CO3 (10.69 g, 77 mmol). The reaction mixture was heated at 110° C. for 16 h. After cooling to RT, the reaction mixture was diluted with water and extracted with AcOEt. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 80 g cartridge; AcOEt/Hex:0/100 to 50/50 over 20 CV). The desired fractions were collected and concentrated to afford title compound 260 (11.29 g, 36.4 mmol, 71% yield) as yellow oil. MS (m/z): 310.97 (M+H).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13](Cl)[C:8]=2[C@H:7]([CH3:15])[CH2:6]1)(=[O:3])[CH3:2].[CH3:16][C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1>CN1C(=O)CCC1.C(OCC)(=O)C>[C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:22]3[CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][C@@H:17]3[CH3:16])[C:8]=2[C@H:7]([CH3:15])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C[C@@H](C)c2c(Cl)ncnc21
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(=O)OC1C[C@@H](C)c2c1ncnc2N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Temperature: 125 °C
Yield: 60.1 %

Procedure:
To a solution of (5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl acetate (0.75 g, 3.3 mmol) in NMP (10 mL) was added (S)-tert-butyl 3-methylpiperazine-1-carboxylate (1.0 g, 5.0 mmol). The mixture was heated to 125° C. for 60 hours. After cooling, the mixture was diluted with ethyl acetate (200 mL) and washed with water (6×100 mL). The organic phase was dried and concentrated. The residue was purified by silica gel chromatography, eluting with ethyl acetate to give (S)-tert-butyl 4-((5R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.775 g, 60%). 1H NMR (CDCl3, 400 MHz) δ 8.60-8.59 (d, 1H), 6.07-5.89 (m, 1H), 4.73-4.60 (m, 1H), 4.30-3.80 (m, 3H), 3.60-3.35 (m, 1H), 3.22 (m, 1H), 3.02 (br, 1H), 2.78 (m, 1H), 2.35-1.60 (m, 5H), 1.49 (s, 9H), 1.32-1.20 (m, 6H). MS (APCI+) [M+H] +391. The resulting mixture of diastereomers was purified by chiral separation by HPLC (Chiralcel ODH column, 250×20 mm, 15 mL/min, Hexane/EtOH 50:50). The first peak (RT=3.864 min) gave (S)-tert-butyl 4-((5R,7R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.281 g, 36%) and the second peak (RT=5.064 min) gave (S)-tert-butyl 4-((5R,7S)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.389 g, 50%). Treatment of the (S)-tert-butyl 4-((5R,7R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate with HCl in dioxane (4M, 2 ml) gave the (5R,7R)-5-methyl-4-((S)-2-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride in quantitative yield.
Reaction SMILES: [NH2:1][C@@H:2]1[C:25](=[O:26])[N:4]2[C:5]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:14])=[C:6]([CH2:9][N:10]=[N+:11]=[N-:12])[CH2:7]S[C@H:3]12.OO.[S:29]([O-:32])([O-])=[O:30].[Na+].[Na+]>C(OCC)(=O)C.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[NH2:1][C@@H:2]1[C:25](=[O:26])[N:4]2[C:5]([C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[O:14])=[C:6]([CH2:9][N:10]=[N+:11]=[N-:12])[CH2:7][S:29](=[O:32])(=[O:30])[C@H:3]12
Reactant: O=S([O-])[O-]
Reactant: COc1ccc(COC(=O)C2=C(CN=[N+]=[N-])CS[C@@H]3[C@H](N)C(=O)N23)cc1
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)C2=C(CN=[N+]=[N-])CS(=O)(=O)[C@@H]3[C@H](N)C(=O)N23)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
p-Methoxybenzyl 7β-amino-3-azidomethyl-3-cephem-4-carboxylate (17.15 g, 0.046 mol) in ethyl acetate was cooled to 15° C., sodium tungstate dihydrate (1.52 g, 0.0046 mol) was added followed by hydrogen peroxide (30%, 20.73 ml) in one portion and the stirring was continued at room temperature. After two hours an additional portion of hydrogen peroxide (5.18 ml) was added and the reaction mixture was stirred at room temperature for a total period of 18 h; the mixture was cooled to 10° C. and a solution of sodium sulphite (10%, 600 ml) was added while stirring. Organic layer was separated out, washed with aq. sodium bicarbonate solution, brine and dried (Na2SO4). Evaporation of the solvent in vacuo gave a foam (12 g) which was purified over a silica column using hexane-ethyl acetate (1:3) as eluant to give the pure product as a white foam (6.8 g, 36.5%). IR (Nujol) ν max 2083 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:40][S:41]([CH2:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:43])=[O:42]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:50]3[CH2:51][CH2:52][N:47]([CH2:46][CH2:45][CH2:44][S:41]([CH3:40])(=[O:42])=[O:43])[CH2:48][CH2:49]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(S(C)(=O)=O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(S(C)(=O)=O)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methanesulfonyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide) gave the title compound. HR-MS (ES, m/z) calculated for C35H43N4O6S2Cl2 [(M+H)+] 749.1996, observed 749.1995.
Reaction SMILES: C(OC([N:8]([C:19]1[CH:20]=[C:21]([CH:25]([CH2:29][P:30]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([OH:32])=[O:31])[C:26]([OH:28])=[O:27])[CH:22]=[CH:23][CH:24]=1)[C:9]([NH2:18])=[N:10]C(OC(C)(C)C)=O)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]([C:19]1[CH:20]=[C:21]([CH:25]([CH2:29][P:30]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([OH:32])=[O:31])[C:26]([OH:28])=[O:27])[CH:22]=[CH:23][CH:24]=1)[C:9]([NH2:18])=[NH:10]
Reactant: CC(C)(C)OC(=O)N=C(N)N(C(=O)OC(C)(C)C)c1cccc(C(CP(=O)(O)CCCCc2ccccc2)C(=O)O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)Nc1cccc(C(CP(=O)(O)CCCCc2ccccc2)C(=O)O)c1
Reaction time: 1.5 h

Procedure:
2-(3-(N,N′-di(t-Butoxycarbonyl)guanidino)phenyl)-3-((4-phenylbutyl)-(hydroxy)phosphinoyl)propanoic acid was dissolved in 9 mL 2:1 methylene chloride:TFA. After 1.5 hours, the reaction mixture was concentrated and purified by prep HPLC to afford 2-(3-guanidinophenyl)-3-((4-phenylbutyl)(hydroxy)-phosphinoyl)propanoic acid, NMR (DMSO-d6) 1.25-1.60 (m, 6), 2.00 (m, 1), 2.40-2.50 (m, 2), 3.85 (m, 1), 7.0-7.45 (m, 9) ppm, (2.9 mg),
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23](O)=O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>N1C=CC=CC=1.CCOC(C)=O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[N:9]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1ccc(F)cc1N
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(F)ccc3[nH]2)CC1
Temperature: 25 °C
Yield: 32 %

Procedure:
This compound is synthesized as described by adaptation of the following reference: Lin et al, Tetrahedron Lett., 2006, 47, 17, 2883. To a stirred mixture of 4-fluorobenzene-1,2-diamine (1.0 g, 7.93 mmol) and 1-[(tert-butoxy)carbonyl]piperidine-4-carboxylic acid (1.82 g, 7.93 mmol) in pyridine (4 mL) is added triphenyl phosphite (2.49 mL, 9.51 mmol). The reaction mixture is heated under reflux for 18 h. The reaction mixture is cooled to room temperature and diluted with EtOAc (40 mL). The solution is washed with 1M aqueous HCl (8 mL) followed by saturated aqueous NaHCO3 (8 mL) and water (5 mL) to give an oily residue. The crude product is purified by column chromatography (Isolute column, eluent: DCM, 3% MeOH) to afford 0.81 g of tert-butyl-4-(5-fluoro-1H-1,3-benzodiazol-2-yl)piperidine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=[O:12])[N:6]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:5]2=[O:20].[CH3:21][N:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](Cl)=[O:24]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[CH:15][C:16]([O:19][C:23](=[O:24])[N:22]([CH3:21])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:17][CH:18]=1)[C:5]2=[O:20]
Reactant: O=C1c2cc(Cl)c(Cl)cc2C(=O)N1c1ccc(O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(N2C(=O)c3cc(Cl)c(Cl)cc3C2=O)cc1)c1ccccc1

Procedure:
The title product was prepared from 5,6-dichloro-2-(4-hydroxy-phenyl)-isoindole-1,3-dione and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (2%,). HPLC-MS: m/z=441.1 (M+1); Rt: 5.00 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[F:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[F:13][C:14]1[CH:15]=[C:16]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cccc(F)c2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 3-fluorobenzenesulfonyl chloride according to METHOD A, giving 0.55 g (80%) of a pink powder: MS (electrospray, [M−H]−) m/z 343.1
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH2:21]>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[N:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: N#Cc1cnc2ncc([N+](=O)[O-])cc2c1Cl
Product: N#Cc1cnc2ncc([N+](=O)[O-])cc2c1Nc1ccc(F)c(Cl)c1
Yield: 95.8 %

Procedure:
By using the method of Example 21, 2.5 g (10.66 mmol) of 4-chloro-6-nitro-[1.8]naphthyridine-3-carbonitrile and 1.55 g (10.66 mmol) of 3-chloro-4-fluoro-aniline was converted to 3.51 g of the title compound, a yellow solid, as its hydrochloride salt: mass spectrum (electrospray, m/e): M+H 344.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:7][C:6](=[O:8])[CH:5](C)[C:4](=[O:10])[O:3]1.C(OC1NC(=O)C1)(=O)C.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH3:1][C:2]1([CH3:11])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:10])[O:3]1
Reactant: CC1C(=O)OC(C)(C)OC1=O
Agent: CC(=O)OC1CC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC1(C)OC(=O)CC(=O)O1
Temperature: 25 °C
Reaction time: 14 h
Yield: 72.9 %

Procedure:
2,2,5-trimethyl-1,3-dioxan-4,6-dione II (17.4 g, 110 mmol), 4-acetoxy-azetidinone I (28.7 g, mmol) and K2CO3 (15.2 g, 110 mmol) were mixed in dry acetonitrile (150 mL, KF=5.6 mg/mL), and the mixture was aged at 45°-50° for 14 hours. Upon completion, the reaction mixture was cooled to room temperature and water (150 mL) was added. The organic layer was separated and the aqueous layer was back extracted with acetonitrile (100 mL). Combined organic extracts were washed with brine (100 mL) and concentrated to ca. 50 mL in volume. The mixture was then diluted with heptane (200 mL) and concentrated to 50 mL. Additional heptane (150 mL) was added and the mixture was aged at room temperature for crystallization. The resulting product was collected by filtration, washed with heptane (50 mL) and dried under vacuum at 40-50 for 15 hours to give an off-white crystalline solid (30.9 g, 80.2 mmol). A second crop was obtained by concentrating the combined filtrate and washed to ca. 50 mL in and aging at room temperature to give a white, fluffy solid (2.07 g, 5.4 mmol). Combined yield was 85.6%. Melting Range (° C.) 78-83 d.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[C:8]([O:12][C:13]([N:15]1[CH2:21][CH2:20][CH2:19][C@H:16]1[CH:17]=[O:18])=[O:14])([CH3:11])([CH3:10])[CH3:9]>CS(C)=O.C1COCC1>[C:8]([O:12][C:13]([N:15]1[CH2:21][CH2:20][CH2:19][C@H:16]1[CH:17]1[O:18][CH2:4]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: C[S+](C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
DMSO (20 ml) was added to sodium hydride (1.55 g, NaH content 60%), and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was cooled to room temperature and THF (20 ml) was added. The mixture was cooled to -5° C., and thereto was dropwise added a solution of trimethylsulfonium iodide (7.90 g) in DMSO (30 ml) over 3 minutes. After stirring for 1 minute, a solution of tert-butoxycarbonyl-L-prolinal (5.13 g) in THF (15 ml) was added quickly, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into ice-water (300 ml), and extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluate: hexane-ethyl acetate) to give two diastereomers of the title compound, 3.12 g of its less polar compound and 1.28 g of its more polar compound. (Configuration of the epoxy moiety of the both has not been identified.) The less polar compound was used in the following reactions.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=2)[N:13]=[CH:12][C:11]=1[C:22]([OH:24])=[O:23].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=2)[N:13]=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: COc1ccc2ncc(C(=O)O)c(Cl)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ncc(C(=O)O)c(OCc3ccccc3)c2n1
Temperature: -40 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
Benzyl alcohol (5.78 g, 53.43 mmol, 2.5 eq) is added at −45° C. to a stirred solution of 4-chloro-6-methoxy-[1,5]naphthyridine-3-carboxylic acid (5.1 g, 21.37 mmol, 1.0 eq) in N,N-dimethylformamide (100 mL), followed by sodium hydride (2.46 g, 53.43 mmol, 2.5 eq). After 2 hours stirring at −40° C. and 24 hours stirring at room temperature, the reaction mixture is quenched with ice water, the pH is adjusted to 3-4 by the addition of a 2N hydrochloric acid aqueous solution. The resulting precipitate is collected by filtration, washed with water and dried under high vacuum to afford 4-benzyloxy-6-methoxy-[1,5]naphthyridine-3-carboxylic acid as a light red solid (6.5 g, 98% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:12][C:11]3([N:16]([CH3:17])[CH2:15][CH2:14][CH2:13]3)[CH2:10]2)[C:6]([N+:18]([O-])=O)=[CH:5][C:4]=1[NH:21][C:22]1[N:27]=[C:26]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH3:37])[CH:29]=2)[CH:25]=[CH:24][N:23]=1.[NH4+].[Cl-].C(O)C>[Fe].O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:12][C:11]3([N:16]([CH3:17])[CH2:15][CH2:14][CH2:13]3)[CH2:10]2)[C:6]([NH2:18])=[CH:5][C:4]=1[NH:21][C:22]1[N:27]=[C:26]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH3:37])[CH:29]=2)[CH:25]=[CH:24][N:23]=1
Reactant: COc1cc(N2CC3(CCCN3C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CC3(CCCN3C)C2)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Yield: 76.7 %

Procedure:
A mixture of N-[2-Methoxy-4-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 147, 200 mg, 0.40 mmol), iron (134 mg, 2.40 mmol) and NH4Cl (16 mg, 0.30 mmol), ethanol (18 mL) and water (6 mL) was heated at reflux for 1 h then the mixture was allowed to cool. The mixture was then filtered and concentrated in vacuo. The resulting residue was triturated in 10% CH3OH in CH2Cl2 (15 mL) for 15 minutes and the mixture was then filtered. The residues were triturated again with 10% CH3OH in CH2Cl2 (15 mL) and the mixture then filtered. The combined filtrates were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2% 7N methanolic ammonia in CH2Cl2 gave the title compound (144 mg, 77%) as a dark green foam; 1H NMR: 1.66-1.80 (2H, m), 2.06-2.16 (2H, m), 2.42 (3H, s), 2.66 (2H, t), 3.59 (2H, d), 3.75 (3H, s), 3.83-3.91 (5H, m), 4.01 (2H, s), 6.30 (1H, s), 7.09 (1H, d), 7.16 (1H, t), 7.21-7.28 (1H, m), 7.31 (1H, s), 7.51 (1H, d), 7.70 (1H, s), 8.23 (1H, d), 8.26 (1H, s), 8.43 (1H, d); m/z: ES+ MH+ 470.7.