Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7]1)=[O:5])[CH3:2]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1CCNC1
Yield: 99.4 %

Procedure:
Palladium hydroxide on carbon (10% by weight, 32 g) was added to a solution of 1-benzyl-pyrrolidine-3-carboxylic acid ethyl ester (320 g, 1.37 mol) in ethanol (3000 mL) and hydrogenated (40 psi, 60° C.) for 16 hours. The reaction mixture was filtered through Arbocel™ then the filtrate was concentrated under reduced pressure to afford the title compound as a brown oil (195 g, 99%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1.[H-].[Na+].C(OCC)(=O)CC([O-])=O.[CH2:23]([O:25][C:26](=[O:45])[CH:27]([C:35]1[C:40]([N+:41]([O-:43])=[O:42])=[CH:39][CH:38]=[C:37](Cl)[N:36]=1)[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH3:24].C([O-])(=O)CC([O-])=O>C1COCC1>[CH2:23]([O:25][C:26](=[O:45])[CH:27]([C:35]1[C:40]([N+:41]([O-:43])=[O:42])=[CH:39][CH:38]=[C:37]([O:11][CH:8]2[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:10][CH2:9]2)[N:36]=1)[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH3:24]
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1nc(Cl)ccc1[N+](=O)[O-]
Reactant: COCCN1CCC(O)CC1
Agent: CCOC(=O)CC(=O)[O-]
Agent: O=C([O-])CC(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OC(C)(C)C)c1nc(OC2CCN(CCOC)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.2 %

Procedure:
To a solution of 1-(2-Methoxy-ethyl)-piperidin-4-ol (5.74 mmol) in THF (20 mL) was added NaH (11.6 mmol). Note: excess NaH was added due to excess tButyl ethyl malonate carried over from 2a. The solution was agitated for 10 minutes. A solution of 2a/2b/malonate (5.15 mmol, corrected for assay) in THF (20 mL) was rapidly added to the first solution. The resulting solution was agitated at 30° C. for 18 hours, then at 55° C. for 2 hours. After allowing to cool to room temperature, the solution was quenched with water (400 μL), dried over Na2SO4 and concentrated in vacuo yielding a yellow oil which was purified by flash chromatography (silica, Gradient system: 1. Ethyl acetate, 2. 10% Methanol in Ethyl acetate). Upon concentration a yellow oil 3 (1.096 g, 45.2% yield) with an isomeric ratio of 3.3:1 was obtained.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17](Cl)=[O:18].Cl.[C:21]1([C:27]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:35]3[CH:31]([CH2:32][NH:33][CH2:34]3)[C:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])([OH:36])[CH:29]([OH:45])[CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:46]1([C:27]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:35]3[CH:31]([CH2:32][N:33]([C:17](=[O:18])[CH2:16][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[O:9][CH3:8])[CH2:34]3)[C:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])([OH:36])[CH:29]([OH:45])[CH2:28]2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: COc1ccccc1CC(=O)Cl
Reactant: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CNCC21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CC(=O)N1CC2C(C1)C(O)(c1ccccc1OC)C(O)CC2(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
4.2 cm3 of triethylamine and then 2.4 g of (2-methoxyphenyl)-acetyl chloride in 50 cm3 of methylene chloride are added to a solution of 4.5 g of (3aRS, 4RS, 5RS, 7aRS )-7,7-diphenyl-4-(2-methoxyphenyl)-perhydroisoindole-4,5-diol hydrochloride in 100 cm3 of methylene chloride, cooled to 0° C. The reaction mixture is stirred at room temperature for 90 minutes; it is washed with twice 10 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid which has crystallised out is taken up in 100 cm3 of diisopropyl ether and then filtered off and washed with 50 cm3 of a saturated solution of sodium bicarbonate and then 50 cm3 of diisopropyl ether. 4.35 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)-acetyl]-perhydroisoindole-4,5-diol are obtained in the form of a light beige solid which melts at 278° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.Cl.[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH2:20])[CH3:16]>>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][N:20]1[C:11](=[O:13])[C:4]2[C:5](=[CH:9][CH:10]=[C:2]([OH:1])[CH:3]=2)[C:6]1=[O:8])[CH3:16]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Agent: Cl
Product: CCOC(=O)CN1C(=O)c2ccc(O)cc2C1=O

Procedure:
Prepared in analogy to example D-100 c) from 4-hydroxy-phthalic acid and glycine ethyl ester HCl salt. 1H NMR (200 MHz, DMSO-d6) δ 11.0 (br s, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.17 (m, 2H), 4.35 (s, 2H), 4.13 (q, J=7.0 Hz, 2H), 1.20 (t, J=7.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[CH:15]=[C:16]([Cl:30])[C:17]([CH3:29])=[C:18]([C:27]#[N:28])[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:30][C:16]1[C:17]([CH3:29])=[C:18]([C:27]#[N:28])[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:15]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1C#N
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c1C#N
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (41 mg, 0.21 mmol), 6-(1-aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-carbonitrile (50 mg, 0.2 mmol), and N,N-diisopropylethylamine (0.060 mL, 0.35 mmol) in isopropyl alcohol (0.7 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C21H17ClFN6 (M+H)+: m/z=407.1. found: 407.1.
Reaction SMILES: C([CH:11]([C:13]([NH:15][CH2:16][CH:17]1[O:31][C:20]2=[C:21]3[C:26](=[C:27]([CH3:29])[CH:28]=[C:19]2[CH2:18]1)[NH:25][C:24](=[O:30])[CH:23]=[CH:22]3)=[O:14])[NH2:12])(OCC1C=CC=CC=1)=O.[H][H].CCOCC>CN(C)C=O.CO.Cl.O1CCOCC1.[Pd]>[NH2:12][CH2:11][C:13]([NH:15][CH2:16][CH:17]1[O:31][C:20]2=[C:21]3[C:26](=[C:27]([CH3:29])[CH:28]=[C:19]2[CH2:18]1)[NH:25][C:24](=[O:30])[CH:23]=[CH:22]3)=[O:14]
Reactant: [H][H]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)C(N)C(=O)OCc1ccccc1)C2
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)CN)C2
Yield: 106.2 %

Procedure:
2-Carbobenzyloxyglycylaminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (2.00 g, 4.75 mmol) was dissolved in dimethylformamide (250 ml). To the obtained solution, 10% palladium-on-carbon (2.00 g) was added, followed by stirring at room temperature for 3 hours in the atmosphere of hydrogen. The reaction mixture was filtered, and the filtrate was condensed under reduced pressure. The resultant residue was dissolved in methanol (20 ml), to which 4N-HCl/dioxane (1.2 ml) was added, and the mixture was condensed under reduced pressure at room temperature. The resultant residue was submitted to a recrystallizing procedure using methanol--ether to obtain 1.45 g of the title compound as pale yellow powdery crystals (94.6%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:19][CH2:18]2)[N:11]=3)=[C:4]([F:26])[CH:3]=1.Cl.[NH2:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:26][C:4]1[CH:3]=[C:2]([NH:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:7]=[CH:6][C:5]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2
Reactant: CC(C)(C)OC(=O)CCN
Reactant: Fc1cc(Br)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCNc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-(4-bromo-2-fluorophenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (76.8 mg, 0.181 mmol), tert-butyl 3-aminopropanoate hydrochloride (43 mg, 0.235 mmol), Pd2(dba)3 (4.1 mg, 4.5 μmol), Xantphos (10 mg, 18 μmol) and sodium tert-butoxide (45 mg, 0.469 mmol) in toluene (1.9 mL) was heated under argon at 80° C. for 18 h, then at 130° C. (microwave) for 30 min, then at 150° C. (microwave) for 30 min. The reaction mixture was then cooled to 25° C. and concentrated onto silica gel. Chromatographic purification (silica gel, 0-50% EtOAc/hexanes) furnished tert-butyl 3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenylamino)-propanoate as a yellow solid. MS (ESI) m/z: Calculated: 489.2; Observed: 490.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][N:19]([CH3:35])[C@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=O)=[O:26])[CH2:21]1>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:28]2[NH:29][C:30]([CH3:32])=[CH:31][C:27]=2[C:25]([N:22]2[CH2:23][CH2:24][C@H:20]([N:19]([CH3:18])[CH3:35])[CH2:21]2)=[O:26])[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Reactant: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 59 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 025 mmol) and 3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(3-Chloro-phenyl)-3-[3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl)5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (70 mg, 59%).
Reaction SMILES: [ClH:1].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13](=[O:58])[C@@H:14]2[CH2:18][C@@H:17]([NH:19][C:20](=O)[C@H:21]([OH:30])[CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][N:15]2[C:32](=[O:57])[C@@H:33]2[CH2:37][C@@H:36]([NH:38]C(=O)CNC(OC(C)(C)C)=O)[CH2:35][N:34]2C(OC(C)(C)C)=O)[CH:3]=1.CO>O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13](=[O:58])[C@@H:14]2[CH2:18][C@@H:17]([NH:19][CH2:20][C@H:21]([OH:30])[CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][N:15]2[C:32](=[O:57])[C@@H:33]2[CH2:37][C@@H:36]([NH2:38])[CH2:35][NH:34]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)N2C[C@H](NC(=O)[C@H](O)CCc3ccccc3)C[C@H]2C(=O)Nc2cnc3ccccc3c2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@H]1CN[C@H](C(=O)N2C[C@H](NC[C@H](O)CCc3ccccc3)C[C@H]2C(=O)Nc2cnc3ccccc3c2)C1
Reaction time: 2 h

Procedure:
A solution of 4 N hydrochloric acid in 1,4-dioxane (4 mL) was added to N-tert-butoxycarbonyl-trans-4-(N-tert-butoxycarbonylglycylamino)-L-prolyl-trans-4-((R)-2-hydroxy-4-phenylbutyrylamino)-L-proline 3-quinolylamide (P, 90 mg) at 0° C., and methanol was added until insoluble materials were disappeared. After stirring for 2 hr, the reaction mixture was evaporated and coevaporated several times with hexane and ethanol in vacuo to give pale yellow solids. The solids were washed with ether to afford the title compound (62 mg) as a colorless solid: 1H-NMR (400 MHz, D2O) δ 1.86-2.03(m, 2H), 2.28-2.47(m, 2H), 2.53-2.69(m, 4H), 3.42-3.50(m, 1H), 3.58-3.66(m, 1H), 3.86-3.94(m, 2H), 4.03-4.14(m, 2H), 4.38-4.46(m, 1H), 4.76-4.83(m, 1H), 4.87-4.94(m, 1H), 7.11-7.29(m, 5H), 7.78-7.84(m, 1H), 7.91-7.98(m,1H), 8.04-8.12(m, 2H), 8.91-8.94(m, 1H), and 9.03-9.28(m, 1H):; IR (KBr) 3300, 3023, 2937, 2852, 1701, 1657, 1651, 1610, 1574, 1549, 1495, 1485, and 1454 cm−1; mass spectrum (FAB+) m/e 531 (M+1); Anal. Calcd for C29H34 N6O4.3HCl.3H2O, C; 50.18, H; 6.24, N; 12.10. Found: C; 50.45, H; 6.15, N; 11.28.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH2:7].Cl[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[N:10]=1.C(OCC)(=O)C.O>CN(C)C=O.C(N(CC)CC)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH:7][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[N:10]=1
Reactant: NCC1OCCO1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(NCC2OCCO2)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 1.1 g of 1-(1,3-dioxolan-2-yl)methanamine in 10 mL of N,N-dimethylformamide, 1.6 mL of triethylamine and 2.0 g of 2-chloro-6-methoxy-3-nitropyridine were added at room temperature, and the mixture was stirred at 55 to 65° C. for 1 hour. The reaction mixture was cooled to room temperature, and ethyl acetate and water were then added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2.7 g of N-(1,3-dioxolan-2-ylmethyl)-6-methoxy-3-nitropyridin-2-amine as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[CH:5]([C:15]1[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])[C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1.OO>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[C:5]1([C:6]2[CH:7]=[CH:8][C:9]([N:12]([CH3:14])[CH3:13])=[CH:10][CH:11]=2)[C:15]2[C:16](=[CH:20][C:21]([N:24]([CH3:26])[CH3:25])=[CH:22][CH:23]=2)[C:17](=[O:19])[O:18]1
Reactant: COc1ccccc1C(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1C(=O)O
Agent: OO
Product: COc1ccccc1C1(c2ccc(N(C)C)cc2)OC(=O)c2cc(N(C)C)ccc21
Yield: 17.3 %

Procedure:
Employing a procedure similar to that described in Example 27, part B above, 6.1 g of 2-(2-methoxy-4'-dimethylaminobenzhydryl)-5-dimethylaminobenzoic acid was oxidized with hydrogen peroxide to obtain 1.05 g of 3-(2-methoxyphenyl)-3-(4-dimethylaminophenyl)-6-dimethylaminophthalide (Formula I: R=CH3 ; X=H; Y=2-CH3OC6H4 ; Z=4-(CH3)2NC6H4), a light yellow-colored solid which melted at 215°-216° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]1[CH2:18][O:17][S:14](=[O:16])(=[O:15])[CH2:13][CH2:12]1>>[S:14]([CH2:13][CH2:12][CH2:11][CH2:18][C:7]1[C:5]2[N:6]=[C:2]([CH3:1])[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1)([OH:17])(=[O:16])=[O:15]
Reactant: Cc1nc2ccccc2s1
Reactant: O=S1(=O)CCCCO1
Product: Cc1nc2c(CCCCS(=O)(=O)O)cccc2s1
Temperature: 135 °C
Yield: 98.1 %

Procedure:
A mixture of 2-methylbenzothiazole (1.49 g, 10 mmol) and 1,4-butane sultone (4.0 g, 30 mmol) was heated in a pressure tube at 130-140° C. for 3 hours. The mixture was allowed to cool to room temperature, and the resulting mass was triturated with ethyl acetate (50 ml) until a gray solid separated. The solid was collected by centrifugation, washed with ethyl acetate and dried under vacuum to yield 2.8 g (96%) of Compound 1.
Reaction SMILES: [CH2:1]([N:5]([CH2:27][CH2:28][CH2:29][CH3:30])[C:6]([C:8]1[N:9]=[C:10]([C:14]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:15]=2[C:16](O)=[O:17])[N:11]([CH3:13])[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[N:31]([CH2:34][C@@H:35]1[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][NH:36]1)=[N+:32]=[N-:33]>>[N:31]([CH2:34][C@@H:35]1[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][N:36]1[C:16]([C:15]1[CH:19]=[C:20]([CH:21]=[CH:22][C:14]=1[C:10]1[N:11]([CH3:13])[CH:12]=[C:8]([C:6](=[O:7])[N:5]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:1][CH2:2][CH2:3][CH3:4])[N:9]=1)[C:23]([O:25][CH3:26])=[O:24])=[O:17])=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=NC[C@@H]1Cc2ccccc2CN1
Reactant: CCCCN(CCCC)C(=O)c1cn(C)c(-c2ccc(C(=O)OC)cc2C(=O)O)n1
Product: CCCCN(CCCC)C(=O)c1cn(C)c(-c2ccc(C(=O)OC)cc2C(=O)N2Cc3ccccc3C[C@H]2CN=[N+]=[N-])n1
Yield: 86.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 271H, 2-(4-(dibutylcarbamoyl)-1-methyl-1H-imidazol-2-yl)-5-(methoxycarbonyl)benzoic acid (230 mg, 0.55 mmol) and (S)-3-(azidomethyl)-1,2,3,4-tetrahydroisoquinoline (135 mg, 0.72 mmol) were converted to the title compound (280 mg, 91%). MS(ESI+) m/z 586.2 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5](=O)[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:8]=1.O=P(Cl)(Cl)[Cl:27].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:27][C:5]1[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:8]=[C:3]([S:2][CH3:1])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ncc(-c2ccnc(Nc3ccc(C#N)cc3)n2)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CSc1ncc(-c2ccnc(Nc3ccc(C#N)cc3)n2)c(Cl)n1
Temperature: 120 °C
Yield: 58 %

Procedure:
4-(4-(2-(Methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl)pyrimidin-2-ylamino)benzonitrile (34) (700 mg, 2.081 mmol) was dissolved in POCl3 (1940 μl, 20.81 mmol), then the reaction mixture was heated at 120° C. for 3 hours. The reaction mixture was cooled to rt, then was slowly poured into an ice-cooled saturated Na2CO3 solution while stirring vigorously. The reaction mixture was then adjusted to pH 7 with additional Na2CO3 solution. DCM was added to the mixture and the aqueous layer was extracted twice with DCM. The organic extracts were combined, washed with brine, dried over sodium sulfate, then concentrated in vacuo to obtain the desired product as a bright yellow solid (428 mg, 53% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.62 (s, 3H) 7.39 (d, J=5.05 Hz, 1H) 7.74 (m, 2H) 8.00 (m, J=9.09 Hz, 2H) 8.69-8.80 (m, 1H) 8.93 (s, 1H) 10.42 (s, 1H). MS (ES+): m/z=355.3 (100) [MH+]. HPLC: tR=1.57 minutes over 3 minutes. Purity: 91% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[S:12][C:13]([CH3:18])([CH2:15][CH2:16]Cl)[CH3:14])[C:5]([O:7][CH3:8])=[O:6].[I-].[Na+]>CC(=O)CC>[CH3:14][C:13]1([CH3:18])[S:12][C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[NH:1][CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(SC(C)(C)CCCl)c(N)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc2c(c1)NCCC(C)(C)S2
Temperature: 70 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
To a solution of methyl 3-amino-4-(4-chloro-2-methylbutan-2-ylthio)benzoate (3.11 g, 10.8 mmol) in 2-butanone (150 mL) was added sodium iodide (4.86 g, 32.4 mmol). The reaction was heated to 70° C. and stirred at that temperature for 16 hours. Thin layer chromatography and LCMS analysis of the reaction mixture indicated consumption of starting material. The solvent was removed under reduced pressure and the resulting red slurry was diluted with EtOAc (200 mL). The organic layer was washed with saturated aqueous NaHCO3 (100 mL) and aqueous sodium hydrosulifte (50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting solid was purified by flash column chromatography using a gradient elution of hexanes with 5-70% EtOAc to provide methyl 2,2-dimethyl-2,3,4,5-tetrahydrobenzo-[b][1,4]thiazepine-7-carboxylate (1.82 g, 7.24 mmol, 67.0% yield) as an off white solid. LCMS (+ESI) m/z=252.1 [M+H]+; 1H-NMR (CDCl3) δ 7.48-7.40 (m, 3H), 4.25-4.06 (br s, 1H), 3.88 (s, 3H), 3.25 (m, 2H), 2.00 (m, 2H), 1.33 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([CH3:24])=[CH:9][C:10]1[S:14][C:13]([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[N:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([CH:8]([CH3:24])[CH2:9][C:10]1[S:14][C:13]([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])=[N:12][CH:11]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(=Cc1cnc(CO[Si](C)(C)C(C)(C)C)s1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(Cc1cnc(CO[Si](C)(C)C(C)(C)C)s1)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 20 h
Yield: 57.7 %

Procedure:
The compound (0.5 g, 1.4 mmol) obtained in step 3 was dissolved in ethanol (20 ml), palladium/carbon (0.1 g) was added, and the mixture was stirred at 50° C. for 20 hours under a hydrogen atmosphere (55 psi). The reaction mixture was filtered, and the solvent was evaporated under reduced pressure to give the title compound (0.3 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(N(CC)CC)C.Br[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:35](=[O:36])[O:34]1.[I-].[Na+]>CN(C)C=O.O.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O:22][CH:33]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:35](=[O:36])[O:34]4)=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(N)n3)[C@H]2SC1
Reactant: O=C1OC(Br)c2ccccc21
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC1=C(C(=O)OC2OC(=O)c3ccccc32)N2C(=O)C(NC(=O)Cc3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
To a solution of 7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (2.0 g) in N,N-dimethylformamide (15 ml) were added triethylamine (0.55 g), 3-bromophthalide (1.2 g) and sodium iodide (0.82 g) in turn in a stream of nitrogen, and the mixture was stirred at ambient temperature for half an hour. After the reaction mixture was poured into a mixture of ethyl acetate (300 ml) and water (200 ml), the organic layer was separated out, washed with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate, followed by treating with charcoal. After the filtrate was concentrated and thereto was added diethyl ether. The precipitated substance was collected by filtration to obtain phthalid-3-yl 7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (1.5 g).
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1.[ClH:13]>C(OCC)(=O)C>[Cl:13][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(CO)n1
Reactant: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(CCl)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the product from step (i) (2.75 g) in ethyl acetate (10 ml) was added 1M ethereal HCl (10 ml). The mixture was stirred for 10 minutes and the precipitate filtered off. This was dissolved in thionyl chloride (20 ml) at 0° C. After 2 hours the mixture was warmed to room temperature. Diethyl ether (100 ml) was added and the precipitate filtered off and used directly in the next step. Yield 1.3 g.