Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([S:23]([CH:25]5[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]5)=[O:24])[C:20]([CH3:22])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:34]=2)=[N:7][C:6]([CH3:35])=[N:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:37].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([S:23]([CH:25]5[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]5)(=[O:37])=[O:24])[C:20]([CH3:22])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:34]=2)=[N:7][C:6]([CH3:35])=[N:5]1)([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)C4CCN(C(C)C)CC4)c(C)cc2OCC3)n(C(C)C)n1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)(=O)C4CCN(C(C)C)CC4)c(C)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 44.8 %

Procedure:
To an ice-cooled solution of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-9-(1-isopropylpiperidine-4-sulfinyl)-8-methyl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene 225 (30 mg, 0.061 mmol) in DCM (3 mL) was added TFA (24 μL, 0.306 mmol) followed by a solution of m-CPBA (14 mg, 0.0796 mmol) in DCM (1 mL). The resulting mixture was stirred for 3 h at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 20-50% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH. The basic fractions were combined and concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient 3-15% MeOH in DCM) affording 243 as a white solid (14 mg, 44%). LCMS: RT 2.83 min [M+H]+ 513.1. 1H NMR (CD3OD, 400 MHz): δ 9.08 (1H, s), 7.76 (1H, s), 7.10 (1H, s), 5.93-5.80 (1H, m), 4.63-4.53 (4H, m), 3.21-3.10 (1H, m), 3.00 (2H, bd, J=11.56 Hz), 2.77-2.67 (1H, m), 2.64 (3H, s), 2.37 (3H, s), 2.24 (2H, t, J=12.17 Hz), 1.97 (2H, d, J=12.67 Hz), 1.87-1.74 (2H, m), 1.56 (6H, d, J=6.65 Hz), 1.04 (6H, d, J=6.56 Hz)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)=[O:22].O>CC(C)=O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([O:1][CH2:20][C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])=[C:3]2[C:7]=1[CH2:6][CH2:5][CH2:4]2
Reactant: O=C(CBr)c1cccs1
Reactant: COc1ccc(O)c2c1CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(OCC(=O)c2cccs2)c2c1CCC2
Reaction time: 1.5 h
Yield: 60.2 %

Procedure:
To the clear solution of 4-Hydroxy-7-methoxy indane (2.0 gm, 0.0121 mole) in Acetone (20 ml), Potassium carbonate (2.52 gm, 0.0182 mole) was added at room temperature and stirred for 1.5 hours. A solution of 2-Bromo-1-thiophene-2-yl-ethanone (3.75 gm, 0.0181 mole) in Acetone (10 ml) was added at 0° C. and stirred for 8 hours at room temperature. The reaction mixture was poured into the water (50 ml) and extracted with Ethyl acetate (2×100 ml). The Ethyl acetate layer was dried over Sodium sulphate and evaporated to give a crude product which was purified by column chromatography using 2% Ethyl acetate in hexane as a mobile phase The collected eluent was evaporated to yield desire product (2.1 gm) as an viscous oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O:19]1[CH2:24][CH2:23][N:22]([CH:25]([CH3:29])[CH2:26][CH2:27]Cl)[CH2:21][CH2:20]1>>[O:19]1[CH2:24][CH2:23][N:22]([CH:25]([CH3:29])[CH2:26][CH2:27][O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[O:5][C:4](=[O:12])[C:3]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:21][CH2:20]1
Reactant: O=c1oc2ccccc2c(O)c1-c1ccccc1
Reactant: CC(CCCl)N1CCOCC1
Product: CC(CCOc1c(-c2ccccc2)c(=O)oc2ccccc12)N1CCOCC1
Yield: 72.5 %

Procedure:
Prepared according to the method of Example 8 from 4-hydroxy-3-phenyl-coumarin and 3-morpholino-1-chlorobutane. An oil is obtained which cannot be crystallised. Yield 72.5%.
Reaction SMILES: CN(C)CCN[C:6]1[N:11]=[C:10]([O:12][C:13]2C3C(=CC=CC=3)C(NC(NC3C=C(C(F)(F)F)C=CC=3OC)=O)=CC=2)[CH:9]=[C:8](C)[N:7]=1.CO[C:43]1[CH:50]=[CH:49][C:46]([CH2:47][NH2:48])=[CH:45][CH:44]=1.C(N(CC)CC)C.C(OCC)(=O)C>CS(C)=O.O>[CH3:13][O:12][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([NH:48][CH2:47][C:46]2[CH:45]=[CH:44][CH:43]=[CH:50][CH:49]=2)[N:11]=1
Reactant: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccc(Oc2cc(C)nc(NCCN(C)C)n2)c2ccccc12
Reactant: COc1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: COc1ccnc(NCc2ccccc2)n1
Reaction time: 8 h
Yield: 56.1 %

Procedure:
(4-Boc-amino-naphthyl)-(2-chloro-6-methyl-pyrimidinyl)-ether (see Example 1) (2.00 g, 5.18 mmol), 4-methoxybenzylamine (0.69 mL, 5.18 mmol) and triethylamine (0.73 mL, 5.18 mmol) were dissolved in 10 mL DMSO in a sealed tube. The tube was sealed and placed into a 95° C. oil bath. The reaction was stirred overnight, then cooled and ethyl acetate and water were added. The aqueous layer was washed twice with EtOAc. The organic extracts were combined, washed once with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was dissolved in dichloromethane and purified by column chromatography on silica gel eluting with EtOAc/hexane, providing 0.625 g of the desired 4-methoxybenzylamino-pyrimidine intermediate as a bright yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[CH:21]=[CH:22][S:23][C:8]=2[C:7]=1Cl)=[O:5])[CH3:2].N12CCN(CC1)CC2.[N:33]1([C:39]([C:41]2[S:42][CH:43]=[CH:44][CH:45]=2)=[O:40])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[CH:21]=[CH:22][S:23][C:8]=2[C:7]=1[N:36]1[CH2:37][CH2:38][N:33]([C:39]([C:41]2[S:42][CH:43]=[CH:44][CH:45]=2)=[O:40])[CH2:34][CH2:35]1)=[O:5])[CH3:2]
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: CCOC(=O)c1c(Cl)c2sccc2n(Cc2cccc(F)c2)c1=O
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2sccc2n(Cc2cccc(F)c2)c1=O
Yield: 90.6 %

Procedure:
A solution of 7-chloro-4-(3-fluoro-benzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (17) (45 g, 123 mmol), 1,4-diazabicyclo[2.2.2]octane (15.9 g, 141 mmol) and piperazin-1-yl-thiophene-2-yl-methanone (27.8 g, 141 mmol) in dry DMF was heated at 110° C. for 7 h under argon. The solution was cooled and poured into 2% ammonium chloride solution. The solids formed were filtered and washed by cold water. The solids were dissolved in dichloromethane and washed by water. The organic phase was dried over MgSO4 and concentrated under vacuum to yield 58.6 g (91%) of 4-(3-fluoro-benzyl)-5-oxo-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester. 1H-NMR (DMSO-d6): δ 1.29 (t, J=7.2 Hz, 3H), 3.37 (m, 4H), 3.82 (m, 4H), 4.27 (q, J=7.2 Hz, 2H), 5.38 (s, 2H), 7.05-7.16 (m, 4H), 7.33 (d, J=5.6 Hz, 1H), 7.36 (m, 1H), 7.48 (dd, J=1.2, 3.6 Hz, 1H), 7.79 (dd, J=1.2, 5.2 Hz, 1H), 8.03 (d, J=5.6 Hz, 1H); EIMS m/z 526 (M+1). Anal. (C26H24FN3O4S2) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:13]2[N:4]([C:5]([CH2:18][C:19]3[CH:27]=[CH:26][C:22]4[O:23][CH2:24][O:25][C:21]=4[CH:20]=3)=[N:6][C:7]3[CH:8]=[C:9]([C:15](O)=[O:16])[CH:10]=[CH:11][C:12]=32)[N:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:59][CH2:60][CH2:61][OH:62]>ClCCl>[OH:62][CH2:61][CH2:60][NH:59][C:15]([C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:4]([N:3]=[C:2]([NH2:1])[N:14]=3)[C:5]([CH2:18][C:19]3[CH:27]=[CH:26][C:22]4[O:23][CH2:24][O:25][C:21]=4[CH:20]=3)=[N:6][C:7]=2[CH:8]=1)=[O:16]
Reactant: Nc1nc2c3ccc(C(=O)O)cc3nc(Cc3ccc4c(c3)OCO4)n2n1
Reactant: NCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nc2c3ccc(C(=O)NCCO)cc3nc(Cc3ccc4c(c3)OCO4)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
To a solution of 2-amino-5-benzo[1,3]dioxol-5-ylmethyl-[1,2,4]triazolo[1,5-c]quinazoline-8-carboxylic acid (0.05 g, 0.14 mmol) prepared as described in Example 19, and N,N-diisopropylethylamine (0.14 mL, 0.81 mmol) in anhydrous dichloromethane (5 mL), TBTU (0.05 g, 0.17 mmol) was added. The reaction was stirred at room temperature for 30 minutes, then 2-aminoethanol (0.02 mL, 0.28 mmol) was added. After stirring for 1 h, the solution washed with NaHCO3 satured solution, then with water and brine. The organic phase was dried over Na2SO4 and evaporated to give a crude that was purified by flash column chromatography on silica gel eluting with DCM/MeOH/NH4OH 8/2/1, to provide the title compound (0.03 g, 53% yield).
Reaction SMILES: [C:1]1([C@H:7]([NH:65][C:66]([O:68][C@@H:69]2[CH:74]3[CH2:75][CH2:76][N:71]([CH2:72][CH2:73]3)[CH2:70]2)=[O:67])[C:8]2[CH:9]=[C:10]([CH:62]=[CH:63][CH:64]=2)[O:11][CH2:12][C:13]2[O:17][C:16]([C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:33][C@@H:34]([C:43]3[CH:52]=[CH:51][C:50]([O:53]CC4C=CC=CC=4)=[C:49]4[C:44]=3[CH:45]=[CH:46][C:47](=[O:61])[NH:48]4)[O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:19])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)=O>CO.CCOCC.CCOC(C)=O.[Pd]>[CH:18]([OH:20])=[O:19].[C:1]1([C@H:7]([NH:65][C:66]([O:68][C@@H:69]2[CH:74]3[CH2:75][CH2:76][N:71]([CH2:72][CH2:73]3)[CH2:70]2)=[O:67])[C:8]2[CH:9]=[C:10]([CH:62]=[CH:63][CH:64]=2)[O:11][CH2:12][C:13]2[O:17][C:16]([C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:33][C@H:34]([O:35][Si:36]([C:39]([CH3:40])([CH3:41])[CH3:42])([CH3:38])[CH3:37])[C:43]3[CH:52]=[CH:51][C:50]([OH:53])=[C:49]4[C:44]=3[CH:45]=[CH:46][C:47](=[O:61])[NH:48]4)=[O:19])=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N(CCCCOC(=O)c1ccc(COc2cccc([C@@H](NC(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)o1)C[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N(CCCCOC(=O)c1ccc(COc2cccc([C@@H](NC(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)o1)C[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 193.8 %

Procedure:
4-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-(tert-butyldimethyl-silyloxy)ethyl) (tert-butoxycarbonyl)amino)butyl 5-((3-((S)-phenyl(((R)-quinuclidin-3-yloxy)carbonylamino)methyl)phenoxy)methyl)furan-2-carboxylate (2.1 g, 1.990 mmol), 10% Pd/C (0.106 g, 0.099 mmol) and formic acid (0.092 mL, 2.388 mmol) were dissolved in MeOH (44.2 mL) and stirred at RT under balloon pressure of H2 After 2 hours reaction was complete and it was filtered on a pad of celite and the filtrate concentrated under reduced pressure to give a colourless viscous oil. The oil was dispersed in Et2O/AcOEt and evaporated 3 times in order to obtain a heavy white foam that was triturated in hexane/Et2O/AcOEt to give a white solid that was collected by filtration. The mother liquor was concentrated to give 0.44 g of a second crop of a whitish foam. The 2 crops were reunited to give 4-(tert-butoxycarbonyl((R)-2-(tert-butyldimethylsilyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl 5-((3-((S)-phenyl(((R)-quinuclidin-3-yloxy)carbonylamino)methyl)phenoxy)-methyl)furan-2-carboxylate formate (1.95 g, 1.928 mmol, 97% yield) as white amorphous solid.
Reaction SMILES: C([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[C:18](Cl)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]1=[O:26])(=O)C1C=CC=CC=1.[NH2:27][C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=1)[C:31]([O:33]CC)=[O:32].[OH-].[Na+]>CO>[C:31]([C:30]1[CH:29]=[C:28]([NH:27]/[C:18](=[C:11]2\[C:10](=[O:26])[NH:9][C:17]3[C:12]\2=[CH:13][CH:14]=[CH:15][CH:16]=3)/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:38]=[CH:37][CH:36]=1)([OH:33])=[O:32]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: O=C1C(=C(Cl)c2ccccc2)c2ccccc2N1C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1Nc2ccccc2/C1=C(/Nc1cccc(C(=O)O)c1)c1ccccc1

Procedure:
Prepared analogously to Example 2c from 1-benzoyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and ethyl 3-aminobenzoate and subsequent total saponification with sodium hydroxide solution in methanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:18])[C@H:9]([C:15]([OH:17])=O)[C:10](=[O:14])[O:11][CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[O:24][N:23]=[C:22]([CH2:25][NH2:26])[CH:21]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]([CH3:18])[C@H:9]([C:15]([NH:26][CH2:25][C:22]1[CH:21]=[C:20]([CH3:19])[O:24][N:23]=1)=[O:17])[C:10](=[O:14])[O:11][CH2:12][CH3:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: Cc1cc(CN)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H](C(=O)NCc1cc(C)on1)N(C)C(=O)OC(C)(C)C
Yield: 67.1 %

Procedure:
N-(t-butoxycarbonyl)-O-ethyl-N-methyl-3-oxoserine (Intermediate 7-1, 2.3 g), 1-(5-methyl-1,2-oxazol-3-yl)methanamine (1.0 g), WSC.HCl (2.4 g), HOBt.H2O (1.9 g), and chloroform (24 mL) were stirred overnight at room temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the desiccant was filtered out. Then, the solvent was distilled off under reduced pressure, and the resulting residue was purified by OH type silica gel column chromatography (gradient elution with chloroform/methanol=98/2→92/8) to obtain 3-({[N-(t-butoxycarbonyl)-O-ethyl-N-methyl-3-oxoseryl]amino}methyl)-5-methyl-1,2-oxazole (pale yellow oil) (2.1 g, 67%).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[C:10]([NH:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([C:24]([NH2:26])=[O:25])=[C:19]([NH2:23])[NH:20]2)=[CH:16][CH:15]=1)(=[O:12])[CH3:11].N.CO>O1CCCC1>[C:10]([NH:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([C:24]([NH2:26])=[O:25])=[C:19]([NH:23][C:3]([NH2:5])=[O:4])[NH:20]2)=[CH:16][CH:15]=1)(=[O:12])[CH3:11]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(=O)Nc1ccc2c(C(N)=O)c(N)[nH]c2c1
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.9 %

Procedure:
Trichloroacetyl isocyanate (48 μL, 0.36 mmol) was added to a solution of 6-acetylamino-2-aminoindole-3-carboxamide (Reference compound 15-1, 26 mg, 0.11 mmol) in anhydrous tetrahydrofuran (1.5 mL), and the mixture was stirred at room temperature for 18 hours. 2.0 M Ammonia in methanol solution (2.0 mL, 4.0 mmol) was added thereto, and the mixture was stirred at room temperature for 6 hours. The precipitated solid was separated by filtration using methanol (0.5 mL), and dried under reduced pressure to give the title compound (13 mg) as a colorless solid (yield 43%).
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].[N:16]1([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C=O>[N:16]1([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([NH:29]/[CH:3]=[C:4]3\[C:5](=[O:15])[NH:6][C:7](=[O:14])[C:8]4[C:13]\3=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:27][CH:28]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc2/C1=C/Nc1ccc(CN2CCCCC2)cc1
Temperature: 110 °C
Yield: 50.9 %

Procedure:
A mixture of 4-methoxymethylene-4H-isoquinoline-1,3-dione (101.5 mg, 0.5 mmol), 4-piperidin-1-ylmethyl-phenylamine (95.14 mg, 0.5 mmol) in 1 mL of N,N-dimethylformamide is heated at 110° C. for 2 h. After cooling in the refrigerator, the precipitate is collected, and washed with ether to give 92 mg (51%) of yellow solid mp 185-186° C.; HRMS (ESI) m/z calcd for C22H23N3O2 362.18546. found 362.18631 (M+H)+1.
Reaction SMILES: C([NH:20][C:21]1[S:25][C:24]([CH2:26][C:27]([NH:29][CH:30]2[C:55](=[O:56])[N:32]3[C:33]([C:39]([O:41]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:40])=[C:34]([CH:37]=[CH2:38])[CH2:35][S:36][C@H:31]23)=[O:28])=[N:23][N:22]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C(Cl)Cl>[NH2:20][C:21]1[S:25][C:24]([CH2:26][C:27]([NH:29][CH:30]2[C:55](=[O:56])[N:32]3[C:33]([C:39]([OH:41])=[O:40])=[C:34]([CH:37]=[CH2:38])[CH2:35][S:36][C@H:31]23)=[O:28])=[N:23][N:22]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3nnc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)s3)[C@H]2SC1
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3nnc(N)s3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25.2 %

Procedure:
To a suspension of benzhydryl 7-[2-(5-tritylamino-1,3,4-thiadiazol-2-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (2.6 g) in methylene chloride (30 ml) and anisole (2.1 g) was added trifluoroacetic acid (7.6 g) under ice-cooling, followed by stirring at ambient temperature for 1.5 hours. The reaction mixture was poured into diisopropyl ether (300 ml), and the precipitates were collected by filtration and suspended in water (40 ml). After adjusting to pH 7 with 10% aqueous sodium hydroxide, the aqueous solution was washed with ethyl acetate and then adjusted to pH 5 with 10% hydrochloric acid. The organic solvent included in the resultant aqueous solution was completely removed by evaporation, and the resultant aqueous solution was adjusted to pH 4 with dilute acetic acid, which was chromatographed on a non-ionic adsorption resin "Diaion HP-20" (50 ml). After washing with water, elution was carried out with 30% isopropyl alcohol, and the fractions containing a desired compound were collected and then concentrated under reduced pressure. The concentrate was lyophilized to obtain 7-[2-(5-amino-1,3,4-thiadiazol-2-yl)-acetamido]-3-vinyl-3-cephem-4-carboxylic acid (0.31 g).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4][C:5]1[CH:14]=[CH:13][C:8]([NH:9][C:10](=[O:12])[CH3:11])=[CH:7][CH:6]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C(O)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][S:4][C:5]3[CH:14]=[CH:13][C:8]([NH:9][C:10](=[O:12])[CH3:11])=[CH:7][CH:6]=3)[CH2:24][CH:23]=2)=[CH:18][CH:17]=1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Reactant: CC(=O)Nc1ccc(SCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(SCCN2CC=C(c3ccc(F)cc3)CC2)cc1

Procedure:
1.8 G. of 4'-[(2-chloroethyl)thio]acetanilide, 2.7 g. of 4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine, 4.5 g. of potassium carbonate and a few crystals of potassium iodide are heated under reflux conditions in 50 ml. of ethanol and 5 ml. of water for 16 hours. The solvent is evaporated under reduced pressure, the residue is taken up in chloroform and washed with water. From the organic phase there is obtained crude 4'-{[2-[4-(p-fluorophenyl)-3,6-dihydro-1(2H)-pyridyl]-ethyl]thio}acetanilide which melts at 150°-152°C. after recrystallization from acetic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][CH:14]=[C:13](B(O)O)[CH:12]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[C:11]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:16]=[CH:15][CH:14]=[C:13]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)[CH:12]=1
Reactant: Brc1cccc2[nH]ccc12
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc(-c2cccc(-c3cccc4[nH]ccc34)c2)cc1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-bromoindole (2.1 g, 10 mmol), and 3-biphenylboronic acid (2.2 g, 10 mmol) in THF (34.5 mL) were added Palladium catalyst Pd(PPh3)4 (0.35 g, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.21 g, 30 mmol in 14 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for overnight. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, and dried over Na2SO4. After filtration, the solvents were evaporated, and the crude product was purified on a silica gel column to give 4-biphenyl-3-yl-1H-indole.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[S:31][CH:32]=[CH:33][N:34]=4)=[O:28])=[C:22]([F:35])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:36]#[N:37])C1C=CC=CC=1.C1(SC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[C:36]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[OH:8])[N:16]=[CH:15][CH:14]=[C:13]2[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]2[S:31][CH:32]=[CH:33][N:34]=2)=[O:28])=[C:22]([F:35])[CH:21]=1)#[N:37]
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)ccnc2cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)ccnc2cc1O
Temperature: 70 °C
Reaction time: 6 h
Yield: 79.7 %

Procedure:
The N-(4-(7-benzyloxy-6-cyanoquinolyl)oxy-2-fluorophenyl)-N′-(2-thiazolyl)urea (5.53 g) synthesized in Example 141 was dissolved in TFA (55 ml), and then thioanisole (5.5 ml) was added and the mixture was heated and stirred at 70° C. for 6 hours. After cooling the reaction solution and concentrating it under reduced pressure, bicarbonate water and methanol were added and the precipitated crystals were filtered. These were washed with diethyl ether to obtain 3.63 g of the title compound (80% yield).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(OCC)(=O)C>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a solution of tert-butyl (1S,2S)-2-hydroxycyclohexylcarbamate (1.30 g, 6.04 mmol), 4-nitrobenzoic acid (1.11 g, 6.64 mmol), triphenylphosphine (1.74 g, 6.64 mmol) in THF (30 mL) was added diethylazo dicarboxylate (1.05 ml, 6.64 mmol) and the resulting solution was stirred at ambient temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried and concentrated to give an orange oil that was purified by column chromatography (hexanes/ethyl acetate, 8:1) to give (1R,2S)-2-(tert-butoxycarbonylamino)cyclohexyl 4-nitrobenzoate (1.95 g, 89%).