Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:7]2[C:11]=1[CH2:10][N:9]([CH3:12])[C:8]2=[O:13])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>C1COCC1>[CH3:12][N:9]1[C:8](=[O:13])[C:7]2[C:11](=[C:3]([CH2:1][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:4]=[CH:5][C:6]=2[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10]1
Reactant: CN1Cc2c(C=O)ccc(NC(=O)OC(C)(C)C)c2C1=O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1Cc2c(CN3CCCC3)ccc(NC(=O)OC(C)(C)C)c2C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of tert-Butyl (7-formyl-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)carbamate (Compound 109C, 23.0 mg, 0.0792 mmol) and sodium triacetoxyborohydride (101 mg, 0.475 mmol) in THF (0.5 mL) was stirred at room temperature for 20 minutes. Pyrrolidine (39.7 uL, 0.475 mmol) was added and the resulting mixture was stirred at room temperature overnight. The THF was removed in vacuo and the crude product was partitioned between EtOAc and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to deliver the desired product. MS (ES+): m/z 346.32 (100) [MH+]; HPLC: tR=0.76 min (UPLC, Analytical).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.[F:12][C:13]([F:33])([F:32])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][C:17]=1[S:28](Cl)(=[O:30])=[O:29]>C1COCC1.[OH-].[Na+]>[F:33][C:13]([F:12])([F:32])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:25])([F:26])[F:27])=[CH:18][C:17]=1[S:28]([NH:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)(=[O:30])=[O:29]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=S(=O)(Cl)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CC[C@H](CNS(=O)(=O)c2cc(OCC(F)(F)F)ccc2OCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of trans-4-aminomethyl-cyclohexanecarboxylic acid (1.5 g, 10 mmol) in THF (10 mL) and 1 M aqueous sodium hydroxide (27 mL) was added a solution of 2,5-bis(2,2,2-trifluoroethoxy)benzenesulfonyl chloride (3.8 g, 10.25 mmol) in THF (10 mL) dropwise and the mixture was stirred at ambient temperature for 2 hr. The resulting mixture was concentrated and 1 M aqueous HCl (22.5 mL) was added. The resulting precipitate was filtered, washed with water and hexanes to give trans-4-{[2,5-bis-(2,2,2-trifluoro-ethoxy)-benzenesulfonylamino]-methyl}-cyclohexanecarboxylic acid as a white powder (2.8 g, 57%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Cl:11])[CH:3]=1.[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=2[Cl:11])[CH:18]=1)[CH3:13]
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: CCOC(=O)Cc1cccc(N)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2ccc(Br)cc2Cl)c1

Procedure:
4-Bromo-2-chlorobenzoic acid (132 mg, 0.56 mmol) was coupled with ethyl ester (6) (100 mg, 0.56 mmol) following Method C to give the title compound.
Reaction SMILES: [N:1]1C=C2C(N=CN2)=NC=1.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]2[N:17]=[C:18]([CH2:29][N:30]3[C:34]4[N:35]=[CH:36][N:37]=[C:38]([NH2:39])[C:33]=4[N:32]=C3)[N:19]([C:22]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:21])[C:12]=12>>[NH2:39][C:38]1[C:33]2[N:32]=[N:1][N:30]([CH2:29][C:18]3[N:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[CH3:28])[C:20](=[O:21])[C:12]4[C:13](=[CH:14][CH:15]=[CH:16][C:11]=4[CH3:10])[N:17]=3)[C:34]=2[N:35]=[CH:36][N:37]=1
Reactant: Cc1ccccc1-n1c(Cn2cnc3c(N)ncnc32)nc2cccc(C)c2c1=O
Reactant: c1ncc2[nH]cnc2n1
Product: Cc1ccccc1-n1c(Cn2nnc3c(N)ncnc32)nc2cccc(C)c2c1=O

Procedure:
1H NMR (300 MHz, d6-DMSO) δ: 8.43 (br s, 1H), 8.19 (s, 1H), 8.10 (br s, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.49-7.28 (m, 5H), 7.22 (d, J=8.1 Hz, 1H), 5.49 (d, J=17.0 Hz, 1H), 5.19 (d, J=17.0 Hz, 1H), 2.73 (s, 3H), 2.11 (s, 3H). Alkylation at purine N7 deter-mined by similarity to nmr spectrum of D-030. LRMS (ES pos.) m/z=399 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6](F)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]=1[CH3:24])#[N:2].C(N(CC)CC)C.[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>CS(C)=O>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6]([NH:39][CH2:38][C:37]2[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]=1[CH3:24])#[N:2]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reactant: COc1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(CNc2c(-c3ccccc3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)cc1
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 48.8 %

Procedure:
4-Cyano-7-fluoro-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-114) (1.0 g, 3-09 mmol) was dissolved in dimethyl sulfoxide (60 ml), then at room temperature, triethylamine (560 μl, 4.02 mmol) was added, followed by heating at 150° C. 4-Methoxybenzylamine (525 μl, 4.02 mmol) was added to the solution all at a time, followed by stirring for 1.5 hours. The reaction liquid was cooled to room temperature, and the solvent was evaporated away under reduced pressure. The residue was fractionated with chloroform and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, chloroform:acetone=98:2, v/v) to obtain the entitled compound (665 mg, 49%) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:23][CH2:24][C:25]1C=CC=CC=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.BrC(O)C>>[CH2:16]([O:23][CH2:24][CH2:25][CH:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:8])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(COCc2ccccc2)cc1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: CC(O)Br
Product: O=C(c1ccccc1)C(CCOCc1ccccc1)c1ccccc1

Procedure:
This compound is prepared from 19.6 g of desoxybenzoin and 21.5 g of benzylether-protected bromoethanol according to the procedure described in Example 1(a).
Reaction SMILES: C([Cu])#N.[F:4][C:5]1[CH:6]=[C:7]([Mg]Br)[CH:8]=[CH:9][CH:10]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([CH2:25]I)[C:23]=1[CH3:24])[C:17]([O:19][CH3:20])=[O:18]>C1COCC1>[Br:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([CH2:25][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([F:4])[CH:6]=2)[C:23]=1[CH3:24])[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cc(Br)c(C)c(CI)c1
Reactant: Fc1cccc([Mg]Br)c1
Agent: N#C[Cu]
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(C)c(Cc2cccc(F)c2)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a THF (0.1 M) suspension of CuCN (2 eq.) was added at −78° C. 3-fluorophenyl magnesium bromide (0.5 M solution in THF, 4 eq.) over a period of 5 min. The resulting mixture was stirred at −78° C. for 20 min and then at 0° C. for another 20 min. The now yellow suspension was re-cooled to −78° C. before methyl 3-bromo-5-(iodomethyl)-4-methylbenzoate (1 eq.) from the previous step was added. The resulting mixture was stirred at −78° C. for 20 min, 0° C. for another 20 min and finally at RT for 16 h. The crude reaction mixture was quenched with a 3:1 (v/v) mixture of sat. aq. NH4Cl:conc. NH4OH and then extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Further purification of the crude product by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[C:16]([C:29](O)=[O:30])=[CH:15]2.[NH2:32][C:33]1[CH:34]=[N:35][C:36]([N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:37][CH:38]=1.C(N(CC)CC)C>CN(C)C=O>[N:39]1([C:36]2[N:35]=[CH:34][C:33]([NH:32][C:29]([C:16]3[N:17]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:18]4[C:14]([CH:15]=3)=[CH:13][C:12]([F:11])=[CH:20][CH:19]=4)=[O:30])=[CH:38][CH:37]=2)[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: Nc1ccc(N2CCCC2)nc1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCCC2)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 87 %

Procedure:
0.28 ml (1.68 mmol) of diethyl cyanophosphonate is added, dropwise, at 20° C. under argon, to a solution of 0.402 g (1.4 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (example 1.1) and of 0.274 g (1.68 mmol) of 3-amino-6-(pyrrolidin-1-yl)pyridine (WO 02/48152) in 10 ml of dry dimethylformamide. The mixture is stirred for ten minutes and then 0.43 ml (3.08 mmol) of triethylamine is added dropwise. The mixture is stirred at ambient temperature for 18 hours, concentrated under reduced pressure, and then taken up with 50 ml of ethyl acetate. This solution is then successfully washed with three times 20 ml of a saturated sodium hydrogen carbonate solution, 50 ml of water and 20 ml of a saturated sodium chloride solution, and then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The solid obtained is triturated in isopropylether under hot conditions. 0.527 g of a solid is obtained, which solid is dried under reduced pressure.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)[C:12]([NH2:24])=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:25](OC)(OC)(OC)[CH3:26].C(O)(C(F)(F)F)=O>C1COCC1>[CH2:22]([C:19]1[CH:18]=[CH:17][C:16]([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:24]=[C:25]2[CH3:26])=[CH:21][CH:20]=1)[CH3:23]
Reactant: CCc1ccc(Nc2nc(OCc3ccccc3)ccc2N)cc1
Reactant: COC(C)(OC)OC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCc1ccc(-n2c(C)nc3ccc(O)nc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(Benzyloxy)-N2-(4-ethylphenyl)pyridine-2,3-diamine (358 mg, 1.12 mmol) was dissolved in THF (1.0 mL). Trimethyl orthoacetate (1.0 mL) was added followed by TFA (10 μL). The mixture was stirred at room temperature overnight and concentrated in vacuo. The benzyl group was then removed as described in Example 1.98, Step B to give the title compound as a white solid (55.3 mg). LCMS m/z=254.3 [M+H]+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:54])([CH3:53])[CH2:15][O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][C:32]=3[O:45][CH3:46])=[C:26]([CH2:47][CH2:48][CH3:49])[N:25]3[N:50]=[CH:51][CH:52]=[C:24]23)[CH2:19][CH2:18]1>C(OCC)(=O)C>[OH:13][C:14]([CH3:53])([CH3:54])[CH2:15][O:16][C@H:17]1[CH2:18][CH2:19][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][C:32]=3[O:45][CH3:46])=[C:26]([CH2:47][CH2:48][CH3:49])[N:25]3[N:50]=[CH:51][CH:52]=[C:24]23)[CH2:21][CH2:22]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2OC)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2OC)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.64 g), sodium hydrogen carbonate (0.97 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C. for 30 min, 4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)-3′-methoxybiphenyl-2-carbonitrile (0.44 g) was added, and the mixture was stirred at 90° C. for 20 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.15 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.34 g, 71%).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>O1CCCC1>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:34]([NH:33][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[C:26]([F:25])([F:36])[F:37])=[O:35])[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C=Nc1ccccc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1C(F)(F)F)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2-trifluoromethylphenyl isocyanate (0.169 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 148 mg (42.1%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:30])=[C:6]([C:26]([F:29])=[CH:27][CH:28]=1)[O:7][C:8]1[CH:9]=[N:10][N:11]([CH:15]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:16](O)=[O:17])[C:12](=[O:14])[CH:13]=1)[CH3:2].[CH3:31][C:32]1([CH3:44])[O:36][C@H:35]([CH2:37][N:38]2[CH:42]=[CH:41][C:40]([NH2:43])=[N:39]2)[CH2:34][O:33]1>>[CH3:31][C:32]1([CH3:44])[O:36][C@H:35]([CH2:37][N:38]2[CH:42]=[CH:41][C:40]([NH:43][C:16](=[O:17])[CH:15]([N:11]3[C:12](=[O:14])[CH:13]=[C:8]([O:7][C:6]4[C:26]([F:29])=[CH:27][CH:28]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=4[F:30])[CH:9]=[N:10]3)[CH2:19][CH:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[N:39]2)[CH2:34][O:33]1
Reactant: CCOc1ccc(F)c(Oc2cnn(C(CC3CCOCC3)C(=O)O)c(=O)c2)c1F
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Product: CCOc1ccc(F)c(Oc2cnn(C(CC3CCOCC3)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)c(=O)c2)c1F

Procedure:
Using the method described in Example 49, 2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid (Intermediate 93) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionamide as an off-white solid as a mixture of diastereoisomers (138 mg, 55%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2].S(=O)(=O)(O)O.[CH2:17]=[C:18]([CH3:20])[CH3:19].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:18]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:20])([CH3:19])[CH3:17]
Reactant: C=C(C)C
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(C#N)cc1
Temperature: 0 °C

Procedure:
In 612 ml of methylene chloride were suspended 45.0 g of 4-cyanobenzoic acid and 3.1 ml of conc. sulfuric acid. To the suspension was added, while stirring at 0° C., 310 ml of isobutene. The mixture was stirred for 13 days. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, which was subjected to extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. Resulting precipitate was collected by filtration and washed with hexane. The filtrate and the washing were combined, which was concentrated under reduced pressure. The concentrate was purified by means of a silica gel chromatography (hexane/ethyl acetate=10/1), followed by crystallization from methylene chloride/petroleum ether to afford 43.1 g of the titled compound as a white crystalline product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12](O)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19](C=O)=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](/[CH:11]=[CH:12]/[C:19]2[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C(O)CS(=O)(=O)c1ccc(Cl)cc1
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 70 %

Procedure:
A solution of 4-chlorophenyl sulfonylacetic acid (0.01 mol) and 4-chlorobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. The title compound was obtained in 70-72% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[N:31]1([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:40]4[CH2:41][CH2:42][CH:37]([N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)[CH2:38][CH2:39]4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Reactant: C1CCN(C2CCNCC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCC(N2CCCCC2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
A mixture of 250 mg (0.51 mmol) of 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide, and 172 mg (1.02 mmol) of 4-piperidinopiperidine in 5.0 ml dimethylformamide was stirred at room temperature for 4 hr and at 60° C. for 1 hr. After the mixture was cooled, the suspension was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were evaporated to an oil and purified by preparative TLC to yield 100 mg (40%) yellow solid: mp 140-144° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)CCC>C1(C)C=CC=CC=1>[Br:8][C:4]1[CH:3]=[C:2]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2ccco2)c1
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
1,3-Dibromobenzene (1.0 g) was dissolved in toluene (20 ml), the solution was added with tri-n-butyl-(2-furyl)tin 1.59 g) and tetrakistriphenylphosphine palladium (0.25 g), and the mixture was stirred for 30 minutes under reflux by heating. The reaction mixture was concentrated under reduced pressure, and then the residue was dissolved in hexane. The solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in diethyl ether, the solution was added with cesium fluoride (1.01 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added with a mixed solvent of hexane:ethyl acetate=10:1, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane alone) to obtain the title compound (0.59 g).
Reaction SMILES: [ClH:1].[I-:2].C(OC([NH:10][C@@H:11]1[C:41](=[O:42])[N:13]2[C:14]([C:25]([O:27]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:26])=[C:15]([CH2:18][N+:19]3[N:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[CH2:16][S:17][C@H:12]12)=O)(C)(C)C.CC(C)=O.C(OCC)(=O)C>C(O)=O>[NH2:10][C@@H:11]1[C:41](=[O:42])[N:13]2[C:14]([C:25]([O-:27])=[O:26])=[C:15]([CH2:18][N+:19]3[N:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[CH2:16][S:17][C@H:12]12.[ClH:1].[IH:2]
Reactant: Cn1ccc[n+]1CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2SC1
Reactant: [I-]
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O=CO
Product: Cn1ccc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1
Product: I
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.1 %

Procedure:
Conc. hydrochloric acid (4.09 g) was added to a solution of benzhydryl 7β-tert-butoxycarbonylamino-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate iodide (27 g) in formic acid (108 ml), and stirred at ambient temperature for 2.5 hours. The reaction mixture was added to a mixture of acetone (720 ml) and ethyl acetate (1440 ml). The precipitates were collected by filtration and successively washed with ethyl acetate to give 7β-amino-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate·hydrochloride·hydroiodide (15.3 g).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]2[C:9]3[C:14]([CH2:15][CH2:16][N:7]2[CH2:6][O:5][CH2:4]1)=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=3.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1>[C:21]([O:1][CH2:2][CH:3]1[CH:8]2[C:9]3[C:14]([CH2:15][CH2:16][N:7]2[CH2:6][O:5][CH2:4]1)=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=3)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1cc2c(cc1OC)C1C(CO)COCN1CC2
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)C1C(COC(=O)c3ccccc3)COCN1CC2
Temperature: 0 °C
Yield: 55 %

Procedure:
0.01 mole (2.79 g) of 1-(hydroxymethyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H,4H-[1,3]oxazino[4,3-a]isoquinoline in 30 ml of absolute pyridine is boiled with 0.012 mole (1.69 g) of benzoyl chloride for 3 hours. The mixture is then poured onto 100 g of ice. The separated crystals are filtered off, washed with water and recrystallized from a mixture of diisopropyl ether and ethanol. Yield: 55%. The melting point and spectroscopical data of the compound are identical with those of the product obtained in Example 25.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:14]([O:16]C)=O)[C:3]=1[CH3:18].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44][NH2:45]>C1COCC1.C(N(CC)CC)C>[NH2:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:5](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:6](=[O:8])[N:45]([CH2:44][CH2:43][N:42]([CH3:46])[CH3:41])[C:14]2=[O:16]
Reactant: CN(C)CCN
Reactant: COC(=O)c1c(C(=O)O)cc([N+](=O)[O-])c(N)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(N)c([N+](=O)[O-])cc2c1C(=O)N(CCN(C)C)C2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.1 %

Procedure:
To a solution of 4-amino-2-(methoxycarbonyl)-3-methyl-5-nitrobenzoic acid (0.43 g, 1.69 mmol), EDCI hydrochloride (0.36 g, 1.86 mmol), and HOBt (0.23 g, 1.69 mmol) in 22 mL of anhydrous THF was added 1.18 mL of triethylamine and stirred for 10 min at rt under an argon atmosphere. N1,N1-dimethylethane-1,2-diamine (0.16 g, 1.86 mmol) was added into above mixture and the reaction mixture was heated at reflux for 14 h under an argon atmosphere. Product was purified by a silica gel column using methylene chloride and methanol (9:1 v/v) as eluent to afford 0.44 g (90%) of the designed compound as yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.21 (s, ArH), 8.12 (br s, 2H, NH2), 3.64 (t, J=6.5 Hz, 2H, CH2), 2.57 (s, 3H, CH3), 2.45 (t, J=6.5 Hz, 2H, CH2), 2.15 (S, 6H, 2×CH3); Mass (ESI, positive) m/z 293.0 [M+H]+.