Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[S:3]1[C:10]2[CH:9]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4]1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20]Br>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20][N:7]1[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][C:10]2[S:3][CH:4]=[CH:5][C:6]1=2
Reactant: CCOC(=O)c1cc2sccc2[nH]1
Reactant: Clc1ccc(CBr)cc1Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc2sccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
Sodium hydride (32 mg, 60%), was added to a solution of ethyl 4H-thieno[3,2-b]pyrrole-5-carboxylate (0.13 g) (from Preparation 4) and the reaction stirred for 30 minutes. 3,4-Dichlorobenzyl bromide (0.22 g) was added and stirring continued for a further 2 hours. The reaction was quenched by addition of water and extracted with ether. Combined organic extracts were dried (MgSO4) and concentrated and the residue purified by column chromatogaphy using isohexane-5% ethyl acetate as eluent to give the product as a yellow solid (0.15 g, 64%), NMR d(DMSO) 1.24 (3H, t), 4.22 (2H, q), 5.73 (2H, s), 6.63 (1H, d), 6.98 (1H, dd), 7.25 (2H, m), 7.37 (1H, s), 7.55 (1H, d); M/z (+) 354 (M+), 214, 158, 129.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:13]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]=2[C:7]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=[N:6]1.C([O-])([O-])=O.[K+].[K+].[C:33](Cl)(=[O:37])[CH:34]([CH3:36])[CH3:35].O>CC#N>[F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:13]2[CH2:12][CH2:11][N:10]([C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH2:9][C:8]=2[C:7]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=[N:6]1
Reactant: N#Cc1cccc(-c2nn(Cc3ccc(F)cc3F)c3c2CNCC3)c1
Reactant: CC(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)C(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2Cc2ccc(F)cc2F)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A mixture of 3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (7c) (0.057 g, 0.163 mmol), K2CO3 (45 mg, 0.327 mmol) and isobutyryl chloride (21 mg, 0.196 mmol) in dry CH3CN (1.5 ml) was stirred at 60° C. for 1 h. Water was added, the solution was extracted 3 times with CH2Cl2, the combined organic layers were washed once with brine, dried over Na2SO4, filtrated and the residue was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 48 mg of 3-[1-(2,4-Difluoro-benzyl)-5-isobutyryl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (8b).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[OH:24])=[CH:5][CH:4]=1.[OH:32][CH:33]([CH:55]([OH:62])[CH:56]([OH:61])[CH:57]([OH:60])[CH2:58][OH:59])[C:34](=[O:54])[CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH:42][C:43]([CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][C:51](O)=[O:52])=[O:44].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:11](=[O:20])[CH:10]([CH2:21][CH2:22][CH:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:24])[CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:51](=[O:52])[CH2:50][O:49][CH2:48][CH2:47][O:46][CH2:45][C:43](=[O:44])[NH:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][C:34](=[O:54])[CH:33]([OH:32])[CH:55]([OH:62])[CH:56]([OH:61])[CH:57]([OH:60])[CH2:58][OH:59])=[CH:4][CH:5]=2)=[CH:18][CH:17]=1
Reactant: NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: O=C(O)COCCOCC(=O)NCCOCCOCC(=O)C(O)C(O)C(O)C(O)CO
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: O=C(COCCOCC(=O)NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)NCCOCCOCC(=O)C(O)C(O)C(O)C(O)CO

Procedure:
30 is prepared similarly to 18 starting from 68 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one, 76 mg of [2-({2-[2-(3,4,5,6,7-pentahydroxy-2-oxoheptyloxy)ethoxy]ethylcarbamoyl}methoxy)-ethoxy]acetic acid (27), 62 μl of diisopropylcarbodiimide and 44 mg of hydroxybenzotriazole in 2 ml of dimethylformamide. This gives 30: C43H55F2N3O14 (875.93) MS (ESI) 876 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][N:7]=1.O=C1CCC(=O)N1[O:21][C:22](=O)[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[N+:30]=[N-:31])=[CH:25][C:24]=1[OH:32].CCN(C(C)C)C(C)C.O>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:22](=[O:21])[C:23]2[CH:28]=[CH:27][C:26]([N:29]=[N+:30]=[N-:31])=[CH:25][C:24]=2[OH:32])=[CH:8][N:7]=1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)ON2C(=O)CCC2=O)c(O)c1
Reactant: COC(=O)COc1ccc(N)cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)COc1ccc(NC(=O)c2ccc(N=[N+]=[N-])cc2O)cn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of (5-aminopyridin-2-yloxy)acetic acid methyl ester (40 mg, 0.19 mmol) and 4-azido-2-hydroxy-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester (50 mg, 0.192 mmol) in DCM (5 mL) was added DIPEA (66 μL, 0.38 mmol). The mixture was stirred for 15 h at an ambient temperature and was poured into water. The aqueous mixture was extracted with ethyl acetate (3×25 mL) and the combined extracts were washed with brine and dried over magnesium sulfate. Filtration and concentration gave a solid residue that was suspended in a small amount of ethyl acetate (3 mL) and was collected by filtration. This afforded 35.6 mg (54%) of (5-(4-azido-2-hydroxy-benzoylamino)pyridin-2-yloxy)-acetic acid methyl ester: 1H NMR (300 MHz, acetone-d6) δ 11.78 (bs, 1H), 9.89 (s, 1H), 7.90 (m, 1H), 7.54 (m, 2H), 6.51 (m, 1H), 6.27 (m, 1H), 6.20 (m, 1H), 4.44 (s, 2H), 3.19 (s, 3H); MS (EI) m/z 341.99 (M−H)−.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O)=[O:4].[C:16]([C:19]1[C:20](=[O:28])[N:21]([CH3:27])[C:22]([CH3:26])=[CH:23][C:24]=1[OH:25])(=[O:18])[CH3:17]>>[OH:25][C:24]1[CH:23]=[C:22]([CH3:26])[N:21]([CH3:27])[C:20](=[O:28])[C:19]=1[C:16](=[O:18])[CH:17]=[CH:10][C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH2:5][C:3]([N:2]([CH3:15])[CH3:1])=[O:4])[CH:8]=1
Reactant: CN(C)C(=O)COc1cccc(C=O)c1
Reactant: CC(=O)c1c(O)cc(C)n(C)c1=O
Product: Cc1cc(O)c(C(=O)C=Cc2cccc(OCC(=O)N(C)C)c2)c(=O)n1C
Yield: 15.7 %

Procedure:
According to the same manner as that of Example a-1 except that 4.29 g of 3-[(dimethylaminocarbonyl)methoxy]benzaldehyde was used in place of 3-[(methoxycarbonyl)methoxy]benzaldehyde, and 3.40 g of 3-acetyl-4-hydroxy-1,6-dimethyl-2(1H)-pyridinone was used in place of 3-acetyl-4-hydroxy-6-methyl-2(1H)-pyridinone, 1.09 g of 4-hydroxy-3-[3-[3-[(dimethylaminocarbonyl)methoxy]phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (38a)] was obtained as a yellow crystal.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:18])[CH2:14][CH2:15][CH:16](Br)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].CS(C)=O.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:18])[CH2:14][CH:15]=[C:16]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1cnc2n(c1=O)C(C)CCC2Br
Solvent: CS(C)=O
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)c1cnc2n(c1=O)C(C)CC=C2Nc1ccccc1
Reaction time: 84 h
Yield: 59.3 %

Procedure:
40.0 g. (0.127 mole) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid ethyl ester are dissolved in 80 ml. of dimethylsulfoxide and 26 ml. (0.285 mole) of aniline are added. The solution is allowed to stand at room temperature for 3-4 days. The mixture is then diluted with 100 ml. of water, shaken out with 3×50 ml. of benzene. The combined organic layers are dried with calcinated sodium sulfate and evaporated in vacuo. The residue is recrystallized from ethanol and thus 24.5 g. (59.3%) of 9-(phenyl-amino)-6-methyl-4-oxo-6,7-dihydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic ethyl ester is obtained, melting point: 119°-120° C.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH2:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:4][CH:3]=1.O.N>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][C:8]3=[N:16][CH:15]=[CH:14][CH:13]=[C:9]3[C:10](=[O:12])[C:17]=2[CH:18]=1
Reactant: Cc1ccc(CCc2ncccc2C(=O)O)cc1
Agent: N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccc2c(c1)C(=O)c1cccnc1CC2
Temperature: 140 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
A mixture consisting of 7.23 g of 2 -(p-methylphenethyl)nicotinic acid and 94.00 g of polyphosphoric acid was stirred for 1 hour at 140° C. The reaction mixture was poured into 94 ml of concentrated ammonia water with ice-cooling. To the resulting mixture was added carbon tetrachloride, and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 5.95 g of brown oily 7-methyl-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one.
Reaction SMILES: C1([CH:7]([SH:23])[CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][C:18](=[O:22])[NH:19]3)=[CH:14][CH:13]=2)C=CC=CC=1.Cl[C:25]1[C:26](=O)[C:27](C#N)=[C:28](C#N)[C:29](=O)[C:30]=1Cl>>[C:25]1([S:23][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[CH:17][C:18](=[O:22])[NH:19]3)=[CH:14][CH:13]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1CCc2ccc(OCCCC(S)c3ccccc3)cc2N1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Product: O=c1ccc2ccc(OCCCCSc3ccccc3)cc2[nH]1

Procedure:
Prepared analogous to Example 86 from 7-(4-phenyl-mercapto-butoxy)-3,4-dihydro-carbostyril and 2,3-dichloro-5,6-dicyano-benzoquinone.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([N:13]1[C:17]2[N:18]=[C:19]([NH2:22])[N:20]=[CH:21][C:16]=2[C:15]([C:23]([C:25]2[CH:26]=[N:27][CH:28]=[C:29]([NH2:31])[CH:30]=2)=[O:24])=[CH:14]1)([CH3:12])[CH3:11])(C(C)(C)C)(C)C.[F:32][C:33]([F:44])([F:43])[C:34]1[N:35]=[N:36][N:37]([CH2:39][C:40](O)=[O:41])[CH:38]=1>>[NH2:22][C:19]1[N:20]=[CH:21][C:16]2[C:15]([C:23]([C:25]3[CH:30]=[C:29]([NH:31][C:40](=[O:41])[CH2:39][N:37]4[CH:38]=[C:34]([C:33]([F:43])([F:32])[F:44])[N:35]=[N:36]4)[CH:28]=[N:27][CH:26]=3)=[O:24])=[CH:14][N:13]([C:10]([CH3:11])([CH3:12])[CH2:9][OH:8])[C:17]=2[N:18]=1
Reactant: O=C(O)Cn1cc(C(F)(F)F)nn1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cnc(N)nc21
Product: CC(C)(CO)n1cc(C(=O)c2cncc(NC(=O)Cn3cc(C(F)(F)F)nn3)c2)c2cnc(N)nc21

Procedure:
The title compound was prepared according to the method described for Example 9 using [7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-2-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl]{5-aminopyridin-3-yl}methanone (see Preparation 48a) and [4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]acetic acid (see Preparation 81) to afford the title compound as a brown solid in 85% yield, 62 mg.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[O:6][C@@H:5]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[C:24](=[O:25])[C:23]4[C:22]5[C:17](=[CH:18][C:19]([C:26]#[N:27])=[CH:20][CH:21]=5)[NH:16][C:15]=4[C:14]([CH3:29])([CH3:28])[C:13]=3[CH:30]=2)[CH2:4][O:3]1.[Cl-].[NH4+].[N-:34]=[N+:35]=[N-:36].[Na+].Cl>CN(C=O)C>[CH3:1][C:2]1([CH3:31])[O:6][C@@H:5]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[C:24](=[O:25])[C:23]4[C:22]5[C:17](=[CH:18][C:19]([C:26]6[N:34]=[N:35][NH:36][N:27]=6)=[CH:20][CH:21]=5)[NH:16][C:15]=4[C:14]([CH3:29])([CH3:28])[C:13]=3[CH:30]=2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)O1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(-c5nn[nH]n5)ccc4c2C3=O)O1
Temperature: 120 °C
Reaction time: 14 h

Procedure:
8-((S)-2,2-Dimethyl-[1,3]dioxolan-4-yl methoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (20.0 mg, 0.048 mmol), ammonium chloride (1.28 mg, 0.024 mmol) and NaN3 (6.24 mg, 0.096 mmol) were dissolved in DMF, and the mixture was stirred at 120° C. for 14 hrs. NaN3 (6.24 mg, 0.096 mmol) was further added to the mixture, which was then stirred at 120° C. for 30 hrs. The reaction solution was added with 1 N aqueous solution of hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure. The resultant solid obtained after concentration was washed with hexane:ethyl acetate=1:1 to obtain 8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-6,6-dimethyl-3-(2H-tetrazol-5-yl)-5,6-dihydro-benzo[b]carbazol-11-one as a white solid.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[CH2:8][O:9][C:10]1[C:11]([C:16]([NH2:18])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25].COC1C=C(OC[C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)C(C(O)=O)=NC=1>>[F:19][C:20]([F:30])([F:31])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([N:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[CH2:8][O:9][C:10]1[C:11]([C:16]([NH2:18])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:25]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: NC(=O)c1ncccc1OC[C@H]1CCCN1
Agent: COc1cnc(C(=O)O)c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Agent: Cl
Product: NC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared according to the procedure described in Step 5 of EXAMPLE 31 using (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride (EXAMPLE 1 Step 3) and 3-(trifluoromethyl)benzoic acid instead of ammonium chloride and 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:35]C(=O)C)[CH:8]=[CH:9][C:10]=1[CH2:11][C:12]1[NH:20][C:19]2[C:18](=[O:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:16](=[O:30])[N:15]([CH2:31][CH2:32][CH2:33][CH3:34])[C:14]=2[N:13]=1)(=[O:3])[CH3:2].[OH-].[K+]>>[NH2:35][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][C:12]2[NH:20][C:19]3[C:18](=[O:21])[N:17]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:16](=[O:30])[N:15]([CH2:31][CH2:32][CH2:33][CH3:34])[C:14]=3[N:13]=2)=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=1
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(C)=O)cc3NC(C)=O)nc21
Agent: [K+]
Agent: [OH-]
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3NC(C)=O)nc21

Procedure:
Prepared from N-{3-acetylamino-4-[3-butyl-1-(2-fluorobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-acetamide by refluxing with 20% aqueous potassium hydroxide. The product was purified by chromatography using silica eluted with 92:8 chloroform/methanol. MS, m/z(M+)=478.2132.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[C:8]([C:13]([OH:15])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:16]O>>[OH:6][C:7]1[C:8]([C:13]([O:15][CH3:16])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)c1ncccc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ncccc1O
Yield: 85 %

Procedure:
Concentrated sulphuric acid (19 mL) was added dropwise to a mixture of 3-hydroxy picolinic acid (23.0 g, 165 mmol) in methanol (700 mL) at rt. The mixture was heated to reflux for 72 hours, cooled and concentrated. The mixture was neutralized with bicarbonate and extracted with EtOAc. The organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to provide 21.7 g (85%) of the desired product methyl 3-hydroxypicolinate (26A): 1H NMR (300 MHz, CDCl3) δ 10.63 (1H, s), 8.28 (1H, dd), 7.39 (2H, m), 4.06 (3H, s).
Reaction SMILES: [H-].[Na+].Br[C@H:4]1[C@H:9](O)[C:8]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:7]=2[O:6][CH2:5]1.[O:17]1CCCC1>>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:7]2[O:6][CH2:5][C:4](=[O:17])[CH2:9][C:8]=2[CH:11]=1
Reactant: C1CCOC1
Reactant: COc1ccc2c(c1)[C@@H](O)[C@H](Br)CO2
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(c1)CC(=O)CO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2.0 g sodium hydride in 100 ml of dry tetrahydrofuran is added with stirring a solution of 20 g of trans-3-bromo-4-hydroxy-6-methoxy-3,4-dihydro-2H-[1]-benzopyran in 200 ml of dry tetrahydrofuran in a dropwise fashion. Afer 30 minutes stirring at room temperature, the reaction mixture is filtered through filter-cel and the solvent is removed in vacuo. The residue is dissolved in 100 ml of toluene, 1.0 g of anhydrous zinc iodide is added and the mixture is heated at 80° for 1 hour. The reaction mixture is filtered through 120 g of silica gel with methylene chloride as the eluent to afford a product which is recrystallized from ether to give 6-methoxy-2H-[1]-benzopyran-3-one, melting point 67°-72°.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(O)C>[N:13]1([C:2]2[N:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: C1CNCCNC1
Solvent: CCO
Product: CCOC(=O)c1cccnc1N1CCCNCC1
Yield: 82.6 %

Procedure:
10.0 g of ethyl 2-chloronicotinate were heated to reflux for 2 h with 21.6 g of homopiperazine in 150 ml of ethanol. After removing the solvent, the residue was partitioned between NaCl solution and ethyl acetate and the aqueous phase was extracted several times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated, 11.1 g (83%) of the product being obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12](=[N:16][O:17][CH2:18][CH3:19])[C:13]([OH:15])=O)[N:11]=1.C[Si](CC(N)=O)(C)C.[NH2:28][CH:29]1[C:49](=[O:50])[N:31]2[C:32]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)=[O:37])=[CH:33][CH2:34][S:35][C@H:30]12.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>O1CCCC1.O.CN(C)C=O>[NH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12](=[N:16][O:17][CH2:18][CH3:19])[C:13]([NH:28][CH:29]2[C:49](=[O:50])[N:31]3[C:32]([C:36]([O:38][CH2:39][C:40]4[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=4)=[O:37])=[CH:33][CH2:34][S:35][C@H:30]23)=[O:15])[N:11]=1
Reactant: CCON=C(C(=O)O)c1csc(N)n1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(N)n1
Reaction time: 0.33 h
Yield: 104.9 %

Procedure:
Phosphoryl chloride (1.764 g.) was added to a suspension of 2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetic acid (syn isomer, 1.0 g.) in tetrahydrofuran (10 ml.) below 5° C. and stirred at the same temperature for 20 minutes. To the solution were added trimethylsilylacetamide (0.4 g.) and N,N-dimethylformamide (0.4 g.), and the solution was stirred below 5° C. for 40 minutes [Solution A]. On the other hand, trimethylsilylacetamide (3.5 g.) was added to a suspension of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (1.5 g.) in tetrahydrofuran (15 ml.), and stirred at room temperature for 1.5 hours. To the solution was added all at once the above Solution A at -20° C., and the solution was stirred at -5° to 0° C. for an hour. Water (20 ml.) was added to the resultant solution at -20° C., and the solution was adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate. Tetrahydrofuran (70 ml.) and a saturated aqueous solution of sodium chloride (50 ml.) were added to the solution, and the solution was shaken sufficiently. The aqueous layer was separated and extracted with tetrahydrofuran. The tetrahydrofuran layer and extract were combined and washed with a saturated aqueous solution of sodium chloride. The solution was dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated with diisopropyl ether to give 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 2.5 g.).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([N:12]([CH3:21])[CH2:13][CH2:14][CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[O:11][C:7]=2[C:6](F)=[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:4]=1[CH3:29])#[N:2].C(N(CC)CC)C.[CH3:37][N:38]([CH3:44])[C@H:39]1[CH2:43][CH2:42][NH:41][CH2:40]1>CS(C)=O.ClCCl>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([N:12]([CH3:21])[CH2:13][CH2:14][CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[O:11][C:7]=2[C:6]([N:41]2[CH2:42][CH2:43][C@H:39]([N:38]([CH3:44])[CH3:37])[CH2:40]2)=[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:4]=1[CH3:29])#[N:2]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N(C)CCCC(=O)N(C)C)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N(C)CCCC(=O)N(C)C)nc2c1C#N
Temperature: 150 °C
Reaction time: 4 h
Yield: 55.6 %

Procedure:
4-[{4-Cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazol-2-yl}(methyl)amino]-N,N-dimethylbutanamide (I-156) (0.32 g, 0.81 mmol) was dissolved in dimethyl sulfoxide (5 ml), then triethylamine (0.24 ml, 1.73 mmol) and (3S)-3-(dimethylamino)pyrrolidine (0.21 ml, 1.66 mmol) were added, followed by stirring in a sealed tube at an external temperature of about 150° C. for 4 hours. This was diluted with dichloromethane, and washed with water and brine. After drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1 to 10:1), then diisopropyl ether was added and the insoluble matter was collected by filtration to obtain a colorless solid (0.22 g, 56%).
Reaction SMILES: [CH2:1]([NH:6][CH2:7][C:8]([OH:10])=[O:9])[CH:2]=[C:3](C)[CH3:4].C/C=C\C>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C(Cl)Cl>[CH2:1]([NH:6][CH2:7][C:8]([OH:10])=[O:9])[CH:2]=[CH:3][CH3:4]
Reactant: CC(C)=CCNCC(=O)O
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: C/C=C\C
Solvent: ClCCl
Product: CC=CCNCC(=O)O
Yield: 84 %

Procedure:
The prenylglycine derivative 19 was subjected to the conventional cross metathesis procedure (Section 7.5.4) with cis-2-butene under the following conditions: (2S)-Methyl 2-N-acetylamino-5-methylhex-4-enoate 19 (16.2 mg, 81.4 μmol), DCM (5 mL), 2nd generation Grubbs' catalyst (3.5 mg, 4.1 μmol, 5 mol %), cis-2-butene (5 psi), 50° C., 14 h, 100% conversion into 81. Purification by flash chromatography (SiO2, light petroleum:DCM:EtOAc:MeOH, 1:2:1:0.2) gave (2S)-methyl 2-N-acetylaminohex-4-enoate 81 as a brown oil (12.6 mg, 84%). GC: tR (E/Z)=4.2 min, 4.4 min (GC column 30QC5/BPX5, 150° C. for 1 min, 10° C. min−1 to 280° C. for 6 min). νmax (neat): 3284s, 2966w, 2954m, 2856w, 1747s, 1658s, 1547s, 1437s, 1375s, 1217m, 1142m, 1072w, 1016w, 968m, 848m cm−1. 1H n.m.r. (300 MHz, CDCl3): δ 1.60 (dd, J=6.3, 1.2 Hz, 3H, H6), 1.95 (s, 3H, CH3CO), 2.36-2.44 (m, 2H, H3), 3.67 (s, 3H, OCH3), 4.55 (dt, J=7.8 Hz, 5.9 Hz, 1H, H2), 5.24 (m, 1H, H5), 5.49 (m, 1H, H4), 6.17 (bd, J=6.4 Hz, 1H, NH). 13C n.m.r. (100 MHz, CDCl3): δ 18.1 (C6), 23.3 (CH3CO), 35.4 (C3), 52.1, 52.4 (C2, OCH3), 124.6, 130.2 (C4, 5), 169.7, 172.6 (C1, CONH). Mass Spectrum (ESI+, MeOH) m/z 208.1 (M+Na)+, C9H15NNaO3 requires 208.1. Spectroscopic data were in agreement with those reported in the literature.117,119