Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7]O.[CH3:9][C:10]([CH3:12])=O.[OH-].[Na+].CCOCC>CCOC(C)=O.O=[Mn]=O>[CH3:12][C:10]1[N:1]=[C:2]2[CH:6]=[CH:5][S:4][C:3]2=[CH:7][CH:9]=1
Reactant: CC(C)=O
Reactant: Nc1ccsc1CO
Agent: O=[Mn]=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1ccc2sccc2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 5 L three neck flask was charged with 562 g (4.35 mol) of 3-amino-2-hydroxymethylthiophene (Step 1). It was suspended in 3 L of EtOAc and cooled to 0° C. (ice bath). 2.0 Kg of MnO2 (23.0 mol.; 5.3 eq) was added portionwise (250 g) over 45 min. with mechanical stirring. Upon addition of the MnO2 the reaction temperature rose to 20° C. The reaction mixture was stirred at 20° C. for 1 h until total consumption of starting material by TLC (Hex/EtOAc 1:1). The solids were removed by filtration over 2 L of celite and washed 3 times with 2 L of EtOAc/THF (1:1). The combined filtrates were evaporated to dryness to give a black residue. The residue was dissolved in 1.28 L of acetone (17.4 mol, 4.0 eq) and transferred to a 10 L three neck flask charged with 3 L of 2.5% NaOH. The mixture was then stirred at 70° C. for 1 h. The two phase mixture was cooled to 20° C., 2 L of ether was added and stirred for 15 min. The phases were separated and the aqueous phase was backwashed with 2×1 L of ether. The organic fractions were combined, washed with 2 L of brine and evaporated to dryness to give a black oil. The latter was distilled under vacuum (@70° C., 0.3 mm Hg) to give the title compound: 492 g; 76%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[C:13]([S:15][CH3:16])[N:12]=[C:11]([C:17]([OH:19])=O)[CH:10]=1.C([N:22](CC)CC)C.[Cl-].[NH4+].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[C:13]([S:15][CH3:16])[N:12]=[C:11]([C:17]([NH2:22])=[O:19])[CH:10]=1
Reactant: CCN(CC)CC
Reactant: COc1ccccc1-c1cc(C(=O)O)nc(SC)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1-c1cc(C(N)=O)nc(SC)n1
Reaction time: 2 h

Procedure:
To a stirred suspension of 6-(2-methoxyphenyl)-2-(methylthio)pyrimidine-4-carboxylic acid (9.8 g, 40 mmol), triethylamine (33 mL, 240 mmol), and ammonium chloride (11 g, 200 mmol) in DMF (40 mL) was added PyBOP (21.9 g, 42 mmol) in five portions. The reaction was complete in 2 h, as determined by LCMS analysis. The reaction mixture was poured into water (1.5 L) and stirred for 10 minutes. The precipitate was collected by filtration and dried overnight under high vacuum to give 6-(2-methoxyphenyl)-2-(methylthio)pyrimidine-4-carboxamide. 1H NMR (300 MHz, CDCl3) δ 8.40 (s, 0.7H), 8.05 (m, 1.3H), 7.74 (bs, 1H), 7.44 (m, 1H), 7.05 (m, 2H), 5.78 (bs, 1H), 3.92 (s, 3H); 2.65 (s, 3H). HPLC ret. time 2.71 min, 10-100% CH3CN, 5 min gradient; ESI-MS m/z 245.9 (M+H)+.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[CH:46]1([C:49]([N:51]2[CH2:56][CH2:55][N:54]([C:57]3[CH:62]=[CH:61][C:60]([C:63]4[CH:64]=[C:65]5[C:71]([C:72]6[CH:73]=[N:74][N:75]([CH2:77][C:78]7[CH:83]=[CH:82][CH:81]=[C:80]([F:84])[CH:79]=7)[CH:76]=6)=[CH:70][N:69](S(C6C=CC(C)=CC=6)(=O)=O)[C:66]5=[N:67][CH:68]=4)=[CH:59][N:58]=3)[CH2:53][CH2:52]2)=[O:50])[CH2:48][CH2:47]1.[OH-].[Li+]>C1COCC1.CO.O>[CH:46]1([C:49]([N:51]2[CH2:56][CH2:55][N:54]([C:57]3[CH:62]=[CH:61][C:60]([C:63]4[CH:64]=[C:65]5[C:71]([C:72]6[CH:73]=[N:74][N:75]([CH2:77][C:78]7[CH:83]=[CH:82][CH:81]=[C:80]([F:84])[CH:79]=7)[CH:76]=6)=[CH:70][NH:69][C:66]5=[N:67][CH:68]=4)=[CH:59][N:58]=3)[CH2:53][CH2:52]2)=[O:50])[CH2:48][CH2:47]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)C6CC6)CC5)nc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(C1CC1)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Yield: 54.4 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, cyclopropyl(4-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-1-yl)methanone (100 mg, 0.148 mmol) was hydrolyzed with lithium hydroxide (31 mg, 0.74 mmol) in THF/methanol/water (3/2/1 mL) to yield 42 mg (54.5% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.53 (s, 2H), 8.49-8.48 (d, 1H), 8.46-8.45 (d, 1H), 8.24 (s, 1H), 7.998-7.995 (d, 1H), 7.74 (s, 1H), 7.50-7.47 (d, 1H), 7.37-7.35 (m, 1H), 7.12-6.98 (m, 3H), 5.44 (s, 2H), 4.08-3.83 (m, 8H), 2.05-1.95 (m, 1H), 0.95-0.87 (m, 2H). MS: m/z=522.4 (M+1), HPLC: 96.90% in method A.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11](F)[CH:12]=3)[C:7](=[O:15])[C:6]([C:16]([OH:18])=[O:17])=[CH:5]2)[CH2:3][CH2:2]1.[CH:19]12[CH2:27][NH:26][CH2:25][CH:24]1[CH2:23][CH2:22][CH2:21][NH:20]2.N12CCN(CC1)CC2>CN1CCCC1=O>[CH:19]12[CH2:27][N:26]([C:11]3[CH:12]=[C:13]4[C:8]([C:7](=[O:15])[C:6]([C:16]([OH:18])=[O:17])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][CH:10]=3)[CH2:25][CH:24]1[CH2:23][CH2:22][CH2:21][NH:20]2
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)ccc2c1=O
Reactant: C1CNC2CNCC2C1
Agent: C1CN2CCN1CC2
Solvent: CN1CCCC1=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CC4CCCNC4C3)ccc2c1=O

Procedure:
741 mg (3 mmol) of 1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid together with 567 mg (4.5 mol) of 2,8-diazabicyclo[4.3.0]nonane and 672 mg of 1,4-diazabicyclo[2.2.2]octane are heated for two hours at 100° C. in 30 ml of N-methylpyrrolidone. The mixture is concentrated under a high vacuum, and the residue is stirred thoroughly with acetonitrile and dried at 100° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([O:10][CH2:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[N:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[N:6]=1)=[O:4].[OH-].[Li+]>O>[CH3:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[CH2:11][O:10][C:8]1[N:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:9]=1
Reactant: COC(=O)c1cc(OCC(=O)C(C)(C)C)n(-c2ccccc2F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)C(=O)COc1cc(C(=O)O)nn1-c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.3 mmol) of 5-(3,3-dimethyl-2-oxo-butoxy)-1-(2-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid methyl ester were dissolved in 5 ml of MOH. 0.7 mmol of lithium hydroxide and 2 ml of water were added and the mixture stirred overnight at room temperature. The solvent was removed in vacuo and the residue subjected to aqueous work-up with a 10% solution of citric acid and DCM. The organic phase was dried and the solvent removed in vacuo to give the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:17][CH2:16][C:11]2[N:12]=[C:13]([Br:15])[S:14][C:10]=2[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:15][C:13]1[S:14][C:10]2[CH2:9][CH:8]([NH2:7])[CH2:17][CH2:16][C:11]=2[N:12]=1
Reactant: CC(C)(C)OC(=O)NC1CCc2nc(Br)sc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCc2nc(Br)sc2C1
Reaction time: 4 h
Yield: 102.9 %

Procedure:
A solution of (2-Bromo-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyl ester (0.50 grams, 1.5 mmol, obtained in preparation 2) in dichloromethane (30 mL) was treated with trifluroacetic acid (1.1 mL, 15 mmol) at 0° C. Reaction mass was stirred for 4 hours. After completion of the reaction, the mass was quenched with ice cold water and adjusted pH to 10, by using 40% aqueous sodium hydroxide solution. The product was extracted with dichloromethane (3×50 mL) and the combined organics were washed with water followed by brine and dried over anhydrous sodium sulphate. The organic volatiles were evaporated under vacuum to obtain the title compound (0.36 grams).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O.[NH4+].[Cl-].O>C(O)C.C1COCC1.CCOC(C)=O>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[OH:1])[C:6]#[N:7]
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(O)c(N)c1
Temperature: 70 °C
Yield: 90.5 %

Procedure:
To a mixed solution of 4-hydroxy-3-nitrobenzonitrile (1 g) and NH4Cl (163 mg) in ethanol (20 ml), THF (10 ml), and water (10 ml) were added Celite (5 g) and reduced iron (1.7 g), followed by heating under reflux at 70° C. for 30 min. The reaction solution was cooled to room temperature, diluted with EtOAc (200 ml), and then filtered through celite. The solution was washed with saturated brine, the organic layer was dried over anhydrous MgSO4, and filtered, and the filtrate was concentrated under reduced pressure to obtain 3-amino-4-hydroxybenzonitrile (740 mg) as a pale brown solid.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]3[S:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[N:21][CH:20]=3)[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[OH-].[Na+]>>[F:33][C:30]([F:31])([F:32])[C:27]1[CH:28]=[CH:29][C:24]([C:22]2[S:23][C:19]([CH2:18][O:17][C:14]3[CH:15]=[C:16]4[C:11]([CH:10]=[CH:9][N:8]4[CH2:7][C:6]([OH:34])=[O:5])=[CH:12][CH:13]=3)=[CH:20][N:21]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(OCc3cnc(-c4ccc(C(F)(F)F)cc4)s3)cc21
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2ccc(OCc3cnc(-c4ccc(C(F)(F)F)cc4)s3)cc21

Procedure:
In analogy to the procedure described in example 2 c], {6-[2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester was treated with NaOH to obtain {6-[2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid as orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[CH:9][CH:8]=[C:7]([Br:27])[CH:6]=2.[C:28](OC)(OC)(OC)[CH2:29][CH2:30][CH3:31]>>[Br:27][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][CH:14]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]4)[C:28]([CH2:29][CH2:30][CH3:31])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2c(N)cnc3cc(Br)ccc23)CC1
Reactant: CCCC(OC)(OC)OC
Product: CCCc1nc2cnc3cc(Br)ccc3c2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 77.9 %

Procedure:
The method described in Part A of Examples 142-144 was used to treat tert-butyl 4-[(3-amino-7-bromoquinolin-4-ylamino)methyl]piperidine-1-carboxylate (15.0 g, 34.5 mmol) with trimethyl orthobutyrate (5.62 g, 37.9 mmol). After completion, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (eluting with 95:5 chloroform:CMA) followed by recrystallization from ethyl acetate to provide 13.1 g of tert-butyl 4-[(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate as a white solid, mp 215-216° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:8](=[O:31])[C:9]3[CH:30]=[CH:29][CH:28]=[N:27][C:10]=3[N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[C:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:14]=3)[N:12]=2)=[O:6])[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:37]>ClCCl>[CH:1]1([NH:4][C:5]([C:7]2[C:8](=[O:31])[C:9]3[CH:30]=[CH:29][CH:28]=[N:27][C:10]=3[N:11]([C:13]3[CH:14]=[C:15]([C:19]#[C:20][C:21]4[CH:22]=[N+:23]([O-:37])[CH:24]=[CH:25][CH:26]=4)[CH:16]=[CH:17][CH:18]=3)[N:12]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(NC1CC1)c1nn(-c2cccc(C#Cc3cccnc3)c2)c2ncccc2c1=O
Solvent: ClCCl
Product: O=C(NC1CC1)c1nn(-c2cccc(C#Cc3ccc[n+]([O-])c3)c2)c2ncccc2c1=O
Yield: 17.7 %

Procedure:
N-cyclopropyl-4-oxo-1-[3-(pyridin-3-ylethynyl)phenyl]-1,4-dihydropyridino[2,3-c]p yridazine-3-formamide (0.15 g, 0.36 mmol) was dissolved in 50 mL of dichloromethane solution, m-chloroperoxybenzoic acid (0.062 g, 0.36 mmol) was added and reacted at room temperature. After reaction was complete, separation was purified by liquid preparation chromatography column to obtain product 27 mg.
Reaction SMILES: O=O.[CH3:3][O:4]/[C:5](=[CH:9]\[C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)/[C:6]([OH:8])=[O:7].C1([C@@H](N)C)C=CC=CC=1.[H][H]>ClCCl.CO>[CH3:3][O:4][C@H:5]([CH2:9][C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Agent: C[C@H](N)c1ccccc1
Agent: O=O
Solvent: CO
Solvent: ClCCl
Product: CO[C@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Reaction time: 16 h

Procedure:
In a glove box (O2 content≦2 ppm), a 50-ml stainless steel autoclave was charged with 1.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (2.30 mmol),1.99 mg of [Ru(η5-2,4-DMP)((R)—(S)—PPF—PtBu2)(NCMe)]BF4 (0.0023 mmol, S/C 1,000), 12 ml of methanol, 8 ml of dichloromethane and 0.06 ml of (S)-1-phenylethylamine (0.47 mmol). The autoclave was sealed and the hydrogenation was run at 40° C. under 30 bar of hydrogen. After 16 h the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford the crude (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.6% (>99.9% conversion) and an enantiomeric purity of 89%.
Reaction SMILES: ClC1C=NC(OC)=C(C=1)C(O)=O.Cl[C:14]1[CH:15]=[N:16][C:17]([O:37][CH3:38])=[C:18]([CH:36]=1)[C:19]([NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33]CC)=[O:32])=[CH:26][CH:25]=1)=[O:20].ClC1C=NC(OC)=C(C=1)C(NCCC1C=CC(CC(O)=O)=CC=1)=O>>[CH3:38][O:37][C:17]1[N:16]=[CH:15][CH:14]=[CH:36][C:18]=1[C:19]([NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:26][CH:25]=1)=[O:20]
Reactant: CCOC(=O)Cc1ccc(CCNC(=O)c2cc(Cl)cnc2OC)cc1
Agent: COc1ncc(Cl)cc1C(=O)NCCc1ccc(CC(=O)O)cc1
Agent: COc1ncc(Cl)cc1C(=O)O
Product: COc1ncccc1C(=O)NCCc1ccc(CC(=O)O)cc1

Procedure:
with 5-chloro-2-methoxynicotinic acid, via ethyl 4-[2-(5-chloro-2-methoxynicotinoylamino)-ethyl]-phenylacetate (oil), 4-[2-(5-chloro-2-methoxynicotinoylamino)-ethyl]-phenylacetic acid; m.p. 157°-158° C., after recrystallization from ethanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][CH2:6][CH:5]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([O:16][CH3:17])[N:10]=2)[CH2:4][O:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(Cl)Cl>CN(C=O)C>[CH3:1][C:2]1([CH3:18])[O:7][CH2:6][CH:5]([NH:8][C:9]2[C:14]([NH:15][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:13][CH:12]=[C:11]([O:16][CH3:17])[N:10]=2)[CH2:4][O:3]1
Reactant: COc1ccc(N)c(NC2COC(C)(C)OC2)n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccc(OC)nc1NC1COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Crude N2-(2,2-dimethyl-1,3-dioxan-5-yl)-6-(methyloxy)-2,3-pyridinediamine prepared in Example 16A(c) (assumed 123.6 mmol) was dissolved in anhydrous DMF (500 ml) under argon and anhydrous potassium carbonate (37.56 g, 2.2 eq.) was added, followed by ethyl bromoacetate (12.31 ml, 0.9 eq.). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the resulting reddish-brown slurry was partitioned between DCM (1.2 L) and water (300 ml). The organic phase was separated and washed with water (300 ml), dried over sodium sulphate, filtered and evaporated under reduced pressure to give a dark red oil, this was taken up in a minimum of DCM and purified by column chromatography on silica (eluted with 5%-60% ethyl acetate in petroleum ether)) (40-60°)). Appropriate fractions were combined and evaporated under reduced pressure to give the title compound as a dark orange oil (35.42 g, 84%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=2)[C:16]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:15]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][OH:40])[CH:12]=[CH2:13].CCN(CC)CC>C(Cl)Cl>[CH2:11]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=2)[C:16]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:15]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]=[O:40])[CH:12]=[CH2:13]
Reactant: C=CCn1c(-c2ccccc2CO)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCn1c(-c2ccccc2C=O)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (2.5 eq., 2M solution in DCM) was added at −70° C. under nitrogen atmosphere to a solution of DMSO (5 eq.) in anhydrous DCM and the mixture was stirred for 30 min; a solution of methyl 1-allyl-3-cyclohexyl-2-[2-(hydroxymethyl)phenyl]-1H-indole-6-carboxylate in DCM was then added and stirring was continued at the same temperature for 30 min. before NEt3 (8 eq.) was added. After stirring for 20 min. at 0° C. the mixture was diluted with DCM, then washed with water, 1N HCl, saturated aq. NaHCO3 solution and brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The residual material was used in the next step without purification. MS (ES+): 402.2 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH2:7][S:8][C@H:3]12.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH2:31][C:32](Cl)=[O:33].C(N(CC)CC)C>C(Cl)Cl>[F:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:6]2[CH2:7][S:8][C@@H:3]3[CH:2]([NH:1][C:32](=[O:33])[CH2:31][C:27]4[S:26][CH:30]=[CH:29][CH:28]=4)[C:24](=[O:25])[N:4]3[C:5]=2[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)C1=C(Cc2ccc(F)cc2)CS[C@@H]2C(N)C(=O)N12
Reactant: O=C(Cl)Cc1cccs1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1=C(Cc2ccc(F)cc2)CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N12
Yield: 46.6 %

Procedure:
The free base (XI) (80 mg) was treated with 2-thienylacetyl chloride (40 mg) and triethylamine (0.05 ml) in dry methylene chloride (5 ml) at -20°. After 15 minutes the solution was washed with brine, dried and evaporated. Chromatography on silica gave the cephem (X) (50 mg) which crystallised on trituration with dry ether. νmax (CHCl3) 3380, 1780, 1710, 1685 cm-1
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([N+]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].[N+]([O-])([O-])=O.[Na+].[ClH:26]>CN(C)C=O.O>[Cl:1][C:2]1[CH:17]=[C:16]([Cl:26])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2Cl)c1
Reactant: Cl
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(Oc2ccc(Cl)cc2Cl)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
The product (10 g) from paragraph (a) was dissolved in dimethyl formamide (150 ml), cooled to 5°-10° C. and concentrated hydrochloric acid (40 ml) added dropwise, the temperature being kept at 10°-15° C. The mixture was then kept at 5° C. while sodium nitrate (5.2 g) in water (20 ml) was added dropwise with stirring over a period of 30 minutes. The solution so prepared was added dropwise to a solution of cuprous chloride (19 g) in concentrated hydrochloric acid (150 ml) kept at 10° C., giving a thick green suspension. When addition was complete, the mixture was left to stand overnight and then heated to 60° C. for 30 minutes. The white solid was filtered off, dried, and recrystallised from petroleum (100°-120° C.) to give 3(2,4-dichlorophenoxy)benzoic acid (5.1 g) with a melting point of 143°-144° C. This compound was used as starting material for compound no 19 of Table 1.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.N([O-])=O.[Na+].[OH-].[Na+].[F:16][B-](F)(F)F.[H+]>>[F:16][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: F[B-](F)(F)F
Reactant: COc1cc(N)ccn1
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Product: COc1cc(F)ccn1
Temperature: 10 °C
Reaction time: 0.75 h

Procedure:
A solution containing 3.6 g of 4-amino-2-methoxypyridine in 15 ml of 48% fluoroboric acid is cooled to 10° C. 3 g of sodium nitrite are added in small portions at a temperature below -5° C. and the mixture is then stirred for 45 minutes at 0° C. It is brought slowly to room temperature and then stirred in a water bath for 30 minutes. It is cooled to -10° C. and then neutralized by the addition of 3M sodium hydroxide solution while being kept at low temperature. The mixture is extracted with 50 ml of ethyl ether and the organic phase is washed with 5 ml of cold water and dried over anhydrous potassium fluoride. The ether is distilled at atmospheric pressure. The oily residue is used as such in the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:3]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[C:34]([O:38][C:39](=[O:47])[N:40]([CH3:46])[CH:41]1[CH2:45][CH2:44][NH:43][CH2:42]1)([CH3:37])([CH3:36])[CH3:35].CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[C:34]([O:38][C:39](=[O:47])[N:40]([CH3:46])[CH:41]1[CH2:45][CH2:44][N:43]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[CH:12]=[CH:11][S:10][CH:9]=3)[CH:3]=2)[CH2:42]1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Reactant: Clc1ccnc(-c2ccsc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccnc(-c3ccsc3)c2)C1
Temperature: 90 °C
Reaction time: 16 h
Yield: 41.7 %

Procedure:
To a solution of 4-chloro-2-thiophen-3-yl-pyridine (50 mg, 0.4 mmol) in toluene (1 mL) was added Pd(OAc)2 (2.3 mg, 0.01 mmol), 2-(di-t-butyl-phosphino)biphenyl (6.0 mg, 0.02 mmol), methyl-pyrrolidin-3-yl-carbamic acid tert-butyl ester (60 mg, 0.45 mmol), and NaOtBu (75 mg, 0.8 mmol). The resulting mixture was stirred at 90° C. for 16 h, then was cooled, poured into water, and extracted with EtOAc. The organic layer was dried and concentrated, and the resulting residue was purified by preparative TLC (hexanes/EtOAc) to yield methyl-[1-(2-thiophen-3-yl-pyridin-4-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester as a white solid (60 mg, 42%).