Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][O:17][CH:18]=[O:19])[C:10]([OH:12])=O)[N:8]=1)=[O:2].[NH2:20][CH:21]1[C:39](=[O:40])[N:23]2[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH2:28][S:29][C:30]3[N:34]([CH3:35])[N:33]=[N:32][N:31]=3)[CH2:26][S:27][C@H:22]12.C[Si](CC(N)=O)(C)C.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][O:17][CH:18]=[O:19])[C:10]([NH:20][CH:21]2[C:39](=[O:40])[N:23]3[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH2:28][S:29][C:30]4[N:34]([CH3:35])[N:33]=[N:32][N:31]=4)[CH2:26][S:27][C@H:22]23)=[O:12])[N:8]=1)=[O:2]
Reactant: O=CNc1nc(C(=NOCCOC=O)C(=O)O)cs1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCOC=O)c3csc(NC=O)n3)[C@H]2SC1
Yield: 34.9 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetic acid (syn isomer, 3.4 g.), 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (4.3 g.), trimethylsilylacetamide (12.6 g.), dry N,N-dimethylformamide (1.0 g.), phosphoryl chloride (2.0 g.), ethyl acetate (139 ml.) PG,71 were treated in a similar manner to that of Example 11-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.47 g.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Cl:11])=[N:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Si:33]([O:40][CH2:41][CH2:42][CH2:43][NH2:44])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>CN(C=O)C.CC(=O)OCC.O>[NH2:1][C:2]1[C:7]([C:8]([NH:44][CH2:43][CH2:42][CH2:41][O:40][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])=[O:10])=[CH:6][C:5]([Cl:11])=[N:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCN
Reactant: Nc1cnc(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCNC(=O)c1cc(Cl)ncc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To a solution of 5-amino-2-chloroisonicotinic acid (5 g, 0.029 mol) in DMF (40 mL) was added EDCI (8.34 g, 0.0435 mol) and HOBT (5.87 g, 0.0435 mol). The reaction was stirred at RT for 30 min then 3-(tert-butyldimethylsilyloxy)propan-1-amine (5.5 g, 0.029 mol) was added. The reaction was stirred at RT for 5 h then poured in EA (50 mL) and water (20 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (2:1) to give 5-amino-N-(3-(tert-butyldimethylsilyloxy)propyl)-2-chloroisonicotinamide (4.3 g, 43% yield) as a white solid. LCMS: MH+ 344 and TR=1.877 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([C:21]([F:24])([F:23])[F:22])=[N:19][NH:18][C:17](=O)[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(Cl)[Cl:27].[P+5]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([Cl:27])[N:18]=[N:19][C:20]=2[C:21]([F:24])([F:23])[F:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClOCl
Reactant: O=c1cc(-c2ccc(OCc3ccccc3)cc2)c(C(F)(F)F)n[nH]1
Agent: [P+5]
Product: FC(F)(F)c1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Temperature: 90 °C

Procedure:
A mixture of the 5-(4-benzyloxy-phenyl)-6-trifluoromethyl-2H-pyridazin-3-one (0.491 mmol, 170 mg) and phosphorus(V) oxychloride may be heated at 90° C. for 2 h. The reaction mixture may be concentrated in vacuo, and ice may be added to the residue. The mixture may be neutralized with solid sodium bicarbonate and extracted with diethyl ether. Purification by column chromatography on silica gel gives 4-(4-benzyloxy-phenyl)-6-chloro-3-trifluoromethyl-pyridazine as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:19](=O)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=O)C.O.[NH2:28][NH2:29]>CCO>[C:15]([O:14][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C:6]2([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:29][NH:28][C:4]2=[O:3])[CH2:7]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: NN
Reactant: CCOC(=O)C1(C(=O)c2ccccc2)CCCN(C(=O)OC(C)(C)C)C1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NN=C2c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of racemic mixture of 3-benzoyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (step 1) (400 mg, 1.1 mmol) in EtOH (4 ml) was added hydrazine hydrate (166 mg, 3.3 mmol). The reaction mixture was stirred at RT for 30 min before heating in the microwave at 120° C. for 3 hours. The reaction mixture was concentrated in vacuo, dissolved in EtOAc (10 ml) and washed with brine (20 ml). The aqueous phase was further washed with EtOAc (10 ml). The organics portions were combined, dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-60% EtOAc in iso-hexane afforded the title compound.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22].CN(C=O)C>C1(C)C=CC=CC=1.CO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[O:6][C:5]([C:7]3[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=3)=[CH:4][CH:3]=2)=[CH:25][CH:24]=1)#[N:22]
Reactant: N#Cc1ccc(-c2ccc(Br)o2)nc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2ccc(-c3ccc(C#N)cn3)o2)cc1
Temperature: 80 °C
Yield: 76 %

Procedure:
Procedure: J. Org. Chem. 49(26), 5237 (1984). Continuing with Scheme 1, a stirred solution of 2 (1.245 g, 5 mmol), and tetrakis(triphenylphosphine) palladium (288 mg) in toluene (10 mL) under a nitrogen atmosphere was added 5 mL of a 2 M aqueous solution of Na2CO3 followed by 4-cyanophenyl boronic acid (821 mg, 4.6 mmol) in 5 mL of methanol. The vigorously stirred mixture was warmed to 80° C. for 24 h, and then cooled, and the precipitate was filtered. The precipitate was partitioned between methylene chloride (300 mL) and 2 M aqueous Na2CO3 (25 mL) containing 3 mL of concentrated ammonia. The organic layer was dried (Na2SO4), and then concentrated to dryness under reduced pressure to afford 3 in 76% yield; mp 301–302° C. (DMF). 1H nmr (DMSO-d6); δ 7.44 (d, J=3.6 Hz, 1H), 7.49 (d, J=3.6 Hz, 1H), 7.92 (d, J=8.4 Hz, 2H), 8.07 (d, J=8.4 Hz, 2H). 8.12 (d, J=8.4 Hz 1H), 8.36 (dd, J=8.4, 1.5 Hz, 1H), 9.0 (d, J=1.5 Hz, 1H). 13C nmr; δ 153.4, 152.6, 152.3, 150.1, 140.7, 133.1, 132.7, 124.4, 118.3, 116.9, 114.6, 111.8, 110.2, 106.7. MS (m/z, rel.int.); 271 (M+, 100), 243 (10), 140 (20), 103 (20). High resolution mass calcd. for C17H9N3O: 271.07456. Observed 271.07392. Calcd. for C17H9N3O: C, 75.26; H, 3.34; N. 15.49. Found. C, 74.95; H, 3.43; N, 15.23.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13](=C=O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2Cl)=[CH:8][CH:7]=1)C.[Cl-].[Al+3].[Cl-].[Cl-].Cl.C[CH2:30][O:31]CC>[N+](C1C=CC=CC=1)([O-])=O>[O:31]=[C:30]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][S:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:3])=[O:23])=[CH:7][C:8]1=2
Reactant: CCOC(=O)Cc1ccc(SC(=C=O)c2ccccc2Cl)cc1
Reactant: CCOCC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CS2

Procedure:
7.0 g of 4-(2-chloro-carbonyl-benzyl-thio)phenylacetic acid ethyl ester are dissolved in 30 cc of nitrobenzene and this solution is added dropwise, at room temperature, to a solution of 3.32 g of aluminium chloride in 50 cc of nitrobenzene. The resulting red solution is then heated in an oil bath of 100° for 3 hours. The reaction solution is subsequently poured on a mixture of ice and 10 N hydrochloric acid, is diluted with ether, and the organic phase is separated, washed with water, dried with sodium sulphate, purified with charcoal and filtered. The solvent is completely removed at reduced pressure and the oily residue is dissolved in ether, the ether phase is washed with a 10% sodium bicarbonate solution and then with water, is dried with sodium sulphate, filtered, and the solvent is removed by distillation at reduced pressure. 6,11-Dihydro-11-oxo-dibenzo[b,e]thiepine-2-acetic acid ethyl ester crystallizes from ether/pentane. M.P. 96°-97°.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](Cl)=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C(C([O-])=O)=NN=N1)C1C=CC=CC=1.[K+].[CH3:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([NH2:41])[C:36]=1[OH:42])=[O:34].N1C=CC=CC=1>C(Cl)Cl>[C:33]([C:35]1[C:36]([OH:42])=[C:37]([CH:38]=[CH:39][CH:40]=1)[NH:41][C:13]([C:12]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=[N:10][N:11]=1)=[O:14])(=[O:34])[CH3:32]
Reactant: O=C(Cl)c1nnnn1Cc1ccccc1
Reactant: CC(=O)c1cccc(N)c1O
Agent: O=C([O-])c1nnnn1Cc1ccccc1
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1cccc(NC(=O)c2nnnn2Cc2ccccc2)c1O
Reaction time: 8 h

Procedure:
A solution of crude 1-benzyl-1H-tetrazole-5-carbonyl chloride (prepared from 2.4 g of potassium 1-benzyl-1H-tetrazole-5-carboxylate in the manner hereinbefore described in Reference Example 3) in dry methylene chloride (50 ml) was added to a stirred solution of 3-amino-2-hydroxyacetophenone (1.5 g) and pyridine (0.9 g) in dry methylene chloride (40 ml) at 10° C. After standing at room temperature overnight, the solution was evaporated in vacuo and the resulting solid residue was recrystallised from a large volume of ethanol to give 3'-acetyl-1-benzyl-2'-hydroxy-1H-tetrazole-5-carboxanilide (1.5 g), in the form of pale yellow needles, m.p. 155°-157° C.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[Br:10][C:11]1[CH:12]=[CH:13][C:14](F)=[N:15][CH:16]=1>CN(C=O)C>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])=[N:15][CH:16]=1
Reactant: CN(C)CCCO
Reactant: Fc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCOc1ccc(Br)cn1
Temperature: 30 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
3-(Dimethylamino)propan-1-ol (3.09 g, 29.95 mmol) was added to a mixture of sodium hydride (2.4 g, 60.00 mmol) in DMF (50 mL) over a period of 20 min at r.t. 5-Bromo-2-fluoropyridine (5.81, g, 33.01 mmol) was added and the resulting solution stirred for 4 h at 30° C. The reaction was then quenched by the addition of a sat. aqueous solution of ammonium chloride and the resulting mixture concentrated under vacuum. The residue was purified by FCC, eluting with DCM/MeOH in Et2O (10:1) to afford the desired material (5.2 g, 67%) as yellow oil. Mass Spectrum: m/z (ES+)[M+H]+=259.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[C:4]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[N:3]=1.O.[CH3:21][C:22]([O:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:27])([CH3:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.COCCOC.C(O)C>[CH3:14][C@H:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[C:6]1[CH:5]=[C:4]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[N:3]=[C:2]([C:32]2[CH:31]=[CH:30][C:29]([NH:28][C:26](=[O:27])[O:25][C:22]([CH3:23])([CH3:21])[CH3:24])=[CH:34][CH:33]=2)[N:7]=1
Reactant: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(-c2ccc(NC(=O)OC(C)(C)C)cc2)n1
Temperature: 90 °C
Yield: 35 %

Procedure:
2-Chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine (1.0 g, 3.27 mmol) was dissolved in a solution of 18% DMF in a mixture of 7:3:2 DME:water:ethanol (7 mL). [4-[(2-Methylpropan-2-yl)oxycarbonylamino]phenyl]boronic acid (1.165 g, 4.91 mmol), 2M sodium carbonate solution (4 mL) and dichlorobis(triphenylphosphine) palladium catalyst (115 mg, 0.16 mmol) were then added to the solution and refluxed at 90° C. for 5 hours under nitrogen atmosphere. The reaction was allowed to cool to room temp then partitioned between ethyl acetate and water. The organics were dried over magnesium sulphate, filtered and concentrated to dryness. The crude oil was dissolved in dichloromethane and filtered to remove insoluble material. A beige solid precipitated from the filtrates and the filtrates were filtered again. The solid was analysed and found to be the excess boronic acid and the filtrates contained the product and some impurities. The filtrates were purified by chromatography on silica, eluting with 0-40% ethyl acetate in isohexane, to give the desired compound as an orange oil (530 mg).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([CH3:6])[CH3:5].N[CH2:8][C@@H:9]1CC[CH2:11][N:10]1CC>>[CH3:1][N:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[CH2:8][CH2:9][NH:10][CH3:11]
Reactant: CNCC(C)C
Reactant: CCN1CCC[C@H]1CN
Product: CNCCN(C)CC(C)C

Procedure:
By using N-methylisobutylamine (1.01 g) as a starting material, the title compound (170 mg) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 19, (3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:14]3[CH2:16][CH2:15]3)[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([CH2:31]Br)[CH:25]=1>C(#N)C>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([CH:25]=1)[CH2:31][N:11]1[C:10](=[O:13])[N:9]([CH:14]2[CH2:16][CH2:15]2)[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:12]1
Reactant: Fc1ccc(Br)cc1CBr
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=c1n(Cc2cc(Br)ccc2F)nc(-c2ccc(Cl)cc2)n1C1CC1

Procedure:
300 mg (1.27 mmol) of 5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one [preparation according to WO 2007/134862 Example 36A] and 622 mg (1.91 mmol) of cesium carbonate were suspended in 5 ml of acetonitrile, and 536 mg (1.40 mmol) of 4-bromo-2-(bromomethyl)-1-fluorobenzene were added. The mixture was stirred under reflux for 18 h. The precipitated solid was then filtered off and the filtrate was concentrated under reduced pressure to a volume of about 1.5 ml. After addition of 0.5 ml of 1 N hydrochloric acid, the mixture was directly purified chromatographically [Method 19]. This gave 427 mg (56% of theory) of the target compound in a purity of 71%.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([N+:21]([O-:23])=[O:22])=[CH:13][C:12]=1[N+:24]([O-])=O)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[OH-].[NH4+].[Cl-].[NH4+].[S-2].[Na+].[Na+]>C(O)C.O>[CH2:1]([O:3][P:4]([CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([N+:21]([O-:23])=[O:22])=[CH:13][C:12]=1[NH2:24])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(CNc1c([N+](=O)[O-])cc([N+](=O)[O-])c2ccccc12)OCC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOP(=O)(CNc1c(N)cc([N+](=O)[O-])c2ccccc12)OCC
Yield: 21 %

Procedure:
1.352 g of (2,4 dinitro-1-naphthylamino)-methanephosphonic acid diethyl ester is dissolved in 32 ml of ethanol and 23 ml of water, to it is added 4.4 ml of 25% ammonium hydroxide solution, 1.61 g of ammonium chloride and 2.81 g of 35% sodium sulfide and the solution is heated for a few hours to 90° C. The ethanol-water mixture is concentrated by evaporation on a rotary evaporator, taken up in water, extracted with ethyl acetate, washed with brine, dried and spun in. The crude product is chromatographed on silica gel with 2 liters of cyclohexane and ethyl acetate 1:1 and 1 liter of pure ethyl acetate as mobile solvent. 262 mg of product is obtained in several fractions as brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][N:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C(OCC)C>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(C)nc1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc(CO)cn1

Procedure:
To a solution of methyl 6-methylnicotinate (25 g, 0.16 mol) in ethyl ether (620 mL) under nitrogen was added dropwise sodium bis(2-methoxyethoxy)aluminium hydride (Red-Al®) (65 wt. % in toluene, 110 mL, 0.37 mol) at room temperature. The mixture was then heated to reflux for 1.5 hr. After cooling, the reaction mixture was quenched with water (500 mL) at 0° C. and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel column to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:15])/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].I[CH3:17]>CN(C=O)C.C1CCN2C(=NCCC2)CC1>[CH3:17][O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:15]
Reactant: O=C(O)/C=C/C(=O)c1ccc(Cl)c(Cl)c1
Reactant: CI
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)/C=C/C(=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 84.9 %

Procedure:
To an ice cooled solution of (E)-4-(3',4'-dichlorophenyl)-4-oxo-2-butenoic acid (2.4 g, 0.01 mol) in dry DMF (80 mL), DBU (1.5 mL, 0.01) was added dropwise on stirring, under nitrogen atmosphere. To the resulting stirred solution iodomethane (3.1 mL, 0.05 mol) dissolved in dry DMF (20 mL) was added dropwise over 20 min. The resulting solution was stirred at 0° C. for 1 hour and 3 hours at room temperature. The resulting reaction mixture was poured into ice-water on stirring, and the precipitate was filtered, washed with water and then with hexane. Recrystallization from diisopropyl ether/hexane provided the pure ester (2.2 g, 86%), pale yellow needles, mp. 108-109°.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]3[NH:16][CH:17]=[C:18]([NH:19][C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=4)[C:10]=23)[CH2:4]1.CCN(C(C)C)C(C)C.C(OC)(OC)OC.[CH:44](=O)[CH:45]([CH3:47])[CH3:46].[BH4-].[Na+]>CO.O>[ClH:1].[Br:15][C:14]1[C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@@H:3]([NH:2][CH2:44][CH:45]([CH3:47])[CH3:46])[CH2:4]2)=[C:10]2[C:18]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=3)=[CH:17][NH:16][C:11]2=[N:12][CH:13]=1
Reactant: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Reactant: CC(C)C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: COC(OC)OC
Solvent: CO
Product: CC(C)CN[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.3 %

Procedure:
(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (0.075 g, 0.14 mmol, Example 1A), DIEA (0.100 mL, 0.57 mmol; d 0.742) and trimethyl orthoformate (0.32 mL, 2.9 mmol) were placed in MeOH (3 mL) at room temperature. Isobutyraldehyde (0.026 mL, 0.29 mmol) was then added, and the reaction was stirred at room temperature for 18 hours. NaBH4 (0.014 g, 0.36 mmol) was then added, and the reaction was stirred for 1 hour. The reaction was then poured into water, and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by reverse phase HPLC (0-50% acetonitrile (“ACN”) in water, Gilson system). The purified product was then dissolved in DCM (with minimal MeOH to aid solubility) and added dropwise to a stirring solution of 1M HCl in ether. The resulting solid was filtered, dried and collected to give (R)—N-(5-bromo-4-(3-(isobutylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (0.050 g, 60% yield). 1H NMR (400 MHz, D2O) δ 9.16-9.16 (m, 1H), 8.83-8.82 (m, 1H), 8.77-8.75 (m, 1H), 8.27 (s, 1H), 7.96-7.93 (m, 1H), 7.42 (s, 1H), 3.78-3.75 (m, 1H), 3.34-3.33 (m, 2H), 3.22-3.17 (m, 1H), 3.09-3.03 (m, 1H), 2.77-2.67 (m, 2H), 2.00-1.97 (m, 1H), 1.81-1.75 (m, 1H), 1.68-1.65 (m, 1H), 1.52-1.49 (m, 1H), 1.35-1.32 (m, 1H), 0.80-0.78 (m, 6H); LCMS (APCI+) m/z 471, 473 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([C:13](=[O:33])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])[CH3:12])C1C=CC=CC=1>Br.C(O)(=O)C>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:24]1[C:16]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=2[NH:14][C:13](=[O:33])[C@H:11]([CH3:12])[N:10]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Agent: Br
Solvent: CC(=O)O
Product: C[C@@H]1N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
130 g (0.27 mol) of (S)-benzyl-[1-[[2-(o-chlorobenzoyl)-4-nitrophenyl]carbamoyl]ethyl]carbamate are dissolved in 350 ml of a 30 to 33 percent solution of hydrogen bromide in glacial acetic acid, the solution is stirred at room temperature for 30 minutes, evaporated, treated with water and extracted three times with ether. The aqueous solution is cooled in ice, neutralized with solid sodium bicarbonate and extracted with methylene chloride. The organic phase is dried over sodium sulphate and evaporated. The residue is treated with 80 ml of glacial acetic acid and 800 ml of toluene, the mixture is heated to boiling under reflux for 20 minutes and then evaporated. The residual oil is taken up in methylene chloride, washed with saturated sodium bicarbonate solution, dried over sodium sulphate and evaporated. The residue is dissolved in 500 ml of benzene, the solution is seeded with racemic 5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one and left to stand at room temperature overnight. The crystalline material is filtered off and the mother liquor is evaporated. After recrystallization of the residue from ether, there is obtained (S)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 200°-202°; [α]25D =+241° (1 percent solution in methylene chloride).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[F:10][B-](F)(F)F.F[N+]1C(C(Cl)(Cl)Cl)=CC=CC=1Cl>ClC(Cl)CCl>[F:10][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([OH:9])=[C:4]([Cl:8])[CH:5]=1
Reactant: Oc1c(Cl)cccc1Cl
Reactant: F[B-](F)(F)F
Agent: F[n+]1c(Cl)cccc1C(Cl)(Cl)Cl
Solvent: ClCC(Cl)Cl
Product: Oc1c(Cl)cc(F)cc1Cl
Temperature: 55 °C

Procedure:
A mixture of 0.82 g of 2,6-dichlorophenol, 1.67 g of N-fluoro-2-chloro-6-(trichloromethyl)pyridinium fluoroborate, and 40 ml of 1,1,2-trichloroethane was placed in a 100 ml 3-necked round bottomed flask equipped with a magnetic stirring bar, a thermometer, and a reflux condenser. The mixture was heated to 55° C. and allowed to react at that temperature for 8 hours under nitrogen. The mixture was then allowed to cool. Analysis by standardized gas-liquid chromatography using a mass spectrometer detector indicated that the title product was present in 24 percent conversion. The product identity was confirmed by its known 19F and 1H NMR spectra.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10](=[O:20])[CH2:9]1)C1C=CC=CC=1>[Pd].C(O)(=O)C>[C:14]1([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]2=[O:20])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CN(Cc2ccccc2)CCN1c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1CNCCN1c1ccccc1
Reaction time: 3 h
Yield: 300.8 %

Procedure:
A mixture of 4-benzyl-1-phenylpiperazin-2-one (13.0 g, 48.8 mmol), 10% palladium on carbon (700 mg), and acetic acid (150 mL) was stirred under hydrogen at atmospheric pressure for 3 hours. The reaction was purged with nitrogen and filtered through a bed of celite. The filtrate was concentrated and the residue was purified via silica gel chromatography using 10% MeOH in CH2Cl2 to obtain the desired piperazinone as a white solid (8.3 g, 146.8 mmol, 96% yield). 1H NMR (400 MHz, CDCl3) δ 7.43-7.38 (m, 2H), 7.30-7.26 (m, 3H), 3.70-3.67 (m, 4H), 3.35 (s, 1H), 3.22 (t, J=5.5 Hz, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=177.2; tR=0.44 min.