Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:15][CH:16]=[C:11]2[N:10]=[CH:9]1)=O)(C)(C)C.C[O:31][C:32](=O)[C:33]1[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[C:35]([C:41]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH:44]=[N:43][CH:42]=2)[CH:34]=1.C([N-]C(C)C)(C)C.[Li+]>O1CCCC1>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[N:13]=[C:12]3[NH:8][C:9]([C:32](=[O:31])[C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[C:35]([C:41]5[C:50]6[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=6)[CH:44]=[N:43][CH:42]=5)[CH:34]=4)=[N:10][C:11]3=[CH:16][CH:15]=2)[CH2:18][CH2:19]1)=[O:24])([CH3:27])([CH3:28])[CH3:29]
Reactant: COC(=O)c1ccc(C#N)c(-c2cncc3ccccc23)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3nc(C(=O)c4ccc(C#N)c(-c5cncc6ccccc56)c4)[nH]c3n2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 23.1 %

Procedure:
The mixture of 5-(4-tert-butoxycarbonyl-piperazin-1-yl)-imidazo[4,5-b]pyridine-3-carboxylic acid tert-butyl ester (56 mg, 0.139 mmole), 4-cyano-3-isoquinolin-4-yl-benzoic acid methyl ester (40 mg, 0.139 mmole), and tetrahydrofuran (2 ml) was cooled to −78° C. Lithium diisopropylamide (2N, 0.14 ml, 0.28 mmole) was added slowly. Reaction mixture was stirred at −78° C. for 2 hours and then was quenched with water, extracted with EtOAc. EtOAc layer was concentrated and crude product was purified by using silica gel chromatography, eluting with 20% to 100% EtOAc in heptane to afford 4-[2-(4-cyano-3-isoquinolin-4-yl-benzoyl)-3H-imidazo[4,5-b]pyridine-5-yl]piperazine-1-carboxylic acid tert-butyl ester (18 mg, 23%) as a yellow solid. 1H NMR (400 MHz, CD2Cl2) δ 1.60 (s, 9H), 3.57 (m, 4H), 3.71 (m, 4H), 6.85 (d, J=9.03 Hz, 1H), 7.70 (d, J=7.53 Hz, 1H), 7.78 (m, 2H), 7.95 (d, J=9.03 Hz, 1H), 8.09 (d, J=8.03 Hz, 1H), 8.19 (d, J=8.03 Hz, 1H), 8.62 (s, 1H), 8.84 (s, 1H), 8.89 (d, J=8.53 Hz, 1H), 9.43 (s, 1H), 10.28 (s, 1H). HR-MS m/z 560.2406 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:6]([C:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[F:20])=[C:9]([CH3:11])[N:10]=2)[N:7]=1.[CH3:28][O:29][C:30]1[CH:43]=[CH:42][C:33]([CH2:34][N:35]2[C:39]([CH3:40])=[CH:38][C:37]([NH2:41])=[N:36]2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O1CCOCC1.O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:8]2[N:6]3[N:7]=[C:2]([NH:41][C:37]4[CH:38]=[C:39]([CH3:40])[N:35]([CH2:34][C:33]5[CH:42]=[CH:43][C:30]([O:29][CH3:28])=[CH:31][CH:32]=5)[N:36]=4)[CH:3]=[C:4]([CH2:21][N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:5]3=[N:10][C:9]=2[CH3:11])=[C:14]([F:20])[CH:15]=1
Reactant: Cc1nc2c(CN3CCOCC3)cc(Cl)nn2c1Cc1ccc(Cl)cc1F
Reactant: COc1ccc(Cn2nc(N)cc2C)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Cn2nc(Nc3cc(CN4CCOCC4)c4nc(C)c(Cc5ccc(Cl)cc5F)n4n3)cc2C)cc1
Yield: 86.1 %

Procedure:
Combine 4-((6-chloro-3-(4-chloro-2-fluorobenzyl)-2-methylimidazo[1,2-b]pyridazin-8-yl)methyl)morpholin (0.36 g, 0.88 mmol), 1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-amine (0.248 g, 1.3 equiv.), potassium carbonate (0.30 g, 2.5 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.076 g, 0.15 equiv.), water (2 mL), and 1,4-dioxane (20 mL) in a round bottom flask. Degas thoroughly with nitrogen then add bis(dibenzylideneacetone)palladium (0.10 g, 0.2 equiv.). Attach a reflux condenser and place under nitrogen. Heat the reaction at reflux overnight. Pass reaction through a Celite plug. Wash the plug with EA. Transfer to a separatory funnel and wash with water. Wash the organic layer with aqueous sodium chloride, and dry over anhydrous magnesium sulfate. Filter and concentrate in vacuo. Purify on silica gel (EA→10% methanol:EA) to give the title compound (0.447 g, 86%) as a pale yellow solid. LCMS (4 min)=590.2, 591.2, M+1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1.[C:18](Cl)(=[O:27])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:17][C:8]1[C:7]2[N:6]=[CH:5][N:4]([CH2:3][CH2:2][NH:1][C:18](=[O:27])[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: NCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)CCc1ccccc1
Product: Nc1nc2ccccc2c2c1ncn2CCNC(=O)CCc1ccccc1
Yield: 37.9 %

Procedure:
Using the method of Example 14, 1-(2-aminoethyl)-1H-imidazo[4,5-c]quinolin-4-amine (100 mg, 0.44 mmol) was reacted with hydrocinnamoyl chloride (0.065 mL, 0.44 mmol) to provide 0.06 g of N1-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-3-phenylpropanamide as a white solid, m.p. 254-256° C. 1H NMR (500 MHz, DMSO-d6) δ 8.16 (d, J=8.0 Hz, 1H), 8.07 (t, J=6.0 Hz, 1H), 7.97 (s, 1H), 7.62 (dd, J=8.0, 1.0 Hz, 1H), 7.45 (dt, J=8.0, 1.0 Hz, 1H), 7.26 (m, 3H), 7.16 (m, 3H), 6.6 (broad s, 2H), 4.61 (t, J=7.0 Hz, 2H), 3.54 (q, J=6.0 Hz, 2H), 2.75 (t, J=7.0 Hz, 2H), 2.31 (t, J=7.0 Hz, 2H); MS (EI) m/e 359.1745 (359.1746 calcd for C21H21N5O).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][CH:32]([F:41])[C:33]1[CH:34]=[CH:35][C:36]([F:40])=[C:37]([CH:39]=1)[NH2:38].CCN(C(C)C)C(C)C>C1COCC1.C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:38][C:37]3[CH:39]=[C:33]([CH:32]([F:31])[F:41])[CH:34]=[CH:35][C:36]=3[F:40])=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)O)c3c(c2[nH]1)CC(C)(C)O3
Reactant: Nc1cc(C(F)F)ccc1F
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)Nc3cc(C(F)F)ccc3F)c3c(c2[nH]1)CC(C)(C)O3
Yield: 7.2 %

Procedure:
The title compound was prepared by following the procedure as described for Example-108 using 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-35, 0.100 g, 0.269 mmol), thionyl chloride (2.0 mL), 5-(difluoromethyl)-2-fluoroaniline (Intermediate-46, 0.065 g, 0.403 mmol), benzene (4 mL), THF (6.0 mL) and DIPEA (4 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.010 g of the desired product. 1HNMR (DMSO-d6): δ 1.56 (s, 6H), 2.24 (s, 3H), 3.14 (s, 2H), 6.88-7.23 (t, J=5.8 Hz, 1H), 7.51-7.13 (m, 5H), 7.54 (s, 1H), 8.78 (d, J=6.9 Hz, 1H), 9.01 (s, 1H), 10.26 (s, 1H), 10.98 (s, 1H); MS [M+H]+: 515.17.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[CH:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]=[CH:15][CH2:16][CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:18])=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=CCC(C)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=CCC(C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using dichlorobis(triphenylphosphine)palladium(II) as the catalyst and the following starting materials: 5-(4-bromo-phenyl)-3-methyl-4-(4-phenyl-pent-1-enyl)-isoxazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[CH:5]([C:7]1[CH:36]=[CH:35][CH:34]=[CH:33][C:8]=1[O:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:32])[CH2:17][NH:18][C:19]([C:21]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:23][N:22]=2)=[O:20])[CH2:12][CH2:11]1)=O.C([O-])(=O)C.[Na+]>CO.O>[CH3:2][O:3][N:4]=[CH:5][C:7]1[CH:36]=[CH:35][CH:34]=[CH:33][C:8]=1[O:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:32])[CH2:17][NH:18][C:19]([C:21]2[CH:25]=[C:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:23][N:22]=2)=[O:20])[CH2:12][CH2:11]1
Reactant: O=Cc1ccccc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CON=Cc1ccccc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reaction time: 4 h
Yield: 31.1 %

Procedure:
O-Methyl-hydroxylamine hydrochloride (23 mg, 0.27 mmol) was added to a stirred cold (0° C.) mixture of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-formyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide (100 mg, 0.23 mmol) and sodium acetate (56 mg, 0.7 mmol) in MeOH (10 mL) and stirring was continued at ambient temperature for 4 hrs. The reaction mixture was diluted with water, extracted with ethyl acetate, dried over sodium sulfate, and the organic layer was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 33 mg (31.13% yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid (2-{4-[2-(methoxyimino-methyl)-phenoxy]-piperidin-1-yl}-2-oxo-ethyl)-amide. LC/MS [M+H]+: 462.2, 96.3%. 1H NMR (300 MHz, DMSO-d6): δ13.7 (s, 1H), 8.4 (s, 1H), 8.1 (t, 1H), 7.8 (t, 2H), 7.7 (d, 1H), 7.5-7.34 (m, 4H), 7.2 (d, 1H), 7.1 (s, 1H), 7.0 (t, 1H), 4.8 (bs, 1H), 4.2 (b, 2H), 3.9 (s, 3H), 3.8-3.6 (bs, 2H), 3.5 (b, 2H), 2.1-1.9 (b, 2H), 1.8-1.6 (b, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>O1CCOCC1>[ClH:24].[N:11]1([C:14]2[CH:15]=[N:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc3ccccc3c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2ncc(N3CCNCC3)cc2c1

Procedure:
Prepared in analogy to example 1.6(d) from 4-quinolin-3-yl-piperazine-1-carboxylic acid tert.-butyl ester and dioxane saturated with gaseous hydrochloric acid. Yellow solid.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[NH:10])=[N:6][CH:7]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1OB(O)O.C(=O)([O-])[O-].[Na+].[Na+]>[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>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][NH:11][C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)=[CH:7][N:6]=1)=[NH:10]
Reactant: OB(O)Oc1cccs1
Reactant: COc1ccccc1CNC(=N)Nc1ccc(I)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccccc1CNC(=N)Nc1ccc(-c2cccs2)cn1
Temperature: 120 °C
Yield: 22.1 %

Procedure:
The preparation was carried out analogously to Example 86, using 0.125 g (0.308 mmol) N-(5-iodopyridin-2-yl)-N′-(2-methoxybenzyl)guanidine, 0.055 g (0.431 mmol) 2-thienylboric acid, 0.098 g (0.925 mmol) sodium carbonate, and 0.018 g (0.015 mmol) tetrakis-(triphenylphosphine)-palladium(0). The mixture was likewise heated for 60 min at 120° C. in a CEM microwave (200 watts). After filtration and purification via preparative HPLC, 23 mg N-(2-methoxybenzyl)-N′-[5-(2-thienyl)pyridin-2-yl]guanidine was isolated, a small portion of which was present in the form of the acetate salt (base/acetate in a ratio of 1:0.3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28](Cl)=[O:29]>C1COCC1.C(Cl)Cl>[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=2)[CH2:10][CH2:11]1)=[O:29]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC(=O)c3ccc(F)c(F)c3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3,4-difluorobenzoyl chloride: ESMS m/e: 458.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:29]#[N:30])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]([F:27])[CH3:26])[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:28])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:29]#[N:30])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]([F:27])[CH3:26])[C:17]([OH:19])=[O:18])[C:10](=[O:28])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC(C)F)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC(C)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
270 mg (0.59 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-fluoropentanoate (mixture of racemic diastereomers) were hydrolysed with TFA according to General Method 6A. Yield: 222 mg (purity 85%, 84% of theory)
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:19]#[N:20])=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C2C=CC(I)=CC=2O[C:23]=1[C:32]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[Cl:41])=[O:33]>>[NH2:20][C:19]1[C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][C:15]=2[O:18][C:23]=1[C:32]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[Cl:41])=[O:33])[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][CH2:10][CH2:11]3
Reactant: Nc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(I)ccc12
Reactant: N#Cc1cc2c(cc1O)N(Cc1ccccc1)CCC2
Product: Nc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc3c(cc12)CCCN3Cc1ccccc1
Yield: 29 %

Procedure:
This compound was prepared from 1-benzyl-7-hydroxy-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (20 mg, 0.08 mmol) from step 4 in the manner described for [(3-amino-6-iodo-benzofuran-2-yl)-(2,4-dichloro-phenyl)-methanone, affording 10 mg (29%) of the title compound as a yellow solid. 1H-NMR (CDCl3) δ 7.44–7.40 (m, 2H), 7.33–7.22 (m, 4H), 7.18 (s, 1H), 7.15–7.13 (m, 2H), 6.25 (s, 1H), 5.96 (bs, 2H), 4.52 (s, 2H), 3.47 (t, J=6.0 Hz, 2H), 2.89 (t, J=5.9 Hz, 2H), 2.03 (m, 2H); MS LC-MS (MH+=451.3), LC MS RT: 3.81 min.
Reaction SMILES: [NH2:1][CH:2]1[C:16](=[O:17])[N:4]2[C:5]([C:13]([OH:15])=[O:14])=[C:6]([CH2:9][N:10]=[N+:11]=[N-:12])[CH2:7][S:8][C@H:3]12.[C:18](=[O:21])(O)[O-:19].[Na+]>O.C(O)(C)(C)C>[N:10]([CH2:9][C:6]1[CH2:7][S:8][C@@H:3]2[CH:2]([NH:1][C:18]([O:19][C:6]([CH3:9])([CH3:7])[CH3:5])=[O:21])[C:16](=[O:17])[N:4]2[C:5]=1[C:13]([OH:15])=[O:14])=[N+:11]=[N-:12]
Reactant: O=C([O-])O
Reactant: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12
Temperature: 25 °C
Reaction time: 72 h
Yield: 71 %

Procedure:
7-Amino-3-azidomethylceph-3-em-4-carboxylic acid (170 g.) was suspended by stirring in water (750 ml.) and sodium bicarbonate (60 g.) added carefully, followed by t-butanol (750 ml.). Bis(O-t-butyl)carbonic anhydride (170 ml.) dissolved in t-butanol (375 ml.) was added and the mixture left to stir at ambient temperature; further portions of reagent (20 ml.) in t-butanol (40 ml.) were added after 24 and 48 hours. After 72 hours, t-butanol was removed by evaporation and the aqueous residue, diluted with water to 21°, was cooled in ice. The pH was reduced to 3 with concentrated hydrochloric acid, and the precipitate filtered, and washed free of acid. After drying under vacuum, the crude product was extracted successively with 500 ml. and two 400 ml. portions of acetonitrile. The combined extracts were evaporated to a small volume and filtered to give 3-azidomethyl-7-t-butoxycarbonylaminoceph-3-em-4-carboxylic acid (84 g.), having the following n.m.r. in solvent A: 1.4(s, 9 H); 3.5(d, 2H); 4.2(d, 2H); 5.0(d, 1H); 5.4(d, 1H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)([CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)[C:5]([NH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:6].[CH3:33][Mg]Br>C(OCC)C>[C:8]12([NH:7][C:5](=[O:6])[C:4]([CH2:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:3](=[O:2])[CH3:33])[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2
Reactant: COC(=O)C(Cc1ccncc1)(Cc1ccncc1)C(=O)NC12CC3CC(CC(C3)C1)C2
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC(=O)C(Cc1ccncc1)(Cc1ccncc1)C(=O)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-adamantan-1-yl-2,2-bis-pyridin4-ylmethyl-malonamic acid methyl ester (750 mg, 1.68 mmol) chilled to 5 ° C., cuprous bromide (10.0 mg) and a 3.0M solution of methyl magnesium bromide in diethyl ether (1.67 ml, 5.03 mmol of methyl magnesium bromide) was added. After 18 hours stirring at ambient temperature, a second 1.67 ml portion of 3.0M methyl magnesium bromide in diethyl ether was added. Three hours thereafter, a final 1.67 ml portion of 3.0M methyl magnesium bromide was added. After 18 hours of additional stirring at ambient temperature, the reaction was quenched by addition of 15 ml of ice water containing 250 μl of concentrated sulfuric acid. The mixture was then extracted with three 50 ml portions of methylene chloride. The combined extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to an oil (520 mg). Flash chromatography of the entire sample (silica gel, 40 micron mesh; elution with methanol/methylene chloride=4:96 in volume) afforded the title compound (free base) as a colorless oil (236 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.[CH3:32][N:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)N>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:33]([CH3:32])[C:35]2[C:40]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:39][CH:38]=[CH:37][CH:36]=2
Reactant: CN(N)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3F)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4F)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 512.2 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:40]=[CH:39][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[N:15]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]2=[O:38])=[CH:10][CH:9]=1.Br[CH2:42][C:43]([O:45][CH3:46])=[O:44]>CC(C)=O>[CH3:46][O:45][C:43]([CH2:42][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[N:15]([C:19]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:14]2=[O:38])=[CH:39][CH:40]=1)=[O:44]
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Reaction time: 1 h

Procedure:
126 g of cesium carbonate were added at room temperature to a solution of 120 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione in 2.5 liters of acetone, followed by 36 ml of methyl bromoacetate, and the resulting mixture was stirred for 1 hour. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the resulting residue was mixed with water. The aqueous mixture was then extracted with ethyl acetate. The extract was washed with water and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, after which 1 liter of diethyl ether was added to the oily residue. The mixture was then agitated ultrasonically for 10 minutes. The solid substance precipitated was collected by filtration, to give 126.3 g of the title compound, melting at 158°-162° C.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[CH2:10]([NH:7][C:5](=[O:6])[CH:4]1[CH2:8][CH2:9][NH:1][CH2:2][CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: NC(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(NCc1ccccc1)C1CCNCC1
Yield: 51.7 %

Procedure:
To a suspension of isonipecotamide (12.3 g, 96 mmol) in 200 mL of dichloromethane, was added, benzaldehyde (10.6 g, 100 mmol) and sodium triacetoxyborohydride (29.7 gm, 140 mmol) and the mixture was stirred at room temperature for 5 days. The thick white mixture was diluted with 100 mL water and extracted with EtOAc (2×20 mL). The aqueous phase was basified with 1N NaOH to pH>12. The resulting white precipitate was collected by suction filtration. The white solid was subsequently taken up in 50 mL of EtOAc, and was washed with 20 mL of brine, then dried (MgSO4), filtered and concentrated to give 10.84 g (50%) of the desired product. 1H-NMR (400 MHz, CDCl3) δ7.85 (m, 5H), 5.45 (s, 1H), 5.34 (s, 1H), 3.5 (s, 2H), 2.93 (d, J=10.96 Hz, 2H), 2.16 (t, J=12.13 Hz, 1H), 2.01 (t, J=11.74 Hz, 2H), 1.87 (d, J=12.52 Hz, 2H), 1.76 (q, J=12.52 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]23[CH2:17][O:16][C@@H:15]([C:18]4[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:7]=1.[C:34](C1C=CC(F)=C([C@]23CO[C@@H](C4ON=C(C)C=4)C[C@H]2CSC(NC(=O)C2C=CC=CC=2)=N3)C=1)#[N:35]>>[C:34]([C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]23[CH2:17][O:16][C@@H:15]([C:18]4[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:9]3)[CH:7]=1)#[N:35]
Reactant: Cc1cc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cc(C#N)ccc3F)CO2)on1
Reactant: Cn1cc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cc(Br)ccc3F)CO2)cn1
Product: Cn1cc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cc(C#N)ccc3F)CO2)cn1

Procedure:
N-[(4aR,6R,8aS)-8a-(5-Bromo-2-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C46) was converted to the product using the method described for synthesis of N-[(4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C37) as in Example 10. The product was obtained as a white solid. Yield: 265 mg, 98%. LCMS m/z 476.2 [M+H+]. 1H NMR (400 MHz, CD3OD) characteristic peaks: δ 8.11 (br d, J=7.4 Hz, 2H), 7.98 (br s, 1H), 7.83-7.85 (m, 1H), 7.64-7.67 (m, 3H), 7.54-7.58 (m, 2H), 7.40-7.53 (m, 1H), 4.77 (dd, J=11.4, 2.2 Hz, 1H), 4.25-4.29 (m, 1H), 4.07-4.12 (m, 1H), 3.96 (d, J=11.5 Hz, 1H), 3.84 (s, 3H), 2.93-2.97 (m, 1H), 2.80 (dd, J=13.2, 2.6 Hz, 1H), 2.13-2.120 (m, 1H), 1.97-2.01 (m, 1H).