Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C[O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20]/[C:21](=[N:28]\[O:29][CH3:30])/[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:6]=1[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])#N>[Pd]>[OH:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20]/[C:21](=[N:28]\[O:29][CH3:30])/[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:18]=2)[CH:8]=[CH:7][C:6]=1[CH2:31][CH2:32][C:33]([OH:35])=[O:34]
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(OC/C(=N\OC)c3ccccc3)cc2)cc1OCC#N
Agent: [Pd]
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)c(O)c2)cc1)c1ccccc1
Yield: 36 %

Procedure:
Compound 96 was synthesized from ethyl 3-{2-(cyanomethoxy)-4-[(4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}benzyl)oxy]phenyl}propanoate (Intermediate 134, 0.1 g, 0.199 mmol) and Pd—C (0.02 g), followed by hydrolysis described in scheme 16 (0.005 g, yield: 36.0%); Purity: 93.97%.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([C:5](B3OC(C)(C)C(C)(C)O3)=[CH:6][CH:7]=[CH:8]2)=[N:3]1.Cl[C:21]1[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=1.CN(C=O)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O>[Cl:27][C:26]1[C:21]([C:5]2[C:4]3[C:9](=[CH:10][N:2]([CH3:1])[N:3]=3)[CH:8]=[CH:7][CH:6]=2)=[N:22][CH:23]=[C:24]([Cl:28])[CH:25]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: Cn1cc2cccc(B3OC(C)(C)C(C)(C)O3)c2n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc2cccc(-c3ncc(Cl)cc3Cl)c2n1
Temperature: 65 °C

Procedure:
A mixture of 2-methyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole (0.040 g, 0.15 mmol), 2,3,5-trichloropyridine (0.274 g, 1.50 mmol), (Ph3P)4Pd(0) (0.019 g, 0.017 mmol), 2 mL of DMF, and 2 mL of a 2 M K3PO4 solution was stirred at 65° C. for. 16 h then allowed to cool. Water (10 mL) was added, and the mixture was extracted with three 5 mL portions of ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated to a brown solid. Column chromatography (0→50% EtOAc/hexanes) afforded of 7-(3,5-dichloro-pyridin-2-yl)-2-methyl-2H-indazole (7:R=Me; R′=H; Ar=3,5-dichloro-pyridin-2-yl; 0.042 g; 93%).
Reaction SMILES: C([C:3]1[C:4]([NH2:15])=[C:5]([C:12](O)=[O:13])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8])C.Cl.[CH:17](N)=[NH:18]>C(O)C>[OH:13][C:12]1[C:5]2[C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=[CH:3][C:4]=2[N:15]=[CH:17][N:18]=1
Reactant: N=CN
Reactant: CCc1ccc(C(=O)O)c(C(=O)O)c1N
Agent: Cl
Solvent: CCO
Product: O=C(O)c1cccc2ncnc(O)c12
Yield: 55.4 %

Procedure:
To a solution of ethyl 3-aminophthalic acid (1.00 g) in ethanol (10 ml) was added formamidine hydrochloride (444 mg) and refluxed for 12 hours. After cooling, the formed precipitate was collected by vacuum filtration and the precipitate was washed with ethanol to give 4-hydroxyquinazoline-5-carboxylic acid (504 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([OH:10])[CH3:9].Cl[C:13]1[C:14]2[C:21]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=3)=[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:19][C:15]=2[N:16]=[CH:17][N:18]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([O:10][C:13]1[C:14]2[C:21]([C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=3)=[C:20]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[O:19][C:15]=2[N:16]=[CH:17][N:18]=1)[CH3:9]
Reactant: COC(=O)CCCCC(C)O
Reactant: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(OC(C)CCCCC(=O)OC)c23)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Put 717 mg (4.48 mmol) (+/−)-6-hydroxyheptanoic acid methyl ester under argon in 10 ml THF and cool to 0° C. Add 2.25 ml (4.48 mmol) of a 2 M solution of phosphazene base P2-tert.-butyl in THF and stir for a further 10 min at RT. Then cool to 0° C. again. Add 1.0 g (2.99 mmol) 4-chloro-5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidine and continue stirring overnight at RT. Dilute with water, acidify with 10% aqueous citric acid solution and extract twice with ethyl acetate. Combine the ethyl acetate phases and wash once with satd. sodium chloride solution. Dry over magnesium sulphate, concentrate by evaporation and purify the residue by column chromatography on silica gel (solvent: cyclohexane/ethyl acetate 9:1). 640 mg (46.7% of theor.) of the target compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:12])[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[NH2:8].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([NH:8][C:7]1[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[N:3]([CH3:12])[C:2]=1[NH2:1])(=[O:15])[CH3:14]
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1c(N)n(C)c(=O)n(C)c1=O

Procedure:
A mixture of acetic anhydride (50 ml) and 4,5-diamino-1,3-dimethylpyrimidine-2,6-dione (5.4 g) was heated at reflux for 30 minutes. The mixture was then cooled, and the crystalline matter which separated was filtered off to give 5-acetylamino-4-amino-1,3-dimethylpyrimidine-2,6-dione as white needles. A suspension of oil-free sodium hydride (1.3 g) in dry dimethylformamide (5.0 ml) was stirred under nitrogen at 0° C. while the acetylamino compound was added. The mixture was then stirred for 30 minutes. Diethylaminoethyl chloride hydrochloride (4.64 g) was added, then the mixture was warmed to room temperature and stirred for 3 hours. Water was added, and the mixture was extracted with chloroform. The organic extracts were washed with water, dried and filtered, and the filtrate was evaporated to dryness. The solid residue was treated with 2 N aqueous sodium hydroxide (50 ml) at 100° C. for 30 minutes, then the mixture was extracted with chloroform, dried, filtered and evaporated to dryness. The oil product was dissolved in ethanol, treated with ethanolic hydrogen chloride and evaporated to dryness. The residue was recrystallised from isopropyl alcohol to give 8-methyl-7-(2-diethylaminoethyl)theophylline hydrochloride (3.1 g), mp 230°-232° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:41]=[CH:40][C:20]3[C:21](=[O:39])[CH2:22][C:23]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[O:24][C:19]=3[C:18]=2[CH2:42][CH2:43][CH3:44])=[CH:4][CH:3]=1.ClC1C=CC(OCCCOC2C=CC3C(=O)CC(CCC(OCC)=O)(CCC(OCC)=O)OC=3C=2CCC)=CC=1>C(OCC)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:41]=[CH:40][C:20]3[C:21](=[O:39])[CH2:22][C:23]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[O:24][C:19]=3[C:18]=2[CH2:42][CH2:43][CH3:44])=[CH:4][CH:3]=1
Reactant: CCCc1c(OCCCOc2ccc(Cl)c3ccccc23)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Agent: CCCc1c(OCCCOc2ccc(Cl)cc2)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Solvent: CCOCC
Product: CCCc1c(OCCCOc2ccc(Cl)c3ccccc23)ccc2c1OC(CCC(=O)O)(CCC(=O)O)CC2=O

Procedure:
The title compound was prepared by the method of Example 22 substituting the title product of Example 34 (515 mg) for the title product of Example 21 to give, after trituration with diethylether, 352 mg as a solid, m.p. 170.5°-171° C.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[N+:18]([O-])=O>CCOC(C)=O.[Pd]>[NH2:18][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:2]=1[NH2:1])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)=[O:7]
Reactant: Nc1ccc(C(=O)Nc2cccc(Cl)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)Nc2cccc(Cl)c2)cc1N
Reaction time: 8 h

Procedure:
To a solution of 4-amino-N-(3-chloro-phenyl)-3-nitrobenzamide (590 mg) in EtOAc (200 mL) was added 10% Pd/C (100 mg). The reaction mixture was stirred overnight under H+ balloon. The reaction mixture was filtered through a Celite pad, washed with EtOAc. The solution was concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, EtOAc:Hexane=20:80 to 100:0) to give of 3,4-diamino-N-(3-chloro-phenyl)-benzamide as a white solid: MS (m/z) 262 (M+1); 1H NMR (DMSO-d6, 400 MHz) δ 9.84 (s, 1H), 7.95 (t, 1H), 7.67 (d, 1H), 7.32 (t, 1H), 7.12 (m, 2H), 7.07 (dd, 1H), 6.54 (d, 1H), 5.12 (s, 2H), 4.63 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:31])=[C:27]([F:30])[CH:28]=4)[NH:23][C:22]3=[O:32])[CH:13]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:11])=[C:5]([O:41][CH3:42])[CH:4]=1)#[N:2].[OH:43]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:31])=[C:27]([F:30])[CH:28]=4)[NH:23][C:22]3=[O:32])[CH:13]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:11])=[C:5]([O:41][CH3:42])[CH:4]=1)(=[O:43])[NH2:2]
Reactant: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)c(F)cc32)C1c1cccc(Cl)c1F
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(C(N)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)c(F)cc32)C1c1cccc(Cl)c1F
Temperature: 10 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-5-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide (0.23 g, 0.38 mmol) prepared in Example 112 in DMSO (2 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.64 g, 5.6 mmol), then aqueous solution (1N) of NaOH (1.9 mL, 1.9 mmol) was added dropwise. The reaction mixture was stirred at 10° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichloromethane and hexanes to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-5-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-2-methoxy-phenyl)-amide as a white solid (Yield 0.17 g, 72%)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH:16]=[O:17])[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Br[C:19]1[CH:20]=[C:21]([O:25][CH3:26])[CH:22]=[CH:23][CH:24]=1>>[CH3:26][O:25][C:21]1[CH:20]=[C:19]([C:13]2[N:9]3[N:10]=[CH:11][CH:12]=[C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[C:8]3=[N:15][C:14]=2[CH:16]=[O:17])[CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1cn2nccc(N3CCOCC3)c2n1
Reactant: COc1cccc(Br)c1
Product: COc1cccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)c1

Procedure:
Compound 5e (162 mg, 0.698 mmol) was coupled with 3-bromoanisole (0.13 mL, 1.04 mmol) according to the procedures described in Example 20, Step A to obtain compound 77a. Mass spectrum (LCMS, ESI pos.) Calcd. For C18H18N4O3 339.1 (M+H). found 339.2.
Reaction SMILES: Cl.C([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:44][O:45][CH2:46][C:47]([O:49]C(C)(C)C)=[O:48])[C:11]([NH:13][CH:14]2[C:42](=[O:43])[N:16]3[C:17]([C:39]([OH:41])=[O:40])=[C:18]([CH:21]([S:33][C:34]4[NH:38][N:37]=[N:36][N:35]=4)[CH2:22][CH2:23][CH:24]([N:30]=C=O)OC(C)(C)C)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1)=O>CO>[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:44][O:45][CH2:46][C:47]([OH:49])=[O:48])[C:11]([NH:13][CH:14]2[C:42](=[O:43])[N:16]3[C:17]([C:39]([OH:41])=[O:40])=[C:18]([CH:21]([S:33][C:34]4[NH:38][N:37]=[N:36][N:35]=4)[CH2:22][CH2:23][CH2:24][NH2:30])[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(CCC(N=C=O)OC(C)(C)C)Sc3nnn[nH]3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: NCCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Conc. hydrochloric acid (20.8 g.) was added to a mixture of 7-[2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-[1-(3-tert-butoxy-carbonylaminopropyl)-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer, 39.1 g.) in methanol (400 ml.), and stirred at room temperature for 4 hours. After removing the solvent in vacuo, tetrahydrofuran (40 ml.) and anisole (40 ml.) were added to the residue and stirred at room temperature for 4 hours. The reaction mixture was added to ethyl acetate at room temperature. The precipitates were collected by filtration and washed with ethyl acetate to give 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (a mixture of syn and anti isomers). The product was subjected to column chromatography on macroporous nonionic adsorption resin "HP-20" (trademark, manufactured by Mitsubishi Chemical Industries Co.) to give the syn isomer of the objective compound.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][CH:3]=1.C1C(=O)N([Cl:19])C(=O)C1>>[Cl:19][C:3]1[N:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:6][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1ncc(C)[nH]1
Product: CCOC(=O)c1nc(Cl)c(C)[nH]1
Yield: 82.1 %

Procedure:
The same operation as in Example (1c) was performed using ethyl 5-methyl-1H-imidazole-2-carboxylate obtained in Example (5a) (0.50 g, 3.23 mmol) and NCS (0.44 g, 3.25 mmol), to obtain 0.50 g of the title compound as a white solid (82%).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:11][C:10]([CH3:17])(OS(C)(=O)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:24]#[N:25].[Na+]>CN(C)C=O>[C:24]([C:10]1([CH3:17])[CH2:11][N:8]([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9]1)#[N:25]
Reactant: [C-]#N
Reactant: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C#N)CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 6 h
Yield: 82.9 %

Procedure:
33.1 g (100 mmol) of 1-diphenylmethyl-3-methyl-3-methylsulphonyloxyazetidine are added to a suspension of sodium cyanide (11 g, 225 mmol) in dimethylformamide (90 ml) and the mixture is stirred at 65°-70° C. for 6 hours. It is cooled and poured onto a water/ice mixture, the product is filtered off, washed with water and dried at 50° C. and 21.75 g (83%) of 3-cyano-1-diphenylmethyl-3-methylazetidine, melting point 86°-88° C., are obtained.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][C:17]([CH3:21])([OH:20])[CH2:16][CH2:15]3)[N:8]2[CH3:11])=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=1.[CH2:28]([C:30]1[NH:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:28]([C:30]1[N:31]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][C:17]([CH3:21])([OH:20])[CH2:16][CH2:15]4)[N:8]3[CH3:11])=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:3]=2)[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: Cn1c(CCN2CCC(C)(O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCN3CCC(C)(O)CC3)n(C)c2n1
Temperature: 120 °C
Yield: 82.9 %

Procedure:
A mixture of 1-[2-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]-4-methylpiperidin-4-ol (45 mg, 0.11 mmol), 2-ethylbenzimidazole (18 mg, 0.13 mmol), Pd2(dba)3 (2.6 mg, 2.5 mol %), Xphos (5.4 mg, 10 mol %) and Cs2CO3 (56 mg, 0.17 mmol) in dioxane (1.0 mL) was purged with argon gas then heated at 120° C., for 17 h, in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (Si—PCC, 0-10% 2 M NH3/MeOH in DCM) to give 452 (46 mg, 80%) as a pale orange solid. LCMS: (Method I): RT 2.46 min; [M+H]+ 505.2. 1H NMR (400 MHz, CHCl3-d): δ 8.01-7.96 (m, 1 H), 7.77-7.73 (m, 1 H), 7.28-7.22 (m, 2 H), 4.47-4.19 (m, 4 H), 3.88-3.83 (m, 4 H), 3.78 (s, 3 H), 3.34 (q, J=7.5 Hz, 2 H), 3.15-3.05 (m, 2 H), 2.98-2.80 (m, 2 H), 2.78-2.73 (m, 2 H), 2.65-2.57 (m, 2 H), 1.69-1.65 (m, 4 H), 1.44 (t, J=7.5 Hz, 3 H), 1.33-1.27 (s, 3 H)
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=1B(O)O>>[NH2:30][C:29]1[S:28][C:27]([C:44]2[CH:45]=[C:40]([Cl:39])[CH:41]=[CH:42][C:43]=2[Cl:46])=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][NH2:8])[CH2:15][CH2:14]1)=[O:24]
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Product: Cn1ncc(NC(=O)c2nc(-c3cc(Cl)ccc3Cl)sc2N)c1N1CCC(CN)CC1
Yield: 19 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 2,5-dichlorobenzeneboronic acid gave 277 as an off-white solid (19 mg, 19%). 1H NMR (400 MHz, d4-MeOD) δ 8.39 (d, J=2.6 Hz, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.48 (s, 1H), 7.37 (dd, J=8.6, 2.6 Hz, 1H), 3.73 (s, 3H), 3.24-3.11 (m, 4H), 2.60 (d, J=6.6 Hz, 2H), 1.85 (d, J=12.5 Hz, 2H), 1.55-1.44 (m, 1H), 1.36 (qd, J=11.9, 4.4 Hz, 2H). LCMS (ES+) m/z 464 (M+1).
Reaction SMILES: [C:1]([C:4]1[NH:8][CH:7]=[C:6]([C:9]([O:11]CC)=[O:10])[C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)(=[O:3])[NH2:2].S(=O)(=O)(O)O>>[C:1]([C:4]1[NH:8][CH:7]=[C:6]([C:9]([OH:11])=[O:10])[C:5]=1[C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)c1c[nH]c(C(N)=O)c1-c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Product: NC(=O)c1[nH]cc(C(=O)O)c1-c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
A solution of 2.8 g (9.232 mmol) of ethyl 5-carbamoyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate in 33.6 cm3 (0.614 mol) of concentrated sulfuric acid is heated at a temperature in the region of 80° C. for 2 hours. The reaction mixture is poured slowly and with stirring into 350 cm3 of ice-water. After stirring for 30 minutes, the reaction mixture is filtered through a No 3 sinter funnel. The solid is washed with 4 times 100 cm3 of ice-water and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 45° C. for 24 hours, to give 2.25 g of 5-carbamoyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylic acid in the form of a beige-coloured solid; ES+: m/z=276: [M+H]+; ES−: m/z=274: [M−H]−.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:9]=1[O:10][CH2:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([C:17]#[N:18])=[N:15]O.S(OC)(OC)(=O)=O>CC(C)=O>[CH3:7][C:8]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:9]=1[O:10][CH2:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([C:17]#[N:18])=[N:15][O:4][CH3:1]
Reactant: Cc1ccc(C)c(OCc2ccccc2C(C#N)=NO)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CON=C(C#N)c1ccccc1COc1cc(C)ccc1C
Reaction time: 0.08 h
Yield: 92.4 %

Procedure:
Potassium carbonate (3.32 g, 0.024 mol) and acetone (200 ml) were added to 2-(2,5-dimethylphenoxymethyl)-α-hydroxyiminobenzyl cyanide (E/Z=15/85) (5.61 g, 0.02 mol). The mixture was stirred for 5 minutes. Then dimethyl sulfate (3.03 g, 0.024 mol) was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the resulting insoluble materials were removed. To the residue obtained after evaporation under reduced pressure, toluene (50 ml) and 1N aqueous sodium hydroxide solution (50 ml) were added. The mixture was stirred for 1 hour. After stirring, water (150 ml) was added. The mixture was extracted with ether (150 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminobenzyl cyanide (5.44 g, Yield: 92.4%, E/Z=15/85).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1([CH2:18][OH:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C.O>[CH3:11][C:12]1([CH:18]=[O:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CC1(CO)CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC1(C=O)CCOCC1
Reaction time: 0.25 h
Yield: 70.3 %

Procedure:
Oxalyl chloride (0.419 mL, 4.80 mmol) was dissolved in dichloromethane (7.5 mL). To this, dimethyl sulfoxide (0.409 mL, 5.76 mmol) was added dropwise under a nitrogen atmosphere at −78° C. and the mixture was stirred for 15 minutes. To this, a dichloromethane solution (2.5 mL) of (4-methyltetrahydro-2H-pyran-4-yl)methanol (250 mg, 1.92 mmol) synthesized according to the method described in WO 08/029,825 was added at the same temperature and the mixture was stirred for 1 hour. To this, triethylamine (1.34 mL, 9.60 mmol) was added and the mixture was stirred at a temperature of −78° C. to room temperature for 1.2 hours. After water was added to the reaction mixture, extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (hexane/ethyl acetate=1/1) to give 4-methyltetrahydro-2H-pyran-4-carbaldehyde (173 mg, yield: 70%).
Reaction SMILES: Cl.[CH3:2][CH:3]([C:37]([O:39]C)=[O:38])[CH2:4][CH2:5][O:6][C:7]1[CH:36]=[CH:35][C:10]([CH2:11][C:12]2[C:13]3[CH:34]=[CH:33][CH:32]=[CH:31][C:14]=3[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=2)=[CH:9][CH:8]=1.[OH-].[Na+].CC(C)=O>CO>[CH3:2][CH:3]([C:37]([OH:39])=[O:38])[CH2:4][CH2:5][O:6][C:7]1[CH:36]=[CH:35][C:10]([CH2:11][C:12]2[C:13]3[CH:34]=[CH:33][CH:32]=[CH:31][C:14]=3[S:15][C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:21][CH:22]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)C(C)CCOc1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: CC(CCOc1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1)C(=O)O

Procedure:
The hydrolysis of the product from Example 31 was carried out at room temperature by NaOH solution using acetone and methanol as the solvent.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C([N:14]=C=NCCCN(C)C)C.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:14])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1c(Br)cccc1C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(Br)c1N
Reaction time: 6 h
Yield: 84.9 %

Procedure:
To 2-amino-3-bromobenzoic acid (0.5 g, 2.3 mmol) in DMF (5 mL) at rt were added hydroxybenzatriazole (0.46 g, 3.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.53 g, 2.8 mmol), ammonium chloride (0.5 g, 9.7 mmol), and diisopropylethylamine (1.7 ml, 9.7 mmol). The mixture was purged with N2 and stirred for 6 h. The mixture was poured into water and extracted with EtOAc (3×50 mL). The combined extracts were washed with brine (2×20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was treated with DCM (10 mL) resulting in a precipitate which was collected by filtration and dried to afford 2-amino-3-bromobenzamide as a pale pink solid (0.42 g, 84%). LCMS (ESI) m/z 215/217 (M+H)+