Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:25]1[CH2:26][CH2:27][CH:22]([OH:21])[CH2:23][CH2:24]1)=[O:13])[CH2:8]2
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Reactant: OC1CCNCC1
Product: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1N1CCC(O)CC1

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol) and 4-hydroxypiperidine (0.31 mL; 3.0 mmol) under microwave irradiation according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 5-(4-hydroxy-piperidin-1-yl)-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (87 mg, 81%) as an off-white powder. ES-HRMS m/e calcd for C20H31N4O2 (M+H+) 359.2442, found 359.2437.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[C:8]([O:12][C:13]([NH:15][OH:16])=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([O:16][NH:15][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])=[O:4]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)NO
Product: CC(C)(C)OC(=O)NOC(=O)C(C)(C)C

Procedure:
[(tert-Butoxy)carbonyl]amino 2,2-dimethylpropanoate is prepared from trimethyl acetyl chloride and N-tert-butoxycarbonyl hydroxylamine according to Scheme 1 described by Carpino et al. J. Am. Chem. Soc. 1959, 955-957. (6.4 g, 78%), 1H NMR (250 MHz, DMSO-d6) δ ppm 10.46 (1H, br. s.), 1.40 (9H, s), 1.20 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:34][Si:35]([CH2:40][CH3:41])([CH2:38][CH3:39])[CH2:36][CH3:37])[C:17]2[C:12](=[CH:13][C:14](I)=[CH:15][C:16]=2[C:18]([F:21])([F:20])[F:19])[N:11]([CH2:23][C@H:24]2[CH2:27][C@H:26]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:25]2)[C:10]1=[O:33].[OH2:42]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:34][Si:35]([CH2:40][CH3:41])([CH2:38][CH3:39])[CH2:36][CH3:37])[C:17]2[C:12](=[CH:13][C:14]([C:4]3[O:42][CH:7]=[CH:2][CH:3]=3)=[CH:15][C:16]=2[C:18]([F:21])([F:20])[F:19])[N:11]([CH2:23][C@H:24]2[CH2:27][C@H:26]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:25]2)[C:10]1=[O:33]
Reactant: O
Reactant: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O[Si](CC)(CC)CC)(c3ccc(Cl)cc3Cl)c3c2cc(I)cc3C(F)(F)F)C1
Solvent: Cc1ccccc1
Product: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O[Si](CC)(CC)CC)(c3ccc(Cl)cc3Cl)c3c2cc(-c2ccco2)cc3C(F)(F)F)C1

Procedure:
A solution of the compound of Example 14-1 (140 mg, 0.188 mmol), 2-tributyltinfuran (80 mg, 0.224 mmol) and tetrakistriphenylphosphine palladium (20 mg, 0.017 mmol) in toluene (5 mL) was stirred at 100° C. under nitrogen for 3 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate, and then the organic layer was washed with saturated saline, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (chloroform/methanol=20/1) to give the titled compound (80 mg, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([CH3:14])[C:6](I)=[C:5]2[O:16][CH2:17][CH3:18].[F:19][C:20]([F:39])([F:38])[O:21][C:22]1[CH:37]=[CH:36][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([CH3:14])[C:6]([C:30]1[CH:29]=[CH:28][C:27]([O:26][C:25]3[CH:36]=[CH:37][C:22]([O:21][C:20]([F:19])([F:38])[F:39])=[CH:23][CH:24]=3)=[CH:32][CH:31]=1)=[C:5]2[O:16][CH2:17][CH3:18]
Reactant: OB(O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Reactant: CCOc1c(I)c(C)nc2cc(OC)c(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1c(-c2ccc(Oc3ccc(OC(F)(F)F)cc3)cc2)c(C)nc2cc(OC)c(Cl)cc12
Temperature: 85 °C
Reaction time: 18 h
Yield: 56.7 %

Procedure:
To a solution of 6-chloro-4-ethoxy-3-iodo-7-methoxy-2-methylquinoline (1.56 g, 4.13 mmol), (4-(4-(trifluoromethoxy)phenoxy) phenyl) boronic acid (1.85 g, 6.20 mmol) and palladium (0) tetrakis triphenylphosphine (239 mg, 0.207 mmol) in degassed dimethylformamide was added 8.25 ml of a 2 N aqueous potassium carbonate solution. The reaction mixture was stirred 18 hours at 85° C., filtered through celite and concentrated in vacuo. The resulting residue was resuspended in dichloromethane and water. The organic layer was extracted with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (0-20% ethyl acetate in dichloromethane) provided 1.18 g 6-chloro-4-ethoxy-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline (57% yield) as a light brown solid. 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.43 (s, 1H), 7.31-7.36 (m, 2H), 7.22-7.26 (m, 2H), 7.07-7.14 (m, 4H), 4.04 (s, 3H), 3.71 (q, J=7.1 Hz, 2H), 2.49 (s, 3H), 1.18 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl.[SH:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].[Cl-].[NH4+]>ClCCl>[SH:2][CH2:3][CH2:4][NH:5][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: NCCS
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NCCS
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
22.7 g of 2-mercaptoethylamine hydrochloride (0.2 mol) and 32.4 g of triethylamine (0.32 mol) were introduced in suspension in 130 ml of dichloromethane at 0° C.-5° C. Over the course of 30 minutes, 12.1 g of pivaloyl chloride (0.1 mol) were added dropwise. The batch was stirred at 0° C. to 5° C. for 1 hour, at 40° C. for 1.5 hours, and then at room temperature for 12 hours. 70 ml of saturated ammonium chloride solution were added and a phase separation was carried out. This was repeated twice and the organic phases were combined, dried over sodium sulfate, and freed of their solvent under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH:13]=[CH:12]2)=[O:10])=[C:4]([Cl:20])[CH:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>O1CCCC1>[Cl:8][C:6]1[CH:7]=[C:2]([NH:1][C:28](=[O:31])[CH2:29][CH3:30])[CH:3]=[C:4]([Cl:20])[C:5]=1[C:9]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH:13]=[CH:12]1)=[O:10]
Reactant: Nc1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)Nc1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.6 %

Procedure:
To a stirred solution of (4-amino-2,6-dichlorophenyl)(1H-pyrrolo[3,2-c]pyridin-1-yl)methanone (45 mg, 0.15 mmol) and triethylamine (0.04 mL, 0.29 mmol) in tetrahydrofuran (1 mL), propanoyl chloride (0.014 mL, 0.16 mmol) was added drop wise at 0° C. The resulting reaction mixture was stirred at room temperature for 30 minutes and concentrated under vacuum. The residue was diluted with water, extracted with ethyl acetate (2×20 mL). The combined organic portion was washed with brine, dried over anhydrous sodium sulphate and concentrated on rotary evaporator. The residue was taken up in methanol (2 mL), potassium carbonate (25 mg) was added and stirred at room temperature for 10 minutes, concentrated on a rotary evaporator, diluted with water (10 mL) and extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulphate and concentrated on rotary evaporator. N-[3,5-dichloro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylcarbonyl)phenyl]propanamide (7.4 mg, 14%) was isolated by silica gel column chromatography using dichloromethane and methanol gradient as eluent.
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][C:6]1[S:7][C:8]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15](N)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)[N:10]=1.C(O)C>O.Cl>[CH3:5][C:6]1[S:7][C:8]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([F:22])([F:20])[F:21])[CH:13]=2)[N:10]=1
Reactant: CCOC(=O)c1sc(C)nc1Oc1ccc(N)c(C(F)(F)F)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1sc(C)nc1Oc1cccc(C(F)(F)F)c1
Reaction time: 0.08 h
Yield: 84.5 %

Procedure:
1.4 g of NaNO2 in 30 ml of water are added dropwise with ice cooling in the course of about 20 minutes to 7 g (0.02 mol) of 2-methyl-5-ethoxycarbonyl-4-(4-amino-3-trifluoromethyl-phenoxy)-thiazole (cf. Example (IV-4) in 40 ml of concentrated hydrochloric acid. After the mixture has been stirred for 5 minutes, 300 ml of ethanol are added, and the mixture is then heated slowly to reflux temperature and refluxed for 30 minutes. The volatile constituents are subsequently removed in vacuo, the oil which remains is then taken up in 50 ml of water, a pH of 8 is established by adding dilute sodium hydroxide solution, the mixture is extracted twice with dichloromethane, the extract is dried (over MgSO4) and evaporated in vacuo, and the crude product which remains is filtered chromatographically through silica gel (eluent: toluene). 5.6 g (83.6 % of theory) of 2-methyl-5-ethoxycarbonyl-4-(3-trifluoromethyl-phenyloxy)-thiazole are obtained; melting point: 56° C.
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([C:14]1[S:18][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:16][CH:15]=1)=[C:7]2[C:11]([OH:13])=[O:12].O.C(=O)(O)[O-].[Na+].[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:36][C:37](Cl)=[O:38]>CC(C)=O>[C:11]([C:7]1[N:8]2[CH:3]([S:4][CH2:5][C:6]=1[C:14]1[S:18][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:16][CH:15]=1)[CH:2]([NH:1][C:37](=[O:38])[CH2:36][C:32]1[S:31][CH:35]=[CH:34][CH:33]=1)[C:9]2=[O:10])([OH:13])=[O:12]
Reactant: NC1C(=O)N2C(C(=O)O)=C(c3cnc(-c4ccccc4)s3)CSC12
Reactant: O=C(Cl)Cc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=C(c3cnc(-c4ccccc4)s3)CSC12
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A solution of 7-amino-2-carboxy-8-oxo-3-(2-phenylthiazol-5-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (3.3 g) in a mixture of distilled water (35 cc) and acetone (24 cc) containing sodium bicarbonate (2 g) is cooled to -10° C. and then treated with a solution of (thien-2-yl)-acetyl chloride (0.86 cc) in acetone (10 cc), which is added dropwise in 8 minutes. The reaction mixture is stirred for 30 minutes at -10° C. and then for 3 hours at 20° C. The acetone is evaporated under reduced pressure (30 mm Hg; 4 kPa) at 30° C. and ethyl acetate (150 cc) and a saturated sodium bicarbonate solution (100 cc) are added. The aqueous layer is extracted with ethyl acetate (100 cc), then treated with decolorising charcoal (1 g) and a filtration aid (diatomaceous earth powder) (5 g), and filtered on the filtration aid, rinsing with distilled water (2×50 cc). The combined filtrates are acidified to pH 2 with 4N hydrochloric acid. The precipitate is filtered off, washed with ethyl acetate (50 cc) and then triturated with isopropyl ether (100 cc) and dried. 2-Carboxy-8-oxo-3-(2-phenyl-thiazol-5-yl)-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.8 g) is obtained in the form of a cream-coloured solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][CH:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[CH2:31][CH2:30]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C=O.[C:51](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1>[CH3:51][N:35]([CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[C@H:32]1[CH2:33][CH2:34][C@H:29]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:30][CH2:31]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](NC3CCOCC3)CC2)c2ncnn12
Agent: C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](N(C)C3CCOCC3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 114 h

Procedure:
To a mixture of 4′-({5-oxo-7-propyl-4-[trans-4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.33 g), sodium sulfate (1.5 g), aqueous formaldehyde solution (0.50 mL) and tetrahydrofuran (4 mL) was gradually added sodium triacetoxyborohydride (0.63 g) at room temperature, and the mixture was stirred at room temperature for 114 hr. 0.5M Aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.13 g, 39%).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:30]([O:36]C(=O)C3C=CC=C(Cl)C=3)=[CH:29][C:28]=2[CH:46]([CH3:48])[CH3:47])=[O:25])[C:6]1=[O:49])[CH2:2][CH2:3][CH3:4].C[O-].[Na+].O>CO>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:30]([OH:36])=[CH:29][C:28]=2[CH:46]([CH3:48])[CH3:47])=[O:25])[C:6]1=[O:49])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(OC(=O)c3cccc(Cl)c3)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(O)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of N-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-[2,6-diisopropyl-4-(3-chlorobenzoyloxy)-phenyl]urea (1.0 g, 1.6 mmol) in methanol (30 ml) is added dropwise a 28% sodium methoxide (0.45 ml, 1.76 mmol) at room temperature, and the mixture is stirred at the same temperature for one hour. To the mixture is added water, and the mixture is extracted with ethyl acetate. The extract is washed with an aqueous ammonium chloride solution and a saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (1% methanol/chloroform→2% methanol/chloroform) to give the title compound (0.79 g, 1.45 mmol) as amorphous.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:31]([O-:33])=[O:32])=[C:6]([CH:30]=1)[C:7]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:8].[CH3:34][NH2:35].CO.O>CN(C=O)C>[CH3:34][NH:35][C:2]1[CH:3]=[CH:4][C:5]([N+:31]([O-:33])=[O:32])=[C:6]([CH:30]=1)[C:7]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:8]
Reactant: CN
Reactant: O=C(NCC1CCN(C(c2ccccc2)c2ccccc2)CC1)c1cc(F)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CNc1ccc([N+](=O)[O-])c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 180 °C

Procedure:
Step 1): A mixture of 5-fluoro-2-nitro-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide (2.68 g, 6 mmol) and 40% methylamine in MeOH (5 ml, 64 mmol) in DMF (30 ml) was heated in a sealed tube at 180° C. for 7 hours. After cooling, the reaction mixture was poured into H2O and extracted with AcOEt. The extract was washed with H2O, dried over MgSO4 and evaporated, followed by crystallization from EtOH to give 5-methylamino-2-nitro-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide, 2.28 g (83%): mp 185° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:24])=[C:4]([N:8]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=[O:16])=[CH:11][N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[C:31]1(=O)[CH2:36][CH2:35][CH2:34][C:33](=[O:37])[CH2:32]1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl.CN(C)C=O>[F:1][C:2]1[C:3]([CH3:24])=[C:4]([N:8]2[C:13](=[O:14])[C:12]([C:15]([O:17][C:31]3[CH2:36][CH2:35][CH2:34][C:33](=[O:37])[CH:32]=3)=[O:16])=[CH:11][N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(F)cccc1-n1c(-c2ccccc2)ncc(C(=O)O)c1=O
Reactant: O=C1CCCC(=O)C1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(F)cccc1-n1c(-c2ccccc2)ncc(C(=O)OC2=CC(=O)CCC2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-(3-fluoro-2-methylphenyl)-1,6-dihydro-6-oxo-2-phenyl-5-pyrimidinecarboxylic acid (i.e. the product from Example 5, Step B) (41.0 g, 126 mmol) in dichloromethane (400 mL) was added oxalyl chloride (31.05 g, 252.0 mmol) at 0° C. followed by a catalytic amount (7 drops) of N,N-dimethylformamide. The reaction mixture was allowed to warm to room temperature and stir for 1 h. The reaction mixture was then concentrated under reduced pressure. To the resulting residue was added dichloromethane (400 mL), 1,3-cyclohexanedione (17.03 g, 152 mmol), followed by triethylamine (38.30 g, 379 mmol) and the reaction mixture was stirred at room temperature for 30 min. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with dichloromethane. The organic layer was washed once with water. Then the organic layer was dried (MgSO4) and concentrated under reduced pressure. The resulting solid was washed with chlorobutane to afford the title product pure as an off-white solid (37.6 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([NH:14][C:15](=[O:30])[CH2:16][C:17](=O)[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH:28]=[CH:27][N:26]=[N:25]3)[CH:19]=2)=[CH:12][C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])=[C:10]([N:38]([CH3:40])[CH3:39])[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:40][N:38]([CH3:39])[C:10]1[C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])=[CH:12][C:13]2[NH:14][C:15](=[O:30])[CH2:16][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N:24]4[CH:28]=[CH:27][N:26]=[N:25]4)[CH:19]=3)=[N:7][C:8]=2[CH:9]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1-c1ccccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1-c1ccccc1F)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {2-dimethylamino-2′-fluoro-5-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example M70) (810 mg, 1.45 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (61 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1)=[O:2].[Mn]([O-])(=O)(=O)=[O:13].[K+]>O.CC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1)([OH:13])=[O:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=Cc1cccc(B(O)O)c1
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-formylphenylboronic acid (3.35 g, 22.34 mmol) (Lancaster) in a 1:1 mixture of distilled water-acetone (64 mL) was slowly treated with potassium permanganate (6.00 g, 37.98 mmol) in small portions. The dark reaction mixture was stirred at room temperature for 1 h and then filtered through a pad of Celite®. The pad of Celite® was washed with 200 mL of distilled water then washed with 200 mL of acetone. The filtrate was concentrated in vacuo to a volume of approximately 200 mL. The resulting aqueous filtrate was treated with concentrated hydrochloric acid until pH=1 and then cooled using an ice/water bath. The desired product precipitated upon cooling. The solid was filtered and washed well with cold distilled water to provide 3-carboxyphenylboronic acid as a cream-colored solid which was used without further purification. (Yield 1.95 g, 53%; mp 232-234° C.).
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].Cl.Cl[C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH:12]=1)=[O:10]>CO>[N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[N:13]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[C:11]([C:9]([NH:5][C:4]([NH2:6])=[NH:3])=[O:10])=[CH:12]1
Reactant: N=C(N)N
Reactant: O=C(Cl)c1cn(-c2ccc3ccccc3n2)c2ncccc12
Agent: Cl
Agent: [Na]
Solvent: CO
Product: N=C(N)NC(=O)c1cn(-c2ccc3ccccc3n2)c2ncccc12

Procedure:
0.477 g (20.73 mmol) of sodium (washed beforehand in toluene) was gradually added to 40 cm3 of methanol at a temperature in the region of 20° C. under an argon atmosphere. After dissolving with stirring, 2.021 g (20.74 mmol) of guanidine hydrochloride were added and the mixture was stirred at a temperature in the region of 20° C. for 2 h. The reaction mixture was filtered and then concentrated to dryness under reduced pressure (2.7 kPa), and the residue was subsequently taken up in a mixture of 70 cm3 of tetrahydrofuran and 70 cm3 of dichloromethane under an argon atmosphere at a temperature in the region of 20° C. 3.46 mmol of 3-chlorocarbonyl-1-(quinolin-2-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride were added thereto with stirring. After stirring at a temperature in the region of 20° C. for 15 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The solid residue was taken up in 100 cm3 of water and stirred for 2 h and then the insoluble material was filtered off. The solid obtained was dried and then triturated in 20 cm3 of cyclohexane. The solid was filtered off and then dried at a temperature in the region of 20° C. under reduced pressure (2.7 kPa), and 0.921 g of N-[1-(quinolin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine was thus obtained in the form of a light yellow solid melting at 242° C. 1H N.M.R. spectrum (300 MHz, (CD3)2SO, δ in ppm): from 6.20 to 7.30 (very broad unresolved peak, 2H), 7.39 (dd, J=8 and 5 Hz, 1H), 7.63 (broad t, J=7.5 Hz, 1H), 7.84 (broad t, J=7.5 Hz, 1H), 8.03 and 8.07 (2 broad d, J=7.5 Hz, each 1H), 8.48 (dd, J=5 and 1.5 Hz, 1H), 8.64 (d, J=9 Hz, 1H), 8.89 (dd, J=8 and 1.5 Hz, 1H), 9.06 (s, 1H), 9.21 (d, J=9 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][C:26]=1[C:34]([F:37])([F:36])[F:35].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:32]=[CH:33][C:25]([F:24])=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:27]=5)[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1ccc(F)c(C(F)(F)F)c1
Yield: 76.1 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (309 mg, 1.00 mmol), 4-fluoro-3-(trifluoromethyl)benzoic acid (312 mg, 1.50 mmol), 1-hydroxybenzotriazole (203 mg, 1.50 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (288 mg, 1.50 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials and in the same manner as in Example 106, the title compound (380 mg, 76%) was obtained as a white powder.