Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=O)[CH:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])O.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1CBr>[Ag]=O.CCOCC>[CH3:10][O:9][C:7]([CH2:6][CH:3]([O:2][CH2:1][C:20]1[CH:19]=[CH:18][CH:17]=[CH:14][C:13]=1[F:12])[CH2:4][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:8]
Reactant: COC(=O)CC(O)C(=O)OC
Reactant: Fc1ccccc1CBr
Agent: O=[Ag]
Solvent: CCOCC
Product: COC(=O)CCC(CC(=O)OC)OCc1ccccc1F
Yield: 131.4 %

Procedure:
46.4 g (0.2 mol) of silver oxide were added in portions, with constant stirring, to a mixture of 16.2 g (0.1 mol) of malic acid dimethyl ester and 57 g (0.30 mol) of 2-fluorobenzyl bromide. An exothermic reaction started slowly, and the temperature rose to 80° C. After cooling, 200 ml of ether were added, the solid was filtered off, the filtrate was concentrated and the residue was distilled at 180° C. in a waterpump vacuum. 19.6 g (72.6% of theory) of 2-(2-fluorobenzyloxy)-butane-1,4-dicarboxylic acid dimethyl ester were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH:15]=O)=[CH:13][C:12]([CH:17]([OH:19])[CH3:18])=[C:11]([CH3:20])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=CC=CC=1C=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[O:8]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:10]=[C:9]1[CH:14]=[CH:15][C:14]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:10][C:11]([CH3:20])=[C:12]([CH:17]([OH:19])[CH3:18])[CH:13]=1
Reactant: Cc1nc(OCc2ccccc2)c(C=O)cc1C(C)O
Reactant: O=Cc1cccnc1OCc1ccccc1
Product: Cc1nc(OCc2ccccc2)c(C=Cc2nc3ccccc3o2)cc1C(C)O

Procedure:
Following substantially the same procedure described in Example 3, Step E, but substituting 2-benzyloxy-5-(1-hydroxyethyl)-6-methylpyridin-3-carboxaldehyde for the benzyloxynicotinaldehyde compound used therein, the title compound is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH2:16][CH2:15][N:14]([C:18]4[S:19][C:20]5[C:21](=[O:29])[NH:22][C:23]([CH3:28])([CH3:27])[CH2:24][C:25]=5[N:26]=4)[C:13]=3[CH:30]=2)[CH:3]=1.C(OC=C)(=O)C.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:27][C:23]1([CH3:28])[NH:22][C:21](=[O:29])[C:20]2[S:19][C:18]([N:14]3[C:13]4[CH:30]=[C:9]([C:4]5[CH:3]=[CH:2][N:7]=[C:6]([CH3:8])[N:5]=5)[CH:10]=[CH:11][C:12]=4[O:17][CH2:16][CH2:15]3)=[N:26][C:25]=2[CH2:24]1
Reactant: Cc1nc(Cl)cc(-c2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C=COC(C)=O
Product: Cc1nccc(-c2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)n1
Temperature: 140 °C
Yield: 36.8 %

Procedure:
To a solution of Example 456 (100 mg, 0.227 mmol) in DMF (4 mL) was added vinyl acetate (0.11 mL, 1.13 mmol), triethylamine (0.06 mL, 0.454 mmol), 1,3-bis-(diphenylphosphino)propane (10 mg, 0.023 mmol) and palladium acetate (2.5 mg, 0.011 mmol). The mixture was heated to 140° C. under microwave irradiation for 1 h. The resulting suspension was partitioned between DCM (50 mL) and water (50 mL); the organic fraction was washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by preparative HPLC (Method 6) to yield the title compound (34 mg, 35%) as an off-white solid. δH (CDCl3) 8.72 (1H, d, J 2.1 Hz), 8.65 (1H, d, J 5.4 Hz), 7.84 (1H, dd, J 8.6 and 2.1 Hz), 7.44 (1H, d, J 5.4 Hz), 7.07 (1H, d, J 8.6 Hz), 5.24 (1H, br. s), 4.47-4.28 (2H, m), 4.30-4.11 (2H, m), 2.90 (2H, s), 2.78 (3H, s), 1.41 (6H, s). LCMS (ES+) 408.0 (M+H)+, RT 2.83 minutes (Method 1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:10])[CH3:9])=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.C([Li])CCC.CN([CH:23]=[O:24])C>>[C:11]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[N:8]([CH3:10])[CH3:9])[CH:23]=[O:24])([CH3:14])([CH3:13])[CH3:12]
Reactant: CN(C)c1ccc(Br)cc1C(C)(C)C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: CN(C)c1ccc(C=O)cc1C(C)(C)C
Yield: 60.9 %

Procedure:
In a manner analogous to example 1 d, the process is carried out by a reaction of 4.1 g (16 mmol) of (4-bromo-2-tert-butylphenyl)dimethylamine with 9.6 ml (24 mmol) of a 2.5M solution of n-butyllithium and 1.9 ml (24 mmol) of DMF. 2 g of 3-tert-butyl-4-dimethylaminobenzaldehyde are obtained in the form of a yellow oil (yield=100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[N:14][NH:13][C:12](=[O:24])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:13]1[C:12](=[O:24])[CH:11]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[C:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[N:14]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(-c2n[nH]c(=O)cc2-c2ccc(OC)c(F)c2)cc1
Reactant: BrCc1ccccc1
Product: COc1ccc(-c2nn(Cc3ccccc3)c(=O)cc2-c2ccc(OC)c(F)c2)cc1
Yield: 95.6 %

Procedure:
Using 5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one and benzyl bromide as starting materials, the procedures of Example 12 were repeated likewise, whereby the title compound was obtained in a yield of 95.6%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].CO.Cl.[CH2:14](N=C=NCCCN(C)C)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([O:7][CH3:14])=[O:6]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To an ice cooled solution of 2-bromoisonicotinic acid (73 g, 0.361 mol) in dichloromethane (500 mL) and methanol (35 g, 1.08 mol) was added 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (67 g, 0.434 mol) by portions. The mixture was stirred at ambient temperature overnight. Then 120 g silica gel was added and the solvent evaporated. The residue was purified by flash chromatography, eluting with 5% ethyl acetate in petroleum ether to afford 58 g (75%) of methyl 2-bromoisonicotinate as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:17][O-:18].[Na+].CO>CN(C=O)C.CCOC(C)=O>[CH3:17][O:18][C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1N1CCCCC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Reaction time: 24 h
Yield: 41 %

Procedure:
To 1-(5-chloro-2-nitro-phenyl)-piperidine (197 mg, 0.810 mmol) in 1.5 mL of DMF was added 4 mL of 0.5 M NaOMe in MeOH (2.5 eq). The resultant solution was heated at 60° C. overnight, then at 90° C. for 24 h. The reaction was diluted with EtOAc (50 mL) and washed with water (50 mL), dried (Na2SO4) and concentrated in vacuo. Purification by preparative TLC (20% EtOAc-hexane) gave 80 mg (41%) of the title compound, along with 80 mg (40%) of recovered starting material. 1H-NMR (CDCl3; 400 MHz): δ 7.95 (d, 1H, J=9.1 Hz), 6.51 (d, 1H, J=2.6 Hz), 6.46 (dd, 1H, J=2.6, 9.1 Hz), 3.87 (s, 3H), 3.01-3.04 (m, 4H), 1.72-1.78 (m, 4H), 1.60-1.64 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5](=[O:24])[CH2:6][C:7]([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)(O)[CH2:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[OH-].[Na+].C(O)(=O)C>CO>[C:14]([O:13][C:11](=[O:12])[NH:10][CH2:9][CH2:8][C:7]1([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:6][C:5](=[O:24])[CH2:4][C:3](=[O:2])[O:25]1)([CH3:15])([CH3:16])[CH3:17]
Reactant: COC(=O)CC(=O)CC(O)(CCNC(=O)OC(C)(C)C)C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCC1(C2CCCC2)CC(=O)CC(=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.8 %

Procedure:
To 7-tert-butoxycarbonylamino-5-cyclopentyl-5-hydroxy-3-oxo-heptanoic acid methyl ester (1.36 g, 3.8 mmol) from Step 3 above dissolved in MeOH (50 mL) was added a NaOH solution (2.8 M, 2.7 mL, 7.6 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was then quenched with acetic acid (0.44 mL, 7.7 mmol) and concentrated by rotary evaporation to an oil. The oil was dissolved in CH2Cl2 and washed with water. The organic layer was separated, and dried over Na2SO4. The solids were removed by filtration, and the liquid was concentrated to yield the product (1.061 g, 86% yield).
Reaction SMILES: C1N(CCS(O)(=O)=O)CC[O:3]C1.[NH:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16].O=C(CCC(O)=O)C(O)=O.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>>[OH:3][C@H:19]1[CH2:20][NH:13][C@H:14]([C:15]([OH:17])=[O:16])[CH2:18]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=S(=O)(O)CCN1CCOCC1
Agent: O=C(O)CCC(=O)C(=O)O
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Product: O=C(O)[C@@H]1C[C@@H](O)CN1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
The enzyme preparation to be determined is added to 80 mM MES buffer (pH 6.5) containing 4 mM L-proline, 8 mM 2-ketoglutaric acid, 2 mM ferrous sulfate and 4 mM L-ascorbic acid to make 250 μl in total, and the mixture was allowed to stand at 30° C. for 20 minutes. The reaction mixture is heated at 100° C. for 2 minutes so as to stop the reaction, and the amount of the trans-4-hydroxy-L-proline produced in the reaction mixture is determined by high performance liquid chromatography (hereinafter referred to as HPLC).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[F:26])=[N:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:27][CH3:28].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[ClH:25].[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:12]2[C:11]3[C:16](=[CH:17][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[C:9]([O:27][CH3:28])[CH:10]=3)[N:15]=[CH:14][N:13]=2)=[C:20]([F:26])[CH:21]=1
Reactant: C1CCNC1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCOCCBr
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCOCCN1CCCC1
Product: Cl
Temperature: 80 °C
Yield: 20 %

Procedure:
A solution of 7-(2-(2-bromoethoxy)ethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (150 mg, 0.32 mmol), (prepared as described for the starting material in Example 63), in pyrrolidine (2 ml) was heated at 80° C. for 5 hours. The mixture was allowed to cool and was partitioned between ethyl acetate and water. The organic layer was washed with water and then brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography on silica eluting with methylene chloride/methanol/triethylamine (80/20/0 followed by 80/20/1). The purified product was dissolved in methylene chloride and 2.9M ethereal hydrogen chloride (1 ml) was added. The volatiles were removed by evaporation, the residue was triturated with ether, collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-pyrrolidin-1-ylethoxy)ethoxy)quinazoline hydrochloride (35 mg, 20%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:28][CH2:29][CH3:30])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:38]([O:40][C:41](=[O:44])[CH2:42]Br)[CH3:39]>CN(C=O)C>[C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:42][C:41]([O:40][CH2:38][CH3:39])=[O:44])[S:18]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)(=[O:19])=[O:20])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:28][CH2:29][CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1nc2cc(N(CC(=O)OCC)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from example 1, step d.) (50 mg, 0.111 mmol) was dissolved in DMF (1 mL), treated with K2CO3 (23 mg, 0.167 mmol), bromo-acetic acid ethyl ester (25 uL, 0.133 mmol), and stirred at ambient temperature overnight. The reaction was heated to 50° C. for 2 hours, then more K2CO3 (23 mg, 0.167 mmol) and bromo-acetic acid ethyl ester (25 uL, 0.133 mmol) were added and the reaction was heated to 80° C. for three hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed several times with water and concentrated under reduced pressure to give the sub-title compound that was used in crude form without purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([N+:11]#[C-:12])([CH3:10])([CH3:9])[CH3:8].[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>Cl(O)(=O)(=O)=O>[C:7]([NH:11][C:12]1[N:6]2[C:2]([S:3][CH:4]=[CH:5]2)=[N:1][C:17]=1[C:16]1[CH:15]=[C:14]([OH:13])[CH:21]=[CH:20][CH:19]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: O=Cc1cccc(O)c1
Reactant: Nc1nccs1
Reactant: [C-]#[N+]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)Nc1c(-c2cccc(O)c2)nc2sccn12

Procedure:
Compound 25 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 2-amino thiazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 3-hydroxybenzaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: C([O:8][C:9](=[O:24])[CH2:10][C@@H:11]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:12][C:13]([NH2:15])=[O:14])C1C=CC=CC=1>C(OCC)(=O)C.[Pd].ClCCl.CCCCC>[Si:17]([O:16][C@H:11]([CH2:10][C:9]([OH:24])=[O:8])[CH2:12][C:13]([NH2:15])=[O:14])([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CC(N)=O)CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CC(N)=O)CC(=O)O
Temperature: 5 °C

Procedure:
(S)-Benzyl-3-(tert-butyl dimethylsilyloxy)glutaramate (100 g) was dissolved in ethyl acetate and placed in pressure flask. To this Palladium on charcoal (5%, 1 g) was added and stirred under hydrogen atmosphere (˜2.8 Kg). Palladium was removed by filtration. The filtrate was mixed with water and adjusted pH to ˜9.0 by using Aq ammonia solution. The reaction mass was stirred and layers were separated. The aqueous phase was washed with dichloromethane and dichloromethane was added to aqueous phase. The reaction mass was cooled to 5° C. and pH was adjusted to 4.0 with Aq phosphoric acid. The reaction mass was stirred and layers were separated. The organic phase was washed with water and dried over sodium sulphate. The organic layer was evaporated under vacuum to yield residue. Residue was dissolved in dichloromethane and to this solution pentane was added, stirred, filtered and dried to yield (S)-3-(tert-butyl dimethylsilyloxy)glutaric acid monoamide.
Reaction SMILES: CCCP(=O)=O.[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[NH:17][C:18]1[N:23]=[C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][N:19]=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:33][CH2:32]1.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C)C=O>[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH:44][C:41]2[CH:40]=[CH:39][C:38]([CH2:37][N:34]3[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]3)=[CH:43][CH:42]=2)=[O:14])=[CH:10][C:9]=1[NH:17][C:18]1[N:23]=[C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][N:19]=1
Reactant: Cc1ccc(C(=O)O)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Agent: CCCP(=O)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution containing ˜50% of propylphosphonic anhydride in N,N-dimethylformamide (Fluka, Buchs, Switzerland; 875 μL, ˜1.5 mmol) is added within 20 minutes to a stirred mixture of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (306 mg, 1.0 mmol), 4-[(4-methyl-1-piperazinyl)methyl]benzeneamine (Chem. Abstr. Reg. Number: 70261-82-4; 205 mg, 1.0 mmol) and triethylamine (83 μL, 6.0 mmol) in 8 mL N,N-dimethylformamide. After stirring for 24 hours at room temperature, the mixture is treated with a saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The solvent is evaporated off under reduced pressure and the residue dried in vacuo. The crude product is crystallised from ethanol-ethyl acetate to give the title compound as a crystalline solid, m.p. 153–155° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:16]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:15]3[C:10](=[N:11][CH:12]=[C:13](I)[CH:14]=3)[O:9][C:5]2=[CH:6][C:7]=1[F:8].[CH3:23][C:24]([OH:28])([C:26]#[CH:27])[CH3:25]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C>[NH2:21][C:18]1[O:19][CH2:20][C:16]2([C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:27]#[C:26][C:24]([CH3:25])([OH:28])[CH3:23])[CH:14]=3)[O:9][C:5]3[C:4]2=[CH:3][C:2]([Br:1])=[C:7]([F:8])[CH:6]=3)[N:17]=1
Reactant: NC1=NC2(CO1)c1cc(Br)c(F)cc1Oc1ncc(I)cc12
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1cnc2c(c1)C1(COC(N)=N1)c1cc(Br)c(F)cc1O2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A vial charged with Pd(PPh3)4 (0.485 g, 0.420 mmol), copper(i) iodide (0.080 g, 0.420 mmol), 7-bromo-8-fluoro-3-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (2.000 g, 4.20 mmol), 2-methylbut-3-yn-2-ol (0.353 g, 4.20 mmol) and 9 mL DMF was degassed with argon and treated with DIPA (2.99 mL, 21.01 mmol). The resulting black mixture was allowed to stir at RT for 3 hours. The reaction mixture was then poured into water (25 mL) and extracted with EtOAc (3×30 mL). The organics were dried over MgSO4 and concentrated in vacuo. Purification of the crude residue by column chromatography [0-50% (9:1 CH2Cl2:MeOH)/CH2Cl2] provided 4-(2′-amino-7-bromo-8-fluoro-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-3-yl)-2-methylbut-3-yn-2-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:11][C:3]=1[C:4]([N:6]([CH2:9]C)CC)=[O:5].N[C:25]1C(C(NC)=O)=C(C)C(Br)=CC=1.NC1C=CC(Br)=CC=1C(N(CC)CC)=O>>[NH2:1][C:2]1[C:3]([C:4]([NH:6][CH3:9])=[O:5])=[C:11]([CH3:25])[C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:13][CH:14]=1
Reactant: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Reactant: CNC(=O)c1c(N)ccc(Br)c1C
Agent: CCN(CC)C(=O)c1cc(Br)ccc1N
Product: CNC(=O)c1c(N)ccc(-c2cnn(CCCO)c2)c1C

Procedure:
Prepared analogously to Compound 3C substituting 6-amino-3-bromo-2-methyl-N-methylbenzamide (Compound 29D) for 2-amino-5-bromo-N,N-diethylbenzamide (Compound 3D). MS (ESI): m/z=289.29 [M+H]+. UPLC: tR=2.33 min (ZQ3: polar—5 min).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=3)[CH2:11][CH2:10]2)[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[F:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH:9]2[NH:8][C:6]2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=[C:2]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH3:28])[CH:27]=3)[N:7]=2)=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NC1CCc2ccc(F)cc21
Reactant: Cc1cc(N)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(Nc2ccc([N+](=O)[O-])c(NC3CCc4ccc(F)cc43)n2)[nH]n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55.8 %

Procedure:
Combine 6-chloro-N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-3-nitropyridin-2-amine (9.00 g, 29.34 mmol) and 3-amino-5-methylpyrazole (4.56 g, 46.95 mmol) in dimethylsulfoxide (60 mL). Add N,N-diisopropylethylamine (8.18 mL, 46.95 mmol) and heat the reaction under nitrogen at 120° C. for 90 minutes. Pour the reaction into ice water (200 mL) and stir 20 minutes, then filter. Suspend the solid obtained in a mixture of dichloromethane and methanol and stir at 40° C. for 20 minutes. Filter the mixture to give the title compound as a yellow solid (6.03 g, 56%). MS (ES) m/z=369 [M+1].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:6]=1[CH:7]=[O:8].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[C:18]([Cl:24])[CH:17]=1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([Br:15])=[CH:17][C:18]=2[Cl:24])[C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1[nH]c(-c2ccccc2)nc1Cl
Reactant: Clc1cc(Br)ccc1CBr
Product: O=Cc1c(Cl)nc(-c2ccccc2)n1Cc1ccc(Br)cc1Cl

Procedure:
The title compound was prepared by reaction of 4-chloro-5-formyl-2-phenylimidazole with 4-bromo-2-chlorobenzyl bromide according to the process mentioned in Example 1a). In this case, starting from 2.0 g (9.68 mmol) of 4-chloro-5-formyl-2-phenylimidazole, 2.6 g of the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:18]([O:22][C:23](=[O:36])[CH:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[C:29]([F:35])[CH:28]=1)[CH3:25])([CH3:21])([CH3:20])[CH3:19].O1C2C=CC(OC3N=CC=CC=3C(O)=O)=CC=2OC1.COC(=O)COC1C=CC(CN)=C(F)C=1>>[C:18]([O:22][C:23](=[O:36])[CH:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:9]([C:8]2[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=3)=[N:15][CH:14]=[CH:13][CH:12]=2)=[O:11])=[C:29]([F:35])[CH:28]=1)[CH3:25])([CH3:19])([CH3:20])[CH3:21]
Reactant: CC(Oc1ccc(CN)c(F)c1)C(=O)OC(C)(C)C
Reactant: O=C(O)c1cccnc1Oc1ccc(F)cc1
Agent: COC(=O)COc1ccc(CN)c(F)c1
Agent: O=C(O)c1cccnc1Oc1ccc2c(c1)OCO2
Product: CC(Oc1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)c(F)c1)C(=O)OC(C)(C)C

Procedure:
The compound of Formula (5.0.24) was prepared in a manner analogous to that described in Preparation 20, substituting 2-(4-fluoro-phenoxy)-nicotinic acid and (±)-2-(4-aminomethyl-3-fluoro-phenoxy)-propionic acid tert-butyl ester for the corresponding 2-(benzo-[1,3]-dioxol-5-yloxy)-nicotinic acid and (4-aminomethyl-3-fluoro-phenoxy)-acetic acid methyl ester materials, respectively.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[C:9]([OH:23])=[N:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][CH:14]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=2)=[O:7])C>CO.C1COCC1>[OH:23][C:9]1[C:8]([C:6]([OH:7])=[O:5])=[C:17]([CH3:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([F:21])([F:20])[F:22])=[CH:14][CH:15]=2)[N:10]=1
Reactant: CCOC(=O)c1c(O)nc2cc(C(F)(F)F)ccc2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)c(O)nc2cc(C(F)(F)F)ccc12
Temperature: 60 °C
Yield: 88.2 %

Procedure:
A 2M aq. LiOH sol. (125 ml) was added to a solution of 15.0 g (50.1 mmol) 2-hydroxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester in a MeOH/THF mixture (in each case 175 ml) and the mixture was subsequently heated to 60° C. for 16 h. The mixture was subsequently concentrated in a vacuum. The residue was taken up with water and adjusted to pH 2 with a 2M hydrochloric acid. Extraction was then carried out with EtOAc. The organic phase was washed with brine, dried over MgSO4 and concentrated in a vacuum. 12.0 g (44.2 mmol, 88%) 2-hydroxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid was obtained as a residue. The raw product was further converted without additional purification.