Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:9]=1)[C:5]#[N:6].[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=2[O:21]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[O:21]1[C:22]2[CH:23]=[CH:24][C:25]([C:2]3[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)[CH:9]=3)[C:5]#[N:6])=[CH:26][C:27]=2[O:28][CH2:20]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: COc1ccc(COc2cc(Br)cc(C#N)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(COc2cc(C#N)cc(-c3ccc4c(c3)OCO4)c2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
To a solution of 3-bromo-5-(4-methoxy-benzyloxy)-benzonitrile (1.1 g) in 1,2-dimethoxyethane (10 mL) were added 3,4-methylenedioxyphenylboronic acid (860 mg), 2 M aq. sodium carbonate solution (3.5 mL) and Pd(PPh3)4 (40 mg) and the resulting mixture was stirred at 90° C. for 4 h. Then the reaction mixture was diluted with ethyl acetate, filtered through Celite and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, filtered through a silica pad, concentrated and triturated with diethyl ether to yield 1.0 g of the title compound (89% yield). HRMS calcd for C22H17O4N M+ 359.1158, observed 359.1158.
Reaction SMILES: P(F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:24][C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:32]=[N:33][N:34]([CH:36]([CH3:40])[C:37]([OH:39])=O)[CH:35]=2)=[CH:27][C:26]=1[O:41][CH:42]([C:44]1[C:49]([Cl:50])=[CH:48][CH:47]=[C:46]([F:51])[C:45]=1[Cl:52])[CH3:43].C(N(CC)CC)C.[CH3:60][N:61]([CH3:66])[CH2:62][CH2:63][CH2:64][NH2:65]>CN(C=O)C>[NH2:24][C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:32]=[N:33][N:34]([CH:36]([CH3:40])[C:37]([NH:65][CH2:64][CH2:63][CH2:62][N:61]([CH3:66])[CH3:60])=[O:39])[CH:35]=2)=[CH:27][C:26]=1[O:41][CH:42]([C:44]1[C:49]([Cl:50])=[CH:48][CH:47]=[C:46]([F:51])[C:45]=1[Cl:52])[CH3:43]
Reactant: CC(Oc1cc(-c2cnn(C(C)C(=O)O)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: CN(C)CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: FP(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(Oc1cc(-c2cnn(C(C)C(=O)NCCCN(C)C)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 3 h

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N, N′,N′-tetramethyluronium phosphorus pentafluoride (HATU) (66 mg, 0.17 mmol) was added to a solution of 2-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-propionic acid (69 mg, 0.16 mmol), triethylamine (0.024 mL, 0.17 mmol) and 3-dimethylamino-propylamine (0.022 mL, 0.17 mmol) in 1.6 mL of DMF. After stirring for 3 hours, the reaction was concentrated by rotary evaporation. The residue was purified by silica gel chromatography using gradient elution of dichloromethane, methanol, ammonium hydroxide to afford 2-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-N-(3-dimethylamino-propyl)-propionamide. (41 mg, 50%).
Reaction SMILES: O.S(=O)(=O)(O)O.[Cl:7][C:8]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][C:9]=1[NH2:10].[C:16]1([C:22](O)([CH3:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[Cl:7][C:8]1[CH:14]=[CH:13][C:12]([S:15][C:22]([CH3:24])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:23])=[CH:11][C:9]=1[NH2:10]
Reactant: Nc1cc(S)ccc1Cl
Reactant: CC(C)(O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Sc1ccc(Cl)c(N)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
To a mixture of water (10 mL) and concentrated sulfuric acid (10 mL) was added 2-chloro-5-mercaptoaniline (1.6 g) at room temperature, and the mixture was stirred for 15 minutes. To the mixture was added a solution of 2-phenyl-2-propanol (1.36 g) in tetrahydrofuran (10 mL) in a dropwise manner, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=4/1) to give the title compound (1.62 g).
Reaction SMILES: ClC1C(OC2CCC(=O)CC2)=CC(F)=C(C=1)C(O)=O.[CH:20]1([C:23]2[C:24]([O:33][CH:34]3[CH2:41][CH2:40][C:37]4([CH2:39][CH2:38]4)[CH2:36][CH2:35]3)=[CH:25][C:26]([F:32])=[C:27]([CH:31]=2)[C:28](O)=[O:29])[CH2:22][CH2:21]1.[CH3:42][S:43]([NH2:46])(=[O:45])=[O:44]>CO>[CH:20]1([C:23]2[C:24]([O:33][CH:34]3[CH2:41][CH2:40][C:37]4([CH2:39][CH2:38]4)[CH2:36][CH2:35]3)=[CH:25][C:26]([F:32])=[C:27]([CH:31]=2)[C:28]([NH:46][S:43]([CH3:42])(=[O:45])=[O:44])=[O:29])[CH2:22][CH2:21]1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(C2CC2)c(OC2CCC3(CC2)CC3)cc1F
Agent: O=C1CCC(Oc2cc(F)c(C(=O)O)cc2Cl)CC1
Solvent: CO
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OC2CCC3(CC2)CC3)cc1F

Procedure:
Following the procedure as described in Example 357 Step 4 and making non-critical variations to replace 5-chloro-2-fluoro-4-((4-oxocyclohexyl)oxy)benzoic acid with 5-cyclopropyl-2-fluoro-4-(spiro[2.5]octan-6-yloxy)benzoic acid and methanol with methanesulfonamide, the title compound was obtained as a colorless solid (0.121 g, 53% yield): 1H NMR (300 MHz, CDCl3) δ8.69 (d, J=16.2 Hz, 1H), 7.55 (d, J=9.2 Hz, 1H), 6.58 (d, J=14.8 Hz, 1H), 4.49-4.42 (m, 1H), 3.39 (s, 3H), 2.11-1.77 (m, 5H), 1.54-1.21 (m, 4H), 0.96-0.89 (m, 2H), 0.67-0.61 (m, 2H), 0.34-0.27 (m, 4H); MS (ES−) m/z 380.20 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][NH:5][C:6](=[O:32])[N:7]([C@H:9]([CH2:16][O:17][C:18](=[O:31])[NH:19][C:20]1[N:21]=[CH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([F:30])=[CH:25][CH:24]=2)[CH2:10][CH2:11][C:12]([O:14]C)=[O:13])[CH3:8].[Li+].[OH-].Cl>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][NH:5][C:6](=[O:32])[N:7]([C@H:9]([CH2:16][O:17][C:18](=[O:31])[NH:19][C:20]1[N:21]=[CH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([F:30])=[CH:25][CH:24]=2)[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH3:8]
Reactant: COC(=O)CC[C@@H](COC(=O)Nc1cc2cc(F)ccc2cn1)N(C)C(=O)NCc1cccc(F)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)O)COC(=O)Nc1cc2cc(F)ccc2cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of (S)-methyl 4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(6-fluoroisoquinolin-3-ylcarbamoyloxy)pentanoate (400 mg, 0.748 mmol, 1.0 equiv.) in 1,4-dioxane (1 mL) was added LiOH (2 N, 1.5 mL, 2.99 mmol, 4.0 equiv.). The reaction mixture was stirred at RT for 1 h., then was acidified to pH 1-3 with HCl (1 N). The mixture was diluted in EtOAc. The organic layer was washed by H2O and brine, and concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give (S)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(6-fluoroisoquinolin-3-ylcarbamoyloxy)pentanoic acid (340 mg, 87%). LRMS (M+H+) m/z 521.2.
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[Br:5][C:6]1[CH:7]=[C:8]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:9]([OH:14])=[C:10]([CH:13]=1)[CH:11]=[O:12]>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:9]([O:14][CH2:1][O:2][CH3:3])=[C:10]([CH:13]=1)[CH:11]=[O:12]
Reactant: COCCl
Reactant: CC(C)(C)c1cc(Br)cc(C=O)c1O
Solvent: ClCCl
Product: COCOc1c(C=O)cc(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.1 %

Procedure:
I-PrNEt2 (834 g, 6.46 g) and chloromethyl methyl ether (451 g, 5.60 mol) were gradually added to a solution of the 5-bromo-3-(tert-butyl)-2-hydroxybenzaldehyde (1333 g, 4.67 mol) in methylene chloride (4000 ml) while cooling on ice, and the mixture was stirred at room temperature for 2 days. After first distilling off the solvent under reduced pressure, ethyl acetate was added to the residue, washing was performed twice with brine, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1338 g) as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.[F:21][C:22]([F:30])([F:29])[C:23](=[O:28])[CH2:24][C:25](=O)[CH3:26]>CCCCCCC.C(OCC)(=O)C>[F:21][C:22]([F:30])([F:29])[C:23]([C:24]1[C:25]([CH3:26])=[N:1][C:2]2[C:3]([C:13]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:4][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:7]=2)=[O:28]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1nc2ccc(OC(F)(F)F)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reaction time: 44 h
Yield: 63 %

Procedure:
The title compound was prepared from (2-Amino-5-trifluoromethoxy-phenyl)-phenyl-methanone [example A6] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that the reaction time was of 44 h and heptane/ethyl acetate (10:1) was used. Yield: 63%; MS: m/z=399 (M).
Reaction SMILES: CO.O1[CH2:8][CH2:7][O:6][CH2:5]C1.Cl.[Cl:10]C1[N:16]=[CH:15][N:14]=[C:13]([N:17]2[C:21](=[O:22])[C:20]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)=[CH:19][NH:18]2)C=1>C1COCC1>[ClH:10].[CH3:5][O:6][C:7]1[N:16]=[CH:15][N:14]=[C:13]([N:17]2[C:21](=[O:22])[C:20]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)=[CH:19][NH:18]2)[CH:8]=1
Reactant: C1COCCO1
Reactant: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(-n2[nH]cc(-n3ccnn3)c2=O)ncn1

Procedure:
0.3 ml (6.6 mmol) methanol are initially introduced into 15 ml dioxane. 1.3 ml (2.7 mmol) of a 2 M solution of the phosphazene base P2-tert-butyl in THF are added slowly, while stirring, and the mixture is stirred at RT for 15 min 350 mg (1.3 mmol) of the compound from Example 52A are subsequently added and the mixture is reacted in a single mode microwave (CEM Explorer) at 150° C. for 2 h. A further 2 ml (49.2 mmol) methanol are then added and the mixture is reacted again in a single mode microwave (CEM Explorer) under the same conditions for 2 h. After cooling, the reaction mixture is concentrated and the residue is purified via preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions are combined and the mixture is concentrated on a rotary evaporator. The residue is dried under a high vacuum and 3 ml of a 4 N solution of hydrogen chloride in dioxane is subsequently added. The mixture is stirred at RT for 30 min and the solid is then filtered off and dried under a high vacuum.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[NH:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH2:26][CH2:27][CH3:28].C(O)(=O)C>CN(C=O)C>[CH2:25]([N:12]1[C:11]2[N:10]=[CH:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:16]=2[C:15](=[O:17])[NH:14][C:13]1=[O:18])[CH2:26][CH2:27][CH3:28]
Reactant: O=c1[nH]c(=O)c2c(ncn2Cc2ccccc2)[nH]1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Yield: 44.9 %

Procedure:
7-benzyl-3,7-dihydro-1H-purine-2,6-dione (17.14 g, 70.8 mmol) [Synthetic Communications, 20(16), 2459-2467, 1990] and potassium carbonate (11.43 g, 82.8 mmol) were suspended in DMF (400 mL) at 40° C. After stirring for thirty minutes, butyl iodide (8.76 mL, 77.0 mmol) was added, and the mixture was stirred at 40° C. overnight. 50% Aqueous acetic acid (60 mL) was added, and the solution was concentrated under reduced pressure. The residue was suspended in water (500 mL), and the products were extracted into chloroform. The organics were collected, concentrated, and product was isolated using flash chromatography eluting with 1% methanol in dichloromethane to provide the product (9.49 g, 45%); 1H NMR (400 MHz; CDCl3) δ: 0.95 (3H, t), 1.34-1.41 (2H, m), 1.70-1.78 (2H, m), 4.05 (2H, t), 5.46 (2H, s), 7.31-7.40 (5H, m), 7.56 (1H, s), 8.21 (1H, br.s); m/z 299 [MH+].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:8]=[C:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[NH:10][CH:11]=2)[CH2:3][CH2:2]1.[OH-].[K+].Br[CH2:28][CH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1>CS(C)=O>[O:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH:31]1[O:30][CH2:29][CH2:28][N:10]1[CH:11]=[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[N:8]=[C:9]1[CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)c[nH]2)CC1
Reactant: BrCCOC1CCCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)cn2CCOC2CCCCO2)CC1
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
Combine tert-butyl 4-(4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate (5.84 g, 17.40 mmol) and potassium hydroxide (5.91 g, 6.0 eq) (freshly powdered) in dimethyl sulfoxide (30 mL). Heat the reaction mixture to 45° C. under nitrogen. After 15 minutes, add 2-(2-bromoethoxy)tetrahydro-2H-pyran (2.90 mL, 1.1 eq). Continue to heat the reaction overnight. Add water and extract with ethyl acetate. Wash the organics with saturated aqueous sodium chloride. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with hexanes to 50% ethyl acetate in hexanes to ethyl acetate to 10% methanol in ethyl acetate, to give the title compound as a thick yellow oil (6.94 g, 86%). MS (ES) m/z=464 [M]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[N:9]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:22]1[N:26]2[CH:27]=[CH:28][C:29]([C:31]([F:34])([F:33])[F:32])=[N:30][C:25]2=[N:24][CH:23]=1)CCC>>[F:16][C:5]1[CH:4]=[CH:3][C:2]([C:22]2[N:26]3[CH:27]=[CH:28][C:29]([C:31]([F:32])([F:33])[F:34])=[N:30][C:25]3=[N:24][CH:23]=2)=[CH:7][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[N:9]=1
Reactant: COc1cccc(-c2cc(Br)ccc2F)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: COc1cccc(-c2cc(-c3cnc4nc(C(F)(F)F)ccn34)ccc2F)n1

Procedure:
2-(5-Bromo-2-fluorophenyl)-6-methoxypyridine (595 mg, 2.1 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazol[1,2-α]pyrimidine (3.2 mmol) by the method of Example 32. Purification by chromatography on silica gel eluting with dichloromethane containing 1% methanol, then crystallisation from methanol, gave 3-[4-fluoro-3-(6-methoxypyridin-2-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a yellow solid: δH (400 MHz, CDCl3) 3.98 (3H, s), 6.79 (1H, d, J 8), 7.26 (1H, d, J 10), 7.38 (1H, dd, J 11 and 9), 7.52-7.56 (2H, m), 7.70 (1H, t, J 8), 8.12 (1H, s), 8.36 (1H, dd, J 7 and 2), 8.85 (1H, d, J 7).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[N:14]=[N:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[O:59]1[CH2:60][CH2:61][CH:56]([NH:55][C:15]([C:12]2[N:13]=[N:14][C:9]([O:8][CH2:7][C:6]3[N:2]([CH3:1])[N:3]=[N:4][C:5]=3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:10][CH:11]=2)=[O:17])[CH2:57][CH2:58]1
Reactant: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)nn1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)NC2CCOCC2)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.4 %

Procedure:
To a solution of 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (98 mg, 0.31 mmol) and TBTU (111 mg, 0.35 mmol) in DMF (2 mL) was added DIPEA (270 μL, 1.57 mmol). Then 4-aminotetrahydropyran (35 mg, 0.35 mmol) was added and the mixture was stirred at room temperature under Ar for 16 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (101 mg, 81%) as an off white solid. MS: m/e=396.2 [M+H]+.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([NH:19][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: O=C(Nc1ccccc1)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and aniline as the starting materials.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Br:15][C:16]1[C:17]([O:27][CH3:28])=[C:18]([CH:24](O)[CH3:25])[CH:19]=[C:20]([Cl:23])[C:21]=1[CH3:22]>C(Cl)Cl>[Br:15][C:16]1[C:21]([CH3:22])=[C:20]([Cl:23])[CH:19]=[C:18]([CH:24]([Cl:3])[CH3:25])[C:17]=1[O:27][CH3:28]
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1Br
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C(C)Cl)cc(Cl)c(C)c1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.1 %

Procedure:
A mixture of cyanuric chloride (1.7 g, 9.2 mmol) and N,N-dimethylformamide (710 μL, 9.2 mmol) was stirred at room temperature for 10 minutes and then a solution of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol (from Example 16, Step 1) (1.72 g, 6.15 mmol) in methylene chloride (34 mL) was added and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with 0 to 10% EtOAc in hexanes, to give the desired product (1.01 g, 60%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:20])[CH2:16][C:17](=[O:19])[CH3:18])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Br:21]Br>CC(O)=O>[Br:21][CH2:18][C:17](=[O:19])[CH2:16][C:15]([NH:14][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[C:2]([F:1])[CH:3]=1)=[O:20]
Reactant: BrBr
Reactant: CC(=O)CC(=O)Nc1ccc(N2CCOCC2)c(F)c1
Solvent: CC(=O)O
Product: O=C(CBr)CC(=O)Nc1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
To a solution of N-(3-fluoro-4-morpholinophenyl)-3-oxobutanamide (11.2 g, 40.0 mmol) and AcOH (100 mL) under N2 was added Br2 (2.4 mL) at rt. At end of addition, the mixture was stirred further at rt for 24 h. The mixture was then concentrated in vacuo and 40 mL of water was added. The resulting mixture was extracted with EtOAc (30 mL×4). The combined organic phases were washed with brine (40 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as a yellow solid (6.80 g, 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)[C:6](=[O:21])[C:5]2([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])[NH:22][CH2:23][CH3:24].C(N(CC)CC)C.[NH2:39][C:40]([CH3:44])([CH3:43])[CH2:41][OH:42].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](=[O:18])[NH:39][C:40]([CH3:44])([CH3:43])[CH2:41][OH:42])=[CH:14][CH:13]=1)[C:6](=[O:21])[C:5]2([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])[NH:22][CH2:23][CH3:24]
Reactant: CC(C)(N)CO
Reactant: CCNC1(c2ccccc2Cl)C(=O)N(Cc2ccc(C(=O)O)cc2)c2ccc(Cl)cc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC1(c2ccccc2Cl)C(=O)N(Cc2ccc(C(=O)NC(C)(C)CO)cc2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.374 g of the compound obtained in step B of EXAMPLE 241 in 5 ml of DCM is cooled to 0° C. and 0.34 ml of triethylamine and then 0.16 ml of 2-amino-2-methylpropan-1-ol and 0.364 g of BOP are added. The reaction mixture is stirred for 1 hour at RT and concentrated under vacuum. The residue is taken up with AcOEt, the organic phase is washed with water, with a 5% solution of potassium carbonate and with a saturated solution of NaCl and dried over sodium sulfate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using DCM and then a DCM/AcOEt mixture (70/30; v/v) as the eluent to give 0.3 g of the expected product after crystallization from a DCM/iso ether mixture. M.p.=170°-172° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[N:57]=[CH:56][C:55]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:54][CH:53]=1>CN(C=O)C>[CH3:50][O:51][C:52]1[N:57]=[CH:56][C:55]([C:58]2[CH:59]=[C:60]([NH:64][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:61]=[CH:62][CH:63]=2)=[CH:54][CH:53]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: COc1ccc(-c2cccc(N)c2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)cn1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(6-methoxy-pyridin-3-yl)-phenylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.022 g of product in 84% yield: LCMS (ESI) m/z 403 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[C:6](F)[C:5]([Br:13])=[CH:4][CH:3]=1.FC1C2C(=O)OC(=O)NC=2C=CC=1.[Cl:27]C1C2C(=O)OC(=O)NC=2C=CC=1>>[NH2:1][C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[C:6]([Cl:27])[C:5]([Br:13])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(N)ccc(Br)c1F
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Agent: O=c1[nH]c2cccc(F)c2c(=O)o1
Product: CNC(=O)c1c(N)ccc(Br)c1Cl

Procedure:
Prepared analogously to Compound 27D replacing 5-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (Compound 27E) with 5-Chloro-1H-benzo[d][1,3]oxazine-2,4-dione (Compound 28E). 1H NMR (CDCl3, 500 MHz) δ=2.95 (d, J=5.2 Hz, 3H), 6.02 (brs, 2H), 6.89 (d, J=8.8 Hz, 1H), 7.25 (d, J=8.8 Hz, 1H), 7.79 (brs, 1H).