Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([C:13]1[CH:51]=[CH:50][C:16]([C:17]([O:19][CH2:20][C:21]([O:23][C@H:24]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]3[CH2:49][CH2:48]3)[CH:36]=2)[CH2:25][C:26]2[C:31]([Cl:32])=[CH:30][N+:29]([O-:33])=[CH:28][C:27]=2[Cl:34])=[O:22])=[O:18])=[CH:15][C:14]=1[O:52][CH2:53][CH:54]1[CH2:56][CH2:55]1)[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.O1CCOCC1>C(Cl)Cl.Cl>[Cl:34][C:27]1[CH:28]=[N+:29]([O-:33])[CH:30]=[C:31]([Cl:32])[C:26]=1[CH2:25][C@@H:24]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:43])[F:44])=[C:37]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)[CH:36]=1)[O:23][C:21](=[O:22])[CH2:20][O:19][C:17](=[O:18])[C:16]1[CH:50]=[CH:51][C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:14]([O:52][CH2:53][CH:54]2[CH2:55][CH2:56]2)[CH:15]=1
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of (S)-4-(2-(2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (2.457 g, 2.91 mmol) in dry DCM (85 ml), HCl 4M in dioxane (7.26 ml, 29.1 mmol) was added, and the reaction was stirred at RT overnight. Then the solvent was evaporated and the residue was purified by flash chromatography on silica gel (eluent: DCM/MeOH 99:1). Combined fractions were evaporated and the resulting solid was triturated with EtOH/MeOH 95:5 to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)-benzoyloxy)acetoxy)ethyl)pyridine 1-oxide as a white solid (1.761 g, 2.362 mmol, 81% yield, MS/ESI+ 745.13 [MH]+, [αD]=−34.69, c=0.49, DCM).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1.Cl.CO>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 50.2 %

Procedure:
A solution of methyl 1-benzyl-2-oxo-4-pyrrolidylcarboxylate (D10, 35.4 g, 0.18 mole) in dry THF (135 ml) was added dropwise over 30 mins to 1M borane-THF solution (228 ml, 0.23 mole) at 0° C. under nitrogen, and when addition was complete the solution was heated under reflux for 1h. The solution was cooled to room temperature, then treated dropwise with 8% hydrogen chloride/methanol (114 ml, 0.25 mole HCl) and stirred for 18h, followed by 3h at reflux. The mixture was then concentrated in vacuo and the residue treated with water (40 ml), washed with ether (2×50 ml), basified with 40% sodium hydroxide solution, saturated with potassium carbonate and extracted with ether (3×70 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a yellow oil, which was purified by distillation (b.p. 146° C.0.7mm) to give the title compound (D11) as a colourless oil (19.8 g, 50%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[CH:10](=O)[CH2:11][CH3:12].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH:8][CH2:10][CH2:11][CH3:12]
Reactant: Cc1c(N)cccc1Br
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCNc1cccc(Br)c1C
Yield: 97.9 %

Procedure:
To a solution of 3-bromo-2-methylphenylamine (1.5 g, 8.06 mmol) in dry CH2Cl2 with 3A molecular sieves was added propionaldehyde (580 μL, 8.06 mmol) and the resultant mixture stirred at room temperature for 20 min under nitrogen. Acetic acid (561 μL, 8.06 mmol) and sodium triacetoxyborohydride (4.78 g, 22.56 mmol) were added and the resultant mixture stirred under nitrogen at room temperature for 16 h. Saturated sodium bicarbonate (60 mL) was added portionwise and the resultant mixture stirred for 0.5 h and extracted with CH2Cl2 (2×100 mL). The organic solution was dried (Na2SO4) and the solvents removed in vacuo to afford the title compound as a yellow oil (1.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][C:14]2[C:24]([F:25])=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[C:16]([F:26])[CH:15]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11].[OH-].[Li+].C1COCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][C:14]2[C:24]([F:25])=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[C:16]([F:26])[CH:15]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: CCOC(=O)c1cc(F)c(Oc2cnc(OCC(C)C)c(Cl)c2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)COc1ncc(Oc2cc(F)c(C(=O)O)cc2F)cc1Cl
Yield: 100.6 %

Procedure:
Ethyl 4-[(5-chloro-6-isobutoxypyridin-3-yl)oxy]-2,5-difluorobenzoate (Preparation 38, 150 mg, 0.389 mmol) and lithium hydroxide (250 mg, 10.44 mmol) were dissolved in water (2.5 mL) and THF (2.5 mL) and stirred at room temperature for 72 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc (10 mL), washed with water (10 mL) and aqueous HCl (2 M, 10 mL), then was dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a white solid (140 mg, 100%):
Reaction SMILES: C1(N[C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([OH:23])=[CH:18][CH:19]=4)[C:14]3=[O:24])[CH:7]=2)CC1.C(OCC)(=[O:28])C>Br>[OH:23][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[CH:22][N:13]([C:8]3[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=3[CH3:12])[C:5]([OH:28])=[O:25])[C:14]2=[O:24])=[CH:19][CH:18]=1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(O)cc2c1=O
Agent: Br
Product: Cc1ccc(C(=O)O)cc1-n1ccc2ccc(O)cc2c1=O
Temperature: 150 °C

Procedure:
N-Cyclopropyl-3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzamide (0.5 g) was stirred in 48% hydrobromic acid (7 mL) and heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 150° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, washed water (×3), brine, dried (magnesium sulfate) and concentrated to a brown solid. The solid was triturated with diethyl ether to yield 3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzoic acid as a brown solid (0.32 g); NMR Spectrum: (DMSOd6) 2.11 (s, 3H), 6.65 (d, 1H), 7.12 (d, 1H), 7.27 (d, 1H), 7.54 (d, 1H), 7.60 (s, 1H), 7.61 (d, 1H), 7.78 (s, 1H), 7.95 (d, 1H), 10.09 (s, 1H), 13.05 (s, 1H); Mass Spectrum: M+H+ 296.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][CH3:15])[CH2:12][O:11][C@H:10]([C:16]([OH:18])=O)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH2:14]([C@H:13]1[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@@H:10]([C:16]([NH:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[O:11][CH2:12]1)[CH3:15]
Reactant: NCc1ccccc1
Reactant: CC[C@@H]1CO[C@H](C(=O)O)CN1C(=O)OC(C)(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC[C@@H]1CO[C@H](C(=O)NCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.1 %

Procedure:
To (2S,5R)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-5-ethyl-2-morpholinecarboxylic acid (0.390 g, 1.504 mmol) in CH2Cl2 (10 mL) were added benzylamine (0.164 mL, 1.504 mmol), HOAt (0.205 g, 1.504 mmol) and EDC (0.346 g, 1.805 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was washed with H2O (3×) and the organics were then dried over Na2SO4 and concentrated to afford the title compound (0.551 g). LC-MS (ES) m/z=249 [M+H-Boc]+.
Reaction SMILES: C[O-].[Na+].[C:4]([CH2:6][C:7]([NH2:9])=[O:8])#[N:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[CH:20]N(C)C)[CH:18]=O)=[CH:13][CH:12]=1>CO>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:20]=[C:6]([C:4]#[N:5])[C:7](=[O:8])[NH:9][CH:18]=2)=[CH:13][CH:12]=1
Reactant: CN(C)C=C(C=O)c1ccc(Cl)cc1
Reactant: N#CCC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1cc(-c2ccc(Cl)cc2)c[nH]c1=O

Procedure:
To a solution of 37.6 g. of sodium methoxide in 650 ml. of methanol is added 29.24 g. of cyanoacetamide followed by 26.1 g. of 2-(4-chlorophenyl)-3-(dimethylamino)-2-propenal. The resulting solution is heated at reflux temperature for 16 hours to separate a yellow solid. Then 50 ml. of glacial acetic acid is added and the mixture is diluted with water, causing a new yellow solid to separate. This solid is collected by filtration and is washed with water to give 60.5 g. of the product of the Example m.p. 285°-290° C.
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11]([CH2:15][CH:16]=[CH2:17])[C:10]([C:18](O)=[O:19])=[N:9][C:8]=2[N:7]([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4].CC[N:28](C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.N>CN(C=O)C>[CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11]([CH2:15][CH:16]=[CH2:17])[C:10]([C:18]([NH2:28])=[O:19])=[N:9][C:8]=2[N:7]([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCN(C(C)C)C(C)C
Reactant: C=CCn1c(C(=O)O)nc2c1c(=O)n(CCCC)c(=O)n2CCCC
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: C=CCn1c(C(N)=O)nc2c1c(=O)n(CCCC)c(=O)n2CCCC

Procedure:
A stirred solution of 1,3-dibutyl-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purine-8-carboxylic acid (1.0 g, 2.9 mmol) in anhydrous DMF (10 ml) was sequentially treated with DIPEA (1.1 ml), PyBOP, and 2M NH3 (3.6 ml). After 2 hours the product mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with sat. NaHCO3 (aq) solution, brine, then dried (MgSO4) and concentrated giving an orange oil (ca. 2 g). The product was purified by Biotage™ chromatography eluting with 5%→40% EtOAc/cyclohexane mixtures. The appropriate fractions were combined and concentrated to give the amide 90% pure (790 mg, 78%). m/z. 392.3[M+formic acid−H]−.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]([C:11]#[C:12][CH3:13])[C:7]([NH2:10])=[N:8][CH:9]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl>CN1C(=O)CCC1>[Br:3][C:4]1[N:5]=[C:6]2[CH:11]=[C:12]([CH3:13])[N:10]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[C:7]2=[N:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC#Cc1nc(Br)cnc1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1ccc(S(=O)(=O)n2c(C)cc3nc(Br)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74 %

Procedure:
To a slurry of NaH (60% dispersion in mineral oil, 2.00 g, 49.9 mmol) in NMP (100 mL) was slowly added a solution of 5-bromo-3-(prop-1-ynyl)pyrazin-2-amine (7.05 g, 33.2 mmol) in NMP (20 mL). The reaction mixture was stirred at ambient temperature for about 20 min and then a solution of p-toluenesulfonyl chloride (6.97 g, 36.6 mmol) in NMP (20 mL) was added. The reaction mixture was stirred at ambient temperature for about 20 h and then aqueous HCl (1 N, 100 mL) was added to the reaction mixture. The resulting solids were collected by filtration. The brown solid was triturated with DCM/EtOAc (1:1, 30 mL) and collected by filtration to provide 2-bromo-6-methyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (9.0 g, 74%) as a brown solid: LC/MS (Table 1, Method a) Rt=2.68 min; MS m/z: 366, 368 (1:1) (M+H)+.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[OH:7][C@@H:8]1[CH2:16][C@@H:11]2[O:12][C:13](=[O:15])[CH2:14][C@@H:10]2[C@H:9]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>ClCCl>[CH2:17]([C@@H:9]1[C@@H:10]2[C@@H:11]([O:12][C:13](=[O:15])[CH2:14]2)[CH2:16][C@H:8]1[O:7][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: C1=COCCC1
Reactant: CCCCCCCC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1O
Solvent: ClCCl
Product: CCCCCCCC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Reaction time: 8 h
Yield: 92.3 %

Procedure:
Dihydropyran (60 μL, 0.66 mmol) and PPTs (11 mg, 0.045 mmol) were added to a solution of 5-3 (81 mg, 0.32 mmol) in dichloromethane (1.2 mL). After overnight stirring, the reaction was washed with 1 M HCl, saturated NaHCO3 solution and brine. The organic layer was dried (Na2SO4), filtered and evaporated. Purification of the residue by flash chromatography on silica gel (Isco Combiflash unit) gave the title compound (100 mg, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10]O)=[C:7]([CH3:12])[C:6]=2[C:13]=1[O:14][CH3:15].P(Br)(Br)[Br:17]>ClCCl.N1C=CC=CC=1>[Br:17][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[C:13]([O:14][CH3:15])[C:6]=2[C:7]=1[CH3:12]
Reactant: BrP(Br)Br
Reactant: COc1c(Cl)ccc2oc(CO)c(C)c12
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(Cl)ccc2oc(CBr)c(C)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a 0° C. solution of (5-chloro-4-methoxy-3-methyl benzofuran-2-yl)-methanol (0.29 g; 1.3 mmol) in dichloromethane (5 mL) was added neat phosphorus tribromide (0.18 mL; 0.52 g; 1.9 mmol; 1.5 eq) and pyridine (3 drops). The ice bath was removed and the reaction was allowed to warm to room temperature overnight. Additional phosphorus tribromide (0.09 mL; 0.26 g; 0.95 mmol; 0.75 eq) was added and stirring continued at room temperature. After two hours, the reaction was quenched with ice and extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated sodium bicarbonate, followed by drying over magnesium sulfate, filtration and concentration in vacuo to give essentially pure 2-bromomethyl-5-chloro-4-methoxy-3-methyl benzofuran (0.37 g; 99%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:21][C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=2.Cl.[CH3:32][NH:33][CH3:34].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C1COCC1>[CH3:32][N:33]([CH3:34])[C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([CH2:21][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:11]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:13])([F:14])[F:15])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[CH:23]=1
Reactant: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1cccc(C(=O)O)c1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1cccc(C(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 61.2 %

Procedure:
A solution of 60 mg (0.139 mmol) of 3-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-benzoic acid (example 31) in 1 mL of THF was treated with 31 mg (0.417 mmol) of dimethylamine hydrochloride, 0.09 mL (0.834 mmol) of N-methylmorpholine, 3.7 mg (0.028 mmol) of HOBT, and 37 mg (0.195 mmol) of EDCI. The mixture was stirred for 10 hrs at RT and the solvent evaporated. Column chromatography on silica gel with n-heptane/EtOAc 4:1 to 1:1 yielded 39 mg (60%) of N,N-dimethyl-3-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-benzamide, colorless solid, MS: 459 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][N:3]=1.[CH3:12][C:13]([CH3:17])=[CH:14][Mg]Br>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:11][O:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[C:13]([CH3:17])[CH3:14])=[N:3][CH:4]=1
Reactant: CC(C)=C[Mg]Br
Reactant: COCOc1ccc(Cl)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: COCOc1ccc(C=C(C)C)nc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2-chloro-5-(methoxymethoxy)pyridine (0.620 g, 3.6 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.13 g, 0.18 mmol) in THF (7 mL) was cooled to 0° C. 2-methyl-1-propenylmagnesium bromide, (0.5 M in THF) (9.3 ml, 4.6 mmol) was added slowly and the reaction was allowed to stir 12 hrs at RT. The reaction was quenched by the addition of a 10:1 aqueous sat. ammonium chloride/ammonium hydroxide solution and extracted into ethyl acetate. The combined organic layers were washed with 10:1 aqueous sat. ammonium chloride/ammonium hydroxide solution, water, brine, dried over sodium sulfate and concentrated. The crude product was purified by filtration through a plug of silica gel (2:1 Hexanes/EtOAc) to afford the title product. MS m/z: 194.1 (100%, M+1).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH:18]1([N:13]2[C:12]([C:37]3[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2c3c(nn2C2CCCCC2)CCNCC3)cc1
Yield: 67.2 %

Procedure:
The title compound (96.8 mg) was prepared as in Example 177, Steps C and D, using 207 mg of 2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 177, Step B) and 224.1 mg of 4-methoxyphenylboronic acid. MS (ESI): exact mass calculated for C20H27N3O, 325.45; found, m/z 326.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.25 (d, J=8.7 Hz, 2H), 7.11 (d, J=8.7 Hz, 2H), 4.00-3.92 (m, 1H), 3.87 (s, 3H), 3.45-3.40 (m, 2H), 3.22-3.17 (m, 2H), 2.81-2.75 (m, 2H), 1.96-1.65 (m, 7H), 1.29-1.19 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[OH:12].C(OCC)(=O)C.C(=O)([O-])O.[Na+].Br[C:25]([CH3:30])([CH3:29])[C:26](Br)=[O:27]>O>[CH3:29][C:25]1([CH3:30])[C:26](=[O:27])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=2[O:12]1
Reactant: CC(C)(Br)C(=O)Br
Reactant: COC(=O)c1ccc(N)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)OC(C)(C)C(=O)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
To a solution of 2-amino-5-methoxycarbonylphenol [Tetrahedron, 46(15), 5177-5186 (1990)] (9.8 g) in a mixed solvent of ethyl acetate (200 ml) and water (200 ml) were added sodium hydrogen carbonate (7.3 g) and 2-bromoisobutyryl bromide (13.7 g) and the mixture was stirred at room temperature for 10 minutes. The organic layer was separated and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in dimethylformamide (500 ml), to the solution was added potassium carbonate (8.9 g) and the mixture was stirred at room temperature for a day. The reaction solution was poured into water to give precipitates, which were taken by filtration and dried to give 2,2-dimethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (10.8 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH2:16][C:17]3[CH:18]=[C:19]([C:23]4[O:24][C:25]([C:28]5[CH:29]=[N:30][N:31]([CH:33]6[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]6)[CH:32]=5)=[CH:26][N:27]=4)[CH:20]=[CH:21][CH:22]=3)[N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[ClH:46]>O1CCOCC1.CO>[ClH:46].[F:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[O:24][C:25]([C:28]5[CH:29]=[N:30][N:31]([CH:33]6[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]6)[CH:32]=5)=[CH:26][N:27]=4)[CH:18]=3)[N:10]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(-c4cccc(Cn5nc(-c6cc(F)cc(F)c6)ccc5=O)c4)o3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=c1ccc(-c2cc(F)cc(F)c2)nn1Cc1cccc(-c2ncc(-c3cnn(C4CCNCC4)c3)o2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 90.4 mg (0.147 mmol) of tert-butyl 4-[4-(2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}oxazol-5-yl)pyrazol-1-yl]piperidine-1-carboxylate in a mixture of 0.22 ml of 4 N hydrogen chloride in dioxane and 0.23 ml of methanol is stirred at room temperature for 16 hours. The solution is evaporated and dried in vacuo, giving 6-(3,5-difluorophenyl)-2-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)oxazol-2-yl]benzyl}-2H-pyridazin-3-one hydrochloride as colourless crystals; ESI 515.
Reaction SMILES: C[O:2][C:3](=[O:13])[C@:4]([CH2:8][O:9][CH:10]([F:12])[F:11])([CH3:7])[CH:5]=[CH2:6].O.[OH-].[Li+].Cl>O1CCCC1.O>[F:11][CH:10]([F:12])[O:9][CH2:8][C@@:4]([CH3:7])([CH:5]=[CH2:6])[C:3]([OH:13])=[O:2]
Reactant: C=C[C@](C)(COC(F)F)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=C[C@](C)(COC(F)F)C(=O)O
Temperature: 5 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A solution of (R)-2-difluoromethoxymethyl-2-methyl-but-3-enoic acid methyl ester (159 mg, 0.8 mmol) in tetrahydrofuran (6 mL) was stirred at 5° C. under nitrogen. A solution of lithium hydroxide monohydrate (100 mg, 2.4 mmol) in water (1.5 mL) was added and the reaction mixture was stirred at 5° C. for 1 h and then at room temperature for 20 h. Water was added and the mixture was acidified to pH 2 with hydrochloric acid (2 M) and the mixture was extracted with diethyl ether. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford the title compound (133 mg, 92%) as a clear oil. 1H NMR (300 MHz, d6-DMSO) 61.24 (s, 3H), 3.80 (d, J=9.4 Hz, 1H), 4.02 (d, J=9.4 Hz, 1H), 5.19 (dd, J=10.6 Hz, 1H), 5.20 (d, J=17.6 Hz, 1H), 5.91 (dd, J=17.6, 10.6 Hz, 1H), 6.68 (t, J=75.6 Hz, 1H), 12.5-13.0 (br s, 1H). LCMS (m/z) 179.1 [M−H], Tr=1.79 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([OH:39])[CH:37]=2)[NH:32][CH:31]=1>CN(C=O)C>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][CH:3]=[C:2]2[O:39][C:36]1[CH:37]=[C:38]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[CH3:29])#[N:13]
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCCCN1CCCC1
Reactant: Cc1c[nH]c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c[nH]c2ccc(Oc3ccnc4cc(OCCCN5CCCC5)c(C#N)cc34)cc12
Temperature: 95 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
A solution of 4-chloro-6-cyano-7-(3-(pyrrolidin-1-yl)propoxy)quinoline (200 mg, 0.63 mmol), (prepared as described for the starting material in Example 11), potassium carbonate (131 mg, 0.95 mmol) and 3-methyl-5-hydroxyindole (102.5 mg, 0.69 mmol), (Can. J. Chem. 1964, 42, 514), in DMF (6 ml) was stirred at 95° C. for 2 hours. After cooling, silica was added and the volatiles was removed under vacuum. The product was eluted with methylene chloride followed by methylene chloride/ethyl acetate (containing 20% methanol) (9/1 followed by 8/2) followed by methylene chloride/methanol (saturated with ammonia) (9/1 followed by 8/2). The fractions containing the expected product were combined and evaporated. The residue was triturated with ether, filtered and dried under vacuum to give 6-cyano-4-(3-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinoline (151 mg, 56%).