Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:4]1[C:3]([O:2][CH3:1])=[N:7][N:6]([CH3:8])[C:5]1=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nn(C)c(=O)n1-c1ccccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1nn(C)c(=O)n1-c1ccccc1CBr
Yield: 34.2 %

Procedure:
To a solution/suspension of 6.7 g 2,4-dihydro-5-methoxy-2-methyl-4-(2-methylphenyl)-3H-1,2,4-triazol-3-one dissolved in 95 mL carbon tetrachloride under N2 was added N-bromosuccinimide (6.53 g) followed by a catalytic amount of benzoyl peroxide. The solution was heated at reflux for 2 h. Another 1.63 g N-bromosuccinimide and a catalytic amount of benzoyl peroxide were added and the solution was heated at reflux for an hour. After cooling, methylene chloride was added and the organic layer was washed successively with water, then 0.1 N sodium thiosulfate solution, then saturated aqueous NaCl. The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (3 -10% diethylether/methylene chloride as eluent) to afford 3.12 g of the title compound of Step D. 1H NMR (CDCl3) δ7.5 (m,1H), 7.44 (m,2H), 7.22 (m,1H), 4.60 (d,1H), 4.36 (d,1H), 3.96 (s,3H), 3.47 (s,3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=C(O)[CH:6]=[CH:7][CH:8]=1.[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH:13]=[CH2:14].[OH-].[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C.O>[CH3:10][O:11][CH:12]1[CH2:13][CH2:14][C:6]2[C:16](=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[O:15]1
Reactant: COc1cccc(O)c1
Reactant: C=CC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: COc1ccc2c(c1)OC(OC)CC2
Reaction time: 3 h
Yield: 34.5 %

Procedure:
A 500-milliliter flask fitted with a dropping funnel was charged with 12.4 g of 3-methoxyphenol, 0.2 g of p-toluenesulfonic acid monohydrate and 100 ml of diethyl ether for dissolution, and the mixture was cooled with ice. To this solution was slowly added dropwise 14.3 g of acrolein dimethyl acetal under room temperature. After the dropwise addition, the solution was stirred for 3 hours while being cooled with ice. The reaction solution was alkalized with the addition of 5 ml of a 5% sodium hydroxide aqueous solution and 30 ml of water. Subsequently, 200 ml of diethyl ether was added thereto for extraction. Thus obtained organic layer was washed with 30 ml of water, the diethyl ether was removed by distillation in vacuo therefrom, and the resulting residue was purified by distillation to obtain 6.7 g of a colorless liquid (yield 32%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]N>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:40][C:35]3[C:36]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:37][CH:38]=[CH:39][C:34]=3[CH3:33])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1NN
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(F)cc3)CC2)c1
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccc(F)cc3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-(5-(4-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 512.2 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1(CN)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.O.[N:14]1C=CC=[CH:16][CH:15]=1>>[C:1]([N:14]([CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)[CH2:15][CH3:16])(=[O:3])[CH3:2]
Reactant: c1ccncc1
Reactant: CC(=O)Cl
Reactant: NCC1CCCCC1
Solvent: O
Product: CCN(C(C)=O)C1CCCCC1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Acetyl chloride (1.1 mL, 15.4 mmol) was added slowly to an ice cooled solution of cyclohexylmethyl amine (1.3 mL, 10 mmol) in pyridine (4 mL) under a nitrogen atmosphere. After stirring at 0-5° C. for 1 h, the reaction mixture was maintained at ambient temperature for 6 h. This mixture was then poured into water (20 mL) and extracted with ethyl acetate (3×25 mL). The combined organic phases were washed with 1N HCl (2×10 mL) and then with a saturated sodium bicarbonate solution (10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give N-acetyl-cyclohexyl-ethyl-amine (1.50 g), yield: 98%. A solution of N-acetyl-cylohexyl-ethyl-amine (0.8 g, 5.0 mmol) in anhydrous THF (10 mL) was prepared under nitrogen, and lithium aluminum hydride (1.0 M solution in ether, 10 mmol) was added to the solution. After stirring for 6 h at RT, the reaction mixture was poured into water (30 mL) and stirred for 1 h. The inorganic salts were then filtered and washed with water (10 mL) and ethyl acetate (3×25 mL). The combined filtrate was collected and the organic phase was separated. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (0.4 g, yield: 56%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:11]([CH2:21][CH2:22][CH:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[OH:24])[C:10]2=[O:32])=[CH:5][CH:4]=1.[S:33]([CH2:37][C:38](O)=[O:39])([OH:36])(=[O:35])=[O:34].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH:23]([OH:24])[CH2:22][CH2:21][CH:11]2[C:10](=[O:32])[N:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:38]([CH2:37][S:33]([OH:36])(=[O:35])=[O:34])=[O:39])=[CH:4][CH:5]=3)[CH:12]2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:30][CH:29]=1
Reactant: O=C(O)CS(=O)(=O)O
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(CN)cc2)cc1
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(CNC(=O)CS(=O)(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 60 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)azetidin-2-one (5) in 1 ml of dimethylformamide was added to a solution of 20 mg of sulfoacetic acid, 55 μl of diisopropylcarbodiimide, 38 mg of hydroxybenzotriazole in 1 ml of dimethylformamide, and the mixture was stirred at room temperature for 12 h. The reaction solution was concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20->10/90). This gave the product of molecular weight 556.61 (C28H29F1N2O7S1); MS (ESI) 539.05 (M+H+—H2O)
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][C:6](=[O:72])[CH:7]([NH:11][C:12](=[O:71])[C@H:13]([NH:35][C:36]([C:38]1([NH:41][C:42](=[O:70])[CH2:43][C@H:44](O)/[CH:45]=[CH:46]/[CH2:47][CH2:48][S:49][C:50]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:40][CH2:39]1)=[O:37])[CH2:14][S:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:8]([CH3:10])[CH3:9].[Li+].[OH-:75].CC1C=CC=C([N+]([O-])=O)C=1C(OC(C1C([N+]([O-])=O)=CC=CC=1C)=O)=O>C1COCC1.O.CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:8]([CH:7]1[NH:11][C:12](=[O:71])[C@@H:13]([CH2:14][S:15][C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[NH:35][C:36](=[O:37])[C:38]2([CH2:39][CH2:40]2)[NH:41][C:42](=[O:70])[CH2:43][C@@H:44](/[CH:45]=[CH:46]/[CH2:47][CH2:48][S:49][C:50]([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[O:75][C:3](=[O:2])[CH2:4][NH:5][C:6]1=[O:72])([CH3:10])[CH3:9]
Reactant: [OH-]
Reactant: COC(=O)CNC(=O)C(NC(=O)[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)C1(NC(=O)C[C@H](O)/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1)C(C)C
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C1NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)C2(CC2)NC(=O)C[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(=O)CNC1=O
Reaction time: 2 h
Yield: 49.6 %

Procedure:
To a solution of 4 (171 mg, 0.17 mmol, 1 eq) in THF (6 mL) at 0° C. was added a solution of LiOH (6.0 mg, 0.25 mmol, 1.5 eq) in H2O (2 mL) dropwise. The mixture was stirred for 2 h, then quenched with 1N HCl (2 mL) and brine (10 mL). The organic layer was separated and the resulting aqueous layer was further extracted with EtOAc (2×15 mL) and CH2Cl2 (15 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The resulting carboxylic acid was then dried under high vacuum for 2 h, To a solution of MNBA (69 mg, 0.21 mmol, 1.2 eq) and DMAP (49.3 mg, 0.40 mmol, 2.4 eq) in CH2Cl2 (150 mL) was added a solution of the crude carboxylic acid in CH2Cl2 (60 mL) and THF (10 mL) dropwise over 3 h. The reaction mixture was then left to stir at rt overnight. The solvent was then removed in vacuo and the residue was further purified by silica gel column chromatography with hexane/EtOAc (2:3) to yield 5 as a white solid (83 mg, 50%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[NH:26][C:25](=[O:27])[CH:24]([CH2:28][O:29][CH3:30])[O:23][C:22]=4[N:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]#[N:48]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[N:26]([CH2:46][C:47]#[N:48])[C:25](=[O:27])[CH:24]([CH2:28][O:29][CH3:30])[O:23][C:22]=4[N:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2NC1=O
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N(CC#N)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
A solution of tert-butyl(1-(4-(3-(methoxymethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (60 mg, 0.116 mmol) in DMF (2 ml) was added potassium carbonate (48 mg) and 2-bromoacetonitrile (41.9 mg, 0.349 mmol). The reaction mixture was stirred at room temperature for 16 h then was diluted with ethyl acetate (20 ml). Washed with water, brine, and dried with Na2SO4, filtered and concentrated to give crude product which was purified by column (biotage, 25 g) eluted with ethyl acetate and cyclohexane to afford product (35 mg). 1H NMR (500 MHz, CDCl3): 7.20-7.33 (m, 10H), 5.10 (t, 1H), 4.97 (s, 1H), 4.82 (dd, 2H), 4.03 (dd, 2H), 3.36 (s, 3H), 2.44-2.50 (m, 4H), 2.06 (m, 1H), 1.80 (m, 1H), 1.24-1.36 (br, 9H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.Cl[C:17]1[CH:22]=[C:21]([CH:23]([F:25])[F:24])[N:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C>CN1CCCC1=O.C(OCC)(=O)C>[F:24][CH:23]([F:25])[C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:12][CH2:11][C:9]2[CH:10]=[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[NH:13][C:6]3=[N:7][CH:8]=2)[CH:22]=1
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Reactant: FC(F)c1cc(Cl)ncn1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)c1cc(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.8 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 100 mg, 0.465 mmol), 4-chloro-6-(difluoromethyl)pyrimidine (Intermediate 22, 117 mg, 0.711 mmol) and DIPEA (0.162 mL, 0.929 mmol) were added together in N-methyl-2-pyrrolidone (3 mL) and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by MDAP. Product containing fractions were combined and evaporated under reduced pressure. The resulting solid was dried under high vacuum at 45° C. for 18 hours to give the title compound as a white solid (30 mg);
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:28])=[C:4]([CH:10]2[N:15]([CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)[C:14](=[O:27])[CH2:13][CH2:12][CH2:11]2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH3:29]C1C=CC(S(O)(=O)=O)=CC=1.C(OCC)(OCC)OCC>CCOC(C)=O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:29][O:28][C:3]=2[C:4]=1[CH:10]1[N:15]([CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[C:14](=[O:27])[CH2:13][CH2:12][CH2:11]1
Reactant: COc1ccc(N)c(O)c1C1CCCC(=O)N1Cc1ccc2ccccc2n1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Solvent: CCOC(C)=O
Product: COc1ccc2ncoc2c1C1CCCC(=O)N1Cc1ccc2ccccc2n1
Temperature: 100 °C

Procedure:
A mixture of 6-(3-amino-2-hydroxy-6-methoxyphenyl)-1-(quinolin-2-ylmethyl)piperidin-2-one (100 mg; 0.26 mmol; synthesis described in example 279), commercially available p-TsOH (2 mg; 0.01 mmol), and commercially available triethyl orthoformate (264 mg; 1.69 mmol) was refluxed (100° C.) for 1 h. After cooling to rt, AcOEt was added, and the obtained mixture was filtered over a pad of celite. The filtrate was then washed with water and brine, and the mixed aq. layers were further extracted with AcOEt. The mixed organic layers were then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Subsequent purification by FC (DCM/MeOH=20/1) afforded the target compound. LC-MS (conditions A): tR=0.53 min.; [M+H]+: 388.05 g/mol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH:7]([CH:10]1[CH2:12][CH2:11]1)[CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].C(O[C:17]([C:19]1[N:20]=[C:21](C#N)[C:22]2[C:27]([C:28]=1[OH:29])=[CH:26][CH:25]=[C:24]([O:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)[CH:23]=2)=[O:18])C.C1CCN2[C:42](=[N:43]CCC2)CC1>CC(N(C)C)=O>[C:1]([O:5][C:6](=[O:13])[CH:7]([CH:10]1[CH2:12][CH2:11]1)[CH2:8][NH:9][C:17]([C:19]1[N:20]=[CH:21][C:22]2[C:27]([C:28]=1[OH:29])=[CH:26][CH2:25][C:24]([C:42]#[N:43])([O:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)[CH:23]=2)=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1nc(C#N)c2cc(Oc3cccnc3)ccc2c1O
Reactant: CC(C)(C)OC(=O)C(CN)C1CC1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)C(CNC(=O)c1ncc2c(c1O)=CCC(C#N)(Oc1cccnc1)C=2)C1CC1
Temperature: 150 °C

Procedure:
A mixture of 3-amino-2-cyclopropyl-propionic acid tert-butyl ester (39 mg), 1-cyano-4-hydroxy-7-(pyridin-3-yloxy)-isoquinoline-3-carboxylic acid ethyl ester (28 mg) and DBU (0.019 mL) in DMA (0.5 mL) was heated in an oil bath (150° C.) for 1 h. The reaction mixture was then partitioned between EtOAc and diluted HCl solution, EtOAc phase was separated and washed with water, diluted NaCl solution and dried over anhydrous sodium sulfate solution, filtered, concentrated and silica gel column purified to give desired product (21 mg). LC-MS ESI+: 475 (M+1)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Cl)=[CH:10][CH:9]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:10][CH:9]=1
Reactant: COc1ccc(CCl)cc1
Reactant: c1nc[nH]n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc(Cn2cncn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To 1,2,4-triazole (2.0 g, 29 mmol) in THF (80 mL) at 0° C. was added 4-methoxybenzyl chloride (4.0 mL, 29 mmol) and DBU (5.20 mL, 34.7 mmol). The reaction mixture was warmed to room temperature and allowed to stir overnight. The solution was filtered and the filtrate was concentrated. The resulting residue was purified by column chromatography (EtOAc/MeOH, 1:9) to give 3.12 g (57%) of 1-(4-methoxybenzyl)-1H-1,2,4-triazole as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH:4]([CH3:35])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1>CO>[C:29]1([S:26]([N:13]([CH2:12][C:8]2[CH:7]=[C:6]([CH2:5][CH:4]([CH3:35])[C:3]([OH:36])=[O:2])[CH:11]=[CH:10][CH:9]=2)[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:19][CH:20]=2)(=[O:28])=[O:27])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)C(C)Cc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2ccccc2)c1
Solvent: CO
Product: CC(Cc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2ccccc2)c1)C(=O)O

Procedure:
The title compound was prepared following the method described in Example 1, Step C, from 3-(3-{[benzenesulfonyl-(4-pyrazol-1-yl-benzyl)-amino]-methyl}-phenyl)-2-methyl-propionic acid methyl ester of Step E, except that the hydrolysis was performed in MeOH at reflux over 24 h. 1H NMR (400 MHz, CD3OD) δ 8.14 (m, 1H), 7.90 (m, 2H), 7.69-7.53 (m, 6H), 7.17 (m, 2H), 7.07 (m, 1H), 6.99 (m, 1H), 6.90 (m, 1H), 6.79 (m, 1H), 6.49 (m 1H), 4.34 (s, 2H), 4.31 (s, 2H), 2.79 (m, 1H), 2.50 (m, 2H), 1.02 (d, 3H); MS 488 (M−1).
Reaction SMILES: [C:1]([O:4][CH2:5][O:6][C:7](=[O:35])[N:8]([C:32](=[O:34])[CH3:33])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:24]=[N:23][C:22]3[C:21]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[N:20][C:19](Cl)=[N:18][C:17]=3[CH:16]=2)[CH:10]=1)(=[O:3])[CH3:2].CC1(C)C(C)(C)OB([C:44]2[CH:45]=[N:46][C:47]([NH2:50])=[N:48][CH:49]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(Cl)(Cl)Cl.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>[C:1]([O:4][CH2:5][O:6][C:7](=[O:35])[N:8]([C:32](=[O:34])[CH3:33])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:24]=[N:23][C:22]3[C:21]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[N:20][C:19]([C:44]4[CH:45]=[N:46][C:47]([NH2:50])=[N:48][CH:49]=4)=[N:18][C:17]=3[CH:16]=2)[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CC(=O)OCOC(=O)N(C(C)=O)c1cccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CC(=O)OCOC(=O)N(C(C)=O)c1cccc(-c2cnc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3c2)c1
Temperature: 82 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
To a 50 mL sealed tube, ((acetyl(3-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)phenyl)carbamoyl)oxy)methyl acetate (0.96 g, 0.0019 mol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.852 g, 0.0038 mol), potassium phosphate tribasic (0.81 g, 0.0038 mol), 1,4-dioxane (45 mL), and water (4 mL) were added. The reaction mixture was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)4 (0.11 g, 0.000096 mol) was added and the mixture was degassed with N2 for 5-10 min. The reaction mixture was stirred at 82° C. for 30 minutes. The volatiles were evaporated to provide a residue. The residue was dissolved in chloroform. The chloroform layer was washed with water, brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure to provide a crude solid. The crude solid was purified by flash column chromatography (0-2% methanol in chloroform) to provide a solid. The solid was washed with methanol to provide the title compound as a light yellow solid (0.4 g, 40%). 1H NMR (400 MHz, DMSO-d6): δ 9.18 (s, 2H), 9.08 (s, 1H), 8.35 (s, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.91 (br s, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.35 (d, J=7.6 Hz, 1H), 7.20 (br s, 2H), 5.68 (s, 2H), 4.52 (br s, 4H), 3.84 (t, J=4.0 Hz, 4H), 2.57 (s, 3H), 2.06 (s, 3H). LC-MS (ESI): Calculated mass: 558.20; Observed mass [M+H]+: 558.8 (RT: 0.40 min).
Reaction SMILES: FC(F)(F)C=CC[O:6]C1C=CC(F)=CC=1Br.[F:17][C:18]([F:32])([F:31])[CH:19]([C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([Br:29])[C:23]=1[OH:30])[CH:20]=C.O=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[OH:6][CH:20]1[CH:19]([C:18]([F:32])([F:31])[F:17])[C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([Br:29])[C:23]=2[O:30]1
Reactant: Fc1ccc(OCC=CC(F)(F)F)c(Br)c1
Reactant: C=CC(c1cc(F)cc(Br)c1O)C(F)(F)F
Agent: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: OC1Oc2c(Br)cc(F)cc2C1C(F)(F)F
Temperature: -78 °C
Reaction time: 64 h

Procedure:
1.0 gm (3.34 mMol) 1-(1-trifluoromethylprop-1-en-3-yloxy)-2-bromo-4-fluorobenzene was heated at 250° C. for 3 hours. The reaction mixture, containing primarily 2-(3-trifluoromethylprop-1-en-3-yl)-4-fluoro-6-bromophenol, was diluted with dichloromethane and the solution cooled to −78° C. This solution was then treated with excess ozone and was stirred at −78° C. until the 2-(3-trifluoromethylprop-1-en-3-yl)-4-fluoro-6-bromophenol was consumed as measured by thin layer chromatography. At this point the ozone was purged from the reaction with oxygen and then 0.88 gm (3.34 mMol) triphenylphosphine were added. The mixture was stored at −20° C. for about 64 hours. The reaction mixture was then concentrated under reduced pressure and the residue subjected to flash silica gel chromatography, eluting with hexane containing 10% ethyl acetate. Fractions containing the desired compound were combined and concentrated under reduced pressure to provide 2-hydroxy-3-trifluoromethyl-5-fluoro-7-bromo-2,3-dihydrobenzofuran. A solution of this dihydrobenzofuran in 10 mL toluene was treated with 4 drops of sulfuric acid and was stirred at reflux for 10 minutes. The reaction mixture was cooled to room temperature and was then washed with saturated aqueous sodium bicarbonate. The organic phase was separated and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with hexane. Fractions containing product were combined and concentrated under reduced pressure to provide the title compound.