Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]([OH:29])[C:25]([O:27][CH3:28])=[O:26].O>CC(C)=O>[CH:1](=[N:8]/[O:9][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]([OH:29])[C:25]([O:27][CH3:28])=[O:26])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(O)c1ccccc1CBr
Reactant: ON=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C(O)c1ccccc1CO/N=C/c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.8 %

Procedure:
Then, benzaldehyde oxime (0.28 g, 2.3 mmol) and potassium carbonate (0.43 g, 3.1 mmol) were added to a solution of methyl 2-bromomethyl-α-hydroxyphenylacetate (0.40 g, 1.5 mmol) in acetone (6 ml), and the mixture was stirred at room temperature for 18 hours. Water was added, and the mixture was extracted with ether, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=3/1) to give the desired compound methyl (E)-2-benzylideneaminooxymethyl-α-hydroxy-phenylacetate (0.08 g, 17%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][C:6](C(O)=O)=[C:5]2[CH3:15].BrC1C(C)=C2C(=CC=1)NC(C(O)=O)=C2C.CCOCC.Cl>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][CH:6]=[C:5]2[CH3:15]
Reactant: Cc1cc2[nH]c(C(=O)O)c(C)c2cc1Br
Agent: [Cu]
Agent: Cc1c(Br)ccc2[nH]c(C(=O)O)c(C)c12
Agent: Cl
Solvent: CCOCC
Solvent: c1ccc2ncccc2c1
Product: Cc1cc2[nH]cc(C)c2cc1Br
Temperature: 240 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
A 1:1 mixture of 5-bromo-3,6-dimethyl-1H-indole-2-carboxylic acid and 5-bromo-3,4-dimethyl-1H-indole-2-carboxylic acid (4.39 g, 16.4 mmol) in quinoline (10 mL) with copper powder (250 mg) was stirred at 240° C. for 3 h to give the corresponding mixture of the decarboxylated products. Upon cooling, ether (200 mL) was added and the mixture acidified with 5N HCl. The layers were separated, the organics were washed with brine, dried and evaporated. Chromatography (silica, 15% CH2Cl2 in hexane) and crystallization from a CH2Cl2/hexane mixture afforded the title compound (1.35 g 37%). 1H NMR (300 MHz, CDCl3) 7.74 (s, 1H), 7.21 (is, 1H), 6.90 (s, 1H), 2.48 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Cl)([O-:18])=[O:17].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][O:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[NH2:1])=[CH:10][CH:9]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: Nc1ccccc1Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccccc1Oc1ccc(OCc2cccc([N+](=O)[O-])c2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 45.3 %

Procedure:
To a solution of 4-(2-aminophenoxy)phenol (0.85 g, 4.2 mmol) in N,N-dimethylformamide (20 ml) were added 3-nitrobenzyl chloride (0.87 g, 5.1 mmol), potassium iodide (0.70 g, 4.2 mmol) and potassium carbonate (0.88 g, 6.4 mmol), followed by stirring at 50° C. for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous sodium chloride solution. After drying, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform) to give 2-[4-(3-nitrobenzyloxy)phenoxy]aniline (0.64 g)
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[C:11]([CH2:12]O)=[CH:10][CH:9]=[CH:8][N:7]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:3][CH2:12][C:11]1[C:6]([CH3:5])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cc1ncccc1CO
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ncccc1CCl
Temperature: 85 °C
Yield: 94.5 %

Procedure:
In a 50 ml round bottomed flask, under argon at 0° C., thionyl chloride (12 mL, 164 mmol) was cautiously added to (2-methyl-3-pyridinyl)methanol (8 g, 65.0 mmol). Process was exothermic and white fumes were formed. At the end of the addition the obtained brown solution was heated at 85° C. for 40 minutes. The reaction mixture was evaporated to get the crude material as solid yellow slurry that was then taken up with NaHCO3 saturated solution (300 ml)/DCM (300 ml). The phases were separated and the aqueous one back extracted with DCM (2×200 ml). The combined organics were dried over Na2SO4 and evaporated to dryness to get 3-(chloromethyl)-2-methylpyridine (8.7 g) as a black/brown waxy solid that was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[NH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:11](=[O:16])[N:10]([CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]cc(-c2ccc(Cl)cc2)n1C1CC1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)n1cc(-c2ccc(Cl)cc2)n(C2CC2)c1=O

Procedure:
500 mg (2.13 mmol) of 5-(4-chlorophenyl)-1-cyclopropyl-1,3-dihydro-2H-imidazol-2-one from Example 118A are dissolved in 5 ml acetonitrile and treated with 386 mg (2.13 mmol) of ethyl 2-bromopropionate and 1388 mg (4.26 mmol) of caesium carbonate. The mixture is stirred under reflux overnight. It is then concentrated, the residue is partitioned between dichloromethane and water, the organic phase is separated, and this is dried over sodium sulphate and again concentrated. The crude product is purified by flash chromatography on silica gel (eluent: first dichloromethane, then dichloromethane/methanol 200:1→100:1) and thus yields 338 mg (45% of theory) of the target compound.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[CH3:17]I>CO>[CH3:17][N:8]1[C:3](=[O:2])[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7]1
Reactant: COc1ccc(NC(=O)OC(C)(C)C)cn1
Reactant: CI
Solvent: CO
Product: Cn1cc(NC(=O)OC(C)(C)C)ccc1=O
Temperature: 25 °C

Procedure:
To a stirred solution of tert-butyl 6-methoxypyridin-3-ylcarbamate (14.4 g, 64.2 mmol) in MeOH (95 mL) was added methyl iodide (14.6 g, 103 mmol). The reaction mixture was heated at reflux for 16 h, cooled to RT and concentrated down. The residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:3]=1[CH2:4][N:5]1[C:10]2[S:11][C:12]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][O:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)=[C:13]([CH2:14][N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH3:16])[C:9]=2[C:8](=[O:33])[N:7]([CH2:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[C:6]1=[O:41].[BH4-].[Na+]>CO.C1COCC1>[F:46][C:42]1[CH:43]=[CH:44][CH:45]=[C:2]([F:1])[C:3]=1[CH2:4][N:5]1[C:10]2[S:11][C:12]([C:21]3[CH:22]=[CH:23][C:24]([NH:27][C:28]([NH:30][O:31][CH3:32])=[O:29])=[CH:25][CH:26]=3)=[C:13]([CH2:14][N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH3:16])[C:9]=2[C:8](=[O:33])[N:7]([CH2:34][CH:35]([OH:40])[C:36]([CH3:37])([CH3:38])[CH3:39])[C:6]1=[O:41]
Reactant: COCCN(C)Cc1c(-c2ccc(NC(=O)NOC)cc2)sc2c1c(=O)n(CC(=O)C(C)(C)C)c(=O)n2Cc1c(F)cccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COCCN(C)Cc1c(-c2ccc(NC(=O)NOC)cc2)sc2c1c(=O)n(CC(O)C(C)(C)C)c(=O)n2Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.5 %

Procedure:
To a mixed solution of compound (120 mg, 0.182 mmol) obtained in Example 63 in methanol (6 ml) and THF (4 ml) was added sodium borohydride (6.9 mg, 0.182 mmol) under ice cooling. The reaction liquid was stirred at room temperature for 1.5 hours and concentrated under reduced pressure. The residue was distributed between water and ethyl acetate, and the organic layer was extracted. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by NH-silica gel (Produced by Fuji Silysia Chemical Ltd.) column chromatography (eluent; ethyl acetate), and recrystallized from ethyl acetate and diethylether to give the title compound (81.1 mg, 68%) as colorless crystals.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[C:20]([C:36]#[N:37])[C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[C:23]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:22]=2)=[O:17])[C:10]([OH:12])=[O:11])=O)(C)(C)C.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[NH2:8][C@@H:9]([CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[C:20]([C:36]#[N:37])[C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[C:23]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:22]=2)=[O:17])[C:10]([OH:12])=[O:11].[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1nc(C(=O)NCC[C@H](N)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-4-(1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxamido)butanoic acid (20 mg, 0.03 mmol) was dissolved in TFA (2 mL) and CH2Cl2 (2 mL). The resulting mixture was stirred at room temperature for 3 hours. The volatiles were removed in vacuo and the residue was dissolved again in CH2Cl2 (2 mL). The volatiles were removed again in vacuo to give the title compound as its TFA salt in 14 mg. MS: (−) m/z 404.91 (M−1).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7]O)[CH:3]=[N:2]1.[NH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[SH:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][S:17][C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[NH2:9])[CH:3]=[N:2]1
Reactant: OCCc1cn[nH]c1
Reactant: Nc1cc(Cl)ccc1S
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Nc1cc(Cl)ccc1SCCc1cn[nH]c1

Procedure:
Following the General Procedure J, the title intermediate was prepared from 2-(1H-pyrazol-4-yl)ethanol (472 mg, 4.218 mmol), 2-amino-4-chlorobenzenethiol (1.01 g, 6.327 mmol), PPh3 (2.21 g, 8.436 mmol) and di-tert-butylazodicarboxylate (1.9 g, 8.436 mmol) in CH2Cl2 (20 ml).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][C:8]([Si:11]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:12][C@@H:13](C)[CH2:14]C(O)=O)([CH3:10])[CH3:9].CN(C=O)C>C(Cl)Cl>[CH3:7][C:8]([Si:11]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[O:12][C@@H:13]([CH3:14])[CH2:1][C:2]([Cl:4])=[O:3])([CH3:9])[CH3:10]
Reactant: C[C@@H](CC(=O)O)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](CC(=O)Cl)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C

Procedure:
Oxalyl chloride (4.1 mL, 48 mmol; conc. 1.5 g/mL) was added dropwise to a stirred solution of intermediate D2 (11 g, 32 mmol) and DMF (1 mL) in DCM (300 mL) at r.t. for 90 min. The reaction mixture was evaporated under reduced pressure and co-evaporated with toluene (×3) to give the crude intermediate D3 as a yellow oil. This material was used in the next step of the reaction sequence without any further purification.
Reaction SMILES: Br[C:2]1[S:10][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[Br:11].[CH3:12][C:13]([OH:17])([C:15]#[CH:16])[CH3:14].CCN(C(C)C)C(C)C>O1CCOCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:11][C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:10][C:2]=1[C:16]#[C:15][C:13]([CH3:14])([OH:17])[CH3:12]
Reactant: C#CC(C)(C)O
Reactant: Brc1sc2cnccc2c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)C#Cc1sc2cnccc2c1Br
Temperature: 50 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a suspension of 2,3-dibromothieno[2,3-c]pyridine (400 mg, 1.37 mmol), 2-methyl-3-butyn-2-ol (121 μL, 1.24 mmol), copper (I) iodide (24 mg, 0.12 mmol) and DIPEA (2.16 mL, 12.41 mmol) in 1,4-dioxane (16 mL) was added Pd(PPh3)2Cl2 (174 mg, 0.25 mmol). The mixture was evacuated and refilled with nitrogen (3×), then stirred at 50° C. for 2 h. Solvent was evaporated and the resultant mixture was dissolved in EtOAc. The organic solution was washed with water and brine, dried over anhydrous sodium sulfate, and purified by ISCO column chromatography (0 to 5% MeOH:DCM) to afford 319 mg (87%) of the title compound as a light-yellow solid. MS (ESI): 296.38, 298.35 [M+H]+; HPLC tR=0.94 min (HPLC: Analytical—2 min).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>C(O)C>[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:2]2[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[CH:4][N:3]=2)=[CH:13][CH:12]=1
Reactant: Cc1ncnc(Cl)c1C
Reactant: Nc1ccc(Cl)cc1
Solvent: CCO
Product: Cc1ncnc(Nc2ccc(Cl)cc2)c1C
Temperature: 130 °C
Yield: 59.9 %

Procedure:
To 4.3 g (0.03 mole) of 4-chloro-5,6-dimethylpyrimidine were added 3.8 g (0.03 mole) of p-chloroaniline and about 10 ml of ethanol; the mixture wasthen heated at 130° C. for about 3 minutes. The reaction mixture quickly became a solution and then the hydrochloride of the desired compound precipitated as the solution was allowed to cool. The crystals thus obtained were separated and ground to a powder and then made alkalineby the addition of a dilute aqueous solution of sodium hydroxide. The insolubles were collected by filtration, washed with water and dried. The resulting crystals were recrystallised from benzene, to give 4.2 g (yield 60%) of the desired Compound No. 25, in the form of colourless needles melting at 170°-173° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=[O:17])[C:5]([C:8]1[CH:9]=[CH:10][C:11]([F:16])=[C:12]([CH:15]=1)[C:13]#[N:14])([CH3:7])[CH3:6].CCN(CC)CC.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[S:34])=[CH:28][C:27]=1[O:35][CH3:36]>C(Cl)Cl>[C:13]([C:12]1[CH:15]=[C:8]([C:5]([CH3:7])([CH3:6])[C:4](=[O:17])[CH2:3][NH:2][C:33]([NH:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[C:27]([O:35][CH3:36])[CH:28]=2)=[S:34])[CH:9]=[CH:10][C:11]=1[F:16])#[N:14]
Reactant: COc1cc(N=C=S)ccc1F
Reactant: CC(C)(C(=O)CN)c1ccc(F)c(C#N)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=S)NCC(=O)C(C)(C)c2ccc(F)c(C#N)c2)ccc1F
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a suspension of 5-(4-amino-2-methyl-3-oxobutan-2-yl)-2-fluorobenzonitrile hydrochloride (2.8 g, 10.9 mmol) in DCM (50 mL) were added Et3N (4.6 mL, 32.7 mmol, 3 eq) and 1-fluoro-4-isothiocyanato-2-methoxybenzene (2.2 g, 12 mmol, 1.1 eq). After stirring 2 h, the reation mixture was partitioned in DCM and water. The organic layer was separated, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography (silica, Hex:EA=1:1) to give 1-(3-(3-cyano-4-fluorophenyl)-3-methyl-2-oxobutyl)-3-(4-fluoro-3-methoxyphenyl)thiourea (3.7 g, 84%). 1H NMR (400 MHz, CDCl3) δ 7.59 (bs, 1H), 7.53-7.49 (m, 2H), 7.26-7.18 (m, 2H), 6.89-6.79 (m, 2H), 6.70 (bs, 1H), 4.44 (d, J=4.4 Hz, 2H), 3.90 (s, 3H), 1.58 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4]([CH2:14][CH2:15][CH3:16])=[CH:5][C:6](=[O:13])[O:7]2.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1.C1COCC1>[C:17]([O:1][C:2]1[CH:11]=[C:10]([O:12][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[C:8]2[C:3]=1[C:4]([CH2:14][CH2:15][CH3:16])=[CH:5][C:6](=[O:13])[O:7]2)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CCCc1cc(=O)oc2cc(O)cc(O)c12
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCc1cc(=O)oc2cc(OC(=O)C(C)(C)C)cc(OC(=O)C(C)(C)C)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 177.9 %

Procedure:
To a solution of 5,7-dihydroxy-4-propylcoumarin (2) (1.10 g, 5 mmol) in pyridine (12 mL) and THF (6 mL) was added pivaloyl chloride (0.673 mL, 5.5 mmol) and the reaction mixture was allowed to stir at room temperature for 24 h. TLC revealed formation of a new less polar spot and unreacted starting material. In an effort to drive the reaction to completion, pivaloyl chloride (0.50 mL) was added and the reaction continued to stir at room temperature for another 72 h. The pyridinium hydrochloride was removed by filtration and washed a few times with ethyl acetate. The organic solutions were combined and washed, successively, with 1 M HCl (2×25 mL), water (25 mL), aqueous saturated sodium bicarbonate (25 mL). After being dried over sodium sulfate and concentrated under vacuum, the crude product was purified by silica gel chromatography (2:1 hexane/ethyl acetate) to obtain 8b as a white solid (1.90 g, 98% yield). mp 110-112° C.; Rf=0.49 (4:1 hexane/ethyl acetate); 1H-NMR (CDCl3),: 1.03 (3H, t, J=7.8 Hz), 1.36 (9H, s), 1.41 (9H, s), 1.69 (2H, sextet, J=7.4 Hz), 2.81 (2H, t, J=7.8 Hz), 6.22 (1H, s), 6.60 (1H, d, J=2.4 Hz), 7.03 (1H, d, J=2.1 Hz); 13C-NMR (CDCl3): 13.5, 20.7, 26.4, 26.8, 26.9, 36.4, 39.2, 39.4, 108.6, 111.5, 113.4, 114.2, 149.4, 152.7, 154.9, 155.4, 159.9, 177.1; IR (film): 3090, 2971, 2941, 2876, 1757, 1615, 1481, 1422, 1273 cm−1; MS m/e 389 (M+1); Anal. Calcd. for C22H28O6: C, 68.02; H, 7.26. Found: C, 67.77; H, 7.18.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([C:13](O)=[O:14])=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ON1C(=O)C2C=CC=CC=2N=N1.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)=[O:14])=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C(=O)O)cc1-c1ccccc1
Reactant: Nc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C(=O)Nc2ccccn2)cc1-c1ccccc1

Procedure:
To a solution of the resultant acid from Example 60A (1.0 equivalent) in DMF is added 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (1.5 equivalents) followed by 2-aminopyridine (1.0 equivalent) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 equivalents). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate which is washed by 1N HCl and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=C[C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14](NC4C=CC=C(O)C=4)[N:13]=3)=[CH:4][C:3]=2O1.CC1OC(C)=CC=1CN.[Cl:36]C1N=C(Cl)C(F)=CN=1>>[Cl:36][C:14]1[N:13]=[C:12]([NH:11][CH2:5][C:4]2[CH:3]=[C:8]([CH3:7])[O:9][C:10]=2[CH3:1])[C:17]([F:18])=[CH:16][N:15]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Cc1cc(CN)c(C)o1
Product: Cc1cc(CNc2nc(Cl)ncc2F)c(C)o1

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of (2,5-dimethyl-3-furyl)methylamine (188 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) gave 2-chloro-N4-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-4-pyrimidineamine. The reaction of 2-chloro-N4-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-4-pyrimidineamine and 3-aminophenol (200 mg, 1.83 mmol) gave N4-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine (50 mg, 51%). 1H NMR (CDCl3): δ 2.22 (s, 3H), 2.23 (s, 3H), 4.39 (d, J=5.1 Hz, 2H), 5.24 (br, 1H), 5.90 (s, 1H), 6.52 (d, J=6.6 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 7.13 (t, J=8.1 Hz, 1H), 7.29 (s, 1H), 7.71 (m, 2H); 19F NMR (282 MHz, CDCl3): δ−167.84; LCMS: ret. time: 19.83 min.; purity: 96.32%; MS (m/e): 329.05 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Cl>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[Cl:20])[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Reactant: ClCc1ccccc1Cl
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(Cc3ccccc3Cl)n2)ccc1F
Yield: 76.4 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 2-chlorobenzyl chloride were reacted. Without purification, the reaction product was reacted further following the procedure of Example 1(7) to yield the title compound as pale yellow needles (yield: 76.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22](O)=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[O:33][NH2:34].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.CCN=C=NCCCN(C)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:34][O:33][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32][O:27]4)=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:25][CH:26]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)nc1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.4 %

Procedure:
To a solution of (2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylic acid (1.58 g) in DMF (16 mL) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (546 mg), HOBt (744 mg), and EDCI HCl (1.06 mg) and the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was diluted with water and extracted with AcOEt. The organic phase was washed with sat NH4Cl aq solution and sat NaHCO3 aq solution, and brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography eluted with chloroform:methanol=97.5:2.5 to give (2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (1.89 g) as colorless oil.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH:22]([CH3:24])[CH3:23].O>CN(C)C=O>[Br:1][C:2]1[S:6][C:5]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH:22]([CH3:24])[CH3:23])=[CH:12][CH:13]=2)=[N:4][N:3]=1
Reactant: CC(C)I
Reactant: Oc1ccc(Oc2nnc(Br)s2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Oc2nnc(Br)s2)cc1
Temperature: 85 °C
Yield: 99.3 %

Procedure:
A solution of Example 24B (1.4 g, 5.11 mmol) in N,N-dimethyl formamide (20 mL) was treated with K2CO3 (1.06 g, 7.66 mmol) and 2-iodopropane (5.1 mL, 51.1 mmol) and the reaction mixture was sealed in a screw-top pressure vessel and heated at 85° C. for 2 hours. The reaction was cooled to 25° C., poured into water (200 mL), and extracted with diethyl ether (2×100 mL). The combined organic layers were washed with water (3×80 mL) and brine (80 mL), dried (Na2SO4), filtered and evaporated to provide 1.6 g of a light brown solid. The residue was purified by flash chromatography on silica gel eluting with a solvent gradient from 1% to 14% ethyl acetate in hexanes to provide 0.8 g (50%) of the title compound as a clear colorless oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.37 (d, J=9.19 Hz, 2H) 7.01 (d, J=9.19 Hz, 2H) 4.63 (heptet, J=5.88 Hz, 1H) 1.27 (d, J=5.88 Hz, 6H); MS (ESI) m/z 316.9 (M+H)+.