Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11].[OH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O:12][CH2:30][CH2:29][O:28][CH2:27][CH2:26][OH:25])=[O:11]
Reactant: OCCOCCO
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: O=C(OCCOCCO)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid (5.6 g, 0.015 mole), 2-hydroxyethyl ether (6.4 g, 0.06 mole) and p-toluenesulfonic acid (200 mg) was heated at 135°-142° C. for 26 hrs. The resulting solution was cooled to room temperature, taken into 400 ml of ether. The ethereal solution was washed three times with water, dried over CaSO4 and concentrated to 4.9 g of a yellowish gum. The gum was chromatographed on silica gel and eluted with hexane-ethyl acetate (90:10); yield 3.4 g of pure 5-hydroxy-3-oxapentyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate as a pale yellow gum; nmr (DMSO-d6) δ 3.56 (s, broad 5H), 3.76 (m, 2H), 4.52 (m, 2H), 7.18-8.40 (m, 6H); ir (CHCl3) 3610, 1750 Cm-1.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12].Cl[CH2:16][CH2:17][N:18]([CH2:26][CH2:27]Cl)[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>CN(C)C=O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1([C:11]([O:13][CH3:14])=[O:12])[CH2:27][CH2:26][N:18]([C:19]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:25])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: COC(=O)Cc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccccc2F)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 17 %

Procedure:
A flask was charged with sodium hydride (2.14 g, 89.2 mmol) and dimethylformamide (70 ml) at 0° C. under nitrogen. Methyl 2-(2-fluorophenyl)acetate (5 g, 29.7 mmol) was added to the flask, and after stirring for 25 min, tert-butyl bis(2-chloroethyl)carbamate (8.6 g, 35.6 mmol) was added. The reaction was allowed to warm to rt and stirred overnight. The reaction was quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate (5×100 mL). The organics were collected, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified via silica gel chromatography (10/90→50/50 ethyl acetate/hexanes) to yield 1.7 g (17%) of the desired product. 1H-NMR (CDCl3, 400 MHz) δ ppm 7.29 (m, 1H), 7.24 (m, 1H), 7.12 (m, 1H), 7.00 (m, 1H), 3.86 (m, 2H), 3.67 (m, 3H), 3.22 (m, 2H), 2.37 (m, 2H), 1.96 (m, 2H), 1.44 (s, 9H). Mass spec.: 360.22 (MNa)+. LC tr=3.503 min (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=4 min, Flow rate=4 mL/min)
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9](Br)=[C:10]3[C:15]=1[CH:14]=[C:13]([O:16][CH2:17][CH:18]([CH2:23][CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:12]=[CH:11]3)=[CH:7][C:6]([O:26][CH2:27][CH:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[CH:5][CH:4]=2.[C:35]1([CH3:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[H-]>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.C1COCC1>[C:35]1([C:41]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:41][C:35]2[CH:40]=[CH:39][C:38]([C:2]3[C:3]4[C:8]([C:9]([C:38]5[CH:39]=[CH:40][C:35]([CH:41]=[C:41]([C:3]6[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=6)[C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)=[CH:36][CH:37]=5)=[C:10]5[C:11]=3[CH:12]=[C:13]([O:16][CH2:17][CH:18]([CH2:23][CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:14]=[CH:15]5)=[CH:7][C:6]([O:26][CH2:27][CH:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[CH:5][CH:4]=4)=[CH:37][CH:36]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1ccccc1
Reactant: CCCCC(CC)COc1ccc2c(Br)c3cc(OCC(CC)CCCC)ccc3c(Br)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCC(CC)COc1ccc2c(-c3ccc(C=C(c4ccccc4)c4ccccc4)cc3)c3cc(OCC(CC)CCCC)ccc3c(-c3ccc(C=C(c4ccccc4)c4ccccc4)cc3)c2c1
Temperature: 0 °C
Yield: 2374.6 %

Procedure:
Into a 500 ml flask equipped with a condenser, 0.6 g (1 mmole) of 9,10-dibromo-2,6-di(2-ethylhexyloxy)anthracene, 0.04 g (5% by mole) of dichlorobis(triphenylphosphine)palladium, 0.1 ml (1 M; 0.1 mmole) of a toluene solution of diusobutylaluminum hydride and 10 ml of THF were placed under a stream of argon. After the Grignard reagent prepared above was added dropwise to the obtained solution at the room temperature, the resultant mixture was heated under stirring for one night. After the reaction was completed, the reaction solution was cooled with ice water. The formed crystals were separated by filtration and washed with 50 ml of methanol and 50 ml of acetone successively, and 0.56 g of a yellow powder was obtained. The obtained yellow powder was identified to be Compound (A1) by the measurements in accordance with NMR, IR and the filed desorption mass spectroscopy (FD-MS) (the yield: 60%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]#[C:5][CH2:6][CH3:7].Cl[C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]#[C:19][CH3:20])[N:13]=[CH:12][N:11]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:17]([O:16][C:14]1[CH:15]=[C:10]([O:8][CH2:3][C:4]#[C:5][CH2:6][CH3:7])[N:11]=[CH:12][N:13]=1)[C:18]#[C:19][CH3:20]
Reactant: CCC#CCO
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(OCC#CCC)ncn1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.1 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.15 g of 2-pentyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes and then cooled to 0° C., to which 0.6 ml of a tetrahydrofuran solution containing 0.3 g of 4-chloro-6-(2-butynyloxy)pyrimidine was slowly added dropwise. The mixture was further stirred at 0° C. for 3.5 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.33 g of 4-(2-butynyloxy)-6-(2-pentynyloxy)pyrimidine (the present compound (6)), m.p.: 67.4° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@H:28]([CH:34]=[C:35]([CH3:37])[CH3:36])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@@H:28]([CH:34]=[C:35]([CH3:37])[CH3:36])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: COC(=O)C[C@@H](C=C(C)C)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2cc(COc3ccc([C@@H](C=C(C)C)CC(=O)O)cc3)ccc2C(C)(C)C)c1
Reaction time: 15 h
Yield: 86.1 %

Procedure:
To a stirred solution of 16.2 (0.047 g, 0.09 mmol) in THF (2.00 mL, 0.10 mmol) and EtOH (2.00 mL, 0.10 mmol) at 23° C. was added a 1 M solution of sodium hydroxide (1 mL, 1 mmol). Stirring was continued for 15 hours. The resulting reaction was concentrated in vacuo. 1 N HCl was added to bring the pH to 1, and the resulting mixture was extracted with EtOAc, dried over MgSO4, and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 14 (38 mg, 82% yield) as a colorless oil. MS ESI (neg.) m/e: 489.2 (M−H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[C:17]1[C:32]([NH2:34])=[O:33].CO>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13](=[O:14])[NH:31][C:28]1[CH:27]=[CH:26][C:25]([C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]([CH3:15])[C:17]=2[C:32]([NH2:34])=[O:33])=[CH:30][CH:29]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Cn1c(C(N)=O)c(-c2ccc(N)cc2)c2ccccc21
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(C(N)=O)c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2ccccc21
Reaction time: 1 h
Yield: 59 %

Procedure:
0.075 g of 2-fluoro-5-trifluoromethylphenyl isocyanate is added to a solution of 0.086 g of 1-methyl-3-(4-aminophenyl)-1H-indole-2-carboxamide in 18 ml of tetrahydrofuran and the stirring is continued for 1 hour. 5 ml of methanol are added, the reaction mixture is then concentrated under reduced pressure, and the residue is purified by chromatography on a silica column, elution being carried out with a mixture of cyclohexane and ethyl acetate (20/80 by volume), to give 90 mg of 3-{4-[3-(2-fluoro-5-trifluoromethyl-phenyl)ureido]phenyl}-1-methyl-1H-indole-2-carboxamide, the characteristics of which are as follows:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[O:10])=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[F:17][C:13]1[CH:12]=[C:11]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)=[O:10])[CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=O)c2cccc(F)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.8 %

Procedure:
3-Fluorophenyl 4-methoxyphenyl ketone (580 mg) obtained in Example 150 was dissolved in dichloromethane (5 ml), a solution of 1.0 M boron tribromide in dichloromethane (23 ml) was added while cooled in ice, and the admixture was stirred at room temperature for 3 days. The reaction mixture was treated in the same manner as described in 121 to obtain 402 mg of the title compound (yield: 74%).
Reaction SMILES: CO.[Si:3]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[C:19][CH:20]1[C:29]2[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[S:23][CH2:22][C:21]1([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[CH3:32])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>[Pd].C(OCC)(=O)C>[Si:3]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[C:29]2[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[S:23][CH2:22][C:21]1([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[CH3:32])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:5]
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 48 h
Yield: 80 %

Procedure:
Methanol (60 ml) and 10% Pd/C (500 mg) were added to 4-[9-(t-butyl-dimethylsilyloxy)-1-nonynyl]-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman (560 mg, 1.01 mmol) obtained in Example 28, and the mixture was stirred for 2 days under hydrogen gas (normal pressure). Ethyl acetate was added to the reaction solution which was then filtered, washed several times with ethyl acetate and concentrated under reduced pressure to remove the organic solvent. To the residue were added methanol (60 ml) and 10% Pd/C (300 mg), and the reaction mixture was stirred for 8 hours at 5 atomsphere under hydrogen gas. Ethyl acetate was added again to the reaction solution which was then filtered and concentrated under reduced pressure to obtain 450 mg (yield: 80%) of the title compound as an oil. The resulting compound was used in the next reaction without further purification.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]3=[CH:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.C(O)(=O)C>CO.[C].[Pd]>[CH2:9]1[NH:8][CH2:17][CH2:16][C:15]2[N:14]=[C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]3=[CH:11][C:10]1=2
Reactant: c1ccc(CN2CCc3nc4ccccc4cc3C2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc2nc3c(cc2c1)CNCC3
Yield: 37.2 %

Procedure:
2-Benzyl-1,2,3,4-tetrahydro-benzo[b][1,6]-naphthyridine (4.4 g, 16.04 mmol) was dissolved in methanol (88 ml), followed by adding thereto acetic acid (1.84 ml, 32.08 mmol) and palladium-carbon (440 mg), and catalytic reduction was carried out overnight at 50° C. The catalyst was filtered off and the filtrate was neutralized with potassium carbonate and filtered. The organic layer thus obtained was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (methylene chloride/methanol=30/1 to 10/1) to obtain the desired compound (1.1 g, 37.2%) as a brown solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]1[O:9][C:8](=[O:10])[CH:7]=[C:6]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(C)=[O:19].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C.C(OCC)(=O)C>CC(C)=O.O>[O:10]=[C:8]1[O:9][CH:5]([CH2:4][CH2:3][C:2]([OH:19])=[O:1])[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7]1
Reactant: O=C1C=C(c2ccccc2)C(CCCO)O1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)CCC1OC(=O)C=C1c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 5-(3-hydroxypropyl)-4-phenyl2(5H)-furanone (90 mg) in acetone (1 ml) was added to a solution of 2N Jones reagent (0.62 ml) in acetone (1 ml) at 0° C. over 10 minutes, and the resulting mixture was stirred at 0° C. for 20 minutes. After addition of isopropyl alcohol (1 ml), the mixture was poured into a mixture of ethyl acetate (20 ml) and water (20 ml). The aqueous layer was separated and extracted with ethyl acetate (10 ml). The organic layers were combined, washed with water and brine succssively, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (3 g) eluting with a mixture of chloroform and methanol (50:1 to 20:1) to give an oily product of 3-(2,5-dihydro5-oxo-3-phenyl-2-furyl)propionic acid, which was crystallized from diethyl ether (60 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]2[C:17]([C:18]3[CH:30]=[CH:29][O:28][C:19]=3[CH:20]=[N:21]2)=[CH:16][CH:15]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]2[C:17]([C:18]3[CH:30]=[CH:29][O:28][C:19]=3[CH:20]=[N:21]2)=[CH:16][CH:15]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: COC(=O)c1c(N)ccc2c1ncc1occc12
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1ncc1occc12
Temperature: 70 °C
Yield: 24.5 %

Procedure:
A solution of 2-bromo-4-fluorobenzenesulfonyl chloride (0.57 g) in pyridine (10 mL) was heated to 70° C. and a solution of methyl 7-amino-furo[2,3-c]quinoline-6-carboxylate (Intermediate 16, 0.33 g) in pyridine (10 mL) was added. The mixture was stirred and heated at 70° C. for 4 hours. Further 2-bromo-4-fluorobenzenesulfonyl chloride (0.57 g) was added and the mixture was stirred and heated at 70° C. overnight. After cooling, the mixture was filtered and the solid was washed with methanol. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 15-60%. The product was triturated with diethyl ether and the solid was collected by filtration to give methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-furo[2,3-c]quinoline-6-carboxylate (0.16 g) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[CH2:20][OH:21])[CH3:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[CH2:20][O:21][C:31]([NH:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)=[O:32])[CH3:2]
Reactant: COc1ccc(N=C=O)cc1
Reactant: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1CO
Product: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1COC(=O)Nc1ccc(OC)cc1

Procedure:
Using dimethyl 2-[4-ethoxy-3-(hydroxymethyl)benzyl]malonate and 4-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]([O:15]CC)=[O:14].[OH-].[Na+].Cl>[Cl-].[Na+].O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)COCCOCCOCCOC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COCCOCCOCCOCC(=O)O
Yield: 67.6 %

Procedure:
The product of step (a) (1.5 g) was stirred in a sodium hydroxide solution (0.1M, 30 mL) for 5 hours. The reaction mixture was adjusted to pH 2 by the addition of hydrochloric acid (2M) and then diluted with brine (300 mL). This was extracted with dichloromethane (2×300 mL) and the combined organic layers were dried and the solvent was removed in vacuo. Purification by chromatography on silica gel (Biotage), eluting with 10% methanol in dichloromethane gave the title compound as a clear oil (900 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[N:18][C:17]([N:20](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[C:16]([C:35]3[O:36][C:37]([C:40]4[CH:45]=[CH:44][C:43]([CH2:46][Br:47])=[CH:42][CH:41]=4)=[N:38][N:39]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[Br:47][CH2:46][C:43]1[CH:42]=[CH:41][C:40]([C:37]2[O:36][C:35]([C:16]3[C:17]([NH2:20])=[N:18][CH:19]=[C:14]([C:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=4)[N:15]=3)=[N:39][N:38]=2)=[CH:45][CH:44]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3nnc(-c4ccc(CBr)cc4)o3)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ncc(C2=CCNCC2)nc1-c1nnc(-c2ccc(CBr)cc2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl-4-[5-[bis(tert-butoxycarbonyl)amino]-6-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (54 mg, 0.07 mmol) was treated with a solution of 4 M hydrogen chloride (376 μL of 4 M, 1.5 mmol) in dioxane and stirred at room temperature for 1 h. The solvent was removed under reduced pressure to yield 3-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-amine as an off white solid, which was used in the next step without further purification. LC/MS m/z 415.5 [M+H]+.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:7][CH:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([O:16][CH3:17])[CH:10]=2)[CH2:5]1.[CH3:18][C:19]1[C:28]2[CH:27]=[N:26][C:25](S(C)=O)=[N:24][C:23]=2[N:22]([C:32]2[CH:33]=[C:34]([NH:38][C:39](=[O:42])[CH:40]=[CH2:41])[CH:35]=[CH:36][CH:37]=2)[C:21](=[O:43])[CH:20]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[F:1][CH2:2][CH2:3][N:4]1[CH2:7][CH:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:25]3[N:26]=[CH:27][C:28]4[C:19]([CH3:18])=[CH:20][C:21](=[O:43])[N:22]([C:32]5[CH:33]=[C:34]([NH:38][C:39](=[O:42])[CH:40]=[CH2:41])[CH:35]=[CH:36][CH:37]=5)[C:23]=4[N:24]=3)=[C:11]([O:16][CH3:17])[CH:10]=2)[CH2:5]1
Reactant: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(S(C)=O)nc32)c1
Reactant: COc1cc(NC2CN(CCF)C2)ccc1N
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(NC5CN(CCF)C5)cc4OC)nc32)c1
Temperature: 80 °C
Yield: 48.6 %

Procedure:
To a suspension of N1-(1-(2-fluoroethyl)azetidin-3-yl)-3-methoxybenzene-1,4-diamine (11c; 373 mg, 1.56 mmol) and N-(3-(5-methyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5b; 440 mg, 1.194 mmol) in tert-butanol (10 mL) was added DIEA (0.62 mL, 3.58 mmol). The mixture was heated in an oil bath at 80° C. for 1 h. The reaction mixture was concentrated to dryness under reduced pressure (rotary evaporator) and the crude residue was purified on silica gel on an ISCO Combiflash RF (40 g Redisep column, using a gradient of 5-10% 2M NH3/MeOH in DCM) affording enriched product. It was then repurified on a Gilson preparatory HPLC (Gemini Phenomenex; 30×150 mm, 5μ, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water). The desired fractions were collected, and concentrated to dryness in a genevac overnight. The resulting solid was dissolved in 9:1=DCM:MeOH and was then passed through a Silicycle SPE-R66030B-20× SiliaSep OT, 5 g/25 mL carbonate column using 10% MeOH/DCM then concentrated and dried under vacuum affording N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (317 mg, 0.58 mmol, 49% yield) as a yellow solid. m/z (ESI, +ve ion) 544.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.37 (1H, s), 8.78 (1H, br. s.), 8.05 (1H, br. s.), 7.84 (1H, d, J=7.0 Hz), 7.60 (1H, s), 7.50 (1H, t, J=8.0 Hz), 7.15 (1H, d, J=9.0 Hz), 6.99 (1H, d, J=9.0 Hz), 6.41-6.51 (1H, m), 6.23-6.34 (2H, m), 6.16 (1H, d, J=2.2 Hz), 5.85 (1H, br. s.), 5.73-5.81 (1H, m), 5.57 (1H, br. s.), 4.49 (1H, t, J=4.8 Hz), 4.37 (1H, t, 1=4.8 Hz), 3.90 (1H, br. s.), 3.73 (5H, br. s.), 2.76-2.88 (2H, m), 2.74 (1H, t, J=4.9 Hz), 2.63-2.71 (1H, m), 2.46 (3H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[O:14][CH3:15])([O-])=O.NC1C2N=C(C)OC=2C(C#N)=CC=1>>[CH3:15][O:14][C:5]1[C:6]([C:10]([F:11])([F:12])[F:13])=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: COc1c([N+](=O)[O-])cccc1C(F)(F)F
Agent: Cc1nc2c(N)ccc(C#N)c2o1
Product: COc1c(N)cccc1C(F)(F)F

Procedure:
The title compound (980 mg) was prepared from compound 17B in a manner similar to that described in Experiment 11C.
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:5]=2[NH:4][C:3]1=[O:15].C([O-])(=O)C.[Na+].[H][H]>C(O)(=O)C.[Pd]>[Cl:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:5]=2[NH:4][C:3]1=[O:15]
Reactant: [H][H]
Reactant: COc1ccc2c(c1)NC(=O)C(Cl)(Cl)CC2
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)NC(=O)C(Cl)CC2
Reaction time: 1 h

Procedure:
A solution of 3,3-dichloro-8-methoxy-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one (20 g) and anhydrous sodium acetate (13.2 g) in glacial acetic acid (250 ml) was hydrogenated at atmospheric pressure using 10% Pd/C (1 g) as catalyst, until the uptake of hydrogen ceased. The catalyst was filtered off and the acetic acid was evaporated under reduced pressure. Water (100 ml) was added to the residue and the suspension stirred for 1 hour. The solid was filtered, washed with water (50 ml), and dried to give 3-chloro-8-methoxy-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one, m.p. 162°-163°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:13])[O:11][CH:12]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21].CO>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:13])[O:11][C:12]=2[CH:20]([CH3:21])[C:19]([O:23][CH3:24])=[O:22])=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2)co1
Reactant: C=CC(=O)OC
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Solvent: CO
Product: COC(=O)C(C)c1oc(=O)[nH]c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.4 %

Procedure:
4-(4-chlorophenyl)-2-oxo-4-oxazoline (5.00 g) was suspended in acetonitrile (15 ml) in a reaction vessel, and the gas in the reaction vessel was substituted for nitrogen gas. The obtained suspension was cooled and conc. sulfuric acid (7.53 g) was added dropwise at 2-10° C. Then methyl acrylate (4.41 g) was added dropwise at 2-3° C. The obtained mixture was stirred at 20-30° C. for 1.5 h and methanol (15 ml) was added dropwise at 22-25° C. After cooling, water was added dropwise at 5-8° C. The precipitated crystals were collected by filtration, washed with water (25 ml), 1% aqueous sodium hydrogencarbonate (25 ml), water (25 ml) and diisopropyl ether (25 ml), and dried under reduced pressure at 40° C. for 7 h to give the title compound (5.72 g, yield 79.4%) as pale-red white crystals.