Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]2[CH:28]=[C:27]3[C:23]([CH:24]=[CH:25][NH:26]3)=[CH:22][CH:21]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19].[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH2:34][C:35](Cl)=[O:36].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[NH:26]1[C:27]2[C:23](=[CH:22][CH:21]=[C:20]([C:3]3[C:2]([NH:1][C:35](=[O:36])[CH2:34][C:30]4[S:29][CH:33]=[CH:32][CH:31]=4)=[CH:10][CH:9]=[C:8]4[C:4]=3/[C:5](=[CH:12]/[C:13]3[NH:14][CH:15]=[CH:16][C:17]=3[O:18][CH3:19])/[C:6](=[O:11])[NH:7]4)[CH:28]=2)[CH:24]=[CH:25]1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(-c3ccc4cc[nH]c4c3)c21
Reactant: O=C(Cl)Cc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(NC(=O)Cc3cccs3)c(-c3ccc4cc[nH]c4c3)c21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (Z)-5-amino-1,3-dihydro-4-(6-indolyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (22 mg, 0.059 mmol) (from Step B above) in 2 mL tetrahydrofuran was added 2-thiopheneacetyl chloride (20 mg, 0.12 mmol) (Aldrich) and a saturated aqueous solution of sodium bicarbonate (0.15 mL). The reaction was stirred at room temperature for 16 hours at which time the reaction was diluted with water (10 mL), and the THF was evaporated in vacuo. The product was then extracted with EtOAc, and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The resulting powder was recrystallized from EtOAc/Hex to give product as yellow crystals. (Yield 19 mg, 66%).
Reaction SMILES: Br[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1B(O)O>>[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1
Reactant: OB(O)c1ccco1
Reactant: COc1cc2c(cc1Br)C(c1cccc(C#N)c1)=NCC(=O)N2C
Agent: OB(O)c1ccccc1
Product: COc1cc2c(cc1-c1ccco1)C(c1cccc(C#N)c1)=NCC(=O)N2C
Yield: 41 %

Procedure:
Prepared from 3-(7-bromo-8-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 9 using the same method described for Example 1 and instead of using benzene boronic acid, we used furan-2-boronic acid. The title compound (40 mg) was obtained as a white solid, (yield=41%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([CH:11]=[O:12])=[CH:5][C:4]=1[CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][C:15]([O:17][CH3:18])=[O:16].[CH2:24]([Mg]I)[CH3:25]>O1CCCC1.C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:12])[CH2:24][CH3:25])=[CH:5][C:4]=1[CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: CC[Mg]I
Reactant: CCCCCC(CC(=O)OC)c1cc(C=O)c(OC)cc1OC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCC(CC(=O)OC)c1cc(C(=O)CC)c(OC)cc1OC
Reaction time: 0.67 h

Procedure:
A solution of 644 mg (2.0 mmol) of methyl 3-(2,4-dimethoxy-5-formylphenyl)octanoate [prepared as described in Preparation 32(ii)] in 10 ml of tetrahydrofuran was added dropwise over a period of 5 minutes to a solution of 1.2 ml (2.2 mmol) of a 1.8 M solution of ethylmagnesium iodide in diethyl ether diluted with 20 ml of tetrahydrofuran, whilst ice-cooling, and the resulting mixture was stirred at the same temperature for 40 minutes. The reaction was then terminated by the addition of a saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with a mixture of ethyl acetate and hexane. The extract was washed several times with water and once with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, giving the title compound as a crude product. This product was dissolved in 40 ml of methylene chloride, and 3.48 g of manganese dioxide were added to the resulting solution. The resulting mixture was stirred for 1 hour, after which a further 3.48 g of manganese dioxide were added. The mixture was then stirred for 12 hours, and then a further 1.72 g of manganese dioxide [8.68 g (99.8 mmol) in total] were added to the mixture, which was then stirred for 8 hours. At the end of this time, the reaction mixture was filtered using a Celite (trade mark) filter aid, and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was triturated with hexane to give approximately pure crystals of the title compound. The compound was firther purified by column chromatography through 10 g of silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 5:1 to 3:1 by volume as the eluent, to give 416 mg (yield 59%) of the desired propionyl derivative, melting at 75.5-77.5° C. (from hexane).
Reaction SMILES: N(OC(C)(C)C)=O.[Cl:8][C:9]1[N:14]=[CH:13][C:12](N)=[CH:11][C:10]=1[CH3:16].[CH2:17]([OH:22])[C:18]([F:21])([F:20])[F:19].C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+]>>[Cl:8][C:9]1[C:10]([CH3:16])=[CH:11][C:12]([O:22][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:13][N:14]=1
Reactant: OCC(F)(F)F
Reactant: Cc1cc(N)cnc1Cl
Agent: CC(C)(C)ON=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCC(F)(F)F)cnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
Tert-butyl nitrite (1.60 g, 0.0156 mol, Sigma-Aldrich) was added drop wise to a stirred solution of 6-chloro-5-methylpyridine-3-amine (2.0 g, 0.0140 mol) in trifluoroethanol (10.05 g, 0.100 mol) and TFA (2.42 g, 0.0212 mol) at ambient temperature, followed by slow addition of potassium carbonate (4.40 g). The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate (2×300 mL). The combined organic layer were washed with brine, dried over sodium sulfate and concentrated. The crude residue was purified by silica gel column chromatography, eluting with 5% ethyl acetate in petroleum ether to give 2-chloro-3-methyl-5-(2,2,2-trifluoroethoxy)pyridine (1.30 g, 41.13% yield) as a reddish oil. MS m/z=225.02 [M+H]+.
Reaction SMILES: CCCCCC.[H-].[Na+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18]#[N:19])[CH:14]=[CH:15][CH:16]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][N:22]=1>CN(C=O)C.CCOCC>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([CH:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH3:9])[CH:12]=2)[C:18]#[N:19])=[N:22][CH:23]=1
Reactant: COc1cccc(CC#N)c1
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1cccc(C(C#N)c2ccc(Br)cn2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
To a suspension of hexane washed 60% sodium hydride (2.65, 66.0 mmol) in DMF (30 mL) at 0° C. was added 3-methoxyphenyl acetonitrile (8.0 g, 54.3 mmol). The reaction mixture was stirred at 0° C. for 30 min. A solution of 2,5-dibromopyridine (15.45g, 65.2 mmol) in DMF(20 mL) was added and the reaction was stirred at room temperature for 20 min and at 50° C. for 30 min. To the reaction mixture was added H20 (20 mL) and Et2O (200 mL). The organic layer was washed with brine (5x50 mL), dried over Na2SO4 and concentrated. Purification by flash chromatography with hexanes/EtOAc (10:1) afforded 10.6 g of (5-Bromopyridin-2-yl)-(3-methoxy-phenyl)-acetonitrile. 1HNMR (400 MHz, CDCl3) 6 8.63 (s,1H), 7.80 (dd, 1H), 7.27 (comp, 2H), 6.98 (d, 1H), 6.87 (s,1H), 6.84 (m, 1H), 5.28 (s, 1H), 5.23 (s, 3H); MS (M+1) 303.0, 305.0.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:26][CH2:27][CH3:28])[C:5]2[S:10][C:9]3[N:11]=[C:12]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=4)[CH:13]=[C:14]([CH3:15])[C:8]=3[C:6]=2[N:7]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C1(C)C=CC=CC=1>[CH2:27]([O:26][C:4]1[C:5]2[S:10][C:9]3[N:11]=[C:12]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=4)[CH:13]=[C:14]([CH3:15])[C:8]=3[C:6]=2[N:7]=[C:2]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[N:3]=1)[CH3:28]
Reactant: C1CNCCN1
Reactant: CCOc1nc(Cl)nc2c1sc1nc(-c3ccc(OC)c(OC)c3)cc(C)c12
Solvent: Cc1ccccc1
Product: CCOc1nc(N2CCNCC2)nc2c1sc1nc(-c3ccc(OC)c(OC)c3)cc(C)c12

Procedure:
1.0 g (2.4 mmol) 2-chloro-4-ethoxy-7-(3,4-dimethoxyphenyl)-9-methyl-pyrido-[3′,2′:4,5]thieno[3,2-d]pyrimidine and 0.83 g (9.6 mmol) piperazine are refluxed in 20 ml toluene for 4 h. Then, the solvent is removed and the residue is suspended in dichloromethane. The organic phase is washed with saturated sodium carbonate solution, dried on sodium sulfate and the solvent is removed. The residue is purified by flash chromatography (ethanol/chloroform 1:5). 0.98 g (87%) of the title substance is obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[N:6][C:5]2=[O:12].[H-].[Na+].Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.O>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:5]2=[O:12]
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1nc[nH]c2ccc(I)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2cnc3ccc(I)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
6-Iodo-1H-quinazolin-4-one (0.50 g, 1.84 mmol) was added to a solution of sodium hydride (0.110 g, 2.76 mmol) in THF (10 mL) and stirred at room temperature for one hour. 1-Chloromethyl-4-methoxy-benzene (0.345 g, 2.21 mmol) was added and the reaction was stirred for several hours. Water was added and the crude product was extracted from ethyl acetate and evaporated in vacuo. The product was purified via silica gel column chromatography in hexane:ethyl acetate (4:1) to give 0.69 g (96%) of 6-iodo-3-(4-methoxy-benzyl)-3H-quinazolin-4-one. 1H NMR (400 MHz, CDCl3) δ 8.57 (d, 1H, J=2.0 Hz), 8.01 (s, 1H), 7.90 (dd, 1H, J=2.0, 8.8 Hz), 7.33 (d, 1H, J=8.8 Hz), 7.22 (d, 2H, J=8.0 Hz), 6.80 (d, 2H, J=8.8 Hz), 5.03 (s, 2H), 3.70 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17](=[O:26])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:13][CH2:12]2)=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1.O>ClCCl.I[Si](C)(C)C>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:17]([CH:14]1[CH2:13][CH2:12][N:11]([CH2:10][C:4]2[C:3](=[O:2])[NH:8][C:7]([CH3:9])=[CH:6][N:5]=2)[CH2:16][CH2:15]1)=[O:26]
Reactant: COc1nc(C)cnc1CN1CCC(C(=O)Cc2ccccc2F)CC1
Agent: C[Si](C)(C)I
Solvent: O
Solvent: ClCCl
Product: Cc1cnc(CN2CCC(C(=O)Cc3ccccc3F)CC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 27.2 %

Procedure:
After dissolving 352 mg of 1-[1-(3-methoxy-5-methyl-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-fluorophenyl)ethanone in 3 ml of dichloromethane, 0.5 ml of iodotrimethylsilane was added and the mixture was stirred for 45 minutes at room temperature. Next, 2 ml of iodotrimethylsilane was added and the mixture was further stirred for 2 hours at room temperature. Water was added to the reaction solution, the mixture was rendered alkaline with sodium carbonate, and extraction was performed with dichloromethane. The extract was dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: ethyl acetate/methanol). Diethyl ether was added and the mixture was filtered to obtain the title compound (92 mg, 27% yield).
Reaction SMILES: O1CCOCC1.N[C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:23])[C:12]=2[C:11](NC2C=CC(O)=CC=2)=[CH:10][C:9]=1C#N.FN1N=C(F)C=C(N2CCCC2)N1.C(=O)([O-])[O-].[K+].[K+]>C(N(CC)CC)C>[CH:15]1[C:14]2[C:13](=[O:23])[C:12]3[C:21](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:20](=[O:22])[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1cc(Nc2ccc(O)cc2)c2c(c1N)C(=O)c1ccccc1C2=O
Agent: FC1=NN(F)NC(N2CCCC2)=C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)c2ccccc21
Temperature: 80 °C
Yield: 235.6 %

Procedure:
To dioxane (100 ml), 1-amino-2-cyano-4-(4-hydroxyanilino)anthraquinone (3.55 g), 2,4-difluoro-6-(1-pyrrolidinyl)triazine (1.9 g), triethylamine (1.1 g) and anhydrous potassium carbonate (1.4 g) were added, and the mixture was heated at 80° C. for 1 hour to effect condensation. The reaction liquor was treated as in Example 6 to produce 4.9 g of an anthraquinone dye of the following formula in a yield of 94%. ##STR46## The dye had a λ max (acetone) of 630 nm.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]1[O:19][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][C@H:10]2[C@@H:20]([OH:24])[CH2:21][C@@H:22]([OH:23])[C@@H:9]2[CH:8]=[CH:7]1.[O:25]=[Cr](=O)=O.C1C=CC=CN=1.C1C=CC=CN=1>C(Cl)Cl>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:19])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:10]([CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([OH:25])=[O:18])[C:20](=[O:24])[CH2:21][C@H:22]1[OH:23]
Reactant: O=[Cr](=O)=O
Reactant: CCCCC[C@H]1C=C[C@@H]2[C@@H](CC=CCCCC(=O)O1)[C@@H](O)C[C@H]2O
Agent: CCCCC[C@H]1/C=C/[C@@H]2[C@@H](C/C=C\CCCC(=O)O1)[C@@H](O)C[C@H]2O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Reaction time: 0.33 h

Procedure:
The mono-trimethylsilyl derivative of PGF2α 1,15-lactone (above) was dissolved in 6 ml of methylene chloride and added in one portion to the rapidly stirred Collins reagent. The ice bath was removed and the reaction mixture was allowed to stir for 20 min. longer. The mixture was then poured onto a column containing 150 g of neutral silica. With the aid of a house-vacuum, the column was eluted into a 2-liter round bottom flask with 1000 ml of ethyl acetate. Removal of the solvent gave PGE2, 1,15-lactone, 11-trimethylsilyl ether.
Reaction SMILES: CS[C:3]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:17])[N:4]=1.[OH-].[NH3:19]>>[NH:19]=[C:3]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:17])[NH:4]1
Reactant: N
Reactant: CCCCCn1c(SC)nc(=O)c2[nH]cnc21
Agent: [OH-]
Product: CCCCCn1c(=N)[nH]c(=O)c2[nH]cnc21
Temperature: 100 °C
Reaction time: 96 h
Yield: 68 %

Procedure:
2-(Methylthio)-3-pentyl-3,7-dihydro-6H-purin-6-one (5.0 g, 0.020 mol) was mixed with 100 ml of 28% ammonia hydroxide in a seal tube. The mixture was stirred at 100° C. for 4 days. After cooling to room temperature, the solid was filtered and dried to yield the desired product (3.0 g, 68%). LCMS calculated for C10H16N5O (M+H): 222.1. found: 222.1.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15]>CO.[C].[Pd]>[F:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:14]([F:15])([F:16])[F:17]
Reactant: O=[N+]([O-])c1ccc(CCCF)c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CCCF)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
1-(3-Fluoropropyl)-4-nitro-2-(trifluoromethyl)benzene (300 mg, 1.8 mmol) was dissolved in methanol (10 mL), and palladium carbon (10%, 60 mg) was added thereto. The resulting mixture was stirred under hydrogen atmosphere at room temperature for 3 hours. The catalyst was removed by filtration to give 4-(3-fluoropropyl)-3-(trifluoromethyl)aniline (247 mg, 93%) as a light-yellow oil.
Reaction SMILES: CN1[CH2:6][CH2:5][N:4]([C:7]2N(C)C=CN=2)[C:3]1=[O:13].[O-]P([O-])([O-])=O.[K+].[K+].[K+].I[C:23]1[CH:24]=[C:25]([CH3:30])[CH:26]=C(C)[CH:28]=1.CNC=O.CCCCCCCCCCCC>C(OCC)(=O)C.[Cu]I.C1(C)C=CC=CC=1>[CH3:30][C:25]1[CH:26]=[C:5]([N:4]([CH3:7])[CH:3]=[O:13])[CH:6]=[C:23]([CH3:28])[CH:24]=1
Reactant: CN1CCN(c2nccn2C)C1=O
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCCCCCCCCC
Solvent: CNC=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(N(C)C=O)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol, 5.0 mol %), 3,1′-dimethyl-4,5-dihydro-3H,1′H-[1,2′]biimidazolyl-2-one (18 mg, 0.10 mmol, 10 mol %), K3PO4 (430 mg, 2.03 mmol), evacuated, backfilled with Ar. 5-Iodo-m-xylene (145 μL, 1.00 mmol), N-methylformamide (72 μL, 1.23 mmol), and toluene (1.0 mL) were added under Ar. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 110° C. for 24 h. The suspension was allowed to reach room temperature. Dodecane (internal GC standard, 230 μL) and ethyl acetate (2 mL) were added. A 0.1 mL sample of the supernatant solution was diluted with ethyl acetate (1 mL) and analyzed by GC to provide 54% yield of N-(3,5-dimethylphenyl)-N-methylformamide.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:7]3[CH:12]=[N:11][N:10](CC4C=CC(OC)=CC=4)[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[CH:1]1([C:4]2[CH:5]=[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:7]3[CH:12]=[N:11][NH:10][C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2c1cnn2Cc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCOC(=O)c1cc(C2CC2)nc2[nH]ncc12
Temperature: 25 °C

Procedure:
To a 20 mL microwave vial were combined ethyl 6-cyclopropyl-1-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (2.05 g, 5.83 mmol), trifluoroacetic acid (6.74 ml, 88 mmol) and anisole (1.912 ml, 17.50 mmol). The reaction vessel was sealed and irradiated (microwave) at 100° C. for 5 minutes. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was diluted with water (20 mL) and then saturated NaHCO3 until basic. The contents were extracted with DCM (4×20 mL). The combined organic layers were washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified via silica gel chromatography (eluent: 0 to 20% EtOAc:Hex). The final product was obtained as 1.06 g (79%). LCMS E-S (M+H)=232.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95-1.21 (m, 4 H) 1.41 (t, J=7.07 Hz, 3 H) 2.33-2.46 (m, 1 H) 4.44 (q, J=7.07 Hz, 2 H) 7.67 (s, 1 H) 8.26 (d, J=1.26 Hz, 1 H) 13.75 (s, 1 H).
Reaction SMILES: [Na].[N:2]1([CH2:8][CH2:9][CH2:10][OH:11])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[Cl:12][C:13]1[CH:14]=[C:15]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28](F)=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[C:16]([F:20])=[CH:17][C:18]=1[Cl:19]>C1COCC1>[Cl:12][C:13]1[CH:14]=[C:15]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:11][CH2:10][CH2:9][CH2:8][N:2]4[CH2:7][CH2:6][O:5][CH2:4][CH2:3]4)=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[C:16]([F:20])=[CH:17][C:18]=1[Cl:19]
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1F
Reactant: OCCCN1CCOCC1
Agent: [Na]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCCN1CCOCC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Sodium metal (5 equivalents) was added, under nitrogen atmosphere, to a solution of 3-(4-morpholinyl)-1-propanol (4 equivalents) in THF. The obtained suspension was stirred at 20° C. for two hours and was thereafter cannulated, under nitrogen atmosphere, into a solution of 4-[(3,4-dichloro-6-fluorophenyl)amino]-7-fluoro-6-nitroquinazoline. The reaction mixture was refluxed for 18 hours, the solvent was thereafter partially removed under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. Drying the combined organic extracts, evaporation and silica gel chromatography (using a mixture of 20% MeOH/30% CH2Cl2/50% EtOAc as elute) gave 4-[(3,4-dichloro-6-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-nitroquinazoline in 72% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[F:15].[C:22]([C:24]1[CH:25]=[C:26]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:27]=[CH:28][C:29]=1F)#[N:23].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[CH2:4][CH2:5][NH:6][C:7]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:29]2[CH:28]=[CH:27][C:26]([CH2:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])=[CH:25][C:24]=2[C:22]#[N:23])=[CH:10][C:9]=1[F:15])=[O:16]
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Reactant: O=C(NCCc1ccc(Cl)cc1Cl)c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3Cl)c(F)c2)c(C#N)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 2.3 %

Procedure:
To a stirred solution of N-(2,4-dichlorophenethyl)-2-fluoro-4-hydroxybenzamide (420 mg, 1.28 mmol) and tert-butyl 2-(3-cyano-4-fluorophenyl)acetate (361 mg, 1.54 mmol) in DMSO (6 ml) was added K2CO3 (265 mg, 1.92 mmol). The reaction was heated stirred at 70° C. for one hour. The reaction was then stirred at 90° C. overnight. The reaction was diluted with water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with 10% Na2CO3 and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography to give tert-butyl 2-(4-(4-((2,4-dichlorophenethyl)carbamoyl)-3-fluorophenoxy)-3-cyanophenyl)acetate (0.0157 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([OH:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH3:20][O:21][CH2:22][CH2:23]Cl>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH2:23][CH2:22][O:21][CH3:20])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: COCCCl
Reactant: COC(=O)c1cc(O)cc(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1cc(C#N)cc(C(=O)OC)c1
Temperature: 140 °C
Yield: 93.8 %

Procedure:
A mixture of methyl 3-cyano-5-hydroxybenzoate (302 mg, 1.7 mmol), potassium carbonate (471 mg, 3.4 mmol) and 2-chloroethyl methyl ether (309 μL mg, 3.4 mmol) in N,N-dimethylformamide (4 mL) was heated in a sealed vial at 140° C. for 15 minutes. The reaction was cooled, diluted with ethyl acetate, washed with water and saturated brine, filtered and concentrated. Filtration through silica gel using dichloromethane afforded 375 mg (93%) of methyl 3-cyano-5-(2-methoxyethoxy)benzoate.
Reaction SMILES: CC1(C)COB([C:8]2[C:9]([F:28])=[CH:10][C:11]([F:27])=[C:12]([C@:14]3([CH3:26])[C:20]([F:22])([F:21])[C:19]([CH3:24])([CH3:23])[O:18][CH2:17][C:16](=[O:25])[NH:15]3)[CH:13]=2)OC1.Cl[C:31]1[O:32][C:33]2[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:34]=2[N:35]=1>[Pd]>[F:41][C:37]1[C:38]([F:40])=[CH:39][C:33]2[O:32][C:31]([C:8]3[C:9]([F:28])=[CH:10][C:11]([F:27])=[C:12]([C@:14]4([CH3:26])[C:20]([F:21])([F:22])[C:19]([CH3:24])([CH3:23])[O:18][CH2:17][C:16](=[O:25])[NH:15]4)[CH:13]=3)=[N:35][C:34]=2[CH:36]=1
Reactant: Fc1cc2nc(Cl)oc2cc1F
Reactant: CC1(C)COB(c2cc([C@@]3(C)NC(=O)COC(C)(C)C3(F)F)c(F)cc2F)OC1
Agent: [Pd]
Product: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3nc4cc(F)c(F)cc4o3)c(F)cc2F)C1(F)F
Yield: 74 %

Procedure:
In a manner analogous to that described in Example 19a), the palladium-catalyzed coupling of (R)-5-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2,4-difluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (intermediate D1.1) and 2-chloro-5,6-difluorobenzo[d]oxazole yielded the title compound (74% yield) as a white powder. MS (ISP): m/z=459.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:6]=1[C:7](OC)=[O:8]>C1(C)C=CC=CC=1>[CH3:16][O:15][C:14]1[C:5]2[O:4][CH2:3][CH2:2][NH:1][C:7](=[O:8])[C:6]=2[CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1cccc(OC)c1OCCN
Solvent: Cc1ccccc1
Product: COc1cccc2c1OCCNC2=O
Temperature: 110 °C
Yield: 101 %

Procedure:
A solution of methyl 2-[(2-aminoethyl)oxy]-3-(methyloxy)benzoate (Preparation 56) (11.9 g, 52.8 mmol) in toluene (200 ml) was stirred and heated at 110° C. for 1 hour then cooled and evaporated to give the title compound (10.3 g) as a sandy coloured solid. MS (ES): C10H11NO3 requires 193; found 194 [M+H]+.