Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH2:8][OH:9])[CH2:3]1.C(N(CC)CC)C.[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12>C1(C)C=CC=CC=1>[OH:9][CH2:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([N:1]2[C:20](=[O:21])[C:19]3[C:18](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:17]2=[O:22])[CH2:3]1
Reactant: N[C@H]1CCC[C@H](CO)C1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@H](CO)C1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
Racemic trans 3-amino-cyclohexyl-methanol (0.65 g, 3.925 mmol) was taken up in toluene (25 mL) and triethylamine (1.6 mL, 11.5 mmol). Phthalic anhydride (0.581 g, 3.925 mmol) was added and the resulting mixture was stirred at reflux overnight. The reaction mixture was allowed to cool to RT before being washed with H2O. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and evaporated. The remaining solid was purified by SiO2 chromatography (40 g SiO2, hexanes/EtOAc 0 to 40%) to give 0.749 g of racemic trans-2-(3-hydroxymethyl-cyclohexyl)-isoindole-1,3-dione as a white solid (73% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH:13]([CH3:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].O.[OH-].[Na+]>C1(C)C=CC=CC=1.S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:13]([CH3:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1CN(C(=O)OCc2ccccc2)CCC1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CN(C(=O)OCc2ccccc2)CCC1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
2.53 g of N-benzyloxycarbonyl-4-hydroxy-3-methyl-piperidine was dissolved in 20 ml of toluene, and to this solution was added 2.96 g of tert-butyl bromoacetate, 0.1 g of tetrabutylammonium sulfate and 1 ml of water. Aqueous solution (10.1 g) of sodium hydroxide was added dropwise to this solution in an ice bath, and the solution was stirred overnight at room temperature. The resulting solution was washed with water and saturated solution of sodium chloride, and dried with anhydrous sodium sulfate. After separating the desiccant by filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography. From the fractions eluted with chloroform-methanol (100:3 v/v) was obtained 1.59 g of N-benzyloxycarbonyl-4-tert-butoxycarbonylmethyloxy-3-methylpiperidine, which was an oily product (yield: 44%).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH2:11][CH3:12].[OH-].[K+]>CO>[CH2:11]([C:5]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:13])=[O:2])[CH3:12]
Reactant: CCc1c(C)cccc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCc1c(C)cccc1C(=O)O
Yield: 99.8 %

Procedure:
A solution of 0.1 g (0.58 mmol) of methyl-2-ethyl-3-methylbenzoate and 1.45 mL (1.45 mmol) of KOH (1M in H2O) in 2 mL of MeOH was stirred at 40° C. for 12 h. The reaction mixture was concentrated and dissolved in 20 mL of CH2Cl2. The pH was adjusted to pH=2-3 with 2N HCl and the aqueous layer was extracted with CH2Cl2. The combined organic fractions were dired over MgSO4, filtered and the filtrate was concentrated to give 0.095 gm of the title compound.
Reaction SMILES: [I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([O:14][C:15]([C:17]1([NH2:28])[CH2:25][C:24]2[C:19](=[CH:20][C:21]([F:27])=[C:22]([F:26])[CH:23]=2)[CH2:18]1)=[O:16])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:12]([O:14][C:15]([C:17]1([NH:28][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[I:1])[CH2:25][C:24]2[C:19](=[CH:20][C:21]([F:27])=[C:22]([F:26])[CH:23]=2)[CH2:18]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)C1(N)Cc2cc(F)c(F)cc2C1
Reactant: Cc1cccc(C(=O)O)c1I
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2cc(F)c(F)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of 2-iodo-3-methyl-benzoic acid (1.50 g, 5.75 mmol), 2-amino-5,6-difluoro-indan-2-carboxylic acid ethyl ester (1.39 g, 5.75 mmol), HATU (2.63 g, 6.90 mmol) in anhydrous DMF (6 mL) is added DIPEA (1.14 mL, 6.90 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (200 mL) and washed with water (1×20 mL) and brine (2×20 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (400 g silica gel, gradient elution: 10%-80% EtOAc in heptane) to give a pure product (156) as white solid (2.32 g, 83%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].C(O)C.Cl.[CH3:16][NH:17][CH3:18]>C(N(CC)CC)C>[CH3:16][N:17]([CH3:18])[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: CNC
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)c1ccc([N+](=O)[O-])c(N)c1
Temperature: 130 °C
Reaction time: 20 h
Yield: 17390.1 %

Procedure:
5-Chloro-2-nitroaniline (50 g; 0.29 mol) was added to a 5 L bomb followed by ethanol (1.1 L) at 0-5° C. Dimethylamine hydrochloride (130 g; 1.59 mmol) was added in one portion followed by triethylamine (260 ml) and the bomb quickly sealed. The bomb was heated to 130° C. with stirring at 4 bar for 20 hours. The reaction mixture was then allowed to cool to room temperature and the ethanol was removed under vacuum. 2 M sodium hydroxide solution (1 L) was added to the crude residue and this was extracted with ethyl acetate (1×1.3 L then 2×500 ml). The combined organic layers were washed with brine (150 ml), dried (magnesium sulphate), filtered and evaporated to give the 5-dimethylamino-2-nitroaniline (50.1 g, 96%).
Reaction SMILES: [Li][P:2]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([CH3:6])([CH3:5])[CH3:4].[Li][As](C(C)(C)C)C(C)(C)C.[Al:21](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])[C:22]([CH3:25])([CH3:24])[CH3:23]>>[Al:21]([P:2]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([CH3:6])([CH3:5])[CH3:4])([C:26]([CH3:29])([CH3:28])[CH3:27])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Al](Cl)C(C)(C)C
Reactant: [Li]P(C(C)(C)C)C(C)(C)C
Agent: [Li][As](C(C)(C)C)C(C)(C)C
Product: CC(C)(C)[Al](P(C(C)(C)C)C(C)(C)C)C(C)(C)C

Procedure:
The process of Example 1 was substantially followed except LiP(t-Bu)2 was substituted for LiAs(t-Bu)2 in the same molar proportions with respect to (t-Bu)2AlCl which was substituted for (t-Bu)2GaCl. The monomeric phosphinoalane, (t-Bu)2AlP(t-Bu)2, was produced. See NMR Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=1>>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([CH2:13][O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)=[CH:19][CH:18]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: CC(C)(C)c1ccc(CBr)cc1
Product: CC(C)(C)c1ccc(COc2ccc(Cl)c([N+](=O)[O-])c2)cc1

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-Bromomethyl-4-tert-butyl-benzene using the conditions described in Example 10C to provide 4-(4-tert-Butyl-benzyloxy)-1-chloro-2-nitro-benzene which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:6].[CH3:21][S:22][C:23]1[N:24]=[CH:25][C:26]2[CH2:32][NH:31][CH2:30][CH2:29][C:27]=2[N:28]=1.CC(C)([O-])C.[Na+]>C1COCC1.CCOC(C)=O.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C>[CH3:21][S:22][C:23]1[N:24]=[CH:25][C:26]2[CH2:32][N:31]([C:2]3[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=3)[C:5]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)=[O:6])[CH2:30][CH2:29][C:27]=2[N:28]=1
Reactant: CSc1ncc2c(n1)CCNC2
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3cccc(C(F)(F)F)c3)c1)C2
Temperature: 80 °C
Yield: 79.6 %

Procedure:
A mixture of 3-bromo-N-[3-(trifluoromethyl)phenyl]benzamide (379 mg, 1.10 mmol), 2-(methylsulfanyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidine (200 mg, 1.10 mmol), RuPhos (15.4 mg, 0.033 mmol), Cl-RuPhos-Pd precatalyst (24 mg, 0.033 mmol), and sodium-t-butoxide (148 mg, 1.54 mmol) in anhydrous THF (30 ml) was heated at 80° C. under nitrogen for 21 hours. Upon cooling, the reaction mixture was diluted with EtOAc and the insolubles were filtered off (celite). The filtrate was concentrated and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, 1:1 hexanes:EtOAc) to obtain a yellow, crystalline solid (389 mg, 80%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:12][NH2:13].[BH4-].[Na+].O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH:13][CH3:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1ccc2[nH]ccc2c1
Reaction time: 3 h
Yield: 88.6 %

Procedure:
Indole-5-carbaldehyde (1.0 g, 6.9 mmol) was dissolved in anhydrous methanol (15 mL). Methylamine (9.9 mL of 2M solution in methanol, 19.8 mmol) was added and the reaction was stirred for 3 hr. The solution was concentrated to a yellow oil and then dissolved into anhydrous methanol (20 mL). Sodium borohydride (262 mg, 6.9 mmol) was added and the mixture was stirred overnight. Water (1 mL) was added and the solution was concentrated. Sodium hydroxide (5 mL, 1N) was added and the product was extracted with ethyl acetate (3×20 mL), dried over MgSO4 and concentrated to afford the title compound as a brown oil (980 mg, 91%). 1H NMR (200 MHz, CDCl3) δ 8.60 (s, 1H), 7.56 (s, 1H), 7.35-7.15 (m, 3H), 6.55 (m, 1H), 3.85 (s, 2H), 2.49 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:6][C:3]=1[CH:4]=[O:5].S(OC)(O[CH3:22])(=O)=O>[OH-].[K+]>[CH3:22][O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: O=Cc1cc(Oc2ccccc2Cl)ccc1O
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(Oc2ccccc2Cl)cc1C=O
Temperature: 25 °C
Yield: 72.8 %

Procedure:
An aqueous solution (30 ml) of potassium hydroxide (8.2 g) was added portionwise to a mixture of 2-hydroxy-5-(2-chlorophenoxy)benzaldehyde (10.4 g) and dimethyl sulfate (10.5 g) with stirring at room temperature, and the mixture was stirred at 70° C. for an hour. After cooling, the reaction mixture was extracted with diethyl ether, and the extract was washed with water, dried and evaporated. The residue was crystallized from methanol to give 2-methoxy-5-(2-chlorophenoxy)benzaldehyde (8 g). mp 65°-66° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10](=[O:12])[NH:9][C:8]2[N:7]=[C:6](Br)[C:5]3[N:14]=[CH:15][CH:16]=[CH:17][C:4]=3[C:3]1=2.[C:18]([Cu])#[N:19].[C-]#N.[K+].CO>O>[CH3:1][CH:2]1[CH2:11][C:10](=[O:12])[NH:9][C:8]2[N:7]=[C:6]([C:18]#[N:19])[C:5]3[N:14]=[CH:15][CH:16]=[CH:17][C:4]=3[C:3]1=2
Reactant: N#C[Cu]
Reactant: CC1CC(=O)Nc2nc(Br)c3ncccc3c21
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC1CC(=O)Nc2nc(C#N)c3ncccc3c21
Yield: 70 %

Procedure:
2 g (0.007 mol) of 1-methyl-6-bromo-1,2-dihydropyrido[2,3-c][1,8]naphthyridin-3(4H)-one, 0.3 g (0.003 mol) of CuCN and 0.3 g (0.005 mol) of KCN are heated for 7 hours at 160° C. in an autoclave with 20 ml of methanol and 10 ml of water. After cooling, the mixture is filtered under suction, and the residue digested in chloroform/methanol, 1:1, under reflux for 4 hours. The organic phase is filtered, dried and concentrated. The residue is purified by recrystallization from ethanol/petroleum ether, and 0.5 g (60.1% of theory) of 1-methyl-6-cyano-1,2-dihydropyrido[2,3-c][1,8]naphthyridin-3(4H)-one is obtained.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:26][NH2:27]>C(O)C>[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:26][NH:27][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[CH:14][CH:13]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Product: O[C@H](CNCc1ccc(F)c(F)c1)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole, 3,4-difluorobenzylamine, and ethanol essentially as described above in Example 112. Purity by LC/MS=97%, [M+H]+=429.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:12][C:13](=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]=[C:20]=[O:21])[CH3:11].[C:23]([O:27][C:28](=[O:56])[NH:29][C:30]([C:32]1[S:33][C:34]([S:54][CH3:55])=[C:35]([S:37]([C:40]2[CH:41]=[C:42]([C:46]3[CH:51]=[CH:50][C:49]([NH2:52])=[CH:48][C:47]=3[CH3:53])[CH:43]=[CH:44][CH:45]=2)(=[O:39])=[O:38])[CH:36]=1)=[NH:31])([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[CH2:10]([O:12][C:13](=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH:52][C:49]1[CH:50]=[CH:51][C:46]([C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([S:37]([C:35]3[CH:36]=[C:32]([C:30]([NH:29][C:28]([O:27][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:56])=[NH:31])[S:33][C:34]=3[S:54][CH3:55])(=[O:39])=[O:38])[CH:41]=2)=[C:47]([CH3:53])[CH:48]=1)=[O:21])[CH3:11]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2ccc(N)cc2C)c1
Reactant: CCOC(=O)CCCCCN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCCCCNC(=O)Nc1ccc(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(C)c1
Yield: 42.7 %

Procedure:
Diisopropylethylamine (35 μL, 0.2 mmol), 6-isocyanato-hexanoic acid ethyl ester (40 μL, 0.2 mmol), and {[4-(4′-amino-2′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 220: step b) 20 mg, 0.04 mmol) were stirred for 24 h in DCM (1 mL). The solution was partitioned between EtOAc (40 mL) and 0.1 N HCl (10 mL) and was washed with additional 0.1N HCl (2×10 mL), NaHCO3 (10 mL), and brine (20 mL). The solution was dried, concentrated in vacuo, and purified by SiO2 preparative TLC to yield the product (12 mg, 43%). 1H-NMR (CDCl3): δ 8.06 (s, 1H), 7.94 (m, 1H), 7.81 (m, 1H), 7.46 (m, 2H), 7.23 (br t, 1H, J=5.4 Hz), 7.15 (m, 1H), 7.07 (m, 2H), 6.97 (m, 1H), 5.32 (br t, 1H), 4.15 (q, 2H, J=7.2 Hz), 2.40 (s, 3H), 2.30 (t, 2H, J=7.3 Hz), 2.11 (s, 3H), 1.54–1–70 (m, 4H), 1.51 (s, 9H) 1.35 (m, 2H), 1.25 (t, 3H, J=7.3 Hz).
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16])([O-:12])=[O:11]>C1COCC1.CCOC(C)=O.[Zn]>[CH2:6]([O:5][C:3](=[O:4])[C:2]([F:9])([F:8])[CH:15]([C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[N+:10]([O-:12])=[O:11])[OH:16])[CH3:7]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)C(O)c1ccccc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
To a slurry of activated zinc (6.25 g, 99.2 mmol) in 75 mL anhydrous THF, was added ethyl bromodifluoroacetate (11.0 mL, 85.8 mmol) and the mixture was heated to reflux. After a visible reaction had occurred, 2-nitrobenzaldehyde (5.0 g, 33.1 mmol) in 30 mL anhydrous THF, was added dropwise to maintain reflux. After 3 h, the solution was cooled to 23° C., diluted with EtOAc (50 mL), washed with 1M KHSO4 (2×50 mL) and brine (1×50 mL), and dried (Na2SO4). Concentration in vacuo yielded a residue which was purified by flash chromatography (chloroform:EtOH, 99:1) to afford 2-(3-ethoxy-3-oxo-2,2-difluoro-1-hydroxypropyl)nitrobenzene (8.28 g, 91%) as an orange oil, which was taken on to the next step without further characterization.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([OH:13])=O)=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH3:14][N:15](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:11]([NH:15][CH3:14])=[O:13])=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1[nH]cc(C(=O)O)c1Cl
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c[nH]c(C(=O)OC)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
To a solution of 4-chloro-5-[(methyloxy)carbonyl]-1H-pyrrole-3-carboxylic acid (0.075 g, 0.368 mmol) in DMF (1 ml) was added HATU (0.168 g, 0.442 mmol), DIPEA (0.097 ml, 0.553 mmol) and methyl amine (2M in THF) (0.276 ml, 0.553 mmol). The reaction mixture was stirred at RT overnight. Purification was accomplished by HPLC, the desired fractions collected and lypholized to afford methyl 3-chloro-4-[(methylamino)carbonyl]-1H-pyrrole-2-carboxylate (0.046 g, 57.6% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.39 (br. s., 1H) 7.73-7.83 (m, 1H) 7.46 (d, 1H) 3.80 (s, 3H) 2.70 (d, 3H). MS: m/z 217.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14](C)(C)C([O-])([O-])[O-].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C>[CH3:13][C:14]1[O:12][C:11]2[C:2]([N:1]=1)=[N:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=1[CH:10]=2
Reactant: CC(C)(C)C([O-])([O-])[O-]
Reactant: Nc1nc2ccccc2cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: Cc1nc2nc3ccccc3cc2o1
Temperature: 60 °C

Procedure:
A mixture of 0.6 g of 2-amino-3-hydroxyquinoline, 3.8 mL of trimethylorthoacetate and 0.1 g of p-toluenesulfonic acid is heated at 60° C. for 7 hours. The reaction mixture is then diluted with ethyl acetate, washed with sodium bicarbonate, and purified by column chromatography on silica gel to yield 0.28 g of 2-methyloxazolo[4,5-b]quinoline. The quinoline is heated with one equivalent of methyl tosylate at 70° C. for one hour to generate the product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:28])[N:15]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:16]=[N:17]3)=[CH:12][C:11]=2[O:29][CH3:30])[CH2:3][CH2:2]1.C=O.[C:33](O)(=O)C.C(O)(=O)C.C(O)(=O)C.C(O)(=O)C.[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:33][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:28])[N:15]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:24])[CH3:25])[CH:16]=[N:17]3)=[CH:12][C:11]=2[O:29][CH3:30])[CH2:3][CH2:2]1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCC1CCNCC1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
To a solution of 7-(2-(piperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (6 g, 14.4 mmol) in methanol (30 ml) and methylene chloride (60 ml) was added 37% aqueous formaldehyde (2.2 ml; 28.9 mmol) followed by acetic acid (990 μl; 17.3 mmol). Sodium borohydride triacetate (4.6 g, 21.6 mmol) was added in portions. After stirring for 1 hour at ambient temperature, the volatiles were removed under vacuum and the residue was partitioned between water (50 ml) and methylene chloride (50 ml). The pH of the aqueous layer was adjusted to 7, washed with water, brine, dried (MgSO4) and evaporated. The solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 7-(2-(1-methylpiperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (4.2 g, 68%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=1[F:10])#[N:2].[CH3:11][C:12]1([CH3:26])[C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:16]=2[NH:15][C:14](=[O:25])[O:13]1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>COCCOC.O.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>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:19]2[CH:20]=[CH:21][C:16]3[NH:15][C:14](=[O:25])[O:13][C:12]([CH3:26])([CH3:11])[C:17]=3[CH:18]=2)=[CH:5][C:4]=1[F:10])#[N:2]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)c(F)c3)cc21
Temperature: 25 °C
Yield: 5.6 %

Procedure:
A solution of 4-cyano-3-fluoro-bromobenzene (0.6 g, 3.0 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 mL) was stirred under N2 for 20 minutes. To this mixture was then added (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid (1.0 g, 4.5 mmol) and sodium carbonate (1.1 g, 10.6 mmol) in water (5 mL). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (3×50 mL). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc:hexane=1:2) to afford the title compound (0.05 g, 6%) as an off-white solid. mp: 272-275° C.; 1H-NMR (DMSO-d6) δ 10.4 (s, 1H), 8.0 (t, 1 H, J=7.7 Hz), 7.9 (dd, 1H, J=10.3, 1.3 Hz), 7.8 (dd, 1H, J=6.8, 1.4 Hz), 7.7 (m, 2H), 6.9 (d, 1H, J=8.9 Hz), 1.7 (s, 6H); MS (EI) M+@m/z 296.
Reaction SMILES: Br[C:2]1[N:7]=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)C(C)(C)OB([C:29]2[CH:47]=[CH:46][C:32]([O:33][C:34]3[CH:35]=[CH:36][C:37]([C:42]([F:45])([F:44])[F:43])=[C:38]([CH:41]=3)[C:39]#[N:40])=[CH:31][CH:30]=2)O1>CN(C=O)C.O>[C:39]([C:38]1[CH:41]=[C:34]([CH:35]=[CH:36][C:37]=1[C:42]([F:43])([F:44])[F:45])[O:33][C:32]1[CH:46]=[CH:47][C:29]([C:2]2[N:7]=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=2)=[CH:30][CH:31]=1)#[N:40]
Reactant: CCOC(=O)/C=C/c1cccc(Br)n1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(C(F)(F)F)c(C#N)c3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cccc(-c2ccc(Oc3ccc(C(F)(F)F)c(C#N)c3)cc2)n1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
(E)-Ethyl 3-(6-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)acrylate (13) was prepared as follows: A mixture of compound 11 (0.6 g, 1.0 eq), K2CO3 (2 eq), 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-(trifluoromethyl)benzonitrile (12) (1.05 eq) and Pd[(o-toly)3P]2Cl2 (0.2 eq) in 10 mL of DMF and water (0.1 mL) was flushed with argon and then shaken at 90° C. for 3 h. After cooling to room temperature, the reaction mixture was quenched with water (20 mL), and extracted with EtOAc. The organic layer was washed with brine, concentrated, and purified by column (EtOAc/hexanes 10/1) to afford compound 13 as a colorless oil (0.8 g): 1H-NMR (400 MHz, CDCl3) δ 8.07 (d, 2H, 8.9 Hz), 7.74-7.84 (m, 4H), 7.39-7.43 (m, 2H), 7.3-7.33 (m, 1H), 7.21 (d, 2H, 8.8 Hz), 7.12 (d, 1H, 15.8 Hz), 4.32 (q, 2H, 7.2 Hz), 1.38 (t, 3H, 7.0 Hz).