Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[CH3:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[Sn](CCCC)(CCCC)CCCC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[F:25][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]=[C:10]([C:31]3[N:30]([CH3:29])[CH:34]=[CH:33][N:32]=3)[C:11]=12)[NH2:24]
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2nc(-c3nccn3C)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 60 °C
Yield: 78.9 %

Procedure:
4-(1-(4-Methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (200 mg, 0.408 mmol, prepared in Example 7, step B), 1-methyl-2-(tributylstannyl)-1H-imidazole (908.4 mg, 2.45 mmol), tetrakis (triphenylphosphine) palladium (94.28 mg, 0.0816 mmol) and toluene (4 mL) were charged in a 25 mL, single-neck, round-bottomed flask. The reaction mixture was stirred at 60° C. until the starting material had been consumed (4 hours). Then the reaction mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and H2O (50 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (0.143 g, 79%). LRMS (APCI pos): >99% purity, 254 nm, m/e 445 (M+1). 1H NMR (400 MHz, CDCl3 δ 8.31 (m, 1H), 7.71 (m, 1H), 7.50 (m, 1H), 7.35 (m, 2H), 6.94 (m, 1H), 6.84 (m, 2H), 6.50 (m, 1H), 6.43 (m, 1H), 6.28 (d, 1H), 5.64 (s, 2H), 3.90 (s, 3H), 3.75 (s, 3H), 3.67 (s, 2H, NH2).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH2:21]([N:23]([CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1)[CH2:24][CH3:25])[CH3:22].C(OCC)(=O)C.CO>C(O)C>[CH2:21]([N:23]([CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4])[CH2:24][CH3:25])[CH3:22]
Reactant: CCN(CC)C[C@@H]1CCCN1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CO
Product: CCN(CC)C[C@@H]1CCCN1CC(=O)N1c2ccccc2C(=O)Nc2cccnc21

Procedure:
The title compound is prepared analogously to Example 31 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and (S)-(+)-2-[(diethylamino)methyl]pyrrolidine to give colorless crystals, mp. 192°-193° C. (ethyl acetate/methanol 99:1 v/v); [α]D20 =29.4° (ethanol).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[F:11][C:12]([F:33])([F:32])[C:13]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:21][CH:20]=1)([OH:18])[C:14]([F:17])([F:16])[F:15].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[F:33][C:12]([F:11])([F:32])[C:13]([C:19]1[CH:20]=[CH:21][C:22]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=3)=[O:8])[CH2:28][CH2:27]2)=[CH:23][CH:24]=1)([OH:18])[C:14]([F:17])([F:16])[F:15]
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=C(O)c1ccc(O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)N1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reaction time: 2 h
Yield: 9.5 %

Procedure:
4-Hydroxybenzoic acid (2.045 mmol, 0.282 g), 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)propan-2-ol (2.045 mmol, 0.7 g) and triethylamine (6.14 mmol, 0.853 mL, 0.621 g) were combined and stirred at room temperature in dichloromethane (5 mL). 1-Propanephosphonic acid cyclic anhydride (3.07 mmol, 1.826 mL, 1.952 g; 50% solution in ethyl acetate) was added and the reaction stirred for 2 hours. The reaction mixture was washed with saturated sodium bicarbonate solution and the organic layer dried over magnesium sulphate and concentrated under vacuum. The residue was dissolved in dichloromethane with a few drops of methanol and purified by column chromatography (dichloromethane—6% methanol in dichloromethane) to afford the title compound (90 mg). MS (ESI) m/z 463.0 [M+H]+
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([NH2:10])=[O:9].P(Br)(Br)[Br:15]>ClCCl>[Br:15][CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([NH2:10])=[O:9]
Reactant: NC(=O)COc1cccc(CO)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: NC(=O)COc1cccc(CBr)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
2-(3-(hydroxymethyl)phenoxy)acetamide (320 mg, 1.76 mmol) was suspended in dichloromethane (12 mL) and the suspension cooled to 0° C. (ice bath). Phosphorus tribromide (1.5 eq) was added slowly and the reaction allowed to warm to rt. After stirring for 18 h the reaction was quenched by addition of NaHCO3 (sat., aq). The product was extracted with dichloromethane, dried (Na2SO4), filtered and concentrated in vacuo to afford 2-(3-(bromomethyl)phenoxy)acetamide as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[O:8][C:9]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:10]=2[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2]>C(O)C.[Pt]=O>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:9]=2[O:8][C:7]1=[O:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2oc1=O
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)C1C(=O)Oc2ccc(Cl)cc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.6 %

Procedure:
To a solution of 6-chloro-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acid ethyl ester (4.4 g) in ethanol (300 ml) was added platinum oxide (0.30 g), followed by stirring at room temperature in a hyarogen atmosphere (3 to 4 atm) for 3 hours. After the catalyst was filtered off, the flitrate was distilled to remove the solvent, followed by treatment of the residue with isopropyl ether, to yield 6-chloro-3,4-dihydro-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acid ethyl ester as colorless crystals (2.24 g).
Reaction SMILES: [H][H].[Cl:3][C:4]1[C:9]([O:10][CH2:11][C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:13])=[CH:8][C:7]([N+:20]([O-])=O)=[C:6]([F:23])[CH:5]=1>[C].[Pd].C1(C)C=CC=CC=1>[Cl:3][C:4]1[C:9]([O:10][CH2:11][C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:13])=[CH:8][C:7]([NH2:20])=[C:6]([F:23])[CH:5]=1
Reactant: CCCCCOC(=O)COc1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCCOC(=O)COc1cc(N)c(F)cc1Cl
Reaction time: 1 h
Yield: 62.1 %

Procedure:
Hydrogen gas (1.3 liters) was introduced into a mixture of the compound (III) (6.4 g), 5% palladium-carbon (0.32 g) and toluene (64 g) at room temperature while stirring in 1 hour. After removal of the catalyst from the reaction mixture, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give 4-chloro-2-fluoro-5-(pentyloxycarbonylmethyloxy)aniline (3.6 g). Yield, 62%.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]3[CH:18]=[C:17]([O:19]C)[CH:16]=[CH:15][C:12]=3[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:21]#[N:22].Cl.N1C=CC=CC=1.[OH-].[NH4+]>>[Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]3[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:12]=3[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:21]#[N:22]
Reactant: COc1ccc2cc3c(Nc4ccc(Cl)cc4Cl)c(C#N)cnc3cc2c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Product: N#Cc1cnc2cc3cc(O)ccc3cc2c1Nc1ccc(Cl)cc1Cl
Temperature: 215 °C
Reaction time: 1 h

Procedure:
According to the procedure of example 105, the reaction mixture of 373.9 mg (0.954 mmol) of 4-(2,4-dichloroanilino)-8-methoxybenzo[g]quinoline-3-carbonitrile and 10 g of pyridine hydrochloride is stirred at 215° C. for 1 hour under N2. After cooling, the mixture is neutralized with 40 mL of a 3% ammonium hydroxide solution and stirred for 0.5 hour. The separated solid is filtered off and washed with water and ether. After drying in vacuo, this yields 333.4 mg (92.6%) of 4-(2,4-dichloroanilino)-8-hydroxybenzo[g]quinoline-3-carbonitrile as a yellow solid, mp 267–269° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:31](O)[CH2:32][CH2:33][OH:34].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:8]2([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)[O:34][CH2:33][CH2:32][CH2:31][O:9]2)[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: OCCCO
Reactant: COc1ccc(C(=O)c2cccc(C)n2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2(c3cccc(C)n3)OCCCO2)cc1OC
Reaction time: 17 h

Procedure:
About 77.1 g. of (3,4-dimethoxyphenyl) (6-methyl-2-pyridyl) ketone, 74.1 g. of p-toluenesulfonic acid and 22.8 ml of 1,3-propanediol in 600 ml of toluene were heated under reflux with stirring for 17 hours. The water evolved during the reaction was neutralized with 500 ml of saturated sodium bicarbonate. Two phases formed and the phases were separated. The organic layer was washed with saturated sodium bicarbonate solution and dried over magnesium sulfate. Removal of the desiccant and solvent gave a solid residue which, on recrystallization from a mixture of acetone and petroleum ether (b.p. 60°-80°C.), yielded 2-(3,4-dimethoxyphenyl)-2-(6-methyl-2-pyridyl)-1,3-dioxane, m.p. 124°-126°C.
Reaction SMILES: [F:1][C:2]([F:15])([O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11])[CH:3]([F:5])[F:4].[O:16]([C:23]1[CH:24]=[C:25]([NH:29][CH2:30][CH:31](O)[C:32]([F:35])([F:34])[F:33])[CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Zn+2].[I-].[I-].C1(C)C=CC=CC=1>[O:16]([C:23]1[CH:24]=[C:25]([N:29]2[CH2:30][CH:31]([C:32]([F:33])([F:34])[F:35])[O:11][CH:10]2[C:9]2[CH:12]=[CH:13][CH:14]=[C:7]([O:6][C:2]([F:15])([F:1])[CH:3]([F:4])[F:5])[CH:8]=2)[CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: OC(CNc1cccc(Oc2ccccc2)c1)C(F)(F)F
Agent: [I-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: FC(F)C(F)(F)Oc1cccc(C2OC(C(F)(F)F)CN2c2cccc(Oc3ccccc3)c2)c1
Yield: 91.7 %

Procedure:
A toluene solution (5 mL) of 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (0.45 g, 2.0 mol) and N-(3-phenoxyphenyl)-3-amino-1,1,1-trifluoro-2-propanol (0.60 g, 2.0 mmol) was refluxed in the presence of molecular sieves and ZnI2 (˜5 mg) for 18 h under N2. The reaction mixture was filtered to remove the sieves, and the filtrate was diluted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to give 0.92 g (92%) of the desired 3-(3-phenoxyphenyl)-2-[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]-5-(trifluoromethyl) oxazolidine product as a colorless oil. The formation of the desired product was monitored by the disappearance of the aldehyde peak (δ˜10) in the 1H NMR spectrum. HRMS calcd. 502.1253 [M+H]+, found: 502.1220.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[N:7]1[CH:12]=[C:11]([Cl:13])[CH2:10][N:9](Cl)[NH:8]1>>[Cl:13][C:11]1[C:12]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:7][N:8]=[N:9][C:10]=1[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: ClC1=CN(Cl)NN(Cl)C1
Product: Clc1c(N2CCCC2)nnnc1N1CCCC1
Reaction time: 1.25 h

Procedure:
Pyrrolidine (28.5 g) is cooled on an ice bath. 1,3,5-Trichlorotriazine (18.4 g) is added with vigorous stirring. After 1-1.5 h the mixture is permitted to warm to 20°-25°. The solid is filtered and rinsed several times with water and dried under reduced pressure to give the monochloro-bis(1-pyrrolidinyl)triazine.
Reaction SMILES: Cl.[CH3:2][C@H:3]1[N:8]([C:9]2[N:17]=[CH:16][N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:18])[C@@H:7]([CH3:19])[CH2:6][N:5]([CH2:20][C:21]([OH:23])=O)[CH2:4]1.[Cl:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27].C(N(CC)C(C)C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[Cl:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH:27][C:21](=[O:23])[CH2:20][N:5]1[CH2:4][C@H:3]([CH3:2])[N:8]([C:9]2[N:17]=[CH:16][N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:18])[C@H:7]([CH3:19])[CH2:6]1
Reactant: C[C@@H]1CN(CC(=O)O)C[C@H](C)N1c1ncnc2c1ncn2C
Reactant: Nc1ccccc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(CC(=O)Nc2ccccc2Cl)C[C@H](C)N1c1ncnc2c1ncn2C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Bromo-tris-oxy-tripyrrolidinophosphonium hexafluorophosphate (known as PyBroP) (0.18 g) was added to a stirred solution of the product from step (iv) (0.14 g), 2-chloroaniline (0.05 g) and N,N-diisopropylethylamine (0.3 g) in anhydrous dimethylformamide (6 ml). After stirring for 4 hours a further aliquot of 2-chloroaniline (0.1 ml) and PyBroP (0.18 g) were added and the mixture further stirred at room temperature for four days. Water was added and the precipitate filtered to give the crude product as a brown solid (0.07 g). This was purified by high pressure liquid chromatography (acetonitrile/0.1% aqueous ammonium acetate, gradient elution 25% to 75% organic phase) to give the title product as a white solid. Yield 0.04 g.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:17])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[N:18]([O-])=O.[Na+]>C(O)(=O)C>[N+:8]([C:6]1[CH:7]=[C:2]2[C:3](=[C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=1)[NH:17][N:18]=[CH:1]2)([O-:10])=[O:9]
Reactant: O=N[O-]
Reactant: Cc1cc([N+](=O)[O-])cc(-c2ccccc2)c1N
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(-c2ccccc2)c2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-Methyl-5-nitro-biphenyl-2-ylamine (91 mg, 0.39 mmole) in pre-heated glacial acetic acid (4 mL) was added 0.44M sodium nitrite solution (1 mL), in a dropwise fashion. The resulting mixture was stirred overnight at room temperature. The crude product was concentrated in-vacuo and the residue re-dissolved in EtOAc (20 mL) and washed with saturated NaHCO3 (2×20 mL) and brine (1×20 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in-vacuo to yield the desired product (67 mg) as a yellow powder. 1H NMR (400 MHz, CDCl3) δ 7.50(1H, m), 7.58(2H, m), 7.69(2H, m), 8.33 (2H, m), 8.75(1H, s), 10.55(br s). MS (ES+): m/e=240, (ES−): m/e=238.
Reaction SMILES: Cl[CH:2]([Cl:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=[O:19]>O1CCCC1>[Cl:10][C:2]1([C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[CH:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)[O:19]1
Reactant: CC(C)(C)OC(=O)C(Cl)Cl
Reactant: O=Cc1ccccn1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(Cl)OC1c1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4 ml of tert.-butyl dichloroacetate in 15 ml of tetrahydrofuran and 2.6 ml of picolinaldehyde were mixed together and cooled to -20° C. to -25° C. Over 15 minutes at this temperature, 28 ml of potassium tert.-butylate in tetrahydrofuran at 0.9M/l were introduced and the mixture was allowed to warm up to ambient temperature. After 1 hour and 25 minutes, 25 ml of water were added, and extraction was effected with tetrahydrofuran. The organic phase was washed with water saturated with sodium chloride and then dried. The resulting solution containing 1,1-dimethylethyl 2-chloro-3-(2-pyridyl)oxirane carboxylate was held at -25° C. and used for the following step of the synthesis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:26][C:27]([NH:29][CH:30]([CH:37]([CH3:39])[CH3:38])[CH:31]([OH:36])[C:32]([F:35])([F:34])[F:33])=[O:28])[C:10](=[O:25])[C:11]([NH:14][C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[O:16])=[CH:12][N:13]=2)=[CH:4][CH:3]=1.CO>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:26][C:27]([NH:29][CH:30]([CH:37]([CH3:39])[CH3:38])[C:31](=[O:36])[C:32]([F:34])([F:35])[F:33])=[O:28])[C:10](=[O:25])[C:11]([NH:14][C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[O:16])=[CH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccc(F)cc2)ncc(NC(=O)OCc2ccncc2)c1=O)C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(C)C(NC(=O)Cn1c(-c2ccc(F)cc2)ncc(NC(=O)OCc2ccncc2)c1=O)C(=O)C(F)(F)F

Procedure:
2-[2-(4-Fluoropheny)-6-oxo-5-(4-pyridylmethoxycarbonylamino)-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide was subjected to a procedure similar to that described in Example 1. Chromatography, with methanol:dichloromethane (gradient, 5:95, 7:93) as the eluent, gave 2-[2-(4-fluorophenyl)-6-oxo-5-(4-pyridylmethoxycarbonylamino)-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide as a white solid; NMR (DMSO/D2O): 8.54 (d,2), 8.44 (s,1), 7.53 (m,2), 7.44 (d,2), 7.22 (t,2), 5.22 (s,2), 4.70 (d,1), 4.49 (d,1), 4.01, (d,1), 2.20 (m,1), 0.85 (d,3), 0.72 (d,3).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C:9]2=[O:21])=[CH:4][CH:3]=1.Br[C:23]1[C:24](=[O:30])[NH:25][N:26]=[C:27]([Cl:29])[CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Cl>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.CN(C=O)C.O1CCOCC1>[Cl:29][C:27]1[CH:28]=[C:23]([NH:1][C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][C:9]3=[O:21])=[CH:4][CH:3]=2)[C:24](=[O:30])[NH:25][N:26]=1
Reactant: O=c1[nH]nc(Cl)cc1Br
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)C(=O)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3cc(Cl)n[nH]c3=O)nc2)C(=O)C1
Temperature: 125 °C
Yield: 37.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 2d (558 mg, 1.91 mmol), 4-bromo-6-chloropyridazin-3(2H)-one (400 mg, 1.91 mmol), cesium carbonate (1.37 g, 4.20 mmol), dioxane (25 mL) and DMF (25 mL). After bubbling nitrogen through the resulting solution for 30 min, Xantphos (94 mg, 0.162 mmol) and tris(dibenzylidene acetone)dipalladium(0) (87 mg, 0.096 mmol) were added and the reaction mixture was heated at 125° C. for 18 h. Water (75 mL) was added after the reaction mixture was cooled to room temperature and the pH adjusted to 6.5 with 2N hydrochloric acid. The resulting precipitate was collected by vacuum filtration, absorbed on silica gel and purified by column chromatography to afford a 37% yield (300 mg) of 2f as a tan foam: 1H NMR (300 MHz, DMSO-d6) δ13.15 (s, 1H), 9.71 (s, 1H), 8.37 (4, 1H, J=2.7 Hz), 8.29 (s, 1H), 7.76 (dd, 1H, J=9.0, 2.7 Hz), 7.55 (d, 1H, J=9.0 Hz), 4.09 (s, 2H), 3.72 (m, 4H), 1.45 (s, 9H); MS (ESI+) m/z 420.1 (M+H).
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:16](COCC[Si](C)(C)C)[N:15]=[CH:14][C:13]=2[C:25]#[N:26])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C(OCC)C>[OH:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[C:13]([C:25]#[N:26])=[CH:14][NH:15][N:16]=2)=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(O)c1ccc(Nc2c(C#N)cnn2COCC[Si](C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOCC
Product: CC(C)(O)c1ccc(Nc2n[nH]cc2C#N)cc1
Temperature: 110 °C
Reaction time: 28 h
Yield: 46.8 %

Procedure:
5-(4-(2-Hydroxypropan-2-yl)phenylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile (480 mg, 1.13 mmol) was taken up in a solution of tetrabutylammonium fluoride (1M, 16.8 ml) and the flask was sealed. The mixture was placed in an oil bath heated to 110° C. and stirred for 28 hours. The mixture was cooled to ambient. Water (60 ml) and diethyl ether (60 ml) were added and the material was shaken in a reparatory funnel and the organic phase was collected. The aqueous phase was back extracted with diethyl ether (2×50 ml). The organic phase was combined, dried from magnesium sulfate, filtered and stripped. The crude remainder was purified through Analogix flash column chromatography using ethyl acetate in hexanes (30% to 90% gradient, 40 g silica gel) to provide 3-(4-(2-hydroxypropan-2-yl)phenylamino)-1H-pyrazol-4-carbonitrile as an off-white powder (128 mg, 47% yield). LC/MS calc'd for C13H14N4O (m/e) 242.28, obs'd 241 (M−H, ES−).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[NH:15][CH:16]=[CH:17][N:18]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.[CH:32](I)([CH3:34])[CH3:33]>>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:32]([CH3:34])[CH3:33])[CH:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: CC(C)I
Reactant: Brc1ccc2c(c1)OCCn1cc(-c3ncc[nH]3)nc1-2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)n1ccnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reaction time: 18 h

Procedure:
To a solution of 9-bromo-2-(1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.237 g, 0.716 mmol) and Cesium Carbonate (0.280 g, 0.859 mmol) in N,N-Dimethylformamide (4.74 mL, 61.2 mmol) was added Isopropyl iodide (0.0859 mL, 0.859 mmol). The reaction was stirred 18 h at 50 C. The reaction was quenched with water then extracted EtOAc 2×. The crude product was purified to give 9-bromo-2-(1-isopropyl-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine. MS: (ESI+)=373.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:32]([CH3:34])[CH3:33])=[C:11]([CH2:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([CH3:31])([CH3:30])[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=2)[OH:16])[N:12]=1.O.[OH-].[Li+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:32]([CH3:34])[CH3:33])=[C:11]([CH2:13][CH2:14][CH:15]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]([CH3:30])([CH3:31])[C:25]([OH:27])=[O:26])=[CH:21][CH:22]=2)[OH:16])[N:12]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(O)CCc2nc(-c3ccccc3Cl)oc2C(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1oc(-c2ccccc2Cl)nc1CCC(O)c1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.1 %

Procedure:
The resulting propionic acid derivative (80 mg, 0.16 mmol) was dissolved in a mixture of ethanol (2 mL) and water (1 mL). To the solution was then added lithium hydroxide monohydrate (10 mg). The mixture was stirred for 20 hours at room temperature, cooled with ice, neutralized by addition of diluted hydrochloric acid, and subjected to extraction using ethyl acetate. The organic layer was collected, washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The ethyl acetate was removed under reduced pressure, to give 55 mg of the desired compound as pale yellow oil residue (yield 73%).