Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:14][N:15]=[N+]=[N-])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C.O>[Pd].CCO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=2)[CH2:14][NH2:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@@H](CN=[N+]=[N-])Oc2ccc(C(F)(F)F)cc2)C1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H]([C@@H](CN)Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
(S)-3-[(S)-2-Azido-1-(4-trifluoromethylphenoxy)ethyl]pyrrolidine-1-carboxylic acid t-butyl ester (2.10 g, 5.24 mmol) was combined with 10% Pd/C, Degussa type, wet 50% (0.05:0.45:0.5, Palladium:carbon black:H2O, 1.1 g, 520 μmol) and EtOH (240 mL). The mixture was stirred under an atmosphere of hydrogen (1 atm) at room temperature for 1 hour. The catalyst was then removed by filtration through Celite (MeOH wash) and the filtrate was concentrated to yield the title compound (1.8 g).
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][NH:9][C:5]=2[C:4]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)=[N:3][CH:2]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>[Cl-].[Na+].O.CN(C)C=O>[N:20]1([C:14]([C:13]2[CH:12]=[C:11]([NH:10][C:4]3[C:5]4[NH:9][CH:8]=[CH:7][C:6]=4[N:1]=[CH:2][N:3]=3)[CH:19]=[CH:18][CH:17]=2)=[O:16])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)c1cccc(Nc2ncnc3cc[nH]c23)c1
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cccc(Nc2ncnc3cc[nH]c23)c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid (153 mg), piperidine (0.078 mL), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173 mg) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 hrs. Piperidine (0.078 mL) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173 mg) were added and the mixture was stirred for 1 hr. 1-Hydroxybenzotriazole (138 mg) was added, and the mixture was stirred for 3 days. Saturated brine was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→20:80). Diisopropyl ether was added and the precipitate was collected by filtration to give the title compound (78 mg) as a pale-brown powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([Br:17])=[C:15]([Br:18])[S:14][C:13]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=[O:23].OO.S(=O)(O)[O-].[Na+]>ClCCl.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([Br:17])=[C:15]([Br:18])[S:14](=[O:23])[C:13]=2[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Brc1sc2cc(OCc3ccccc3)ccc2c1Br
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=S1C(Br)=C(Br)c2ccc(OCc3ccccc3)cc21
Reaction time: 0.17 h
Yield: 62 %

Procedure:
Dissolve 6-benzyloxy-2,3-dibromo-benzo[b]thiophene (20 g, 50 mmol) in dichloromethane (88 mL) and add trifluoroacetic acid (88 mL). Stir for 10 minutes, then add 30% aqueous solution of hydrogen peroxide (5.1 mL, 50 mmol) and stir for 4 hours. Add solid sodium bisulfite (2.2 g, 21 mmol), dilute with water (30 mL), stir for 15 minutes, and then concentrate in vacuo. Partition residue between dichloromethane (150 mL) and saturated aqueous sodium bicarbonate (150 mL), separate layers, wash organic layer with additional saturated aqueous sodium bicarbonate (150 mL) and brine (100 mL). Dry with sodium sulfate, filter, and concentrate in vacuo. Chromatograph on a SiO2 column eluting with 100% dichloromethane to give 12.8 g of 6-benzyloxy-2,3-dibromo-benzo[b]thiophene 1-oxide (62%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](=[NH:7])[NH2:6].[F:11][C:12]([F:22])([F:21])[C:13](=O)[CH2:14][C:15](OCC)=[O:16].C[O-].[Na+].CO>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:6][C:15](=[O:16])[CH:14]=[C:13]([C:12]([F:22])([F:21])[F:11])[N:7]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: N=C(N)c1cccc(Cl)c1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: O=c1cc(C(F)(F)F)nc(-c2cccc(Cl)c2)[nH]1
Temperature: 0 °C
Yield: 51.8 %

Procedure:
A 500-mL round bottomed flask was charged with 3-chlorobenzimidamide (4.81 g, 25.3 mmol), ethyl 4,4,4-trifluoro-3-oxobutanoate (5.00 g, 27.1 mmol), and ethanol (90 mL) and cooled to 0° C. A 25% sodium methoxide solution in methanol (13.0 mL, 55.3 mmol) was added to the mixture. The resulting mixture was stirred at reflux for 20 h. After this time, the mixture was cooled to room temperature and concentrated under reduced pressure to 25 mL. The residual slurry was cautiously treated with 2N HCl (50 mL) forming a solid. The solid was collected by filtration and washed with water followed by ether to afford the title compound (3.60 g, 48%) as a white solid, which was carried forward into the next step without further purification. MW=274.63. 1H NMR (DMSO-d6, 500 MHz) δ 13.39 (s, 1H), 8.18 (s, 1H), 8.10 (d, J=7.5 Hz, 1H), 7.73-7.69 (m, 1H), 7.60 (t, J=8.0 Hz, 1H), 6.94 (s, 1H).
Reaction SMILES: CC1(C)C2C1CCC2=O.C(OCC)(=O)C(OCC)=O.CC(C)([O-])C.[K+].[CH2:26]([O:28][C:29](=[O:41])[C:30]([CH:32]1[CH2:37][CH:36]2[CH:34]([C:35]2([CH3:39])[CH3:38])[C:33]1=O)=O)[CH3:27].Cl.[NH2:43][NH2:44]>C(O)C.O>[CH2:26]([O:28][C:29]([C:30]1[NH:44][N:43]=[C:33]2[C:32]=1[CH2:37][CH:36]1[C:35]([CH3:39])([CH3:38])[CH:34]12)=[O:41])[CH3:27]
Reactant: NN
Reactant: CCOC(=O)C(=O)C1CC2C(C1=O)C2(C)C
Agent: CC(C)(C)[O-]
Agent: CC1(C)C2CCC(=O)C21
Agent: Cl
Solvent: O
Solvent: CCOC(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1[nH]nc2c1CC1C2C1(C)C
Temperature: 80 °C

Procedure:
(±)-6,6-Dimethyl-bicyclo[3.1.0]hexan-2-one (1.49 g, 12.0 mmol), diethyl oxalate (2.46 g, 16.8 mmol) and potassium t-butoxide (18.0 mL, 1M in THF, 18.0 mmol) were stirred in ethanol (40 mL) at room temperature for 2 hours. The desired (6,6-dimethyl-2-oxo-bicyclo[3.1.0]hex-3-yl)-oxo-acetic acid ethyl ester was observed by LCMS (m/z (ES+): 247 [M+Na]+, 225 [M+H]+) but not isolated. Hydrazine monohydrochloride (0.168 g, 24.4 mmol) in water (2.0 mL) was added and the solution heated to 80° C. for 18 hours. Solvent was removed under reduced pressure and the resulting oil poured into 0.1M aqueous hydrochloric acid (30 mL) and extracted into DCM (200 mL). Solvent was removed under reduced pressure and the residue purified by column chromatography (0–50% EtOAc/n-hexane, silica) to give (±)-1,1-dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester as a pale yellow oil which solidified upon standing. m/z (ES+): 243 [M+Na]+, 221 [M+H]+, 175 [M-OEt]+; 1H NMR (CD3OD): δ 4.4–4.3 (m, 2H, OCH2), 2.90 (dd, 1H, J1=17.5, J2=6.9), 2.65 (d, 1H, J=17.5), 2.1–2.0 (m, 1H), 1.95 (t, 1H, J=12.9), 1.37 (td, J1=7.1, J2=2.0), 1.13 (s, 3H, exo-CH3), 0.74 (d, 3H, J=2.0, endo-CH3).
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@H:12]([CH2:21][OH:22])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.COC1CC2CC[C@@H]3[C@@H](C=2CC=1)CC[C@@]1(C)[C@@H]3CC[C@H]1CO>>[OH:22][CH2:21][C@@H:12]1[CH2:11][CH2:10][C@@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@@H:18]1[C:5](=[CH:4][C:3](=[O:2])[CH2:20][CH2:19]1)[CH2:6][CH2:7]3
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](CO)CC[C@H]12
Agent: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C)[C@H](CO)CC[C@H]32)C1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@H]1CC[C@H]2CO

Procedure:
Birch reduction of the (14β,17α)-3-methoxyestra-1,3,5(10)-triene-17-methanol derivatives thus obtained [Caine, D. in Org. Reactions 23, p. 1, Wiley, New York, 1976] and hydrolysis of the resulting (14β,17α)-3-methoxyestra-2,5(10)-diene-17-methanol derivative then provides a (14β,17α)-17-(hydroxymethyl)estr-4-en-3-one derivative of the invention.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([NH:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][N:38]([C:41](=[O:47])[CH2:42][O:43]C(=O)C)[CH2:37][CH2:36]2)=[O:31])[C:25]=1[CH3:48])(=[O:12])=[O:11].C(=O)([O-])[O-].[K+].[K+]>O.CO>[OH:43][CH2:42][C:41]([N:38]1[CH2:39][CH2:40][N:35]([CH2:34][CH2:33][NH:32][C:30]([C:26]2[C:25]([CH3:48])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:31])[CH2:36][CH2:37]1)=[O:47]
Reactant: CC(=O)OCC(=O)N1CCN(CCNC(=O)c2c(C)[nH]c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)Cc5c(Cl)cccc5Cl)cc43)c2C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCN1CCN(C(=O)CO)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of acetic acid 2-{4-[2-({5-[5-(2,6-dichlorophenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl ester (from the above reaction) and 10% potassium carbonate (2.67 g) in water (20 mL) and methanol (10 mL) was stirred at 40° C. for overnight. The precipitate was collected by vacuum filtration, washed with methanol, water and dried to give 305 mg (45% for 4 steps) of the titled compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[C@@H:7]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][O:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH2:18][CH2:17]2)[CH2:6]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[C@@H:7]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][O:23][CH2:24][CH2:25][CH2:26][NH:27][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:18][CH2:17]2)[CH2:6]1
Reactant: NCCCOCC1CCN(C[C@H]2CN(Cc3ccc(Cl)cc3Cl)C[C@@H]2c2ccsc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)NCCCOCC1CCN(C[C@H]2CN(Cc3ccc(Cl)cc3Cl)C[C@@H]2c2ccsc2)CC1

Procedure:
A solution of 0.030 g (0.06 mmol) of 1-(2,4-dichlorobenzyl)-3-(S)-(4-(3-aminopropyloxymethyl)piperidinylmethyl)-4-(S)-(3-thienyl)pyrrolidine, 0.02 mL (0.24 mmol) of methanesulfonyl chloride, and 0.03 mL (0.15 mmol) of diisopropylethyl amine in 0.5 mL of CH2Cl2 was stirred at rt for 18 h. The reaction mixture was concentrated and the residue was purified by chromatography (silica, CH2Cl2:methanol, 95:5) to give the title compound. Mass Spectrum (ESI) m/e=574 (M+1 35Cl, 35Cl), 576 (M+1 35Cl, 37Cl), and 578 (M+1 37Cl, 37Cl). [a]D=+11.0 (c=0.815, CHCl3).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1N.Cl.N([O-])=[O:18].[Na+].F[B-](F)(F)F.[H+]>C(O)(=O)C.O>[O:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:2]([CH3:1])[C:3]=1[OH:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cccc(Oc2ccccc2)c1N
Reactant: O=N[O-]
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc(Oc2ccccc2)c1O
Yield: 38.7 %

Procedure:
A solution of 2-methyl-6-phenoxyaniline (19.3 g) in a mixture of conc. hydrochloric acid (17 ml) and water (60 ml), aqueous solution (10 ml) of sodium nitrite (6.7 g) and 42% fluoroboric acid (19 ml) were treated in a similar manner to that of Example 14-(1). The resultant diazonium salt was treated with acetic acid (400 ml) in a similar manner to that of Example 14-(1) to give oily 6-phenoxy-o-cresol (7.5 g).
Reaction SMILES: C(O)C.[NH2:4][C:5]([NH2:28])=[N:6][C:7]([C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:22]([O-])=O)[CH:17]=3)[N:12]([CH:25]([CH3:27])[CH3:26])[C:11]=2[CH:10]=1)=[O:8]>[C].[Pd].C1COCC1>[NH2:22][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:25]([CH3:27])[CH3:26])[C:11]1[CH:10]=[C:9]([C:7]([N:6]=[C:5]([NH2:4])[NH2:28])=[O:8])[CH:21]=[CH:20][C:19]2=1
Reactant: CC(C)n1c2ccc([N+](=O)[O-])cc2c2ccc(C(=O)N=C(N)N)cc21
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)n1c2ccc(N)cc2c2ccc(C(=O)N=C(N)N)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 132.5 %

Procedure:
A 20 mg portion of 10% palladium-carbon was added to an ethanol 5 ml-THF 3 ml solution of 106 mg N-(diaminomethylene)-9-isopropyl-6-nitro-9H-carbazole-2-carboxamide, followed by stirring at room temperature for 4 hours under an atmosphere of hydrogen gas. After carrying out Celite filtration, the solvent was evaporated to obtain 128 mg of 6-amino-N-(diaminomethylene)-9-isopropyl-9H-carbazole-2-carboxamide.
Reaction SMILES: N12CCN(CC1)CC2.[CH3:9][N:10]([CH3:15])[S:11](Cl)(=[O:13])=[O:12].[CH2:16]([O:18][C:19]([C:21]1[NH:22][N:23]=[C:24]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)=[O:20])[CH3:17]>CC#N.O>[CH2:16]([O:18][C:19]([C:21]1[N:22]([S:11](=[O:13])(=[O:12])[N:10]([CH3:15])[CH3:9])[N:23]=[C:24]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)=[O:20])[CH3:17]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cc(COc2ccccc2)nn1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
1,4-Diazabicylo[2.2.2]octane (1.0 g, 8.93 mmol) and dimethylsulfamoyl chloride (0.88 mL, 8.2 mmol) were sequentially added to a solution of 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (2.0 g, 8.12 mmol) in CH3CN (10 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was diluted with H2O and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents concentrated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 40/60). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-dimethylsulfamoyl-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (2.42 g, 84% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:21])([F:20])[C:13]1[N:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[N:8]=[C:7]2O.P(Br)(Br)(Br)=O.CCN(C(C)C)C(C)C.[CH3:37][C:38]1[NH:42][N:41]=[C:40]([NH2:43])[CH:39]=1>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:21])([F:20])[C:13]1[N:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[N:8]=[C:7]2[NH:43][C:40]1[CH:39]=[C:38]([CH3:37])[NH:42][N:41]=1
Reactant: Oc1nc(C(F)(F)c2ncc(F)cn2)nc2c(Cl)cccc12
Reactant: Cc1cc(N)n[nH]1
Agent: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(C(F)(F)c3ncc(F)cn3)nc3c(Cl)cccc23)n[nH]1
Temperature: 105 °C
Reaction time: 0.75 h
Yield: 30.3 %

Procedure:
To 8-chloro-2-(difluoro(5-fluoropyrimidin-2-yl)methyl)quinazolin-4-ol (200 mg, 0.61 mmol) were added phosphoryl tribromide (1.2 g) and toluene (2 mL) followed by DIEA (0.214 mL, 1.22 mmol). The mixture was heated at 105° C. for 45 min. The mixture was allowed to cool and was partitioned between EtOAc and saturated aq sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the crude residue was added a solution of 5-methyl-1H-pyrazol-3-amine (137 mg, 1.41 mmol) in DMF (4 mL) and the mixture was stirred at rt for 45 min. The crude mixture was purified by preparative HPLC (Varian diphenyl reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O) to afford 8-chloro-2-(difluoro(5-fluoropyrimidin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (75 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.18 (s, 3H) 5.91 (s, 1H) 7.63 (t, J=8.01 Hz, 1H) 8.07 (d, J=7.54 Hz, 1H) 8.67 (d, J=8.29 Hz, 1H) 9.14 (s, 2H) 10.91 (br s, 1H) 12.24 (br s, 1H); LC-MS (ESI) m/z 406 (M+H)+.
Reaction SMILES: C[N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]#[N:8].[B].[CH3:10][C:11]1([CH3:23])[O:21][C:19](=[O:20])[NH:18][C:17]2[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]1=2>>[CH3:10][C:11]1([CH3:23])[C:12]2[CH:13]=[C:14]([C:6]3[NH:2][C:3]([C:7]#[N:8])=[CH:4][CH:5]=3)[CH:15]=[CH:16][C:17]=2[NH:18][C:19](=[O:20])[O:21]1
Reactant: Cn1cccc1C#N
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Agent: [B]
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21

Procedure:
In still a further embodiment, 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile is prepared according to the present invention. This process includes reacting 1-methyl-pyrrole-2-carbonitrile and a boron agent; coupling the boronated carbonitrile with 6-bromo-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoazin-2-one (the Brofoxine™ reagent) to give 5-(4,4-dimethyl-2-oxo-1,4- dihydro -2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile. See, Scheme 8. Desirably, the boron agent is tri-isopropylborate. The boron agent is typically reacted with the carbonitrile in the presence of lithium di-isopropylamide (LDA) and tri-isopropylborate to give a boronate/borinate mixture which is not isolated. The coupling is typically performed in situ in the presence of a soluble palladium (0) catalyst to give 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile in an unpurified form.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:37][N:38]([CH3:43])[CH2:39][CH2:40][CH2:41]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:37][N:38]([CH3:43])[CH2:39][CH2:40][CH2:41][O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:4][CH:3]=1
Reactant: COC(=O)c1cccc(-c2ncc(O)cn2)c1
Reactant: CN(C)CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(-c2ncc(OCCCN(C)C)cn2)c1

Procedure:
A solution, kept under nitrogen, of 6.1 g (26.5 mmol) of methyl 3-(5-hydroxypyrimidin-2-yl)benzoate, 10.5 g (39.8 mmol) of triphenylphosphine and 4.76 ml (39.8 mmol) of 3-(dimethylamino)-1-propanol in 200 ml of THF is cooled in an ice bath, and 8.21 ml (39.8 mmol) of diisopropyl azodicarboxylate are subsequently slowly added dropwise with stirring. After stirring at room temperature for 2 hours, the reaction mixture is evaporated in vacuo. The residue is partitioned between dichloromethane and saturated aqueous potassium hydrogensulfate solution. The aqueous phase is separated off, adjusted to a pH of 12 using saturated aqueous sodium hydroxide solution and extracted twice with dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent:methyl 3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzoate as colourless crystals; m.p. 66° C.; ESI 316 (M+H); HPLC: 2.18 min (method B).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH2:19][C:18]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[O:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C1COCC1>CO>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[CH2:19][C:18]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[O:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cccc(OCc3ccccc3)c2)=NO1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cccc(O)c2)=NO1
Yield: 98.3 %

Procedure:
A mixture of di-tert-butyl 2,2′-(3-(3-(benzyloxy)phenyl)-4,5-dihydro-1,2-oxazole-5,5-diyl)diacetate (765 mg), a palladium carbon-ethylenediamine complex (38 mg), THF (10 mL), and methanol (10 mL) was stirred at room temperature for 30 hours under a hydrogen atmosphere. The catalyst was filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (611 mg).
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].Cl>C(O)C>[NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)NCC(=O)O
Reaction time: 1 h
Yield: 78.4 %

Procedure:
7.3 Grams of Boc-Val-Leu-Gly-OEt was dissolved in 50 ml of ethanol. Thereto was added 20 ml of 1N aqueous sodium hydroxide solution with ice-cooling, and the mixture was stirred for 1 hour. The reaction mixture was adjusted to pH 7 with 1N hydrochloric acid and concentrated under reduced pressure. The residue was washed with diethyl ether. The aqueous layer was adjusted to pH 2 with 1N hydrochloric acid with ice-cooling and extracted with three 60-ml portions of ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure to remove ethyl acetate. The residue was mixed with petroleum ether to crystallize the residue, whereby 5.33 g (yield: 78.4%) of the objective compound was obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].Cl.[CH3:10][NH:11][O:12][CH3:13].C(N(CC)CC)C.Cl>ClCCl.O>[CH3:13][O:12][N:11]([CH3:10])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:7]
Reactant: O=C(Cl)c1cccs1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
To a solution of thiophene-2-carbonyl chloride (100.6 mL, 940 mmol) and N,O-dimethylhydroxylamine hydrochloride (100.9 g, 1.03 mol) in dichloromethane (1 L) at 0° C. was added dropwise triethylamine (262 mL, 1.88 mol). After stirring at room temperature for 3 h, the reaction mixture was poured into a mixture of water (2 L) and concentrated aq. HCl (36%, 80 mL), the layers were separated and the aqueous layer extracted with dichloromethane (2×200 mL). The combined organic layers were washed with water (200 mL), then dried over MgSO4 and concentrated in vacuo to afford N-methoxy-N-methylthiophene-2-carboxamide [153.4 g, yield 95%; HPLC/MS: m/z=172 (M+H); log P(HCOOH)=1.44].