Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])/[CH:4]=[CH:5]/[C:6]1[C:14]2[C:10](=[C:11]3[N:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]5([NH:29]C(OC(C)(C)C)=O)[CH2:28][CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[C:16]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:15][N:12]3[N:13]=2)[CH:9]=[CH:8][CH:7]=1>Cl.O1CCOCC1>[CH3:1][O:2][C:3](=[O:43])/[CH:4]=[CH:5]/[C:6]1[C:14]2[C:10](=[C:11]3[N:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]5([NH2:29])[CH2:28][CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[C:16]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:15][N:12]3[N:13]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)/C=C/c1cccc2c1nn1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc21
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1cccc2c1nn1cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
275 mg of the crude (E)-3-{2-[4-(1-tert-Butoxycarbonylaminocyclobutyl)phenyl]-3-phenylpyrimido[1,2-b]indazol-7-yl}acrylic acid methyl ester were stirred in 15 mL 4M hydrogen chloride in dioxane for 18 hours at room temperature. The solvent was evaporated and the residue was stirred with saturated sodium bicarbonate for one hour at room temperature. After addition of dichloromethane stirring was continued for another hour. The organic phase was separated and the aqueous phase was extracted once more with dichloromethane. The combined organic extracts were washed with water and brine, dried and filtrated. The solvent was evaporated and the residue purified by HPLC 35.7 mg (15.7%) of the title compound.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].C[O:10][C:11]1[C:16]([CH2:17][NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:33]4[C:28](=[N:29][CH:30]=[N:31][C:32]=4[NH2:34])[N:27]([C@H:35]4[CH2:40][CH2:39][C@H:38]([N:41]5[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]5)[CH2:37][CH2:36]4)[N:26]=3)=[CH:21][CH:20]=2)=[CH:15][CH:14]=[CH:13][N:12]=1>Br.C(O)(=O)C>[C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[NH2:34][C:32]1[N:31]=[CH:30][N:29]=[C:28]2[N:27]([C@H:35]3[CH2:40][CH2:39][C@H:38]([N:41]4[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]4)[CH2:37][CH2:36]3)[N:26]=[C:25]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][CH2:17][C:16]4[C:11](=[O:10])[NH:12][CH:13]=[CH:14][CH:15]=4)=[CH:24][CH:23]=3)[C:33]=12
Reactant: COc1ncccc1CNc1ccc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)cc1
Agent: Br
Solvent: CC(=O)O
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(NCc5ccc[nH]c5=O)cc4)c4c(N)ncnc43)CC2)CC1

Procedure:
Trans-3-(4-[(2-methoxy-3-pyridyl)methyl]aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate (0.105 g, 0.000199 mol) was dissolved in 30% hydrogen bromide in acetic acid (4 mL) and the mixture was refluxed for 1.5 hours. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile—0.1M ammonium acetate over 25 min, 21 mL/min) to yield trans-3-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}anilino)methyl]-1,2-dihydro-2-pyridinone diacetate (0.0204 g, 0.0000324 mol) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][CH:4]=1)=O.[N:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[N+]=[N-].C[O-].[Na+].N(C(=CC1C=CC=CC=1)C([O-])=O)=[N+]=[N-]>CO.O.C1(C)C(C)=CC=CC=1>[CH3:23][O:22][C:20]([C:19]1[NH:16][C:15]2[C:3]([CH:1]=1)=[CH:4][CH:5]=[C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:14]=2)=[O:21]
Reactant: COC(=O)CN=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Agent: C[O-]
Agent: [N-]=[N+]=NC(=Cc1ccccc1)C(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)c1cc2ccc(C(=O)OC(C)(C)C)cc2[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A solution of t-butyl 4-formylbenzoate (8.52 g, 41 mmol) and methyl azidoacetate [M. S. Allen, L. K. Hamaker, A. J. La Loggia, J. M. Cook, Synth. Commun., 1992, 22, 2077-2102] (28.5 g, 248 mmol) in dry MeOH (200 mL) was added dropwise over 1 h to a solution of NaOMe (60 mL of a 3.3M solution in MeOH, 197 mmol) under nitrogen with cooling in an ice-salt bath. The yellow suspension was stirred for a further 1 h at 0° C., allowed to stand at 4° C. for 15 h, then diluted with water and the solid filtered off and dried in the dark. A solution of this crude azidocinnamate (8.76 g, 29 mmol) in dry xylene (400 mL) was added dropwise over 2 h to xylene (100 mL) at ref lux under nitrogen, the solution stirred at reflux for a further 1 h, then cooled and evaporated. Recrystallisation from MeOH gave t-butyl 2-(methoxycarbonyl)indole-6-carboxylate as a white solid (4.72 g, 42%), mp 189-190.5° C. 1H NMR [(CD3)2SO] δ12.26 (s, 1H, NH), 8.08 (s, 1H, H-3 or H-7), 7.73 (d, J=8.4 Hz, 1H, H-4), 7.61 (dd, J=8.4, 1.3 Hz, 1H, H-5), 7.21 (d, J=1.3 Hz, 1H, H-3 or H-7), 3.89 (s, 3H, CO2Me), 1.56 (s, 9H, CO2 tBu); 13C NMR δ165.5 (Co2 tBu), 161.4 (CO2Me), 136.5, 130.0, 129.9, 127.3 (C-2,6,8,9), 121.9, 120.3, 114.4, 107.5 (C-3,4,5,7), 80.4 (OCMe3), 52.1 (OCH3), 27.8 (tBu). Anal. (C15H17NO4) C,H,N.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[N:14]=[C:13]([CH3:15])[CH:12]=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[N:21]([O-])=O.[Na+]>O>[CH3:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([N:8]2[C:3]3=[N:4][CH:5]=[CH:6][CH:7]=[C:2]3[N:1]=[N:21]2)[N:14]=1
Reactant: O=N[O-]
Reactant: Cc1cccc(Nc2ncccc2N)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cccc(-n2nnc3cccnc32)n1

Procedure:
A mixture of 1.0 g. of the crude amine from Step B, 20 ml. of water and 3 ml. of concentrated sulfuric acid was stirred, cooled to 0°-5° C. and treated dropwise with a solution of 0.345 g. of sodium nitrite in 2 ml. of water. After an additional hour at 0°-5° C. and storage at room temperature over the weekend, the precipitate was collected and recrystallized from 6 ml. of ethanol to give 3-(2-methyl-6-pyridyl)-3H-1,2,3-triazolo[4,5-b]pyridine, m.p. 144°-145° C.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:19]([C:20](O)=[O:21])=[CH:18][C:12]2[NH:13][C:14](=[O:17])[CH2:15][O:16][C:11]=2[C:10]=1[F:23].ClC(OCC(C)C)=O>C1COCC1>[F:8][C:9]1[C:19]([CH2:20][OH:21])=[CH:18][C:12]2[NH:13][C:14](=[O:17])[CH2:15][O:16][C:11]=2[C:10]=1[F:23]
Reactant: O=C1COc2c(cc(C(=O)O)c(F)c2F)N1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1COc2c(cc(CO)c(F)c2F)N1
Reaction time: 2 h
Yield: 34 %

Procedure:
Triethylamine (2.4 mL, 17.3 mmol) was added to a suspension of 7,8-difluoro-4H-benzo[1,4]oxazine-3-one-6-carboxylic acid (3.6 g, 15.7 mmol) in anhydrous THF (250 mL). Isobutyl chloroformate (2.2 mL, 17.3 mmol) was added to the mixture at ice cold temperature over 0.5 hour. Stirring was continued for further 2 hours at room temperature. It was then cooled in ice and the solid was removed by filtration. The filtrate was added to a cold solution of sodium borohydride (3.2 g) in water. The mixture was stirred in cold for 1 hour before it was concentrated in vacuo to half and acidified with 2M hydrochloric acid. The resulting solid precipitate was collected by filtration and dried to give the title compound (1.15 g, 22%).
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[N:18]=1>C1(C)C=CC=CC=1.C(OCC)C>[Cl:23][C:19]1[N:18]=[C:17]([C:2]([CH3:4])([CH3:3])[C:1]#[N:5])[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)C#N
Reactant: Clc1cccc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C#N)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of isobutyronitrile (T) (830 mg, 12 mmol, 1 equiv.) in toluene (16 mL) at 0° C., a solution of KHMDS 0.5 M in toluene (26 mL, 13 mmol, 1.05 equiv.) was added. The resulting mixture was warmed to room temperature and stirred for 15 min. This mixture was then added to a solution of 2,6-dichloropyridine (S)(4.39 g, 29.7 mmol, 2.5 equiv.) in toluene (10 mL) and the resulting solution was stirred at room temperature for 1 h. The reaction was quenched with a saturated solution of NH4Cl, followed by aqueous NaHCO3. The crude reaction was diluted in diethyl ether, washed with brine, dried over anhydrous Na2SO4 and the solvent was then removed under reduced pressure. The resulting material was purified by flash chromatography on silica gel, eluting with mixtures of dichloromethane/hexanes (2:1). The title compound U was isolated as a white solid (1.1 g, 51%). 1-(6-chloropyridin-2-yl)cyclopropanecarbonitrile (V), 1-(6-chloropyridin-2-yl)cyclopentanecarbonitrile (W), 1-(6-chloropyridin-2-yl)cyclohexanecarbonitrile (X), and ethyl 2-(6-chloropyridin-2-yl)-2-methylpropanoate (Y) were made following the procedure for 2-(6-chloropyridin-2-yl)-2-methylpropanenitrile (U).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[C:9]([O:18]CC)(=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[O-]CC.[Na+]>C(O)C>[CH2:15]([O:14][C:12](/[C:11](=[CH:7]/[C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)/[CH2:10][C:9]([OH:18])=[O:17])=[O:13])[CH3:16]
Reactant: Cc1ccc(C=O)o1
Reactant: CCOC(=O)CCC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)/C(=C/c1ccc(C)o1)CC(=O)O
Temperature: 25 °C
Yield: 5.4 %

Procedure:
To a vigorously stirred solution of 5-methyl-2-furaldehyde (264 mL, 2650 mmol) and diethyl succinate (840 mL, 5050 mmol) in ethanol (1.820 L) at room temperature was added sodium ethoxide (0.93 L of a 21 weight % solution in ethanol) in one portion. The reaction mixture was then heated at reflux for 13 hours. After cooling to room temperature, the mixture was concentrated in vacuo (all batches were combined at this point). The resulting residue was partitioned between ethyl acetate (1 L) and hydrochloric acid (1 L of a 2M aqueous solution). After separation, the aqueous layer was extracted with ethyl acetate (2×1 L). The combined organic extracts were then extracted with sodium hydrogen carbonate (2×1 L of a saturated aqueous solution). These aqueous extracts were combined and adjusted to pH 2 with hydrochloric acid (2M aqueous solution) then extracted with ethyl acetate (2×1 L). These organic extracts were combined and concentrated in vacuo to give desired (E)-3-(ethoxycarbonyl)-4-(5-methylfuran-2-yl)but-3-enoic acid (I-1a: 34.34 g, 5%). The original organic extract was extracted with sodium hydroxide (2 L of a 2M aqueous solution). This aqueous extract was adjusted to pH 2 with hydrochloric acid (2M aqueous solution) then extracted with ethyl acetate (2×1 L). These organic extracts were combined and concentrated in vacuo to give additional desired materials (395.2 gram, 63%) as red liquid. 1H NMR (CDCl3, 300 MHz) δ ppm 7.48 (s, 1H), 6.57 (d, 1H), 6.09 (d, 1H), 4.24 (q, 2H), 3.87 (s, 2H), 2.32 (s, 3H), 1.31 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3](B(O)O)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[C:20]1[CH:21]=[C:22]([CH:25]=[O:26])[S:23][CH:24]=1>>[CH3:1][C:2]1[C:3]([C:20]2[CH:21]=[C:22]([CH:25]=[O:26])[S:23][CH:24]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Reactant: O=Cc1cc(Br)cs1
Product: Cc1cc2c(cc1-c1csc(C=O)c1)C(C)(C)CCC2(C)C

Procedure:
In a similar manner to Example 3(b), by reaction of 4.2 g (17 mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylboronic acid with 2.17 g (11.3 mmol) of 4-bromo-2-thiophenecarboxaldehyde, 2.75 g (78%) of the expected aldehyde are obtained, with a melting point of 144-6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([NH:22][O:23]C(=O)NC2C=CC=CC=2)[CH2:10][N:9]=1.[Cl:33][C:34]1[CH:35]=[C:36]([N:41]=[C:42]=[O:43])[CH:37]=[CH:38][C:39]=1[Cl:40]>C(O)C>[Cl:33][C:34]1[CH:35]=[C:36]([NH:41][C:42]([O:23][NH:22][C:11]2[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]3[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=3[N:12]=2)=[O:43])[CH:37]=[CH:38][C:39]=1[Cl:40]
Reactant: O=C(Nc1ccccc1)ONC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2Cl)=NC1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: O=C(Nc1ccc(Cl)c(Cl)c1)ONC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2Cl)=NC1

Procedure:
1 g of 5-(2-chlorophenyl)-2-hydroxyamino-7-nitro-3H-1,4-benzodiazepine of Example 18 is reacted with 0.56 g of 3,4-dichlorophenyl isocyanate and worked up as in Example 18. Yield: 1.1 g, melting point: 190° to 192° C. decomposition (from ethanol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[CH:4][N:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:9]=[CH:10][C:5]2=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ncc2cn[nH]c2n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Clc1ncc2cnn(-c3ccccc3)c2n1
Temperature: 80 °C
Yield: 92 %

Procedure:
A suspension of 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (100 mg, 0.65 mmol), benzene boronic acid (1.5 eq), copper acetate (2 eq) and pyridine (2 eq) in dichloromethane (2 mL) was heated in the microwave at 80° C. for 15 min. After cooling to rt, the mixture was filtered and the resulting filtrate concentrated to give 6-chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine as a green oil (138 mg, 92%) which was used without further purification in the next step.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][N:13]([C@@H:16]2[S:22][C@H:21]([CH:23]([C:25]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[OH:24])[C@@H:19]([OH:20])[C@H:17]2[OH:18])[C:12](=[O:48])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:49][C:50]([Si:53](Cl)([CH3:55])[CH3:54])([CH3:52])[CH3:51]>C1COCC1.C(OCC)(=O)C.[N+]([O-])([O-])=O.[Ag+]>[C:1]([NH:9][C:10]1[CH:15]=[CH:14][N:13]([C@@H:16]2[S:22][C@H:21]([CH:23]([C:25]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)[OH:24])[C@@H:19]([OH:20])[C@@:17]2([Si:53]([C:50]([CH3:52])([CH3:51])[CH3:49])([CH3:55])[CH3:54])[OH:18])[C:12](=[O:48])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C(c2ccccc2)(c2ccc(OC)cc2)C(O)[C@H]2S[C@@H](n3ccc(NC(=O)c4ccccc4)nc3=O)[C@H](O)[C@@H]2O)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(c2ccccc2)(c2ccc(OC)cc2)C(O)[C@H]2S[C@@H](n3ccc(NC(=O)c4ccccc4)nc3=O)[C@@](O)([Si](C)(C)C(C)(C)C)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
Compound 21 (200 mg, 0.3 mmol), silver nitrate (100 mg, 0.6 mmol), and TBDMS-Cl (70 mg, 0.45 mmol) were dissolved in dry THF and stirred at room temperature overnight. The reaction was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (30% ethyl acetate in hexanes) to give Compound 23 (100 mg) in 45% yield. The 3-protected analog (N-benzoyl-1-[5-(4,4′-dimethoxytrityl)-3-(t-butyldimethylsilyl)-4-thio-β-D-ribofuranosyl]cytosine) was also isolated as a minor product.
Reaction SMILES: [CH3:1][C:2]([C:17]#[N:18])([CH3:16])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([C:14]#[N:15])([CH3:13])[CH3:12])[CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:12][C:11]([CH3:13])([CH2:14][NH2:15])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][C:2]([CH3:1])([CH3:16])[CH2:17][NH2:18])[CH:5]=1
Reactant: CC(C)(C#N)Cc1cccc(CC(C)(C)C#N)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(CN)Cc1cccc(CC(C)(C)CN)c1
Temperature: 25 °C
Yield: 45.3 %

Procedure:
In a 1-liter flask, equipped with a paddle stirrer, a reflux condenser, capped with a nitrogen bubbler, and an addition funnel, was placed 7.50 g of 1,3-bis(2-methyl-2-cyanopropyl)benzene and 250 ml of reagent grade toluene which had been passed through acid alumina under nitrogen directly into the reaction vessel. With stirring at room temperature, 107 ml of a 25% solution of diisobutylaluminum hydride in toluene was added in 1 hr. The mixture was refluxed for 17 hrs 15 min. The mixture was then worked up as described in Example 9(a). Upon distillation of the isolated product through a small Vigreux still, there was obtained 3.51 g of 1,3-bis(2,2-dimethyl-3-aminopropyl)benzene as a colorless liquid distilling at 105°-110°/0.05 mm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:31])=[C:8]2[C:16](Br)=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C([O-])=O.[NH4+]>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:31])=[C:8]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:14]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(-c1ccc(F)cc1)n2-c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CCOC(=O)c1nc(C#N)c2c(cc(-c3ccc(F)cc3)n2-c2ccccc2)c1O

Procedure:
Prepared in analogy to that of Example 6(a) from 3-bromo-7-cyano-2-(4-fluoro-phenyl)-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, ammonium formate and Pd/C. The title compound, ESI MS (m/z): 402 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:21])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Cl)(Cl)(Cl)=O.[CH3:27][C:28]1[NH:32][N:31]=[C:30]([NH2:33])[CH:29]=1.CCN(C(C)C)C(C)C.[I-].[K+]>CN(C=O)C.C(O)(=O)C>[F:1][C:2]([F:21])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[C:3]1[N:12]=[C:11]([NH:33][C:30]2[CH:29]=[C:28]([CH3:27])[NH:32][N:31]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Oc1nc(C(F)(F)c2ccc(F)cn2)nc2ccccc12
Reactant: Cc1cc(N)n[nH]1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3ccccc23)n[nH]1
Temperature: 90 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-ol (200 mg, 0.68 mmol) was added phosphorous oxychloride (4 mL) and the mixture was heated at 90° C. for 1 h. The mixture was concentrated and toluene (4 mL) was added and evaporated. This crude material was partitioned between EtOAc and a saturated sodium bicarbonate solution and the organic layer was dried over sodium sulfate and concentrated to afford a yellow solid. To this solid was added a solution of 5-methyl-1H-pyrazol-3-amine (100 mg, 1.03 mmol), DIEA (0.18 mL, 1.54 mmol), and potassium iodide (113 mg, 1.03 mmol) in DMF (4 mL) and the mixture was stirred at rt overnight. Acetic acid (0.2 mL) was added and the 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 2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (88 mg, 35%). 1H NMR (300 MHz, DMSO-d6) δ 2.18 (s, 3H), 5.99 (s, 1H), 7.65 (t, 1H), 7.83-7.94 (m, 2H), 7.97-8.07 (m, 2H), 8.58-8.78 (m, 2H), 10.70 (s, 1H), 12.18 (bs, 1H); LC-MS (ESI) m/z 371 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH:11]3[CH2:13][CH2:14][CH:8]([CH2:9][CH2:10]3)[C:7]=2[C:6]([OH:15])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24].C(OC1C=CC(OC)=C2C=1C1CCC2CC1)C=C.C(OCC=C)C=C.C1(C)C=C(C)C=C(C)C=1>>[CH2:24]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]2[CH:11]3[CH2:13][CH2:14][CH:8]([CH2:9][CH2:10]3)[C:7]=2[C:6]=1[OH:15])[CH:23]=[CH2:22]
Reactant: COc1ccc(O)c2c1C1CCC2CC1
Reactant: C=CCBr
Agent: C=CCOCC=C
Agent: C=CCOc1ccc(OC)c2c1C1CCC2CC1
Agent: O=C([O-])[O-]
Solvent: Cc1cc(C)cc(C)c1
Product: C=CCc1cc(OC)c2c(c1O)C1CCC2CC1

Procedure:
Treatment of 8-methoxy-1,2,3,4-tetrahydro-1,4-ethanonaphthalen-5-ol (11.30 g, 0.055 mol) with potassium carbonate (22.94 g, 0.166 mol) and allyl bromide (7.36 g, 0.061 mol) generally according to the procedure described for Intermediate 1 afforded 5-(allyloxy)-8-methoxy-1,2,3,4-tetrahydro-1,4-ethanonaphthalene. Treatment of the allyl ether in refluxing mesitylene generally according to the procedure described for Intermediate 1 gave 6-allyl-8-methoxy-1,2,3,4-tetrahydro-1,4-ethanonaphthalen-5-ol. Treatment of the phenyl with potassium carbonate (20.04 g, 0.145 mol), benzyl bromide (9.09 g, 0.053 mol), and tetrabutylammonium iodide (1.79 g, 0.005 mol) generally according to the procedure described for Intermediate 1 provided 15.05 g (82%) of 6-allyl-5-(benzyloxy)-8-methoxy-1,2,3,4-tetrahydro-1,4-ethanonaphthalene as a colorless oil. Anal. calcd. for C23H26O2.0.1H2O: C, 82.16; H, 7.85. Found: C, 81.98; H, 7.71.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH:23]4[CH2:28][O:27][CH2:26][CH2:25][N:24]4[C:29]([O-])=O)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.C(OCC)C>CO.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH:28]4[O:27][CH2:26][CH2:25][NH:24][CH2:29]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OC1COCCN1C(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CO
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCC1CNCCO1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
To a suspension of 1,1-dimethylethyl 2-({[4-[(3,4-dichlorophenyl)amino]-6-(methoxy)quinazolin-7-yl]oxy}morpholine-4-carboxylate (4.77 g, 8.91 mmol) in methanol (50 mL) was added a 4M solution of HCl in 1,4-dioxane (50 mL), and the reaction mixture was refluxed for 5 min. After cooling to room temperature, diethyl ether (100 mL) was added and the precipitate was filtered and dried. The solid was dissolved in methanol (200 mL) and treated with Bio-Rad 1-X8 resin hydroxide form until pH 8. Filtration and concentration in vacuo provided 3.32 g (86%) of N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(morpholin-2-ylmethyl)oxy]quinazolin-4-amine as a brown solid. 1H NMR (400 MHz, d4-MeOH): 8.47 (s, 1H), 8.14 (d, 1H), 7.73 (m, 2H), 7.49 (d, 1H), 7.15 (s, 1H), 4.24-4.13 (m, 2H), 4.09-3.97 (m, 5H), 3.76 (m, 1H), 3.22 (dd, 1H), 3.02-2.90 (m, 3H); MS (EI) for C20H20N4O3Cl2: 435 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:17][NH:18][C:19](=[O:24])[CH2:20][CH2:21][CH2:22][Cl:23])[C:13](OC)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[Cl:23][CH2:22][CH2:21][CH2:20][C:19]([NH:18][CH2:17][C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][OH:14])=[O:24]
Reactant: COC(=O)[C@@H](CNC(=O)CCCCl)NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(CCCCl)NC[C@H](CO)NC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of (R)-methyl 2-(benzyloxycarbonylamino)-3-(4-chlorobutanamido)propanoate (5.0 g, 14 mmol) in 100 mL of anhydrous MeOH was added NaBH4 (12.9 g, 0.33 mol) and the mixture was stirred at it overnight. The pH of the reaction mixture was adjusted to 8-9 using NaHCO3, the mixture was evaporated to near dryness, followed by extraction with EtOAc. The organic layer was washed with water, dried over Na2SO4, filtered and concentrated to give (R)-benzyl 1-(4-chlorobutanamido)-3-hydroxypropan-2-ylcarbamate (3.9 g, yield 85%) that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 7.37-7.30 (m, 5H) 5.13 (d, 2H), 3.77 (m, 1H), 3.57 (m, 4H), 2.32 (t, 2H), 2.08 (t, 2H).