Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[N:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[C:25]=[O:26].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:27]([NH:24][C:25]([NH:23][C:22]1[CH:21]=[N:20][N:17]2[CH:18]=[CH:19][C:14]([N:10]3[CH2:11][CH2:12][CH2:13][C@@H:9]3[C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])=[N:15][C:16]=12)=[O:26])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)N=C=O
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)NC(=O)Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reaction time: 4 h
Yield: 82.5 %

Procedure:
To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol) was added 2-isocyanato-2-methylpropane (9.4 mg, 0.095 mmol) at ambient temperature drop-wise, followed by addition of DIEA (0.028 mL, 0.16 mmol). The reaction was stirred for 4 hours then concentrated, and the residue was directly purified by reverse-phase column chromatography, eluting with 5 to 65% acetonitrile/water to yield the final product as a pale-yellowish solid (27 mg, 82% yield). MS (apci) m/z=415.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:24]([NH2:26])=O)[N:6]2[CH2:21][O:22][CH3:23].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:24](=[S:36])[NH2:26])[N:6]2[CH2:21][O:22][CH3:23]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COCn1c(C(N)=O)cc2c(F)ccc(N(C)S(=O)(=O)c3cccs3)c21
Solvent: C1CCOC1
Product: COCn1c(C(N)=S)cc2c(F)ccc(N(C)S(=O)(=O)c3cccs3)c21
Temperature: 60 °C
Reaction time: 3 h
Yield: 58.6 %

Procedure:
A mixture of 4-fluoro-1-(methoxymethyl)-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (0.41 g), Lawesson's reagent (0.50 g) and tetrahydrofuran (40 mL) was stirred at 60° C. for 3 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=2:8-4:6) to give the title compound (0.25 g, yield 59%) as pale-yellow crystals.
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6]1[CH:13]=[N:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9].[F-].C([N+](CCCC)(CCC)CCCC)CCC>C1COCC1>[OH:5][C:6]1[CH:13]=[N:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: C[Si](C)(C)CCOc1cnccc1C#N
Agent: CCCC[N+](CCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1ccncc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
A flask was charged with 3-(2-(trimethylsilyl)ethoxy)isonicotinonitrile (1.30 g, 5.90 mmol), THF (5 mL) and N,N-dibutyl-N-propylbutan-1-aminium fluoride (11.8 ml, 11.8 mmol) in THF was added. The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated. The crude product was purified by silica gel chromatography, eluting with DCM and 5% methanol in DCM to give the desired product (0.7 g, 99% yield) as dark brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[CH2:21]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14][CH2:5][C:4]1[CH:9]=[CH:10][CH:11]=[CH:2][CH:3]=1)=[O:13])[CH:6]=[CH:5]2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc2cc(O)ccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1ccc2cc(OCc3ccccc3)ccc2n1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a solution of 6-hydroxyquinoline-2-carboxylic acid (2.00 g) in N,N-dimethylformamide (20.0 mL) were added potassium carbonate (3.07 g) and benzyl bromide (3.02 mL), followed by stirring at 50° C. for 6 hours. The reaction mixture was left to be cooled, 1 M hydrochloric acid, ethyl acetate, and tetrahydrofuran were added thereto, and the organic layer was extracted. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by hexane-ethyl acetate to obtain benzyl 6-(benzyloxy)quinoline-2-carboxylate (1.80 g).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Br[C:6]1[N:10]([C@H:11]2[O:23][C@@H:22]([CH2:24][O:25]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@@H:12]2[O:13]C(=O)C)[C:9]2[CH:29]=[C:30]([Cl:34])[C:31]([Cl:33])=[CH:32][C:8]=2[N:7]=1.C(O)C.CCOCC>CN(C=O)C.C(OCC)(=O)C>[Cl:33][C:31]1[C:30]([Cl:34])=[CH:29][C:9]2[N:10]([C@H:11]3[O:23][C@@H:22]([CH2:24][OH:25])[C@H:17]([OH:18])[C@@H:12]3[OH:13])[C:6]([NH:4][CH2:3][CH2:1][OH:2])=[N:7][C:8]=2[CH:32]=1
Reactant: CC(=O)OC[C@@H]1O[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: NCCO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: OCCNc1nc2cc(Cl)c(Cl)cc2n1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Ethanolamine (25 ml) and 2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (0.62 g, 1.2 mmol) were combined with absolute ethanol (50 mL) and stirred at 80° C. for 24 h. The reaction mixture was concentrated and purified on a silica gel column (2.5 cm×16 cm, 230-400 mesh) with 1:20 methanol:dichloromethane (500 mL), then 1:9 methanol:dichloromethane. Crude product was obtained which was ether purified on a silica gel filter pad with 1:1 acetone: dichloromethane and then with 1:2 ethanol:dichloromethane. Further purification on a chromatotron fitted with a 2 mm rotor, using 1:6 ethanol:ethyl acetate provided pure product (0.064 g, 0.17 mmol, 14%); [a]20D=(−) 14.2 (c=0.5 DMF).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[CH3:22][N:23]([CH3:29])[CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1>C1COCC1>[CH3:22][N:23]([CH3:29])[CH:24]1[CH2:28][CH2:27][N:26]([C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:25]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-nitrobenzoyl chloride (1.8 g, 10 mmol) and diisopropylethylamine (2.8 mL, 20 mmol) in THF at room temperature is added 3-(dimethylamino)pyrrolidine (1.4 mL, 11 mmol). The reaction is stirred for 2 hours at room temperature and concentrated in vacuo to give 3-dimethylamino-1-(4-nitrobenzoyl)pyrrolidine, identified by HPLC and MS [264.3 m/e (M+H)] analyses.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl>[OH:1][CH2:2][CH:3]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([NH:49][CH2:50][C:51]2[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=2[CH3:57])=[O:17])=[CH:18][CH:19]=1)[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: O=C(O)c1ccc(C(CO)Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(CO)Oc3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19.8 %

Procedure:
The 4-(2-hydroxy-1-phenoxyethyl)benzoic acid (100 mg, 0.3870 mmol), was dissolved into dichloromethane (20 mL), and then N-hydroxybenzotriazole (0.5814 mmol, 80 mg), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.5814 mmol, 112 mg), triethylamine (1.69 mmol, 2 mL) was added to the mixture. After the mixture was stirred at room temperature for 10 minutes, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.387 mol, 58 mg) was added. The mixture was stirred at room temperature for 18 hours. Then washed with water (20 mL), extracted with dichloromethane (20 mL). The organic layer were concentrated and subjected to column chromatography (silica gel, dichloromethane/menthol=15:1) to give 4-(2-hydroxy-1-phenoxyethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (30 mg, 15%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:53])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([O:43][Si](C(C)(C)C)(C)C)[C:39]([CH3:42])([CH3:41])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:21][C:20]=2[CH3:52])=[CH:15][CH:14]=1)[OH:12]>ClCCl>[CH3:8][O:9][C:10](=[O:53])[CH:11]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH2:26][CH3:27])([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([OH:43])[C:39]([CH3:41])([CH3:42])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)[CH2:28][CH3:29])=[CH:21][C:20]=2[CH3:52])=[CH:17][CH:18]=1)[OH:12]
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C(O)C(=O)OC)cc2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C(O)C(=O)OC)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
Trifluoroacetic acid (0.18 mL) was added to a solution of [4′-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2′-methyl-biphenyl-4-yl]-hydroxy-acetic acid methyl ester (Example 155-(1); 24.4 mg, 0.0378 mmol) in dichloromethane (0.90 mL) at room temperature, and the mixture was stirred at room temperature for one hour. The solvent in the reaction solution was distilled off under reduced pressure, and the residue was diluted with diethyl ether. The mixture was adjusted to pH 7 to 8 with aqueous sodium bicarbonate solution, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (17.5 mg, 87%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[CH3:23][O:24][C:25]1[C:26]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O.[O-]CC.[Na+]>C(O)C>[CH3:23][O:24][C:25]1[C:26]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[C:27](/[CH:28]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:22][CH:21]=[CH:20][N:5]3[C:6](=[O:19])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][CH:9]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: COCCOc1c(C=O)cccc1OC
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COCCOc1c(/C=C/c2nc3sccn3c(=O)c2-c2ccc(OC(F)(F)F)cc2)cccc1OC
Yield: 51.5 %

Procedure:
The title compound was synthesized by condensation of Intermediate 15 (350 mg, 1.072 mmol) with 3-methoxy-2-(2-methoxyethoxy)benzaldehyde (316 mg, 1.501 mmol) in presence of sodium ethoxide (146 mg, 2.147 mmol) in ethanol (15 ml) according to the procedure of Example 24 to give 286 mg of the desired product as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 3.33-3.40 (m, 3H), 3.45-3.51 (m, 2H), 3.78 (s, 3H), 3.95-4.03 (m, 2H), 6.82 (d, J=15.6 Hz, 1H), 6.85-6.91 (m, 1H), 7.00 (d, J=4.2 Hz, 2H), 7.45-7.52 (m, 5H), 8.00 (d, J=4.8 Hz, 1H), 8.19 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 518.19 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][C:25]2[CH:27]=[CH:28][C:22]([F:21])=[CH:23][C:24]=2[C:29]([F:32])([F:30])[F:31])=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: Nc1ccc(F)cc1C(F)(F)F
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(Nc1ccc(F)cc1C(F)(F)F)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 4-fluoro-2-trifluoromethyl-aniline (69 mg, 0.39 mmol). The title compound was obtained as a solid (60 mg, 36% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.55 (1H, s), 8.99 (2H, m), 8.64 (1H, s), 7.73 (1H, m), 7.64 (1H, m), 7.58 (1H, m). MS m/z: 510.02, 512.00 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19]Br)[NH:12][C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[N:10]1.[CH:26]12[NH:37][CH:30]([CH:31]([CH2:33][C:34]([OH:36])=[O:35])[CH2:32]1)[CH2:29][O:28][CH2:27]2>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][N:37]2[C@H:30]3[C@H:31]([CH2:33][C:34]([OH:36])=[O:35])[CH2:32][C@@H:26]2[CH2:27][O:28][CH2:29]3)[NH:12][C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[N:10]1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Br
Reactant: O=C(O)CC1CC2COCC1N2
Product: COC(=O)C1=C(CN2[C@H]3COC[C@@H]2[C@H](CC(=O)O)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Br
Yield: 24.2 %

Procedure:
The title compound was prepared in analogy to compound 1a in Example 1 starting from methyl (4R)-4-(2-bromo-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 53a (73 mg, 0.15 mmol) and 2-(3-oxa-8-azabicyclo[3.2.1]octan-6-yl)acetic acid (121 mg, 0.7 mmol) 64c. 21 mg of the title compound was isolated by preparative HPLC as a yellow powder (yield was 16%).
Reaction SMILES: [CH:1]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[N:9][N+:10]([O-:12])=[O:11])=[CH:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][N:25]=1>O>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:6]2[CH2:7][CH2:8][N:4]([CH:1]=[CH:2][CH3:3])[C:5]2=[N:9][N+:10]([O-:12])=[O:11])=[CH:26][N:25]=1
Reactant: CC=CN1CCNC1=N[N+](=O)[O-]
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC=CN1CCN(Cc2ccc(Cl)nc2)C1=N[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture comprising 6.0 g of 1-(1-propenyl)-2nitroiminoimidazolidine, 7.0 g of potassium carbonate, 70 ml of DMSO and 7.4 g of 2-chloro-5-chloromethylpyridine was stirred at 60° C. for one hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried (with anhydrous MgSO4) and concentrated to give an oily residue. This was purified by column chromatography (silica gel, eluent: ethyl acetate/hexane=2/1) to give 8.6 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino -3- (1propenyl)imidazolidine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[N:12][O:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[N:12][O:13][CH:14]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2conn2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2conn2)cc1
Temperature: 75 °C

Procedure:
A mixture of 4-nitrophenyloxadiazole (2.87 g, 0.015 mol, prepared according to Lin et al., J. Org. Chem., 1979, 44, 4160) and SnCl2.2H2O (16.92 g, 0.075 mol) in 75 mL of ethyl acetate was heated at 75° C. for 30 minutes. The yellow reaction mixture was cooled to room temperature, poured into ice-water and the pH was made slightly basic (pH 7-8) by the addition of 5% NaHCO3. The reaction mixture was then extracted with ethyl acetate, dried over MgSO4 and concentrated in vacuo. The remaining yellow solid was triturated with hexane, collected and dried to yield 2.07 g of the title A compound, m.p. 97°-99° C. TLC, silica gel, EtOAc/hexanes (2:1), Rf =0.55; M.S. (M+H)+ at 162, M.W. 161. This compound was used without further purification.
Reaction SMILES: C([Li])CCC.[C:6]1([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.CN(C)[CH:23]=[O:24]>CCCCCC.CCOCC>[N:16]1([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:15]=2[C:14]([CH:23]=[O:24])=[CH:13][CH:12]=[CH:11]3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN(C)C=O
Reactant: c1ccc2c(N3CCCC3)cccc2c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=Cc1cccc2cccc(N3CCCC3)c12
Temperature: -20 °C

Procedure:
n-Butyllithium (14.7 ml of a 1.7 M solution in hexane) was added dropwise to a stirred solution of 1-(1-naphthyl)pyrrolidine (25.00 mmol, 5.00 g) in dry ether (50 ml) at −20° C. under argon. After 48 hours a solution of dry N,N-dimethylformamide (6.2 ml, 75.00 mmol) in ether (10 ml) was added dropwise at −78° C. to the reaction mixture. The mixture was allowed to warm to −20° C. over 4 hours, then quenched with a solution of methanol (15 ml) and allowed to warm to room temperature. The reaction mixture was diluted with ether (100 ml), washed with water (3×150 ml) and with brine (150 ml), dried over MgSO4 and evaporated under reduced pressure. The residue was purified by column chromatography using dichloromethane as eluent to afford the aldehyde which was crystallized from hexane.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:21])[CH2:4][C:5](=[O:20])[CH2:6][C:7]([O:9][C:10]([CH3:19])([CH3:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8].ClCC(O)CC(=O)CC(OC(C)(C)CC1C=CC=CC=1)=O>>[Br:1][CH2:2][C@@H:3]([OH:21])[CH2:4][C@@H:5]([OH:20])[CH2:6][C:7]([O:9][C:10]([CH3:18])([CH3:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8]
Reactant: CC(C)(Cc1ccccc1)OC(=O)CC(=O)CC(O)CBr
Agent: CC(C)(Cc1ccccc1)OC(=O)CC(=O)CC(O)CCl
Product: CC(C)(Cc1ccccc1)OC(=O)C[C@H](O)C[C@H](O)CBr

Procedure:
The procedure was carried out in the same manner as in Example 3, except that the crude compound (2-methyl-1-phenylpropan-2-yl 6-bromo-5-hydroxy-3-oxohexanoate (7b, 80.0 g) prepared in Example 2 was used in place of (2-methyl-1-phenylpropan-2-yl 6-chloro-5-hydroxy-3-oxohexanoate (7a, 80.0 g). The crude title compound was obtained (12.0 g). A portion of the crude compound was purified by silica gel column (ethyl acetate:n-hexane=3:7(v/v)) to obtain the following NMR data.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([N:15]([CH2:25][CH:26]=[CH2:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH:13]=[CH2:14].N1C=CC=CC=1.O>C(Cl)(Cl)Cl>[CH2:25]([N:15]([CH2:12][CH:13]=[CH2:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH:26]=[CH2:27]
Reactant: C=CCN(CC=C)CCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: C=CCN(CC=C)CCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 24 h
Yield: 40.1 %

Procedure:
4-Toluene-sulphonyl chloride (12.5 g, 0.066 mol) was added slowly to a stirred solution of 8-diallylaminooctan-1-ol (10.0 g, 0.044 mol) and pyridine (7.0 g, 0.088 mol) in chloroform (100 cm3) at 0° C. After 24 h, water (100 cm3) was added and the solution washed with dilute hydrochloric acid (20%, 100 cm3), sodium carbonate solution (100 cm3), water (100 cm3), dried (MgSO4) and concentrated to a yellow oil which was purified by column chromatography [silica gel, 4% diethyl ether in hexane eluting to DCM:ethanol 10:1] to yield the desired product (6.7 g, yield 40%).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[N:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=2)=[C:12]([CH3:24])[CH:11]=1)=[O:8])=[O:5].[C:29](Cl)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([NH:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[N:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=2)=[C:12]([CH3:24])[CH:11]=1)=[O:8])=[O:5])(=[O:31])[CH3:30]
Reactant: Cc1cc(NC(=O)NC(=O)c2ccccc2N)ccc1Oc1ncc(Br)cn1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccccc1C(=O)NC(=O)Nc1ccc(Oc2ncc(Br)cn2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.3 g of N-(2-aminobenzoyl)-N'-[4-(5-bromo-2-pyrimidinyloxy)-3-methylphenyl]urea (Compound No. 27 as described hereinafter) as prepared in accordance with Preparation Example 3, was added to 30 ml of pyridine, and 0.25 ml of acetyl chloride was dropwise added thereto under cooling with ice. The mixture was stirred at room temperature for 2 hours and 30 minutes. Then, pyridine was distilled off, and the residue was purified by silica gel column chromatography (developing solvent; methylene chloride:ethyl acetate=7:3) to obtain 1.18 g of the desired product (melting point: 186°-191° C.) (Compound No. 49 as described hereinafter).
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[CH3:19][CH:20]([CH2:26][C:27]#[C:28][CH3:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22].CN(P(N(C)C)(N(C)C)=O)C.CI.C(O)(=O)C>C1COCC1>[CH3:19][C:20]([CH3:1])([CH2:26][C:27]#[C:28][CH3:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CC#CCC(C)C(=O)OCC
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC#CCC(C)(C)C(=O)OCC
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
Under argon atmosphere, a solution of n-butyl lithium in hexane (1.64N, 26 ml, 0.043 mol) was dropwise added with stirring into a solution of anhydrous diisopropylamine (4.3 g, 0.043 mol) in anhydrous THF (35 ml) at -20° C. and the reaction mixture was stirred for 30 min. at -20° C. To the mixture was added dropwise a solution of ethyl 2-methyl-4-hexynoate (5.4 g, 0.035 mol) in anhydrous THF (15 ml) at -20° C. To the mixture was added anhydrous HMPA (2.25 ml, 0.013 mol). The reaction mixture was heated to room temperature and then stirred for 40 min. The mixture was again cooled to -30° C. and to the mixture was dropwise added a solution of methyl iodide (6.05 g, 0.043 mol) in anhydrous THF (5 ml). After warming to room temperature, the mixture was stirred for one hour, acetic acid (2.5 ml, 0.043 mol) was added, and the resulting mixture was concentrated. The residue was diluted with water (50 ml) and extracted with ethyl acetate (100 ml×2). The combined ethyl acetate layer were washed with water (30 ml) and with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated. Distillation of the residue in vacuo give ethyl 2,2-dimethyl-4-hexynoate (3.7 g, 0.022 mol, 62%, B.p.: 65°-68° C./10 mmHg). The product was assigned the structure by the following data.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:19]=[N:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1>>[F:26][C:27]1[C:32]([C:2]2[CH:3]=[C:4]([C:8]3([C:18]4[CH:23]=[N:22][C:21]([O:24][CH3:25])=[N:20][CH:19]=4)[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10]([NH2:17])=[N:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: OB(O)c1cccnc1F
Reactant: COc1ncc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)cn1
Product: COc1ncc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)c3ccccc32)cn1
Yield: 34 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(2-methoxypyrimidin-5-yl)-1H-isoindol-3-amine (Example 106) as described in Example 67 Scheme #10, D in 34% yield using 2-fluoropyridine-3-boronic acid. 1H NMR (DMSO-d6) δ 8.47 (s, 2 H), 8.19-8.13 (m, 1 H), 8.01-7.91 (m, 1 H), 7.88-7.81 (m, 1 H), 7.77 (d, J=5.56 Hz, 1 H), 7.52-7.48 (m, 1 H), 7.46-7.32 (m, 6 H), 6.88 (br s, 2 H), 3.80 (s, 3 H); MS (ESI) m/z 412 [M+1]+.