Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCC([NH:5][C:6]1([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[O:9][CH2:8][CH2:7]1)=O.NC(N)=S>CCO.CC(O)=O.CCOC(C)=O>[F:26][C:23]([F:24])([F:25])[O:22][C:19]1[CH:20]=[CH:21][C:16]([C:6]2([NH2:5])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[O:9][CH2:8][CH2:7]2)=[CH:17][CH:18]=1
Reactant: O=C(CCl)NC1(c2ccc(OC(F)(F)F)cc2)CCOc2cccnc21
Agent: NC(N)=S
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: NC1(c2ccc(OC(F)(F)F)cc2)CCOc2cccnc21
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 2-chloro-N-(4-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)acetamide (1.5 g, 3.8 mmol) in EtOH (5 times) and AcOH (cat.), was added thiourea (0.3 g, 4.2 mmol). The reaction was stirred at 60° C. for 12 h. The progress of reaction was monitored by TLC (50% EtOAc in petroleum ether). The reaction was diluted with EtOAc (10 mL) and quenched slowly with saturated NaHCO3 (25 mL). The aqueous layer was extracted with EtOAc (10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, and concentrated to give the product as a residue. Purification by column chromatography (60-120 mesh silica, 0-50% EtOAc/hexanes) gives the title compound as a brown oil. MS (ESI pos. ion) m/z: 294.1 (M-NH2). 1H NMR (300 MHz, CDCl3): δ 8.2 (d, J=4.0 Hz, 1H), 7.3 (m, 2H), 7.1-7.2 (m, 4H), 4.3 (m, 1H), 4.0 (m, 1H), 2.35-2.45 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:18])=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:19][N:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][C:10]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:23]3[CH:22]=[N:21][N:20]([CH3:19])[CH:24]=3)[CH:7]=2)=[CH:14][N:13]=[C:12]([N+:15]([O-:17])=[O:16])[CH:11]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc([N+](=O)[O-])ncc1Oc1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc([N+](=O)[O-])ncc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 80 °C
Yield: 130.8 %

Procedure:
A solution of 5-((2-chloropyridin-4-yl)oxy)-4-methyl-2-nitropyridine (1.5 g, 5.65 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.527 g, 7.34 mmol) in dioxane (20 mL) was sparged with Ar, treated with a solution of K2CO3 (1.171 g, 8.47 mmol) in water (5 mL) and Pd(PPh3)4 (0.326 g, 0.282 mmol) and heated at 80° C. overnight. The mixture was cooled to RT, treated with water, extracted with DCM (4×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-2-nitropyridine (2.3 g, 75%). 1H NMR (400 MHz, DMSO-d6): δ 8.48 (s, 1H), 8.43-8.42 (m, 2H), 8.27 (s, 1H), 7.98 (s, 1H), 7.30 (d, J=2.4 Hz, 1H), 6.83 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 2.34 (s, 3H); MS (ESI) m/z: 312.1 (M+H+).
Reaction SMILES: C1(S(N[CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:20]C(C4C(C5C=CC(C(F)(F)F)=CC=5)=CC=CC=4)=O)[CH:17]=3)[CH2:12]2)(=O)=O)C=CC=CC=1.[Br:39][C:40]1[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][C:41]=1[C:42](Cl)=[O:43].NC1C=C2C(=CC=1)CCC2>>[Br:39][C:40]1[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][C:41]=1[C:42]([NH:20][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH2:11][CH2:19]2)=[O:43]
Reactant: O=C(Nc1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Br
Agent: Nc1ccc2c(c1)CCC2
Product: O=C(Nc1ccc2c(c1)CCC2)c1cc([N+](=O)[O-])ccc1Br

Procedure:
2-Bromo-N-indan-5-yl-5-nitro-benzamide is prepared similarly to the title E compound of Example 1 using the title A compound, 2-bromo-5-nitrobenzoyl chloride (1.07 g, 4.06 mmol) and 5-aminoindan (0.54 g, 4.06 mmol). 1H NMR (DMSO-d6, 300 MHz): δ 10.52 (1H, s), 8.34 (1H, d), 8.21 (1H, dd), 8.03 (1H, d), 7.60 (1H, s), 7.38 (1H, d), 7.19 (1H, d), 2.85 (4H, m), 2.02 (2H, m).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](Cl)=[S:26].CN(C)C=O.C(N(CC)CC)C.[C:40]([NH:43][NH2:44])(=[O:42])[CH3:41]>CN(C)C1C=CN=CC=1.O>[CH3:1][C@@H:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25]([NH:44][NH:43][C:40](=[O:42])[CH3:41])=[S:26]
Reactant: CC(=O)NN
Reactant: C[C@@H]1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=S)Cl)OCO3
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NNC(=S)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C[C@H]1C)OCO3
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of 4.04 g (10.0 mmol) of the starting material XII, 3 ml of dimethylformamide, 1.40 ml (10.0 mmol) of triethylamine and 0.06 g (0.5 mmol) of 4-dimethylaminopyridine 1.48 g (20.0 mmol) of acetic hydrazide was added. The reaction mixture was stirred at 50° C. for 5 h, then diluted with water, the precipitated crystals were filtered off and washed with water. The so obtained 4.5 g of (R)—N′-{8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-7-carbothioyl}-acetic hydrazide according to its 1H-NMR spectrum was a mixture of rotation isomers. (The analyzed sample was purified by column chromatography using a mixture of n-hexane-ethyl acetate (1:1) as eluent and it was crystallized with 0.5 mol of ethyl acetate, Mp.: 118° C.).
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[CH2:34]([NH2:36])[CH3:35].[OH-].[Na+]>>[CH2:34]([NH:36][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:35]
Reactant: Oc1cccc2ccccc12
Reactant: CCN
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Product: CCNc1cccc2ccccc12
Yield: 90 %

Procedure:
288 parts of α-naphthol, 10 parts of triphenyl phosphite and 100 parts of ethylamine gas are heated for 20 hours at 240° C, whilst stirring. After the mixture has cooled, it is next stirred for 20 minutes at 70° C with 1,000 parts of 2.5 percent strength by weight aqueous sodium hydroxide solution. The organic phase is separated off, washed with 2,000 parts of water at 30° C, again separated off and distilled. 308 parts of N-ethyl-α-naphthylamine boiling at 119° - 120° C/0.1 mm Hg are obtained, corresponding to a yield of 90% of theory.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10]([CH:19]=O)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]1([C:27]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:28]2[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1CCCC1>C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10](/[CH:19]=[C:32]2\[CH2:33][N:28]([C:27]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:29][CH2:30][C:31]\2=[O:34])=[N:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)Cc1cc(C=O)nn1C(=O)OC(C)(C)C
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Solvent: C1CCNC1
Solvent: c1ccccc1
Product: CCOC(=O)Cc1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2=O)nn1C(=O)OC(C)(C)C
Yield: 57 %

Procedure:
Following a procedure similar to that described in Example 132-(c), ethyl [1-(t-butoxycarbonyl)-3-formyl-1H-pyrazol-5-yl]acetate (7.84 g) was subjected to the reaction with 1-(triphenylmethyl)piperidin-4-one in benzene using pyrrolidine. The crude product thus obtained was purified by silica gel chromatography using hexane, ethyl acetate, and dichloromethane (3:1:1) as an eluent to afford the title compound (9.64 g, yield: 57%) as a yellow amorphous solid.
Reaction SMILES: C([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[Cl:26])[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:26][C:19]1[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=1[C:13]1[CH:12]=[CH:11][NH:10][C:9](=[O:8])[C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: COc1ccc(-c2ccnc(OCc3ccccc3)c2[N+](=O)[O-])c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cc[nH]c(=O)c2[N+](=O)[O-])c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 104.2 %

Procedure:
2-Benzyloxy-4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridine (1.51 g, 4.07 mmol) was dissolved in TFA (20 mL) and stirred at room temperature for 4 h. The reaction mixture was concentrated, washed with toluene, and concentrated in vacuo to yield 1.19 g (100%) of 4-(2-chloro-4-methoxy-phenyl)-3-nitro-1H-pyridin-2-one as a solid: MS (AP) m/z 280.7 [(M+H)+, 100].
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1([C:25](Cl)=[O:26])[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:18][C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2>>[CH2:1]([NH:5][C:25]([C:11]1([CH2:10][CH2:9][CH2:8][CH2:7][Br:6])[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:18][C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:26])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: CCCCN
Product: CCCCNC(=O)C1(CCCCBr)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 1 from n-butylamine and 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid chloride.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[F:16][CH:17]([F:29])[O:18][C:19]1[CH:28]=[CH:27][C:22]2[NH:23][C:24]([SH:26])=[N:25][C:21]=2[CH:20]=1>>[F:29][CH:17]([F:16])[O:18][C:19]1[CH:28]=[CH:27][C:22]2[NH:23][C:24]([S:26][CH:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:15])([CH3:1])[CH:3]3[OH:14])=[N:25][C:21]=2[CH:20]=1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: FC(F)Oc1ccc2[nH]c(S)nc2c1
Product: CC1(C)Oc2ccc(C#N)cc2C(Sc2nc3cc(OC(F)F)ccc3[nH]2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 5-difluoromethoxy-1H-benzoimidazole-2-thiol as starting material, the title compound was prepared as a white solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][O:7][CH2:8][CH:9]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23](O)=[O:24])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN.C1C=CC2N(O)N=[N:43][C:41]=2C=1.C(N(C(C)C)CC)(C)C.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1.C(#N)C>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=1)[CH2:6][O:7][CH2:8][CH:9]([N:16]1[CH2:17][CH2:18][N:19]([CH2:22][C:23]([NH:43][CH3:41])=[O:24])[CH2:20][CH2:21]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)CN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: C1CCOC1
Product: CNC(=O)CN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1

Procedure:
In a round-bottomed flask fitted with a reflux condenser and a thermometer are introduced 1.5 g (3 mmoles) of {4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazin-1-yl}-acetic acid (compound 229 prepared at example 1.4.2 above), 7 ml of THF and 7 ml of acetonitrile. Then 1.85 ml (3.7 mmoles) of a 2M solution of methylamine in THF are added, followed by 234 mg (1.5 mmoles) of HOBT, 1.33 ml (7.6 mmoles) of diisopropylethylamine and 880 mg (4.3 mmoles) of DCC. The mixture is stirred until completion of the reaction, and filtered. Volatile substances are removed under reduced pressure, and the residue is partitioned between ethyl acetate and 0.1 N sodium hydroxide. The organic phase is washed with brine, dried over magnesium sulfate and volatile substances are removed under reduced pressure. This yields crude 2-{4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazin-1-yl}-N-methyl-acetamide (compound 292) which is directly converted into its dimaleate salt in 2-butanone (1.44 g of a white solid; yield 65%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].C(OC1C(OC(=O)C)=C(I)C=CC=1)(=[O:11])C.CC1(C)N([O])C(C)(C)CCC1>C(#N)C.O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:11])=[O:8]
Reactant: OCC1CCCCO1
Reactant: CC(=O)Oc1cccc(I)c1OC(C)=O
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: O
Solvent: CC#N
Product: O=C(O)C1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(Tetrahydro-2H-pyran-2-yl)methanol (0.51 g, 4.30 mmol) was dissolved in 10 mL of 1:1 ACN/water mixture, and bis-acetoxyiodobenzene [BAIB] (3.04 g, 9.46 mmol) was added to the mixture. It was then cooled to 0 C in an ice bath, and TEMPO (0.134 g, 0.86 mmol) was added under argon flow. The mixture was stirred at room temperature for 3 hours, and the reaction was quenched by addition of 2×20 mL of 1 M NaOH. Basic solution was washed 3×30 mL of EtOAc, and re-acidified with 1 M HCl to ca. pH 2. Aqueous layer was then extracted 6×30 mL of EtOAc, organic layers were combined, dried over sodium sulfate and evaporated. The title compound was isolated as an oil (0.34 g, 61%) was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ4.11 (d, 1H, J=10.5 Hz), 3.98 (d, 1H, J=9.9 Hz), 3.53 (m, 1H), 2.10-1.92 (m, 3H), 1.60-1.54 (m, 3H).
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[C:6](=[O:8])[N:7]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH:19]1([NH:22][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)/[C:6](=[O:8])[N:7]=2)[CH2:21][CH2:20]1
Reactant: NC1CC1
Reactant: CSC1=NC(=O)C(=Cc2c[nH]c3ncccc23)S1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1N=C(NC2CC2)S/C1=C\c1c[nH]c2ncccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 70.4 %

Procedure:
The suspension of 2-methylsulfanyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-thiazol-4-one (55 mg, 02 mmol, example 14a), cyclopropylamine (23 mg, 0.4 mmol) and diisopropylethylamine (DIEA) (70 uL, 0.4 mmol) in acetonitrile (1.0 mL) was stirred under at 80° C. for 12 h. After cooling to room temperature, the solid was collected by filtration, washed with a little bit of acetonitrile and dried. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 0%-10% methanol in methylene chloride in 30 min) afforded 2-cyclopropylamino-5-[1-(1H-pyrrolo[2,3-b]pyridin-3-yl)-meth-(Z)-ylidene]-thiazol-4-one (40 mg, 71%) as a light yellow solid. LC-MS m/e 285 (MH+).
Reaction SMILES: FC(F)(F)C1C=CC(C=C)=CC=1.Br[C:14]1[CH2:18][CH2:17][O:16][N:15]=1.[OH:19][C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1>>[N:22]1[CH:21]=[C:20]([O:19][C:14]2[CH2:18][CH2:17][O:16][N:15]=2)[CH:25]=[N:24][CH:23]=1
Reactant: BrC1=NOCC1
Reactant: Oc1cncnc1
Agent: C=Cc1ccc(C(F)(F)F)cc1
Product: c1ncc(OC2=NOCC2)cn1

Procedure:
3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-168a and I-168b were prepared in 2 steps from 1-(trifluoromethyl)-4-vinylbenzene using the cycloaddition conditions from Method 1. The resulting bromo-4,5-dihydroisoxazole was reacted with 5-hydroxypyrimidine to provide racemic compound I-168 using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=309.8 m/z. Activity: B
Reaction SMILES: [OH-].[K+].S([O-])([O-])(=O)=O.[Na+].[Na+].[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[NH:15][C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3.[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH2:24][CH:26]3[O:28][CH2:27]3)[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3
Reactant: Clc1ccc2[nH]c3ccccc3c2c1
Reactant: ClCC1CO1
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: Clc1ccc2c(c1)c1ccccc1n2CC1CO1
Temperature: 25 °C

Procedure:
Compound (3) may be prepared according to the following procedure. A mixture of potassium hydroxide powder (KOH, 85%, 198 g, 3 mol) and anhydrous sodium sulfate (Na2SO4, 51 g, 0.369 mol) is added in three stages to a mixture of 3-chloro-9H-carbazole (1 mol) and epichlorohydrin (1.5 mol), while keeping the reaction mixture at 20-25° C. The 3 stage quantities added are 33 g of Na2SO4 and 66 g of KOH initially; 9.9 g of Na2SO4 and 66 g of KOH after 1 hour of reaction; and 9.9 g of Na2SO4 and 66 g of KOH after 2 hours of reaction. The reaction mixture is stirred vigorously at 35-40° C. until 3-chloro-9H-carbazole disappears (approximately 3-4 hours). Subsequently, the mixture is cooled to room temperature, and any remaining solids are removed by filtration. The liquid organic phase is treated with a solvent such as diethyl ether and washed with distilled water until the washed water reaches a neutral pH. The organic layer is dried over anhydrous magnesium sulfate, treated with activated charcoal, and filtered. The solvent and excess epichlorohydrin are removed by evaporation in a rotory evaporator. The residue is purified by recrystallization, chromatography, or a combination of both to produce 3-chloro-9-(2,3-epoxypropyl)carbazole.
Reaction SMILES: C(N(CC)CC)C.C(Cl)Cl.[CH2:11]([N:15]1[C:23]([N:24]2[CH2:29][CH2:28][NH:27][C@H:26]([CH3:30])[CH2:25]2)=[N:22][C:21]2[C:16]1=[N:17][C:18]([C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=1)=[N:19][C:20]=2[N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[CH:12]([CH3:14])[CH3:13].[C:44](OC(=O)C)(=[O:46])[CH3:45]>C(Cl)Cl.CO>[C:44]([N:27]1[CH2:28][CH2:29][N:24]([C:23]2[N:15]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:16]3[C:21]([N:22]=2)=[C:20]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:19]=[C:18]([C:37]2[CH:42]=[N:41][C:40]([NH2:43])=[N:39][CH:38]=2)[N:17]=3)[CH2:25][C@H:26]1[CH3:30])(=[O:46])[CH3:45]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Cn1c(N2CCN[C@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(C)C)C[C@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
Triethylamine (79.9 μl, 0.57 mmol) was added to a methylene chloride solution (3.0 ml) of 5-{9-isobutyl-8-[(3R)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (108.1 mg, 0.24 mmol) at room temperature followed by the addition of acetic anhydride (27.1 μl, 0.29 mmol) with ice cooling. The resulting mixture was stirred at room temperature for 1 hour and then the reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (110.9 mg, 94%) as a pale yellow solid.
Reaction SMILES: [CH:1](=[C:8]1[C:13](=[O:14])[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)[C:25](O)=[O:26]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]([C:10]1[CH:11]=[C:12]([C:15]([CH3:16])([CH3:18])[CH3:17])[C:13]2[O:14][C:25](=[O:26])[CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]=2[CH:9]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)C1=CC(=Cc2ccccc2)C(=O)C(C(C)(C)C)=C1
Reactant: O=C(O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccccc1
Temperature: 80 °C
Yield: 90 %

Procedure:
A solution of 589 mg (2.0 mmol) of a mixture of 6-benzylidene-2,4-di-tert-butyl-cyclohexa-2,4-dienone (compound (302), Table 3) and the corresponding dimer (compound (402), Table 4), prepared according to Example 2b, in 7 ml of toluene is degassed using argon and then 58 mg (0.05 mmol) of tetrakis(triphenylphosphine)palladium(0) and 23 mg (0.20 mmol) of trifluoroacetic acid are added. The autoclave is flushed with carbon monoxide and sealed, and a carbon monoxide pressure of 5 bar is then applied. The reaction mixture is maintained at 80° C. for 20 hours. After cooling to room temperature, the reaction mixture is poured into water and extracted three times using ethyl acetate. The organic phases are combined, dried over sodium sulfate and concentrated using a vacuum rotary evaporator. Crystallisation of the residue from isopropanol yields 580 mg (90%) of 5,7-di-tert-butyl-3-phenyl-3H-benzofuran-2-one (compound (102), Table 1), m.p. 116-119° C. Analysis, calculated: C 81.95; H 8.13%. Analysis, found: C 81.93; H 8.13%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:13][C:14]#[N:15])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8]C)=[O:7]>CO>[C:14]([CH2:13][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7])#[N:15]
Reactant: COC(=O)c1cccc(OC)c1CC#N
Solvent: CO
Product: COc1cccc(C(=O)O)c1CC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 86847.4 %

Procedure:
Into a 500 mL 3-neck round bottom flask was added 10 g (61.75 mmol) of 2-bromomethyl, 3-methoxy methyl benzoate, 4.0 g (81.6 mmol) of NaCN, 0.30 g (2 mmol) of NaI, 100 mL of CH3CN, and 50 mL of DMF. The reaction mixture was heated and refluxed for 10 hours. The precipitate (NaBr) was filtered off, and the solution was concentrated on an evaporator. 300 mL of water and 200 mL of ether were added and then shaken in a separatory funnel. The water was extracted twice with 100 mL of ether. The ether fractions were dried over MgSO4, and concentrated to yield methyl 3-methoxy-2-cyanomethylbenzoate (95-100% yield). This ester (0.053 mmol, 10.51 g) was stirred vigorously in 100 mL of CH3OH. Ba(OH)2 H2O (0.079 mmol, 14.97 g) was added and the mixture stirred at room temperature overnight. The CH3OH was removed on a rotary evaporator. 150 mL of water, 200 mL of CH2Cl2, and 50 mL of 6N HCl were added, and then stirred in a flask to dissolve all residues. The mixture was transferred to a separatory funnel, acidified with 6N HCl to pH 1-2. The CH2Cl2 phase was separated and the aqueous phase extracted twice with 50 mL of CH2Cl2. The CH2Cl2 extracts were combined, dried over MgSO4 and charcoal, filtered, and evaporated to yield 8.8 g of a white solid, 2-cyanomethyl-3-methoxybenzoic acid, (87%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].Cl.[CH3:15]O>CO>[C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N#Cc1cc(CC(=O)O)ccc1F
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccc(F)c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of crude (3-cyano-4-fluorophenyl)acetic acid (980 mg, 5.6 mmol) in methanol (10 mL) was added 5 M HCl/MeOH (10 mL). The reaction was stirred at ambient temperature overnight and concentrated. The residue was purified with preparative TLC to afford methyl (3-cyano-4-fluorophenyl)acetate. 1H-NMR (300 MHz, CDCl3) δ ppm 7.49˜7.55 (m, 2H), 7.17 (t, J=8.2 Hz, 1H), 3.71 (s, 3H), 3.63 (s, 2H).