Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]3[N:13]([C:18]4[CH:23]=[CH:22][C:21](B5OC(C)(C)C(C)(C)O5)=[CH:20][CH:19]=4)[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.FC(F)(F)S(O[C:39]1[CH:47]=[CH:46][C:42]2[CH:43]=[CH:44][O:45][C:41]=2[CH:40]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[O:45]1[C:41]2[CH:40]=[C:39]([C:21]3[CH:22]=[CH:23][C:18]([N:13]4[C:12]([CH2:11][C@@H:8]5[CH2:9][CH2:10][N:6]([C:4]([CH:1]6[CH2:3][CH2:2]6)=[O:5])[CH2:7]5)=[N:16][NH:15][C:14]4=[O:17])=[CH:19][CH:20]=3)[CH:47]=[CH:46][C:42]=2[CH:43]=[CH:44]1
Reactant: O=S(=O)(Oc1ccc2ccoc2c1)C(F)(F)F
Reactant: CC1(C)OB(c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4ccoc4c3)cc2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
A solution of 5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (0.235 mmol) in dioxane (1.5 mL) was treated with 1-benzofuran-6-yl trifluoromethanesulfonate (0.230 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (11.5 mg), and 2M aq potassium carbonate (0.705 mmol). The reaction mixture was purged with nitrogen, sealed, and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). The aqueous layer was acidified to pH ˜4 using 1N aq HCl and was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (0-8% methanol/dichloromethane), followed by purification by reverse phase HPLC (LUNA C-18: 30×50 mm column; 20-45% acetonitrile w/0.1% TFA/water w/0.1% TFA). The combined product fractions were neutralized with the addition of saturated aqueous sodium bicarbonate, concentrated under reduced pressure, and extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound as an off-white amorphous solid (16 mg, 15% yield). MS(ES)+ m/e 428.9 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:25]=[O:26]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:25]=[O:26])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Fc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(-c2ccc(F)cc2)nc2ccc(Br)cn12

Procedure:
6-Bromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridine (7 g, 0.024 moles) was treated with phosphorous oxychloride (3.4 mL, 36 mmol) in N,N-dimethylformamide in a similar manner as described in Example 2 to give, after recrystallization from acetonitrile, 6-bromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde (6.12 g, 80%) as a white solid. 1H NMR (CDCl3): δ 10.08 (s, 1H), 9.88 (s, 1H), 7.86 (q, 2H), 7.72 (m, 2H), 7.28 (t, 2H); 19F NMR (CDCl3) δ −110.6; MS m/z 320 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[C:4]([Cl:17])[C:3]=1[CH2:18][C:19](O)=[O:20].[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[C:4]([Cl:17])[C:3]=1[CH2:18][C:19]([NH:27][C:26]1[CH:28]=[CH:29][CH:30]=[C:24]([C:23]([F:22])([F:31])[F:32])[CH:25]=1)=[O:20]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)Cc1c(Cl)cc(-n2cnc3cccnc32)cc1Cl
Solvent: ClCCl
Product: O=C(Cc1c(Cl)cc(-n2cnc3cccnc32)cc1Cl)Nc1cccc(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 7 but using (2,6-dichloro-4-imidazo[4,5-b]pyridin-3-yl-phenyl)acetic acid (Step 56.1) and 3-(trifluoromethyl)aniline. Title compound: ES-MS: 462.9/464.9 [M-H]−; tR=5.08 min (System 1); Rf=0.37 (CH2Cl2/(2N NH3 in MeOH), 95:5).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][N:5]=[C:6]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[C:7]([O:9]CC)=[O:8].Cl>CO>[CH3:3][O:4][N:5]=[C:6]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(=NOC)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CON=C(C(=O)O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
5 ml (10 mmol) of a 2N aqueous solution of sodium hydroxide were added to a solution of 1.28 g (5.07 mmol) of ethyl α-methoxyimino-4-nitrophenylacetate in methanol, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off to give 1.0 g (88% yield) of the title compound as a crude product, which was used in the following reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][C:6]([CH2:7][O:8][N:9]=[C:10]([C:13]2[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([OH:21])=O)=[CH:15][CH:14]=2)[CH2:11][CH3:12])=[CH:5][CH:4]=1.[O:28]1[CH2:33][CH2:32][CH:31]([CH2:34][NH2:35])[CH2:30][CH2:29]1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C.C1C=CC2N(O)N=NC=2C=1>[O:28]1[CH2:33][CH2:32][CH:31]([CH2:34][NH:35][C:19](=[O:21])[CH2:18][O:17][C:16]2[CH:15]=[CH:14][C:13]([C:10](=[N:9][O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:26])([F:1])[F:27])=[CH:25][CH:24]=3)[CH2:11][CH3:12])=[CH:23][CH:22]=2)[CH2:30][CH2:29]1
Reactant: NCC1CCOCC1
Reactant: CCC(=NOCc1ccc(C(F)(F)F)cc1)c1ccc(OCC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCC(=NOCc1ccc(C(F)(F)F)cc1)c1ccc(OCC(=O)NCC2CCOCC2)cc1
Reaction time: 16 h
Yield: 57.3 %

Procedure:
To a solution of the product of step 4 (23 g, 0.0602 moles) in DMF (69 mL), (tetrahydro-2H-pyran-4-yl)methanamine (7.6 gm, 0.0662 moles), HOBT (50 mg, catalytic amount), EDC.HCl (17.5 g, 0.0903 moles) and DMAP (50 mg, catalytic amount) were added and reaction mixture was srirred at 25° C. for 16 hours. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evapourated under reduced pressure. The crude product was purified by coloumn chromatography using ethyl acetate:Hhexane (1:1) as eluent to yield 16.5 g (57%) of product as white solid. 1H NMR: DMSO-d6 δ 1.10 (t, J=6.6 Hz, 3H), 1.13-1.16 (m, 2H), 1.46-1.49 (m, 2H), 1.61-1.70 (m, 1H), 2.74 (q, J=7.6 Hz, 2H), 3.01 (t, J=6.6 Hz, 2H), 3.17-3.23 (m, 2H), 3.78-3.81 (dd, J=11.4 & 2.6 Hz, 2H), 4.51 (s, 2H), 5.26 (s, 2H), 6.96 (dd, J=6.8 & 2.0 Hz, 2H), 5.57-5.61 (m, 4H), 7.72 (d, J=8.0 Hz, 2H), 8.10 (t, J=6.0 Hz, NH).
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9](Cl)[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[C:5](O)=[CH:4][C:3]=1OC1C=CC=CC=1O.C(N(CC)C1C=CC=CC=1)C.FN1N=C(F)C=C(NCCC#N)N1>O1CCCC1>[CH:9]1[C:8]2[C:7](=[O:18])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1c(Oc2ccccc2O)cc(O)c2c1C(=O)c1cccc(Cl)c1C2=O
Agent: N#CCCNC1=CC(F)=NN(F)N1
Solvent: C1CCOC1
Solvent: CCN(CC)c1ccccc1
Product: O=C1c2ccccc2C(=O)c2ccccc21
Yield: 254.4 %

Procedure:
To a solution of 1-amino-2-(2-hydroxyphenyloxy)-4-hydroxy-5-chloroanthraquinone (3.82 g) in tetrahydrofuran (50 ml), N,N-diethylaniline (1.7 g) and 2,4-difluoro-6-(β-cyanoethyl)aminotriazine (1.85 g) were added and the mixture was subjected to condensation as in Example 3. The reaction liquor was treated as in Example 1 to produce 5.3 g of anthraquinone dye (λ max in acetone=527 nm) of the following formula in a yield of 93%. ##STR12## A dye dispersion was made from a mixture of the anthraquinone dye (16 parts), polyoxyethylene glycol nonylphenyl ether with an HLB of 13.3 (7 parts), naphthalene-sulfonic acid-formaldehyde condensate (3 parts) and water (74 parts) by grinding it with a sand grinder. Using the dye dispersion, a padding bath having the following formulation was prepared.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:9][CH:10]=1)(=[O:4])=[O:3].[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:30][CH2:31][CH3:32])[C:28]=1[F:29])[CH:24]=O)[CH3:19].C(N(C(C)C)C(C)C)C.C(O)(=O)C.C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:30][CH2:31][CH3:32])[C:28]=1[F:29])[CH2:24][N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][N:9]=2)[CH2:13][CH2:14]1)[CH3:19]
Reactant: CCOc1cc(C=O)cc(OCC)c1F
Reactant: CS(=O)(=O)c1ccc(NC2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC(Nc3ccc(S(C)(=O)=O)cn3)CC2)cc(OCC)c1F
Temperature: 50 °C
Yield: 70.9 %

Procedure:
To a solution of (5-methanesulfonyl-pyridin-2-yl)-piperidin-4-yl-amine (0.12 g, 0.5 mmol, 1.0 equiv; intermediate B16) and 3,5-diethoxy-4-fluoro-benzaldehyde (0.11 g, 0.5 mmol, 1.0 equiv; intermediate E5) in ethanol (5 mL) under an atmosphere of Ar was added N-ethyl diisopropylamine (0.19 mL, 0.15 g, 1.2 mmol, 2.3 equiv) and glacial acetic acid (0.05 mL, 0.06 g, 1.0 mmol, 2.0 equiv) and the mixture heated to 50° C. for 2 h. After cooling down to 35° C., sodium cyanoborohydride (0.16 g, 2.5 mmol, 5.1 equiv) was added and the reaction mixture heated again to 50° C. for 1.5 h. It was then poured into crashed ice, the pH of the water phase adjusted to ˜10 by addition of a sat. solution of sodium carbonate and the mixture extracted twice with dichloromethane. The combined organic phases were washed with water, dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 0.16 g (71%) of the title compound as colorless foam. MS (ISP): 452.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(CC(=O)O)c1
Yield: 99 %

Procedure:
The 3-nitrophenylacetic acid described in Example 7 is hydrogenated in methanol in the presence of palladium-charcoal to give a yield of 99% of theory of 3-aminophenylacetic acid (m.p. 116°-121° C.). In a manner analogous to that described for the p-compound (see Example 6), there is obtained therefrom, by diazotisation, 3-cyanophenylacetic acid (yield 45% of theory; m.p. 93°-98° C. (decomp.)) and by hydrogenation in dilute hydrochloric acid in the presence of platinum catalyst there is obtained 3-aminomethylcyclohexylacetic acid; yield 66% of theory; m.p. 127°-130° C. The diphosphonic acid is obtained therefrom by means of phosphorus trichloride/phosphorous acid in the manner described in Example 1 in the form of the monohydrate; yield 28% of theory; m.p. 216°-221° C. (decomp.); Mrel =0.27.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][O:13][C:14]([C@@H:16]1[CH2:20][C@@H:19]([OH:21])[CH2:18][N:17]1[S:22]([C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)(=[O:24])=[O:23])=[O:15].[CH3:35][C:36]([Si:39](Cl)([CH3:41])[CH3:40])([CH3:38])[CH3:37]>C(#N)C>[CH3:12][O:13][C:14]([C@@H:16]1[CH2:20][C@@H:19]([O:21][Si:39]([C:36]([CH3:38])([CH3:37])[CH3:35])([CH3:41])[CH3:40])[CH2:18][N:17]1[S:22]([C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)(=[O:24])=[O:23])=[O:15]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccc2ccccc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
29 ml (194 mmol, 1.6 eq) DBU were added to a suspension of 41.4 g (121.4 mmol) (2S,4R)-4-Hydroxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester in 150 ml acetonitrile at 0° C. To the resulting solution 29.25 g (194 mmol, 1.6 eq) TBDMSCl were added in portions and the reaction was stirred at RT overnight. After concentrating the crude oil was purified by column chromatography with EtOAc/hexane 1:2 on silica gel to give 49.2 g (90%) (2S,4R)-4-(tert-butyl-dimethyl-silanyloxy)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[Na+].[CH3:30][S:31]([O-:33])=[O:32].N1CCC[C@H]1C(O)=O.[OH-].[Na+]>CS(C)=O>[CH3:30][S:31]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1)(=[O:33])=[O:32]
Reactant: CS(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(Br)cn3)cc2)CC1
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cn3)cc2)CC1
Yield: 74.6 %

Procedure:
The title compound (0.20 g, 80%) was prepared as a white solid from 1,1-dimethylethyl 4-({[4-(5-bromo-2-pyridinyl)phenyl]oxy}methyl)-1-piperidinecarboxylate (0.25 g, 0.60 mmol), methanesulfinic acid sodium salt (0.12 g, 80%, 0.91 mmol), L-proline (14 mg, 0.12 mmol), Cul (12 mg, 0.06 mmol) and NaOH (5 mg, 0.12 mmol) in DMSO (3 mL) in a manner similar to Example 76, Step 3. 1H NMR (400 MHz, CD3OD): δ 9.05 (d, 1H, J=2.2 Hz), 8.30 (dd, 1H, Ja=8.4 Hz, Jb=2.3 Hz), 8.09 (d, 2H, J=8.8 Hz), 8.04 (d, 1H, J=8.5 Hz), 7.06 (d, 2H, J=8.8 Hz), 4.20-4.10 (m, 2H), 3.93 (d, 2H, J=6.4 Hz), 3.21 (s, 3H), 2.90-2.70 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 447 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]1[CH:13]=[CH:14][N:15]=[C:7]1[C:6](=O)[NH:5]2.C[Si](C)(C)N[Si](C)(C)C.S([O-])([O-])(=O)=O.[NH4+].[NH4+].[NH2:33][CH2:34][CH2:35][CH2:36][OH:37]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]1[CH:13]=[CH:14][N:15]=[C:7]1[C:6]([NH:33][CH2:34][CH2:35][CH2:36][OH:37])=[N:5]2
Reactant: O=c1[nH]c2cc(F)c(F)cc2n2ccnc12
Reactant: NCCCO
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: OCCCNc1nc2cc(F)c(F)cc2n2ccnc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
A mixture of 7,8-difluoroimidazo[1,2-a]quinoxalin-4(5H)-one (Eur. J. Med. Chem. 1998, 33, 943) (20 mg, 0.090 mmol), hexamethyldisilazane (66 μL, 0.31 mmol), ammonium sulphate (2.4 mg, 0.018 mmol) and 3-aminopropan-1-ol (34 μL, 0.45 mmol) was stirred under argon at 120° C. overnight. The reaction mixture was allowed to cool down to room temperature and the white residue was diluted in ethyl acetate and water. A white precipitate was filtered off and the filtrate was washed with brine. The organic phase was dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC (silica gel, dichloromethane/methanol 90/10) to afford the title compound as white crystals (4.5 mg, 18%)
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([NH:15][C:16](=[O:37])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH:24][C:25]3[C:30]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][N:32]=4)=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:18]=2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.[I-].[Na+].O>CN(C=O)C>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:7]2[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]([O:4][CH2:3][CH2:2][N:42]3[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]3)[CH:6]=2)=[O:37])=[CH:18][C:19]=1[NH:24][C:25]1[C:30]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][N:32]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: Cc1ccc(C(=O)Nc2cc(OCCCl)cc(C(F)(F)F)c2)cc1Nc1ncccc1-c1ccncn1
Reactant: CN1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cc(OCCN3CCN(C)CC3)cc(C(F)(F)F)c2)cc1Nc1ncccc1-c1ccncn1
Temperature: 100 °C

Procedure:
A mixture of N-(3-(2-chloroethoxy)-5-(trifluoromethyl)phenyl)-4-methyl-3-(3-(pyrimidin-4-yl)pyridin-2-ylamino)benzamide (200 mg, 0.38 mmol), 1-methylpiperazine (76 mg, 0.76 mmol) and sodium iodide (catalytic amount) in DMF (5 ml) was heated at 100° C. for 20 hr. After cooling to RT, water (50 ml) was added and the mixture was extracted with EtOAc (3×50 ml). The combined organic layer was washed with brine (3×50 ml) and dried over Na2SO4. The solvent was removed in vacuo and the product was purified by flash column chromatography eluting with MeOH(NH3)/DCM (1 to 5%) to afford the title compound as a light yellow solid. MS m/z=592 [M+1]+. Calc'd for C31H32F3N7O2: 591.6.
Reaction SMILES: C(OC([N:11]1[CH2:18][C@@H:17]2[C@@H:13]([N:14]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=4)=[CH:21][CH:20]=3)[CH2:15][CH2:16]2)[CH2:12]1)=O)C1C=CC=CC=1>FC(F)(F)C(O)=O>[N:14]1([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:15][CH2:16][C@@H:17]2[CH2:18][NH:11][CH2:12][C@H:13]12
Reactant: N#Cc1ccc(-c2ccc(N3CC[C@@H]4CN(C(=O)OCc5ccccc5)C[C@@H]43)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(-c2ccc(N3CC[C@@H]4CNC[C@@H]43)cc2)cc1
Yield: 64.4 %

Procedure:
The product of Example 1D ((3aR,6aR)-1-(4′-Cyano-biphenyl-4-yl)-hexahydro-pyrrolo[3,4-b]pyrrole-5-carboxylic acid benzyl ester) (750 mg, 1.77 mmole) was refluxed in 10 ml trifluoroacetic acid for 2.5 hours. The solution was concentrated and triturated with dichloromethane. The residue was redissolved in dichloromethane and stirred with sodium bicarbonate powder. The solution was loaded on a silica gel column and purified by chromatography (0.6% ammonium hydroxide and 6% methanol in dichloromethane) to provide the title compound (330 mg, 64%), 1H NMR (CDCl3) δ ppm 7.64 (d, J=2.71 Hz, 4H) 7.51 (d, J=8.81 Hz, 2H) 6.66 (d, J=8.82 Hz, 2H) 4.07-4.17 (m, 1H) 3.50-3.65 (m, 1H) 3.24-3.36 (m, 1H) 2.86-3.10 (m, 5H) 2.15-2.29 (m, 1H) 1.74-1.93 (m, 1H). MS: (M+H)+=290.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[C:9]([CH3:13])=[N:10][S:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[C:23](=[O:25])=[O:24]>C1COCC1>[C:1]([O:5][C:6]([NH:7][C:8]1[C:9]([CH3:13])=[N:10][S:11][C:12]=1[C:23]([OH:25])=[O:24])=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=O
Reactant: Cc1nscc1NC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nsc(C(=O)O)c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3-methyl-isothiazol-4-yl)-carbamic acid tert-butyl ester (method 55) (21.4 g, 100 mmol) in anhydrous THF (200 mL) at -78° C., LDA (139 mL, 1.8 M solution, 250 mmol) was added dropwise over a period of 1 h. The reaction mixture was stirred at that temperature for a further 3 h after which powdered dry ice was added and the reaction slowly allowed to warm to room temperature overnight. The reaction mixture was quenched by adding saturated NH4Cl solution and extracted with ether (3×100 mL) and the combined ether layers were back extracted with satd. NaHCO3 (3×100 mL). The aqueous layers were combined and acidified to pH 5 using 6M HCl and extracted with ether (4×100 mL). The combined ether layers were dried (Na2CO3) and concentrated to give the pure acid as an off white powder. Yield 11 g (39%). 1H NMR (300 MHz) δ 1.47 (s, 9H), 2.44 (s, 3H), 8.53 (bs, 1H), 9.68 (bs, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[CH:5]=[CH:6][C:7]2=[O:12].[Br:14]Br.C(O)(=O)C.C(O)C>C(Cl)(Cl)Cl>[CH:10]1[CH:11]=[C:2]([OH:1])[C:3]2[C:4]([C:5]([Br:14])=[CH:6][C:7](=[O:12])[C:8]=2[CH:9]=1)=[O:13]
Reactant: BrBr
Reactant: O=C1C=CC(=O)c2c(O)cccc21
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1C=C(Br)C(=O)c2c(O)cccc21
Yield: 80 %

Procedure:
To a solution of 5-hydroxynaphthalene-1,4-dione (171 mg, 1 mmol) in chloroform was added bromine, and the mixture was stirred. Then, to the resulting mixture were added acetic acid and ethanol, and the mixture was stirred under reflux to give 3-bromojuglone (80%). To the resulting 3-bromojuglone was added dimethylamine, and the mixture was stirred in toluene at room temperature to give 2-dimethylaminojuglone and 3-dimethylaminojuglone (85%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH:2]=1.[H][H]>CO.O.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH2:2]1
Reactant: NC(=O)c1cccc2nc(-c3ccc(-c4cccnc4)cc3)oc12
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Solvent: O
Product: NC(=O)c1cccc2nc(-c3ccc(C4CCCNC4)cc3)oc12
Yield: 9.8 %

Procedure:
2-(4-(Pyridin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide (100 mg, 0.35 mmol) and platinum (IV) oxide monohydrate (55 mg) in methanol (20 mL) was purged with 20 atm of hydrogen at 50° C. for 24 h. Then the mixture was filtered and adjusted to pH=9. The solvent was removed in vacuum. The crude was purified by pre-HPLC. 11 mg of 2-(4-(piperidin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained, yield: 11%. 1H-NMR (400 MHz, DMSO-d6) δ 1.45 (s, 3H), 1.74-1.77 (m, 2H), 1.89-1.96 (m, 2H), 2.87-2.90 (m, 1H), 3.06-3.09 (m, 2H), 7.85-7.90 (brs, 2H), 7.94-7.96 (d, J=8.0 Hz, 2H), 8.26-8.28 (d, J=8.2 Hz, 2H); LC-MS (ESI) m/z: 316 (M+1)+.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C@@H:7]([CH2:10][CH2:11][CH2:12][OH:13])[C@H:6]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([CH3:28])([CH3:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][C:15]=3[OH:29])[CH2:5]2)[O:3]C1.Cl.O1CCCC1.[Cl-].[Na+]>CCOCC>[CH3:28][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C@H:6]2[C@H:7]([CH2:10][CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][C:4](=[O:3])[CH2:5]2)=[C:15]([OH:29])[CH:16]=1)([CH3:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCC(C)(C)c1ccc([C@@H]2CC3(CC[C@H]2CCCO)OCCO3)c(O)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1ccc([C@@H]2CC(=O)CC[C@H]2CCCO)c(O)c1
Yield: 82 %

Procedure:
A mixture of 4.0 g. (9.56 mmoles) of trans-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-4-(3-hydroxypropyl)cyclohexanone ethylene ketal, 50 ml. of 2N hydrochloric acid and 100 ml. of tetrahydrofuran was heated at reflux for 2 hours. The reaction was cooled and added to 500 ml. saturated sodium chloride and 250 ml. ether. The ether extract was separated and washed once with 500 ml. saturated sodium chloride, once with 500 ml. saturated sodium bicarbonate, dried over magnesium sulfate and evaporated (aspirator) to an oil. The crude oil was purified via column chromatography on 200 g. of silica gel eluted with 80% ether-hexane to yield 2.93 g. (82%) of the title compound as an oil.