Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]([CH:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=2)[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:4]([C:27](O)=[O:28])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>O1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)[N:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[C:27](=[O:28])[C:4]=2[CH:3]=1
Reactant: CC(C)n1c(Br)cc(C(=O)O)c1C(Nc1ccc(F)c(Cl)c1)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N(c1ccc(F)c(Cl)c1)C2=O
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-2-[(3-chloro-4-fluoro-phenylamino)-(4-chloro-phenyl)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid (Step D1) (1.483 mmol), HATU (1.632 mmol) and NMM (4.45 mmol) in dioxane (75 mL) was heated at 80° C. for 17 h. After cooling to rt, the reaction mixture was diluted with EtOAc and washed with a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with EtOAc (2×). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a light-yellow solid. tR: 5.31 min (HPLC 2); ESI-MS: tR=1.40 min, [M+H]+481/483/485 (LC-MS 1); TLC: Rf=0.27 (1:3 EtOAc/hexanes).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([O:13][C:14]1[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20](Cl)=[O:21])=[CH:16][CH:15]=1)[CH:7]=[N:6]2.[C:28]([CH:31](C(=O)C(OC1C=CC(OC2C=NC3C(=CC=C(F)C=3)N=2)=CC=1)C)[C:32]([O:34][CH3:35])=[O:33])(=[O:30])[CH3:29].C(Cl)(=O)C(Cl)=O.[Na].COC(=O)CC(C)=O>>[C:28]([CH:31]([C:20](=[O:21])[CH:19]([O:18][C:17]1[CH:24]=[CH:25][C:14]([O:13][C:8]2[CH:7]=[N:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:27])([F:26])[F:1])[CH:4]=3)[N:9]=2)=[CH:15][CH:16]=1)[CH3:23])[C:32]([O:34][CH3:35])=[O:33])(=[O:30])[CH3:29]
Reactant: CC(Oc1ccc(Oc2cnc3cc(C(F)(F)F)ccc3n2)cc1)C(=O)Cl
Reactant: COC(=O)C(C(C)=O)C(=O)C(C)Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1
Agent: COC(=O)CC(C)=O
Agent: O=C(Cl)C(=O)Cl
Agent: [Na]
Product: COC(=O)C(C(C)=O)C(=O)C(C)Oc1ccc(Oc2cnc3cc(C(F)(F)F)ccc3n2)cc1

Procedure:
In the same manner, 2-[4-(6-trifluoromethyl-2-quinoxalinyloxy)phenoxy]propionic acid chloride is prepared from the corresponding propionic acid and oxalyl chloride, and is then reacted with the sodium salt of methylacetoacetate to give methyl 2-acetyl-4-[4-(6-trifluoromethyl-2-quinoxalinyloxy)phenoxy]-3-oxopentanoate (XIV; X' is CF3 and X" is hydrogen). The pentanoate is then heated with sodium chloride and DMSO to yield 5-[4-(6-trifluoromethyl-2-quinoxalinyloxy)phenoxy]-2,4-hexanedione (XV; X' is CF3 and X" is hydrogen).
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([N+:17]([O-])=O)[CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[H][H]>[Ni].C(O)C>[N:1]1([CH:6]([C:10]2[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:7]([CH3:8])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: [H][H]
Reactant: CC(C)C(c1ccc(N)c([N+](=O)[O-])c1)n1ccnc1
Agent: [Ni]
Solvent: CCO
Product: CC(C)C(c1ccc(N)c(N)c1)n1ccnc1
Yield: 99.9 %

Procedure:
(a-5) A mixture of 31 parts of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-2-nitrobenzenamine and 240 parts of ethanol was hydrogenated at room temperature in a Parr apparatus at 0.5 105Pa with 30 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over diatomaceous earth and the filtrate was evaporated, yielding 27.4 parts (99.9%) of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-1,2-benzenediamine as a residue (int. 105).
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[CH3:37][O:38][C:39]1[CH:40]=[CH:41][C:42]2[O:46][CH:45]=[C:44]([C:47](=O)[CH3:48])[C:43]=2[CH:50]=1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:47]([C:44]2[C:43]4[CH:50]=[C:39]([O:38][CH3:37])[CH:40]=[CH:41][C:42]=4[O:46][CH:45]=2)[CH:48]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: COc1ccc2occ(C(C)=O)c2c1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2occ(-c3ccc4cc(-c5nc6cc(C(=O)O)ccc6n5C5CCCCC5)ccc4n3)c2c1
Yield: 8 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(5-methoxy-benzofuran-3-yl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (10 mg, 8% yield). MS: 518.24 (M+H+); HPLC Procedure B, retention time=7.60 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[CH:9]=O.[OH-].[K+].O.Cl.[CH2:15]1C[O:18][CH2:17][CH2:16]1>>[Cl:8][C:6]1[CH:7]=[C:2]2[C:3]([CH:9]=[C:17]([OH:18])[C:16]([CH3:15])=[N:1]2)=[CH:4][N:5]=1
Reactant: Nc1cc(Cl)ncc1C=O
Reactant: C1CCOC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2cc(Cl)ncc2cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Treat a mixture of 4-amino-6-chloro-pyridine-3-carbaldehyde (39 g, 0.25 mol) and 2-hydroxy acetone (28 g, 0.375 mol) in THF (400 mL) with KOH (52.5 g, 0.75 mol), stir at RT for 1 h, add water and acidify with 1N HCl. Collect the resulting solids by filtration, wash with water (3×), then EtOAc (2×) and dry to afford the title compound (45 g, 93%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.00 (s, 1H), 7.77 (s, 1H), 7.53 (s, 1H), 2.54 (s, 3H).
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[C:14]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=2[C:12]2[C:11](=[O:20])[NH:10][CH:9]=[CH:8][C:7]=2[N:6]=1)[CH3:4].C(#N)C.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:5]([CH:3]([CH3:4])[CH2:2][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[N:6][C:7]3[CH:8]=[CH:9][NH:10][C:11](=[O:20])[C:12]=3[C:13]=2[CH:18]=1
Reactant: C1COCCN1
Reactant: CC(CBr)c1nc2cc[nH]c(=O)c2c2cc(F)ccc12
Solvent: CC#N
Product: CC(CN1CCOCC1)c1nc2cc[nH]c(=O)c2c2cc(F)ccc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A suspension of 6-(2-bromo-1-methylethyl)-9-fluorobenzo[c]-1,6-naphthyridin-1(2H)-one (HBr salt) (25 mg, 0.060 mmol) in morpholine (1.0 mL) was stirred at 100° C. for 1 h. After cooling to room temperature, acetonitrile was added, and the resulting solution was concentrated to a crude residue. The resulting crude residue was purified by preparative reverse phase HPLC eluting with an acetonitrile/water (with 0.05% TFA as a modifier) gradient to afford 9-fluoro-6-(1-methyl-2-morpholin-4-ylethyl)benzo[c]-1,6-naphthyridin-1(2H)-one. 1H NMR (500 MHz, DMSO-D6). δ 11.86 (br d, 1H), 9.76 (dd, 1H), 8.63 (dd, 1H), 7.62 (br t, 1H), 7.57 (br t, 1H), 6.76 (d, 1H), 4.20 (br m, 1H), 3.47 (br s, 4H), 2.80 (br dd, 1H), 2.65 (br m, 1H), 2.43 (br s, 4H), 1.33 (d, 3H). LRMS (ESI) calc'd for (C19H20FN3O2) [M+H]+, 342.2; found 342.1.
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][OH:20])[CH:13]=2)=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)=[O:2].[C:21]([Si:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)Cl)([CH3:24])([CH3:23])[CH3:22].N1C=CN=C1>CN(C)C=O.CN(C)C1C=CN=CC=1>[Si:25]([O:20][CH2:19][CH2:18][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:3]([CH:1]=[O:2])=[CH:8][N:7]=[C:6]([S:9][CH3:10])[N:5]=2)[CH:17]=[CH:16][CH:15]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CSc1ncc(C=O)c(Nc2cccc(CCO)c2)n1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CSc1ncc(C=O)c(Nc2cccc(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)n1
Reaction time: 18 h
Yield: 100.4 %

Procedure:
A solution of 3.4 g (11.7 mmol) of 5-formyl-4-(3-(2-hydroxyethyl)phenylamino)-2-methylthiopyrimidine of Example 37(e) in 50 ml of dimethylformamide was treated with 3.9 g (14 mmol) of tert-butyldiphenylchlorosilane, 2.4 g (35 mmol) of imidazole and 50 mg (0.4 mmol) of 4-(dimethylamino)pyridine. The mixture was stirred for 18 hours and then evaporated. The residue was partitioned between 150 ml of ethyl acetate and 100 ml of 2M aqueous hydrochloric acid. The organic phase was washed with a further 100 ml of 2M aqueous hydrochloric acid, dried over magnesium sulfate, filtered and evaporated to yield 6.2 g (100%) of 4-(3-(2-(tert-butyldiphenylsilyloxy)ethyl)phenylamino)-5-formyl-2-methylthiopyrimidine as a white solid. [Mass spectrum (ESI) MH+ =528].
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[F:6][C:7]([F:15])([F:14])[C:8]#[C:9][C:10]([F:13])([F:12])[F:11]>>[F:6][C:7]([F:15])([F:14])[C:8]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:4]2[CH2:5][C:1]=1[CH2:2][CH2:3]2
Reactant: FC(F)(F)C#CC(F)(F)F
Reactant: C1=CCC=C1
Product: FC(F)(F)C1=C2CCC(=C1C(F)(F)F)C2

Procedure:
Reaction of cyclopentadiene with hexafluoro-but-2-yne at 100° C for 24 hours gives 2,3-bis (trifluoromethyl) bicyclo [2.2.1] heptadiene which, upon hydrogenation over platinum, gives 2,3-bis(trifluoromethyl) bicyclo [2.2.1] heptane.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C@@H:25]([C:39]([OH:41])=O)[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=3)=[O:23])[CH2:18][CH2:17]2)[CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[NH:10]1.[CH2:46]([O:48][C:49](=[O:64])[CH2:50][N:51]1[CH2:56][CH2:55][C:54]([CH3:63])([N:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:53][CH2:52]1)[CH3:47].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[O:8]=[C:9]1[N:15]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C@H:25]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=3)[C:39]([N:60]3[CH2:61][CH2:62][N:57]([C:54]4([CH3:63])[CH2:55][CH2:56][N:51]([CH2:50][C:49]([O:48][CH2:46][CH3:47])=[O:64])[CH2:52][CH2:53]4)[CH2:58][CH2:59]3)=[O:41])=[O:23])[CH2:20][CH2:21]2)[CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[NH:10]1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Reactant: CCOC(=O)CN1CCC(C)(N2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCC(C)(N2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.25 mL (1.18 mmol) triethylamine were added to a mixture of 250 mg (0.45 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f), 250 mg (0.50 mmol) ethyl(4-methyl-4-piperazin-1-yl-piperidin-1-yl)-acetate (Example A7f) and 160 mg (0.50 mmol) TBTU in 2 mL DMF and the reaction mixture was stirred for 4 h at RT. It was evaporated down i. vac. and the residue was purified by HPLC; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [SH:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])=[C:11]2[C:6]([N:7]([CH3:24])[C:8](=[O:23])[N:9]([CH3:22])[C:10]2=[O:21])=[CH:5]1.[Cl:25][C:26]1[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1.[O-]S(C(F)(F)F)(=O)=O.[Bi+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.C(OCC)C>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:25][C:26]1[O:30][C:29]([CH:31]2[C:5]3=[C:6]4[N:7]([CH3:24])[C:8](=[O:23])[N:9]([CH3:22])[C:10](=[O:21])[C:11]4=[C:12]([C:13]4[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=4)[C:16]#[N:17])[N:4]3[CH2:3][CH2:2][S:1]2)=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(Cl)o1
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCS)cc2n(C)c1=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Bi+3]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n3c(c2n(C)c1=O)C(c1ccc(Cl)o1)SCC3
Temperature: 100 °C

Procedure:
A suspension comprising 3-(6-(2-mercaptoethyl)-1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Intermediate G) (150 mg, 0.441 mmol), 5-chlorofuran-2-carbaldehyde (57.5 mg, 0.441 mmol) and bismuth triflate (28.9 mg, 0.044 mmol) in toluene (5 ml) was heated to 100° C. for 10 min using microwave radiation. After cooling to RT, the reaction mixture was diluted with EtOAc (25 ml) and washed with water. The layers were separated and the aqueous extracted with EtOAc (3×20 ml). The combined organics were dried over MgSO4, filtered and concentrated to yield a brown oil. Purification was carried out by chromatography on silica eluting with 0-45% EtOAc in iso-hexane. The relevant fraction were combined and concentrated in vacuo to yield a pale yellow oil. Diethyl ether (5 ml) was added to the oil to give a white solid. The solid was isolated by suction filtration to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:13][C:14]([OH:16])=[O:15])C(O)=O)[CH:6]=[CH:7][CH:8]=1.[CH2:17](O)[CH3:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: CCO
Reactant: COc1cccc(C(CC(=O)O)C(=O)O)c1
Product: CCOC(=O)CCc1cccc(OC)c1
Yield: 93 %

Procedure:
A solution of 3-methoxyphenylsuccinic acid (1.500 g, 8.32 mmol) in dry ethanol (15 mL) with a small quantity of DOWEX™ strong acid ion exchange resin was refluxed for 22 h. The reacion mixture was filtered and the solvent evaporated in vacuo to give 1.618 g of ester 25. Yield 93%. 1H NMR (300 MHz, CDCl3) δ ppm: 7.15 (q, J=8.6 Hz, 1H), 6.72 (d, J=7.8 Hz, 1H), 6.65-6.70 (m, 2H), 4.06 (q, J=7.1 Hz, 2H), 3.72 (s, 3H), 2.86 (t, J=7.9 Hz, 2H), 2.54 (t, J=7.9 Hz, 2H), 1.17 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ ppm: 172.9, 159.7, 142.2, 129.4, 120.6, 114.0, 111.6, 60.4, 55.1, 35.8, 31.0, 14.2; HRMS (EI) m/z: calcd for C12H16O3: 208.1099. found: 208.1104.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[C:14]([NH2:19])[C:13]3[N:20]=[C:21]([CH2:24][CH3:25])[N:22]([CH3:23])[C:12]=3[C:11]=2[CH:10]=1)C1C=CC=CC=1.C(OC1C=CC2C3N(CC(C)C)C(CCC)=NC=3C(N)=NC=2C=1)C1C=CC=CC=1>>[NH2:19][C:14]1[C:13]2[N:20]=[C:21]([CH2:24][CH3:25])[N:22]([CH3:23])[C:12]=2[C:11]2[CH:10]=[C:9]([OH:8])[CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CCc1nc2c(N)nc3ccc(OCc4ccccc4)cc3c2n1C
Agent: CCCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Product: CCc1nc2c(N)nc3ccc(O)cc3c2n1C
Reaction time: 4 h
Yield: 20.6 %

Procedure:
The general method described in Example 5 was followed using 8-benzyloxy-2-ethyl-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine (0.47 g, 1.4 mmol), prepared as described in Example 57, in lieu of 7-benzyloxy-2-propyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine. The hydrogenation was complete in four hours, and after the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure to a small volume. Hexanes were added, and a precipitate formed, which was isolated by filtration and washed with hexanes. The solid was recrystallized from methanol to provide 70 mg of 4-amino-2-ethyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-ol as a white, crystalline solid, mp>240° C.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1Cl)=[O:13])[CH2:8]2.[NH:24]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25]1>CN1CCCC1=O>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[N:24]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25]1)=[O:13])[CH2:8]2
Reactant: OC1CCNC1
Reactant: CC(C)(C)n1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Solvent: CN1CCCC1=O
Product: CC(C)(C)n1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1N1CCC(O)C1
Temperature: 25 °C
Yield: 22 %

Procedure:
A mixture of 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 36, 101 mg; 0.30 mmol) and pyrrolidin-3-ol (+/−) (0.25 mL; 3.0 mmol) in N-methylpyrrolidinone (1 mL) was heated to 250° C. in a sealed vial under microwave irradiation for 4 hr. The mixture was allowed to cool to room temperature and the crude product was purified by reverse phase HPLC to provide 1-tert-butyl-5-(3-hydroxy-pyrrolidin-1-yl)-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (25 mg, 22%) as an off white solid. ES-HRMS m/e calcd for C22H35N4O2 (M+H+) 358.2602, found 358.2602.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.[NH2:10][C:11]1[CH:12]=[C:13]([C:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=2)=[CH:20][C:21]#[N:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].CCOC(C)=O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH2:32]([O:31][C:25]1[CH:24]=[C:23]([C:19]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:11]([N:10]3[CH:3]=[CH:7][CH:6]=[CH:5]3)[CH:12]=2)=[CH:20][C:21]#[N:22])[CH:28]=[CH:27][C:26]=1[O:29][CH3:30])[CH3:33]
Reactant: CCOc1cc(C(=CC#N)c2ccc(OC)c(N)c2)ccc1OC
Reactant: COC1CCC(OC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOc1cc(C(=CC#N)c2ccc(OC)c(-n3cccc3)c2)ccc1OC
Temperature: 25 °C

Procedure:
2,5-Dimethoxytetrahydrofuran (0.2 g, 1.7 mmol) was added to a stirred solution of 3-(3-amino-4-methoxy-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile (0.5 g, 1.5 mmol) in acetic acid (10 mL). The reaction mixture was heated to reflux under nitrogen for one hour. The mixture was cooled down to room temperature. The mixture was stirred with EtOAc (100 mL) and saturated NaHCO3 (40 mL) was added slowly. The EtOAc solution was washed with water (60 mL), brine (60 mL) and dried (MgSO4). Solvent was removed and the residue was purified by flash chromatography (silica gel, Hexane:EtOAc 6:4) to afford mixture of isomers of 3-(3-ethoxy-4-methoxy-phenyl)-3-(4-methoxy-3-pyrrol-1-yl-phenyl)-acronitrile (0.4 g, 60%) as a white solid: mp 109-111° C.; 1H NMR (CDCl3) δ 7.00 (m, 2H), 7.47-6.81 (m, 6H), 6.30 (m, 2H), 5.59 (5.57) (s, 1H), 4.05 (m, 2H), 3.91 (m, 6H), 1.45 (m, 3H); 13C NMR (CDCl3) δ 161.67(161.61), 153.93(154.35), 151.56(151.00), 148.27(148.00), 131.40(132.10), 129.83(130.06), 129.03(127.16), 125.93(127.93), 123.07, 122.21, 122.05(121.93), 118.52(118.43), 114.00, 112.01(112.06), 111.09(112.70), 109.15(109.28), 92.45, 64.56, 56.05(56.00), 14.69; Anal. Calcd for C23H22N2O3. Theoretical: C, 73.78; H, 5.92, N, 7.48. Found: C, 73.46; H, 5.71; N, 7.35.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11]Br.[CH2:20]([O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)[CH3:21].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:29][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([O:22][CH2:20][CH3:21])=[CH:31][CH:30]=1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Reactant: CCOc1ccc(C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.6 %

Procedure:
In a reaction vessel were placed 0.29 g of 3,5-dichloro-4-(3-bromopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 0.12 g of 4-ethoxybenzoic acid, 0.12 g of potassium carbonate and 10 ml of N,N-dimethylformamide, followed by stirring at room temperature for 12 hours. The reaction mixture was poured into water, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.30 g of 3,5-dichloro-4-(3-(4-ethoxybenzoyloxy)propyloxy)-1-(3,3-dichloro-2-propenyloxy)-benzene (86% yield), nD24.0 1.5715.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[I-].C[S+](C)C.[H-].[Na+].[Cl-].[NH4+].C([BH3-])#N.[Na+].C(O)(=O)C[C:27](CC(O)=O)(C(O)=O)[OH:28]>O1CCCC1.CS(C)=O>[F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][CH2:27][OH:28]
Reactant: COc1ccc(F)c(C=O)c1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: C[S+](C)C
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1ccc(F)c(CCO)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixed solution of 2-fluoro-5-methoxybenzaldehyde (0.8 ml) in tetrahydrofuran (4 ml) and dimethylsulfoxide (4 ml), 1.97 g of trimethylsulfonium iodide and 308 mg of sodium hydride were added under ice-cooling, and the reaction solution was stirred at room temperature for 2 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (98:2-50:50)) to afford a crude product as a colorless oil. To a solution of the crude product in tetrahydrofuran (2 ml), 200 mg of Sodium cyanoborohydride and 0.4 ml of trifluoroborane-diethylether complex were added under ice-cooling, and the reaction solution was stirred at room temperature for 2 hours. To the reaction solution was added 10% aqueous citric acid, and the mixture was extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (95:5-30/70)) to afford the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:17]=[CH:16][C:15]=3[CH3:34])=[O:12])[S:8][C:5]2=[N:6][CH:7]=1.[CH2:35]([O:37]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:36].Cl>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:35]([C:2]1[N:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:17]=[CH:16][C:15]=3[CH3:34])=[O:12])[S:8][C:5]2=[N:6][CH:7]=1)(=[O:37])[CH3:36]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2nc(Cl)cnc2s1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)c1cnc2sc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.6 %

Procedure:
A solution of 2-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 24 (50 mg, 0.102 mmol), bis(triphenylphosphine)palladium(ii) chloride (7.16 mg, 10.2 μmol) and 1-ethoxyvinyltri-n-butyltin (0.103 mL, 0.306 mmol) toluene (3 mL) was stirred at 100° C. for 2 h. Cooled down to rt, 4N HCl in Dioxane (1 mL) was added and stirred for 1 h. Diluted with EtOAC, filtrated and evaporated. Purification by chromatography (0-10% EtOAc in CH2Cl2) gave the title compound 2-acetyl-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 25g (13 mg, 25.6%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.28 (s, 3H), 2.76 (s, 3H), 7.33 (d, J=8.2 Hz, 1H), 7.58-7.68 (m, 2H), 7.76 (d, J=7.8 Hz, 1H), 7.91 (d, J=1.9 Hz, 1H), 7.96 (d, J=7.8 Hz, 1H), 8.06 (s, 1H), 8.65 (s, 1H), 9.20 (s, 1H), 10.39 (s, 1H), 10.57 (s, 1H). (m/z)=498 (M+H)+.