Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+]>C(O)(=O)C.O.[Fe]>[S:11]1[CH:12]=[CH:13][N:14]=[C:10]1[C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(-c2nccs2)cc1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(-c2nccs2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
Iron powder (0.5 g, 8.92 mmol) was added portion wise to a solution of 2-(4-nitrophenyl)-thiazole (200 mg, 0.97 mmol) in acetic acid (5 ml) and stirred at room temperature for 2 hr. The reaction mixture was diluted with water, basified with dilute sodium hydroxide, filtered and the filtrate was extracted with ethyl acetate. The organic layer was washed with water, brine and dried. Evaporation of the solvent yielded 4-thiazol-2-yl-phenylamine (150 mg, 88%) as solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:15])=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]#[CH:13])[C:6]=2[CH:14]=1.[CH2:16]=[C:17]1[O:21][C:19](=[O:20])[CH2:18]1.N1(C2C=CN=CC=2)CCCC1>C1C=CC=CC=1>[C:19]([NH:1][C:2]1[C:3]([F:15])=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]#[CH:13])[C:6]=2[CH:14]=1)(=[O:20])[CH2:18][C:17]([CH3:16])=[O:21]
Reactant: C=C1CC(=O)O1
Reactant: C#CCn1c(=O)sc2cc(F)c(N)cc21
Agent: c1cc(N2CCCC2)ccn1
Solvent: c1ccccc1
Product: C#CCn1c(=O)sc2cc(F)c(NC(=O)CC(C)=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 4.7 g of 5-amino-6-fluoro-3-(2-propynyl)-2-benzothiazolinone, 1.93 g of diketene and 0.05 g of 4-pyrrolidinopyridine in 250 ml of benzene is stirred at room temperature for 30 minutes and subsequently held at 50° C. for 30 minutes. In this manner there is obtained a solution of 5-acetoacetylamino-6-fluoro-3-(2-propynyl)-2-benzothiazolinone which is used as such in the next reaction step without isolation of the product.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].[F:8][C:9]1[CH:26]=[CH:25][C:12]([C:13]([NH:15][CH:16]([C:21](OC)=[O:22])[C:17](OC)=[O:18])=[O:14])=[CH:11][CH:10]=1.[Na]>C(O)C>[OH:22][C:21]1[C:16]([NH:15][C:13](=[O:14])[C:12]2[CH:25]=[CH:26][C:9]([F:8])=[CH:10][CH:11]=2)=[C:17]([OH:18])[N:7]=[CH:5][N:6]=1
Reactant: N=CN
Reactant: COC(=O)C(NC(=O)c1ccc(F)cc1)C(=O)OC
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(Nc1c(O)ncnc1O)c1ccc(F)cc1
Yield: 64.9 %

Procedure:
Formamidine acetate (0.46 g, 4.46 mmol) and dimethyl 2-(4-fluorobenzamido)malonate (1.0 g, 3.71 mmol) were added to a solution of sodium (0.17 g, 7.43 mmol) in ethanol (37 ml). The reaction mixture was refluxed for 3 hours. After cooling down, the precipitate was filtered off and washed with ethanol. The product was dissolved in a minimal volume of water and acidified to pH 4-5 with 5M HCl. The precipitate was collected, washed with water and dried to yield the title compound as a white solid (0.60 g, 64%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[N:7][N:8]([CH2:10][CH2:11][NH2:12])[CH:9]=1)([O-:4])=[O:3].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21].O>O1CCCC1>[N+:2]([C:5]1[CH:6]=[N:7][N:8]([CH2:10][CH2:11][NH:12][C:20](=[O:22])[CH3:21])[CH:9]=1)([O-:4])=[O:3]
Reactant: NCCn1cc([N+](=O)[O-])cn1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NCCn1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-nitro-1H-pyrazol-1-yl)ethanamine hydrochloride (1.0 g) obtained in Step B of Example 348 in tetrahydrofuran (30 mL) were successively added triethylamine (2.2 mL) and acetyl chloride (0.44 mL) in an ice bath, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized (hexane/ethyl acetate) to give the title compound (610 mg).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22](O)[CH2:23][CH2:24][C:25]\3=[CH2:26])/[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:29]1(=[O:39])[N:33]([CH:22]2[CH2:23][CH2:24][C@@:25]3([CH3:26])[CH:20]([CH2:19][CH2:18][C@@H:17]4[C@@H:16]3[CH2:15][CH2:14][C@@:13]3([CH3:28])[C@H:12]4[CH2:11][CH2:10][C@@H:9]3[C@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:21]2)[C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]12
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(N5C(=O)c6ccccc6C5=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of dihydrocholesterol (5.0 g, 12.9 mmol, Aldrich), phthalimide (2.0 g, 13.6 mmol, Aldrich), and triphenylphosphine (3.8 g, 13.6 mmol, Aldrich) in THF (20 ml, Aldrich) stirred at 0° C. under a nitrogen atmosphere was added dropwise diethylazodicarboxylate (2.3 ml, 14.5 mmol, Aldrich). Upon the completion of addition the reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was concentrated in vacuo to a residue. This residue was dissolved in 50 ml hexane/ethyl acetate 95/5 and a precipitate formed. The mixture was filtered. The filtrate was concentrated to dryness in vacuo, dissolved in 25 ml of hexane/ethyl acetate 95/5 and chromatographed on 200 g silica gel (eluent 2 L hexane/ethyl acetate 95/5 then 1 L hexane/ethyl acetate 90/10). A 76% yield of the desired 3-phthalimidocholestane (5.43 g) was obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1.NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.[F:61][C:62]([F:73])([F:72])C1C=CC=CC=1N=C=S>>[CH3:33][CH:32]([CH3:34])[C@H:27]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][CH:25]=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[C:62]([F:73])([F:72])[F:61])=[S:35])=[CH:16][CH:15]=3)[CH:18]=2)[C:22]1=[O:26])[C:28]([O:30][CH3:31])=[O:29]
Reactant: FC(F)(F)c1ccccc1N=C=S
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4C(F)(F)F)cc3)ccc2C1=O

Procedure:
The compound of example 270 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 2-trifluoromethyl phenyl isothiocyanate. The compound of example 270 was used directly without isolation, for the preparation of compound of example 271.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4]([CH:5]=[C:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:11](O)=[O:12].S(Cl)([Cl:17])=O>>[CH3:1][C:2]1([CH3:14])[C@@H:4]([CH:5]=[C:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:11]([Cl:17])=[O:12]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C=C1CCCC1
Reactant: O=S(Cl)Cl
Product: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C1CCCC1

Procedure:
A mixture of (1R,cis) 2,2-dimethyl-3-(cyclopentylidenemethyl)-cyclopropane-carboxylic acid and thionyl chloride in petroleum ether (b.p.=40° to 70° C.) was refluxed to obtain (1R,cis) 2,2-dimethyl-3-(cyclopentylidenemethyl)-cyclopropane-carboxylic acid chloride which was then reacted with R,S α-hydroxy-6-phenoxy-2-pyridine-acetonitrile in benzene in the presence of pyridine to obtain (R,S)α-cyano-(6-phenoxy-2-pyridyl)-methyl (1R,cis) 2,2-dimethyl-3-(cyclopentylidenemethyl)-cyclopropane-carboxylate.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](=O)[C:15]([OH:17])=[O:16].C(O)C>O>[OH:3][N:2]=[C:14]([C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)[C:15]([OH:17])=[O:16]
Reactant: O=C(O)C(=O)c1cccs1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)C(=NO)c1cccs1

Procedure:
A cooled solution of hydroxylamine hydrochloride (0.884 g) and sodium bicarbonate (1.08 g) in water (20 ml.) was added to a cooled (0° ) solution of thien-2-yl-glyoxylic acid (2.0 g) and sodium bicarbonate (1.08 g) in water (20 ml.). After two days at 20° the solution was extracted with ether, cooled and acidified with concentrated hydrochloric acid. The resulting white solid was filtered off (0.564 g) and the filtrate was then thoroughly extracted with ether. The combined extracts were washed with brine, dried and concentrated. The solid residue was triturated with benzene to give the exime (synisomer) (1.05 g; 51%), m.p. 132°, λmax. (ethanol) 284 nm (Ε9,500),νmax. (Nujol) 2590 and 1706 (SO2H) and 1655 cm-1 (C=N), τ (DMSO-d6), -2.5 to -0.5 (broad multiplet; N-OH and COOH), 2.36 (multiplet; thienyl C-5 H) and 2.82 (multiplet; thienyl C-3 H and C-4 H).
Reaction SMILES: C([C:8]1[C:9]([OH:30])=[C:10]([C:14]([C:16]2[CH:21]=CC=[C:18]([CH2:22][C:23]3[CH:28]=[CH:27]C=CC=3)[C:17]=2O)=[O:15])[CH:11]=[CH:12][CH:13]=1)C1C=CC=CC=1.C(N)=O>O>[O:30]1[C:9]2[C:10](=[CH:11][CH:12]=[CH:13][CH:8]=2)[C:14](=[O:15])[C:16]([C:17]2[CH:18]=[CH:22][CH:23]=[CH:28][CH:27]=2)=[CH:21]1
Reactant: O=C(c1cccc(Cc2ccccc2)c1O)c1cccc(Cc2ccccc2)c1O
Solvent: NC=O
Solvent: O
Product: O=c1c(-c2ccccc2)coc2ccccc12
Yield: 21.7 %

Procedure:
Benzyl-2-hydroxyphenyl ketone (29.0 g) and formamide (29.0 g). were heated together at 208° for 1 hr. The reaction mixture was cooled and diluted with water. The oily product was extracted into chloroform and the solution washed with water, dried and evaporated. The residue was chromatographed on alumina, eluting with toluene, and the product recrystallised once from petroleum ether (80°-100°) and once from toluene to yield isoflavone (3.55 g), m.pt. 132°-134°
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.[CH:38]12[N:44]([C:45](=O)[CH2:46]Br)[CH:41]([CH2:42][CH2:43]1)[CH2:40][CH2:39]2>>[CH:38]12[N:44]([CH2:45][CH2:46][O:10][C:8]3[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]4[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=4[CH:12]4[CH2:21][CH2:20][C:19]5[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=5[CH2:13]4)=[CH:6][CH:7]=3)[CH:41]([CH2:42][CH2:43]1)[CH2:40][CH2:39]2
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CBr)N1C2CCC1CC2
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3C4CCC3CC4)cc2)c1
Yield: 133.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 1-(7-azabicyclo[2.2.1]hept-7-yl)-2-bromoethanone (18 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (14 mg) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:6])[CH2:5][CH2:4]1.[CH3:7][C:8]([CH3:13])([CH3:12])[CH2:9][CH:10]=O.[S-:14][C:15]#[N:16].[K+].II>C(#N)C>[C:8]([C:9]1[S:14][C:15](=[NH:16])[N:1]([CH2:2][C:3]2([OH:6])[CH2:5][CH2:4]2)[CH:10]=1)([CH3:13])([CH3:12])[CH3:7]
Reactant: CC(C)(C)CC=O
Reactant: N#C[S-]
Reactant: NCC1(O)CC1
Agent: II
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)c1cn(CC2(O)CC2)c(=N)s1
Yield: 95.7 %

Procedure:
A mixture of 1-(aminomethyl)cyclopropanol (ChemPacific, 1.0 g, 11.5 mmol), 3,3-dimethylbutanal (1.6 mL, 12.6 mmol), 4 Å molecular sieves (3 g, 8-12 mesh beads), potassium thiocyanate (1.5 g, 15 mmol) and iodine (2.9 g, 11.5 mmol) in acetonitrile (25 mL) were processed as described in Example 18A to provide the title compound (2.5 g, 11 mmol, 95% yield). MS (DCI/NH3) m/z 227 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:27])[C:13]([CH3:26])([O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH3:14])[S:9][CH:10]=1)C.[Li+].[OH-]>C1COCC1.CO.O>[CH3:26][C:13]([O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)([CH3:14])[C:12]([NH:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][C:4]([OH:28])=[O:3])[N:7]=1)=[O:27]
Reactant: CCOC(=O)Cc1csc(NC(=O)C(C)(C)Oc2cccc3ccccc23)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(Oc1cccc2ccccc12)C(=O)Nc1nc(CC(=O)O)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.6 %

Procedure:
To a solution of {2-[2-Methyl-2-(naphthalen-1-yloxy)-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester (0.196 g, 5 mmol) in THF (2 ml) and MeOH (1 ml) added a solution of LiOH (0.021 g, 25 mmol) in H2O (1 ml) and stirred at r.t. for 18 h. Solvents were evaporated under reduced pressure and residue was dissolved in water (5 ml) and extracted with ether (2×2 ml). The aqueous phase was acidified with citric acid solution, extracted in EtOAc (2×30 ml), dried over Na2SO4 and the solvent was evaporated under reduced pressure to obtain {2-[2-Methyl-2-(naphthalen-1-yloxy)-propionylamino]-thiazol-4-yl}-acetic acid (0.16 g, 89%). 1H NMR (400 MHz, CDCl3): δ1.72 (s, 6H), 3.42 (s, 2H), 6.34 (s, 1H), 6.74 (d, J=7.2 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.49-7.55 (m, 3H), 7.83-7.85 (m, 1H), 8.23-8.25 (m, 1H), MS (EI) m/z: 371.00 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=CN=3)=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36].[CH2:39]([N:41](CC)CC)C>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)(=[O:37])=[O:36])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:39]=[N:41][CH:24]=[N:25][CH:26]=3)=[CH:19][CH:20]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: CCN(CC)CC
Agent: Cl
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3cncnc3)cc2)S(=O)(=O)c2ccccn2)c1

Procedure:
The title compound of Step A was prepared from 3-{3-[(4-pyrazin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11x, and pyridine-2-sulfonyl chloride hydrochloride, of Preparation 47, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.98 (d, 1H), 8.69 (m, 1H), 8.62 (m, 1H), 8.50 (d, 1H), 7.99 (m, 1H), 7.86 (m, 3H), 7.48 (m, 1H), 7.26 (m, 2H), 7.11 (m, 1H), 7.01 (d, 1H), 6.94 (d, 1H), 6.89 (s, 1H), 4.56 (s, 2H), 4.48 (s, 2H), 3.65 (s, 3H), 2.80 (t, 2H), 2.49 (t, 2H); MS 503 (M+1).
Reaction SMILES: [C:1]([C:3]([CH3:32])([CH3:31])[CH:4]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([CH:20]3[CH2:22][CH2:21]3)[N:18]=2)[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:12]=1)=[O:10])[CH:5]1[CH2:7][CH2:6]1)#[N:2].CC[OH:35]>O.[PtH]1([P](O[H]O[P]1(C)C)(C)C)[P](O)(C)C>[C:1]([C:3]([CH3:32])([CH3:31])[CH:4]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([CH:20]3[CH2:22][CH2:21]3)[N:18]=2)[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[CH:12]=1)=[O:10])[CH:5]1[CH2:6][CH2:7]1)(=[O:35])[NH2:2]
Reactant: CCO
Reactant: CC(C)(C#N)C(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12)C1CC1
Solvent: O
Product: CC(C)(C(N)=O)C(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-cyano-1-cyclopropyl-2,2-dimethyl-ethyl)-amide (163 mg, 0.36 mmol) in EtOH (9 mL) and H2O (1 mL) was added [PtH(PMe2OH)(PMe2O)2H] (15 mg, 0.036 mmol). The reaction mixture was heated at reflux for 6 h. Additional catalyst (10 mg, 0.023 mmol) was added and heating was continued overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by SiO2 chromatography (50% to 100% EtOAc/hexanes) to provide 108 mg (64%) of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-carbamoyl-1-cyclopropyl-2-methyl-propyl)-amide as a viscous colorless oil.
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][C:11](=[O:14])[CH:10](O)[C:9]=2[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.Cl>C1(C)C=CC=CC=1.CN(C=O)C>[C:1]([C:5]1[C:13]2[O:12][C:11](=[O:14])[C:10](=[C:10]3[C:9]4[CH:8]=[C:7]([CH3:16])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:13]=4[O:12][C:11]3=[O:14])[C:9]=2[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Agent: Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1cc2c(c(C(C)(C)C)c1)OC(=O)C2=C1C(=O)Oc2c1cc(C)cc2C(C)(C)C
Temperature: 99.85000000000002 °C

Procedure:
22 g of 7-tert-butyl-3-hydroxy-5-methyl-3H-benzofuran-2-one (prepared as described in Ex. 2 of U.S. Pat. No. 5,614,572) are placed in 50 ml of toluene, and 3 drops of DMF and 15 ml of thionyl chloride are added thereto. The solution is then slowly heated to 373 K at such a rate that the evolution of HCl and SO2 remains vigorous yet controllable. It is then stirred at 373 K for a further hour. Approximately 50 ml of liquid are then distilled off in order to remove the excess thionyl chloride. The residue is diluted with 160 ml of toluene and, at room temperature, 14 ml of triethylamine are added dropwise. The thick, red reaction mixture is then heated under reflux for 30 min. After cooling to room temperature, the triethylamine hydrochloride which has precipitated is filtered off, and the residue is concentrated to an oily consistency using a rotary evaporator. The isoxindigo is crystallised out by adding 200 ml of acetonitrile, is filtered off, washed with acetonitrile and dried, yielding 11.6 g (57% of the theoretical yield) of 7,7′-di-tert-butyl-5,5′-dimethyl-[3,3′]bibenzofuranylidene-2,2′-dione of formula (LIa).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[CH:55]=[CH:54][C:53]([NH2:56])=[N:52][CH:51]=1>CN(C)C=O>[N:50]1[CH:55]=[CH:54][C:53]([NH:56][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])=[N:52][CH:51]=1
Reactant: Nc1ccncn1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3ccncn3)c(=O)oc12
Temperature: 25 °C
Yield: 11.2 %

Procedure:
DIEA (0.044 mL, 0.25 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.030 g, 0.14 mmol) and HATU (0.095 g, 0.25 mmol) in 1 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, pyrimidin-4-ylamine (0.009 g, 0.09 mmol) was added and allowed to react overnight, when a solid precipitated out of solution. The precipitate was filtered and dried under suction and then in vacuo to give 0.003 g of 1541E in an 11% yield: LCMS (ESI) m/z 298 (MH+).
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)[C:3]=1[CH3:21].CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.[Cl:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51]Cl)=[CH:49][CH:48]=1>O1CCCC1>[ClH:46].[Cl:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][N:10]2[C:9]3[C:4](=[N:5][CH:6]=[CH:7][C:8]=3[N:11]3[CH2:20][CH2:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:12]3)[C:3]([CH3:21])=[C:2]2[CH3:1])=[CH:49][CH:48]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Cc1[nH]c2c(N3CCc4ccccc4C3)ccnc2c1C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(C)n(Cc2ccc(Cl)cc2)c2c(N3CCc4ccccc4C3)ccnc12
Product: Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.4 %

Procedure:
2-(2,3-dimethyl-1H-pyrrolo[3,2-b]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline (30 mg, 0.108 mmol) prepared in Step 1, potassium tert-butoxide (13.6 mg, 0.162 mmol), and a catalytic amount of 18-crown-6 were added to anhydrous tetrahydrofuran (2 ml). 4-Chlorobenzyl chloride (0.09 ml, 0.162 mmol) was added to the reaction mixture, which was then stirred for 12 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/methylene chloride/methanol=10/10/1, (v/v/v)), dissolved in ethyl acetate (1 ml), and then saturated with hydrochloric acid gas. The resulting precipitate was filtered to give the titled compound as a white solid (6.9 mg, 15.8%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:3]=1[CH3:19].[NH2:20][C:21]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24].Cl.O1CCOCC1>CN1C(=O)CCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:20][C:21]3[CH:28]=[C:27]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)[CH:26]=[CH:25][C:22]=3[C:23]#[N:24])=[C:3]([CH3:19])[C:4]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(N2CCOCC2)cc1N
Reactant: Cc1c(-c2cccnc2)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2cccnc2)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)ccc1C#N

Procedure:
Prepared according to general Procedure K using 4-chloro-7-fluoro-3-methyl-2-(pyridin-3-yl)quinoline (150 mg, 0.55 mmol), 2-amino-4-morpholinobenzonitrile (112 mg, 0.55 mmol) and a 4.0M solution of HCl in dioxane (0.028 mL, 0.11 mmol) in NMP (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification 2-((7-fluoro-3-methyl-2-(3-pyridinyl)-4-quinolinyl)amino)-4-(4-morpholinyl)benzonitrile was obtained as a yellow film. 1H NMR (500 MHz, chloroform-d) δ ppm 8.87 (1H, dd, J=2.0, 0.5 Hz), 8.73 (1H, dd, J=4.9, 1.7 Hz), 7.99 (1H, dt, J=7.8, 2.0 Hz), 7.92 (1H, dd, J=9.3, 5.9 Hz), 7.80 (1H, dd, J=9.8, 2.4 Hz), 7.44-7.51 (2H, m), 7.33 (1H, ddd, J=9.2, 8.0, 2.6 Hz), 6.46 (1H, s), 6.43 (1H, dd, J=8.9, 2.3 Hz), 5.72 (1H, d, J=2.2 Hz), 3.63-3.76 (4H, m), 2.95-3.09 (4H, m), 2.35 (3H, s). Mass Spectrum (ESI) m/e=440.0 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[N:4][N:3]1[C:9]1[CH:10]=[CH:11][C:12]([CH3:27])=[C:13]([CH:26]=1)[C:14]([NH:16][CH2:17][C:18]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:15].Br[CH2:29][C:30]([NH2:32])=[O:31]>CS(C)=O.O>[C:30]([CH2:29][N:7]1[C:6](=[O:8])[CH:5]=[N:4][N:3]([C:9]2[CH:10]=[CH:11][C:12]([CH3:27])=[C:13]([CH:26]=2)[C:14]([NH:16][CH2:17][C:18]2([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:15])[C:2]1=[O:1])(=[O:31])[NH2:32]
Reactant: NC(=O)CBr
Reactant: Cc1ccc(-n2ncc(=O)[nH]c2=O)cc1C(=O)NCC1(O)CCCCCC1
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-n2ncc(=O)n(CC(N)=O)c2=O)cc1C(=O)NCC1(O)CCCCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 45.5 %

Procedure:
A slurry of 5-(3,5-Dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxy-cycloheptylmethyl)-2-methyl-benzamide (200.0 mg, 0.537 mmol) and Cs2CO, (290.3 mg, 0.891 mmol) were stirred in DMSO (1.79 mL, 0.3 M) at ambient temperature for 15 minutes. 2-Bromoacetamide (74.1 mg, 0.537 mmol) was added and the reaction stirred at ambient temperature for 14 hours. The reaction was diluted with water (15-fold) and the aqueous extracted with CH2Cl2 (3×). The organics were dried over sodium sulfate, and concentrated in vacuo to a tan oil. The crude was triturated from IPE/Et2O/CH2Cl2 to give the title compound as a tan solid (105 mg). LCMS (m/z) 430.5 M+1.