Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH3:27])=[C:20]([O:23][CH3:24])[CH:21]=3)[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][C@@H:14]([OH:28])[CH2:15]3)[N:10]=2)=[CH:5][N:4]=1.[O:30]=[C:31]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])[C:32](O)=[O:33]>ClCCl>[O:30]=[C:31]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])[C:32]([O:28][C@@H:14]1[CH2:13][CH2:12][C@@H:11]2[C@@H:16]([C:17]3[C:22]([C:9]([C:6]4[CH:7]=[N:8][C:3]([N:2]([CH3:1])[CH3:29])=[N:4][CH:5]=4)=[N:10]2)=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=3)[CH2:15]1)=[O:33]
Reactant: CCOc1cc2c(cc1OC)C(c1cnc(N(C)C)nc1)=N[C@@H]1CC[C@@H](O)C[C@H]21
Reactant: O=C(O)CCC(=O)C(=O)O
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1cnc(N(C)C)nc1)=N[C@@H]1CC[C@@H](OC(=O)C(=O)CCC(=O)O)C[C@H]21
Yield: 58.9 %

Procedure:
(2R,4aR,10bR)-6-(2-Dimethylamino-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol (39.4 mg, 0.1 mmol) are dissolved in 1.0 ml of dichloromethane. 16.1 mg (0.11 mmol) of 2-oxo-pentanedioic acid (dissolved in 0.5 ml of acetone) are added. The crystals are filtered off and dried to obtain 30.9 mg (57%) of the title compound (m.p.: 112° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[CH2:9][CH2:10]Br)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([N:21]2[C:25](=[O:26])[CH2:24][N:23]([CH3:27])[C:22]2=[O:28])[CH:17]=[C:18]([Cl:20])[CH:19]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@:24]3([C:25](=[O:26])[N:21]([C:16]4[CH:17]=[C:18]([Cl:20])[CH:19]=[C:14]([Cl:13])[CH:15]=4)[C:22](=[O:28])[N:23]3[CH3:27])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: ClC(CCBr)c1ccc(Br)cc1
Reactant: CN1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CC[C@H]2c1ccc(Br)cc1

Procedure:
Using the same procedure as in Example 1 starting from 1-bromo-4-(3-bromo-1-chloropropyl)benzene (Preparation 7) and 3-(3,5-dichlorophenyl)-1-methylimidazolidine-2,4-dione, the above titled compound was obtained after reverse phase HPLC purification (gradient from CH3CN/H2O/TFA: 5/95/0.05 to CH3CN/H2O[[FA: 80/20/0.05). 1H NMR (CDCl3): 7.44 (2H, d, J=8.4 Hz), 7.25 (1H, m), 6.95–7 (4H, m), 4.05 (1H, t, J=10.1 Hz), 3.22 (3H, s), 2.65–2.85 (1H, br q), 2.4–2.65 (2H, m), 2.1–2.3 (1H, br q).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].I[C:8]1[C:13]2[N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]=[N:16][C:12]=2[CH:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[CH3:6][O:5][C:1](=[O:4])[CH:2]=[CH:3][C:8]1[C:13]2[N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]=[N:16][C:12]=2[CH:11]=[C:10]([C:23]([F:25])([F:26])[F:24])[CH:9]=1
Reactant: FC(F)(F)c1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Yield: 92.4 %

Procedure:
Methyl acrylate (2.7 ml, 30 mmol), 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (3.48 g, 10 mmol), triethylamine (2.79 ml, 20 mmol), palladium acetate (45 mg, 0.2 mmol), tri-o-tolylphosphine (161 mg, 0.53 mmol) and acetonitrile (50 ml) were combined and the mixture heated at reflux under an argon atmosphere for 17 h. The mixture was cooled, filtered through Dicalite and the filtrate was concentrated under reduced pressure. Crystals formed and were isolated by filtration and dried to give the title compound (3.2 g, 92%), m/z 347.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.C([Li])CCC.[C:17]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].O>O1CCCC1>[C:20]([O:19][C:17]([N:24]1[CH2:29][CH2:28][C:27]([OH:30])([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=2)[CH2:26][CH2:25]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: FC(F)(F)c1cccc(Br)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(C(F)(F)F)n2)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 97.7 %

Procedure:
A mixture of 2-bromo-6-(trifluoromethyl)pyridine (300 mg, 1.33 mmol) in tetrahydrofuran (10 mL) under a nitrogen atmosphere cooled to −78° C. was treated with n-butyl lithium (2M solution in tetrahydrofuran, 0.83 mL, 1.33 mmol). The mixture was stirred at −78° C. for 15 min. At this time, the reaction was treated with 1-boc-4-piperidone (265 mg, 1.33 mmol). The mixture was then allowed to slowly warm to 25° C. and was stirred at 25° C. for 1 h. At this time, the reaction was poured into water. The aqueous layer was extracted with ethyl acetate. The organics were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 4′-hydroxy-6-trifluoromethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (450 mg, 98%) as a yellow oil; LRMS for C16H21F3N2O3 (M+H)+ at m/z=346. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([NH2:13])[CH:9]=2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17]([N:13]([C:17](=[O:18])[C:16]1[C:15]([Cl:14])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:24])[C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[O:12][N:11]=1)=[O:18]
Reactant: Nc1cc(-c2ccc(Cl)cc2)on1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Product: O=C(c1c(Cl)cccc1Cl)N(C(=O)c1c(Cl)cccc1Cl)c1cc(-c2ccc(Cl)cc2)on1

Procedure:
5-(4-Chlorophenyl)-3-aminoisoxazole (400 milligrams prepared according to the teaching of Examples 11-14) was added to 2,6-dichlorobenzoylchloride (430 milligrams) in 50 ml. toluene and refluxed for 48 hours. The solvent was then evaporated and ethyl alcohol added; upon subsequent heating and filtering the bis acylated product was recovered; m.p. 219°-223° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)#[CH:13].N>>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: C#Cc1cccnc1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Agent: N
Product: Clc1cncc(-c2cc(-c3cccnc3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 3-ethynylpyridine (Aldrich, 31.0 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.65 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 7.92 (s, 1H), 8.30 (dt, J=7.7, 2.2, 2.0 Hz, 1H), 8.45 (t, J=2.2 Hz, 1H), 8.75 (dd, J=4.8, 1.6 Hz, 1H), 8.82 (d, J=2.4 Hz, 1H), 9.09 (d, J=2.0 Hz, 1H), 9.13 (dd, J=2.4, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 260 (M+H)+, 258 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[C:11]2[C:5]([C:6](=[O:13])[NH:7][S:8]2(=[O:10])=[O:9])=[N:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:19][OH:20]>>[CH3:19][O:20][C:6]([C:5]1[C:11]([S:8]([NH2:7])(=[O:10])=[O:9])=[CH:12][C:2]([CH3:1])=[CH:3][N:4]=1)=[O:13]
Reactant: CO
Reactant: Cc1cnc2c(c1)S(=O)(=O)NC2=O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ncc(C)cc1S(N)(=O)=O

Procedure:
1 mol of 6-methyl-4-azasaccharine is suspended in 10 times the volume of methanol and heated at 100° C. with 1/10 molar equivalent of concentrated sulfuric acid in a bomb tube. After 18 hours the batch is concentrated by evaporation and the residue is washed with CHCl3 /NaHCO3 to give 3-(aminosulfonyl)-5-methylpyridine-2-carboxylic acid methyl ester in the form of a beige powder having a melting point of 86°-88° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][CH2:13][CH3:14])[C:5]([CH:15]=[O:16])=[CH:4][C:3]=1[O:17][CH3:18].[H-].[Na+].[CH3:21][O:22][CH2:23]Cl.O>CN(C)C=O>[CH3:18][O:17][C:3]1[CH:4]=[C:5]([CH:15]=[O:16])[C:6]2[C:11]([C:2]=1[O:1][CH2:21][O:22][CH3:23])=[C:10]([CH2:12][CH2:13][CH3:14])[CH:9]=[CH:8][CH:7]=2
Reactant: CCCc1cccc2c(C=O)cc(OC)c(O)c12
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Temperature: 10 °C
Reaction time: 0.33 h

Procedure:
322 g of 4-hydroxy-3-methoxy-5-propyl-1-naphthalenecarbaldehyde was dissolved in 1.3 liters of N,N-dimethylformamide and cooled to 10° C. 63.3 g of 60% sodium hydride was added to the solution at 30° C. or below and agitated for 20 minutes. The reaction solution was cooled to 5° C., to which 190 ml of chloromethyl methyl ether was added. After agitation at room temperature for 2 hours, the solution was poured into iced water and extracted with ethyl acetate. The resultant organic phase was washed with a saturated saline solution, after which it was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (10% ethyl acetate/hexane) to obtain 294.5 g of the captioned compound as a brown oily substance.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([CH3:40])([CH3:39])[CH2:11][N:12]1[CH:21]=[C:20]([CH:22]=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:24]3[CH:25]=[C:26]([CH:33]=[C:34]([F:37])[C:35]=3[CH3:36])[C:27]([NH:29][CH:30]3[CH2:32][CH2:31]3)=[O:28])[CH:18]=2)[C:13]1=[O:38])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:41][Mg]Cl>>[Si:1]([O:8][CH2:9][C:10]([CH3:40])([CH3:39])[CH2:11][N:12]1[CH:21]=[C:20]([CH:22]([OH:23])[CH3:41])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:24]3[CH:25]=[C:26]([CH:33]=[C:34]([F:37])[C:35]=3[CH3:36])[C:27]([NH:29][CH:30]3[CH2:31][CH2:32]3)=[O:28])[CH:18]=2)[C:13]1=[O:38])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[Mg]Cl
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(C=O)c2c1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(C(C)O)c2c1

Procedure:
3-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-4-formyl-1-oxo-1,2-dihydroisoquinolin-6-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide (Example 26f, 1.10 g) was reacted with methylmagnesium chloride (3 M in THF) (1.62 mL) by the method of Example 38a to afford the subtitle compound (1.10 g) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]1[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:27][O:28][C:29]1[N:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][CH:33]=[C:32]2[CH:39]=[O:40]>C1COCC1>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH:6]1[CH2:15][CH2:14][C:9]2([O:10][CH2:11][CH2:12][O:13]2)[CH2:8][CH2:7]1)[CH:39]([OH:40])[C:32]1[C:31]2[C:36](=[CH:37][CH:38]=[C:29]([O:28][CH3:27])[N:30]=2)[N:35]=[CH:34][CH:33]=1)[CH3:2]
Reactant: CCOC(=O)CC1CCC2(CC1)OCCO2
Reactant: COc1ccc2nccc(C=O)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C1CCC2(CC1)OCCO2)C(O)c1ccnc2ccc(OC)nc12
Temperature: -40 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
To a solution of (1,4-dioxa-spiro[4.5]dec-8-yl)-acetic acid ethyl ester (3.6 g, 15.77 mmol) in THF (50 mL) cooled to −78° C. was added LiHMDS (1M in THF, 18.1 mL) under argon. The resulting solution was stirred for 1 h at −40° C., then recooled to −78° C. 6-methoxy-[1,5]naphthyridine-4-carbaldehyde (3.56 g, 18.92 mmol; prepared according to WO 2006/032466) was added portionwise and stirring was continued for 30 min at −78° C. The reaction mixture was quenched by the addition of aq. NH4Cl. The two layers were separated and the aq. layer was extracted with EA. The combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was chromatographed (Hept-EA 1-2→EA) to afford a diastereoisomeric 1:1 mixture of the title compound as a pale yellow oil (4.44 g, 68% yield).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:36])[N:33]([CH3:35])[CH3:34])=[CH:27][CH:26]=2)=[N:4]1)[CH3:2].[CH3:37][NH:38]C>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:38][CH3:37])[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:36])[N:33]([CH3:35])[CH3:34])=[CH:27][CH:26]=2)=[N:4]1)[CH3:2]
Reactant: CNC
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4cccc(C=O)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Product: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CNC)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
Following the procedure described for Intermediate 101 using N′-(4-{1-ethyl-4-[2-(3-formylphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)-N,N-dimethylurea and 2M dimethylamine provided the title compound. ESMS [M+H]+: 494.0.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:19][C:20]#[C:21][CH2:22][CH3:23])[C:12](=[O:13])[CH:11]=[CH:10][CH:9]1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCCCCC.CC(C)=O.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[C:1]([O:5][C:6]([C:8]1([CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH3:23])[C:12](=[O:13])[CH:11]=[CH:10][CH:9]1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC#CCC1(C(=O)OC(C)(C)C)C(=O)C=CC1CC(=O)OC
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CC/C=C\CC1(C(=O)OC(C)(C)C)C(=O)C=CC1CC(=O)OC

Procedure:
A 690 mg quantity of 5-tert-butoxycarbonyl-4-methoxycarbonylmethyl-5-(2-pentynyl)-2-cyclopentenone (compound (1-a)) is dissolved in a mixture of 5 ml of n-hexane and 5 ml of acetone and reduced at room temperature and atmospheric pressure with addition of 3.2 g of a Lindlar catalyst. The catalyst is filtered off from the reaction mixture, and the solvent distilled off. The residue is purified by a silica gel column and distilled in a vacuum, giving 5-tert-butoxycarbonyl-4-methoxycarbonylmethyl-5-(cis-2-pentenyl)-2-cyclopentenone (compound (1-b), R1 =t-Bu, R2 =CH3) in a yield of 99.8%, b.p. 81°-84° C./0.005 mm Hg.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19].[C:21]1([CH3:28])[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1>>[C:11]([O:10][CH:5]1[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([O:1][CH2:28][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)[C:3]([CH3:20])([CH3:19])[CH2:4]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc(C)c1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Product: Cc1cccc(CON2C(C)(C)CC(OC(=O)c3ccccc3)CC2(C)C)c1
Yield: 29.5 %

Procedure:
A mixture of 13.77 g (0.05 mol) of 1-oxyl-4-benzoyloxy-2,2,6,6-tetramethylpiperidine and 106.17 g (1.0 mol) of m-xylene under a nitrogen atmosphere is heated at reflux for 50 hours. The reaction mixture is filtered to remove the hydroxylamine, and the filtrate is washed with 10 w/v % ascorbic acid (1×50 mL) and distilled water (2×50 mL). The organic phase is dried over anhydrous sodium sulfate and the volatiles are removed in vacuo. The residue is recrystallized from isopropyl alcohol to give 5.62 g (59% yield) of a white solid melting at 64-65° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][C:5]([C:8]#[CH:9])=[CH:6][CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=1.C(N(CC)CC)C>C(#N)C.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.[Cu](I)I>[NH2:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][C:5]([C:8]#[C:9][C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: C#Cc1ccc(N)c(C#N)n1
Reactant: Clc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1nc(C#Cc2ccc(Cl)cc2)ccc1N

Procedure:
This compound is prepared in a manner analogous to that of Step C of Example 9, using 3.1 grams (0.022 mole) of 3-amino-2-cyano-6-ethynylpyridine, 7.4 grams (0.031 mole) of 4-chlorophenyl iodide, 10.7 grams (0.077 mole) of triethylamine, 0.5 gram (catalyst) of bis(triphenylphosphine)palladium(II) chloride, and 0.5 gram (catalyst) of copper iodide in 100 mL of acetonitrile, yielding 3-amino-2-cyano-6-[(4-chlorophenyl)ethynyl]pyridine.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O-:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[NH2:15].C1(N=C=NC2CCCCC2)CCCCC1>>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:8]([CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:10])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: CCOC(=O)C(C)C(=O)[O-]
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCOC(=O)C(C)C(=O)Nc1cc(Cl)cc(Cl)c1
Yield: 10 %

Procedure:
Monoethyl methylmalonate (5.0 grams, 0.03 mole), 3,5-dichloroaniline (5.54 grams, 0.03 mole) and 1,3-dicyclohexylcarbodiimide (7.06 grams, 0.03 mole) were reacted in a manner similar to that described in Example LVII to give 1.0 gram (0.003 mole) of ethyl 2-(3,5-dichlorophenylaminocarbonyl)propanoate having a melting point of 89° C.-90° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2.[I:18]I>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[I:18]
Reactant: II
Reactant: Fc1cccc(Cl)c1-c1ccc2[nH]ccc2c1
Product: Fc1cccc(Cl)c1-c1ccc2[nH]cc(I)c2c1
Yield: 103.2 %

Procedure:
This title compound was prepared analogously to compound 25c using 5-(2-chloro-6-fluorophenyl)-1H-indole (15 g, 0.06 mol) and I2 (17.1 g, 0.15 mol) to obtain the crude title compound (23 g). MS (ESI, m/z): 370.8 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:40])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[CH2:36][CH2:35][CH2:34]3)[CH:30]=1)=O)C.[CH2:41]([NH2:43])[CH3:42]>CO>[CH2:41]([NH:43][C:4]([C:6]1[C:7](=[O:40])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:22]4[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[CH2:36][CH2:35][CH2:34]3)[CH:30]=1)=[O:3])[CH3:42]
Reactant: CCN
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CN4CCN(C)CC4)cc3)ncc2c1=O
Solvent: CO
Product: CCNC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CN4CCN(C)CC4)cc3)ncc2c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 56.9 %

Procedure:
8-Indan-5-yl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (9.2 mg, 0.017 mmol) was dissolved in MeOH (1 mL) and ethylamine (1 mL of 1.0 M solution in THF, 1.0 mmol) was added and the reaction mixture was heated at 80° C. After 16 h, the solution was cooled to rt and purified by preparative HPLC (C-18 column, 32 mL/min 5-100% MeCN/H2O gradient over 15 min) and lyophilized to provide 5.2 mg of 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide. 1H NMR TFA salt (400 MHz, CDCl3) δ (ppm): 9.38 (br s, 1H), 9.37 (s, 1H), 8.84 (s, 1H), 7.58-7.60 (m, 1H), 7.40-7.47 (m, 2H), 7.16 (dd, 2H, J=2.0 Hz, J=7.9 Hz), 7.05 (br s, 2H), 3.43-3.55 (m, 4H), 3.07 (t, 2H, J=7.3 Hz), 2.99 (t, 2H, J=7.4 Hz), 2.53 (br s, 8H), 2.36 (s, 3H), 2.18-2.27 (m, 2H), 1.15-1.39 (m, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C31H35N7O2: 537.29, Found: 538.3 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[N+:1]([C:4]1[CH:12]=[C:8]([C:9]([O:11][CH2:19][CH3:20])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1O
Yield: 85 %

Procedure:
To a solution of 5-nitrosalicylic acid (10.8 g) in ethanol (100 ml) was added concentrated sulfuric acid (92.0 g) at room temperature and the mixture was heated under reflux for 7.5 hours. After neutralization with aqueous sodium hydroxide, the reaction mixture was extracted with ethyl acetate. The extractant was washed with saturated aqueous sodium hydrogencarbonate, 0.5M hydrochloric acid and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo to give the desired compound (10.7 g, yield 85%) as a yellow solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][C@H:21]([CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].[BH4-].[Na+].[C:28](O)(=O)[CH3:29]>>[CH2:28]([N:22]1[C:10]2[C:11](=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:14]=[C:13]3[C:15]([F:18])([F:17])[F:16])[O:19][CH2:20][C@H:21]1[CH:23]([CH3:25])[CH3:24])[CH3:29]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@H](C(C)C)CO3
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: CCN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OC[C@H]1C(C)C
Yield: 60 %

Procedure:
Compound 122 was prepared according to General Method 5 (EXAMPLE 2) from (3R)-3,4-dihydro-8-isopropoxy-3-isopropyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (50 mg, 0.14 mmol) and NaBH4 pellets (>10 equiv) in 2 mL acetic acid to afford 30 mg (ca. 60%) of (3R)-4-ethyl-3,4-dihydro-8-isopropoxy-3-isopropyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline. This material (30 mg, 0.08 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with 4 mL of 1:1 acetic acid:concentrated HCl (0.02M) heated at 90° C. for 4 h to afford 15 mg (57%) of Compound 122, a yellow solid, after column chromatography (3:1 hexanes:EtOAc to 1:1 hexanes:EtOAc, gradient elution). 1H NMR (500 MHz, CDCl3) δ 11.87 (bs, 1H), 7.13 (d, J=9.3, 1H), 7.12 (s, 1H), 6.96 (d, J=8.9, 1H), 4.49 (d, J=10.8, 1H), 3.69 (dd, J=10.7, 2.7, 1H), 3.49 (m, 1H), 3.24 (m, 1H), 2.88 (bd, J=7.9, 1H) 1.83 (m, 1H), 1.64 (t, J=7.1, 3H), 0.98 (d, J=10.6, 3H), 0.96 (d, J=10.6, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:24]([O:26][C:27]([CH3:29])=[CH2:28])=[O:25]>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:24](=[O:25])[O:26][C:27]([CH3:29])=[CH2:28])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C(C)OC(=O)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C)OC(=O)Nc1cc(C(C)(C)C)nn1-c1ccccc1
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 78 %

Procedure:
To a solution of Example B1 (10.00 g, 46.4 mmol, 1.00 eq) and pyridine (7.58 ml, 92.9 mmol, 2.00 eq) in CH2Cl2 (225 ml) at 0° C. was added isopropenyl chloroformate (5.33 ml, 4.8.8 mol, 1.05 eq). After 45 min at 0° C., the completed reaction was washed with 3M HCl (2×), satd. NaHCO3 (1×), and brine (1×), dried (MgSO4), filtered and evaporated to afford crude product (14.9 g) as an oil that solidified on the pump. The crude material obtained was upgraded by triturating in warm (60° C.) hexanes (70 ml) for 20-30 min until a powdery precipitate was obtained. After cooling to RT, the solids were collected by filtration, rinsing forward with hexanes. The cake was washed with more hexanes and then dried on the filter to afford prop-1-en-2-yl 3-t-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate (10.79 g, 78% yield) as a tan powder which was used as is in the next reaction. MS (ESI) m/z: 300.3 (M+H+).