Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([CH3:12])=[N:4][CH:3]=1.C(N)(N)=[O:14].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([CH3:12])=[N+:4]([O-:14])[CH:3]=1
Reactant: COC(=O)c1nc(Cl)cnc1C
Reactant: NC(N)=O
Agent: OO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1nc(Cl)c[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a solution of methyl 6-chloro-3-methylpyrazine-2-carboxylate (8.6 g, 46.1 mmol) and hydrogen peroxide urea adduct (8.1 g, 86 mmol) in dichloromethane (100 mL) was added 2,2,2-trifluoroacetic anhydride (10.9 ml, 78 mmol) dropwise. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM and quenched with water. The aqueous layer was extracted with DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the crude product 5-chloro-3-(methoxycarbonyl)-2-methylpyrazine 1-oxide (8.83 g, 43.6 mmol, 95% yield) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ ppm 8.31 (1H, s), 4.02 (3H, s), 2.65 (3H, s).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:18]4[C:17]5[CH:19]=[C:20]([NH:23][C:24]([C:26]6[C:27]([NH:32]CC7C=CC(OC)=CC=7)=[N:28][CH:29]=[CH:30][CH:31]=6)=[O:25])[CH:21]=[CH:22][C:16]=5[CH2:15][CH2:14][C:13]=4[C:12]([C:42]([NH2:44])=[O:43])=[N:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:32][C:27]1[C:26]([C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:16]3[CH2:15][CH2:14][C:13]4[C:12]([C:42]([NH2:44])=[O:43])=[N:11][N:10]([C:8]5[CH:7]=[CH:6][C:5]6[O:1][CH2:2][O:3][C:4]=6[CH:9]=5)[C:18]=4[C:17]=3[CH:19]=2)=[O:25])=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: COc1ccc(CNc2ncccc2C(=O)Nc2ccc3c(c2)-c2c(c(C(N)=O)nn2-c2ccc4c(c2)OCO4)CC3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3cccnc3N)cc1-2
Yield: 32.5 %

Procedure:
The title compound of Example 209 (1.96 g, 0.0033 mol) was dissolved in 6 mL CH2Cl2 and reacted with 5 mL TFA at room temperature for 36 h. The crude reaction mixture was diluted with CH2Cl2 and basified with a saturated aqueous solution of Na2CO3. The layers were separated and the organic layer was dried over MgSO4. The residue obtained after removal of the solvent under vacuum was triturated with EtOH to afford 0.503 g of title compound (yield: 32%). Mp: 265-267° C. 1H NMR (300 MHz, d6-DMSO): δ 2.88-2.95 (m, 4H), 6.12 (s, 2H), 5.58-6.62 (dd, 1H, J=7.6 Hz, 4.7 Hz), 6.97-7.08 (m, 4H), 7.17 (d, 1H, J=1.9 Hz), 7.28 (s, 1H), 7.32 (s, 2H), 7.55 (s, 2H), 7.95-7.98 (dd, 1H, J=7.7 Hz, 1.7 Hz), 8.11-8.13 (dd, 1H, J=4.7 Hz, 1.7 Hz), 9.99 (s, 1H). M+1=469.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=2)O1.Br[C:35]1[C:36]([NH2:41])=[N:37][CH:38]=[CH:39][CH:40]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:14]([N:12]1[CH:13]=[C:9]([C:35]2[C:36]([NH2:41])=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:10]=[N:11]1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC1(C)OB(c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)OC1(C)C
Reactant: Nc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1ncccc1-c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
4-(4,4,5,5-Tetramethyl-(1,3,2)dioxaborolan-2-yl)-1-trityl-1H-pyrazole (3.2 g, 7.33 mmol) described in Manufacturing Example 32-1-2, 3-bromo-pyridine-2-ylamine (1.14 g, 6.60 mmol), tetrakis(triphenylphosphine)palladium (0) (424 mg, 0.37 mmol), toluene (40 mL), 2 M aqueous sodium carbonate solution (10 mL) and ethanol (20 mL) were stirred for 1 hour at 95° C. The reaction solution was allowed to room temperature, and partitioned into water and ethyl acetate. The ethyl acetate layer was washed with water once, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel chromatography (heptane:ethyl acetate=1:2) to obtain the title compound (2.3 g, 78.0%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:15])=[C:12]([CH3:23])[CH:11]=1.CON(C)[C:27](=[O:29])[CH3:28]>C1COCC1>[Br:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([N:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[O:15])=[C:12]([CH2:23][C:27](=[O:29])[CH3:28])[CH:11]=1
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1C
Reactant: CON(C)C(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(Br)cc1CC(C)=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 2M solution of LDA (35.2 mL, 70.3 mmol) in THF (176 mL) cooled to −78° C. was treated with slow addition of 4-bromo-N,N-diethyl-2-methylbenzamide (19 g, 70.3 mmol) in dry THF (176 mL). The reaction was allowed to stir at −78° C. for 1 hour before it was quenched with N-methoxy-N-methylacetamide (22.43 mL, 211 mmol) and allowed to slowly warm to room temp. The reaction was stirred overnight and then partitioned between 1N HCl (200 mL) and EtOAc (400 mL). The aqueous layer was further extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine (150 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was an oil out of which the product precipitated. The oil was decanted off and the solid was washed with hexanes and dried using a buchner funnel to afford 4-bromo-N,N-diethyl-2-(2-oxopropyl)benzamide: LC-MS: (M+H)+312.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]#[C:12][CH2:13][OH:14])[CH:4]=[CH:3][N:2]=1>C(O)C.CO.[Pd]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][CH2:12][CH2:13][OH:14])[CH:4]=[CH:3][N:2]=1
Reactant: OCC#Cc1cccc2ccncc12
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: OCCCc1cccc2ccncc12
Reaction time: 20 h
Yield: 33.3 %

Procedure:
A solution of 0.4 g of 3-(8-isoquinolinyl)-2-propyn-1-ol in a mixture of 10 mL of ethanol and 5 mL of methanol was hydrogenated over 0.06 g 10% Pd/C at room temperature and atmospheric pressure for 22 hours andthen at 50 psi for 20 hours. After the catalyst was removed by filtration and the filtrate was concentrated, the residual oil was purified by HPLC (methanol-chloroform; 1:19) and crystallized from ethyl acetate-hexane to yield 0.136 g of 8-isoquinolinepropanol, mp 66°-69° C.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]O)[CH2:15]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:42][C:43]1[CH:48]=[CH:47][C:46]([N:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[CH:45][CH:44]=1>>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH3:32])[C:24]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:15][CH:16]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:52]1[CH2:51][CH2:50][N:49]([C:46]2[CH:45]=[CH:44][C:43]([F:42])=[CH:48][CH:47]=2)[CH2:54][CH2:53]1)=[O:35]
Reactant: COc1ccc(C(=O)N2c3ccccc3C(n3c4ccccc4c4ccccc43)CC2CCCCCO)cc1OC
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: COc1ccc(C(=O)N2c3ccccc3C(n3c4ccccc4c4ccccc43)CC2CCCCCN2CCN(c3ccc(F)cc3)CC2)cc1OC
Yield: 51.2 %

Procedure:
Starting with 5-[4-(9H-9-carbazolyl)-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-2-quinolinyl]-1-pentanol (0.13 g, 0.22 mmol) prepared in Example 135 and 4-(4-fluorophenyl)piperazine (79 mg, 0.44 mmol), the same procedure as shown in Example 136 was repeated to give the titled compound (0.08 g, yield: 51%) as a white crystal (cis:trans=4:1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:6]=[C:5]3[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH:23]([CH3:24])[C:3]=1[C:4]=23.C([O-])([O-])=O.[K+].[K+].[CH2:38](I)[CH3:39]>CC(C)=O>[CH2:38]([O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:6]=[C:5]3[CH2:20][CH2:21][NH:22][CH:23]([CH3:24])[C:3]=1[C:4]=23)[CH3:39]
Reactant: CC1c2c(O)ccc3c2c(cn3S(=O)(=O)c2ccccc2)CCN1C(=O)OC(C)(C)C
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc2c3c(cn2S(=O)(=O)c2ccccc2)CCNC(C)c13
Temperature: 62 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
tert-Butyl 7-hydroxy-6-methyl-1-(phenylsulfonyl)-1,3,4,6-tetrahydro-5H-azepino[5,4,3-cd]indole-5-carboxylate, Intermediate 15 (16 mg, 0.036 mmol), acetone (5 mL), K2CO3 (50 mg, 0.36 mmol) and EtI (34 mg, 0.22 mmol) were added into a 16 mm test tube with screw cap and the suspension was stirred at 62° C. over night. The solvent from the filtered mixture was evaporated at reduced pressure and the residue was dissolved in DCM/TFA 50/50 (1 mL) and left in room temperature for two hours. The solvent was evaporated at reduced pressure and the crude was purified by preparative HPLC (Xterra C18, 10 mM NH4CO3 (pH 10)-CH3CN) to give 9.0 mg (67%) of the title compound as a brown oil. MS m/z 371 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[Cl:9][C:10]1[CH:15]=[C:14]([N+]([O-])=O)[CH:13]=[CH:12][N+:11]=1[O-].C(=O)(O)[O-].[K+]>CC(O)C>[NH:6]1[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:14]2[CH:13]=[CH:12][N:11]=[C:10]([Cl:9])[CH:15]=2)[N:8]=[CH:7]1
Reactant: NCCc1c[nH]cn1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)O
Product: Clc1cc(NCCc2c[nH]cn2)ccn1

Procedure:
38 mg (0.34 mmol) of histamine and 55 mg (0.31 mmol) of 2-chloro-4-nitropyridine N-oxide in 15 ml of 2-propanol are stirred with potassium bicarbonate at 21° C. for 3 days. The mixture is then filtered and evaporated. The resulting solid residue is chromatographed on a column of silica gel, using a chloroform/methanol (10/1) mixture. The pure fractions are evaporated under reduced pressure to give the title compound which, after crystallization from a 2-propanol/ether (1/1) mixture, melts at 164°-165° C.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])=O.[Cl:14][C:15]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:16]=1[O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:30]([O-:32])=[O:31])=[C:22]([CH:29]=1)[C:23]([O:25]CCO)=[O:24]>CCOCC>[Cl:14][C:15]1[CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=[CH:33][C:16]=1[O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:30]([O-:32])=[O:31])=[C:22]([CH:29]=1)[C:23]([O:25][CH2:2][CH2:3][O:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])=[O:24]
Reactant: O=C(OCCO)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: O=C(OCCOC(=O)C(F)(F)F)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 42.2 %

Procedure:
Trifluoroacetic anhydride (8.4 g, 0.04 mole) was added portionwise to a solution of 2-hydroxyethyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate (7 g, 0.017 mole) and 50 ml of ether. After holding at 30°-35° C. for an hour, the solution was allowed to stand at room temperature overnight. Excess trifluoroacetic anhydride was removed and 300 ml of ether was added. The ethereal solution was washed three times with water, dried over CaSO4 and concentrated to an oil. Kugelrohr distillation afforded 3.6 g of pure 2-(trifluoroacetoxy)ethyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate as a gumming material (yield: 42.2%); nmr (CDCl3) δ 4.62 (s, 4H), 7.02-8.19 (m, 6H); ir (CHCl3) 1752, 1803 Cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:15][C:14](=[O:16])[O:13][C:11](=[O:12])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][C:11]([N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:17])=[O:12])[CH2:15][C:14]([OH:13])=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNCc1ccccc1
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1ccccc1)C(=O)CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,4-Dichlorophenyl)glutaric anhydride (5.0 g) in CH2Cl2 (100 mL) at 0° C. was treated sequentially with N-methyl-N-(phenylmethyl)amine (3.0 mL), triethylamine (3.36 mL) and N,N-dimethylaminopyridine (0.26)). The mixture was stirred at 0° C. for two hours then allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was washed with 1N HCl (100 mL) and water (2×100 mL). The organic layers were dried over MgSO4, filtered and concentrated to afford the title compound (6.9 g).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:3][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O[C@H]1CN2CCC1CC2)C(NS(=O)(=O)c1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.7 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (150 mg, 0.45 mmol) in DCM (5 ml) and triethylamine (190 ul, 1.35 mmol), was added 4-chlorobenzene-1-sulfonyl chloride (114 mg, 0.54 mmol). The reaction was stirred at RT for 3 hours, and then the solvent was evaporated. The crude was taken up with EtOAc and washed with water, brine and then with K2CO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness to obtain (R)-quinuclidin-3-yl 2-(4-chlorophenylsulfonamido)-2-phenylacetate (62 mg; 32% yield), which was used as such in the next step.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]1[CH:25]=CN(C)C.N1C2C(=CC=CC=2)C(=[O:40])NC=1>O.O1CCCC1>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]1[CH:25]=[O:40]
Reactant: CN(C)C=Cc1nc2ccccc2c(=O)n1-c1ccccc1Cl
Reactant: O=c1[nH]cnc2ccccc12
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1nc2ccccc2c(=O)n1-c1ccccc1Cl

Procedure:
To a well stirred mixture of sodium periodate (1.38 g, 6.45 mmol) in water (6 mL) and tetrahydrofuran (6 mL) was added 3-(2-chloro-phenyl)-2-(2-dimethylamino-vinyl)-3,4-dihydro-quinazolin-4-one (0.70 g, 2.15 mmol) all at once. The mixture warmed slightly to the touch and was stirred for 1 hour at ambient temperature. The reaction was filtered through celite and the pad was rinsed with ether. The filtrate was rendered basic by addition of saturated aqueous sodium bicarbonate and phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over potassium carbonate, and concentrated. The residue was flash chromatographed on silica gel (1×3 inches) with elution proceeding as follows: 50% methylene chloride/hexane (400 mL), nil; (100 mL) and 50% ethyl acetate/hexane (150 mL), 0.51 g (82%) of 3-(2-chloro-phenyl)-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde as about a 1:1 mixture of free aldehyde and hydrate which contained about 20% of 3-(2-chloro-phenyl)-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (from simple hydrolysis of the enamine; exists exclusively in its enolized form to take advantage of an internal hydrogen bond to N1 of the quinazolin-4-one). Identifying features of each of the components of this mixture can be observed in the NMR spectrum as defined in the table below:
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=O)[CH:12]([F:14])[F:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.CC1C=CC(S(O)(=O)=O)=CC=1.O.[NH:28]1[CH:32]=CC=[N:29]1>C1(C)C=CC=CC=1>[F:13][CH:12]([F:14])[C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:28]([CH3:32])[N:29]=1
Reactant: c1cn[nH]c1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cn(C)nc1C(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
The aminal (1.00 g, 2.81 mmol) was dissolved in 7 mL of toluene. Then, ethyl α-ethoxymethylene-4,4-difluoro-3-oxobutyrate (1.25 g, 5.62 mmol) and p-TsOH (107 mg, 0.56 mmol) were added, followed by water (101 mg, 5.62 mg). The mixture was stirred at rt for 90 min, then GC control showed >97% conversion to the pyrazole. The reaction mixture was extracted with water (2×1 mL); then, the organic phase was concentrated under reduced pressure and the residue purified by column chromatography (SiO2, cyclohexane/EtOAc 100:0→70:30) to give the product (840 mg, 4.12 mmol, 73% yield) as a colorless solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.I[CH2:10][C:11](=[CH2:21])[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>>[C:17]([Si:14]([O:13][CH2:12][C:11]([CH2:21][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)=[CH2:10])([CH3:15])[CH3:16])([CH3:19])([CH3:20])[CH3:18]
Reactant: C=C(CI)CO[Si](C)(C)C(C)(C)C
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=C(COc1ccc(I)cc1)CO[Si](C)(C)C(C)(C)C
Yield: 94 %

Procedure:
Alkylation of 4-iodophenol with iodide 165 (see Example 2GGG) and K2CO3 as in Example 2GGG above for 6 h, followed by chromatography of the product on silica gel, eluting with petroleum ether (foreruns) and then with 5% CH2Cl2/petroleum ether, gave tert-butyl({2-[(4-iodophenoxy)methyl]-2-propenyl}oxy)dimethylsilane (167) (94%) as an oil; 1H NMR (CDCl3) δ 7.54 (dt, J=8.9, 2.7 Hz, 2H), 6.70 (dt, J=8.9, 2.7 Hz, 2H), 5.25 (d, J=1.0 Hz, 1H), 5.19 (d, J=1.2 Hz, 1H), 4.51 (s, 2H), 4.23 (s, 2H), 0.91 (s, 9H), 0.07 (2 s, 6H); HRFABMS calcd for C16H26H26Si m/z [M+H]+ 405.0747. found 405.0739.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:2]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:46][C:47]1[C:48]([F:68])=[CH:49][C:50]([F:67])=[C:51]([NH:53][C:54](=[O:66])[C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([C:61]([C:64]#[N:65])([CH3:63])[CH3:62])[CH:56]=2)[CH:52]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:64]([C:61]([C:57]1[CH:56]=[C:55]([CH:60]=[CH:59][CH:58]=1)[C:54]([NH:53][C:51]1[C:50]([F:67])=[CH:49][C:48]([F:68])=[C:47]([NH:46][C:10]([C:8]2[S:7][C:3]3=[N:4][CH:5]=[CH:6][N:1]=[C:2]3[CH:9]=2)=[O:12])[CH:52]=1)=[O:66])([CH3:63])[CH3:62])#[N:65]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(N)c(F)cc2F)c1
Reactant: O=C(O)c1cc2nccnc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(NC(=O)c3cc4nccnc4s3)c(F)cc2F)c1
Reaction time: 0.25 h
Yield: 20.5 %

Procedure:
A mixture of thieno[2,3-b]pyrazine-6-carboxylic acid (57.1 mg, 0.317 mmol), HATU (145 mg, 0.381 mmol) and DIPEA (0.105 mL, 0.634 mmol) in DMF (3 mL) was stirred for 15 min. N-(5-amino-2,4-difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide 73 (100 mg, 0.317 mmol) was added and stirred for 2 h at 80° C. Citric acid solution (3%) was added and the resulting precipitate was collected. Purification by HPLC gave the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2,4-difluorophenyl)thieno[2,3-b]pyrazine-6-carboxamide 74 (31 mg, 20%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 7.61 (m, 2H), 7.79 (m, 1H), 7.85 (t, J=7.8 Hz, 1H), 7.97 (d, J=7.8 Hz, 1H), 8.10 (t, J=2.0 Hz, 1H), 8.56 (s, 1H), 8.77 (d, J=2.3 Hz, 1H), 8.89 (d, J=2.3 Hz, 1H), 10.35 (s, 1H), 10.80 (br s, 1H). (m/z)=478 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.[CH:9]([NH2:12])([CH3:11])[CH3:10]>C(O)C.C(O)CO>[CH:9]([NH:12][C:3](=[O:5])[CH:2]([F:1])[F:8])([CH3:11])[CH3:10]
Reactant: CC(C)N
Reactant: CCOC(=O)C(F)F
Solvent: CCO
Solvent: OCCO
Product: CC(C)NC(=O)C(F)F

Procedure:
A solution of 20 grams (0.16 mole) of ethyl difluoroacetate in 20 milliliters ethyl alcohol was added slowly in a solution of 9.5 grams (0.16 mole) isopropylamine amine and 5 drops of ethylene glycol in 30 milliliters ethyl alcohol. The temperature rose slowly to 27° C. The mixture was then refluxed for 3 days. After this reflux period, the solution was evaporated at 100 millimeters and the residue was distilled at atmospheric pressure to yield 18.0 grams, b.p. 86°-88°, identified by infrared spectroscopy as the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH:9]([C:13]([O:15][CH3:16])=[O:14])[NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:17]([O:24][C:25]1[C:33]([O:34][CH3:35])=[CH:32][C:28]([C:29](Cl)=[O:30])=[C:27]([N+:36]([O-:38])=[O:37])[CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C2C(=CC=CC=2)CC1.C(N(CC)CC)C>O1CCCC1>[CH2:17]([O:24][C:25]1[C:33]([O:34][CH3:35])=[CH:32][C:28]([C:29]([N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=3)[CH2:8][CH:9]2[C:13]([O:15][CH3:16])=[O:14])=[O:30])=[C:27]([N+:36]([O-:38])=[O:37])[CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1cc(C(=O)Cl)c([N+](=O)[O-])cc1OCc1ccccc1
Reactant: COC(=O)C1Cc2ccc([N+](=O)[O-])cc2N1
Agent: c1ccc2c(c1)CCN2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C1Cc2ccc([N+](=O)[O-])cc2N1C(=O)c1cc(OC)c(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 41.4 %

Procedure:
Methyl 6-nitroindoline-2-carboxylate (258a) (0.233 g, 1.048 mmol) was dissolved in anhydrous tetrahydrofuran (4 ml) in a separate flask and cooled to 0° C. an ice bath. In another flask 4-(benzyloxy)-5-methoxy-2-nitrobenzoyl chloride (4) (0.371 g, 1.153 mmol) was dissolved in anhydrous tetrahydrofuran (4 ml) and cooled to 0° C. in an ice bath. To the flask containing the indoline was added triethylamine (0.438 ml, 3.15 mmol) via syringe and the acetyl chloride 4 was added quickly to the reaction mixture via cannula at 0° C. The reaction was stirred for 90 minutes at 0° C. and then at room temperature for an additional 1 hour. The reaction was then quenched with 5% HCl and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography using 30% Acetone in hexane to give methyl 1-(4-(benzyloxy)-5-methoxy-2-nitrobenzoyl)-6-nitroindoline-2-carboxylate (258b) (0.220 g, 0.434 mmol, 41.4% yield) as a yellowish foam. 1H NMR (400 Hz, CDCl3): δ 3.30 (m, 1H), 3.60 (s, 3H), 3.69 (m, 1H), 3.86 (s, 3H), 4.64 (dd, 1H, J=2.4 Hz, 10.8), 5.23 (s, 2H), 7.31 (m, 1H), 7.46 (m, 6H), 7.99 (dd, 1H, J=2.0, 8.0 Hz), 9.04 (d, 1H, J=2.0 Hz). MS (m/z): found 530.1 ([M]++Na).