Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([CH:6]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])[NH2:7])[CH2:3][CH2:4][CH3:5].C(=O)([O-])[O-].[Na+].[Na+].[C:20]([O:24][C:25](=O)[O:26]C(C)(C)C)([CH3:23])([CH3:22])[CH3:21]>O1CCOCC1>[C:25]([NH:7][CH:6]([CH2:2][CH2:3][CH2:4][CH3:5])[C:8]([CH3:12])([CH3:13])[C:9]([OH:11])=[O:10])([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26]
Reactant: CCCCC(N)C(C)(C)C(=O)O
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCCC(NC(=O)OC(C)(C)C)C(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
β-n-butyl-α,α-dimethyl-β-alanine hydrochloride (3.65 g, 17.40 mmol) was dissolved into 10% aqueous sodium carbonate (18.4 ml). To the resulting solution was added dioxane solution (50 ml) of di-t-butylcarbonate (4.6 g, 20.87 mmol) under cooling with ice and stirred at room temperature overnight. The solvent was distilled off and the resulting residue was dissolved into water, washed with ether and adjusted to pH 3 with citric acid under cooling with ice, followed by the several times of ethyl acetate extraction. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate. The solvent were removed in vacuo, and recrystallized from ether-hexane mixed solvent to give crystal of N-Boc-β-n-butyl-α,α-dimethyl-β-alanine (3.16 g, 66.4%).
Reaction SMILES: [O-]CC.[Na+].C1(C)C=CC=CC=1.O=[C:13]1[CH2:17][CH2:16][CH2:15][N:14]1[N:18]=[C:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[CH2:20][C:21]([OH:23])=[O:22].Cl>O>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:19]1[C:20]([C:21]([OH:23])=[O:22])=[C:13]2[CH2:17][CH2:16][CH2:15][N:14]2[N:18]=1
Reactant: O=C(O)CC(=NN1CCCC1=O)c1ccccn1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1c(-c2ccccn2)nn2c1CCC2
Temperature: 100 °C
Yield: 93.2 %

Procedure:
Add sodium ethoxide (145 g, 2.03 mol), followed by toluene (7 L) and 3-(2-oxo-pyrrolidin-1-ylimino)-3-pyridin-2-yl-propionic acid (280 g, 1.02 mol) to a 22 L flask equipped with mechanical stirrer, nitrogen inlet and a reflux condenser. Heat the mixture to 100° C. for 21 h. Cool to room temperature. Add water (6 L) and adjust to pH 5 with concentrated hydrochloric acid. Separate the organic layer and extract the aqueous layer with 10% isopropyl alcohol in chloroform (2×9 L). Combine the organic layers, dry (sodium sulfate), filter and concentrate in vacuo to yield the title compound as a yellow solid (218 g, 93%). MS ES+ m/e 230 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)=[O:4].[S-:12][C:13]#[N:14].[K+].O>C(O)C>[Br:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][S:12][C:13]#[N:14])[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1cccc(Br)c1
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 92.7 %

Procedure:
A mixture of 2,3′-dibromoacetophenone (13.5436 g, 48.7 mmol) and potassium thiocyanate (5.2125 g, 53.6 mmol) in 200 mL of absolute ethanol was stirred under nitrogen at room temperature for 5.5 h. The reaction was added to 600 mL of water and the mixture stirred at room temperature for 2 h. The solid present was collected by filtration, rinsed with water, ice-cold ethanol, hexane and then dried under high vacuum to give 2-(3-bromophenyl)-2-oxoethyl thiocyanate (11.5591 g, 93%) as a white solid, mp 91-93° C.; MS (ES) m/z 253.8 [M+H]+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6]3=[C:7]([C:12](=[O:28])[N:13]([C:16]4[C:21]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=4[CH:25]([CH3:27])[CH3:26])[C:14](=[O:15])[C:5]3=[CH:4][CH:3]=1)[CH:8]=[CH:9][CH:10]=2.[Cu][C:30]#[N:31].O>CN1CCCC1=O>[C:30]([C:2]1[C:11]2[C:6]3=[C:7]([C:12](=[O:28])[N:13]([C:16]4[C:17]([CH:25]([CH3:27])[CH3:26])=[CH:18][CH:19]=[CH:20][C:21]=4[CH:22]([CH3:24])[CH3:23])[C:14](=[O:15])[C:5]3=[CH:4][CH:3]=1)[CH:8]=[CH:9][CH:10]=2)#[N:31]
Reactant: CC(C)c1cccc(C(C)C)c1N1C(=O)c2cccc3c(Br)ccc(c23)C1=O
Reactant: N#C[Cu]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)c1cccc(C(C)C)c1N1C(=O)c2cccc3c(C#N)ccc(c23)C1=O
Yield: 71.8 %

Procedure:
24.8 g of 4-bromo-N-(2,6-diisopropylphenyl)naphthalene-1,8-dicarboximide and 7.5 g of copper(I) cyanide in 150 ml of N-methylpyrrolidone were heated at 210° C. for 4 hours. After cooling, water was added to the reaction mixture, producing a precipitate. The precipitate was filtered off, washed and dried. Column chromatography of the precipitate on silica gel (eluent: dichloromethane) gave 15.6 g of 4-cyano-N-(2,6-diisopropylphenyl)naphthalene-1,8-dicarboximide having a melting point of 291° C.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[N:4][CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.[CH:14]([CH:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[OH:17])=[CH2:15].C(=O)(O)[O-].[Na+].BrC1C=CC=CN=1>C(OCC)(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].CN(C)C=O>[CH3:13][O:12][C:3]1[C:2]([CH2:15][CH2:14][C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[O:17])=[CH:7][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:5][N:4]=1
Reactant: C=CC(O)c1ccc(Cl)c(Cl)c1
Reactant: COc1ncc(S(C)(=O)=O)cc1Br
Agent: [Pd+2]
Agent: Brc1ccccn1
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ncc(S(C)(=O)=O)cc1CCC(=O)c1ccc(Cl)c(Cl)c1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A mixture of 2.7 g of 3-bromo-2-methoxy-5-(methylsulfonyl)pyridine, 3.1 g of α-ethenyl-3,4-dichlorobenzenemethanol, 1.3 g of sodium bicarbonate, 10 ml of dimethylformamide and 0.11 g of palladium diacetate was stirred under nitrogen and heated to 120° C. After 6 hours, thin layer chromatography showed no unreacted bromopyridine starting material. The mixture was then cooled, diluted with ethyl acetate and filtered through Celite. The ethyl acetate solution was washed with water and then twice with aqueous saturated sodium chloride solution and dried over magnesium sulfate. The solution was then filtered and concentrated to a black oil. Excess alcohol was removed by Kugelrohr distillation and the glassy residue was taken up in methylene chloride and chromatographed on silica gel to give a pale yellow solid. This was recrystallized from ethanol/ethyl acetate to give 3-[2-methoxy-5-(methylsulfonyl)-3-pyridinyl]-1-(3,4-dichlorophenyl)propan-1-one melting at about 145°-146° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:13]([C:14](OC3C=CC([N+]([O-])=O)=CC=3)=[O:15])[C:12]([O:26]C)=[N:11][C:10]([CH3:28])=[C:9]2[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH:5]=[CH:6][CH:7]=1.[C:39]1([CH:45]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:46][CH2:47][NH2:48])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]([C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])=[C:10]([CH3:28])[NH:11][C:12](=[O:26])[N:13]2[C:14](=[O:15])[NH:48][CH2:47][CH2:46][CH:45]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: COC1=NC(C)=C(C(=O)OCc2ccccc2)C(c2cccc(Cl)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: CC1=C(C(=O)OCc2ccccc2)C(c2cccc(Cl)c2)N(C(=O)NCCC(c2ccccc2)c2ccccc2)C(=O)N1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
10 ml of acetonitrile was added to a mixture of 200 mg (0.373 mmol) of 5-benzyl 1-(4-nitrophenyl) 6-(3-chlorophenyl)-2-methoxy-4-methyl-6H-pyrimidine-1,5-dicarboxylate and 78.9 mg (0.373 mmol) of 3,3-diphenylpropylamine, and they were stirred at 60° C. for 30 minutes. The solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH2:9]([O:12][C@@H:13]([CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:14][CH:15]=O)[CH:10]=[CH2:11].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O.C(O)C>[CH2:9]([O:12][C@@H:13]([CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:14][CH:15]=[N:2][OH:3])[CH:10]=[CH2:11]
Reactant: NO
Reactant: C=CCO[C@H](CC=O)COCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: C=CCO[C@H](CC=NO)COCc1ccccc1
Reaction time: 20 h
Yield: 53.9 %

Procedure:
Potassium carbonate (5.14 g) and methyl iodide (4.90 mL) were added to a mixed solution of 2-((R)-2-allyloxy-3-benzyloxy-propyl)-[1,3]dithiane (12 g) in acetonitrile (27 mL) and water (4.5 mL), and then the mixture was stirred at 40° C. After four hours, water (3 mL) and methyl iodide (2 mL) were added to the reaction solution. After further three hours, methyl iodide (1 mL) was added to the reaction solution. After stirring for eight hours in total, water and t-butyl methyl ether were added to the reaction solution, and the organic layer was separated. The organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain crude (R)-3-allyloxy-4-benzyloxy-butyraldehyde (about 10 g). The crude product was used for the next reaction without further purification. Hydroxylamine hydrochloride (4.29 g) and sodium acetate (4.92 g) were sequentially added to a solution of ethanol (60 mL) and water (15 mL). The above aldehyde (10 g) was added to the mixture, followed by stirring for 20 hours. A saturated sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was sequentially washed with a saturated sodium bicarbonate solution and brine and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure to obtain a residue. The residue was subjected to silica gel column chromatography to obtain the title compound (5.74 g).
Reaction SMILES: [CH2:1]([C:3]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH3:19])[CH:13]=1)([C:6]1[S:7][CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH2:4][CH3:5])[CH3:2].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:25][O:24][C:22](=[O:23])[CH2:21][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:3]([CH2:4][CH3:5])([C:6]2[S:7][CH:8]=[C:9]([CH3:11])[CH:10]=2)[CH2:1][CH3:2])=[CH:13][C:14]=1[CH3:19]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1cc(C)cs1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)OC)c(C)c1)c1cc(C)cs1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
4-[1-Ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenol (10.66 g, 38.9 mmol) is reacted with methyl bromoacetate (4.4 ml, 46.7 mmol) and K2CO3 (10.70 g, 77.81 mmol) in acetone (100 m) at refluxing temperature overnight. The reaction is cooled to RT, filtered and washed with Et2O and concentrated. The crude product is purified by chromatography to give the titled compound (12.15 g, 35.1 mmol, 90%). 1H NMR (CD3Cl3), δ 0.70 (t, J=7.2 Hz, 6H), 2.04-2.12 (m, 4H), 2.21 (s, 3H), 2.26 (s, 3H), 3.81 (s, 3H), 4.63 (s, 2H), 6.57-6.61 (m, 2H), 6.69-6.71 (m, 1H), 7.02-7.06 (m, 2H). LC/MS (m/z): calcd for C20H27O3S (M+H)+:347.5; found: 347.1.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:18]=[C:17]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:5])C.[OH-].[Na+]>>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:18]=[C:17]1[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCCCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1

Procedure:
1-(10-Ethoxycarbonyldecyl)-2,4,5-triphenylimidazole (1.3 g) was reacted with 2N sodium hydroxide in a method similar to Example 10 to give, after column chromatography on silica gel eluted with a dichloro-methane:methanol gradient and recrystallisation from ethyl acetate/hexane, 1-(10-carboxydecyl)-2,4,5-triphenylimidazole (0.25 g, 19.2%) as a cream solid, m.p. 76°-78°; Found: C, 79.68%; H, 7.56%; N, 5.78%; C32H36N2O2 requires: C, 79.96%; H, 7.55; N, 5.83%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc2nccnc2c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2nccnc2c1
Yield: 47 %

Procedure:
A solution of quinoxalin-6-amine (14.0 g, 0.97 mol) in acetic anhydride (120 mL) was stirred at 100° C. for 1 h. Excess acetic anhydride was removed under reduced pressure. To the residue was added 150 mL of saturated aqueous sodium bicarbonate solution. The mixture was extracted with DCM (3×150 mL), and the combined organic layers were dried over sodium sulfate and concentrated under reduce pressure to give N-(quinoxalin-6-yl)acetamide as a yellow solid (8.4 g, yield 47%). ESI MS: m/z 188.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.[OH:31][C:32]1[C:36](/[CH:37]=[CH:38]/[C:39]2[N:40]=[C:41]([N:45]3[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]3)[S:42][C:43]=2[CH3:44])=[CH:35][N:34]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[N:33]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:11]2[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]3[CH:27]=[CH:28][C:3]([CH2:2][O:31][C:32]4[C:36](/[CH:37]=[CH:38]/[C:39]5[N:40]=[C:41]([N:45]6[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]6)[S:42][C:43]=5[CH3:44])=[CH:35][N:34]([C:58]5[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=5)[N:33]=4)=[CH:4][C:5]=3[O:29][CH3:30])[N:10]=2)=[CH:20][CH:19]=1)[CH3:26]
Reactant: Cc1sc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1/C=C/c1cn(-c2ccccc2)nc1O
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4nc(N5CCN(C(=O)OC(C)(C)C)CC5)sc4C)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (0.66 g), tert-butyl 4-{4-[(E)-2-(3-hydroxy-1-phenyl-1H-pyrazol-4-yl)ethenyl]-5-methyl-1,3-thiazol-2-yl}piperazine-1-carboxylate (0.81 g), potassium carbonate (0.22 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 1 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with tetrahydrofuran-hexane (1:5, v/v) to give tert-butyl 4-{4-[(E)-2-(3-{[4-({2-[4-(2-ethoxy-2-oxoethyl)phenyl]-5-methyl-1,3-oxazol-4-yl}methoxy)-3-methoxybenzyl]oxy}-1-phenyl-1H-pyrazol-4-yl)ethenyl]-5-methyl-1,3-thiazol-2-yl}piperazine-1-carboxylate as crystals (0.53 g, yield 41%). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 112-114° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][P:10]([OH:12])[OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[O-:15][Mn](=O)(=O)=O.[K+].P(O)O.Cl.S(=O)(O)[O-].[Na+]>CC(C)=O.O>[C:1]1([CH2:7][CH2:8][CH2:9][P:10](=[O:15])([OH:12])[OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OP(O)CCCc1ccccc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: O=S([O-])O
Agent: OPO
Solvent: CC(C)=O
Solvent: O
Product: O=P(O)(O)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-phenylpropyl phosphonous acid (0.92 g, 0.005 mole) in acetone (10 ml) and water (10 ml) was added a solution of sodium hydroxide (0.2 g, 0.005 mole) in water (10 ml) until a pH of about 7 was reached. A solution of KMnO4 (0.474 g, 0.003 mole) in water (10 ml) was added slowly to the vigorously stirred solution of phosphonous acid at 20°-25° C. After the addition (5 minutes), the reaction mixture was stirred for 5 minutes at ambient temperature and acidified with concentrated HCl acid until a pH of 1 was reached. Saturated sodium bisulfite solution was added to the reaction mixture thereby resulting in formation of a precipitate.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH:25]4[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26]4)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[N+](C1C=CC(OC(=O)[NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:55][CH2:54][CH2:53][CH2:52]3)=[CH:47][CH:46]=2)=CC=1)([O-])=O>>[N:51]1([C:48]2[CH:49]=[CH:50][C:45]([NH:44][C:6]([N:8]3[CH2:9][CH2:10][CH:11]([C:14]4[C:23]5[C:18](=[CH:19][C:20]([O:24][CH:25]6[CH2:26][N:27]([C:29](=[O:31])[CH3:30])[CH2:28]6)=[CH:21][CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:12][CH2:13]3)=[O:5])=[CH:46][CH:47]=2)[CH2:52][CH2:53][CH2:54][CH2:55]1
Reactant: O=C(Nc1ccc(N2CCCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)N1CC(Oc2ccc3c(C4CCN(C(=O)OC(C)(C)C)CC4)ncnc3c2)C1
Agent: Cl
Product: CC(=O)N1CC(Oc2ccc3c(C4CCN(C(=O)Nc5ccc(N6CCCC6)cc5)CC4)ncnc3c2)C1
Yield: 26 %

Procedure:
The title compound was prepared from 4-[7-(1-Acetyl-azetidin-3-yloxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (44.1 mg, 103 μmol), as synthesized in the previous step, using (4-pyrrolidin-1-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride, prepared in Example 74a, and using essentially the reaction and work-up procedure described in Example 110b. The title compound was purified by silica flash cartridge chromatography (9:1 DCM/acetone/3% DMEA eluent). The combined fractions (10 mL) were washed with 1M NaHCO3 (1×5 mL) to remove a DMEA+ impurity, and were dried (Na2SO4) and concentrated to provide the title compound (13.8 mg, 26%). 1H-NMR (400 MHz, 95:5 CDCl3/CD3OD) δ 9.13 (s, 1H), 8.16 (d, 1H), 7.31 (dd, 1H), 7.17 (m, 2H), 7.03 (d, 1H), 6.54 (m, 2H), 5.16 (m, 1H), 4.67 (ddd, 1H), 4.51 (dd, 1H), 4.32-4.23 (m, 3H), 4.15 (dd, 1H), 3.70 (tt, 1H), 3.26 (m, 4H), 3.11 (tt, 2H), 2.17-1.97 (m, 8H), 1.94 (s, 3H). LC/MS (ESI): calcd mass 514.3, found 515.3 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.Cl[C:23]1[C:28]2=[N:29][CH:30]=[C:31]([O:33][CH3:34])[N:32]=[C:27]2[CH:26]=[CH:25][N:24]=1>>[F:20][C:5]1[C:4]([F:21])=[CH:3][C:2]([NH:1][C:23]2[C:28]3=[N:29][CH:30]=[C:31]([O:33][CH3:34])[N:32]=[C:27]3[CH:26]=[CH:25][N:24]=2)=[CH:7][C:6]=1[C@:8]1([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]1
Reactant: COc1cnc2c(Cl)nccc2n1
Reactant: C[C@@]1(c2cc(N)cc(F)c2F)C[C@@H](C(F)(F)F)OC(N)=N1
Product: COc1cnc2c(Nc3cc(F)c(F)c([C@]4(C)C[C@@H](C(F)(F)F)OC(N)=N4)c3)nccc2n1

Procedure:
The titled compound was synthesized by procedure and steps analogous to those described in Method B, Example 8 above, but using (4S,6S)-4-(5-amino-2,3-difluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (17i, Example 163, Method Y, step 9) and 5-chloro-2-methoxypyrido[3,4-b]pyrazine (intermediate 3) in step 2. MS m/z=469.1 [M+H]+. Calculated for C20H17F5N6O2: 468.4
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26](=[N:34][C:35]#[N:36])OC2C=CC=CC=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[NH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1>>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)=[N:34][C:35]#[N:36])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NC#N)Oc2ccccc2)c1
Reactant: NCc1ccccn1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NC#N)NCc2ccccn2)c1

Procedure:
Prepared according to the procedure described in Example 33, Step 6, using the following starting materials: [2′-(3-cyano-1-ethyl-2-phenyl-isoureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester and 2-(aminomethyl)pyridine.
Reaction SMILES: Cl.[C:2](=[NH:7])(OCC)[CH3:3].CCN(CC)CC.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[C:24]([C:32]([NH:34][NH2:35])=[O:33])=[CH:25][N:26]([CH3:31])[C:27](=[O:30])[C:28]=2[F:29])=[C:18]([F:36])[CH:17]=1.Cl>CN(C=O)C.C1COCC1>[NH:7]=[C:2]([NH:35][NH:34][C:32]([C:24]1[C:23]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][C:18]=2[F:36])=[C:28]([F:29])[C:27](=[O:30])[N:26]([CH3:31])[CH:25]=1)=[O:33])[CH3:3]
Reactant: CCOC(C)=N
Reactant: Cn1cc(C(=O)NN)c(Nc2ccc(Br)cc2F)c(F)c1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=N)NNC(=O)c1cn(C)c(=O)c(F)c1Nc1ccc(Br)cc1F
Reaction time: 1.5 h

Procedure:
Ethyl acetimidate HCl salt (40 mg, 0.32 mmol) and Et3N (0.049 mL, 0.35 mmol) were added to a stirred suspension of 4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid hydrazide (0.10 g, 0.27 mmol) in 2:1 THF:DMF (3 mL) at 0° C. After 1.5 hours at 0° C. and 17 hours at room temperature, the reaction mixture was poured onto water, neutralized with dilute aqueous HCl and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Trituration with methylene chloride gave the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH:9]([NH:12][C:13]([CH:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]2)=O)[CH2:10][OH:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:24][C:13]([CH:15]3[CH2:16][CH2:17][N:18]([C:21](=[O:23])[CH3:22])[CH2:19][CH2:20]3)=[N:12][C:9]=2[CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: CC(=O)N1CCC(C(=O)NC(CO)C(=O)c2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CC(=O)N1CCC(c2nc(CO)c(-c3ccc(F)cc3)o2)CC1
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
To a slurry of 1-Acetyl-piperidine-4-carboxylic acid [2-(4-fluoro-phenyl)-1-hydroxymethyl-2-oxo-ethyl]-amide, prepared as in Part B, (100 g, 0.30 mol) and pyridine (100 mL, 1.20 mole) in dichloromethane (900 mL) at -40° C. is added trifluoroacetic anhydride (200 mL, 1.40 mole) over 1.5 hrs. The reaction is allowed to warm to -10° C. over 2 hrs and stirred at -10° C. for 1.5 hrs. Water (200 mL) is added, keeping the temperature at 0°--5° C. The layers are separated and the dichloromethane is washed with water (6×400 mL), dried (MgSO4) and concentrated to a yellow oil. The oil is taken up in methanol (600 mL) and silica gel (100 g) is added and the mixture stirred at 20° C. for 16 hrs. The silica gel is removed by filtration, rinsed with methanol (400 mL) and the filtrate is concentrated. Ether (500 mL) is added to the residue and stirred for 2 hrs and the resulting solid is filtered to afford 1-(4-[5-(4-fluoro-phenyl)-4-hydroxymethyl-oxazol-2-yl]-piperidin-1-yl)-ethanone as a pale yellow solid.