Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([NH2:34])[CH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[O:14][CH2:15][C:16]([N:18]1[CH2:23][C@H:22]([CH3:24])[N:21]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:20][C@H:19]1[CH3:33])=[O:17])C.O.[OH-].[Li+]>O1CCCC1.CO.O>[NH2:34][CH:5]([CH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[O:14][CH2:15][C:16]([N:18]1[CH2:23][C@H:22]([CH3:24])[N:21]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH2:20][C@H:19]1[CH3:33])=[O:17])[C:4]([OH:35])=[O:3]
Reactant: CCOC(=O)C(N)Cc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CC(N)C(=O)O

Procedure:
To a solution of 2-amino-3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-propionic acid ethyl ester (0.033 g, 0.065 mmol) in tetrahydrofuran, methanol and water (1 ml each) was added lithium hydroxide hydrate (0.014 g, 0.33 mmol). After 3 hours the reaction was concentrated in vacuo and the title compound was isolated by chromatography on silica gel (0.031 g, LRMS 478.5).
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[C:23]=1Br>C(Cl)Cl.C1CCCCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2c1cc(Br)c(N)c2Br
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc(N)ccc21

Procedure:
From 20 g (0.061 mol) of 7-amino-5-(o-chlorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one there is obtained, in analogy to the details of Example 45, 7-amino-6,8-dibromo-5-(o-chlorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one of melting point 110° (methylene chloride/cyclohexane).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].O=[C:7]1[NH:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]2[S:19][C:20]([CH3:22])=[CH:21][C:8]1=2.CN(C)C1C=CC=CC=1>>[Cl:3][C:7]1[C:8]2[CH:21]=[C:20]([CH3:22])[S:19][C:9]=2[N:10]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:12]=1
Reactant: Cc1cc2c(=O)[nH]c(-c3cccnc3)nc2s1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reaction time: 4 h

Procedure:
The substitution of the keto group by Cl, with formation of the aromatic pyrmidine ring, takes place under standard conditions. A mixture of 18 ml of POCl3 and 6 g of 3,4-dihydro-4-oxo-2-(pyridin-3-yl)-6-methylthieno[2,3-d]pyrimidine with addition of 1.8 ml of N,N-dimethylaniline is boiled for 4 hours. After customary work-up, 5 g of 4-chloro-2-(pyridin-3-yl)-6-methylthieno[2,3-d]pyrimidine are obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[C:27]([CH2:28]O)=[CH:26][CH:25]=[CH:24][N:23]=2)[O:17][N:16]=1.[CH2:30]([N:32](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>O.CS(C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[C:27]([CH2:28][C:30]#[N:32])=[CH:26][CH:25]=[CH:24][N:23]=2)[O:17][N:16]=1
Reactant: CCN(CC)CC
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(COc2ncccc2CO)on1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1COc1cc(COc2ncccc2CC#N)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a mixture of [2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]-3-pyridyl]methanol (1.47 g), triethylamine (760 mg) and ethyl acetate (150 mL) was dropwise added methanesulfonyl chloride (860 mg) under ice-cooling and the mixture was stirred at room temperature or 2 hrs. The reaction mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated to give an oil. To a mixture of this oil and dimethyl sulfoxide (50 mL) was added an aqueous solution (5 mL) of sodium cyanide (280 mg) at room temperature and the mixture was stirred at room temperature for 12 hrs. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give crystals (1.40 g, 68%) of 2-[2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]-3-pyridyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals (1.07 g, 71%). melting point: 110-111° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:22][CH3:23])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH2:20])=[O:19])=[C:14]([F:21])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+]>CO.C(#N)C>[NH2:30][CH:1]([C:4]1[C:5]([O:22][CH3:23])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH2:20])=[O:19])=[C:14]([F:21])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1-c1ccc(C(N)=O)c(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: COc1c(C(C)N)cc(Cl)c(C)c1-c1ccc(C(N)=O)c(F)c1
Temperature: 65 °C

Procedure:
A mixture of 3′-acetyl-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxamide (25 mg, 0.074 mmol), ammonium acetate (57 mg, 0.74 mmol) and sodium cyanoborohydride (9 mg, 0.15 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. overnight in a sealed tube. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and concentrated to dryness. The resulting crude product was used directly in next step (20 mg, 80%). LCMS calculated for C17H16ClFNO2 (M−NH2)+: m/z=320.1. found: 320.1.
Reaction SMILES: C(O[C:4](=[O:19])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[CH3:20][NH:21][C:22]([NH2:24])=[O:23].C[O-].[Mg+2].C[O-].CO>>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH:5]([CH2:6][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]2)[C:4]([NH:24][C:22]([NH:21][CH3:20])=[O:23])=[O:19])=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc(Cl)cc1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 5.8 %

Procedure:
A mixture of 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid ethyl ester (1.65 g, 5.89 mmol) and methyl urea (654 mg, 8.83 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 16.9 mL, 11.78 mmol) was refluxed at 100° C. for 6 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 1-[2-(4-chloro-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea (105.3 mg, 5.8%) as a white solid: mp 145-147° C.; EI-HRMS m/e calcd for C16H21ClN2O2 (M+) 308.1292, found 308.1291. The methyl ester of the starting material was recovered from the reaction mixture due to transesterification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[N:16]=[C:15]([OH:17])[CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1>N1CCCCC1>[N:16]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]4[N:16]=[C:15]([OH:17])[CH:14]=[CH:13][CH:12]=4)=[N:9][N:10]=3)[N:7]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: Oc1cccc(-c2nnc3ccc(Cl)nn23)n1
Solvent: C1CCNCC1
Product: Oc1cccc(-c2nnc3ccc(N4CCCCC4)nn23)n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 142.8 %

Procedure:
A mixture of 6-(6-chloro-1,2,4-triazolo[4,3-b]pyridazin-3-yl)pyridin-2-ol (960 mg) and piperidine (10 ml) was stirred at 100° C. for 3 hours. After allowing to cool to room temperature, the reaction solution was concentrated under reduced pressure, and the resultant crystalline residue was recrystallized from ethanol to obtain 6-(6-piperidin-1-yl-1,2,4-triazolo[4,3-b]pyridazin-3-yl) pyridin-2-ol (820 mg) as grayish white crystals.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:29][CH2:30][C@H:31]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[C:32]([O:34][CH3:35])=[O:33])(=[O:28])=[O:27])=[CH:22][CH:21]=1>CC(C)=O>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[CH2:8][O:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:29][CH2:30][C@H:31]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[C:32]([O:34][CH3:35])=[O:33])(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: COC(=O)[C@H](CNS(=O)(=O)c1ccc(O)cc1)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2ccc3ccccc3c2)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
420 mg (1.3 mmol) of cesium carbonate, followed by 280 mg (1.3 mmol) of 2-bromomethylnaphthalene, are added to a solution of 400 mg (1.2 mmol) of methyl(S)-3-(4-hydroxybenzenesulfonylamino)-2-piperidin-1-ylpropanoate (prepared as described in 3.1) in 10 ml of acetone. The reaction medium is stirred at ambient temperature for 18 h and then filtered. The filtrate is concentrated under vacuum and purified by chromatography on silica gel, elution being carried out with a 70/30 heptane/ethyl acetate mixture. 420 mg (80%) of methyl(S)-3-[4-(naphthalen-2-ylmethoxy)benzenesulfonylamino]-2-piperidin-1-ylpropanoate are obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11](N3CCCC3)=[N:10][C:9]=2[C:18]2[CH:19]=[C:20]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1.ClC1N=C(/C=[C:44](/[C:46]2[CH:47]=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=C[CH:51]=2)\O)C=CN=1.CC(C)(C)C(=S)N>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:46]([CH3:47])([CH3:51])[CH3:44])=[N:10][C:9]=2[C:18]2[CH:19]=[C:20]([NH:24][S:25]([C:28]3[C:29]([F:35])=[CH:30][CH:31]=[CH:32][C:33]=3[F:34])(=[O:26])=[O:27])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)sc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: CC(C)(C)C(N)=S
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Yield: 53.3 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 6, using N-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide (1.00 g, 2.36 mmol) and 2,2-dimethylpropanethioamide (0.277 g, 2.36 mmol) the title compound was obtained (690 mg, 53.3% yield). MS (ESI): 521.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:4]=[CH:5][N:6]=[CH:7][C:8]=2[C:9]([CH3:19])([CH3:18])[C:10](=[O:17])[C:11]=1[C:12]([O:14]CC)=O.Cl.[NH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(N(C(C)C)C(C)C)C>O1CCOCC1.O.CCOC(C)=O>[OH:1][C:2]1[C:3]2[CH:4]=[CH:5][N:6]=[CH:7][C:8]=2[C:9]([CH3:18])([CH3:19])[C:10](=[O:17])[C:11]=1[C:12]([NH:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:14]
Reactant: CCOC(=O)C1=C(O)c2ccncc2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccncc2C(C)(C)C1=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 7.2 %

Procedure:
A mixture of ethyl 5-hydroxy-8,8-dimethyl-7-oxo-7,8-dihydroisoquinoline-6-carboxylate (0.2 g, 0.8 mmol) and tert-butyl 2-aminoacetate hydrochloride (0.2 g, 0.9 mmol) in 1 mL dioxane was treated with N-ethyl-N-isopropylpropan-2-amine (0.4 mL, 2 mmol). The mixture was warmed to 100° C. and stirred for 2.5 hours, M+1=347. The mixture was cooled to room temperature, diluted with 20 mL H2O, and 100 mL EtOAc. The organic layer was concentrated. The crude product was purified by column eluting with 10-20% EtOAc/hexane to give 0.02 g of the product as an off-white solid. MS m/e: (M+H)+ 347.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[C:13]([F:21])=[C:14]([F:20])[C:15]4[N:16]=[CH:17][O:18][C:19]=4[C:11]=3[NH:10][C:9]2=[O:22])=[C:4]([F:23])[CH:3]=1.[CH3:24][N:25]([CH3:30])[S:26](Cl)(=[O:28])=[O:27].[H-].[Na+]>>[CH3:24][N:25]([CH3:30])[S:26]([N:10]1[C:11]2[C:19]3[O:18][CH:17]=[N:16][C:15]=3[C:14]([F:20])=[C:13]([F:21])[C:12]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:23])[C:9]1=[O:22])(=[O:28])=[O:27]
Reactant: O=c1[nH]c2c3ocnc3c(F)c(F)c2n1-c1ccc(Br)cc1F
Reactant: CN(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: CN(C)S(=O)(=O)n1c(=O)n(-c2ccc(Br)cc2F)c2c(F)c(F)c3ncoc3c21
Yield: 14.5 %

Procedure:
Intermediate I-24a was prepared from 6-(4-bromo-2-fluoro-phenyl)-4,5-difluoro-6,8-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d]oxazol-7-one (I-16a: 350 mg, 0911 mmol), N,N-dimethylaminosulfonyl chloride (196.32 mg, 1.36 mmol) and NaH (54.4 mg, 1.36 mmol) using procedures analogous to those described above for Intermediate I-19a to afford 65 mg of the product (14.5% yield). H1NMR (DMSO-d6, 300 MHz): δ 8.96 (s, 1H), 7.95 (dd, 1H), 7.79 (t, 1H), 7.69 (dd, 1H), 3.08 (s, 6H). HPLC: 95.7%
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].[H-].[Na+].O>O1CCCC1>[CH3:33][O:32][CH2:31][C@H:30]([CH3:34])[O:29][C:14]1[CH:13]=[C:12]([C:9]2[NH:8][C:7]([C:5]3[O:6][CH2:2][CH2:3][N:4]=3)=[CH:11][CH:10]=2)[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH:15]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCCCl)[nH]2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCCO3)[nH]2)c1
Temperature: 0 °C
Reaction time: 19 h
Yield: 71.9 %

Procedure:
N-(2-Chloroethyl)-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxamide (177 mg, 0.349 mmol) synthesized in Example (18b) was dissolved in tetrahydrofuran (5 mL), and cooled to 0° C. Sodium hydride (40 mg, 0.917 mmol) was added, and the temperature was raised to room temperature, followed by stirring for 19 hours. After the reaction solution was cooled to 0° C., water (5 mL) was added, and extraction was carried out with ethyl acetate (10 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-100%) to afford the desired compound (118 mg, yield 72%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.FC(F)(F)S(O[C:18]1[CH2:24][CH:23]2[N:25]([CH3:26])[CH:20]([CH2:21][CH2:22]2)[CH:19]=1)(=O)=O.C[Sn](C)C.C[Sn](C)C.[Cl-].[Li+].[F-].[K+]>O1CCOCC1.C(OCC)(=O)C>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=[CH:11][C:2]=1[C:18]1[CH2:19][CH:20]2[N:25]([CH3:26])[CH:23]([CH2:22][CH2:21]2)[CH:24]=1
Reactant: Clc1cnc2ccccc2n1
Reactant: CN1C2C=C(OS(=O)(=O)C(F)(F)F)CC1CC2
Agent: C[Sn](C)C
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN1C2C=C(c3cnc4ccccc4n3)CC1CC2
Temperature: 25 °C

Procedure:
A mixture of 2-chloroquinoxaline, 3-trifluoromethanesulfonyloxy-8-methyl-8-azabicyclo[3.2.1]-oct-2-ene, hexamethylditin, lithium chloride, and [tetrakis(triphenylphosphine)]palladium in dioxane is stirred at reflux for 18 hours. The reaction mixture is cooled to room temperature and then poured into a mixture of saturated aqueous potassium fluoride and ethyl acetate. After stirring for two hours, the phases are separated. The organic phase is washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue is subjected to flash silica gel chromatography. Fractions containing product are combined and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][N:8]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]Br)=[CH:12][CH:11]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([OH:37])[CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34]>>[CH:19]1([N:8]([CH3:7])[C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:37][C:29]3[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:27]([O:26][CH3:25])[CH:28]=3)=[CH:12][CH:11]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1cc(O)cc(OC)c1OC
Reactant: CN(C(=O)c1ccc(CBr)cc1)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(OCc2ccc(C(=O)N(C)C3CCCCC3)cc2)cc(OC)c1OC

Procedure:
The reaction and workup were carried out in the same manner as for Example 21 using K2CO3 (576 mg, 4.17 mmol), 4-bromomethylbenzoic acid N-methyl-N-cyclohexyl amide (1.124 g, 3.62 mmol) and 3,4,5-trimethoxyphenol (648 mg, 3.52 mmol). The crude product was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as a crystalline solid that could be recrystallized from ethyl acetate and hexane, m. pt. 115.53° C. (DSC).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.I[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:9]([N:5]1[CH:6]=[CH:7][C:2](=[O:1])[CH:3]=[CH:4]1)[CH2:10][CH3:11]
Reactant: Oc1ccncc1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCn1ccc(=O)cc1
Temperature: 25 °C

Procedure:
The starting material may be prepared as follows: A solution of 4-hydroxypyridine (950 mg.) and 1-iodopropane (2.34 ml.) in acetone (30 ml.) was stirred under reflux for 2 hours with powdered potassium carbonate (2.76 g.). The reaction mixture was cooled to room temperature and filtered. The solvent was evaporated from the filtrate and the residue was purified by chromatography on Kieselgel 60 (100 g.) eluating with methylene chloride/MeOH 100:0 to 80:20 v/v to give 1-n-propyl-4-pyridone (1.05 g.), an oil having n.m.r. in CDCl3 : 0.9(t, 3H); 1.75(m, 2H); 3.7(t, 2H); 6.23(d, 2H); 7.28(d, 2H). This material was chlorinated as described in the second part of Example 56 to give 4-chloro-1-n-propylpyridinium toluene-p-sulphonate.
Reaction SMILES: [C:1]([O:11][C:12]([C:15]([CH2:18][CH2:19][S:20](Cl)(=[O:22])=[O:21])([F:17])[F:16])([F:14])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[CH3:24][N:25]([CH2:27][CH2:28][CH2:29][NH2:30])[CH3:26]>>[C:1]([O:11][C:12]([C:15]([CH2:18][CH2:19][S:20]([NH:30][CH2:29][CH2:28][CH2:27][N:25]([CH3:26])[CH3:24])(=[O:22])=[O:21])([F:17])[F:16])([F:14])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: O=S(=O)(Cl)CCC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)F
Reactant: CN(C)CCCN
Product: CN(C)CCCNS(=O)(=O)CCC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)F
Temperature: 75 °C
Yield: 87.2 %

Procedure:
C3F7OCF2CF2CH2CH2SO2Cl (100 g, 0.242 mol, 66.8% in toluene) was added dropwise to a mixture of dimethylaminopropylamine (DMAPA) at 45° C. After the addition, the reaction was heated at 75° C. overnight. The reaction mass was filtered and the wet cake was washed with 60° C. toluene. After stripping off the toluene, the concentrated organic product was washed with 200 mL of 95° C. deionized water. The product Intermediate 1, C3F7OCF2CF2CH2CH2SO2N(H)—CH2CH2CH2N(CH3)2 (101 g, 87.2%) was obtained as an amber colored solids after removing water under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([Cl: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:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(OCC)(=O)C>CN(C=O)C>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:16])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29](=[O:30])[C:26]3[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][N:27]=3)[CH:3]=[C:4]([F:21])[C:5]=2[Cl:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: C[C@@]1(c2cc(N)cc(F)c2Cl)C[C@@H](C(F)(F)F)OC(N)=N1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)cn3)cc(F)c2Cl)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.4 %

Procedure:
To a mixture of (4S,6S)-4-(5-amino-2-chloro-3-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.060 g, 0.184 mmol) and 5-chloropicolinic acid (0.035 g, 0.221 mmol) in DMF (1.5 mL) at 0° C. was added 1-propanephosphonic acid cyclic anhydride, 50% solution in ethyl acetate (0.130 mL, 0.221 mmol). The reaction was gradually warmed to rt and stirred for 2 h. The reaction mixture was partitioned between EtOAc and saturated solution of NaHCO3. The organic layer was separated, washed twice with water, then washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude was purified by flash chromatography on silica gel (12 g, 0-100% EtOAc/DCM in 15 min). The fractions were combined and concentrated in vacuo. The resulting white solid was dissolved in MeOH and purified by reverse phase prep HPLC: 10-80% MeCH in Water (with 0.1% TFA). The fractions were collected and neutralized with solid Na2CO3, extracted with DCM three times. The organic solution was dried over sodium sulfate and concentrated in vacuo to give N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-chloro-5-fluorophenyl)-5-chloropicolinamide (20 mg, 23.3% yield). MS m/z=465 [M+H]+. Calculated for C18H14Cl2F4N4O2: 465.2.
Reaction SMILES: CON(C)[C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:11][C:10]1[C:9]2[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:8]=2[O:7][C:6]=1[CH:4]=[O:5]
Reactant: CON(C)C(=O)c1oc2ccc(C)cc2c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2oc(C=O)c(C)c2c1
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a solution (50 mL) of N-methoxy-N,3,5-trimethyl-1-benzofuran-2-carboxamide (3.78 g) synthesized above in tetrahydrofuran was added lithium aluminum hydride (307 mg) at −78° C., and the mixture was stirred for 2 hr. Water (350 μL) was added to quench the reaction, 1N aqueous sodium hydroxide solution (700 μL) was added, and the mixture was stirred at room temperature for 1 hr. The resulting insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was washed with hexane to give the title object compound (2.08 g, 74%) as a yellow solid.