Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:15](Br)[CH:16]=[N:17][C:10]=2[N:9]([CH3:27])[C:8]1=[O:28])=O.C([O-])([O-])=O.[Cs+].[Cs+].CN(C)CC(O)=O.[Cl:42][C:43]1[CH:44]=[C:45]([OH:49])[CH:46]=[CH:47][CH:48]=1>O1CCOCC1.CC(=O)OCC.O.[Cu]I>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:28])[N:9]([CH3:27])[C:10]=3[N:17]=[CH:16][C:15]=2[O:49][C:45]2[CH:46]=[CH:47][CH:48]=[C:43]([Cl:42])[CH:44]=2)=[CH:21][CH:22]=1
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(Br)cnc21
Reactant: Oc1cccc(Cl)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cccc(Cl)c3)cnc21
Temperature: 25 °C
Yield: 12.3 %

Procedure:
To a mixture of 3-(6-bromo-5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (80 mg, 0.17 mmol), CuI (4.2 mg, 0.022 mmol), Cs2CO3 (167.6 mg, 0.51 mmol) and 2-(dimethylamino)acetic acid (8.8 mg, 0.085 mmol) in dioxane (2 mL) was added 3-chlorophenol (55.1 mg, 0.43 mmol). The reaction was heated at 140° C. (MW) for 2 h, cooled to RT then diluted with EA (15 mL) and water (10 mL). The organic layer was washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-6-(3-chlorophenoxy)-3-(3-hydroxypropyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (10.2 mg, 12% yield) as a white solid. 1H NMR (CDCl3) δ: 8.35 (s, 1H), 7.23 (d, J=8.2 Hz, 1H), 7.17 (s, 4H), 7.09 (d, J=8.0 Hz, 1H), 6.84-6.73 (m, 2H), 4.71 (s, 2H), 4.24 (t, J=6.1 Hz, 2H), 3.72 (s, 3H), 3.55 (s, 2H), 3.02 (s, 1H), 2.00-1.86 (m, 2H). LCMS: MH+ 486 and TR=3.332 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:23]=[C:22]([CH2:24][CH3:25])[S:21][C:10]=2[N:11]([CH3:20])[C:12](=[O:19])[C:13]=1[C:14]([O:16]CC)=[O:15].[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:23]=[C:22]([CH2:24][CH3:25])[S:21][C:10]=2[N:11]([CH3:20])[C:12](=[O:19])[C:13]=1[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1c(-c2ccccc2Cl)c2cc(CC)sc2n(C)c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1cc2c(-c3ccccc3Cl)c(C(=O)O)c(=O)n(C)c2s1
Temperature: 80 °C
Yield: 89.4 %

Procedure:
A mixture of ethyl 4-(2-chlorophenyl)-6,7-dihydro-2-ethyl-7-methyl-6-oxothieno[2,3-b]pyridine-5-carboxylate (1.10 g), KOH (0.49 g) and 80% ethanol (10 ml) was heated at 80° C. for 20 minutes and water was added. Then, the mixture was made acidic with 2N HCl and extracted with ethyl acetate. The extract was washed with water and dried over MgSO4, and then the solvent was distilled off. To the residue was added hexane to obtain 4-(2-chlorophenyl)-6,7-dihydro-2-ethyl-7-methyl-6-oxothieno[2,3-b]pyridine-5-carboxylic acid as crystals (0.91 g, 89.2%). The crystals were recrystallized from ethanol to obtain colorless prisms, mp: 155°-156° C.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:21]([S:24][CH2:25][CH2:26][C:27](Cl)=[O:28])(=[O:23])[CH3:22]>O.C(OCC)(=O)C>[C:21]([S:24][CH2:25][CH2:26][C:27]([N:9]1[CH:10]([C:12]([OH:14])=[O:13])[CH2:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8]1)=[O:28])(=[O:23])[CH3:22]
Reactant: O=C(O)C1CC(c2ccccc2)=NN1
Reactant: CC(=O)SCCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)SCCC(=O)N1N=C(c2ccccc2)CC1C(=O)O
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
A suspension of 8.0 g of 4,5-dihydro-3-phenyl-1H-pyrazole-5-carboxylic acid in 200 ml of distilled water is treated slowly with 2.6 g of sodium carbonate. The solution is layered with 50 ml of ethyl acetate, cooled to 5° C. and treated with 7.0 g of 3-(acetylthio)propionyl chloride in 10 ml of ethyl acetate. The pH of the reaction mixture is maintained at 7.5-8.0 by the addition of concentrated sodium carbonate solution. The mixture is stirred at room temperature for 30 minutes. The ethyl acetate layer is then discarded and the aqueous layer is washed twice with fresh ethyl acetate. Using 6 N hydrochloric acid, the pH of the aqueous layer is adjusted to 2.5 and then it is extracted with two 100 ml portions of ethyl acetate. The combined extracts are dried over magnesium sulfate and concentrated to a point where precipitation begins. Cooling affords 10.6 g of the title compound, melting point 137°-139° C.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([N:7]2[N:11]=[C:10]([OH:12])[CH:9]=[N+:8]2[O-:13])=[CH:3][CH:2]=1.[C:15](=O)([O-])[O-].[K+].[K+].CI.S(=O)(=O)(O)O>CN(C)C=O.O>[C:1]1([CH3:14])[CH:2]=[CH:3][C:4]([N:7]2[N:11]=[C:10]([O:12][CH3:15])[CH:9]=[N+:8]2[O-:13])=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(-n2nc(O)c[n+]2[O-])cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1c[n+]([O-])n(-c2ccc(C)cc2)n1
Temperature: 60 °C
Reaction time: 6 h
Yield: 64.7 %

Procedure:
81.4 g of 2-(p-tolyl)-4-hydroxy-2H-1,2,3-triazole-1-oxide (m.p. 150°-154° C. with decomp., prepared in accordance with Synthesis 1974 (March), pp. 198-199) are dissolved in 810 ml of dimethyl formamide at room temperature. Then 141.3 g of potassium carbonate are suspended in this solution and 48.3 ml of methyl iodide are poured into the suspension with good stirring. The batch is then heated to 60° C. over 30 minutes and kept thereat for 6 hours. The fine suspension is thereafter poured into 6 liters of water, and the pH is adjusted to 4-5 with 2N sulphuric acid. After cooling to room temperature, the solid is collected with suction, washed with water and dried to yield 56.5 g of 2-(p-tolyl)-4-methoxy-2H-1,2,3-triazole-1-oxide with a melting point of 62°-64° C. After recrystallisation from alcohol/water the product melts at 70°-72° C.
Reaction SMILES: Cl.[OH:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[N:16]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:4]2[N:3]([O:2][C:22]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:23])[CH:7]=[CH:6][N:5]=2)=[CH:13][CH:12]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: COc1ccc(-c2nccn2O)cc1
Agent: Cl
Product: COc1ccc(-c2nccn2OC(=O)N2CCOCC2)cc1

Procedure:
The title compound was prepared from 1-hydroxy-2-(4-methoxyphenyl)imidazole, hydrochloride and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc) (49%, crystals).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:17][CH3:18])[CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([F:16])[CH:11]=1)=[O:9].C(N(CCN[C:35]([C:37]1[CH:46]=[N:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([I:47])[CH:43]=2)[N:38]=1)=[O:36])CCOC1C(F)=NC=CC=1)C>>[CH2:17]([N:4]([CH2:3][CH2:2][NH:1][C:35]([C:37]1[CH:46]=[N:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([I:47])[CH:43]=2)[N:38]=1)=[O:36])[CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([F:16])[CH:11]=1)=[O:9])[CH3:18]
Reactant: CCN(CCN)CCNC(=O)c1ccnc(F)c1
Reactant: CCN(CCNC(=O)c1cnc2cc(I)ccc2n1)CCOc1cccnc1F
Product: CCN(CCNC(=O)c1ccnc(F)c1)CCNC(=O)c1cnc2cc(I)ccc2n1
Yield: 63 %

Procedure:
This compound was prepared, starting from compound 38 (0.26 g, 1.02 mmol), according to the procedure developed for compound 10. Reaction time under reflux: 24 h; the purification was performed using column chromatography (Al2O3, CH2Cl2/EtOH, 98/2, v/v) to give compound 39 (236 mg, 0.45 mmol) as a beige solid. Yield 63%; Rf (Al2O3, CH2Cl2/EtOH, 98/2, v/v) 0.50; mp 146-148° C.; IR (KBr) ν 1524, 1542, 1662, 2800-3000, 3335, 3388 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.02 (t, 3H, J=7.1 Hz), 2.65 (q, 2H, J=7.1 Hz), 2.79 (m, 4H), 3.59 (m, 4H), 7.33 (s, 1H), 7.52 (d, 1H, J=5.1 Hz), 7.64 (d, 2H, J=8.8 Hz), 8.01 (dd, 1H, J=1.7, 8.8 Hz), 8.14 (d, 1H, J=5.1 Hz), 8.22 (m, 1H), 8.55 (d, 1H, J=1.7 Hz), 9.48 (s, 1H); ESI-MS m/z 537.0 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[CH:18]=[CH:17][C:8]2[C:9](=[O:16])[C:10]([C:14]#[N:15])=[C:11]([CH3:13])[O:12][C:7]=2[CH:6]=1)(=O)C.[OH-].[Na+].Cl>CO>[OH:4][C:5]1[CH:18]=[CH:17][C:8]2[C:9](=[O:16])[C:10]([C:14]#[N:15])=[C:11]([CH3:13])[O:12][C:7]=2[CH:6]=1
Reactant: CC(=O)Oc1ccc2c(=O)c(C#N)c(C)oc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1oc2cc(O)ccc2c(=O)c1C#N
Reaction time: 0.08 h

Procedure:
A slurry of 7.3 g of 7-acetoxy-4-oxo-2-methyl-4H-1-benzopyran-3-carbonitrile in 45 ml of methanol was treated with 75 ml of 1N sodium hydroxide solution. The mixture was stirred for 5 minutes, cooled in ice and acidified with 4N HCl. The solid was filtered and recrystallized from methanol, mp > 300° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]([CH3:18])=[CH:7][C:8]([S:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:9]>C(Cl)Cl.[Cl-].[Na+].O>[CH3:5][C:6]1([CH3:18])[C:12]2[C:11](=[CH:16][CH:15]=[C:14]([Br:17])[CH:13]=2)[S:10][C:8](=[O:9])[CH2:7]1
Reactant: CC(C)=CC(=O)Sc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CC(=O)Sc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred, ice-cooled suspension of 15.9 g (119 mmol) of aluminum chloride in 140 ml of methylene chloride was added under nitrogen a solution of 21.64 g (79.9 mmol) of S-(4-bromophenyl) 3,3-dimethyl-thioacrylate (Compound 30) in 100 ml of methylene chloride. The mixture was then stirred at room temperature for 72 h and then poured into 250 g of an ice and brine mixture. The mixture was extracted with methylene chloride and the combined organic extracts were washed with saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue recrystallized from hexanes to give the title compound as white crystals. PMR (CDCl3): & 1.40 (6 H, s), 2.67 (2 H, s), 7.31-7.40 (3 H, m). MS exact mass, m/e 269.9714 (calcd. for C11H11SOBr, 269.9714).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9]Cl)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[NH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:6]2[C:7]3[CH2:8][CH2:9][N:25]([CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[C:2]=3[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:5]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Reactant: NCc1cccnc1
Product: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3Cc2cccnc2)c1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 3-aminomethylpyridine, the desired compound was obtained.
Reaction SMILES: C([O:8][C:9](=[O:23])[NH:10][C@@H:11]([CH3:22])[C@H:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=1[C:46]1[CH:47]=[C:48]([C:54]2[CH:59]=[CH:58][C:57]([C:60]([O:62][CH3:63])=[O:61])=[CH:56][C:55]=2[CH3:64])[CH:49]=[CH:50][C:51]=1[O:52][CH3:53]>CC(N(C)C)=O.C1COCC1>[CH3:53][O:52][C:51]1[CH:50]=[CH:49][C:48]([C:54]2[CH:59]=[CH:58][C:57]([C:60]([O:62][CH3:63])=[O:61])=[CH:56][C:55]=2[CH3:64])=[CH:47][C:46]=1[C:37]1[CH:38]=[CH:39][C:40]([C:42]([F:45])([F:43])[F:44])=[CH:41][C:36]=1[CH2:35][N:10]1[C@@H:11]([CH3:22])[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[O:23][C:9]1=[O:8]
Reactant: COc1cccc([C@@H](O)[C@H](C)NC(=O)OCc2ccccc2)c1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CBr)c2)c(C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cccc(OC)c4)[C@@H]3C)c2)c(C)c1
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of benzyl[(1S,2R)-2-hydroxy-2-(3-methoxyphenyl)-1-methylethyl]carbamate (40 mg, 0.126 mmol) in DMA (1.5 mL) was added NaHMDS (0.246 mL of a 1M solution in THF, 0.246 mmol). After 5 minutes, a solution of methyl 2″-(bromomethyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (68 mg, 0.138 mmol) in DMA (2.5 mL) was added via cannula. After 5 minutes, the reaction was quenched with saturated NH4Cl solution (10 mL), diluted with EtOAc (20 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 25% acetone/hexanes), followed by reverse-phase chromatography (C-18, 10 to 95% MeCN/water with 0.1% TFA) afforded methyl 4′-methoxy-2″-{[(4S ,5R)-5-(3-methoxyphenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate. LCMS=644.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, rotamers present) δ 7.94-7.86 (m, 2H), 7.71-7.62 (m, 2H), 7.43-7.36 (m, 2H), 7.31-7.22 (m, 2H), 7.3 (m, 1H), 7.08-7.05 (m, 1H), 6.85-6.83 (m, 1H), 6.75-6.68 (m, 2H), 5.45 (d, J=8.0 Hz), 5.23 (d, J=8.0 Hz), 4.89 (d, J=16.0 Hz), 4.82 (d, J=16.0 Hz), 4.20 (d, J=15.8 Hz), 3.96 (d, J=15.8 Hz), 3.91 (s, 3H), 3.85 (s, 3H), 3.77-3.75 (m, 3H), 3.72-3.69 (m, 1H), 2.31 (s), 2.08 (s), 0.54 (d, J=6.4 Hz), 0.44 (d, J=6.4 Hz).
Reaction SMILES: [N+:1](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-:2].[CH2:9]([N:16]1[C:20](=[O:21])[CH:19]=[CH:18][C:17]1=[O:22])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(OCC)C>[CH2:9]([N:16]1[C:20](=[O:21])[CH:19]2[CH:18]([NH:2][N:1]=[C:3]2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:17]1=[O:22])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C1=NNC2C(=O)N(Cc3ccccc3)C(=O)C12
Temperature: 25 °C
Reaction time: 96 h
Yield: 90.3 %

Procedure:
Ethyl diazoacetate (30.3 mL, 288.5 mmol) was added dropwise over a period of 30 min to a solution of N-benzylmaleimide (49.5 g, 264.7 mmol) in diethyl ether (300 mL) and the mixture was stirred for 4 days at room temperature. The resulting precipitate was filtered off, washed with diethyl ether (100 mL) and dried under vacuum to provide title compound as a white solid (72 g, 90%). Method B HPLC-MS: MH+ requires m/z=302. Found: m/z=302, Rt=1.74 min (83%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:4]([CH2:9][OH:10])[O:3]1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C1COCC1>[C:15]1([CH2:14][O:8][CH2:7][C@@H:5]2[C@@H:4]([CH2:9][O:10][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:3][C:2]([CH3:11])([CH3:1])[O:6]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1(C)O[C@H](CO)[C@@H](CO)O1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)O[C@H](COCc2ccccc2)[C@@H](COCc2ccccc2)O1
Reaction time: 0.75 h
Yield: 120.7 %

Procedure:
A solution of (4R-trans)-(-)-2,2-dimethyl-1,3-dioxolane-4,5-dimethanol (51 g) in THF (400 ml) was added dropwise to a stirred suspension of sodium hydride (17.5 g of 80% in oil) in THF (200 ml). After 0.75 h, benzyl bromide (116.3 g) was added dropwise and the resulting mixture was stirred for 18 h, and was then heated at reflux for 2 h. After stirring for a further 20 h at 20°, the mixture was cooled in ice, water (10 ml) was added and the mixture was evaporated to dryness. The residue was extracted with ER, and the organic solution was dried and the solvent was evaporated giving a crude product (130 g) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH2:18][C:19]1[O:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=1>>[CH3:1][C:2]1[N:3]([CH2:18][C:19]2[O:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1ccc(CBr)o1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1ccc(C(F)(F)F)o1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 2-(bromomethyl)-5-(trifluoromethyl)furan: 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J=8.6 Hz, 1H), 7.51 (d, J=8.6 Hz, 1H), 6.70 (d, J=2.9 Hz, 1H), 6.63 (s, 1H), 6.11 (d, J=2.9 Hz, 1H), 5.32 (s, 2H), 2.55 (s, 3H); MS (ES) m/z 373 (M+1).
Reaction SMILES: [F:1][C:2]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:3][CH2:4][C:5]1[N:6]=[C:7]([C:14]([NH2:16])=O)[N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12.P(Cl)(Cl)(Cl)=O>>[F:21][C:2]([F:1])([C:17]([F:19])([F:18])[F:20])[CH2:3][CH2:4][C:5]1[N:6]=[C:7]([C:14]#[N:16])[N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12
Reactant: NC(=O)c1nc(CCC(F)(F)C(F)(F)F)c2ncccn12
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1nc(CCC(F)(F)C(F)(F)F)c2ncccn12

Procedure:
A solution of the intermediate from Step E in phosphoryl chloride (9.43 mL, 101 mmol) was heated at 105° C. for 30 min. The majority of the phosphoryl chloride was removed in vacuo. The crude product was partitioned between saturated aq. NaHCO3 and EtOAc. The aqueous layer was separated and further extracted with EtOAc (2×). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the desired product, as a yellow solid. 1H NMR (600 MHz, CHCl3-d) δ 8.47 (dd, J=7.1, 1.6 Hz, 1H); 8.41 (dd, J=3.8, 1.7 Hz, 1H); 6.98 (dd, J=7.1, 3.8 Hz, 1H); 3.35-3.31 (m, 2H); 2.68-2.57 (m, 2H). m/z=291.1 (M+H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:25]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=[CH:26]1>>[N:25]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1=CC=CNC=C1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Product: N#Cc1ccc(-c2ccc3oc(CCN4CCCCCC4)cc3c2)cc1

Procedure:
The product from Example 1C and azepine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 345 (M+H)+;
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH2:13])[N:7]=[N:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:13][N+:14]([O-:16])=[O:15])[N:7]=[N:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOc1cc(N)nnc1OCC
Agent: O=S(=O)(O)O
Product: CCOc1cc(N[N+](=O)[O-])nnc1OCC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
5,6-Diethoxypyridazin-3-ylamine (analogously to T. Horie in Chemical & Pharmaceutical Bulletin (1963), 11(9), 1157-67; 160 mg) was initially charged dissolved in concentrated sulfuric acid (4 ml) at RT. The mixture was then cooled to 0° C. and 2 ml of a 1:1 mixture of concentrated nitric acid and concentrated sulfuric acid were added dropwise. After 20 min at 0° C., the ice bath was removed and the mixture was stirred for 4 h. Then it was cooled again to 0° C., a further 0.5 ml of the acid mixture was added and the mixture was stirred at 0° C. for another hour. Then it was admixed with ice while cooling with ice. After adding DCM, the phases were separated and extracted three times with DCM. The combined DCM phases were dried over sodium sulfate, filtered and concentrated. 188 mg of the title compound were obtained. LC-MS rt: 0.81 min [M+H]+: 236.2 (met. b)
Reaction SMILES: [Cl-:1].[Li+].[F:3][C:4]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:5]OS(C1C=CC(C)=CC=1)(=O)=O>CN1CCCC1=O>[Cl:1][CH2:5][C:4]([F:21])([F:3])[C:17]([F:20])([F:19])[F:18]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)(F)F)cc1
Reactant: [Cl-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: FC(F)(F)C(F)(F)CCl

Procedure:
Until HCFC-225ca becomes available in commercial quantities, HCFC-225ca may be prepared by a standard and well-known organic synthesis technique. For example, to prepare 1,1-dichloro-2,2,3,3,3-pentafluoropropane, 2,2,3,3,3-pentafluoro-1-propanol and p-toluenesulfonate chloride are reacted together to form 2,2,3,3,3-pentafluoropropyl-p-toluenesulfonate. Then, N-methylpyrrolidone, lithium chloride, and the 2,2,3,3,3-pentafluoropropyl-p-toluenesulfonate are reacted together to form 1-chloro-2,2,3,3,3-pentafluoropropane. Chlorine and the 1-chloro-2,2,3,3,3-pentafluoropropane are then reacted together to form 1,1-dichloro-2,2,3,3,3-pentafluoropropane. A detailed synthesis is set forth below.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][OH:18])[CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([F:15])=[CH:13][CH:14]=1.Cl[C:20]1[CH:21]=[C:22]2[N:29]([CH3:30])[C:28]([CH3:32])([CH3:31])[CH2:27][N:23]2[C:24](=[O:26])[N:25]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([F:15])=[CH:13][CH:14]=1)[CH2:17][O:18][C:20]1[CH:21]=[C:22]2[N:29]([CH3:30])[C:28]([CH3:32])([CH3:31])[CH2:27][N:23]2[C:24](=[O:26])[N:25]=1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1cc(F)c(Oc2ccc(F)nc2)c(F)c1
Product: CN1c2cc(OCc3cc(F)c(Oc4ccc(F)nc4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluoro-4-((6-fluoropyridin-3-yl)oxy)phenyl)methanol and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:17][CH2:16][C:9]2[N:10]=[N:11][C:12](NN)=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2]>CC(C)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:17][CH:16]([NH:11][N:10]=[C:9]([CH3:16])[CH3:8])[C:9]2[N:10]=[N:11][CH:12]=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2nnc(NN)cc2C1
Solvent: CC(C)=O
Product: CCOC(=O)N1Cc2ccnnc2C(NN=C(C)C)C1

Procedure:
A suspension of 23.7 g of 3-hydrazino-5,6,7,8-tetrahydro-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester in 100 cc of acetone is heated at reflux for 4 hours while stirring. The title compound has a M.P. of 171°-174° (decomp., from methanol).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30](CCCC(O)=O)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]([C:47]([O:49]C(C)(C)C)=[O:48])[C@H:43]([CH2:45][CH3:46])[CH3:44].Cl>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:22][CH2:23][CH2:24][C:25]([NH:41][C@H:42]([C:47]([OH:49])=[O:48])[C@H:43]([CH2:45][CH3:46])[CH3:44])=[O:26])=[CH:29][CH:28]=2)=[CH:39][CH:40]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Product: CC[C@H](C)[C@H](NC(=O)CCCc1ccc(Oc2ccc(CN(Cc3ccccc3)c3cccc(NS(C)(=O)=O)c3C)cc2)cc1)C(=O)O

Procedure:
The product from Example 100 (56 mg, 0.1 mmole) and H-Ile-OtBu HCl (45 mg, 0.2 mmole) were processed as in Example 213A-B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ11.81-12.98 (br.s, 1 H), 8.95 (s, 1 H), 7.93 (d, 1 H), 7.26 (m, 6 H), 7.18 (m, 3 H), 7.04 (t, 1 H), 6.96 (m, 2 H), 6.88 (d, 4 H), 4.19 (dd, 1 H), 4.05 (s, 2 H), 4.02 (s, 2 H), 2.91 (s, 3 H), 2.53 (t, 2 H), 2.39 (s, 3 H), 2.18 (m, 2 H), 1.76 (m, 3 H), 1.39 (m, 1 H), 1.20 (m, 1 H), 0.83 (m, 6 H); MS (APCI+) m/z 673 (M+H)+.