Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11](=[O:14])([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:14][C:11]1[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=1[N+:8]([O-:10])=[O:9])([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccccc1Oc1ccccc1[N+](=O)[O-]
Yield: 41.7 %

Procedure:
A solution of 3-[[[3[(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenol (100 mg, 0.23 mmol), 1-bromo-2-nitrobenzene (52.4 mg, 0.26 mmol), copper(I) trifluoromethanesulfonate benzene complex (3 mg, 2.5 mol %) and cesium carbonate (100 mg, 0.31 mmol) in toluene (1 mL) and ethyl acetate (1 mL) was heated at 95° C. in a sealed vial for 4 d. The reaction mixture was filtered through celite, and the solvent was evaporated. The residue was purified by reverse phase HPLC eluting with 50% to 90% acetonitrile in water to afford 14.1 mg (11%) of the desired 2-nitrophenyl ether product as an orange oil. HRMS calcd. for C24H20F7N2O5: 549.1260 [M+H]+, found: 549.1235. 1H NMR (CDCl3) δ3.63 (dd, 1H), 3.84 (dd, 1H), 4.35-4.42 (m, 1), 4.64 (s, 2H), 5.90 (tt, 1H), 6.47-6.67 (m, 3H), 6.98-7.50 (m, 8H), 7.97 (d, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[N:9]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[CH:12]=[C:8]2[C:7](=[O:20])[NH:6][CH2:5]1.[S:21](Cl)([CH3:24])(=[O:23])=[O:22].O>C(Cl)Cl>[CH3:24][S:21]([O:1][CH2:2][CH2:3][CH:4]1[N:9]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[CH:12]=[C:8]2[C:7](=[O:20])[NH:6][CH2:5]1)(=[O:23])=[O:22]
Reactant: O=C1NCC(CCO)n2cc(-c3cccc(Cl)c3)cc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCC1CNC(=O)c2cc(-c3cccc(Cl)c3)cn21
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a solution of 4-(2-hydroxyethyl)-7-(3-chlorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (128 mg, 0.44 mmol) in DCM (10 ml), mesyl chloride (58 ul, 0.748 mmol) and TEA (200 ul, 1.48 mmol), were added. The resulting solution was stirred at room temperature, after 1 h the reaction mixture was portioned between DCM and water. The organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude was triturated with diethyl ether and filtered to give 2-[1-oxo-7-(3-chlorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl]ethyl methanesulfonate as a solid 157 mg (97%).
Reaction SMILES: Br[C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C@@H:18]([O:23][C:24](=[O:31])[CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH2:17][C@@:16]2([CH3:32])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:33].O1C=CCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.CO>[CH2:27]([N:26]([CH2:25][C:24]([O:23][C@H:18]1[CH2:17][C@@:16]2([CH3:32])[C@@H:9]([CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[C@H:8]2[C@H:19]1[C@:20]1([CH3:22])[C@@H:5]([CH2:6][CH2:7]2)[CH2:4][C@H:3]([OH:33])[CH:2]=[CH:21]1)=[O:31])[CH2:29][CH3:30])[CH3:28]
Reactant: CCN(CC)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(C)=O)CC[C@H]2[C@@H]2CC[C@H]3C[C@H](O)[C@@H](Br)C[C@]3(C)[C@H]21
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CO
Product: CCN(CC)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(C)=O)CC[C@H]2[C@@H]2CC[C@H]3C[C@H](O)C=C[C@]3(C)[C@H]21
Reaction time: 0.33 h

Procedure:
2β-Bromo-11β-diethylaminoacetoxy-3α-hydroxy-5α-pregnan-20-one (1 g) was stirred and warmed with dihydropyran (2 ml) in benzene (40 ml) containing p-toluene sulphonic acid monohydrate (406 mg) until a clear solution was achieved. After 20 mins, the mixture was washed with excess sodium bicarbonate solution and brine (2x) and dried with magnesium sulphate. Evaporation of the benzene left a gum which was dissolved in N,N-dimethylformamide (25 ml) and stirred at 120° with calcium carbonate (2.5 g) and lithium bromide (3.3 g) for 5.5 hours. When reaction was complete, the mixture was diluted with methanol and filtered. The methanolic filtrate was made acidic by addition of 2N hydrochloric acid (4 ml). After 4 hours at 20°, excess sodium bicarbonate solution was added and the mixture evaporated to a small volume, extracted with ethyl acetate (twice) and the combined organic solutions were washed with brine (twice) and dried with magnesium sulphate. Evaporation of the solvent left a gum which was filtered through silica gel (30 g) in ethyl acetate and the eluate concentrated. Further purification was achieved by preparative TLC and recrystallisation from aqueous methanol to give title compound m.p. 134°-138°, [α]D +51.6° (270 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.N1C=CC=C[C:19]=1[O:24]C(=O)OC1C=CC=CN=1>ClCCl.C(OCC)(=O)C>[O:10]1[C:4]2([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:3][NH:2][C:19]1=[O:24]
Reactant: NCC1(O)CCCCC1
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1NCC2(CCCCC2)O1
Reaction time: 0.25 h
Yield: 74.7 %

Procedure:
1-Aminomethyl-cyclohexanol hydrogen chloride (250 mg, 1.5 mmol) and triethylamine (0.21 mL, 1.5 mmol) were mixed in dichloromethane (5 mL), and the mixture was stirred for 15 min. Carbonic acid dipyridin-2-yl ester (326 mg, 1.5 mmol) was then added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (10 mL), washed with water (2×4 mL), brine (2×4 mL); dried over anhydrous sodium sulfate and concentrated to give the title compound as a white powder (174 mg, 74%). 1H NMR (300 MHz, CDCl3): δ 6.42 (br, 1H), 3.31 (s, 2H), 1.86 (m, 2H), 1.76 (m, 2H), 1.65 (m, 2H), 1.47 (m, 4H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[C:16](OCC)(=[O:21])[CH2:17][C:18]([CH3:20])=[O:19]>>[C:16]([O:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15])(=[O:21])[CH2:17][C:18]([CH3:20])=[O:19]
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Reactant: CCOC(=O)CC(C)=O
Product: CC(=O)CC(=O)OCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 53.9 %

Procedure:
A solution of 22.8 g (0.111 mol) of N-3-hydroxypropyl phthalimide and 14.46 g (0.111 mol) of ethyl acetoacetate was heated at 145°-150° C. for 12 hours. Ethanol was removed with nitrogen flow during the course of the reaction. The mixture was cooled to room temperature, dissolved in dichloromethane, and washed with brine. The separated organic phase was dried over magnesium sulfate, concentrated in vacuo, and distilled at 211°-219° C. (0.125 mm Hg) to yield 17.3 g (54%) of a white solid; m.p. 67°-71° C. NMR: (CDCl3) δ 2.0 (2H,m), 2.2 (3H,s), 3.3 (2H,s), 3.7 (2H,t), 4.05 (2M,t), 7.62 (4H,d).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH:21]([F:23])[F:22]>CC(C)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:20][CH:21]([F:23])[F:22])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(O)ccc1Cl
Reactant: FC(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCC(F)F)ccc1Cl

Procedure:
To a suspension of methyl 2-chloro-5-hydroxybenzoate (50 mg) and potassium carbonate (111 mg) in acetone (1 mL) was added 2-iodo-1,1-difluoroethane (35 μL), and the suspension was reacted at 120° C. for 10 minutes in a microwave synthesizer (Biotage, Initiator). After reaction at 130° C. for additional 15 minutes, the reaction mixture was directly purified on silica gel column chromatography to obtain the titled compound (55 mg) as yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH:5]([C:9]1[O:10][C:11]2[C:16]([C:17](=[O:26])[C:18]=1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:15][CH:14]=[C:13]([Cl:27])[CH:12]=2)[CH:6]([CH3:8])[CH3:7].C(N(CC)CC)C.[C:35]1([CH3:44])[CH:40]=[CH:39][C:38]([C:41](Cl)=[O:42])=[CH:37][CH:36]=1>C(Cl)Cl.CCOCC>[CH2:19]([C:18]1[C:17](=[O:26])[C:16]2[C:11](=[CH:12][C:13]([Cl:27])=[CH:14][CH:15]=2)[O:10][C:9]=1[CH:5]([NH:4][CH2:3][CH2:2][NH:1][C:41](=[O:42])[C:38]1[CH:39]=[CH:40][C:35]([CH3:44])=[CH:36][CH:37]=1)[CH:6]([CH3:7])[CH3:8])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)C(NCCN)c1oc2cc(Cl)ccc2c(=O)c1Cc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCCNC(c2oc3cc(Cl)ccc3c(=O)c2Cc2ccccc2)C(C)C)cc1
Temperature: 0 °C
Yield: 50.6 %

Procedure:
To a cooled (0° C.) solution of 2-[1-(2-amino-ethylamino)-2-methyl-propyl]-3-benzyl-7-chloro-chromen-4-one (4.1 g, 11 mmol) and triethylamine (2.2 mL, 17 mmol) in methylene chloride (100 mL) was added a solution of p-toluoyl chloride (1.7 g, 11 mmol) in methylene chloride (20 mL). The reaction was maintained at 0° C. for 2 hours, at which time it was diluted with ether (250 mL). The resultant solution was washed with 1 N hydrogen chloride (2×200 mL), saturated sodium bicarbonate (200 mL) and brine (150 mL), dried over magnesium sulfate, and concentrated. The residue was purified by flash chromatography (0→60% ethyl acetate/hexanes) to give 2.8 g (50%) of the title compound. MS (ES+) m/e 503 [M+H]+.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([F:8])[C:5]([Cl:9])=[C:4](F)[N:3]=1.[CH3:11][CH:12]1[CH2:17][CH:16]([CH3:18])[CH2:15][NH:14][CH2:13]1>O1CCCC1>[Cl:9][C:5]1[C:6]([F:8])=[N:7][C:2]([F:1])=[N:3][C:4]=1[N:14]1[CH2:15][CH:16]([CH3:18])[CH2:17][CH:12]([CH3:11])[CH2:13]1
Reactant: CC1CNCC(C)C1
Reactant: Fc1nc(F)c(Cl)c(F)n1
Solvent: C1CCOC1
Product: CC1CC(C)CN(c2nc(F)nc(F)c2Cl)C1

Procedure:
Into 6 ml of tetrahydrofuran solution of 0.5 g of 2,4,6-trifluoro-5-chloropyrimidine was added dropwise 0.34 g or 3,5-dimethylpiperidine (cis/trans diastereomer=about 4/1) at room temperature, and the mixture was stirred for one-and-half hour at same temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.56 g of 5-chloro-2,4-difluoro-6-(3,5-dimethylpiperidino)pyrimidine. This compound had the cis/trans diastereomer originated two ethyls on the pyperidine ring. The ratio of the cis/trans diastereomer was about 5/1.
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[Cl:15][CH2:16][C:17]([NH:19][CH:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])=[O:18].O.Cl>O1CCCC1>[Cl:15][CH2:16][C:17]([NH:19][C@H:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:21]1[OH:30])=[O:18]
Reactant: O=C(CCl)NC1CCc2ccccc2C1=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCl)N[C@H]1CCc2ccccc2[C@H]1O
Yield: 70.8 %

Procedure:
Lithium tri-sec-butylborohydride (1.0 M solution in tetrahydrofuran, 70 ml, 70 mmol) was added to a solution of 2-chloro-N-(1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide (7.58 g, 31.9 mmol) in tetrahydrofuran (500 ml). When the reaction was complete (checked by thin layer chromatography), excess reagent was decomposed by the addition of water and pH was adjusted to 5-6 with 3N aqueous hydrochloric acid. The residue was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford 2-chloro-N-((1RS,2SR)-cis-1-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-acetamide (5.4 g, 22.6 mmol, 71%) as white crystals.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](Cl)=[O:21].[F:23][C:24]([F:33])([F:32])[C:25]1[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=1.CN1CCOCC1>ClCCl>[O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([NH:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([F:32])([F:23])[F:33])=[CH:30][N:29]=1)=[O:21]
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=C(Cl)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)Nc1ccc(C(F)(F)F)cn1
Reaction time: 18 h

Procedure:
To a solution of 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetyl chloride (Example 246A, 0.157 g, 0.5 mmol) dissolved in dichloromethane (5 mL) was added 5-(trifluoromethyl)pyridin-2-amine (0.081 g, 0.5 mmol) and N-methylmorpholine (0.085 mL, 0.75 mmol) under nitrogen. After stirring for 18 hours, the reaction mixture was concentrated, loaded onto silica gel column (Analogix®, Burlington, Wis.) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes (Flow=30 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.70 (s, 1H), 8.53 (s, 1H), 8.24 (d, J=8.7, 1H), 7.90 (dd, J=2.3, 8.8, 1H), 7.44-7.18 (m, 10H), 4.21 (s, 2H), 3.55 (t, J=6.5, 2H), 2.88 (t, J=6.5, 2H); MS (DCI) m/z 440.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[C:14]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[CH3:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([CH3:33])[C:31]=1[OH:32].[O-]CC.[Na+]>C(O)C.C(OCC)(=O)C>[OH:5][C:4]([C:7]([F:10])([F:8])[F:9])([CH2:3][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[C:14]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:13]=1)([CH3:1])[CH3:11])[CH2:6][N:28]1[CH:29]=[C:30]([CH3:33])[C:31](=[O:32])[C:26]([CH3:25])=[CH:27]1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cc(S(C)(=O)=O)cc2c1OCC2
Reactant: Cc1cncc(C)c1O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cn(CC(O)(CC(C)(C)c2cc(S(C)(=O)=O)cc3c2OCC3)C(F)(F)F)cc(C)c1=O
Temperature: 85 °C

Procedure:
To a suspension of 7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-5-methanesulfonyl-2,3-dihydrobenzofuran (51.0 mg) and 3,5-dimethylpyridin-4-ol (B. Boduszek et al., Synthesis, 1979, pp. 452-453) (34 mg) in anhydrous ethanol (0.40 mL) was added sodium ethoxide (21 wt. % solution in ethanol, 52.0 μL). After heating at 85° C. for 16 hours, the reaction mixture was diluted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo.
Reaction SMILES: C(N(CC)C(Cl)=O)C.[CH2:9]([N:11]([C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH2:12][CH3:13])[CH3:10].[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][C:28]1[C:37]2[C:32](=[CH:33][C:34]([O:40][CH3:41])=[C:35]([O:38][CH3:39])[CH:36]=2)[N:31]=[CH:30][CH:29]=1)[NH2:23].C1(C)C=CC=CC=1>C(O)C>[CH2:9]([N:11]([C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH2:12][CH3:13])[CH3:10].[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:17]([NH:16][C:14]([N:11]([CH2:12][CH3:13])[CH2:9][CH3:10])=[O:15])=[S:18])[CH:24]=[CH:25][C:26]=1[O:27][C:28]1[C:37]2[C:32](=[CH:33][C:34]([O:40][CH3:41])=[C:35]([O:38][CH3:39])[CH:36]=2)[N:31]=[CH:30][CH:29]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: CCN(CC)C(=O)Cl
Agent: CCN(CC)C(=O)N=C=S
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
(Diethylamino)methanoyl isothiocyanate was prepared using commercially available N,N-diethylcarbamic chloride (80 mg) as a starting compound according to the description of the literature. (Diethylamino)methanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (52 mg, yield 38%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1([F:14])[CH2:9][CH2:8][C:7](O)([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1.S([O:20][CH3:21])(OC)(=O)=O.[CH2:22]1COCC1>>[F:3][C:4]1([F:14])[CH2:9][CH2:8][C:7]([O:20][CH3:21])([C:10]([O:12][CH3:22])=[O:11])[CH2:6][CH2:5]1
Reactant: C1CCOC1
Reactant: O=C(O)C1(O)CCC(F)(F)CC1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1(OC)CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaH (60%, 2.2 equiv) was added to a cold (0° C.) stirred solution of 4,4-difluoro-1-hydroxycyclohexanecarboxylic acid (1 equiv) in THF (2 mL) and the mixture was allowed to warm rt (30 min). Then neat dimethyl sulfate (2.4 equiv) was added at 0° C. and the mixture was allowed to warm rt and stirred at rt overnight. Excess Me2SO4 was quenched with TEA and the reaction mixture was acidified with 1 N HCl, extracted with ether to afford methyl 4,4-difluoro-1-methoxycyclohexanecarboxylate which was saponified (1 N NaOH, THF-MeOH) to afford Cap-10 as a beige semi-solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 3.36 (s, 3H), 2.17-1.98 (m, 8H).
Reaction SMILES: [O:1]=[C:2]([N:24]1[CH2:29][CH2:28][N:27]2[C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][N:32]=[C:26]2[CH2:25]1)[CH2:3][C@H:4]([NH:15][C@@H](C1C=CC=CC=1)C)[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14].C(O)(=[O:39])C.[H][H].[P:43](=[O:47])([OH:46])([OH:45])[OH:44]>CO.[Pd]>[CH:11]1[C:6]([CH2:5][C@@H:4]([NH2:15])[CH2:3][C:2]([N:24]2[CH2:25][C:26]3=[N:32][N:31]=[C:30]([C:33]([F:36])([F:35])[F:34])[N:27]3[CH2:28][CH2:29]2)=[O:1])=[C:7]([F:14])[CH:8]=[C:9]([F:13])[C:10]=1[F:12].[OH2:39].[OH:45][P:43]([OH:47])([OH:46])=[O:44]
Reactant: [H][H]
Reactant: CC(=O)O
Reactant: C[C@@H](N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F)c1ccccc1
Agent: [Pd]
Agent: O=P(O)(O)O
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Product: O
Temperature: 5 °C
Yield: 81.5 %

Procedure:
(2R)-4-oxo-N-[(1R)-1-phenylethyl]-1-(2,4,5-trifluorophenyl)-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]butan-2-amine [F] (25 g, 0.049 mol) was subjected to hydrogenolysis in methanol (75 ml) containing acetic acid (3.0 ml, 0.052 mol) using 5% palladium on charcoal as catalyst at 52±2° C. at hydrogen pressure of 2.0±0.5 kg/cm2. After completion on reaction the catalyst was removed by filtration and reaction mass was concentrated under vacuum. Obtained residue was suspended in water and pH was set to 10.0±0.4 with solution of potassium carbonate. Product was extracted into dichloromethane. The extract was concentrated and degassed. The obtained syrupy mass was dissolved in ethanol, phosphoric acid (3.5 ml, 0.060 mol) was added and the solution refluxed for 30 min. Cooled to 5±3° C., filtered the solid and dried to obtain 20.9 g sitagliptin phosphate, chromatographic purity was 99.8%; chiral purity (determined by chiral HPLC) was 100%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11].[F:32][C:33]([F:42])([F:41])[C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[C:8]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH:38][C:37]1[CH:39]=[CH:40][C:34]([C:33]([F:41])([F:42])[F:32])=[CH:35][CH:36]=1)=[O:11]
Reactant: COc1c(C)c(Cc2cccc(C(=O)O)c2-c2ccncc2)c(OC)c(OC)c1OC
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C)c(Cc2cccc(C(=O)Nc3ccc(C(F)(F)F)cc3)c2-c2ccncc2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.8 %

Procedure:
To a solution of 3-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoic acid (18 mg, 0.0424 mmol) in methylene chloride (3 ml) were added 4-trifluoromethylaniline (10.2 mg, 0.0633 mmol), triethylamine (8.6 mg, 0.0851 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (21.5 mg, 0.1272 mmol) followed by stirring at room temperature for 16 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (17 mg, 0.0300 mmol, 71%).
Reaction SMILES: C([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9]C=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=O)C.[OH2:17].O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].C([O:33][C:34](=[O:36])[CH3:35])(=O)C>C(O)(=O)C.O>[C:34]([C:35]1[C:9](=[O:17])[C:8]2[C:13](=[CH:12][CH:11]=1)[C:14]1[C:6](=[CH:5][CH:4]=[CH:16][CH:15]=1)[CH:7]=2)([OH:33])=[O:36]
Reactant: CC(=O)c1ccc2c(c1)Cc1ccccc1-2
Reactant: O
Reactant: CC(=O)OC(C)=O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)C1=CC=C2C(=Cc3ccccc32)C1=O
Temperature: 120 °C
Reaction time: 16 h

Procedure:
2-Acetylfluorene (25.5 g, 0.12 mole) was dissolved in glacial acetic acid (325 mL). Sodium dichromate dihydrate (345 g, 1.16 mole) and acetic anhydride (138.4 mL, 1.46 mole) were added to the solution. The temperature of the reaction solution was increased to 120° C. (with reflux apparatus). The reaction was allowed to proceed for 16 hours. The reaction solution was cooled and diluted with distilled water (1.8 L). The solution was heated to approximately 80° C. and filtered. The precipitate was dissolved in 1M sodium hydroxide. The solution was washed with dichloromethane (3×160 mL). The aqueous solution was heated to approximately 80° C. and acidified with concentrated hydrochloric acid (pH approximately 2). The material was filtered and placed under vacuum to dry with phosphorus pentoxide present. The NMR spectrum was consistent with the loss of the acetyl methyl singlet and retention of other characteristic peaks.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C@@H:11]1[C:17](=[O:18])[N:16]2[C@H:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:21][CH2:22][N:15]2[C:14](=[O:30])[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([NH:10][C@@H:11]1[C:17](=[O:18])[N:16]2[C@H:19]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:20][CH2:21][CH2:22][N:15]2[C:14](=[O:30])[CH2:13][CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](N)C(=O)N12
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NC(=O)c3ccccc3)C(=O)N12
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A solution of benzoyl chloride (1.61 g, 11.47 mmol) in CH2Cl2 (15 ml) was added dropwise to a stirred ice cold mixture of (1S,9S) t-butyl 9-amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate (GB 2,128,984; 3.1 g, 10.43 mmol), dry CH2Cl2 (20 ml) and diisopropylethylamine (4.54 ml, 26.06 mmol). The mixture was kept cold for 1 h then left at room temperature for 0.5 h. The mixture was diluted with CH2Cl2, washed twice with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (0-5% methanol in CH2Cl2) to afford 211e (4.0 g, 96%) of a colourless glass: mp 74-76° C.; [α]D30 −75.0° (c 0.12, CH2Cl2). IR (KBr) 3350, 2979, 2938, 1736, 1677, 1662, 1536, 1422, 1276, 1250, 1155; 1H NMR (CDCl3) δ 8.72 (2H, m), 7.53-7.40 (3H, m), 7.07 (1H, d, J=7.2), 5.30 (1H, dd, J=3.0, 5.8), 5.12 (1H, m), 4.66 (1H, m), 3.51 (1H, m), 2.90 (2H, m), 2.38 (1H, dd, J 13.2, 6.8), 2.25 (1H, m), 1.9 (2H, m), 1.70 (1H, m).