Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(O)C>[C:4]([C:3]1[CH:12]=[CH:13][C:14]([O:16][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][C:2]=1[OH:1])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(=O)c2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.4 %

Procedure:
A mixture of 15.0 g (70.0 mmol) of 2,4-dihydroxybenzophenone, 10.7 g (70 mmol) of methyl bromoacetate, 19.3 g (0.14 mol) of potassium carbonate, and 125 ml of N,N-dimethylformamide is stirred at 25° C. for 18 hours. The reaction mixture is partitioned between diethyl ether and 0.5 N hydrochloric acid. Solids are removed by filtration, and the filtrate is dried over magnesium sulfate and concentrated. The concentrate is partially dissolved in diethyl ether, and solids are removed by filtration. The solid material is recrystallized from dichloromethane: 2-propanol to afford 13.7 g (69% yield) of the title compound, a pale yellow solid, mp 131°-4° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH2:10][OH:11])[C:7]([O:12][CH2:13][CH3:14])=[CH:6][C:5]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:3][CH2:2]1>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:9]=[C:8]([CH:10]=[O:11])[C:7]([O:12][CH2:13][CH3:14])=[CH:6][C:5]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:3][CH2:2]1
Reactant: CCOc1cc(-c2ccc(F)cc2F)c(C2CC2)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCOc1cc(-c2ccc(F)cc2F)c(C2CC2)cc1C=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Manganese dioxide (45.9 g) was added to a toluene (80 mL) solution of (2-cyclopropyl-5-ethoxy-2′,4′-difluorobiphenyl-4-yl)methanol (16.1 g), and the mixture was stirred at 60° C. for 1 hour in a nitrogen atmosphere. The reaction mixture was filtered, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (12.8 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20](O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CCCCCC.C(OCC)(=O)C>O1CCCC1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=Cc1ccc(O)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=O)cc2)CC1
Yield: 75.9 %

Procedure:
4-Hydroxybenzaldehyde (2.0 g, 16.4 mmol) was dissolved in tetrahydrofuran (20 ml) and treated with 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (4.1 g, 20.5 mmol) and by column chromatography on silica eluting with 4-1 hexane-ethyl acetate to afford the title compound as a colourless viscous oil (3.8 g)
Reaction SMILES: [NH2:1][C@@H](C(O)=O)CC1C=CC(O)=CC=1.N[C@@H](C(O)=O)CC1C=CC(OCC)=CC=1.N[C@H](C(O)=O)CC1C=CC=CC=1.N[C@H](C(O)=O)C(C)C.[NH2:49][C@H:50]([C:58]([OH:60])=O)[CH2:51][CH2:52][CH2:53][NH:54][C:55](=[NH:57])[NH2:56].N(C)[C@H](C(O)=O)CCCNC(=N)N.NCC(O)=O>>[NH2:49][C@H:50]([C:58]([NH2:1])=[O:60])[CH2:51][CH2:52][CH2:53][NH:54][C:55](=[NH:57])[NH2:56]
Reactant: N[C@H](Cc1ccc(O)cc1)C(=O)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: CC(C)[C@H](N)C(=O)O
Agent: CCOc1ccc(C[C@@H](N)C(=O)O)cc1
Agent: CN[C@@H](CCCNC(=N)N)C(=O)O
Product: N=C(N)NCCC[C@H](N)C(N)=O

Procedure:
A compound of claim 1 in which A is D-Tyr or D-Tyr(Et); B is Phe; C is Val; m, p and q are each 0 or 1; W is a D or L isomer of Pro, Arg or N-MeArg; X is a D or L isomer of Arg or Gly; Y is Gly; and Z is NHR or a D or L isomer of Arg-NH2, provided that X is not Gly when m is 0, and q is 0 if both m and p are 0.
Reaction SMILES: [NH:1]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:14]([N:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([O:20]CC1C=CC=CC=1)=[O:19])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])=[O:4].N(C(OC(C)(C)C)=O)CC(NCC(O)=O)=O>C(O)(=O)C>[NH:1]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:14]([N:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])=[O:4]
Reactant: CC(C)[C@H](NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Solvent: CC(=O)O
Product: CC(C)[C@H](NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
IV (6.2 g, 0.012 mole) in acetic acid was hydrogenated and worked up as for II to obtain V quantitatively, no sharp m.p. 743°-783° C. Rf3, 0.25; Rf4, 0.15. Anal. Calcd. for C19H32N4O7 : C, 51.10; H, 7.67; N, 12.54%. Found: C, 51.28: H, 7.50, N, 12.38%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([CH2:28][CH3:29])=[C:26]([NH:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[CH2:40][CH2:39][CH2:38][NH:37][C:36]=3[N:35]=2)[N:25]=[CH:24][N:23]=1)[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].C1(C)C=CC=CC=1>ClCCl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([CH2:28][CH3:29])=[C:26]([NH:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[CH2:40][CH2:39][CH2:38][NH:37][C:36]=3[N:35]=2)[N:25]=[CH:24][N:23]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1c(NCCCc2ccc3c(n2)NCCC3)ncnc1NCC(NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCc1c(NCCCc2ccc3c(n2)NCCC3)ncnc1NCC(NC(=O)OCc1ccccc1)C(=O)O

Procedure:
65 mg (0.11 mmole) of tert-butyl 2-benzyloxycarbonylamino-3-[5-ethyl-6-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)propylamino]-pyrimidin-4-ylamino]-propionate in 5 ml of dichloromethane with 0.5 ml of trifluoroacetic acid is stirred at ambient temperature for 16 hours. Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloromethane with a little methanol then poured into diisopropyl ether. The precipitate is filtered. 45 mg of expected product is obtained in the form of a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:13]3([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[NH:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[S:20](=[O:24])(=[O:23])([OH:22])[OH:21]>>[S:20]([OH:24])([OH:23])(=[O:22])=[O:21].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[NH:12][CH2:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(F)cc2)CCCNC12CCCCC2
Agent: O=S(=O)(O)O
Product: Fc1ccc(C2=CCCNC23CCCCC3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(4-Fluorophenyl)-5-hydroxy-1-azaspiro[5.5]undecane (1.27 g, prepared in a similar manner to that described in Example F) was dissolved in concentrated sulphuric acid (25 ml) and stirred at ambient temperature for 2 hours, then the solution was carefully poured onto ice (50 ml), and the sticky solid collected by filtration. The solid was triturated with ether (2×50 ml), collected by filtration, washed with ether and dried in vacuo at ambient temperature to give a solid which was triturated with hot ether (70 ml), collected by filtration washed with ether and dried in vacuo at 60° C. to give 5-(4-fluorophenyl)-1-azaspiro[5.5]undec-4-ene sulphate as a white solid. Yield 1.3 g, mp 195°-200° C.
Reaction SMILES: [NH2:1][C@H:2]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:3][NH:4][C:5](=[O:41])[CH2:6][NH:7][C:8]([CH:10]([CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:9].C(N(CC)CC)C.[C:54]1([S:60](Cl)(=[O:62])=[O:61])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.O>ClCCl>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([CH2:12][CH2:11][CH:10]([C:8]([NH:7][CH2:6][C:5]([NH:4][CH2:3][C@H:2]([NH:1][S:60]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)(=[O:62])=[O:61])[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:41])=[O:9])[CH2:26][CH2:27][CH:28]2[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:32][CH2:33]2)[CH2:14][CH2:15]1)=[O:20])([CH3:23])([CH3:24])[CH3:25]
Reactant: CCOC(=O)[C@@H](N)CNC(=O)CNC(=O)C(CCC1CCN(C(=O)OC(C)(C)C)CC1)CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CNC(=O)CNC(=O)C(CCC1CCN(C(=O)OC(C)(C)C)CC1)CCC1CCN(C(=O)OC(C)(C)C)CC1)NS(=O)(=O)c1ccccc1
Reaction time: 2 h
Yield: 73.5 %

Procedure:
tert-Butyl 4-{3-{[(2-{[(2S)-2-amino-3-ethoxy-3-oxopropyl]amino}-2-oxoethyl)amino]carbonyl}-5-[1-(tert-butoxycarbonyl)-4-piperidyl]pentyl}tetrahydro-1(2H)-pyridinecarboxylate (compound 37) (3.31 g, 4.8 mmol) is dissolved in 50 ml of dichloromethane containing triethylamine (1.04 g, 5 mmol) and benzenesulphonyl chloride (0.9 g, 5 mmol) is then added at about 5° C. After 2 hours at room temperature, water is added. The organic phase is washed with 1N HCl and then with water, dried over sodium sulphate and then evaporated to give the crude product, which is purified by flash chromatography (15/1 dichloromethane/methanol) to give 2.8 g of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C@H:11]3[CH2:13][C@H:8]([CH2:9][CH2:10]3)[C:7]=2[C:6]([OH:14])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>>[CH2:21]([O:14][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]2[C:7]=1[C@@H:8]1[CH2:13][C@H:11]2[CH2:10][CH2:9]1)[CH:22]=[CH2:23]
Reactant: C=CCBr
Reactant: COc1ccc(O)c2c1[C@@H]1CC[C@H]2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1ccc(OC)c2c1[C@H]1CC[C@@H]2C1
Yield: 89.1 %

Procedure:
Treatment of (1R*,4S*)-8-methoxy-1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-ol (14.61 g, 0.077 mol) with potassium carbonate (31.84 g, 0.23 mol) and allyl bromide (10.68 g, 0.088 mol) generally according to the procedure described for Intermediate 1 provided 15.8 g (89%) of (1R*,4S*)-5-(allyloxy)-8-methoxy-1,2,3,4-tetrahydro-1,4-methanonaphthalene as a colorless oil. Anal. calcd. for C15H18O2.0.3H2O: C, 76.44; H, 7.95. Found: C, 76.43; H, 7.79.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[C:21]([F:22])=[C:20]([CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24]O>>[F:15][C:16]1[C:21]([F:22])=[C:20]([CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(CO)c(F)c1F
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: Cc1ccc(COc2ccnn2-c2cc(C#N)ccn2)c(F)c1F

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2,3-difluoro-4-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.32 (3H, s), 5.28 (2H, s), 5.80 (1H, s), 6.98 (1H, d, J=6.8 Hz), 7.11 (1H, d, J=7.2 Hz), 7.40 (1H, d, J=5.2 Hz), 7.58 (1H, s), 8.01 (1H, s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H12F2N4O, 327; Found, 327.
Reaction SMILES: O.OO.N[C:5]([NH2:7])=[O:6].[OH-].[Na+].[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([N:21]2[CH2:46][CH2:45][C:24]3([CH2:27][N:26]([C@H:28]4[C:36]5[C:31](=[CH:32][C:33]([C:37]6[CH:44]=[CH:43][C:40](C#N)=[CH:39][N:38]=6)=[CH:34][CH:35]=5)[CH2:30][CH2:29]4)[CH2:25]3)[CH2:23][CH2:22]2)=[O:20])=[N:16][CH:17]=1>CCO>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([N:21]2[CH2:22][CH2:23][C:24]3([CH2:27][N:26]([C@H:28]4[C:36]5[C:31](=[CH:32][C:33]([C:37]6[CH:44]=[CH:43][C:40]([C:5]([NH2:7])=[O:6])=[CH:39][N:38]=6)=[CH:34][CH:35]=5)[CH2:30][CH2:29]4)[CH2:25]3)[CH2:45][CH2:46]2)=[O:20])=[N:16][CH:17]=1
Reactant: COc1ccc(CC(=O)N2CCC3(CC2)CN([C@@H]2CCc4cc(-c5ccc(C#N)cn5)ccc42)C3)nc1
Reactant: NC(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(CC(=O)N2CCC3(CC2)CN([C@@H]2CCc4cc(-c5ccc(C(N)=O)cn5)ccc42)C3)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 2.8 %

Procedure:
To a solution of water (30 mL) and urea hydrogen peroxide (165 mg, 1.70 mmol) was added sodium hydroxide (39.8 mg, 0.99 mmol) and the reaction was stirred at room temperature. Once a clear solution was obtained, the reaction was placed in an ice bath and fitted with an addition funnel. A solution of 6-((R)-1-{7-[2-(5-methoxy-pyridin-2-yl)-acetyl]-2,7-diaza-spiro[3.5]non-2-yl}-indan-5-yl)-nicotinonitrile (11-1c, 379 mg, 0.85 mmol) in 1 mL of EtOH was added dropwise via the funnel over a period of 30 minutes. The solution became cloudy and was stirred overnight while warming to room temperature. After 18 hours, the reaction was concentrated. The crude product was purified on a Biotage (Biotage Inc.) 10 g reverse phase column, eluting with 0-50% acetonitrile in water to give the title compound 12 mg (8%). MS (ES+) 512.0 (M+H)+. 1H NMR (CD3OD) δ 1.61-1.75 (m, 4H), 1.90 (td, 1H), 2.24 (ddd, 1H), 2.83-2.94 (m, 1H), 3.05-3.17 (m, 1H), 3.20-3.27 (m, 2H), 3.48-3.56 (m, 5H), 3.83 (s, 4H), 3.85 (s, 2H), 4.04 (dd, 1H), 7.21-7.29 (m, 1H), 7.30-7.38 (m, 1H), 7.46 (d, 1H), 7.81-7.88 (m, 1H), 7.89-7.95 (m, 2H), 8.13 (d, 1H), 8.27 (dd, 1H), 9.05 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH:7]([CH3:15])[C:8](=O)[CH:9]=[CH:10][N:11]([CH3:13])C)=[CH:4][CH:3]=1.NC1[N:23]=[C:22]([CH3:24])[NH:21][N:20]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([C:8]2[N:20]3[N:21]=[C:22]([CH3:24])[N:23]=[C:13]3[N:11]=[CH:10][CH:9]=2)[CH3:15])=[CH:16][CH:17]=1
Reactant: CC(Oc1ccc(Cl)cc1)C(=O)C=CN(C)C
Reactant: Cc1nc(N)n[nH]1
Solvent: CC(=O)O
Product: Cc1nc2nccc(C(C)Oc3ccc(Cl)cc3)n2n1
Temperature: 25 °C

Procedure:
A solution of 4-(4-chlorophenoxy)-1-(dimethylamino)-1-penten-3-one (1.58 g, prepared in a similar manner to that described in Example 2 above) in glacial acetic acid (5 ml) was added to a stirred solution of 3-amino-5-methyl-1,2,4-triazole (0.62 g) in glacial acetic acid (10 ml). The mixture was heated under reflux for 2 hours and 30 minutes and then cooled to room temperature. The mixture was then poured into ice-water (50 ml) and extracted with toluene. The toluene extracts were washed with a 10% aqueous solution of sodium hydrogen carbonate followed by water, then dried over anhydrous magnesium sulphate and the solvent was evaporated under reduced pressure. The residue was triturated with cold diethyl ether and the solid was collected by filtration, followed by recrystallisation from a mixture of ethyl acetate and petroleum ether (b.p. 40°-60° C.), to give 7-[1-(4-chlorophenoxy)ethyl]-2-methyl-1,2,4-triazolo [1,5-a]pyrimidine. Yield 1.13 g, (mp 138° C.).
Reaction SMILES: [C:1]([C:4]1[S:5][C:6](Br)=[CH:7][CH:8]=1)(=O)[CH3:2].[Br:10][C:11]1[S:15][C:14]([C:16]([CH2:18][C:19]#[N:20])=[O:17])=[CH:13][CH:12]=1.C1(=O)CCCCC1.N1CCOCC1.[S]>>[NH2:20][C:19]1[S:5][C:6]2[CH2:2][CH2:1][CH2:4][CH2:8][C:7]=2[C:18]=1[C:16]([C:14]1[S:15][C:11]([Br:10])=[CH:12][CH:13]=1)=[O:17]
Reactant: CC(=O)c1ccc(Br)s1
Reactant: N#CCC(=O)c1ccc(Br)s1
Agent: [S]
Solvent: O=C1CCCCC1
Solvent: C1COCCN1
Product: Nc1sc2c(c1C(=O)c1ccc(Br)s1)CCCC2
Yield: 66 %

Procedure:
The procedure of Example 1 was followed except that 2-acetyl-5-bromothiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(5-bromothiophene-2-carbonyl)acetonitrile (Steps A and B). Cyclohexanone (Aldrich), 2-(5-bromothiophene-2-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 66%; IR (KBr) cm−1: 3379, 3247, 2918, 1577, 1548, 1432, 1416, 1273, 761; 1H NMR (CDCl3):δ1.63 (m, 2H), 1.79 (m, 2H), 2.24 (t, 2H, J=5.8 Hz), 2.55 (t, 2H, J=5.8 Hz), 6.11 (bs, 2H), 7.02 (d, 1H, J=4 Hz), 7.13 (d, 1H, J=4 Hz); orange solid, mp: 160-163° C. (petroleum ether).
Reaction SMILES: [C:1]([O-:4])(O)=[O:2].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1.O=[C:18]1[CH:25]2[CH2:26][C:21]3([NH:28][C:29](=[O:31])[CH3:30])[CH2:22][CH:23]([CH2:27][CH:19]1[CH2:20]3)C2.S(=O)(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:2]=[C:1]1[CH:23]2[CH2:22][C:21]3([NH:28][C:29](=[O:31])[CH3:30])[CH2:20][CH:19]([CH2:18][CH:25]([CH2:26]3)[O:4]1)[CH2:27]2
Reactant: O=C([O-])O
Reactant: CC(=O)NC12CC3CC(C1)C(=O)C(C3)C2
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NC12CC3CC(C1)OC(=O)C(C3)C2
Temperature: 25 °C
Yield: 90 %

Procedure:
Solid NaHCO3 (1.2 mol) and mCPBA (1 2 mmol, 77% purity) were added to a solution of ketone 1A (0.6 mmol) in DCM (5 mL) at 0° C. The reaction mixture was allowed to warm to rt and was maintained for 1 h. The reaction mixture was diluted with a saturated, aqueous solution of sodium bisulfate (10 mL) and was extracted with DCM (3×10 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (10/90 to 30/70 EtOAc/hexane) to provide lactone 16A in 90% yield. Data: LC/MS (ESR) m/z 224 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2=[C:14](OS(C(F)(F)F)(=O)=O)[N:15]([CH:17]([CH3:19])[CH3:18])[N:16]=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2=[C:14]([C:30]3[CH:31]=[CH:32][S:28][CH:29]=3)[N:15]([CH:17]([CH3:18])[CH3:19])[N:16]=[C:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1ccsc1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(Cc1ccccc1)C2
Product: CC(C)n1nc2c(c1-c1ccsc1)CCN(Cc1ccccc1)C2
Yield: 27.5 %

Procedure:
The title compound (69 mg) was prepared according to Example 287 using 300 mg of trifluoro-methanesulfonic acid 6-benzyl-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-yl ester and 133 mg of 3-thiopheneboronic acid. MS (ESI): exact mass calculated for C20H23N3S, 337.16; found, m/z 338.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.66-7.65 (m, 1H), 7.60-7.57(m, 3H), 7.55-7.53 (m, 3H), 7.21-7.20 (m, 1H), 4.65-4.52 (m, 3H), 4.42-4.33 (m, 2H), 3.82-3.79 (m, 1H), 3.44-3.40 (m, 1H), 2.94-2.91 (m, 2H), 1.46-1.35 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][CH2:14][CH:10]3[CH2:9][N+:8]([O-:16])=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1.[OH-].[NH4+].C[N+]([O-])(C)C>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][CH:14]=[C:10]3[CH2:9][N+:8]([O-:16])=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1
Reactant: CC1=NCC2C[N+]([O-])=C(c3ccccc3F)c3cc(Cl)ccc3N12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+](C)(C)[O-]
Solvent: ClCCl
Product: Cc1ncc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=[N+]([O-])C2

Procedure:
8-Chloro-6-(2-fluorophenyl)-3a,4-dihydro-1-methyl-3H-imidazo[1,5-a][1,4]benzodiazepine-5-oxide (IX, EXAMPLE 7, 20.00 g, 46 mmol) is partitioned between ammonium hydroxide (10%, 100 ml) and methylene chloride (100 ml). The layers are separated and the aqueous phase is extracted with additional methylene chloride (2×50 ml). The combined organic extracts are concentrated to dryness and the solids are redissolved in acetonitrile (200 ml). To this mixture is added powdered molecular sieves (20 g) and trimethylamine-N-oxide (7.6 g, 68 mmol) followed by one activated TPAP sample from above. The reaction mixture is heated to reflux and the next sample of TPAP and an additional trimethylamine-N-oxide (7.66 g, 68 mmol) is added after 6 hr and again after 18 hr. The mixture is heated at reflux for 42 hr at which time HPLC shows only 6% starting material remaining. The reaction mixture is concentrated to dryness and ethyl acetate (100 ml) is added back. The slurry is chromatographed (magnesol, 100 g) until no more product is eluding with ethyl acetate. The combined column fractions are concentrated to about 60 ml and heptane (140 ml) is added slowly. The product is cooled to -15° overnight, collected by vacuum filtration, washed with cold heptane and dried in the vacuum oven at 40° to give the title compound.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.Cl[CH2:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][C:16]2[N:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[N:21]=[CH:22][C:15]1=2)=[O:13].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C>[F:29][C:26]1[CH:27]=[CH:28][C:23]([N:20]2[C:16]3[CH2:17][CH2:18][CH2:19][N:14]([C:12](=[O:13])[CH2:11][N:5]4[CH:4]=[C:3]([C:2]([F:9])([F:8])[F:1])[CH:7]=[N:6]4)[C:15]=3[CH:22]=[N:21]2)=[CH:24][CH:25]=1
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: O=C(CCl)N1CCCc2c1cnn2-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cn1cc(C(F)(F)F)cn1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 65 °C
Yield: 113.7 %

Procedure:
A mixture of 4-(trifluoromethyl)-1H-pyrazole (0.030 g, 0.22 mmol), 2-chloro-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridine-4-yl]ethanone (0.025 g, 0.085 mmol) and K2CO3 (0.060 g, 0.43 mmol) in THF (0.8 mL) and DMF (0.4 mL) was heated at 65° C. for 1 hr. It was then cooled to rt. The mixture was partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by reverse phase HPLC to afford the desired product (0.038 g, 100%). 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.89 (s, 1H), 7.77 (s, 1H), 7.44 (dd, J=8.8, 4.6 Hz, 2H), 7.16 (dd, J=8.8, 8.4 Hz, 2H), 5.20 (s, 2H), 3.83 (m, 2H), 2.85 (t, J=6.2 Hz, 2H), 2.10 (m, 2H); MS: (ES) m/z calculated for C18H15F4N5O [M+H]+ 394.1, found 394.1.
Reaction SMILES: [CH3:1][S:2]([NH:5][NH2:6])(=[O:4])=[O:3].CCN(C(C)C)C(C)C.C[O:17][C:18](=O)[C:19]1[CH:24]=[C:23]([C:25]2[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=2)[C:22]([C:31]([F:34])([F:33])[F:32])=[CH:21][C:20]=1[NH:35][C:36](OC1C=CC(Cl)=CC=1)=[O:37]>O1CCOCC1>[CH3:30][N:28]1[CH:29]=[C:25]([C:23]2[CH:24]=[C:19]3[C:20](=[CH:21][C:22]=2[C:31]([F:32])([F:33])[F:34])[NH:35][C:36](=[O:37])[N:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:18]3=[O:17])[CH:26]=[N:27]1
Reactant: COC(=O)c1cc(-c2cnn(C)c2)c(C(F)(F)F)cc1NC(=O)Oc1ccc(Cl)cc1
Reactant: CS(=O)(=O)NN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cn1cc(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)cn1
Temperature: 90 °C
Reaction time: 19 h
Yield: 42 %

Procedure:
CH3SO2NHNH2 (130 mg, 2.4 equiv) and i-Pr2NEt (169 μL, 2 equiv) were added to a solution of 2-(4-chloro-phenoxycarbonylamino)-5-(1-methyl-1H-pyrazol-4-yl)-4-trifluoromethyl-benzoic acid methyl ester (224 mg, 0.49 mmol) in dioxane (11 mL). The mixture was stirred for 19 h (TLC control) at 90° C. The mixture was evaporated to dryness. The crude product was triturated with hexanes and DCM. The formed precipitate was filtered and washed with hexanes to give N-[6-(1-methyl-1H-pyrazol-4-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (83 mg, 42%) as a white solid. ESI-MS: m/z 404 [M+H]+, 1H-NMR (DMSO-d6, 400 MHz) 7.91 (s, 2H), 7.57 (s, 1H), 7.54 (s, 1H), 3.88 (s, 3H), 3.14 (s, 3H).