Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C:9]([CH3:17])=[CH:8][C:7]1=[O:18].C([Li])CCC.[C:28](=[O:30])=[O:29].Cl>CCCCCC.O1CCCC1.O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C:9]([CH2:17][C:28]([OH:30])=[O:29])=[CH:8][C:7]1=[O:18]
Reactant: Cc1cc(=O)n(Cc2ccc(Cl)c(Cl)c2)c2cc(F)ccc12
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: O=C(O)Cc1cc(=O)n(Cc2ccc(Cl)c(Cl)c2)c2cc(F)ccc12
Reaction time: 1 h
Yield: 66 %

Procedure:
1-(3,4-Dichlorobenzyl)-1,2-dihydro-7-fluoro-4-methyl-2-oxoquinoline (7g.) was added portionwise to a solution of n-butyl-lithium (9.8 ml. of a 2.32 N-solution in hexane) and triethylamine (1.15 g.) in dry tetrahydrofuran (150 ml.) maintained at -40° C. The mixture was stirred at -30° C. to -40° C. for one hour under an atmosphere of dry argon, and then added to a saturated solution of dry carbon dioxide in dry tetrahydrofuran (200 ml.). The mixture was stirred at -30° C. for 2 hours and then allowed to reach ambient temperature overnight. Water (400 ml.) was added and the concentrated hydrochloric acid to bring the pH of the mixture to 3-4. The crude acid was filtered off and recrystallised from methanol to give 1-(3,4-dichlorobenzyl)-1,2-dihydro-7-fluoro-2-oxoquinol-4-ylacetic acid, m.p. 205°-207° C. (dec.), in 66% yield.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH:20]2[O:24][C:23](=[O:25])[NH:22][CH2:21]2)[CH:9]=1)([CH3:3])[CH3:2].[F:28][C:29]([F:43])([F:42])[C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:33]Br>>[F:28][C:29]([F:42])([F:43])[C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:37]=1)[CH2:33][N:22]1[CH2:21][CH:20]([C:11]2[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=2[C:8]2[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=2[O:26][CH3:27])[O:24][C:23]1=[O:25]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C1CNC(=O)O1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C1CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)O1

Procedure:
Following the procedure described in EXAMPLE 50, 44 mg of 5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-one, enantiomer B, and 43 mg of 3,5-bis(trifluoromethyl)benzyl bromide gave the title compound. Analytical HPLC on Chiralpak AS 4.6×250 mm, eluting with 5% isopropanol in heptane at 0.5 mL/min: tR=11.0 min
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])([CH3:10])[CH3:9])[CH:5]=[N:6][CH:7]=1.[Cl:17][C:18]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:19]=1[C:20]#[N:21].C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:17][C:18]1[CH:25]=[C:24]([C:2]2[CH:3]=[C:4]([C:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])([CH3:10])[CH3:9])[CH:5]=[N:6][CH:7]=2)[CH:23]=[CH:22][C:19]=1[C:20]#[N:21]
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Reactant: CCS(=O)(=O)NC(C)(C)c1cncc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NC(C)(C)c1cncc(-c2ccc(C#N)c(Cl)c2)c1
Yield: 2.8 %

Procedure:
A mixture of N-(2-(5-bromopyridin-3-yl)propan-2-yl)ethanesulfonamide (30 mg, 0.098 mmol), 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (27.0 mg, 0.103 mmol), PdCl2(dppf).CH2Cl2 adduct (1.994 mg, 2.441 μmol) and sodium carbonate (98 μl, 0.195 mmol) in DMF (10 mL) was heated to 100° C. overnight. After concentration, the residue was purified by column (MeOH—CH2Cl2, v/v, 10-20%) yielded the title compound as oil (1 mg). ESI-MS m/z: [M+1]+ 364.0, Retention time=1.40 min. 1H NMR (400 MHz, CDCl3): δ 1.31 (t, J=7.37 Hz, 3H), 1.76 (s, 6H), 2.86-2.91 (m, 2H), 4.54 (brs, 1H), 7.52 (dd, J=1.7, 8 Hz, 1H), 7.67 (d, J=1.6 Hz, 1H), 7.72 (d, J=8 Hz, 1H), 7.95 (t, J=2.2 Hz, 1H), 8.67 (d, J=2.2 Hz, 1H), 8.76 (d, J=2.2 Hz, 1H).
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9](O)[CH:10]=[CH2:11].C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:11]([C:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:10]=[CH2:9]
Reactant: C=CCO
Reactant: O=CC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C=CCC1(C=O)CCCCC1
Yield: 78 %

Procedure:
A mixture of cyclohexanecarboxaldehyde ((10 mL, 0.825 mol), allyl alcohol (60 mL, 98% purity, 0.882 mol), benzene (15 mL), and p-toluenesulfonic acid monohydrate (0.120 g, 0.63 mmol) was heated from 130° C. to 180° C. in an oil bath, under a Vigreaux distillation column, topped by a Dean-Stark trap. After 15 hour no more water was added over the 15 mL collected in the trap, and the reaction was judged completed. Subsequent distillation of the reaction crude gave 98 g (78% yield) of 1-allyl-cyclohexanecarboxaldehyde as a colourless liquid (b.p. 69-71° C./5 mm Hg).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)=[O:2].C1C=CC2N(O)N=NC=2C=1.[OH:22][CH2:23][C:24]([NH:26][CH2:27][CH:28]([OH:43])[CH2:29][O:30][C:31]1[C:36]([CH3:37])=[CH:35][C:34]([C:38](=[NH:41])[NH:39]O)=[CH:33][C:32]=1[CH3:42])=[O:25].CCN=C=NCCCN(C)C.Cl>C1COCC1.CN(C=O)C>[CH:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:41]=[C:38]([C:34]3[CH:33]=[C:32]([CH3:42])[C:31]([O:30][CH2:29][CH:28]([OH:43])[CH2:27][NH:26][C:24](=[O:25])[CH2:23][OH:22])=[C:36]([CH3:37])[CH:35]=3)[N:39]=2)[CH:9]=[CH:10][CH:11]=1)=[O:2]
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC(O)CNC(=O)CO
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(-c2noc(-c3cccc(C=O)c3)n2)cc(C)c1OCC(O)CNC(=O)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
A solution of 3-formyl-benzoic acid (170 mg, 1.13 mmol), HOBt (184 mg, 1.36 mmol) and rac-2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide (352 mg, 1.13 mmol) in THF (4 mL) and DMF (6 mL) was cooled to 0° C. before EDC hydrochloride (239 mg, 1.24 mmol) was added in portions. The mixture was stirred at rt for 1 h before it was diluted with THF (4 mL) and heated to 80° C. for 16 h. The mixture was concentrated and then separated by prep. HPLC (Waters XBridge Prep C18, 75×30 mm ID, 5 μm, 90% to 10% water (containing 0.5% of formic acid) in MeCN) to give the title compound as a white solid (130 mg). LC-MS*: tR=0.75 min; [M+1]+=425.90, 1H NMR (D6-DMSO): δ 2.35 (s, 6H), 3.20-3.29 (m, 1H), 3.40-3.49 (m, 1H), 3.71-3.82 (m, 2H), 3.84 (d, J=5.0 Hz, 2H), 3.92-4.00 (m, 1H), 5.30 (d, J=4.8 Hz, 1H), 5.55 (t, J=5.5 Hz, 1H), 7.70 (br t, J=4.8 Hz, 1H), 7.81 (s, 2H), 7.91 (t, J=7.8 Hz, 1H), 8.24 (d, J=7.5 Hz, 1H), 8.49 (d, J=7.8 Hz, 1H), 8.69 (s, 1H), 10.18 (s, 1H).
Reaction SMILES: [C:1]([N:11]([CH3:17])[C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:51][CH:52]([C:78]([CH3:81])([CH3:80])[CH3:79])[C:53]([N:55]1[CH2:59][CH2:58][CH:57]2[N:60]([CH:73]3[CH2:77][CH2:76][CH2:75][CH2:74]3)[CH2:61][CH:62]([C:63]3[C:71]4[C:66](=[CH:67][C:68]([F:72])=[CH:69][CH:70]=4)[NH:65][CH:64]=3)[CH:56]12)=[O:54]>CN1C(=O)CCC1.CCOC(C)=O>[CH2:4]([O:3][C:1](=[O:2])[N:11]([CH:12]([C:14](=[O:16])[NH:51][CH:52]([C:53]([N:55]1[CH2:59][CH2:58][CH:57]2[N:60]([CH:73]3[CH2:77][CH2:76][CH2:75][CH2:74]3)[CH2:61][CH:62]([C:63]3[C:71]4[C:66](=[CH:67][C:68]([F:72])=[CH:69][CH:70]=4)[NH:65][CH:64]=3)[CH:56]12)=[O:54])[C:78]([CH3:81])([CH3:80])[CH3:79])[CH3:13])[CH3:17])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Reactant: CC(C)(C)C(N)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C1CCCC1)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution containing Cbz-N(Me)Ala-OH (116 mg, 0.5 mmol) in anhydrous NMP (5 mL) was cooled to 0° C. HATU (191 mg, 0.5 mmol) and DIPEA (148 mg, 0.7 mmol) were added followed by the addition of crude 39 (218 mg, 0.5 mmol) in anhydrous NMP (5 mL). The reaction mixture was slowly warmed to ambient temperature. After 3 h, the reaction mixture was diluted with EtOAc and washed successively with aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 300 mg of crude 40 as an amber-colored oil which was used without further purification. Mass spectrum, m/z [646.4] (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[C:6]=2[CH:27]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39](=[O:42])[NH:40][CH:41]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:36]4[CH:37]=[CH:38][C:39](=[O:42])[NH:40][CH:41]=4)=[CH:27][C:6]=3[N:7]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=3)[CH2:8][C@@H:9]([CH3:16])[C:10]2=[N:14][N:13]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(S(C)(=O)=O)cc1)C[C@H]2C
Reactant: CC1(C)OB(c2ccc(=O)[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nnc2n1-c1ccc(-c3ccc(=O)[nH]c3)cc1N(c1ccc(S(C)(=O)=O)cc1)C[C@H]2C
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 44.6 %

Procedure:
To a solution of (R)-8-bromo-1,4-dimethyl-6-(4-(methylsulfonyl)phenyl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (150 mg, 0.34 mmol) in 1,4-dioxane and H2O (10:1, 5 mL) were added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (218.50 mg, 88.95 mmol), Cs2CO3 (218.5 mg, 0.67 mmol) and Tetrakis(triphenylphosphine)palladium(0) (24.5 mg, 0.03 mmol). The mixture was purged with N2 and stirred in the microwave at 130° C. for 20 min. The reaction solution was concentrated and purified by prep-TLC (elute: DCM:CH3OH=15:1) to give (R)-5-(1,4-dimethyl-6-(4-(methylsulfonyl)phenyl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)pyridin-2(1H)-one (70 mg, 45%).
Reaction SMILES: [ClH:1].[N:2]1([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:19][S:20]([O:23][C:24]1[CH:25]=[CH:26][C:27]2[CH:31]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([O:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:34][CH:33]=3)[S:29][C:28]=2[CH:43]=1)(=[O:22])=[O:21].[Cl-].[Al+3].[Cl-].[Cl-]>>[ClH:1].[CH3:19][S:20]([O:23][C:24]1[CH:25]=[CH:26][C:27]2[C:31]([C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][N:2]4[CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:18][CH:17]=3)=[C:30]([C:32]3[CH:33]=[CH:34][C:35]([O:38][S:39]([CH3:42])(=[O:40])=[O:41])=[CH:36][CH:37]=3)[S:29][C:28]=2[CH:43]=1)(=[O:21])=[O:22]
Reactant: CS(=O)(=O)Oc1ccc(-c2cc3ccc(OS(C)(=O)=O)cc3s2)cc1
Reactant: O=C(O)c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCCN3CCCC3)cc2)cc1
Reaction time: 0.25 h

Procedure:
The acid chloride of 20.4 g. of 4-(2-pyrrolidinoethoxy)benzoic acid, hydrochloride was prepared as described in Example 1, and was used to acylate 20 g. of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)benzo[b]thiophene as described in Example 1, except that the amount of aluminum chloride was 60 g., of which 30 g. was added initially, and the rest was added in 10 g. portions at 15 minute intervals. The reaction mixture was stirred for 16 hours, and was worked up as described in Example 1 to obtain an oil, which was crystallized from denatured ethanol to obtain 27.5 g. of purified product, m.p. 196°-199°. A 4 g. sample was purified further by chromatography to obtain an analytical sample, m.p. 207°-207.5°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14](F)[CH:13]=1.O>C1COCC1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[C:16]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:17]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: Nc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(Br)cc1Nc1ccnc(Cl)n1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloropyrimidin-4-amine (8.83 g, 68.18 mmol) in THF (250 mL) at 0° C. was added sodium hydride (60% dispersion in oil, 4.36 g, 181.82 mmol) portionwise. The reaction mixture was stirred at 0° C. to RT for 10 minutes before addition of 4-bromo-2-fluoro-1-nitrobenzene (10 g, 45.45 mmol). The reaction mixture was stirred at 65° C. for 1 hr, then after cooling to RT, water was added resulting in formation of a yellow precipitate. The solid was collected by suction filtration and was washed with water. The filtrate was extracted with DCM. The organics were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Isolute column, 1% MeOH in DCM) then combined with the solid collected by suction filtration to give the title compound: 1HNMR (250 MHz, DMSO) δ 6.91 (1H, d, J=5.79 Hz), 7.61 (1H, dd, J=8.76, 2.21 Hz), 7.91-8.05 (2H, m), 8.29 (1H, d, J=5.79 Hz), 10.40 (1H, s); LC-MS: m/z=+328.9, 330.8 (M+H)+.
Reaction SMILES: I[CH2:2][C:3](=[CH2:18])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[CH:16]=O.ClCC(=C)COC1C=CC(C(OC)=O)=CC=1C=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[O-].[Na+]>CO.C(#N)C>[CH2:2]=[C:3]1[CH:18]=[CH:16][C:7]2[CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4]1
Reactant: C=C(CI)COc1ccc(C(=O)OC)cc1C=O
Agent: C=C(CCl)COc1ccc(C(=O)OC)cc1C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: C=C1C=Cc2cc(C(=O)OC)ccc2OC1
Reaction time: 1 h
Yield: 54 %

Procedure:
333 mg (1 mmol) of a 60/40 mixture of methyl 4-{[2-(iodomethyl)-2-propenyl]oxy}-3-formylbenzoate and of methyl 4-{[2-(chloromethyl)-2-propenyl]oxy}-3-formylbenzoate and then 297 mg (1.133 mmol) of triphenylphosphine are successively introduced into the 50 ml single-necked flask. The combined mixture is subjected to a stream of nitrogen and then 20 ml of acetonitrile are introduced via a hollow tube. After complete dissolution, the solution is brought to reflux overnight. After cooling the solution, 0.23 ml (1 mmol) of a solution of sodium methoxide in methanol is added dropwise and the medium is stirred for a further one hour. After the usual treatments, 120 mg (54%) of methyl 3-methylene-2,3-dihydro-1-benzoxepin-7-carboxylate are obtained in the form of a white solid; 1H NMR (300 MHz, CDCl3): 7.95 (d, J=1.8 Hz, 1H), 7.82 (dd, J=1.8 Hz and 8.4 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.51 (d, J=12 Hz, 1H), 6.38 (d, J=12 Hz, 1H), 5.28 and 5.11 (2s, 2H), 4.61 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([CH:7]([O:12][CH:13]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:14]1[CH:34]=[CH:33][C:17]([C:18]([N:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6])#[N:2]>C(O)=O>[C:1]([CH2:3][NH:4][C:5](=[O:6])[CH:7]([O:12][CH:13]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:14]1[CH:34]=[CH:33][C:17]([C:18]([N:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)=[O:19])=[CH:16][CH:15]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])#[N:2]
Reactant: CC(C)CC(OC(c1ccccc1)c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)NCC#N
Solvent: O=CO
Product: CC(C)CC(OC(c1ccccc1)c1ccc(C(=O)N2CCNCC2)cc1)C(=O)NCC#N
Reaction time: 2 h

Procedure:
Tert-butyl 4-{4-[(1-{[(cyanomethyl)amino]carbonyl}-3-methylbutoxy)(phenyl)methyl]benzoyl}piperazine-1-carboxylate from step 6 (0.09 g, 0.16 mmol) was dissolved in formic acid (1 mL). The mixture was aged for 2 hours and evaporated under reduced pressure. The crude residue was neutralized using a saturated aqueous solution of NaHCO3. The mixture was extracted 3 times with dichloromethane and the organic layers were dried and evaporated. The crude product was chromatographed on silica gel using 1% NH4OH and 9% methanol in dichloromethane to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:8]1(S(C2C=CC(C)=CC=2)(=O)=O)[CH:12]([C:13]2[N:14]=[N:15][N:16]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)[C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)O[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:49].CO>C1(C)C(C)=CC=CC=1>[CH2:1]([C:8]1[NH:9][CH:10]=[N:49][C:12]=1[C:13]1[N:14]=[N:15][N:16]([CH2:24][C:25]2[CH:26]=[C:27]([C:35]([F:38])([F:36])[F:37])[CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=2)[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)C2(Cc3ccccc3)N=COC2c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)cc1
Reactant: N
Solvent: CO
Solvent: Cc1ccccc1C
Product: FC(F)(F)c1cc(Cn2nnc(-c3nc[nH]c3Cc3ccccc3)c2-c2ccccc2)cc(C(F)(F)F)c1
Temperature: 136 °C
Reaction time: 18 h

Procedure:
Combine 4-[4-benzyl-4-(toluene-4-sulfonyl)-4,5-dihydro-oxazol-5-yl]-1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole (0.084 mmol), 1.0 mL of xylene, and 7N solution of ammonia in methanol (48.0 μL, 0.337 mmol). Heat in a sealed pyrex tube to 136° C. After 18 hours, cool to RT, and concentrate the mixture to 1.0 mL and apply to a 2 mm chromatotron plate with CH2Cl2 and elute with a EtOAc/hexanes gradient to provide the title compound. Exact Mass 527.2: mass spectrum (IS): m/z=529.1 (M+1), 527.1 (M−1); 1H NMR (250 MHz, CDCl3) 7.84 (s, 1H), 7.67 (s, 1H), 7.65-7.05 (m, 13H), 5.60 (s, 2H), 4.28 (s, 2H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]2[CH:4]([CH2:5]2)[N:3]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Br[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[O:1]=[C:2]1[N:7]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH:6]2[CH:4]([CH2:5]2)[N:3]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: O=C1NC2CC2N1C(=O)OCc1ccccc1
Reactant: FC(F)(F)c1cc(Br)ccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1C(=O)N(c2ccnc(C(F)(F)F)c2)C2CC21
Yield: 74 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, benzyl 3-oxo-2,4-diazabicyclo[3.1.0]hexane-2-carboxylate (100 mg, 0.43 mmol) was heated with 4-bromo-2-(trifluoromethyl)pyridine (107 mg, 0.474 mmol), xantphos (22.36 mg, 0.038 mmol), Pd2(dba)3 (12 mg, 0.012 mmol), cesium carbonate (210 mg, 0.64 mmol) and 1,4-dioxane (6.0 mL) at 100° C. for 1 hour to yield the crude product. Purification by column chromatography on silica gel (35% ethyl acetate in hexane) afforded 120 mg of the product (74% yield).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[CH2:11][C:10]3=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:18]([O-])([OH:20])=[O:19]>>[N+:18]([CH:11]1[C:10](=[O:17])[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)[C:12]1=[O:16])([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: O=C1CC(=O)c2cc(-c3ccccc3)ccc21
Product: O=C1c2ccc(-c3ccccc3)cc2C(=O)C1[N+](=O)[O-]

Procedure:
Nitration of 5-phenyl indane-1,3-dione with fuming nitric acid as described in Example 16 (c) gave 2-nitro-5-phenyl indane-1,3-dione, m.p. (water, hydrochloric acid) 119°C. (Found: C, 65.54; H, 3.39; N, 4.93; C15H9NO4. 1/2 H2O requires: C, 65.21; H, 3.65; N, 5.07%).
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:8]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O)[C:4]([O:6][CH3:7])=[O:5].C([O-])=O.[NH4+].C(OCC)(=O)C>C(O)C.[Pd]>[NH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][N:8]([S:19]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)(=[O:21])=[O:20])[CH:3]([CH2:2][OH:1])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(CO)N(Cc1ccccc1[N+](=O)[O-])S(=O)(=O)c1ccc(OC)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
To a mixture under nitrogen of 1.5 g (3.53 mmol) of methyl 3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(2-nitrobenzyl)amino]propionate in 5 ml of dry ethanol was added 1.12 g (17.69 mmol) of ammonium formate followed by the addition of 0.50 g of 10% palladium on carbon. The mixture was stirred overnight at room temperature and heated at 80° C. for 2 hours. The mixture was filtered through diatomaceous earth and the filtrate concentrated to dryness under vacuum to give a semisolid. Trituration with ethyl acetate gave 0.65 g (47%) of white crystals, m.p. 138-140° C.; Anal. for C18H22N2O6S: Calc'd: C,54.8; H,5.6; N,7.1; Found: C,53.0; H,5.6; N,6.8.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.C(N(C(C)C)C(C)C)C.[CH3:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.CCOC(C)=O>[CH2:21]([N:20]([CH3:19])[C:6]1[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CNCc1ccccc1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccccc1)c1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To a suspension of 2,4-dichloro-5-fluoropyrimidine (0.30 g, 1.80 mmol) in dioxane (3.6 mL) were added N-ethyl-N-isopropylpropan-2-amine (0.23 g, 1.80 mmol) and N-methyl-1-phenylmethanamine (0.24 g, 1.98 mmol), and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc (15 mL) and the resulting solution was washed with H2O (2×5 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to a light yellow oil which was purified by normal phase chromatography (40 g SiO2; gradient, EtOAc/hexanes) to give a colorless oil which solidified upon cooling. The solid was dried under high vacuum at 23° C. for 16 h to give N-benzyl-2-chloro-5-fluoro-N-methylpyrimidin-4-amine (0.34 g, 76%) as a white solid: mp 47-49° C.; 1H NMR (300 MHz, CDCl3) δ 8.18 (d, J=6.4, 1H), 7.43-7.23 (m, 5H), 4.82 (s, 2H), 3.17 (d, J=3.3, 3H); EIMS m/z 251 (M)+.