Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][N:4]=1)#[N:2].[Cl:18][C:19]1[CH:20]=[C:21]([OH:40])[CH:22]=[CH:23][C:24]=1[CH:25]([CH3:39])[C:26]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([Cl:38])[CH:33]=1)([OH:31])[C:27]([F:30])([F:29])[F:28]>CN(C1C=CN=CC=1)C.C(#N)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:24]=1[CH:25]([CH3:39])[C:26]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([Cl:38])[CH:33]=1)([OH:31])[C:27]([F:30])([F:29])[F:28])[O:40][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(c1ccc(Oc2ccc(C#N)nc2)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Copper(II)acetate (55 mg), 2-cyanopyridine-5-boronic acid pinacol ester (CAS Reg. No. 741709-63-7, 69 mg), and DMAP (61 mg) were added to a solution of 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (Example 19 step 5, 37 mg) in acetonitrile (3 ml). The mixture was stirred with molecular sieves under air atmosphere for 4 h at 80° C., and then filtered over Celite concentrated to an oil. The residue was purified by prep. HPLC (C18-column, solvent gradient 20-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (24 mg) as a white solid. MS (m/e)=468.1 [M+H+].
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=O)=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:18].[NH2:19][OH:20]>C(O)C>[ClH:18].[C:1]1([C:7]2[C:15]([CH:16]=[N:19][OH:20])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1c(-c2ccccc2)nn2ccccc12
Reactant: NO
Agent: Cl
Solvent: CCO
Product: ON=Cc1c(-c2ccccc2)nn2ccccc12
Yield: 45.5 %

Procedure:
A mixture of 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (0.5 g) and hydroxylamine hydrochloride (0 17 g) in ethanol (5 ml) was refluxed for 1.5 hours and evaporated in vacuo. The residue was triturated with ethyl acetate and recrystallized from a mixture of ethanol and ethyl acetate to give 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde oxime hydrochloride (0.28 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].[C:16](=O)([O-])[O-].[Cs+].[Cs+].IC>CC(C)=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[N:15]([CH3:16])[CH:14]=[CH:13][N:12]=1)[CH3:10]
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc([C@H](C)c2ncc[nH]2)c1C
Agent: [Cs+]
Solvent: CI
Solvent: CC(C)=O
Product: Cc1cccc([C@H](C)c2nccn2C)c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of the compound of Example 58 (100 mg, 0.5 mmol) and caesium carbonate (407 mg, 1.25 mmol) in acetone (4 ml) was added iodomethane (78 μl, 1.25 mmol). The reaction mixture was stirred at room temperature, under nitrogen, for 4 h and then concentrated in vacuo. to the residue was added water (10 ml) and the solution was extracted with ethyl acetate (2×10 ml). The combined extracts were dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=N)N.[CH:13]1(C(Cl)=O)[CH2:18][CH2:17]C[CH2:15][CH2:14]1>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[C:17]2[C:7](=[CH:15][CH:14]=[CH:13][CH:18]=2)[NH:6][CH:5]=1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: O=C(Cl)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
A stock solution of 9.1 mg/mL α-interferon in 20 mM sodium phosphate buffer at pH 7.2 was prepared. A stock solution of perturbant was prepared by dissolving 800 mg of perturbant (L-arginine acylated with cyclohexanoyl chloride) in 2 mL of 20 mM Sodium Phosphate buffer (pH 7).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=O)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl.[CH2:23]([O:26][NH2:27])[CH:24]=[CH2:25]>C(O)C>[CH2:23]([O:26][N:27]=[CH:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)[CH:24]=[CH2:25]
Reactant: O=Cc1cn(Cc2ccccc2)c2ccccc12
Reactant: C=CCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCON=Cc1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Yield: 13.1 %

Procedure:
To a solution of 1-benzyl-1H-indole-3-carbaldehyde (1.086 g, 4.61 mmol) in 4:1 ethanol:2.5 M NaOH solution (16 mL) was added O-allyl hydroxylamine hydrochloride hydrate(0.768 g, 7.17 mmol). The reaction mixture was heated to reflux for 30 minutes and allowed to cool back down to room temperature. The reaction mixture was concentrated to a small volume and the pH of the mixture was then adjusted to 7 using 2 M hydrochloric acid. The mixture was extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude oil was purified by flash chromatography through silica gel using ethyl acetate/hexanes (10/90) to give 1-benzyl-1H-indole-3-carbaldehyde O-allyl-oxime (0.176 g, 88%) as a colorless oil. 1H NMR (400 MHz, CDCl3); δ 8.30(s, 1H), 8.15 (m, 1H), 7.24 (m, 7H), 7.10 (d, 2H), 6.10 (m, 1H), 5.30 (m, 4H), 4.68 (d, 2H).
Reaction SMILES: [N:1]1([NH2:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1Cl>C(O)(C)C>[ClH:12].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[NH:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nn1ccc2ccccc21
Reactant: Clc1ccncc1Cl
Agent: Cl
Solvent: CC(C)O
Product: Clc1cnccc1Nn1ccc2ccccc21

Procedure:
The title compound was prepared from 1H-indol-1-amine and 3,4-dichloropyridine hydrochloride in isopropanol at 100° C. for 4 hours in substantially the same manner as in Example 1, m.p. >230°.
Reaction SMILES: C(=O)([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)OC.Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24].CC1C(CN2CCC(N3CCC(N4C(=O)NC5C4=CC=CC=5)CC3)CC2)=CC=CC=1.C(=O)([O-])[O-]>>[C:5]1([O:4][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[N+:23]([O-:25])=[O:24])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: COC(=O)Oc1ccccc1
Agent: Cc1ccccc1CN1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Agent: O=C([O-])[O-]
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1ccccc1
Temperature: 150 °C
Yield: 99 %

Procedure:
A mixture of 3.8 g of methyl phenyl carbonate, 5.64 g of 4-chloro-3-nitrobenzotrifluoride, and 0.17 g of TBPB was heated at 150° C. for 1 hour. All of the carbonate was converted with a 99 percent yield of 2-nitro-4-trifluoromethylphenyl phenyl ether. Distillation of the product yielded 6.65 g (94 percent) of the ether, b.p. 148°-9° C./2 mm.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1.[CH:20](B1OC(C)(C)C(C)(C)O1)=[CH2:21].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:20]([C:2]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1)=[CH2:21]
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C=Cc1csc2c1OC(C)CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Yield: 68 %

Procedure:
A mixed solution of tert-butyl 8-bromo-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (418 mg) obtained in Example 6, steps 1-6, vinylboronic acid pinacol ester (0.221 mL), dichlorobis(triphenylphosphine)palladium (42 mg) and potassium carbonate (498 mg) in DME-water (1:1, 10 ml,) was stirred at 85° C. for 1.5 hr under a nitrogen stream. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→10% ethyl acetate/hexane) to give the title compound (239 mg, 68%) as a colorless oil.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.Cl.[NH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].C(N(C(C)C)CC)(C)C>>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:9])(=[O:3])[CH3:2]
Reactant: COC(=O)CCCCCCN
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCCCCNC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
2-Acetylthiomethyl-3-phenylpropanoic acid is reacted with oxalyl chloride and the resulting acid chloride is then reacted with 7-aminoheptanoic acid, methyl ester, hydrochloride in the presence of diisopropylethylamine as more fully described in Example 8 of European Patent Application 136,883 to give (±)-7-[[2-[(acetylthio)methyl]-1-oxo-3-phenylpropyl]amino]heptanoic acid, methyl ester.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:13]=[C:14]([C:19]3[O:20]C(C4C=CC=CC=4)=N[N:23]=3)[C:15]([NH2:18])=[N:16][CH:17]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.NC1C(C(O)=O)=NC(N2CCN(S(CC)(=O)=O)CC2)=CN=1.O[N:64]=[C:65](N)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>CN(C=O)C.O>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:13]=[C:14]([C:19]3[O:20][N:64]=[C:65]([C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)[N:23]=3)[C:15]([NH2:18])=[N:16][CH:17]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: NC(=NO)c1ccccc1
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3nnc(-c4ccccc4)o3)n2)CC1
Agent: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)O)n2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3nc(-c4ccccc4)no3)n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
5-(4-(ethylsulfonyl)piperazin-1-yl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (Compound I-19) CDI (102.8 mg, 0.6342 mmol) was added to a solution of 3-amino-6-(4-ethylsulfonylpiperazin-1-yl)pyrazine-2-carboxylic acid (100 mg, 0.3171 mmol) and N′-hydroxybenzamidine (86.35 mg, 0.6342 mmol) in DMF (3.000 mL) and the resulting solution stirred at RT for 3 hours and then heated at 100° C. overnight. The mixture was allowed to cool, poured in water and extracted with EtOAc. The organic extract was washed with water (2×), brine, dried over Na2SO4, filtered and concentrated in vacuo. The resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as a bright yellow solid (53.6 mg, 30% Yield). 1H NMR (400.0 MHz, DMSO) d 1.24 (3H, t), 3.11 (2H, q), 3.33 (4H, m), 3.55 (4H, m), 7.18 (2H, br s), 7.59-7.66 (3H, m), 8.19 (2H, m), 8.42 (1H, s) ppm; MS (ES+) 416
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:5]=2[CH2:4][CH2:3]1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])[C:19]([Cl:33])=[CH:18][N:17]=1.C(O)(C)C.Cl.O1CCOCC1>>[Cl:33][C:19]1[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[N:21][C:16]([NH:13][C:10]2[CH:11]=[CH:12][C:5]3[CH2:4][CH2:3][C:2]([F:14])([F:1])[CH2:8][CH2:7][C:6]=3[CH:9]=2)=[N:17][CH:18]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCC(F)(F)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(F)(F)CC3)ncc1Cl
Reaction time: 0.17 h
Yield: 27.7 %

Procedure:
Into a microwave vial was placed 7,7-difluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (79 mg, 0.00040 mol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (100 mg, 0.0003 mol) in isopropyl alcohol (4 mL, 0.05 mol). 4N HCl-dioxane (0.04 g, 0.0003 mol) was added to the reaction mixture and the contents subjected to microwaves at 120° C. for 10 min. The reaction mixture was resubjected to the same microwave conditions for an additional 10 min. A solid had precipitated out of the reaction mixture, was collected by filtration then redissolved in methylene chloride (6 mL) and washed with sat. aqueous sodium bicarbonate (1×5 mL) and water (2×5 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give 2-[5-Chloro-2-(7,7-difluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a brown solid (38 mg, 29%). MP: 160-168° C.; 1HNMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 9.46 (s, 1H), 8.80 (d, 1H, J=4.5 Hz), 8.74 (d, 1H, J=7.6), 8.26 (s, 1H), 7.79 (d, 1H, J=7.8 Hz), 7.61 (s, 1H), 7.53 (t, 1H, J=7.6), 7.45 (d, 1H, J=7.8), 7.2 (t, 1H, J=7.3), 2.85 (d, 3H, J=4 Hz), 2.69-2.77 (m, 4H), 2.06 (m, 4H); MS (m/e) 458 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:22])([CH3:21])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[O:12].Br[CH2:29][CH2:30][CH2:31][C:32]([CH3:38])([CH3:37])[C:33]([O:35][CH3:36])=[O:34]>CN(C)C=O>[CH3:3][C:4]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:22])([CH3:21])[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:29][CH2:30][CH2:31][C:32]([CH3:38])([CH3:37])[C:33]([O:35][CH3:36])=[O:34])=[CH:18][CH:19]=1)=[O:12]
Reactant: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Nc2ccc(O)cc2)c1
Reactant: COC(=O)C(C)(C)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)CCCOc1ccc(NC(=O)C(C)(C)CCCOc2cc(C)ccc2C)cc1
Reaction time: 8 h
Yield: 48 %

Procedure:
Sodium hydride, 50% dispersion in mineral oil, 2.2 g, is added to 15.3 g of 5-(2,5-dimethylphenoxy)-N-(4-hydroxyphenyl)-2,2-dimethylpentanamide in 200 ml of N,N-dimethylformamide (DMF). Then 10 g of methyl 5-bromo-2,2-dimethylpentanoate (Journal of Medicinal Chemistry, Vol. 26, pp 1020-1027 (1983)) is added to the previous mixture. The mixture is stirred overnight and then stirred three hours on a steam bath, the DMF is removed on a rotary evaporator and water is added to the residue. The product is taken up in diethyl ether, extracted with base, washed with water and concentrated on a steam bath. Isopropyl ether is added to afford 10.4 g of 5-[4-[[5-(2,5-dimethylphenoxy)-2,2-dimethyl-1-oxopentyl]amino]-phenoxy]-2,2-dimethylpentanoic acid, methyl ester after recrystallization from isopropyl ether (2X); mp 62°-63° C.
Reaction SMILES: C(O[C:4](=O)[C:5]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[N:16]([CH3:17])[C:12]=2[C:11]=1[C:29]#[N:30])(C)[C:6](=O)[CH3:7])C.O.S(=O)(=O)(O)[OH:34].[OH-].[NH4+]>C(O)(=O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:15]2[N:16]([CH3:17])[C:12]3[C:11]4[C:29](=[O:34])[NH:30][C:6]([CH3:7])=[C:5]([CH3:4])[C:10]=4[CH:28]=[CH:27][C:13]=3[N:14]=2)=[C:20]([CH3:26])[CH:21]=1
Reactant: CCOC(=O)C(C)(C(C)=O)c1ccc2nc(Nc3ccc(F)cc3C)n(C)c2c1C#N
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C)[nH]c(=O)c3c2n1C
Temperature: 100 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
To a 500 mL round-bottom flask equipped with a magnetic stir-bar was added 2-[4-cyano-2-(4-fluoro-2-methyl-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyric acid ethyl ester (8.25 g, 1.95 mmole), followed by a freshly prepared mixture of water (25 mL), acetic acid (25 mL), and concentrated sulfuric acid (25 mL) at 60° C. The flask was fitted with a reflux condenser and heated to a bath temperature of 100° C. under a nitrogen atmosphere. After 5 hours, the reaction was allowed to cool to room temperature, and stirred for an additional 14 hours. The mixture was then poured onto ice and brought to a slightly basic pH by careful addition of concentrated ammonium hydroxide, while maintaining a temperature of less than 15° C. The resulting precipitate was isolated by filtration, and washed with several volumes of water. The solid was then slurried in methanol for 1 hour, and filtered. The isolated solid was washed with cold methanol until the filtrate was colorless, to provide 2-(4-fluoro-2-methyl-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (6.11 g, 89%) as a light gray solid. 1H NMR (400 MHz, DMSO-d6+TFA) δ 11.43 (br s, 1H), 10.49 (br s, 1H), 7.70-7.65 (m, 2H), 7.57 (dd, 1H, J1=5.5 Hz, J2=8.6 Hz), 7.37 (dd, 1H, J1=3.1 Hz, J2=9.8 Hz), 7.27 (td, 1H, J1=3.1 Hz, J2=11.7 Hz), 4.23 (s, 3H), 2.32 (app s, 6H), 2.23 (s, 3H); ESMS (m/z): 351 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[S:11][CH2:12][C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[F:20].[CH2:21]([Li])CCC.C(OC)=O.Cl>O1CCCC1>[Cl:8][C:7]1[C:6]([O:9][CH3:10])=[CH:5][C:4]2[CH:21]=[C:12]([C:13]3[C:14]([F:20])=[CH:15][CH:16]=[CH:17][C:18]=3[F:19])[S:11][C:3]=2[C:2]=1[Cl:1]
Reactant: [Li]CCCC
Reactant: COc1ccc(SCc2c(F)cccc2F)c(Cl)c1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: COC=O
Product: COc1cc2cc(-c3c(F)cccc3F)sc2c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 15 g of (2,3-dichloro-4-methoxyphenyl)(2',6'-difluorobenzyl)sulfide in 140 ml of dry tetrahydrofuran at -75° is added dropwise 25 ml of 2.2 M n-butyllithium over a period of 20 mins, maintaining the temperature below -65°. After stirring at this temperature for 1 hr, 10 ml of dried methyl formate is added dropwise, maintaining the temperature below -60°. The reaction mixture is poured onto 100 ml of 10 N hydrochloric acid. The mixture is extracted with ethyl ether. The ether extract is dried over anhydrous magnesium sulfate, filtered and the solvent is removed to give an oil. The oil is heated to 120° and 240 g of warm polyphosphoric acid is added. The reaction mixture is warmed at 130° for 20 mins. The mixture is allowed to cool and to the mixture is added 400 ml of ice water. The aqueous solution is extracted with ethyl ether. The ether extract is washed, dried over anhydrous magnesium sulfate, filtered and the solvent is removed to give an oil. Crystallization from hexane, followed by recrystallization from acetone-hexane, gives 7 g of 6,7-dichloro-2-(2',6'-difluorophenyl)-5-methoxybenzo[b]thiophene.
Reaction SMILES: [C:1]1([C:7]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=CC=CC=1.[F:15][C:16]([F:34])([F:33])[C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[CH2:20][N:21]1[CH2:25][C@H:24]2[C@@H:26]([NH2:29])[CH2:27][CH2:28][C@H:23]2[CH2:22]1.C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[F:34][C:16]([F:33])([F:15])[C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[CH2:20][N:21]1[CH2:25][C@H:24]2[C@@H:26]([NH:29][C:12]([CH:7]3[CH2:1][CH2:6][CH2:8][CH2:9][CH2:10][CH2:11]3)=[O:14])[CH2:27][CH2:28][C@H:23]2[CH2:22]1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: O=C(N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)C1CCCCCC1

Procedure:
The title compound was prepared by substituting cycloheptanecarboxylic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4S*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 1: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.79 (d, J=6.9, 1H), 7.71 (s, 1H), 7.62 (d, J=7.7, 1H), 7.56 (s, 1H), 7.47 (t, J=7.7, 1H), 4.48-4.40 (m, 1H), 3.54 (d, J=13.2, 1H), 3.46 (d, J=13.2, 1H), 2.86 (ddd, J=3.0, 7.8, 16.6, 1H), 2.76 (dd, J=3.0, 9.5, 1H), 2.51-2.39 (m, 2H), 2.37-2.30 (m, 2H), 2.26 (dd, J=7.5, 9.4, 1H), 2.00-1.80 (m, 5H), 1.75-1.60 (m, 4H), 1.49-1.41 (m, 4H), 1.33 (ddt, J=7.2, 8.9, 12.1, 3H); MS (ESI+) m/z 409 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH2:5][C:4]([N:7]2[CH2:11][CH2:10][C:9]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:8]2=[O:17])=[CH:3]1.[CH3:18][C:19]1[C:27]2[CH2:26][O:25][C:24](=[O:28])[C:23]=2[CH:22]=[CH:21][C:20]=1[C@@H:29]1[CH2:31][O:30]1>C(O)C>[OH:30][C@H:29]([C:20]1[CH:21]=[CH:22][C:23]2[C:24](=[O:28])[O:25][CH2:26][C:27]=2[C:19]=1[CH3:18])[CH2:31][N:14]1[CH2:13][CH2:12][C:9]2([C:8](=[O:17])[N:7]([C:4]3[CH2:5][O:6][C:2](=[O:1])[CH:3]=3)[CH2:11][CH2:10]2)[CH2:16][CH2:15]1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: O=C1C=C(N2CCC3(CCNCC3)C2=O)CO1
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCC3(CC2)CCN(C2=CC(=O)OC2)C3=O)ccc2c1COC2=O
Temperature: 145 °C

Procedure:
2-(5-Oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-16, 200 mg, 0.846 mmol) was combined with 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (I-4B) (177 mg, 0.931 mmol) in ethanol (5 mL) and heated in a microwave apparatus at 145° C. for 3 hours. The solvent was removed and the residue was purified by preparative TLC, eluting with 25% methanol/EtOAc to afford the title compound. LC-MS (IE, m/z): 427 (M+1)+.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[O:19]>C(Cl)Cl>[C:5]([O:4][C:3]([NH:2][O:1][C:18]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[O:19])=[O:9])([CH3:8])([CH3:7])[CH3:6]
Reactant: COCCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)NO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOC(=O)ONC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl N-hydroxycarbamate (1.5 g, 11.3 mmol) in DCM (50 ml) is added triethylamine (1.6 ml, 11.3 mmol) at 0° C. Chloro(2-methoxyethoxy)methanone (1.56 g, 11.3 mmol) is added dropwise. Reaction is stirred for 18 hours at room temperature before being washed with water (2×10 ml), NaHCO3 (2×10 ml), dried (MgSO4) and concentrated in vacuo to give the title product as an oil. (0.67 g, 25%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.74-8.46 (1H, m), 4.23-4.73 (2H, m), 3.45-3.84 (2H, m), 3.34 (3H, s), 1.41 (9H, s).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25](Br)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([C:32]3[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Br)cccc2[nH]1
Reactant: OB(O)c1ccncc1
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(-c3ccncc3)cccc2[nH]1

Procedure:
This compound is synthesized from compound 194 (see example 156) and pyridin-4-yl-boronic acid analogously to the method described in Example 156.
Reaction SMILES: Cl.C(C1C=CC2[NH:14][CH:13]([CH2:15]C(OC)=O)[C:12](=[O:20])N(C)CC=2C=1)(O)=O.O[N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:14][CH:13]([C:15]1[NH:24][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=1)[CH2:12][OH:20]
Reactant: On1nnc2ccccc21
Reactant: COC(=O)CC1Nc2ccc(C(=O)O)cc2CN(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(CO)c1nc2ccccc2[nH]1

Procedure:
HCl (Maekawa; Ohtani, Agric. Biol. Chem., 40, 1976, 791) and 0.88 g of methyl 7-carboxy-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate are dissolved in 30 ml of DMF and treated with 0.49 g of 1-hydroxybenzotriazole and 0.58 g of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide.hydrochloride and 1.55 g of diisopropylethylamine.