Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[N:20]=[CH:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:32]4[CH:36]=[CH:35][CH:34]=[N:33]4)=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:37])[N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:32]1([CH2:31][C:28]2[CH:29]=[CH:30][C:25]([CH2:24][N:22]3[CH:23]=[C:19]([C:17]([NH:16][CH2:15][C:11]4[C:10]([CH3:37])=[N:9][C:8]([NH2:7])=[CH:13][C:12]=4[CH3:14])=[O:18])[N:20]=[CH:21]3)=[CH:26][CH:27]=2)[CH:36]=[CH:35][CH:34]=[N:33]1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn(Cc2ccc(Cn3cccn3)cc2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N)nc(C)c1CNC(=O)c1cn(Cc2ccc(Cn3cccn3)cc2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [4,6-Dimethyl-5-({[1-(4-pyrazol-1-ylmethyl-benzyl)-1H-imidazole-4-carbonyl]-amino}-methyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (260 mg, 0.37 mmol), 5 mL TFA and 10 mL DCM was stirred of room temperature for 1 h. The mixture was evaporated in vacuo and the residue was purified by preparative HPLC (Macherey-Nagel Nucleosil 250×40 mm, 5 to 100% ACN and 0.1% TFA, flow 40ml/min). Aq. NaHCO3-solution was added to the product containing fractions and after evaporation the aq. layer was extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated to give the title compound. 1H-NMR (DMSO-d6, 400 MHz) 7.80 (s, 2H), 7.66-7.69 (m, 2H), 7.45 (s, 1H), 7.28 (d, 2H), 7.20 (d, 2H), 6.26 (s, 1H), 6.21 (s, 1H), 6.04 (s, 2H), 5.31 (s, 2H), 5.19 (s, 2H), 4.30 (d, 2H), 2.34 (s, 3H), 2.21 (s, 3H); LCMS (method A) RtA=0.832 min; [M+H]+=416.0
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:11][C@H:12]([C:14]([NH:16][CH:17]1[C:23](=[O:24])[N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]2[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=2[N:19]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:18]1=[O:41])=[O:15])[CH3:13]>>[CH:1]1([CH2:6][C:7]([NH:11][C@H:12]([C:14]([NH:16][CH:17]2[C:18](=[O:41])[N:19]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:20]3[CH:34]=[CH:33][CH:32]=[CH:31][C:21]=3[N:22]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:23]2=[O:24])=[O:15])[CH3:13])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[C@H](N)C(=O)NC1C(=O)N(c2ccccc2)c2ccccc2N(c2ccccc2)C1=O
Reactant: O=C(O)CC1CCCC1
Agent: Cl
Product: C[C@H](NC(=O)CC1CCCC1)C(=O)NC1C(=O)N(c2ccccc2)c2ccccc2N(c2ccccc2)C1=O

Procedure:
Following General Procedure I above using cyclopentylacetic acid (Aldrich) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-W), the title compound was prepared as an amorphous white solid. Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1). Rf=0.44 (CH2Cl2/EtOAc, 1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][CH3:13])[C:5]([NH:7][CH3:8])=[O:6].[NH2:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=S>C(Cl)CCl>[CH3:8][NH:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[N:12]([CH3:29])[C:13]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:1][C:2]=2[CH:3]=1)=[O:6]
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: CNC(=O)c1ccc(NC)c(N)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 8.2 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl amide (74 mg) was prepared by following General Procedure D starting from 3-amino-N-methyl-4-methylamino-benzamide (460 mg), 2-amino-6-(trifluoromethoxy)benzothiazole (499 mg), 1,1′-thiocarbonyl-diimidazole (454 mg), and EDC (611 mg). LC/MS: m/z 423.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.39 (bs, 1H), 8.42 (s, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.75 (d, 2H), 7.50 (d, 1H), 7.36 (d, 1H), 3.68 (bs, 3H), 2.81 (d, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH2:33][CH3:34])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:35][NH:36][CH3:37]>>[CH3:35][N:36]([CH3:37])[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH2:33][CH3:34])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Product: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N(C)C)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 4b using (R)-6-(6-chloropyridine-3-sulfonyl)-4a-ethoxymethyl-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene and dimethylamine. LCMS (Method C): 512 (M+H)+, Retention time 12.1 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH:29]2[CH2:32][O:33][CH2:34][CH:28]2[CH2:27]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:19][CH2:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][CH:29]5[CH2:32][O:33][CH2:34][CH:28]5[CH2:27]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: ClCCCN1CCC2COCC2C1
Reactant: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1OCCCN1CCC2COCC2C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
A mixture of 4-((4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (140 mg, 0.44 mmol, 1 eq), 5-(3-chloropropyl)octahydrofuro[3,4-c]pyridine (90 mg, 0.44 mmol, 1 eq) and K2CO3 (135 mg, 0.98 mmol, 2 eq) in DMF (10 mL) was heated to 80° C. and stirred overnight, then cooled to room temperature. To the resulted mixture was added 50 mL of CH2Cl2. The mixture was washed with brine (20 mL×3) and water (20 mL×2). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound as a yellow solid (50 mg, 25.00%), HPLC: 96.56%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 453.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.76-1.77 (2H, m), 2.24-2.48 (3H, m), 2.50-2.64 (3H, m), 2.68-2.71 (2H, m), 2.73-2.75 (2H, m), 2.96-3.03 (3H, m), 3.07-3.12 (2H, m), 3.61-3.90 (2H, m), 4.24-4.27 (2H, m), 7.02 (1H, s), 7.06-7.10 (1H, m), 7.16 (1H, s), 7.76-7.82 (1H, m), 7.82 (1H, s), 8.09-8.11 (1H, m), 8.59 (1H, s) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[CH:36]=[CH:37][CH:38]=[CH:39][C:40](Cl)=[O:41]>CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][CH2:10][N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C:40](=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][C:30]2[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:29]=2[Cl:28])=[CH:6][CH:7]=1
Reactant: Fc1ccc(CNCC=Cc2ccc(Cl)cc2)cc1F
Reactant: O=C(Cl)C=CC=Cc1ccc(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C=CC=Cc1ccc(Cl)cc1Cl)N(CC=Cc1ccc(Cl)cc1)Cc1ccc(F)c(F)c1
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of [3-(4-chloro-phenyl)-allyl]-(3,4-difluoro-benzyl)-amine (1.49 g, 5.1 mmol), triethylamine (1.06 mL, 7.6 mmol, 1.5 eq.), DMAP (i.e., dimethylaminopyridine) (62 mg, 0.51 mmol, 0.1 eq.) in 15 mL dichloromethane at 0° C. was added a solution of 5-(2,4-dichloro-phenyl)-penta-2,4-dienoyl chloride (6.3 mmol) in 15 mL dichloromethane and stirred for 1 hr. After aqueous work-up, the crude product was purified by chromatography with 20% ethyl acetate-hexanes to provide 2.05 g of 5-(2,4-dichloro-phenyl)-penta-2,4-dienoic acid [3-(4-chloro-phenyl)-allyl]-(3,4-difluoro-benzyl)-amide.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[C:20][C:21]4[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][N:22]=4)[CH:17]=3)[S:12][C:11]([CH3:33])([CH3:32])[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+].Cl>C1COCC1.CCO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][C:21]4[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[CH:23][N:22]=4)[CH:17]=3)[S:12][C:11]([CH3:32])([CH3:33])[CH:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CC(C)(C)S3)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1ccc(C2=CC(C)(C)Sc3ccc(CCc4ccc(C(=O)O)cn4)cc32)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of ethyl 6-[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-nicotinate (Compound 241, 110.0 mg, 0.24 mmol) in 3.0 mL THF and 3.0 mL EtOH was added NaOH (120.0 mg, 3.0 mmol, 3.0 mL of a 1M aqueous solution). This mixture was heated to 40° C. for 1 hour, cooled to room temperature, and the resulting solution was stirred overnight. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure to give 100 mg (96%) of the title compound as a colorless solid. 1H NMR (300 MHz, d6 -acetone) δ: 9.08 (1H, d, J=2.0 Hz), 8.30 (1H, dd, J=2.2, 8.2 Hz), 7.66 (1H, d, J=8.2 Hz), 7.46 (2H, s), 7.31-7.21 (5H, m), 5.95 (1H, s), 2.69 (2H, q, J=7.6 Hz), 1.48 (6H, s), 1.25 (3H, t, J=7.6 Hz).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH2:33])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2].[C:35]1([CH2:41][S:42](Cl)(=[O:44])=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH:33][S:42]([CH2:41][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:44])=[O:43])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:17]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccccc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Product: CC(C)OC(=O)CCCCCOc1cc2c(cc1NS(=O)(=O)Cc1ccccc1)nc(-c1ccccc1)n2-c1ccccc1

Procedure:
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid isopropyl ester was reacted with benzenemethanesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[C:5]([N+:14]([O-])=O)=[CH:4][C:3]=1[N:17]1[C:22](=[O:23])[C:21]([CH3:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[N:19]([CH3:29])[C:18]1=[O:30].C(O)(=O)C.O>[Fe].C(O)C>[NH2:14][C:5]1[C:6]([C:8]#[C:9][Si:10]([CH3:13])([CH3:11])[CH3:12])=[CH:7][C:2]([F:1])=[C:3]([N:17]2[C:22](=[O:23])[C:21]([CH3:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[N:19]([CH3:29])[C:18]2=[O:30])[CH:4]=1
Reactant: Cc1c(C(F)(F)F)n(C)c(=O)n(-c2cc([N+](=O)[O-])c(C#C[Si](C)(C)C)cc2F)c1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Cc1c(C(F)(F)F)n(C)c(=O)n(-c2cc(N)c(C#C[Si](C)(C)C)cc2F)c1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 69.1 %

Procedure:
A mixture consisting of 3-{2-fluoro-5-nitro-4-[2-(trimethylsilyl)-1-ethynyl]phenyl}-1,5-dimethyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (11.95 g), iron powder (15.68 g), acetic acid (14 ml), water (14 ml) and ethanol (280 ml) was heated to 80° C. and stirred for 3 hours. Then, the solvent was distilled off under reduced pressure. An aqueous sodium hydroxide solution was added thereto to make it alkaline. Then, methylene chloride was added thereto for extraction. After washing with water, it was dried over anhydrous magnesium sulfate. Then, methylene chloride was distilled off, and the resulting residue was crystallized from a mixed solvent of ethyl acetate and n-hexane (1:3 v/v) to obtain 3-{5-amino-2-fluoro-4-[2-(trimethylsilyl)-1-ethynyl]-phenyl}-1,5-dimethyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (7.70 g).
Reaction SMILES: [CH2:1]([C:10]1[S:11][C:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)=[N:13][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O.[CH2:28]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1O)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([C:10]1[S:11][C:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([O:21][C:40]3[CH:41]=[CH:42][C:37]([O:36][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:38][CH:39]=3)=[O:20])=[CH:17][CH:16]=2)=[N:13][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCc1nnc(-c2ccc(C(=O)O)cc2)s1
Reactant: CCCCCCCCOc1ccccc1O
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCc1nnc(-c2ccc(C(=O)Oc3ccc(OCCCCCCCC)cc3)cc2)s1

Procedure:
4-(2-n-Nonyl-1,3,4-thiadiazole-5-yl)-benzoic acid (0.005 moles, 1.66 g) is reacted with 5 mL of thionyl chloride and heated 2 hours at the boiling point. After that, the excess thionyl chloride is distilled off in the rotary evaporator and the residue is treated with 0.006 moles (1.33 g) octyloxyphenol, dissolved in 20 mL toluene, 5 mL triethylamine and 100 mg 4-dimethylaminopyridine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(O)[CH2:11][CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:14]1([CH:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH:2]=[CH:3][C:4]=3[CH:9]=2)[CH2:11][CH3:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCC(O)(c1ccccc1)c1ccc2occc2c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(c1ccccc1)c1ccc2occc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1-(benzofuran-5-yl)-1-phenylpropan-1-ol (3.14 g, 12.4 mmol) and triethylsilane (2.39 mL, 14.9 mmol) in DCM (10 mL) under nitrogen at 0° C. was added trifluoroacetic acid (4.62 mL, 62.2 mmol) dropwise via syringe. The reaction mixture was stirred at 0° C. for 3 h. Additional triethylsilane (2.39 mL, 14.9 mmol) followed by trifluoroacetic acid (4.62 mL, 62.2 mmol) were added via syringe, and the reaction was brought to room temperature and stirred for 2 h. The reaction mixture was quenched with 1M aqueous NaOH. DCM was added, and the aqueous layer was separated and extracted again with DCM. The combined organic layers were dried (MgSO4) and concentrated to give a crude oil. The crude product was purified by silica flash chromatography to give 5-(1-phenylpropyl)-benzofuran as a transparent oil. MS (ESI) m/z: Calculated: 236.1; Observed: 237.2 (M++1).
Reaction SMILES: Br.[OH:2][C:3]1[C:19]([OH:20])=[CH:18][C:6]2[CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[OH-].[Na+].[C:23](Cl)([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>CN(C)C=O>[OH:2][C:3]1[C:19]([OH:20])=[CH:18][C:6]2[CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][N:9]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: Oc1cc2c(cc1O)C(c1ccccc1)CNCC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCc2cc(O)c(O)cc2C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7.10 g. (18.6 mole) of 7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide in 120 ml. of aqueous dimethyl-formamide at 0° under an argon atmosphere is basified to pH 10.0 with 10% sodium hydroxide solution. To this cold mixture is added 13.0 g. (76 mole) of carbobenzyloxy chloride in small portions over 15 minutes with concomitant addition of 10% alkali so as to maintain a pH of 10 to 10.5. The reaction is allowed to warm to room temperature after stirring at 0° for 11/2 hours. The mixture is diluted with saturated salt and extracted with three portions of ethyl acetate. The combined organic extract is backwashed twice with saturated salt. The dried extract is concentrated in vacuo and heated at 75°/0.1 mm Hg to remove any benzyl alcohol to yield 7,8-dihydroxy-N-carbobenzyloxy-1-phenyl-2,3,4,5-tetrahydro-1-H-3-benzazepine.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH:36]([OH:40])[CH2:35]1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]([N:34]2[CH2:39][CH2:38][CH2:37][CH:36]([OH:40])[CH2:35]2)=[O:18])[N:8]([C:6]([C:31]2[CH:30]=[CH:29][C:28]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)=[O:7])[CH2:12]1
Reactant: OC1CCCNC1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CON=C1C[C@@H](C(=O)N2CCCC(O)C2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and (3RS)-3-piperidinol, the title compound was obtained in 78% purity by HPLC. MS(ESI+): m/z=422.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:4].Br[C:25]1[C:26]2[C:27]3[CH:40]=[CH:39][S:38][C:28]=3[C:29](=[O:37])[NH:30][C:31]=2[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]>>[OH:1][CH2:2][CH:3]([NH:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([C:25]2[C:26]3[C:27]4[CH:40]=[CH:39][S:38][C:28]=4[C:29](=[O:37])[NH:30][C:31]=3[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])=[CH:13][CH:14]=1)(=[O:7])=[O:8])[CH3:4]
Reactant: CC(CO)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NC(C)CO)cc1
Yield: 16.3 %

Procedure:
Following General Procedure B, N-(1-hydroxypropan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (570 mg, 1.7 mmol) was reacted with 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one, (471 mg, 1.5 mmol) to afford the desired product (109 mg, 16%) as an off-white powder. ESI MS m/z 445 [C21H20N2O5S2+H]+;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].F[C:22]1[C:27]([CH3:28])=[CH:26][C:25]([N+:29]([O-:31])=[O:30])=[CH:24][C:23]=1[CH3:32]>CS(C)=O>[CH3:28][C:27]1[CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=[C:23]([CH3:32])[C:22]=1[O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1F
Reactant: CC(C)Cc1n[nH]c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc2[nH]nc(CC(C)C)c2c1
Yield: 37.9 %

Procedure:
In an analogous manner to the procedure of Example XVIII, 136 mg (0.715 mmol) of 5-hydroxy-3-isobutyl-1H-indazole are reacted with 99 mg (0.715 mmol) of potassium carbonate and 121 mg (0.715 mmol) of 4-fluoro-3,5-dimethylnitrobenzene in 5 ml of DMSO to give 92 mg (38%) of 5-(2,6-dimethyl-4-nitrophenoxy)-3-isobutyl-1H-indazole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1.[I:17]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>C(#N)C>[CH3:1][O:2][C:3](=[O:16])[O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([O:14][CH3:15])=[O:13])=[C:9]([I:17])[CH:10]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)Nc1ccc(OC(=O)OC)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)Nc1ccc(OC(=O)OC)cc1I
Temperature: 0 °C
Reaction time: 72 h
Yield: 92.1 %

Procedure:
A mixture of carbonic acid 4-methoxycarbonylamino-phenyl ester methyl ester (20.0 g, 88.8 mmol) and N-iodosuccinimide (23.8 g, 105.78 mmol) in acetonitrile (330 mL) was cooled to 0° C. (ice-bath). Trifluoromethanesulfonic acid (1.6 mL, 18.2 mmol) was added dropwise. The cooling bath was removed and the reaction stirred 72 h at room temperature. TLC showed the reaction was complete. The mixture was poured into 1M pH7 phosphate buffer, and washed with ethyl acetate. The phases were separated, the aqueous phase was extracted with ethyl acetate and the combined organic phases washed with 10% sodium thiosulfate solution, brine, dried over sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel (500 g, 3:2 hexane/ethyl acetate eluant) to afford the product as an off-white solid (28.7 g, 92%), which was used without further purification. m.p. 106° C.
Reaction SMILES: C1C=CC(OC(OC2C=CC=CC=2)=[N:9][C:10]#[N:11])=CC=1.C[CH2:20][N:21]([CH:25]([CH3:27])C)[CH:22]([CH3:24])C.Cl.[CH3:29][C@@H:30]1[CH2:35][CH2:34][NH:33][CH2:32][C@@H:31]1[C:36]1[N:40]2[C:41]3[CH:47]=[CH:46][NH:45][C:42]=3[N:43]=[CH:44][C:39]2=[CH:38][N:37]=1.N1CCCC1>CC#N>[C:36]1([C@@H:31]2[C@H:30]([CH3:29])[CH2:35][CH2:34][N:33]([C:20]([N:21]3[CH2:22][CH2:24][CH2:27][CH2:25]3)=[N:11][C:10]#[N:9])[CH2:32]2)[N:40]2[C:41]3[CH:47]=[CH:46][NH:45][C:42]=3[N:43]=[CH:44][C:39]2=[CH:38][N:37]=1
Reactant: C[C@@H]1CCNC[C@@H]1c1ncc2cnc3[nH]ccc3n12
Reactant: CCN(C(C)C)C(C)C
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Agent: Cl
Solvent: C1CCNC1
Solvent: CC#N
Product: C[C@@H]1CCN(C(=NC#N)N2CCCC2)C[C@@H]1c1ncc2cnc3[nH]ccc3n12
Temperature: 80 °C
Yield: 11.7 %

Procedure:
To a solution of diphenyl cyanocarbonimidate (0.163 g, 0.685 mmol) and DIEA (0.239 mL, 1.371 mmol) in MeCN (5 mL) was added 1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (0.20 g, 0.68 mmol). The reaction was heated at about 80° C. for about 2 h. The reaction mixture was concd in vacuo. The residue was dissolved in pyrrolidine (1.0 mL, 12 mmol) and transferred to a sealed microwave vessel. The reaction was heated at about 120° C. for about 30 min in a CEM microwave. The reaction mixture was concd in vacuo and purified by RP-HPLC (Table 1, Method i) to give N-(((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(pyrrolidin-1-yl)-methylene)cyanamide (0.030 g, 11%): LC/MS (Table 1, Method b) Rt=1.62 min; m/z: 377 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[N:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=1[CH3:21].N1C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[C:7]([S:8]([NH:20][C:18]2[CH:17]=[CH:16][C:15]([CH3:21])=[C:14]([O:13][CH3:12])[N:19]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: COc1nc(N)ccc1C
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1nc(NS(=O)(=O)c2cccnc2Cl)ccc1C
Yield: 79.8 %

Procedure:
The title compound (1.60 g, 5.10 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (1.35 g, 6.39 mmol), 6-methoxy-5-methylpyridin-2-amine (IntC10) (970 mg, 7.02 mmol) and pyridine (1.55 mL, 19.2 mmol) in 1,4-dioxane (25 mL) at rt using the methods of (IntC1).