Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:7][CH2:6][C:5]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]2)([C:8]([NH2:10])=O)[CH2:4][CH2:3]1.C1COCC1.[AlH4-].[Li+]>>[F:17][C:2]1([F:1])[CH2:3][CH2:4][C:5]([CH2:8][NH2:10])([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]2)[CH2:6][CH2:7]1
Reactant: Cc1cn(C2(C(N)=O)CCC(F)(F)CC2)cn1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cn(C2(CN)CCC(F)(F)CC2)cn1
Yield: 49.2 %

Procedure:
Into a round bottom flask was added 4,4-Difluoro-1-(4-methyl-imidazol-1-yl)-cyclohexanecarboxylic acid amide (99 mg, 0.39 mmol) and THF (10 mL, 100 mmol) at room temperature, to the reaction mixture was added lithium tetrahydroaluminate (365 mg, 9.62 mmol). The reaction was refluxed for 6 hours, before being quenched with water (0.4 ml), 2M NaOH (0.4 ml) and water (0.8 ml). The reaction mixture was filtered and cone. The residue was purified by flash column chromatography on silica gel (eluding w a mixture of 5% Et3N/10% MeOH185% AcOEt) to give the title compound (44 mg, 47%). 1H NMR (CDCl3 500 MHz): δppm 7.55 (s, 1H), 6.71 (s, 1H), 2.70 (s, 2H), 2.4-1.7 (m, 8H), 2.21 (s, 3H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Br:12]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.S(=O)(=O)(O)O>[Br:12][C:8]1[C:9]([NH2:11])=[CH:10][C:5]2[O:4][CH2:3][CH2:2][O:1][C:6]=2[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc2c(c1)OCCO2
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cc2c(cc1Br)OCCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 115.6 %

Procedure:
A solution of 2,3-dihydro-benzo[1,4]dioxin-6-ylamine (80 g, 530 mmol, 1 eq) in tetrahydrofuran (1000 mL) at −78° C. was treated with concentrated sulfuric acid (50 drops) then N-bromosuccinimide (94.2 g, 530 mmol, 1 eq) was added over 0.5 hour. After the addition the mixture was stirred at −78° C. for 1 hour then treated with solid sodium carbonate (12 g, 113 mmol, 0.21 eq). The mixture was evaporated and the residue partitioned between ether and water. The organic extract was dried, filtered and evaporated to give to oil that was chromatographed on silica gel eluting with dichloromethane to afford oil (141 g, 92%). LC/MS (ES) m/z 230 (MH+ 91%); 1H-NMR (400 MHz, d6-DMSO), 6.85 (1H, s, CHCNH2), 6.34 (1H, s, CHCBr), 4.79 (2H, s, NH2), 4.16 (4H, dd, J=16, 2×(CH2O))
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][OH:9]
Reactant: O=Cc1ccncc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1ccncc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
To a 0° C. solution of 3-chloropyridine-4-carbaldehyde (1.08 g, 7.5 mmol) in anhydrous methanol (75 mL) was added sodium borohydride (405 mg, 10.7 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. Water (75 mL) was added, and the reaction mixture was evaporated. The resultant residue was extracted with EtOAc (3×50 mL). The organic extracts were combined, washed with brine (2×100 mL), dried over MgSO4, filtered, evaporated, and dried in vacuo, affording (3-chloropyridin-4-yl)methanol (1.0 g, 96%). The product was used in the next step without further purification.
Reaction SMILES: [N:1]#[C:2]Br.[C:4]([NH:9][NH2:10])(=[O:8])[CH2:5][CH2:6][CH3:7]>CO>[CH2:5]([C:4]1[O:8][C:2]([NH2:1])=[N:10][N:9]=1)[CH2:6][CH3:7]
Reactant: N#CBr
Reactant: CCCC(=O)NN
Solvent: CO
Product: CCCc1nnc(N)o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.2 %

Procedure:
To a solution of 5.0 g (47.0 mmol) cyanogen bromide in 50 ml of methanol was added dropwise over a period of 30 min a solution of 4.80 g (47.0 mmol) butyric acid hydrazide in 50 ml of methanol. The mixture was then refluxed for 15 min, and then concentrated in vacuo till cristallisation began. The cristals (9 g) were filtered off, taken up in 60 ml of ethanol. Then 5 g of finely powdered potassium carbonate were added and the suspension was stirred for 5 min at room temperature. The resulting orange suspension was filtered, and the filtrate was concentrated in vacuo. The resulting orange powder (5.5 g) was purified by flash chromatography on silicagel with a 80:10:1 mixture of methylene chloride/methanol/28% ammonia as eluent to yield 3.95 g (31.1 mmol, 66%) of 5-propyl-[1,3,4]oxadiazol-2-ylamine as white cristals, MS: m/e=127 (M+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(Cl)Cl.O[CH2:10][CH2:11][C:12]1[S:16][CH:15]=[N:14][C:13]=1[CH3:17].C(N(CC)CC)C>O>[CH3:1][S:2]([CH2:10][CH2:11][C:12]1[S:16][CH:15]=[N:14][C:13]=1[CH3:17])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ncsc1CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ncsc1CCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (5.4 mmol) was added to a methylene chloride (0.2 M) solution of 5-(2-hydroxyethyl)-4-methyl-thiazole (4.5 mmol) and triethylamine (23 mmol), and stirred at room temperature overnight. The mixture was poured into water and extracted with methylene chloride. The organic extracts were washed with NaHCO3 (sat), and the product was extracted with 1M aq. HCl. The aqueous extracts were neutralized with NaHCO3 (sat) and then extracted with methylene chloride. The organic extracts were dried (MgSO4) and filtered. Solvent removal afforded product (5).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[C:5](N)[CH:6]=[CH:7][CH:8]=1.N([O-])=O.[Na+].C([O-])(O)=O.[Na+].[BrH:22]>O>[Br:22][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: Br
Reactant: COc1cccc(N)c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cccc(Br)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
3-Methoxy-2-nitro-phenylamine (360 mg, 2.14 mmol) was dissolved in HBr (48%, 4.8 mL) at 0° C. A solution of sodium nitrite (0.16 g, 2.40 mmol) in water (360 μL) was added dropwise to the stirred solution over one hour period while the temperature was maintained at 0° C. Then a cold (0° C.) freshly prepared solution of CuBr2 (from CuSO4.5H2O (1.0 g) and HBr (48%, 1.0 mL) mixed 30 min at room temperature to give a dark purple solution) was added at 0° C. to the reaction mixture. The resulting solution was stirred at 0° C. for 3 hours and at room temperature for 2 days. The reaction mixture was poured onto ice and neutralized carefully with a saturated solution of NaHCO3. The aqueous phase was extracted with AcOEt. The resulting organic phase was washed with brine, dried over MgSO4, filtered and evaporated to yield 482 mg (2.08 mmol, 97%) of 1-bromo-3-methoxy-2-nitrobenzene as an orange solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.[H-].[Na+].CN(C=O)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=1>C1C=CC=CC=1.ClCCl>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([O:8][C@@H:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][C@H:4]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:25][CH:24]=1
Reactant: CN1CCC(O)C(c2ccccc2)C1
Reactant: Fc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccccc1
Product: CN1CC[C@@H](Oc2ccc(Cl)cc2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 7.65 g of 1-methyl-3-phenyl-4-piperidinol (approximately a 50:50 mixture of isomers) of Example 1 in 100 ml of benzene is added to a suspension of 1.2 g of sodium hydride in 50 ml dry benzene. The mixture is heated to reflux, and 25 ml of dry DMF are added dropwise over a 10-minute period. After refluxing for 1 hour, the mixture is cooled to room temperature and a solution of 6.53 g of p-chlorofluorobenzene in 50 ml of benzene is added all at once. After stirring for 18 hours at room temperature, 100 ml of DMF are added and the mixture is refluxed for 5 hours, then stirred for 18 hours at room temperature and then refluxed an additional 4 hours. The mixture is partitioned between ether and saturated aqueous NaCl solution. The aqueous phase is extracted with ether. The combined extracts are washed with water, saturated aqueous NaCl solution and dried over anhydrous MgSO4. Removal of the solvent in vacuo affords an oil. This material is dissolved in dichloromethane and extracted with 2 N HCl solution. The dichloromethane phase is washed with saturated aqueous NaHCO3 solution, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford an oil which crystallizes on standing. This material is chromatographed on silica gel, using acetone and then 25% methanol/acetone as solvent. A pure product, trans-4-(4-chlorophenoxy)-1-methyl-3-phenylpiperidine, is thus obtained, m.p. s 83.5°, 84.5°-87° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[C:14]([O-:16])=O.C(Cl)(=O)C(Cl)=O.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:14](=[O:16])[C:4]2[CH:5]=[C:6]([CH:12]=[CH:13][C:3]=2[O:2][CH3:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1ccc(OC)c(C(=O)[O-])c1
Reactant: Nc1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OC)c(C(=O)Nc2ccc(Cl)cc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.6 %

Procedure:
1-Ethyl 4-methoxyisophthalate (100 mg) obtained in step D of Example 1-2-1, and 2 μL of N,N-dimethylformamide were dissolved in 5 mL of dichloromethane, and the solution was cooled to 0° C. To this solution, 59 μL of oxalyl chloride was added little by little, and the mixture was stirred for 20 minutes at 0° C., followed by stirring the mixture for 16 hours at room temperature. The reaction mixture was distilled under reduced pressure, and dried to obtain a light yellow solid. This solid was dissolved in 3 mL of dichloromethane, and the solution was added to a solution of 63 mg of 4-chloroaniline and 234 μL of N,N-diisopropylethylamine dissolved in 2 mL of dichloromethane. The mixture was stirred for 3 hours at room temperature, and then dichloromethane was distilled off under reduced pressure. The resulting residue was purified by column chromatography (5 g of silica gel) using a 1:1 mixture of dichloromethane and n-hexane as an elution solvent, thereby obtaining 134 mg (94%) of ethyl N-(4-chlorophenyl)-4-methoxyisophthalamate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:61])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([C@@H:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:60])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:62]OC(NC(C1C=CC=CC=1C)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:61])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:60])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=6[CH3:62])=[N:40][CH:41]=5)=[CH:35][CH:36]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)O)c1ccccc1C
Reactant: COC(=O)NC(C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1C
Yield: 50 %

Procedure:
This compound was prepared following the procedure for [1-(2-{5-[6-(4-{2-[1-(2S)-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using Methoxycarbonylamino-o-tolyl-acetic acid (0.03 g, 0.12 mmol, 1.75 equiv.) to provide [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-o-tolyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.03 g, 50%) as a white powder. LCMS-ESI+: calc'd for C48H52N8O6: 836.4 (M+). Found: 837.4 (M+H+). 1H-NMR: 400 MHz, (CDCl3) 8: (Mixture of diastereomers) 7.61-8.00 (m, 16H), 7.18-7.41 (m, 12H), 7.10 (s, 2H), 5.28-5.63 (m, 10H), 4.36 (t, 2H), 3.72-3.86 (m, 4H), 3.68 (s, 6H), 3.66 (s, 6H), 2.79-3.07 (m, 8H), 2.50 (s, 3H), 2.44 (s, 3H), 2.38 (m, 4H), 1.86-2.28 (m, 8H), 0.88-0.94 (m, 12H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCCCCBr
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCc1ccc(CN2CCCCC2)cc1
Temperature: 25 °C

Procedure:
The mixture of (4-aminomethyl-benzyl)-carbamic acid tert-butyl ester (4.06 g, 17.2 mmol), 1,5-dibromo-pentane (2.60 mL, 19.1 mmol) and potassium carbonate (8.96 g, 65.1 mmol) in acetonitrile (160 mL) was refluxed overnight under N2. The reaction was cooled to r.t. and filtered. The filtrate was concentrated in vacuo and chomatographed on silica (CH2Cl2→CH2Cl2/MeOH with 2N NH3=25/1) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36].C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([N:26]([S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:35](=[O:36])[O:37][CH2:38][CH3:39])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCS(=O)(=O)N(C(=O)OCC)c1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.1 %

Procedure:
To a suspension of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfonamide (0.2 g, 0.41 mmol) in dioxane (15 mL) were added ethyl chloroformate (EtOCOCl, 44 mg, 0.41 mmol) and triethylamine (0.14 g, 1.38 mmol). The reaction was stirred at rt for 1.5 h, then concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/EtOAc (v/v)=4/1) to afford the title compound as a white solid (0.12 g, 50%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].Br.[Br:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=O>>[BrH:15].[N:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[S:3][CH:16]=2)=[CH:20][CH:21]=1
Reactant: O=C(CBr)c1ccncc1
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Agent: Br
Product: COC(=O)c1ccc(-c2nc(-c3ccncc3)cs2)cc1
Yield: 66 %

Procedure:
In the same manner as in Example 28, methyl 4-thiocarbamoylbenzoate was reacted with 4-bromoacetylpyridine hydrobromide to obtain methyl 4-[4-(4-pyridyl)-2-thiazolyl]benzoate hydrobromide. The product was recrystallized from ethanol. Yield: 66%. Pale yellow prisms. Melting point: 238 to 240° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=[CH:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.Cl.[CH3:34][C:35]1[C:43]2[C:42]([N:44]3[CH2:49][CH2:48][CH:47]([NH2:50])[CH2:46][CH2:45]3)=[N:41][CH:40]=[N:39][C:38]=2[NH:37][CH:36]=1>ClCCl>[CH3:1][N:2]1[C:6]([C:7]([NH:50][CH:47]2[CH2:46][CH2:45][N:44]([C:42]3[C:43]4[C:35]([CH3:34])=[CH:36][NH:37][C:38]=4[N:39]=[CH:40][N:41]=3)[CH2:49][CH2:48]2)=[O:9])=[CH:5][N:4]=[CH:3]1
Reactant: Cc1c[nH]c2ncnc(N3CCC(N)CC3)c12
Reactant: Cn1cncc1C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2ncnc(N3CCC(NC(=O)c4cncn4C)CC3)c12

Procedure:
To a mixture of 1-methyl-1H-imidazole-5-carboxylic acid (61.2 mg, 0.486 mmol, commercially available from e.g. Maybridge, Apollo or Butt Park), EDC (107 mg, 0.560 mmol), HOBt (86 mg, 0.560 mmol) and N,N-diisopropylethylamine (0.163 nit, 0.934 mmol) in Dichloromethane (DCM) (2 mL), prestirred for 10 minutes, was added 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine hydrochloride
Reaction SMILES: NC1C2C(=CC=CC=2)C=CC=1.[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].[C:22]1([O:28][CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(Cl)(=O)C1C=CC(OC)=CC=1>>[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([C:25]1[CH:26]=[CH:27][C:22]([O:28][CH3:29])=[CH:23][CH:24]=1)=[O:16]
Reactant: O=C(Cl)c1ccccc1F
Reactant: COc1ccccc1
Agent: COc1ccc(C(=O)Cl)cc1
Agent: Nc1cccc2ccccc12
Product: COc1ccc(C(=O)c2ccccc2F)cc1

Procedure:
The procedure of Example 10 was followed except as follows. In Part A, 1-amino napthalene (47 g) was used in place of 4-methoxy aniline. In Step 1 of Part B, 2-fluorobenzoyl chloride (15.8 g) and anisole (10.8 g) were used in place of 1,3-dimethoxybenezene and p-anisoyl chloride respectively to produce (2-fluoro-phenyl)-(4-methoxy-phenyl)-methanone. An NMR spectrum showed the final product to have a structure consistent with 12-ethoxy-3-(2-fluorophenyl)-3-(4-methoxy)-3H-benzo[h]pyrano[3,2-c]quinoline.
Reaction SMILES: OO.C(O)(=[O:5])C.Cl[C:8]1[C:13]([C:14]2[CH:19]=[CH:18]C=[CH:16][CH:15]=2)=[CH:12][N:11]=[C:10]([CH3:20])[C:9]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[C:26]([Cl:30])(Cl)(Cl)Cl>>[Cl:30][C:26]1[CH:18]=[CH:19][C:14]([C:13]2[CH:8]=[C:9]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]([CH3:20])=[N+:11]([O-:5])[CH:12]=2)=[CH:15][CH:16]=1
Reactant: CC(=O)O
Reactant: CCOC(=O)c1c(C)ncc(-c2ccccc2)c1Cl
Reactant: ClC(Cl)(Cl)Cl
Agent: OO
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)c[n+]([O-])c1C

Procedure:
Hydrogen peroxide (100 vol.; 65.6 ml) was added to glacial acetic acid (250 ml) with stirring and the solution was heated to 50°. 5-(p-Chlorophenyl-2-methyl-3-ethoxycarbonylpyridine (27.55 g) was added and the solution stirred at 50°-55° for 16 hours. The volume of the solution was halved by evaporation in vacuo at below 50° C., and the mixture was then poured into water and neutralised with 2M-sodium hydroxide. The precipitate so formed was filtered off and washed with water to give a white solid which was recrystallied from carbon tetrachloride to give, as white crystals, the title compound, m.p. 130°.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.OS(O)(=O)=O.[C:15]([O-])(O)=O.[Na+].[OH-].[Na+]>CO.C(Cl)(Cl)Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:15])=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)o1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(C)o1
Temperature: 50 °C
Yield: 82 %

Procedure:
To a 200 mL round-bottomed flask with condenser was added 5-methyl-2-furancarboxylic acid (2.5 g, 19.82 mmol) in Methanol (100 mL). H2SO4 (10.5 mL, 197 mmol) was added slowly at room temperature. The reaction mixture was heated to 50° C. overnight. The reaction mixture was cooled to 0° C. and a saturated solution of NaHCO3 was added to neutral pH followed by 5N NaOH to pH 10. CHCl3 was added and the organic phase was separated, dried with Na2SO4 and concentrated affording the title compound (2.3 g, 16.3 mmol, 82%): LC-MS (ES) m/z=141 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[C:8]([O:12][C:13]([NH:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:24]([N+:35]([O-:37])=[O:36])[CH:23]=2)[CH:19]=[CH:20][CH:21]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CI>C(OCC)C.O>[C:8]([O:12][C:13]([N:15]([CH3:3])[C:16]1[CH:17]=[C:18]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[C:24]([N+:35]([O-:37])=[O:36])[CH:23]=2)[CH:19]=[CH:20][CH:21]=1)=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CCOCC
Product: CN(C(=O)OC(C)(C)C)c1cccc(-c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)c1
Reaction time: 0.25 h

Procedure:
Under ice-cooling, 60% sodium hydride (24 mg) was added to an N,N-dimethylformamide (3.0 mL) solution of tert-butyl 4-(3-(tert-butoxycarbonylamino)phenyl)-2-nitrobenzoate (0.17 g), followed by stirring at the same temperature for 15 minutes and then at room temperature for 20 minutes. Methyl iodide (0.037 mL) was added to the reaction mixture under ice-cooling, followed by stirring at room temperature for 1 hour. Water and diethyl ether was added to the reaction mixture, and the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layer and the extract were combined, and the resulting mixture was washed with a 10% aqueous solution of citric acid and a saturated aqueous solution of sodium chloride sequentially and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: 95-85% hexane/ethyl acetate] to obtain 0.17 g of tert-butyl 4-(3-((tert-butoxycarbonyl)(methyl)amino)phenyl)-2-nitrobenzoate as a brown oily substance.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]3[C:32](=[CH:33][CH:34]=2)[C:15]2[NH:16][C:17]([C@@H:19]4[CH2:24][C@@H:23]5[C@@H:21]([CH2:22]5)[N:20]4[C:25]([O:27]C(C)(C)C)=O)=[N:18][C:14]=2[CH:13]=[CH:12]3)[O:3]1.Cl.[CH3:37][O:38][C:39]([NH:41][C@@H:42]([CH:46]([CH3:48])[CH3:47])C(O)=O)=[O:40].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>C(Cl)Cl.CO>[CH3:47][CH:46]([CH3:48])[C@H:42]([NH:41][C:39](=[O:40])[O:38][CH3:37])[C:25](=[O:27])[N:20]1[C@H:19]([C:17]2[NH:16][C:15]3[C:32]4[C:11]([CH:12]=[CH:13][C:14]=3[N:18]=2)=[CH:10][C:9]([B:4]2[O:3][C:2]([CH3:1])([CH3:35])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:34][CH:33]=4)[CH2:24][C@@H:23]2[C@H:21]1[CH2:22]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2[nH]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86.7 %

Procedure:
To a solution of (1R,3S,5R)-tert-butyl 3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (0.60 g, 1.3 mmol) in a mixture of CH2Cl2 (12.0 mL) and MeOH (2.5 mL) was added HCl (4M in 1,4-dioxane, 9.4 mL, 37.6 mmol). The solution was stirred at room temperature for 2.5 h and concentrated to dryness. The crude intermediate was suspended in CH2Cl2 (12 mL). (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.25 g, 1.4 mmol), HATU (0.58 g, 1.5 mmol), and DIPEA (0.7 mL, 4.0 mmol) were sequentially added to the reaction. The homogenous solution was then stirred at room temperature for 1.5 h. The solution was diluted with CH2Cl2 and washed with HCl (aqueous, 1N) and aqueous bicarbonate (sat.). The aqueous layers were back extracted with CH2Cl2 and the combined organic layers were dried over Na2SO4 and concentrated. The crude oil was then purified by silica gel chromatography (30 to 100% EtOAc (5% MeOH)/Hexanes) to provide methyl (S)-3-methyl-1-oxo-1-((1R,3S,5R)-3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)butan-2-ylcarbamate (0.60 g, 89%). LCMS-ESI+: calc'd for C29H37BN4O5: 532.29 (M+); Found: 533.11 (M+H+).