Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:5]2[C:6]3[CH:16]4[NH:17][CH:13]([CH2:14][CH2:15]4)[CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[Na+].[C:26]1([S:32]([O-:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([S:32]([C:2]2[CH:3]=[C:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:5]3[C:6]4[CH:16]5[NH:17][CH:13]([CH2:14][CH2:15]5)[CH2:12][C:7]=4[N:8]([CH3:11])[C:9]=3[CH:10]=2)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)cc(Br)cc31)C1CCC(C2)N1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)cc(S(=O)(=O)c4ccccc4)cc31)C1CCC(C2)N1
Yield: 35 %

Procedure:
Prepared from the product of step B and benzene sulfinic acid sodium salt according to the procedure of Example 27, step C. Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 50:50) provided tert-butyl 3-phenylsulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (53 mg, 35%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.95 (m, 3H), 7.52 (m, 5H), 5.21 (m, 1H), 4.68 (m, 1H), 3.67 (s, 3H), 3.39 (m, 1H), 2.53 (d, J=17.0 Hz, 1H), 2.32 (m, 2H), 2.17 (m, 1H), 1.88 (t, J=10.1 Hz, 1H), 1.37 (brs, 9H).
Reaction SMILES: [CH2:1]([O:5][P:6]([O-:8])[O-:7])[CH2:2][CH2:3][CH3:4].C[Si](C)(C)N[Si](C)(C)C.[C:18]([O:21][C@@H:22]([CH3:26])[C:23](Cl)=[O:24])(=[O:20])[CH3:19]>>[PH:6](=[O:8])([O:7][C:23](=[O:24])[C@@H:22]([O:21][C:18](=[O:20])[CH3:19])[CH3:26])[O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: CCCCOP([O-])[O-]
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: CCCCO[PH](=O)OC(=O)[C@H](C)OC(C)=O
Temperature: 15 °C
Yield: 109.9 %

Procedure:
A mixture of di-ter.butylphosphite (2.13 g; 0.11 mol) and hexamethyldisilazane (8.87 g; 0.055 mol) was kept under nitrogen at 100° C. for 2 hours. The mixture was slowly cooled at 15° C. 2(S)-acetoxypropionyl chloride (15.0 g; 0.1 mol) was added under nitrogen at 15° C. in 15 minutes, thereafter the low-boiling compounds were removed by distillation under vacuum (20°-30° C./10 mmHg). Di-ter.butyl 2(S)-acetoxypropionyl phosphonate (27.72 g) was thereby obtained as oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][CH:26]([CH2:29][NH:30]C(=O)OC(C)(C)C)[CH2:25][CH2:24]2)[C:5]2[C:10]([C:11]#[N:12])=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][N:48]([C:51](=[O:53])[CH3:52])[CH2:47][CH2:46]2)=[CH:41][CH:40]=1.C[Si](Cl)(C)C>CCCCO>[C:51]([N:48]1[CH2:47][CH2:46][N:45]([C:42]2[CH:43]=[CH:44][C:39]([NH:38][C:2]3[N:3]=[C:4]([N:23]4[CH2:24][CH2:25][CH:26]([CH2:29][NH2:30])[CH2:27][CH2:28]4)[C:5]4[C:10]([C:11]#[N:12])=[CH:9][NH:8][C:6]=4[N:7]=3)=[CH:40][CH:41]=2)[CH2:50][CH2:49]1)(=[O:53])[CH3:52]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C#N)c3c(N4CCC(CNC(=O)OC(C)(C)C)CC4)nc(Cl)nc32)cc1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(N4CCC(CN)CC4)c4c(C#N)c[nH]c4n3)cc2)CC1
Yield: 16 %

Procedure:
A mixture of tert-butyl (1-(2-chloro-5-cyano-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (180 mg, 0.330 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (137 mg, 0.625 mmol) and trimethylsilyl chloride (0.300 mL, 2.37 mmol) in n-BuOH (5 mL) was stirred at 135° C. for 40 h. n-BuOH was removed in vacuo. The residue was purified by HPLC to give the titled compound (25 mg). MS 474.5 (M+H); UV 200.8, 277.8 nm.
Reaction SMILES: C(OC([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[N:14]([O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:13](=[O:23])[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.CO.[ClH:28]>FC(F)(F)C(O)=O>[ClH:28].[CH3:22][O:21][C:19]([CH2:18][O:17][N:14]1[C:13](=[O:23])[CH2:12][C:11]2([CH2:24][CH2:25][NH:8][CH2:9][CH2:10]2)[C:15]1=[O:16])=[O:20]
Reactant: COC(=O)CON1C(=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CON1C(=O)CC2(CCNCC2)C1=O
Reaction time: 0.17 h

Procedure:
In trifluoroacetic acid (3 ml) was dissolved 8-tert-butyloxycarbonyl-2-methoxycarbonylmethyloxy-2,8-diazaspiro[4,5]decane-1,3-dione (0.5 g), and the solution was left standing at room temperature for 10 minutes. To the solution was added methanol (20 ml), to which was added 2 ml of a methanol solution of 1N hydrogen chloride. The solvent was evaporated off under reduced pressure, and the residual oil was crystallized from ether-methanol to obtain 0.32 g of a coloress solid, m.p. 174° to 178° C.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br-:32].[Li+].[CH2:34]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47](O)[CH2:46][CH2:45]1)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[CH2:34]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47]([Br:32])[CH2:46][CH2:45]1)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: [Br-]
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Li+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(Br)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40 %

Procedure:
Diethylazodicarboxylate (24.6 ml) was added dropwise to a stirred solution of triphenylphosphine (39.3 g) in THF (120 ml) at 0° C. under argon. The mixture was stirred for 20 minutes, then treated sequentially with lithium bromide (26.1 g) and a solution of 1-benzyloxycarbonylpiperidine-4-ol (7.1 g) in THF (50 ml). The mixture was allowed to warm to room temperature and stirring was continued for 1 hour. The mixture was concentrated, the residue treated with ether (100 ml) and silica (60 ml), and the solvent was evaporated under reduced pressure. The resulting powder was added to the top of a flash column and the column was eluted with hexane/ether (4:1) to give 1-benzyloxycarbonyl-4-bromopiperidine (3.6 g) as a colourless oil. NMR: (CDCl3): δ, 1.8-2.0(2H,m); 2.0-2.2(2H,m); 3.3-3.5(2H,m); 3.6-3.8(2H,m); 4.35(1H,m); 5.1(2H,s); 7.3(5H,m) m/e 298/300(M+H)+ ; 320/322(M+Na)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([C:26]2([CH2:30][C:31]#[N:32])[CH2:29][NH:28][CH2:27]2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([C:26]2([CH2:30][C:31]#[N:32])[CH2:29][N:28]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:27]2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CNC5)n4)n3Cc3ccccc3)n12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CN(S(C)(=O)=O)C5)n4)n3Cc3ccccc3)n12
Reaction time: 0.07 h
Yield: 84.2 %

Procedure:
To {3-[3-(6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (6.0 mg, 0.014 mmol, from Example 90) was added methanesulfonyl chloride (1.3 μL, 0.017 mmol, Aldrich) in DCM (0.50 mL), followed by triethylamine (4.0 μL, 0.028 mmol). The reaction was complete in 4 minutes. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) afforded product (5.9 mg, 83%).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[C:5]([F:7])[CH:4]=[C:3]1[C:8]([O:10]C)=O.C(O/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])C.C1(C)C(S(O)(=O)=O)=CC=CC=1.CC(C)([O-])C.[Na+]>C(O)C.O>[F:7][C:5]1[CH:4]=[C:3]2[C:8]([OH:10])=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=[N:1][N:2]2[CH:6]=1
Reactant: COC(=O)c1cc(F)cn1N
Reactant: CCO/C=C/C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1S(=O)(=O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnn2cc(F)cc2c1O
Temperature: 85 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
A mixture of methyl 1-amino-4-fluoro-1H-pyrrole-2-carboxylate (0.980 g, 6.20 mmol), (E)-ethyl 3-ethoxyacrylate (1.25 g, 8.68 mmol) and toluenesulfonic acid (0.059 g, 0.310 mmol) in ethanol (15 mL) was heated at 85° C. for 2 h then at reflux (100° C. bath) for an additional 2 h. The mixture was cooled and concentrated to remove the ethanol/water and additional ethanol was added and reconcentrated. The process was repeated until all of the water had been removed then residue was dissolved in ethanol (15 mL) and sodium tert-butoxide (1.190 g, 12.39 mmol) was added to make orange clear solution. This mixture was heated at 85° C. for 1 h, then cooled and concentrated to remove the ethanol and the reaction mixture was neutralized with HCl in dioxane (0.5 mL of 4N solution) then concentrated to afford a tan semi solid. This material was slurried in water and stirred for 1 h and the resulting solid was collected and rinsed with water and filtered and dried to afford the title compound (740 mg, 3.30 mmol, 53.3% yield) as a light yellow solid. HPLC (condition B): retention time=3.57 min. LCMS (condition B): m/z 224.9 +ve.
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:10]1([OH:18])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[CH3:17].[OH-].[K+]>CCOCC>[CH3:17][C:11]1[C:12]([CH3:16])=[CH:13][CH:14]=[CH:15][C:10]=1[O:18][CH2:6][CH:7]([OH:9])[CH2:8][NH:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cccc(O)c1C
Reactant: CC(C)(C)N1CC(O)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1cccc(OCC(O)CNC(C)(C)C)c1C
Temperature: 155 °C

Procedure:
To a mixture of 6.5 parts of 1-(tert.-butyl)-3-azetidinol and 6.7 parts of 2,3-xylenol 0.2 part of potassium hydroxide was added, and the mixture was heated at 155° C. for 20 hours. The reaction mixture was cooled and then dissolved in 100 parts of ether. The solution was washed three times with 50 parts of 2 N-sodium hydroxide aqueous solution and extracted three times with 2 N-hydrochloric acid aqueous solution. The extract was washed with 50 parts of ether and was made alkaline by adding 2 N-sodium hydroxide solution gradually thereto. Then, the ether extraction was conducted three times and the extract was condensed and allowed to stand in a cool place. As a result, crystals were formed which were recrystallized twice from ether to yield 8.3 parts of 1-(2', 3'-dimethylphenyloxy)-3-(tert.-butylamino)-2-propanol having a melting point of 57° C. Results of infra-red spectrum analysis and ultraviolet ray absorption analysis of the product are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12](F)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[N-:17]=[N+]=[N-].[Na+].O>CS(C)=O>[NH2:17][C:12]1[CH:13]=[CH:14][C:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[OH:16])=[CH:10][CH:11]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(Cl)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(C(O)c2ccc(Cl)cn2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 30.1 %

Procedure:
A solution of 5-chloro-2-(4-fluorobenzoyl)pyridine (3.0 g) and sodium azide (0.84 g) in DMSO (60 ml) was stirred for 20 hours at 90° C. To the reaction mixture was added water, and the mixture was extracted with diethylether. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and a solution of the residue (3.19 g) in. THF (60 ml) was added dropwise to a suspension of aluminum lithium hydride (0.97 g) in THF (10 ml) at 0° C. The mixture was stirred at 0° C. for 10 minutes, and water (0.97 ml), 15% aqueous solution of sodium hydroxide (0.97 ml) and water (2.9 ml) were sequentially and slowly added dropwise to the solution. The mixture was stirred at room temperature for 18 hours, magnesium sulfate was added to the mixture, and the precipitates were removed by filtration (Celite). The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:hexane 1:1→2:1), to give (4-aminophenyl)(5-chloropyridin-2-yl)methanol (0.90 g) as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CC([O-])(C)C.[Na+]>O1CCOCC1>[NH:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11][CH2:12]1
Reactant: NCC1CCNCC1
Reactant: Clc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: c1ccc(NCC2CCNCC2)cc1
Temperature: 80 °C
Yield: 83.6 %

Procedure:
Following general procedure F, a mixture of chlorobenzene (102 μL, 1.0 mmol), 4-(aminomethyl)piperidine (137 mg, 1.2 mmol), NaOt-Bu (192 mg, 2.0 mmol), 10 (8 mg, 1 mol %), 1 (5 mg, 1 mol %), and dioxane (1 mL) was heated to 80° C. for 15 h. The crude product was purified via the Biotage SP4 (silica-packed 50 g snap; 7-9% MeOH/CH2Cl2) to provide the title compound as a white solid (159 mg, 84%), mp 60-61° C. 1H NMR (300 MHz, DMSO) δ: 7.02 (t, J=7.5 Hz, 2H), 6.52 (d, J=8.0 Hz, 2H), 6.46 (t, J=8.0 Hz, 1H), 5.58 (s, 1H), 3.11 (s, 1H), 2.92 (d, J=11.5 Hz, 2H), 2.82 (t, J=6.0 Hz, 2H), 2.41 (t, J=10 Hz, 2H), 1.64 (m, 3H), 1.02 (m 2H) ppm. 13C NMR (75 MHz, DMSO) δ: 149.8, 129.5, 115.8, 112.5, 50.0, 46.5, 36.2, 31.7 ppm. IR (neat, cm−1): 3326, 2919, 1602, 1509, 1427, 1325, 1263, 749, 694.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([OH:25])=O)=[CH:13][C:12]=2[N:11]=1.C(Cl)(=O)C(Cl)=O.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([CH3:43])([CH3:42])[C:40]#[N:41])=[CH:35][CH:34]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:40]([C:39]([C:36]1[CH:35]=[CH:34][C:33]([NH:32][C:23]([C:14]2[C:15]3[O:19][C:18]([CH3:20])=[N:17][C:16]=3[C:21]3[NH:22][C:10]([NH:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])=[N:11][C:12]=3[CH:13]=2)=[O:25])=[CH:38][CH:37]=1)([CH3:43])[CH3:42])#[N:41]
Reactant: Cc1nc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Reactant: CC(C)(C#N)c1ccc(N)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(o1)c(C(=O)Nc1ccc(C(C)(C)C#N)cc1)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Yield: 8.7 %

Procedure:
The title compound was prepared following the procedure described for Example-177 using 7-[(2,6-dichlorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylic acid (Intermediate-55, 0.100 g, 0.265 mmol), oxalyl chloride (0.2 mL), 2-(4-aminophenyl)-2-methylpropanenitrile (Intermediate-22, 0.063 g, 0.397 mmol), THF (5.0 mL), DIPEA (0.103 g, 0.795 mmol) and TEA (0.2 mL). The obtained crude product was further purified by column chromatography on neutral alumina eluting with 1.5-2.0% MeOH:DCM to afford 0.012 g of the desired product. 1HNMR (DMSO-d6): δ 1.69 (s, 6H), 2.66 (s, 3H), 7.42 (t, J=7.8 Hz, 1H), 7.51 (d, J=8.7 Hz, 2H), 7.61 (s, 3H), 7.82 (d, J=9.0 Hz, 2H), 9.45 (s, 1H), 10.11 (s, 1H), 11.58 (s, 1H); MS [M+H]+: 519.32.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:47])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]([C@H:34]4[CH2:39][O:38][CH2:37][CH2:36][N:35]4C(OC(C)(C)C)=O)=[O:33])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:47])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]([C@H:34]4[CH2:39][O:38][CH2:37][CH2:36][NH:35]4)=[O:33])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)[C@H]4COCCN4C(=O)OC(C)(C)C)c3)c3ccccc23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)[C@H]4COCCN4)c3)c3ccccc23)cc1
Yield: 51.3 %

Procedure:
A solution of the carbamate (8) (28 mg, 0.04 mmol) in DCM/TFA (1:1 v/v, 2.0 mL) was stirred at RT for 30 min. The reaction mixture was evaporated in vacuo and the resulting residue was subjected to capture and release on SCX and then triturated from diethyl ether (10 mL) to afford the title compound (Example 10) as an off-white solid (13 mg, 53%): m/z 634 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.26 (9H, s), 2.39 (3H, s), 2.73-2.92 (3H, overlapping m), 3.56-3.64 (4H, overlapping m), 3.82 (1H, m), 5.38 (2H, s), 6.35 (1H, s), 7.00 (1H, d), 7.29 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.58-7.62 (3H, overlapping m), 7.92 (1H, m), 8.28-8.35 (3H, overlapping m), 8.58 (1H, br s), 8.79 (1H, br s), 10.09 (1H, br s) [partial assignment].
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:36])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([C:29]4[N:30]=[CH:31][C:32]([OH:35])=[N:33][CH:34]=4)[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:39]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:36])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([C:29]4[N:30]=[CH:31][C:32](=[O:35])[N:33]([CH3:39])[CH:34]=4)[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cnc(-c2cnc(O)cn2)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cnc(-c2cn(C)c(=O)cn2)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.6 %

Procedure:
1-(benzoyl)-4-[(4-methoxy-7-(2-hydroxyl-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine (6 mg), MeI (5 mg) and K2CO3 (4 mg) were dissolved in acetone (5 ml). The reaction was stirred for four hours at room temperature. After solid was filtered away, the mother liquid was concentrated to give a residue which was purified using a Shimadzu automated preparative HPLC System to provide 3.0 mg of the desired compound, 1-(benzoyl)-4-[(4-methoxy-7-(1-methylpyrazin-2-on-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H)+ Calc'd for C26H25N6O5: 501.19; found 501.14. HPLC retention time: 1.08 minutes (column G).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[S:9][CH:10]=[CH:11][C:5]=2[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3]1.[C:18]12([CH2:28][C:29](O)=[O:30])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2>>[C:18]12([CH2:28][C:29]([NH:1][N:2]3[C:7](=[O:8])[C:6]4[S:9][CH:10]=[CH:11][C:5]=4[C:4]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:3]3)=[O:30])[CH2:25][CH:24]3[CH2:23][CH:22]([CH2:21][CH:20]([CH2:26]3)[CH2:19]1)[CH2:27]2
Reactant: Nn1nc(-c2ccccc2)c2ccsc2c1=O
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1nc(-c2ccccc2)c2ccsc2c1=O

Procedure:
The product from Example 29B and 2-(adamant-1-yl)acetic acid was processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.52-1.81 (m, 12H) 1.95 (s, 3H) 2.07 (s, 2H) 7.46-7.64 (m, 4H) 7.71 (dd, J=7.48, 1.98 Hz, 2H) 8.35 (d, J=5.49 Hz, 1H) 11.36 (s, 1H); MS (ESI) m/z 420 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]([N+:25]([O-])=O)=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH:12]=[CH:11]2)(=[O:3])[CH3:2].C(O)C.[Cl-].[NH4+].O>[Fe]>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]([NH2:25])=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH:12]=[CH:11]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCNc1ccc2c(=O)n(CCOC(C)=O)ccc2c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=O)OCCNc1ccc2c(=O)n(CCOC(C)=O)ccc2c1N
Reaction time: 1 h

Procedure:
A mixture of 2-(2-(2-acetoxyethyl)-5-nitro-1-oxo-1,2-dihydroisoquinolin-6-ylamino)ethyl acetate (350 mg, 0.00093 mol), ethanol (20 mL, 0.3 mol), ammonium chloride (496.1 mg, 0.009275 mol) and water (10 mL, 0.6 mol) was added at 85° C. Iron (207 mg, 0.00371 mol) was added in two portions, five minutes apart, and was stirred at that temperature for 1 hour. The reaction mixture was then poured onto methylene chloride (100 mL) and the layers were separated. The organic layer was washed with brine and dried. the solvent was removed under reduced pressureunder reduced pressure and the product was used in the next step without purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=1[O:17][CH3:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.[CH:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[OH:31])=[CH:12][C:11]=1[O:17][CH3:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: COc1cc(Br)ccc1CO[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(O)c2ccccc2)ccc1CO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To 2-(tert-Butyldimethylsilanyloxymethyl)-5-bromoanisole (500 mg, 1.51 mmol) in THF (10 ml) at -78° C. was added n-BuLi (1.13 ml of a 1.6M solution in penthane, 1.81 mmol) and the mixture allowed to stir for 1 h at -78° C. Benzaldehyde (176 mg, 1.66 mmol) was added and the mixture allowed to warm to room temperature and stirred for 1 h. Water (20 ml) was added and the mixture extracted with ether (3×10 ml). The combined extracts were washed with water (10 ml), brine (10 ml), dried (Na2SO4) and evaporated under reduced pressure. The resulting residue was purified by chromatography (SiO2, 50% ether/petrol) to give the title compound as a colourless oil (303 mg, 56%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[O:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: CCOC(=O)CCc1nc(CCl)co1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: CCOC(=O)CCc1nc(COc2ccc(CCCn3ccnc3)cc2)co1
Yield: 70 %

Procedure:
In substantially the same manner as in Working Example 47, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with ethyl 4-chloromethyl-2-oxazole-propionate to give ethyl 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-oxazolepropionate as an oily product. The yield was 70%.
Reaction SMILES: NC1C=NC=CC=1[C@@H:8]1[O:13][C@H:12]([CH3:14])[C@:11]([OH:16])([CH3:15])[C@H:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:9]1.[CH3:25][N:26]1[C:30](C=O)=[C:29]([N+:33]([O-])=O)[CH:28]=[N:27]1>>[NH2:33][C:29]1[CH:28]=[N:27][N:26]([CH3:25])[C:30]=1[C@@H:8]1[O:13][C@H:12]([CH3:14])[C@:11]([OH:16])([CH3:15])[C@H:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:9]1
Reactant: C[C@H]1O[C@@H](c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@]1(C)O
Reactant: Cn1ncc([N+](=O)[O-])c1C=O
Product: C[C@H]1O[C@@H](c2c(N)cnn2C)C[C@@H](NC(=O)OC(C)(C)C)[C@]1(C)O

Procedure:
Prepared in an analogous manner to tert-butyl ((2R*,3S*,4R*,6R*)-6-(3-aminopyridin-4-yl)-3-hydroxy-2,3-dimethyltetrahydro-2H-pyran-4-yl)carbamate (WO2012/004217), replacing 3-nitroisonicotinaldehyde with 1-methyl-4-nitro-1H-pyrazole-5-carbaldehyde (Intermediate 3).