Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([C:19]3[C:27]([O:28][CH3:29])=[CH:26][C:25]([CH3:30])=[C:24]4[C:20]=3[CH:21]=[CH:22][N:23]4[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH3:18])=[N:14][C:13]=2[CH:38]=1)#[N:8].C1OCCOCCOCCOCCOCCOC1.[C:57]([O:61][CH3:62])(=[O:60])[CH:58]=[CH2:59]>C1COCC1>[C:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]([C:19]3[C:27]([O:28][CH3:29])=[CH:26][C:25]([CH3:30])=[C:24]4[C:20]=3[CH:21]=[CH:22][N:23]4[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])([CH2:59][CH2:58][C:57]([O:61][CH3:62])=[O:60])[CH3:18])=[N:14][C:13]=2[CH:38]=1)#[N:8]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)c1nc2cc(C#N)ccc2o1
Reactant: C=CC(=O)OC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CCC(C)(c1nc2cc(C#N)ccc2o1)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Reaction time: 0.08 h

Procedure:
To a mixture of potassium tert-butoxide (15.60 mg, 0.139 mmol) in THF (329 μl) at −78° C. under nitrogen was added (±)-tert-butyl 4-(1-(5-cyanobenzo[d]oxazol-2-yl)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 150-A) (50 mg, 0.116 mmol) in THF (659 μL). After stirring for 5 min a solution of 18-crown-6 (3.06 mg, 0.012 mmol) in THF (412 μl) that was degassed and placed under nitrogen was added to the mixture at the same temperature and stirred for another 5 min. Then a solution of methyl acrylate (210 μl, 2.318 mmol) in THF (329 μl) was degassed and added dropwise and stirred at the same temp for 30 min. The reaction mixture was allowed to reach rt over 1 hr and then was stirred at rt for 30 hrs. The reaction mixture was quenched with a saturated solution of ammonium chloride, diluted with DCM and water, passed through a phase separator and concentrated to give the title compound that was taken to the next step without further purification. MS (ESI+) m/z 518.5 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:40][CH3:41])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH:27]5[N:30](C(OC(C)(C)C)=O)[CH2:31][CH2:32][CH:26]5[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)Cl.Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:40][CH3:41])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH:27]5[NH:30][CH2:31][CH2:32][CH:26]5[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2C(CCN2C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2NCCC2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.2 %

Procedure:
To a mixture of tert-butyl 5-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy) propyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (0.64 g) in the mixture solvent of CH2Cl2 and MeOH was added a solution of HCl in EtOAC (30 mL). The reaction mixture was stirred at room temperature for another 4 h and filtered to give the title compound as a solid (0.33 g, 62.00%), HPLC: 98.69%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 486.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.45 (m, 2H), 1.78 (m, 3H), 1.80 (m, 2H), 2.10 (m, 1H), 2.42 (m, 5H), 2.72 (m, 3H), 4.03 (s, 3H), 4.10 (m, 2H), 6.76 (s, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.24 (s, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.41 (s, 1H), 8.54 (s, 1H) ppm.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([O:9][C:10]([N:12]1[CH2:18][CH2:17][CH2:16][CH:15]([N:19]([C:35](=[O:37])[CH3:36])[CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[C:14]2[CH:38]=[C:39]([NH2:42])[CH:40]=[CH:41][C:13]1=2)=[O:11])([CH3:8])[CH3:7].N1C=CC=CC=1>ClCCl>[C:35]([N:19]([CH2:20][C:21]1[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1)[CH:15]1[CH2:16][CH2:17][CH2:18][N:12]([C:10]([O:9][CH:6]([CH3:8])[CH3:7])=[O:11])[C:13]2[CH:41]=[CH:40][C:39]([NH:42][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:38][C:14]1=2)(=[O:37])[CH3:36]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccc(N)cc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccc(NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
Add methanesulfonyl chloride (8 μl, 0.103 mmol) dropwise to a suspension of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-amino-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.050 g, 0.094 mmol) and pyridine (8 μl, 0.103 mmol) in dichloromethane (2 mL) at 0° C. under atmosphere of nitrogen. Stir the suspension for 30 min, then remove the cooling bath and warm to room temperature while stirring overnight. Dilute the mixture with dichloromethane (30 mL) and wash with 2 N hydrochloric acid, water, and brine (10 mL each). Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with ethyl acetate/hexanes (10:1 to 1:2), to provide the title compound as a white solid (0.037 g, 65%): ESI MS 610 (M+H).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:26])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](O)=[O:24])[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][N:28]1CCOCC1.ClC(OCC(C)C)=O>C1COCC1>[CH2:1]([NH:8][C:9](=[O:26])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:24])[NH:28][CH3:27])[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Oc2ncccc2C(=O)NCc2ccccc2)c1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccccc2)c1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
N-Benzyl 2-(3-carboxyphenoxy)nicotinamide (1.00 gram, 2.87 mmol) is placed into a 100 ml 3-neck round bottom flask equipped with magnetic stir bar, thermometer, nitrogen inlet and a rubber septum. The flash is charged with 15 ml of THF and N-methylmorpholine (0.29 grams, 2.87 mmol) is added via syringe. The reaction is chilled to -10° C. and isobutyl chloroformate 0.39 grams, 2.87 mmol) added to the reaction via syringe while maintaining the temperature at less than 0° C. The reaction is stirred at -10° C. for 30 minutes. Monomethylamine gas is bubbled into the reaction via syringe while maintaining the temperature below 0° C. The reaction is allowed to slowly warm to room temperature. After stirring for 21/2hours, water (20 ml) is added to the reaction which is then extracted with ethyl acetate (2×100 ml). The organics are combined and washed with 2N sodium hydroxide (4×75 ml) and (1×100 ml) water. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield a paste. The crude product is purified by trituration with diethyl ether to yield 0.63 grams (60.6%) of the title product as a white solid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5].[NH:13]([CH2:17][CH2:18][OH:19])[CH2:14][CH2:15][OH:16]>>[NH2:10][C:7]1[CH:8]=[CH:9][C:2]([N:13]([CH2:17][CH2:18][OH:19])[CH2:14][CH2:15][OH:16])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: OCCNCCO
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Product: N#Cc1cc(N)ccc1N(CCO)CCO
Yield: 77.7 %

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthetic Example 4 using 2-chloro-5-nitrobenzonitrile (25.5 g) and diethanolamine (102 g), the title compound (24 g) was obtained. melting point: 38° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]3[N:14]=[C:15]4[C:21]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])=[CH:20][N:19](COCC[Si](C)(C)C)[C:16]4=[N:17][CH:18]=3)=[N:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]3[N:14]=[C:15]4[C:21]([C:22]([NH:24][CH:25]([CH3:26])[CH3:27])=[O:23])=[CH:20][NH:19][C:16]4=[N:17][CH:18]=3)=[N:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)C)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: CCn1nc(-c2cnc3[nH]cc(C(=O)NC(C)C)c3n2)c2ccc(Cl)cc21
Reaction time: 4 h
Yield: 90.8 %

Procedure:
2-(6-Chloro-1-ethyl-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (78 mg, 152 μmol) was dissolved in dichloromethane and to this was added trifluoroacetic acid (1.73 g, 1.17 mL, 15.2 mmol). The mixture was stirred for 4 h then concentrated en vacuo. The residue was diluted in dichloromethane and re-concentrated, and finally diluted again in dichloromethane and to this was added ethylenediamine (685 mg, 770 μL, 11.4 mmol). After 15 h the mixture was concentrated in vacuo, triturated with water and the collected solid was filtered and dried. The solid was purified by chromatography (Silica, SiliCycle 25 g cartridge, 0-5% methanol in dichloromethane, 15 min gradient) to give 2-(6-chloro-1-ethyl-1H-indazol-3-yl)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (53 mg, 138 μmol, 91.1%) as a pale yellow powder. MS (M+H)+=383; 1H NMR (CDCl3) δ: 11.74 (br. s., 1H), 9.11-9.15 (m, 1H), 8.41 (d, J=8.7 Hz, 1H), 8.20 (d, J=3.0 Hz, 1H), 8.14 (d, J=7.9 Hz, 1H), 7.44 (s, 1H), 7.15 (dd, J=8.5, 1.3 Hz, 1H), 4.28-4.48 (m, 3H), 1.53 (t, J=7.2 Hz, 3H), 1.33 (d, J=6.4 Hz, 6H)
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([N:20]=[C:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:13]=2)[C:9](=[O:34])[CH2:8][N:7](C(OCC=C)=O)[CH2:6]1)=[O:4].N1CCOCC1>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([CH:5]1[CH2:6][NH:7][CH2:8][C:9](=[O:34])[N:10]1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([N:20]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:13]=1)=[O:4]
Reactant: C=CCOC(=O)N1CC(=O)N(Cc2ccc(C#N)c(N=C(c3ccccc3)c3ccccc3)c2)C(C(=O)OC)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: ClCCl
Product: COC(=O)C1CNCC(=O)N1Cc1ccc(C#N)c(N=C(c2ccccc2)c2ccccc2)c1
Reaction time: 0.08 h
Yield: 97 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (237 mg, 0.2 mmol) is added to a solution containing (±)-4-[3-(benzhydrylidene-amino)-4-cyano-benzyl]-5-oxo-piperazine-1,3-dicarboxylic acid 1-allyl ester 3-methyl ester (1.10 g, 2.05 mmol) and morpholine (894 mg, 10.2 mmol) in CH2Cl2 (30 mL). After ˜5 min, the reaction mixture is absorbed onto silica gel and chromatographed (CH2Cl2 to 10% MeOH/CH2Cl2) to provide 900 mg (97%) of the title compound as a viscous yellow oil. 1H NMR (300 MHz, CDCl3) δ1.83 (br s, 1H), 2.95 (dd, J=13.5, 4.3 Hz, 1H), 3.27 (br d, J=13.5 Hz, 1H), 3.46-3.72 (m, 4H), 3.73 (s, 3H), 5.40 (d, J=15.3 Hz, 1H), 6.57 (br s, 1H), 6.83 (dd, J=8.0, 1.2 Hz, 1H), 7.17-7.50 (m, 9H), 7.75-7.77 (m, 2H) ppm; MS (ion spray): m/z 453 (M+H).
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21](Br)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[OH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:28]4[CH:29]=[CH:30][C:25]([CH2:24][OH:23])=[CH:26][CH:27]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: OCc1ccc(B(O)O)cc1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3ccc(CO)cc3)c2s1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
60 mg (0.15 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 22.7 mg (0.15 mmol) of 4-(hydroxymethyl)phenylboronic acid are introduced into 1 ml of DMF. Addition of 0.22 ml of 2 M aqueous sodium carbonate solution and 6.1 mg (0.01 mmol) of PdCl2(dppf) is followed by heating to 80° C. After 14 h, the reaction mixture is filtered through kieselguhr and evaporated to dryness. The crude product is purified by preparative HPLC. The product is dissolved in methanol and an excess of 4N hydrogen chloride in dioxane is added. Drying under high vacuum results in 9 mg (9% of theory) of the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].[Cl:28][C:29]1[N:34]=[CH:33][C:32]([NH2:35])=[C:31]([CH3:36])[CH:30]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C2C=CC=CC=2)C=CC=C(P(C(C)(C)C)C(C)(C)C)C=1>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([NH:35][C:32]3[CH:33]=[N:34][C:29]([Cl:28])=[CH:30][C:31]=3[CH3:36])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reactant: Cc1cc(Cl)ncc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1cccc(-c2ccccc2)c1)C(C)(C)C
Solvent: C1COCCO1
Product: Cc1cc(Cl)ncc1Nc1ncnc(OC2CCN(C(=O)OC(C)C)CC2)c1C
Temperature: 120 °C
Yield: 29.1 %

Procedure:
A mixture of 4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (1.80 g, 5.74 mmol), palladium acetate (155 mg, 0.69 mmol), biphenyl-3-yl-di-tert-butyl-phosphane (21.5 mg, 0.072 mmol), sodium tert-butoxide (1.38 g, 14.4 mmol), and 6-chloro-4-methyl-pyridin-3-ylamine (838 mg, 5.80 mmol) in 20 mL dioxane was heated in microwave for 1 hour at 120° C. Solids were filtered off and mixture was purified by column chromatography (hexane/AcOEt) to give Compound A98 as a tanned solid (702 mg, 29%). 1H NMR (CDCl3, 400 MHz) δ 1.24-1.26 (d, 6H), 1.72-1.81 (m, 2H), 1.95-2.02 (m, 2H), 2.10 (s, 3H), 2.27 (s, 3H), 3.37-3.43 (m, 2H), 3.74-3.77 (m, 2H), 4.90-4.97 (m, 1H), 5.29-5.34 (m, 1H), 5.91 (s, 1H), 7.00 (s, 1H), 8.22 (s, 1H), 8.57 (s, 1H). Exact mass calculated for C20H26ClN5O3 419.17, found 420.4 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:10]([Cl:20])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]([C:33]3[N:37]([CH3:38])[CH:36]=[N:35][CH:34]=3)([C:23]3[CH:24]=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=3)[OH:22])[CH:8]=2)[N:3]=1.[O-:39][CH2:40][CH3:41].[Na+]>>[Cl:20][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]([C:33]3[N:37]([CH3:38])[CH:36]=[N:35][CH:34]=3)([C:23]3[CH:24]=[N:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=3)[OH:22])[CH:8]=2)[N:3]=[C:2]([O:39][CH2:40][CH3:41])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(Oc3ccc(F)cc3)c(Cl)c2c1
Reactant: CC[O-]
Agent: [Na+]
Product: CCOc1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1Oc1ccc(F)cc1

Procedure:
The title compound was prepared using (2,4-dichloro-3-(4-fluorophenoxy)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (Example 11) in place of (4-chlorophenyl)(2,4-dichloro-3-phenoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (Example 1) according to the procedure of Example 2a except only one equivalent of sodium ethoxide was used. 1H NMR (400 MHz, MeOH-d4) δ 8.78 (d, J=1.96 Hz, 1H), 8.14 (d, J=1.96 Hz, 1H), 8.02 (dd, J=2.20, 8.31 Hz, 1H), 7.88 (d, J=8.56 Hz, 1H), 7.84 (d, J=8.31 Hz, 1H), 7.74 (s, 1H), 7.66 (dd, J=2.20, 8.80 Hz, 1H), 6.97-7.07 (m, 2H), 6.87 (dd, J=4.28, 9.17 Hz, 2H), 6.36 (s, 1H), 4.47 (q, J=7.09 Hz, 2H), 3.49 (s, 3H), 1.23 (t, J=7.09 Hz, 3H); MS m/e 574.2 [M+H]+.
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH:10]([C:16](=[O:21])[NH:17][CH2:18][C:19]#[N:20])[CH2:11][S:12][C:13](=O)[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[C:24]([C:26]1[CH:27]=C([CH:31]=[CH:32][CH:33]=1)CBr)#[N:25]>CN(C)C=O.O>[CH2:1]([S:8][CH2:9][CH:10]([CH2:11][S:12][CH2:13][C:14]1[CH:31]=[CH:32][CH:33]=[C:26]([C:24]#[N:25])[CH:27]=1)[C:16]([NH:17][CH2:18][C:19]#[N:20])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC(=O)SCC(CSCc1ccccc1)C(=O)NCC#N
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCNC(=O)C(CSCc1ccccc1)CSCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.8 %

Procedure:
A solution of thioacetic acid S-[3-benzylsulfanyl-2-(cyanomethyl-carbamoyl)propyl] ester (0.105 g) in dimethylformamide (1 mL) and water (0.8 mL) was cooled on ice and treated with 1 N aqueous potassium hydroxide (0.65 mL). 3-Cyanobenzylbromide (0.129 g) in dimethylformamide (0.8 mL) was added. The reaction mixture was allowed to warm to room temperature while stirring overnight. The reaction mixture was then poured into ice water and extracted with ethyl acetate (50 mL) and washed with water and saturated aqueous sodium chloride. The solution was dried over magnesium sulfate and evaporated to give 2-benzylsulfanylmethyl-3-(3-cyano-benzylsulfanyl)-N-cyanomethyl-propionamide (0.135 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:59][CH3:60])[C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=[O:58])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][OH:57])[CH:33]=2)=[C:8]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][N:29]=2)[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:14])[CH:9]=1)[CH3:2].C(N(CC)CC)C.[C:68]1([CH3:78])[CH:73]=[CH:72][C:71]([S:74](Cl)(=[O:76])=[O:75])=[CH:70][CH:69]=1>C(Cl)Cl>[CH3:78][C:68]1[CH:73]=[CH:72][C:71]([S:74]([O:57][CH2:56][CH2:55][O:54][CH2:53][CH2:52][O:51][CH2:50][CH2:49][O:48][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([C:31](=[O:58])[NH:30][C:7]3[CH:6]=[CH:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:59][CH3:60])=[CH:9][C:8]=3[C:10]3[CH:11]=[C:12]([C:13](=[O:14])[NH:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:27]=[CH:28][N:29]=3)[CH:33]=2)(=[O:76])=[O:75])=[CH:70][CH:69]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(COCCOCCOCCOCCOCCOCCO)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(NC(=O)c2cccc(COCCOCCOCCOCCOCCOCCOS(=O)(=O)c3ccc(C)cc3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 16 h

Procedure:
To a mixture of Example 168 (500 mg, 0.595 mmol) and triethylamine (167 μL, 1.19 mmol) in DCM (3 mL) was added p-toluenesulfonyl chloride (136 mg, 0.714 mmol) in several portions and the solution stirred for 16 h. The solution was then diluted with DCM and washed with aqueous HCl and H2O, then dried over Na2SO4 and the solvent removed. The residue was purified by silica gel chromatography, using a gradient of 20% to 100% EtOAc in hexanes as eluent and the solvent removed. This gave 560 mg (95%) of the product as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][N:3]=1.[Br:13]Br.C([O-])([O-])=O.[K+].[K+].[O-]S([O-])=O.[Na+].[Na+]>CO.CC(C)=O.C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([Br:13])[C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: COc1ccc2c(N)noc2c1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(C)=O
Product: COc1cc2onc(N)c2cc1Br
Temperature: 25 °C
Yield: 67.7 %

Procedure:
To a stirred solution of 3-amino-6-methoxy-1,2-benzisoxazole (14 g) in methanol (1 L) was added a solution of bromine (13.6 g) and methanol (200 ml) dropwise at -50° C. under N2. The mixture was allowed to warm to room temperature after the addition was complete. After 24 hours an additional 1/4 equivalent of bromine was added. TLC (10% acetone/CHCl3) showed no starting material 24 hours later. The reaction was neutralized with saturated K2CO3 solution, treated with saturated Na2SO3 solution triturated with water, filtered, and washed with water. The crude product was dried in vacuo affording 14 g of product, m.p. 226°-227° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[H-].[Na+].[C:13]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C>O1CCCC1>[NH2:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([NH:1][C:21]([C:20]2[CH:24]=[CH:25][C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:18][CH:19]=2)=[O:22])[CH:7]=1
Reactant: CSc1nc(N)cc(N)n1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CSc1nc(N)cc(NC(=O)c2ccc(C(C)(C)C)cc2)n1
Temperature: 50 °C

Procedure:
To a solution of 4,6-diamino-2-methylmercaptopyrimidine (50 mg, 0.032 mmol) in anhydrous tetrahydrofuran was added sodium hydride, followed by the addition of 4-t-butylbenzoyl chloride (0.084 mL, 0.32 mmol) and N, N-diisopropylethylamine. The mixture was heated at 50° C. for 16 hours after which it was subjected to aqueous work up. The product was extracted with ethyl acetate and purified by HPLC to give N-(6-amino-2-methylthiopyrimidin-4-yl)[4-(tert-butyl)phenyl]carboxamide. M+1=317.3.
Reaction SMILES: NCCC1C=CC(S(C2CCN(C(NCCCCCC)=O)CC2)(=O)=O)=CC=1.[Si]([O:45][C:46]1[CH:83]=[CH:82][C:49]([O:50][CH2:51][C@@H:52]([OH:81])[CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([S:63]([CH:66]3[CH2:71][CH2:70][N:69]([C:72]([NH:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH3:80])=[O:73])[CH2:68][CH2:67]3)(=[O:65])=[O:64])=[CH:59][CH:58]=2)=[CH:48][CH:47]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C([Si](OC1C=CC(OCC2CO2)=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[CH2:75]([NH:74][C:72]([N:69]1[CH2:68][CH2:67][CH:66]([S:63]([C:60]2[CH:61]=[CH:62][C:57]([CH2:56][CH2:55][NH:54][CH2:53][C@H:52]([OH:81])[CH2:51][O:50][C:49]3[CH:48]=[CH:47][C:46]([OH:45])=[CH:83][CH:82]=3)=[CH:58][CH:59]=2)(=[O:65])=[O:64])[CH2:71][CH2:70]1)=[O:73])[CH2:76][CH2:77][CH2:78][CH2:79][CH3:80]
Reactant: CCCCCCNC(=O)N1CCC(S(=O)(=O)c2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3)cc2)CC1
Agent: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Agent: CCCCCCNC(=O)N1CCC(S(=O)(=O)c2ccc(CCN)cc2)CC1
Product: CCCCCCNC(=O)N1CCC(S(=O)(=O)c2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 24.3 %

Procedure:
4-{[4-(2-{[(2S)-3-(4-{[tert-butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)phenyl]sulfonyl}-N-hexyl-1-piperidinecarboxamide 4-{[4-(2-aminoethyl)phenyl]sulfonyl}-N-hexyl-1-piperidinecarboxamide (0.53 g, 1.34 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenylsilane (0.461 g, 1.14 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.260 g, 0.325 mmol).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:17])([CH2:14][CH2:15][OH:16])[CH2:12][OH:13].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:16][CH2:15][CH2:14][C:11]([CH3:17])([CH3:10])[CH2:12][OH:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CO)CCO
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CO)CCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
Benzoyl chloride (3.13 mL) was added to a cooled (−78° C.) solution of 2,2-dimethylbutane-1,4-diol from Step 1 (3.18 g), triethylamine (7.5 mL) and 4-(dimethylamino)pyridine (0.05 g) in dichloromethane (100 mL). The mixture was then slowly warmed up to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo and the compound was purified by silica gel chromatography (hexanes/ethyl acetate 95:5 to 60:40) to afford 3,3-dimethyl-4-hydroxy-1-butyl benzoate (2.6 g, 44% yield) as a colorless oil.