Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.[C:4](Cl)([CH3:7])([CH3:6])[CH3:5].C([Mg]Cl)(C)(C)C.[C:15]1([Si:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(Cl)[Cl:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Cu].COCCOC>[C:4]([Si:21]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[Cl:22])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)Cl
Agent: [Cu]
Agent: CC(=O)/C=C(/C)O
Agent: CC(C)(C)[Mg]Cl
Solvent: COCCOC
Product: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
48.6 g (2.0 mol) of magnesium filings and a spatula-tip of iodine are initially introduced into a 2 1 three-necked flask with a precision glass stirrer, straight enclosed-scale thermometer, Dimroth condenser and dropping funnel under a blanket of inert gas. By addition of 600 ml of ethylene glycol dimethyl ether and 203.7 g (2.2 mol) of tert-butyl chloride, tert-butylmagnesium chloride is prepared. Initially 5.2 g (0.02 mol) of copper(II) acetylacetonate and then, at 50° C. over 2 hours, 455.8 g (1.8 mol) of diphenyldichlorosilane are subsequently added dropwise. The internal temperature of the flask rises slightly, and the mixture is subsequently stirred at 70° C. for a further 3 hours to bring the reaction to completion. To remove the precipitated magnesium salt from the solution, the reaction mixture is filtered through a pressure suction filter maintained under an argon atmosphere. The filter cake is rinsed with ethylene glycol dimethyl ether. A concluding fractional distillation of the combined filtrates in vacuo gives 420.6 g of tert-butyldiphenylchlorosilane (85% yield, based on the diphenyldichlorosilane) as a colorless liquid in a GC purity of 92%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:12])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH:10]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)([CH3:12])[CH3:9]
Reactant: Cc1ccc(N)cc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1ccc(NC(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
To a stirred solution of 5.65 g (52.7 mmol) p-Toluidine and 3.21 g (55.4 mmol, 1.05 equiv) Acetone in 50 mL DCE is added 14.52 g (68.5 mmol, 1.3 equiv) Sodium triacetoxyborohydride and stirred 18 h at ambient temperature. The reaction mixture is diluted with DCM (200 mL), washed successively with H2O (75 mL), satd. NaHCO3 (75 mL), and brine (75 mL), dried (MgSO4), filtered and concentrated in vacuo to give 7.67 g (51.4 mmol) of Isopropyl-p-tolyl-amine as a pale amber oil: 1H NMR (CDCl3, 300 MHz) δ7.00 (d, 2H, J=8.3), 6.54 (d, 2H, J=8.4), 3.61 (m, 1H), 2.25 (s, 3H), 1.21 (d, 6H, J=6.3); TLC Rf =0.50 (EtOAc/Hexanes, 1:9).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH2:9])[CH:8]=1.Br[C:23]1[CH:37]=[CH:36][C:26]([O:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH:9][C:23]2[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[CH:36][CH:37]=2)[CH:8]=1
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Reactant: Brc1ccc(OCCN2CCCCC2)cc1
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1Nc1ccc(OCCN3CCCCC3)cc1)C2
Yield: 72.4 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (150 mg) and 1-[2-(4-bromophenoxy)ethyl]piperidine (150 mg) according to an analogous synthetic method to Example 116, the title compound (186 mg) was obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([O:17][C:18]2[CH:23]=[C:22]([O:24][CH2:25][CH3:26])[CH:21]=[C:20]([O:27][CH2:28][CH3:29])[CH:19]=2)[C:14](O)=[O:15])=[CH:9][CH:8]=1>[Cl-].[Zn+2].[Cl-]>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[C:14](=[O:15])[C:19]3[C:20]([O:27][CH2:28][CH3:29])=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[CH:23][C:18]=3[O:17]2)=[CH:9][CH:8]=1
Reactant: CCOc1cc(OCC)cc(OC(C(=O)O)c2ccc(Br)cc2)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1cc(OCC)c2c(c1)OC(c1ccc(Br)cc1)C2=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
38 ml (407 mmol) of phosphoryl chloride are added to 16.1 g (40.7 mmol) of (4-bromophenyl)-(3,5-diethoxyphenoxy)acetic acid under argon at RT. The mixture is cooled to 0° C., and 8.32 g (61.0 mmol) of zinc chloride are added. After 10 min, the ice bath is removed and the mixture is stirred at RT overnight. The reaction mixture is poured into a large amount of ice-water and stirred for 15 min. Dichloromethane is added, the phases are separated, and the organic phase is washed with water, dried over sodium sulfate, filtered and concentrated. Gradient chromatography on silica gel 60 (mobile phase: toluene/ethyl acetate) results in 10.2 g (67% of theory) of the product.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:3]=1[CH:4]=[O:5].CC1(C)C(C)(C)OB([C:23]2[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:30])=[N:27][CH:28]=2)O1>O1CCOCC1.O.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]>[Cl:14][C:6]1[C:3]([CH:4]=[O:5])=[C:2]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:30])=[N:27][CH:28]=2)[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(Cl)c2C=O)cn1
Temperature: 90 °C

Procedure:
2,6-Dichloro-4-(trifluoromethyl)benzaldehyde (3.2 g, 13.2 mmol), ethyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamido)propanoate (1.5 g, 4.4 mmol), Pd(dppf)Cl2 (320 mg, 0.4 mmol) and K3Pa4hydrate (3.0 g, 13.2 mmol) were dissolved in 1,4-dioxane (200 mL) and the resulting mixture was heated to 90° C. After 10 h the resulting mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [OH:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[C:41]([C:42](Cl)=[O:43])=[C:40]([CH3:45])[O:39][N:38]=1>>[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[C:41]([C:42]([O:1][CH:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:13]=3)[CH2:10][CH2:11]2)=[O:43])=[C:40]([CH3:45])[O:39][N:38]=1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(O)c3ccccc3)CC2)c1
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)OC(CCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(4-hydroxy-4-phenylbutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2-chlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 614.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3=[N:19][CH:20]=[C:21]([NH2:24])[C:22]([CH3:23])=[C:17]3[N:16]=[C:15]2[CH2:25][CH3:26])=[CH:10][CH:9]=1)(=[O:4])[CH2:2][CH3:3].N1C=CC=CC=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[C:1]([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3=[N:19][CH:20]=[C:21]([NH:24][S:34]([CH3:33])(=[O:36])=[O:35])[C:22]([CH3:23])=[C:17]3[N:16]=[C:15]2[CH2:25][CH3:26])=[CH:10][CH:9]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)OCCc1ccc(-n2c(CC)nc3c(C)c(N)cnc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)OCCc1ccc(-n2c(CC)nc3c(C)c(NS(C)(=O)=O)cnc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.9 %

Procedure:
To a stirred solution of 2-[4-(6-amino-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl propionate (step 4, 1.0 g, 3.0 mmol) and pyridine (280 mg, 3.5 mmol) in dichloromethane (18 mL) was added methanesulfonyl chloride (372 mg, 3.3 mmol) at 0° C., and the mixture was stirred at room temperature for 16 h. The reaction was quenched with water (10 mL), and the mixture was extracted with dichloromethane (50 mL). The organic layer was washed with brine (50 mL), dried (MgSO4), and concentrated. Purification by flash column chromatography on silica gel eluting with ethyl acetate (gradient elution from 1:1 to 1:2) afforded 890 mg (70%) of the title compound as an amber oil: 1H-NMR (CDCl3) δ 8.26 (1H, s), 7.43 (2H, d, J=8.4 Hz), 7.32 (2H, d, J=8.2 Hz), 7.00 (1H, br.s), 4.35 (2H, t, J=7.0 Hz), 3.03–3.01 (5H, m), 2.85 (2H, q, J=7.5 Hz), 2.75 (3H, s), 2.35 (2H, q, J=7.5 Hz), 1.30 (3H, t, J=7.5 Hz), 1.14 (3H, t, J=7.5 Hz).
Reaction SMILES: O=S(Cl)Cl.C([N:12]1[CH2:19][C@H:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])(OC(C)(C)C)=O.[CH3:29]O>>[CH3:29][O:16][C:14](=[O:15])[C@@H:13]1[CH2:17][C@@H:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[CH2:19][NH:12]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccc(Br)cc2)C[C@H]1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1C[C@@H](OCc2ccc(Br)cc2)CN1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
SOCl2 (0.27) was carefully added dropwise to 2.7 mL of MeOH at −5° C. To this mixture was added trans-N-Boc-4-(4-bromo-benzyloxy)-L-proline (0.25 g) in 2.7 mL of MeOH. The reaction mixture was allowed to warm to 20° C. and stirred overnight. The solvent was evaporated under reduced pressure and the residue dissolved in DCM. The organic layer was washed with water, dried over MgSO4, and evaporated in vacuo to afford the above-titled compound (60 mg). NMR (CDCl3, 200 MHz): 7.45 (2H, d), 7.2 (2H, d), 4.44 (2H, s), 4.15-4.05 (1H, m), 4.0 (1H, t), 3.7 (3H, s), 3.2-3.05 (2H,m), 2.27 (1H, dd), 2.05-1.9 (1H, m).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([C:12]([NH2:14])=O)[CH:10]=2)[CH:5]=[C:4]([NH:17][C:18]2[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([C:12]#[N:14])[CH:10]=2)[CH:5]=[C:4]([NH:17][C:18]2[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=2)[N:3]=1
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(O)c2cc1C(N)=O
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1C#N
Temperature: 130 °C
Yield: 70 %

Procedure:
A mixture of 1-Hydroxy-6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-7-carboxylic acid amide (0.4 g, 1.28 mmol) in POCl3 (10 ml) was sealed in microwave process vial (20 ml). The mixture was heated at 130° C. for 30 minutes under microwave irradiation. The mixture was concentrated, and the residue was poured into ice water, and the precipitate was collected and purified by preparative HPLC to give product (0.28 g, 70%). LC-MS: m/e 314 (MH+).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[C:12]1([CH3:18])[CH:17]=CC=[CH:14][CH:13]=1>>[C:3]([C:2]1([C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH2:14][CH:13]1[C:12](=[CH2:17])[CH3:18])(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: C=C(C)C1CC1(C(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Ethyl acetoacetate (125.8 g) in 400 ml of toluene was added dropwise to a suspension of sodium hydride (68.3 g of a 60% oil dispersion washed with pentane) in 1 L of toluene under an N2 blanket at -6° C. to 2° C. After 20 minutes, 1,4-dibromo-2-methyl-2-butene (220.6 g) in 300 ml of toluene was added dropwise at -2° C. to 0° C. The reaction mixture was allowed to warm to ambient temperature and after 22 hours, was diluted with water and extracted with ethyl acetate (thrice). The combined organic extracts were washed with water, brine, dried and concentrated in vacuuo. GLC of the crude material indicated 77% of the two desired isomers. The isomers were separated by flash chromatography using 7.5% ethyl acetate in hexane, giving ca 90% pure isomers.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[C:7](Cl)(=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[C:7]([NH:1][C@@H:2]([CH3:3])[C:4]([OH:6])=[O:5])(=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C[C@H](N)C(=O)O
Reactant: CCCCCC(=O)Cl
Product: CCCCCC(=O)N[C@@H](C)C(=O)O

Procedure:
L-Alanine (10 mmol) and hexanoyl chloride (11 mmol) were reacted using the method described in Example 5 Part A to give the title compound as a white crystalline material (1.091 g, 58%) after recrystallization from isopropyl ether (~6 ml).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([C:31]([O:33][CH3:34])=[O:32])=[N:17][N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([F:30])[CH:23]=3)[C:19](=[O:21])[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35].O1CCOCC1.CCOCC>C(Cl)Cl>[ClH:35].[C:28]([C:25]1[CH:26]=[CH:27][C:22]([N:18]2[C:19](=[O:21])[CH:20]=[C:15]([O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:16]([C:31]([O:33][CH3:34])=[O:32])=[N:17]2)=[CH:23][C:24]=1[F:30])#[N:29]
Reactant: COC(=O)c1nn(-c2ccc(C#N)c(F)c2)c(=O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)c1nn(-c2ccc(C#N)c(F)c2)c(=O)cc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyano-3-fluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate (142 mg, 0.30 mmol) in DCM (3 mL) at room temperature under argon was added 4 M HCl in dioxane (0.375 mL, 1.5 mmol). The reaction mixture was stirred at room temperature overnight. Et2O (10 mL) was added to the reaction mixture. The solid product was collected by filtration and further washed with ether (2 mL×2). After drying under reduced pressure for 2 hours, 105 mg of methyl 1-(4-cyano-3-fluorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carboxylate HCl salt was obtained as an off-white solid. MS (ESI) 373 (M+H).
Reaction SMILES: [CH:1]1([C:7]2[N:11]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:10]([CH3:21])=[C:9]([C:22]([O:24]CC)=[O:23])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([C:7]2[N:11]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:10]([CH3:21])=[C:9]([C:22]([OH:24])=[O:23])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(C2CCCCC2)n(CCc2ccc(F)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(=O)O)cc(C2CCCCC2)n1CCc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 40 h

Procedure:
A 2.987 g portion of ethyl 5-cyclohexyl-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylate was dissolved in 16 ml of ethanol, and 13.37 ml of a 5 M sodium hydroxide aqueous solution was added thereto, followed by stirring at 80° C. for 40 hours. The reaction liquid was concentrated under a reduced pressure, and water was added to the residue. After washing with diethyl ether, 37% hydrochloric acid was added thereto until pH became 1. The resulting solid was collected by filtration and washed with water to obtain 1.859 g of 5-cyclohexyl-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylic acid as a light brown solid.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:14])=[CH:9][N:10]2[CH3:13])=[CH:6][C:5]=1[O:15][C:16](=[CH:19]COC)[C:17]#[N:18])([CH3:3])[CH3:2].C(=O)(O)O.[NH2:27][C:28]([NH2:30])=[NH:29].C[O-].[Na+].Cl>C(O)C.C(OCC)C>[CH:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:14])=[CH:9][N:10]2[CH3:13])=[CH:6][C:5]=1[O:15][C:16]1[C:17]([NH2:18])=[N:29][C:28]([NH2:30])=[N:27][CH:19]=1)([CH3:2])[CH3:3]
Reactant: COCC=C(C#N)Oc1cc2c(C)cn(C)c2cc1C(C)C
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: O=C(O)O
Solvent: CCOCC
Solvent: CCO
Product: Cc1cn(C)c2cc(C(C)C)c(Oc3cnc(N)nc3N)cc12
Reaction time: 18 h

Procedure:
5-(6-Isopropyl-1,3-dimethyl-1H-indol-5-yloxy)-pyrimidine-2,4-diamine was prepared from 2-(6-isopropyl-1,3-dimethyl-1H-indol-5-yloxy)-4-methoxy-but-2-enenitrile by treatment with guanidine carbonate and sodium methoxide using the procedure of step 7 of Example 2 above. This material was dissolved in 2.5 ml absolute ethanol, and 820 ml of 1 N HCl in diethyl ether was added with stirring. Diethyl ether was added slowly until small crystals formed, and the solution was then placed in a −10 C freezer for 18 hours. The solid that had formed was collected by filtration, washed with diethyl ether, and dried under vacuum at 45 C. to give 171 mg. of the hydrochloride salt, Mp: 185.1° C.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][O:8][CH:7]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[O:6][CH2:5]1)[CH2:2][CH3:3].C([Li])CCC.Br[C:24]1[CH:29]=[C:28]([F:30])[C:27]([C:31]([F:34])([F:33])[F:32])=[C:26]([F:35])[CH:25]=1.O>C1COCC1.CCCCCC.[Cl-].[Zn+2].[Cl-]>[CH2:1]([CH:4]1[CH2:5][O:6][CH:7]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([C:24]3[CH:25]=[C:26]([F:35])[C:27]([C:31]([F:32])([F:33])[F:34])=[C:28]([F:30])[CH:29]=3)=[C:12]([F:17])[CH:11]=2)[O:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: Fc1cc(Br)cc(F)c1C(F)(F)F
Reactant: CCCC1COC(c2cc(F)cc(F)c2)OC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC1COC(c2cc(F)c(-c3cc(F)c(C(F)(F)F)c(F)c3)c(F)c2)OC1
Temperature: -60 °C
Reaction time: 1.5 h
Yield: 24.3 %

Procedure:
5-Propyl-2-(3,5-difluorophenyl)-1,3-dioxane (5.0 g; 20.6 mmol), which had been synthesized in Step 1 of Example 1, was dissolved in THF (50 ml), and the solution was cooled to -60° C. in a nitrogen atmosphere. A solution (16.1 ml; 25.8 mmol) of 1.60M n-butyl lithium in hexane was added dropwise thereto so that the temperature of the mixture did not exceed -45° C. The mixture was stirred for 1.5 hours with the temperature being maintained below -45° C. Subsequently, a solution (51.6 ml; 25.8 mmol) of 0.5M zinc chloride in THF was added dropwise so that the temperature, of the mixture did not exceed -50° C. Thereafter, the mixture was warmed to room temperature and stirred for 30 minutes. Tetrakistriphenylphosphine palladium (0.5 g) and 1-bromo-3,5-difluoro-4-trifluoromethylbenzene (6.73 g; 25.8 mmol) were added, and the mixture was refluxed for 2 hours and 20 minutes. Water (100 ml) was added to the resultant reaction mixture, and the material produced was extracted with toluene. The extract was sequentially washed with saturated aqueous ammonium chloride solution, saturated sodium bicarbonate solution, and saturated brine, and then dried over magnesium sulfate. Subsequently, the solvent was evaporated. The residue was purified by column chromatography (eluent: toluene). The solvent was evaporated, and the residue was recrystallized twice from heptane, to thereby obtain 2.1 g (5.0 mmol) of 5-propyl-2-(4-(3,5-difluoro-4-trifluoromethylphenyl)-3,5-difluorophenyl)-1,3-dioxane. The yield of this compound from 5-propyl-2-(3,5-difluorophenyl)-1,3-dioxane was 24.3%.
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH:5]=[N:6][C:2]([C:25]3[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=3)=[N:3]2)=[CH:8][CH:9]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-n2cnc(Br)n2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 120 °C
Yield: 74.5 %

Procedure:
To 3-bromo-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole (5.64 g, 18.35 mmol) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (7.42 g, 33.9 mmol), tetrakis(triphenylphosphine) palladium(0) (3.30 g, 2.86 mmol), and potassium carbonate (7.82 g, 56.6 mmol) in 1,2-dimethoxyethane (75 mL) and water (18 mL). The mixture was degassed with nitrogen for 10 minutes. The reaction mixture was heated at 120° C. for 20 h. The reaction was cooled to room temperature and diluted with ethyl acetate (100 mL). The resultant salts were filtered and the filtrated layers were separated. The aqueous layer was separated with ethyl acetate (2×25 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated onto Celite®. Purification by silica gel chromatography using 0-100% ethyl acetate/hexanes as eluent provided the title compound as a yellow solid (4.16 g, 68%): 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.03-7.97 (m, 2H), 7.88 (d, J=8.4 Hz, 2H), 7.77 (d, J=8.5 Hz, 2H), 6.79-6.74 (m, 2H), 3.88 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 163.94, 148.07, 139.68, 129.67, 129.34, 128.04, 127.07, 127.04, 127.00, 126.96, 125.05, 120.50, 119.35, 114.87; 19F NMR (376 MHz, CDCl3) δ −62.43; ESIMS m/z 305.1 ([M+H]+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH3:13])=[CH:5][C:6]([CH2:11][OH:12])=[N:7][C:8]=1[O:9][CH3:10].[Br:14][C:15]1[CH:16]=[C:17]([C:28](O)=[O:29])[C:18]2[C:19]([CH3:27])=[CH:20][N:21]([CH:24]([CH3:26])[CH3:25])[C:22]=2[CH:23]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl.CN(C=O)C.CCOC(C)=O>[Br:14][C:15]1[CH:16]=[C:17]([C:28]([NH:1][CH2:2][C:3]2[C:8]([O:9][CH3:10])=[N:7][C:6]([CH2:11][OH:12])=[CH:5][C:4]=2[CH3:13])=[O:29])[C:18]2[C:19]([CH3:27])=[CH:20][N:21]([CH:24]([CH3:25])[CH3:26])[C:22]=2[CH:23]=1
Reactant: COc1nc(CO)cc(C)c1CN
Reactant: Cc1cn(C(C)C)c2cc(Br)cc(C(=O)O)c12
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COc1nc(CO)cc(C)c1CNC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a stirred solution of (5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)methanol (0.29 g, 1.591 mmol), 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylic acid (0.48 g, 1.621 mmol), and HOAt (0.22 g, 1.616 mmol) in Dichloromethane (15 mL) and DMF (5 mL) was added EDC free base (0.30 g, 1.932 mmol). The reaction was stirred at RT for 3 h then evaporated to dryness under vacuum. The remaining was purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 20% EtOAc in CH2Cl2) to give the product 6-bromo-N-((6-(hydroxymethyl)-2-methoxy-4-methylpyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxamide (0.73 g, 1.586 mmol, 100% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.46 (t, J=4.9 Hz, 1 H), 7.77 (d, J=1.8 Hz, 1 H), 7.33 (d, J=1.0 Hz, 1 H), 6.99 (d, J=1.5 Hz, 1 H), 6.90 (s, 1 H), 5.31 (t, J=5.9 Hz, 1 H), 4.74 (quin, J=6.6 Hz, 1 H), 4.45 (d, J=5.1 Hz, 1 H), 4.43 (d, J=5.8 Hz, 2 H), 3.83 (s, 3 H), 2.40 (s, 3 H), 2.10 (s, 3 H), 1.38 (d, J=6.8 Hz, 6 H). MS(ES)+m/e 460.2 [M+H]+.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:15]=[CH:14][O:13][N:12]=1)([O-:3])=[O:2].[CH2:18]([NH2:20])[CH3:19]>>[N+:1]([CH:4]=[C:5]([NH:20][CH2:18][CH3:19])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:15]=[CH:14][O:13][N:12]=1)([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1ccon1
Reactant: CCN
Product: CCNC(=C[N+](=O)[O-])NCCSCc1ccon1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-(3-isoxazolylmethylthio)-ethylamino]ethylene (see Example 31 (ii)) with ethylamine by the procedure of Example 8(ii) gives the title product.