Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)CCC>O1CCOCC1.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.[Cu]I>[CH3:18][C:17]([C:15]1[CH:14]=[CH:13][N:12]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[N:7]=3)=[CH:9][N:10]=[C:11]2[N:16]=1)([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:27]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(-c4ccncc4)n3)cnc2n1

Procedure:
3-(2-Chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)-imidazo[1,2-α]pyrimidine (from Example 34) (403 mg, 1.0 mmol), 4-tributylstannylpyridine (736 mg, 2.0 mmol), tetrakis(triphenylphosphine)palladium(0) (115 mg, 10 mol %) and copper(I) iodide (115 mg) in 1,4-dioxane (20 ml) were heated at reflux overnight. Purification by column chromatography on silica using 3-6% MeOH/CH2Cl2 as the eluent afforded 7-(1-methyl-1-triethylsilanyloxyethyl)-3-[2-(pyridin-4-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidine: 1H NMR (400 MHz, d6-DMSO) δ 10.23 (1H, d, J 7.3), 8.98 (1H, d, J 5.4), 8.89 (1H, s), 8.85-8.80 (2H, m), 8.36 (2H, d, J 5.9), 8.14 (1H, d, J 5.5), 7.70 (1H, d, J 7.3), 1.65 (6H, s), 0.95 (9H, t, J 7.8), 0.66 (6H, q, J 7.8).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:8]=2[OH:18])=[CH:5][CH:4]=[N:3]1.[C:19]([C:21]1[CH:22]=[C:23]([S:28]([NH:31][C:32]2[S:33][CH:34]=[CH:35][N:36]=2)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1F)#[N:20]>>[C:19]([C:21]1[CH:22]=[C:23]([S:28]([NH:31][C:32]2[S:33][CH:34]=[CH:35][N:36]=2)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[O:18][C:8]1[CH:9]=[CH:10][C:11]([O:13][C:14]([F:15])([F:16])[F:17])=[CH:12][C:7]=1[C:6]1[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=1)#[N:20]
Reactant: Cn1nccc1-c1cc(OC(F)(F)F)ccc1O
Reactant: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1F
Product: Cn1nccc1-c1cc(OC(F)(F)F)ccc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1C#N
Yield: 97 %

Procedure:
2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethoxy)phenol (Preparation 533, 50.0 mg, 0.20 mmol) and 3-cyano-4-fluoro-N-(1,3-thiazol-2-yl)benzenesulfonamide (Preparation 46, 57 mg, 0.20 mmol) were used to prepare the title compound using Method F above. The product was purified by flash column chromatography (SiO2) eluting with dichloromethane:ethyl acetate (gradient 8:2 to 2:8, by volume) to afford the title compound, 98 mg, 97% yield.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23](=[O:26])[NH:24][CH3:25])=[CH:19][C:18]=4[O:27][CH3:28])[N:12]=[CH:11][C:10]=3[N:9]3[CH:29]=[N:30][C:31]([C:32]([OH:34])=[O:33])=[C:8]3[C@H:7]2[CH2:35][CH3:36])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:49](O)[CH:50]=[CH2:51]>CN(C=O)C>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23](=[O:26])[NH:24][CH3:25])=[CH:19][C:18]=4[O:27][CH3:28])[N:12]=[CH:11][C:10]=3[N:9]3[CH:29]=[N:30][C:31]([C:32]([O:34][CH2:51][CH:50]=[CH2:49])=[O:33])=[C:8]3[C@H:7]2[CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC[C@@H]1c2c(C(=O)O)ncn2-c2cnc(Nc3ccc(C(=O)NC)cc3OC)nc2N1C1CCCC1
Reactant: C=CCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ncn2c1[C@@H](CC)N(C1CCCC1)c1nc(Nc3ccc(C(=O)NC)cc3OC)ncc1-2
Temperature: 42.5 °C
Reaction time: 0.67 h
Yield: 77.3 %

Procedure:
(R)-5-cyclopentyl-6-ethyl-3-(2-methoxy-4-(methylcarbamoyl)phenylamino)-5,6-dihydroimidazo[1,5-f]pteridine-7-carboxylic acid 1-2 (44 mg, 0.09 mmol) in DMF (0.5 mL) was treated with carbonyldiimidazole (19 mg, 0.12 mmol) and stirred at 40-45° C. for 40 minutes. Allyl alcohol (1 ml, 14.7 mmol) was then added and the reaction mixture was stirred at 40° C. for 18 hours. The mixture was partitioned between an aqueous solution of sodium carbonate and ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate and concentrated to give the desired compound as a pale brown solid (37 mg, 77% yield); LC/MS M+1 (obs.) 532.68, LC/MS M−1 (obs.) 530.81.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:13]=[C:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.Cl[CH2:29][C:30]([NH:32][CH:33]([CH3:35])[CH3:34])=[O:31].CO>O>[CH:33]([NH:32][C:30](=[O:31])[CH2:29][N:2]1[CH2:3][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH:13]=[C:12]([C:18]5[N:19]([CH:23]([CH3:24])[CH3:25])[N:20]=[CH:21][N:22]=5)[N:11]=4)[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH2:5]1)([CH3:35])[CH3:34]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2
Reactant: CC(C)NC(=O)CCl
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)NC(=O)CN1CC(c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)C1

Procedure:
Following the procedure for 143, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (Example 65) was reacted with 2-chloro-N-isopropyl acetamide. The crude product was subjected to reverse phase HPLC (Gemini C18 column gradient 0 to 70% MeOH in H2O+0.1% HCO2H) to give 200 as a white solid. 1H NMR δ (ppm) (CDCl3): 8.46 (1H, d, J=8.28 Hz), 7.85 (1H, s), 7.63 (1H, s), 7.05 (1H, dd, J=8.32, 1.82 Hz), 6.94-6.92 (1H, m), 6.00-5.90 (1H, m), 4.49-4.40 (4H, m), 4.12-4.02 (1H, m), 3.88 (2H, t, J=7.51 Hz), 3.82-3.71 (1H, m), 3.41 (2H, t, J=7.23 Hz), 3.23 (2H, s), 1.56 (6H, d, J=6.63 Hz), 1.16 (6H, d, J=6.57 Hz). 1 Exchangeable proton not seen. LCMS: RT=6.8 min, M+H+=450
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CC(OC)(C)C>[F:11][C:5]1[CH:4]=[CH:3][C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: OB(O)c1ccccc1
Solvent: O
Solvent: COC(C)(C)C
Product: O=C(O)c1cc(-c2ccccc2)ccc1F

Procedure:
5-Bromo-2-fluoro-benzoic acid (49) (2.0 g, 9.00 mmol) was coupled to phenyl boronic acid (1.23 g, 10.00 mmol) using method F, except that after the 2 hour reaction, water (50 mL) and TBME (50 mL) were added. The mixture was filtered and the aqueous layer was washed with TBME. The aqueous layer was then acidified with 1N HCl and the precipitated solid was collected and dried. Yield: 1.6 g, 82%
Reaction SMILES: [CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][O:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][CH2:12][C@H:13]1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1COCC(=O)N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1COCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-4-Benzyl-5-methylmorpholin-3-one (5.05 g, 24.6 mmol) was dissolved in THF (12.3 mL) before lithium aluminum hydride (1.87 g, 49.2 mmol) was added and the mixture stirred at RT for 1 h. The reaction mixture was quenched with ethyl acetate before a few drops of ammonium chloride was added. The colorless oil was filtered, washed with dichloromethane, concentrated, and purified by flash chromatography to give the title compound. MS (ES+): 192(M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12](=O)[CH:13]([CH3:18])[CH2:14][C:15](O)=[O:16])=[CH:11][C:5]=2[O:4][CH2:3]1.[CH3:20][NH:21][NH2:22]>C(O)C>[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]3[CH:13]([CH3:18])[CH2:14][C:15](=[O:16])[N:21]([CH3:20])[N:22]=3)=[CH:11][C:5]=2[O:4][CH2:3]1
Reactant: CNN
Reactant: CC(CC(=O)O)C(=O)c1ccc2c(c1)OCC(=O)N2
Solvent: CCO
Product: CC1CC(=O)N(C)N=C1c1ccc2c(c1)OCC(=O)N2

Procedure:
4-(3,4-Dihydro-3-oxo-1,4(2H)-benzoxazin-7-yl)-4-oxo-3-methylbutyric acid (1.56 g, 6.0 mmoles) was dissolved in ethanol (300 ml) and methylhydrazine (0.33 ml, 6.0 mmoles) was added. The mixture was heated at reflux for 2 hours, and then cooled to yield to yield the titled compound. The crystals were collected by filtration, recrystallized from ethanol, and recollected by filtration. The solid was dried under vacuum to yield 1.0 g of the titled compound, mp 204°-206° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1O[CH:6]=[CH:7][C:8](=[O:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.[CH2:20]([NH2:22])[CH3:21].[OH-].[Na+]>C(O)C>[CH2:20]([N:22]1[CH:6]=[CH:7][C:8](=[O:18])[C:9]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:4]1[CH2:3][O:2][CH3:1])[CH3:21]
Reactant: COCc1occc(=O)c1OCc1ccccc1
Reactant: CCN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCn1ccc(=O)c(OCc2ccccc2)c1COC
Temperature: 70 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 2-methoxymethyl-3-benzyloxy-pyran-4(1H)-one (2.46 g, 10 mmol, 1 eq.) in ethanol (10 ml)/water (10 ml) was added 1.93 g (30 mmol, 3 eq.) of 70% aqueous ethylamine followed by 2N sodium hydroxide solution until pH 13 was obtained. The reaction mixture was sealed in a thick-walled glass tube and stirred at 70° C. overnight. After adjustment to pH 1 with concentrated hydrochloric acid, the solvent was removed by rotary evaporation prior to addition of water (50 ml) and washing with diethyl ether (3×50 ml). Subsequent adjustment of the aqueous fraction to pH 7 with 10N sodium hydroxide solution was followed by extraction into dichloromethane (4×50 ml), the combined organic layers then being dried over anhydrous sodium sulphate, filtered and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel (eluant: 15% CH3OH/85% CHCl3) to afford the title compound (2.05 g, 75.1%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:21])[CH2:18][CH2:19]Cl)[CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[OH:28])[N:3]=1.[I-].[Na+].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(#N)C.O>[NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:21])[CH2:18][CH2:19][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[OH:28])[N:3]=1
Reactant: C1CCNCC1
Reactant: Nc1nc(-c2ccccc2O)cc(-c2cccc(NC(=O)CCCl)c2)c1CO
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Nc1nc(-c2ccccc2O)cc(-c2cccc(NC(=O)CCN3CCCCC3)c2)c1CO
Temperature: 75 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of N-{3-[2-amino-3-(hydroxymethyl)-6-(2-hydroxyphenyl)-4-pyridinyl]phenyl}-3-chloropropanamide (0.065 g, 0.16 mmol) and sodium iodide (0.007 g, 0.05 mmol) in acetonitrile (5 mL) was added piperidine (0.16 mL, 1.63 mmol), and the mixture was stirred at 75° C. overnight. After cooled to room temperature, the resulting mixture was diluted with water and extracted with ethyl acetate. The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica-gel (chloroform:methanol, 85:15) to give N-{3-[2-amino-3-(hydroxymethyl)-6-(2-hydroxyphenyl)-4-pyridinyl]phenyl}-3-(1-piperidinyl)propanamide as a white foam (0.055 g, yield 75%).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[F:20][CH:21]([F:31])[O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=1>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:30][CH2:29][C:26]2[CH:25]=[CH:24][C:23]([O:22][CH:21]([F:20])[F:31])=[CH:28][CH:27]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: NCc1ccc(OC(F)F)cc1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CCCCN1C(=O)C(NCc2ccc(OC(F)F)cc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1-[4-(difluoromethoxy)phenyl]methanamine in a similar manner as described for e.g. Example 6 and 7. 1H NMR (CD3CN) δ 7.46-7.41 (m, 1H), 7.39-7.33 (m, 2H), 7.29-7.25 (m, 2H), 6.98-6.93 (m, 2H), 6.86-6.81 (m, 2H), 6.72 (t, J=74.4 Hz, 1H), 6.48-6.39 (m, 1H), 4.16 (d, J=6.6 Hz, 2H), 3.67 (t, J=7.2 Hz, 2H), 1.81-1.72 (m, 2H), 1.49-1.38 (m, 2H), 0.98 (t, J=7.3 MHz, 3H); Mass spectrum: M+H+ 437.
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:7]=[C:6]([CH3:19])[C:5]=1[C:20](O)=[O:21])([CH3:3])[CH3:2].[N:23]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:1]([C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[CH:10]=2)[N:7]=[C:6]([CH3:19])[C:5]=1[C:20]([N:31]1[CH2:32][CH2:33][CH:28]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:29][CH2:30]1)=[O:21])([CH3:3])[CH3:2]
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C(C)C)c1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C(C)C)c1C(=O)N1CCC(N2CCCC2)CC1
Yield: 64 %

Procedure:
In analogy to the procedure described in Example 18], 5-isopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid and 4-pyrrolidine-1-yl-piperidine gave the title compound in 64% yield as light yellow oil. MS: 449.3 (MH+).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([F:14])[C:10]([Cl:13])=[N:11][CH:12]=1.CN([CH:18]=[O:19])C.CCOC(C)=O>CCOCC>[Cl:13][C:10]1[N:11]=[CH:12][C:7]([CH:18]=[O:19])=[CH:8][C:9]=1[F:14]
Reactant: Fc1cc(Br)cnc1Cl
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=Cc1cnc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Butyl lithium (2.5 M in hexane, 2.5 mL, 6.3 mmol) was added to 5-bromo-2-chloro-3-fluoro-pyridine (1 g, 4.75 mmol) in 10 mL of ether at −78° C. After 10 minutes, DMF (5 mL) was added and the mixture was warmed to room temperature over 1 h. The mixture was poured into 20 mL of EtOAc and the mixture was washed with water (20 mL) and brine (20 mL), dried over magnesium sulfate and concentrated to afford the crude 53a (0.92 g) as a brown oil: LC-MS160.0 (MH+).
Reaction SMILES: [NH2:1][C@:2]([CH3:26])([CH2:24][CH3:25])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[CH2:18][O:17][C:16]3([CH3:23])[CH3:22])=[CH:8][CH:7]=1)=[O:4].C1N=CN([C:32](N2C=NC=C2)=[O:33])C=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C>[CH3:23][C:16]1([CH3:22])[C:15]2[CH:14]=[C:13]([O:12][C:9]3[CH:8]=[CH:7][C:6]([N:5]4[C:3](=[O:4])[C@:2]([CH2:24][CH3:25])([CH3:26])[NH:1][C:32]4=[O:33])=[CH:11][CH:10]=3)[CH:21]=[CH:20][C:19]=2[CH2:18][O:17]1
Reactant: CC[C@@](C)(N)C(=O)Nc1ccc(Oc2ccc3c(c2)C(C)(C)OC3)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Product: CC[C@@]1(C)NC(=O)N(c2ccc(Oc3ccc4c(c3)C(C)(C)OC4)cc2)C1=O
Reaction time: 8 h

Procedure:
(2R)-2-amino-N-[4-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]phenyl]-2-methyl-butanamide (Intermediate 71, 140 mg, 0.39 mmol) was dissolved in ethyl acetate (2 mL) and the resulting solution was added drop wise to a suspension of CDI (1.4 equiv) in ethyl acetate (0.5 mL). The resulting suspension was stirred overnight. A new solution of CDI was freshly prepared (60 mg in 0.5 mL of ethyl acetate) and added drop wise to the mixture. A third portion of CDI (50 mg) was added and the reaction mixture was left stirring over week-end at room temperature. The mixture was treated with 10% w/w aqueous citric acid solution, two layers were separated and the organic layer washed with water and brine, then dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate from 80:20 to 60:40 as eluent. The fractions containing the product were combined, evaporated to dryness and further purified by crystallization from ethyl acetate/n-heptane. The slurry was stirred for 2 hours, and then the solid collected, washed with n-heptane and dried under vacuum. The residue was re-purified by flash chromatography on silica gel using dichloromethane/methanol from 100:0 to 90:10. The fractions containing the product were combined, evaporated to dryness and the residue further purified by crystallization from methyl tertbutyl ether/n-heptane to afford the title compound (47 mg) as white solid.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[OH:13][C:14]1[CH:23]=[CH:22][C:21]([S:24]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)(=[O:26])=[O:25])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:53]1([CH2:59]O)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C1(C)C=CC=CC=1.CCOCC>[CH3:33][N:30]1[CH2:29][CH2:28][N:27]([S:24]([C:21]2[CH:22]=[CH:23][C:14]([O:13][CH2:59][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[C:15]([CH:20]=2)[C:16]([O:18][CH3:19])=[O:17])(=[O:26])=[O:25])[CH2:32][CH2:31]1
Reactant: OCc1ccccc1
Reactant: COC(=O)c1cc(S(=O)(=O)N2CCN(C)CC2)ccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)c1cc(S(=O)(=O)N2CCN(C)CC2)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
DEAD (0.24 ml, 1.51 mmol) was slowly added to a mixture of methyl 2-hydroxy-5-[(4-methyl-1-piperazinyl)sulfonyl]benzoate (may be prepared as described in Description 70; 430 mg, 1.37 mmol), Ph3P (395 mg, 1.51 mmol) and phenylmethanol (163 mg, 1.505 mmol) in toluene (15 ml) cooled in an ice bath at 0° C. The mixture was stirred for 2 h at room temperature. Ether was added to the mixture and the mixture was filtered. The filtrate was evaporated to yield the title compound. 260 mg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].C1(C)C=CC=CC=1.[CH3:17][N:18](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[C:17]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9])#[N:18]
Reactant: Cc1ccc(Br)c(F)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: Cc1ccc(C#N)c(F)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a deoxygenated solution of 4-bromo-3-fluorotoluene (25.0 g, 132 mmol) in DMF (500 mL) was added Zn(CN)2 (10.1 g, 86 mmol) and Pd(PPh3)4 (15 g, 13 mmol). The reaction was stirred at 100° C. for 18 hrs, then cooled to room temperature. The solution was poured into toluene (1 L), washed with 30% aqueous NH4OH (2×1 L), then brine (800 mL), then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. Purification by silica gel chromatography, eluting with a gradient of hexane −0% to 7% EtOAc, yielded the titled product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:4])=[O:3].[CH:19](Br)([CH3:21])[CH3:20]>>[CH:19]([N:16]1[CH2:15][CH2:14][N:13]([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)[CH2:18][CH2:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)Br
Reactant: COc1ccc(N2CCNCC2)cc1S(C)(=O)=O
Product: COc1ccc(N2CCN(C(C)C)CC2)cc1S(C)(=O)=O

Procedure:
Beginning with 1-(3-Methanesulfonyl-4-methoxy-phenyl)-piperazine and isopropylbromide, the title compound was recovered by the procedure described in Example 2: MS m/z (rel. intensity, 70 eV)) 312 (M+, 43), 297 (bp), 84 (35), 71 (33), 56 (73).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([NH2:32])(=[O:31])=[O:30]>C1C=CC=CC=1>[CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:31])(=[O:30])[NH2:32])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=C(O)c1cccc(OCC2CCCCC2)c1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.3 %

Procedure:
A benzene (30 ml) solution containing 3.00 g (12.8 mmol) of 3-cyclohexylmethoxybenzoic acid and 3 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methylene chloride (30 ml), this solution was added dropwise under ice-cooling to a pyridine (50 ml) solution containing 2.43 g (14.1 mmol) of 2-aminobenzenesulfonamide, the mixture was stirred at room temperature for 18 hours and then methylene chloride was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a 1 n hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus obtained crude crystals were recrystallized from acetonitrile to obtain 2.80 g (yield: 56.0%) of the title compound NMR (CDCl3) δ: 1.00-1.39 (5 H, m), 1.68-1.90 (6 H, m), 3.82 (2 H, d J=7 Hz), 4.95 (2 H, s), 7.10 (1 H, ddd, J=8 Hz, 2 Hz, 1 Hz), 7.25 (1 H, ddd, J=8 Hz, 8 Hz, 1 Hz), 7.38 (1 H, dd, J=8 Hz, 8 Hz), 7.45-7.50 (2 H, m), 7.62 (1 H, ddd, J=8 Hz, 8 Hz, 2 Hz), 7.96 (1 H, dd, J=8 Hz, 2 Hz), 8.53 (1 H, dd, J=8 Hz, 1 Hz), 10.03 (1 H, s)
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[NH2:18][C:19]1[CH:31]=[C:30]([C:32]2[O:33][C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[CH:36]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(Cl)Cl>[O:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[CH:36]=[C:32]1[C:30]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])=[C:19]([NH:18][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:9]([F:8])=[CH:10][CH:11]=2)[CH:31]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cc3ccccc3o2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(-c2cc3ccccc3o2)cc1NC(=O)c1ccc(F)cc1
Reaction time: 5 h

Procedure:
0.054 mL of triethylamine and 0.035 mL of 4-fluorobenzoyl chloride were added to 3.5 mL of methylene chloride solution containing 60 mg of tert-butyl 2-amino-4-(benzofuran-2-yl)benzoate at room temperature sequentially and stirred at the same temperature for 5 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1]to obtain tert-butyl 4-(benzofuran-2-yl)-2-(4-fluorobenzamido)benzoate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([OH:21])[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1>>[CH3:9][C:4]1[N:5]=[C:6]([NH:10][C:11]2[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:14]=[C:13]([OH:21])[CH:12]=2)[CH:7]=[C:2]([NH:10][C:11]2[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:14]=[C:13]([OH:21])[CH:12]=2)[N:3]=1
Reactant: Nc1cc(O)cc(C(F)(F)F)c1
Reactant: Cc1nc(Cl)cc(Cl)n1
Product: Cc1nc(Nc2cc(O)cc(C(F)(F)F)c2)cc(Nc2cc(O)cc(C(F)(F)F)c2)n1
Yield: 43 %

Procedure:
This compound was obtained (yield 43%) based on the method described in Production Example 2B using 4,6-dichloro-2-methylpyrimidine instead of the 4,6-dichloro-2-ethylpyrimidine, and using 3-amino-5-trifluoromethyl-phenol instead of the 3-aminophenol.