Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][C:4]([OH:6])=[O:5].[CH3:12][CH:13]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:15]O>>[CH3:12][CH:13]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:15][O:5][C:4](=[O:6])[CH2:3][CH:2]([CH3:1])[CH2:7][C:8]([CH3:10])([CH3:9])[CH3:11]
Reactant: CC(CC(=O)O)CC(C)(C)C
Reactant: CC(CCO)CC(C)(C)C
Product: CC(CCOC(=O)CC(C)CC(C)(C)C)CC(C)(C)C

Procedure:
The preparation from 3,5,5-trimethylhexanoic acid and 3,5,5-trimethylhexanol was analogous to Example 3; colorless liquid of medium viscosity; B.P. (1.3 mbar=134°-138° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][C:8]=1[OH:9])[CH3:2].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1.O>CN(C=O)C>[Si:13]([O:9][C:8]1[CH:7]=[CH:6][C:5]([C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[CH2:1][CH3:2])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCc1cc(C(C)=O)ccc1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(C(C)=O)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
To a stirred solution of 1-(3-ethyl-4-hydroxyphenyl)-1-ethanone (9.24 g, 56.27 mmol) in DMF (60 ml) was added tert-butyldimethylsilyl chloride (9.33 g, 61.9 mmol), imidazole (4.6 g, 67.52 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was fractionally distilled under reduced pressure 180° c., 0.5 mmHg) to give title compound (12.3 g, 78% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:16])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Br:17]Br>C(Cl)(Cl)(Cl)Cl>[Br:17][C:7]1[CH:6]=[CH:5][C:4]([C:8]([CH3:16])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:9])=[CH:3][C:2]=1[OH:1]
Reactant: BrBr
Reactant: CCCCCCC(C)(C)c1cccc(O)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCC(C)(C)c1ccc(Br)c(O)c1
Reaction time: 0.25 h

Procedure:
To a 0° C. solution of 110 g. (0.50 mole) of 2-(3-hydroxyphenyl)-2-methyloctane in 200 ml. of carbon tetrachloride was added dropwise a solution of 80 g. (0.50 mole) of bromine in 90 ml. of carbon tetrachloride (reaction temperature ≤30° C. with cooling). The reaction mixture was stirred an additional 15 minutes and was then evaporated to yield 150 g. (100%) of product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]2[N:14]=[C:15]([OH:18])[C:16]([I:17])=[C:12]2[CH:11]=[N:10][N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:27][C:28]1[N:29]([CH3:33])[N:30]=[CH:31][N:32]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]2[N:14]=[C:15]([O:18][CH2:27][C:28]3[N:29]([CH3:33])[N:30]=[CH:31][N:32]=3)[C:16]([I:17])=[C:12]2[CH:11]=[N:10][N:9]=1
Reactant: Oc1nn2c(-c3ccccc3F)nncc2c1I
Reactant: Cn1ncnc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1I
Temperature: 25 °C
Reaction time: 25 h
Yield: 81.2 %

Procedure:
To a stirred solution of 7-(2-fluorophenyl)-3-iodopyrazolo[1,5-d][1,2,4]triazin-2-ol (0.4098 g, 1.15 mmol) in anhydrous DMF (16 ml) under nitrogen was added cesium carbonate (1.5009 g, 4.61 mmol), then solid 3-chloromethyl-2-methyl-2H-[1,2,4]triazole hydrochloride (0.2328 g, 1.39 mmol). The mixture was stirred at room temperature for 25 h, then partitioned between water (75 ml) and ethyl acetate (75 ml). The aqueous layer was further extracted with ethyl acetate (2×75 ml), and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 0-5% MeOH/EtOAc) to give 0.4212 g (81%) of the title compound as a white solid: mp=218-219° C. (CH2Cl2-EtOAc); 1H NMR (360 MHz, CDCl3) δ 3.88 (3H, s), 5.52 (2H, s), 7.28 (1H, m), 7.39 (1H, td, J=7.6 and 1.0 Hz), 7.65 (1H, m), 7.76 (1H, m), 7.87 (1H, s), 9.14 (1H;, s); MS (ES+) m/e 452 [MH]+; Anal. Found C, 39.66; H, 2.16; N, 21.34%. C15H11FIN7O requires C, 39.93; H, 2.46; N, 21.73%.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]([NH2:18])=[O:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH2:24]([O+](CC)CC)[CH3:25].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH:12]1[C:10]2[C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6][N:7]([C:16](=[NH:18])[O:17][CH2:24][CH3:25])[CH2:8][C:9]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CC[O+](CC)CC
Reactant: NC(=O)N1Cc2ccccc2-c2ccccc2C1
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.19 g of 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboxamide are dissolved in 10 ml of methylene chloride, and the solution is treated with 1.14 g of triethyloxonium tetrafluoroborate and stirred at room temperature for 20 hours. The mixture is then poured on to 10% sodium carbonate solution/ice and the whole is extracted with methylene chloride. The combined extracts are washed with 10% sodium carbonate solution, dried over anhydrous sodium sulphate and evaporated under reduced pressure. In this manner there is obtained crude ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-caboximidate which is purified by a filtration on silica gel [eluent: n-hexane/ethyl acetate (1:1)]; m.p. 74°-76° C. (crystallized from n-hexane).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[Br:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C:36](=O)[CH2:35][CH2:34]2>C1COCC1>[Br:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)/[C:36](=[CH:2]/[O:3][CH3:4])/[CH2:35][CH2:34]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CO/C=C1\CCc2cc(Br)ccc21
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 93.2 %

Procedure:
To a suspension of (methoxymethyl)triphenylphosphonium chloride (39.7 g, 116 mmol) in THF (210 ml) at −20° C. was added dropwise 1M potassium t-butoxide (95 ml, 95 mmol) and the solution stirred at −20° C. for 20 min. To this solution was added dropwise a solution of 5-bromo-2,3-dihydro-1H-inden-1-one (10.0 g, 47.4 mmol) in THF (230 ml) and stirring was continued at −20° C. for 30 min then warmed to room temperature and stirred for 2 h. The solution was filtered through Celite and the filtrate was concentrated in vacuo to give crude product which was purified by chromatography on a silica gel cartridge eluting with CH2Cl2/hexane to give the title compound (10.56 g, 93%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[S:25]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>N1C=CC=CC=1.C(OCC)(=O)C>[F:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)=[CH:3][C:2]=1[NH:1][C:31](=[O:32])[CH2:30][C:27]1[CH:28]=[CH:29][S:25][CH:26]=1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Reactant: O=C(O)Cc1ccsc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Cc1ccsc1)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 80 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
N-[5-(3-Amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (55 mg, 0.16 mmol) produced in Example 16(vi) was dissolved in pyridine (2.0 mL), thiophen-3-ylacetic acid (45 mg, 0.32 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (120 mg, 0.32 mmol) were added, and the mixture was stirred at 80° C. for 12 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), and washed successively with 5% aqueous ammonium chloride solution (5 mL), saturated aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate/heptane to give the title compound (51 mg, 68%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:13]([F:26])=[CH:14][C:15]([N+:23]([O-])=O)=[C:16]([N:18]([CH3:22])[CH2:19][CH2:20][CH3:21])[CH:17]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([N:18]([CH3:22])[CH2:19][CH2:20][CH3:21])[C:15]([NH2:23])=[CH:14][C:13]=2[F:26])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:8])[F:9]
Reactant: CCCN(C)c1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: CCCN(C)c1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1N
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
A solution of 5.2 g (0.013 mole) 5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-fluoro-N-methyl-2-nitro-N-propylbenzenamine in 100 mL acetic acid was heated to 80° C. under a nitrogen atmosphere. The heat and nitrogen were removed and 2.2 g (0.039) mole iron powder was added in 3 portions over 5 min. The solution was stirred at 80° C. for an additional 30 min. The solution was cooled and filtered through Celite®. The filtrate was diluted with 100 mL water and extracted three times with ethyl acetate. The ethyl acetate extracts were washed with a saturated NaHCO3 solution, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified chromatographically using 30% ethyl acetate in hexane as the eluent to give 3.85 g (80%) of 5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-fluoro-N-methyl-N-propyl-1,2-benzenediamine as a light yellow oil, nD25 1.5352.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[CH2:12][CH2:11][CH:10]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:9][C:8]2=1)=[O:4].[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][N:14]1[C:13]2[CH2:12][CH2:11][CH:10]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:9][C:8]=2[C:7]2[C:15]1=[CH:16][CH:17]=[C:5]([C:3](=[O:4])[C:2]([F:1])([F:24])[F:25])[CH:6]=2
Reactant: Fc1cccc(CBr)c1
Reactant: CC(C)C(=O)NC1CCc2[nH]c3ccc(C(=O)C(F)(F)F)cc3c2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)NC1CCc2c(c3cc(C(=O)C(F)(F)F)ccc3n2Cc2cccc(F)c2)C1
Yield: 15.9 %

Procedure:
Mix N-[6-(2,2,2-trifluoro-acetyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide (Preparation 74) (428 mg, 0.93 mmol), m-fluorobenzyl bromide (216 mg, 1.11 mmol), Cs2CO3 (650 mg, 2 mmol) and DMF (10 mL). Warm the reaction at 50° C. for 18 h, cool and partition between water/brine/EtOAc. Separate and dry the organic layer (MgSO4), filter and concentrate to give 590 mg of crude product. Purify by silica gel chromatography, using 10% to 60% EtOAc/hexane to obtain 68 mg (16%) of the title compound as a pale yellow solid. MS (ES) m/z 461 (M+1); HPLC: Rt=3.43 min (95%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CS(O[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(Br)c2)CC1
Temperature: 65 °C
Yield: 85 %

Procedure:
The mixture of 3-bromophenol (2.0 g, 11.56 mmol), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (3.87 g, 13.872 mmol) and caesium carbonate (11.27 g, 34.68 mmol) in DMF (25 ml) was heated at 65° C. for 14 hours. Cooled to RT and diluted with ether. Ether layer was washed with water and brine, dried over sodium sulphate and distilled off the solvent to afford 3.5 g (85.3% yield) of the titled product after purification with (60/120 silica gel) column chromatography using 5% ethyl acetate in hexane as eluent. MS: m/z=356.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][S:27]([C:30]1[C:39]2[C:34](=[C:35]([N:40]([CH3:42])[CH3:41])[CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][S:27]([C:30]3[C:39]4[C:34](=[C:35]([N:40]([CH3:42])[CH3:41])[CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH:13]=2)[N:6]=1
Reactant: CN(C)c1cccc2c(S(=O)(=O)NCCN=[N+]=[N-])cccc12
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CN(C)c1cccc2c(S(=O)(=O)NCCn3cc(CCCCCc4cn(C(=O)OC(C)(C)C)c(N)n4)nn3)cccc12

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.112 g, 0.403 mmol) was reacted with N-(2-azidoethyl)-5-(dimethylamino)naphthalene-1-sulfonamide (0.140 g, 0.403 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(5-(dimethylamino)naphthalene-1-sulfonamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 8.48 (d, 1H), δ 8.24 (d, 1H), δ 8.17 (d, 1H), δ 7.44 (m, 3H), δ 7.07 (d, 1H), δ 6.44 (s, 1H), δ 6.09 (bs, 2H), δ 4.32 (s, 2H), δ 3.36 (s, 2H), δ 2.52 (s, 2H), δ 2.22 (s, 2H), δ 1.43 (m, 13H), δ 1.22 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 176.9, 152.1, 149.6, 148.0, 138.6, 135.1, 130.7, 130.1, 129.7, 129.4, 128.5, 123.3, 122.4, 119.1, 115.5, 84.9, 67.5, 50.3, 50.2, 45.6, 42.9, 37.9, 29.1, 28.9, 28.2, 28.0, 25.5 ppm; HRMS (ESI) calcd for C29H40N8O4S (M+) 596.2893. found 596.2881, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-5-(dimethylamino)naphthalene-1-sulfonamide hydrochloride (0.139 g, 65% yield). 1H NMR (400 MHz, CD3OD) δ 8.70 (t, 2H), δ 8.31 (s, 1H), δ 8.08 (s, 2H), δ 7.82 (s, 2H), δ 6.43 (s, 1H), δ 4.55 (s, 2H), δ 3.32 (s, 8H), 2.63 (s, 2H), δ 2.48 (s, 2H), δ 1.66 (s, 4H), δ 1.40 (s, 2H) ppm; 13C NMR (100 MHz, CD3OD) δ 159.9, 147.3, 140.7, 136.8, 129.9, 129.3, 127.8, 127.7, 126.5, 119.3, 108.6, 108.4, 76.7, 67.3, 51.5, 42.3, 37.4, 36.5, 28.3, 27.9, 27.6, 24.1, 24.0, 23.7 ppm; HRMS (ESI) calcd for C24H32N8O2S (M+) 496.2369. found 496.2359.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][OH:13].[H][H]>[Pd].C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][OH:13]
Reactant: [H][H]
Reactant: Nc1c(CCO)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(CCO)c1N

Procedure:
A suspension of 10% palladium on carbon (66 mg) and 2-(2-amino-3-nitrophenyl)ethanol [See Seno, Kaoru; Hagishita, Sanji; Sato, Tomohiro; Kuriyama, Kaoru; J. Chem. Soc. Perkin Trans. 1; 2012 (1984) for the synthesis of this reagent] (531.5 mg, 2.92 mmol) in absolute ethanol (50 mL) was shaken under 40 psi hydrogen for 3 hours. After filtration and concentration, crude 2-(2,3-diaminophenyl)ethanol (474.4 mg) was obtained as a red oil, which crystallized on standing: Rf=0.08 (75% ethyl acetate in hexanes); 1H NMR (DMSO-d6) δ 2.58 (t, 2H, J=6.9 Hz), 3.53 (t, 2H, J=7.2 Hz), 4.32 (br s, 5H), 6.29 (m, 2H), 6.40 (dd, 1H, J=6.9, 2.1 Hz).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:32])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[C@H:28]([CH2:29][OH:30])[CH2:27][O:26][C:25]5=[O:31])=[CH:20][CH:19]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Br[CH2:34][CH2:35][O:36][CH3:37]>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH3:32])[C:7]([N:10]3[CH2:11][CH2:12][N:13]([C:16]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[C@H:28]([CH2:29][O:30][CH2:34][CH2:35][O:36][CH3:37])[CH2:27][O:26][C:25]5=[O:31])=[CH:22][CH:23]=4)=[O:17])[CH2:14][CH2:15]3)=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: COCCBr
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3CO)cc2)CC1
Product: COCCOC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)cc1
Yield: 43.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-3-{4-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-4-hydroxymethyloxazolidin-2-one (655 mg) described in Example 299 and 1-bromo-2-methoxyethane (250 mg), the title compound (323 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:15][C:14]=2[O:24][CH:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]>CN(C=O)C.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:15][C:14]=3[O:24][CH:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[O:9][C:7](=[O:8])[C:6]=2[CH:10]=1
Reactant: CN1CCC(Oc2cc(N3CCCC3)ccc2C(=O)Nc2ccc(F)cc2C(=O)O)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(Oc2cc(N3CCCC3)ccc2-c2nc3ccc(F)cc3c(=O)o2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
A solution of 5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)-benzoylamino]benzoic acid (7.4 g, 16.8 mmol) in dry DMF (120 mL) was treated with S1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.42 g, 33.5 mmol). The reaction was stirred at ambient temperature overnight. The mixture was poured into brine (300 mL) and extracted with 10% MeOH in EtOAc (3×100 mL). The combined extracts were washed with water (2×400 mL), then brine (2×400 mL), dried over MgSO4, and concentrated to a solid which was purified by chromatography on silica, using 40/55/5 THF/Hex/Et3 N in hexanes, to give 3.4 g (48%) of a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:44]=[CH:43][C:39]3=[N:40][O:41][N:42]=[C:38]3[CH:37]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[N:40]1[O:41][N:42]=[C:38]2[CH:37]=[C:36]([C:2]3[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]4[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=4[CH3:25])=[O:16])[C:5]4[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=4[N:7]=3)[CH:44]=[CH:43][C:39]=12
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Reactant: CC1(C)OB(c2ccc3nonc3c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc4nonc4c3)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Reaction time: 8 h

Procedure:
The title compound was prepared in the same manner as described in example 74 using 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.180 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,1,3-benzoxadiazole (57.7 mg, 0.235 mmol), DMSO(2 mL), sodium carbonate (0.271 mL, 0.541 mmol), and bis(triphenylphosphine)palladium(II) chloride (12.67 mg, 0.018 mmol) wherein the reaction time was 8 h. The final product was collected as 17 mg (20%). LCMS LCMS E-S (M+H)=472.4 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (d, J=6.8 Hz, 6 H), 2.12 (s, 3 H), 2.27 (s, 3 H) 4.42 (d, J=4.8 Hz, 2 H) 5.32 (quin, J=6.6 Hz, 1 H), 5.90 (s, 1 H), 8.00 (s, 1 H), 8.23 (d, J=9.4 Hz, 1 H), 8.54-8.64 (m, 1 H), 8.79 (t, J=4.7 Hz, 1 H), 8.91 (s, 1 H), 11.54 (br. s., 1 H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1.[C:12]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C>[CH:12]1([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH3:3])[CH:6]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1CCCCC1
Reactant: COc1cccc(N)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cccc(NC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Under ice cooling, 45 ml of acetic acid was added dropwise over 1 hour to 300 ml of a dichloroethane suspension of 8 g of sodium borohydride. To said mixture were added slowly a solution of 17.48 g of m-anisidine and 16 ml of cyclohexanone in 50 ml of dichloroethane, and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was poured into an aqueous saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed, dried and then purified by silica gel column chromatography [ethyl acetate-hexane (1:5)] to afford 29.37 g of cyclohexyl-(3-methoxyphenyl)-amine as an oil. IR (Neat) (cm-1): 3400, 2920, 2850, 1615, 1510, 1500, 1450, MS (m/z): 205 (M+), 162.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:24]2=[CH:25][CH:26]=[N:27][CH:28]=[C:23]2[C:5]2[C:6]([OH:22])=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH3:11])=[CH:9][C:4]=2[O:3]1.[CH2:30](Br)[CH:31]=[CH2:32]>>[CH3:29][C:2]1([CH3:1])[C:24]2=[CH:25][CH:26]=[N:27][CH:28]=[C:23]2[C:5]2[C:6]([O:22][CH2:32][CH:31]=[CH2:30])=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: C=CCBr
Product: C=CCOc1cc(C(C)CCCc2ccc(F)cc2)cc2c1-c1cnccc1C(C)(C)O2

Procedure:
5,5-Dimethyl-8-[5-(4-fluorophenyl)-2-pentyl]-10-(2-propenyloxy)-5H-[1]benzopyrano[3,4-d]pyridine was prepared by reacting 5,5-dimethyl-8-[5-(4-fluorophenyl)-2-pentyl]-10-hydroxy-5H-[1]benzopyrano[3,4-d]pyridine with 2-propenyl bromide following the procedure of Example 51.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1[O:12][S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14].[NH2:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1>C(Cl)Cl>[CH3:30][O:29][C:23]1[CH:24]=[C:25]([O:27][CH3:28])[N:26]=[C:21]([NH:20][C:17](=[O:18])[NH:16][S:13]([O:12][C:5]2[C:6]([O:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([O:2][CH3:1])=[O:19])(=[O:15])=[O:14])[N:22]=1
Reactant: COC(=O)c1cccc(OC)c1OS(=O)(=O)N=C=O
Reactant: COc1cc(OC)nc(N)n1
Solvent: ClCCl
Product: COC(=O)c1cccc(OC)c1OS(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.9 %

Procedure:
A solution of 5.4 g (0.02 mol) of the product from Example 1 in 10 ml of methylene chloride is added dropwise to 3.1 g (0.02 mol) of 2-amino-4,6-dimethoxypyrimidine in 50 ml of methylene chloride at 0° C. The mixture is subsequently stirred at 25° C. for 24 hours and diluted with 50 ml of methylene chloride and the organic phase is washed twice with 50 ml of 2N hydrochloric acid each time and once with 50 ml of water. After drying with sodium sulfate and removing the solvent on a rotary evaporator, an oily product remains, which crystallizes on trituration with diethylether. 6.8 g (77% of theory) of methyl 2-[3-(4,6-dimethoxypyrimidin-2-yl)-ureidosulfonyloxy]-3-methoxy-benzoate of melting point 169°-170° C. are obtained.