Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH2:7][NH2:8].CC1[O:11]C=CC=1C(OC)=O.C[O-].[Na+]>C(N)=O>[CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:8])=[O:11]
Reactant: COC(=O)c1ccoc1C
Reactant: Cc1occc1CN
Agent: C[O-]
Agent: [Na+]
Solvent: NC=O
Product: Cc1occc1C(N)=O
Temperature: 0 °C
Yield: 83 %

Procedure:
(2-Methylfuran-3-yl)methanamine: A solution of 10 mmol (1.256 ml) of methyl 2-methylfuran-3-carboxylate and 38.9 mmol (2.1 g) of NaOMe in 20 ml of formamide was stirred at 100° C. for 30 min. The reaction mixture was poured into ice-water (20 ml) and extracted with ethyl acetate (3×). The extract was dried over MgSO4 and concentrated to give 1.05 g (83%) of 2-methylfuran-3-carboxamide as oil (m/e=126.2 [M+1]). The amide was dissolved in dry THF (10 ml) and drop-wise added to 15 ml of 1M LiAlH4 with 15 ml THF at 0° C. under argon. Then the mixture was stirred for 5 hrs at 60° C. Following cooling, 50% aqueous THF (30 ml) was added to the mixture at 5-10° C. The resulting precipitate was removed by filtration and the filtered solution was dried and concentrated to give an oily product (0.93 g, 84%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[C:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][N:17]=2)[CH3:15])=[O:12])=[CH:4][CH:3]=1.Br.Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:10][C@@H:9]2[C:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[CH:18][N:17]=2)[CH3:15])=[O:12])=[CH:6][CH:7]=1
Reactant: BrCc1ccccn1
Reactant: C[C@@H](NC(=O)[C@H]1C[C@@H]1c1ccc(O)cc1)c1ccc(OCC(F)(F)F)cn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](NC(=O)[C@H]1C[C@@H]1c1ccc(OCc2ccccn2)cc1)c1ccc(OCC(F)(F)F)cn1
Reaction time: 48 h
Yield: 27.2 %

Procedure:
A mixture of (1S*,2S*)-2-(4-hydroxyphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide (15 mg, 0.039 mmol), 2-(Bromomethyl)pyridine hydrobromide (100 mg, 0.394 mmol) and potassium carbonate (27 mg, 0.197 mmol) in DMF (2 mL) was heated at 70 oC with stirring for 2 days. The mixture was poured into water, and the aqueous layer was extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative LC-MS to give 5 mg (27% yield) of the title compound.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:11])[CH2:6][CH2:7][CH2:8][CH2:9]Cl)(=[O:3])[CH3:2].[I-:12].[Na+]>>[C:1]([O:4][C@H:5]([CH3:11])[CH2:6][CH2:7][CH2:8][CH2:9][I:12])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCCl
Reactant: [I-]
Agent: [Na+]
Product: CC(=O)O[C@H](C)CCCCI
Yield: 96.4 %

Procedure:
A solution of 4.80 g (R)-5-acetoxy-1-chlorohexane (26.89 mmol) (prepared in accordance with procedures set forth in U.S. Pat. No. 5,629,423) was added to 5.39 g sodium iodide (36 mmol) in a round bottomed flask fitted with magnetic stirrer bar and a reflux condenser and refluxed for 12 h with stirring. Acetone was removed under reduced pressure. The crude product was partitioned between 60 ml ethyl acetate and 60 ml water layer. The organic layer was washed with 10% sodium thiosulphate solution followed by 20 ml water and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield 7 g (96%) (R)-5-Acetoxy-1-iodohexane.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([S:10]([O-:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.[Na+].Br[C:17]1[CH:25]=[CH:24][C:23]2[N:22]([CH3:26])[C:21]3[CH2:27][CH:28]4[NH:32][CH:31]([C:20]=3[C:19]=2[C:18]=1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29]4>>[F:14][C:2]([F:1])([F:13])[O:3][C:4]1[CH:5]=[C:6]([S:10]([C:17]2[CH:25]=[CH:24][C:23]3[N:22]([CH3:26])[C:21]4[CH2:27][CH:28]5[NH:32][CH:31]([C:20]=4[C:19]=3[C:18]=2[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29]5)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=S([O-])c1cccc(OC(F)(F)F)c1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cccc(OC(F)(F)F)c4)ccc31)C1CCC(C2)N1
Yield: 32 %

Procedure:
Intermediate 3 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude material was purified by flash column chromatography (SiO2, 7:3 hexane/ethyl acetate) to give tert-butyl 2-(3-trifluoromethoxyphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (110 mg, 32%) as an off-white solid: 1H NMR (CDCl3, 300 MHz): δ 8.18 (s, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.81 (s, 1H), 7.67 (dd, J=8.6, 1.4 Hz, 1H), 7.50 (t, J=8.1 Hz, 1H), 7.29-7.38 (m, 2H), 5.13-5.40 (m, 1H), 4.49-4.84 (m, 1H), 3.61 (s, 3H), 3.20-3.52 (m, 1H), 2.50 (d, J=16.2 Hz, 1H), 2.12-2.41 (m, 2H), 1.86-2.00 (m, 1H), 1.58-1.68 (m, 1H), 1.37 (br s, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:31].CCOCC>O1CCOCC1>[ClH:31].[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[NH:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2nc3ccccc3[nH]2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: c1ccc2[nH]c(Oc3ccc(OC[C@H]4CCCN4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a 20 mL vial which contained a solution of the product from step 3 (21 mg, 0.05 mmol) in dioxane (1 mL) was added HCl (4 N in dioxane, 2 mL) at 0° C. The mixture was allowed to warm to rt and stirred at rt for 16 h. The solvent was reduced to 1 mL and ether (15 mL) was added to this vial. The resulting solid was filtered out and dried in vacuo to yield the title product (15 mg, 90%); LCMS); 87%, ESI+, Calcd. 309.4. Found m/z 310.5 (M+1). 1H NMR (400 MHz, DMSO-d6); δ 1.66-1.79 (m, 1H), 1.84-2.05 (m, 2H), 2.05-2.18 (m, 1H), 3.17-3.28 (m, 2H), 3.97-4.07 (m, 1H), 4.11-4.18 (m, 1H), 4.29 (dd, J1=10.4 Hz, J2=3.2 Hz, 1H), 6.69-6.73 (m, 1H), 6.80-6.83 (m, 1H), 7.06-7.11 (m, 3H), 7.33-7.38 (m, 3H):
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:23]=[CH:22][C:21]2[O:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:24])[C:12]=2[CH:11]=1.C(Cl)(Cl)(Cl)Cl>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>[Br:1][CH2:9][C:10]1[CH:23]=[CH:22][C:21]2[O:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:24])[C:12]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2oc3ccccc3c(=O)c2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1c2ccccc2oc2ccc(CBr)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.3 %

Procedure:
Benzoyl peroxide (4.6 g, 19 mmol) and N-bromosuccinimide (67.6 g, 380 mmol) were added to a mixture of 2-methyl-9H-xanthen-9-one (79.9 g, 380 mmol) and carbon tetrachloride (800 ml) with heating under reflux, and the mixture was stirred for 4 hours. After spontaneous cooling to room temperature, water was added to the reaction mixture, and the reaction product was extracted with chloroform. The extract was washed with saturated sodium bicarbonate aqueous solution, water and saturated sodium chloride aqueous solution in that order, dried over anhydrous magnesium sulfate, and then concentrated under a reduced pressure. The resulting residue was recrystallized from ethyl acetate to give the title compound (78.3 g, 271 mmol, 71%) as yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:20](=[O:21])[CH2:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CCOC(=O)c1[nH]ccc1C
Product: CCOC(=O)c1[nH]cc(C(=O)Cc2ccc(F)cc2)c1C

Procedure:
4-[2-(4-Fluorophenyl)-acetyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (94) was synthesized from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (4-fluorophenyl)-acetyl chloride following the procedure described in Example 32. Crude yield: 94%. 1H-NMR (400 MHz, CDCl3): δ 1.36 (t, 3H), 2.61 (s, 3H), 4.01 (s, 2H), 4.35 (q, 2H), 7.01 (m, 2H), 7.22 (m, 2H), 7.50 (d, 1H), 9.70 (s broad, 1H) ppm. 13C-NMR (100 MHz, CDCl3): □ 11.79, 14.38, 46.36, 60.89, 115.51, 127.27, 129.93, 130.77, 162.04, 193.62 ppm. DEPT (100 MHz, CDCl3): CH3 carbons: 11.79, 14.38; CH2 carbons: 46.36, 60.89; CH carbons: 115.51, 127.27, 129.93, 130.77 ppm. LC/MS: 77.48%, m/z=289.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH3-]C#N.[Na+]>CO>[CH2:19]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=2)=[CH:17][CH:18]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: N#Cc1ccc(Oc2ccc(CCN)cc2)nc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(Oc2ccc(CCNCc3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve 6-[4-(2-aminoethyl)phenoxy]nicotinonitrile (2.09 g, 8.75 mmol) in methanol. Add 3 Å molecular sieves and benzaldehyde (0.89 mL, 8.75 mmol). Stir at room temperature for 18 hours. Add NaBH3CN (1.10 g). After the bubbling subsides, filter. Purify by flash chromatography, eluting with 3% (2.0 M NH3 in methanol) in dichloromethane to give the title compound: HRMS calcd for C22H20N3O 330.1620 (M+H)+, found 330.1620, time 0.39 min, MS TOF ES+ 330.2 (M+H)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=2.4 min, 100% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]([CH3:28])[CH:23]5[CH2:27][CH2:26][NH:25][CH2:24]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][C:44]([NH2:46])=[O:45]>CN(C=O)C>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]([CH3:28])[C@@H:23]5[CH2:27][CH2:26][N:25]([CH2:43][C:44]([NH2:46])=[O:45])[CH2:24]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1)C1CCNC1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1)[C@@H]1CCN(CC(N)=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To a solution of 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(methyl-pyrrolidin-3-yl-amino)-thiazol-4-one (90 mg, 0.17 mmol) in DMF (2 mL) was added potassium carbonate (72 mg, 0.52 mmol) followed by 2-Bromo-acetamide (28 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 4 hours and partitioned between water and ethyl acetate. The ethyl acetate layer was washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (5% methanol in dichloromethane) to yield the title compound (80 mg, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[O:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:36]=[C:35]([NH:37][C:38](=O)[O:39]C3C=CC=CC=3)[O:34][N:33]=2)[CH2:28][CH2:27]1.COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(NC(NC2ON=C(C(C)C)C=2)=O)C=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([NH:22][C:38]([NH:37][C:35]2[O:34][N:33]=[C:32]([CH:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)[CH:36]=2)=[O:39])[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Nc1cc(C2CCOCC2)no1)Oc1ccccc1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C5CCOCC5)no4)c3)c2cc1OC
Yield: 20.2 %

Procedure:
Prepared from 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (60 mg, 0.176 mmol) and phenyl 3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-ylcarbamate from Example 123A (56 mg, 0.194 mmol) according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B to afford 1-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-yl)urea as a colorless solid (19 mg, 20%). 1H NMR (300 MHz, DMSO-d6) δ 10.70 (brs, 1H), 9.38 (brs, 1H), 8.55 (s, 1H), 7.57 (s, 2H), 7.38-7.42 (m, 2H), 7.32 (m, 1H), 6.98 (m, 1H), 6.00 (s, 1H), 4.34-4.35 (m, 2H), 3.99 (s, 3H), 3.87-3.90 (m, 2H), 3.77-3.78 (m, 2H), 3.42-3.46 (m, 2H), 3.35 (s, 3H), 2.88 (m, 1H), 1.76-1.81 (m, 2H), 1.60-1.65 (m, 2H); LC-MS (ESI) m/z 536 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.C(O)C.Cl.[O:23]1[C:27]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)=[CH:26][N:25]=[CH:24]1>O1CCOCC1>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:16][CH3:17])=[C:8]([C:6]2[N:5]=[C:4]([NH2:18])[N:3]=[C:2]([NH:34][C:31]3[CH:30]=[CH:29][C:28]([C:27]4[O:23][CH:24]=[N:25][CH:26]=4)=[CH:33][CH:32]=3)[CH:7]=2)[CH:13]=1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Reactant: Nc1ccc(-c2cnco2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(-c3cnco3)cc2)nc(N)n1
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
To a mixture of 4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-ylamine (100 mg, 0.37 mmol) and ethanol (20 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4 M, 0.1 ml). After stirring for 10 minutes, 4-oxazol-5-yl-phenyl-amine (60 mg, 0.37 mmol) was added and the mixture was heated under reflux for 5 hours. After concentrating under reduced pressure, the residue was stirred with ethyl acetate (10 ml) and saturated aqueous sodium bicarbonate solution (10 ml). The solid was filtered and purified by flash chromatography eluting with ethyl acetate-hexane (1:1 followed by 3:2) to yield the title compound (110 mg, 75% yield). 1H NMR (acetone-d6) δ 1.44 (t, 3H, J=7.0 Hz, CH3), 4.17 (q, 2H, J=7.0 Hz, CH2), 5.88 (br s, 2H, NH), 7.04 (s, 1H, Ar), 7.12 (d, 1H, J=8.5 Hz, Ar), 7.37 (dd, 1H, J=8.8 Hz, J=2.9 Hz, Ar), 7.46 (s, 1H, Ar), 7.68 (d, 2H, J=8.7 Hz, Ar), 7.88-7.91 (m, 2H, Ar), 8.07 (d, 1H, J=2.8 Hz, Ar), 8.16 (s, 1H, Ar), 8.64 (br s, 1H, NH).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[C:20]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])=[O:11])[S:7][CH:8]=1.[CH3:27][N:28]([CH2:30][C:31](O)=[O:32])[CH3:29]>>[CH:22]1([C:20]([C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:10](=[O:11])[NH:9][C:6]2[S:7][CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:31](=[O:32])[CH2:30][N:28]([CH3:29])[CH3:27])[N:5]=2)=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CN(C)CC(=O)O
Reactant: Cc1ccc(NC(=O)Nc2nc(CCN)cs2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2nc(CCNC(=O)CN(C)C)cs2)c(C(=O)C2CCCC2)c1
Yield: 62.2 %

Procedure:
N-(2-{-2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-ethyl)-2-dimethylamino acetamide (37 mg, 61%) was prepared from 1-[4-(amino-ethyl)-thiazol-2-yl]-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (0.05 g, 0.13 mmol), dimethylamino acetic acid (0.02 g, 0.13 mmol) following the general procedure K.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][C:5]=1[C:8](=[O:10])[CH3:9]
Reactant: OB(O)c1cccs1
Reactant: COc1cc(I)ccc1C(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2cccs2)ccc1C(C)=O
Temperature: 25 °C
Yield: 97.1 %

Procedure:
Ex-57a: 4′-iodo-2′-methoxyacetophenone (1.08 g, 3.9 mmol) in ethylene glycol dimethyl ether (50 ml) was degassed for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.456 g, 0.39 mmol), thiophene-2-boronic acid (0.75 g, 5.9 mmol), and sodium carbonate solution (2 m, 4 ml, 8 mmol) were added. The mixture was stirred at reflux under nitrogen for 24 hours. Upon cooling to room temperature, it was poured into water and extracted with dichloromethane. The organic phase was dried over sodium sulfate and evaporated. Silica gel chromatography (hexane/ethyl acetate, 3:1) gave 0.88 g (98%) of the desired 2′-methoxy-4′-(thien-2-yl)acetophenone.
Reaction SMILES: [C:1]1([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.N1C=CN=C1.[Cl-].[C:17]([SiH:21]([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.CCOCC>[Si:21]([O:8][CH2:7][C:3]1[CH:2]=[C:1]([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: OCc1cccc(CO)c1
Reactant: C[SiH](C)C(C)(C)C
Agent: [Cl-]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CO)c1
Reaction time: 12 h

Procedure:
A solution of 1,3-benzenedimethanol (2 g; 14.47 mmol) in 50 ml of dimethylformamide is stirred at ambient temperature. Imidazole (1.97 g; 28.94 mmol) and tert-butyl(dimethyl)silane chloride (2.18 g; 14.47 mmol) are added in succession. After stirring for 12 hours, the reaction mixture is diluted with ether and washed with a saturated aqueous sodium chloride solution. After extraction, the ethereal phase is dried over magnesium sulphate and concentrated to yield the expected compound.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[C:18]([NH:22][NH2:23])(=O)[CH2:19][CH3:20]>C(O)CCC>[CH2:19]([C:18]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:23][N:22]=1)[CH3:20]
Reactant: FC(F)(F)c1ccc(-c2ccc(Cl)nn2)cc1
Reactant: CCC(=O)NN
Solvent: CCCCO
Product: CCc1nnc2ccc(-c3ccc(C(F)(F)F)cc3)nn12

Procedure:
As in Example 65, 5.0 g. of 3-chloro-6-(α,α,α-trifluoro-p-tolyl)pyridazine and 3.40 g. of propionic acid hydrazide in 100 ml. of butanol is refluxed for 48 hr. to give 3.1 g of white crystals (from CHCl3 -hexane), m.p. 194°-196° C.
Reaction SMILES: Br.[N:2]1([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:14]=[C:15]1[NH:24][C:23]2[N:22]=[C:21]([O:25][CH2:26][CH2:27][CH2:28][CH:29]=O)[CH:20]=[CH:19][C:18]=2[CH:17]=[CH:16]1>>[N:13]1[CH:12]=[CH:11][CH:10]=[N:9][C:8]=1[N:2]1[CH2:7][CH2:6][N:5]([CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:21]2[N:22]=[C:23]3[C:18]([CH:17]=[CH:16][C:15](=[O:14])[NH:24]3)=[CH:19][CH:20]=2)[CH2:4][CH2:3]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Agent: Br
Product: O=c1ccc2ccc(OCCCCN3CCN(c4ncccn4)CC3)nc2[nH]1

Procedure:
In a manner similar to that of other examples above, 2-piperazin-1-yl-pyrimidine hydrobromide was coupled by reductive amination to 4-(7-Oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound, MS: APCI: M+1: 381.1 (Exact Mass: 380.20).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[NH:12][C:11](=[O:19])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH2:37])[CH:35]=3)[NH:30][N:29]=2)[CH:24]=[CH:25][CH:26]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH:37][C:15]([C:14]4[CH:9]([C:4]5[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=5)[NH:10][C:11](=[O:19])[NH:12][C:13]=4[CH3:18])=[O:17])[CH:35]=3)[NH:30][N:29]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: CC1=C(C(=O)O)C(c2ccc(F)c(F)c2)NC(=O)N1
Reactant: Nc1ccc2[nH]nc(Nc3cccc(F)c3)c2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4cccc(F)c4)c3c2)C(c2ccc(F)c(F)c2)NC(=O)N1

Procedure:
The titled compound was prepared following the procedure of Example 175 using 4-(3,4-Difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, N3-(3-fluoro-phenyl)-1H-indazole-3,5-diamine, PyBroP and diisopropylethylamine in methylene chloride. MS (ESI) m/z=493 [M+H]+.
Reaction SMILES: [CH2:1]([OH:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C=O)C>[Si:30]([O:24][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCCCCCCCCCCCCCCCCCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCCCCCCCCCCCCCCCO
Temperature: 25 °C
Yield: 83.2 %

Procedure:
1,22-Docosanediol 1 (2.00 g, 5.84 mmol) and imidazole (0.817 g, 12.0 mmol) were placed in each of two nitrogen-purged 150 mL three-necked flasks fitted with a thermometer and magnetic stir bar. The flasks were resealed and purged with nitrogen. Dimethylformamide (40 mL) was added to each flask and the cloudy mixtures were heated until they became homogenous at 63° C. tert-Butyldimethylsilyl chloride (0.904 g, 6.00 mmol, in 10 mL DMF) was slowly added to the reaction mixture (the transfer was aided with an additional 5 mL of DMF) and the mixture was allowed to react for 24 hours at 60°-65° C. The solutions were cooled down to room temperature and filtered to recover starting material using water (25 mL) to aid in transfer. The filtrate was diluted with water (300 mL) and extracted with methylene chloride (500 mL). The organic layer was dried (Na2SO4) and concentrated. A very low mass balance led to the discovery that much of the desired material was contained in the recovered solid that had been previously filtered off. None of the desired compound was found in the aqueous wash by TLC. The recovered solid was suspended in methylene chloride (100 mL), stirred, and refiltered. The filtrate was combined with the previously isolated material and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10% ethyl acetate/hexane). Concentration of the desired fractions using acetone to reduce violent bumping yielded the desired material 2 as a white solid (2.22 g, 46.7%).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([O:16]C)=[O:15])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[Li+].[OH-]>C1COCC1.O>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: COC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 70 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
methyl 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate (3.5 g, 10.8 mmol) and LiOH (0.52 g, 21.7 mmol) were dissolved in a mixture of THF:H2O (1:1, 150 mL). After the resulting mixture was stirred at 70° C. for 2 h, the water phase of the reaction mixture was separated, adjusted to pH 4.0 and extracted with EtOAc (100 mL×4). The organic phase was pooled and concentrated to give product (3.0 g, 90.5%). LCMS (ESI): m/z 310.6 (M+H+)