Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]3)=[O:30])[CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:37]1[CH2:39][C@@H:38]1[CH2:40][O:41][C:42]1[CH:51]=[CH:50][CH:49]=[C:48]2[C:43]=1[CH:44]=[CH:45][CH:46]=[N:47]2>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3[CH2:39][C@@H:38]([OH:37])[CH2:40][O:41][C:42]3[CH:51]=[CH:50][CH:49]=[C:48]4[C:43]=3[CH:44]=[CH:45][CH:46]=[N:47]4)=[O:30])[CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCN(C(=O)C2CCCCN2)C1
Solvent: CCO
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCN(C(=O)C2CCCCN2C[C@@H](O)COc2cccc3ncccc23)C1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
1-(Piperidine-2-carbonyl)-piperidine-3-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (28) (234.4 mg; 0.497 mmol) is dissolved in ethanol (12 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added, then the mixture is refluxed for 15 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (90% ethyl acetate in hexanes, 50%→100% acetone in hexanes, then 5% ethanol in acetone) affording the desired product (250 mg) as a white solid. ESMS: MH+691.4
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.[OH-].[Na+]>CO>[O:5]1[CH:3]([CH2:1][O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][N:6]=3)[CH:14]=2)[CH2:4]1
Reactant: Oc1cccc(Cc2ccccn2)c1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: c1ccc(Cc2cccc(OCC3CO3)c2)nc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
19 g of epichlorohydrin is added to a mixture of 18.5 g of 3-(2-pyridylmethyl)phenol, 4.2 g of sodium hydroxide and 200 ml of methanol, and the resulting mixture is stirred at about 50°C for 3 hours. The methanol is then removed, water is added to the residue, and the aqueous solution is extracted with 200 ml of benzene. The benzene layer is washed with 5% sodium hydroxide and with water, and dried over anhydrous magnesium sulfate. The benzene is removed to give 15.0 g of 1,2-epoxy-3-[3-(2-pyridylmethyl)-phenoxy] propane as oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[CH3:12].N#N.O.NN>CO.[Ni]>[NH2:9][C:5]1[CH:4]=[C:3]([CH3:12])[C:2]([Br:1])=[CH:7][C:6]=1[CH3:8]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Br
Agent: [Ni]
Agent: N#N
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1cc(Br)c(C)cc1N
Yield: 86.6 %

Procedure:
316 g of 2-bromo-5-nitro-p-xylene were dissolved in 3000 ml of methanol, freshly produced Raney nickel (about 4 g) was added under a vigorous stream of N2, and the mixture was heated to reflux with vigorous stirring. 275 ml of hydrazine hydrate (80% in water) were then slowly added dropwise. When the dropwise addition was complete (duration about 5 hours), the mixture was refluxed for about a further 6 hours. The catalyst was filtered off, the methanol was removed in a rotary evaporator, the residue was taken up in ethyl acetate, and the solution was washed by shaking with water, dried and re-evaporated in a rotary evaporator. The resultant crude product was recrystallized from heptane, giving 238 g (87%) of pale-green crystals.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C([O:28][CH2:29][CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36])(=O)C>CO>[CH3:1][O:36][C:32]12[CH2:33][CH2:34][CH2:35][CH:31]1[CH2:30][CH2:29][O:28]2
Reactant: CC(=O)OCCC1CCCC1=O
Reactant: Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC12CCCC1CCO2
Yield: 95 %

Procedure:
A reaction vessel was charged with 21 parts of anhydrous toluene, 0.6 parts of methanol, 0.2 part of pyridinium paratoluene sulfonate (PPTS), 2.0 parts of 2-(2-acetoxyethyl)cyclopentanone (8) obtained in Preparation Example 1 at room temperature. The mixture was refluxed for seven hours with stirring. After the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate=19:1) to obtain 1.6 parts of 1-methoxy-2-oxabicyclo[3.3.0]octane (9) (yield: 95%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[C:5]([C:12]([F:15])([F:14])[F:13])[C:4]=1[NH2:16]>O1CCCC1.[Zn]>[Br:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[C:5]([C:12]([F:15])([F:14])[F:13])[C:4]=1[NH2:16]
Reactant: Nc1c(Br)cc([N+](=O)[O-])cc1C(F)(F)F
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Nc1cc(Br)c(N)c(C(F)(F)F)c1
Reaction time: 1 h
Yield: 99.2 %

Procedure:
Aqueous hydrochloric acid (2 M, 45 mL) was added slowly to a mixture of zinc dust (8.6 g) and 2-bromo-4-nitro-6-trifluoromethyl-phenylamine (2.5 g) in tetrahydrofuran (50 mL). The reaction mixture was stirred for 1 hour, filtered and neutralized with saturated aqueous sodium bicarbonate (100 mL). Water (100 mL) was added and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with water (2×200 mL) and brine (200 mL), dried over sodium sulfate and concentrated in vacuo to furnish 2.22 g (98% yield) of the title compound as a red solid. 1H NMR (500 MHz, DMSO-d6): 4.55 (s, 2H), 4.91 (s, 2H), 6.76 (d, 1H), 7.01 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.Cl>O1CCCC1>[CH2:4]([C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1)[CH2:3][CH2:2][CH2:7][CH2:6][CH3:5]
Reactant: Cc1cc(Br)cc(Br)c1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCc1cc(C)cc(Br)c1
Temperature: 57 °C
Reaction time: 0.25 h

Procedure:
After adding anhydrous tetrahydrofuran (2 L), 3,5-dibromotoluene (477 g, 1.91 mol) and 1,1-bis(diphenylphosphino)ferrocene dichloropalladium(II) dichloromethane complex (Pd(dppf).CH2Cl2, CAS:851232-71-8, 6.24 g, 7.64 mol) in a 6 L flask under an inert gas atmosphere, the mixture was stirred at 57° C. for 15 minutes. Next, solution 1-1 was added dropwise at rate which maintained a temperature of no higher than 60° C., and the mixture was stirred at 57° C. for 2 hours. The reaction mixture was then added to 10 wt % hydrochloric acid that had been cooled with an ice bath, and stirred, and extraction was performed with toluene. The obtained organic layer was rinsed twice with water and the organic layer was concentrated under reduced pressure to remove the solvent. This was followed by vacuum distillation and purification by column chromatography, to obtain 326 g of the target 3-n-hexyl-5-methylbromobenzene (compound 1-1 represented by the following formula).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[S:11][C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Li+].[OH-].Cl>CO.C1COCC1.O>[F:10][C:8]1[CH:7]=[CH:6][C:5]([S:11][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([CH:9]=1)[C:3]([OH:31])=[O:2]
Reactant: COC(=O)c1cc(F)ccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(F)ccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A mixture of 5-fluoro-2-tritylsulfanyl-benzoic acid methyl ester (4.74 g, 11.2 mmol) and LiOH (1.74 g, 41.4 mmol) in 80 mL of MeOH/THF/H2O (1/2/1) was stirred at rt overnight. The reaction mixture was acidified to pH 4 using 1 N HCl. The precipitate was collected by filtration, rinsed with water and dried in vacuo to provide 5-fluoro-2-tritylsulfanyl-benzoic acid (4.16 g). MS ESI(+) m/e: 415.13 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[NH2:13].[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O>C1COCC1>[CH3:1][O:2][C:3](=[O:14])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[NH:13][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1N
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(Cl)cc1NC(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
(E)-3-(2-Amino-4-chlorophenyl)-acrylic acid methyl ester (Carling, Robert W.; et al. J. Med. Chem. (1993), 36(22), 3397-408) (3.3 g, 15.6 mmol) in THF (63 ml) was combined with (BOC)2O (6.8 g, 31.2 mmol) and refluxed for 4 hours. THF was evaporated and a second portion of (BOC)2O added (6.8 g, 31.2 mmol). The mixture was heated to 100° C. for 18 hours. Recrystallisation from TBME/hexanes rendered the title compound as colorless crystals (4.6 g; 94%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.Cl.[NH2:12][CH2:13][C:14]([NH2:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:12][CH2:13][C:14]([NH2:16])=[O:15])[CH:3]=1
Reactant: NCC(N)=O
Reactant: N#Cc1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Br)cc1NCC(N)=O
Temperature: 120 °C
Yield: 100.3 %

Procedure:
9.1 g (45.5 mmol) 4-bromo-2-fluorobenzonitrile, 10.0 g (91.0 mmol) glycinamide hydrochloride and 15.7 g (114 mmol) K2CO3 were suspended in 80 ml DMSO and heated at 120° C. for 5.5 h. Having cooled down to room temperature, the solvent was concentrated and water was added. The resulting precipitate was sucked off and washed with water. 11.6 g (100%) 2-(5-bromo-2-cyano-phenylamino)acetamide was obtained. ESI-MS [m/z]: 254, 256 [M+H]+
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]([NH:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:22]([F:25])([F:24])[F:23])[CH:9]=2)[N:4]=1)#[N:2]>ClCCl.C(O)(C(F)(F)F)=O>[C:1]([C:3]1[CH:12]=[C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:22]([F:25])([F:24])[F:23])[CH:9]=2)[N:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)CNc1cc(C#N)nc2ccc(C(F)(F)F)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(NCC(=O)O)c2cc(C(F)(F)F)ccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 25 mL vial, was placed a solution of tert-butyl 2-(2-cyano-6-(trifluoromethyl)quinolin-4-ylamino)acetate (as prepared in the previous step, 80 mg, 0.23 mmol, 1.00 equiv) in dichloromethane (10 mL) and CF3COOH (2 mL). The reaction mixture was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The title compound was obtained as a white solid
Reaction SMILES: [OH:1][CH:2]([C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:19])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.Cl>C(Cl)Cl.CS(C)=O>[CH3:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([C@@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:19])=[O:1])=[CH:10][CH:9]=1
Reactant: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)NCc2ccccc2)cc1
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccc(OCC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)NCc2ccccc2)cc1
Temperature: -18 °C
Reaction time: 1.5 h
Yield: 76.9 %

Procedure:
(S)-2-[[(S)-2-[1-Hydroxy-2-(p-methoxyphenoxy)ethyl]-1-pyrrolidinyl]carbonyl]-N-(phenylmethyl)-1-pyrrolidinecarboxamide (5.00 g) was dissolved in methylene chloride (40 ml) and DMSO (20 ml). The mixture was cooled to -18° C. and added with diphosphorus pentaoxide (6.09 g). After stirring for 90 minutes, the reaction mixture was poured into 1.5N aqueous solution of hydrochloric acid and extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium bicarbonate and water in order, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in ethyl acetate and the mixture was left standing at room temperature for a day to give the title compound (3.83 g).
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:35])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].Cl.F[CH2:38][C:39](C1ON=C(NC(=O)NC2C=CC(NC(=O)C3C=CC(OC4CCNCC4)=CN=3)=CC=2)C=1)(C)[CH2:40]F>>[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:35])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:33][CH2:32][N:31]([CH:39]([CH3:40])[CH3:38])[CH2:30]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNC4)cn3)cc2)no1
Reactant: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)nc2)C1
Yield: 27 %

Procedure:
N-(4-(3-(5-tert-Butylisoxazol-3-yl)ureido)phenyl)-5-(1-isopropylpyrrolidin-3-yloxy)picolinamide (30 mg, 27%) was prepared using a procedure analogous to that described Example 20, substituting N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-5-(pyrrolidin-3-yloxy)picolinamide hydrochloride from Step 2 of this example for N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride used in Example 20. LC-MS (ESI) m/z 507 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.39 (s, 1H), 9.58 (br. s., 1H), 8.89 (br. s., 1H), 8.33 (br. s., 1H), 8.08 (d, J=8.48 Hz, 1H), 7.81 (d, J=8.48 Hz, 2H), 7.56 (d, J=8.67 Hz, 1H), 7.42 (d, J=8.29 Hz, 2H), 6.50 (s, 1H), 5.05 (br. s., 1H), 2.84-2.95 (m, 1H), 2.69-2.84 (m, 2H), 2.21-2.47 (m, 3H), 1.69-1.87 (m, 1H), 1.30 (s, 9H), 1.03 (d, J=5.65 Hz, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=2)[CH:3]=1.[F:21][C:22]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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].ClCCl>[F:21][C:22]1[C:27]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=[C:4]([C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=3)[CH:3]=2)=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CC1(C)OB(c2cccnc2F)OC1(C)C
Reactant: Nc1ccc(-c2cc(Cl)nc(N3CCOCC3)n2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: Nc1ccc(-c2cc(-c3cccnc3F)nc(N3CCOCC3)n2)cn1
Temperature: 120 °C

Procedure:
To a solution of 5-(6-chloro-2-morpholin-4-yl-pyrimidin-4-yl)pyridin-2-ylamine, prepared as in Example 2, (252 mg, 0.87 mmol) and 2-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (183 mg, 1.30 mmol) in DME (4 mL) was added an aqueous solution of Na2CO3 (2 M, 1 mL), followed by dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane (71 mg, 0.087 mmol). The mixture was heated in a microwave for 20 min at 120° C. The aqueous phase was separated from DME, and extracted with EtOAc. The combined organic phases were washed with brine, dried, filtered, and concentrated to give crude desired product which was carried on to the next step without further purification. LC/MS (m/z): 353.3 (MH+), 1.84 minutes.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]([CH3:10])([CH2:8][CH3:9])[CH2:6][OH:7])[CH3:4].[O:11]([C:18]1[N:23]=[C:22]([CH2:24]Cl)[CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:3]([C:5]([CH3:10])([CH2:8][CH3:9])[CH2:6][O:7][CH2:24][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:23]=1)[CH3:4]
Reactant: CCC(C)(CC)CO
Reactant: ClCc1cccc(Oc2ccccc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC(C)(CC)COCc1cccc(Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
Under a nitrogen atmosphere, 3.83 g of a 45% aqueous sodium hydroxide solution, 120 mg of tetrabutylammonium bromide and 5 ml of toluene were mixed, and to the resulting mixture solution, a solution of 1.0 g of 2-ethyl-2-methylbutanol and 1.51 g of 6-phenoxy-2-chloromethylpyridine in 5 ml of toluene was added at room temperature. After stirring at room temperature for 16 hours, the reaction solution was poured into dilute hydrochloric acid-ice water and extracted twice with toluene. The toluene layers were combined, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to column chromatography on silica gel (developing solvent, n-hexane:ethyl acetate=50:1) to obtain 1.48 g of desired 6-phenoxy-2-pyridylmethyl 2-ethyl-2-methylbutyl ether [present compound (35)] as a colorless oily product.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.FC(F)(F)S(O)(=O)=O.[C:21](Cl)(=[O:23])[CH3:22].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C:2]([F:11])([F:12])[F:1])=[CH:5][C:6]=1[C:21](=[O:23])[CH3:22]
Reactant: Oc1ccc(CC(F)(F)F)cc1
Reactant: CC(=O)Cl
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(CC(F)(F)F)ccc1O
Temperature: 150 °C

Procedure:
To a solution of 4-(2,2,2-trifluoroethyl)phenol (1.00 g, 5.68 mmol) in CH2Cl2 (5.0 ml) was added trifluoromethanesulfonic acid (0.0151 ml, 0.170 mmol) with stirring. A solution of acetic chloride (0.444 ml, 6.25 mmol) in CH2Cl2 (5.0 ml) was added drop wise to the reaction. After stirred 45 min at RT, all the phenol was consumed. The product mixture was diluted with CH2Cl2, washed with saturated sodium bicarbonate. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was dried in vacuum until no weight loss was observed. To the above residue was added anhydrous aluminum(III) chloride (0.757 g, 5.68 mmol). The mixture was heated at 150° C. for 1 h until all the starting material was consumed (monitored by TLC). The resulted brown gum was cooled to 0° C., diluted with diethyl ether and 1N HCl. Layers were separated. The aqueous layer was extracted with ether. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel column (2-15% EtOAc/hexane) to afford the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2=[CH:17][S:18][C:19]([CH3:20])=[C:6]12)=[O:4].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1CCCCC1.C(OCC)(=O)C>[CH2:3]([N:5]([CH2:11][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][N:21]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2=[CH:17][S:18][C:19]([CH3:20])=[C:6]12)=[O:4])[CH2:6][CH3:19])[CH3:2]
Reactant: Cc1scc2c1N(C(=O)CCl)c1ccccc1NC2=O
Reactant: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2ccccc2NC(=O)c2csc(C)c21

Procedure:
The title compound is prepared analogously to Example 2 from 4-(chloroacetyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-(diethylamino)methyl]piperidine to give colorless crystals, mp. 147°-149° C. (cyclohexane/ethyl acetate 9:1 v/v).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6].[CH2:18]([SnH:22]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]>>[F:17][C:2]([F:1])([F:16])[C:3]([O:11][Si:12]([CH3:14])([CH3:15])[CH3:13])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4]/[CH:5]=[CH:6]/[Sn:22]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C#CCC(CCCC)(O[Si](C)(C)C)C(F)(F)F
Reactant: CCCC[SnH](CCCC)CCCC
Product: CCCCC(C/C=C/[Sn](CCCC)(CCCC)CCCC)(O[Si](C)(C)C)C(F)(F)F

Procedure:
A stirred mixture of 6.66 g of 4-trifluoromethyl-4-trimethylsiloxy-1-octyne and 26 mg. of azabisisobutyronitrile, under argon, is treated with 6.95 ml. of tri-n-butyl tin hydride, via a syringe. After treatment, a condenser is attached to the reaction vessel and the reaction mixture, under argon, is slowly heated to 130°-135° C. and maintained at that temperature for 1.5 hours. Subsequent fractional distillation of the reaction mixture at approximately 0.07 mm pressure gives the desired product, b.p. 125°-135° C. (containing a minor amount of the corresponding cis isomer).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([N:28]=[S:29]([CH3:32])([CH3:31])=[O:30])=[CH:24][C:25]=2[CH3:27])[N:20]=[CH:19][N:18]=1)C1C=CC=CC=1.B(Br)(Br)Br.O>C(Cl)Cl>[CH3:32][S:29](=[N:28][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([NH:16][C:10]3[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=3[OH:8])=[N:18][CH:19]=[N:20]2)=[C:25]([CH3:27])[CH:24]=1)([CH3:31])=[O:30]
Reactant: Cc1cc(N=S(C)(C)=O)cc2ncnc(Nc3ccc(F)cc3OCc3ccccc3)c12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1cc(N=S(C)(C)=O)cc2ncnc(Nc3ccc(F)cc3O)c12
Reaction time: 0.25 h

Procedure:
3.5 g (7.8 mmol) of N-(2-benzyloxy-4-fluoro-phenyl)-7-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-5-methyl-quinazolin-4-amine in DCM are cooled to 0° C., 0.9 ml (9.3 mmol) boron tribromide are added dropwise and the reaction mixture is stirred for 15 min. Water is added cautiously and the aqueous layer is separated and extracted with DCM. The organic phases are pooled, washed with water, dried and evaporated. The residue is treated with isopropanol, filtered and dried.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:25])[C:19]2[N:20]=[C:21]([Cl:24])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=[O:2].[OH-].[Na+]>CO>[C:1]([CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:25])[C:19]2[N:20]=[C:21]([Cl:24])[S:22][CH:23]=2)[CH3:15])=[CH:11][CH:12]=1)([OH:3])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(Cl)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(Cc1ccc(OCC(=O)O)cc1)NCC(O)c1csc(Cl)n1

Procedure:
Prepared by analogy to Example 97 by reaction of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2- chloro-thiazol-4-yl)ethanamine with 1N sodium hydroxide solution in methanol
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:25]2[CH:26]=[C:27](C3C=CC=C(OC)C=3)[C:28]([OH:31])=[CH:29][CH:30]=2)([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br:41]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([Br:41])[CH:26]=2)([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C2(c3ccc(O)c(-c4cccc(OC)c4)c3)N=C(NC(=O)OC(C)(C)C)c3ccccc32)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2(c3ccc(O)c(Br)c3)N=C(NC(=O)OC(C)(C)C)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
To an ice cold solution of [3-(4-hydroxy-phenyl)-3-(4-methoxy-phenyl)-3H-isoindol-1-yl]-carbamic acid tert-butyl ester (Scheme #2, D) (663 mg, 1.540 mmol) in dry chloroform was added N-bromosuccinimide (274 mg, 1.540 mmol) portion-wise over 30 minutes and the reaction stirred for 25 minutes. The solvent was removed under reduced pressure and the mixture chromatographed on 80 g silica eluting with 5% acetone in dichloromethane.