Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)#[N:25].Cl.CCOCC>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][N:10]([C:30]([C:29]4[CH:33]=[CH:34][C:26]([C:24]#[N:25])=[CH:27][CH:28]=4)=[O:31])[CH2:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: N#Cc1ccc(C(=O)N2CCc3[nH]c4ncc(Cl)cc4c3C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) and DIEA (0.05 mL, 0.29 mmol) were dissolved in THF (2 mL). 4-Cyanobenzoyl chloride (47.84 mg; 0.29 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 1 h. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. The resulting precipitate was filtered and dried under vacuum to provide 22 (40 mg, 45% yield) as a pale yellow solid. LC-MS (M+H=337, obsd.=337).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:5][O:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[C:35]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)#[N:36].[OH-].[K+].CO>O1CCCC1.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:35]([C:37]1[CH:42]=[CH:41][C:40]([C:2]2[CH:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[C:4]([CH2:5][O:6][CH2:7][C:8]3([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:12][CH2:13]3)[CH:3]=2)=[CH:39][CH:38]=1)#[N:36]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(C(F)(F)F)c2)(c2ccccc2F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2ccccc2F)CC1
Temperature: 120 °C

Procedure:
A sealable vial was charged with tert-butyl 4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(2-fluorophenyl)piperidine-1-carboxylate (0.138 g, 0.25 mmol) and 4-cyanophenylboronic acid (0.111 g, 0.75 mmol) in tetrahydrofuran (2 mL) at 0° C. To the reaction solution was added 1N potassium hydroxide (0.88 mL, 0.88 mmol) and Tetrakis(triphenylphosphine)palladium(0) (0.058 g, 0.05 mmol). The vial was purged with nitrogen and sealed. The sealed vial was heated in a microwave reactor at 120° C. for 2 hr. The reaction was cooled to room temperature and diluted with 4 mL ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated in vacuo. The crude oil was purified by silica gel chromatography (5% ethyl acetate/95% hexanes→35% ethyl acetate/65% hexanes) to afford 0.123 g (87%) of the desired ether. Mass spec.: 591.22 (MNa)+; LC tr=4.318 min. (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=4 min, Flow rate=4 mL/min).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][S:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([CH2:41][NH2:42])=[CH:40][C:35]=2[O:34][CH2:33]1>>[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([CH2:41][NH:42][C:3]([C:5]3[N:14]4[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][S:21][C:22]5[CH:23]=[CH:24][C:25]([Br:28])=[CH:26][CH:27]=5)[C:11]5[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=5[CH2:13]4)=[CH:7][CH:6]=3)=[O:4])=[CH:40][C:35]=2[O:34][CH2:33]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: O=C(CSc1ccc(Br)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Product: O=C(NCc1ccc2c(c1)OCO2)c1ccc2n1Cc1ccccc1N(C(=O)CSc1ccc(Br)cc1)C2

Procedure:
The title compound was synthesized in the manner of Example 81 from 2,2,2-trichloro-1-[10-{[(4-bromophenyl)thio]acetyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl]-ethanone of Example 80 and C-benzo[1,3]dioxol-5-yl-methylamine, m.p. 154-155° C. MS [(+)ESI, m/z]: 590 [M+H]+ Anal. Calcd for C29H24BrN3O4S: C, 58.99; H, 4.10; N, 7.12. Found: C, 58.96; H, 4.26; N, 7.03.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].O(C(C)(C)C)[K]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[CH:11]=[C:10]([Cl:12])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Clc1cc(Cl)c2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[K]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)c3ccccc3n2)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a degassed solution of 2,4-dichloro-quinoline (1.00 g, 5.05 mmol, 1.0 equiv; commercially available from Specs Research Laboratory, The Netherlands) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.21 g, 6.06 mmol, 1.2 equiv; commercially available) in dimethoxyethane (15 mL) was added KOtert-Bu (0.79 g, 7.07 mmol, 1.4 equiv), (R)-(−)-1-[(S)-2-(dicyclohexyl-phosphino)-ferrocenyl]ethyl-di-tert-butylphosphine (2.80 mg, 0.0051 mmol, 0.1 mol %; Josiphos ligand [CAS RN 158923-11-6]; commercially available from Strem Chemicals, USA) and palladium(II) acetate (1.13 mg, 0.0051 mmol, 0.1 mol %). The reaction mixture was stirred at 90° C. for 2 h, concentrated by evaporation under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane (+1% triethylamine)/ethyl acetate providing 0.22 g (12%) of the title compound. 1H NMR (300 MHz, DMSO): δ1.27-1.41 (m, 2H), 1.42 (s, 9H), 1.93-1.97 (m, 2H), 2.95-3.03 (m, 2H), 3.86-3.90 (m, 2H), 4.09-4.16 (m, 1H), 6.96 (s, 1H), 7.14 (d, J=7.7 Hz, 1H), 7.24-7.30 (m, 1H), 7.55-7.57 (m, 2H), 7.86 (d, J=7.7 Hz, 1H). MS (ISP): 362.4 [M+H]−.
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])C(=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=[C:4](OC)[CH:3]=1.[CH3:40]C1C=CC=CC=1B(O)O>C(Cl)Cl.CO>[CH3:37][S:34]([CH2:33][CH2:32][NH:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[CH3:40])(=[O:35])=[O:36]
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: Cc1ccccc1B(O)O
Solvent: CO
Solvent: ClCCl
Product: Cc1ccccc1-c1ccncc1NCCS(C)(=O)=O

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2-methanesulfonyl-ethyl)-amine (example 158, intermediate b) and 2-methylphenylboronic acid (CAS RN 16419-60-6) and using a gradient of CH2Cl2: methanol (100:0 to 85:15) for the chromatographic purification. Brown oil (85%). MS (ESI): m/z=291.12 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]=[N+]=[N-])=[CH:12][CH:11]=2)[C:5]([C:22]#[N:23])=[C:4]([S:24][CH2:25][C:26]2[N:27]=[C:28]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[S:29][CH:30]=2)[N:3]=1.[H][H].[ClH:41]>O1CCOCC1.[Pd]>[ClH:41].[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][NH2:19])=[CH:14][CH:15]=2)[C:5]([C:22]#[N:23])=[C:4]([S:24][CH2:25][C:26]2[N:27]=[C:28]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)[S:29][CH:30]=2)[N:3]=1
Reactant: [H][H]
Reactant: N#Cc1c(N)nc(SCc2csc(Nc3ccc(F)cc3)n2)c(C#N)c1-c1ccc(OCCN=[N+]=[N-])cc1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1c(N)nc(SCc2csc(Nc3ccc(F)cc3)n2)c(C#N)c1-c1ccc(OCCN)cc1
Reaction time: 3 h

Procedure:
1000 mg (1.84 mmol) of the compound from Example 39A are dissolved in 100 ml of dioxane, 150 mg (1.41 mmol) of palladium-on-activated carbon are added and the mixture is hydrogenated with hydrogen at 3 bar. After 3 h, 4 ml of 2M hydrochloric acid are added and the mixture is hydrogenated with hydrogen at 3 bar for a further 20 h. The mixture is then filtered off with suction through a Seitz clarifying sheet filter, the product is then washed with 50 ml of dioxane, and 50 ml of toluene are added to the filtrate. After removal of the solvent on a rotary evaporator, the residue is taken up in a mixture of 50 ml of water and 50 ml of ethyl acetate. By cautious addition of aqueous dilute sodium bicarbonate solution, the pH is adjusted to about pH 9. The phases formed are separated. The organic phase is dried over magnesium sulphate, the solvent is then removed using a rotary evaporator and the residue is purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5, with addition of 0.5% concentrated hydrochloric acid). The product-containing fractions are combined and concentrated using a rotary evaporator.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11]Br)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[NH2:14][C:15]([NH2:17])=[S:16].C([O-])(O)=O.[Na+]>CCO.O>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:15]([NH2:17])[S:16][CH:11]=2)=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: NC(N)=S
Reactant: [N-]=[N+]=Nc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=Nc1ccc(-c2csc(N)n2)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-azidophenyl)-2-bromoethanone (1.37 g, 5.71 mmol) in EtOH (15 mL) at room temperature was added thiourea (0.476 g, 6.25 mmol). The reaction mixture was heated to 70° C. for 3 d, poured into a solution of NaHCO3 (602 mg) in water (50 mL) and stirred for 30 min. The precipitate that formed was collected by filtration, washed with water, and dried under high vacuum to give 4-(4-azidophenyl)thiazol-2-amine.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:10]=1[NH2:11].[Cl:17][CH2:18][C:19](Cl)=[O:20]>O1CCCC1>[Cl:17][CH2:18][C:19]([NH:11][C:10]1[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=1[OH:8])=[O:20]
Reactant: Cc1ccc(N)c(O)c1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)CCl)c(O)c1
Temperature: 26 °C
Yield: 73.6 %

Procedure:
95 ml of triethylamine (0.674 mol) were added to a solution of 83 g of 2-hydroxy-4-methylaniline (0.674 mol) in 2.5 liters of tetrahydrofuran, with stirring and under an inert atmosphere, followed, after 30 minutes, by dropwise addition of a solution of 54 ml of chloroacetyl chloride (0.678 mol) in 60 ml of tetrahydrofuran, while maintaining the temperature at 25-27° C. The reaction medium was stirred at room temperature for 4 hours, filtered through a sinter funnel and the inorganic salts were rinsed with 500 ml of tetrahydrofuran. The combined organic phases were poured into 3 liters of ice-cold water with stirring. The precipitate formed was spin-filtered, washed with twice 600 ml of water and once with pentane, and dried under vacuum to constant weight, to give 99 g of 2-chloro-N-(2-hydroxy-4-methylphenyl)acetamide in the form of a beige-coloured powder, in a yield of 74%.
Reaction SMILES: Br.[N:2]1([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH2:26]1[O:37][C:36]2[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]=2[O:27]1.O>CN(C=O)C>[CH2:26]1[O:37][C:36]2[CH:35]=[CH:34][C:30]([C:31]([N:5]3[CH2:6][CH2:7][N:2]([C:8]4[CH:9]=[C:10]5[C:15](=[CH:16][CH:17]=4)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]5)[CH2:3][CH2:4]3)=[O:32])=[CH:29][C:28]=2[O:27]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: O=c1ccc2cc(N3CCNCC3)ccc2[nH]1
Agent: Br
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)OCO2)N1CCN(c2ccc3[nH]c(=O)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
6-(1-Piperazinyl)carbostyril hydrobromide (2.0 g) was suspended in 20 ml of DMF. After adding 2.34 ml of triethylamine, a solution of 1.43 g of 3,4-methylenedioxybenzoyl chloride in 2 ml of DMF was added dropwise to the mixture. After completion of addition, the mixture was stirred at room temperature for 30 minutes and the reaction mixture was poured in a large amount of water. Crystals which formed were collected by filtration and dried. Then, the crystals were purified through silica gel column chromatography and recrystallized from chloroform-methanol to give 1.9 g of 6-[4-(3,4-methylenedioxybenzoyl)-1-piperazinyl]carbostyril, m.p. 266°-267° C. (decomp.), yellow powders.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])[CH3:4].[NH:17]([C:24]1([C:30]([NH2:32])=[O:31])[CH2:29]CNC[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[O:16]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH2:15][CH:6]1[CH2:5][N:3]1[CH2:2][CH2:25][C:24]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:30]([NH2:32])=[O:31])[CH2:29][CH2:4]1
Reactant: NC(=O)C1(Nc2ccccc2)CCNCC1
Reactant: CN(C)CC1CCc2ccccc2C1=O
Agent: Cl
Solvent: CCO
Product: NC(=O)C1(Nc2ccccc2)CCN(CC2CCc3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-[(Dimethylamino)methyl]-3,4-dihydro-1(2H)-naphthalenone, hydrochloride (10.0 g) and 4-anilino isonipecotamide (10.2 g) are dissolved in absolute ethanol (150 ml) by brief heating. The reaction mixture is stirred at room temperature under nitrogen for 16 hours. The resulting precipitate is collected by filtration, washed with additional absolute ethanol, and dried in vacuo to give the title compound.
Reaction SMILES: C([Li])CCC.C([O:10]O)(C)(C)C.[F:12][C:13]([F:27])([F:26])/[CH:14]=[C:15](/[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18])\[CH3:16]>O1CCCC1.C(OCC)(=O)C>[C:20]1([S:17]([C:15]2([CH3:16])[CH:14]([C:13]([F:12])([F:26])[F:27])[O:10]2)(=[O:18])=[O:19])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C/C(=C\C(F)(F)F)S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OO
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(S(=O)(=O)c2ccccc2)OC1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 49 %

Procedure:
To a solution of 15.2 mmol n-butyllithium solution (1.6 M in hexane) in 20 ml tetrahydrofuran at −78° C. was added dropwise 15.2 mmol tert-butyl hydroperoxide solution (5.5 M in nonane) and the mixture was stirred at −78° C. for 10 min, then warmed to −50° C. and re-cooled to −78° C. A solution of 10.1 mmol ((E)-4,4,4-trifluoro-but-2-ene-2-sulfonyl)-benzene in 6 ml tetrahydrofuran was then added dropwise and stirring continued for a further 30 min at −78° C. and then the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate and washed sequentially with 1 M hydrochloric acid and with brine. The organic phase was then dried over sodium sulphate and concentrated in vacuo. The residue was purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as a colourless oil (yield 49%). EI-MS (m/e): 251.1 ([M−CH3]+, 6%), 250.1 ([M−O]+, 20%), 126.1 (PhSOH+, 61%), 125.0 ([M−PhSO2]+, 100%), 78.2 (PhH+, 21%), 77.2 (Ph+, 44%), 43.3 (CH3CHCH3+, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:12]C(=O)OC(C)(C)C)[CH2:10][OH:11])=[CH:5][CH:4]=1.Cl.[OH-].[Na+]>CO>[NH2:12][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:10][OH:11]
Reactant: COc1ccc(C(CO)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(N)CO)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
A mixture of 3.4 g of tert-butyl 1-(4-methoxyphenyl)-2-hydroxyethylcarbamate in 32 cm3 of methanol containing 10% by mass of anhydrous hydrogen chloride is stirred for 1 hour at a temperature in the region of 20° C. The reaction medium is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue is taken up in 9 cm3 of aqueous 5% sodium hydrogen carbonate solution and the mixture is then extracted with 3 times 30 cm3 of dichloromethane. The aqueous phase is concentrated as above and the white solid obtained is then taken up in 17 cm3 of aqueous 1N sodium hydroxide solution. The precipitate is extracted with 3 times 30 cm3 of dichloromethane. The combined organic extracts are evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The white solid obtained is dried under reduced pressure (10 Pa) at a temperature in the region of 40° C. 1.3 g of 2-amino-2-(4-methoxyphenyl)-1-ethanol are obtained in the form of a white solid melting at 96° C. tert-Butyl 1-(4-methoxyphenyl)-2-hydroxyethylcarbamate: 2.24 g of lithium chloride are added to a solution of 7.8 g of methyl N-Boc-(4-methoxyphenyl)glycinate in 35 cm3 of tetrahydrofuran cooled to a temperature of 0° C., followed by portionwise addition of 1.99 g of sodium borohydride and finally 74 cm3 of ethanol. The temperature is allowed to return to about 20° C. and the reaction is then completed by stirring the mixture for 18 hours at this same temperature. The medium is re-cooled to about 5° C. and a sufficient amount of aqueous 1M sodium hydrogen sulfate solution to give a pH in the region of 2 is then added thereto. The mixture is stirred for 3 hours and is then evaporated under reduced pressure (5 kPa) at a temperature in the region of 50° C. 60 cm3 of dichloromethane and 30 cm3 of aqueous 1M sodium hydrogen sulfate solution are added to the residue obtained. After stirring the mixture and then separating out the organic phase after settling of the phases has taken place, the aqueous phase is extracted with twice 30 cm3 of dichloromethane. The combined organic extracts are dried over sodium sulfate and concentrated as above. A white solid is obtained, which is taken up in 30 cm3 of cyclohexane and filtered. The crystals are dried under reduced pressure (10 Pa) at a temperature in the region of 60° C. 3.47 g of tert-butyl 1-(4-methoxyphenyl)-2-hydroxyethylcarbamate are obtained in the form of a white solid melting at 130° C.
Reaction SMILES: C([O:4][CH:5]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][N:8]=1)[CH3:6])(=O)C.[OH-].[K+].C(O)C>O>[O:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([CH:5]([OH:4])[CH3:6])=[N:8]1
Reactant: CC(=O)OC(C)c1noc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(O)c1noc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2.6 g of 3-(1-acetoxyethyl)-1,2-benzisoxazole, 0.9 g of potassium hydroxide, 40 ml of ethanol and 3 ml of water is stirred for 1 h at room temperature. The reaction mixture is then concentrated under vacuum and diluted with water. This aqueous phase is extracted three times with diethyl ether, the combined ethereal extracts are then washed with a saturated solution of sodium chloride and dried over sodium sulfate, giving 1-(1,2-benzisoxazol-3-yl)ethanol as an oil having a refractive index nD20 of 1.5555.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[NH2:15]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:15][C:14]1[CH:13]=[C:12]([Cl:11])[CH:18]=[C:17]([Cl:19])[CH:16]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: Clc1nc2ccccc2[nH]1
Product: Clc1cc(Cl)cc(Nc2nc3ccccc3[nH]2)c1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3,5-dichloroaniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (solid, mp 317-318° C.). MS(ES+) m/z 278 (M+, 100).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C:12]1[NH:13][CH:14]=[CH:15][N:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:11][C:12]1[N:13]([C:2]2[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=2)[CH:14]=[CH:15][N:16]=1
Reactant: O=C(O)c1cnc(Cl)nc1
Reactant: Cc1ncc[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ncc(C(=O)O)cn1
Temperature: 25 °C

Procedure:
2-Chloropyrimidine-5-carboxylic acid (0.75 g), 2-methylimidazole (0.117 g) and potassium carbonate (1.96 g) in 3.75 mL of N,N-dimethylformamide are heated in microwave at 50° C. for 30 min, then cooled to room temperature and acidified with 3 mL of 1 N HCl, followed by addition of conc. HCl to pH 2. The precipitate is filtered, washed with minimum amount of water, diethyl ether and dried in vacuo to afford the title compound. LC (method 20): tR=0.48 min; Mass spectrum (APCI): m/z=205 [M+H]+.
Reaction SMILES: [F:1]/[C:2](/[C:5](/[CH3:19])=[CH:6]/[CH2:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([O:15][CH3:16])=[C:10]([CH3:17])[C:9]=1[Cl:18])=[CH:3]\[OH:4]>CCOCC.[O-2].[O-2].[Mn+4]>[F:1]/[C:2](=[C:5](/[CH3:19])\[CH:6]=[CH:7]\[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([O:15][CH3:16])=[C:10]([CH3:17])[C:9]=1[Cl:18])/[CH:3]=[O:4]
Reactant: COc1cc(Cl)c(C/C=C(C)/C(F)=C/O)c(Cl)c1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Product: COc1cc(Cl)c(/C=C/C(C)=C(\F)C=O)c(Cl)c1C
Reaction time: 14 h
Yield: 95 %

Procedure:
A solution of 5.6 g. (18.4 mmol) of 2Z,4E-2-fluoro-3-methyl-5-(2,6-dichloro-3-methyl-4-methoxyphenyl)pentadien-1-ol in ether was added to a stirred suspension of 24 g. of activated manganese dioxide in ether. After 14 hours, thin layer chromatography indicated that all of the alcohol had reacted. The mixture was filtered through Celite. The filtrate was concentrated and the residue was chromatographed on silica gel to give 5.4 g. (95% yield) of 2Z,4E-2-fluoro-3-methyl-5-(2,6-dichloro-3-methyl-4-methoxyphenyl)pentadien-1-al.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([CH3:14])[C@H:11](/[CH:15]=[CH:16]/[C:17]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][C:29]=2[O:30][CH2:31][CH3:32])[N:26]=[CH:25][C:24]([C:33]#[N:34])=[C:23]3[NH:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)=[C:38]([Cl:50])[CH:37]=2)=[O:18])[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[Cl:50][C:38]1[CH:37]=[C:36]([NH:35][C:23]2[C:22]3[C:27](=[CH:28][C:29]([O:30][CH2:31][CH3:32])=[C:20]([NH:19][C:17](=[O:18])/[CH:16]=[CH:15]/[C@@H:11]4[CH2:10][C@@H:9]([OH:8])[CH2:13][N:12]4[CH3:14])[CH:21]=3)[N:26]=[CH:25][C:24]=2[C:33]#[N:34])[CH:41]=[CH:40][C:39]=1[O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)/C=C/[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)/C=C/[C@@H]1C[C@@H](O)CN1C
Reaction time: 12 h
Yield: 40.5 %

Procedure:
(E)-3-[(2S,4R)-4-(tert-Butyl(dimethyl)silyl)oxy-1-methyl-pyrrolidin-2-yl]-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]prop-2-enamide 3f (50 mg, 0.07 mmol) and tetrabutyl ammonium fluoride (51 mg, 0.21 mmol) were dissolved in 5 mL of tetrahydrofuran, and the mixture was stirred for 12 hours. The reaction mixture was added with 1 mL of water, concentrated under reduced pressure and extracted with dichloromethane (50 mL×3). The combined organic extracts were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-3-[(2S,4R)-4-hydroxy-1-methyl-pyrrolidin-2-yl]prop-2-enamide 3 (17 mg, yield 40.4%) as a yellow solid.