Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1.[CH2:18]([N:22]=[C:23]=[O:24])[CH2:19][CH2:20][CH3:21].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:18]([NH:22][C:23]([N:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=1)[CH2:4][CH2:3][N:2]([CH3:1])[CH3:17])=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCN=C=O
Reactant: COC(=O)c1ccc(CNCCN(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)N(CCN(C)C)Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
To a solution of methyl 4-[[[2-(dimethylamino)ethyl]amino]methyl]benzoate (compound obtained in Reference Example 36(1), 200 mg) in methylene chloride (4 mL) is added n-butyl isocyanate (143 μL) and the mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with chloroform (5 mL) and thereto is added a saturated sodium hydrogencarbonate solution (10 mL). After stirring, the organic layer is separated and concentrated. The resultant crude product is purified by column chromatography on silica gel (Solvent; chloroform:methanol=100:0→90:10) to give methyl 4-[[N-(butylcarbamoyl)-N-[2-(dimethylamino)ethyl]amino]methyl]-benzoate (261 mg, yield; 92%) as a pale yellow oil. MS (APCI) m/z: 336 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[H-].[Na+].[CH2:13]([N:20]1[C:24]2[N:25]=[C:26]([NH2:30])[N:27]=[C:28](Cl)[C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[C:24]2[N:25]=[C:26]([NH2:30])[N:27]=[C:28]([O:10][C:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: Nc1nc(Cl)c2ccn(Cc3ccccc3)c2n1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C)c(Oc2nc(N)nc3c2ccn3Cc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.5 %

Procedure:
To a solution of 2,4,6-trimethylphenol (161 mg, 1.16 mmol) in 1-methyl-2-pyrridone (2 mL) in a sealed tube was added NaH (46 mg, 1.16 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (100 mg, 0.39 mmol) in 1-methyl-2-pyrridone (1 mL) was added to the mixture. The mixture was heated at 150° C. for 16 h and cooled to room temperature. The reaction mixture was poured into ice water and extracted with EtOAc (2×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 107 mg (77%) of 7-benzyl-4-(2,4,6-trimethyl-phenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.Cl>O>[N+:15]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])[C:2]=1[N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:6]([OH:8])=[O:7])([O-:17])=[O:16]
Reactant: C1CCNCC1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: Cl
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1N1CCCCC1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (2.8 g), piperidine (3.4 g), and water (13 ml) was stirred at 95°C for 2 hours. Then the reaction mixture was adjusted to a pH of 2.5 by the addition of 4N hydrochloric acid, and the precipitated 3-nitro-4-piperidino-5-sulphamyl-benzoic acid was collected and recrystallized from aqueous methanol. The melting point was 237°-238°C (decomp.).
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([NH:11][C@@H:12]([CH:29]([CH3:31])[CH3:30])[C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C@H:16]1[C:24]([O:26]CC)=[O:25])=[O:14])=[O:10])([CH3:7])([CH3:6])[CH3:5]>O.C1COCC1.CO>[C:4]([O:8][C:9]([NH:11][C@@H:12]([CH:29]([CH3:31])[CH3:30])[C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C@H:16]1[C:24]([OH:26])=[O:25])=[O:14])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.7 %

Procedure:
Lithium hydroxide monohydrate (187 mg, 4.46 mmol, Eq: 3) in water (4.5 mL) was added to an ice-bath cooled solution of (S)-ethyl 1-((S)-2-(tert-butoxycarbonylamino)-3-methylbutanoyl)indoline-2-carboxylate (0.58 g, 1.49 mmol, Eq: 1.00) in THF (13.5 mL) and MeOH (4.5 mL). The cooling bath was removed and the reaction was stirred at rt for 1 h. 0.1 M Aqueous KHSO4 (50 mL) was added to the reaction mixture and the resulting mixture was extracted with DCM (2×50 mL). The aqueous layer was further acidified with 1 M aqueous HCl (˜5 mL) and extracted again with DCM (2×50 mL). The organic layers were combined, dried over Na2SO4 and concentrated in vacuo. The residue was azeotroped with hexanes to give (S)-1-((S)-2-(tert-butoxycarbonylamino)-3-methylbutanoyl)indoline-2-carboxylic acid (0.56 g), m/z=363 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:14]([Cl:17])=[N:15][CH:16]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2S(C1C=CC=CC=1)(=O)=O.N1C=CC=CC=1.[CH3:38][C:39]1[S:40][CH:41]=[C:42]([C:44](Cl)=[O:45])[N:43]=1>C(Cl)Cl>[Cl:17][C:14]1[N:15]=[CH:16][C:11]([C:9]2[CH:8]=[C:7]3[C:3]([CH:4]=[N:5][NH:6]3)=[C:2]([NH:1][C:44]([C:42]3[N:43]=[C:39]([CH3:38])[S:40][CH:41]=3)=[O:45])[CH:10]=2)=[CH:12][C:13]=1[NH:18][S:19]([CH3:22])(=[O:20])=[O:21]
Reactant: CS(=O)(=O)Nc1cc(-c2cc(N)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cnc1Cl
Reactant: Cc1nc(C(=O)Cl)cs1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(C(=O)Nc2cc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)cc3[nH]ncc23)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.1 %

Procedure:
N-{5-[4-Amino-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-chloro-3-pyridinyl}methane sulfonamide (100 mg) was dissolved in DCM (5 ml) and pyridine (0.02 ml) was added. 2-Methyl-1,3-thiazole-4-carbonyl chloride (41 mg) was added and the reaction stirred at RT for 1 h. The reaction was evaporated to dryness and the residue was stirred in MeOH:2M NaOH (aq) (5 ml, 1:1, v/v) for 15 min. The reaction was neutralised with 2M HCl and evaporated to dryness. The residue was dissolved in DMSO (1 ml), filtered and purified by MDAP (method E). The pure fraction was evaporated to dryness to give title compound (33 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([F:25])[C:22]([N:26]2[C:30](=[O:31])[N:29]([CH:32]([F:34])[F:33])[C:28]([CH3:35])=[N:27]2)=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]([CH3:20])[C:13]([O:15]C(C)(C)C)=[O:14])=[CH:7][N:6]=1.ClC(C)C(OC(C)(C)C)=O>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:24]=[C:23]([F:25])[C:22]([N:26]2[C:30](=[O:31])[N:29]([CH:32]([F:34])[F:33])[C:28]([CH3:35])=[N:27]2)=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]([CH3:20])[C:13]([OH:15])=[O:14])=[CH:7][N:6]=1
Reactant: Cc1nn(-c2cc(Oc3ccc(OC(C)C(=O)OC(C)(C)C)cn3)c(Cl)cc2F)c(=O)n1C(F)F
Agent: CC(Cl)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(-c2cc(Oc3ccc(OC(C)C(=O)O)cn3)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
A mixture of 1.2 g (0.0023 mole) of t-butyl 2-[2-[2-chloro-4-fluoro-5-(4-difluoromethyl -4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]pyridin-5-yloxy]propionate (prepared by the method of Example 3, Step E using t-butyl 2-chloropropionate) in 7 mL of trifluoroacetic acid was stirred at room temperature for 30 minutes. The excess trifluoroacetic acid was removed by evaporation under reduced pressure leaving an oil. The oil was partitioned between diethyl ether and water. The organic phase was separated, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure leaving a thick oil. Upon standing, the oil crystallized as a white solid. The solid was triturated with petroleum ether to give 0.66 g of 2-[2-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]pyridin-5-yloxy]propionic acid, m.p. 49°-51° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22]O.C(P(CCCC)CCCC)CCC.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C.O>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][O:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cnc([N+](=O)[O-])c(O)c1
Reactant: OCc1ccccc1F
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cnc([N+](=O)[O-])c(OCc2ccccc2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2 g of methyl 5-hydroxy-6-nitronicotinate, 1.62 ml of (2-fluorophenyl)methanol, and 3.99 ml of tributylphosphine in 40 ml of THF was added 2.54 ml of diethyl azodicarboxylate under ice-cooling, followed by stirring for 1 hour under ice-cooling and at room temperature for 2 hours. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2.58 g of methyl 5-[(2-fluorobenzyl)oxy]-6-nitronicotinate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].[Br:17][C:18]1[CH:25]=[C:24](F)[CH:23]=[CH:22][C:19]=1[CH:20]=[O:21].Cl>CN(C=O)C.CCOC(C)=O>[Br:17][C:18]1[CH:25]=[C:24]([CH:23]=[CH:22][C:19]=1[CH:20]=[O:21])[O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[F:1]
Reactant: O=Cc1ccc(F)cc1Br
Reactant: N#Cc1ccc(O)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(C=O)c(Br)c2)c(F)c1
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 61.6 %

Procedure:
To a solution of 3-fluoro-4-hydroxy-benzonitrile (5 g, 36 mmol) in DMF (anhydrous, 100 mL) was slowly added K2CO3 (5.54 g, 40.1 mmol). After stirring for 5 minutes, to the solution was added 2-bromo-4-fluoro-benzaldehyde (8.89 g, 43.8 mmol). The reaction was heated at 70° C. and monitored by T.L.C. After 4 hours, the heating was stopped and after cooling to the room temperature, 100 mL of EtOAc was added. With stirring, 1 M HCl (˜50 mL) was slowly added until the pH was 7. The organic layer was then washed with H2O (3×50 mL), dried over MgSO4 and filtered. The filtrate was evaporated under vacuum. The residue was purified over silica gel, eluting with 12.5% EtOAc/hexanes to afford 4-(3-bromo-4-formyl-phenoxy)-3-fluoro-benzonitrile (3) 7.1 g in 61% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.28 (s, 1 H), 7.96 (d, J=8.60 Hz, 1 H), 7.51-7.59 (m, 2 H), 7.21-7.29 (m, 3 H), 7.03 (dd, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:24])[CH2:16][N:17]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[N:18]3)[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([NH:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15](=[O:24])[CH2:16][N:17]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[N:18]3)[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1)=[O:30]
Reactant: Cc1cc(C)n(CC(=O)N2CCN(c3ncc(Cl)cc3N)CC2)n1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C)n(CC(=O)N2CCN(c3ncc(Cl)cc3NC(=O)c3cccc(Cl)c3)CC2)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1-[4-(3-amino-5-chloro-pyridin-2-yl)-piperazin-1-yl]-2-(3,5-dimethyl-pyrazol-1-yl)-ethanone (0.040 g, 0.11 mmol) in methylene chloride (2 mL) is added 3-chlorobenzoyl chloride (0.020 mL, 0.160 mmol) followed by of N,N-diisopropylethylamine (0.045 mL, 0.25 mmol). The mixture is stirred at room temperature for 3 days. The mixture is concentrated under a stream of nitrogen and the residue is purified by preparative reverse phase HPLC to provide, after removal of the eluent under reduced pressure, 0.030 g of 3-chloro-N-(5-chloro-2-{4-[2-(3,5-dimethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-pyridin-3-yl)-benzamide as a white solid in 53% yield. MS; MH+=487.7
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:7]2[CH2:20][CH2:21][N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:6]12)=O.[Li+].[BH4-].CO.O>C1COCC1>[C:26]([O:25][C:23]([N:22]1[CH:6]2[CH:7]([N:8]([C:10]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:11])[CH2:9][CH:5]2[CH2:3][OH:2])[CH2:20][CH2:21]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)C2CCN(C(=O)OC(C)(C)C)C12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2C1C(CO)CN2C(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 75.3 %

Procedure:
A solution of ester 76 (2.7 g, 6.7 mmol) in THF (15 mL) was cooled to 0° C. and treated with LiBH4 (10 mL, 2M in THF). After 3 h, the solution was slowly treated with MeOH followed by H2O. The solution was then concentrated and diluted with EtOAc. The solution was slowly treated with 1M HCl until gas generation ceased. The solution was extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was absorbed onto SiO2 and purified by flash chromatography (1:1 hexane/EtOAc to 1:2 hexane/EtOAc) to afford alcohol 77 (1.9 g, 75%) as a light yellow-colored oil. 1H NMR (CDCl3, 300 MHz): δ7.39-7.27 (m, 5H), 5.13-5.09 (m, 2H), 4.43-4.41 (m, 1H), 4.13-4.08 (m, 2H), 3.70-3.29 (m, 6H), 2.48-2.46 (m, 1H), 2.53-2.05 (m, 1H), 2.03-1.99 (m, 1H), 1.48 (s, 9H) ppm. Mass spectrum, m/z [377.5] (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].FC(F)(F)C1C=CC(COC2C=CC(N3CCNCC3)=CC=2)=CC=1.ClCC(Cl)=O.[N+:58]([C:61]1[CH:66]=[CH:65][C:64]([NH:67][C@H:68]2[CH2:73][CH2:72][C@H:71]([OH:74])[CH2:70][CH2:69]2)=[CH:63][C:62]=1[C:75]([F:78])([F:77])[F:76])([O-:60])=[O:59]>>[N+:58]([C:61]1[CH:66]=[CH:65][C:64]([NH:67][C@H:68]2[CH2:73][CH2:72][C@H:71]([O:74][CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=5)=[CH:13][CH:12]=4)[CH2:7][CH2:6]3)=[O:4])[CH2:70][CH2:69]2)=[CH:63][C:62]=1[C:75]([F:76])([F:77])[F:78])([O-:60])=[O:59]
Reactant: O=C(CCl)N1CCN(c2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)CC1
Reactant: O=[N+]([O-])c1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Agent: FC(F)(F)c1ccc(COc2ccc(N3CCNCC3)cc2)cc1
Agent: O=C(Cl)CCl
Product: O=C(CO[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(c2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)CC1

Procedure:
2-[Trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-{4-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-piperazin-1-yl}-ethanone was prepared using a two-step synthesis. In the first step, 1-chloracetyl-4-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-piperazine (also known as 2-chloro-1-{4-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-piperazin-1-yl}-ethanone) was prepared with a 46% yield from 1-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-piperazine (prepared in accordance with Example 19) and chloroacetyl chloride using the procedure illustrated in Example 4. In the second step, the 2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-{4-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-piperazin-1-yl}-ethanone was prepared from the 1-chloracetyl-4-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-piperazine and trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 5) using the procedure illustrated in Example 11. This afforded the product as a yellow solid (10% yield). The structure was confirmed using Protocol II-A. Calculated mass=681; observed mass=681; HPLC retention time=4.75 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17]([OH:19])=[O:18])=[N:9]2)[CH:3]=1.[H-].[Na+].C[C:23]([N:25](C)C)=O>C(OCC)(=O)C.CO.[C-]#N.[Zn+2].[C-]#N.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:23]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17]([OH:19])=[O:18])=[N:9]2)[CH:3]=1)#[N:25]
Reactant: CC(=O)N(C)C
Reactant: O=C(O)c1nn(-c2cc(Br)ccn2)c2c1C[C@H]1C[C@@H]21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1ccnc(-n2nc(C(=O)O)c3c2[C@@H]2C[C@@H]2C3)c1
Reaction time: 0.08 h

Procedure:
(1aR,5aR)-2-(4-Bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (1.00 g, 3.12 mmol) was dissolved in DMA (10 mL). Sodium hydride (60 wt %, 0.125 g, 3.12 mmol) was added and the mixture was stirred vigorously for 5 min. Nitrogen was bubbled through the mixture for 10 min. Zinc(II) cyanide (0.734 g, 6.25 mmol) and tetrakis(triphenylphosphine)palladium (0.180 g, 0.156 mmol) were added. The reaction was microwaved at 120° C. for 1 h. The reaction was diluted with ethyl acetate (20 mL) and methanol (5 mL), filtered, and concentrated. The residue was purified by preparative HPLC to give the title compound (0.557 g) as a white solid. LCMS m/z=267.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1C(O)=O.C([O-])([O-])=O.[Cs+].[Cs+].[C:28]([O:36][CH2:37][CH3:38])(=[O:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCOCC1.O.C(OCC)(=O)C>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:28]([O:36][CH2:37][CH3:38])=[O:35])=[CH:3][CH:4]=2)[N:9]=1
Reactant: Cc1ccc2ccc(Br)cc2n1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C(O)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1ccc2ccc(C)nc2c1
Temperature: 100 °C
Yield: 25.7 %

Procedure:
A mixture of 7-bromo-2-methylquinoline (2.00 g, 9.01 mmol), Cu(I)I (0.172 g, 0.90 mmol), picolinic acid (0.222 g, 1.80 mmol), Cs2CO3 (8.80 g, 27.0 mmol) and diethyl malonate (2.73 mL, 18.0 mmol) in dioxane (25 mL) was stirred at 100° C. for hours. After cooling to ambient temperature, ethyl acetate (30 mL) and water (15 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography on silica gel (3:2 hexane/ethyl acetate) to give diethyl 2-(2-methylquinolin-7-yl)malonate (0.7 g, 2.32 mmol, 26% yield) as oil.
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:30])[CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@@H:18]3[C:22]3[C:23](=[O:29])[NH:24][CH:25]=[C:26]([F:28])[CH:27]=3)=[N:13][C:12]=12)=[O:7].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:28][C:26]1[CH:27]=[C:22]2[C:23](=[N:24][CH:25]=1)[O:29][CH2:2][C@H:3]([OH:30])[CH2:4][NH:5][C:6](=[O:7])[C:8]1=[C:12]3[N:13]=[C:14]([CH:15]=[CH:16][N:11]3[N:10]=[CH:9]1)[N:17]1[C@@H:18]2[CH2:19][CH2:20][CH2:21]1
Reactant: O=C(NC[C@@H](O)CCl)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1NC[C@@H](O)COc2ncc(F)cc2[C@H]2CCCN2c2ccn3ncc1c3n2
Temperature: 85 °C
Yield: 36.4 %

Procedure:
A suspension of N-((R)-3-chloro-2-hydroxypropyl)-5-((R)-2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (30 mg, 0.069 mmol) and Cs2CO3 (112 mg, 0.34 mmol) in DMF (0.7 mL) was heated at 85° C. for 1 hour. The reaction mixture was filtered through a GF/F paper and directly purified on reverse phase column chromatography (Biotage SP4 system C-18 12+M column, 0 to 50% acetonitrile/water), to provide the title product as a white solid (10 mg, 36% yield). Unlike Example 6, no erosion of the enantiomeric integrity of the chiral center where HO group resides was observed for this final product. MS (apci) m/z=399.2 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:17]([OH:19])=O)[CH:6]=[C:7]2[C:12]=1[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]2([CH3:16])[CH3:15])#[CH:2].C(N(CC)CC)C.ClC(OCC)=O.[N-:33]=[N+:34]=[N-:35].[Na+]>O1CCCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([C:17]([N:33]=[N+:34]=[N-:35])=[O:19])[CH:6]=[C:7]2[C:12]=1[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]2([CH3:16])[CH3:15])#[CH:2]
Reactant: C#Cc1cc(C(=O)O)cc2c1OC(C)(C)CC2(C)C
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C#Cc1cc(C(=O)N=[N+]=[N-])cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
A stirred, cooled (ice bath) solution of 8-ethynyl-2,2,4,4-tetramethyl-chroman-6-carboxylic acid (Intermediate 210, 0.52 g, 2 mmol) in anhydrous tetrahydrofuran (10 mL) under argon, was treated with triethyl amine (0.86 mL, 6 mmol) follwed by ethyl chloroformate (0.25 mL, 2.6 mmol) and the resulting reaction mixture was allowed to warm to ambient temperature and stirred for 2 h. Sodium azide 0.19 g, 3 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was then diluted with water and extracted with diethyl ether. The organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated to a residue that was purified by flash column chromatography over silica gel (230-400 mesh) to afford the title compound as a yellow solid (0.32 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)[OH:9])=[CH:4][CH:3]=1.[OH-].[Na+].C1(C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1)[N+]([O-])=O.[I-].[K+].[CH2:42]([O:49][CH2:50]Cl)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(#N)C>[CH2:42]([O:49][CH2:50][N:14]1[CH:13]=[CH:12][N:11]=[C:10]1[C:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[OH:9])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: ClCOCc1ccccc1
Reactant: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1ncc[nH]1
Agent: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1nccn1COCc1ccccc1
Temperature: 50 °C

Procedure:
A mixture of 125 ml. of acetonitrile, 9.2 g of α,α-bis(p-chlorophenyl)imidazole-2-methanol (prepared according to Example III) and 1.5 g of sodium hydroxide was stirred for one hour. To the--now homogeneous--reaction mixture 500 mg of picric acid and a few crystals of potassium iodide were added and the mixture was heated to 50° C. A solution of 5.2 g of benzyloxymethyl chloride in 50 ml. of acetonitrile was then added dropwise and the reaction mixture was subsequently refluxed for 4 hours. The mixture was cooled and filtered and the filtrate was concentrated under reduced pressure. The residue was suspended in water and the suspension was extracted with diethyl ether. The extract was dried over sodium sulphate and the ether was distilled off. The solid residue obtained was crystallized from isopropyl alcohol. The product was then boiled four times with 75 ml. of petroleum ether (boiling range 60°-80° C.), the petroleum ether being decanted each time, after which it was once again crystallized from isopropyl alcohol. The substance was dried in vacuo for 10 hours at 110° C. 1-[(Benzyloxy)methyl]-α,α-bis(p-chlorophenyl)imidazole-2-methanol was obtained. Melting point 139°-141° C.