Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:33]=[CH:32][C:15]([C:16]([NH:18][C@H:19]([C:27]([O:29]CC)=[O:28])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:17])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[C:34]([C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([C:38]1[CH:43]=[CH:42][C:41]([S:44]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH2:11][C:12]2[CH:33]=[CH:32][C:15]([C:16]([NH:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:17])=[CH:14][CH:13]=2)[CH:6]=[CH:5]3)(=[O:46])=[O:45])=[CH:40][CH:39]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(Cn2ccc3cc(N)ccc32)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3c(ccn3Cc3ccc(C(=O)N[C@@H](Cc4ccccc4)C(=O)O)cc3)c2)cc1

Procedure:
The title compound was prepared from ethyl N-{4-[(5-amino-1H-indol-1-yl)methyl]benzoyl}phenylalaninate and 4-tert-butylphenyl sulfonyl chloride following the procedure of Example 10: MS (ESI) m/z 610; MS (ESI) m/z 608.
Reaction SMILES: C(O)C.[OH-].[K+].[Br:6][C:7]1[N:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([O:37]CC)=[O:36])[N:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([CH2:16][N:17]1[C:21]([CH2:22][OH:23])=[C:20]([Cl:24])[N:19]=[C:18]1[CH2:25][CH2:26][CH2:27][CH3:28])[CH:12]=[CH:11]2>O>[Br:6][C:7]1[N:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([OH:37])=[O:36])[N:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([CH2:16][N:17]1[C:21]([CH2:22][OH:23])=[C:20]([Cl:24])[N:19]=[C:18]1[CH2:25][CH2:26][CH2:27][CH3:28])[CH:12]=[CH:11]2
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nn(-c3ccccc3C(=O)OCC)c(Br)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nn(-c3ccccc3C(=O)O)c(Br)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.8 %

Procedure:
Ethanol (1.2 ml), ion-exchanged water (0.3 ml), and potassium hydroxide (45 mg) were added to 1-[3-bromo-2-(2-ethoxycarbonylphenyl)-2H-indazol-5-yl]methyl-2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazole (106 mg, 0.205 mmol) as obtained in Example 2, and the mixture was stirred at room temperature for one day. The mixture was concentrated in an evaporator, and partitioned by ion-exchanged water (2.5 ml) and diethyl ether (5 ml). The water layer was separated and conc. hydrochloric acid was dropwise added thereto to adjust its pH to 5-6. The resultant solid was filtered off and washed twice with ion-exchanged water (1 ml). One drop of conc. hydrochloric acid was added to the filtrate to precipitate solid, which was filtered off, washed with water, and combined with the previously-obtained solid. They were dried in vacuo at 37° C. for two days to give 56 mg of 1-[3-bromo-2-(2-carboxyphenyl)-2H-indazol-5-yl]methyl-2-butyl-4-chloro-5 -(hydroxymethyl)-1-H-imidazole.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:22])=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18]([F:21])([F:20])[F:19])([O-:3])=[O:2].[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl>[CH3:26][S:23]([O:22][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[C:9]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][C:18]([F:21])([F:19])[F:20])[N:8]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)nc1Nc1ccccc1OC(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc([N+](=O)[O-])c(Nc2ccccc2OC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
5-Nitro-6-(2-(trifluoromethoxy)phenylamino)pyridin-2-ol (1.5 g, 4.8 mmol) was taken up in CH2Cl2 (25 mL). TEA (1.3 ml, 9.5 mmol) was added followed by mesylchloride (0.45 ml, 5.7 mmol). The reaction mixture was stirred at ambient temperature for 1 hour and quenched with 1 N HCl. The layers were separated and the aqueous layer was back extracted with additional CH2Cl2. The combined organic portions were dried over Na2SO4 and concentrated under reduced pressure to give the title compound (1.8 g). 1H NMR (400 MHz, CDCl3) δ ppm 3.26 (s, 3H), 6.54 (d, J=8.8 Hz, 1H), 7.26 (m, 1H), 7.39 (m, 2H), 8.22 (m, 1H), 8.67 (d, J=8.8, 1H), 10.46 (s, 1H).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1.C([Mg]Br)C.[N+:30]([C:33]1[CH:42]=[CH:41][CH:40]=[C:39]2[C:34]=1[CH2:35][CH2:36][CH2:37][C:38]2=O)([O-:32])=[O:31].[Cl-].[NH4+]>ClCCl>[N+:30]([C:33]1[CH:42]=[CH:41][CH:40]=[C:39]2[C:34]=1[CH2:35][CH2:36][CH:37]=[C:38]2[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1)([O-:32])=[O:31]
Reactant: O=C1CCCc2c1cccc2[N+](=O)[O-]
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc2c1CCC=C2c1c[nH]cn1
Reaction time: 0.5 h

Procedure:
A solution of 4-iodo-1-trityl-1H-imidazole (5.5 g, 13 mmol) (prepared as described by Kirk, K. J. Heterocyclic Chem. (1985), 22, 57-59) in dichloromethane (50 mL) was treated with ethylmagnesium bromide (3.0 M in diethyl ether, 4.2 mL) over 4 minutes, stirred for 30 minutes, treated with 5-nitrotetralone (prepared as described by Zhang, M J. Amer. Chem. SoC, (1994), 116, 4852-4857), stirred for 6 hours, treated with ammonium chloride solution (50 mL) and extracted with a mixture of diethyl ether (300 mL) and ethyl acetate (50 mL). The organic layer was isolated, treated with dichloromethane (500 mL) to dissolve the product which started to crystallize, dried (MgSO4), filtered, concentrated, treated with trifluoroacetic acid (80 mL), stirred for 48 hours, concentrated to an oil, neutralized with sodium bicarbonate solution and extracted twice with dichloromethane. The combined dichloromethane layers were dried (MgSO4), filtered and concentrated. The residue was purified on silica gel with a gradient of 5%-10% methanol/dichloromethane to provide the desired compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[O:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[C:11]([OH:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CC(C)=O>[CH2:1]([O:8][C:9]1[C:18]2[O:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[C:11]([O:19][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1cc2c(c(OCc3ccccc3)c1)OCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc2c(c(OCc3ccccc3)c1)OCCC2
Yield: 99.5 %

Procedure:
0.82 g of 8-benzyloxy-3,4-dihydro-6-hydroxy-2H-1-benzopyran (0.82 g) was dissolved in 300 ml of anhydrous acetone, and 0.88 g of anhydrous potassium carbonate and 1.07 g of ethyl bromoacetate were added. The mixture was stirred under reflux for 7 hours. After the reaction, the insoluble matter was removed by filtration, and the solvent was distilled off. The residue was dissolved in 50 ml of chloroform, washed with water and dried. The solvent was distilled off to give 1.09 g (yield 99.5%) of 8-benzyloxy-3,4-dihydro-6-ethoxycarbonylmethoxy-2H-1-benzopyran.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[CH2:34]([O:41][C:42]1[CH:47]=[CH:46][C:45]([C:48](=[O:50])[CH3:49])=[CH:44][C:43]=1[N+:51]([O-:53])=[O:52])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[CH2:34]([O:41][C:42]1[CH:47]=[CH:46][C:45]([C:48](=[O:50])[CH2:49][Br:1])=[CH:44][C:43]=1[N+:51]([O-:53])=[O:52])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: [Br-]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.7 %

Procedure:
Phenyltrimethylammonium tribromide (109.00 g, 290.00 mmol) was added to a solution of 1-(4-benzyloxy-3-nitrophenyl)ethanone (2) (65.60 g, 242.00 mmol) in anhydrous THF (600 mL) in three portions, and the reaction mixture was stirred at rt for 12 h. The solids were then collected by filtration and the filtrate concentrated. The product was precipitated from chloroform upon the addition of hexanes, then collected by filtration and dried under vacuum to give bromo ketone 3 as a light yellow solid (63.33 g, 75% yield): 1H NMR (500 MHz, CDCl3) δ 4.37 (s, 3H), 5.35 (s, 2H), 7.21 (d, 1H), 7.40 (m, 5H), 8.15 (dd, 1H), 8.49 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([Cl:9])[N:3]=1.[CH2:10]([NH2:13])[CH2:11][CH3:12].[OH-].[Na+]>CC(C)=O>[NH2:1][C:2]1[N:3]=[C:4]([Cl:9])[N:5]=[C:6]([NH:13][CH2:10][CH2:11][CH3:12])[N:7]=1
Reactant: Nc1nc(Cl)nc(Cl)n1
Reactant: CCCN
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCNc1nc(N)nc(Cl)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
6-Amino-2,4-dichloro-[1,3,5]triazine (XXXVII) (30.0 g, 187 mmol) was dissolved in acetone (100 mL) and poured into ice-water (100 mL) to form a very fine suspension. To this mixture, a solution of propan-1-amine (11.0 g, 187 mmol) in acetone (20 mL) was added at 0° C. To this reaction, 2 N NaOH (94 mL, 187 mmol) was added dropwise at a rate to keep the temperature between 0° C. and 5° C. The mixture was stirred for 30 min at ambient temperature and for an additional 60 min at 50° C. The mixture was concentrated and then the precipitate was filtered off and washed with water (3×100 mL). After drying over calcium chloride under high vacuum, 6-amino-2-chloro-4-n-propylamino-[1,3,5]triazine (XXXVIII) was isolated as a white powder (35 g, 100% yield). LCMS (ESI) m/z=188 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[N+:9]([O-])([OH:11])=[O:10].S(=O)(=O)(O)O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: Cc1ccc(F)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 81.1 %

Procedure:
4-Fluorotoluene (14 g) is added slowly with stirring to a solution of fuming nitric acid (18 g) and concentrated sulfuric acid (30 g) over 30 minutes and alternately warmed and cooled to keep the temperature between 40 and 50° C. This is followed by heating at 100° C. for 30 minutes more. The organic material is cooled and extracted with methylene chloride to give 16 g of 4-fluoro-2-nitrotoluene.
Reaction SMILES: [Cl:1]Cl.[C:3]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[OH:15])[CH:10]=[O:11])([CH3:6])([CH3:5])[CH3:4].O>C(O)(=O)C>[C:3]([C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([Cl:1])[C:14]=1[OH:15])[CH:10]=[O:11])([CH3:6])([CH3:4])[CH3:5]
Reactant: ClCl
Reactant: CC(C)(C)c1cc(C=O)ccc1O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc(C=O)cc(Cl)c1O

Procedure:
Chlorine gas was passed into a solution of 3-tert-butyl-4-hydroxybenzaldehyde (2.5 gm) in acetic acid (20 ml) for 1 hour. The solution was poured into water and the product collected. Recrystallisation from aqueous ethanol gave 3-tert-butyl-5-chloro-4-hydroxybenzaldehyde m.p. 123° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)(=[O:3])[CH3:2].[H-].[Na+].[CH3:24]I>CN(C)C=O.O>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][C:5]([N:4]([CH3:24])[C:1](=[O:3])[CH3:2])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CI
Reactant: CC(=O)Nc1cnc2ccc(Cl)cc2c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(C)c1cnc2ccc(Cl)cc2c1-c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 3-acetamido-6-chloro-4-phenylquinoline (1 g) in N,N-dimethylformamide (10 ml) was added 60% sodium hydride in oil (0.15 g). After stirring for 30 mins. at room temperature, to the mixture was added dropwise methyl iodide(0.25 ml) under stirring and then followed by stirring for 1 hr. at room temperature. After the mixture was diluted with water, the resultant precipitate was collected by filtration, and recrystallized from a mixture of methanol and chloroform to give 6-chloro-3-(N-methylacetamido)-4-phenylquinoline as colorless crystals. Yield 0.96 g (91.4%). m.p. 268°-270° C.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=1)[C:9]([NH:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=1)=[O:10])([O-:5])=[O:4].I[CH3:24].Cl>CN(C)C=O>[N+:3]([C:6]1[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=1)[C:9]([N:11]([CH3:24])[C:12]1[CH:13]=[C:14]([Cl:19])[CH:15]=[C:16]([Cl:18])[CH:17]=1)=[O:10])([O-:5])=[O:4]
Reactant: O=C(Nc1cc(Cl)cc(Cl)c1)c1cccc([N+](=O)[O-])c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1cccc([N+](=O)[O-])c1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (60% in oil, 1.1 g) in N,N-dimethylformamide (20 ml) was added dropwise a solution of 3-nitro-N-(3,5-dichlorophenyl)benzamide (5.89 g) in N,N-dimethylformamide (40 ml). The mixture was stirred at room temperature for 1 hour, then iodomethane (3 ml) was added thereto. After stirring at room temperature for 1 hour, dilute hydrochloric acid was added to the mixture and extracted with ethyl acetate twice. The combined organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was solidified with isopropyl ether to give 3-nitro-N-methyl-N-(3,5-dichlorophenyl)benzamide (4.62 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:19])[C:7]=1[N:8]1[CH2:18][CH2:17][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>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(#N)C>[Cl:19][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]=1[N:8]1[CH2:18][CH2:17][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1
Reactant: OB(O)c1ccccc1
Reactant: O=C1NCCC12CCN(c1c(Cl)cncc1Cl)CC2
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: CC#N
Product: O=C1NCCC12CCN(c1c(Cl)cncc1-c1ccccc1)CC2
Yield: 28 %

Procedure:
General procedure E was followed using 8-(3,5-dichloropyridin-4-yl)-2,8-diazaspiro[4.5]decan-1-one E59 (38 mg, 0.13 mmol), phenyl boronic acid (19 mg, 0.16 mmol), tetrakis(triphenylphosphine)palladium(0) (7.3 mg, 5 mol %), acetonitrile (1.4 ml) and 0.5 M sodium carbonate (0.35 ml, 0.18 mmol). The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, 97:3) followed by preparative hplc (CH3CN, H2O, gradient 1:9 to 9:1) to furnish the title compound as a white solid (12 mg, 28%), along with recovered starting material as a clear colourless oil (10 mg, 23% RSM), LC-MS (ESI, 4 min) Rt 2.22 min, m/z 342 (100%, [M+H]+); m/z (ESI) C19H20N3ClO requires 341.1295, found [M+H]+ 341.1301.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH2:26]([O:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33])[CH3:27]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:32]([C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([O:28][CH2:26][CH3:27])[CH:30]=4)=[O:33])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CCOc1cccc(C(=O)Cl)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: CCOc1cccc(C(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)c1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 3-ethoxybenzoyl chloride as starting compounds. The crude product is purified by column chromatography (silica gel and EA) and crystallization of the product containing fractions from EA and diethyl ether to yield the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=O)=[CH:9][CH:10]=2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:3]12.[F:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=O)=[CH:24][CH:23]=1>O=S(Cl)Cl>[F:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]2[O:14][C:12]([C:8]3[CH:7]=[C:6]4[C:11]([C:2](=[O:1])[N:3]5[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:4]5=[N:5]4)=[CH:10][CH:9]=3)=[N:29][N:28]=2)=[CH:24][CH:23]=1
Reactant: NNC(=O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc2c(=O)n3c(nc2c1)CCCCCC3
Solvent: O=S(Cl)Cl
Product: O=c1c2ccc(-c3nnc(-c4ccc(F)cc4)o3)cc2nc2n1CCCCCC2
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 6.4 %

Procedure:
A solution of 13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxylic acid (80 mg, 0.28 mmol) in SOCl2 (3 mL) was stirred at reflux for 0.5 h. The reaction mixture was concentrated and diluted with toluene (5 mL). 4-fluorobenzohydrazide (54.4 mg, 0.35 mmol) was added to the solution and heated to 60° C. After stirring for 1.5 h, the toluene was evaporated. Phosphoryl trichloride (3 mL) was added to the residue and heated at 80° C. for 1.5 h. Excess phosphoryl trichloride was removed under reduced pressure and diluted with water (25 mL). The mixture was adjusted to pH around 7 with aqueous Na2CO3 solution. The aqueous mixture was extracted with ethyl acetate (3×20 mL), dried over Na2SO4. After filtration, the filtrate was concentrated and purified by column chromatography to give the desired product (7 mg). MS (ESI): 391 (MH+); 1H NMR (300 MHz, CDCl3) δ 8.43-8.39 (m, 2H), 8.23-8.16 (m, 3H), 7.29 (s, 1H), 7.24 (s, 1H), 4.38 (s, 2H), 3.11-3.07 (t, J=6.1 Hz, 2H), 2.05-1.93 (m, 4H), 1.65 (m, 2H), 1.49 (broad, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([C:39]([CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:40])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: O=C(Cl)C1CCCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)C5CCCCC5)CC4)cn3)nc2n1C1CCCC1
Yield: 50.3 %

Procedure:
Following General Procedure G, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and cyclohexane carbonyl chloride (37 mg, 0.690 mmol) gave 2-[5-(4-cyclohexanecarbonyl-piperazin-1-yl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (63 mg, 49%). MS(ESI) m/z 545.3 (M+H)+
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:11][N:10]([C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([C:31]3([CH3:34])[CH2:33][CH2:32]3)=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:7][CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:11][N:10]([C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([C:31]3([CH3:34])[CH2:33][CH2:32]3)=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C(=O)N2CCC(C(=O)N3CC(N)C(c4ccc(Cl)c(Cl)c4)C3)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.1 %

Procedure:
To a solution of rac-(3S,4R)-{4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (5.747 g, 0.011 mol) in dichloromethane (55 mL) was added trifluoroacetic acid (8.39 mL, 0.110 mol) and the reaction mixture was stirred for 4 h at ambient temperature. The reaction mixture was basified by addition of aqueous sodium carbonate (1M, 10 mL). The organic layers were washed with water (8 mL) and the aqueous layers were extracted with dichloromethane (10 mL). The combined org. layers were dried over sodium sulfate and concentration afforded 4.30 g (92%) of the title compound as a light brown foam. ES-MS m/e: 524.2 (M+H+).
Reaction SMILES: C([O-])(=O)C.[Na+].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH3:14])=[CH:9][CH:8]=1.C(O)C.Cl.[NH2:20][OH:21]>O>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:20][OH:21])[CH3:14])=[CH:9][CH:8]=1
Reactant: NO
Reactant: CC(=O)c1ccc(O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=NO)c1ccc(O)cc1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
115.2 g (1.405 moles) of sodium acetate, 108.9 g (0.800 mole) of p-hydroxyacetophenone and 1000 ml of ethanol were added to a solution of 56.8 g (0.817 mole) of hydroxylamine hydrochloride in 1000 ml of water, and then the mixture was refluxed for 4 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure to a volume of about 500 ml, and the concentrate was allowed to cool at room temperature for 23 hours to precipitate crystals. The crystals were washed with 500 ml of water, and dried in air for 24 hours and in vacuo for a further 6 hours to give 102.1 g (84.5%) of p-hydroxyacetophenone oxime in the form of colorless needles melting at 145°-146°.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][O:13][C:14]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[C:15]=1[C:16](O)=[O:17]>>[CH3:12][O:13][C:14]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[C:19]([C:27]([F:28])([F:29])[F:30])[C:15]=1[C:16]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:17]
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=425.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-methoxy-4,6-bis(trifluoromethyl)benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])[NH:6]2.[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])[N:6]2[C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([F:17])[CH:23]=1
Reactant: CON(C)C(=O)c1cc2c(Cl)cccc2[nH]1
Reactant: OB(O)c1cccc(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cc2c(Cl)cccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
Activated molecular sieves (4.9 g) 4 Å were placed in an oven dried flask and cooled to room temperature under nitrogen. To the flask was charged with 4-chloro-N-methoxy-N-methyl-1H-indole-2-carboxamide (0.35 g, 1.5 mmol), (3-fluorophenyl)boronic acid (0.62 g, 4.4 mmol) and cupric acetate (0.40 g, 2.2 mmol), methylene chloride (65 mL) and then pyridine (0.47 mL, 5.9 mmol). The reaction mixture was stirred at room temperature overnight, then filtered through a pad of Celite. The filtrate was concentrated and purified on silica gel (eluting with 0-20% EtOAc in hexane) to give the desired product (0.44 g, 90%). LCMS calculated for C17H15ClFN2O2(M+H)+: m/z=333.1. Found: 333.0.