Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][N:9]([CH2:22][CH2:23][CH2:24][OH:25])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[C:12]=2[Cl:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][O:33][C:34](=[O:42])[C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH3:32][O:33][C:34](=[O:42])[C:35]1[CH:40]=[CH:39][C:38]([O:25][CH2:24][CH2:23][CH2:22][N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[C:12]=2[Cl:21])[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:37][CH:36]=1
Reactant: OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)cc1

Procedure:
To a solution of N-(2,2-diphenylethyl)-N-(3-hydroxy-propyl)-N-(2-chloro-3-trifluoromethyl-benzyl)amine (0.60 g, 1.33 mmol) in toluene (4 ml) at ambient temperature was added 4-hydroxy-benzoic acid methyl ester (0.22 g, 1.45 mmol) under Argon with stirring. The mixture was treated with polymer bound PPh3 (0.71 g, 2.13 mmol). After 15 minutes of stirring the mixture was treated with DIAD (0.32 mL, 1.66 mmol) and was stirred at room temperature overnight. The reaction mixture was filtered, and concentrated in-vacuo. The resulting oil was dissolved in DMSO and was purified via preparative reverse-phase HPLC (TMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile:H2O, UV detection at 254 nm) to yield the title compound, 0.24 g (32%); MS (ESI) m/e 583 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH3:18][N:19](C=O)C.CN>O>[N+:15]([C:3]1[CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:19][CH3:18])([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: CN(C)C=O
Agent: CN
Solvent: O
Product: CNc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 6 h

Procedure:
To a mixture of 2-chloro-1,3-dinitro-5-trifluoromethyl-benzene (20 g) and DMF (30 mL), 40% of aqueous methylamine solution (15 mL) was added dropwise under ice-cooling. The mixture was stirred for 6 hours under ice-cooling, and then the reaction mixture was added to iced water. The precipitated powder was collected by filtration, and washed with water to give 20 g of (2,6-dinitro-4-trifluoromethyl-phenyl)-methyl-amine.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[CH:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)[CH2:4][C:3]=1[O:15][CH3:16].[C:17]([Mg]Cl)([CH3:20])([CH3:19])[CH3:18]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:15][CH3:16])[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]2[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Mg]Cl
Reactant: COC1=C(Br)C=C2C(=O)CCC(C)(C)C2C1
Product: COc1cc2c(cc1Br)C(C(C)(C)C)=CCC2(C)C
Yield: 34 %

Procedure:
Following General Procedure A, 7-bromo-6-methoxy-4,4-dimethyl-dihydro-2H-naphthalen-1-one (Compound 92, 1.5 g, 5.3 mmol) was reacted with t-butylmagnesium chloride to afford 0.5743 g (34%) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH3:42][N:43]([C:50]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=1)C1C=CC=CC=1>C(Cl)Cl>[CH3:42][N:43]([C:50]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=1)[C:8]([C:5]1[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:27])([F:28])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10]
Reactant: COCN(c1cc(Cl)cnc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CN(c1ccccc1)c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCN(c1cc(Cl)cnc1C(=O)N(C)c1ccc(F)cc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid (458 mg, 1.00 mmol) in anhydrous methylene chloride (5 mL) was added oxalyl chloride (1.0 mL) at room temperature. The reaction was heated at reflux for 1 h then was concentrated to dryness. The residue was dissolved in methylene chloride (4 mL) and this solution was added dropwise to a magnetically stirred solution of triethylamine (1.0 mL) and N-methyl-N-(4-fluorophenyl)aniline (0.50 mL, 3.5 mmol) in methylene chloride (2 mL). The reaction mixture was stirred 1 h (the reaction was monitored by LCMS) then quenched with saturated aqueous NH4Cl (50 mL), and extracted with EtOAc (3×75 mL). The combined extracts were washed with 0.5M HCl (50 mL), washed with water (50 mL), dried (MgSO4), filtered and concentrated. The residue was purified by chromatography on silica gel using a gradient of ethyl acetate-hexane (0:100 to 100:0) to afford pure 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid N-methyl-N-(4-fluorophenyl)amide. MS m/z 570.1 (M+Na); 526.0 (M+H−MeOH).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:45])([F:44])[C:17]([F:43])([F:42])[C:18]([F:41])([F:40])/[CH:19]=[CH:20]/[C:21]([F:39])([F:38])[C:22]([F:37])([F:36])[C:23]([F:35])([F:34])[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([N+:31]([O-])=O)[CH:25]=2)=[CH:12][C:11]=1[N+:46]([O-])=O.C>O.CO.C1(C)C=CC=CC=1.C(=O)=O>[OH:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:35])[C:22]([F:36])([F:37])[C:21]([F:38])([F:39])[CH:20]=[CH:19][C:18]([F:40])([F:41])[C:17]([F:42])([F:43])[C:16]([F:44])([F:45])[C:13]2[CH:14]=[CH:15][C:10]([OH:9])=[C:11]([NH2:46])[CH:12]=2)=[CH:25][C:26]=1[NH2:31]
Reactant: O=[N+]([O-])c1cc(C(F)(F)C(F)(F)C(F)(F)/C=C/C(F)(F)C(F)(F)C(F)(F)c2ccc(O)c([N+](=O)[O-])c2)ccc1O
Agent: O=C=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: Nc1cc(C(F)(F)C(F)(F)C(F)(F)C=CC(F)(F)C(F)(F)C(F)(F)c2ccc(O)c(N)c2)ccc1O
Yield: 54.2 %

Procedure:
Sodium dithionite (10 g) in 30 ml of water was added slowly with stirring at room temperature to a solution of 1.0 g (0.0017 mole) of trans-1,2-bis[3-(4-hydroxy-3-nitrophenyl)perfluoropropyl]ethylene (prepared as described in Example I) in 250 ml of methanol. The methanolic solution turned bright yellow and then slowly faded to water-white as reduction occurred. After addition of the sodium dithionite was completed, stirring was continued for an additional 30 minutes at which time water was added, resulting in a total solution volume of 750 ml. The resultant white slurry was extracted three times with 200 ml portions of ether and the combined ether extracts were washed repeatedly with water. The ether solution was then dried over anhydrous magnesium sulfate and stripped to dryness under reduced pressure to give a white residue. Most of this solid was soluble in 900 ml of hot toluene which was treated with charcoal and reduced in volume to 100 ml. Cooling in dry ice gave 0.5 g (55% yield) of the olefinic product as white platelets, mp 187°-188° C.
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:13]=[C:14]([CH3:30])[N:15]([CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]4[F:29])[C:5]=3[C:4]=2[CH:3]=1.[Cl:31][C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][C:44]=1B1OC(C)(C)C(C)(C)O1)[O:35][C:36]1[N:41]=[CH:40][CH:39]=[CH:38][N:37]=1.C([O-])([O-])=O.[Na+].[Na+].CO.C(Cl)Cl>C1(C)C=CC=CC=1.C(O)C.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>[Cl:31][C:32]1[CH:33]=[C:34]([O:35][C:36]2[N:37]=[CH:38][CH:39]=[CH:40][N:41]=2)[CH:42]=[CH:43][C:44]=1[C:2]1[C:11]([F:12])=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:13]=[C:14]([CH3:30])[N:15]([C@H:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][C@@H:17]4[F:29])[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1nc2cnc3cc(F)c(Br)cc3c2n1C1CCN(C(=O)OC(C)(C)C)CC1F
Reactant: CC1(C)OB(c2ccc(Oc3ncccn3)cc2Cl)OC1(C)C
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: Cc1ccccc1
Solvent: CCO
Solvent: CO
Product: Cc1nc2cnc3cc(F)c(-c4ccc(Oc5ncccn5)cc4Cl)cc3c2n1[C@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1F
Temperature: 90 °C
Yield: 93.3 %

Procedure:
tert-Butyl 4-(8-bromo-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidine-1-carboxylate (9 g, 0.018 mol) was dissolved in toluene:ethanol (8:2, 50 ml) in a 250 ml seal tube and degasified the reaction mixture with argon gas for 15 minutes. Tetrakis (2.1 g, 0.0018 mol) was added and degasified the reaction mixture with argon gas for 5 minutes, 2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidine (8 g, 0.024 .mol), followed by 2M Na2CO3(5 ml) was added and finally degasified the reaction mixture with argon gas for 10 minutes. The resulting reaction mixture was heated 5 h at 90° C. The reaction was monitored by TLC (5% MeOH/DCM), after completion of reaction by TLC the reaction mixture poured into ice water and extracted with EtOAc (3×100 mL). The combined organic layers were washed water, brine solution, dried over sodium sulphate and evaporated under vacuum. The residue was purified by column chromatography on silica gel (0-3% MeOH/DCM) to afford (3S,4S)-tert-butyl 4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidine-1-carboxylate, 4 (10.2 g, 95% yield). 1HNMR (CDCl3, 400 MHz): δ 9.28 (d, 1H), 8.68-8.60 (m, 2H), 8.34-8.31 (d, 0.8H), 8.17 (d, 0.2H), 8.09-8.02 (m, 1H), 7.58-7.44 (m, 2H), 7.30 (dd, 1H), 7.16-7.10 (m, 1H), 5.62-5.04 (m, 1H), 4.89-4.25 (m, 3H), 3.10-2.75 (m, 5H), 2.40-2.20 (m, 2H), 1.51 (s, 9H); LCMS: 98.99%, m/z=607.45 (M+1); HPLC: 96.89%, rt: 4.32 min.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][CH:20]=4)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]4[N:36]=[C:37]([CH3:39])[N:38]=[C:12]34)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C([BH3-])#N.[Na+].B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+]>O1CCCC1>[OH:1][CH2:2][CH2:3][O:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[C:37]([CH3:39])[N:38]=[C:12]23)[CH2:7][CH2:6]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C)nn12
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@@H](OCCO)CC2)c2nc(C)nn12

Procedure:
A mixture of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.0 g), sodium cyanoborohydride (0.32 g), boron trifluoride etherate (0.64 mL) and tetrahydrofuran (20 mL) was heated under reflux for 15 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.44 g, 42%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[CH:5]=[N:4][C:3]=1[C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH2:28][C:29](N)=[O:30]>C(O)(=O)C>[CH:13]1([NH:12][C:10](=[O:11])[C:9]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:7]([N:6]3[CH:5]=[N:4][C:3]4[C:2]3=[N:1][C:29]([OH:30])=[N:28][C:20]=4[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:8]=2)[CH2:15][CH2:14]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc(C(=O)c2ccccc2)c1N
Reactant: NC(N)=O
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(-c3ccccc3)nc(O)nc21
Temperature: 180 °C
Yield: 23.9 %

Procedure:
To a stirred solution of 3-(5-amino-4-benzoyl-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide (9.2 mg, 0.026 mmol) in 0.3 mL acetic acid was added urea (20 mg) and the mixture was heated at 180° C. for 20 min. in the microwave. The crude product was purified by HPLC to give a colorless solid (2.4 mg, 24%). HPLC tR=1.63 min; MS m/z 386 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)/[CH:5]=[N:23]/[S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1cccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.5 %

Procedure:
(Ref: Angew. Chem. Int. Ed., 48:914-917 (2009)). To a stirred suspension of 3-chloro-2-fluorobenzaldehyde (1.308 g, 8.25 mmol) and Cs2CO3 (4.03 g, 12.38 mmol) in DCM (10 mL) was added a solution of (R)-2-methylpropane-2-sulfinamide (1 g, 8.25 mmol) in DCM (50 mL) dropwise for 10 min. The solution was then stirred for 2 h at rt. LC/MS indicated that the reaction was complete. The reaction mixture was then diluted with EtOAc (50 mL) and washed with brine (20 mL×3). The organic layers were dried over Na2SO4 and concentrated in vacuo to give (R,E)-N-(3-chloro-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (2.3 g, 107%) as a clear oil. MS (ESI) m/z: 262.1 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=1[Br:22].C(N(CC)CC)C>ClCCl>[Br:22][C:11]1[CH:12]=[C:13]([N:16]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:1](=[O:3])[CH3:2])[CH:14]=[CH:15][C:10]=1[O:9][CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(NCC(F)(F)F)cc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N(CC(F)(F)F)C(C)=O)cc1Br
Yield: 53.1 %

Procedure:
Acetic anhydride (1.26 ml, 13.4 mmol) was added to a cooled (0° C.) solution of 2-methoxy-5-(2,2,2-trifluoroethylamino)bromobenzene (Description 56, 2.1 g) and triethylamine (1.9 ml, 1.37 g, 13.4 mmol) in dichloromethane and the mixture was heated under reflux for 18 h. The mixture was cooled and the solvent was evaporated under reduced pressure. 1,2-Dichloroethane (20 ml) was added and the mixture was heated under reflux for 24 h. Further acetic anhydride (0.6 ml) and triethylamine (0.95 ml) were added and the mixture was heated under reflux for 24 h., cooled and diluted with dichloromethane (100 ml). The mixture was diluted with water (3×50 ml) and brine (50 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was triturated with ethyl acetate and the solid was collected and dried in vacuo to give the title compound as an off-white solid (1.28 g, 59%). 1H NMR (360 MHz, CDCl3) δ7.44 (1 H, d, J 2.5 Hz), 7.17 (1 H, dd, J 8.7, 2.5 Hz), 6.93 (1 H, d, J 8.7 Hz), 4.29 (2 H, q, J 8.8 Hz), 3.94 (3 H, s), and 1.90 (3 H, m), m/z (ES+) 326, 328 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35]C[C@@H]5CCCO5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[O:46]1[CH2:50][CH2:49][CH2:48][C@H:47]1CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:49][CH2:48][CH2:47][O:46][CH3:50])[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:11])=[O:12])[CH3:9]
Reactant: NC[C@@H]1CCCO1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC[C@@H]5CCCO5)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNCCCOC)c4)cc23)CC1
Yield: 48.7 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 3-(methyloxy)-1-propanamine (46 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 27.3 mg of the title compound (48.7%).
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[C:11](Cl)[CH:12]=[CH:13][CH:14]=2)[C:9]([NH2:17])=[N:8]1)[CH3:2].C1(=O)N(C2C3C(=CC=CC=3)NN=2)C(=O)C2=CC=CC=C12.Br.BrCCCN1CCCC1.C1(=O)N(C2C3C(=CC=CC=3Cl)NN=2)C(=O)C2=CC=CC=C12.Br.BrCCCN(CC)CC>>[N:3]1([CH2:4][CH2:5][CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([NH2:17])=[N:8]2)[CH2:18][CH2:19][CH2:2][CH2:1]1
Reactant: CCN(CC)CCCn1nc(N)c2c(Cl)cccc21
Agent: Br
Agent: BrCCCN1CCCC1
Agent: CCN(CC)CCCBr
Product: Nc1nn(CCCN2CCCC2)c2ccccc12

Procedure:
The same procedures for preparing 1-(3-diethylaminopropyl)-3-amino-4-chloroindazole as described in Example 89 were repeated except that 8 g of 3-phthalimidoindazole and 9.5 g of 3-bromopropylpyrrolidine hydrobromide were employed instead of the 3-phthalimido-4-chloroindazole and the 3-bromopropyldiethylamine hydrobromide, respectively. As a result, 8.2 g of 1-(3-pyrrolidinopropyl)-3-aminoindazole was obtained.
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][NH:5][CH3:6].F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:6][N:5]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[CH2:4][CH2:3][N:2]([CH3:1])[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1
Reactant: CNCCN(C)c1ccncc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCN(C)c1ccc([N+](=O)[O-])cc1)c1ccncc1
Reaction time: 0.5 h

Procedure:
A mixture of the product of part (i) (0.83 g), 4-fluoronitrobenzene (0.71 g) and sodium bicarbonate (1.0 g) in N,N-dimethylformamide (20 ml ) was heated at 100° with stirring for 0.5 hour and then evaporated. The residue was stirred with water (2 ml) and the insoluble material was filtered off, washed with water and dried. The solid was chromatographed on silica gel. Elution with ethyl acetate/methanol (10:1) gave, after combination and evaporation of appropriate fractions, pure product (0.60 g), m.p. 126°-127° (from ethyl acetate/hexane).
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)[C:16](=[O:29])[C:17]4[CH:22]=[N:21][N:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N([O-])=[O:38].[Na+].C([O-])(O)=O.[Na+]>C(#N)C.O.OS(O)(=O)=O>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([N:15]2[C:16](=[O:29])[C:17]3[CH:22]=[N:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]=3[N:19]=[C:14]2[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2](=[O:38])[NH:7][CH:6]=3)=[CH:9][CH:10]=2)=[CH:35][CH:34]=1
Reactant: Nc1ccc(-c2ccc(-c3nc4c(cnn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)cn1
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=c1ccc(-c2ccc(-c3nc4c(cnn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)c[nH]1
Temperature: 100 °C

Procedure:
To a solution of 6-[4-(6-amino-pyridin-3-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (28.1 mg, 0.057 mmol) in acetonitrile (0.5 mL) is added a solution of NaNO2 (5.4 mg, 0.078 mmol) in H2O (0.5 mL) at 0° C., followed by addition of one drop of concentrated H2SO4. The reaction mixture is then heated at 100° C. for 30 minutes, cooled down to 0° C., neutralized by saturated NaHCO3 to pH= 4-5, and extracted with ethyl acetate. The organic layer is concentrated and purified by preparative LC/MS to provide the title compound; 1H NMR (CDCl3, 400 MHz) δ 8.34 (s, 1H), 8.14 (d, 2H), 7.91 (dd, 1H), 7.75 (d, 1H), 7.52 (t, 2H), 7.44 (d, 2H), 7.36 (m, 5H), 7.13 (d, 2H), 6.88 (d, 1H); HPLC-MS calculated for C28H18ClN5O2 (M+H+) 492.1. Found: 492.1.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O.[NH2:18][OH:19]>CCO.O>[O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[N:18][OH:19]
Reactant: O=Cc1ccccc1OCCN1CCNC1=O
Reactant: NO
Solvent: CCO
Solvent: O
Product: O=C1NCCN1CCOc1ccccc1C=NO
Temperature: 5 °C
Reaction time: 6 h

Procedure:
A solution of 2-[2-(2-oxoimidazolidin-1-yl)ethoxy]benzaldehyde (10.0 g, 0.043 mol) in EtOH (100 mL) is heated to 50° C. At this temperature, a hydroxylamine solution (4.5 g, 0.068 mol, 50% in water, Aldrich) in EtOH (10 mL) is added. The reaction medium is then stirred for 6 hours at a temperature between 50° C. and 70° C. The reaction medium is evaporated under reduced pressure (Tbath 45° C., 65-70 mbar) until a suspension is obtained. The crude reaction product is then taken up in water (5 mL). The solution obtained is cooled to 5° C. and maintained at this temperature for 15 hours. The precipitate obtained is filtered and washed on the filter with an EtOH/water mixture (2 mL/2 mL) and then with an EtOH/petroleum ether mixture (1 mL/4 mL) and then with petroleum ether (2*10 mL). The solid is then dried under atmospheric pressure at room temperature.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([O:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
tert-butyl 3-hydroxyazetidine-1-carboxylate (21) (1 gm, 5.77 mmol) was dissolved in dry DMF (15 ml) and was cooled to 0° C. under nitrogen and was added sodium hydride (0.35 gm, 8.66 mmol). The reaction mixture was allowed to stir at room temperature for 30 min and was added benzylbromide (22; 1.08 gm, 6.35 mmol) at 0° C. The reaction mixture was then allowed warm to room temperature and stirred for 2 h. After completion of the reaction it was quenched by the addition of sat. ammonium chloride solution and extracted with ether. The organic layer was then dried over sodium sulfate and concentrated under vacuum. The crude product was purified column chromatography to yield compound 23 (1.21 gm, 80%).