Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:15][CH2:14][CH:13]([CH:16]3[CH2:25][CH2:24][C:19]4([O:23][CH2:22][CH2:21][O:20]4)[CH2:18][CH2:17]3)[CH2:12][CH:11]=2)=[C:6]([F:26])[C:5]=1[F:27])[CH3:2].C([OH:30])C.[OH-].[Na+].OO>C1COCC1.O>[O:23]1[C:19]2([CH2:24][CH2:25][CH:16]([CH:13]3[CH2:14][CH:15]([OH:30])[CH:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([F:27])[C:6]=4[F:26])[CH2:11][CH2:12]3)[CH2:17][CH2:18]2)[O:20][CH2:21][CH2:22]1
Reactant: CCO
Reactant: CCOc1ccc(C2=CCC(C3CCC4(CC3)OCCO4)CC2)c(F)c1F
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(C2CCC(C3CCC4(CC3)OCCO4)CC2O)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
550 ml (0.55 mol) of borane/THF complex (1 M solution) are added at −5° C. to a solution of 154.0 g (0.41 mol) of 8-[4-(4-ethoxy-2,3-difluorophenyl)-cyclohex-3-enyl]-1,4-dioxaspiro[4.5]decane in 1500 ml of THF, and the reaction mixture is stirred at room temperature for 3 h. 99 ml (1.7 mol) of ethanol, 250 ml (1.0 mol) of aqueous sodium hydroxide solution (16%) and 140 ml (1.6 mol) of aqueous hydrogen peroxide soln. (35%) are added successively to the batch, during which the internal temperature does not exceed 46° C. (ice bath). When the addition is complete, the mixture is refluxed for 2 h, and the solution is cooled, added to water and stirred vigorously. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The solution is concentrated to dryness, and the crude product is purified by column chromatography (SiO2, toluene:ethyl acetate=8:2), giving 5-(1,4-dioxaspiro[4.5]dec-8-yl)-2-(4-ethoxy-2,3-difluorophenyl)cyclohexanol as colourless, viscous oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[C:11]([O:20][CH2:21][C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][C:41]=1[F:42])[NH2:38].C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:38][C:37]3[CH:39]=[CH:40][C:41]([F:42])=[C:35]([Cl:34])[CH:36]=3)=[N:14][CH:15]=[N:16]2)=[C:11]([O:20][CH2:21][C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(OCc2ccccc2)cc2ncnc(Cl)c12
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(OCc2ccccc2)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Temperature: 70 °C

Procedure:
The crude tert-butyl (2R)-2-({[7-(benzyloxy)-4-chloroquinazolin-5-yl]oxy}methyl)-pyrrolidine-1-carboxylate was taken up in THF (5 ml) and 3-chloro-4-fluoroaniline (160 mg) and N,N-diisopropylethylamine (580 μl) were each added in one portion and the solution was heated at 70° C. for 18 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to leave a thick brown oil. Purification by flash chromatography, using 1.5% methanol in DCM as eluent, gave the tert-butyl (2R)-2-[({7-(benzyloxy)-4-[3-chloro-4-fluoroanilino]quinazolin-5-yl}oxy)methyl]pyrrolidine-1-carboxylate as a beige foam (350 mg, 54% over 2 steps); Mass spectrum MH+ 481.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6](Cl)[C:7]=1[F:8].[F-:14].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([F:14])[C:7]=1[F:8]
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: [F-]
Agent: [K+]
Product: Fc1cc(C(F)(F)F)cc(Cl)c1F

Procedure:
reacting the 3,5-dichloro-4-fluorobenzotrifluoride product of step (B) with potassium fluoride in the liquid phase at a temperature of about 170° to about 270° Celsius to form 3-chloro-4,5-difluorobenzotrifluoride.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)([O-])=O.[H][H]>[Pd].C(O)C>[N:12]1([CH2:11][CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1CCN1CCOCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1CCN1CCOCC1
Yield: 77.3 %

Procedure:
4-[(2-Nitrophenyl)ethyl]morpholine (11.4 g, 40 mmol) and palladium on carbon (10%, 500 mg) in ethanol (200 ml) were hydrogenated under 1 Atm. of hydrogen at room temperature for 3 h. The reaction was filtered through hyflo and the filtrate reduced to dryness under vacuum. The residue was recrystallized from toluene/hexane to give 2-(2-morpholin-4-ylethyl)aniline (6.375 g). Microanalysis: calculated C 69.87, H 8.80, N 13.58; found C 69.80; H, 8.95; N, 13.60.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](O)=[O:11])=[CH:9][C:4]=2[N:3]=[N:2]1.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[BH4-].[Na+]>O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][OH:11])=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=C(O)c1ccc2snnc2c1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCc1ccc2snnc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
Benzo[1,2,3]thiadiazole-5-carboxylic acid (2.70 g, 15.0 mmol) was dissolved in tetrahydrofuran (25 mL) and cooled to 0° C. To this was added triethylamine (2.50 mL, 18.0 mmol) followed by isobutylchloroformate (2.15 mL, 16.5 mmol) in a dropwise manner. The resulting slurry was stirred for a further 30 minutes at 0° C. and then filtered into a mixture of sodium borohydride (1.14 g, 30 mmol) in ice water (20 mL). The resulting mixture was stirred at 0° C. for 15 minutes, evaporated to one quarter of its volume and then partitioned between a saturated aqueous solution of sodium hydrogen carbonate (20 mL) and ethyl acetate (3×50 mL). The organic phases were combined and then dried over sodium sulfate. This was followed by concentration under reduced pressure to provide an oil which was purified by column chromatography on silica gel using an ethyl acetate and hexane solvent system. This provided the desired product as a yellow solid (1.40 g, 56%).
Reaction SMILES: [CH2:1]([N:4]([CH:15]([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[O:31]1[CH2:3][CH:2]1[CH2:1][N:4]([CH:15]([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: C=CCN(C(C)c1ccccc1)S(=O)(=O)c1ccc(O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(c1ccccc1)N(CC1CO1)S(=O)(=O)c1ccc(O)cc1
Yield: 85.3 %

Procedure:
5 ml of chloroform solution containing 1 g (3.2 mmol) of N-allyl-N-α-methylbenzyl-4-hydroxybenzenesulfonamide was added to 30 ml of a chloroform solution of 828 mg (4.8 mmol) of metachloroperbenzoic acid, followed by refluxing for 2 hours. After completion of the reaction, the chloroform solution was washed with an aqueous sodium thiosulfate solution and then an aqueous sodium bicarbonate solution. After drying, the solvent was distilled off and the resulting crude product was purified by the silica gel column chromatography (hexane-ethyl acetate) to obtain 910 mg of N-(2,3-epoxypropyl)-N-α-methylbenzyl-4-hydroxybenzenesulfonamide (Compound No. 37). The melting point was found to be 82.0° to 86.0° C. The results of the elemental analysis are shown below.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([CH:16]=1)[NH:7][C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)=[N:7][C:6]=2[CH:16]=1
Reactant: O=C(Nc1cc(Br)ccc1Nc1ccccc1)c1ccccn1
Solvent: Cc1ccccc1C
Product: Brc1ccc2c(c1)nc(-c1ccccn1)n2-c1ccccc1
Temperature: 25 °C
Yield: 68 %

Procedure:
Suspending 3.1 g (8.4 mmol) of 5′-bromo-2′-(N-phenylamino)-picoline anilide obtained in the above step (1) into 30 milliliter of xylene, and adding 0.48 g (2.5 mmol) of p-toluenesulfonic acid 1 hydrate, the resultant solution was azeotropically dehydrated while refluxing with heating for 5 hours. The reacted solution was cooled down to room temperature, and the solvent was removed by distillation. Dissolving the resultant solid into ethyl acetate, and after sequentially washing with water, with 10% potassium carbonate aqueous solution and with saturated solution of sodium chloride, it was dried with the use of magnesium sulfuric anhydride, followed by removing the solvent by distillation under reduced pressure, 2.0 g of 5-bromo-1-phenyl-2-(2-pyridyl)-1H-benzimidazole was obtained (yield: 69%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH2:24][OH:25])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH:24]=[O:25])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 86.3 %

Procedure:
Dimethylsulphoxide (1.35 ml, 18.8 mmol) was added dropwise to a solution of oxalyl chloride (1.65 ml, 18.8 mmol) in dichloromethane (20 ml) at −78° C. When the addition was complete, the reaction was stirred for a further 15 minutes at −78° C. 1-(tert-Butoxycarbonyl)-3-(hydroxymethyl)piperidine (2.7 g, 12.6 mmol) was added and the reaction warmed to −20° C. and stirred at this temperature for 20 minutes. Triethylamine (5.25 ml, 37.6 mmol) was added and the reaction allowed to warm to room temperature and stirred for 1 hour. The mixture was diluted with dichloromethane and washed with water (×2). The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was taken up in tetrahydrofuran and filtered through cotton wool. The filtrate was evaporated in vacuo to give the title compound (2.32 g, 89%).
Reaction SMILES: C(O[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][C:21](=[C:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20][CH2:19]2)=[C:14]([Cl:31])[CH:13]=1)=[O:10])C1C=CC=CC=1>C(OCC)(=O)C.[Pt]=O>[Cl:31][C:14]1[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:25]([O:27][CH3:28])=[O:26])[CH:17]=[CH:16][C:15]=1[CH:18]1[CH2:23][CH2:22][CH:21]([CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20][CH2:19]1
Reactant: CCOC(=O)C(C)=C1CCC(c2ccc(NC(=O)OCc3ccccc3)cc2Cl)CC1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)C1CCC(c2ccc(NC(=O)C(=O)OC)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Platinum oxide (300 mg) was added in one portion to a stirred solution of ethyl 2-[4-(4-{[(benzyloxy)carbonyl]amino}-2-chlorophenyl)cyclohexylidene]propanoate (1.5 g, 3.39 mmol) in ethyl acetate (30 mL) and the mixture was stirred at room temperature under a hydrogen atmosphere for 7 h. A further portion of platinum oxide (1.0 g) was added in one portion and the mixture was stirred for 1 h at room temperature under a hydrogen atmosphere. The reaction mixture was filtered and concentrated in vacuo to leave a residue, which was purified by column chromatography, using a gradient of 11-50% ethyl acetate:isohexane as eluent, to give the aniline product as a mixture of cis- and trans-cyclohexane isomers, that was used with no further purification.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:10]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:8][C:6]1[CH:7]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:18][CH:19]=2)[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Cc1cnc(N)c(Br)c1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
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: COCCOC
Solvent: O
Product: Cc1cnc(N)c(-c2ccc(Oc3ccccc3)cc2)c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (40.8 mg) was added to a suspension of 3-bromo-5-methylpyridin-2-amine (220 mg), 4-phenoxyphenylboronic acid (327 mg) and sodium carbonate (249 mg) in DME (8 mL) and water (1.5 mL) and the mixture was stirred at 85° C. under nitrogen overnight. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with EtOAc in hexane) to give the title compound (315 mg) as a white solid.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([N+:19]([O-:21])=[O:20])[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)=[C:14]([CH:29]([NH2:31])[CH3:30])[CH:13]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([N+:19]([O-:21])=[O:20])[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)=[C:14]([CH:29]([NH:31][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:30])[CH:13]=1
Reactant: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1[N+](=O)[O-]
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (41 mg, 0.21 mmol), 1-(4-chloro-3′-fluoro-5-methyl-6-nitrobiphenyl-2-yl)ethanamine (54 mg, 0.17 mmol), and N,N-diisopropylethylamine (0.06 mL, 0.35 mmol) in isopropyl alcohol (0.7 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C20H17ClFN6O2 (M+H)+: m/z=427.1. found: 427.1.
Reaction SMILES: C([O-])([O-])=[O:2].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].[NH2:19][C:20]1[N:21]=[C:22]([NH:31][C:32]2[CH:33]=[C:34]3[C:38](=[C:39]([C:41]4[S:45][C:44]5[CH:46]=[CH:47][CH:48]=[CH:49][C:43]=5[CH:42]=4)[CH:40]=2)[NH:37][N:36]=[CH:35]3)[C:23]2[C:28]([C:29]#[N:30])=[CH:27][NH:26][C:24]=2[N:25]=1.NC1N=C2N=CN(C#N)C(Cl)=C2C=1.O=P(Cl)(Cl)Cl.Cl>[OH-].[K+]>[NH2:19][C:20]1[N:21]=[C:22]([NH:31][C:32]2[CH:33]=[C:34]3[C:38](=[C:39]([C:41]4[S:45][C:44]5[CH:46]=[CH:47][CH:48]=[CH:49][C:43]=5[CH:42]=4)[CH:40]=2)[NH:37][N:36]=[CH:35]3)[C:23]2[C:28]([C:29]([NH2:30])=[O:2])=[CH:27][NH:26][C:24]=2[N:25]=1
Reactant: N#Cc1c[nH]c2nc(N)nc(Nc3cc(-c4cc5ccccc5s4)c4[nH]ncc4c3)c12
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: N#Cn1cnc2nc(N)cc-2c1Cl
Agent: OO
Solvent: O=P(Cl)(Cl)Cl
Product: NC(=O)c1c[nH]c2nc(N)nc(Nc3cc(-c4cc5ccccc5s4)c4[nH]ncc4c3)c12
Reaction time: 21 h
Yield: 7 %

Procedure:
Sodium percarbonate (0.040 g, 0.25 mmol) was added to a mixture of 2-amino-4-(7-benzo[b]thiophen-2-yl-1H-indazol-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (prepared via General Procedure N from the reaction of Example #F.8.1 with 6-amino-4-chloro-3-cyano-pyrrolo[2,3-d]pyrimidine [prepared by chlorination of the 4-oxo derivative (J. Med. Chem., 2001, 44(12), 1993-2003) using POCl3 (Tet., 2004, 60, 943-959), 0.10 g, 0.24 mmol) in 1N KOH (2.4 mL) at ambient temperature. After about 21 hours, the reaction mixture was acidified with 5N HCl and filtered. The resulting solid was purified by preparative HPLC (Thermo Hypersil-Keystone 250×21.2 mm 8μ Hypersil® HS C18 column; 5% CH3CN/50 mM aqueous ammonium acetate hold for 5 min, 5-100% CH3CN/50 mM aqueous ammonium acetate over 30 min, hold at 100% CH3CN for 5 minutes, 21 mL/min) to give an impure solid that was triturated with heptane and filtered to give 2-amino-4-(7-benzo[b]thiophen-2-yl-1H-indazol-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (6.9 mg, 7%); RP-HPLC (Table 1, Method e) Rt 1.64 min; m/z (ESI+): 441.0 (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[N:7][C:8]([O:11][CH2:12][C:13]2[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=2[CH3:18])=[CH:9][CH:10]=1)=[O:4].[O:23]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]1>>[O:23]1[CH2:27][CH2:26][CH:25]([NH:28][C:3]([C:5]2[N:6]=[N:7][C:8]([O:11][CH2:12][C:13]3[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=3[CH3:18])=[CH:9][CH:10]=2)=[O:4])[CH2:24]1
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)nn1
Reactant: NC1CCOC1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NC2CCOC2)nn1
Yield: 92 %

Procedure:
As described for example 1e, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid methyl ester (120 mg, 0.39 mmol) was converted, using rac-tetrahydrofuran-3-amine instead of isopropylamine, to the title compound (130 mg, 92%) which was obtained as a light yellow oil after purification by chromatography (silica, 0 to 5% methanol in dichloromethane). MS: m/e=361.5 [M+H]+.
Reaction SMILES: C[Al](C)C.[NH4+:5].[Cl-].[CH2:7]([O:14][C:15]([N:17]1[C@H:21]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C@@H:20]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:19]([C:40]([O:42]C)=O)[C@@H:18]1[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.O>[CH2:7]([O:14][C:15]([N:17]1[C@H:21]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:28])[CH3:29])([CH3:26])[CH3:25])[C@@H:20]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@H:19]([C:40](=[O:42])[NH2:5])[C@@H:18]1[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: [NH4+]
Reactant: COC(=O)[C@H]1[C@H](COCc2ccccc2)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@@H](COCc2ccccc2)[C@H](C(N)=O)[C@H](c2ccccc2)N1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 94.1 %

Procedure:
Under an atmosphere of N2, a 2.0M solution of Me3Al in toluene (PhMe) (Aldrich, 150 ml, 300 mmol) was added dropwise to a stirred and ice-cooled suspension of NH4Cl (14.9 g, 278 mmol) in dry PhMe (280 ml). The stirring at room temperature for 30 minutes gave rise to the clear and homogeneous reaction mixture. To this was added a solution of (2R*,3S*,4S*,5S*)-1-benzyloxycarbonyl-4-benzyloxymethyl-5-(t-butyldimethylsilyloxy)methyl-3-methoxycarbonyl-2-phenylpyrrolidine (16.8 g, 27.8 mmol) in dry PhMe (30 ml) dropwise. The resultant turbid reaction mixture was stirred and heated at an inner temperature of 50 C. for 24 hours. H2O (20 ml) was added cautiously to the ice-cooled and stirred reaction mixture. To this was then added a 1.0M potassium sodium tartrate aqueous solution (280 ml, 280 mmol), and the stirring was continued under the same cooling conditions for an hour. The mixture was filtered through a pad of Celite, and the filter cake was washed with AcOEt throughly. From the combined filtrate and AcOEt washings the organic layer was separated, and the aqueous layer was extracted with AcOEt (100 ml×3). The combined organic layer and AcOEt extracts were washed with sat. NaCl aq. solution (×1), dried (MgSO4), and concentrated in vacuo to give a foam (15.4 g). This was chromatographed over SiO2 (Merck Kieselgel 60, 160 g). Elution with n-hexane-AcOEt (6:1→4:1→1:1) gave pure title compound (12.0 g, 73%) as a white glass: IRmax (film): 3350(m), 3200(m), 1699(vs), 1680(vs), 1605(m), 1490(m), 1100(s), 780(s), 730(s), 697(s) cm-1 ; 1H-NMR δ: 7.53-7.40(m, 3H), 7.40-7.03(m, 12H), 5.60(br.s, 1H), 5.27(d, J=9.2 Hz, 1H), 5.03(br.s, 2H), 4.48(br.s, 2H), 4.47(dd, J=10.3, 8.1 Hz, 1H), 4.27(br.s, 1H), 3.99(dd, J=10.3, 2.9 Hz, 1H), 3.88-3.76(m, 1H), 3.70(dd, J=10.3, 3.3 Hz, 1H), 3.60(dd, J=10.3, 4.7 Hz, 1H), 3.32(dd, J=11.7, 9.2 Hz, 1H), 3.24-3.08(m, 1H), 0.90(br.s, 9H), 0.05(br.s, 6H) ppm.
Reaction SMILES: C([O:3][C:4](=[O:31])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][N:10]2[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:24])[CH:17]=3)=[CH:14][N:15]=[C:9]2[CH:8]=1)C.C([O-])([O-])=O.[Na+].[Na+].Cl>CCO>[F:30][C:27]([F:28])([F:29])[CH2:26][NH:25][C:23](=[O:24])[NH:22][C:18]1[CH:17]=[C:16]([C:13]2[N:10]3[CH:11]=[CH:12][C:7](/[CH:6]=[CH:5]/[C:4]([OH:31])=[O:3])=[CH:8][C:9]3=[N:15][CH:14]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)/C=C/c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)/C=C/c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Temperature: 80 °C

Procedure:
To a solution of (E)-3-(3-{3-[3-(2,2,2-Trifluoro-ethyl)-ureido]-phenyl}-imidazo[1,2-a]pyridin-7-yl)-acrylic acid ethyl ester (83 mg, 0.19 mmol) in EtOH (10 ml) was added 1M Na2CO3 (4 ml) and the reaction heated to 80° C. for 1.5 h. The reaction was neutralised using 1M HCl and then concentrated. The residue was taken up in hot EtOH, filtered and the solvent removed in vacuo to afford the product. MS: [M+H]+ 405.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[C:5]([N:8]2[CH2:13][CH2:12][O:11][C:10]([CH3:15])([CH3:14])[CH2:9]2)=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([N:8]2[CH2:13][CH2:12][O:11][C:10]([CH3:14])([CH3:15])[CH2:9]2)=[N:6][CH:7]=1
Reactant: CC1(C)CN(c2ncc(Br)cc2[N+](=O)[O-])CCO1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)CN(c2ncc(Br)cc2N)CCO1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 4-(5-bromo-3-nitropyridin-2-yl)-2,2-dimethylmorpholine (2.22 g, 7.03 mmol) in EtOAc (30 mL) was added tin(II) chloride dihydrate (8.94 g, 39.6 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 90° C. After 1 h, the reaction was cooled to rt, then washed with 1M NaOH, water, and brine. After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was purified with silica gel chromatography (0-35% EtOAc in hexanes) to provide a colorless film as 5-bromo-2-(2,2-dimethylmorpholino)-pyridin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.59 (1H, d, J=2.2 Hz), 7.13 (1H, d, J=2.3 Hz), 5.10 (2H, s), 3.83 (2H, m), 2.90 (2H, m), 2.77 (2H, s), 1.24 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(O)C.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]=[C:37]=[S:38])=[O:35])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:36][C:34](=[O:35])[C:31]2[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=2)=[S:38])=[C:18]([F:23])[CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (77 mg, yield 98%).