Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:26][CH2:25][CH:16]3[N:17]([C:21](=O)[CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][CH:15]3[C:13]=2[CH:14]=1>O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:26][CH2:25][CH:16]3[N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][CH:15]3[C:13]=2[CH:14]=1
Reactant: CCC(=O)N1CCCC2c3cc(OC)ccc3OCC21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCN1CCCC2c3cc(OC)ccc3OCC21
Temperature: 25 °C

Procedure:
To a suspension of 3.8 g of lithium aluminum hydride in a 100 ml of tetrahydrofuran, 3,6 g of concentrated sulfuric, acid is first added dropwise at -5° to -10°, then 5.0 g of 9-methoxy-4-propionyl-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine is added slowly with stirring. The reaction mixture is allowed to warm to room temperature, stirred for 18 hours and finally heated under reflux for 1 hour. After cooling the reaction mixture is quenched with ethyl acetate, then treated with a small volume of water and 3N sodium hydroxide, filtered and concentrated in vacuo. The residue is redissolved in ethyl acetate and the ethyl acetate solution is washed with water, dried and evaporated to yield 9-methoxy-4-propyl-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]#[C:13][Si](C)(C)C>CO>[O:1]1[C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[CH:12]=[CH:13]1
Reactant: COC(=O)c1ccc(O)c(C#C[Si](C)(C)C)c1
Solvent: CO
Product: COC(=O)c1ccc2occc2c1
Temperature: 60 °C
Yield: 33.5 %

Procedure:
Methyl 4-hydroxy-3-[(trimethylsilyl)ethynyl]benzoate (11 g, 44.5 mmol) is combined with DIA (7.1 ml, 50 mmol) and cuprous iodide (423 mg, 2.2 mmol) in 100 ml MeOH in a flask under nitrogen. The reaction is warmed to 60° C. for 6 h, the volatiles are removed in vacuo, and the brown-green residue is chromatographed over 500 g silica gel (230-400 mesh) eluting with 20% EtOAc/hexane. The appropriate fractions are combined and concentrated to give 2.63 g (34%) of methyl benzofuran-5-carboxylate as a pale oil which crystallized on standing. 1H NMR (300 MHz, CDCl3): δ 3.95, 6.86, 7.53, 7.70, 8.03, 8.36 ppm.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:12]1[CH:27]=[CH:26][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH:23](O)[CH3:24])[CH:20]=[CH:21][CH:22]=2)=[C:14]([CH2:28][CH2:29][CH3:30])[CH:13]=1)([O:8]COC)[C:4]([F:7])([F:6])[F:5].[CH3:33][CH:34]([O:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2([CH3:50])[NH:47][C:46](=[O:48])[NH:45][C:44]2=[O:49])=[CH:39][CH:38]=1)[CH3:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCOC(/N=N/C(OCC)=O)=O>[F:32][C:2]([F:31])([F:1])[C:3]([C:12]1[CH:27]=[CH:26][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH:23]([N:45]3[C:44](=[O:49])[C:43]([C:40]4[CH:41]=[CH:42][C:37]([O:36][CH:34]([CH3:33])[CH3:35])=[CH:38][CH:39]=4)([CH3:50])[NH:47][C:46]3=[O:48])[CH3:24])[CH:20]=[CH:21][CH:22]=2)=[C:14]([CH2:28][CH2:29][CH3:30])[CH:13]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)cc1
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cccc(C(C)O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1Oc1cccc(C(C)N2C(=O)NC(C)(c3ccc(OC(C)C)cc3)C2=O)c1
Yield: 44.2 %

Procedure:
To a solution of 1-(3-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)phenyl) ethanol (40.0 mg, 85.8 mmol), 5-(4-(1-methylethoxy)phenyl)-5-methylimidazolidine-2,4-dione (32.0 mg) and triphenylphosphine (56.3 mg) in tetrahydrofuran (5 mL), diethylazodicarboxylate (about 2.2 mol/L toluene solution, 97.5 μL) was added under ice-cold conditions. After completion of the reaction, the reaction solution was concentrated in vacuo. The obtained residue was purified using silica-gel thin-layer chromatography (hexane/ethyl acetate). The obtained compound was added with 2 mol/L hydrogen chloride-ethyl acetate solution (1 mL) at room temperature. After completion of the reaction, the solution was concentrated in vacuo and purified using thin-layer silica-gel column chromatography (hexane/ethyl acetate) and the title compound (37.2 mg, yield 66%) was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[F:19][C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>>[F:19][C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH2:22][NH:23][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1]
Reactant: NCc1ccc(F)cc1F
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NCc1ccc(F)cc1F)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-(2,4-difluorobenzyl)-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.33 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.49 mmol of 2,4-difluorobenzylamine. LC/MS [6.28 min; 484 (M+1)]
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:14][OH:15])[NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(Cl)(Cl)=O>C(Cl)Cl>[C:7]1([C:6]2[O:15][CH2:14][C@@H:4]([C:3]([O:2][CH3:1])=[O:16])[N:5]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)[C@H](CO)NC(=O)c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)[C@@H]1COC(c2ccccc2)=N1
Yield: 78.7 %

Procedure:
A stirred mixture of N-benzoyl-L-serine methyl ester (21.0 g), thionyl chloride (21.0 g), and methylene chloride (150 ml) is stirred at reflux for 1 hour. The solvent is evaporated and the residue is diluted with cold water. Neutralize with sodium bicarbonate, and extract with ethyl acetate. Purification on silica gel (250 g), eluting with methanol:methylene chloride (01:99), yields methyl (S)-2-phenyl-2-oxazoline-4-carboxylate (15.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][N:19]([CH3:35])[C@@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=O)=[O:26])[CH2:21]1>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:28]2[NH:29][C:30]([CH3:32])=[CH:31][C:27]=2[C:25]([N:22]2[CH2:23][CH2:24][C@@H:20]([N:19]([CH3:18])[CH3:35])[CH2:21]2)=[O:26])[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Reactant: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.8 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3-[(3R)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(3-chloro-phenyl)-3-[3-[(3R)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one as a yellow solid (71 mg, 60%).
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][C:11]([F:22])=[CH:10][CH:9]=2)=[O:5])C.[C:23]1([NH:29][NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(=O)C>[F:22][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:4](=[O:5])[N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:30]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]=3[C:13]=2[CH:12]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C(=O)c1c(C(=O)OCC)[nH]c2ccc(F)cc12
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(-c2ccccc2)c(=O)c2[nH]c3ccc(F)cc3c12

Procedure:
The preparation is carried out as in Example 1.3, from 5 g (16.2 mmol) of ethyl 2-(ethoxycarbonyl)-5-fluoro-α-oxo-1H-indole-3-acetate and from 9.5 ml of phenylhydrazine in 150 ml of acetic acid. 3.9 g (11 mmol) of solid are isolated, which solid is used as is in the following stage.
Reaction SMILES: COC1C2CC(N(CCC)CC#N)CSC=2C=CC=1.[CH3:20][O:21][C:22]1[C:27]2[CH2:28][CH:29]([N:32]([CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][C:36]#[N:37])[CH2:30][S:31][C:26]=2[CH:25]=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[C:27]2[CH2:28][CH:29]([N:32]([CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH2:30][S:31][C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: CCCN(CCCC#N)C1CSc2cccc(OC)c2C1
Agent: CCCN(CC#N)C1CSc2cccc(OC)c2C1
Product: CCCN(CCCCN)C1CSc2cccc(OC)c2C1

Procedure:
Using the procedure described in Example 51, but replacing the compound of Example 50 by the compound of Example 53, the product of the title is obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14](=[O:40])[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]2[C:25]([C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=3[OH:39])=[N:26][N:27]([CH2:29][CH2:30][OH:31])[CH:28]=2)=[CH:18][CH:17]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:38][C:36]1[CH:35]=[CH:34][C:33]([OH:39])=[C:32]([C:25]2[C:24]([C:23]#[C:22][C:19]3[CH:18]=[CH:17][C:16]([NH:15][C:14]([C@H:9]4[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]4)=[O:40])=[CH:21][CH:20]=3)=[CH:28][N:27]([CH2:29][CH2:30][OH:31])[N:26]=2)[CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)[C@H]1CCCCN1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Compound 4A (8.2 g) was dissolved in dichloromethane (50 mL) and cooled to 0° C. with ice-water bath. TFA (50 mL) was added slowly to the above solution at 0° C. The mixture was stirred at 0° C. for 1.5 hour. LC-MS indicated the reaction was complete. Dichloromethane and TFA were removed with a rotavapor at rt. Dichloromethane (˜100 mL) was added to the residua and removed again. The process was repeated twice more. The resultant residua were suspended in ethyl acetate (˜50 mL). 5% Aqueous NaHCO3 and solid NaHCO3 were added slowly to neutralize any residual TFA. The mixture was filtered and the solid was washed with water and ethyl acetate. The solid was collected and dried under high vacuum in the presence of Drierite. The filtrate was collected and the organic layer was separated and dried over sodium sulfate. It was then filtered and the solvent was removed to give yellowish solid. The solid from filtration and the solid from filtrate were combined and the title compound 5A was obtained in quantitative yield. Using the same procedure for the preparation of 5A, the treatment of compound 16A (870 mg) with TFA (10 mL) in methylene chloride (10 mL) gives compound 17A in 74.0% yield. 1H NMR (DMSO-d6, 500 MHz) δ 10.68 (s, 1H), 9.95 (br s, 1H), 8.36 (s, 1H), 8.28 (s, 1H), 7.73 (d, 2H, J=8.5 Hz), 7.46 (d, 2H, J=8.5 Hz), 7.29 (d, 1H, J=9.0 Hz), 6.99 (d, 1H, J=9.0 Hz), 5.01 (s, 1H), 4.26 (s, 2H), 3.78 (d, 2H, J=4.0 Hz), 2.99 (d, 1H, J=12.0 Hz), 2.60 (t, 1H, J=11.0 Hz), 1.84 (s, 1H), 1.77 (s, 1H), 1.51 (d, 1H, J=11.0 Hz), 1.41 (m, 3H). LCMS (ESI) m/z 465.06 (MH+, 100); HPLC: tR=4.02 min.
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[C:11]([O:24][CH3:25])[CH:10]=1)(C)C)(C)(C)C.Br[C:27]1[S:31][C:30]([N:32]([CH3:43])[CH:33]2[CH2:38][C:37]([CH3:40])([CH3:39])[NH:36][C:35]([CH3:42])([CH3:41])[CH2:34]2)=[N:29][N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=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>[CH3:25][O:24][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[C:27]1[S:31][C:30]([N:32]([CH3:43])[CH:33]2[CH2:38][C:37]([CH3:39])([CH3:40])[NH:36][C:35]([CH3:42])([CH3:41])[CH2:34]2)=[N:29][N:28]=1
Reactant: CN(c1nnc(Br)s1)C1CC(C)(C)NC(C)(C)C1
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C)ccc1B1OC(C)(C)C(C)(C)O1
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: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(O)ccc1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Temperature: 120 °C

Procedure:
To a stirred suspension of tert-butyl(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane (Intermediate 3) (3.28 g, 9.00 mmol) and 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (Intermediate 4) (1 g, 6.00 mmol) in dioxane (48 mL) under nitrogen was added Pd(PPh3)4 (0.347 g, 0.30 mmol) followed by a solution of Na2CO3 (1.272 g, 12.00 mmol) in water (12 mL). The resulting mixture was refluxed at 120° C. for 18 hours. The reaction mixture was cooled to room temperature, then diluted with EtOAc (150 mL) and washed with water (100 mL). The organic phase was separated and the aqueous phase re-extracted with EtOAc (150 mL). The combined organics were dried over MgSO4, filtered, and the filtrate concentrated in vacuo to afford an oily brown residue. The residue was suspended in EtOAc (10 mL) and sonicated, then the resulting suspension was filtered under vacuum to afford the crude product as an off-white solid. The crude mixture was purified by flash chromatography using 3% [7M NH3 in MeOH]/DCM as the eluent to afford the title compound as a pale yellow glass-like solid (0.534 g, 23% yield). LC-MS: Rt 0.75 min; MS m/z 377.3 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.99 (br. s., 1H), 7.88 (d, J=8.59 Hz, 1H), 6.54 (d, J=2.53 Hz, 1H), 6.50 (dd, J=8.34, 2.27 Hz, 1H), 4.34-4.25 (m, 1H), 3.86 (s, 3H), 2.94 (s, 3H), 1.59 (dd, J=11.62, 3.03 Hz, 2H), 1.40 (t, J=12.38 Hz, 2H), 1.26 (br. s., 1H), 1.20 (s, 6H), 1.08 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C([Li])CCC.[Cl:19]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Cl:19][C:11]1[N:10]([CH3:13])[N:9]=[C:8]([N:3]2[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]2[CH3:7])[CH:12]=1
Reactant: Cc1ccc(C)n1-c1ccn(C)n1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(Cl)n(C)n1
Temperature: -70 °C
Reaction time: 2.6 h
Yield: 59 %

Procedure:
A solution of 3-(2,5-dimethyl-pyrrol-1-yl)-1-methyl-1H-pyrazole (Intermediate 7, 0.51 g, 2.91 mmol) in tetrahydrofuran (25 mL) cooled to −70° C. was treated dropwise with a 2.5M solution of n-butyllithium in hexanes (1.3 mL, 3.25 mmol). The reaction was stirred at −70° C. for 2.6 h. After this time, the reaction was treated dropwise over 2-3 min with a solution of hexachloroethane (0.77 g, 3.2 mmol) in tetrahydrofuran (2.5 mL). The reaction was maintained at −70° C. for 20-25 min. After this time, the cooling bath was removed. The reaction continued to stir for 90 min, at which time the reaction was concentrated in vacuo. The residue was then partitioned between water (50 mL) and diethyl ether (1×50 mL). The organics were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered, rinsed with diethyl ether and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 40 g, 5-10% ethyl acetate/hexanes) afforded 5-chloro-3-(2,5-dimethyl-pyrrol-1-yl)-1-methyl-1H-pyrazole (0.36 g, 60%) as a light brown solid; ES+-HRMS m/e calcd for C10H12N3Cl [M+H+] 210.0793, found 210.0792.
Reaction SMILES: Cl[CH:2]([O:7][CH2:8][CH:9]=[CH2:10])[CH2:3][CH2:4][CH2:5][CH3:6].[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1>>[N:11]1([CH:2]([O:7][CH2:8][CH:9]=[CH2:10])[CH2:3][CH2:4][CH2:5][CH3:6])[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C=CCOC(Cl)CCCC
Reactant: c1nc[nH]n1
Product: C=CCOC(CCCC)n1cncn1

Procedure:
Following the procedure of Example 2, allyl 1-chloropentyl ether (3 g) and 1,2,4-triazole (3.8 g) were reacted to give the title compound as a colourless oil, which was purified by distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH2:14])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.[OH-].[Na+].[Cl-].[Na+]>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:18]([Cl:17])=[CH:19][CH:20]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: N[C@@H]1CCCN(C(=O)c2ccc(Cl)cc2)C1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Product: O=C(N[C@@H]1CCCN(C(=O)c2ccc(Cl)cc2)C1)c1ccc(Cl)cc1
Temperature: 15 °C
Reaction time: 3 h
Yield: 49.5 %

Procedure:
To the aqueous solution of (R)-1-(p-chlorobenzoyl)-3-amino piperidine obtained in Example 14 (amount: 3 g), p-chlorobenzoyl chloride (0.15 g) was added. The pH of the mixture was kept from pH 8.0 to 9.0 using sodium hydroxide. The mixture was stirred at 15° C. for 3 hours, and chlorobenzene (3 ml) and sodium chloride (0.5 g) were added. The mixture was stirred at 90° C. for 10 minutes. The water layer was removed, and the solvent was evaporated under reduced pressure to obtain the title compound as yellow crystal (0.16 g, yield: 36%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8]C)=O.[H-].[Na+].[C:21]1(C)[CH:26]=CC=C[CH:22]=1>>[CH3:1][O:2][C:3]1[C:4]2[O:13][C:14]([CH2:26][CH:21]=[CH2:22])([C:15]([O:17][CH3:18])=[O:16])[C:6](=[O:8])[C:5]=2[CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ccccc1
Reactant: COC(=O)COc1c(OC)cccc1C(=O)OC
Agent: [H-]
Agent: [Na+]
Product: C=CCC1(C(=O)OC)Oc2c(OC)cccc2C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
Methyl 3-methoxy-2-(methoxycarbonylmethoxy)benzoate (19.39 g) was dissolved in toluene (200 ml). To this solution, sodium hydride (3.36 g) was added and the resultant was stirred at room temperature for 20 minutes, followed by refluxing the mixture for 2 hours. Toluene was evaporated off under reduced pressure and the residue was dissolved in DMF (150 ml). To this solution, acetic acid (2 ml) was added and the solvent was evaporated off under reduced pressure. The residue was dissolved in toluene (200 ml) and the solution was refluxed for 1 hour. The reaction solution was cooled to room temperature and poured into water (150 ml), followed by separating the organic layer. The aqueous layer was extracted with ethyl acetate (100 ml) and the organic layers were combined. The resultant was washed with saturated aqueous sodium hydrogen carbonate solution and with saturated brine, followed by drying the resultant over sodium sulfate. After removing sodium sulfate by filtration, the solvent was evaporated off, and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=3/1) using silica gel to obtain the desire compound (18.42 g, yield: 92%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:14]([N+:26]([O-:28])=[O:27])=[CH:13][N:12]=1.[C:29]1([N:35]2[CH:39]=[C:38]([NH2:40])[CH:37]=[N:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>O1CCOCC1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15]2[C:14]([N+:26]([O-:28])=[O:27])=[CH:13][N:12]=[C:11]([NH:40][C:38]3[CH:37]=[N:36][N:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:39]=3)[N:16]=2)=[CH:19][CH:20]=1
Reactant: Nc1cnn(-c2ccccc2)c1
Reactant: COc1ccc(Nc2nc(Cl)ncc2[N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(Nc3cnn(-c4ccccc4)c3)ncc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
284 g (19.0 mmol) Diisopropylethylamine are added to a solution of 561 mg (2.00 mmol) (2-chloro-5-nitro-pyrimidin-4-yl)-(4-methoxy-phenyl)-amine and 350 mg (2.00 mmol) 1-phenyl-1H-pyrazol-4-ylamine in 6 ml dioxane. The mixture is stirred for 16 hours at room temperature. Then water is added to the reaction mixture, the resulting precipitate is filtered off, washed with water and dried under vacuum giving N4-(4-methoxy-phenyl)-5-nitro-N2-(1-phenyl-1H-pyrazol-4-yl)-pyrimidine-2,4-diamine as yellow crystals; HPLC/MS (B): 2.50 min, [M+H] 404.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([O:15][C:16]2[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Br:24])[CH:17]=2)[C:7]=1[F:25])[CH3:2].[NH4+].[Cl-]>CCO.O.[Fe]>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([O:15][C:16]2[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Br:24])[CH:17]=2)[C:7]=1[F:25])[CH3:2]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])c(Oc2cc(Br)cc(C#N)c2)c1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1ccc(N)c(Oc2cc(Br)cc(C#N)c2)c1F
Temperature: 25 °C
Yield: 98.7 %

Procedure:
A solution of ester (117a, 4.34 g, 10.26 mmol), Fe powder (2.40 g, 43.07 mmol), and NH4Cl (2.30 g, 43.07 mmol) in EtOH (80 mL) and H2O (40 mL) was heated to reflux for 2 h. The solution was cooled to RT and filtered through CELITE®. The filter cake was washed with EtOAc (200 mL), the aqueous and organic layers were separated, and the organic layer was washed with brine (2×60 mL). The solution was dried with anhydrous MgSO4, and evaporated to provide 3.98 g (98%) of the [4-amino-3-(3-bromo-5-cyano-phenoxy)-2-fluoro-phenyl]-acetic acid ethyl ester (117b).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9](O)=[O:10])[CH2:5][CH2:4]1>O1CCCC1>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][OH:10])[CH2:5][CH2:4]1
Reactant: COC1CCC(C(=O)O)CC1
Solvent: C1CCOC1
Product: COC1CCC(CO)CC1
Reaction time: 1 h

Procedure:
4-Methoxycyclohexanecarboxylic acid (7 g) in tetrahydrofuran (20 mL) was treated with 1 M (in tetrahydrofuran) borane-tetrahydrofuran complex (100 mL) overnight. The mixture was concentrated and the residue was dissolved in methanol (100 mL) and concentrated HCl (10 mL). The resulting mixture was stirred for 1 hour and concentrated. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([Cl:19])[C:10]=1[C:20]1[N:25]=[C:24]2[NH:26][N:27]=[C:28](I)[C:23]2=[CH:22][N:21]=1.[CH2:30]([N:32]1[CH2:40][C:39]2[C:34](=[N:35][CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=2)[C:33]1=[O:50])[CH3:31]>>[Cl:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([Cl:19])[C:10]=1[C:20]1[N:25]=[C:24]2[NH:26][N:27]=[C:28]([C:37]3[CH:38]=[C:39]4[CH2:40][N:32]([CH2:30][CH3:31])[C:33](=[O:50])[C:34]4=[N:35][CH:36]=3)[C:23]2=[CH:22][N:21]=1
Reactant: CCN1Cc2cc(B3OC(C)(C)C(C)(C)O3)cnc2C1=O
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Solvent: O=C(O)C(F)(F)F
Product: CCN1Cc2cc(-c3n[nH]c4nc(-c5c(Cl)c(OC)cc(OC)c5Cl)ncc34)cnc2C1=O

Procedure:
This compound was prepared as a TFA salt by using procedures analogous to those described for the synthesis of Example 1, Step 7 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 6-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Example 55, Step 3). LCMS (M+H)+=485.0/487.0.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[F:11][C:12]([F:16])([F:15])[CH2:13]O.S(=O)(=O)(O)O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:13][C:12]([F:16])([F:15])[F:11])=[O:6]
Reactant: O=C(O)c1cccc(O)c1
Reactant: OCC(F)(F)F
Agent: O=S(=O)(O)O
Product: O=C(OCC(F)(F)F)c1cccc(O)c1
Temperature: 95 °C

Procedure:
Into a 250 mL round bottom flask equipped with magnetic stirrer and heating mantle was added 10 parts of 3-hydroxy benzoic acid, 100 parts of 2,2,2-trifluoroethanol and 0.5 parts of concentrated sulfuric acid. The reaction mixture was heated at 95° C. for 48 hours. The solvent was evaporated under reduced pressure and the solid material was dissolved in 250 mL of ethyl acetate. The organic layer was washed with 250 mL of water, 250 mL 5% solution of sodium bicarbonate in 100 mL of water and finally with 250 mL of water. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure, yield 4.1 parts. TLC on silica gel plate showed a single spot. The structure was confirmed on the basis of 1H NMR. The reaction proceeded as follows: