Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:11]2[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[C:11]3[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: CCc1cc2c(NCc3ccc(F)cc3)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc(F)cc3)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-ethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-ethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13](F)=[C:14]([N+:16]([O-])=O)[CH:15]=3)=[N:7][C:6]=2[CH:20]=1.C(N(CC)CC)C.[CH2:28]([NH2:31])[CH2:29][CH3:30].[H][H]>C(#N)C.[C].[Pd].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:31][CH2:28][CH2:29][CH3:30])=[C:14]([CH:15]=3)[NH2:16])=[N:7][C:6]=2[CH:20]=1
Reactant: CCCN
Reactant: O=[N+]([O-])c1cc(-c2nc3cc(Cl)ccc3o2)ccc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCNc1ccc(-c2nc3cc(Cl)ccc3o2)cc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.9 %

Procedure:
To a suspension of 5-chloro-2-(2-fluoronitrobenzen-5-yl)benzoxazole (see Working Example 100-1) (1.5 g, 5.13 mmol) in acetonitrile (10 mL) was added triethylamine (779 mg, 7.70 mmol) and propylamine (364 mg, 6.16 mmol), and this was heated to reflux for 4 hours. After the reaction was complete, this was cooled to room temperature, water was added, and the precipitated crystals were filtered, washed with water and then dried. To a solution of the crystals obtained in ethanol/tetrahydrofuran (1:2, 15 mL) was added 10% palladium-carbon (200 mg). A hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature for 18 hours. After the reaction was finished, this was filtered through Celite, and the filtrate was concentrated to yield the title compound (1.5 g, 97% yield) as orange crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH2:21][C:22]([O:25][CH3:26])([CH3:24])[CH3:23])[N:9]=[C:10]([NH:11][C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:5]2=[CH:4][N:3]=1.C1COCC1.[CH3:32][NH:33]C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>O1CCOCC1>[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36].[Cl:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:19])[C:12]=1[NH:11][C:10]1[C:5]2[C:6](=[N:7][C:2]([NH:33][CH3:32])=[N:3][CH:4]=2)[N:8]([CH2:20][CH2:21][C:22]([O:25][CH3:26])([CH3:23])[CH3:24])[N:9]=1
Reactant: COC(C)(C)CCn1nc(Nc2c(Cl)cccc2Cl)c2cnc(Cl)nc21
Reactant: CNC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CNc1ncc2c(Nc3c(Cl)cccc3Cl)nn(CCC(C)(C)OC)c2n1
Temperature: 100 °C
Reaction time: 23 h

Procedure:
A sealed tube containing 55 mg (0.13 mmol) of 6-chloro-N-(2,6-dichlorophenyl)-1-(3-methoxy-3-methylbutyl)-1H-pyrazolo[3,4-d]pyrimidin-3-amine (prepared as described in Example 1, Step B), 650 μl (2.0 M, 1.3 mmol) of a THF solution of dimethylamine and 120 μl (1.6 mmol) of TFA in 3 mL 1,4-dioxane was heated at 100° C. for 21 h. After this time, 650 μl (2.0 M, 1.3 mmol) of a THF solution of dimethylamine and 120 μl (1.6 mmol) of TFA were added, and heating was continued at 100° C. for an additional 23 h. The orange solution was concentrated, and the residue was purified by HPLC (Capcell Pak C18 5 μm, gradient of 80% A:20% B to 30% A:70% B over 45 min; A=0.5% TFA in water, B=0.5% TFA in acetonitrile) to give the title compound. 1H-NMR (CDCl3) δ 1.25 (s, 6H), 2.01-2.08 (m, 2H), 3.05 (s, 3H), 3.22 (s, 3H), 4.19-4.26 (m, 2H), 6.60 (s, 1H), 7.24 (t, J=8.4 Hz, 1H), 7.46 (d, J=8.1 Hz, 2H), 7.77 (s, 1H), 9.49 (s, 1H). Mass Spectrum (ESI) m/e=409.1.
Reaction SMILES: Cl.O1CCCC1.[C:7]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([O:26][Si](C(C)(C)C)(C)C)[CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:13][C:12]=1[NH:34][C:35](=[O:51])[CH2:36][CH:37]1[C:50]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[O:44][C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)([CH3:10])([CH3:9])[CH3:8].C(OCC)(=O)C>O>[C:7]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([OH:26])[CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:13][C:12]=1[NH:34][C:35](=[O:51])[CH2:36][CH:37]1[C:50]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[O:44][C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1ccc(CC(CC2CCCCC2)O[Si](C)(C)C(C)(C)C)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CC(O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
1.5 ml of 2N aqueous hydrochloric acid were added to 15 ml of a tetrahydrofuran solution containing 813 mg (1.30 mmol) of N-[2-t-butyl-5-(3-cyclohexyl-2-t-butyldimethylsilyloxypropyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared by a procedure similar to that described in Preparation 11), and the mixture was stirred for 2.5 hours at 50° C. The reaction mixture was then allowed to return to room temperature. Addition of a mixture of ethyl acetate and water caused the title compound to be distributed between the organic solvent and water. The organic layer was separated and washed with a saturated aqueous solution of sodium hydrogen carbonate, and then with a saturated aqueous solution of sodium chloride. The solvent was removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 50 g of silica gel. Elution with mixtures of ethyl acetate and hexane ranging from 1:2 to 2:3 by volume afforded 650 mg (yield 98%) of the title compound as crystals, melting at 177°-178° C. (after recrystallization from diisopropyl ether).
Reaction SMILES: [CH:1](=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.CO.[C:22]([C:24]1[N:25]=[C:26]([NH2:38])[C:27]2[N:28]([N:30]=[C:31]([C:33]3[O:34][CH:35]=[CH:36][CH:37]=3)[N:32]=2)[CH:29]=1)#[CH:23]>O>[O:34]1[CH:35]=[CH:36][CH:37]=[C:33]1[C:31]1[N:32]=[C:27]2[C:26]([NH2:38])=[N:25][C:24]([C:22]#[C:23][CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:29][N:28]2[N:30]=1
Reactant: C(=Nc1ccccc1)c1ccccc1
Reactant: C#Cc1cn2nc(-c3ccco3)nc2c(N)n1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C#CC(Nc2ccccc2)c2ccccc2)cn2nc(-c3ccco3)nc12
Temperature: 40 °C

Procedure:
To a solution of benzylidene-phenyl-amine (0.05 mmol) (prepared by heating neat phenylamine (0.05 mmol) and benzaldehyde (0.05 mmol) at 60° C. for 2 hours) in a 1:1 mixture of THF (250 uL) and methanol (250 uL) was added the above 6-ethynyl-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine (11 mg, 0.05 mmol). CuBr (2.2 mg, 0.015 mmol, 30 mol %) was added to the reaction mixture followed by RuCl3 (0.03 mg, 0.0015, 3 mol %) in water (50 μL). The reaction vessel was degassed and heated at 40° C., for 18 hours. After cooling, water was added and the residue was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, and concentrated in vacuo to yield a crude product, which was purified using preparative HPLC to afford 2-furan-2-yl-6-(3-phenyl-3-phenylamino-prop-1-ynyl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine. 1H NMR (300 MHz, Acetone-d6) δ 8.20 (s, 1H), 7.79-7.71 (3H), 7.43-7.40(3H), 7.15-7.11(4H), 6.90-6.87(2H), 6.67-6.65 (2H), 5.70 (s, 1H), 2.55(s, 1H). MS: m/z 407 [M+1].
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:23]([CH3:33])[CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:12]=[C:13]([O:15]CC2C=CC=CC=2)[CH:14]=1)C1C=CC=CC=1.C(O)C.Cl.[H][H]>C(OCC)(=O)C.[Pd]>[OH:15][C:13]1[CH:12]=[C:11]([CH:23]([CH3:33])[CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:10]=[C:9]([OH:8])[CH:14]=1
Reactant: CC(CCOc1ccccc1)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(CCOc1ccccc1)c1cc(O)cc(O)c1
Reaction time: 2 h

Procedure:
A solution of 3-(3,5-dibenzyloxyphenyl)-1-phenoxybutane (14.7 g., 133.5 mM) in a mixture of ethyl acetate (110 ml.), ethanol (110 ml.) and concentrated hydrochloric acid (0.7 ml.) is hydrogenated for 2 hours under 60 p.s.i. hydrogen in the presence of 10% palladium-on-carbon (1.5 g.). Removal of the catalyst by filtration and concentration of the filtrate gives an oil. The oil is purified by chromatography on silica gel (100 g.) and eluting with benzene-ethyl acetate consisting of 0-10% ethyl acetate. The middle fractions are combined and concentrated to give the title product: 7.8 g. (80%), as an oil.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:22])[C:4]([C:7]2[CH:12]=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:9](=[O:21])[CH:8]=2)=[N:5][N:6]=1.[OH-].[Na+].[CH2:25](O)C.IC>O>[CH3:22][N:3]1[C:2]([S:1][CH3:25])=[N:6][N:5]=[C:4]1[C:7]1[CH:12]=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:18])[CH3:20])[C:9](=[O:21])[CH:8]=1
Reactant: CCO
Reactant: Cn1c(S)nnc1-c1ccn(COCC[Si](C)(C)C)c(=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CSc1nnc(-c2ccn(COCC[Si](C)(C)C)c(=O)c2)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
The title compound of example 21.1 (21.6 g, 63.8 mmol) was dissolved in a solution of NaOH (5.36 g, 134 mmol) in water (134 mL). When a clear solution was observed, ethanol (40 mL) was added followed by iodomethane (6.37 mL, 102 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was then extracted four times with chloroform and the combined organic layer was dried over sodium sulfate and concentrated to give the title product (22.0 g, 98%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)#N.[OH-:15].[Na+].C[OH:18]>>[C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([OH:18])=[O:15]
Reactant: [OH-]
Reactant: CO
Reactant: CC(C(=O)O)c1ccc(CC#N)cc1
Agent: [Na+]
Product: CC(C(=O)O)c1ccc(CC(=O)O)cc1
Temperature: 85 °C
Yield: 71 %

Procedure:
A suspension of 2-(4-bromomethyl)phenylpropionic acid (2.0 g, 8.2 mmol) and potassium cyanide (1.6 g, 24.7 mmol) in EtOH (10 mL) and water (2 mL) was heated at 80° C. in a sealed tube for 1 h. The mixture was cooled to room temperature, diluted with water (10 mL) and the EtOH was removed under reduced pressure. The remaining aqueous mixture was extracted once with EtOAc then acidified carefully with 2N HCl until pH˜3 is reached. The aqueous layer was extracted with EtOAc and the combined organic layer was dried over MgSO4, filtered, and concentrated to give 2-[4-(cyanomethyl)phenyl]propionic acid in ˜90% purity. This material was used directly in the next step. A mixture of 2-[4-(cyanomethyl)phenyl]propionic acid (1.4 g, 7.4 mmol) in MeOH (8 mL) and aqueous NaOH (5N, 8 mL, 40 mmol) was heated at 85° C. in a sealed tube for 1.5 h. The mixture was cooled to room temperature, the MeOH was removed under reduced pressure, and the remaining aqueous was extracted with once ether. The aqueous layer was acidified with 2N HCl until pH˜2 to generate a precipitate that was filtered and dried under vacuum to afford 2-[4-(carboxymethyl)phenyl]propionic acid (1.1 g, 71%) as an off-white solid; 1H NMR (400 MHz, DMSO-d6) δ 12.27 (br s, 1H), 7.15-7.22 (m, 4H), 3.61 (q, J=6.8 Hz, 1H), 3.50 (s, 2H), 1.30 (d, J=7.2 Hz, 3H); MS (Electrospray): m/z 163.1 (M−CO2H). To a suspension of (R)-1-[5-(2,2,2-trifluoroethoxy)pyridine-2-yl]ethanamine bis-HCl (0.39 g, 1.3 mmol), 2-[4-(carboxymethyl)phenyl]propionic acid (0.35 g, 1.7 mmol), EDC (0.35 g, 1.8 mmol), and 1-hydroxy-7-azabenzotriazole (0.25 g, 1.8 mmol) in DMF (5 mL) was added diisopropylethylamine (1.2 mL, 6.7 mmol). After stirring for 2 h at room temperature, the mixture was diluted with water (20 mL) and extracted with dichloromethane. The organic layer was dried over MgSO4, filtered, and concentrated to give a crude oil that was purified by preparative reversed-phase HPLC to give 2-{4-[2-oxo-2-(((1R)-1-[5-(2,2,2-trifluoroethoxy)pyridine-2-yl]ethyl)amino)ethyl]phenyl}propionic acid mono-TFA salt as a foam; 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J=7.6 Hz, 1H), 8.33 (d, J=2.8 Hz, 1H), 7.49 (dd, J=2.8 and 8.8 Hz, 1H), 7.28 (d, J=8.8 Hz, 1H), 7.19 (s, 4H), 4.88-4.93 (m, 1H), 4.85 (q, J=8.8 Hz, 2H), 3.62 (q, J=7.2 Hz, 1H), 3.44 (s, 2H), 1.35 (d, J=8.0 Hz, 3H), 1.33 (d, J=7.6 Hz, 3H); MS (Electrospray): m/z 411.4 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[OH:22][C:23]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:26]4[CH2:25][CH2:24][C:23]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)([OH:22])[CH2:28][CH2:27]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(O)(c2ccccc2)CC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-hydroxy4-phenylpiperidine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=463.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([NH2:16])=O)[C:5]([CH2:11][O:12][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]#[N:16])[C:5]([CH2:11][O:12][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: COCc1cc([N+](=O)[O-])c(Cl)cc1C(N)=O
Solvent: O=P(Cl)(Cl)Cl
Product: COCc1cc([N+](=O)[O-])c(Cl)cc1C#N

Procedure:
A sample of 4-chloro-α-methoxy-5-nitro-o-toluamide (0.8 g) is added to phosphorus oxychloride (10 ml) and the slurry gradually heated to reflux. After about 10 minutes at reflux, all the solid has dissolved giving a clear yellow solution. The solution is concentrated in vacuo and the crude residue is portioned between ether and water. The ether layer is separated and dried. Removal of the drying agent and concentration of the filtate in vacuo leaves a crude solid (0.7 g.) with mp 57°-59°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[C:10]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:12][N:11]=1.C(N[C:24](=O)[O-:25])C>O>[Cl:8][C:7]1[C:2]2[NH:1][C:24](=[O:25])[N:11]3[N:12]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=[C:10]3[C:3]=2[CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: CCNC(=O)[O-]
Reactant: Nc1c(Cl)cc(Cl)cc1-c1n[nH]c(-c2ccccc2)n1
Solvent: O
Product: O=c1[nH]c2c(Cl)cc(Cl)cc2c2nc(-c3ccccc3)nn12
Reaction time: 16 h

Procedure:
A mixture of 3-(2-amino-3,5-dichlorophenyl)-5-phenyl-1H-1,2,4-triazole (6 g) and ethylcarbamate (50 g) is heated under nitrogen at 195° for 6 hours after which it is cooled to 80°, poured into water (1000 ml) and stirred 16 hours. The product is collected, washed with water, then methanol (300 ml) and air dried. The crude material is recrystallized from 12:1 2-methoxyethanol-water to afford pure 7,9-dichloro-2-phenyl-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)one, mp 309°-311°.
Reaction SMILES: F[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([N+:15]([O-])=O)[C:3]=1[NH2:18].Cl.CON.N1C=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[CH:14]1([N:11]2[CH2:12][CH2:13][N:8]([C:7]3[CH:2]=[C:3]([NH2:18])[C:4]([NH2:15])=[CH:5][CH:6]=3)[CH2:9][CH2:10]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Reactant: c1ccncc1
Agent: CON
Agent: Cl
Solvent: CCO
Product: Nc1ccc(N2CCN(C3CCCC3)CC2)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 25 mL round bottom flask was charged with a suspension of 1 (600 mg, 2.2 mmol), methoxyamine HCl (202 mg, 2.42 mmol), and pyridine (0.22 mL, 2.6 mmol) in ethanol (9 mL) and stirred at RT overnight. Crude product concentrated and absorbed onto silica gel, then chromatographed using 97:3 CH2Cl2/MeOH to give 2 as an orange solid. LCMS m/z 303.2 (MH+), Rt 2.40 min.
Reaction SMILES: C1(S(O)(=O)=O)C=CC=CC=1.[NH2:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2.[F:25][C@@H:26]1[CH2:30][N:29]([C:31](=[O:43])[CH2:32]OS(C2C=CC=CC=2)(=O)=O)[C@H:28]([C:44]#[N:45])[CH2:27]1>>[CH2:23]([O:22][C:20]([C:15]12[CH2:14][CH2:13][C:12]([NH:11][CH2:32][C:31]([N:29]3[CH2:30][C@@H:26]([F:25])[CH2:27][C@H:28]3[C:44]#[N:45])=[O:43])([CH2:19][CH2:18]1)[CH2:17][CH2:16]2)=[O:21])[CH3:24]
Reactant: CCOC(=O)C12CCC(N)(CC1)CC2
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)COS(=O)(=O)c1ccccc1
Agent: O=S(=O)(O)c1ccccc1
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Yield: 101.1 %

Procedure:
Using ethyl 4-aminobicyclo[2.2.2]octane-1-carboxylate benzenesulfonate (609 mg) and (2S,4S)-4-fluoro-1-[2-(benzenesulfonyloxy)acetyl]pyrrolidine-2-carbonitrile (783 mg), the same procedure was followed as in Example 7 to give (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]ac etyl]-4-fluoropyrrolidine-2-carbonitrile (609 mg, 87% yield). This compound was identical to the compound obtained in Example 7.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH2:8]([CH:10]([CH:15]1[NH:19][CH2:18][CH2:17][O:16]1)[CH2:11][CH2:12][CH2:13][CH3:14])[CH3:9].C(NCC(=CCCCC)O)C.[C:31](=[S:33])=[S:32]>CCOCC>[CH2:8]([CH:10]([CH:15]1[N:19]([C:31]([S-:33])=[S:32])[CH2:18][CH2:17][O:16]1)[CH2:11][CH2:12][CH2:13][CH3:14])[CH3:9].[CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2]
Reactant: S=C=S
Reactant: CCN(CC)CC
Reactant: CCCCC(CC)C1NCCO1
Agent: CCCCC=C(O)CNCC
Solvent: CCOCC
Product: CCCCC(CC)C1OCCN1C(=S)[S-]
Product: CC[NH+](CC)CC
Reaction time: 17 h

Procedure:
To a solution of 117 g (1.16 moles) of triethylamine and 133 g (0.77 mole) of 2-(1-ethylpentyl)oxazolidine [containing mainly the tautomer, N-α-ethylpentylidene-2-hydroxyethylamine, and prepared according to A. Cope, J.A.C.S. 64, 1503 (1942)] in one liter of ether was added 88 g (1.16 moles) of carbon disulfide at 10°-20° over a period of 35 minutes. Stirring was continued for 17 hours at ambient temperatures. Solids (13 g of triethylammonium N-(2-hydroxyethyl)dithiocarbamate were filtered off and the resulting filtrate was removed of volatiles at 25°/150 mm Hg to give 242g of crude triethylammonium 2-(1-ethylpentyl)-3-oxazolidinecarbodithioate.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][N:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.[N:23]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>C(OCC)(=O)C.O.CN(C)C=O>[CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][N:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:23])=[O:13])=[CH:8]2
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1nccs1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1nccs1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
A mixture of 7-[methyl(1,3-thiazol-2-ylsulfonyl)amino]-1H-indole-2-carboxylic acid (1.65 g), 1H-1,2,3-benzotriazol-1-ol (991 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.41 g) and N,N-dimethylformamide (10 mL) was stirred at 60° C. for 30 min. The mixture was cooled to 0° C., 28% aqueous ammonia (600 μL) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (200 mL) and water (200 mL). The organic layer was washed with saturated brine (200 mL), dried over sodium sulfate, and filtrated, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography with 50% ethyl acetate-hexane mixture as an eluate to give the title compound (1.30 g, yield 79%) as a white solid. melting point 220-221° C.
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:12]([C:13]([O:15][C@H:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:17]([F:20])([F:19])[F:18])=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C@H:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:17]([F:18])([F:19])[F:20])=[O:14])=[CH:27][CH:28]=1
Reactant: CCCCCC[C@@H](OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCCC[C@@H](OC(=O)c1ccc(O)cc1)C(F)(F)F

Procedure:
To a solution of the compound obtained in (1) above (3.8 g) in methanol (100 ml), was added 10% Pd on carbon (0.4 g). The mixture was subjected to hydrogenation in an atmosphere of hydrogen to obtain the titled compound (2.8 g).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:30][CH2:31][CH3:32])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][C:25]([O:27]CC)=[O:26])[N:19]=[CH:18]4)=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.[OH-].[Na+].O.Cl>C(O)C.C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:30][CH2:31][CH3:32])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][C:25]([OH:27])=[O:26])[N:19]=[CH:18]4)=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3c(cnn3CC(=O)OCC)c2)ncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3c(cnn3CC(=O)O)c2)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethyl 2-(5-(6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxamido)-1H-indazol-1-yl)acetate (Intermediate 39, 106 mg; 0.24 mmol) in ethanol (10 ml) was treated with 10% NaOH solution (5 ml). After stirring at RT for 2 hours the solvent was reduced in vacuo to one quarter of its original volume and water (20 ml) added. The mixture was acidified with dilute HCl and DCM (50 ml) added. After stirring at RT for 30 minutes the mixture was filtered through a hydrophobic frit and the solvent removed in vacuo. The solid formed was washed with water and dried to give the title compound as a pale yellow solid.
Reaction SMILES: [Mg].[CH2:2]([C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6].[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[CH2:2]([C:7]1[CH:12]=[CH:11][C:10]([C:25]2[CH:26]=[CH:27][C:22]([O:21][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:23][CH:24]=2)=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCc1ccc(Br)cc1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Reaction time: 24 h
Yield: 62 %

Procedure:
Magnesium (1.06 g: 88.3 mmol) and 4-n-pentylbromobenzene (10.0 g: 44.01 mmol) were dissolved in 50 ml of dried tetrahydrofuran, and a Grignard reagent was prepared from the mixture. To the Grignard reagent was added 11.6 g (44.1 mmol) of 4-(benzyloxy)bromobenzene synthesized in the step (i). The reaction system was purged with argon. To the reaction system was added 600 mg of dichloro(1,4-diphenylphosphinobutane)palladium (II) [Pd(dppb)Cl2], and the reaction was conducted for 24 hours. The reaction mixture was poured into an iced water, and the resultant mixture was acidified by adding hydrochloric acid. The resultant solid was collected by filtration, washed with water, dried, and recrystallized from a mixed solvent of hexane/toluene to give 9.0 g (27.3 mmol) of 4-n-pentyl-4′-benzyloxybiphenyl.