Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@@H:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27]([OH:29])=O)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:33]C[C@H](C1C=CC=CC=1)O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[N:8]=[C:9]([C@@H:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27]([NH2:33])=[O:29])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc(C[C@@H]2CCC[C@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: NC[C@@H](O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc(C[C@@H]2CCC[C@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 122 %

Procedure:
To a mixture of 3-{[(1S,2R)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}benzoic acid (76 mg, 0.18 mmol) and (S)-2-amino-1-phenylethanol (30 mg, 0.22 mmol) in DMF (4 ml) was added 1-hydroxybenzotriazole (36 mg, 0.27 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (69 mg, 0.36 mmol). After stirring the resulting mixture at room temperature for 2 hours, the reaction mixture was diluted with EtOAc (30 ml), washed with 1N-hydrochloric acid, water, saturated sodium hydrogencarbonate solution, water and brine successively, dried dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc, 1:1 elution) to give N-1(2S)-2-hydroxy-2-phenylethyl]-3-{[(1S,2R)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}benzamide (92.8 mg, 95%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].C([Li])CCC.CCCCCC.[CH2:27]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38](/[CH:39]=[C:6](\[F:7])/[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[CH:41][CH:42]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C/c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
A solution of triethyl 2-fluoro-2-phosphonoacetate (4.90 g, 20.2 mmol) in tetrahydrofuran (40 mL) was stirred under a nitrogen atmosphere at 0° C., and 1.6 M n-butyl lithium/hexane solution (13.1 mL, 21.0 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min and a solution of 4-benzyloxybenzaldehyde (4.29 g, 20.2 mmol) in tetrahydrofuran (20 mL) was added dropwise. The obtained mixture was stirred at room temperature for 3 hr and ice-cooled aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:97-20:80) to give the title compound (4.90 g, yield 81%) as a yellow oil.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16](/[C:18](=[N:46]/[OH:47])/[C:19]([NH:21][CH:22]2[C:44](=[O:45])[N:24]3[C:25]([C:32]([O:34][CH:35]([O:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[CH3:36])=[O:33])=[C:26]([CH2:29][O:30][CH3:31])[CH2:27][S:28][C@H:23]23)=[O:20])[N:17]=1.O>CC(C)=O>[C:3]1([CH3:13])[C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=[CH:1][CH:2]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16](/[C:18](=[N:46]/[OH:47])/[C:19]([NH:21][CH:22]2[C:44](=[O:45])[N:24]3[C:25]([C:32]([O:34][CH:35]([O:37][C:38](=[O:43])[C:39]([CH3:41])([CH3:42])[CH3:40])[CH3:36])=[O:33])=[C:26]([CH2:29][O:30][CH3:31])[CH2:27][S:28][C@H:23]23)=[O:20])[N:17]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COCC1=C(C(=O)OC(C)OC(=O)C(C)(C)C)N2C(=O)C(NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccccc1S(=O)(=O)O

Procedure:
A solution of 570 mg (3 mmol) of p-toluenesulfonic acid in 1 ml of acetone was added to a solution of 1.08 g (2 mmol) of α-(2,2-dimethylpropanoyloxy)ethyl 7-[2-(2-aminothiazol-4-yl)-2-(Z)-hydroxyimino-acetamido]-3-methoxymethyl-3-cephem-4-carboxylate in 3 ml of acetone. 28 ml of water was then slowly added dropwise with stirring to the rapidly forming crystal suspension. The crystalline precipitate was then filtered off with suction, washed eight times with 3 ml of water and dried in vacuo over calcium chloride/paraffin. 1.08 g of the desired title compound were obtained, which consisted of an approximately 1:1 mixture of the two diastereomers according to HPLC and was characterized as crystalline under the polarization microscope. M.p.: from 190° C. (with decomposition).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][N:13]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[N:11]=1.Cl>O.CO>[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][N:13]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[N:11]=1
Reactant: COC(=O)CCCCc1noc(-c2ccccc2O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCc1noc(-c2ccccc2O)n1
Reaction time: 2 h
Yield: 97.4 %

Procedure:
Add boron tribromide (4.9 mL, 51.7 mmol) dropwise to a stirred solution of methyl 5-[5-(2-methoxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate (3.0 g, 10.3 mmol) in methylene chloride (70 mL) at 0° C. under nitrogen. Allow to warm to room temperature and stir for 5 hours. Cool the mixture to 0° C., 1 add methanol (20 mL) dropwise and allow to warm to room temperature. Remove the solvents under reduced pressure and purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:9), to provide methyl 5-[5-(2-hydroxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate, which is used without further purification. Add a solution of sodium hydroxide (800 mg, 20 mmol) in water (15 mL) to a solution of methyl 5-[5-(2-hydroxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate (2.6 g, 9.4 mmol) in methanol (30 mL) at room temperature and stir the mixture for 2 hours. Adjust the pH of the mixture to 2 with 1 N HCl and extract with ethyl acetate (2×150 mL). Wash the combined organic extracts with water (3×150 mL), dry over sodium sulfate and remove the solvent under reduced pressure. Triturate the residue with hexanes/ethyl acetate and collect the solids by vacuum filtration to afford the title compound (2.4 g, 89% over two steps). APCI MS m/z 261 [C13H14N2O4−H]−.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[N:5]([CH2:8][C@H:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21](OC3C(F)=C(F)C(F)=C(F)C=3F)=[O:22])=[C:17]([F:35])[CH:16]=2)[CH2:10]1)=[N+:6]=[N-:7].C(N(C(C)C)CC)(C)C>C1COCC1>[N:5]([CH2:8][C@H:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:4][O:3][CH3:2])=[O:22])=[C:17]([F:35])[CH:16]=2)[CH2:10]1)=[N+:6]=[N-:7]
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c(F)c2)C(=O)O1
Reactant: CON
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CONC(=O)c1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
N-Methoxyamine hydrochloride (123 mg, 1.5 mmol) was added to a solution of 5-(S)-azidomethyl-3-[4′-(pentafluorophenoxy)carbonyl-3′-fluorophenyl]-oxazolidine-2-one (600 mg, 1.3 mmol) and diisopropylethylamine (0.26 ml, 1.5 mmol) in THF (8 ml), and the mixture stirred overnight at r.t. Solvent was removed under vacuum, and ethyl acetate with 3% aq. citric acid added. Organic layer was washed twice with 3% citric acid, brine, and dried (Na2SO4). Solvent was removed under vacuum, and the crude material crystallized from ethanol-ether to give a white crystalline product (335 mg, 83%). HPLC Rt=4.8. MS (m/z): [M+H]+=310.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][O:5][C:4](=[O:7])[C@@H:3]1C(=C)C([O-])=O.[CH2:14]=[CH:15][C:16](=[CH2:18])[CH3:17]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:18][C:16]1[CH2:17][CH2:2][C@@H:3]([C:4]([O:7][C@H:3]2[C:2]([CH3:1])([CH3:13])[CH2:6][O:5][C:4]2=[O:7])=[O:5])[CH2:14][CH:15]=1
Reactant: C=C(C(=O)[O-])[C@H]1C(=O)OCC1(C)C
Reactant: C=CC(=C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1=CC[C@H](C(=O)O[C@@H]2C(=O)OCC2(C)C)CC1
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
(S)-4,4-dimethyl-2-oxotetrahydrofuran-3-ylacrylate 501 (2.05 g, 11.1 mmol) in dichloromethane (17.5 mL) and hexanes (2.5 mL) was cooled to −10° C. and treated with titanium tetrachloride (2.2 mL, 1 M in dichloromethane, 2.2 mmol). The yellow solution was stirred for 15 minutes and treated with isoprene (1.67 mL, 16.7 mmol) dropwise over 5 minutes. After stirring for 2 hours, an additional portion of isoprene (1.67 mL, 16.7 mmol) was added and the reaction mixture was stirred at −10 to 0° C. for 3.5 hours. The reaction mixture was quenched with ammonium chloride (sat. aq.). Water and ethyl acetate:hexanes (1:1) were added. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate:hexanes (1:1). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (10-50% EtOAc:Hex, 80 g column) to afford 1.30 g (46% yield) of (R)—((S)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl) 4-methylcyclohex-3-enecarboxylate 502 as a clear oil.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:18]([O:19]C(=O)C)[C@H:17]([CH3:23])[O:16][C@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@@H:6]1[F:24])(=O)C.C[O-].[Na+]>CO>[F:24][C@@H:6]1[C@H:5]([OH:4])[C@H:18]([OH:19])[C@H:17]([CH3:23])[O:16][C@@H:7]1[O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)O[C@H]1[C@@H](F)[C@@H](OCc2ccccc2)O[C@@H](C)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1O[C@H](OCc2ccccc2)[C@H](F)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
Benzyl 3,4-di-O-acetyl-2,6-dideoxy-2-fluoro-β-L-talopyranoside (1.66 g) obtained in Example 1-(1) above was suspended in 50 ml of anhydrous methanol. The resulting suspension was added with 0.5 ml of a solution of 4.9 M sodium methoxide in methanol and then stirred at room temperature for 30 minutes to effect the reaction intended. The homogenous reaction solution so obtained was neutralized by addition thereto of an ion-exchange resin, Dowex 50 W×2 (H+-form) and then filtered to remove the resin therefrom. The filtrate obtained was concentrated to a small volume and the concentrated solution was allowed to stand at −10° C. and the deposited needles were separated by filtration, affording 1.11 g (yield 89%) of the titled Compound (4).
Reaction SMILES: Cl[O-].[Na+].[CH3:4][C:5]1[CH:10]2[C:11]([CH3:13])([CH3:12])[CH:8]([CH2:9]2)[CH2:7][CH:6]=1.Cl[O-]>>[CH:10]12[CH2:9][CH:8]([C:11]1([CH3:13])[CH3:12])[CH2:7][CH2:6][CH:5]2[CH3:4]
Reactant: CC1=CCC2CC1C2(C)C
Agent: [Na+]
Agent: [O-]Cl
Product: CC1CCC2CC1C2(C)C

Procedure:
Hypochlorite treatment of the α-pinene raised the chloride level to about 100 ppm (as elemental chloride) based on pinene feed. Hydrogenation of this pinene was fast and yielded a good ratio (96.8/3.2). Reuse of the catalyst heel went quickly with a slightly reduced ratio, when used at either the 3% level or 1% level. Repoisoning (1/2% sodium hypochlorite-treated α-pinene) was achieved by mixing hypochlorite-treated feed with fresh α-pinene and yielded pinane with a 97.5/2.5 cis-:trans- ratio. A ratio of 98.1/1.9 was achieved in 30 hours' reaction at a lower temperature of about 30° C. using hypochlorite-treated feed.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([OH:22])=O)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C(=O)O)CC1
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccccc1N1CCNCC1)N1CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.4 %

Procedure:
The 1-Boc-4-(2-carboxy-phenyl)-piperazine (1 g, 3.26 mmol), piperidine (278 mg, 3.26 mmol), EDCI (625 mg, 3.26 mmol) and DMAP (50 mg, catalytic) were dissolved in DCM (20 mL) and stirred at r.t. for about 12 hours. The mixture was washed with water, dried, filtered, and concentrated. The resultant foam was taken up in DCM (10 mL) and TPA (5 mL) was added, and the mixture stirred at r.t. for about 2 hours. The reaction was concentrated and subjected to SCX ion exchange chromatography followed by silica gel chromatography to afford the final product (868 mg, 71%) as a white foam. LRMS (ESI+): 274.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl.[CH:11]12[O:16][CH:12]1[CH2:13][CH2:14][CH2:15]2>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH:5][C@@H:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[OH:16]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: C1CC2OC2C1
Agent: Cl
Product: O[C@@H]1CCC[C@H]1Nc1ccc(Cl)c(Cl)c1
Yield: 49 %

Procedure:
A solution of 3,4-dichloroaniline (200 g., 1.23 mole), cyclopentene oxide (400 ml.), and concentrated HCl (2 ml.) is heated at reflux temperature for seven (7) days. The unreacted epoxide is evaporated at 60° C. and the residue is treated with excess ethereal HCl, and a syrup results. This is washed with 1000 ml. of ether. The residue is crystallized and recrystallized from methanol/ether (1/5.5, v/v) to give 170.0 g. (49% yield) of trans-3,4-dichloro-N-(2-hydroxycyclopentyl)aniline, hydrochloride salt.
Reaction SMILES: O.[OH-].[Li+].C(OC([N:11]([C:33]1[C:38]([O:39][CH3:40])=[N:37][C:36]([CH3:41])=[CH:35][N:34]=1)[S:12]([C:15]1[C:16]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29]([O:31]C)=[O:30])=[CH:23][CH:22]=2)=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13])=O)C(C)C.CO.O>O1CCCC1>[C:29]([CH:28]=[CH:27][C:24]1[CH:25]=[CH:26][C:21]([C:16]2[C:15]([S:12]([NH:11][C:33]3[C:38]([O:39][CH3:40])=[N:37][C:36]([CH3:41])=[CH:35][N:34]=3)(=[O:13])=[O:14])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:22][CH:23]=1)([OH:31])=[O:30]
Reactant: COC(=O)C=Cc1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(C=CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.8 %

Procedure:
Lithium hydroxide monohydrate (87 mg) was added to a solution of N-isobutoxycarbonyl-2-[4-(2-[methoxycarbonyl]vinyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (250 mg) in tetrahydrofuran (6.2 ml) followed by methanol (2.5 ml) and water (2.5 ml). The reaction mixture was stirred at ambient temperature for 18 hours then evaporated to dryness. The residue was dissolved in water (50 ml), washed with ethyl acetate (50 ml), acidified with 8% aqueous citric acid to pH 3-4 and extracted with ethyl acetate (100 ml). The organic layer was extracted with saturated sodium bicarbonate solution (50 ml) and the aqueous phase separated, acidified with 8% aqueous citric acid and extracted with ethyl acetate (3×30 ml). The combined organic extracts were dried (MgSO4) and evaporated to give 2-[-4-(2-carboxyvinyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (108 mg) as a solid, m.p. 233-235° C.: 1H NMR (d6-DMSO): 2.2 (s, 3H), 3.8 (s, 3H), 6.55 (d, 1H), 7.35 (br s, 1H), 7.45 (d, 2H), 7.55-7.75 (m, 4H), 8.45 (dd, 1H), 8.8 (dd, 1H), 10.1 (br s, 1H); mass spectrum (+ve ESP) 427 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[C:29]([CH3:36])[CH:28]=1.CCN(CC)CC>ClCCCl>[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:35])=[C:29]([CH3:36])[CH:28]=1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: COC(=O)c1ccc(N=C=O)c(C)c1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(C)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (example 11.1) was reacted with 3-methyl-4-isocyanato-benzoic acid methyl ester (example 14.1) in 1,2-dichloroethane in the presence of Et3N (1.4 eq.) for 2 days under reflux conditions to give the title compound as brown solid. MS: m/e=517.1 [M+H+].
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][C:11]1([CH3:23])[O:22][CH:19]([CH:20]=[CH2:21])[CH:13]([CH:14]([OH:18])[CH2:15][C:16]#[N:17])[O:12]1.[CH3:24][O:25][CH2:26]Cl>C(OCC)C>[CH3:10][C:11]1([CH3:23])[O:22][CH:19]([CH:20]=[CH2:21])[CH:13]([CH:14]([O:18][CH2:24][O:25][CH3:26])[CH2:15][C:16]#[N:17])[O:12]1
Reactant: C=CC1OC(C)(C)OC1C(O)CC#N
Reactant: COCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: C=CC1OC(C)(C)OC1C(CC#N)OCOC
Temperature: 0 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
Nine milliliters of diisopropylethylamine were added to 2.11 g of 4,5-(dimethylmethylenedioxy)-3-hydroxy-6-heptenenitrile, and 2 ml of methoxymethyl chloride was then added to the mixture gradually at 0° C. After stir-ring at 0° C. for 16 hours, the reaction mixture was diluted with 300 ml of diethyl ether, and washed with 1N hydrochloric acid, a saturated sodium hydrogen carbonate aqueous solution and a sodium chloride aqueous solution in sequence. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was filtered by a silica gel column to afford 2.28 g of 4,5-(dimethylmethylenedioxy)-3-methoxymethoxy-6-heptenenitrile having the following properties (yield 88 %).
Reaction SMILES: CN(C=O)C.[F:6][C:7]([F:18])([F:17])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[CH2:19](Br)[CH:20]=[CH2:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CCOC(C)=O.O>[F:6][C:7]([F:17])([F:18])[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:21][CH:20]=[CH2:19])=[CH:14][CH:15]=1
Reactant: Oc1ccc(OCC(F)(F)F)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(OCC(F)(F)F)cc1
Temperature: 60 °C

Procedure:
To a DMF 30 ml solution of 4-(2,2,2-trifluoroethoxy)phenol (2.6 g, 13.6 mmol) and allyl bromide (3.53 ml, 40.8 mmol) was added cesium carbonate (4.85 g, 14.9 mmol). This suspension was heated to 60° C. for 18 hr, diluted with AcOEt and water. The organic layer was separated, and the aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel eluting with 10% AcOEt/hexanes to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.Cl.[NH2:17][C@@H:18]([CH3:22])[C:19]([NH2:21])=[O:20].CCN(C(C)C)C(C)C>C(#N)C>[NH2:21][C:19](=[O:20])[C@@H:18]([NH:17][C:4]1[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=1)[CH3:22]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(Cl)n1
Reactant: C[C@H](N)C(N)=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1cc(C(=O)OC(C)(C)C)nc(Cl)n1)C(N)=O
Temperature: 50 °C
Yield: 83.3 %

Procedure:
To a solution of the tert-butyl 2,6-dichloropyrimidine-4-carboxylate (0.626 g, 2.51 mmol) in acetonitrile (10 mL) was added (S)-2-aminopropanamide hydrochloride (0.319 g, 2.56 mmol) and iPr2NEt (0.96 mL, 5.5 mmol). The mixture was heated at 50° C. for 6 h then concentrated in vacuo. The residue was chromatographed over silica gel using 50-100% EtOAc in hexanes. The product fractions were evaporated in vacuo to give (S)-tert-butyl 6-((1-amino-1-oxopropan-2-yl)amino)-2-chloropyrimidine-4-carboxylate as an off-white foam (0.628 g, 2.09 mmol, 83% yield). LC/MS: m/z=301.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:34]=[CH:33][C:14]3[CH2:15][CH2:16][C:17]4[C:18]([C:30]([NH2:32])=[O:31])=[N:19][N:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]#[CH:29])=[CH:24][CH:23]=5)[C:21]=4[C:13]=3[CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1>CN(C=O)C.CS(C)=O>[Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:34]=[CH:33][C:14]3[CH2:15][CH2:16][C:17]4[C:18]([C:30]([NH2:32])=[O:31])=[N:19][N:20]([C:22]5[CH:27]=[CH:26][C:25]([CH:28]=[CH2:29])=[CH:24][CH:23]=5)[C:21]=4[C:13]=3[CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4cccnc4Cl)ccc2CC3)cc1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: C=Cc1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4cccnc4Cl)ccc2CC3)cc1
Yield: 46.9 %

Procedure:
A solution of 8-{[(2-chloropyridin-3-yl)carbonyl]amino}-1-(4-ethynylphenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (557 mg, 1.19 mmol) in DMF-DMSO (20 mL-1 mL) was treated at RT with H2 (5 psi) and Pd-CaSO4 (5%, 100 mg) for 12 min. The mixture was filtered through celite pad, concentrated and added water. The solid product was collected via filtration, washed with water and ether, and dried to give product (262 mg, 47%). 1H NMR was consistent with its structure.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][C:24]=1[O:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:27][C:26]1[CH:28]=[CH:29][C:23]([F:22])=[C:24]([O:30][C:31]2[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=2)[CH:25]=1)=[O:6]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Reactant: Nc1ccc(F)c(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(F)c(Oc3ccc([N+](=O)[O-])cc3)c2)c1Cl
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (1.98 g, 8.85 mmol) produced in Example A41(ii) in tetrahydrofuran (40 mL) were added oxalyl chloride (1.41 g, 11.1 mmol) and N,N-dimethylformamide (10 μL), and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in N,N-dimethylacetamide (40 mL). 4-Fluoro-3-(4-nitrophenoxy)aniline (4.69 g, 20.4 mmol) was added, and the mixture was stirred at room temperature for 14 hr. To the reaction mixture were added water (100 ml), 1N aqueous sodium hydroxide solution (50 mL) and ethyl acetate (200 mL). The organic layer was separated, washed with saturated brine (10 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give 2-chloro-3-(1-cyano-1-methylethyl)-N-[4-fluoro-3-(4-nitrophenoxy)phenyl]benzamide (2.01 g, 99%). The obtained compound was used in the next reaction without a further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12]C)=[O:11])=[CH:5][CH:4]=1.[C:14]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.[ClH:33]>O1CCOCC1>[ClH:33].[C:14]1([N:20]2[CH2:25][CH2:24][N:23]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=3)[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(CN2CCN(c3ccccc3)CC2)cc1

Procedure:
Using 2.3 g of methyl 4-bromomethylphenylacetate, 2.0 g of 1-phenylpiperazine, 2 ml of triethylamine, and 80 ml of dioxane, the reaction procedure of Example 2 was otherwise repeated and the reaction product was converted to the hydrochloride using 2N-hydrochloric acid and recrystallized from methanol-ether to provide 2.0 g of the title compound melting at 231° C.-234° C.