Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([O:19]CC)=[O:18])=[C:12]3[C@@H:11]3[CH2:22][CH2:23][N:10]3[C:9](=[O:24])[C:8]=2[C:25]=1[F:26]>C(O)C.O>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([OH:19])=[O:18])=[C:12]3[C@@H:11]3[CH2:22][CH2:23][N:10]3[C:9](=[O:24])[C:8]=2[C:25]=1[F:26]
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2ccc(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2ccc(F)c1F
Yield: 89.3 %

Procedure:
8.6 ml (34.3 mmol) of 4N sodium hydroxide solution were added dropwise to a suspension of 8.8 g (26.4 mmol) of ethyl (S)-7,8-difluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate in 20 ml of ethanol and 30 ml of water and the mixture was heated at reflux for 30 minutes. Subsequently, the ethanol was distilled off. The aqueous phase was washed twice with methylene chloride and adjusted to pH=3 with 4N hydrochloric acid. Extraction with methylene chloride (five times), drying over sodium sulfate, filtration and evaporation yielded 7.2 g (89%) of (S)-7,8-difluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid as colourless needles of m.p. 218.0°-219.5° (dec.).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH:17]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:24][CH:23]=2)[C:18]([O:20]C)=[O:19])[CH3:16])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]([CH:17]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:26][CH:27]=2)[C:18]([OH:20])=[O:19])[CH3:16])(=[O:13])=[O:14])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)c2ccc(OCCCNC(=O)OCC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)O)c2ccc(OCCCNC(=O)OCC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
A mixture of methyl [{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino}(4-{3-[(ethoxycarbonyl)amino]propoxy]phenyl)acetate (0.45 g, 0.85 mmol) and 1N NaOH (4.2 ml, 4.23 mmol) in THF (5 ml) and methanol (5 ml) was stirred at room temperature for 2 h. After removing the solvent, the residue was dissolved in water, neutralized with HCl to pH˜5-6 and extracted with dichloromethane. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to provide 0.36 g of [{[4-(2-butynyloxy)phenyl]-sulfonyl}(methyl)amino}(4-{3-[(ethoxycarbonyl) amino]propoxy]phenyl)acetic acid as a solid . Yield 81.8%. Electrospray Mass Spec 519.1 (M+H)+.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH2:4][CH2:5][CH3:6].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[OH-].[Na+].C(OCC)(=O)C>C1C=CC=CC=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O.O>[CH2:13]([O:12][C:10]([NH:1][C@@H:2]([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:7][O:9][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCCC[C@@H](COCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 74 %

Procedure:
To a stirred solution of Z-L-Nle-ol (0.20 g, 0.8 mmol) in benzene (0.8 mL), tert-butyl bromoacetate (0.47 g, 2.4 mmol) and subsequently aqueous NaOH 50% (0.8 mL) and the phase transfer catalyst Bu4NHSO4 (0.07 g, 0.2 mmol) were added. The reaction mixture was vigorously stirred for 2 h. Ethyl acetate (10 mL) and H2O (10 mL) were added and the aqueous layer was separated and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine and dried over Na2SO4. The organic solvent was evaporated under reduced pressure and the residue was purified by column-chromatography using petroleum ether (bp 40-60° C.)/ethyl acetate 8:2 as eluent. Yield 74%; Oil; [a]D=−12.2 (c 1CHCl3); 1H NMR (200 MHz, CDCl3) δ 7.34-7.22 (m, 5H), 5.30 (d, J=8 Hz, 1H), 5.06 (s, 2H), 3.91 (s, 2H), 3.80-3.62 (m, 1H), 3.55 (dd, Ji=9.0 Hz, J2=4.0 Hz, 1H), 3.46 (dd, Ji=9.2 Hz, J2=4.2 Hz, 1H), 1.62-1.45 (m, 2H), 1.43 (s, 9H), 1.37-1.21 (m, 4H), 0.85 (t, J=6.8 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ 169.5, 156.0, 136.6, 128.3, 128.0, 127.8, 81.5, 73.0, 68.7, 66.3, 50.9, 31.4, 28.0, 27.9, 22.4, 13.8. Anal. Calcd for C20H31NO5: C, 65.73; H, 8.55; N, 3.83. Found: C, 65.52; H, 8.71; H, 3.70.
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@@H:13]2[NH:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@:15]3([C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:12])=[CH:6][C:5]=1[O:41][CH3:42].[OH-].[Na+]>CO.O1CCCC1>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C@:15]3([C@@H:14]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=4[F:40])[C@H:13]([C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[C:5]([O:41][CH3:42])[CH:6]=4)=[O:12])[NH:17][C@H:16]3[CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)ccc1C(=O)O

Procedure:
In a manner similar to the method described in Example 6, rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-2-methoxy-benzoic acid methyl ester prepared in Example 15 (0.1 g, 0.16 mmol), was heated with aqueous NaOH in methanol and tetrahydrofuran at 78° C. to give rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-2-methoxy-benzoic acid as a off white solid (Yield 0.075 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:13](C(OC)=O)[C:14]([O:16][CH3:17])=[O:15])([CH:10]([CH3:12])[CH3:11])[CH3:9])=[CH:4][CH:3]=1.[Cl-].[Li+].O.C(OCC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:9])([CH:10]([CH3:11])[CH3:12])[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:7]=1
Reactant: COC(=O)C(C(=O)OC)C(C)(c1ccc(Cl)cc1)C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CC(C)(c1ccc(Cl)cc1)C(C)C

Procedure:
3.38 g (10.81 mmol) of dimethyl [2-(4-chlorophenyl)-3-methylbutan-2-yl]malonate, 0.92 g (21.61 mmol) of lithium chloride and 0.2 ml of water in 10 ml of DMSO were heated under reflux for 4 h. After cooling, about 50 ml of diethyl ether were added to the reaction solution, and the phases were separated. The organic phase was washed twice with water, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 2.3 g (84% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:30])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([C:21](=O)[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:14]=1)[C:5]([O:7][CH3:8])=[O:6].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:30])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:14]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(Oc2ccc(OC)c(C(=O)c3ccc(F)cc3)c2)c(Cl)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)c(Oc2ccc(OC)c(Cc3ccc(F)cc3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
To a stirred solution of methyl 3,5-dichloro-4-[3′-(4-fluorobenzoyl)-4′-methoxyphenoxy]benzoate (350 mg, 0.78 mmol) and TFA (2 mL) in CH2Cl2 (50 mL) at room temperature was added triethylsilane (0.5 mL, 3.1 mmol). The reaction mixture was stirred at room temperature for 16 h, quenched with water (25 mL) and extracted with ether (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated with hexanes, filtered and dried under reduced pressure to afford methyl 3,5-dichloro-4-[3′-(4-fluorobenzyl)-4′-methoxyphenoxy]benzoate as a brown solid (0.31 g, 92%): mp 108-110° C.; 1H NMR (300 MHz, CDCl3): δ 7.98 (s, 2H), 7.06 (dd, J=6.0, 9.0 Hz, 2H), 6.88 (t, J=8.7 Hz, 2H), 6.70 (d, J=9.0 Hz, 1H), 6.58 (d, J=3.0 Hz, 1H), 6.48 (dd, J=3.3, 9.0 Hz, 1H), 3.89 (s, 3H), 3.83 (s, 2H), 3.71 (s, 3H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (2:8); Rf=0.8.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([S:7]([O-:10])(=[O:9])=O)=[CH:4][CH:3]=1.[Na+].P(Cl)(Cl)(Cl)(Cl)Cl.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>CCOCC>[C:18]([NH:22][S:7]([C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:9])=[O:10])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)[O-])o1
Reactant: CC(C)(C)N
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)NC(C)(C)C)o1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 61.5 %

Procedure:
At a temperature of 30° to 50° C., 248 gm (1.35 mol) of sodium 5-methyl-furan-2-sulfonate were admixed in portions with 281 gm (1.35 mol) of phosphorus pentachloride and the mixture was stirred for 15 minutes at 50° C. The reaction mixture was then poured over ice and extracted with ether. The ether phase was washed until neutral, dried and evaporated. The residue (200 gm of 5-methyl-furan-2-sulfonic acid chloride) was dissolved in 500 ml of ether, and the solution was added dropwise to a solution of 280 ml (2.7 mol) of tert.-butylamine in 500 ml of ether at a temperature of 5° to 10° C. After stirring at room temperature and at reflux temperature, each for 2 hours, the reaction mixture was washed with ice water, dilute hydrochloric acid and water and then evaporated. The residue was recrystallized from cyclohexane, yielding 180.5 gm (61.5L % of theory) of N-tert.-butyl-5-methyl-furan- 2-sulfonamide.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@H:21]([OH:30])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:16]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>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.C(O)C>[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:15]2[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@H:21]([OH:30])[CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:17][CH:16]=2)=[CH:36][CH:35]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)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: CCO
Solvent: Cc1ccccc1
Product: O[C@H](CCc1cccnc1)COc1ccc(-c2ccc(F)cc2)cc1
Temperature: 110 °C

Procedure:
Prepared according to the method described in Example 33a) from toluene (5 ml), aqueous sodium carbonate (2 M, 1 ml), (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.25 g), ethanol (1 ml), 4-fluorobenzeneboronic acid (0.119 g) and tetrakis(triphenylphosphine)palladium(0) (22 mg) with heating at 110° C. for 4 hours. The residue obtained after work up was purified by column chromatography over silica eluting with ethyl acetate to give the title compound as a white solid after recrystallisation from ethyl acetate:hexane (1:1) (0.18 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[O:16][C:17]([CH2:20]Cl)=[N:18][N:19]=3)=[CH:13][N:12]3[CH:22]=[CH:23][N:24]=[C:11]3[C:10]=2[Cl:25])=[C:4]([F:26])[CH:3]=1.[I-].[K+].[NH3:29]>O1CCCC1>[NH2:29][CH2:20][C:17]1[O:16][C:15]([C:14]2[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[F:26])=[C:10]([Cl:25])[C:11]3[N:12]([CH:22]=[CH:23][N:24]=3)[CH:13]=2)=[N:19][N:18]=1
Reactant: Fc1cc(Br)ccc1Nc1c(-c2nnc(CCl)o2)cn2ccnc2c1Cl
Reactant: N
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: NCc1nnc(-c2cn3ccnc3c(Cl)c2Nc2ccc(Br)cc2F)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
(4-Bromo-2-fluoro-phenyl)-[8-chloro-6-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridin-7-yl]-amine (38 mg, 0.083 mmol) was dissolved in tetrahydrofuran (1 mL). Potassium iodide (14 mg, 0.083 mmol) was added and then ammonia (7 M solution in methanol, 0.30 mL, 2.08 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (gradient of 20:1 dichloromethane/methanol to 5:1) to yield the desired product (26 mg, 71%) as a yellow solid. MS ESI (+) m/z 437, 439 (M+, Cl, Br pattern) detected. 1H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.33 (s, 1H), 8.17 (d, 1H), 7.70 (d, 1H), 7.51 (dd, 1H), 7.16 (d, 1H), 6.65 (t, 1H), 3.94 (s, 2H). 19F (376 MHz, DMSO-d6) −128.3 (t).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:2]=1>C(O)C.[Rh]>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2]1
Reactant: CCOC(=O)C=Cc1cccnc1
Agent: [Rh]
Solvent: CCO
Product: CCOC(=O)CCC1CCCNC1
Yield: 62.9 %

Procedure:
A solution of ethyl 3-[pyrid-3-yl]prop-2-enoate (60 g, 0.34 mol) in ethanol (600 ml) was treated with 5% rhodium on alumina powder (17.2 g). The mixture was placed under a hydrogen atmosphere (55 psi) for five hours at 60° C. The reaction was stopped by removing the hydrogen and the reaciton mixture was filtered through a layer of CELITE™. The residue was washed with hot ethanol. The filtrate was concentrated and purified by flash chromatography to provide 39.6 grams (63%) of the desired title product.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([C:35]1([O:38]C(=O)C)[CH2:37][CH2:36]1)=[O:34]>>[OH:38][C:35]1([C:33]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[O:27][CH2:28][CH:29]5[CH2:30][CH2:31]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:34])[CH2:37][CH2:36]1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1
Product: O=C(N[C@H]1CC[C@H](NC(=O)C2(O)CC2)CC1)c1c[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc12

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A157) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: C([Li])CCC.[CH:6]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:8])[CH3:7].[CH3:19][O:20][CH:21]([O:28][CH3:29])/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25].P(O)(O)([O-])=O.[Na+]>O1CCCC1.CCCCCC>[C:15]1([CH3:18])[CH:16]=[CH:17][C:12]([S:9]([C:6]([CH3:7])([CH3:8])[CH:22]([CH:21]([O:28][CH3:29])[O:20][CH3:19])[CH2:23][C:24]([O:26][CH3:27])=[O:25])(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: COC(=O)/C=C/C(OC)OC
Reactant: Cc1ccc(S(=O)(=O)C(C)C)cc1
Agent: O=P([O-])(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CC(C(OC)OC)C(C)(C)S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.25 h

Procedure:
3.4 ml of a 1.95 M of butyllithium per liter of hexane were added at -70° C. to a mixture of 1.24 g of p-tolyl isopropyl sulfone in 13 ml of tetrahydrofuran and after stirring the mixture for 15 minutes, a solution of 1 g of methyl (E) 4,4-dimethoxy-2-butenoate in 20 ml of tetrahydrofuran was slowly added thereto. The mixture was stirred at -20° C. for one hour and was then poured into an aqueous monosodium phosphate solution. The mixture was extracted with methylene chloride and the organic phase was dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an ether-petroleum ether (b.p. =40° to 70° C.) mixture to obain 1.1 g of methyl 4-p-tolylsulfonyl-4-methyl-3-dimethoxymethyl-pentanoate melting at 110° C.
Reaction SMILES: [Na].CS(O)(=O)=O.O[CH2:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][C:12]1=[O:20]>C(O)C>[O:20]1[C:12]2=[N:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:11]2[CH2:10][CH2:9][CH2:8]1
Reactant: O=c1[nH]c2ccccc2n1CCCO
Agent: CS(=O)(=O)O
Agent: [Na]
Solvent: CCO
Product: c1ccc2c(c1)nc1n2CCCO1

Procedure:
To a solution of 0.5 parts of sodium in 40 parts of absolute ethanol are added in the cold 5.4 parts of 1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate. The whole is stirred until all solid enters solution. The solution is further stirred and refluxed for 2 hours. After cooling, the reaction mixture is filtered from some inorganic matter and the filtrate is evaporated. The residue is dissolved in 80 parts of methylbenzene, boiled with activated charcoal, filtered and the filtrate is evaporated again. The solid residue is washed with cold methylbenzene and crystallized from 16 parts of methylbenzene, yielding 2.6 parts of 3,4-dihydro-2H-[1,3]oxazino[3,2-a]benzimidazole; mp. 116.5-118.5° C.
Reaction SMILES: P(Cl)(Cl)Cl.[C:5]([OH:9])(=O)[CH2:6][CH3:7].C(Cl)(=O)CC.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:20]([CH3:22])[CH3:21].CCCCC1C=CC=CC=1.Cl>C(Cl)Cl>[CH2:19]([C:23]1[CH:28]=[CH:27][C:26]([C:5](=[O:9])[CH2:6][CH3:7])=[CH:25][CH:24]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)Cc1ccccc1
Reactant: CCC(=O)O
Agent: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Solvent: ClCCl
Solvent: CCCCc1ccccc1
Solvent: ClP(Cl)Cl
Product: CCC(=O)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
In a 500 ml. 3-necked, round bottomed flask there was placed 25.50 ml. (40.14 g., 0.29 mmole) of phosphorus trichloride and 43.65 ml. (43.34 g., 0.58 mmole) of propionic acid. This mixture was stirred for 2.25 hours under nitrogen atmosphere at room temperature to prepare the propionyl chloride. By NMR propionyl chloride formation was complete in about 1.5 hours. Then 80 ml. of anhydrous methylene chloride was added and the resulting solution was cooled to about -5° C. (an ice-methanol bath). While stirring the cooled mixture, 87.50 g. (0.66 mmole) of aluminum chloride (technical grade) was added. After 10 minutes of stirring, 67.11 g. (0.50 mmole) of isobutylbenzene was added dropwise from an addition funnel over 55 minutes while maintaining the temperature of the mixture at about 0° to 5° C. The isobutylbenzene was about 99.6% pure and contained about 0.3% n-butylbenzene. The mixture was stirred for an additional 1.25 hours to insure as complete a reaction as possible and then poured into a solution of 250 ml. of ice water and 150 ml. of concentrated hydrochloric acid with vigorous stirring. The Friedal-Crafts reaction was complete in about 45 minutes under these conditions (by GLC analyses). The resulting mixture was extracted three times with 300 ml. portions of methylene chloride. The combined methylene chloride extracts were washed with 250 ml. of water and three times with 250 ml. of molar concentration aqueous sodium carbonate solution. The aqueous sodium carbonate extracts were back-extracted with 100 ml. of methylene chloride and the combined methylene chloride layers were dried over sodium sulfate. The dried methylene chloride solution was concentrated under vacuum to give crude p-isobutylpropiophenone as a pale yellow oil weighing 97.85 g. By GLC analyses, 3% methylene chloride was present. The chemical yield was about 95 g. or about 100% of theory.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[N:25][OH:26])=[CH:19][CH:18]=1.C(N(CC)CC)C>O1CCCC1>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[CH:2]=[C:1]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=3)[O:26][N:25]=2)=[CH:19][CH:18]=1
Reactant: C#Cc1cccnc1
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccn2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: c1ccc(COc2ccc(Cc3cc(-c4cccnc4)on3)cc2)nc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 42.6 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynylpyridine (50 mg, 0.485 mmol) and (4-(pyridin-2-ylmethoxy)-phenyl)-acetohydroximoyl chloride (215 mg, 0.776 mmol) described in Manufacturing Example 203-1-4 was added triethylamine (270 μL, 1.94 mmol), which was stirred for 2.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4 to 1:2, then 1:1) to obtain the title compound (71 mg, 43%).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:25])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[C:12]([C:10]1[N:11]=[C:6]([C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5])[C:7]([OH:25])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:9]=12)#[N:13]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2cccc(F)c2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccn(Cc3cccc(F)c3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 7-cyano-1-(3-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 369 (M+H)+.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[F:13]>C1COCC1>[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]([OH:10])[CH3:1])=[CH:7][C:6]=1[F:13]
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Methylmagnesium bromide (3M in diethylether, 6.77 mL, 20.31 mmol) was added dropwise over ˜15 min to a solution of 4-bromo-3-fluorobenzaldehyde (3.1 g, 15.27 mmol) in THF (50 mL) under argon at a temperature of −60° C. to −50° C. The ice bath was removed and the reaction mixture was allowed to warm to room temperature and stirred ˜20 hr. The reaction mixture was slowly diluted/quenched with saturated aqueous ammonium chloride solution (20 mL) and further diluted with water (10 mL). The separated aqueous layer was extracted with ethyl acetate (2×40 mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide crude 1-(4-bromo-3-fluorophenyl)ethanol as a pale yellow oil, which was directly used without further purification.