Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([C:22]#[C:23][CH2:24][CH2:25][CH2:26][OH:27])=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)=[CH:9][CH:8]=1)(C)C.C([O-])([O-])=O.[K+].[K+]>CO>[C:6]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([C:22]#[C:23][CH2:24][CH2:25][CH2:26][OH:27])=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)=[CH:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(-n2ccc3cc(C#CCCCO)ccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(-n2ccc3cc(C#CCCCO)ccc32)cc1
Yield: 87.4 %

Procedure:
970 mg (2.6 mmol) 5-[1-(4-Trimethylsilanylethynyl-phenyl)-1H-indol-5-yl]-pent-4-yn-1-ol in 10 ml MeOH were treated with 41.4 mg (3 mmol) K2CO3. The solution was concentrated, the residue dissolved in ether and 0.5M HCl and the organic phase was washed with water and dried over Na2SO4. Column chromatography on silica gel with ether yielded 680 mg (87%) 5-[1-(4-Ethynyl-phenyl)-1H-indol-5-yl]-pent-4-yn-1-ol as orange oil, MS: 299 (M).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]=1.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[N:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:17]2[CH:18]=[N:19][CH:20]=[C:15]([F:14])[CH:16]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cnccc2c1Cl
Reactant: OB(O)c1cncc(F)c1
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+]
Product: Cc1c(-c2cncc(F)c2)nc2cnccc2c1Cl

Procedure:
Prepared according to procedure F using 2,4-dichloro-3-methyl-1,7-naphthyridine (100 mg, 0.469 mmol), 5-fluoropyridine-3-boronic acid (66.1 mg, 0.469 mmol), sodium carbonate (87 mg, 0.821 mmol) and Pd(PPh3)4 (54.2 mg, 0.047 mmol). Product used without further purification in the next step. Mass Spectrum (ESI) m/e=274.0 (M+1).
Reaction SMILES: C([O:4][CH2:5][CH:6]1[CH2:11][CH:10]([N:12]([C:17]([C:19]2[C:20]([NH:29][CH2:30][C:31]3[O:32][CH:33]=[CH:34][CH:35]=3)=[N:21][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[N:23][CH:24]=2)=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:9][N:8]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:7]1)(=O)C.O.[OH-].[Na+]>CO>[C:25]([C:22]1[N:21]=[C:20]([NH:29][CH2:30][C:31]2[O:32][CH:33]=[CH:34][CH:35]=2)[C:19]([C:17]([N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:10]2[CH2:11][CH:6]([CH2:5][OH:4])[CH2:7][N:8]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:9]2)=[O:18])=[CH:24][N:23]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(=O)OCC1CC(N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2NCc2ccco2)CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)C1CC(CO)CN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 7 h
Yield: 97.9 %

Procedure:
To a solution of tert-butyl 3-[(acetyloxy)methyl]-5-[({2-tert-butyl-4-[(furan-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]piperidine-1-carboxylate (780 mg) in methanol (10 ml)-water (9 ml) was added 8 M aqueous sodium hydroxide solution (0.83 ml), and the mixture was stirred at 70° C. for 7 hr and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (5:95-100:0) was concentrated under reduced pressure to give the object compound (709 mg).
Reaction SMILES: B(F)(F)F.CCOCC.[CH2:10]([O:17][C:18]1[CH:36]=[CH:35][C:21]([C:22]([O:24][CH2:25][C:26]([C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=2)=O)=O)=[CH:20][CH:19]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C([NH2:40])(=O)C>C(Cl)Cl>[Br:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]2[N:40]=[C:22]([C:21]3[CH:35]=[CH:36][C:18]([O:17][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:19][CH:20]=3)[O:24][CH:25]=2)=[CH:29][CH:30]=1
Reactant: CCCCCCCOc1ccc(C(=O)OCC(=O)c2ccc(Br)cc2)cc1
Reactant: CC(N)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCCOc1ccc(-c2nc(-c3ccc(Br)cc3)co2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 28.6 %

Procedure:
To boron trifluoride etherate (0.322 mL, 2.5 mmol) was added 2-(4-bromophenyl)-2-oxoethyl 4-(heptyloxy)benzoate (1.0 g, 2.3 mmol) and acetamide (4.91 g, 83.0 mmol) in DCM (10 mL). The reaction mixture was heated to 50° C. then 140° C. for 16 h, DCM was distilled off. The reaction mixture was cooled, diluted with acetonitrile and stirred at RT for 1 h. The precipitate was isolated by filtration to afford 273 mg (23%) of 4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)oxazole as a brown solid. LCMS-ESI (m/z) calculated for C22H24BrNO2: 414.3; found 414.0 [M+H]+, tR=3.00 min. (Method 4).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[SH:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].C(N(C(C)C)C(C)C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([S:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:7]=[N:6][C:5]=1[O:8][CH3:9]
Reactant: COc1cc(Br)cnc1OC
Reactant: COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCSc1cnc(OC)c(OC)c1
Yield: 105.1 %

Procedure:
To a solution of 5-bromo-2,3-dimethoxypyridine (2 g, 9.17 mmol) in dioxane (30 ml) was added methyl 3-sulfanylpropanoate (1.21 g, 10.1 mmol), N-ethyl-N-isopropylpropan-2-amine (3.03 ml, 18.3 mmol), Pd2(dba)3 (0.34 g, 0.37 mmol) and Xantphos (0.43 g, 0.73 mmol) at room temperature under an atmosphere of nitrogen. The reaction was degassed by evacuating and flushing with nitrogen and heated at reflux for 18 hours and then allowed to cool and filtered, washing with ethyl acetate. The filtrate was concentrated under reduced pressure to give an orange oil. Purification by column chromatography (SiO2; 0-20% ethyl acetate in petrol), gave methyl 3-[(5,6-dimethoxypyridin-3-yl)sulfanyl]propanoate as a yellow oil (2.48 g, quantitative yield).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:8]=[CH:9][N:10]=1.Cl[CH2:23][C:24]1[N:25]=[C:26]([CH:29]=[CH:30][C:31]2[CH:36]=[CH:35][C:34]([S:37]([C:39]([F:42])([F:41])[F:40])=[O:38])=[CH:33][CH:32]=2)[O:27][CH:28]=1.O>CN(C=O)C>[F:42][C:39]([F:40])([F:41])[S:37]([C:34]1[CH:35]=[CH:36][C:31](/[CH:30]=[CH:29]/[C:26]2[O:27][CH:28]=[C:24]([CH2:23][O:21][C:18]3[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:7]4[CH:8]=[CH:9][N:10]=[C:6]4[CH2:5][CH2:4][OH:3])=[CH:20][CH:19]=3)[N:25]=2)=[CH:32][CH:33]=1)=[O:38]
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(c1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnc4CCO)cc3)co2)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 35.4 %

Procedure:
13.0 mg (0.50 mmol) 95% sodium hydride were given to a solution of 130 mg (0.50 mmol) 4-{4-[2-(2-Hydroxyethyl)-imidazol-1-yl]-butyl}-phenol in 4.0 ml DMF and stirred for 15 min. 168 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 10 ml water the resulting precipitate was washed twice with water, 10 ml methanol/water 1:1 and with diethyl ether. The residue was purified by chromatography on silica gel (eluent: ethyl acetate/methanol 9:1) to yield 99 mg colorless powder that was further purified by HPLC-MS.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]([N:25]3[C@@H:34]4[C@@H:29]([C:30]5[CH:38]=[CH:37][C:36]([C:39]([NH2:41])=O)=[CH:35][C:31]=5[CH2:32][CH2:33]4)[CH2:28][CH2:27][CH2:26]3)=[O:24])=[CH:22][C:17]=2[N:16]=[CH:15]1.C(N(CC)CC)C>ClCCl>[NH:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]([N:25]3[C@@H:34]4[C@@H:29]([C:30]5[CH:38]=[CH:37][C:36]([C:39]#[N:41])=[CH:35][C:31]=5[CH2:32][CH2:33]4)[CH2:28][CH2:27][CH2:26]3)=[O:24])=[CH:22][C:17]=2[N:16]=[CH:15]1
Reactant: NC(=O)c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic anhydride (0.4 mL) is added to a solution of cis-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-8-carboxylic acid amide (140 mg) and triethylamine (0.6 mL) in dichloromethane (4 mL) chilled in an ice bath. The cooling bath is removed and the solution is stirred at room temperature for 3 h. Another portion of trifluoroacetic anhydride (0.4 mL) and triethylamine (0.6 mL) are then added and stirring is continued at 35° C. overnight. The solution is diluted with dichloromethane and washed with water and brine. After drying (MgSO4), the solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane/methanol 20:1→1:1) to furnish the title compound as a yellowish solid. Yield: 50 mg (38% of theory); Mass spectrum (ESI+): m/z=357 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[CH:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O.C(O[Na])(C)=O.[NH2:32][C@H:33]([C:36]([O:38][CH3:39])=[O:37])[CH2:34][SH:35].Cl>C(O)C.O>[CH3:39][O:38][C:36]([CH:33]1[CH2:34][S:35][CH:12]([CH2:11][CH:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:22])[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:32]1)=[O:37]
Reactant: COC(=O)[C@@H](N)CS
Reactant: CC(C)(C)OC(=O)NC(CC=O)C(=O)OCc1ccccc1
Agent: CC(=O)O[Na]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: COC(=O)C1CSC(CC(NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)N1
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To a solution of 2 (0.7 g, 2.25 mmol), AcOH (0.14 g, 2.25 mmol), AcONa (0.38 g, 4.50 mmol) in ethanol and water (10:1, 11 mL) was added L-Cys-OMe.HCl (0.39 g, 2.25 mmol). After being stirred overnight, the mixture was poured into 100 mL water, extracted with ethyl acetate, and the organic phase was dried and concentrated to give an oily crude product (0.8 g, 82%), which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ1.43 (s, 9 H), 1.95-2.15 (m, 2 H), 2.29-2.41 (m, 1H), 2.87 (m, 1 H), 3.68 (m, 1 H), 3.77 (s, 3 H), 3.96 (m, 0.6 H), 4.50 (m, 1 H), 4.70 (m, 0.4 H), 5.12-5.23 (m, 2 H), 5.35 (d, 0.4 H), 5.75 (d, 0.6 H), 7.36 (m, 5H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([N:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[C:24]#[N:25])=[O:18])[C:12]2[C:7](=[CH:8][C:9]([CH3:26])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].[OH-].[Na+]>C1COCC1>[C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[C:17](=[O:18])[CH2:16][O:15][C:13]1[C:12]2[C:7](=[CH:8][C:9]([CH3:26])=[CH:10][CH:11]=2)[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=1)#[N:25]
Reactant: COC(=O)c1cc(OCC(=O)N2CCC[C@H]2C#N)c2ccc(C)cc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc2c(OCC(=O)N3CCC[C@H]3C#N)cc(C(=O)O)nc2c1
Reaction time: 2 h

Procedure:
To a solution of 772 mg 4-[2-((S)-2-Cyano-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid methyl ester in 10 ml THF were added 2.1 ml aqueous NaOH (1 M) at 0° C. After 2 h the mixture was brought to pH 4 by using Amberlite IR-120 ion exchange resin. The reaction mixture was filtered and concentrated and the crude product purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 310 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[S:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[S:15].C([O-])(=O)C.[Na+].C(O)(=O)C>O>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[C:19]1[S:13][C:14](=[S:15])[NH:16][C:17]1=[O:18]
Reactant: COc1cccc(C=O)c1OC
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(C=C2SC(=S)NC2=O)c1OC
Yield: 95.6 %

Procedure:
A mixture of 2,3-dimethoxybenzaldehyde (5.2 g, 30 mmoles), rhodanine (4.0 g, 29 mmoles), sodium acetate (8.4 g, 102 mmoles), and acetic acid (50 ml) is stirred under an inert atmosphere and heated to reflux. After 4 hours the mixture is stirred into water (250 ml) and the precipitate is filtered off, rinsed successively with water (3X), ethanol (2X), and ether (2X), and dried to afford the pure product (7.8 g), mp 268°-269° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[CH:4][N:3]=1.[CH3:19][NH2:20]>>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:20][CH3:19])=[N:3][CH:4]=2
Reactant: Fc1ccccc1Cn1cnc2cnc(Cl)nc21
Reactant: CN
Product: CNc1ncc2ncn(Cc3ccccc3F)c2n1

Procedure:
In a manner analogous to that described in Example 2 it is also possible, by reacting 2-chloro-9-(2-fluorobenzyl)-9H-purine (Example 7) with N-methylamine, to obtain the 9-(2-fluorobenzyl)-2-(N-methylamino)-9H-purine, which has a melting range of from 184° to 185° (methanol/diethyl ether), the reaction mixture being heated for 24 hours at from 80° to 85°.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH3:8])[CH2:3][C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(OC(=O)[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35]([C:37]1[S:38][C:39]([CH2:42][NH2:43])=[CH:40][CH:41]=1)=[O:36])(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C1COCC1>[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35]([C:37]1[S:38][C:39]([CH2:42][NH:43][C:4](=[O:6])[CH2:3][CH:2]([CH3:1])[CH2:7][CH3:8])=[CH:40][CH:41]=1)=[O:36]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CN)s1
Reactant: CCC(C)CC(=O)O
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCC(C)CC(=O)NCc1ccc(C(=O)Nc2ccccc2N)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
To a solution of 33.43 mg (0.288 mmol) 3-methylpentanoic acid in 1 ml THF were added 46.67 mg (0.288 mmol) 1,1′-carbonyldiimidazol. After 1 h at rt 100 mg (0.288 mmol) {2-[(5-aminomethyl-thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid t-butyl ester were added and the reaction mixture was stirred for 3 h at rt. 1.7 ml trifluoroacetic acid were added and after 2 h at rt sat. aqueous NaHCO3 was added carefully and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over Na2SO4. The solvent was evaporated and the residue was subjected to silica gel chromatography (ethyl acetate/heptane 6:4) to yield 59.3 mg (0.171 mmol) 5-[(3-Methyl-pentanoylamino)-methyl]-thiophene-2-carboxylic acid (2-amino-phenyl)-amide; exact MW [M+H] calc'd: 346.16; MW found [M+H]: 346.4.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:14][CH2:13]2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][N:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[Br:15][C:16]1[N:17]=[CH:18][C:19]([NH:1][C:2]2[CH:11]=[CH:10][C:9]([CH:12]3[CH2:14][CH2:13]3)=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc(C2CC2)ccc1N
Reactant: Brc1ccc(I)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1cc(C2CC2)ccc1Nc1ccc(Br)nc1

Procedure:
Obtained (0.155 g, 43% of yield) following the procedure described in Intermediate 15 starting with methyl 2-amino-5-cyclopropylbenzoate (described in Intermediate 8 (step A)) (1.05 mmol, 0.200 g), 2-bromo-5-iodopyridine (1.05 mmol, 0.297 g) and Cs2CO3 (2.09 mmol, 0.682 g) instead of NaOtBu.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:24]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:19][S:29]([C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)(=[O:31])=[O:30])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Reactant: O=S(=O)(Cl)c1cccnc1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccnc3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 72 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (3 g, 9.1 mmol) and pyridine-3-sulfonyl chloride (1.93 g, 10.9 mmol) the title compound was obtained (3.1 g, 72% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.57-10.63 (br, 1H), 8.84 (d, J=2.2 Hz, 1H), 8.74-8.78 (m, 1H), 8.50 (d, J=5.3 Hz, 1H), 8.07-8.12 (m, 1H), 7.55-7.59 (m, 1H), 7.31-7.37 (m, 1H), 7.17-7.28 (m, 3H), 6.92 (d, J=5.3 Hz, 1H), 3.24-3.34 (m, 1H), 1.34 (d, J=6.8 Hz, 6H). MS (ES+): 472 [M+H]+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]3[C:16](=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[CH:19][CH:20]=3)[C:15]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([Cl:35])[CH:28]=3)=[N:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[ClH:36]>>[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]3[C:16](=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[CH:19][CH:20]=3)[C:15]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([Cl:35])[CH:28]=3)=[N:14][N:13]=2)[CH2:8][CH2:7]1)([OH:5])=[O:3].[ClH:36].[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]3[C:16](=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[CH:19][CH:20]=3)[C:15]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([Cl:35])[CH:28]=3)=[N:14][N:13]=2)[CH2:8][CH2:7]1)([OH:5])=[O:3]
Reactant: CCOC(=O)C1CCN(c2nnc(NCc3ccc(OC)c(Cl)c3)c3cc([N+](=O)[O-])ccc23)CC1
Agent: Cl
Product: COc1ccc(CNc2nnc(N3CCC(C(=O)O)CC3)c3ccc([N+](=O)[O-])cc23)cc1Cl

Procedure:
1-(4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-nitrophthalazine was prepared from the compound prepared in Example 55 in a similar manner to that of Example 43 and further converted into the title compound in the same manner as that employed in Example 4 for the formation of hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]=[CH2:13])[C:5]([O:7][CH3:8])=[O:6]>C(O)C.[Pd]>[CH2:12]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[F:1])[CH3:13]
Reactant: C=Cc1ccc(C(=O)OC)cc1F
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(C(=O)OC)cc1F
Yield: 60.2 %

Procedure:
N-(4-chlorophenyl)-N-[(2S,4R)-1-(4-ethyl-3-fluorobenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide was prepared following general procedure B, substituting 4-ethyl-3-fluorobenzoyl chloride for 6-trifluoromethyl nicotinyl chloride. (4-ethyl-3-fluorobenzoyl chloride was prepared in five steps from commercially available 4-bromo-3-fluorobenzoic acid. 4-Bromo-3-fluorobenzoic acid (0.828 g, 3.8 mmol) was dissolved in 20 mL of benzene/methanol (5:1) mixture. To the above mixture was added trimethylsilyldiazomethane until the reaction showed a light yellow color. Let stir for 30 minutes and concentrate down to yield methyl 4-bromo-3-fluorobenzoate. Methyl 4-bromo-3-fluorobenzoate was dissolved in 2 mL of DMF and vinyl tributyl tin (0.431 mL, 1.5 mmol), and degassed for 5 min with nitrogen gas. To the above mixture was added Pd(PPh3)2Cl2 (0.086 g, 0.12 mmol) and heated at 80° C. with a condenser for 16 h. Cool to room temperature and dilute with ethyl acetate and wash with a 10% solution of KF in water. The mixture was allowed to stir for ˜30 min at room temperature, then filter and extract the aqueous with ethyl acetate (3×). Dry over MgSO4, filter and concentrate down. The residue was concentrated down and purified with 100% hexane to 10% ethyl acetate/90% hexane to yield 0.140 g, 63% of methyl 3-fluoro-4-vinylbenzoate. Methyl 3-fluoro-4-vinylbenzoate (0.750 g, 4.1 mmol) was reduced in the presence of Pd on carbon (10%) in ethanol to provide methyl 4-ethyl-3-fluorobenzoate (0.450 g, 59%). Methyl 4-ethyl-3-fluorobenzoate was hydrolyzed to the acid by dissolving in tetrahydrofuran and methanol and sodium hydroxide (1N) was added. The mixture was stirred at room temperature overnight. The mixture was cooled to rt, acidified to pH=5 with 1N HCl to form a white precipitate (0.270 g, 65%). The solid was filtered to give 4-ethyl-3-fluorobenzoic acid. The acid was converted to the acid chloride as described in general procedure B).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O:14][CH2:15][CH:16]([CH2:21]Br)[C:17]([CH3:20])([CH3:19])[CH3:18])(=O)C.O>CN(C)C=O>[CH2:3]([S:10][CH2:21][CH:16]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:15][OH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)OCC(CBr)C(C)(C)C
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(CO)CSCc1ccccc1
Yield: 33.7 %

Procedure:
Sodium hydride (2 g; 80%) was added to a stirred solution of benzyl mercaptan (9.4 g) in dry dimethylformamide (100 ml) at room temperature under a nitrogen atmosphere. The resulting mixture was heated at reflux for 1 hour when a solution of 2-bromomethyl -3,3-dimethylbutyl acetate (13.3 g) in DMF (10 ml) was added. After a further hour at reflux, the mixture was allowed to cool and then poured into water (300 ml). The aqueous mixture was extracted with ether and then the combined ethereal extracts were washed with water before drying over anhydrous magnesium sulphate and evaporation in vacuo. The resulting residue was taken up in a mixture of 10% aqueous potassium hydroxide and ethanol (1:1, 50 ml) and heated to reflux for 1 hour. After cooling, the aqueous solution was exhaustively extracted with ether. The combined ethereal extracts were dried over anhydrous magnesium sulphate and then evaporated in vacuo. The residue was purified by column chromatography on silica. Gradient elution with hexane/diethylether mixtures gave 2-benzylthiomethyl-3,3-dimethylbutanol as an oil (4.5 g).
Reaction SMILES: [OH-].[Na+].C([S:6][C@H:7]1[CH:12]2[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]2)[CH2:8]1)(=O)C.C(O)(=O)C>CO>[SH:6][C@H:7]1[CH:12]2[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]2)[CH2:8]1
Reactant: CC(=O)S[C@@H]1CN2CCC1CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: S[C@@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
10N aqueous sodium hydroxide solution (30 cc) is added slowly to a solution of (3S)-3-(acetylthio)quinuclidine (29 g) in methanol (30 cc) maintained at approximately 25° C. The reaction mixture is stirred for 2 hours at a temperature in the region of 20° C. The pH of the reaction mixture is then brought to a value in the region of 9 by adding acetic acid (approximately 10 cc). The mixture obtained is extracted with methylene chloride (3×100 cc). The combined organic phases are dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) and 30° C. The residue obtained is purified by distillation under reduced pressure (970 Pa). (3S)-3-Mercaptoquinuclidine (12 g) is thereby obtained in the form of white crystals which melt at 46° C. and distil at 95° C. under 970 Pa (αD20 =-118°, C=1.1, methanol).