Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:6]=1[C:7]([OH:9])=[O:8])(O)=[O:2]>C(Cl)(=O)C>[F:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:5]2[C:6]=1[C:7](=[O:9])[O:8][C:1](=[O:2])[CH2:4]2
Reactant: O=C(O)Cc1cccc(F)c1C(=O)O
Solvent: CC(=O)Cl
Product: O=C1Cc2cccc(F)c2C(=O)O1
Yield: 102.5 %

Procedure:
2-Carboxymethyl-6-fluoro-benzoic acid (130 mg, 0.65 mmol) in acetyl chloride (2 ml) was heated under microwave irradiation at 150° C. for 10 min then concentrated in vacuo to give the title product (120 mg, 100% yield). The compound is hydroscopic and slowly decomposes back to the starting diacid in wet solvents or under moisturized atmosphere. 1H NMR (500 MHz, DMSO-d6): 4.29 (s, 2H), 7.27 (d, J=7.8 Hz, 1H), 7.34 (dd, J=8.5 Hz, J=11 Hz, 1H), 7.76 (dt, J=5.3 Hz, J=8 Hz, 1H).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10].[CH:24]1([C:27]2[C:28]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[N:29][CH:30]=[C:31]([CH3:33])[CH:32]=2)[CH2:26][CH2:25]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[O:23]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:21])=[O:22])[CH:13]=[CH:12][C:8]=1[C:9]([N:37]1[CH2:38][CH2:39][N:34]([C:28]2[C:27]([CH:24]3[CH2:25][CH2:26]3)=[CH:32][C:31]([CH3:33])=[CH:30][N:29]=2)[CH2:35][CH2:36]1)=[O:10]
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1N1CCCS1(=O)=O
Reactant: Cc1cnc(N2CCNCC2)c(C2CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N3CCCS3(=O)=O)CC2)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-Bis(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (200 mg) described in Preparation Example 34, 1-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine (121 mg) described in Preparation Example 86, and 1-hydroxybenzotriazole 1 hydrate (79 mg) were dissolved in N,N-dimethylformamide (3 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (112 mg) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (ethyl acetate:hexane) to give [2,4-bis(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(3-cyclopropyl-5-methylpyridin-2-yl)piperazin-1-yl]methanone. The obtained [2,4-bis(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(3-cyclopropyl-5-methylpyridin-2-yl)piperazin-1-yl]methanone (240 mg) was dissolved in ethyl acetate, 4N hydrogen chloride/ethyl acetate (0.11 mL) was added, and the precipitate was collected by filtration to give the title compound (104 mg).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][C:14]=1[C:22]([F:25])([F:24])[F:23].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=2)=[CH:15][C:14]=1[C:22]([F:23])([F:24])[F:25]
Reactant: CCOC(=O)c1ccc(Br)o1
Reactant: OB(O)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(F)c(C(F)(F)F)c2)o1
Yield: 83.4 %

Procedure:
To a solution of ethyl 5-bromofuran-2-carboxylate (150 mg, 0.69 mmol) in DME (5 mL) were added 4-fluoro-3-(trifluoromethyl)phenylboronic acid (171 mg, 0.82 mmol), 2M Na2CO3 (1.03 mL, 2.06 mol), and catalytic amounts of Pd(Ph3)4 (158 mg, 0.14 mmol). The reaction mixture was refluxed for 5 h, diluted with water and extracted with EtOAc. The extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (EtOAc/n-Hex=1:5) to give title compound (174 mg, 70%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11]N)=[CH:4][C:3]=2[O:2]1.C1C[O:29]CC1.CC(C[AlH]CC(C)C)C.Cl>C(O)C>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[O:29])=[CH:4][C:3]=2[O:2]1
Reactant: NCC(c1ccc2c(c1)OCO2)C(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: CCO
Product: O=CC(c1ccc2c(c1)OCO2)C(c1ccccc1)c1ccccc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Compound 98 was prepared as follows: A mixture of 2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropylamine (18.0 g, 0.055 mol) and anhydrous THF (120 mL) at −70° C. was treated dropwise with a 1.0M solution of DiBAL (100 mL, 0.110 mol). The reaction was stirred for 1 hour at −70° C. and then at 25° C. for 1.5 hours. The reaction was cooled to 0° C. and treated with ethanol (20 mL) followed by 10% aqueous HCl (150 mL). Extraction with ethyl acetate, drying over anhydrous MgSO4, evaporation and purification by flash chromatography (silica gel) afforded 2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropionaldehyde a solid. A mixture of this material (8.0 g, 0.024 mol), Rink amine resin (8.73 g, 0.0044 mol), and trimethylorthoformate (60 mL) was shaken for 4 days, filtered and washed twice with trimethylorthoformate, methylene chloride, and dichloroethane. The resulting resin was shaken with NaBH(Oac)3 (4.63 g, 0.022 mol), acetic acid (1.83 mL) and dichloroethane (60 mL) for two days. The resulting resin was washed with methanol, methylene chloride, 10% acetic acid/methylene chloride, 10% triethylaminelmethylene chloride, methylene chloride, and methanol. This resin (0.235 g, 0.0001 mol) was shaken for 2 days with HATU (0.090 g, 0.00024 mol), diisopropylethylamine, (175 μL), 4-chlorophenylacetic acid (0.085 g, 0.0005 mol), and DMF (2 mL). The resin was filtered and washed three times each with DMF, methylene chloride, and methanol and dried. The dried resin was treated with 10% TFA/methylene chloride and filtered. The filtrate was blown dry with nitrogen to afford 0.042 g (87%) of compound 98, electrospray mass spectrometry m/e=484.
Reaction SMILES: [CH2:1]([NH2:7])[CH:2]1O[CH2:5][CH2:4][CH2:3]1.[ClH:8].S(Cl)([Cl:11])=O>>[ClH:11].[Cl:8][CH:2]([CH2:3][CH2:4][CH2:5][Cl:11])[CH2:1][NH2:7]
Reactant: O=S(Cl)Cl
Reactant: NCC1CCCO1
Agent: Cl
Product: NCC(Cl)CCCCl

Procedure:
An N-alkenyl-2-aminomethyl-pyrrolidine is prepared by firstly reacting tetrahydrofurfurylamine with gaseous hydrochloric acid and thionyl chloride to produce 2,5 dichloropentylamine hydrochloride. This is acetylized, possibly by acetyl chloride in dichloroethane in the presence of triethylamine, into N-acetyl-2,5-dichloropentylamine which is condensed with an alkenylamine into an N-alkenyl-2-acetylaminomethyl pyrrolidine from which the acetyl group is separated, for example by boiling with concentrated hydrochloric acid.
Reaction SMILES: [NH2:1][CH:2]([P:6](=[O:9])([OH:8])[OH:7])[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].[C:12]1([CH2:18][CH2:19][C:20](Cl)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[CH3:4][CH:3]([CH3:5])[CH:2]([P:6](=[O:8])([OH:7])[OH:9])[NH:1][C:20](=[O:21])[CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC(C)C(N)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C(NC(=O)CCc1ccccc1)P(=O)(O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 11 %

Procedure:
1-Amino-2-methylpropylphosphonic acid (2.7 g) described in Synthesis 370(1988) was dissolved in water (27 ml), and the solution was added with 5 N aqueous sodium hydroxide (10.5 ml) and 3-phenylpropanoyl chloride (2.6 ml) and stirred at room temperature for 16 hours. The reaction mixture was washed with diethyl ether and acidified with hydrochloric acid. The organic substances were extracted with ethyl acetate, and the extract was washed with saturated brine to obtain 2-methyl-1-(3-phenylpropanoylamino)propylphosphonic acid (554 mg, 11%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11]>[Pd].CO>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C=Cc1ccccc1O
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccccc1O
Reaction time: 3 h
Yield: 100.1 %

Procedure:
A mixture of methyl 3-(2-hydroxyphenyl)acrylate (2.47 g) and 10% palladium on carbon (0.50 g) in methanol (30 ml) was stirred under hydrogen atmosphere for 3 hours. The mixture was filtered and the filtrate was evaporated under reduced pressure to afford methyl 3-(2-hydroxyphenyl)propionate (2.50 g).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([C:13](=O)[CH3:14])=[CH:9][C:8]=2[CH3:16])=[CH:4][CH:3]=1.[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([CH:13]([NH:25][S@@:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24])[CH3:14])=[CH:9][C:8]=2[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(Oc2ccc(Cl)cc2)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1Oc1ccc(Cl)cc1
Yield: 83 %

Procedure:
The title compound is prepared in 83% yield (2.36 g, white solid) from 1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethanone (2.02 g, 7.72 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.40 g, 11.6 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][F:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[O:6]C(C2C=CC=CC=2)=[N:4]1.Cl.C(OCC)(=O)C>ClCCl>[NH2:4][C@H:3]([CH2:2][F:1])[C@@H:7]([C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH2:17][F:18])(=[O:16])=[O:15])=[CH:12][CH:13]=1)[OH:6]
Reactant: O=S(=O)(CF)c1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CF)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N[C@H](CF)[C@H](O)c1ccc(S(=O)(=O)CF)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of sulfone 22 (1.47 g, 4.19 mmol) in dichloromethane (50 mL) was mixed with 6N HCl (40 mL). Dichloromethane was distilled out and the resulting white suspension was stirred at reflux for 14 hours. It was cooled to room temperature and treated with aqueous NaHCO3 to pH=8˜9. Extraction with dichloromethane (3×50 mL) afforded an oil residue which was subjected to flash chromatography (SiO2, hexanes/ethyl acetate=2:1 to ethyl acetate 100%) to provide 1.0 g of the desired product, as a light yellow oil. 1H NMR (400 MHz, CDCl3) 3.05-3.15 (m, 1H), 4.24-4.52 (m, 2H), 4.72 (d, J=6 Hz, 1H), 5.09 (s, 1H), 5.21 (s, 1H), 7.62 (d, J=9 Hz, 2H), 7.93 (d, J=9 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:22](=[S:25])[NH:23][NH2:24])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26](OC)(OC)(OC)[CH2:27][CH2:28][CH2:29][CH3:30]>COCCO>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([CH2:20][N:21]2[C:26]([CH2:27][CH2:28][CH2:29][CH3:30])=[N:24][NH:23][C:22]2=[S:25])=[CH:18][CH:19]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CNC(=S)NN)cc1
Reactant: CCCCC(OC)(OC)OC
Solvent: COCCO
Product: CCCCc1n[nH]c(=S)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
A solution of 1.11 g (3.1 mmole) of 4-[[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl]-3-thiosemicarbazide and 792 μl (745 mg, 4.6 mmole) of trimethyl orthovalerate in 10 ml of 2-methoxyethanol was stirred at reflux under N2 for 15 hours. The cooled solution was concentrated, and the residue was purified by column chromatography on silica gel (gradient elution with 0-1% methanol in CH2Cl2) to give a gum which could be crystallized by trituration with petroleum ether. The product (828 mg, 63%, mp 135°-137° C.) was homogeneous by TLC in 19:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 424 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C:10](=[O:14])[C@@H:9]1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[F:36][C:37]([F:52])([F:51])[C:38]1[CH:39]=[C:40]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[C:41](Cl)=[O:42]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([O:14][C:41](=[O:42])[C:40]2[CH:44]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:46]=[C:38]([C:37]([F:36])([F:51])[F:52])[CH:39]=2)[C@@H:9]1[C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1OCCN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O[C@H]1OCCN(Cc2ccccc2)[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.75 h
Yield: 77 %

Procedure:
A solution of 2.67 g (10.0 mmol) of 4-benzyl-3-(S)-(4-fluorophenyl)-2-morpholinone (Description 2) in 40 ml of dry THF was cooled to -78° C. The cold solution was treated with 12.5 ml of 1.0M L-Selectride® solution in THF, maintaining the internal reaction temperature below -70° C. The resulting solution was stirred cold for 45 minutes and the reaction was charged with 3.60 ml(20.0 mmol) of 3,5-bis(trifluoromethyl)benzoyl chloride. The resulting yellow mixture was stirred cold for 30 minutes and the reaction was quenched with 50 ml of saturated aqueous sodium bicarbonate solution. The quenched mixture was partitioned between 300 ml of ether and 50 ml of water and the layers were separated. The organic layer was dried over magnesium sulfate. The aqueous layer was extracted with 300 ml of ether; the extract was dried and combined with the original organic layer. The combined organics were concentrated in vacuo. Flash chromatography on 150 g of silica gel using 37:3 v/v hexanes/ether as the eluant afforded 4.06 g (80%) of the title compound as a solid. 1H NMR (200 MHz, CDCl3) δ2.50 (1H, dt, J=3.4, 12.0 Hz), 2.97 (1H, app d, J=12.0 Hz), 2.99 (1H, d, J=13.6 Hz), 3.72-3.79 (1H, m), 3.82 (1H, d, J=2.6 Hz), 4.00 (1H, d, J=13.6 Hz), 4.20 (dt, J=2.4, 11.6 Hz), 6.22 (1H, d, J=2.6 Hz), 7.22-7.37 (7H, m), 7.57 (2H, app d, J=6.8 Hz), 8.07 (1H, s), 8.47 (2H, s). MS (FAB) m/z 528 (M+H, 25%), 270 (100%). Analysis Calcd. for C26 H20F7NO3 : C, 59.21; H, 3.82; N, 2.66; F, 25.21. Found: C, 59.06; H, 4.05; N, 2.50; F, 25.18%
Reaction SMILES: [OH-].[Li+].[CH2:3]([S:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[C:22]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=3)[CH:21]=2)=[CH:13][C:12]=1[O:42][CH3:43])(=[O:9])=[O:8])[CH2:4][CH2:5][CH3:6].O.Cl>O1CCCC1>[CH2:3]([S:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:22]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=3)[CH:21]=2)=[CH:13][C:12]=1[O:42][CH3:43])(=[O:8])=[O:9])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCS(=O)(=O)Oc1ccc(CCCc2ccc(CCC(=O)OC)c(OCc3cccc(OC)c3)c2)cc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCS(=O)(=O)Oc1ccc(CCCc2ccc(CCC(=O)O)c(OCc3cccc(OC)c3)c2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
0.62 ml (0.62 mmol) of 1M lithium hydroxide solution is added to a solution of 181.6 mg (0.31 mmol) of methyl 3-[4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-2-(3-methoxybenzyloxy)phenyl]propanoate in 5 ml of tetrahydrofuran. The reaction mixture is stirred overnight at room temperature. The reaction is treated by adding 10 ml of water, acidified with hydrochloric acid and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. After evaporating off the solvents, the residue is purified by chromatography on a column of silica eluted with a 95/5 dichloromethane/methanol mixture. 162 mg (92%) of 3-[4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-2-(3-methoxybenzyloxy)phenyl]propanoic acid are obtained in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.[C:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][C:26](O)=[O:27])[C:20](=[O:29])[CH:19]=[CH:18]2)#[N:14]>>[Cl:1][C:2]1[C:3]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([NH:7][C:26](=[O:27])[CH2:25][N:21]2[C:22]3[C:17](=[CH:16][C:15]([C:13]#[N:14])=[CH:24][CH:23]=3)[CH:18]=[CH:19][C:20]2=[O:29])[S:5][CH:6]=1
Reactant: Nc1scc(Cl)c1-c1nc[nH]n1
Reactant: N#Cc1ccc2c(ccc(=O)n2CC(=O)O)c1
Product: N#Cc1ccc2c(ccc(=O)n2CC(=O)Nc2scc(Cl)c2-c2nc[nH]n2)c1

Procedure:
The title compound was prepared from 4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-amine (215 mg, 1.07 mmol) and 2-(6-cyano-2-oxoquinolin-1(2H)-yl)acetic acid (325 mg, 1.42 mmol) using protocol A. HPLC purification gave N-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(6-cyano-2-oxoquinolin-1(2H)-yl)acetamide. Method [7] Retention time 3.83 min by HPLC (M+=411 and 413). 1H NMR (300 MHz, DMSO-d6) δ 8.37 (s, 2H), 8.13 (d, J=9.9 Hz, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.70 (d, J=9.3 Hz, 1H), 7.17 (s, 1H), 6.86 (d, J=9.9 Hz, 1H), 5.31 (s, 2H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH:14]([C:19]1C=C[C:22]([O:25][CH3:26])=[CH:21][C:20]=1CCN)[CH2:13][CH2:12]2)(C(C)(C)C)(C)C.Cl.[N:31]1([CH2:38][CH2:39][C:40]2[CH:48]=[CH:47][C:43]([C:44](O)=O)=[CH:42][CH:41]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:38][CH2:39][C:40]2[CH:48]=[CH:47][C:43]([CH2:44][CH2:36][CH2:37][NH:31][C:32]3[CH:33]=[C:22]([O:25][CH3:26])[CH:21]=[CH:20][C:19]=3[CH:14]3[CH2:13][CH2:12][C:11]4[CH:10]=[C:9]([OH:8])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:42][CH:41]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COc1ccc(C2CCc3cc(O[Si](C)(C)C(C)(C)C)ccc3C2)c(CCN)c1
Reactant: O=C(O)c1ccc(CCN2CCCCCC2)cc1
Agent: Cl
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCc2ccc(CCN3CCCCCC3)cc2)c1

Procedure:
Synthesized from {2-[6-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]-5-methoxyphenyl}ethylamine and 4-(2-azepan-1-ylethyl)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, 4-(2-azepan-1-ylethyl)benzyl]{2-[6-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]-5-methoxyphenyl}ethylamine (59 mg) was used according to an analogous synthetic method to Example 325 described below to provide the title compound (38 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:31])[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>>[C:24]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])(=[O:31])[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: O=C(O)c1ccncc1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1ccncc1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and isonicotinic acid to yield (3aR,4S,7aR)-methyl 4-(isonicotinoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=391; RT=6.510 min; LC-MS Method II
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1([C:17]([NH:19][CH:20]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:21][CH2:22][CH2:23][OH:24])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl[C:33]1[C:34]2[CH:41]=[CH:40][NH:39][C:35]=2[N:36]=[CH:37][N:38]=1>C(O)C>[NH2:10][C:11]1([C:17]([NH:19][CH:20]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:21][CH2:22][CH2:23][OH:24])=[O:18])[CH2:16][CH2:15][N:14]([C:33]2[C:34]3[CH:41]=[CH:40][NH:39][C:35]=3[N:36]=[CH:37][N:38]=2)[CH2:13][CH2:12]1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: NC1(C(=O)NC(CCCO)c2ccc(Cl)cc2)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: NC1(C(=O)NC(CCCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
DIPEA (2.85 mL, 16.0 mmol) was added to 4-amino-N-(1-(4-chlorophenyl)-4-hydroxybutyl)piperidine-4-carboxamide (Intermediate 72) (1.04 g, 3.19 mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.490 g, 3.19 mmol) in ethanol (15.96 mL) at 25° C. The resulting solution was stirred at 65° C. overnight. The crude product was analysed by LCMS and evaporated to dryness. The crude solid was then purified by ion exchange chromatography, using an SCX-2 column. The product was eluted from the column using 20% 7N ammonia in methanol/DCM. The crude mixture was then re-purified by flash silica chromatography (eluent 0-10% 7N ammonia/MeOH in DCM) and pure fractions evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)-4-hydroxybutyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (63.9%) (racemate) as a fine white solid. The racemate was chirally resolved by supercritical flow chromatography (SFC) to afford the pure enantiomers in yields of 272 mg (19%) and 245 mg (17%) respectively. The NMR spectra for both enantiomers were identical.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[C:15](F)=[N:14][CH:13]=[CH:12][N:11]=2)=O)[CH:5]=[CH:4][CH:3]=1.[NH2:17][NH2:18]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:10]3[C:15](=[N:14][CH:13]=[CH:12][N:11]=3)[NH:18][N:17]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1cccc(Cl)n1)c1nccnc1F
Solvent: C1CCOC1
Product: Clc1cccc(-c2n[nH]c3nccnc23)n1
Yield: 63.5 %

Procedure:
To a solution of (6-chloro-2-pyridyl)-(3-fluoropyrazin-2-yl)methanone (1.12 g, 4.713 mmol) in THF (10 mL) was added hydrazine (1M in THF) (9.897 mL of 1 M, 9.897 mmol). Mixture turned orange and an exothermic reaction occurred, cream precipitate rapidly formed and mixture became difficult to stir. Stirred for 45 mins. Added sat. NaHCO3 solution and collected solid by filtration, washing solid with water then petrol. Solid then dried in vacuum oven overnight at 80° C. to leave title compound as an off-white solid (693 mg, 64%). 1H NMR (DMSO-d6) δ 7.58 (d, 1H), 8.07 (t, 1H), 8.52 (d, 1H), 8.70 (d, 1H), 8.80 (d, 1H), 14.55 (br s, 1H). ES+232.13.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:31])[C:21]1[CH:26]=[CH:25][C:24](F)=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1.[C-:32]#[N:33].[Na+].O>CN(C)C=O>[C:32]([C:24]1[CH:25]=[CH:26][C:21]([C:20]([NH:19][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([C:8]([F:17])([C:13]([F:15])([F:16])[F:14])[C:9]([F:12])([F:10])[F:11])=[CH:5][C:4]=2[CH3:18])=[O:31])=[CH:22][C:23]=1[N+:28]([O-:30])=[O:29])#[N:33]
Reactant: [C-]#N
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C#N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.1 %

Procedure:
To a solution of N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-4-fluoro-3-nitro-benzamide (2.008 g, 4.4 mmol) (prepared according to WO 05/073165) in N,N-dimethylformamide (25 ml) was added sodium cyanide (0.237 g, 4.84 mmol). The reaction mixture was stirred at ambient temperature for 48 hours. Then water (20 ml) was added and the organic phase extracted three times with ethyl acetate (3×100 ml). The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:4) to give 4-cyano-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-3-nitro-benzamide (1.0 g, 49% yield). 1H-NMR (400 MHz, CDCl3): 8.85 (d, 1H), 8.38 (q, 1H), 8.11 (d, 1H), 7.55 (s, 1H), 7.40 (s, 2H), 2.33 (s, 6H) ppm.