Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.CN(C1C=CC=CN=1)C.[Cl:47][C:48]1[CH:56]=[CH:55][C:51]([C:52](Cl)=[O:53])=[CH:50][N:49]=1>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:10][N:9]2[C:52]([C:51]2[CH:50]=[N:49][C:48]([Cl:47])=[CH:56][CH:55]=2)=[O:53])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)CC1CN(C(=O)c2ccc(Cl)nc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reaction time: 2 h
Yield: 82.9 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (53 mg, 0.125 mmol), diisopropylethylamine (64.7 mg, 0.50 mmol), dimethylaminopyridine (3 mg, 0.024 mmol, Aldrich) in CH2Cl2 (6 mL) and 6-chloro-nicotinoyl chloride (41.0 mg, 0.232 mmol, Aldrich) was stirred at room temp. for 2 hrs before diluted with EtOAc, washed with aqueous Na2CO3, brine, and concentrated. The residue was purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-1-(6-chloro-pyridine-3-carbonyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (58.3 mg, 83%) as a white solid. HRMS (ES+) m/z Calcd for C28H24Cl3F2N3O+H [(M+H)+]: 562.1026; Found: 562.1026
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:15]([OH:17])=[O:16].[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C>[CH2:18]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:15]([OH:17])=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCBr
Reactant: O=C(O)c1ccc2[nH]c(C(=O)O)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCn1c(C(=O)O)cc2cc(C(=O)O)ccc21
Temperature: 25 °C
Yield: 72.5 %

Procedure:
Sodium hydride (60% suspension, 125 mg, 5 mmol) was added to a stirred solution of 1H-indole-2,5-dicarboxylic acid (525 mg, 2 mmol) in dry DMF (10 mL) and maintained at ambient temperature for 1 hour. The reaction was cooled to 0° C. and then octyl bromide (1.5 mL, 13 mmol) was added. After 3 days the reaction was quenched by addition of 5% aqueous NH4Cl. The mixture was concentrated to dryness and then purified on a silica gel column using toluene. The product was then dissolved in 30 mL ethanol and 10 mL of 2 M NaOH was added. The solution was heated at 55° C. for 2 days. The ethanol was removed in vacuo and the resulting aqueous solution was acidified with 0.01 M HCl to pH 3. The resulting precipitate was filtered and rinsed twice with water. The isolated product was dried by evaporation from absolute ethanol (3×) to give 460 mg (73%) of 84.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:47]=[CH:46][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:26]=4)=[CH:20][C:19]=3[N:37](C)[C:38](=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1.[ClH:48].O1CCOCC1>>[ClH:48].[ClH:48].[CH3:38][N:37]1[C:19]2[CH:20]=[C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH:26]=3)[CH:22]=[CH:23][C:18]=2[N:17]=[C:15]1[CH2:14][O:13][C:12]1[CH:46]=[CH:47][C:9]([CH2:8][CH:4]2[S:3][C:2](=[O:1])[NH:6][C:5]2=[O:7])=[CH:10][CH:11]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(N3CCOCC3)c2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3cccc(N4CCOCC4)c3)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-[3-(morpholin-4-yl)phenoxy]phenyl)-N-methylcarbamate and 20 ml of 4N hydrochloric acid/dioxane was stirred at room temperature for 3 hours. The reaction mixture was evaporated to dryness under reduced pressure, followed by the addition of ether. The insoluble product was collected by filtration and washed with ether, whereby 1.27 g of the title compound were obtained.
Reaction SMILES: C([O:3][C:4](=[O:9])[CH2:5][CH:6]([NH2:8])[CH3:7])C.I[C:11]1[CH:19]=[CH:18][C:14]2[N:15]=[CH:16][S:17][C:13]=2[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CO>CN(C=O)C.C(Cl)(Cl)Cl.[Cu](I)I>[S:17]1[C:13]2[CH:12]=[C:11]([NH:8][CH:6]([CH3:7])[CH2:5][C:4]([OH:3])=[O:9])[CH:19]=[CH:18][C:14]=2[N:15]=[CH:16]1
Reactant: Ic1ccc2ncsc2c1
Reactant: CCOC(=O)CC(C)N
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(CC(=O)O)Nc1ccc2ncsc2c1
Temperature: 110 °C
Yield: 22.2 %

Procedure:
3-Amino-butyric acid ethyl ester (2 g, 15.27 mmol), 6-iodo-benzothiazole (3.98 g, 15.27 mmol) and potassium carbonate (5.27 g, 38.18 mmol) were dissolved in DMF (50 mL) and the reaction mixture was purged with argon for 10 minutes. This was followed by the addition of copper iodide (290 mg, 1.527 mmol) and the resulting mixture was heated to 110° C. overnight. The reaction was monitored by TLC (10% MeOH in CHCl3) which showed the presence of starting material. The reaction mixture was heated to 120° C. for a further 24 hours. The reaction mixture was concentrated and adjusted the pH to 5 using acetic acid. The reaction mixture was partitioned between water and ethylacetate. The organic layer was dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (1% MeOH in CHCl3) afforded 800 mg of the product (22.22% yield).
Reaction SMILES: CO[C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[OH-].[Na+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([C:31]2[C:35]([NH2:36])=[CH:34][NH:33][N:32]=2)=[O:30])=[CH:24][CH:23]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CS(C)=O.O>[F:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29]([C:31]2[C:35]([NH:36][C:3](=[O:18])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:10][CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)=[CH:34][NH:33][N:32]=2)=[O:30])=[CH:26][CH:27]=1
Reactant: Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Reactant: COC(=O)c1ccccc1OCCN1CCCC1
Agent: On1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1)c1ccccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 13.7 %

Procedure:
2-(2-Pyrrolidin-1-yl-ethoxy)-benzoic acid methyl ester (0.104 g, 0.42 mmol) was treated with 2 M aqueous NaOH (20 ml) and water (20 ml). The reaction mixture was stirred at room temperature for 20 hours, then reduced in vacuo and azeotroped with toluene (3×5 ml). Water (50 ml) was added and the mixture taken to pH 5 using 1M aqueous HCl. The resulting solution was reduced in vacuo and azeotroped with toluene (3×5 ml) to give a white solid, which was combined with 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)-amide (Example 2B) (0.055 g, 0.25 mmol), EDC (0.058 g, 0.3 mmol) and HOBt (0.041 g, 0.3 mmol) and stirred at room temperature in DMSO (3 ml) for 20 hours. The reaction mixture was poured into water (30 ml) and the resultant solid was collected by filtration and dried in a vacuum oven to give the title compound as a grey solid (0.015 g, 14%). (LC/MS: Rt 2.18, [MH]+ 438.06).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21])[CH:9]=[O:10])[CH3:4].O1CCCC1.CO>O>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:19][C:20]=1[CH3:21])[CH2:9][OH:10])[CH3:4]
Reactant: CCOc1cc(C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCOc1cc(CO)ccc1OCc1nc(-c2ccccc2)oc1C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
Sodium borohydride (378 mg) was added slowly to a mixture of 3-ethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (3.37 g), tetrahydrofuran (50 ml) and methanol (50 ml) at room temperature, which was stirred for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated to obtain 3-ethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol (3.28 g, yield 97%) as colorless crystals. This was recrystallized from tetrahydrofuran-hexane. Melting point: 130–131° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:21]C=O)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.Cl.C(OCC)C>CO>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:21])[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: O=CNc1ccc2ncnc(N3CCc4ccc(Cl)cc43)c2c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Nc1ccc2ncnc(N3CCc4ccc(Cl)cc43)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-[4-(6-Chloro-2,3-dihydro-indol-1-yl)-quinazolin-6-yl]-formamide (1.0055 g, 3.10 mmol) was slurried into 20 mL methanol, treated with 20 mL 1N HCl in methanol, and stirred at room temperature for one hour. Dilution to 125 mL with diethyl ether afforded yellow solid, 0.8430 g (82%; another 0.089 g obtained from subsequent cooling of mother liquor): M.P. 289°-290° C. (dec); LC-MS: 297 (MH+), 299 ((M+2)H+).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C@@H:2]([CH3:4])[OH:3].I[CH2:9][CH2:10][CH3:11]>>[CH2:9]([O:3][CH:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])[CH2:10][CH3:11]
Reactant: COC(=O)[C@@H](C)O
Reactant: CCCI
Product: CCCOC(C)C(=O)OC
Reaction time: 1 h
Yield: 71.7 %

Procedure:
160 g of methyl D-lactate and 524 g of 1-iodopropane were mixed in a four-necked flask, and 471 g of freshly prepared Ag2O was gradually added. Then, the mixture was stirred at 60°-65° C. for 1 hour and subjected to filtration. The filtrated product was washed with ether and the ether was distilled off from the filtrate, which was then distilled in vacuo to obtain 161 g of methyl 2-propoxypropionate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22]O>>[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][O:15][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9](=[O:10])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O
Reactant: OCc1cccs1
Product: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)OCc1cccs1

Procedure:
Following General Procedure C above, and using N-(3-chlorophenylacetyl alanine (from Example D above) and 2-thiophenemethanol (Aldrich) the title compound can be prepared. The reaction was monitored by tlc on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:26]=1[NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])[O:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([C:18]([O:20]C)=[O:19])[CH:16]=2)[N:11]=[CH:10][CH:9]=1.Cl>CO>[Cl:3][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:26]=1[NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])[O:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=2)[N:11]=[CH:10][CH:9]=1
Reactant: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)OC)cc23)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)O)cc23)cc1Cl
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 93.7 %

Procedure:
After adding methanol (14 ml) and 2N sodium hydroxide aqueous solution (7 ml) to methyl 4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylate (1.50 g, 3.49 mmol), the mixture was stirred at 60° C. for 90 minutes. The reaction solution was allowed to cool to room temperature, and after neutralization by addition of 2N hydrochloric acid, the methanol was distilled off and the precipitated white crystals were filtered out, thoroughly washed with water and dried at 60° C. to obtain the title compound (1.36 g, 3.27 mmol, 94%).
Reaction SMILES: [CH3:1][C@H:2]([OH:6])[CH2:3][C:4]#[CH:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.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>[F:7][C:8]1[C:9]([C:5]#[C:4][CH2:3][C@@H:2]([OH:6])[CH3:1])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CC[C@H](C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC[C@H](C)O)c21

Procedure:
Using Method C above, (S)-pent-4-yn-2-ol (44 mg, 0.52 mmol) (see below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg, 0.01 mmol) and Cul (2 mg) in a mixture of DMF (5 mL) and Et3N (5 mL) as a solvent at 80° C. for 7 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-1,3-Dihydro-5-fluoro-4-(4-hydroxy-1-pentynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-70% EtOAc in hexanes gradient and trituration with Et2O. (Yield 30 mg, 65%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH:11]3[O:15][C:16](=[O:18])[CH:17]=[C:10]23)=[CH:4][CH:3]=1.[C:19]([Li])(C)(C)C.CI>O1CCCC1.CCCCC>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C:11]3([CH3:19])[O:15][C:16](=[O:18])[CH:17]=[C:10]23)=[CH:4][CH:3]=1
Reactant: O=C1C=C2C(CCCN2Cc2ccc(Cl)nc2)O1
Reactant: [Li]C(C)(C)C
Solvent: CI
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC12CCCN(Cc3ccc(Cl)nc3)C1=CC(=O)O2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
43 mg (0.16 mmol) of 4-[(6-chloropyridin-3-yl)methyl]-5,6,7,7a-tetrahydrofuro[3,2-b]pyridin-2(4H)-one (1-2) are dissolved in 2.5 ml of tetrahydrofuran, the mixture is cooled to −78° C. and 96 μl (0.16 mmol) of a 1.7M solution of tert-butyllithium in pentane are added. After 30 minutes of stirring at −78° C., 15 μl (0.24 mmol) of methyl iodide are added, and the mixture is stirred at −78° C. for a further 30 min, warmed to room temperature and stirred at room temperature for a further 3 hours. Concentration under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase ethyl acetate gives 16 mg (35% of theory) of 4-[(6-chloropyridin-3-yl)methyl]-7a-methyl-5,6,7,7a-tetrahydrofuro[3,2-b]pyridin-2(4H)-one.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:13]O)=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.S(Cl)([Cl:17])=O.O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:17][CH2:13][C:3]1[C:2]([CH3:1])=[N:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=1
Reactant: Cc1nn(-c2ccccc2)nc1CO
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1nn(-c2ccccc2)nc1CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
5.0 g of (5-methyl-2-phenyl-1,2,3-triazol4-yl)methan-1-ol was dissolved in 35 ml of dichloromethane, then 6.3 g of thionyl chloride was added dropwise thereto under cooling with ice. After stirring for 1 hour at room temperature, 100 ml of water was added. The resulting solution was made alkaline with 8 g of potassium carbonate, then extracted with chloroform. The organic phase was washed with water and a saturated salt solution, then dried over anhydrous sodium sulfate. After the solvent was distilled off, 5.2 g of the aimed compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].[OH-].[K+].Br[CH:13]([CH3:19])[C:14]([O:16]CC)=[O:15]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH:13]([CH3:19])[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)C(C)Br
Reactant: Sc1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(Sc1ccc(Cl)cc1Cl)C(=O)O
Temperature: 25 °C
Yield: 25 %

Procedure:
A mixture of 11.78 g of 2,4-dichlorothiophenol and 12.0 g of potassium hydroxide in 50 ml of acetone was stirred and heated to reflux. 11.77 g of ethyl 2-bromopropionate were added gradually and the mixture was heated under reflux for 22 hours. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated to dryness. The residue was taken up in 400 ml of diethyl ether and the solution was washed with 400 ml of water and 400 ml of 10% sodium carbonate solution, dried over anhydrous sodium sulfate and evaporated to dryness. A solution of the residue in a mixture of 30 ml of ethanol and 17 ml of 10% potassium hydroxide solution was heated under reflux for 21 hours. The solution was evaporated to dryness and the residue was dissolved in 50 ml of water. The resulting solution was washed twice with 50 ml of diethyl ether each time and then acidified with concentrated hydrochloric acid and extracted twice with 150 ml of ethyl acetate each time. The combined organic extracts were washed twice with 200 ml of water each time, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was recrystallized from diethyl ether to give 4.08 g of 2(RS)-(2,4-dichlorophenyl-thio)propionic acid in the form of a yellow solid of melting point 95°-98° C.
Reaction SMILES: [CH:1]1([C:5]2[O:9][C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([CH:23]5[CH2:28][O:27][CH:26]([CH2:29][C:30]([O:32]CC6C=CC=CC=6)=[O:31])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)=[CH:13][CH:12]=3)=[N:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH:1]1([C:5]2[O:9][C:8]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([CH:23]5[CH2:28][O:27][CH:26]([CH2:29][C:30]([OH:32])=[O:31])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[N:7][N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(CC1CCC(c2ccc(-c3ccc(Nc4nnc(C5CCC5)o4)cc3)cc2)CO1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(O)CC1CCC(c2ccc(-c3ccc(Nc4nnc(C5CCC5)o4)cc3)cc2)CO1

Procedure:
Benzyl 2-(5-(4′-((5-cyclobutyl-1,3,4-oxadiazol-2-yl)amino)-[1,1′-biphenyl]-4-yl)tetrahydro-2H-pyran-2-yl)acetate was dissolved in EtOAc and hydrogenated with 10% Pd(OH)2/C under H2 balloon for 1 hr. The reaction mixture was filtered off to remove the catalyst and the filtrate was concentrated. The residue was purified by reverse HPLC (10 to 50% ACN-water (0.1% NH4OH) with X-bridge C8 column) to give the title compound 19.8 mg. HR/MS [M+H]+: found 434.2060, calc. 434.2080. RT: 2.61 (Condition L). The ratio of cis to trans was determined to be ˜1.1:1 by NMR studies. cis-isomer: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33-1.47 (m, 1H), 1.51-1.62 (m, 1H), 1.86-2.13 (m, 4H), 2.27-2.46 (m, 6H), 2.83 (t, J=3.79 Hz, 1H), 3.62-3.79 (m, 2H), 3.81-3.94 (m, 1H), 4.02 (dd, J=11.62, 3.28 Hz, 1H), 7.48 (d, J=8.34 Hz, 2H), 7.53-7.68 (m, 6H), 10.50 (br. s., 1H). trans-isomer 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31-1.47 (m, 1H), 1.73-2.13 (m, 5H), 2.24-2.46 (m, 6H), 2.75 (ddd, J=11.37, 7.45, 4.17 Hz, 1H), 3.35-3.44 (m, 1H), 3.62-3.79 (m, 2H), 3.81-3.94 (m, 1H), 7.32 (d, J=8.34 Hz, 2H), 7.53-7.68 (m, 6H), 10.50 (br. s., 1H).
Reaction SMILES: [C:1](=[O:3])=[O:2].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[CH:17]=[CH:16][C:15]=2Br)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[Mg].Cl.[OH-].[Na+]>O1CCCC1.O>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[CH:17]=[CH:16][C:15]=2[C:1]([OH:3])=[O:2])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(-c2c(Br)ccc3cc(Cl)ccc23)cc1OC
Reactant: O=C=O
Agent: Cl
Agent: [Mg]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2c(C(=O)O)ccc3cc(Cl)ccc23)cc1OC

Procedure:
Dry carbon dioxide from -5° to 0° is introduced into a solution consisting of 20,0 g of 1-(3,4-dimethoxyphenyl)-6-chloro-2-bromomagnesium naphthalene in 110 ml of tetrahydrofurane, made from 18,8 g of 1-(3,4-dimethoxyphenyl)-6-chloro-2-bromonaphthalene and 1,2 of magnesium. The introduction of carbon dioxide is continued for one hour after the exothermic reaction is finished. While cooling, 30 ml of 10% hydrochloric acid and thereafter 200 ml of water are then added dropwise, and the acid reaction solution is rendered alkaline with concentrated sodium hydroxide solution and extracted twice with 150 ml of ether each time. The aqueous phase is adjusted to pH 1 with 20% hydrochloric acid. The acid which precipitates is filtered off, washed with a small amount of water and dried in a vacuum drying cabinet at 80°. M.p. of the beige title compound >200°.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14](F)[CH:13]=[C:12]([N:17]([CH3:19])[CH3:18])[N:11]=2)[CH2:6][CH2:5]1)(=O)C.[CH3:20][O-:21].[Na+].O>CO>[CH3:19][N:17]([CH3:18])[C:12]1[CH:13]=[C:14]([O:21][CH3:20])[N:15]=[C:10]([N:7]2[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]2)[N:11]=1
Reactant: CC(=O)N1CCN(c2nc(F)cc(N(C)C)n2)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(N(C)C)nc(N2CCNCC2)n1
Yield: 123.9 %

Procedure:
1-Acetyl-4-(6-(dimethylamino)-4-fluoropyrimidin-2-yl)piperazine (1.0 g) obtained in Example 109(1) and sodium methoxide (1.1 g) were refluxed under heating in methanol (10 ml) for 28 hr. The reaction mixture was poured into water (100 ml) and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated to give the title compound (1.1 g) as a pale-yellow oil.