Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S-:4])[CH2:2][CH3:3].[Na+].Cl[C:7]1[C:20]2[C:11](=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][CH:14]=[N:13]3)[N:10]=[C:9]([CH3:21])[CH:8]=1>CO>[CH3:21][C:9]1[CH:8]=[C:7]([S:4][CH2:1][CH2:2][CH3:3])[C:20]2[C:11](=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][CH:14]=[N:13]3)[N:10]=1
Reactant: Cc1cc(Cl)c2ccc3cccnc3c2n1
Reactant: CCC[S-]
Agent: [Na+]
Solvent: CO
Product: CCCSc1cc(C)nc2c1ccc1cccnc12
Yield: 76.1 %

Procedure:
Solid sodium 1-propanethiolate (2.35 g, 24.0 mmol) was added to a 100 mL round-bottomed flask containing a solution of 4-chloro-2-methyl-[1,10]phenanthroline (1.10 g, 4.8 mmol) in methanol (50 mL). The reaction mixture was refluxed for 18 hours and allowed to reach room temperature. The solvent was removed in a rotary evaporator and the residue was treated with methylene choride (100 mL) and saturated NaHCO3 (100 mL) and transferred to a separatory funnel. The organic layer was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The solid residue was treated with ethyl ether, filtered, and dried yielding 0.98 g of a dark orange solid (76%).
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22].C(N(CC)CC)C>C(Cl)Cl>[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCCCCCC/C=C\CCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oleyl alcohol (26.8 grams) is placed in a three-neck flask under a blanket of nitrogen. The entire reaction contents are cooled in an ice bath. Methacryloyl chloride (10.5 grams) dissolved in about 50 mL of methylene chloride is added slowly to the cooled oleyl alcohol with vigorous stirring in about 2 hours. Triethylamine (11.5 g) dissolved in 25 mL of methylene chloride is subsequently added in about an hour. After addition of triethylamine, the solution is allowed to warm to ambient temperature and is stirred for another 4 hours in order to complete the reaction. The precipitated triethylammonium chloride is removed by filtration, and the filtrate is washed with brine solution (saturated NaCl) followed by washings with dil. NaOH and dil. HCl. The organic layer is dried with anhydrous magnesium sulfate and the solvent is removed in vacuo to yield oleyl methacrylate in good yields. Oleyl methacrylate is stabilized from polymerization by addition of approximately 10 ppm hydroquinone. The structure of the product is verified by 1H and 13C NMR spectroscopy.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1.C1(N=C=NC2CCCCC2)CCCCC1.N1C=CC=CC=1.FC(F)(F)C(O)=O.C(O)(=O)C(O)=O>CS(C)=O.CO.O>[O:8]([CH:7]1[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH2:3][C:2]1=[O:1])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](Oc2ccccc2)[C@H](O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C1CN(C(=O)OCc2ccccc2)CCC1Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
15.0 g (0.045 mol) of the trans-3-hydroxy-4-phenoxy-1-carbobenzyloxy-piperidine described in Example 14 are dissolved, together with 28.34 g (0.13 mol) of dicyclohexylcarbodiimide and 3.7 ml (0.045 mol) of pyridine, in 80 ml of dry dimethylsulphoxide. The mixture is cooled to 0° with an ice-water bath and treated with 2.6 g (0.023 mol) of trifluoroacetic acid. The cooling bath is removed again and the reaction mixture is stirred for a further 4 hours at room temperature in a nitrogen atmosphere. The white suspension is diluted with 250 ml of ethyl acetate and treated dropwise with a solution of 12.3 g (0.13 mol) of oxalic acid in 200 ml of methanol. After the evolution of gas has ceased, the reaction mixture is cooled to 0° in an ice-water bath and diluted with 400 ml of water and the dicyclohexylurea which has precipitated is separated off. The aqueous phase of the filtrate is extracted with 250 ml of ethyl acetate and the combined organic phases are dried over sodium sulphate and evaporated to dryness under a water pump vacuum. The resulting crude product is dissolved in benzene and the solution is filtered through a layer of silica gel. 4-Phenoxy-1-carbobenzyloxy-3-piperidone is obtained in the form of a pale yellow oil by elution with a benzene/ethyl acetate mixture (95:5).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=2)[CH2:5][CH2:4]1.C(O)(=O)C.C(N(CC)CC)C.[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][C:33]=1[O:40][CH2:41][CH3:42].C([BH3-])#N.[Na+]>C(O)C>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:3]2[CH2:4][CH2:5][CH:6]([NH:9][C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=3)[CH2:7][CH2:8]2)=[CH:34][C:33]=1[O:40][CH2:41][CH3:42]
Reactant: CC(=O)Nc1cccc(NC2CCNCC2)c1
Reactant: CCOc1cc(C=O)ccc1Cl
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(Nc3cccc(NC(C)=O)c3)CC2)ccc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
To a solution of N-[3-(piperidin-4-ylamino)-phenyl]-acetamide dihydrochloride (61.2 mg, 0.2 mmol, 1.0 equiv; intermediate B1), acetic acid (60.1 mg, 1.0 mmol, 5.0 equiv) and triethylamine (40.5 mg, 0.4 mmol, 2.0 equiv) in ethanol (1 mL) was added 4-chloro-3-ethoxy-benzaldehyde (46.1 mg, 0.25 mmol, 1.25 equiv; intermediate E2, vide infra) and the mixture stirred at 50° C. After 1 h, sodium cyanoborohydride (15.1 mg, 0.24 mmol, 1.2 equiv), dissolved in ethanol (1 mL), was added and the mixture stirred at 50° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 10.0 mg (12%) of the title compound. MS (ISP): 402.3 [M+H]+.
Reaction SMILES: O.NN.[F:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1/[CH:13]=[CH:14]/[CH2:15][N:16]1C(=O)C2C(=CC=CC=2)C1=O.Cl>CCO>[F:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1/[CH:13]=[CH:14]/[CH2:15][NH2:16]
Reactant: COc1ccc(F)c(/C=C/CN2C(=O)c3ccccc3C2=O)c1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(F)c(/C=C/CN)c1
Temperature: 0 °C

Procedure:
Hydrazine hydrate (88%)(358 mg, 6.3 mmol) was slowly added to a stirring solution of trans - 2-[3-(2-fluoro-5-methoxyphenyl)prop-2-en-1-yl]-isoindole-1,3-dione (650 mg, 2.1 mmol) in EtOH (40mL) and the solution was heated to reflux for 5 h. The resulting mixture was made acidic (pH<2.0) (10N HCl) followed by heating on a steam bath for 60 min. Cooling of the suspension to 0° C. precipitated the hydrazide which was filtered off, the filtrate was then diluted with H2O (20 mL) and extracted with EtOAc(2×). The aqueous layer was made basic (50% NaOH), and extracted with Et2O(3×). The ethereal layers were combined, washed with brine, dried over MgSO4, and concentrated to give a crude white wax. Purification by Kugelrohr distillation afforded the titled compound as a clear oil, 380 mg, quantitative: 1H NMR (300 MHz, CDCl3) δ 1.49 (s, 2H, br), 3.43 (m, 2H), 3.71 (s, 3H), 5.75 (m, 1H), 6.28 (d, J=11.4 Hz, 1H), 6.65 (m, 2H), 6.90 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:37][C:38](=[NH:57])[C:39]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:40]=1[CH:41]=[N:42][N:43]2[CH2:48][C:49]([CH3:56])([CH3:55])[C:50]([O:52][CH2:53][CH3:54])=[O:51]>CN(C)C=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:14][N:37]=[C:38]([C:39]3[CH:47]=[CH:46][CH:45]=[C:44]4[C:40]=3[CH:41]=[N:42][N:43]4[CH2:48][C:49]([CH3:55])([CH3:56])[C:50]([O:52][CH2:53][CH3:54])=[O:51])[N:57]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Reactant: CCOC(=O)C(C)(C)Cn1ncc2c(C(=N)NO)cccc21
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOC(=O)C(C)(C)Cn1ncc2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)cccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (D31) (70.9 mg, 0.329 mmol), triethylamine (0.092 ml, 0.657 mmol), HOBT (60.4 mg, 0.394 mmol) then EDC (76 mg, 0.394 mmol) followed by ethyl 3-{4-[(hydroxyamino)(imino)methyl]-1H-indazol-1-yl}-2,2-dimethylpropanoate (D103) (100 mg, 0.329 mmol) were dissolved in N,N-Dimethylformamide (DMF) (5 ml). The resulting mixture was stirred at 50° C. overnight then cooled to room temperature and diluted in EtOAc. The organic phase was washed with H2O, dried and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel [15-40% EtOAc/cyclohexane] gave the title compound (30 mg, 17%) as a light yellow solid. MS (ES) C24H26ClN5O4 requires 483, found 484 [M+H]+
Reaction SMILES: Cl.[CH2:2]([N:6]1[C:10](CC#N)=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=[C:7]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][CH2:4][CH3:5].O.[C:27]([O:30][CH2:31]C)(=[O:29])[CH3:28]>CO>[CH3:31][O:30][C:27](=[O:29])[CH2:28][C:10]1[N:6]([CH2:2][CH2:3][CH2:4][CH3:5])[C:7]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:8][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(C)=O
Reactant: CCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1CC#N
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1CC(=O)OC
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Hydrogen chloride gas is bubbled into solution of (3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetonitrile (187) (640 mg, 2.03 mmol) in methanol (30 mL) at 0° C. for 10 minutes, followed by stirring for 30 minutes. Water (0.0365 ml, 2.03 mmol) is then added and the reaction refluxed at 80° C. for 2 hours. The methanol is then removed in vacuo, the reaction crude is dissolved in ethyl acetate (100 mL), and the organic layer is washed with saturated sodium bicarbonate (1×100 mL), brine (1×100 mL), and dried over magnesium sulfate. The sample is filtered, concentrated and purified by flash chromatography on SiO2 using an eluent of 2:3 ethyl acetate:hexane to afford (3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetic acid methyl ester (188) as a colorless oil.
Reaction SMILES: C(OC([N:8]([CH2:47][CH2:48][NH:49]C(OC(C)(C)C)=O)[CH:9]1[CH2:12][CH:11]([CH2:13][C:14]([NH:16][C@H:17]([B:34]2[O:42][CH:41]3[C:36]([CH3:46])([CH:37]4[CH2:43][CH:39]([CH2:40]3)[C:38]4([CH3:45])[CH3:44])[O:35]2)[CH2:18][C:19]2[C:20]([O:32][CH3:33])=[C:21]([CH:29]=[CH:30][CH:31]=2)[C:22]([O:24]C(C)(C)C)=[O:23])=[O:15])[CH2:10]1)=O)(C)(C)C.Cl>>[NH2:49][CH2:48][CH2:47][NH:8][CH:9]1[CH2:12][CH:11]([CH2:13][C:14]([NH:16][C@H:17]([B:34]2[O:42][CH:41]3[C:36]([CH3:46])([CH:37]4[CH2:43][CH:39]([CH2:40]3)[C:38]4([CH3:45])[CH3:44])[O:35]2)[CH2:18][C:19]2[C:20]([O:32][CH3:33])=[C:21]([CH:29]=[CH:30][CH:31]=2)[C:22]([OH:24])=[O:23])=[O:15])[CH2:10]1
Reactant: COc1c(C[C@H](NC(=O)CC2CC(N(CCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: Cl
Product: COc1c(C[C@H](NC(=O)CC2CC(NCCN)C2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O

Procedure:
Prepared from of tert-butyl 3-((R)-2-(2-(3-(tert-butoxycarbonyl(2-(tert-butoxycarbonylamino)ethyl)amino)cyclobutyl)acetamido)-2(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate (Step 4 of Example 55) and 4 N HCl following the procedure described in Step 1 of Example 53.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([Mg]Br)#[C:11][CH3:12].C1COCC1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[O:7])[C:10]#[C:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CC#C[Mg]Br
Reactant: O=Cc1ccc(Br)cc1
Solvent: C1CCOC1
Product: CC#CC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To an ice cold solution of 4-bromobenzaldehyde (1.3 g, 7 mmol) 0.5 M solution of propynyl magnesium bromide in THF (15 ml, 7.5 mmol) was added under N2. The mixture was stirred for 10 min, quenched with saturated NH4Cl solution and diluted to 50 ml with EtOAc. The organic layer was washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was dissolved in 1,4-dioxane (25 ml). To it MnO2 (2 g) was added and the resulting suspension was stirred for 4 h at reflux. The mixture was filtered through Celite pad and the filtrate was evaporated to dryness and dried in vacuo to give the title compound (1.29 g, 83%) as a pale solid. 1H-NMR (CDCl3) 7.97 (d, 2H, J=9 Hz); 7.61 (d, 2H, J=9 Hz); 2.14 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:5][CH2:4][O:3]1.[CH:17]1([C:20]2[CH:21]=[C:22]([CH3:32])[C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][CH:25]=2)[CH2:19][CH2:18]1>>[CH:17]1([C:20]2[CH:21]=[C:22]([CH3:32])[C:23]([N:26]3[CH2:27][CH2:28][N:29]([C:12]([C:11]4[CH:10]=[CH:9][C:8]([CH2:7][N:6]5[CH2:5][CH2:4][O:3][C:2]5=[O:1])=[CH:16][CH:15]=4)=[O:14])[CH2:30][CH2:31]3)=[N:24][CH:25]=2)[CH2:19][CH2:18]1
Reactant: O=C(O)c1ccc(CN2CCOC2=O)cc1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(CN3CCOC3=O)cc2)CC1
Yield: 42.3 %

Procedure:
Using 4-(2-oxooxazolidin-3-ylmethyl)benzoic acid (133 mg) described in Preparation Example 62 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (156 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 87, the title compound (107 mg) was obtained.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][N:14]2[C:19]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(N(CC)C(C)C)(C)C>C1COCC1.C(OCC)(=O)C.O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][N:14]2[C:19]([N:21]2[CH2:26][CH2:25][N:24]([S:28]([CH3:27])(=[O:30])=[O:29])[CH2:23][CH2:22]2)=[O:20])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2C(=O)N2CCNCC2)no1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2C(=O)N2CCN(S(C)(=O)=O)CC2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-1-(piperazine-1-carbonyl)-piperidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide (60 mg; 0.165 mmol) in THF (1 mL) is added methane sulfonyl chloride (0.013 mL; 0.17 mmol), followed by N,N-diisopropylethylamine (0.03 mL; 0.17 mmol). The mixture is stirred at room temperature for 18 hours. The mixture is diluted with ethyl acetate and water. The layers are separated and the organic layer is concentrated in vacuo. Purification by flash chromatography on silica gel using ethyl acetate/Hexanes provides the title compound, m/z 442 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11]N=C[N:8]=1.S1C(N)=N[CH:20]=[N:19]1.S1C=NN=C1N>>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][CH:20]=[N:19][N:8]=1
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: Nc1ncns1
Agent: Nc1nncs1
Product: COc1ccc(CNc2nncs2)c(OC)c1

Procedure:
N-(2,4-dimethoxybenzyl)-1,3,4-thiadiazol-2-amine (INTERMEDIATE Y) was prepared in a manner analogous to INTERMEDIATE A wherein 1,2,4-thiadiazol-5-amine was replaced with 1,3,4-thiadiazol-2-amine.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[C:6]([C:11](OC)=[O:12])=[N:7][CH:8]=[CH:9][CH:10]=1.CO>C(O)C>[OH:12][CH2:11][C:6]1[C:5]([O:4][CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: COC(=O)c1ncccc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: COc1cccnc1CO
Reaction time: 8 h
Yield: 57.5 %

Procedure:
Sodium borohydride (6.3 g) was added slowly over 75 minutes to a solution of 3-methoxy-2-methoxycarbonylpyridine (9.2 g) in ethanol. Methanol (100 ml) was then added and after the initial vigorous reaction had subsided, further sodium borohydride (8.3 g) was added over a further 3 hours, and the mixture was left to stand overnight. The solvent was evaporated, the residue dissolved in water and extracted with chloroform and the chloroform solution dried. Evaporation, and crystallisation from ether gave 2-hydroxymethyl-3-methoxypyridine (4.4 g) m.p. 72.5°-73.5°.
Reaction SMILES: [Cl:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13]>N1C=CC=CC=1>[Cl:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH:6][C:12](=[O:13])[O:14][CH2:15][CH3:16])=[C:4]([F:10])[CH:3]=1
Reactant: Nc1cc(F)c(Cl)cc1F
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cc(F)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4-Chloro-2,5-difluoroaniline (XXXIX) (2.1 g, 12.8 mmol) was mixed with pyridine (20 ml) at 0° C., to it was dropwise added ethyl chloroformate (1.5 g, 13.8 mmol). After stirring for 2.5 hr while temperature slowly raised to room temperature, pyridine was evaporated and the residue crystallized in ice-water (100 ml). The crystals were filtered, washed with water and dried in fume hood overnight (2.7 g). 1H NMR (CDCl3, 300 MHz) 1.33 (3H, t, J=7.1 Hz), 4.23 (2H, q, J=7.1 Hz), 6.89 (1H, br), 7.12 (1H, dd, J=6.5, 6.5 Hz), 8.05 (1H, dd, J=7.8, 9.6 Hz) ppm.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1.[CH2:24]([NH:27][CH3:28])[CH:25]=[CH2:26]>>[CH2:24]([N:27]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1)[CH3:28])[CH:25]=[CH2:26]
Reactant: C=CCNC
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1
Product: C=CCN(C)CCCCOc1ccc2c(-c3ccc(Br)cc3)c(C)sc2c1

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene and Allyl-methyl-amine were converted to yield Allyl-{4-[3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-methyl-amine, MS: 444 (MH+, 1Br).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH:11][C:12](=[O:27])[CH2:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][N:7]1[CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[CH:28]([N:7]1[CH2:8][C@@H:9]([NH:11][C:12](=[O:27])[CH2:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:6]1[C:4]([OH:5])=[O:3])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CCOC(=O)[C@@H]1C[C@H](NC(=O)CC(c2ccccc2)c2ccccc2)CN1C(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(CC(c1ccccc1)c1ccccc1)N[C@H]1C[C@@H](C(=O)O)N(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
To the solution of (2S,4S)-1-benzhydryl-4-(3,3-diphenyl-propionylamino)-pyrrolidine-2-carboxylic acid ethyl ester (37) (0.25 g, 0.5 mmol) in THF (15 ml), MeOH (5 ml) and water (5 ml) was added LiOH (0.1 g, 2.45 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue was neutralized with 2N HCl to pH˜2 and dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×), dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2: MeOH (10:1) to give 0.12 g of desired product.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][N:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:26])([C:22]([F:25])([F:24])[F:23])[CH:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[CH3:13])=[CH:7][C:6]1=[O:27].[OH-].[Na+].Cl>CO>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:12]([CH3:13])[C:11]([C:8]1[CH:9]=[CH:10][N:5]([CH2:4][C:3]([OH:28])=[O:2])[C:6](=[O:27])[CH:7]=1)([OH:26])[C:22]([F:23])([F:24])[F:25]
Reactant: COC(=O)Cn1ccc(C(O)(C(C)c2ccc(Cl)cc2Cl)C(F)(F)F)cc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccn(CC(=O)O)c(=O)c1)C(F)(F)F
Temperature: 55 °C
Reaction time: 2 h

Procedure:
{4-[2-(2,4-Dichloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-2-oxo-2H-pyridin-1-yl}-acetic acid methyl ester (Example 121, 40 mg) was dissolved in MeOH (1 mL), and treated with 1N NaOH (0.183 mL). The reaction mixture was stirred at 55° C. (Bath temperature) for 2 h. The reaction mixture was then cooled down to r.t., pH adjusted to pH2 by addition of 1N aqueous HCl, and the MeOH evaporated in vacuo. The resulting suspension was then extracted twice with ethyl acetate, the combined organic phases washed with brine, dried over MgSO4 and concentrated in vacuo, leading to the title compound as off-white solid (33 mg). MS (m/e)=424.1 (MH+).
Reaction SMILES: [CH:1]([N:14]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH2:22][OH:23])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]=[C:25]1[O:29][C:27](=[O:28])[CH2:26]1>>[C:27]([O:23][CH2:22][CH2:21][N:17]1[CH2:18][CH2:19][CH2:20][N:14]([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:15][CH2:16]1)(=[O:28])[CH2:26][C:25]([CH3:24])=[O:29]
Reactant: OCCN1CCCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: C=C1CC(=O)O1
Product: CC(=O)CC(=O)OCCN1CCCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 81.8 %

Procedure:
4-Benzhydrylhomopiperazine-1-ethanol (2.6 g) was reacted with diketene in the same manner as Reference Example 1-(2) to give 2-(4-benzhydrylhomopiperazin-1-yl)ethyl acetoacetate as an oil (2.7 g, 81.8%). IR(Neat): 1735, 1715 cm-1. NMR(CDCl3)δ: 1.6-1.9(2H, m), 2.26(3H, s), 2.5-2.9(10H, m), 3.40(2H, s), 4.20(2H, t, J=6), 4.57(1H, s), 7.1-7.5(10H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9](O)[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:15]N1C(=O)CCC1=O.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(Cl)Cl>[Br:15][CH:9]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: OC(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)C(Br)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 39.8 %

Procedure:
To a stirred solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanol (4.0 g, 16.3 mmol) in CH2Cl2 (50 mL), were added N-bromosuccinimide (NBS; 2.9 g, 16.3 mmol) and triphenyl phosphite (5.06 g, 16.3 mmol), and the resultant reaction mixture was heated at reflux for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to 25° C. and was concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 100% pentane) afforded the title compound as a liquid (2.0 g, 40%): 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 3H), 5.00 (m, 1H); EIMS m/z 306 GMT).