Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[CH3:7][O:8][C:9]([CH:11]([NH:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([N+:21]([O-:23])=[O:22])[C:15]=1[CH3:24])[CH3:12])=[O:10]>>[CH3:7][O:8][C:9]([CH:11]([N:13]([C:4](=[O:5])[CH2:3][O:2][CH3:1])[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([N+:21]([O-:23])=[O:22])[C:15]=1[CH3:24])[CH3:12])=[O:10]
Reactant: COC(=O)C(C)Nc1c(C)ccc([N+](=O)[O-])c1C
Reactant: COCC(=O)Cl
Product: COCC(=O)N(c1c(C)ccc([N+](=O)[O-])c1C)C(C)C(=O)OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
15.2 g of methoxyacetyl chloride are added dropwise at room temperature to 32 g of N-(1'methoxycarbonylethyl)-2,6-dimethyl-3-nitroaniline. After the weakly exothermic reaction has subsided, the reaction solution is stirred for 20 hours at room temperature. The solvent is then removed and the dark red oily residue is distilled in a high vacuum. Compound 28 distills at a temperature of 170°-174° C. and a pressure of 0.07 mbar as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccn2)CC1

Procedure:
A mixture of tert-Butyl-4-hydroxy-1-piperidine-carboxylate (2.0 g, 9.64 mmol) and 2-Fluoropyridine (0.93 mL, 10.6 mmol) in DMF (10 mL) is treated with 60% NaH in mineral oil (600 mg, 12.5 mmol) at RT. After completion, the reaction mixture is quenched by H2O, EtOAc is added and the organic layer is washed with brine, dried over MgSO4 and evaporated in vacuo. Silica gel flash chromatography of the residue affords the title compound as a white powder; ES-MS: M+H=279.0: DtRet=2.82.
Reaction SMILES: O[C:2]([CH3:11])([CH2:7][CH2:8][CH:9]=[CH2:10])[CH2:3][C:4](O)=[O:5].C([O-])(=O)C.[K+].C1(C)C=CC=CC=1>C(OC(=O)C)(=O)C>[CH3:11][C:2]1[C@H:3]2[C@H:9]([CH2:10][C:4]2=[O:5])[CH2:8][CH:7]=1
Reactant: C=CCCC(C)(O)CC(=O)O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC1=CC[C@H]2CC(=O)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Hydroxy-3-methylhept-6-enoic acid (5.24 g, 36.4 mmol) was dissolved in acetic anhydride (40 mL). To the solution, potassium acetate (12.52 g, 127 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was heated to reflux and stirred for 4 hours. To the reaction solution, ice water and toluene were then added, and this mixture was stirred overnight at room temperature. The mixture was separated into aqueous and organic layers by the addition of diethyl ether and saturated saline. Then, the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to obtain the compound of interest as a pale yellow oil substance (1.10 g, 17%, diastereomeric mixture).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9](CC3C=CC(OC)=CC=3OC)[CH:10]=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:9][CH:10]=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(Cn2cnc(-c3ccc(F)cc3)c2-c2ccnc(Br)c2)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(-c2nc[nH]c2-c2ccnc(Br)c2)cc1
Yield: 64.5 %

Procedure:
2-Bromo-4-[3-(2,4-dimethoxy-benzyl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyridine (720 mg, 1.54 mmol) is dissolved in DCM (12 mL) and trifluoroacetic acid (3.0 mL) is added at room temperature. The mixture is stirred for 60 hrs before saturated NaHCO3 aqueous solution is used to adjust the pH to about 7.5. Then the mixture is extracted with EtOAc (3×30 mL). The organic layers are combined and concentrated to give the crude product. The crude is purified by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) to give 316 mg of desired product.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:4][NH:3]1.[CH2:17]([N:20]=[C:21]=[O:22])[CH:18]=[CH2:19]>O1CCCC1.O>[CH3:1][C@H:2]1[C@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)[CH2:4][N:3]1[C:21]([NH:20][CH2:17][CH:18]=[CH2:19])=[O:22]
Reactant: C[C@@H]1NC[C@H]1Oc1cccc(C(F)(F)F)c1
Reactant: C=CCN=C=O
Solvent: C1CCOC1
Solvent: O
Product: C=CCNC(=O)N1C[C@@H](Oc2cccc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 16 h
Yield: 8.5 %

Procedure:
A solution of 6 g (0.015 mole) of crude trans-2-methyl-3-[3-(trifluoromethyl)phenoxy]azetidine (56.6%) in 50 ml of tetrahydrofuran was treated with 1.54 g (0.0165 mole) of 2-propenyl isocyanate all at once and stirred under a blanket of nitrogen for 16 hr. The reaction mixture was diluted with water until an oil separated. The oil failed to crystallize and after 7 weeks it was triturated with isopropyl ether (3×25 ml). The combined triturates gave 400 mg of white granular crystals (8.5%), m.p. 55°-57° C.
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3B2OC(C)(C)C(C)(C)O2)=[N:8][N:9]=1)([CH3:3])[CH3:2].Br[C:39]1[CH:40]=[N:41][CH:42]=[C:43]([CH:47]=1)[C:44]([OH:46])=[O:45].O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=2)(=[O:20])=[O:21])[CH:14]=[C:13]3[C:39]2[CH:40]=[N:41][CH:42]=[C:43]([CH:47]=2)[C:44]([OH:46])=[O:45])=[N:8][N:9]=1)([CH3:3])[CH3:2]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C(=O)O)c3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 90 °C
Yield: 75.7 %

Procedure:
To a solution of N-isopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (4.0 g, 7.662 mmol) and 5-bromonicotinic acid (2.3 g, 11.49 mmol, Sigma-Aldrich) in DME (75 mL)/water (18 mL) was added Na2CO3 (2.7 g, 22.98 mmol) and Pd(PPh3)4 (878 mg, 0.76 mmol) and Ar gas was bubbled for 5 min. The reaction mixture was heated at 90° C. for 4 h. The reaction was quenched with water (200 mL) to get a brown precipitate. The precipitate was filtered, washed with water (2×100 mL) and dried to give crude product (3.0 g), which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 518.2 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[C:5]([N:16]2[CH2:21][CH2:20][CH:19]([C:22](O)=[O:23])[CH2:18][CH2:17]2)[N:4]=1.C(O)(C(F)(F)F)=O.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH2:37].Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[C:5]([N:16]2[CH2:17][CH2:18][CH:19]([C:22]([NH:37][CH2:36][C:35]3[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=3[C:33]([F:32])([F:42])[F:43])=[O:23])[CH2:20][CH2:21]2)[N:4]=1
Reactant: CNc1nc(N2CCC(C(=O)O)CC2)nc(N2CCN(C)CC2)n1
Reactant: NCc1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)nc(N2CCN(C)CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
A solution of 1-[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3,5-triazin-2-yl]-4-piperidinecarboxylic acid as the TFA salt (44.7 mg, 0.100 mmol, 1.00 equiv), 2-trifluoromethyl benzylamine (26.6 mg, 0.150 mmol, 1.50 equiv) and DMAP (3.3 mg, 0.26 equiv) in dichloromethane (1 ml) was cooled in an ice bath. 1-Ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI, 32 mg, 0.17 mmol, 1.7 equiv) was added. The reaction mixture was stirred at room temperature for 2 h. The solution was diluted with dichloromethane (1 ml) and washed with saturated sodium bicarbonate and water. The solvent was removed, and the residue was purified by reverse-phase HPLC to give the title compound (66 mg, 82.5% yield). MS (ES+): m/e 493.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.Cl.Cl.[NH2:22][CH:23]1[CH2:30][CH:29]2[N:31]([CH3:32])[CH:25]([CH2:26][CH2:27][CH2:28]2)[CH2:24]1>>[CH3:32][N:31]1[CH:25]2[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:30][CH:23]([NH:22][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:10]3[O:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:12][C:11]=13)=[O:19])[CH2:24]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cccc2oc(-c3ccc(Cl)cc3)nc12
Agent: Cl
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4ccc(Cl)cc4)nc13)C2
Yield: 16 %

Procedure:
N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-chlorophenyl)benzoxazole-4-carboxamide was prepared from 2-(4-chlorophenyl)benzoxazole-4-carboxylic acid and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride using the method outlined in Step C of Example 14. This compound was obtained in 16% yield as a white solid: mp 185-187° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.72 (d, J=7.7 Hz, 1H), 8.27 (d, J=8.5 Hz, 2H), 7.99 (d, J=8.1 Hz, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.76 (d, J=8.5 Hz, 2H), 7.56 (t, J=8.0 Hz, 1H), 4.01 (m, 1H), 3.02 (m, 2H), 2.44 (s, 3H), 2.41 (m, 2H), 2.09 (m, 1H), 1.97 (m, 2H), 1.47 (m, 3H), 1.00 (m, 2H); MS (ESI) m/z 410 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1B1OC(C)(C)C(C)(C)O1>>[C:23]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[C:26]([C:2]2[CH:16]=[CH:15][CH:14]=[C:4]([CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=2)[CH:25]=1)#[N:24]
Reactant: CC(C)(C)OC(=O)NCc1cccc(Br)c1
Reactant: COc1ccc(C#N)cc1B1OC(C)(C)C(C)(C)O1
Product: COc1ccc(C#N)cc1-c1cccc(CNC(=O)OC(C)(C)C)c1
Yield: 67.4 %

Procedure:
Proceeding as in Reference 19, but substituting tert-butyl (3-bromo-benzyl)-carbamate (0.9 g, 3.2 mmol) and 4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (0.9 g, 3.5 mmol), gave tert-butyl (5′-cyano-2′-methoxybiphenyl-3-ylmethyl)carbamate (0.73 g, 68%) as white foam.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[Br:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH:15]=O)[CH:10]=1>CO>[Br:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](/[CH:15]=[N:1]/[CH:2]2[CH2:6][CH2:5][NH:4][C:3]2=[O:7])[CH:10]=1
Reactant: O=Cc1cc(Br)ccn1
Reactant: NC1CCNC1=O
Solvent: CO
Product: O=C1NCCC1/N=C/c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.9 %

Procedure:
To a suspension of 3-aminopyrrolidin-2-one (2.83 g, 28.22 mmol) in methanol (100 mL) was added 4-bromopicolinaldehyde (5 g, 26.88 mmol) and 4 A molecular sieves (20 g, 26.88 mmol). The reaction mixture was stirred for 16 hours at room temperature and then filtered through a pad of Celite. The filtrate was concentrated to give 3-[(E)-(4-bromo-2-pyridyl)methyleneamino]pyrrolidin-2-one as a brown gum (3.09 g, 11.53 mmol). This was dissolved in THF (120 mL) and treated with phenyl vinyl sulfone (1.94 g, 11.53 mmol), silver acetate (1.92 g, 0.59 mL, 11.53 mmol) and DBU (1.72 mL, 11.53 mmol). The reaction mixture was stirred for 3 hours at room temperature and then filtered through a pad of Celite and washed with dichloromethane. The filtrate was concentrated at reduced pressure to give a brown foam (9.53 g). This was dissolved in THF (120 mL) at 0° C. and treated with 1.7 M potassium tert-butoxide in THF (51.93 mL, 88.28 mmol) dropwise over 5 minutes. The reaction mixture was stirred at 0° C. for 1.5 hours. The reaction was quenched by the addition of acetic acid (5.04 mL, 88.28 mmol) and then filtered, washed with dichloromethane and the filtrate concentrated at reduced pressure to give a brown gum. The product was purified by silica gel chromatography eluting with 0-10% methanol in ethyl acetate to give 2-(4-bromo-2-pyridyl)-1,7-diazaspiro[4.4]non-1-en-6-one as an orange solid (830 mg);
Reaction SMILES: [CH3:1]OS(OC)(=O)=O.[CH3:8][C:9]1[O:15][CH:14]=[CH:13][C:11](=[O:12])[C:10]=1[OH:16]>[OH-].[K+]>[CH3:1][O:16][C:10]1[C:11](=[O:12])[CH:13]=[CH:14][O:15][C:9]=1[CH3:8]
Reactant: Cc1occc(=O)c1O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Product: COc1c(C)occc1=O
Yield: 36749.8 %

Procedure:
Dimethylsulphate (3.8 ml, 5.05 g, 0.04 mmol) was added to a solution of maltol (5.0 g, 0.04 mmol) in 10% aqueous potassium hydroxide (22.5 ml). After stirring for 5h the reaction mixture was extracted into CH2Cl2 (x3). The organic extract was dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica gel 60 eluting with 60% ethyl acetate in hexane to give the title compound (2.06 g, 37%) as a pale yellow oil; νmax (film) 3080, 1620, and 1580 cm-1 ; δH (CDCl3) 2.3 (3H, s), 3.8 (3H, s), 6.3 (1H, d, J 6 Hz), 7.6 (1H, d, J 6 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.CN(C)C1C=CC=CC=1.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)c1ccccc1
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 74.8 %

Procedure:
To a mixture of 306 mg (purity: 99.0%; 1.84 mmol) of 4-hydroxy-3,6-dichloropyridazine and 830 mg (5.51 mmol) of 2-cyclopropyl-6-methylphenol were added dimethylaniline (2.76 g) and 331 mg (5.62 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 381 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 75%) and 3.4 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.7%) were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9](Cl)(=[O:11])=[O:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([Cl:19])[CH:21]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cc1ccc(Br)cc1
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Cc1ccc(Br)cc1)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.3 %

Procedure:
To a solution of (4-bromo-phenyl)-methanesulfonyl chloride (1.4 g, 5.2 mmol) in DCM (20 mL) at room temperature was added pyridine (1.26 mL, 15.6 mmol) followed by 3-chloroaniline (1.1 mL, 10.4 mmol) and the reaction was stirred at room temperature for 3 hours. 1 M aqueous HCl was added and then extracted with DCM, filtered through a separator, concentrated, dry loaded onto silica and purified by silica gel column chromatography (0-100% DCM in cyclohexane) to give C-(4-bromo-phenyl)-N-(3-chloro-phenyl)-methanesulfonamide (0.61 g, 1.68 mmol). 1H NMR (300 MHz, CDCl3): δ 7.49 (d, 2H), 7.26 (m, 1H), 7.13-7.15 (m, 4H), 6.96-6.98 (m, 1H), 6.31 (s, 1H), 4.31 (s, 2H).
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][C:24]=1[F:37])[CH2:2][CH2:3][CH3:4].O1CCCC1.[BH4-].[Na+]>CO>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][C:24]=1[F:37])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4′-{[7-butyl-5-oxo-4-(4-oxocyclohexyl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (2.61 g), tetrahydrofuran (10 mL) and methanol (10 mL) was added sodium borohydride (0.15 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless oil (2.14 g, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCOCCc1ccc(Br)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCOCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 3-[2-(4-bromophenyl)ethoxy]propanoate (Example 10a), 1.0 g) was dissolved in dichloromethane (10 mL) and treated with trifluoroacetic acid (2.5 mL). The mixture was stirred at room temperature for 3 hours, then concentrated in vacuo and azeotroped with dichloromethane (2×10 mL). The residue was taken up in dichlormethane (10 mL) and extracted with 1M sodium hydroxide (20 mL). The basic layer was washed with dichloromethane (20 mL) then acidified with 2M hydrochloric acid. The acidic layer was extracted with dichloromethane (2×20 mL). The organic layers were combined, washed with brine, dried over anhydrous magnesium sulphate, filtered and concentrated to yield the sub-titled compound (0.81 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:3](N2C=NC=N2)=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[Na].C(O)(=O)C.[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([O:26][C:3]1[C:2]([CH3:1])=[CH:7][NH:6][C:5](=[O:8])[N:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1c[nH]c(=O)nc1-n1cncn1
Reactant: OCc1ccccc1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1c[nH]c(=O)nc1OCc1ccccc1
Temperature: 100 °C
Yield: 67.9 %

Procedure:
1.06 g (6 mmol) of 5-methyl-4-(1,2,4-triazol-1-yl)-pyrimidin-2(1H)-one are added to a solution of 2.34 g (18 mmol) of sodium benzylate in 25 ml of dry benzyl alcohol and 25 ml of dry dimethylformamide are added. The mixture is heated for 2 hours with stirring to 100° C. The cooled solution is neutralized with acetic acid, concentrated and chromatographed on silica gel using ethylacetate/methanol 9/1. 880 mg (67.9% of theory) of 4-benzyloxy-5-methylpyrimidin-2(1H)-one are obtained with melting point 181°-182°C. 1H NMR (270 MHz, d6 -DMSO), δ[ppm]: 11.14 (s, 1H), 7.56 (d, 1H), 7.41 (m, 5H), 5.35 (s, 2H), 1.87 (s, 3H).
Reaction SMILES: [O-]CC.[Na+].[C:5]1([SH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:12][C:13]([F:31])([F:30])[C:14]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18](Cl)[CH:17]=[C:16]([C:26]([F:29])([F:28])[F:27])[N:15]=1>C(O)C>[F:30][C:13]([F:12])([F:31])[C:14]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([S:11][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:17]=[C:16]([C:26]([F:29])([F:28])[F:27])[N:15]=1
Reactant: Sc1ccccc1
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(Sc2ccccc2)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 65.5 %

Procedure:
To a mixture of 1.70 g (0.025 mol) of sodium ethoxide in 100 ml ethanol was added 2.74 g (0.025 mol) of thiophenol followed by 5.3 g (0.016 mol) of product of Example 19. The reaction mixture was held at reflux for 2 days and filtered. The filtrate was poured into water and extracted into ether. The ether extract was washed with 10% NaOH, dried (MgSO4) had concentrated to give 4.14 g (63.6%) of product as a solid; mp 58°-61° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[CH2:10]([O:12][C:13](=[O:16])[CH2:14]Cl)[CH3:11].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:10]([O:12][C:13](=[O:16])[CH2:14][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:11]
Reactant: CCOC(=O)CCl
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(OC)c1
Temperature: 0 °C

Procedure:
3-Methoxy-phenol (43.4 ml, 400 mmol) is dissolved in acetone (800 ml) and after addition of chloro-acetic acid ethyl ester (42.6 ml, 400 mmol) and K2CO3 (111 g, 800 mmol) the mixture is refluxed for 22 h. After cooling down to 0° C., the mixture is filtrated and the filtrate is evaporated under reduced pressure. The residue is diluted in ethyl acetate, cooled to 0° C. and washed with aqueous NaOH solution. The organic layer is dried over sodium sulfate and evaporated under reduced pressure.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:17])[C@H:6]([CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:7])[CH3:3].[C:18]([NH:25][C:26]([CH3:31])([C:28](O)=[O:29])[CH3:27])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:17])[C@H:6]([CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:7][C:28](=[O:29])[C:26]([NH:25][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:31])[CH3:27])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CCOC(=O)[C@@H](N)CSCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](CSCc1ccccc1)NC(=O)C(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of S-benzyl-L-cysteine ethyl ester hydrochloride (7.98 g, 29 mmol), BOC-α-methylalanine (5.89 g, 29 mmol), triethylamine (2.93 g, 29 mmol), 1-hydroxybenzotriazole (HOBT, 3.92 g, 29 mmol) and EDCI (5.57 g, 29 mmol) in methylene chloride (200 mL) is stirred under an argon atmosphere at room temperature overnight. The reaction mixture is evaporated to dryness and the residue is dissolved in ethyl acetate (200 mL). The solution is washed with water (50 mL), 1 N HCl (50 mL), water (50 mL), 5% sodium bicarbonate (50 mL), water (50 mL) and finally brine (25 mL). The solution is then dried over sodium sulfate, filtered and evaporated to dryness to give N-[2-(BOC-amino)-2-methylpropionyl]-S-benzyl-L-cysteine ethyl ester.