Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCCBr.[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]#[N:20])=[C:14]([F:21])[CH:13]=2)[CH:9]=[CH:10][CH:11]=1.BrCC([O-])=O.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.BrCC(OCC)=O.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+].[Zn].CC(O)=O>[NH2:20][CH:19]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[CH:7]=2)=[CH:13][C:14]=1[F:21])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: N#CCc1ccc(-c2cccc(Cl)c2)cc1F
Reactant: CCOC(=O)CBr
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])CBr
Agent: O=C([O-])[O-]
Solvent: BrCCBr
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)CC(N)Cc1ccc(-c2cccc(Cl)c2)cc1F
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
A suspension of zinc (479 mg, 7.33 mmol) and 1,2-dibromoethane (0.032 ml, 0.366 mmol) in THF (8 ml) is heated at 70° C. under nitrogen then a few drops of ethyl bromoacetate is added. After stirring for 20 min, a solution of 2-(3′-chloro-3-fluorobiphenyl-4-yl)acetonitrile (300 mg, 1.221 mmol) in THF (2 ml) is added in one portion. The remaining bromoacetate is added dropwise over 50 min (total amount of ethyl bromoacetate: 4.88 mmol). After stirring for 15 min at the same temperature, the reaction mixture is cooled to ambient temperature. To the reaction mixture, sodium triacetoxyborohydride (2588 mg, 12.22 mmol) and AcOH (8 ml) are added. The reaction mixture is allowed to stir for 13 hours, and concentrated to give crude. The crude is diluted with EtOAc, and 2M aqueous Na2CO3 is added to be pH of 10. The products are extracted with EtOAc. The organic layer is dried over K2CO3, filtered, and concentrated to give crude. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% NH4OH) to 100% MeCN to give ethyl 3-amino-4-(3′-chloro-3-fluorobiphenyl-4-yl)butanoate (148 mg) as orange oil; HPLC retention time=0.85 minutes (condition B); MS (m+1)=336.13; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J=7.1 Hz, 3 H) 2.36 (A of ABX, Jab=15.9 Hz, Jax=8.8 Hz, 1 H) 2.52 (B of ABX, Jab=15.9 Hz, Jbx=4.0 Hz, 1 H) 2.71-2.76 (m, 1 H) 2.82-2.87 (m, 1 H) 3.51-3.57 (m, 1 H) 4.15 (d, J=7.1 Hz, 2 H) 7.24-7.39 (m, 5 H) 7.42-7.44 (m, 1 H) 7.54-7.55 (m, 1 H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:31])[CH:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:22])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:49])[C@@H:15]2[CH2:32][CH2:33][C@H:34]2[O:39][C:38](=[O:40])[CH2:37][C@H:36]([O:41][Si](C(C)(C)C)(C)C)[CH2:35]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:31])[CH:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:22])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:49])[C@@H:15]2[CH2:32][CH2:33][C@H:34]2[O:39][C:38](=[O:40])[CH2:37][C@H:36]([OH:41])[CH2:35]2)=[CH:10]1
Reactant: Cc1ccccc1OC(C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccccc1OC(C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 62 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.03 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(2-methylphenoxy)propionyloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 121, above] and 30.9 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 434 mg of the title compound as white crystals, melting at between 85° and 87° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C@@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C@H:10]([C:21]([OH:23])=O)[CH2:9]1.[N:34]1([C:40]2[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=2[C:42]#[N:43])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[F:29][C:28]([F:31])([F:30])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:32])([F:1])[F:33])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C@@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[C@H:10]([C:21]([N:37]2[CH2:36][CH2:35][N:34]([C:40]3[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=3[C:42]#[N:43])[CH2:39][CH2:38]2)=[O:23])[CH2:9]1
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1C[C@@H](C(=O)O)N(Cc2ccc(Cl)cc2)C1
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1C[C@@H](C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccc(Cl)cc2)C1
Yield: 9 %

Procedure:
As described for Example 64e, (2S,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methyl-amino]-1-(4-chloro-benzyl)-pyrrolidine-2-carboxylic acid (1 mmol) was converted, using 2-piperazin-1-yl-benzonitrile instead of 2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one, to the title compound (60 mg) in 9% yield as colorless oil. MS m/e=665.1 [M+H]+.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:27])[CH:23]([CH3:26])[CH2:24][CH3:25])=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:27])[CH:23]([CH3:26])[CH2:24][CH3:25])=[O:19]
Reactant: CCC(C)C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCC(C)C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 2.5 h
Yield: 91.8 %

Procedure:
A mixture of (2S,5R)-6-(benzyloxy)-N′-(2-methylbutanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]-octane-2-carbohydrazide 247 (0.26 g, 0.69 mmol) and Pd/C (0.30 g) in methanol (80 mL) was hydrogenated at 1 atm at room temperature for 2.5 h. The mixture was filtered through Celite pad and concentrated to provide 248 (0.18 g) as an off-white solid which was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH2:16][OH:17])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.[CH2:18](Br)[C:19]#[CH:20]>>[CH3:1][C:2]1[N:3]([CH2:15][CH2:16][O:17][CH2:20][C:19]#[CH:18])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1
Reactant: C#CCBr
Reactant: Cc1nc2cnc3ccccc3c2n1CCO
Product: C#CCOCCn1c(C)nc2cnc3ccccc3c21
Yield: 77.1 %

Procedure:
Using the general method of Example 1 Part A, 2-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (4.0 g, 17.6 mmol) was reacted with propargyl bromide (80% in toluene, 5.9 mL, 52.8 mmol) to provide 3.6 g of 2-methyl-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline as a dark brown oil.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[CH:10]2)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[Na+].[Na+].[I:20]I.Cl>O.C1COCC1>[OH:13][C:9]1[C:10]([I:20])=[C:11]2[C:6]([CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:12]2)=[CH:7][CH:8]=1
Reactant: II
Reactant: N#Cc1ccc2ccc(O)cc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc2ccc(O)c(I)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
A mixture of 7-cyano-2-naphthol (22.3 g, 131.8 mmol), sodium carbonate (29.3 g, 277 mmol) and I2 (31.8 g, 125.2 mmol) in water (500 mL) and THF (80 mL) at 0° C. was stirred at room temperature for 3 h, acidified with 1M HCl and extracted with ethyl acetate. The extracts were washed with saturated Na2S2O3 and brine, dried (Na2SO4) and concentrated. The product was recrystallized from ethyl acetate to yield 33 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.O[N:37]=[C:38]([C:40]1[C:41]2[CH2:42][CH2:43][CH:44]([OH:49])[C:45]=2[CH:46]=[CH:47][CH:48]=1)[NH2:39].[Na+].[Cl-]>CN(C=O)C>[CH2:13]([O:12][C:11]1[CH:10]=[CH:9][C:5]([C:6]2[O:8][N:39]=[C:38]([C:40]3[CH:48]=[CH:47][CH:46]=[C:45]4[C:41]=3[CH2:42][CH2:43][CH:44]4[OH:49])[N:37]=2)=[CH:4][C:3]=1[C:1]#[N:2])[CH3:14]
Reactant: NC(=NO)c1cccc2c1CCC2O
Reactant: CCOc1ccc(C(=O)O)cc1C#N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc(-c3cccc4c3CCC4O)no2)cc1C#N
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
In a microwave vial, a stirring solution of 3-cyano-4-ethoxybenzoic acid (200 mg, 1.05 mmol) in DMF was treated with HOBt (185 mg, 1.36 mmol) and EDCI (260 mg, 1.36 mmol) at room temperature. The reaction was stirred for 20 min followed by addition, in a single portion, of N′,1-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide (261 mg, 1.36 mmol). The reaction was stirred for additional 30 min at room temperature and then heated to 130° C. for 35 min in the initiator. The reaction was diluted using a saturated solution of NaCl and extracted with EtOAc (80 ml×3). The organic phase was dried over Na2SO4 anhydrous and concentrated under reduced pressure. The product was purified by column chromatography using CH2Cl2:MeOH (9:1) to offer the product as pale yellow solid in 79% yield (274 mg).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:10]([C:12](OC)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].OS([O-])(=O)=O.[K+].[OH-].[Na+]>C1COCC1.O>[C:1]1([C:7]2[O:8][C:9]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:10]([CH2:12][OH:13])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1nc(-c2ccccc2)oc1-c1cccnc1
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1nc(-c2ccccc2)oc1-c1cccnc1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
To a solution of methyl 2-phenyl-5-(pyridin-3-yl)oxazole-4-carboxylate (1.33 g, 4.75 mmol) in THF (25 mL) was added dropwise at 0-5° C. lithium aluminum hydride (1M solution in THF, 4.75 mL, 4.75 mmol) over a period of 15 min. The reaction mixture was stirred at 0-5° C. for 1 h. Water (20 mL) was added dropwise over a period of 10 min. The reaction mixture was poured into KHSO4 (10% aqueous solution, 75 mL) and extracted with ethyl acetate (2×100 mL). The organic phase was washed with water (2×50 mL) and brine (1×50 mL), dried over MgSO4 and concentrated in vacuo to give 490 mg crude product. The combined aqueous phases were adjusted to pH 8 with NaOH (1M solution) and extracted with dichloromethane (3×100 mL). The dichloromethane phase was dried over MgSO4, filtered and evaporated to give 480 mg brown foam. The product was obtained after purification of the combined crude products by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as light brown solid (210 mg, 832 μmol, 17.5%).
Reaction SMILES: ClC(OCC)=O.[CH2:7]([O:9][C:10]([NH:12][CH2:13][C:14]([OH:16])=O)=[O:11])[CH3:8].C(N(CC)CC)C.[NH:24]([C:26]1[N:27]=[N:28][C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:30]([CH3:32])[N:31]=1)[NH2:25]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:7]([O:9][C:10]([NH:12][CH2:13][C:14]([NH:25][NH:24][C:26]1[N:27]=[N:28][C:29]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[C:30]([CH3:32])[N:31]=1)=[O:16])=[O:11])[CH3:8]
Reactant: CCOC(=O)NCC(=O)O
Reactant: Cc1nc(NN)nnc1-c1ccccc1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCC(=O)NNc1nnc(-c2ccccc2)c(C)n1
Reaction time: 0.08 h
Yield: 33.4 %

Procedure:
A solution of ethyl chloroformate (3.689 g) in methylene chloride (10 ml) was added dropwise to a stirred solution of N-ethoxycarbonylglycine (4.998 g) and triethylamine (3.434 g) in methylene chloride (60 ml) under cooling in 5 minutes, and the stirring was continued for 5 minutes under cooling. To the solution of the mixed anhydride was added a solution of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (3.417 g) in chloroform (40 ml) and reacted in a similar manner to that of Example 17-(1). The reaction mixture was washed with water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was dissolved in ethanol (50 ml) and a solution of sodium hydroxide (1.6 g) in water (10 ml) was added dropwise to the solution with stirring under ice cooling in 5 minutes. After stirring for 30 minutes at room temperature, the solution was evaporated, and the residue was dissolved in a small amount of water. The solution was salted out and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and evaporated. The residue was dissolved in chloroform containing a small amount of ethanol and the solution was chromatographed on silica gel (50 g). The eluent with a mixture of chloroform and ethanol (30:1) gave a colorless solid of 3-[2-(N-ethoxycarbonylglycyl)hydrazino]-5-methyl-6-phenyl-1,2,4-triazine (1.872 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][CH2:16]C(=O)[C@@H:14]2[C:19]2[CH:24]=[CH:23][C:22]([CH:25]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:21][CH:20]=2)=[CH:8][CH:9]=1)=[O:4].CCN(CC)CC.[CH:48]([Cl:51])(Cl)[Cl:49]>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][CH2:16][C:48]([Cl:51])([Cl:49])[C@@H:14]2[C:19]2[CH:20]=[CH:21][C:22]([CH:25]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:24]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: ClC(Cl)Cl
Reactant: CCCCCC(OCc1ccc(OC)cc1)c1ccc([C@H]2C(=O)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCCC(OCc1ccc(OC)cc1)c1ccc([C@@H]2[C@@H](CCCc3ccc(C(=O)OC)s3)CCC2(Cl)Cl)cc1
Reaction time: 1 h
Yield: 49 %

Procedure:
A solution of Hydrazone 2 (prepared from 0.11 mmol of ketone as described above) in 1 mL CHCl3 was cannula transferred to a mixture of CuCl2 (107 mg, 0.80 mmol) and Et3N (50 μL, 0.36 mmol) in MeOH (1.2 mL), rinsing with 1 mL CHCl3. After 1 h, a solution of 10% conc. NH4OH/saturated NH4Cl (8 mL) was added and the mixture was extracted with CH2Cl2 (3×30 mL). The combined CH2Cl2 solution was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (0%→20% ethyl acetate/hexanes) gave compound 4 (34 mg, 49%).
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:18]([CH2:20][CH:21](OC)OC)[CH3:19])=[O:17])=[CH:11][C:10]=2[O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>O>[CH3:19][N:18]1[CH:20]=[CH:21][N:15]([C:12]2[CH:13]=[CH:14][C:9]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:8])=[C:10]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:11]=2)[C:16]1=[O:17]
Reactant: CCCCOc1cc(NC(=O)N(C)CC(OC)OC)ccc1S(=O)c1ccccc1
Agent: Cl
Solvent: O
Product: CCCCOc1cc(-n2ccn(C)c2=O)ccc1S(=O)c1ccccc1

Procedure:
N-[4-(Phenylsulfinyl)-3-butoxyphenyl]-N'-(2,2-dimethoxyethyl)-N'-methylurea(0.02 mole), water (30 ml) and concentrated hydrochloric acid (3 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. The mixture is refluxed for a period of about 30 minutes and then cooled and extracted with ethyl acetate. The extract is washed with dilute aqueous sodium bicarbonate, with two portions of water and is then dried. The ethyl acetate is removed by mild warming under reduced pressure to yield the desired product 1-methyl-3-[4-(phenylsulfinyl)-3-butoxyphenyl]-4-imidazolin-2-one.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][O:26]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:14]1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.CO>[OH:26][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([CH:18]2[CH2:17][CH2:16][N:15]([C:46]([O:48][C:49]([CH3:52])([CH3:50])[CH3:51])=[O:47])[CH2:14][CH:13]2[O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.6 %

Procedure:
A solution of 1.07 g (1.48 mmol) of tert-butyl (3RS,4RS)-3-naphthalen-2-ylmethoxy-4-(4-trityloxymethyl-phenyl)-piperidine-1-carboxylate in 15 ml of methylene chloride was treated at room temperature with 2 ml of 2N hydrogen chloride in methanol and the mixture was stirred at room temperature for 15 minutes. Subsequently, the solution was poured into 30 ml of saturated sodium carbonate solution and this was extracted twice with 50 ml of ethyl acetate each time. The combined organic phases were dried over sodium sulphate and evaporated under reduced pressure. For purification, the crude product was chromatographed on silica gel using a 99:1 mixture of methylene chloride and methanol as the eluent. There were obtained 580 mg (82% of theory) of tert-butyl (3RS,4RS)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 447 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]=[C:12]([NH2:14])[NH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24](=O)[CH2:25][C:26](OCC)=[O:27])=[CH:23][C:18]=2[N:17]=[N:16]1.CC1C=CC(S(O)(=O)=O)=CC=1>CCCCO>[NH:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3[NH:14][C:12]4[N:11]([N:10]=[C:9]([C:4]5[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)[N:13]=4)[C:26](=[O:27])[CH:25]=3)=[CH:23][C:18]=2[N:17]=[N:16]1
Reactant: Nc1nc(-c2ccc(Cl)c(Cl)c2)n[nH]1
Reactant: CCOC(=O)CC(=O)c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: O=c1cc(-c2ccc3[nH]nnc3c2)[nH]c2nc(-c3ccc(Cl)c(Cl)c3)nn12
Temperature: 130 °C
Reaction time: 24 h
Yield: 40.1 %

Procedure:
To a solution of 3-(3,4-dichlorophenyl)-1H-1,2,4-triazol-5-amine (100 mg, 0.44 mmol) in n-BuOH (1 ml) was added ethyl 3-(1H-benzo[d][1,2,3]triazol-5-yl)-3-oxopropanoate (300 mg, 1.28 mmol) and TsOH (5 mg, 0.03 mmol), and the resulting mixture was stirred for 24 h at 130° C. The solids were collected by filtration and washed with methanol (10 ml) to afford 5-(1H-benzo[d][1,2,3]triazol-5-yl)-2-(3,4-dichlorophenyl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a light yellow solid (70.2 mg, 40%).
Reaction SMILES: C([O:8][C:9]1[CH:42]=[C:41]([CH3:43])[C:12]([CH2:13][CH:14]([C:24]([NH:26][C@@H:27]([C:29]([N-:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:30])[CH3:28])=[O:25])[N:15]([C:17](OC(C)(C)C)=O)C)=[C:11]([CH3:44])[CH:10]=1)C1C=CC=CC=1.CO.[ClH:47]>O1CCOCC1>[ClH:47].[CH3:17][NH:15][CH:14]([C:24]([NH:26][C@@H:27]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:30])[CH3:28])=[O:25])[CH2:13][CH:12]1[C:11]([CH3:44])=[CH:10][C:9]([OH:8])=[CH:42][C:41]1([CH3:43])[CH2:44][C:11]1[CH:12]=[CH:41][CH:42]=[CH:9][CH:10]=1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1CC(C(=O)N[C@H](C)C(=O)[N-]CCCc1ccccc1)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CNC(CC1C(C)=CC(O)=CC1(C)Cc1ccccc1)C(=O)N[C@H](C)C(=O)NCCCc1ccccc1

Procedure:
O-Benzyl-N-methyl-BOC-2,6-dimethyl (DL)-tyrosyl-(D)-alanylphenylpropylamide was treated with methanol (1.5 ml) and 6.8N HCl in dioxane (1 ml) for 24 hr. The mixture was evaporated in a stream of nitrogen, and dissolved in aqueous methanol. The solution was filtered through Whatman 50 filter paper, reduced in volume in a nitrogen stream, and lyophilized. The product is
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[CH:2].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])#[CH:2]
Reactant: C#Cc1cccc(C(=O)Cl)c1
Reactant: Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#Cc1cccc(C(=O)Oc2ccccc2)c1

Procedure:
Air in a 20 ml Schlenk tube was replaced by Ar gas and 1.02 g (7 mmol) of m-ethynylbenzoic acid and 5 g (42 mmol) of thionyl chloride were added to the tube and the mixture was stirred at 50° C. for 2 hours and then excess thionyl chloride was removed by distillation under reduced pressure to obtain m-ethynylbenzoyl chloride. To the m-ethynylbenzoyl chloride obtained was added a solution having 692 mg (7.35 mmol) of phenol and 3.4 ml (42 mmol) of pyridine dissolved in 7 ml of dichloromethane under ice-cooling and then the resultant mixture was stirred at room temperature for one hour. After completion of the stirring, dichloromethane was removed by distillation under reduced pressure and 35 ml of water was added to the resultant residue. The mixture was extracted with 35 ml of ethyl acetate, the extract was dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure using an evaporator. The resultant crude reaction product was purified by column chromatography (Hexane/AcOEt=10/1) using silica gel to obtain 0.55 q of phenyl 3-ethynylbenzoate which is a desired product as yellow solid. (Yield: 35%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([NH2:11])=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8].CO[C:14](OC)([N:16]([CH3:18])[CH3:17])[CH3:15]>>[CH3:17][N:16]([CH3:18])[C:14](=[N:11][C:9]([C:4]1[CH:5]=[N:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:10])[CH3:15]
Reactant: NC(=O)c1cnc(Cl)c(Cl)c1
Reactant: COC(C)(OC)N(C)C
Product: CC(=NC(=O)c1cnc(Cl)c(Cl)c1)N(C)C
Temperature: 120 °C
Yield: 42 %

Procedure:
A mixture of 5,6-dichloro-3-pyridinecarboxamide (4.0 g, 0.02 mol), dimethylacetamide dimethyl acetal (8 mL) was heated in an oil bath at 120° C. for three hours. The reaction mixture was cooled to room temperature and the solid recrystallised from ethyl acetate:hexane in the presence of activated carbon to give the desired product (2.3 g, 42%) as an orange solid.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[CH:26][CH:25]=4)[C:20](=[O:21])[N:19]([CH3:22])[C:18]([NH2:23])=[N:17]3)[CH:11]=2)[CH2:7]1)C.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[NH2:23][C:18]1[N:19]([CH3:22])[C:20](=[O:21])[C:16]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH:31]([F:33])[F:32])=[CH:28][CH:29]=2)([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH:8]3[CH2:9][C:6](=[CH:5][CH2:4][OH:3])[CH2:7]3)[CH:11]=2)[N:17]=1
Reactant: CCOC(=O)C=C1CC(c2cccc(C3(c4ccc(OC(F)F)cc4)N=C(N)N(C)C3=O)c2)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C3CC(=CCO)C3)c2)N=C1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
(3-{3-[2-Amino-4-(4-difluoromethoxy-phenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-phenyl}-cyclobutylidene)-acetic acid ethyl ester (0.202 g, 0.430 mmol) was dissolved in tetrahydrofuran (THF, 2 mL) and chilled in an ice bath. To this solution was added a 1 M solution of diisobutylaluminum hydride (DIBAL) in THF (11 ml). The reaction was stirred for 1 hour at ambient temperature, and then quenched with crushed ice, followed by addition of sodium chloride and ammonium chloride salts. The crude mixture was extracted with diethyl ether and dried with magnesium sulfate to yield a yellow oil 33 mg (18%); MS (ES) m/z 426.1 [M−H]−.