Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([Sn](CCCC)(CCCC)C=C)[CH2:11]CC.[F-].[K+]>ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([CH:10]=[CH2:11])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Product: C=Cc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
A mixture of 2,4-dichloro-5-fluoropyrimidine (5.0 g, 30.0 mmol, 1.0 equiv), tributyl(vinyl)tin (10.4 g, 33.0 mmol, 1.1 equiv) in dichloromethane (50 mL) was degassed with a stream of nitrogen for 10 minutes. Bis(triphenylphosphine)palladium(II) chloride (0.53 g, 0.75 mmol, 0.025 equiv) was added. The resulting mixture was degassed with a stream of nitrogen for an additional 15 minutes and heated at reflux for 24 hours. The reaction mixture was cooled to room temperature and quenched with an aqueous potassium fluoride solution (2 M, 75 mL, 5 equiv). The resulting mixture was allowed to stir for 2 hours and filtered through Celite®. The filtrate was poured into a separatory funnel and separated. The organic layer was washed with water (20 mL) and saturated brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure at 20° C. The resulting crude product was purified on an AnaLogix® (SF40-115 g) column. The gradient utilized for the purification was 10 minutes isocratic pentane, followed by a 20 minutes ramp to 5% diethyl ether in pentane. The pure fractions were combined and concentrated under reduced pressure at 20° C. to give 2-chloro-5-fluoro-4-vinylpyrimidine as an oil (3.65 g, 77% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.Br[C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([Br:15])[N:14]=1>C(O)(C)C>[Br:15][C:13]1[N:14]=[C:9]([NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=1
Reactant: Nc1cccnc1
Reactant: Cn1cc(Br)nc(Br)c1=O
Solvent: CC(C)O
Product: Cn1cc(Br)nc(Nc2cccnc2)c1=O
Temperature: 25 °C
Yield: 49.8 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with pyridin-3-amine (940 mg, 10 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (5.4 g, 20 mmol), i-propanol (50 mL), and di-1-propylethylamine (10 mL). The mixture was heated at reflux for 5 h. After the completion of the reaction, it was cooled to room temperature. The solvent was removed under reduced pressure. The crude was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 186a (1.4 g, 50%) as a yellow solid. MS-ESI: [M+H]+ 281.6.
Reaction SMILES: Cl.[O:2]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][NH:5][CH2:4][CH2:3]1.[CH:20]([C:23]1[S:24][CH:25]=[C:26]([C:28](O)=[O:29])[N:27]=1)([CH3:22])[CH3:21].C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CC1OCCC1.C1COCC1.O>[CH:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([N:5]2[CH2:6][C:7]3([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)[O:2][CH2:3][CH2:4]2)=[O:29])[N:27]=1)([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Reactant: CC(C)c1nc(C(=O)O)cs1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: O
Solvent: CC1CCCO1
Solvent: C1CCOC1
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cs1
Temperature: 12.5 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
A mixture of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (limiting reagent) and 2-isopropylthiazole-4-carboxylic acid (1.1 molar equivalents) was suspended in 2-MeTHF (10 volumes) and cooled to 10-15° C. Triethylamine (7.2 molar equivalents) was added in portions at 10-15° C. The thick suspension was cooled to 5-10° C. and T3P (1.3 molar equivalents of a 1.57M solution in THF) was added dropwise at 5-10° C. over 0.5 hr. The reaction mixture was allowed to warm to ambient temperature (35 min) and stirred for 2.5 hr. The mixture was diluted with water (10 volumes, 5° C. exotherm) and the mixture vigourously stirred; the aqueous (pH10) was separated and extracted with 2-MeTHF (2×2 volumes). The combined organics were washed with saturated aq sodium bicarbonate soln (2 volumes) and water (2×2 volumes). The organic phase was evaporated and azeotroped with MeCN (2×2 volumes) to give a brown gum, which was dried at 35° C. in vacuo for 24 hr. Yield: 89% of theoretical.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:6]=2[CH:21]=1.[CH2:22]([NH2:26])[C:23]#[C:24][CH3:25]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:26][CH2:22][C:23]#[C:24][CH3:25])[CH2:9][N:8]=[C:7]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:6]=2[CH:21]=1
Reactant: CC#CCN
Reactant: Fc1cccc(F)c1C1=NCC(=S)Nc2ccc(Cl)cc21
Solvent: C1CCOC1
Product: CC#CCNC1=Nc2ccc(Cl)cc2C(c2c(F)cccc2F)=NC1

Procedure:
A mixture of 10.0 g. of 7-chloro-1,3-dihydro-5-(2,6-difluorophenyl)-2H-1,4-benzodiazepine-2-thione (V), 10.0 g. of 2-butynylamine, and 150 ml. of dry tetrahydrofuran is stirred under nitrogen at ambient temperature for about 5 hours and then concentrated in vacuo. The residue thus obtained is recrystallized from methanol to give 7-chloro-5-(2,6-difluorophenyl)-2-(2-butynylamino)-3H-1,4-benzodiazepine.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH2:11][C:12]2[N:13]=[C:14]([N:17]3[CH2:20][CH:19](OS(C)(=O)=O)[CH2:18]3)[S:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([O-:29])(=[S:28])[CH3:27].[K+]>CN(C)C=O>[C:26]([S:28][CH:19]1[CH2:18][N:17]([C:14]2[S:15][CH:16]=[C:12]([CH2:11][NH:10][S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[N:13]=2)[CH2:20]1)(=[O:29])[CH3:27]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CN(c2nc(CNS(=O)(=O)c3ccccc3)cs2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(CNS(=O)(=O)c3ccccc3)cs2)C1
Temperature: 90 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
To a solution of 1-[4-(benzenesulfonylamino)methyl-1,3-thiazol-2-yl]-3-methanesulfonyloxyazetidine (1.16 g, 2.98 mmol) (obtained as described in Reference Example 65(3)) in dimethylformamide (35 ml) was added potassium thioacetate (2.04 g, 17.9 mmol) at room temperature, and the mixture was stirred in an oil bath (90° C.) for 4 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride:ethyl acetate (5:1) as the eluant to afford 3-acetylthio-1-[4-(benzenesulfonylamino)methyl-1,3-thiazol-2-yl]azetidine (1.00 g, yield 91%) as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:31]=[CH:30][C:25]([C:26](OC)=[O:27])=[C:24]([O:32][CH3:33])[CH:23]=2)[N:17]=1.[F:34][C:35]([F:44])([F:43])[C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:15])[C:11]([F:12])([F:14])[F:13])=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([NH:39][C:38]3[CH:40]=[CH:41][CH:42]=[C:36]([C:35]([F:34])([F:43])[F:44])[CH:37]=3)=[O:27])=[C:24]([O:32][CH3:33])[CH:23]=2)[N:17]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)(F)F)c1
Yield: 67.1 %

Procedure:
To a solution of methyl 4-(3-(2-chloro-5-((2,2,2-trifluoroacetamido) methyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (0.200 g, 0.413 mmol) in dry toluene (3 mL) was added 3-(trifluoromethyl)aniline (0.100 g, 0.619 mmol) followed by addition of trimethyl aluminium (2M solution in toluene) (2 mL). The reaction mass was refluxed for 3-4 h. The reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.170 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.95 (s, 3H), 4.46 (d, J=6.0 Hz, 2H), 7.56 (t, J=6.0 Hz, 2H), 7.59-7.85 (m, 6H), 7.96 (d, J=7.8 Hz, 1H), 8.26 (s, 1H), 10.09 (s, 1H), 10.37 (s, 1H), 12.65 (s, 1H); MS (m/z): (M)+ 614.08.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[C:18](=[O:23])[NH:17][N:16]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:24]=1.[C:25]([Cu])#[N:26]>>[CH:20]([N:19]1[C:18](=[O:23])[NH:17][N:16]=[C:15]1[C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:25]#[N:26])=[CH:24][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)([CH3:22])[CH3:21]
Reactant: CC(C)n1c(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)n[nH]c1=O
Reactant: N#C[Cu]
Product: CC(C)n1c(-c2cc3c(s2)-c2ccc(C#N)cc2OCC3)n[nH]c1=O

Procedure:
Following the procedure of Example 53, 3-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-4-isopropyl-1H-1,2,4-triazol-5(4H)-one and CuCN were reacted to give 259. MS: (ESI+) 353.1
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:19])[C:4]([N:6]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:7]1[N:8]=[N:9][C:10]([Cl:13])=[CH:11][CH:12]=1)=[O:5].[OH-].[Na+].[H][H]>[Pd].C(O)C>[ClH:13].[ClH:1].[CH3:2][N:3]([CH3:19])[C:4]([N:6]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:7]1[N:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:5]
Reactant: CN(C)CCN(C(=O)N(C)C)c1ccc(Cl)nn1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CN(C)CCN(C(=O)N(C)C)c1cccnn1

Procedure:
N,N-Dimethyl-N'-(2-dimethylaminoethyl)-N'-(6-chloro-3-pyridazinyl) urea hydrochloride (10.5 g, 0.034 mole) (Example 8) and 1.5 g of 5% palladium on carbon catalyst are added to a mixture of 35 ml of 2 N sodium hydroxide in 250 ml of ethyl alcohol. Treatment with hydrogen is performed in a Parr apparatus at 40-50 lbs. per sq. in. pressure and ambient temperature. The catalyst is removed by filtration, the filtrate is concentrated under reduced pressure, water is added and the mixture is extracted with benzene. The extracts are concentrated, the residue is dissolved in ether, hydrogen chloride is added and N,N-dimethyl-N'-(2-dimethylaminoethyl)-N'-(3-pyridazinyl) urea dihydrochloride melting at 187.5°-188.5° C. is obtained.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[Li+].[OH-].Cl>C1COCC1.O>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 4-(phenylethynyl)benzoate (7.81 g, 31.2 mmol) in THF (80 mL) was added MeOH (15 mL) and a solution of LiOH (5.24 g, 124 mmol) in water (15 mL). The reaction was stirred at room temperature and for 4 h. The reaction was acidified with 1 N HCl (50 mL), and 4-(phenylethynyl)benzoic acid was isolated (5.78 g, 83%) as a white solid; 1H-nmr (400 MHz, CDCl3) δ 8.11 (d, J=8.0 Hz, 2H), 7.75-7.68 (m, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.62-7.56 (m, 2H), 7.52-7.47 (m, 1H), 7.43-7.36 (m, 3H); LC (275 nM) 5.12 min (>98%); MS (ESI) m/z=222.9.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH:10]=2)O1.[NH2:17][C:18]1[C:19]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[C:27]([F:38])[CH:26]=2)=[N:20][C:21](Br)=[CH:22][N:23]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCOCC>[NH2:17][C:18]1[C:19]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])=[C:27]([F:38])[CH:26]=2)=[N:20][C:21]([C:9]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH:10]=2)=[CH:22][N:23]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc(Br)cnc2N)cc1F
Reactant: CC1(C)OB(C2=CC(=O)CCC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)c1ccc(-c2nc(C3=CC(=O)CCC3)cnc2N)cc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
A 250 ml RB was charged with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-enone (7.00 g, 31.5 mmol) (in about 70 ml dioxane), tert-butyl 4-(3-amino-6-bromopyrazin-2-yl)-2-fluorobenzoate (5.8 g, 15.75 mmol)), Pd(dppf)Cl2.DCM (0.576 g, 0.788 mmol), and then Saturated Na2CO3 (25 mL). The resultant mixture was flushed with nitrogen for 15 min. DME (10 mL) was then added. The mixture was stirred at 100° C. overnight. Ethyl acetate (150 ml) and water (50 ml) were added, and the resultant mixture was stirred for 30 min. Organics was separated and the aqueous layer was extracted with ethyl acetate (30 ml×3). Organic layers were combined and dried over Na2SO4, filtered and evaporated to provide crude desired material as a sticky dark color semi solid. This solid was taken to about 30 ml of ether, sonicated for 10 min, and the precipitated yellow solid was filtered, and washed with cold ether(5 ml×3), dried under high vacuum to afford the desired product (3.1 g, 51.3%) as a yellow solid. LC-MS (m/z): (MH+) 384.2, 0.92 min.
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Cl:12][C:13]1[CH:18]=[C:17]([O:19][C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:15][C:14]=1[N:24]1[C:28]([CH3:29])=[C:27]([C:30](O)=[O:31])[N:26]=[N:25]1.[NH2:33][C:34]1[C:35](=[O:48])[N:36]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[F:47])[N:37]([CH3:40])[C:38]=1[CH3:39].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[C:17]([O:19][C:20]([F:21])([F:23])[F:22])[CH:16]=[CH:15][C:14]=1[N:24]1[C:28]([CH3:29])=[C:27]([C:30]([NH:33][C:34]2[C:35](=[O:48])[N:36]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[F:47])[N:37]([CH3:40])[C:38]=2[CH3:39])=[O:31])[N:26]=[N:25]1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2F)n1C
Reactant: Cc1c(C(=O)O)nnn1-c1ccc(OC(F)(F)F)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2c(C)n(C)n(-c3ccccc3F)c2=O)nnn1-c1ccc(OC(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
DMF (43 μL, 0.56 mmol) was dissolved in DCM (1 mL) and cooled to 0° C. Oxalyl chloride (27 μL, 0.308 mmol) was added followed by 1-(2-chloro-4-(trifluoromethoxy)phenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (90 mg, 0.28 mmol) and the reaction mixture was stirred for 10 min. 4-Amino-2-(2-fluorophenyl)-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate B) (62 mg, 0.28 mmol) was added, followed by triethylamine (117 μL, 0.839 mmol). The reaction was allowed to warm to RT and stirred for 4 h. Saturated aqueous NaHCO3 was added to the reaction mixture and the product was extracted with DCM. The organic extract was dried and concentrated under reduced pressure. The crude material was purified by reversed phase chromatography (Prep Method G) to afford the title compound.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:32][C:33]([N:35]2[CH2:40][CH2:39][CH:38]([N:41]3[CH2:50][C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[NH:43][C:42]3=[O:51])[CH2:37][CH2:36]2)=[O:34])[C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]([O:29]CC)=[O:28])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)=[O:13])=[CH:6][C:5]=1[CH3:52].Cl>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:32][C:33]([N:35]2[CH2:36][CH2:37][CH:38]([N:41]3[CH2:50][C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[NH:43][C:42]3=[O:51])[CH2:39][CH2:40]2)=[O:34])[C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]([OH:29])=[O:28])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)=[O:13])=[CH:6][C:5]=1[CH3:52]
Reactant: CCOC(=O)CN1CCN(C2CCN(C(=O)C(Cc3ccc(Br)c(C)c3)NC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(CC(=O)O)CC3)CC2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.0 mL (1.00 mmol) 1 M NaOH were added to a solution of 80 mg (0.11 mmol) ethyl {4-[1-(3-(4-bromo-3-methyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-carbonyl]-amino}-propionyl)-piperidin-4-yl]-piperazin-1-yl}-acetate (Example 14.4) in 4 mL THF. The reaction mixture was stirred overnight at RT and the solvent was eliminated i. vac. 1 mL 1 M HCl was added to the residue and it was evaporated to dryness again. The residue was taken up in EtOH and after filtration the mother liquor was concentrated by evaporation i.vac. The residue was triturated with diisopropylether and after filtration dried in the air.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[CH:4][CH:3]=1.C[O-].[Na+].Cl.Cl.[NH2:17][C:18]1[C:23](N)=[CH:22][CH:21]=[CH:20][C:19]=1[OH:25]>CO>[OH:25][C:19]1[C:18]2[NH:17][C:8]([CH2:7][O:6][C:5]3[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=3)=[N:9][C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1cccc(O)c1N
Reactant: Cc1ccc(OCC#N)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(OCc2nc3cccc(O)c3[nH]2)cc1

Procedure:
In a 50 ml single neck round bottom flask, under a nitrogen atmosphere, 4-methylphenoxyacetonitrile (2.79 mmol) was admixed in methanol (11 ml). The contents were stirred to achieve dissolution. To this solution were added sodium methoxide (0.164 g, 3.0 mmol). The resulting mixture was stirred for about 40 minutes. To this mixture was added 2,3-diaminophenol dihydrochloride salt (0.5 g, 2.5 mmol) and the resulting mixture was stirred for two hours at room temperature. The reaction mixture was filtered and the filtrate was added to 60 ml of water. A light brown precipitate formed and this precipitate is removed by filtration, and washed with 20 ml of water. The solid was dried in a vacuum oven overnight.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:17]=[CH:16][C:15](Cl)=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19]C1C=CC(C(N)=O)=C(F)C=1>>[CH2:1]([S:8][C:9]1[CH:17]=[C:16]([Cl:19])[CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Cl)cc1F
Reactant: NC(=O)c1cc(Cl)ccc1SCc1ccccc1
Product: NC(=O)c1ccc(Cl)cc1SCc1ccccc1

Procedure:
A method similar to the preparation of 2-benzylsulphanyl-5-chlorobenzamide (see page 17 above) was followed using 4-chloro-2-fluorobenzamide (400 mg, 2.31 mmol). The title compound was isolated as a white solid (376 mg, 59%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23]C)=[O:22])[CH2:14][C@H:13]1[O:28][CH3:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([OH:23])=[O:22])[CH2:14][C@H:13]1[O:28][CH3:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CO[C@@H]1CN(c2cccc(C(=O)O)c2)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Methyl cis(±)-3-(4-{[benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)benzoate obtained in Example (42a) (250 mg, 0.63 mmol) was dissolved in methanol (5 mL). A 1 N aqueous sodium hydroxide solution (4 mL) was added, and the mixture was stirred at 70° C. for one hour. The reaction solution was neutralized with 1 N hydrochloric acid, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH:3]([CH3:24])[CH2:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:7][C:8]([O:10]C)=[O:9].C(=O)([O-])[O-].[K+].[K+].CO.Cl>O>[CH3:25][N:2]([CH3:1])[CH:3]([CH3:24])[CH2:4][C:5]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: COC(=O)CCC(CC(C)N(C)C)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(CC(CCC(=O)O)(c1ccccc1)c1ccccc1)N(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 6-dimethylamino-4,4-diphenyl-heptanoate (obtained above), potassium carbonate (500 mg), methanol (5 ml) and water (1 ml) was stirred at room temperature for 24 hours. The reaction mixture was diluted with water, acidified with 1N HCl to pH 1, and extracted with chloroform (3×). The combined extracts were washed with water and brine (once each). After drying over magnesium sulfate, the solution was rotary evaporated to yield 40 mg of 6-dimethylamino-4,4-diphenyl-heptanoic acid.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[N+:22]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Cl)([O-:24])=[O:23]>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=2)[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Product: O=C1C(CCO)Oc2ccccc2N1Cc1cccc([N+](=O)[O-])c1

Procedure:
The intermediate silyl protected alcohol was prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Method F, alkylating with 3-nitrobenzyl chloride. Deprotection to the indicated product was carried out by method I.
Reaction SMILES: [Na].[OH:2][C:3]1[C:8]([CH2:9][CH2:10][CH3:11])=[C:7]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]=1[C:26](=[O:28])[CH3:27].[OH-].[Na+].[Br:31][CH2:32][CH2:33][CH2:34]Br>C1COCC1>[C:26]([C:4]1[CH:5]=[CH:6][C:7]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]3[N:22]=[N:23][N:24]([CH2:34][CH2:33][CH2:32][Br:31])[N:25]=3)=[CH:16][CH:15]=2)=[C:8]([CH2:9][CH2:10][CH3:11])[C:3]=1[OH:2])(=[O:28])[CH3:27]
Reactant: BrCCCBr
Reactant: CCCc1c(COc2ccc(Cc3nnn[nH]3)cc2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1c(COc2ccc(Cc3nnn(CCCBr)n3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 15.8 %

Procedure:
1-[2-Hydroxy-3-propyl-4-((4-(1H-tetrazol-5-ylmethyl)phenoxy)methyl)phenyl]ethanone sodium salt (15 g, 0.039 mol) was added to THF (150 ml) and the minimum amount of lN sodium hydroxide soluton was added to effect solution. 1,3-Dibromopropane (12.12 g, 0.06 mol) was added and the reaction solution was stirred at room temperature for 24 hours. The reaction mixuture was concentrated in vacuo. Water was added to the concentrate and the resultant mixture was extracted with ethyl acetate (3×). The organic layers were combined, washed with water, dried over sodium sulfate, filtered, and concentrated. The resultant residue was chromatographed by HPLC on a silica gel column eluted with a mixture of 9:1 toluene:ethyl acetate to yield 3.0 g of a light yellow oil of the 2H-tetrazole-2-isomer of the above product.