Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([NH:13][CH3:14])=[S:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl>>[CH3:14][N:13]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][NH:10][C:11]1=[S:12]
Reactant: CNC(=S)NNC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1c(-c2ccccc2)n[nH]c1=S

Procedure:
A stirred mixture of 1-benzoyl-4-methylthiosemicarbazide (20.9 g, 1.00×10-1 mole) and 1 molar aqueous NaHCO3 (1000 ml, 1 mole) was heated to reflux. After refluxing overnight the reaction was cooled in an ice bath. With stirring the solution was carefully acidified by the dropwise addition of conc. HCl (92 ml, 1.1 mole). A colorless precipitate formed and this was subsequently collected by filtration.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.S[C:8]1[O:9][C:10]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:11]=2[N:12]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:8]2[O:9][C:10]3[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:11]=3[N:12]=2)[CH2:22][CH2:21]1
Reactant: CN1CCNCC1
Reactant: Sc1nc2cc(Cl)cc(Cl)c2o1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CN1CCN(c2nc3cc(Cl)cc(Cl)c3o2)CC1
Temperature: 100 °C

Procedure:
Phosphorus pentachloride (454 mg) was dissolved in anhydrous toluene (6 ml), the resulting solution was mixed with 2-mercapto-5,7-dichlorobenzoxazole (400 mg) which has been obtained in the same manner as described in Reference Example 1, and the mixture was then stirred with heating at 100° C. for 2 hours. With cooling in an ice bath, to this was added dropwise N-methylpiperazine (2.0 ml). After 20 minutes of stirring, the thus obtained mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order. After drying with magnesium sulfate, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography (methylene chloride:methanol=10:1) to obtain the title compound 2-(4-methyl-1-piperazinyl)-5,7-dichlorobenzoxazole (89.9 mg).
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[BH4-].[Na+]>CO.O>[O:3]1[C:4]2([CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]2)[O:11][CH2:1][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.1 %

Procedure:
1,4-Cyclohexanedione mono-ethylene ketal (5.0 g, 32 mmol) in 20 mL of MeOH/water (1:1) was added NaBH4 (1.21 g, 32 mmol). The mixture was stirred at room temperature overnight. The MeOH was removed via rotary evaporation. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), and concentrated to give an oil which was stored on a high vacuum line overnight to afford 5.12 g of 1,4-dioxaspiro[4.5]decan-8-ol as as an oil. MS (EI) calcd: (M+H)+=159.1; found: 159.2.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][C:17]1[C:22]([SH:23])=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.ClCCl>[Cl:9][C:5]1[N:4]=[N:3][C:2]([S:23][C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:16])=[N:7][C:6]=1[Cl:8]
Reactant: Cc1ccccc1S
Reactant: Clc1nnc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccccc1Sc1nnc(Cl)c(Cl)n1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 116.5 %

Procedure:
3,5,6-Trichloro-1,2,4-triazine (0.50 g) was dissolved in dry tetrahydrofuran (8 ml) and dry potassium carbonate (0.37 g) and 4Å molecular sieves (180 mg, activated overnight at 180° C.) were added. The stirred mixture was cooled to 0° C. and a solution of o-thiocresol (0.36 g) in dry tetrahydrofuran (4 ml) was added dropwise. After 45 minutes at 0-5° C. and standing overnight at 10° C., the mixture was diluted with dichloromethane (20 ml) and filtered through Hyflo Supercel filter aid covered with a layer of Merck silica 60. The filtrate was concentrated under reduced pressure to afford a single dichloro-(2-methylphenylthio)-1,2,4-triazine (unidentified regioisomer) as a yellow oil (0.86 g) which crystallised on standing. Recrystallisation from ether-n-hexane yielded a pale yellow powder (0.57 g, 77%); m.p. 93-95° C.; IR max (nujol mull): 1460, 1250 cm-1 ; 1H NMR: δ2.38 (3H,s), 7.24-7.37(1H,m), 7.37-7.54(3H,m) ppm.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[CH3:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][OH:17].N1C=CC=CC=1>ClCCl>[C:2](=[O:3])([O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH3:7])[O:4][CH2:5][Cl:6]
Reactant: COCCOCCOCCO
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCOCCOCCOC(=O)OCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Chloromethyl chloroformate (2.94 ml) was added to an ice-cold solution of triethyleneglycol monomethylether (4.70 ml) in dichloromethane (30 ml) followed by pyridine (2.93 ml) at such a rate that the temperature was kept below 10° C. After stirring overnight at room temperature the reaction mixture was washed twice with 0.5 M HCl followed by water and aqueous sodium bicarbonate. Drying over magnesium sulfate, filtration, evaporation in vacuo followed by distillation in vacuo, b.p.: 102-108° C. at 0.03 mbar, afforded the title compound as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH:6]=[CH:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:9].Br[C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[O:32][CH2:31][CH2:30][O:29]2)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:6](/[C:22]2[CH:27]=[CH:26][C:25]([CH:28]3[O:29][CH2:30][CH2:31][O:32]3)=[CH:24][CH:23]=2)=[CH:7]\[C:8]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[O:9])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: Brc1ccc(C2OCCO2)cc1
Reactant: COc1ccc(C=CC(=O)N2CCOCC2)cc1OC
Product: COc1ccc(/C(=C\C(=O)N2CCOCC2)c2ccc(C3OCCO3)cc2)cc1OC

Procedure:
This compound was obtained in analogy to the preceding Examples from 3,4-dimethoxycinnamic acid morpholide and 2-(4-bromophenyl)-1,3-dioxolane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[C:5]([OH:7])=[O:6].[CH2:20]([Zn]CC)[CH3:21].CCCCCC>O1CCCC1>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[CH2:20][CH3:21]
Reactant: O=C(O)c1ccc(Oc2ccc(Cl)c(Cl)c2)c(Br)c1
Reactant: CC[Zn]CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1cc(C(=O)O)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
3-Bromo-4-(3,4-dichlorophenoxy)benzoic acid (Preparation 8, 240 mg, 0.663 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL) and cooled to 0° C. Bis(tributylphosphine)palladium (0) (33.7 mg, 0.07 mmol) was added followed by the slow addition of a 1M solution of diethyl zinc in hexane (3.32 mL, 3.32 mmol). The reaction mixture was stirred overnight under an atmosphere of nitrogen. The reaction mixture was then quenched with a 1M aqueous solution of hydrogen chloride and extracted with ethyl acetate. The combined organic phase was concentrated in vacuo and the resulting residue then purified by reverse phase column chromatography (Trilution method) to afford the title compound as a white solid (75 mg, 36%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:4]=1[Cl:13].[P:14](OCC)([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15]>>[Cl:13][C:4]1[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]([F:9])=[CH:8][C:3]=1[CH2:2][P:14](=[O:15])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]
Reactant: CCOP(=O)(OCC)OCC
Reactant: O=[N+]([O-])c1cc(Cl)c(CBr)cc1F
Product: CCOP(=O)(Cc1cc(F)c([N+](=O)[O-])cc1Cl)OCC

Procedure:
1-(Bromomethyl)-2-chloro-5-fluoro-4-nitrobenzene (6.7 g, 18.62 mmol) and triethyl phosphate (5.64 mL) were heated in an oil bath for 3 hours at 140° C. The reaction mixture was concentrated and chromatographed on silica eluting with dichloromethane/methanol (1:0-1%) to give the title compound (4.06 g).
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][C:6]([CH3:17])=[CH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29].O>CN(C=O)C>[F:2][C:3]1[C:8]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[N:13]([CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[CH:14]=2)=[CH:7][C:6]([CH3:17])=[CH:5][N:4]=1
Reactant: COC(CCBr)OC
Reactant: Cc1cnc(F)c(-c2c[nH]c(=O)[nH]c2=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2cc(C)cnc2F)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
A mixture of 5-(2-fluoro-5-methyl-pyridin-3-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep99, 300 mg, 1.16 mmol), and K2CO3 (241 mg, 1.7 mmol) in DMF (5 ml) was stirred for one hour at room temperature. 3-Bromo-1,1dimethoxy-propane (234 mg, 1.3 mmol) was added and stirring was continued for three days. Water was added and the product was extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography eluting with DCM-MeOH—NH4OH (95:5:0.5) to give 200 mg of the final compound as oil (53% yield).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[N:17][CH:18]=1>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[N+:17]([O-:9])[CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(Br)cn1
Solvent: ClCCl
Product: Cc1ccc(Br)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
39 g (0.16 mol) 3-chloroperbenzoic acid in 450 mL DCM (dried on sodium sulphate) were added dropwise within 2 h to 25 g (0.15 mol) 5-bromo-2-methylpyridine in 50 mL DCM. Then the reaction mixture was stirred for 20 h at RT and extracted with 15% potassium carbonate solution. The organic phase was dried on sodium sulphate and evaporated down.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:15]([CH3:29])([CH3:28])[CH2:14]2)[N:5]=[C:4]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]2[CH2:40][C:39]([CH3:42])([CH3:41])[N:38]([O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)[C:37]([CH3:51])([CH3:50])[CH2:36]2)[N:3]=1.[OH-].[Na+].Cl[CH2:55][CH:56]([OH:59])[CH2:57][OH:58]>>[O:59]1[CH2:55][CH:56]1[CH2:57][O:58][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:15]([CH3:29])([CH3:28])[CH2:14]2)[N:5]=[C:4]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]2[CH2:40][C:39]([CH3:42])([CH3:41])[N:38]([O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)[C:37]([CH3:51])([CH3:50])[CH2:36]2)[N:3]=1
Reactant: OCC(O)CCl
Reactant: CC1(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)nc(OCC3CO3)n2)CC(C)(C)N1OC1CCCCC1

Procedure:
The title compound is prepared by the reaction of 2-chloro-4,6-bis[N-(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine with sodium hydroxide and 3-chloro-1,2-propanediol.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([N:18]([CH2:26][CH2:27][NH:28]C(=O)C(F)(F)F)[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:28][CH2:27][CH2:26][N:18]([CH:15]1[CH2:16][CH2:17][N:13]([C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:14]1)[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24]
Reactant: COc1ccc2nccc(N3CCC(N(CCNC(=O)C(F)(F)F)C(=O)OC(C)(C)C)C3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc2nccc(N3CCC(N(CCN)C(=O)OC(C)(C)C)C3)c2n1
Reaction time: 12 h
Yield: 87.7 %

Procedure:
To a solution of 1,1-dimethylethyl {1-[6-(methyloxy)-1,5-naphthyridin-4-yl]-3-pyrrolidinyl}{2-[(trifluoroacetyl)amino]ethyl}carbamate (1.8 g, 3.65 mmol) in MeOH/H2O (75 mL, 2:1) was added K2CO3 (2.52 g, 18.25 mmol). After 12 h at 25° C., the reaction was concentrated under reduced pressure and purified via column chromatography [silica, 5% MeOH in DCM (2% NH4OH)] affording the title compound (1.24 g, 88%) as an off-white solid: LC/MS (ES) m/e 388 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][N:3]=1.[NH2:20][NH2:21]>C1COCC1>[NH:20]([C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][N:3]=1)[NH2:21]
Reactant: CCOC(=O)c1cnc(Cl)nc1Cc1ccccc1
Reactant: NN
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(NN)nc1Cc1ccccc1
Yield: 99 %

Procedure:
The title compound was prepared as described in Example 18, but employing a solution of ethyl 2-chloro-4-benzylpyrimidine-5-carboxylate (0.34 g, 1.2 mmol) and hydrazine (0.2 g, 6.1 mmol) in THF resulting in a 99% yield (0.33 g, oil); GC/MS, 272(M+).
Reaction SMILES: [CH3:1][NH:2][S:3]([NH:6][CH2:7][C:8]([O:10]CC)=O)(=[O:5])=[O:4].O(C(C)(C)C)[K]>CN(C=O)C>[CH3:1][N:2]1[C:8](=[O:10])[CH2:7][NH:6][S:3]1(=[O:5])=[O:4]
Reactant: CCOC(=O)CNS(=O)(=O)NC
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Product: CN1C(=O)CNS1(=O)=O
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of ethyl 2-((N-methylsulfamoyl)amino)acetate from the previous step (3.5 mmol) in DMF (50 mL) is added KO-t-Bu (1.56 g, 13.88 mmol) in portions under N2 at RT. The mixture is stirred overnight then quenched with HCl/methanol (2 M). After the solvent is removed in vacuo, the residue is washed with water to afford 2-methyl-1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-3-one (480 mg, 54%). 1H-NMR (CDCl3): δ 7.36 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 4.87 (m, 1H), 4.68 (s, 2H), 4.03 (d, J=7.2 Hz, 2H), 3.80 (s, 3H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)[C:7](=[O:16])[CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][N:8]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)[C:7](=[O:16])[CH:6]=1
Reactant: [N-]=[N+]=NCc1ccn(-c2ccsc2)c(=O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccn(-c2ccsc2)c(=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
To a solution of crude 4-azidomethyl-1-thiophen-3-yl-1H-pyridin-2-one in tetrahydrofuran (2 mL) is added triphenylphosphine (0.19 g). The mixture is stirred for 10 minutes before the addition of water (200 μL). After stirring for 16 hours at room temperature, the mixture is purified by reverse-phase high performance liquid chromatography (5% acetonitrile/95% water to 75% acetonitrile/25% water over 45 minutes) to provide 4-aminomethyl-1-thiophen-3-yl-1H-pyridin-2-one (60 mg, 34% over 2 steps).
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)/[CH:11]=C/C)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(Cl)Cl.[BH4-].[Na+].C[OH:37]>>[C:1]([O:7][CH2:8][C@@H:9]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[C@@H:10]([C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:18][CH:19]=1)[CH2:11][OH:37])(=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5]
Reactant: CO
Reactant: C/C=C/[C@H](c1ccc(C(F)(F)F)cc1)[C@@H](COC(=O)C(C)(C)C)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](COC(=O)C(C)(C)C)[C@H](CO)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
(2S,3S,E)-2-(tert-Butoxycarbonyl)-3-(4-(trifluoromethyl)phenyl)hex-4-enyl pivalate (1.8 g, 4.1 mmol) was taken up in 40 mL of 1:1 MeOH:CH2Cl2 and chilled to −78° C. Ozone was bubbled through the mixture until a blue color persisted. Nitrogen was then bubbled through the mixture for 15 minutes. Sodium borohydride (0.77 g, 20 mmol) was added, and the mixture was warmed to room temperature. The mixture was stirred for 2 hours. The mixture was quenched with 40 mL of aqueous NH4Cl. After 30 minutes, the mixture was diluted with 20 mL of water and extracted three times with 40 mL of CH2Cl2. The combined organic extracts were dried over MgSO4. Filtration and concentration under reduced pressure afforded (2S,3S)-2-(tert-butoxycarbonyl)-4-hydroxy-3-(4-(trifluoromethyl)phenyl)butyl pivalate (1.8 g, 100% yield) as a white crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9](OC(=O)C)(=[O:11])[CH3:10]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:9](=[O:11])[CH3:10]
Reactant: Nc1ccccc1Br
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-bromoaniline (22.0 g, 12.8 mmol), acetic anhydride (13.06 g, 12.8 mmol) and a catalytic amount of DMAP in CH2Cl2 (100 mL) was stirred at 0° C. The mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was washed with saturated aqueous NaHCO3 solution and concentrated. The residue was triturated with hexanes/CH2Cl2, the solid was filtered and rinsed with hexanes to give aa (25.4 g, 92.8%). HPLC Rt=1.523 min.
Reaction SMILES: C(ON[C:10](=[O:36])[CH2:11][C:12]([S:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])([CH2:23][CH3:24])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C1C=CC=CC=1.CC[OH:39]>[Pd]>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([S:25]([C:12]([CH2:23][CH3:24])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][C:10]([OH:39])=[O:36])(=[O:26])=[O:27])=[CH:33][CH:32]=1
Reactant: CCC(CCCCc1ccccc1)(CC(=O)NOCc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: CCO
Agent: [Pd]
Product: CCC(CCCCc1ccccc1)(CC(=O)O)S(=O)(=O)c1ccc(OC)cc1
Yield: 26 %

Procedure:
A solution of 0.463 g (0.91 mmol) of N-benzyloxy-3-(4-methoxyphenylsulfonyl)-3-ethyl-7-phenylheptanamide in 75 mL of EtOH is shaken for 3 days under 50 psi of H2 with 0.2 g of 10% Pd on carbon. The mixture is filtered and concentrated in vacuo. Purification by flash silica gel chromatography afforded 0.1 g (26%) of 3-(4-methoxybenzenesulfonyl)-3-ethyl-7-phenylheptanoic acid hydroxamide in the form of a white foam, m.p. 44-46° C.1H NMR (DMSO-d6) δ (TMS)0.97 (t, 3H), 1.45-1.9 (m, 8H), 2.4 (s, 2H), 2.55 (m, 2H), 3.87 (s, 3H), 7.1-7.25(m, 5H), 7.28 (d, 2H), 7.65 (d, 2H), 8.83 (s,1H), 10.6 (s,1H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27](I)[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH2:31]([OH:34])[C:32]#[CH:33].C(NCC)C>[Cu]I.CCOC(C)=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:33]#[C:32][CH2:31][OH:34])[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4ccc(I)cc34)CC2)cc1
Reactant: C#CCO
Agent: [Cu]I
Solvent: CCNCC
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4ccc(C#CCO)cc34)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.5 %

Procedure:
A mixture of 4-(6-iodo-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide (1.056 g, 2.05 mmol), as prepared in Example 11d, CuI (3.9 mg, 20.5 μmol), trans-PdCl2[P(C6H5)3]2 (26.8 mg, 38.2 μmol), propargyl alcohol (139 μL, 2.36 mmol), and diethylamine (3.4 mL) was flushed with a stream of argon for 30 s, and then quickly sealed and vigorously stirred at rt under argon for 5 h. The resulting dark brown bilayer was concentrated under reduced pressure at rt, dissolved in DCM (10 mL), and vigorously shaken with 0.75 M EDTA (tetrasodium salt) (1×2 mL). The light green aqueous layer was extracted with DCM (1×10 mL), the organic layers were combined, dried (Na2SO4), and concentrated to give a beige foam soluble in 9:1 EtOAc/DCM (˜5 mL). Flash chromatography (1:9 hex/EtOAc→EtOAc) provided the title compound as a yellow foam (825 mg, 91%). 1H-NMR (300 MHz, CDCl3) δ 9.24 (s, 1H), 8.26 (d, 1H), 8.01 (d, 1H), 7.87 (dd, 1H), 7.25 (m, 2H), 6.85 (m, 2H), 6.33 (br s, 1H), 4.59 (d, 2H), 4.48 (heptet, 1H), 4.32-4.23 (m, 2H), 3.71 (m, 1H), 3.22-3.10 (m, 2H), 2.21-1.94 (m, 5H), 1.32 (d, 6H). LC/MS (ESI): calcd mass 444.2, found 445.2 (MH)+.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:22]>>[ClH:22].[F:21][C:18]([F:19])([F:20])[CH2:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:16]2
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(CC(F)(F)F)cc2C1
Agent: Cl
Product: FC(F)(F)Cc1ccc2c(c1)CNC2

Procedure:
Prepared in analogy to Example A3(e) from 5-(2,2,2-trifluoro-ethyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl Ester and hydrochloric acid. Off-white solid. MS (m/e): 202.4 ([M+H]+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[CH2:11]Cl.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[CH2:15]([O:14][P:13]([CH2:11][C:4]1[CH:5]=[C:6]([CH:7]=[O:8])[CH:9]=[CH:10][C:3]=1[O:2][CH3:1])(=[O:20])[O:17][CH2:18][CH3:19])[CH3:16]
Reactant: COc1ccc(C=O)cc1CCl
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cc(C=O)ccc1OC)OCC

Procedure:
In a ratio of 1:1 4-methoxy-3-chloromethylbenzaldehyde and triethyl phosphite were heated together until no more gas evolved. The reaction solution was then vacuum distilled to give the desired product. bp 172°-174° C. at 1 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.Cl.[NH2:35][CH2:36][CH:37]1[CH2:39][CH2:38]1>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:35][CH2:36][CH:37]3[CH2:39][CH2:38]3)=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Reactant: NCC1CC1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(NCC1CC1)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Yield: 62.7 %

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 110 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (121 μM), 0.026 cm3 of triethylamine and 21 mg of aminomethylcyclopropane hydrochloride. 68 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-cyclopropylmethylbenzamide are thus obtained in the form of a yellow foam [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 0.24 (mt, 2H), 0.44 (mt, 2H), 1.03 (mt, 1H), 2.98 (s, 3H), 3.15 (t, J=6 Hz, 2H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.86 (broad s, 1H), 7.89 (broad d, J=8 Hz, 1H), 8.64 (t, J=6 Hz, 1H)].