Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17](B1OC(C)(C)C(C)(C)O1)([CH3:19])=[CH2:18].C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH4+].[Cl-]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:17]([C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:19])=[CH2:18]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(-c2ccccc2)c(Br)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C=C(C)c1sc(C(=O)OC)cc1-c1ccccc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 5-bromo-4-phenylthiophene-2-carboxylate in dioxane were added 2-isopropenyl-4,4,5,5-tetramethyl 1,3,2-dioxaborolane and a 2 M aqueous Na2CO3 solution. To the reaction mixture were added palladium acetate and PPh3, followed by stirring at 100° C. for 5 hours. After leaving to be cooled, a saturated aqueous NH4Cl solution was added thereto, followed by extraction with EtOAc. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure, followed by purification by silica gel column chromatography (hexane:EtOAc=95:5 to 80:20) to obtain methyl 5-isopropenyl-4-phenylthiophene-2-carboxylate as a colorless liquid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[N:11]=[CH:12][S:13][CH:14]=1.[CH3:15][C:16]([S:19]([N:21]=[C:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:20])([CH3:18])[CH3:17].C[Al](C)C.CCCCCCC>C1COCC1.C1(C)C=CC=CC=1>[CH3:18][C:16]([S:19]([NH:21][C:22]1([C:12]2[S:13][CH:14]=[C:10]([CH3:9])[N:11]=2)[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:20])([CH3:15])[CH3:17]
Reactant: CC(C)(C)S(=O)N=C1CCOCC1
Reactant: Cc1cscn1
Agent: CC(C)[N-]C(C)C
Agent: C[Al](C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: Cc1csc(C2(NS(=O)C(C)(C)C)CCOCC2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
A 2.0M solution of lithium diisopropylamide in THF (492 μl, 984 μmol) was added dropwise to a solution of 4-methylthiazole (97.5 mg, 984 μmol) in dry THF (0.3 ml) cooled to −78° C. and once the addition was complete the reaction was stirred for 30 minutes at −78° C. followed by addition of dry toluene (0.6 ml). To a solution of 2-methyl-N-(2H-pyran-4(3H,5H,6H)-ylidene)propane-2-sulfinamide (CAN 861857-62-7, 100 mg, 492 μmol) in dry toluene (1 mL) was added a 2.0M solution of trimethylaluminum in heptane (271 μl, 541 μmol). The former solution was then added to the reaction mixture cooled at −78° C. The reaction was allowed to warm up to room temperature overnight. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride and was then diluted with ethyl acetate. The bi-phasic mixture was poured into a separatory funnel and extracted. The organic phase was collected, dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane/methanol gradient to yield the title compound (102 mg, 69%). MS (ESI, m/z): 303.5 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:8]=2[C:9]2[C:10]([CH2:22][O:23][CH3:24])=[C:11]([CH:20]=O)[N:12]=[CH:13][C:14]=2[NH:15]3)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:8]=2[C:9]2[C:10]([CH2:22][O:23][CH3:24])=[C:11]([CH:20]=[N:28][OH:29])[N:12]=[CH:13][C:14]=2[NH:15]3)=[CH:25][CH:26]=1
Reactant: NO
Reactant: COCc1c(C=O)ncc2[nH]c3cccc(Cc4ccc(Cl)cc4)c3c12
Agent: Cl
Solvent: c1ccncc1
Product: COCc1c(C=NO)ncc2[nH]c3cccc(Cc4ccc(Cl)cc4)c3c12
Yield: 63.2 %

Procedure:
0.75 g (0.002 mol) of 5-(4-chlorobenzyl)-4-methoxymethyl-β-carboline-3-carbaldehyde is heated one hour to 105° C. with 0.18 g (0.0026 mol) of hydroxylaminehydrochloride in 19 ml of pyridine. 0.48 g (61% of theory) of 5-(4-chlorobenzyl)-4-methoxymethyl-β-carboline-3-carbaldehyde-oxime is obtained from the evaporation residue after recrystallization from ethanol, melting point 224°-228° C.
Reaction SMILES: [Cl:1]C1C2C(=CC=C(C(Cl)=O)C=2)C(Cl)=CN=1.ClN1C(=O)CCC1=O.[Br:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][NH:31][C:32]2=[O:35])=[CH:27][CH:26]=1>CC#N>[Br:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([Cl:1])=[CH:30][NH:31][C:32]2=[O:35])=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: O=c1[nH]ccc2ccc(Br)cc12
Agent: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: O=c1[nH]cc(Cl)c2ccc(Br)cc12
Temperature: 25 °C

Procedure:
1,4-Dichloro-7-isoquinolinecarbonyl chloride ##STR166## A solution of N-chlorosuccinimide (4.13 g, 31 mmol) in MeCN (50 mL) was added dropwise to a stirred solution of 7-bromo-1-(2H)-isoquinolone (6.6 g, 29.5 mmol) in MeCN (150 mL) which was heating under reflux. The mixture was heated under reflux for an additional 3 h and then cooled to room temperature. The resulting precipitate was collected by filtration, with MeCN rinsing, and then dried in vacuo to give 7-bromo-4-chloro-1(2h)-isoquinolone (6.72 g, 26.0 mmol) as a white solid.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=C(C3C(OC)=CC=CC=3OC)C=CC=2)CCCCC1>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: Brc1ccccn1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1cccc(P(C2CCCCC2)C2CCCCC2)c1
Solvent: Cc1ccccc1
Product: c1ccc(-n2c3ccccc3c3ccccc32)nc1
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
9-H-carbazole (20 g, 120 mmol), and 2-bromopyridine (13 mL, 132 mmol) were mixed in dry toluene (500 mL). The solution was bubbled nitrogen while stirring for 15 min. Pd2(dba)3 (0.6 g, 0.66 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-3-yl)phosphine (1 g, 0.24 mmol) and sodium tert-butoxide (20 g, 200 mmol) were added in sequence. The mixture was heated to reflux overnight under nitrogen. After cooling, the reaction mixture was filtered through Celite®/silica pad and the solvent was then evaporated. The residue was then purified by silica gel column chromatography using toluene:hexane (1:1, v/v) as eluent to obtain 24.3 g (83%) of the desired product.
Reaction SMILES: N([O-])=O.[Na+].S(=O)(=O)(O)O.N[C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[CH2:21][CH3:22])[C:14]([O:16][CH3:17])=[O:15].[ClH:23]>C(O)(=O)C.Cl[Cu]>[Cl:23][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[CH2:21][CH3:22])[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCc1ccc(C(=O)OC)cc1N
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCc1ccc(C(=O)OC)cc1Cl
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
Charge NaNO2 (579 mg, 8.37 mmol) and concentrated sulfuric acid (6 mL) to a flask. As methyl 3-amino-4-ethylbenzoate (1.37 g, 7.62 mmol, PREPARATION 5) in acetic acid (18 mL) was added at 0° C., color of the mixture turned to yellow, and then stirred at 5° C. for 1.5 h. The solution above was added to a dark mixture of CuCl (1.65 g, 16.65 mmol) in concentrated HCl (18 mL) slowly at 0° C., stirred for 2 h, and poured into ice water, extracted with DCM, the organic phase was concentrated to give 582 mg of the title compound (38%). 1H NMR (400 MHz, CDCl3): δ 1.25 (3H, t, J=8.0 Hz), 2.80 (2H, q, J=7.6 Hz), 3.91 (3H, s), 7.30 (1H, d, J=7.6 Hz), 7.85 (1H, dd, J=1.2, 7.6 Hz), 8.01 (1H, d, J=1.6 Hz).
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].[C:14]([NH:21][C@@H:22]([CH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[C@@H:23]([OH:38])[CH2:24][C@@H:25]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:26]([OH:28])=[O:27])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>CN(C=O)C>[C:14]([NH:21][C@@H:22]([CH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[C@@H:23]([O:38][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12])[CH2:24][C@@H:25]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:26]([OH:28])=[O:27])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C[C@H](C[C@H](O)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
133 g (1.95 mol) of imidazole and 164 g (1.09 mol) of tert-butyldimethylchlorosilane are added, under an argon atmosphere, to an ice-cold solution of 124 g (238 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoic acid in 800 ml of DMF. After 17 h at RT, the reaction mixture is poured onto 1.9 l of ice-water and extracted 3× with 0.8 l of ethyl acetate on each occasion. The organic phases are washed with water, sat. NaHCO3 solution, water, 10% citric acid solution, water and, finally, saline, dried with Na2SO4 and evaporated. The residue is dissolved in 700 ml of methanol and 175 ml of THF, and 175 g of K2CO3 in 820 ml of water are added to this solution, which is then stirred at RT for 1 h. The resulting emulsion is partially evaporated on an RE, and the residue is diluted with ice-water, and this mixture is acidified to pH 4 with 10% citric acid solution while stirring vigorously. The mixture is extracted 3× with ethyl acetate, and the organic phases are washed with water and saline, dried with Na2SO4 and evaporated. Column chromatography (SiO2, hexane→hexane/ethyl acetate 95:5→9:1→2:1→1:1) results in the title compound: TLC Rf (E)=0.15; tRet (II)=22.7 min.
Reaction SMILES: [S:1]1[C:5]2([CH2:10][CH2:9][S:8][CH2:7][CH2:6]2)[CH:4]([C:11]([O:13]CC)=[O:12])[N:3]=C1.[ClH:16]>>[ClH:16].[NH2:3][CH:4]([C:5]1([SH:1])[CH2:6][CH2:7][S:8][CH2:9][CH2:10]1)[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)C1N=CSC12CCSCC2
Agent: Cl
Product: NC(C(=O)O)C1(S)CCSCC1
Yield: 100 %

Procedure:
27.2 g (0.11 mole) of ethyl 1,8-dithia-3-azaspiro[4.5]dec-2-ene-4-carboxylate are dissolved in 865 ml of 6N hydrochloric acid and boiled under reflux for 5 hours. The reaction mixture is then concentrated in vacuo in a rotary evaporator. The residue is taken up several times in dry benzene to eliminate traces of water and is then triturated in diethyl ether and filtered. There are obtained 27 g (approx. 100% of theory) of alpha-amino-4-mercapto-2,3,5,6-tetrahydro-4H-thiopyran-4-acetic acid hydrochloride. The product gives a straight spot by thin layer chromatography on silica (eluent: butanol, acetic acid, water: 4:1:1; Rf=0.45); M.P. 193 -197° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([CH2:12][S:13][C:14]1[C:25]2[O:24][C:23]([CH3:27])([CH3:26])[O:22][C:21]=2[C:20]([C:28]([C:53]2[C:63]3[O:64][C:65]([CH3:68])([CH3:67])[O:66][C:62]=3[C:61]([S:69][CH2:70][C:71](OCC)=[O:72])=[C:55]3[O:56][C:57]([CH3:60])([CH3:59])[O:58][C:54]=23)([C:30]2[C:40]3[O:41][C:42]([CH3:45])([CH3:44])[O:43][C:39]=3[C:38]([S:46][CH2:47][C:48](OCC)=[O:49])=[C:32]3[O:33][C:34]([CH3:37])([CH3:36])[O:35][C:31]=23)[OH:29])=[C:19]2[C:15]=1[O:16][C:17]([CH3:77])([CH3:76])[O:18]2)=O)C.C(#N)C.O>C(OCC)C.C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC>[OH:9][CH2:10][CH2:12][S:13][C:14]1[C:15]2[O:16][C:17]([CH3:76])([CH3:77])[O:18][C:19]=2[C:20]([C:28]([C:30]2[C:40]3[O:41][C:42]([CH3:45])([CH3:44])[O:43][C:39]=3[C:38]([S:46][CH2:47][CH2:48][OH:49])=[C:32]3[O:33][C:34]([CH3:36])([CH3:37])[O:35][C:31]=23)([C:53]2[C:63]3[O:64][C:65]([CH3:67])([CH3:68])[O:66][C:62]=3[C:61]([S:69][CH2:70][CH2:71][OH:72])=[C:55]3[O:56][C:57]([CH3:59])([CH3:60])[O:58][C:54]=23)[OH:29])=[C:21]2[C:25]=1[O:24][C:23]([CH3:27])([CH3:26])[O:22]2
Reactant: CCOC(=O)CSc1c2c(c(C(O)(c3c4c(c(SCC(=O)OCC)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(SCC(=O)OCC)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c1OC(C)(C)O3)OC(C)(C)O2
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Al+3]
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: CC1(C)Oc2c(c(C(O)(c3c4c(c(SCCO)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(SCCO)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c(c2SCCO)OC(C)(C)O3)O1
Yield: 97.8 %

Procedure:
LiAlH4 (15.2 mg, 0.40 mmol) was added to a solution of tris(8-ethoxycarbonylmethylthio-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-bis(1,3)dioxole-4-yl)methanol (10.5 mg 0.10 mmol (Example 27)) in diethyl ether (10 mL) under nitrogen at 20° C. The reaction was followed by HPLC (reversed phase C18, acetonitrile:water (3:1), 5 mM tetrabutylammonium acetate). The mixture was quenched with ethylacetate when no more substrate was seen by HPLC. Dilute sulfuric acid was then added until pH 6-7. The ether phase was separated, and the water phase was extracted with diethyl ether. The combined etheric phases were dried (MgSO4) and evaporated, yielding 0.0901 g (97.8%, 0.0978 mmol) of a yellowish oil, which gradually crystallized upon standing.
Reaction SMILES: Br.[Br:2][CH:3]1[CH:9]([CH3:10])[CH2:8][NH:7][CH2:6][CH2:5][C:4]1=O.[C:12]([NH2:15])(=[S:14])[CH3:13]>C(O)C>[BrH:2].[CH3:13][C:12]1[S:14][C:3]2[CH:9]([CH3:10])[CH2:8][NH:7][CH2:6][CH2:5][C:4]=2[N:15]=1
Reactant: CC(N)=S
Reactant: CC1CNCCC(=O)C1Br
Agent: Br
Solvent: CCO
Product: Cc1nc2c(s1)C(C)CNCC2
Yield: 92.5 %

Procedure:
18.5 g 5-bromo-6-methylazepan-4-one hydrobromic acid salt and 5.0 g thioacetamide were dissolved in 125 mL ethanol. The mixture was heated for 3 h under reflux. The solids were removed by filtration and the filtrate was concentrated in vacuo. 100 mL acetonitrile was added and the precipitate formed was isolated by filtration to yield 15.7 g of the desired product.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7]([F:10])([F:9])[F:8])[C:3](O)=[O:4].C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C)C=O>[CH3:1][CH:2]([CH2:6][C:7]([F:10])([F:9])[F:8])[C:3]([Cl:14])=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(CC(F)(F)F)C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(CC(F)(F)F)C(=O)Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 2-methyl-4,4,4-trifluorobutyric acid (172 g) in methylene chloride (150 mL) and N,N-dimethylformamide (3.5 mL) at 0° C., under nitrogen was added (dropwise) oxalyl chloride (125 mL). The mixture was allowed to warm to ambient temperature and stirred for 16 hours. After distillation of the solvent, distillation using a concentric tube distillation column (40 cm×15 mm) afforded 2-methyl-4,4,4-trifluorobutyryl chloride (about 99% purity, 79.87 g, 42%); bp 115.0°-116.0° C. (at atmospheric pressure, measured at room temperature as 763.27 mm Hg); GLC: tR =5.04 min; MS(CI): 139 (M+H-HCl).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1>C(Cl)Cl>[C:20]1([N:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:15]3[C:10]([C:11]([C:16]([F:18])([F:19])[F:17])=[CH:12][CH:13]=[CH:14]3)=[N:9]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1cccc2c(-c3ccccc3)n[nH]c12
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: FC(F)(F)c1cccc2c(-c3ccccc3)n(-c3ccccc3)nc12
Yield: 15.6 %

Procedure:
3-Phenyl-7-trifluoromethylindazole (0.2 g, 0.76 mmol), phenyl boronic acid (186 mg, 1.53 mmol), copper II acetate (208 mg, 1.14 mmol), and pyridine (93 uL, 1.14 mmol) in 6 mL methylene chloride were stirred at room temperature for 72 hours. The reaction mixture was filtered through Celite®, poured into NH4Cl (sat. soln.) and extracted with EtOAc. The combined organic layers were dried with Na2SO4, concentrated and the resulting residue was purified by HPLC (10-100% CH3CN—H2O) to provide the desired compound as a white solid (40 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[C:12]([NH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:14])[CH3:13].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:12](=[O:14])[CH3:13])[CH2:17][CH2:18]1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CC(=O)NC1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC1CCN(S(=O)(=O)c2ccccc2Br)CC1
Yield: 94.9 %

Procedure:
A solution of 2-bromobenzene-1-sulfonyl chloride (0.500 g, 1.96 mmol), 4-acetamidopiperidine (0.335 g, 2.45 mmol), and diisopropylethyl amine (1.0 mL, 5.8 mmol) in CH2Cl2 (5 mL) was stirred for 15 min at rt. The reaction mixture was then washed with 1 N HCl (2×5 mL) followed by brine (10 mL). The organic layer was isolated, dried over MgSO4, filtered, and concentrated to dryness to give the title compound (0.672 g, 95%). The product was used without further purification. 1H NMR (400 MHz, CDCl3) δ 8.09-8.05 (m, 1H), 7.77-7.74 (m, 1H), 7.49-7.38 (m, 2H), 6.08 (d, J=8.0, 1H), 3.87-3.79 (m, 2H), 2.93-2.85 (m, 2H), 2.00-1.93 (m, 5H), 1.59-1.51 (m, 3H).
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH2:14]([O:21][CH2:22][CH2:23][CH2:24][C@H:25]([CH3:28])[CH2:26][OH:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH2:14]([O:21][CH2:22][CH2:23][CH2:24][C@H:25]([CH3:28])[CH2:26][O:27][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@H](CO)CCCOCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H](CCCOCc1ccccc1)CO[Si](C)(C)C(C)(C)C
Temperature: 40 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
Imidazole (1.230 g, 18.06 mmol, 2.6 equiv) and tert-butyl-dimethylsilyl chloride (1.230 g, 9.03 mmol, 1.3 equiv) are added to a solution of (S)-5-benzyloxy-2-methyl-pentan-1-ol- 4 (1.447 g, 6.95 mmol) in dimethyl formamide (5.5 ml). The mixture is stirred for 1 h at 40° C. Purification of the reaction mixture by flash column chromatography (pentane/diethyl ether 20:1) affords (s)-1-benzyloxy-5-(tert-butyldimethylsilyloxy)-4-methyl-pentane 5 (1.985 g, 89%) as a colouriess oil (the reaction mixture is poured directly without aqueous workup onto a flash chromatography column which is pre-wetted with the eluent). 13C-NMR (100 MHz, CDCl3): δ=138.7; 128.3; 127.5; 127.4; 72.8; 70.8; 68.2; 35.6; 29.6; 27.2; 25.9; 18.3; 16.6; −5.4.
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1/[C:13](/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:14]\[C:15]([O:17]CC)=[O:16].O.Cl>C(O)C.O1CCCC1>[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1/[C:13](/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:14]\[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)/C=C(/c1ccccc1)c1ccc2ccccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)/C=C(/c1ccccc1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
24 ml of a 10% w/v aqueous solution of sodium hydroxide were added to a solution of 2.411 g of ethyl (Z)-3-(2-naphthyl)-3-phenylacrylate (prepared as described in Preparation 112) in 48 ml of ethanol and 24 ml of tetrahydrofuran. The mixture was stirred for 15 hours at room temperature and then poured into water. The pH of the resulting mixture was adjusted to a value of 2 by the addition of concentrated hydrochloric acid, and the mixture was then extracted twice with methylene chloride. The combined extracts were washed with water and dried over anhydrous sodium sulfate; the solvent was then removed by evaporation under reduced pressure. The residue was recrystallized from a mixture of methylene chloride and hexane, to give 2.005 g of the title copound, melting at 170°-172° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6](Cl)[N:5]=[C:4]([CH3:10])[N:3]=1.[OH-].[NH4+:12]>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([CH3:10])[N:5]=[C:6]([NH2:12])[C:7]=1[CH3:8]
Reactant: [NH4+]
Reactant: Cc1nc(Cl)c(C)c(Cl)n1
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(N)c(C)c(Cl)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A microwave vial was charged with 4,6-dichloro-2,5-dimethylpyrimidine (523 mg, 2.95 mmol) and ammonium hydroxide (8 mL) in ethanol (4 mL). The vial was heated to 80° C. and stirred for 8 h. After concentration under reduced pressure, the reaction mixture was extracted with EtOAc (15 mL×8). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give 6-chloro-2,5-dimethylpyrimidin-4-amine as a yellow solid (411 mg). MS (ESI): m/z 158 [M+H]+.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][C:3](=[O:6])[CH2:2]1.[F:8][CH:9]([F:17])[C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.CO>O>[F:8][CH:9]([F:17])[C:10]1[CH:11]=[C:12]([NH:13][C:1]2[CH2:5][CH2:4][C:3](=[O:6])[CH:2]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cccc(C(F)F)c1
Reactant: O=C1CCC(=O)C1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: CO
Product: O=C1C=C(Nc2cccc(C(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of cyclopentane-1,3-dione (2.00 g, 20.4 mmol), 3-(difluoromethyl)aniline (2.92 g, 20.4 mmol) and Ytterbium(III) trifluormethanesulfonate (63 mg, 0.10 mmol, 0.5 mol %) is stirred at room temperature for 2 h. Methanol and water are added and the resulting precipitate is filtered and dried. Yield: 2.75 g; ESI mass spectrum: [M+H]+=224; Retention time HPLC: 0.82 min (V012_S01).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].C1(C(C2C=CC=CC=2)[N:18]2[CH2:21][CH:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[CH2:19]2)C=CC=CC=1>C(Cl)Cl>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[Cl:29])[O:22][CH:20]1[CH2:19][N:18]([C:1]([Cl:4])=[O:2])[CH2:21]1
Reactant: O=C(Cl)Cl
Reactant: Clc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Cl)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Reaction time: 1 h
Yield: 39.5 %

Procedure:
A solution of 14 g (0.144 mole) of phosgene in 200 ml of methylene chloride was treated with 19.9 g (0.144 mole) of anhydrous potassium carbonate and stirred for 1 hr, then 45.9 g (0.12 mole) of 1-diphenylmethyl-3-(3,4-dichlorophenoxy)azetidine in 100 ml of methylene chloride was added dropwise and stirring was continued for 72 hr. The reaction mixture was filtered to remove the inorganic salts and then concentrated in vacuo to a pale yellow oil (67 g). Trituration of the residue with cyclohexane yielded a crude pale yellow solid (23.6 g). The filtrate was treated with ligroin and upon standing, an additional 13.3 g of tacky material was obtained. After several recrystallizations from cyclohexane to remove traces of diphenylmethyl chloride a portion was obtained as fine white crystals, in 70.1% yield, m.p. 96°-99° C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH:11]([N:24]1[CH2:27][CH:26]([OH:28])[CH2:25]1)([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.C(N(CC)CC)C>C(Cl)Cl>[CH:11]([N:24]1[CH2:27][C:26](=[O:28])[CH2:25]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 104.4 %

Procedure:
To a stirring solution of DMSO (12.45 ml, 176 mmol) in DCM (150 mL) at −78° C. under an argon atmosphere was added dropwise oxalyl chloride (8.61 mL, 100 mmol). After stirring for 30 minutes at −78° C., a solution of 1-benzhydrylazetidin-3-ol (20 g, 84 mmol) in DCM (75 mL) was added dropwise. The reaction mixture was stirred for 1 h at −78° C. before triethylamine (58.2 ml, 418 mmol) was added. The reaction mixture was allowed to reach 0° C. and was quenched with saturated NH4Cl (150 mL), and then extracted with DCM (3×). The combined organic layers were washed with water, brine, dried on Na2SO4 and concentrated to give crude 1-benzhydrylazetidin-3-one (20.8 g, 105%) as a yellow solid.