Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.CN1CCOCC1.[CH3:17][N:18]1[C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([C:28]([Cl:30])=[O:29])[C:22]=2[O:21][CH2:20][C:19]1=[O:31]>C(Cl)(Cl)Cl>[ClH:30].[CH3:17][N:18]1[C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([C:28]([NH:1][CH:2]3[CH:7]4[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]4)[CH2:3]3)=[O:29])[C:22]=2[O:21][CH2:20][C:19]1=[O:31]
Reactant: NC1CN2CCC1CC2
Reactant: CN1C(=O)COc2c(C(=O)Cl)cccc21
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)COc2c(C(=O)NC3CN4CCC3CC4)cccc21
Product: Cl

Procedure:
To a solution of 2.91 g of 3-aminoquinuclidine and 2.46 g of N-methylmorpholine in 30 ml of chloroform is added a solution of 5.0 g of 3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid chloride in 70 ml of chloroform under cooling and stirring followed by stirring for 7 hours. The resultant solution is washed with water, aqueous sodium hydrogen carbonate and then water, and dried over magnesium sulfate. After the solvent is distilled off under reduced pressure, the residue is purified with column chromatography using chloroform as an eluent and treated with ethanolic hydrochloric acid to give 3,4-dihydro-4-methyl-3-oxo-N-(3 -quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide hydrochloride, melting at 271°-272° C. with decomposition.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:26]([C:33](O)=[O:34])=[N:25]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:26]2[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:24][N:25]=2)=[O:34])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1noc2ccccc12
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2noc3ccccc23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with Benzo[d]isoxazole-3-carboxylic acid. LC-MS (basic): tR=0.93 min; [M+H]+=473.3.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][N:33]=2)[C:28]([CH:35]=O)=[CH:27]1.N1CCCCC1>CO>[NH:26]1[C:34]2=[N:33][CH:32]=[CH:31][CH:30]=[C:29]2[C:28](/[CH:35]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[CH:27]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ncccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 58.3 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) obtained in Example A16, Step 1 in methanol (1 mL) was added with 7-aza-1H-indole-3-carboxaldehyde (0.0502 g, 0.344 mmol) and piperidine (0.00244 g, 0.0287 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the precipitated solid was collected by filtration to obtain tert-butyl (Z)-4-({2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0798 g, 58%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[I:17]I>CCCCCC.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][C:9]([I:17])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Reactant: II
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
Following the procedures in U.S. Pat. No. 6,492,383, 2.5 M of n-butylithium (9.4 mL, 22.48 mmol) in hexane solution was added to a mixture of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine 4 (3.0 g, 11.74 mmol) in 60 mL of THF at −78° C. The reaction mixture was allowed to warm to −40° C. and stirred for 30 min. A solution of iodine (6.0 g, 23.48 mmol) in 10 mL of THF was added dropwise. After the addition was completed. The reaction mixture was brought to room temperature and stirred for 2 h. The mixture was quenched by diluting with dichloromethane and extracting with H2O (2×100 mL). The organic layer was washed with Na2S2O3 (2×100 mL), H2O (2×100 mL), dried over MgSO4, filtered and evaporated to afford 2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (3.4 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:5]([O:7]C)=[O:6].C(=O)([O-])[O-:15].[Cs+].[Cs+].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4]([OH:15])([CH2:9][CH:10]([CH3:12])[CH3:11])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)C(CC(C)C)C(=O)OC
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(O)(CC(C)C)C(=O)O
Reaction time: 24 h
Yield: 73.6 %

Procedure:
Air was bubbled for 1 hour at room temperature through a suspension of 0.5 g (3 mmol) dimethyl-(2-methylpropyl)malonate and 1.73 g (5 mmol) cesium carbonate in 7 ml dimethylformamide. Stirring was continued at room temperature for 24 hours. 25 ml water was added and the mixture was extracted with diethylether. Acidification with aqueous 1 N hydrochloric acid to pH=1 and extraction with ethylacetate yielded 0.42 g (83%) (R/S)-2-hydroxy-2-isobutyl-malonic acid monomethyl ester, MS (m/e): 189.4 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:10][S:11](=[O:13])(=[O:12])[C:6]=2[C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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[C:7]2[N:8]=[C:9]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:10][S:11](=[O:13])(=[O:12])[C:6]=2[C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccccn1
Reactant: O=S1(=O)NC(C2CCCCC2)=Nc2c(Cl)ccc(B(O)O)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=S1(=O)NC(C2CCCCC2)=Nc2c(Cl)ccc(-c3ccccn3)c21
Yield: 58.2 %

Procedure:
A mixture of 5-chloro-3-cyclohexyl-8-(dihydroxyboryl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (440 mg, 1.28 mmol), 2-bromopyridine (0.14 ml, 1.50 mmol), Pd(PPh3)2Cl2 (10 mg, 2 mol %) in 1,2-dimethoxyethane (30 ml) and Na2CO3 (2M, 3 ml, 6 mmol) were refluxed under N2 for 24 h. The solvents were removed under reduced pressure and the residue was treated with saturated NH4Cl (10 ml) and extracted with EtOAc (2×40 ml). The organic layer was washed with water (20 ml), dried (Na2SO4) and the solvent was removed under reduced pressure. The product was purified by flash chromatography on SiO2 using EtOAc:n-hexane (2:1, v/v) as eluent, yielding 280 mg (58%) of 5-chloro-3-cyclohexyl-8-(2-pyridyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as colorless crystals.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(S)CCC.C[CH:14]1[CH2:20][C:19](C)(C)[CH2:18][C:16](=[O:17])[CH2:15]1.Cl.[OH-].[Na+]>O>[CH:20]1[CH:19]=[C:18]([C:3]2[CH:4]=[CH:5][CH:6]=[C:1]([OH:7])[CH:2]=2)[C:16]([OH:17])=[CH:15][CH:14]=1
Reactant: Oc1ccccc1
Reactant: CC1CC(=O)CC(C)(C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCS
Solvent: O
Product: Oc1cccc(-c2ccccc2O)c1
Temperature: 30 °C
Reaction time: 70 h

Procedure:
564 (6 mol) of phenol, 10.8 g (0.12 mol) of butanethiol and 140 g (1 mol) of dihydroisophorone (3,3,5-trimethylcyclohexan-1-one) are introduced into a stirring apparatus equipped with a stirrer, thermometer, reflux condenser and gas inlet pipe at 30° C. At this temperature 44 g of 37% HCl are added. The reaction mixture is stirred for about 70 h at 28°-30° C. When 95% of the ketone has been converted (examined by GC) 2 l of water are added to the reaction mixture and a pH value of 6 is adjusted by adding a 45% NaOH solution. The reaction mixture is stirred for one hour at 80° C. and is then cooled to 25° C. The aqueous phase is decanted off and the remaining residue is washed with water at 80° C. The resulting crude product is filtered off and hot-extracted twice with n-hexane and twice with toluene and then filtered at 30° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[O:14][CH2:15][C:16]([F:19])([F:18])[F:17].[CH3:20][N:21]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:40].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:12]([S:9]([CH2:8][C:6]1[CH:5]=[CH:4][C:3]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:2]([C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:40])[N:21]([CH3:20])[CH:30]=2)[CH:7]=1)(=[O:11])=[O:10])[CH3:13]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Reactant: CCS(=O)(=O)Cc1ccc(OCC(F)(F)F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)Cc1ccc(OCC(F)(F)F)c(-c2cn(C)c(=O)c3ccccc23)c1
Temperature: 70 °C
Yield: 64.5 %

Procedure:
The title compound from Step 5 (200 mg, 0.58 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (197 mg, 0.69 mmol), Pd(PPh3)4 (67 mg, 58.0 umol) and Na2CO3 (184 mg, 1.74 mmol) in dioxane (6 mL) and water (6 drops) was degassed and then heated to 70° C. for 18 hours under N2. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (PE:EA=5:1˜1:1) followed by prep-HPLC purification to afford the title compound (164.44 mg, 67%) as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 8.52 (d, J=8.0 Hz, 1H), 7.58-7.48 (m, 3H), 7.40 (d, J=2.4 Hz, 1H), 7.22 (d, J=8.0, 1H), 7.07 (t, J=8.0, 2 H), 4.30 (q, J=8.0 Hz, 2H), 4.23 (s, 2H), 3.67 (s, 3H), 2.98 (q, J=7.6 Hz, 2H), 1.43 (t, J=7.6 Hz, 3H). LCMS: 440.0 (M+1)+
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.C(N(CC)CC)C.[Cl:31][C:32]1[CH:33]=[C:34]([N:39]=[C:40]=[O:41])[CH:35]=[CH:36][C:37]=1[CH3:38]>C1COCC1>[Cl:31][C:32]1[CH:33]=[C:34]([NH:39][C:40]([NH:2][CH2:3][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[C:6](=[O:23])[N:7]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:8]([CH3:14])=[N:9]3)=[O:41])[CH:35]=[CH:36][C:37]=1[CH3:38]
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: Cc1ccc(N=C=O)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)NCc2cccc3nc(C)n(C4CCC(=O)NC4=O)c(=O)c23)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a stirred suspension of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.51 g, 1.5 mmol) and triethylamine (0.30 mL, 2.1 mmol) in THF (15 mL) at 5˜10° C., was added 3-chloro-4-methyl phenyl isocyanate (0.27 mL, 1.9 mmol). Then the mixture was stirred at room temperature overnight. The mixture was quenched with methanol (˜1 mL), and the solvent was evaporated. The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-(3-chloro-4-methyl-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-urea as an off-white solid (520 mg, 73% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.58 min (99.1%); mp, 250-252° C.; 1HNMR (DMSO-d6) 2.17-2.22 (m, 4H, CHH, ArCH3), 2.59-2.93 (m, 6H, CHCH2, CH3), 4.71 (d, J=6 Hz, 2H, CH2NH), 5.27 (dd, J=6, 11 Hz, 11H, CH), 6.64 (t, J=6 Hz, 1H, CH2NH), 7.06-7.78 (m, 6H, Ar), 8.88 (s, 1H, NH), 11.04 (s, 1H, NH); 13C NMR (DMSO-d6) δ 18.69, 20.70, 23.31, 30.62, 42.31, 56.52, 116.24, 117.46, 117.81, 125.78, 126.28, 127.24, 130.98, 132.96, 133.99, 139.66, 141.30, 148.49, 154.76, 154.88, 161.02, 169.49, 172.65. LCMS MH=468, 470; Anal Calcd For C23H22N5O4Cl+0.2H2O: C, 58.59; H, 4.79; N, 14.85; Cl, 7.52. Found: C, 58.42; H, 4.55; N, 14.57; Cl, 7.83.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(Cl)(Cl)Cl.C(#N)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=[C:10]([CH2:14][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: Cc1ccc(-c2cccc(CO)c2-c2ccc(C)cc2)cc1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: Cc1ccc(-c2cccc(CN3CCCCC3)c2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Compound 23 described above (0.17 g, 0.589 mmol) was dissolved in chloroform (4 mL) (Wako Pure Chemical Industries, Ltd.), and thionyl chloride (0.5 mL) (Wako Pure Chemical Industries, Ltd.) was added dropwise while cooling with ice. The mixture was returned to room temperature and stirred for 1 hour, and then the solvent was distilled off under reduced pressure, to thereby obtain a residue. The residue was dissolved in acetonitrile (4 mL) (Wako Pure Chemical Industries, Ltd.), and piperidine (0.19 g, 2.23 mmol) (Wako Pure Chemical Industries, Ltd.) was added thereto. The mixture was refluxed for 45 minutes and allowed to cool to room temperature. The solvent was distilled off under reduced pressure, and then a saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) was added to the concentrated residue, and mixture was extracted with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was washed with water and brine. After that, the organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to alumina column chromatography (n-hexane (Wako Pure Chemical Industries, Ltd.) as an eluent), to thereby obtain the title compound (0.17 g, 81% yield).
Reaction SMILES: Cl.Br[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CCCCCC.[CH2:27]([Sn:31](Cl)([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH3:30].O>C1COCC1>[CH2:36]([Sn:31]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:32][CH2:33][CH2:34][CH3:35])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH2:37][CH2:38][CH3:39]
Reactant: Brc1c(COC2CCNCC2)ccc2ccccc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1c(COC2CCNCC2)ccc2ccccc12
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A solution of 1 (0.5 g, 1.6 mmole) in dry THF (50 ml) was cooled to -70° C. under argon. This was followed by the addition of 2.5 M solution of n-butylithiumin hexane (0.8 ml, 2.1 mmole) and tributyltin chloride (1.7 g, 5 mmole) and the reaction mixture was stirred for 30 min at -70° C. and then for 1 hr at room temperature. The rations mixture was then added to 50 ml of water and extracted with methylene chloride. The methylene chloride fractions were washed with saturated solution of NaHCO3, H2O, brine, dried with anhydrous MgSO4 and evaporated in vacuo to give 64 as light semi-solid. A single component was detected by TLC (ammonium hydroxide/methanol/ethyl acetate/hexane; 1:1:8:2) Rf, 0.5; NMR (CDCl3) d 0.8-1.5 (m, 27H, 3× n-butyl); d 4.6 (s, --CH--O-ring); d 7.8-8.0 (m, 6H, naphthyl).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3].OC/C=C(/C)\CCC=C(C)C.O=O>O>[CH3:3][C:2](=[CH:4][CH2:5][CH2:6][C:7](=[CH:9][CH:10]=[O:11])[CH3:8])[CH3:1]
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: CC(C)=CCC/C(C)=C\CO
Agent: O=O
Solvent: O
Product: CC(C)=CCCC(C)=CC=O

Procedure:
The resulting catalyst precursor was reduced by passing a gaseous stream of geraniol and nerol (65% geraniol/35% nerol; 670 mg/min, 4.3 mmol/min), O2 (73 ml/min, 3.3 mmol/min), and steam (10 ml/min water) through the reactor tube at 360° C. to produce citral in 80% yield (moles of citral produced per mole of nerol/geraniol introduced; determined by capillary weight percent gas chromatograph).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].C([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C.[CH2:26]([OH:28])[CH3:27]>CCOCC>[C:20]1([CH2:19][O:18][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[NH:10][CH:9]=[C:17]3[C:1](=[O:5])[C:2]([O:28][CH2:26][CH3:27])=[O:3])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCO
Reactant: CCc1cc2cccc(OCc3ccccc3)c2[nH]1
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1c[nH]c2c(OCc3ccccc3)cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Oxalyl chloride (3.2 g, 2.2 mL, 24.7 mmol) was added dropwise under nitrogen to an ice cold solution of ethyl 7-(phenylmethoxy)-indole (2.3 g, 10.3 mmol) in anhydrous ether (40 mL). The mixture was stirred for 1 hour at room temperature during which time a yellow precipitate was formed. The solvent and the excess of oxalyl chloride was removed at reduced pressure to yield 7-(phenylmethoxy)-indol-3-yl-glyoxyl chloride. Ethanol (50 mL) was then added to the residue and the solution was stirred overnight under nitrogen at room temperature. Removal of the solvent in vacuo provided ethyl 7-(phenylmethoxy)-indol-3-yl-glyoxylate as a tan solid (3 g, 94%).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([CH:18]=[N:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[N:23][NH:24]2)([OH:17])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6].B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl>[Br:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH3:16])=[C:8]2[C:13]=1[CH:18]([NH:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]3[C:21]=1[CH:22]=[N:23][NH:24]3)[C:3]([C:2]([F:29])([F:1])[F:30])([OH:17])[CH2:4][C:5]2([CH3:7])[CH3:6]
Reactant: COc1ccc(Br)cc1C(C)(C)CC(O)(C=Nc1cccc2[nH]ncc12)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(Br)c2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2[nH]ncc12
Temperature: -30 °C
Yield: 21 %

Procedure:
100 mg (0.206 mmol) of 1,1,1-trifluoro-4-(5-bromo-2-methoxyphenyl)-2-[(1H-indazol-4-yl)iminomethyl]-4-methylpentan-2-ol is dissolved in one milliliter of dichloromethane, and the reaction mixture is cooled to −30° C. Four milliliters of a 1 M solution of BBr3 in dichloromethane is added in drops within 15 minutes, and the batch is then stirred for 45 more minutes at −30° C. At −30° C., about 10 ml of a saturated sodium bicarbonate solution is carefully added in drops. After dilution with ethyl acetate, it is stirred for ten minutes and then extracted twice with 50 ml each of ethyl acetate. The combined organic extracts are washed with water and brine. The residue that is obtained after the solvent is dried and spun off is chromatographed several times on silica gel (mobile solvent ethyl acetate/dichloromethane). 21 mg of the desired compound (together with the corresponding Desbrom compound) is isolated.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CC(C)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CCn1ccc([N+](=O)[O-])n1
Reaction time: 16 h
Yield: 70.5 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 100 mg, 0.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and a 60% dispersion of sodium hydride in mineral oil (42 mg, 1.06 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 10 min before 1-bromo-3-methyl-butane (0.133 mL, 1.06 mmol) was added. The reaction continued to stir under nitrogen for 4 h. The reaction was stored at −25° C. for 16 h. The solution was diluted with ethyl acetate (30 mL), washed with water (2×10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 25% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-nitro-1-iso-pentyl-1H-pyrazole (115 mg, 59%) as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]([CH3:20])([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]([NH2:19])=[S:18])[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:22](I)[CH3:23]>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]([CH3:9])([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[NH:19])[S:18][CH2:22][CH3:23])[CH:11]=1)[CH3:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1cccc(NC(N)=S)c1
Reactant: CCI
Product: CCSC(=N)Nc1cccc(C(C)(C)NC(=O)OC(C)(C)C)c1
Yield: 97 %

Procedure:
Using the compound obtained in Example 3 as a starting material and also using ethyl iodide as a reagent, reaction was performed as in Example 29 to give 110 mg of the titled compound (yield, 97%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[N:13][C:14]([N:17]2[CH2:29][CH2:28][C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][C:19]=3[CH2:18]2)=[N:15][CH:16]=1)=[O:10].[H-].[Na+].[C:32](Cl)(=[O:34])[CH3:33]>CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[N:13][C:14]([N:17]2[CH2:29][CH2:28][C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([C:32](=[O:34])[CH3:33])[C:19]=3[CH2:18]2)=[N:15][CH:16]=1)=[O:10]
Reactant: O=C(NOC1CCCCO1)c1cnc(N2CCc3c([nH]c4ccccc34)C2)nc1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)n1c2c(c3ccccc31)CCN(c1ncc(C(=O)NOC3CCCCO3)cn1)C2
Reaction time: 0.33 h
Yield: 60.2 %

Procedure:
To a stirred solution of N-(tetrahydro-2H-pyran-2-yloxy)-2-[1,3,4,9-tetrahydro-2H-b-carbolin-2-yl]pyrimidine-5-carboxamide (120 mg, mmol) in DMF (5 mL) was added sodium hydride (22 mg) at 0° C. and the mixture was stirred for 20 min. Acetyl chloride (30 mg, mmol) was added and the reaction was allowed to attain room temperature and stirred 3 hours. After completion, the reaction mixture was partitioned between EtOAc and water. The organic layer was separated and washed with water, saturated sodium bicarbonate and concentrated. Pure N-(tetrahydro-2H-pyran-2-yloxy)-2-[9-acetyl-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl]pyrimidine-5-carboxamide (80 mg, 60% yield) was obtained by column chromatography m/e=436 (M+1).
Reaction SMILES: [OH-].[K+].[CH:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[C:10](\Br)/[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:5][CH:4]=1>O.O.CC(C)=O>[CH:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:5][CH:4]=1
Reactant: O=C(/C(Br)=C/c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(C#Cc1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
Potassium hydroxide (3.48 mmol), dissolved in water (0.87 M (4.0 ml)), is added over about 30 minutes to a refluxing solution of the alpha-bromochalcone (3.48 mmol) in 0.35 M of 1:1 water/acetone (5 ml each). After 20 minutes of further refluxing, the solution is cooled and diluted with water. The water is extracted with ether, which is dried with MgSO4 and evaporated. Chromatography on silica gel yielded 1,3-diphenylpropynone and its derivatives.