Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1([NH2:7])[CH2:6][O:5][CH2:4]1.C(N(CC)CC)C.[Cl:15][C:16]1[N:17]=[C:18](Cl)[C:19]2[S:24][CH:23]=[CH:22][C:20]=2[N:21]=1.O>ClCCl>[NH2:7][C:3]1([CH2:2][NH:1][C:18]2[C:19]3[S:24][CH:23]=[CH:22][C:20]=3[N:21]=[C:16]([Cl:15])[N:17]=2)[CH2:6][O:5][CH2:4]1.[NH2:1][CH2:2][C:3]1([NH:7][C:18]2[C:19]3[S:24][CH:23]=[CH:22][C:20]=3[N:21]=[C:16]([Cl:15])[N:17]=2)[CH2:6][O:5][CH2:4]1
Reactant: Clc1nc(Cl)c2sccc2n1
Reactant: NCC1(N)COC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: NC1(CNc2nc(Cl)nc3ccsc23)COC1
Product: NCC1(Nc2nc(Cl)nc3ccsc23)COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %
Yield: 153.9 %

Procedure:
To a mixture of 3-aminomethyloxetan-3-ylamine (0.98 g, 9.6 mmol) in dichloromethane (15 mL) and triethylamine (4 mL, 28.7 mol) was added a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (1.0 g, 4.8 mmol) dropwise in dichloromethane (5 mL). The mixture was stirred at room temperature overnight, then water (50 mL) was added. The mixture was extracted with dichloromethane. The organic phase was washed with brine, dried with anhydrous sodium sulfate. The solvent was then removed and the residue was purified by flash column chromatography (eluting with 10%˜30% methanol in dichloromethane) to give 1.0 g of N-[(3-aminooxetan-3-yl)methyl]-2-chlorothieno[3,2-d]pyrimidin-4-amine and N-[3-(aminomethyl)oxetan-3-yl]-2-chlorothieno[3,2-d]pyrimidin-4-amine (yield was 77%). MS obsd. (ESI+) [(M+H)+] 271.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[C:6]([CH3:14])=[CH:5][C:4]1=[O:15])[CH3:2].[C:16]([NH:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33]Cl)[CH2:27][CH2:26]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([NH:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][O:13][C:10]2[CH:11]=[C:12]3[C:7]([C:6]([CH3:14])=[CH:5][C:4](=[O:15])[N:3]3[CH2:1][CH3:2])=[CH:8][CH:9]=2)[CH2:27][CH2:26]1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCn1c(=O)cc(C)c2ccc(O)cc21
Reactant: O=C(NC1CCN(CCCCl)CC1)c1ccccc1
Product: CCn1c(=O)cc(C)c2ccc(OCCCN3CCC(NC(=O)c4ccccc4)CC3)cc21
Yield: 59 %

Procedure:
In a manner analogous to that described in Example 11, by the reaction of 1-ethyl-7-hydroxy-4-methyl-2-oxo-1,2-dihydroquinoline with 3-(4-benzamidopiperidino)-propyl chloride, there is obtained, in a yield of 59% of theory, 7-[3-(4-benzamido-piperidino)-propoxy]-1-ethyl-4-methyl-2-oxo-1,2-dihydroquinoline; m.p. 164°-165° C. (after recrystallization from dichloromethane/diethyl ether).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Cl-].[Al+3].[Cl-].[Cl-].[C:12]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1)(=[O:14])[CH3:13]>ClCCCl>[C:12]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])=[CH:21][CH:22]=2)[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1CCc2ccccc21
Reactant: CCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCCC(=O)c1ccc2c(c1)CCN2C(C)=O
Temperature: 0 °C
Yield: 67.7 %

Procedure:
Pentanoyl chloride (10.8 g) was added dropwise to a mixture of anhydrous aluminium chloride (28.2 g) and 1-acetyl-2,3-dihydro-1H-indole (10 g) in 1,2-dichloroethane (100 mL) with mechanical stirring. The mixture was stirred at reflux for 16 hours, then cooled, then poured into ice-water. The mixture was extracted with dichloromethane. The extracts were washed with 1M aqueous sodium hydroxide, then dried over magnesium sulphate, then evaporated to give the title compound (10.3 g) as a dark gum.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(COC)OC.C(Cl)[Cl:34]>>[ClH:34].[CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:34])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: ClCCl
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Product: Cl

Procedure:
A cold solution of 25 g. of 4-(hexadecylamino)benzoic acid in 500 ml. of dimethoxyethane-methylene chloride (4:1) is prepared and dry hydrochloric acid is bubbled through the solution until no more precipitate forms. The solution is treated with 25 ml. of thionyl chloride and refluxed until all of the precipitate has re-dissolved. The solvents are evaporated to yield an orange, semi-crystalline mass.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[Br:24][C:25]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][CH:32]=[C:33]([CH3:34])[C:25]=3[Br:24])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: Cc1cccc(C(=O)O)c1Br
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1c2ccc(NC(=O)c3cccc(C)c3Br)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (25 mg) with 2-bromo-3-methylbenzoic acid (19 mg) under the agency of HATU (68 mg) and N,N-diisopropylethylamine (32 l) in dichloromethane (4 ml) was performed according to the method described in example 11.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:21]([C:20]([N:1]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:25])([CH3:24])([CH3:23])[CH3:22]
Reactant: C1COCCOCCOCCN1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N1CCOCCOCCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3.81 mmol of 1-aza-4,7,10-trioxacyclododecane are dissolved in 50 ml of CH2Cl2. 0.6 ml of triethylamine are added and 0.1 g of DMAP (=4-dimethylaminopyridine) is added as catalyst 3.82 mmol of pivalyl chloride are subsequently added, and the mixture is stirred at room temperature for 18 hours.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:8]([NH:11][CH2:12][CH:13]=[CH2:14])[CH:9]=[CH2:10].[OH-].[Na+]>>[CH2:8]([N:11]([CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH:9]=[CH2:10]
Reactant: Clc1ccncc1
Reactant: C=CCNCC=C
Agent: [Na+]
Agent: [OH-]
Product: C=CCN(CC=C)c1ccncc1

Procedure:
4-Chloropyridine (13.24 g) was refluxed with excess diallylamine (28.04 g) under a nitrogen atmosphere for 3 days. The product mixture was neutralized with aqueous NaOH and extracted with ether. After drying, the ether was removed by simple distillation and the product purified by fractional distillation under reduced pressure. The pure 4-(diallylamino)pyridine (DAAP) was characterized by elemental analysis, FTIR, 13C NMR, and GC.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH:4]1[CH:8]([CH3:9])[O:7][C:6]([C:14]([Cl:17])([F:16])[F:15])([C:10]([Cl:13])([F:12])[F:11])[O:5]1)[OH:3].[O-:19][C:20]#[N:21].[Na+].FC(F)(F)C(O)=O.O>C(Cl)Cl>[C:20]([O:3][C:2]([CH3:1])([CH3:18])[CH:4]1[CH:8]([CH3:9])[O:7][C:6]([C:14]([Cl:17])([F:16])[F:15])([C:10]([Cl:13])([F:11])[F:12])[O:5]1)(=[O:19])[NH2:21]
Reactant: CC1OC(C(F)(F)Cl)(C(F)(F)Cl)OC1C(C)(C)O
Reactant: N#C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC1OC(C(F)(F)Cl)(C(F)(F)Cl)OC1C(C)(C)OC(N)=O
Reaction time: 24 h

Procedure:
A solution of 31.5 grams (0.1 mol) of α,α,5-trimethyl-2,2-bis(chlorodifluoromethyl)-1,3-dioxolane-4-methanol in 180 ml methylene dichloride is treated with 13.0 grams sodium cyanate (0.2 mol) while 22.8 grams of trifluoroacetic acid (0.2 mol) is added dropwise. The reaction is carried out at 25°-35° C. for 24 hours. After the reaction is completed, a small amount of water is added to dissolve salts and the methylene dichloride solution is separated and extracted once more with water. Vacuum stripping yields the product α,α,5-trimethyl-2,2-bis(chlorodifluoromethyl)-1,3-dioxolane-4-methanol carbamate. The product is purified by crystallization from a mixture of benzene and hexane.
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5]CC)=[O:4].[CH2:10]([NH:17][CH2:18][CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:28](N(CC)CC)[CH3:29]>C1C=CC=CC=1>[C:3]([CH2:2][CH2:8][CH:18]1[CH2:19][N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:29][CH2:28][N:17]1[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([OH:5])=[O:4]
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Reactant: CCOC(=O)C(Br)CBr
Reactant: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(O)CCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Yield: 89.7 %

Procedure:
To a solution of 43.29 g (166.0 mmol) of ethyl 2,3-dibromopropionate in 145 ml of benzene warmed at 40° C. was added dropwise a solution of 40 g (166.0 mmol) of N,N'-dibenzylethylenediamine and 46.2 ml (166.0 mmol) of triethylamine in 40 ml of benzene. The vigourous stirred suspension was heated under reflux overnight, cooled and filtered. The benzene layer was washed three times with 50 ml of water. The organic layer was dried over magnesium sulfate. After evaporation 58.95 g of a thick oil was obtained which was purified by chromatography using dichloromethane/ethyl acetate (90:10) to yield 50.4 g (89.7%) of title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10](S(C)=O)SC)[C:7]([F:16])=[CH:6][C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:18].O>C1COCC1>[F:1][C:2]1[CH:9]=[C:8]([CH:10]=[O:18])[C:7]([F:16])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=S(=O)(O)O
Reactant: CSC(c1cc(F)c(C#N)cc1F)S(C)=O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(F)c(C=O)cc1F
Reaction time: 144 h

Procedure:
2,5-Difluoro-4-[(methylsulfinyl)(methylthio)methyl]benzonitrile (2.8 g, 0.0107 mol; see step (i) above) was dissolved in 100 mL of THF and 6.5 g of concentrated sulfuric acid was added. The mixture was left at room temperature for 6 days and subsequently poured into 500 mL of water. Extraction three times with diethyl ether followed and the combined ethereal phase washed several times with water, dried (Na2SO4) and evaporated. The crude product was flash chromatographed on silica gel using heptane:EtOAc (8:2). Yield: 1.2 g (67%). The position of the formyl group was established by use of 13C NMR. The carbon signals from the fluorinated carbons at 160.1 and 158.4 respectively were doublets and not quartets, which they would have been if the formyl group had been in the 2-position.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][C:3]1=[O:9].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:23][C:24]1[CH:38]=[CH:37][C:27]([C:28]2[CH:29]=[CH:30][C:31]([CH2:35][CH3:36])=[C:32]([Pb+3])[CH:33]=2)=[CH:26][CH:25]=1.CN(C1C=CC=CN=1)C.C(Cl)(Cl)Cl>ClCCl.Cl.C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:38]=[CH:37][C:27]([C:28]2[CH:33]=[CH:32][C:31]([CH2:35][CH3:36])=[C:30]([CH:4]3[C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[CH2:7][CH2:6][C:5]3=[O:8])[CH:29]=2)=[CH:26][CH:25]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Reactant: CC1(C)CCC(=O)CC1=O
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)CCC(C)(C)C1=O
Temperature: 80 °C

Procedure:
To a mixture of 4,4-dimethyl-1,3-cyclohexanedione (0.21 g, 1.5 mmol), 4′-chloro-4-ethylbiphen-3-yllead triacetate (1.0 g, 1.7 mmol) and dimethylaminopyridine (0.93 g, 7.6 mmol) is added anhydrous chloroform (11 ml) and anhydrous toluene (2.8 ml). The reaction mixture is heated at 80° C. for 4 hours and then cooled to room temperature. The mixture is diluted with dichloromethane (50 ml) and 2M aqueous hydrochloric acid (50 ml) and filtered through diatomaceous earth. The filtrate is partitioned, the aqueous layer is extracted with dichloromethane (50 ml) and the organic extracts are combined, washed with 2M aqueous hydrochloric acid (50 ml), brine (50 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The crude product is purified by preparative reverse phase HPLC to give 2-(4′-chloro-4-ethylbiphen-3-yl)-4,4-dimethyl-1,3-cyclohexanedione.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11]C(C)(C)C)=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[CH:5]=O.Cl.[NH2:17]O.C(O)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C(O)CCC>[Br:1][C:2]1[C:3]2[S:11][N:17]=[CH:5][C:4]=2[C:7]([F:10])=[CH:8][CH:9]=1
Reactant: CC(C)(C)Sc1c(Br)ccc(F)c1C=O
Reactant: NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Solvent: CCCCO
Product: Fc1ccc(Br)c2sncc12
Temperature: 70 °C
Yield: 40 %

Procedure:
A mixture of 3-bromo-2-(tert-butylsulfanyl)-6-fluorobenzaldehyde (1.20 g, 4.12 mmol) and hydroxylamine hydrochloride (1.432 g, 20.60 mmol) in isopropanol (60 mL, 800 mmol) and water (10 mL) was heated to 70° C. for 20 min. The organic solvent was removed in vacuo, and saturated aqueous sodium bicarbonate was added to bring the pH to 8.5. The material was extracted with DCM and water, and the organic layer was concentrated in vacuo. The residue was treated with p-toluenesulfonic acid (141.9 mg, 0.8242 mmol) in n-butanol (60 mL) and the solution was heated to 120° C. overnight. The solvent was removed in vacuo. The residue was purified by column chromatography (1 to 2% EtOAc:hexanes) to afford 382 mg (40%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.01 (dd, J=9.1, 8.3 Hz, 1 H), 7.60 (dd, J=8.3, 4.0 Hz, 1 H), 9.10 (s, 1 H).
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.[NH2:8][C:9](=[NH:42])[N:10]1[CH2:14][C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C@H:12]([C:22]([N:24]2[CH2:28][CH2:27][C@H:26]([N:29]([C@H:35]3[CH2:40][CH2:39][C@@H:38]([CH3:41])[CH2:37][CH2:36]3)[C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH2:25]2)=[O:23])[CH2:11]1.C(OC(=O)C)(=O)C>C(Cl)Cl>[C:2]([NH:42][C:9](=[NH:8])[N:10]1[CH2:14][C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C@H:12]([C:22]([N:24]2[CH2:28][CH2:27][C@H:26]([N:29]([C@H:35]3[CH2:36][CH2:37][C@@H:38]([CH3:41])[CH2:39][CH2:40]3)[C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH2:25]2)=[O:23])[CH2:11]1)(=[O:1])[CH3:4]
Reactant: CC(C)C(=O)N([C@H]1CCN(C(=O)[C@@H]2CN(C(=N)N)C[C@H]2c2ccc(Cl)cc2)C1)[C@H]1CC[C@@H](C)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC(=N)N1C[C@@H](C(=O)N2CC[C@H](N(C(=O)C(C)C)[C@H]3CC[C@@H](C)CC3)C2)[C@H](c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of N-[(3S)-1-{[(3S,4R)-1-[amino(imino)methyl]-4-(4-chlorophenyl)pyrrolidine-3-yl]carbonyl}pyrrolidine-3-yl]-2-methyl-N-(cis-4-methylcyclohexyl)propaneamide TFA salt (185 mg, 0.3 mmol) prepared in Example E9 in DCM (3 ml) was added acetic acid anhydride (46 mg, 0.45 mmol) and TEA (71 mg, 0.7 mmol), and stirred at rt for 6 h. After the reaction finished, the solvent was concentrated in vacuo, extracted with water and EtOAc, and the organic layer was dried over MgSO4. The organic solution was concentrated in vacuo, and purified by HPLC to give the title compound (139 mg, 85%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Na].C1(C)C(C)=CC=CC=1.Br[C:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([CH3:31])[CH2:29][OH:30]>C(O)C>[S:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([CH3:31])[CH2:29][OH:30])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1
Reactant: Oc1ccc(C2CCSc3ccccc32)cc1
Reactant: CC(Br)(CO)c1ccccc1
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1C
Product: CC(CO)(Oc1ccc(C2CCSc3ccccc32)cc1)c1ccccc1
Temperature: 20 °C
Reaction time: 6 h

Procedure:
A mixture of 2.42 g. of 4p-hydroxyphenyl-thiochromane and 0.23 g. of sodium in 50 ml. of xylene is boiled for 3 hours. The mixture is allowed to cool to 20° C., 2.15 g. of 2-bromo-2-phenylpropanol in 10 ml. of xylene are added and the suspension is stirred for 6 hours at the boil, cooled and treated with 2 ml. of ethanol. The inorganic precipitate is filtered off, the filtrate is evaporated, the residue is taken up in ether and the solution is washed with NaHCO3 solution and saturated NaCl solution, dried over MgSO4 and evaporated, to give 2-[4-(4-thiochromanyl)-phenoxy]-2-phenylpropanol, nD20 1.6172.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([CH2:16][OH:17])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=[O:20].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O.CCOCC>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:13])[F:14])=[C:10]([C:16]([OH:20])=[O:17])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1onc(-c2ccccc2)c1C(F)(F)F
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CCOCC
Product: O=C(O)c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)methanol (5.24 g, 21.6 mmol) in acetone (75 mL) at room temperature (immersed in a water bath) was added Jones' Reagent (43.8 mL, 53.9 mmol) via addition funnel slowly over 1.5 h. The dark reaction mixture was stirred at room temperature overnight. By HPLC, the reaction was 93% complete. An additional 0.5 equivalents (9 mL) of the Jones' Reagent was added. After 1 h, the reaction was 95% complete. After an additional 3 h, the reaction was 96% complete. An additional 0.5 equivalents (9 mL) of the Jones' Reagent was added. The reaction mixture was stirred for an additional 2.5 h. By HPLC, the reaction was 97% complete. Isopropyl alcohol (6 mL) was added, and the mixture was stirred for 90 min, resulting in a dark green precipitate. The mixture was diluted with ether (600 mL), washed with a 2% aqueous solution of sodium hydrogen sulfite (5×100 mL), and the organic layer was collected. The aqueous layer was back-extracted with ether (2×100 mL). By HPLC, there was no additional product in the aqueous layer. The combined organic layers were washed with water (100 mL), washed with a saturated aqueous solution of brine (100 mL), and dried over anhydrous sodium sulfate. The aqueous layer was back-extracted with ether (100 mL), and the organic layer was added to the previous organic layers. The solution was concentration under reduced pressure to give 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid as an off-white solid. The solid was diluted with dichloromethane (200 mL), washed with a 2% aqueous solution of sodium hydrogen sulfite, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (3.84 g, 14.93 mmol, 69.3% yield) as a pale yellow solid. The product was 96% pure by HPLC with a ret. time=1.60 min.—Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=258.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:12][C:13]([CH3:18])([CH3:17])[CH2:14][CH:15]=O.N1CCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:15]/[CH2:14][C:13]([CH3:18])([CH3:17])[CH3:12])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CC(C)(C)CC=O
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)C/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 100 °C
Yield: 99.4 %

Procedure:
To the mixture of 6-chlorooxindole (0.26 g, 1.49 mmol) (Crescent) and 3,3-dimethyl-butyraldehyde (0.21 g, 2.09 mmol) (Aldrich) in methanol (20 mL) was added pyrrolidine (0.15 g, 2.09 mmol) (Aldrich) dropwise. The mixture was then heated at 100° C. for 1 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over Na2SO4, concentrated, and dried in vacuo to give the crude E/Z-6-chloro-3-(3,3-dimethyl-butylidene)-1,3-dihydro-indol-2-one as a white solid (Yield 0.37 g, 100%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:18][C:17]2[NH:16][N:15]=[C:14]([CH3:19])[C:13]=2[C:12](=[O:20])[CH2:11]1.[C:21]1([CH2:27][CH2:28][CH2:29]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:18][C:17]2[N:16]([CH2:29][CH2:28][CH2:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:15]=[C:14]([CH3:19])[C:13]=2[C:12](=[O:20])[CH2:11]1.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:18][C:17]2[C:13](=[C:14]([CH3:19])[N:15]([CH2:29][CH2:28][CH2:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:16]=2)[C:12](=[O:20])[CH2:11]1
Reactant: Cc1n[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: BrCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c2c(nn1CCCc1ccccc1)CC(c1ccccc1Cl)CC2=O
Product: Cc1nn(CCCc2ccccc2)c2c1C(=O)CC(c1ccccc1Cl)C2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 60% sodium hydride (0.068 g, washed with hexane thrice) in dimethylformamide (10 ml) was added a solution of 6-(2-chlorophenyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (0.4 g) in dimethylformamide (2 ml) at 0° C., and the mixture was stirred at room temperature for 40 minutes. To the mixture was added 3-phenylpropyl bromide (0.32 g), and the mixture was stirred at the same temperature for 19 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (ethyl acetate-hexane) to give 6-(2-chlorophenyl)-3-methyl-1-(3-phenylpropyl)-4,5,6,7-tetrahydroindazol-4-one (0.20 g) as colorless crystals and 6-(2-chlorophenyl)-3-methyl-2-(3-phenylpropyl)-4,5,6,7-tetrahydroindazol-4-one (0.26 g) as oil.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:5][CH2:4]1.C1C2C(=CC=CC=2)CCN=1>>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH2:11][CH2:12][N:13]=[CH:14]3)[CH2:5][CH2:4]1
Reactant: COC1CCN(c2cccc3c2CCNC3)CC1
Agent: C1=NCCc2ccccc21
Product: COC1CCN(c2cccc3c2CCN=C3)CC1
Yield: 100 %

Procedure:
Intermediate 3B was oxidized as described for Intermediate 2 to afford 6.32 g (100%) of Intermediate 3 as a yellow viscous oil. MS (ESI) m/z: 245.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][C:8]([C@H:14]2[S:18][C@H:17]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)[CH2:16][S:15]2)=[CH:7][C:6]=1[O:31][CH3:32])[CH:2]=[CH2:3].[Cl-].[Ca+2].[Cl-]>C(O)C.O.[Zn]>[CH2:1]([O:4][C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C@H:14]2[S:18][C@H:17]([C:19]3[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=3)[CH2:16][S:15]2)=[CH:7][C:6]=1[O:31][CH3:32])[CH:2]=[CH2:3]
Reactant: C=CCOc1c(OC)cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc1[N+](=O)[O-]
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: C=CCOc1c(N)cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc1OC

Procedure:
Trans-2-(4-allyloxy-3-methoxy-5-nitrophenyl)-4-(3,4,5-trimethoxy-phenyl)-1,3-dithiolane (24) 2.60 g, 5.43 mmole) was predissolved in 33 ml absolute ethanol. To this solution was added calcium chloride (0.602 g, 5.43 mmole) predissolved in 7 ml H2O followed by freshly activated zinc dust (7.09 g, 108 mmole). The reaction was refluxed for 12 hours. The solid was removed by vacuum filtration through celite and was washed with ethyl acetate. The filtrate was washed with 10% NaHCO3, dried over MgSO4, and