Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:6][N:7]([CH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[C:33]1[C:38]([O:39][CH3:40])=[CH:37][N:36]=[C:35]([O:41][CH3:42])[N:34]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>CO>[F:51][C:2]([F:1])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:47])([F:49])[F:48])[CH:45]=1)[CH2:6][N:7]([CH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][C:24]=1[C:33]1[C:38]([O:39][CH3:40])=[CH:37][N:36]=[C:35]([O:41][CH3:42])[N:34]=1)[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: COC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2nc(OC)ncc2OC)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ncc(OC)c(-c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(OCCCC(=O)O)cn2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
Methyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(2,5-dimethoxy-pyrimidin-4-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (52 mg) is dissolved in methanol (4 ml), and thereto is added 1N-aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 3 hours. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(2,5-dimethoxy-pyrimidin-4-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (49 mg). MS (m/z): 720 [M+H]+
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[CH:4][N:3]=1.[CH:10]1([CH:13]=[O:14])[CH2:12][CH2:11]1.O>C1COCC1>[Cl:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH:13]([CH:10]2[CH2:12][CH2:11]2)[OH:14])[C:7]=1[CH3:8]
Reactant: O=CC1CC1
Reactant: Cc1c(Cl)ccnc1Br
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cl)ccnc1C(O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
A solution of 2-bromo-4-chloro-3-methylpyridine (7 g, 28.1 mmol) in dry THF (150 mL) was cooled down to 0° C. An isopropyl magnesium chloride-Lithium chloride complex (26 mL, 33.8 mmol) was added carefully so temperature would not rise above 5° C. during the addition. The mixture was allowed to warm up to room temperature and was stirred for 1 h. The reaction mixture was cooled down to 0° C. and cyclopropane carboxaldehyde (2.5 mL, 33.5 mmol) was added carefully so temperature would not rise above 5° C. during the addition. The mixture was allowed to warm up to room temperature and was stirred for 1 h. The reaction mixture was cooled to 0° C. and water (150 mL) was added carefully so temperature would not rise above 10° C. during the addition. The mixture was allowed to warm up to room temperature and was stirred for 1 h. The mixture was extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with brine (100 mL), dried over sodium sulfate and evaporated. The residue was purified by flash chromatography over silica gel (0-30% ethyl acetate in heptane) yielding a yellow oil (3.47 g, 16.8%).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH2:10][CH2:9]1.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH3:7][C:1]1[CH:6]=[CH:5][C:4]([C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:14])=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)O1
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)CCC(=O)O)cc1
Yield: 75 %

Procedure:
Toluene 10b (99.9%, 5.5 eq) was reacted with succinic anhydride (99%, 1 eq) and AlCl3 (95%, 2 eq) for 24 h according to the general procedure. Yellow crystals of 11b were obtained in 75% yield. 1H-NMR: 7.88 (d, 2H, J=8.2 Hz, Ar--H); 7.26 (d, 2H, J=4.8 Hz, Ar--H); 3.29 (t, 2H, J=6.6 Hz, CH2CH2COOH); 2.80 (t, 2H, J=6.6 Hz, CH2CH2COOH); 2.41 (s, 3H, CH3). 13C-NMR: 192.44; 178.70; 144.13; 133.91; 129.29; 128.14; 33.02; 28.06; 21.63.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:44][C:45]1[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][C:46]=1[Cl:53]>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]2[CH:41]=[C:40]([NH:44][C:45]3[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][C:46]=3[Cl:53])[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: N#Cc1ccc(N)c(Cl)c1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccc(C#N)cc3Cl)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 4-amino-3-chloro-benzonitrile according to procedure B followed by deprotection yielded the title compound as a white solid. MS (ESI): m/z=414.1 and 416.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]2[C:9]([C:11]3[C:16]([OH:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=3[CH2:19][C:4]=2[CH:3]=1)=[O:10]>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]2[C:9](=[O:10])[C:11]3[C:16]([OH:17])=[CH:15][C:14]([OH:18])=[C:13]4[C:12]=3[C:19](=[C:19]3[C:12]5=[C:13]4[C:14]([OH:18])=[CH:15][C:16]([OH:17])=[C:11]5[C:9](=[O:10])[C:5]4[C:6]([OH:8])=[CH:7][C:2]([CH3:1])=[CH:3][C:4]3=4)[C:4]=2[CH:3]=1
Reactant: Cc1cc(O)c2c(c1)Cc1cc(O)cc(O)c1C2=O
Solvent: CCO
Product: Cc1cc(O)c2c(=O)c3c(O)cc(O)c4c5c(O)cc(O)c6c(=O)c7c(O)cc(C)cc7c(c65)c(c2c1)c34

Procedure:
Emodin anthrone is dimerized to give the 10,10'-coupled bianthrones by reacting emodin anthrone with ferric chloride (FeCl3) in ethanol, as described in Kinget, R., Planta. Med., vol. 15, pp. 233-39 (1967), which is also incorporated herein by specific reference. This reaction results in two diastereomers, the meso and the dl-pair. These compounds are readily separated on reverse phase high pressure liquid chromatography ("HPLC"). Subsequent oxidation of the bianthrones with oxygen in methanol containing triethylamine produces protohypericin, which is converted into hypericin upon exposure to sunlight. Alternatively air oxidation of the bianthrones in hot ammonium hydroxide and exposure to sunlight give rise to hypericin. The resulting compounds are characterized by HPLC, thin layer chromatography ("TLC"), and ultraviolet/visual spectrometry.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C@@H:17]([N:19]3[CH2:24][CH2:23][C:22]4([CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]4)[O:21][C:20]3=[O:31])[CH3:18])=[CH:13][CH:12]=2)=[CH:7][N:6]=1)=[O:4]>CO.O>[CH3:32][N:2]([CH3:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([N:19]3[CH2:24][CH2:23][C:22]4([CH2:25][CH2:26][CH:27]([OH:30])[CH2:28][CH2:29]4)[O:21][C:20]3=[O:31])[CH3:18])=[CH:13][CH:12]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: C[C@@H](c1ccc(-c2ccc(C(=O)N(C)C)nc2)cc1)N1CCC2(CCC(=O)CC2)OC1=O
Solvent: CO
Solvent: O
Product: CC(c1ccc(-c2ccc(C(=O)N(C)C)nc2)cc1)N1CCC2(CCC(O)CC2)OC1=O

Procedure:
The title compound is prepared from 5-{4-[(S)-1-(2,9-dioxo-1-oxa-3-aza-spiro[5.5]undec-3-yl)-ethyl]-phenyl}-pyridine-2-carboxylic acid dimethylamide following a procedure analogous to that described in Example 22; after HPLC on reversed phase (methanol/water) the title compound is obtained in a ca. 1:1 mixture of cis- and trans-isomer. Yield: 53% of theory; LC (method 2): tR=1.58 min; Mass spectrum (ESI+): m/z=438 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CO[CH2:28][CH2:29]OC>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>[CH:28]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:4][CH:3]=1)=[CH2:29]
Reactant: COCCOC
Reactant: O=C1c2ccccc2C(=O)N1Nc1ccc(Br)cc1
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: [K+]
Solvent: O
Product: C=Cc1ccc(NN2C(=O)c3ccccc3C2=O)cc1
Temperature: 150 °C
Yield: 13 %

Procedure:
To a solution of 2-(4-bromophenylamino)isoindoline-1,3-dione (2 g, 6 mmol) in 1,2-dimethoxyethane (20 mL) and H2O (4 mL) were added vinyl boronic anhydride pyridine complex (4.57 g, 18.98 mmol) and K2CO3 (1.3 g, 9.5 mmol) followed by Pd(PPh3)4 (0.219 g, 0.189 mmol). The resultant reaction mixture was heated at 150° C. in a microwave for 30 min and then was concentrated under reduced pressure. Purification by column chromatography (SiO2, 15% EtOAc in petroleum ether) afforded the title compound as a solid (200 mg, 13%): mp 174-176° C.; 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.94 (m, 4H), 7.29 (d, J=8.4 Hz, 2H), 6.72 (d, J=8.4 Hz, 2H), 6.61 (m, 1H), 5.61 (d, J=17.6 Hz, 1H), 5.05 (d, J=11.2 Hz, 1H); ESIMS m/z 263.18 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:24])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31](Br)[C:32]#[CH:33].C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:18])([OH:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:33][C:32]#[CH:31])=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1ccc2c(c1)nc(N)c1nc(COCC)n(CC(C)(C)O)c12
Reaction time: 8 h
Yield: 68.8 %

Procedure:
4-Amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol (2.35 g, 7.1 mmol), cesium carbonate (4.6 g, 14.2 mmol), and DMF (50 mL) were combined. Propargyl bromide (80% in toluene, 3.2 g, 21.3 mmol) was added and the reaction was stirred overnight. The reaction was poured into 500 mL of water and solid potassium carbonate was added to keep the mixture basic. A precipitate formed. Filtration of the reaction followed by air drying of the recovered solid provided 1.8 g of 1-[4-amino-2-ethoxymethyl-7-(prop-2-ynyloxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as an off white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([CH:10]2[CH2:15][CH2:14][N:13](C)[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:23](Cl)(=[O:27])[O:24][CH2:25][CH3:26]>CC1C=CC=CC=1C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([CH:10]1[CH2:15][CH2:14][N:13]([C:23]([O:24][CH2:25][CH3:26])=[O:27])[CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1cccc(C(=O)C2CCN(C)CC2)c1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCOC(=O)N1CCC(C(=O)c2cccc(C)c2)CC1
Reaction time: 6 h

Procedure:
To a stirred mixture of 35 parts of (3-methylphenyl) (1-methyl-4-piperidinyl)methanone, 1 part of sodium carbonate and 225 parts of dimethylbenzene are added dropwise 22 parts of ethyl carbonochloridate at 20° C. Upon completion, stirring is continued for 6 hours at reflux temperature. The reaction mixture is evaporated, yielding 12 parts of ethyl 4-(3-methylbenzoyl)-1-piperidinecarboxylate as an oily residue.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:11])[C:4](=[S:10])[S:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:12](OCC)(OCC)(OCC)[CH2:13][CH3:14]>C(OC(=O)C)(=O)C>[CH2:13]([C:14]1[NH:9][C:7](=[O:8])[C:6]2[S:5][C:4](=[S:10])[N:3]([CH3:11])[C:2]=2[N:1]=1)[CH3:12]
Reactant: Cn1c(N)c(C(N)=O)sc1=S
Reactant: CCOC(CC)(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCc1nc2c(sc(=S)n2C)c(=O)[nH]1
Yield: 65 %

Procedure:
The general procedure of Gewald, J. Prakt. Chem., 32, 26-30 (1966) was used to prepare 4-amino 3-methylthiazoline-2-thione-5-carboxamide, of which 27.3 g (0.14 mole) was suspended in a mixture of approximately 144ml of acetic anhydride and about 144ml of triethyl orthopropionate. The resultant mixture was refluxed for approximately one half hour, then cooled in an ice bath. The solid which precipitated was separated by filtration, washed with diethyl ether and dried in a vacuum oven at approximately 100° C. to provide 21.4g (65%) of 5-ethyl-3-methyl-6H-thiazolo[4,5-d]pyrimidin-7-one-2-thione. Infrared spectral analysis confirmed the structural assignment.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([CH:10]([CH3:15])[C:11]([O:13]C)=[O:12])=[C:5]([F:16])[CH:4]=1.[O:17]=[C:18]1[CH2:22][CH2:21][CH2:20][CH:19]1C(OC)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:16][C:5]1[CH:4]=[C:3]([CH2:2][CH:19]2[CH2:20][CH2:21][CH2:22][C:18]2=[O:17])[C:8]([F:9])=[CH:7][C:6]=1[CH:10]([CH3:15])[C:11]([OH:13])=[O:12]
Reactant: COC(=O)C(C)c1cc(F)c(CBr)cc1F
Reactant: COC(=O)C1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C(=O)O)c1cc(F)c(CC2CCCC2=O)cc1F
Yield: 75.6 %

Procedure:
Compound (32a) (4.8 g, 16.4 mmol), methyl 2-oxocyclo-pentanecarboxylate (2.5 mL, 21.9 mmol), and anhydrous potassium carbonate (4.0 g, 28.9 mmol) in acetone (200 mL) were allowed to react in the same manner as in Example 15. The obtained crude product was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (4:1) solution followed by conventional decarboxylation and hydrolysis to give 3.5 g (60%) of compound (33a) of interest as clear yellow oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[OH-].[K+:34]>O1CCOCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([O-:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[K+:34]
Reactant: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c([O-])c(=O)n2C)o1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A flask (100 ml) was charged with Raltegravir free hydroxy (500 mg) completely dissolved in 1,4-dioxane (35 ml) at room temperature. A solution of 30% aqueous KOH (0.162 ml) was added. The resulting mixture was stirred for 24 h at room temperature. A solid precipitated and was filtered under reduced pressure to provide wet Raltegravir potassium crystalline Form VII.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Br:14][C:15]1[C:16]([F:22])=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1>CC(C)=O>[Br:14][C:15]1[C:16]([F:22])=[C:17]([O:21][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:18]=[CH:19][CH:20]=1
Reactant: CCCCCCBr
Reactant: Oc1cccc(Br)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCOc1cccc(Br)c1F
Yield: 86.8 %

Procedure:
117 g of potassium carbonate and 55.6 g of bromohexane are added to a solution of 53.6 g of 3-bromo-2-fluorophenol in 650 ml of acetone, and the mixture is refluxed for 8 hours. The mixture is filtered, evaporated to ⅓ of the original volume and poured into 600 ml of water. The pH is adjusted to 1 using hydrochloric acid, and the mixture is extracted three times with 150 ml of tert-butyl methyl ether each time. The combined organic phases are concentrated under reduced pressure, and the residue is subjected to vacuum distillation (103° C.; 1 mbar), giving 67 g of 6-bromo-2-hexyloxyfluorobenzene as a colorless oil. 1H-NMR (CDCl3): 6.9-7.1 (m; 3H); 4.0 (t; 2H), 0.9-1.8 (m, 11H), 19F-NMR (CDCl3): −128 ppm. A solution of 67.3 g of 6-bromo-2-hexyloxyfluorobenzene, 24.7 g of 2-methyl-3-butyn-2-ol [115-19-5], 0.7 g of bis(triphenylphosphine)palladium(II) chloride and 0.7 g of copper iodide in 340 ml of triethylamine is refluxed for 5 hours. The mixture is then poured into 1.5 of ice-water, the pH is adjusted to 1 using hydrochloric acid, and the mixture is extracted three-times with 200 ml of tert-butyl methyl ether each time. The combined organic phases are dried under reduced pressure. The crude 4-(2-fluoro-3-hexyloxyphenyl)2methyl-3-butyn-1-ol is refluxed for 3 hours in 1000 ml of toluene together with three mole-equivalents of sodium hydroxide. The mixture is filtered and washed with dilute hydrochloric acid, the solvent is removed by distillation, and the residue is distilled (90° C.; 0.5 mbar), giving 34 g of 1-(2-fluoro-3-hexyloxyphenyl)ethyne.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7]CN2CC(C)NS2(=O)=O)[CH2:3][CH2:2]1.N1CCC([CH2:23][CH2:24][N:25]2[CH:29](C)[CH2:28][NH:27][S:26]2(=[O:32])=[O:31])CC1.Cl>>[NH:1]1[CH2:2][CH2:3][CH:4]([CH2:7][N:27]2[CH2:28][CH2:29][CH:24]([CH3:23])[NH:25][S:26]2(=[O:31])=[O:32])[CH2:5][CH2:6]1
Reactant: CC1CN(CCC2CCNCC2)S(=O)(=O)N1
Reactant: CC1CNS(=O)(=O)N1CCC1CCNCC1
Agent: Cl
Product: CC1CCN(CC2CCNCC2)S(=O)(=O)N1

Procedure:
2-[2-(4-piperidyl)ethyl]-4-methyl-1,2,5-thiadiazolidine-1,1-dioxide and 2-[2-(4-piperidyl)ethyl]-3-methyl-1,2,5-thiadiazolidine-1,1-dioxide as a 3:1 mixture (crude hydrochloride, oil).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][NH2:11])[CH:6]=[C:7]([Cl:9])[CH:8]=1.[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[C:13]([CH3:15])=O>C(O)C>[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][NH:11][CH:13]([CH3:15])[C:12]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: CCOC(=O)C(C)=O
Reactant: NNc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(C)NNc1cc(Cl)cc(Cl)c1

Procedure:
A mixture of 3,5-dichlorophenylhydrazine hydrochloride (5.07 g) and ethyl pyruvate (3.96 ml) in ethyl alcohol (30 ml) was refluxed for 2 hours, and the solvent was evaporated under reduced pressure. The residual solid was triturated with hexane to give ethyl 2-(3,5-dichlorophenylhydrazino)propionate (5.60 g). APCI-Mass m/Z 275/277 (M+H).
Reaction SMILES: [CH:1]([CH:4]1[CH2:8][NH:7][C@@H:6]([CH2:9][OH:10])[CH2:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[S:18](Cl)(Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH:1]([CH:4]1[CH2:8][N:7]2[S:18](=[O:20])(=[O:19])[O:10][CH2:9][C@H:6]2[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1CN[C@@H](CO)C1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C1C[C@@H]2COS(=O)(=O)N2C1
Temperature: 25 °C
Yield: 9 %

Procedure:
A solution of ((2R)-4-isopropylpyrrolidin-2-yl)methanol (1.639 g, 11.44 mmol) and triethylamine (3.18 mL, 22.89 mmol) in DCM (100 mL) was cooled to −78° C. To this mixture was added sulfuryl chloride, 1.0 M solution in DCM (13.73 mL, 13.73 mmol) dropwise. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was concentrated onto a plug of silica gel and purified by ISCO, chromatograph through a REDISEP™ pre-packed silica gel column (40 g), eluting with a gradient of 0% to 10% MeOH (with 2 M NH3) in DCM to give (3aR)-5-isopropyltetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (211.9 mg, 1.032 mmol, 9% yield) as light yellow oil. m/z (ESI, +ve) 206 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:10]2[CH:11]=[C:12]([CH3:14])[NH:13][C:9]=2[CH:8]=[CH:7][N:6]=1.I[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C1COCC1>[CH3:3][O:4][C:5]1[C:10]2[CH:11]=[C:12]([CH3:14])[N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:9]=2[CH:8]=[CH:7][N:6]=1
Reactant: COc1nccc2[nH]c(C)cc12
Reactant: CCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCn1c(C)cc2c(OC)nccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of NaH (98 mg, 2.5 mmol, 60% in mineral oil) in THF (10 mL), 4-methoxy-2-methyl-1H-pyrrolo[3,2-c]pyridine 3 (280 mg, 1.72 mmol) in THF (3 mL) was added. The mixture was stirred at room temperature for 30 min, and then 1-iodooctane (0.41 mL, 2.2 mmol) was added, stirring was continued for 18 h. The reaction mixture was quenched with saturated NH4Cl (20 mL), extracted with EtOAc (3×40 mL). The combined organic extracts were washed with water (40 mL), brine (40 mL), dried over Na2SO4 and evaporated. Flash chromatography of the residue over silica gel, using 10% EtOAc in hexanes to 20% EtOAc in hexanes) gave product 8 as a yellow oil. Yield: 231 mg (49%).
Reaction SMILES: [CH:1]1[C:5]2=[C:6]([OH:15])[C:7]3[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:8]=3[CH:9]=[C:4]2[O:3][CH:2]=1.[O:16]([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[O:16]([CH2:23][CH2:24][CH2:25][CH2:26][O:15][C:6]1[C:7]2[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:8]=2[CH:9]=[C:4]2[O:3][CH:2]=[CH:1][C:5]=12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1ccc2c(O)c3ccoc3cc2o1
Reactant: BrCCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=c1ccc2c(OCCCCOc3ccccc3)c3ccoc3cc2o1
Reaction time: 0.29 h

Procedure:
700 mg (3.462 mmol) of 5-hydroxypsoralen (crystallized) and 600 mg (3.462 mmol) of 4-phenoxybutyl bromide was refluxed in 30 ml of 2-butanone in the presence of an excess (2 g) of anhydrous potassium carbonate and catalytic amounts of potassium iodide for 24 hours. The progress of the reaction was monitored by thin layer chromatography. After 24 hours the reaction mixture was concentrated under reduced pressure. The oily residue was cooled and diluted with water. The aqueous solution was then acidified with concentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20 min and extracted with 3×100 ml of dichloromethane. The dichloromethane layer was extracted with 25 ml of 1% sodium hydroxide to separate the un-reacted 5-hydroxypsoralen. The dichloromethane layer was washed with 30 ml of 2% hydrochloric acid, dried over anhydrous sodium sulfate and concentrated. The solid residue was dissolved in a methanol-acetone mixture, treated with charcoal and re-crystallized from a methanol-acetone (80:20) mixture.
Reaction SMILES: [N:1](=[C:3]1[CH2:8][S:7][CH2:6][CH2:5][S:4]1)[OH:2].[CH3:9][N:10]([S:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=1)[C:11](F)=[O:12].C(N(CC)CC)C>O1CCOCC1>[CH3:9][N:10]([S:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=1)[C:11]([O:2][N:1]=[C:3]1[CH2:8][S:7][CH2:6][CH2:5][S:4]1)=[O:12]
Reactant: CN(SSc1ccc(C(C)(C)C)cc1)C(=O)F
Reactant: ON=C1CSCCS1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(SSc1ccc(C(C)(C)C)cc1)C(=O)ON=C1CSCCS1

Procedure:
2-[[O-[N-Methyl-N-(4-tert.butylphenylthiosulfenyl)carbamoyl]oximino]]-1,4-dithiane was prepared according to the procedure described in Example I, by reacting 1.09 g (0.0073 m) of 2-oximino-1,4-dithiane, 2.0 g (0.0073 m) of N-methyl-N-(4-tert.butylphenylthiosulfenyl)carbamoyl fluoride and 0.736 g (0.0073 m) of triethylamine in 25 ml of dioxane. Weight of the residual oil 1.95 g IR (Neat) 5.75μ (C=O). NMR (CDCl3) 1.28δ(s), 9H, t-butyl; 3.10δ(s), 4H, (CH2), 3.20δ(s), 3H, CH3N; 3.52δ(s) 2H, CH2 ; 7.37δ(d), JAB =8.5 Hz 2H and 7.54δ(d) JBA =85 Hz, 2H. Aromatic.