Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([S:9][CH3:10])[C:5]=2[C:11](=[O:23])[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][C:13]=2[CH3:22])[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([S:9]([CH3:10])=[O:32])[C:5]=2[C:11](=[O:23])[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:14][C:13]=2[CH3:22])[CH2:3][CH2:2]1
Reactant: CSc1noc(C2CC2)c1C(=O)c1ccc(S(C)(=O)=O)cc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(S(C)(=O)=O)ccc1C(=O)c1c(S(C)=O)noc1C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
To a solution of 5-cyclopropyl-3-methylthio-4-(2-methyl-4-methylsulfonylbenzoyl)isoxazole (750 mg, 2.127 mmol) in dichloromethane (35 mL) was added 3-chloroperbenzoic acid (650 mg, 57-87%, Aldrich). The resulting mixture was stirred at r.t. for 2 hours, then diluted with dichloromethane, washed with aqueous sodium bicarbonate, brine, dried and evaporated to dryness. The crude product was purified by preparative thin-layer chromatography to give crystalline 5-cyclopropyl-3-methylsulfinyl-4-(2-methyl-4-methylsulfonylbenzoyl)isoxazole (436 mg), rp. 147° C. and 5-cyclopropyl-3-methylsulfonyl-4-(2-methyl-4-methylsulfonylbenzoyl)isoxazole (378 mg), m.p. 142° C.
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([S:13](=[O:16])(=[O:15])[NH2:14])[S:10][C:9]=2[CH:17]=1.[CH3:19][OH:20]>S(=O)(=O)(O)O>[CH3:19][O:20][CH2:18][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([S:13](=[O:15])(=[O:16])[NH2:14])[S:10][C:9]=2[CH:17]=1
Reactant: NS(=O)(=O)c1cc2ccc(OCC3CO3)cc2s1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COCC(O)COc1ccc2cc(S(N)(=O)=O)sc2c1
Reaction time: 18 h

Procedure:
One drop of concentrated sulfuric acid was added to a solution of 6-[2,3-epoxypropoxy]-2-sulfamoylbenzo[b]thiophene (2.0 g, 7.0 mmol) in methanol (25 ml). After 18 hours, the methanol was removed under vacuum. The residue was dissolved in ethyl acetate (200 ml), washed with water (2×25 ml), brine (2×25 ml) and dried (Na2SO4). The ethyl acetate was removed under vacuum. The white solid remaining was recrystallized from boiling ethyl acetate, 1.5 g, m.p. 128°-129° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@H:36]([NH2:40])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@H:36]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([F:14])[C:10]([O:12][CH3:13])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CCCN(C(=O)OC(C)(C)C)C4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A80) and (S)-3-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].Cl[CH2:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12].[H-].[Na+].CC(=C)COCC1C=C(C=CC=1)C(O)=O>>[CH2:1]([O:5][CH2:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12])[CH2:2][CH:3]=[CH2:4]
Reactant: O=C(O)c1cccc(CCl)c1
Reactant: C=CCCO
Agent: C=C(C)COCc1cccc(C(=O)O)c1
Agent: [H-]
Agent: [Na+]
Product: C=CCCOCc1cccc(C(=O)O)c1

Procedure:
The reaction of But-3-en-1-ol and 3-chloromethyl-benzoic acid in the presence of sodium hydride was performed as described for Compound 37 to give 3-But-3-enyloxymethyl-benzoic acid as colorless oil. 1H-NMR (400 MHz, d6-DMSO): 7.89 (m, 1 arom.H); 7.84 (m, 1 arom.H); 7.54 (m, 1 arom.H); 7.47 (m, 1 arom.H); 5.80 (m, —CH═CH2); 5.06 (2 d-like, —CH═CH2); 4.61 (s, —OCH2—C6H4); 3.49 (m, CH2—CH—CH2CH2O); 2.31 (m, CH2═CH—CH2CH2O). 13C-NMR (100 MHz, d6-DMSO): 167.14 (—C═O); 139.11; 135.52; 131.72; 130.76; 128.54; 128.27; 128.10; 126.44; 71.17; 69.06; 33.70.
Reaction SMILES: [CH3:1][C:2]([C:6]1([OH:11])[CH2:10][CH2:9][NH:8][CH2:7]1)([CH3:5])[CH2:3][CH3:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:22](O)=[O:23])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([C:22]([N:8]3[CH2:9][CH2:10][C:6]([C:2]([CH3:1])([CH3:5])[CH2:3][CH3:4])([OH:11])[CH2:7]3)=[O:23])[CH2:20][CH2:21]2)=[CH:17][CH:18]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: CCC(C)(C)C1(O)CCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C)(C)C1(O)CCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(1,1-Dimethylpropyl)pyrrolidin-3-ol (29.5 mg, 0.000188 mol) was dissolved in DMF and to this solution were added 1-(4-chlorophenyl)cyclopropanecarboxylic acid (44.3 mg, 0.000225 mol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (99.6 mg, 0.000225 mol) and N,N-diisopropylethylamine (49 μL, 0.00028 mol), and the resulting solution was stirred at rt overnight. The product was purified by prep-HPLC. LCMS (M+H)=336
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:11]=[CH:10][S:9][N:8]=1.[O:12]1[C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1>CCCCCC.O1CCCC1>[CH3:6][C:7]1[CH:11]=[C:10]([C:19]2([OH:22])[CH2:20][CH2:21][C:16]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:17][CH2:18]2)[S:9][N:8]=1
Reactant: Cc1ccsn1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C2(O)CCC3(CC2)OCCO3)sn1
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
At −78° C., 1.5 M of n-butyllithium in hexane (6.7 mL) was slowly added to a solution of 3-methylisothiazole (1.0 g, 0.010 mol) in tetrahydrofuran (15 mL) over a period of 20 min. After being stirred for another 30 min, 1,4-dioxa-spiro[4.5]decan-8-one (1.56 g, 0.00999 mol) in tetrahydrofuran (5 mL) was added within 10 min. The reaction mixture was stirred for another 2 hour at −78° C. and allowed to warm up overnight to room temperature. After quenching with brine, the mixture was extracted with EtOAc. The organic layer was dried and concentrated. Chromatography on silica gel eluting with hexane/EtOAc (1:5˜1:1) provided 1.8 g (70.6%) of the title compound. MS (M+H)+ 256.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([O-:3])=[O:2].C([O-])([O-])=O.[Na+].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:11][CH2:12][N:13]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:14][CH2:15]1)([O-:3])=[O:2]
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1N1CCN(Cc2ccccc2)CC1
Yield: 97.4 %

Procedure:
To a 500 mL round-bottomed flask equipped with magnetic stirring was added 1-(2-nitrophenyl)piperazine (Emka-Chemie) (30 g, 145 mmol) in CH2Cl2 (300 mL). A solution of Na2CO3 in H2O (61.2 g in 100 mL) was added, and the reaction mixture was stirred for 5 min. Stirring was stopped, benzyl bromide (18.6 mL, 159 mmol) was added, and the reaction was heated at reflux for 4 h. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). All organic fractions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 1-(2-nitrophenyl)-4-benzylpiperazine as an orange oil (42 g). MS (ESI, pos. Ion) m/z: 298 (M+H); MS (ESI, neg. Ion) m/z: 296 (M−H). Calc'd for C17H19N3O2: 297.15.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([O:10][C:11]2[CH:12]=[C:13]([CH3:27])[C:14]3[CH:18]([CH2:19][C:20]([O:22]CC)=[O:21])[O:17][B:16]([OH:25])[C:15]=3[CH:26]=2)[S:8][CH:9]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[C:20]([CH2:19][CH:18]1[O:17][B:16]([OH:25])[C:15]2[CH:26]=[C:11]([O:10][C:7]3[S:8][CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=3)[CH:12]=[C:13]([CH3:27])[C:14]1=2)([OH:22])=[O:21]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nc(C(=O)OC)cs3)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2nc(C(=O)O)cs2)cc2c1C(CC(=O)O)OB2O
Yield: 7.4 %

Procedure:
A solution of 2-(3-ethoxycarbonylmethyl-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yloxy)-thiazole-4-carboxylic acid methyl ester (500 mg, 1.28 mmol) in THF (30 mL) was treated with LiOH (107 mg, 2.55 mmol) in water (15 mL) at room temperature for 1 h. The reaction was concentrated to dryness. The residue was diluted with water and adjusted to pH 3. The mixture was purified by preparative HPLC to give the title compound (33 mg). 1H NMR (300 MHz, CD3OD) δ 7.87 (s, 1H), 7.35 (s, 1H), 7.25 (s, 1H), 5.70-5.66 (m, 1H), 3.27-3.10 (m, 1H), 2.39 (s, 3H), 2.36-2.31 (m, 1H). MS found: (M+H)+: 350.1.
Reaction SMILES: [CH3:1][N:2]([CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[C:8]([N+:14]([O-])=O)[CH:7]=1)(=[O:5])=[O:4].ClCCl.C(O)C>CO.[H][H].[Pd]>[CH3:1][N:2]([CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[C:8]([NH2:14])[CH:7]=1)(=[O:5])=[O:4]
Reactant: [H][H]
Reactant: CNc1ccc(S(=O)(=O)N(C)C2CCN(C)CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: CNc1ccc(S(=O)(=O)N(C)C2CCN(C)CC2)cc1N

Procedure:
1.5 g (4.4 mMol) of 4-methylamino-3-nitrobenzenesulphonic acid-N-methyl-N-(1-methyl-piperidin-4-yl)-amide were dissolved in 100 ml methanol and catalytically hydrogenated at room temperature and under 5 bar hydrogen pressure (10% palladium on charcoal). Then the catalyst was filtered off and the filtrate was evaporated down. The resulting oily product was further reacted without any purification. Yield: 1.4 g (100% of theory), C14H24N4O2S (312.4) Rf value: 0.33 (silica gel; dichloromethane/ethanol=4:1)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([P:8]([N:24]([CH2:28][CH2:29][Cl:30])[CH2:25][CH2:26][Cl:27])([O:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=1)=[O:9])[CH2:5][CH2:6][Cl:7].C(N(C(C)C)CC)(C)C.[CH2:40]([O:42][C:43](=[O:46])[CH2:44][NH2:45])[CH3:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[Cl:27][CH2:26][CH2:25][N:24]([P:8]([N:4]([CH2:3][CH2:2][Cl:1])[CH2:5][CH2:6][Cl:7])([O:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:45][CH2:44][C:43]([O:42][CH2:40][CH3:41])=[O:46])=[O:22])=[CH:17][CH:16]=1)=[O:9])[CH2:28][CH2:29][Cl:30]
Reactant: O=C(O)c1ccc(CSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl)cc1
Reactant: CCOC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1ccc(CSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl)cc1
Temperature: 0 °C

Procedure:
To α-[[2-[[Bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]thio]-4-carboxytoluene, 411 mg, in 10 mL dichloromethane was added 400 μL diisopropylethylamine and glycine ethyl ester, 212 mg. The solution was cooled to 0° C. and HBTU, 317 mg, in 2 mL dimethylformamide was added, after which the mixture was allowed to warm to room temperature. The reaction mixture was diluted with dichloromethane, then washed 3 times with 1 M hydrochloric acid, 5 times with saturated aqueous sodium bicarbonate, and once with brine. The organic layer was dried over MgSO4, filtered, and the solvents removed under vacuum to give α-[[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]thio]-4-[(ethoxycarbonylmethyl)aminocarbonyl]toluene as a clear oil, 411 mg, with product identity verified by LC-MS.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]([OH:15])[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][C:9]=1[OH:10])[CH3:2].N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].[CH2:29]([O:31]CC)[CH3:30]>C(Cl)Cl>[C:22]([O:15][CH:11]([C:6]1[CH:7]=[CH:8][C:9]([O:10][C:29](=[O:31])[CH3:30])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[C:12]([OH:14])=[O:13])(=[O:24])[CH3:23]
Reactant: CCOc1cc(C(O)C(=O)O)ccc1O
Reactant: CCOCC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1cc(C(OC(C)=O)C(=O)O)ccc1OC(C)=O
Reaction time: 3 h

Procedure:
Intermediate 2 (45.0 g, 0.212 mol, 1 eq.) was dissolved in DCM (225 mL), pyridine (80 mL, 0.989 mol, 6 eq.) was added and the mixture was cooled in an ice bath under nitrogen. Acetic anhydride (100 mL, 1.06 mol, 4 eq.) was added slowly via addition funnel. The mixture was stirred (˜3 hr) until reaction was complete and then diluted with diethyl ether (500 mL) and washed with 1N HCl (4×250 mL). The mixture was extracted into 8% sodium bicarbonate solution (4×80 mL), acidified to ˜pH 4 with 6N HCl, and the product extracted into diethyl ether, giving 41.1 g of intermediate 3 as a white crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[C:17]([C:19]#N)[CH:16]=[CH:15][N:14]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-:21].[Na+].Cl.C[OH:25]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[C:17]([C:19]([OH:25])=[O:21])[CH:16]=[CH:15][N:14]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: N#Cc1ccnc(-n2nccc2-c2ccc(Br)cc2)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1ccnc(-n2nccc2-c2ccc(Br)cc2)c1
Temperature: 0 °C
Yield: 87 %

Procedure:
To a solution of 2-[5-(4-bromophenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile (100 mg, 0.31 mmol) in MeOH (4 mL) was added 10 N NaOH (4 mL), and the solution was heated under reflux conditions for 1 h. The solution was then cooled to 0° C. and the pH was adjusted to pH=2 by dropwise addition of 12 N HCl. The resulting precipitate was filtered to give the title compound (92 mg, 87%) as an off-white solid. 1H NMR (400 MHz, CD3OD): δ 6.64 (1H, s), 7.16 (2H, d, J=8.8 Hz), 7.48 (2H, d, J=8.8 Hz), 7.79 (1H, s), 7.84 (1H, d, J=8.4 Hz), 8.13 (1H, s), 8.42 (1H, d, J=8.4 Hz). [M+H] Calc'd for C15H10BrN3O2, 344; Found, 344.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[O:20][CH3:21])[CH:7]=[CH:6][C:5]=1[NH2:22].[H-].[Na+].[CH3:26]I>CN(C)C=O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[O:20][CH3:21])[CH:7]=[CH:6][C:5]=1[NH:22][CH3:26]
Reactant: CI
Reactant: COC(=O)c1cc(CCc2cc(OC)ccc2OC)ccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1ccc(CCc2cc(OC)ccc2OC)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
110 mg of 5-[2-(2,5-dimethoxyphenyl)ethyl]-2-amino benzoic acid methylester are dissolved in 6 ml of dry dimethylformamide and treated with 13 mg of sodium hydride (80% in mineral oil). After stirring for 30 minutes at room temperature, 0.2 ml of methyl iodide are added and stirring continued overnight. The solvent is distilled off in vacuo, and the residue is partitioned between aqueous ph7 buffer solution and ethyl acetate. The separated organic layer is dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel (hexane/ethyl acetate=7/1) to give the title compound as colourless crystals. mp: 73°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8](=[P:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]2=[O:31].[Br:32][CH2:33][C:34]1[CH:35]=[CH:36][C:37]([F:44])=[C:38]([CH:43]=1)[C:39]([O:41][CH3:42])=[O:40]>C(#N)C>[Br-:32].[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([F:44])=[C:38]([C:39]([O:41][CH3:42])=[O:40])[CH:43]=1)[N:9]=[C:8]([P+:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:7]2=[O:31]
Reactant: COC(=O)c1cc(CBr)ccc1F
Reactant: O=C1C(=P(c2ccccc2)(c2ccccc2)c2ccccc2)N=Nc2c(F)cccc21
Solvent: CC#N
Product: COC(=O)c1cc(Cn2nc([P+](c3ccccc3)(c3ccccc3)c3ccccc3)c(=O)c3cccc(F)c32)ccc1F
Product: [Br-]

Procedure:
A solution of D3 and methyl 5-(bromomethyl)-2-fluorobenzoate (prepared as described in US 2007/0021427) (1 eq) in ACN (0.1 M) was heated to reflux for 1 h 30 min. After cooling down, evaporation of the solvent under reduced pressure afforded the title compound as yellow foam.
Reaction SMILES: N[C:2]1[CH:3]=[C:4](O)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N+]([O-])([O-])=[O:14].[Na+].[I-:18].[K+]>O.Cl.C(OCC)C>[I:18][C:3]1[C:2]([OH:14])=[CH:11][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: [I-]
Reactant: O=[N+]([O-])[O-]
Reactant: Nc1cc(O)c2ccccc2c1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Oc1cc2ccccc2cc1I
Temperature: 10 °C
Yield: 21.8 %

Procedure:
To a stirring solution of 3-aminonaphthol (5.41 g, 34 mmol) in 25 g of crushed ice, 30 mL of water and 10 mL of concentrated HCl at 10° C. was slowly added a solution of sodium nitrate (2.46 g, 36 mmol) in 10 mL water. A solution of potassium iodide (6.21 g, 37 mmol) in 20 mL water was slowly added with stirring at 10° C. The reaction mixture was stirred for 16 hours at room temperature, then diluted with diethyl ether and washed with water and 10% aqueous sodium sulfite solution. The organic layer was filtered through a Celite pad and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica (15% EtOAc/hexanes) to give 2.0 g of 3-iodo-naphthalen-2-ol.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.Cl.[CH3:11][C:12]1([CH3:19])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C.O>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([N:15]2[CH2:16][CH2:17][CH2:18][C:12]([CH3:19])([CH3:11])[CH2:13][CH2:14]2)=[O:9])[CH:3]=1
Reactant: CC1(C)CCCNCC1
Reactant: O=C(O)c1csc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(C)CCCN(C(=O)c2csc(Br)c2)CC1
Reaction time: 8 h
Yield: 71.9 %

Procedure:
5-Bromo-thiophene-3-carboxylic acid (0.5 g, 2.42 mmol), 4,4-dimethyl-azepane hydrochloride (0.475 g, 2.91 mmol), triethylamine (1.01 mL, 7.25 mmol) and HATU (1.20 g, 3.16 mmol) were dissolved in acetonitrile (10 mL) and the resulting mixture stirred overnight. The mixture was diluted with water and extracted with DCM (×2). The organics were dried over sodium sulfate, filtered and evaporated. The crude material was purified by chromatography on a silica II cartridge, eluting with 10-25% ethyl acetate in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give (5-bromo-thiophen-3-yl)-(4,4-dimethyl-azepan-1-yl)methanone (0.55 g).
Reaction SMILES: [Mg].[CH3:2]I.[CH2:4]1[CH2:23][O:22][CH:21]2[CH:6]([C@@H:7]([C@@H:19]([CH2:24][CH2:25][C:26](=[O:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:20]2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:5]1.[Cl-].[NH4+]>CCOCC.O>[CH2:4]1[CH2:23][O:22][CH:21]2[CH:6]([C@@H:7]([C@@H:19]([CH2:24][CH2:25][C:26]([OH:32])([CH3:2])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:20]2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:5]1
Reactant: CI
Reactant: CCCCCC(=O)CC[C@H]1CC2OCCOC2[C@@H]1CCCCCCC(=O)OCC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CCCCCC(C)(O)CC[C@H]1CC2OCCOC2[C@@H]1CCCCCCC(=O)OCC

Procedure:
To a Grignard solution prepared from 207 mg. of magnesium and 1.3 g. of methyl iodide in 10 ml. of ether under nitrogen atmosphere is added a solution of 1.77 g. of ethyl 9-ethylenedioxy-15-oxo-prostanoate (Example 56) in 10 ml. of ether and the resulting mixture is stirred at room temperature for 18 hours. Saturated ammonium chloride (20 ml.) is added followed by 10 ml. of water and 50 ml. of ether. The ethereal solution is washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 1.77 g. (94%) of viscous oil; λ max. 2.94 (hydroxyl group) and 5.77 μ (carbonyl group).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:37][CH:38]1[CH2:42][CH2:41][O:40][CH2:39]1)(=O)=O>CN(C=O)C>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:37][CH:38]3[CH2:42][CH2:41][O:40][CH2:39]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Reactant: CS(=O)(=O)OCC1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CC1CCOC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A stirring mixture of 2-[(2-cyclopropylethyl)oxy]-8-(methoxy)-1H-purin-6-amine trifluoroacetic acid salt (2.89 g), potassium carbonate (4.41 g) and dry DMF (32 ml) was heated at 60° C. under nitrogen for 90 minutes. Tetrahydro-3-furanylmethyl methanesulfonate (1.869 g, isomer 1) was then added and stirring continued at 70° C. for 1 h, then at 90° C. for 2 h. The solvent was evaporated and the residue treated with water and extracted three times with ethyl acetate. The combined extracts were washed with water then brine, dried by passing through a hydrophobic frit and evaporated to a brown oil. This was purified on a 360 gm C18 column using water (+0.1% formic acid)/acetonitrile (+0.05% formic acid). Appropriate fractions were combined and evaporated, yield 814 mg.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH2:13]([Mg]Br)[CH3:14].B(F)(F)F>C(OCC)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]1([NH2:6])[CH2:14][CH2:13]1
Reactant: N#Cc1ccccc1C(F)(F)F
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: CCOCC
Product: NC1(c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 214.2 %

Procedure:
To a cold solution of 2-(trifluoromethyl)benzonitrile (1.0 g, 0.58 mmol) in diethyl ether (20 mL) was added titanium isopropoxide (2.0 g, 0.70 mmol) at −70° C. and ethyl magnesium bromide (4.30 mL, 12.86 mmol). The reaction mass was stirred at RT for 2-3 h. Followed by addition of boron trifluoride solution (1.5 mL) and continued stirring for 2 h at RT. The reaction mass was quenched in 1N HCl and basified with NaOH solution. The obtained crude product was further purified by column chromatography on silica gel eluting with 1% EtOAC: DCM eluent to afford 0.250 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.82-0.84 (s, 2H), 0.91-0.93 (br s, 2H), 2.24 (br s, 2H), 7.41 (t, J=6.6 Hz, 1H), 7.58-7.67 (m, 3H).