Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10])[CH3:2].[CH2:20]1[C@@H:24]([CH2:25][CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])[S:23][S:22][CH2:21]1>>[CH2:1]([N:3]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[CH2:20][CH2:21][S:22][S:23]1)[CH3:2]
Reactant: CCN(CCCCCCN)Cc1ccccc1OC
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Product: CCN(CCCCCCNC(=O)CCCCC1CCSS1)Cc1ccccc1OC
Yield: 43 %

Procedure:
It was synthesized from N1-ethyl-N1-(2-methoxy-benzyl)-hexane-1,6-diamine (patent application PCT/IT03/0227) (300 mg, 1.13 mmol) and lipoic acid (350 mg, 1.70 mmol) following the procedure described for 17, and purified by gravity column. Elution with a gradient of mobile phase petroleum ether/toluene/CH2Cl2/EtOH/aqueous 30% ammonia solution (7:2:1:1:0.05 to 7:1:1:1:0.5) afforded 18 as a waxy solid: 43% yield, 1H NMR (200 MHz, CDCl3) δ 7.42-7.48 (m, 1H); 7.18-7.26 (m, 1H), 6.85-6.99 (m, 2H), 5.43 (br t, 1H, exchangeable with D2O), 3.84 (s, 3H), 3.53-3.64 (m, 1H+s, 2H), 3.08-3.27 (m, 4H), 2.43-2.57 (m, 5H), 2.17 (t, J=7.4 Hz, 2H), 1.82-2.00 (m, 1H), 1.29-1.73 (m, 14H), 1.07 (t, J=7.0 Hz, 3H); MS (ESI+) m/z 453 (M+H)+. Anal. Calculated for C24H40N2O2S2: C, 63.67; H, 8.91; N, 6.19. Found: C, 63.79; H, 8.93, N, 6.17.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[CH:7]=1.C(Cl)Cl>CCOCC>[O:12]=[C:8]1[CH2:9][CH2:10][CH2:11][C:6]([CH2:5][CH2:4][CH2:3][CH:2]=[O:1])=[CH:7]1
Reactant: O=C1C=C(CCCCO)CCC1
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCCCC1=CC(=O)CCC1
Reaction time: 25 h

Procedure:
Following the procedure of Corey, Tetrahedron Lett 2647 (1975), a mixture of 3-(4-hydroxybutyl)-cyclohex-2-en-1-one (539 mg) pyridinium dichromate (2.05 g) and methylene chloride (8.0 ml) is stirred for 25 hr at 20°-25°. The reaction is diluted with ether, filtered, dried over magnesium sulfate and concentrated to give the title compound, IR (neat) 2950, 1724, 1666, 1255, 1193, 888 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][S:19]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([NH2:31])[CH:26]=[C:25]2[CH3:32])(=[O:21])=[O:20].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.CCOC(C)=O>[CH3:18][S:19]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([NH:31][C:15]([C:11]1[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=1)=[O:17])[CH:26]=[C:25]2[CH3:32])(=[O:21])=[O:20]
Reactant: Cc1cn(N)c2ccc(S(C)(=O)=O)cc12
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(C)c2cc(S(C)(=O)=O)ccc21
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 13.7 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (1.77 mmol) and 5-methanesulfonyl-3-methyl-indol-1-ylamine (452 mg, 1.95 mmol) in DMF (15 mL) is stirred at rt for 1 h. The mixture is treated with DMTMM (538 mg, 1.95 mmol) and stirred at 60° C. for 1.5 h. The mixture is diluted with EtOAc (50 mL), and washed with saturated aqueous Na2CO3 (50 mL). The organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0%-100% EtOAc in heptane, and then by triturating in Et2O to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-methanesulfonyl-3-methyl-indol-1-yl)-amide (106 mg, 14%). MS: 439 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.15 (s, 1H), 8.37 (d, 1H), 8.24 (m, 2H), 7.82 (m, 1H), 7.59 (d, 1H), 7.54 (m, 1H), 7.34 (s, 1H), 7.29 (m, 1H), 3.13 (s, 3H), 2.83 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:52]=[CH:53][CH:54]=2)[O:44][CH2:45][CH2:46]OS(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:54]=[CH:53][CH:52]=[C:43]([O:44][CH2:45][CH2:46][N:55]3[CH2:60][CH2:59][O:58][CH2:57][CH2:56]3)[CH:42]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN5CCOCC5)c4)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A solution of Intermediate 154a (50.5 mg, 0.067 mmol) and morpholine (29 μL, 0.33 mmol) in THF (1 mL) was stirred at 60° C. for 20 h in a sealed tube. Additional morpholine (29 μL, 0.33 mmol) was added and the mixture subsequently stirred at 60° C. in a sealed tube for 24 h. The mixture was concentrated in vacuo and the residue purified by MDAP (Method 7). The title product was isolated as an off-white solid (25 mg, 50%). LCMS (Method 5): Rt 3.66 min, m/z 748.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.0 Hz), 1.27 (9H, s), 1.46-1.56 (2H, m), 1.61-1.73 (2H, m), 1.75-1.98 (4H, m), 1.99-2.19 (2H, m), 2.42 (4H, t, J=4.0 Hz), 2.67 (2H, t, J=8.0 Hz), 2.86-2.95 (1H, m), 3.12-3.20 (1H, m, obscured by water), ˜3.30 (1H, m, obscured by water), 3.53 (4H, t, J=8.0 Hz), 4.12 (2H, t, J=8.0 Hz), 4.77-4.86 (1H, m), 5.52 (1H, t, J=4.0 Hz), 6.33 (1H, s), 6.95-6.99 (1H, m), 7.07-7.13 (3H, m), 7.19 (1H, dd, J=8.0 Hz, 4.0 Hz), 7.25-7.43 (5H, m), 7.64 (1H, d, J=8.0 Hz), 7.69 (1H, d, J=4.0 Hz), 8.13 (1H, s), 8.21 (0.5H, s).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@:6]12[C@@H:25]3[C@H:14]([C@H:15]4[C@:22]([CH3:26])([CH2:23][CH2:24]3)[C@@:18]([O:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([C:19](=[O:21])[CH3:20])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]1=[CH:10][C:9](=[O:35])[CH2:8][CH2:7]2)(=[O:3])[CH3:2].[CH3:36]OCOC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)Cl>[C:1]([O:4][CH2:5][C@@:6]12[C@@H:25]3[C@H:14]([C@H:15]4[C@:22]([CH3:26])([CH2:23][CH2:24]3)[C@@:18]([O:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([C:19](=[O:21])[CH3:20])[CH2:17][CH2:16]4)[CH2:13][C:12](=[CH2:36])[C:11]1=[CH:10][C:9](=[O:35])[CH2:8][CH2:7]2)(=[O:3])[CH3:2]
Reactant: COCOC
Reactant: CCCCCC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(COC(C)=O)[C@H]3CC[C@@]21C
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(OC(=O)CCCCC)C(C)=O)[C@@]2(COC(C)=O)CCC(=O)C=C12

Procedure:
Analogously to Example 1, 1.0 g of 19-acetoxy-17-hexanoyloxy-4-pregnene-3,20-dione in 7 ml of methylene chloride is reacted with 4.9 ml of formaldehyde dimethylacetal and a mixture of 200 mg of phosphorus pentoxide and 1.5 g of kieselguhr W 20, and worked up. The crude product is purified on 110 g of silica gel with a hexane/acetone gradient (0-20% acetone), thus isolating 563 mg of 19-acetoxy-17-hexanoyloxy-6-methylene-4-pregnene-3,20-dione, mp 111°-112° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[NH:19][C:20](=[O:30])[C:21]2[CH:26]=[N:25][N:24]([CH2:27][CH2:28][CH3:29])[C:22]=2[N:23]=1)[CH3:10]>CN(C=O)C>[Br:1][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:9][CH3:10])=[C:13]([C:18]2[NH:19][C:20](=[O:30])[C:21]3[CH:26]=[N:25][N:24]([CH2:27][CH2:28][CH3:29])[C:22]=3[N:23]=2)[CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCn1ncc2c(=O)[nH]c(-c3ccccc3OCC)nc21
Solvent: CN(C)C=O
Product: CCCn1ncc2c(=O)[nH]c(-c3cc(Br)ccc3OCC)nc21
Reaction time: 20 h
Yield: 76.9 %

Procedure:
A solution of N-bromosuccinimide (1.0 g, 0.0056 mol) in DMF (10 ml) was added dropwise to a stirred solution of 6-(2-ethoxyphenyl)-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 1; 0.84 g, 0.0028 mol) in DMF (10 ml) and the resulting red solution stirred for 20 hours. The solvent was removed by evaporation under vacuum and the residue partitioned between saturated aqueous sodium bicarbonate solution (20 ml) and ethyl acetate (20 ml). The organic phase was removed and the aqueous phase extracted with ethyl acetate (3×30 ml). The combined organic solutions were dried and the solvent removed by evaporation under vacuum to give an orange crystalline solid. Recrystallisation from ethyl acetate-hexane gave the title compound as colourless crystals (0.812 g, 78%), m.p. 172-173° C. Found: C,51.13; H,4.41; N,14.84. C16H17BrN4O2 requires C,50.94; H,4.54; N,14.85%.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[O:12][C:13]([CH:15]=O)=[CH:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:4]=2[NH:3]1.[NH3:23]>C(O)(C)C.O=[Mn]=O>[O:1]=[C:2]1[C:11]2[O:12][C:13]([C:15]#[N:23])=[CH:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:4]=2[NH:3]1
Reactant: O=Cc1cc2c(o1)c(=O)[nH]c1c(N3CCCCC3)cccc12
Reactant: N
Agent: O=[Mn]=O
Solvent: CC(C)O
Product: N#Cc1cc2c(o1)c(=O)[nH]c1c(N3CCCCC3)cccc12
Reaction time: 1.5 h

Procedure:
A solution of 4-oxo-6-piperidin-1-yl-4,5-dihydro-furo[2,3-c]quinoline-2-carbaldehyde (v) in isopropanol (“iPrOH”) is treated with ammonia gas at room temperature. After 90 min, the reaction is treated with MnO2 and stirred for an additional 16 h. The reaction is filtered and evaporated onto celite. Chromatography on silica gel affords 4-oxo-6-piperidin-1-yl-4,5-dihydro-furo[2,3-c]quinoline-2-carbonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:15][C:9]2=[CH:10][N:11]=[C:12](Br)[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].[CH3:16][N:17](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH3:4][CH2:6][CH2:7][CH:8]([CH3:9])[CH3:13].[CH2:1]([O:3][C:4]([C:6]1[NH:15][C:9]2=[CH:10][N:11]=[C:12]([C:16]#[N:17])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(Br)ncc2[nH]1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: CCCC(C)C
Product: CCOC(=O)c1cc2cc(C#N)ncc2[nH]1
Temperature: 25 °C

Procedure:
To a solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (Preparation 26, 0.160 g, 0.590 mmol) in DMF (anhydrous, 5 mL) was added zinc (II) cyanide (0.041 g, 0.35 mmol) then tetrakis-triphenylphosphine palladium (0). The reaction mixture was degassed by bubbling argon through it for 10 min. The reaction mixture was heated to reflux temperature for 4.5 h then allowed to cool to rt. Water (30 mL) was added and the mixture extracted with ethyl acetate (2×50 mL). The combined organics were washed with brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate then adsorbed onto silica gel. Purification via flash column chromatography (SiO2, ethyl acetate: isohexane, 1:3, v/v) gave the title compound as a white solid. δH (CDCl3): 1.45 (3H, t), 4.49 (2H, quartet), 7.31 (1H, s), 8.09 (1H, s), 8.97 (1H, s), 9.60 (1H, br s); m/z (ES+)=216 [M+H]+; RT=3.03 min.
Reaction SMILES: [Na].[CH3:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([C:10]([CH2:12][C:13](=O)[CH3:14])=[O:11])=[CH:5][N:4]=1.[ClH:16].S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[ClH:19].[CH3:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([CH:10]([OH:11])[CH2:12][CH:13]([Cl:16])[CH3:14])=[CH:5][N:4]=1
Reactant: CC(=O)CC(=O)c1cnc(C)nc1C
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: [Na]
Solvent: Cc1ccccc1
Product: Cc1ncc(C(O)CC(C)Cl)c(C)n1

Procedure:
A suspension of the sodium salt of (2,4-dimethyl-5-pyrimidylcarbonyl)-acetone in anhydrous toluene is saturated with hydrogen chloride and then reacted with thionyl chloride in a known manner. Reduction of the reaction product gives 1-(2,4-dimethyl-5-pyrimidyl)-3-chloro-butan-1-ol hydrochloride which is used without additional purification.
Reaction SMILES: [S:1]1(=O)[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.[F:8][C:9]([F:20])([F:19])[C:10]([O:12]C(=O)C(F)(F)F)=[O:11]>C1COCC1>[F:8][C:9]([F:20])([F:19])[C:10]([O-:12])=[O:11].[S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH+:2]1
Reactant: O=S1CCCSC1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: O=C([O-])C(F)(F)F
Product: [CH+]1SCCCS1
Yield: 100 %

Procedure:
To a stirred solution of 1,3-dithiane (6.1 g, 50 mmol) in methanol (280 mL) at 0° C. was added dropwise a solution of sodium periodate (10.8 g, 50 mmol) in water (85 mL). After stirring overnight the precipitated solids were removed by filtration and the filtrate was evaporated. The residue was dissolved in dichloromethane, dried over MgSO4 and the solvent was evaporated to dryness. The resultant oil was column purified over silica gel eluting with 5% MeOH/DCM to provide 1,3-dithiane-1-oxide (6.5 g) in 94% yield. A THF (10 mL) solution of 1,3-dithiane-1-oxide (1 g, 7.3 mmol) was treated with trifluoroacetic anhydride (1 mL, 7.3 mmol) providing a solution of 1,3-dithian-2-ylium trifluoroacetate (AIa) (7.3 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[O:14][CH3:15].[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O1CCCC1.C1(C)C=CC=CC=1>[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: OCCCCCCCCCl
Reactant: COC(=O)/C=C/c1ccc(O)c(OC)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(OCCCCCCCCCl)c(OC)c1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 90.4 %

Procedure:
20.0 g (96.06 mmol) methyl (2E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoate, 16.6 g (100.9 mmol) 8-chlor-1-octanol and 27.7 g (105.7 mmol) of triphenylphosphine were dissolved in 400 ml of tetrahydrofurane. The colorless solution was subsequently cooled to 0° C. and 46.0 g (105.7 mmol) of a 40% solution of azodicarboxylic acid diethyl ester in toluene was added dropwise thereto over a period of 25 minutes. The mixture was subsequently allowed to react for 4 hours at 0° C. The reaction mixture reduced in volume by evaporation. The resulting residue was added to a mixture of methanol and water (3:2) and was then extracted with a mixture of tert.-butyl-methylether:hexane 1:1. The tert.-butyl-methylether:hexane phase was washed repeatedly with water, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The crude product was recrystallised from 2-propanol yielded 30.8 g (90%) methyl (2E)-3-{4-[(8-chloroctyl)oxy]-3-methoxyphenyl}-2-propenoate as white crystals.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:28]([S:31]([NH2:34])(=[O:33])=[O:32])([CH3:30])[CH3:29]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:34][S:31]([CH:28]([CH3:30])[CH3:29])(=[O:33])=[O:32])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)S(N)(=O)=O
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)C(C)C)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and isopropylsulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method B described hereinabove. Yield (13%); 1H NMR (d6-DMSO) δ 11.60 (br s, 1H), 7.46 (d, J=15.7 Hz, 1H), 7.40–7.09 (m, 12H), 6.86 (d, J=8.1 Hz, 2H), 6.48 (d, J=15.7 Hz, 1H), 3.64 (m, 1H), 2.37 (q, J=7.3 Hz, 2H), 1.23 (d, J=7.0 Hz, 6H), 0.83 (t, J=7.3 Hz, 3H); APcI m/z: 460 (M+H+).
Reaction SMILES: N1C2C(=CC=CC=2[CH2:11][S:12]([NH2:15])(=[O:14])=[O:13])C=CC=1.Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].[CH3:39][C:40]#[N:41]>>[N:41]1[C:19]2[C:18](=[CH:23][CH:22]=[CH:21][C:20]=2[NH:15][S:12]([CH3:11])(=[O:14])=[O:13])[CH:17]=[CH:39][CH:40]=1
Reactant: CC#N
Reactant: NS(=O)(=O)Cc1cccc2cccnc12
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CS(=O)(=O)Nc1cccc2cccnc12
Yield: 63 %

Procedure:
N-(quinolin-8-yl)methanesulfonamide was synthesized as previously described. 2N-(quinolin-8-yl)methanesulfonamide (0.08 g, 0.34 mmol), was reacted with 4-bromomethylphenyl boronic acid pinacol ester (0.11 g, 0.37 mmol), in the presence of K2CO3 (0.14 g, 1.0 mmol) in 3 mL MeCN in a microwave reactor at 90° C. for 30 min affording B15 in 63% yield (0.09 g, 0.21 mmol). 1H NMR (400 MHz, CDCl3) δ=8.97 (dd, J1=4 Hz, J2=1.6 Hz, 1H), 8.18 (dd, J1=8.4 Hz, J2=1.6 Hz, 1H), 7.74 (dd, J1=8.4 Hz, J2=1.2 Hz, 1H), 7.64 (d, J=8 Hz, 2H), 7.50 (dd, J1=7.2 Hz, J2=1.2 Hz, 1H), 7.46 (dd, J1=8.4 Hz, J2=4.4 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H), 7.22 (d, J=8 Hz, 2H), 5.20 (s, 2H), 3.20 (s, 3H), 1.30 (s, 12H). 13C NMR (100 MHz, CDCl3) δ=150.30, 145.18, 140.39, 137.00, 135.36, 135.17, 134.93, 129.74, 129.06, 128.25, 126.75, 121.68, 83.98, 55.08, 40.37, 25.08. ESI-MS(+): m/z 438.96 [M+H]+, 460.97 [M+Na]+.
Reaction SMILES: [Br-].[OH:2][C:3]1[N+:10]2[C:9]3[CH2:11][CH2:12][CH2:13][CH2:14][C:8]=3[S:7][C:6]=2[S:5][C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)Cl>O>[C:15]1([CH:4]2[S:5][CH:6]3[S:7][C:8]4[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=4[N:10]3[C:3]2=[O:2])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Oc1c(-c2ccccc2)sc2sc3c([n+]12)CCCC3
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: O=C1C(c2ccccc2)SC2SC3=C(CCCC3)N12
Yield: 63 %

Procedure:
9.7 g. (0.026 moles) of 3-hydroxy-2-phenyl-5,6,7,8-tetrahydrothiazolo[2,3-b]benzothiazolium bromide, prepared according to Example 10, is suspended in a mixture of 1000 ml. methylene chloride and 500 ml. water, and the mixture is stirred at room temperature for 5 hours. The layers are separated and the methylene chloride layer is dried over anhydrous magnesium sulfate. The drying agent is removed by filtration and the filtrate is reduced in volume. The residual solid is triturated with ether and the yellow solid is collected. The crude material is recrystallized from 1.5 l. of acetonitrile to yield a yellow solid weighing 4.7 g. (63% yield). The product melts at ca. 200° C.(dec.).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11]([O:13]CC)=O)=O.O.[NH2:17][NH2:18]>CCO>[NH2:17][N:18]1[C:3](=[O:2])[C:5]2[S:6][CH:7]=[CH:8][C:9]=2[NH:10][C:11]1=[O:13]
Reactant: NN
Reactant: CCOC(=O)Nc1ccsc1C(=O)OC
Solvent: O
Solvent: CCO
Product: Nn1c(=O)[nH]c2ccsc2c1=O
Temperature: 90 °C
Yield: 61.9 %

Procedure:
To a solution of 3-ethoxycarbonylamino-thiophene-2-carboxylic acid methyl ester (3.43 g, 15.0 mmol) in EtOH (100 mL) was added hydrazine monohydrate (7.98 mL, 164.6 mmol). After heating at 90° C. for 12 h, the mixture was filtered to afford a fine yellow powder (1.70 g), which was used in the next step without further purification. MS: 184.2. 1H NMR (400 MHz, CD3OD) δ ppm 7.93 (d, J=5.3 Hz, 1H), 6.95 (d, J=5.3 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[Br:10]Br.S(=O)(O)[O-].[Na+]>C(Cl)Cl.[Fe]>[Br:10][C:6]1[CH:7]=[C:2]([F:1])[C:3]([OH:9])=[C:4]([F:8])[CH:5]=1
Reactant: Oc1c(F)cccc1F
Reactant: BrBr
Agent: [Fe]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1c(F)cc(Br)cc1F
Temperature: 0 °C

Procedure:
A stirred mixture of 2,6-difluorophenol (20.0 g, 0.154 mole), bromine (25.57 g, 0.16 mole) and powdered iron (1 g) in methylene chloride (250 ml) was heated at reflux overnight. The cooled reaction mixture was poured into ice-water (300 ml) containing sodium bisulfite (5 g) and the organic phase separated. The aqueous phase was washed with additional methylene chloride. The organic phase was combined, dried (MgSO4) and the solvent evaporated to give a light yellow oil which solidified upon standing. NMR (CDCL3) of this material was consistent with the assigned structure. No additional analysis or purification was attempted. This material was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[CH:8][C:9]=2[Cl:11])[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.[CH2:28](N(CC)CC)C.CCCCCC>C(Cl)Cl.C(OCC)(=O)C>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](=[O:24])[CH2:28][NH:1][C:2]2[C:10]3[C:5](=[CH:6][C:7]([Cl:12])=[CH:8][C:9]=3[Cl:11])[NH:4][C:3]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1N
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCC(=O)c1ccc(F)cc1
Yield: 52.1 %

Procedure:
Dissolve 3-amino-2-carbethoxy-4,6-dichloroindole (2.0 g, 7.13 mmol) in methylene chloride (125 mL) and add p-fluorobenzoyl chloride (0.886 mL, 7.5 mmol) followed by triethylamine (1.05 mL, 7.5 mmol). Stir the reaction at room temperature overnight. Add an additional amount of p-fluorobenzoyl chloride (0.20 mL) and triethylamine (0.20 mL) and stir for 6 hours. Dilute the reaction with ethyl acetate, wash with 1N HCl, saturated sodium bicarbonate, saturated sodium chloride, dry over magnesium sulfate, filter and concentrate, in vacuo give a solid. Dissolve the solid in hot ethyl acetate (250 mL), reduce to 200 mL and add hot hexane (50 mL). Cool the solution and collect to resulting solid to yield the title compound as fluffy white crystals (1.52 g, 53%); 241°-243° C.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[S:19][C:18]4[C:17](=[O:20])[N:16]([CH:21]5[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]5)[C:15](=[O:27])[N:14]([CH2:28][C:29]5[N:30]=[N:31][N:32]([CH2:34][CH3:35])[N:33]=5)[C:13]=4[CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3]1.[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=3)[C:54](O)=[O:55])=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[S:19][C:18]4[C:17](=[O:20])[N:16]([CH:21]5[CH2:22][CH2:23][N:24]([C:54]([C:53]6[CH:57]=[CH:58][CH:59]=[C:51]([C:45]7[C:46]8[CH:47]=[C:48]([O:49][CH3:50])[C:39]([O:38][CH2:36][CH3:37])=[CH:40][C:41]=8[C@H:42]8[CH2:63][S:62][CH2:61][CH2:60][C@H:43]8[N:44]=7)[CH:52]=6)=[O:55])[CH2:25][CH2:26]5)[C:15](=[O:27])[N:14]([CH2:28][C:29]5[N:30]=[N:31][N:32]([CH2:34][CH3:35])[N:33]=5)[C:13]=4[CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc5c(c4)OCO5)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)O)c1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccc7c(c6)OCO7)cc5n(Cc5nnn(CC)n5)c4=O)CC3)c1)=N[C@@H]1CCSC[C@H]21

Procedure:
6-(1,3-benzodioxol-5-yl)-1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (94 mg; compound B77) is reacted with 3-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (72 mg; compound C8) and HBTU (151 mg) in DCM/DMF (14 ml/1 ml) in the presence of DIPEA (188 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc/DCM, 100/0/0 to 50/40/10 to 30/60/10 to 0/90/10 (v/v/v)] and preparative HPLC as a solid.