Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N+](C1C=CC([O:30][C:31](=O)[NH:32][C:33]2[CH:34]=[N:35][C:36]([O:39][CH:40]3[CH2:43][CH2:42][CH2:41]3)=[CH:37][CH:38]=2)=CC=1)([O-])=O.C(Cl)Cl>CC(C)=O>[CH:40]1([O:39][C:36]2[N:35]=[CH:34][C:33]([NH:32][C:31]([N:18]3[CH2:19][CH2:20][CH:15]([C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)[CH2:16][CH2:17]3)=[O:30])=[CH:38][CH:37]=2)[CH2:41][CH2:42][CH2:43]1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Reactant: O=C(Nc1ccc(OC2CCC2)nc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(OC5CCC5)nc4)CC3)c2cc1OC
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
A mixture of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (114.1 mg, 418 μmol), as prepared in Example 1d, (6-cyclobutoxy-pyridin-3-yl)-carbamic acid 4-nitro-phenyl ester (151 mg, 459 μmol), as prepared in the preceding step, and DCM (818 μL) was treated with TEA (63 μL, 455 μmol) in one portion, and stirred under air at 45° C. for 30 min. The reaction mixture was then directly applied to a flash silica column (3:4 hex/acetone) to provide the title compound as a foam (141.1 mg, 73%). This material was taken up in 2 M K2CO3 (2 mL) and extracted with DCM (2×2 mL). The combined organic layers were dried (Na2SO4), concentrated, and repurified with a silica flash column (9:2 EtOAc/acetone) to provide analytically pure title compound as an off-white foam (84.4 mg, 44%). 1H NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 7.97 (d, 1H), 7.77 (dd, 1H), 7.34 (s, 1H), 7.26 (s, 1H), 6.67 (d, 1H), 6.39 (br s, 1H), 5.11 (m, 1H), 4.32-4.22 (m, 2H), 4.07 (s, 3H), 4.06 (s, 3H), 3.60 (tt, 1H), 3.18 (td, 2H), 2.51-2.37 (m, 2H), 2.24-1.94 (m, 6H), 1.89-1.57 (m, 2H). LC-MS (ESI): calcd mass 463.2, found 464.3 (MH+). Anal. Calcd for C25H29N5O4: C, 64.78; H, 6.31; N, 15.11. Found: C, 64.64; H, 6.24; N, 15.04.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:17]([O:19]CC)=[CH2:18])CCC.O>CN(C=O)C>[N:7]1([C:4]2[N:3]=[C:2]([C:17](=[O:19])[CH3:18])[S:6][N:5]=2)[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1nc(-n2ccnc2)ns1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1nc(-n2ccnc2)ns1
Temperature: 67.5 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
A catalytic amount of dichloropalladium(II)bis(triphenylphosphine) (189 mg, 268 μmol) was added to a solution of 5-chloro-3-imidazol-1-yl-[1,2,4]thiadiazole (500 mg, 2.68 mmol) and tributyl-(1-ethoxy-vinyl)-stannane (904 μL, 2.68 mmol) in DMF (10 mL) under a nitrogen atmosphere at r.t. prior to heating at 65-70° C. for 21 h. The reaction was then cooled to r.t., H2O (70 mL) was added, filtered through celite, and washed with EtOAc (200 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated to a yellow residue. The yellow residue was diluted with a 5:1 mixture of 5N HCl/THF (48 mL) and stirred at r.t. for a period of 2 hours prior to concentrating to a white residue. The crude product was diluted with EtOAc (100 mL), washed with 1M NaOH (75 mL), brine (75 mL), dried over Na2SO4, filtered and concentrated to a white solid. Purification was achieved using column chromatography (CH2Cl2 to 9:1 CH2Cl2/MeOH) to afford 398 mg (77%) of 1-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-ethanone as a white solid. [M+H]+ 195.35.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.I[CH2:13][CH2:14][CH3:15].[BH4-].[Na+]>>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:13][CH2:14][CH3:15])[CH2:7]2
Reactant: CCCI
Reactant: Nc1cccc2cnccc12
Agent: [BH4-]
Agent: [Na+]
Product: CCCN1CCc2c(N)cccc2C1

Procedure:
The title compound was prepared by treatment of 5-aminoisoquinoline with iodopropane followed by reduction with sodium borohydride using procedures analogous to those described in Preparation 1 and Preparation 2.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][CH:7]([C:12](Cl)=[O:13])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.[CH2:17]([OH:19])[CH3:18].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][CH:7]([C:12]([O:19][CH2:17][CH3:18])=[O:13])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1
Reactant: CCO
Reactant: CC1(C)OC(C(=O)Cl)Oc2ccc(Cl)cc21
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)C1Oc2ccc(Cl)cc2C(C)(C)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.4 %

Procedure:
A solution of 9.4 g of 6-chloro-4,4-dimethyl-[4H]-1,3-benzodioxin-2-carboxylic acid chloride in 50 ml of anhydrous benzene was added dropwise at room temperature with stirring to a mixture of 2.3 g of ethanol, 30 ml of anhydrous benzene and 3.03 g of triethylamine and the solution was stirred for 6 hours at room temperature and was vacuum filtered. The filtrate was washed with 70 ml of an aqueous saturated sodium bicarbonate solution and twice with 70 ml of water, was dried over magnesium sulfate, treated with activated carbon and filtered. The filtrate was evaporated to dryness under reduced pressure and the 8.4 g of residue were chromatographed over silica gel H. Fractional elution with methylene chloride and evaporation of the solvent yielded 5.3 g of ethyl 6-chloro-4,4-dimethyl-[4H]-1,3-benzodioxin-2-carboxylate in the form of an oil which crystallized at less than 50° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[CH3:18][O:19][CH2:20]/[CH:21]=[CH:22]/B1OC(C)(C)C(C)(C)O1>C([O-])([O-])=O.[Na+].[Na+].C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](/[CH:22]=[CH:21]/[CH2:20][O:19][CH3:18])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC/C=C/c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Yield: 67.9 %

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (150 mg), 85 mg of (E)-2-(3-methoxy-1-propen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 14 mg of bis(triphenylphosphine)palladium(II) dichloride in 1 mL of 1M Na2CO3 aqueous solution and 1 mL of acetonitrile was heated to 100° C. in a sealed microwave reactor for 10 min. The reaction mixture was evaporated. The crude product was purified by flash chromatography eluting with 5-50% EtOAc/hexane to yield 2-chloro-6-((E)-3-methoxyprop-1-enyl)-4-morpholinothieno[3,2-d]pyrimidine (87 mg, 68%). 2-Chloro-6-((E)-3-methoxyprop-1-enyl)-4-morpholinothieno[3,2-d]pyrimidine (40 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 29.1 mg of 334. MS (Q1) 408.1 (M)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:24][OH:25])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:33]([CH3:35])[CH3:34].O>CN(C)C=O>[Cl:1][C:2]1[C:3](/[C:9](=[N:24]/[O:25][CH:33]([CH3:35])[CH3:34])/[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:20])([F:22])[F:21])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)I
Reactant: O=C(NCC(=NO)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)O/N=C(\CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.7 %

Procedure:
To a suspension of 300 mg of N-[2-(3,5-dichloropyridin-2-yl)-2-(hydroxyimino)ethyl]-2-(trifluoromethyl)benzamide and 315 mg of potassium carbonate in 3 ml of N,N-dimethylformamide, 195 mg of 2-iodopropane was added, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was mixed with 20 ml of water and extracted with ethyl acetate (10 ml×2), the resulting organic layers were combined, washed with water (10 ml×2), the resulting organic layer was dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 258 mg of the desired product as white crystals.
Reaction SMILES: [BH4-].[Na+].C([C:5]1[CH:6]=[CH:7][C:8]2[S:13][CH2:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:16]=1)=O.[CH2:17]([OH:19])C>>[OH:19][CH2:17][CH:12]1[CH2:11][C:10]([CH3:14])([CH3:15])[C:9]2[CH:16]=[CH:5][CH:6]=[CH:7][C:8]=2[S:13]1
Reactant: CC1(C)CCSc2ccc(C=O)cc21
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Product: CC1(C)CC(CO)Sc2ccccc21
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Sodium borohydride (NaBH4) (0.36 g, 9.7 mmol) is added at 0° C. to a solution of the previous 6-formyl-4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyran (2.00 g, 9.7 mmol) in 20 ml of ethanol. The agitation was continued at this temperature for 30 minutes. After evaporation of the ethanol, it is taken up again in 100 ml of ethyl ether and acidified by an aqueous 3N solution of HCl to pH 1. The mixture is extracted with ether, dried over MgSO4 filtered and the solvents evaporated. The crude product is purified by flash chromatography on silica (eluent petroleum ether:ethyl ether:100:10). 1.85 g of 6-(hydroxymethyl-4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyrane is obtained (gross yield=92%).
Reaction SMILES: [OH-:1].[Na+].BrBr.[Cl:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([Cl:13])[C:7]=1[C:14](=[O:16])C.Br[O-].[Na+]>O.O1CCOCC1>[Cl:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([Cl:13])[C:7]=1[C:14]([OH:16])=[O:1]
Reactant: [OH-]
Reactant: CC(=O)c1c(Cl)ccc(F)c1Cl
Agent: BrBr
Agent: [Na+]
Agent: [O-]Br
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (−5° C.) solution of sodium hydroxide (252 g, 6.3 mol) in water (800 mL) was added bromine (86 mL, 1.68 mol) dropwise. The temperature of the reaction mixture was kept below −5° C. during the addition. A solution of 1-(2,6-Dichloro-3-fluorophenyl)ethanone (100 g, 480 mmol) in dioxane (800 ml) was added to the solution of sodium hypobromide in 1 h while maintaining the temperature below 0° C. The reaction mixture was warmed to room temperature and stirred for 2 h. After the TLC showed absence of starting material, the excess sodium hypobromide was destroyed with sodium sulfite (100 g in 100 mL water). The resulting solution was heated to 90° C. for 2 h. The reaction mixture was acidified with conc. HCl with vigorous stirring. The acidic solution was concentrated to remove all the dioxane and then extracted with dichloromethane (2×500 mL). The organic layer was dried (Na2SO4) and concentrated to give an oily residue, which after trituration with hexanes gave the title compound as a white solid. 1H NMR (CDCl3, 300 MHz): δ=7.20 (dd, 1H, J=8.7, 8.4 Hz), 7.33 (dd, 1H, J=9.3, 4.5 Hz).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](O)=[O:43].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[F:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:42](=[O:43])[C:41]2[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=2[CH2:39][N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3([CH2:31][O:30][C:29]4[CH:32]=[C:33]5[C:37](=[CH:38][C:28]3=4)[CH2:36][CH2:35][O:34]5)[C:19]2=[O:18])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: Cc1c(N)cccc1F
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: Cc1c(F)cccc1NC(=O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 3-fluoro-2-methylaniline to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(3-fluoro-2-methylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (84%) as a colorless solid: mp>230° C.; 1H NMR (300 MHz, DMSO-d6) δ10.23 (s, 1H), 7.68 (d, J=6.6 Hz, 1H), 7.51-7.37 (m, 2H), 7.33-7.13 (m, 5H), 7.11-6.97 (m, 2H), 6.89 (d, J=7.8 Hz, 1H), 6.58 (s, 1H), 6.39 (s, 1H), 5.16-5.02 (m, 2H), 4.85 (d, J=9.4 Hz, 1H), 4.70 (d, J=9.4 Hz, 1H), 4.47 (t, J=8.8 Hz, 2H), 2.93 (t, J=8.8 Hz, 1H), 2.21-2.14 (m, 3H); 13C NMR (75 MHz, DMSO-d6) δ177.8, 167.8, 162.8, 161.6, 161.2, 159.6, 142.8, 138.3, 138.2, 136.1, 134.6, 132.7, 131.0, 129.1, 128.5, 127.9, 127.1, 127.0, 126.9, 124.2, 123.6, 122.7, 121.1, 126.9, 120.3, 119.6, 113.0, 112.7, 109.7, 92.9, 80.4, 72.6, 65.4, 57.4, 41.4, 28.8, 15.6, 10.4, 10.3; MS (ES+) m/z 543.1 (M+23).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.[Br:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26]Br)=[N:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][O:1][C:2]2[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=3)[C:4](=[O:18])[CH:3]=2)=[N:24][CH:25]=1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Reactant: BrCc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccc(Br)cn2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1.23 g (5.00 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 8.0 mL DMF is added 1.26 g (5.00 mmol) 5-bromo-2-bromomethyl-pyridine and 2.07 g (15.0 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT, diluted with 80 mL of water, the formed precipitate is collected and dissolved in DMF. The solution is directly transferred to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [NH:1]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:14].P(Cl)(Cl)(Cl)(Cl)Cl.II.[Br:23]Br>C(Cl)(Cl)Cl>[Br:23][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:1][C:2]1=[O:14]
Reactant: BrBr
Reactant: O=C1CCCCCc2ccccc2N1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: II
Solvent: ClC(Cl)Cl
Product: O=C1Nc2ccccc2CCCCC1Br

Procedure:
To a solution of 1,3,4,5,6,7-hexahydro-1-benzazonin-2-one (4.7 g) in chloroform (75 ml), phosphorus pentachloride (5.9 g) is added in portions, while maintaining the temperature at 0°-5°. When addition is complete, iodine (60 mg) is added, followed by bromine (4.5 g), which is added dropwise over five minutes. The mixture is then refluxed for 4 hours. The chloroform solution is evaporated and the residue partitioned between ice/water (60 ml) and dichloromethane (100 ml). The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. The crude residue is purified by chromatography on silica gel, eluting with ether/hexane mixtures. Concentration of the appropriate fractions yields 3-bromo-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one.
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.[NH2:12]OS(O)(=O)=O>O>[Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:12])=[C:4]([F:11])[CH:3]=1
Reactant: NOS(=O)(=O)O
Reactant: O=Cc1cc(F)c(Br)cc1F
Solvent: O
Product: N#Cc1cc(F)c(Br)cc1F
Yield: 66.3 %

Procedure:
4-Bromo-2,5-difluorobenzaldehyde (1.82 g, 8.3 mmol) and hydroxylamine-O-sulphonic acid (1.1 eq., 1.03 g) in water (40 ml) were heated to 100° C. for 6 h, cooled and extracted with ethyl acetate. The organic layer was dried (sodium sulphate) and evaporated to give the title compound as a pale yellow solid (1.2 g).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8](=[NH:10])[N:7]([CH2:11][CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:30][C:31]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:32]=1[C:33](Cl)=[O:34]>O1CCCC1>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:33](=[O:34])[C:32]2[CH:36]=[C:37]([C:40]([F:41])([F:42])[F:43])[CH:38]=[CH:39][C:31]=2[F:30])/[N:7]([CH2:11][CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: CC(C)(C)OC(=O)N1CC(Cn2cc(C(C)(C)C)sc2=N)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(Cn2cc(C(C)(C)C)s/c2=N\C(=O)c2cc(C(F)(F)F)ccc2F)C1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
To a solution of the product of Example 42A (4.1 g, 12.5 mmol) in tetrahydrofuran (40 mL) was added triethylamine (5.2 mL, 37.6 mmol) followed by 2-fluoro-5-(trifluoromethyl)benzoyl chloride (2.0 mL, 13.2 mmol). This mixture was warmed to 50° C. and was allowed to stir for 90 min then the mixture was cooled to ambient temperature and was stirred for 16 h. The mixture was quenched with saturated, aqueous NH4Cl (20 mL) and diluted with ethyl acetate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 60% hexanes in ethyl acetate) to give the title compound (5.2 g, 10.0 mmol, 80% yield). MS (DCI/NH3) m/z 516 (M+H)+.
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[C:21]([CH2:28][CH2:29][CH2:30][CH3:31])[N:22]=[CH:23]2>N1C=CC=CC=1>[CH2:28]([C:21]1[N:22]=[CH:23][C:24]2[C:19]([CH:20]=1)=[C:18]([N:17]=[C:4]1[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]1)[CH:27]=[CH:26][CH:25]=2)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCc1cc2c(N)cccc2cn1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Agent: [I-]
Solvent: c1ccncc1
Product: CCCCc1cc2c(N=C3SC[C@@H]4Cc5ccccc5CN34)cccc2cn1
Reaction time: 96 h
Yield: 54.5 %

Procedure:
(S)-3-Methylthio-1,5,10,10a-tetrahydrothiazolo-[3,4-b]isoquinolinium iodide (5.25 g) is added to a solution of 5-amino-3-butylisoquinoline (3 g) in pyridine (100 cc). The suspension obtained dissolves gradually. After 4 days at a temperature of about 20° C., the mixture is concentrated to dryness under reduced pressure (25 mm Hg) at 50° C. The residue is dissolved in chloroform (200 cc). This solution is washed with N aqueous sodium hydroxide solution (3×100 cc) and then with water (2×50 cc), dried over sodium sulphate, filtered and the filtrate is then concentrated to dryness under reduced pressure (40 mm Hg) at 40° C. The residue obtained is recrystallised from diisopropyl ether (50 cc). (S)-3-[(3-Butylisoquinol-5-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]-isoquinoline (3.05 g), which melts at 82° C., is thus obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.Cl>>[N:24]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:13]=[CH:14]/[C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: ClCCCCOc1ccccc1/C=C/c1nc2ccccc2s1
Reactant: C1CCNC1
Agent: Cl
Product: C(=C/c1ccccc1OCCCCN1CCCC1)\c1nc2ccccc2s1
Yield: 33 %

Procedure:
The title compound was prepared in accordance with Example 38 starting with (H) of Example 38 (3.0 g, 8.7 mmol) and using pyrrolidine in place of dipropylamine to produce 1.1 g (33% yield) of the title compound as the HCl salt, mp 220°-222° C. IR(KBr): 3410, 1600 cm-1. MS: 379(MH+). 1H NMR (CD3OD): δ 8.02-6.91 (m, 10H), 4.12 (t, J=5.2 Hz, 2H), 3.23 (m, 6H), 2.54 (m, 4H), 2.21 (m, 4H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(=O)=O)=CC=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CS(C)=O.CCOCC>[N:25]([CH2:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CN=[N+]=[N-]
Temperature: 70 °C
Yield: 90.6 %

Procedure:
(S)-2-[[[(4-Methylphenyl)sulfonyl]oxy]methyl]-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester (3.55 g, 10 mmol, see J. Das et al, J. Med Chem, 1992, Vol. 35,2610 for preparation) was dissolved in dimethyl sulfoxide (DMSO) (40 mL) and treated with sodium azide (980 mg, 15 mmol). The mixture was heated at 70° C. for 5 hours, then cooled and diluted with ether. After washing with water (3×50 mL), the ether layer was dried (MgSO4) and freed of solvent in vacuo to give title compound as a colorless oil (2.05 g, 91%) which was used without further purification.
Reaction SMILES: P(Cl)(Cl)[Cl:2].[CH2:5](O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[CH2:5]([Cl:2])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: ClP(Cl)Cl
Reactant: CCCCCCCCO
Product: CCCCCCCCCl
Reaction time: 0.05 h
Yield: 98 %

Procedure:
Into a reactor system in accordance with Example 1 there were pumped octyl alcohol and phosphorus trichloride in a molar ratio of 2.90 : 1. The pressure in the flow line was 30 atm. The residence time in reaction zone 1 was 3 minutes; in the preheater, 2 minutes; and, in reaction zone 2, 28 minutes. The temperature at the outlet of reaction zone 1 was 100° C. Following preheating to 150° C, an average temperature of 150° to 155° C was maintained in reaction zone 2. One obtained in the organic phase 96% octyl chloride in a yield of 98% with respect to octyl alcohol. The product contained 0.19% dioctyl ether. Space-time yield: 1.4 kg/hour, liter.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](=O)[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1)[CH3:2].[CH:14]1[C:19]([NH:20][NH2:21])=[CH:18][CH:17]=[C:16]([S:22]([NH2:25])(=[O:24])=[O:23])[CH:15]=1.Cl>O>[CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[N:21][NH:20][C:19]3[CH:18]=[CH:17][C:16]([S:22]([NH2:25])(=[O:23])=[O:24])=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)NC(=O)C2=O
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: O
Product: CCc1ccc2c(c1)NC(=O)C2=NNc1ccc(S(N)(=O)=O)cc1
Yield: 79 %

Procedure:
The title compound was prepared from 6ethyl-1H-indole-2,3-dione (Krantz and Young, 1989, U.S. Pat. No. 4,873,232) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 79% yield: 1H NMR (DMSO-d6): δ 1.16 (t, J=7.5 Hz, 3H), 2.60 (q, J=7.5 Hz, 2H), 6.74 (s, 1H), 6.89 (d, J=7.5 Hz, 1H), 7.22 (s, 2H), 7.46 (d, J=7.5 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.75 (d, J=8.7 Hz, 2H), 11.02 (s, 1H), 12.70 (s, 1H); APCI−MS m/z 343 (M−H)−. Anal. Calcd for C16H16N4O3S.0.32 H2O: C, 54.88, H, 4.79; N, 16.00; S, 9.16. Found C, 54.81, H, 4.59; N, 16.06; S, 9.04.