Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:31]([NH:33][C:34]([C:36]2[N:37]=[C:38](Cl)[S:39][CH:40]=2)=[O:35])[CH3:32])[CH:22]=[C:23]([F:30])[C:24]=1[NH:25][S:26]([CH3:29])(=[O:28])=[O:27].C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:30][C:23]1[CH:22]=[C:21]([CH:31]([NH:33][C:34]([C:36]2[N:37]=[C:38]([C:5]3[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=3)[S:39][CH:40]=2)=[O:35])[CH3:32])[CH:20]=[C:19]([F:18])[C:24]=1[NH:25][S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(NC(=O)c1csc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1csc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 28.2 %

Procedure:
3,5-Bis(trifluoromethyl)phenylboronic acid (67.1 mg, 0.26 mmol) and 2-chloro-thiazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylaminophenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (21 mg, 28%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[O:24]([CH:31]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>O1CCCC1>[CH3:8][C:6]1[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=[C:2]([N:33]2[CH2:34][CH2:35][CH2:36][CH:31]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32]2)[N:7]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: c1ccc(OC2CCCNC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCC(Oc3ccccc3)C2)nc1-c1ccc(C)cc1
Yield: 19.3 %

Procedure:
This compound was prepared according to the method C from methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.095 g; 0.285 mmol), 3-phenoxypiperidine (0.152 g; 0.856 mmol) and triethyl amine (0.200 mL; 1.43 mmol) in tetrahydrofuran (2 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.026 g (38%) of the titled compound as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:5][CH:4]=1.[C:17](O)(=[O:19])[CH3:18]>C(OC(=O)C)(=O)C>[C:17]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:15][CH:16]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)O
Reactant: NCc1ccc(OCCn2ccnc2)cc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NCc1ccc(OCCn2ccnc2)cc1

Procedure:
1-[2-(4-Aminomethylphenoxy)ethyl]imidazole (1.1 g) was heated on a steam bath for 2 hours in a mixture of acetic acid (10 ml) and acetic anhydride (1 ml). The solution was then evaporated and the residue was dissolved in a small volume of water. The solution was made basic with sodium bicarbonate and the resulting solid was filtered off, washed with water and crystallised from water to give 1-[2-(4-acetylaminomethylphenoxy)ethyl]imidazole (0.70 g), m.p. 115°-166° C. Found: C, 60.45; H, 6.72; N, 15.35. C14H17N3O2.H2O requires: C, 60.63; H, 6.91; N, 15.15%.
Reaction SMILES: [Cl:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13]>N1C=CC=CC=1>[Cl:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH:6][C:12](=[O:13])[O:14][CH2:15][CH3:16])=[C:4]([F:10])[CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1cc(F)c(Cl)cc1F
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cc(F)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4-Chloro-2,5-difluoroaniline (XXXIX) (2.1 g, 12.8 mmol) was mixed with pyridine (20 ml) at 0° C., to it was dropwise added ethyl chloroformate (1.5 g, 13.8 mmol). After stirring for 2.5 hr while temperature slowly raised to room temperature, pyridine was evaporated and the residue crystallized in ice-water (100 ml). The crystals were filtered, washed with water and dried in fume hood overnight (2.7 g). 1H NMR (CDCl3, 300 MHz) 1.33 (3H, t, J=7.1 Hz), 4.23 (2H, q, J=7.1 Hz), 6.89 (1H, br), 7.12 (1H, dd, J=6.5, 6.5 Hz), 8.05 (1H, dd, J=7.8, 9.6 Hz) ppm.
Reaction SMILES: [OH-].[Na+].[I:3][C:4]1[CH:15]=[CH:14][C:7]2[C:8](=[O:13])[O:9][C:10](=O)[NH:11][C:6]=2[CH:5]=1.O>CO>[NH2:11][C:6]1[CH:5]=[C:4]([I:3])[CH:15]=[CH:14][C:7]=1[C:8]([O:9][CH3:10])=[O:13]
Reactant: O=c1[nH]c2cc(I)ccc2c(=O)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(I)cc1N
Temperature: 60 °C
Yield: 80.2 %

Procedure:
To a stirred solution of sodium hydroxide (0.048 g, 1.2 mM) in methanol (4.5 mL) was added 7-iodo-2H-3,1-benzoxazine-2,4(1H)-dione (2.6 g, 9.0 mM). The mixture was heated at 60° C. for 7 hr and the resulting solution was cooled, poured into water and extracted with ethyl acetate. The combined extracts were washed once with dilute sodium hydroxide, dried (MgSO4), filtered and concentrated to leave the title compound (2.0 g, 80%) as a brown oil which slowly crystallized; MS(CI): 278 (M+H).
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:20][CH2:19][C@@H:18]([N:21]2[CH:28]=[CH:27][C:25](=[O:26])[NH:24][C:22]2=[O:23])[CH2:17][C@@H:16]1[OH:29])([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2].C(O)(=O)C.[CH2:34]([NH2:37])[CH:35]=[CH2:36].C(O)(=O)C>C([O-])(=O)C.[Na+].O>[P:1]([O:13][CH2:14][C@H:15]1[O:20][CH2:19][C@@H:18]([N:21]2[CH:28]=[C:27]([CH2:36][CH:35]=[CH:34][NH2:37])[C:25](=[O:26])[NH:24][C:22]2=[O:23])[CH2:17][C@@H:16]1[OH:29])([O:4][P:5]([O:8][P:9]([OH:11])([OH:12])=[O:10])([OH:7])=[O:6])(=[O:2])[OH:3]
Reactant: O=c1ccn([C@@H]2CO[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)C2)c(=O)[nH]1
Reactant: C=CCN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NC=CCc1cn([C@@H]2CO[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)C2)c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
100 mg (0.19 mmol)of 1,5-Anhydro-2-(uracil-1yl)-2,3-dideoxy-D-arabino-hexitol 6 triphosphate and 106 mg (0.33 mmol) mercury II acetate were dissolved in 5 ml 0.1 M sodium acetate buffer pH5 The mixture was stirred for 4 h at 50° C. after cooling to room temperature the mixture was diluted with 40 ml water. A freshly prepared allylamine acetate solution. (0.77 ml (13 mmol) were neutralized with 4M acetic acid) and 150 mg (1.5 mmol) dipotassium tetrachloropalladinate were added and the mixture was stirred for 24 h at room temperature. The reaction mixture was filtered through a 0.45 μm membrane filter and the filtrate was applied on a DEAE-Sephadex column and it was eluated with a gradient from 0.1-1 M Trieethylammoniumbicarbonate pH8 monitoring at 260 nm. The major UV peak was collected (Ninhydrine reaction positive) and further purified by reversed phase chromatography with a gradient from buffer 100% A: 0.1M triethylammonium acetate pH 8.0 to 100% buffer B: 0.1 M triethylammonium acetate/Acetonitril 1:1 monitoring at 260 nm on a RP 18 Hypersil column) The fractions containing the aminoallyl triphosphate were collected and evaporated under vacuum. The presence of the aminogroup was verified by ninhydrine reaction Excess triethylammonium-acetate was removed by several coevaporations with water. Yield 80 mg
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[O:10])O[C:2]1=[O:11].[CH2:12]1[C@@H:15](C(O)=O)[NH:14][CH2:13]1>CN(C)C=O.C(O)(=O)C>[S:9]1[C:5]2[C:4](=[O:10])[N:14]3[CH2:15][CH2:12][C@H:13]3[C:2](=[O:11])[NH:1][C:6]=2[CH:7]=[CH:8]1
Reactant: O=C(O)[C@@H]1CCN1
Reactant: O=c1[nH]c2ccsc2c(=O)o1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1Nc2ccsc2C(=O)N2CC[C@@H]12
Yield: 42.7 %

Procedure:
A solution of 26.9 g (171mmol) of 2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione (EP 27214) and 16.1 g (171 mmol) of L-azetidine-2-carboxylic acid in 200 ml of dimethylformamide and 40 ml of acetic acid was stirred at 120° for 3 hours. The brown solution was evaporated and the brown residue obtained was crystallized from ethanol. There were obtained 15.2 g (43%) of (S)-6,7-dihydroazeto[1,2-a]thieno[3,2-e][1,4]diazepine-5,9(4H,5aH)-dione as a colourless crystallizate of m.p. 274°.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:13]=[C:12]([NH:14][C:15](=[O:24])[C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[C:6]2[O:7][C:8]([CH3:11])=[C:9]([CH3:10])[C:5]=2[CH:4]=1.ClC(Cl)(Cl)[C:27]([N:29]=C=O)=[O:28]>C(N(CC)CC)C>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[C:15]([NH:14][C:12]1[C:6]2[O:7][C:8]([CH3:11])=[C:9]([CH3:10])[C:5]=2[CH:4]=[C:3]([NH:2][C:27]([NH2:29])=[O:28])[CH:13]=1)=[O:24]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cc(N)cc2c1C
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cc(NC(N)=O)cc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture of 5-amino-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzo[b]furan hydrochloride (155 mg), triethylamine (61 mg) and trichloroacetyl isocyanate (115 mg) was stirred at ambient temperature for 1 hour. Then, the mixture was concentrated in vacuo and to the residue was added methanol (3 ml) and aqueous 1N-sodium hydroxide (2 ml). The mixture was stirred at 60° C. for 15 minutes and the methanol was evaporated in vacuo. The separated solid was collected, washed with water and dried to give 7-(2,6-dichlorobenzoylamino)-2,3-dimethyl-5-ureidobenzo[b]furan (130 mg).
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH3:22])/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[CH2:7][C@H:8]([C@H:10]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C@:11]1([CH3:21])[CH2:12][CH2:13][CH2:14][C:15]2=[O:20])[CH3:9].[Si:24](C1NC=CN=1)([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[CH3:9][C@@H:8]([C@H:10]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C@:11]1([CH3:21])[CH2:12][CH2:13][CH2:14][C:15]2=[O:20])[CH2:7]/[CH:6]=[CH:5]/[CH:4]=[CH:3]/[C:2]([CH3:22])([O:1][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH3:23]
Reactant: C[Si](C)(C)c1ncc[nH]1
Reactant: C[C@H](C/C=C/C=C/C(C)(C)O)[C@H]1CCC[C@H]2C(=O)CCC[C@]12C
Solvent: ClCCl
Product: C[C@H](C/C=C/C=C/C(C)(C)O[Si](C)(C)C)[C@H]1CCC[C@H]2C(=O)CCC[C@]12C

Procedure:
323 mg of (4aR,5R,8aR)-5-((3E,5E)-(R)-7-hydroxy-1,7-dimethyl-octa-3,5-dienyl)-4a-methyl-octahydro-naphthalen-1-one, was reacted at 40° with 1.33 ml of TMS-imidazole (9 equivalents) in 8 ml of CH2Cl2. After a few hours the mixture was poured onto crushed ice, extracted with ether, washed with water, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=9/1) yielded 326 mg of (4aR,5R,8aR)-5-[(3E,5E)-(R)-(1,7-dimethyl-7-trimethylsilanyloxy-octa-3,5-dienyl)]-4a-methyl-octahydro-naphthalen-1-one as colourless oil.
Reaction SMILES: [F-].[NH4+].[CH3:3][O:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][O:10][C:11]([C@@H:13]2[C@@H:16]([CH2:17][CH:18]=[CH2:19])[C:15](=[O:20])[N:14]2[Si](C(C)(C)C)(C)C)=[O:12])=[CH:7][CH:6]=1.C(O)(=O)C>CO>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][C:11]([C@@H:13]2[C@@H:16]([CH2:17][CH:18]=[CH2:19])[C:15](=[O:20])[NH:14]2)=[O:12])=[CH:28][CH:29]=1
Reactant: C=CC[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C(=O)OCc1ccc(OC)cc1
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)O
Product: C=CC[C@H]1C(=O)N[C@@H]1C(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 6.2 mL of 0.5 M ammonium fluoride in methanol (3.1 mmol) was added to a mixture of compound 58 (1.0 g, 2.57 mmol), acetic acid (530 uL, 9.0 mmol) and methanol (25 mL). The mixture was stirred at room temperature for 2 h. The solvent was removed and the residue was taken up in toluene (2˜3 mL) to assist removal of AcOH. After solvent was removed, the residue was taken up in DCM. The resulting white solids were filtered off. Concentration of the filtrate gave 0.70 g of the crude 59 with purity: 91.1%, 1HNMR (300 MHz, CDCl3): 2.60 (m, 2H), 3.38 (m, 1H), 3.87 (s, 3H), 3.98 (d, 1H), 5.22 (m, 4H), 5.83 (m, 1H), 6.15 (b, s, 1H), 6.90 (d, 2H), 7.35 (d, 2H). Anal. C15H17NO4, Mol. Wt.: 275.3. Found: ESI-MS: 275.8 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][CH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#N.C(O)=[O:19]>[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][CH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:19]
Reactant: N#Cc1ccccc1COc1cccc(Cl)c1
Reactant: O=CO
Agent: [Ni]
Product: O=Cc1ccccc1COc1cccc(Cl)c1
Temperature: 150 °C
Reaction time: 17 h

Procedure:
Raney nickel alloy (9.72 g) was added to a solution of part of the crude (2-(3-chlorophenoxymethyl)benzonitrile (9.72 g) in 75% formic acid (150 ml). The resulting mixture was heated at 150° C. for about 5 hours, further Raney nickel alloy (3 g) was added, and heating at 150° C. was continued for a further 17 hours. The mixture was filtered and the solid was washed with a little methanol. The combined filtrate and washings were diluted with water and extracted with ether. The extracts was washed successively with water, aqueous potassium carbonate and brine, then dried and concentrated to give 2-(3-chlorophenoxymethyl)benzaldehyde (5.80 g) as a yellow-brown oil, 1H NMR delta 5.51 (2H, s), 10.18 (1H, s) ppm. A mixture of this crude benzaldehyde, methyl(methylthiomethyl)sulphoxide (1.73 g) and Triton B [(40 weight % solution of benzyltrimethylammonium hydroxide in methanol) 1.21 ml] in THF (6 ml) was heated at 110° C. for 3 hours. Further Triton B (2 ml) was added and the mixture was heated for a further 4 hours at 110° C. Further Triton B (2 ml) and methyl (methylthiomethyl)sulphoxide (1.5 ml ) were then added and the mixture was heated for a further 6 hours at 110° C. After cooling, the mixture was poured into water and extracted with ether. The extracts were washed with water and brine, dried, concentrated and chromatographed using ether as eluant to give a single stereoisomer of the sulphoxide (A) [1.10 g, 7% yield from 2-(bromomethyl)benzonitrile] as a viscous oil, 1H NMR delta 2.18 (3H, s), 2.74 (3H, s), 5.04 and 5.12 (each 1H, d J 12 Hz), 7.85 (1H, s) ppm. ##STR53##
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][C:12]([NH:19]C=O)=[N:13][C:14]=2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[C:25](O)(=[O:27])C>CO>[NH2:19][C:12]1[N:11]=[C:10]2[C:15]([N:16]=[CH:17][N:9]2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([O:27][CH3:25])[N:13]=1
Reactant: CC(=O)O
Reactant: O=CNc1nc(Cl)c2ncn(OCc3ccccc3)c2n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc2c1ncn2OCc1ccccc1
Yield: 76 %

Procedure:
A mixture of 9-benzyloxy-6-chloro-2-formamidopurine (440mg, 1.60mmol), 1.2M sodium methoxide in methanol (5.3ml) and methanol (10ml) was heated at reflux temperature for 1 hour and then cooled. Acetic acid (4ml) was added and the solution evaporated to dryness. The residue was suspended in water and extracted with chloroform (2×25ml). The combined chloroform extracts were washed with brine, dried (magnesium sulphate) and evaporated under reduced pressure. Column chromatography on silica gel (eluted with chloroform-methanol, 100:1) afforded the title compound (331mg, 76%). IR: υmax (KBr) 3480, 3310, 1625, 1585, 1505, 1485, 1460, 1400cm-1 ; 1H NMR: δH [(CD3)2SO] 3.96 (3H, s, CH3), 5.31 (2H, s, CH2Ph), 6.64 (2H, br.s, D2O exchangeable, NH2), 7.42 (5H, s, Ph), 7.75 (1H, s, H-8). Found: C, 57.18, H, 4.84; N, 25.85%). m/e 271.1075. C13H13N5O2 requires: C, 57.56, H, 4.83, N, 25.82%; m/e 271.1069.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:17][S:18](Cl)(=[O:20])=[O:19].[Na+].[Cl-]>O.C1(C)C=CC=CC=1>[CH3:17][S:18]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)(=[O:20])=[O:19]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)OC1CCN(Cc2ccccc2)CC1

Procedure:
1-Benzyl-4-piperidinol (23.98 g), 168.66 g of toluene and 83.56 g of a 30% aqueous solution of NaOH were respectively weighed and placed in a 500-mL four-necked flask. While the mixture was stirred, the flask inside temperature was lowered to 6.7° C. Then, 31.73 g of methanesulfonyl chloride was added dropwise over 4 hours and 30 minutes at a flask inside temperature of 5 to 10° C. Water (33 mL) was added to dissolve the NaCl which had precipitated out in the aqueous phase, and the mixture was separated into the toluene phase and aqueous phase. A toluene solution of 1-benzyl-4-piperidinol methanesulfonate was thus obtained in a yield of 40.3 mole percent.
Reaction SMILES: C[O:2][C:3](=[O:46])[C@@H:4]([NH:23][C:24]([C:26]1[CH:45]=[CH:44][C:29]2[N:30]([CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[C:31]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[N:32][C:28]=2[CH:27]=1)=[O:25])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]([C:19]([OH:21])=[O:20])([CH3:18])[CH3:17])[CH:13]=2)[N:8]([CH3:22])[CH:7]=1.[OH-].[Na+].C(O)(C(F)(F)F)=O>CS(C)=O>[C:19]([C:16]([CH3:18])([O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:22])[CH:7]=[C:6]2[CH2:5][C@H:4]([NH:23][C:24]([C:26]1[CH:45]=[CH:44][C:29]2[N:30]([CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[C:31]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[N:32][C:28]=2[CH:27]=1)=[O:25])[C:3]([OH:46])=[O:2])[CH3:17])([OH:21])=[O:20]
Reactant: COC(=O)[C@H](Cc1cn(C)c2ccc(OC(C)(C)C(=O)O)cc12)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: Cn1cc(C[C@H](NC(=O)c2ccc3c(c2)nc(-c2ccoc2)n3C2CCCCC2)C(=O)O)c2cc(OC(C)(C)C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The title compound of example 115 (6 mg) was dissolved in DMSO (0.4 mL) and 2.5N NaOH (0.2 mL) was added. After stirring for 30 min at room temperature, the reaction mixture was acidified with TFA (0.1 mL) and the product of example 116 isolated directly by preparative C18 reversed-phase HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:28])[N:10]1[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[NH:35][S:36]([CH3:39])(=[O:38])=[O:37].[CH2:40]([NH2:42])[CH3:41].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][C:25]([NH:42][CH2:40][CH3:41])=[O:26])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:28])[N:10]1[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[NH:35][S:36]([CH3:39])(=[O:38])=[O:37]
Reactant: CCN
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NCCCC(=O)O)C1c1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Product: CCNC(=O)CCCNC(=O)C1c2ccccc2C(=O)N(C2CCCCC2NS(C)(=O)=O)C1c1ccc(Cl)cc1Cl

Procedure:
By condensing 4-({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)butanoic acid and ethylamine using WSC and HOBt in accordance with Example 1, (3RS,4RS)-3-(2,4-dichlorophenyl)-N-[4-(ethylamino)-4-oxobutyl]-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide was obtained as a colorless crystal.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][CH:12]=[C:13]2[C:17](Br)=[C:16]([CH3:19])[N:15]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:36]=[O:37]>CCCCCC.O1CCCC1>[CH2:1]([O:8][C:9]1[N:10]=[N:11][CH:12]=[C:13]2[C:17]([CH:36]=[O:37])=[C:16]([CH3:19])[N:15]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2c(C)c(Br)c3cnnc(OCc4ccccc4)c32)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(C)c(C=O)c3cnnc(OCc4ccccc4)c32)cc1
Yield: 36 %

Procedure:
440 mg (1.0 mmol) of 7-benzyloxy-3-bromo-1-(4-methoxybenzyl)-2-methylpyrrolo[2,3-d]pyridazine, 735 μl (1.2 mmol) of a 15% strength solution of n-butyllithium in hexane and 160 μl (1.2 mmol) of dimethylformamide are reacted in 25 ml of tetrahydrofuran as described for Example 2a. Yield: 36%, m.p.: 139°-145° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:11])(=[O:10])[NH2:9])=[CH:4][C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].[Br:16]Br.[OH-].[K+]>CC(O)=O>[NH2:1][C:2]1[C:7]([Br:16])=[CH:6][C:5]([S:8](=[O:10])(=[O:11])[NH2:9])=[CH:4][C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13]
Reactant: BrBr
Reactant: Nc1ccc(S(N)(=O)=O)cc1S(N)(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1c(Br)cc(S(N)(=O)=O)cc1S(N)(=O)=O
Temperature: 70 °C
Yield: 62.6 %

Procedure:
A stirred solution of 2-amino-5-sulfamoylbenzenesulfonamide (3.77 g; 15 mmol) in AcOH (50 ml) was added a solution of Br2 (0.78 ml; 15 mmol) in AcOH (10 ml). The reaction mixture was heated to 70° C. for 6 days, evaporated to dryness, resuspended in MeOH (85 ml) and added solid KOH (3.8 g; 68 mmol). The reaction mixture was heated to 60° C. for 2.5 h (hydrolysis of 3-methyl-, 3-bromomethyl-, 3-dibromomethyl and 3-tribromomethyl-1,2-dihydro-1,2,4-benzothiadiazine isomers formed in situ), filtered, neutralized and evaporated to dryness. Column chromatography gave 3.1 g (63%) product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].CC[O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:18]([O:17][C:15]([C:14]1[CH:20]=[N:5][C:4]2[C:6]([C:13]=1[OH:12])=[CH:7][C:8]([F:9])=[C:2]([Cl:1])[CH:3]=2)=[O:16])[CH3:19]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(Cl)c(F)cc2c1O

Procedure:
A mixture of 3-chloro-4-fluoroaniline (1) (87.3 g) and diethyl ethoxymethylene malonate (129.7 g) and Dowtherm (700 mL) (diphenyl ether) was refluxed for 4 h. It was cooled and the resulting solid was removed by filtration. The solid was recrystallized from DMF to give 55.O g (4). m.p.=>300° C.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]([O:18]CC)=[O:17])[CH:8]=[C:9]([C:11]([O:13]CC)=[O:12])[CH:10]=1)=[O:4].[OH-].[Na+]>CC(C)=O>[OH:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]([OH:18])=[O:17])[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)=[O:4]
Reactant: CCOC(=O)c1cc(C(=O)NO)cc(C(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(O)c1cc(C(=O)O)cc(C(=O)NO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
To a solution of diethyl 5-[(hydroxyamino)carbonyl]-1,3-benzenedicarboxylate (0.281 g, 1.0 mmol) in acetone (5 mL) was added 1.0 N NaOH (5 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was taken up with 1 N HCl (15 nL) to give white precipitate. This material was dried under vacuum to give 0.096 g of white solid (43% yield).