Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([C:14]([F:13])([F:23])[F:24])[CH:16]=1
Reactant: NNC(=S)NC1CC2C=CC1C2
Reactant: O=Cc1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(C=NNC(=S)NC2CC3C=CC2C3)c1

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.56 mmol) and 3-(trifluoromethyl)benzaldehyde (75 μL, 0.56 mmol) similar to Example 3 and isolated as a white solid (15 mg, 8%). 1H NMR (CDCl3): 9.43 (s, 1H), 7.86-7.80(m, 3H), 7.67 (d, J=8.1 Hz, 1H), 7.56 (t, J=7.7 Hz, 1H), 7.45 (d, J=6.6 Hz, 1H), 6.25-6.15 (m, 2H), 4.32-4.28 (m, 1H), 3.08 (s, 1H), 2.99 (s, 1H), 1.96-1.89 (m, 1H), 1.69 (d, J=9.0 Hz, 1H), 1.50 (d, J=9.6 Hz, 1H), 1.48-1.41 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>CN(C)C=O.FC(F)(F)C(O)=O.[Mn]>[CH3:11][S:8]([NH:7][CH2:6][C:5]1[CH:12]=[CH:13][C:2]([CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CCOC(=O)C(C)Cl
Reactant: CS(=O)(=O)NCc1ccc(Br)cc1
Agent: [Mn]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)c1ccc(CNS(C)(=O)=O)cc1
Temperature: 60 °C
Reaction time: 36 h

Procedure:
To a stirred solution of N-(4-bromobenzyl)methanesulfonamide (675 mg, 2.555 mmol) in dimethylformamide were added ethyl 2-chloropropionate (0.42 mL), manganese (280 mg) and (2,2′-bipyridine)nickel(II)-dibromide (67 mg, 0.17885 mmol). Trifluoroacetic acid (2 drops) was added. The reaction mixture was stirred for 36 h at 60° C. After cooling down to room temperature, the mixture was hydrolysed by 1N HCl and extracted with diethyl ether. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography to obtain ethyl 2-(4-(methylsulfonamidomethyl)phenyl)propanoate (325 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[C:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]1=[O:23])[O:9][CH2:8]2.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C1COCC1>[O:23]=[C:15]1[C:14](=[C:10]2[C:11]3[C:7](=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][O:1][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:13][CH:12]=3)[CH2:8][O:9]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16]1
Reactant: O=C1Nc2ccccc2C1=C1OCc2cc(CCCO)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCCc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79.3 %

Procedure:
To a stirred suspension of 3-[5-(3-hydroxy-propyl)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one (440 mg, 1.43 mmol) and triethylamine (289 mg, 2.86 mmol) in THF (7 ml), was added methanesulfonyl chloride (327 mg, 2.86 mmol). The mixture was stirred for 20 minutes and poured into an ice water (150 ml, containing 0.5 ml of AcOH). The solid was filtered, washed with water and dried under vacuum to afford a crude product. The crude product was purified by silica gel column chromatography, eluted with 5% MeOH in CHCl3, to give methanesulfonic acid 3-[1-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-5-yl]-propyl ester as a yellow solid (437 mg, 79%).
Reaction SMILES: [CH2:1]([OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH3:14].C(O)CCCCCCC/C=C\CCCCCCCC.C=CC/C=C/C>C1COCC1>[CH2:1]([OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]/[CH3:14]
Reactant: CCCC/C=C\CCCCCCCCO
Agent: C=CC/C=C/C
Agent: CCCCCCCC/C=C\CCCCCCCCO
Solvent: C1CCOC1
Product: C/C=C/C/C=C\CCCCCCCCO
Yield: 68 %

Procedure:
According to the procedure for compound 3, oleyl alcohol (1.0 g, 3.7 mmol) and 1,4-trans-hexadiene (4 mL) in THF (4 mL) were reacted with 1 (0.023 g, 1 mol %) to provide 15 0.53 g, 68% yield, 88% Z as determined by 1H-NMR) as a colorless oil; 1H NMR (CDCl3): δ 5.32-5.49 (4H, m), 3.64 (2H, br t, J=6.6 Hz), 2.71 (2H, m), 2.03 (2H, m), 1.03 (3H, m), 1.56 (2H, m), 1.25-1.39 (11H, m); 13C NMR (CDCl3): δ 130.4, 129.6, 127.7, 125.1, 63.1, 32.8, 30.4, 29.6, 29.5, 29.4, 29.2, 27.1, 25.7, 17.9; HRMS (FAB): 209.1906, [C14H26O−H]+ requires 209.1905.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[H-].[Na+].[CH3:15][O:16][C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21]Br>C(#N)C>[CH3:15][O:16][C:17]([CH2:18][CH2:19][CH2:20][CH2:21][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1)=[O:23]
Reactant: COC(=O)CCCCBr
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)CCCCn1ccc2cc([N+](=O)[O-])ccc21
Reaction time: 21 h
Yield: 90.5 %

Procedure:
To a stirred solution of 5-nitroindole (0.324 g, 2.0 mmol) in anhydrous acetonitrile (10 ml) was added sodium hydride (0.057 g, 2.38 mmol). The resulting red-brown solution was stirred for 45 minutes, before the addition of a solution of methyl-5-bromovalerate (0.429 g, 2.2 mmol) in anhydrous acetonitrile (1 ml). The solution was stirred for 21 hours, during which time a solid precipitated. Analysis by TLC in chloroform:ethanol (99:1) after 2 hours showed 2 components (starting material: Rf=0.5, 1-(4-methoxycarbonyl butyl)5-nitroindole: Rf=0.8). Further analysis after 21 hours indicated the reaction was essentially complete. The reaction mixture was poured into ethyl acetate (20 ml) and molar HCl (20 ml) and the phases separated. The aqueous phase was extracted with ethyl acetate (20 ml) and the combined organic layer washed with molar sodium bicarbonate solution. The ethyl acetate solution was dried over anhydrous sodium sulphate, filtered and rotary evaporated to give a yellow oil (0.5 g, 1.81 mmol, 91%).
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH:5]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH:21]1[O:23][CH2:22]1)(=[O:3])[CH3:2].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25].[ClH:29].C(OCC)(=O)C>C(O)C>[ClH:29].[C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH:5]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH:21]([OH:23])[CH2:22][NH:28][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2SC1c1ccccc1OCC1CO1
Reactant: CC(C)(C)N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)N1c2ccccc2SC1c1ccccc1OCC(O)CNC(C)(C)C
Yield: 81 %

Procedure:
1.31 g of 3-acetyl-2-[2-(2,3-epoxypropoxy)phenyl]benzothiazoline and 4.21 ml of t-butylamine are dissolved in 10 ml of ethanol and the solution is refluxed for 1 hour. After cooling, 2 ml of 2N HCl/ethyl acetate is added to the reaction mixture and the solution is concentrated in vacuo. To the residue ether is added to produce crystals. Crystals are collected by filtration to give 1.3 g (81%) of the titled compound.
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].ClCCl.[C:18]1([C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N+]=[N-])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)(=O)C.CCCCCC>[OH:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([C:6]([O:8][CH:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:7])=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)cc(OC)c1O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)OC(c2ccccc2)c2ccccc2)cc(OC)c1O
Reaction time: 1 h

Procedure:
Combine 4-hydroxy-3,5-dimethoxybenzoic acid (2.0 g, 12.6 mmol) and dichloromethane (200 mL). Add diphenyl diazomethane (2.67 g). After 1 hour, add an additional portion of diphenyl diazomethane (1.2 g). After 1 hour, add 4-hydroxy-3,5-dimethoxybenzoic acid (0.5 g). Concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting sequentially with 20% ethyl acetate/hexane and 50% ethyl acetate/hexane to obtain the diphenylmethyl 4-hydroxy-3,5-dimethoxybenzoate: Rf=0.56 (silica gel, 50% ethyl acetate/hexane).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([N+:15]([O-])=O)[CH:9]=2)[CH:3]=1>C(O)C.[Pd]>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=2)=[CH:9][C:10]=1[NH2:15]
Reactant: Cc1ccnc(-c2ccc(C)c([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccnc(-c2ccc(C)c(N)c2)c1
Yield: 100 %

Procedure:
A suspension of 4-(4-methylpyridin-2-yl)-2-nitrotoluene (342 mg) in ethanol (7 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 103 mg) under a hydrogen atmosphere for 3 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 2-methyl-5-(4-methylpyridin-2-yl)aniline (297 mg).
Reaction SMILES: [NH:1]([C:3](=[O:24])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:15][CH2:14]2)=[N:11][CH:12]=1)=[O:5])[NH2:2].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]=[C:40]=S)=[CH:35][CH:34]=2)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:40]3[O:24][C:3]([C:4]([NH:6][C:7]4[CH:8]=[CH:9][C:10]([N:13]5[CH2:14][CH2:15][CH:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:18]5)=[N:11][CH:12]=4)=[O:5])=[N:1][N:2]=3)=[CH:35][CH:34]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)CC1CCN(c2ccc(NC(=O)C(=O)NN)cn2)CC1
Reactant: S=C=Nc1ccc(Oc2ccc(Cl)cc2)cc1
Product: COC(=O)CC1CCN(c2ccc(NC(=O)c3nnc(Nc4ccc(Oc5ccc(Cl)cc5)cc4)o3)cn2)CC1

Procedure:
Prepared using the procedures described above for Example 631 except using methyl [1-(5-{[hydrazino(oxo)acetyl]amino}pyridin-2-yl)piperidin-4-yl]acetate (Intermediate 77) and 1-chloro-4-(4-isothiocyanatophenoxy)benzene.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:56])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@H:26]2[C@H:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=3[F:38])[C@:29]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=3[F:48])([C:39]#[N:40])[C@H:28]([CH2:49][C:50]([CH3:53])([CH3:52])[CH3:51])[NH:27]2)=[O:25])=[C:19]([O:54][CH3:55])[CH:18]=1)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:56])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@H:26]2[C@H:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=3[F:38])[C@:29]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=3[F:48])([C:39]#[N:40])[C@H:28]([CH2:49][C:50]([CH3:52])([CH3:53])[CH3:51])[NH:27]2)=[O:25])=[C:19]([O:54][CH3:55])[CH:18]=1)=[O:11]
Reactant: COc1cc(C(=O)OCCOC(=O)CNC(=O)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)OCCOC(=O)CN)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-(2-tert-butoxycarbonylamino-acetoxy)-ethyl ester (Example 29) was treated with trifluoroacetic acid to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-(2-amino-acetoxy)-ethyl ester. MS (ES+) m/z calcd. for C35H37Cl2F2N4O6: [(M+H)+]: 717. found: 717.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[N:16]1[N+:20]([O-])=[C:19]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:18]2=[N:17]1.C1(C)C=CC=CC=1.C(N(CCCC)CCCC)CCC.[H][H]>[Ni].O.CC(O)CC>[OH:1][C:2]1[C:7]([C:8]([CH3:10])([CH3:11])[CH3:9])=[CH:6][C:5]([C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:4][C:3]=1[N:16]1[N:20]=[C:19]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:18]2=[N:17]1
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(-n2nc3cc(Cl)ccc3[n+]2[O-])c(O)c(C(C)(C)C)c1
Agent: [Ni]
Solvent: CCC(C)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Yield: 79.1 %

Procedure:
37.4 g (0.1 mol) of 2-(2'-hydroxy-3',5'-di-t-butylphenyl)-5-chlorobenzotriazole-N-oxide, 100 ml of toluene, 60 ml of 2-butanol, 120 ml of water, 7 g of tributylamine and 5 g of Raney nickel were charged into a 500-ml stainless autoclave equipped with an agitator. After the air in the autoclave had been replaced by hydrogen, the pressure of hydrogen was set to 10 kg/cm2. The temperature of the resultant mixture was increased under agitation to 65° C. at which the mixture was then subjected to reaction for 7 hours until the absorption of hydrogen was stopped. After the reaction had been completed, the autoclave was cooled, and the catalyst was filtered off. After the toluene layer had been separated, most part of toluene was distilled off, and the residual solid was washed with ethanol and then dried to obtain 28.3 g of 2-(2'-hydroxy-3',5'-di-t-butylphenyl)-5-chlorobenzotriazole (yield, 79.2%; melting point, 152° to 154° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][C:14]([CH3:17])([CH3:16])[CH2:13][NH:12][C:11]2[N:18]([CH3:22])[N:19]=[C:20]([CH3:21])[C:10]1=2.[H-].[Na+].CI.[C:27](=O)(O)[O-].[Na+].Cl>CN(C=O)C.C(OCC)(=O)C.C(Cl)Cl.C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][C:14]([CH3:17])([CH3:16])[CH2:13][N:12]([CH3:27])[C:11]2[N:18]([CH3:22])[N:19]=[C:20]([CH3:21])[C:10]1=2
Reactant: Cc1nn(C)c2c1C(c1ccc(Cl)cc1Cl)SC(C)(C)CN2
Reactant: O=C([O-])O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nn(C)c2c1C(c1ccc(Cl)cc1Cl)SC(C)(C)CN2C
Temperature: 25 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
To 4-(2,4-dichlorophenyl)-1,3,6,6-tetramethyl-7,8-dihydro-4H-pyrazolo[3,4-e][1,4]thiazepine (0.12 g, 0.33 mmol, Example #D.4) dissolved in DMF (10 mL), was added NaH (0.133 g, 3.33 mmol, 60% dispersion in mineral oil) and methyl iodide (0.21 mL, 3.33 mmol). The reaction mixture was stirred for about 24 h at rt. To the reaction mixture was added 5% aqueous sodium bicarbonate (30 mL) and ethyl acetate (25 mL). The layers were separated and the organic layer was washed with water (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, ethyl acetate/DCM (1:9 followed by 1:4)), to 4-(2,4-dichlorophenyl)-1,3,6,6,8-pentamethyl-4,7-dihydropyrazolo[3,4-e]thiazepine (0.07 g, 0.189 mmol, 57%), which was dissolved in ethyl acetate and converted into the HCl salt (using 1M HCl/ethanol). The precipitated solid is collected by filtration and washed with a small amount of diethyl ether to afford 4-(2,4-dichlorophenyl)-1,3,6,6,8-pentamethyl-4,7-dihydropyrazolo[3,4-e][1,4]thiazepine hydrochloride (0.053 g, 0.13 mmol, 39%) as an off white solid. LC-MS (Table 1, Method d) Rr=3.05 min, m/z 370 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[N:3]=1.C(N(CC)CC)C.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=[C:6]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:7]=1
Reactant: CS(=O)(=O)Cc1cc(Cl)nc(Cl)n1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Cc1cc(N2CCOCC2)nc(Cl)n1
Temperature: -5 °C

Procedure:
A suspension of 2,4-dichloro-6-(methylsulfonylmethyl)pyrimidine (10.56 g) in DCM (230 mL) was stirred magnetically (under nitrogen) and cooled to −5° C. Triethylamine (6.78 mL) was added followed by the dropwise addition of a solution of morpholine (3.85 mL) in DCM (30 mL) maintaining the reaction temperature below −5° C. The reaction was stirred at room temperature for 1 hour and then the organic mixture washed with water (300 mL). The organic phase was dried (MgSO4), filtered and evaporated to a brown solid which was chromatographed on silica, eluting with 50% ethyl acetate in DCM, to give the desired material (6.81 g) as a white solid.
Reaction SMILES: CO[CH:3]([O:6][CH3:7])[O:4]C.[O:8]=[C:9]1[CH2:13][CH2:12][CH:11](C(O)=O)[CH2:10]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.COC=O.C[O-].[Na+]>CO>[CH3:7][O:6][C:3]([CH:11]1[CH2:12][CH2:13][C:9](=[O:8])[CH2:10]1)=[O:4]
Reactant: O=C1CCC(C(=O)O)C1
Reactant: COC(OC)OC
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: COC=O
Product: COC(=O)C1CCC(=O)C1
Temperature: 10 °C

Procedure:
318.36 g (3 mol) of trimethylorthoformate are added gradually to a solution of 128.2 g (1 mol) of nonracemic 3-oxocyclopentanecarboxylic acid and 11.4 g (0.06 mol) of p-toluene sulfonic acid hydrate in 380 ml of methanol within 5-10 minutes while stirring, The mixture is heated and during 25 minutes a mixture of formic acid methyl ester and methanol is distilled off (about 185 g of distillate), Thereafter 29 g of 30% sodium methylate solution (0.16 mol) are added and the reaction mixture is kept boiling under reflux for 2 hours; methanol is distilled off, the residue cooled to 10° C. and dissolved by adding 230 ml of methylene chloride and 200 ml of water. By adding 5% sulfuric acid the mixture is adjusted to pH 1.4 and stirred at 10° C. for 30 minutes. The methylene chloride phase is separated and the aqueous phase extracted again with 100 ml of methylene chloride. The combined organic phases are stirred with 50 ml of water, separated and the solvent is distilled off in vacuo. The residue is fractionated in vacuo.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12])C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[H-].Cl>C(OCC)C.O>[CH3:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=1[CH2:4][OH:3]
Reactant: CCOC(=O)c1c(C)cccc1C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: Cc1cccc(C)c1CO
Reaction time: 8 h
Yield: 77.3 %

Procedure:
17 g of 2,6-dimethyl benzoic acid ethyl ester (0.095 mole) dissolved in 50 ml of ethyl ether are added dropwise as a function of the vigor of reflux to a suspension of 3.72 g (0.095 mole) of LiAlH4 in 100 ml of ether. When the addition is complete, the mixture is heated at reflux for 2h and left to stand overnight. Excess hydride is decomposed by the gradual addition of water (while cooling the flask in an ice-water bath), then 10% HCl. After the usual work-up, the product is crystallized from petroleum ether. 10 g of product are obtained. M.p.=84°. Yield 77.5%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[H-].[Na+].[N+]([C:15]1[CH:16]=[C:17]([CH3:22])[N+:18]([O-:21])=[CH:19][CH:20]=1)([O-])=O>CN(C=O)C.CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]2[CH:20]=[CH:19][N+:18]([O-:21])=[C:17]([CH3:22])[CH:16]=2)=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(Br)c(F)c2)cc[n+]1[O-]
Temperature: 180 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 4-bromo-3-fluorophenol (6 g, 31.41 mmol) in DMF (20 ml) was added NaH (0.81 g, 56 mmol, 60% in mineral oil) at room temperature. The resulting reaction mixture was stirred for 10 min., then, 4-nitro-2-picoline N-oxide (5.6 g, 36.12 mmol) was added. The resulting solution was subjected to microwave heating at 180° C. for 1 h. The mixture was cooled to room temperature and diluted with EtOAc and H2O. Layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue thus obtained was purified by column chromatography (silica gel; DCM/MeOH(NH3) up to 2% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound D14 (3.61 g, 39%) as dark orange solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][F:10].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(#N)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:8][CH2:9][F:10])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(CCF)CC1
Yield: 56.9 %

Procedure:
Potassium carbonate (1.85 g, 13.4 mmol) and 1-bromo-2-fluoroethane (440 μl, 5.9 mmol) were added to a solution of tert-butyl-1-piperazinecarboxylate (1 g, 5.4 mmol) in acetonitrile (12 ml). The reaction mixture was stirred at 65?C for 3.5 hours after which time more 1-bromo-2-fluoroethane (160 μl, 2.1 mmol) was added. The reaction was heated for a further 3 hours then filtered to remove the inorganic solids. The filtrate was concentrated and the crude product was purified using column chromatography eluting with ethyl acetate to give 4-(2-fluoroethyl)-piperazine-1-carboxylic acid tert-butyl ester (714 mg, 57%). NMR Spectrum: (CDCl3) 1.46 (s, 9H); 2.50 (t, 4H); 2.70 (dt, 2H); 3.45 (t, 4H); 3.45 (t, 4H); 4.57 (dt, 2H) MS-ESI: 233 [MH]+
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[CH:12]=[C:11]1[CH2:19][N:20]1[C:25](=[O:26])[CH2:24][N:23]([S:27]([CH:30]=[CH:31][C:32]2[S:33][C:34]([Cl:37])=[CH:35][CH:36]=2)(=[O:29])=[O:28])[CH2:22][CH:21]1[C:38](OC)=[O:39])=[O:9])([CH3:6])([CH3:5])[CH3:4].C(OC(N1C2C=CN=CC=2C=C1CN1C(=O)CNCC1C(OC)=O)=O)(C)(C)C.ClC1SC(C=CS(Cl)(=O)=O)=CC=1>CO>[C:3]([O:7][C:8]([N:10]1[C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[CH:12]=[C:11]1[CH2:19][N:20]1[C:25](=[O:26])[CH2:24][N:23]([S:27]([CH:30]=[CH:31][C:32]2[S:33][C:34]([Cl:37])=[CH:35][CH:36]=2)(=[O:29])=[O:28])[CH2:22][CH:21]1[CH2:38][OH:39])=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: COC(=O)C1CN(S(=O)(=O)C=Cc2ccc(Cl)s2)CC(=O)N1Cc1cc2cnccc2n1C(=O)OC(C)(C)C
Agent: COC(=O)C1CNCC(=O)N1Cc1cc2cnccc2n1C(=O)OC(C)(C)C
Agent: O=S(=O)(Cl)C=Cc1ccc(Cl)s1
Agent: [BH4-]
Solvent: CO
Product: CC(C)(C)OC(=O)n1c(CN2C(=O)CN(S(=O)(=O)C=Cc3ccc(Cl)s3)CC2CO)cc2cnccc21
Reaction time: 6 h

Procedure:
Sodium borohydride (0.005 g, 0.13 mmol) is added to a solution of 2-{4-[2-(5-chloro-thiophen-2-yl)-ethenesulfonyl]-2-(±)-methoxycarbonyl-6-oxo-piperazin-1-ylmethyl}-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.04 g, 0.07 mmol), (prepared from 2-(2-(±)-methoxycarbonyl-6-oxo-piperazin-1-ylmethyl)-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester, EXAMPLE 71, and 2-(5-chloro-thiophen-2-yl)-ethenesulfonyl chloride, EXAMPLE 3, using the procedure described in EXAMPLE 214, Part A) in MeOH (3 mL) at RT. The reaction mixture is stirred for 6 h then quenched with water and concentrated in vacuo. The crude product (0.04 g) is taken onto the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[ClH:28].O1CCOCC1>C(O)C>[ClH:28].[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Reactant: CCOC(=O)CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)CN1CCc2ccc([N+](=O)[O-])cc2C1

Procedure:
7-Nitro-1,2,3,4-tetrahydroisoquinoline (5.78 g) was dissolved in ethanol (400 ml), triethylamine (7.8 ml) and ethyl bromoacetate (4.5 g) were added, and the mixture was heated and refluxed for 1 hour. Most of the solvent was distilled off under reduced pressure, concentrated residue was extracted with ethyl acetate and the extracted solution was dried with anhydrous magnesium sulfate. The solvent distilled off under reduced pressure and the crude product obtained was purified by silica gel column chromatography using a solvent mixture, ethyl acetate:n-hexane=1:3, as a developer. The compound obtained was treated with a hydrochloric acid/dioxane solution to obtain ethyl 7-nitro-1,2,3,4-tetrahydro-isoquinoline-2-acetate hydrochloride (4.2 g).