Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)[OH:10].C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O.O.O.O.O.S1(OSO1)(=O)=O.[Na]>C(Cl)Cl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)=[O:10]
Reactant: Cc1cccc(C(O)c2ccncn2)c1Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S1(=O)OSO1
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(C(=O)c2ccncn2)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-bromo-3-methylphenyl)(pyrimidin-4-yl)methanol (0.40 g, 1.433 mmol) in DCM (10 mL) were added sodium bicarbonate (0.223 mL, 5.73 mmol) and Dess-Martin periodinane (0.790 g, 1.863 mmol) in one portion. The resulting mixture was stirred at RT for 1 h then quenched with sat NaHCO3 and sodium thio sulfate pentahydrate (1.778 g, 7.17 mmol). The quenched mixture was stirred for 1 h more and extracted with DCM. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to afford (2-bromo-3-methylphenyl) (pyrimidin-4-yl)methanone which was used without purification.
Reaction SMILES: C1C2C(COC([NH:18][C:19]3([C:24]([NH:26][C@H:27]([C:31]([N:33]([C@@H:35]([C@@H:68]([CH3:71])[CH2:69][CH3:70])[C@H:36]([O:66][CH3:67])[CH2:37][C:38]([N:40]4[CH2:44][CH2:43][CH2:42][C@H:41]4[C@H:45]([O:64][CH3:65])[C@@H:46]([CH3:63])[C:47](=[O:62])[NH:48][C@H:49]([C:57]4[S:58][CH:59]=[CH:60][N:61]=4)[CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)=[O:39])[CH3:34])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>O1CCCC1>[NH2:18][C:19]1([C:24]([NH:26][C@H:27]([C:31]([N:33]([C@@H:35]([C@@H:68]([CH3:71])[CH2:69][CH3:70])[C@H:36]([O:66][CH3:67])[CH2:37][C:38]([N:40]2[CH2:44][CH2:43][CH2:42][C@H:41]2[C@H:45]([O:64][CH3:65])[C@@H:46]([CH3:63])[C:47](=[O:62])[NH:48][C@H:49]([C:57]2[S:58][CH:59]=[CH:60][N:61]=2)[CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)=[O:39])[CH3:34])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C1(NC(=O)OCC2c3ccccc3-c3ccccc32)CCCC1)C(C)C
Solvent: CCNCC
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C1(N)CCCC1)C(C)C
Reaction time: 18 h
Yield: 96.5 %

Procedure:
To a mixture of #46 (500 mg, 0.504 mmol, 1 eq.) in tetrahydrofuran (8 mL, 0.06 M) was added diethylamine (4 mL). After stirring for 18 hours, the reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane) to give #47 (374 mg, 96%) as a white solid. LC-MS: m/z 769.6 [M+H+], retention time=0.70 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [8.64 (br d, J=8.4 Hz) and 8.87 (br d, J=8.6 Hz), total 1H], [8.22 (br d, J=9.4 Hz) and 8.26 (br d, J=9.4 Hz), total 1H], [7.77 (d, J=3.3 Hz) and 7.80 (d, J=3.3 Hz), total 1H], [7.63 (d, J=3.1 Hz) and 7.66 (d, J=3.3 Hz), total 1H], 7.13-7.31 (m, 5H), [5.39 (ddd, J=11.1, 8.5, 4.2 Hz) and 5.54 (ddd, J=11.7, 8.8, 4.1 Hz), total 1H], [4.53 (dd, J=9.2, 7.6 Hz) and 4.64 (dd, J=9.2, 6.6 Hz), total 1H], 3.16, 3.20, 3.21 and 3.25 (4 s, total 6H), 2.93 and 3.03 (2 br s, total 3H), [1.05 (d, J=6.8 Hz) and 1.10 (d, J=6.6 Hz), total 3H], 0.73-0.80 (m, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[O:9]=[C:10]1[NH:14][C@@H:13]([CH2:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][CH:20]=[CH:19]3)[CH2:12][O:11]1>C(O)(=O)C>[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:19]2[C:18]3[C:22](=[CH:23][CH:24]=[C:16]([CH2:15][C@H:13]4[CH2:12][O:11][C:10](=[O:9])[NH:14]4)[CH:17]=3)[NH:21][CH:20]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(=O)CC1
Reactant: O=C1N[C@@H](Cc2ccc3[nH]ccc3c2)CO1
Solvent: CC(=O)O
Product: CN1CC=C(c2c[nH]c3ccc(C[C@H]4COC(=O)N4)cc23)CC1
Yield: 25.5 %

Procedure:
1-Methyl-4-piperidone (0.47 g, Aldrich) was added to a stirred solution of the product from step (b) (0.30 g) in glac. acetic acid (2.0 ml) and the mixture stirred at 100° C. for 2 hours. The cooled mixture was poured onto ice/NH4OH (20 ml) and the resulting solid filtered off. The latter was eluted through a silica column using DCM/EtOH/NH4OH (60:8:1) as eluant and crystallised from ethyl acetate to give the desired product as a colourless solid (0.11 g), mp 225°-227° C., [α]D20 -45.4° (c=0.5. 1N aqu. HCl). Elemental analysis and 1H NMR were consistent with the proposed structure.
Reaction SMILES: COC([C:5]1[C:14]2[C:8]([CH:9]=[CH:10][C:11]([CH:15]([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[C:7]([CH2:18][CH2:19][CH2:20][CH2:21][NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:6]=1)=O>P(=O)(O)(O)O>[CH:15]([C:11]1[CH:10]=[CH:9][C:8]2[C:14](=[CH:13][CH:12]=1)[CH:5]=[CH:6][C:7]=2[CH2:18][CH2:19][CH2:20][CH2:21][NH:22][S:23]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:24])([CH3:17])[CH3:16]
Reactant: COC(=O)c1cc(CCCCNS(=O)(=O)c2ccccc2)c2ccc(C(C)C)ccc1-2
Agent: O=P(O)(O)O
Product: CC(C)c1ccc2ccc(CCCCNS(=O)(=O)c3ccccc3)c-2cc1
Yield: 92.6 %

Procedure:
A solution of 6-Isopropyl-3-[4-(benzenesulfonylamino)butyl]-azulene-1-carboxylic acid methyl ester (1.53 g) in 100% phosphoric acid (13 ml) was stirred at 120° C. for 20 min. The reaction mixture was poured on ice-water, and extracted with ethyl acetate. The ethyl acetate extracts were washed with water and dried over MgSO4. Removal of the solvent and the purification by silica gel columnchromatography (ethyl acetate-n-hexane, 1:3) afforded the title compound (1.23 g 94%) as a violet crystal 75°~76° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@:14]2([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[CH:35][CH:34]=4)[CH:26]=3)[O:24][C@@:11]([CH2:42][OH:43])([CH2:12][O:13]2)[C@H:10]1[OH:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:45](Cl)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46].N1C=CN=C1.[Na]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@:14]2([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([CH2:32][C:33]4[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH3:41])=[CH:37][CH:38]=4)[CH:26]=3)[O:24][C@@:11]([CH2:42][O:43][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])([CH2:12][O:13]2)[C@H:10]1[OH:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: [Na]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](CO[Si](C)(C)C(C)(C)C)(O3)[C@@H](O)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 115 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-3,4-dibenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octan-2-ol 28d (11.68 g, 18.9 mmol) in dichloromethane (40 mL) were added tert-butyldimethylsilyl chloride (3.4 g, 22.68 mmol), imidazole (2.57 g, 37.8 mmol) and a catalytic amount of 4-dimethylaminopyridine in turn at 0° C. The mixture was stirred at room temperature for 30 min and adjusted with saturated aqueous sodium bicarnonate till pH becomes 7. The resulting mixture was extracted with dichloromethane (50 mL×3). The combined organic phases were washed with saturated aqueous sodium chloride (30 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 28e as a white solid (15.9 g, 100%). The crude product was used for next step without further purification.
Reaction SMILES: [S:1]1[C:5]([C:6]#[N:7])=[CH:4][N:3]=[CH:2]1.Cl.[NH2:9][OH:10].CCN(C(C)C)C(C)C>CCO>[S:1]1[C:5]([C:6](=[N:9][OH:10])[NH2:7])=[CH:4][N:3]=[CH:2]1
Reactant: N#Cc1cncs1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: NC(=NO)c1cncs1
Yield: 72.3 %

Procedure:
Hydroxylamine hydrochloride (3.07 g, 44 mmol) was added to a solution of 1,3-thiazole-5-carbaldehyde (5 g, 44 mmol) and pyridine (3.7 mL) in DCM (25 mL). The reaction mixture was stirred overnight at room temperature and then washed once with water. The product was recovered by filtration to give 5.23 g of 1,3-thiazole-5-carbaldehyde oxime (yield 92%). 1,3-thiazole-5-carbaldehyde oxime (2.5 g, 19.5 mmol, 1 equiv) was dissolved in 12 mL of dioxane and then TEA (6.8 mL, 2.5 equiv) was added. The reaction mixture was cooled to 0° C. and then trifluoroacetic anhydride (3.0 mL, 1.1 equiv) was added dropwise to the reaction. The solution was stirred overnight at room temperature and then 1.1 equivalent of trifluoroacetic anhydride was added to complete the reaction. The solution was stirred overnight at room temperature and then evaporated. The residue was dissolved in DCM and then washed five times with water. The organic layer was dried over MgSO4 and then evaporated under reduced pressure to give 1.25 g of 1,3-thiazole-5-carbonitrile (Yield 58%). 1,3-thiazole-5-carbonitrile (1 g, 9.08 mmol, 1 equiv), hydroxylamine hydrochloride (0.95 g, 1.5 equiv) and DIEA (2.5 mL, 1.6 equiv) were mixed in absolute EtOH (30 mL). The reaction mixture was refluxed 5 h and then the solvent was evaporated under reduced pressure. The residue was dissolved in AcOEt, washed twice with water and once with brine. The organic layer was dried over MgSO4 and then evaporated under reduced pressure to give 940 mg of 1,3-thiazole-5-amidoxime (yield 72%).
Reaction SMILES: [CH:1]([CH:3]1[CH:8]([CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][O:6][CH:5]([CH3:19])[O:4]1)=O.[C:20]1([NH:26][C:27](=[S:30])[NH:28][NH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C.C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:18][O:17][C:15]([CH2:14][CH2:13][CH2:12]/[CH:11]=[CH:10]\[CH2:9][C@H:8]1[CH2:7][O:6][C@@H:5]([CH3:19])[O:4][C@H:3]1[CH:1]=[N:29][NH:28][C:27]([NH:26][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[S:30])=[O:16]
Reactant: COC(=O)CCC/C=C\CC1COC(C)OC1C=O
Reactant: NNC(=S)Nc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1C=NNC(=S)Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 114.3 %

Procedure:
To a mixture of 2R,4R, 5S)-4-formyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (62 mg) and 4-phenyl-3-thiosemicarbazide (46 mg) in ethanol (2 ml) was added acetic acid (1 drop) and the solution was stirred at room temperature for 4 hours. The mixture was diluted with chloroform (15 ml) and the solution was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give (2R,4R,5S)-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-4-[4-(phenyl)thiosemicarbazonomethyl]-1,3-dioxane (110 mg) as an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C1(C2C3SC(NC(=O)C4C=CN=C(CN5CCCC5)C=4)=NC=3C(OC)=CC=2)CCCCC1>>[CH3:25][O:24][C:14]1[C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:26]=[CH:27][N:28]=[C:3]([CH2:2][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:4]=3)[S:10][C:11]=2[C:17]([CH:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:16][CH:15]=1
Reactant: C1CCNC1
Reactant: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(CCl)c3)nc12
Agent: COc1ccc(C2CCCCC2)c2sc(NC(=O)c3ccnc(CN4CCCC4)c3)nc12
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(CN4CCCC4)c3)nc12

Procedure:
The title compound was prepared from 2-chloromethyl-N-[7-(tetrahydro-pyran-4-yl)-4-methoxy-benzothiazol-2-yl]-isonicotinamide (prepared from 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine and 4-(2-chloromethyl)-isonicotinic acid chloride as described for 2-chloromethyl-N-(7-cyclohexyl-4-methoxy-benzothiazol-2-yl)-isonicotinamide) and pyrrolidine as described for N-(7-Cyclohexyl-4-methoxy-benzothiazol-2-yl)-2-pyrrolidin-1-ylmethyl-isonicotinamide and obtained as light yellow solid (62% yield), mp 200-202° C. MS: m/e=453 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH2:9])[C:3]=1[N+:10]([O-:12])=[O:11].FC(F)(F)C(O)=O.[NH2:20][C@@H:21]1[C@@H:26]2[CH2:27][C@@H:23]([CH:24]=[CH:25]2)[C@@H:22]1[C:28]([NH2:30])=[O:29].C(N(CC)C(C)C)(C)C>C(O)(C)C>[NH2:9][C:4]1[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:20][C@@H:21]2[C@@H:26]3[CH2:27][C@@H:23]([CH:24]=[CH:25]3)[C@@H:22]2[C:28]([NH2:30])=[O:29])[C:7]([Cl:8])=[CH:6][N:5]=1
Reactant: NC(=O)[C@@H]1[C@H](N)[C@H]2C=C[C@@H]1C2
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2[N+](=O)[O-])[C@H]2C=C[C@@H]1C2
Temperature: 60 °C
Yield: 94.9 %

Procedure:
4,5-Dichloro-3-nitro-pyridin-2-ylamine (1.01 g, 4.86 mmol) and (1S,2S,3R,4R)-3-Amino-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide trifluoroacetic acid salt (1.5 g, 5.5 mmol) were combined with N,N-diisopropylethylamine (3.3 g, 26 mmol) in isopropanol (15 mL) and heated at 60° C. overnight. The reaction was permitted to cool to room temperature and the orange solid which had formed was isolated by filtration. The solid was washed with 3 mL cold isopropanol and was dried in an air stream to afford 1.493 g (95%) of the desired product.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[C:23]([F:32])=[C:24]([CH:28]=[CH:29][C:30]=1[F:31])[C:25](O)=O>>[Cl:21][C:22]1[C:23]([F:32])=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(F)c(Cl)c3F)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-chloro-2,4-difluorobenzoic acid: MS (ES) m/z 439 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[CH2:11]([CH:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:28])[C:25](O)=[O:26])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)C>[CH2:11]([CH:18]1[CH2:19][CH2:20][N:21]([C:24](=[O:28])[C:25]([NH:1][C:2]2[CH:10]=[CH:9][C:5]3[NH:6][CH:7]=[N:8][C:4]=3[CH:3]=2)=[O:26])[CH2:22][CH2:23]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc2nc[nH]c2c1
Solvent: CCOCC
Product: O=C(Nc1ccc2[nH]cnc2c1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 5-amino-benzimidazole and (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) according to the method described in Example 1c. Melting Point: 85-87° C. (diethylether)
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[NH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:7])=[CH:3][C:4]([NH:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:5]
Reactant: CC(C)=CC(=O)Cl
Reactant: COC(=O)c1ccccc1N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1NC(=O)C=C(C)C
Reaction time: 0.5 h

Procedure:
A solution of 12.5 ml of 3-methylbut-2-enoyl chloride in 110 ml of toluene is added dropwise at room temperature to a solution of 13.4 ml of methyl 2-aminobenzoate and 21.8 ml of triethylamine in 110 ml of toluene. After 30 minutes, the reaction mixture is diluted with toluene, washed with 1N HCl (2×), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a white solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.34 (1:10 EtOAc-heptane); Rt=4.78.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.N1C=CC=CC=1.[CH:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][C:40]=1[S:49](Cl)(=[O:51])=[O:50]>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:49]([C:40]3[CH:41]=[CH:42][C:43]4[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH:39]=3)(=[O:51])=[O:50])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4ccc5ccccc5c4)ccc3N2)=C(O)c2ccccc21
Yield: 39.1 %

Procedure:
A mixture of Example 39H (23.8 mg, 0.050 mmol), pyridine (31.6 mg, 0.40 mmol), and 2-naphthalenesulfonyl chloride (45.3 mg, 0.20 mmol) in acetone (1.5 mL) was stirred at rt for 18 h. The reaction mixture was evaporated in vacuo and partitioned between ethyl acetate and 1 N HCl. The organic phase was separated, dried (MgSO4), filtered, and evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with 4:1 hexane/ethyl acetate to provide the title compound (12.3 mg, 39% yield). 1H NMR (300 MHz, DMSO-d6) 8 ppm 0.37 m, 1 H) 0.66 (d, J=6.62 Hz, 3 H) 0.68 (d, J=6.62 Hz, 3 H) 0.77 m, 1 H) 1.29 m, 1 H) 1.52 (s, 3 H) 2.02 m, 1 H) 2.18 m, 1 H) 7.52 (m, 4 H) 7.68 m, 2 H) 7.73 (d, J=4.04 Hz, 2 H) 7.79 (dd, J=8.46, 1.84 Hz, 1 H) 8.01 (d, J=7.72 Hz, 1 H) 8.13 (m, 3H) 8.50 (s, 1 H) 10.93 (s, 1 H) 13.71 (s, 1 H). MS (ESI+) m/z 630.0 (M+H)+, 647.1 (M+NH4)+, (ESI−) m/z 628.1 (M−H)−.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH:13]([CH2:22][OH:23])[CH2:14][O:15][C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1.Cl>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:23][CH2:22][CH:13]([OH:12])[CH2:14][O:15][C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC(O)COc1ncccn1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(O)COc2ncccn2)cc1
Temperature: -10 °C
Reaction time: 15 h

Procedure:
13.6 g of p-toluenesulphonyl chloride are introduced over the course of 15 minutes, whilst stirring, into a solution of 11.8 g of 2-(2',3'-dihydroxy-propoxy)-pyrimidine in 18 ml of pyridine which is cooled to -10° C. The reaction mixture is kept at 0° C. for 15 hours. Ice is then added followed by 20 ml of 6 N hydrochloric acid introduced whilst stirring. The mixture is then twice extracted with 150 ml of methylene chloride at a time. The extracts are washed with sodium bicarbonate solution, dried over sodium sulphate and evaporated. 2-(3'-p-Toluenesulphonyloxy-2'-hydroxy-propoxy)-pyrimidine is obtained as a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH2:10].[N:11]([O-])=O.[Na+].Cl[Sn]Cl>Cl.C(O)(C(F)(F)F)=O.O>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][NH2:11]
Reactant: Nc1c(Cl)cc(F)cc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NNc1c(Cl)cc(F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 156.1 %

Procedure:
To a 0° C. solution of 2,6 Dichloro-4-fluorophenylamine (3.0 g, 16.6 mmol) in 12 M HCl (30 mL) and TFA (20 mL) is added slowly and dropwise NaNO2 (20 mmol, 1.37 mL) in water (6 mL). The reaction is stirred at 0° C. for 1 h. A solution of SnCl2 (5.74 g, 25.6 mmol) in 12 M HCl (16 mL) is added over 15 minutes. The ice bath is removed and the reaction is stirred for 18 h. The reaction is filtered and the solid is washed with isopropyl alcohol. The solid is dried to yield the title compound (3.0 g, 96%). LC-ES/MS m/e 194.0 (M+1)
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([C:20]#N)([CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:12][CH:7]2[CH2:6]1)=[O:4].[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=[O:34].[Na+].[K+]>ClCCl>[CH3:1][N:2]([CH3:22])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)([CH:20]=[O:34])[CH2:12][CH:7]2[CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)N1CC2CC(C#N)(CC3CCCCC3)CC2C1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [K+]
Solvent: ClCCl
Product: CN(C)C(=O)N1CC2CC(C=O)(CC3CCCCC3)CC2C1
Temperature: 0 °C
Yield: 33 %

Procedure:
Upon cooling to 0° C. by an ice-water bath, 5-cyano-5-cyclohexylmethyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 15a (1.2 g, 3.95 mmol) was dissolved in 30 mL of dichloromethane with stirring followed by dropwise addition of diisobutylaluminium hydride (11.8 mL, 11.8 mmol). The reaction mixture was reacted for 1 hour. The reaction was monitored by TLC until the disappearance of the starting materials. Then a solution of saturated aqueous potassium sodium tartrate was added. The mixture was stirred until the solution was clear and extracted with ethyl acetate (100 mL×3). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 5-cyclohexylmethyl-5-formyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 15b (0.4 g, yield 33%) as a light yellow oil.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([O-:10])=[O:9])=[C:6]([I:11])[C:5]([I:12])=[C:4]([C:13]([O-:15])=[O:14])[C:3]=1[I:16].[Na+].[Na+].[I-].[Na+].ClC(C)CO>CN(C)C=O>[I:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([I:11])[C:5]([I:12])=[C:4]([C:13]([OH:15])=[O:14])[C:3]=1[I:16]
Reactant: O=C([O-])c1c(I)c(I)c(C(=O)[O-])c(I)c1I
Agent: CC(Cl)CO
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1c(I)c(I)c(C(=O)O)c(I)c1I
Yield: 60 %

Procedure:
21.4 g Di-sodium tetra-iodoterephthalate, 0.5 g sodium iodide, and 10 g 2-chloropropanol were heated with stirring in 150 ml dimethylformamide at 100° C for 10 hours. The solvent was distilled off, and the residue was suspended in water and purified as described in Example 1. 14.15 g Bis-1-hydroxy-2-propyl ester of tetra-iodoterephthalic acid (60% yield) was recovered. It melted and decomposed at about 225° C.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][NH2:9])([O-:4])=[O:3].[OH-].[Na+]>C(Cl)(Cl)Cl>[N+:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][N:9]([CH2:8][CH2:7][CH3:10])[CH2:12][CH2:5][CH3:6])([O-:4])=[O:3]
Reactant: NCc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
Commercially available 3-nitrobenzylamine hydrochloride (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (1.62 g) was suspended in chloroform (15 ml) and then added with a 1 mol/l sodium hydroxide aqueous solution (15 ml). The aqueous layer was extracted with chloroform and the extract was then dried with anhydrous magnesium sulfate, followed by distilling the solvent off. Subsequently, the residue was dissolved in anhydrous methanol (25 ml) and then added with propionaldehyde (1.49 ml), trimethyl orthoformate (2.82 ml), and sodium cyanoborohydride (1.62 g), followed by stirring at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off. Then, the residue was added with water and extracted with chloroform. The extract was dried with anhydrous magnesium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (608.1 mg) as a yellow oily substance.