Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([C:22]3[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[CH:23]=3)=[O:21])[CH:14]=2)=[CH:9]C(C(O)=O)=[CH:4][N:3]=1.[CH3:29][S:30]([C:39]1[CH:40]=[C:41]([CH2:45][C:46]([O:48][CH3:49])=[O:47])[CH:42]=[CH:43][CH:44]=1)(=[N:32][C:33](=[O:38])[C:34](F)(F)F)=[O:31]>>[NH2:1][C:2]1[N:3]=[CH:4][C:34]([C:33]([N:32]=[S:30]([C:39]2[CH:40]=[C:41]([CH2:45][C:46]([O:48][CH3:49])=[O:47])[CH:42]=[CH:43][CH:44]=2)([CH3:29])=[O:31])=[O:38])=[CH:9][C:10]=1[C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([C:22]2[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[CH:23]=2)=[O:21])[CH:14]=1
Reactant: Cc1cc(C(=O)Nc2cccc(C#Cc3cc(C(=O)O)cnc3N)c2)n(C)n1
Reactant: COC(=O)Cc1cccc(S(C)(=O)=NC(=O)C(F)(F)F)c1
Product: COC(=O)Cc1cccc(S(C)(=O)=NC(=O)c2cnc(N)c(C#Cc3cccc(NC(=O)c4cc(C)nn4C)c3)c2)c1

Procedure:
In a manner similar to that described in Example 496 (step 5), 6-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinic acid and methyl {3-[S-methyl-N-(trifluoroacetyl)sulfonimidoyl]phenyl}acetate were reacted to give the title compound
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH2:9].[C:10](OC(=O)C)(=[O:12])[CH3:11].O.[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][C:10](=[O:12])[CH3:11]
Reactant: NCc1ccccc1Cl
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)NCc1ccccc1Cl
Reaction time: 0.5 h

Procedure:
42.8 kg (0.3 kmoles) of (2-chlorophenyl)methylamine was dissolved in 118.3 kg of dichloromethane and 32.2 kg (0.315 kmoles) of acetic anhydride was added dropwise at 20 to 40° C. over 1.5 hours, followed by aging at room temperature for 30 minutes. After the completion of the reaction, 60 kg of water was added 55.2 kg of an aqueous 25% sodium hydroxide solution was added dropwise at 20 to 40° C. over 20 minutes. The organic layer was partitioned to obtain 169.9 kg of a dichloromethane solution of N-[(2-chlorophenyl)methyl]acetamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([NH:16]CC4C=C(OC)C(OC)=C(OC)C=4)=[N:12][N:11]3[CH:30]=2)=[CH:4][C:3]=1[NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].C(O)(C(F)(F)F)=O>>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]2=[N:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:31][C:32](=[O:37])[C:33]([CH3:34])([CH3:35])[CH3:36])[CH:4]=3)=[CH:30][N:11]2[N:12]=1
Reactant: COc1cc(CNc2ccc3nc(-c4ccc(C)c(NC(=O)C(C)(C)C)c4)cn3n2)cc(OC)c1OC
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cn3nc(N)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 50 °C
Reaction time: 16 h
Yield: 90.2 %

Procedure:
A 40-mL vial is charged with N-(2-methyl-5-(6-(3,4,5-trimethoxybenzylamino)imidazo[1,2-b]pyridazin-2-yl)phenyl)pivalamide (0.604 g, 1.2 mmol) and TFA (5 mL) and the mixture is stirred at 50° C. for 16 hours. The reaction mixture is concentrated, taken up in CH3CN and water is added. The mixture is concentrated to form solid from aqueous solution. The mixture is frozen and water is removed on a lyophilizer to afford the title compound (0.350 g). LCMS (m/z)=324.5 [M+H]+, tR=1.96 min.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2nc[nH]c2c1
Reactant: O=[N+]([O-])O
Product: Cc1cc2[nH]cnc2cc1[N+](=O)[O-]
Temperature: -15 °C
Reaction time: 3 h
Yield: 17 %

Procedure:
To a solution of 20 ml of fuming nitric acid was added 5-methylbenzimidazole (1.6 g, 12 mmol) slowly over 0.5 hand reaction mixture was stirred for 3 h at −15° C. During addition of substrate, reaction temperature was kept below −10° C. Sticky reaction mixture was then poured into ice water to form a yellow precipitation, which was collected and dried in vacuo to provide 0.37 g (2.1 mmol, 17%) of 5-methyl-6-nitrobenzimidazole. The nitrobenzimidazole was converted to the corresponding amine (0.32 g, 95%) on hydrogenation (H2, Pd/C).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:27]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28]1.[OH-].[Na+]>ClC(Cl)C>[CH2:1]([NH:8][CH2:32][C:29]1[CH:30]=[CH:31][O:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccoc1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: c1ccc(CNCc2ccoc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Benzylamine (16 g, 150 mmol) was dissolved in dichloroethane (320 ml), and the solution was mixed with acetic acid (77 ml, 1.3 mol), sodium triacetoxyborohydride (57 g, 590 mmol) and 3-furaldehyde (13 g, 130 mmol) and stirred at room temperature for 16 hours. 5 N Sodium hydroxide aqueous solution was added to the reaction solution until it became basic, and the reaction product was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 19 g (100 mmol, 77% in yield) of the title compound.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)([OH:12])[CH2:10][CH3:11])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:30]([N:32]([CH2:37][CH3:38])[C:33](=[O:36])[CH2:34]Cl)[CH3:31]>CC(C)=O>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:4]=[C:5]([C:9]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:34][C:33](=[O:36])[N:32]([CH2:37][CH3:38])[CH2:30][CH3:31])=[CH:17][CH:18]=2)([OH:12])[CH2:10][CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCN(CC)C(=O)CCl
Reactant: CCC(O)(c1ccc(O)cc1)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)C(=O)COc1ccc(C(O)(CC)c2cccc(C(F)(F)F)c2)cc1

Procedure:
14.8 g. 1-(3-trifluoromethylphenyl)-1-(4-hydroxyphenyl)-propan-1-ol, 7.6 g. of anhydrous potassium carbonate, 2 g. of potassium iodide, 8.2 g. of monochloroacetic acid diethylamide and 150 ml. of dry acetone are boiled for 5 hours, under stirring. The reaction mixture is cooled and the solvent is distilled off under reduced pressure. To the residue water is added and it is extracted with benzene. The benzene phase is shaken with water and subsequently a 5% aqueous sodium hydroxide solution and washed to neutral with water. It is dried over anhydrous sodium sulfate, filtered off and the solution is evaporated in vacuo. The solid residue is crystallized from a mixture of n-hexane and ethyl acetate. 17.6 g. of the named compound are obtained, melting at 83°-84° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH2:16]([CH:18]1[CH2:23][NH:22][CH:21]([CH3:24])[CH2:20][CH2:19]1)[CH3:17]>>[CH2:16]([CH:18]1[CH2:23][N:22]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[O:15])[CH:21]([CH3:24])[CH2:20][CH2:19]1)[CH3:17]
Reactant: CCC1CCC(C)NC1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Product: CCC1CCC(C)N(C(=O)c2cnoc2-c2ccc(C)cc2)C1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 5-ethyl-2-methylpiperidine (7.6 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (5.5 mg). HRMS calcd for C19H24N2O2: 312.1838, found 312.1841.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([NH2:14])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)[CH3:2].C(O)(=O)C.CO[CH:25]1[CH2:29][CH2:28][CH:27](OC)O1>CCCCCCC>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([N:14]2[CH:25]=[CH:29][CH:28]=[CH:27]2)=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(OCC)c(N)c(OCC)c1
Reactant: COC1CCC(OC)O1
Solvent: CCCCCCC
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(OCC)c(-n2cccc2)c(OCC)c1
Yield: 82 %

Procedure:
To a solution of 4-amino-3,5-diethoxy-benzoic acid ethyl ester (3.0 g, 11.84 mmol, 1.0 equiv; prepared as described in I. Kompis and A. Wick Helv. Chim. Acta 1977, 60, 3025-3034) in heptane (10 mL) and conc. acetic acid (0.2 mL) was added 2,5-dimethoxy-tetrahydro-furan (1.88 g, 14.21 mmol, 1.2 equiv). After heating to reflux for 5 h, a Dean-Stark apparatus was attached and the reaction mixture heated for an additional time period of 5 h. Filtration of the crude reaction mixture and crystallization at 0° C. from heptane provided 2.94 g (82%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.15 (t, J=7.0 Hz, 6H), 1.27 (t, J=7.1 Hz, 3H), 3.98 (q, J=7.0 Hz, 4H), 4.28 (q, J=7.1 Hz, 2H), 6.07-6.08 (m, 2H), 6.73-6.74 (m, 2H), 7.22 (s, 2H). 13C NMR (75 MHz, DMSO): δ 14.11, 14.35, 61.06, 64.57, 106.87, 107.64, 122.61, 123.33, 129.29, 153.75, 165.06. MS (ISP): 303.4 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@@](OC)(C)C2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H]([N:55](C)C)[C@H]2O)[C@@](OC)(C)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@@]1(O)C.[OH-].[Na+]>>[C:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][NH:55][C:9]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCCC1Cc1ccccc1
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1NCCCCC1Cc1ccccc1
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
A mixture of polyphosphoric acid (150 g) and 2-(phenylmethyl)cyclohexanone, oxime (9 g, 45 mmol), which had been prepared as described by W. G. Kofron et al., J. Org. Chem., 41, 439 (1976), was heated with manual stirring to 120° C. for 20 minutes and then at 130° C. for ten minutes. The hot solution was poured onto 1000 g of ice, the pH adjusted to 4 with solid NaOH, and extracted 3× with EtOAc. After washing with brine, drying over Na2SO4, and concentration, the residue was chromatographed on silica gel using 1:1 EtOAc/hexane to elute a 1:1 mixture of the two isomeric lactams. The mixture was separated by prep HPLC using a C18 reverse phase YMC S15 column with 68% solvent B as eluant to yield 2.3 g (26%) of the title compound and 1.8 g of the isomeric hexahydro-3-(phenylmethyl)-2H-azepin-2-one.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C@@H:6]([O:11][C@H:12]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N+:21]([CH2:25][CH2:26][O:27][CH3:28])[CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5].C(O)(=O)C>[Pt]=O.C(O)C>[CH3:28][O:27][CH2:26][CH2:25][N:21]1[CH2:22][CH2:23][CH2:24][CH:19]([C:16]2[CH:17]=[CH:18][C:13]([C@@H:12]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[O:11][C@@H:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4]([O:3][CH3:2])=[O:5])=[CH:14][CH:15]=2)[CH2:20]1
Reactant: COCC[n+]1cccc(-c2ccc([C@H](O[C@@H](CC(C)C)C(=O)OC)c3ccccc3)cc2)c1
Agent: O=[Pt]
Agent: [Br-]
Solvent: CC(=O)O
Solvent: CCO
Product: COCCN1CCCC(c2ccc([C@H](O[C@@H](CC(C)C)C(=O)OC)c3ccccc3)cc2)C1
Reaction time: 18 h

Procedure:
A mixture of 3-{4-[(R)-{[(1S)-1-(methoxycarbonyl)-3-methylbutyl]oxy}(phenyl)methyl]phenyl}-1-(2-methoxyethyl)pyridinium bromide from example 41 step 1 (870 mg, 1.64 mmol), ethanol (50 mL), acetic acid (197 mg, 3.28 mmol) and platinum oxide (hydrated) 79-84% (63 mg) was hydrogenated at 60 psi for 18 hours. The mixture was filtered, concentrated and then concentrated twice with n-heptane. The residue was chromatographed on silica gel using 10% methanol in dichloromethane to obtain the title compound as a thick oil.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([O:13][CH3:14])[CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd].[C]>[C:20]([O:19][C:17]([NH:16][CH2:15][C:10]1([O:13][CH3:14])[CH2:11][CH2:12][NH:8][CH2:9]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC1(CNC(=O)OC(C)(C)C)CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: COC1(CNC(=O)OC(C)(C)C)CCNC1

Procedure:
12 g (37.4 mmol) 1-benzyl-3-(tert.-butoxy-carbonylamino-methyl)-3-methoxypyrrolidine is desolved in 150 ml ethanol. This solution is hydrogeneted at 4 g Pd-carbon (10 %) at 100° C./100 bar H2. The catalyst is removed by filtration, and the organic solvents are removed in vacuo. The residue is destilled.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=2[C:4]2[S:12](=[O:22])(=[O:21])[NH:13][C:14]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([OH:16])[C:3]1=2.[OH-].[Na+].[CH3:25]I>CO>[OH:16][C:15]1[C:3]2[N:2]([CH3:1])[C:10]3[CH:9]=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=3[C:4]=2[S:12](=[O:22])(=[O:21])[N:13]([CH3:25])[C:14]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C1=C(O)c2c(c3cc(C)ccc3n2C)S(=O)(=O)N1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1=C(O)c2c(c3cc(C)ccc3n2C)S(=O)(=O)N1C
Yield: 84.6 %

Procedure:
1.7 gm of methyl 2,5-dihydro-5,8-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxylate-1,1-dioxide were reacted analogous to Example 18(f) with 5.3 ml of 1 N sodium hydroxide and 2.6 gm of methyl iodide in 20 ml of methanol to yield 1.5 gm (84% of theory) of methyl 2,5-dihydro-4-hydroxy-2,5,8-trimethyl-1,2-thiazino [5,6-b]indole-3-carboxylate-1,1-dioxide; M.p.: 144°-145° C.
Reaction SMILES: [Si:1]([O-:5])([O-:4])([O-:3])[O-:2].[Mg+2].[Mg+2].C(=O)([O-])[O-:9].[Na+:12].[Na+]>>[Si:1]([O-:5])([O-:4])([O-:3])[O-:2].[Na+:12].[Na+:12].[Na+:12].[Na+:12].[OH-:9].[Na+:12]
Reactant: O=C([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Agent: [O-][Si]([O-])([O-])[O-]
Product: [OH-]

Procedure:
Accordingly, the process of the present invention comprises melting a mixture of finely divided a natural magnesium silicate and sodium carbonate, preferably, under slightly reducing conditions whereby a clear melt is obtained which upon quenching and dissolving with water provides a solution of sodium silicate and sodium hydroxide which is recovered after separation from the insoluble fraction comprising predominantly magnesium oxide.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](N)[CH:18]=1)[CH3:3].N([O-])=O.[Na+].[I:29]I>CCOCC.C(O)(=O)C>[CH2:2]([O:4][C:5](=[O:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([I:29])[CH:18]=1)[CH3:3]
Reactant: CCOC(=O)CCCCCCCCCCCc1cccc(N)c1
Reactant: II
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)CCCCCCCCCCCc1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 174.9 %

Procedure:
Glacial acetic acid (4 ml) and concentrated HCl (2.5 ml) were added to a 50 ml Erlenmeyer flask containing ethyl-12-(m-amino-phenyl)-dodecanoate (3.92 g, 12.28 mmol). The mixture was cooled in a Nacl/ice bath. A cold aqueous solution of NaNO2 (4 ml, 3.1 M) was added to the mixture. The reaction was stirred for 40 minutes before a cold aqueous solution of KI/I2 (2.31/1.78 g, 7 ml) was added. The reaction mixture was allowed to warm to room temperature and was stirred overnight. Ether was added to the reaction mixture. The ether layer was separated and extracted with H2O, 10% Na2S2O3, H2O, sat. NaHCO3, and brine. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give a reddish oil. The crude product was purified by column chromatography (120 g silica gel, hexanes:ethyl acetate 20:1) to yield a clear oil, compound 6, ethyl-12-(m-iodophenyl)-dodecanoate (5.28 g, 56.8% yield).
Reaction SMILES: [Na].[CH2:2]([OH:6])[CH2:3][CH2:4][CH3:5].[CH2:7]([N:11]1[C:15]2=[N:16][C:17]([CH3:26])=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19](Cl)=[C:14]2[N:13]=[CH:12]1)[CH2:8][CH2:9][CH3:10]>C1C=CC=CC=1>[CH2:2]([O:6][C:19]1[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]([CH3:26])[N:16]=[C:15]2[N:11]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:12]=[N:13][C:14]=12)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCO
Reactant: CCCCn1cnc2c(Cl)c(C(=O)OCC)c(C)nc21
Agent: [Na]
Solvent: c1ccccc1
Product: CCCCOc1c(C(=O)OCC)c(C)nc2c1ncn2CCCC

Procedure:
0.03 g. of sodium and 0.8 g. of n-butyl alcohol are refluxed for 5 hours in 50 ml. of dry benzene. After this time, 3 g. of 3-butyl-7-chloro-5-methyl-3H-imidazo[ 4,5-b]-pyridine-6-carboxylic acid, ethyl ester obtained in Example 3 c are added and the mixture is refluxed for 12 hours. After the inorganic precipitate has been filtered off, the solvent is removed in vacuo and the residue distilled to obtain 7-butoxy-3-butyl-5-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester, b.p. 210°-220° /0.01. Yield 2.1 g. (66%).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:15][C:16]1[CH:25]=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>CN(C=O)C>[N:4]1([CH2:3][CH2:2][N:26]([C:24]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([Cl:15])[CH:25]=2)[S:27]([CH3:30])(=[O:28])=[O:29])[CH:8]=[CH:7][CH:6]=[CH:5]1
Reactant: BrCCn1cccc1
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(CCn2cccc2)S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
200 μL of 1-(2-bromoethyl)-1H-pyrrole and 556 mg of Cesium Carbonate were added to 150 mg of methyl 2-chloro-4-(methylsulfonamido)benzoate in DMF and stirred at room temperature for 16 hours. The reaction mixture was extracted in Ethyl Acetate twice with saturated bicarbonate and once with brine, dried over Magnesium Sulfate, filtered and concentrated to give methyl 4-(N-(2-(1H-pyrrol-1-yl)ethyl)methylsulfonamido)-2-chlorobenzoate. 230 mg of methyl 4-(N-(2-(1H-pyrrol-1-yl)ethyl)methylsulfonamido)-2-chlorobenzoate was hydrolyzed via Procedure M to yield 221 mg of crude 4-(N-(2-(1H-pyrrol-1-yl)ethyl)methylsulfonamido)-2-chlorobenzoic acid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:19][C:18](=[O:20])[N:17](CC3C=CC(OC)=CC=3OC)[S:16]2(=[O:33])=[O:32])=[CH:10][CH:9]=1)(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[OH:41][C:35]([C:37]([F:40])([F:39])[F:38])=[O:36].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[S:16](=[O:33])(=[O:32])[NH:17][C:18](=[O:20])[CH2:19]2)=[CH:10][CH:9]=1
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc(NC(=O)OC(C)(C)C)cc3)S2(=O)=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(CN2CC(=O)NS2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the title C compound, {4-[5-(2,4-dimethoxybenzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]phenyl}carbamic acid t-butyl ester (20 mg, 0.041 mmol) in CH2Cl2 (1 mL) is added TFA (1 mL). The reaction is stirred at RT overnight. Upon addition the reaction becomes light pink colored, progressing to deep purple after overnight. The solvent is evaporated and the residue is taken up in 2 mL of MeCN/water (50/50). This is filtered through a 0.2 micron PTFE membrane filter and the filtrate is collected. MeCN is removed under reduced pressure and water via lyophilization to give 5-(4-amino-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one TFA salt as a yellow foam: [M−1]−=240.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:43]1([CH2:49][NH2:50])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH:43]1([CH2:49][NH:50][C:28]([C:25]2[C:24]3[CH:33]=[C:20]([CH2:19][OH:18])[C:21]([N:35]4[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]4)=[C:22]([F:34])[C:23]=3[O:27][N:26]=2)=[O:30])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: NCC1CCCCC1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Product: C[C@@H]1CN(c2c(CO)cc3c(C(=O)NCC4CCCCC4)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and cyclohexylmethanamine
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.Cl.[CH2:31]([O:33][C:34](=[O:38])[CH2:35][CH2:36][NH2:37])[CH3:32].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl>[CH2:31]([O:33][C:34](=[O:38])[CH2:35][CH2:36][NH:37][C:16]([C:13]1[CH:12]=[C:11]([CH3:19])[C:10]([CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:21])=[O:22])=[CH:15][N:14]=1)=[O:17])[CH3:32]
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)CCNC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (106 mg, 0.252 mmol) obtained in Example 12 in methylene chloride (3 ml), β-alanine ethyl ester hydrochloride (46 mg, 0.302 mmol), 1-hydroxybenzotriazole (34 mg, 0.252 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride mg, 0.302 mmol) and 4-methylmorpholine (66 μl, 0.604 mmol) were added. The reaction solution was stirred for 15 hours at room temperature, and was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with hexane:ethyl acetate (=1:1) was concentrated under reduced pressure, to obtain the title compound (126 mg, 0.242 mmol, 96%) as an amorphous substance.
Reaction SMILES: C([O:8][C:9]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:10]=1[O:11][CH2:12][C@H:13]1[CH2:15][O:14]1)C1C=CC=CC=1.[C:23](=O)(O)[O-].[Na+].C(O)C>[Pd].CN1C(=O)CCC1>[N+:20]([C:18]1[CH:17]=[CH:16][C:10]2[O:11][CH2:12][C@@H:13]([CH:15]([OH:14])[CH3:23])[O:8][C:9]=2[CH:19]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(OC[C@H]2CO2)c(OCc2ccccc2)c1
Reactant: O=C([O-])O
Agent: [Pd]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCO
Product: CC(O)[C@@H]1COc2ccc([N+](=O)[O-])cc2O1
Temperature: 51 °C

Procedure:
A 500 mL three necked Morton flask equipped with magnetic stir bar, thermocouple, gas inlet adapter and gas outlet adapter is charged with (2R)-2-{[2-(benzyloxy)-4-nitrophenoxy]methyl}oxirane (20.00 g, 66.4 mmol), sodium bicarbonate (5.58 g, 66.4 mmol), palladium (5% on carbon, 50% water, 3 g), ethanol (136 mL) and NMP (24 mL). The flask is immersed in an oil bath and heated to 50-52° C. (internal) to effect solution. The stirring is stopped and the flask is flushed with hydrogen gas (300 mL). Stirring is resumed and hydrogen gas is titrated into the solution [1550 mL (69.2 mmol) over 5.5 h]. Heating is discontinued, and a flow of nitrogen is used to sweep the head space for 20 min. Once the solution is cooled to 25° C., the mixture is filtered through a pad of celite and the filter cake is washed with ethanol (50 mL). The resulting solution is concentrated by rotary evaporation removing ˜200 mL of ethanol. The solution is transferred to a separatory funnel and i-PrOAc (220 mL) is added followed by water (200 mL). The mixture is thoroughly shaken and the bottom aqueous layer is drained and discarded. The product containing organic layer is washed with water (3×50 mL), and transferred to a 500 mL three necked flask equipped with a magnetic stir bar, thermocouple, heating mantel, and a distillation head. The i-PrOAc is removed by distillation at atmospheric pressure. Once ˜180 mL has been collected, pyridine (80 mL) is added and the distillation is continued until the head temperature is 108° C. The solution is allowed to cool to room temperature and used directly as illustrated in Schemes I and II, and as described in the Examples below.