Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26][CH:27]1[CH2:32][CH2:31][N:30]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:29][CH2:28]1
Reactant: c1ccc2cc(SC3CCNCC3)ccc2c1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: O=C(C1CCN(c2ccncc2)CC1)N1CCC(Sc2ccc3ccccc3c2)CC1
Yield: 62 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 4-(2-naphthylthio)piperidine to give 4-(2-naphthylthio)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperidine in 62% yield;
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[N:6]=[C:5]2[C@@H:14]([NH2:16])[CH3:15])[CH2:3][CH2:2]1.Cl[C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[CH:1]1([N:4]2[C:8]3[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[N:6]=[C:5]2[C@@H:14]([NH:16][C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)[CH3:15])[CH2:3][CH2:2]1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1C1CC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CC1
Temperature: 100 °C
Yield: 48.8 %

Procedure:
A mixture of (S)-1-(1-cyclopropyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamine (166 mg, 0.76 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (180 mg, 0.76 mmol) and DIPEA (0.7 mL, 3.8 mmol) in n-butanol (3 mL) was heated at 100° C. for 18 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 374 as a white solid (125 mg, 49%). LCMS (Method K): RT 2.72 min [M+H]+ 338.1. 1H NMR (DMSO-d6, 400 MHz): δ 8.23-8.09 (2H, m), 7.90 (1H, br s), 7.56 (1H, dd, J=8.77, 4.94 Hz), 7.37 (1H, dd, J=9.27, 2.53 Hz), 7.05-6.97 (1H, m), 5.94 (1H, br s), 3.43-3.36 (1H, m), 1.69 (3H, d, J=6.80 Hz), 1.33-1.00 (4H, m)
Reaction SMILES: C(O[CH:5]([C:22]1[CH:26]=[CH:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH:23]=1)[C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])(=O)C.C([O-])=O.[NH4+].CCOC(C)=O.C(Cl)Cl>[Pd].CCOC(C)=O.CCO>[CH2:13]([C@H:12]1[CH2:11][O:10][C:9]([CH3:21])([CH3:20])[N:8]1[C:6](=[O:7])[CH2:5][C:22]1[CH:26]=[CH:25][N:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:31][CH:32]=2)[CH:23]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)OC(C(=O)N1[C@@H](Cc2ccccc2)COC1(C)C)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)Cc1ccn(-c2ccc(-c3ccccc3)cc2)c1
Reaction time: 40 h
Yield: 26.8 %

Procedure:
To a mixture of crude 2-acetoxy-1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-[1-(biphenyl-4-yl)-1H-pyrrol-3-yl]-ethanone (1.82 mmol) and 10% palladium on carbon (120 mg) in EtOAc (4.5 mL) and EtOH (4.5 mL) was added ammonium formate (0.58 g, 9.2 mmol). After 40 hours at ambient temperature, the resultant mixture was filtered and the filtrate concentrated to a residue which was dissolved in EtOAc, washed with 1M pH 7 phosphate buffer, dried over Na2SO4, and evaporated under reduced pressure to give a crude product. Flash column chromatography with 0-4% EtOAc/CH2Cl2 gradient eluant yielded 220 mg (43%) of 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-[1-(biphenyl-4-yl)-1H-pyrrol-3-yl]-ethanone as a pale yellow amorphous solid. 1H NMR: δ 7.62 (t, 4H, J=9.4 Hz), 7.47 (d, 2H, J=7.4 Hz), 7.42 (d, 2H, J=8.5 Hz), 7.35 (t, 2H, J=6.6 Hz), 730-7.21 (m, 4H), 7.08 (t, 1H, J=2.6 Hz), 7.05 (s, 1H), 6.28 (t, 1H, J=2.21 Hz), 4.16-4.10 (m, 1H), 3.82 (m, 2H), 3.62, 3.54 (AB quartet, 2H, J=15.5 Hz), 3.07 (dd, 1H, J=3.9, 13.8 Hz), 2.91 (dd, 1H, J=9.9, 13.6 Hz), 1.78 (s, 3H), 1.59 (s, 3H). Anal. Calculated for C30H30N2O2.0.25 H2O: C, 79.18; H, 6.76; N, 6.16. Found: C, 79.24; H, 6.79; N, 6.12.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:55]1[CH2:60][CH2:59][CH:58]([C:61]2[C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[NH:63][CH:62]=2)[CH2:57][CH2:56]1>CN(C=O)C>[NH:63]1[C:64]2[C:69](=[CH:68][CH:67]=[CH:66][CH:65]=2)[C:61]([CH:58]2[CH2:59][CH2:60][N:55]([C:6]([C:5]3[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=3)[C:1]#[N:2])=[O:8])[CH2:56][CH2:57]2)=[CH:62]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cccc(C(=O)N2CCC(c3c[nH]c4ccccc34)CC2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-Cyano-benzoic acid (0.09 g, 0.6 mmol) is dissolved in 3 ml of DMF, then HBTU (0.28 g, 0.75 mmol), HOBt (0.10 g, 0.75 mmol) and DIPEA (0.26 g, 2.0 mmol) are added. The mixture is stirred at RT for 20 min before adding the 3-piperidin-4-yl-1H-indole (0.09 g, 0.6 mmol). The reaction was stirred at RT for 3 hours, monitored with LC/MS. The organic solvent is removed under the reduced pressure and the residue is purified by a silica gel flash column using heptane and ethyl acetate as the elutes.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].[C:14](Cl)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>O>[C:14]([NH:7][NH:6][C:2]([CH3:5])([CH3:4])[CH3:3])(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)NN
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)NNC(=O)C(C)(C)C
Temperature: 10 °C
Reaction time: 3 h

Procedure:
A solution of 40.8 g. (0.33 m.) of tert.-butylhydrazine hydrochloride in 300 ml. of distilled water was placed in a 500 ml. 4 neck, round bottom flask equipped with a high speed mechanical stirrer, a thermometer and a condenser, and cooled to 10° C. The solution was made basic by adding 24.3 g. (0.225 m.) of sodium carbonate and then 18.9 g. (0.15 m.) of pivaloyl chloride was added dropwise over 1 hour holding the temperature below 10° C. with an ice bath. The mixture was stirred for 3 hours and the white solid which formed was filtered off and dried. The product weight 16.5 g. after drying and had a melting range of 97°-105° C.
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:47]=[N:46][C:8]2[O:9][C:10]([CH3:45])([CH3:44])[C:11](=[O:43])[N:12]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[O:33][C@H:34]([CH3:39])[CH2:35][C:36]([OH:38])=[O:37])=[CH:23][C:22]=4[N+:40]([O-])=O)=[O:20])[CH2:15][CH2:14]3)[C:7]=2[CH:6]=1.[Cl-].[NH4+]>[Fe].O>[NH2:40][C:22]1[CH:23]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C@H:34]([CH3:39])[CH2:35][C:36]([OH:38])=[O:37])[CH:25]=[CH:26][C:21]=1[C:19]([N:16]1[CH2:17][CH2:18][CH:13]([N:12]2[C:11](=[O:43])[C:10]([CH3:45])([CH3:44])[O:9][C:8]3[N:46]=[CH:47][C:5]([Cl:4])=[CH:6][C:7]2=3)[CH2:14][CH2:15]1)=[O:20]
Reactant: C[C@H](CC(=O)O)Oc1ccccc1-c1ccc(C(=O)N2CCC(N3C(=O)C(C)(C)Oc4ncc(Cl)cc43)CC2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: C[C@H](CC(=O)O)Oc1ccccc1-c1ccc(C(=O)N2CCC(N3C(=O)C(C)(C)Oc4ncc(Cl)cc43)CC2)c(N)c1
Yield: 32.2 %

Procedure:
To an 80% aqueous ethanol solution (7.50 ml) of (3R)-3-[(4′-{[4-(7-chloro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)piperidin-1-yl]carbonyl}3′-nitrobiphenyl-2-yl)oxy]butanoic acid (132 mg) were added at room temperature ammonium chloride (11.3 mg) and iron powder (59.0 mg), followed by stirring under heating at reflux for 1 hour. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford (3R)-3-[(3′-amino-4′-{[4-(7-chloro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)piperidin-1-yl]carbonyl}biphenyl-2-yl)oxy]butanoic acid (40.5 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][N:6]3[C:7]=2[C:3]=1[C:4]1[CH2:18][CH2:17][CH2:16][C:5]=13.C([BH3-])#N.[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][N:6]3[C:7]=2[C:3]=1[CH:4]1[CH2:18][CH2:17][CH2:16][CH:5]13
Reactant: Fc1ccc2c3c1c1c(n3CCNCC2)CCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Fc1ccc2c3c1C1CCCC1N3CCNCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of 8-fluoro-2,3,4,5,10,11-hexahydro-1H,9H-cyclopenta[b][1,4]diazocino[7,8,1-hi]indole (0.41 g, 1.68 mmole) in acetic acid (50 mL) was added sodium cyanoborohydride (0.33 g, 4.99 mmole) and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was diluted with methylene chloride (200 mL) and washed with aqueous sodium hydroxide (1N, 150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, 1.5% to 5% methanol in methylene chloride) provided 0.35 g of the title compound as a colorless oil. The oil was further treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 169-170° C. MS (ES) m/z 247.13 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:28][CH:27]=3)=[CH:24][N:25]=2)=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCOCC1.[Pd]>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:28][CH:27]=3)=[CH:24][N:25]=2)=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C=C(NC(=O)OC(C)(C)C)C(=O)OC)cc3)s2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(CC(NC(=O)OC(C)(C)C)C(=O)OC)cc3)s2)cc1
Yield: 41.8 %

Procedure:
A stirring mixture of Methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl) thiazol-2-yl)phenyl)acrylate (50 mg, 0.091 mmol) dissolved in dioxane (5 mL) was hydrogenated using an H-Cube hydrogenator (10% Pd/C, 30×4 mm, full hydrogen, 40° C., 1 mL/min). The reaction mixture was concentrated in vacuo to afford 21 mg (29%) of methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl) thiazol-2-yl)phenyl)propanoate as a yellow solid. LCMS-ESI (m/z) calculated for C31H40N2O5S: 552.7. found 553.0 [M+H]+, tR=1.85 min. (Method 8).
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Br[CH2:18]Br>CN(C=O)C>[O:1]1[CH:2]2[CH2:3][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH:6]2[O:7][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@@H](O)C1
Reactant: BrCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2OCOC2C1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
tert-Butyl (3R,4S)-3,4-dihydroxypyrrolidine-1-carboxylate (34.6 g; 0.17 mol) was dissolved in DMF (400 mL) under argon and cooled down to 0-5° C. Sodium hydride (15 g; 0.375 mol) was added portionwise. The reaction mixture formed a foam which was difficult to stir. After 1 hour at 5° C., dibromomethane (15.6 mL; 0.22 mol) was added. After an additional 30 minutes at the same temperature, the reaction mixture was left to rise to ambient temperature. The temperature rose to 35° C. and was stirred overnight. The DMF was evaporated off and the residue partitioned between ethyl acetate and water. The water phase was extracted with ethyl acetate, the organic phases were combined and washed with water, brine, dried over magnesium sulphate and evaporated. The residue was dissolved in a minimum of dichloromethane and purified by flash chromatography using ethyl acetate/petroleum ether (3/7). Evaporation of the solvent gave tert-butyl tetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate (19.77 g; 54%) as a colorless oil.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[S:24][C:23]([CH2:25][C:26]([NH2:28])=[O:27])=[N:22][N:21]=1>>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[S:24][C:23]([CH2:25][C:26](=[O:27])[NH2:28])=[N:22][N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: NC(=O)Cc1nnc(S)s1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Product: NC(=O)Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Yield: 69.8 %

Procedure:
7-ACA and 5-mercapto-1,3,4-thiadiazol-2-ylacetamide were reacted as described in example 23a to give the title compound in 69.8% yield; δ(CF3CO2H) 3.93 (2H,s, C2 methylene), 4.63 (2H,s, --CH2CO--), 4.82 (2H,bs, --CH2S--), 5.47 (2H,s, β-lactam protons), 7.2-7.8 (2H,m, --CONH2).
Reaction SMILES: OC(C1N=C(CCC)NC=1C(OCC)=O)C.[C:17]([C:20]1[N:21]=[C:22]([CH2:30][CH2:31][CH2:32][CH3:33])[NH:23][C:24]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])(=[O:19])[CH3:18]>>[CH2:30]([C:22]1[NH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:20]([CH:17]([OH:19])[CH3:18])[N:21]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCc1nc(C(C)=O)c(C(=O)OCC)[nH]1
Agent: CCCc1nc(C(C)O)c(C(=O)OCC)[nH]1
Product: CCCCc1nc(C(C)O)c(C(=O)OCC)[nH]1
Yield: 85.2 %

Procedure:
Following a procedure similar to that described in Preparation 23(iii), but using 0.64 g of ethyl 4-acetyl -2-butylimidazole-5-carboxylate [prepared as described in step (ii) above], 0.55 g of the title compound was obtained as crystals, melting at 149° C.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15]Br)=[CH:11][CH:10]=1)C1C=CC=CC=1.[ClH:19].[F:20][C:21]1[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=1[CH2:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:19].[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:27]2[CH2:28][CH2:29][CH:24]([CH2:23][C:22]3[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=3[F:20])[CH2:25][CH2:26]2)=[CH:17][CH:18]=1
Reactant: Fc1ccccc1CC1CCNCC1
Reactant: BrCCOc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Oc1ccc(OCCN2CCC(Cc3ccccc3F)CC2)cc1

Procedure:
The title compound was prepared from 2-(4-benzyloxyphenoxy)ethyl bromide (0.393 g, 1.28 mmol), 4-(2-fluorobenzyl)piperidine hydrochloride (0.294 g, 1.28 mmol) and potassium carbonate (0.442 g, 3.2 mmol) in two steps as an off white solid (0.237 g), mp 196-198° C. 1H NMR (CD3OD) 1.629 (m, 2 H), 1.900 (m, 3 H), 2.704 (m, 2 H), 3.052 (m, 2 H), 3.500 (m, 2 H), 3.612 (m, 2 H), 4.252 (m, 2 H), 6.703 (d, J=9. 0 Hz, 2 H), 6.825 (6, J=9.0 Hz, 2 H), 7.057-7.248 (m, 2 H), 7.248 (m, 2 H). Anal. Calcd for C20H25ClFNO2.1.2H2O: C, 61.70; H, 7.15; N, 3.60. Found: C, 61.45; H, 6.90; N, 3.53.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7]([NH2:10])(=[O:9])=[O:8])[N:4]=[CH:3]1.Cl[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([S:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=2[F:29])[N:13]=1>>[F:29][C:23]1[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][S:20][C:14]1[N:13]=[C:12]([NH:10][S:7]([C:5]2[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=2)(=[O:9])=[O:8])[CH:17]=[C:16]([O:18][CH3:19])[N:15]=1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: Cn1cnc(S(N)(=O)=O)c1
Product: COc1cc(NS(=O)(=O)c2cn(C)cn2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared from 1-methyl-1H-imidazole-4-sulfonamide (0.19 g) and 4-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of Example 35, step i) (0.25 g) according to the procedure outlined in Example 1, step iv). The crude material was purified by column chromatography using EtOAc/isohexane (2:8) as eluent.
Reaction SMILES: [N:1]([C:4]1[CH:15]=[CH:14][C:7]([C:8]([NH:10][CH2:11][CH2:12]Br)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].C(=O)([O-])[O-].[K+].[K+].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(#N)C>[N:1]([C:4]1[CH:15]=[CH:14][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)NCCBr)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCN(CCNC(=O)c2ccc(N=[N+]=[N-])cc2)CC1
Temperature: 75 °C
Reaction time: 7 h
Yield: 32.2 %

Procedure:
4-Azido-N-(2-bromoethyl)benzamide (2.0 g) obtained in Example 63a) and potassium carbonate (1.34 g, 9.70 mmol, 1.0 eq.) were suspended in acetonitrile (40 ml), N-methylpiperazine (1.63 ml, 14.6 mmol, 1.5 eq.) was added, and the mixture was stirred at room temperature for 16 hr and at 75° C. for 7 hr. The reaction mixture was concentrated, diluted with water (40 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted twice with water (20 ml). The aqueous layers were combined, concentrated, saturated with sodium chloride and extracted with ethyl acetate (40 ml and 30 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated at 30° C. or below to give the title compound as a pale-yellow solid (0.69 g, 2.39 mmol, 24.7%).
Reaction SMILES: CN(C)[CH:3]=[O:4].ClCCl.P(Cl)(Cl)(Cl)=O.[CH3:14][C:15]1[NH:16][CH:17]=[C:18]([CH3:24])[C:19]=1[CH2:20][C:21]([OH:23])=[O:22]>C(OCC)(=O)C.CCCCCC.C(O)(=O)C>[CH:3]([C:17]1[NH:16][C:15]([CH3:14])=[C:19]([CH2:20][C:21]([OH:23])=[O:22])[C:18]=1[CH3:24])=[O:4]
Reactant: CN(C)C=O
Reactant: Cc1c[nH]c(C)c1CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1[nH]c(C=O)c(C)c1CC(=O)O
Temperature: 20 °C
Yield: 96.3 %

Procedure:
Dimethylformamide (230 mL, 3.13 mol) and 1200 mL of dichloromethane were cooled to 4° C. and 222 mL of phosphorus oxychloride was added with stirring. The temperature increased to 20° C. The mixture was cooled to 2° C. (2,4-Dimethyl-1H-pyrrol-3-yl)-acetic acid (240 g, 1.57 mol) was slowly added. The mixture was refluxed for 20 minutes. Thin layer chromatography (ethyl acetate:hexane:acetic acid 4:6:0.5) showed no starting material at Rf 0.7 and a heavy spot at the origin. The mixture was cooled to 5° C. and 1200 mL of ice water were added. The maximum temperature reached was 30° C. The mixture was stirred in an ice bath for 30 minutes. The dichloromethane layer was separated and discarded. The aqueous layer was cooled to 9° C. and adjusted to pH 12 with about 1650 mL of 9 N potassium hydroxide. The maximum temperature reached was 50° C. The mixture was cooled in an ice bath and adjusted to pH 3 with about 800 mL of 10 N hydrochloric acid. The solids were collected by vacuum filtration, washed three times with 300 mL of water each time and air dried to give 274 g (96% yield) of (5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-acetic acid as a brown solid. 1H-NMR (dimethylsulfoxide-d6) δ 2.15, 2.18 (2×s, 2×3H, 2×CH3), 3.28 (s, 2H, CH2), 9.44 (s, 1H, CHO), 11.50 (s, 1H, pyrrole NH), 12.07 (s, 1H, COOH). MS m/z 182, [M+1].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Br:12][C:13]1[N:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:12][C:13]1[N:14]=[CH:15][C:16]([NH:19][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:17][CH:18]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Nc1cnc(Br)cn1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Nc2cnc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 10.4 %

Procedure:
Into a 50 mL roundbottom flask, was placed 4-methoxyphenylboronic acid (5.4 g, 35.54 mmol). To this was added 5-bromo-pyrazin-2-ylamine (3 g, 17.24 mmol). Cu(OAc)2 (3.45 g, 19.06 mmol) was added, followed by addition of a solution of DMAP (4.2 g, 34.43 mmol) in CH2Cl2 (20 mL). The resulting solution was stirred at room temperature for 12 hours. The reaction progress was monitored by thin layer chromatography (TLC) (ethyl acetate/petroleum ether=1:2). When the reaction was complete, the mixture was filtered, then concentrated under vacuum. The residue was dissolved in ethyl acetate (EtOAc), then washed with water. The organic layer was dried over Na2SO4, then filtered and concentrated. The crude product was purified by silica gel chromatography (SGC) eluting with ethyl acetate/petroleum ether (1:5, v/v) to provide (5-bromo-pyrazin-2-yl)-(4-methoxy-phenyl)-amine (i) (500 mg, yield 10%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O[C@@H:19]1[CH:24]2C[CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1>C1(C)C=CC=CC=1>[N:21]12[CH2:22][CH2:23][CH:24]([CH2:19][CH2:20]1)[C@@H:1]([O:2][C:3](=[O:17])[C:4]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([OH:11])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:26]2
Reactant: COC(=O)C(O)(c1ccccc1)C1CCCC1
Reactant: O[C@H]1CN2CCC1CC2
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1ccccc1)C1CCCC1
Yield: 69 %

Procedure:
Prepared using the same method as for Intermediate I-1, but from 13.5 g (0.0576 mol) of 2-Cyclopentyl-2-hydroxy-2-phenylacetic acid methyl ester (commercially available) dissolved in 350 ml of toluene, 8.0 g (0.063 mol) of (3R)-3-hydroxy-1-azabicyclo[2.2.2]octane and 0.91 g (0.023 mol) of HNa (60% dispersion in mineral oil). The yield was 13.1 g (69%) of the title product as an oil mixture of diastereomers, structure confirmed by 1H-NMR. The two diastereomers I-5a and I-5b were separated after several crystallizations.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][C:22]2[CH:23]=[N:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Nc1cnc2ccccc2c1
Product: O=C(Nc1cnc2ccccc2c1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and 3-aminoquinoline (73.7 mg, 0.51 mmol). The title compound was obtained as a yellow solid (40 mg, 20% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.97 (1H, br), 9.066 (1H, m), 9.02 (2H, m), 8.77 (1H, m), 8.65 (1H, m), 7.95 (2H, m), 7.69 (1H, m), 7.59 (1H, m). MS m/z: 475.23, 477.28 [M+H]+.