Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]=[CH:3]1>C(O)C.C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]=[CH:3]1
Reactant: COC(=O)C1CN(C)C=N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cn(C)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
19.0 g of manganese dioxide was added to a stirred solution of 4.7 g of 38D in ethanol-free, chloroform and the mixture was stirred overnight at room temperature. The mixture was heated at reflux for 1 hour, cooled, 9.5 g of manganese dioxide was added; the mixture was stirred at room temperature for 2 hours and at reflux for 30 minutes. The mixture was cooled and filtered and the filtrate was stripped of solvent to give methyl 1-methylimidazole-4-carboxylate (38E), as a yellow solid, m.p.: 72.5°-81° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[N:17]([CH3:18])[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7](=[O:19])[N:6]([CH3:20])[CH2:5]1.C(O)(C)C.[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[CH3:18][N:17]1[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7](=[O:19])[N:6]([CH3:20])[CH2:5][CH:4]1[CH2:3][CH2:2][N:37]1[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]1
Reactant: CN1CCNCC1
Reactant: CN1CC(CCCl)N(C)c2nc3ccccc3n2C1=O
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)O
Product: CN1CCN(CCC2CN(C)C(=O)n3c(nc4ccccc43)N2C)CC1
Temperature: 60 °C

Procedure:
To 20 mL of N-methylpiperazine was added 3.0 g (0.01 mol) of 2-(2-chloroethyl)-3,4-dihydro-1,4-dimethyl-1H-[1,3,5]triazepino[3,2-a]benzimidazol-5(2H)-one. The reaction mixture was heated to 60° C. for 24 hr. The excess amine was removed at 70° C., 0.5 mm Hg. The residual oil was taken up in 60 mL of CH2Cl2 and washed with 2×50 mL of 1N NaOH. The organic layer was dried over Na2SO4, filtered, concentrated by rotary evaporation, and further concentrated at 90° C., 0.5 mm Hg. The residual oil/glass was treated with 2 equivalent of fumaric acid isopropyl alcohol to give 3.4 g of solid. This was recrystallized from isopropyl alcohol to give 3.0 g (51%) off-white analytically pure material, mp 171°-79° C.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:21]=[CH:20][C:14]2[S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][C:13]=2[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.O.[OH-].[Li+]>C(O)C.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:21]=[CH:20][C:14]3[S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][C:13]=3[CH:12]=2)[C:3]([OH:22])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc2c(c1)CCS2(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(CC1CCCC1)c1ccc2c(c1)CCS2(=O)=O
Temperature: 25 °C
Yield: 64.9 %

Procedure:
3-Cyclopentyl-2-(1,1-dioxo-2,3-dihydro-benzo[b]thiophen-5-yl)-propionic acid methyl ester (184 mg, 0.57 mmol) was dissolved in ethanol (4 mL) and treated with a solution of lithium hydroxide monohydrate (34 mg, 1.43 mmol) in water (1.5 mL) at 25° C. It was stirred at 25° C. until the starting material was all consumed by TLC (˜1 hr). The reaction was then concentrated in vacuo to remove the ethanol. The remaining aqueous layer was then acidified to pH=2 with an aqueous 1N hydrochloric acid solution. This was then extracted with ethyl acetate (3×20 mL), the organic layers combined and dried over magnesium sulfate, filtered and concentrated in vacuo to afford 3-cyclopentyl-2-(1,1-dioxo-2,3-dihydro-benzo[b]thiophen-5-yl)-propionic acid (114 mg, 65%) as a white solid: EI-HRMS m/e calcd for C16H20O4S (M+) 308.1082, observed 308.1075.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([N+:31]([O-])=O)[CH:25]=2)[C:14]([N:16]2[CH2:21][CH2:20][S:19](=[O:22])[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:34].[CH:35](O)=O>[Pd]>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]3[NH:30][CH:35]=[N:31][C:26]=3[CH:25]=2)[C:14]([N:16]2[CH2:21][CH2:20][S:19](=[O:22])[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:34]
Reactant: O=CO
Reactant: Nc1ccc(CC(NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)C(=O)N2CCS(=O)CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Product: Nc1c(Cl)cc(S(=O)(=O)NC(Cc2ccc3[nH]cnc3c2)C(=O)N2CCS(=O)CC2)cc1Cl

Procedure:
Prepared from 4-amino-N-[1-((4-amino-3-nitro-phenyl)methyl)-2-(1-oxido-thiomorpholin-4-yl)-2-oxo-ethyl]-3,5-dichloro-benzenesulphonamide and cyclising with formic acid in the presence of palladium/charcoal analogously to Example 1.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:6]=1[CH:7]=O)([CH3:3])[CH3:2].[C:16]1([CH3:25])[CH:21]=[CH:20][C:19]([S@@:22]([NH2:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[CH:1]([S:4][C:5]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:6]=1/[CH:7]=[N:24]/[S@:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:25])=[CH:17][CH:18]=1)=[O:23])([CH3:3])[CH3:2]
Reactant: CC(C)Sc1ccc([N+](=O)[O-])cc1C=O
Reactant: Cc1ccc([S@@](N)=O)cc1
Solvent: ClCCl
Product: Cc1ccc([S@](=O)/N=C/c2cc([N+](=O)[O-])ccc2SC(C)C)cc1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To 2-(isopropylthio)-5-nitrobenzaldehyde (234 mg, 1.0 mmol) and (S)-(+)-p-toluenesulfinamide (161 mg, 1.0 mmol) in CH2Cl2 (10 mL) was added Ti(OEt)4 (25% tech, 0.54 mL). The mixture was heated at 75° C. for 3.0 h. TLC indicated a clean reaction. Solvent was removed and the residue was redissolved in EtOAc, under stirring sat. Na2SO4 solution was added and the slurry was stirred at rt for 30 min before it was filtered through a pad of Celite®. The filtrate was extracted with EtOAc, washed with brine and dried over Na2SO4. After evaporation of solvent, 98A (320 mg, 88% yield) was obtained as a solid used for next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 1.34 (d, J=6.59 Hz, 6H) 2.34 (s, 3H) 3.51-3.61 (m, 1H) 7.27 (d, J=7.91 Hz, 2H) 7.45 (d, J=8.79 Hz, 1H) 7.59 (d, J=8.35 Hz, 2H) 8.14 (dd, J=8.79, 2.64 Hz, 1H) 8.69 (d, J=2.64 Hz, 1H) 9.17 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([NH2:6])[C:3]([NH2:7])=[CH:2]1.[Cl:8][CH2:9][C:10](OCC)(OCC)OCC.CCCCCC>C(COC)OC>[Cl:8][CH2:9][C:10]1[NH:7][C:3]2=[CH:2][S:1][CH:5]=[C:4]2[N:6]=1
Reactant: Nc1cscc1N
Reactant: CCOC(CCl)(OCC)OCC
Solvent: CCCCCC
Solvent: COCCOC
Product: ClCc1nc2cscc2[nH]1
Temperature: 95 °C
Reaction time: 24 h

Procedure:
3,4-Thiophenediamine (0.5 g, Toronto Research Chemicals, Chemical Abstracts #90069-81-1) and 2-chloro-1,1,1-triethoxyethane (0.9 g) were combined in dimethoxyethane (7 mL) in a sealed tube and heated at 95° C. for one hour. After allowing to cool to room temperature and stirring for 24 hours, the mixture was treated with hexane (10 mL) and filtered. The filter cake was dried under reduced pressure to provide the title compound. MS (DCI/NH3) m/z 173 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:20](O)=[O:21])=[CH:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:27][NH2:28].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([C:20]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:31]([F:32])=[C:24]([Cl:23])[CH:25]=2)=[O:21])=[CH:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(F)c(Cl)c1
Reactant: CN1CCn2cc(C(=O)O)c(OCc3ccccc3)c2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCn2cc(C(=O)NCc3ccc(F)c(Cl)c3)c(OCc3ccccc3)c2C1=O

Procedure:
To a mixture of 8-(benzyloxy)-2-methyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylic acid (200 mg, 0.67 mmol), 3-chloro-4-fluorobenzylamine (0.16 g, 1.00 mol), and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophophate (BOP, 0.35 g, 0.79 mmol) in anhydrous dichloromethane (10 mL), diisopropylethylamine (0.17 g, 1.33 mmol) was added. The resultant solution was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum, and the residue partitioned between dichloromethane and aq HCl. The organic extract was washed with aq sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the titled amide.
Reaction SMILES: [C:1]([C@@H:4]([NH:9][C:10](=[O:41])[C@@H:11]([C@H:33]1[C:37](=[O:38])[O:36][C:35]([CH3:40])([CH3:39])[O:34]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)=[CH:20][CH:19]=1)[C:5]([CH3:8])([CH3:7])[CH3:6])(O)=[O:2].[CH3:42][O:43][CH2:44][C@@H:45]([NH2:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(OCC)(=O)C>[CH3:39][C:35]1([CH3:40])[O:34][C@@H:33]([C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[C:22]([CH3:24])[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=3)=[CH:20][CH:19]=2)[C:10]([NH:9][C@H:4]([C:1]([NH:52][C@@H:45]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:44][O:43][CH3:42])=[O:2])[C:5]([CH3:6])([CH3:7])[CH3:8])=[O:41])[C:37](=[O:38])[O:36]1
Reactant: COC[C@@H](N)c1ccccc1
Reactant: COc1cccc(-c2ccc(CCCCCC[C@@H](C(=O)N[C@H](C(=O)O)C(C)(C)C)[C@@H]3OC(C)(C)OC3=O)cc2C)c1
Solvent: CCOC(C)=O
Product: COC[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCCCCCc1ccc(-c2cccc(OC)c2)c(C)c1)[C@@H]1OC(C)(C)OC1=O)C(C)(C)C)c1ccccc1
Yield: 64.9 %

Procedure:
According to the method of Example 25(a), (2R)-N-[(1S)1-(carboxy)-2,2-dimethylpropyl]-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-5-[(3′-methoxy-2-methylbiphen-4-yl)propyl]pentanamide (Preparation 34)(220 mg, 0.42 mmol) was reacted with (1S)-2-methoxy-1-phenylethylamine (63 mg, 0.42 mmol) at room temperature for 2.5 h. The mixture was poured into ethyl acetate (75 mL) and washed with 0.5M aqueous sodium dihydrogenphosphate (2×50 mL) and 5% aqueous sodium bicarbonate (50 mL)(solid sodium chloride was added to give phase separation). The organic solution was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane:ethyl acetate=30:70 to 60:40) to give a white solid which was purified again by flash chromatography (sorbsil C60, (20-40μ) silica gel, eluting with hexane:ethyl acetate 35:65) to give (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-N-[(1S)-2,2-dimethyl-1-({[(1S)-2-methoxy-1-phenylethyl]amino}carbonyl)propyl]-5-[(3′-methoxy-2-methylbiphen-4-yl)propyl]pentanamide as a white solid (191 mg, 69%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Mg].[CH2:16]([NH:23][CH2:24][CH:25]1[CH2:27][O:26]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:16]([N:23]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:24][CH:25]([OH:26])[CH2:27][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(CNCC2CO2)cc1
Reactant: Brc1cccc(CN2CCCCC2)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(Cc1cccc(CN2CCCCC2)c1)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
10.2 g (0.04 mol) of 3-(1-piperidylmethyl)-bromobenzene in 20 ml of tetrahydrofuran are added dropwise to 0.97 g (0.04 mol) of magnesium filings in 5 ml of tetrahydrofuran at a reaction temperature of 60° C. This operation is followed by 30 minutes' stirring at 60° C., and the solution is then cooled to 10° C. 10.2 g (0.04 mol) of 2-benzylaminomethyl-oxirane in 20 ml of tetrahydrofurane are slowly added dropwise and the solution obtained is stirred at room temperature for 2 hours. After the addition of 20 ml of ice water and 4.5 g of ammonium chloride, the aqueous phase is separated and extracted with 25 ml of methylene chloride. The combined organic phases are dehydrated with sodium sulphate and concentrated by evaporation to yield a yellow resin which is chromatographed with methylene chloride/methanol (9:1) against silica gel. After concentration by evaporation, the second fraction yields the title compound as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:13]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O>CN(C=O)C>[Br:1][C:2]1[C:9]([O:10][CH3:13])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C=O)c(Br)c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(C=O)c(Br)c1OC
Temperature: -10 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A stirred suspension of 2-bromo-3-hydroxy-4-methoxybenzaldehyde (commercially available, 24 g, 104 mmol) and K2CO3 (29.4 g, 213 mmol) in DMF (125 ml) was cooled to −10° C. Dimethylsulfate (9.6 ml, 102 mmol) was added, the reaction was warmed to room temperature and stirred overnight. The resulting solution was quenched with water (375 ml) and the resulting suspension stirred overnight. The resulting suspension was filtered and the solid dried in vacuo at 50° C. to give 23.1 g of the subtitle product (91%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:29])=[C:13]([C:15]2[CH2:19][C:18]([CH2:24][C:25]([O:27]C)=[O:26])([C:20]([O:22]C)=[O:21])[O:17][N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:29])=[C:13]([C:15]2[CH2:19][C:18]([CH2:24][C:25]([OH:27])=[O:26])([C:20]([OH:22])=[O:21])[O:17][N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC1(C(=O)OC)CC(c2cc(OCc3ccccc3)ccc2C)=NO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(OCc2ccccc2)cc1C1=NOC(CC(=O)O)(C(=O)O)C1
Yield: 99.7 %

Procedure:
A mixture of methyl 3-(5-(benzyloxy)-2-methylphenyl)-5-(2-methoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (6.80 g), THF (70 mL), methanol (70 mL), and a 1 M aqueous sodium hydroxide solution (70 mL) was stirred at room temperature for 30 minutes. The reaction mixture was rendered acidic using 6 M hydrochloric acid at 0 C, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (6.30 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[O:12][CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C.[ClH:26].O1CCOCC1>>[ClH:26].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[O:12][CH2:13][CH2:14][NH2:15]
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(C#Cc2ccccn2)c1
Agent: Cl
Solvent: C1COCCO1
Product: NCCOc1cccc(C#Cc2ccccn2)c1

Procedure:
Deprotection of tert-butyl 2-(3-(pyridin-2-ylethynyl)phenoxy)ethylcarbamate with HCl-dioxane following the method used in Example 13 gave 2-(3-(pyridin-2-ylethynyl)phenoxy)ethanamine hydrochloride as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (dt, J=5.2, 0.8 Hz, 1H), 8.20 (br s, 3H), 7.92 (dt, J=8.0, 2.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.47 (ddd, J=7.6, 5.2, 1.2 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.19-7.20 (m, 1H), 7.08 (ddd, J=8.0, 2.4, 0.8 Hz, 1H), 4.21 (t, J=5.2 Hz, 2H), 3.18 (dt, J=5.6, 5.2 Hz, 2H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][C:33]([F:36])([F:35])[F:34])[CH2:6][NH:7][C:8]([C@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][N:11]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:9].Cl[C:38]1[S:39][C:40]2[C:45]([Cl:46])=[N:44][C:43]([CH:47]3[CH2:49][CH2:48]3)=[N:42][C:41]=2[N:50]=1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[F:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][C:33]([F:36])([F:34])[F:35])[CH2:6][NH:7][C:8]([C@H:10]1[CH2:15][N:14]([C:38]2[S:39][C:40]3[C:45]([Cl:46])=[N:44][C:43]([CH:47]4[CH2:48][CH2:49]4)=[N:42][C:41]=3[N:50]=2)[CH2:13][CH2:12][N:11]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:17])=[O:18])=[O:9]
Reactant: O=C(NCc1ccc(OC(F)(F)F)c(F)c1)[C@H]1CNCCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: Clc1nc2nc(C3CC3)nc(Cl)c2s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(OC(F)(F)F)c(F)c1)[C@H]1CN(c2nc3nc(C4CC4)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a mixture of the crude product (about 0.095 mmol) obtained in Step 5 and 2,7-dichloro-5-cyclopropyl-thiazolo[4,5-d]pyrimidine (24 mg) in chloroform (1.0 ml) was added N,N-diisopropylethylamine (42 μl) at room temperature. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (methanol:chloroform=1:10) to give the title compound (52 mg). 1H-NMR (CDCl3, 300 MHz) δ: 1.03-1.09 (2H, m), 1.17-1.22 (2H, m), 2.18-2.27 (1H, m), 3.14-3.35 (2H, m), 3.43-3.53 (1H, m), 3.96 (1H, d, J=13.6 Hz), 4.22-4.36 (2H, m), 4.45-4.69 (3H, m), 6.97-7.06 (3H, m), 7.20 (1H, t, J=8.5 Hz), 7.83 (2H, d, J=8.3 Hz), 8.02 (2H, d, J=8.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].[CH3:12][CH2:13][CH2:14][CH:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][CH:15]([CH2:16][CH2:17][CH3:18])[CH2:14][CH2:13][CH3:12])=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: CCCC(N)CCC
Reactant: Cc1cc(C(=O)O)ccc1Cl
Product: CCCC(CCC)NC(=O)c1ccc(Cl)c(C)c1

Procedure:
Prepared in a similar manner to example 4 using 4-chloro-3-methyl benzoic acid and heptan-4-amine. MS (M+H, 268).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:44][C:45]1([F:50])[CH2:49][CH2:48][NH:47][CH2:46]1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([N:47]3[CH2:48][CH2:49][C:45]([F:50])([F:44])[CH2:46]3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: FC1(F)CCNC1
Agent: Cl
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)N3CCC(F)(F)C3)(CC1)CC2
Yield: 85.8 %

Procedure:
In a similar manner to Example 13, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 3,3-difluoropyrrolidine hydrochloride (18.7 mg) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(3,3-difluoropyrrolidin-1-yl)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (40.8 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[C:4]([NH:11][C:12]2[NH:13][CH2:14][CH2:15][N:16]=2)[CH:3]=1.[Br:17]Br.N>CC(O)=O>[Br:17][C:5]1[C:6]2[NH:10][CH:9]=[N:8][C:7]=2[C:2]([Cl:1])=[CH:3][C:4]=1[NH:11][C:12]1[NH:13][CH2:14][CH2:15][N:16]=1
Reactant: Clc1cc(NC2=NCCN2)cc2[nH]cnc12
Reactant: BrBr
Agent: N
Solvent: CC(=O)O
Product: Clc1cc(NC2=NCCN2)c(Br)c2[nH]cnc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 33 %

Procedure:
To a solution of 7-chloro-5-(2-imidazolin-2-ylamino)benzimidazole (0.61 g, 2.6 mmol) in 10 ml of AcOH was added 0.3 ml of Br2. Resulting reaction mixture was stirred for 12 h at 25° C. and concentrated in vacuo, yielding an oil, which was subjected to column chromatography (NH3 sat'd 30% MeOH/EtoAc) to yield 0.23 g (0.85 mmol, 33%) of the desired product. The product obtained was converted to the fumarate salt and recrystallized from MeOH to afford 0.12 g (12%) of the product as a light yellow solid: mp 244-246° C.; Anal. Calc. for C10H9N5BrCl.1.0C4H4O4.0.5H2O requires C, 37.77; H, 3.17; N, 18.35. Found: C, 37.75; H, 3.08; N, 18.21.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3]1.[C:13]1([NH:19]N)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.O>C(O)(=O)C>[CH3:1][C:2]1([CH3:12])[C:3]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:19][C:4]=2[C:5]2[C:10]1=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: NNc1ccccc1
Reactant: CC1(C)CC(=O)c2ccccc21
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)c2ccccc2-c2[nH]c3ccccc3c21
Reaction time: 2 h

Procedure:
A solution of 3,3-dimethyl-1-indanone (20,0 q, 0,125 mol) prepared by the method described by R. Knorr et al., Leibig's Annalen, 1207 (1980) and phenylhydrazine (12.3 cm3, 0.125 mol) in glacial acetic acid (200 cm3), was heated to reflux. Concentrated hydrochloric acid (10 cm3) was added via the condenser, and boiling continued for a further 2 hours. The solution was allowed to cool, and then poured into water (500 cm3). The water was extracted with diethylether three times, the combined extracts were washed with brine and water, and dried (MgSO4). The solvent was removed, and petrol (60°-80° C.) added to the residue. The suspension was heated until boiling, The solid product was filtered off and the mother liquor concentrated. On cooling, more solid was obtained, and additional product separated out as the mother liquor was concentrated further. The solids were combined and crystallised from petrol to give the title compound. Yield: 10,2 g (35%). M.p. 160 ° C. 1H NMR: (CDCl3) δ: 1.60 (6H, s,), 7.1-7.7 (8H, m,), 8.16 (1H, s,).
Reaction SMILES: [Se]=[O:2].[C:3]([C:6]1[S:7][C:8]([Cl:11])=[CH:9][CH:10]=1)(=[O:5])[CH3:4]>O1CCOCC1.O>[Cl:11][C:8]1[S:7][C:6]([C:3](=[O:5])[CH:4]=[O:2])=[CH:10][CH:9]=1
Reactant: O=[Se]
Reactant: CC(=O)c1ccc(Cl)s1
Solvent: C1COCCO1
Solvent: O
Product: O=CC(=O)c1ccc(Cl)s1
Temperature: 25 °C

Procedure:
Selenium oxide (6.88%) is heated to dissolve in 100 ml aqueous dioxane (95:5 dioxane: H2O). The 2-acetyl-5-chlorothiophene (5.00 g) is added to the mixture. The resulting mixture is refluxed overnight, then cooled. The precipitated selenium metal is filtered after solvent removal a brown thick oil results which solidifies on standing. The solid is heated to dissolve in 400 ml hot water, filtered and allowed to cool to room temperature. The precipitate is collected by filtration, washed with fresh H2O and dried to obtain a light brown flake. The second crop is obtained by extracting the mother liquid with ethylacetate, separated, dried (MgSO4) and concentrated in vacuo to give a light yellow solid which upon treatment with HPLC gives 2-chloro-5-glyoxyloylthiophene, which is used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][C:14](=O)[NH:13][C:12]=2[CH:19]=1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][C:14](=[S:30])[NH:13][C:12]=2[CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)NC(=O)CCC2
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)NC(=S)CCC2
Reaction time: 12 h
Yield: 94.5 %

Procedure:
A solution of (2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-yl)-carbamic acid tert-butyl ester (5.0 g, 18.1 mmol) in THF (400 mL) was treated with Lawesson's Reagent (7.5 g, 18.5 mmol). After stirring for 12 hours, the precipitate was removed and the filtrate was concentrated. The residue was purified by silica gel chromatography with DCM to give (2-thioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-yl)-carbamic acid tert-butyl ester (5.0 g, 17.1 mmol, 94%): MS (m/e) 293 (M+1).