Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.C([S:39][C:40]([CH3:48])([CH3:47])[C@@H:41]([C:43]([O:45][CH3:46])=[O:44])[NH2:42])C1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH:42][C@H:41]([C:43]([O:45][CH3:46])=[O:44])[C:40]([SH:39])([CH3:48])[CH3:47])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)[C@@H](N)C(C)(C)SCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(C)(C)S
Temperature: -70 °C

Procedure:
146 g of t-butoxycarbonyl proline are dissolved in 1500 ml of methylene chloride. 150 ml of N-methylmorpholine are added to the solution. The solution is cooled to -70° C. 89 ml of isobutylchloroformate are added. The reaction mixture is warmed to -15° C. and then cooled to -70° C. 197 g of methyl S-benzylpenicillaminate hydrochloride are added to the reaction mixture. The reaction mixture is stirred for sixteen hours at room temperature. The reaction mixture is extracted three times with 1.0 M potassium bisulfate and once with brine. The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and stripped of solvent. The residue is dissolved in a minimum of diethyl ether. The ether solution is added to cold rapidly stirring hexane. The white precipitate is filtered and dried to afford the product, methyl t-butoxycarbonylprolylpenicillaminate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([N:25](C)[C:26](=O)OC(C)(C)C)[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36](=[O:41])[CH2:37][CH2:38][O:39][CH3:40])[C:15]3[CH:42]=[CH:43][CH:44]=[CH:45][C:14]1=3)=[C:7]([O:46][CH3:47])[CH:6]=[CH:5]2.[ClH:48]>CO.CCOCC>[ClH:48].[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([NH:25][CH3:26])[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36](=[O:41])[CH2:37][CH2:38][O:39][CH3:40])[C:15]3[CH:42]=[CH:43][CH:44]=[CH:45][C:14]1=3)=[C:7]([O:46][CH3:47])[CH:6]=[CH:5]2
Reactant: COCCC(=O)N1c2ccccc2N(Cc2c(OC)ccc3cc(Br)ccc23)C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(OC)ccc3cc(Br)ccc23)c2ccccc2N(C(=O)CCOC)[C@H]1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a rt solution of tert-butyl(S)-1-((3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-5-(3-methoxypropanoyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (51.2 mg, 71.9 μmol) in MeOH (71.9 μl) was added 2 M HCl in Et2O (288 μl). The reaction was stirred at rt for 3 h, then concentrated, taken up in H2O, and lyophilized to provide (S)-N-((3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-5-(3-methoxypropanoyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (42.3 mg, 91%) as a white solid. MS m/z 611/613 (MH)+.
Reaction SMILES: Cl[CH2:2][C:3]([O:5]C)=[O:4].[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:2][C:3]([OH:5])=[O:4])[CH2:10][CH2:9]1
Reactant: CN1CCNCC1
Reactant: COC(=O)CCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN1CCN(CC(=O)O)CC1
Temperature: 70 °C
Yield: 70 %

Procedure:
165 g of methyl 2-chloroacetate are dropped into a solution of 152 g of N-methylpiperazine and 212 ml of triethylamine in 1.5 l of toluene, with stirring and under inert gas atmosphere; then the reaction mixture is heated to 70° C. for 4 hours. After that, the reaction mixture is cooled to room temperature, the resulting precipitate is filtered and washed on the filter with 100 ml of toluene. The resulting organic solution is extracted with water (5×200 ml) and the combined organic extracts are refluxed for about 20 hours, then water is distilled off under reduced pressure. The residue is crystallized from isopropanol, to obtain 168 g of 2-(N-methylpiperazino) acetic acid, m.p. 160°-161° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[NH:25]1[CH:29]=[CH:28][N:27]=[N:26]1>>[N:25]1([CH2:2][C:3]2[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[CH:11]=3)=[O:8])=[CH:5][CH:4]=2)[CH:29]=[CH:28][N:27]=[N:26]1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)cc1
Reactant: c1c[nH]nn1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cn2ccnn2)cc1

Procedure:
88 mg of 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was coupled to 40 μL of 1H-1,2,3-triazole via Procedure P. The reaction was evaporated to dryness and purified by reverse phase HPLC to yield 4-((1H-1,2,3-triazol-1-yl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 390.1 (M)+.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C:16]2[O:15][CH:14]=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.[O:17]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]1>O1CCCC1>[CH3:6][O:7][C:8]1[C:16]2[O:15][C:14]([C:19]3([OH:22])[CH2:20][CH2:21][O:17][CH2:18]3)=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCOC1
Reactant: COc1cccc2ccoc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc2cc(C3(O)CCOC3)oc12
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 27 %

Procedure:
Methyl sulfoxide (1.16 ml) was added dropwise to a stirred solution of oxalyl chloride (0.71 ml) in dry dichloromethane (15 ml) at −60° C. under an inert atmosphere. After stirring at this temperature for 30 minutes a solution of 3-hydroxytetrahydrofuran (0.55 ml) in dry dichloromethane was added carefully. After a further 30 minutes triethylaamine was added dropwise and the reaction allowed to warm to room temperature. The reaction was poured onto water (40 ml) and extracted with dichloromethane (30 ml). The organic phase was washed with water (50 ml), brine (2×50 ml) and saturated aqueous sodium hydrogen carbonate solution (2×50 ml). After drying over magnesium sulphate the solvent was removed in vacuo to afford tetrahydro-furan-3-one as a yellow gum (0.19 g). n-Butyllithium (0.72 ml, 1.6M in hexanes) was added dropwise to a stirred solution of 7-methoxybenzofuran (0.15 g) in dry tetrahydrofuran (5 ml) at −78° C. under a dry nitrogen atmosphere. After stirring for 20 minutes a solution of tetrahydrofuran-3-one (90 mg) in dry tetrahydrofuran (2 ml) was added carefully. After stirring for a further 15 minutes at −78° C. the reaction was allowed to warm to room temperature. The reaction was carefully quenched with water and the solvent removed in vacuo. The residue was partitioned between ethyl acetate (2×15 ml ) and water (15 ml). The combined organic extracts were dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 50% ethyl acetate in hexane to give the title compound as an orange gum (64 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6](=[O:7])[C:5]2=[CH:15][CH:16]=1.O>CO.[BH4-].[K+]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:15][CH:16]=1)[C:6](=[O:7])[N:8]([CH2:11][CH:12]([CH3:13])[CH3:14])[CH:9]2[OH:10]
Reactant: CC(C)CN1C(=O)c2ccc(Cl)cc2C1=O
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)CN1C(=O)c2ccc(Cl)cc2C1O
Temperature: 20 °C
Reaction time: 20 h

Procedure:
5-Chloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-chloro-3-hydroxy-2isobutyl-2,3-dihydroinsoindol-1-one are prepared as described in Example 1, starting with 12 g of 4-chloro-N-isobutylphthalimide in 100 cm3 of methanol and 3 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours and is then cooled to a temperature in the region of 0° C. and 100 cm3 of distilled water are added dropwise. The methanol is then partially evaporated off under reduced pressure (2 kPa) at a temperature in the region of 40° C. The aqueous phase is extracted twice with 150 cm3 of ethyl acetate. The organic extracts are combined, washed with 50 cm3 of brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 12 g of 5-chloro-3-hydroxy-2-isobutyl-2,3-dihydroinsoindol-1-one and 6-chloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a white powder. (Rf=0.15, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([CH2:8][C:9]([O:11]CC)=O)=O.[NH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[NH2:20]>C(O)C>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:19]1[C:9]([OH:11])=[CH:8][C:6]([C:5]2[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=2)=[N:20]1
Reactant: CCOC(=O)CC(=O)c1cccc(C(F)(F)F)c1
Reactant: NNc1ccccn1
Solvent: CCO
Product: Oc1cc(-c2cccc(C(F)(F)F)c2)nn1-c1ccccn1

Procedure:
Ethyl 3-trifluoromethylbenzoylacetate (10 mmol, manufactured by Aldrich) and ethanol (10 mL) were charged in a 100 mL round-bottom flask to which a solution of 2-hydrazinopyridine (10 mmol, manufactured by Aldrich) in ethanol (10 mL) was then added.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1([S:20]([NH2:23])(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:13]=[C:11]([NH:23][S:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:22])=[O:21])[CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.9 %

Procedure:
3-(Tert-butoxycarbonylamino)propanoic acid (4 g, 21.2 mmol, 1.0 equiv) was dissolved in DCM (100 mL). Then phenylsulfonamide (15.1 mmol, 0.7 equiv), EDCI (3.45 g, 18.2 mmol, 0.85 equiv) and DMAP (0.37 g, 3 mmol, 0.15 equiv) were added to the mixture and stirred for 2 h at room temperature. The reaction mixture was cooled down to 0° C., ice water (100 mL) was added. The mixture was stirred for 15 min, separated and the water layer was extracted twice with dichloromethane. The combined organic layer was washed by 5% HCl, brine, dried over Na2SO4, concentrated to give tert-butyl 3-oxo-3-(phenylsulfonamido)propylcarbamate 5.3 g, gray oil, 100%. EDI-MS: 329.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ: 9.52˜9.43 (brs, 1H), 8.02˜7.96 (m, 2H), 7.61˜7.55 (m, 1H), 7.50-7.45 (m, 2H), 5.02˜4.93 (m, 1H), 3.30˜3.24 (m, 2H), 2.48˜2.41 (m, 2H), 1.34 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[OH:13])=[CH:6][CH:5]=1.[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]([C@@H:39]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH2:40]Br)=[C:32]2[C:37]=1[NH:36][C:35](=[O:38])[CH:34]=[CH:33]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CS(C)=O>[OH:13][C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:1][CH2:40][C@@H:39]([C:31]2[CH:30]=[CH:29][C:28]([O:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:37]3[C:32]=2[CH:33]=[CH:34][C:35](=[O:38])[NH:36]3)[O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: NCCc1ccc(NC[C@@H](O)c2ccccc2)cc1
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1ccc(NC[C@@H](O)c2ccccc2)cc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 120 °C

Procedure:
Under nitrogen, (S)-2-[4-(2-aminoethyl)-phenylamino]-1-phenylethanol (1.7 g, 6.6 mmol) and 8-benzyloxy-5-[(R)-2-bromo-1-(tert-butyldimethylsilanyloxy)ethyl]-1H-quinolin-2-one (1.5 g, 3.1 mmol) were treated with dimethyl sulfoxide (4.0 mL) and heated to 120° C. for 40 minutes. The mixture was cooled slowly to room temperature and partitioned between water and ethyl acetate (after removal of some insoluble gummy residue by decantation). The organics were washed with 0.9 M sodium acetate/acetic acid, saturated sodium hydrogen carbonate and saturated sodium chloride, dried over sodium sulfate and evaporated to dryness. The title intermediate was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1.[C:14]([Cu])#[N:15].C(OCC)(=O)C>CN(C=O)C>[F:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([O:12][CH3:13])[C:5]=1[N+:9]([O-:11])=[O:10])[C:14]#[N:15]
Reactant: COc1cc(Br)cc(F)c1[N+](=O)[O-]
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C#N)cc(F)c1[N+](=O)[O-]
Temperature: 160 °C

Procedure:
A mixture of 5-bromo-1-fluoro-3-methoxy-2-nitrobenzene (1.5 g, 6 mmol), and CuCN (698 mg, 7.8 mmol) in 10 mL of DMF was heated in a sealed tube at 160° C. overnight. It was then cooled down, diluted to ethyl acetate, washed by brine and water. The organic extract was dried and concentrated to a red solid (1 g, 85%) which was used for next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.01 (s, 3H) 7.14 (s, 1H) 7.17 (d, J=8 Hz, 1H).
Reaction SMILES: BrN1C(=[O:7])CCC1=O.C[C:10]1[C:15]2[O:16]C3C(=NC=2[C:13]([C:63]([NH:65][C@@H]2C(=O)N[C@H](C(C)C)C(=O)N4[C@@H](CCC4)C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]2C)=O)=[CH:12][CH:11]=1)C(C(N[C@@H]1C(=O)N[C@H](C(C)C)C(=O)N2[C@@H](CCC2)C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]1C)=O)=C(N)C(=O)C=3C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC1C=CC=CC=1>[CH2:12]([CH2:13][CH2:63][NH2:65])[CH2:11][CH2:10][C:15]([OH:7])=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c2oc3c(C)ccc(C(=O)N[C@@H]4C(=O)N[C@H](C(C)C)C(=O)N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)c3nc-2c(C(=O)N[C@@H]2C(=O)N[C@H](C(C)C)C(=O)N3CCC[C@H]3C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]2C)c(N)c1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: NCCCCCC(=O)O
Temperature: 80 °C

Procedure:
Bromination with N-bromosuccinimide (NBS) is accomplished by adding 2.24 mmoles of actinomycin D in chlorobenzene to 2 mmoles of NBS and a trace of dibenzoyl peroxide. The mixture is heated to 80° C. and allowed to react for 6 hours. The yield of AMD--CH2Br is 70-80%. The brominated derivative is then reacted further with aminocaprioic acid to yield an AMD-aminocaproic acid complex (AMD--CH2NH (CH2)5COOH).
Reaction SMILES: [C:1]([C:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C>[CH3:2][CH:1]([C:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1)[OH:3]
Reactant: CC(=O)C1=CCCCCCCCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)C1=CCCCCCCCCCC1

Procedure:
30 g of the 1-acetyl-1-cyclododecene obtained as described in Example 2 are dissolved in 100 ml of ethanol and 3 g of sodium borohydride are added in portions. The reaction temperature is kept at 30° C. by cooling. After a further hour of reaction time at room temperature, the alcohol is distilled off under reduced pressure at 50° C. and the residue is hydrolyzed with ice-cold 2 N sulfuric acid. The methyl-1-cyclododecen-1-yl-carbinol obtained is isolated by extraction with ether, and distillation. Boiling point=98°-100° C./0.01 mm Hg, nD25 =1.5014; 29 g yield (95% of theory)).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl:10][S:11](O)(=[O:13])=[O:12]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:11]([Cl:10])(=[O:13])=[O:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCO2
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1ccc2c(c1)CCO2
Yield: 30.2 %

Procedure:
2,3-dihydrobenzofuran (6.0 g, 49.94 mmol) is added over 20 minutes to chlorosulfonic acid (29.09 g, 249.69 mmol) at -20° C. The reaction mixture is quenched by addition of ice followed by water (20 mL). The mixture is then extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (30% ethyl acetate/hexane) to give 2,3-dihydrobenzofuran-5-sulfonyl chloride (3.3 g).
Reaction SMILES: [C-:1]#[N:2].[K+].Cl.CN(C)[CH2:7][CH:8]([CH3:24])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20](=[O:23])[NH:21][N:22]=2)=[CH:13][CH:12]=1)=[O:10].C(O)(=O)C>O>[C:1]([CH2:7][CH:8]([CH3:24])[C:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[CH:19][C:20](=[O:23])[NH:21][N:22]=2)=[CH:15][CH:16]=1)=[O:10])#[N:2]
Reactant: CC(CN(C)C)C(=O)c1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(CC#N)C(=O)c1ccc(-c2ccc(=O)[nH]n2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
Potassium cyanide (0.32 g) was added to a cooled (5° C.) solution of 6-[4-(3-dimethylamino-2-methylpropionyl)phenyl]pyridazin-3(2H)-one hydrochloride (1.28 g) and acetic acid (0.25 ml) in water (30 ml). The solution was stirred for 2 hours at less than 23° C., then cooled and a further amount of potassium cyanide (0.32 g) was added. After stirring for one hour the temperature was raised to 50° C. and the reaction mixture was stirred for 2 hours to afford 6-[4-(3-cyano-2-methylpropionyl)phenyl]pyridazin-3(2H)-one (0.61 g), m.p. 196°-201° C. (dec), ν(C=N) 2240 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:7]([C:9]3[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=3[C:11](/[N:13]=[C:14](/[N:16](C)C)\[CH3:15])=O)=[N:8][C:4]=2[CH:3]=1.[NH2:29]N>C(O)(=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:7]([C:9]3[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=3[C:11]3[N:13]=[C:14]([CH3:15])[NH:16][N:29]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: NN
Reactant: C/C(=N\C(=O)c1ccccc1-c1nc2cc(Br)ccc2n1C(C)(C)C)N(C)C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a round bottom flask is added 2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-N-[1-dimethylamino-eth-(E)-ylidene]-benzamide (237 mg, 0.537 mmol) in glacial acetic acid (3 mL), followed by the addition of hydrazine (35% wt solution in water) (2 mL). The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with EtOAc, is washed with sat. NaHCO3, brine, dried under anhy. Na2SO4, filtered and concentrated. The residue is loaded to a silica gel column. The column is eluted with 0-3% 2M NH3 in MeOH/CH2Cl2. The product fractions are collected and concentrated to afford 5-bromo-1-tert-butyl-2-[2-(5-methyl-1H-1,2,4-triazol-3-yl)-phenyl]-1H-benzimidazole (78 mg, 35%) as a light brown solid. LCMS (ESMS): m/z 410.68, 412.71 (M++1)
Reaction SMILES: [NH2:1][C:2]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:38])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH3:13])[CH:9]=2)[N:4]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:3]1=[O:31].[C:39](Cl)(=[O:41])[CH3:40]>>[C:39]([NH:1][C:2]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:38])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH3:13])[CH:9]=2)[N:4]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:25])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C:3]1=[O:31])(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: CCOc1ccc2c(c1)C(N)(c1ccccc1Cl)C(=O)N2S(=O)(=O)c1ccc(NC(=O)N(CC)CC)cc1
Product: CCOc1ccc2c(c1)C(NC(C)=O)(c1ccccc1Cl)C(=O)N2S(=O)(=O)c1ccc(NC(=O)N(CC)CC)cc1

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 2 from the compound obtained in EXAMPLE 87 and acetyl chloride. Crystallization from a DCM/iso ether mixture gives the expected product, which crystallizes with 0.25 mol of iso ether.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1C(OC(C)(C)C)=O.[ClH:16]>O1CCOCC1>[ClH:16].[NH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@@H:3]1[CH2:2][OH:1]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1CO
Agent: Cl
Solvent: C1COCCO1
Product: OC[C@H]1CCCCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.4 %

Procedure:
A mixture of (R)-tert-butyl 2-(hydroxymethyl)piperidine-1-carboxylate (840 mg, 3.9 mmol) in 1,4-dioxane (15 mL) was treated with hydrogen chloride (4.0N solution in dioxane, 9.8 mL, 39 mmol), and stirred at ambient temperature for 3 hours. The solvent was evaporated in vacuo to afford the title compound as a white solid (594 mg). 1H NMR (400 MHz, d6-DMSO) δ 8.75 (s, 1H), 4.72 (t, J=5.3, 1H), 3.35 (m, 1H), 3.28-3.15 (m, 3H), 2.72 (m, 1H), 2.59-2.52 (m, 1H), 1.88-1.72 (m, 2H), 1.72-1.53 (m, 2H), 1.16 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:6][N:5]=[C:4]([CH:15]=O)[CH:3]=1.[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@@:21](/[N:23]=[CH:15]/[C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([O:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:6][N:5]=1)=[O:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[S@](N)=O
Reactant: Cc1cc(C=O)ncc1OCCC(F)(F)F
Product: Cc1cc(/C=N/[S@@](=O)C(C)(C)C)ncc1OCCC(F)(F)F
Yield: 65 %

Procedure:
The title compound is prepared in 65% yield (1.67 g, white solid) from 4-methyl-5-(3,3,3-trifluoropropoxy)picolinaldehyde (1.79 g, 7.68 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (1.40 g, 11.5 mmol) in a similar manner to Step-6 of Amine-49.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:31])=[C:9]([CH3:30])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:16]=[C:17](/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:19][CH:20]=3)[C:11]=2[C:28]=1[CH3:29])=[O:5].C(OCC)(=O)C>[Pd].C(O)C>[CH3:32][C:2]([CH3:1])([CH3:33])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:31])=[C:9]([CH3:30])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:16]=[C:17]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:19][CH:20]=3)[C:11]=2[C:28]=1[CH3:29])=[O:5]
Reactant: CCOC(=O)/C=C/c1cccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)c1
Yield: 81.1 %

Procedure:
A mixed solution of ethyl(2E)-3-(3-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)acrylate (400 mg, 0.89 mmol) obtained in Example 177 and 10% palladium on carbon (water content: 50%, 40 mg) in ethanol (3 mL)-ethyl acetate (5 mL) was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure to obtain 326 mg (yield: 81%) of the title compound. Melting point: 136-138° C. (ethyl acetate-hexane).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[N:2]1.CO[CH:21]1[CH2:25][CH2:24][CH:23](OC)O1.O>C(O)(=O)C>[N:18]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2/[CH:11]=[CH:10]/[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)[CH:21]=[CH:25][CH:24]=[CH:23]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Solvent: O
Solvent: CC(=O)O
Product: C(=C/c1n[nH]c2ccccc12)\c1ccccc1-n1cccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
Compound 2 (0.060 g, 0.25 mmol) was dissolved in acetic acid (1.0 mL) and the solution was added with 2,5-dimethoxytetrahydrofuran (99 μL, 0.77 mmol), followed by stirring at room temperature for 2 hours. Then, to the reaction mixture, water was added and the precipitated solid was filtered. The solid was recrystallized from ethanol to obtain Compound 162 (14 mg, 20%).