Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(NC2CCCCC2)CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:37]([O:44][C:45](=[O:48])[CH2:46][NH2:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)(Cl)Cl>[CH2:37]([O:44][C:45](=[O:48])[CH2:46][NH:47][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Yield: 95.7 %

Procedure:
In 80 ml of chloroform were dissolved 14.8 g (42 mmol) of t-butyloxycarbonylglycine-dicyclohexylamine and 14.0 g (41.5 mmol) of glycine benzyl ester p-toluenesulfonic acid salt. To this solution, 70 ml of a chloroform solution containing 8.75 g (45.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC) were added at -5° C. with stirring. The resulting mixture was stirred for 24 hours. The resulting chloroform solution was successively washed twice with a 10% by weight aqueous citric acid solution, then twice with water, then twice with a 4% by weight aqueous sodium hydrogen carbonate solution and finally twice with water. Thereafter, the organic phase was dried over anhydrous sodium sulfate. The solvent was then completely removed in vacuo to obtain a white oily material. This was crystallized from hexane to obtain 12.8 g (yield: 96%) of t-butyloxycarbonyl-glycylglycine benzyl ester as a white solid. In 10 ml of ethyl acetate were dissolved 8.0 g (24.8 mmol) of t-butyl oxycarbonyl-glycylglycine benzyl ester, to which 120 ml of 4N HCl/ethyl acetate were added. The mixture was stirred for 4 hours and then the solvent was removed in vacuo to obtain white precipitates. The precipitates were washed well with diethyl ether to obtain 6.4 g (yield: 100%) of glycylglycine benzyl ester hydrochloride as a white solid having the following physical properties:
Reaction SMILES: O=[C:2]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:14][CH2:15][C:16]([OH:18])=[O:17].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:3]12[CH2:14][CH2:15][C:16](=[O:17])[O:18][C:2]=1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2
Reactant: O=C(O)CCC1CCCCCCCCCCC1=O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C1CCC2=C(CCCCCCCCCC2)O1

Procedure:
One part of β-(2-oxocyclododecyl)propionic acid, 1 part of acetic anhydride, 10 parts of glacial acetic acid, and 0.5 part of Amberlyst 15 were allowed to react at 50° C for 4 hours and the reaction solution was withdrawn and analyzed by gas chromatography to find that β-(2-oxocyclododecyl)propionic acid was not present and 13-oxabicyclo(10.4.0)hexadec-1(12)-en-14-one was produced in 99% selectivity.
Reaction SMILES: CO[C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:39]2[C:40]([C:45]3[CH:50]=CC=C(F)C=3)=[N:41][O:42][C:43]=2C)=NC=1.NC1CCOCC1>>[C:21]1([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:41][CH:40]4[CH2:45][CH2:50][O:42][CH2:43][CH2:39]4)=[O:27])=[CH:5][N:6]=3)=[C:16]([C:17]([F:19])([F:20])[F:18])[O:15][N:14]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Agent: NC1CCOCC1
Product: O=C(NC1CCOCC1)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Yield: 94 %

Procedure:
As described for example 90, 6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (100 mg, 0.26 mmol), instead of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester was converted, using 4-aminotetrahydropyran instead of cyclopropylmethylamine, to the title compound (111 mg, 94%) which was obtained as a white solid. MS: m/e=448.3 [M+H]+.
Reaction SMILES: [C:1]([C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.O1CCOCC1.[Pd]>[C:1]([C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:25]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C=Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)CCc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Temperature: 25 °C
Reaction time: 10.5 h

Procedure:
The compound obtained in Example 31 is dissolved in a methanol/dioxane mixture and then a catalytic amount of palladium-on-carbon is added. The reaction is stirred at ambient temperature under a hydrogen atmosphere for from 6 to 15 hours. The carbon is then filtered off and the solvents are removed by evaporation in vacuo. The resulting residue is recrystallised from methanol to yield the title product.
Reaction SMILES: ClC1C=CC(OCC2CCNCC2C2C=CC(Cl)=CC=2)=NC=1.Cl.C([N:31]1[CH2:36][CH2:35][C@@H:34]([C@@H:37]([O:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][N:41]=2)[CH3:38])[C@H:33]([C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=2)[CH2:32]1)C1C=CC=CC=1>>[Cl:46][C:43]1[CH:44]=[CH:45][C:40]([O:39][C@H:37]([C@@H:34]2[CH2:35][CH2:36][NH:31][CH2:32][C@H:33]2[C:47]2[CH:48]=[CH:49][C:50]([Cl:53])=[CH:51][CH:52]=2)[CH3:38])=[N:41][CH:42]=1
Reactant: C[C@H](Oc1ccc(Cl)cn1)[C@@H]1CCN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Agent: Cl
Agent: Clc1ccc(C2CNCCC2COc2ccc(Cl)cn2)cc1
Product: C[C@H](Oc1ccc(Cl)cn1)[C@@H]1CCNC[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of 5-chloro-2-[(3RS, 4RS)-3-(4-chloro-phenyl)-piperidin-4-ylmethoxy]-pyridine; hydrochloride (example 1, step h) the title compound was prepared from 2-{(S)-1-[(3R,4R)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethoxy}-5-chloro-pyridine as light yellow viscous oil. MS (m/e): 351.2 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]([NH:18]C(=O)C)([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.[OH-].[Na+].[C:25]1([S:31]([OH:34])(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[C:25]1([S:31]([OH:34])(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]([NH2:18])([CH3:16])[CH3:17])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(C(C)(C)NC(C)=O)cn2)cc1
Agent: Cl
Agent: O=S(=O)(O)c1ccccc1
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2ccc(C(C)(C)N)cn2)cc1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
The product of Step C, 1-C, (23.34 g, 82 mmol) was suspended in H2O (66 mL) and cone. HCl (58.1 mL, 708 mmol). The reaction mixture was heated at 100° C. for 24 h. The reaction mixture was cooled to rt and partitioned with MTBE. The organic layer was discarded. The aqueous layer was treated with aq. 5.0 M NaOH (160 mL, 800 mmol) and extracted with EtOAc (2×˜700 mL). The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to about ¼ of the original volume. Benzenesulfonic acid (12.98 g, 82 mmol) was added as a solid and the mixture was agitated and allowed to stand at rt for 10 min. The solids were isolated by vacuum filtration, rinsed with hexanes and dried under high vacuum. HPLC/MS: 243.0 (M+1); Rt=1.49 min.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:29][Si](C)(C)C>CC(CC)=O>[ClH:29].[CH3:28][N:2]([CH3:1])[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4][CH2:5][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(=CC(=O)NCCc2ccc(F)cc2)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
2-(4-Dimethylamino-4-phenylcyclohexylidene)-N-[2-(4-fluorophenyl)ethyl]acetamide (252 mg, 0.66 mmol) was dissolved in ethyl methyl ketone (5 ml), and chlorotrimethylsilane (0.126 ml, 1.0 mmol) was added. After 2 h the hydrochloride was isolated as a colourless solid with an m.p. of 157-160° C. and a yield of 74% (203 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:15]=[C:16]([C:17]3[S:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(=O)CC1)=O)(C)(C)C.C(N)C1C=CC=CC=1.CC1SC(C=C[N+]([O-])=O)=CC=1>C1(C)C=CC=CC=1>[CH2:23]([N:14]1[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=2[C:16]([C:17]2[S:18][C:19]([CH3:22])=[CH:20][CH:21]=2)=[CH:15]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1ccc(-c2cn(Cc3ccccc3)c3c2CN(C(=O)OC(C)(C)C)CC3)s1
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(C=C[N+](=O)[O-])s1
Solvent: NCc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Benzyl-3-(5-methyl-thiophen-2-yl)-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester. A mixture of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.54 g) and 300 μL of benzylamine in toluene (10 mL) was heated at reflux for 6 h using a Dean-Stark apparatus. The solution was cooled to RT and 0.47 g of 2-methyl-5-(2-nitro-vinyl)-thiophene was added. The mixture was stirred for 16 h at RT and then was concentrated in vacuo. The residue was chromatographed on SiO2 (1 to 30% EtOAc/hexanes) to afford 281.9 mg of the desired compound. TLC (SiO2, 33% EtOAc/hexanes): Rf=0.54.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[C:13]2=[CH:14][CH2:15][CH2:16][CH2:17][N:12]2[C:11]1=[O:20].[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C(#N)C>[CH:21]1([O:9][C:5]2[C:6]([Cl:8])=[CH:7][C:2]([Cl:1])=[C:3]([N:10]3[C:18](=[O:19])[C:13]4=[CH:14][CH2:15][CH2:16][CH2:17][N:12]4[C:11]3=[O:20])[CH:4]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1C2=CCCCN2C(=O)N1c1cc(O)c(Cl)cc1Cl
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Product: O=C1C2=CCCCN2C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1Cl
Yield: 60.3 %

Procedure:
An acetonitrile (10 mL) solution of 2-(2,4-dichloro-5-hydroxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.50 g, 1.61 mmol), cyclopentylbromide (0.19 mL, 1.77 mmol) and potassium carbonate (0.22 g, 1.61 mmol) was stirred for 2 hours under reflux. A saturated ammonium chloride solution (20 mL) was added to the resulting mixture and the organic layer was separated. The aqueous layer was extracted with diethyl ether (10 mL×2 times), and the organic layer combined was washed with a saturated sodium chloride solution (40 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane=1/4-1/2) to obtain a white solid of 2-(5-cyclopentyloxy-2,4-dichlorophenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.37 g, yield:60.7%).
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[N:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[C:7]([CH3:23])=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>N1C=CC=CC=1>[CH2:39]([O:38][C:36]([NH:1][C:2]1[N:34]=[C:5]2[N:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[CH:25]=3)[C:7]([CH3:23])=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1)=[O:37])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(N)nn2C1c1ccc(C#N)cc1
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(NC(=O)OCc3ccccc3)nn2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, ethyl 2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (130 mg, 278 μmol) was dissolved in abs. pyridine (3.6 ml). At 0° C., benzyl chloroformate (379 mg, 2.2 mmol, 8 eq.) was added in four portions and the mixture was stirred for 12 h with warming to RT. Once HPLC analysis showed substantial conversion, the reaction mixture was concentrated under reduced pressure, and the residue was taken up in acetonitrile, acidified with 1 N hydrochloric acid and then purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (146.3 mg, 87% of theory).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][CH:29]=1>>[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:14]2[C:15]3[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=3[C:12]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)=[N:13]2)=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1
Yield: 25.3 %

Procedure:
The title compound (0.03 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.3 mmol) using 4-bromomethyl-benzoic acid methyl ester (0.5 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C22H22ClN3O2, 395.14; found, m/z 396.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.63-7.19 (m, 7H), 7.03-7.02 (m, 2H), 5.27 (s, 2H), 3.15 (s, 2H), 2.79-2.67 (m, 8H).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[S:20][C:21](Cl)=[C:22]([Cl:25])[C:23]=2[Cl:24])[N:16]([CH3:27])[N:15]=1.[Br:28]Br>C1COCC1.O>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[S:20][C:21]([Br:28])=[C:22]([Cl:25])[C:23]=2[Cl:24])[N:16]([CH3:27])[N:15]=1
Reactant: BrBr
Reactant: Cn1nc(-c2c(Cl)cccc2Cl)nc1-c1sc(Cl)c(Cl)c1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(-c2c(Cl)cccc2Cl)nc1-c1sc(Br)c(Cl)c1Cl
Reaction time: 1 h
Yield: 17.2 %

Procedure:
n-Butyllithium (2.5 mmol) was slowly added to a solution of 3-(2,6-dichlorophenyl)-5-(3,4,5-trichlorothien-2-yl)-1-methyl[1,2,4]triazole (325 mg, 1.0 mmol) in THF at −78° C., and the mixture was stirred one hour. Bromine (3.0 mmol) was added and the reaction stirred two hours, then diluted with water, extracted with ether, washed with brine, and dried over magnesium sulfate. The product was concentrated to 620 mg of dark oil. This was chromatographed (SiO2, 10% EtOAc-Hex) to give 79 mg of the title product as a pink solid. MP 197-199° C.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][N:6]2[CH:11]=[CH:10][C:9](O)=[C:8]([C:13]#[N:14])[C:7]2=[O:15])[CH2:3][CH2:2]1.O(Br)[Br:17].[P+3]>CN(C=O)C>[Br:17][C:9]1[CH:10]=[CH:11][N:6]([CH2:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:7](=[O:15])[C:8]=1[C:13]#[N:14]
Reactant: BrOBr
Reactant: N#Cc1c(O)ccn(CCC2CC2)c1=O
Agent: [P+3]
Solvent: CN(C)C=O
Product: N#Cc1c(Br)ccn(CCC2CC2)c1=O
Temperature: 110 °C
Yield: 89.2 %

Procedure:
To a solution of intermediate 6 (6.0 g, 29.37 mmol) in DMF (150 ml) was added phosphorus(III) oxybromide (16.84 g, 58.75 mmol) and the mixture was heated at 110° C. for 3 hours. After cooling in an ice bath the solution was partitioned between water and EtOAc. After three extractions with EtOAc the combined organic fractions were washed with brine, dried over Na2SO4 and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 9 (7.0 g, 89%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[N:5]=[N:4][C:3]=1[NH2:24].[Cl:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[S:36](Cl)(=[O:38])=[O:37]>>[Cl:25][C:26]1[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[CH:28][C:27]=1[S:36]([NH:24][C:3]1[N:4]=[N:5][C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)(=[O:16])=[O:17])=[CH:11][CH:10]=2)=[CH:7][C:2]=1[CH3:1])(=[O:38])=[O:37]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: Cc1cc(Sc2ccc(S(=O)(=O)N3CCCCC3)cc2)nnc1N
Product: Cc1cc(Sc2ccc(S(=O)(=O)N3CCCCC3)cc2)nnc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1Cl

Procedure:
Can be prepared from 4-methyl-6-[4-(piperidine-1-sulfonyl) -phenylsulfanyl]-pyridazin-3-ylamine and 2-chloro-4-trifluoromethylbenzenesulfonyl chloride. 1H NMR (CDCl3) 8.30 (1H, d) 7.75 (2H, m) 7.70(1H, s) 7.6(3H, m) 7.05(1H, s) 3.0 (4H, m) 2.1 (3H, s) 1.6(4H, m) 1.40(2H, m) LCMS Polarity/Scan type: Negative Q1 Scan. M.wt. 605 (—H), 607 (—H). Retention time 7.39 minutes. HPLC MS8 Retention time 5.36 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]1([O:17][CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:14]2[CH:15]=[CH:16][C:11]([O:17][CH3:18])=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(Br)cc2)cc1
Yield: 100.9 %

Procedure:
To a cooled (ice bath, 5° C.) mixture of 4-bromobenzoyl chloride (25.0 g, 0.114 mol) and anisole (15.5 g, 0.143 mol, 1.25 eq) in CH2Cl2 (500 mL) was added AlCl3 (19.0 g, 0.143 mol, 1.25 eq) portion-wise over a period of 20 minutes with stirring under a nitrogen atmosphere. The resulting reaction mixture was allowed to stir between 5° C. and 20° C. for 3 h. The reaction mixture was poured slowly into 20% aqueous HCl (500 mL), stirred for 15 min, and layers were separated. The aqueous layer was further extracted with CH2Cl2 (3×250 mL). The combined organic layer washed with water (200 mL), brine (200 mL) dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 33.48 g (100%) of compound 1 as a white solid. 1H NMR (300 MHz, CDCl3): δ 3.91 (s, 3 H), 6.99 (d, J=8.7 Hz, 2 H), 7.65 (s, 4 H), 7.82 (d, J=8.7 Hz, 2 H).
Reaction SMILES: C(OC([N:11]1[CH2:16][C@@H:15]([OH:17])[C@H:14]([OH:18])[C@@H:13]([OH:19])[C@H:12]1[C:20]([OH:22])=[O:21])=O)C1C=CC=CC=1.[H][H].O>CO.[Pd].O.CO>[OH:19][C@@H:13]1[C@@H:14]([OH:18])[C@H:15]([OH:17])[CH2:16][NH:11][C@@H:12]1[C:20]([OH:22])=[O:21]
Reactant: O=C(O)[C@@H]1[C@H](O)[C@@H](O)[C@H](O)CN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: O=C(O)[C@H]1NC[C@@H](O)[C@H](O)[C@H]1O
Yield: 72 %

Procedure:
To the solution of 2S,3S,4S,5R)-N-Benzyloxycarbonyl-3,4,5-trihydroxypiperidine-2-carboxylic acid (Example 40) (41.7 mg, 0.14 mmol) in MeOH (4 mL) was added Pd/C catalyst (5% wt, 60 mg). The reaction mixture was stirred under the atmosphere of hydrogen gas for 6 h. Catalyst was filtered through celite pad and volatiles were removed. Pure product was isolated by flash chromatography on silicagel using H2O-MeOH (2:98) as an eluent (16.7 mg, 72% yield). [α]D=−8.6° (C=0.21, H2O). 1H NMR (360 MHz, D2O+ two drops of MeOD-d4) δ 4.09-4.00 (m, 1H), 3.89-3.75 (m, 3H), 3.23 (dd, J=13.1, 1.9 Hz, 1H), 3.08 (dd, J=13.1, 3.8 Hz, 1H);
Reaction SMILES: [C:1](/[C:3](=[C:5]1/[C:6]2[CH:35]=[CH:34][CH:33]=[CH:32][C:7]=2[O:8][CH2:9][C:10]2[CH:15]=[C:14]([CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([C:26](O)=[O:27])[C:20]=4[N:19]=[C:18]3[CH2:29][CH2:30][CH3:31])[CH:13]=[CH:12][C:11]/1=2)/[CH3:4])#[N:2].[NH2:36][CH2:37][CH2:38][OH:39].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C=O)C>[OH:39][CH2:38][CH2:37][NH:36][C:26]([C:25]1[C:20]2[N:19]=[C:18]([CH2:29][CH2:30][CH3:31])[N:17]([CH2:16][C:14]3[CH:13]=[CH:12][C:11]4/[C:5](=[C:3](\[C:1]#[N:2])/[CH3:4])/[C:6]5[CH:35]=[CH:34][CH:33]=[CH:32][C:7]=5[O:8][CH2:9][C:10]=4[CH:15]=3)[C:21]=2[CH:22]=[CH:23][CH:24]=1)=[O:27]
Reactant: NCCO
Reactant: CCCc1nc2c(C(=O)O)cccc2n1Cc1ccc2c(c1)COc1ccccc1/C2=C(\C)C#N
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCc1nc2c(C(=O)NCCO)cccc2n1Cc1ccc2c(c1)COc1ccccc1/C2=C(\C)C#N
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.1 %

Procedure:
[step 1] (E)-1-[11-(1-Cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl-2-propylbenzimidazole-4-carboxylic acid (220 mg, 0.48 mmol) obtained in Example 100, step 2 was dissolved in DMF (4.0 mL), 2-aminoethanol (57 μL, 0.95 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (109 mg, 0.57 mmol) and 1-hydroxybenzotriazole (87 mg, 0.57 mmol) were added, and the mixture was stirred at room temperature for 15 hr. Saturated aqueous sodium hydrogen carbonate solution (15 mL) was added to the mixture, and the precipitated solid was collected by filtration. The residue was purified by silica gel column chromatography (chloroform/methanol=99/1 to 95/5) to give (E)-N-(2-hydroxyethyl) 1-[11-(1-cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl-2-propylbenzimidazole-4-carboxamide (241 mg, 99%). [step 2] Using (E)-N-(2-hydroxyethyl) 1-[11-(1-cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl-2-propylbenzimidazole-4-carboxamide (240 mg, 0.47 mmol) obtained in step 1 and in the same manner as in Example 5, the title compound (compound 102) (70 mg, 26%) was obtained.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([CH3:22])([CH3:21])[CH:19]=[O:20])=[CH:16][CH:17]=1
Reactant: CC(C)(CO)c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C=O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
The DMSO (436 mL, 61.4 mmol) was dissolved in 100 mL of DCM and treated with oxalyl chloride (4.02 μL, 46.6 mmol) at −78° C. The solution stirred for 30 minutes at −78° C. before the 2-(4-chlorophenyl)-2-methyl-propan-1-ol (5.67 g, 30.7 mmol) was added dropwise as a solution in 10 mL of DCM. After addition was complete, the solution was stirred for two hours at −78° C., and then treated with triethyl amine (25.7 mL, 184 mmol). The solution was allowed to warm to ambient temperature and stir for three hours. The solution was quenched with the addition of water and partitioned with more DCM. The aqueous was extracted with DCM, and the combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica, hexanes/ethyl acetate gradients) to afford 2-(4-chlorophenyl)-2-methylpropionaldehyde as a yellow oil (5.60 g, 99%). 1H NMR (CDCl3, 400 MHz) δ 9.48 (s, 1H), 7.35 (d, J=8.8 Hz, 2H), 7.21 (d, J=8.8 Hz, 1H), 1.45 (s, 6H).