Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:17]([OH:19])=[O:18])=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12].[CH:20]1(B(O)O)[CH2:22][CH2:21]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>C1(C)C=CC=CC=1.O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH:20]1([C:2]2[CH:3]=[CH:4][C:5]([C:17]([OH:19])=[O:18])=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH2:22][CH2:21]1
Reactant: O=C(O)c1ccc(Br)c(OCC(F)(F)C(F)(F)F)n1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1ccc(C2CC2)c(OCC(F)(F)C(F)(F)F)n1
Temperature: 100 °C
Reaction time: 22 h
Yield: 76.4 %

Procedure:
A mixture of 5-bromo-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid (501 mg, 1.43 mmol), cyclopropylboronic acid (CAN 411235-57-9, 184 mg, 2.15 mmol), palladium diacetate (CAN 3375-31-3, 16.1 mg, 71.6 μmol), tricyclohexylphosphine (CAN 2622-14-2, 8.03 mg, 28.6 μmol) and potassium phosphate (1.06 g, 5.01 mmol) in toluene/water (20/1 v/v, 10.5 mL) was stirred at 100° C. for 22 hours. After cooling the mixture was poured into ice-water (80 mL). 2 M Hydrochloric acid (25 mL) was added and the mixture was extracted with TBME, organic layers were washed twice with water, pooled, dried with Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, ethyl acetate/n-heptane gradient) to give the title compound (340 mg, 76%) as off-white solid; LC-MS (UV peak area, ESI) 96.6%, 310.0513 [M−H−].
Reaction SMILES: [Cl-].[NH4+:2].CC1C=CC(S([O:13][C@@H:14]2[CH2:18]O[C@@H:16]3[C@@H:19](Br)[CH2:20][O:21][C@H:15]23)(=O)=O)=CC=1.N.CO>O.CC(O)C.[Zn]>[NH2:2][CH2:18][C@@H:14]([C@@H:15]1[CH:16]=[CH:19][CH2:20][O:21]1)[OH:13]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@@H]3Br)cc1
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Agent: [Zn]
Solvent: CC(C)O
Solvent: O
Solvent: CO
Product: NC[C@H](O)[C@@H]1C=CCO1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
A solution of ammonium chloride (560 mg, 10.5 mmol) in water (7 mL) was added to a solution of bromotosylate (46) (2.86 g, 7.88 mmol) in propan-2-ol (14 mL) under argon. Zinc dust (560 mg, 8.67 mmol) was then added in portions over 4 minutes then the suspension stirred for 16 hours before filtering through celite in vacuo. The filter cake was washed with diethyl ether (60 mL). Hydrochloric acid (1M, 60 mL) was added to the filtrate then the organic phase separated. The aqueous layer was extracted with diethyl ether (60 mL) then the combined organic phase was washed with brine (60 mL), then dried (MgSO4), filtered and reduced in vacuo. The residue was dissolved in ammonium hydroxide (18 mL) and a solution of ammonia in propan-2-ol (12 mL, 2.0M, 24 mmol) then divided into three equal portions and heated in sealed tubes at 75° C. for 16 hours. The mixtures were combined using methanol then the solvents were removed in vacuo. The residue was azeotroped with diethyl ether (3×10 mL) to obtain (S)-2-amino-1-((S)-2,5-dihydrofuran-2-yl)ethanol which was used without further purification.
Reaction SMILES: COC(=O)NC(C(N1CCCC1C1NC(C2C=CC(C3C=CC(C4NC(C5CCCN5)=NC=4)=CC=3)=CC=2)=CN=1)=O)CCC(F)(F)F.C(OC([N:54]1[CH2:58][CH2:57][CH2:56][CH:55]1[C:59]1[NH:60][C:61]([C:64]2[CH:69]=[CH:68][C:67]([C:70]3[CH:75]=[CH:74][C:73]([C:76]4[NH:77][C:78]([CH:81]5[CH2:85][CH2:84][CH2:83][N:82]5[C:86](=[O:101])[CH:87]([NH:96][C:97]([O:99][CH3:100])=[O:98])[CH2:88][CH2:89][O:90][CH2:91][C:92]([F:95])([F:94])[F:93])=[N:79][CH:80]=4)=[CH:72][CH:71]=3)=[CH:66][CH:65]=2)=[CH:62][N:63]=1)=O)(C)(C)C>>[CH3:100][O:99][C:97](=[O:98])[NH:96][CH:87]([C:86]([N:82]1[CH2:83][CH2:84][CH2:85][CH:81]1[C:78]1[NH:77][C:76]([C:73]2[CH:74]=[CH:75][C:70]([C:67]3[CH:68]=[CH:69][C:64]([C:61]4[NH:60][C:59]([CH:55]5[CH2:56][CH2:57][CH2:58][NH:54]5)=[N:63][CH:62]=4)=[CH:65][CH:66]=3)=[CH:71][CH:72]=2)=[CH:80][N:79]=1)=[O:101])[CH2:88][CH2:89][O:90][CH2:91][C:92]([F:95])([F:93])[F:94]
Reactant: COC(=O)NC(CCOCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Agent: COC(=O)NC(CCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5)[nH]4)cc3)cc2)[nH]1
Product: COC(=O)NC(CCOCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5)[nH]4)cc3)cc2)[nH]1

Procedure:
This compound was made by the same procedure as [4,4,4-Trifluoro-1-(2-{5-[4′-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-butyl]-carbamic acid methyl ester, using 2-{5-[4′-(2-{1-[2-Methoxycarbonylamino-4-(2,2,2-trifluoro-ethoxy)-butyryl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester as the starting material. LCMS-ESI+: calculated for C34H38F3N7O4: 665.29; observed [M+1]+: 666.20.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)c1cc(-c2ccncc2)ccc1Cl
Product: CS(=O)(=O)c1cc(-c2ccncc2)ccc1NCc1ccccc1
Temperature: 160 °C

Procedure:
A suspension of 4-(4-chloro-3-methanesulfonyl-phenyl)-pyridin (5.5 g) in benzylamine (23 ml) was heated to 160° C. for 4 h, concentrated under high vacuum. The residue was quenched with ice/water and extracted with ethyl acetate. The organic layers were washed, dried and concentrated; the residue was chromatographed on silica gel with heptane/ethyl acetate. The compound containing fractions were evaporated, and the residue crystallized from methanol/ether to obtain the desired compound (5.75 g) as an off-white solid. MS (ISP): 339.1 (M+H)+
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([F:42])[CH:36]=1)[CH2:10][O:11][C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])[CH3:13])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[F:42][C:37]1[CH:36]=[C:35]([CH:40]=[CH:39][C:38]=1[CH3:41])[CH2:34][C@@H:30]1[CH2:31][CH2:32][CH2:33][N:29]1[CH2:28][C@@H:9]([OH:8])[CH2:10][O:11][C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])[CH3:13]
Reactant: COC(=O)C(C)(C)Cc1ccccc1[C@@H](C)OC[C@@H](CN1CCC[C@H]1Cc1ccc(C)c(F)c1)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)(C)Cc1ccccc1[C@@H](C)OC[C@H](O)CN1CCC[C@H]1Cc1ccc(C)c(F)c1
Temperature: 25 °C
Yield: 83 %

Procedure:
A solution of methyl 3-{2-[(1R)-1-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-3-[(2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidin-1-yl]propyl}oxy)ethyl]phenyl}-2,2-dimethylpropanoate (308 mg, 0.51 mmol), which had been obtained in Example 179 (179c), in THF (3.1 mL) was added with 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.72 mL, 0.72 mmol), and stirred at room temperature. After stirring for 2 hours, a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.5 mL, 1.50 mmol) was added and further stirred for 48 hours. Upon the completion of the reaction, water (5 mL) was added and the mixture was extracted with ethyl acetate. The solvent was removed under reduced pressure. The residue was purified silica gel chromatography (n-hexane/ethyl acetate=3/7) to give the title compound as a pale yellow oily substance (206 mg, yield 83%).
Reaction SMILES: FC1C=C(F)C=CC=1[OH:9].[F:10][C:11]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:12]=1[O:13][C:14]1[C:15](=[O:31])[O:16][C:17]([CH3:30])([CH3:29])[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1>ClCCl>[CH3:29][C:17]([O:16][C:15](=[O:31])[CH2:14][O:13][C:12]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:11]=1[F:10])([CH3:30])[C:18]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)=[O:9]
Reactant: Oc1ccc(F)cc1F
Reactant: CC1(C)OC(=O)C(Oc2ccc(F)cc2F)=C1c1ccc(S(C)(=O)=O)cc1
Solvent: ClCCl
Product: CC(C)(OC(=O)COc1ccc(F)cc1F)C(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride, 60% dispersion (66 mg, 1.66 mmol), was rinsed with hexane, suspended in 7 mL of DMF and cooled to 0° C. To this suspension was added 2,4-difluorophenol (170 μL, 1.79mmol). After 5 minutes at 0° C., 2-bromoacetic acid 2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one ester (Step 1) (233 mg, 1.79 mmol) was added and the reaction mixture was stirred for 30 minutes. Dichloromethane was added and the mixture was washed with 1N HCl and the organic solvent was evaporated under vacuum. The residue was dissolved in 25% EtOAc/Et2O and washed with 1N NaOH, water (2×) brine and dried over MgSO4. After filtration and evaporation of the solvent under vacuum 470 mg of the title compound was obtained.
Reaction SMILES: C(O[C:4](=[O:42])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[N:13]=[C:14]([CH3:41])[N:15]=[C:16]([NH:17][CH2:18][C@@H:19]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[NH:20][S:21]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:11]=2[CH:10]=[CH:9]1)C.[NH:43]1[CH2:48][CH2:47][CH2:46][N:45]=[C:44]1[NH2:49]>CN(C=O)C>[C:37]([O:36][C:34](=[O:35])[C@@H:19]([NH:20][S:21]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:22])=[O:23])[CH2:18][NH:17][C:16]1[C:11]2[CH:10]=[CH:9][N:8]([CH2:7][CH2:6][CH2:5][C:4](=[O:42])[NH:49][C:44]3[NH:45][CH2:46][CH2:47][CH2:48][N:43]=3)[C:12]=2[N:13]=[C:14]([CH3:41])[N:15]=1)([CH3:38])([CH3:39])[CH3:40]
Reactant: NC1=NCCCN1
Reactant: CCOC(=O)CCCn1ccc2c(NC[C@H](NS(=O)(=O)c3cccc4ccccc34)C(=O)OC(C)(C)C)nc(C)nc21
Solvent: CN(C)C=O
Product: Cc1nc(NC[C@H](NS(=O)(=O)c2cccc3ccccc23)C(=O)OC(C)(C)C)c2ccn(CCCC(=O)NC3=NCCCN3)c2n1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 128 mg (0.215 mmol) of 4-{4-[(2S)-2-tert-butoxycarbonyl-2-(naphthalene-1-sulfonylamino)-ethylamino]-2-methyl-pyrrolo[2,3-d]pyrimidin-7-yl}-butyric acid ethyl ester (example 3b) in 1 ml of DMF was added 105 mg (1.05 mmol) of 1,4,5,6-tetrahydro-pyrimidin-2-ylamine and the reaction mixture was stirred at room temperature for 4.5 hours. The solvent was removed in vacuo and the residue was taken up in DCM and washed with a saturated NaCl solution. The organic phase was dried over MgSO4, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with DCM/MeOH/AcOH/H2O (95:5:0.5:0.5). Yield: 72 mg.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[F:32][C:33]1[C:38]([F:39])=[CH:37][CH:36]=[C:35]([NH:40][CH:41]=[C:42]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[C:43]([O:45][CH2:46][CH3:47])=[O:44])[C:34]=1[O:53][CH2:54][CH:55](O)[CH3:56]>O1CCCC1>[F:39][C:38]1[CH:37]=[CH:36][C:35]2[N:40]([CH:41]=[C:42]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:55]([CH3:56])[CH2:54][O:53][C:34]=2[C:33]=1[F:32]
Reactant: CCOC(=O)C(=CNc1ccc(F)c(F)c1OCC(C)O)C(=O)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(=CN1c2ccc(F)c(F)c2OCC1C)C(=O)OCC

Procedure:
To a solution of 341 mg of triphenylphosphine in 5 ml of anhydrous tetrahydrofuran was added dropwise 226 mg of diethyl azodicarboxylate and the mixture was stirred under cooling with ice for 20 minutes. To this solution was added a solution of 373 mg of the compound obtained in Example 3 in 3 ml of anhydrous tetrahydrofuran, and the mixture was stirred at room temperature overnight.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].Br[CH2:19][C:20]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:24][CH2:23][CH2:22][O:21]1.O>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:19][C:20]3([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[O:21][CH2:22][CH2:23][O:24]3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: BrCC1(c2ccccc2)OCCO1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC2(c3ccccc3)OCCO2)CCN(C)C1
Temperature: 100 °C

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2 g, 10 mmol) was dissolved in 20 mL of DMF. The resulting solution was cooled in an ice-water bath and sodium hydride (840 mg, 4.2 mmol) was added under nitrogen atmosphere. 2-Bromomethyl-2-phenyl[1,3]dioxolane (2.43 g, 10 mmol) was added and the reaction mixture was heated at 100° C. overnight. Water was added and the product was extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-5% MeOH:DCM.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][CH2:9][CH2:10][CH2:11][C@:12]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[OH:13].C(N(CC)CC)C.Cl[C:42]([O:44][CH3:45])=[O:43]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:45][O:44][C:42]([NH:8][CH2:9][CH2:10][CH2:11][C@:12]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[OH:13])=[O:43]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](O)(CCCN)c2cccc(Cl)c2)C1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)NCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
To a 100 mL round bottom flask were added the TFA salt of (R)-tert-butyl 3-((S)-4-amino-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate (0.8164 g, 1.64 mmol, 1.0 equiv), DMAP (0.542 g), CH2Cl2 (40 mL) and triethylamine (6 mL). The mixture was cooled in an ice bath and a solution of methyl chloroformate (0.550 g, 5.82 mmol, 3.5 equiv) in CH2Cl2 (10 mL) was added. The reaction mixture was allowed to slowly warm to rt and stirred overnight. After the solvents were removed in vacuo, the residue was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C18(2) 100A, 250×21.20 mm, 5 micron, 70%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 1.5 min, flow rate 25 mL/min) to give 0.5020 g (69%) of (R)-tert-butyl 3-((S)-4-(methoxycarbonyl-amino)-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate. LC-MS (3 min) tR=1.91 min, m/z 463 (MNa+), 441 (MH+), 343 341; 1H NMR (400 MHz, CDCl3) □ 7.37-7.36 (m, 1H), 7.28-7.17 (m, 3H), 4.90 (br s, 2H), 4.37 (d, J=12.0 Hz, 1H), 3.97 (d, J=12.3 Hz, 1H), 3.64 (s, 3H), 3.16-3.04 (m, 2H), 2.58-2.49 (m, 2H), 1.98-1.86 (m, 2H), 1.76-1.70 (m, 1H), 1.61-1.56 (m, 1H), 1.45 (s, 9H), 1.48-1.13 (m, 5H); 13C NMR (100 MHz, CDCl3) □ 157.60, 155.31, 146.51, 134.31, 129.36, 126.72, 125.96, 123.76, 80.08, 77.65, 52.21, 46.45, 44.91, 44.56, 40.91, 35.97, 28.42, 25.33, 25.25, 24.34.
Reaction SMILES: O=[C:2]1[CH:7]=[CH:6][O:5][CH:4]=[CH:3]1.[F:8][C:9]([F:20])([F:19])[O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][NH2:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl>[F:8][C:9]([F:19])([F:20])[O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][NH:15][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: NCc1cccc(OC(F)(F)F)c1
Reactant: O=c1ccocc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: FC(F)(F)Oc1cccc(CNC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
To a solution of 4-oxo-1H-pyran (200 mg) in chloroform (2 mL), 3-trifluoromethoxybenzylamine (380 mg) was added and the resulting mixture was stirred at room temperature for 30 minutes. Sodium (triacetoxy)borohydride (850 mg) was added and the resulting mixture was stirred for an hour. To the reaction mixture, an aqueous solution of 6 M sodium hydroxide was added and extraction was conducted with ethyl acetate. The solvents were distilled off under reduced pressure and the resulting residue was purified by column chromatography (NH silica gel cartridge; hexane/ethyl acetate=9:1 to 1:9) to give the titled compound (450 mg).
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1.CCN(C(C)C)C(C)C.Cl[CH2:43][CH2:44][S:45](Cl)(=[O:47])=[O:46].C(Cl)Cl.CCOC(C)=O>C(Cl)Cl>[F:32][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([CH:20]3[CH2:21][CH2:22][N:23]([S:45]([CH:44]=[CH2:43])(=[O:47])=[O:46])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(C2CCNCC2)nc(N2CCOCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CS(=O)(=O)N1CCC(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a mixture of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-piperidinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (Example 13) (0.891 mg, 2 mmol) and DIPEA (0.77 g, 6 mmol) in CH2Cl2 (100 mL) was added dropwise 2-chloroethanesulfonyl chloride (0.49 g, 3 mmol) at 0° C. After addition, the reaction mixture was stirred at 0° C. for additional 2 hrs. The reaction mixture was quenched with water (100 mL). The organic layer was washed successively with aqueous HOAc (1%, 100 mL) and aqueous NH3, and dried. Chromatography on silica eluting with CH2Cl2/EtOAc (9:1) gave 0.589 g (55% yield) of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[1-(vinylsulfonyl)-4-piperidinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole: mp (MeOH) 229-232° C.; 1H NMR (CDCl3) δ 7.99 (dd, J=8.4, 0.7 Hz, 1H), 7.54 (t, JHF=53.6 Hz, 1H), 7.39 (t, J=8.3 Hz, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.47 (dd, J=16.6, 9.9 Hz, 1H), 6.27 (d, J=16.6 Hz, 1H), 6.05 (d, J=9.9 Hz, 1H), 4.06 (s, 3H), 4.00-3.97 (m, 4H), 3.89-3.79 (m, 6H), 2.78 (m, 3H), 2.17 (br dd, J=13.6, 3.0 Hz, 2H), 2.01 (ddd, J=25.2, 11.7, 4.1 Hz, 2H); Anal. Calcd. for C23H27F2N7O4S: C, 51.6; H, 5.1; N, 18.3. Found: C, 51.7; H, 5.2; N, 18.25%.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:28][C@H:29]1[NH:34][C@@H:33]([CH3:35])[CH2:32][N:31]([C:36]2[S:37][C:38]3[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=3[N:40]=2)[CH2:30]1>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:34]2[C@H:33]([CH3:35])[CH2:32][N:31]([C:36]3[S:37][C:38]4[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=4[N:40]=3)[CH2:30][C@@H:29]2[CH3:28])[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: C[C@@H]1CN(c2nc3ccccc3s2)C[C@H](C)N1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: C[C@@H]1CN(c2nc3ccccc3s2)C[C@H](C)N1CCCCC1(C(=O)NCC(F)(F)F)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-benzothiazole.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([NH:13][C:14]1[C:15]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][N:23]=2)=[O:21])=[CH:16][S:17][CH:18]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.O>ClCCl.C(OCC)(=O)C>[C:6]([O:10][C:11]([NH:13][C:14]1[C:15]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][O:29][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:24][N:23]=2)=[O:21])=[CH:16][S:17][CH:18]=1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cscc1NC(=O)c1ccc(CO)cn1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cscc1NC(=O)c1ccc(COS(C)(=O)=O)cn1
Reaction time: 2 h
Yield: 91 %

Procedure:
Under ice cooling, methanesulfonyl chloride (71 μL, 0.92 mmol) was added to a solution of N-(4-t-butoxycarbonylaminothiophen-3-yl)-5-hydroxymethylpyridine-2-carboxylic acid amide (Reference Compound No. 3-1, 0.32 g, 0.93 mmol) and triethylamine (0.32 mL, 2.3 mmol) in anhydrous dichloromethane (20 mL), and then the reaction mixture was stirred for 2 hour. Water (0.15 L) and ethyl acetate (0.15 L) were added thereto and the whole was partitioned. The organic layer was washed with brine (0.15 L), dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to give 0.36 g of the title reference compound as a yellow solid. (Yield 91%)
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29]([OH:31])=O)([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:4]=1.CCN=C=NCCCN(C)C.[CH:51]1([S:54]([NH2:57])(=[O:56])=[O:55])[CH2:53][CH2:52]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29]([NH:57][S:54]([CH:51]5[CH2:53][CH2:52]5)(=[O:56])=[O:55])=[O:31])([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:4]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1nc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)cc(-c2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A solution of the acid 13e (150 mg, 0.28 mmol) and EDAC (65 mg, 0.34 mmol) in dry DCM (3 ml) was stirred overnight. Cyclopropane sulphonamide (72.7 mg, 0.6 mmol) and DBU (120 mg, 0.8 mmol) was added and the mixture was stirred overnight at room temperature. 5% Citric acid was added and the mixture was extracted with ethyl acetate. The organic phase was washed two times with 5% citric acid and water, dried with sodium sulphate and evaporated under reduced pressure. Purification by HPLC gave the title compound, (100 mg, 56%), (M+H)+638
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8](=[O:10])[CH3:9].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C>[C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:11]=[N+:12]=[N-:13])(=[O:10])[CH3:9]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OCCCCCCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCCCN=[N+]=[N-]
Temperature: 80 °C

Procedure:
To a 500 mL flask was added 5.0 g (32.8 mmol, 1.0 eq) of 5-chloropentylacetate and dissolved in 100 mL of DMF. Next, 2.6 g (40 mmol, 1.2 eq) of sodium azide was added by a glass pipette. A water condenser was placed onto the flask and the reaction heated to 80° C. for 16 hrs with stirring. The reaction was then cooled to room temperature and quenched with 300 mL of water to dissolve the sodium salts. The aqueous solution was extracted with diethyl ether 3×100 mL. The organic layers were combined and dried with MgSO4. The solution was filtered and concentrated under vacuum with no external heat, resulting in 5-azido-1-pentylacetate (4.46), which was carried onto the next step (described in Example 20) without further purification. 1H NMR (500 mHz, DCM): δ: d 4.08 (t, J=6.0 Hz, 2H), 3.33 (t, J=6.2 Hz, 2H), 2.06 (s, 3H), 1.66-1.47 (m, 6H)13C NMR (100 MHz, DCM): δ: 171.37, 64.58, 51.89, 29.02, 28.71, 23.73, 21.27