Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)CCCCCCCO.FC1C=C(F)C=CC=1CBr.[F:21][C:22]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:23]=1[CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34].FC1C=C(F)C=CC=1COCCCCCCCC(O)=O.Cl.Cl.[CH2:62]([O:69][C:70](=[O:78])[CH2:71][C@@H:72]([NH2:77])[CH2:73][N:74]([CH3:76])[CH3:75])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>>[CH2:62]([O:69][C:70](=[O:78])[CH2:71][C@@H:72]([NH:77][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][CH2:24][C:23]1[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:22]=1[F:21])[CH2:73][N:74]([CH3:75])[CH3:76])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: OCCCCCCCCOCc1ccc(F)cc1F
Agent: Cl
Agent: Fc1ccc(CBr)c(F)c1
Agent: O=C(O)CCCCCCCOCc1ccc(F)cc1F
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCOCc1ccc(F)cc1F

Procedure:
The title compound, m/e=413.1 ([M−H]−), was produced in analogy with example 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated in step 1 with 2,4-difluorobenzyl bromide, leading to 8-(2,4-difluoro-benzyloxy)-octan-1-ol, which was oxidized in step 2 to 8-(2,4-difluoro-benzyloxy)-octanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-3-[8-(2,4-difluoro-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[CH:24]1([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([C:30]2[CH:31]=[CH:32][C:33]([NH:34][C:1]([C:4]34[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]5[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]5[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]3)[CH2:6][CH2:5]4)=[O:2])=[CH:35][CH:36]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(C4CCCCC4)cc3)(CC1)CC2
Yield: 30 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-cyclohexylaniline (60.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-cyclohexylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (22.3 mg).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C@H:13]([NH:26][C:27](=O)[O:28]C(C)(C)C)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH3:24])=[CH:16][CH:15]=1.FC(F)(F)C(O)=O.S1[CH:45]=[CH:44][CH:43]=[C:42]1[CH:46]1[CH2:48][CH:47]1[C:49](Cl)=O.C(N(CC)CC)C>ClCCl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C@H:13]([NH:26][C:27](=[O:28])[C@H:44]([C:43]1[CH:42]=[CH:46][CH:48]=[CH:47][CH:49]=1)[CH3:45])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH3:24])=[CH:16][CH:15]=1
Reactant: O=C(Cl)C1CC1c1cccs1
Reactant: CC[C@H](C)COc1ccc([C@H](CN2C(=O)c3ccccc3C2=O)NC(=O)OC(C)(C)C)cc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](C)COc1ccc([C@H](CN2C(=O)c3ccccc3C2=O)NC(=O)[C@@H](C)c2ccccc2)cc1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A precooled (0° C.) solution of t-butyl (R)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-1-(4-((S)-2-methylbutoxy)phenyl)ethylcarbamate (250 mg, 0.55 mmol) and dichloromethane (10 mL) was treated dropwise with trifluoroacetic acid (2 mL). The resulting solution was maintained at room temperature for 16 h, then concentrated to afford a yellow oil that was dissolved in dichloromethane (5 mL) and added to a room temperature solution of 2-thiophen-2-yl-cyclopropane carbonylchloride (100 mg, 0.60 mmol), triethylamine (0.20 mL, 1.4 mmol) and dichloromethane (4 mL). The resulting reaction was maintained overnight, then transferred to a separatory funnel and partitioned between ethyl acetate (15 mL) and saturated aqueous sodium bicarbonate (15 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (15 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL), then dried (MgSO4), filtered and concentrated to afford a residue that was purified by column chromatography on silica gel (10%→50% ethyl acetate in hexanes) to afford (S)-N-((R)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-1-(4-((S)-2-methyl-butoxy)-phenyl)-ethyl)-2-phenyl-propionamide (220 mg, 81% yield) as a white powder: 1H NMR (400 MHz, CDCl3) δ 7.87 (dd, J=5.6, 3.0 Hz, 2H), 7.76 (dd, J=5.4, 3.2 Hz, 2H), 7.22-7.34 (m, 5H), 7.05 (d, J=8.6 Hz, 2H), 6.80 (d, J=8.8 Hz, 2H), 6.27 (d, J=8.1 Hz, 1H), 5.26 (td, J=8.3, 5.3 Hz, 1H), 3.86-3.90 (m, 2H), 3.79 (dd, J=9.1, 6.1 Hz, 1H), 3.70 (dd, J=8.8, 6.6 Hz, 1H), 3.50 (q, J=7.2 Hz, 1H), 1.80-1.90 (m, 1H), 1.52-1.59 (m, 1H), 1.39 (d, J=7.1 Hz, 3H), 1.23-1.32 (m, 1H), 1.01 (d, J=6.8 Hz, 3H), 0.96 (t, J=7.5 Hz, 3H); LRMS (ESI) m/e 485.0 [(M+H)+, calcd for C30H32N2O4 485.6].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[C:10]2[CH2:18][CH:19]([C:21]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])([CH3:24])[CH2:22][OH:23])[CH2:20][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:36]I>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[C:10]2[CH2:18][CH:19]([C:21]([S:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)(=[O:26])=[O:27])([CH3:24])[CH2:22][O:23][CH3:36])[CH2:20][C:9]1=2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)n1c2c(c3cc(Cl)ccc31)CC(C(C)(CO)S(=O)(=O)c1ccccc1)C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(C)(C1Cc2c(n(C(=O)OC(C)(C)C)c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Reaction time: 0.33 h
Yield: 103.2 %

Procedure:
50 mg (0.1 mmol) (RS,SR)-2-(1-benzenesulfonyl-2-hydroxy-1-methyl-ethyl)-7-chloro-2,3-dihydro-1H-cyclopenta[b]indole-4-carboxylic acid tert-butyl ester were dissolved in 5 mL dry THF at 0° C. 5 mg (0.11 mmol, 1.1 eq) NaH (55%) were added and the reaction mixture was stirred for 20 minutes. 10 μL (0.15 mmol, 1.5 eq) methyliodide were then added and the reaction was stirred for 1 hour at 0° C. The reaction was quenched with a saturated NaHCO3 solution. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated to dryness to yield 52 mg (100%) (RS,SR)-2-(1-benzenesulfonyl-2-methoxy-1-methyl-ethyl)-7-chloro-2,3-dihydro-1H-cyclopenta[b]indole-4-carboxylic acid tert-butyl ester as a white powder.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][N:11]([CH2:12][C:13](O)=[O:14])[C:6]2=[CH:5][C:4]([O:16][CH2:17][C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=2)=[N:3]1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[O:14]=[C:13]([N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:12][N:11]1[CH2:10][CH2:9][CH2:8][N:7]2[C:2](=[O:1])[N:3]=[C:4]([O:16][CH2:17][C:18]3[CH:19]=[C:20]([F:26])[C:21]([F:25])=[C:22]([F:24])[CH:23]=3)[CH:5]=[C:6]12
Reactant: C1CCNC1
Reactant: O=C(O)CN1CCCn2c1cc(OCc1cc(F)c(F)c(F)c1)nc2=O
Product: O=C(CN1CCCn2c1cc(OCc1cc(F)c(F)c(F)c1)nc2=O)N1CCCC1

Procedure:
The title compound was prepared by a procedure similar to that described for E13 starting from 2-(6-oxo-8-((3,4,5-trifluorobenzyl)oxy)-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidin-1-yl) acetic acid and pyrrolidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:2].Br[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]=[CH:21]1>O1CCCC1.[Ag]=O>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][CH:14]([O:17][CH:25]3[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]3)[CH2:15][CH2:16]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: BrC1C=CCCC1
Reactant: CCOC(=O)c1ccc(N2CCC(O)CC2)cc1
Agent: O=[Ag]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N2CCC(OC3C=CCCC3)CC2)cc1

Procedure:
A solution of 4-(4-hydroxypiperidin-1-yl)benzoic acid ethyl ester (5.4 g), silver oxide (5.31 g) and 3-bromocyclohexene (3.24 ml) in tetrahydrofuran (52 ml) was stirred for 1 day at room temperature. The reaction mixture was filtered off, and the filtrate was concentrated by evaporation under reduced pressure. To the residue was added ethyl acetate, and the resulting precipitate was collected by filtration and dried. The residue was purified by silica gel chromatography (3:2 hexane-ethyl acetate elution) to give 4-[4-(2-cyclohexenyloxy)piperidin-1-yl]benzoic acid ethyl ester (3.84 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:31])[C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)=[C:4]([OH:32])[CH:3]=1.Br[CH2:34][C:35]#[N:36]>>[C:35]([CH2:34][O:32][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH3:31])[C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)#[N:36]
Reactant: N#CCBr
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccc(F)cc1O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccc(F)cc1OCC#N

Procedure:
The title compound was prepared in analogy to example 49, from N-[4-(4-fluoro-2-hydroxy-phenyl)-pyridin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 48) and bromoacetonitrile (CAS RN 590-17-0). Yellow solid (32%). MS (ESI): m/z=497.8 [M+H]+.
Reaction SMILES: C([O:5][CH2:6][C:7]([O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=[O:21]>C(Cl)Cl>[C:6]([CH2:7][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)([OH:5])=[O:21]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1ccc(OC(=O)COC(C)(C)C)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC(=O)O)cc1
Reaction time: 2 h

Procedure:
Ester 24-1 was dissolved in 15 mL CH2Cl2, then 15 mL TFA was added. After 2 h, the mixture was concentrated providing 24-2 as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:28])=[O:29])[CH:13]=2)[N:6]=1
Reactant: [N-]=[N+]=NCCNS(=O)(=O)c1ccccc1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNS(=O)(=O)c3ccccc3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.114 g, 0.410 mmol) was reacted with N-(2-azidoethyl)benzenesulfonamide (0.104 g, 0.410 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(phenylsulfonamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J=6.9 Hz, 2H), δ 7.44 (m, 5H), δ 6.44 (s, 1H), δ 6.07 (s, 2H), δ 4.42 (t, J=5.7 Hz, 2H), δ 3.36 (t, J=5.4 Hz, 2H), δ 2.57 (t, J=7.2 Hz, 2H), δ 2.20 (s, 2H), δ 1.47 (m, 13H), δ 1.29 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 202.9, 149.5, 148.2, 140.2, 132.8, 129.4, 127.1, 122.5, 106.5, 85.0, 53.7, 50.3, 42.9, 32.7, 31.2, 29.9, 29.2, 28.9, 28.2, 26.3, 25.5 ppm; HRMS (ESI) calcd for C23H33N7O4S (M+) 503.2315. found 503.2310, which was subsequently deprotected to give tert-butyl 2-amino-4-(5-(1-(2-(phenylsulfonamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate hydrochloride (0.142 g, 64% yield). 1H NMR (300 MHz, CD3OD) δ 7.81 (d, J=6.6 Hz, 2H), δ 7.56 (m, 4H), δ 6.47 (s, 1H), δ 4.62 (s, 2H), δ 3.41 (s, 2H), δ 2.78 (s, 2H), δ 2.48 (s, 2H), δ 1.72 (s, 2H), δ 1.63 (s, 2H), δ 1.42 (s, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 176.2, 165.6, 159.9, 147.3, 140.2, 132.8, 129.3, 127.7, 126.8, 108.5, 108.4, 515.8, 42.3, 28.1, 27.9, 27.6, 24.1 ppm; HRMS (ESI) calcd for C18H25N7O2S (M+) 403.1790. found 403.1781.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[CH3:24])=[O:15])[C:5]2[N:9]=[C:8]([N:10]([CH3:12])[CH3:11])[NH:7][C:6]=2[CH:13]=1.C(N(CC)C(C)C)(C)C.[Cl:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:36]=1[C:37](Cl)=[O:38]>C1COCC1.C(OCC)(=O)C>[Cl:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:36]=1[C:37]([NH:1][C:2]1[CH:3]=[C:4]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[CH3:24])=[O:15])[C:5]2[N:9]=[C:8]([N:10]([CH3:11])[CH3:12])[NH:7][C:6]=2[CH:13]=1)=[O:38]
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc(N)cc2[nH]c(N(C)C)nc12
Reactant: O=C(Cl)c1c(F)cccc1Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2c(F)cccc2Cl)cc2[nH]c(N(C)C)nc12

Procedure:
To a solution of 6-amino-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (30 mg) in THF (1 mL), was added N,N-diisopropylethylamine (22 μL). The mixture was stirred under ice-cooling, 2-chloro-6-fluorobenzoyl chloride (13 μL) was added slowly, and it was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified on column chromatography to obtain 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (30 mg) as pale yellow powder. This was suspended in MeOH (1 mL), and 1N hydrogen chloride/MeOH (1 Eq) was added to obtain a homogeneous solution, and MeOH was removed under reduced pressure. The residue was triturated in n-hexane/ethyl acetate (1:1), and the precipitate was collected by filtration and dried under reduced pressure to obtain the titled compound (23 mg) as pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].O.O1CCC[CH2:19]1>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:19])[C:9](=[O:14])[C:10]([F:11])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cccc(Br)c1)C(F)(F)F
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN(C(=O)C(F)(F)F)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-(3-Bromophenyl)-2,2,2-trifluoroacetamide (J. Chem. Soc., 1952, 4014) in tetrahydrofuran (3 ml) was added dropwise to sodium hydride (0.16 g) in tetrahydrofuran (5 ml). The reaction mixture was stirred for 30 minutes at room temperature. lodomethane (0.25 ml) was added dropwise to the reaction mixture and it was stirred overnight at room temperature. Water was added and the product extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluting with iso-hexane: dichloromethane (1: 1) to give the sub-title compound as an oil (0.385 g).
Reaction SMILES: [OH:1][CH:2]([CH3:15])[CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[C:23]([O:1][CH:2]([CH3:15])[CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6])(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: CC(O)CCC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)CCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
63 g (302.5 mmol) of benzyl 4-hydroxypentanoate and 46.4 ml (332.8 mmol) of triethylamine are charged under nitrogen at room temperature to 300 ml of CH2Cl2. The mixture is cooled to 0° C. and 21.5 ml (302.5 mmol) of acetyl chloride are added dropwise at 0°-5° C. When the dropwise addition is complete, the ice bath is removed and stirring is continued overnight at room temperature. The reaction mixture is mixed with ice-water and the organic phase is separated and washed twice with water. The aqueous phases are extracted twice with CH2Cl2. The organic phases are combined, dried over MgSO4, filtered and concentrated by evaporation. Distillation of the residue gives benzyl 4-acetoxypentanoate as a colourless oil of b.p. 126°-127° C./2.10-2 torr.
Reaction SMILES: [CH3:1]N1C=NNC1=O.I[CH2:9][C:10]1[N:14]([CH3:15])[C:13]([S:16](C)(=O)=O)=[N:12][N:11]=1.CNC(=S)NN>>[CH2:9]([C:10]1[N:14]([CH3:15])[C:13](=[S:16])[NH:12][N:11]=1)[CH3:1]
Reactant: Cn1c(CI)nnc1S(C)(=O)=O
Reactant: Cn1cn[nH]c1=O
Agent: CNC(=S)NN
Product: CCc1n[nH]c(=S)n1C

Procedure:
Introduction of the 4-methyl-2,4-dihydro-[1,2,4]triazol-3-one moiety is accomplished by O-alkylation of A-5 with 3-iodomethyl-5-methanesulfonyl-4-methyl-4H-[1,2,4]triazole which is prepared as depicted in SCHEME B. Condensation of ethyl hydroxy acetate and 4-methyl-3-thiosemicarbazide afforded 5-ethyl-4-methyl-2,4-dihydro-[1,2,4]triazole-3-thione (B-3) which is S-alkylated (step 2), converted to the chloromethyl compound (step 3), oxidized to the sulfone (step 4) and converted to the desired iodomethyl compound B-5b via a Finkelstein reaction (step 5).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[S:20][C:21]3[C:27](Br)=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2.[N:29]1([C:35]2[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[S:20][C:21]3[C:27]([C:38]4[CH:37]=[CH:36][C:35]([N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)=[CH:40][CH:39]=4)=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3ccc(N4CCOCC4)cc3)c2s1
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
0.22 ml of 2 M aqueous sodium carbonate solution and 6.1 mg (0.007 mmol) of PdCl2(dppf) are added to a mixture of 60 mg (0.15 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 30.9 mg (0.15 mmol) of 4-(4-morpholinyl)phenylboronic acid in 1 ml of DMF. The reaction mixture is heated to 80° C. After 4.5 h, a further 6.1 mg (0.007 mmol) of PdCl2(dppf) are added. After a further 12 h, the reaction mixture is filtered through kieselguhr and evaporated to dryness. The crude product is purified by preparative HPLC. The product is dissolved in methanol, and an excess of 4N hydrogen chloride in dioxane is added. Drying under high vacuum results in 20.6 mg (25% of theory) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[N:12][CH:11]=[CH:10]2)=[O:5].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[CH3:23][S:24]([O:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[N:12][CH:11]=[CH:10]2)=[O:5])(=[O:26])=[O:25]
Reactant: O=C(Nc1ccc2cnccc2c1)C(CO)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC(C(=O)Nc1ccc2cnccc2c1)c1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To 3-hydroxy-N-(isoquinolin-6-yl)-2-phenylpropanamide (E402) in pyridine at 0° C. was added MsCl, and this solution was stirred at 0° C. for 2.5 h. The mixture was poured into NaHCO3(sat) and extracted with EtOAc. The combined organics were dried (Na2SO4), filtered, and evaporated to give 3-(isoquinolin-6-ylamino)-3-oxo-2-phenylpropyl methanesulfonate (E403).
Reaction SMILES: F[C:2]1[C:7]([C:8](=O)[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][NH2:12].C(Cl)Cl>C(O)CO>[CH3:9][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:12][N:11]=1
Reactant: CC(=O)c1cccnc1F
Reactant: NN
Solvent: OCCO
Solvent: ClCCl
Product: Cc1n[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 1.10 g (7.91 mmol) of 1-(2-fluoropyridine-3-yl)ethanone in 5 mL of ethylene glycol under nitrogen was treated with 265 μL (8.31 mmol) of hydrazine. This solution was stirred for 2 hours at room temperature and then heated at 165° C. for 1.5 hours. The solution was cooled to room temperature, poured into CH2Cl2 (25 mL), and extracted with H2O (2×50 mL). The organic portions were combined, dried (MgSO4), filtered and concentrated in vacuo to give the title product as a fluffy off-white solid. 1H NMR (CDCl3): δ 2.61 (s, 3H), 7.14 (m, 1H), 8.06 (dd, 1H), 8.58 (dd, 1H), 11.18 (br s, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[NH:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[Cl:17][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:20]2[NH:19][N:18]=[CH:22][CH:21]=2)[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: CC1(C)OB(c2ccn[nH]2)OC1(C)C
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: NC(=O)C1CCN(c2c(Cl)cncc2-c2ccn[nH]2)CC1
Yield: 66.9 %

Procedure:
General procedure D (See Example 4) was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide (24 mg, 0.088 mmol), 1H-pyrazole-5-boronic acid pinacol ester (19 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile (1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 10:1) to furnish the title compound as a white solid (18 mg, 67%), LC-MS (ESI) Rt 1.06 min, m/z 306 (100%, [M+H]+); m/z (ESI) C14H17ClN5O requires 306.1116 found [M+H]+ 306.1114.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][NH:14][C:13](=[O:18])[C:12]=3[CH:19]=2)=[CH:4][C:3]1=[O:20].[H-].[Na+].Cl.Cl[CH2:25][C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>CN(C=O)C>[CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([CH2:25][C:26]4[N:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:13](=[O:18])[C:12]=3[CH:19]=2)=[CH:4][C:3]1=[O:20]
Reactant: Cn1ccc(-c2ccc3c(c2)C(=O)NCCO3)cc1=O
Reactant: ClCc1ncccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc(-c2ccc3c(c2)C(=O)N(Cc2ncccn2)CCO3)cc1=O
Temperature: 25 °C

Procedure:
7-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (50 mg, 0.185 mmol) was dissolved in DMF (3 mL) and cooled down in a ice/water bath and treated with sodium hydride (60% dispersion) (17 mg, 0.41 mmol) portion wise. After 10 min a solution of 2-(chloromethyl)pyrimidine hydrochloride (37 mg, 0.22 mmol) in DMF (2 mL) was added and the reaction mixture was warmed up to room temperature and quenched with 6 mL of water after it was complete. The reaction mixture was extracted with EtOAc and water and the organic phase was dried, evaporated and purified by silica gel chromatography (95% DCM/MeOH) and then purified by reverse phase chromatography to afford 7-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one.