Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:18]=2[CH3:25])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.C1COCC1.O.[Li+].[OH-]>CC(O)C.C(Cl)Cl>[CH3:24][O:23][C:19]1[C:18]([CH3:25])=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:26]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(OC)c2C)Cc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: O
Product: COc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1C
Reaction time: 36 h
Yield: 103.6 %

Procedure:
A 40 mL vial containing the 2-(3-methoxy-2-methyl-benzoylamino)-indane-2-carboxylic acid ethyl ester (0.65 g, 1.84 mmol) is charged with THF (10 mL) MeOH (10 mL) and a stirring bar is added. Stirring is initiated. After dissolution, water (5 mL) is added followed by the LiOH (267 mg, 6.36 mmol). After 36 h, tlc analysis (silica, 5% i-PrOH/DCM) indicates that the starting material is completely consumed. The pH of the reaction mixture is carefully adjusted to pH 2 by slowly adding dilute aqueous HCl (3%, ˜10 mL). The contents of the flask are poured into an addition funnel containing EtOAc (30 mL). The layers are separated. The aqueous layer is extracted with EtOAc (20 mL). The combined organic extracts are washed with water (20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated to yield 620 mg of amorphous white solid. The sample is purified by column chromatography (silica, 2% to 15% CH3OH in DCM) using an ISCO Companion and a 40 g cartridge. Fractions 14-16 are collected and evaporated by pumping to constant weight gives 380 mg of dry white powder.
Reaction SMILES: [N:1]([CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:14][CH3:15])[CH2:6][CH:5]1[OH:16])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:14][CH3:15])[CH2:6][CH:5]1[OH:16]
Reactant: COc1cccc2c1CC(N=[N+]=[N-])C(O)C2
Agent: [Pd]
Solvent: CO
Product: COc1cccc2c1CC(N)C(O)C2
Yield: 90.6 %

Procedure:
A solution of 3-azido-5 -methoxy-1,2,3,4-tetrahydronaphthalen-2-ol (1.8 g, 8.0 mmol) in 150 ml of MeOH was stirred with 10% Pd/C (20 mg) under H2 (18 psi) for 4 h. The reaction mixture was filtered and concentrated in vacuo to provide 1.4 g (91%) of the desired product as a colorless oil which was used in the next reaction without purification. 1H NMR (300 MHz, CDCl3 ): δ 2.0 (broad s, 2H), 2.24 (dd, 1H, J=10.4, 16.8 Hz), 2.84 (m, 2H), 3.16 (m, 2H), 3.59 (m, 1H), 3.78 (s, 3H), 6.66 (m, 2H), 7.09 (t, 1H, J=7.9 Hz).
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:20]2[C:21]([CH3:25])=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[N:17][C:16]([CH:67]=[C:68]=[O:69])([NH:33][C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]3[N:47](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:46]=[N:45][N:44]=3)[CH:38]=2)=[O:35])[C:15]1=[O:70])=[O:5])C.[OH-].[Na+].Cl.O>COCCOC.C(OCC)(=O)C>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:18]1[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=2[N:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:4]([OH:5])=[O:3])[C:15](=[O:70])[C:16]([CH:67]=[C:68]=[O:69])([NH:33][C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]3[NH:47][N:46]=[N:45][N:44]=3)[CH:38]=2)=[O:35])[N:17]=1
Reactant: CCOC(=O)COc1ccccc1N1C(=O)C(C=C=O)(NC(=O)Nc2cccc(-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)N=C(c2ccccc2F)c2cccc(C)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1cccc2c1N(c1ccccc1OCC(=O)O)C(=O)C(C=C=O)(NC(=O)Nc1cccc(-c3nnn[nH]3)c1)N=C2c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
A mixture of N-[(3RS)-1-(2-ethoxycabonylmethoxyphenyl)-carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-{3-[1-(triphenylmethyl)tetrazol-5-yl]phenyl}urea (196 mg) and 1N NaOH in 1,2-dimethoxyethane (2 ml) was stirred at room temperature overnight. 4N-HCl in ethyl acetate (2 ml) was added to the reaction mixture and stirred at room temperature for three days. Ethyl acetate and water were added to the reaction mixture. The separated organic layer was washed with water and brine successively, and dried over magnesium sulfate. Removal of the solvent in vacuo afforded N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-carboxymethoxyphenyl)-carbonylmethyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]urea (66.0 mg, 47.4%).
Reaction SMILES: C(OC(=O)[C@H](O)C)(C)(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.N1C(C)=CC=CC=1C.Cl.[CH2:35]([O:42][C:43](=[O:61])[C@@H:44](N)[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[C:56]([Cl:58])[CH:55]=[CH:54][C:53]=2[Cl:59])=[CH:48][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C.[F:69][C:70]([F:85])([F:84])[S:71]([O:74][C@H:75]([CH3:83])[C:76]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:77])(=[O:73])=[O:72]>C(Cl)Cl>[F:84][C:70]([F:69])([F:85])[S:71]([O:74][C@H:75]([CH3:83])[C:76]([O:78][C:79]([CH3:80])([CH3:81])[CH3:82])=[O:77])(=[O:72])=[O:73].[CH2:35]([O:42][C:43](=[O:61])[CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[C:56]([Cl:58])[CH:55]=[CH:54][C:53]=2[Cl:59])=[CH:48][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: N[C@@H](Cc1ccc(-c2cc(Cl)ccc2Cl)cc1)C(=O)OCc1ccccc1
Agent: C[C@@H](O)C(=O)OC(C)(C)C
Agent: C[C@@H](OS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccc(-c2cc(Cl)ccc2Cl)cc1)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
Step 3′: t-Butyl (R)-2-(trifluoromethylsulfonyloxy)propionate was prepared from (R)-2-hydroxy-propionic acid tert-butyl ester (602 mg, 4.12 mmol), triflic anhydride (0.696 mL, 4.12 mmol) and 2,6-lutidine (0.480 mL, 4.12 mmol) in DCM (5 mL). To a suspension of ((S)-2-amino-3-(2′,5′-dichloro-biphenyl-4-yl)-propionic acid benzyl ester hydrochloride (600 mg, 1.38 mmol) in dichloromethane (10 mL) was added triethylamine (0.574 mL, 4.12 mmol) at 0° C. After stirred for 10 min, a half amount of the freshly prepared t-butyl (R)-2-(trifluoromethylsulfonyloxy)propionate was added at room temperature and stirred for 1 hour. Additional triethylamine (0.574 mL, 4.12 mmol) and the rest of t-butyl (R)-2-(trifluoromethylsulfonyloxy)propionate were added at room temperature and stirred for additional 2 hours. The reaction mixture was washed with H2O and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/heptane) to give (S)-2-(S)-1-tert-butoxycarbonyl-ethylamino)-3-(2′,5′-dichloro-biphenyl-4-yl)-propionic acid benzyl ester (580 mg). 1H NMR (400 MHz, CDCl3) δ 1.24 (t, 3H, J=6.8 Hz), 1.41 (s, 9H), 3.00-3.07 (m, 2H), 3.26 (dd, 1H, J=7.1, 13.9 Hz), 3.70 (dd, 1H, J=7.1, 7.1 Hz), 5.09 (s, 2H), 7.20-7.42 (m, 12H); MS: m/z (MH+) 528.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:23][CH2:24][CH2:25][CH3:26])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[C:12]3[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:13]=3[N:14]=2)[CH:8]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.CCCCCC>CC(=O)CC>[CH3:18][N:17]1[C:12]2[C:11](=[O:22])[NH:10][C:9]([C:7]3[CH:8]=[C:3]([CH2:2][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:4]=[CH:5][C:6]=3[O:23][CH2:24][CH2:25][CH3:26])=[N:14][C:13]=2[C:15]([CH2:19][CH2:20][CH3:21])=[N:16]1
Reactant: CCCOc1ccc(CCl)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Reactant: C1COCCN1
Solvent: CCCCCC
Solvent: CCC(C)=O
Product: CCCOc1ccc(CN2CCOCC2)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 52.9 %

Procedure:
A solution of 5-(5-chloromethyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (Preparation 16, 0.60 g, 0.0016 mol) in 2-butanone (10 ml) was added dropwise to a stirred solution of morpholine (0.42 g, 0.0048 mol) in 2-butanone (40 ml) at 0° C. The solution was then heated under reflux for 16 hours, cooled and evaporated under vacuum. The residue was suspended in water (50 ml) and the suspension extracted with ethyl acetate (3×20 ml). The organic extracts were combined, washed with brine (2×30 ml), dried (Na2SO4) and evaporated under vacuum. The residue was chromatographed on silica gel (12 g), using an elution gradient of methanol in dichloromethane (0-2% methanol), to give an oil which solidified on trituration with hexane. Crystallisation from ethyl acetate-hexane gave the title compound as a colourless solid (0.36 g, 53%), m.p. 106°-107° C. Found C,64.76; H,7.34; N,16.36. C23H31N5O3 requires C,64.92; H,7.34; N,16.46%.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.[S:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[S:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]4[N:19]5[C:20]6[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=6[N:16]=[CH:17][C:18]5=[O:21])[CH2:10]4)[CH2:4][CH2:3]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: O=Cc1cc2c(cn1)OCCS2
Reactant: NC1CCN(CC2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=c1ccc2ncc(=O)n3c2n1C[C@@H]3CN1CCC(NCc2cc3c(cn2)OCCS3)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
Racemic 2-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (for a preparation see Example 16A(j)) (360 mg, 1.195 mmol) was stirred with 2,3-dihydro[1,4]oxathiino[2,3-c]pyridine-7-carbaldehyde (for a synthesis see WO2004058144, Example 60) (195 mg, 0.9 eq.) in chloroform:methanol (9:1, v:v, 15 ml) at room temperature for 30 mins; the mixture was then treated with sodium triacetoxyborohydride (760 mg, 3.0 eq.) with vigorous stirring at room temperature for 30 mins. The reaction was quenched by addition of saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred at room temperature for 5 mins. The organic phase was separated, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica (eluting with 0-12% (2M ammonia in methanol) in DCM, appropriate fractions were combined and evaporated under reduced pressure to give the free base of the title compound as a pale yellow foam (235 mg, 42%).
Reaction SMILES: C(O[C:6]([N:8](C)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:19]>O1CCOCC1>[ClH:19].[CH3:6][NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 10 °C

Procedure:
A solution of 5.15 g (20.0 mmol) of trans-4-(tert-butoxycarbonyl-methyl-amino)-cyclohexanecarboxylic acid was dissolved in 50 mL of dioxane, cooled to 10° C. and treated with 50 mL (200 mmol, 10 eq) of 4M HCl in dioxane, then warmed to RT overnight. The solution was evaporated to ca. 15 mL, cooled to 0° C. and precipitated with ˜100 mL of Et2O. The solid precipitate was filtrated, washed with Et2O (×3) and dried under reduced pressure to yield 3.76 g (97%) of trans-4-methylamino-cyclohexanecarboxylic acid-HCl, MS: 156 (M−H−), MP: 249° C., dec.
Reaction SMILES: C([O-])(=[O:3])C.[Na+].[Cl:6][C:7]1[CH:8]=[C:9]([CH2:25][C:26]([OH:28])=[O:27])[CH:10]=[C:11]([Cl:24])[C:12]=1[O:13][C:14]1[N:15]=[N:16][C:17](Cl)=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=1>C(O)(=O)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH2:25][C:26]([OH:28])=[O:27])[CH:10]=[C:11]([Cl:24])[C:12]=1[O:13][C:14]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[C:17](=[O:3])[NH:16][N:15]=1
Reactant: CC(=O)[O-]
Reactant: CC(C)c1cc(Oc2c(Cl)cc(CC(=O)O)cc2Cl)nnc1Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1cc(Oc2c(Cl)cc(CC(=O)O)cc2Cl)n[nH]c1=O
Temperature: 125 °C
Yield: 65 %

Procedure:
A mixture of glacial acetic acid (200 mL), sodium acetate (6.1 g, 74.4 mmol) and [3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-acetic acid (18) (8.3 g, 21.96 mmol) was heated to 125° C. for 24 h. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was diluted with methylene chloride (200 mL) and was washed with water (150 mL). The organic layer was separated. Hexanes (3×200 mL) were added to the residue in portions and then subsequently concentrated under vacuum. The resulting semi-solid was diluted with a minimum amount of ether, scratched, and slurried. The resulting white solid was filtered, washed with cold ether and dried under high vacuum overnight to afford [3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-acetic acid (19) (5.1 g, 65%) as a white solid; LRMS for C15H14Cl2N2O4 (M+) m/z=357. Molecular Weight=357.1958; Exact Mass=356.0331
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([S@@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>ClCCl.[O-]S([O-])(=O)=O.[Cu+2]>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1/[CH:4]=[N:17]/[S@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16]
Reactant: O=Cc1ccc(F)cc1F
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/c1ccc(F)cc1F
Temperature: 37 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
2,4-difluorobenzaldehyde, 20-a, (10 g, 70.4 mmol) in dichloromethane (300 ml) were added (S)-2-methylpropane-2-sulfinamide (8.5 g, 70.4 mmol), PPTS (1.85 g, 7.4 mmol) and anhydrous CuSO4 (22.5 g, 0.14 mol) and the resulting mixture was stirred at 37° C. overnight. The mixture was then filtrated and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate=8/1) to provide the product, 21-a, (15.77 g, 91%).
Reaction SMILES: [CH2:1]([N:8]([CH:10]([C:15]([O:17]C)=O)[C:11]([O:13][CH3:14])=[O:12])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][NH2:20].CO>CO>[CH3:14][O:13][C:11](=[O:12])[CH:10]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:9])[C:15]([NH:20][CH3:19])=[O:17]
Reactant: COC(=O)C(C(=O)OC)N(C)Cc1ccccc1
Reactant: CN
Solvent: CO
Product: CNC(=O)C(C(=O)OC)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 26 h
Yield: 56 %

Procedure:
To a methanol (39 mL) solution of dimethyl [benzyl(methyl)amino]propanedioate (Intermediate 1-2, 13 g), a 9 mol/L-methylamine-methanol solution (14 mL) was added at room temperature, followed by stirring the mixture for 26 hours at room temperature. The reaction mixture was concentrated under reduced pressure, whereafter ethyl acetate and water were added to the resulting residue to isolate the organic layer. The extract was washed with brine, and dried over anhydrous sodium sulfate. Then, the desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (hexane/ethyl acetate=50/50→chloroform/acetone=95/5) to obtain ({[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)amino}methyl)benzene (pale yellow oil) (7.1 g, 56%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:26][C:27](=O)[CH2:28][CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1.[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1.C([BH3-])#N.[Na+].C(O)(C(F)(F)F)=O>C(O)C>[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=5)[CH2:26][CH:27]([N:41]5[CH2:45][CH2:44][CH2:43][CH2:42]5)[CH2:28][CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1
Reactant: C1CCNC1
Reactant: COc1cc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1cc(Nc2nc3n(n2)CCC(N2CCCC2)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 44.4 %

Procedure:
2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (50 mg, 0.107 mmol, from example 137) was added to a mixture of pyrrolidine (7.62 mg, 0.107 mmol), and sodium cyanoborohydride (1.0 M in THF, 428 μL, 0.428 mmol) in ethanol (0.535 mL). The mixture was stirred at rt for 48 h and then concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford the titled compound (24.8 mg, 35% yield) as a TFA salt. LC-MS (M+H)+ 522.4. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.80 (1 H, d, J=1.5 Hz), 7.35 (1 H, d, J=2.1 Hz), 6.98-7.22 (7 H, m), 4.96 (1 H, br. s.), 4.65-4.74 (1 H, m), 3.97-4.09 (1 H, m), 3.78-3.97 (5 H, m), 3.38 (1 H, br. s.), 2.92-3.02 (1 H, m), 2.84 (2 H, d, J=4.9 Hz), 2.36-2.53 (2 H, m), 2.03-2.31 (5 H, m).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.C([O:13][CH2:14][CH3:15])(=O)C.O>O1CCCC1>[CH2:14]([O:13][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=1)[C:8]#[N:9])[C:15]1[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1ccnc(Cl)c1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccnc(OCc2ccccc2)c1
Yield: 62 %

Procedure:
A solution of 2-chloro-4-cyanopyridine (0.40 g, 2.9 mmol) in tetrahydrofuran (1 ml) was added to the mixture and the mixture was refluxed for 6 hrs. The reaction mixture was combined with ethyl acetate and water and stirred. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel (30 g) column chromatography, eluted with hexane-ethyl acetate (4:1, v/v) to give the titled compound (0.37 g, 62%).
Reaction SMILES: [CH2:1]([N:5]([CH2:23][CH2:24][CH2:25][CH3:26])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=2)=[C:8]([O:21][CH3:22])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:27]([C:29]1[C:30](=[C:40]([C:43]#[N:44])[C:41]#[N:42])[O:31][C:32]([CH3:39])([C:35]([F:38])([F:37])[F:36])[C:33]=1[CH3:34])#[N:28]>C(O)C.O1CCCC1>[CH2:23]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[CH:34][C:33]3[C:32]([CH3:39])([C:35]([F:38])([F:36])[F:37])[O:31][C:30](=[C:40]([C:41]#[N:42])[C:43]#[N:44])[C:29]=3[C:27]#[N:28])=[CH:16][CH:15]=2)=[C:8]([O:21][CH3:22])[CH:7]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C(F)(F)F)s2)c(OC)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
In 4 ml of ethanol and 1.5 ml of tetrahydrofuran were dissolved 100 mg (0.27 mmol) of 5-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]thiophene-2-carboaldehyde and 75 mg (0.3 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. After the mixture was stirred at 50° C. for 2 hours, the solvent was evaporated off. The residue was washed with ethanol to give 120 mg of a brown powdered crystal (yield: 73.5%; mp: 191-193° C.)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C@@H:9]1[CH2:22][OH:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C@@H:9]1[CH:22]=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](CO)CN1C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C=O)CN1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 121.1 %

Procedure:
To (2R,5R)-2-hydroxymethyl-5-methyl-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (1.42 g, 4.3 mmol) in DCM (18.7 mL) was added Dess-Martin periodinane (1.83 g, 4.3 mmol) at room temperature. The reaction was stirred at this temperature for 1 h. Saturated aqueous sodium hydrogen carbonate and sodium thiosulfate (1:1) was added and the solution extracted with ethyl acetate (3×). The combined organic extracts were washed with saturated aqueous hydrogen carbonate and sodium thiosulfate (1:1) (3×), dried over sodium sulfate, filtered and concentrated to give the title compound (1.71 g, 96%) as a pale yellow solid, used without further purification. 1H NMR (CDCl3): 9.58 (1H, s), 4.78-4.08 (3H, m), 3.73 (1H, m), 3.39-3.06 (2H, m), 1.53-1.41 (18H, m), 1.18 (3H, t).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][N:4]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]2=[N:24][N:25]=[C:26]([C:27]3[CH:31]=[C:30]([CH3:32])[O:29][N:28]=3)[N:16]2[N:15]=1>>[CH3:11][C:9]([NH2:12])([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:1][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]3=[N:24][N:25]=[C:26]([C:27]4[CH:31]=[C:30]([CH3:32])[O:29][N:28]=4)[N:16]3[N:15]=2)=[N:4][CH:5]=1)[CH3:10]
Reactant: CC(C)(N)c1ccc(CO)nc1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(C(C)(C)N)cn4)nn23)no1

Procedure:
The reaction was carried out as described in Example 1, Step 4 using 1-[2-(hydroxymethyl)pyridin-5-yl](1-methyl)ethylamine (330 mg, 1.98 mmol) and 6-chloro-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine to give after column chromatography on silica, eluting with 4% MeOH/CH2Cl2 containing 1% NH3 solution, the title compound (504 mg, 61%) which was recrystallised from CH2Cl2/hexanes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Cl.Cl.[NH2:22][CH:23]1[CH2:30][CH:29]2[N:31]([CH3:32])[CH:25]([CH2:26][CH2:27][CH2:28]2)[CH2:24]1>>[CH3:32][N:31]1[CH:25]2[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:30][CH:23]([NH:22][C:17]([C:16]1[C:10]3[O:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:12][C:11]=3[CH:13]=[CH:14][CH:15]=1)=[O:19])[CH2:24]2
Reactant: O=C(O)c1cccc2nc(-c3ccc(F)cc3)oc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: Cl
Product: CN1C2CCCC1CC(NC(=O)c1cccc3nc(-c4ccc(F)cc4)oc13)C2
Yield: 15 %

Procedure:
N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-fluorophenyl)benzoxazole-7-carboxamide was prepared from 2-(4-fluorophenyl)benzoxazole-7-carboxylic acid and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride using the method outlined in Step C of Example 14. This compound was obtained in 15% yield as an off-white solid: mp 229-231° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.26 (m, 2H), 8.20 (d, J=8.3 Hz, 1H), 7.94 (dd, J=1.0, 7.9 Hz, 1H), 7.71 (dd, J=1.0, 7.6 Hz, 1H), 7.50 (m, 3H), 4.39 (m, 1H), 3.02 (m, 2H), 2.43 (s, 3H), 2.32 (m, 2H), 2.08 (m, 1H), 1.93 (m, 2H), 1.48 (m, 3H), 0.96 (m, 2H); MS (ESI) m/z 394 [M+H]+.