Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[OH:14])[CH2:9]1)=O)(C)(C)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[C:42]=1O.CC(OC(/N=N/C(OC(C)C)=O)=O)C.Cl.O1CCOCC1>CCO.C1COCC1>[CH:15]1([C@H:13]([O:14][C:42]2[C:41]([Cl:40])=[CH:46][CH:45]=[CH:44][C:43]=2[Cl:47])[C@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)C2CCCCC2)C1
Reactant: Oc1c(Cl)cccc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Clc1cccc(Cl)c1O[C@@H](C1CCCCC1)[C@H]1CCNC1
Reaction time: 2 h

Procedure:
(S)-3-((R)-Cyclohexylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester (190 mg, 670 μmmol), was combined with PPh3 (79 mg, 0.3 mmol), THF (0.2 mL), and 2,6-dichlorophenol (73 mg, 0.5 mmol). DIAD (59 μL, 0.3 mmol) was added and the mixture was allowed to stand at room temperature for 2 hours. EtOH (1.0 mL) and 4.0 N HCl in dioxane (0.5 mL, 2.0 mmol) were added, and the mixture was allowed to stand at room temperature overnight. The solvent was removed under reduced pressure, and the remaining material was dissolved in 50% AcOH (6 mL) and purified by preparative HPLC (1″ C18 column; 10-50% MeCN over 1 hour). The clean fractions were pooled and lyophilized to yield the title compound as a mono-TFA salt (37 mg, 95% purity). MS m/z: [M+H]+ calcd for C17H23Cl2NO, 328.12; found 328.4.
Reaction SMILES: [C:1]([C:3]1[C:4]([OH:10])=[N:5][C:6]([OH:9])=[CH:7][CH:8]=1)#[N:2].[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>>[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([O:9][C:6]1[N:5]=[C:4]([OH:10])[C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)=[O:15]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: N#Cc1ccc(O)nc1O
Product: N#Cc1ccc(OC(=O)c2ccccc2Cl)nc1O
Yield: 54.8 %

Procedure:
The general procedure of Example 81 was followed using 2.00 g of 3-cyano-2,6-dihydroxypyridine and 2.57 g of 2-chlorobenzoyl chloride, thereby producing 2.21 g of the title compound in a yield of 55%.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([C:13]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])([CH3:18])[C:14]([F:17])([F:16])[F:15])=[N:11][N:12]=2)[C:5]([NH2:30])=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32].C([O-])([O-])=O.[K+].[K+].[CH:41]1(B(O)O)[CH2:43][CH2:42]1>O1CCOCC1.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>[CH:41]1([C:2]2[N:7]=[C:6]([C:8]3[O:9][C:10]([C:13]([O:19][Si:20]([CH:21]([CH3:23])[CH3:22])([CH:27]([CH3:28])[CH3:29])[CH:24]([CH3:25])[CH3:26])([CH3:18])[C:14]([F:15])([F:16])[F:17])=[N:11][N:12]=3)[C:5]([NH2:30])=[CH:4][C:3]=2[C:31]([F:32])([F:33])[F:34])[CH2:43][CH2:42]1
Reactant: CC(C)[Si](OC(C)(c1nnc(-c2nc(Br)c(C(F)(F)F)cc2N)o1)C(F)(F)F)(C(C)C)C(C)C
Reactant: OB(O)C1CC1
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: [K+]
Solvent: C1COCCO1
Product: CC(C)[Si](OC(C)(c1nnc(-c2nc(C3CC3)c(C(F)(F)F)cc2N)o1)C(F)(F)F)(C(C)C)C(C)C
Temperature: 120 °C

Procedure:
To a stirring solution of 6-bromo-2-(5-(1,1,1-trifluoro-2-(triisopropylsilyloxy)propan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (step 3) (200 mg, 0.346 mmol) in dry 1,4-dioxane (10 ml) under N2 at RT was added K2CO3 (144 mg, 1.039 mmol) followed by cyclopropylboronic acid (89 mg, 1.039 mmol) and palladiumtetrakis (40.0 mg, 0.035 mmol). The resulting suspension was stirred and heated at reflux (120° C.) overnight for 4 days. The mixture was filtered through Celite® (filter material) and washed through with water (30 ml) and EtOAc (50 ml). The filtrate was separated and the organic portion was dried (MgSO4) and concentrated in vacuo to afford the title compound which was used in the next step without further purification; LC-MS Rt=7.75 min [M+H]+ 539.6 Method 10minLC_v003.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4](=[O:17])[CH2:5][CH:6]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[C:7]([OH:9])=[O:8].[CH:18]1([CH2:24][CH2:25]Br)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C>[NH2:3][C:4](=[O:17])[CH2:5][CH:6]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:25][CH2:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:15]=1)[C:7]([OH:9])=[O:8]
Reactant: NC(=O)CC(C(=O)O)c1ccc(O)cc1
Reactant: BrCCC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)CC(C(=O)O)c1ccc(OCCC2CCCCC2)cc1
Temperature: 25 °C
Yield: 14 %

Procedure:
Aqueous sodium hydroxide solution (2.0 M; 50 μL, 100 μmol) was added in one portion to a stirred solution of 4-amino-2-(4-hydroxyphenyl)-4-oxobutanoic acid (10 mg, 47 μmol) in ethanol (1 mL) at room temperature. After stirring for 10 min cyclohexylethylbromide (9.0 mg, 47 μmol) was added and the resulting mixture heated at reflux for 12 h. On cooling to room temperature the volatiles were evaporated and the residue purified by mass directed auto-preparative reverse phase HPLC to give the title compound as a white solid (2.1 mg, 14%). LC/MS: 3.34 min; z/e 320, calcd (M+1) 320. 1H NMR (400 MHz: MeOD): 7.20 (2H), 6.85 (2H), 4.00 (3H), 2.95 (1H), 2.55 (1H), 1.70 (6H), 1.50 (1H), 1.25 (4H), 0.92 (2H). The absolute regiochemistry of the product was unambiguously assigned using an HMBC correlation experiment.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH2:5]=[O:6].[CH2:7]1[CH2:11]O[CH2:9][CH2:8]1>>[CH:9]#[C:8][CH2:7][C:11]#[C:11][CH2:7][CH2:8][CH2:9][CH2:1][CH3:2].[CH2:5]([OH:6])[C:9]#[C:8][CH2:7][C:11]#[C:11][CH2:7][CH2:8][CH2:9][CH2:1][CH3:2]
Reactant: C=O
Reactant: CC[Mg]Br
Reactant: C1CCOC1
Product: C#CCC#CCCCCC
Product: CCCCCC#CCC#CCO
Reaction time: 0.75 h

Procedure:
A solution of deca-1,4-diyne in THF was prepared following the method indicated in Example 1 and then an equivalent of ethylmagnesium bromide was added thereto at 0°. The mixture was kept at 60° for 45 min. After having added 1,2 equivalent of paraformaldehyde, the mixture was brought to reflux for 3 h. Once cooled, it was extracted with petroleum ether 80:100° and the organic phases were washed with water, then with an aqueous solution saturated with NaCl, dried and evaporated. The obtained residue was chromatographed on a column filled with silica, using as eluting agent a mixture of 1 to 10% of ethyl acetate in cyclohexane. Undeca-2,5-diyn-1-ol was thus obtained in 40% yield.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35](O)=[O:36])[CH:12]=[CH:13][CH:14]=1.[NH2:39][C:40]1[CH:41]=[CH:42][C:43]([NH:46][C:47](=[O:49])[CH3:48])=[N:44][CH:45]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:47]([NH:46][C:43]1[N:44]=[CH:45][C:40]([NH:39][C:35]([CH:16]2[CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:38])[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:33])([CH3:34])[CH3:32])[NH:17]2)=[O:36])=[CH:41][CH:42]=1)(=[O:49])[CH3:48]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(=O)Nc1ccc(N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)cn1
Yield: 89.2 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 52c (0.16 g, 0.28 mmol) was reacted with N-(5-amino-pyridin-2-yl)-acetamide (Aldrich) (0.12 g, 0.79 mmol), HATU (0.1 g, 0.26 mmol) and iPr2NEt (0.2 g, 1.5 mmol) in CH2Cl2 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-acetylamino-pyridin-3-yl)-amide as a white solid (0.15 g, 89%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([CH3:12])[O:7][CH2:8][CH2:9][CH2:10]I)[CH3:2].[Cl:14]CCCO.C(OC(=O)/C=C/C)C.[H-].[Na+]>>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([CH3:12])[O:7][CH2:8][CH2:9][CH2:10][Cl:14])[CH3:2]
Reactant: CCOC(=O)CC(C)OCCCI
Reactant: OCCCCl
Agent: C/C=C/C(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(C)OCCCCl

Procedure:
The 7-iodo-3-methyl-4-oxaheptanoic acid ethyl ester was obtained in the following manner: The 3-chloropropanol was added to the crotonic acid ethyl ester in the presence of sodium hydride to obtain the 7-chloro-3-methyl-4-oxaheptanoic acid ethyl ester (boiling point1 : 74° - 82° C). Then the 7-iodo-3-methyl-4-oxaheptanoic acid ethyl ester (boiling point0.05 : 62° - 65° C) was obtained in acetone with sodium iodide according to Finkelstein.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:17][CH2:16][C:5]2=[C:6]([C:13](=[O:15])[CH3:14])[S:7][C:8]([C:9]([F:12])([F:11])[F:10])=[C:4]2[CH2:3]1.[CH2:19]([C:21]1[CH:26]=[C:25]([CH:27]=O)[CH:24]=[C:23]([CH3:29])[C:22]=1[CH:30]=[CH:31][C:32]([OH:34])=[O:33])[CH3:20].Cl.[CH2:36](O)[CH3:37]>C(O)(C)C.C([O-])(O)=O.[Na+]>[CH2:36]([O:34][C:32](=[O:33])[CH:31]=[CH:30][C:22]1[C:23]([CH3:29])=[CH:24][C:25]([CH:27]=[CH:14][C:13]([C:6]2[S:7][C:8]([C:9]([F:12])([F:10])[F:11])=[C:4]3[CH2:3][C:2]([CH3:18])([CH3:1])[CH2:17][CH2:16][C:5]=23)=[O:15])=[CH:26][C:21]=1[CH2:19][CH3:20])[CH3:37]
Reactant: CCO
Reactant: CC(=O)c1sc(C(F)(F)F)c2c1CCC(C)(C)C2
Reactant: CCc1cc(C=O)cc(C)c1C=CC(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)C=Cc1c(C)cc(C=CC(=O)c2sc(C(F)(F)F)c3c2CCC(C)(C)C3)cc1CC
Temperature: 65 °C
Reaction time: 64 h

Procedure:
A solution of 1-(5,5-dimethyl-3-trifluoromethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (500 mg, 1.81 mmol) and 3-(2-ethyl-4-formyl-6-methyl-phenyl)-acrylic acid (395 mg, 1.81 mmol) in ethanol (25 mL) is treated with 5 N HCl in isopropanol (15 mL). The orange brown reaction mixture is stirred at 65° C. for 64 h. The mixture is diluted with sat. aq. NaHCO3 solution and extracted twice with EA. The organic extracts are washed with sat. NaHCO3 solution, dried over MgSO4, filtered and the solvent of the filtrate is evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 3-{4-[3-(5,5-dimethyl-3-trifluoromethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propenyl]-2-ethyl-6-methyl-phenyl}-acrylic acid ethyl ester (634 mg, contains traces of the corresponding isopropyl ester) as a colourless oil; LC-MS: tR=1.32 min, [M+1]=505.04.
Reaction SMILES: S(O[CH2:9][C:10]([CH3:23])([N+:20]([O-:22])=[O:21])[CH2:11]OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.C(N(C(C)C)C(C)C)C.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(#N)C>[CH3:23][C:10]1([N+:20]([O-:22])=[O:21])[CH2:9][N:40]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:11]1
Reactant: NCc1ccccc1
Reactant: CC(COS(=O)(=O)C(F)(F)F)(COS(=O)(=O)C(F)(F)F)[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1([N+](=O)[O-])CN(Cc2ccccc2)C1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A solution of 2-methyl-2-nitro-1,3-propanediol ditriflate [the product of step 1] (4.0 g, 10 mmol) in acetonitrile (70 ml) is cooled to 0° C.-5° C. and N-ethyl-diisopropylamine (3.23 g, 25 mmol) is added, followed by benzylamine (1.60 g, 15 mmol) and the mixture is stirred at a temperature of 80° C. for 12 hours. The cooled reaction mixture concentrated under reduced pressure, dissolved in ethyl acetate and transferred to a separating funnel. This is then washed with water (2×) and brine, dried (Na2SO4), filtered, and concentrated. The crude liquid product is used in the next step without further purification. The crude product is purified by chromatography using a 3:1 mixture of Hexane:Ethyl acetate as eluant; the product is obtained as an oil. 1H-NMR (CDCl3): 7.3 (m, 5H), 3.75 (d, 2H), 3.68 (s, 2H), 3.42 (d, 2H), 1.88 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH2:3][CH2:2]1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][N:24]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[O:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:17])[CH2:5][CH2:6]1
Reactant: C[C@H](N)c1nc2ccccc2n1C1CCOCC1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCOCC1
Temperature: 120 °C
Reaction time: 72 h

Procedure:
A mixture of (S)-1-[1-(tetrahydropyran-4-yl)-1H-benzoimidazol-2-yl]ethylamine from Example 17 (195 mg, 0.796 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (266 mg, 1.11 mmol) and DIPEA (0.25 mL, 1.43 mmol) in n-butanol (2 mL) was stirred in a sealed vial for 3 days at 120° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was loaded into an Isolute® SCX-2 which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) and then triturated with a mixture EtOAc and MeOH affording 127 as an off-white solid (148 mg, 51%). LCMS: RT 2.29 min [M+H]+ 364.0. 1H NMR (DMSO, 400 MHz): δ 12.93 (1H, bs), 8.30-7.81 (3H, m), 7.61-7.59 (2H, m), 7.17-7.03 (2H, m), 5.96 (1H, bs), 4.81-4.63 (1H, m), 3.94 (1H, d, J=11.07 Hz), 3.74 (1H, d, J=11.25 Hz), 3.35 (1H, bs), 2.84 (1H, bs), 2.47-2.35 (1H, m), 2.30-2.17 (1H, m), 1.75 (1H, bd), 1.64 (3H, d, J=6.71 Hz), 1.50 (1H, bs)
Reaction SMILES: NC[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.ClC[C:18]1[NH:19][C:20]2C=CC=CC=2N=1.NCCCN.CN=C=S.N1C2C=CC=CC=2NC=1CNC[CH2:48][CH2:49][NH:50][C:51]([NH:54][C:55]#[N:56])=[N:52]C>>[N:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH:11][C:7]=1[CH2:6][NH:5][CH2:4][CH2:3][NH:52][C:51]([NH:54][C:55]#[N:56])=[N:50][CH2:49][CH2:48][N:19]([CH3:20])[CH3:18]
Reactant: CN=C(NC#N)NCCCNCc1nc2ccccc2[nH]1
Reactant: NCCCNCc1nc2ccccc2[nH]1
Reactant: ClCc1nc2ccccc2[nH]1
Agent: CN=C=S
Agent: NCCCN
Product: CN(C)CCN=C(NC#N)NCCNCc1nc2ccccc2[nH]1

Procedure:
Using the above procedure, 2-[(3-aminopropyl)aminomethyl]benzimidazole prepared by reacting 2-chloromethylbenzimidazole with 1,3 -diaminopropane) and methyl isothiocyanate, the product is N-[3-(2-benzimidazolylmethylamino)propyl]-N'-cyano-N"-methylguanidine.
Reaction SMILES: [O:1]=[C:2]([CH3:15])[CH2:3][CH2:4][N-:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[CH:20]=O.N1CCCCC1.C(O)(=[O:34])C>CC(O)C>[C:2]([C:3](=[CH:20][C:19]1[CH:18]=[C:17]([Cl:16])[CH:24]=[C:23]([Cl:25])[CH:22]=1)[C:4]([NH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:34])(=[O:1])[CH3:15]
Reactant: CC(=O)CC[N-]CCCc1ccccc1
Reactant: CC(=O)O
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1cc(Cl)cc(Cl)c1)C(=O)NCCCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.22 g (10.1 mmol) of 3-oxo-N-(3-phenylpropyl)butylamide and 1.77 g (10.1 mmol) of 3,5-dichlorobenzaldehyde were dissolved in 30 ml of 2-propanol. 86.0 mg (1.01 mmol) of piperidine and 60.7 mg (1.01 mmol) of acetic acid were added and stirred at room temperature for one day. After the solvent was evaporated under reduced pressure, ethyl acetate was added thereto. The reaction mixture was washed with 1 N hydrochloric acid and then with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1) to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[C:17]3[CH:18]=[C:19]([C:22]#[N:23])[CH:20]=[CH:21][C:16]=3[O:15][C:14]([CH3:25])([CH3:24])[CH:13]=2)[CH:4]=1)#[N:2]>CO.C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[C:22]([C:19]1[CH:20]=[CH:21][C:16]2[O:15][C:14]([CH3:25])([CH3:24])[CH2:13][CH:12]([N:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:3]([C:1]#[N:2])=[CH:4]3)[C:17]=2[CH:18]=1)#[N:23]
Reactant: CC1(C)C=C(n2cc(C#N)c3ccccc32)c2cc(C#N)ccc2O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)CC(n2cc(C#N)c3ccccc32)c2cc(C#N)ccc2O1
Reaction time: 48 h

Procedure:
4-(3-Cyano-1H-indol-1-yl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (25 mg, prepared according to Example 1) in methanol/ethyl acetate (3:1) was treated with an equal weight of palladium hydroxide catalyst and shaken under an atmosphere of hydrogen at 55 psi over 2 days, recharging the catalyst midway, to provide a 53:30 mixture of the desired compound and the starting material along with minor amounts of by-products. Another 250 mg of starting material was treated in an identical manner. Purification of the desired product from the combined reaction mixtures was effected by preparative reverse phase chromatography on a C-18 column, eluting with 85% of 90:10 MeOH:H2O with 0.1% trifluoroacetic acid and 15% of 10:90 MeOH:H2O with 0.1% trifluoroacetic acid at a flow rate of 49 mL/min. and injections of 75 mg. Product-containing fractions were concentrated to remove methanol and extracted twice with ethyl acetate. The organic extracts were washed with saturated sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue of 50 mg. Final hexane trituration (decanted) gave the title compound (45 mg), m.p. 175°-178° C.: 1H NMR (CDCl3) δ 7.80-7.88 (m, 1H), 7.48-7.65 (m, 2H), 7.25-7.40 (m, 2H), 7.10-7.30 (m, 1H), 6.95-7.05 (m, 2H); 13C NMR (CDCl3) δ 157.8, 134.0, 133.8, 133.7, 133.6, 132.2, 124.7, 123.1, 120.8, 120.7, 119.6, 118.6, 115.4, 111.0, 110.9, 104.3, 77.4, 51.0, 39.4, 29.7, 24.7.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]([CH3:18])([CH2:16]O)[CH2:14][OH:15]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH:10]1[O:15][CH2:14][C:13]([CH3:18])([CH3:16])[CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCOCc1ccccc1
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)COC(COCc2ccccc2)OC1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
To a mixture of benzyloxyacetaldehyde (5 g, 33.3 mmol), 2,2-dimethyl-1,3-propanediol (4.16 g, 40 mmol) and toluene (70 ml), p-toluenesulfonic acid monohydrate (287 mg, 1.51 mmol) was added and refluxed for 4 hours while removing water by the Dean-Stark apparatus. After the reaction mixture was cooled to room temperature, triethylamine (4 ml) was added to the reaction mixture and the solvent was removed by evaporation. The residue was purified by silica gel column chromatography (silica gel: 200 g, elution solvent: ethyl acetate/heptane=1/9) to obtain the title compound (7.6 g, yield: 96.6%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>O1CCCC1>[C:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)CCc1ccc(OCc2ccc(N)cc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCc2ccc(NC(=O)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 134.2 %

Procedure:
To a solution of methyl 4-[(4-aminophenyl) methoxy]benzenepropanoate (0.13 g, 0.44 mmol) and triethylamine (0.50 mL) in tetrahydrofuran (9 mL) was added benzoyl chloride (74 mg, 0.53 mmol), and the mixture was stirred at room temperature for 2 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=18:1) to give the title compound (0.23 g, quantitative). oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH2:22])[CH:16]=1>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:22][C:17]2[CH:16]=[C:15]([CH3:14])[CH:20]=[C:19]([CH3:21])[N:18]=2)[CH:7]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: Cc1cc(C)nc(N)c1
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cc(C)cc(C)n1
Temperature: 140 °C
Yield: 15.1 %

Procedure:
To a solution of ethyl 4,6-dichloropyridazine-3-carboxylate (790 mg, 3.57 mmol) in acetonitrile (11.9 mL) was added 4,6-dimethylpyridin-2-amine (873 mg, 7.15 mmol) and heated at 140° C. in a sealed vial for 20 h. The mixture was concentrated in vacuo then purified by chromatography (silica, 0-8% acetone in dichloromethane) to give ethyl 6-chloro-4-(4,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxylate (165 mg, 538 μmol, 15%) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.60 (s, 1H), 9.24 (s, 1H), 8.75 (s, 1H), 8.59 (s, 1H), 4.58 (q, J=7.1 Hz, 2H), 2.53 (s, 3H), 2.33 (s, 3H), 1.52 (t, J=7.1 Hz, 3H); MS (EI/CI) m/z: 306.1 [M+H].
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([CH2:7][NH:8][CH2:9][C@@H:10]([OH:27])[C@@H:11]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1)#[N:2].[C:30](ON1C(=O)CCC1=O)([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31].CCN(CC)CC>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:9][C@@H:10]([OH:27])[C@@H:11]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24])[CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])=[CH:28][CH:29]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](O)CNCc1ccc(C#N)cc1
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](O)CN(Cc1ccc(C#N)cc1)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl (2S,3R)-4-(4-cyanobenzylamino)-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate (600 mg, 1.5 mmol) in CH2Cl2 (30 mL) was treated with Teoc-OSu (762 mg, 3.0 mmol, 2.0 equiv) and Et3N (304 mg, 3.0 mmol, 2.0 equiv). The mixture was allowed to stir overnight at rt. LC-MS analysis showed that all of the free amine had been consumed. The solution was washed with water, 1.0 M aq HCl, and brine, then over dried over Na2SO4, filtered and evaporated to leave tert-butyl (2S,3R)-4-(N-(4-cyanobenzyl)-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate. NMR analysis showed that the compound was of sufficient purity to use in the next step.