Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[ClH:11].NCCC1C=CC(OC)=C2C=1[CH2:17][C:18](=[O:26])[NH:19]2>>[ClH:11].[NH2:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]2[C:5]=1[CH2:17][C:18](=[O:26])[NH:19]2
Reactant: COc1ccc(CN)cc1
Reactant: COc1ccc(CCN)c2c1NC(=O)C2
Agent: Cl
Product: COc1ccc(CN)c2c1NC(=O)C2

Procedure:
Using 65 g of p-methoxybenzylamine for the starting material of Example 1 gives 4-aminomethyl-7-methoxy-2(3H)-indolone hydrochloride. This material (2 g) was converted to the base and alkylated using 1 mole equivalent of isovaleraldehyde as in Example 2 to give 4-isopentylaminomethyl-7-methoxy-2(3H)-indolone hydrobromide and 4-isopentylaminomethyl-7-hydroxy-2(3H)-indolone hydrobromide after demethylation using boron tribromide in methylene chloride at -20°.
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH2:8].CN1CCOCC1.[C:20]1(=[O:45])[N:24]([NH:25][C@H:26]([C:37](O)=[O:38])[CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][CH:29]=2)[C:23](=[O:40])[C:22]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:21]12.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(Cl)Cl>[C:23]1(=[O:40])[N:24]([NH:25][C@H:26]([C:37]([NH:8][C@H:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][OH:2])=[O:38])[CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][CH:29]=2)[C:20](=[O:45])[C:21]2=[CH:44][CH:43]=[CH:42][CH:41]=[C:22]12
Reactant: COC(=O)[C@@H](N)CCCCO
Reactant: O=C(O)[C@H](Cc1c[nH]c2ccccc12)NN1C(=O)c2ccccc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@H](CCCCO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The above crude 6-hydroxy-L-norleucine, methyl ester, hydrochloride was dissolved in dimethylformamide (6 ml.) and methylene chloride (25 ml.) and treated with 4-methylmorpholine (1.30 ml., 1.20 g., 11.8 mmol.). The solution was cooled to 0° C. and treated with N-phthalimido-L-tryptophan followed by hydroxybenzotriazole (925 mg., 6.8 mmol.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.438 g., 7.5 mmol.). The mixture was stirred at 0° C. for 0.5 hour and then at room temperature for 2.5 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed successively with 0.5 N hydrochloric acid, water, 5% sodium bicarbonate, and brine, then dried (sodium sulfate), filtered and stripped to give 3.06 g., of title product as a yellow foam. TLC: (ethyl acetate) Rf =0.35.
Reaction SMILES: C([O:3][C:4](=[O:23])/[CH:5]=[C:6](\[CH3:22])/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:21])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[C:16]([CH3:19])[O:15][C:14]=1[CH3:20])C.[OH-].[K+].C(O)(=O)C>C(O)C.O>[CH3:22]/[C:6](/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:21])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[C:16]([CH3:19])[O:15][C:14]=1[CH3:20])=[CH:5]\[C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(C)/C=C/c1c(C)oc(C)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(/C=C/c1c(C)oc(C)c1C)=C\C=C\C(C)=C\C(=O)O
Temperature: 25 °C

Procedure:
(E,E,E,E)-3,7-Dimethyl-9-(2,4,5-trimethyl-3-furyl)-2,4,6,8-nonatetraenoic acid ethyl ester (2.8 g.) was dissolved in ethanol (50 ml.) treated with potassium hydroxide (1.6 g.) in water (5 ml.) and heated at reflux for 30 minutes. After cooling to room temperature, water followed by acetic acid (until acid) was added and the solids were filtered off. Crystallization from ethylacetate gave pure (E,E,E,E)-3,7-dimethyl-9-(2,4,5-trimethyl-3-furyl)-2,4,6,8-nonatetraenoic acid (1.5 g.) m.p. 213°-214°.
Reaction SMILES: [H-].[Na+].[Cl-].[Cl:4][C:5]1[CH:6]=[C:7]([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:8]=[C:9]([Cl:11])[CH:10]=1.[CH2:32]1[O:42][C:35]2([CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]2)[O:34][CH2:33]1.O>CS(C)=O>[Cl:11][C:9]1[CH:8]=[C:7]([CH:12]=[C:38]2[CH2:39][CH2:40][C:35]3([O:42][CH2:32][CH2:33][O:34]3)[CH2:36][CH2:37]2)[CH:6]=[C:5]([Cl:4])[CH:10]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Clc1cc(Cl)cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Clc1cc(Cl)cc(C=C2CCC3(CC2)OCCO3)c1
Temperature: 90 °C
Yield: 32.4 %

Procedure:
Under a nitrogen atmosphere, a stirred mixture of 4.2 grams (0.11 mole) of sodium hydride (60% in mineral oil) in 200 mL of anhydrous dimethyl sulfoxide was heated to about 90° C. where it was maintained for 10 minutes. After this time the reaction mixture was cooled to 25° C., and 46.0 grams (0.10 mole) of 3,5-dichlorophenylmethyltriphenylphosphonium chloride was added, followed by 14.0 grams (0.10 mole) of 1,4-cyclohexanedione mono-ethylene ketal. Upon completion of addition the reaction mixture was again warmed to 90° C., then it was allowed to cool to ambient temperature. After this time the reaction mixture was poured into 400 mL of water, and the mixture was extracted with two 250 mL portions of diethyl ether. The combined extracts were then washed with two 100 mL portions of water. The organic layer was concentrated under reduced pressure to an oily solid residue. The oily solid was taken up in a solution of 90 mL of petroleum ether and 10 mL of diethyl ether, and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography using silica gel. Elution was accomplished using 10% diethyl ether in petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 9.7 grams of 8-(3,5-dichlorophenylmethylene)-1,4-dioxaspiro[4.5]decane, mp about 66° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:2]1.C(Cl)(=O)OCC.[CH3:17][O:18][C:19]1[CH:24]=[C:23]2[C:25]([NH2:35])=[N:26][C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:28][C:22]2=[CH:21][C:20]=1[O:36][CH3:37]>C(N(CC)CC)C.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][C:8]([N:32]2[CH2:33][CH2:34][N:29]([C:27]3[N:26]=[C:25]([NH2:35])[C:23]4[C:22](=[CH:21][C:20]([O:36][CH3:37])=[C:19]([O:18][CH3:17])[CH:24]=4)[N:28]=3)[CH2:30][CH2:31]2)=[O:10])=[CH:2]1
Reactant: O=C(O)C=Cc1ccoc1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc2nc(N3CCN(C(=O)C=Cc4ccoc4)CC3)nc(N)c2cc1OC
Reaction time: 3 h
Yield: 59 %

Procedure:
To a mixture of 276 mg. (2 mM) of 3-(furan-3-yl)acrylic acid, and 242 mg. (2.4 mM) of triethylamine in 10 ml. of ethyl acetate was added dropwise under ice-cooling a solution of 260 mg. (2.4 mM) of ethyl chlorocarbonate in 5 ml. of ethyl acetate. The resulting mixture was stirred for 3 hours and 761 mg. (2 mM) of 2-piperazine-4-amino-6,7-dimethoxyquinazoline and 484 mg. (4.8 mM) of triethylamine were odded thereto. Stirring was continued at room temperature for further one day. The precipitate thus separated was recovered by filtration and washed well with water to give 480 mg. of the desired product.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([Cl:17])(=O)C>>[Cl-:17].[CH:6](=[N+:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)Cl
Reactant: O=Cc1ccccc1
Reactant: C1CCNC1
Product: C(c1ccccc1)=[N+]1CCCC1
Product: [Cl-]

Procedure:
The reaction of 16.4 ml (0.200 mol) pyrrolidine and 10.1 ml (0.100 mol) benzaldehyde in accordance with general synthesis instructions 2 and subsequent reaction with 6.0 ml (0.100 mol) acetyl chloride in accordance with general synthesis instructions 3 gave 14.1 g (corresponding to 72% of the yield calculated by theory) 1-benzylidene-pyrrolidinium chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:19][CH2:18][C@H:17]1[CH:20]=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:19][CH2:18][C@H:17]1[CH2:20][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C=O
Reactant: Nc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H]1CNc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a solution of 4-chloro-aniline (0.57 g, 4.5 mmol) in methanol (18 ml) were added acetic acid (2 ml), (S)-2-formyl-azetidine-1-carboxylic acid tert.butyl ester (1.74 g, 9.4 mmol) and after 15 min stirring sodium cyanoborohydride (0.57 g, 9.0 mmol). The resulting suspension was stirred for 2 hours at room temperature. Aqueous sodium bicarbonate solution (20 ml) was added and the mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were dried with magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2: heptane/ethyl acetate=9:1) to yield a colourless oil (0.99 g, 74%); MS (ISP): 297.1 ((M+H)+.); 241.3 ((M−C(CH3)3+H)+.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([NH2:12])[C:8]([NH2:11])=[CH:9][CH:10]=1)=[O:4].N1C=CC=CC=1.[C:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>C(#N)C>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([NH:12][C:7]2[C:8]([NH2:11])=[CH:9][CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=2)=[O:28])=[CH:30][CH:31]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: COC(=O)c1ccc(N)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Reaction time: 3 h

Procedure:
To a stirring solution of 4-methoxycarbonyl-1,2-benzenediamine (8.5 g, 51 mmol) and pyridine (4.1 mL, 51 mmol) in acetonitrile (225 mL) at 0° C. was added via an addition funnel a solution of 4-t-butylbenzoyl chloride (10 g, 51 mmol) in acetonitrile (25 mL). After 3 h, the mixture was concentrated to a volume of about 20 mL in vacuo and then diluted with ethyl acetate (300 mL) and water (100 mL). The phases were separated and the organic phase was washed twice with 1 M citric acid, once with brine, twice with satd aq NaHCO3 and once again with brine. The organic phase was then dried with MgSO4, filtered and partially concentrated in vacuo. After standing for 48 h, the resulting precipitate was filtered, washed with ethyl acetate and dried in vacuo to give 8.2 g (48%) of off white solid. By a similar procedure, a second crop of 2.6 g (16%) was isolated from the mother liquor.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:7][CH:8]([Cl:12])[C:9]([OH:11])=[O:10]>ClCCl>[Cl:7][CH:8]([Cl:12])[C:9]([O-:11])=[O:10].[NH+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C(Cl)Cl
Reactant: c1ccncc1
Solvent: ClCCl
Product: O=C([O-])C(Cl)Cl
Product: c1cc[nH+]cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pyridinium dichloroacetate was prepared in situ by addition of 1.3 equivalents of pyridine (0.49 mL, 6.07 mmol) to dry dichloromethane (4 mL) followed by addition of 1.2 eq. of dichloroacetic acid (0.46 mL, 5.60 mmol). To this mixture was added bisamidite reagent (1.78 mL, 5.60 mmol) followed by the dropwise addition of 2′-deoxy-5′-O-DMT-4-N-benzoylcytidine (2.97 g, 4.67 mmol) dissolved in dry dichloromethane (6 mL). The reaction mixture was stirred under argon at ambient temperature for 2 hours and transferred directly to the top of a short silica gel column. The amidite product was eluted with 70% tOAc/hexanes (1% triethylamine). The appropriate fractions ere collected and evaporated to give 3.47 g (89%) of the title compound as a white foam. 31P NMR (CDCl3) δ 149.29, 149.88.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH2:21]>>[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:3]=1
Reactant: COCc1cc(Cl)nc(-c2cccc(C)c2)n1
Reactant: COc1ccc(Cl)c(N)c1
Product: COCc1cc(Nc2cc(OC)ccc2Cl)nc(-c2cccc(C)c2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine (50 mg, 0.201 mmol) and 2-chloro-5-methoxyaniline (39 mg, 0.201 mmol) similar to Example 13 and isolated as a white solid (18 mg, 24%). 1H NMR (CDCl3): 8.27–8.25 (m, 3H), 7.40 (t, J=7.7 Hz, 1H), 7.34 (d, J=8.7 Hz, 1H), 7.33 (s, 1H), 7.19 (s, 1H), 6.83 (s, 1H), 6.66 (dd, J=3.0, 9.0 Hz, 1H), 4.59 (s, 2H), 3.93 (s, 3H), 3.58 (s, 3H), 2.47 (s, 3H).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:14]([C:15]3[N:16]=[CH:17][S:18][C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[Cl:27])=[CH:13][C:12]([Br:28])=[CH:11][N:10]=2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:28][C:12]1[CH:13]=[C:14]([C:15]2[N:16]=[CH:17][S:18][C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=2[Cl:27])[C:9]([NH2:8])=[N:10][CH:11]=1
Reactant: COc1ccc(CNc2ncc(Br)cc2-c2ncsc2-c2cccc(Cl)c2Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(Br)cc1-c1ncsc1-c1cccc(Cl)c1Cl
Yield: 2 %

Procedure:
A solution of N-(4-methoxybenzyl)-5-bromo-3-(5-(2,3-dichlorophenyl)thiazol-4-yl)pyridin-2-amine (110 mg) and TFA (100 μL) in methylene chloride (2 mL) was stirred at 40° C. overnight. The reaction was concentrated and purified by reversed-phase HPLC to give 5-bromo-3-(5-(2,3-dichlorophenyl)thiazol-4-yl)pyridin-2-amine as a white solid [1.1 mg, 2% yield; LC-MS M+H=519.9; 1H-NMR (300 MHz, methanol-d4) 9.17 (1H, d), 7.95 (1H, d), 7.60-7.63 (2H, m), 7.34-7.35 (1H, m), 7.27 (1H, dd)].
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C[CH:13]([NH2:16])[CH:14]=[O:15].[C:17](OCC)(=O)C>>[CH3:17][N:16]([CH2:13][CH:14]=[O:15])[C:10]([NH:9][C:7]1[S:8][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][N:6]=1)=[O:11]
Reactant: CCOC(C)=O
Reactant: CC(N)C=O
Reactant: O=C=Nc1nnc(C2CC2)s1
Product: CN(CC=O)C(=O)Nc1nnc(C2CC2)s1

Procedure:
A mixture of 5-cyclopropyl-1,3,4-thiadiazol-2-yl isocyanate dimer (7 grams), the dimethyl acetal of 2-methyl-aminoacetaldehyde (5 grams) and ethyl acetate (50 ml) were charged into a glass reaction vessel equipped with a mechanical sirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 2 hours. After this time the mixture is stripped of solvent under reduced pressure to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)ureido]-acetaldehyde as an oil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([O:6][C:7]1[CH:8]=[C:9]([O:22][C:23]2[N:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=2)[CH:10]=[C:11]([C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:12]=1)[CH2:4][CH3:5].Cl.[NH:33]1[CH2:36][CH2:35][CH2:34]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>CN(C=O)C.O>[N:33]1([C:29]([C:26]2[N:27]=[CH:28][C:23]([O:22][C:9]3[CH:10]=[C:11]([CH:12]=[C:7]([O:6][C@H:3]([CH2:2][OH:1])[CH2:4][CH3:5])[CH:8]=3)[C:13]([NH:15][C:16]3[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=3)=[O:14])=[N:24][CH:25]=2)=[O:30])[CH2:36][CH2:35][CH2:34]1
Reactant: C1CNC1
Reactant: CC[C@@H](CO)Oc1cc(Oc2cnc(C(=O)O)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC[C@@H](CO)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)Nc2ccn(C)n2)c1

Procedure:
A solution of 5-[(3-{[(1S)-1-(hydroxymethyl)propyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylic acid (12 mg, 0.03 mmol), azetidine hydrochloride (4 mg, 0.06 mmol), HATU (14 mg, 0.04 mmol) and DIPEA (0.02 mL, 0.11 mmol) in DMF (1 mL) was stirred at RT over the weekend. Water (15 mL) was added and the solution extracted with ethyl acetate (25 mL). The ethyl acetate layer was washed with brine (20 mL), dried (MgSO4), and evaporated to a residue which was chromatographed by preparative HPLC on C18 reversed phase, eluting with 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA), to give the required product along with 15% of a co-eluting impurity (5 mg). 1H NMR δ (CDCl3): 0.92 (t, 3H), 0.97 (t, 0.45H), 1.69 (quin, 2H), 1.76 (m, 0.3H), 2.34 (quin, 2H), 3.76 (m, 2H), 3.86 (s, 3H), 4.23 (t, 2H), 4.49 (sextet, 1H), 4.66 (t, 2H), 4.77 (m, 0.15H), 6.93 (t, 1H), 6.99 (d, 1H), 7.34 (s, 1H), 7.46 (s, 1H), 7.50 (s, 1H), 8.29 (s, 1H), 8.78 (s, 1H), 10.68 (s, 1H), 10.78 (s, 0.15H); m/z 468 (M+H)+
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][C:4](/[N:6]=[C:7](/[N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)\SC)=O.C(O)(=O)C(O)=O.[CH2:22]([NH:24][NH2:25])[CH3:23].C(N(CC)C(C)C)(C)C>O1CCOCC1.C(OCC)(=O)C>[CH2:22]([N:24]1[C:4]([CH:3]=[C:2]([CH3:15])[CH3:1])=[N:6][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:25]1)[CH3:23]
Reactant: CS/C(=N\C(=O)C=C(C)C)N1CCCC1
Reactant: CCNN
Agent: O=C(O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCn1nc(N2CCCC2)nc1C=C(C)C
Temperature: 100 °C
Reaction time: 3 h
Yield: 38.1 %

Procedure:
A mixture of (Z)-methyl N-3-methylbut-2-enoylpyrrolidine-1-carbimidothioate (1.19 g, 5.26 mmol, Eq: 1.00), ethylhydrazine oxalate (2.37 g, 15.8 mmol, Eq: 3) and N,N-diisopropyl ethyl amine (5.44 g, 7.15 ml, 42.1 mmol, Eq: 8) in dioxane (20 ml) was heated to 100° C., the resulting suspension was stirred for 3 hours at 100° C. The mixture was diluted with ethyl acetate and washed with water for 3 times. The organic layer was separated, dried over magnesium sulfate, filtrated and evaporated. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using heptane/ethyl acetate 30-70% as eluent affording 1-ethyl-5-(2-methyl-propenyl)-3-pyrrolidin-1-yl-1H-[1,2,4]triazole (441 mg/38.1%) as a light yellow oil. MS: m/e=221.0 (M+H+)
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]3[N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([CH2:27][OH:28])[CH:12]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>ClCCl>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]3[N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([CH2:27][O:28][S:37]([CH3:36])(=[O:39])=[O:38])[CH:12]=2)=[CH:7][CH:6]=1
Reactant: COCOc1ccc(-c2cc(CO)c3c(C)nn(C4CCCCO4)c3n2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COCOc1ccc(-c2cc(COS(C)(=O)=O)c3c(C)nn(C4CCCCO4)c3n2)cc1

Procedure:
A solution of 120 mg [6-(4-methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-methanol and 44 mg of triethylamine in 4 ml of dry dichloromethane was cooled to 0° C. and 47 mg of methanesulfonyl chloride were added. The reaction was brought to room temperature, dichloromethane and water were added and the phasese were separated. The aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulphate, filtrated and concentrated. 170 mg (quant.) of the crude product were obtained as a yellow solid, which was used without further purification.
Reaction SMILES: BrC1C=C(O[Si:9]([CH2:14][CH3:15])([CH2:12][CH3:13])[CH2:10][CH3:11])C=CC=1.[CH2:16]([Li])[CH2:17][CH2:18][CH3:19].CCO[C:24]([CH3:26])=[O:25].Cl>C(OCC)C.O>[CH2:10]([Si:9]([CH2:14][CH3:15])([CH2:12][CH3:13])[C:17]1[CH:16]=[C:24]([OH:25])[CH:26]=[CH:19][CH:18]=1)[CH3:11]
Reactant: CC[Si](CC)(CC)Oc1cccc(Br)c1
Reactant: [Li]CCCC
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CC[Si](CC)(CC)c1cccc(O)c1
Temperature: -10 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
A 500 ml flask equipped with a magnetic stirring bar and a pressure equalizing addition funnel, maintained under static argon atmosphere, was charged with silane (J) (45 g, 157 mmol) dissolved in diethyl ether (100 ml). To this vigorously stirred mixture, maintained at -10° C. in an ice-acetone bath, n-butyllithium (2.5M solution in hexane, 75 ml, 188 mmol) was added dropwise over a period of 20 min. Then the mixture was allowed to warm to room temperature. The reaction was complete in 3 h (TLC, ligroin 950:EtOAc=5:1). The mixture was poured into 250 ml of cold water and acidified with hydrochloric acid. The organic layer was separated and the aqueous layer extracted with 3×75 ml portions of ether. The combined extracts were dried over magnesium sulfate, and solvents removed on a rotary evaporator to yield an orange oil, which on purification by flash chromatography (ligroin 950:Et2O=7:1) furnished 3-triethylsilylphenol (K) (23.7 g, 73% yield) as a pale yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:14])[N:8]([CH3:15])[C:7]=2[CH:6]=[CH:5][C:4]=1[N+:16]([O-])=O.O.NN>[Pd].C(O)C>[NH2:16][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH3:15])[C:9](=[O:14])[CH2:10][CH2:11][CH2:12][C:13]=2[C:3]=1[O:2][CH3:1]
Reactant: COc1c([N+](=O)[O-])ccc2c1CCCC(=O)N2C
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1c(N)ccc2c1CCCC(=O)N2C
Temperature: 60 °C
Yield: 92.5 %

Procedure:
6-Methoxy-1-methyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (530 mg, 2.12 mmol) in a 4:1 mixture of ethanol (17 mL) and hydrazine hydrate (4.5 mL) was heated to 60° C. and to it was added a ¼ mass equivalent of 10% Palladium/Carbon (50% H2O) (135 mg). The reaction was monitored by LC/MS to ensure that complete reduction occurred, and upon completion was cooled to room temperature. The Pd/C was filtered through celite, and the resulting filtrate concentrated to a minimal volume. This was then brought up in ˜120 mL of CH2Cl2 and washed with ˜25 mL of brine to remove excess hydrazine. The organic layer was then dried with MgSO4 and concentrated to give 7-Amino-6-methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a yellow gummy solid (432 mg, 93%). 1H-NMR (CDCl3) δ 6.78 (d, J=8.6 Hz, 1H), 6.65 (d, J=8.6 Hz, 1H), 3.81 (br s, 2H), 3.75 (s, 3H), 3.28 (s, 3H), 2.35-2.75 (br pk, 2H), 2.30 (t, J=6.9 Hz, 2H), 2.15 (m, 2H); LC/MS (ESI-pos) m/z 221.13 (M+H).
Reaction SMILES: C(N(CCC)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)CC.[CH3:31][O:32][C:33]1[C:38]([CH3:39])=[CH:37][N:36]=[C:35]([CH:40]=O)[C:34]=1[CH3:42].[C:43]([BH3-])#[N:44].[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH2:6]([N:44]([CH2:43][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:20]([CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)[CH2:40][C:35]3[C:34]([CH3:42])=[C:33]([O:32][CH3:31])[C:38]([CH3:39])=[CH:37][N:36]=3)=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)[CH2:7][CH2:8][CH3:9])[CH2:5][CH3:10]
Reactant: [BH3-]C#N
Reactant: CCCN(CCC)c1ccc(NC(=O)c2ccc(CNCc3ncc[nH]3)cc2)cc1
Reactant: COc1c(C)cnc(C=O)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc(C)c(OC)c3C)cc2)cc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
The compound (70.1 mg) obtained in Example 47-3 was dissolved in methanol (5.0 ml) and added with the compound (55.2 mg) obtained in Example 64-1, followed by the addition of sodium cyanoborohydride (31.5 mg). Then, the reaction solution was adjusted to about pH 5 with acetic acid, followed by stirring at room temperature for 21 hours. The reaction solution was added with a saturated aqueous sodium bicarbonate solution and then extracted with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off. The resulting crude product was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (36.4 mg) of the subject compound as a white solid.