Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[F:12].[NH2:13][C:14]1[N:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=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>[C:26]([N:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:12])[CH:4]=3)=[N:19][CH:18]=2)[CH2:25][CH2:24]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: O=C(O)Cc1ccc(Cl)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(Cl)c(F)c3)nc2)CC1
Temperature: 25 °C

Procedure:
To a mixture of 2-(4-chloro-3-fluorophenyl)acetic acid 168-1 (188 mg, 1.0 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (220 mg, 1.0 mmol) and HATU (400 mg, 1.05 mmol) in DMF (4 mL) was added DIEA (521 uL, 3.0 mmol) and the mixture was stirred at room temperature over night. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over Na2SO4 and the solvent was evaporated. The residue was subject to silica gel flash chromatography to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-chloro-3-fluorophenyl)acetamide 168-2. MS m/z 391.1 (M+1).
Reaction SMILES: [CH3:1][C@H:2]1[C@H:6]([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)[O:5][C:4](=[O:12])[NH:3]1.[H-].[Na+].[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[C:18]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:17]=1>CN(C=O)C>[Cl:15][C:16]1[N:17]=[C:18]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:19]=[C:20]([N:3]2[C@@H:2]([CH3:1])[C@H:6]([C:7]3[S:8][CH:9]=[CH:10][N:11]=3)[O:5][C:4]2=[O:12])[CH:21]=1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Reactant: C[C@@H]1NC(=O)O[C@H]1c1nccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1[C@H](c2nccs2)OC(=O)N1c1cc(Cl)nc(N2CCOCC2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
(4S,5R)-4-Methyl-5-thiazol-2-yl-oxazolidin-2-one (4.70 g, 20.1 mmol) was dissolved in 70 mL of DMF and cooled to 0° C. NaH (964 mg, 60% in oil, 24.1 mmol) was added under argon, and the reaction mixture was stirred for 30 minutes at 0° C. 4-(4,6-dichloropyrimidin-2-yl)morpholine (3.70 g, 20.1 mmol) dissolved in 30 mL of DMF was added, and the reaction mixture was stirred for 3 hours at 0° C., followed by stirring at RT for 2 hours. The reaction was then quenched by addition of aqueous NH4Cl, followed by dilution with EtOAc; the organic solvents were separated, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (80 g SiO2) using EtOAc in hexane from 0% to 100% in order to give the title compound (3.64 g, 48%). LC-MS: [M+H] 382.2, 384.1; Rt 1.10 min; (LCMS method 1). 1H NMR (400 MHz, CHCl3-d): 7.77 (d, 1H), 7.38-7.33 (m, 2H), 5.39 (d, 1H), 5.07-4.98 (m, 1H), 3.75-3.55 (m, 8H), 1.64 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=1.C(N(C(C)C)C(C)C)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1cc(N)n[nH]1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2ccnc(Cl)n2)n[nH]1
Temperature: -10 °C
Reaction time: 2 h
Yield: 19.2 %

Procedure:
A mixture of 2,4-dichloropyrimidine (0.967 g, 6.49 mmol), 3-amino-5-methylpyrazole (0.63 g, 6.40 mmol), and ethyldiisopropylamine (2.8 mL, 16.22 mmol) in ethanol (13 mL) was stirred at −10° C. for 2 h, then at r.t. overnight, and finally at 50° C. for 3.5 h. The mixture was concentrated to a total volume of approximately 10 mL. Upon repeated addition of diethylether, (2-chloropyrimidin-4-yl)-(5-methylpyrazol-3-yl)amine (0.258 g, 1.23 mmol, 19%) was obtained as colourless crystals. LC/ESI-MS: m/z=210 [M(35Cl)+H]+; m/z=208 [M(35Cl)−H]−; Rt=230 min.
Reaction SMILES: [OH-].[K+].[CH:3]([NH:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])=[S:8])=O.Cl>O>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:9]1[CH:3]=[N:5][N:6]=[C:7]1[SH:8]
Reactant: O=CNNC(=S)Nc1ccccc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Fc1ccccc1-n1cnnc1S
Reaction time: 1 h

Procedure:
One and one-tenth grams (20 mmoles) of potassium hydroxide were dissolved in 50 ml. of water. 1-Formyl-4-(2-fluorophenyl)thiosemicarbazide, 3.5 g. (16.5 mmoles), was dissolved in the basic solution by warming on the steam bath until solution was completed. The heating was continued for one hour. The cooled reaction mixture was poured into a dilute solution of hydrochloric acid. The insoluble product was recovered from the acidic solution by filtration. The product was washed with water, collected and dried. The yield was 2.5 g. of 4-(2-fluorophenyl)-1,2,4-triazole-3-thiol, m.p. about 166°-167° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([C:31]3[CH:32]=[CH:33][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=3)[N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2nc(Cl)ncc2Cl)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2nc(-c3ccc(S(C)(=O)=O)cc3)ncc2Cl)CC1

Procedure:
The title compound is prepared from 4-(2,5-dichloro-pyrimidin-4-ylethynyl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(methanesulfonyl)phenylboronic acid following a procedure analogous to that described for Intermediate 14. LC (method 7): tR=1.58 min; Mass spectrum (ESI+): m/z=476 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[N+:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33])([O-:28])=[O:27]>O1CCCC1>[N+:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6])=[O:33])([O-:28])=[O:27]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CC(N)c1ccc(OC)c(OC)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CC(NC(=O)c1cccc([N+](=O)[O-])c1)c1ccc(OC)c(OC)c1
Yield: 95.3 %

Procedure:
To an ice bath cooled stirred suspension of methyl 3-amino-3-(3,4-dimethoxyphenyl)propionate hydrochloride (1.38 grams, 5.00 mmol) and triethylamine (1.5 milliliters, 10.8 mmol) in 10 milliliters of tetrahydrofuran was added 3-nitrobenzoyl chloride (0.928 grams, 5.00 mmol) in a single portion. A thick slurry resulted. The cooling bath was removed after 15 minutes, the mixture diluted with 10 milliliters of tetrahydrofuran and the mixture stirred for an additional hour. The reaction mixture was diluted with 50 milliliters of water and then partially concentrated in vacuo to remove the tetrahydrofuran. The reaction slurry was filtered, the solid washed with copious amounts of water, air-dried, and dried in vacuo (60° C., <1 mm) to afford 1.85 grams (95%) of the product as an off white powder: 1H NMR (CDCl3, 250 MHz) δ 8.63 (t, J=1.9 Hz, 1 H), 8.35 (m, 1 H, Ar), 8.20 (m, 1 H, Ar), 7.77 (d, J=8 Hz, 1 H, NH), 7.63 (t, J=8.0 Hz, 1 H), 6.95-6.75 (m, 3 H, Ar), 5.86 (m, 1 H, CHCO), 3.85 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3), 3.68, (s, 3 H, CO2CH3), 3.01 (m, 2 H, CH2); 13C NMR (CDCl3) δ 172.0, 164.1, 149.1, 148.6, 148.2, 135.8, 133.1, 132.7, 129.8, 126.1, 122.0, 118.2, 111.2, 109.9, 55.9, 55.8, 52.0, 50.2, 39.5.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=O)[C:15]([OH:17])=[O:16])[N:13]=1)=[O:7].Cl.[O:20]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[NH2:21].Cl>O>[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:21][O:20][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:15]([OH:17])=[O:16])[N:13]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)CON
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
Sodium bicarbonate (4.2 g.) was added to a suspension of 2-(2-formamidothiazol-4-yl)glyoxylic acid (10 g.) in water (500 ml.) to prepare a solution. t-Butyl 2-aminoxyacetate hydrochloride (8.1 g.) was added to the solution and stirred at room temperature for 3 hours while adjusting to pH 6 with sodium bicarbonate. The resultant solution was adjusted to pH 1.5 with hydrochloric acid, salted out and extracted with ethyl acetate three times. The extract was dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diethyl ether, and the precipitates were collected by filtration and dried to give 2-(2-formamidothiazol-4-yl)-2-t-butoxycarbonylmethoxyiminoacetic acid (syn isomer, 11.3 g.), mp 117° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[C:14]([NH:16][CH2:17][C:18]#[N:19])=[O:15])[CH:7]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>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]>[Cl:20][C:5]1[CH:4]=[CH:3][C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][C:6]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([NH:16][CH2:17][C:18]#[N:19])=[O:15]
Reactant: N#CCNC(=O)C1CCCCN1c1cc(Br)ccc1Cl
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: N#CCNC(=O)C1CCCCN1c1cc(-c2ccccc2)ccc1Cl
Temperature: 110 °C

Procedure:
A mixture of 1-(5-bromo-2-chlorophenyl)-N-(cyanomethyl)piperidine-2-carboxamide (125 mg, 0.35 mmol), phenylboronic acid (64 mg, 0.53 mmol), PdCl2(dppf) (29 mg, 0.035 mmol) and 2 N Na2CO3 (0.5 mL, 1.1 mmol) in DMF (3.5 mL) was degassed and then heated to 110° C. for 4 h. The mixture was cooled and partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×) and the combined organic layers were dried over Na2SO4 and concentrated. Purification by flash chromatography (50% Et2O/hexanes) afforded 1-(4-chloro-1,1′-biphenyl-3-yl)-N-(cyanomethyl)piperidine-2-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8](C(O)=O)[S:7][C:6]=2[CH:13]=1.Cl>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:13]=1
Reactant: O=C(O)c1cc2ccc(Br)cc2s1
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Product: Brc1ccc2ccsc2c1
Temperature: 195 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
Copper powder (100 g, 1.57 mol) is added to a solution of 6-bromo-benzo[b]-thiophene-2-carboxylic acid (1.04 Kg, 4.04 mol) in quinoline (2.5 L) at room temperature. The reaction mixture is heated to reflux (195° C.) for 10 h. The reaction mixture is cooled to room temperature and poured onto ice (2.5 Kg). Concentrated HCl (2.5 L) is added while stirring the resulting mass for 1 h. The reaction mixture is extracted with hexane (4×3 L) and washed with dilute HCl (1×2 L), aqueous bicarbonate (1×5 L), and brine solution (1×5 L). The layers are separated and the organic layer is dried over sodium sulfate and concentrated to give the title compound (0.54 Kg, 62%) as a light yellow solid.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[C@H:14]([CH3:19])[CH2:13]3)[CH2:9]2)C=CC=CC=1>[OH-].[Pd+2].[OH-].[C].CO>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C@H:14]([CH3:19])[CH2:13]2)[CH2:9]1
Reactant: C[C@@H]1CN(C2CN(C(c3ccccc3)c3ccccc3)C2)CCN1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1CN(C2CNC2)CCN1C
Yield: 166.2 %

Procedure:
To a mixed solution of (2R)-4-(1-(diphenylmethyl)azetidin-3-yl)-1,2-dimethylpiperazine (342 mg, 1.02 mmol) described in Production Example 5-2 and methanol (10 mL) was added palladium hydroxide-carbon (200 mg) at room temperature. The resultant mixture was stirred under a hydrogen atmosphere at room temperature and at 0.35 MPa to 0.40 MPa for 5 hours. The reaction mixture was purged with a nitrogen atmosphere, and then filtrated using Celite. A filtrate was concentrated under a reduced pressure to give a mixture (287 mg) of the title compound and benzylbenzene. The product was used in the subsequent reaction without further purification.
Reaction SMILES: C[Al](C)C.[C:5]([N:9]1[C:13]([NH2:14])=[CH:12][C:11]([CH:15]2[CH2:18][C:17]([O:21][CH3:22])([O:19][CH3:20])[CH2:16]2)=[N:10]1)([CH3:8])([CH3:7])[CH3:6].C([O:25][C:26](=O)[C:27]([CH3:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH3:28])C.[NH4+].[Cl-]>CCCCCCC.C(Cl)Cl>[C:5]([N:9]1[C:13]([NH:14][C:26](=[O:25])[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)([CH3:35])[CH3:28])=[CH:12][C:11]([CH:15]2[CH2:16][C:17]([O:19][CH3:20])([O:21][CH3:22])[CH2:18]2)=[N:10]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CCOC(=O)C(C)(C)c1ccccn1
Reactant: COC1(OC)CC(c2cc(N)n(C(C)(C)C)n2)C1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCCCCCC
Product: COC1(OC)CC(c2cc(NC(=O)C(C)(C)c3ccccn3)n(C(C)(C)C)n2)C1
Reaction time: 0.25 h

Procedure:
A solution of trimethylaluminum in heptane (2.0 M, 19.5 mL) was added slowly to a solution of 2-tert-butyl-5-(3,3-dimethoxy-cyclobutyl)-2H-pyrazol-3-ylamine (8.98 g) in CH2Cl2 (60 mL) at room temperature. After 15 min, a solution of 2-methyl-2-pyridin-2-yl-propionic acid ethyl ester (6.85 g) in CH2Cl2 (60 mL) was added. The reaction mixture was heated to reflux overnight. Saturated aqueous NH4Cl solution was added and the mixture was extracted with CH2Cl2 (2×). The combined organic layers were dried over Na2SO4 and concentrated to afford N-[2-tert-butyl-5-(3,3-dimethoxy-cyclobutyl)-2H-pyrazol-3-yl]-2-pyridin-2-yl-isobutyramide as an oil that was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:13])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=[N:24]C=2C=1.N.O1CCOCC1.CN1CCOCC1>C(Cl)Cl>[NH2:24][C:10](=[O:11])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:13]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: On1nnc2ccccc21
Agent: N
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: ClCCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)C(N)=O
Reaction time: 1 h
Yield: 23 %

Procedure:
(R)-2-(tert-Butoxycarbonylamino)propanoic acid (1 g, 5.29 mmol), EDC (1.216 g, 6.34 mmol), and HOBt (0.971 g, 6.34 mmol) were dissolved in CH2Cl2 (5 mL). Ammonia (0.5 M) in dioxane (52.9 mL, 26.4 mmol) and 4-methylmorpholine (3.49 mL, 31.7 mmol) were added to the reaction mixture. After stirring for 1 h, the solvent was removed and ethyl acetate was added. This was washed with brine and saturated NaHCO3 solution. The organic layer was dried and concentrated to provide the product (R)-tert-butyl 1-amino-1-oxopropan-2-ylcarbamate (Int-X-A, 229 mg, 1.217 mmol, 23.02% yield); [M+Na]+=211.2; 1H NMR (400 MHz, methanol-d4) δ ppm 4.06 (1 H, q), 1.44 (9 H, s), 1.31 (3 H, d, J=7.04 Hz).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:8][CH:7]([CH:9]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[N:16](COCC[Si](C)(C)C)[CH:15]=2)=[O:13])[CH3:10])[CH2:6]1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]([CH:9]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[NH:16][CH:15]=2)=[O:13])[CH3:10])[CH2:8]1)(=[O:3])=[O:4]
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CN(S(C)(=O)=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: CC(NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CN(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.7 %

Procedure:
To a solution of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(1-methanesulfonyl-azetidin-3-yl)-ethyl]-amide (30 mg, 0.049 mmol) in CH2Cl2 (2 mL) was added TFA (0.3 mL, 3.89 mmol). The yellow reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in CH2Cl2 (2 mL) and ethylenediamine (0.3 mL, 4.49 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then quenched with water and extracted with MeOH/CH2Cl2 (1:9). The organic layer was washed with water and the aqueous was back-extracted with CH2Cl2. The combined organics were concentrated and the residue was triturated with MeOH/EtOAc/Et2O to afford 15 mg (63%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(1-methanesulfonyl-azetidin-3-yl)-ethyl]-amide as a pale yellow solid. MS (M+H)+=488; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 9.05 (br. s., 1H), 8.86 (s, 1H), 8.63 (s, 1H), 8.41 (d, J=8.7 Hz, 1H), 7.92 (s, 1H), 7.26 (d, J=8.7 Hz, 1H), 4.35-4.45 (m, 1H), 4.22-4.33 (m, 1H), 4.12 (s, 3H), 4.04-4.10 (m, 1H), 3.62-3.74 (m, 1H), 3.45-3.58 (m, 1H), 3.25 (s, 3H), 2.57-2.68 (m, 1H), 1.38 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][CH2:10][CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1>CO.O>[C:1]1([C:7]2[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:11][C:10]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2=NCCN=C2c2ccccc2)cc1
Reactant: COc1ccc(C=O)cc1
Solvent: CO
Solvent: O
Product: COc1ccc(Cc2cnc(-c3ccccc3)c(-c3ccccc3)n2)cc1

Procedure:
The same procedures as in Example 3 were repeated using 2,3-diphenyl-5,6-dihydropyrazine and p-anisaldehyde. 2,3-Diphenyl-5-(p-methoxybenzyl)pyrazine was obtained as colorless prisms, m.p. 102°-103° C. (recrystallized from methanol-water). Physical properties of the product support a chemical structure of the below formula (VIII).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9]([C:12]([CH3:14])=O)([CH3:11])[CH3:10]>>[CH3:14][C:12]1[C:9]([CH3:11])([CH3:10])[C:7]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:8]=2)[N:6]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(=O)C(C)C
Product: CC1=Nc2ccc(Cl)cc2C1(C)C
Yield: 86 %

Procedure:
p-Chloroaniline was reacted with methyl isopropyl ketone in the same way as in Example 3. 2,3,3-Trimethyl-5-chloro-3-H-indole was formed in a yield of 86% of the theoretical yield.
Reaction SMILES: CO[C:3](=O)[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].CC(C[AlH]CC(C)C)C.[CH3:33][O:34][C:35]([CH2:37]P(OC)(OC)=O)=[O:36]>>[CH2:9]([O:8][C:6]([NH:5][CH:4]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:3]=[CH:37][C:35]([O:34][CH3:33])=[O:36])=[O:7])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: CC(C)C[AlH]CC(C)C
Product: COC(=O)C=CC(Cc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
N-Benzyloxycarbonyl phenylalanine methyl ester is reduced with DIBAL to the aldehyde using the procedure of Boger et al., J. Med. Chem. (1985) 28, 1779, which is homologated with the sodio derivative of trimethyl phosphonoacetate using the procedure of Wadsworth and Emmons, Org. Synth. (1965) 45, 44 to give methyl 4-(benzyloxycarbonyl)amino-5-phenyl-2-pentenoate.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20]C)[CH:16]=2)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.C(O)(=O)C>O>[CH2:1]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2cc(CNCc3ccccc3)ccc2c1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc2cc(CNCc3ccccc3)ccc2c1
Yield: 61.4 %

Procedure:
A mixture of benzyl-(6-methoxy-naphthalen-2-ylmethyl)-amine (1.3 g, 4.7 mmol), prepared in the previous step, 65 mL of 48% HBr and 50 mL of glacial acetic acid was refluxed under nitrogen for 19 h (overnight). The solvent was removed under reduced pressure to give a red solid. The solid was suspended in 250 mL of water and heated until most of the solid dissolved. The mixture was filtered, the filtrate made basic with sodium bicarbonate and extracted three times with ethyl acetate. The organic extracts were combined, dried (MgSO4) and the solvent removed under reduced pressure to give 6-(benzylamino-methyl)-naphthalen-2-ol (0.76 g, 62%) as a green solid, mp 120-122° C.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:15]2[N:16]=[N:17][N:18]([C:20]3[CH:41]=[CH:40][C:23]([CH2:24][CH2:25][N:26]4[CH2:35][CH2:34][C:33]5[C:28](=[CH:29][C:30]([O:38][CH3:39])=[C:31]([O:36][CH3:37])[CH:32]=5)[CH2:27]4)=[CH:22][CH:21]=3)[N:19]=2)=[C:9]([N+:42]([O-])=O)[CH:8]=1.C(Cl)(Cl)Cl.CO.C(Cl)(Cl)Cl>[Fe].O>[CH3:37][O:36][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[O:38][CH3:39])[CH2:27][N:26]([CH2:25][CH2:24][C:23]1[CH:40]=[CH:41][C:20]([N:18]3[N:17]=[N:16][C:15]([C:10]4[CH:11]=[C:12]([O:13][CH3:14])[C:7]([O:6][CH3:5])=[CH:8][C:9]=4[NH2:42])=[N:19]3)=[CH:21][CH:22]=1)[CH2:35][CH2:34]2
Reactant: COc1cc2c(cc1OC)CN(CCc1ccc(-n3nnc(-c4cc(OC)c(OC)cc4[N+](=O)[O-])n3)cc1)CC2
Agent: [Fe]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(N)c(-c2nnn(-c3ccc(CCN4CCc5cc(OC)c(OC)cc5C4)cc3)n2)cc1OC
Temperature: 80 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
Iron (433 g, 7.76 mol) and 5.4 L of 50% aqueous acetic acid were added to a reactor, and stirred for 1 hour at 80° C. 2-(4-(5-(4,5-dimethoxy-2-nitrophenyl)-2H-tetrazol-2-yl)phenethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (1.06 kg, 1.94 mol) obtained in Step 4 was slowly added thereto for two hours, followed by stirring for 1 hour. After checking completion of the reaction by thin layer chromatography (eluent: chloroform/methanol=15/1), the reactor was cooled to room temperature. 5.3 L of chloroform and 2.4 L of water were added thereto and the resulting mixture was filtered through a Celite pad. The organic layer was collected, 6.6 L of saturated sodium bicarbonate solution was slowly added thereto with stirring. The organic layer was collected, and the aqueous layer was further extracted using 1.25 L of chloroform. The resulting organic layer was dried over magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was mixed with 10.6 L of methanol, followed by stirring. The resulting mixture was filtered, and dried with hot air at 40° C. in an oven to obtain the title compound (0.87 kg, 87%).