Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][CH:13]1[O:18][CH2:17][CH2:16][NH:15][CH2:14]1.C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:12][CH:13]1[CH2:14][N:15]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=2)[NH2:7])[CH2:16][CH2:17][O:18]1
Reactant: CC1CNCCO1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC1CN(c2ccc([N+](=O)[O-])c(N)c2)CCO1
Temperature: 100 °C
Yield: 70 %

Procedure:
5-Chloro-2-nitroaniline (200 mg, 1.159 mmol) was added to a solution of 2-methylmorpholine (176 mg, 1.738 mmol) in NMP (5 mL) in the presence of triethylamine (0.404 mL, 2.90 mmol). The reaction mixture was heated via microwave irradiation to 100° C. for 1 h. and upon cooling, the solvent was removed by vacuum. Purification by flash column chromatography (5% CH3OH/CH2Cl2) afforded the title compound as a solid in a 70% yield. 1H NMR: (400 MHz, DMSO-d6): δ 7.79 (d, 1H, J=9.6 Hz), 7.25 (bs, 2H), 6.39 (dd, 1H, J=2.8 and 9.6 Hz), 6.20 (d, 1H, J=2.8 Hz), 3.88 (dd, 1H, J=2.8 and 12.0 Hz), 3.69 (d, 1H, J=12.8 Hz), 3.56 (m, 2H), 2.82 (m, 1H), 2.15 (t, 1H, J=7.6 Hz), 1.88 (m, 1H), 1.12 (d, 3H, J=6.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[N+](=[CH2:13])=[N-]>CCOCC>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:13])=[O:6]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1cccc(F)c1
Solvent: CCOCC
Product: COC(=O)c1cccc(F)c1
Temperature: 0 °C
Yield: 84.4 %

Procedure:
To an ice-cooled and stirred solution of m-fluorobenzoic acid (8.0 g, 57 mmol) in 50 ml of ether was added an excess solution of diazomethane in ether. After concentration, the residue was distilled under reduced pressure to give a colorless transparent oil of methyl m-fluorobenzoate (7.4 g, 48.1 mmol, yield 84.4%, b.p. 80°-82° C./16 mmHg), which was assigned the structure by the following data:
Reaction SMILES: [CH3:1][C@H:2]([OH:5])[C:3]#[CH:4].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.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.[Cu]I>[F:6][C:7]1[C:8]([C:4]#[C:3][C@@H:2]([OH:5])[CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#C[C@H](C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@H](C)O)c21

Procedure:
Using Method C above, (S)-but-3-yn-2-ol (38 mg, 0.54 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.14 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (16 mg, 0.01 mmol) and CuI (2 mg) in a mixture of DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-butynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one was obtained after silica gel column with a 0-10% MeOH in CH2Cl2 gradient and trituration with Et2O. (Yield 21 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]=[C:13]1[O:17][C:15](=O)[CH2:14]1.C(OC(=O)C)(=O)C>CC(C)=O>[CH3:11][C:7]1[C:3]2[C:4](=[O:6])[O:5][C:15]([CH2:14][C:13](=[O:17])[CH3:12])=[N:1][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: C=C1CC(=O)O1
Reactant: Cc1cccc(N)c1C(=O)O
Solvent: CC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Cc1nc2cccc(C)c2c(=O)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a solution of 2-amino-6-methylbenzoic acid (20 g, 0.132 mol) in acetone (100 mL), diketene (15.3 mL, 0.198 mol) was added dropwise at room temperature, and the mixture was stirred overnight at room temperature. The reaction solvent and excess diketene were concentrated and evaporated under reduced pressure, and tetrachloride (80 mL) were added to the residue, and subsequently acetic anhydride (27 g, 0.265 mol) was added thereto, and the mixture was heated under reflux for 3 hours. The reaction solvent and excess acetic anhydride were concentrated and evaporated under reduced pressure, and the resulting powder was collected, and washed with diethylether to give crude 5-methyl-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one (13.75 g, 48% yield). A solution of the compound (12.99 g, 0.06 mol) and 2-hydrazinopyridine (7.18 g, 0.066 mol) in ethanol (100 mL) was heated under reflux for 1 hour. The reaction solution was allowed to cool to room temperature, the reaction solvent was concentrated and evaporated under reduced pressure. A solution of the residue in phosphorous oxychloride (45.8 g, 0.3 mol) was heated and stirred at 100° C. for 1 hour. The reaction solution was allowed to cool to room temperature, and the solvent was concentrated and evaporated under reduced pressure, and the residue was poured into iced water. A sodium hydroxide solution was added to the mixture to become basic, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate:methanol=98:2) to give the title compound (4.4 g, 24% yield)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1(O[CH2:17]1)[C@H:10](OS(C)(=O)=O)[CH3:11].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.[OH-:24].[Na+].Cl>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:17][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[C@H:10]([CH3:11])[O:24]1
Reactant: c1nc[nH]n1
Reactant: C[C@@H](OS(C)(=O)=O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 36 %

Procedure:
In DMF (130 ml), (2R,3R)-3-(2,4-difluorophenyl)-3,4-epoxy-2-methanesulfonyloxybutane (82.8 g, 0.3 mol) and 1,2,4-triazole (26.7 g, 0.39 mol) were dissolved and heated to about 60° C. with stirring. 20% aqueous sodium hydroxide solution (103.8 g, 0.37 mol) was dropped thereto over about 1.5 hours and further stirred for 7 hours at the same temperature for the reaction. After the reaction, the mixture was cooled and toluene (150 ml) was added thereto. The obtained mixture was neutralized (pH 7-8) with 35% hydrochloric acid and subjected to phase separation. The water layer was extracted with toluene (150 ml) three times. The combined toluene layer was washed with diluted hydrochloric acid, aqueous sodium hydrogen carbonate solution and water subsequently, and the solvent was distilled off under a reduced pressure. The concentrated residue was subjected to recrystallization from a mixed solvent of toluene/heptane (20/80; v/v, 400 ml) to give (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (27.1 g, yield 36.0%, optical purity (HPLC condition-1) 100% e.e., mp 89° C.).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].Cl[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:9]>>[OH:4][CH2:3][CH:2]([NH:1][C:8](=[O:9])[O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:5][OH:6]
Reactant: NC(CO)CO
Reactant: CCCCOC(=O)Cl
Product: CCCCOC(=O)NC(CO)CO

Procedure:
The general procedure described in Example 2 was followed using serinol and n-butyl chloroformate to prepare nBuDHPC.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:48][CH3:49])=[N:4][C:5]([CH2:46][CH3:47])=[CH:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[N:23]=[N:24][N:25]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=2)=[CH:12][CH:11]=1.[CH3:50]C(C)([O-])C.[K+].O1CCOCCOCCOCCOCCOCC1.IC>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:48][CH3:49])=[N:4][C:5]([CH2:46][CH3:47])=[CH:6][C:7]=1[N:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[N:23]=[N:24][N:25]([C:27]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=2)=[CH:14][CH:15]=1)[CH3:50]
Reactant: CC(C)(C)[O-]
Reactant: CCc1cc(NCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(Cl)c(CC)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CCc1cc(N(C)Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(Cl)c(CC)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.3 %

Procedure:
3-Chloro-2,6-diethyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methylamino]pyridine (335 mg) was added to a mixture of potassium t-butoxide (75 mg) and 1,4,7,10,13,16-hexaoxacyclooctadecane (10 mg) in THF (10 ml) and the mixture was stirred for 15 minutes. Iodomethane (0.04 ml) was added and the solution heated at reflux for 6 hours. The mixture was cooled to ambient temperature and solvent was removed by evaporation. The residue was purified by flash chromatography eluting with ethyl acetate/hexane (1:1 v/v) to give 3-chloro-2,6-diethyl-4-[N-(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl-N-methylamino]-pyridine (A) (220 mg) as a foam; NMR (CDCl3): 1.28(double t, 6H), 2.60(s, 3H), 2.72(q, 2H), 2.96(q, 2H), 4.24(s, 2H), 6.59(s, 1H), 6.89(m, 6H), 7.13(m, 3H), 7.30(complex m, 14H), 7.95(m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)[CH:3]=1
Reactant: Brc1cccc(-c2nnn[nH]2)c1
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccccc1-c1cccc(-c2nnn[nH]2)c1
Reaction time: 8 h
Yield: 66.8 %

Procedure:
5-(3-Bromo-phenyl)-1H-tetrazole 8b (20 g, 89 mmol) and 2-methoxybenzeneboronic acid (14.2 g, 93.3 mmol) were dissolved in 530 mL of 1,4-dioxane followed by addition of tetrakis(triphenylphosphine)palladium (1.84 g) and sodium carbonate (18.9 g, 178 mmol) under argon atmosphere. The reaction mixture was heated to reflux overnight. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure to remove 1,4-dioxane and then hydrochloric acid (200 mL, 6 mol/L) was added. The mixture was cooled for 2 hours and the layers were separated. The organic layer was collected and concentrated. The residue was dissolved in 500 mL of ethyl acetate and washed with 250 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in 25 mL of ethyl acetate and standing overnight. The mixture was filtered to obtain the title compound 5-(2′-methoxy-biphenyl-3-yl)-1H-tetrazole 8c (15 g, yield 68.2%) as a light yellow solid.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[CH3:7][C:8]([CH3:26])=[CH:9][CH2:10][N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(O)(=[O:29])C.[OH2:31]>CC(C)=O>[OH:31][C:8]([CH3:26])([CH3:7])[C:9](=[O:29])[CH2:10][N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13]
Reactant: CC(C)=CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O
Reactant: CC(=O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N(CC(=O)C(C)(C)O)C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
Potassium permanganate (114 mg, 0.72 mmol) was added to a solution of di-tert-butyl (3-methylbut-2-en-1-yl)imidodicarbonate (115 mg, 0.40 mmol) in acetone (0.8 mL), water (0.2 mL), and glacial acetic acid (20 μL). After 4 h, the reaction was quenched with saturated aqueous sodium sulfite. The mixture was adjusted to pH 5 with aqueous hydrochloric acid and extracted with ethyl acetate (3×). The combined organic extracts were washed with saturated aqueous sodium bicarbonate, saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 340.1 (M+Na).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[F:33][C:34]([F:46])([F:45])[O:35][C:36]1[CH:37]=[C:38]([C@@H:42]([NH2:44])[CH3:43])[CH:39]=[CH:40][CH:41]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[F:33][C:34]([F:45])([F:46])[O:35][C:36]1[CH:37]=[C:38]([C@@H:42]([NH:44][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=2)=[O:22])[CH3:43])[CH:39]=[CH:40][CH:41]=1
Reactant: C[C@H](N)c1cccc(OC(F)(F)F)c1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
A 10 ml round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.23 mmol) and (S)-1-(3-trifluoromethoxy-phenyl)-ethylamine hydrochloride (155 mg, 0.45 mmol). DMF (1.1 ml) was added followed by N,N-diisopropylethylamine (0.28 ml, 1.6 mmol) and HATU (95 mg, 0.25 mmol). The yellow reaction mixture was stirred at room temperature overnight then water and petroleum ether were added. The resulting off-white precipitate was collected by filtration. The filter cake was washed with water and petroleum ether then dried under high vacuum to afford 126 mg (89%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(S)-1-(3-trifluoromethoxy-phenyl)-ethyl]-amide as an off-white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=2[F:26])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([F:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=1[F:26]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2c(F)cc([N+](=O)[O-])cc2F)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2c(F)cc([N+](=O)[O-])cc2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
6.0 g of 5-(4-chlorophenyl)-4-(2,6-difluoro-4-nitrophenyl)-6-methyl-2H-pyridazin-3-one and 30 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 6.15 g of 3-chloro-5-(4-chlorophenyl)-4-(2,6-difluoro-4-nitrophenyl)-6-methylpyridazine (hereinafter, referred to as compound (ix) of the present invention).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:16][CH2:15][CH2:14][CH2:13][O:8][C:6]1[CH:5]=[CH:4][C:3]([C:9](=[O:11])[CH3:10])=[C:2]([OH:1])[CH:7]=1
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCCCCl)cc1O
Temperature: 25 °C
Yield: 86.8 %

Procedure:
10 g (66 mmole) of 2',4'-dihydroxyacetophenone, 10 ml (101 mmole) of 1-bromo-3-chloropropane and 22.7 g (164 mmole) of anhydrous potassium carbonate in 250 ml of acetone were mixed and refluxed under heating for 16 hours. The mixture was cooled to room temperature, the solid insoluble was separated by filtration, and the filtrate was evaporated to dryness. The residue was dispersed in ethyl ether, filtered and dried to give 13.1 g (87%) of the product, melting point 74° C.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@H:10]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[C@@H:9]([C:25]([O:27][CH3:28])=[O:26])[CH2:8][C@H:7]([O:29][CH2:30][C:31]([OH:33])=O)[CH2:6]1)=[O:4].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[O:33]=[C:31]([N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:30][O:29][C@@H:7]1[CH2:6][N:5]([C:3]([O:2][CH3:1])=[O:4])[C@H:10]([C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][CH2:18]2)=[O:12])[C@@H:9]([C:25]([O:27][CH3:28])=[O:26])[CH2:8]1
Reactant: COC(=O)[C@H]1C[C@H](OCC(=O)O)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: C1CCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1C[C@H](OCC(=O)N2CCCC2)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of ((3S,5S,6S)-1,5-bis(methoxycarbonyl)-6-[(4-phenylpiperazin-1-yl)carbonyl]piperidin-3-yloxy)acetic acid (57 mg, 0.00012 mol), pyrrolidine (0.0308 mL, 0.000369 mol), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (163 mg, 0.000369 mol) in N,N-dimethylformamide (0.50 mL, 0.0064 mol) was added N,N-diisopropylethylamine (0.0857 mL, 0.000492 mol). The mixture was stirred at rt for 2 h, then diluted with ethyl acetate, washed with water, brine and dired. After concentrated to dry, the residue was used directly in next step.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]([CH3:18])[CH2:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12].C(N(CC)C(C)C)(C)C.[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([C:39]3[N:40]=[C:41]4[C:47]([C:48](O)=[O:49])=[CH:46][N:45]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[C:42]4=[N:43][CH:44]=3)=[N:34][N:35]2[CH3:38])=[CH:31][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:18][C@@H:9]([NH:8][C:48]([C:47]1[C:41]2[C:42](=[N:43][CH:44]=[C:39]([C:33]3[C:32]4[C:36](=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=4)[N:35]([CH3:38])[N:34]=3)[N:40]=2)[N:45]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[CH:46]=1)=[O:49])[CH2:10][C:11](=[O:12])[N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: C[C@@H](N)CC(=O)N1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](CC(=O)N1CCCC1)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a solution of (R)-3-amino-1-pyrrolidin-1-yl-butan-1-one trifluoroacetate (crude from step 2, 118 mg, 0.44 mmol) in DMF (2 mL) were added N,N-diisopropylethylamine (0.19 mL, 1.09 mmol), 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.22 mmol), and HATU (91 mg, 0.24 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (3×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 50% to 100% EtOAc/hexanes to afford 125 mg (96%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-methyl-3-oxo-3-pyrrolidin-1-yl-propyl)-amide as a white solid.
Reaction SMILES: [CH:1]1([CH2:5][NH:6][CH2:7][CH2:8]O)[CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:12]>>[Cl-:12].[CH:1]1([CH2:5][NH2+:6][CH2:7][CH2:8][Cl:12])[CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: OCCNCC1CCC1
Product: ClCC[NH2+]CC1CCC1
Product: [Cl-]

Procedure:
2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclobutylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3-dimethylphenyl isothiocyanate to give 2-(2,3-dimethylphenylimino)-3-(cyclobutylmethyl)-1,3-thiazolidine.
Reaction SMILES: NN=C([C:10]1[C:20]2[CH2:19][CH2:18][C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[N:15](N)[C:14]=2[CH:13]=[CH:12][C:11]=1CC1C=CC=CC=1)C1C=CC=CC=1.[ClH:33].[NH:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1.S(=O)(=O)(O)O.N>O.C(O)C>[ClH:33].[CH2:24]1[C:16]2[N:15]3[C:37]4[CH:38]=[CH:39][N:34]=[CH:35][C:36]=4[C:13]4[CH2:12][CH2:11][CH:10]=[C:20]([C:14]=43)[CH:19]=[CH:18][C:17]=2[CH2:21][CH2:22][CH2:23]1
Reactant: O=C1CCNCC1
Reactant: NN=C(c1ccccc1)c1c(Cc2ccccc2)ccc2c1CCc1ccccc1N2N
Agent: Cl
Agent: N
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: C1=CC2=C(CCCC2)n2c3c(c4cnccc42)CCC=C13
Reaction time: 0.67 h

Procedure:
A mixture of 24.6 g of N-aminoiminodibenzyl (5-amino-10,11-dihydro-5H-dibenz[b,f]azepine) and 14.8 g. of 4-piperidone hydrochloride in 250 ml. ethanol was heated on a steam bath for 15 minutes and cooled; a solution of 20 g. of concentrated sulfuric acid in 250 ml. ethanol was added. The resulting mixture was reheated on the steam bath for additional 40 minutes; the solution which formed was cooled, basified with ammonia, and diluted with 1 l. of water. The crude, semisolid material which separated was taken up in ether, and the aqueous mother liquors were extracted with additional portions of ether. The combined ethereal extracts were concentrated to 500 ml. and treated, under an atmosphere of nitrogen and with vigorous stirring, with 50 ml. of 5N hydrochloric acid. The resulting precipitate was filtered off, washed with ether and 1N hydrochloric acid, and dried in vacuo at 100° to yield 1,2,3,4,8,9-hexahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine hydrochloride, m.p. 309°, a salt only very slightly soluble in water. Dissolving the above salt in aqueous acetic acid, basifying with ammonia, filtering off the crude product and recrystallizing it from benzene regenerated the free 1,2,3,4,8,9-hexahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine.
Reaction SMILES: [C:1]([NH:5][N:6]=[C:7]([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:17]Cl>CCCCC>[C:1]([N:5]=[N:6][C:7]([Cl:17])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCl
Reactant: CC(C)=NNC(C)(C)C
Solvent: CCCCC
Solvent: CCN(CC)CC
Product: CC(C)(C)N=NC(C)(C)Cl
Reaction time: 0.25 h

Procedure:
To a stirred solution of 64 grams (0.5 moles) of acetone t-butylhydrazone and 51 grams (0.504 moles) of triethylamine in 400 ml of pentane in a 1 liter 4 neck flask equipped with a mechanical stirrer, thermometer and gas inlet tube, was added 35.5 grams (0.5 moles) of chlorine gas, holding the temperature at -5° to 0° C. After the chlorine addition was complete, the reaction mixture was stirred an additional 15 minutes and the insoluble triethylamine hydrochloride filtered off. The filter cake was washed with an additional 150 ml pentane and the filtrate used in the subsequent reaction.