Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[NH:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.COCCO[AlH2-]OCCOC.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CNCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 60.2 %

Procedure:
In a 32 mL reaction vial was placed a stir bar and 4-methylcarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (0.97 g) dissolved in 12.8 mL anhydrous THF. The solution was cooled to 0° C. with an ice-bath. A 65% toluene solution of Red-Al (3.66 mL) was added dropwise at 0° C. After the addition was completed, the mixture was stirred under N2 at room temperature until all the starting materials were just consumed. The reaction mixture was worked up with H2O at 0° C., extracted with EtOAc (×3). The EtOAc extract was washed with saturated NaCl solution. After drying over Na2SO4, the organic layer was concentrated to give 550 mg of crude product.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4]/[N:5]=[C:6](/[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH2:21])\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]1[C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[NH:21][C:3](=[O:2])[CH2:4][N:5]=1
Reactant: COC(=O)C/N=C(/c1cc(F)ccc1N)c1ccccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CN=C(c2ccccc2Br)c2cc(F)ccc2N1
Yield: 83.7 %

Procedure:
A solution of 72.7 g (0.199 moles) of (Z)-N-[(2-amino-5-fluorophenyl)(2-bromophenyl)methylene]glycine methyl ester), 1450 mL of toluene, and 42.8 g (0.225 moles) of p-toluenesulfonic acid monohydrate was heated to reflux for 3 hours under nitrogen After cooling, the product crystallized out of the reaction mixture The resultant suspension was filtered and the collected solid was washed twice with 100 mL of toluene, followed by two washes with 100 mL of hexane. The solid was partitioned between 1.0 L of methylene chloride and 1.0 L of saturated NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with 250 mL of methylene chloride. The combined organic layers were washed twice with 250 mL of 1:1 mixture brine/water, dried with Na2SO4, filtered, and concentrated under vacuum. The residue was redissolved in 800 mL of methylene chloride and concentrated to give 55.5 g of 5-(2-bromophenyl)-7-fluoro-1,3-dihydro-1,4-benzodiazepine-2 (2H)-one as a light yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]2[CH2:6][S:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:15]=[CH:16][C:3]1=2.S(=O)(=O)(O)O.[CH2:27](O)[CH:28]=[CH2:29]>O>[O:1]=[C:2]1[CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]2[CH2:6][S:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18]([O:20][CH2:29][CH:28]=[CH2:27])=[O:19])[CH:15]=[CH:16][C:3]1=2
Reactant: CC(C(=O)O)c1ccc2c(c1)SCC1CCCCC1C2=O
Reactant: C=CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: C=CCOC(=O)C(C)c1ccc2c(c1)SCC1CCCCC1C2=O
Temperature: 110 °C

Procedure:
To a solution of 2-(6,6a,7,8,9,10,10a,11-octahydro-11-oxodibenzo[b,e]thiepin-3-yl)propionic acid (2.0 g) in allyl alcohol (20 ml) was added concentrated sulfuric acid (1 ml) and the mixture was heated under reflux for one hour in an oil bath maintained at 110° C. The reaction mixture was diluted with water and extracted with toluene. The toluene layers were washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel, using toluene as an eluent, to give the title compound (1.2 g) as an oil. IR νmaxfilm cm-1 : 1720, 1670 (C=O). HRMS m/e: 344.1415 (Molecular weight calculated for C20H24O3S: 344.1445).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:29][C:30]3[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:31]=3[N:32]=2)=[CH:24][CH:23]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[F:15][C:2]([F:1])([F:16])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[S:29][C:30]4[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:31]=4[N:32]=3)=[CH:26][CH:27]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reactant: O=C(O)c1ccc(OCCC(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(OCCC(F)(F)F)cc4)cc3)sc2c1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
A mixture of 4-(3,3,3-trifluoropropoxy)benzoic acid (0.32 g, 1.39 mmol) and thionyl chloride (0.33 g, 2.78 mmol) in chloroform (5 ml) was heated under reflux for 5 h. The reaction mixture was cooled to room temperature and the excess reagent and solvent was removed under reduced pressure to give the crude acid chloride. The amide was prepared as described in the Amide Coupling section using the crude acid chloride and 2-(4-aminophenyl)-6-methoxybenzothiazole (0.36 g, 1.39 mmol) in dry pyridine (10 ml) to give the title compound (0.59 g, 90%) as a pale yellow solid after work-up.
Reaction SMILES: O.O.[OH-].[Li+].C([O:7][C:8](=[O:33])[CH2:9][NH:10][C:11](=[O:32])[CH2:12][NH:13][C:14](=[O:31])[C@H:15]([CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[NH:16][C:17]([C:19]1[O:20][CH:21]=[CH:22][CH:23]=1)=[O:18])C>O1CCCC1.O.C(O)C>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:17]([NH:16][C@H:15]([C:14]([NH:13][CH2:12][C:11]([NH:10][CH2:9][C:8]([OH:33])=[O:7])=[O:32])=[O:31])[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:18]
Reactant: CCOC(=O)CNC(=O)CNC(=O)[C@H](CC1CCCCC1)NC(=O)c1ccco1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(O)CNC(=O)CNC(=O)[C@H](CC1CCCCC1)NC(=O)c1ccco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
Water (0.1 mL) and 2.7 mg of lithium hydroxide hydrate (0.0643 mmol) were added to a solution of 22.5 mg of 2-furoyl-β-cyclohexyl-L-alanyl-glycyl-glycine ethyl ester (0.0552 mmol) in tetrahydrofuran (0.2 mL). After stirring for 1 hour at room temperature, water-ethanol (1:10, 0.5 mL) and 48.1 mg of IRC-50 (about 0.48 mg equivalent) were added and the mixture was stirred for 0.5 hour. IRC-50 (0.3 mg) was swelled in water-ethanol (1:10), and filled in a glass tube, and the mixture was placed on the column, and then the column was eluted by water-ethanol (1:10, 7.5 mL). The eluate was concentrated under reduced pressure, whereby 20.3 mg of the title compound was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[OH-].[Na+].[C:10]([O:14][N:15]=[C:16]([CH2:18]Cl)[CH3:17])([CH3:13])([CH3:12])[CH3:11].Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O1CCCC1>[C:10]([O:14][N:15]=[C:16]([CH2:18][O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:7])[CH3:17])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(CCl)=NOC(C)(C)C
Reactant: OCCCCCO
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(COCCCCCO)=NOC(C)(C)C
Yield: 58.7 %

Procedure:
First, 13.02 g of 1,5-pentanediol, 2.40 g of sodium hydroxide (powdery), 1.14 g of benzyltriethylammonium chloride, and 100 ml of tetrahydrofuran were placed in a reaction vessel, to which 8.18 g of chloroacetone O-tert-butyloxime was slowly added dropwise with stirring under heating under reflux. After further stirring for 8 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with diluted hydrochloric acid and water in this order, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 6.79 g (yield, 59%) of 5-hydroxypentyloxyacetone O-tert-butyloxime, nD20.0 1.4493.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:25]=1.[CH3:26][C:27]1[O:31][N:30]=[C:29]([C@:32]([OH:36])([C:34]#[CH:35])[CH3:33])[CH:28]=1>>[OH:36][C@:32]([C:29]1[CH:28]=[C:27]([CH3:26])[O:31][N:30]=1)([CH3:33])[C:34]#[C:35][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:7](=[N:14][C:13]([C:15]([NH2:17])=[O:16])=[C:12]3[CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:6]=2[CH:25]=1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: NC(=O)c1nc2n(c1CN1CCOCC1)CCOc1ccc(Br)cc1-2
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(CN4CCOCC4)n2CCO3)no1

Procedure:
Following Procedure F, 10-bromo-3-(morpholinomethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol to give the titled compound as a colorless solid after purification by SFC. LC MS: 478.2 [M+H]+; 1H NMR (400 MHz, DMSO) δ 8.52 (d, J=1.9 Hz, 1H), 7.57 (s, 1H), 7.33 (dd, J=8.5, 2.0 Hz, 1H), 7.09 (s, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.50 (s, 1H), 6.46 (s, 1H), 6.35 (s, 1H), 4.50 (br m, 4H), 3.97 (br s, 2H), 3.52 (br m, 4H), 2.40 (s, 3H), 2.39 (m, 2H), 1.80 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[O:7]2)[CH2:3][CH2:2]1.[CH:16]([O:29][CH2:30][CH2:31]Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH:16]([O:29][CH2:30][CH2:31][N:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[O:7]2)[CH2:3][CH2:2]1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCCOC(c1ccccc1)c1ccccc1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Product: O=C1OC2(CCN(CCOC(c3ccccc3)c3ccccc3)CC2)c2ccccc21

Procedure:
Reaction of 1,3-dihydrospiro[isobenzofuran1,4'-piperidine]-3-one and 2-benzhydryloxy-1-chloroethane by the method described in Example 5d provides 1'-(2-benzhydryloxyethyl)-1,3-dihydrospiro[isobenzofuran-1,4'-piperidine]- 3-one as colorless crystals, m.p. 99°-100°.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[CH:26]=[O:27])=[CH:22][N:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1.C1(C)C=CC(S([CH2:48][N+:49]#[C-:50])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CO>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]4[O:27][CH:50]=[N:49][CH:48]=4)=[CH:22][N:21]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2cnco2)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 53.4 %

Procedure:
A mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenaldehyde (0.40 g), p-toluenesulfonylmethylisocyanide (0.17 g), potassium carbonate (0.11 g) and methanol (20 mL) was heated under 1 reflux for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-(2-furyl)-4-({2-methoxy-4-[({4-[(E)-2-(1,3-oxazol-5-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole as colorless crystals (0.23 g, yield 53%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 137-138° C.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:17][C:18]([NH:20][CH:21]2[CH2:30][CH2:29][CH2:28][C:27]3[CH:26]=[C:25](OS(C(F)(F)F)(=O)=O)[CH:24]=[CH:23][C:22]2=3)=[O:19])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[C:41]([O:45][C:46](=[O:51])[NH:47][CH2:48][CH:49]=[CH2:50])([CH3:44])([CH3:43])[CH3:42].C([O-])([O-])=O.[K+].[K+]>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=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.[Fe+2]>[C:41]([O:45][C:46](=[O:51])[NH:47][CH2:48][C:49]([C:25]1[CH:24]=[CH:23][C:22]2[CH:21]([NH:20][C:18](=[O:19])[CH2:17][CH:13]3[CH2:14][CH2:15][CH2:16][N:12]3[S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:39])([F:40])[F:1])[CH:4]=3)(=[O:11])=[O:10])[CH2:30][CH2:29][CH2:28][C:27]=2[CH:26]=1)=[CH2:50])([CH3:44])([CH3:43])[CH3:42]
Reactant: C=CCNC(=O)OC(C)(C)C
Reactant: O=C(CC1CCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1)NC1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: C=C(CNC(=O)OC(C)(C)C)c1ccc2c(c1)CCCC2NC(=O)CC1CCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of trifluoro-methanesulfonic acid 5-{2-[1-(3-trifluoromethyl-benzenesulfonyl)-pyrrolidin-2-yl]-acetylamino}-5,6,7,8-tetrahydro-naphthalen-2-yl ester (150 mg, 0.244 mmol, 1.0 eq), allyl carbamic acid tert-butyl ester (230 mg, 1.47 mmol, 6.0 eq), palladium acetate (Strem Chemicals, 3.3 mg, 0.015 mmol, 0.06 eq), DPPF (Aldrich, 36 mg, 0.064 mmol, 0.26 eq) and K2CO3 (Aldrich, 51 mg, 0.37 mmol, 1.5 eq) in CH3CN (2 mL) was flushed with N2 for 10 min. The reaction was heated to 80° C. and stirred at 80° C. under N2 for 20 h. The reaction was quenched with H2O (60 mL), extracted with CH2Cl2 (60 mL×3). The extract phase was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated in vacuo. Flash column chromatography (silica gel, 0–4% MeOH—CH2Cl2) afforded the title compound as a colorless thin film. MS (ESI, pos. ion) m/z: 622 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([C:27]([OH:29])=O)[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:4][C:3]=1[Cl:30].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=N1.N1CCCC1>C(N(CC)CC)C>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([C:27]([N:38]5[CH2:39][CH2:44][CH2:43][CH2:42]5)=[O:29])[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:4][C:3]=1[Cl:30]
Reactant: Nc1c(Cl)cc(Nc2ncnc3cnc(N[C@H]4CC[C@H](C(=O)O)CC4)nc23)cc1Cl
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCNC1
Solvent: CCN(CC)CC
Product: Nc1c(Cl)cc(Nc2ncnc3cnc(N[C@H]4CC[C@H](C(=O)N5CCCC5)CC4)nc23)cc1Cl

Procedure:
Prepared from 4-[(4-amino-3,5-dichlorophenyl)amino]-6-[(trans-4-carboxycyclohexyl)amino]pyrimido[5,4-d]pyrimidine by reaction with O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, triethylamine and pyrrolidine. Melting point: 228°-230° C,; Rf : 0.43 (silica gel; petroleum ether/ethyl acetate/methanol=10:10:4) Calculated: C 55.09 H 5.23 N 22.35; Found: 55.07 5.19 22.33 14.22
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][OH:9])=[CH:5][CH:4]=1.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[S:18]([NH:21][C:22]1[C:27](Cl)=[N:26][CH:25]=[CH:24][N:23]=1)(=[O:20])=[O:19]>>[NH2:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][O:9][C:27]2[C:22]([NH:21][S:18]([C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=3[Cl:10])(=[O:20])=[O:19])=[N:23][CH:24]=[CH:25][N:26]=2)=[CH:5][CH:4]=1
Reactant: NCc1ccc(CO)o1
Reactant: O=S(=O)(Nc1nccnc1Cl)c1cccc(Cl)c1Cl
Product: NCc1ccc(COc2nccnc2NS(=O)(=O)c2cccc(Cl)c2Cl)o1

Procedure:
Prepared by the method of Example 28 using (5-aminomethyl-2-furanyl)methanol (0.2 g) and 2,3-dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (Example 28) (0.3 g). Purified by silica gel chromatography eluting with methanol/dichloromethane mixtures. Yield 0.2 g.
Reaction SMILES: COC1C=CC(C[N:8]([CH2:23][C:24]2[N:25]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:26]=[CH:27][N:28]=2)[CH2:9][C:10]2[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[CH:13][N:14]=2)=CC=1>C(O)C.[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-]>[CH3:20][Si:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][O:16][CH2:15][N:11]1[CH:12]=[CH:13][N:14]=[C:10]1[CH2:9][NH:8][CH2:23][C:24]1[N:25]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:26]=[CH:27][N:28]=1
Reactant: COc1ccc(CN(Cc2nccn2COCC[Si](C)(C)C)Cc2nccn2COCC[Si](C)(C)C)cc1
Agent: [Pd+2]
Agent: [C+4]
Agent: [OH-]
Solvent: CCO
Product: C[Si](C)(C)CCOCn1ccnc1CNCc1nccn1COCC[Si](C)(C)C
Temperature: 65 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
To a solution of the compound 1 (665 mg) in ethanol (5 mL), 20% palladium hydroxide carbon (500 mg) was added under an argon atmosphere. The reaction mixture was stirred under a hydrogen gas atmosphere at 65° C. for 3 hours. The reaction mixture was filtered through Celite (trade name) and then concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane:methanol:28% ammonia water=10:1:0→80:10:1) to obtain the title compound (467 mg) having the following physical properties.
Reaction SMILES: [CH2:1]([N:5]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([OH:14])[CH:7]=1)[CH2:2][CH2:3][CH3:4].N1C=CN=C1.[C:24]([Si:28](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:27])([CH3:26])[CH3:25].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:5]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([O:14][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1ccc(C=O)c(O)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCN(CCCC)c1ccc(C=O)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
In 40 ml of N,N-dimethylformamide were dissolved 5.39 g (21.6 mmol) of 4-dibutylamino-2-hydroxybenzaldehyde and 4.08 g (60.0 mmol) of imidazole. Next, 6.13 g (22.3 mmol) of tert-butylchlorodiphenylsilane was added dropwise thereto with stirring at room temperature. The mixture was stirred for 3.5 hours. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 10.3 g of a colorless oily matter (yield: 97.7%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:5][CH2:4]1.C[Al](C)C.C[O:11][C:12]([C:14]1[N:15]=[N:16][C:17]([NH:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:24][O:25][C:26]=2[CH3:27])=[CH:18][CH:19]=1)=O.O>O1CCOCC1>[CH:3]1([CH2:2][NH:1][C:12]([C:14]2[N:15]=[N:16][C:17]([NH:20][CH2:21][C:22]3[C:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:24][O:25][C:26]=3[CH3:27])=[CH:18][CH:19]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: NCC1CC1
Reactant: COC(=O)c1ccc(NCc2c(-c3ccccc3)noc2C)nn1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)NCC2CC2)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of aminomethylcyclopropane (0.11 mL, 1.2 mmol) in dioxane (5 mL) was added dropwise trimethylaluminum solution (2 M solution in hexane, 0.62 mL, 1.24 mmol). After stirring for 1 h at room temperature a suspension of 6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-pyridazine-3-carboxylic acid methyl ester (100 mg, 0.3 mmol) in dioxane (5 mL) was added. The reaction mixture was stirred at 90° C. for 2 h, cooled to room temperature and poured into water. Extraction (ethyl acetate/saturated aqueous Seignette salt solution) followed by drying of the organic phase over sodium sulfate and evaporation afforded an oil. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 0:100) afforded the title compound (60 mg, 54%) which was obtained as a light yellow foam. MS: m/e=364.5 [M+H]+.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14]C)=[O:13])=[CH:8][CH:7]=1.Cl>CO>[F:22][C:4]([F:3])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(CC(F)(F)c2ccccn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CC(F)(F)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Aqueous 4 N sodium hydroxide solution (300 μL) was added to a methanol solution (5 mL) of methyl 4-(2,2-difluoro-2-pyridin-2-ylethyl)benzenecarboxylate (90 mg) obtained in Production Example 21-2, and stirred at room temperature for 3 hours. The reaction liquid was neutralized with aqueous 1 N hydrochloric acid, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain a crude product of 4-(2,2-difluoro-2-pyridin-2-ylethyl)benzenecarboxylic acid. Next, diisopropylethylamine (86 μL) was added to a DMF (5 mL) solution of the obtained carboxylic acid, the compound (61 mg) obtained in Production Example 39-4 and HATU (94 mg), and stirred at room temperature for 4 hours. Water was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline water, and then dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform/methanol=90/1) to obtain the entitled compound (20 mg) as a white solid.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[CH:46]1([CH2:49][C:50]([N:52]2[CH2:57][CH2:56][N:55]([C:58]3[CH:63]=[CH:62][C:61]([C:64]4[CH:65]=[C:66]5[C:72]([C:73]6[CH:74]=[N:75][N:76]([CH2:78][C:79]7[CH:84]=[CH:83][CH:82]=[C:81]([F:85])[CH:80]=7)[CH:77]=6)=[CH:71][N:70](S(C6C=CC(C)=CC=6)(=O)=O)[C:67]5=[N:68][CH:69]=4)=[CH:60][CH:59]=3)[CH2:54][CH2:53]2)=[O:51])[CH2:48][CH2:47]1.[OH-].[Li+]>C1COCC1.CO.O>[CH:46]1([CH2:49][C:50]([N:52]2[CH2:53][CH2:54][N:55]([C:58]3[CH:59]=[CH:60][C:61]([C:64]4[CH:65]=[C:66]5[C:72]([C:73]6[CH:74]=[N:75][N:76]([CH2:78][C:79]7[CH:84]=[CH:83][CH:82]=[C:81]([F:85])[CH:80]=7)[CH:77]=6)=[CH:71][NH:70][C:67]5=[N:68][CH:69]=4)=[CH:62][CH:63]=3)[CH2:56][CH2:57]2)=[O:51])[CH2:47][CH2:48]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)CC6CC6)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(CC1CC1)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2)CC1
Yield: 19.3 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 2-cyclopropyl-1-(4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)ethanone (60 mg, 0.087 mmol) was hydrolyzed with lithium hydroxide (19 mg, 0.435 mmol) in THF/methanol/water (5/1/1 mL) to yield 9 mg (16.0% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.58-8.57 (d, 1H), 8.51 (s, 1H), 8.26 (s, 1H), 7.97 (s, 1H), 7.75 (s, 1H), 7.65-7.63 (s, 2H), 7.40-7.35 (m, 1H), 7.13-7.11 (d, 3H), 7.07-7.02 (m, 2H), 6.93-6.86 (m, 1H), 6.51-6.46 (dt, 1H), 5.44 (s, 2H), 3.84-3.81 (t, 4H), 3.27 (s, 4H), 2.33-2.17 (m, 2H), 1.13-1.10 (t, 3H). MS: m/z=534.9 (M+1), HPLC: 95.19% in method B.