Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]=O.[NH2:12][C@@H:13]([CH3:16])[CH2:14][OH:15].C([BH3-])#N.[Na+].Cl.[OH-].[Na+]>CO>[ClH:1].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:12][C@@H:13]([CH3:16])[CH2:14][OH:15]
Reactant: O=CCc1cccc(Cl)c1Cl
Reactant: C[C@H](N)CO
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: C[C@@H](CO)NCCc1cccc(Cl)c1Cl
Reaction time: 2.5 h
Yield: 48.4 %

Procedure:
To a solution of 13.0 g (0.074 mole) of crude 2,3-dichlorobenzeneacetaldehyde in 50 ml of MeOH was added 5.7 ml (0.074 mole) of (S)-2-amino-1-propanol. The reaction was placed under an atmosphere of argon and 3.6 g (0.058 mole) of sodium cyanoborohydride was added. After stirring for 2.5 hr, the reaction was made acidic by adding ethereal hydrogen chloride. After stirring of 30 min enough 3N sodium hydroxide was added to make the reaction basic. The reaction mixture was extracted with ether and the ether layer was washed with water, brine and dried (K2CO3). Evaporation of the solvent in vacuo gave a yellow oil. The oil was treated with ethereal hydrogen chloride and the solid was collected. The solid was recrystallized from 2-propanol to give 5.10 g of the title compound (28% yield), mp 148°-151° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH:18]=[CH2:19])[CH:13]([NH:20][C:21]2[C:26]([CH3:27])=[C:25]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH3:37])=[CH:31][CH:30]=3)[N:24]3[N:38]=[CH:39][CH:40]=[C:23]3[N:22]=2)[CH2:12]1)=O)C1C=CC=CC=1>CCO.[Pd]>[CH2:36]([O:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:25]2[N:24]3[N:38]=[CH:39][CH:40]=[C:23]3[N:22]=[C:21]([NH:20][CH:13]3[CH:14]([CH2:17][CH2:18][CH3:19])[CH2:15][CH2:16][NH:11][CH2:12]3)[C:26]=2[CH3:27])=[CH:34][CH:33]=1)[CH3:37]
Reactant: C=CCC1CCN(C(=O)OCc2ccccc2)CC1Nc1nc2ccnn2c(Nc2ccc(OCC)cc2)c1C
Agent: [Pd]
Solvent: CCO
Product: CCCC1CCNCC1Nc1nc2ccnn2c(Nc2ccc(OCC)cc2)c1C
Yield: 59.8 %

Procedure:
A solution of 4-Allyl-3-[7-(4-ethoxy-phenylamino)-6-methyl-pyrazolo[1,5-a]pyrimidin-5-ylamino]-piperidine-1-carboxylic acid benzyl ester (3.1 mg) in EtOH (1.5 mL) was hydrogenated in the presence of 10% palladium on carbon (7.5 mg) for 45 min. The mixture was filtered through a pad of Celite and evapotrated. The residue was purified on preparative TLC to give the title compound (1.4 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([N:8]([CH3:14])[C:9](=O)[CH2:10][O:11][CH3:12])[CH:7]=1.[Cl-].[Cl-].[Ca+2].C([O-])(O)=O.[Na+]>CC(O)=O.[Zn]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:15]=[C:9]([CH2:10][O:11][CH3:12])[N:8]([CH3:14])[C:6]=2[CH:7]=1
Reactant: COCC(=O)N(C)c1cc(Br)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CC(=O)O
Product: COCc1nc2ccc(Br)cc2n1C
Yield: 76.2 %

Procedure:
To a solution of N-(5-bromo-2-nitrophenyl)-2-methoxy-N-methylacetamide (477 mg) in AcOH (8 ml) was added zinc (400 mg) at 0° C. The mixture was stirred at 80° C. under a dry atmosphere (CaCl2 tube) for 3 h and then at room temperature overnight. The mixture was neutralized with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (306 mg) as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24]([OH:26])=O)=[CH:6]2)#[N:2].Cl.[NH2:28][CH2:29][C:30]1([OH:34])[CH2:33][CH2:32][CH2:31]1>>[OH:34][C:30]1([CH2:29][NH:28][C:24]([C:7]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:21])([F:23])[F:22])[CH:14]=3)[C:9]3[C:5]([CH:6]=2)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)=[O:26])[CH2:33][CH2:32][CH2:31]1
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Reactant: NCC1(O)CCC1
Agent: Cl
Product: N#Cc1ccc2c(c1)cc(C(=O)NCC1(O)CCC1)n2Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] in a manner similar to that described in Example 11, and 1-aminomethyl-cyclobutanol hydrochloride (prepared from cyclobutanone and trimethylsilyl cyanide) in a manner similar to that described in Example 65.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C:31]([O:33]CC2C=CC=CC=2)=[O:32])=[CH:22]1.[OH-].[Na+].[Cl-].Cl>ClCCl.O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]([CH2:30][C:31]([OH:33])=[O:32])=[CH:22]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1csc(-c2cc3cc(CCl)ccc3o2)n1
Reactant: O=C(Cc1c[nH]c2ccccc12)OCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(CC(=O)O)c5ccccc54)ccc3o2)n1
Yield: 43 %

Procedure:
A mixture of 4-tert-butyl-2-[5-(chloromethyl)benzofuran-2-yl]thiazole (0.30 g), benzyl indole-3-acetate (0.25 g), sodium hydroxide (0.24 g) and small amount of cetyl trymethylammonium chloride in dichloromethane (10 ml) was stirred under reflux for 3 hours. After water was added to the reaction mixture, the mixture was neutralized with diluted hydrochloric acid and the resulting mixture was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of dichloromethane and methanol. The fractions containing the objective compound were combined and concentrated under reduced pressure to give 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}indole-3-acetic acid (0.18 g).
Reaction SMILES: Cl.N[CH2:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([S:11]([CH3:14])(=[O:13])=[O:12])[C:5]=1[OH:15].C1N2CN3CN(C2)CN1C3.FC(F)(F)C(O)=[O:29]>>[CH:3]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([S:11]([CH3:14])(=[O:13])=[O:12])[C:5]=1[OH:15])=[O:29]
Reactant: O=C(O)C(F)(F)F
Reactant: CS(=O)(=O)c1cc(Cl)cc(CN)c1O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: CS(=O)(=O)c1cc(Cl)cc(C=O)c1O

Procedure:
2.4 g (0.009 mol) of 2-aminomethyl-4-chloro-6methylsulfonylphenol hydrochloride are reacted with 1.6 g of urotropine in 18 ml of trifluoroacetic acid to give 2-formyl-4-chloro-6-methylsulfonylphenol in analogy to Example 1.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([CH:14]=[CH2:15])[CH:11]=[C:10]2[C:16]#[N:17])=[CH:5][CH:4]=1.N1C=CC=CC=1.CS([Cl:28])(=O)=O>ClCCl.CN(C)C1C=CN=CC=1>[Cl:28][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([CH:14]=[CH2:15])[CH:11]=[C:10]2[C:16]#[N:17])=[CH:5][CH:4]=1
Reactant: C=Cc1cc(C#N)n(-c2ccc(CO)cc2)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=Cc1cc(C#N)n(-c2ccc(CCl)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
To a solution of 1-(4-hydroxymethylphenyl)-4-vinylpyrrole-2-carbonitrile (910 mg) in dichloromethane (15 ml) was added pyridine (385 mg), 4-dimethylaminopyridine (20 mg), methanesulfonyl chloride (560 mg) successively at 5° C. The mixture was stirred at ambient temperature for 4 hours and then pyridine (385 mg) and methanesulfonyl chloride (560 mg) was added therein. The mixture was stirred at the same temperature overnight, washed with aqueous hydrochloric acid, dried, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted by dichloromethane to yield 1-(4-chloromethylphenyl)-4-vinylpyrrole-2-carbonitrile (831 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[C:6](=[O:7])[CH2:5][CH2:4][O:3]1.[H-].[Na+].[CH2:11]([OH:13])C.C(OCC)=O>CCOCC.O>[OH:13][CH:11]=[C:5]1[CH2:4][O:3][C:2]([CH3:8])([CH3:1])[C:6]1=[O:7]
Reactant: CC1(C)OCCC1=O
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC=O
Solvent: CCOCC
Product: CC1(C)OCC(=CO)C1=O
Temperature: 0 °C
Yield: 43 %

Procedure:
An ether solution of dihydro-2,2-dimethyl-3(2H)-furanone (4.55 g, 39.9 mmol) in 30 mL of ether was added dropwise to a suspension of sodium hydride (3.2 g of 60%, 80 mmol) in 150 mL of ether containing three drops of ethanol and 6.5 mL (80 mmol) of ethyl formate stirred at 0° C. After stirring overnight at room temperature, the reaction mixture was taken up into water, the ether layer separated, washed with additional ether, acidified with 6N HCl and with water and brine, dried over MgSO4, decolorized with charcoal, filtered and evaporated to leave 2.4 g of 4-hydroxymethylene-dihydro-2,2-dimethyl-3(2H)furanone as a colorless oil (43%).
Reaction SMILES: C=[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[O:4][CH2:3]1.C([O:14]C1C(Br)=NC=CC=1)C=C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])=O.[K+]>CN(C=O)C.O.[Cl-].C([N+](CC)(CC)CC)C.CCOC(C)=O.C([O-])(O)=O.[Na+].CC([O-])=O.CC([O-])=O.[Pd+2]>[O:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:2](=[O:14])[CH2:3]1
Reactant: C=CCOc1cccnc1Br
Reactant: C=C1COc2cccnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1COc2cccnc21
Temperature: 110 °C
Reaction time: 16 h

Procedure:
3-methylene-2,3-dihydrofuro[3,2-b]pyridine. To a solution of 3-(allyloxy)-2-bromopyridine (1 eq.) in DMF (0.2 M), PPh3 (0.25 eq.), Pd(OAc)2 (0.1 eq), and KOAc (5 eq.), is added, under an argon atmosphere, tetraethyl ammonium chloride hydrate (2 eq.). The flask is purged with argon for 15 min, and the resulting reaction mixture is stirred at 110° C. for 16 h. The reaction progress is monitored by TLC. The reaction mixture is diluted with EtOAc and saturated NaHCO3 solution. The organic layer is separated and dried over Na2SO4, and concentrated. The product that may be thus obtained is purified by column chromatography to afford the title compound.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][C@@H:6]([NH:8][CH3:9])[C@H:5]([OH:10])[CH2:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.O>C(Cl)Cl>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:8]([C@H:6]2[C@H:5]([OH:10])[CH2:4][N:3]([CH2:1][CH3:2])[CH2:7]2)[CH3:9])=[O:23])=[CH:20][CH:19]=1
Reactant: CCN1C[C@@H](O)[C@H](NC)C1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCN1C[C@@H](O)[C@H](N(C)C(=O)c2ccc(Cl)cc2)C1
Temperature: -5 °C
Reaction time: 18 h
Yield: 74.9 %

Procedure:
A solution of 17.0 g (118 mmoles) of trans-1-ethyl-4-methylamino-3-pyrrolidinol in 180 ml of methylene chloride was mixed with 15 g of powdered anhydrous potassium carbonate and cooled to -5° C. The mixture was kept at or below 0° C. while a solution of 20.6 g (118 mmoles) of p-chlorobenzoyl chloride in 100 ml of methylene chloride was added dropwise. After the mixture was stirred at ambient temperature for 18 hr, it was poured into 100 ml of water. The organic layer was separated, dried and concentrated. The residue was crystallized from cyclohexane to give 25 g (75%) of white crystals, m.p. 91°-93° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1.[C:18]1(=[O:28])[C@@H:26]2[C@@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)[C:20](=O)[O:19]1.Cl.C([O-])(O)=O.[Na+]>C(#N)C>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:8]2[C:7]3[CH:6]=[CH:5][C:4]([OH:17])=[CH:3][C:2]=3[N:1]=[C:20]2[C@H:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C@H:26]2[C:18]([OH:28])=[O:19])=[CH:11][CH:12]=1
Reactant: Nc1cc(O)ccc1NCc1ccc(Br)cc1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C(O)[C@@H]1CCCC[C@@H]1c1nc2cc(O)ccc2n1Cc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
3-Amino-4-((4-bromobenzyl)amino)phenol (7.8 g, 27 mmol) and cis-hexahydroisobenzofuran-1,3-dione (4.1 g, 27 mmol) were dissolved in acetonitrile (200 mL) and the mixture heated to 80° C. After 18 h, HCl (50 mL, 6 N) was added and the resulting mixture stirred at 60° C. for 16 h. The mixture was then cooled to RT and the pH was adjusted to ˜pH 7 with sat.NaHCO3. The aqueous was then extracted with EtOAc (3×200 mL). The combined organics were washed with water (200 mL), dried with Na2SO4, filtered and concentrated to dryness. The residue was purified by FCC to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.93 (s, 1H), 7.47 (d, J=8.4, 2H), 7.06 (dd, J=8.6, 2.7, 3H), 6.89 (d, J=2.1, 1H), 6.60 (dd, J=8.6, 2.2, 1H), 5.52-5.26 (m, 2H), 3.63 (d, J=4.4, 1H), 2.70 (d, J=10.7, 1H), 2.55 (d, J=8.9, 1H), 1.81 (d, J=8.9, 2H), 1.61 (dd, J=32.5, 21.3, 3H), 1.34 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[O:11][C:10]2=[O:20])[CH:5]=[CH:4][N:3]=1.[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1>N1C=CC=CC=1>[O:20]=[C:10]1[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:24]([CH:21]3[CH2:23][CH2:22]3)=[O:25])[CH:7]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[O:11]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Solvent: c1ccncc1
Product: O=C(Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(2-amino-pyridin-4-ylmethyl)-1H-benzo[d][1,3]oxazine-2,4-dione (1.1 g, see preparation 7b) in pyridine (15 ml) was added cyclopropanecarbonyl chloride (512 mg). The reaction mixture was stirred at room temperature for 30 minutes, and the solvent was evaporated under reduced pressure. The remaining oil was dissolved in EtOAc and washed with water and brine. The organic layer was concentrated under reduced pressure and the resulting solid material was isolated by filtration and dried in vacuo, affording cyclopropanecarboxylic acid [4-(2,4-dioxo-4H-benzo[d][1,3]oxazin-1-ylmethyl)-pyridin-2-yl]-amide. Step 2: The above obtained anhydride intermediate was converted into the title compound by reaction with O-cyclopentyl-methylhydroxyl-amine hydrochloride (see preparation 66), using general procedure 1A. 13C-NMR (DMSO-d6) δ 172.4, 166.9, 152.3, 151.3, 148.5, 147.8, 132.4, 127.9, 117.3, 114.7, 113.3, 111.4, 111.3, 79.4, 45.4, 37.6, 28.9, 24.9, 14.1, 7.4.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11]([Cl:14])(Cl)Cl.C(O)=[O:16]>[Fe](Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11]([Cl:14])=[O:16]
Reactant: Fc1cc(C(Cl)(Cl)Cl)c(F)c(F)c1F
Reactant: O=CO
Agent: Cl[Fe](Cl)Cl
Product: O=C(Cl)c1cc(F)c(F)c(F)c1F
Yield: 93 %

Procedure:
268 g of 2,3,4,5-tetrafluorobenzotrichloride were added to the distillation residue (approximately 20 g) and 2.7 g of iron(III) chloride were added. The mixture was reacted with formic acid in a similar manner to a). 198 g (93% of theory) of 2,3,4,5-tetrafluorobenzoyl chloride were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[CH3:14][CH2:15][N:16](C(C)C)C(C)C.BrCC#N>C1COCC1>[C:15]([CH2:14][NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])#[N:16]
Reactant: CCc1ccc(C(=O)OC)cc1N
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)OC)cc1NCC#N
Temperature: 25 °C

Procedure:
To a stirred solution of methyl 3-amino-4-ethylbenzoate (6.10 g) in THF (56.7 mL) at room temperature was added Hunig's Base (11.89 mL) followed by bromoacetonitrile (4.74 mL). The mixture was heated at reflux for 16 h. The reaction was cooled to room temperature and concentrated in vacuo. 1N aqueous HCl and DCM were added. The organic layer was separated, dried (MgSO4) and concentrated to give the subtitle compound as an oil (7.46 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:20]([O:22]CC)=[O:21])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[N:11]=[C:10]([C:20]([OH:22])=[O:21])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(F)c2)n(-c2ccc(F)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(-c2cccc(F)c2)n(-c2ccc(F)cc2)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
23.9 g (72.8 mmol) of the compound of Example 40A are provided in 100 ml of 1,4-dioxane, 100 ml (200 mmol) of a 2N solution of lithium hydroxide in water are added, and the mixture is stirred at 50° C. for 1 h. The mixture is concentrated, the residue is diluted with water, a conc. aqueous hydrogen chloride solution is subsequently added until the pH is acidic, the mixture is extracted with dichloromethane, and the organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is stirred in a little diethyl ether, collected by filtration and dried under high vacuum. 22.0 g (100% of theory) of the title compound are obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.FC(F)(F)C(O)=O.[Cl:38][CH2:39][CH2:40][CH2:41]/[C:42](=[CH:46]\[C:47]1[CH:52]=[CH:51][C:50]([N:53]2[CH:57]=[C:56]([CH3:58])[N:55]=[CH:54]2)=[C:49]([F:59])[CH:48]=1)/[C:43]([OH:45])=O.Cl.[NH2:61][C@H:62]([C:66]1[CH:71]=[CH:70][C:69]([F:72])=[C:68]([F:73])[CH:67]=1)[C@H:63]([OH:65])[CH3:64]>CN(C=O)C.C(OCC)(=O)C>[F:73][C:68]1[CH:67]=[C:66]([C@@H:62]([NH:61][C:43](=[O:45])/[C:42](=[CH:46]/[C:47]2[CH:52]=[CH:51][C:50]([N:53]3[CH:57]=[C:56]([CH3:58])[N:55]=[CH:54]3)=[C:49]([F:59])[CH:48]=2)/[CH2:41][CH2:40][CH2:39][Cl:38])[C@H:63]([OH:65])[CH3:64])[CH:71]=[CH:70][C:69]=1[F:72]
Reactant: C[C@@H](O)[C@H](N)c1ccc(F)c(F)c1
Reactant: Cc1cn(-c2ccc(/C=C(\CCCCl)C(=O)O)cc2F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cn(-c2ccc(/C=C(\CCCCl)C(=O)N[C@H](c3ccc(F)c(F)c3)[C@@H](C)O)cc2F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
A solution of 4 N hydrogen chloride in ethyl acetate (10 mL) was added to a solution of tert-butyl [(1R,2R)-1-(3,4-difluorophenyl)-2-hydroxypropyl]carbamate (960 mg) in methanol (10 mL) at room temperature, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain (1R,2R)-1-amino-1-(3,4-difluorophenyl)propan-2-ol hydrochloride (747 mg). DIEA (1.59 mL), WSC (880 mg), and HOBT (620 mg) were added to a solution of (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]valeric acid trifluoroacetate (1.00 g) and (1R,2R)-1-amino-1-(3,4-difluorophenyl)propan-2-ol hydrochloride (612 mg) in DMF (20 mL) at room temperature, and the reaction solution was stirred at room temperature for one hour. Ethyl acetate was added to the reaction solution, which was then sequentially washed with saturated sodium bicarbonate water, water, a saturated ammonium chloride solution, and brine. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The resulting solid was washed with heptane to obtain (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valeric acid [(1R,2R)-1-(3,4-difluorophenyl)-2-hydroxypropyl]amide (977 mg). (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valeric acid [(1R,2R)-1-(3,4-difluorophenyl)-2-hydroxypropyl]amide (977 mg) was dissolved in DMF (25 mL). 60% sodium hydride (95 mg) was added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate-methanol system), solidified with ethyl acetate and heptane, and separated by filtration to obtain 740 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:21][C:22]([O:24]C)=[O:23])=[N:11]1.[OH-].[K+]>CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:21][C:22]([OH:24])=[O:23])=[N:11]1
Reactant: COC(=O)Cc1nn(-c2nc3ccccc3s2)c(=O)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1nn(-c2nc3ccccc3s2)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.5 %

Procedure:
A solution of methyl 3-(2-benzothiazolyl)-4-oxo-3H-phthalazin-1-ylacetate (1.92 g) in methanol (50 ml) containing 10% aqueous potassium hydroxide (5 ml) was stirred at room temperature for 4 hours. The solution was concentrated to remove methanol and the concentrate was diluted with water (75 ml) and then extracted with ethyl acetate. The aqueous portion was separated and acidified with concentrated hydrochloric acid to pH 2.0. The precipitated solid was collected and crystallized from isopropyl alcohol to give 3-(2-benzothiazolyl)-4-oxo-3-H-phthalazin-1-ylacetic acid (876 mg; m.p. 205° C.(d)).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=O)[CH:8]([CH3:11])[CH2:9][NH:10][C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>O1CCCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[S:24])[CH:8]([CH3:11])[CH2:9][NH:10][C:4]=2[CH:3]=1
Reactant: CC1CNc2cc(Br)ccc2NC1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC1CNc2cc(Br)ccc2NC1=S
Yield: 77.9 %

Procedure:
A solution of 7-bromo-3-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (1.8 g, 7.1 mmol) and Lawesson's reagent (4.2 g, 10.4 mmol) in tetrahydrofuran (50 mL) was heated at 80° C. for 12 hours. The mixture was concentrated in vacuo. To the residue was added water (50 mL), extracted with ethyl acetate (50 mL×3). The combined layers were washed with brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to afford 7-bromo-3-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione (1.5 g, 79%).
Reaction SMILES: C[C:2]1[N:7]=[C:6]([C:8]#[N:9])[N:5]=[C:4]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:3]=1Br.[F:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[C:3]1[C:4]([O:10][CH2:11][CH:12]([CH3:13])[CH3:14])=[N:5][C:6]([C:8]#[N:9])=[N:7][CH:2]=1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: Cc1nc(C#N)nc(OCC(C)C)c1Br
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(-c2cnc(C#N)nc2OCC(C)C)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
Under an argon atmosphere, to a solution of methyl 5-bromo-4-isobutoxypyrimidine-2-carbonitrile (1.71 g) in toluene (20 mL) were added 2-fluoro-5-methoxyphenylboronic acid (1.70 g), tris(dibenzylideneacetone)dipalladium(0) (245 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (439 mg) and 2.0 M aqueous sodium carbonate solution (10.0 mL), and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was filtered through celite, and water was added at room temperature. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.78 g) as a yellow oil.