Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:14]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][N:12]([C:20](Cl)=[O:21])[CH:11]3[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[F:30])[C:5]2=[CH:4][CH:3]=1.CC1(C)[O:37][C@@H:36]([CH2:38][CH2:39][NH2:40])[CH2:35][O:34]1.C(N(CC)CC)C.Cl>O1CCCC1>[OH:37][C@H:36]([CH2:35][OH:34])[CH2:38][CH2:39][NH:40][C:20]([N:12]1[CH2:13][CH:14]([CH2:15][C:16]([CH3:18])([CH3:17])[CH3:19])[C:10]2([C:5]3[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:9]2=[O:31])[CH:11]1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[F:30])=[O:21]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CC(C)(C)CC1CN(C(=O)Cl)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)CC1CN(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
To a solution of rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carbonyl chloride (0.14 g, 0.28 mmol) in tetrahydrofuran (5 mL) was added 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine prepared in Example 7 (49 mg, 0.34 mmol) and triethylamine (0.078 mL, 0.56 mmol). The reaction mixture was stirred at room temperature for 1 h. An aqueous HCl solution (1 N, 2 mL) was added. The reaction mixture was stirred at room temperature for 0.5 h. The solvents were removed and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichlormethane and hexanes to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (Yield 75 mg, 50%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:27]=[C:28]([NH:33]N)[CH:29]=[CH:30][C:31]=1[CH3:32]>>[F:25][C:26]1[CH:27]=[C:28]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:29]=[CH:30][C:31]=1[CH3:32]
Reactant: Cc1ccc(NN)cc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: Cc1ccc(-n2nccc2-c2nn(-c3cccc(S(C)(=O)=O)c3)ccc2=O)cc1F

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and (3-fluoro-4-methyl-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=425.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[C:4]([N:14]2[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]2)[CH:3]=1.[NH2:20][C:21]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C@H:34]([NH:38]C(OC(C)(C)C)=O)[C:35]([OH:37])=[O:36])=[CH:29][CH:28]=2)[CH:24]=[C:23](Cl)[N:22]=1.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[NH2:38][C@@H:34]([CH2:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[CH:24]=[C:23]([O:13][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[N:14]3[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]3)[C:9]([F:12])([F:11])[F:10])[N:22]=[C:21]([NH2:20])[N:26]=2)=[CH:28][CH:29]=1)[C:35]([OH:37])=[O:36]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(Cl)nc(N)n2)cc1)C(=O)O
Reactant: Cc1ccn(-c2cc(Cl)ccc2C(O)C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1ccn(-c2cc(Cl)ccc2C(Oc2cc(-c3ccc(C[C@H](N)C(=O)O)cc3)nc(N)n2)C(F)(F)F)n1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
1-[4-Chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-trifluoro-ethanol (0.120 g, 0.41 mmol), (S)-3-[4-(2-amino-6-chloro-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid (0.176 g, 0.45 mmol), 1,4-dioxane (4 ml), and Cs2CO3 (0.533 g, 1.64 mmol) were combined in a 20 ml sealed tube, and the mixture was heated at 100° C. for 12 h. The mixture was concentrated. To the residue, 10% methanol in DCM (50 ml) was added and the mixture was filtered. The filtrate was concentrated to give a crude product, which was taken in THF/3N HCl (30 ml/15 ml) and the resulting mixture was stirred at 40-45° C. for 12 h. LCMS indicated the completion of reaction with desired product. The mixture was concentrated to give a crude product, which was dissolved in MeOH and H2O (1:1) and purified by preparative HPLC using MeOH/H2O/TFA as solvent system to give (S)-2-amino-3-[4-(2-amino-6-{1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-trifluoro-ethoxy}-pyrimidine-4-yl)-phenyl]-propionic acid as a TFA salt. LCMS: M+1=547. 1H-NMR (400 MHz, CD3OD): δ (ppm) 2.30 (s, 3H), 3.10-3.30 (m, 2H), 4.20 (t, 1H), 6.32 (d, 1H), 6.74 (s, 1H), 7.0 (q, 1H), 7.38 (d, 2H), 7.50 (m, 2H), 7.72 (m, 1H), 7.90 (m, 3H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[CH2:16][OH:17])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[CH2:16][O:17][Si:22]([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
The title compound is prepared by the procedure of Example 50 using 20.0 g of (R)-2-pyrrolidinemethanol, 44.0 g of benzyl chloroformate and 200 ml of diethyl ether to give 56.4 g of (R)-2-hydroxymethyl-1-pyrrolidine carboxylic acid phenyl methyl ester. Forty-five g of (R)-2-hydroxymethyl-1-pyrrolidine carboxylic acid phenylmethyl ester is reacted with 38.4 g of (1,1-dimethylethyl)dimethylsilylchloride, 58 ml of triethylamine, 1.3 g of 4-(dimethylamino)pyridine and 450 ml of methylene chloride to give 41.5 g of the desired product as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1.ClC1N=CN=C2C=1NC=N2.[OH:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][C:28]=1[O:35][CH3:36].C(N(CC)CC)C>C(O)CC>[OH:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)=[CH:29][C:28]=1[O:35][CH3:36]
Reactant: Clc1ncnc2c1ncn2C1CCCO1
Reactant: COc1cc(CN)ccc1O
Agent: Clc1ncnc2nc[nH]c12
Solvent: CCCO
Solvent: CCN(CC)CC
Product: COc1cc(CNc2ncnc3c2ncn3C2CCCO2)ccc1O
Yield: 80 %

Procedure:
A mixture of 10 mmol (2240 mg) of 6-chloro-9-(tetrahydrofuran-2-yl)-purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (1838 mg) of 4-hydroxy-3-methoxybenzylamine and 5 mL of triethylamine was refluxed in n-propanol for 3 hours. After removal of the n-propanol by vacuum evaporation, the resulting material was treated with water and extracted into ethyl acetate. The ethyl acetate phase was evaporated and the residuum subsequently washed with 30 ml of petroleum ether. The solid residue was filtered off and the crude product crystallized from methanol. Yield 80%, white solid. TLC (EtOAc:hexane) (1:1) (v:v): single spot; HPLC: purity >98%. 1H NMR (400 MHZ, DMSO): 0.90d (3H, J=6.6 Hz); 1.32m (1H); 1.57m (1H); 1.84m (1H); 1.95m (1H); 2.12m (2H); 2.29m (1H); 3.26m (1H); 3.51bs (2H); 3.73m (1H); 3.89m (1H); 4.40t (1H, J=5.1 Hz); 6.12d (1H, J=5.2 Hz); 7.74bs (1H); 8.18s (1H); 8.28s (1H. MS (ES): [M+H]+=342 (100).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C@@H:29]1[O:46][C@H:45]([CH2:47][O:48]C(=O)C)[C@@H:40]([O:41]C(=O)C)[C@H:35]([O:36]C(=O)C)[C@H:30]1[O:31]C(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.ClCCl>[O:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:24][CH:23]=1)[C@@H:29]1[O:46][C@H:45]([CH2:47][OH:48])[C@@H:40]([OH:41])[C@H:35]([OH:36])[C@H:30]1[OH:31]
Reactant: Oc1ccccc1Cc1ccc(CCOCc2ccccc2)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OC[C@H]1O[C@@H](Oc2ccccc2Cc2ccc(CCOCc3ccccc3)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 14 h
Yield: 70.4 %

Procedure:
To a solution of 2-[4-(2-benzyloxyethyl)benzyl]phenol (3.2 g) and 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (12 g) in toluene (34 mL) and dichloromethane (17 mL) was added boron trifluoride diethyl ether complex (3.8 mL), and the mixture was stirred at room temperature for 14 hours. To the reaction mixture were added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in methanol (50 mL), and to the solution was added sodium methoxide (28% methanol solution, 0.39 mL). The resulting mixture was stirred at room temperature for 2.5 hours. The solvent of the reaction mixture was removed under reduced pressure, and to the residue was added water. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 2-[4-(2-benzyloxyethyl)benzyl]phenyl β-D-glucopyranoside (3.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:31]([O:34][CH2:35][C:36](Cl)=[O:37])(=[O:33])[CH3:32]>O1CCCC1>[C:31]([O:34][CH2:35][C:36]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1)=[O:37])(=[O:33])[CH3:32]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(N)c3)cs2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(NC(=O)COC(C)=O)c3)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To a solution (4 mL) of the crude compound (310 mg, 0.88 mmol) obtained in Example 26a in tetrahydrofuran were added triethylamine (0.16 mL, 1.1 mmol) and acetoxyacetylchloride (145 mg, 1.1 mmol), and the mixture was stirred at room temperature overnight. After confirmation of the termination of the reaction by TLC, the resulting salt was removed. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=7/3) to give the title compound (270 mg, 72% in 2 steps) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:2]#[CH:3].[H-].[Na+].[CH2:14](I)[CH3:15]>CN1CCCC1=O>[CH2:14]([N:4]([CH2:1][C:2]#[CH:3])[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])[CH3:15]
Reactant: CCI
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: C#CCN(CC)C(=O)OC(C)(C)C

Procedure:
The sub-titled compound was prepared from tert-butyl prop-2-ynylcarbamate (0.6g), 60% sodium hydride (0.186 g), ethyl iodide (1.55 ml) and anhydrous N-methyl-2-pyrrolidinone (4 ml) by the method of Example 2(ii). The crude product was purified by chromatography on silica gel eluting with iso-hexane:ethyl acetate (19:1) to afford (0.34 g) of a colourless oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[OH:16][C@@H:17]([C@H:19]1[CH2:23][N:22]([C@@H:24]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH3:25])[C:21](=[O:34])[CH2:20]1)[CH3:18].[Cl:35][C:36]1[N:41]=[C:40](S(C)(=O)=O)[C:39]2[N:46]([CH3:49])[CH:47]=[N:48][C:38]=2[CH:37]=1>CN(C=O)C>[Cl:35][C:36]1[N:41]=[C:40]([O:16][C@@H:17]([C@H:19]2[CH2:23][N:22]([C@@H:24]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[CH3:25])[C:21](=[O:34])[CH2:20]2)[CH3:18])[C:39]2[N:46]([CH3:49])[CH:47]=[N:48][C:38]=2[CH:37]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)O)CC2=O)cc1
Reactant: Cn1cnc2cc(Cl)nc(S(C)(=O)=O)c21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cc4ncn(C)c34)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.3 h

Procedure:
A solution of NaHMDS in THF (1.0 M, 1.05 mL, 1.05 mmol) was added to a solution of (R)-4-((R)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.04 (277 mg, 1.05 mmol) in DMF (14 mL) at room temperature. After 18 minutes, a suspension of 6-chloro-3-methyl-4-(methylsulfonyl)-3H-imidazo[4,5-c]pyridine 2.04 (237 mg, 0.967 mmol) in DMF (4 mL) was added and mixture stirred at room temperature. After 40 minutes, LC/MS indicated full conversion to desired product. Reaction mixture was quenched with 15 mL of water, poured into 30 mL of water and extracted with ethyl acetate (3×50 mL). Combined organics were washed with 50% Brine (2×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. This residue was purified by silica gel column chromatography (0-10% methanol in dichloromethane) to yield (R)-4-((R)-1-(6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.05.
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=2[C:17]2[N:18]([CH3:22])[N:19]=[CH:20][CH:21]=2)[CH2:3]1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][C:26]=1[CH3:34].C(N(CC)CC)C>C1COCC1>[F:23][C:2]1([F:1])[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([F:24])=[C:26]([CH3:34])[CH:27]=3)=[CH:12][C:11]=2[C:17]2[N:18]([CH3:22])[N:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCC(F)(F)C1
Reactant: Cc1cc(C(=O)Cl)ccc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2ccc(OCCN3CCC(F)(F)C3)c(-c3ccnn3C)c2)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.6 %

Procedure:
A mixture of 4-[2-(3,3-Difluoro-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (64 mg, 0.20 mmole), 4-fluoro-3-methyl-benzoyl chloride (52 mg, 0.30 mmole), and triethylamine (56.5 μL, 0.40 mmole) in 1 mL THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give the title compound as a white solid (TFA salt, 29 mg, 32% yield). Exact mass calculated for C24H25F3N4O2 458.2, found 459.3 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH:15]=[C:16]([CH2:19][C:20]([OH:22])=[O:21])[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[N+:23]([O-:28])([N+]([O-])=O)=[O:24]>C(#N)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH:15]=[C:16]([CH2:19][C:20]([OH:22])=[O:21])[CH:17]=[CH:18][C:13]=3[O:12][C:11]=2[N+:23]([O-:28])=[O:24])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(O)Cc1ccc2occ(-c3ccc(C(=O)O)cc3)c2c1
Solvent: CC#N
Product: O=C(O)Cc1ccc2oc([N+](=O)[O-])c(-c3ccc(C(=O)O)cc3)c2c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a suspension of 2 g. of the product of step B in 10 ml. of acetonitrile is added 0.2 g. of cupric nitrate hydrate and 1 g. of dinitrogen tetraoxide in 2 ml. of acetonitrile. The mixture is stirred at 20° C. for two hours, 0.5 g. of additional dinitrogen tetraoxide is added, and the mixture is stirred for an additional 18 hours. It is then concentrated, and the solid is separated by filtration and recrystallized from acetic acid to provide light yellow crystals of 3-(4-carboxyphenyl)-2-nitrobenzofuran-5-acetic acid, m.p. 290° C. (dec.).
Reaction SMILES: [Ti](Cl)(Cl)(Cl)[Cl:2].C1(C)C=CC=CC=1.[Cl-:13].[C:14]1([N:20]2[CH2:28][CH2:27][N:26]([Ti+3:29])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Cl-]>C(OCC)C>[Cl-:2].[Cl-:13].[C:14]1([N:20]2[CH2:28][CH2:27][N:26]([Ti+2:29])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: [Ti+3]N1CCNCCN(c2ccccc2)CC1
Reactant: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: [Ti+2]N1CCNCCN(c2ccccc2)CC1
Temperature: 40 °C

Procedure:
Separately, 0.647 g (3.41 millimoles) of titanium tetrachloride was dissolved in 20 milliliters of diethyl ether at −50° C. The resulting solution was dropwise added at −60° C. over 2 hours to the toluene mixed solution prepared previously, and the resulting mixture was then heated to 40° C. and then subjected to reaction for a further 6 hours. Subsequently, the reaction mixture obtained was subjected to recrystallization from a hexane/methylene chloride mixed solvent to isolate the product, thereby obtaining N-phenyl-1,4,7-triazacyclononanyltitanium chloride in a yield of 35%.
Reaction SMILES: [F:1][C:2]1([F:46])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([OH:33])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[C@@H:34]([F:45])[C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH2:4][CH2:3]1.C1(C)C=CC(S(O[CH2:57][CH2:58][CH2:59][S:60]([CH3:63])(=[O:62])=[O:61])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].ClC1N=CC(O)=CN=1>CN(C)C=O.O>[F:46][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:57][CH2:58][CH2:59][S:60]([CH3:63])(=[O:62])=[O:61])=[CH:29][N:28]=4)[CH2:25][CH2:26]3)[C:9]=2[C@@H:34]([F:45])[C:35]2[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=2)[CH2:6][CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: Oc1cnc(Cl)nc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OCCCS(C)(=O)=O)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
To a solution of 145 mg (0.224 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Reference Example 23, in 0.7 ml of N,N-dimethylformamide, 130 mg (0.445 mmol) of 3-(methylsulfonyl)propyl p-toluenesulfonate and 135 mg (0.977 mmol) of potassium carbonate were added, and the mixture was stirred at 80° C. for 4 hours. 44 mg (0.337 mmol) of 2-chloro-5-hydroxypyrimidine was further added thereto, and the mixture was stirred at 80° C. for 3 hours. After completion of the reaction, the reaction solution was poured into water and extracted with toluene twice. The obtained organic phases were combined and washed with saturated sodium chloride aqueous solution, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=55/45-25/75 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 137.0 mg of the title compound as a white solid (yield: 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>O1CCCC1.CN(C)C=O>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:24]([NH:23][C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)=[O:25])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(Oc2ccnc(N)c2)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccn1
Reaction time: 1 h

Procedure:
After dissolving 0.53 g of 2-amino-4-(4-aminophenoxy)pyridine in a mixture of 20 ml of tetrahydrofuran and 10 ml of dimethylformamide, 0.36 ml of p-fluorophenyl isocyanate was added and the mixture was stirred for 1 hour. NH type silica gel was added to the reaction solution, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (chloroform:methanol=20:1, followed by 10:1). The solvent was distilled off under reduced pressure to obtain 610 mg of the target substance as a white powder.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[CH:3][CH:2]=1.O.NN>C(O)COCCO>[CH:10]1[C:11]2[CH2:12][C:13]3[C:5](=[N:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[N:7]=[CH:8][CH:9]=1
Reactant: O=C1c2cccnc2-c2ncccc21
Agent: NN
Solvent: O
Solvent: OCCOCCO
Product: c1cnc2c(c1)Cc1cccnc1-2
Temperature: 170 °C
Yield: 91.6 %

Procedure:
A mixture of 18.2 g (100 mmol) of 4,5-Diazafluoren-9-one, 27 ml (400 mmol) of hydrazine monohydrate, and 500 ml diethylene glycol was degassed and placed under nitrogen, and then heated at 170° C. for 12 h. After the reaction finish, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed to give product 15.4 g (91.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:12]=[CH:11][C:3]=1[NH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:12]=[CH:11][C:3]=1[N:4]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:5](=[O:10])[C:6]([F:8])([F:7])[F:9]
Reactant: CCOC(=O)CBr
Reactant: O=C(Nc1ccc(CCOC2CCCCO2)cc1Cl)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(C(=O)C(F)(F)F)c1ccc(CCOC2CCCCO2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2′-chloro-4′-[2-((RS)-tetra-hydropyran-2-yloxy)ethyl]-2,2,2-trifluoroacetanilide (352 mg) in N,N-dimethylformamide (3 ml) was added sodium hydride (48 mg) under ice-cooling, and the mixture was stirred for 30 minutes at room temperature. Ethyl bromoacetate (133 μl) was added to the reaction mixture, and the mixture was stirred for 16 hours. Ethyl acetate was added to the reaction mixture, and the resulting mixture was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed in vacuo, purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/diethyl ether=2/1) gave ethyl N-[2-chloro-4-[2-((RS)-tetrahydropyran-2-yloxy)ethyl]phenyl]-N-trifluoroacetylamino-acetate (250 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH2:16]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C:26]1=O)[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O>C(O)(=O)C>[C:19]1([C:17]2[N:1]([C:2]3[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][C:3]=3[C:12]([F:13])([F:14])[F:15])[C:26]3[CH2:27][CH2:28][CH2:29][CH2:30][C:25]=3[CH:16]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1cc(C(=O)O)c(O)cc1C(F)(F)F
Reactant: O=C(CC1CCCCC1=O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCCC3)c(C(F)(F)F)cc1O

Procedure:
A mixture of 6.5 g. (0.029 mole) of 5-amino-4-trifluoromethylsalicylic acid, 6.35 g. (0.029 mole) of 2-phenacylcyclohexanone, and 30 ml. of glacial acetic acid was heated under reflux for 3 hours, cooled and filtered. The filter cake was recrystallized from acetic acid to provide 4.6 g. (39%) of gold crystals, m.p. 188°-190°.