Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:16][CH2:15][C@H:14]([OH:17])[C:13]2=[O:18])[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][C:7]2=[O:11].[Br:19][C:20]1[CH:25]=[C:24](O)[CH:23]=[CH:22][N:21]=1>>[Br:19][C:20]1[CH:25]=[C:24]([O:17][C@@H:14]2[CH2:15][CH2:16][N:12]([C:4]3[CH:5]=[C:6]4[C:10](=[C:2]([F:1])[CH:3]=3)[CH2:9][CH2:8][C:7]4=[O:11])[C:13]2=[O:18])[CH:23]=[CH:22][N:21]=1
Reactant: Oc1ccnc(Br)c1
Reactant: O=C1CCc2c(F)cc(N3CC[C@H](O)C3=O)cc21
Product: O=C1CCc2c(F)cc(N3CC[C@@H](Oc4ccnc(Br)c4)C3=O)cc21

Procedure:
Typical Procedure 3 was followed. Reaction of (S)-1-(7-fluoro-3-oxo-indan-5-yl)-3-hydroxy-pyrrolidin-2-one with 2-bromo-pyridin-4-ol provided the title compound. MS ESI+: m/z=405 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][CH:18]=[C:5]12.[CH3:19][N:20]([CH2:22][CH2:23][CH2:24]Cl)[CH3:21]>CN(C)C=O>[CH3:19][N:20]([CH3:21])[CH2:22][CH2:23][CH2:24][N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:4]([CH3:3])[C:5]2=[CH:18][S:17][CH:16]=[C:6]2[C:7]1=[O:15]
Reactant: CN(C)CCCCl
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCN1C(=O)c2cscc2N(C)c2ccccc21
Reaction time: 18 h

Procedure:
A mixture of 0.3 g. of 55% sodium hydride-mineral oil dispersion and 0.35 g. of 4,9-dihydro-4-methyl-10H-thieno-[3,4-b][1,5]benzodiazepin-10-one in 25 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.45 g. of dimethylaminopropyl chloride and stirring at room temperature is continued for 18 hours. The reaction mixture is cooled, quenched with water, acidified, decolorized and filtered. The filtrate is made alkaline and extracted with chloroform. The dried chloroform extracts are concentrated under reduced pressure to give an oil which is crystallized by dissolving in boiling hexane and a minimal volume of ethyl acetate and cooling to give off-white crystals, m.p. 52°-56° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[C:15]([CH:17]=[C:18]([O-])[CH3:19])#[N:16].[Na+].[NH2:22][C:23](=[CH:25][C:26](=[O:32])[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:24].C(O)(=O)C>CC(O)C>[CH3:19][C:18]1[NH:22][C:23]([CH3:24])=[C:25]([C:26](=[O:32])[CH2:27][CH2:28][CH:29]([CH3:30])[CH3:31])[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:17]=1[C:15]#[N:16]
Reactant: CC([O-])=CC#N
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CC(N)=CC(=O)CCC(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2cccc3c(=O)cc(C)oc23)C(C(=O)CCC(C)C)=C(C)N1

Procedure:
100 mg (0.53 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 55.8 mg (0.53 mmol) of sodium 1-cyanoprop-1-en-2-olate, 82.4 mg (0.53 mmol) of 2-amino-7-methyloct-2-en-4-one (example 14, stage a) and 31.9 mg (0.53 mmol) of acetic acid in 5 ml of 2-propanol and heated under reflux under argon for 6 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 47 mg (22% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]3[N:21](C4C=CC(S(C)(=O)=O)=CC=4F)[N:22]=[CH:23][C:16]=23)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])C.Cl.Cl.[F:37][C:38]1[CH:43]=[C:42]([S:44]([CH3:47])(=[O:46])=[O:45])[CH:41]=[CH:40][C:39]=1N1C2=NC=NC(SC3CCNCC3)=C2C=N1.C(N(CC)CC)C.ClC(OC(C)C)=O>CN(C=O)C.C1(C)C=CC=CC=1>[CH:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([SH:14]([C:39]2[CH:40]=[CH:41][C:42]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:43][C:38]=2[F:37])[C:15]2[N:20]=[CH:19][N:18]=[C:17]3[NH:21][N:22]=[CH:23][C:16]=23)[CH2:10][CH2:9]1)=[O:7])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2F)CC1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(SC4CCNCC4)ncnc32)c(F)c1
Agent: CC(C)OC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)N1CCC([SH](c2ccc(S(C)(=O)=O)cc2F)c2ncnc3[nH]ncc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylic acid tert-butyl ester (3.54 g, 6.97 mmol) was treated with 4M HCl in 1,4-dioxanes (40 mL). After 2 hours stirring at room temperature, 1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-ylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride was collected by filtration. To a mixture of 1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-ylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (3.0 g, 6.76 mmol) in DMF (27 mL) was added triethyl amine (2.05 g, 20.28 mmol). After 30 minutes stirring, isopropyl chloroformate (7.44 mmol) as a 1.0M solution in toluene was added to the reaction and reaction was stirred for two hours. HCl salts had crashed out and were removed by filtration. Filtrate was extracted with ethyl acetate (100 mL) and washed with water (4×100 mL). Organic was dried over anhydrous MgSO4, filtered and concentrated in vacuo to yield Compound A214 as a white solid. 1H NMR(CDCl3, 400MHz) δ 1.27 (d, J=6.3 Hz, 6H), 1.77 (2H, m), 2.18 (2H, m), 3.13 (3H, s), 3.21 (2H, m), 4.04 (2H, m), 4.48-4.40 (1H, m), 4.99-4.90 (1H, m), 7.98-7.92 (3H, m), 8.30 (1H, s), 8.79 (1H, s). Exact mass calculated for C21H24FN5O4S2 493.1, found 494.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.[CH2:32]([N:34]([CH2:37]C)[CH2:35]C)[CH3:33].ClC(Cl)([O:42][C:43](=O)[O:44]C(Cl)(Cl)Cl)Cl.CN(C)CCO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:43](=[O:42])[O:44][CH2:33][CH2:32][N:34]([CH3:37])[CH3:35])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: CCN(CC)CC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CN(C)CCO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCN(C)C)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 35 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (80 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (111 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-dimethylaminoethanol (31 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (41 mg, yield 35%).
Reaction SMILES: C[N:2]1[CH2:11][C:10]2([CH2:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[C:20]1([O:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[O:26]([C:27]([N:2]1[CH2:11][C:10]2([CH2:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1Cc2ccccc2C2(Cc3ccccc3O2)C1
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1Cc2ccccc2C2(Cc3ccccc3O2)C1
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a previously flamed 2000 ml round-bottom flask is added N-methylspiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (32.5 g) in dichloromethane (700 ml). To this is added phenylchloroformate (20 ml). The mixture is stirred overnight. Removal of the solvent yields an oil. Trituration with n-propanol followed by recrystallization of 4.0 g of the solid so formed from ethyl acetate yields 2.6 g (69.7%) of product, mp 128°.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[I:11][C:12]1[CH:13]=[N:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C>N1C=CC=CC=1.ClCCl.[Cu]=O>[I:11][C:12]1[CH:13]=[N:14][N:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:16]=1
Reactant: Ic1cn[nH]c1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1-n1cc(I)cn1
Yield: 76.2 %

Procedure:
A mixture of 1-fluoro-2-nitrobenzene (14.5 g, 0.1 mol), 4-iodopyrazole (20 g, 0.1 mol), potassium carbonate anhydrous (14 g, 0.1 mol) and catalytical amounts of copper(II) oxide in pyridine (35 ml) was heated to reflux for 16 hours. After cooling, the mixture was diluted with dichloromethane (1 litre). Activated charcoal (12 g) was then added and the mixture was heated to reflux for 1 hour. After cooling, it was filtered through celite. The filtrate was evaporated and the remaining oil was purified by silica gel chromatography using ethyl acetate and hexane as eluents, giving 4-iodo-1-(2-nitro-phenyl)-1H-pyrazole (24 g).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([N:22]=[CH:23][N:24]=2)[N:21]=1.Cl>CN(C)C=O.O>[CH2:11]([C:5]([CH2:13][CH3:14])([CH2:6][S:7](=[O:8])(=[O:9])[NH2:10])[CH2:4][O:3][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([N:22]=[CH:23][N:24]=2)[N:21]=1)[CH3:12]
Reactant: Clc1ccc2ncnn2n1
Reactant: CCC(CC)(CO)CS(N)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)(COc1ccc2ncnn2n1)CS(N)(=O)=O
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
In 20 ml of dimethylformamide was suspended 0.64 g of 60% sodium hydride in oil, followed by addition of 1.56 g of 3-hydroxy-2,2-diethyl-1-propanesulfonamide and the mixture was stirred under reduced pressure at room temperatue for 30 minutes. Then, 1.24 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine was added and the mixture was further stirred at room temperature for 1.5 hours. Following addition of 100 ml of iced water, the reaction mixture was adjusted to pH 6 with 1N-hydrochloric acid and the resulting crystals were collected by filtration and washed with 20 ml of water and 20 ml of ethyl ether. The washed crystals were recrystallized from hot ethanol to provide 1.57 g of the title compound. m.p. 194°-197° C.
Reaction SMILES: [C:1]1([O:9][Si](C)(C)C)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[B-](F)(F)(F)[F:15].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.FF>CN(C=O)C>[F:15][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]1=[O:9]
Reactant: C[Si](C)(C)OC1=CCCCCCC1
Reactant: F[B-](F)(F)F
Agent: FF
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CN(C)C=O
Product: O=C1CCCCCCC1F
Reaction time: 12 h

Procedure:
To a solution of silyl enol ether 6 (57.8 g, 291 mmol) in DMF (350 mL) was added a solution of Selectfluor (124 g, 349 mmol) in DMF (150 mL) over 1 h at rt. The solution was allowed to stir for 12 h. The reaction was quenched with 30 mL of H2O, and the DMF was removed on a rotary evaporator. The residue was diluted with hexanes (500 mL), washed with H2O (3×200 mL) and brine (1×50 mL), and dried over MgSO4. Following column chromatography (30:1 to 15:1 pentane/ether), a white solid was isolated (38.4 g, 91%, Rf=0.30 in 9:1 pentane/ether), mp 48.1-49.8° C. IR: 3429, 2932, 2859, 1721, 1709 cm−1. (Lit: 1710 cm−1) (Rozen and Menahem. J. Fluorine Chem. (1980), 16, 19-31). 1H NMR (CDCl3, 400 MHz): δ 1.25 (m, 1H), 1.38-1.55 (m, 4H), 1.61 (m, 1H), 1.73 (m, 1H), 2.05 (m, 3H), 2.30 (m, 1H), 2.55 (m, 1H), 4.86 (ddd, 1H, J=49.6, 6.4, 2.8 Hz). (Lit: 1H NMR (CDCl3, 250 MHz): δ 1.36-2.7 (m, 12H), 4.9 (dm, 1H, J=49.5 Hz) (Chambers and Hutchinson J. Fluorine Chem. (1998) 89, 229-232)13C NMR (CDCl3, 100 MHz): δ 20.3 (d, J=4.0 Hz), 24.4 (d, J=6.0 Hz), 24.5, 26.9, 32.2 (d, J=11.0 Hz), 39.3, 94.7 (d, J=185.0 Hz), 213.4 (d, J=21.0 Hz). (Lit: 13C NMR (CDCl3, 50 MHz): δ 20.5 (d, J=3.6 Hz), 24.6 (d, J=3.7 Hz), 24.7, 27.2, 32.7 (d, J=21.0 Hz), 39.6, 91.5 (d, J=184.7 Hz), 213.9 (d, J=20.9 Hz) (Chambers and Hutchinson (1998) supra) 19F NMR (CDCl3, 376 MHz): δ −190.7 (m). (Lit: 19F NMR (CDCl3, 235 MHz): δ −191.6 (m) (Chambers and Hutchinson (1998) supra)
Reaction SMILES: [CH3:1][P:2]([CH3:5])(=[O:4])[OH:3].[OH-].[CH2:7]([N+:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10]>O.CC(O)C>[CH3:1][P:2]([CH3:5])(=[O:3])[O-:4].[CH2:20]([N+:11]([CH2:7][CH2:8][CH2:9][CH3:10])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:21][CH2:22][CH3:23]
Reactant: CP(C)(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CP(C)(=O)[O-]

Procedure:
To a flask were added 11.0 g dimethylphosphinic acid, 4.5 g of a 55-60% solution of tetrabutylammonium hydroxide in water and 20 ml 2-propanol. After heating to 50 C under nitrogen for 1 hour, the solvent was removed and another 20 ml of 2-propanol were added and removed by distillation under reduced pressure. After drying, a yellow partially solidified product was obtained.
Reaction SMILES: CN(C)C=O.[NH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=1>O.C1(C)C=CC=CC=1>[C:20]([C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][CH2:12][CH:9]2[CH2:10][CH2:11][N:6]([CH2:31][CH2:32][CH2:33][O:34][C:35]3[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=3)[CH2:7][CH2:8]2)=[CH:23][CH:22]=1)#[N:21]
Reactant: N#Cc1ccc(OCCCBr)cc1
Reactant: N#Cc1ccc(OCCCC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(OCCCC2CCN(CCCOc3ccc(C#N)cc3)CC2)cc1
Reaction time: 18 h
Yield: 83.9 %

Procedure:
To an N,N-dimethylformamide (150 mL) solution of 10.2 g of 4-[3-(4-piperidinyl)propoxy]benzonitrile were sequentially added 11.2 g of potassium carbonate and 9.72 g of 4-(3-bromopropoxy)benzonitrile at room temperature, which was then stirred at the same temperature for 18 hours. Toluene and water were added to the reaction mixture. The precipitate was collected by filtration to provide 13.7 g of 4-(3-{4-[3-(4-cyanophenoxy)propyl]-1-piperidinyl}propoxy)benzonitrile as white solid form.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:9]([O:10]C(=O)C)[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:38]#[N:39])=[N:18][C:19]=3[NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:7][C@@H:6]1[CH2:40][O:41]C(=O)C)(=O)C.N>[Pd].C(O)C>[NH2:39][CH2:38][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@H:8]2[C@H:9]([OH:10])[C@H:5]([OH:4])[C@@H:6]([CH2:40][OH:41])[O:7]2)=[C:19]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:18]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Agent: N
Solvent: CCO
Product: NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.5 %

Procedure:
10% w/w Palladium on carbon (200 mg) was added to a solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-{2-cyano-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}tetrahydro-3-furanyl acetate (Preparation 18) (1.9 g, 3.2 mmol) in ethanol saturated with ammonia (100 ml). The reaction mixture was stirred under an atmosphere of hydrogen 414 kPa (60 psi) for 16 hours at room temperature. The solids were removed by filtration through Arbocel (Trade Mark) and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:1 by volume gradually changing to 80:20:2 by volume) to give the title compound as a solid (770 mg).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[NH:8][C:7]([C:9](OCC)=[O:10])=[C:6]([NH:14][C:15](=[NH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:5]=1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[CH2:16]([C:15]1[NH:20][C:9](=[O:10])[C:7]2[NH:8][C:4]([CH3:3])=[CH:5][C:6]=2[N:14]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCC(=N)Nc1cc(C)[nH]c1C(=O)OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCc1nc2cc(C)[nH]c2c(=O)[nH]1
Temperature: 25 °C

Procedure:
Aqueous sodium hydroxide solution (6M, 138 mL) was added dropwise to a solution of ethyl 5-methyl-3-pentanimidamido-1H-pyrrole-2-carboxylate (58.9 g, 0.2 mol) in ethanol (550 mL) cooled in an ice-bath. The reaction mixture was heated at reflux for 2.5 hours then cooled to room temperature. Water (700 mL) was added and the pH adjusted to pH 6.5 using aqueous citric acid (2M). The resultant mixture was stirred for 45 minutes then filtered and the solid material washed with water. The material was dried in a vacuum oven at 50° C. to give the title compound.
Reaction SMILES: C(OCC)(=O)C.[Cl:7][C:8]1[C:9]([O:18][C:19]2[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=2)=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.C(N(CC)CC)C.CC1C=CC(OC2C=CC(CN[C:46]([C:48]3[N:52]([CH3:53])[N:51]=[C:50]([CH2:54][CH3:55])[C:49]=3[Cl:56])=[O:47])=CC=2)=CC=1>O>[Cl:7][C:8]1[C:9]([O:18][C:19]2[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:46]([C:48]3[N:52]([CH3:53])[N:51]=[C:50]([CH2:54][CH3:55])[C:49]=3[Cl:56])=[O:47])=[CH:21][CH:20]=2)=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=1
Reactant: CCc1nn(C)c(C(=O)NCc2ccc(Oc3ccc(C)cc3)cc2)c1Cl
Reactant: NCc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1nn(C)c(C(=O)NCc2ccc(Oc3ncc(C(F)(F)F)cc3Cl)cc2)c1Cl
Reaction time: 1 h

Procedure:
Into 50 ml solution of ethyl acetate containing 2.49 g of 4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)benzylamine and 1.21 g of triethylamine, was dropped 2.07 g of 4-chloro-3-ethyl-1-methyl-5-pyrazolecarboxylic acid chloride synthesized in Example 2. After the completion of dropping, the mixture was stirred for 1 hour, poured into iced water and then extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous solution of sodium carbonate, water and a saturated aqueous solution of sodium chloride. After drying over anhydrous sodium sulfate, the solution was concentrated under a reduced pressure. The residue was purified on silica gel column chromatography to obtain 3.35 g of the titled compound (No. 75) shown in Table 1.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)=O.Br[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21].[OH-].[Na+].[Cl-].[Na+]>CO.C(Cl)Cl>[NH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[C:20]#[N:21])=[CH:11][CH:12]=1
Reactant: O=C(NCc1ccc(O)cc1)C(F)(F)F
Reactant: N#Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: N#Cc1cccc(Oc2ccc(CN)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 15 %

Procedure:
Use a method similar to Preparation 40 (Step 2), using 2,2,2-trifluoro-N-(4-hydroxybenzyl)-acetamide (1.0 g, 5.5 mmol) and 3-bromobenzonitrile (673 mg, 3.7° mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 3:1). Concentrate in vacuo. Dissolve the residue (287 mg, 0.89 mmol) in methanol (25 mL) and add 5N NaOH (7 mL). Stir at room temperature for 4 h. Dilute with DCM and add solid sodium chloride to the mixture. Extract the aqueous layer three times with DCM. Combine organic extracts, dry over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol (94:6) to obtain the title compound (124 mg, 62%). MS (ES+) m/z: 500 (M+H)+.
Reaction SMILES: C(OC(=O)[N:7]([CH2:33][CH2:34][CH3:35])[C@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:14]=2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.[Cl:44]CCl>>[ClH:44].[CH2:33]([NH:7][C@H:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([NH:18][S:19]([C:22]3[CH:23]=[CH:24][C:25]([CH2:28][C:29]([F:32])([F:30])[F:31])=[CH:26][CH:27]=3)(=[O:21])=[O:20])[CH:12]=[CH:11][C:10]=2[CH2:9]1)[CH2:34][CH3:35]
Reactant: CCCN(C(=O)OC(C)(C)C)[C@H]1CCc2cc(NS(=O)(=O)c3ccc(CC(F)(F)F)cc3)ccc2C1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN[C@H]1CCc2cc(NS(=O)(=O)c3ccc(CC(F)(F)F)cc3)ccc2C1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Propyl-{(S)-6-[4-(2,2,2-trifluoro-ethyl)-benzenesulfonylamino]-1,2,3,4-tetrahydronaphthalen-2-yl}-carbamic acid tert-butyl ester (1.22 g, 2.07 mmol) was dissolved in dichloromethane (40 ml). Trifluoroacetic acid (2 ml) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness. Diethyl ether (100 ml) was added and the mixture was extracted with saturated NaHCO3 solution. The organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The residue was dissolved with ethyl acetate and ethereal hydrochloride solution was added. The crystalline product was filtered off to give pure product (625 mg, 65% yield).
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]2[NH:16][C:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][N:13]=2)[C:9]([OH:25])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][C:27]1=[O:32].O>CN1CCCC1=O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:15]2[NH:16][C:12]([C:10]3[C:9]([OH:25])=[C:8]4[C:3]([CH:4]=[CH:5][CH:6]=[N:7]4)=[C:2]([N:29]4[CH2:30][CH2:31][NH:26][C:27](=[O:32])[CH2:28]4)[N:11]=3)=[N:13][N:14]=2)=[CH:19][CH:20]=1
Reactant: O=C1CNCCN1
Reactant: Oc1c(-c2nnc(Cc3ccc(F)cc3)[nH]2)nc(Br)c2cccnc12
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1CN(c2nc(-c3nnc(Cc4ccc(F)cc4)[nH]3)c(O)c3ncccc23)CCN1
Yield: 55.6 %

Procedure:
A solution of 5-bromo-7-[5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-yl)-1,6-naphthyridin-8-ol (10 mg, 0.03 mmol) and piperazin-2-one (60 mg, 0.60 mmol) in 1-methylpyrrolidin-2-one (2 mL) was heated at 150° C. for 18 hours. The resultant solution was cooled to room temperature and water was added. The solids which formed were removed by filtration and further purified by prep HPLC to give 4-{7-[5-(4-Fluorobenzyl)-4H-1,2,4-triazol-3-yl]-8-hydroxy-1,6-naphthyridin-5-yl}piperazin-2-one (7 mg, 67%) as a white solid. 1H NMR (CD3OD/CDCl3): δ 9.03 (d, J=4.4 Hz, 1 H), 8.48 (d, J=8.4 Hz, 1 H), 7.64 (dd, J=8.4, 4.4 Hz, 1 H), 7.32 (dd, J=8.4, 5.6Hz, 2 H), 6.97 (t, J=8.4Hz, 2 H). 4.13 (s, 2 H), 4.10 (5,2 H), 3.60 (m, 2 H), 3.42 (m, 2 H); 19F NMR (CD3OD/CDCl3): δ −117.93; MS m/z 420 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].[Br:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:14]([F:21])[C:13]=1[S:22](Cl)(=[O:24])=[O:23]>>[Br:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:14]([F:21])[C:13]=1[S:22]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:2]([OH:1])[CH:3]=1)(=[O:24])=[O:23]
Reactant: COc1ccc(N)cc1O
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1Br
Product: COc1ccc(NS(=O)(=O)c2c(F)c(F)c(F)c(F)c2Br)cc1O

Procedure:
The title compound was prepared in a manner similar to that described in Example 6 of WO 97/30677, beginning with 3-hydroxy-4-methoxyaniline and 2-bromo-3,4,5,6-tetrafluorophenylsulfonyl chloride (Example D, above).