Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:7]=[C:8]3[N:16]([CH3:17])[CH:15]=[CH:14][C:9]3=[N:10][C:11]=2[C:12]#[N:13])[CH2:3]1.[CH3:18][Mg]Br.CCOCC.[BH4-].[Na+]>C1COCC1>[NH2:13][CH:12]([C:11]1[N:10]=[C:9]2[CH:14]=[CH:15][N:16]([CH3:17])[C:8]2=[CH:7][C:6]=1[N:4]1[CH2:5][CH:2]([OH:1])[CH2:3]1)[CH3:18]
Reactant: C[Mg]Br
Reactant: Cn1ccc2nc(C#N)c(N3CC(O)C3)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(N)c1nc2ccn(C)c2cc1N1CC(O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(3-hydroxyazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (2.6 g, 11 mmol) in THF 100 mL at 0° C. was slowly added 3M methylmagnesium bromide in ether (15.2 mL, 45.6 mmol) to give a yellow solution. After 1 hour, the reaction mixture was warmed to RT and was stirred for an additional 2.5 hours. The reaction was then quenched with MeOH (5 mL). The mixture was stirred for 15 minutes. Sodium borohydride (0.862, 22.8 mmol) was added and the reaction mixture was stirred for 1 hour. The reaction was subsequently quenched with 1M HCl (5 mL). The mixture was stirred for 15 minutes, diluted with EtOAc, and washed with saturated aqueous NH4Cl (3×). The aqueous layer was concentrated to give the title compound as a brown solid, which was used without further purification.
Reaction SMILES: [C:1]1([CH2:17][C:18]([OH:20])=O)[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH3:21]>>[C:1]1([CH2:17][C:18]([NH2:21])=[O:20])[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: O=C(O)Cc1cccc2c1C(=O)c1ccccc1C2=O
Product: NC(=O)Cc1cccc2c1C(=O)c1ccccc1C2=O

Procedure:
Under the stated conditions, the ester of anthraquinone-acetic acid reacts with the NH3 to form, directly, the 1-aza-2-hydroxybenzanthrone, without the necessity of isolating the intermediate product 1-anthraquinone acetamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:34])([CH2:28][N:29]1[CH:33]=[N:32][N:31]=[N:30]1)[C:10]([C:13]1[N:18]=[CH:17][C:16]([O:19][C:20]2[CH:27]=[CH:26][C:23](C#N)=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)([F:12])[F:11].[F:35]C1C=CC(B(O)O)=CC=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:34])([CH2:28][N:29]1[CH:33]=[N:32][N:31]=[N:30]1)[C:10]([F:11])([F:12])[C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:21]=[CH:22][C:23]([F:35])=[CH:26][CH:27]=2)=[CH:17][N:18]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: N#Cc1ccc(Oc2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)cc1
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(Oc2ccc(F)cc2)cn1
Yield: 42.4 %

Procedure:
Compound 6 was prepared in a similar manner to compound 5 from (4-fluorophenyl)boronic acid to afford a solid 6 (0.1 g, 0.22 mmol, 42.4%). 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H), 8.20 (d, J=2.5 Hz, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.43-7.38 (m, 2H), 7.27 (d, J=2.5 Hz, 1H), 7.26-7.03 (m, 4H), 6.79-6.70 (m, 2H), 5.49 (d, J=14.5 Hz, 1H), 5.15 (d, J=14.5 Hz, 1H). MS(ESI): m/z 494.1 [M++1]. HPLC: 99.43%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[F:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: COc1cc(Br)ccn1
Reactant: COc1ccc(B(O)O)c(F)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(-c2ccnc(OC)c2)c(F)c1
Temperature: 90 °C
Yield: 56.6 %

Procedure:
4-Bromo-2-methoxypyridine (1.39 g, 7.42 mmol), 2-fluoro-4methoxyphenylboronic acid (2.40 g, 14.1 mmol), K2CO3 (2.05 g, 14.8 mmol) and bis(triphenylphosphine) palladium(II)chloride (Pd(PPh3)2Cl2) (52 mg, 0.74 mmol) were stirred in DMSO (8.5 mL) under vacuum for 20 min. The flask was flushed with argon and the mixture was heated to 90° C. for 3 h. Upon cooling, the mixture was diluted with brine, and the aqueous solution was extracted with CH2Cl2 (3×50 mL). The combined organic extracts were washed with water (3×20 mL), dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography (40+M Biotage column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 to 80:20) provided the title compound (0.98 g, 57%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J=5.4 Hz, 1H), 7.42-7.38 (m, 1H), 7.07 (d, J=5.4 Hz, 1H), 6.93 (s, 1H), 6.80 (dd, J=8.6, 2.5 Hz, 1H), 6.74 (dd, J=12.6, 2.5 Hz, 1H), 3.99 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: [OH-].[Na+].[C:3]([CH2:5][C:6]([O:8]C)=[O:7])#[N:4].[CH3:10][N:11]([CH3:20])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.Cl>C(O)C>[C:3]([C:5](=[CH:16][C:15]1[CH:18]=[CH:19][C:12]([N:11]([CH3:20])[CH3:10])=[CH:13][CH:14]=1)[C:6]([OH:8])=[O:7])#[N:4]
Reactant: COC(=O)CC#N
Reactant: CN(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)c1ccc(C=C(C#N)C(=O)O)cc1
Reaction time: 51 h
Yield: 27.4 %

Procedure:
In 400 ml of an aqueous solution of 13.77 g of sodium hydroxide, 34.80 g of methyl cyanoacetate was dissolved and 34.01 g of p-dimethylamino benzaldehyde was then added under a nitrogen atmosphere, followed by adding 200 ml of ethanol to obtain a uniform solution. Under reflux, the stirring was continued for 51 hours and the reaction mixture was added to 12 N hydrochloric acid to obtain the precipitates. The resultant solid was repeated twice to recrystallize from a methanol/ethanol mixture to obtain 13.51 g of the needles.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3]I.C(=O)([O-])[O-].[K+].[K+].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([Cl:21])[CH:15]=1.O>CN(C)C=O>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:3][C:2]([F:6])([F:5])[F:1])=[C:16]([Cl:21])[CH:15]=1
Reactant: FC(F)(F)CI
Reactant: Oc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(Br)cc1Cl
Temperature: 80 °C
Reaction time: 20 h
Yield: 43 %

Procedure:
2,2,2-Trifluoroethyliodide (15.2 g) and potassium carbonate (10.0 g) were added to a solution of 4-bromo-2-chlorophenol (5.0 g) in N,N-dimethylformamide (20 mL), and the mixture was stirred at 80° C. for 20 hours. The reaction solution was cooled to room temperature and water was added, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane only) to give 4-bromo-2-chloro-1-(2,2,2-trifluoroethoxy)benzene as a colorless oil (3.0 g, 43%).
Reaction SMILES: [C:1]([CH:4]([CH3:29])[CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=2[O:27][CH3:28])=[CH:8][CH:7]=1)(O)=[O:2].Cl.C[N:32](C)[CH2:33][CH2:34][CH2:35]N=C=NCC.C(N)CC.C(Cl)Cl>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:33]([NH:32][C:1]([CH:4]([CH3:29])[CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=2[O:27][CH3:28])=[CH:8][CH:7]=1)=[O:2])[CH2:34][CH3:35]
Reactant: COC(=O)c1ccc(Cc2cccc3ccc(CC(C)C(=O)O)cc23)c(OC)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCN
Product: CCCNC(=O)C(C)Cc1ccc2cccc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Reaction time: 18 h
Yield: 70 %

Procedure:
A mixture of methyl 4-[7-(2-carboxypropyl)naphth-1-ylmethyl]-3-methoxybenzoate (1.176 g), 4-dimethylaminopyridine (440 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (690 mg), propylamine (0.295 ml) and methylene chloride (20 ml) was stirred for 18 h. Ethyl acetate (100 ml) was added, the solution was washed (1N hydrochloric acid, brine) and dried (MgSO4). Evaporation and flash chromatography, eluting with 2:30:70 triethylamine:ethyl acetate:petroleum ether, gave a solid. Recrystallization from methylene chloride and hexane, followed by grinding to a powder and vacuum drying, afforded methyl 4-[7-[2-(propylcarbamoyl)propyl]naphth-1-ylmethyl]-3-methoxybenzoate (910 mg, 70%) as a colorless solid; mp 129.5°-130.0° C.; MS(CI), m/e=434(M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][OH:7].[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=1>>[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([O:7][CH2:6][C:5]2[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:15]=1
Reactant: COc1cc(CO)cc(OC)c1
Reactant: Clc1cncc(Cl)n1
Product: COc1cc(COc2cncc(Cl)n2)cc(OC)c1

Procedure:
The title compound was prepared according to the procedure of example 50, step 1, starting from 3,5-dimethoxybenzyl alcohol (2.16 g, 12.8 mmol), K-t-BuO (1.34 g, 11.9 mmol) and 2,6-dichloropyrazine (1.59 g, 10.7 mmol). The yield of the title compound was 2.56 g (84%) and was obtained as a white solid. HRMS m/z calcd for C13H13ClN2O3 (M)+ 280.0615, found 280.0627. Anal. (C13H13ClN2O3) C, H, N.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)=[C:20]([C:38]([F:41])([F:40])[F:39])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:43]>C(O)C>[ClH:43].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)=[C:20]([C:38]([F:39])([F:40])[F:41])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3ccc4ccccc4c3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2ccc3ccccc3c2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Compound 59-3 (500 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (400 mg) as a white powder.
Reaction SMILES: C([N:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:37])[CH2:5][C:6]([O:8]CC)=[O:7])(=O)C.Cl.O>O1CCOCC1>[C:6]([CH2:5][NH:4][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:37])([OH:8])=[O:7]
Reactant: CCCCCCNc1c(F)cc(F)c2oc(-c3ccc(N(CC(=O)OCC)C(C)=O)c(F)c3)cc(=O)c12
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCNc1c(F)cc(F)c2oc(-c3ccc(NCC(=O)O)c(F)c3)cc(=O)c12
Yield: 76.8 %

Procedure:
143 mg (0.276 mmol) of Compound 74 obtained in Example 74 was dissolved in 12 ml of dioxane, 8 ml of concentrated hydrochloric acid was added and the mixture was heated ar reflux for 10 minutes. The reaction solution was cooled on ice, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give 95 mg (77%) of Compound 75.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])C.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][NH:27][CH2:28]2.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][N:27]([C:11]1[N:10]=[C:9]3[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:3])=[O:5])=[CH:7][N:8]3[CH:19]3[CH2:20][CH2:21]3)=[CH:13][C:12]=1[F:17])[CH2:28]2
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: COc1cccc2c1CNC2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cccc2c1CN(c1nc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2
Yield: 29.9 %

Procedure:
310 mg of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4- oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 298 mg of 4-methoxyisoindoline, 0.42 ml of triethylamine, and 5 ml of anhydrous chloroform were processed in the same manner as in Example 107 to produce 118 mg of 7-(4-methoxy-2- isoindolinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acid.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]=[CH:17][C:18]([C:21]([NH:23][C:24]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:25]=3[C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=3)=[O:27])=[O:22])=[N:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C1(OC)C=CC=CC=1>[F:40][C:37]1[CH:38]=[CH:39][C:24]([NH:23][C:21]([C:18]2[CH:17]=[N:16][C:15]([N:11]3[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]3)=[CH:20][N:19]=2)=[O:22])=[C:25]([CH:36]=1)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cnc(C(=O)Nc3ccc(F)cc3C(=O)Nc3ccc(Cl)cn3)cn2)CC1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1)c1cnc(N2CCCNCC2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-[5-(4-t-butoxycarbonylhexahydro-1,4-diazepin-1-yl)pyrazin-2-ylcarbonylamino]-5-fluoro-N-(5-chloropyridin-2-yl)benzamide (Example P1, 11.4 g) in methylene chloride (30 mL) and anisole (10 mL) was added trifluoroacetic acid (30 mL) dropwise. The mixture was stirred overnight at room temperature before the solvent was evaporated. The residue was purified by using an SCX column. Yield 8.1 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([C:19](=[O:25])[CH:20](OCC)O)=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][C:27]([NH2:36])([CH3:35])[CH2:28][CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1.C(O)(=O)C(O)=O>C(O)C>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH:19]([OH:25])[CH2:20][NH:36][C:27]([CH3:35])([CH3:26])[CH2:28][CH2:29][N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(C(=O)OC)c1
Reactant: CC(C)(N)CCn1cncn1
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: COC(=O)c1cc(C(O)CNC(C)(C)CCn2cncn2)ccc1OCc1ccccc1

Procedure:
9.5 g of methyl 2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 3.1 g of 1,1-dimethyl-3-[1,2,4]triazol-1-yl-propylamine are reacted and worked up analogously to the method described for Example 2a. The crude product is dissolved in 100 mL 95% ethanol and combined with an ethanolic solution of 1.8 g of oxalic acid. After the addition of a crystallisation aid the precipitated product is separated off and washed. Yield: 8 g (64%, bisoxalate), m.p.=220-222° C.
Reaction SMILES: [P:1]([Cl:5])(Cl)(Cl)=[O:2].[C:6]1([CH3:13])[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][CH:7]=1>>[P:1]([Cl:5])(=[O:2])([O:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:13])[O:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:13]
Reactant: Cc1ccccc1O
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccccc1OP(=O)(Cl)Oc1ccccc1C

Procedure:
While it is known to form compounds of the formula (ArO)2P(O)Cl (see U.S. Pat. No. 3,965,220), only a few disclosures are known to exist in which such polyphosphate compounds are formed in which the initial reaction is between monohydroxy compound and phosphorus oxychloride with the second reaction step using diol as the reagent. In U.S. Pat. No. 4,133,846 it is taught in Example 4 that bis(2-chloroethyl) chlorophosphate and pentaerythritol were to be reacted to form the desired product. Presumably, the bis(2-chloroethyl) chlorophosphate could be formed by reaction of phosphorus oxytrichloride and appropriate monohydroxy compound (i.e., 2-chloroethanol). U.S. Pat. No. 3,254,973, at Col. 5, line 66 and following, illustrates preparation of 4,4'-isopropylidene diphenol bis(di-o-tolylphosphate) by first reacting phosphorus oxychloride with o-cresol to form a reaction mixture in which di-o-tolyl phosphorochloridate cuts are removed by distillation. The di-o-tolyl phosphorochloridate from the first reaction step was then reacted with the diol (i.e., bisphenol A) to make the desired bisphosphate.
Reaction SMILES: [F:1][C:2](=[CH:5][CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:3]=[O:4].[Na].C1(S)C=CC=CC=1.O>CCCCCC>[F:1]/[C:2](=[CH:5]\[CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:11])/[CH:3]=[O:4]
Reactant: CC(C)(C)[Si](C)(C)OCCC=C(F)C=O
Agent: Sc1ccccc1
Agent: [Na]
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCC/C=C(\F)C=O

Procedure:
5.50 Grams of 2-fluoro-5-(tert-butyldimethylsilyloxy)-2-pentenal (E form:Z form=11:1) was dissolved in 50 ml of dry hexane, and after adding 20 mg of the sodium salt of thiophenol, the resulting solution was heated under reflux for 20 hours with stirring. Thereafter, 10 ml of water was added to the reaction solution, and the toluene layer was separated. The aqueous layer was extracted twice with ether, and the ether extracts were combined with the above toluene layer. This mixture was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain 5.50 g of (Z)-2-fluoro-5-(tert-butyldimethylsilyloxy)-2-pentenal.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[CH:10]=[C:4]2[CH:3]=1.[CH:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1>C(OCC)(=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.Cl[Pd]Cl.[Fe+2].O>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[CH:10]=[C:4]2[CH:3]=[C:2]([C:24]3[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=3)[CH:18]=[O:19])[CH:7]=[CH:6][N:5]2[N:8]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Fc1ccccc1-c1cc2cc(Br)ccn2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1cccc(-c2ccn3nc(-c4ccccc4F)cc3c2)c1
Yield: 79 %

Procedure:
The procedure described in stage 2.4 is followed, starting with 0.150 g (0.52 mmol) of 5-bromo-2-(2-fluorophenyl)pyrazolo[1,5-a]pyridine obtained in stage 7.1, 0.092 g (0.61 mmol) of 3-formylphenylboronic acid, 0.502 g (1.54 mmol) of caesium carbonate and 0.042 g (0.050 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in 5 ml of a 9/1 mixture of tetrahydrofuran and water. After chromatography on silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate (8/2), 0.130 g (79%) of the expected product is obtained in the form of a beige powder.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C@@H:6]([F:9])[CH2:7][CH3:8])[CH2:4][OH:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C(=O)([O-])O.[Na+]>C1COCC1.O>[CH2:20]([O:19][C:17](=[O:18])[NH:2][C@@H:3]([C@@H:6]([F:9])[CH2:7][CH3:8])[CH2:4][OH:5])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC[C@H](F)[C@H](N)CO
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@H](F)[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
A solution of (2R,3S)-2-amino-3-fluoropentan-1-ol hydrochloride (2.0 g) in THF (60 mL) was cooled in ice, a solution of potassium carbonate (4.4 g) in water (6 mL) and a solution of benzyl chloroformate (2.4 g) in THF (6 mL) were added thereto, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate=88:12-0:100) to afford benzyl[(2R,3S)-3-fluoro-1-hydroxypentan-2-yl]carbamate (2.5 g).
Reaction SMILES: C([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]=[CH:17][C:18]2C=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]=1C=CC1C=CC=CC=1)=CC1C=CC=CC=1.S([O-])([O-])(=O)=O>>[CH2:12]([OH:15])[CH2:13][CH2:14][CH2:9][CH2:10][CH2:11][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Oc1ccc(C=Cc2ccccc2)c(C=Cc2ccccc2)c1C=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Product: CCCCCCCCCCCCCO

Procedure:
1% mixture of tristyrylphenol (EO) 8 sulfate and tallowamine (EO) 5 (DV-4636);
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[C:13](=[O:33])[C:14]([CH2:19][CH:20]4[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]4)=[C:15]([OH:18])[C:16]([OH:17])=[C:9]3[C:8]2=[O:34])=[CH:4][CH:3]=1.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C(Cl)Cl>[OH:41][C:39]([C:38]([F:43])([F:42])[F:37])=[O:40].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[C:13](=[O:33])[C:14]([CH2:19][CH:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]4)=[C:15]([OH:18])[C:16]([OH:17])=[C:9]3[C:8]2=[O:34])=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2c(O)c(O)c3n(c2=O)CCN(Cc2ccc(F)cc2)C3=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2c(O)c(O)c(CC3CCNCC3)c(=O)n2CCN1Cc1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a cold (0° C.) solution of tert-butyl 4-{[2-(4-fluorobenzyl)-8,9-dihydroxy-1,6-dioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methyl}piperidine-1-carboxylate (1.12 g, 2.23 mmol) in methylene chloride (10 mL), trifluoroacetic acid (3.4 mL, 45 mmol) was added and the mixture was stirred for 2 hours. The mixture was concentrated in vacuo and the residue was purified by prep HPLC (Waters prep LC 4000 System using a Waters Nova Pak column [3*10×40 mm I.D. cartridges, C18, 6 μM pore size) eluting with 95-5% water (0.10% TFA)/acetonitrile (0.10% TFA) gradient at 60 mL/min]. Combined and concentrated the product fractions to give a yellow solid. The solids were triturated with acetonitrile and collected by vacuum filtration.
Reaction SMILES: [NH2:1][C:2]([CH3:8])=[C:3]([C:6]#[N:7])[C:4]#[N:5].[Cl:9][C:10]1[CH:21]=[C:20]([F:22])[C:19]([N:23]=[C:24]=[O:25])=[CH:18][C:11]=1[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13]>>[NH2:5][C:4]1[N:23]([C:19]2[C:20]([F:22])=[CH:21][C:10]([Cl:9])=[C:11]([CH:18]=2)[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:24](=[O:25])[N:1]=[C:2]([CH3:8])[C:3]=1[C:6]#[N:7]
Reactant: CC(N)=C(C#N)C#N
Reactant: CC(C)OC(=O)c1cc(N=C=O)c(F)cc1Cl
Product: Cc1nc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(N)c1C#N

Procedure:
using 3-amino-2-cyanocrotononitrile and isopropyl 2-chloro-4-fluoro-5-isocyanatobenzoate there is obtained isopropyl 5-[6-amino-5-cyano-4-methyl-2-oxo-1(2H)-pyrimidinyl]-2-chloro-4-fluorobenzoate, m.p. 255°-257° C.
Reaction SMILES: [CH:1]1([CH2:6][C:7](Cl)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([F:21])[CH:12]=1.NC1C=CC(C(OC)=O)=CC=1>>[CH:1]1([CH2:6][C:7]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([F:21])[CH:12]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: COC(=O)c1ccc(N)cc1F
Agent: COC(=O)c1ccc(N)cc1
Product: COC(=O)c1ccc(NC(=O)CC2CCCC2)cc1F

Procedure:
The title compound was prepared as described in Example 52A, substituting 2-cyclopentylacetyl chloride for 2-cyclopentylacetyl chloride and methyl 4-amino-2-fluorobenzoate for methyl 4-aminobenzoate.