Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[CH2:23]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[CH2:23][O:10][C:7]1[CH:8]=[CH:9][C:4]([I:3])=[CH:5][CH:6]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Oc1ccc(I)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
To a 250 mL flask which contained a suspension of NaH (60% in mineral oil, 500 mg, 12 mmol) in DMF (50 mL) was added 4-iodo-phenol (2200 mg, 10 mmol), at 0° C. The mixture was allowed to warm to rt and stir at rt for 30 min then cooled to 0° C. To this reaction mixture was added (R)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3600 mg, 10 mmol) at 0° C. The resulting mixture was allowed warm to rt and stir at rt for 30 min and then was heated to 95° C. and stirred at 95° C. for 16 h. After cooling to rt, the mixture was poured onto 2000 mL ice-water solution and this solution was allowed to stir at 0° C. for 30 min. The solid which formed was filtered out, dried through air to afford the title product (2480 mg, 60%); 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.81-2.07 (m, 4H), 3.27-3.48 (m, 2H), 3.70-3.95 (m, 1H), 4.00-4.19 (m, 2H), 6.66-6.69. (m, 2H), 7.53 (d, J=8.4 Hz, 2H):
Reaction SMILES: [OH-].[Na+].C([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH2:22][CH:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:14][CH:15]([CH2:20][CH3:21])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9][CH:8]=1)(=O)C.C(O)C>O>[CH2:20]([CH:15]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14][N:13]([CH2:22][CH:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27])[C:10]1[CH:9]=[CH:8][C:7]([NH2:6])=[CH:12][CH:11]=1)[CH3:21]
Reactant: CCCCC(CC)CN(CC(CC)CCCC)c1ccc(NC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCC(CC)CN(CC(CC)CCCC)c1ccc(N)cc1
Yield: 53.4 %

Procedure:
A mixed solution comprising 8 ml of 30% sodium hydroxide solution, 1.012 g of N-acetyl-N',N'-di(2-ethylhexyl)-p-phenylenediamine and 10 ml of ethanol was allowed to react at 75° C. for a period of 5 hr. After the completion of the reaction, the reacted solution was introduced into water and the product was extracted by ethyl acetate. After ethyl acetate was distilled away, the residue was purified by silica gel column chromatography to obtain 501 mg of oil of N,N-di(2-ethylhexyl)-p-phenylenediamine (yield 53.4%).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([N:10]=[C:11]([S-])[S-:12])(=[O:9])=[O:8].[K+].[K+].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[C:14]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[S:7]([N:10]=[C:11]=[S:12])(=[O:9])=[O:8])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=S(=O)(N=C([S-])[S-])c1ccccc1-c1ccccc1
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=S(=O)(N=C=S)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
77 g of potassium N-(2-biphenylylsulfonyl)carbonimidodithioate were suspended in 100 ml of toluene, and 37 ml of thionyl chloride were added dropwise at 0° to 10° C. over the course of 1 hour. After the addition, the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and distilled under reduces pressure to give 30 g of 2-phenylbenzenesulfonyl isothiocyanate represented by the following formula: ##STR27##
Reaction SMILES: C(OC[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1)C.CC(C)=O.Cl>O>[F:17][C:12]([F:18])([C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=1)[C:13]([F:14])([F:16])[F:15]
Reactant: CCOCOc1ccc(C(F)(F)C(F)(F)F)cc1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: Oc1ccc(C(F)(F)C(F)(F)F)cc1
Temperature: 50 °C

Procedure:
7.39 g of 1-ethoxymethoxy-4-pentafluoroethyl benzene, 30 ml of acetone and 30 ml of 6 M hydrochloric acid were stirred while heating at 50° C. for 2.5 hours. The reaction mixture was cooled to room temperature, and then poured into water, followed by extraction with ethyl acetate. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 4-(pentafluoroethyl)phenol.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:25](I)[CH3:26]>CN(C)C=O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([C@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:13][CH2:14]2)[CH2:25][CH3:26])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CC[C@H](c2ccccc2)CC1)c1ccc(Cl)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccccc2)CC1

Procedure:
1 g of trans-N-(4-chlorobenzoyl)-4-phenylcyclohexylamine in 20 ml of dimethylformamide are mixed with 0.14 g of 55% sodium hydride and after 15 minutes 0.62 g of ethyliodide are added. After 1 hour at ambient temperature the reaction solution is evaporated down, the residue is taken up in water, extracted with ethyl acetate and the organic phase is dried and evaporated down. After purification by column chromatography (silica gel, petroleum ether/ethyl acetate=4:1 to 3:1, v:v), 0.73 g of the title compound are obtained, melting point 127°-129° C.
Reaction SMILES: [CH:1]1([O:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11]1(C)C=CC(S(O)(=O)=O)=CC=1.CO>O>[CH:1]1([O:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)COC1CCCC1
Solvent: CO
Solvent: O
Product: COC(=O)COC1CCCC1
Temperature: 25 °C
Yield: 4424.1 %

Procedure:
In a three necks 500 ml flask were introduced, in the following order, 65 g (451 mmol) of (cyclopentyloxy)acetic acid (obtained according to U.S. Pat. No. 4,735,932), 1.4 g of para-toluenesulfonic acid and 280 ml of MeOH. After 6 hours at reflux, the reaction mixture was cooled at room temperature diluted into 300 ml of water and extracted with 300 ml of ether. The organic phase thus obtained was washed twice with water, dried over MgSO4 and concentrated. It was thus obtained 56.9 g of product (yield=80%) having a GC purity of 99%.
Reaction SMILES: [NH2:1][C:2]1[C:17]([F:18])=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[C:4]([F:19])[CH:3]=1.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C:27](O)=[O:28])[C:23](=[O:30])[N:22]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.CCOC(C)=O>[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C:27]([NH:1][C:2]2[C:17]([F:18])=[CH:16][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=3)=[C:4]([F:19])[CH:3]=2)=[O:28])[C:23](=[O:30])[N:22]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: NC(=O)c1cc(Oc2cc(F)c(N)cc2F)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(C(N)=O)c3)cc2F)c(=O)n(-c2ccccc2)n1C
Temperature: 45 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
To a solution of 4-(4-amino-2,5-difluorophenoxy)picolinamide (200 mg, 0.76 mmol), and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (165 mg, 0.75 mmol) in DCM (10 mL) was added EDCI (175 mg, 0.93 mmol), and HOAT (26 mg, 0.15 mmol). The reaction was stirred at 45° C. for 16 hours, cooled to rt and diluted with EtOAc (20 mL). The solid was collected through filtration, dried at 45° C. in vacuo overnight to give the title compound as a white solid (230 mg, 63.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:3]=1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)cc1N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a mixture of 4-chloro-2-fluoronitrobenzene (175 mg, 1.00 mmol) and K2CO3 (139 mg, 1.00 mmol) in toluene (2 mL), morpholine (87 μL, 1.0 mmol) was added at 0° C. The resulting mixture was allowed to warm to RT and stirred overnight. The reaction mixture was concentrated and the product was isolated by flash chromatography on silica (20% EtOAc/hexane) to obtain 4-(5-Chloro-2-nitro-phenyl)-morpholine (205 mg, 67%). This compound (243 mg, 1.00 mmol) was dissolved in 1-methylpiperazine (1 mL) and the resulting mixture was heated at 130° C. overnight. The reaction mixture was diluted with water and the product was extracted with DCM (3×10 mL). The DCM layers were combined, dried (Na2SO4) and concentrated to obtain the title compound (177 mg, 58%). 1H-NMR (CDCl3; 400 MHz): δ 8.04 (d, 1H, J=9.4 Hz), 6.46 (dd, 1H, J=9.4, 2.6 Hz), 6.31 (d, 1H, =2.6 Hz), 3.89 (m, 4H), 3.40 (m, 4H), 3.07 (m, 4H), 2.50 (m, 4H), 2.36 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH3:10])[CH2:7][S:8][C@H:3]12.C1(N=C=NC2CCCCC2)CCCCC1.[S:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[S:46]([CH2:48][C:49](O)=[O:50])=[O:47]>C1C=CC=CC=1>[S:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[S:46]([CH2:48][C:49]([NH:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:13][N:14]=[N:15][N:16]=3)[CH3:10])[CH2:7][S:8][C@H:3]12)=[O:50])=[O:47]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(O)CS(=O)c1cccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccccc1
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)CS(=O)c3cccs3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
154 mg of t-butyl 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate and 83 mg of dicyclohexylcarbodiimide were dissolved in 5 ml of benzene, and 76 mg of 2-thienylsulfinylacetic acid ([α]D22° : +11.0°, C=1.00, ethanol) was added to the solution. This liquid reaction mixture was agitated at 25° C. for 2 hours. The mixture was filtered, made adsorbed on 2 g of silica gel and subjected to chromatography using benzene-ethyl acetate (50:50) on 20 g of silica gel to obtain 145 mg of t-butyl 7-(2-thienylsulfinylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate. The so obtained ester was dissolved in 1 ml of trifluoroacetic acid, and the solution was agitated at 25° C. for 5 minutes. Then, the solution was added dropwise to 70 ml of ether. The resulting precipitate was collected and dissolved in 5% aqueous sodium bicarbonate solution to form 100 ml of a solution. Then, the solution was extracted with ethyl acetate, and the pH of the aqueous layer was adjusted to 2.0 and the aqueous layer was further extracted with ethyl acetate. The organic layer was dried and concentrated until the volume was reduced to 5 ml. The resulting residue was mixed with a 30% solution of sodium 2-ethylhexanoate in propanol, and ether was added to the mixture. The precipitated salt was collected, recrystallized from methanol-ether and dried under reduced pressure to obtain 51 mg of sodium 7-(2-thienylsulfinylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate of the R form optically active in the sulfoxide. The NMR spectrum was found to be in agreement with that of the intended product. The bacterium-inhibiting activity of the so obtained compound was much superior to that of the product derived in the same manner by using 2-thienylsulfinylacetic acid having [α]D22° of -9.2° as the starting compound.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][C:12](=[O:17])[N:13]([CH3:16])[C:14](=[O:15])[C:9]2=[N:8][C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]3C=CC=CC=3)[CH:19]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4].[CH3:31][O:32]C1C=C(C=CC=1OC)C=O>>[CH2:1]([N:5]1[C:10]2=[N:11][C:12](=[O:17])[N:13]([CH3:16])[C:14](=[O:15])[C:9]2=[N:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:32][CH3:31])=[C:20]([O:24][CH3:25])[CH:19]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc(-c2cccc(Oc3ccccc3)c2)nc2c(=O)n(C)c(=O)nc1-2
Reactant: COc1ccc(C=O)cc1OC
Product: CCCCn1nc(-c2ccc(OC)c(OC)c2)nc2c(=O)n(C)c(=O)nc1-2

Procedure:
Compound 21 is prepared, as described in 4, by reacting the hydrazine 20 (176 mg, 0.54 mmol) with 3,4-dimethoxybenzaldehyde (88 mg, 0.54 mmol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[C:8]1(=O)[CH2:11][CH2:10][CH2:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)CCl>[CH:8]1([N:1]2[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]2)[CH2:11][CH2:10][CH2:9]1
Reactant: OC1CCNCC1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: OC1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.3 %

Procedure:
A solution of 4-piperidinol (80 g, 0.792 moles) and cyclobutanone (67.2 g, 0.96 moles) in ethylene dichloride (1 L) was treated with sodium triacetoxyborohydride (251.1 g, 1.184 moles) portion wise and the mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched in chilled water (1 L) and the resulting mass was basified with lye solution. The layers were separated, and the aqueous layer was extracted with dichloromethane (2×500 mL). The combined organic layers were washed with water, dried over sodium sulfate and concentrated to afford the title compound 100 g (Yield: 81.46%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1>C(O)(=O)C.[OH-].[Na+].[Pt]=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:16])[CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]2)=[CH:4][CH:3]=1
Reactant: OC(Cc1ccccn1)c1ccc(Br)cc1
Agent: O=[Pt]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: OC(CC1CCCCN1)c1ccc(Br)cc1
Reaction time: 3 h

Procedure:
1 mmol of the compound obtained in Example 58 is dissolved in 20 ml of acetic acid, and 8 mg of platinum oxide are added. The hydrogenation is carried out starting from an initial pressure of 3 atmospheres at 24° C. After reacting for 3 hours, the catalyst is filtered off and washed with dichloromethane. The solvents are evaporated off and the residue obtained is dissolved in 10% sodium hydroxide solution and extracted with dichloromethane. The organic phase is washed with water, dried over MgSO4 and then evaporated off to yield the title compound in the form of a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([N:16]([CH2:34][CH2:35][CH2:36][O:37][Si](C(C)(C)C)(C)C)[S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1([N:16]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:34][CH2:35][CH2:36][OH:37])[CH2:12][CH2:13][CH2:14][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCN(C1(C(=O)OCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C1(N(CCCO)S(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCCC1
Reaction time: 1 h
Yield: 102.5 %

Procedure:
To a solution of the crude 1{[3-(tert-butyl-dimethylsilanyloxy)-propyl]-[4-(4-fluorophenoxy)benzenesulfonyl]-amino}cyclopentanecarboxylic acid benzyl ester (279 grams) in methylene chloride (1 L) at room temperature was added boron trifluoride etherate (103 mL, 0.84 mole). After 1 hour, the reaction was quenched by sequential addition of saturated ammonium chloride solution and water. The organic phase was separated, washed with water and brine and dried over magnesium sulfate. Evaporation of the solvent under vacuum provided crude 1-[[4-(4-fluorophenoxy)benzenesulfonyl]-(3-hydroxypropyl)amino]cyclopentanecarboxylic acid benzyl ester as an amber oil (235 grams).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH3:11].[Br:12]Br>>[Br:12][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH2:10][CH3:11])=[C:2]([Cl:1])[C:7]=1[F:8]
Reactant: BrBr
Reactant: CCOc1cccc(F)c1Cl
Product: CCOc1ccc(Br)c(F)c1Cl
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
606 g of the compound (b43) was added to a reactor in a nitrogen atmosphere, to which 570 g of bromine was added dropwise over 1 hour in a temperature range of 20 to 40° C., followed by stirring for 30 minutes. The resulting reaction mixture was washed with a saturated sodium thiosulfate aqueous solution, a 10% sodium hydroxide aqueous solution, and water. The resulting reaction mixture having been washed was subjected to fractional distillation under reduced pressure to obtain 760 g of 1-bromo-3-chloro-4-ethoxy-2-fluorobenzene (C2). The resulting compound (C2) was white solid and had a melting point of 65.4 to 66.1° C. and a boiling point of 125 to 127° C./8 mmHg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:17]1[NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Reactant: Clc1nc2ccccc2[nH]1
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1nc2ccccc2[nH]1
Temperature: 100 °C
Yield: 30.8 %

Procedure:
(RS)-2-Aminomethyl-piperidine-1-carboxylic acid tert butyl ester (0.25 g) and 2-chlorobenzimidazole (0.15 g) were combined and warmed to 100° C. for 48 hours. After cooling to room temperature the mixture was column chromatographed (silica gel, ethyl acetate/pentane 1:4-ethyl acetate/pentane 1:1 eluant) to give the title compound (0.1 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[C:18]3[CH2:17][N:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[C:15](=[O:28])[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:37](=[O:45])[C:38]([C:42](O)=[O:43])=[CH:39][NH:40][CH:41]=2)=[CH:32][CH:31]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:16]2[CH2:17][C:18]3[C:9]([O:8][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:42]([C:38]5[C:37](=[O:45])[C:36]([C:33]6[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=6)=[CH:41][NH:40][CH:39]=5)=[O:43])=[N:7][CH:6]=4)=[CH:10][CH:11]=[N:12][C:13]=3[NH:14][C:15]2=[O:28])=[CH:21][CH:22]=1
Reactant: COc1ccc(CN2Cc3c(Oc4ccc(N)nc4)ccnc3NC2=O)cc1
Reactant: O=C(O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CN2Cc3c(Oc4ccc(NC(=O)c5c[nH]cc(-c6ccc(F)cc6)c5=O)nc4)ccnc3NC2=O)cc1
Yield: 31.8 %

Procedure:
A solution of 5-[(6-aminopyridin-3-yl)oxy]-3-(4-methoxybenzyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one (100.00 mg; 0.26 mmol; 1.00 eq.), 5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (67.97 mg; 0.29 mmol; 1.10 eq.), pybop (179.26 mg; 0.34 mmol; 1.30 eq.), DMF (4.00 ml), and N,N-diisopropylethylamine (131.72 μl; 0.79 mmol; 3.00 eq.) was stirred at room temperature for 4 days. The reaction was concentrated, redissolved in DMSO, and purified via prep HPLC to afford 49 mg (26%) of 284 as a tan solid. LC-MS (M+H=593, obsd.=593).
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:18][NH:19]C(=O)OC(C)(C)C)[CH2:8][CH2:7][N:6]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:5][CH2:4]1.C(OC([NH:34][C:35]1[S:39][C:38]([C:40]2[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:41]=2[F:47])=[N:37][C:36]=1[C:48](O)=[O:49])=O)(C)(C)C>>[NH2:34][C:35]1[S:39][C:38]([C:40]2[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:41]=2[F:47])=[N:37][C:36]=1[C:48]([NH:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[N:6]1[CH2:5][CH2:4][C:3]([CH2:18][NH2:19])([O:2][CH3:1])[CH2:8][CH2:7]1)=[O:49]
Reactant: COC1(CNC(=O)OC(C)(C)C)CCN(c2c([N+](=O)[O-])cnn2C)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Product: COC1(CN)CCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnn2C)CC1
Yield: 7 %

Procedure:
Following the procedure for Example 101 starting from tert-butyl (4-methoxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid gave 458 as an off-white solid (30 mg, 7% over three steps). 1H NMR (400 MHz, d4-MeOD) δ 8.56 (s, 1H), 7.56-7.42 (m, 2H), 7.15 (t, J=8.7 Hz, 2H), 3.74 (s, 3H), 3.42-3.33 (m, 4H), 3.23 (s, 2H), 3.12-2.95 (m, 3H), 1.97 (d, J=13.6 Hz, 2H), 1.76-1.66 (m, 2H). LCMS (ES+) m/z 478 (M+1)
Reaction SMILES: [F:1][C:2]([F:25])([O:7][C:8]([F:24])([F:23])[C:9]([F:22])([F:21])[O:10][C:11]([F:20])([F:19])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[C:3]([F:6])([F:5])[F:4].[CH2:26]([O:32][C:33]1[CH:34]=[N:35][C:36]([C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)=[N:37][CH:38]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O>[CH2:26]([O:32][C:33]1[CH:38]=[N:37][C:36]([C:39]2[CH:40]=[CH:41][C:42]([O:45][CH2:17][CH2:16][CH2:15][CH2:14][O:13][CH2:12][C:11]([O:10][C:9]([F:22])([F:21])[C:8]([F:24])([F:23])[O:7][C:2]([F:25])([F:1])[C:3]([F:6])([F:5])[F:4])([F:20])[F:19])=[CH:43][CH:44]=2)=[N:35][CH:34]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: FC(F)(COCCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F
Reactant: CCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Solvent: O
Product: CCCCCCOc1cnc(-c2ccc(OCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 4-(2-(2-(pentafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromobutane (14.9 g, 32.0 mmol, Example 19) with 5-hexyloxy-2-(4-hydroxyphenyl)pyrimidine (8.0 g, 29.4 mmol). The resulting product was isolated by addition of water (160 mL), followed by filtration and recrystallization from ethanol. The recrystallized precipitate was dried at about 130° C., and the resulting product was further purified by distillation using a Kugelrohr apparatus (b.p. 190-205° C. at 0.3 torr; yield of 15.2 g).
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([F:19])=[CH:5][C:6]2[N:15]=[C:14]([NH2:16])[C:13]3[CH:12]=[C:11]([CH3:17])[S:10][C:9]=3[NH:8][C:7]=2[CH:18]=1.[CH3:20][O:21][CH2:22][CH2:23][CH:24]1[CH2:29]N[CH2:27][CH2:26][NH:25]1.CS(C)=O>C1(C)C=CC=CC=1>[F:2][C:3]1[C:4]([F:19])=[CH:5][C:6]2[N:15]=[C:14]([N:16]3[CH2:27][CH2:26][NH:25][C@@H:24]([CH2:23][CH2:22][O:21][CH3:20])[CH2:29]3)[C:13]3[CH:12]=[C:11]([CH3:17])[S:10][C:9]=3[NH:8][C:7]=2[CH:18]=1
Reactant: Cc1cc2c(s1)Nc1cc(F)c(F)cc1N=C2N
Reactant: COCCC1CNCCN1
Agent: Cl
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: COCC[C@H]1CN(C2=Nc3cc(F)c(F)cc3Nc3sc(C)cc32)CCN1
Temperature: 115 °C
Yield: 66.4 %

Procedure:
Add 6,7-difluoro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (65.0 g, 215 mmol) and 2-(2-methoxy-ethyl)-piperazine (96.3 g, 668 mmol) to a solution of DMSO (650 mL) and toluene (1300 mL) with stirring under nitrogen. Heat at gentle reflux (115° C.) for 2 days, and then allow cooling to ambient temperature. Remove most of the organic portion under reduced pressure, and then partition the residue between ethyl acetate (450 mL) and aqueous saturated ammonium chloride solution (450 mL). Separate the layers, and then extract the aqueous layer with ethyl acetate (3×200 mL). Extract the combined organic layers with brine (3×200 mL). Concentrate the organic layer under reduced pressure. Purify the crude product by flash chromatography, eluting with 90:10/methylene chloride:MeOH to give 56 g (66%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 6.74 (m, 2H), 6.36 (s, 1H), 3.86 (bm, 2H), 3.39 (m, 2H), 3.23 (s, 3H), 2.88 (bd, 1H), 2.72 (bm, 3H), 2.44 (bt, 1H), 2.31 (s, 3H), 2.31 (bm, 1H), 1.53 (m, 2H). HRMS (ES) exact mass M+H calcd for C19H22F2N4OS 393.1561; found 393.1554.