Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH:4]=[CH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([S:23]([OH:25])=[O:24])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH:4]([S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:26])=[CH:18][CH:19]=1)(=[O:25])=[O:24])[CH2:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: Cc1ccc(S(=O)O)cc1
Reactant: CC(C)(C)C(=O)C=Cc1ccc(Cl)cc1Cl
Product: Cc1ccc(S(=O)(=O)C(CC(=O)C(C)(C)C)c2ccc(Cl)cc2Cl)cc1
Temperature: 0 °C
Yield: 99.5 %

Procedure:
A mixture of 10 g of 2,4-dichlorobenzalpinacolone, 7.3 g of p-toluenesulfinic acid, 4.1 g of NaH2PO3 and 70 ml of 90% aqueous alcohol was heated under reflux for 8 hours. After cooling, 400 ml of ice water was added to the reaction mixture and extracted with 500 ml of ethyl acetate. The organic solvent layer was washed with 400 ml of 5% sodium bicarbonate aqueous solution and 400 ml of ice water and evaporated under reduced pressure to give 16 g of the captioned compound (yield 99%). nD27 1.5563.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:30][CH:29]4[C:31]([O:33]CC)=[O:32])=[C:24]([F:36])[CH:23]=3)[CH:15]=2)=[C:9]([CH3:37])[CH:8]=1)[CH3:2].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[ClH:53].C(OCC)(=O)C>C(O)C.O1CCCC1.C(OCC)(=O)C.O>[ClH:53].[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:37])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:30][CH:29]4[C:31]([OH:33])=[O:32])=[C:24]([F:36])[CH:23]=3)[CH:15]=2)=[C:11]([CH3:13])[CH:12]=1)[CH3:2]
Reactant: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(C4CC4C(=O)OCC)c(F)c3)c2)c(C)c1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(C4CC4C(=O)O)c(F)c3)c2)c(C)c1
Temperature: 50 °C
Reaction time: 7 h
Yield: 73 %

Procedure:
To a mixed solution of ethyl 2-[4-({[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methyl}amino)-2-fluorophenyl]cyclopropanecarboxylate (0.451 g, 0.892 mmol) in ethanol (2 mL) and tetrahydrofuran (4 mL) was added 2 M aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 7 hr. Water was added to the reaction mixture, and the mixture was mildly-acidified with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-100:0) to give a yellow oil. To a solution of the obtained oil in ethyl acetate (3.2 mL) was added 4 M hydrogen chloride/ethyl acetate solution (0.8 mL) and the mixture was concentrated under reduced pressure. The residue was crystallized from diethyl ether-ethyl acetate to give the title compound (0.349 g, yield 73%) as colorless crystals.
Reaction SMILES: N#N.I[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][CH3:14].[S:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.C([O-])(=O)C.[K+]>CN(C=O)C>[CH3:14][O:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[C:19]1[S:15][CH:16]=[N:17][CH:18]=1
Reactant: COc1ccc([N+](=O)[O-])cc1I
Reactant: c1cscn1
Agent: CC(=O)[O-]
Agent: N#N
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1-c1cncs1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
N2 was bubbled through a solution of 2-iodo-4-nitroanisole (2.8 g, 10.0 mmol), thiazole (2.55 g, 30.0 mmol), potassium acetate (1.47 g, 15.0 mmol), and tetrakis(triphenyl phosphine)palladium(0) (0.81 g, 0.70 mmol) in DMF (15 mL) for 10 min. The mixture was then heated to 100° C. and stirred overnight. Solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane:MeOH=96:4) to afford the title compound. 1H-NMR (CDCl3, 400 MHz): δ=4.08 (s, 3H), 7.09 (d, J=9.2 Hz, 1H), 8.25 (dd, J=2.8, 9.2 Hz, 1H), 8.37 (s, 1H), 8.54 (d, J=3.2 Hz, 1H), 8.88 (s, 1H). MS (ES+): m/z 237.13 [MH+]. HPLC: tR=3.07 min (ZQ2000, polar—5 min).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)O)C1C=CC=CC=1.Cl>CO.[OH-].[Pd+2].[OH-]>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: OC(c1cccc(F)c1)c1ccccc1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: Oc1ccccc1Cc1cccc(F)c1
Reaction time: 120 h
Yield: 40.8 %

Procedure:
To a solution of (2-benzyloxyphenyl)-(3-fluorophenyl)methanol (2.54 g, 7.51 mmol) in methanol (30 ml), a 20% palladium hydroxide catalyst (300 mg) was added and furthermore 2N—HCl (0.3 mL) was added thereto. The mixture solution was stirred under a hydrogen atmosphere for five days, and then the catalyst was filtered off. The solvent was distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (620 mg, 42%).
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[CH:10]=1)(C)(C)C.Cl[CH2:22]Cl>FC(F)(F)C(O)=O>[Br:15][C:13]1[CH:12]=[C:11]([C:16]([O:18][CH2:19][CH3:22])=[O:17])[CH:10]=[C:9]([CH:14]=1)[O:8][CH2:7][C:6]([OH:5])=[O:20]
Reactant: ClCCl
Reactant: COC(=O)c1cc(Br)cc(OCC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(Br)cc(OCC(=O)O)c1
Reaction time: 2 h

Procedure:
A solution of 2-(5-bromo-3-methoxycarbonyl-phenoxy)-acetic acid tert-butyl ester (12.8 g) in a mixture of dichloromethane (100 ml) and trifluoroacetic acid (100 ml) was stored at room temperature for 2 h. The solution was concentrated under reduced pressure. The residual solid was suspended in toluene and the solvent removed under reduced pressure to give the title compound as a brown solid (10.6 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([OH:30])[N:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:38])[C@@H:13]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([O:30][CH2:40][C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])[N:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3cccc(F)c3)n2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3cccc(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4.0 g 4-((S)-3-tert-Butoxycarbonyl-2-{[1-(3-fluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid ethyl ester in 20 ml DMF were added 1.242 ml benzyl bromoacetate and 4.884 g cesium carbonate. After stirring at RT for 12 h the solution was reduced to a volume of 50 ml, diluted with 200 ml ethyl acetate and extracted with aqueous LiCl (4% w/w) and aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used in the subsequent reaction.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[Cl:11].C(O)(=O)C.[N:17]([O-])=O.[Na+].O.O.Cl[Sn]Cl>O.Cl>[ClH:11].[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH:10][NH2:17])[CH:7]=[CH:6][C:5]=1[Cl:11]
Reactant: COC(=O)c1cc(N)ccc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(NN)ccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 183.3 %

Procedure:
To 5-amino-2-chloro-benzoic acid methyl ester (14.0 g, 75.0 mmol) in water (100 mL) was added concentrated HCl (100 mL), followed by glacial acetic acid (100 mL). The solution was stirred at ambient temperature for 15 minutes. The reaction was then cooled to 0° C., and a solution of sodium nitrite (5.69, 82.5 mmol) in water (15 mL) was added dropwise over 30 minutes, maintaining the temperature at 0° C. The resulting reaction was stirred for 30 minutes at 0° C., then a solution of SnCl2.2H2O (50.8 g, 225 mmol) in concentrated HCl (100 mL) was added over 30 minutes, maintaining the temperature at 0° C. The slurry was stirred at 0° C. for 30 minutes, and the resulting precipitate collected by filtration, washed with water, followed by hexane. The solid was dried in a vacuum oven at 50° C. to give the title compound (16.3 g).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)=O)=[CH:11][CH:10]=1)([O-])=O.[H][H]>C(O)(=O)C.[Pd]>[CH3:25][C:21]1[CH:20]=[C:19]([CH2:18][CH2:17][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([NH2:6])=[CH:14][CH:13]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: [H][H]
Reactant: Cc1cccc(/C=C/C(=O)c2ccc([N+](=O)[O-])cc2)c1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cccc(CCCc2ccc(N)cc2)c1
Yield: 103.3 %

Procedure:
46 g (0.47 mole) of concentrated sulfuric acid and 8 g of palladium on 80% active carbon are added to a solution of 130 g (0.49 mole) of E-(3-methylstyryl) 4-nitrophenyl ketone in 1.3 l of glacial acetic acid, and the mixture is saturated with nitrogen. Thereafter, hydrogen gas is passed into the stirred mixture under atmospheric pressure. After about 30 l of hydrogen has been absorbed, the mixture is heated to 50°-70° C. and hydrogenated until the theoretical amount of hydrogen (about 66 l) has been consumed. The mixture is filtered under suction over kieselguhr, the filtrate is evaporated to dryness and the residue is stirred with 1 l of ice water, 200 ml of 50% strength sodium hydroxide solution and 800 ml of methyl tert-butyl ether. The aqueous phase is washed with 3 times 250 ml of methyl tert-butyl ether, and the combined organic phases are washed once with 250 ml of water and once with 250 ml of saturated NaCl solution, dried over Na2SO4 and evaporated down under reduced pressure to give 114 g of a brown oil of boiling point 158°-163° C./0.3 mm, which is about 95% pure (corresponding to 98% of theory) according to the gas chromatogram.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C([O-])=[O:12].[Na+]>>[OH:12][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C[O-]
Reactant: O=C(CBr)c1ccccc1
Agent: [Na+]
Product: O=C(CO)c1ccccc1

Procedure:
85% Ethanolic solution (1200 mL) of 2-bromo-1-phenylethanone (99.52 g, 500 mmol) and sodium formate (215.0 g, 3160 mol) was heated to reflux for 5 hours. After the solvent was evaporated in vacuo, water (1000 mL) was added to the residue and extraction with ethyl acetate was conducted. The organic layers were combined and dried over anhydrous sodium sulfate and the solvent was evaporated therefrom in vacuo. Petroleum ether was added to the residual oily product to crystallize whereupon 2-hydroxy-1-phenylethanone (59.67 g, 88%) was produced. Mp. 86-89° C. 1H-NMR (DMSO-d6) δ: 4.81 (d, J=5.8 Hz, 2H), 5.07 (t, J=5.8 Hz, 1H), 7.50-7.55 (m, 2H), 7.63-7.67 (m, 1H), 7.92-7.95 (m, 2H)
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][C:27]1([CH3:33])[O:31][C:30](=[O:32])[NH:29][CH2:28]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[N:7][C:2]([N:29]5[CH2:28][C:27]([CH3:33])([CH3:26])[O:31][C:30]5=[O:32])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: CC1(C)CNC(=O)O1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)nn2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CC(C)(C)OC3=O)nn2)CC1
Yield: 16.1 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (107 mg) described in Preparation Example 233 and 5,5-dimethyloxazolidin-2-one (35 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (21 mg) was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.C[O:11][CH:12]1[CH2:16][CH2:15][CH2:14]O1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[C:3]([CH:14]([C:3]2[C:4]3[C:9](=[N:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:15][CH2:16][CH2:12][OH:11])=[CH:2]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: COC1CCCO1
Product: OCCCC(c1c[nH]c2ncccc12)c1c[nH]c2ncccc12

Procedure:
This compound is prepared in the same way as described in example 1/1 starting from 7-azaindol and 2-methoxy-tetrahydrofuran.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+]([O-])=O)[C:4]=1[C:12]#[N:13])#[N:2].[C:14]([OH:18])([CH3:17])([CH3:16])[CH3:15]>>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]=1[C:12]#[N:13])#[N:2]
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Reactant: CC(C)(C)O
Product: CC(C)(C)Oc1cccc(C#N)c1C#N
Yield: 70 %

Procedure:
As in Synthesis Example 1 but using 1.73 grams of 1,2-dicyano-3-nitrobenzene and 2.20 grams of t-butylalcohol, there was obtained 1.40 grams of 1,2-dicyano-3-t-butoxybenzene (yield of 70%). Next, as in Synthesis Example 1 but using 1.40 grams of this benzene compound and 0.58 gram of BBr3, there was obtained 2.9 grams of the end product (yield 60%, mp 184°-186° C.).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[S:9]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]([S:19](Cl)(=[O:21])=[O:20])=[CH:16][CH:15]=2)=[CH:10]1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:19]([C:17]1[S:18][C:14]([C:11]2[CH:12]=[CH:13][S:9][CH:10]=2)=[CH:15][CH:16]=1)(=[O:20])=[O:21]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccsc2)s1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3ccsc3)s2)c1Br
Yield: 40 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-thienyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-(3-thienyl)thiophene-2-sulfonyl chloride in 40% yield. This was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) give a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:12]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:12]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([NH:25][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCCCC1
Reactant: O=C(O)C(c1cccc(Cl)c1)C1(O)CCCCC1
Product: O=C(NC1CCCCC1)C(c1cccc(Cl)c1)C1(O)CCCCC1

Procedure:
In an analogous manner to Example 1, step 1 2-(3-chlorophenyl-N-cyclohexyl-2-(1-hydroxycyclohexyl)acetamide was prepared from (3-chlorophenyl)(1-hydroxycyclohexyl)acetic acid (Reference Example 1-a) and cyclohexylamine. MS (ESI) m/z 350/352 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH:12]([CH2:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[OH:28][N:29]1C2C=CC=CC=2N=N1.Cl.NO.CN1CCOCC1>CN(C)C=O>[OH:28][NH:29][C:13](=[O:14])[CH:12]([CH2:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C(CS(=O)(=O)c1ccc(Cl)cc1)CS(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(NO)C(CS(=O)(=O)c1ccc(Cl)cc1)CS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 0.33 h

Procedure:
A mixture of 2-(4-chlorobenzenesulfonylmethyl)-3-(4-chlorobenzenesulfonyl)-propionic acid (0.52 g, 1.1 mmol), 1-hydroxybenzotriazole hydrate (0.16 g, 1.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiinde hydrochloride (0.25 g, 1.3 mmol), and hydroxylamine hydrochloride (0.083 g, 1.2 mmol) is stirred in an ice bath for 20 minutes and 4-methylmorpholine (0.28 mL, 2.5 mmol) in dimethylformamide (10 mL) is added. After stirring overnight at ambient temperature, the mixture is partitioned between ethyl acetate and aqueous 10% hydrochloric acid. The organic phase is further extracted with aqueous acid, aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The concentrate is chromatographed over silica gel (230-400 mesh) with chloroform/acetone/acetic acid (79/20/1) and the eluate concentrated in vacuo, to yield the title compound as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]2[NH:29][N:30]=[C:31]([C:32](O)=[O:33])[C:25]=2[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[Cl:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:10]1[CH2:15][CH2:14][N:13]([C:32]([C:31]2[C:25]3[CH2:24][N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:28][CH2:27][C:26]=3[NH:29][N:30]=2)=[O:33])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)O)c2C1
Reactant: Fc1cccc(C2CCNCC2)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)N3CCC(c4cccc(F)c4Cl)CC3)c2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.4 %

Procedure:
To a solution of 4-(2-chloro-3-fluorophenyl)piperidine hydrochloride (14, 90 mg, 0.36 mmol), 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (96 mg, 0.36 mmol), and diisopropylethylamine (0.19 mL, 1.08 mmol) in DMF (7.8 mL) was added EDCI (83 mg, 0.43 mmol) and HOBt (58 mg, 0.43 mmol). The resulting solution was stirred at ambient temperature for 24 h. The reaction mixture was diluted with H2O (30 mL), and the resulting precipitate was collected by filtration. The obtained solids were chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 5% CH3OH in CH2Cl2 with 0.1% NH4OH in CH2Cl2) to provide tert-butyl 3-(4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl)-6,7-dihydro-1Hpyrazolo[4,3-c]pyridine-5(4H)-carboxylate (41) as a white foam (139 mg, 82%): 1H NMR (500 MHz, DMSO-d6) δ 13.11-12.91 (m, 1H), 7.39-7.32 (m, 1H), 7.30-7.22 (m, 2H), 5.28-5.13 (m, 1H), 4.75-4.60 (m, 1H), 4.49-4.36 (m, 2H), 3.65-3.53 (m, 2H), 3.33-3.25 (m, 1H, overlaps with H2O), 3.24-3.08 (m, 1H), 2.91-276 (m, 1H), 2.67 (t, J=5.5 Hz, 2H), 1.91-1.75 (m, 2H), 1.67-1.50 (m, 2H), 1.41 (s, 9H); ESI MS m/z 463 [M+H]+.
Reaction SMILES: [Mg].II.Br[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[F:13].[CH2:14]([N:21]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>C(OCC)C>[CH2:14]([N:21]1[CH2:25][CH2:24][C:23]([CH2:5][C:6]2[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=2[F:13])([OH:26])[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: Fc1ccc(Cl)cc1CBr
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: OC1(Cc2cc(Cl)ccc2F)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring suspension of magnesium strip (1.39 g, 57.06 mmol) in diethyl ether (10 mL) was added a crystal iodine followed by 0.5 mL of 2-(bromomethyl)-4-chloro-1-fluorobenzene under nitrogen. The reaction was initiated with a high intensity heat gun, then a solution of 2-(bromomethyl)-4-chloro-1-fluorobenzene (12.75 g, 57.06 mmol) in diethyl ether was added at such a speed that gentle reflux was maintained. After addition was complete the reaction mixture was kept on stirring at reflux for 3.5 h, cooled to room temperature and a solution of 1-benzylpyrrolidin-3-one (10.0 g, 57.06 mmol) in diethyl ether (20 mL) was added dropwise with vigorous stirring. After addition was complete the reaction mixture was left overnight at room temperature. This reaction mixture was treated with aqueous ammonium chloride (NH4Cl) solution and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulphate (Na2SO4), filtered, concentrated and the residue was purified by silica gel flash chromatography (0-2% methanol in dichloromethane, 0.2% ammonium hydroxide, NH4OH) to give the subtitled compound (650 mg).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[N:12]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1>C(N)CC>[CH2:14]([NH:13][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[N:12]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Nc1cccc(Br)n1)c1cc(-c2ccc(F)cc2)n(C2CCCCO2)n1
Solvent: CCCN
Product: O=C(Nc1cccc(NCc2ccccc2)n1)c1cc(-c2ccc(F)cc2)n(C2CCCCO2)n1
Yield: 124.4 %

Procedure:
A solution of 6-bromo-N-(5-bromopyridin-2-yl)nicotinamide 3 (1.1 g, 3.0 mmol) in n-propylamine (neat, 5 ml) was heated at 80° C. for 2 days. Then the solvent was evaporated to give 6-(propylamino)-N-(5-(propylamino)pyridin-2-yl)nicotinamide 4 as a white solid (880 mg, 91%). Mp. 134-135° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:9][C:10]([C:12]2[C:13]([OH:42])=[C:14]3[C:19](=[C:20]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[N:21]=2)[N:18]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:17](=[O:35])[C:16]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:15]3)=[O:11])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].CO.C1COCC1>C([O-])(O)=O.[Na+]>[CH2:28]([N:18]1[C:19]2[C:14](=[C:13]([OH:42])[C:12]([C:10]([NH:9][C:6]3([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]3)=[O:11])=[N:21][C:20]=2[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:15]=[C:16]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:17]1=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)C1(NC(=O)c2nc(-c3cccnc3)c3c(cc(-c4ccccc4)c(=O)n3Cc3ccccc3)c2O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NC1(C(=O)O)CC1)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.8 %

Procedure:
A mixture of 1-[(1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carbonyl)-amino]-cyclopropanecarboxylic acid ethyl ester (24 mg, 0.043 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 16 h, then concentrated to approximately one-third of its original volume. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (10-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 13 mg of the title compound as a light yellow solid. MS: (+) m/z 533.37 (M+1).