Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[CH3:37][O:38][C:39]1[CH:44]=[C:43]([NH2:45])[CH:42]=[CH:41][N:40]=1>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:45][C:43]1[CH:42]=[CH:41][N:40]=[C:39]([O:38][CH3:37])[CH:44]=1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: COc1cc(N)ccn1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)ccn1
Temperature: 50 °C

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (38.9 mg, 0.141 mmol) in dry dichloromethane (2 mL) was added triethylamine (0.049 mL, 0.352 mmol), 2-chloro-1-methylpyridinium iodide (53.3 mg, 0.209 mmol), and 2-methoxy-4-aminopyridine (20.2 mg, 0.163 mmol) sequentially at room temperature under nitrogen. The reaction was then heated to 50° C. for 1.5 hours. LC/MS showed reaction complete. The reaction mixture was concentrated and purified by HPLC on a 30×100 mm Waters Sunfire column to afford the title compound as an orange solid after lyophilization.
Reaction SMILES: [N:1]1[N:5]2[CH2:6][CH2:7][CH2:8][NH:9][C:4]2=[C:3]([CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])[CH:2]=1.Cl>[OH-].[Na+]>[N:1]1[N:5]2[CH2:6][CH2:7][CH2:8][NH:9][C:4]2=[C:3]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:2]=1
Reactant: CCOC(=O)CCc1cnn2c1NCCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCc1cnn2c1NCCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of ethyl 3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)propionate (20 g) and 1 mol/l aqueous sodium hydroxide solution (100 ml) was stirred at room temperature for 16 hours. The reaction mixture was neutralized with concentrated hydrochloric acid, and the mixture was concentrated in vacuo. The residue was dissolved in methanol, and the insoluble sodium chloride was removed by filtration. The filtrate was concentrated in vacuo to give crude 3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)propionic acid as an oil. This product was used in the next step without further purification.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.C[O:14][C:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][NH:23][C:22]=2[N:21]=1>C1COCC1>[CH3:4][O:3][P:2]([CH2:1][C:15](=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][NH:23][C:22]=2[N:21]=1)(=[O:7])[O:5][CH3:6]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)CCCCc1ccc2c(n1)NCCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)CCCCc1ccc2c(n1)NCCC2)OC
Reaction time: 0.75 h

Procedure:
A solution of dimethyl methylphosphonate (13.20 g, 106.5 mmol) in anhydrous THF (165 mL) was cooled to −78° and treated dropwise with 2.5 M n-BuLi (42.3 mL). After stirring at −78° for 45 min, a solution of ester 1-5 (6.6 g, 26.6 mmol) in THF (35 mL) was added dropwise and the resulting solution stirred for 30 min at −78°, quenched with sat. NH4Cl (100 mL), then extracted with ethyl acetate (3×150 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated to afford a yellow oil. Chromatography on silica gel (5% MeOH/CH2Cl2) afforded 1-6 as a yellow oil.
Reaction SMILES: [OH-].[Na+].[NH2:3][C@@H:4]([C:9]([OH:11])=[O:10])[C:5]([SH:8])([CH3:7])[CH3:6].Br[CH2:13][CH2:14][CH2:15][OH:16].Cl>C(O)C>[NH2:3][C@H:4]([C:5]([S:8][CH2:13][CH2:14][CH2:15][OH:16])([CH3:7])[CH3:6])[C:9]([OH:11])=[O:10]
Reactant: OCCCBr
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(SCCCO)[C@@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 2N sodium hydroxide (11.3 mL, 22.7 mmol) was added to D-(−)-penicillamine (2.5 g, 16.8 mmol) at 0° C. Once all the solid was dissolved, a solution of 3-bromopropanol (3.03 g, 21.8 mmol) in ethanol (17 mL) was slowly added at 0° C. and the resulting mixture was stirred for 15 h at room temperature. The mixture was treated with 1N hydrochloric acid until pH is ˜6 and the solvents were removed to obtain (2S)-2-amino-3-[(3-hydroxypropyl)sulfanyl]-3-methylbutanoic acid as a white solid. This solid was used for the next step without further purification; Electrospray Mass Spec 208.1 (M+H)+
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[F:22][C:23]([F:27])([F:26])[CH2:24][NH2:25].C(OCC)(=O)C>O>[N+:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:21])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:7](=[O:15])[NH:8]2)=[CH:3][C:2]=1[NH:25][CH2:24][C:23]([F:27])([F:26])[F:22])([O-:14])=[O:13]
Reactant: NCC(F)(F)F
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NCC(F)(F)F)cc2c1=O
Temperature: 140 °C
Yield: 25.3 %

Procedure:
A mixture of 200 mg (0.628 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide and 1.08 ml (13.68 mmol) of 2,2,2-trifluoro-ethylamine in a closed vial is heated in a microwave reactor at 140° C. for 20 hours. After cooling, the reaction mixture is distributed between ethyl acetate and water, the organic phase dried and concentrated to yield a precipitate which is filtered off and submitted to purification by medium pressure chromatography on a RP-C18 column (20 μM material) with tetrahydrofuran/water 4:3 as eluent, containing 0.1% TFA. During concentration of the fractions the product precipitates and is collected by filtration, giving 63 mg of a red powder, m.p. 250° C. (decomp.).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15]I)=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH:17]([C:19]1[NH:20][CH:21]=[CH:22][N:23]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][N:20]2[CH:21]=[CH:22][N:23]=[C:19]2[CH:17]=[O:18])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ncc[nH]1
Reactant: CC(C)(C)Oc1ccc(CCCCI)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)Oc1ccc(CCCCn2ccnc2C=O)cc1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A suspension of 1-tert-butoxy-4-(4-iodobutyl)benzene (10.0 g), 2-formyl-1H-imidazole (3.47 g) and potassium carbonate (4.16 g) in DMF (100 ml) was stirred at 70° C. for 17 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was successively washed with water (3 times) and saturated brine, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crude 1-[4-(4-tert-butoxyphenyl)butyl]-1H-imidazole-2-carbaldehyde as a pale brown oil. Sodium borohydride (1.25 g) was added to a solution of the compound in methanol (200 ml) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was combined with water, concentrated and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Chromatorex, 100-200 mesh, Fuji silicia chemical) (eluent; hexane:ethyl acetate=1:3 to ethyl acetate) to give the titled compound (8.29 g) as a colorless amorphous form.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH:8]1[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C:29](Cl)=[O:30])[CH:25]=1>C(Cl)Cl>[C:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH:8]1[CH2:9][N:10]([C:29]([C:26]2[CH:25]=[C:24]([CH3:23])[O:28][N:27]=2)=[O:30])[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: CC(C)(C)c1ccccc1OC1CNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2CC(Oc3ccccc3C(C)(C)C)C2)no1
Yield: 83.5 %

Procedure:
To a stirred solution of 3-(2-tert-butylphenoxy)azetidine (0.18 g, 0.80 mmol) and triethylamine (0.24 g, 2.4 mmol) in methylene chloride (4.0 mL) was added 5-methylisoxazole-3-carbonyl chloride (0.12 g, 0.80 mmol) at room temperature. After 2 h the reaction mixture was directly purified by flash column chromatography (silica gel, 80:20 heptane/ethyl acetate) to provide (3-(2-tert-butylphenoxy)azetidin-1-yl)(5-methylisoxazol-3-yl)methanone (0.21 g, 83%) as a white solid.
Reaction SMILES: COC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1[CH2:18][S:19](N)(=[O:21])=[O:20].[F:23][C:24]1[CH:25]=[C:26]([CH:64]=[CH:65][CH:66]=1)[CH2:27][N:28]1[CH:32]=[C:31]([C:33]2[C:41]3[C:36](=[N:37][CH:38]=[C:39]([C:42]4[CH:47]=[CH:46][C:45]([N:48]5[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]5)=[CH:44][CH:43]=4)[CH:40]=3)[N:35]([S:54]([C:57]3[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=3)(=[O:56])=[O:55])[CH:34]=2)[CH:30]=[N:29]1.CS(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[F:23][C:24]1[CH:25]=[C:26]([CH:64]=[CH:65][CH:66]=1)[CH2:27][N:28]1[CH:32]=[C:31]([C:33]2[C:41]3[C:36](=[N:37][CH:38]=[C:39]([C:42]4[CH:47]=[CH:46][C:45]([N:48]5[CH2:49][CH2:50][N:51]([S:19]([CH3:18])(=[O:21])=[O:20])[CH2:52][CH2:53]5)=[CH:44][CH:43]=4)[CH:40]=3)[N:35]([S:54]([C:57]3[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=3)(=[O:55])=[O:56])[CH:34]=2)[CH:30]=[N:29]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1CS(N)(=O)=O
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(S(C)(=O)=O)CC5)cc4)cnc32)cc1
Yield: 71.42 %

Procedure:
Using similar reaction conditions as described in step i of intermediate 17, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (product of step 1 of example 124) (75 mg, 0.123 mmol) was mesylated with methane sulfonyl chloride (17 mg, 0.148 mol) using triethylamine (35 μL, 0.247 mmol) in DCM (5 mL) to afford 60 mg (71.42% yield) of the titled compound. MS: m/z=685.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[F:27][C:28]([F:40])([F:39])[O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34]>>[CH3:26][CH:6]1[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[C:30]([O:29][C:28]([F:27])([F:39])[F:40])[CH:31]=2)[CH2:7]1
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cccc(OC(F)(F)F)c2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-(trifluoromethoxy)-benzoic acid
Reaction SMILES: C1C(=O)N(OC(CCCCCN[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]2[S:27][CH2:26][C@@H:25]3[NH:28][C:29]([NH:31][C@H:24]23)=[O:30])=[O:18])=O)C(=O)C1.C(=O)([O-])[O-:33]>>[OH:33][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]1[C@@H:24]2[C@@H:25]([NH:28][C:29]([NH:31]2)=[O:30])[CH2:26][S:27]1)=[O:18]
Reactant: O=C([O-])[O-]
Reactant: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NCCCCCC(=O)ON1C(=O)CCC1=O
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Following the above-mentioned method, labeled antibodies were produced using monoclonal antibodies. Anti-α-subunit monoclonal antibody (IM0365) (5 μg/mL) dissolved in 0.1 M carbonate buffer (pH 8.5) and NHS-LC-BIOTIN (PIERCE, 25 μg/mL) were mixed and stirred at room temperature for four hours using a stirrer. IgG and NHS-LC-BIOTIN were mixed at a mole ratio of 1:60. After stiring, this solution was dialyzed against physiological phosphate buffered saline (PBS) to obtain biotin-labeled antibodies.
Reaction SMILES: [C:1]1([N:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3[O:17][CH2:18][CH2:19][C:9]=3[C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:30]2)=CC=1>C1(C)C=CC=CC=1>[C:1]1([N:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3[O:17][CH2:18][CH2:19][C:9]=3[C:8]2=[S:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=c1c2c(c3cccnc3n1-c1ccccc1)OCC2
Solvent: Cc1ccccc1
Product: S=c1c2c(c3cccnc3n1-c1ccccc1)OCC2

Procedure:
A suspension of 3,5-dihydro-5-phenyl-furo[3,2-c][1, 8]naphthyridin-4(2H)-one (3 g.) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's Reagent; 5 g.) in dry toluene (100 ml.) was stirred in an atmosphere of nitrogen and heated to reflux for 6 hrs. After cooling, the organic layer was washed with water, dried and evaporated. The product was purified by chromatography over silica gel in CH2Cl2 containing increasing amounts of ethyl acetate (0-5%). The fractions containing pure product were combined, evaporated, suspended in ethanol, filtered and dried to yield the desired product, m.p. 242°-244.5° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]2[C:11]([CH2:21][C:22](O)=[O:23])=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:13]=[C:3]12.[CH3:25][NH2:26]>O1CCCC1>[CH3:25][NH:26][C:22](=[O:23])[CH2:21][C:11]1[N:4]2[C:3]([N:2]([CH3:1])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=32)=[N:13][C:12]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1
Reactant: CN
Reactant: Cc1ccc(-c2nc3n(C)c4ccccc4n3c2CC(=O)O)cc1
Solvent: C1CCOC1
Product: CNC(=O)Cc1c(-c2ccc(C)cc2)nc2n(C)c3ccccc3n12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 1.9 g (0.006 mol) of 9-methyl-2-(4-methylphenyl)-9H-imidazo[1,2-a]benzimidazole-3-acetic acid is prepared in 50 ml of dry tetrahydrofuran, 1.45 g (0.009 mol) of N,N'-carbonyldiimidazole are added, in small portions, under an inert atmosphere and the mixture is stirred at room temperature for 2 h. The mixture is cooled in an ice-cold water bath, and treated with an excess of dry methylamine. Stirring is maintained for 16 h at room temperature. The solvent is evaporated under reduced pressure, and the residue is taken up in water, separated by filtration, washed with water, dried under vacuum and purified by recrystallization from methanol. 1 g of compound is obtained. Melting point: 251°-252° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]3[C:23]4[C:22](=[O:24])[NH:21][CH:20]=[N:19][C:18]=4[CH:17]=[C:16](Cl)[N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH2:26]([NH2:29])[CH2:27][NH2:28]>>[NH2:28][CH2:27][CH2:26][NH:29][C:16]1[N:15]=[C:14]([NH:13][C:10]2[CH:11]=[N:12][C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:8][CH:9]=2)[C:23]2[C:22](=[O:24])[NH:21][CH:20]=[N:19][C:18]=2[CH:17]=1
Reactant: O=c1[nH]cnc2cc(Cl)nc(Nc3ccc(N4CCOCC4)nc3)c12
Reactant: NCCN
Product: NCCNc1cc2nc[nH]c(=O)c2c(Nc2ccc(N3CCOCC3)nc2)n1
Temperature: 150 °C

Procedure:
A mixture of starting material 5-(6-morpholinopyridin-3-ylamino)-7-chloropyrido[4,3-d]pyrimidin-4(3H)-one (20 mg, 0.055 mmol) and ethylene diamine (200 uL, used as solvent as well) was heated at 150° C. overnight. The excess diamine was removed under reduced pressure, and the residue was subject to HPLC-MS for purification to the final product 7-(2-aminoethylamino)-5-(6-morpholinopyridin-3-ylamino)pyrido[4,3-d]pyrimidin-4(3H)-one.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6](OCC)=[O:7])#[N:2].N>CO.[Ni]>[C:11]1([C:5]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:4][CH2:3][CH2:1][NH:2][C:6]2=[O:7])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(CCC#N)(c1ccccc1)c1ccccc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: O=C1NCCCC1(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product of Example 68B (14.4 g, 49.1 mmol) and 7 M ammonia in methanol (150 mL) were added to solvent-washed Raney®-nickel (72.0 g, 1227 mmol), and the mixture was stirred at room temperature for 24 hours under hydrogen (30 pounds per square inch). The mixture was filtered through a nylon membrane. The reaction mixture was concentrated. The residue was dissolved in dichloromethane/methanol (1:1) and filtered through a pad of diatomaceous earth to remove a greenish residue. The filtrate was concentrated to obtain a solid which was slurried in methanol, filtered, and dried to obtain the title compound. MS (DCI+) m/z 251 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:31]([C:34]([NH:36][C:37]2[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=2[F:44])=[O:35])=[CH:30][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:18][CH:19]([CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[C:20]([O:22]C)=[O:21])=[O:17])[CH:12]=2)[CH:6]=1.[OH-].[Na+].O.Cl>CO>[F:1][C:2]1[CH:33]=[CH:32][C:31]([C:34]([NH:36][C:37]2[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=2[F:44])=[O:35])=[CH:30][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:18][CH:19]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:20]([OH:22])=[O:21])=[O:17])[CH:12]=2)[CH:6]=1
Reactant: COC(=O)CCC(NC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NC(CCC(=O)O)C(=O)O)c[nH]4)c3)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of dimethyl 2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]pentanedioate (320 mg, 0.53 mmol) in MeOH (20 ml) was added 1M NaOH solution (2 ml, 2 mmol). The mixture was stirred at room temperature for 16 hours and poured into 100 ml of water. 1M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]pentanedioic acid as white solid. Yield: 305 mg, 100%.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][OH:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37]>>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][O:28][CH2:27][C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:11]=[CH:10][C:9]([C:6]3([C:4]([OH:3])=[O:5])[CH2:7][CH2:8]3)=[CH:14][CH:13]=2)=[CH:16][CH:17]=1
Reactant: Clc1ccccc1CBr
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CO)cc3)cc2)CC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1COCc1ccccc1Cl

Procedure:
Prepared according to the procedure described in Example 45, Step 2, using 1-[4′-(4-hydroxymethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 1-bromomethyl-2-chloro-benzene.
Reaction SMILES: Cl.C([O:6][C:7](=[O:41])[CH2:8][O:9][CH2:10][CH:11]([CH2:16][O:17][C:18]1[C:19]2[C:26]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=3)=[C:25]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:24][C:20]=2[N:21]=[CH:22][N:23]=1)[C:12]([CH3:15])([CH3:14])[CH3:13])(C)(C)C>O1CCOCC1>[CH2:33]([C:30]1[CH:29]=[CH:28][C:27]([C:26]2[C:19]3[C:18]([O:17][CH2:16][CH:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][O:9][CH2:8][C:7]([OH:41])=[O:6])=[N:23][CH:22]=[N:21][C:20]=3[O:24][C:25]=2[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:32][CH:31]=1)[CH3:34]
Reactant: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC(COCC(=O)OC(C)(C)C)C(C)(C)C)c23)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC(COCC(=O)O)C(C)(C)C)c23)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Add 1.0 ml 4 N hydrogen chloride in dioxan to 155 mg (0.29 mmol) [2-({[5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}methyl)-3,3-dimethylbutoxy]acetic acid tert.-butyl ester and stir for 48 h at RT. After concentrating the reaction solution by evaporation under vacuum, purify the residue by preparative RP-HPLC (gradient: water/acetonitrile). 122 mg (88% of theor.) of the desired product (racemate) is obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.C[N:19]([CH3:22])C=O>ClCCl>[CH2:22]([NH:19][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[F:1])[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(NCc1ccccc1)c1cc([N+](=O)[O-])ccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-fluoro-5-nitrobenzoic acid (313 mg) in dichloromethane (4 mL) were added thionyl chloride (0.17 mL) and dimethylformamide (0.05 mL), and the mixture was heated for 36 hours under reflux. After evaporation of the solvent, the residue was dissolved in dichloromethane (4 mL). To this solution were added benzylamine (0.19 mL) and triethylamine (0.47 mL), and the mixture was stirred for 30 minutes at 0° C. After evaporation of the solvent, the residue was dissolved in ethyl acetate and washed successively with diluted hydrochloric acid, an aqueous sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The resulting residue was triturated with diisopropyl ether to give N-benzyl-2-fluoro-5-nitrobenzamide (436 mg) as a solid substance.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:35])[N:27]3[C:30]([O:32][CH2:33]Cl)=[O:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.[C:36]([O-:39])(=[O:38])[CH3:37].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:35])[N:27]3[C:30]([O:32][CH2:33][O:38][C:36](=[O:39])[CH3:37])=[O:31])=[CH:22][CH:21]=2)[CH2:13][CH2:14]1
Reactant: CC(=O)[O-]
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1C(=O)OCCl
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCOC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of chloromethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (1.20 g, 2.22 mmol) in dimethyl formamide (20 mL) was added cesium acetate (639 mg, 3.33 mmol). The reaction was then stirred at ambient temperature overnight. The reaction was diluted with ethyl acetate (50 mL) and quenched with water/brine (1:1, 50 mL). The reaction was extracted with ethyl acetate (3×50 mL). The combined organics were washed with water (50 mL) then brine (50 mL) and dried (MgSO4) and concentrated. The crude product was purified by column chromatography on silica eluting with 0-10% tetrahydrofuran/dichloromethane with 1% Et3N to give the product which required further purification. The product was purified by column chromatography on silica eluting with 0.5% Et3N/ethyl acetate to give acetoxymethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate, Compound-87 (243 mg, 19% over 2 steps).