Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([CH3:11])[CH:5]=1)([O-:3])=[O:2].[CH2:12](Cl)Cl.[OH-].[Na+].S(OC)(OC)(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:11][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:12])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: ClCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A reaction mixture of 2-nitro-p-cresol (23.58 g, 0.154 mmol), methylene chloride (200 ml), tetra-n-butylammonium hydrogensulfate (5.15 g, 15.2 mmol), 1N sodium hydroxide (170 ml) and dimethyl sulfate (16.0 ml, 0.169 mmol) was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with methylene chloride. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The concentrate was immediately used for the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:19])[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:19])[CH2:10][CH2:11][C:12](=[O:13])[CH2:17][CH2:18]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OC1(c2ccc(F)c(F)c2)CCC2(CC1)OCCO2
Solvent: CC(C)=O
Product: O=C1CCC(O)(c2ccc(F)c(F)c2)CC1
Yield: 62 %

Procedure:
A solution of 8-(3,4-difluorophenyl)-1,4-dioxaspiro[4.5]decan-8-ol (5.4 g, 20 mmole) in acetone-1N hydrochloric acid (1:1) was stirred for 4 hr. The acetone was removed in vacuo and the crude material crystallized from isopropyl ether to give the product (62%, mp: 84°-85° C.).
Reaction SMILES: [K].[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.F[C:15]1[CH:16]=[CH:17][C:18]([N+:24]([O-:26])=[O:25])=[C:19]([CH:23]=1)[C:20]([O-:22])=[O:21].Cl>CS(C)=O.O>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([O:13][C:15]1[CH:16]=[CH:17][C:18]([N+:24]([O-:26])=[O:25])=[C:19]([CH:23]=1)[C:20]([OH:22])=[O:21])[CH:7]=[CH:6]2
Reactant: Oc1ccc2cc(Cl)ccc2n1
Reactant: O=C([O-])c1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [K]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cc(Oc2ccc3cc(Cl)ccc3n2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A reactor is charged with 4.34 grams (0.02 mole) of the potassium salt of 6-chloro-2-hydroxyquinoline (Formula II Compound) in 25 milliliters of dimethylsulfoxide. To this mixture is added 4.46 grams (0.02 mole) of the potassium salt of 5-fluoro-2-nitrobenzoate (Formula III Compound). After stirring at about 100° C. for about 16 hours, the reaction mixture is poured into 200 milliliters of water and acidified with concentrated hydrochloric acid. Filtration and air drying affords 5-(6-chloro-2-quinolinoxy)-2-nitrobenzoic acid (Formula IV Compound).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH:17]=[C:16]2[C@H:32]1[CH2:34][C@H:33]1[CH2:35][OH:36])#[N:12].C(N(CC)CC)C>ClCCl>[C:11]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH:17]=[C:16]2[C@H:32]1[CH2:34][C@H:33]1[CH:35]=[O:36])#[N:12]
Reactant: Cc1ccc(S(=O)(=O)n2cc([C@H]3C[C@H]3CO)c3cc(C#N)ccc32)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc([C@H]3C[C@H]3C=O)c3cc(C#N)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a −78° C. solution of oxalyl chloride (52 μL, 0.60 mmol) in anhydrous dichloromethane (20 ml) was added dimethylsulfoxide (50 μL, 0.70 mmol) dropwise. After stirring 10 min, a solution of cis-2-[5-Cyano-1-(p-toluenesulfonyl)indol-3-yl]cyclopropanemethanol (129 mg, 0.35 mmol) in dichloromethane (5 ml) was added dropwise. After stirring 20 min at −78° C., triethylamine (294 □L, 2.10 mmol) was added dropwise. The reaction was stirred for 5 min at −78° C. and then allowed to warm to room temperature. The reaction was washed with water (2×5 ml), dried with anhydrous magnesium sulfate and the solvent was evaporated to give the crude cis-2-[5-Cyano-1-(p-toluenesulfonyl)indol-3-yl]cyclopropanecarboxaldehyde.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=[O:4].OC1C=C(C=CC=1)C(OCC)=O.OC1CCOC1.[C:31]1([P:37]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[C:44]1([P:37](=[O:4])([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)c1cccc(O)c1
Agent: OC1CCOC1
Solvent: C1CCOC1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Diethyl azodicarboxylate (2.09 g) was added to a stirred mixture of ethyl 3-hydroxybenzoate (1.662 g), 3-hydroxytetrahydrofuran (0.881 g), triphenylphosphine (3.41 g) and THF (40 ml) which had been cooled to 0° C. The resultant mixture was allowed to warm to ambient temperature and was stirred for 18 hours. The mixture was evaporated and the residue was triturated under a 9:1 mixture of hexane and ethyl acetate. The solid triphenylphosphine oxide so formed was filtered off. The filtrate was evaporated and the residue was purified by column chromatography on silica using a 99:1 mixture of methylene chloride and methanol as eluent. There was thus obtained ethyl 3-(tetrahydrofuran-3-yloxy)benzoate (1.56 g); NMR Spectrum: (DMSOd6) 1.27 (t, 3H), 1.93 (m, 1H), 2.22 (m, 1H), 3.82 (m, 4H), 4.27 (m, 2H), 5.08 (m, 1H), 7.19 (m, 1H), 7.42 (m, 2H), 7.52 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[OH:1][C:2]1[N:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(O)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1nc(O)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
To a solution of 2-hydroxy-6-methylnicotinic acid (14.0 g, 91.5 mmol, 1.00 equiv) in sulfuric acid (conc.) (140 mL) at 0° C. was added dropwise a solution of HNO3 (12.0 g, 190 mmol, 2.00 equiv) in sulfuric acid (conc.) (10 mL). The resulting mixture was then stirred for 2 h at 90° C., cooled to ambient temperature, and then quenched with 250 mL of ice water. The resulting solids were collected by filtration and dried in an oven under reduced pressure to yield 15.8 g (87%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=1[NH:12][CH:13]1[CH2:15][CH2:14]1.[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:29]([C@@H:25]([NH:24][C:22]([O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:23])[CH3:26])=[N:11][C:6]=2[CH:7]=[CH:8][C:9]=1[F:10])=[O:16]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)c1c(F)ccc(N)c1NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: COC(=O)c1c(F)ccc2nc([C@H](C)NC(=O)OC(C)(C)C)n(C3CC3)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
A mixture of 3-amino-2-cyclopropylamino-6-fluorobenzoic acid methyl ester (756 mg, 3.37 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (702 mg, 3.71 mmol), HOAt (505 mg, 3.71 mmol) and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (711 mg, 3.71 mmol) in DCM (20 mL) was stirred at 0° C. for 1 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was dried and concentrated in vacuo. The resulting residue was taken up in AcOH (20 mL) and heated at 70° C. for 21 h. After cooling to RT, the volatiles were evaporated in vacuo and the residue partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with EtOAc and the combined organic fractions washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in DCM) to afford the title compound (700 mg, 55% over 2 steps). LCMS (Method C): RT 3.27 min [M+H]+ 378.18
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][C@H:10]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH2:18]O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.FC1C=CC(C[C@H]2CC[C@H](N3CCC[C@H]3CO)CC2)=CC=1.N1C=CC=CC=1.C1(C)C=CC(S([Cl:58])(=O)=O)=CC=1>C(Cl)Cl.C(OCC)(=O)C>[Cl:58][CH2:18][C@@H:14]1[CH2:15][CH2:16][CH2:17][N:13]1[C@H:10]1[CH2:11][CH2:12][C@@H:7]([CH2:6][C:5]2[CH:20]=[CH:21][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:8][CH2:9]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@@H]1CCCN1[C@H]1CC[C@@H](Cc2ccc(F)cc2)CC1
Agent: OC[C@@H]1CCCN1[C@H]1CC[C@H](Cc2ccc(F)cc2)CC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Fc1ccc(C[C@H]2CC[C@@H](N3CCC[C@H]3CCl)CC2)cc1
Reaction time: 16 h

Procedure:
To a stirring solution of {(2S)-1-[cis-4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methanol and {(2S)-1-[trans-4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methanol (390 mg, 1.34 mmol) in 5 ml of methylene chloride at 25° C. under N2 was added pyridine (0.22 ml, 2.75 mmol, EM Science) followed by p-toluenesulfonyl chloride (288 mg, 1.51 mmol, Aldrich). Worked up after 16 hours by adding ethyl acetate then rinsing 3 times with sat'd sodium bicarbonate followed by 1 time time with brine. The organic was dried over magnesium sulfate, and concentrated in vacuo to obtain an oil which was purified over silica gel in 100% ethyl acetate to yield 87 mg of product. MS (ESI) detects 310 (M+H). The other isomer was isolated and used for example 16.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][O:10][C:11](=[O:28])[C:12]1[C:13](=[C:18]([NH:22]CCCCC)[CH:19]=[CH:20][CH:21]=1)[C:14]([O:16][CH3:17])=[O:15]>C(OCC)C>[CH3:9][O:10][C:11](=[O:28])[C:12]1[C:13](=[C:18]([NH:22][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:19]=[CH:20][CH:21]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCCCCNc1cccc(C(=O)OC)c1C(=O)OC
Reactant: O=Cc1cccnc1
Solvent: CCOCC
Product: COC(=O)c1cccc(NCc2cccnc2)c1C(=O)OC
Yield: 61 %

Procedure:
3-Pyridinecarboxaldehyde (0.94 ml, 10 mmol) was treated in the same manner as described above for the synthesis of 3-pentylamino-phthalic acid dimethyl ester. After removal of pyridine the residue was dissolved in methylene chloride (100 ml) and washed with water (2×100 ml), saturated NaHCO3 (2×100 ml), brine (1×100 ml), dried (magnesium sulfate), and filtered. The solvent was evaporated in vacuo to give an oil. The oil was dissolved in diethyl ether (100 ml) and extracted with 0.1 N HCl (2×100 ml). The combined aqueous HCl extracts were washed with diethyl ether (2×100 ml) and the pH adjusted to 10 by dropwise addition of saturated Na2CO3. The product was extracted with diethyl ether (3×100 ml). The combined ether extracts were washed with brine (1×100 ml), dried (magnesium sulfate), and filtered. The solvent was evaporated in vacuo to give 0.91 g (61%) of product as a light yellow oil which was used without further purification: 1H NMR CDCl3) δ8.61 (d, J=2.0 Hz, 1H), 8.53 (dd, J=1.1 Hz and 4.8 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.31-7.21 (m, 3H), 6.85 (d, J=7.3 Hz, 1H), 6.69 (d, J=8.5 Hz, 1H), 4.45 (d, J=5.7 Hz, H), 3.87 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[CH3:13][O:14][C:15](=[O:25])[CH2:16][N:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.BrCCC=C>O1CCCC1.CCCCCC.O>[CH3:13][O:14][C:15](=[O:25])[CH:16]([CH2:11][CH2:10][CH:9]=[CH2:8])[N:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [Li]CCCC
Reactant: COC(=O)CN=Cc1ccccc1
Agent: C=CCCBr
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(N=Cc1ccccc1)C(=O)OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Dissolve diisopropylamine (15.4 mL, 110 mmol) in tetrahydrofuran (250 mL), place under a nitrogen atmosphere and cool to -78° C. Add n-butyllithium (39 mL of a 2.7M solution in hexane, 105 mmol). Stir for 30 minutes and add, by dropwise addition, a solution of N-(phenylmethylene)glycine methyl ester (17.7 g, 100 mmol) in tetrahydrofuran (25 mL). Stir for 15 minutes and add 4-bromobutene (13.5 g, 100 mmol) and allow to warm slowly to room temperature. Add hexamethylphosmhoramide (20 mL, 100 mmol) and stir under a nitrogen atmosphere for 3 hours. Pour into water, extract into ethyl ether and wash with brine several times. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound as an amber oil (25 g).
Reaction SMILES: N1CCCCC1.C1C2C(COC(=O)[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34](=[O:69])[NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[C:37]=3[C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([S:49]([C:52]4[CH:56]=[C:55]([C:57]([NH:59][C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])=[NH:58])[S:54][C:53]=4[S:67][CH3:68])(=[O:51])=[O:50])[CH:44]=3)C3C(=CC=CC=3)C=2C=CC=1>CN(C=O)C>[C:63]([O:62][C:60](=[O:61])[NH:59][C:57]([C:55]1[S:54][C:53]([S:67][CH3:68])=[C:52]([S:49]([C:45]2[CH:44]=[C:43]([C:37]3[C:38]([CH3:42])=[CH:39][CH:40]=[CH:41][C:36]=3[NH:35][C:34](=[O:69])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][NH2:23])[CH:48]=[CH:47][CH:46]=2)(=[O:51])=[O:50])[CH:56]=1)=[NH:58])([CH3:66])([CH3:65])[CH3:64]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCCCCCCCCCNC(=O)OCC2c3ccccc3-c3ccccc32)c1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCCCCCCCCCN)c1
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
A solution of 50% piperidine in DMF [1 mL] was added to (10-{3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylcarbamoyl}-decyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (0.040 g, 0.043 mmol) [example 211, step a] and stirred for 0.5 hours, followed by evaporation. Column chromatography (10% MeOH in dichloromethane) of the residue yielded the title compound (0.024 g, 77%) as a solid. ESI-MS (m/z): Calcd. for C35H48N4O5S3: 700.28; found: 701.0.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:8][C:7]1=[O:20])(=O)[CH2:2][CH2:3][CH3:4].[Cl-].[CH2:22]([O:24][NH3+:25])[CH3:23].C([O-])(=O)C.[Na+]>C(O)C>[CH2:22]([O:24][NH:25][CH2:4][CH2:3][CH2:2][CH:1]=[C:6]1[C:11](=[O:12])[CH2:10][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:8][C:7]1=[O:20])[CH3:23]
Reactant: CCO[NH3+]
Reactant: CCCC(=O)C1C(=O)CC(c2ccc(Cl)cc2)CC1=O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CCONCCCC=C1C(=O)CC(c2ccc(Cl)cc2)CC1=O

Procedure:
13.5 parts of 2-butyryl-5-(4-chlorophenyl)-cyclohexane-1,3-dione, 4.5 parts by weight of ethoxyammonium chloride, 4.5 parts by weight of anhydrous sodium acetate and 100 parts by volume of ethanol are reacted, and the mixture is worked up, in a manner similar to that in Example 1. 2-(Ethoxyaminobutylidene)-5-(4-chlorophenyl)-cyclohexane-1,3-dione is obtained as a solid, which is recrystallized from cyclohexane. The product has a melting point of 77° C. (active ingredient No. 2)
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][C:12](=O)[C:13](F)([F:15])[F:14])[CH:3]=1.FC(F)(F)S(OCC(F)F)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][CH2:12][CH:13]([F:15])[F:14])[CH:3]=1
Reactant: COC(=O)c1sc(Br)cc1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1sc(Br)cc1NCC(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of methyl 5-bromo-3-[(trifluoroacetyl)amino]thiophene-2-carboxylate (500 mg, 1.51 mmol), 2,2-difluoroethyl trifluoromethanesulfonate (441 mg, 2.06 mmol), cesium carbonate (1.23 g, 3.78 mmol) and DMF (10 mL) was microwave-irradiated at 90° C. for 1 h. Then, water was added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was dissolved in MeOH (3 mL). To the solution were added potassium carbonate (100 mg) and water (1.5 mL). The mixture was stirred at room temperature for 0.5 h. After removal of the solvent at reduced pressure, the organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, hexane to 85:15 hexane/EtOAc) to give the title compound (290 mg, 64%) as a yellow solid:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)[C@@]2(C3C(=CC4OCCOC=4C=3)OC2)C1=O.Br[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:48]=1[Cl:54].BrCCCCC>>[Cl:54][C:48]1[CH:49]=[C:50]([F:53])[CH:51]=[CH:52][C:47]=1[CH2:46][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Solvent: CCCCCBr
Product: O=C1N(Cc2ccc(F)cc2Cl)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 7.3 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 1-(bromomethyl)-2-chloro-4-fluorobenzene to replace 1-bromopentane, 1′-(2-chloro-4-fluorobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (81%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 7.52-7.60 (m, 1H), 7.35-7.17 (m, 4H), 7.10-7.02 (m, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 6.24 (s, 1H), 4.97 (ABq 2H), 4.75 (ABq, 2H), 4.22-4.08 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.7, 154.8, 144.2, 142.1, 137.8, 132.9, 131.7, 130.1, 129.5, 129.4, 128.9, 123.8, 123.2, 121.0, 117.2, 116.9, 114.9, 111.3, 109.3, 98.8, 79.6, 64.2, 63.6, 57.2, 41.1; MS (ES+) m/z 437.6 (M+1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[C:23](=[O:24])[N:7]2[C@H:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=[CH:10][C@H:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:6]2[C:5]1=[O:25]>C(O)C.[Pd]>[Cl:1][CH2:2][CH2:3][N:4]1[C:23](=[O:24])[N:7]2[CH:8]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:9][CH2:10][CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:6]2[C:5]1=[O:25]
Reactant: CCOC(=O)[C@H]1C=C[C@@H](c2ccccc2)n2c(=O)n(CCCl)c(=O)n21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CCC(c2ccccc2)n2c(=O)n(CCCl)c(=O)n21
Yield: 65.8 %

Procedure:
4.73 g (0.013 mol) of ethyl cis-2-(2-chloroethyl)-2,3,5,8-tetrahydro-1,3-dioxo-8-phenyl-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate were dissolved in 300 ml of ethanol and hydrogenated in the presence of 10% palladium-on-charcoal at room temperature. The catalyst was filtered off and the filtrate was evaporated to give 3.13 g (66%) of ethyl 2,3,5,6,7,8-hexahydro-2-(2-chloroethyl)-1,3-dioxo-8-phenyl-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate of melting point 87°-89° C. (from ethanol).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[CH3:19][N:20]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([N:20]([CH3:19])[CH:28]2[CH2:33][CH2:32][N:31]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=3)[CH2:30][CH2:29]2)=[CH:26][CH:25]=1
Reactant: CN(c1ccc(N)cc1)C1CCNCC1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(c1ccc(N)cc1)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Yield: 28.9 %

Procedure:
2-(4-(Bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (1.948 mmol, 0.657 g), N1-methyl-N1-(piperidin-4-yl)benzene-1,4-diamine (1.948 mmol, 0.4 g) and potassium carbonate (5.84 mmol, 0.808 g) were combined and stirred at room temperature for 1 hour in acetonitrile (50 mL). The reaction mixture was filtered and concentrated under vacuum. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was separated, dried and concentrated under vacuum. The residue was purified by silica column chromatography (eluent: dichloromethane to 8% methanol in dichloromethane) to afford the title compound (260 mg). MS (ESI) m/z 462.4 [M+H]+
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[CH:41]=[N:42][C:43]([CH:46]([CH3:48])[CH3:47])=[CH:44][CH:45]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:41]=[N:42][C:43]([CH:46]([CH3:48])[CH3:47])=[CH:44][CH:45]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CC(C)c1ccc(CCl)cn1
Agent: Cl
Product: CC(C)c1ccc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)cn1
Yield: 83.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 3-chloromethyl-6-isopropylpyridine (0.51 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-isopropylpyridin-3-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.77 g) was obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=1.[CH3:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[CH2:29][NH:30][CH3:31].C1C=CC2N(O)N=NC=2C=1.O.CCN(CC)CC.C(Cl)CCl>CN(C=O)C.C(Cl)Cl>[NH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:30]([CH3:31])[CH2:29][C:21]2[N:20]([CH3:19])[C:28]3[C:23]([CH:22]=2)=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:9])=[C:5]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=1
Reactant: CNCc1cc2ccccc2n1C
Reactant: Nc1ccc(C(=O)O)c(Oc2ccccc2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(Cc1cc2ccccc2n1C)C(=O)c1ccc(N)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.3 %

Procedure:
To 4-amino-2-phenoxybenzoic acid hydrochloride (1.0 g, 3.4 mmole) in 1:1 DMF/CH2Cl2 (75 mL) was added 1-methyl-2-(methylaminomethyl)indole (0.61 g, 3.5 mmole), HOBt.H2O (0.47 g, 3.5 mmole), Et3N (1.0 mL, 7.1 mmole), then EDC (0.67 g, 3.5 mmole). The reaction was stirred at RT for 16 hr then was concentrated under vacuum. The residue was taken up in EtOAc (200 mL) and-the solution was washed with water, dried (Na2SO4), and concentrated. Flash chromatography on silica gel (2% MeOH/CHCl3, then rechromatography using 70% EtOAc/hexanes) gave the title compound (0.62 g, 42%) as a white solid: MS (ES) m/e 386.2 (M+H)+.