Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH2:24])(=[O:23])=[O:22]>N1C=CC=CC=1>[S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][S:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH2:2][CH2:3]2)(=[O:12])=[O:11])(=[O:22])(=[O:23])[NH2:24]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=S(=O)(Cl)c1ccc2c(c1)CCC2
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)c1ccc2c(c1)CCC2
Reaction time: 8 h
Yield: 31.2 %

Procedure:
Indan-5-sulfonyl chloride (43 mg, 0.2 mmol) was added to a pyridine stock solution of 1.34M 2-amino-benzenesulfonamide (0.150 mL, 0.2 mmol). The reaction mixture was shaken overnight followed by solvent removal under vacuo. The crude mixture was dissolved in DMSO and purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (22 mg, 32%) as a white solid. MS m/z M−H 351. Rf 0.91 min (see above system in General procedure for Examples 23-43).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([C@H:5]1[C@H:9]([CH3:10])[CH2:8][N:7](C(OCC2C=CC=CC=2)=O)[CH2:6]1)=[O:4].C(Cl)CCl.CNC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][N:2]([CH3:21])[C:3]([C@H:5]1[C@H:9]([CH3:10])[CH2:8][NH:7][CH2:6]1)=[O:4]
Reactant: C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1C(=O)N(C)C
Agent: CN(C)c1ccncc1
Agent: CNC
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@@H]1CNC[C@H]1C(=O)N(C)C

Procedure:
A solution of commercially available phenylmethyl (trans)-3-[(dimethylamino)carbonyl]-4-methyl-1-pyrrolidinecarboxylate (1.06 g, 3.4 mmol), DMAP (0.63 g, 5.2 mmol), and EDC (1.0 g, 5.2 mmol) in DCM (18 mL) was stirred for 5 min and dimethylamine (1.9 mL, 3.8 mmol, 2M in THF) was added. The reaction was allowed to stir until it was judged to be complete by LCMS and was quenched with 1 M HCl. A standard work-up provided the desired amide intermediate. This material was immediately dissolved in degassed MeOH (20 mL) and 10% Pd/C (120 mg) was added. The reaction mixture was allowed to stir under a hydrogen balloon until complete deprotection was observed by LCMS. The catalyst was removed by filtration to yield (trans)-N,N,4-trimethyl-3-pyrrolidinecarboxamide. LCMS: (M+H)+: 157.2.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:22][C:23]1(C)[C:27](C)(C)OB(C(C)=C)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:15]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:2]=1[C:23]([CH3:27])=[CH2:22])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)c(Oc2ccccc2)c1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)c1ccc(C(=O)OC(C)(C)C)cc1Oc1ccccc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A mixture of tert-butyl 4-bromo-3-phenoxybenzoate (400 mg, 1.15 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (193 mg, 1.15 mmol) and sodium carbonate (366 mg, 3.45 mmol), tetrakis(triphenylphosphine)palladium (40 mg, 0.035 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was stirred at 90° C. overnight under nitrogen atmosphere. After being cooled to room temperature, the reaction was concentrated. The residue was purified by pre-HPLC to get tert-butyl 3-phenoxy-4-(prop-1-en-2-yl)benzoate (309 mg, 87%) as a yellow solid LRMS (M+H+) m/z: calcd 311.16. found 311.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:16]([F:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[CH:20]=[CH:21][C:22]4[O:27][CH2:26][C:25](=O)[NH:24][C:23]=4[CH:29]=3)[N:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.O.Cl>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:16]([F:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[CH:20]=[CH:21][C:22]4[O:27][CH2:26][CH:25]=[N:24][C:23]=4[CH:29]=3)[N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1COc2ccc(Nc3ncc(F)c(Nc4cccc([N+](=O)[O-])c4)n3)cc2N1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cccc(Nc2nc(Nc3ccc4c(c3)N=CCO4)ncc2F)c1
Yield: 21.2 %

Procedure:
N4-(3-Nitrophenyl)-N2-[(2H)1,4-benzoxazin-3(4H)-one-6-yl]-5-fluoro-2,4-pyrimidinediamine (940 mg, 2.5 mmol) and Pd/C10% (300 mg, 50% water content) were suspended in EtOH (7 mL) and 10% aqueous HCl (5 mL) and hydrogenated in a Parr apparatus for 3 hours (22° C., 60 psi). The suspension was filtered over celite and neutralized by addition of K2CO3. The solvents were removed and the resulting black slurry was suspended in MeOH. Silica gel (4 g) was added and the volatiles were removed under reduced pressure. The residue was subjected to column chromatography on silica gel (CHCl3-Acetone, 2:1) to give 186 mg of N4-(3-aminophenyl)-N2-(1,4-benzoxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine as brownish solid. 1H NMR (DMSO-d6): δ 8.92 (s, 1H), 8.64 (s, 1H), 7.95 (d, 1H, J=3.6 Hz), 7.11 (s, 1H), 6.84-6.95 (m, 3H), 6.66 (dd, 1H, J=2.4, 9.0 Hz), 6.46 (d, 1H, J=8.1 Hz), 6.28 (d, 1H, J=8.1 Hz), 5.62 (s, 1H), 4.98 (s, 2H), 4.03 (m, 2H), 3.31 (m, 2H); LCMS purity: 98.4%; MS (m/e): 352.7 (M+, 100).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:11]=[N:12][C:13]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:14][CH:15]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([CH:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:30][OH:31])[CH:26]=[CH:25][CH:24]=1>>[OH:31][CH2:30][CH:29]([C:27]1[N:28]=[C:23]([NH:1][C:2]2[S:3][C:4]([C:10]3[CH:11]=[N:12][C:13]([N:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)=[CH:14][CH:15]=3)=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])[CH:24]=[CH:25][CH:26]=1)[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: OCC(c1cccc(Br)n1)N1CCOCC1
Reactant: NC(=O)c1cc(-c2ccc(N3CCCCC3)nc2)sc1N
Product: NC(=O)c1cc(-c2ccc(N3CCCCC3)nc2)sc1Nc1cccc(C(CO)N2CCOCC2)n1

Procedure:
The title compound was prepared by using the procedure listed in Example 1 with 2-amino-5-(6-piperidin-1-ylpyridin-3-yl)thiophene-3-carboxamide (70 mg, 0.23 mmol) and 2-(6-bromopyridin-2-yl)-2-morpholin-4-ylethanol (Example 141, Step 1) (66 mg, 0.23 mmol) as the starting materials.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][C:12]1=[O:20].[Cl-].[Cl-].[Cl-].[Al+3]>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([C:17]2[CH:18]=[CH:19][C:14]3[NH:13][C:12](=[O:20])[O:11][C:15]=3[CH:16]=2)=[O:9])[CH:3]=1
Reactant: O=c1[nH]c2ccccc2o1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: O=C(c1ccc2[nH]c(=O)oc2c1)c1cc(Cl)ncn1
Temperature: 0 °C

Procedure:
3.93 g (22.2 mmol) 6-chloropyrimidine-4-carboxylic acid chloride, 3.00 g (22.2 mmol) 2-benzoxazolinone and 14.8 g (111 mmol) aluminium trichloride were combined and heated for 3 h to 130° C. Then the mixture was combined with ice water and EtOAc, the solid was suction filtered and the phases were separated. The aqueous phase was extracted twice with EtOAc, the organic phases were combined, dried and evaporated down. The residue was triturated in DIPE, suction filtered and dried.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[O:14][C:13](=[O:15])[NH:12][CH2:11]2)[C:5]([O:16][CH2:17][CH3:18])=[C:4]([CH:19](O)[CH3:20])[CH:3]=1.CN(C)C=O.S(Cl)([Cl:29])=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[O:14][C:13](=[O:15])[NH:12][CH2:11]2)[C:5]([O:16][CH2:17][CH3:18])=[C:4]([CH:19]([Cl:29])[CH3:20])[CH:3]=1
Reactant: CCOc1c(C(C)O)cc(Cl)c(C#N)c1C1CNC(=O)O1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1c(C(C)Cl)cc(Cl)c(C#N)c1C1CNC(=O)O1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 6-chloro-3-ethoxy-4-(1-hydroxyethyl)-2-(2-oxo-1,3-oxazolidin-5-yl)benzonitrile (58 mg, 0.19 mmol) (mixture of four diastereomers from step 4), N,N-dimethylformamide (36 μL) in methylene chloride (1 mL), thionyl chloride (40.0 μL, 0.56 mmol) was added and the mixture was stirred at room temperature for 20 minutes The mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate, filtered and concentrated to give the desired compound as a mixture of four diastereomers, 55 mg, 91%. LCMS calculated for C14H15Cl2N2O3 (M+H)+: m/z=329.0; found: 329.1.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]([C:21]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:22])[C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][C:10]=2[CH:20]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([C:21]([O:23][CH2:24][CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:22])[C:9]2[O:13][C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:11][C:10]=2[CH:20]=1)(=[O:3])[CH3:2]
Reactant: Nc1cc(C(=O)OCCN2CCCCC2)c2oc(-c3ccccc3)cc2c1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(C(=O)OCCN2CCCCC2)c2oc(-c3ccccc3)cc2c1
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
A solution of 147 mg of acetyl chloride in 2 ml of toluene is added dropwise to a mixture of 522 mg of 2-piperidinoethyl 5-amino-2-phenylbenzofuran-7-carboxylate, 210 mg of sodium bicarbonate and 10 ml of ethyl acetate under ice-cooling. The mixture is stirred at the same temperature for 30 minutes and the reaction mixture is extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is recrystallized from ethyl acetate to give 467 mg of 2-piperidinoethyl 5-acetamido-2-phenylbenzofuran-7-carboxylate as pale yellow needles.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[O:13]=[C:14]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]1[CH2:31][C:32](O)=[O:33].[CH3:35][N:36]1[CH:40]=[CH:39][C:38]([CH2:41][NH2:42])=[N:37]1>ClCCl>[CH3:35][N:36]1[CH:40]=[CH:39][C:38]([CH2:41][NH:42][C:32](=[O:33])[CH2:31][N:15]2[CH2:16][CH2:17][C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:14]2=[O:13])=[N:37]1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: Cn1ccc(CN)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cn1ccc(CNC(=O)CN2CCC(c3ccccc3)(c3ccccc3)C2=O)n1
Reaction time: 8 h

Procedure:
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.050 g, 0.169 mmol) and (1-methyl-1H-pyrazol-3-yl)methanamine (0.021 g, 0.186 mmol) were combined and stirred together in dichloromethane (0.5 mL) at room temperature. After stirring overnight, the reaction was loaded directly onto a SF10-8 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 0.4% to 7.5% methanol/dichloromethane over 20 minutes (flow=20 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.23-7.34 (m, 11H), 6.40 (t, J=6.0 Hz, 1H), 6.06 (d, J=2.2 Hz, 1H), 4.38 (d, J=5.3 Hz, 2H), 4.05 (s, 2H), 3.82 (s, 3H), 3.50 (t, J=6.4 Hz, 2H), 2.82 (t, J=6.4 Hz, 2H); MS (ESI−) m/z 387 (M−H)−.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1.C(N(CC)CC)C.[C:21]12([C:31](Cl)=[O:32])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>CN(C=O)C>[CH2:7]([N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:31]([C:21]23[CH2:30][CH:25]4[CH2:24][CH:23]([CH2:29][CH:27]([CH2:26]4)[CH2:28]2)[CH2:22]3)=[O:32])[CH2:3]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(Cc2ccccc2)C1)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
(S)-3-Amino-1-benzylpyrrolidine (10 g) and triethylamine (24 ml) were dissolved in DMF (100 ml). Under ice-cooling, 1-adamantanecarbonyl chloride (12.4 g) was added thereto, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure. To the obtained residue was added ethyl acetate and the mixture was washed with saturated brine. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform:methanol=30:1). The obtained eluate was concentrated and IPE was added to the obtained residue. The precipitated crystals were collected by filtration to give (S)-N-(1-benzylpyrrolidin-3-yl)-1-adamantanecarboxamide (14.8 g), melting point 130-132° C.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][C@@H:33]1[CH2:38][CH:37]=[CH:36][CH2:35][C@H:34]1[C:39]([O:41][CH2:42][CH3:43])=[O:40].[C:44](O)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C1COCC1>[C:44]([O:32][C@H:33]1[CH2:38][CH:37]=[CH:36][CH2:35][C@H:34]1[C:39]([O:41][CH2:42][CH3:43])=[O:40])(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CCOC(=O)[C@@H]1CC=CC[C@H]1O
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CC=CC[C@@H]1OC(=O)c1ccccc1
Reaction time: 0.08 h
Yield: 68.2 %

Procedure:
DEAD (2.06 g, 11.8 mmol) was added dropwise to a solution of triphenylphosphine (3.08 g, 11.8 mmol) in THF (35 ml) at 0° C. over a period of 5 min. Trans 1-Hydroxy-2-carboethoxycyclohex-4-ene 2a (1.00 g, 5.88 mmol in 5 ml THF) was then added slowly, the mixture was stirred for 5 min, and then benzoic acid (1.44 g, 11.8 mmol, in 5 ml THF) was added. The mixture was stirred at RT for 2 hours. Solvents were evaporated, an the residue purified by chromatography on silica gel (EtOAc:hexane 2:8 as eluant). The product was then distilled under vacuum to yield ethyl cis-2-benzoyloxy-cyclohex-4-enecarboxylate (4, 1.1 g, 71%).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([O:18][CH2:19][CH:20]([F:22])[F:21])[N:10]=1>CO.C(Cl)Cl>[CH3:1][O:14][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([Cl:8])=[N:10][C:11]=1[O:18][CH2:19][CH:20]([F:21])[F:22]
Reactant: O=C(O)c1ccc(Cl)nc1OCC(F)F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(Cl)nc1OCC(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Trimethylsilyl diazomethane (2 M in hexane; 15.0 mL, 30.0 mmol) is added to a mixture of 6-chloro-2-(2,2-difluoro-ethoxy)-nicotinic acid (6.0 g, 25.3 mmol) in MeOH (50 mL) and DCM (100 mL). The reaction mixture is stirred at rt for 10 min, quenched with AcOH and concentrated. The residue is diluted with water and filtered. The filtercake is washed with water and dried at 40° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:18])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:7](OCC)=[O:8].Cl.Cl[C:21]([NH2:23])=[NH:22].CS(C)(=O)=O.N>O>[NH2:23][C:21]1[NH:1][C:2]2[S:3][C:4]([CH3:18])=[C:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[C:7](=[O:8])[N:22]=1
Reactant: N=C(N)Cl
Reactant: CCOC(=O)c1c(N)sc(C)c1-c1ccccc1
Agent: CS(C)(=O)=O
Agent: Cl
Agent: N
Solvent: O
Product: Cc1sc2[nH]c(N)nc(=O)c2c1-c1ccccc1
Temperature: 135 °C
Yield: 94.1 %

Procedure:
A mixture of ethyl 2-amino-5-methyl-4-phenylthiophene-3-carboxylate (1 g, 3.8 mmol), chloroformamidine hydrochloride (1.1 g, 9.6 mmol) and dimethylsulfone (1.798 g, 19.1 mmol) was heated at 135° C. for 45 minutes. Water was added and the mixture was cooled down to room temperature. An aqueous ammonia solution was added to adjust the solution to pH 9. The precipitate was filtered off, yielding the title compound (920 mg) as a yellowish powder. 13C NMR δ (75 MHz, DMSO-d6) 166.50, 157.60, 153.02, 135.16, 133.40, 130.30 (2C), 127.35 (2C), 126.79, 124.22, 113.80, 13.33. MS (m/z) 258 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:18]=2)[CH:12]=1)[S:6]([CH3:9])(=[O:8])=[O:7].[CH3:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](O)=[O:37]>>[OH:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][NH:23][C:19]2[N:18]=[C:17]([C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=3)[CH2:10][N:5]([S:6]([CH3:9])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2][NH:1][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=3[CH3:33])[CH:22]=[CH:21][N:20]=2)=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Reactant: Cc1ccccc1C(=O)O
Product: Cc1ccccc1C(=O)NCCCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1)S(C)(=O)=O

Procedure:
Compound 2 was coupled with 2-methylbenzoic acid by procedure K. LC-MS showed the product had the expected M+H+ of 574. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H) 8.2 (s, 1H) 8.0 (d, 1H) 7.6 (m, 2H) 7.3 (m, 7H), 6.8 (d, 2H), 4.4 (s, 2H), 3.7 (t, 2H), 3.3 (d, 2H), 3.2 (d, 2H) 184 (s, 3H), 2.3 (s, 3H), 1.8 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][NH:10][C:9](=O)[C:8]=2[CH:13]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:16])=O.C(N(CCCC)CCCC)CCC>C(Cl)Cl>[Cl:16][C:9]1[C:8]2[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[S:11][N:10]=1
Reactant: O=c1[nH]sc2ccc([N+](=O)[O-])cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2snc(Cl)c2c1
Temperature: 109 °C
Reaction time: 8 h

Procedure:
A mixture of 5-nitro-1,2-benzisothiazol-3(2H)-one (10.0 g, 0.0510 mol), phosphorus oxychloride (40.0 mL, 0.429 mol) and tributylamine (12.0 mL, 0.050 mol) is heated at 103-115° C. for six hours, stirred at room temperature overnight, and poured into an ice-water mixture. The resultant aqueous mixture is extracted with methylene chloride. The combined organic extracts are washed sequentially with water and saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a gum. Column chromatography of the gum using silica gel and methylene chloride gives the title product as an orange-yellow solid which is identified by NMR spectral analysis.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC=CC=3)=[CH:18][C:17]=2[O:30]CC2C=CC=CC=2)[CH2:12][CH2:11]1)=[O:9].CO>C(OCC)(=O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=2[OH:30])[CH2:12][CH2:11]1)=[O:9]
Reactant: O=C(Nc1ccccn1)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccn1)N1CCC(c2ccc(O)cc2O)CC1
Reaction time: 18 h
Yield: 39 %

Procedure:
20 mg of 4-(2,4-Bis(benzyloxy)phenyl)piperidine-1-carboxylic acid pyridin-2-ylamide are dissolved in 20 ml of ethyl acetate and then 1 ml of methanol is added. 10 mg of palladium-on-charcoal at 10% are added, and then the reaction mixture is stirred for 18 hours under a hydrogen atmosphere. The mixture is filtered and the residue is then crystallized from an ethyl acetate/heptane mixture. 5 mg of 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid pyridin-2-ylamide. Yield: 39%
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12]2)=[CH:4][C:5]([NH:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].[F:21][C:22]([F:44])([F:43])[C:23]1[CH:39]=[CH:38][C:26]([CH2:27][NH:28][C:29]([C:31]2([C:34]([F:37])([F:36])[F:35])[CH2:33][CH2:32]2)=[O:30])=[CH:25][C:24]=1[N:40]=[C:41]=S.CC(C)N=C=NC(C)C>CN(C=O)C>[F:21][C:22]([F:44])([F:43])[C:23]1[CH:39]=[CH:38][C:26]([CH2:27][NH:28][C:29]([C:31]2([C:34]([F:37])([F:36])[F:35])[CH2:33][CH2:32]2)=[O:30])=[CH:25][C:24]=1[NH:40][C:41]1[N:9]([CH3:10])[C:5]2[CH:4]=[C:3]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]([F:19])([F:20])[F:18])[CH2:13][CH2:12]3)[C:2]([Cl:1])=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(NCc1ccc(C(F)(F)F)c(N=C=S)c1)C1(C(F)(F)F)CC1
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(Cl)cc1N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2C(F)(F)F)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21

Procedure:
The title compound was prepared in analogy to Example 76 using 5-chloro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (185 mg, 0.60 mmol), N-(4-trifluoromethyl-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (221 mg, 0.60 mmol), DIC (76 mg, 0.60 mmol) and DMF (4 mL).
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](F)[CH:12]=2)[C:7](=[O:15])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]1)[CH:2]=[CH2:3].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CN(C)C=O.CO>[CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:12]=2)[C:7](=[O:15])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C1CNCCN1
Reactant: C=CCn1cc(C(=O)OCC)c(=O)c2ccc(F)cc21
Solvent: CN(C)C=O
Solvent: CO
Product: C=CCn1cc(C(=O)OCC)c(=O)c2ccc(N3CCNCC3)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.3 %

Procedure:
A solution of ethyl 1-allyl-7-fluoro-4-quinolone-3-carboxylate (390 mg, 1.41 mmol) and piperazine (1.22 g, 14.1 mmol) in dry N,N-dimethylformamide was heated for 7 hours at 110° C., then stirred at room temperature for 2 days. The solvent was evaporated to dryness, and the residue was purified by column chromatography on silica gel using dichloromethane:methanol (gradient from 98:2 to 85:15) as eluent affording 300 mg (62% yield) of ethyl 1-allyl-4-oxo-7-(4-piperazinyl)quinoline-3-carboxylate.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[S:48]1[C:52]([CH2:53][NH2:54])=[CH:51][C:50]2[CH:55]=[CH:56][CH:57]=[CH:58][C:49]1=2>>[S:48]1[C:52]([CH2:53][NH:54][C:41]([C:39]2[S:40][C:36]([N:33]3[CH2:34][CH2:35][N:31]([CH2:30][C:29]4[CH:46]=[CH:47][C:26]([F:25])=[CH:27][CH:28]=4)[C:32]3=[O:45])=[CH:37][C:38]=2[CH3:44])=[O:43])=[CH:51][C:50]2[CH:55]=[CH:56][CH:57]=[CH:58][C:49]1=2
Reactant: NCc1cc2ccccc2s1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cc2ccccc2s1
Yield: 78 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with benzo[b]thiophen-2-ylmethanamine, the title compound was obtained as a colorless solid in 78% yield: 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J=7.6 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.36-7.22 (m, 5H), 7.08-6.99 (m, 2H), 6.14 (t, J=5.4 Hz, 1H), 6.10 (s, 1H), 4.82 (d, J=5.4 Hz, 2H), 4.42 (s, 2H), 3.83-3.74 (m, 2H), 3.47-3.38 (m, 2H), 2.51 (s, 3H); MS (ES+) m/z 480.2 (M+1).