Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH2:9]([O:11][C:12](=[O:23])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:10]>CS(C)=O.O>[CH2:9]([O:11][C:12]([C@@H:13]1[CH2:2][C@H:14]1[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)=[O:23])[CH3:10]
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)C=Cc1ccc(OC)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(OC)cc1
Reaction time: 0.67 h
Yield: 26.8 %

Procedure:
Trimethylsulfoxonium iodide (14.15 g, 63 mmol) is suspended in dry DMSO (126 mL) and Sodium hydride (60% in mineral oil, 2.52 g, 63 mmol) is added. The mixture is stirred for 40 minutes and then a solution of 4-methoxycinnamic acid ethyl ester (5 g, 24.2 mmol) in dry DMSO (64 mL) is added and the mixture stirred for 3 hours at room temperature. The mixture is diluted with water and extracted with ethyl acetate, the organic phase is dried by passing through a phase seperator and the solvent is removed under vacuum. The residue is purified by flash chromatography (10% ethyl acetate in cyclohexane) to give the title compound (yield 1.43 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)[C:3]([NH:5][C@@H:6]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@@H:7]([OH:15])[CH2:8][CH:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=[CH2:11])=[O:4].C(N(C(C)C)C(C)C)C.[CH2:35]([CH:42]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:43](O)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[CH2:46]([CH:42]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:43]([NH:1][C@@H:2]([CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)[C:3]([NH:5][C@@H:6]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@@H:7]([OH:15])[CH2:8][C@@H:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=[CH2:11])=[O:4])=[O:44])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C(O)C(Cc1ccccc1)Cc1ccccc1
Reactant: C=CC(C[C@H](O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=C[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(Cc1ccccc1)Cc1ccccc1)C(C)C
Yield: 16 %

Procedure:
0.65 g of (S)-α-amino-N-[(1S,2S,4RS)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]imidazole-4-propionamide in 20 ml of acetonitrile were added together with 0.36 ml of ethyldiisopropylamine to a solution of 0.45 g of 2-benzyl-3-phenylpropionic acid (which was prepared according to the method described in J. Am. Chem. Soc. 71 1863 (1949)) and 0.8 g of BOP in 30 ml of acetonitrile and the mixture was stirred at room temperature for 20 hours. Subsequently, the reaction mixture was evaporated under reduced pressure, the residue was dissolved in 50 ml of ethyl acetate and the organic solution was washed twice with 100 ml of water each time, dried over sodium sulfate and evaporated. The residue Was separated by flash chromatography on 100 g of silica gel with a 250:15 mixture of methylene chloride and methanol as the eluting agent, to obtain there was obtained 0.17 g of (S)-α-(2,2-dibenzylacetamido)-N-[(1S,2S,4S)-2 -hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]imidazole-4-propionamide as a white powder, melting point 120°. This compound corresponds to the less polar isomer and has a Rf value of 0.14.
Reaction SMILES: [CH:1]([O:3][C:4]([N:6]1[CH2:30][C@:29]2([C:31](=[O:34])[CH2:32][OH:33])[C@@H:8]([CH2:9][C@H:10]3[C@H:23]4[C@@:14]([F:27])([C@:15]5([CH3:26])[C:20]([C@@H:21]([F:24])[CH2:22]4)=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]5)[C@@H:13]([OH:28])[CH2:12][C@@:11]32[CH3:35])[CH2:7]1)=[O:5])=[CH2:2].[CH3:36][S:37](Cl)(=[O:39])=[O:38].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:1]([O:3][C:4]([N:6]1[CH2:30][C@:29]2([C:31](=[O:34])[CH2:32][O:33][S:37]([CH3:36])(=[O:39])=[O:38])[C@@H:8]([CH2:9][C@H:10]3[C@H:23]4[C@@:14]([F:27])([C@:15]5([CH3:26])[C:20]([C@@H:21]([F:24])[CH2:22]4)=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]5)[C@@H:13]([OH:28])[CH2:12][C@@:11]32[CH3:35])[CH2:7]1)=[O:5])=[CH2:2]
Reactant: C=COC(=O)N1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=COC(=O)N1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
A mixture of 164 (840 mg, 1.709 mmol), methansulfonyl chloride (160 μA, 2.051 mmol) and DIPEA (448 μl, 2.56 mmol) in DCM is stirred at RT under nitrogen overnight. The solution is partitioned between DCM and water, then the aqueous phase is extracted with DCM. The combined organic phases are washed with brine, dried over Na2SO4 and filtered. The solvent is evaporated to give the title compound (774 mg, 80% yield).
Reaction SMILES: [NH3:1].C(O[C:6]1[C:9](=[O:10])[C:8](=[O:11])[C:7]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=2)[O:15][C:14]([CH3:25])([CH3:24])[CH:13]=1)(C)C>C(#N)C>[NH2:1][C:6]1[C:9](=[O:10])[C:8](=[O:11])[C:7]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=2)[O:15][C:14]([CH3:24])([CH3:25])[CH:13]=1
Reactant: N
Reactant: CC(C)Oc1c(C2=CC(C)(C)Oc3ccc(C#N)cc32)c(=O)c1=O
Solvent: CC#N
Product: CC1(C)C=C(c2c(N)c(=O)c2=O)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
Ammonia gas was bubbled into a solution of 361 mg (1.12 mmol) of 4-(2-isopropoxy-3,4-dioxo-cyclobut-1-enyl)-2,2-dimethyl-2H-chromene-6-carbonitrile in acetonitrile (11 ml) for 30 min. The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with H2O (50 mL) and was extracted into 20% THF-CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4 and then concentrated and recrystallized from acetone-petroleum ether to give 110 mg of the title compound (35% yield), mp>250° C., as an off white solid: 1H-NMR (DMSO-d6 ; 400 MHz) δ9.18 (bs, 1H), 8.68 (bs, 1H), 7.79 (d, 1H), 7.67 (dd, 1H), 7.01 (d, 1H), 6.29 (s, 1H), and 1.47 ppm (s, 6H); IR (KBr) 3300, 3100, 1780, 1730, 1720, 1665, and 1610 cm-1 ; mass spectrum (PBEI), m/e 281 (M+H), 280 (M+), 252, and 209.
Reaction SMILES: [CH:1](/[C:9]1[N:10]=[CH:11][S:12][C:13]=1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:19][O:20][CH:21](OC)N(C)C>>[CH3:19][O:20]/[CH:21]=[C:14](\[C:13]1[S:12][CH:11]=[N:10][C:9]=1[CH:1]=[CH:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)/[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)Cc1scnc1/C=C/c1ccccc1
Agent: CO/C=C(/C(=O)OC)c1scnc1/C=C/c1ccccc1
Product: CO/C=C(/C(=O)OC)c1scnc1C=Cc1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 2.5 g of the product of Step A and 25 ml of dimethylformamide dimethyl acetal was heated to 50° C. and after 4 hours at this temperature, the mixture was allowed to return to 25° C. The reaction mixture was evaporated to dryness and the residue was dissolved in 30 ml of tetrahydrofuran and 5 ml of an aqueous solution of 2N hydrochloric acid. After standing for 2 hours at 25° C., the mixture was decanted followed by extraction with methylene chloride. The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. The residue was dissolved in 30 ml of acetone and 4 g of potassium carbonate and 6 ml of methyl iodide were added. The mixture was stirred for 16 hours at 20° to 25° C. and after filtering and evaporating to dryness, the residue was chromatographed on silica, eluting with a hexane-ethyl acetate mixture (7-3) to obtain 1.1 g of the desired product. Thin layer chromatography; Rf=0.17 [eluant: hexane-acetate of ethyl (7-3)].
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[CH:7][CH:6]=1)[NH2:4].CCN(C(C)C)C(C)C.[Br:28][CH2:29][CH2:30][CH2:31][C:32](Cl)=O>C(Cl)Cl>[Br:28][CH2:29][CH2:30][CH2:31][C:32]1[O:1][N:2]=[C:3]([C:5]2[CH:6]=[CH:7][C:8]([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)=[CH:9][CH:10]=2)[N:4]=1
Reactant: O=C(Cl)CCCBr
Reactant: NC(=NO)c1ccc(COC2CCCCO2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: BrCCCc1nc(-c2ccc(COC3CCCCO3)cc2)no1
Temperature: 0 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
To a solution of N′-hydroxy-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]benzenecarboximidamide (Intermediate 27; 211 mg, 0.84 mmol) in DCM (3 mL) was added DIEA (0.176 mL, 1.01 mmol). The mixture was cooled to 0° C. and a solution of 4-bromobutanoyl chloride (0.108 mL, 0.88 mmol) in DCM (1 mL) was added dropwise. The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the crude obtained was purified by column chromatography with silica gel, eluting with a mixture of Hexane:ether give the title compound as a solid (198 mg, 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[N:15]=[CH:14][C:13]([CH2:19]Cl)=[C:12]([Cl:21])[C:11]=3[CH:10]=[CH:9]2)=[CH:5][CH:4]=1>[Ni].O.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[N:15]=[CH:14][C:13]([CH3:19])=[C:12]([Cl:21])[C:11]=3[CH:10]=[CH:9]2)=[CH:22][CH:23]=1
Reactant: COc1ccc(Cn2ccc3c(Cl)c(CCl)cnc3c2=O)cc1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cn2ccc3c(Cl)c(C)cnc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Raney Nickel 2800, slurry in H2O, active catalyst (2.5 g, 43 mmol) (wet weight) was rinsed off with ethanol and added to a suspension of 7-(4-methoxybenzyl)-4-chloro-3-(chloromethyl)-1,7-naphthyridin-8(7H)-one (1.00 g, 2.9 mmol) in 50 ml of EtOH. The reaction was stirred at RT for 30 min and then filtered off through a small pad of celite. The filtrate was concentrated under reduced pressure to give 7-(4-methoxybenzyl)-4-chloro-3-methyl-1,7-naphthyridin-8(7H)-one as a clear film. MS (M+H)+ 315.
Reaction SMILES: [CH2:1]([C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([C:22]([OH:24])=O)=[CH:17][C:18]=3[CH2:19]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:27])=O>CN(C)C=O>[CH2:1]([C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([C:22]([Cl:27])=[O:24])=[CH:17][C:18]=3[CH2:19]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc2c(c1)Cc1cc(C(=O)O)ccc1-2
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc2c(c1)Cc1cc(C(=O)Cl)ccc1-2

Procedure:
To 0.70 g (2.17 mM) of 7-octyl-2-fluorenecarboxylic acid, 2.1 ml of thionyl chloride and a drop of N,N-dimethylformamide (DMF) were added, followed by heat-refluxing for 20 minutes under stirring. After the reaction, an excessive thionyl chloride was distilled-off under reduced pressure to obtain 7-octyl-2-fluorenecarbonyl chloride.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]4[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20][O:19][C:15]4=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:31]N1C(=O)CCC1=O.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)(Cl)Cl>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[Cl:31][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]3[O:19][CH2:20][CH2:21][NH:22][CH2:23][C:14]3=2)[N:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1ccccc1)n1cc(Cl)c2c3c(ccc21)OCCNC3
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl 8-(phenylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 17, 15 mg, 0.035 mmol) was dissolved in CHCl3 (2 mL) and N-chlorosuccinimide (7.0 mg, 0.053 mmol) was added. The mixture was heated at 70° C. overnight. The mixture was cooled to room temperature, TFA (1 mL) was added and the mixture was stirred for 10 minutes and evaporated. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound as a light yellow solid (4.1 mg) in the form of the trifluoroacetate salt. MS m/z 363 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=1[O:25][CH2:26][CH:27]1[CH2:29][O:28]1>>[Cl:22][C:23]1[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=1[O:25][CH2:26][CH:27]([OH:28])[CH2:29][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Clc1ccccc1OCC1CO1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC(O)COc3ccccc3Cl)CC1)O2

Procedure:
Compound 172 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-[(2-chlorophenoxy)methyl]oxirane and conditions outlined in procedure X. LCMS: 486 [M+H]; Rt=1.04 min.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][C:13]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16]>>[CH3:12][C:13]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:14]=1[C:15]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:16]
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: Cc1cc(C(F)(F)F)ccc1C(=O)O
Product: Cc1cc(C(F)(F)F)ccc1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, yellow gum, MS: m/e=341.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-methyl-4-trifluoromethyl-benzoic acid (CAS 23984-82-9).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([NH:28][C:29]3[N:34]=[C:33]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])[N:32]=[C:31]([NH:41][C:42]4[CH:64]=[CH:63][C:45]([C:46]([NH:48][CH2:49][CH:50]5[CH2:54][CH2:53][CH2:52][CH:51]5[NH:55][C:56](=[O:62])[C:57](OCC)=[O:58])=[O:47])=[CH:44][CH:43]=4)[N:30]=3)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1>CCO>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([NH:28][C:29]3[N:34]=[C:33]([O:35][CH2:36][C:37]([F:38])([F:39])[F:40])[N:32]=[C:31]([NH:41][C:42]4[CH:43]=[CH:44][C:45]([C:46]([NH:48][CH2:49][CH:50]5[CH2:54][CH2:53][CH2:52][CH:51]5[NH:55][C:56](=[O:62])[C:57]([NH:15][C:14]5[CH:16]=[CH:17][C:11]([F:10])=[CH:12][CH:13]=5)=[O:58])=[O:47])=[CH:63][CH:64]=4)[N:30]=3)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(=O)NC1CCCC1CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Reactant: Nc1ccc(F)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)cc1)C(=O)NC1CCCC1CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Temperature: 155 °C
Reaction time: 72 h

Procedure:
iPr2NEt (0.2 mL) and 4-fluoroaniline (39.2 mg) added into the solution of ethyl 2-((2-((4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)methyl)cyclopentyl)amino)-2-oxoacetate (40 mg) in EtOH (2 mL) and the reaction was stirred at 155° C. for 3 days. The product was isolated by preparative HPLC system.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[C:10]([CH3:23])=[C:11]([CH3:22])[C:12]2[O:16][C:15]([CH2:18][Br:19])([CH3:17])[CH2:14][C:13]=2[C:20]=1[CH3:21]>C(O)C.[C].[Pd]>[Br:19][CH2:18][C:15]1([CH3:17])[CH2:14][C:13]2[C:20]([CH3:21])=[CH:9][C:10]([CH3:23])=[C:11]([CH3:22])[C:12]=2[O:16]1
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)(CBr)O2
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(C)c2c(c1C)OC(C)(CBr)C2
Yield: 92.2 %

Procedure:
Triethylamine (5.0 ml, 35.6 mmol) was added to a solution of 5-bromo-2-bromomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (12.4 g, 35.6 mmol) in ethanol (100 ml). Catalytic hydrogenation decomposition reaction was carried out on 5% palladium carbon under a hydrogen atmosphere. After the completion of the reaction, the catalyst was filtered and the filtrate was concentrated. The residue was dissolved in isopropyl ether, washed with water, dried and the solvent was distilled off. The residue was crystallized from methanol to obtain the desired compound (8.84 g, yield: 92.2%), m.p. 39°-40° C.
Reaction SMILES: [NH2:1][C:2]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:14][C:15](=[CH2:18])[CH:16]=O>C(O)(=O)C>[CH3:18][C:15]1[CH:14]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:1][CH:16]=1
Reactant: C=C(C)C=O
Reactant: CCOC(=O)C=C(N)C(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C)cnc1C(=O)OCC
Temperature: 80 °C
Yield: 28.7 %

Procedure:
Ethyl β-amino-β-ethoxycarbonylacrylate 18.7 g (0.1 mol), 2-methyl-2-propenal 7.5 g (0.107 mol), and glacial acetic acid 50 g were placed in a 100 ml four neck distillation flask with a reflux condenser and the temperature of the mixture was raised to 80° C. on an oil bath over a period of 1 hour. Then, the mixture was reacted at 80° to 85° C. for 5 hours. After completion of the reaction, the reaction mixture was distilled to give 6.8 g of 5-methyl-2,3-diethoxycarbonylpyridine (bp3.5 : 160° to 161° C.).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]([CH3:22])=[N:20][N:21]=2)=[CH:13][C:12]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=1.[CH2:32]([N:34]([CH2:39][CH3:40])[CH2:35][CH2:36][CH2:37][NH2:38])[CH3:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:32]([N:34]([CH2:39][CH3:40])[CH2:35][CH2:36][CH2:37][NH:38][C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:12]2[CH:13]=[C:14]([C:17]3[O:18][C:19]([CH3:22])=[N:20][N:21]=3)[CH:15]=[CH:16][C:11]=2[CH3:10])=[CH:28][CH:27]=1)=[O:30])[CH3:33]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: CCN(CC)CCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCCNC(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 66 h
Yield: 63.7 %

Procedure:
DIPEA (130 μl, 1.0 mmol) was added to a solution of 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (100 mg, 0.34 mmol), 3-diethylaminopropylamine (49 mg, 0.37 mmol), HBTU (155 mg, 0.41 mmol) and HOBT (46 mg, 0.34 mmol) in DMF (1.0 ml). The reaction was stirred at room temperature for 66 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (5 ml) and water (5 ml) The organic phase was absorbed onto a silica flash column and eluted with DCM/ethanol/ammonia (100:8:1). The product fractions were concentrated under vacuum to give N-[3-(diethylamino)propyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide (88 mg, 64%).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:53]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[C:55]([C:63]2[CH:64]=[C:65]([NH2:69])[CH:66]=[CH:67][CH:68]=2)[CH:54]=1>CN(C=O)C>[N:53]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[C:55]([C:63]2[CH:64]=[C:65]([NH:69][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:66]=[CH:67][CH:68]=2)[CH:54]=1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: Nc1cccc(-c2cnc3ccccc3c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cnc3ccccc3c2)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 67.9 %

Procedure:
DIEA (0.013 mL, 0.075 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.019 g, 0.068 mmol) and HATU (0.028 g, 0.075 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-quinolin-3-yl-phenylamine (0.015 g, 0.068 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.022 g of product in 68% yield: LCMS (ESI) m/z 477 (MH+).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:5][CH:4]=1)=O.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C:14]1=[O:22].N1CCCC1>C(O)C>[C:3]1([CH:1]=[C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:13][C:14]2=[O:22])[C:12]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc2cccccc1-2
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNC1
Product: O=C1Nc2ccccc2C1=Cc1ccc2cccccc1-2
Yield: 101.7 %

Procedure:
1-Formylazulene (2 mmol) was dissolved in 40 mL ethanol. 266 mg oxindole (2 mmol) and 200 mL ethanol were then added. Next, a 4 mL solution containing 1M pyrrolidine and ethanol was added to react at room temperature for three days. After removal of solvent, the resulting solution was extracted by 150 mL acetyl acetate and 50 mL water. The resulting solution was extracted again by 50 mL citric acid aqueous solution and ethyl acetate. The ethyl acetate layer was collected, dried with anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was then purified by column chromatography (Silica Gel 60, dichloromethane) and dried to give Compound 001 (552 mg, 95%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].IC.[C:33](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][N:17]([CH3:33])[S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Agent: [Cs+]
Solvent: CI
Solvent: CC(=O)N(C)C
Product: CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1C(F)(F)F

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with iodomethane and cesium carbonate in N,N-dimethylacetamide to give N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-N-methyl-2-trifluoromethyl-benzenesulfonamide as a light yellow semi-solid. MS: 506.9 ([M+H]+)
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[I-].[Na+].CCOCC>COCCOC>[NH:24]1[C:25]2[C:21](=[CH:20][CH:19]=[C:18]([NH:17][C:9]3[C:8]4[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:33]5[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]5)=[C:6]([O:27][CH3:28])[CH:7]=4)[N:12]=[CH:11][C:10]=3[C:15]#[N:16])[CH:26]=2)[CH:22]=[N:23]1
Reactant: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Reactant: CN1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCN1CCN(C)CC1
Temperature: 135 °C
Yield: 51.5 %

Procedure:
A reaction mixture of 196.5 mg (0.5 mmol) of the 7-(2-chloro-ethoxy)-4-(1H-indazol-6-ylamino)-6-methoxy-quinoline-3-carbonitrile, 500.9 mg (5 mmol) of 1-methylpiperazine and 74.5 mg (0.5 mmol) of sodium iodide in 10 mL of DME was heated at 135° C. for 15 hr under N2 in a sealed tube. After cooling, the solvent was removed and the residue was taken into 15 mL of brine. The aqueous solution was extracted with 15% methanol/methylene chloride. The organic solvent was dried over Na2SO4 and filtered. Removal of the solvent gave the crude product solid. Purification of the crude product on preparative TLC (developing solvent: 15% methanol/methylene chloride) to give a yellow foam solid. Trituration of the foam solid with ether yielded 117.9 mg (51.6%) of the product as a yellow solid, m.p. 179° C. (dec.), mass (electrospray, m/e): M+H 458.0.