Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15]([OH:25])(=[O:24])[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH2:17]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([OH:25])=[O:24])[CH2:11][CH2:10]1
Reactant: C=C(C(=O)O)c1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCO
Product: COc1ccccc1N1CCN(CC(C(=O)O)c2ccccc2)CC1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
1-(2-Methoxyphenyl)piperazine (22.6 g, 0.118 mol) and atropic acid (174 g, 0.118 mol) in ethanol (300 ml) were heated under reflux for 18 hours, cooled to room temperature, and evaporated in vacuo. The solid was triturated with acetone (3×100 ml) to give a first crop of product (13.8 g) as white crystals. The filtrate was evaporated in vacuo to give an oil which slowly crystallised over 1 month. The solid was triturated with acetone (200 ml) to give a second crop of the hemihydrate of the product (9.01 g) as white crystals, m.p. 160°-163°.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](Cl)[N:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].Cl.Cl.[CH2:21]([N:23]1[CH2:27][CH2:26][C:25]2([CH2:31][CH2:30][NH:29][CH2:28]2)[CH2:24]1)[CH3:22]>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:29]3[CH2:30][CH2:31][C:25]4([CH2:26][CH2:27][N:23]([CH2:21][CH3:22])[CH2:24]4)[CH2:28]3)[N:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: CCN1CCC2(CCNC2)C1
Agent: Cl
Product: CCN1CCC2(CCN(c3nc4c(cc3F)c(=O)c(C(=O)O)cn4CC)C2)C1

Procedure:
The title compound was prepared according to example 24 by reacting 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid with 2-ethyl-2,7diazaspiro[4.4]nonane dihydrochloride; mp 215°-217° C. (dec).
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH:24]([CH3:33])[CH2:25][S:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]=[C:35]=[O:36]>C1(C)C=CC=CC=1>[C:35]([C:10](=[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:24]([CH3:33])[CH2:25][S:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)=[O:12])(=[O:36])[CH3:34]
Reactant: CC(CSc1ccccc1)C(=CC(=O)OCc1ccc([N+](=O)[O-])cc1)NCc1ccccc1
Reactant: C=C=O
Solvent: Cc1ccccc1
Product: CC(=O)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=C(NCc1ccccc1)C(C)CSc1ccccc1

Procedure:
p-Nitrobenzyl 3-benzylamino-4-methyl-5-phenylthio-2-pentenoate (505 mg; 1 mmole) was dissolved in toluene (5 ml), and gaseous ketene was introduced therein at room temperature. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give p-nitrobenzyl 2-acetyl-3-benzylamino-4-methyl-5-phenylthio-2-pentenoate.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)C=[C:9]1C(O)=O>C(Cl)Cl>[CH3:9][N:8]1[C:16]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:1]([C:2]([Cl:4])=[O:3])=[CH:7]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1c(C(=O)O)cc2ccccc21
Solvent: ClCCl
Product: Cn1cc(C(=O)Cl)c2ccccc21
Temperature: 25 °C

Procedure:
Oxalyl chloride (7.1 mL, 81.4 mmol) in 50 mL of methylene chloride was added under nitrogen dropwise to a solution of 1-methyl-1H-indole carboxylic acid (2.86 g, 16.3 mmol) in 100 mL of methylene chloride at room temperature. After the addition the reaction was stirred at room temperature until the reaction was determined by NMR analysis to be complete. The solvent and excess oxalyl chloride were removed under reduced pressure. The residue was taken up in benzene and then concentrated to dryness under reduced pressure to give 1-methyl-1H-indole-3-carbonyl chloride, which was used in the following reaction without purification.
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]([CH:14]([CH3:16])[CH3:15])=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[CH:17]([CH3:19])[CH3:18])(=[O:3])[CH3:2].S(Cl)([Cl:22])=O>CN(C=O)C>[C:1]([O:4][C:5]1[C:13]([CH:14]([CH3:16])[CH3:15])=[CH:12][C:8]([C:9]([Cl:22])=[O:10])=[CH:7][C:6]=1[CH:17]([CH3:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Solvent: CN(C)C=O
Product: CC(=O)Oc1c(C(C)C)cc(C(=O)Cl)cc1C(C)C

Procedure:
A mixture of 4-acetoxy-3,5-diisopropylbenzoic acid (634 mg), thionyl chloride (3 ml) and DMF (1 drop) was refluxed for 40 minutes, concentrated and evaporated to obtain 4-acetoxy-3,5-diisopropylbenzoyl chloride. The resultant was dissolved in dichloromethane (20 ml), to which 3-amino-4-(2-chlorophenyl)-6,8-dimethylquinoline (566 mg) and triethylamine (0.30 ml) were added. Thus obtained solution was stirred at room temperature for one night. After dilution with water, the solution was extracted with dichloromethane. The dichloromethane layer was washed with 2N-hydrochloric acid and water, and then dried (MgSO4). The solvent was removed and the residue was recrystallized from ethanol to obtain 3-(4-acetoxy-3,5-diisopropylbenzamido)-4-(2-chlorophenyl)-6,8-dimethylquinoline (815 mg, 77.0%) as colorless prisms.
Reaction SMILES: [C:1]([N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)(=[O:4])[CH:2]=[CH2:3].[CH2:16]([NH:23][CH3:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]([CH2:3][CH2:2][C:1]([N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4])[CH3:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNCc1ccccc1
Reactant: C=CC(=O)N(C)c1ccc([N+](=O)[O-])cc1
Product: CN(CCC(=O)N(C)c1ccc([N+](=O)[O-])cc1)Cc1ccccc1

Procedure:
Prepared from N-acryloyl-N-methyl-4-nitro-aniline and N-benzyl-N-methyl-amine
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([S:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]4[CH2:27][CH2:26]4)=[O:24])=[CH:18][CH:17]=3)[N:9]=2)=[N:4][CH:3]=1.Cl.Cl.[CH3:30][N:31]([CH3:36])[CH:32]1[CH2:35][NH:34][CH2:33]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[C:12]([N:34]3[CH2:35][CH:32]([N:31]([CH3:36])[CH3:30])[CH2:33]3)[N:11]=[C:10]([S:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]4[CH2:27][CH2:26]4)=[O:24])=[CH:18][CH:17]=3)[N:9]=2)=[N:4][CH:3]=1
Reactant: CN(C)C1CNC1
Reactant: Cc1cnc(Nc2cc(Cl)nc(Sc3ccc(NC(=O)C4CC4)cc3)n2)s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cnc(Nc2cc(N3CC(N(C)C)C3)nc(Sc3ccc(NC(=O)C4CC4)cc3)n2)s1
Temperature: 90 °C
Yield: 66.7 %

Procedure:
A suspension of N-(4-(4-(5-methylthiazol-2-ylamino)-6-chloropyrimidin-2-ylthio)phenyl)cyclopropanecarboxamide (138 mg, 0.33 mmol), 3-dimethylaminoazetidine dihydrochloride (178 mg, 1.0 mmol), N,N-diisopropylethylamine (0.34 ml, 1.98 mmol) in n-butanol (10 ml) was heated at 90° C. for 17 h. Reaction mixture was then allowed to cool to room temperature, concentrated in vacuo. The crude product was purified on HPLC to give the title compound as an off-white solid (106 mg, 58%). 1H NMR (DMSO) 0.82-0.81 (4H, m), 1.87-1.81 (1H, m), 2.07 (3H, s), 2.78-2.77 (6H, m), 4.20 (5H, s), 5.56 (1H, s), 6.94 (1H, s), 7.52 (2H, d), 7.76 (2H, d), 10.55 (1H, s) MS(ES+): 482.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:13]3[CH2:14][CH2:15][CH:9]2[CH2:10][NH:11][CH2:12]3)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>ClCCl>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([N:11]2[CH2:12][CH:13]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[CH:9]([CH2:15][CH2:14]3)[CH2:10]2)=[O:28])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: Clc1cccnc1N1C2CCC1CNC2
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)N2CC3CCC(C2)N3c2ncccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8-(3-Chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octane (102 mg, 456 μmol) and 1-tert-butyl-4-isocyanatobenzene (80 mg, 456 μmol) were combined in dry dichloromethane (4.5 mL) and stirred overnight at room temperature. The mixture was concentrated and the residue was purified by chromatography on silica gel (7:3, hexanes:ethyl acetate) to provide the title compound. MS (ESI) m/z: 399 (M+H)+; 1H NMR (DMSO-d6) δ 1.25 (s, 9H), 1.73 (m, 2H), 1.85 (m, 2H), 3.20 (dd, 2H), 3.92 (dd, 2H), 4.51 (dd, 2H), 6.94 (dd, 1H), 7.24 (d, 2H), 7.37 (d, 2H), 7.79 (dd, 1H), 8.17 (dd, 1H), 8.30 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][N:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]([C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])=[CH:28]3)=[CH:20][CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.C(Cl)Cl.Cl>CO>[NH2:7][C:8]([CH2:9][OH:10])([CH2:13][OH:12])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([C:36](=[O:41])[C:37]([F:38])([F:39])[F:40])=[CH:28]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(CCCn3cc(C(=O)C(F)(F)F)c4ccccc43)cc2)COC(C)(C)OC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: NC(CO)(CO)CCc1ccc(CCCn2cc(C(=O)C(F)(F)F)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of the product of Step E (0.15 g, 0.03 mmol) in a mixture of MeOH, CH2Cl2 and 30% HCl (1 ml, 3 ml, 15 drops respectively) was stirred at room temperature for 3 h. The solvent was distilled and co-distilled with iso-propanol (iPrOH), to give the product (0.01 g; 69%), as colourless solid. 1H-NMR (CDCl3) 1.89-1.92 (m, 2H); 2.12-2.22 (m, 2H); 2.53-2.61 (b, 4H); 3.65-3.75 (m, 4H); 4.13 (tr, 2H, J=7.02 Hz); 6.97 (d, 2H, J=7.71 Hz); 7.07 (d, 2H, J=7.8 Hz); 7.28-7.32 (m, 3H); 7.82 (s, 1H); 8.28-8.31 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][CH:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:33](Cl)=[O:34]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:31][CH:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:33]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1)=[O:34]
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
To a solution of 0.61 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 8 ml of methylene chloride is added 0.30 g of triethylamine followed by 0.47 g of (±)-2-chloro-2-phenylacetyl chloride in 2 ml of methylene chloride. The mixture is stirred at room temperature for 1 hour and then diluted with 10 ml of 50% NaHCO3. The methylene chloride is evaporated and the residue is extracted with ethyl acetate. The separated organic layer is washed with saturated NaHCO3 and brine and then dried with Na2SO4 followed by filtering through a pad of hydrous magnesium silicate. The filtrate is evaporated to a residue which is stirred with ether-hexane to give 0.98 g of pink solid. MS(CI):456(M+H).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:18]=[C:17]([C:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])([O-:8])=[O:7].[CH2:22]=[C:23]([CH3:25])[CH3:24]>O1CCOCC1.CCOC(C)=O>[CH3:14][O:13][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][C:17]([C:19]([O:21][C:23]([CH3:25])([CH3:24])[CH3:22])=[O:20])=[CH:18][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: C=C(C)C
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 120 h
Yield: 73 %

Procedure:
Sulfuric acid conc (5 ml) was added to a solution of 1-methyl 2-nitroterephthalate (25.2 g, 0.112 mmol) in dioxane (120 ml) in a Parr shaker bottle and cooled to 0° C. Isobutene (100 ml) was added, the vessel was sealed, and vigorously shaken for 5 days. The crude product was dissolved in EtOAc after evaporation of the excess isobutene and washed with sat NaHCO3. The organic layer was dried over MgSO4, filtered, and evaporated leaving 23.0 g (73%) of 2-nitroterephthalic acid 4-tert-butyl ester 1-methyl ester as a yellow liquid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH:4]1([N:7]([CH:34]2[CH2:36][CH2:35]2)[C:8]([C:10]2[N:31]([CH2:32][CH3:33])[C:13]3=[N:14][C:15]([NH:22][C:23]4[S:24][C:25]([C:28]([OH:30])=O)=[CH:26][N:27]=4)=[C:16]4[N:20]=[CH:19][N:18]([CH3:21])[C:17]4=[C:12]3[CH:11]=2)=[O:9])[CH2:6][CH2:5]1>>[CH:4]1([N:7]([CH:34]2[CH2:35][CH2:36]2)[C:8]([C:10]2[N:31]([CH2:32][CH3:33])[C:13]3=[N:14][C:15]([NH:22][C:23]4[S:24][C:25]([C:28]([N:2]([CH3:3])[CH3:1])=[O:30])=[CH:26][N:27]=4)=[C:16]4[N:20]=[CH:19][N:18]([CH3:21])[C:17]4=[C:12]3[CH:11]=2)=[O:9])[CH2:6][CH2:5]1
Reactant: CNC
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C(=O)O)s3)nc21
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C(=O)N(C)C)s3)nc21

Procedure:
This compound was prepared according to Example 20 using N,N-dimethylamine and 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)thiazole-5-carboxylic acid (example 20A) to give 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-N,N-dimethylthiazole-5-carboxamide.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][C:29]([NH:32][S:33]([C:36]1[S:37][C:38]([CH3:42])=[C:39]([NH2:41])[CH:40]=1)(=[O:35])=[O:34])([CH3:31])[CH3:30]>>[OH:27][CH2:28][C:29]([NH:32][S:33]([C:36]1[S:37][C:38]([CH3:42])=[C:39]([NH:41][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:25])([F:26])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:40]=1)(=[O:35])=[O:34])([CH3:31])[CH3:30]
Reactant: Cc1sc(S(=O)(=O)NC(C)(C)CO)cc1N
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1sc(S(=O)(=O)NC(C)(C)CO)cc1NC(=O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 4-amino-5-methyl-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.12) according to general procedure II. Yellow solid. MS (ISP) 620.3 [(M−H)−]; mp 225° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:6][C:7]1[C:8]([C:5]#[C:4][CH2:3][NH:2][CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCNC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNCC#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, N-methylpropargylamine (44.9 mg, 0.65 mmol) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.26 mmol) (Starting Matenal 6, supra) using (Ph3P)4Pd (32 mg) and CuI (5.3 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 18 h to yield (Z)-1,3-Dihydro-5-fluoro-4-[3-(N-methylamino)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 10 mg, 12%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:13]([C:14]([O:16]C)=[O:15])=[C:12]([CH2:18][O:19][CH3:20])[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].O.[OH-].[Li+]>C1COCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH2:18][O:19][CH3:20])[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COCc1onc(-c2cccc(C#N)c2)c1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCc1onc(-c2cccc(C#N)c2)c1C(=O)O
Reaction time: 24 h
Yield: 75.6 %

Procedure:
Methyl 3-(3-cyanophenyl)-5-(methoxymethyl)isoxazole-4-carboxylate (1.12 g, 4.1 mmol) was dissolved in 3 mL THF and 1 mL water. Lithium hydroxide monohydrate (0.20 g, 4.9 mmol) was added and the reaction was allowed to stir for 24 hours under N2. The solvent was removed in vacuo and redissolved in 100 mL of water. The resulting solution was extracted with 30 mL EtOAc twice then acidified with 1N HCl to pH 3. The acidic solution was extracted three times with 30 mL of EtOAc. The combined organic were dried with MgSO4 and concentrated in vacuo to give the desired white solid (0.80 g, 75%). 1H NMR (CDCl3) δ: 7.98 (m, 1H); 7.91 (dd, J=8.1, 2.9, 1H); 7.79 (dd, J=8.1 , 2.9, 1H); 7.59 (t, J=8.1, 1H); 4.89 (s, 2H); 3.53 (s, 3H).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][CH2:11][C:12]([NH:14][N:15]1[C:19]([C:20]([NH2:22])=[O:21])=[CH:18][N:17]=[CH:16]1)=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.CCO>[CH2:3]([O:10][CH2:11][C:12]1[NH:22][C:20](=[O:21])[C:19]2=[CH:18][N:17]=[CH:16][N:15]2[N:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NC(=O)c1cncn1NC(=O)COCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=c1[nH]c(COCc2ccccc2)nn2cncc12
Temperature: 110 °C
Yield: 71.9 %

Procedure:
A solution of KOH (4.4 g, 78.5 mmol) in water (50 mL) was added dropwise to a solution of compound 3 (7.3 g, 26.6 mmol) in EtOH (60 mL) at room temperature. The resulting solution was heated to 110° C. for 3 hours. After removal of the organic solvent, the mixture was poured into ice water and the pH was adjusted to 7.0 with 1M aqueous HCl solution. The suspension was filtered and the filtrate was dried to afford compound 4 (4.9 g, 71% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.05 (s, 1H), 8.45 (s, 1H), 7.74 (s, 1H), 7.39˜7.29 (m, 5H), 4.59 (s, 2H), 4.36 (s, 2H). LC-MS: m/z 257.2 [M+H]+.
Reaction SMILES: [Li+].[OH-:2].Cl.[CH2:4]1[CH2:8][O:7][CH2:6][CH2:5]1>CO>[C:4]1(=[CH:5][C:6]([OH:2])=[O:7])[CH2:8][CH2:6][CH2:5][CH2:4][CH2:8]1
Reactant: C1CCOC1
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: CO
Product: O=C(O)C=C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude intermediate 23 was dissolved in 15 mL THF and 15 mL methanol. 30 mL aqueous 1N LiOH solution was added, and it was stirred at ambient temperature overnight. The next day, pH of the reaction system was adjusted to 1 with 6N hydrochloric acid, and the reaction mixture was extracted with ethyl acetate three times, and the ethyl acetate layers were combined and washed with water once, saturated aqueous NaCl solution once, dried over anhydrous MgSO4 for 2 hours, filtrated, and the filtrate was dried under vacuum to give 0.796 g of oily crude title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.Cl.[CH3:26][NH2:27]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:27][CH3:26])=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1
Reactant: CN
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: CNC(=O)c1ccc(OC)c(/C=C/c2ccc(OC(F)(F)F)cc2)c1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and methylamine hydrochloride in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [ClH:1].[C:2]1([C:8]2([CH2:14][O:15][CH:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=3)[CH2:17][OH:18])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>>[ClH:1].[C:2]1([C:8]2([CH2:14][O:15][CH:16]([C:19]3[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[C:21]([C:29]([F:32])([F:30])[F:31])[CH:20]=3)[CH2:17][O:18][CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)CBr
Agent: Cl
Product: COC(=O)COCC(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
This was prepared in a similar manner as Example 2 using the compound of Example 1 (d) and methyl bromoacetate. 1H NMR (360 MHz, d6 -DMSO) δ7.98 (1H, s), 7.75 (2H, s), 7.41-7.24 (5H, m), 4.68 (1H, t, J=5 Hz), 4.11 (2H, s), 3.62 (3H, s), 3.69-3.30 (4H, m), 3.29-3.10 (2H, m), 2.78-2.60 (2H, m), 2.39-2.00 (4H, m). MS (Cl+) 520 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[NH3:21]>>[NH2:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: N
Reactant: CCOC(=O)c1cnc2ccc(OC(C)C)cc2c1Cl
Product: CCOC(=O)c1cnc2ccc(OC(C)C)cc2c1N

Procedure:
Prepared as in Example 1a from ethyl 4-chloro-6-isopropoxyquinoline-3-carboxylate (Example 10b) and ammonia as an off white solid (75%). MS 275 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:14][N:13]=[C:12]([CH:15]([O:31]C(OCC)C)[CH:16]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:21][CH:20]=3)[O:17][CH3:18])[N:11]=2)=[CH:4][C:3]=1[O:37][CH3:38].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[Br:1][C:2]1[C:3]([O:37][CH3:38])=[CH:4][C:5]([C:10]2[O:14][N:13]=[C:12]([CH:15]([OH:31])[CH:16]([O:17][CH3:18])[C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:21][CH:20]=3)[N:11]=2)=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCOC(C)OC(c1noc(-c2cc(OC)c(Br)c(OC)c2)n1)C(OC)c1ccc(N2CCOCC2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COc1cc(-c2nc(C(O)C(OC)c3ccc(N4CCOCC4)cc3)no2)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 79 %

Procedure:
To a solution of 4-(4-(2-(5-(4-bromo-3,5-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-(1-ethoxyethoxy)-1-methoxyethyl)phenyl)morpholine (0.335 g, 0.57 mmol) in MeOH (15 mL) was added pyridinium para-toluenesulfonate (0.15 g, 0.6 mmol) and the mixture was stirred at room temperature for 16.5 hrs. The reaction was then heated at 40° C. for 6 hrs, cooled to room temp, and concentrated in vacuo. The residue was dissolved in EtOAc and washed with H2O, saturated NaHCO3 and brine then dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (50-60% EtOAc-hexanes) gave 1-(5-(4-bromo-3,5-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-methoxy-2-(4-morpholinophenyl)ethanol as a colorless residue (0.234, 79% yield).