Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:12]([CH3:19])=[N+:13]([O-])[CH:14]=[C:15]([CH3:17])[N:16]=1.O=P(Cl)(Cl)[Cl:22]>CN(C=O)C>[Cl:22][C:14]1[C:15]([CH3:17])=[N:16][C:11]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])=[C:12]([CH3:19])[N:13]=1
Reactant: COc1ccc(-c2nc(C)c[n+]([O-])c2C)c(OC)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(C)c(Cl)nc2C)c(OC)c1

Procedure:
The product from step 2 (444 mg) is dissolved in POCl3 (1 mL) and DMF (N,N-dimethylformamide, 15 mL), and the resulting solution is stirred at 60° C. for 5 hours. The reaction mixture is cooled, and the volatiles removed under reduced pressure. Flash chromatography (30% ethyl acetate in hexanes) affords 2-chloro-5-(2,4-dimethoxy-phenyl)-3,6-dimethyl-pyrazine as a clear oil. MS: 279.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[CH:25]=[C:24]([CH2:26][CH2:27][C:28]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:29])[NH:23][C:22]=1[CH:37]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:37][C:22]4[NH:23][C:24]([CH2:26][CH2:27][C:28]([N:30]5[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]5)=[O:29])=[CH:25][C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1cc(CCC(=O)N2CCN(C)CC2)[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(CCC(=O)N2CCN(C)CC2)[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 65 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3-methyl-5-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrole-2-carbaldehyde (79 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred in an oil bath at 65° C. for 2 hours. The reaction was cooled at room temperature for overnight. The precipitate was collected by vacuum filtration, washed with ethanol (5×) and dried to give 88.9 mg (68%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.15 (s, 1H, NH), 11.55 (br s, 1H, NH), 9.08 (s, 1H), 8.27 (s, 1H), 7.69 (dd, J=2.5 & 6.9 Hz, 1H), 7.30-7.40 (m, 3H), 6.08 (d, J=2.23 Hz, 1H), 3.43 (m, 4H, 2×CH2), 2.89 (t, J=7.4 Hz, 2H, CH2), 2.68 (t, J=7.4 Hz, 2H, CH2), 2.24 (m, 4H, 2×CH2), 2.16 (s, 6H, 2×CH3). MS 524 [M++1].
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8].[Cl-].CN1[C:19](=[O:20])N(C)CCC1.C1[CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:26][O:25][CH2:24][CH2:23][O:3][C:4]1[C:5]([O:20][CH3:19])=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8]
Reactant: CN1CCCN(C)C1=O
Reactant: C1CCOC1
Reactant: N#Cc1cccc(O)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Product: COCCOc1cccc(C#N)c1OC
Reaction time: 3 h

Procedure:
To a cooled (0° C.) suspension of sodium hydride (840 mg, 60% dispersion in mineral oil, 21 mmol) in THF (20 mL) is added a solution comprising 3-hydroxy-benzonitrile (2.4 g, 20 mmol), MEM Chloride (2.25 mL, 20 mmol) and DMPU (2 mL) in THF (20 mL). On complete addition, the cold bath is removed and stirring continued for 3 h. The reaction mixture is then diluted with ether, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 30% ethyl acetate 10% dichloromethane in hexane) to give the title compound as an oil. MS (ESI) 207 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([C:23](=[O:26])[CH2:24]Cl)[CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][NH:15][CH2:24][C:23]2=[O:26])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(C)(C)OC(=O)NCCN(CCc1ccc(C#N)c(Br)c1)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(CCN2CCNCC2=O)cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-Butyl (2-{[2-(3-bromo-4-cyanophenyl)ethyl](chloroacetyl)amino}ethyl)carbamate (530 mg, 1.2 mmol) in 5 mL of DCM was added 2 mL of TFA and the mixture was stirred at RT for 3 hours, then concentrated in vacuo. The residue was redissolved in ethanol (2 mL) and added K2CO3 (169 mg, 1.22 mmol). The mixture was stirred at reflux for 1.5 hours. Then water (10 ml) was added, and the mixture was extracted with ethyl acetate (5 mL×3), dried over Na2SO4 and concentrated in vacuo to give the title product. 1H-NMR (400 MHz, CD3CN) δ 7.68-7.70 (m, 2H), 7.39 (dd, J=1.6, 7.6 Hz, 1H), 3.55 (t, J=5.6 Hz, 2H), 3.27 (s, 2H), 3.18 (t, J=5.6 Hz, 2H), 2.88-2.92 (m, 4H). MS m/z: 308 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.Cl.[CH2:20]([NH:27][NH2:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:27]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:28]=1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Oc1ccccc1-c1nc(-c2ccccc2O)n(Cc2ccccc2)n1

Procedure:
5.0 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one are boiled under reflux for 4 h with 3.4 benzylhydrazine hydrochloride and 5.9 ml of triethylamine in 50 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying, 3,5-bis(2-hydroxyphenyl)-1-benzyl-1H-[1,2,4]triazole remains as colorless crystals of m.p. 166-168° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[N:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[C:32]1([S:42]([NH2:45])(=[O:44])=[O:43])[CH:37]=[CH:36][CH:35]=[C:34]([S:38]([NH2:41])(=[O:40])=[O:39])[CH:33]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[N:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:45][S:42]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([S:38]([NH2:41])(=[O:40])=[O:39])[CH:33]=3)(=[O:44])=[O:43])=[O:31])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cn2)c(C)c1-c1ccccc1
Reactant: NS(=O)(=O)c1cccc(S(N)(=O)=O)c1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3cccc(S(N)(=O)=O)c3)cn2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[6-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)pyridin-3-yl]ethylcarbamate (step 5 of Example 83) and 1,3-benzenedisulfonamide: 1H-NMR (CDCl3) δ 8.48-8.43 (1H, m), 8.10-7.76 (3H, m), 7.48-7.20 (8H, m), 6.61 (1H, br.s), 3.43-3.24 (2H, m), 2.73-2.59 (2H, m), 2.37 (3H, s), 2.25 (3H, s).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:11](=[O:12])[CH2:10][CH:9]([CH3:13])[C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=2[CH2:6]1)#[N:2].[C:18](OC(=O)C)(=[O:20])[CH3:19].C([O-])(=O)C.[Na+]>>[C:18]([NH:2][CH2:1][CH2:3][CH2:4][N:5]1[C:11](=[O:12])[CH2:10][CH:9]([CH3:13])[C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=2[CH2:6]1)(=[O:20])[CH3:19]
Reactant: CC1CC(=O)N(CCC#N)Cc2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)NCCCN1Cc2ccccc2C(C)CC1=O
Reaction time: 4 h
Yield: 74 %

Procedure:
A solution of 8 g. (0.034 moles) of 2-(2-cyanoethyl)-5-methyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one in 220 ml. of acetic anhydride is introduced into a 2-liter autoclave, 12 g. of anhydrous sodium acetate and approximately 5 g. of W-5 -Raney nickel, washed twice with 20 ml. of acetic anhydride, are added thereto. The reaction mixture is brought to a temperature of 50° C. and then stirred for 4 hours under a hydrogen pressure (initial pressure of 3.5 bars). The reaction mixture is filtered, the catalyst is washed with a little acetic anhydride and the solvent is evaporated in vacuo. The residual oil is suspended in water and the pH of the mixture is adjusted to 8 by the addition of aqueous sodium hydroxide solution. It is extracted with chloroform and the organic phase is washed with water and dried over anhydrous sodium sulfate. The syrup obtained after filtration and evaporation of the solvent in vacuo is purified by chromatography on a silica column. 7 g. (74% of theory) of syrupy 2-(3-acetamidopropyl)-5-methyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.[OH-].[Li+].S(OC)(O[CH3:18])(=O)=O>C1COCC1.C(OCC)C>[CH3:18][O:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COS(=O)(=O)OC
Reactant: Cc1ccc(C#N)c(O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)ccc1C#N
Temperature: 25 °C
Yield: 89.5 %

Procedure:
To a solution of 2-Hydroxy-4-methylbenzonitrile (0.46 g, 3.46 mmol) in THF (17 mL) was added lithium hydroxide monohydrate (0.292 g, 6.95 mmol) followed by dimethyl sulfate (0.50 mL, 5.28 mmol). The resultant mixture was heated to reflux for 2 hours then cooled to room temperature. The mixture was diluted with diethyl ether (50 mL), washed with saturated aqueous NaHCO3 (3×15 mL), dried (MgSO4) and concentrated. Purification of the crude material by column chromatography on silica gel (4:1 hexanes-EtOAc) provided 0.456 g (90%) of 2-methoxy-4-methylbenzonitrile as a white solid. 1H NMR (CDCl3) δ 2.41 (s, 3H), 3.91 (s, 3H), 6.77 (s, 1H), 6.81 (d, 1H, J=6Hz), 7.43 (d, 1H, J=6 Hz). ES-MS m/z 148 (M+H).
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH2:8][CH2:9][C@H:10]([OH:13])[CH2:11][OH:12])[C:6]#[CH:7])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[C:1]([O:4][C@@H:5]([CH2:8][CH2:9][C@H:10]([OH:13])[CH2:11][O:12][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[C:6]#[CH:7])(=[O:3])[CH3:2]
Reactant: C#C[C@H](CC[C@H](O)CO)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#C[C@H](CC[C@H](O)COS(=O)(=O)c1ccc(C)cc1)OC(C)=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 10 %

Procedure:
A solution of(3S,6S)-3-acetoxy-6,7-dihydroxy-hept-1-yne 14 (4.3 g, 23.1 mmol) in CH2Cl2 (50 mL) containing pyridine (3.7 mL, 46.2 mmol) was cooled to 0° C. and treated with p-toluene sulfonyl chloride (4.4 g, 23.1 mmol) and stirred at room temperature for 5 h. The reaction mixture was diluted with CH2Cl2 (25 mL) and washed with aqueous CuSO4 solution (2×25 mL) followed by water (2×25 n mL). Organic layer was dried (Na2SO4), evaporated and purified by chromatography (Si-gel, 15% EtOAc-hexane); first eluted was (3S,6S)-3-acetoxy-6,7-di-p-toluene sulfonyloxy-hept-1-yne 15a (1.14 g) in 10% yield as a yellow syrup. 1HNMR (CDCl3, 200 MHz): δ1.48-1.8 (m, 4H, H-3,4), 2.0 (s, 3H, OAc), 2.31 (d, 1H, J 2.5 Hz, H-7) 2.4 (s, 3H, Ar—CH3), 3.94 (d, 2H, J 4.5 Hz, H-1), 4.5-4.64 (m, 1H, H-2), 5.06-5.18 (m, 1H, H-5), 7.20-7.3, 7.56-7.7 (m, 4H each, Ar—H).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:19])[NH2:18])=O)C1C=CC=CC=1.[CH:23]1([S:29]([Cl:32])(=[O:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[ClH:32].[NH:19]=[C:17]([NH:18][S:29]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)(=[O:31])=[O:30])[NH:16][CH2:15][CH2:14][CH2:13][C@@H:12]([C:20]([N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:22])[NH2:11]
Reactant: C1CCNC1
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: Cl
Product: N=C(NCCC[C@H](N)C(=O)N1CCCC1)NS(=O)(=O)C1CCCCC1

Procedure:
Starting from (S)-N2-(benzyloxycarbonyl)-arginine, cyclohexanesulphonyl chloride and pyrrolidine, the expected product is obtained according to the procedure described in Example 1.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[CH:3]=1.[C:8]1([CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(N(CCCC)CCCC)CCC>[CH3:7][C:4]1[CH:3]=[C:2]2[N:1]=[C:15]([OH:16])[C:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:20]([OH:21])[N:6]2[N:5]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: Cc1cc(N)[nH]n1
Solvent: CCCCN(CCCC)CCCC
Product: Cc1cc2nc(O)c(-c3ccccc3)c(O)n2n1
Temperature: 25 °C

Procedure:
A solution of 4.5 g 5-amino-3-methylpyrazole and 12.2 ml diethyl phenylmalonate in N,N-dibutylbutan-1-amine is stirred at 185° C. over night. After cooling to room temperature the reaction mixture forms two layers. The top layer is removed and the lower layer is diluted with dichloromethane and methanol. The resulting solution is concentrated and extracted with a mixture of diethyl ether and 10% w/w NaOH solution. The organic layer is discarded and aqueous layer acidified with concentrated HCl. The precipitated product is collected by filtration.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[CH:23]=[CH:24][CH:25]=[CH:26][C:6]1=2)=[O:4].[Cl:27][C:28]1[CH:29]=[C:30]2[C:35](=O)[O:34][C:32](=[O:33])[C:31]2=[CH:37][CH:38]=1.O.CCCCCC>C1(C)C=CC=CC=1>[CH2:16]([N:8]1[C:9](=[O:15])[C@H:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[N:5]([C:3](=[O:4])[CH2:2][N:1]2[C:35](=[O:34])[C:30]3=[CH:29][C:28]([Cl:27])=[CH:38][CH:37]=[C:31]3[C:32]2=[O:33])[C:6]2[CH:26]=[CH:25][CH:24]=[CH:23][C:7]1=2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Reactant: NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: O
Product: O=C1c2ccc(Cl)cc2C(=O)N1CC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Yield: 75.5 %

Procedure:
A suspension of (3aR*,10aS*)-4-(aminoacetyl)-9-benzyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta-[e][1,4]diazepin-10(1H)-one (0.58 g, 1.7 mmol) and 4-chlorophthalic anhydride (0.31 g, 1.7 mmol) in toluene (10 mL) was refluxed for 3.5 hours using a Dean-Stark water separator. The reaction mixture was left standing for cooling at room temperatures, to which was added hexane. The resulting solid was collected by filtration, which was recrystallized from chloroform-hexane to give 0.66 g (yield 75%) of the titled compound, m.p. 237°-238° C.
Reaction SMILES: C(N(CC)CC)C.C(O)(C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1.Br[CH2:24][C:25](=[O:28])[CH2:26][CH3:27]>[Cl-].[Zn+2].[Cl-].C1C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH2:21][CH2:24][C:25](=[O:28])[CH2:26][CH3:27])=[CH:16][CH:15]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: CCC(=O)CBr
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCC(=O)CCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.3 %

Procedure:
Anhydrous zinc chloride (3.71 g, 27.2 mmol) was placed into a round bottom flask and dried by melting under vacuum at 250-350° C. for 15 minutes. After cooling under vacuum to room temperature, benzene (15 ml.), triethylamine (2.7 ml, 19.42 mmol) and tert-butanol (1.83 ml, 19.42 mmol) were successively added. The mixture was stirred until zinc chloride was fully dissolved (approx. 2 hour) and 1-(4-chlorophenyl)ethan-1-one (3.0 g, 19.42 mmol) and 1-bromobutan-2-one (2.05 g, 13.6 mmol) were successively added. The mixture was stirred for 1 hour and allowed to stand for 4 days at room temperature, and thereafter quenched with 5% aq. sulfuric acid. The organic layer was separated, washed with water (2×50 ml), brine (1×25 ml), dried over anhydrous sodium sulfate and the solvent evaporated off. The crude product was purified by column chromatography over silica gel (100-200 mesh) using chloroform as eluent to give 2.30 g (75.63%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8]([OH:10])=[O:9].[CH2:16](O)C>[Pd]>[CH3:16][O:9][C:8](=[O:10])[CH2:7][CH2:6][C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:4]=1
Reactant: O=C(O)C=Cc1cccc(C(F)(F)F)c1
Reactant: CCO
Agent: [Pd]
Product: COC(=O)CCc1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
A mixture of 2.20 g of 3-(trifluoromethyl) cinnamic acid, 166 mg of palladium/carbon (10%, wet), and 40 ml of ethanol was stirred overnight under a hydrogen atmosphere at 1 atm. Palladium/carbon was separated by filtration, and the filtrate was concentrated under reduced pressure. 20 ml of methanol and 4 drops of concentrated sulfuric acid were added and the mixture was stirred at 60° C. for 2 hours, and then left to cool down. After concentration under reduced pressure, 20 ml of a saturated sodium bicarbonate aqueous solution was added, and the resultant was extracted with 20 ml of dichloromethane. The extract was dried with anhydrous sodium sulfate and then concentrated under reduced pressure to afford 2.40 g of the captioned compound as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:20]4[C:15]3=[CH:16][CH:17]=[CH:18][CH:19]=4)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB(C2C=CC([C:41]3[CH:46]=[CH:45][C:44]([N:47]4[C:59]5[CH:58]=CC=C[C:54]=5C5C4=CC=CC=5)=[CH:43][CH:42]=3)=NC=2)O1.C([O-])([O-])=O.[Na+].[Na+].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.C1COCC1>[CH:25]1[C:26]2[N:14]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[N:6]=[CH:7][C:2]([C:2]5[CH:7]=[N:6][C:5]([C:8]6[CH:13]=[CH:54][C:59]([N:47]7[C:44]8[CH:45]=[CH:46][CH:41]=[CH:42][C:43]=8[C:15]8[C:20]7=[CH:19][CH:18]=[CH:17][CH:16]=8)=[CH:58][CH:9]=6)=[CH:4][CH:3]=5)=[CH:3][CH:4]=4)=[CH:9][CH:10]=3)[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: Brc1ccc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)nc1
Reactant: CC1(C)OB(c2ccc(-c3ccc(-n4c5ccccc5c5ccccc54)cc3)nc2)OC1(C)C
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: C1CCOC1
Product: c1ccc2c(c1)c1ccccc1n2-c1ccc(-c2ccc(-c3ccc(-c4ccc(-n5c6ccccc6c6ccccc65)cc4)nc3)cn2)cc1
Temperature: 80 °C
Yield: 180 %

Procedure:
A mixture of 6 (4.11 g, 10.3 mmol), 7 (4.60 g, 10.3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.595 g, 0.515 mmol), Na2CO3 (5.41 g, 51.0 mmol), H2O (55 mL) and THF (92 mL) was degassed with argon for about 1 h while stirring. The stirring reaction mixture was then maintained under argon at about 80° C. for about 18 h. Upon confirming consumption of the starting materials by TLC (SiO2, 49:1 dichloromethane-acetone), the reaction was cooled to RT, filtered and filtrant washed with EtOAc and H2O to afford 8 (5.92 g, 90%) as an off-white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[NH2:16]>C(O)=O.CO>[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[N:16]=[C:1]([C:4]1[N:5]=[C:6]([C:10](=[N:16][C:15]2[C:17]([CH3:22])=[CH:18][C:19]([CH3:21])=[CH:20][C:14]=2[Cl:13])[CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: Cc1cc(C)c(N)c(Cl)c1
Solvent: CO
Solvent: O=CO
Product: CC(=Nc1c(C)cc(C)cc1Cl)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
In a 200 ml round bottom flask, 2.0 g of 2,6-diacetylpyridine (M=163.176 g/mol, 0.0123 mol) and 75 ml of methanol were placed. Next 3.81 g of 2-chloro-4,6-dimethylaniline (M=155.627 g/mol, 0.0245 mole) and three drops of formic acid were added and the solution stirred at room temperature under nitrogen for four days, at which time no precipitate had formed. The reaction then was refluxed for 24 h. GC analysis indicated that the reaction was incomplete. Refluxing was continued for a total of 1 week. Solvent was stripped from the reaction mixture via rotary evaporator. Flash chromatography through a basic alumina column (eluted with hexane/ethyl acetate 20:1) lead to isolation of an oil. The oil was then crystallized from methanol/methylene chloride to receive pale yellow crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([Cl:25])[C:14]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:23])[Cl:24])[CH:16]=[C:15]([Cl:25])[C:14]=1[O:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(CCO)cc1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(CCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.8 %

Procedure:
To a mixture of 3.88 g of 4-(2-hydroxyethyl)benzaldehyde, 6.7 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 100 ml of tetrahydrofuran, and 6.0 g of triphenylphosphine was added dropwise a solution of 4.7 g of diisopropyl azodicarboxylate dissolved in 20 ml of tetrahydrofuran at the ice temperature over 1 hour. After completion of the addition, the reaction mixture was stirred at room temperature for 24 hours, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, which afforded 6.63 g (yield, 69%) of 4-(2-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)ethyl)benzaldehyde, m.p., 54. 2° C.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:18]=[CH:17][N:16]=[N:15][CH:14]=3)[CH:9]=[C:8]([C:19]([O:21]C)=[O:20])[C:7]=2[C:6]([CH3:23])=[CH:5]1)([CH3:3])[CH3:2].CO.[OH-].[Li+].O>O1CCCC1>[CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:18]=[CH:17][N:16]=[N:15][CH:14]=3)[CH:9]=[C:8]([C:19]([OH:21])=[O:20])[C:7]=2[C:6]([CH3:23])=[CH:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(-c2ccnnc2)cc2c1c(C)cn2C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cn(C(C)C)c2cc(-c3ccnnc3)cc(C(=O)O)c12
Temperature: 55 °C
Yield: 95.4 %

Procedure:
To a 100 ml round bottom flask was added methyl 1-isopropyl-3-methyl-6-(pyridazin-4-yl)-1H-indole-4-carboxylate (74.0 mg, 0.239 mmol), Methanol (1595 μl), Tetrahydrofuran (THF) (3189 μl) and a magnetic stir bar. To the same was added lithium hydroxide, H2O (30.1 mg, 0.718 mmol) and the mixture was stirred at 55° C. Reaction progress was monitored by LCMS. LCMS (weekend) showed 50% conversion. To the reaction mixture was added lithium hydroxide, H2O (20.08 mg, 0.478 mmol) The reaction was continued to stir and heated to 55° C. After complete conversion the reaction solvent was removed and the remaining residue dissolved with water (1.5 ml). The aqueous solution was made acidic drop wise with 1N HCl until precipitation was complete. The solid was collected by vacuum filtration and washed with water (5 ml). The solid was dried under vacuum open to the air overnight. The product, 1-isopropyl-3-methyl-6-(pyridazin-4-yl)-1H-indole-4-carboxylic acid (68 mg, 0.228 mmol, 95% yield), was obtained as a brown solid. 1H NMR (400 MHz, DMSO-δ6) δ 9.71-9.83 (m, 1H), 9.23 (dd, J=1.26, 5.56 Hz, 1H), 8.32 (s, 1H), 8.11 (dd, J=2.65, 5.43 Hz, 1H), 7.86 (s, 1H), 7.58 (s, 1H), 4.90-5.09 (m, 1H), 2.34 (s, 3H), 1.47 (d, J=6.82 Hz, 6H). MS(ES) [M+H]+ 296.2.