Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[NH:4][C:3]=1[CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:27]=1.C1COCC1.[OH-].[K+].Cl>C(O)C>[CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[NH:4][C:3]=1[CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)[CH:27]=1
Reactant: CCOC(=O)c1ccccc1-c1ccc2[nH]c(COc3cccc(OCC4CCOCC4)c3)c(C)c(=O)c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(COc2cccc(OCC3CCOCC3)c2)[nH]c2ccc(-c3ccccc3C(=O)O)cc2c1=O
Temperature: 65 °C
Reaction time: 15 h
Yield: 68.9 %

Procedure:
To an ice-cold suspension of ethyl 3-methyl-4-oxo-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}-1,4-dihydroquinoline-6-benzoate (158 mg) in ethanol (5.0 mL)-THF (3.0 mL) was added dropwise a 4M aqueous potassium hydroxide solution (0.18 mL), and the mixture was stirred at 65° C. for 15 hours. The reaction mixture was ice-cooled, and adjusted to a pH of 7 by adding 1M hydrochloric acid. The resulting solid was collected by filtration, washed with water, and dried to obtain 3-methyl-4-oxo-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}-1,4-dihydroquinoline-6-benzoic acid (103 mg).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:15])[N:5]([C:7]2[CH:12]=[N:11][N:10]([CH3:13])[C:9](=[O:14])[CH:8]=2)[CH:6]=1.[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1)#[CH:17]>>[CH3:13][N:10]1[C:9](=[O:14])[CH:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:17]#[C:16][C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[N:3]=[C:4]2[CH3:15])[CH:12]=[N:11]1
Reactant: C#Cc1cccc(C)c1
Reactant: Cc1nc(I)cn1-c1cnn(C)c(=O)c1
Product: Cc1cccc(C#Cc2cn(-c3cnn(C)c(=O)c3)c(C)n2)c1

Procedure:
The title compound, colorless resin, MS: m/e=305.2 (M+H+), was prepared in accordance with the general method of example 21a from 5-(4-iodo-2-methyl-imidazol-1-yl)-2-methyl-2H-pyridazin-3-one and 1-ethynyl-3-methyl-benzene.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[CH3:20][O:21][CH2:22][CH2:23]Br>C(#N)C>[CH3:20][O:21][CH2:22][CH2:23][N:2]([C:3]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[CH:5][CH:4]=1)[CH3:1]
Reactant: COCCBr
Reactant: CNc1ccc(OC)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCCN(C)c1ccc(OC)cc1
Temperature: 80 °C
Yield: 84.3 %

Procedure:
To a stirred solution of 1.00 g (7.29 mmol) N-methyl-p-anisidine in 15 ml acetonitrile at 0° C. were added dropwise 1.36 ml (8.02 mmol) N-ethyldiisopropylamine and 1.01 g (7.29 mmol) 2-bromoethyl methyl ether. The mixture was heated at 80° C. for 2 days and then concentrated in vacuo. Flash chromatography (1/9 ethyl acetate/hexane) afforded 1.20 g (84%) (2-methoxy-ethyl)-(4-methoxy-phenyl)-methyl-amine as an orange oil. ES-MS m/e (%): 196 (M+H+, 100).
Reaction SMILES: Cl.C([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:23])[NH:13][C:14]2[S:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][N:18]=2)=[CH:8][CH:7]=1)(=O)C>O1CCCC1>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([NH:13][C:14]2[S:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][N:18]=2)=[O:23])=[CH:8][CH:7]=1
Reactant: CC(=O)Oc1ccc(C(=O)Nc2ncc(S(C)(=O)=O)s2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cnc(NC(=O)c2ccc(O)cc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
2 M hydrochloric acid (45.0 mL) was added to a suspension of 78 (0.439 g, 1.29 mmol) in tetrahydrofuran (20.0 mL), and the suspension was warmed to reflux. The reaction became homogeneous upon heating. After refluxing for 4 hours, the reaction was allowed to cool to room temperature, and stood at room temperature overnight before the reaction was filtered. The filter pad was washed with water then dried in vacuo at 70° C. to give 80 (0.2489 g, 64.6%) as a white crystalline solid.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]([NH2:15])=O)[CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[NH2:15][CH2:13][CH:10]1[CH2:11][CH2:12][N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:8][CH2:9]1
Reactant: CCCCCCN1CCC(C(N)=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCCN1CCC(CN)CC1
Yield: 74.8 %

Procedure:
Prepared from 1-hexylpiperidine-4-carboxamide (6.6 g, 31.0 mmol) and LAH (1.93 g, 62.0 mmol) according to general the procedure used for Example 8 (Step B) to give 4.6 g of title compound as a waxy solid.
Reaction SMILES: C([NH:4][CH:5]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7])(=O)C>C(O)C.Cl>[ClH:14].[NH2:4][CH:5]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:6]([C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)=[O:7]
Reactant: COc1ccc(C(NC(C)=O)C(=O)c2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(C(N)C(=O)c2ccc(Cl)cc2)cc1
Yield: 162.9 %

Procedure:
45 g of 2-acetylamino-1-(4-chlorophenyl)-2-(4-methoxyphenyl)ethanone, dissolved in 300 cm3 of ethanol containing 135 cm3 of hydrochloric acid (d=1.18), are heated to reflux for 7 hours. After filtration through kieselguhr and concentration to dryness under vacuum, 200 cm3 of acetone are added to the solid residue, which is drained and washed with the same solvent, twice 75 cm3. 36 g (80%) of 2-amino-1-(4-chlorophenyl)-2-(4-methoxyphenyl)ethanone hydrochloride, an amorphous white powder, melting point 230° C., are obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([N+:15]([O-])=O)[CH:7]=2)[CH2:3][CH2:2]1.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]3[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=3)=[O:32])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]3[N:12]=[C:37]([C:36]4[CH:35]=[CH:34][C:33]([C:31]([NH:30][C:27]5[CH:26]=[CH:25][C:24]([N:21]6[CH2:20][CH2:19][O:18][CH2:23][CH2:22]6)=[CH:29][CH:28]=5)=[O:32])=[CH:40][CH:39]=4)[NH:15][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Reactant: O=[N+]([O-])c1ccc(OCC2CC2)cc1[N+](=O)[O-]
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc(-c2nc3ccc(OCC4CC4)cc3[nH]2)cc1

Procedure:
Compound 640 was prepared according to the procedure similar to that described in Scheme III from 1-cyclopropylmethoxy-3,4-dinitrobenzene and 4-(4-(4-morpholinophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C28H28N4O3: 469.22; found: 469.03.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[C:26][Si](C)(C)C)[CH:22]=[C:21]([Cl:31])[CH:20]=2)[C:12]=1[F:32])=[O:8].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:39])([CH3:38])[CH3:40])[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[CH:26])[CH:22]=[C:21]([Cl:31])[CH:20]=2)[C:12]=1[F:32])=[O:8]
Reactant: C[Si](C)(C)C#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Reaction time: 2 h
Yield: 96.8 %

Procedure:
To a solution of 4-chloro-N-{[4-chloro-3-({3-chloro-5-[(trimethylsilyl)ethynyl]phenyl}oxy)-2-fluorophenyl]methyl}-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (120 mg, 0.187 mmol) in THF (5 ml) was added TBAF (1.0 M solution in THF) (0.281 ml, 0.281 mmol) and the reaction mixture was stirred for 2 hours. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-chloro-5-ethynylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (103 mg, 0.181 mmol, 97% yield). LC-MS (ES−) m/z 566 [M−H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([N+:19]([O-])=O)[CH:13]=1.CCO.[Cl-].[NH4+]>[Fe].O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH2:19])[CH:13]=1
Reactant: Nc1ccc(-c2c(F)cccc2C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2c(F)cccc2C(F)(F)F)cc1N
Temperature: 80 °C
Reaction time: 14 h
Yield: 98 %

Procedure:
2′-Fluoro-3-nitro-6′-trifluoromethyl-biphenyl-4-ylamine (754 mg, 2.51 mmol, as prepared in the previous step) was placed in a 40 mL vial equipped with a magnetic stir bar, then EtOH (20 mL) and water (5 mL) were added. Ammonium chloride (10 eq., 1.34 g, 25.1 mmol) was added as a solid, and then iron powder (5 eq., 701 mg, 12.6 mmol) was added. The vial was tightly capped and placed in a heating block where the reaction was stirred at 80° C. for 14 h. The reaction was cooled to rt, poured into water, and extracted three times with EtOAc (40 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure to give 662 mg (98%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 7.52 (d, J=7.8 Hz, 1H), 7.39 (td, J=7.9, 5.7 Hz, 1H), 7.25-7.32 (m, 1H), 6.71-6.77 (m, 1H), 6.60-6.67 (m, 2H), 3.45 (br. s., 4H).
Reaction SMILES: C=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4][CH2:3]1.BrC1C(N(CCC=C)C(=O)[O:28]C(C)(C)C)=CC=CN=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])=O.[K+]>CN(C=O)C.O.[Cl-].C([N+](CC)(CC)CC)C.CCOC(C)=O.C([O-])(O)=O.[Na+].CC([O-])=O.CC([O-])=O.[Pd+2]>[O:28]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4][CH2:3]1
Reactant: C=CCCN(C(=O)OC(C)(C)C)c1cccnc1Br
Reactant: C=C1CCN(C(=O)OC(C)(C)C)c2cccnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=O)c2ncccc21
Temperature: 110 °C
Reaction time: 16 h

Procedure:
tert-butyl 4-methylene-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate. To a solution of tert-butyl (2-bromopyridin-3-yl)(but-3-en-1-yl)carbamate (1 eq.) in DMF (0.2 M), PPh3 (0.25 eq.), Pd(OAc)2 (0.1 eq), and KOAc (5 eq.), is added, under an argon atmosphere, tetraethyl ammonium chloride hydrate (2 eq.). The flask is purged with argon for 15 min, and the resulting reaction mixture is stirred at 110° C. for 16 h. The reaction progress is monitored by TLC. The reaction mixture is diluted with EtOAc and saturated NaHCO3 solution. The organic layer is separated and dried over Na2SO4, and concentrated. The compound that may be thus obtained is purified by column chromatography to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[C:4]([Cl:12])[C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C=O)C>[Br:1][C:2]1[C:3]([F:13])=[C:4]([Cl:12])[C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([Cl:17])=[O:8]
Reactant: O=C(O)c1cc(Br)c(F)c(Cl)c1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(Br)c(F)c(Cl)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A quantity of 5.2 g of 5-bromo-3-chloro-2,4-difluorobenzoic acid is suspended in 30 ml of dichloromethane; then 2.92 g of oxalyl chloride is added, and 3 drops of dry DMF are added. The mixture is stirred at room temperature for 3 hours and the desired compound is isolated after evaporation of the solvent.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)=[CH:7][C:6]=1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][C:37]=1[C:38]([F:41])([F:40])[F:39])[NH:34][CH2:33][CH2:32]2>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:34]2[C:35]3[C:31](=[CH:30][C:29]([O:28][CH3:27])=[C:37]([C:38]([F:40])([F:41])[F:39])[CH:36]=3)[CH2:32][CH2:33]2)=[O:20])=[CH:7][C:6]=1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Reactant: CC(C)(C)c1ccc(NC(=O)Oc2ccccc2)cc1-c1cccnc1
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1ccc(C(C)(C)C)c(-c3cccnc3)c1)CC2
Yield: 23 %

Procedure:
The title compound (0.055 g, 23%) was prepared from phenyl N-[4-t-butyl-3-(pyrid-3-yl)phenyl]carbamate (D22) (0.18 g, 0.00052 mole) and 5-methoxy-6-trifluoromethylindoline (D11) using the method of Example 28.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])[CH2:7][CH2:8][CH3:9])=[O:5])[CH3:2].Cl.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH3:9][CH2:8][CH2:7][C@H:6]([NH:10][C@H:11]([C:13]([N:10]1[C@H:6]([C:4]([OH:5])=[O:3])[CH2:7][C@H:24]2[C@@H:25]1[CH2:26][CH2:27][CH2:28][CH2:23]2)=[O:15])[CH3:12])[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCCCCC
Reactant: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCC[C@H](N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@@H]21)C(=O)OCC
Reaction time: 1.5 h

Procedure:
To a slurry of N-[1-(S)-ethoxycarbonyl-1-butyl]-(S)-alanine (1.5 g, 0.0069 moles, as obtained in Step-IV, Method-I and Step-II, Method-II) in n-hexane (10 ml) was purged dry hydrogen chloride gas at 25-30° C. under agitation. To this was added finely ground phosphorous pentachloride (1.8 g, 0.0086 moles) in four lots, each after an interval of 10 mns. After the complete addition the reaction mixture was agitated for 1.5 hrs. The solid precipitated was filtered, washed with hexane to give 1.88 g of the title compound (I).
Reaction SMILES: C([O:8][C:9]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1.C(OCC)(=O)C.C(Cl)(Cl)Cl>CO.O1CCOCC1.[C].[Pd]>[OH:8][C:9]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-c2ccccn2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-c2ccccn2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-4-(pyridin-2-yl)benzamido)-4-phenylbenzoate (0.13 g) in methanol (2 mL), dioxane (2 mL), and ethyl acetate (4 mL), 10% palladium-carbon (67 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours and 30 minutes. Chloroform was added to the reaction mixture. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: chloroform] to obtain 0.11 g of tert-butyl 2-(2-hydroxy-4-(pyridin-2-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([N:59]3[CH2:64][CH2:63][O:62][CH2:61][CH2:60]3)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:27][CH:28]=1
Reactant: C1COCCN1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1cc2ccccc2n1Cc1ccc(Cl)cc1)N1CCC(C(=O)N2CCOCC2)CC1
Reaction time: 8 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (100 mg, 0.252 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (97 mg, 0.504 mmol), and 1-Hydroxybenzotriazole (68 mg, 0.504 mmol) were dissolved in 3.0 mL of DCM. The reaction was allowed to stir for 10 minutes before N,N-Diisopropylethylamine (88 μL, 0.504 mmol) and morpholine (44 μL, 0.504 mmol) were added. The reaction was allowed to stir overnight. The reaction was diluted with water and ethyl acetate. The layers were separated and the organic layer was washed with another aliquot of water. The ethyl acetate layer was washed with saturated citric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude material was purified in silica gel using the gradient 100% DCM to 5% 7M NH3 in methanol diluted with 95% DCM. After purification, pure white solid was obtained. Yield: 47.6 mg (White solid)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([S:11][CH3:12])=[N:6]2.[C:23]1(B(O)O)C=CC=CC=1.CB1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=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>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([S:11][CH3:12])=[N:6]2.[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:4]2[N:5]3[C:10]([CH:9]=[N:8][C:7]([S:11][CH3:12])=[N:6]3)=[C:2]([CH3:23])[CH:3]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: CSc1ncc2c(Br)cc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Solvent: CN(C)C=O
Product: CSc1ncc2c(C)cc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Temperature: 130 °C
Yield: 65 %

Procedure:
Into a 30 mL vial, 5-Bromo-7-(4-methanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.480 g, 0.00120 mol) (Note: 5-Bromo-7-(4-methanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine was prepared in an analogous fashion as Example 99b replacing Phenylboronic acid with $-methylsulfonuphenylboronic acid), Trimethylboroxine (1.37 g, 0.0109 mol), Tetrakis(triphenylphosphine)palladium (0) (0.14 g, 0.00012 mol) and Potassium carbonate (7.49 g, 0.0542 mol) were added and purged under an atmosphere of Nitrogen for 10 minutes. N,N-Dimethylformamide (25.0 mL, 0.323 mol) was then added and heated at 130° C. for 4 hours. The reaction was partitioned with water and EtOAc. The organic was separated, washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with EtOAc. The solvent was removed under vacuum. The product was isolated via ISCO column chromatography with DCM and MeOH as eluant (0 to 5% MeOH). The collected fractions afforded 7-(4-Methanesulfonyl-phenyl)-5-methyl-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid (0.26 g, 65%).
Reaction SMILES: O1CCCC1.C(Cl)(=O)C(Cl)=O.[CH2:12]([O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([Cl:27])[CH:25]=2)[C:20](=[O:29])[N:19]([CH3:30])[C:18]=1[CH2:31][OH:32])[CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>O.CS(C)=O>[CH2:12]([O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([Cl:27])[CH:25]=2)[C:20](=[O:29])[N:19]([CH3:30])[C:18]=1[CH:31]=[O:32])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCOc1c(CO)n(C)c(=O)c2cc(Cl)c(Cl)cc12
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCCCOc1c(C=O)n(C)c(=O)c2cc(Cl)c(Cl)cc12
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 81.7 %

Procedure:
To a solution of dimethyl sulfoxide;(1.7 ml, 24 mmol) in tetrahydrofuran (10 mmol) was added oxalyl chloride (1.05 ml, 12 mmol) at −78° C. and the obtained mixture was stirred at −78° C. for 15 min. To the mixture was added 4-butoxy-6,7-dichloro-3-hydroxymethyl-2-methyl-1(2H)-isoquinolinone (synthesized according to the method similar to that in Example 36 (3)) (2.43 g, 5mmol) and the obtained mixture was stirred at −78° C. for 5 min. To the mixture was added triethylamine (5.6 ml, 40mmol) and the obtained mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from tetrahydrofuran-diisopropyl ether to give 4-butoxy-6,7-dichloro-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinealdehyde (2.14 g, 81.7%) as crystals.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH2:25][N:26]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:27][Si](C)(C)C)CCC.C(ON(C(C)C1C=CC=CC=1)C[Si](C)(C)C)CCC.C(OCN(C(C)C1C=CC=CC=1)[Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.ClCCl>[CH2:32]([N:26]1[CH2:27][CH:11]2[CH:12]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][C:10]2=[O:13])[CH2:25]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C1C=CC(c2ccccc2)(c2ccccc2)CC1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Agent: CCCCOCN(C(C)c1ccccc1)[Si](C)(C)C
Agent: CCCCON(C[Si](C)(C)C)C(C)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC12
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
5 drops of trifluoroacetic acid are added to a solution of 155 g of 4,4-diphenyl-2-cyclohexen-1-one and 202 cm3 of N-butoxymethyl-N-trimethylsilylmethylbenzylamine in 1000 cm3 of dry dichloromethane and the reaction mixture is refluxed for 45 minutes. 50 cm3 of N-butoxy-methyl-N-trimethylsilylmethylbenzylamine and 3 drops of trifluoroacetic acid are added and the mixture is further stirred for 45 minutes under reflux before again adding 25 cm3 of N-butoxymethyl-N-trimethylsilyl-methylbenzylamine and 3 drops of trifluoroacetic acid. The reaction mixture is stirred under reflux for 45 minutes and then treated with 50 g of potassium carbonate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is dissolved in 200 cm3 of isopropyl oxide and the solution is cooled at 0° C. for 1 hour. The crystals are drained, washed twice with 15 cm3 of isopropyl oxide and dried to give 193 g of (3aRS,7 aRS)-2-benzyl-7,7-diphenyl-4-perhydroisoindolone in the form of white crystals; melting point 132° C.