Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[F:12][C:13]1[C:34]([NH:35][S:36]([CH2:39][CH2:40][CH3:41])(=[O:38])=[O:37])=[CH:33][CH:32]=[C:31]([F:42])[C:14]=1[C:15]([NH:17][C:18]1[CH:19]=[C:20]2[C:26]([C:27](OC)=[O:28])=[CH:25][NH:24][C:21]2=[N:22][CH:23]=1)=[O:16]>C1(C)C=CC=CC=1>[F:12][C:13]1[C:34]([NH:35][S:36]([CH2:39][CH2:40][CH3:41])(=[O:37])=[O:38])=[CH:33][CH:32]=[C:31]([F:42])[C:14]=1[C:15]([NH:17][C:18]1[CH:19]=[C:20]2[C:26]([C:27]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:28])=[CH:25][NH:24][C:21]2=[N:22][CH:23]=1)=[O:16]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)OC)c3c2)c1F
Reactant: Nc1ccccc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)Nc4ccccc4)c3c2)c1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 35.6 %

Procedure:
A round bottom flask equipped with a stir bar and nitrogen inlet was charged with aniline (4.2 mg, 0.046 mmol) and dry toluene (0.5 mL) under a nitrogen atmosphere. Trimethyl aluminum (8.0 μL, 0.160 mmol, 7 eq.) was added to this solution, and this mixture was stirred at room temperature for 20 minutes. Methyl 5-(2,6-difluoro-3-(propylsulfonamido)benzamido)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (13.5 mg, 0.023 mmol, see Example 14) was added in one portion, and the reaction mixture warmed to 90° C. for 30 minutes. The reaction mixture was then allowed to cool to room temperature. The mixture was then quenched carefully with 30% aqueous sodium potassium tartrate and extracted with ethyl acetate (2×). The extracts were dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in THF (1 mL), and a 1M aqueous LiOH solution (1 mL) was then added. The mixture was stirred at room temperature for 16 hours, diluted with AcOH/water and extracted with EtOAc (2×). The extracts were washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated. The resulting residue was subjected to preparative TLC purification (2×0.5 mm plates, 10% MeOH/DCM) to afford 5-(2,6-difluoro-3-(propylsulfonamido)benzamido)-N-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (4.2 mg, 36%). 1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 10.97 (s, 1H), 9.76-9.87 (m 2H), 8.89-8.96 (m, 1H), 8.42-8.55 (m 2H), 7.73-7.80 (m, 2H), 7.51-7.59 (m, 1H), 7.20-7.38 (m, 3H), 7.03-7.11 (m, 1H), 3.06-3.14 (m, 2H), 1.71-1.82 (m, 2H), 0.94-1.04 (m, 3H); m/z (APCI-neg) M−1=512.1; (APCI-pos) M+1=514.0.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[O:7])=[CH:4][CH:3]=1.Br[C:27]([CH3:34])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH3:33][C:27]([O:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:24]=[CH:25][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:12][CH:13]=2)=[CH:18][CH:19]=1)([CH3:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=C(NCCc1ccc(-c2ccc(O)cc2)cc1)c1ccc(F)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CCNC(=O)c3ccc(F)cc3)cc2)cc1
Yield: 20 %

Procedure:
Ethyl 2-Methyl-2-{4-[2-(4-fluoro-benzamido)-ethyl]-biphenyl-4'-oxy}-propionate was prepared from 4-[2-(4-fluoro-benzamido)ethyl]-4'-hydroxy-biphenyl and ethyl 2-bromo-2-methyl-propionate analogous to Example 1. Yield: 20% of theory; m.p. 135° C.
Reaction SMILES: [CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](#[N:31])[CH:29]=[CH2:30].C(N(CC)CC)C>CO>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[CH2:30][CH2:29][C:28]#[N:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCNC(Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: C=CC#N
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCN(CCC#N)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 60 °C

Procedure:
Into a 25 mL screw-cap vial were added 3-benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (206 mg, 0.562 mmol), acrylonitrile (55 μL, 0.83 mmol), triethylamine (500 μL), and MeOH (5 mL). The reaction mixture was heated at 60° C. for 4 h then cooled to room temperature. The reaction mixture was concentrated and adsorbed onto silica gel then purified by silica gel flash chromatography with a 0-10% MeOH/CH2Cl2 gradient to afford the title compound as a yellow waxy solid (181 mg, 77%). LC/MS (Method B) 2.77 min, [M+1]+ 420.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[C:12]([CH3:17])[CH:13]=[CH:14][C:15]=1F)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18]C1C=CC(C)=CC=1O.C(Cl)(=O)C1C=CC=CC=1.CCN(CC)CC>C(Cl)Cl>[C:1]([O:9][C:10]1[CH:11]=[C:12]([CH3:17])[CH:13]=[CH:14][C:15]=1[Cl:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: Cc1ccc(F)c(OC(=O)c2ccccc2)c1
Solvent: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Cl)c(OC(=O)c2ccccc2)c1
Yield: 94 %

Procedure:
The title compound was prepared by adapting the method for 3-benzoyloxy-4-fluorotoluene using 4-chloro-3-hydroxytoluene (3.92 g, 27.5 mmol), benzoyl chloride (3.51 g, 25 mmol) and NEt3 (5 mL) in CH2Cl2 (100 mL) to give 3-benzoyloxy-4-chlorotoluene as a white solid (5.82 g, 94%), which was used without further purification. δH (400 MHz, CDCl3) 2.38 (s, 3H,), 7.05 (d, J=8.2, 1H), 7.11 (s, 1H), 7.36 (d, J=8.2, 1H), 7.51-7.56 (m, 2H), 7.64-7.70 (m, 1H), 8.22-8.28 (m, 2H); δC (100 MHz, CDCl3) 21.41, 123.97, 124.58, 128.07, 128.85, 129.15, 130.07, 130.55, 134.01, 138.38, 146.98, 164.51.
Reaction SMILES: [H-].[Na+].C(OCC)(=O)[CH2:4][C:5]([O:7]CC)=[O:6].Br[CH2:15][C:16]1[O:20][C:19]([CH3:21])=[N:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1>CN(C)C=O.O>[Cl:28][C:24]1[CH:23]=[C:22]([C:17]2[N:18]=[C:19]([CH3:21])[O:20][C:16]=2[CH2:15][CH2:4][C:5]([OH:7])=[O:6])[CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1nc(-c2cccc(Cl)c2)c(CBr)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(Cl)c2)c(CCC(=O)O)o1

Procedure:
60% Sodium hydride in oil (0.47 g) was added portionwise to a solution of diethyl malonate (3.4 g) in N,N-dimethylformamide (20 ml) and under ice-cooling a solution of 5-bromomethyl-4-(3-chlorophenyl)-2-methyloxazole (3 g) in N,N-dimethylformamide (10 ml) was added. The mixture was stirred under ice-cooling for 30 minutes, diluted with water and extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was dissolved in ethanol (20 ml), followed by addition of 2N sodium hydroxide (20 ml). The mixture was refluxed for 5 minutes, diluted with water and washed with ethyl ether. The aqueous layer was adjusted to pH 2 with hydrochloric acid and extracted with ethyl ether The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the oily residue (mostly, half-ester) was dissolved in pyridine (20 ml). The solution was refluxed for 2.5 hours. The pyridine was then distilled off and the residue [mostly, ethyl 4-(3-chlorophenyl)-2-methyloxazole-5-propionate] was dissolved in a mixture of ethanol (10 ml) and 2N sodium hydroxide (10 ml). The solution was refluxed for 5 minutes, diluted with water and acidified with hydrochloric acid to give crsytals of 4-(3-chlorophenyl)-2-methyloxazole-5-propionic acid, yield 1.6 g (56.7%), m.p. 159°-160° C.
Reaction SMILES: [I:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.[C:22](Cl)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26]>ClCCl.N1C=CC=CC=1>[I:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH:15][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH3:2])=[N:10][C:11]([NH:14][C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])=[N:12][CH:13]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Reactant: CCCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC(=O)Nc1ncc(Oc2cc(I)c(OC)cc2C(C)C)c(NC(=O)CCCC)n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 19.8 %

Procedure:
To a 0° C. solution of 5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (1.0 g, 2.5 mmoles) in dichloromethane (80 ml) and pyridine (3 ml), was slowly added valeryl chloride (2.4 ml, 20.2 mmoles). The mixture was stirred at room temperature for 60 hours, and then solvent was removed under reduced pressure. The residue was washed twice with water and then dissolved in dichloromethane. This organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was passed through a silica gel plug (40% ethyl acetate in hexane). The crude mixture was dissolved in a mixture of concentrated ammonium hydroxide aqueous solution and methanol (3 ml/27 ml) and stirred at room temperature for 15 minutes. Solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (20%, 35% ethyl acetate in hexane), to give crude pentanoic acid [5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-2-pentanoylamino-pyrimidin-4-yl]-amide was obtained, which was crystallized from ether and hexane to give pure pentanoic acid [5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-2-pentanoylamino-pyrimidin-4-yl]-amide (141 mg) as white solid, MS (M+H)=569. The filtrate from the recrystallization was dried and re-dissolved in a mixture of concentrated ammonium hydroxide aqueous solution and methanol (10 ml/40 ml) and stirred at room temperature for 5 hours. This solution was concentrated under reduced pressure, and the residue was partitioned between dichloromethane and water. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% ethyl acetate in hexanes), and recrystallized from ethyl acetate and hexane to give pure pentanoic acid [4-amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-amide (395 mg) as white solid, MS (M+H)=485.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=O)[NH:6][C:7]1[C:8]([CH3:32])=[C:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25].[NH2:36][CH2:37][CH:38]([OH:40])[CH3:39]>C(O)C.CCCCCC>[OH:40][CH:38]([CH3:39])[CH2:37][NH:36][C:5]([NH:6][C:7]1[C:8]([CH3:32])=[C:9]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:4]
Reactant: Cc1c(NC(=O)OCC(Cl)(Cl)Cl)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Reactant: CC(O)CN
Solvent: CCCCCC
Solvent: CCO
Product: Cc1c(NC(=O)NCC(C)O)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Yield: 58 %

Procedure:
Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 142 and 1-amino-2-propanol, the title compound was synthesized in the same manner as in Example 143. Yield: 58%. Melting point: 171-182° C. (ethanol-hexane).
Reaction SMILES: COC1C=C(C=CC=1OC)C[NH:7][C:8]1[N:9]=[C:10]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)[C:11]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:12]=2[N:13]=1>C(O)(C(F)(F)F)=O>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:14]1[C:12]2[N:13]=[C:8]([NH2:7])[N:9]=[C:10]([C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[C:11]=2[CH:16]=[CH:15]1
Reactant: COc1ccc(CNc2nc(-c3ccco3)c3ccn(Cc4ccccc4F)c3n2)cc1OC
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(-c2ccco2)c2ccn(Cc3ccccc3F)c2n1
Yield: 51.4 %

Procedure:
A solution of N-(3,4-dimethoxybenzyl)-7-(2-fluorobenzyl)4-(2-furyl)-7H-pyrrolo[2,3-d]pyrimidine-2-amine (110 mg, 0.24 mmol) in TFA (1 mL) was heated to 50° C. for 3 h, concentrated in vacuo, treated with saturated NaHCO3, extracted with EtOAc, dried (MgSO4), concentrated in vacuo, purified by chromatography (EtOAc:Heptane, 1:4) and recrystallised (EtOAc) to give the title compound (38 mg, 51%) as a cream solid.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:34]=[C:35]([OH:39])[CH:36]=[CH:37][CH:38]=1>C1COCC1>[OH:39][C:35]1[CH:34]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]5[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=5)=[O:22])=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:31])[CH:38]=[CH:37][CH:36]=1
Reactant: Nc1cccc(O)c1
Reactant: CC(=O)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)s1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3cccc(O)c3)cc2)s1
Temperature: 65 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
A small screw cap test tube was charged with 5-Acetyl-thiophene-2-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 34, 40 mg, 0.093 mmol) and THF (2 mL). To the resulting solution was added 3-aminophenol (13 mg, 0.1191 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜2 mL of i-prOH affording the title compound in 64% yield (0.031 g, 0.0592 mmol).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.Cl[CH2:14][N:15]1[CH2:19][CH:18]([CH2:20][CH2:21][CH3:22])[CH2:17][C:16]1=[O:23].O>CN(C=O)C>[Cl:3][C:4]1[N:5]([CH2:14][N:15]2[CH2:19][CH:18]([CH2:20][CH2:21][CH3:22])[CH2:17][C:16]2=[O:23])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CCCC1CC(=O)N(CCl)C1
Reactant: Clc1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC1CC(=O)N(Cn2c(Cl)cc3ccccc32)C1
Temperature: -20 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
At −78° C., NaH (60% in mineral oil; 220 mg, 5.52 mmol, 1.1 eq) is added to a solution of 2-chloro-1H-indole x160 (0.76 g, 5.02 mmol, 1 eq) in dry DMF (50 ml). The temperature is raised to −20° C. during 20 minutes, then 1-(chloromethyl)-4-propylpyrrolidin-2-one x63 (0.76 g, 5.02 mmol, 1 eq) dissolved in DMF (10 ml) is added drop wise. After 2 hours at room temperature, water (50 ml) is added. The aqueous layer is extracted with CH2Cl2 (3×30 ml). The combined organic layers are dried on anhydrous MgSO4, filtered off and concentrated under reduced pressure to obtain a liquid that is purified on silicagel (AcOEt/Benzine 1/9) yielding 1-[(2-chloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one 274 as a colorless liquid (605 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=[O:15])[C:8](=[N:13]O)[C:9](=[O:12])[CH2:10][CH3:11])=[CH:3][CH:2]=1.[H][H].Cl>C(O)(=O)C.[Pd]>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:15])[CH:8]([NH2:13])[C:9](=[O:12])[CH2:10][CH3:11])=[CH:3][CH:2]=1
Reactant: CCC(=O)C(=NO)C(=O)c1ccncc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: CCC(=O)C(N)C(O)c1ccncc1

Procedure:
In 1000 ml acetic acid was dissolved 23.0 g (0.11 mol) of 1-(4-pyridyl)-1,3-diketo-2-oximinopentane. The solution is charged with 1.0 g of 10% palladium on carbon and hydrogenated until three equivalents of hydrogen were taken up. The mixture was acidified with 18.5 ml of 12N hydrochloric acid, filtered and the solvent evaporaed to give the title compound as the dihydrochloric acid salt; m.p. 225° C.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:10][Si:11]([C:14]#[C:15][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([CH3:13])[CH3:12]
Reactant: C#C[Si](C)(C)C
Reactant: O=Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
As shown in the following Reaction 6, 500 mg (2.15 mmol) of 4-iodobenzaldehyde was melted in 2.7 mL of tetrahydrofuran, and 0.45 mL (3.22 mmol, 1.5 eq) of trimethylsilylacetylene, 0.6 mL (3.44 mmol, 1.6 eq) of diisopropylethylamine (DIEA), 7 mg (0.01 mmol, 0.5 mol %) of dichlorobis-(triphenylphosphine)palladium(II), and 3 mg (0.02 mmol, 1 mol %) of copper iodide was added thereto, and then the reaction solution was stirred under nitrogen atmosphere for 12 hours at room temperature. Next, the reaction solution was filtered with ether, and then was extracted with 1M sodium chloride aqueous solution 1 time. The organic solvent layer was dehydrated with magnesium sulfate, filtered, and then distilled under reduced pressure. The compound distilled under reduced pressure was purified with a column chromatography (mobile phase volume ratio; ethylacetate:n-hexane=1:10) to obtain 420 mg of 4-trimethylsilylethynyl benzaldehyde with the yield of 98%. NMR data of the obtained compound is as follows. [1H NMR (400 MHz, CDCl3): δ 9.81 (s, 1H), 7.63 (d, 2H), 7.42 (d, 2H), 0.13 (s, 9H)].
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:24]=[C:25]1[NH:29][C@H:28]([CH2:30][O:31]C(=O)C2C=CC=CC=2)[CH2:27][O:26]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:29]4[C@H:28]([CH2:30][OH:31])[CH2:27][O:26][C:25]4=[O:24])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)nc3)CC2)c(C)c1
Yield: 64 %

Procedure:
By reaction and treatment in the same manner as in Example 19 and using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (940 mg) described in Preparation Example 73 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (814 mg), the title compound (660 mg) was obtained.
Reaction SMILES: [F:1][C:2](=[CH:7][C:8]([CH3:21])([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)[CH3:9])[C:3](OC)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[F:1][C:2](=[CH:7][C:8]([CH3:21])([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:12][CH:11]=1)[CH3:9])[CH2:3][OH:4]
Reactant: COC(=O)C(F)=CC(C)(C)c1ccc(OC(F)(F)F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C=C(F)CO)c1ccc(OC(F)(F)F)cc1
Yield: 92.7 %

Procedure:
The method of Example 6 was repeated using methyl 2-fluoro-4-methyl-4-(4-trifluoromethoxyphenyl)pent-2-enoate (Example 5) (0.19 g), diethyl ether (10 ml) and lithium aluminium hydride (90 mg) to yield the title compound (0.16 g, 93%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2F)n1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2F)n1
Yield: 64.9 %

Procedure:
Using the procedure in Example 118A, 3-tert-butyl-1-(2-fluorophenyl)-1H-pyrazol-5-amine (1.23 g, 5.27 mmol) and phenyl chloroformate (2.0 mL, 16.0 mmol) were reacted to give phenyl 3-tert-butyl-1-(2-fluorophenyl)-1H-pyrazol-5-ylcarbamate (1.21 g, 3.42 mmol, 59%). 1H NMR (300 MHz, DMSO-d6) δ 10.13 (s, 1H), 7.55-7.35 (m, 6H), 7.23 (t, 1H), 7.08 (br s, 2H), 6.34 (s, 1H), 1.29 (s, 9H); LC-MS (ESI) m/z 354 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12](Cl)(=[O:15])[CH2:13][CH3:14].Cl>N1C=CC=CC=1>[C:12]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:15])[CH2:13][CH3:14]
Reactant: CCC(=O)Cl
Reactant: COC(=O)c1ccnc(N)c1
Agent: Cl
Solvent: c1ccncc1
Product: CCC(=O)Nc1cc(C(=O)OC)ccn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
To a stirred solution of methyl 2-aminoisonicotinate (1.00 g, 6.57 mmol) in pyridine (22 mL) is added propionyl chloride (0.69 mL, 7.89 mmol) at 0° C. After stirring at 0° C. for 2 hours, the reaction mixture is poured into 2M hydrochloric acid (100 mL) and extracted with ethyl acetate (100 mL). The organic layer is dried over sodium sulfate, and concentrated under reduced pressure to give 1.07 g (78% yield) of the title compound as a yellow solid. This material is used for the next reaction (Step-2) without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C[Al](C)C.C1(C)C=CC=CC=1.[Cl:20][C:21]1[C:26]([CH2:27][CH2:28][C:29](OC)=[O:30])=[C:25]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[CH:24]=[C:23]([Cl:40])[N:22]=1.Cl>ClCCl.O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:29](=[O:30])[CH2:28][CH2:27][C:26]1[C:21]([Cl:20])=[N:22][C:23]([Cl:40])=[CH:24][C:25]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:39]
Reactant: COC(=O)CCc1c(-c2ccccc2Cl)cc(Cl)nc1Cl
Reactant: Nc1ccccc1Cl
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(CCc1c(-c2ccccc2Cl)cc(Cl)nc1Cl)Nc1ccccc1Cl
Reaction time: 17 h
Yield: 85 %

Procedure:
2-Chloroaniline (0.87 ml, 8.21 mmol) in dichloromethane (80 ml) was treated with 2M trimethylaluminium in toluene (4.1 ml, 8.2 mmol) at 0-5° under nitrogen. After stirring for 15 min. a solution of methyl 3-[2,6-dichloro-4-(2-chlorophenyl)-3-pyridinyl]propanoate (1.40 g, 4.063 mmol) in dichloromethane (40 ml) was added and the solution stirred at 21° for 17 h. Water (15 ml) was added (very slowly at first), followed by sufficient 2M hydrochloric acid to dissolve all the precipitated aluminium salts. The organic phase was separated and the aqueous phase further extracted with dichloromethane (50 ml). The combined organic extracts passed through a hydrophobic frit, evaporated in vacuo, and the oily residue purified by column chromatography over silica (70 g) eluting with cyclohexane-ethyl acetate (100:0-65:35) to afford the title compound as a gum (1.52 g, 85%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1>>[Cl:37][C:38]1[CH:43]=[C:42]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:27][CH2:28]2)=[O:22])[CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(C(=O)N5CCCCC5)CC4)cc3c2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(C(=O)N4CCCCC4)CC2)n3-c2cccc(Cl)c2)CC1
Yield: 49 %

Procedure:
The title compound was synthesized in analogy to example 5, from {4-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carbonyl]-piperazin-1-yl}-piperidin-1-yl-methanone (example 14) and 3-chlorophenylboronic acid to afford the desired product as a light-brown foam (49%). MS (ISP): 605.2 (M+H)+.