Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[NH2:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=1>CS(C)=O>[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:16]2[CH2:4][C@H:17]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:15]=1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1ccc(N)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Reaction time: 8 h

Procedure:
To a suspension of sodium hydride (36 mg, 0.89 mmol) in DMSO (2 mL) was added the solid trimethyl sulfoxonium iodide (185 mg, 1.05 mmol). The mixture was stirred for 25 min before a solution of ethyl (E)-3-(4-aminophenyl)prop-2-enoate (100 mg, 0.52 mmol) in DMSO (2 mL) was added quickly at RT. The mixture was left to stir overnight. The bulk mixture was quenched with NH4Cl (sat.) and the mixture diluted with water and EtOAc. The layers were separated and the aqueous layer extracted into EtOAc (3×30 mL). The organic fractions were combined, dried with brine then MgSO4 and the solvent removed. Flash chromatography on silica gel, eluting with 20-50% ethyl acetate gradient in n-heptane, gave ethyl (1R,2R)-2-(4-aminophenyl)cyclopropanecarboxylate, 70 mg. 1H NMR (400 MHz, CDCl3) δ 6.96-6.89 (m, 2H), 6.68-6.61 (m, 2H), 4.17 (q, J=7.1 Hz, 2H), 2.44 (ddd, J=9.2, 6.6, 4.2 Hz, 1H), 1.80 (ddd, J=8.4, 5.2, 4.2 Hz, 1H), 1.53 (ddd, J=9.2, 5.2, 4.5 Hz, 1H), 1.28 (t, J=7.1 Hz, 3H), 1.24 (ddd, J=8.3, 6.6, 4.5 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][N:32]3[CH2:31][CH2:30][N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][CH3:21])[CH2:34][CH2:33]3)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NOC(CCC=O)C2)cc1OC
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C2=NOC(CCCN3CCN(c4ccccc4OC)CC3)C2)cc1OC
Yield: 59.4 %

Procedure:
3-[3-(3,4-Dimethoxyphenyl)-4,5-dihydroisoxazol-5-yl]propanal (25.8 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.5 mg, 0.262 mmol) and diisopropylethylamine (26.9 L, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 22.7 mg (60.0%) of the target compound was obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:13].[CH:20]1([CH3:32])[CH2:25][CH2:24][CH:23]([CH:26]([CH3:28])[CH3:27])[CH:22]([C:29](Cl)=[O:30])[CH2:21]1.Cl>C(Cl)Cl>[OH:13][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:10][C:29]([CH:22]1[CH2:21][CH:20]([CH3:32])[CH2:25][CH2:24][CH:23]1[CH:26]([CH3:28])[CH3:27])=[O:30]
Reactant: NCC(O)c1ccccc1
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCC(C(C)C)C(C(=O)NCC(O)c2ccccc2)C1
Temperature: 0 °C
Yield: 84.9 %

Procedure:
A 500 mL round bottom flask equipped with stir bar was charged with CH2Cl2 (200 mL), DIEA (28 g, 0.219 mol), and 2-Amino-1-phenyl-ethanol (10 g, 0.073 mol) and cooled to 0° C. Menthoyl chloride (14.8 g, 0.073 mol) was added drop wise over a 15 min period. Once the addition was complete the reaction was allowed to warm to ambient temperature and stirred 2 h. CH2Cl2 (100 mL) and 1N HCl (100 mL) was added to the reaction mixture and stirred for an additional 20 min. The heterogeneous mixture was transferred to a separatory funnel where the aqueous phase was separated and re-extracted with CH2Cl2 (2×100 mL). The organic phases were combined and washed with 1N HCl (8×100 mL), H2O (1×100 mL), 1N NaOH (2×100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was eluted through a plug of silica gel (50% ethyl acetate/hexane for elution) provided the title compounds as colorless solid (18.8 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.CC([O-])=O.[Na+].Br[CH2:16][C:17]([C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1)=O>O.CO>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]2[CH:16]=[C:17]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[NH:9][C:4]=2[N:3]=1
Reactant: Nc1cc(O)nc(N)n1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(-c2cc3c(O)nc(N)nc3[nH]2)cc1
Temperature: 100 °C

Procedure:
A mixture of 2,6-diaminopyrimidin-4-ol (1 g, 7.93 mmol) and NaOAc (0.846 g, 10.31 mmol) in water (180 mL) was heated to 100° C. for 20 minutes. To this was added a suspension of 4-(2-bromoacetyl)benzonitrile (2.2 gm, 8.73 mmol) [prepared according to procedure mentioned in J. Med. Chem., 2011, 54(12), 4042-4056] in MeOH (25 mL) and heated overnight at 100° C. After completion of reaction, the reaction mixture was cooled to 0° C. Resultant solid product was filtered off and dried under reduced pressure to provide title compound XI-10-I (1.2 g, 100%). LCMS: m/z 252 (M+1)+.
Reaction SMILES: [F-].[Cs+].[Br:3][C:4]1[S:8][C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1.[F:11][C:12]([Si](C)(C)C)([F:14])[F:13]>COCCOC>[Br:3][C:4]1[S:8][C:7]([CH:9]([OH:10])[C:12]([F:14])([F:13])[F:11])=[CH:6][CH:5]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(Br)s1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: OC(c1ccc(Br)s1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
CsF (400 mg, 2.6 mmol) was added to a solution of 5-bromothiophene-2-carbaldehyde (5.0 g, 26.17 mmol) in dry 1,2-dimethoxyethane (20 mL), followed by trifluoromethyl trimethylsilane (4.6 mL, 31.4 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 3 h, quenched with 1.5N HCl, and stirred for an additional 30 min. The crude product was extracted with CH2Cl2. The combined extracts were dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 5-10% EtOAc in petroleum ether) to get 1-(5-bromothiophen-2-yl)-2,2,2-trifluoroethanol (4 g, yield 59%). 1H NMR (400 MHz, CDCl3) δ 7.01 (m, 1H), 6.95 (m, 1H), 5.23-5.18 (q, J=5.9 Hz, 1H), 3.07 (br s, 1H). MS (ESI) m/z: Calculated for C6H4BrF3OS: 261.91. found: 260.7 (M−1)−.
Reaction SMILES: FC(F)O[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]([OH:15])=[O:14].[F:17][CH:18]([F:29])[O:19]C1C=C2C(C=CN2)=CC=1>>[F:17][CH:18]([F:29])[O:19][C:12]1[CH:11]=[C:10]2[C:6]([C:7]([C:13]([OH:15])=[O:14])=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: FC(F)Oc1ccc2cc[nH]c2c1
Reactant: O=C(O)c1c[nH]c2ccc(OC(F)F)cc12
Product: O=C(O)c1c[nH]c2cc(OC(F)F)ccc12

Procedure:
Prepared as for 5-(difluoromethoxy)-1H-indole-3-carboxylic acid (Example 6) starting with 6-difluoromethoxyindole (WO 97/45408 A1). MS (m/e) 227.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=1)#[CH:2].Cl[C:17]1[N:22]=[CH:21][C:20](I)=[CH:19][N:18]=1>O.C(N)(CC)C.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>[CH:10]([NH:12][C:17]1[N:22]=[CH:21][C:20]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=2)=[CH:19][N:18]=1)([CH2:9][CH3:6])[CH3:11]
Reactant: Clc1ncc(I)cn1
Reactant: C#Cc1ccc(CC(C)NC(C)=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCC(C)N
Solvent: O
Product: CCC(C)Nc1ncc(C#Cc2ccc(CC(C)NC(C)=O)cc2)cn1

Procedure:
2.50 g (12.4 mmol) N-(1-(4-ethynylphenyl)propan-2-yl)acetamide (I58.3), 3.0 g (12.42 mmol) 2-chloro-5-iodopyrimidine and 872 mg (1.24 mmol) bis(triphenylphosphine)dichloropalladium in 10 mL water and 10 mL sec-butylamine are stirred at r.t. over night. The reaction mixture is diluted with water and extracted with DCM. The organic layer is dried with Na2SO4 and the solvent is removed in vacuo. The residue is purified by column chromatography (silica gel, DCM/MeOH 98/2).
Reaction SMILES: [CH:1]1([C:4]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([CH2:17][CH3:18])[CH:5]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH:53]1[CH2:58][CH2:57][CH:56]([C:59]2[CH:66]=[CH:65][C:62]([C:63]#[N:64])=[CH:61][CH:60]=2)[CH2:55][CH2:54]1>CN(C)C=O>[C:63]([C:62]1[CH:61]=[CH:60][C:59]([CH:56]2[CH2:57][CH2:58][N:53]([C:8]([C:7]3[C:6]([CH2:17][CH3:18])=[CH:5][C:4]([CH:1]4[CH2:2][CH2:3]4)=[C:12]([CH:11]=3)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[CH2:54][CH2:55]2)=[CH:66][CH:65]=1)#[N:64]
Reactant: CCc1cc(C2CC2)c(C(=O)OC)cc1C(=O)O
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(C2CC2)c(C(=O)OC)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.1 %

Procedure:
To a round-bottom flask, which was purged and maintained with a nitrogen atmosphere, was added a solution of 4-cyclopropyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound 226.6., 500 mg, 2.01 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL). HBTU (1.53 g, 4.03 mmol, 2.00 equiv), DIEA (780 mg, 6.04 mmol, 3.00 equiv) were added to the reaction solution, and it was stirred for 5 min at 25° C. 4-(piperidin-4-yl)benzonitrile (compound 1.5, 410 mg, 2.20 mmol, 1.10 equiv) was added to the above mixture. After stirring for 15 h at 25° C., the reaction was quenched by the addition of water. The mixture was extracted with 100 mL of ethyl acetate and the combined organic layers were washed with 4×40 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (4:1) as eluent to furnish 0.830 g (99%) of methyl 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:10][CH3:11])=[C:6]([CH2:8]O)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:10][CH3:11])=[C:6]([CH2:8][Br:32])[CH:7]=1
Reactant: COc1c(C)cc(Br)cc1CO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(C)cc(Br)cc1CBr
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(5-Bromo-2-methoxy-3-methylphenyl)methanol (2.0 g, 8.7 mmol) and triphenylphosphine (4.5 g, 17.4 mmol) were combined in tetrahydrofuran (30 mL) and cooled to 0° C. N-Bromosuccinimide (3.2 g, 17.4 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with concentrated sodium bicarbonate (2×), then brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (hexanes) gave 1.87 g (73%) as a white powder. 1H-NMR (CDCl3, 300 MHz) δ 7.32-7.33 (m, 1H), 7.23-7.24 (m, 1H), 4.46 (s, 2H), 3.82 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33](C1NC=CN=1)(C1NC=CN=1)=[O:34]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[CH2:16][O:17][C:33]2=[O:34])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(CO)Cc2ccc(Cl)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)OCC2Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 80 %

Procedure:
4-[1-(4-Chloro-benzyl)-2-hydroxy-ehtylamino]-piperidine-1-carboxylic acid tert-butyl ester, the intermediate alcohol was dissolved in 15 mL of methylene chloride. Triethylamine (0.423 g, 0.00418 mol, 583 uL 1.2 equiv) was added followed by portionwise addition of carbonyl diimidazole (0.68 g, 0.00418 mol, 1.2 equiv). The mixture was stirred at room temperature and then quenched with water (15 mL). The organic layers were separated and the remaining aqueous layer was extracted with methylene chloride (3×15 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow solid. The crude oil was purified by silica gel chromatography (methylene chloride to 10% methanol in methylene chloride gradient) to afford 4-[4-(4-chloro-benzyl)-2-oxo-oxazolidin-3-yl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (1.1 g, 80%).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1.COC1C=C([Br:30])C=CC=1C=O>>[Br:30][C:3]1[CH:2]=[CH:7][C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([O:18][CH3:19])[CH:4]=1
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Reactant: COc1cc(Br)ccc1C=O
Product: COc1cc(Br)ccc1C(O)C#Cc1ccccc1
Yield: 96 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2-methoxy-4-bromobenzaldehyde was reacted to give the title compound as a pale yellow oil (1.43 g, 96%). LCMS (Method B): RT=4.53 min, [M+H]+=299/301.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:7][C:8]1[CH:13]=[C:12]([C:14]([Cl:17])([Cl:16])[Cl:15])[CH:11]=[CH:10][N:9]=1.Cl>N1C=CC=CC=1>[C:1]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([Cl:15])([Cl:17])[Cl:16])[CH:11]=[CH:10][N:9]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: Nc1cc(C(Cl)(Cl)Cl)ccn1
Agent: Cl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1cc(C(Cl)(Cl)Cl)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
7.3 ml (0.07 mol) of butyryl chloride were added to 10.6 g (0.05 mol) of 2-amino -4-trichloromethylpyridine and 70 ml of pyridine at 0° C. while cooling with ice. After stirring for three hours at 25° C., the reaction mixture was added to 5% strength hydrochloric acid and this mixture was extracted with ether. 12.7 g (90%) of the product wre obtained from the organic phase. Mp.: 88°-90° C., Active ingredient Example 1.003
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]1(C)C=CC=C[CH:14]=1.C([Sn](CCCC)(CCCC)C=C)CCC>C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([CH:13]=[CH2:14])[N:11]=[C:10]([Cl:12])[CH:9]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Reactant: Cc1ccccc1
Agent: [Pd]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Product: C=Cc1cc(C(=O)OC)cc(Cl)n1
Yield: 70 %

Procedure:
Add methyl 2,6-dichloroisonicotinate (3.8 g, 18.4 mmol), tetrakis(triphenylphosphine)palladium (0) (1.15 g, 0.99 mmol), triphenyhlphosphine (524 mg, 2 mmol) and toluene (40 mL) in a previously nitrogen-filled sealed vessel. Flush the reactants with nitrogen again. Add tributyl(vinyl)tin (6.98 mL, 24.0 mmol) under nitrogen and heat the sealed mixture at 95° C. overnight with vigorous stirring. Cool the reaction to room temperature, dilute with diethyl ether and filter through a filtering agent. Wash the organic filtrate with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 5:95 to 10:90 ethyl acetate:hexanes) to give the title compound (70%).
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].[CH3:5][O:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:3][C:1]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([O:6][CH3:5])=[O:15])=[CH:9][CH:10]=1)=[O:2]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(OC(=O)Cl)cc1

Procedure:
A 20% solution of phosgene (170 mL, 0.33 mol) in toluene was added to a 500 mL pear-shaped flask (flame-dried, N2). To the flask was added methyl-p-hydroxybenzoate (42.6 g, 0.28 mol) with stirring. Through an addition funnel was added pyridine (26.7 mL, 0.33 mol) in toluene while the reaction mixture was cooled in an ice bath so that the temperature did not exceed 20° C. The solution turned a yellowish color during the addition. The reaction mixture was stirred for 3 h, at which point the mixture was filtered on a buchner funnel. The pyridinium salts were washed with toluene (150 mL) and the combined organic phase washed with 1 N HCl (2×), water (2×), dried over CaCI2 and Na2SO4, and the toluene removed in vacuo to yield yellowish crystals. After continued drying, the product (38 g, 63%) turned a greyish color. m.p. 52-53° C. (lit. 51-52° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1.[CH:16]1([C:19](=[S:21])[NH2:20])[CH2:18][CH2:17]1>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:19]([CH:16]2[CH2:18][CH2:17]2)[S:21][C:5]=1[C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)=[O:15]
Reactant: COC(=O)C(=O)C(Cl)c1cccc(C)c1
Reactant: NC(=S)C1CC1
Product: COC(=O)c1nc(C2CC2)sc1-c1cccc(C)c1

Procedure:
prepared by reaction of 3-chloro-2-oxo-3-m-tolyl-propionic acid methyl ester with cyclopropanecarbothioic acid amide. LC-MS: tR=0.99 min; [M+H]+=274.3.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:29][O:30][CH2:31][CH2:32]Br>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:32][CH2:31][O:30][CH3:29])[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2cc[nH]c2c(=O)n1C
Reactant: COCCBr
Product: COCCn1ccc2c(-c3ccc(Cl)cc3)c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 from methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 2-bromoethyl methyl ether. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.59-7.65 (m, 1H) 7.45-7.51 (m, 2H) 7.39-7.45 (m, 1H) 7.10-7.16 (m, 1H) 5.91-5.99 (m, 1H) 5.30-5.38 (m, 1H) 4.67-4.87 (m, 2H) 3.72-3.86 (m, 2H) 3.67 (s, 3H)) 3.34 (s, 3H) 1.01 (s, 9H); LCMS (m/z) ES+=447 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1F.[NH2:14][C:15]1[N:19]=[CH:18][NH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[NH2:14][C:15]1[N:19]=[CH:18][N:17]([C:7]2[C:2]([Cl:1])=[CH:3][C:4]([C:10]([F:13])([F:12])[F:11])=[CH:5][C:6]=2[Cl:9])[N:16]=1
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: Nc1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 100 °C

Procedure:
To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (1.0 g) in dimethylformamide (5 ml) was added 3-amino-1,2,4-triazole (360 mg) and potassium carbonate (296 mg), the mixture was heated at 100° C. for 2 hrs. The reaction was cooled to room temperature, diluted with water (100 ml) and extracted with ether (100 ml). The organic extracts were evaporated to dryness to give the title compounds as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([OH:19])[CH:3]=1.Br[CH:21]([CH2:25][CH3:26])[C:22](=[O:24])[CH3:23]>C(#N)C>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([O:19][CH:21]([CH2:25][CH3:26])[C:22](=[O:24])[CH3:23])[CH:3]=1
Reactant: CCC(Br)C(C)=O
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Solvent: CC#N
Product: CCC(Oc1cc(N)c(Cl)cc1C(=O)NCCN(CC)CC)C(C)=O
Reaction time: 3 h
Yield: 20.3 %

Procedure:
A solution of the tetrabutylammonium salt of 4-amino-5- chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (10.5 g, 20 mmoles) (from Preparation No. 3) in acetonitrile (150 ml) was treated with 3-bromo-2-pentanone (3.3 g of 80%, 20 mmoles, contaminated with 15% of 1-bromo-2-pentanone) [obtained according to the procedure of E. T. Borrows, D. O. Holland and J. Kenyon, J. Chem. Soc. 1083, (1946)]. After 3 hours, the solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with water, dried, and the solvent evaporated. The semisolid residue was triturated with ether to yield a solid which was recrystallized from etherpetroleum ether to yield 1.5 g of the title compound, mp. 75°-78°. The NMR spectrum (90 MHz) in CDCl3 gave the following resonances: δ8.26 (s, 1H); 8.14 (bs, 1H); 6.1 (s, 1H); 4.5 (t, 1H); 4.4 (s, 2H); 3.69 (q, 2H); 2.64 (m, 6 H); 2.1 (s, 3H); 2.1-1.7 (m, 2H); 1.05 (m, 9H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[Li+].Cl[CH2:16][C:17]([CH3:24])=[CH:18][CH2:19][O:20][C:21](=[O:23])[CH3:22]>CN(C)C=O>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([CH2:16][C:17]([CH3:24])=[CH:18][CH2:19][O:20][C:21](=[O:23])[CH3:22])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: CC(=O)OCC=C(C)CCl
Reactant: O=S([O-])c1ccc(C(F)(F)F)cc1
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(=O)OCC=C(C)CS(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
A mixture of the sulfinic acid salt (26.0 g.) and 1-chloro-2-methyl-4-acetoxy-but-2-ene (9.75 g.) in 125 ml. of dimethylformamide was heated to 60°C. for 33/4 hours, cooled, poured into 1.21. of water and extracted with ethyl acetate. The extracts were washed with water and brine and dried. Removal of the solvent afforded 18.72 g. of the desired product. Chromatography of a 3.5 g. portion on silica gel gave 3.25 g. of the 1-(p-trifluoromethylphenylsulfonyl)-2-methyl-4-acetoxy-but-2-ene as a colorless oil. Anal. calcd. for C14H15F3O4S: C 50.00, H 4.50, S 9.53; found C 49.77, H 4.68, S 9.71%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2B(O)O)[CH:7]=1.Br[C:26]1[N:31]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C=CC=CC=1.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:26]2[N:31]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=[CH:28][CH:27]=2)[CH:7]=1
Reactant: CCOC(=O)c1cccc(Br)n1
Reactant: OB(O)c1ccccc1-c1cc(Cl)ccc1OCc1ccccc1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2OCc2ccccc2)n1
Temperature: 90 °C
Yield: 83.4 %

Procedure:
A mixture of {5′-chloro-2′-[(phenylmethyl)oxy]-2-biphenylyl}boronic acid (1.32 g, 3.9 mmol), ethyl 6-bromopicolinate (851 mg, 3.7 mmol), potassium carbonate (2.76 g, 20 mmol) and tetrakis(triphenylphosphine)palladium(0) (232 mg, 0.2 mmol) in 1:1 toluene/ethanol (25 ml) was stirred and heated at 90° C. under nitrogen for 1.5 hours. After cooling and dilution with diethyl ether/water the organic phase was separated, dried (magnesium sulphate) and evaporated. The residue was chromatographed on silica eluting with ethyl acetate/iso-hexane (3:17) to give 1.37 g of white solid. LC/MS t=3.76, [MH+] 444.3