Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClCCCl.[CH3:9][NH2:10].ClC(Cl)C.[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[O:20][CH2:19]2>>[Br:15][C:16]1[CH:24]=[CH:23][C:22]([C:21]([NH:10][CH3:9])=[O:25])=[C:18]([CH2:19][OH:20])[CH:17]=1
Reactant: CN
Reactant: O=C1OCc2cc(Br)ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: CNC(=O)c1ccc(Br)cc1CO
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 59.5 %

Procedure:
A 500 mL RB flask was charged with aluminum(III) chloride (4.1 g, 31 mmol) and 10 mL of 1,2-dichloroethane (90 ml, 1142 mmol), then cooled to 0° C. A separate 250 mL flask was charged with 90 mL of 1,2-dichloroethane (90 ml, 1142 mmol) and cooled to 0° C.; methylamine (gas) (1.8 g, 59 mmol) was bubbled through the solution for 10 minutes. The dichloroethane solution was slowly poured into the aluminum chloride solution, resulting in the formation of a thick white slush. This was warmed to room temperature. 5-bromoisobenzofuran-1(3H)-one (5.00 g, 23 mmol) was added in one portion and the reaction mixture was stirred for 2.5 hours and quenched with water. The mixture was filtered to remove the solid impurities, then the filtrate was washed with 0.5N aqueous HCl (100 mL) and brine (200 mL). The organic layer was dried with MgSO4, filtered, and concentrated to give a white solid. This was triturated with EtOAc and filtered to give 4-bromo-2-(hydroxymethyl)-N-methylbenzamide (3.34 g, 58% yield) as a white solid.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@H:2]([CH2:4][CH:5]([CH3:7])[CH3:6])[OH:3].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CO.O.O>[OH:3][CH:2]([CH2:4][CH:5]([CH3:7])[CH3:6])[C:1]([O:9][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)=[O:8]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)C[C@H](O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: COc1ccc(COC(=O)C(O)CC(C)C)cc1
Reaction time: 8 h

Procedure:
To D/L-leucic acid (7.58 g, 57.36 mmol) in MeOH/H2O (9:1, 100 mL) was added a 20% solution of Cs2CO3 in water until the pH reached 7.0. The reaction mixture was concentrated in vacuo to dryness, DMF was added and concentrated in vacuo to dryness again. The solid was suspended in DMF (100 mL) at 0° C., 4-methoxybenzyl chloride (7.8 mL, 51.6 mmol) was added dropwise and the reaction mixture stirred overnight. The mixture was added to water and the product extracted with Et2O, dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 2/8, then 3/7) to afford 4-methoxybenzyl 2-hydroxy-4-methylpentanoate.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)#[CH:25]>>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([C:24]2[N:3]=[N:2][N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[CH:25]=2)=[CH:27][CH:28]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#Cc1ccc(OC)cc1
Product: COc1ccc(-c2cn(C3CCc4c(CC(=O)O)c5ccccc5n4C3)nn2)cc1

Procedure:
The title compound was prepared using analogous procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 1-ethynyl-4-methoxybenzene. 1H NMR (400 MHz, DMSO-d6): δ 12.14 (s, 1 H), 8.67 (s, 1 H), 7.78 (d, 2 H), 7.48 (d, 1 H), 7.42 (d, 1 H), 7.13-6.99 (m, 4 H), 5.40-5.30 (m, 1 H), 4.74 (dd, 1 H), 4.40 (dd, 1 H), 3.80 (s, 3 H), 3.61 (s, 2 H), 3.12-3.01 (m, 2 H). MS (+ESI) m/z: 403.1.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[S:5][C:6]=1[CH:7]([OH:9])[CH3:8].[Cl:20][C:21]1[CH:28]=[C:27](O)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:20][C:21]1[CH:28]=[C:27]([O:9][CH:7]([C:6]2[S:5][C:4]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[N:3][C:2]=2[CH3:1])[CH3:8])[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)O
Reactant: N#Cc1ccc(O)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)Oc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.3 %

Procedure:
2.0 g 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol and 1.18 g 2-chloro-4-hydroxybenzonitrile were dissolved in 50 ml tetrahydrofuran. At −20° C. 2.74 g triphenylphosphine and 1.82 g diethylazodicarboxylate were added. The cooling bath was removed and the reaction mixture stirred at room temperature for four hours. Then the reaction mixture was poured on 100 ml ice cold saturated NH4Cl solution and extracted five times with portions of 80 ml ethyl acetate. The combined organic layers were washed with 100 ml brine then dried over MgSO4. The solvent was evaporated in vacuo and the resulting residue purified by chromatography on silica gel with the eluent n-heptane: ethyl acetate=4:1 to obtain 2.1 g 2-chloro-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-benzonitrile as pale yellow solid.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[H-].[Na+].[C:16](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>O1CCCC1.C(OCC)(=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(I)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
To a solution of 27.5 g of 3-iodo-5-nitro-1H-indazole in 300 ml tetrahydrofuran at 0° C. in an atmosphere of nitrogen gas was added 6.1 g of 60% sodium hydride, and the mixture was stirred at the same temperature for 10 minutes. To the mixture was added 39.8 g of trityl chloride, followed by stirring at room temperature for 1 hour. Water was added and the mixture was diluted with ethyl acetate. The organic layer was sequentially washed with saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The resulting crude crystals were washed with diethyl ether, to give 48.5 g of the title compound as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([O:8][CH2:9][CH:10]([CH3:13])[CH2:11][CH3:12])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:22]([O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O1CCCC1>[C:22]([O:32][C:33]1[CH:34]=[CH:35][C:36]([C:37]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH:10]([CH3:13])[CH2:11][CH3:12])=[O:7])=[CH:14][CH:15]=2)=[O:38])=[CH:40][CH:41]=1)([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23]
Reactant: CCC(C)COC(=O)c1ccc(O)cc1
Reactant: O=C(OCc1ccccc1)Oc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCC(C)COC(=O)c1ccc(OC(=O)c2ccc(OC(=O)OCc3ccccc3)cc2)cc1
Reaction time: 8 h
Yield: 62.7 %

Procedure:
A solution of 16 mmol (3.3 g) of the 2-methylbutyl p-hydroxybenzoate obtained in 1.(2) in a solvent mixture of 20 ml of THF (tetrahydrofuran) and 40 ml of pyridine was cooled, and to the solution was added dropwise a THF solution of 10 mmol (2/9 g) of the 4-carbobenzoxyoxybenzoyl chloride obtained in 1.(4). The temperature was gradually returned to room temperature, and then the mixture was stirred for 8 hours. After conclusion of the reaction, the reaction solution and purified by column chromatography to obtain 2.9 g of 2-methylbutyl 4-(4'-carbobenzoxyoxybenzoyloxy)benzoate [m.p.: 64.4°-65.4° C⟧ (Yield: 63%)
Reaction SMILES: [N-]=[C:2]=[O:3].[N-]=[C:5]=[O:6].[N-]=[C:8]=[O:9].[N-]=C=O.[C:13]1(C(C2C=CC=CC=2)C2C=CC=CC=2)[CH:18]=CC=C[CH:14]=1>>[CH2:8]([C:14]([CH2:2][OH:3])([CH2:5][OH:6])[CH2:13][CH3:18])[OH:9]
Reactant: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Reactant: [N-]=C=O
Product: CCC(CO)(CO)CO

Procedure:
The polyfunctional isocyanate usable in the present invention can be any isocyanate if it contains at least two isocyanate groups. Examples of such compounds usable in the present invention are methane diisocyanate, buthane-1,1-diisocyanate, ethane-1,2-diisocyanate, buthane-1,2-diisocyanate, transvinylene diisocyanate, propane-1,3-diisocyanate, buthane-1,4-diisocyanate, 2-buthene-1,4-diisocyanate, 2-methylbuthane-1,4-diisocyanate, pentane-1,5-diisocyanate, 2,2-dimethylpentane-1,5-diisocyanate, hexane-1,6-diisocyanate, heptane-1,7-diisocyanate, octane-1,8-diisocyanate, nonane-1,9-diisocyanate, decane-1,10-diisocyanate, dimethylsilane diisocyanate, diphenylsilane diisocyanate, ω,ω'-1,3-dimethylbenzene diisocyanate, ω,ω'-1,4-dimethylbenzene diisocyanate, ω,ω'-1,3-dimethylcyclohexane diisocyanate, ω,ω'-1,4-dimethylcyclohexane diisocyanate, ω,ω'-1,4-dimethylnaphthalene diisocyanate, ω,ω'-1,5-dimethylnaphthalene diisocyanate, cyclohexane-1,3-diisocyanate, cyclohexane-1,4-diisocyanate, dicyclohexylmethane-4,4'-diisocyanate, 1,3-phenylene diisocyanate, 1,4-phenylene diisocyanate, 1-methylbenezene-2,4-diisocyanate, 1-methylbenzene-2,5-diisocyanate, 1-methylbenzene-2,6-diisocyanate, 1-methylbenzene-3,5-diisocyanate, diphenylether-4,4'-diisocyanate, diphenylether-2,4'-diisocyanate, naphthalene-1,4-diisocyanate, naphthalene-1,5-diisocyanate, biphenyl-4,4'-diisocyanate, 3,3'-dimethylbiphenyl-4,4'-diisocyanate, 2,3'-dimethoxybiphenyl-4,4'-diisocyanate, diphenylmethane-4,4'-diisocyanate, 3,3'-dimethoxydiphenylmethane-4,4'-diisocyanate, 4,4'-dimethoxydiphenylmethane-3,3'-diisocyanate, diphenylsulfide-4,4'-diisocyanate, diphenylsulfone-4,4'-diisocyanate, bifunctional isocyanates obtained by a reaction with tetramethylene diol and the above described bifunctional isocyanates, polymethylene polyphenyl isocyanate, triphenylmethane triisocyanate, tris(4-phenyl isocyanate thiophosphate), 3,3',4,4'-diphenylmethane tetraisocyanate, three or more isocyanates obtained by a reaction with trimethylol propane and the above described bifunctional isocyanates. Further, dimers and trimers of the above described isocyanates, liquid isocyanates obtained by partial conversion of diphenylmethane-4,4'-diisocyanate to carbodiimide, and the like, can be used. Of these compounds, the liquid isocyanate obtained by partial conversion of diphenylmethane-4,4'-diisocyanate to carbodiimide, and hexane-1,6-diisocyanate are preferable.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:23][CH3:24])=[C:18]([CH:22]=1)[C:19](O)=[O:20]>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:19](=[O:20])[C:18]2[CH:22]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=2[O:23][CH3:24])[CH2:7]1
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: CN1CCc2c(N)cccc2C1
Product: COc1ccc(Cl)cc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 5-chloro-2-methoxybenzoic acid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14]NCC(O)CO)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].COC(C1N=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH:38]([OH:45])[CH2:39]NC(C)(C)C)=[CH:32][CH:31]=2)NC=1)=O.[OH2:46]>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][CH2:39][CH:38]([OH:45])[CH2:37][O:36][C:33]2[CH:34]=[CH:35][C:30]([CH:27]=[O:46])=[CH:31][CH:32]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COC(=O)c1c[nH]c(-c2ccc(OCC(O)CNC(C)(C)C)cc2)n1
Reactant: COc1ccc(CCNCC(O)CO)cc1OC
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCCC(O)COc2ccc(C=O)cc2)cc1OC
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a suspension of NaH (60% oil dispersion, 1.2 g, 0.03 mol) in DMF (20 ml) was added at 70° C. under N2 a solution 3 (37 g, 0.03 ml) in DMF (30 ml). After stirring for 15 minutes at 70° C. a solution of (S) 2 in DMF (50 ml) was added dropwise. After the addition, the mixture was heated at 120° C. for 18 hours. The solution was then poured into H2O and extracted with EtOAc (3X). The organic extracts were washed with H2O (2X), saturated NaCl (1X), dried, filtered and concentrated to dryness. The residue was treated with H2O (250 ml) and AcOH (25 ml) and stirred overnight at room temperature. The solution was extracted with EtOAc (2X), neutralized with saturated Na2CO3 and extracted with CHCl3 (9X). The organic extracts were dried, filtered and concentrated to yield 8.5 g of 4; 'H NMR (CDCl3) δ 2.7 (6H, m), 3.8 (6H, s), 4.1 (3H, m), 6.7 (3H, bs), 6.95 (2H, d), 7.75 (2H, d). ##STR152##
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O)(=[O:12])[CH3:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:44]=[C:45]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)[CH2:46][NH:47][C:48]([C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:52][CH:51]=1)=[O:49]>CN(C=O)C.O>[C:10]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([N:65]1[CH2:64][CH2:63][N:62]([C:45](=[O:44])[CH2:46][NH:47][C:48]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[CH:52][CH:51]=2)=[O:49])[CH2:67][CH2:66]1)=[O:17])(=[O:12])[CH3:11]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: CC(=O)c1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1C(=O)N1CCN(C(=O)CNC(=O)c2ccc(-c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
DIPEA (179.8 mg, 1.39 mmol) was added to the stirred solution of 2-acetyl-benzoic acid (50.75 mg, 0.31 mmol) in DMF (3 mL), HOBt (45.95 mg, 0.34 mmol) and EDCI.HCl (148.14 mg, 0.77 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (120 mg, 0.37 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 50% EtOAc in hexane as eluent) to afford 30 mg (20.6% yield) of biphenyl-4-carboxylicacid {2-[4-(2-acetyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 95.52%, 1H NMR: (DMSO) δ 8.64 (s, 1H), 8.0 (dd, 3H), 7.84-7.72 (q, 4H), 7.7-7.64 (t, 1H), 7.6 (t, 1H), 7.5 (t, 2H), 7.44-7.32 (m, 2H), 4.26-4.1 (dd, 2H), 3.76-3.62 (d, 4H), 3.46 (s, 2H), 3.3 (d, 2H), 2.6 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1.[CH3:12][OH:13].C[O-].[Na+]>O>[CH3:12][O:13][CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1
Reactant: CO
Reactant: ClCc1cn2ccccc2n1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COCc1cn2ccccc2n1
Temperature: 50 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
[step 2] To 2-(chloromethyl)imidazo[1,2-a]pyridine (4.04 g, 24 mmol) obtained in step 1 were added methanol (121 mL) and sodium methoxide (3.93 g, 73 mmol), and the mixture was stirred at 50° C. for 6 hr. The reaction was discontinued with water, and the mixture was extracted with chloroform and the extract was dried over sodium sulfate. Filtration and concentration under reduced pressure gave 2-(methoxymethyl)imidazo[1,2-a]pyridine (3.45 g, 88%).
Reaction SMILES: F[C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:12][C@H:13]1[O:18][C@@H:17]([CH3:19])[CH2:16][NH:15][CH2:14]1.CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[CH3:19][C@@H:17]1[CH2:16][N:15]([C:2]2[C:3]([C:9]([OH:11])=[O:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=2)[CH2:14][C@H:13]([CH3:12])[O:18]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=C(O)c1ncc(F)cc1F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2cc(F)cnc2C(=O)O)C[C@H](C)O1
Yield: 102.2 %

Procedure:
A solution of 3,5-difluoropicolinic acid (20.5 g, 128.86 mmol), cis-2,6-dimethylmorpholine (63.5 ml, 515.43 mmol) and DIEA (45.0 ml, 257.72 mmol) in THF (200 ml) was stirred at room temperature for 3 days. The mixture was diluted with EtOAc and extracted 3 times with aqueous Na2CO3. The aqueous layer was acidified with 1N HCl to bring pH to about 3 and was then saturated with NaCl before being extracted 10 times with EtOAc. The EtOAc layers were dried (MgSO4) and solvent was removed to give 33.5 g of product as a solid.
Reaction SMILES: COC1C=CC2CC3C(=O)C(C)(C=2C=1)CCCC3.Cl[CH2:20][CH2:21][CH2:22][CH2:23][C:24]1([CH3:37])[C:33]2[C:28](=[CH:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=2)[CH2:27][CH2:26][C:25]1=[O:36]>>[CH3:35][O:34][C:30]1[CH:31]=[CH:32][C:33]2[C:24]3([CH3:37])[C:25](=[O:36])[CH:26]([CH2:20][CH2:21][CH2:22][CH2:23]3)[CH2:27][C:28]=2[CH:29]=1
Reactant: COc1ccc2c(c1)CCC(=O)C2(C)CCCCCl
Agent: COc1ccc2c(c1)C1(C)CCCCC(C2)C1=O
Product: COc1ccc2c(c1)CC1CCCCC2(C)C1=O

Procedure:
Using a procedure analogous to that described in Example X for the preparation of 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen 12-one, there is obtained from 30.5 g. of 1-(4-chlorobutyl)-1-methyl-6-methoxy-2-tetralone 15 g. of the title product, b.p. 140° to 145° C. (0.5 mm.).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:24][CH2:23]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc2c(cc(NC3CCNCC3)c3nnc(C)n32)n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc2c(cc(NC3CCN(S(C)(=O)=O)CC3)c3nnc(C)n32)n1Cc1ccccc1
Reaction time: 0.42 h

Procedure:
To 6-benzyl-1,7-dimethyl-N-piperidin-4-yl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-4-amine (7.0 mg, 0.019 mmol, from Example 206) in DCM (2.4 mL) was added methanesulfonyl chloride (1.6 μL, 0.020 mmol, Aldrich) and triethylamine (5.2 μL, 0.037 mmol). After 25 minutes, the solvent was removed in vacuo, and the product was purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (4.2 mg, 50%).
Reaction SMILES: [OH:1][C:2]1[CH:6]([CH:7]([CH3:9])[CH3:8])[N:5]([CH3:10])[C:4](=[O:11])[CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH3:30]>>[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[C:4](=[O:11])[N:5]([CH3:10])[CH:6]([CH:7]([CH3:9])[CH3:8])[C:2]=1[OH:1])=[C:24]2[CH3:30]
Reactant: Cc1c[nH]c2ccc(F)cc12
Reactant: O=Cc1ccccc1
Reactant: CC(C)C1C(O)=CC(=O)N1C
Product: Cc1c(C(C2=C(O)C(C(C)C)N(C)C2=O)c2ccccc2)[nH]c2ccc(F)cc12

Procedure:
Using general procedure C, 4-hydroxy-5-isopropyl-1-methyl-1,5-dihydro-pyrrol-2-one (Lit. 12) was reacted with benzaldehyde and 5-fluoro-3-methyl-1H-indole to give the title compound as a yellow solid. MS: 391.3 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:15]#[C:16][Si](C)(C)C>CN(C=O)C.[Cu]I>[NH:1]1[C:2]2[C:3](=[CH:4][C:5]([C:8]3([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]3)=[CH:6][CH:7]=2)[CH:15]=[CH:16]1
Reactant: COC(=O)C1(c2ccc(N)c(C#C[Si](C)(C)C)c2)CC1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccc3[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
To a degassed solution of methyl 1-(4-amino-3-((trimethylsilyl)ethynyl)phenyl)cyclopropanecarboxylate (4.69 g, 0.02 mol) in DMF (20 mL) was added CuI (1.5 g, 0.008 mol) under N2 at room temperature. The mixture was stirred for 3 hr at room temperature. The insoluble solid was filtered off and washed with EtOAc (50 mL×3). The filtrate was evaporated under reduced pressure to give a residue, which was purified by chromatography column on silica gel (petroleum ether/ethyl acetate=20:1) to give methyl 1-(1H-indol-5-yl)cyclopropanecarboxylate (2.2 g, 51%). 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1 H), 7.33 (d, J=8.4 Hz, 1 H), 7.23-7.18 (m, 2 H), 6.52-6.51 (m, 1 H) 3.62 (s, 3 H), 1.65-1.62 (m, 2 H), 1.29-1.23(m, 2 H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57]/[CH:58]=[CH:59]\[C:60]([CH2:71][CH3:72])([O:63][Si:64]([CH2:69][CH3:70])([CH2:67][CH3:68])[CH2:65][CH3:66])[CH2:61][CH3:62]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:57]/[CH:58]=[CH:59]\[C:60]([CH2:71][CH3:72])([O:63][Si:64]([CH2:69][CH3:70])([CH2:65][CH3:66])[CH2:67][CH3:68])[CH2:61][CH3:62])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCC(/C=C\CBr)(CC)O[Si](CC)(CC)CC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(/C=C\CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Yield: 97.7 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5 (10 μl) and (Z)-1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene (103 mg, 0.321 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (83.6 mg, 98%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[C:16](Cl)=[CH:15][C:12]([NH:13][CH3:14])=[C:11]([N+:18]([O-:20])=[O:19])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:8][C:9]1[C:16]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:15][C:12]([NH:13][CH3:14])=[C:11]([N+:18]([O-:20])=[O:19])[CH:10]=1
Reactant: CNc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNc1cc(N2CCN(C)CC2)c(Cl)cc1[N+](=O)[O-]

Procedure:
The sub-title compound was prepared from N-methylpiperazine (200 mg, 2.0 mmol), 4,5-dichloro-N-methyl-2-nitroaniline (442 mg, 2.0 mmol) and potassium carbonate (304 mg, 2.2 mmol) in DMF (10 mL) in accordance to example 9 step (d).