Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:6][CH:7]=1.Cl[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]([OH:38])=[O:37])[CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([C:36]([OH:38])=[O:37])[CH:31]=3)[CH2:24][CH2:23]2)=[N:6][CH:7]=1
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: COC(=O)c1ccc(NCC2CCNCC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Product: COC(=O)c1ccc(NCC2CCN(c3ccnc(C(=O)O)c3)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Yield: 82.5 %

Procedure:
Using a similar procedure to that described in Example 52, N-(5-chloropyridin-2-yl)-5-methoxycarbonyl-2-[(4-piperidinylmethyl)amino]benzamide (0.30 g, 0.74 mmol) and 4-chloropicolinic acid (0.23 g, 1.5 mmol) afforded 320 mg (82%) of the title compound.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[C:10]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][N:29]([CH2:37][C@H:38]([OH:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)C(=O)OC(C)(C)C)=[CH:23][CH:22]=3)[CH:11]=[CH:12][C:13]=2[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:46]>O1CCOCC1>[ClH:46].[CH:1]1([O:7][C:8]2[CH:9]=[C:10]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][NH:29][CH2:37][C@H:38]([OH:45])[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)=[CH:25][CH:26]=3)[CH:11]=[CH:12][C:13]=2[C:14]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C(=O)NS(C)(=O)=O)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)NC(=O)c1ccc(-c2ccc(CCNC[C@H](O)c3ccccc3)cc2)cc1OC1CCCCC1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl [2-[3′-(cyclohexyloxy)-4′-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]ethyl][(2R)-2-hydroxy-2-phenylethyl]carbamate (89 mg) in 1,4-dioxane (2 ml) was added 4N hydrogen chloride solution in 1,4-dioxane (4 ml) at room temperature and the mixture was stirred at the same temperature for 2 hours. The mixture was evaporated under reduced pressure to give 3-(cyclohexyloxy)-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-N-(methylsulfonyl)-4-biphenylcarboxamide hydrochloride (76 mg).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].Br[CH2:9][CH:10]1[CH2:12][CH2:11]1>[OH-].[Na+].O1CCOCC1>[NH2:1][C@@H:2]([CH2:3][S:4][CH2:9][CH:10]1[CH2:12][CH2:11]1)[C:5]([OH:7])=[O:6]
Reactant: BrCC1CC1
Reactant: N[C@@H](CS)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N[C@@H](CSCC1CC1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An ice water bath cooled solution of L-cysteine in 1N sodium hydroxide (740 mL) and dioxane (740 mL) was treated with bromomethylcyclopropane (50 g, 370 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 16 h. Dioxane was removed under reduced pressure and the resulting aqueous solution was adjusted to pH 6 with 6N HCl and placed in a refrigerator for 20 h. The product was collected by vacuum filtration, washed with hexanes and lyophilized to give 2(R)-amino-3-cyclopropylmethylsulfanylpropionic acid (57.28 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=2)[CH:3]=1.Br[C:28]1[CH:29]=[C:30]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:31]=[N:32][CH:33]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[CH:19]=[C:20]([C:28]3[CH:29]=[C:30]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:31]=[N:32][CH:33]=3)[CH:21]=[CH:22][CH:23]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(B(O)O)c2)c1
Reactant: NS(=O)(=O)c1cncc(Br)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cncc(S(N)(=O)=O)c3)c2)c1

Procedure:
The title compound was prepared from 3-[4-methyl-6-(4-trifluoromethyl-phenyl)pyridin-2-yl]-benzeneboronic acid (example G.10) (0.407 g, 1.14 mmol) and commercially available 5-bromo-pyridine-3-sulfonic acid amide (178 mg, 1.14 mmol) according to the general procedure VI. Obtained as a white solid (0.101 g, 19%). MS (ISP) 470.3 [(M+H)+]; mp 217° C.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([NH:8][C:9]2[C:14]([C:15]3[N:16]=[C:17]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:18]4=[N:19][CH:20]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:2]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[CH3:29][Si:28]([CH3:31])([CH3:30])[CH2:27][CH2:26][O:25][CH2:24][N:21]1[C:18]2=[N:19][CH:20]=[C:15]([C:14]3[C:9]([NH:8][CH:3]4[CH2:4][CH2:5][CH2:6][CH2:7][N:1]([C:32](=[O:34])[CH3:33])[CH2:2]4)=[N:10][CH:11]=[CH:12][CH:13]=3)[N:16]=[C:17]2[CH:23]=[CH:22]1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3NC3CCCCNC3)cnc21
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCCCC(Nc2ncccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
1-(3-{3-[5-(2-Trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-ylamino}-azepan-1-yl)-ethanone was prepared from azepan-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and acetic anhydride, following the general synthetic procedures described in the above Examples.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:21]([OH:23])=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:21]([N:33]1[CH2:34][CH2:35][N:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:31][CH2:32]1)=[O:23])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)N1CCN(c2ccccc2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.6 %

Procedure:
12.3 g of N-benzyloxycarbonyltyrosine and 6.6 g of N-phenylpiperazine were dissolved in 150 ml of methylene chloride, and to the solution was added 8.4 g of DCC, and the mixture was stirred at a room temperature for 5 hours. Precipitated insoluble matter was filtered off and the filtrate was concentrated under a reduced pressure, and resulting residue was applied to a silica gel column and eluted with hexane/ethyl acetate (1:1 to 1:2) to obtain 10.5 g of the title compound in a colorless amorphous form.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[CH2:11]([C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[O:26])[CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C:18]1[CH:19]=[C:20]([NH:24][C:25]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:26])[CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: O=C=Nc1cccc(Cc2ccccc2)c1
Product: NC(=O)CC[C@H](NC(=O)Nc1cccc(Cc2ccccc2)c1)C(=O)O
Yield: 72.8 %

Procedure:
Preparation from L-(+)-glutamine (0.487 g, 3.33 mmol) and 3-benzylphenyl isocyanate (0.719 g, 3.33 mmol) (final pH value after 24 h stirring: 5-6) gave N2-[(3-benzylphenylamino)carbonyl]-L-glutamine (0.862 g, 73%, white solid).
Reaction SMILES: [C:1]([C:3]1[CH:39]=[CH:38][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:29]([N:31]([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])=[O:30])=[C:18]([CH:28]=2)[O:19][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:41][OH:42].[O-]CC.[Na+]>C(O)C>[NH2:2][C:1](=[N:41][OH:42])[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:29](=[O:30])[N:31]([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:33])[CH3:34])=[C:18]([CH:28]=2)[O:19][C:20]([CH3:26])([CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:38][CH:39]=1
Reactant: CCOC(=O)C(C)(C)Oc1cc(OCCCCCOc2ccc(C#N)cc2)ccc1C(=O)N(C(C)C)C(C)C
Reactant: NO
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1cc(OCCCCCOc2ccc(C(N)=NO)cc2)ccc1C(=O)N(C(C)C)C(C)C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A stirred solution of ethyl 2-[5-[5-(4-cyanophenoxy)pentyloxy]-2-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]-2-methylpropanoate (1.2 g, 2.3 mmol) in 30 mL of anhydrous ethanol is treated with hydroxylamine hydrochloride (480 mg, 6.8 mmol) and 21% sodium ethoxide solution in ethanol (2.6 mL, 6.8 mmol) and stirred at 50° C. overnight. The reaction is concentrated in vacuo and purified by chromatography on silica gel (20 g) with 80% ethyl acetate/hexane as the eluent to afford ethyl 2-[5-[5-[4-[amino(hydroxyimino)methyl]-phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxy]-2-methylpropanoate as a colorless foam;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:25][C@@:23]3([CH3:24])[C@@H:19]([CH2:20][C@@H:21]([CH3:31])[C@@H:22]3[C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[C@H:18]3[C:9]2=[C:10]2[C:15]([CH2:16][CH2:17]3)=[CH:14][C:13](=[O:32])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[F:33][C:34]1[N:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH:28]1([C:26]([C@H:22]2[C@H:21]([CH3:31])[CH2:20][C@H:19]3[C@H:18]4[C:9]([C@@H:8]([C:5]5[CH:4]=[CH:3][C:2]([C:37]6[CH:38]=[N:39][C:34]([F:33])=[CH:35][CH:36]=6)=[CH:7][CH:6]=5)[CH2:25][C@:23]23[CH3:24])=[C:10]2[C:15](=[CH:14][C:13](=[O:32])[CH2:12][CH2:11]2)[CH2:16][CH2:17]4)=[O:27])[CH2:29][CH2:30]1
Reactant: OB(O)c1ccc(F)nc1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(Br)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(-c4ccc(F)nc4)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Yield: 65 %

Procedure:
(11β,16α,17β)-11-(4-Bromophenyl)-17-cyclopropylcarbonyl-16-methylestra-4,9-dien-3-one and 6-fluoro-3-pyridinylboronic acid were used as described in example 1 step h. Purification by LCMS followed by lyophilisation gave the product (65% yield). 1H NMR (400 MHz, CDCl3): δ 0.34 (s, 3H), 0.80-2.85 (m, 24H), 4.45 (d, J=7 Hz, 1H), 5.80 (s, 1H), 7.00 (dd, J=8 and 3 Hz, 1H), 7.25-7.29 (m, 2H), 7.44-7.48 (m, 2H), 7.95 (dt, J=8 and 3 Hz, 1H), 8.41 (d, J=3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13](=[N:15]O)[CH3:14])=[CH:9][CH:8]=2)=[C:4]([F:19])[CH:3]=1.N.[H][H]>CO.[Ni]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]([NH2:15])[CH3:14])=[CH:11][CH:12]=2)=[C:4]([F:19])[CH:3]=1
Reactant: CC(=NO)c1ccc(Oc2ccc(Cl)cc2F)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(N)c1ccc(Oc2ccc(Cl)cc2F)cc1
Yield: 89 %

Procedure:
2.60 g (9.3 mmol) of 1-[4-(4-chloro-2-fluoro-phenoxy)-phenyl]-ethanone-oxime were dissolved in 20 mL methanol, then combined with 30 mL 7N methanolic ammonia solution and after the addition of 0.2 g Raney nickel hydrogenated at ambient temperature and 50 psi hydrogen pressure. Then the catalyst was filtered off and the filtrate was evaporated down. The crude product thus obtained was reacted further without any further purification.
Reaction SMILES: [NH2-].[Li+].N.[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH:9]([O:13][CH3:14])[CH2:10][C:11]#[CH:12].Br[CH2:16][CH2:17][CH2:18][C:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21]>O1CCCC1>[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH:9]([O:13][CH3:14])[CH2:10][C:11]#[C:12][CH2:16][CH2:17][CH2:18][C:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21]
Reactant: C#CCC(OC)c1ccco1
Reactant: COC(CCCBr)(OC)OC
Agent: N
Agent: [Li+]
Agent: [NH2-]
Solvent: C1CCOC1
Product: COC(CC#CCCCC(OC)(OC)OC)c1ccco1
Yield: 120.9 %

Procedure:
To a stirred solution of 4.09 g of lithium amide and 200 ml of liquid ammonia was added dropwise a solution of 24.3 g of 4-(2-furyl)-4-methoxy-1-butyne in 20 ml of tetrahydrofuran during 10 minutes. The mixture was stirred under reflux for 30 minutes and then treated dropwise with a solution of 40.4 g of 1-bromo-4,4,4-trimethoxybutane (U.S. Pat. No. 3,864,387) in 40 ml of tetrahydrofuran during 10 minutes. This solution was stirred under reflux for 60 minutes, the ammonia was allowed to evaporate over one hour and the resulting solution stirred at 20° C. for 10 minutes. The solution was then partitioned between ether and water, the organic layer separated, washed with brine, dried and concentrated, giving 58 g of crude 8-(2-furyl)-1,1,1,8-tetramethoxy-5-octyne as a liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[C:14]([OH:21])[CH:15]=[CH:16][CH:17]=4)[N:12]=3)=[N:9][N:10]=[C:4]2[CH:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:36][CH2:35][C:32]2([O:34][CH2:33]2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[OH:34][C:32]1([CH2:33][O:21][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[C:11]([C:8]2[N:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]4=[N:10][N:9]=2)[CH:20]=[CH:19]3)[CH2:31][CH2:30][N:29]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: Cc1ccn2c(-c3ccc4cccc(O)c4n3)nnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1ccn2c(-c3ccc4cccc(OCC5(O)CCN(C(=O)OC(C)(C)C)CC5)c4n3)nnc2c1
Temperature: 98 °C
Yield: 48.2 %

Procedure:
A mixture of 2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol (prepared according to Example 1; 20 mg, 0.72 mmol), tert-butyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate (178 mg, 0.83 mmol) and cesium carbonate (472 mg, 1.5 mmol) in dimethylacetamide (2.5 mL) was heated to 98° C. overnight. The mixture cooled to ambient temperature, filtered through celite and concentrated under reduced pressure. The residue was purified by silica gel chromatography with a gradient of dichloromethane to 1:9 methanol/dichloromethane to provide 170 mg (48%) of desired product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]2)[CH2:3][CH2:2]1.[CH3:31][C:32]([CH3:36])([CH3:35])[CH:33]=O>>[CH3:31][C:32]([CH3:36])([CH3:35])[CH2:33][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)C=O
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCNCC2)cn1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCN(CC(C)(C)C)CC2)cn1

Procedure:
Following the procedure for Example 81; 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (1-piperidin-4-yl-1H-imidazol-4-yl)-amide was reacted with trimethylacetaldehyde to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 18.8, 27.8, 30.5, 33.3, 33.8, 36.0, 43.1, 53.1, 53.3, 55.9, 69.6, 102.6, 102.9, 103.1, 105.8, 112.3, 112.6, 131.5, 137.6, 138.7, 162.0, 164.4, 169.2; MS 490.3 m/z (M+1).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])=[C:20]([CH:24]=1)[C:21](O)=[O:22]>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])=[C:20]([CH:24]=1)[C:21]([NH:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4])=[O:22]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1Oc1ccc(F)cc1F
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2ccc(F)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5) and 5-chloro-2-(2,4-difluorophenoxy)benzoic acid (step 2): 1H-NMR (CDCl3) δ 8.16 (1H, d, J=2.6 Hz), 7.98 (2H, d, J=8.1 Hz), 7.80–7.70 (1H, m), 7.39 (2H, d, J=8.1 Hz), 7.34 (1H, dd, J=8.9, 2.6 Hz), 7.14–6.87 (3H, m), 6.73 (1H, d, J=8.9 Hz), 5.45–5.27 (1H, m), 3.90 (3H, s), 1.55 (3H, d, J=6.9 Hz); MS (ESI) m/z 446 (M+H)+, 444 (M−H)−.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:16](O)[CH3:17]>S(=O)(=O)(O)O>[C:1]1([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: O=C(O)CCc1cccc2ccccc12
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCc1cccc2ccccc12

Procedure:
A stirred solution of 50 grams (0.25 mole) of 3-(naphth-1-yl) propanoic acid and 20 drops (catalyst) of concentrated sulfuric acid in 250 mL of ethanol was heated at reflux for about 24 hours. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in diethyl ether, and the solution was washed with two 150 mL portions of an aqueous solution saturated with sodium bicarbonate and then with 150 mL of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 56.0 grams of ethyl 3-(naphth-1-yl)propanoate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:20])([F:19])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])=[O:9]>ClCCl>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][C:15]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:16][C:11]=1[NH:10][C:8](=[O:9])[C:7]([F:6])([F:20])[F:19]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccccc1NC(=O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Cl)cc1NC(=O)C(F)(F)F
Reaction time: 2 h

Procedure:
Placed chlorosulfonic acid (33 mL, 274 mmol) in a 500 mL four necked round bottomed flask. Then added, 2,2,2-Trifluoro-N-(2-methoxyphenyl)acetamide (20 grams, 91.3 mmol) in dichloro methane (100 mL) drop wise, under stirring in 45 minutes at 0° C. The reaction mass was allowed to reach room temperature and stirred for another 2 hours. Quenched the reaction mass into ice cold water and extracted with ethyl acetate (4×200 mL), the combined organic layer was washed with brine solution (1×50 mL), dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to obtain syrupy product. Yield: 17.5 grams.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:29])[O:13][C:14](=O)[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:25])[C:17]=2[S:26][CH3:27])=[CH:3]1.C[N:31](C=O)C>N>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:29])[NH:31][C:14](=[O:13])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:25])[C:17]=2[S:26][CH3:27])=[CH:3]1
Reactant: CN(C)C=O
Reactant: CSc1c(C2=C(c3cn(C)c4ccccc34)C(=O)OC2=O)c2ccccc2n1C
Agent: N
Product: CSc1c(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc2n1C

Procedure:
A solution of 804 mg of 3-(1-methyl-3-indolyl)-4-[1-methyl-2-(methylthio)-3-indolyl]furan-2,5-dione in 12 ml of DMF and 50 ml of 33% aqueous ammonia was heated to 130° C. for 2 hours. The product was filtered off and dried to give 675 mg of 3-(1-methyl-3-indolyl)-4-[1-methyl-2-(methylthio)-3-indolyl]-1H-pyrrole-2,5-dione, m.p. 281°-283° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH3:23])=[CH:17][CH:16]=3)=[CH:11][C:10]=2[F:24])[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])CCC.CCCCCC.B(OC)(OC)[O:37]C.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH3:23])=[CH:17][CH:16]=3)=[CH:11][C:10]=2[F:24])[CH:5]=[C:6]([F:8])[C:7]=1[OH:37]
Reactant: CCCc1ccc(-c2ccc(-c3cc(F)cc(F)c3)c(F)c2)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCc1ccc(-c2ccc(-c3cc(F)c(O)c(F)c3)c(F)c2)cc1
Temperature: -40 °C
Yield: 74.4 %

Procedure:
Under a nitrogen atmosphere, the 3,5-difluoro-[2-fluoro-4-(4-propylphenyl)phenyl]benzene (18.7 g) obtained in the process (1-1) was dissolved in THF (90 mL), and the solution was cooled to −40° C. or lower. Then, 1.6 mol/L of an n-butyllithium/hexane solution (40 mL) was added thereto at a rate which did not allow the internal temperature to be −35° C. or higher, and the product was stirred at −40° C. for an hour. Then, trimethyl borate (7.1 g) was added thereto at −40° C. at a rate which did not allow the internal temperature to be −35° C. or higher. The temperature was slowly increased to room temperature, the product was further stirred for 30 minutes at room temperature, 10% hydrochloric acid (50 mL) was subsequently added thereto under cooling with ice to separate the organic layer, and the organic layer was washed with a saturated salt solution. Then, a 30% hydrogen peroxide solution (8.4 g) was slowly added thereto, and then the product was stirred at 40° C. for 14 hours. The product was cooled with ice, and a 10% aqueous sodium sulfite solution was added thereto at a rate which did not allow the internal temperature to exceed 20° C., thereby separating the organic layer. Toluene was added to the water layer for extraction, the organic layer was added thereto and then washed with a saturated salt solution, and sodium sulfate was added thereto for dehydration. The solvent was distilled off under reduced pressure, and the product was purified by silica gel column chromatography and then recrystallized from hexane, thereby yielding 14.6 g of 2,6-difluoro-4-[2-fluoro-4-(4-propylphenyl)phenyl]phenol (A).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:10]([Sn](CCCC)(CCCC)C=C)[CH2:11]CC>CN(C)C=O.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]([C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1)=[CH2:11]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1cnccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: C=Cc1ccncc1C#N
Temperature: 120 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of compound (20)(1.00 g, 7.21 mmol) in dimethylformamide (15 ml) were added tributyl(vinyl)tin (2.50 ml, 8.65 mmol) and dichlorobis(triphenylphosphine)palladium (0.40 g, 0.58 mmol), and the mixture was stirred at 120° C. under an argon atmosphere for one hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was combined and washed with brine and dried (MgSO4). The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to give a white powder (0.93 g, 99%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:12]([CH2:16][C:17]1[N:18]=[CH:19][NH:20][C:21]=1[C:22]([O:24][CH3:25])=[O:23])[CH2:13][CH2:14]O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[CH2:5]([N:12]([CH2:16][C:17]1[N:18]=[CH:19][NH:20][C:21]=1[C:22]([O:24][CH3:25])=[O:23])[CH2:13][CH2:14][Cl:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)c1[nH]cnc1CN(CCO)Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1[nH]cnc1CN(CCCl)Cc1ccccc1
Temperature: 45 °C
Reaction time: 16 h

Procedure:
Thionyl chloride (0.5 ml, 4 equiv.) was added to a solution of methyl 4-((benzyl(2-hydroxyethyl)amino)methyl)-1H-imidazole-5-carboxylate (1.7 mmol, 1 equiv.) in DCM (10 ml), and the mixture was stirred for 16 h at 45° C. The reaction mixture was cooled to 25° C. and concentrated in vacuo. The residue was taken up in acetonitrile, the solvent was removed, and the residue was dried for 24 h in vacuo. The desired product was thus obtained in the form of a white solid. This was used in the following stage without further purification. Yield: quantitative