Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:35])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([O:28][C@@H:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].Cl.F[CH2:38][C:39](C1ON=C(NC(=O)NC2C=CC(NC(=O)C3C=CC(OC4CCNCC4)=CN=3)=CC=2)C=1)(C)[CH2:40]F>>[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:35])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([O:28][C@@H:29]4[CH2:33][CH2:32][N:31]([CH:39]([CH3:40])[CH3:38])[CH2:30]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(O[C@@H]4CCNC4)cn3)cc2)no1
Agent: Cl
Product: CC(C)N1CC[C@@H](Oc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)nc2)C1
Yield: 94 %

Procedure:
(R)-N-(4-(3-(5-tert-Butylisoxazol-3-yl)ureido)phenyl)-5-(1-isopropylpyrrolidin-3-yloxy)picolinamide (95 mg, 94%) was prepared using a procedure analogous to that described in Example 20, substituting (R)-N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-5-(pyrrolidin-3-yloxy)picolinamide hydrochloride from Step 1 of this example for N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride used in Example 20. LC-MS (ESI) m/z 507 (M+H)+.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][N:8]=1.[CH3:9][O:10][C:11](=[O:15])[CH2:12][C:13]#[N:14]>C1COCC1>[CH3:9][O:10][C:11](=[O:15])[C:12]([C:13]#[N:14])=[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][NH:8]1
Reactant: COC(=O)CC#N
Reactant: COC1=NCCCC1
Solvent: C1CCOC1
Product: COC(=O)C(C#N)=C1CCCCN1
Temperature: 70 °C
Yield: 79.9 %

Procedure:
A mixture of 2,3,4,5-tetrahydro-6-methoxypyridine (1.1 g, 9.72 mmol) and cyanoacetic acid methyl ester (1 g, 10.1 mmol) in 40 mL THF was heated at 70° C. overnight. The reaction was cooled, and solvent was removed in vacuo. The resulting residue was purified on flash column to afford cyano-2-piperidinylidene-ethanoic acid methyl ester (1.4 g, 80%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][NH:19][CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]3)[CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[Cl:35][C:36]1[C:37]2[CH:47]=[CH:46][CH:45]=[CH:44][C:38]=2[S:39][C:40]=1[C:41](Cl)=[O:42]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][N:19]([C:41]([C:40]3[S:39][C:38]4[CH:44]=[CH:45][CH:46]=[CH:47][C:37]=4[C:36]=3[Cl:35])=[O:42])[CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:22][CH2:21]3)[CH:11]=2)=[CH:8][CH:9]=1)(=[O:3])[NH2:2]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: COc1ccc(-c2ccc(C(N)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(C(N)=O)cc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 55 (267 mg, 0.57 mmol) is treated with 3-chloro-benzo[b]thiophene-2-carbonyl chloride (158 mg, 0.69 mmol) using Method D to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C(OCC)(=O)C>CS(C)=O>[CH3:13][C:4]1[CH:3]=[C:2]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: NCc1ccccn1
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc(NCc2ccccn2)c2cccc(O)c2n1
Temperature: 160 °C
Yield: 43.9 %

Procedure:
A mixture of the 4-chloro-2-methylquinolin-8-ol (2.00 g, 10.3 mmol) and 2-aminomethyl pyridine (3.35 g, 30.9 mmol) in DMSO (5 mL) was heated at 160° C. for 2 h under nitrogen atmosphere. The mixture was cooled, poured into ice/NaHCO3 and extracted with ethyl acetate and dichloromethane. Evaporation gave a crude mixture that was mixed with ethyl acetate. The yellow solid precipitated and was filtered and dried to give 1.20 g of 2-methyl-4-((pyridin-2-ylmethyl)amino)quinolin-8-ol (44%). MS (+APCI) 266 (M+). 1H-NMR (CDCl3, δ): 8.56 (m, 1H), 7.79 (t, J=6.0 Hz, 1H), 7.75 (dt, J=2.0, 7.6 Hz, 1H), 7.63 (dd, J=1.2, 8.4 Hz, 1H), 7.34 (d, J=7.6 Hz, 1H), 7.25 (m, 2H), 6.96 (d, J=7.6 Hz, 1H), 6.29 (s, 1H), 4.62 (d, J=6.0 Hz, 2H), 2.41 (s, 3H).
Reaction SMILES: [ClH:1].C([O:5][C:6]1[CH:15]=[C:14]([O:16]C(=O)C)[CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[C:11]2[CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=1)(=O)C.[H][H]>C(O)C.[Pt](=O)=O>[ClH:1].[OH:5][C:6]1[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][NH:10][CH:11]2[CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=1
Reactant: [H][H]
Reactant: COc1cc(Cc2nccc3c(OC(C)=O)cc(OC(C)=O)cc23)cc(OC)c1OC
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: COc1cc(CC2NCCc3c(O)cc(O)cc32)cc(OC)c1OC
Temperature: 50 °C
Yield: 93 %

Procedure:
0.78 g of 5,7-diacetoxy-1-(3,4,5-trimethoxybenzyl)-isoquinoline hydrochloride is dissolved in 200 ml of ethanol, and 0.3 g of platinum dioxide is added thereto. The mixture is shaken at 25° C in a hydrogen atmosphere. After the hydrogen uptake is completed, the catalyst is removed by filtration. 50 ml of a hydrochloric acid-ethanol solution (the content of hydrochloric acid: 9%) are added to the filtrate, and this mixture is heated at 50° C for 5 minutes. Then, the mixture is evaporated to remove solvent, and the residue thus obtained is recrystallized from a mixture of ethanol and isopropyl ether. 0.6 g of 5,7-dihydroxy-1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride is thereby obtained. Yield: 94.6% M.p. 240° - 243° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([CH:34]=[CH:35][CH:36]=1)[CH2:25][N:26]1[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[O:33]=[S:29]1(=[O:32])[CH2:30][CH2:31][N:26]([CH2:25][C:24]2[CH:23]=[C:22]([NH:20][C:18]3[N:19]=[C:15]4[CH:14]=[CH:13][CH:12]=[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)[N:16]4[N:17]=3)[CH:36]=[CH:35][CH:34]=2)[CH2:27][CH2:28]1
Reactant: O=S1(=O)CCN(Cc2cccc(Br)c2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccc3nc(N)nn23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccc3nc(Nc4cccc(CN5CCS(=O)(=O)CC5)c4)nn23)cc1

Procedure:
N-{3-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-5-[4-(methylsulfonyl)phenyl][1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 4-(3-bromo-benzyl)-thiomorpholine 1,1-dioxide (90.0 mg, 0.296 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.042 g, 32%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.26 (d, J=8.5 Hz, 2H), 8.14 (d, J=8.5 Hz, 2H), 7.45 (dd, J=8.2, 1.8 Hz, 1H), 7.30 (t, J=7.7 Hz, 1H), 7.07 (t, J=4.3 Hz, 1H), 6.96-6.91 (m, 2H), 3.65 (s, 2H), 3.16 (s, 3H), 3.07-2.97 (m, 8H). MS=512 (MH)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)[C:5]([NH2:7])=[O:6].[CH3:14][C:15]1[CH:19]=[C:18]([CH:20]([OH:22])[CH3:21])[O:17][N:16]=1>>[NH2:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([NH2:7])=[O:6])=[CH:3][C:2]=1[O:22][CH:20]([C:18]1[O:17][N:16]=[C:15]([CH3:14])[CH:19]=1)[CH3:21]
Reactant: NC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: Cc1cc(C(C)O)on1
Product: Cc1cc(C(C)Oc2cc(C(N)=O)ccc2N)on1

Procedure:
Is prepared in a similar manner as intermediate III.4 from 3-fluoro-4-nitro-benzamide and 1-(3-methylisoxazol-5-yl)ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:13][C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.[CH2:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](O)=O)=[CH:31][CH:30]=1)[CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:10]1([CH2:9][N:8]2[C:7]3[CH:6]=[CH:5][C:4]([NH:13][C:14](=[O:16])[CH3:15])=[CH:3][C:2]=3[N:1]=[C:36]2[CH2:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH2:26][CH3:27])=[CH:30][CH:31]=2)[CH2:11][CH2:12]1
Reactant: CC(=O)Nc1ccc(NCC2CC2)c(N)c1
Reactant: CCOc1ccc(CC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ccc(Cc2nc3cc(NC(C)=O)ccc3n2CC2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
Following procedure 13B, N-{3-amino-4-[(cyclopropylmethyl)amino]phenyl}acetamide (5.50 g, 25.11 mmol), DIPEA (6.50 ml, 37.5 mmol), 4-ethoxyphenylacetic acid (5.40 g, 30.0 mmol) and HATU (11.40 g, 30.0 mmol) in DMF (100 ml) were stirred at room temperature overnight. Isolated the desired product (4.5 g, 86%).
Reaction SMILES: COC[O:4][C:5]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)=[CH:9][C:8]([C:18](=[O:36])[NH:19][CH2:20][C:21]2([CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:23][CH2:22]2)=[CH:7][C:6]=1[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=1.C[Si](Br)(C)C>C(Cl)Cl>[Cl:17][C:13]1[CH:12]=[C:11]([C:10]2[CH:9]=[C:8]([C:18](=[O:36])[NH:19][CH2:20][C:21]3([CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:22][CH2:23]3)[CH:7]=[C:6]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=3)[C:5]=2[OH:4])[CH:16]=[CH:15][CH:14]=1
Reactant: COCOc1c(-c2cccc(Cl)c2)cc(C(=O)NCC2(COCCCCc3ccccc3)CC2)cc1-c1cccc(Cl)c1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=C(NCC1(COCCCCc2ccccc2)CC1)c1cc(-c2cccc(Cl)c2)c(O)c(-c2cccc(Cl)c2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of (3,3″-dichloro-5′-{[1-(4-phenylbutoxymethyl)-cyclopropylmethyl]-carbamoyl}-[1,1′;3′1″]terphenyl-2′-yloxy)methyl methyl ether (0.681 g, 1.10 mmol) in CH2Cl2 (15 mL) at −30° C. containing 4 Å molecular sieves was added trimethylsilyl bromide (0.581 mL, 4.40 mmol). After stirring at this temperature for 1 h, it was warmed to 0° C. and stirred an additional 5 h. Only slight conversion to product so warmed to room temperature and stirred at this temperature for 18 h. At this point, the mixture was quenched with sat. aq. NaHCO3 (10 mL) and extracted with EtOAc (250 mL). The organic layer was washed with brine (25 mL) and dried (MgSO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (10 to 30% EtOAc/petroleum ether gradient) to afford the product (0.455 g, 72%) as a solid; 1H NMR (DMSO-d6) δ 0.32–0.41 (m, 2H), 0.47–0.55 (m, 2H), 1.40–1.62 (m, 4H), 2.46–2.58 (m, 2H), 3.28 (s, 2H), 3.28–3.42 (m, 4H), 7.11–7.20 (m, 3H), 7.20–7.29 (m, 2H), 7.42–7.55 (m, 6H), 7.65 (s, 2H), 7.79 (s, 2H), 8.34 (t, J=6.3 Hz, 1H), 9.19 (s, 1H); mass spectrum [(+) ESI], m/z 574 (M)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].CCN(C(C)C)C(C)C.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>C1COCC1>[Cl:13][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:26]([CH:23]2[CH2:25][CH2:24]2)=[O:27])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)c1cc(CN)ccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cc(CNC(=O)C2CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a solution of methyl 5-(aminomethyl)-2-chlorobenzoate (15.0 g, 75 mmol) in dry THF (150 mL) was added DIPEA (15 mL) under nitrogen atmosphere. Cyclopropanecarbonyl chloride was added to the reaction mixture at 10° C. and (11.81 g, 113 mmol). The reaction mixture was stirred at RT for 5-6 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with dilute HCl, followed with sodium bicarbonate solution and concentrated to afford 10.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.69 (m, 4H), 1.59 (m, 1H), 3.86 (s, 3H), 4.29 (d, J=6.0 Hz, 2H), 7.43 (d, J=6.6 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.67 (s, 1H), 8.64 (br s, 1H); MS (m/z): 268.16 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].I[CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:18]=3)([CH2:13][CH2:14]1)[O:11][CH2:10]2>N1C=CC=CC=1.CCOC(C)=O.[Zn]>[O:23]([C:19]1[CH:18]=[C:17]([C:12]23[CH2:15][CH2:16][C:9]([CH2:8][CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])([CH2:14][CH2:13]2)[CH2:10][O:11]3)[CH:22]=[CH:21][CH:20]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C=CC(=O)OC
Reactant: ICC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Agent: [Zn]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)CCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 50 °C
Yield: 70.2 %

Procedure:
A mixture of Zn (622 mg, 9.52 mmol), anhydrous pyridine (5 mL) and methyl acrylate (0.95 mL, 9.52 mmol) was warmed to 50° C., after which NiCl2.6H2O (283 mg, 1.19 mmol) was added. The resulting mixture was heated to 65° C. for 1 h and stirred until the color of the solution became reddish-brown, then was cooled to 0° C., after which a solution of 4-(iodomethyl)-1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octane (500 mg, 1.190 mmol) in pyridine (2 mL) was added. The reaction mixture was allowed to warm to rt overnight, then was diluted with EtOAc (10 mL) and the resulting mixture was filtered off through a pad of CELITE®. The filtrate was washed with 1 N aq. HCl and brine, dried (MgSO4), and concentrated in vacuo. The residual crude oil was purified by flash chromatography (SiO2; gradient from 0 to 50% EtOAc:hexanes) to afford the title compound as a colorless oil (318 mg, 73% yield). LCMS, [M+H]+=381, 1H NMR (400M Hz, CDCl3) δ 7.39-7.24 (m, 3H), 7.19-7.06 (m, 3H), 7.04-6.98 (m, 2H), 6.86 (ddd, J=8.1, 2.4, 0.9 Hz, 1H), 3.82 (s, 2H), 3.70 (s, 3H), 2.31 (t, J=7.3 Hz, 2H), 2.10-1.98 (m, 4H), 1.76-1.57 (m, 6H), 1.22-1.12 (m, 2H).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:12][CH:13]=1.[C:21]([C:23]1[CH:36]=[CH:35][C:26]([O:27][CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1)#[CH:22]>C1COCC1.[Cu]I>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:10]=[CH:9][C:8]([C:22]#[C:21][C:23]3[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:35][CH:36]=3)=[CH:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: C#Cc1ccc(OCCN2CCCC2)cc1
Reactant: Clc1ccc(-c2ccc(Br)cn2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CCCC4)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under an N2 atmosphere 773 mg (2.25 mmol) Cs2CO3, 14 mg (0.08 mmol) CuI and 87 mg (0.08 mmol) tetrakis-triphenylphosphane-palladium are added to a solution of 403 mg (1.5 mmol) 5-bromo-2-(4-chloro-phenyl)-pyridine and 322 mg (1.5 mmol) 1-[2-(4-ethynyl-phenoxy)-ethyl]-pyrrolidine in 10 mL THF and the reaction mixture is stirred for 4 h at RT. Then it is heated to 60° C. for 16 h. The mixture is evaporated down i. vac., the residue is combined with 30 mL water, 5 mL 3% NH3 solution and 60 mL EtOAc, the organic phase is separated off and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified first by chromatography (silica gel, EtOAc/MeOH/NH3 19:1:0.1) and then by HPLC.
Reaction SMILES: COC(=O)N[C@H](C(=O)[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([N:30]([S:35]([C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:24][O:25][P:26]([OH:29])([OH:28])=[O:27])CC1C=CC2C(=CC=CC=2)C=1.[C:47]([NH:50][C@@H:51]([CH:55]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:52](O)=[O:53])(=[O:49])[CH3:48]>>[C:47]([NH:50][C@@H:51]([CH:55]([C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)[C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[C:52]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([N:30]([S:35]([C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:33])[CH3:34])[CH2:24][O:25][P:26](=[O:27])([OH:28])[OH:29])=[O:53])(=[O:49])[CH3:48]
Reactant: COC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)NCCCC[C@@H](COP(=O)(O)O)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1
Reactant: CC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Product: CC(=O)N[C@H](C(=O)NCCCC[C@@H](COP(=O)(O)O)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1
Yield: 30 %

Procedure:
This compound was made as for the preparation of the product of example 3 (step D) with 100 mg of (2S)-2-acetylamino-3,3-diphenyl-propionic acid (this example step A). The final product was obtained in 30% yield (30 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH:23][C:24](OC2C=CC=CC=2)=[O:25])[C:16](=[CH:21][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:24]([NH:23][C:15]2[CH:14]=[C:13]([Cl:12])[CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])=[O:25])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: COC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1ccc(N)cc1
Yield: 131.1 %

Procedure:
From 2.7 g (15.7 mmol) of 4-aminobenzenesulfonamide and 4.8 g (15.7 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate in a manner similar to Preparation Example 1, 7.9 g (yield 94%) of methyl 2-{[(4-aminobenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate was obtained. Property: colorless amorphous, PMR (δppm, DMSO-d6): 3.59 (3H, s), 5.37 (2H, s), 6.45 (2H, d), 6.83 (1H, dd), 7.41 (2H, d), 7.81 (1H, d), 8.66 (1H, d), 9.64 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]2[C:10](=[O:23])/[C:11](=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)/[CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([Cl:24])[CH:3]=1>CC(O)=O.CCOC(C)=O.[Zn]>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]2[C:10](=[O:23])[CH:11]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([Cl:24])[CH:3]=1
Reactant: COC1=C(c2c(Cl)cc(Br)cc2Cl)C(=O)/C(=C/c2ccccn2)C1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC1=C(c2c(Cl)cc(Br)cc2Cl)C(=O)C(Cc2ccccn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of (5E)-2-(4-bromo-2,6-dichloro-phenyl)-3-methoxy-5-(2-pyridylmethylene)cyclopent-2-en-1-one (235 mg, 0.55 mmol) in glacial AcOH (2.4 ml) at 0°C. was added zinc dust (126 mg, 1.94 mmol) portionwise over 10 minutes. The reaction was stirred at room temperature for 2 hours and then diluted with EtOAc (25 ml), filtered through Celite and washed through with further EtOAc (2×20 ml). The filtrate was evaporated to dryness under reduced pressure and then azeotroped with toluene and then MeOH to give the desired product (235 mg, 99%) as a brown gum. 1H NMR (400 MHz, CDCl3) δ ppm 8.52 (d, 1H), 7.60 (dd, 1H), 7.45 (2×s, 2×1H), 7.25 (d, 1H), 7.15 (dd, 1H), 3.80 (s, 3H), 3.45-3.35 (1H, m), 3.20-3.10 (m, 1H), 3.00-2.90 (1H, m), 2.90-2.85 (m, 2H).
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[Br:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[C:33]([Cl:39])[CH:32]=1>>[Br:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[C:2]([CH3:4])[CH3:3])=[C:33]([Cl:39])[CH:32]=1
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Product: CC(C)=Cc1ccc(Br)cc1Cl

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 23 (23d) using isopropyltriphenylphosphonium iodide (5.4 g, 12.6 mmol), potassium t-butoxide (1.5 g, 13.5 mmol) and 4-bromo-2-chlorobenzaldehyde (2.0 g, 9.0 mmol) that was obtained in Example 24 (24f). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:10 to 6:94) as the eluent to afford the title compound (2.1 g) in a yield of 94% as a colourless oily product.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.ClCCC[N:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30](=[O:32])[CH3:31])=[CH:29][C:24]=2[O:23][C:22]1=[O:33].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([N:21]4[C:25]5[CH:26]=[CH:27][C:28]([C:30](=[O:32])[CH3:31])=[CH:29][C:24]=5[O:23][C:22]4=[O:33])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)c1ccc2c(c1)oc(=O)n2CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc2c(c1)oc(=O)n2N1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.0 g, 9 mmol), N-(3-chloropropyl)-6-acetyl-2-benzoxazolinone (2.4 g, 9 mmol), K2CO3 (3.6 g), a few crystals of KI, and acetonitrile (50 ml) was stirred and refluxed for 13 hours. The reaction was poured into water, and a dark, brown solid that separated was collected to afford 3.3 g of crude product. The solid was chromatographed on a Waters Prep 500 HPLC. Concentration of appropriate fractions afforded 2.3 g of a yellow solid, and recrystallization from ethyl acetate yielded 1.2 g (31%) of N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-6-acetyl-2-benzoxazolinone, m.p.=152°-154° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[C:26]([CH3:31])[CH:25]=[N:24]2.C([O-])(O)=O.[Na+]>ClCCl>[CH3:31][C:26]1[CH:25]=[N:24][C:23]2[C:28](=[CH:29][CH:30]=[C:21]([NH:20][S:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[CH:22]=2)[N:27]=1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cnc2cc(N)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1ccc(S(=O)(=O)Nc2ccc3nc(C)cnc3c2)cc1
Reaction time: 0.08 h
Yield: 98.4 %

Procedure:
To a solution of 4n-propylbenzenesulphonyl chloride (115 mg, 0.528 mmol) in dichloromethane (3 mL) was added pyridine (100 μL, 1.26 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-amino-2-methylquinoxaline (80 mg, 0.50 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (8 mL) was added and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a white solid (168 mg, 95%), single spot at Rf 0.72 (ethyl acetate). mp 135.6-136.2° C., HPLC purity 99+% (tR 2.23 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 8.66 (1H, s), 7.89 (1H, di-J=9.2 Hz), 7.77 (2H, d, J=8.4 Hz), 7.67 (1H, d, J=2.5 Hz), 7.54 (1H, dd, J=8.9, 2.5 Hz), 7.22 (2H, d, J=8.4 Hz), 2.71 (3H, s), 2.56 (2H, t, J=7.7 Hz), 1.58 (2H, sextet, J=7.7 Hz), 0.87 (3H, t, J=7.4 Hz). LCMS: 340.25 (M−). FAB-MS (MH+, C18H19N3O2S): calcd 342.1276, found 342.1290.