Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>C(#N)C>[ClH:1].[CH2:15]([N:17]([CH2:18][CH3:19])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH3:16]
Reactant: CCNCC
Reactant: O=[N+]([O-])c1ccc(OCCCCl)cc1
Solvent: CC#N
Product: CCN(CC)CCCOc1ccc([N+](=O)[O-])cc1
Product: Cl

Procedure:
Heat 19.41 g (0.09 mol) of 1-(3-chloropropoxy)-4-nitrobenzene and 50 mL (0.48 mol) of diethylamine in 100 mL of acetonitrile at 45°-50° C. Follow the progress of the reaction by thin-layer chromatography on silica gel (acetonitrile:ammonium hydroxide, 95:5). At the completion of the reaction remove the solvent in vacuo. Dissolve the residue in 100 mL of H2O and make the mixture acidic (pH=1) with concentrated hydrochloric acid. Extract the acidic solution with 3×100 mL of diethyl ether. Neutralize the acid solution (pH=7) with 20% aqueous sodium hydroxide solution and extract with 3×100 mL of diethyl ether. Adjust the pH of the aqueous layer to 12 with 20% aqueous sodium hydroxide solution and extract with 3×100 mL of diethyl ether. Wash the ether extracts from the basic solution with 50 mL of saturated sodium chloride solution, combine them and dry over anhydrous sodium sulfate. Remove the drying agent by filtration and evaporate the solvent in vacuo. Dissolve the residue in 100 mL of methanol and add concentrated hydrochloric acid until pH=1. Stir the solution with 2 g of charcoal, filter and remove the solvent in vacuo. Recrystallize the residue from acetonitrile to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[F:13])([O-])=O.C(O)C.C(O)(=O)C.[H][H]>[Fe].[Rh].O>[F:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Fe]
Agent: [Rh]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc([N+](=O)[O-])ccc1F
Yield: 78.8 %

Procedure:
In a 500 ml Parr hydrogenation reactor were placed 8.50 g (0.0457 mole) of 2,4-dinitrofluorobenzene, 1.0 g (0.018 mole) of powdered iron, 0.15 g of 5% rhodium on alumina, 100 ml of ethanol, 100 ml of acetic acid, and 5 ml of water. The reaction was stopped after 140 psi of hydrogen had been absorbed, and the reaction mixture was then filtered. The filtrate was concentrated under reduced pressure, and water was added to the residue. Filtration yielded 5.62 g of crude 2-fluoro-5-nitroaniline. Analysis of the nmr spectrum of the product showed it to be >90% pure 2-fluoro-5-nitroaniline.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[CH2:5][NH:4][CH2:3]1.Cl[C:15]1[N:20]=[C:19]2[N:21]([CH3:35])[C:22](=[O:34])[N:23]([C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:33])[C:24](=[NH:25])[C:18]2=[CH:17][N:16]=1.ClC1N=C2NC(=O)N(C3C(Cl)=CC=CC=3Cl)C(=N)C2=CN=1>>[Cl:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:33])[C:26]=1[N:23]1[C:24](=[NH:25])[C:18]2[C:19](=[N:20][C:15]([NH:12][C:8]3[CH:7]=[C:6]4[C:11]([C:2]([CH3:13])([CH3:1])[CH2:3][NH:4][CH2:5]4)=[CH:10][CH:9]=3)=[N:16][CH:17]=2)[N:21]([CH3:35])[C:22]1=[O:34]
Reactant: CC1(C)CNCc2cc(N)ccc21
Reactant: Cn1c(=O)n(-c2c(Cl)cccc2Cl)c(=N)c2cnc(Cl)nc21
Agent: N=c1c2cnc(Cl)nc2[nH]c(=O)n1-c1c(Cl)cccc1Cl
Product: Cn1c(=O)n(-c2c(Cl)cccc2Cl)c(=N)c2cnc(Nc3ccc4c(c3)CNCC4(C)C)nc21

Procedure:
160 mg of the entitled compound was obtained as a white solid according to the same method as in Example 2, for which, however, 4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine was used in place of 2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine in Example 2, and 7-chloro-3-(2,6-dichlorophenyl)-4-imino-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one obtained in Production Example 7 was used in place of 7-chloro-3-(2,6-dichlorophenyl)-4-imino-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.C([Cl:18])(=O)C>>[Cl-:18].[CH3:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[N+:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccccc1C=O
Reactant: CC(=O)Cl
Reactant: C1CCNC1
Product: Cc1ccccc1C=[N+]1CCCC1
Product: [Cl-]

Procedure:
The reaction of 8.2 ml (0.100 mol) pyrrolidine and 7.0 g (0.050 mol) 2-methylbenzaldehyde in accordance with general synthesis instructions 2 and subsequent reaction with 3.9 g (0.050 mol) acetyl chloride in accordance with general synthesis instructions 3 gave 6.6 g (corresponding to 63% of the yield calculated by theory) 1-(2-methyl-benzylidene)-pyrrolidinium chloride.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]([CH:18]2[CH2:23][NH:22][CH2:21][CH2:20][N:19]2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])=[O:17])[CH2:12][CH2:11]1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]([CH:18]2[CH2:23][N:22]([S:40]([C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([O:33][CH3:32])[CH:35]=3)(=[O:42])=[O:41])[CH2:21][CH2:20][N:19]2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])=[O:17])[CH2:12][CH2:11]1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNCCN3c3ccc(F)cc3C)CC2)c1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc(S(=O)(=O)N2CCN(c3ccc(F)cc3C)C(C(=O)N3CCN(c4cc(C)ccc4C)CC3)C2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of [4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-[1-(4-fluoro-2-methyl-phenyl)-piperazin-2-yl]-methanone hydrochloride (42 mg) in DMF (1 mL) was added 3-methoxybenzene sulfonyl chloride (21.4 mg) and triethyl amine (40 μL). The reaction mixture was stirred at ambient temperature for 2 h, was diluted with ethyl acetate and washed with a saturated aqueous solution of NaHCO3. The combined organic phases were washed with water and brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by column chromatography (SiO2, n-heptane/ethyl acetate 2:1) to give [4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-[1-(4-fluoro-2-methyl-phenyl)-4-(3-methoxy-benzenesulfonyl)-piperazin-2-yl]-methanone (42 mg) as white solid, MS: 581.3 ([M+H]+).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([NH:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[O:8])[O:3]1.Cl.O1CCOCC1>C(Cl)Cl.CO>[O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([NH:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:8])[O:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCNC(=O)c2c[nH]c(=O)o2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NCCC1CCNCC1)c1c[nH]c(=O)o1
Temperature: 25 °C

Procedure:
Tert-butyl 4-(2-(2-oxo-2,3-dihydrooxazole-5-carboxamido)ethyl)piperidine-1-carboxylate (step 2) (257.8 mg, 0.760 mmol) was solubilised in DCM (1.5 ml). 4M HCl in dioxane (1.9 ml, 7.60 mmol) was added and the reaction mixture stirred at RT. After all gas had ceased to be evolved, the reaction mixture was solubilised with in MeOH and evaporated under reduced pressure to afford the title compound;
Reaction SMILES: C[O:2][P:3]([CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]([CH2:27][CH3:28])=[C:14]2[CH2:29][C:30]([NH2:32])=[O:31])(=[O:6])[O:4]C.C[Si](Br)(C)C.CO>C(Cl)Cl>[NH2:32][C:30](=[O:31])[CH2:29][C:14]1[C:13]2[C:17](=[CH:18][CH:19]=[C:11]([O:10][CH2:9][CH2:8][CH2:7][P:3](=[O:2])([OH:6])[OH:4])[CH:12]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]=1[CH2:27][CH3:28]
Reactant: CCc1c(CC(N)=O)c2cc(OCCCP(=O)(OC)OC)ccc2n1Cc1ccccc1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CO
Product: CCc1c(CC(N)=O)c2cc(OCCCP(=O)(O)O)ccc2n1Cc1ccccc1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
[3-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]propyl]phosphonic acid dimethyl ester (150 mg, 0.33 mmol) and 0.35 mL (2.6 mmol) of trimethylsilyl bromide in 2 mL of methylene chloride was stirred for 16 hours, 5 mL of MeOH added, stirred 1.0 hour and concentrated at reduced pressure. The residue was crystallized from EtOAc/MeCN/HOAc/water to give 138 mg (97% yield) of [3-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]propyl]phosphonic acid, mp, 194°-196° C.
Reaction SMILES: [N:1]1([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].[K+].[F:15][C:16]([F:21])([F:20])[C:17](F)=[O:18]>C1(C)C=CC=CC=1>[F:15][C:16]([F:21])([F:20])[C:17](=[O:18])[C:8](=[CH:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C(F)C(F)(F)F
Reactant: COC(=O)C=CN1CCCCC1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C(=CN1CCCCC1)C(=O)C(F)(F)F
Temperature: -30 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
Methyl 3-piperidin-1-ylacrylate (97%, 25 g, 0.14 mol) and KF (12.5 g, 76.3 mmol) were initially charged in 250 ml of toluene and cooled to −30° C. At this temperature, trifluoroacetyl fluoride (99.5%, 18.3 g, 0.16 mol) was then introduced. The reaction mixture was stirred at −30° C. for 3 h and then, over a period of one hour, warmed to room temperature. The reaction mixture was washed with deionized water (100 ml). After phase separation, the aqueous phase was extracted once with toluene (100 ml). The toluene phases were combined, washed with an aqueous sat. NaCl solution (100 ml) and then freed from the solvent under reduced pressure. Methyl 4,4,4-trifluoro-3-oxo-2-(piperidin-1-ylmethylidene)butyrate was obtained as an orange solid (amount: 38.0 g; purity according to GC: 98%; yield: 98%). 1H-NMR (CDCl3): δ=1.75 (m, 6H), 3.3 (m, 2H), 3.6 (m, 2H), 3.75 (s, 3H), 7.65 ppm (s, 1H).
Reaction SMILES: FC(F)(F)C1C=CC(CN)=CC=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][NH2:22])[CH:17]=[C:18]([Cl:20])[CH:19]=1.[C:23]([NH:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=1)[C:35](O)=[O:36])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:23]([NH:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=1)[C:35]([NH:22][CH2:21][C:16]1[CH:15]=[C:14]([Cl:13])[CH:19]=[C:18]([Cl:20])[CH:17]=1)=[O:36])(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Reactant: NCc1cc(Cl)cc(Cl)c1
Agent: NCc1ccc(C(F)(F)F)cc1
Product: O=C(NCc1cc(Cl)cc(Cl)c1)c1ccnc(NC(=O)c2ccccc2)c1
Yield: 41 %

Procedure:
Following the procedure as described in Example 1, making variations as required to replace (4-(trifluoromethyl)phenyl)methanamine with (3,5-dichlorophenyl)-methanamine to react with 2-benzamidoisonicotinic acid, 2-benzamido-N-(3,5-dichlorobenzyl)isonicotinamide was obtained as a colorless solid in 41% yield: mp 248-251° C. (dichloromethane/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 11.01 (br s, 1H), 9.42 (br s, 1H), 8.63-8.54 (m, 2H), 8.06 (s, 2H), 7.60-7.39 (m, 7H), 4.53-4.51 (d, J=4.5 Hz, 2H).
Reaction SMILES: C([NH:8][C@H:9]([C:31]([OH:33])=[O:32])[CH2:10][S:11]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OC(C)(C)C)=O.C[O:35][C:36](=[O:56])[C@H:37]([CH2:52][CH2:53][S:54][CH3:55])[NH:38][C:39]([C:41]1[C:50]2[C:45](=[CH:46]C=CC=2)[C:44]([NH2:51])=[CH:43][CH:42]=1)=[O:40].[Li+].[OH-]>C1COCC1>[NH2:8][C@H:9]([C:31]([OH:33])=[O:32])[CH2:10][SH:11].[NH2:51][C:44]1[CH:43]=[CH:42][C:41]([C:39]([NH:38][C@H:37]([C:36]([OH:56])=[O:35])[CH2:52][CH2:53][S:54][CH3:55])=[O:40])=[CH:50][C:45]=1[CH3:46]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CSCC[C@H](NC(=O)c1ccc(N)c(C)c1)C(=O)O
Product: N[C@@H](CS)C(=O)O
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
N-BOC-S-trityl-cysteine-4-amino-1-naphthoyl methionine methyl ester (83.3 mg, 0.11 mmol) was taken up in THF (0.7 ml) and to this mixture was added 0.5 M LiOH (0.43 ml) at 0° C. The mixture was stirred at 0° C. for 35 minutes. The solvent was removed in vacuo using a cold water bath. The residue was worked up as described for TFA.cysteine-4-amino-3-methylbenzoyl methionine in Example 2, and 74.1 mg of the free acid was obtained. This was then dissolved into CH2Cl2 (1 ml) and Et3SiH (0.015 ml) was added followed by TFA (1 ml). The reaction mixture was stirred at room temperature for 1 h and worked up as further described for TFA.cysteine-4-amino-3-methylbenzoyl methionine in Example 2. After lyophilization, 42.4 mg of crude material was obtained which was then purified on the HPLC using 0.1% TFA in water and acetonitrile. mp 121-125° C.; [α]25D =+2.4° (c=0.8, H2O); 1H NMR (CD3OD) 2.03-2.13 (4H, m), 2.22-2.36 (1H, m), 2.59-2.74 (2H, m), 3.16-3.33 (2H, m), 4.42 (1H, m), 4.84-4.89 (1H, m), 7.57-7.61 (2H, m), 7.64 (1H, d, J=7.7 Hz), 7.70 (1H, d, J=7.7 Hz), 8.08-8.11 (1H, m), 8.29-8.32 (1H, m), 8.98 (1H, d, J=7.7 Hz); 13C NMR (CD3OD) 15.19, 26.45, 31.50, 31.63, 53.20, 56.72, 122.52, 123.43, 126.43, 126.12, 127.02, 127.96, 128.32, 129.49, 132.27, 134.15, 135.12, 168.11, 172.41, 175.17; anal. calc. for C21H23F3N3O6S2, C: 47.19, H: 4.34, N: 7.86; found, C: 46.53, H: 4.56, N: 7.59; Note: difference for C is 0.65.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH2:14][C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:24]1([NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH2:30].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(CC)CC>CN(C=O)C>[NH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:31][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=2)=[CH:23][CH:22]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1ccc(CNc2ccc(N3CCOCC3)cc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1ccc(CNc2ccc(N3CCOCC3)cc2)cc1

Procedure:
To a solution of acid 402a (2.61 g; 8.36 mmol; 1 eq), 1,2-phenylenediamine (903 mg; 8.36 mmol; 1 eq) and BOP (3.70 g; 8.36 mmol; 1 eq) in dry DMF (20 ml) was added Et3N (4.64 ml; 33.4 mmol; 4 eq). After stirring overnight most of the DMF was removed under reduced pressure and chromatographed (Hex:EtAcO: 1:2/EtAcO). The crystal 402 was obtained in 70% (2.35 g). 1H-NMR (300.07 MHz; DMSO-d6) δ (ppm): 9.65 (s, 1H), 7.97 (d, J=7.9, 2H), 7.53 (d, J=7.9, 2H), 7.22 (d, J=7.5, 1H), 7.03 (dd, J=7.0, 7.5, 1H), 6.83 (d, J=7.9, 1H), 6.77 (d, J=8.8, 2H), 6.65 (dd, J=7.5, 7.0, 1H), 6.57 (d, J=8.8, 2H), 4.93 (bs, 2H), 4.36 (d, J=5.7, 2H), 3.75 (m, 4H), 2.93 (m, 4H). LRMS: calc 402.49. found: 403.4.
Reaction SMILES: [OH:1][C:2]1([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[C:24]([CH3:32])[CH:23]=1)=[O:20].C([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl>[CH2:8]([C:2]1([OH:1])[CH2:7][CH2:6][N:5]([CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[C:24]([CH3:32])[CH:23]=2)=[O:20])[CH2:4][CH2:3]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cc(NC(=O)NCCCl)c2ccccc2n1
Reactant: OC1(Cc2ccccc2)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(NC(=O)NCCN2CCC(O)(Cc3ccccc3)CC2)c2ccccc2n1
Temperature: 45 °C
Reaction time: 144 h

Procedure:
To a solution of 4-hydroxy-4-benzyl-piperidine (380.6 mg, 2 mmol) in dry THF (10 mL) is added 1-(2-chloro-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (263.7 mg, 1 mmol) and solid NaHCO3 (672 mg, 8 mmol). The reaction mixture is stirred at 45° C. for 6 days. The reaction mixture is diluted with CH2Cl2 (100 mL) and washed with sat. Na2CO3 (2×30 mL). The aqueous phase is re-extracted with CH2Cl2 (2×25 mL), the combined organic phases are washed with brine (20 mL), dried (Na2SO4), filtered and evaporated. The residue is purified by preparative HPLC to provide the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H-].[Na+].[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br.O>O1CCCC1>[CH3:1][N:2]([CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([Br:14])[CH:16]=1)[C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: BrCc1cccc(Br)c1
Reactant: CCCCCCCC(=O)NC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCC(=O)N(C)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
5 g (31.8 mmol) of N-methyloctanamide (1a) are added at 0° C. to a suspension of 1.4 g (35 mmol) of sodium hydride (60% in grease) in 60 mL of tetrahydrofuran. The reaction mixture is stirred for 30 minutes at room temperature and a solution of 8.9 g (35 mmol) of 3-bromobenzyl bromide in 15 mL of tetrahydrofuran is then added. The mixture is stirred for 16 hours at room temperature. The reaction is stopped by adding 100 mL of water and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (75/25 heptane/ethyl acetate). 7.4 g of N-methyl-N-(3-bromobenzyl)octanamide are obtained. Yield=71%.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6](=[C:10]1[C:19]2[CH:18]=[C:17]([C:20]([NH2:22])=O)[S:16][C:15]=2[CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:7][CH2:8][CH3:9].CN(C)C=O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH:6](=[C:10]1[C:19]2[CH:18]=[C:17]([C:20]#[N:22])[S:16][C:15]=2[CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCC=C1CCCCc2sc(C(N)=O)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC=C1CCCCc2sc(C#N)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Phosphorus oxychloride (0.30 ml) was added to a mixture of 4-n-butylidene-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamide (0.55 g) and dimethylformamide (DMF) (6 ml) with ice-water cooling under nitrogen atmosphere, and the mixture was stirred under the same condition for 1 hour. The reaction mixture was poured into an ice-cooled mixture of an aqueous solution of NaHCO3 and AcOEt to precipitate. The precipitate was collected by filtration, washed with water, and dried in vacuo to give 4-n-butylidene-5,6,7,8-tetrahydro-2-cyano-4H-cyclohepta[b]thiophene (0.42 g), which was immediately used in the next reaction.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([C:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:11]=1[CH2:22][C:23]([OH:25])=O)([CH3:9])[CH3:8].[S:26](=[O:44])(=[O:43])([O:28][C:29]1[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][C:32]([C:38]#[N:39])=[CH:31][C:30]=1[CH:40]([CH3:42])[CH3:41])[NH2:27].C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C=O>[C:38]([C:32]1[CH:31]=[C:30]([CH:40]([CH3:42])[CH3:41])[C:29]([O:28][S:26](=[O:43])(=[O:44])[NH:27][C:23](=[O:25])[CH2:22][C:11]2[C:10]([CH:7]([CH3:8])[CH3:9])=[CH:15][C:14]([CH:16]([CH3:17])[CH3:18])=[CH:13][C:12]=2[CH:19]([CH3:21])[CH3:20])=[C:34]([CH:35]([CH3:37])[CH3:36])[CH:33]=1)#[N:39]
Reactant: CC(C)c1cc(C#N)cc(C(C)C)c1OS(N)(=O)=O
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)O)c(C(C)C)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(C#N)cc2C(C)C)c(C(C)C)c1
Reaction time: 8 h
Yield: 45.8 %

Procedure:
Oxalyl chloride (0.48 mL, 5.5 mmol) was added dropwise to a solution of 2,4,6-triisopropylphenyl acetic acid (1.21 g, 4.6 mmol) in 100 mL toluene with 4 drops of N,N-dimethylformamide as a catalyst. The resulting solution was stirred overnight and then concentrated in vacuo. The residue was re-dissolved in 150 mL dichloromethane. 2,6-Bis(l-methylethyl)-4-cyanophenyl sulfamate (1.30 g, 4.6 mmol) and triethylamine (1.6 mL) were added, and the resulting mixture was stirred for 6 hours. Washed with 1 M HCl, dried the organic layer over magnesium sulfate, filtered, and concentrated to give an oily solid. Chromatography on silica gel (20% ethyl acetate/hexanes) gave 1.11 g of the title compound as a white solid; mp 79-84° C.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH2:29]([NH2:32])[CH2:30][CH3:31]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:25])([CH3:26])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([NH:32][CH2:29][CH2:30][CH3:31])=[O:20])[C:14]1([CH3:21])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCN
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)O)C1(C)C
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)NCCC)C1(C)C

Procedure:
The product from Example 173 and propylamine hydrochloride (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR 1H NMR (DMSO-d6) δ 0.48 (s, 3H), 0.83 (t, J=7.3 Hz, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.19 (s, 3H), 1.23 (s, 3H), 1.26-1.43 (m, 5H), 1.56 (s, 9H), 1.56-1.67 (m, 3H), 1.96-2.09 (m, 1H), 2.62-2.69 (m, 3H), 2.72-2.95 (m, 2H), 3.06-3.17 (m, 1H), 7.53-7.57 (m, 1H), 8.50 (s, 1H). MS (ESI+) m/z 436 (M+H)+. Anal. calcd. for C24H41N3O2S: C, 66.16; H, 9.49; N, 9.65. Found: C, 65.76; H, 9.51; N, 9.68.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[Cl:31])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[Cl:31][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[O:15][C:14]1[CH:32]=[CH:33][C:11]([C:9](=[O:10])[NH:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([C:38]4[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=4)[N:7]=3)=[CH:12][CH:13]=1)[O:23][CH2:22][CH2:21][CH:20]2[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(Br)n4)cc3)c(Cl)cc21
Reactant: OB(O)c1ccc(Cl)cc1
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(Cl)cc5)n4)cc3)c(Cl)cc21
Temperature: 100 °C
Reaction time: 12 h
Yield: 94.7 %

Procedure:
Ethyl 7-(4-(6-bromopyridin-2-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (50 mg, 0.094 mmol), 4-chlorophenylboronic acid (59 mg, 0.38 mmol), Na2CO3 (30 mg, 0.28 mmol) and Pd(PPh3)4 (11 mg, 0.0094 mmol) were place in a 1 mL vial and diluted with toluene (800 μL) and water (80 μL). The vial was purged with argon, sealed and heated to 100° C. After stirring for 12 hours, the reaction was cooled and loaded directly onto a biotage 25 cartridge eluting with 5% ethyl acetate/hexanes to 60% ethyl acetate/hexanes to yield ethyl 6-chloro-7-(4-(6-(4-chlorophenyl)pyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (50 mg, 0.089 mmol, 94% yield).