Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([C:20]([NH2:22])=[O:21])=[N:4][C:5]([CH2:18][CH3:19])=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:7]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH2:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:18]([C:5]1[N:4]=[C:3]([C:20]([NH2:22])=[O:21])[C:2]([NH:35][C:34]2[CH:33]=[CH:32][C:31]([CH2:30][N:27]3[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]3)=[CH:37][CH:36]=2)=[N:7][C:6]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[CH3:19]
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Oc1cccc([N+](=O)[O-])c1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1nc(C(N)=O)c(Nc2ccc(CN3CCN(C)CC3)cc2)nc1Oc1cccc([N+](=O)[O-])c1
Yield: 18.4 %

Procedure:
Under an argon atmosphere, a mixture of 3-chloro-6-ethyl-5-(3-nitrophenoxy)pyrazine-2-carboxamide (50 mg), 4-[(4-methylpiperazin-1-yl)methyl]aniline (48 mg), tris(dibenzylideneacetone)dipalladium (0) (14 mg), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (30 mg), cesium carbonate (101 mg), and dioxane (2 mL) was heated and refluxed for 4 hours. The reaction mixture was cooled and then diluted with ethyl acetate, and the organic phase was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate:methanol:28% aqueous ammonia=95:4.5:0.5-90:9:1, chloroform: methanol=1:0-9:1) to obtain 6-ethyl-3-({4-[(4-methylpiperazin-1-yl)methyl]phenyl}amino)-5-(3-nitrophenoxy)pyrazine-2-carboxamide (14 mg) as a yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][CH2:14][CH2:15][B:16]3[O:20]C(C)(C)C(C)(C)[O:17]3)[C@:10]([NH:29]C(=O)C(F)(F)F)([C:25]([O:27]C)=[O:26])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.O.[OH-].[Li+].[ClH:41]>C1COCC1.O>[ClH:41].[NH2:29][C:10]1([C:25]([OH:27])=[O:26])[CH:11]([CH2:13][CH2:14][CH2:15][B:16]([OH:20])[OH:17])[CH2:12][N:8]([C:6](=[O:7])[C:5]2[CH:36]=[CH:37][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: COC(=O)[C@]1(NC(=O)C(F)(F)F)CN(C(=O)c2ccc(F)cc2)C[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC1(C(=O)O)CN(C(=O)c2ccc(F)cc2)CC1CCCB(O)O
Yield: 30 %

Procedure:
A stirred solution of racemic methyl (3R,4S)-1-(4-fluorobenzoyl)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]-3-[(trifluoroacetyl)amino]pyrrolidine-3-carboxylate (200 mg, 0.377 mmol) in THF 94.2 mL) and water (3.7 mL) was sparged with nitrogen for 5 min. Lithium hydroxide monohydrate (33.2 mg, 0.792 mmol) was added, and the mixture was sparged with nitrogen for 10 min and stirred under nitrogen at room temperature for 4 days, during which additional lithium hydroxide monohydrate (39.6 mg, 0.943 mmol) was added. The mixture was diluted with water (5 mL) and acidified to pH<1 with 3 M aqueous HCl. The resulting solution was washed with ethyl acetate (2×20 mL) and methylene chloride (2×20 mL). The aqueous phase was concentrated under reduced pressure and purified by reverse phase HPLC. Product fractions were pooled, concentrated, re-dissolved in 1M aqueous HCl, concentrated and lyophilized to give racemic (3R,4S)-3-amino-4-[3-(dihydroxyboryl)propyl]-1-(4-fluorobenzoyl)pyrrolidine-3-carboxylic acid hydrochloride (42 mg, 30%) as a white amorphous solid. MS (ESI+) m/z 321 (M−H2O+H+), 303 (M−2 H2O+H+) and MS (ESI−) m/z 319 (M−H2O−H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:19][CH3:20].[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][C:31]#[N:32])=[CH:29][C:24]=2[O:23][CH2:22]1>>[O:21]1[C:25]2[CH:26]=[CH:27][C:28](/[C:30](=[CH:13]/[C:12]3[CH:15]=[C:16]([O:17][CH3:18])[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[C:10]([O:19][CH3:20])[CH:11]=3)/[C:31]#[N:32])=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: N#CCc1ccc2c(c1)OCO2
Reactant: COc1cc(C=O)cc(OC)c1OCCCCCCO
Product: COc1cc(/C=C(\C#N)c2ccc3c(c2)OCO3)cc(OC)c1OCCCCCCO
Yield: 95 %

Procedure:
(2Z)-2-(1,3-benzodioxol-5-yl)-3-{4-[(6-hydroxyhexyl)oxy]-3,5-dimethoxyphenyl}prop-2-enenitrile is prepared starting from 4-[(6-hydroxyhexyl)oxy]-3,5-dimethoxybenzaldehyde and 1,3-benzodioxol-5-ylacetonitrile according the same procedure following for example 10 in 95% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O.[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1c(F)ccc(Br)c1Oc1ccccc1
Reactant: NCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1c(NCCN2CCOCC2)ccc(Br)c1Oc1ccccc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 78.9 %

Procedure:
A solution of 1-bromo-4-fluoro-3-nitro-2-phenoxybenzene (0.057 g, 0.18 mmol) and cesium carbonate (0.0715 g, 0.220 mmol) in dimethyl sulfoxide (0.20 mL, 2.8 mmol) was treated with N-(2-aminoethyl)morpholine (0.0289 mL, 0.220 mmol) and stirred at 20° C. for 24 h, after which time the reaction mixture was diluted with water and ethyl acetate. Layers were separated and the organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo to give the crude product. Purification by flash column chromatography (100% hexanes to 100% EtOAc) gave the desired product (60 mg, 78%) a brown oil. LCMS calculated for C18H21BrN3O4 (M+H)+: m/z=422.1, 424.1. found: 422.1, 424.1.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:16][N:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]=2[CH2:19][CH2:20][CH2:21][CH3:22])=[C:10]([C:34]([N:36]2[C@H:45]([CH2:46]O)[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37]2)=[O:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.P([N:97]=[N+:98]=[N-:99])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>C1COCC1.CCOC(C)=O>[N:97]([CH2:46][C@@H:45]1[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][N:36]1[C:34]([C:10]1[CH:9]=[C:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH:13]=[CH:12][C:11]=1[C:14]1[C:15]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:16][N:17]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]=1[CH2:19][CH2:20][CH2:21][CH3:22])=[O:35])=[N+:98]=[N-:99]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C(=O)OCC)nn1-c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2Cc3ccccc3C[C@H]2CN=[N+]=[N-])c(C(=O)OCC)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of ethyl 4-(4-(tert-butoxycarbonyl)-2-((S)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5-butyl-1-phenyl-1H-pyrazole-3-carboxylate (113 mg, 0.177 mmol) in THF (2 mL) was added triphenylphosphine (55.8 mg, 0.213 mmol) followed by DIAD (0.041 mL, 0.213 mmol) and diphenyl phosphorazidate (58 mg, 0.21 mmol). After stirring at room temperature overnight, a second addition of all three reagents was added (1.2 eq each) and stirring was continued for 3 h. The reaction mixture was diluted with EtOAc, washed with sat. aq. sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (Isco 40 g column eluting with 0-50% EtOAc/hexanes) to give the title compound (86 mg, 73%). 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.25 (s, 0.5H), 8.15-8.10 (m, 1H), 7.97 (s, 0.5H), 7.51-7.34 (m, 5H), 7.25-6.90 (m, 5H), 5.04-4.97 (m, 1.5H), 4.41-3.97 (m, 3.5H), 3.50-3.01 (m, 3.5H), 2.88-2.46 (m, 3.5H), 1.66-1.62 (m, 3H), 1.61 (s, 4.5H), 1.60 (s, 4.5H), 1.18-0.94 (m, 4H), 0.64-0.56 (m, 3H); MS(ESI) m/z 663.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12]([O:14]CC)=O)[N:8]=1.Cl.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH2:33][CH2:34][NH2:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CO.[OH-].[Na+].O.CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH2:33][CH2:34][NH:35][C:12]([C:9]1[N:8]=[C:7]([CH2:6][C:5]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:3]([O:2][CH3:1])[CH:4]=2)[O:11][N:10]=1)=[O:14]
Reactant: CCOC(=O)c1noc(Cc2ccc(OC)c(OC)c2)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cc2nc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)no2)cc1OC
Yield: 31.8 %

Procedure:
This compound was prepared according to method F with ethyl 5-(3,4-dimethoxybenzyl)-1,2,4-oxadiazole-3-carboxylate (0.126 g; 0.433 mmol) in methanol (2 mL) and sodium hydroxide in water (2M, 2 mL); and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), HATU (0.164 g; 0.432 mmol), N,N diisopropylethylamine (0.075 mL; 0.432 mmol) in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.0607 g (32%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(3,4-dimethoxybenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43](O)=[O:44])=[CH:31][CH:32]=2)[N:27]=1.C(N(CC)C(C)C)(C)C.[NH2:55][C@@H:56]([CH2:61][C:62]1[CH:67]=[CH:66][C:65]([O:68][CH:69]([CH3:71])[CH3:70])=[CH:64][CH:63]=1)[C:57]([O:59][CH3:60])=[O:58]>CN(C)C=O>[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]2)[C:33]2[C:28](=[CH:29][C:30]([C:43]([NH:55][C@@H:56]([CH2:61][C:62]3[CH:63]=[CH:64][C:65]([O:68][CH:69]([CH3:71])[CH3:70])=[CH:66][CH:67]=3)[C:57]([O:59][CH3:60])=[O:58])=[O:44])=[CH:31][CH:32]=2)[N:27]=1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC(C)C)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: COC(=O)[C@H](Cc1ccc(OC(C)C)cc1)NC(=O)c1ccc2c(N3CCN(C)CC3)nc(N)nc2c1
Reaction time: 0.17 h
Yield: 39.5 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (20 mg, 0.052 mmol) was added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (10 mg, 0.03 mmol) in N,N-dimethylformamide (2 mL) and N,N-diisopropylethylamine (12 uL, 0.070 mmol). The reaction was stirred for 10 min, and the methyl (2S)-2-amino-3-(4-isopropoxyphenyl)propanoate (16 mg, 0.070 mmol) was added. The reaction mixture was stirred for 2 h. at r.t. and was purified by RP-HPLC (pH=2) to afford the desired product (6 mg, 30%) as a white solid TFA salt. Analytical LCMS (M+H)+: m/z=507.0.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[C:11]3([CH2:16][CH2:15]3)[CH2:10][N:9]([C@@H:17]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]3)[C:8]=2[N:24]=1.[CH3:25]I>>[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[N:13]([CH3:25])[C:12](=[O:14])[C:11]3([CH2:16][CH2:15]3)[CH2:10][N:9]([C@@H:17]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]3)[C:8]=2[N:24]=1
Reactant: O=C1Nc2cnc(Cl)nc2N([C@@H]2CCC(F)(F)C2)CC12CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CN1C(=O)C2(CC2)CN([C@@H]2CCC(F)(F)C2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 91.5 %

Procedure:
60% sodium hydride in mineral oil (0.25 g, 6.23 mmol) was added to a mixture of (R)-2′-chloro-9′-(3,3-difluorocyclopentyl)-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepin]-6′(5′H)-one (1.95 g, 5.94 mmol) and methyl iodide (0.41 ml, 6.53 mmol) dimethylacetamide (20 mL). The reaction mixture was stirred at room temperature for 25 minutes. Ice was added to the reaction mixture. A solid crashed out and was filtered off, rinsing with water. The solid was dried in a pistol under vacuo for 3 hours. The compound was obtained as a light pink solid (1.863 g, 92% yield).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][CH:9]([C:16]1[CH:17]=[C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:19]=[N:20][C:21]=1[O:22][CH3:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.O>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:8][CH:9]([C:16]1[CH:17]=[C:18]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:19]=[N:20][C:21]=1[O:22][CH3:23])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1nnc(-c2ccccc2)cc1C(O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1nnc(-c2ccccc2)cc1C(OC(C)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.0 ml of acetic acid anhydride was slowly added dropwise into a solution of 1.39 g of 5-(α-hydroxybenzyl)-3-phenyl-6-methoxypyridazine, 174 mg of 4-dimethylaminopyridine and 1.0 ml of triethylamine in 10 ml of dichloromethane under ice-cooling. After stirring at room temperature for one hour, water was added to the reaction solution. After extracting with dichloromethane, the organic phase was washed with brine. After removing the solvent, the residue was subjected to NH-silica gel (Fuji Silicia) and eluted with ethyl acetate, to give 1.58 g of the target compound.
Reaction SMILES: BrC(Br)=O.[C:5]1([S:11][CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:13](Cl)(=[O:15])[CH3:14]>>[CH3:14][C:13]([C:8]1[CH:9]=[CH:10][C:5]([S:11][CH3:12])=[CH:6][CH:7]=1)=[O:15]
Reactant: CC(=O)Cl
Reactant: CSc1ccccc1
Agent: O=C(Br)Br
Product: CSc1ccc(C(C)=O)cc1

Procedure:
The synthesis of bromoketone 2 begins with the Friedel-Crafts reaction between thioanisole and acetyl chloride, to give 4-(methylthio)acetophenone 3 herein referred to as ketosulfide 3).
Reaction SMILES: N[C@@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=O.[CH:10]1([NH:17][C:18]([NH2:20])=[S:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([NH:17][C:18]2[S:19][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3](=[O:5])[N:20]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NC(=S)NC1CCCCCC1
Reactant: CC(C)C[C@H](N)C(=O)O
Product: CC(C)CC1SC(NC2CCCCCC2)=NC1=O

Procedure:
Synthesis was performed from (2S)-2-amino-4-methylpentanoic acid and N-cycloheptylthiourea according to Method E and C.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:9])(=O)[CH3:7].CC(C1C=[CH:17][C:16]([F:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)=O.C(OO)(=O)C>O>[F:19][C:16]1[CH:17]=[CH:7][C:6]([OH:9])=[CH:14][C:15]=1[N+:20]([O-:22])=[O:21]
Reactant: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(=O)O
Agent: CC(=O)OO
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cc(O)ccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 20 %

Procedure:
Concentrated sulfuric acid (200 mL) and acetic acid (120) mL are mixed at 0° C. To this solution is added 15 g (0.082 mol) of 4-fluoro-3-nitroacetophenone with stifling. To the cold reaction mixture is added 36 mL of 36% peracetic acid. The reaction mixture is then stirred at room temperature for 4 hours. Water (500 mL) is added to the mixture, and the crude product is extracted into diethyl ether. The combined ether fractions are washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified using column chromatography on silica gel, eluting with 3% methanol/chloroform, giving 3.2 g of Compound 23 (20% yield). mp: 86-87° C. 1H-NMR (CDCl3) 7.56 (dd, 1H); 7.29 (t, 1H), 7.12 (m, 1H); 5.36 (s, 1H). 19F-NMR (d6-DMSO) 147.60 (s). Anal. calc. for C6H4FNO3: C, 45.87; H, 2.57; N, 8.92. Found: C, 45.80; H, 2.51; N, 8.69.
Reaction SMILES: [CH:1]1([CH:7]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C@H:21]([O:28][CH3:29])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8](O)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:62][C@H:63]1[CH2:68][CH2:67][C@H:66]([OH:69])[CH2:65][CH2:64]1>CN(C=O)C>[CH:1]1([CH:7]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C@H:21]([O:28][CH3:29])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:8]([NH:62][CH:63]2[CH2:68][CH2:67][CH:66]([OH:69])[CH2:65][CH2:64]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CO[C@H](c1ccccc1)c1nc2cc(F)ccc2n1C(C(=O)O)C1CCCCC1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CO[C@H](c1ccccc1)c1nc2cc(F)ccc2n1C(C(=O)NC1CCC(O)CC1)C1CCCCC1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 40.5 %

Procedure:
To a solution of cyclohexyl-[5-fluoro-2-((R)-methoxy-phenyl-methyl)-benzoimidazol-1-yl]-acetic acid (100 mg, 0.25 mmol, 1.0 equiv) in DMF (1.5 mL) was added triethylamine (51.1 mg, 70.0 μL, 0.50 mmol, 2.0 equiv) and HATU (124.7 mg, 0.33 mmol, 1.3 equiv) and the mixture stirred at 40° C. After 15 min, trans-4-amino-cyclohexanol hydrochloride (50.03 mg, 0.33 mmol, 1.3 equiv; [CAS RN 50910-54-8]) was added and stirring continued at 50° C. for 2 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 50 mg (40%) of the title compound. MS (ISP): 494.5 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl.[CH:27]([Cl:30])(Cl)Cl>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[C:1]1([C:7]2[C:27]([Cl:30])=[C:15]([CH2:16][CH2:17][CH:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2[nH]c3ccccc3c2CCC2CCNCC2)cc1
Reactant: ClC(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: Clc1c(-c2ccccc2)nc2ccccc2c1CCC1CCNCC1

Procedure:
The operation is as in Example 1, but starting from 12 g of 4-[2-(2-phenyl-3-indolyl)-ethyl]-piperidine and 0.2 g of triethylbenzylammonium chloride in 110 ml of chloroform and 12 g of sodium hydroxide in 24 ml of water. 1.05 g of 2-phenyl-3-chloro-4-[2-(4-piperidyl)-ethyl]-quinoline are finally obtained in the form of the hydrochloride melting at 233° C.
Reaction SMILES: [Li+].[OH-:2].C[O:4][C:5](=O)[CH2:6][NH:7][C:8]([C:10]1([NH:13][C:14](=[O:78])[C@H:15]([NH:37][C:38](=[O:77])[C@H:39]([NH:47][C:48](=[O:76])[CH2:49][C@H:50](O)/[CH:51]=[CH:52]/[CH2:53][CH2:54][S:55][C:56]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:40][C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)[CH2:16][S:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:12][CH2:11]1)=[O:9].Cl.CC1C=CC=C([N+]([O-])=O)C=1C(OC(=O)C1C([N+]([O-])=O)=CC=CC=1C)=O>O.C1COCC1.[Cl-].[Na+].O.C(Cl)Cl.C1COCC1.CN(C)C1C=CN=CC=1.C(Cl)Cl.CCOC(C)=O>[N:44]1[CH:45]=[CH:46][C:41]([CH2:40][C@H:39]2[NH:47][C:48](=[O:76])[CH2:49][C@H:50](/[CH:51]=[CH:52]/[CH2:53][CH2:54][S:55][C:56]([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)([C:63]3[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=3)[C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[O:2][C:5](=[O:4])[CH2:6][NH:7][C:8](=[O:9])[C:10]3([CH2:12][CH2:11]3)[NH:13][C:14](=[O:78])[C@@H:15]([CH2:16][S:17][C:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:37][C:38]2=[O:77])=[CH:42][CH:43]=1
Reactant: COC(=O)CNC(=O)C1(NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)[C@@H](Cc2ccncc2)NC(=O)C[C@H](O)/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: [OH-]
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1C[C@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(=O)CNC(=O)C2(CC2)NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)[C@@H](Cc2ccncc2)N1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 54.5 %

Procedure:
LiOH (13 mg, 0.54 mmol) in water (2 mL) was added to 4 (384 mg, 0.36 mmol) in THF (8 mL) at 0° C. After 1.5 h of stirring at 0° C. the reaction mixture was neutralized with aqueous 0.5 M HCl then brine (50 mL) and EtOAc (50 mL) were added. The phases were separated and the aqueous phase was extracted with EtOAc (3×10 mL). The organic phases were combined, dried over MgSO4, filtered then concentrated under reduced pressure. The crude product was dried under high vacuum before to be use for the next step. The crude carboxylic acid in CH2Cl2/THF (250 mL, 12:1 v/v) was added dropwise over a period of 3 h to 2-methyl-6-nitrobenzoic anhydride (149 mg, 0.43 mmol) and 4-(dimethylamino)pyridine (105 mg, 0.86 mmol) in CH2Cl2 (120 mL) at rt under Ar(g). After 19 h the reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with CH2Cl2/CH3OH (100:2 then 100:10) to yield 5 as a white solid (203 mg, 54%).
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([C:12](=[C:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].Cl>C(OCC)C>[CH2:1]([C:18]1([CH:12]([C:10]#[N:11])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C#N)=C1CCCCC1
Reactant: Cl[Mg]Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C(C#N)C1(Cc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1 M Benzylmagnesium chloride in diethyl ether (18.92 ml) was added dropwise to ethyl 2-cyano-2-cyclohexylideneacetate (1.828 g, 9.46 mmol) in diethyl ether (6.31 ml) at 23° C. The mixture was stirred at room temperature for 3 days. Then 10% hydrochloric acid (7.83 ml, 255 mmol) was added dropwise at 0° C. while stirring. The organic layer was separated, washed with water, dried over Na2SO4, filtered, and concentrated.