Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:26])[C:19]([O:21]C(C)(C)C)=[O:20])=[CH:14][CH:13]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1>C(O)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:12]3[CH:13]=[CH:14][C:15]([CH:18]([CH3:26])[C:19]([OH:21])=[O:20])=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(N2Cc3ccc(Cl)cc3C2=O)cc1
Solvent: O=CO
Product: CC(C(=O)O)c1ccc(N2Cc3ccc(Cl)cc3C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A mixture of tert-butyl 2-(4-(6-chloro-1-oxoisoindolin-2-yl)phenyl)propanoate (0.157 g, 0.422 mmol) and formic acid (15.7 mL) was stirred overnight at room temperature. The mixture was then concentrated under reduced pressure, suspended in hexanes (5 mL), sonicated, and the solids collected by filtration to afford 2-(4-(6-chloro-1-oxoisoindolin-2-yl)phenyl)propanoic acid (0.118 g, 89%) as a white solid: mp 235-248° C. (dec); 1H NMR (500 MHz, DMSO-d6) δ 12.35 (br s, 1H), 7.83 (d, J=8.5 Hz, 2H), 8.44 (s, 1H), 7.78 (m, 2H), 7.51 (m, 2H), 5.02 (s, 2H), 3.69 (q, J=7.0 Hz, 1H), 1.38 (d, J=7.0 Hz, 3H); ESI MS m/z 348 [M+H+CH3OH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[C:4]([O:11][CH3:12])[CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:5](/[C:6](=[CH:17]/[C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[CH:15]=2)/[C:7]#[N:8])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: COc1cc(Cl)ccc1CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)ccc1/C(C#N)=C/c1cccc(Cl)c1
Yield: 62.5 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chloro-2-methoxybenzyl cyanide (2 g, 10 mmol) prepared in Example 58a Step B was reacted with 3-chlorobenzaldehyde (2 g, 14 mmol), methanolic solution (25 wt %) of sodium methoxide (15 mL, 66 mmol) in methanol (50 mL) at 50° C. for 5 h to give (Z)-2-(4-chloro-2-methoxy-phenyl)-3-(3-chloro-phenyl)-acrylonitrile as a white powder (1.9 g, 63%).
Reaction SMILES: I[C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[NH:20][C:21]3[C:26]([C:27]=2[CH:28]=1)=[CH:25][CH:24]=[CH:23][CH:22]=3.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:2]3[C:7]4[S:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[C:6]=4[CH:5]=[CH:4][CH:3]=3)[C:21]3[C:26]([C:27]=2[CH:28]=1)=[CH:25][CH:24]=[CH:23][CH:22]=3
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Reactant: Ic1cccc2c1sc1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)c1ccccc1n2-c1cccc2c1sc1ccccc12
Temperature: 160 °C
Yield: 57.9 %

Procedure:
A mixture of 10.9 g (35.1 mmol) 4-iododibenzo[b,d]thiophene, 8.6 g (35.1 mmol) of 3-bromo-9H-carbazole, 4.46 g (70.2 mmol) of Cu, 14.55 g (100.1 mmole) of K2CO3 was stirred in 100 ml dimethylformamide, the reaction mixture was then heat to 160° C. for about overnight under nitrogen. Then cooled to 100° C., the solution was filtered. To receive the filtrate, and most of the dimethylformamide was removed under reduced pressure from the filtrate. The distillation was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica(hexane-dichloromethane) to give product 8.7 g (58%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24].O[N:28]=[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH3:38])[NH2:30].CCN(C(C)C)C(C)C>>[CH3:38][O:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:29]1[N:28]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[CH3:7])=[C:15]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)[O:22][N:30]=1
Reactant: COc1ccccc1C(N)=NO
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(-c3ccccc3C)c(C(F)(F)F)c2)n1

Procedure:
Oxalyl chloride (109 μL; 1.28 mmol; 3 eq.), Intermediate 34 (120 mg; 0.43 mmol; 1 eq.), Intermediate 1 (71 mg; 0.43 mmol, 1 eq.) and DIEA (95 μL; 1.28 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 95/5) afforded the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8](=[O:13])[NH:7][C:6]=2[C:5]2[CH2:14][CH:15]([NH:17][C:18](=[O:20])[CH3:19])[CH2:16][C:4]=2[CH:3]=1.[N+:21]([O-])([OH:23])=[O:22]>FC(F)(F)C(O)=O>[Br:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8](=[O:13])[NH:7][C:6]=2[C:5]2[CH2:14][CH:15]([NH:17][C:18](=[O:20])[CH3:19])[CH2:16][C:4]=2[C:3]=1[N+:21]([O-:23])=[O:22]
Reactant: CC(=O)NC1Cc2cc(Br)c3[nH]c(=O)c(=O)[nH]c3c2C1
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC1Cc2c([N+](=O)[O-])c(Br)c3[nH]c(=O)c(=O)[nH]c3c2C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
N-(5-Bromo-2,3-dioxo-2,3,4,7,8,9-hexahydro-1H-cyclopenta[f]quinoxalin-8-yl)-acetamide (0.24 g, 0.7 mmol) was dissolved in trifluoroacetic acid (10 mL), cooled in an ice bath to 0° C., and then treated with fuming nitric acid (0.5 mL) and stirred for 4 h at 0° C. After removing the solvent by rotoevaporation, the syrupy residue was triturated with water and the resulting solid was collected by filtration, washed with water and then ether and dried in vacuo (0.22 g, 81% yield). Anal. calc'd for C13H11BrN4O5.H2O: C, 38.92; H, 3.27; N, 13.94. Found: C, 38.60; H, 3.00; N, 13.66.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][CH:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)[C:16]([N:18]1[CH2:22][CH2:21][S:20][CH2:19]1)=[O:17]>>[Cl:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][CH:15]([NH:14][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13])[C:16](=[O:17])[N:18]1[CH2:22][CH2:21][S:20][CH2:19]1
Reactant: NC(Cc1cccc(Cl)c1)C(=O)N1CCSC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Product: O=C(NC(Cc1cccc(Cl)c1)C(=O)N1CCSC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
From 5-chloro-1H-indole-2-carboxylic acid and (±)-2-amino-3-(3-chloro-phenyl)-1-thiazolidin-3-yl-propan-1-one. mp 188-190° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH2:13][CH3:14])=[C:7]([CH2:11][CH3:12])[CH:8]=2)[CH2:3]1.[Li]>N>[CH2:11]([C:7]1[CH2:8][C:9]2[CH2:10][CH:2]([NH2:1])[CH2:3][C:4]=2[CH2:5][C:6]=1[CH2:13][CH3:14])[CH3:12]
Reactant: CCc1cc2c(cc1CC)CC(N)C2
Agent: N
Agent: [Li]
Product: CCC1=C(CC)CC2=C(C1)CC(N)C2
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Liquid ammonia (50 ml) is condensed at −78° C. and 2-amino-5,6-diethylindane (WO 0075114; 1 g, 4.43 mmol) is added, followed by lithium wire (0.615 g, 88 mmol) portionwise over 5 minutes. The reaction is stirred at −78° C. for 3 hours, then cautiously quenched with ethanol (100 ml) and warmed to ambient temperature overnight. Water is added, the mixture is extracted with ether and the combined organic extracts are washed with brine, dried (MgSO4) and evaporated to afford 5,6-diethyl-2,3,4,7-tetrahydro-1H-inden-2-ylamine. δH 0.95 (t J 7.3 6H), 1.95-2.10 (m 2H), 2.08 (q J 4H), 2.6 (m 6H), 3.65 (m 1H)
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([N+:35]([O-:37])=[O:36])=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:12]([C:22]3[N:23](S(C(F)(F)F)(=O)=O)[CH:24]=[CH:25][N:26]=3)[C:11]=2[CH:34]=1)(=O)=O.[CH3:40][O:41][C:42]1[CH:51]=[CH:50][C:49](B2OC(C)(C)C(C)(C)O2)=[CH:48][C:43]=1[C:44]([O:46][CH3:47])=[O:45].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[O:14][C:10]3[CH:9]=[C:8]([N+:35]([O-:37])=[O:36])[C:7]([C:49]4[CH:50]=[CH:51][C:42]([O:41][CH3:40])=[C:43]([CH:48]=4)[C:44]([O:46][CH3:47])=[O:45])=[CH:34][C:11]=3[C:12]=2[C:22]2[NH:26][CH:25]=[CH:24][N:23]=2)=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1cc2oc(-c3ccc(F)cc3)c(-c3nccn3S(=O)(=O)C(F)(F)F)c2cc1OS(=O)(=O)C(F)(F)F
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(-c2cc3c(-c4ncc[nH]4)c(-c4ccc(F)cc4)oc3cc2[N+](=O)[O-])ccc1OC
Temperature: 100 °C

Procedure:
A mixture of 2-(4-fluorophenyl)-6-nitro-3-(1-((trifluoromethyl)sulfonyl)-1H-imidazol-2-yl)benzofuran-5-yl trifluoromethanesulfonate (500 mg, 0.829 mmol), methyl 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (290 mg, 0.994 mmol), potassium phosphate (352 mg, 1.657 mmol) in a mixture of dioxane (40 mL)/water (4 mL) in a pressure tube at rt was degassed, and then added with PdCl2(dppf)-CH2Cl2 adduct (67.7 mg, 0.083 mmol). The reaction mixture was heated to 100° C. and maintained at the same temperature overnight. The reaction mixture was filtered through celite, and the celite bed washed with EtOAc. The filtrate was concentrated, and the residue was purified by Combiflash using a mixture of petroleum ether and EtOAc as an eluant and a 40 g silica column. The title compound was collected at 70% EtOAc in pet. ether. Yield: 375 mg (93%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.52 (br s, 1H) 8.52 (s, 1H) 8.10-8.20 (m, 1H) 7.58-7.82 (m, 2H) 7.56 (dd, J=8.53, 2.51 Hz, 1H) 7.36-7.47 (m, 4H) 7.18-7.32 (m, 2H) 3.89 (s, 3H) 3.80 (s, 3H); LCMS: (ES−) m/z=486.0 (M−H); Column—Acentis Express C8 (50×2.1 mm; 2.7 u); M phase A: 10 mM Ammonium Formate in Water:MeCN (90:10); M phase B: 10 mM Ammonium Formate in Water:MeCN (10:90)
Reaction SMILES: [CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2].[CH3:28][CH:29]1[C:34](=O)[CH2:33][CH2:32][O:31][CH2:30]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:34]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[CH3:28])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)CC[C@@H](N)C1
Reactant: CC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)cyclopentanamine (80 mg, 0.2 mmol), 3-methyltetrahydro-4H-pyran-4-one (71 mg, 0.62 mmol) and triethylamine (0.12 mL, 0.83 mmol) in dichloromethane (10 mL) was added sodium triacetoxyborohydride (130 mg, 0.62 mmol). After being stirred at room temperature overnight, the solution was diluted with dichloromethane. The resulting solution was washed with NaHCO3 and brine, dried over MgSO4 and concentrated. The residue was purified on silica gel to give the desired product which was further separated by chiral HPLC affording four isomers. MS calculated for C26H38F3N3O2: (M+H) 482; found 482.2 for four isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=O)[NH:8][CH:7]=[C:6]2[C:16]#[N:17].P(Br)(Br)([Br:20])=O.C(Cl)Cl>C1(OC)C=CC=CC=1>[Br:20][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2)[C:6]([C:16]#[N:17])=[CH:7][N:8]=1
Reactant: COc1cc2c(C#N)c[nH]c(=O)c2cc1OC
Reactant: O=P(Br)(Br)Br
Solvent: ClCCl
Solvent: COc1ccccc1
Product: COc1cc2c(C#N)cnc(Br)c2cc1OC
Temperature: 80 °C
Yield: 73.1 %

Procedure:
The mixture of 6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carbonitrile (8 g, 35 mmol) and phosphorus oxybromide (70 g, 244 mmol) in anisole (30 mL) was heated to 80° C. for 12 h. The solvent and excess POBr3 were removed by rotary evaporator. The resulting solid was washed with hexane and dried. The solid was slowly added to ice and the product was extracted with chloroform. The organic layer was washed with saturated aqueous sodium carbonate solution, saturated aqueous sodium chloride solution (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford a brown solid. Flash chromatography (Merck Silica gel 60, 70–230 mesh, methylenechloride) afforded 1-bromo-6,7-dimethoxy-isoquinoline-4-carbonitrile (7.5 g, 75%) as a brown solid. LC-MS m/e calcd for C12H9BrN2O2 (MH+) 293. found 293.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[CH:24]=[C:23]2[C:10]([S:11](=[O:26])(=[O:25])[NH:12][C:13]3[C:22]2=[CH:21][CH:20]=[C:19]2[C:14]=3[N:15]=[CH:16][CH:17]=[CH:18]2)=[CH:9][CH:8]=1)=[O:6].Cl>CO>[O:26]=[S:11]1(=[O:25])[C:10]2[C:23](=[CH:24][C:7]([C:5]([OH:6])=[O:4])=[CH:8][CH:9]=2)[C:22]2[C:13](=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12]1
Reactant: COC(=O)c1ccc2c(c1)-c1ccc3cccnc3c1NS2(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2c(c1)-c1ccc3cccnc3c1NS2(=O)=O
Temperature: 65 °C
Yield: 88.5 %

Procedure:
LiOH (9 mg, 0.21 mmol) was added to a solution of 6,6-dioxo-5,6-dihydro-6λ*6*-thia-4,5-diaza-chrysene-9-carboxylic acid methyl ester 307 (33 mg, 0.097 mmol) in MeOH (2 ml) and the mixture was heated at 65° C. for 18 h. After cooling, the pH was adjusted to 7-8 with methanolic HCl. The mixture was concentrated in vacuo. The crude residue was purified by column chromatography with DCM/MeOH (90:10) as the eluent to give the title compound (28 mg, 90%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[N:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]=3[NH:9][C:8]2=[O:20])[CH2:3][CH2:2]1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:39]=[C:38]([CH3:40])[C:33]3[NH:34][C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:40][C:38]1[C:33]2[NH:34][C:35](=[O:37])[O:36][C:32]=2[CH:31]=[C:30]([C:28]([C:24]2[N:25]=[CH:26][N:27]=[C:22]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C:11]5[CH:12]=[N:13][C:14]6[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=6[C:10]=5[NH:9][C:8]4=[O:20])[CH2:5][CH2:6]3)[CH:23]=2)=[O:29])[CH:39]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Reactant: O=c1[nH]c2c3ccccc3ncc2n1C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5c6ccccc6ncc54)CC3)ncn2)cc2oc(=O)[nH]c12

Procedure:
134 mg (0.500 mmol) 3-piperidin-4-yl-1,3-dihydroimidazo[4,5-c]quinolin-2-one, 145 mg (0.500 mmol) 6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and 0.174 mL (1.00 mmol) DIPEA were stirred overnight in 5 mL DMF at RT. The mixture was purified by preparative HPLC-MS. The fractions containing the product were combined, the organic solvent was eliminated i. vac. and the aqueous phase remaining was neutralised with a 4N aqueous NaOH solution. The precipitate was suction filtered, washed with water and dried in the CAD.
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:22](O)(=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[C:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][N:13]=2)=[CH:16][CH:17]=1)(=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCc1ccc(-c2ccc(O)cc2)nc1
Reactant: CCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCc1ccc(-c2ccc(OC(=O)CCCCCC)cc2)nc1
Yield: 65.8 %

Procedure:
4-(5-Octyl-2-pyridyl)phenol (0.5 g), 0.2 g of heptanoic acid and 0.04 g 4-(dimethylamino)pyridine were dissolved in 50 ml of dichloromethane and the solution was treated portion wise with 0.4 g of N,N'-dicyclohexylcarbodiimide within 10 minutes while stirring. The mixture was stirred at room temperature overnight and then filtered. The filtrate was diluted with dichloromethane, washed twice with 50 ml of saturated sodium carbonate solution each time and then with water, dried over magnesium sulphate, filtered and subsequently concentrated. The crude product obtained was purified by chromatography on silica gel with toluene. Recrystallization from ethanol gave 0.4 g of 4-(5-octyl-2-pyridyl)phenyl heptanoate with a m.p. (C--S) 57° C. and cl.p. (S--I) 77° C.
Reaction SMILES: ClC(N(C)C)=C(C)C.[O:9]=[C:10]1[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][C:17]([OH:19])=O)[CH2:11]1.[F:20][C:21]([F:42])([F:41])[C:22]1[CH:23]=[C:24]([S:28]([CH2:31][CH2:32][S:33][C:34]2[C:39]([NH2:40])=[CH:38][CH:37]=[CH:36][N:35]=2)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1.CCCCCC>C(Cl)Cl.O>[O:9]=[C:10]1[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][C:17]([NH:40][C:39]2[C:34]([S:33][CH2:32][CH2:31][S:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:41])([F:42])[F:20])[CH:23]=3)(=[O:30])=[O:29])=[N:35][CH:36]=[CH:37][CH:38]=2)=[O:19])[CH2:11]1
Reactant: Nc1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)CC1CCCC(=O)C1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: O
Solvent: CCCCCC
Product: O=C1CCCC(CC(=O)Nc2cccnc2SCCS(=O)(=O)c2cccc(C(F)(F)F)c2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 10.4 %

Procedure:
560 μl (4.23 mmol) 1-chloro-N,N,2-trimethylprop-1-en-1-amine were added at 0° C. to a solution of 550 mg (35.2 mmol) 2-(3-oxocyclohexyl)acetic acid in DCM (7 ml). After stirring for 15 min at 0° C., 1.5 g (4.23 mmol) [2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]amine (VPF-001) were added. Then the reaction solution was stirred for a further 16 h at 0° C. It was then diluted with water (30 ml) and extracted with DCM (3×50 ml). The combined organic phases were washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 6:4) of the residue yielded 220 mg (0.44 mmol, 13%) 2-(3-oxocyclohexyl)-N-[2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]acetamide. MS: m/z 501.1 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1OC)[NH:7][CH:6]=[C:5]2CCO.O1C=CCC1.Cl.FC1C=CC(NN)=CC=1OC.S(=O)(=O)(O)O>C(#N)C>[NH:7]1[C:8]2[C:4](=[CH:3][CH:2]=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: COc1cc2[nH]cc(CCO)c2cc1F
Agent: C1=COCC1
Agent: COc1cc(NN)ccc1F
Agent: Cl
Solvent: CC#N
Product: c1ccc2[nH]ccc2c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2-(5-Fluoro-6-methoxy-1H-indol-3-yl)ethanol (Ind-26) A solution of dihydrofuran (242 mg, 3.46 mmol) in acetonitrile (10 ml) was added dropwise to a solution of (4-fluoro-3-methoxyphenyl)hydrazine hydrochloride [1.00 g, 3.46 mmol (based on a purity of the educt of 68%)] in acetonitrile (30 ml) and 4% aqueous sulfuric acid (30 ml) at room temperature. Thereafter, the temperature was increased to 80° C. and the reaction mixture was stirred at this temperature for 2 h and then cooled to room temperature and the solvent was removed i. vac. 5% sodium bicarbonate solution was added to the residue and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([OH:14])[CH:8]=[CH:7]2.Br[CH2:16][O:17][CH3:18].[OH-].[Na+]>CN(C)C=O>[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH2:16][O:17][CH3:18])[CH:10]=2)[CH:5]=1
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COCOc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60%, 4.5 g, 112 mmol) was added in small portions to a mixture of 6-bromo-2-naphthol (25.0 g, 112 mmol), bromomethylmethylether (21.0 g, 168 mmol) and dimethylformamide (150 ml). The mixture was stirred at room temperature for 1 h. Sodium hydroxide (200 ml, 1 M) was added and the mixture was extracted with diethyl ether. The product was purified chromatographically, using dichloromethane as solvent. Yield 15.7 g, 52%. Mp 46.8–49.2° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:50])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][CH:20]=[C:21]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:33]5[CH:38]=[CH:37][C:36]([C:39](=[O:49])[CH2:40][NH:41]C(OC(C)(C)C)=O)=[CH:35][CH:34]=5)[CH:29]=4)[CH:24]=3)[N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].Cl.CCN(C(C)C)C(C)C.[C:61]([N:68]1[CH2:72][CH2:71][S:70][C@H:69]1[C:73]([OH:75])=O)([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O1CCOCC1.CN(C=O)C.CCOC(C)=O>[C:64]([O:63][C:61]([N:68]1[CH2:72][CH2:71][S:70][CH:69]1[C:73](=[O:75])[NH:41][CH2:40][C:39]([C:36]1[CH:37]=[CH:38][C:33]([C:28]2[CH:27]=[CH:26][C:25]3[C:30](=[CH:31][CH:32]=[C:23]([C:21]4[N:22]=[C:18]([CH:17]5[CH2:16][C:13]6([CH2:15][CH2:14]6)[CH2:12][N:11]5[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:50])[CH:6]([CH3:7])[CH3:8])[NH:19][CH:20]=4)[CH:24]=3)[CH:29]=2)=[CH:34][CH:35]=1)=[O:49])=[O:62])([CH3:65])([CH3:66])[CH3:67]
Reactant: CC(C)(C)OC(=O)N1CCS[C@H]1C(=O)O
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1nc(-c2ccc3cc(-c4ccc(C(=O)CNC(=O)OC(C)(C)C)cc4)ccc3c2)c[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1nc(-c2ccc3cc(-c4ccc(C(=O)CNC(=O)C5SCCN5C(=O)OC(C)(C)C)cc4)ccc3c2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.4 %

Procedure:
{1-[6-(4-{6-[4-(2-tert-Butoxycarbonylamino-acetyl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-5-aza-spiro[2.4]heptane-5-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (395.0 mg, 0.581 mmol) was dissolved in DCM (4 mL) and HCl in dioxane (4M, 4 mL) was added and stirring at room temperature was continued. After 60 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (2.0 mL) and DIEA (110.8 mg, 0.860 mmol) was added. A solution of N-Boc (S) thiazolidine-2-carboxylic acid (100.0 mg, 0.430 mmol), HATU (163.0 mg, 0.430 mmol) and DIEA (55.4 mg, 0.430 mmol) in DMF (1 mL) was added. The reaction was stirred at room temperature. After 20 minutes, the reaction was diluted with EtOAc and was washed with brine, sodium hydroxyl solution (1M), brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material (350 mg), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][N:6]2[C:11]=1[CH:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2)[CH3:2].[C:22]([C:28]([O:30][CH3:31])=[O:29])#[C:23][C:24]([O:26][CH3:27])=[O:25].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[C:11]2[N:6]3[C:7]([CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)=[C:23]([C:24]([O:26][CH3:27])=[O:25])[C:22]([C:28]([O:30][CH3:31])=[O:29])=[C:5]3[C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH3:2]
Reactant: CCc1c(-c2ccc(OC)cc2)cn2ccc(OC)cc12
Reactant: COC(=O)C#CC(=O)OC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCc1c(-c2ccc(OC)cc2)c2c(C(=O)OC)c(C(=O)OC)c3cc(OC)cc1n32
Yield: 90.1 %

Procedure:
A solution of 1-ethyl-7-methoxy-2-(4-methoxyphenyl)indolizine (25.0 g, 0.089 mol) in 800 ml of toluene was stirred in an ice bath, while dimethyl acetylenedicarboxylate (12.6 ml, 0.103 mol) was added dropwise. When the starting material had been consumed according to TLC, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (21.18 g, 0.093 mol) was added in portions. When the addition was complete, the mixture was refluxed for one hour. The resulting hydroquinone was filtered off, and the filtrate was concentrated to dryness. The residue was triturated with petroleum ether (40-60) and isolated to afford 33.8 g (92%) of the title compound. M.p. 153-5° C. 1H-NMR (DMSO-d6, 200 MHz) δ: 1.36 (t, 3H), 3.07 (q, 2H), 3.76 (s, 3H), 3.86 (s, 3H), 3.89 (s, 3H), 4.10 (s, 3H), 7.15 (d, 2H), 7.53 (d, 2H), 7.84 (d, 1H), 8.00 (d, 1H). (Compound 1).