Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[CH2:14]([N+:18]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>CO>[C:1]([O-:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.[CH2:27]([N+:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:28][CH2:29][CH3:30].[CH2:27]([N+:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:28][CH2:29][CH3:30]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1ccc(C(=O)[O-])cc1
Yield: 93.4 %

Procedure:
Terephthalic acid (0.439 g., 2.64×10-3 mol) (dried in vacuo at 60° C.) partially dissolved in 10 mL of methanol was titrated under an argon atmosphere with 5.3 mL (1.4 g, 5.3×10-3 mol) of tetrabutylammonium hydroxide solution (1 M) in methanol. A fine white precipitate which had formed was removed by centrifugation, washed with methanol, and dried in vacuo, weighed (0.037 g) and discarded. The solvent was removed from the filtrate by rotary vacuum evaporation and the salt residue was dried in vacuo at 60° C. for 18 h to obtain 1.60 g (92%) of product. NMR spectra of the salt were obtained in CDCl3, FIGS. 41 and 42.
Reaction SMILES: [Cl:1]C(OC)=O.[CH3:6][O:7][C:8](=[O:21])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17]N(C)C)=[O:10]>C1(C)C=CC=CC=1>[CH3:6][O:7][C:8](=[O:21])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][Cl:1])=[O:10]
Reactant: COC(=O)C(=O)c1ccccc1CN(C)C
Reactant: COC(=O)Cl
Solvent: Cc1ccccc1
Product: COC(=O)C(=O)c1ccccc1CCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
15.9 g of methyl chloroformate (165 mmol) are added at from 20 to 25° C. to a solution of 18.3 g of o-(N,N-dimethylaminomethyl)-phenylglyoxylic acid methyl ester Va (content 88.6%; 73.3 mol) in 100 ml of toluene. The reaction mixture is stirred at RT overnight, heated at 60° C. for 1 h, cooled and concentrated by evaporation in vacuo. 15.3 g (content 83%; yield 82%) of product are obtained.
Reaction SMILES: [Li][CH3:2].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[CH2:14][CH:15]=[O:16].O>CCOCC.Cl[Ti](Cl)(Cl)Cl>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[CH2:14][CH:15]([OH:16])[CH3:2]
Reactant: COc1cc([N+](=O)[O-])ccc1CC=O
Reactant: [Li]C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1CC(C)O
Temperature: -10 °C
Yield: 83.8 %

Procedure:
To a stirred −78° C. solution of TiCl4 (1.0 M in CH2Cl2, 1.43 mL, 1.43 mmol) in anhydrous Et2O (7 mL) was added MeLi (1.6 M in Et2O, 0.9 mL, 1.43 mmol) dropwise over a period of 20 min. The reaction mixture was allowed to slowly warm to −30° C. at which point a solution of 2-(2-methoxy-4-nitrophenyl)acetaldehyde (275 mg, 1.43 mmol) (prepared as described in PCT WO 2000/73288 A1) in anhydrous Et2O (0.750 mL) was added dropwise and allowed slowly warm to −10° C. The reaction mixture was poured into cold water and extracted with Et2O (3×50 mL). The combined ether extracts were washed with water (1×100 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure to afford 0.253 g (85%) of the title compound as an orange solid. 1H NMR (500 MHz, CDCl3) δ 1.25 (d, J=6.0 Hz, 3 H), 1.62 (br. s., 1 H), 2.81 (dd, J=13.2, 7.7 Hz, 1 H), 2.89-2.94 (m, 1 H), 3.93 (s, 3 H), 4.06-4.15 (m, 1 H), 7.32 (d, J=8.2 Hz, 1 H), 7.72 (d, J=2.2 Hz, 1 H), 7.82 (dd, J=8.2, 2.2 Hz, 1 H); HPLC (Method #1): 2.68 min retention time, (89%); LCMS (ES): m/z 194 [M−H2O+H]+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH2:19]([C:23]1[O:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1)[CH2:20][CH2:21][CH3:22]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:28]([C:26]3[N:27]=[C:23]([CH2:19][CH2:20][CH2:21][CH3:22])[O:24][C:25]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:29])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CCCCc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CCCCc1nc(C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)c(-c2ccccc2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-butyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.11 min; [M+H]+=433.37.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:23]1([CH2:36][O:37][C:38]([NH:40][C@H:41]([C:54](O)=[O:55])[CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:39])[C:35]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1.[NH2:57][C:58]1[C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH:61]=[CH:60][CH:59]=1>O.C(OCC)(=O)C>[C:58]1([NH:57][C:54](=[O:55])[C@H:41]([CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:47]([O:49][C:50]([CH3:52])([CH3:51])[CH3:53])=[O:48])[NH:40][C:38]([O:37][CH2:36][C:23]2[C:35]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]=3[CH:26]=[CH:25][CH:24]=2)=[O:39])[C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH:61]=[CH:60][CH:59]=1
Reactant: Nc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1cccc2c1Cc1ccccc1-2)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1cccc2c1Cc1ccccc1-2)C(=O)Nc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
Under cooling with ice water, 2.97 g (22 mmol) of 1-hydroxybenzotriazole and 4.60 g (24 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added to an ethyl acetate solution (50 ml) of 9.37 g (20.0 mmol) of Nα-fluorenylmethyloxycarbonyl-Nε-t-butoxycarbonyl-L-lysine and 2.86 g (20.0 mmol) of 1-aminonaphthalene. The mixture was stirred overnight as it was. Water was added to the reaction mixture, and a solid deposited was collected by filtration, washed with ethyl acetate and dried, thereby obtaining 7.95 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:14]1CCC(N=C=NC2CCCCC2)C[CH2:15]1>CCO>[CH2:14]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:2]([NH2:1])[CH:3]=1)[CH3:15]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Solvent: CCO
Product: CCOC(=O)c1cc(N)cc([N+](=O)[O-])c1

Procedure:
3-Amino-5-nitrobenzoic acid (910 mg, 5.0 mmol) was dissolved in EtOH (25 mL). DCC (1.51 g, 7.3 mmol) was added, and the mixture was stirred under reflux overnight. The solid precipitation was filtered off and the filtrate was evaporated. The residue was triturated in the solvent mixture ether:hexane:ethyl acetate, 5:5:1. The title compound was isolated as a fine light yellow powder (0.9 g, 85.7%).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[S:5]1[CH2:11][C:9](=[O:10])[NH:8][C:6]1=S.CCN(C(C)C)C(C)C>>[CH:1]1([NH:4][C:6]2[S:5][CH2:11][C:9](=[O:10])[N:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1CSC(=S)N1
Reactant: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(NC2CC2)=N1

Procedure:
Similar procedure as described in example 1f was used, starting cyclopropylamine, rhodanine (2-thioxo-thiazolin-4-one) and DIEA to give 2-cyclopropylamino-thiazol-4-one. LC-MS m/e 157 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C(N(CC)CC)C>C(Cl)Cl>[CH:9]12[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:13]([CH2:14][CH2:15]1)[CH2:12][N:11]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:10]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 22 h
Yield: 86.6 %

Procedure:
A mixture of 8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octane (238 mg, 1.12 mmol), benzyl chloroformate (160 μL, 1.12 mmol) and triethylamine (280 μL, 2.0 mmol) in DCM (20 mL) was stirred at room temperature for 22 h. The reaction mixture was diluted with DCM (20 mL) and washed with water (25 mL). The organic phase was dried (magnesium sulfate) and the solvent was removed in vacuo to give the title compound (336 mg, 87%) as a clear oil. δH (DMSO-d6) 7.45-7.28 (5H, m), 5.17-5.03 (2H, m), 4.18-4.06 (2H, m), 3.79-3.69 (2H, m), 3.10-2.90 (2H, m), 1.85-1.72 (2H, m), 1.60-1.49 (2H, m), 1.41 (9H, s).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][NH:11][CH3:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][C:15]=1[CH3:24]>O1CCCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:11]([CH3:12])[CH3:10])(=[O:22])=[O:21])=[CH:16][C:15]=1[CH3:24]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Br
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(S(=O)(=O)N(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
Diisopropylethylamine (4.95 mL, 27.8 mmol) was added at 0° C. to a stirred solution of dimethylamine (3.70 mL, 55.6 mmol) in tetrahydrofuran (25 mL) and the reaction mixture was stirred at room temperature for 15 minutes. A 0.1 M solution of 4-bromo-3-methyl-benzenesulfonyl chloride (3.0 g, 11 mmol) in tetrahydrofuran was added at room temperature and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated off under reduced pressure. The residue was diluted with ethyl acetate, and the inorganic salts were filtered through a celite bed. The filtrate was washed with 2 N aqueous HCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 2.90 g (94%) of 4-bromo-3-methyl-N,N-dimethyl-benzenesulfonamide, which was used in subsequent reactions without further purification. MS cald. for C9H12BrNO2S [M+] 278.2, obsd. 280.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[NH:20][CH2:19][CH2:18][N:9]2[C:10](=[O:17])[C:11]2[N:12]([CH:14]=[CH:15][CH:16]=2)[CH2:13]3)=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:25](Cl)(=[O:27])[CH3:26]>ClCCCl.C([O-])(O)=O.[Na+]>[C:25]([C:15]1[CH:16]=[C:11]2[C:10](=[O:17])[N:9]3[CH2:18][CH2:19][NH:20][C:8]3([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:13][N:12]2[CH:14]=1)(=[O:27])[CH3:26]
Reactant: O=C1c2cccn2CC2(c3ccc(Cl)cc3)NCCN12
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1cc2n(c1)CC1(c3ccc(Cl)cc3)NCCN1C2=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
10a-(4-chlorophenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (50 mg, 0.17 mmol) and aluminium chloride (53 mg, 0.40 mmol) were suspended in 1,2-dichloroethane (1 mL). Acetyl chloride (15 μL, 0.21 mmol) in 1,2-dichloroethane was added dropwise to the reaction mixture. After 16 h at room temperature the reaction was not completed and another portion of acetyl chloride (15 μL, 0.21 mmol) was added. The reaction was still incomplete after a further 6 h at room temperature, therefore further acetyl chloride (15 μL, 0.21 mmol) and aluminium chloride (53 mg) were added and the reaction mixture was heated at 60° C. for 2 h. LCMS analysis showed a large amount of doubly acetylated product (372 m/z), along with target product (330 m/z) and a smaller amount of starting material (288 m/z). The reaction mixture was diluted with saturated aqueous solution of NaHCO3 (25 mL) and extracted with CH2Cl2 containing 20% of propan-2-ol (2×25 mL). The organic layers were combined, dried and concentrated in vacuo to give a brown oil. The crude mixture was purified using flash chromatography (Biotage SP4, 12 g cartridge, 0-20% MeOH gradient in CH2Cl2′) to give 7-acetyl-10a-(4-chlorophenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (23 mg, 40% yield). ESI-MI m/z [M+H]+ 329.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([NH:13][C:14](=O)[CH2:15][CH3:16])[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:33]2)=CC=1.C1(C)C=CC=CC=1.Cl>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([NH:13][C:14](=[S:33])[CH2:15][CH3:16])[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCC(=O)Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCC(=S)Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Yield: 61.4 %

Procedure:
175 mg of 5-(4-fluorophenyl)-3-propionylamino-4-(4-pyridyl)pyrazole and 450 mg of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide were added to 30 ml of toluene, followed by heating under reflux for 2 hours. After the reaction mixture was cooled, 10% hydrochloric acid and ethyl acetate were added thereto. The aqueous layer was separated, neutralized with a saturation solution of sodium hydrogen carbonate, and extracted with chloroform-methanol (5:1). After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (using chloroform-methanol (10:1) as the developing solvent). Thus, 113 mg (61% yield) of the title compound was obtained as pale-yellow crystals.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]1[N:24]3[CH2:25][CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][C:23]3=[N:22][C:15]=1[CH:16]=[N:17]2.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[O-:9][N+:17]1[C:18]2[C:13](=[CH:12][CH:21]=[CH:20][CH:19]=2)[C:14]2[N:24]3[CH2:25][CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][C:23]3=[N:22][C:15]=2[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(nc3cnc4ccccc4c32)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCn2c(nc3c[n+]([O-])c4ccccc4c32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
mCPBA (26.1 g of 77% pure material, 118 mmol) was added in small portions to a solution of tert-butyl 10,11-dihydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate (29.54 g, 91.06 mmol) in chloroform (500 mL), and the reaction was stirred for one hour at ambient temperature. Aqueous sodium carbonate (400 mL of a 1% solution) was added, and the mixture was stirred for 30 minutes. The organic layer was separated, washed with 1% aqueous sodium carbonate (2×300 mL). Citric acid (10% aqueous solution) was added to aid in the separation. The organic layer was then washed twice with 10% aqueous citric acid, and the combined aqueous washings were extracted with chloroform (3×150 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was dried overnight under vacuum to provide 28.49 g of tert-butyl 5-oxido-10,11-dihydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-].[Li+].[Br-].[CH2:23]([Zn+])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(N1C=CN(C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C.O.CN1CCCC1=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cl)cc21
Reactant: [Zn+]Cc1ccccc1
Agent: CC(C)n1ccn(C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Br-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cc3ccccc3)cc21
Temperature: 20 °C
Reaction time: 24 h

Procedure:
To a nitrogen-degassed mixture of 6-chloro-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (1.12 g, 4 mmol), lithium bromide (1.39 g, 16 mmol), (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium (II) dichloride (0.056 g, 0.08 mmol), 1-methyl-2-pyrrolidinone (10 mL) and THF (10 mL) was added a solution of benzylzinc bromide in THF (0.5 M, 32 mL) and resulting mixture was stirred at 20° C. for 24 h. The mixture was poured into water (100 mL) and 5% aqueous citric acid (30 mL) and the resulting mixture extracted with 1:1 EtOAc-petrol. The organic phase was washed with water (3×50 mL), dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2, eluted with petrol-Et2O 0-80%) gave the title compound (1.1 g) as an oil. 1H NMR (CDCl3): 8.20 (1H, s), 7.32 (4H, d), 7.27-7.03 (2H, m), 4.13 (2H, s), 3.71 (2H, s), 1.51 (9H, s), 1.37 (6H, s).
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].N1C=CC=CC=1.[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>C(Cl)Cl>[S:26]([O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:19])([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: OCCOCCOCCOCCOCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCCOCCO)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.2 %

Procedure:
25 g (88.5 mmol) of hexaethyleneglycol was stirred at 0° C. in 200 mL of CH2Cl2, and 14.3 mL of pyridine (177 mmol; 2 eq.) was added to the mixture followed by 17.4 g (88.5 mmol) of tosylchloride. The reaction mixture was stirred at room temperature for 24 hours and partitioned between 400 ml of 1N HCl and 200 ml of CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated to provide 31 g of a light yellow oil. Purification by silica gel chromatography (CH2Cl2/MeOH) provided 15.32 g (40%) of 1 as a light yellow oil: 1H NMR (CDCl3) δ2.45 (s, 3H), 3.55-3.75 (m, 22H), 4.15 (t, 2H), 7.35 (d, 2H), 7.80 (d, 2H); HRMS (FAB) calculated for C19H33O9S (M+H): 437.1845. Found: 437.1834.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH3:22])[CH:17]=[C:16]([O:23][CH2:24][CH3:25])[C:15]=2[F:26])[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1)#[N:2].[CH2:27](O)[CH2:28][CH2:29][CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:27]([O:12][C:11](=[O:13])[CH:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH3:22])[CH:17]=[C:16]([O:23][CH2:24][CH3:25])[C:15]=1[F:26])[CH2:28][CH2:29][CH3:30]
Reactant: CCOc1cc(OCC)c(F)c(C(Nc2ccc(C#N)cc2)C(=O)O)c1
Reactant: CCCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(OCC)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.8 %

Procedure:
The (RS)-(4-cyano-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid (220 mg) described in example 2.15 was dissolved in THF (3.3 ml). n-Butanol (64 mg), triphenylphosphine (179 mg) and diethylazo dicarboxylate (122 mg) were added and the mixture was stirred for 3 h at room temperature. The mixture was concentrated and the product was purified by column chromatography to give 109 mg of (RS)-(4-cyano-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid butyl ester as an off-white solid. MS: 414 ([M+H]+)
Reaction SMILES: BrC1C2C=NC=CC=2N(CCCS(C)(=O)=O)C=1C[N:19]1[C:23]2[CH:24]=[N:25][CH:26]=[CH:27][C:22]=2[N:21]([CH:28]2[CH2:30][CH2:29]2)[C:20]1=[O:31].[Cl:32][C:33]1[CH:34]=[C:35]2[CH:41]=[C:40]([CH2:42]O)[N:39]([CH2:44][CH2:45][CH2:46][CH2:47][F:48])[C:36]2=[CH:37][N:38]=1>>[Cl:32][C:33]1[CH:34]=[C:35]2[CH:41]=[C:40]([CH2:42][N:19]3[C:23]4[CH:24]=[N:25][CH:26]=[CH:27][C:22]=4[N:21]([CH:28]4[CH2:29][CH2:30]4)[C:20]3=[O:31])[N:39]([CH2:44][CH2:45][CH2:46][CH2:47][F:48])[C:36]2=[CH:37][N:38]=1
Reactant: CS(=O)(=O)CCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)c(Br)c2cnccc21
Reactant: OCc1cc2cc(Cl)ncc2n1CCCCF
Product: O=c1n(Cc2cc3cc(Cl)ncc3n2CCCCF)c2cnccc2n1C1CC1

Procedure:
3-((5-chloro-1-(4-fluorobutyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one P11 was synthesized following the procedure reported for the synthesis of 3-((3-bromo-1-(3-(methylsulfonyl)propyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one P17, using (5-chloro-1-(4-fluorobutyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanol 10 instead of (3-bromo-1-(3-(methylsulfonyl)propyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)methanol 12. 1H NMR (360 MHz, DMSO-d6) δ ppm 0.87-0.97 (m, 2H), 1.02-1.13 (m, 2H), 1.57-1.78 (m, 4H), 2.99 (tt, J=6.9, 3.6 Hz, 1H), 4.30-4.43 (m, 3H), 4.49 (m, J=5.7, 5.7 Hz, 1H), 5.35 (s, 2H), 6.53 (s, 1H), 7.29 (d, J=5.5 Hz, 1H), 7.56 (s, 1H), 8.26 (d, J=5.1 Hz, 1H), 8.37 (s, 1H), 8.70 (s, 1H); m/z=414 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[K+].[Cl-].[Mg+2:22].[Cl-]>O>[Mg:22].[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [Mg+2]
Agent: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: [Mg]
Reaction time: 0.5 h

Procedure:
1.6 g 2-butyl-5-methanesulfonamido-benzofuran II was added to the solution of 0.28 g 85% potassium hydroxide in 16 ml water. The reaction mixture was stirred for 30 minutes. To the obtained solution 0.76 g magnesium chloride dissolved in 5 ml water was added in 10 minutes, the resulting suspension was stirred at 20-25° C. for 1 hour and then at 5° C. for 2 hours. The product was filtered off and dried.
Reaction SMILES: [CH3:1][NH:2][N:3]=[C:4]([CH3:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7].O1CCCC1.C(N(CC)CC)C.[CH2:23]([C:25]1([C:35](=[O:39])[C:36](Cl)=[O:37])[CH:30]=[C:29]([CH2:31][CH3:32])[CH:28]=[C:27]([CH2:33][CH3:34])[CH2:26]1)[CH3:24]>CCCCCC>[CH2:23]([C:25]1([C:35](=[O:39])[C:36]([N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7])=[O:37])[CH:30]=[C:29]([CH2:31][CH3:32])[CH:28]=[C:27]([CH2:33][CH3:34])[CH2:26]1)[CH3:24]
Reactant: CNN=C(C)CS(C)(=O)=O
Reactant: CCC1=CC(CC)(C(=O)C(=O)Cl)CC(CC)=C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCC1=CC(CC)(C(=O)C(=O)N(C)N=C(C)CS(C)(=O)=O)CC(CC)=C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a 3 L volume four-necked flask, 1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine (5-2-1) (116.0 g), tetrahydrofuran (anhydrous) (600 ml), and triethylamine (98.5 ml) were added under a nitrogen atmosphere, and cooled to about 1° C. to the mixture, 2-(1,3,5-triethylphenyl)-2-oxoacetyl chloride (6-b) (178.5 g) was added dropwise, and stirred at 0° C. for 1 hour. The reaction mixture was added dropwise to hexane (3 L) at room temperature, and stirred for 1 hour. The precipitated solids were collected by filtration, washed with hexane (0.5 L×2) and water (0.5 L×6), and dried under reduced pressure to give 200.9 g of 1-[2-(1,3,5-triethylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine ((4-34)-(1)-40).