Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[Na+].[CH2:3]1[CH:7]2[CH2:8][NH:9][CH2:10][CH:6]2[CH2:5][N:4]1[CH2:11][CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N:23]3[CH:27]=[N:26][N:25]=[CH:24]3)[CH:21]=2)[NH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44](=[O:46])[CH3:45])=[CH:39][CH:38]=1>COCCOC>[N:26]1[N:25]=[CH:24][N:23]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[CH2:13][CH2:12][CH2:11][N:4]2[CH2:5][C@@H:6]3[CH2:10][N:9]([CH2:35][CH2:36][C:37]4[CH:42]=[CH:41][C:40]([NH:43][C:44](=[O:46])[CH3:45])=[CH:39][CH:38]=4)[CH2:8][C@@H:7]3[CH2:3]2)[CH:27]=1
Reactant: CC(=O)Nc1ccc(CCBr)cc1
Reactant: c1cc2[nH]cc(CCCN3CC4CNCC4C3)c2cc1-n1cnnc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)Nc1ccc(CCN2C[C@H]3CN(CCCc4c[nH]c5ccc(-n6cnnc6)cc45)C[C@H]3C2)cc1
Yield: 30 %

Procedure:
Sodium iodide (98 mg, 0.65 mmol) was added to a mixture of 3-(3-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)propyl)-5-(1,2,4-triazol-4-yl)-1H-indole (200 mg, 0.59 mmol), sodium carbonate (95 mg, 0.90 mmol) and N-(4-(2-bromoethyl)phenyl)acetamide (158 mg, 0.65 mmol) in dry 1,2-dimethoxyethane (5 ml) at room temperature under nitrogen. The mixture was then stirred and heated to reflux, protected from light, for 16 h. Upon cooling, the volatiles were removed in vacuo and the residue was partitioned between dichloromethane and water. The aqueous was further extracted with dichloromethane (x2). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with CH2Cl2 /MeOH/NH3 (60:8:1→50:8:1) to give the title indole (88 mg, 30%) as a foam. The bis hydrogen oxalate. 0.75 hydrate was prepared (Et2O/MeOH): mp 151-155° C. (Found: C, 57.43; H, 6.26; N, 14.35. C29H35N7O.2(C2H2O4).0.75(H2O) requires C, 57.34; H, 5.91; N, 14.18%). δ (360 MHz, d6 -DMSO) 1.94-2.02 (5H, m, includes NC(O)CH3), 2.7-3.3 (18H, m), 7.16 (2H, d, J=8.5 Hz, Ar--H), 7.30-7.36 (2H, m, Ar--H), 7.48-7.52 (3H, m, Ar--H), 7.81 (1H, s, Ar--H), 9.03 (2H, s, Triazole-H), 9.89 (1H, s, N--H), 11.17 (1H, s, N--H).
Reaction SMILES: [CH2:1]=[O:2].[OH-].[Na+].[CH:5]1([CH:11]=[O:12])[CH2:10][CH2:9][CH:8]=[CH:7][CH2:6]1>O>[OH:12][CH2:11][C:5]1([CH2:1][OH:2])[CH2:10][CH2:9][CH:8]=[CH:7][CH2:6]1
Reactant: O=CC1CC=CCC1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCC1(CO)CC=CCC1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To a 5-liter volume four-necked flask provided with a stirrer, a thermometer, a Dimroth condenser and a dropping funnel, 633.3 g (purity 92%, 19 mol) of paraformaldehyde dissolved in 1004.0 g of water was charged, 465.6 g of sodium hydroxide (purity 98.5%, 11.5 mol) dissolved in 1397.0 g of water were dropwise added. Next, the mixture was cooled in an ice bath to 10° C. and 880.7 g of 3-cyclohexene-1-carboaldehyde (purity 97%, 7.8 mol) was dropwise added over 1 hour to the mixture. After dropwise addition, the solution temperature was increased to 20° C. The mixture was stirred at that temperature for 1 hour, then the flask was immersed in a hot water bath and was further stirred at 55° C. for 1 hour. Next, the reaction mixture was cooled down to 15° C. in a water bath and the precipitated solid was obtained by filtration. The solid thus obtained was washed with water to obtain a wet crude crystal of 4,4-bis[(hydroxy)methyl]cyclohexene (II) in an amount of 1396.0 g.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[O:13][C:14]3([C:24]([CH3:26])([CH3:25])[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([O:27][CH3:28])[CH:22]=4)[N:17]3[CH3:29])[CH:15]=[N:16][C:11]=2[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=O.[C:30]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])#[N:31]>>[C:30]([C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:1][C:3]1[C:12]2[O:13][C:14]3([C:24]([CH3:26])([CH3:25])[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([O:27][CH3:28])[CH:22]=4)[N:17]3[CH3:29])[CH:15]=[N:16][C:11]=2[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)#[N:31]
Reactant: COc1ccc2c(c1)C(C)(C)C1(C=Nc3c(c(C=O)cc4ccccc34)O1)N2C
Reactant: CCOC(=O)CC#N
Product: CCOC(=O)C(C#N)=Cc1cc2ccccc2c2c1OC1(C=N2)N(C)c2ccc(OC)cc2C1(C)C

Procedure:
This compound is prepared according to the method employed for Example 10, from 0.39 g (1 mmol) of the compound of Example 2 and from 0.18 g (1.5 mmol) of ethyl cyanoacetate.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:21][OH:22])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:23]1([C:29]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C1COCC1.C(#N)C>[CH2:1]([O:17][CH2:18][C@@H:19]([CH2:21][O:22][C:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCC/C=C\CCCCCCCCOCC(O)CO
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCC/C=C\CCCCCCCCOC[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
9.07 grams of 1-(cis-9-hexadecenyl)-glycerol was dissolved in a mixture of dry THF (160 ml) and dry acetonitrile (40 ml). 10.52 grams triphenylchloromethane and 10 ml triethylamine were added, and the reaction mixture was refluxed for 15 hours. The reaction mixture was cooled to room temperature, poured on ice (100 grams), transferred to a separatory funnel, and extracted thrice with 100 ml chloroform. The organic phase was washed consecutively with 100 ml water, 100 ml dilute (1.0%) sulfuric acid, 100 ml water, 100 ml saturated aqueous sodium bicarbonate, and again with 100 ml water. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The obtained residue was dissolved in hot hexane (100 ml) and the resulting solution was cooled at 4° C. for 36 hours. Filtration of precipitated by-products and removal of solvent under reduced pressure yielded 14.57 grams of crude product. The crude product was purified by chromatography over silica gel (200 grams). 9.81 grams of pure 1-(cis-9-hexadecenyl)-3-trityl-sn-glycerol was eluted with chloroform. The yield was 61.1%.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[C:4](=[O:22])[CH2:5][CH:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[C:7]=1[C:8]([O:10]C)=[O:9].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:3]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[C:4](=[O:22])[CH2:5][CH:6]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:16][CH:17]=2)[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)C1=C(C)N(Cc2cccc(OC)c2)C(=O)CC1c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(CN2C(=O)CC(c3ccc(C(F)(F)F)cc3)C(C(=O)O)=C2C)c1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
The product from Step 1 (0.762 g, 1.76 mmol, 1.00 equiv) was dissolved in MeOH (20 mL) and NaOH (2.0 M, 3.5 mL) and the mixture was heated to reflux for 1.5 hours. The reaction was cooled to room temperature and concentrated en vacuo. The residue was dissolved in H2O and 6N HCl was added to acidify the solution to pH 1. The crystalline precipitate was isolated by filtration, washed with H2O and air dried. The residue was further dried en vacuo to provide 0.586 g (80%) of the product as an amorphous solid. MS (ES+) m/e 420 [M+H]+
Reaction SMILES: [CH:1]1([C:6]([CH3:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:10]([Cl:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CCCCCC.O>O1CCCC1>[Cl:18][C:10]1([O:7][C:6]1([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:8])[C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12]
Reactant: CC(=O)C1CCCC1
Reactant: CC(C)(C)OC(=O)C(Cl)Cl
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(Cl)OC1(C)C1CCCC1
Temperature: -30 °C

Procedure:
A mixture of 12.3 g of cyclopentylmethyl ketone and 18.5 g of tert.-butyl dichloroacetate was cooled to -30°C with stirring under an inert atmosphere and a solution of 12.2 g of potassium tert.butylate in 60 ml of tetrahydrofuran was added thereto at the said temperature. After returning to room temperature, hexane and water were added and the organic phase was separated, washed with water and dried over magnesium sulfate. The solvents were evaporated off to leave an oily residue of tert.-butyl 2-chloro-3-cyclopentyl-2,3-epoxy-butanoate. 26.5 g of the latter product were added to a solution of 3 g of lithium carbonate and 20 g of lithium bromide in 100 ml of hexamethylphosphorotriamide and after stirring for 1 hour at room temperature, petroleum ether and water were added thereto. The organic phase was washed with water, dried over magnesium sulfate and filtered. The solvent was evaporated to obtain an oily residue which was tert. butyl 3-cyclopentyl-2-oxo-3-butenoate which was used as is for the next step.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C@H:15]([C:16]([F:19])([F:18])[F:17])[C@@H:14]3[C:20](=O)[CH2:21][CH2:22][N:13]3[C:12]2=[O:24])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.Cl.[NH2:32][OH:33]>CO.O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C@H:15]([C:16]([F:17])([F:18])[F:19])[C@@H:14]3[C:20](=[N:32][OH:33])[CH2:21][CH2:22][N:13]3[C:12]2=[O:24])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: NO
Reactant: Cc1c(N2C(=O)N3CCC(=O)[C@H]3[C@H]2C(F)(F)F)ccc(C#N)c1Cl
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: O
Product: Cc1c(N2C(=O)N3CCC(=NO)[C@H]3[C@H]2C(F)(F)F)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To 68A (96.0 mg, 0.269 mmol) in MeOH (2.7 mL) and water (5 drops) was added pyridine (109 μL) and hydroxylamine hydrochloride (93.0 mg, 1.34 mmol) and the whole was stirred overnight at rt. The reaction was concentrated then diluted with ethyl acetate and washed with water and brine. The organic layer was dried (MgSO4), filtered and concentrated. The resulting residue was purified via preparative HPLC (YMC ODS C-18, 30×100 mm, eluting with 60-100% solvent B (A=90% H2O—10% MeOH and B=10% H2O—90% MeOH) over 10 min; Flow rate at 40 mL/min; UV detection at 220 nm) to provide a solid which was re-purified via preparative HPLC (YMC ODS C-18, 30×100 mm, eluting with 40-70% solvent B (A=90% H2O—10% CH3CN and B=10% H2O—90% CH3CN) over 12 min; Flow rate at 40 mL/min; UV detection at 220 nm) to provide the title compound (48.0 mg) as a white solid. MS: m/z 371 [M−H]−.
Reaction SMILES: C[C:2]1[N:10]([CH2:11][C:12]2[C:13]([O:20][CH3:21])=[N:14][C:15]([CH3:19])=[C:16]([F:18])[CH:17]=2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:22](O)=[O:23].Cl.[F:26][CH2:27][CH2:28][NH2:29].C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>ClCCl.O>[F:18][C:16]1[CH:17]=[C:12]([CH2:11][N:10]2[C:9]3[C:4](=[N:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:22]([NH:29][CH2:28][CH2:27][F:26])=[O:23])=[CH:2]2)[C:13]([O:20][CH3:21])=[N:14][C:15]=1[CH3:19]
Reactant: COc1nc(C)c(F)cc1Cn1c(C)c(C(=O)O)c2ncccc21
Reactant: NCCF
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1nc(C)c(F)cc1Cn1cc(C(=O)NCCF)c2ncccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
See FIG. 20(b). To the stirred solution of methyl 1-((5-fluoro-2-methoxy-6-methylpyridin-3-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (0.15 g, 0.47 mmol) in dichloromethane (10 mL), were added 2-fluoroethan-1-amine hydrochloride (71 mg, 0.71 mmol), triethylamine (0.142 g, 1.41 mmol) and T3P (0.9 g, 1.41 mmol) and the mixture was stirred for 16 h at room temperature. Then the reaction mixture was poured into water and extracted with dichloromethane. The combined organic layer was washed with water, brine, dried over sodium sulfate, and concentrated at reduced pressure. The residue was purified by silica gel column chromatography to yield 1-((5-fluoro-2-methoxy-6-methylpyridin-3-yl)methyl)-N-(2-fluoroethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide as a white solid. Yield: 30 mg (18%). ES+MS m/z: 361 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 2.31 (d, 3H, J=2.9 Hz), 3.64-3.68 (m, 2H), 3.71-3.75 (m, 2H), 3.85 (s, 3H), 4.49-4.51 (m, 2H), 4.61-4.63 (m, 2H), 5.41 (s, 2H), 7.28-7.32 (m, 1H), 7.45 (d, 1H, J=9.0 Hz), 8.08-8.11 (m, 1H), 8.29 (s, 1H), 8.49-8.50 (m, 1H), 8.92 (t, 1H, J=5.8 Hz).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Cl[CH2:14][C:15]([O:21][CH3:22])=[CH:16][C:17]([O:19][CH3:20])=[O:18].O>CN(C=O)C>[O:6]=[C:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1](=[O:11])[N:5]1[CH2:14]/[C:15](/[O:21][CH3:22])=[CH:16]/[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C=C(CCl)OC
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C=C(/CN1C(=O)c2ccccc2C1=O)OC
Temperature: 60 °C

Procedure:
18.5 potassium phthalimide are suspended in 50 ml DMF, the mixture is heated to 60° C. and 16.5 g methyl 4-chloro-3-methoxy-but-2-enoate in 50 ml DMF are added. After 2 days the reaction mixture is poured into 500 ml of water. The precipitate formed is suction filtered and washed with water. The residue is dissolved in ethyl acetate, dried and the solution is evaporated to dryness. The residue is triturated with ether. 21.77 g of the product are obtained as a powder.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1[CH:8]=[C:7]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:25]=[C:24]([CH3:26])[C:17]([O:18][CH2:19][CH:20]([OH:23])[CH2:21]O)=[C:16]([CH2:27][CH3:28])[CH:15]=3)[N:10]=2)[CH:6]=[C:5]([CH2:29][CH3:30])[N:4]=1.CC[N:34](C(C)C)C(C)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.N>C1COCC1.CO>[NH2:34][CH2:21][CH:20]([OH:23])[CH2:19][O:18][C:17]1[C:24]([CH3:26])=[CH:25][C:14]([C:11]2[N:10]=[C:9]([C:7]3[CH:6]=[C:5]([CH2:29][CH3:30])[N:4]=[C:3]([N:2]([CH3:31])[CH3:1])[CH:8]=3)[O:13][N:12]=2)=[CH:15][C:16]=1[CH2:27][CH3:28]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(CC)c3)no2)cc(N(C)C)n1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(-c2nc(-c3cc(C)c(OCC(O)CN)c(CC)c3)no2)cc(N(C)C)n1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a solution of rac-3-{4-[5-(2-dimethylamino-6-ethyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propane-1,2-diol (78 mg, 0.183 mmol) and DIPEA (47 mg, 0.365 mmol) in THF (5 mL) is added methanesulfonylchloride (23 mg, 0.201 mmol) at 0° C. The mixture is stirred at 0° C. for 3 h (Mesylate: LC-MS: tR=0.88 min; [M+1]+=505.12) before it is added to 7 N NH3 in methanol (10 mL). The mixture is stirred at 65° C. for 16 h. The solvent is removed in vacuo and the crude product is purified on prep. TLC plates with DCM containing 5% of methanol and 10% of 7 N NH3 in methanol to give rac-1-amino-3-{4-[5-(2-dimethylamino-6-ethyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phen-oxy}-propan-2-ol as a yellow resin. This material is dissolved in DCM and to the solution glycolic acid (29 mg, 0.375 mmol) and DIPEA (70 mg, 0.540 mmol) is added. The mixture is cooled to 0° C. before TBTU (71 mg, 0.221 mmol) is added. The mixture is stirred at 0° C. for 1 h before it is diluted with EA (100 mL), washed twice with sat. aq. NaHCO3-solution (25 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified on prep. TLC plates with heptane:EA 7:3 to give rac-N-(3-{4-[5-(2-dimethylamino-6-ethyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide (32 mg) as a yellow resin; LC-MS: tR=0.76 min; [M+1]+=484.19.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([C:14]3[C:22]4[N:21]5[CH:23]=[CH:24][CH:25]=[C:20]5[CH:19]([NH2:26])[C:18]=4[CH:17]=[CH:16][CH:15]=3)[NH:11][C:10]=2[CH:27]=1.[NH:28]1[C:32]2[N:33]=[CH:34][CH:35]=[C:36]([C:37](O)=[O:38])[C:31]=2[CH:30]=[CH:29]1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[F:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([C:14]3[C:22]4[N:21]5[CH:23]=[CH:24][CH:25]=[C:20]5[CH:19]([NH:26][C:37]([C:36]5[C:31]6[CH:30]=[CH:29][NH:28][C:32]=6[N:33]=[CH:34][CH:35]=5)=[O:38])[C:18]=4[CH:17]=[CH:16][CH:15]=3)[NH:11][C:10]=2[CH:27]=1
Reactant: O=C(O)c1ccnc2[nH]ccc12
Reactant: NC1c2cccc(-c3nc4ccc(F)cc4[nH]3)c2-n2cccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: O=C(NC1c2cccc(-c3nc4ccc(F)cc4[nH]3)c2-n2cccc21)c1ccnc2[nH]ccc12
Reaction time: 1 h
Yield: 23.2 %

Procedure:
A mixture of 42 mg of 5-(6-fluoro-1H-benzimidazol-2-yl)-9H-pyrrolo[1,2-a]indol-9-ylamine acetate obtained according to the preceding stage, 19 mg of 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (which can be obtained according to WO 2003/000688), 39 mg of o-((ethoxycarbonyl)cyanomethylene-amino)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TOTU) and 16 μl of diisopropylethylamine in 3 ml of N-methylpyrrolidone is stirred in a 100 ml round-bottomed flask. After 1 hour, the reaction medium is evaporated to dryness, the residue is taken up with 30 ml of a saturated solution of sodium bicarbonate and the aqueous phase is extracted with 4 times 30 ml of ethyl acetate. The combined organic phases are washed with 3 times 30 ml of a saturated solution of sodium chloride, dried over magnesium sulphate, and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (15-40 μm), elution being carried out with a gradient of methanol (2% to 5% v/v) in dichloromethane, and then on a second column of silica gel (15-40 μm), elution being carried out with pure ethyl acetate. 12 mg of 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid [5-(6-fluoro-1H-benzimidazol-2-yl)-9H-pyrrolo[1,2-a]indol-9-yl]amide are obtained in the form of a brown solid, the characteristics of which are the following:
Reaction SMILES: CO[CH:3](OC)[CH2:4][N:5]([CH3:24])[C:6]([C:8]1[NH:9][CH:10]=[C:11]([C:13](=[O:23])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[CH:12]=1)=[O:7].O=P(Cl)(Cl)Cl.C(Cl)Cl.CO>O1CCOCC1>[F:22][C:16]1[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][C:13]([C:11]1[C:12]2[CH:3]=[CH:4][N:5]([CH3:24])[C:6](=[O:7])[C:8]=2[NH:9][CH:10]=1)=[O:23]
Reactant: COC(CN(C)C(=O)c1cc(C(=O)Cc2cccc(F)c2F)c[nH]1)OC
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cn1ccc2c(C(=O)Cc3cccc(F)c3F)c[nH]c2c1=O
Reaction time: 14 h
Yield: 40.3 %

Procedure:
To 4-[(2,3-Difluoro-phenyl)-acetyl]-1H-pyrrole-2-carboxylic acid (2,2-dimethoxy-ethyl)-methyl-amide (200 mg, 0.55 mmol) in dioxane (50 mL) was added POCl3 (50 μL, 0.55 mmol) at 0C. The reaction solution was heated to 60C and stirred for 14 hr. The reaction was quenched with water and extracted with ethyl acetate, dried (Na2SO4). Flash chromatography (methylene chloride/methanol) gave 67 mg (41% yield)of title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:4][C:3]=1[CH:14]=[O:15].[OH-:16].[Na+]>[N+]([O-])([O-])=O.[Ag+].C(O)C>[CH3:1][C:2]1[CH:6]=[C:5]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: [OH-]
Reactant: Cc1cc(Oc2ccccc2)sc1C=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Oc2ccccc2)sc1C(=O)O

Procedure:
3-Methyl-5-phenoxy-thiophene-2-carbaldehyde, (example 22.a, 5.68 g, 25.9 mmol) was added to 26 mL of ethanol. To the mixture were added 21 mL of 5 N NaOH(aq) and silver nitrate (8.81 g, 52 mmol), and the resultant mixture was stirred for 19 hours at room temperature. The mixture was filtered through a pad of celite, washing the solid with ca. 50-100 mL portions of 1 N NaOH solution three times. The basic solution was washed with ethyl ether, then acidified with concentrated H2SO4, and extracted twice with ethyl acetate. The organic fractions were dried over anhydrous sodium sulfate and concentrated under high vacuum to 5.7 g of a yellow solid: MS: (−) m/z 232.9 (M−1)
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][S:9][C:8]2=[S:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[C:18](=[O:20])[CH3:19])(=O)C>>[OH:20][C:18](=[C:10]1[S:9][C:8](=[S:13])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]1=[O:12])[CH2:19][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CSC(=S)N1c1ccccc1
Product: O=C1C(=C(O)Cc2ccccc2)SC(=S)N1c1ccccc1
Reaction time: 4 h

Procedure:
A mixture of 25 g. (0.12 m.) of 3-phenylrhodanine, 80 g. (0.34 m.) of triethylorthophenylacetate [prepared as described in J.A.C.S. 68, 1917 (1946)] and 250 ml. of acetic anhydride is heated under reflux for 20 hours and the solution is then concentrated in vacuo. The residue is filtered and the solid is stirred with 160 ml. of dioxane, 160 ml. of water and 40 ml. of 10% sodium hydroxide for 4 hours. The solution is concentrated in vacuo at 35°-40°C. to evaporate the dioxane. The aqueous solution, after washing with ether and decolorizing with charcoal, is made acidic with dilute hydrochloric acid. The solid product is purified by chromatography to give 5-(1'-hydroxy-2'-phenylethylidene)-3-phenyl-rhodanine, m.p. 146-148°C.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C@H:2]([CH3:4])[OH:3].[OH:7][CH:8]([CH2:12][CH3:13])[C:9]([OH:11])=[O:10]>>[C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[OH:7][CH:8]([CH2:12][CH3:13])[C:9]([OH:11])=[O:10]
Reactant: C[C@H](O)C(=O)O
Agent: CCC(O)C(=O)O
Product: CC(O)C(=O)O

Procedure:
A 90 wt % aqueous solution of L-lactic acid (50 g) and 50 g of hydroxybutyric acid were put into a reaction vessel equipped with a stirrer and a nitrogen-introducing tube. After substitution of nitrogen gas was carried out three times, the mixture was concentrated at 120° C. for 5 hours with stirring in a stream of nitrogen to give 65 g of lactic acid-hydroxybutyric acid oligomer. To the obtained oligomer was added 1.3 g of Baylith 5A with which sodium elution (381 ppm) had been observed. Then, the temperature was raised to 200° C., and the pressure was reduced gradually to 20 mmHg over 30 minutes. The mixture was stirred at 195±5° C. for 3 hours. After the pressure was reduced gradually to 1 mmHg over 30 minutes, the mixture was stirred at 195±5° C. for 7 hours to give lactic acid-hydroxybutyric acid copolymer in the molten state. The product was cooled to room temperature to give 28.15 g of lactic acid-hydroxybutyric acid copolymer as a light brown solid. The weight-average molecular weight of this copolymer was 58,000.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([CH3:16])=[O:15])[C:5]=1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].S(OCC)(O[CH2:21][CH3:22])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([CH3:16])=[O:15])[C:5]=1[C:6]([O:8][CH2:21][CH3:22])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOS(=O)(=O)OCC
Reactant: CC(=O)Nc1cccc(C(C)=O)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(NC(C)=O)cccc1C(C)=O
Temperature: 0 °C
Yield: 91 %

Procedure:
The mixture of 4.0 g of 2-acetyl-6-acetaminobenzoic acid, 3.1 g of diethyl sulfate and 2.8 g of potassium carbonate in 40 ml of acetone was allowed to react under stirring under refluxing for 5 hours. After the reaction was over, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water and concentrated to obtain 4.1 g of ethyl 2-acetyl-6-acetaminobenzoate.