Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.FC(F)(F)C(O)=O.[CH:26]([C:29]1[S:30][CH:31]=[C:32]([C:34]([N:36]2[CH2:41][C:40]3([CH2:46][CH2:45][N:44]([CH2:47][CH2:48][C:49]4[CH:50]=[C:51]([CH:60]=[CH:61][CH:62]=4)[CH2:52][CH2:53][O:54][CH2:55][CH2:56][C:57](O)=[O:58])[CH2:43][CH2:42]3)[O:39][CH2:38][CH2:37]2)=[O:35])[N:33]=1)([CH3:28])[CH3:27].[CH3:63][O:64][CH:65]([O:72][CH3:73])[CH2:66][NH:67][CH2:68][CH2:69][CH2:70][CH3:71].C(N(CC)CC)C>CN(C=O)C>[CH2:68]([N:67]([CH2:66][CH:65]([O:64][CH3:63])[O:72][CH3:73])[C:57](=[O:58])[CH2:56][CH2:55][O:54][CH2:53][CH2:52][C:51]1[CH:60]=[CH:61][CH:62]=[C:49]([CH2:48][CH2:47][N:44]2[CH2:45][CH2:46][C:40]3([O:39][CH2:38][CH2:37][N:36]([C:34]([C:32]4[N:33]=[C:29]([CH:26]([CH3:27])[CH3:28])[S:30][CH:31]=4)=[O:35])[CH2:41]3)[CH2:42][CH2:43]2)[CH:50]=1)[CH2:69][CH2:70][CH3:71]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4cccc(CCOCCC(=O)O)c4)CC3)C2)cs1
Reactant: CCCCNCC(OC)OC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCN(CC(OC)OC)C(=O)CCOCCc1cccc(CCN2CCC3(CC2)CN(C(=O)c2csc(C(C)C)n2)CCO3)c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
T3P (15.67 mL of 1.57M solution in THF) was added dropwise over 15 minutes to a stirred solution of 3-(3-(2-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenethoxy)propanoic acid trifluoroacetate salt [Example 34a, step c] (14.4 g) and N-(2,2-dimethoxyethyl)butan-1-amine [J. Am. Chem. Soc. 1949, 71(6), 2272] (3.97 g) and triethylamine (21.83 mL) in DMF (180 mL). The mixture was stirred at 20° C. for 3 hours and then partitioned between ethyl acetate and aqueous brine. The organic layer was washed with aqueous brine (×2), dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to give the subtitled compound. Yield 15.00 g.
Reaction SMILES: C(OC[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([O:21][CH3:22])=[CH:15][C:16]=2[OH:20])[N:11]=[CH:10]1)(=O)C(C)(C)C.[O:23]1[CH2:28][CH2:27][CH:26](O)[CH2:25][CH2:24]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C(Cl)Cl>[CH3:22][O:21][C:14]1[CH:13]=[C:12]2[C:17]([C:18](=[O:19])[NH:9][CH:10]=[N:11]2)=[C:16]([O:20][CH:26]2[CH2:27][CH2:28][O:23][CH2:24][CH2:25]2)[CH:15]=1
Reactant: COc1cc(O)c2c(=O)n(COC(=O)C(C)(C)C)cnc2c1
Reactant: OC1CCOCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(OC2CCOCC2)c2c(=O)[nH]cnc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a solution of (5-hydroxy-7-methoxy-4-oxoquinazolin-3(4H)-yl)methyl pivalate (2.50 g, 8.16 mmol), tetrahydro-4H-pyran-4-ol (1.02 g, 10 mmol), and Ph3P (3.41 g, 13 mmol) in CH2Cl2 (40 mL) at 0° C. was added di t-butyl azodicarboxylate (3.993 g, 13 mmol). It was stirred at room temperature for 2 hour. After solvent was evaporated under reduced pressure, to the residue was added 7 N NH3/MeOH (80 mL) and stirred at room temperature overnight. A solid was precipitated. It was filtered, washed with MeOH, and dried under vacuum to afford 7-methoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4(3H)-one as solid (1.091 g, 76%). 1H NMR (300 MHz, DMSO-d6) δ 10.6 (br, 1H), 7.98 (s, 1H), 6.74 (d, 1H), 6.69 (d, 1H), 4.79 (m, 1H), 3.97 (m, 2H), 3.91 (s, 3H), 3.57 (m, 2H), 1.98 (m, 2H), 1.74 (m, 2H); LC-MS (ESI) m/z 277 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.[CH2:11]([O:13][CH:14]([O:19][CH2:20][CH3:21])[CH2:15][CH2:16][CH2:17][NH2:18])[CH3:12].C(OC)(OC)OC.[BH4-].[Na+]>CO>[CH2:20]([O:19][CH:14]([O:13][CH2:11][CH3:12])[CH2:15][CH2:16][CH2:17][NH:18][CH2:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)[CH3:21]
Reactant: CCOC(CCCN)OCC
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CCOC(CCCNCc1ccc(C#N)cc1)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.9 %

Procedure:
4-Formylbenzonitrile (612.0 mg) was dissolved in methanol (18.4 ml), and 4,4-diethoxybutylamine (752.5 mg) and trimethyl orthoformate (1.53 ml) were added thereto. The whole was stirred at room temperature for 18 hours. Subsequently, the solution was added with sodium borohydride (529.7 mg) under ice-cooling and stirred at room temperature for additional 30 minutes. The reaction solution was concentrated under reduced pressure. The residue was added with water and the whole was subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (1.16 g) as a yellow oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[CH:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:22]([O:29][C:30]1[CH:37]=[CH:36][C:35]([Br:38])=[CH:34][C:31]=1[CH2:32]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([O:29][C:30]1[CH:37]=[CH:36][C:35]([Br:38])=[CH:34][C:31]=1[CH2:32][N:8]([C:9]1[N:10]=[CH:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][CH:14]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: BrCc1cc(Br)ccc1OCc1ccccc1
Reactant: CCOC(=O)c1cnc(NC(=O)OC(C)(C)C)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N(Cc2cc(Br)ccc2OCc2ccccc2)C(=O)OC(C)(C)C)cn1
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a solution of ethyl 5-(tert-butoxycarbonylamino)pyrazine-2-carboxylate (10.7 g 0.04 mol) in DMF (160 ml) at 20° C., under argon atmosphere, was added sodium hydride dispersion (50% in oil, 1.85 g, 0.04 mol) and stirred for 1 hour until effervescence ceased. Next was added 2-benzyloxy-5-bromobenzylbromide (14.3 g, 0.04 mol) and stirring continued at 20° C. under argon for 2 hours. The solvent was evaporated at reduced pressure and the residue partitioned between dichloromethane (500 ml) and water (250 ml), the organic layer was dried over magnesium sulphate and evaporated at reduced pressure to give a crude solid (21 g). Purification was by chromatography on silica, eluting with 5% ethyl acetate in dichloromethane to give ethyl 5-(N-(2-benzyloxy-5-bromobenzyl)-N-tert-butoxycarbonylamino)pyrazine-2-carboxylate as a white solid (16 g, mp 116°-7° C.).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=O)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)=[CH:24][CH:23]=1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1ccc(Cl)cc1
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(Cl)cc3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 4-chlorobenzoic acid: MS (ESI): m/z 403 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:32])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]2[N:29]=[C:28]([NH2:30])[N:27]=[C:26]([NH2:31])[N:25]=2)=[CH:18][CH:17]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:32])[C:16]1[CH:17]=[CH:18][C:19]([CH:22]=[CH:23][C:24]2[N:25]=[C:26]([NH2:31])[N:27]=[C:28]([NH2:30])[N:29]=2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=Cc2nc(N)nc(N)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(N)nc(C=Cc2ccc(C(=O)Nc3ccccc3N)cc2)n1
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a stirred solution at room temperature of 219 (25 mg, 0.056 mmol) in CH2Cl2 (1.5 mL) was added TFA (0.3 mL, 4.3 mmol). After 30 min, a solution of sat. NaHCO3 was slowly added until pH 8 is reached, CH2Cl2 was removed under reduced pressure, AcOEt was added, and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (MeOH/CH2Cl2: 10/90) to afford the title compound 220 (19 mg, 0.054 mmol, 98% yield). 1H NMR: (300 MHz, acetone-d6) δ (ppm): 8.33, 8.13 (2d, J=7.5 Hz, 1H), 8.22 (d, J=15.9 Hz, 1H), 8.01 (d, J=8.1 Hz, 2H), 7.84 (d, J=8.1 Hz, 2H), 7.38-6.96 (m, 2H), 7.03 (d, J=15.9 Hz, 1H), 6.94-6.62 (m, 2H).
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:21])[CH:7]([S:11][C:12]1[CH:17]=[C:16]([NH2:18])[C:15]([F:19])=[CH:14][C:13]=1[Cl:20])[CH2:8][CH2:9]Cl)C>C(O)C>[NH2:18][C:16]1[C:15]([F:19])=[CH:14][C:13]([Cl:20])=[C:12]([S:11][C:7]2([C:6]([OH:5])=[O:21])[CH2:8][CH2:9]2)[CH:17]=1
Reactant: CCOC(=O)C(CCCl)Sc1cc(N)c(F)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(SC2(C(=O)O)CC2)c(Cl)cc1F
Reaction time: 18 h
Yield: 73.7 %

Procedure:
A solution of 2.4 g of potassium hydroxide in 50 ml of ethanol is added dropwise while stirring at a temperature of +5° C. to a solution of 14.2 g of 2-(5-amino-2-chloro-4-fluorophenylthio)-4-chlorobutyric acid ethyl ester in 25 ml of ethanol. After stirring for 18 hours, 0.9 g of potassium hydroxide is added a further 3 times, and the reaction mixture is stirred for 6 hours each time until the reaction is complete. The reaction mixture is then concentrated, water is added and extraction is carried out 3 times with ethyl acetate. The combined organic phases are dried over sodium sulfate and then concentrated by evaporation. Recrystallisation of the residue from ethyl acetate/n-hexane yields 8.4 g of 1-(5-amino-2-chloro-4-fluoro-phenylthio)-cyclopropanecarboxylic acid having a melting point of from +266° to +267° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[N:15]([CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ccn12
Reactant: FC(F)(F)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(CCC(F)(F)F)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ccn12
Temperature: 80 °C
Yield: 58.6 %

Procedure:
To a stirring mixture of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg, 0.14 mmol) and K2CO3 (40 mg, 0.28 mmol) in DMF (0.47 mL) at 20° C. was added 3-bromo-1,1,1-trifluoropropane (50 mg, 0.28 mmol). The resulting reaction mixture was heated at 80° C. for 60 min. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature, diluted with water, and extracted twice with diethyl ether. The combined organic extract was washed with saturated aqueous NaHCO3 solution, then brine, then dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (37 mg, 0.082 mmol) as a yellow oil. MS: [M+H]+=452.
Reaction SMILES: CC1C=CC=C(C#CC=C2CCNCC2)N=1.[F:17][C:18]1[CH:19]=[C:20]([C:25]#[C:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]2)[CH:21]=[C:22]([F:24])[CH:23]=1>>[F:17][C:18]1[CH:19]=[C:20]([C:25]#[C:26][CH2:27][CH:28]2[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]2)[CH:21]=[C:22]([F:24])[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC#Cc2cc(F)cc(F)c2)CC1
Agent: Cc1cccc(C#CC=C2CCNCC2)n1
Product: Fc1cc(F)cc(C#CCC2CCNCC2)c1

Procedure:
The title compound was prepared following the procedure described for the Compound of Example 3, using the Compound of Example 247 instead of the Compound of Example 2. After the usual work-up procedure, the crude was used for the next step without further purification.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[CH3:7][C:8]1[NH:9][C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[OH-].[Na+]>CN(C)C=O>[CH:2]([C:11]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([CH3:7])[NH:9][C:10]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1cc(-c2ccccc2Oc2ccccc2)[nH]c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)[nH]c(-c2ccccc2Oc2ccccc2)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
Oxalyl dichloride (0.053 mL, 0.625 mmol) was added dropwise to N,N-dimethylformamide (0.387 mL, 5 mmol) at 0° C. The reaction mixture was removed from the cooling bath and stirred for thirty minutes at ambient temperature. N,N-Dimethylformamide (1 mL) was added to the reaction mixture and stirring was continued for another 30 minutes. The mixture was again cooled to 0° C. and a solution of Example 72b (0.161 g, 0.5 mmol) in N,N-dimethylformamide (2 mL) was added. Stirring was continued at 0° C. for two hours and then at ambient temperature for 3.5 hours. A solution of sodium hydroxide (10 mL, 4 N aqueous) was added and the mixture was stirred for 20 minutes. The reaction mixture was then partitioned between ethyl acetate and water, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 5-50% ethyl acetate in hexanes) to give 0.16 g (92%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH3:22][C:23]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](O)=[O:26].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[CH3:22][C:23]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23)=[O:26]
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)Nc2cc3c4c(c(-c5ccccc5)[nH]c4c2)C=NNC3=O)c1C
Yield: 58.2 %

Procedure:
Preparation of example 98 from the title compound of Example 7 (hydrochloride) (42 mg, 0.134 mmol), 2,3-dimethyl-benzoic acid (24 mg, 0.161 mmol), triethylamine (0.056 mL, 0.402 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (61 mg, 0.161 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. The mixture was stirred as a thick slurry and additional 2,3-dimethyl-benzoic acid (12 mg, 0.08 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (30 mg, 0.08 mmol) were added after 48 hours to drive the reaction to completion. The mixture was filtered to collect the solids which were then washed with methanol. After drying the solids under high vacuum, the title compound (32 mg, 0.078 mmol) was obtained as a yellow powder in 58% yield.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([OH:17])=O)[C:13]=1[C:21]([OH:23])=O.Cl.[NH2:25][CH:26]1[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]1=[O:28]>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:14]2[C:13]=1[C:21](=[O:23])[N:25]([CH:26]1[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]1=[O:28])[C:15]2=[O:17]
Reactant: O=C(O)c1cccc(OCc2cc3ccccc3o2)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4cc5ccccc5o4)c3C2=O)C(=O)N1
Yield: 65 %

Procedure:
A mixture of 3-(benzofuran-2-ylmethoxy)-phthalic acid (0.55 g, 1.8 mmol) and rac-α-aminoglutarimide hydrochloride (0.30 g, 1.8 mmol) in pyridine (10 mL) was heated to reflux for 16 h. The mixture was cooled and evaporated under vacuum. The residue was dissolved in CH2Cl2 (100 mL) and washed with dilute aqueous HCl (2×100 mL) and water (2×100 mL) and was evaporated. The residue was chromatographed using a CH2Cl2-methanol gradient, eluting the title compound at 95:5 CH2Cl2-methanol, 0.46 g, in 65% yield; mp 234-236° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 4.16 (98.58%); 1H NMR (DMSO-d6) δ 1.99-2.04 (m, 1H), 2.43-2.61 (m, 2H), 2.81-2.95 (m, 1H), 5.08 (dd, J=12.7 Hz, J=5.3 Hz, 1H), 5.55 (s, 2H), 7.14 (s, 1H), 7.23-7.37 (m, 2H), 7.50 (d, J=7.0 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.86 (t, J=7.8 Hz, 1H), 11.11 (s, 1H); 13C NMR (DMSO-d6) δ 23.9, 30.9, 48.8, 63.1, 107.4, 111.3, 115.9, 116.7, 120.2, 121.6, 123.1, 125.0, 127.5, 133.3, 137.0, 152.0, 154.6, 155.0, 165.2, 166.7, 169.9, 172.7; Anal. Calcd for C22H16N2O6.0.15H2O: C, 64.91; H, 4.04; N, 6.88. Found: C, 64.89; H, 3.99; N, 6.84.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][CH:20]([O:22][C:23]([O:26][CH3:27])([CH3:25])[CH3:24])C)[CH:18]=[C:13]3[CH:12]=[C:11]2[C:28](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:46][S:47]([C:50]1[CH:55]=[CH:54][C:53](B(O)O)=[CH:52][CH:51]=1)(=[O:49])=[O:48].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][CH:20]4[CH2:27][O:26][C:23]([CH3:25])([CH3:24])[O:22]4)[CH:18]=[C:13]3[CH:12]=[C:11]2[C:28]([C:53]2[CH:54]=[CH:55][C:50]([S:47]([CH3:46])(=[O:49])=[O:48])=[CH:51][CH:52]=2)=[CH:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(C)(C)OC(C)Cc1cnc2c(c1)cc(C(=CC1CCCC1)OS(=O)(=O)c1ccc(C)cc1)n2S(=O)(=O)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1(C)OCC(Cc2cnc3c(c2)cc(C(=CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)n3S(=O)(=O)c2ccccc2)O1
Yield: 43.9 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-{1-benzenesulfonyl-5-[2-(1-methyloxy-1-methyl-ethoxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-2-cyclopentyl-vinyl ester (1.12 g, 1.76 mmol), 4-(methanesulfonyl)phenylboronic acid (704 mg, 3.52 mmol), dichlorobis(triphenylphosphine)palladium (II) (124 mg, 0.17 mmol) in dioxane (5 mL) was added an aqueous sodium carbonate solution (2 M, 2.2 mL). The resulting mixture was subjected to microwave irradiation for 1 h at 100° C. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 33% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (480 mg, 44%) as a light yellow solid: LC/MS m/e calcd for C33H36N2O6S2 [M+H]+ 621.79, observed 621.0.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=1)([CH3:29])[CH3:28].Cl.C(=O)([O-])[O-].[NH4+:44].[NH4+]>C(O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37](=[NH:44])[NH2:38])=[CH:33][CH:32]=1)([CH3:28])[CH3:29]
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(C(C)(C)Oc1ccc(C#N)cc1)n2C)S(=O)(=O)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(c1ccc2c(c1)nc(C(C)(C)Oc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1ccccc1

Procedure:
Prepared analogously to Example 1e from 1-methyl-2-[1-(4-cyanophenoxy)-1-methyl-ethyl]-5-[N-(ethoxycarbonylmethyl)-benzenesulphonylamino]-benzimidazole and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][OH:9])(=[O:5])=[O:4])[CH3:2].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:9][CH2:8][CH2:7][CH2:6][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCS(=O)(=O)CCCO
Solvent: ClCCl
Product: CCS(=O)(=O)CCCOS(=O)(=O)c1ccc(C)cc1
Yield: 66.4 %

Procedure:
A mixture of 3-(ethylsulfonyl)-1-propanol (from step (i) above; 13.4 g, 88 mmol) and p-toluenesulfonyl chloride (16.8 g, 88 mmol) in DCM (150 mL) was treated with TEA (13.4 g, 132 mmol), added dropwise. The resulting mixture was stirred at rt for 3h before being washed with aqueous ammonium chloride solution. The organic layer was then separated, dried and concentrated in vacuo. The product was crystallised from ether containing a small amount of DCM to yield 17.9 g (66%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]=O)[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].Cl.[NH2:18][OH:19].N1C=CC=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13](/[CH:15]=[N:18]/[OH:19])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C=O)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1cc(Br)cc(/C=N/O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of tert-butyl 3-bromo-5-formylbenzoate (440 mg, 1.54 mmol) in dioxane (7 mL) were added hydroxylamine hydrochloride (107 mg, 1.54 mmol) and pyridine (0.13 mL, 1.54 mol). The reaction mixture was stirred at ambient temperature. After 72 h, additional hydroxylamine hydrochloride (29 mg, 0.29 mmol) and pyridine (25 μL, 0.31 mol) were added. The mixture was stirred at ambient temperature. Ater 3 h, the mixture was concentrated. Saturated aqueous NaHCO3 was added the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated (470 mg). MS 243 (M-ten-butyl).