Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+].[CH2:21]([N:23]1[C:29](=[O:30])[C:28]([CH3:32])([CH3:31])[C:27](=[O:33])[N:26]([CH3:34])[C:25]2[CH:35]=[C:36]([O:39][CH2:40][CH2:41][CH2:42]I)[CH:37]=[CH:38][C:24]1=2)[CH3:22]>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:42][CH2:41][CH2:40][O:39][C:36]2[CH:37]=[CH:38][C:24]3[N:23]([CH2:21][CH3:22])[C:29](=[O:30])[C:28]([CH3:32])([CH3:31])[C:27](=[O:33])[N:26]([CH3:34])[C:25]=3[CH:35]=2)[C:4](=[O:12])[C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=c1[nH]c2ccccc2c(Cl)c1-c1ccccc1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCI)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(=O)c(-c4ccccc4)c(Cl)c4ccccc43)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.8 %

Procedure:
4-Chloro-3-phenyl-1H-quinoline-2-one (0.3 g) was suspended in DMF (6 ml). Sodium hydride (60% in oil) (51 mg) was added, and the mixture was stirred for 15 minutes at room temperature. 1-Ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.55 g) was added thereto and the mixture was stirred at room temperature for 7 days. The reaction mixture was poured to ice water (50 ml), and the generated insoluble matter was separated. The insoluble matter was dissolved in ethyl acetate. The liquid was dried over sodium sulfate and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→1:3). The purified product was condensed under reduced pressure, and the residue was recrystallized from ether, thereby obtaining the title compound (0.28 g) as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2C=C[C:11]3[N:15]=[C:14]([C@@H:16]4[CH2:20][CH2:19][CH2:18][N:17]4[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[NH:13][C:12]=3[CH:28]=2)=[CH:4][CH:3]=1.[C:29]([C:31]1[NH:35][C:34]([C@@H:36]2[CH2:40][CH2:39][CH2:38][N:37]2[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[N:33][CH:32]=1)#[CH:30].[CH2:48](N(CC)CC)[CH3:49].N#N>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:44]([O:43][C:41]([N:37]1[CH2:38][CH2:39][CH2:40][C@H:36]1[C:34]1[NH:33][C:32]2[CH:48]=[C:49]([C:2]3[CH:3]=[CH:4][C:5]([C:8]#[C:28][C:12]4[NH:13][C:14]([C@@H:16]5[CH2:20][CH2:19][CH2:18][N:17]5[C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[N:15][CH:11]=4)=[CH:6][CH:7]=3)[CH:30]=[CH:29][C:31]=2[N:35]=1)=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: CCN(CC)CC
Reactant: C#Cc1cnc([C@@H]2CCCN2C(=O)OC(C)(C)C)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc(Br)cc3)cc2[nH]1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(C#Cc2ccc(-c3ccc4nc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]c4c3)cc2)[nH]1
Temperature: 50 °C

Procedure:
A solution of (S)-tert-butyl 2-(6-(4-bromophenyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (674 mg, 1.53 mmol, for its preparation, see PCT Publication No. WO 2008/021927)), (S)-tert-butyl 2-(5-ethynyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (518 mg, 1.98 mmol), copper(I) iodide (29.0 mg, 0.152 mmol) and triethylamine (0.64 mL, 4.6 mmol) in DMF (15 mL) was degassed under vacuum for 10 min and backfilled with N2. Pd(Ph3P)4 (176 mg, 0.152 mmol) was then added and the reaction was sealed and heated at 50° C. for 16 h. The reaction mixture was concentrated to remove the volatiles and the residue was dissolved into a minimal amount of MeOH and then partitioned between EtOAc and water. The layers were separated and the organic layer was concentrated and purified on a BIOTAGE® (300 g silica gel, eluted with 20 to 100% EtOAc/DCM) to yield (S)-tert-butyl 2-(5-((4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)phenyl)ethynyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (305 mg) and a mixture of this product with (2S,2′S)-tert-butyl 2,2′-(5,5′-(buta-1,3-diyne-1,4-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate. The mixture was further purified by preparative HPLC (acetonitrile/water/0.1% TFA) to provide a TFA salt of (S)-tert-butyl 2-(5-((4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)phenyl)ethynyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (100 mg) and a TFA salt of (2S,2′S)-tert-butyl 2,2′-(5,5′-(buta-1,3-diyne-1,4-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate (128 mg) as white solid.
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.[CH:9]1([N:15]=[C:16]=[N:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>CS(C)=O>[CH:18]1([NH:17][C:16]([NH:15][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)=[O:1])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1CCC(=O)N1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
To a solution consisting of 0.3 g (0.67 mmol) N-(2-aminoethyl) trans-1,2-diaminocyclohexane-N,N',N',N",N"pentaacetic acid in 20 ml dimethylsulfoxide was added 0.62 g (5.4 mmol) N-hydroxysuccinimide and 0.41 g (2.0 mmol) dicyclohexylcarbodiimide. This was stirred at room temperature for 24 hr. A white fluffy solid of dicyclohexyl urea formed in the reaction and was filtered. The filtrate was concentrated to a thick oil under reduced pressure. A solid precipitated from the oil upon the addition of acetonitrile. This solid was collected, washed with acetonitrile and dried under vacuum to give 0.25 g of the final product. NMR showed an average of 2 NHS esters so the yield is 58%. No further purification was attempted; mp 100°-130° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3](OCC)=[O:4].[K].C(C(C(Cl)=O)C(Cl)=O)C.[NH3:22]>>[C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([NH2:22])=[O:4]
Reactant: N
Reactant: CCOC(=O)CC(=O)OCC
Agent: CCC(C(=O)Cl)C(=O)Cl
Agent: [K]
Product: CCOC(=O)CC(N)=O

Procedure:
Biguanide was prepared fresh by refluxing anhydrous biguanide sulfate in a methanol solution of freshly prepared sodium methylate by the method of Slotta et al. (Slotta, K. H., Tschesche, R., Ber. Dtsch. Chem. Ges. 1929, B62, 1390-1398). The biguanide was used in solution as prepared for all of the reactions. Because sodium sulfate formed in the preparation of biguanide did not interfere with subsequent reactions, it was not necessary to separate it from the biguanide. Ethyl malonamate used in the preparation of Ib (see Example I below) was prepared as follows by methods of Galat and Marguery (Galat, A., J. Am. Chem. Soc. 1948, 70, 2596 and Marguery, M. F., Bull. Soc. Chem. France 1905, 33, 541; J. Recherces Centr. Nalt. Recherche Sci., Labs. Bellevue (Pairs) 1959, 47, 147), through Chem. Abstr. 1962, 56, 4744g.): Diethyl malonate was converted to the mono-potassium salt of the half-ester. The latter was converted to ethyl malonyl chloride, which in turn was reacted with anhydrous ammonia in ice-cold ether to form ethyl malonamate.
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[NH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([O:18][N+:19]([O-:21])=[O:20])[CH2:14][CH2:13]1.CO.[O-:24][C:25]#[N:26].[K+].C(=O)([O-])[O-].[K+].[K+]>O>[NH2:26][C:25]([NH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([O:18][N+:19]([O-:21])=[O:20])[CH2:14][CH2:13]1)=[O:24]
Reactant: NCCN1CCC(O[N+](=O)[O-])CC1
Reactant: N#C[O-]
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: NC(=O)NCCN1CCC(O[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.53 g. 1-(2-aminoethyl)-4-nitroxypiperidine fumarate are dissolved in 15 ml. methanol and 5 ml. water. 1.62 g. Potassium cyanate is added thereto and the reaction mixture is stirred overnight at ambient temperature. A pH value of 10 is adjusted by the addition of potassium carbonate. The reaction mixture is extracted with ethyl acetate and the extracts are dried with anhydrous sodium sulphate. After evaporation and trituration of the residue with diethyl ether, the resultant crystals are filtered off with suction. There is obtained 1 g. of the title compound, i.e. 86% of theory; m.p. 114°-116° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:18]([NH:23][S:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[CH2:19][CH2:20]C=C)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N+:30]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[CH2:38])=[CH:35][CH:34]=1)([O-:32])=[O:31].[CH2:41](Cl)Cl>>[CH3:27][C:26]([S@@:24]([NH2:23])=[O:25])([CH3:29])[CH3:28].[C:4]([Si:1]([CH3:2])([CH3:3])[O:8][C@H:9]([CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C@H:18]([CH3:41])[CH2:19][CH2:20]/[CH:38]=[CH:37]/[C:36]1[CH:39]=[CH:40][C:33]([N+:30]([O-:32])=[O:31])=[CH:34][CH:35]=1)([CH3:5])([CH3:6])[CH3:7]
Reactant: C=Cc1ccc([N+](=O)[O-])cc1
Reactant: C=CCC[C@@H](NS(=O)C(C)(C)C)[C@@H](COc1ccccc1)O[Si](C)(C)C(C)(C)C
Reactant: ClCCl
Product: CC(C)(C)[S@@](N)=O
Product: C[C@H](CC/C=C/c1ccc([N+](=O)[O-])cc1)[C@@H](COc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 35 °C
Reaction time: 20 h

Procedure:
The major product alkene, N-[(1R)-1-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-phenoxyethyl)pent-4-en-1-yl]-2-methylpropane-2-sulfinamide (160 mg; 0.364 mmol) from Step F, 4-nitrostyrene (220 mg; 1.475 mmol) and Grubbs-II metathesis catalyst (45 mg; 0.053 mmol) were combined in anhydrous methylene chloride (6 ml) and the resulting reaction mixture stirred for 20 hours at 35° C. The crude product solution was concentrated under reduced pressure and the residues purified by silica gel plate chromatography on (20 cm×20 cm×1000 microns) eluted with hexanes and ethyl acetate (2:1 v/v) from which 116 mg of the desired metathesis product was obtained, m/z (ES) 561.22 (M+H)+.
Reaction SMILES: [S:1](Cl)(Cl)(=[O:3])=[O:2].[Br:6][C:7]1[CH:8]=[C:9]([CH2:15][C:16]([O:18]C)=[O:17])[CH:10]=[C:11]([Br:14])[C:12]=1S.S(Cl)Cl.[CH:23]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[OH:34])[CH2:27][CH2:26][CH2:25][CH2:24]1.[Sn](Cl)(Cl)(Cl)Cl>ClCCl.CO>[Br:14][C:11]1[CH:10]=[C:9]([CH2:15][C:16]([OH:18])=[O:17])[CH:8]=[C:7]([Br:6])[C:12]=1[S:1]([C:32]1[CH:31]=[CH:30][C:29]([OH:34])=[C:28]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:33]=1)(=[O:3])=[O:2]
Reactant: Oc1ccccc1C1CCCC1
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)Cc1cc(Br)c(S)c(Br)c1
Agent: ClSCl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(O)Cc1cc(Br)c(S(=O)(=O)c2ccc(O)c(C3CCCC3)c2)c(Br)c1
Temperature: 0 °C

Procedure:
Sulfuryl chloride (0.5 mL) was added dropwise to a solution of methyl 3,5-dibromo-4-mercaptophenylacetate (Preparation E, 0.8 g) in 50 mL of dichloromethane for 1 hour. The sulfenyl chloride product was then added dropwise to an ice-cooled suspension of 2-cyclopentylphenol (0.44 g) and tin (IV) chloride (0.53 mL) in methanol. Following the procedures of Examples 1 and 3, the product methyl 3,5-dibromo-4-(3-cyclopentyl-4-hydroxyphenylsulfonyl)phenylacetate, MP: 171°-173.5° C., (0.7 g) was purified and converted to 3,5-dibromo-4-(3-cyclopentyl-4-hydroxyphenylsulfonyl)phenylacetic acid, MP: 196°-198° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=O)[N:14]=[N:13]2)=[C:8]([O:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)=[O:5])[CH3:2].C1C=CC2N(O)N=[N:36]C=2C=1.N.C(N(CC)CC)C.CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([NH2:36])=[O:19])[N:14]=[N:13]2)=[C:8]([O:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)O)nn2)c(OCCCc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)c1ccc(-n2cc(C(N)=O)nn2)c(OCCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a solution of 1-{4-[(ethylamino)carbonyl]-2-(3-phenylpropoxy)phenyl}-1H-1,2,3-triazole-4-carboxylic acid (0.14 g) obtained in Example 133e) in DMF (4 ml) were successively added HOBt-NH3 (0.07 g), triethylamine (0.06 ml) and WSC (0.08 g), and the reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the deposited precipitate was collected by filtration, washed with water, and recrystallized from ethanol-water to give the title compound as a white powder (0.13 g, 89%).
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15](O)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C1CCC(N=C=NC2CCCCC2)CC1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Reactant: C1COCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCOCC2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 8 %

Procedure:
To a solution of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl) acetic acid (100 mg, 0.38 mmol) in DCM (10 ml) was added DCC (95 mg, 0.46 mmol), DMAP (56 mg, 0.46 mmol), and stirred for 5 min at RT, morpholine (1 ml, 11.5 mmol) was added and stirred at 25 deg C. for 14 h. The reaction mixture was concentrated to dryness and The resulting crude was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 10 mg (Yield 5.8%) of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-morpholino ethanone as TFA salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][O:15][S:16]([CH3:19])(=[O:18])=[O:17].[N-:20]=[N+:21]=[N-:22].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][N:20]=[N+:21]=[N-:22].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][O:15][S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: [N-]=[N+]=[N-]
Agent: COc1ccc(CCCCOS(C)(=O)=O)c(OC)c1
Agent: [Na+]
Product: COc1ccc(CCCCN=[N+]=[N-])c(OC)c1

Procedure:
Azide 78 was prepared by typical procedure C from ester 77 (4.6 g, 0.015 mol) and sodium azide (1.5 g, 0.023 mol). Compound 77 (4.06 g, 75%) was isolated as a yellow oil. 1H NMR (300 MHz, CDCl3) δ1.62 (m, 4H), 2.58 (m, 2H), 3.30 (m, 2H), 3.80 (s, 6H) 7.00 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:4][C:5]([CH3:22])=[C:6]([CH3:21])[C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].[CH2:30]([O:32][CH2:33][C:34](Cl)=[O:35])[CH3:31]>ClCCl>[CH2:30]([O:32][CH2:33][C:34]([NH:1][C:2]1[C:3]([O:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:4][C:5]([CH3:22])=[C:6]([CH3:21])[C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:35])[CH3:31]
Reactant: CCOCC(=O)Cl
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCCCNC(=O)OC(C)(C)C)c1C
Solvent: ClCCl
Product: CCOCC(=O)Nc1c(Oc2ccccc2)nc(C)c(C)c1NCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylaminie (3.3 mL, 23.7 mmol) was added to a chilled (0° C.) mixture of tert-butyl 4-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]butylcarbamate (8.60 g, 21.5 mmol) and anhydrous dichloromethane (200 mL). Ethoxyacetyl chloride (2.76 g, 22.5 mmol) was added. After one hour the reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to provide tert-butyl 4-({3-[(ethoxyacetyl)amino]-5,6-dimethyl-2-phenoxypyridin-4-yl}amino)butylcarbamate as a brown oil. The oil was combined with pyridine (130 mL) and heated at reflux overnight. The reaction mixture was concentrated under reduced pressure to provide a brown oil. The oil was dissolved in dichloromethane and was washed with water. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in diethyl ether and then concentrated under reduced pressure to provide 8.21 g of tert-butyl 4-[2-(ethoxymethyl)-6,7-dimethyl4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]butylcarbamate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH2:14](I)[CH3:15].N1C=CC=CC=1>C(O)(C)C>[CH2:14]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)[CH3:15]
Reactant: CCI
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: c1ccncc1
Solvent: CC(C)O
Product: CCNc1ccc(CC(=O)OCC)cc1
Yield: 32 %

Procedure:
Ethyl p-aminophenylacetate (5.4 g), ethyl iodide (4.7 g), pyridine (2.4 g) and isopropanol (50 ml) are boiled together during 6 hours. The reaction mixture is concentrated in vacuo, taken up into water, extracted with ether and dried, and the solvent is then removed. Ethyl p-ethylaminophenylacetate (2 g) is isolated by chromatography over silica. Saponification in the cold, in methanolic sodium hydroxide, gives 1.2 g of p-ethylaminophenylacetic acid. M.p. inst. = 123°C after recrystallization from ethyl acetate.
Reaction SMILES: ClC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50]CC)=O)=[C:33]2[S:53](Cl)(=[O:55])=[O:54].Cl.CN.Cl.[NH2:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([S:69]([NH2:72])(=[O:71])=[O:70])=[CH:65][CH:64]=1>>[NH2:72][S:69]([C:66]1[CH:65]=[CH:64][C:63]([CH2:62][NH:61][S:53]([C:33]2[C:32]3[C:36](=[CH:37][CH:38]=[C:30]([Br:29])[CH:31]=3)[NH:35][C:34]=2[C:48]([NH2:7])=[O:50])(=[O:54])=[O:55])=[CH:68][CH:67]=1)(=[O:70])=[O:71]
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Agent: CN
Agent: Cl
Product: NC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)NCc1ccc(S(N)(=O)=O)cc1

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride with 4-(aminomethyl)benzene-sulfonamide hydrochloride, the title compound was obtained. HRMS (ES) exact mass calculated for C16H16BrN4O5S2 (M+H+): 486.9740. Found 486.9749.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][N:19]3[CH:26]=2)=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1.B(Br)(Br)Br.CO>ClCCl>[OH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:17]=[C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][N:19]3[CH:26]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc2nc(-c3ccc(OC(=O)c4ccccc4)cc3)cn2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc(-c2cn3cc(O)ccc3n2)cc1
Temperature: -15 °C
Reaction time: 17 h
Yield: 89.5 %

Procedure:
4.90 g (corresponding to 14.83 mmol) of 2-(4′-benzoyloxyphenyl)-6-methoxyimidazo[1,2-a]pyridine that was sufficiently dried to remove moisture was dissolved in 245 mL of chloroform and cooled down to −15° C. To this solution, a solution of 12.62 mL (corresponding to 133.48 mmol) of boron tribromide in 134 mL of dichloromethane was added dropwise. After the temperature of the resulting solution was raised to room temperature, the solution was stirred for 17 hours. After the completion of the reaction, the reaction solution was cooled with ice and supplemented with 668 mL of methanol, and further stirred at room temperature for 3 hours. The reaction mixture was then concentrated under reduced pressure. The resulting crude product was supplemented with 290 mL of chloroform and 29 mL of methanol to obtain slurry, and then precipitates were filtered and recovered. The precipitates recovered were washed with chloroform and then dried under reduced pressure, to obtain 3.00 g (corresponding to 13.28 mmol) of 2-(4′-hydroxyphenyl)-6-hydroxyimidazo[1,2-a]pyridine (FIG. 3, Step 6).
Reaction SMILES: [CH3:1][CH:2](P(O)(O)=O)/[C:3](/[CH3:9])=C(\C)/C([O-])=O.[CH:14]([N-:17][CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15].[Li+:21]>C1COCC1>[CH:14]([NH:17][CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15].[CH2:1]([Li:21])[CH2:2][CH2:3][CH3:9]
Reactant: CC(C)[N-]C(C)C
Reactant: [Li+]
Reactant: C/C(C(=O)[O-])=C(/C)C(C)P(=O)(O)O
Solvent: C1CCOC1
Product: CC(C)NC(C)C
Product: [Li]CCCC

Procedure:
Alternatively, the solution of trimethyl-4-phosphonocrotonate in THF is deprotonated at -78° C. with a solution of lithium diisopropylamide (LDA), obtained from diisopropylamine and n-butyllithium, in THF, and the obtained anion reacted at -78° C. with a solution of an aldehyde IX in THF.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]2=[N:4][C:3]=1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].[H-].[Na+].Cl[S:23]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>CN(C=O)C.CCOC(C)=O>[C:15]([O:14][C:13]([N:12]([C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][N:6]2[C:2]=1[CH3:1])[S:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:34][CH:35]=1)(=[O:25])=[O:24])=[O:19])([CH3:16])([CH3:18])[CH3:17]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cccn2c(C)c(NC(=O)OC(C)(C)C)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(=O)(=O)N(C(=O)OC(C)(C)C)c2nc3c(C)cccn3c2C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 49.3 %

Procedure:
To a solution of compound 2-B (0.799 g, 3.06 mmol) in DMF (22 mL), cooled to 0° C., was added 60% NaH (0.147 g, 3.67 mmol) and the reaction mixture was stirred at 0° C. for 20 min. Methyl 4-(chlorosulfonyl)benzoate (2.15 g, 9.17 mmol) was added in small portions and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with EtOAc, washed with H2O (2×), brine, dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure to afford a crude solid. The crude material was purified by flash column chromatography (SiO2) eluting with a heptanes-EtOAc gradient to afford compound 2-C as a white solid (0.693 g, 49%). 1H-NMR (CDCl3): δ 8.38-8.40 (dd, 2H), 8.23-8.25 (dd, 2H), 7.75-7.77 (d, 1H), 7.00-7.02 (d, 1H), 6.79-6.83 (m, 1H), 3.98 (s, 3H), 2.51 (s, 3H), 1.59 (s, 3H), 1.34 (s, 9H); MS: m/z 460.2 (MH+).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.[OH-].[Na+].Br[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(OCC)(=O)C>O1CCCC1.O>[N:2]1([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][CH2:4][CH2:3]1
Reactant: C1CNC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1CCC1
Reaction time: 0.17 h

Procedure:
A solution of azetidine hydrochloride (1 g, Aldrich) in a mixture of tetrahydrofuran (20 ml) and water (5 ml) was added with 2 N aqueous sodium hydroxide (10.7 ml) at 0° C., and then gradually added with tert-butyl bromoacetate (1.052 ml), and the mixture was stirred at the same temperature for 10 minutes, and further stirred at room temperature for 45 minutes. The reaction mixture was added with water and ethyl acetate, and the organic layer was separated. The aqueous layer was extracted three times with ethyl acetate, the combined organic layer was washed three times with saturated brine, and the solvent was evaporated under reduced pressure to obtain the title compound (688 mg).