Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@H](O[C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:26][CH3:27])[N:13]2[CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23]O2)=[C:9]([NH2:28])[N:8]=1)CCC.FC(F)(F)[C:31]([OH:33])=O.[CH2:36]([NH:40]C1N=C2C(N=C(OC)N2)=C(N)N=1)[CH2:37][CH2:38][CH3:39].BrCCCBr.O1CCCC1CCN>>[CH2:36]([NH:40][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:26][CH3:27])[N:13]2[CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH:25]2[CH2:24][CH2:23][CH2:31][O:33]2)=[C:9]([NH2:28])[N:8]=1)[CH2:37][CH2:38][CH3:39]
Reactant: O=C(O)C(F)(F)F
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCNCC3CCCO3)c2n1
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Agent: BrCCCBr
Agent: NCCC1CCCO1
Product: CCCCNc1nc(N)c2nc(OC)n(CCCNCCC3CCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 26 from N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt, 1,3-dibromopropane, and [2-(tetrahydro-2-furanyl)ethyl]amine.
Reaction SMILES: [N+](=[C:3]([C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH:17]1[C:22](O)=[CH:21][CH:20]=[C:19]([CH3:24])[CH:18]=1>C(Cl)(Cl)(Cl)Cl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[CH3:24][C:19]1[CH:20]=[CH:21][C:22]([CH:3]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:17][CH:18]=1
Reactant: Cc1ccc(O)cc1
Reactant: CCOC(=O)C(=[N+]=[N-])C(=O)c1ccccc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C(=O)c1ccccc1)c1ccc(C)cc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 26.1 %

Procedure:
A mixture of 7.66 g of ethyl α-diazobenzoylacetate, 3.8 g of p-cresol and 150 mg of rhodium(II) acetate in 40 cc of carbon tetrachloride was stirred at a temperature of 40-50° C. for 2 hours. After cooling, the insoluble materials were filtered off and the solvent was distilled off. The crude product thus obtained was purified by a silica gel column chromatography (eluent: chloroform/hexane=1/2) to obtain 2.59 g of compound E. Yield: 24.7%.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[C:22]([F:29])[CH:21]=1.O>O1CCCC1>[CH2:1]([N:8]([CH2:9][CH2:10][OH:11])[C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([Br:19])=[CH:21][C:22]=1[F:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCNCc1ccccc1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Br)cc1F)N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.8 %

Procedure:
To a solution of N-benzylethanolamine (6.37 g, 42.1 mmol), triethylamine (8.81 ml, 63.2 mmol) in tetrahydrofuran (200 ml) was added under ice-cooling 4-bromo-2-fluorobenzoylchloride (10.0 g, 42.1 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (1.45 g, 98.0%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[I:12]N1C(=O)CCC1=O>CN(C)C=O.O>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(I)cc(C(=O)O)c1N
Temperature: 60 °C
Yield: 43.5 %

Procedure:
2-Amino-3-methylbenzoic acid (10 g, 66 mmol) was dissolved in 70 mL of N,N-dimethyl-formamide (DMF) and treated with N-iodosuccinimide (16.4 g, 73 mmol). The mixture was heated at 60° C. for 17 hours and allowed to cool to 25° C. The mixture was diluted with water (150 mL and filtered. The air-dried solid was dissolved in ethyl acetate (200 mL) and dried over magnesium sulfate. Evaporation of the solvent provided the title compound of Step A (7.95 g). 1H NMR (CDCl3): δ 7.87 (1H), 7.44 (1H), 2.09 (3H).
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][CH:4]1[CH:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:11])[CH3:10].[O:13]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C-:28]#[N:29].[Na+].CS(Cl)(=O)=O>C1(C)C=CC=CC=1.CN1CCCC1=O>[Cl:1][C:2]([Cl:12])=[CH:3][CH:4]1[CH:6]([C:7]([O:9][CH:23]([C:28]#[N:29])[C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:21]=2)=[O:8])[C:5]1([CH3:10])[CH3:11]
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: [C-]#N
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1

Procedure:
Following the procedure of Example 1, to a mixture of 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (50 mmol), 3-phenoxybenzaldehyde (9.90 g, 50 mmol), N-methylpyrrolidinone (10 g) and "mixed" picolines (8.5 g) in toluene is added sodium cyanide (2.57 g, 52.5 mmol), followed ca. 3 hours later by slow addition of methanesulfonyl chloride (6.87 g, 60 mmol). The reaction mixture is worked up and the solvent is removed to give α-cyano-3-phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([O:4][C:5]([C@H:7]([NH:25][C@H:26]([C:31]([OH:33])=O)[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])=[O:6])[CH3:3].OC1C2N=N[NH:41]C=2C=CC=1.NC[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([S:54]([NH2:57])(=[O:56])=[O:55])=[CH:50][CH:49]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.O.CN(C=O)C>[CH3:3][C:2]([O:4][C:5](=[O:6])[C@H:7]([NH:25][C@H:26]([C:31]([NH:41][CH2:47][C:48]1[CH:53]=[CH:52][C:51]([S:54](=[O:56])(=[O:55])[NH2:57])=[CH:50][CH:49]=1)=[O:33])[CH2:27][CH:28]([CH3:29])[CH3:30])[CH2:8][CH2:9][N:10]1[C:11](=[O:24])[C:12]2[CH:13]=[C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]3=[CH:16][C:17]=2[C:18]1=[O:19])([CH3:34])[CH3:1]
Reactant: Oc1cccc2[nH]nnc12
Reactant: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)O
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1ccc(S(N)(=O)=O)cc1
Reaction time: 72 h

Procedure:
100 mg of N-[(R)-1-[(1,1-dimethylethoxy)carbonyl]-3-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)propyl]-L-leucine, prepared as in Example L, was added to 0.8 mL DMF. 39 mg of hydroxybenzotriazol.H2O was added to the mixture followed by 57 mg of 4-aminoethylbenzenesulfonamide, 0.03 mL of N-methyl-4-morpholine, and 53 mg of dicyclohexylcarbodiimide. The mixture was stirred 72 h, and diluted with dichloromethane. The solvents were removed by evaporation and the resulting solid was purified by reverse phase H.P.L.C. The solvents were removed by lyopholization to give the title compound as a white solid; 104 mg.
Reaction SMILES: CCN([CH:7]([CH3:9])C)C(C)C.[Li+].[Cl-].[Si:12]([O:19][CH2:20][CH:21]=O)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C([C:25](CC)(P(O)(OC)=O)[C:26]([O-:28])=[O:27])C>CC#N>[Si:12]([O:19][CH2:20]/[CH:21]=[CH:25]/[C:26]([O:28][CH2:7][CH3:9])=[O:27])([C:15]([CH3:16])([CH3:17])[CH3:18])([CH3:13])[CH3:14]
Reactant: CCC(CC)(C(=O)[O-])P(=O)(O)OC
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Product: CCOC(=O)/C=C/CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.6 %

Procedure:
DIEA (2.75 mL, 16.6 mmol) and LiCl (5.54 g, 129 mmol) were added to a solution of tert-butyldimethylsilyloxy acetaldehyde (3.22 g, 18.5 mmol) and diethylmethylphosphonoacetate (4.66 g, 22.2 mmol) in CH3CN (40 mL) and the mixture was stirred at rt for 24 hrs. The mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL). The organic layer was dried over MgSO4 and concentrated. The residue was purified via flash chromatography eluting with 25% EtOAc/heptane to give the title compound as a colorless oil (3.27 g, 72% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 6.91 (dt, J=15.42, 3.49 Hz, 1H) 6.01 (dt, J=15.61, 2.27 Hz, 1H) 4.25 (dd, J=3.27, 2.27 Hz, 2H) 4.12 (q, J=7.22 Hz, 2H) 1.21 (t, J=7.18 Hz, 3H) 0.84 (s, 9H) 0.00 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[O:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1>>[O:28]1[CH:32]=[CH:31][C:30]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:29]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: OB(O)c1ccoc1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccoc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 3-furanboronic acid in General Procedure A. Purification on silica yielded 231. NMR (CDCl3): 2.66-2.68 (m, 4H, 2×CH2), 2.80 (s, 3H, CH3), 3.28-3.31 (m, 4H, 2×CH2), 3.86-3.88 (m, 6H, 3×CH2), 3.98-4.01 (m, 4H, 2×CH2), 7.04 (d, H, ArH, J=1.65 Hz), 7.26 (ms, H, ArH—part under CDCl3), 7.46 (ms, H, ArH), 8.18 (s, H, ArH). MS: (ESI+): MH+464.16
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH:10]([CH3:12])[O:9][CH:8]([CH3:13])[CH2:7]1.C(Cl)(Cl)[Cl:15].S(Cl)([Cl:20])=O>C(OCC)C>[ClH:15].[Cl:20][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH:10]([CH3:12])[O:9][CH:8]([CH3:13])[CH2:7]1
Reactant: ClC(Cl)Cl
Reactant: O=S(Cl)Cl
Reactant: CC1CN(CCCCO)CC(C)O1
Solvent: CCOCC
Product: CC1CN(CCCCCl)CC(C)O1
Product: Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a dry flask under a nitrogen atmosphere was added 0.9 g. (4.8 mmoles) of 4-(4-hydroxybutyl)-2,6-dimethylmorpholine in 2.5 ml. of chloroform. The solution was stirred and heated to 40° C. and 0.49 ml. (6.72 mmoles) of thionyl chloride in 2.5 ml. of chloroform was added slowly. The mixture was slowly heated to reflux and held for two hours, then was cooled and diluted with diethyl ether to precipitate the crude product. The crystals were filtered and washed of residual thionyl chloride using diethyl ether to obtain 1.0 g. (85% yield) of 4-(4-chlorobutyl)-2,6-dimethylmorpholine hydrochloride.
Reaction SMILES: [Cl-:1].[C:2]([NH+:6]1[CH2:10][C@@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[C@@H:8]([C:19]([N:21]2[CH:26]3[CH2:27][CH2:28][CH:22]2[CH2:23][C:24]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)([CH2:29][S:30]([CH3:32])=[O:31])[CH2:25]3)=[O:20])[CH2:7]1)([CH3:5])([CH3:4])[CH3:3].[OH:39]OS([O-])=O.[K+].Cl>C(O)C.O.CCOCC>[Cl-:1].[C:2]([NH+:6]1[CH2:10][C@@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[C@@H:8]([C:19]([N:21]2[CH:26]3[CH2:27][CH2:28][CH:22]2[CH2:23][C:24]([CH:33]2[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]2)([CH2:29][S:30]([CH3:32])(=[O:39])=[O:31])[CH2:25]3)=[O:20])[CH2:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=S([O-])OO
Reactant: CS(=O)CC1(C2CCCCC2)CC2CCC(C1)N2C(=O)[C@H]1C[NH+](C(C)(C)C)C[C@H]1c1ccc(F)cc1F
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CC(C)(C)[NH+]1C[C@H](C(=O)N2C3CCC2CC(CS(C)(=O)=O)(C2CCCCC2)C3)[C@H](c2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (3R,4R)-1-tert-butyl-3-({3-cyclohexyl-3-[(methylsulfinyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl}carbonyl)-4-(2,4-difluorophenyl)pyrrolidinium chloride (3-8) (50 mg, 0.090 mmol) in ethanol (2.0 mL) was added a solution of the oxone® (276 mg, 0.451 mmol) in 2.0 mL of water. The mixture was stirred at room temperature for 40 min. The solid was filtered and filtrate was concentrated, diluted with methylene chloride dried over anhydrous Na2SO4, filtered, and concentrated, followed by the addition of one equivalent HCl in ether to afford (3-9) as white solid (in/z (ES) 551 (MH+)).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cccc2cnccc12
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cccc3cnccc23)cc1

Procedure:
prepared by reaction of isoquinolin-5-ylamine with 4-tert-butyl-benzenesulfonyl chloride
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.[NH2:14][CH:15]1[CH2:19][CH:18]([CH2:20][OH:21])[N:17]([CH2:22][CH3:23])[CH2:16]1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.O1CCCC1>[ClH:11].[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:14][CH:15]2[CH2:19][CH:18]([CH2:20][OH:21])[N:17]([CH2:22][CH3:23])[CH2:16]2)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: CCN1CC(N)CC1CO
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCN1CC(NC(=O)c2cc(Cl)c(N)cc2OC)CC1CO
Product: Cl
Yield: 116.2 %

Procedure:
Into a reaction vessel, were placed 1.00 g of 4-amino-5-chloro-2-methoxy benzoic acid, 0.75 g of 3-amino-1-ethyl-5-hydroxymethyl pyrrolidine, 0.83 g of 1-hydroxy-1H-benzotriazole monohydrate, 1.13 g of dicyclohexyl carbodiimide (DCC), 15 ml of tetrahydrofuran (THF) and 2 ml of dimethyl formamide (DMF), and thus obtained mixture was stirred at room temperature for 14 hours. Thereafter, the precipitated dicyclohexyl carbonyl urea (DCU) was removed off, the filtrate was concentrated under reduced pressure and the residue was added with a dilute hydrogen chloride solution and washed twice with chloroform. The aqueous solution was alkalized with sodium bicarbonate and then extracted twice with chloroform. The organic extract was washed with a saturated aqueous saline solution and dried over magnesium sulfate. The extract was concentrated under reduced pressure and the residue was added with toluene, from which crystalline material was precipitated and separated. This was treated in isopropyl alcohol with HCl gas to convert to its hydrochloride and the thus formed hydrochloride precipitate was separated to obtain 1.05 g of 4-amino-5-chloro-2-methoxy-N-(1-ethyl-5-hydroxymethyl pyrrolidin-3-yl) benzamide hydrochloride (Compound of Example 1 in Table 1) M.p. 162° to 165° C.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].C1C=CC([CH2:31][C:32]([NH:34]CN[C@H](C(O)=O)CC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1.C(N)C>CS(C)=O.C(N(CC)C(C)C)(C)C.[Cl-].[Na+].O>[NH2:1][C:2]1[N:23]=[C:22]([NH:34][CH2:32][CH3:31])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Reactant: O=C(Cc1ccccc1)NCN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: CCN
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CCNc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Temperature: 135 °C
Yield: 57 %

Procedure:
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-101 (200 mg, 0.56 mmol) was dissolved in a mixture solution of dimethylsulfoxide (1 mL) and N,N-diisopropylethylamine (0.5 mL), ethylamine (2M tetrahydrofuran solution) (2 mL, 4 mmol) was added thereto, followed by heating in a sealed tube for 17 hours (oil bath temperature: 135° C.). The reaction mixture was allowed to room temperature, poured into brine, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then concentrated, the obtained residue was purified by NH silica gel column chromatography (ethyl acetate:hexane=2:1), and the title compound (117 mg, 0.32 mmol, 57%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:9](S(C)(=O)=O)=[N:10][C:4]=2[CH:3]=1.[Si:23]([O:30][C@H:31]1[C@H:35]2[O:36][CH2:37][C@@H:38]([OH:39])[C@H:34]2[O:33][CH2:32]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].N12CCCC=C1CCCCN2>CN(C=O)C>[Si:23]([O:30][C@H:31]1[C@H:35]2[O:36][CH2:37][C@@H:38]([O:39][C:9]3[N:8]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:5]4[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=4[N:10]=3)[C@H:34]2[O:33][CH2:32]1)([C:26]([CH3:29])([CH3:27])[CH3:28])([CH3:25])[CH3:24]
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(Cl)ncc21
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Agent: C1=C2CCCCNN2CCC1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)ncc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirring solution of 6-chloro-2-(methylsulfonyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c]pyridine (100 mgs, 0.276 mmol) and (3R,3aR,6R,6aS)-6-((tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-ol (72.0 mg, 0.276 mmol) in anhydrous DMF (2.3 mL) was added diazabicyclo[5.4.0]undec-7-ene (DBU, 0.06 mL, 0.42 mmol). The reaction was stirred under N2 at RT for 20 h, then evaporated under reduced pressure. Flash chromatography of the resulting residue utilizing a 24 g silica RediSep Rf® Gold column and employing a 0-90% EtOAc/hexane gradient afforded the title compound. LC-MS: calculated for C24H40ClN3O5Si2 541.22 observed m/e: 542.08 (M+H)+ (Rt 1.74/2.0 min)
Reaction SMILES: OC1[CH:7]=[CH:6][C:5]([C:8]2([C:21]3[CH:26]=CC(O)=CC=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3C2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4]C=1.C1(=O)O[CH2:31][CH2:30][O:29]1.[C:34](=[O:37])([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>>[OH:29][CH2:30][CH2:31][O:37][C:34]1[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1[C:15]1[C:20]2[C:8]3[C:5](=[CH:6][CH:7]=[CH:26][CH:21]=3)[CH2:4][C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: Oc1ccc(C2(c3ccc(O)cc3)c3ccccc3-c3ccccc32)cc1
Reactant: O=C1OCCO1
Reactant: O=C([O-])[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Product: OCCOc1ccccc1-c1cccc2c1-c1ccccc1C2
Temperature: 25 °C
Reaction time: 6 h
Yield: 970.1 %

Procedure:
A mixture of 84.4 g (0.241 mol) of 9,9-bis(4-hydroxyphenyl)fluorene, 46.7 g (0.53 mol) of ethylene carbonate, 3.3 g (0.024 mol) of potassium carbonate, and a catalytic amount of 18-crown-6 in 400 mL of xylenes was heated at reflux with mechanical stirring for 6 h. The mixture was allowed to cool slowly to room temperature, and the solvent was decanted from the precipitated product. The resulting white solid was washed with ligroin (to prevent the formation of a gummy mass), and dried under a stream of nitrogen. The product was recrystallized from methanol, providing 70.4 g (67%) of a white powder.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)Cl.[OH2:38]>C(#N)C.C(OCC)(=O)C>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:38])=[O:32])[CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCc1cccc(CCCCCCO)c1)(c1ccccc1)c1ccccc1
Reactant: O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)(C)[Si](OCc1cccc(CCCCCC(=O)O)c1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 6-[3-(t-Butyldiphenylsilyloxymethyl)-phenyl]-hexanol (5.9 g, 13.2 mmol) in acetonitrile (28 mL) is added CCl4 (28 mL) and water (43 mL). To this mixture is added NaIO4 (11.7 g, 54 mmol) and RuCl3(H2O) (100 mg, 0.5 mmol). The resulting mixture is stirred for 2 h then diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and activated charcoal, filtered through celite and concentrated. The residue is purified by flash chromatography (silica, 20% ethyl acetate/5% dichloromethane in hexanes) to give the title compound (3.46 g) as an oil. MS (ESI) 461 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=2)[C:10]([OH:12])=O)[NH:5][CH:4]=[C:3]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[CH2:64]([NH2:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CN(C=O)C>[CH2:64]([NH:71][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][N:15]=[C:7]([N:6]2[C:2](=[O:1])[C:3]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:4][NH:5]2)[CH:8]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
60.0 mg (213 μmol) of the compound from Example 41 are dissolved in 24 ml DMF, 2.6 mg (21 μmol) 4-N,N-dimethylaminopyridine, 65.9 mg (510 μmol) N,N-diisopropylethylamine and 265 mg (510 μmol) (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate are added and the mixture is stirred at RT for 45 min. 68.3 mg (638 μmol) benzylamine are added and the mixture is stirred overnight at RT. To bring the conversion to completion, a further 65.9 mg (510 μmol) N,N-diisopropylethylamine and 265 mg (510 μmol) (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate are added, the mixture is stirred at RT for 45 min, a further 68.3 mg (638 μmol) benzylamine are added and the mixture is then stirred overnight at RT. It is concentrated and the residue is purified by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:31]=[CH:30][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:23][CH:22]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[CH2:20])[CH:14]=2)=[N:11][N:12]=1.[OH2:32].OO.[OH-].[Na+]>C1COCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:31]=[CH:30][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:23][CH:22]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][OH:32])[CH:14]=2)=[N:11][N:12]=1
Reactant: C=Cc1cccc(-c2nnc(-c3nc(-c4ccc(C(=O)N(C)C)cc4)cnc3N)o2)c1
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4cccc(CCO)c4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.6 %

Procedure:
To a solution of 4-[5-amino-6-[5-(3-vinylphenyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-N,N-dimethyl-benzamide (100 mg, 0.2425 mmol) in THF (9.172 mL) at 0° C., borane-THF complex (606.3 μL of 1 M, 0.6063 mmol) was added dropwise and the reaction mixture stirred overnight at room temperature. Water (43.69 mg, 43.69 μL, 2.425 mmol) was added to the reaction mixture followed by hydrogen peroxide (299.9 μL of 27.5% w/v, 2.425 mmol) and NaOH (606.5 μL of 2 M, 1.213 mmol) and the mixture stirred vigorously for 1 h. The mixture was partitioned between ethyl acetate (5 mL) and water (5 mL) and the layers separated. The aqueous layer was extracted further with ethyl acetate (2×5 mL) and combined organic extracts dried over MgSO4 and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. Product fractions were combined and lypholised to give the product as a yellow solid (5.8 mg, 11% yield); 1H NMR (400 MHz, DMSO) d 2.89 (t, 2H), 2.98 (m, 6H), 3.70 (q, 2H), 4.75 (t, 1H), 7.55-7.62 (m, 4H), 7.80 (br s, 2H), 8.01 (m, 2H), 8.17 (m, 2H) and 8.99 (s, 1H) ppm; MS (ES+) 431.24