Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].FC(S(O)(=O)=O)(F)F>N1C=CC=CC=1>[CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:4][CH2:3][CH2:2][CH2:1][CH:7]4[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]4)=[CH:20][CH:19]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)s2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: c1ccncc1
Product: CCCCCCc1ccc(-c2ncc(-c3ccc(CCCCC4CCCCC4)cc3)s2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 203.1 %

Procedure:
1.20 g of 4-{2-(4-hexylphenyl)thiazole-5-yl}phenol was dissolved in 2 ml of pyridine and cooled on an ice bath to which common salt was added. To the solution, 0.9 ml of anhydrous trifluoromethylsulfonic acid was added, followed by stirring for 1 hour. After the reaction, the reaction mixture was poured into ice water and subjected to extraction with ethyl acetate. The resultant organic layer was acidified by diluted hydrochloric acid, washed with common salt water (or brine) and dried with anhydrous sodium sulfate, followed by distilling-off of the solvent to obtain 1.66 g of an objective product.
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH:23]1([NH:26][C:27](=[O:44])[C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:29]=2)[CH2:25][CH2:24]1>>[CH:23]1([NH:26][C:27]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([C:2]3[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=4)=[O:7])=[CH:4][N:3]=3)[CH:29]=2)=[O:44])[CH2:24][CH2:25]1
Reactant: CS(=O)(=O)Nc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCc2cccc(NS(C)(=O)=O)c2)cn1

Procedure:
6-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-N-(3-methylsulphonylaminobenzyl)-nicotinamide was prepared from 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8) using General Method B. LCMS: retention time 2.71 min, MH+ 479. NMR: δH [2H6]-DMSO 9.33,(1H, t), 9.15,(1H, s), 8.48–8.33,(3H, m), 7.89,(1H, s), 7.81,(1H, d), 7.73,(1H, d), 7.41,(1H, d), 7.31,(1H, t), 7.21,(1H, s), 7.10,(2H, m), 4.51,(2H, d), 2.99,(3H, s), 2.86,(1H, m), 2.38,(3H, s), 0.69,(2H, m), 0.57,(2H, m).
Reaction SMILES: CS([C:5]1[N:12]=[C:11]([CH2:13][O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])(=O)=O.[CH2:25]([Mg]Br)[CH3:26].CCOCC>>[CH2:25]([C:5]1[N:12]=[C:11]([CH2:13][O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])[CH3:26]
Reactant: CC[Mg]Br
Reactant: CC(C)[Si](OCc1ccc(C#N)c(S(C)(=O)=O)n1)(C(C)C)C(C)C
Solvent: CCOCC
Product: CCc1nc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1C#N

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 24 (24c) using 2-(methylsulfonyl)-6-{[(triisopropylsilyl)oxy]methyl}nicotinonitrile (0.78 g, 2.1 mmol) that was obtained in Example 24 (24b) and a 3.0 M solution of ethylmagnesium bromide in ether (1.4 ml, 4.2 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:10 to 1:9) as the eluent to afford the title compound (0.65 g) in a yield of 97% as a white crystalline solid.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C@@H:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH2:25][CH2:26][CH3:27])[CH:22]=2)[C@H:17]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[C@H:16]1[C:37]([O:39]C)=[O:38])([O:3]C)=[O:2].[OH-].[Na+:42]>C(O)(C)C.O>[Na+:42].[Na+:42].[C:1]([CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C@@H:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH2:25][CH2:26][CH3:27])[CH:22]=2)[C@H:17]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[C@H:16]1[C:37]([O-:39])=[O:38])([OH:3])=[O:2].[C:1]([CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C@@H:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH2:25][CH2:26][CH3:27])[CH:22]=2)[C@H:17]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[C@H:16]1[C:37]([O-:39])=[O:38])([OH:3])=[O:2]
Reactant: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCC(=O)OC)[C@H](C(=O)OC)[C@H]2c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCC(=O)O)[C@H](C(=O)[O-])[C@H]2c1ccc2c(c1)OCO2
Reaction time: 16 h

Procedure:
To a solution of (+) Methyl (1S, 2R, 3S)-3-(2-carbomethoxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (49.2 g) in isopropanol (1000 mL) and water (48 mL) was added a 50% aqueous solution of sodium hydroxide (179.4 g). The mixture was stirred under nitrogen for 16 hours then concentrated to approximately 200 mL. Water (400 mL) was added and the solution was extracted with t-butyl methyl ether (300 mL). The aqueous layer was acidified with dilute HCl and extracted twice with 300 mL portions of TBME. The organic layer was washed 4 times with water (4×200 mL), then concentrated under reduced pressure. Absolute ethanol was added (400 mL) and the solution was further concentrated to approximately 150 mL. The solution was diluted to 800 mL with absolute ethanol and 60 mL of water. The solution was titrated to pH=11-12 with 1.25 N sodium hydroxide solution then after stirring for 15 minutes, concentrated to an oil. Absolute ethanol (250 mL) was added and the solution reconcentrated to a solid which was triturated with hexane, and filtered. The solid was dried to a constant weight to afford (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid disodium salt.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:17])[CH:15]=[CH2:16]>O1CCOCC1.C1(C=CC(O)=CC=1)O>[CH3:12][O:13][C:14](=[O:17])[CH2:15][CH2:16][C:7]1([CH2:16][CH2:15][C:14]([O:13][CH3:12])=[O:17])[CH2:6][C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[C:8]1=[O:11]
Reactant: C=CC(=O)OC
Reactant: O=C1CCc2ccc(Br)cc21
Agent: Oc1ccc(O)cc1
Solvent: C1COCCO1
Product: COC(=O)CCC1(CCC(=O)OC)Cc2ccc(Br)cc2C1=O
Temperature: 50 °C
Reaction time: 14 h
Yield: 82.6 %

Procedure:
To 6-bromo-1-indanone (25 g, 0.12 mol) in dioxane (150 mL) was added Triton B (2.48 mL, 6.3 mmol) and hydroquinone (5 mg, 0.05 mmol). After stirring the mixture for 10 min at 50° C. methylacrylate (21.5 mL, 0.24 mol) in 50 mL dioxane was added. The mixture was stirred for 4 h at 50° C. and 14 h at RT. Then 2 mL methylacrylate was added and the reaction was stirred for 1 h at 50° C. The reaction mixture was poured onto water, extracted with EA and the solvents were evaporated. The residue was purified by MPLC (340 g silicagel, gradient:CH/EA 100:0 to 50:50) to give 3-[6-Bromo-2-(2-methoxycarbonyl-ethyl)-1-oxo-indan-2-yl]-propionic acid methyl ester (38 g, 84%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8]O)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8][N:36]1[C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]2[C:32]1=[O:42])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In tetrahydrofuran (225 ml) was dissolved 15 g of 3-nitrophenethyl alcohol, followed by adding triphenylphosphine (26 g) and phthalimide (13.9 g). Then, the resulting mixture was ice-cooled, followed by dropwise addition of diethyl azodicarboxylate (15.5 ml). After stirring at room temperature for 1 hour, the resulting crystals were collected by filtration, washed with diethyl ether and dried, to give N-(3-nitrophenethyl)phthalimide as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[C@H:4]([CH2:59][CH:60]([CH3:62])[CH3:61])[NH:5][C:6](=[O:58])[C@@H:7]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[NH:8][C:9](=[O:50])[C@H:10]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1)[NH:11][C:12](=[O:41])[C@H:13]([CH2:39][OH:40])[NH:14][C:15](=[O:38])[C@H:16]([CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)[NH:17]C(OCC1C=CC=CC=1)=O>[Pd].CO>[CH3:1][O:2][C:3](=[O:63])[C@H:4]([CH2:59][CH:60]([CH3:61])[CH3:62])[NH:5][C:6](=[O:58])[C@@H:7]([CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[NH:8][C:9](=[O:50])[C@H:10]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1)[NH:11][C:12](=[O:41])[C@H:13]([CH2:39][OH:40])[NH:14][C:15](=[O:38])[C@H:16]([CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)[NH2:17]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12

Procedure:
Nα -benzyloxycarbonyl-L-tryptophyl-L-seryl-L-tyrosyl-D-phenylalanyl-L-leucine methyl ester, 6.0 g., is dissolved in 140 ml. of absolute methanol and 800 mg. of 20% palladium on carbon added. The mixture is reduced under a hydrogen atmosphere, monitoring by thin layer chromatography. The catalyst is removed by filtration using a filter aid (Super-Cel). The solvent is evaporated to leave a solid residue which is dried under reduced pressure and used without further treatment.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:24]=[C:23]3[C:15]([C:16]4[CH:17]=[CH:18][C:19]([S:26]([NH:29][C:30]5[CH:31]=[C:32]([NH:36][C:37](=[O:39])[CH3:38])[CH:33]=[CH:34][CH:35]=5)(=[O:28])=[O:27])=[CH:20][C:21]=4[C:22]3=O)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:41][OH:42]>N1C=CC=CC=1>[OH:42][N:41]=[C:22]1[C:21]2[CH:20]=[C:19]([S:26]([NH:29][C:30]3[CH:31]=[C:32]([NH:36][C:37](=[O:39])[CH3:38])[CH:33]=[CH:34][CH:35]=3)(=[O:27])=[O:28])[CH:18]=[CH:17][C:16]=2[C:15]2[C:23]1=[CH:24][C:12]([S:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)(=[O:11])=[O:10])=[CH:13][CH:14]=2
Reactant: NO
Reactant: CC(=O)Nc1cccc(NS(=O)(=O)c2ccc3c(c2)C(=O)c2cc(S(=O)(=O)Nc4cccc(O)c4)ccc2-3)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(NS(=O)(=O)c2ccc3c(c2)C(=NO)c2cc(S(=O)(=O)Nc4cccc(O)c4)ccc2-3)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
The product from Example 6A (223 mg, 0.396 mmol) in pyridine (3 mL) was treated with hydroxylamine hydrochloride (30 mg, 0.435 mmol) and heated at reflux. After 30 minutes, the mixture was allowed to cool to ambient temperature and partitioned between ethyl acetate and H2O. The separated organic phase was washed with 1 N HCl, brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (75% ethyl acetate/hexanes) to provide the title compound as a light yellow solid (91 mg, 40% yield). 1H NMR (300 MHz, DMSO-d6) δ 13.32 (bs, 1H), 10.2-10.4 (bs, 2H), 9.89 (s, 1H), 9.43 (d, 1H), 8.75 (m, 1H), 8.03-8.17 (m, 3H), 7.8-7.95 (m, 2H), 7.45 (m, 1H), 7.25 (m, 1H), 7.1 (m, 1H), 6.98 (m, 1H), 6.75 (m, 1H), 6.58 (m, 1H), 6.52 (m, 1H), 6.4 (m, 1H), 1.98 (s, 3H); MS (ESI) 577 (M−H)−.
Reaction SMILES: Br[CH2:2][C:3]([CH3:16])=[CH:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1.[CH2:17]([OH:21])[CH:18]([CH3:20])[CH3:19]>>[CH2:17]([O:21][CH2:2][C:3]([CH3:16])=[CH:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)CO
Reactant: CC(=CCOc1ccc2c(c1)OCO2)CBr
Product: CC(=CCOc1ccc2c(c1)OCO2)COCC(C)C

Procedure:
1.6 g (0.0165 mol) of sodium-isobutylate in 75 cc of isobutanol are added dropwise at 70° during the course of 15 minutes to 4.3 g (0.015 mol) of 5-(4-bromo-3-methyl-2-butenyloxy)-1,3-benzodioxol which is dissolved in 130 cc of isobutanol. After 3 hours at this temperature the reaction mixture is filtered, the solvent is distilled off at reduced pressure and the residue is dissolved in ether. The ether solution is washed with saturated salt solution, is dried with sodium sulphate and evaporated. The residue is chromatographed on silica gel with chloroform. 5-(4-isobutoxy-3-methyl-2-butenyloxy)-1,3-benzodioxol is obtained as colourless oil. nD20 = 1.5158.
Reaction SMILES: [CH:1]1([CH:4]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[CH:5]2C(=O)OC(C)(C)[O:7][C:6]2=[O:14])[CH2:3][CH2:2]1.O>CN(C=O)C>[CH:1]1([CH:4]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[CH2:5][C:6]([OH:14])=[O:7])[CH2:3][CH2:2]1
Reactant: COc1cc(C(C2CC2)C2C(=O)OC(C)(C)OC2=O)ccc1F
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(CC(=O)O)C2CC2)ccc1F
Temperature: 90 °C
Reaction time: 15 h
Yield: 74.4 %

Procedure:
To a solution of 5-(cyclopropyl(4-fluoro-3-methoxyphenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.00 g) in DMF (20 mL) was added water (2.0 mL), and the mixture was stirred at 90° C. for 15 hr. The reaction mixture was allowed to cool to room temperature, and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.10 g) as a yellow oil.
Reaction SMILES: Cl.[C:2](=N)(OCC)[CH3:3].[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([NH2:16])[CH:10]=1>C(O)C>[CH3:2][C:3]1[NH:16][C:11]2[CH:10]=[C:9]([F:8])[CH:14]=[CH:13][C:12]=2[N:15]=1
Reactant: Nc1ccc(F)cc1N
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Product: Cc1nc2ccc(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
Ethyl acetimidate hydrochloride (37.1 g, 0.3 mol) was added to a stirred suspension of 4-fluoro-ortho-phenylenediamine (12.6 g, 0.1 mol) in ethanol (150 ml) at 0° C. The mixture was allowed to warm up to room temperature and stirred overnight. The solvent was removed under, reduced pressure and the residue extracted into ethyl acetate (100 ml), washed with water (3×100 ml), dried over anhydrous magnesium sulphate, filtered and evaporated. Crystallisation from ethyl acetate gave 2-methyl-5-fluorobenzimidazole (7.7 g, 51%) as a brown crystalline solid.
Reaction SMILES: [Br:1]Br.ClCCl.[C:6]1([C:12]2[CH:16]=[CH:15][O:14][C:13]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[Br:1][C:15]1[O:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:16]=1
Reactant: CCOC(=O)c1occc1-c1ccccc1
Reactant: BrBr
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1oc(Br)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bromine (1.29 ml) was added to a dichloromethane (40 ml) solution of ethyl 3-phenyl-2-furancarboxylate (3.60 g) at 0° C. and stirred overnight at 25° C. The reaction solution was diluted with chloroform and washed with saturated aqueous sodium hydrogencarbonate solution, 20% aqueous sodium thiosulphate solution, and saturated brine. The organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure, thereby giving 3.50 g of ethyl 5-bromo-3-phenyl-2-furancarboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:8]=2)[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1.[C:29](O)(=[O:31])[CH3:30].C1CCC(N=C=NC2CCCCC2)CC1.C(Cl)(Cl)Cl>O>[C:29]([NH:1][C:2]1[N:6]([C:7]2[N:8]=[C:9]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[N:10]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:12]=2)[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1)(=[O:31])[CH3:30]
Reactant: Nc1nc2ccccc2n1-c1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nc2ccccc2n1-c1nc(N2CCOCC2)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
9.32 g (70 mmol) of 2-aminobenzimidazole dissolved in DMF (300 ml) was added and reacted with 60% sodium hydride (2.80 g, 70 mmol) at room temperature for 30 minutes. This suspension was added to a solution of 14.3 g (50 mmol) of 2-chloro-4,6-dimorpholino-1,3,5-triazine dissolved in DMF (200 ml) and stirred at room temperature for 2 hours. The reaction solution was poured into water and the resulting precipitates were washed with water and methanol to obtain 17.7 g (yield: 93%) of 2-(2-aminobenz-imidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine. (2) 0.38 g (1.0 mmol) of 2-(2-aminobenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine and 0.24 g (4.0 mmol) of acetic acid were added to and further 0.83 g (4.0 mmol) of DCC was added to chloroform (5 ml) and stirred at room temperature for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 0.31 g (yield: 73%) of the titled compound as colorless crystals.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].Cl[C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[N:11][N:10]2[C:18]=1[S:19]([NH2:22])(=[O:21])=[O:20].Cl>CN(C=O)C.O>[CH2:3]([S:5][C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[N:11][N:10]2[C:18]=1[S:19]([NH2:22])(=[O:21])=[O:20])[CH3:4]
Reactant: CCCc1ccc2nc(Cl)c(S(N)(=O)=O)n2n1
Reactant: CCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1ccc2nc(SCC)c(S(N)(=O)=O)n2n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60%, 0.73 g, 18.2 mmol) was suspended in DMF (10.0 ml) under ice-cooling, and ethanethiol (1.35 ml, 18.2 mmol) was added dropwise thereto, and the mixture was stirred at 0° C. for 2 hours. 2-Chloro-6-propylimidazo[1,2-b]pyridazin-3-ylsulfonamide (1.00 g, 3.64 mmol) was added thereto and heated at 110° C. for 2.5 hours under stirring. The reaction mixture was left, cooled, diluted with water and acidified by dropwise addition of conc. hydrochloric acid. The precipitated solids were collected by filtration and washed with water, and the solids were suspended in a mixed solvent of chloroform and ethyl acetate, and the insoluble solids were collected by filtration, and the solids were washed with chloroform to give the title compound as gray crystals. The yield was 0.45 g (41.2%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Cl[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:6]=1
Reactant: Ic1cn[nH]c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Cn2cc(I)cn2)cc1
Temperature: 60 °C
Yield: 88.2 %

Procedure:
According to Scheme 6 Step 1: A suspension of 4-iodo-1H-pyrazole (26.3 mmol, 5.11 g), 1-(chloromethyl)-4-methoxybenzene (29.0 mmol, 3.95 mL) and K2CO3 (39.5 mmol, 5.46 g) in acetonitrile (150 mL) was heated at 60° C. overnight. The reaction mixture was cooled to room temperature and was filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel using DCM as eluent to afford 4-iodo-1-(4-methoxybenzyl)-1H-pyrazole (23.2 mmol, 7.3 g, 88%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH3:3].I[CH2:26][CH2:27][CH3:28]>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH2:26][CH2:27][CH3:28]
Reactant: CCCI
Reactant: CCCOc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3
Product: CCCCCCOc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3

Procedure:
Following the procedure for the preparation of 10-(2-propoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole and substituting 1-iodohexane for 1-iodopropane while making non-critical variations the title compound was obtained as 360 mg (66%) of a yellow foam: 1H NMR (400 MHz, CDCl3) δ 7.83 (br s, 1H), 7.36-7.27 (m, 3H), 7.17-7.13 (m, 1H), 7.05-7.01 (m, 1H), 6.98 (d, J=8.2 Hz, 1H), 6.93 (d, J=7.2 Hz, 1H), 3.95-3.85 (m, 2H), 3.12-3.10 (m, 1H), 3.06-3.01 (m, 1H), 2.98-2.93 (m, 2H), 2.90-2.85 (m, 1H), 2.82-2.79 (m, 1H), 2.42-2.37 (m, 2H), 1.57-1.51 (m, 2H), 1.22-1.16 (m, 6H), 0.83 (t, J=6.9 Hz, 3H); HRMS (FAB) calcd for C24H30N2O+H1: 363.2436 found 363.2444.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[CH2:49])[CH2:4][O:5][C:6]1[CH:48]=[CH:47][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:46]=[CH:45][C:28]([C:29]([NH:31][CH2:32][C:33]([CH3:44])([CH3:43])[CH2:34][NH:35]C(=O)OC(C)(C)C)=[O:30])=[CH:27][N:26]=3)[CH:13]=2)=[CH:8][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:35][CH2:34][C:33]([CH3:44])([CH3:43])[CH2:32][NH:31][C:29](=[O:30])[C:28]1[CH:45]=[CH:46][C:25]([NH:24][C:14]2[CH:13]=[C:12]([NH:11][CH2:10][C:9]3[CH:47]=[CH:48][C:6]([O:5][CH2:4][C:3]([CH2:2][Cl:1])=[CH2:49])=[CH:7][CH:8]=3)[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=2)=[N:26][CH:27]=1
Reactant: C=C(CCl)COc1ccc(CNc2cc(Nc3ccc(C(=O)NCC(C)(C)CNC(=O)OC(C)(C)C)cn3)nc(OCC(F)(F)F)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(CCl)COc1ccc(CNc2cc(Nc3ccc(C(=O)NCC(C)(C)CN)cn3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
To a solution of tert-butyl (3-(6-((6-((4-((2-(chloromethyl)allyl)oxy)benzyl)amino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)nicotinamido)-2,2-dimethylpropyl)carbamate (45 mg) in DCM (3 mL) was added TFA (0.3 ml). The mixture was stirred at room temperature for 3 hours. All the solvents were removed under vacuum to give N-(3-amino-2,2-dimethylpropyl)-6-(6-(4-(2-(chloromethyl)allyloxy)benzylamino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-ylamino)nicotinamide (30 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:15]2[C:16]([C:25](OC)=[O:26])=[CH:17][C:18]([O:23][CH3:24])=[CH:19][C:20]=2[O:21][CH3:22])=[C:7]([O:13][CH3:14])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:2][CH2:3][C:5]1[C:6]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][C:16]=2[CH2:25][OH:26])=[C:7]([O:13][CH3:14])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COC(=O)c1cc(OC)cc(OC)c1-c1c(OC)cc(OC)cc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CO)c(-c2c(CO)cc(OC)cc2OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
4,6,4′,6′-tetramethoxy-biphenyl-2,2′-dicarboxylic acid dimethyl ester (2.5 g) was dissolved in THF (96 mL), and 1M LiAlH4 in THF (9.6 mL) was added . After stirring at room temperature for overnight, the mixture was quenched with water and 2N HCl (24 mL) was added. The mixture was evaporated under vacuum and partitioned with DCM (300 mL) and water (200 mL). The organic layer was dried over Na2SO4 and crystallized with DCM to provide (6′-hydroxymethyl-4,6,2′,4′-tetramethoxy-biphenyl-2-yl)-methanol (1.7 g, 77%) as a pale blue white triclinic crystals.