Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[N:10][N:11]=[C:12]3[C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:25]=2)[C:22]([OH:24])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:34][C:35]1[CH:36]=[C:37]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH:38]=[CH:39][CH:40]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:45][S:42]([NH:41][C:37]1[CH:36]=[C:35]([NH:34][C:22](=[O:24])[C:21]2[CH:25]=[C:17]([C:12]3[C:13]4[C:8](=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH:16]=[CH:15][CH:14]=4)[C:9]([NH:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[N:10][N:11]=3)[CH:18]=[N:19][CH:20]=2)[CH:40]=[CH:39][CH:38]=1)(=[O:44])=[O:43]
Reactant: O=C(O)c1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Reactant: CS(=O)(=O)Nc1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cccc(NC(=O)c2cncc(-c3nnc(NCc4ccccn4)c4c(-c5ccccc5)cccc34)c2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 27.5 %

Procedure:
5-(5-Phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)nicotinic acid (15.0 mg, 0.0350 mmol) was added to N-(3-aminophenyl)methanesulfonamide (7.73 mg, 0.0420 mmol) and a solution of HATU (19.7 mg, 0.0520 mmol) and DIPEA (0.0180 mL, 0.104 mmol) in DMF (0.5 mL) was added. The reaction mixture was stirred for 5 hours at room temperature. The volatile components were removed under high vacuum and the residue was purified by reverse phase preparative HPLC (Condition 36 as described in general methods) to afford N-(3-(methylsulfonamido)phenyl)-5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)nicotinamide (5.79 mg, 26.4%) as a white solid. LCMS (Condition 37): retention time 1.63 min, [M+1]=602.1, purity 95.02%. 1H NMR (400 MHz, DMSO-d6) δ 3.01 (s, 3 H), 4.67 (d, J=4.4 Hz, 2 H), 6.34 (t, J=4.4 Hz, 1 H), 6.95-6.99 (m, 1 H), 7.21-7.24 (m, 1 H), 7.28 (d, J=8.0 Hz, 1 H), 7.30 (t, J=8.0 Hz, 1 H), 7.50-7.58 (m, 6 H), 7.68-7.77 (m, 3 H), 7.90-7.94 (m, 2 H), 8.22-8.24 (m, 1 H), 8.61 (t, J=2.0 Hz, 1 H), 9.05 (d, J=2.0 Hz, 1 H), 9.26 (d, J=2.0 Hz, 1 H), 10.60 (s, 1 H).
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11])=O.[NH2:13][S:14]([C:17]1[CH:18]=[C:19]([C:23](=[S:25])[NH2:24])[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15]>>[CH3:12][C:2]1[S:25][C:23]([C:19]2[CH:18]=[C:17]([S:14]([NH2:13])(=[O:15])=[O:16])[CH:22]=[CH:21][CH:20]=2)=[N:24][C:3]=1[C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: NC(=S)c1cccc(S(N)(=O)=O)c1
Reactant: Cc1ccncc1C(=O)C(C)Br
Product: Cc1ccncc1-c1nc(-c2cccc(S(N)(=O)=O)c2)sc1C
Yield: 65.2 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(4-methylpyridin-3-yl)propan-1-one hydrobromate (520 mg) and 3-(aminosulfonyl)benzenecarbothioamide (361 mg), the title compound (376 mg) was obtained as colorless powder crystals.
Reaction SMILES: [CH3:1][C@@H:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][CH2:17][C:18](=[O:38])[C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[CH:30]=[C:29]5[CH2:32][CH2:33][CH2:34][C:35](=[O:36])[C:28]5=[CH:27][C:26]=4[O:25][CH2:24][C:23]=3[CH:37]=2)=[O:15])[CH2:4][CH2:3]1.[Br-:39].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.CO.Cl>[CH3:1][C@@H:2]1[N:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[C@H:5]([C:14]([O:16][CH2:17][C:18]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[CH:30]=[C:29]5[CH2:32][CH2:33][CH:34]([Br:39])[C:35](=[O:36])[C:28]5=[CH:27][C:26]=4[O:25][CH2:24][C:23]=3[CH:37]=2)=[O:38])=[O:15])[CH2:4][CH2:3]1
Reactant: [Br-]
Reactant: C[C@H]1CC[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCCC4=O)N1C(=O)OC(C)(C)C
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CO
Product: C[C@H]1CC[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCC(Br)C4=O)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2S,5 S)-1-tert-butyl 2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl) 5-methylpyrrolidine-1,2-dicarboxylate (1.29 g, 2.48 mmol) was dissolved in a solution of DCM (17.5 mL) and MeOH (7 mL), then treated with pyridinium tribromide (873 mg, 2.73 mmol). After stirring at RT for 1 h, the reaction mixture was diluted with DCM and 10% HCl, and extracted with DCM. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure and the crude material was carried on without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH:10]=[CH:11][C:12]([CH3:22])=[CH:13][CH:14]=[CH:15][C:16]([CH3:21])=[CH:17][C:18](Cl)=[O:19])=[C:5]([CH3:23])[C:4]=1[CH3:24].[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:18](=[O:19])[CH:17]=[C:16]([CH3:21])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:22])[CH:11]=[CH:10][C:6]1[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:24])[C:5]=1[CH3:23])([CH3:27])[CH3:26]
Reactant: COc1cc(C)c(C=CC(C)=CC=CC(C)=CC(=O)Cl)c(C)c1C
Reactant: CC(C)N
Product: COc1cc(C)c(C=CC(C)=CC=CC(C)=CC(=O)NC(C)C)c(C)c1C

Procedure:
9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid chloride is reacted with isopropyl amine to produce 9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid isopropyl amide, m.p. 200° C.;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:27][CH2:26][CH2:25][N:24]([CH3:29])[CH3:23])[C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 85.5 %

Procedure:
3.01 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 1.74 g of 3-(dimethylamino)propyl chloride hydrochloride are dissolved in 30 ml of acetone, and 3.04 g of potassium carbonate are added thereto. The mixture is refluxed overnight under stirring. After the reaction, the mixture is condensed under reduced pressure, and the residue is dissolved in ethyl acetate and water. The ethyl acetate layer is collected, dried and then evaporated to remove solvent. 3.3 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[3-(dimethylamino)-propyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are thereby obtained as an oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][N:7]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)=[N:8]1>CN(C=O)C.O>[N:1]([CH2:6][N:7]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)=[N:8]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCn1cc(Cl)c(-c2cc(Cl)cc(Cl)c2)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCn1cc(Cl)c(-c2cc(Cl)cc(Cl)c2)n1
Reaction time: 12 h
Yield: 85.9 %

Procedure:
0.70 g (0.010 mol) of sodium azide is added, at room temperature, to a solution of 1.85 g (0.005 mol) of 1-chloromethyl-4-chloro-3-(3,5-dichlorophenyl)pyrazole in 25 ml of DMF. The reaction mixture is stirred for 12 h, diluted with 100 ml of H2O and extracted with ether. After drying the organic phase and concentration under vacuum, the residue is triturated with 20 ml of heptane, filtered and dried. We obtain 1.30 g of 1-azidomethyl-4-chloro-3-(3,5-dichlorophenyl)pyrazole, melting at 74° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[O:21])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19][CH:20]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[OH:21])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH3:9])=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N(CCC(=O)c1ccc(F)cc1)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H](c1ccc(Br)cc1)N(CCC(O)c1ccc(F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
To a stirred solution of (S)-tert-butyl 1-(4-bromophenyl)ethyl(3-(4-fluorophenyl)-3-oxopropyl)carbamate (500 mg, 1.11 mmol) in MeOH (20 mL) was added an NaBH4 caplet (1 g, 26 mmol). The mixture was stirred at rt overnight and concentrated under reduced pressure. The residue was partitioned between EtOAc (80 mL) and water (20 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated to leave tert-butyl (S)-1-(4-bromophenyl)ethyl(3-(4-fluorophenyl)-3-hydroxypropyl)carbamate (474 mg, 94%) as an oil. LC-MS (3 min) tR=2.33 min, 454. 452, 380, 378.
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:3]=12.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2c(c1O)CCCCCCCCCC2
Product: CCOC(=O)c1cnc2c(c1Cl)CCCCCCCCCC2

Procedure:
A solution of 2 g of ethyl 5,6,7,8,9,10,11,12,13,14-decahydro-4-hydroxycyclododeca[b]pyridine-3-carboxylate in 25 ml phosphorus oxychloride is refluxed for 2 hours and evaporated to dryness under reduced pressure. The residue is dissolved in methylene chloride, treated with ice and basified with saturated sodium carbonate solution. The layers are separated, the aqueous phase re-extracted with methylene chloride, and the combined organic layers dried with magnesium sulfate, filtered, and evaporated to dryness to obtain ethyl 4-chloro-5,6,7,8,9,10,11,12,13,14-decahydrocyclododeca[b]pyridine-3-carboxylate as an oil.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:31]1([CH2:37][C:38](Cl)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[C:31]1([CH2:37][C:38]([NH:23][CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 12.4 %

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (200 mg, 0.63 mmol) and triethylamine (93 μL, 0.66 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere at 0° C. was added dropwise a solution of phenylacetyl chloride (93 μL, 0.66 mmol) in anhydrous dichloromethane (2 mL). After stirring for 3 h at 0° C., the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with water then dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with DCM:MeOH (98:2) to give the title compound (34 mg, 12%). 1H NMR (400 MHz, CDCl3) δ7.32-7.31 (m, 3H), 7.12-7.10 (m, 2H), 6.89-6.87 (d, 2H), 6.76-6.74 (d, 2H), 4.91 (t, 1H), 4.02 (t, 2H), 3.79-3.74 (m, 2H), 3.53-3.51 (m, 2H), 3.47 (s, 2H), 3.37-3.35 (d, 2H), 2.62 (m, 6H), 2.08-2.06 (m, 2H), 1.93-1.85 (m, 6H), 1.76-1.74 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[S:8][CH2:7][C@@H:6]([CH3:9])[NH:5][C:4]1=[O:10].N1C=CN=C1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].O>C(Cl)Cl>[Si:20]([O:1][CH2:2][C@@H:3]1[S:8][CH2:7][C@@H:6]([CH3:9])[NH:5][C:4]1=[O:10])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C[C@@H]1CS[C@@H](CO)C(=O)N1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1CS[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the above crude compound (11, 9.0 g, 0.057 mol) in DCM (150 mL) was added imidazole (7.70 g, 0.113 mol) followed by tert-butyl(chloro)diphenylsilane (17.2 g, 0.0630 mol) under N2 atmosphere. After the addition, the resulting solution was stirred at ambient temperature for 2 hours. Water (100 mL) was added and the mixture was extracted with DCM (3×200 mL). The combined organic fractions were concentrated in vacuo, and the resultant residue was purified by silica gel chromatography (PE: EtOAc=10:1 to 2:1) to give (2S,5R)-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-methylthiomorpholin-3-one (12) that gave a proton NMR spectra consistent with theory.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9](=[N:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:10](=O)[CH3:11])=[CH:4][CH:3]=1.C(O[C:26](=[O:30])[CH2:27][C:28]#[N:29])C.C([O-])(=O)C.[NH4+]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:10]([CH3:11])=[C:27]([C:28]#[N:29])[C:26](=[O:30])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:13]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(NN=C(Sc2ccc(C)cc2)C(C)=O)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: ClCCl
Product: COc1ccc(-n2nc(Sc3ccc(C)cc3)c(C)c(C#N)c2=O)cc1
Temperature: 160 °C

Procedure:
An intimate, magnetically stirred mixture of 440 mg (1.40 mmol) of 1-[(4-methylphenyl)thio]-1-[(4-methoxyphenyl)hydrazono]-2-propanone 370 μl of ethylcyanoacetate and 178 mg of ammonium acetate was heated under a nitrogen atmosphere at 160° C. for 30 min. The reaction mixture was cooled and dissolved in methylene chloride. The organic layer was washed successively with saturated aqueous sodium bicarbonate and water. The organic layer was dried over magnesium sulfate and evaporated in vacuo to yield semi-pure product. The residue was recrystallized from ethanol to yield 6-[(4-methylphenyl)thio]-2,3-dihydro-2-(4-methoxyphenyl)-5-methyl-3-oxo-4-pyridazinecarbonitrile, mp 148-149° C.(EtOH). 1H NMR(400 MHz, CDCl3) 2.35 (s, 3 H), 2.52 (s, 3 H), 3.78 (s, 3 H), 6.82 (d, J=9.2 Hz, 2 H), 7.18 (d, J=8 Hz, 2 H), 7.34 (d, J=8 Hz, 2 H), 7.36 (d, J=9.2 Hz, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11].[C:13]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([O:10][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:19][C:16]2[CH:15]=[CH:14][C:13]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:18][CH:17]=2)[CH:7]=[CH:6][C:5]=1[OH:11]
Reactant: BrCCCCCCOc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCCCCCCOc2ccc(-c3ccccc3)cc2)ccc1O
Yield: 55.5 %

Procedure:
A mixture of 1.0 g (6 mmol) of 2,5-dihydroxybenzoic acid methyl ester, 2.0 g (6 mmol) of 6-([1,1'-biphenyl]-4-yloxy)hexyl bromide and 1.24 g (9 mmol) of potassium carbonate in 50 ml of acetone and 5 ml of DMF was stirred at reflux for 27 hours. The solvents were removed at reduced pressure, water was added to the residue and the product was extracted with ethyl acetate. The dried extract was concentrated to a solid which was purified by chromatography on 40 g of silica gel using 50% toluene-hexane to give 1.4 g (56% yield, mp 91°-92°) of 5-[[6-([1,1'-biphenyl]4-yloxy)hexyl]oxy]-2-hydroxybenzoic acid methyl ester. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=O)[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][NH:24][CH3:25].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH2:15][N:24]([CH2:23][CH2:22][N:21]([CH3:26])[CH3:20])[CH3:25])[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCCN(C)C
Reactant: CC(C)(C)OC(=O)NCc1cc(C=O)cc(Cl)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)CCN(C)Cc1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1

Procedure:
was prepared according to Scheme C2 (step C) from (3-chloro-2-fluoro-5-formyl-benzyl)-carbamic acid tert-butyl ester (200 mg, 0.59 mmol), N,N,N′-trimethyl-ethylendiamine (71 mg, 0.70 mmol), acetic acid (0.06 mL, 1.0 mmol) and sodium triacetoxyborohydride (368 mg, 1.7 mmol) in THF (8 mL). MS (LC-MS): 374.0 [M]+; tR (HPLC conditions c): 3.53 min.
Reaction SMILES: O1CCOCC1.[H][H].CO.[C:11]([C:15]1[CH:20]=[C:19]([CH:21](Cl)[CH3:22])[CH:18]=[C:17]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]=1[OH:28])([CH3:14])([CH3:13])[CH3:12]>[Cr]([O-])([O-])=O.[Cu+2].CCCCCC.Cl>[C:11]([C:15]1[CH:20]=[C:19]([CH:21]=[CH2:22])[CH:18]=[C:17]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]=1[OH:28])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(Cl)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: [H][H]
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Agent: Cl
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: CO
Product: C=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 95 %

Procedure:
Eight hundred milliliters of dry CCl4 was cooled to 0° to 5° C. Anhydrous AlCl3, 96.4 grams (0.70 mole) was added followed by the dropwise addition of 50 milliliters (0.70 mole) of acetyl chloride. After the addition of acetyl chloride was completed, 103 grams (0.50 mole) of 2,6-di-t-butylphenol dissolved in 100 milliliters of CCl4 was added over a 1 hour period while maintaining a temperature below 10° C. The mixture was slowly warmed to room temperature and stirred an additional hour. The aluminum chloride/3,5-di-t-butyl-4-hydroxyacetophenone complex was hydrolyzed by pouring the reaction mixture into an excess of cold dilute hydrochloric acid. The lower CCl4 layer was separated, and the solvent was evaporated to obtain 118 grams of 3,5-di-t-butyl-4-hydroxyacetophenone with a 95 percent yield and a melting point of 146 to 148° C. A high pressure autoclave was charged with 100 grams (.403 mole) of 3,5-di-t-butyl-4-hydroxyacetophenone, 500 milliliters of dioxane and 10 grams of copper chromite catalyst. Pressure was raised to 1000 psi, and the mixture was heated to 125° to 135° C. until no more hydrogen was absorbed. The mixture was cooled, the catalyst filtered off and the solvent removed to obtain 96 grams of carbinol with a 95 percent yield and a melting point of 86° to 88° C. The carbinol was quantitatively converted to the 2,6-di-t-butyl-4-(α-chloro)ethylphenol by vigorous stirring of 50 grams (0.20 mole) of the carbinol dissolved in 100 milliliters of hexane with 100 milliliters of concentrated HCl for one hour at room temperature. The hexane layer was separated and the solvent removed. The residue was used in the final step. To the residue of 2,6-di-t-butyl-4-(α-chloro)ethylphenol was added 100 milliliters of pyridine. This solution was refluxed for 30 minutes. The pyridine was then removed by the vacuum distillation. The residue was washed thoroughly with water, then dissolved in a small amount of acetone and recrystallized at -78° C. to obtain 44 grams of 2,6-di-t-butyl-4-vinylphenol with a 95 percent yield of a melting point of 36 to 39° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([O:9][C:10]2[C:24]([CH:25]3[CH2:29][CH2:28][CH2:27][NH:26]3)=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:32]([O:36][C:37]([NH:39][CH2:40][C:41](O)=[O:42])=[O:38])(C)(C)[CH3:33]>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[C:24]([CH:25]3[CH2:29][CH2:28][CH2:27][N:26]3[C:41](=[O:42])[CH2:40][NH:39][C:37](=[O:38])[O:36][CH2:32][CH3:33])=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:30][CH:31]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cc1
Product: CCOC(=O)NCC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1

Procedure:
The entitled compound was obtained in the same method as in Example 171 and 181 or in accordance with the method or by combining it with an ordinary method but using 5-(4-methanesulfonyl-phenoxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole obtained in Example 162 (step 7) and N-t-butoxycarbonyl-glycine.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[C:10]([OH:18])(=[O:17])[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]>C(O)C>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[C:10]([O-:18])(=[O:17])[CH2:11][CH2:12][CH2:13][C:14]([O-:16])=[O:15]
Reactant: O=C(O)CCCC(=O)O
Agent: CN(C)C(=N)NC(=N)N
Solvent: CCO
Product: O=C([O-])CCCC(=O)[O-]
Temperature: 10 °C
Yield: 94.9 %

Procedure:
9.75 g (2.5 molar equivalents) of metformin free-base was stirred in 100 ml of ethanol at room temperature, after which a solution of 3.98 g (1 molar equivalent) of glutaric acid in ethanol was added dropwise thereto and stirred at 10° C. The produced crystal was filtered and dried in hot air, thus obtaining 7.41 g (yield: 62.8%) of metformin glutarate.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CO.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[OH-].[Na+].S([O-])([O-])(=O)=O.[Cu+2]>[NH2:1][C@@H:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][CH:9]=1)[C:11]([OH:13])=[O:12]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: ClCc1ccccc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 60 °C

Procedure:
To a solution of L-tyrosine of the formula (10) (250 g) in 2N NaOH solution (552 ml), copper sulphate solution (172 g of CuSO4 in 600 ml of water) was added and heated at 60° C. for 2 h. The reaction mixture was cooled to room temperature and methanol (2.5 L) and 2N NaOH (83 ml) was added and then benzyl chloride (15 ml) was added drop wise. The reaction mass was allowed to warm to room temperature. The precipitate was filtered and washed to give the title compound as white to off-white solid (260 g, 70%) (Ref: Bodansky & Bodansky pp50).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[F:27][C:28]([F:37])([F:36])[C:29]1[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=1>C(Cl)Cl.CN(C=O)C.O>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([F:27])([F:36])[F:37])[CH:30]=1)=[O:7]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1I
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3-iodo-4-methylbenzoic acid (3.00 g, 11.4 mmol) in DCM (30 mL) at 0° C. was added oxalyl chloride (1.45 mL, 17.2 mmol) followed by two drops of DMF. The reaction was stirred at 0° C. for 30 minutes followed by warming to ambient temperature for 40 minutes. The mixture was concentrated in vacuo. To the resulting residue was added DCM (30 mL), DIPEA (2.99 mL, 17.2 mmol) and 3-(trifluoromethyl)-benzenamine (1.42 mL, 11.4 mmol). The reaction was stirred at ambient temperature for 1 hour. The mixture was then poured into water, and the product was extracted with DCM. The combined organic extracts were washed with water, followed by saturated sodium bicarbonate, and then dried over sodium sulfate. An equal volume of hexane was added and most of the DCM was then removed in vacuo. The resulting yellow solid was filtered, rinsed with hexane and air dried. (4.27 g, 92%).