Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]2[N:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.[O:13]1CCC[CH2:14]1.[Na]>CO>[Br:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:2]([O:13][CH3:14])[N:3]=[CH:4][C:5]=2[N:11]=1
Reactant: C1CCOC1
Reactant: Brc1ccc2nc(Br)ncc2n1
Agent: [Na]
Solvent: CO
Product: COc1ncc2nc(Br)ccc2n1
Temperature: 40 °C

Procedure:
A 3-necked roundbottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 2,6-dibromopyrido[3,2-d]pyrimidine (10.7 g, 37.04 mmol). To this was added tetrahydrofuran (500 ml) and methanol (150 ml). A solution of sodium (89 mg, 3.87 mmol, 0.10 equiv) in methnaol (60 ml) was then added dropwise with stirring, while warming to a temperature of 40° C. The resulting solution was allowed to react, with stirring, for 1.5 hours while the temperature was maintained at 40° C. The reaction progress was monitored by TLC. The reaction mixture was then quenched by adding 1.5 L of water. The mixture was concentrated under reduced pressure. The resulting slurry was filtered and the solids collected. The solids were then dissolved in 2 L of ethyl acetate. The resulting mixture was washed once with 500 ml of brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified recrystallization from 2:1 tetrahydrofuran:methanol to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:16][CH2:15][N:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[CH:30]1[CH:31]=[CH:32][C:33]2[N:38](O)N=[N:36][C:34]=2[CH:35]=1.C1(N)C=CC=CC=1N>CN(C=O)C.CCOC(C)=O>[NH2:36][C:34]1[CH:35]=[CH:30][CH:31]=[CH:32][C:33]=1[NH:38][C:21]([C:20]1[CH:24]=[CH:25][C:17]([N:14]2[CH2:13][CH2:12][C:10]3([CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:11]3)[CH2:16][CH2:15]2)=[N:18][CH:19]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)N1CC2(CCN(c3ccc(C(=O)O)cn3)CC2)C1
Reactant: On1nnc2ccccc21
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2(CCN(c3ccc(C(=O)Nc4ccccc4N)cn3)CC2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of tert-butyl 2,7-diazaspiro[3.5]nonane (660 mg, 2.91 mmol), methyl 6-chloronicotinate (500 mg, 2.91 mmol) and Et3N (0.487 mL, 3.50 mmol) in 2 mL of N-methylpyrrolidine was stirred under microwave irradiation for 20 min at a temperature of 180° C. The mixture was poured into EtOAc and washed with sat'd NaHCO3, dried (MgSO4), filtered and concentrated, giving tert-butyl 7-[5-(methoxycarbonyl)pyridine-2-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate. The methyl ester was dissolved in 2 mL of 1:1 THF/water, treated with LiOH.H2O (26 mg, 0.62 mmol) and stirred for 20 hours. The mixture was poured into EtOAc and washed with 1M HCl followed by brine, dried (MgSO4), filtered and concentrated, providing 6-[2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]non-7-yl]nicotinic acid. A mixture of the carboxylic acid in 2 mL of DMF was treated with EDC (132 mg, 0.69 mmol), HOBt (93 mg, 0.69 mmol) and phenylenediamine (125 mg, 1.15 mmol), stirred for 15 h at room temperature. The reaction mixture was then diluted with EtOAc and washed with sat.'d NaHCO3, dried (MgSO4), filtered and concentrated. The crude oil was purified by reverse phase flash chromatography (10-100% MeCN/H2O with 0.05% TFA) and formation of the desired product, tert-butyl 7-(5-{[(2-aminophenyl)amino]carbonyl}pyridine-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate, which was confirmed by MS (ESI+): cal'd [M+H]+ 438.2, obs'd 438.3.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:21][CH2:22][CH3:23])[NH:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[O:12]1)#[N:2].[ClH:24].CC([OH:28])C>CO>[ClH:24].[ClH:24].[O:12]1[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15][CH2:16][CH:11]1[CH2:10][NH:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]([NH:21][CH2:22][CH3:23])=[N:3][C:1]([NH2:2])=[O:28]
Reactant: CC(C)O
Reactant: CCNC(=NC#N)NCCCNCC1CCc2ccccc2O1
Agent: Cl
Solvent: CO
Product: CCNC(=NC(N)=O)NCCCNCC1CCc2ccccc2O1

Procedure:
A mixture of 3.1 g (±)-N"-cyano-N-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]propyl]-N'-ethylguanidine in a solution of 10 ml hydrochloric acid in 2-propanol and 50 ml methanol was stirred and refluxed for 30 minutes. The solvent was evaporated. The residue was dissolved in water and this mixture was alkalized with aqueous NaOH (10%). This mixture was extracted with CH2Cl2. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/(NH3) 90:10). The pure fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanol and converted into the hydrochloric acid salt (1:2) with 2-propanol saturated with HCl. The salt was filtered off and recrystallized from 2-propanol. The crystals were filtered off and dried, yielding 2.95 g (±)-N-[[[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]propyl]amino](ethylamino)methylene]urea dihydrochloride; mp. 182.2° C. (interm. 51).
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.Br[CH2:8][CH2:9]Cl.C([O-])([O-])=O.[K+].[K+].[C:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CS(C)=O>[I:1][C:2]1[N:3]=[CH:4][N:5]([CH2:8][CH2:9][N:27]2[CH2:26][CH2:25][N:24]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:29][CH2:28]2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Ic1c[nH]cn1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CCn2cnc(I)c2)CC1
Temperature: 80 °C
Yield: 7.6 %

Procedure:
To a stirred solution of 4-iodoimidazole (25 g, 129 mmol) and 1-bromo-2-chloroethane (12.87 ml, 155 mmol) in DMSO (250 ml) under nitrogen was added K2CO3 (26.7 g, 193 mmol). The reaction mixture was heated at 80° C. for 30 min. More 1-bromo-2-chloroethane (1.28 ml, 15.5 mmol) was added and the reaction mixture was heated at 80° C. for an additional 30 min. Finally, 1-Boc-piperazine (28.8 g, 155 mmol) was added and the reaction mixture heated at 80° C. for 1 h, cooled to RT and partitioned between water and AcOEt. The organic layer was collected, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 340 g cartridge; Hexane/AcOEt:40/60 to 0/100 over 15 CV) followed by another purification under different conditions (SNAP 100 g cartridge; MeOH/DCM: 0/100 to 5/95 over 15 CV), to afford title compound 304 (4 g, 9.85 mmol, 8% yield) as white solid. MS (m/z): 407.18 (M+H).
Reaction SMILES: CC([O:4][C@@H:5]1[C@@:9]2([CH3:24])[CH2:10][CH2:11][C@@H:12]3[C@:22]4([CH3:23])[C:16](=[CH:17][C:18]([CH2:20][CH2:21]4)=[O:19])[CH2:15][CH2:14][C@H:13]3[C@@H:8]2[CH2:7][CH2:6]1)=O.C=O.[C:27]1(S)C=CC=CC=1>N(CCO)(CCO)CCO.[Cl-].[Na+].O>[CH3:27][C:17]1[C:18](=[O:19])[CH2:20][CH2:21][C@@:22]2([CH3:23])[C:16]=1[CH2:15][CH2:14][C@@H:13]1[C@@H:12]2[CH2:11][CH2:10][C@@:9]2([CH3:24])[C@H:8]1[CH2:7][CH2:6][C:5]2=[O:4]
Reactant: Sc1ccccc1
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: OCCN(CCO)CCO
Solvent: O
Product: CC1=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CCC1=O
Reaction time: 0.25 h

Procedure:
A mixture of Testosterone acetate (available from Steraloids Inc, Wilton, N.H. USA) (3.3 g, 10 mmol.), aqueous formaldehyde (1 mL) and thiophenol (0.9 g, 8 mmol ) is stirred in triethanolamine (30 mL) for 10 h under an atmosphere of argon at 110° C. After 4 h. additional aqueous formaldehyde (0.7 mL) and thiophenol (0.5 mg) are added. After cooling, the mixture is poured in brine and extracted with methylene chloride. The organic phase is washed with dilute sodium hydroxide solution and with water, dried and evaporated. The residue is purified by chromatography on "flash" silica gel using mixtures of ethyl acetate and hexane as eluant. The purified residue in acetone (15 mL) is added to Raney nickel (35 g) in acetone (60 mL) which is heated at reflux since 1 h. The reflux is continued for 15 min. The hot organic phase is decanted and the metal is washed with hot acetone. The combined filtrates were concentrated and purified by chromatography on "flash" silica gel using a mixture of ethyl acetate and hexane as eluant. The purified residue is dissolved in methanolic potassium hydroxide solution (50 mL, 3%) and kept at room temperature for 4 h. under an atmosphere of argon. After concentration, the mixture is poured in water and extracted with methylene chloride. The organic phase is washed with brine, dried and evaporated to dryness. The residue, purified by chromatography on "flash" silica gel using a mixture of ethyl acetate and hexane as eluant, is dissolved in acetone (30 mL) and treated at 0° C. with a slight excess of Jones' reagent (8N chromium trioxide)(until a red color). After 15 min., isopropanol (1 mL) is added and the mixture is poured in brine and extracted with ethyl acetate. The organic phase is washed with brine, dried and evaporated to dryness. Purification of the residue by chromatography on "flash" silica gel using a mixture of ethyl acetate and hexane as eluant give pure 4-methyl-4-androsten-3,17-dione.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si]([C:30]#[N:31])(C)C.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[C:1]([C:30]#[N:31])(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: C[Si](C)(C)C#N
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: COc1ccc(C(=O)C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
p-Anisoyl cyanide was prepared according to the general procedure reported by G. A. Olah et al. [supra]. Under dry conditions, 1.8740 g of p-anisoyl chloride (99%, Aldrich) (10.98 mmol), 30 mL of methylene chloride, freshly distilled from phosphorus pentoxide under nitrogen, and 1.7 mL of trimethylsilyl cyanide (13 mmol) were added to a 100-mL round bottom flask. To this solution, 0.27 mL of tin (IV) chloride (2.3 mmol) was added. The reaction was stirred for 2 hr at room temperature. During the 2 hr, the color of the solution changed from clear to dark brown. After the 2 hr of stirring, the reaction was quenched with 75 mL of ice-cold water and then extracted with two 75-mL portions of methylene chloride. The methylene chloride extracts were combined, washed with two 75-mL portions of ice-cold water, dried with MgSO4, and filtered. The methylene chloride was removed by rotary evaporation to yield 1.592 g (90%) of p-anisoyl cyanide as a dark orange solid: IR (CHCl3) (partial) 3020, 2220, 1675, 1600 cm-1.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8](Cl)[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[Cl:16][C:17]1[C:18]([N:23]2[CH2:28][CH2:27][NH:26][C@H:25]([CH3:29])[CH2:24]2)=[N:19][CH:20]=[CH:21][CH:22]=1>>[Br:1][C:2]1[C:10]2[NH:9][C:8]([N:26]3[CH2:27][CH2:28][N:23]([C:18]4[C:17]([Cl:16])=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:24][C@H:25]3[CH3:29])=[N:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)[nH]c2c1
Reactant: C[C@@H]1CN(c2ncccc2Cl)CCN1
Product: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1

Procedure:
4-Bromo-2-chloro-6-trifluoromethyl-1H-benzoimidazole (1.2 g, 4 mmol, Example 6b) reacted with (3R)-1-(3-chloropyridin-2-yl)-3-methylpiperazine (0.95 g, 4.5 mmol, Example 74a) under the conditions of Example 3c to give the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 474 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](C(=NO)C)[CH:15]=2)[CH:10]=1.C1(C)C=CC(S(Cl)(=O)=[O:30])=CC=1.Cl.C(Cl)(Cl)Cl.CO.[N:41]1C=CC=[CH:43][CH:42]=1>>[C:42]([NH:41][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:10]=2)[CH:15]=1)(=[O:30])[CH3:43]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccncc1
Reactant: CC(=NO)c1ccc2cc(OCc3ccccn3)ccc2c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)Nc1ccc2cc(OCc3ccccn3)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
To a solution of 2-(2-pyridylmethyloxy)-6-(1-hydroxyiminoethyl)-naphthalene (1.23 g) in pyridine (15 ml) was added p-toluenesulfonyl chloride (1.45 g) and the resultant-mixture was stirred at room temperature for 24 hours. The reaction mixture was made acid with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium hydroxide and a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a residue. The residue was subjected to column chromatography on silica gel eluting with CHCl3 /MeOH to obtain the title compound (0.76 g, yield=62%). The NMR spectrum is as follows.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([C:11]2[C:15]([CH3:16])=[C:14]([CH:17]([F:19])[F:18])[O:13][N:12]=2)=[CH:9][CH:10]=1)=[O:5])C.O.[OH-].[Li+]>C1COCC1>[F:19][CH:17]([F:18])[C:14]1[O:13][N:12]=[C:11]([C:8]2[S:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][CH:9]=2)[C:15]=1[CH3:16]
Reactant: CCOC(=O)c1ccc(-c2noc(C(F)F)c2C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)F
Reaction time: 20 h
Yield: 99.8 %

Procedure:
A solution of 5-(5-Difluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid ethyl ester (Preparative Example 25, 1.0 g, 3.48 mmol) in THF (20 mL) was treated with an aqueous solution (5 mL) of lithium hydroxide monohydrate (292 mg, 6.96 mmol) and allowed to stir for 20 hr. The reaction was then evaporated to a small volume and treated with a 1 N aqueous hydrochloric acid solution to a pH of ˜2 and the resulting solids filtered, washed with water and air dried to afford product as a colorless solid (900 mg, 99%). 1H NMR (DMSO-d6) 2.29 (s, 3H), 7.44 (t, J=51.9, 1H), 7.66 (d, J=2.6, 1H), 7.78 (d, J=2.6, 1H). 13C NMR 7.7, 108.1 (t, J=236), 115.0, 130.3, 134.3, 134.5, 137.4, 157.8, 159.6 (t, J=26), 163.1. 19F NMR −118.8 (J=51.5). LC/MS 5.41 min, [M+1]+ 260.
Reaction SMILES: [O:1]=[S:2]1(=[O:7])[CH2:6][CH2:5][CH2:4][NH:3]1.[H-].[Na+].Cl.[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH2:18]Cl)[CH:17]=1>CN(C=O)C>[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH2:18][N:3]2[CH2:4][CH2:5][CH2:6][S:2]2(=[O:7])=[O:1])[CH:17]=1
Reactant: O=S1(=O)CCCN1
Reactant: ClCc1cncc(Br)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)CCCN1Cc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A 40 mL scintillation vial was charged with 1,1-dioxo-isothiazolidine (115 mg, 0.949 mmol) and DMF (3 mL). The reaction mixture was cooled to 0° C. and sodium hydride (95 mg, 2.373 mmol) was added. The reaction was left to stir at room temperature for 20 min followed by the addition of 3-bromo-5-(chloromethyl)pyridine hydrochloride (277 mg, 1.139 mmol). The reaction was stirred at room temperature for 3 h, then quenched with water and extracted with ethyl acetate. The organic layer was washed with water twice, dried over sodium sulfate and concentrated in vacuo. The crude was purified by silica gel flash chromatography using heptane-ethyl acetate (60-40, v/v) to afford 3-bromo-5-(1,1-dioxo-isothiazolidin-2-ylmethyl)-pyridine as a colorless oil. MS (ESI) m/z 292.9 (M+H)+
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>N1C=CC=CC=1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:16](=[O:17])[O:18][CH2:19][CH3:20])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Oc2ccccc2)cc1
Temperature: 4 °C
Reaction time: 0.5 h

Procedure:
4-Phenoxybenzenamine (18.5 grams; 0.1 mole) and pyridine (50 ml) were charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer and cooled to about 4° C. Ethyl chloroformate (13.5 grams; 0.125 mole) was added and the reaction stirred at about 4° C. for a period of about 30 minutes, stirring was then continued at room temperature for another 16 hours. Crystallization occured, whereupon the precipitate was filtered from the reaction medium, washed with water, and air dried to give the desired product ethyl (4-phenoxyphenyl)carbamate.
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[C:4]([C:8]1[N:9]([Ti+3:21])[C:10]([C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:12]=1)([CH3:7])([CH3:6])[CH3:5].[CH3:22][O-:23].[Li+].[Cl-].[Li+]>C1(C)C=CC=CC=1>[CH3:22][O-:23].[CH3:22][O-:23].[Cl-:1].[C:4]([C:8]1[N-:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[C:10]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=1)([CH3:7])([CH3:6])[CH3:5].[Ti+4:21]
Reactant: CC(C)(C)c1nc(C(C)(C)C)n([Ti+3])c1C(C)(C)C
Agent: C[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc(C(C)(C)C)c(C(C)(C)C)[n-]1
Product: [Ti+4]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a Solution of 0.500 g (1.28 mmol) of 2,4,5-tri-tert-butyl-imidazolyltitanium trichloride in 7 ml of toluene was added to 0.235 g (6.2 mmol) of lithium methoxide at RT. The slurry was agitated at RT for 2 days followed by 16 hours at 50° C. During the treatment the color of the slurry changed from deep red to yellow. Mixture of lithium methoxide and lithium chloride was filtered off and solvent was distilled under vacuum at 50° C. Residue analysis by 1H and 13C NMR indicated presence of a mixture of 2,4,5-tri-tert-butyl-imidazolyltitanium dichloride methoxide (˜13 mol %) and 2,4,5-tri-tert-butylimidazolyltitanium chloride dimethoxide (˜87 mol %):
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([Cl:16])[C:5]2[N:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[NH:8][C:4]=2[C:3]=1[S:17]([OH:20])(=O)=[O:18].S(Cl)([Cl:23])=O>CN(C)C=O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([Cl:16])[C:5]2[N:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[NH:8][C:4]=2[C:3]=1[S:17]([Cl:23])(=[O:20])=[O:18]
Reactant: O=S(=O)(O)c1c(Cl)c(Cl)c(Cl)c2nc(C(F)(F)F)[nH]c12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1c(Cl)c(Cl)c(Cl)c2nc(C(F)(F)F)[nH]c12
Temperature: 80 °C
Yield: 91 %

Procedure:
The 5,6,7-trichloro-2-trifluoromethylbenzimidazole-4-sulphonic acid (155 parts) was added to a stirred mixture of thionyl chloride (770 parts) and dimethylformamide (24 parts). A vigorous effervescence took place, and when this had subsided the mixture was slowly heated to reflux temperature (80°C) and maintained at this temperature for three hours. The reaction mixture was then cooled and the solid crystals filtered off, washed with benzene (160 parts) and dried to give 5,6,7-trichloro-2-trifluoromethylbenzimidazole-4-sulphonyl chloride (138 parts), melting point (with decompoition) 208°-209°C. Evaporation of the filtrate yielded a further 10 parts of the product, giving a total yield of 148 parts (91% yield).
Reaction SMILES: [CH2:1]1[CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][CH:30]=[C:29]2[O:38][C:39]1[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:1]1[CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:5]([NH:6][C:13]([NH:45][C:42]3[CH:41]=[CH:40][C:39]([O:38][C:29]4[C:28]5[C:33](=[CH:34][C:35]([O:36][CH3:37])=[C:26]([O:25][CH3:24])[CH:27]=5)[N:32]=[CH:31][CH:30]=4)=[CH:44][CH:43]=3)=[O:15])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc5c(c4)OCCO5)cc3)c2cc1OC
Yield: 77.7 %

Procedure:
3,4-Ethylenedioxyaniline (80 mg) was dissolved in toluene (5 ml), triethylamine (0.5 ml) and then triphosgene (50 mg) were added, and the admixture was refluxed with heat for 1 hour. 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was added, and the admixture was refluxed with heat for 100 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 62 mg of the title compound (yield: 74%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]3[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25]3)=[CH:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.Cl.CCOC(C)=O>C1COCC1.CO>[F:30][C:26]1([F:29])[CH2:27][CH2:28][CH:24]([C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([S:12]([C:9]3[CH:8]=[CH:7][C:6]([C:5]([OH:31])=[O:4])=[CH:11][CH:10]=3)(=[O:14])=[O:13])[CH:16]=2)[CH2:25]1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CCC(F)(F)C3)c3ccccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCC(F)(F)C3)c3ccccc32)cc1
Yield: 93.1 %

Procedure:
Add aqueous sodium hydroxide (5N, 0.72 ml, 3 eq) to a solution of 4-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-benzoic acid methyl ester (500 mg, 1.20 mml, 1 eq) in 5 ml THF, 2.5 ml MeOH. Stir reaction at room temperature for 2 hours. Remove solvent on rotovap and add 1N HCl and EtOAc. Extract products into organics, separate organics, and then dry organics with MgSO4. Filter off drying agent, and remove organics on rotovap to give 4-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-benzoic acid (450 mg, 92% yield) which was used without further purification.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][S:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=1)[O:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=O.[NH2:31][C@H:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C@H:33]1[OH:38].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[OH:38][C@@H:33]1[CH2:34][CH2:35][CH2:36][CH2:37][C@@H:32]1[NH:31][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][CH:26]=[N:27][C:19]=1[O:18][C:17]1[CH:28]=[CH:29][CH:30]=[C:15]([S:14][CH3:13])[CH:16]=1
Reactant: N[C@H]1CCCC[C@H]1O
Reactant: CSc1cccc(Oc2ncccc2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncccc2C(=O)N[C@H]2CCCC[C@H]2O)c1
Reaction time: 18 h
Yield: 48.5 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (293 mg, 1.53 mmol) was added to a solution of 2-(3-methylsulfanyl-phenoxy)-nicotinic acid (200 mg, 0.765 mmol), (1R,2S)-2-aminocyclohexanol hydroformate [8151/195/2] (123 mg, 0.765 mmol), 1-hydroxybenzotriazole (114 mg, 0.842 mmol) and triethylamine (430□l, 3.10 mmol) in dimethylformamide (5 ml) under nitrogen at room temperature. The reaction was stirred for 18 h and partitioned between diethyl ether (25 ml) and water (25 ml). The organic phase was washed with brine (30 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (50:50 as eluant) to give N-[(1 S,2R)-2-hydroxycyclohexyl]-2-[3-(methylsulfanyl)phenoxy]nicotinamide (133 mg) as a gum.