Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:27][O:28][CH2:29][CH3:30])[N:14]([CH2:15][C:16]([NH:19]C(=O)OC(C)(C)C)([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl>CCO>[NH2:19][C:16]([CH3:17])([CH3:18])[CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH2:27][O:28][CH2:29][CH3:30]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)N
Yield: 84.5 %

Procedure:
Tert-butyl 2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethylcarbamate (1.26 g, 3.05 mmol) was dissolved in 10 mL of EtOH and treated with 10 mL of 2 M HCl in EtOH. After heating at reflux for 2 hours, the reaction mixture was cooled and concentrated under reduced pressure. The resulting yellow solid was dissolved in 50 mL of H2O and extracted with CHCl3 (20 mL). The organic layer was discarded and the aqueous portion was made basic (pH˜12) by addition of concentrated NH4OH solution. This was then extracted with CHCl3 (4×20 mL) and the combined organic portions were dried with Na2SO4 and concentrated to give 1-(2-amino-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline-4-amine (808 mg) as a light brown powder. m.p. 161.0-162.0° C.;
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[Br:11]N1C(=O)CCC1=O>CC#N>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=1[Br:11]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(=O)c1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a solution of 4-aminoacetophenone (5.67 g, 0.0419 mol) in 30 mL of CH3CN at 0° C. was added N-bromosuccinimide (7.83 g, 0.0439 mol) in 20 mL of CH3CN dropwise. The reaction was allowed to warm to room temperature and concentrated in vacuo after stirring 16 h. The crude residue was dissolved in EtOAc (100 mL), washed with saturated aqueous NaHCO3 (1×100 mL), brine (1×100 mL) and dried (Na2SO4). The solvent was removed under vacuum to afford the title compound (7.62 g, 85%) as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C8H8BrNO, 213.9 (M+H). found 214.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:19]=[O:20])C>C1COCC1>[CH:8]1([C:5]2[CH:6]=[CH:7][C:2]([CH:19]=[O:20])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1
Reactant: CN(C)C=O
Reactant: Brc1ccc(C2CC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(C2CC2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
To a solution of 1-bromo-4-cyclopropylbenzene [synthesized in analogy to a procedure described in J. Org. Chem. 1976, 41, 2262-2266] (1.58 g, 8.04 mmol) in THF at −78° C. was added n-BuLi (5.08 ml, 1.6M solution in hexane, 8.11 mmol) and the reaction mixture was stirred at −78° C. for 10 min. DMF (1.25 ml, 16.08 mmol) was then added and the reaction mixture was stirred at −78° C. for 15 min. The reaction mixture was then warmed to 0° C. slowly (over 2 h) and stirred at 0° C. for 1 h. The reaction was quenched with sat. NH4Cl (aq) solution and the aqueous phase was extracted with ether. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography (1:9 diethyl ether/pentane) to give 4-cyclopropyl benzaldehyde (1.10 g, 94%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 9.94 (s, 1H), 7.76 (d, J=8.5 Hz, 2H), 7.19 (d, J=8.5 Hz, 2H), 1.97 (m, 1H), 1.13-1.06 (m, 2H), 0.84-0.78 (m, 2H).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:15]=[CH:14][C:9]([C:10](OC)=[O:11])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.O.[NH2:17][NH2:18]>CCO>[NH:1]1[C:5]([C:6]2[CH:15]=[CH:14][C:9]([C:10]([NH:17][NH2:18])=[O:11])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1
Reactant: COC(=O)c1ccc(-c2nnn[nH]2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
To a suspension of methyl 4-(1H-tetrazol-5-yl)benzoate (1.00 g, 4.16 mmol) in EtOH (15 mL) was added hydrazine hydrate (3.0 mL). After stirring for 15 hrs at reflux, the reaction mixture was allowed to warm up to rt. A white solid precipitated out. Filtration, washing with EtOH (2×3 mL), EtOH/water (2×3 mL) and water (2×3 mL) and drying under vacuo at 70° C. for 5 hrs gave 677 mg of the title compound as a white solid in a 80% yield.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][CH:5]=[C:4]([F:12])[C:3]=1[OH:13].[CH2:14]([O:16][C:17](=[O:21])[C:18]#[C:19][CH3:20])[CH3:15].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:14]([O:16][C:17](=[O:21])/[CH:18]=[C:19](/[O:13][C:3]1[C:4]([F:12])=[CH:5][CH:6]=[C:7]([O:8][CH:9]([CH3:11])[CH3:10])[C:2]=1[F:1])\[CH3:20])[CH3:15]
Reactant: CC(C)Oc1ccc(F)c(O)c1F
Reactant: CC#CC(=O)OCC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)/C=C(\C)Oc1c(F)ccc(OC(C)C)c1F
Yield: 73.6 %

Procedure:
To a stirred mixture of 2,6-difluoro-3-isopropoxy-phenol (5.74 g, 0.031 mol) and ethyl-2-butynoate (6.85 g, 0.061 mol) in tetrahydrofuran (50 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.64 g, 0.030 mol) slowly. After addition was complete the mixture was stirred at reflux for 6 h. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated which afforded (E)-3-(2,6-difluoro-3-isopropoxy-phenoxy)-but-2-enoic acid ethyl ester as a brown oil (6.85 g, 75%) and used without further purification.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(=O)(=O)(O)O>C(OCC)C>[C:11]1([CH:10]([OH:17])[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: OC(c1ccccc1)C(Cc1ccccc1)c1ccccc1

Procedure:
Four liters of an ethyl ether solution containing 500 g of benzyl magnesium chloride were added slowly to a mixture of 1.5 Kg benzoyl chloride and 1 l of ethyl ether while cooling the whole mass. Thereafter, the whole mass was incorporated with 1 l of 30% sulphuric acid, agitated, incorporated with an alkali for neutralizing the sulphuric acid, washed with water and then distilled to remove therefrom 183 g of a distillate (phenyl-o-tolylketone) boiling in the range of 164°-169° C. at 9 mm Hg and then obtain 200 g of a distillate (1,2,3-triphenylpropanol) boiling in the range of 224°-235° C. at 8 mm Hg. This propanol (180 g) was incorporated with 150 cc of toluene and 35 g of potassium sulphite to form a mixture which was heated under reflux and, after distillation-off of the toluene, obtain 153 g of 1,2,3-triphenylpropene-1 as the distillate boiling in the range of 185°-188° C. at 0.03 mm Hg. The thus obtained distillate (128 g) was incorporated with 14 g of a rhodium-activated carbon catalyst (rhodium content: 5 wt.%) and 500 cc of n-hexane in a 2-liter autoclave where the resulting mixture was heated to 65° C. for 20 minutes and then at 95° C. for one hour under a hydrogen pressure of 100 Kg/cm2, and further heated to 200° C. for 5 hours under a hydrogen pressure of 200 Kg/cm2 to distil off the n-hexane and then obtain 124 g of a distillate boiling in the range of 140°-146° C. at 0.025 mm Hg and having a refractive index (nD25) of 1.4959. It was found from the NMR spectrum of this distillate that at least 95% of hydrogenation of the aromatic nuclei and aliphatic unsaturated bonds in the distillate had been effected. The distillate was 1,2,3-tricyclohexylpropane having a kinetic viscosity of 7.69 cSt (98.9° C.) and a traction coefficient of 0.075. The distillate or conventional traction fluid obtained herein had a comparatively high viscosity but it was very unsatisfactory in traction coefficient as compared with the traction fluids (II) of this invention (traction coefficient: 0.092~0.094 as indicated in Examples 3-5). Further, it is very uneconomical that the synthesis of such a conventional traction fluid will require a Grignard's reaction using benzyl magnesium chloride and benzoyl chloride.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C:12]([C:26]([O:28][CH2:29][CH3:30])=[O:27])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C:12]([C:26]([O:28][CH2:29][CH3:30])=[O:27])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)(Cc1ccc(CC)c(CC)c1)C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(CC(=O)O)(Cc1ccc(CC)c(CC)c1)C(=O)OCC

Procedure:
To a solution of 20.30 g (48.27 mmol) tert. butyl 4-(3,4-diethyl-phenyl)-3,3-bis-ethoxycarbonyl-butyrate (Intermediate product 61) in 100 mL CH2Cl2 was added 40 mL TFA while cooling with ice and the mixture was refluxed for 1 hour. The reaction mixture was evaporated down i. vac., the residue was combined with water and the aqueous phase exhaustively extracted with EtOAc. The combined org. extracts were washed with sat. aqueous NaCl solution, dried over sodium sulphate and evaporated i. vac.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[CH:10]=[CH:11][C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[C:1]1([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[CH:10]=[CH:11][C:12]([N:27]2[CH2:26][CH2:25][N:24]([CH2:23][C:22]3[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:20]([O:19][CH3:18])[CH:21]=3)[CH2:29][CH2:28]2)=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Reactant: O=C(O)C=Cc1cccc(-c2ccccc2)c1
Product: COc1cc(CN2CCN(C(=O)C=Cc3cccc(-c4ccccc4)c3)CC2)cc(OC)c1OC
Yield: 85.1 %

Procedure:
Following a procedure similar to that described in Example 61, but using 0.500 g of 3-phenylcinnamic acid and 0.653 g of 1-(3,4,5-trimethoxybenzyl)piperazine, 0.897 g of the title compound was obtained as a powder.
Reaction SMILES: [N:1]1([CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>>[N:1]1([CH2:14][CH2:15][CH2:16][CH:17]=[O:18])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: OCCCCn1cnc2cnc3ccccc3c21
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CCCCn1cnc2cnc3ccccc3c21
Yield: 50.4 %

Procedure:
The general method described in Step 6 of Example 1 was used to oxidize 4-(1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (20.0 g, 82.9 mmol) with DMSO (48.6 g, 620 mmol), oxalyl chloride (58.0 g, 456 mmol), and triethylamine (126 g, 1.25 mol) to provide 4-(1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde (10.0 g) as a light orange oil after chromatography on silica gel (elution with 10% methanol in dichloromethane) followed by brief treatment with trifluoroacetic acid (0.10 g, 1 mmol) in a mixture of THF (50 mL) and water (20 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH:26]1[C:34]2[CH2:33][CH2:32][NH:31][CH2:30][C:29]=2[N:28]=[CH:27]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:31]1[CH2:32][CH2:33][C:34]2[NH:26][CH:27]=[N:28][C:29]=2[CH2:30]1)=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: c1nc2c([nH]1)CCNC2
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCc3[nH]cnc3C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.80 minutes; C23H20Cl2N6O2 (483.36); mass spectrum: (M−H)−=482/484/486 (chlorine isotope).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:17]=[CH:16][C:7]([C:8]([CH2:10][C:11](OCC)=O)=[O:9])=[CH:6][CH:5]=1.[CH3:18][C:19]1[O:23][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:21][C:20]=1CCl>C1COCC1>[CH3:18][C:19]1[O:23][C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:21][C:20]=1[CH2:11][CH2:10][C:8]([C:7]1[CH:6]=[CH:5][C:4]([Br:3])=[CH:17][CH:16]=1)=[O:9]
Reactant: CCOC(=O)CC(=O)c1ccc(Br)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 64.7 %

Procedure:
Sodium hydride (1.3 g, 55 mmol) was suspended in THF (75 mL) and cooled to 0° C. The title compound of Example 1 (14.9 g, 55 mmol) was dissolved in THF (75 mL) and added dropwise to the suspension over 30 minutes. The resulting solution was stirred an additional 30 minutes after which time solid 5-methyl-2-phenyl-4-oxazolyl methyl chloride (10.0 g, 48 mmol) was added in portions over five minutes. The reaction mixture was refluxed for 48 hours, cooled to room temperature and concentrated in vacuo. The residue was dissolved in acetic acid (120 mL) and concentrated HCI (30 mL), and refluxed for five hours. The reaction mixture was cooled to room temperature and poured onto ice-water (300 mL). The aqueous solution was extracted twice with ethyl acetate (500 mL) and the organic extracts were combined and washed with brine (250 mL), dried (MgSO4) and concentrated in vacuo. Purification on silica gel, eluting with hexane/ethyl acetate (4/1), resulted in a crude solid which was further purified by recrystallization from hexane to afford the title compound (11.5 g, 65%) as white crystals. mp 80-81° C. 1HNMR (60 MHz, CDCl3): δ2.2 (s, 3H), 2.8 (m, 2H), 3.2 (m, 2H), 7.2-8.0 (m, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]2[CH2:16][CH:15]2[C:17]([OH:19])=O)=[CH:4][CH:3]=1.[CH3:20][NH:21][C@@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:23]>>[CH3:20][N:21]([C@@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:23])[C:17]([CH:15]1[CH2:16][CH:14]1[C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:19]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C1CC1C(=O)O
Reactant: CN[C@H](C)c1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C1CC1C(=O)N(C)[C@H](C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using 2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-cyclopropanecarboxylic acid and methyl-((R)-1-phenyl-ethyl)-amine.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH:8]=O.Cl.[CH3:17][C:18]([CH3:20])=[O:19]>C(O)C.O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:17][C:18](=[O:19])[CH3:20])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15]
Reactant: CCOc1ccc(C=O)cc1OC
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1ccc(C=CC(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.5 %

Procedure:
10% sodium hydroxide aqueous (40 ml) was added under stirring to a solution of 3-methoxy-4-ethoxybenzaldehyde (9.09 g, 50 mmol) in acetone (25 ml), 95% ethanol (25 ml) and water (200 ml). The reaction mixture was stirred for 24 hr at room temperature, after the reaction completed, the reaction mixture was neutralized with 6N hydrochloric acid to adjust pH=7.0. The precipitated solid was collected by filtrating and washed with water and ethanol successively, dried, and then recrystallized from 95% ethanol to give 7.38 g of a pale yellow solid, mp: 95-97° C., yield: 66.5%.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([CH3:38])([CH3:37])[CH2:5][C:6]1[N:7]=[C:8]([CH:17]([OH:36])[C:18]2([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[CH:26][CH:25]=3)SCCCS2)[N:9]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH:10]=1>C(O)C.[Ni]>[CH3:3][C:4]([CH3:38])([CH3:37])[CH2:5][C:6]1[N:7]=[C:8]([CH:17]([OH:36])[CH2:18][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[CH:28][CH:29]=2)[N:9]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH:10]=1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(O)C1(c2ccc(-c3ccccn3)cc2)SCCCS1
Agent: [Ni]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(O)Cc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Rainey Nickel (600 mg) followed by 1 M aqueous potassium hydroxide (1 mL) were added to an ambient temperature solution of 4-(2,2-dimethylpropyl)-2-{hydroxy[2-(4-pyridin-2-ylphenyl)-1,3-dithian-2-yl]methyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (21 mg, 0.04 mmol) in ethanol (2 mL). After stirring at ambient temperature overnight, the reaction mixture was filtered through celite and concentrated in vacuo. Prep plate chromatography (70% ethyl acetate/hexane) afforded 4-(2,2-dimethyl-propyl)-2-[1-hydroxy-2-(4-pyridin-2-ylphenyl)ethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: C(OC([C:6]1[O:17][C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([CH3:18])[C:8]=2[C:7]=1[OH:19])=O)C.[OH-].[Na+].Cl>C(O)C>[CH3:18][N:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:16]2[O:17][CH2:6][C:7](=[O:19])[C:8]1=2
Reactant: CCOC(=O)c1oc2c3ccccc3n(C)c2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c2c(c3ccccc31)OCC2=O
Temperature: 0 °C
Yield: 53.1 %

Procedure:
A mixture of 47.0 g (0.18 mole) of 3-hydroxy-4-methyl-4H-furo[3,2-b]indole-2-carboxylic ethyl ester (Prep. described in U.S. patent application Ser. No. 369,448) in 450 ml of 95% ethanol was treated with 450 ml of 30% aqueous sodium hydroxide. The mixture was stirred at reflux for two hours, cooled, added to 3.0 kg ice/water, and acidified with 6.0 N hydrochloric acid. The product was filtered, washed with water, and recrystallized from ethanol-water to yield 17.9 g (53% yield) of the product, mp 113°-116° C. An additional recrystallization as above raised the mp to 115.5°-118° C.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13](Cl)[CH:12]=[C:11]([Cl:16])[N:10]=1.O>CN(C)C=O>[Cl:8][C:9]1[CH:14]=[C:13]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:12]=[C:11]([Cl:16])[N:10]=1
Reactant: OCC1CC1
Reactant: Clc1cc(Cl)nc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(OCC2CC2)cc(Cl)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40.3 %

Procedure:
109 mg of cyclopropylcarbinol was dissolved in 2 ml of dimethylformamide, and 60 mg of 60% sodium hydride was added thereto under ice water cooling, and the mixture was stirred at room temperature for 20 minutes. To the reaction solution was added 400 mg of 2,4,6-trichloropyridine, and stirred at room temperature for 30 minutes. The reaction solution was added with water and subjected to extraction with ethyl acetate. The organic layer was washed with brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 133 mg of the objective compound as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](/[CH:8]=[CH:9]/[C:10]([O:12]C)=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C[O-].[Na+]>CO>[NH:1]1[C:2]2[C:3](=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:8]=[CH:9][C:10]1=[O:12]
Reactant: COC(=O)/C=C/c1ncccc1N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1ccc2ncccc2[nH]1
Temperature: 60 °C

Procedure:
To a room temperature solution of (E)-methyl 3-(3-aminopyridin-2-yl)acrylate (3.63 g, 20.37 mmol) in MeOH (40 mL) was added sodium methoxide, 25 wt % solution in methanol (20.00 mL, 90 mmol). The reaction was heated at 60° C. for 6 h, the mixture was cooled to room temperature and the solvent was removed in vacuo to give tan solid. ESI-MS 147.0 [M+1].
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[C:8]([NH2:21])[N:7]=1)[CH2:2][CH2:3][CH3:4].[Br:22]NC(=O)CCC(N)=O>ClCCl>[Br:22][C:11]1[N:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:13]2[C:9]([N:10]=1)=[C:8]([NH2:21])[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=2
Reactant: NC(=O)CCC(=O)NBr
Reactant: CCCCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Solvent: ClCCl
Product: CCCCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
The product from step (ii) (30 g) was dissolved in dry dichloromethane (200 ml). The solution was stirred at room temperature whilst N-bromosuccinamide (27 g) was added portionwise. The mixture was stirred at ambient temperature overnight. 20% (w/v)-Sodium sulfate (200 ml) was added and the separated aqueous phase extracted with dichloromethane. The combined organic phase was washed with saturated sodium hydrogen carbonate solution and brine. After concentration in vacuo, the residue was dissolved in ethyl acetate, washed with water, brine and dried. The solution was filtered through silica gel and concentrated in vacuo. The residue was triturated with diethyl ether and isohexane (1/1, 200 ml) then filtered to give the subtitle compound (26 g). The filtrate was concentrated in vacuo and the residue purified by column chromatography (ethyl acetate/isohexane) to give a further 2.5 g of product. The solids were combined to give the subtitle compound as a yellow solid. Yield 28.5 g. mp 148-50° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.COP([CH2:17][C:18](=[O:20])[CH3:19])(=O)OC.C([O-])([O-])=O.[K+].[K+]>O>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:17]/[C:18](=[O:20])[CH3:19]
Reactant: COP(=O)(CC(C)=O)OC
Reactant: O=Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)/C=C/c1ccc(F)cc1F
Temperature: 0 °C
Yield: 78.1 %

Procedure:
A two necked flask was charged with 2,4-difluorobenzaldehyde (4.0 g, 28.1 mmol) and (2-oxo-propyl)-phosphonic acid dimethyl ester (5.78 g, 33.0 mmol) and cooled down at at 0° C. K2CO3 (7.62 g, 55.1 mmol) in H2O (14 mL) was added dropwise. Stirring was continued over night at RT. The product was extracted with EtOAc, and the organic phase was dried over Na2SO4. Flash chromatography (SiO2, Heptane/EtOAc 1:3) afforded 4.0 g (79%) of the title compound as alight yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][C:8]2[CH:9]=[C:10]([C:17]([OH:19])=O)[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=O)=[CH:3][CH:2]=1.Cl.[CH2:21]([O:25][C:26](=[O:29])[CH2:27][NH2:28])[CH2:22][CH2:23][CH3:24]>O>[CH2:21]([O:25][C:26](=[O:29])[CH2:27][N:28]1[C:17](=[O:19])[C:10]2[C:11](=[CH:15][CH:16]=[C:8]([S:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH:9]=2)[C:12]1=[O:14])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOC(=O)CN
Reactant: O=C(O)c1ccc(Sc2ccncc2)cc1C(=O)O
Agent: Cl
Solvent: O
Product: CCCCOC(=O)CN1C(=O)c2ccc(Sc3ccncc3)cc2C1=O
Temperature: 250 °C
Yield: 69.8 %

Procedure:
A solid mixture of 4-(pyridin-4-ylsulfanyl)-phthalic acid (11.40 g) and glycine n-butyl ester hydrochloride salt (6.95 g) was heated in a oil bath (250° C.) with efficient stirring for 20 min. until the water bubble evaporation ceased. After cooling, it was partitioned between ethyl acetate (300 ml) and saturated sodium bicarbonate aqueous solution (150 ml). Two layers were separated and the aqueous layer was extracted with ethyl acetate (300 ml). Combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound 10.70 g. MS-(+)-ion: M+1=371.2.