Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[C:9]([CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:16])[C:5]1=[O:25])([CH3:3])[CH3:2].[O:26]1[C:28]2([CH2:33][CH2:32][N:31]([C:34]([O:36]C(C)(C)C)=[O:35])[CH2:30][CH2:29]2)[CH2:27]1.[CH3:41][OH:42]>>[C:34]([OH:36])(=[O:35])[C:41]([OH:16])=[O:42].[OH:26][C:28]1([CH2:27][N:22]2[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:15]([C:6]3[C:5](=[O:25])[N:4]([CH:1]([CH3:3])[CH3:2])[C:13]4[C:8]([CH:7]=3)=[C:9]([CH3:14])[CH:10]=[CH:11][CH:12]=4)=[O:16])[CH2:20][CH2:21]2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: CO
Reactant: Cc1cccc2c1cc(C(=O)NCC1CCNCC1)c(=O)n2C(C)C
Product: Cc1cccc2c1cc(C(=O)NCC1CCN(CC3(O)CCNCC3)CC1)c(=O)n2C(C)C
Product: O=C(O)C(=O)O
Temperature: 25 °C
Yield: 45 %

Procedure:
A solution of 1-isopropyl-5-methyl-2-oxo-N-(piperidin-4-ylmethyl)-1,2-dihydroquinoline-3-carboxamide (150 mg, 0.44 mmol, step 4 in preparation 3) and tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (112 mg, 0.53 mmol, Castro Jose L. et al., J. Med. Chem., 1998, 41, 2667) in methanol (5 mL) was heated at 80° C. overnight. After cooled to room temperature, concentrated gave yellow oil. The residue was chromatographed on a column of silica gel eluting with 25% ammonium hydroxide/methanol/dichloromethane (2/10/100) to give 111 mg (45%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:19])=[C:4]([C:15]([F:18])=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].C(N([CH2:25][CH3:26])CC)C.[CH2:27]([S:30](Cl)(=[O:32])=[O:31])[CH2:28][CH3:29]>ClCCl>[Cl:19][C:3]1[C:2]([N:1]([S:30]([CH2:27][CH2:25][CH3:26])(=[O:32])=[O:31])[S:30]([CH2:27][CH2:28][CH3:29])(=[O:32])=[O:31])=[CH:17][CH:16]=[C:15]([F:18])[C:4]=1[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1ccc(F)c(C(=O)OCc2ccccc2)c1Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)OCc2ccccc2)c1Cl)S(=O)(=O)CCC
Temperature: 0 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
Benzyl 3-amino-2-chloro-6-fluorobenzoate (330 mg, 1.2 mmol) was dissolved in dry dichloromethane (11.8 mL). Triethylamine (0.494 mL, 3.54 mmol) was added, and the mixture was chilled to 0° C. Propane-1-sulfonyl chloride (0.332 mL, 2.95 mmol) was then added via syringe. Once the addition was complete, the mixture was allowed to warm to ambient temperature and stir for 16 hours. The mixture was diluted with dichloromethane (11 mL) and washed with water (2×50 mL) and brine (25 mL), dried over sodium sulfate, and concentrated. The resulting residue was applied directly to a silica gel column and eluted with a gradient (5% to 40%) of ethyl acetate-hexanes to provide benzyl 2-chloro-6-fluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate (413 mg, 0.840 mmol, 71.1% yield). 1H NMR (400 MHz, d6-DMSO) δ 8.00-7.94 (q, 1H), 7.59-7.52 (t, 1H), 7.50-7.35 (m, 5H), 5.48-5.44 (s, 2H), 3.80-3.60 (m, 4H), 1.89-1.75 (m, 4H), 1.05-0.98 (t, 6H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[CH2:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.O>C(OCC)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:12][CH:11]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)[CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2CC(c3ccc(OC)cc3)C2)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Oc1ccc(C2CC(c3ccc(O)cc3)C2)cc1
Temperature: 210 °C

Procedure:
A mixture of 1,3-bis-(p-methoxyphenyl)cyclobutane (13.57 g., 0.051 mole) and pyridine hydrochloride (46.8 g., 0.41 mole) is heated at 210°C. under a nitrogen atmosphere for 30 minutes and then poured into 500 ml. of water. Several ethyl acetate extracts are taken, combined, washed (dilute HCl, water), dried (MgSO4), and evaporated. The desired product after recrystallization from benzene weighs 8.1 g. (67%), m.p. 148°-163.5°C.
Reaction SMILES: [C:1]([OH:26])(=[O:25])[CH2:2][CH2:3][C@H:4]([C@@H:6]1[C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C@H:20]([CH2:21][CH2:22]2)[C@:18]2([CH3:19])[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[CH3:5].[N+:27]([C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)([O-:29])=[O:28].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.C(OCC)(=O)C>[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([O:25][C:1](=[O:26])[CH2:2][CH2:3][C@H:4]([C@@H:6]2[C@:23]3([CH3:24])[C@H:9]([C@H:10]4[C@H:20]([CH2:21][CH2:22]3)[C@:18]3([CH3:19])[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:12][CH2:11]4)[CH2:8][CH2:7]2)[CH3:5])=[CH:32][CH:31]=1)([O-:29])=[O:28]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](CCC(=O)Oc1ccc([N+](=O)[O-])cc1)[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C

Procedure:
Cholanic acid (3.6 g, 10.0 mmoles) is suspended in methylene chloride (200 mL) and stirred well at ambient temperature. 4-Nitrophenol (1.4 g, 10.1 mmoles) and N,N′-dicylcohexylcarbodiimide (2.1 g, 10.2 mmoles) are added, and the mixture is stirred overnight. The mixture is then filtered, the solid washed with a little methylene chloride, and the filtrate is evaporated to dryness to give a yellow solid. The crude product is dissolved in ethyl acetate (100 mL). The solution is filtered and the filtrate si evaporated to give an off-white solid. The solid is crystallized from hot hexanes. The yield is 3.9 g (80%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[C:12](Cl)(=[O:16])[C:13]([CH3:15])=[CH2:14]>C1C=CC=CC=1>[C:12]([O:4][CH2:3][CH2:2][Br:1])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: C=C(C)C(=O)Cl
Reactant: OCCBr
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCBr
Temperature: 25 °C
Yield: 60.4 %

Procedure:
An egg-plant type flask which contained benzene (500 ml) was charged with 2-bromoethanol (46.7 g, 0.37 mol) and triethylamine (29.1 g, 0.29 mol) and was capped with a rubber plug. Methacryloyl chloride (30 g, 0.29 mol) was added to the flask in ice water, using a syringe while being stirred with a stirrer. The stirring was continued for some time, and then, the mixture was warmed to a room temperature and was stirred overnight. Triethylamine hydrochloride was removed by suction filtration, and the mixture was washed three times with water (300 ml) to extract the unreacted substance. The mixture was transferred to a conical flask and was dried over anhydrous sodium sulfate. The mixture was concentrated by an evaporator under reduced pressure and purified by vacuum distillation to give a colorless and clear liquid (33.8 g) (yield: 61%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[SH:11].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[Cl:5][CH2:4][CH2:3][CH2:2][S:11][C:7]1[S:6][CH:10]=[CH:9][CH:8]=1
Reactant: Sc1cccs1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: ClCCCSc1cccs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.7 mL 1-bromo-3-chloropropane was added to a mixture of 2 mL thiophen-2-thiol, 5.86 g potassium carbonate and 40 mL N,N-dimethylformamide under ice-cooling and then stirred at room temperature for 2 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated, washed with water plus brine (×2) and then with brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was evaporated. The resulting residue was purified by silica gel column chromatography (hexane) to give 4.19 g of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](C(O)=O)=[CH:7][C:6]=2[C:13]=1[O:14][CH3:15].C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[C:13]=1[O:14][CH3:15]
Reactant: COc1c(F)ccc2sc(C(=O)O)cc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: COc1c(F)ccc2sccc12
Temperature: 200 °C
Yield: 23.5 %

Procedure:
(2Z)-3-(3-Fluoro-2-methoxyphenyl)-2-mercapto-2-propenoic acid (4.865 g, 21.315 mmol) was added in one portion to a solution of iodine (8.255 g, 31.973 mmol) in dimethoxyetheane (30 mL). This was heated in the microwave with 300W at 120° C. for 25 mins. After this time the reaction was allowed to cool to room temperature and poured onto saturated sodium metabisulphite (200 mL) and ether (400 mL). Ether layer was separated and product extracted with aqueous sodium hydroxide (2 N, 2×100 mL). This was then acidified to pH 2 with aqueous hydrochloric acid (2 N, 250 mL), and product extracted with ether (2×150 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give a tan coloured solid (3.240 g, 14.322 mmol, 67%). Which was used without further purification in the next step. 5-Fluoro-4-methoxy-1-benzothiophene-2-carboxylic acid (0.883 g, 3.903 mmol) was added in one portion to DBU (2.04 mL, 13.661 mmol) and dimethyl acetamide (10 mL). This was heated in the microwave with 300 W at 200° C. for 1 h. Reaction was allowed to cool and poured onto water (100 mL). Product was extracted with hexane (2×100 mL), washed with aqueous hydrochloric acid (2 N, 50 mL), aqueous sodium hydroxide (2 N, 50 mL), and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with hexane:ethyl acetate [96:4] to give a pale yellow oil (0.167 g, 23%); δH (300 MHz, CDCl3) 7.60-6.80 (4H, m, Ar), 4.10 (3H, s, OCH3).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[CH:8]=1.Cl[C:18](=[O:26])[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23].C(Cl)Cl>ClCCCl>[O:26]=[C:18]([C:8]1[C:9]([O:15][CH3:16])=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:7]=1[O:6][CH3:5])[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: COc1cc(OC)cc(OC)c1
Reactant: COC(=O)CCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)CCCC(=O)c1c(OC)cc(OC)cc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) suspension of aluminum chloride (9.316 g; 69.87 mmol) in anh. DCE (50 ml) was treated with commercially available 1,3,5-trimethoxybenzene (7.664 g; 45.56 mmol), and stirring at 0° C., under nitrogen, was continued for 10 min. Commercially available methyl 5-chloro-5-oxopentanoate (5.000 g; 30.37 mmol) was then added, and the mixture was stirred at rt for 26 h. The resulting reaction mixture was poured onto crushed ice (150 g), and DCM (100 ml) was added. The separated aq. layer was further extracted with DCM (3×50 ml). The mixed organic layers were washed successively with water (75 ml) and brine (2×75 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=10/1 to AcOEt) afforded methyl 5-oxo-5-(2,4,6-trimethoxyphenyl)pentanoate as a yellow oil. LC-MS (conditions D): tR=0.94 min.; [M+H]+: 297.13 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:45])=[C:7]2[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][C:28]([C:31](=[O:41])[NH:32][CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])([CH3:30])[CH3:29])=[CH:16][CH:15]=3)=[C:11]([C:42]#[N:43])[CH:10]=[N:9][N:8]2[CH:44]=1)=[O:4]>C(O)(C(F)(F)F)=O.C(Cl)Cl.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:45])=[C:7]2[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][C:28]([C:31](=[O:41])[NH:32][CH2:33][C:34]([OH:36])=[O:35])([CH3:30])[CH3:29])=[CH:16][CH:15]=3)=[C:11]([C:42]#[N:43])[CH:10]=[N:9][N:8]2[CH:44]=1)=[O:4]
Reactant: COC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)NCC(=O)OC(C)(C)C)cc3)c2c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)NCC(=O)O)cc3)c2c1C
Yield: 87.8 %

Procedure:
A solution of ester 388 (292 mg, 0.476 mmol) in TFA/CH2Cl2/H2O (5 ml, 48/48/4) was stirred for 2 h at rt, concentrated and purified by silica gel flash column chromatography to afford the title compound (233 mg, 89%) as a crystalline yellow powder (4%-12% MeOH—CH2Cl2). LCMS Found: (M+H)+=558.0
Reaction SMILES: [ClH:1].N[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:6]#[N:7].N([O-])=O.[Na+].[S:18](=[O:20])=[O:19]>O.C(O)(=O)C.[Cu](Cl)Cl>[C:6]([C:5]1[CH:4]=[C:3]([S:18]([Cl:1])(=[O:20])=[O:19])[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=1)#[N:7]
Reactant: N#Cc1cc(N)cc([N+](=O)[O-])c1
Reactant: Cl
Reactant: O=S=O
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])cc(S(=O)(=O)Cl)c1
Temperature: -5 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of acetic acid (7.5 mL) and hydrochloric acid, 37% (1.5 mL) was added Intermediate 71A (1.49 g, 9.13 mmol). The suspension was cooled to −5° C. A solution of sodium nitrite (0.882 g, 12.79 mmol) in water (2 mL) was added dropwise. The resulting mixture was stirred at 0° C. for 2 hours. A mixture of copper (II) chloride (0.31 g, 2.28 mmol) in acetic acid (15 mL) was saturated with sulfur dioxide by bubbling for 40 min. The reaction mixture containing the diazonium salt was slowly poured into the copper (II) chloride-SO2 mixture. The resulting mixture was stirred at 0° C. for 30 minutes, diluted with ice-water, and extracted with DCM (three times). The combined organic layers were dried over MgSO4, filtered and concentrated to give Intermediate 71B (1.9 g, 84%) as yellow oil. HPLC: Rt=1.622 min. (CHROMOLITH® column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min., monitoring at 220 nm).
Reaction SMILES: [CH:1]1([CH2:7]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:9]=[N+:10]=[N-:11].[Na+].CS(C)=O>>[CH:1]1([CH2:7][N:9]=[N+:10]=[N-:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: BrCC1CCCCC1
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC1CCCCC1
Reaction time: 21 h

Procedure:
Cyclohexylmethyl bromide (200 mg, 1.13 mmol) was added to a stirred solution of 0.5 M sodium azide in DMSO (2.48 mL, 1.24 mmol) at room temperature, under an atmosphere of nitrogen. After 21 h, the reaction was quenched by the addition of water (5 mL) and extracted with diethyl ether (3×4 mL). The combined organic layers were washed with brine (5 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a crude oil (136 mg) which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.[NH2:15][C@@H:16]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[F:37])[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].FC1C=CC=C(F)C=1C[C@@H](C(O)=O)N.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[CH2:29][C@H:16]([NH:15][C:12]([C:9]1[S:10][CH:11]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:14])[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28]
Reactant: N[C@@H](Cc1ccc(F)cc1F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1csc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N[C@@H](Cc1c(F)cccc1F)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1nccc1-c1csc(C(=O)N[C@@H](Cc2ccc(F)cc2F)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (222 mg, 0.80 mmol) [prepared according to the procedure of Example 146], 2-[(2S)-2-amino-3-(2,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (331 mg, 0.78 mmol) [prepared according to the procedure of Preparation 18 except substituting 2,5-difluoro-L-phenylalanine (1.0 g, 4.97 mmol) for 2,6-difluoro-L-phenylalanine] and PyBrop (448 mg, 0.96 mmol) in chloroform (10 mL). DIEA (700 μL, 4.01 mmol) was added and the reaction stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (25-75% EtOAc/Hex) affording the title compound (249 mg, 0.36 mmol, 46%): LC-MS (ES) m/z=507 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([N:17]1[CH2:22][CH2:21][C:20]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([OH:23])[CH2:19][CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: OC1(c2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Reaction time: 1.5 h
Yield: 89 %

Procedure:
To a solution of 4-fluorophenylmagnesium bromide (110.0 mmol, 55.0 mL of 2.0 M solution) in 150.0 mL THF at 0° C. was added 1-benzyl-4-piperidone (55.0 mmol, 10.2 mL) dropwise. The resulting solution was stirred under argon atmosphere for 1.5 h and then quenched with 100.0 mL of saturated NH4Cl solution. The organic layer was separated and the aqueous layer was extracted with 100.0 mL of Et2O. The combined organic extracts were washed with brine, separated and dried over Na2SO4. The solution was filtered and the solvent was removed in vacuo to obtain a yellow oil which was purified by passing through a silica gel column with 4:1 hexane/EtOAc followed by 1:1 hexane/EtOAc as the eluting system. 1-Benzyl-4-(4-fluoro-phenyl)-piperdin-4-ol was obtained as a pale yellow oil in 89% yield (13.9 g). It was dissolved in 150.0 mL of toluene and p-toluenesulfonic acid monohydrate (50.0 mmol, 9.5 g) was added. The organic extracts were combined, washed with brine and the organic layer was dried over Na2SO4. The solvent was removed in vacuo to obtain 1-benzyl-4-(fluoro-phenyl)-1,2,3,6-tetrahydropyridine as a yellow viscous oil (12.0 g, 92% yield) which was used in the next step without further purification.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br.Br[CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.O>CN(C)C=O>[N:17]1[CH:18]=[CH:19][C:14]([CH2:13][S:1][C:2]2[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=2)=[CH:15][CH:16]=1
Reactant: BrCc1ccncc1
Reactant: O=C(O)c1cccnc1S
Agent: Br
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cccnc1SCc1ccncc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 61 %

Procedure:
2-Mercaptonicotinic acid (7.8 g, 50 mmol) and 4-(bromomethyl)pyridine hydrobromide (12.6 g, 50 mmol) were suspended in N,N-dimethylformamide (100 mL) under ice-cooling. Triethylamine (21 ml, 150 mmol) was added dropwise to the suspension, and the whole was stirred at room temperature for 6 hours. Water (300 mL) was added to the reaction mixture, then the aqueous layer was washed with ethyl acetate (100 mL). 2 N hydrochloric acid was added to the aqueous layer to adjust to pH 7, and the precipitated solid was filtered off. The solid was washed with water and diethyl ether, and dried at 50° C. under reduced pressure to give 7.5 g of the title reference compound as a gray solid. (Yield 61%)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[C:13]1([CH:19]=[CH:20][S:21]([NH2:24])(=[O:23])=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.IC1C=CC=CC=1OC.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:24][S:21](/[CH:20]=[CH:19]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:22])=[O:23])=[O:8])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Br)ccc1C(=O)O
Reactant: NS(=O)(=O)C=Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: COc1ccccc1I
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(Br)ccc1C(=O)NS(=O)(=O)/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-bromo-2-methoxy-benzoic acid (159 mg, 0.69 mmol) and 2-phenyl-ethenesulfonic acid amide (108 mg, 0.59 mmol) (which was prepared analogously to example 1-1 steps i) to iii) starting from iodoanisole) in dichloromethane (5 mL) and N,N-dimethylformamide (DMF) (2 mL) is added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDCI) (170 mg, 0.89 mmol) and 4-(dimethylamino)-pyridine (DMAP) (89 mg, 0.73 mmol) at RT. The mixture was stirred at RT for 20 h, and solvent removed under reduced pressure. The crude reaction mixture is partitioned between water (15 mL) and ethyl acetate (15 mL). The organic phase is separated and washed with aq. 1M HCl (4×10 mL), and the aqueous phases combined and back extracted with ethyl acetate (3×10 mL). The organic phases were combined and washed with water (15 mL), brine (2×10 mL) and dried (sodium sulfate) and concentrated in vacuo. After flash chromatography (CH2Cl2/MeOH 10:1) (E)-2-phenyl-ethenesulfonic acid 4-bromo-2-methoxy-benzoylamide can be isolated as a white solid. Yield 65 mg (24%)
Reaction SMILES: C(N(CC)[C:4](=[O:14])[C:5]1C=CC(C)=[CH:7][C:6]=1[O:12][CH3:13])C.CN(C)CCN(C)C.[C:25]([Li])([CH3:28])([CH3:27])[CH3:26].[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:33]=1[CH:34]=[O:35]>O1CCCC1.O>[CH3:26][C:25]1[CH:28]=[CH:7][C:6]([O:12][CH3:13])=[C:5]2[C:27]=1[CH:34]([C:33]1[CH:36]=[C:37]([O:40][CH3:41])[CH:38]=[CH:39][C:32]=1[O:31][CH3:30])[O:35][C:4]2=[O:14]
Reactant: CCN(CC)C(=O)c1ccc(C)cc1OC
Reactant: [Li]C(C)(C)C
Reactant: COc1ccc(OC)c(C=O)c1
Agent: CN(C)CCN(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(OC)c(C2OC(=O)c3c(OC)ccc(C)c32)c1
Temperature: -70 °C

Procedure:
2-Methoxy-4-methylbenzoic acid diethyl amide (27 g) was dissolved in dry tetrahydrofuran (250 ml) with tetramethylethylenediamine (15 g). The solution was stirred under nitrogen and cooled to -70° C. Tert-Butyl lithium (1.7N in pentane, 100 ml) was added over 15 minutes and the solution was stirred for 45 minutes. 2,5-Dimethoxybenzaldehyde (20 g) in dry tetrahydrofuran (80 ml) was added over 10 minutes. The reaction mixture was stirred for one hour at -70° C. and then allowed to warm to room temperature. After 30 minutes water (10 ml) was added and the reaction mixture was concentrated down under reduced pressure. The resulting slurry was taken up in ethyl acetate (300 ml) and washed with 0.5N HCl (aq) (300 ml) and brine. The organic phase was dried (MgSO4), filtered and concentrated to dry under reduced pressure. The resulting oil was dissolved in toluene, para-toluenesulfonic acid (1 g) was added and the solution was heated under reflux for 3 hours. The solution was allowed to cool, washed with 1N NaHCO3 (aq), dried (MgSO4) and filtered. The solution was evaporated to dryness under reduced pressure. The resulting solid was dissolved in ethyl acetate (250 ml) and hexane was added (150 ml). The solution was allowed to stand over night at -20° C. The resulting precipitate was collected by filtration and dried to give 4-methyl-7-methoxy-3-(2',5'-dimethoxyphenyl)-1-(3H)-isobenzofuranone, m.p. 121°-123° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)C1C=CC=CC=1.CS(O)(=O)=O>ClCCl.C(OCC)(=O)C>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([C:11]2[C:12]3[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=3[CH:23]=[C:9]([OH:8])[CH:10]=2)=[N:25][CH:26]=1)#[N:31]
Reactant: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(-c3ccc(C#N)cn3)c2s1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(O)cc(-c3ccc(C#N)cn3)c2s1
Reaction time: 2 h
Yield: 90.7 %

Procedure:
A stirred solution of 1-[5-Benzyloxy-7-(5-cyano-pyridin-2-yl)-benzothiazol-2-yl]-3-ethyl-urea (110 mg, 0.26 mmol) in anhydrous dichloromethane (3 ml) was treated with methanesulfonic acid (1 ml) and kept at ambient temperature for 2 h. The organic layer was diluted with ethyl acetate then washed with water (3×30 ml), dried (MgSO4) and the solvent removed in vacuo to give the crude 1-[7-(5-Cyano-pyridin-2-yl)-5-hydroxy-benzothiazol-2-yl]-3-ethyl-urea (80 mg, 90%) as an off-white solid which was used without further purification.