Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8](C(O)=O)=[CH:7][CH:6]=1)=[O:4].[C:14]1([S:20]([NH2:23])(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.Cl.[C:36](OCC)(=[O:38])C>ClCCl.CN(C1C=CN=CC=1)C>[C:14]1([S:20]([NH:23][C:8]2[CH:7]=[CH:6][CH:5]([C:3]([O:2][CH3:1])=[O:4])[C:13](=[C:36]=[O:38])[CH:12]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(C)=O
Reactant: NS(=O)(=O)c1ccccc1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C1C=CC(NS(=O)(=O)c2ccccc2)=CC1=C=O
Reaction time: 18 h
Yield: 98 %

Procedure:
4-Methoxycarbonyl-benzoic acid (from Preparation 11) (5.0 g, 28 mmol) was dissolved in 100 mL of anhydrous dichloromethane. After the addition of DMAP (3.39 g, 28 mmol) and benzenesulfonamide (4.36 g, 28 mmol), EDCI (5.85 g, 31 mmol) was gradually added to the stirred mixture. After 18 hours at room temperature, rotary evaporation of the mixture gave a residue which was mixed with ethyl acetate and 1 N HCl. The organic phase was washed with water (1×) and brine (2×), dried (Na2SO4), rotary evaporated, and dried at high volume to afford 8.7 g (98%) of methyl 4-phenylsulfonamido-carbonyl-benzoate (4-C6H5SO2 --NHCO--C6H4 --COOCH3) as a white solid. A solution of this material (3.2 g, 10 mmol) in 130 mL of dioxane/water (3:1) was cooled to 0° C. 1 N Sodium hydroxide was added dropwise, followed by vigorous stirring at 0° C. for 20 minutes, then at room temperature for 2 hours. The mixture was again cooled to 0° C., and then acidified to pH 2 by gradual addition of 1 N HCl. The mixture was rotary evaporated, and the aqueous residue was extracted with ethyl acetate (3×). The combined extracts were washed with brine, dried (Na2SO4), rotary evaporated, and dried at high vacuum to afford the product (4-C6H5SO2NHCO--C6H4 --COOH), m.p. 267°-270° C.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([NH2:13])=[CH:5][N:4]=1)#[N:2].[C:14](Cl)(Cl)=[S:15]>O>[N:13]([C:6]1[CH:7]=[C:8]([C:9]([F:12])([F:10])[F:11])[C:3]([C:1]#[N:2])=[N:4][CH:5]=1)=[C:14]=[S:15]
Reactant: S=C(Cl)Cl
Reactant: N#Cc1ncc(N)cc1C(F)(F)F
Solvent: O
Product: N#Cc1ncc(N=C=S)cc1C(F)(F)F
Yield: 74 %

Procedure:
A solution of 2-hydroxy-3-(trifluoromethyl)pyridine C in a mixture of N-iodosuccinimide (NIS), acetonitrile, and dimethylformamide (DMF) is heated at 80° C. for 2 hours to produce 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I (greater than 80% yield). The 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I is then mixed with POCl3 in DMF and heated to 130° C. in a microwave for 20 minutes to produce 2-chloro-3-trifluoromethyl-5-(iodo)pyridine J (yield of 50 to 55%). The 2-chloro-3-trifluoromethyl-5-(iodo)pyridine K is reacted in a solution of pMBnNH2, palladium(II)acetate, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), triethylamine, and cesium carbonate in toluene to produce 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K (yield of 40%). The 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K is reacted in a solution of zinc cyanide, tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), and 1,1′-bis(diphenylphosphino)ferrocene (dppf) in DMF to provide 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K (yield of 92%). The 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K is reacted in a solution of dichloromethane and trifluoroacetic acid to provide 2-cyano-3-trifluoromethyl-5-(amino)pyridine H (yield greater than 95%). The 2-cyano-3-trifluoromethyl-5-(amino)pyridine H is reacted with thiophosgene in water at 25° C. for 2 hours to provide 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile A (yield of 74% to 95%).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9](CC1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[NH2:45][C:46]1[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=1.N[C:53]1C=CC=C[CH:54]=1>>[CH:8]12[N:7]([C:13]3[N:18]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:45][C:46]5[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=5)=[O:27])=[CH:23][CH:24]=4)[N:16]=[C:15]4[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=34)[CH:6]([CH2:53][CH2:54]1)[CH2:5][O:12][CH2:9]2
Reactant: Nc1ccccc1
Reactant: Nc1ccncc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Product: CCn1ncc2c(N3C4CCC3COC4)nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-aminopyridine as the aniline component. (15%, MS=471.4 (M+H))
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=1)=O.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:1][C:3]2[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=2)[CH2:15][CH2:14]1
Reactant: O=Cc1cccc(C(=O)O)n1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCN(Cc2cccc(C(=O)O)n2)CC1
Reaction time: 8 h

Procedure:
To a solution of 6-formyl-2-pyridinecarboxylic acid [Chemstep Product List] (0.25 g) in dichloromethane (6.8 ml) was added 1-methylpiperazine (0.481 ml) and acetic acid (0.083 ml). The mixture was stirred at room temperature for 15 min when sodium triacetoxyborohydride (0.459 g) was added and the mixture stirred overnight. The crude reaction mixture was diluted with dichloromethane (60 ml) and methanol was added until a clear solution was observed. The mixture was loaded onto an aminopropyl-SPE cartridge (5 g) pre-eluted with dichloromethane. The cartridge was eluted with dichloromethane and methanol and fractions containing product were combined and blown to dryness under a stream of nitrogen. The crude product was taken up in dichloromethane (2×25 ml) and washed with 2M sodium hydroxide solution (25 ml). The aqueous layer was acidified to pH7 using 5N hydrochloric acid and concentrated under vacuum to approximately 25 ml. The solution was loaded onto an Oasis cartridge (6 g) and eluted with water (one volume) and methanol. Fractions containing product were combined and dried to give the title compound (0.171 g).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:16])[N:6]1[CH2:15][CH2:14][NH:13][CH2:12][CH:7]12.[CH:19](O)=O.C=O>O.C(=O)(O)[O-].[Na+]>[CH3:19][N:13]1[CH2:14][CH2:15][N:6]2[C:5](=[O:16])[C:4]3[C:8]([CH:7]2[CH2:12]1)=[CH:9][CH:10]=[CH:11][C:3]=3[C:2]([F:17])([F:1])[F:18]
Reactant: O=C1c2c(cccc2C(F)(F)F)C2CNCCN12
Reactant: O=CO
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCN2C(=O)c3c(cccc3C(F)(F)F)C2C1
Temperature: 60 °C
Yield: 53.1 %

Procedure:
To a stirring solution of (±)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (60 mg, 0.23 mmol) in water (1 mL) was added formic acid (0.22 mL, 5.9 mmol) and formaldehyde (190 mg, 2.3 mmol; 37% sol. in water). The reaction flask was sealed with a rubber septum (no nitrogen inlet) and warmed to 60° C. The reaction was maintained at this temperature for 24 h and was then cooled. The reaction was then diluted with saturated aqueous sodium bicarbonate, washed with ethyl acetate (3×50 mL), and the combined organic layers were dried over sodium sulfate, filtered, an concentrated. The resulting residue was purified by radial chromatography (2% ammonium hydroxide in 8% methanol in dichloromethane) to afford the desired product (33 mg, 52%) as a pale yellow residue. MS (ESI) 271.6 (M+H).
Reaction SMILES: CC1(C)C(C)(C)OB(C2C=[CH:11][C:12]3[N:13]([C:31]4[C:40]5[C:35](=CC=CC=5)[CH:34]=CC=4)[C:14]4[C:19]([C:20]=3C=2)=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=4)O1.Br[C:43]1[CH:44]=[CH:45][C:46]([C:49]2[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=2)=[N:47][CH:48]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1[CH2:68][CH2:67]OCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N:47]1[CH:48]=[C:43]([C:17]2[CH:16]=[CH:15][C:14]3[N:13]([C:31]4[C:67]5[C:68](=[CH:11][CH:12]=[CH:20][CH:19]=5)[CH:34]=[CH:35][CH:40]=4)[C:12]4[C:20]([C:19]=3[CH:18]=2)=[CH:16][C:15]([C:43]2[CH:44]=[CH:45][C:46]([C:49]3[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=3)=[N:47][CH:48]=2)=[CH:14][CH:11]=4)[CH:44]=[CH:45][C:46]=1[C:49]1[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=1
Reactant: CC1(C)OB(c2ccc3c(c2)c2cc(B4OC(C)(C)C(C)(C)O4)ccc2n3-c2cccc3ccccc23)OC1(C)C
Reactant: Brc1ccc(-c2cccnc2)nc1
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: c1cncc(-c2ccc(-c3ccc4c(c3)c3cc(-c5ccc(-c6cccnc6)nc5)ccc3n4-c3cccc4ccccc34)cn2)c1
Temperature: 25 °C

Procedure:
Into a flask, 1.50 g of 3,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-9-naphthalene-1-yl-carbazole, 1.32 g of 5-bromo-2,3′-bipyridine, 194 mg of Pd(PPh3)4, 2.40 g of tripotassium phosphate, 25 ml of 1,4-dioxane, and 5 ml of water were put, and the solution was stirred at reflux temperature for 10 hours under argon atmosphere. After heating, the reaction liquid was cooled to room temperature, and washed by a saturated sodium chloride aqueous solution. The organic layer was concentrated in an evaporator, and the concentrates were washed by methanol. After washing, the concentrates were purified by silica gel column chromatography, recrystallized in a chloroform/ethyl acetate mixed solvent, and thus 475 mg of 3,6-bis(2,3′-bipyridine-5-yl)-9-naphthalene-1-yl-carbazole was obtained.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[C:5]([CH3:8])=[N:4][CH:3]=1.[CH2:9]([Sn:13]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])Cl)[CH2:10][CH2:11][CH3:12]>>[CH3:7][N:6]1[C:2]([Sn:13]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:9][CH2:10][CH2:11][CH3:12])=[CH:3][N:4]=[C:5]1[CH3:8]
Reactant: Cc1ncc(Br)n1C
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(C)n1C

Procedure:
The title compound was prepared following a similar procedure to previous example using 5-bromo-1,2-dimethyl-1H-imidazole and tributylchlorostannane.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[F:21][C:22]([C:25]1[CH:26]=[N:27][CH:28]=[C:29]([CH:32]=1)[CH:30]=O)([CH3:24])[CH3:23].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(O)(=O)C.CCOC(C)=O>[F:21][C:22]([C:25]1[CH:32]=[C:29]([CH2:30][NH:1][CH2:2][C@@H:3]([OH:20])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:28]=[N:27][CH:26]=1)([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN
Reactant: CC(C)(F)c1cncc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNCc1cncc(C(C)(C)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
A solution of tert-butyl (2S,3R)-4-amino-3-hydroxy-1-phenylbutan-2-ylcarbamate (297 mg, 1.06 mmol) in THF was added 5-(2-fluoropropan-2-yl)nicotinaldehyde (180 mg, 1.06 mmol) and stirred for 30 min at room temperature, NaB(OAc)3H (460 mg, 2.12 mmol) was then added portionwise in 30 min., finally 5 drops of acetic acid was added and the resulting mixture was stirred at the same temperature overnight. The reaction mixture was diluted with EtOAc, and washed with saturated aqueous NaHCO3. The organic layer was separated and dried (MgSO4). Concentration in vacuo, followed purification with flash chromatography to give tert-butyl (2S,3R)-4-((5-(2-fluoropropan-2-yl)pyridin-3-yl)methylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate as a white solid (230 mg, 70% yield). 1H NMR (CDCl3): d: 8.776 (d, J=11.5 Hz, 2H), 7.952 (s, 1H), 7.330-7.205 (m, 5H), 4.823 (d, J=7.7 Hz, 1H), 3.900 (s, 2H), 3.842 (m, 1H), 3.586 (m, 1H), 2.995 (m, 1H), 2.856 (m, 1H), 2.762 (m, 2H), 1.363 (s, 9H).
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@:3]1([CH3:26])[C:9]1[CH:10]=[N:11][N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[C:21][Si](C)(C)C)[CH:15]=2)[CH:13]=1.C[O-].[Na+].C(=O)=O>CO.O.ClCCl>[C:20]([C:16]1[CH:15]=[C:14]([N:12]2[CH:13]=[C:9]([C@:3]3([CH3:26])[C:2]([F:1])([F:27])[CH2:7][O:6][C:5]([NH2:8])=[N:4]3)[CH:10]=[N:11]2)[CH:19]=[CH:18][CH:17]=1)#[CH:21]
Reactant: C[C@]1(c2cnn(-c3cccc(C#C[Si](C)(C)C)c3)c2)N=C(N)OCC1(F)F
Agent: C[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: C#Cc1cccc(-n2cc([C@@]3(C)N=C(N)OCC3(F)F)cn2)c1
Yield: 51.8 %

Procedure:
A solution of (R)-5,5-difluoro-4-methyl-4-(1-(3-((trimethylsilyl)ethynyl)phenyl)-1H-pyrazol-4-yl)-5,6-dihydro-4H-1,3-oxazin-2-amine (68.6 mg, 177 μmol) in methanol (2 ml) was treated at room temperature with sodium methoxide (5.4M in methanol; 1 μl, 5.4 μmol). After 90 minutes a small quantity of dry ice was added to neutralize the reaction mixture. After evaporation at reduced pressure the residue thus obtained was dissolved in a mixture of water and dichloromethane. The aqueous layer was extracted with dichloromethane, thereafter, the combined organic layers were washed with water, dried over sodium sulphate, and evaporated. The residue was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 0:100 as the eluent. The (R)-4-[1-(3-ethynyl-phenyl)-1H-pyrazol-4-yl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (29 mg, 52% yield) was obtained as a light yellow solid. MS (ISP): m/z=317.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br.Cl[C:13]1[N:18]2[C:19]([CH3:23])=[C:20]([CH3:22])[N:21]=[C:17]2[CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[C:4]1([CH2:3][O:10][C:13]2[N:18]3[C:19]([CH3:23])=[C:20]([CH3:22])[N:21]=[C:17]3[CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1nc2cccc(Cl)n2c1C
Reactant: OCc1ccccc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2cccc(OCc3ccccc3)n2c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (50% in oil, 4.8 g) is added to a solution of benzyl alcohol(6.48 g) in dimethylformamide (200 ml). 5-chloro-2,3-dimethylimidazo[1,2-a]pyridine hydrobromide (10.5 g) is addedand the mixture is stirred at room temperature for two hours.
Reaction SMILES: [OH:1][C@@:2]1([CH2:16][CH2:17]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:7][C@H:6]2[CH2:8][CH2:9][C@@H:3]1[CH:4]=[C:5]2[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[CH2:38][CH2:39][CH2:40][NH:41][CH3:42]>CCN(C(C)C)C(C)C>[NH:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[CH2:38][CH2:39][CH2:40][N:41]([CH3:42])[CH2:17][CH2:16][C:2]1([OH:1])[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]2[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@]2(O)C[C@H]3CC[C@@H]2C=C3c2ccccc2)cc1
Reactant: CNCCCc1nc2ccccc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCc1nc2ccccc2[nH]1)CCC1(O)CC2CCC1C=C2c1ccccc1
Temperature: 110 °C
Yield: 28.4 %

Procedure:
A mixture of 115 mg of rac-toluene-4-sulfonic acid (1R*,2R*,4R*)-2-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-ethyl ester and 55 mg of [3-(1H-benzoimidazol-2-yl)-propyl]-methyl-amine in 2 mL of DIPEA was heated to 110° C. for 30 min. The reaction mixture was cooled to rt, quenched with MeOH-water and extracted with EtOAc. The organic phase was separated, dried and evaporated and the residue was purified by CC with EtOAc-MeOH (3:1) to give 34 mg of rac-(1R*,2R*,4R*)-2-(2-{[3-(1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol as beige foam.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.[CH3:15][C:16]1[C:17]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:26]2[CH2:27][CH2:28][N:23]([C:17]3[C:16]([CH3:15])=[CH:21][C:20]([CH3:22])=[CH:19][N:18]=3)[CH2:24][CH2:25]2)=[O:8])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 68.4 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 4-bromo-2-methanesulfonylbenzoic acid (2.79 g) and 1-(3,5-dimethylpyridin-2-yl)piperazine (1.91 g) described in Preparation Example 47, the title compound (3.09 g) was obtained. MS (ESI) m/z:452(M+H)+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10](O)([CH3:12])[CH3:11])=[N:6][C:5]=12.C(N(S(F)(F)[F:20])CC)C>ClCCl>[F:20][C:10]([C:7]1[CH:8]=[CH:9][N:4]2[CH:3]=[CH:2][N:1]=[C:5]2[N:6]=1)([CH3:12])[CH3:11]
Reactant: CC(C)(O)c1ccn2ccnc2n1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(F)c1ccn2ccnc2n1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 17.3 %

Procedure:
To a cooled (−78° C.) suspension of 2-(imidazo[1,2-α]pyrimidin-7-yl)propan-2-ol (1.02 mg, 5.8 mmol) in dichloromethane (25 ml) was added (diethylamino)sulfur trifluoride (1.22 mg, 7.5 mmol) dropwise over 5 min. The mixture was stirred at −78° C. for 40 min then quenched with methanol (1 ml). The mixture was warmed to ambient temperature, made basic with saturated sodium hydrogencarbonate solution (25 ml) and extracted with dichloromethane (2×25 ml). The combined organics were washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated to dryness. Purification of this material by chromatography on silica eluting with dichloromethane (containing 0.5% conc. ammonia) on a gradient of methanol (1-3%) gave 7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidine (180 mg, 17%) as a yellow solid: δH (360 MHz, CDCl3) 1.78 (6H, d, J 22), 7.21 (1H, dd, J 7 and 1), 7.54 (1H, d, J 1), 7.79 (1H, d, J 1), 8.45 (1H, d, J 7).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:42])[CH2:10][C:11]1[CH:41]=[CH:40][C:14]2[CH:15]=[C:16]([C:18]([NH:20][C:21]3[C:25]([NH:26]C(=O)OC(C)(C)C)=[CH:24][N:23]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:22]=3)=[O:19])[S:17][C:13]=2[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(OCC)(=O)C.CO.O1CCOCC1>[NH2:26][C:25]1[C:21]([NH:20][C:18]([C:16]2[S:17][C:13]3[CH:12]=[C:11]([CH2:10][C:9]([NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:42])[CH:41]=[CH:40][C:14]=3[CH:15]=2)=[O:19])=[N:22][N:23]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1cn(-c2ccccc2)nc1NC(=O)c1cc2ccc(CC(=O)NCc3ccccc3)cc2s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cn(-c2ccccc2)nc1NC(=O)c1cc2ccc(CC(=O)NCc3ccccc3)cc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
To a solution of crude tert-butyl {3-[({6-[2-(benzylamino)-2-oxoethyl]-1-benzothien-2-yl}carbonyl)amino]-1-phenyl-1H-pyrazol-4-yl}carbamate (from step A) in ethyl aceate (10 mL) and methanol (10 mL) was added 4M HCl in dioxane (10 mL) and the resulting solution was stirred for 16 hours at ambient temperature. The reaction was evaporated to dryness and purified by reverse phase LC to give 148 mg (40%, 2 steps) of N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-6-[2-(benzylamino)-2-oxoethyl]-1-benzothiophene-2-carboxamide as a white solid. 1H NMR (DMSO-d6) δ 11.01 (s, 1H), 8.59 (t, J=5.87 Hz, 1H), 8.35 (s, 1H), 7.89 (t, J=3.82 Hz, 2H), 7.80 (s, 1H), 7.67 (d, J=7.92 Hz, 2H), 7.42 (t, J=7.33 Hz, 2H), 7.36 (d, J=9.1 Hz, 1H), 7.28 (t, J=7.92 Hz, 2H), 7.19 (m, 4H), 4.25 (d, J=5.87 Hz, 2H), 3.61 (s, 2H). ESIMS calcd 482.2 (M++H), found 482.1 (M++H).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH2:22])[CH:10]=[C:11](S([O-])(=O)=O)[C:12]=3[OH:17])[C:7](=[O:23])[C:6]=2[C:5]([OH:24])=[C:4](S([O-])(=O)=O)[CH:3]=1.[Na+].[Na+].[CH2:31]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:32][CH2:33][CH3:34]>B(O)(O)O.S(=O)(=O)(O)O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH2:22])[CH:10]=[CH:11][C:12]=3[OH:17])[C:7](=[O:23])[C:6]=2[C:5]([OH:24])=[CH:4][C:3]=1[C:39]1[CH:40]=[CH:41][C:36]([O:35][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:37][CH:38]=1
Reactant: CCCCOc1ccccc1
Reactant: Nc1cc(S(=O)(=O)[O-])c(O)c2c1C(=O)c1c(O)c(S(=O)(=O)[O-])cc(N)c1C2=O
Agent: O=S(=O)(O)O
Agent: OB(O)O
Agent: [Na+]
Product: CCCCOc1ccc(-c2cc(O)c3c(c2N)C(=O)c2c(O)ccc(N)c2C3=O)cc1
Temperature: 80 °C

Procedure:
4.0 g of sodium 4,8-diamino-1,5-dihydroxy-anthraquinone-2,6-disulfonate is dissolved in a mixture of 2.0 g of boric acid and 30 ml concentrated sulphuric acid heated to 80° C. The blue solution obtained is cooled to a temperature of 0° to 5° C., and 2.8 g of butoxybenzene is stirred in drop by drop, the colour then changing from blue to reddish brown. The mixture is agitated for a further two hours at 0° to 10° C., then poured onto ice. The suspension obtained is heated on reflux for 4 hours to destroy the boric ester, and a violet precipitate is filtered off after cooling, corresponding to 4,8-diamino-1,5-dihydroxy-3-p-butoxyphenyl-anthraquinone-6-sulphonic acid. The moist precipitate is dissolved hot in a mixture of 24 ml of 33% ammonia and 160 ml of water, and the sulphonic groups are separated by adding 2.2 g of sodium dithionate in stages. The mixture is finally heated to 95° C. for approximately 2 hours, then cooled and filtered. The precipitate thus obtained is washed with slightly acidified water, then with a great excess of water, and dried. The desired product may further be purified by crystallisation or chromatography if necessary.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[H][H].[Cl:11][C:12]([Cl:16])=[CH:13][CH2:14]Cl>O>[Cl:11][C:12]([Cl:16])=[CH:13][CH2:14][O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6]
Reactant: ClCC=C(Cl)Cl
Reactant: [H][H]
Reactant: OCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: OCCCCOCC=C(Cl)Cl
Temperature: 60 °C
Reaction time: 3 h
Yield: 14 %

Procedure:
In a reaction vessel containing 9.02 g of 1,4-butanediol was put 2.20 g of 60% sodium hydride (in oil), and the mixture was stirred until the evolution of hydrogen gas ceased, to which 7.28 g of 1,1,3-trichloro-1-propene was added dropwise under ice cooling. The reaction mixture was slowly warmed and stirred at 60° C. for 3 hours, which was then poured into water and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over magnesium sulfate and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 1.40 g of 4-(3,3-dichloro-2-propenyloxy)butanol (yield, 14%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11].[CH2:15]([O:17][CH:18](OCC)OCC)[CH3:16].[C:25](OC(=O)C)(=O)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:9](=[CH:18][O:17][CH2:15][CH3:16])[C:10]([O:12][CH2:13][CH3:25])=[O:11])=[O:14]
Reactant: CCOC(OCC)OCC
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CC(=O)c1ccccc1Cl
Product: CCOC=C(C(=O)OCC)C(=O)c1ccccc1Cl
Temperature: 130 °C
Reaction time: 2 h

Procedure:
To a flask containing 3-(2-chlorophenyl)-3-oxo-propionic acid, methyl ester (20 g, 94 mmol) was added triethylorthoformate (37.5 mL, 225.6 mmol) and acetic anhydride (63 mL, 667 mmol). The resulting mixture was heated to 130° C. with stirring for a total of 2 hours, then stirred over night at room temperature. The reaction mixture was concentrated under reduced pressure to provide a crude oil, which was used directly in the next step.