Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:16]([C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1F)([O-:18])=[O:17]>CN(C)C=O>[CH2:1]([NH:8][C:20]1[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a solution of 2.68 g (25,0 mmol) benzylamine in 100 ml dry dimethylformamide was added 2.55 g (25.2 mmol) dry triethylamine. A solution of 4.65 g (25.0 mmol) 2,4-dinitro-1fluorbenzen in 20 ml dry dimethylformamide was added dropwise, and the reaction mixture was stirred at 25° C. for 1 h. The mixture was evaporated, and then dissolved in 50 ml ethylacetate and washed with 100 ml water. The ethyl acetate was evaporated to give 6.1 g (89 % ) N-benzyl-2,4- dinitroaniline. M.p. 106,2° C. 1H-NMR (CDCl3): 9.1 (1H, d), 8.9 (1H, broad s), 8.2 (1H, dd), 7.3 (5H,s), 6.9 (1H, d), 4.2 (2H, d).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:22]([CH:25]4[CH2:30][CH2:29][N:28]([CH2:31][C:32]([F:35])([F:34])[F:33])[CH2:27][CH2:26]4)[N:23]=[CH:24][C:10]=13)[CH2:2]2.[CH2:36]([N:38]([CH2:41]C)CC)C.ClC(Cl)([O:46]C(=O)OC(Cl)(Cl)Cl)Cl.CN>ClCCl.O1CCCC1>[CH3:36][NH:38][C:41]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([C:13]2[N:12]=[C:11]3[N:22]([CH:25]4[CH2:26][CH2:27][N:28]([CH2:31][C:32]([F:34])([F:35])[F:33])[CH2:29][CH2:30]4)[N:23]=[CH:24][C:10]3=[C:9]([N:3]3[CH2:4][CH:5]4[O:8][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)[N:14]=2)=[CH:16][CH:17]=1)=[O:46]
Reactant: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(CC(F)(F)F)CC4)c3n2)cc1
Reactant: CCN(CC)CC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(CC(F)(F)F)CC4)c3n2)cc1

Procedure:
A solution of 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (110 mg, 0.22 mmol) in a mixture of dichloromethane (10 mL) and tetrahydrofuran (10 mL) was treated with triethylamine (0.10 mL), followed by triphosgene (100 mg, 0.34 mmol). After the passage of five minutes, 2.0 M methylamine solution in tetrahydrofuran (10 mL) was added. The mixture was concentrated to dryness under reduced pressure. The resultant residue was purified via reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 10% acetonitrile/90% of 0.1% aqueous trifluoroacetic acid to 95% acetonitrile. After the concentration of fractions under reduced pressure, 1-methyl-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}phenyl)urea was obtained. MS (ES+): 545.2 (M+H)+
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=1)[N:31]([CH2:34][CH3:35])[CH2:32][CH3:33]>CC#N>[Br-:23].[CH2:34]([N:31]([CH2:32][CH3:33])[C:30]1[CH:29]=[C:28]([O:27][CH2:26][CH2:25][CH2:24][N+:1]23[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)([CH2:3][CH2:2]2)[CH2:7][CH2:8]3)[CH:38]=[CH:37][CH:36]=1)[CH3:35]
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: CCN(CC)c1cccc(OCCCBr)c1
Solvent: CC#N
Product: CCN(CC)c1cccc(OCCC[N+]23CCC(C(O)(c4ccccc4)c4ccccc4)(CC2)CC3)c1
Product: [Br-]
Yield: 63 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0257 g, 0.0876 mmol) and 3-[(3-bromopropyl)oxy]-N,N-diethylaniline (0.0314 g, 0.110 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.032.0 g, 63.0%). EI-MS m/z 500 (M+) Rt (1.58 min).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([NH:13][N:14]([CH3:16])[CH3:15])=[O:12])[S:10][C:3]=12.[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[OH:27].C([O-])([O-])=O.[K+].[K+].O(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[O:27][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([NH:13][N:14]([CH3:16])[CH3:15])=[O:12])[S:10][C:3]=12
Reactant: CN(C)NC(=O)c1cc2nccc(Cl)c2s1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: CN(C)NC(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 170 °C
Reaction time: 12 h
Yield: 65.5 %

Procedure:
A mixture of 7-chloro-N′,N′-dimethylthieno[3,2-b]pyridine-2-carbohydrazide (237) (798 mg, 3.13 mmol), 2-fluoro-4-nitrophenol (740 mg, 4.70 mmol), K2CO3 (830 mg, 6.26 mmol) and Ph2O (4.2 mL) was stirred in a sealed tube for 12 h at 170° C. The mixture was diluted with DCM, extracted with water, the organic phase dried with anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (EtOAc/hexanes 1:1) giving 238 (772.5 mg, 2.05 mmol, 66% yield) as a brown foam. MS (m/z): (M+1) 377.0 (100%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.CN(C=O)C.F[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=1[O:26][CH3:27]>C(OCC)(=O)C.O>[N:7]1([C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=2[O:26][CH3:27])[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: COc1cc(C=O)ccc1F
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C=O)ccc1-n1ccnc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
Potassium carbonate (2.0 g) and imidazole (662 mg) were added to a DMF (20 mL) solution of 4-fluoro-3-methoxybenzaldehyde (1.50 g). The reaction solution was agitated at 80° C. overnight, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane:ethyl acetate=3:1→ethyl acetate →ethyl acetate:methanol=10:1), and 960 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [OH-:1].[K+].CCCCCC.[CH3:9][CH:10]([CH2:15][C:16](N)=[O:17])[CH2:11][CH2:12][CH2:13][CH3:14].N>C(O)C>[CH3:9][CH:10]([CH2:15][C:16]([OH:17])=[O:1])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: [OH-]
Reactant: CCCCC(C)CC(N)=O
Agent: N
Agent: [K+]
Solvent: CCCCCC
Solvent: CCO
Product: CCCCC(C)CC(=O)O

Procedure:
In this preparation 2 ml. of 30% aqueous potassium hydroxide is admixed with 0.1 mole of exobicyclo[3.1.0]hex-2-yl acetamide in 20 ml. of ethanol and warmed to 70° C and stirred at this temperature until no more ammonia evolves. The ethanol solvent is then removed by evaporation under vacuum and the residue poured into 100 ml. of water and extracted three times with ethyl ether. The aqueous solution is acidified to about pH 2 with 5N aqueous hydrochloric acid and then extracted three times with ethyl ether. The ethyl ether extracts are combined and dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under vacuum to remove the ethyl ether, affording exobicyclo[3.1.0]hex-2-yl acetic acid as a residue.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]P(=O)(OCC)OCC)[CH:5]=[CH:6][CH:7]=1.[CH3:17][N:18]1[CH:23]2[CH2:24][CH2:25][CH:19]1[CH2:20][C:21](=O)[CH2:22]2>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:21]2[CH2:22][CH:23]3[N:18]([CH3:17])[CH:19]([CH2:25][CH2:24]3)[CH2:20]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN1C2CCC1CC(=O)C2
Reactant: CCOP(=O)(Cc1cccc(Br)c1)OCC
Solvent: C1CCOC1
Product: CN1C2CCC1CC(=Cc1cccc(Br)c1)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.9 %

Procedure:
To a solution of diethyl [(3-bromophenyl)methyl]phosphonate (3.07 g, 10 mmol) in THF (20 mL) was added 8-methyl-8-azabicyclo[3.2.1]octan-3-one (1.67 g, 12 mmol) then KOBu-t (1.234 g, 11 mmol). The reaction mixture was stirred at room temperature for 5 h before it was quenched with NH4Cl (5 mL, saturated aqueous). The organic layer of the reaction mixture was separated and the aqueous layer was extracted with DCM (5 mL). The combined organic layers were loaded onto a Combiflash Redisep silica gel column (40 g) and purified by Combiflash chromatograph to afford 2.48 g (85%) of the title compound. LC-MS m/z 292 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1.O.[NH2:17][NH2:18]>C(O)C>[Cl:12][C:11]1[C:2]([NH:17][NH2:18])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)c(Cl)nc2c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1nc2ccc([N+](=O)[O-])cc2nc1Cl
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A mixture of 6.1 g (25 mmol) of 2,3-dichloro-6-nitroquinoxaline and 2.75 g (55 mmol) of hydrazine hydrate in 150 ml of ethanol was stirred at room temperature over night. The precipitate was isolated and washed with water, cold ethanol and ether to give 5.67 g (95%) of crude product.
Reaction SMILES: [C:1](C([O-])=O)([C:10]([O-:12])=[O:11])=[C:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5].[Na+].[Na+].[Na+].[Na+].Cl.C(=O)=O>O>[CH2:3]([C:4]([OH:6])=[O:5])/[C:2](/[C:7]([OH:9])=[O:8])=[CH:1]\[C:10]([OH:12])=[O:11]
Reactant: O=C([O-])CC(C(=O)[O-])=C(C(=O)[O-])C(=O)[O-]
Agent: Cl
Agent: O=C=O
Agent: [Na+]
Solvent: O
Product: O=C(O)/C=C(\CC(=O)O)C(=O)O

Procedure:
Nine grams of the product as prepared in Example XXIII, i.e. tetrasodium propene-1,1,2,3-tetracarboxylate, is dissolved in 100 mls water and acidified with dilute HCl (10%). Liberation of CO2 is instantaneous. The residue, after evaporation of water, is extracted with acetone. The acetone is evaporated to leave a residue consisting of a 1:1 by weight mixture of cis:trans aconitric acid. The structure of the product is confirmed by NMR analysis (D2O): ##STR77##
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[CH:27]=[C:26](Cl)[N:25]=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)C1O[C:36]([CH2:39][CH:40]2[O:44][CH2:43][CH2:42][O:41]2)=[CH:37][CH:38]=1)CCC.[O:53]1CCOCC1>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[CH:27]=[C:26]([C:38]5[O:53][C:39]([CH:40]6[O:41][CH2:42][CH2:43][O:44]6)=[CH:36][CH:37]=5)[N:25]=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CC2OCCO2)o1
Reactant: C1COCCO1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: c1ccc(Cn2ncc3cc(Nc4ncnc5cnc(-c6ccc(C7OCCO7)o6)cc45)ccc32)cc1

Procedure:
(1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine (4.28 g), 2-(tributylstannyl)-5-(1,3-dioxolan-2-ylmethyl)-furan (J. Chem Soc., Chem. commun., (1988), p560) (10 g) and 1,4-bis(diphenylphosphino)butane palladium (II) chloride (1 g) were heated at reflux in dioxane (150 ml) for 24 hr (Procedure B). The solvent was removed in vacuo and the residue chromatographed on silica. Subsequent trituration gave the title compound as a yellow solid: δH [2H6]-DMSO 10.46 (1H,s), 9.17 (1H,s), 8.74 (1H,s), 8.52 (1H,s), 8.23 (1H,s), 8.18 (1H,s), 7.80-7.68 (2H,m), 7.41-7.22 (5H,m), 7.17 (1H,d), 6.80 (1H,d), 6.06 (1H,s), 5.71 (2H,s), 4.20-3.96 (4H,m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][S@@](C(C)(C)C)=O)[CH3:9])=[C:4]([O:17][CH3:18])[CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[C:23]([O:26][CH3:27])=[N:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[Cl:19][C:20]1[CH:21]=[C:22]([C:2]2[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[C:4]([O:17][CH3:18])[CH:3]=2)[C:23]([O:26][CH3:27])=[N:24][CH:25]=1
Reactant: COc1cc(Br)ccc1C(C)N[S@](=O)C(C)(C)C
Reactant: COc1ncc(Cl)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc(-c2cc(Cl)cnc2OC)ccc1[C@@H](C)N
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 4-bromo-2-hydroxyacetophenone (0.460 g, 2.0 mmol), titanium tetraethoxide (1.0 g, 4.0 mmol) and (R)-2-methyl-2-propanesulfinamide (0.266 g, 2.2 mmol) in dichloromethane (3.0 ml) was heated in a microwave oven at 120° C. for 15 min. The mixture was cooled in ice and added to a stirred mixture of sodium borohydride (0.30 g, 8.0 mmol) in tetrahydrofuran (50 ml). This mixture was stirred for 1 h at ambient temperature, treated with brine (30 ml) and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and the solvent evaporated The residue was flash chromatographed on silica gel eluting with 3:1 heptane/ethyl acetate to give (R)-2-methyl-propane-2-sulfinic acid [1-(4-bromo-2-methoxy-phenyl)-ethyl]-amide. A mixture of (R)-2-methyl-propane-2-sulfinic acid [1-(4-bromo-2-methoxy-phenyl)-ethyl]-amide (0.130 g, 0.4 mmol), 5-chloro-2-methoxy-pyridine-3-boronic acid (0.150 g, 0.8 mmol), tetrakis(triphenylphosphine)palladium (0) (0.025 g, 0.02 mmol), 2M aqueous sodium carbonate solution (2 ml), toluene (1 ml) and ethanol (1 ml) was heated in a microwave oven at 120° C. for 15 min. The mixture was partitioned between ethyl acetate and dilute aqueous sodium carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the solvent evaporated and the residue dissolved in methanol. This solution was treated with 2M hydrogen chloride in diethyl ether solution. After standing for 2 hours, the mixture was poured onto an SCX column, washed with methanol and then eluted with 1M ammonia in methanol solution. The solvent was evaporated and the residue flash chromatographed on silica gel eluting with 98:2 ethyl acetate/2M ammonia in methanol to give (R)-1-[4-(5-chloro-2-methoxy-pyridin-3-yl)-2-methoxy-phenyl]-ethylamine. The title compound was prepared in a similar manner to 1-methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonic acid [1-(3,5′-difluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (Example 30) using (R)-1-[4-(5-chloro-2-methoxy-pyridin-3-yl)-2-methoxy-phenyl]-ethylamine instead of 1-(3,5′-difluoro-2′-methoxy-biphenyl-4-yl)-ethylamine. MS (ESI) m/z: 505.0 [M+H]+.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2[N:20]3[CH:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:19]3[C:18](Cl)=[N:17][N:16]=2)[CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCOCC1>[CH2:31]([NH:38][C:18]1[C:19]2[N:20]([CH:21]=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15]([C:13]2[CH:14]=[C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])[CH:10]=[N:11][CH:12]=2)=[N:16][N:17]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(Cl)c3c(-c4ccccc4)ccn23)c1
Reactant: NCc1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)ccn23)c1
Temperature: 100 °C
Yield: 129.5 %

Procedure:
To a solution of N-(tert-butyl)-5-(1-chloro-8-phenylpyrrolo[1,2-d][1,2,4]triazin-4-yl)pyridine-3-sulfonamide (0.100 g, 0.226 mmol) in 1,4-dioxane (10 mL) was added benzylamine (0.124 mL, 1.13 mmol) at room temperature. The resulting reaction mixture was heated at 100° C. for 12 h in a sealed tube. The reaction mixture was diluted with ice cold water (150 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give a residue which was purified by silica gel column chromatography using CombiFlash (REDISEP®, silica gel, 12 g, 50% EtOAc/hexanes) to yield 5-(1-(benzylamino)-8-phenylpyrrolo[1,2-d][1,2,4]triazin-4-yl)-N-(tert-butyl)pyridine-3-sulfonamide (0.150 g, 33.0%). LCMS Method B-4: retention time 1.15 min, [M+1]=513.43. 1H NMR (400 MHz, DMSO-d6) δ ppm: 1.17 (s, 9H), 4.31 (d, J=5.2 Hz, 2H), 5.65 (t, J=5.2 Hz, 1H), 6.96 (d, J=2.8 Hz, 1H), 7.22-7.35 (m, 5H), 7.42-7.44 (m, 1H), 7.47-7.50 (m, 2H), 7.55-7.57 (m, 2H), 7.69 (d, J=2.8 Hz, 1H), 7.75 (s, 1H), 8.65 (t, J=2.0 Hz, 1H), 9.12 (d, J=2.0 Hz, 1H), 9.34 (d, J=2.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH2:28][CH2:29]CO)[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[CH2:32]([N:34]([CH:38]([CH3:40])C)[CH:35](C)C)[CH3:33].CS(Cl)(=O)=[O:43].[Cl-].[NH4+]>O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH2:28][CH2:29][CH2:35][N:34]5[CH2:38][CH2:40][O:43][CH2:33][CH2:32]5)[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2cc1OCCCO
Reactant: CCN(C(C)C)C(C)C
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2cc1OCCCN1CCOCC1
Reaction time: 1 h
Yield: 26.5 %

Procedure:
To a mixture of 0.070 g (0.15 mmole) of 4-(3-chloro-phenyl)-2-[6-(3-hydroxy-propoxy)-5-methoxy-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.42a), 0.039 g (0.30 mmole) of ethyldiisopropylamine and 3 mL of dimethylformamide at 0 degrees was added 0.021 g (0.18 mmole) of methanesulfonyl chloride. Stirring was continued for 1 hour and then 1 mL of saturated ammonium chloride solution was added. The mixture was poured into 25 mL of water and extracted three times with 20 mL of ethyl acetate. The combined organic extracts were washed three times with 25 mL of water, once with 25 mL of saturated sodium bicarbonate solution, once with 25 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was heated at 80 degrees for 1 hour with 2 mL of dimethylformamide and 0.080 mL of morpholine. The cooled mixture was poured into 25 mL of water and extracted three times with 20 mL of ethyl acetate. The combined organic extracts were washed three times with 25 mL of water, once with 25 mL of saturated sodium bicarbonate solution, once with 25 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (8:92) to give 0.021 g of 4-(3-chloro-phenyl)-2-[5-methoxy-6-(3-morpholin-4-yl-propoxy)-benzoimidazol-1-yl]-thiazole 5-carboxylic acid amide (I.43) as a pink solid. MH+/Z=528
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:35]=[CH:34][C:17]([CH2:18][N:19]4[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[C:21]([C:29]5[S:30][CH:31]=[CH:32][CH:33]=5)=[N:20]4)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:35]=[CH:34][C:17]([CH2:18][N:19]4[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[C:21]([C:29]5[S:30][CH:31]=[CH:32][CH:33]=5)=[N:20]4)=[CH:16][CH:15]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Temperature: 80 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
A mixture of ethyl 1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylate (750 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at 80° C. for 5 hours. After cooling, 1N hydrochloric acid (3 ml) was added to the mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylic acid (640 mg, yield: 90%). This was recrystallized from acetone-hexane. Melting point: 187˜188° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: OCc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.8 %

Procedure:
At 0° C., 859 ml (859 mmol) of a 1 M solution of borane-tetrahydrofuran complex in tetrahydrofuran are added dropwise to 110 g (573 mmol) of 5,6-dichloronicotinic acid in 250 ml of tetrahydrofuran. The mixture is warmed to room temperature and stirred at this temperature for 3 hours. After cooling to 0° C., the reaction mixture is made alkaline using saturated aqueous potassium carbonate solution, most of the tetrahydrofuran is removed using a rotary evaporator and the residue is extracted repeatedly with ethyl acetate. The combined organic phases are washed with water and saturated aqueous sodium chloride solution and dried over sodium sulphate. Concentration under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (1:2) gives 62 g (61% of theory) of (5,6-dichloropyridin-3-yl)methanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([NH:11][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]([C:22](Cl)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([N:11]([C:22]([C:17]3[C:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:23])[CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2CNC2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2CN(C(=O)c3ccccc3-c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.2 %

Procedure:
3,8-Diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester (Intermediate 1, 300 mg, 1.42 mmol), biphenyl-2-carbonyl chloride (429 mg, 1.98 mmol) and tri-ethyl amine (0.6 mL, 3.95 mmol) were dissolved into DCM (5 mL) and stirred at room temperature for 18 h. The reaction mixture was diluted with DCM (25 mL) and washed with 1N NaOH (10 mL) and water (2×20 mL). The organic layers were combined, dried, filtered and concentrated under reduced pressure to yield 8-(Biphenyl-2-carbonyl)-3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester (380 mg, 68.6%). MS (ESI) mass calcd. for C24H28N2O3, 392.49; m/z found, 293.2 [M+H]+ (mass without Boc group). 1H NMR (CDCl3): 7.57-7.30 (m, 9H), 4.60-4.35 (m, 0.5H), 4.17-3.98 (m, 0.5H), 3.90-3.71 (m, 1H), 3.60-3.25 (m, 3H), 3.22-2.66 (m, 2H), 2.54-2.38 (m, 0.5H), 2.37-2.22 (m, 0.5H), 2.10-1.92 (m, 0.5H), 1.85-1.56 (m, 1.5H), 1.55-1.27 (m, 9H).