Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][C:13]([CH2:19]O)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([Cl:30])(=O)=O)=CC=1.C(N(CC)CC)C.O>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][C:13]([CH2:19][Cl:30])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1=Cc2cccc(OCc3ccccc3)c2CC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCC1=Cc2cccc(OCc3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.5 %

Procedure:
Under an argon atmosphere, to a solution of 1.82 g of 5-(benzyloxy)-2-(hydroxymethyl)-3,4-dihydronaphthalene and 0.55 g of 4-(dimethylamino)pyridine in 30 ml of dichloromethane, 1.43 g of p-toluenesulfonyl chloride was added. After 1.2 ml of triethylamine was added dropwise, the mixture was stirred at room temperature for 1.5 hours. The reaction solution was poured into iced water and then extracted with diethyl ether. The extract was washed in turn with 5% hydrochloric acid, water and an aqueous saturated sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.06 g of the desired compound as a colorless oily substance.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH2:5]([N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)[CH3:6]>C(OCC)C>[C:1]([O-:4])(=[O:3])[CH3:2].[CH2:5]([N+:7]1[CH:11]=[CH:10][NH:9][CH:8]=1)[CH3:6]
Reactant: CCn1ccnc1
Reactant: CC(=O)O
Solvent: CCOCC
Product: CC(=O)[O-]
Product: CC[n+]1cc[nH]c1

Procedure:
First, 6 ml of 99.7% acetic acid was added to 10 g of N-ethylimidazole, and the resultant mixture was stirred for 12 hours at a temperature kept at 0° C. The resultant reaction product was added dropwise to 1000 ml of diethyl ether under stirring. The diethyl ether was distilled off at room temperature, and the residue was dried under vacuum to precipitate crystals. The precipitated crystals were recovered to obtain 15.9 g of N-ethylimidazolium acetate. The product had a glass transition temperature of −51.7° C.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[S:9]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]([S:19](Cl)(=[O:21])=[O:20])=[CH:16][CH:15]=2)=[CH:10]1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:19]([C:17]1[S:18][C:14]([C:11]2[CH:12]=[CH:13][S:9][CH:10]=2)=[CH:15][CH:16]=1)(=[O:20])=[O:21]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(-c2ccsc2)s1
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3ccsc3)s2)c1Br
Yield: 40 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-thienyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-(3-thienyl)thiophene-2-sulfonyl chloride in 40% yield. This was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) to give a solid.
Reaction SMILES: [C:1]([CH:7]1[CH2:12][CH2:11][N:10]([CH:13]2[C:23]3[C:24]4[C:16](=[C:17]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[NH:18][C:19]=4[CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:14]2)[CH2:9][CH2:8]1)([C:3](OC)=[O:4])=[O:2].[BH4-].[Li+].O>O1CCCC1>[OH:4][CH2:3][C:1]([CH:7]1[CH2:8][CH2:9][N:10]([CH:13]2[C:23]3[C:24]4[C:16](=[C:17]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[NH:18][C:19]=4[CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:14]2)[CH2:11][CH2:12]1)=[O:2]
Reactant: COC(=O)C(=O)C1CCN(C2CCc3c(-c4ccccc4)[nH]c4cccc2c34)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CO)C1CCN(C2CCc3c(-c4ccccc4)[nH]c4cccc2c34)CC1
Reaction time: 0.08 h
Yield: 48.4 %

Procedure:
To a suspension of the compound (100 mg) obtained in Example 157 in anhydrous tetrahydrofuran (THF; 20 ml) was added lithium borohydride (5.5 mg) under cooling with ice. The mixture was stirred for 5 minutes. After adding another lithium borohydride (5.5 mg), the mixture was stirred for further 5 minutes. Water was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/methylene chloride=1:1) to yield 45 mg (48%) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:29][CH2:28]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[CH2:33]([N:30]1[CH2:29][CH2:28][CH:27]([O:26][C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:14]([C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:12]=3[CH3:13])=[O:16])=[CH:25][C:22]=2[C:23]#[N:24])[CH2:32][CH2:31]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Reactant: N#Cc1cc(N)ccc1OC1CCN(Cc2ccccc2)CC1
Product: Cc1c(C(=O)Nc2ccc(OC3CCN(Cc4ccccc4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 29.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.0 g) and 5-amino-2-(1-benzylpiperidin-4-yloxy)benzonitrile (1.2 g), the title compound (0.6 g) was obtained, melting point: 194° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:2]1.[CH3:28][C:29]([CH3:31])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.CC(O)=O>[CH:29]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:2]1)([CH3:31])[CH3:28]
Reactant: CC(C)=O
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1[C@@H]1CCCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N1CCC[C@@H](n2c([C@H](C)Nc3ncnc4[nH]cnc34)nc3ccccc32)C1
Reaction time: 0.08 h
Yield: 34.6 %

Procedure:
To a mixture of [(S)-1-((R)-1-piperidin-3-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine from Example 16 (150 mg, 0.414 mmol) in anhydrous DCM (3 mL) was added acetone (90 μL, 1.24 mmol) followed by AcOH (1 drop). After stirring for 5 min, sodium triacetoxyborohydride (132 mg, 0.621 mmol) was added and stirring was continued for 22 h. The mixture was then treated with NaOH (1N, 2 mL) and then vigorously stirred for 10 min. Volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-15% 2M NH3/MeOH in DCM) affording 132 (58 mg, 35%). LCMS: RT 1.91 min [M+H]+ 405.1. 1H NMR (DMSO, 400 MHz): δ 12.97 (1H, s), 8.33-8.06 (2H, m), 7.96 (1H, br), 7.72 (1H, d, J=7.33 Hz), 7.62 (1H, d, J=7.14 Hz), 7.24-7.07 (2H, m), 5.93 (1H, s), 4.66-4.52 (1H, m), 3.00-2.83 (2H, m), 2.81-2.65 (2H, m), 2.23 (1H, t, J=11.59 Hz), 2.15-2.01 (1H, m), 1.84-1.57 (5H, m), 1.26-1.07 (1H, m), 0.96 (6H, d, J=6.51 Hz)
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.[CH3:14][O-:15].[Na+]>CO>[CH3:14][O:15][CH2:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: ClCc1cc2ccccc2cn1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1cc2ccccc2cn1
Temperature: 20 °C
Yield: 87.6 %

Procedure:
A mixture of 3-chloromethylisoquinoline hydrochloride (96 g) and sodium methoxide (80 g) in methanol (1.5 liters) is heated under reflux for 8 hours. After cooling to 20° C., the mixture is filtered and the filtrate is evaporated to dryness at 50° C. under reduced pressure (20 mm Hg). The residue is taken up in methylene chloride (1 liter), the mixture is washed with water (3×150 cc), the organic phase is dried over magnesium sulphate and filtered, and the filtrate is evaporated to dryness at 40° C. under reduced pressure (20 mm Hg). The oily residue is distilled at 82° C. under reduced pressure (0.6 mm Hg). 3-Methoxymethylisoquinoline (68 g), a colourless oil, is obtained.
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH:11]([C:13]2[N:14]=[C:15]([C:21](=[S:23])[NH2:22])[NH:16][C:17]=2[N+:18]([O-:20])=[O:19])[CH3:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:25][CH2:26][C:27]([CH2:29]Cl)=O.O.O1CCOC[CH2:33]1>>[CH3:33][N:16]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:13][N:14]=[C:15]1[C:21]1[S:23][CH:29]=[C:27]([CH2:26][Cl:25])[N:22]=1.[C:1]1([CH3:24])[CH:2]=[CH:3][C:4]([S:7]([O:10][CH:11]([C:13]2[N:14]=[C:15]([C:21]3[S:23][CH:29]=[C:27]([CH2:26][Cl:25])[N:22]=3)[NH:16][C:17]=2[N+:18]([O-:20])=[O:19])[CH3:12])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: O=C(CCl)CCl
Reactant: C1COCCO1
Reactant: Cc1ccc(S(=O)(=O)OC(C)c2nc(C(N)=S)[nH]c2[N+](=O)[O-])cc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC(C)c2nc(-c3nc(CCl)cs3)[nH]c2[N+](=O)[O-])cc1
Product: Cn1c([N+](=O)[O-])cnc1-c1nc(CCl)cs1
Temperature: 130 °C

Procedure:
The 2-thiocarbamyl compounds from Example 1 (0.27 mole) and 1,3-dichloroacetone (0.55 mole) in dioxan (55 ml.) were stirred and heated at 130° C. for 2 hours. The mixture was poured into water, the resultant precipitate washed with hot water and dried to yield 2-(1-methyl-5-nitroimidazol-2-yl)-4-chloromethylthiazole m.p. 160°-2° C. and 2-(1-p-toluenesulphonyloxyethyl-5-nitroimidazol-2-yl)-4-chloromethylthiazole respectively. The 1-p-toluenesulphonyloxy compound, on treatment as described at the end of Example 2, yielded 2-(1-vinyl-5-nitroimidazol-2-yl)-4-chloromethylthiazole.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[NH:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)(O)[O-].[Na+].Br[CH2:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29]>C(O)(C)C>[OH:32][C:27]1([C:28]([F:31])([F:30])[F:29])[CH2:26][N:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[C:12]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[N:13]1
Reactant: O=C(CBr)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccncc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccncc2)cc1
Temperature: 77.5 °C
Yield: 25.1 %

Procedure:
To a mixture of the amidine of step 1 (4.75 g, 16 mmol) and sodium bicarbonate (2.86 g, 34.4 mmol) in isopropanol (400 ml), 3-bromo-1,1,1-trifluoroacetone (2.7 ml, 26 mmol) was added. After heating at 75-80° C. for 24 hours, the reaction mixture was cooled and filtered. The residue was washed with methylene chloride and the combined organic fractions were dried over sodium sulfate, filtered and concentrated. The crude product (16.2 g) was purified by chromatography (silica gel, ethyl acetate/isopropanol (95/5)) to give 4-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine (1.55 g, 23%) as a white solid: mp 219° C., Anal. Calc'd. for C16H14N3SO3F3 C, 49.87, H, 3.66, N, 10.90, S, 8.32. Found: C. 49.93, H, 3.51, N, 10.79, S, 8.66.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH2:19][CH3:20])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][CH2:24][CH2:25][P:26]([O:31][CH2:32][CH3:33])(=[O:30])[O:27][CH2:28][CH3:29]>>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:22][CH2:23][CH2:24][CH2:25][P:26](=[O:30])([O:31][CH2:32][CH3:33])[O:27][CH2:28][CH3:29])[C:13](=[O:18])[N:12]([CH2:19][CH3:20])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(CCCCCl)OCC
Reactant: CCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Product: CCOP(=O)(CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(CC)c1=O)OCC

Procedure:
The title substance was prepared from 0.04 mol of 7-benzyl-3-ethyl-xanthine and 0.048 mol of diethyl 4-chlorobutanephosphonate analogously to Example 23.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:20])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N+:8]([O-:20])[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1ccc[n+]([O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold solution of 3-ethoxycarbonylpyridine (25 g, 165.4 mmol, 1 eq) in DCM was slowly added mCPBA (70% wt, 198.5 mmol) and the reaction mixture was stirred at rt overnight. Reaction was cooled and diluted with DCM and then neutralized with slow addition of sat. NaHCO3.Aqueous layer was washed with DCM (3×) and the combined organic layer was dried and evaporated to give a residue, which was purified by column chromatography (EtOAc/MeOH) to give 3-ethoxycarbonylpyridine N-oxide (13.6 g). MS: exact mass calculated for C8H9NO3, 167.06; m/z found, 168 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.O.CN([CH:20]=[O:21])C>O=P(Cl)(Cl)Cl>[CH:20]([N:14]1[C:15]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]2[C:13]1=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:21]
Reactant: COc1cccc2c1[nH]c1ccccc12
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1cccc2c3ccccc3n(C=O)c12
Temperature: 0 °C
Yield: 96 %

Procedure:
In a 50 mL round bottomed flask was dissolved POCl3 (0.6 mL, 15.23 mM) in 20 mL of dry DMF. The reaction mixture was stirred at 0° C. in an ice bath. To this was added slowly, 1-methoxy-9H-carbazole (1 g, 5.07 mM) dissolved in 30 mL of dry DMF. The reaction mixture was stirred for 2 hrs. Water was added to the reaction mixture and the precipitated product was filtered off. The residue was dissolved in EtOAc and was washed with brine and dried over anh. Na2SO4. Ethyl acetate was then evaporated to obtain the desired product as a white fluffy solid with a yield of 96% (1.1 g); mp 161-163° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:21])[CH:18]=[N+]=[N-])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:22].CC(O)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:21])[CH2:18][Br:22])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=CC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(CBr)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
4-(2-Diazo-acetyl)-piperidine-1-carboxylic acid benzyl ester (44 g, 0.15 mol) in EtOAc (300 mL) was cooled to 0° C. The solution was treated with 33% HBr/HOAc (75 mL, 0.42 mol) over 15 min and stirred at ambient temperature for 2 hours. The mixture was slowly treated with saturated NaHCO3 solution (300 mL) until pH was neutral or slightly basic and filtered. The solution was dried over MgSO4 and subjected to a 330 g SiO2 COMBIFLASH column (0-100% EtOAc-hexanes gradient) to afford 4-(2-bromo-acetyl)-piperidine-1-carboxylic acid benzyl ester (38.1 g, 81%): MS (ESI) m/z 341 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:19]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=3[F:18])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:2]3[N:19]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=5[F:18])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: COc1cccc(-c2cccn3nc(Cl)nc23)c1F
Product: COc1cccc(-c2cccn3nc(Nc4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc23)c1F

Procedure:
4-{4-[8-(2-Fluoro-3-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-fluoro-3-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridine (0.248 g, 0.893 mmol) and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.296 g, 1.07 mmol) in a manner analogous to Example 311a and 311b to give product (0.312 g, 67%). MP=98-102° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.63 (s, 1H), 8.83 (d, 1H), 7.60 (m, 3H), 7.25 (m, 3H), 7.10 (m, 3H), 4.05 (m, 2H), 3.90 (s, 3H), 2.80 (br m, 2H), 2.60 (m, 1H), 1.45 (m, 2H), 1.75 (m, 2H), 1.41 (s, 9H). MS=518 (MH)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH3:7][C:8]1[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][CH:13]=1>>[CH3:7][C:8]1[CH:13]=[C:12]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: Brc1cccs1
Product: Cc1cccc(-c2cccs2)c1

Procedure:
2-Bromothiophene and 3-methylphenylboronic acid were treated in a manner similar to Reference Example 26-(2) to give 2-(3-methylphenyl)thiophene as colorless oil.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([CH3:18])[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([CH3:17])[C:8]([CH3:16])=[C:9]([OH:15])[C:10]=2[CH3:14])[O:5]1>CCCCCC>[Br:1][CH2:14][C:10]1[C:9]([OH:15])=[C:8]([CH3:16])[C:7]([CH3:17])=[C:6]2[C:11]=1[CH2:12][CH2:13][C:4]([CH3:18])([CH3:3])[O:5]2
Reactant: BrBr
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C)O2
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(CBr)c1O)CCC(C)(C)O2
Reaction time: 2 h
Yield: 100.3 %

Procedure:
A solution of Br2 (0.540 mL, 10.5 mmol) in hexane (70 mL) was quickly added to the round bottom flask equipped with a CaCl2 drying tube and containing a stirred solution of 2,2,5,7,8-pentamethyl-6-chromanol (2.20 g, 10.0 mmol) in hexane (340 mL). After stirring the reaction mixture for 2 h the solvents were evaporated yielding of 5-bromomethyl-2,2,7,8-tetramethyl-chroman-6-ol as a pale yellow solid (3.0 g), which was immediately used in the next step without further purification. 1H-NMR (300 MHz, CDCl3) δ (ppm): 4.68 (s, 2H), 2.81 (t, J=7, 2H), 2.17 (s, 3H), 2.14 (s, 3H), 1.84 (t, J=7, 2H), 1.32 (s, 6H). MS (ESI-Pos) m/z 219.2 (M−Br+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]>ClCCl>[C:15]([Si:19]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[I:9])([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]
Reactant: Oc1ccc(Cl)cc1I
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cl)cc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of 4-chloro-2-iodophenol (1.587 g, 6.238 mmol) in dichloromethane (10 ml) was added 1H-imidazole (1.01 g, 14.3 mmol) followed by a solution of tert-butyl(chloro)dimethylsilane (2.63 ml, 13.7 mmol) in dichloromethane (10 ml) dropwise. The resulting white suspension was stirred for 16 hours at room temperature before concentrating in vacuo. The residue was diluted with ethyl acetate (20 ml) and water (20 ml). The aqueous phase was acidified with hydrochloric acid (2 M aqueous solution) and extracted with ethyl acetate. The combined organic layers were washed with hydrochloric acid (2 M aqueous solution), saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel column) eluting with ethyl acetate:heptane (gradient 0:1 to 3:7, by volume) to afford the title compound as pale yellow oil, 2.2 g, 95% yield.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C1C=CC2N(O)N=[N:38]C=2C=1.CCN(CC)CC.CCN=C=NCCCN(C)C.N>ClCCl.O1CCOCC1>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([C:24]([NH2:38])=[O:26])=[CH:27][CH:28]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: C[C@H]1CCCN1c1cccc(Nc2cc(-c3ccc(C(=O)O)cc3)nn3ccnc23)n1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CCCN1c1cccc(Nc2cc(-c3ccc(C(N)=O)cc3)nn3ccnc23)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.3 %

Procedure:
To a stirred solution of (S)-4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (90 mg), HOBT (49 mg, 0.365 mmol), Et3N (49 mg, 0.486 mmol) and EDCI (70 mg, 0.365 mmol) in dichloromethane (20 mL) and dioxane (100 mL) was bubbled NH3 gas until saturation and the mixture stirred for 16 h at room temperature. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200-300 mesh, MeOH:dichloromethane=1:50) to afford (S)-4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamide (38 mg, 47%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.74 (s, 1H), 7.94-7.86 (m, 5H), 7.49 (s, 1H), 7.32 (t, 1H, J=8.1 Hz), 6.18 (d, 1H, J=6.0 Hz), 5.98 (d, 1H, J=8.4 Hz), 4.17-4.14 (m, 1H), 3.55-3.49 (m, 1H), 3.38-3.32 (m, 1H), 2.07-1.93 (m, 3H), 1.68 (s, 1H), 1.10 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 414, tR=1.505 min, HPLC: 97.48% at 214 nm, 97.67% at 254 nm, tR=6.027 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:14]=[CH:13][C:12]3=[N:15][C:16](NC)=[N:17][C:11]3=[CH:10]2)=[CH:4][CH:3]=1.[C:20](Cl)(=[O:23])[O:21][CH3:22].[CH2:25]([N:27](CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH:14]=[CH:13][C:12]3=[N:15][C:16]([CH2:25][NH:27][C:20](=[O:23])[O:21][CH3:22])=[N:17][C:11]3=[CH:10]2)=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: CNc1nc2ccn(Cc3ccc(F)cc3)cc-2n1
Reactant: COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)NCc1nc2ccn(Cc3ccc(F)cc3)cc-2n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3.0 parts of 5-[(4-fluorophenyl)methyl]-N-methyl-5H-imidazo[4,5-c]pyridin-2-amine, 2.4 parts of methyl carbonochloridate, 1.2 parts of N,N-diethylethanamine and 260 parts of dichloromethane was stirred for 2 days at room temperature. The reaction mixture was evaporated. The solid residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (94:6 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanone, yielding 1 part of methyl [[5-[(4-fluorophenyl)methyl]-5H-imidazo[4,5-c]pyridin-2-yl]methyl]carbamate; mp. 178.8° C. (intermediate 98).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][C@@H:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2)#[N:2].CO.C([O-])([O-])=O.[Ca+2].[Br-:30].[Br-].[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C([N+](CC)(CC)CC)C1C=CC=CC=1.C([N+](CC)(CC)CC)C1C=CC=CC=1>C1COCC1.C(Cl)Cl>[Br:30][C:11]1[CH:12]=[C:3]([C:1]#[N:2])[CH:4]=[C:5]2[C:10]=1[NH:9][CH2:8][CH:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2
Reactant: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2
Reactant: [Br-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1cc(Br)c2c(c1)CC(NS(=O)(=O)c1ccccc1)CN2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 77 %

Procedure:
To a suspension of racemate 1G (323 mg, 1.03 mmol) in mixed solvents of MeOH (3 mL), CH2Cl2 (3 mL) and THF (3 mL) at RT was added CaCO3 (103 mg, 1.03 mmol), followed by benzyltriethylammonium tribromide (445 mg, 1.03 mmol). After addition, the mixture was stirred at RT for 45 min. The resultant precipitate was collected by filtration, washed with 0.2 N aqueous HCl, H2O, then dried to provide the title compound (311 mg, 77%) as a white solid.