Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[F:2][C:3]1[C:22]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:21][C:6]([O:7][C:8]2[C:9]([O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:10][CH:11]=[CH:12][CH:13]=2)=[C:5]([N+:36]([O-])=O)[CH:4]=1>C(O)(=O)C.[Fe]>[NH2:36][C:5]1[CH:4]=[C:3]([F:2])[C:22]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:21][C:6]=1[O:7][C:8]1[C:9]([O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Temperature: 35 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
To a mixture of 17 g of an iron powder, 30 ml of acetic acid and 3 ml of water was added a solution of 17.28 g of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-(ethoxycarbonyl)methoxypyridine [present compound 9-46] in 20 ml of acetic acid dropwise while maintaining the temperature of the reaction solution at 35° C. or lower. After completion of the addition, the mixture was stirred for 1 hour at room temperature, for 3 hours at 40° C., then, the reaction solution was filtrated through Celite, and diluted with ethyl acetate. The mixture was neutralized with saturated aqueous sodium bicarbonate solution, the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. Then, the resulted residue was subjected to silica gel column chromatography to obtain 15.46 g of 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(ethoxycarbonyl)methoxypyridine.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:41])=[O:40])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49](C1C=C(CS(Cl)(=O)=O)C=CC=1)#[N:50]>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:34][CH:35]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[C:47]([C:49]#[N:50])[CH:48]=1)(=[O:41])=[O:40])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#Cc1cccc(CS(=O)(=O)Cl)c1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: N#Cc1cccc(CS(=O)(=O)NCCc2c(CCOc3ccc(C(=O)O)cc3)c3cc(Cl)ccc3n2C(c2ccccc2)c2ccccc2)c1

Procedure:
The title compound was prepared from 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester (Step 6, Example 1) and (3-cyano-phenyl)-methanesulfonyl chloride according to Example 1 Step 7.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C:16]([C:17]#[N:18])=[C:12]2[NH:11][CH2:10][CH2:9]1.Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][CH:24]=3)[C:16]([C:17]#[N:18])=[C:12]2[NH:11][CH2:10][CH2:9]1
Reactant: BrCc1ccccc1
Reactant: N#Cc1c(-c2ccc(O)cc2)nn2c1NCCC2c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1c(-c2ccc(OCc3ccccc3)cc2)nn2c1NCCC2c1ccccc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
To a solution of 7-(2-aminophenyl)-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidine-3-carbonitrile (331 mg, 1.0 mmol) in acetone (10 mL) was added (bromomethyl)benzene (204 mg, 1.2 mmol) and K2CO3 (276 mg, 2.0 mmol). The mixture was stirred at RT for 16 hr. 50 mL of acetone was added and filtered. The filtrate was concentrated to afford 400 mg (95%) of 7-(2-aminophenyl)-2-(4-(benzyloxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile as a yellow solid. MS (ESI) m/e [M+1]+ 421.9.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=2)[NH:3]1.[NH:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=2[N:18]=[N:17]1>>[NH:16]1[C:20]2[CH:21]=[CH:22][C:23](/[CH:25]=[C:10]3/[C:2](=[O:1])[NH:3][C:4]4[C:9]/3=[CH:8][C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][CH:5]=4)=[CH:24][C:19]=2[N:18]=[N:17]1
Reactant: O=Cc1ccc2[nH]nnc2c1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)CC(=O)N2
Product: CS(=O)(=O)Nc1ccc2c(c1)/C(=C\c1ccc3[nH]nnc3c1)C(=O)N2

Procedure:
According to the method of Example A20, except substituting N-(2-oxoindolin-5-yl)methanesulfonamide (12 mg, 0.053 mmol) and 1H-benzo[d][1,2,3]triazole-5-carbaldehyde (9 mg, 0.058 mmol), the title compound was obtained as an orange solid (8 mg, 42%). 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 8.00 (d, J=8.6 Hz, 1H), 7.93 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.61 (s, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.91 (d, J=8.3 Hz, 1H), 2.86 (s, 3H); MS ESI 356.0 [M+H]+, calcd for [C16H13N5O3S+H]+ 356.1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9]2[N:13]([C:14]3[CH:19]=[C:18]([NH:20][CH3:21])[N:17]=[CH:16][N:15]=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[CH:6][C:5]([NH2:23])=[CH:4][CH:3]=1.[CH:24]([NH:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[C:32](O)=[O:33])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:24]([NH:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1)[C:32]([NH:23][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([NH:8][C:9]2[N:13]([C:14]3[CH:19]=[C:18]([NH:20][CH3:21])[N:17]=[CH:16][N:15]=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)[CH:6]=1)=[O:33])([CH3:26])[CH3:25]
Reactant: CC(C)NCc1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1cc(-n2nc(C)cc2Nc2cc(N)ccc2C)ncn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNc1cc(-n2nc(C)cc2Nc2cc(NC(=O)c3cc(CNC(C)C)cc(C(F)(F)F)c3)ccc2C)ncn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6-methyl-N1-(3-methyl-1-(6-(methylamino)pyrimidin-4-yl)-1H-pyrazol-5-yl)benzene-1,3-diamine 39 (360 mg, 1.16 mmol, 1 eq) is dissolved in dry DMF (10 mL), followed by 3-((isopropylamino)methyl)-5-(trifluoromethyl)benzoic acid (0.504 mg, 1.02 mmol, 0.9 eq), HATU (663 mg, 1.74 mmol, 1.5 eq), and DIEA (0.5 mL, 3.49 mmol, 3 eq). The reaction mixture is stirred at room temperature for about 4 hours until the reaction is complete as evidenced by the LC/MS product peak. The reaction mixture is then quenched by NaHCO3 solution and extracted with ethyl acetate. The organic layers are combined and dried over magnesium sulfate. The solvents are removed under vacuo and the residue is purified by flash column chromatography to afford 3-((isopropylamino)methyl)-N-(4-methyl-3-(3-methyl-1-(6-(methylamino)pyrimidin-4-yl)-1H-pyrazol-5-ylamino)phenyl)-5-(trifluoromethyl)benzamide. MS: m/z [M+H+]) 553.20, 1H NMR: 11.07 (s, 1H), 10.61 (s, 1H), 9.17 (bs, 1H), 8.58 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 7.95 (s, 1H), 7.69 (s, 1H), 7.39 (m, 1H), 7.24 (m, 1H), 6.88 (s, 1H), 6.16 (s, 1H), 4.36 (m, 2H), 3.34-3.48 (m, 1H), 2.87 (m, 3H), 2.49 (m, 3H), 2.22 (m, 3H), 1.33-1.34 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][NH2:14])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH2:15]([O:17][C:18](Cl)=[O:19])[CH3:16].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:15]([O:17][C:18](=[O:19])[NH:14][CH2:13][CH2:12][C:4]1[CH:5]=[CH:6][C:7]([C:8]([F:10])([F:11])[F:9])=[C:2]([F:1])[CH:3]=1)[CH3:16]
Reactant: CCOC(=O)Cl
Reactant: NCCc1ccc(C(F)(F)F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NCCc1ccc(C(F)(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
2-(3-Fluoro-4-trifluoromethyl-phenyl)-ethylamine (I-47b: 2.46 g, 11.88 mmol) was reacted with ethylchloroformate (1.54 g, 14.26 mmol), 2N Na2CO3 solution (24.0 mL) and chloroform (24 mL). The resulting mixture was stirred for 30 minutes at 0° C. to afford 3.0 g of the crude product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33]Cl)=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([NH2:39])[CH2:36][CH2:37][CH3:38]>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][NH:39][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCN
Reactant: ClCCOc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1
Product: CCCCNCCOc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1
Yield: 63 %

Procedure:
From (+,-) cis 7-Benzyloxy4-[4-(2-chloroethyloxy)-phenyl]-3-phenyl-chroman (235 mg, 0.5 mmol) and butylamine (183 mg, 2.5 mmol). The evaporated product was precipitated from ether-petrolether to give 160 mg of material, which was chromatographed as described above.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:15]=2)[CH:11]=[CH:12][CH:13]=1)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:6][CH2:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ccc(-c2cccc(CO[Si](C)(C)C(C)(C)C)c2)cc1CNC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(CO)c2)cc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 53 %

Procedure:
To a solution of 1,1-dimethylethyl {[3′-({[(1,1-dimethylethyl)(dimethyl)silyl]-oxy}methyl)-4-methyl-3-biphenylyl]methyl}carbamate (3.60 g, 8.2 mmol) in THF (30 mL), was added a solution of nBu4NF (2.34 g, 9.0 mmol) in THF (20 mL). This mixture was stirred at room temperature over night. The solvent was removed under reduced pressure, and the residue was diluted with CH2Cl2 (50 mL), washed with water (15 mL×2), brine (15 mL×2), and dried over Na2SO4. The product 1,1-dimethylethyl {[3′-(hydroxymethyl)-4-methyl-3-biphenylyl]methyl}carbamate (1.5 g) was purified by flash column chomatography (PE:EA=4:1) (yield: 53%). 1H NMR (400 MHz, CDCl3) δ 1.47 (s, 9H), 2.37 (s, 3H), 4.37 (d, J=5.6 Hz, 2H), 4.76 (m, 3H), 7.23-7.58 (m, 7H); 13C NMR (100 MHz, CDCl3) δ 18.6, 28.4, 42.9, 65.3, 79.5, 125.6, 125.7, 126.2, 126.8, 129.0, 130.9, 135.5, 138.9, 141.2, 141.4, 155.8; HPLC: retention time: 14.965 min; purity: 95.4%; MS m/z 327 (M+).
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][CH:4]([Cl:12])[C:5]([O:7][CH2:8][C:9](Cl)=[O:10])=[O:6].O>C(Cl)Cl>[CH3:1][NH:2][C:9](=[O:10])[CH2:8][O:7][C:5](=[O:6])[CH:4]([Cl:12])[Cl:3]
Reactant: O=C(Cl)COC(=O)C(Cl)Cl
Reactant: CN
Solvent: ClCCl
Solvent: O
Product: CNC(=O)COC(=O)C(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A solution was made by combining while cooling in an ice bath, 2.33 g (0.03 mole) of a 40% aqueous solution of methylamine and 100 ml of methylene chloride. A second solution containing 3.08 g (0.015 mole) dichloroacetoxyacetyl chloride dissolved in 5 ml methylene chloride was slowly added to the first solution. The mixture was stirred in the ice bath for one half hour. After remaining at room temperature for one hour, it was refluxed for ten minutes and cooled again. The reaction product was water washed twice and dried over magnesium sulfate. It was decolorized with a decolorizing agent and charcoal. The solvent was removed by reduced pressure evaporation and oil pumped. A semi-solid consisting of 1.5 g (50% yield) of N-methyl dichloroacetoxyacetamide was obtained. The structure was confirmed by infrared spectraphotometric analysis (IR).
Reaction SMILES: [NH:1]=[C:2]([NH:16][CH2:17][NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:3][CH2:4][C@@H:5]1[NH:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]1=[O:15].S(Cl)(Cl)=O.[CH3:33]O>>[CH3:33][O:13][C:12](=[O:14])[CH2:11][N:7]1[CH2:8][CH2:9][NH:10][C@@H:5]([CH2:4][CH2:3][C:2]([NH:16][CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:20])=[O:21])=[NH:1])[C:6]1=[O:15]
Reactant: CO
Reactant: Cc1ccc(S(=O)(=O)NCNC(=N)CC[C@@H]2NCCN(CC(=O)O)C2=O)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)CN1CCN[C@@H](CCC(=N)NCNS(=O)(=O)c2ccc(C)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of the compound of Example 15 (198 mg) in MeOH at 0° C., was treated with excess thionyl chloride (20 eq). The mixture was stirred at room temperature overnight and evaporated to give the title compound (100% yield).
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1.ClCCl>C(#N)C>[NH2:28][C:19]1[C:18]2[N:17]=[C:16]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][S:2]([CH3:1])(=[O:5])=[O:3])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: COc1ccc(Cc2nc3c(N)nc4ccccc4c3n2CCCCN)cc1
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc(Cc2nc3c(N)nc4ccccc4c3n2CCCCNS(C)(=O)=O)cc1
Temperature: 25 °C
Yield: 61.8 %

Procedure:
Methanesulfonic anhydride (0.19 g, 1.1 mmol) was added to a stirring solution of 1-(4-aminobutyl)-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.4 g, 1.07 mmol), dichloromethane (75 ml) and acetonitrile (100 ml). The reaction was maintained at room temperature for 60 hours. The solvent was removed in vacuo and the residue was purified by flash column chromatography (silica gel, 9:1 dichloromethane\methanol). The fractions containing product were combined, washed with saturated aqueous sodium bicarbonate, dried (MgSO4), filtered, and concentrated to provide 0.3 g of N-[4-(4-amino-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl]methanesulfonamide as a white solid, m.p. 78.1-79.5° C. 1H NMR (300 MHz, DMSO-d6) δ 7.99 (d, J=7.6 Hz, 1H), 7.62 (dd, J=8.3, 1.2 Hz, 1H), 7.42 (m, 1H), 7.27-7.21 (m, 3H), 6.98 (t, J=5.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 2H), 6.58 (broad s, 2H), 4.45 (broad s, 2H), 4.33 (s, 2H), 3.72 (s, 3H), 2.87 (m, 5H), 1.55 (broad s, 2H); MS (CI) m/e 454 (M+H).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C@@H:17]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[CH:26]=3)[CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].CCOC(C)=O>N1C=CC=CC=1>[ClH:1].[C:39]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([C@@H:17]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[CH:26]=3)[CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)=[CH:6][CH:5]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([C@@H](Cc2ccncc2)c2ccc(Oc3ccc(N)cc3)cc2)cc1OC1CCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H](Cc2ccncc2)c2ccc(Oc3ccc(NC(C)=O)cc3)cc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of the free base of compound of Example 7 (322 mg, 0.67 mmol) in pyridine (10 ml) was heated with acetic anhydride (126 μl) and the mixture stirred at RT for 24 h. The solvent was removed in vacuo, the residue azeotroped twice with toluene and partitioned between aqueous NaOH (pH 13) and EtOAc. The aqueous layer was further extracted with EtOAc and the combined organic layer dried (Na2SO4) then concentrated in vacuo to give an off-white glass. Chromatography (SiO2 ; EtOAc) afforded the title compound free base (303.6 mg) as an off-white glass.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[CH:13][CH:12]=1
Reactant: OC1CN2CCC1CC2
Reactant: Brc1ccc(I)cc1
Product: Brc1ccc(OC2CN3CCC2CC3)cc1

Procedure:
3-Hydroxy quinuclidine (Aldrich, 1.27 g, 10 mmol) was treated with 4-bromo-iodobenzene (Aldrich, 2.82 g, 10 mmol) according to the procedure of Example 14A. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.20) as oil (0.85 g, yield, 30%). 1H NMR (MeOH-d4, 300 MHz) δ 1.40–1.56 (m, 1H), 1.64–1.80 (m, 2H), 1.90–2.08 (m, 1H), 2.10–2.21 (m, 1H), 2.60–3.00 (m, 5H), 3.34–3.40 (m, 1H), 4.46 (m, 1H), 6.83 (d, J=9.5 Hz, 2H) 7.37 (d, J=9.2, Hz, 2H), ppm. MS (DCl/NH3) m/z 282 (M+H)+, 284 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32](O)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[C:45]([O:44][C:43](=[O:49])[NH:42][C@H:39]1[CH2:40][CH2:41][C@@H:36]([NH:35][C:32]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:7]4[CH:8]=[C:9]([CH3:13])[C:10]([F:12])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:15]=3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:21]=2[CH3:31])=[O:33])[CH2:37][CH2:38]1)([CH3:46])([CH3:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: Cc1cc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Product: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c11) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[N:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH:22]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:22]2[CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=2)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(Cl)nc(Cl)c2)C1
Temperature: 65 °C
Yield: 52.8 %

Procedure:
To a mixture of 2,6-dichloro-4-iodo-pyridine (500 mg, 1.826 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (646.7 mg, 2.191 mmol, 1.2 equiv.), potassium carbonate (510 mg, 3.651 mmol, 2 equiv.), and PD(dppf)Cl2 DCM (223.6 mg, 0.274 mmol, 0.15 equiv.) in 1,4-dioxane (6 mL) and water (2 mL) was capped in a large CEM vial, de-gassed with N2, heated in oil bath @ 65° C. o/n. It was diluted with water, extracted with EtOAc (2×50 mL), dried over Na2SO4, filtered, concentrated in vacuo. Purification by column chromatography (ISCO), 40 g column, eluded with 0-10% EtOAc/Heptane to afford 304 mg (52.8%) of product as white foam. 1H NMR (400 MHz, CDCl3) δ 7.42 (s, 0.5H), 7.22 (s, 0.5H), 7.04 (s, 2H), 3.93 (s, 2H), 2.90 (s, 2H), 1.53 (s, 9H). LC-MS: m/z=316 (M+H+).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:28][CH3:29])[C:5]([N:8](COCC[Si](C)(C)C)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])(=[O:11])=[O:10])=[N:6][CH:7]=1.[CH2:30]([N:32]([CH2:37][CH3:38])[C:33](=[O:36])[CH2:34][OH:35])[CH3:31]>>[Cl:19][C:13]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[N:6]=[CH:7][C:2]([O:35][CH2:34][C:33]([N:32]([CH2:37][CH3:38])[CH2:30][CH3:31])=[O:36])=[N:3][C:4]=1[O:28][CH3:29])(=[O:10])=[O:11]
Reactant: COc1nc(Br)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Reactant: CCN(CC)C(=O)CO
Product: CCN(CC)C(=O)COc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OC)n1

Procedure:
Prepared as for Example 115b using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (Example 55a) (0.35 g) and N,N-diethyl-2-hydroxyacetamide (0.13 g). Yield 0.2 g
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[F:39]>>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][O:1][C:2]2[CH:3]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])[CH:5]=[CH:6][CH:7]=2)=[C:33]([F:39])[CH:34]=1
Reactant: Fc1cc(Cl)ccc1CBr
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccc(Cl)cc2F)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 1-Bromomethyl-4-chloro-2-fluoro-benzene following the procedure of Example 478: MS (ESI) m/z 536.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([CH3:16])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Br[CH:18]([C:20](=O)[CH3:21])[CH3:19]>CO>[CH3:16][C:5]1[CH:6]=[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:2]2[N:3]([C:18]([CH3:19])=[C:20]([CH3:21])[N:1]=2)[N:4]=1
Reactant: CC(=O)C(C)Br
Reactant: Cc1cc(OCc2ccccc2)c(N)nn1
Solvent: CO
Product: Cc1cc(OCc2ccccc2)c2nc(C)c(C)n2n1
Temperature: 25 °C

Procedure:
A mixture of (0.01 mole) 3-amino-6-methyl-4-phenylmethoxypyridazine, [prepared following the methodology of Becket, et al. J. Pract. Chem., 311, 285(1969) and references cited therein], and (0.012 mole) 2-bromo-3-butanone in methanol is heated for 24 hours in a bath maintained at 100°. The mixture is cooled to room temperature and partitioned between aqueous sodium bicarbonate and methylene chloride. The layers are separated and the aqueous phase extracted with methylene chloride. The organic extracts are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to give 6-methyl-8-phenylmethoxy-2,3-dimethylimidazo[1,2-b]pyridazine.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:2].I[C:14]1[CH:15]=[C:16]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([CH2:30][N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[CH:28]=[CH:29][C:23]=3[N:22]=2)[CH:17]=[CH:18][C:19]=1[CH3:20]>>[CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[C:12][C:14]2[CH:15]=[C:16]([C:21]3[NH:25][C:24]4[CH:26]=[C:27]([CH2:30][N:31]5[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]5)[CH:28]=[CH:29][C:23]=4[N:22]=3)[CH:17]=[CH:18][C:19]=2[CH3:20])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(NC(C)C)nn1
Reactant: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1I
Product: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1C#Cc1ccc(NC(C)C)nn1

Procedure:
The title compound was synthesized from N-isopropyl-6-ethynylpyridazin-3-amine and 2-(3-iodo-4-methylphenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]-imidazole (as prepared in Example 1) in a manner similar to that described for in Example 1. The intermediate compound N-isopropyl-6-ethynylpyridazin-3-amine was made as for Example 1 (Step 1 to 3) with the spectra below: 1H NMR (300 MHz, CDCl3) δ: 7.26-7.29 (1H, d, J=9.0 Hz), 6.54-6.57 (1H, d, J=9.0 Hz), 5.00 (1H, s), 3.97-4.04 (1H, m), 3.25 (1H, s), 1.29 (3H, s), 1.27 (3H, s).