Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Li+].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.[CH2:25]([O:27][C:28](=[O:38])[CH2:29]P(OCC)(OCC)=O)[CH3:26].[Cl:39][C:40]1[CH:41]=[C:42]([C@@H:47]2[O:53][CH2:52][CH2:51][N:50]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:49][C@H:48]2[CH:61]=O)[CH:43]=[CH:44][C:45]=1[Cl:46]>C(#N)C>[Cl:39][C:40]1[CH:41]=[C:42]([C@@H:47]2[O:53][CH2:52][CH2:51][N:50]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:49][C@H:48]2/[CH:61]=[CH:29]/[C:28]([O:27][CH2:25][CH3:26])=[O:38])[CH:43]=[CH:44][C:45]=1[Cl:46]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](C=O)C1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Product: CCOC(=O)/C=C/[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of lithium chloride (136 mg) and diazabicycloundecene (0.403 mL) in acetonitrile (26.7 mL) was added ethyl(diethoxyphosphoryl)acetate (0.642 mL), and the mixture was stirred at 20 min. tert-Butyl (6R,7R)-7-(3,4-dichlorophenyl)-6-formyl-1,4-oxazepane-4-carboxylate (1.00 g) was added and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, distilled water was added, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (902 mg).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[CH3:10][O:11]/[N:12]=[C:13](/[C:37]1[N:38]=[CH:39][S:40][CH:41]=1)\[C:14]([NH:16][CH:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([O-:34])=[O:33])=[C:21]([CH2:24][S:25][C:26]3[S:30][N:29]=[C:28]([CH3:31])[N:27]=3)[CH2:22][S:23][C@H:18]12)=[O:15].[Na+].C(OCC)(=O)C.O>CN(C)C=O>[CH3:10][O:11]/[N:12]=[C:13](/[C:37]1[N:38]=[CH:39][S:40][CH:41]=1)\[C:14]([NH:16][CH:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([O:34][CH2:2][C:3]3[O:4][C:5](=[O:9])[O:6][C:7]=3[CH3:8])=[O:33])=[C:21]([CH2:24][S:25][C:26]3[S:30][N:29]=[C:28]([CH3:31])[N:27]=3)[CH2:22][S:23][C@H:18]12)=[O:15]
Reactant: Cc1oc(=O)oc1CBr
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(CSc3nc(C)ns3)CS[C@H]12)c1cscn1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OCc3oc(=O)oc3C)=C(CSc3nc(C)ns3)CS[C@H]12)c1cscn1
Reaction time: 1.3 h
Yield: 62.3 %

Procedure:
4-Bromomethyl-5-methyl-1,3-dioxolene-2-one (386 mg) was added to a solution of sodium 7-[(Z)-2-methoxyimino-2-(thiazol-4-yl)acetamido]-3-(3-methyl-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylate (536 mg) in dimethylformamide (5 ml) at -5° C. The mixture was stirred at this temperature for 1.3 hr and then poured into a mixture of ethyl acetate (130 ml) and water (30 ml, adjusted to pH 3 with dil HCl) with stirring. The ethyl acetate layer was separated, washed successively with water (30 ml, adjusted to pH 3 with dil. HCl), 10% aqueous K2HPO4 solution (30 ml) twice, and saturated saline water, dried over MgSO4, concentrated in vacuo, and the residue was added dropwise to a mixture of diethyl ether (40 ml) and petroleum ether (40 ml). The formed crystals were filtered, washed with petroleum ether, and dried in vacuo to give the title compound (390 mg). ##STR38##
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[C:11](=[O:12])[NH:10][C:9](=[O:13])[O:8]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=O)[CH:24]=2)=[C:19]([CH3:31])[CH:18]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+:49]>C1COCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH:1][C:2]3[CH:15]=[CH:14][C:5]([CH2:6][N:7]4[C:11](=[O:12])[N-:10][C:9](=[O:13])[O:8]4)=[CH:4][CH:3]=3)[CH:24]=2)=[C:19]([CH3:31])[CH:18]=1.[Na+:49]
Reactant: Nc1ccc(Cn2oc(=O)[nH]c2=O)cc1
Reactant: Cc1cc(Cl)ccc1-c1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1-c1cccc(CNc2ccc(Cn3oc(=O)[n-]c3=O)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.9 %

Procedure:
A mixture of 2-(4-aminobenzyl)-1,2,4-oxadiazolidine-3,5-dione (500 mg), 4′-chloro-2′-methylbiphenyl-3-carbaldehyde (668 mg), acetic acid (0.33 ml) and THF (40 ml) was stirred at room temperature for 24 hours. Sodium triacetoxyborohydride (767 mg) was added to the reaction mixture, followed by stirring at room temperature for 15 minutes. The solvent was evaporated under a reduced pressure, and water was added to the residue, followed by extraction with chloroform. The organic layer was washed with a saturated sodium chloride aqueous solution, the solvent was evaporated under a reduced pressure, toluene was added to the residue, and the solvent was again evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), and THF (5 ml), methanol (5 ml) and a 1 M sodium hydroxide aqueous solution (1.47 ml) were added to the resulting pale yellow foamy substance (620 mg), followed by stirring at room temperature for 5 minutes. The solvent was evaporated under a reduced pressure, the residue was purified by an ODS column chromatography (water-acetonitrile) and made into a solid by adding diethyl ether. The solid was collected by filtration and then dried by heating under a reduced pressure to obtain sodium 2-(4-{[(4′-chloro-2′-methylbiphenyl-3-yl)methyl]amino}benzyl)3,5-dioxo-1,2,4-oxadiazolidin-4-ide (160 mg) as a white solid.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=1)[NH:18][CH:17]=[CH:16]2.[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH:35](O)[CH:36]1[CH2:38][CH:37]1[C:39]#[N:40]>ClCCl>[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH:35]([C:16]1[C:15]2[C:19](=[C:20]([CH2:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=[C:13]([F:12])[CH:14]=2)[NH:18][CH:17]=1)[CH:36]1[CH2:38][CH:37]1[C:39]#[N:40]
Reactant: N#CC1CC1C(O)c1ccc(F)cc1F
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Cc1cc(F)cc2c(C(c3ccc(F)cc3F)C3CC3C#N)c[nH]c12

Procedure:
96.9 mg (0.44 mmol) of indium(III) chloride and 0.06 ml (0.72 mmol) of trifluoroacetic acid were added to 113 mg (0.40 mmol) of the compound from Example 87A with a purity of 80% and 100 mg (0.48 mmol) of the compound from Example 162A under argon in 4 ml of dichloromethane, and the mixture was heated under reflux for 1 h. It was diluted with dichloromethane and washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 69.0 mg (41% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: Br.Br.[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH:4]1[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16][CH2:15]1.[O-2].[Ca+2].[N:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[C:25]=[S:26]>CO>[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH:4]1[CH2:13][N:14]1[CH2:15][CH2:16][CH:17]([CH2:20][NH:21][C:25]([NH:24][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[S:26])[CH2:18][CH2:19]1
Reactant: COc1ccc(N=C=S)cc1
Reactant: NCC1CCN(CC2COc3ccccc3O2)CC1
Agent: Br
Agent: [Ca+2]
Agent: [O-2]
Solvent: CO
Product: COc1ccc(NC(=S)NCC2CCN(CC3COc4ccccc4O3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6.4 parts of (1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinemethanamine dihydrobromide, 4 parts of calcium oxide and 80 parts of methanol was stirred for 3 hours at room temperature. Then there were added 5 parts of 1-isothiocyanato-4-methoxybenzene and the whole was stirred for 3 hours at room temperature. The whole was filtered and the filtrate was evaporated. The sticky residue was suspended in a mixture of 1,1'-oxybisethane and 2,2'-oxybispropane, the latter was decanted (the residue was set aside) and allowed to crystallize, yielding a first fraction of 1 part of N-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]-N'-(4-methoxyphenyl)thiourea (intermediate 91). The residue, which was set aside, yield a second fraction of 5 parts of N-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]-N'-(4-methoxyphenyl)thiourea (intermediate 91).
Reaction SMILES: NC1C=CC=CN=1.[OH:8][C:9]1[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=1.[CH2:16]([N:20]([CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:45]=[CH:44][C:32]([C:33]([C:35]2N=C3C=CC=CN3[CH:43]=2)=[O:34])=[CH:31][CH:30]=1)[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>>[CH2:16]([N:20]([CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([C:35]2[N:15]=[C:10]3[C:9]([OH:8])=[CH:14][CH:13]=[CH:12][N:11]3[CH:43]=2)=[O:34])=[CH:44][CH:45]=1)[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN(CCCC)CCCOc1ccc(C(=O)c2cn3ccccc3n2)cc1
Reactant: Nc1ncccc1O
Agent: Nc1ccccn1
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)c2cn3cccc(O)c3n2)cc1

Procedure:
When in the above procedure, 2-aminopyridine or 3-hydroxy-2-aminopyridine is used in place of 5-bromo-2-aminopyridine, 2-(4-dibutylaminopropoxybenzoyl)imidazo[1,2-a]pyridine or 2-(4-dibutylaminopropoxybenzoyl)-8-hydroxyimidazo[1,2-a]pyridine is obtained.
Reaction SMILES: [O:1]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH2:28][C:29]#[N:30])[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][CH:19]4[CH:18]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH:17]=[CH:16][C@@H:15]35)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(OCC)C>[O:1]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH2:28][CH2:29][NH2:30])[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][CH:19]4[CH:18]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[CH3:34])[CH:17]=[CH:16][C@@H:15]35)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c3c1OC1C(O[Si](C)(C)C(C)(C)C)C=C[C@H]4[C@@H](C2)N(CCC#N)CC[C@]314
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c3c1OC1C(O[Si](C)(C)C(C)(C)C)C=C[C@H]4[C@@H](C2)N(CCCN)CC[C@]314
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
A solution of 3,6-bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxy-17-cyanoethylmorphinan (200 mg, 0.36 mmol) in dry ethyl ether (5 ml) was added dropwise to a suspension of lithium aluminum hydride (0.13 g, 3.6 mmol) in dry ethyl ether (5 ml). After stirring for 3 h at room temperature the reaction mixture was added wet ether followed by 10% sodium hydroxide (1.5 ml). The solution was filtered, and the white precipitate was washed with ether. The ether layer was evaporated under reduced pressure to give the amine as a clear liquid (yield=0.2 g, 99%).
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[C:7]([C:10]([O:12]C)=[O:11])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+]>CO.O>[S:1]1[C:9]2[CH:8]=[C:7]([C:10]([OH:12])=[O:11])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)c1cc2sccc2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2sccc2cn1
Temperature: 25 °C
Yield: 43 %

Procedure:
Methyl thieno[3,2-c]pyridine-6-carboxylate (C155) (678 mg, 3.5 mmol) is dissolved in MeOH (16 mL) and H2O (2 mL). 2M NaOH (1.8 mL, 3.6 mmol) is added drop-wise, and the solution stirred at rt. After 2 days (complete disappearance of ester by TLC), the solution is concentrated in vacuo. The residue is dissolved in H2O (12 mL), and the pH is adjusted to 3.5 with 10% HCl. The precipitated solid is removed by filtration, and the solid is rinsed with ether, affording thieno[3,2-c]pyridine-6-carboxylic acid (C160) as a white solid (43% yield). HRMS (FAB) calculated for C8H5NO2S+H: 180.0119, found 180.0123 (M+H).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)([OH:4])=[O:3].[C:19](ON1C(=O)CCC1=O)([O:21][CH2:22][CH:23]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20]>C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>[C:19]([NH:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:2]([OH:4])=[O:3])[CH:6]=2)=[CH:18][CH:17]=1)([O:21][CH2:22][CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30]2[C:35]1=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:20]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: NCc1ccc(-c2cccc(C(=O)O)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NCc1ccc(-c2cccc(C(=O)O)c2)cc1)OCC1c2ccccc2-c2ccccc21
Yield: 47.5 %

Procedure:
A solution of 4-(3-carboxyphenyl)benzylamine hydrochloride (20 g, 0.075 mol) in 10% Na2CO3 (350 mL) and dioxane (100 mL) was cooled to 0° C. with stirring. A solution of Fmoc-OSu (30.7 g, 0.091 mol) in dioxane (100 mL) was added in one portion and the reaction mixture was stirred at RT for 3 h. Acidified with 1.5 N aqueous solution of HCl and extracted with EtOAc (3×400 mL). The organic layer was washed with water (3×500 mL), brine dried over Na2SO4 and concentrated, purification by column chromatography using dichloromethane/methanol (9:1) to give N-Fmoc-4-(3-carboxyphenyl)benzylamine (16 g). This was further purified by recrystallization from THF/PetEther gave the title pure product (8 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15]C3C=CC(C(F)(F)F)=CC=3)[CH:13]=2)[N:8]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=2)[C:7]=1CC(O)=O)=[O:5])C.Cl[C:41]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][N:42]=1>>[CH3:1][O:3][C:4]([C:7]1[N:8]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=2)[C:9]2[C:14]([C:6]=1[C:4]([O:3][CH3:1])=[O:5])=[CH:13][C:12]([O:15][C:41]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][N:42]=1)=[CH:11][CH:10]=2)=[O:5]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCOC(=O)c1c(CC(=O)O)n(-c2ccc(OC(C)C)cc2)c2ccc(Oc3ccc(C(F)(F)F)cc3)cc12
Product: COC(=O)c1c(C(=O)OC)n(-c2ccc(OC(C)C)cc2)c2ccc(Oc3ccc([N+](=O)[O-])cn3)cc12

Procedure:
The title compound was prepared in accordance with step (c) Example 38 from 5-hydroxy-1-(4-isopropoxyphenyl)indole-2,3-dicarboxylic acid dimethyl ester (150 mg, 0.39 mmol, see (b) Example 12) and 2-chloro-5-nitropyridin (75 mg, 0.47 mmol). Yield 169 mg (86%).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.[N:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>ClCCl>[OH:23][N:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18](=[O:19])[C:17]1[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=Nc1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(C(=O)N(O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (7.61 mg, 0.05 mmol) was added under argon to a solution of 4-methoxybenzaldehyde (136 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (18.15 mg, 0.05 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]1[C:21]2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=[C:17]([NH2:24])[C:16]=2[N:15]=[C:14]1[CH3:25].C(N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:24][C:17]1[C:16]2[N:15]=[C:14]([CH3:25])[N:13]([CH2:12][CH2:11][O:10][CH2:9][CH2:8][NH:7][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C:21]=2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=1
Reactant: CC(C)C(=O)Cl
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(N)c2nc(C)n(CCOCCNC(=O)C(C)C)c2c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.4 %

Procedure:
Under a nitrogen atmosphere, isobutyryl chloride (330 μL, 3.15 mmol) was added to a solution of 1-[2-(2-aminoethoxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine (0.757 g, 2.875 mmol) in chloroform (11 mL) and triethylamine (520 μL, 3.78 mmol). The reaction mixture was stirred at ambient temperature for about 3 hours; then it was diluted with chloroform (20 mL) and washed with saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (10 g of silica gel eluting with 2% methanol in chloroform containing 0.5% triethylamine) to provide 0.3486 g of N-{2-[2-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)ethoxy]ethyl}-2-methylpropanamide as a solid, m.p. 179.5-182° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:39]1[C:47]2[C:42](=[C:43](B3OC(C)(C)C(C)(C)O3)[C:44]([F:48])=[CH:45][CH:46]=2)[CH:41]=[CH:40]1)(C(C)(C)C)(C)C>>[F:48][C:44]1[C:43]([C:2]2[N:3]=[C:4]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[C:5]3[N:11]=[C:10]([CH2:12][CH:13]4[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:42]2[C:47](=[CH:46][CH:45]=1)[NH:39][CH:40]=[CH:41]2
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc3nc(-c4c(F)ccc5[nH]ccc45)nc(N4CCOCC4)c3n2)CC1

Procedure:
tert-butyl 4-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidine-1-carboxylate (0.2 g) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A and purified via reverse phase hplc to produce 57.5 mg of 137. MS (Q1) 547.3 (M)+
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:28]=[CH:27][C:26]([N:29]([CH2:34][CH:35]2[CH2:37][CH2:36]2)[S:30]([CH3:33])(=[O:32])=[O:31])=[CH:25][C:10]=1[C:11]([O:13][CH2:14][C:15]([O:17]CC1C=CC=CC=1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([O:8][C:9]1[CH:28]=[CH:27][C:26]([N:29]([CH2:34][CH:35]2[CH2:36][CH2:37]2)[S:30]([CH3:33])(=[O:32])=[O:31])=[CH:25][C:10]=1[C:11]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Oc1ccc(N(CC2CC2)S(C)(=O)=O)cc1C(=O)OCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Oc1ccc(N(CC2CC2)S(C)(=O)=O)cc1C(=O)OCC(=O)O
Reaction time: 3 h
Yield: 89.8 %

Procedure:
A mixture of 2-(benzyloxy)-2-oxoethyl 2-(tert-butoxycarbonyloxy)-5-(N-(cyclopropylmethyl)methylsulfonamido)benzoate (0.288 g, 0.540 mmol) and 10% w/w Pd/C (0.030 g, 0.028 mmol) in MeOH (20 ml) and EtOAc (5 ml) was hydrogenated at 20 psi for 3 hours. The catalyst was filtered off and the solvent was removed affording 2-(2-(tert-butoxycarbonyloxy)-5-(N-(cyclopropylmethyl)-methylsulfonamido)benzoyloxy)-acetic acid (0.215 g, 0.485 mmol, 90% yield). This product was used without purification.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].ClCCl.C(N(C(C)C)CC)(C)C.[CH2:19]1[CH:23]2[CH2:24][NH:25][CH2:26][CH:22]2[CH2:21][N:20]1[C:27]1[CH:28]=[CH:29][C:30]2[N:31]([C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][N:35]=2)[N:32]=1>C1(C)C=CC=CC=1>[CH2:1]([S:3]([N:25]1[CH2:24][CH:23]2[CH2:19][N:20]([C:27]3[CH:28]=[CH:29][C:30]4=[N:35][N:34]=[C:33]([C:36]([F:39])([F:37])[F:38])[N:31]4[N:32]=3)[CH2:21][CH:22]2[CH2:26]1)(=[O:5])=[O:4])[CH3:2]
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)N1CC2CN(c3ccc4nnc(C(F)(F)F)n4n3)CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.5 %

Procedure:
Ethanesulfonyl chloride (0.024 g, 0.19 mmol) and then dichloromethane (0.5 mL) were added sequentially to a mixture of diisopropylethylamine (0.044 g, 0.34 mmol) and 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.050 g, 0.17 mmol) in toluene (1.5 mL). The reaction mixture was stirred for 1 hour at ambient temperature and then for 1.5 hours at 50° C. and then evaporated to give an involatile residue. The residue was purified by preparative hplc using a Phenomenex Luna C18 100A column (10μ silica, 21 mm diameter, 150 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% trifluoroacetic acid) and acetonitrile as eluents to give 6-(5-ethylsulfonyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[3,4-f]pyridazine (0.0143 g, 22%) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.[Cu](I)I>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: Brc1ccccn1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnn(-c2ccccn2)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
A mixture of ethyl 1H-pyrazole-4-carboxylate (1.57 g, 11.2 mmol), 2-bromopyridine (5.5 mL, 57.7 mmol), copper iodide (0.463 g, 2.43 mmol), N,N′-dimethylethane-1,2-diamine (1.00 mL, 9.17 mmol) and potassium carbonate (3.32 g, 24.0 mmol) in toluene (50 mL) was allowed to stir at 110° C. overnight. The reaction mixture was allowed to cool to rt and then diluted with EtOAc. The organic mixture was filtered (filter paper) and the residue was purified by column chromatography to give ethyl 1-pyridin-2-yl-1H-pyrazole-4-carboxylate (1.66 g) as a white solid. LCMS: (FA) ES+ 218.4.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[CH3:16])=[CH:4][CH:3]=1.[CH2:19]=O>C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[CH3:16])[CH3:19])=[CH:17][CH:18]=1
Reactant: C=O
Reactant: Cc1nccn1CCCNCc1ccc(Cl)cc1
Solvent: O=CO
Product: Cc1nccn1CCCN(C)Cc1ccc(Cl)cc1

Procedure:
In a similar manner to Example 90, N-(4-chlorobenzyl)-3-(2-methylimidazol-1-yl)propylamine was treated with formaldehyde and formic acid to give N-(4-chlorobenzyl)-N-methyl-3-(2-methylimidazol-1-yl)propylamine, b.p. 160°-166° C. (0.2 mmHg).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7]I.[Br:9][C:10]1[CH:11]=[N:12][N:13](C)[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1>CN(C=O)C>[Br:9][C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[N:13][N:12]([CH3:7])[CH:11]=1
Reactant: Cn1ncc(Br)c1-c1ccc(Cl)cc1
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1cc(Br)c(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cs2CO3 (38.0 g, 116.0 mmol) was added to a solution of Ex 3-Step 1 product (15.0 g, 58.0 mmol) in DMF (63 mL). Methyl iodide (3.74 mL, 58.2 mmol) was added and the resulting pink colored solution was stirred at rt for 2 hr. The mixture was concentrated and the residue was partitioned between EtOAc and water. The organic phase was separated and washed with brine, dried (MgSO4) and concentrated. Silica gel chromatography using 40% heptane/CH2Cl2 yielded 10.1 g (64%) of Ex 3-Step 2 product as a white solid. 1H NMR (CDCl3) showed ˜5% of the corresponding regioisomer (4-bromo-5-(4-chlorophenyl)-1-methyl-1H-pyrazole). The identities of the two regiosomers were established via NMR NOE (Nuclear Overhauser Effect) experiments. This material was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.80-7.82 (m, 2H), 7.43 (s, 1H), 7.35-7.38 (m, 2H), 3.90 (s, 3H).