Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C@H:15]([N:19]2[CH2:22][C:21]4([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH2:20]2)[CH2:14][CH2:13]3)[CH:5]=1.C(N(CC)CC)C.Cl.[CH3:36][C:37]1[S:41][C:40]2=[N:42][C:43]([CH2:45][C:46](O)=[O:47])=[CH:44][N:39]2[CH:38]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[CH3:36][C:37]1[S:41][C:40]2=[N:42][C:43]([CH2:45][C:46]([N:25]3[CH2:26][CH2:27][C:21]4([CH2:22][N:19]([C@H:15]5[C:16]6[C:12](=[CH:11][C:10]([C:6]7[CH:5]=[C:4]([CH3:3])[N:9]=[CH:8][N:7]=7)=[CH:18][CH:17]=6)[CH2:13][CH2:14]5)[CH2:20]4)[CH2:23][CH2:24]3)=[O:47])=[CH:44][N:39]2[CH:38]=1
Reactant: Cc1cc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)ncn1
Reactant: Cc1cn2cc(CC(=O)O)nc2s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCN(C(=O)Cc4cn5cc(C)sc5n4)CC3)C2)ncn1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 2-[(R)-5-(6-methyl-pyrimidin-4-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane dihydrochloride (540 mg, 1.22 mmol) in 10 mL of dichloromethane was added triethylamine (492 mg, 4.90 mmol). Once the mixture became a homogenous solution, it was added to a solution of 2-(2-methylimidazo[2,1-b]thiazol-6-yl)acetic acid hydrochloride (251 mg, 1.28 mmol) in 3 mL of dichloromethane. The mixture was stirred for 5 minutes and HBTU (462 mg, 1.22 mmol) in 2 mL of DMF was added. The reaction was stirred at room temperature for 1.5 hours. The reaction was quenched by the addition of 10 mL of NaHCO3 and was diluted with 50 mL of dichloromethane. The organic layer was washed with saturated brine, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was dissolved in 5 mL of CH3CN and the solution was heated to 100° C. for 1 hour with stirring. The mixture was cooled to room temperature and the resulting solids were vacuum filtered to afford the desired product as an off white powder (428 mg, 69%). MS (ES+) 513.5 (M+H)+. 1H NMR (CD3OD) δ 1.70-1.74 (m, 4H), 1.88-1.96 (m, 1H), 2.27-2.34 (m, 2H), 2.40 (s, 3H), 2.58 (s, 3H), 2.86-2.97 (m, 1H), 3.11-3.15 (m, 1H), 3.31-3.34 (m, 3H), 3.52-3.55 (m, 4H), 3.78 (s, 2H), 4.05-4.09 (m, 1H), 7.33 (s, 2H), 7.55 (d, 1H), 7.78-7.79 (m, 1H), 7.94-8.03 (m, 2H), 8.93 (s, 1H). [α]D20=+45.3 deg (c=2.5 mg/mL, MeOH).
Reaction SMILES: C1([C:7]2O[N:10]=[C:9]([NH2:12])[N:8]=2)C=CC=CC=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:22])[F:21]>>[F:23][C:20]([F:21])([F:22])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:13]1[CH:7]=[N:8][C:9]([NH2:12])=[N:10]1
Reactant: Nc1noc(-c2ccccc2)n1
Reactant: Nc1ccccc1C(F)(F)F
Product: Nc1ncn(-c2ccccc2C(F)(F)F)n1
Yield: 94 %

Procedure:
Prepared in analogy to example 18a), starting with 5-phenyl-[1,2,4]oxadiazol-3-ylamine and 2-aminobenzotrifluoride. The title compound was obtained as brownish solid in a yield of 94%. MS ISP (m/e): 229.2 (64) [(M+H)+].
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>CN(C=O)C.CCOC(C)=O>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: CCNCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)c1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 115 °C

Procedure:
A mixture of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline (1.44 g, 3.33 mmol, Intermediate 3: step c) and diethylamine (6.91 mL, 66.5 mmol) in DMF (10 mL) in a sealed tube was heated in a 115° C. oil bath for 23 h. The mixture was diluted with EtOAc and extracted with water (5×, sat. aq. NaCl added as needed to achieve phase separation). The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, dry loading, 2-10% EtOAc-heptanes first column, 0-4% EtOAc-heptanes second column) to afford the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:7]([N:6]3[C:2]([OH:1])=[C:3]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=4)[CH:4]=[N:5]3)=[N:8][CH:9]=2)[CH2:26][CH2:25]1
Reactant: COc1cc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccn1
Reactant: NC1CC1
Product: COc1cc(-c2cnn(-c3ccc(C(=O)NC4CC4)cn3)c2O)ccn1

Procedure:
The title compound was prepared in a manner similar to Example 198 using 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H-pyrazol-1-yl)nicotinic acid and cyclopropanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 0.49-0.57 (m, 2 H) 0.63-0.71 (m, 2 H) 2.80 (td, J=7.3, 3.8 Hz, 1 H) 3.82 (s, 3 H) 7.41 (br. s., 1 H) 7.48 (d, J=5.6 Hz, 1 H) 8.01 (d, J=5.8 Hz, 1 H) 8.27-8.35 (m, 1 H) 8.38 (br. s., 1 H) 8.51-8.68 (m, 2 H) 8.76-8.85 (m, 1 H). MS m/z 352 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C(N(CC)CC)C.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.O>C(Cl)Cl>[CH3:2][O:3][N:4]([CH3:5])[C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(C(F)(F)F)cc1

Procedure:
A suspension of 19.9 grams (0.204 mole) of N-methoxy-N-methylamine hydrochloride in 500 ml of methylene chloride was stirred, and 39.3 grams (0.389 mole) of triethylamine was added. Upon completion of addition, the reaction mixture was stirred for ten minutes, and a solution of 4-trifluoromethylbenzoyl chloride in 25 ml of methylene chloride was added dropwise. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 18 hours. After this time the reaction mixture was stirred vigorously with 300 ml of water. The aqueous layer was separated from the organic layer and was washed with three portions of methylene chloride. The washes were combined with the organic layer, and the combination was dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure, yielding 42.5 grams of N-methoxy-N-methyl-4-trifluoromethylbenzamide as an oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=O)[NH:7][CH:8](OC)[CH:9]([F:12])[C:10]=2[CH:11]=1.P(Cl)(Cl)([Cl:18])=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([F:12])[CH:8]=[N:7][C:6]=2[Cl:18]
Reactant: COC1NC(=O)c2ncc(Cl)cc2C1F
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Fc1cnc(Cl)c2ncc(Cl)cc12
Temperature: 75 °C
Reaction time: 15 h
Yield: 79.1 %

Procedure:
A vial was charged with 3-chloro-5-fluoro-6-methoxy-6,7-dihydro-1,7-naphthyridin-8(5H)-one (7.5 g, 32.5 mmol), acetonitrile (130 mL) and phosphorus oxychloride (9.09 mL, 98 mmol), and the mixture was stirred at 75° C. for 15 hours. The mixture was concentrated, and the crude material was purified by silica gel chromatography, eluting with 0-50% ethyl acetate in heptanes, to provide the title compound (5.57 g, 25.7 mmol, 79% yield) as a white solid. LC/MS (ESI+) m/z=217 (M+H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])=[N+]=[N-].Cl>[Pd].CO>[NH2:1][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc(CN=[N+]=[N-])ccc1Cc1ccc(F)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(CN)ccc1Cc1ccc(F)cc1
Yield: 91.5 %

Procedure:
A mixture of methyl 5-azidomethyl-2-(4-fluorobenzyl)benzoate (3.23 g), 10% palladium on carbon (0.5 g), 1M. ethereal HCl (20 ml) and methanol (100 ml) was stirred under an atmosphere of hydrogen for 6 hours. The catalyst was filtered off and the filtrate was evaporated to dryness. The residue was treated with saturated aqueous sodium bicarbonate (100 ml) and extracted with ethyl acetate. The solution obtained was dried and evaporated to dryness to give methyl 5-aminomethyl-2-(4-fluorobenzyl)benzoate as a colourless gum (2.7 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])[CH2:9][C:10]1[N:14]2[CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21](Cl)=[CH:20][C:19]=3[C:13]2=[N:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[H][H]>[Pd].CO>[C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])[CH2:9][C:10]1[N:14]2[CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:13]2=[N:12][N:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)Cc1nnc2n1CCOc1ccc(Cl)cc1-2
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)Cc1nnc2n1CCOc1ccccc1-2

Procedure:
A mixture of 20 mg (0.0407 mmol) of tert-butyl[(1R)-2-(10-chloro-5,6-dihydro[1,2,4]triazolo[4,3-d][1,4]benzoxazepin-3-yl)-1-(2,5-difluorobenzyl)ethyl]carbamate, 0.007 mL (5.1 mg, 0.05 mmol) of triethylamine, 9.3 mg of 10% palladium on carbon, and 0.5 mL of methanol was shaken with hydrogen (45 psig) for 3 h. The catalyst was removed by filtration, and the filtrate was concentrated to yield the title compound. LC-MS 457 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[C:8]([N+:15]([O-:17])=[O:16])=[CH:9][C:10]([CH3:14])=[N+:11]([O-])[CH:12]=1)=[O:4].[F:18][C:19]([F:30])([F:29])[C:20]([O:22]C(=O)C(F)(F)F)=[O:21]>>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[C:8]([N+:15]([O-:17])=[O:16])=[CH:9][C:10]([CH2:14][O:22][C:20](=[O:21])[C:19]([F:30])([F:29])[F:18])=[N:11][CH:12]=1)=[O:4]
Reactant: COC(=O)COc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)COc1cnc(COC(=O)C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The pyridine N-oxide (d) (3.8 g) in trifluoroacetic anhydride (120 ml) was refluxed under argon for 24 hours, the solvent evaporated and the residue partitioned between chloroform and aqueous NaHCO3 (50 ml each). The aqueous fraction was re-extracted with chloroform (3×50 ml) and the combined organic solution dried and evaporated to give the product (1.8 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9]1)=O)CCC>C(O)(C(F)(F)F)=O>[CH2:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCOC(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1CCNCC1

Procedure:
960 mg (3 mmol) of N-butoxycarbonyl-N'-benzyloxycarbonylpiperazine was dissolved in 8 ml of TFA and aged for 1 hour. The TFA was evaporated in a stream of N2 and then to the residue was added water and NaOH to pH12. The basic mixture was extracted with 3×15 ml of ethyl acetate, backwashed with saturated aqueous NaCl, dried with Na2SO4 and concentrated to 566 mg of an oil whose mass spectrum had a parent peak at m/e=220. NMR (3CDCl, δ from TMS) δ2.8 (m, 4), δ3.5 (t, 4), δ5.12 (s, 2), δ7.38 (m, 5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:10]=2)[N:7]=1.[Cl:19]N1C(=O)CCC1=O.O>C(OCC)(=O)C>[Cl:19][C:8]1[N:6]2[N:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[C:11]([CH3:17])([CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(C)(C)c1nc2ccc(Cl)nn2c1Cl
Yield: 97.5 %

Procedure:
4.07 g of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate was suspended in 60 ml of ethyl acetate; 2.13 g of N-chlorosuccinimide was added, followed by thermal refluxing for 4 hours. After cooling, water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (5:1). The desired fraction was collected and concentrated under reduced pressure to yield 4.48 g of the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:16]P(OCC)(OCC)=O)=[N:11][C:12]=2[CH:13]=[CH:14][CH:15]=1)=[O:5])C.[H-].[Na+].[Cl:27][C:28]1[CH:29]=[C:30]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[C:31]2[N:32]([C:34]([C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)=[C:35]([CH:37]=O)[N:36]=2)[N:33]=1>CN(C=O)C>[Cl:27][C:28]1[CH:29]=[C:30]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[C:31]2[N:32]([C:34]([C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)=[C:35](/[CH:37]=[CH:16]/[C:10]3[CH:9]=[CH:8][C:7]4[C:6]([C:4]([OH:3])=[O:5])=[CH:15][CH:14]=[CH:13][C:12]=4[N:11]=3)[N:36]=2)[N:33]=1
Reactant: CCOC(=O)c1cccc2nc(CP(=O)(OCC)OCC)ccc12
Reactant: O=Cc1nc2c(N3CCOCC3)cc(Cl)nn2c1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cccc2nc(/C=C/c3nc4c(N5CCOCC5)cc(Cl)nn4c3-c3cccnc3)ccc12
Reaction time: 0.17 h
Yield: 80.2 %

Procedure:
To a solution of compound 73d (90 mg, 0.26 mmol) in DMF (3 mL) was added NaH (29 mg, 0.72 mmol) in one portion. Compound 73f (88 mg, 0.26 mmol) was then added as a slurry in DMF (1 mL). The reaction mixture was stirred for 10 min, quenched with water (1 mL) and acidified to pH 5 with 10% citric acid. The solid formed was collected by filtration, washed with water (2 mL), diethyl ether (5 mL), and dried under reduced pressure to afford compound 73g (107 mg). Mass spectrum (LCMS, ESI pos.) Calcd. For C27H21ClN6O3: 513.1 (M+H). found 512.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([NH:15][CH3:16])[N:7]=[C:6]2[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=1.C(N(CC)CC)C.C(O)C.[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([NH:15][CH3:16])[N:7]=[C:6]2[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:18]=1
Reactant: CNc1nc(-c2cccc(C#Cc3ccccc3)c2)c2cc(OC)c(OC)cc2n1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNc1nc(-c2cccc(CCc3ccccc3)c2)c2cc(OC)c(OC)cc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.6 %

Procedure:
70.0 mg of 6,7-dimethoxy-2-methylamino-4-[3-(2-phenyl ethynyl)phenyl]quinazoline obtained in Example 65, 50.0 mg Lindlar catalyst and 50.0 mg triethylamine were suspended in a mixed solvent of 5 ml ethanol and 5 ml tetrahydrofuran. After the atmosphere was replaced with hydrogen, the mixture was stirred for 6 hours at ordinary pressure at room temperature. The reaction solution was filtered, and the filtrate was evaporated. Then, the crude product was purified and separated by silica gel column chromatography (hexane:ethyl acetate=2:1). The product was recrystallized from hexane-isopropanol to give 45.0 mg of the title compound as colorless crystals.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.S(Cl)(Cl)=O.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[CH:14][CH:13]=2)=[CH:23][C:22]=1[N:28]1[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: O=C(O)c1ccc(-n2cncn2)cc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2ccc(-n3cncn3)cc2)cc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
Ethyl 4-(1,2,4-triazol-1-yl)benzoate (520 mg, 2.4 mmol) was heated at reflux in 5N HCl (40 ml) for 1 h, and the product filtered off and dried in vacuo to afford the acid (88%). 4-(1,2,4triazol-1-yl)benzoic acid (0.395 g, 2.1 mmol) was suspended in dry toluene (40 ml) and thionyl chloride (2 ml) added under argon. The mixture was heated to reflux for 1.5 h and then evaporated to dryness under reduced pressure. The oil was dissolved in dichloromethane under argon and 4-methoxy-3-(4-methyl-1-piperazinyl)phenylamine (460 mg, 2.1 mmol) was added followed by triethylamine (2 ml). The mixture was stirred at room temperature under argon for 2 h and then partitioned between dichloromethane (50 ml) and saturated potassium carbonate (50 ml), and the organic extracts dried (sodium sulphate). The organic solution was filtered, evaporated to dryness under reduced pressure and purified by column chromatography (silica, chloroform/methanol 5-10%) to afford the amide (757 mg, 92%) which was crystallised from methanol diethyl ether as the oxalate salt.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][CH2:17][OH:18])[C:9]([CH2:11][O:12][C:13](=[O:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH2:1]([N:8]([CH2:16][CH:17]=[O:18])[C:9]([CH2:11][O:12][C:13](=[O:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OCC(=O)N(CCO)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)OCC(=O)N(CC=O)Cc1ccccc1
Temperature: -15 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
Acetic acid [benzyl-(2-hydroxyethyl)carbamoyl]methyl ester (1.28 g, 5.10 mmol) was weighed into a 200 mL round bottom flask and purged with nitrogen. Dichloromethane (50 mL) was added, and the reaction was cooled to −15° C. for 10 minutes. Dimethylsulfoxide (3.61 mL, 51.0 mmol.), N,N-diisopropylethylamine (4.43 mL, 25.5 mmol), and pyridine sulfur trioxide complex (4.06 g, 25.5 mmol) were then added sequentially at −15° C. The reaction was allowed to warm slowly to room temperature and stirred overnight. The reaction was complete by thin layer chromatography, and was diluted with ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was separated and dried over anhydrous magnesium sulfate. The drying agent was removed via filtration and solvent was removed in vacuo to give crude title compound as a yellow oil. The crude material was chromatographed on silica gel using 1:1 ethyl acetate:dichloromethane as the mobile phase. Fractions were combined and solvent was removed in vacuo to give pure title compound as a colorless oil (0.72 g, 57% yield). (m/z): [M+H]+ calcd for C13H15NO4 250.11, found 250.0.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]4[O:18][CH2:19][O:20][C:14]=4[CH:13]=3)[C:9](=[O:11])[NH:10][C:5]2=[CH:4][CH:3]=1.[OH-].[K+].[CH2:23](Br)[CH:24]=[CH2:25]>CC(C)=O>[CH2:25]([N:10]1[C:5]2[C:6](=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:8]([C:12]2[CH:17]=[CH:16][C:15]3[O:18][CH2:19][O:20][C:14]=3[CH:13]=2)[C:9]1=[O:11])[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: O=c1[nH]c2ccc(Cl)nc2n1-c1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=CCn1c(=O)n(-c2ccc3c(c2)OCO3)c2nc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of 4.6 g. (0.016 mole) of the imidazopyridine product of Step C in 175 ml. of acetone, was added 1.8 g. (0.032 mole) of powdered potassium hydroxide. After stirring at room temperature for 20 minutes, 3.9 g. (0.032 mole) of allylbromide was added. Stirring at room temperature was continued overnight and the mixture then was concentrated to one-half volume. The concentrate was diluted with 150 ml. of water and the crude product was collected by filtration. The crude product was crystallized from 70 ml. of ethanol giving 2.0 g. of needles melting at 146°-148° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.2 %

Procedure:
Commercially available 4-bromobenzylalcohol (4.00 g, 21.5 mmol) was dissolved in DMF (100 mL), and tert-butyldimethylsilyl chloride (4.86 g, 32.2 mmol) and imidazole (2.20 g, 32.3 mmol) were added to the solution, followed by stirring at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:80) to obtain 4-bromobenzyloxy-tert-butyldimethylsilane (5.52 g, yield 85%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@:9]2([OH:17])[CH2:14][CH2:13][NH:12][CH2:11][C@:10]2([CH3:16])[OH:15])=[CH:5][CH:4]=1.[CH:18]1([C:23]([NH:25][C:26]([CH3:32])([CH3:31])[CH2:27][C:28](O)=[O:29])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1.C(O)(C(F)(F)F)=O.C(#N)C.O.C(O)(C(F)(F)F)=O>O.CC#N>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@:9]2([OH:17])[CH2:14][CH2:13][N:12]([C:28](=[O:29])[CH2:27][C:26]([NH:25][C:23]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:24])([CH3:32])[CH3:31])[CH2:11][C@@:10]2([OH:15])[CH3:16])=[CH:5][CH:4]=1
Reactant: CC(C)(CC(=O)O)NC(=O)C1CCCC1
Reactant: C[C@]1(O)CNCC[C@]1(O)c1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CC(=O)N1CC[C@](O)(c2ccc(Cl)cc2)[C@@](C)(O)C1)NC(=O)C1CCCC1

Procedure:
Example 96 was prepared from (3S,4S)-4-(4-chlorophenyl)-3-methylpiperidine-3,4-diol hydrochloride and 3-(cyclopentanecarboxamido)-3-methylbutanoic acid using the procedure described in Example 93, step 6. MS (ESI+)=437.3 (M+H)+. 1H NMR (CD3OD, 500 MHz) (NMR shows several rotamers) δ ppm 7.55-7.50 (m, 2 H), 7.31 (d, J=8.5 Hz, 2 H), 4.53 (dd, J=10.7, 1.9 Hz, 0.4 H), 4.28 (dt, J=12.4, 0.8 Hz, 0.6 H), 4.04 (dd, J=13.2, 2.7 Hz, 0.6 H), 3.69 (dd, J=13.1, 2.3 Hz, 0.4 H), 3.59-3.52 (m, 1 H), 3.24 (d, J=14.6 Hz, 0.4 H), 3.09 (d, J=12.1 Hz, 1 H), 2.65-2.49 (m, 2 H), 2.42 (td, J=13.3, 4.7 Hz, 0.4 H), 1.89-1.53 (m, 10 H), 1.47-1.40 (m, 6 H), 0.93 (s, 1.1 H), 0.92-0.86 (m, 2.4 H); HPLC Method: Inj. Vol.=5 uL, Start % B=10, 12 Min. 100%, 15 Min. 100%, Flow Rate=2 mL/min (1 mL/min on each column), Wavelength 1=220 nm, Wavelength 2=254 nm, Solvent Pair=TFA−ACN/H2O, Solvent A=0.05% TFA in H2O:MeCN (95:5), Solvent B=0.05% TFA in H2O:MeCN (5:95), Col-1: Sunfire C18 3.5 um, 4.6×150 mm; Retention Time=8.27 minutes, Col-2: Xbridge Phenyl 3.5 um, 4.6×150 mm; Retention Time=7.76 minutes.