Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Br:7][C:8]1[CH:9]=[N:10][C:11](I)=[N:12][CH:13]=1.[OH:15][CH2:16]/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:7][C:8]1[CH:9]=[N:10][C:11]([C:22]2[CH:23]=[CH:24][C:19](/[CH:18]=[CH:17]/[CH2:16][OH:15])=[CH:20][CH:21]=2)=[N:12][CH:13]=1
Reactant: OC/C=C/c1ccc(B(O)O)cc1
Reactant: Brc1cnc(I)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: OC/C=C/c1ccc(-c2ncc(Br)cn2)cc1
Yield: 17.9 %

Procedure:
2 M aq. Na2CO3 (2 mL) was added to a mixture of 5-bromo-2-iodopyrimidine (0.57 g, 2.00 mmol), Pd(Ph3P)4 (23 mg, 0.020 mmol), and [4-[(1E)-3-hydroxy-1-propenyl]phenyl]boronic acid (360 mg, 2.02 mmol, prepared as described in Reference Example 238) in toluene (5 mL) and the resulting mixture was heated to reflux for 24 h. The cooled reaction mixture was diluted with ethyl acetate (20 mL) and the organic layer was separated, washed with brine (10 mL), dried (MgSO4) and concentrated. Purification by chromatography (SiO2, 3:1 hexane/ethyl acetate) provided 104 mg (18%) of the title compound as a yellow solid. MS 291, 293 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH:24]=[CH:23][CH:22]=[CH:21]3)[C:17]([I:25])=[CH:16][C:15]=2[N+:26]([O-])=O)=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].O.O.Cl[Sn]Cl>CCO>[I:25][C:17]1[C:18]([N:20]2[CH:24]=[CH:23][CH:22]=[CH:21]2)=[CH:19][C:14]2[NH:13][C:11](=[O:12])[CH2:10][C:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[C:1]#[N:2])=[N:26][C:15]=2[CH:16]=1
Reactant: N#Cc1cccc(C(=O)CC(=O)Nc2cc(-n3cccc3)c(I)cc2[N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: N#Cc1cccc(C2=Nc3cc(I)c(-n4cccc4)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from 3-(3-cyano-phenyl)-N-(4-iodo-2-nitro-5-pyrrol-1-yl-phenyl)-3-oxo-propionamide (Example M9) by reductive cyclization with SnCl2.2H2O in EtOH at 70° C. according to the general procedure J (method b). Obtained as a yellow solid (344 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:26]([F:29])([F:28])[F:27])=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>CO>[C:20]1([C:18]2[CH:19]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:15]=[N:16][C:17]=2[C:26]([F:29])([F:28])[F:27])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccccc3)c(C(F)(F)F)nn2)CC1
Solvent: CO
Product: FC(F)(F)c1nnc(N2CCNCC2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.8 %

Procedure:
To a solution of 4-(5-phenyl-6-trifluoromethyl-pyridazin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (D4) (1.8 g, 0.0044 mol) in methanol (125 ml) was added Amberlyst® 15 ion exchange resin, acidic form (4.1 mmol/g) (5.3 g, 0.022 mol) and the reaction mixture was shaken at room temperature for 18 h. After this period, the mixture was filtered and then a saturated solution of ammonia in methanol was added. The mixture was shaken for 1 h, filtered and the filtrate evaporated in vacuo. The crude product was crystallised from ether/heptane to yield E1 (1.3 g, 96%). C15H15F3N4 requires 308; Found 309 (MH+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH2:14][NH:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[S:17])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[CH2:25](Br)[CH:26]=[CH2:27]>O1CCCC1>[CH2:27]([S:17][C:16](=[N:15][CH2:14][C:5]1[C:4]([Cl:3])=[CH:9][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:7][N:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: FC(F)(F)c1cnc(CNC(=S)c2ccccc2Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCSC(=NCc1ncc(C(F)(F)F)cc1Cl)c1ccccc1Cl
Reaction time: 0.33 h

Procedure:
To a mixture of sodium hydride (0.33 g) in tetrahydrofuran (10 ml) was added N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-2-chlorobenzenethioamide (for preparation see PCT/GB/99/00304) (3.07 g) in tetrahydrofuran (50 ml) dropwise with stirring for 20 minutes until effervescence had ceased. Allyl bromide (0.09 g) in tetrahydrofuran (5 ml) was added to the reaction mixture, and the solution was stirred overnight at room temperature. The mixture was evaporated to dryness and the residue partitioned between dichloromethane (10 ml), water (5 ml) and brine (5 ml). The organic phase was separated and the solvent and any residual water evaporated in vacuo. The residue was purified by silica gel chromatography, gradient eluting with light petroleum (b.p. 60-80° C.)/diethyl ether to give the title product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]1[CH2:8][C@@H:7](O)[CH2:6][N:5]1[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(S(F)(F)[F:25])CC)C.N1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]1[CH2:8][C@H:7]([F:25])[CH2:6][N:5]1[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1C[C@H](F)CN1C(=O)c1ccccc1
Temperature: -45 °C
Yield: 64 %

Procedure:
A solution of (trans)-1-benzoyl-4-hydroxy-L-proline methyl ester prepared as described in Example 1 Part A(2) (6 g, 24.1 mmole) was dissolved in dichloromethane and cooled to -45° C. under an argon atmosphere. To the above solution diethylaminosulfur trifluoride (5.2 ml, 42 mmole) was added dropwise. The resulting solution was stirred and warmed to -35° C. To the above solution pyridine was added dropwise (9 ml, 116 mmole). The reaction was allowed to stir overnight while warming to room temperature. The solvent was removed in vacuo and the oily residue treated with ethyl acetate and 1N HCl. The mixture was transferred to a separatory funnel, the aqueous layer removed, and the organic layer washed with additional 1N HCl, then water and saturated sodium bicarbonate solution. The organic solution was dried over sodium sulfate, filtered and concentrated to a yellow oil. The crude product was chromatographed on silica gel using 1:1 ethyl acetate:hexane as eluent. Combination and concentration of product containing fractions produced 3.9 gm (64%) of title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][O:8][C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]([OH:22])=O)[CH:16]=3)[N:11]([CH3:23])[CH:10]=2)=[CH:5][CH:4]=1.[N:26]1([CH2:31][CH2:32][NH2:33])[CH2:30][CH2:29][CH2:28][CH2:27]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][O:8][C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]([NH:33][CH2:32][CH2:31][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[O:22])[CH:16]=3)[N:11]([CH3:23])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2cn(C)c3ccc(C(=O)O)cc3c2=O)cc1
Reactant: NCCN1CCCC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(COc2cn(C)c3ccc(C(=O)NCCN4CCCC4)cc3c2=O)cc1
Temperature: 30 °C
Reaction time: 24 h
Yield: 78.8 %

Procedure:
To a suspension of 3-((4-methoxybenzyl)oxy)-1-methyl-4-oxo-1,4-dihydroquinoline-6-carboxylic acid (Example 5e) (0.588 g, 1.733 mmol), 2-(pyrrolidin-1-yl)ethanamine (0.240 ml, 1.906 mmol), EDC (0.3865 g, 2.016 mmol), HOAt (0.1218 g, 0.895 mmol) in dichloromethane (16 ml) was added triethylamine (1.7 ml, 12.20 mmol), and the mixture was allowed to stir at 30° C. for 24 h. After cooling, the reaction was concentrated and the residue was purified on a silica gel column (24 g), eluting with 0-20% methanol/dichloroethane (2% ammonium hydroxide). The desired fractions were collected, concentrated. The solid was washed with water, filtered, and dried in vacuo to afford 3-((4-methoxybenzyl)oxy)-1-methyl-4-oxo-N-(2-(pyrrolidin-1-yl)ethyl)-1,4-dihydroquinoline-6-carboxamide (0.595 g, 1.366 mmol, 79% yield) as white solid. LCMS: (M+H)+: 436.2.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([NH:9][C:10](=[O:12])[CH3:11])[CH2:2]2.C(N1CCC(NC2[C:36]3[C:31](=[C:32](OC)[CH:33]=[C:34](OC)[CH:35]=3)[C:30]([C:41]3[CH:46]=[CH:45]C(OC)=C[CH:42]=3)=NN=2)CC1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].BrCC1C=CC2C(=CC=CC=2)C=1.[OH-].[Na+]>CC(C)=O>[CH:30]1[C:31]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:45]=[CH:46][C:41]=1[CH2:42][N:8]1[CH:5]2[CH2:6][CH2:7][CH:1]1[CH2:2][CH:3]([NH:9][C:10](=[O:12])[CH3:11])[CH2:4]2
Reactant: COc1ccc(-c2nnc(NC3CCN(Cc4ccccc4)CC3)c3cc(OC)cc(OC)c23)cc1
Reactant: CC(=O)NC1CC2CCC(C1)N2
Agent: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)NC1CC2CCC(C1)N2Cc1ccc2ccccc2c1
Reaction time: 18 h
Yield: 84 %

Procedure:
1.6 g (9.5 mmol) of N-[8-azabicyclo[3.2.1]oct-3-yl]acetamide prepared according to Dostert et al. (European Journal of Medicinal Chemistry 1984, 19 (2), 105-110) are dissolved in 45 mL of acetone, and 5.2 g of potassium carbonate and 2.5 g (11.4 mmol) of 2-(bromomethyl)naphthalene are added. The mixture is refluxed with stirring for 18 hours. After cooling, the acetone is partially evaporated off. Water is added to the residue, and the mixture is extracted with dichloromethane. The organic phase is extracted with 1N hydrochloric acid. The acidic aqueous phase obtained is basified with 1N sodium hydroxide and then extracted with dichloromethane. The extract is washed with water and with brine, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue obtained is filtered on silica gel (solvent: 95/5 (v/v) dichloromethane/methanol). 2.2 g of a pasty oil are obtained (84% yield).
Reaction SMILES: [CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH2:27][CH3:28])[CH2:7][CH2:6]1)([CH3:3])[CH3:2].[OH-].[Na+].O.CC#N>C(O)C.O1CCCC1>[CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=3)=[CH:10][C:9]=2[CH2:27][CH3:28])[CH2:6][CH2:7]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC(C)C)CC3)c(CC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC#N
Product: CCc1cc(C#Cc2ccc(C(=O)O)cc2)ccc1C1(OC(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-benzoate (Compound 95, 110.0 mg, 0.29 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up and isolation by HPLC (partisil 10-pac, 10% H2O/CH3CN) afforded the title compound as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][C:8]=1[C:9]([O:11]C(C)(C)C)=[O:10])=[O:5]>C(Cl)Cl.FC(F)(F)C(O)=O>[OH:1][C:2]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[N:34][CH:33]=[N:32][CH:31]=2)=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][C:8]=1[C:9]([OH:11])=[O:10])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2cncnc2)ccc1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(-c2cncnc2)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
A solution mixture of the obtained tert-butyl 2-(2-hydroxy-5-(pyrimidin-5-yl)benzamido)-4-phenylbenzoate (0.73 g) in methylene chloride (25 mL) and trifluoroacetic acid (10 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and water was added to the obtained residue. After adjusting the pH to 6.5 with a saturated aqueous solution of sodium bicarbonate, the solid substance was collected by filtration to obtain 0.49 g of 2-(2-hydroxy-5-(pyrimidin-5-yl)benzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[N:6]=1)=[O:4].[OH-].[Na+].O1CCOCC1>CO>[NH2:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[C:8]([C:12]([F:13])([F:14])[F:15])[CH:9]=1
Reactant: COC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(C(F)(F)F)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cc(C(F)(F)F)c(-c2ccc(Cl)cc2Cl)nc1C(=O)O

Procedure:
3-Amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (0.9 g, 2.465 mmol) was suspended in MeOH (15 ml) and NaOH 2M (2.465 ml, 4.93 mmol) was added under stirring. 1,4-Dioxane (15.00 ml) was added and the solution was left standing at RT over night. The solvent was removed in vacuo and the resulting residue was dissolved in water (10 ml) and carefully acidified to pH4 with slow addition of 2M HCl (2 ml) whilst stirring. The mixture was extracted with EtOAc (20 ml) and the organic portion was washed with brine and concentrated in vacuo. The residue was purified by reverse phase chromatography (130 g C18 column) eluting with water/MeOH to afford the title compound; LS-MS Rt=1.57 mins [M+H]+ 351.0 (Method 2minLC_v002).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:14][CH2:15][C:16](Cl)=[O:17].Cl>C(=S)=S>[Cl:14][CH2:15][C:16]([C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[C:3]([O:2][CH3:1])[CH:8]=1)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: COc1ccccc1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1cc(C(=O)CCl)ccc1O
Temperature: 0 °C
Yield: 64 %

Procedure:
To a cooled (ice bath) stirred solution of 130.3 g (1.05 mole) of 2-methoxyphenol in 750 mL of carbon disulfide was continuously added 306.6 g (2.3 mole) of anhydrous aluminum chloride portionwise. The stirred, cooled mixture was then treated dropwise with 80 mL (113 g, 1.0 mole) of 2-chloroacetyl chloride. After the addition was completed, the mixture was heated at reflux temperature for 20 hr, cooled, and poured into a mixture of 2 kg of crushed ice and 200 ml of concentrated hydrochloric acid. The solid which gradually crystallized was washed with water and carbon disulfide and dried. The solid was recrystallized from isopropyl ether containing a few drops of 2-propanol to yield 128.3 g (64% yield) of the title compound, mp 102°-103° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:29](O)=[O:30]>>[OH:14][C:11]1[CH:10]=[CH:9][C:8]([N:7]2[C:3]([C:2]([F:1])([F:15])[F:16])=[N:4][N:5]=[N:6]2)=[CH:13][C:12]=1[CH:29]=[O:30]
Reactant: O=C(O)C(F)(F)F
Reactant: Oc1ccc(-n2nnnc2C(F)(F)F)cc1
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1cc(-n2nnnc2C(F)(F)F)ccc1O

Procedure:
A solution of 4-(5-trifluoromethyl-tetrazol-1-yl)-phenol (45 mmol) in trifluoroacetic acid (200 ml) and hexamethylenetetramine (186.9 mmol) was heated at 100° under nitrogen for 16 h. The reaction mixture was quenched with 2N sulphuric acid (250 ml) and extracted with ether (3×250 ml)). The combined organics were dried (Na2SO4) and evaporated to give a dark yellow oil. Purification by FCC (hexane/ether (2:1)) afforded the title compound (8.8 g) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([CH3:23])=[CH2:22]>CC(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:22][C:21]([CH3:23])=[CH2:20]
Reactant: COC(=O)c1ccc(Br)c(O)c1
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(C)COc1cc(C(=O)OC)ccc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
To a heterogeneous mixture of methyl 4-bromo-3-hydroxybenzoate (1.5 g, 6.49 mmol) and potassium carbonate (1.795 g, 12.98 mmol) in anhydrous acetone (50 mL) was added 3-bromo-2-methylprop-1-ene (2.62 mL, 26.0 mmol) at rt. The mixture was stirred rt for 4 h. The insoluble material was removed by filtration. The filtrate was concentrated under vacuum. The residue was diluted with ethyl acetate (100 mL), washed sequentially with 1 N NaOH solution (30 mL), water (2×40 mL), and brine (30 mL). The organic solution was dried over anhydrous MgSO4 and concentrated under vacuum. The residue was applied to ISCO (80 g silica gel, 5-10% ethyl acetate/hexane) to provide the desired product, methyl 4-bromo-3-(2-methylallyloxy)benzoate (1.81 g, 6.35 mmol, 98% yield), as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH2:14](Br)[CH:15]([CH3:17])[CH3:16]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC#N)c1
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(C(C#N)CC(C)C)c1
Yield: 62.3 %

Procedure:
By working in a way similar to that described in example 16 but using 3-methoxy-phenyl-acetonitrile (4.4 g, 30 mmoles), anhydrous DMF (30 ml), NaH (55-65%, 1.44 g, 36 mmoles) and isobutylbromide (4.97 g, 36 mmoles), 3.8 g of the title compound were obtained (yield: 62.3%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12](O)=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([Cl:19])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Solvent: ClCCl
Product: CC(C)Cc1ccc(C(C)C(=O)Cl)cc1
Temperature: 25 °C

Procedure:
To a well-stirred solution consisting of 3.1 g. (0.015 mole) of α-(4-isobutylphenyl)propionic acid (ibuprofen) dissolved in 200 ml. of methylene chloride, there were added 3.8 g. (0.030 mole) of oxalyl chloride. The resulting reaction mixture was refluxed for a period of two hours and then cooled to room temperature. The clear colorless solution so obtained was thereafter concentrated in vacuo to dryness to yield a residue that was substantially free of solvent and excess oxalyl chloride. In this way, there was readily obtained substantially pure α-(4-isobutylphenyl)-propionyl chloride in the form of a clear colorless oil. The latter product was used as such in the next reaction step without any purification being necessary. The yield of product was assumed to be quantitative.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([NH:9][C:10]([CH:12]3[C:14]([CH3:16])([CH3:15])[C:13]3([CH3:18])[CH3:17])=[O:11])[S:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:23][O:24][CH2:25][CH2:26]Br>CN(C=O)C.C1COCC1>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH2:26][CH2:25][O:24][CH3:23])[C:7](=[N:9][C:10]([CH:12]3[C:13]([CH3:18])([CH3:17])[C:14]3([CH3:16])[CH3:15])=[O:11])[S:8][C:4]=2[CH:3]=1
Reactant: CC1(C)C(C(=O)Nc2nc3ccc(F)cc3s2)C1(C)C
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCn1c(=NC(=O)C2C(C)(C)C2(C)C)sc2cc(F)ccc21

Procedure:
To a solution of the product of Example 112A (1 equiv) in 1:1 DMF/THF (0.1 M) was added sodium hydride (60% dispersion in mineral oil, 1.2 equiv) and 2-bromoethyl methyl ether (1.2 equiv).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:46](O)(=[O:49])[CH2:47][OH:48]>C(Cl)Cl.CO.C(Cl)CCl>[CH:24]1([NH:23][C:21]([C:16]2[CH:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:6]4[O:7][C:3]([CH2:2][NH:1][C:47](=[O:48])[CH2:46][OH:49])=[N:4][N:5]=4)=[CH:13][CH:12]=3)[C:19]([CH3:20])=[CH:18][CH:17]=2)=[O:22])[CH2:26][CH2:25]1
Reactant: O=C(O)CO
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CO
Solvent: ClCCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CNC(=O)CO)o2)cc1

Procedure:
4′-[5-(Aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Example 53) (30 mg), HOBt (11.7 mg), EDC (19.8 mg), DIPEA (0.018 ml) and glycolic acid (6.6 mg) were mixed in DCM (6 ml) and methanol (1 ml) and the reactions stirred at room temperature for 96 hours. The reaction was reduced to dryness under vacuum and the residue partitioned between DCM and water. The organic phase was evaporated and the residue purified by bond-elut (silica, 5 g) eluting with an ethyl acetate/cyclohexane gradient and then by preparative HPLC to give, after evaporation of the solvents, N-cyclopropyl-4′-{5-[(glycoloylamino)methyl]-1,3,4-oxadiazol-2-yl}-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][CH2:12][C:13]([NH2:16])([CH3:15])[CH3:14]>N1C=CC=CC=1>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:11][CH2:12][C:13]([CH3:15])([NH2:16])[CH3:14]
Reactant: CC(C)(N)CN
Reactant: Clc1nc2ccccc2s1
Solvent: c1ccncc1
Product: CC(C)(N)CNc1nc2ccccc2s1

Procedure:
A solution of 2-chlorobenzothiazole (5.0 g) in 1,2-diamino-2-methlypropane (20 ml) and pyridine (2.3 ml) was stirred 2 h at RT. The solvent was evaporated. Flash chromatography (silica gel; CH2Cl2/MeOH) provided 6.2 g of a colorless oil, which crystallized upon standing.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=[C:8]2[CH:7]=1.C(Cl)(=O)C(Cl)=O.[F:24][C:25]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:26]=1[CH2:27][N:28]1[C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([NH2:37])[C:31]=2[CH:30]=[N:29]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O.C(Cl)Cl.CN(C=O)C>[F:24][C:25]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:26]=1[CH2:27][N:28]1[C:36]2[C:31](=[C:32]([NH:37][C:15]([C:12]3[N:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]4=[N:14][CH:13]=3)=[O:17])[CH:33]=[CH:34][CH:35]=2)[CH:30]=[N:29]1
Reactant: Nc1cccc2c1cnn2Cc1ccc(F)cc1F
Reactant: COCCOc1ccn2c(C(=O)O)cnc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3ccc(F)cc3F)cnc2c1
Yield: 49.5 %

Procedure:
7-(2-Methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (0.070 g, 0.296 mmol) and a 2M solution of oxalyl chloride in methylene chloride (0.163 mL, 0.326 mmol) were suspended in methylene chloride (2 mL) with a catalytic amount of DMF. The mixture was stirred for a few minutes and then treated with 1-(2,4-difluorobenzyl)-1H-indazol-4-amine (0.084 g, 0.326 mmol) as a solution in about 1 mL methylene chloride, followed by addition of diisopropylethylamine (0.062 mL, 0.356 mmol). After stirring the mixture overnight, the residue was shaken in water/methylene chloride and suspended solids collected by filtration to provide N-(1-(2,4-difluorobenzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide (0.070 g, 50% yield). MS (APCI) m/z=478 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:16]1([N:22]=[C:23]=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:22]([CH3:23])[CH3:16])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 16 h

Procedure:
To 1-(tert-butoxycarbonyl)-L-proline (5.0 g) in DCM (50 ml) at 5° C. was added dicyclohexylcarbodiimide (5.22 g) and N-hydroxysuccinimide (2.91 g). The mixture was stirred at this temperature for 16 h. The solid was filtered and the filtrate cooled to 5° C. To this mixture was added triethylamine (9.80 ml) and dimethylamine hydrochloride (2.80 g). The mixture was stirred at room temperature for 2 days. H2O (50 ml) was added and the phases were separated and the organics were washed with saturated sodium carbonate (2×20 ml) and brine (20 ml). This was then dried (MgSO4) and evaporated to dryness to afford the title compound as a white solid. Yield: 6.0 g.