Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Li+].[Li+].Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[OH:17][C:18]1[C:23]([OH:24])=[C:22]([OH:25])[CH:21]=[CH:20][C:19]=1[C:26]([C:28]1[CH:33]=[C:32]([OH:34])[C:31]([OH:35])=[C:30]([OH:36])[CH:29]=1)=[O:27]>CN(C)C=O>[OH:17][C:18]1[C:23]([OH:24])=[C:22]([OH:25])[CH:21]=[CH:20][C:19]=1[C:26]([C:28]1[CH:33]=[C:32]([OH:34])[C:31]([O:35][CH2:8][C:9](=[O:10])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:30]([OH:36])[CH:29]=1)=[O:27]
Reactant: O=C(c1cc(O)c(O)c(O)c1)c1ccc(O)c(O)c1O
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(COc1c(O)cc(C(=O)c2ccc(O)c(O)c2O)cc1O)c1ccccc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 37.3 %

Procedure:
3.0 g of lithium carbonate then 3.5 g of ω-bromoacetophenone are added to a solution of 5.0 g of [2,3,4-trihydroxyphenyl] [3',4',5'-trihydroxyphenyl] methanone in 20 cm3 of dimethyl-formamide maintained at 50° C., under a nitrogen atmosphere. The reaction mixture is then agitated for 6 hours at 50° C. Then 400 cm3 of a molar aceto-acetic buffer solution, the pH of which is about 4.50, are added. The resultant solution is extracted with 800 cm3 of ethyl acetate. The combined organic phases are washed with 300 cm3 of distilled water, then dried over anhydrous sodium sulphate. After filtration then evaporation to dryness under reduced pressure (2.7 kPa) at 40° C. of the ethyl acetate, 9 g of a residue are obtained and purified by chromatography on a fritted disc which contains 50 g of silica gel [eluant: dichloromethane/acetone (90/10 by volume)], collecting 30 cm3 fractions. The fractions containing the mixture of monoacetylated derivatives in position -4 and -4' are concentrated to dryness under reduced pressure (2.7 kPa), at a temperature close to 40° C. After crystallization from a dichloromethane/acetone mixture (98/2 by volume), 2.6 g of [2,3,4-trihydroxyphenyl] [3',5'-dihydroxy-4'-(2-oxo-2-phenyl-ethoxy)-phenyl] methanone is obtained in the form of a yellow powder melting at around 180° C. (with decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([N+:17]([O-])=O)=[CH:12][CH:13]=2)[CH2:8]1)=[O:5])[CH3:2]>C(O)C.[H][H].[C].[Pd]>[NH2:17][C:11]1[CH:10]=[C:9]2[C:14]([CH2:15][CH2:16][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:8]2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)CN1CCc2ccc([N+](=O)[O-])cc2C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CN1CCc2ccc(N)cc2C1
Yield: 90.2 %

Procedure:
1.1 g of 2-(ethoxycarbonylmethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline was dissolved in 20 ml of ethanol, and a catalytic amount of 10% palladium-carbon was added to the solution. The solution was stirred overnight in hydrogen atmosphere. The catalyst was separated by filtration and the solvent was distilled off under reduced pressure to obtain 0.88 g of 7-amino-2-(ethoxycarbonylmethyl)-1,2,3,4-tetrahydroisoquinoline, which was an oily product. This product with no further purification was dissolved in 10 ml of N,N-dimethylformamide (DMF), and 1.3 g of 1-(benzyloxy-carbonyl)-4-(carboxymethoxy)piperidine and 1.1 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide which have been separately synthesized were added to the solution. After adding water, the solution was extracted with ethyl acetate, washed with saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride in this order, and dried with anhydrous sodium sulfate. After separating the desiccant by filtration, the product was purified by silica gel column chromatography to obtain 1.7 g of 7-[1-(benzyloxycarbonyl)piperidine-4-yloxyacetylamino]-2-(ethoxycarbonylmethyl)-1,2,3,4-tetrahydroisoquinoline. (Yield: 90%, oily product).
Reaction SMILES: [CH2:1]([CH2:8][NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:13]([C:23](O)=[O:24])=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][C@H:29]([OH:37])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=1.Cl>>[OH:37][CH:29]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=1)[CH2:28][N:27]([CH3:26])[C:23]([C:13]1[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[N:15][C:10]([NH:9][CH2:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:11][CH:12]=1)=[O:24]
Reactant: CNC[C@H](O)c1cccc(O)c1
Reactant: O=C(O)c1cnc(NCCc2ccccc2)nc1-c1ccccc1Cl
Agent: Cl
Product: CN(CC(O)c1cccc(O)c1)C(=O)c1cnc(NCCc2ccccc2)nc1-c1ccccc1Cl

Procedure:
The material is prepared according to the method described in Example 17. starting from 2-(Benzylmethylamino)-4-(2-chlorophenyl)pyrimidine-5-carboxylic acid and L-phenylephrine hydrochloride. M.p.: 139° C.
Reaction SMILES: C[Si](C)(C)[O-].[Na+].O.C([O:10][C:11]([C:13]1([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)[CH2:17][CH2:16][N:15]([C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:14]1)=[O:12])C>C(#N)C>[C:42]([C:39]1[CH:40]=[CH:41][C:36]([C:33]2[CH:32]=[CH:31][C:30]([O:29][CH2:28][C:13]3([C:11]([OH:12])=[O:10])[CH2:17][CH2:16][N:15]([C:18](=[O:27])[C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[CH2:14]3)=[CH:35][CH:34]=2)=[CH:37][CH:38]=1)#[N:43]
Reactant: CCOC(=O)C1(COc2ccc(-c3ccc(C#N)cc3)cc2)CCN(C(=O)c2ccc(OC)cc2)C1
Agent: C[Si](C)(C)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(C(=O)N2CCC(COc3ccc(-c4ccc(C#N)cc4)cc3)(C(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.8 %

Procedure:
Sodium trimethyl silanolate (72.1 g) and water (7.72 mL, 428.6 mmol) were added to a stirred solution of 3-(4′-cyano-biphenyl-4-yloxymethyl)-1-(4-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (see Preparation 28) (207.7 g, 428.6 mmol) in acetonitrile (2090 mL). The resulting mixture was stirred at RT for 18 hours. The reaction mixture was filtered and the solid was partitioned between ethyl acetate (2000 mL) and aqueous hydrogen chloride solution (2000 mL, 2M). The organic layer was washed with water (1000 mL) then concentrated under reduced pressure to afford a pale orange foam. This was recrystallised twice, from ethyl acetate (700 mL) then isopropyl alcohol (700 mL) to afford the title compound as a white solid (107.2 g, 55%).
Reaction SMILES: F[C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:15]=1[NH2:16].[NH2-].[Li+].Cl>C(#N)C>[F:12][C:7]1[CH:8]=[C:9]([F:11])[CH:10]=[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([I:21])=[CH:20][C:14]=2[F:13])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(F)cc(F)cc1F
Reactant: Nc1ccc(I)cc1F
Agent: Cl
Agent: [Li+]
Agent: [NH2-]
Solvent: CC#N
Product: O=C(O)c1c(F)cc(F)cc1Nc1ccc(I)cc1F
Temperature: 60 °C
Yield: 59.2 %

Procedure:
2,4,6-Trifluorobenzoic acid (643 mg, 3.65 mmol) and 2-fluoro-4-iodoaniline (1.0 g, 4.22 mmol) were taken into acetonitrile (30 mL) followed by addition of lithium amide (290 mg, 12.7 mmol) and the mixture was heated to 60° C. under a nitrogen atmosphere for one hour. On cooling to room temperature the mixture was added to 1 N aqueous hydrochloric acid (100 mL) and the precipitate formed was collected by filtration and washed once with water then hexanes and dried in vacuo to give 2,4-difluoro-6-[(2-fluoro-4-iodophenyl)amino]benzoic acid (849 mg, 59% yield) as a tan solid. 1H-NMR (400 MHz, D6-DMSO): 13.72 (br s, 1H), 9.46 (s, 1H), 7.75 (d, 1H), 7.56 (d, 1H) 7.28 (tr, 1H), 6.73-6.67 (m, 1H), 6.53 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12](O)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([NH:33][CH:12]([CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:13])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(CC(C)O)cc1OC
Reactant: NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(CC(C)NCc2ccccc2)cc1OC

Procedure:
The 1-(3,4-dimethoxyphenyl)-2-propanol obtained above was subjected to sulfonylation by p-toluenesulfonyl chloride and reacted with benzylamine to give N-benzyl-3,4-dimethoxyamphetamine. The resultant compound was converted into 3,4-dimethoxyamphetamine by hydrogenation decomposition under hydrogen atmosphere with 5% Pd-C.
Reaction SMILES: [CH2:1]1[C:11]2[C:12]3[C:3](=[CH:4][CH:5]=[C:6]4[C:16](=[O:17])[O:15][C:13](=[O:14])[C:8](=[CH:9][CH:10]=2)[C:7]4=3)[CH2:2]1.[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.O>CC(N(C)C)=O>[CH:18]1([N:24]=[C:16]([C:6]2[C:7]3=[C:12]4[C:3]([CH2:2][CH2:1][C:11]4=[CH:10][CH:9]=[C:8]3[C:13]([OH:15])=[O:14])=[CH:4][CH:5]=2)[OH:17])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1OC(=O)c2ccc3c4c(ccc1c24)CC3
Reactant: NC1CCCCC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc2c3c(ccc(C(O)=NC4CCCCC4)c13)CC2
Temperature: 157.5 °C
Reaction time: 0.17 h
Yield: 93 %

Procedure:
A slurry of 5,6-acenaphthenedicarboxylic acid anhydride (33.6 g, 0.150 mol) (B. M. Trost, G. Michael Bright, Charles Frihart, and David Brittelli, Journal of the American Chemical Society, 93(3), 737-45 (1971); James J. Jordan, Jr; U.S. Pat. No. 3,935,226) in 175 ml of DMAc was treated with cyclohexylamine (34.2 ml, 0.300 mol) over one minute and a thick paste formed. This mixture was heated at 155-160° C. for 2 hours. The resulting deep green solution was poured into 2 liters of water. The mixture was stirred for 10 minutes and then was filtered. The accumulated solid was washed with water and air-dried to provide a yellow solid (45.1 g, 98.5%), mp 264-265° C. A portion (2.00 g) of this material was recrystallized from a mixture of n-propyl acetate and heptanes (200 ml, 1:1 v/v) to provide fine yellow needles (1.42 g, 70%), mp 266-267° C. Anal. Calcd for C20H19NO2: C, 78.66; H, 6.27; N, 4.59. Found C, 78.39; H, 6.15; N, 4.83.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[CH:3]1.C([Li])CCC.CN(C)[CH:20]=[O:21]>C1COCC1.CCOC(C)=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]=[C:3]1[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: Cn1cnc(-c2ccccc2)c1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccccc2)nc1C=O
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-methyl-4-phenyl-1H-imidazole 42 (0.512 g, 3.24 mmol) in THF (15 mL) at −40° C. was added n-butyllithium (2.40 mL, 3.84 mmol) (1.6 M in hexanes), stirred at −40° C. for 30 min, cooled to −78° C., and N,N-dimethylformamide (0.325 mL, 4.21 mmol) was added. The reaction mixture was warmed to room temperature over 1 h, stirred at room temperature for 2 h, diluted with EtOAc, washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. The crude product was dissolved in DCM (˜20 mL), diluted with hexanes (˜50 mL), and concentrated to a volume of approximately 30 mL. The solution was cooled to 0° C. and the solid was collected by filtration, washed with hexanes, and dried under high vacuum to give 1-methyl-4-phenyl-1H-imidazole-2-carbaldehyde 43. Mass spectrum: calculated for C11H10N2O 186.1; found 187.1 (M++1).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([Cl:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: OB(O)c1ccc(Br)cc1
Product: Clc1nc2c(-c3ccc(Br)cc3)cccn2n1

Procedure:
8-(4-Bromo-phenyl)-2-chloro-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (1.0 g, 4.5 mmol) and 4-bromobenzeneboronic acid (1.0 g, 5.0 mmol) in a manner analogous to Example 2c. Product isolated as an off-white solid (1.0 g, 72%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.5 Hz, 1H), 7.88 (d, J=7.1 Hz, 2H), 7.70 (d, J=7.0 Hz, 1H), 7.65 (d, J=7.1 Hz, 2H), 7.16 (t, J=7.5 Hz, 1H). MS=310, 312 (MH)+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1>CN1C(=O)CCC1>[Br:1][C:2]1[C:3]([NH:23][CH:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)c(Br)cn1
Reactant: CN1CCC(N)CC1
Solvent: CN1CCCC1=O
Product: CN1CCC(Nc2cc(NC(=O)C(C)(C)C)ncc2Br)CC1
Yield: 99 %

Procedure:
A solution of N-(5-bromo-4-chloropyridin-2-yl)pivalamide (0.547 g, 1.87 mmol), 1-methylpiperidin-4-amine (0.600 g, 5.25 mmol) in NMP (3.3 mL) was heated under microwave irradiation for 3 hr at 220° C. The crude mixture was purified by flash chromatography on silica, eluting with methanol and dichloromethane (1/9), to give the title compound as a colourless oil (0.684 g, 99%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([OH:8])[CH:7]=1.[CH3:12]I.[H-].[Na+]>CN(C=O)C.CC(=O)OCC>[OH:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([O:8][CH3:12])[CH:7]=1
Reactant: CC(=O)c1cc(O)cc(O)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(O)cc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
1-(3,5-Dihydroxyphenyl)ethanone (3 g) and methyl iodide (2.80 g) were dissolved in DMF (40 ml), and sodium hydride (568 mg) was added. After stirring at RT for 2 h, the DMF was drawn off. The residue was taken up in EA and washed with water, dried, filtered and concentrated. The residue was purified using silica gel (89 g cartridge, n-heptane/EA 0-50% within 30 min). 1.12 g of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([S:4]([NH:6][C:7]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17]C(=O)C)=[CH:13][CH:12]=2)[CH2:10][O:9][CH2:8]1)=[O:5])[CH3:3].O>C(OCC)(=O)C>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([C:7]2([NH:6][S:4]([C:2]([CH3:21])([CH3:3])[CH3:1])=[O:5])[CH2:8][O:9][CH2:10]2)=[CH:16][CH:15]=1
Reactant: CC(=O)Nc1ccc(C2(NS(=O)C(C)(C)C)COC2)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)NC1(c2ccc(N)cc2)COC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Claisen's alkali (potassium hydroxide, 12.7 g in 9 ml water and 33 ml methanol) was added to N-(4-(3-(1,1-dimethylethylsulfinamido)oxetan-3-yl)phenyl)acetamide (300 mg, 0.966 mmol) and the reaction was stirred at 90° C. for 2 hours. The mixture was cooled to room temperature when water and ethyl acetate were added. The aqueous layer was extracted twice with ethyl acetate and the combined organics were dried with magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by regular phase flash column chromatography to give the title compound.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](N(OC)C)=[O:14])=[CH:8][CH:7]=1>C1COCC1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](=[O:14])[CH2:1][CH3:2])=[CH:8][CH:7]=1
Reactant: CC[Mg]Cl
Reactant: CON(C)C(=O)Cc1ccc(Br)cc1
Solvent: C1CCOC1
Product: CCC(=O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
To a round bottom flask contained EtMgCl (10 mL, 2M in THF, 20 mmol) at 0° C., was added a solution of 70A (516 mg, 2 mmol) in 10 mL THF. The solution was stirred at rt for 30 min, then was quenched with sat. NH4Cl and extracted with EtOAc (3×20 mL). The organic layer washed with brine, dried (Na2SO4) and concentrated. Purification via flash chromatography (0-30% EtOAc/hexanes) afforded 70B (288 mg, 65%). MS (ESI) m/z 227.1 (M+H)+.
Reaction SMILES: C1(C[O:8][C:9](=[O:31])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[N:18]([C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:17](=[O:30])[CH2:16]3)C=CC=CC=1.[H][H]>O1CCCC1.[Pd]>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([N:18]2[C:19]3[C:15](=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:10][C:9]([OH:31])=[O:8])[CH2:16][C:17]2=[O:30])=[O:29])=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: COc1ccc(C(=O)N2C(=O)Cc3cccc(CC(=O)OCc4ccccc4)c32)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2C(=O)Cc3cccc(CC(=O)O)c32)cc1

Procedure:
A solution of 29.5 g (0.1 mole) 2,3-dihydro-1-(4-methoxybenzoyl)-2-oxo-1H-indole-7-acetic acid phenylmethyl ester in tetrahydrofuran is reduced with hydrogen over 2 g of 20% Pd/C catalyst. After the theoretically calculated amount of hydrogen has been consumed, the solution is filtered through filter aid. The filtrate is concentrated at reduced pressure and the oily residue is triturated with anhydrous diethyl ether to yield 2,3-dihydro-1-(4-methoxybenzoyl)-2-oxo-1H-indole-7-acetic acid.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12](I)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1.C([N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1)(OC(C)(C)C)=O>>[Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:31]4[CH:32]=[N:28][NH:29][CH:30]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: NC(=O)c1nc2n(c1I)CCOc1cc(F)c(Br)cc1-2
Product: NC(=O)c1nc2n(c1-c1cn[nH]c1)CCOc1cc(F)c(Br)cc1-2

Procedure:
10-Bromo-9-fluoro-3-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (0.14 g) was reacted with 1-Boc-4-pyrazoleboronic acid pinacol ester similar to as described in Example 4 and triturated from water followed by methanol to give 100 mg of 10-bromo-9-fluoro-3-(1H-pyrazol-4-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide. This intermediate was reacted with 2-Methyl-3-butyne-ol via similar to as described in Procedure E to afford 47.5 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-(1H-pyrazol-4-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase hplc purification. MS (Q1) 396 (M)+. 1H NMR (400 MHz, DMSO) δ 13.10 (s, 1H), 8.62 (s, 1H), 8.10 (s, 1H), 7.81 (s, 1H), 7.57 (s, 1H), 7.01 (s, 1H), 6.99 (s, 1H), 5.50 (s, 1H), 4.54-4.41 (m, 2H), 4.38-4.20 (m, 2H), 2.07 (s, 1H), 1.51 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:36][CH:37]1[CH2:39][O:38]1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:36][CH:37]3[CH2:39][O:38]3)[N:9]=2)[CH:7]=1
Reactant: ClCC1CO1
Reactant: O=C(Nc1c[nH]nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1cn(CC2CO2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.9 %

Procedure:
To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (1.00 g, 2.47 mmol) in N,N-dimethylformamide (10 mL), Cs2CO3 (970 mg, 2.977 mmol) was added and stirred for 10 minutes at room temperature. Then 2-(chloromethyl)oxirane (2.28 g, 24.64 mmol) was added dropwise at room temperature. The resulting mixture was stirred for 14 hour at room temperature and diluted with ethyl acetate (100 mL), washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/petroleum ether (60/40) to give 500 mg (44%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(oxiran-2-ylmethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 24), [M+H]+=461.1, RT=1.30 min.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:37][CH3:38])=[C:7](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][C:26]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:25][C:24]=2[CH2:34]OC)[CH:8]=[C:9]([C:11]2[C:12]([O:19]C)=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[BrH:39].C([O-])(O)=O.[Na+]>CC(O)=O>[Br:39][CH2:34][C:24]1[CH:25]=[C:26]([NH:29][S:30]([CH3:33])(=[O:31])=[O:32])[CH:27]=[CH:28][C:23]=1/[CH:22]=[CH:21]/[C:7]1[CH:8]=[C:9]([C:11]2[C:12](=[O:19])[NH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]=1[O:37][CH3:38]
Reactant: Br
Reactant: COCc1cc(NS(C)(=O)=O)ccc1/C=C/c1cc(-c2ccc(OC)nc2OC)cc(C(C)(C)C)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(/C=C/c3ccc(NS(C)(=O)=O)cc3CBr)c(OC)c(C(C)(C)C)c2)c(=O)[nH]1
Yield: 83.7 %

Procedure:
step 2—A solution of 322 (104 mg, 0.193 mmol), HBr 48% (0.100 mL, 0.871 mmol) in HOAc (4 mL) was heated at 75° C. for 4 h in a sealed tube. The reaction mixture was carefully poured into a mixture of saturated NaHCO3 and ice, extracted with EtOAc, dried (Na2SO4), filtered and concentrated to afford 93 mg (84%) of N-(3-bromomethyl-4-{(E)-2-[3-tert-butyl-2-methoxy-5-(6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl)-phenyl]-vinyl}-phenyl)-methanesulfonamide (324) as a purple oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[N:10][NH:9][C:8]=2[C:12]2[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.[F:30][C:31]([F:35])([F:34])[CH2:32]I.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:8]([C:12]3[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:28][CH:29]=3)=[N:9][N:10]([CH2:32][C:31]([F:35])([F:34])[F:30])[CH:11]=2)=[CH:5][CH:6]=1
Reactant: FC(F)(F)CI
Reactant: c1ccc2nc(COc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Temperature: 60 °C

Procedure:
To a solution of 2-[4-(4-Pyridin4-yl-2H-pyrazol-3-yl)-phenoxymethyl}-quinoline (26.5 g) in dimethyl formamide (140 mL) was added 1,1,1-Trifluoro-2-iodo-ethane (21 mL, 2.0 eq.) and cesium carbonate (68.3 g, 3 eq.) and the reaction mixture heated at 60° C. for 24 h. The reaction mixture was diluted with water, extracted 3× methylene chloride, dried with magnesium sulfate, filtered and concentrated. Purification via flash chromatography eluting with 5% methanol/70% ethyl acetate/hexanes provided the title compound 20.85 g as an 8:1 regioisomeric mixture. Preparative HPLC eluting with acetonitile/methanol (98:2) on a chiralpak AD column with a flow rate of 430 ml/Min provided the pure title compound as a free base 13.4 g. 1H NMR (400 MHz, CDCl3) δ 8.45 (m, 2 H), 8.16 (d, J=8.3 Hz, 1 H), 8.04 (d, J=8.3 Hz, 1H), 7.96 (s, 1H), 7.79 (d, J=8.3 Hz, 1 H), 7.69 (m, 1 H), 7.64 (d, J=8.3 Hz, 1 H), 7.50 (m, 1H), 7.36 (d, J=8.7 Hz, 2 H), 7.14 (d, J=6.2 Hz, 2H), 6.98 (d, J=9.1 Hz, 2 H), 5.35 (s, 2H), 4.75 (q, J=8.3 Hz, 2 H); MS: (M+H m/z=427.1).MS: (M+H m/z=461.2).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:9]=2[C:8]1=[O:27].[N:37]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>>[F:32][C:31]([F:34])([F:33])[C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([C:2]([F:35])([F:36])[F:1])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:45]3[CH2:46][CH2:47][CH:42]([N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)[CH2:43][CH2:44]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:9]=2[C:8]1=[O:27]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=C1c2c(-c3ccccc3Cl)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C1c2c(-c3ccccc3Cl)cc(N3CCC(N4CCCC4)CC3)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 47.5 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-chlorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (100 mg) was reacted with 4-(pyrrolidine-1-yl)piperidine (70.2 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-chlorophenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (57.7 mg, 48%).