Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1Oc1ccc(F)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(4-fluorophenoxy)benzoic acid (step 2 of Example 67) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.16 (1H, d, J=2.6 Hz), 7.95 (2H, dd, J=6.6, 1.8 Hz), 7.88 (1H, d, J=7.4 Hz), 7.36–7.29 (3H, m), 7.23–6.96 (4H, m), 6.78 (1H, d, J=8.7 Hz), 5.32 (1H, dq, J=7.4, 6.9 Hz), 3.90 (3H, s), 1.51 (3H, d, J=6.9 Hz); MS (ESI) m/z 428 (M+H)+, 426 (M−H)−.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)([O-:10])=[O:9].Cl.[CH3:21][NH:22][O:23][CH3:24].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:24][O:23][N:22]([CH3:21])[C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (4.89 mL, 35.184 mmol) was added slowly to a mixture of commercially available 4-nitrobenzoic acid (3.0 g, 17.592 mmol), N,O-dimethylhydroxylamine hydrochloride (1.92 g, 19.351 mmol), and EDCI (4.05 g, 21.11 mmol) in CH2Cl2 (30 mL). The mixture was stirred at room temperature overnight then quenched with saturated aqueous NaHCO3. Water (50 mL) was added followed by additional CH2Cl2. The mixture as stirred for 10 minutes and layers were separated. The CH2Cl2 layer was dried over Na2SO4, then filtered. The solvent was removed under reduced pressure and the residual oil chromatographed (CH2Cl2/EtOAc) to provide the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].[C:11](OC)(OC)(OC)[O:12][CH3:13].[OH-].[Na+]>C(O)(=O)C>[CH3:11][O:12][C:13]1[NH:1][C:2]2[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: Cc1cc(O)cc(N)c1N
Reactant: COC(OC)(OC)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1nc2c(C)cc(O)cc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.60 g (4.34 mmol) 3,4-diamino-5-methylphenol were placed in 2 mL acetic acid. 4.0 mL (0.03 mol) tetramethyl orthocarbonate were added and the mixture was stirred for 4 h at RT. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with a 1M aqueous NaOH solution and extracted with ethyl acetate. The organic phase was dried and evaporated down i.vac.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[C:12]1[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[CH:15]=[CH:14][C:13]=1[Cl:21].[C:22]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])(=[O:24])[CH3:23].[Cl-].[NH4+]>C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1(C)C=CC=CC=1>[Cl:21][C:13]1[CH:14]=[CH:15][C:16]([CH:18]([CH3:20])[CH3:19])=[CH:17][C:12]=1[CH2:23][C:22]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: CC(=O)OC(C)(C)C
Reactant: CC(C)c1ccc(Cl)c(Br)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)c1ccc(Cl)c(CC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
Add bis(dibenzylideneacetone)palladium (49.2 mg, 85.6 μmol) to a round bottom flask and seal with a septum. Flush with nitrogen. Add tri-tert-butylphosphine (85.6 μL, 85.6 μmol, 1M in toluene) and lithium bis(trimethylsilyl)amide (12.8 mL, 11.56 mmol, 0.9M in methylcyclohexanes) via a syringe. Add 2-bromo-1-chloro-4-isopropyl-benzene (1.0 g, 4.28 mmol) and t-butyl acetate (865.2 μL, 6.42 mmol) via a syringe. Add toluene (10.7 mL) via a syringe and the reaction mixture becomes hot to the touch. Place on an ambient temperature water bath and stir for 3 hours. Store the reaction mixture in the freezer over the weekend. Warm the reaction mixture to ambient temperature. Dilute the reaction mixture with diethyl ether and add saturated ammonium chloride solution. Separate the layers and wash the diethyl ether layer with saturated sodium chloride solution. Dry over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel chromatography eluting with acetone: hexanes (0-2% gradient) to give the title compound (1.04 g). Purify again by silica gel chromatography eluting with dichloromethane: hexanes (0-20% gradient) to give the title compound (490 mg, 1.82 mmol). MS (m/z): 213.0 (M-tBu+1).
Reaction SMILES: C(OC(=O)[NH:7][C@@:8]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:30][CH:31]3[CH2:36][CH2:35][CH:34]([C:37]([CH3:41])([CH3:40])[CH2:38][CH3:39])[CH2:33][CH2:32]3)[C:22]=2[C:26]([F:29])([F:28])[F:27])[CH:17]=1)([CH3:15])[CH2:9][O:10][P:11]([OH:14])([OH:13])=[O:12])(C)(C)C.O1CCOCC1>Cl>[NH2:7][C@@:8]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:30][CH:31]3[CH2:32][CH2:33][CH:34]([C:37]([CH3:40])([CH3:41])[CH2:38][CH3:39])[CH2:35][CH2:36]3)[C:22]=2[C:26]([F:27])([F:28])[F:29])[CH:17]=1)([CH3:15])[CH2:9][O:10][P:11](=[O:12])([OH:13])[OH:14]
Reactant: CCC(C)(C)C1CCC(Oc2ccc3cc([C@](C)(COP(=O)(O)O)NC(=O)OC(C)(C)C)ccc3c2C(F)(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCC(C)(C)C1CCC(Oc2ccc3cc([C@@](C)(N)COP(=O)(O)O)ccc3c2C(F)(F)F)CC1
Yield: 66.3 %

Procedure:
A solution of ((R)-1-{6-[4-(1,1-dimethyl-propyl)-cyclohexyloxy]-5-trifluoromethyl-naphthalen-2-yl}-1-methyl-2-phosphonooxy-ethyl)-carbamic acid tert-butyl ester (45 mg, 0.07 mmol) in 4 M of HCl in dioxane (3 mL, 10 mmol) was stirred at room temperature for 3 hrs. After the solution was concentrated, the crude product was treated with acetonitrile to form precipitate. The precipitate was purified with a silica gel column eluted with 10% TFA in MeOH and DCM from 0 to 30% to give 24 mg of product, 63%. ESI-MS (M+H)+: 518.30, room temperature 1.70 min. 1H NMR (400 MHz, CD3OD) δ: 8.24 (d, 1H), 8.11 (d, 1H), 7.99 (s, 1H), 7.69 (s, 1H), 7.58 (s, 1H), 4.48 (m, 1H), 4.35 (m, 1H), 4.22 (m, 1H), 2.20 (d, 2H), 1.85 (s, 5H), 1.49 (m, 2H), 1.38˜1.16 (m, 6H), 0.85 (m, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([SH:21])=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[S:28](Br)([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29].C(Cl)(Cl)(Cl)Cl>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([S:21][S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Reactant: CC(C)(C)OC(=O)n1ccc2cc(S)c(C(C)(C)C)cc21
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)Sc2cc3ccn(C(=O)OC(C)(C)C)c3cc2C(C)(C)C)cc1

Procedure:
The title compound was prepared according to General Method 15 using 6-tert-butyl-5-mercapto-indole-1-carboxylic acid tert-butyl ester (prepared in Example FF), pyridine, tosyl bromide, carbon tetrachloride, and EtOAc.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=[O:9])[CH:2]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:26][C:27]([CH3:29])=[CH2:28].O>O1CCCC1.CO.ClCCl>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH2:28][C:27]([CH3:29])=[CH2:26])[C:8]([OH:10])=[O:9])[CH:2]=1
Reactant: C=C(C)CBr
Reactant: O=C(O)Cc1cccc(-c2ccccc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C(C)CC(C(=O)O)c1cccc(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A solution of biphenyl-3-yl acetic acid (7.0 g, 33 mmol) in anhydrous tetrahydrofuran (84 mL) was added dropwise to a solution of lithium diisopropyl amide (36.4 mL, 2M solution in hexanes) in anhydrous tetrahydrofuran (84 mL) at −78° C. The mixture was allowed to warm to 0° C. and stirred for 40 min. The mixture was then cooled to −78° C. and 3-bromo-2-methylpropene (4.97 mL) rapidly added. The mixture was stirred for 1 h at −78° C. then water (28 mL) added and the organics removed under reduced pressure. The mixture was then acidified with hydrochloric acid (6M, 14 ml), extracted with ethyl acetate (3×100 ml), dried (MgSO4) and evaporated under reduced pressure to afford a residue. Flash chromatography of the residue over silica (400 g) using methanol:dichloromethane (3:97) as the eluent afforded impure 2-biphenyl-3-yl-4-methylpent-4-enoic acid (8.3 g). Flash chromatography over silica (400 g) using methanol:dichloromethane (1.5:98.5) afforded pure 2-biphenyl-3-yl-4-methylpent-4-enoic acid, yield 5.27 g, (60%), TLC (single UV spot, Rf=0.28, 5% methanol in dichloromethane), analytical HPLC Rt=19.99 min, HPLC-MS (single main UV peak with Rt=9.57 min, 267.1 [M+H]+).
Reaction SMILES: [C:1]12(O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C(Cl)Cl.S(=O)(=O)(O)O>O>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:17]1[CH:18]=[C:13]([Br:12])[CH:14]=[CH:15][C:16]=1[O:19][CH3:20])[CH2:8]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Br)cc1C1C2CC3CC(C2)CC1C3

Procedure:
In a 1 L flask equipped with a stirrer, a reflux condenser and a dropping funnel, a mixture of 50 g (0.33 M) 1-adamantanol, 68 g (45.5 mL, 0.36 M) 4-bromoanisole and 500 mL of methylene chloride is prepared. The mixture is stirred until dissolved and then 35 g (19 mL, 0.36 M) sulfuric acid added during one hour. The reaction mixture is stirred for 4 hours, 200 mL of water added, stirred for another 10 min, transferred to separating funnel and the organic layer collected, which is neutralized by two portions of 100 mL 10% sodium carbonate solution. Methylene chloride is distilled off completely, the residue dissolved in 300 mL of ethyl acetate, filtered, concentrated to 200 mL and left to crystallize at 0° C. for 16 h. The crystals are filtered off, washed by 50 mL of cold ethyl acetate and dried at 100° C. for one hour. 2-adamantyl-4-bromoanisole, 76 g (72%) with m.p. 140-141° C. is obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1.[OH-].[Na+:28]>C(O)C>[CH3:1][CH:2]([CH3:26])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([O-:23])=[O:22])=[CH:24][CH:25]=1.[Na+:28]
Reactant: CC(C)CCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CCCCCCCCCCCCCNc1ccc(C(=O)[O-])cc1

Procedure:
To a solution of 10 g. (27.7 m moles) 4-(14-methylpentadecylamino)benzoic acid in 300 ml. hot ethanol is added 6.0 ml. (1.1 eq) 5 N sodium hydroxide. As the solution cools, the title compound crystallizes as a white mass. This is collected and dried in vacuo.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[CH:7][NH:6][N:5]=1.[Cl:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:11]=1[C:17]([N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][C:22]2[N:30]=[CH:31][CH:32]=[CH:33][C:21]=2[CH2:20]1)=[O:18]>CCCCCC>[Cl:9][C:10]1[CH:15]=[C:14]([N:6]2[CH:7]=[CH:8][C:4]([CH3:3])=[N:5]2)[CH:13]=[CH:12][C:11]=1[C:17]([N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][C:22]2[N:30]=[CH:31][CH:32]=[CH:33][C:21]=2[CH2:20]1)=[O:18]
Reactant: Cc1cc[nH]n1
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccnc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(Cl)c2)n1
Reaction time: 2 h

Procedure:
Sodium hydride (60% suspension in oil, 1.8 g, 45.19 mmol) was washed with hexane, dried under nitrogen and resuspended in dry dimethylformamide (130 mL). Neat 3-methyl pyrazole (3.71 g, 45.19 mmol) was added dropwise at 0° C. After the gas evolution subsided the cooling bath was removed and stirring was continued at room temperature. The (2-chloro-4-fluorophenyl)-(6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-methanone of Step D (8.11 g, 22.59 mmol) was added in one portion and the mixture was placed in an oil bath (preheated at 130° C.) for 2 hrs. After cooling, the mixture was partitioned between water and ethyl acetate. The organic extracts were dried over sodium sulfate, and evaporated to dryness in vacuo. The residue was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with a hexane-ethyl acetate gradient (from 95:5 to 3:2) provided the desired product along with some mixed fractions containing the title compound and its more polar 5-methylpyrazole regioisomer of Example 2. The title compound crystallized by sonication from hexane-ethanol as a white solid (6.4 g), m.p. 207° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]2[CH2:7][C:6](Br)([CH2:17][CH2:18][CH3:19])[C:5](=[O:21])[C:4]=2[C:3]=1[CH3:22].O.Cl>CS(C)=O>[CH3:1][C:2]1[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]2[CH:7]=[C:6]([CH2:17][CH2:18][CH3:19])[C:5](=[O:21])[C:4]=2[C:3]=1[CH3:22]
Reactant: CCCC1(Br)Cc2c3c(c(C)c(C)c2C1=O)OC(C(=O)O)C3
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: CCCC1=Cc2c3c(c(C)c(C)c2C1=O)OC(C(=O)O)C3

Procedure:
A solution of 4,5-dimethyl-6-oxo-7-bromo-7-propyl-1,2,7,8-tetrahydro-6H-indeno[5,4-b]furan-2-carboxylic acid (0.70 g., 0.0019 mole) and 1,5-diazabicyclo-[4.3.0]-5-one (0.5 ml.) in dimethylsulfoxide (5 ml.) is stirred at 25°C. in an inert atomsphere for 1 1/2 hours, treated with water (15 ml.) acidified with hydrochloric acid, extracted with ether washed with water and dried over magnesium sulfate. The ether is evaporated at reduced pressure and the crude product crystallized from nitromethane (10 ml.) affording 4,5-dimethyl-6-oxo-7-propyl-1,2-dihydro-6H-indeno[5,4-b]furan-2-carboxylic acid as a red solid which melts at 212°C.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[CH3:30][O:31][CH2:32]Cl>CCCCCC.C1COCC1>[CH3:30][O:31][CH2:32][C:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCCl
Reactant: O=C(O)C1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCC1(C(=O)O)CCCCC1
Temperature: 60 °C

Procedure:
11.8 g (0.093 mole) of cyclohexylcarboxylic acid were added to a solution of lithium diisopropylamide prepared using 125 cm3 of a 1.50 M solution of butyllithium in hexane, 18.9 g of diisopropylamine and 200 cm3 of THF as the starting materials. After the mixture had been heated at 60° C. for 2 hours, 8 g of methoxymethyl chloride were added, at a temperature of -30° C. After the customary treatment, methoxymethylcyclohexylcarboxylic acid was distilled; this was in the form of a colourless liquid which crystallised on cooling.
Reaction SMILES: ClC1C=CC([C@@H](C2C=CN(C)N=2)N)=CC=1F.[F:17][C:18]1[CH:19]=[C:20]([C@@H:26]([C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)[NH2:27])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].[F:34][C:35]1[CH:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[C:41]2[C:36]=1[CH:37]=[N:38][C:39]([NH:48][C@@H:49]1[CH2:53][CH2:52][O:51][CH2:50]1)=[N:40]2>>[F:34][C:35]1[CH:44]=[C:43]([C:45]([NH:27][C@@H:26]([C:20]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([F:17])[CH:19]=2)[C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)=[O:46])[CH:42]=[C:41]2[C:36]=1[CH:37]=[N:38][C:39]([NH:48][C@@H:49]1[CH2:53][CH2:52][O:51][CH2:50]1)=[N:40]2
Reactant: COc1ccc([C@H](N)c2cnn(C)c2)cc1F
Reactant: O=C(O)c1cc(F)c2cnc(N[C@@H]3CCOC3)nc2c1
Agent: Cn1ccc([C@@H](N)c2ccc(Cl)c(F)c2)n1
Product: COc1ccc([C@H](NC(=O)c2cc(F)c3cnc(N[C@@H]4CCOC4)nc3c2)c2cnn(C)c2)cc1F

Procedure:
5-Fluoro-N-((S)-(3-fluoro-4-methoxyphenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-2-((R)-tetrahydrofuran-3-ylamino)quinazoline-7-carboxamide (I-61) was prepared analogously except 32b was replaced with 40f and 84b was replaced with 87d.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C:4]([NH:29]C(OCC1C=CC=CC=1)=O)=[CH:5][C:6]1[C:15]([CH2:16][P:17]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:27][CH3:28])=[C:11]([O:25][CH3:26])[CH:12]=2)[N:7]=1>[Pd].CO>[CH3:1][O:2][C:3](=[O:40])[CH:4]([NH2:29])[CH2:5][C:6]1[C:15]([CH2:16][P:17]([O:19][CH2:20][CH3:21])([O:22][CH2:23][CH3:24])=[O:18])=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:27][CH3:28])=[C:11]([O:25][CH3:26])[CH:12]=2)[N:7]=1
Reactant: CCOP(=O)(Cc1cc2cc(OC)c(OC)cc2nc1C=C(NC(=O)OCc1ccccc1)C(=O)OC)OCC
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(Cc1cc2cc(OC)c(OC)cc2nc1CC(N)C(=O)OC)OCC
Yield: 81.7 %

Procedure:
A mixture of α-(benzyloxycarbonylamino)-3-(diethylphosphonomethyl)-6,7-dimethoxy-2-quinolineacrylic acid methyl ester (0.14 g, 0.25 mmol) and a catalytic amount of palladium on charcoal (10%) in MeOH (10 ml) was hydrogenated at 4 bar for 20 h. Filtration and chromatographic purification gave 0.09 g α-amino-3-(diethylphosphonomethyl)-6,7-dimethoxy-2-quinolinepropanoic acid methyl ester.
Reaction SMILES: C([NH:4][CH2:5][C:6]([C:9]1[CH:18]=[CH:17][C:12]2[N:13]=[C:14]([CH3:16])[NH:15][C:11]=2[CH:10]=1)([CH3:8])[CH3:7])(=O)C.Cl>C(O)C>[NH2:4][CH2:5][C:6]([C:9]1[CH:18]=[CH:17][C:12]2[N:13]=[C:14]([CH3:16])[NH:15][C:11]=2[CH:10]=1)([CH3:8])[CH3:7]
Reactant: CC(=O)NCC(C)(C)c1ccc2nc(C)[nH]c2c1
Agent: Cl
Solvent: CCO
Product: Cc1nc2ccc(C(C)(C)CN)cc2[nH]1

Procedure:
2.4 g. 5-(2-acetamidomethylpropan-2-yl)-2-methylbenzimidazole (prepared in Example 29) are boiled under reflux for 24 hours in 60 ml. ethanol and 60 ml. concentrated hydrochloric acid. The solvent is then removed in a vacuum, the residue is neutralised with 2N aqueous ammonia solution and the organic phase is dried over anhydrous sodium sulphate. After filtration and evaporation, there is obtained 0.87 g. of the title compound in the form of an oil.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[N:7]3)[N:4]=[C:3]1[CH2:15][OH:16]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[N:7]3)[N:4]=[C:3]1[CH:15]=[O:16]
Reactant: Cn1c(CO)nc2c3nccnc3ccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cn1c(C=O)nc2c3nccnc3ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.2 %

Procedure:
To a solution of (3-methyl-3H-imidazo[4,5-f]quinoxalin-2-yl)methanol (880 mg, 4.03 mmol) in DCM (100 mL) was added activated manganese (IV) dioxide (3.5 g, 40.3 mmol). The mixture was stirred at room temperature for 16 h. Then the mixture was filtered and the filtrate was concentrated under reduce pressure to give the crude product, which was purified by silica gel column (eluting with DCM/MeOH v/v 30:1) to give 3-methyl-3H-imidazo[4,5-f]quinoxaline-2-carbaldehyde as a yellow solid (310 mg, yield 36%). ESI MS: m/z 213.0 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 10.25 (s, 1H), 9.02 (d, J=2.0 Hz, 1H), 8.95 (d, J=2.4 Hz, 1H), 8.15 (d, J=9.2 Hz, 1H), 7.88 (d, J=9.2 Hz, 1H), 4.33 (s, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(NC1C=CC=CC=1)C.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[C:24](/[N:31]2[CH:35]=[N:34][CH:33]=[N:32]2)\[C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:19][CH:18]=1.Cl>C(OCC)C.C(Cl)(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[C:24](/[N:31]2[CH:35]=[N:34][CH:33]=[N:32]2)\[CH:25]([OH:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:19][CH:18]=1
Reactant: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1)n1cncn1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCNc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(C)(C)C(O)/C(=C\c1ccc(Cl)cc1)n1cncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.6 %

Procedure:
To a solution of 1.08 g (0.0284 mole) of LiAlH4 in 85 cc of ethyl ether, while being cooled in ice, was added dropwise 22 cc of an ether solution containing 6.86 g (0.0284 mole) of (+)-2-N-benzyl-N-methylamino-1-phenylethanol followed by 40 cc of an ether solution containing 6.90 g (0.0564 mole) of N-ethylaniline. After having been stirred at room temperature for 3 hours, the mixture was cooled to -78° C. To the mixture was added dropwise 55 cc of an ether solution containing 2.75 g (0.0095 mole) of (E)-1-(4-chlorphenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one. The mixture was stirred at said temperature for 3 hours and left standing overnight at room temperature. To the mixture was then added 105 cc of 2 N hydrochloric acid to effect decomposition. The organic layer was separated, washed successively with 100 cc of a saturated aqueous sodium hydrogencarbonate solution and 100 cc of ice-cooled water, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2.83 g of a crude product: [α]D24 -6.44 (c=1.05, CHCl3). A 2.8 g portion of the crude product was recrystallized three times from a cyclohexane-methanol mixture to obtain 0.82 g of (-)-(E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol: [α]D24 -14.9 (c=1.0, CHCl3).
Reaction SMILES: CS(O[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7]=1[C:16]([CH3:19])([CH3:18])[CH3:17])(=O)=O.C(O)=O.[OH-].[Li+].CO>[Pd].[C].O>[C:12]([C:9]1[CH:10]=[CH:11][CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:8]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccc(OS(C)(=O)=O)c(C(C)(C)C)c1
Agent: [Pd]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: O=CO
Product: CC(C)(C)c1cccc(C(C)(C)C)c1
Yield: 99.7 %

Procedure:
In a nitrogen atmosphere under normal pressure, 2,4-di-tert-butylphenyl methanesulfonate (500 g, 1.76 mols), formic acid (162 g, 3.52 mols), lithium hydroxide (84 g, 3.52 mols) and methanol (3000 g) were mixed at 25° C., and with stirring, 10 mass % Pd/carbon (50 mass % water-containing product) (100 g) (as metal palladium; 1 mass % relative to 2,4-di-tert-butylphenyl methanesulfonate) as supported by a carbon carrier having a specific surface area of 780 m2/g (by BET method) was put into it. With stirring, the reaction liquid was reacted at the same temperature for 2 hours. Water (100 mL) was added to the reaction liquid and Pd-carbon was separated through filtration, then heptane (500 g) was added to the filtrate. The organic layer obtained after extraction was concentrated under reduced pressure to give crude 1,3-di-tert-butylbenzene (334 g, yield 100%, by mass). The result is shown in Table II-2.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:12]([O:14]C)=[O:13])[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[CH:8]2.[OH-].[Li+]>CO.O1CCCC1>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[CH:8]2
Reactant: COC(=O)c1cc(C(F)(F)F)c2[nH]ncc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(C(F)(F)F)c2[nH]ncc2c1
Temperature: 60 °C
Yield: 29.5 %

Procedure:
To a solution of methyl 7-(trifluoromethyl)-1H-indazole-5-carboxylate (62 mg, 0.25 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL) was added 1 N aqueous lithium hydroxide (0.76 mL, 0.76 mmol). The reaction was heated to 60° C. for 17 hours. The reaction was concentrated and the residue was diluted with water and acidified to pH=3 with 1 N aqueous hydrochloric acid. The solution was extracted with dichloromethane (3×). The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated to give the title compound (17 mg, 29%) as an off-white powder. +ESI (M+H) 231.1.