Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:21](=O)[CH2:22][CH2:23][CH3:24].[H][H]>[Pt]>[CH:15]1([NH:14][C:10]2[CH:11]=[CH:12][C:13]([CH2:21][CH2:22][CH2:23][CH3:24])=[C:8]([NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCCC=O
Reactant: [H][H]
Reactant: c1cc(NC2CCCCC2)cc(NC2CCCCC2)c1
Agent: [Pt]
Product: CCCCc1ccc(NC2CCCCC2)cc1NC1CCCCC1
Temperature: 180 °C

Procedure:
To 263.1 g of N1,N3-dicyclohexyl-1,3-benzenediamine prepared as described in Example 2 were added 59.5 g butyraldehyde, and 2.0 g wet (as received) sulfided platinum on carbon catalyst. The autoclave was pressurized with 4,647 KPa (660 psig) of hydrogen. The reaction was heated to 180° C. over 4 hours, and held at for 180° C. 17 hours. The reaction mass was cooled and filtered, and volatiles were removed by rotary evaporation. The reaction mass was contained and the N1,N3-dicyclohexyl-4-butyl-1,3-benzenediamine was isolated by column chromatography as an oil, 93.5% pure by GCMS analysis. It has the characteristics reported below.
Reaction SMILES: N[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C1C=CC=CC=1.C([BH3-])#[N:35].[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH:13]([CH2:2][C:3]([NH2:35])([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=2)[OH:4])[CH3:27])=[CH:17][CH:18]=1)=[O:24]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: NCC(O)c1cccc(Br)c1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)CC(N)(O)c2cccc(Br)c2)cc1
Yield: 56.8 %

Procedure:
Following a procedure similar to that described in Example 3, but using 3.0 g of 2-amino-1-(3-bromophenyl)-ethanol (prepared as described in Preparation 41), 3.67 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 80 ml of benzene, 60 ml of absolute methanol and 3.1 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 3.33 g of the title compound were obtained having an Rf=0.25 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: C[N:2]([C:10]1([CH2:15][CH3:16])[O:14][CH2:13][CH2:12][O:11]1)[C@H:3]([C:7]([OH:9])=[O:8])[CH:4]([CH3:6])[CH3:5].[CH2:17](N(CC)CC)C.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.CCOCC>ClCCl>[CH3:17][C@@:3]([C:7]([OH:9])=[O:8])([CH:4]([CH3:5])[CH3:6])[N:2]([C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([F:24])=[CH:26][CH:27]=1)[C:10]1([CH2:15][CH3:16])[O:11][CH2:12][CH2:13][O:14]1
Reactant: CCC1(N(C)[C@H](C(=O)O)C(C)C)OCCO1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CCC1(N(C(=O)c2ccc(F)cc2)[C@](C)(C(=O)O)C(C)C)OCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a stirred solution of Methyl-N-[2-(2-ethyl)-1,3-dioxolanyl]valine (3 g, 13 mmoles) and triethylamine (3.6 ml, 26 mmoles) in 20 ml of dichloromethane (CH2CL2) cooled to 0° C. was added a solution of 4-fluorobenzoyl chloride (1.65 ml, 14 mmoles) in 10 ml of (CH2CL2). The solution was stirred 60 minutes at 0° C. and 60 minutes at room temperature. It was then poured into ether and washed with water, saturated aq. bicarbonate, brine, and dried (MgSO4). Flash chromatography on silica gel eluting with 1:1 hexane-ethyl acetate provided 3 g of the title compound. 90 MHz NMR (CDCl3) δ 0.90, (brd, J=7 Hz, 6H), 1.8-2.5 (m, 3H), 3.45 (br, dd, J=6, 8 Hz, 1H), 3.72 (s, 3H), 3.80 (m, 6H), 4.80 (m, 1H), 6.9-7.5 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=O.Cl.[NH2:10][OH:11].C(=O)(O)[O-].[Na+]>C(O)C>[OH:11][N:10]=[CH:7][C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1
Reactant: NO
Reactant: Cn1ccnc1C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cn1ccnc1C=NO
Yield: 55.7 %

Procedure:
A mixture consisting of 118.4 grams of 1-methylimidazole-2-carboxaldehyde, 82.5 grams of hydroxylamine hydrochloride, 113.9 grams of sodium bicarbonate and 1300 ml of absolute ethanol was heated under reflux for 2 hours and then filtered while still hot. The filtrate was concentrated to give a colorless residue which was recrystallized from 2-propanol to give 75 grams of 2-(hydroxyimino)methyl-1-methylimidazole as colorless crystals melting at 170°-172° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:24]1(Br)[CH2:28][CH2:27][CH2:26][CH2:25]1.O>CN(C)C=O.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrC1CCCC1
Reactant: O=Cc1ccc(OCc2ccccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: O=Cc1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A stirred solution of 4-benzyloxy-3-hydroxybenzaldehyde (60.9 g; that is prepared as described in Reference Example 36) in dry dimethylformamide (270 mL) under nitrogen is treated portionwise with potassium carbonate (79.5 g). After stirring at room temperature for 45 minutes, it is treated with cyclopentyl bromide (34.3 mL), and the resulting suspension is heated at 60° C. for 8 hours. After cooling, the solution is evaporated to low bulk under reduced pressure, to give an oil. This oil is treated with water (250 mL) and diethyl ether (300 mL), and the aqueous layer is washed with further quantities of diethyl ether (2×50 mL). The combined ethereal extracts are washed with brine (1×50 mL) and with water (3×50 mL), dried over magnesium sulfate and evaporated. The resulting residue is crystallized from methanol, to give 4-benzyloxy-3-cyclopentyloxybenzaldehyde (79 g), m.p. 55-56° C. [Elemental analysis: C,77.1; H,6.9%; calculated: C,77.0; H,6.8%].
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)=[CH:3][C:4]=1[C:10]([F:13])([F:12])[F:11])#[N:7]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)c(C(F)(F)F)c2)CC1
Temperature: 100 °C
Yield: 52.1 %

Procedure:
To a solution of 4-fluoro-2-(trifluoromethyl)benzonitrile (5 g, 26 mmol,) in DMSO (50 ml) was added tert-butyl 4-aminopiperidine-1-carboxylate (5.3 g, 26.5 mmol, 1 eq.) and potassium carbonate (7.3 g, 52.8 mmol, 2 eq.). The resulting solution was stirred with heating overnight at 100° C. (oil bath). The resulting solution was diluted with of ethyl acetate (300 ml) and washed with sodium chloride (sat., 300 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was applied onto a silica gel column and eluted with ethyl acetate to afford tert-butyl 4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]piperidine-1-carboxylate as a white powder (5 g, 51%). (ES, m/z):[M+H]+ 370.1.
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]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[N:35]1([CH2:41][CH2:42][CH:43]([OH:47])[CH2:44][CH2:45][CH3:46])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[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]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:24](=[O:26])[O:47][CH:43]([CH2:42][CH2:41][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH2:44][CH2:45][CH3:46])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCC(O)CCN1CCCCC1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(CCN1CCCCC1)OC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Yield: 87.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-piperidino-3-hexanol (48 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (75 mg, yield 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](Cl)=[O:6].C(N(CC)C(C)C)(C)C.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:6]
Reactant: CN1CCC(N)CC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCC(NC(=O)c2ccc([N+](=O)[O-])c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
3-chloro-4-nitro-benzoyl chloride (Intermediate 54; 2.2 g, 10.00 mmol) was dissolved in DCM (20 mL) and N,N-diisopropylethylamine (2.095 mL, 12.00 mmol) added. The mixture was cooled in an ice/water bath and 4-amino-1-methylpiperidine (Fluorochem; 1.14 g, 10.00 mmol) in DCM (10 mL) added dropwise. The mixture was allowed to warm to room temperature and stirred for 0.5 hr. A white precipitate resulted. The reaction mixture was washed with 2N NaOH, filtered and the filter cake washed with water and dried on a sinter over the weekend to give the title compound as a white solid (1.80 g, 60%) as a white solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@@H:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=[C:11]2[NH:10][C:9]1=[O:20].[Cl:21][C:22]1[N:27]=[C:26](Cl)[CH:25]=[CH:24][N:23]=1.C(N(CC)CC)C.O>C(O)C>[Cl:21][C:22]1[N:27]=[C:26]([N:5]2[CH2:6][CH2:7][C@@H:2]([CH3:1])[C@@H:3]([N:8]3[C:12]4=[C:13]5[CH:19]=[CH:18][NH:17][C:14]5=[N:15][CH:16]=[C:11]4[NH:10][C:9]3=[O:20])[CH2:4]2)[CH:25]=[CH:24][N:23]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C[C@@H]1CCNC[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@@H]1CCN(c2ccnc(Cl)n2)C[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Temperature: 25 °C
Reaction time: 17 h
Yield: 45.9 %

Procedure:
To the mixture of rel-1-[(3R,4R)-4-methyl-3-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one-(100 mg) and 2,4-dichloropyrimidine (82 mg) in ethanol (2 mL), triethylamine (75 mg) was added at ambient temperature. Then After the mixture was stirred at ambient temperature for 17 hours, water (10 mL) was added. The resulting precipitate was collected, to afford rel-1-[(3R,4R)-1-(2-chloro-4-pyrimidinyl)-4-methyl-3-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (65 mg) as yellow powder. From NMR, it was found that the obtained powder was mixture of regioisomer (4:1).
Reaction SMILES: CC([O-])(C)C.[K+].CC1C=CC(S([CH2:17][N+:18]#[C-])(=O)=O)=CC=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH:24]=O.CO>C1COCC1.O>[Cl:20][C:21]1[CH:22]=[C:23]([CH2:24][C:17]#[N:18])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(C=O)cc1Cl
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CC#N)cc1Cl
Reaction time: 0.17 h
Yield: 82.6 %

Procedure:
To a suspension of t-BuOK (4.8 g, 40 mmol) in THF (30 mL) was added a solution of TosMIC (3.9 g, 20 mmol) in THF (10 mL) at −78° C. The mixture was stirred for 10 minutes, treated with a solution of 3-chloro-4-methoxy-benzaldehyde (1.7 g, 10 mmol) in THF (10 mL) dropwise, and continued to stir for 1.5 hours at −78° C. To the cooled reaction mixture was added methanol (10 mL). The mixture was heated at reflux for 30 minutes. Solvent of the reaction mixture was removed to give a crude product, which was dissolved in water (20 mL). The aqueous phase was extracted with EtOAc (20 mL×3). The combined organic layers were dried and evaporated under reduced pressure to give crude product, which was purified by column chromatography (petroleum ether/ethyl acetate 10:1) to afford 2-(3-chloro-4-methoxyphenyl)acetonitrile (1.5 g, 83%). 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=2.4 Hz, 1H), 7.20 (dd, J=2.4, 8.4 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 3.91 (s, 3H), 3.68 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 154.8, 129.8, 127.3, 123.0, 122.7, 117.60, 112.4, 56.2, 22.4.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH3:22]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[C:6]([CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH2:20][CH2:21][CH3:22])[CH:7]=[O:8]
Reactant: COc1cc(C=O)cc(Br)c1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1c(Br)cc(C=O)cc1OC
Temperature: 70 °C
Reaction time: 72 h
Yield: 56.9 %

Procedure:
50 g (0.43 mole) of 5-bromovanillin in 130 ml of DMF was added 150 g (1.08 mole) of potassium carbonate and 55 ml (0.606 mole) of bromopropane. The mixture was stirred for 72 hours at 70° C. The solution was then poured into 1 liter ice water. The aqueous solution was extracted with 3×200 ml CH2Cl2, the combined organic extracts were dried over MgSO4. The solution was filtered and the filtrate was concentrated to dryness to yield 66.80 g of 3-bromo-5-methoxy-4-propoxybenzaldehyde as a yellow oil. (95% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:28][CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].[OH-].[K+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:28][CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(F)c3)c[nH]2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(F)c3)cn2CCO[Si](C)(C)C(C)(C)C)CC1
Yield: 97.9 %

Procedure:
Combine 4-[4-(3,4-difluoro-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (10.0 g; 0.028 mol; 1.0 equiv), (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (13.16 g; 0.055 mol; 2.0 equiv), powdered KOH (7.72 g; 0.14 mol; 5.0 equiv) in THF (100 mL) and stir at 40° C. for 16 h. Quench the reaction with water and extract with EA. Evaporate to give the title compound (14.3 g, crude). MS (ES+): m/z=522 (M+H)
Reaction SMILES: [F:1][C:2]1[C:10]([OH:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:14](I)([CH3:16])[CH3:15].O.[OH-].[Na+]>C(O)C>[F:1][C:2]1[C:10]([O:11][CH:14]([CH3:16])[CH3:15])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)c(O)c1F
Reactant: CC(C)I
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Oc1c(F)c(F)cc(C(=O)O)c1F

Procedure:
2,4,5-Trifluoro-3-hydroxybenzoic acid (4.0 g) was added together with isopropyl iodide (4.7 g) to a mixed liquid of distilled water (10 ml) and ethanol (20 ml), in which sodium hydroxide (1.83 g) had been dissolved. The mixture was stirred and heated under reflux for 23 hours. The reaction mixture was concentrated under reduced pressure. The resultant residue was acidified with concentrated hydrochloric acid, and water (25 ml) was added to conduct extraction twice with chloroform (25 ml). A collected chloroform layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to column chromatography (silica gel: 75 g, eluent; chloroform: methanol:acetic acid=500:20:1) to obtain 2,4,5-trifluoro-3-isopropyloxybenzoic acid as a solid residue.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[CH2:16][OH:17].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:15][C:11]1[C:10]([CH2:16][OH:17])=[C:9]([NH:8][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])[CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccc(F)c1CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cccc(F)c1CO
Reaction time: 1 h

Procedure:
Trimethylacetyl chloride (0.25 mL, 1.99 mmol) was added to a solution of (2-amino-6-fluorophenyl)methanol (268 mg, 1.90 mmol) in CH2Cl2 (10 mL) at 0° C., followed by the addition of DIEA (1.0 mL, 5.7 mmol). The mixture was stirred for 1 hr, followed by normal aqueous work-up to afford the expected crude product, N-(3-fluoro-2-(hydroxymethyl)phenyl)pivalamide, as a colorless oil (415 mg, 97% yield), which was used directly in the next step; 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (s, 9H), 2.64 (s, 1H), 4.78 (d, J=4.78 Hz, 2H), 6.75-6.84 (m, 1H), 7.23 (td, J=8.62, 5.92 Hz, 1H), 7.86 (d, J=8.31 Hz, 1H), 8.97 (s, 1H); Mass spec. 226.11 (MH+), Calc. for C12H16FNO2 225.12.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH:10]([NH:12][C:13](=[O:35])[C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH2:22][C:23]2[N:24]=[C:25]3[C:30](=[N:31][CH:32]=2)[N:29]=[C:28]([NH2:33])[N:27]=[C:26]3[NH2:34])[CH3:21])=[CH:16][CH:15]=1)[CH3:11])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.O.CO>CN(C=O)C>[NH2:33][C:28]1[N:27]=[C:26]([NH2:34])[C:25]2[C:30](=[N:31][CH:32]=[C:23]([CH2:22][N:20]([CH3:21])[C:17]3[CH:16]=[CH:15][C:14]([C:13]([NH:12][CH:10]([CH3:11])[CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[O:35])=[CH:19][CH:18]=3)[N:24]=2)[N:29]=1
Reactant: CCOP(=O)(CC(C)NC(=O)c1ccc(N(C)Cc2cnc3nc(N)nc(N)c3n2)cc1)OCC
Agent: C[Si](C)(C)Br
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CC(CP(=O)(O)O)NC(=O)c1ccc(N(C)Cc2cnc3nc(N)nc(N)c3n2)cc1
Temperature: 70 °C
Yield: 38 %

Procedure:
To a solution of crude (2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-propyl)-phosphonic acid diethyl ester post silica column chromatography (32.2 mg, 66.2 μmol) in dry DMF (0.50 mL) was added TMSBr (68.0 μL, 529.6 μmol) at ambient temperature. The solution was then heated at 70° C. for 1.0 hour, when LCMS analysis demonstrated the reaction to be complete. The reaction mixture was allowed to cool to room temperature, and water (60 μL) and methanol (60 μL) were added. The crude reaction mixture was purified by RP HPLC on C18 column using H2O/acetonitrile (2-95%) to provide 11.2 mg (38%) of the desired compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 1.50 (m, 2H), 1.61 (m, 2H), 3.22 (s, 3H), 3.25-3.40 (m, 2H), 4.84 (s, 2H), 6.80 (d, 2H, J=9 Hz), 7.69 (d, 2H, J=9 Hz), 8.20 (br s, 1H), 8.69 (s, 1H). 31P (121.4 MHz, DMSO-d6) δ 26.3. MS (m/z) 447.3 [M−H]−.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[Cl:14][CH2:15][C:16](Cl)=[O:17].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Cl:14][CH2:15][C:16]([N:12]1[CH2:11][CH2:10][O:9][C:8]2[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]1=2)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(CCl)N1CCOc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A suspension of 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (8 g, 44.4 mmol) in anhydrous toluene (100 mL) under positive argon pressure was treated dropwise with 2-chloroacetyl chloride (3.91 mL, 48.8 mmol). The mixture was heated at reflux for 25 minutes and became a bright yellow solution. The solution was allowed to cool to room temperature, and a saturated NaHCO3 solution (150 mL) was added. The mixture was transferred to a separatory funnel, and the product was extracted with CH2Cl2 (2×200 mL). The combined organic layers were filtered through a pad of silica gel, washed with CH2Cl2 (50 mL), and concentrated to give a yellow solid (10 g, 88%). 1H-NMR (DMSO-d6) δ 8.22 (d, J=9.0 Hz, 1H), 7.80 (dd, J=2.7, 9.3 Hz, 1H), 7.72 (d, J=2.7 Hz, 1H), 4.74 (s, 2H), 4.40 (t, J=4.2 Hz, 2H), 3.94 (t, J=4.8 Hz, 2H); ESI-MS (m/z, %): 279 (MNa+, 30), 257 (MH+, 100).
Reaction SMILES: [NH2:1][CH:2]([CH3:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1.[CH2:17]([O:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25])[CH2:18][CH2:19][CH3:20]>>[CH2:17]([O:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([NH:1][CH:2]([CH3:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)=[O:25])[CH2:18][CH2:19][CH3:20].[CH2:17]([O:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([NH:1][CH:2]([CH3:16])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1)=[O:25])[CH2:18][CH2:19][CH3:20]
Reactant: CCOC(=O)Cc1ccc(CC(C)N)cc1
Reactant: CCCCOc1ccccc1C(=O)Cl
Product: CCCCOc1ccccc1C(=O)NC(C)Cc1ccc(CC(=O)O)cc1
Product: CCCCOc1ccccc1C(=O)NC(C)Cc1ccc(CC(=O)OCC)cc1

Procedure:
In an analogous manner, by the reaction of ethyl 4-(2-aminopropyl)-phenylacetate with o-butoxybenzoyl chloride, there is obtained, via ethyl 4-[2-(2-butoxybenzamido)-propyl]-phenylacetate (oil), 4-[2-(2-butoxybenzamido)-propyl]-phenylacetic acid; m.p. 91°-92° C., after recrystallization from isopropanol/water.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)/[S:6][C:5]1=[O:20].Cl[C:22]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23].CCN(C(C)C)C(C)C.C(OC1C=CC(/C=C2/C(=O)N(CCNC(=O)C)C(=O)S/2)=CC=1)C>>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11](/[CH:10]=[C:7]2/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][C:22](=[O:23])[O:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:5](=[O:20])[S:6]/2)=[CH:12][CH:13]=1)[CH3:19]
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Reactant: CC(C)COC(=O)Cl
Agent: CCOc1ccc(/C=C2\SC(=O)N(CCNC(C)=O)C2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(/C=C2\SC(=O)N(CCNC(=O)OCC(C)C)C2=O)cc1

Procedure:
The title compound 26c was prepared from compound 76 (70 mg, 0.17 mmol), isobutyl chloroformate (25 μL, 0.19 mmol) and DIPEA (75 μL, 0.43 mmol) in a manner similar to that described for 25a in 96.4% (65 mg) yield as a light-yellow solid.