Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][NH:13][C:12](=[O:15])[CH:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[CH2:34]([N:13]1[CH2:14][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][CH:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]1=[O:15])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CC(O[Si](C)(C)C(C)(C)C)CNC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CC(O[Si](C)(C)C(C)(C)C)CN(Cc2ccccc2)C1=O
Reaction time: 0.08 h
Yield: 77.5 %

Procedure:
To a stirred solution of compound 1D (0.403 g, 1.17 mmol) in 5 mL of THF at room temperature under argon was added (in one portion) 1.20 mL (in THF, 1.2 mmol) of 1M lithium bis(trimethylsilyl)amide and, after 5 min, 153 μL of benzyl bromide (1.29 mmol). After 15 h, additional portions of the base and alkylating agent were added as before. After 1 h more, the reaction mixture was quenched with saturated NaCl and extracted twice with EtOAc. The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure. Purification by silica gel chromatography (7:33 EtOAc/CH2Cl2) provided the title compound (394 mg, 77%) as a colorless oil and a 61:39 mixture of diastereomers of unknown assignment. MS [M+H]+: found 435.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])[CH3:2].[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][Br:13])[CH3:2]
Reactant: CCOC(=O)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccccc1CBr
Temperature: 25 °C

Procedure:
To a solution of 2-methylbenzoic acid ethyl ester (16.4 g, 99.87 mmol) in CCl4 (100 mL) is added N-bromosuccinimide (17.8 g, 100 mmol) and 2,2′-azobisisobutyronitrile (3.28 g, 19.97 mmol). The resulting mixture is heated at reflux for 2 h. After the mixture is cooled to RT, the solid is filtered off and the filtrate is concentrated and extracted with EtOAc. The EtOAc solution is washed with brine and dried over MgSO4, filtered and concentrated to afford the title compound as a pale yellow oil.
Reaction SMILES: [Br-:1].[NH2:2][C:3]1[C:4]([C:11]([NH:13][CH2:14][CH2:15][N+:16]([CH2:19][CH2:20][N:21]2C(=O)C3C(=CC=CC=3)C2=O)([CH3:18])[CH3:17])=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.O.NN>CCO>[Br-:1].[NH2:21][CH2:20][CH2:19][N+:16]([CH2:15][CH2:14][NH:13][C:11]([C:4]1[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=1)=[O:12])([CH3:17])[CH3:18]
Reactant: C[N+](C)(CCNC(=O)c1nc(Cl)c(N)nc1N)CCN1C(=O)c2ccccc2C1=O
Agent: NN
Agent: [Br-]
Solvent: CCO
Solvent: O
Product: C[N+](C)(CCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 40 °C

Procedure:
A mixture of {2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-dimethyl-ammonium bromide (47 g, 92 mmol) and hydrazine monohydrate (20 mL, 412 mmol) in EtOH (500 mL) is heated at 40° C. for 4 h. After cooling to RT the resulting solid is removed by filtration and washed with diethyl ether. The filtrate is concentrated in vacuo to afford the title product. [M+H]+ 302.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[Cl:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)[N:12]=[C:11](NN)[C:10]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>S([O-])([O-])(=O)=O.[Cu+2].C(O)CC>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[Cl:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:22]=2)[N:12]=[CH:11][C:10]=1[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nc(NN)c(-c2ccccc2)c1Cl
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCCO
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)ncc(-c2ccccc2)c1Cl
Temperature: 100 °C
Yield: 26.1 %

Procedure:
A mixture of 4-chloro-6-hydrazinyl-2-(4-phenoxyphenyl)-5-phenylnicotinonitrile TFA salt (72.6 mg, 0.138 mmol), 1.0 M aqueous copper(II) sulfate (0.276 mL, 0.276 mmol) and 1-propanol (1 mL) was heated to 100° C. in a sealed tube for 2 h. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated and purified by reverse phase HPLC (isocratic 100% solvent B for 25 min, 40 mL/min, Sunfire 30×250 mm to give 4-chloro-2-(4-phenoxyphenyl)-5-phenylnicotinonitrile TFA salt as white solid (17.9 mg, 26% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.78 (1H, s), 7.87-7.96 (2H, m), 7.46-7.56 (5H, m), 7.37-7.45 (2H, m), 7.20 (1H, t, J=7.40 Hz), 7.09-7.17 (4H, m); MS (ES+) m/z: 383 (M+H); LC retention time: 4.790 min (analytical HPLC Method A).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[Se:10][C:6]=2[N:5]=[CH:4][N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19]>C(O)(C)C>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[C:7]3[C:8]4[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=4[Se:10][C:6]=3[N:5]=[CH:4][N:3]=2)[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Clc1ncnc2[se]c3c(c12)CCCC3
Solvent: CC(C)O
Product: Fc1ccc(Nc2ncnc3[se]c4c(c23)CCCC4)cc1Cl
Yield: 88 %

Procedure:
To a solution of step b compound (300 mg, 1.10 mmol) in isopropyl alcohol (10 mL) was added 3-chloro-4-fluoroaniline (640 mg, 4.4 mmol) at rt and the mixture was refluxed for 7 h. The mixture was allowed to rt and the contents were poured into ice cold water. The solution was extracted with chloroform (3×100 mL) and the combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-ethyl acetate (95:5) as eluents to give the product (370 mg, 88%). The crude product was further recrystallized from chloroform-hexane to give the pure product as a pale pink color solid, mp 146-148° C. IR (neat) νmax 3458, 2931, 1605, 1564, 1254, 1195, 1121, 1041, 965 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 8.36 (1H, s), 8.20 (1H, s), 7.89 (1H, dd, J=6.8, 2.8 Hz), 7.58-7.62 (1H, m), 7.39 (1H, t, J=9.0 Hz), 3.10 (2H, br s), 2.91 (2H, br s), 1.84 (4H, br s); LC-MS (negative ion mode): m/z 380, 382 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]2([O:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22][CH2:21]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH3:2].[H][H].[OH-].[Na+]>FC(F)(F)C(O)=O.O.[Pt](=O)=O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]2([O:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:21][CH2:22][CH2:23]2)[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH3:2]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CCC1
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOCc1nc2c(N)nc3c(c2n1CC1(OCCS(C)(=O)=O)CCC1)CCCC3
Yield: 69.1 %

Procedure:
A mixture of 2-(ethoxymethyl)-1-({1-[2-(methylsulfonyl)ethoxy]cyclobutyl}methyl)-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 26, 0.500 g, 1.16 mmol) and platinum(IV) oxide (0.5 g) in trifluoroacetic acid (5 mL) was hydrogenated on a Parr apparatus at 50 psi (3.5×105 Pa) hydrogen pressure for 1 day. The mixture was filtered through CELITE filter agent, which was washed afterwards with dichloromethane. The filtrate was concentrated under reduced pressure to afford an oil that was suspended in water (20 mL) and adjusted to pH 13 with 50% aqueous sodium hydroxide. A white solid formed that was isolated by filtration, washed with water, and recrystallized from acetonitrile. The crystals were isolated and dried under vacuum at 65° C. to afford 0.35 g of 2-(ethoxymethyl)-1-({1-[2-(methylsulfonyl)ethoxy]cyclobutyl}methyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 186-188° C.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:14][CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:1][C:2]1[N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=2)[C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc2ccccc2c(=O)[nH]1
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc2ccccc2c(=O)n1CCOc1ccc(C=O)cc1
Yield: 38.9 %

Procedure:
The title compound (0.6 g, 39%) was prepared from 2-methyl-4-oxo-3,4-dihydroquinazoline (0.8 g, 5 mmol) and 4-[2-bromoethoxy]benzaldehyde (1.37 g, 6 mmol) in the presence of K2CO3 (1.38 g, 10.0 mmol) as base, by a similar procedure to that described in preparation 1.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][CH:12]1[C:23](=[O:24])[N:14]2[CH:15]([C:20]([OH:22])=[O:21])[C:16](=[CH2:19])[CH2:17][S:18][C@H:13]12>CN(C)C=O>[CH:1]([NH:11][CH:12]1[C:23](=[O:24])[N:14]2[CH:15]([C:20]([OH:22])=[O:21])[C:16](=[CH2:19])[CH2:17][S:18][C@H:13]12)=[O:2]
Reactant: C=C1CS[C@@H]2C(N)C(=O)N2C1C(=O)O
Reactant: O=CO
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: C=C1CS[C@@H]2C(NC=O)C(=O)N2C1C(=O)O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of formic acid (1 l) and acetic anhydride (2.5 l) was stirred at 50° C. for 1 hour and cooled at 40°C. To the mixture were added 7-amino-3-methylenecepham-4-carboxylic acid (1,070 g) and N,N-dimethylformamide (500 ml). The mixture was stirred for 1 hour at 55° C. and cooled in an ice-water bath. A resultant precipitate was collected by filtration and washed with a small amount of a mixture of ethyl acetate and diisopropyl ether (1:1) to give 7-formamido-3-methylenecepham-4-carboxylic acid (1.02 g).
Reaction SMILES: [CH:1]1([C:4]2[N:5](COCC[Si](C)(C)C)[C:6]3[C:11]([N:12]=2)=[C:10]([NH:13][C:14]2[C:19](=[O:20])[N:18]4[C:21]([CH3:29])([C:25]([F:28])([F:27])[F:26])[NH:22][C:23](=[O:24])[C:17]4=[CH:16][CH:15]=2)[N:9]=[CH:8][N:7]=3)[CH2:3][CH2:2]1.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH:1]1([C:4]2[NH:5][C:6]3[C:11]([N:12]=2)=[C:10]([NH:13][C:14]2[C:19](=[O:20])[N:18]4[C:21]([CH3:29])([C:25]([F:26])([F:28])[F:27])[NH:22][C:23](=[O:24])[C:17]4=[CH:16][CH:15]=2)[N:9]=[CH:8][N:7]=3)[CH2:2][CH2:3]1
Reactant: CC1(C(F)(F)F)NC(=O)c2ccc(Nc3ncnc4c3nc(C3CC3)n4COCC[Si](C)(C)C)c(=O)n21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C(F)(F)F)NC(=O)c2ccc(Nc3ncnc4[nH]c(C5CC5)nc34)c(=O)n21
Temperature: 70 °C

Procedure:
To a solution of 6-[[8-cyclopropyl-9-(2-trimethylsilylethoxymethyl)purin-6-yl]amino]-3-methyl-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridine-1,5-dione (8, 0.25 g, 0.47 mmol) in tetrahydrofuran (50 mL) was added tetrabutylammonium fluoride hydrate (0.61 g, 2.33 mmol). The mixture was heated at 70° C. for 4 h. After TLC showed consumption of 8, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude mixture was purified via column chromatography (silica, methanol/dichloromethane=2%) to afford 6-[(8-cyclopropyl-9H-purin-6-yl)amino]-3-methyl-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 37) as yellow solid. Yield: 135 mg, 71%; MS (ESI) m/z 406.29 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.24 (s, 1H), 10.55 (s, 1H), 8.80 (d, J=7.6 Hz, 1H), 8.64 (s, 1H), 8.49 (s, 1H), 7.10 (d, J=7.6 Hz, 1H), 2.16 (m, 1H), 2.15 (s, 3H), 1.12 (m, 4H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O-:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+].[C:12]1([CH2:18][CH2:19][CH2:20]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1OCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:20][CH2:19][CH2:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [O-]CCCN1CCCCC1
Reactant: BrCCCc1ccccc1
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(CCCOCCCN2CCCCC2)cc1

Procedure:
Sodium 3-piperidinopropanolate (20 mmol), 20 mmol of 3-phenylpropyl bromide, and 0.5 mmol of 15-crown-5 in 30 ml of dry toluene were refluxed for 4 hours. The solvent was evaporated and the residue purified by column chromatography on silica gel (eluent: methylene chloride/methanol/aqueous ammonia (90/10/0.5)). After removing the solvent under reduced pressure the residue was crystallized with oxalic acid from diethyl ether/ethanol.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C@H:14]([CH2:23][CH:24]([CH:28]([CH3:30])[CH3:29])[C:25](O)=[O:26])[O:13][C:12]1([CH3:32])[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([NH2:37])[CH2:34][CH2:35][CH3:36].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[C@H:14]([CH2:23][C@@H:24]([CH:28]([CH3:29])[CH3:30])[C:25]([NH:37][CH2:33][CH2:34][CH2:35][CH3:36])=[O:26])[O:13][C:12]1([CH3:32])[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC1CCCCC1)C(=O)O
Reactant: CCCCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCNC(=O)[C@@H](C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC1CCCCC1)C(C)C
Reaction time: 8 h

Procedure:
The crude carboxylic acid (I) (551 mg) was dissolved in DMF (10 ml) containing triethylamine (126 mg). Butylamine (109 mg), HOBT (169 mg) and EDAC (240 mg) were added and the solution was allowed to stand overnight. The solvent was removed by evaporation and the residue partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was separated and washed with saturated sodium hydrogen carbonate solution (20 ml), followed by water (20 ml) and then saturated sodium chloride solution (20 ml). The organic phase was dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by flash chromatography eluting with ethyl acetate/hexane (1:4 v/v), to give initially (2S)-2-[(4S,5S)-3-benzyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-1,3-oxazolidin-5-yl]methyl-N-butyl-3-methylbutanamide (J), as a clear oil (103 mg); NMR (CDCl3): 0.9 (m, 9H), 1.0-2.1 (complex m, 27H), 3.25 (q, 2H), 3.75 (m, 2H), 5.1 (dd, 2H), 5.6 (br, 1H), 7.3 (m, 5H); and then the corresponding (2R)-isomer, as a clear oil (133 mg); NMR (CDCl3): 0.9 (m, 9H), 1.0-2.1 (complex m, 27H), 3.25 (m, 2H), 3.75 (m, 1H), 3.9 (m, 1H), 5.1 (dd, 2H), 5.4 (br, 1H), 7.4 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:30])=[C:5]([C:23]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:7]=1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9]>C(O)(=O)C.[O-2].[Cr+6].[O-2].[O-2]>[CH3:1][C:2]1[C:7]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:5]([C:23]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[O:24])=[C:4]([CH3:30])[N:3]=1
Reactant: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+](=O)[O-])c1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: COCCOC(=O)c1c(C)nc(C)c(C(=O)OC(C)C)c1-c1cccc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
6.8 g of chromium(VI) oxide were added in portions to a boiling solution of 41.8 g (100 mmols) of isopropyl 2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate in 160 ml of glacial acetic acid. The mixture was then heated under reflux for a further 30 minutes and, after cooling down, poured into ammoniacal ice-water. The mixture was extracted with chloroform and the extracts, after drying over sodium sulphate, were evaporated in vacuo. 35.9 g (86% of theory) of an oil resulted.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[S:8]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[S:8]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
Methyl 4-(N-(4-fluorobenzyl)-N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-10a) (3.7 g, 8.3 mmol) was dissolved in MeOH/THF (1:1.5, 30 mL) and treated with aqueous NaOH (3 N, 15 mL). The mixture was stirred at ambient temperature overnight, then MeOH and THF were removed in vacuo. The resulting aqueous solution was acidified with 6 N aq HCl to a pH of ˜3 and extracted with EtOAc (3×40 mL). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated. The crude product was purified by recrystallization from EtOH to afford pure 4-(N-(4-fluorobenzyl)-N-(4-methoxybenzyl)sulfamoyl)benzoic acid as a white crystalline solid (2.1 g, 58.6%). MS (M−H, 428.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.66 (s, 3H), 4.23 (s, 2H), 4.26 (s, 2H), 6.72 (d, 2H, J=8 Hz), 6.95 (m, 6H), 7.92 (d, 2H J=8 Hz), 8.07(d, 2H, J=8 Hz). The compound had an IC50 on hT2R14 bitter receptor of 1.97 μM.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1
Reactant: COc1cc(Cl)nc(S(C)(=O)=O)n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(Cl)nc(OCc2ccccc2)n1
Temperature: 25 °C
Yield: 102.1 %

Procedure:
4-Chloro-6-methoxy-2-(methylsulfonyl)pyrimidine (Compound III-29) (0.80 g, 0. 0036 mol) and benzyl alcohol (Compound II-64) (0.39 g, 0.0036 mol) were dissolved in toluene (10 ml), and then 60% sodium hydride (0.16 g, 0.0036×1.1 mol) was added while cooling with ice. After stirred for one night at room temperature, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and thereafter, the solvent was distilled off to afford a crude product (0.92 g), which was then purified on silica gel column chromatography to obtain the compound (I-346) as an oily product.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[Br:27][C:28]1[C:29]([NH2:35])=[N:30][CH:31]=[N:32][C:33]=1Cl.[F-].[Cs+].C(N(CC)C(C)C)(C)C>>[NH2:35][C:29]1[N:30]=[CH:31][N:32]=[C:33]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:8](=[O:16])[C:7]3=[C:17]([S:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[C:28]=1[Br:27]
Reactant: C[C@H](N)c1nn2ccc(Sc3ccccc3)c2c(=O)n1-c1ccccc1
Reactant: Nc1ncnc(Cl)c1Br
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1Br)c1nn2ccc(Sc3ccccc3)c2c(=O)n1-c1ccccc1
Yield: 110.3 %

Procedure:
(S)-2-(1-Aminoethyl)-3-phenyl-5-(phenylthio)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (142 mg, 0.39 mmol) was treated with treated 5-bromo-6-chloropyrimidin-4-amine (245 mg, 1.18 mmol), cesium fluoride (178 mg, 1.17 mmol), N,N-diisopropylethylamine (341 μl, 1.96 mol) according to Preparation 13 to give 0.23 g (75% yield) of the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([C:15]([OH:17])=O)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([C:15]([Cl:20])=[O:17])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1cn(-c2ccc(F)cc2)nc1C(=O)O
Reactant: O=S(Cl)Cl
Product: COc1cn(-c2ccc(F)cc2)nc1C(=O)Cl

Procedure:
E2 (100 mg, 0.42 mmol, 1.0 eq.) was heated in thionyl chloride (1 mL) for 4 h under reflux. Solvent was removed in vacuo and the crude material was resolved in dry toluene and evaporated under reduced pressure again to yield E3. The crude material was used in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH:9]1[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:17][O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH:9]([CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10]1)=[O:15]
Reactant: COC(=O)N1CCN(C(=O)OC(C)(C)C)C(CCOc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N1CCNC(CCOc2ccccc2)C1
Yield: 99.2 %

Procedure:
A solution of (RS)-1-(tert-butyloxycarbonyl)-4-methoxycarbonyl-2-(2-phenoxyethyl)piperazine (D8) (1.4 g, 3.85 mmol) in dichloromethane (30 ml) and trifluoroacetic acid (5 ml) was stirred at 35° C. for 0.75 h. On cooling, the mixture was evaporated in vacuo and the residue partitioned between dichloromethane and 1N sodium hydroxide (50 ml each). The organic layer was dried (Na2SO4) and evaporated in vacuo to afford the title compound as a colourless oil (1.01 g, 99%). Mass spectrum (AP+): Found 265 (MH+). C14H20N2O3 requires 264.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([NH:16][C@H:17]([C:22]([O:24]C)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])=[O:11].[OH-].[Li+]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([NH:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][CH:19]([CH3:20])[CH3:21])[C:10]([NH:12][CH:13]([CH3:14])[CH3:15])=[O:11]
Reactant: COC(=O)[C@H](CC(C)C)N[C@@H](C(=O)NC(C)C)c1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](N[C@@H](C(=O)NC(C)C)c1ccc(F)cc1F)C(=O)O
Reaction time: 1.5 h
Yield: 79.6 %

Procedure:
To a solution of methyl N-[(1R)-1-(2,4-difluorophenyl)-2-(isopropylamino)-2-oxoethyl]-L-leucinate (1.32 g) in methanol (15 ml) was added a solution of lithium hydroxide (294 mg) in water (15 ml). The reaction was rapidly stirred for 1.5 hours and then evaporated in vacuo. The residue was dissolved in water and neutralised using 2N hydrochloric acid. The resulting solid was collected by filtration and dried in vacuo. The filtrate was applied to 4 Oasis cartridges (6 g), which were eluted with water (×2) and methanol (×2). The required fractions were combined and concentrated in vacuo to afford N-[(1R)-1-(2,4-difluorophenyl)-2-(isopropylamino)-2-oxoethyl]-L-leucine (1.01 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([OH:12])(=[O:11])=[O:10].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>[Cu]>[N:13]1([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[S:9]([OH:12])(=[O:11])=[O:10])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: Cc1ccc(F)c(S(=O)(=O)O)c1
Reactant: C1CNCCN1
Agent: [Cu]
Product: Cc1ccc(N2CCNCC2)c(S(=O)(=O)O)c1
Yield: 65.4 %

Procedure:
According to the method described in Example 1 of Japanese Patent Application Laid-Open No. 3-7263, 2-fluoro-5-methylbenzene sulfonic acid (0.76 g) was reacted with piperazine (3.44 g) in the co-presence of cuprous iodide (0.76 g) and copper powder (0.26 g) in a sealed tube at 160° C. for 8 hours. Then, the reaction product was purified on silica gel column chromatography (eluent=chloroform: methanol: acetic acid=100: 100: 3) to give anhydrous crystal of 2-(1-piperazinyl)-5-methylbenzenesulfonic acid derivative (0.67 g, yield=65.0%).