Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.[CH2:14]([O:16][C:17]([CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)=[O:18])[CH3:15].O>C(OCC)C>[CH2:14]([O:16][C:17]([CH:19]1[CH2:24][CH2:23][C:22]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=2)([OH:25])[CH2:21][CH2:20]1)=[O:18])[CH3:15]
Reactant: Clc1ccc(Br)nc1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C1CCC(O)(c2ccc(Cl)cn2)CC1
Reaction time: 0.5 h

Procedure:
Butyllithium (15% in hexane; 15 ml) was added dropwise to a solution of 2-bromo-5-chloropyridine (3.8 g) in diethyl ether (80 ml) at −78° C. and, after one hour, a solution of 4-oxocyclohexanecarboxylic acid ethyl ester (3.7 g) in diethyl ether (10 ml) was added dropwise. After 30 minutes, water was cautiously added and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 283.76 (C14H18ClNO3); MS (ESI): 284 (M+H+) was obtained in this way.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]3[C:29](=[CH:30][CH:31]=2)[O:28][C:15]2([CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH2:14][C:13]3=[O:32])=[N:8][CH:9]=1)(=[O:3])[NH2:2].[ClH:33].CCOCC>O1CCOCC1>[ClH:33].[ClH:33].[O:32]=[C:13]1[C:12]2[C:29](=[CH:30][CH:31]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:1]([NH2:2])=[O:3])=[CH:9][N:8]=3)[CH:11]=2)[O:28][C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3ccc(C(N)=O)cn3)ccc1O2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NC(=O)c1ccc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)nc1
Reaction time: 18 h

Procedure:
To a suspension of tert-butyl 6-(5-carbamoylpyridin-2-yl)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate in dioxane (125 ml) was added 4N HCl in dioxane (125 ml) and the mixture was stirred for 18 h. After Et2O was added to the mixture, the resulted precipitate was collected by aeration, washed with Et2O to give intended compound as a colorless solid.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH2:32][C@@H:33]5[CH2:37][CH2:36][CH2:35][O:34]5)[CH:27]=4)[C:22]3=[O:38])=[CH:17][C:16]=2[O:39][CH3:40])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[N:11]1([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH2:32][C@@H:33]5[CH2:37][CH2:36][CH2:35][O:34]5)[CH:27]=4)[C:22]3=[O:38])=[CH:17][C:16]=2[O:39][CH3:40])[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1N1CCCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1N1CCCNCC1

Procedure:
Reaction of 4-(2-Methoxy-4-{1-oxo-6-[(S)-1-(tetrahydro-furan-2-yl)methoxy]-1H-isoquinolin-2-yl}-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester with trifluoroacetic acid by method H2 resulted in the desired product with the molecular weight of 449.55 (C26H31N3O4); MS (ESI): 450 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@@H:8]([CH2:11][OH:12])[O:7][C:6]=2[CH:13]=1.[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@@H:8]([CH2:11][O:12][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:7][C:6]=2[CH:13]=1
Reactant: OC[C@@H]1COc2ccc(Br)cc2O1
Reactant: Oc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)O[C@H](COc1ccccc1)CO2
Temperature: 0 °C
Yield: 37.2 %

Procedure:
A mixture of [(2R)-7-bromo-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (0.648 g, 2.64 mmol), phenol (0.248 g, 2.64 mmol), triphenylphosphine (0.692 g, 2.64 mmol) and THF (26 mL) is cooled in a 0° C. bath under N2. Diethylazodicarboxylate (0.42 ml, 2.7 mmol) is added and the mixture allowed to warm to rt overnight. The mixture is concentrated, partitioned between EtOAc and H2O, the organic layer dried (MgSO4), adsorbed onto SiO2, and chromatographed (Biotage 40S+SIM, (1:19) EtOAc:hexane). The product fractions are pooled and concentrated to afford 0.315 g (37%) of (2R)-7-bromo-2-(phenoxymethyl)-2,3-dihydro-1,4-benzodioxine as an oil. A solution of this oil (0.280 g, 0.87 mmol) and THF (30 ml) is cooled in a CO2 (s)/acetone bath under N2. To this is added a solution of tert-butyl lithium in pentane (1.7 M, 1.10 ml, 1.9 mmol). After stirring for 5 min, CO2 (g) is bubbled through the solution for an additional 10 min. The mixture is treated with MeOH/HCl and allowed to warn to rt. The mixture is concentrated, and the residue is chromatographed (Biotage 40S, (1:499) MeOH:CH2Cl2). The product fractions are pooled and concentrated to afford 0.103 g (41%) of (3R)-3-(phenoxymethyl)-2,3-dihydro-1,4-benzodioxine-6-carboxylic acid as a solid. Example 12 is obtained in 45% yield as a monohydrate solid following the procedures outlined in Example 1, making non-critical changes: 1H NMR (400 MHz, CD3OD) δ 7.40-7.55, 7.25-7.35, 6.90-7.05, 4.35-4.65, 4.20-4.35, 3.75-3.90, 3.25-3.55, 2.30-2.40, 2.15-2.30, 2.05-2.15, 1.85-2.00; MS (EI) m/z 394 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1.[CH:17](O)=[O:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([NH:16][CH:17]=[O:18])[CH:3]=1
Reactant: CN(c1ccccc1)c1ccc(Cl)cc1N
Reactant: O=CO
Product: CN(c1ccccc1)c1ccc(Cl)cc1NC=O
Reaction time: 2 h
Yield: 100 %

Procedure:
4-Chloro-N1-methyl-N1-phenylbenzene-1,2-diamine (9.3 g, 40.1 mmol) was dissolved in formic acid (60 mL) and heated to reflux. After 2 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (500 mL) and washed with aq. NaHCO3 (5%, 500 mL). The organic layer was dried, filtered and concentrated under reduced pressure. The residual oil was chromatographed over silica (cyclohexane/CH2Cl2, 9/1, v/v) to give pure title compound (10.4 g, 100% yield). Data: Rf 0.25 (heptane/ethyl acetate, 3/1, v/v). (m/z)=261 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=1.[NH3:28]>CO>[NH2:28][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=1
Reactant: COc1cccc(C(=O)Nc2ccc(OCCBr)c(-c3ccnn3C)c2)c1
Reactant: N
Solvent: CO
Product: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Temperature: 150 °C
Yield: 53 %

Procedure:
A mixture of N-[4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide (0.5000 g, 1.161 mmol) and ammonia (0.2515 g, 11.62 mmol) in 20 mL of methanol were heated to 150° C. for 30 minutes under microwave irradiation in a heavy walled sealed tube. The reaction mixture was concentrated to produce the crude product that was subjected to purification on HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid (TFA salt) in 53% yield. LCMS m/z (%)=367 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ 10.2 (s, 1H), 7.83 (dd, J=2.53 and J2=8.89 Hz, 1H), 7.68 (d, J1=2.53 Hz, 1H), 7.53 (d, J1=8.08 Hz, 1H), 7.48 (m, 1H), 7.46 (d, 31=1.78 Hz, 1H), 7.43 (d, J1=8.08 Hz, 1H), 7.19-7.13, (m, 2H), 6.27 (d, J1=1.77 Hz, 1H), 3.95 (t, J1=5.80 Hz, 2H), 3.83 (s, 3H), 3.69 (s, 3H), 2.8 (t, J1=5.80 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[NH2:21])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[NH:21][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)N2CCc3cccc(N)c32)cc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N2CCc3cccc(NC(=O)c4ccncc4)c32)cc1
Yield: 82 %

Procedure:
To a stirred mixture of 19 (0.2 g, 0.52 mmol), isonicotinoyl chloride hydrochloride (0.18 g, 1.04 mmol), and cesium carbonate (0.68 g, 2.08 mmol) in acetonitrile (20 ml) was heated to reflux for 16 h. The reaction mixture was quenched with ice water and extracted with CH2Cl2. The combined organic layer was dried over MgSO4 and evaporated to give a residue that was purified by silica gel flash column chromatography (EtOAc:n-hexane :NH3(aq)=3:2:1%) and recrystallized (CH2Cl2/EtOAc) to afford compound 26, yield 82%.
Reaction SMILES: CS(O[C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:15]2[CH:20]=[CH:19][C:18](OS(C)(=O)=O)=[CH:17][CH:16]=2)([CH3:14])[CH3:13])=[CH:8][CH:7]=1)(=O)=O.C(N(CC)CC)C>C(OCC)(=O)C.[Pd]>[C:9]1([C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:14])[CH3:13])[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(c1ccc(OS(C)(=O)=O)cc1)c1ccc(OS(C)(=O)=O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(c1ccccc1)c1ccccc1
Yield: 84 %

Procedure:
0.5 mol of Compound A were stirred at 40° C. and under 20 bar of H2 in 3,000 ml of ethyl acetate with the addition of 27 g of palladium/carbon (5% Pd) and 1 mol of triethylamine; during the course of the reaction a further 15 g of Pd/C were added in total. After distillation, 84% of Compound B was obtained.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=[CH:27][C:28]=2[CH3:29])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7].[OH-].[Na+]>C(O)C>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:32])=[O:2])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=[CH:27][C:28]=2[CH3:29])=[CH:19][CH:18]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(C)ccn(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(-c2c(C)ccn(C)c2=O)cc1)C(=O)O
Temperature: 42.5 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a suspension of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (22 mg, 0.048 mmol) in ethanol (1 mL) was added 1N aqueous sodium hydroxide solution (0.5 mL) at room temperature. The resulting solution was heated to 40-45° C. and stirred for 2 h. Then, the ethanol was removed under vacuum and the residue was diluted with water (25 mL). The aqueous solution was washed with diethyl ether (25 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N HCl and the product was extracted into ethyl acetate (2×25 mL). The combined extracts were washed with brine solution (50 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration afforded 18 mg (86% yield) of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine as an amorphous white solid. ES-HRMS m/e calcd for C24H23ClN2O4 (M+H) 439.1419, found 439.1425.
Reaction SMILES: [NH2:1][C:2]1[C:25]([Cl:26])=[CH:24][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:11]2)=[O:7])=[C:4]([O:27][CH2:28][CH3:29])[CH:3]=1.[OH:30]O>CO>[NH2:1][C:2]1[C:25]([Cl:26])=[CH:24][C:5]([C:6]([NH+:8]([O-:30])[CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:11]2)=[O:7])=[C:4]([O:27][CH2:28][CH3:29])[CH:3]=1
Reactant: OO
Reactant: CCOc1cc(N)c(Cl)cc1C(=O)NCC1CN(Cc2ccccc2Cl)CCO1
Solvent: CO
Product: CCOc1cc(N)c(Cl)cc1C(=O)[NH+]([O-])CC1CN(Cc2ccccc2Cl)CCO1
Reaction time: 24 h
Yield: 14.5 %

Procedure:
To a stirred solution of 4-amino-5-chloro-N-[[4-(2-chlorobenzyl)-2-morpholinyl]methyl]-2-ethoxybenzamide (4.0 g) in methanol (150 ml) is added 30% aqueous hydrogen peroxide (1.2 g). After the mixture is heated under reflux for 8 hours, an additional 30% aqueous hydrogen peroxide (1.2 g) is added, and the reaction mixture is refluxed with stirring for an additional 24 hours. The solvent is distilled off under reduced pressure, and chloroform and water are added to the residue. The mixture is stirred for about 30 minutes. The precipitate is collected and recrystallized from isopropyl alcohol-diisopropyl ether to give the title compound (0.6 g), mp 154°-157° C.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH2:16][CH2:17][C:18]([OH:20])=O)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[NH2:31])[C:25]([OH:27])=[O:26].Cl>CN(C=O)C>[OH:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[NH:31][C:18](=[O:20])[CH2:17][CH2:16][NH:15][S:12]([C:9]1[CH:8]=[CH:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:11][CH:10]=1)(=[O:13])=[O:14])[C:25]([OH:27])=[O:26]
Reactant: CCCCCc1ccc(S(=O)(=O)NCCC(=O)O)cc1
Reactant: Nc1ccc(C(=O)O)cc1O
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCCc1ccc(S(=O)(=O)NCCC(=O)Nc2ccc(C(=O)O)cc2O)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 115.8 %

Procedure:
To a solution of the product of Step 1 (200 mg, 0.67 mmol) in dry DMF (7 mL) was added 1,1-carbonyldiimidazole (CDI) (120 mg, 0.73 mmol). The resulting mixture was stirred at 40° C. for 1 h, then treated with 3-hydroxy-4-aminobenzoic acid (107 mg, 0.7 mmol). The mixture was stirred at 40° C. for 16 h, then poured into 1N aqueous HCl (100 mL). The resulting yellow precipitate was filtered, washed with diethyl ether, and azeotroped to dryness once from toluene to give the crude title compound (337 mg), which was used directly in the next step without further purification. MS m/e 434.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[C:18]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[O:23][CH:24]([CH3:26])[CH3:25].[ClH:27]>CC#N.[Cu]Cl>[Cl:27][C:9]1[C:18]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[O:23][CH:24]([CH3:26])[CH3:25]
Reactant: COC(=O)c1cc(OC(C)C)c(N)c(OC(C)C)c1
Reactant: Cl
Agent: Cl[Cu]
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: COC(=O)c1cc(OC(C)C)c(Cl)c(OC(C)C)c1
Temperature: 65 °C
Yield: 36 %

Procedure:
A suspension of copper (I) chloride (129 mg, 1.31 mmol) and tert-butyl nitrite (155 μL, 1.31 mmol) in anhydrous MeCN (2 mL) was stirred at 65° C. A solution of methyl 4-amino-3,5-diisopropoxybenzoate (4) (233 mg, 0.872 mmol) in anhydrous MeCN (1 mL) was added dropwise. Once the addition was complete the mixture was allowed to cool to RT and poured on to 20% HCl (5 mL). The mixture was partitioned between DCM (10 mL) and aq. ammonia (35%, 5 mL), the phases were separated and the organic solution was further washed with ammonia solution (17.5%, 10 mL), and brine (2×20 mL). The solvent was removed in vacuo and the residue was purified by silica gel chromatography (40 g, 0-100% EtOAc in isohexane) to afford methyl 4-chloro-3,5-diisopropoxybenzoate (93 mg, 36% yield) as a colourless oil: m/z 287 [M+H]+ (ES+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:14]=[C:13](O)[C:12]([CH2:16][O:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:21]=[CH:20][C:19]=2[CH3:27])=[C:11]([CH3:28])[N:10]=1.P(Cl)(Cl)([Cl:31])=O>>[Cl:31][C:13]1[C:12]([CH2:16][O:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:25])[CH3:26])[CH:21]=[CH:20][C:19]=2[CH3:27])=[C:11]([CH3:28])[N:10]=[C:9]([C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(C(C)C)cc1OCc1c(C)nc(-c2c(C)cccc2C)nc1O
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(-c2c(C)cccc2C)nc1Cl
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(2,6-dimethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-6-methylpyrimidin-4-ol (760 mg, 2.0 mmol) and phosphorous oxychloride (5 mL) is heated at 80° C. under nitrogen with magnetic stirring for 2 h (until starting material is consumed as determined by LC/MS analysis). The reaction mixture is evaporated at reduced pressure, diluted with DCM (50 mL), extracted with sat. NaHCO3 (20 mL×3), dried over anhydrous sodium sulfate, filtered and evaporated to obtain a pale yellow oil. Purification by chromatography on silica gel (10-40% EtOAc/Hexanes) provides the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.08-7.25 (m, 4H), 6.88 (s, 1H), 6.82 (d, J=9 Hz, 1H), 5.28 (s, 2H), 2.91 (m, 1H), 2.74 (s, 3H), 2.21 (s, 3H), 2.14 (s, 6H), 1.28 (d, J=6.8 Hz, 6H); LC-MS found 395.4 (MH+), rt=3.33 min, Method 3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]([C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=2)[N:23]=1>>[N:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]([C:31]2[CH:32]=[CH:33][C:34]([C:35]([N:8]([C@@H:9]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]3)[C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)=[O:36])=[CH:38][CH:39]=2)[N:23]=1
Reactant: O=C(O)c1ccc(-n2nnc3cccnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncccc2Cl)C1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](N(C(=O)c2ccc(-n3nnc4cccnc43)cc2)c2ncccc2Cl)C1
Yield: 78.9 %

Procedure:
Prepared according to General Procedure A and C starting from Preparation 1 tert-butyl (3R)-3-[(3-chloropyridin-2-yl)amino]piperidine-1-carboxylate (26.7 g, 85.5 mmol) and Preparation 5 4-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)benzoic acid (20.1 g, 83.5 mmol) to provide 35.2 g (79%) of the product as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:20](O)=[O:21])=[N:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:37][C:38]1[CH:46]=[CH:45][C:41]([CH2:42][NH:43][CH3:44])=[CH:40][CH:39]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:20]([N:43]([CH2:42][C:41]2[CH:45]=[CH:46][C:38]([F:37])=[CH:39][CH:40]=2)[CH3:44])=[O:21])=[N:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCc1ccc(F)cc1
Reactant: CN1CCn2nc(C(=O)O)c(OCc3ccccc3)c2C1=O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(Cc1ccc(F)cc1)C(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-benzyloxy-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid (50 mg, 0.166 mmol) in DMF (2 mL) were added EDC (32 mg, 0.166 mmol), HOBT (27 mg, 0.199 mmol), and 4-fluoro-N-methylbenzylamine (23 mg, 0.166 mmol). The reaction was stirred at room temperature overnight and partitioned between EtOAc and brine. The aqueous layer was extracted several times with EtOAc, and the combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA) and collection and concentration of the appropriate fractions afforded the title product. 1H NMR (400 MHz, CDCl3) δ 7.44-7.42 (m, 1H), 7.38-7.29 (m, 4H), 7.16-7.12 (m, 1H), 6.98-6.92 (m, 3H), 5.30-5.24 (m, 4H), 4.39-4.34 (m, 2H), 3.80-3.73 (m, 2H), 3.19-3.17 (d, 3H), 2.89-2.86 (d, 3H); ES MS (M+1)=423.
Reaction SMILES: [CH:1]([O:6]C)(OC)[O:2][CH3:3].C([C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)(O)=O>C1(C)C(S(O)(=O)=O)=CC=CC=1.CO>[CH3:3][O:2][C:1]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)=[O:6]
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: COC(OC)OC
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CO
Product: COC(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 70 °C
Yield: 95.9 %

Procedure:
A glass reaction vessel fitted with a reflux condenser and magnetic stir bar was charged with trimethyl orthoformate (34.28 grams), 4-carboxybenzenesulfonamide (50.00 grams), toluenesulfonic acid (2.5 grams) and methanol (197 mL). The mixture was heated to 70° C. for 16 hours. The cooled mixture was concentrated on a rotary evaporater. Diethyl ether (200 mL) was added to the concentrate and stirred. The resulting solid was filtered to afford 51.3 grams of the desired 4-methoxycarbonyl benzenesulfonamide. In a glass reaction vessel fitted with a reflux condenser, a thermometer, a pressure-equalizing addition funnel, and a nitrogen inlet was placed a 60 weight percent dispersion of NaH in mineral oil (16.22 grams). The dispersion was washed three times with heptane by stirring the mixture for several minutes, allowing the mixture to stand, and using a pipette to decant the supernatant heptane. NMP (50 grams) was added to the flask and the mixture was stirred. To this stirred mixture was added a solution of camphoric anhydride (14 grams), 4-methoxycarbonyl benzenesulfonamide (15 grams), and NMP (61 grams) slowly via the addition funnel. The resulting mixture was stirred at room temperature for approximately 1 hour, poured into a beaker of deionized water that was vigorously stirred. The basic mixture was acidified with 1.0N HCl and subsequently extracted with EtOAc. The volatile components were removed using a rotary evaporator to afford a solid intermediate. This intermediate was combined with THF (111 grams), acetic anhydride (8.54 grams), and triethylamine (23.3 grams) and stirred for 1 hour at 60° C. The mixture was poured into aqueous 1N HCl and the resultant solid isolated by filtration. The solid was combined with methanol and this mixture was heated to boiling, cooled to room temperature, filtered, and washed sequentially with methanol and diethyl ether. The solid was dried overnight in a vacuum oven at room temperature and 67 Pa (0.5 mm Hg) to give the desired product.
Reaction SMILES: [C:1]1(=O)[CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH:10]12[CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]1[CH2:13][NH:12][CH2:11]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([N:12]2[CH2:11][CH:10]3[CH:14]([CH:15]3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1C2CNCC21
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1C2CN(C3CCC3)CC21
Temperature: 0 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
A mixture of cyclobutanone (157 mg, 2.19 mmol) in acetic acid (0.11 mL, 1.56 mmol) was added to a stirred solution of ethyl 3-aza bicyclo[3.1.0]hexane-6-carboxylate (243 mg, 1.56 mmol, obtained in the above step) in dichloromethane, cooled at 0° C. Solid sodium triacetoxy borohydride (727 mg, 3.43 mmol) was added portion wise over a period of 15 minutes. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. The reaction mixture was cooled to 0° C. and basified with saturated sodium bicarbonate solution (pH: 7.5). The two layers were separated, the organic layer was washed with brine, dried over anhydrous sodium sulfate and the volatiles were removed under reduced pressure to obtain ethyl 3-cyclobutyl-3-aza bicyclo[3.1.0]hexane-6-carboxylate (219 mg).