Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11](O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15][CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Br:15][CH2:16][CH2:17][CH2:18][C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1
Reactant: BrCCCBr
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: BrCCCc1ccc(Oc2ccccc2)cc1
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
To a 22 L flask was added 4-phenoxyphenol (900 g), 1,3-dibrompropane (5858 g), powered potassium carbonate (1335 g), and methyl ethyl ketone (9 L). The mixture was stirred for 30 minutes at 22° C. The off-white slurry was heated to a gentle reflux (˜83° C.) and held at that temperature for 16 hours. The off white slurry was cooled to 25° C. and vacuum filtered, washing the cake of inorganic salts with methyl ethyl ketone (4 L). The filtrate was concentrated on a rotary evaporator while increasing the temperature to 90° C. under house vacuum. After the condensation had stopped, the oil was held at 90° C. under vacuum for an additional two hours to ensure the remaining 1,3-dibrompropane below 8% by GC analysis. The residue was dissolved in 3 L of methyl alcohol, and the white slurry was cooled slowly to about 0–5° C. and held at that temperature overnight. The product was filtered, washed with cold methyl alcohol (6 L), and dried at 30° C. for about 20 hours to afford about 1234 g of compound (a) in 84% yield (99.4% pure by GC). 1H-NMR (CDCl3): 7.3(2H, m), 7.1(2H, m), 7.0(2H, m), 6.9(2H, m), 4.1(2H, m); 3.6(2H, m); 2.3(2H, m).
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH3:11])[NH:6][C:5](=[O:12])[CH:4]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[F:13][CH:2]([F:1])[C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH3:11])[N:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[C:5](=[O:12])[CH:4]=1
Reactant: CCCc1nc(C(F)F)cc(=O)[nH]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCc1nc(C(F)F)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
A mixture of 6-(difluoromethyl)-2-propylpyrimidin-4(3H)-one (5.6 g), 4′-(bromomethyl)biphenyl-2-carbonitrile (9 g) and potassium carbonate (8.3 g) in acetonitrile (60 mL) was stirred overnight at 50° C. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow solid (4.4 g, 38%).
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:31][CH:30]=2)O1>>[F:19][C:14]([F:20])([O:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH:5]=[N:6][C:2]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:31][CH:30]=3)=[N:3]2)=[CH:8][CH:9]=1)[C:15]([F:18])([F:17])[F:16]
Reactant: COC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: FC(F)(F)C(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Product: COC(=O)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared as described in Example 3 using 3-bromo-1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazole (C1a) and methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (C2) and isolated as a white solid (3.57 g, 59%): 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.18-8.04 (m, 4H), 7.68-7.58 (m, 2H), 7.48-7.38 (m, 2H), 3.78 (s, 2H), 3.65 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −85.20 (d, J=2.9 Hz), −86.93; ESIMS m/z 428 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12](=[O:17])[NH:13][CH2:14][C:15]#[CH:16])[O:7]1)=[O:5])[CH3:2].[N:25]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1)=[N+:26]=[N-:27].CCCC[Sn](OC(C)=O)(CCCC)CCCC>CC(O)(C)C.CCO.O.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12](=[O:17])[NH:13][CH2:14][C:15]2[N:27]=[N:26][N:25]([C:28]3[CH:29]=[CH:30][C:31]([S:34](=[O:36])(=[O:35])[NH2:37])=[CH:32][CH:33]=3)[CH:16]=2)[O:7]1)=[O:5])[CH3:2]
Reactant: [N-]=[N+]=Nc1ccc(S(N)(=O)=O)cc1
Reactant: C#CCNC(=O)[C@H](Cc1cscn1)NC(=O)[C@H]1O[C@@H]1C(=O)OCC
Agent: [Cu+2]
Agent: CCCC[Sn](CCCC)(CCCC)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: CC(C)(C)O
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)NCc1cn(-c2ccc(S(N)(=O)=O)cc2)nn1
Yield: 69.8 %

Procedure:
The general click procedure was used substituting the following quantities using: 37 (109.0 mg, 0.31 mmol): 4-azidobenzenesulfonamide (61.5 mg, 0.31 mmol); CuSO4 (10.0 mg, 0.06 mmol); NaAsc (20.0 mg, 0.03 mmol); TBTA (10.0 mg, 0.02 mmol); in t-BuOH/EtOH/H2O (4:4:2); afforded the 42 as a white solid (119 mg, 69.8%). 1H NMR (CDCl3, 400 MHz): δ 8.93 (s, 1H); 8.45 (s, 1H); 8.39-8.05 (q, 4H); 7.33 (s, 1H); 4.83-4.77 (t, 1H); 4.57-4.48 (q, 2H); 4.28-4.23 (q, 2H); 3.64 (s, 1H); 3.50 (s, 1H); 3.40-3.21 (m, 2H); 1.28-1.23 (t, 3H). 13C NMR (MeOD-d4, 100 MHz): 170.94, 166.80, 166.72, 153.45, 151.92, 145.70, 143.49, 138.85, 127.31, 120.74, 139.76, 115.56, 61.42, 52.72, 52.67, 51, 47, 33.93, 31.91, 12.52.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:28])[C:7]3[C:14](=[O:15])[N:13]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH:20]=[CH:19][CH:18]=4)[C:12](=[O:27])[C:8]=3[NH:9][C:10]=2[CH:11]=1.CS(O)(=O)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:28])[C:7]3[C:14]([OH:15])=[N:13][N:16]([C:17]4[C:18]5[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH:24]=[CH:25][CH:26]=4)[C:12](=[O:27])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: O=C1c2[nH]c3cc(Cl)ccc3c(=O)c2C(=O)N1Nc1cccc2ccccc12
Agent: CS(=O)(=O)O
Solvent: CO
Product: O=c1c2ccc(Cl)cc2[nH]c2c(=O)n(-c3cccc4ccccc34)nc(O)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.1 %

Procedure:
6-Chloro-2-(1-naphthylamino)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (1.30 g, 3.34 mM) was stirred in methanol (0.65 L) and methanesulfonic acid (65 mL) was added. The brown suspension was heated to reflux for 16 hours during which the solids dissolved to give a brown solution. This solution was cooled to room temperature. Addition of ice (10 mL) gave a tan suspension which was stirred for 1.5 hours. The suspension was filtered (the filtrate was saved for use in Example 24) and the collected solids were washed with methanol and ether to give the title compound (0.560 g, 43%) as a dull yellow pow der, mp 374-376° C.; MS(CI): 390 (M+H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[CH:10]=[CH:9][C:8]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.N1C=CC=CC=1.Cl[C:35](Cl)([O:37]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1.C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:14][O:15][C:35](=[O:37])[O:17][CH2:16]3)[CH:10]=[CH:9][C:8]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C(CO)CO)cc2C2=CCCCC2)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3COC(=O)OC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of 4-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(2-hydroxy-1-hydroxymethyl-ethyl)-phenyl]-amide (as prepared in the previous step, 5.4 mg, 0.015 mmol) and pyridine (3.0 μL, 0.037 mmol) in 0.5 mL of THF at −78° C. was added a solution of triphosgene (1.8 mg, 0.0061 mmol) in 0.5 mL of DCM. The resulting mixture was warmed to RT and continued to stir for 1 h under Ar. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1-2% MeOH-DCM) gave 2.8 mg (48%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.01 (s, 1H), 7.66 (dd, 1H, J=8.6, 2.3 Hz), 7.59 (d, 1H, J=2.3 Hz), 7.29 (d, 1H, J=8.6 Hz), 5.66 (m, 1H), 4.65 (dd, 2H, J=10.9, 10.9 Hz), 4.45 (dd, 2H, J=10.9, 4.9 Hz), 3.72 (m, 1H), 2.24 (m, 4H), 1.70-1.88 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C21H20N4O4, 393.2 (M+H). found 393.1.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:11]C(=O)C(F)(F)F.O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CO>[NH2:11][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[N:8][C:7]=2[C:2]=1[CH3:1]
Reactant: Cc1c(NC(=O)C(F)(F)F)ccc2ocnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(N)ccc2ocnc12
Temperature: 90 °C
Yield: 109.9 %

Procedure:
A solution of 4-methyl-5-trifluoroacetamidobenzoxazole (3.45 g, 14.13 mmol) in a 20% mixture of water in methanol (20 mL) is treated with anhydrous potassium carbonate (7.80 g, 56.52 mmol). A reflux condenser is attached and the mixture is heated to 90° C. with an oil bath for five hours. The mixture is cooled to room temperature and distributed between ethyl acetate (100 mL) and water (100 mL). The ethyl acetate layer is dried over magnesium sulfate and concentrated under reduced pressure to yield a black residue. This material is purified by chromatography (silica gel, 50% ethyl acetate/hexanes) to afford 2.30 g of 5-amino-4-methylbenzoxazole as an off-white solid.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[C:3]=1[O:15][CH2:16][O:17][CH3:18].[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C(OCC)C.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:14][O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3]([O:15][CH2:16][O:17][CH3:18])=[C:2]([C:21]1[CH:22]=[CH:23][S:19][CH:20]=1)[C:11]([CH3:12])=[CH:10]2
Reactant: COCOc1c(Br)c(C)cc2cc(OC)ccc12
Reactant: OB(O)c1ccsc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: COCOc1c(-c2ccsc2)c(C)cc2cc(OC)ccc12
Temperature: 160 °C

Procedure:
2-bromo-6-methoxy-1-(methoxymethoxy)-3-methylnaphthalene (14) (0.35 g, 1.12 mmol), thiophene 3-boronic acid (0.359 g, 2.81 mmol), tetrakis(triphenylphosphino)palladium (0) (0.031 g, 0.027 mmol), 2 M sodium carbonate (4 mL) and ethylene glycol dimethyl ether (4 mL) were added in a sealed tube and heated at 160° C. for 20 min. Reaction mixture was cooled to room temperature then diluted with diethyl ether. The mixture was washed with water followed by brine, dried over Na2SO4, filtered and concentrated. The crude material purified with a gradient of 1% EtOAc to 4% EtOAc in hexanes over 45 min to afford the title compound (199) as oil, 0.347 g, (98%). 1H NMR (400 MHz, d-CDCl3): δ 2.29 (s, 3H), 3.23 (s, 3H), 3.93 (s, 3H), 4.76 (s, 2H), 7.06-7.07 (m, 1H), 7.10-7.15 (m, 2H), 7.25-7.26 (m, 1H), 7.40-7.42 (m, 2H), 8.04 (d, J=9.2 Hz, 1H).
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:47])[C@@H:8]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]4[CH:34]=[C:33]([C:35](=[O:45])[NH:36][O:37]C(OCC(C)C)C)[S:32][C:31]=4[CH:46]=3)=[CH:20][CH:19]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([O:6][C:7](=[O:47])[C@@H:8]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]4[CH:34]=[C:33]([C:35](=[O:45])[NH:36][OH:37])[S:32][C:31]=4[CH:46]=3)=[CH:20][CH:19]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)COC(C)ONC(=O)c1cc2ccc(CNCc3ccc(CN[C@@H](Cc4ccccc4)C(=O)OC4CCCC4)cc3)cc2s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: O=C(NO)c1cc2ccc(CNCc3ccc(CN[C@@H](Cc4ccccc4)C(=O)OC4CCCC4)cc3)cc2s1
Reaction time: 1 h
Yield: 59 %

Procedure:
(S)-2-[4-({[2-(1-Isobutoxy-ethoxycarbamoyl)-benzo[b]thiophen-6-ylmethyl]-amino}-methyl)-benzylamino]-3-phenyl-propionic acid cyclopentyl ester was dissolved in DCM (2 mL) and MeOH (2 mL) and treated with TFA (1 mL). The mixture was stirred for 1 h at r.t then concentrated to dryness and DCM (5 mL) and heptane (5 mL) added. The mixture was evaporated to dryness. This process was repeated three times to yield compound (104) (20 mg, 59%) as a oil. LCMS purity 95%, m/z 558 [M++H]+, 1H NMR (300 MHz, MeOD), δ: 1.25-1.91 (8H, m, 4×CH2), 3.12-3.47 (2H, m, CH2), 4.26 (1H, m, CH), 4.33 (2H, d, J=5.5 Hz, CH2), 4.36 (2H, s, CH2), 4.43 (1H, s, CH2), 5.16 (1H, s, CH), 5.13 (1H, m, CH), 7.25-7.37 (6H, m, ArH), 7.54-7.63 (4H, m, ArH), 7.94 (2H, m, ArH), 8.09 (1H, s, ArH).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([CH:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[OH:10])=[N:8][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.O[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1.[OH-].[K+].[OH-].[Na+]>C1COCC1.N1C=CC=CC=1>[F:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([CH:9]([O:10][C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:20])([F:19])[F:21])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: Oc1cccnc1
Reactant: OC(c1ccc(OC(F)(F)F)cc1)c1nc2cc(F)ccc2[nH]1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Fc1ccc2[nH]c(C(Oc3cccnc3)c3ccc(OC(F)(F)F)cc3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.2 %

Procedure:
The compound of Example 1 (150 mg) was dissolved in THF (5 mL), and thionyl chloride (60 mg) and pyridine (146 mg) were added thereto. The mixture was stirred for 30 minutes at room temperature, and then 3-hydroxypyridine (87 mg) and potassium hydroxide (65 mg) were added thereto. The mixture was heated to reflux for 30 minutes while being stirred. A 10% aqueous solution of sodium hydroxide was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (60% to 100% ethyl acetate/hexane), and thus the title compound (19 mg) was obtained as a yellow amorphous material.
Reaction SMILES: [C:1]([S:5]([NH:7][C:8]1([CH:12]([CH2:16][CH3:17])[C:13]([OH:15])=[O:14])[CH2:11][O:10][CH2:9]1)=[O:6])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1)=[O:21]>>[C:1]([S:5]([NH:7][C:8]1([CH:12]([CH2:16][CH3:17])[C:13]([O:15][CH2:19][C:20](=[O:21])[C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:24][CH:23]=2)=[O:14])[CH2:9][O:10][CH2:11]1)=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Reactant: CCC(C(=O)O)C1(NS(=O)C(C)(C)C)COC1
Product: CCC(C(=O)OCC(=O)c1ccc(OC(F)(F)F)cc1)C1(NS(=O)C(C)(C)C)COC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
Prepared by Method E using 2-{3-[(tert-butylsulfinyl)amino]oxetan-3-yl}butanoic acid (Preparation 27, 2.658 g, 10.1 mmol) and 2-bromo-1-[4-(trifluoromethoxy)phenyl]-ethanone (3.14 g, 11.1 mmol). The reaction was stirred at room temperature for 3 hours. The residue was purified by silica gel column chromatography to afford the title compound (3.435 g, 73% yield).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=5)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C>CO.Cl>[Cl:38][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][NH:30][C:26]1[N:25]=[C:24]([C:23]2[C:18]3[C:19](=[N:20][C:15]([NH:14][CH:11]4[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]4)=[N:16][CH:17]=3)[NH:21][N:22]=2)[CH:29]=[CH:28][N:27]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4ccnc(NCc5cccc(Cl)c5)n4)n[nH]c3n2)CC1
Agent: Cl
Solvent: CO
Product: NC1CCC(Nc2ncc3c(-c4ccnc(NCc5cccc(Cl)c5)n4)n[nH]c3n2)CC1

Procedure:
To a solution of (4-{3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester (30 mg, 0.0548 mmol) in methanol (30 mL) was bubbled in HCl (gas) for 3 hours at room temperature. The mixture was concentrated by evaporation to afford N-{3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-cyclohexane-1,4-diamine; hydrochloride. (Yield 29 mg, 98.0%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[C:6]=2[C:5]([Cl:14])=[CH:4][C:3]=1[Cl:15].Cl[C:17](OC(Cl)(Cl)Cl)=[O:18]>C1(C)C=CC=CC=1>[Cl:14][C:5]1[C:6]2[C:7](=[O:13])[C:8]([CH3:12])([CH3:11])[O:9][C:10]=2[C:2]([N:1]=[C:17]=[O:18])=[C:3]([Cl:15])[CH:4]=1
Reactant: CC1(C)Oc2c(N)c(Cl)cc(Cl)c2C1=O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1(C)Oc2c(N=C=O)c(Cl)cc(Cl)c2C1=O

Procedure:
To a solution of 4.00 g (0.0163 mole) of 7-amino-4,6-dichloro-2,3-dihydro-2,2-dimethylbenzofuran-3-one in 80 mL of toluene at ambient temperature was added 3.22 g (0.0163 mole) of trichloromethyl chloroformate. This mixture was stirred for fifteen minutes before being heated at reflux for three hours. The solvent was evaporated under reduced pressure, leaving 4,6-dichloro-2,3-dihydro-2,2-dimethylbenzofuran-3-on-7-yl isocyanate as a pale yellow oil. Upon standing, this oil solidified. The IR spectrum was consistent with an isocyanate. Step E Synthesis of 3-(4,6-dichloro-2,3-dihydro-2,2-dimethylbenzofuran-3-on-7-yl)-6-trifluoromethyluracil
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].N1C=CC=CC=1.Cl.[CH3:18][O:19][NH:20][CH3:21].O>S(Cl)(Cl)=O.ClCCl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([N:20]([O:19][CH3:18])[CH3:21])=[O:8]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CNOC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CON(C)C(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.2 %

Procedure:
Heat a solution of 5-bromo-nicotinic acid (50 g, 248 mmol) in thionyl chloride (200 mL) to reflux. After 4 hours, cool to ambient temperature and concentrate under reduced pressure to give a residue. Dissolve residue in dichloromethane (1.0 L). Add pyridine (58.7 g, 743 mmol) followed by O,N-dimethyl-hydroxylamine hydrochloride (26.6 g, 272 mmol) and stir. After 18 hours, add water (1.0 L) and extract with dichloromethane. Combine the organic layers, dry with sodium sulfate, filter and concentrate under reduced pressure to yield the title product as a clear oil (59.1 g, 97%): 1H NMR (DMSO-d6) δ 3.29 (bs, 3H), 3.57 (bs, 3H), 8.24 (dd, 1H), 8.75 (d, 1H), 8.83 (d, 1H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([OH:15])[CH:9]=1>>[C:1]([NH:14][C:13]1[CH:12]=[CH:11][C:10]([OH:15])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(O)cc1

Procedure:
A process as set forth in claim 22 wherein acetic anhydride is reacted with the p-aminophenol contained in said purified raffinate to produce N-acetyl-p-aminophenol, and N-acetyl-p-aminophenol is recovered from the acetylation reaction mixture.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6](=[O:34])[C:5]([CH:35]=O)=[CH:4]1)[CH3:2].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CC(O)=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:6](=[O:34])[C:5]([CH2:35][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:4]1)[CH3:2]
Reactant: C1CCNC1
Reactant: CCn1cc(C=O)c(=O)c2cc(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCn1cc(CN2CCCC2)c(=O)c2cc(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.8 %

Procedure:
To a solution of 1-ethyl-6-fluoro-7,8-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carbaldehyde (15 g, 30.5 mmol) in 1,2-Dichloroethane (DCE) (100 mL) was added pyrrolidine (3.78 mL, 45.8 mmol), sodium triacetoxyborohydride (12.94 g, 61.0 mmol) and AcOH (0.087 mL, 1.526 mmol). The reaction mixture was stirred at 25° C. for 3 h. LCMS showed completion of the reaction. The mixture was extracted with DCM and washed with brine. The organic solution was dried over sodium sulfate and evaporated in vacuo. The crude material was purified by normal phase automatic silica column chromatography (Combiflash RF), using a 40 g golden column and eluting with MeOH/DCM (0-20%). The product was further purified with reverse phase automatic silica column chromatography (Combiflash RF), using a 150 g golden column and eluting with acetonitrile/water (0-60%) to afford 1-ethyl-6-fluoro-7,8-bis((4-methoxybenzyl)oxy)-3-(pyrrolidin-1-ylmethyl)quinolin-4(1H)-one (9.8 g, 17.93 mmol, 58.7% yield) as a yellow solid. LCMS: (M+H)+: 547.4.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)O)[CH:5]=[CH:6][CH:7]=1.[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[CH:5]=[CH:6][CH:7]=1
Reactant: c1nc[nH]n1
Reactant: Oc1cccc(C(O)c2cccc(O)c2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Oc1cccc(C(c2cccc(O)c2)n2cncn2)c1
Yield: 88.4 %

Procedure:
Bis-(3-hydroxyphenyl)methanol (0.75 g, 3.47 mmol), 1,2,4-triazole (0.48 g, 6.94 mmol), p-TSA (125 mg) and toluene (300 mL) were dissolved/suspended in toluene and heated at reflux with a Dean-Stark separator for 24 h. The reaction mixture was allowed to cool, and the solvent was removed in vacuo. The resulting residue was dissolved in EtOAc (75 mL) and the organic layer was washed with H2O (3×75 mL), dried (MgSO4) and the solvent was removed in vacuo to give a brown solid. The crude product was purified by flash column chromatography (EtOAc:Hexane 3:1) to give the title compound (0.82 g, 88%) as a pale yellow oil which formed a foam after a prolonged period under high vacuum; δH (270 MHz, d6-DMSO) 9.50 (2H, br s, ArOH), 8.55 (1H, s, NCHN), 8.06 (1H, s, NCHN), 7.16 (2H, t, J=7.9, ArH), 6.89 (1H, s, CH), 6.75-6.68 (2H, m, ArH), 6.67-6.60 (4H, m, ArH); δC (100 MHz, d6-DMSO) 158.0 (2×C), 152.3 (CH), 144.9 (CH), 141.0 (2×C), 130.2 (2×CH), 119.3 (2×CH), 115.6 (2×CH), 115.6 (2×CH), 66.2 (CH); LRMS (FAB+) 268.3 ([M+H]+, 100%), 199.2 (85); HRMS (FAB+) Found 268.1091, C15H14N3O2 requires 268.1086; HPLC (CH3CN/H2O, 90:10) tR=1.79 min (purity: 99+%).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][N:5]=[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([O:9]CC)=[O:8].Cl>CO>[CH3:3][O:4][N:5]=[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(=NOC)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CON=C(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An aqueous solution of 0.90 g (22.6 mmol) of sodium hydroxide was added to a solution in methanol of 0.47 g (2.3 mmol) of ethyl α-methoxyiminophenylacetate (the less polar isomer prepared above). The resulting mixture was stirred overnight at room temperature. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated to give the title compound as a crude product, which was used in the subsequent reaction without further purification.