Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][OH:23].N1C=CC=CC=1>ClCCl>[C:2](=[O:3])([O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH3:13])[O:4][CH:5]([Cl:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COCCOCCOCCO
Reactant: O=C(Cl)OC(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCOCCOCCOC(=O)OC(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
α-Chlorobenzyl chloroformate (1 g) was added to an ice-cold solution of triethyleneglycol monomethylether (0.7 ml) in dichloromethane (5 ml) followed by pyridine (0.43 ml) at such a rate that the temperature was kept below 10° C. After stirring overnight at room temperature the reaction mixture was washed twice with 0.5 M HCl followed by water and aqueous sodium bicarbonate. Drying over magnesium sulfate, filtration, evaporation in vacuo followed by chromatography on silica gel with hexane/ethyl acetate (1:1) as eluent gave the title compound as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:22]=1)=[CH:5]2.[C:31](O)(=[O:34])[CH2:32][OH:33].C(N(CC)CC)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][N:28]([C:32](=[O:33])[CH2:31][OH:34])[CH2:27][CH2:26]3)[N:22]=1)=[CH:5]2
Reactant: Clc1cc(NC2CCOCC2)c2[nH]c(C3=N[C@H](CCN4CCNCC4)CS3)cc2c1
Reactant: O=C(O)CO
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CO)N1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)=N2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.8 %

Procedure:
The compound (23 mg, 0.05 mmol) prepared in Example 117 was dissolved in N,N-dimethylformamide (5 ml). Glycolic acid (15.1 mg, 0.2 mmol), triethylamine (28 ul, 0.2 mmol), EDC (45 mg, 0.23 mmol) and HOBT (40 mg, 0.29 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, 1N hydrochloric acid solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (5 mg, Yield 19%).
Reaction SMILES: [C:1]([N:4]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](Cl)=[O:13])[C:7]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:6]1=2)(=[O:3])[CH3:2].O.[NH2:36][NH2:37].CCOC(C)=O>CO>[F:33][C:31]([F:32])([F:34])[C:23]1[CH:22]=[C:21]([CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:24]=1)[CH2:20][N:4]([CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([NH:36][NH2:37])=[O:13])[C:7]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:6]1=2)[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)Cl)c2cc(Cl)ccc21
Reactant: NN
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)NN)c2cc(Cl)ccc21
Temperature: 70 °C

Procedure:
A mixture of 5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-8-chloro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carbonyl chloride (1.0 mmol, 0.52 g) and hydrazine hydrate (50.0 mmol, 1.56 mL) in MeOH (5 mL) was refluxed at 70° C. for 12 h with vigorous stirring. The solvent was removed in vacuo and the crude product was purified by crystallization using EtOAc. The product was obtained as white solid; Rf 0.2 (EtOAc); MS (ES+): 523 (M+H+).
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Br:5][C:6]1[CH:11]=[CH:10][N+:9](O)=[C:8](C)[C:7]=1C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[CH:8][N:9]=[C:2]([CH2:1][OH:4])[C:11]=1[CH3:10]
Reactant: CC(=O)[O-]
Reactant: Cc1c(Br)cc[n+](O)c1C
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1c(Br)ccnc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
To a stirred solution of 4-bromo-1-hydroxy-2,3-dimethyl-pyridin-1-ium acetate (which may be prepared as described in Description 5) (18120 mg, 69.13 mmol) in DCM (100 mL) was added trifluoroacetic anhydride (23.89 mL, 171.9 mmol) dropwise and the reaction was stirred at room temperature for 8 hours, then additional trifluoroacetic anhydride (23.89 mL, 171.9 mmol) was introduced. After 1 day, the reaction mixture was concentrated in vacuo to remove excess TFAA & DCM. The residue was then diluted with MeOH (200 mL) and a solution of saturated aqueous K2CO3 (approximately 100 mL) was added with caution [exotherms]. The resultant suspension was stirred for 3 hours and then concentrated in vacuo. The residue was then partitioned between DCM (200 mL) and water (200 mL). The organics were separated and dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in DCM (100 mL) and trifluoroacetic anhydride (23.89 mL, 171.9 mmol) was added dropwise and the reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, and the residue, diluted with MeOH (200 mL) and a solution of saturated aqueous K2CO3 (approximately 100 mL) was added with caution, and the resulting suspension was stirred for 3 hours. The reaction mixture was then concentrated in vacuo, and the residue was partitioned between DCM (200 mL) and water (200 mL). The organics were separated and dried over MgSO4, filtered and concentrated in vacuo. The residue was purified over silica (100 g SNAP), using the Isolera instrument, eluting with EtOAc: isohexane 0%-50%. Fractions containing desired product were combined and concentrated in vacuo to give (4-bromo-3-methyl-2-pyridyl)methanol (D6) (7055 mg, 34.917 mmol, 50.5% yield) as a yellow solid;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(O[C:36](N(C)C)=[N+:37](C)[CH3:38])=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C([N:57]([CH:60]([CH3:62])[CH3:61])[CH2:58][CH3:59])(C)C.FC(F)(F)C(O)=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:57]([CH2:58][CH3:59])[CH:60]1[CH2:61][CH2:38][NH:37][CH2:36][CH2:62]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CCN(C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl)C1CCNCC1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (1-tert.-butxyloxycarbonyl-piperidin-4-yl)-ethyl-amine in DMSO at ambient temperature and subsequent treatment with trifluoroacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[O:5][C:6]1[N:7]([CH:15]([CH3:17])[CH3:16])[C:8](=[O:14])[N:9]([CH3:13])[C:10]=1[CH2:11][OH:12].[H-].[Na+].[H][H].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH2:26]([O:12][CH2:11][C:10]1[N:9]([CH3:13])[C:8](=[O:14])[N:7]([CH:15]([CH3:17])[CH3:16])[C:6]=1[O:5][C:4]1[CH:18]=[C:19]([Cl:21])[CH:20]=[C:2]([Cl:1])[CH:3]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)n1c(Oc2cc(Cl)cc(Cl)c2)c(CO)n(C)c1=O
Reactant: BrCc1ccccc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c(Oc2cc(Cl)cc(Cl)c2)c(COCc2ccccc2)n(C)c1=O
Reaction time: 1 h

Procedure:
To 115 mg of 4-(3,5-dichlorophenoxy)-5-hydroxymethyl-3-isopropyl-1-methyl-1,3-dihydro-2-imidazolone in 5 ml of dimethylformamide was added 15 mg of sodium hydride (60% dispersion in oil). The reaction mixture was stirred at rt for 30 min until hydrogen gas evolution had ceased. The solution was then treated with 45 μL of benzyl bromide and stirring continued for 1 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, dried and evaporated to dryness to give 190 mg of an oily residue. This residue was purified by flash chromatography on silica gel using ethyl acetate/hexane (1:1) for the elution to give 41 mg of a colourless oil. Mass spectrum (ESI) m/z 421 [M+H]+.
Reaction SMILES: O[Li].O.[C:4]([C:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[N:10]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[C:23]([NH:28][CH3:29])[CH:22]=[CH:21]3)[N:9]=1)([CH3:7])([CH3:6])[CH3:5]>O.C1COCC1.CCO.Cl>[C:4]([C:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[C:23]([NH:28][CH3:29])[CH:22]=[CH:21]3)[N:9]=1)([CH3:7])([CH3:5])[CH3:6]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc2nc(NC)ccc2c1
Agent: Cl
Agent: [Li]O
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CNc1ccc2cc(-n3nc(C(C)(C)C)cc3C(=O)O)ccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
LiOH.H2O (0.143 g, 3.40 mmol) was added to a solution of ethyl 3-tert-butyl-1-(2-(methylamino)quinolin-6-yl)-1H-pyrazole-5-carboxylate (0.240 g, 0.68 mmol) in a mixture of water/THF/EtOH (1:1:1, 9 mL). The reaction mixture was stirred overnight at RT, diluted with 3 M HCl and extracted with EtOAc and THF. The combined organics were washed with brine, dried (MgSO4) and concentrated under vacuum to obtain 3-tert-butyl-1-(2-(methylamino)quinolin-6-yl)-1H-pyrazole-5-carboxylic acid (0.22 g, 100% yield). 1H-NMR (DMSO-d6) δ 7.90 (d, J=9.2 Hz, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.46 (dd, J=9.2, 2.8 Hz, 1H), 7.14 (m, 1H), 6.88 (brs, 1H), 6.79 (d, J=9.2 Hz, 1H), 2.92 (d, J=4.8 Hz, 3H), 1.31 (s, 9H); MS (ESI) m/z: 325.2 (M+H+).
Reaction SMILES: [I:1][C:2]1[C:3]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[O:15])[CH:11]=3)[C:4]=2[NH:5][N:6]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32](Cl)[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[CH:28][CH:27]=1.CCN(CC)CC>CN(C=O)C.[Cl-].[Na+].O>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([CH:32]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[N:5]2[C:4]3[C:7]4[C:12]([CH2:13][C:3]=3[C:2]([I:1])=[N:6]2)=[CH:11][C:10]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:15])=[CH:9][CH:8]=4)=[CH:38][CH:37]=1
Reactant: O=C(NCc1ccccn1)c1ccc2c(c1)Cc1c(I)n[nH]c1-2
Reactant: COc1ccc(C(Cl)c2ccc(OC)cc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(c2ccc(OC)cc2)n2nc(I)c3c2-c2ccc(C(=O)NCc4ccccn4)cc2C3)cc1

Procedure:
A mixture of Example 124A (0.176 g, 0.423 mmol), bis-(4-methoxy-phenyl)-methyl chloride (0.122 g, 0.465 mmol), and Et3N (71 μL, 0.507 mmol) in DMF (2.0 mL) was stirred at room temperature for 4 hours. The reaction mixture was diluted with 50% brine and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, concentrated, and purified by flash chromatography eluted with EtOAc to give 0.166 g (61%) of the desired as pale yellow solid. MS (ESI) m/z: 643.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[NH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([NH:24][C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:20][N:19]=2)=[O:23])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: NN1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)nc1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NN2CCOCC2)nc1
Yield: 49 %

Procedure:
As described for example 4c, 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using N-aminomorpholine instead of N,N-dimethylhydrazine, to the title compound (62 mg, 49%) which was obtained as a light yellow oil. MS: m/e=395.3 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]([O:13][CH3:14])=[O:12].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[N:23]1[CH:32]=[C:26]2[C:27]([NH2:31])=[N:28][CH:29]=[CH:30][C:25]2=[N:24]1>C(Cl)Cl>[CH3:14][O:13][C:11](=[O:12])[NH:31][C:27]1[C:26]2=[CH:32][N:23]([C:17]3[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=3[Cl:15])[N:24]=[C:25]2[CH:30]=[CH:29][N:28]=1
Reactant: COC(=O)Cl
Reactant: Nc1nccc2nn(-c3c(Cl)cccc3Cl)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Nc1nccc2nn(-c3c(Cl)cccc3Cl)cc12
Temperature: 25 °C
Yield: 49.4 %

Procedure:
DIPEA (51 μL, 0.3 mmol) and then methyl chloroformate (19 μL, 0.25 mmol) were added to a solution of 2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-4-ylamine (60 mg, 0.21 mmol) in DCM (2 mL). The reaction was stirred at room temperature until completion as determined by TLC. The mixture was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (40-50% ethyl acetate in cyclohexane) to afford the title compound as a white solid (35 mg, 49% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.54 (d, J=0.9 Hz, 1H), 7.97 (d, J=7.3 Hz, 1H), 7.86 (d, J=1.4 Hz, 1H), 7.84 (d, J=0.6 Hz, 1H), 7.80-7.78 (m, 1H), 7.72 (dd, J=7.3, 0.9 Hz, 1H), 3.97 (s, 3H). LCMS (Method B): RT=2.71 min, m/z: 337 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.O=[C:19]([CH2:26][CH2:27][CH3:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH2:26][CH2:27][CH3:28])[NH:12][C:13]2=[N:14][NH:15][CH:16]=[C:17]12)[CH3:2]
Reactant: Nc1cc[nH]n1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: CCOc1ccccc1C=O
Product: CCCC1=C(C(=O)OCC)C(c2ccccc2OCC)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2-ethoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[H-].[Na+].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH2:24][C:25]([O:29][CH3:30])([O:27][CH3:28])[CH3:26])[C:16]=1[F:31]>CN(C=O)C>[CH3:30][O:29][C:25]([O:27][CH3:28])([CH3:26])[CH2:24][C:17]1[C:16]([F:31])=[C:15]([N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])[CH:20]=[CH:19][C:18]=1[N+:21]([O-:23])=[O:22]
Reactant: COC(C)(Cc1c([N+](=O)[O-])ccc(F)c1F)OC
Reactant: O=C1NC(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)(Cc1c([N+](=O)[O-])ccc(N2C(=O)c3ccccc3C2=O)c1F)OC
Temperature: 100 °C
Yield: 62.7 %

Procedure:
To a solution of phthalimide (4.4 g; 30 mmol) in anhydrous DMF (40 ml) cooled to 0° C. was added sodium hydride (1.29 g, 32 mmol, 60% in oil). The mixture was stirred at this temperature for 30 minutes before the addition of 1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene (6 g, 23 mmol), (prepared as described for the starting material in Example 11). The reaction mixture was heated at 100° C. for 3 hours under argon. Upon cooling to ambient temperature, the reaction mixture was poured over ice/water (200 ml) and the formed precipitate was collected by filtration and washed with water and ether. The solid was purified by flash chromatography using methylene chloride/methanol (99/1). Evaporation of the solvent gave 2-(2,2-dimethoxypropyl)-3-fluoro-4-phthalimidonitrobenzene (5.6 g, 63%) as a yellow solid.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[O-])([O-:3])=[O:2].[Na+].C(OC(=O)C)(=O)C.C(N(CC)CC)C>O1CCCC1>[N+:1](/[CH:4]=[CH:5]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])CC([O-])c1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])/C=C/c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 139.5 %

Procedure:
A solution of sodium 2-nitro-1-(4-phenoxy-phenyl)-ethanolate (1.17 g, 4.16 mmol) described in Manufacturing Example 17-1-1, acetic anhydride (510 mg, 4.99 mmol) and triethylamine (696 μL, 4.99 mmol) in anhydrous tetrahydrofuran (20 mL) was stirred overnight under nitrogen atmosphere at room temperature. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure to obtain the title compound (1.4 g, 70%, purity: ca. 50%) as a crude product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21](=[O:24])[NH:22][N:23]=3)[CH:15]=2)[CH2:10]1.Br.[C:26](Cl)(=[O:30])[CH2:27][CH2:28][CH3:29]>O.C(OCC)(=O)C.O1CCCC1>[C:26]([NH:7][CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21](=[O:24])[NH:22][N:23]=3)[CH:15]=2)[CH2:10]1)(=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: NCC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Reactant: CCCC(=O)Cl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCC(=O)NCC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Reaction time: 3 h
Yield: 81.3 %

Procedure:
An aqueous solution (100 ml) containing 3.30 g of potassium carbonate dissolved in water was added to 100 ml of a suspension containing 3.50 g of 2-aminomethyl-5-[pyridazin-3(2H)-on-6-yl]indane·hydrobromide suspended in ethyl acetate. Then, under ice cooling, 2.30 g of butyryl chloride dissolved in 30 ml of tetrahydrofuran was added to the mixture, and the resulting mixture was stirred for 3 hours. Crystals precipitated were collected by filtration, washed with water, dried and then recrystallized from methanol to obtain 2.75 g of 2-(butyrylamino)methyl-5-[pyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [CH2:1]([N:7]1[C:15]2[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=2[N:9]=[CH:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:19][O:20][C:21]1[CH:34]=[CH:33][C:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)=[CH:23][CH:22]=1>>[CH2:1]([N:7]1[C:15]2[C:14](=[O:16])[N:13]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:24]3[CH:33]=[CH:34][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[C:12](=[O:17])[N:11]([CH3:18])[C:10]=2[N:9]=[CH:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: COc1ccc(OCCCCCCBr)cc1
Product: CCCCCCn1cnc2c1c(=O)n(CCCCCCOc1ccc(OC)cc1)c(=O)n2C
Yield: 71 %

Procedure:
7-Hexyl-3-Methylxanthine and 6-(4-methoxyphenoxy)hexyl bromide were reacted and treated in substantially the same manner as described in Example 9 (a) to give 7-hexyl-1-[6-(4-methoxyphenoxy)hexyl]-3-methylxanthine (71%) as an oil.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].ClCC#N.[13CH4]>C(OC(=O)C)C>[C:1](#[N:5])[CH3:2].[CH2:1]([NH+:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCOCC1
Agent: N#CCCl
Agent: [13CH4]
Solvent: CCOC(C)=O
Product: CC#N
Product: CCCC[NH+]1CCOCC1
Temperature: 60 °C

Procedure:
Combined were 10 g of butylbromide, 6.36 g morpholine, and 28.0 g anhydrous sodium carbonate with 150 ml of acetone in a large round bottom flask. This mixture was refluxed for 8 hours at the boiling point of acetone or approximately 60° C., then cooled to room temperature and the solid sodium carbonate filtered. Acetone was removed using a roto-evaporator. The resulting oil was dissolved in ether and washed twice with water and once with brine solution. The ether solution was dried over anhydrous sodium sulfate. After filtering, ether was removed in-vacuo leaving 5.15 g of product estimated at 49.3% yield. Gas chromatography showed the product to be N-butyl morpholine in approximately 95% purity. Combined 7.2 g of N-butyl morpholine together with 3.0 ml of chloroacetonitrile in a small vial. After capping the vial was heated to 60° C. for approximately 24 hours. An oil resulted which solidified upon addition of a small amount of ethylacetate. The solid was filtered and washed with excess ethylacetate, then dried in a vacuum dessicator resulting in a white solid in nearly stoichiometric yield. Carbon-13 NMR analysis revealed the desired product present with no other detectable impurities noted.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][N:8]=[C:7](Cl)[C:6]=1[Cl:12])[CH3:2].[C:14]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1.O>O1CCOCC1.C1C=CC([P]([Pd]([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)=CC=1>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:14])[C:6]=1[Cl:12])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccnc(Cl)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccnc(C)c1Cl

Procedure:
A mixture of 2,3-dichloroisonicotinic acid ethyl ester (3.15 mmol), K2CO3 (4.73 mmol) and trimethylboroxine (3.15 mmol) in 4 mL dioxane was degassed with Ar. Then, tetrakis(triphenylphosphine)palladium (0.31 mmol) was added and the mixture was heated to reflux overnight. At RT, the reaction mixture was poured into water and extracted with DCM. The combined organic layers were dried over K2CO3, filtered over a pad of celite and concentrated in vacuo. Purification by CC (KP-SIL™ from Biotage) using Hept/EtOAc (8/2) gives the desired product as brown oil;
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:10](=[O:18])OC3C=CC=CC=3)[N:6]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:5]=2)[CH2:3][CH2:2]1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][N:31]=[C:30]2[S:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43].O>CS(C)=O>[CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:10]([NH:43][C:42]3[CH:44]=[CH:45][CH:46]=[C:40]([S:39][C:30]4[C:29]5[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=5)[N:33]=[CH:32][N:31]=4)[CH:41]=3)=[O:18])[N:6]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: O=C(Nc1cc(C2CC2)nn1-c1ccccc1)Oc1ccccc1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C5CC5)nn4-c4ccccc4)c3)c2cc1OC
Temperature: 40 °C
Yield: 47 %

Procedure:
A stirred mixture of phenyl 3-cyclopropyl-1-phenyl-1H-pyrazol-5-ylcarbamate as described in Example 353A (250 mg, 0.78 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as described in Example 115B) (200 mg, 0.64 mmol) in DMSO (1 mL) was heated to 40° C. for 48 h. After cooling to rt, water (20 mL) was added. The resulting suspension was filtered and the collected solid purified via preparative silica gel thin-layer chromatography (eluting with a mixture of 10:10:1 ethyl acetate: dichloromethane: methanol) to give a solid which was triturated with diethyl ether (50 mL) to afford 1-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (162 mg, 47%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ9.21 (s, 1H), 8.68 (s, 1H), 8.49 (s, 1H), 7.77 (s, 1H), 7.22-7.51 (m, 10H), 6.15 (s, 1H), 3.99 (s, 6H), 1.86 (m, 1H), 0.85-0.91 (m, 2H), 0.65-0.68 (m, 2H); LC-MS (ESI) m/z 539 (M+H)+.