Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[C:26]([O:30][C:31](=[O:51])[N:32]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]=[O:49])=[C:44]([F:50])[N:43]=1)[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)([CH3:29])([CH3:28])[CH3:27]>O1CCCC1>[C:26]([O:30][C:31](=[O:51])[N:32]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]([OH:49])[C:2]2[C:10]3[CH:9]=[N:8][CH:7]=[N:6][C:5]=3[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=2)=[C:44]([F:50])[N:43]=1)[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cncnc21
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C=O)c(F)n2)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncncc34)c(F)n2)cc1
Temperature: 0 °C
Yield: 85.3 %

Procedure:
To 5-iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine (38, 30 g, 74.7 mmol) in 300 mL of tetrahydrofuran under an atmosphere of nitrogen at −20° C., isopropylmagnesium chloride (43.6 mL, 2 M in tetrahydrofuran, 87 mmol) was added and the reaction allowed to warm to 0° C. over 30 minutes. The reaction was cooled to −40° C. and (6-fluoro-5-formyl-pyridin-2-yl)-(4-methoxy-benzyl)-carbamic acid tert-butyl ester (66, 17.96 g, 49.8 mmol) in tetrahydrofuran was added. The reaction was allowed to warm to 0° C. over an hour, then quenched with brine and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 0-40% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (67, 27 g, 42.5 mmol, 85% yield).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(OC(=O)[NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(C)(C)C>>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[N:23]1[CH2:24][CH2:25][CH:20]([NH2:19])[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Fc1ccc2nccc(Br)c2c1
Product: NC1CCN(c2ccnc3ccc(F)cc23)CC1

Procedure:
Starting from 4-bromo-6-fluoroquinoline (commercial) and piperidin-4-yl-carbamic acid tert-butyl ester (commercial) the title compound was prepared according to procedure F followed by procedure E and was isolated as a yellow solid (223 mg, 40% over two steps).
Reaction SMILES: Br[C:2]1[N:3]([CH3:17])[CH:4]=[C:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[N:6]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1>COCCOC.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>[CH3:17][N:3]1[CH:4]=[C:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[N:6]=[C:2]1[C:30]1[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cn1cc(C(=O)OCc2ccccc2)nc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cn1cc(-c2nc(C(=O)OCc3ccccc3)cn2C)cn1
Temperature: 90 °C

Procedure:
Into a flask containing a solution of benzyl 2-bromo-1-methyl-1H-imidazole-4-carboxylate (2 g, 6.77 mmol) in 1,2-dimethoxyethane (40 ml), potassium phosphate (2.3 g, 20.3 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.41 g, 6.77 mmol) were added at RT under argon atmosphere. The resulting mixture was degassed and purged with argon for 10 minutes. Then Pd(PPh3)4 (0.310 g, 0.2 mmol) was added to the reaction mixture and heated at 90° C. for 12 h. The reaction mixture was filtered through a celite bed and the filtrate was diluted with water and extracted with EtOAc. The organic layer was concentrated and purified by flash chromatography. Yield 1.1 g. 1H-NMR (400 MHz; CDCl3): δ 3.77 (s, 3H), 3.95 (s, 3H), 5.36 (s, 2H), 7.30-7.37 (m, 3H), 7.45 (d, 2H), 7.59 (s, 1H), 7.79 (s, 1H), 7.89 (s, 1H).
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[CH3:7][C:8](=[CH2:10])[CH3:9].[Cl-].[Al+3].[Cl-].[Cl-]>O>[Cl:4][C:3]([Cl:6])([Cl:5])[CH:2]([OH:1])[CH2:9][C:8]([CH3:10])=[CH2:7]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: C=C(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: C=C(C)CC(O)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of anhydrous chloral (738 g), isobutylene (309 g), and petroleum ether (boiling range 40° to 60° C, 800 ml) was stirred at a temperature in the range -5° to -8° C whilst aluminium chloride (54.5 g) was added in small portions over a period of 2 hours. The mixture was stirred for a further period of one hour at 0° C. Water (450 ml) was then added over 15 minutes, the temperature being maintained at 0° C, after which the mixture was allowed to attain to the ambient temperature. The organic phase was separated, washed with brine (3 × 250 ml) and dried over anhydrous magnesium sulphate. After removal of the solvent by evaporation under reduced pressure the residual oil was distilled under reduced pressure and the fraction boiling range 101° to 111° C at 16 to 18 mm Hg pressure collected. This was shown by gas liquid chromatographic examination to consist of approximately 90%, 1,1,1-trichloro-2-hydroxy-4-methyl-4-pentene and approximately 10% 1,1,1-trichloro-2-hydroxy-4-methyl-3-pentene. Careful distillation afforded almost pure (by g.l.c.) 1,1,1-trichloro-2-hydroxy-4-methyl-4-pentene as a colourless oil (boiling point 99° -100° C/16 mm Hg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br[CH2:10][CH2:11][OH:12].C([O-])(O)=O.[Na+]>O>[I:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(I)c1
Reactant: OCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: OCCNc1cccc(I)c1
Temperature: 160 °C
Yield: 63.6 %

Procedure:
A mixture of 3-iodoaniline (2.0 g, 9.1 mmol) and 2-bromoethanol (0.32 mL, 4.6 mmol) in a sealed tube was heated at 160° C. for 2 hours. Cooled to room temperature, sat. NaHCO3 and water were added. The resulting mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried, evaporated under reduced pressure. The crude product was purified on a ISCO MPLC to provide the titled compound as a light brown oil (770 mg, 38.6% yield). MS (ESI(+)) m/e 264 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH2:16]OC)=[N:14][CH:13]=[CH:12][N:11]3[C:19]=2[C:20]2[CH:25]=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=2)=[CH:4][CH:3]=1.[NH2:30][CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[N:14][CH:13]=[CH:12][N:11]3[C:19]=2[C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:30][CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])[N:21]=2)=[CH:6][CH:7]=1
Reactant: COCc1nccn2c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3)nc12
Reactant: CC(C)(CN)CO
Solvent: CC#N
Product: Cc1nccn2c(-c3ccnc(NCC(C)(C)CO)n3)c(-c3ccc(F)cc3)nc12
Temperature: 80 °C
Yield: 1.7 %

Procedure:
In a round bottom flask charged with 2-(4-fluorophenyl)-3-(2-methanesulfonylpyrimidin-4-yl)-8-methoxymethylimidazo[1,2-a]pyrazine (˜2-3% impurity within 3.05 g, 7.95 mmol of 2-(4-fluorophenyl)-3-(2-methanesulfonylpyrimidin-4-yl)-8-methylimidazo[1,2-a]pyrazine) was dissolved in ACN (70 mL) to which was added 3-amino-2,2-dimethyl-propan-1-ol (Lancaster, 4.1 g, 96.8 mmol) at ambient temperature followed by heating to about 80° C. for about 3 h. After this time the reaction was cooled to ambient temperature and purified in 200-300 mg batches using RP-HPLC (Table 1, Method i). The pure fractions were combined and concentrated to remove the organic solvent. The resulting precipitate was filtered from the aqueous layer and dried in a vacuum overnight to give the title compound as a white solid (0.054 g, 1.5% yield). LC/MS (Table 1, Method b) Rt=1.77 min; MS m/z: 414.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][CH2:8][C:9]1[N:10]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:11](=[O:33])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([O:25]CC1C=CC=CC=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.C(O)C.[C].[Pd]>[C:1]([O:5][C:6](=[O:38])[NH:7][CH2:8][C:9]1[N:10]([CH2:34][CH:35]([CH3:36])[CH3:37])[C:11](=[O:33])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([OH:25])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(O)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
A suspension of tert-butyl(6-benzyloxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (2.05 g, 4 mmol) and 5% palladium carbon (0.6 g) in tetrahydrofuran (10 mL) and ethanol (10 mL) was stirred under a hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give tert-butyl(6-hydroxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (1.56 g, 92.3%) as crystals.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:10][C:11]1[CH:16]=[C:15]([C:17]([O:19]C(C)(C)C)=[O:18])[CH:14]=[C:13]([O:24][CH2:25][CH3:26])[C:12]=1[C:27]1[CH:32]=[CH:31][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:28]=1)[CH3:9]>C(Cl)(Cl)Cl>[CH2:25]([O:24][C:13]1[CH:14]=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=[C:11]([O:10][CH2:8][CH3:9])[C:12]=1[C:27]1[CH:28]=[CH:29][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:32]=1)[CH3:26]
Reactant: CCOc1cc(C(=O)OC(C)(C)C)cc(OCC)c1-c1ccc(C(=O)OC)cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(C(=O)O)cc(OCC)c1-c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TFA (4 ml) was added to a stirred solution of 4-tert-butyl 4′-methyl 2,6-diethoxybiphenyl-4,4′-dicarboxylate (850 mg, 2.12 mmol) in CHCl3 (2 ml) and the reaction mixture was stirred at room temperature overnight. After the solvents were removed under reduced pressure, CHCl3 and MeOH were added to the residue. The solvents were removed under reduced pressure again, and the residue was dried in vacuo to give the crude intended compound as a colorless solid. Thus obtained crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](O)=[O:22])=[CH:15][CH:14]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:22])=[CH:17][CH:18]=1
Reactant: CC1=C(C)C(=O)C(Cc2ccc(CCC(=O)O)cc2)=C(C)C1=O
Reactant: C1COCCN1
Product: CC1=C(C)C(=O)C(Cc2ccc(CCC(=O)N3CCOCC3)cc2)=C(C)C1=O
Yield: 68.8 %

Procedure:
3-[4-(3,5,6-trimethyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (25 mg, 0.08 mmol) and morpholine (0.010 ml, 0.12 mmol) were used, and a method similar to that described in Production Example 46 was employed to obtain the title compound (21 mg, 0.055 mmol, yield 69%).
Reaction SMILES: C(N(CC)CC)C.[C:8](O)(=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(Cl)(=O)OCC.[NH2:38][C:39]1[CH:40]=[C:41]([CH:47]=[CH:48][C:49]=1[NH:50][CH2:51][CH2:52][N:53]([CH3:55])[CH3:54])[C:42]([N:44]([CH3:46])[CH3:45])=[O:43]>C(Cl)(Cl)Cl>[CH3:54][N:53]([CH3:55])[CH2:52][CH2:51][N:50]1[C:49]2[CH:48]=[CH:47][C:41]([C:42]([N:44]([CH3:46])[CH3:45])=[O:43])=[CH:40][C:39]=2[N:38]=[C:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CN(C)CCNc1ccc(C(=O)N(C)C)cc1N
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCCCc1nc2cc(C(=O)N(C)C)ccc2n1CCN(C)C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
Triethylamine (1.52 ml) was added to a suspension containing n-docosanoic acid (3.339 g) in chloroform (34 ml), and then ethyl chlorocarbonate (1.04 ml) was added thereto while being cooled with ice. The reaction mixture was stirred for 1.5 hours, and then a solution containing 3-amino-4-{[2-(dimethylarnino)ethyl]amino}-N,N-dimethylbenzamide (2.454 g) in chloroform (12 ml) was added thereto. After being stirred for 3 hours while being cooled with ice, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (8.2 ml) was added to a suspension containing the residue (6.094 g) in ethanol (61 ml). After being stirred for 1.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (5.119 g) was purified by silica gel column chromatography (silica gel 100 g, chloroform:methanol=50:1-30:1), thereby yielding the entitled compound (3.320 g) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH:28]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([OH:34])=[O:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][N:30]3[CH2:37][CH2:36][CH2:35][C@H:31]3[C:32]([OH:34])=[O:33])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC=O)cn(C)c34)no2)cc1Cl
Reactant: O=C(O)[C@@H]1CCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCN5CCC[C@H]5C(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 3 h
Yield: 19.3 %

Procedure:
To a stirred solution of [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]acetaldehyde (D88) (50 mg), L-proline (28 mg) and acetic acid (0.1 mL) in DCM (10 mL) stirred at 20° C. was added sodium triacetoxyborohydride (52 mg). The reaction was stirred at 20° C. for 3 h. The mixture was concentrated and the residue was partitioned between ethyl acetate (25 mL) and aqueous HCl (2 M, 25 mL). The organic phase was washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulphate and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford 1-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}-L-proline (E69) (12 mg, TFA salt). δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 1.71 (1H, m), 1.94 (2H, m), 2.16 (1H, m), 2.95 (1H, m), 3.05 (2H, m), 3.25 (2H, m), 3.60 (2H, m), 3.65 (3H, s), 4.88 (1H, m), 7.20 (1H, t), 7.31 (1H, s), 7.45 (2H, m), 7.86 (1H, dd), 8.13 (1H, dd), 8.20 (1H, d). MS (ES): C27H29ClN4O4 requires 508; found 509.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:18]=[C:19]([N+:21]([O-])=O)[CH:20]=2)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:5]=[CH:4][N:3]=1.[H][H]>CO.[Pd]>[NH2:21][C:19]1[CH:18]=[C:10]([CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[CH:20]=1)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: [H][H]
Reactant: Cc1cc(-c2cc(C(=O)OC(C)(C)C)cc([N+](=O)[O-])c2)ccn1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(-c2cc(N)cc(C(=O)OC(C)(C)C)c2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A mixture of tert-butyl 3-(2-methylpyridin-4-yl)-5-nitrobenzoate (1.5 g, 4.8 mmol) and 300 mg of 10% wet Pd/C (˜50% H2O) in 25 mL of methanol under a balloon of hydrogen was allowed to stir at room temperature overnight. Upon completion, the mixture was concentrated and the residue was dried to give 1.31 g of tert-Butyl 3-amino-5-(2-methylpyridin-4-yl)benzoate 49.1B. LCMS (ES+) m/z 285.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11].[OH-].[Na+].I[CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1>CN(C)C=O>[O:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]1[O:19][CH2:18][CH2:17][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc2ccccc2[nH]1
Reactant: ICCOC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccccc2n1CCOC1CCCCO1
Yield: 83 %

Procedure:
The reaction was carried out in a manner similar to Reference Example 5 except for using 2.0 g (11.4 mmol) of methyl 2-indolecarboxylate, 0.55 g (13.7 mmol) of 60% sodium hydroxide, 3.63 g (13.7 mmol) of 2-(2-iodo-ethoxy)tetrahydropyran (prepared from 2-iodoethanol and 3,4-dihydro-2H-pyran) and 50 ml of dimethylformamide. Thus, 2.87 g (83.0%) of methyl 1-[2-(2-tetrahydro-pyranyl)oxyethyl]-2-indolecarboxylate was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:19])[C:5]2[CH:6]=[N:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=3)[C:9]=2[CH:10]=1.[CH2:20](C([Sn])=C(CCCC)CCCC)[CH2:21]CC>C(COC)OC>[CH:20]([C:2]1[CH:3]=[C:4]([OH:19])[C:5]2[CH:6]=[N:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=3)[C:9]=2[CH:10]=1)=[CH2:21]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Oc1ccc(-n2ncc3c(O)cc(Br)cc32)cc1F
Solvent: COCCOC
Product: C=Cc1cc(O)c2cnn(-c3ccc(O)c(F)c3)c2c1
Temperature: 90 °C
Yield: 33.7 %

Procedure:
To a solution of 6-bromo-1-(3-fluoro-4-hydroxyphenyl)-1H-indazol-4-ol (360 mg, 1.11 mmol) (E5) in dimethoxyethane (10 mL) was added dichlorobis(tris-o-tolylphosphine)palladium (44 mg, 0.056 mmol) and tributylvinyltin (0.65 mL, 2.22 mmol). The reaction mixture was heated at 90° C. under argon overnight. After cooling to room temperature, the mixture was filtered through a pad of celite. The filtrate was concentrated and the crude product purified by silica gel chromatography eluting with 5-100% ethyl acetate in hexane. The product was further purified by MDAP to yield the title compound (E6) (101 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[N:9]=[CH:8][NH:7][C:6]2=O.CN(C=O)C.C1(C)C=CC=CC=1.S(Cl)([Cl:36])=O>>[Cl:36][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCn1cncn1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCn1cncn1
Yield: 65 %

Procedure:
A solution of 6-methoxy-7-(2-(1,2,4-triazol-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (1.11 g, 3.86 mmol) and DMF (0.6 ml) in thionyl chloride (15 ml) was heated at reflux for 1 hour. The mixture was allowed to cool, toluene was added and the volatiles were removed by evaporation. The residue was partitioned between methylene chloride and water and the aqueous layer was adjusted to pH8.5 with saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried (MgSO4), and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5). The purified solid was triturated with ether, collected by filtration, washed with water and then ether, and dried under vacuum to give 4-chloro-6-methoxy-7-(2-(1,2,4-triazol-1-yl)ethoxy)quinazoline (756 mg, 65%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([CH:6]=[C:7]([CH3:21])[C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([Cl:20])=[CH:12][CH:11]=1)[NH2:5].[Cl:23][C:24]1[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=1[C:26]([N:28]=[C:29]=[O:30])=[O:27]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([NH:5][C:29]([NH:28][C:26](=[O:27])[C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]=2[Cl:23])=[O:30])[CH:6]=[C:7]([CH3:21])[C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([Cl:20])=[CH:12][CH:11]=1
Reactant: O=C=NC(=O)c1ccccc1Cl
Reactant: Cc1cc(N)c(C)c(Cl)c1Oc1ccc(Cl)c2ccccc12
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)NC(=O)c2ccccc2Cl)c(C)c(Cl)c1Oc1ccc(Cl)c2ccccc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
Into a solution containing 3.0 grams (9.0 mmol) of 3-chloro-4-(4-chloro-1-naphthoxy)-2,5-dimethylaniline prepared in Part B in 25 milliliters of toluene which solution was warmed to a temperature of 50° C. and placed under a nitrogen atmosphere was slowly added a solution containing 2.5 grams (13.8 mmol) of 2-chlorobenzoyl isocyanate in 5 milliliters of toluene. After stirring for 1 hour at a temperature of 50° C., the reaction mixture was cooled to room temperature, placed in an ice bath, and filtered through a Buchner funnel. The collected solid was dried under vacuum at a temperature of 50° C. to afford 3.15 grams of 1-[3-chloro-4-(4-chloro-1-naphthoxy)-2,5-dimethylphenyl]-3-(2-chlorobenzoyl)urea as a white solid having a melting point of 187° C. Elemental analysis of the white solid indicated the following:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[C:12]([NH:19][C:20]2[CH:32]=[CH:31][C:23]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])=[CH:22][CH:21]=2)[N:11]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][NH:16]3)=[C:12]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])=[CH:31][CH:32]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: CCCCOC(=O)c1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Product: CCCCOC(=O)c1ccc(Nc2nc(N[C@H]3CC[C@H](N)CC3)nc3[nH]cnc23)cc1

Procedure:
2850 mg of trans-1,4-diaminocyclohexane are heated to its melting point (70° C.) and 2190 mg of the product obtained in stage 1 above are added. 60 mg of the expected product are thus obtained.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13](Cl)=[O:14])=[CH:10][CH:9]=2)[C:4]=1[CH3:16].Cl.[NH:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([CH2:26][OH:27])[CH2:21]1>>[OH:27][CH2:26][C@@H:22]1[CH2:23][CH2:24][CH2:25][N:20]([C:13]([C:11]2[S:12][C:8]([C:5]3[C:4]([CH3:16])=[C:3]([C:2]([F:18])([F:17])[F:1])[O:7][N:6]=3)=[CH:9][CH:10]=2)=[O:14])[CH2:21]1
Reactant: OC[C@H]1CCCNC1
Reactant: Cc1c(-c2ccc(C(=O)Cl)s2)noc1C(F)(F)F
Agent: Cl
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@@H](CO)C3)s2)noc1C(F)(F)F

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carbonyl chloride (74 mg, 0.25 mmol, as prepared in Example 2 Method B) and (S)-1-piperidin-3-yl-methanol, hydrochloride (76 mg, 0.5 mmol) in the same manner as the S isomer (Example 69). Gummy solid (56 mg, 60%). LC/MS 5.86 min, [M+1]+ 375.