Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH:3]=1.C([O-])(O)=O.[Na+].[ClH:21]>CCOC(C)=O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:21])[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH:3]=1
Reactant: Cl
Reactant: CC(C)OC(=O)c1cc(N)c(F)c(F)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)c1cc(N)c(F)c(Cl)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
Propan-2-yl 4-amino-5,6-difluoropicolinate (4.25 g, 19.7 mmol) was dissolved in HCl (4 M in dioxane; 65 mL) in a 100 mL Hastalloy stirred Parr reactor. The reactor was heated at 100° C. for 2 h. Upon standing at room temperature overnight, a yellow crystalline solid formed. This solid was not soluble in EtOAc but did dissolve upon shaking with satd aq NaHCO3 (500 mL) and EtOAc (300 mL). The aqueous layer was extracted with EtOAc (2×250 mL). The combined organic extracts were washed with H2O (5×50 mL) and then with satd aq NaCl. The extracts were dried (MgSO4) and concentrated under vacuum to provide an off-white solid. The crude product was purified by column chromatography (120 g silica column; 0-100% hexane-EtOAc gradient) to give a white solid (2.11 g, 46%): mp 190.7-192.4° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.543 (d, JF-H=5.7 Hz, 1H), 6.91 (br s, 2H, NH2), 5.09 (septet, J=6 Hz, 1H, CHMe2), 1.29 (d, J=6 Hz, 6H, CHMe2); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.8 (CO2R), 144.8 (d, JF-C=12 Hz, C2/C4), 143.4 (d, JF-C=254 Hz, C5), 142.7 (d, JF-C=4.8 Hz, C2/C4), 136.5 (d, JF-C=17 Hz, C6), 112.8 (d, JF-C=5 Hz, C3), 68.9 (CHMe2), 21.6 (Me); 19F NMR (376 MHz, DMSO-d6) δ −141.0 (d, JF-H=6 Hz). Anal. Calcd for C9H10ClFN2O2: C, 46.47; H, 4.33; N, 13.75. Found: C, 46.50; H, 4.33; N, 11.96.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5].[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1>>[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([C:4]([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH2:14][CH2:15][N:16]4[CH2:20][CH2:19][CH2:18][C@H:17]4[CH3:21])=[CH:11][C:10]=3[CH:22]=2)=[O:5])=[CH:27][CH:26]=1
Reactant: CON(C)C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Reactant: Cc1ccc([Mg]Br)cc1
Product: Cc1ccc(C(=O)c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)cc1

Procedure:
The product from Example 71E and 4-methylphenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.48 (d, 3H), 1.75 (m, 1H), 2.1 (m, 2H), 2.38 (m, 1H), 2.45 (s, 3H), 3.30 (m, 4H), 3.57 (m, 1H), 3.80 (m, 2H), 6.85 (s, 1H), 7.38 (dd, 2H), 7.60 (dd, 1H), 7.70 (dd, 2H), 7.75 (dd, 1H), 8.0 (d, 1H); MS (ESI) m/z 348 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[C:6]([CH2:14][OH:15])[C:5]=1[OH:16])(=[O:3])[CH3:2].[Na].[C:18](OCC)(=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl.[CH2:29](O)[CH3:30]>C(OCC)(=O)C.C(Cl)(Cl)Cl>[CH2:29]([O:15][CH2:14][C:6]1[C:5]2[O:16][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:2][C:1](=[O:3])[C:4]=2[CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11]2)[CH3:30]
Reactant: CC(=O)c1cc2c(c(CO)c1O)CCCC2
Reactant: CCO
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOCc1c2c(cc3c(=O)cc(C(=O)OCC)oc13)CCCC2
Yield: 30 %

Procedure:
A solution of the product of step (b) (15.4 g) in ethanol (50 ml) was added to one of sodium (4.0 g) in ethanol (50 ml). To this mixture was added diethyl oxalate (50 g) and the whole mixture was heated at-reflux for 2 hours, then poured into a mixture of chloroform (500 ml) and concentrated HCl (100 ml). The organic layer was separated, evaporated to dryness and the residue was heated at reflux in ethanol (200 ml) containing concentrated hydrochloric acid (5 ml) for 2 hours. The solution was evaporated to dryness and the residue was taken up in ethyl acetate. This solution (was washed well with water, dried (MgSO4), filtered and the filtrate was evaporated to dryness leaving an oil. This was dissolved in a small amount of ethyl acetate and the solution was allowed to crystallise to give the title ester 6.3 g (30%), mp 115°-6°. It should be noted that under these reaction conditions the hydroxymethyl group of the starting naphthol has been converted into an ethoxymethyl grouping.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:11][CH2:12][CH2:13][C:14]([F:17])(F)F)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:20][S:21]([C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][N:25]=1)(=[O:23])=[O:22].CS([C:37]1C2C(=CN=CC=2)N[N:38]=1)(=O)=O>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C:11]3[CH:37]=[N:38][C:14]([F:17])=[CH:13][CH:12]=3)[C:7]([CH2:9][N:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:24]([S:21]([CH3:20])(=[O:22])=[O:23])=[N:25]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1n[nH]c2ccccc12
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Reactant: FC(F)(F)CCCn1c(CCl)nc2cc(Cl)ccc21
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2-c2ccc(F)nc2)c2ccccc12

Procedure:
Example 3-1 was prepared in analogy to Example 2-1 by using 5-chloro-2-chloromethyl-1-(4,4,4-trifluoro-butyl)-1H-benzoimidazole and 3-methanesulfonyl-1H-indazole instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12]OC.FC1C(C)=C(C2C=CC(C(O)=O)=CC=2COC)C=CC=1.[C:35]([O-:38])(=[O:37])[CH3:36].[Na+]>CC(O)=O>[C:35]([O:38][CH2:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[Br:1])[C:6]([O:8][CH3:9])=[O:7])(=[O:37])[CH3:36]
Reactant: COCc1cc(C(=O)OC)ccc1Br
Reactant: CC(=O)[O-]
Agent: COCc1cc(C(=O)O)ccc1-c1cccc(F)c1C
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(Br)c(COC(C)=O)c1
Temperature: 100 °C
Reaction time: 15 h
Yield: 79.3 %

Procedure:
To a solution of methyl 4-bromo-3-(bromomethyl)benzoate (Intermediate 1 Step 1, 6.5 g, 21 mmol) in AcOH (32.5 mL) was added sodium acetate (3.46 g, 42 mmol) and the reaction mixture was stirred at 100° C. for 15 hours. After concentration in vacuo, the residue was partitioned between EtOAc and water. The organic layer was washed with a 5% aqueous solution of NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo. Purification by chromatography (silica, chex/EtOAc) afforded the title compound as a white solid (4.78 g, 79%). 1H NMR (DMSO-d6) δ 8.03 (m, 1H), 7.85 (m, 2H), 5.18 (s, 2H), 3.87 (s, 3H), 2.11 (s, 3H). HPLC (Method A) Rt 4.37 min (purity 98.1%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[NH:12]1[CH2:22][CH2:21][CH2:20][CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13]1.CCN(C(C)C)C(C)C>CC#N>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:12]2[CH2:22][CH2:21][CH2:20][CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13]2)[N:3]=1
Reactant: CCOC(=O)C1CCCNC1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C1CCCN(c2nc(Cl)nc3[nH]cnc23)C1
Yield: 34.9 %

Procedure:
A solution of 2,6-dichloropurine (189 mg, 1.00 mmol), ethyl nipecotate (0.155 mL, 1.00 mmol) and DIEA (0.300 mL, 1.72 mmol) in CH3CN (5 mL) was stirred at room temperature for 20 h, during which time white solids precipitated out, which was collected to give ethyl 1-(2-chloro-9H-purin-6-yl)piperidine-3-carboxylate (108 mg).
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][CH2:6][O:7][C@@H:8]1[C@H:12]([OH:13])[C@@H:11]([CH2:14][OH:15])[O:10][C@H:9]1[N:16]1[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]1=[O:18])#[N:2].N1C=CC=CC=1.[CH3:30][O:31][C:32]1[CH:53]=[CH:52][C:35]([C:36](Cl)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[CH:34][CH:33]=1>CO>[CH3:44][O:43][C:40]1[CH:39]=[CH:38][C:37]([C:36]([O:15][CH2:14][C@H:11]2[O:10][C@@H:9]([N:16]3[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]3=[O:18])[C@H:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][C:1]#[N:2])[C@@H:12]2[OH:13])([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:35]2[CH:52]=[CH:53][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)=[CH:42][CH:41]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#CCCOCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OCOCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
2′-O-(2-Cyanoethoxymethyl)uridine (14 g, 43 mmol) was subjected to azeotropic distillation with pyridine, and then was dried with a vacuum pump for 30 minutes. The residue was dissolved in 300 mL of THF, and 68 g of pyridine (856 mmol), and 20 g of molecular sieve 4 A was added under an argon atmosphere, and the mixture was stirred for 10 minutes. To the solution was added 19.6 g of 4,4′-dimethoxytritylchloride (57.8 mmol) by 3 portions every 1 hour, and the mixture was further stirred for 1 hour. After 10 mL of methanol was added and the reaction solution was stirred for 2 minutes, the reaction solution was filtrated with a celite, and was washed with ethyl acetate. After concentrating the filtrate, the residue was dissolved in ethyl acetate, and was washed with a saturated aqueous sodium bicarbonate solution. After the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, the solvent was distilled off. The obtained residue was purified by silica gel chromatography to obtain the objective compound (26.5 g, yield 98%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[I-].[Na+].[OH-].[Na+].Cl[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)(CC)(C)C.C1(C)C=CC=CC=1>[C:15]1([CH2:14][CH2:13][CH2:12][CH2:11][N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCCCCc1ccccc1
Reactant: c1c[nH]nn1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)(C)O
Solvent: Cc1ccccc1
Product: c1ccc(CCCCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
1,2,3-Triazole (1623 mg, 23.5 mmol), sodium iodide (2353 mg, 15.7 mmol) and sodium hydroxide (940 mg, 23.5 mmol) were added to t-amyl alcohol (6.2 ml), and the mixture was refluxed under stirring for 1 hour. 1-Chloro-4-phenylbutane (2648 mg, 15.7 mmol) was dissolved in t-amyl alcohol (6.2 ml) and added dropwise under reflux over 1 hour. The mixture was refluxed under stirring for 2 hours and cooled to room temperature, and toluene (50 ml) was added. The mixture was washed with water (50 ml×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1→1/3) to give 1-(4-phenylbutyl)-1H-1,2,3-triazole (2.56 g) as colorless oil. yield 81%. 2-(4-Phenylbutyl)-2H-1,2,3-triazole (360 mg) was obtained as a colorless oil (yield 11%). 1-(4-phenylbutyl)-1H-1,2,3-triazole
Reaction SMILES: [NH2:1][C@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21](Cl)(=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24].C(N(CC)CC)C.CCOCC>C(Cl)Cl>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@H:2]([NH:1][C:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24])[C:3]1=[O:20]
Reactant: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Reactant: CC(C)CC(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)N[C@H]1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reaction time: 0.17 h

Procedure:
Equimolar amounts of 3(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, isovaleryl chloride and triethylamine were mixed in CH2Cl2 at room temperature and stirred 10 minutes. Flash chromatography of the reaction solution on silica gel (10% Et2O in CH2Cl2) provided the title compound as a white foam from Et2O: m.p. 83°-102° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]([C:21]#[N:22])=[C:11]([NH2:20])[N:12]([C:14]3C=CC=CC=3)[CH:13]=2)[CH:6]=[CH:7][CH:8]=1.CN([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28]N=1)C.O.[CH:33]([NH2:35])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[C:11]([NH2:20])=[N:12][CH:14]=[N:22][C:21]=3[N:35]([C:33]3[CH:26]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cn(-c3ccccc3)c(N)c2C#N)c1
Reactant: NC=O
Reactant: CN(C)c1ccccn1
Solvent: O
Product: COc1cccc(-c2cn(-c3ccccc3)c3ncnc(N)c23)c1
Temperature: 25 °C

Procedure:
1.27 g of 4-(3-methoxyphenyl)-1-phenyl-2-amino-3-cyanopyrrole are heated at 180° C. with a spatula tipful of dimethylaminopyridine for 7 h in 14 ml of formamide under a nitrogen atmosphere. After cooling to RT, the mixture is treated with water and the crystals obtained are filtered off, washed with water and dried. After chromatography on silica gel (ethyl acetate/hexane 4:1), the product-containing fractions are concentrated, slurried in ether and filtered. 5-(3-Methoxyphenyl)-7-phenyl-4-aminopyrrolo[2,3-d]pyrimidine having a melting point of 159°-160° C. is obtained. 1H--NMR (d6 -DMSO): delta (ppm)=3.8 (s, 3H), 6.3 (br. s, 2H), 6.9 (br. d, 1H), 7.1 (m, 2H), 7.3-7.45 (m, 2H), 7.55(t, 2H), 7.75 (s, 1H), 7.9 (d, 2H), 8.2 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([CH3:27])[N:21]=1>>[Br:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([CH3:27])[N:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Br
Reactant: Cc1cc(Br)nc(C)n1
Product: Cc1cc(-c2cc(C)c(Br)c(C)c2)nc(C)n1

Procedure:
The title compound is prepared from 2-bromo-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 4-bromo-2,6-dimethyl-pyrimidine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 7): tR=1.01 min; Mass spectrum (ESI+): m/z=291/293 (Br) [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]([CH2:17][CH2:18][CH:19]([OH:31])[C@H:20]1[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:22][CH2:21]1)[C:10]([O:12]C(C)(C)C)=O>ClCCl.O>[CH3:8][CH:9]1[CH2:17][CH2:18][CH:19]([C@H:20]2[CH2:21][CH2:22][C@H:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:24][CH2:25]2)[O:31][C:10]1=[O:12]
Reactant: CCCCC[C@H]1CC[C@H](C(O)CCC(C)C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCCC[C@H]1CC[C@H](C2CCC(C)C(=O)O2)CC1

Procedure:
A solution of 14.2 mL (185 mmol) of trifluoroacetic acid dissolved in 60 mL of dichloromethane was added dropwise under cooling with ice to a solution of 12.6 g (37.0 mmol) of tert-butyl 2-methyl-5-hydroxy-5-(trans-4-pentylcyclohexyl)pentanoate (36) obtained in the first step dissolved in 60 mL of dichloromethane, and reacted at room temperature for 5 hours. The reaction mixture was put in 200 mL of water, and then extracted with 100 mL of dichloromethane. The resulting organic layer was washed with water (150 mL×2) and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (developing solvent: heptane/ethyl acetate=9/1, column packing: silica gel) and then recrystallized from heptane to obtain 3.7 g (13.7 mmol) of 3-methyl-6-(trans-4-pentyl cyclohexyl)tetrahydro-2-pyranone (Compound No. 6). The resulting compound was in the form of colorless crystals, and the yield based on the compound (36) was 37%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[CH3:14]I>C1COCC1.CCOC(C)=O>[CH3:14][O:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: CI
Reactant: O=C(O)c1cccc(CO)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1cccc(C(=O)O)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 300 mg (1.96 mmol) 6-hydroxymethyl-pyridine-2-carboxylic acid in 20 mL THF was added 188 mg (4.31 mmol) NaH in mineral oil (55%) at 0° C. After gas formation ceased, 310 μL (4.90 mmol) methyl iodide was added dropwise, then the mixture was stirred for 1 h at 0° C. and for 1 h at RT. The reaction mixture was diluted with EtOAc, extracted with water, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([N:6]([CH2:17][CH2:18][O:19][CH2:20][CH3:21])[CH2:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:4]([CH:24]=O)[CH:3]=1.CC(C)([O-])C.[K+].O>C1(C)C=CC=CC=1.CC(O)(C)C>[Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:17][CH2:18][O:19][CH2:20][CH3:21])[CH2:7][CH2:8][C:9]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[CH:24][C:4]=2[CH:3]=1
Reactant: CCOCCN(CCCC(=O)OC(C)(C)C)c1ccc(Br)cc1C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CCOCCN1CCC(C(=O)OC(C)(C)C)=Cc2cc(Br)ccc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 6.5 %

Procedure:
In toluene (4.8 ml)/2-methyl-2-propanol (0.48 ml) was dissolved tert-butyl 4-[4-bromo(2-ethoxyethyl)-2-formylanilino]butyrate (2.4 g). To the solution was added potassium tert-butoxide. (72 mg), the mixture was stirred at 100° C. for 1 hour and cooled to room temperature. The reaction solution was added to water, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=6/1) to give tert-butyl 7-bromo-1-(2-ethoxyethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.15 g).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[N:29]=[C:30]([CH2:33][NH:34][CH2:35]C(C)C)[S:31][CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:42][CH:43](C)CN>>[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[N:29]=[C:30]([CH2:33][N:34]5[CH2:35][CH2:3][CH2:2][CH2:43][CH2:42]5)[S:31][CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)CN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CNCC(C)C)n4)cc23)CC1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCCC5)n4)cc23)CC1
Yield: 51.6 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-{[(2-methylpropyl)amino]methyl}-1,3-thiazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting piperidine (78 mg, 0.3 mmol) for 2-methyl-1-propanamine to afford 15.5 mg of the title compound (51.6%).
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13].O1CCCC1.[CH2:20]([N:23]1[C:31](=[O:32])[C:30]2[C:25](=[N:26][C:27]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([N:40]4[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]4)=[CH:36][CH:35]=3)=[N:28][CH:29]=2)[N:24]1[C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([NH2:53])[N:48]=1)[CH:21]=[CH2:22]>O>[CH2:20]([N:23]1[C:31](=[O:32])[C:30]2[C:25](=[N:26][C:27]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([N:40]4[CH2:41][CH2:42][N:43]([CH3:46])[CH2:44][CH2:45]4)=[CH:36][CH:35]=3)=[N:28][CH:29]=2)[N:24]1[C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([N:53]2[CH2:9][CH2:10][CH2:11][C:12]2=[O:13])[N:48]=1)[CH:21]=[CH2:22]
Reactant: C=CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc2n1-c1cccc(N)n1
Reactant: O=C(Cl)CCCCl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc2n1-c1cccc(N2CCCC2=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.8 %

Procedure:
With cooling with ice, 0.012 mL of triethylamine and 12.4 mg of 4-chlorobutyric acid chloride were added to tetrahydrofuran (1 mL) solution of 20 mg of the compound obtained in Example 50, 2-allyl-1-(6-aminopyridin-2-yl)-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, and stirred at room temperature for 1 hour. Water was added to the reaction mixture, extracted with chloroform, and the organic layer was washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, the resulting residue was dissolved in 1 mL of N,N-dimethylformamide, and 5 mg of potassium tert-butoxide was added thereto and stirred at room temperature for 30 minutes. Saturated ammonium chloride solution was added to the reaction mixture, extracted with ethyl acetate, and the organic layer was washed with saturated saline water and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through preparative thin-layer chromatography (chloroform/methanol=10/1) to obtain 5 mg of the entitled compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc2ccccc2c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1c(OCc2ccccc2)ccc2ccccc12
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a suspension of 1-bromo-2-naphthol (15.0 g, 67.3 mmol) and K2CO3 (18.6 g, 135 mmol) in DMF (100 mL) was added benzyl bromide (9.6 mL, 81 mmol) and the mixture was stirred at 60° C. for 5 h. After cooling to room temperature, the solvent was evaporated in vacuo and the residue, dissolved in a small amount of CH2Cl2, passed through a thin pad of flash silica. Fractions containing the product were evaporated in vacuo to give an off-white solid. Crystallisation from CH2Cl2/petrol gave the title compound, 1-bromo-2-(phenylmethoxy)naphthalene, as a white crystalline solid (16.0 g, 76%). The mother liquor was concentrated and purified by flash chromatography (petrol/CH2Cl2, 2/1) to give an additional amount of the product (3.7 g, 17%; total yield: 93%). Rf =0.50 (petrol/CH2Cl2, 2/1); mp 104-106° C. (CH2Cl2/petrol); 1H NMR (250 MHz, CDCl3) δ5.35 (s, 2H), 7.32 (d, J=9.0 Hz, 1H), 7.38-7.50 (m, 4H), 7.57-7.66 (m, 2H), 7.79-7.86 (m, 3H), and 8.31 (d, J=8.5 Hz, 1H); 13C NMR (63 MHz, CDCl3) δ71.81, 110.0, 115.6, 124.6, 126.3, 127.2, 127.8, 128.1 (2C), 128.7, 128.9, 130.1, 133.2, 136.7 and 153.0; IR (CHCl3) νmax 1626, 1596, 1502, 1350, and 1268 cm−1; MS (EI+) m/z (rel intensity) 314/312 (25%, M+) and 91 (100); HRMS calcd for C17H13BrO (M+) 312.0150, found 312.0150. Anal. Calcd for C17H13BrO: C, 65.19; H, 4.18; Br, 25.51. Found: C, 64.94; H, 4.12; Br, 25.71.
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20]I>C1COCC1.O>[CH3:20][N:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(Nc2ccccc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(c1ccccc1)c1ccc(C(=O)O)cc1
Reaction time: 0.17 h
Yield: 39.8 %

Procedure:
NaH 60% dispersed in mineral oil (0.030 g; 0.745 mmol) was added to a solution of methyl 4-(phenylamino)benzoate (0.113 g; 0.497 mmol) in THF (3 mL). After stirring the resulting solution for 10 minutes, methyl iodide (0.062 mL; 0.994 mmol) was added and the resulting mixture was stirred overnight at room temperature. The mixture was diluted in water and extracted with ethyl acetate. The organic layer was washed with brine and dried to yield 0.045 g (40%) of the title compound as a white solid.