Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[N:15]([CH2:27][CH2:28][OH:29])[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[C:21]([CH3:26])[CH:20]=4)[N:18]=3)[CH2:10][CH2:9]2)[C:3]=1Br.[C:31]([O:35][C:36]([N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C([O-])([O-])=O.[Cs+].[Cs+]>O>[NH2:1][C:2]1[C:3]([C:41]2[CH:40]=[N:39][N:38]([C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[CH:42]=2)=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[N:15]([CH2:27][CH2:28][OH:29])[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[C:21]([CH3:26])[CH:20]=4)[N:18]=3)[CH2:10][CH2:9]2)[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(-c2cn(CCO)c(C3CCN(c4ncnc(N)c4Br)CC3)n2)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: Cc1cc(-c2cn(CCO)c(C3CCN(c4ncnc(N)c4-c4cnn(C(=O)OC(C)(C)C)c4)CC3)n2)ccc1F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
a mixture of 2-[2-[1-(6-amino-5-bromo-pyrimidin-4-yl)-piperidin-4-yl]-4-(4-fluoro-3-methyl-phenyl)-imidazol-1-yl]-ethanol (1333.00 mg; 2.80 mmol; 1.00 eq.), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (1237.31 mg; 4.21 mmol; 1.50 eq.), Cs2CO3 (548 mg, 1.68 mmol) in doxane 10 ml and water 1 ml, purged with argon, added Pd(0) (tBu3)2 (143 mg, 0.28 mmol) stirred at 50° C. for overnight. LC-MS showed desired as major product, removed off solvent, purified by prep HPLC (Basic), collected title compound 400 mg, 25.4%
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[S:10][CH:9]=1)=[O:7])C>O>[CH:13]1([C:11]2[S:10][CH:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:12]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CCOC(=O)c1csc(C2CCCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1csc(C2CCCCC2)c1
Yield: 107.5 %

Procedure:
Sodium hydroxide (1 N, 2.5 mL) was added to 5-(cyclohexyl)-thiophene-3-carboxylic acid ethyl ester (0.485 g) in IMS (3 mL). The reaction was irradiated in a microwave at 140° C. for 10 minutes. Water was added (5 mL) and the mixture washed with DCM. The aqueous layer was acidified to pH 1 and extracted with DCM. The organic solution was dried over magnesium sulphate, filtered and the solvent removed to give the title compound (460 mg, 86%). Recrystallisation from IMS/water gave a red solid (0.2 g). LCMS m/z 210.99 [M+H]+ RT=3.75 min (Analytical Method 4).
Reaction SMILES: N#N.[Si:3]([O:10][CH2:11][C:12]1[N:13]=[C:14]([CH:17]([OH:19])[CH3:18])[O:15][CH:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>C(C#N)(C)=O.O=[Mn]=O>[Si:3]([O:10][CH2:11][C:12]1[N:13]=[C:14]([C:17](=[O:19])[CH3:18])[O:15][CH:16]=1)([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4]
Reactant: CC(O)c1nc(CO[Si](C)(C)C(C)(C)C)co1
Agent: O=[Mn]=O
Agent: CC(=O)C#N
Agent: N#N
Product: CC(=O)c1nc(CO[Si](C)(C)C(C)(C)C)co1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)oxazol-2-yl)ethanol (260 mg, 1.01 mmol) in AcCN (7.1 mL) was treated at rt with MnO2 (1488 mg, 5.05 mmol) and the resulting mixture was stirred overnight at rt. The reaction mixture was filtered and the solvent was removed under reduced pressure to give the title compound as a yellow oil. TLC: rf (2:1 hept-EA)=0.55. LC-MS-conditions 07: tR=0.96 min, [M]+=255.89.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]3[C:20]4[CH2:30][NH:29][CH2:28][CH2:27][CH2:26][C:21]=4[N:22]([CH3:25])[C:23]=3[CH:24]=2)[C:12](=[O:31])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]3[C:20]4[CH2:30][N:29]([CH3:34])[CH2:28][CH2:27][CH2:26][C:21]=4[N:22]([CH3:25])[C:23]=3[CH:24]=2)[C:12](=[O:31])[CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCCC2
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CO
Product: CN1CCCc2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc3n2C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 48.4 %

Procedure:
4-(Benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride (54 mg, 0.12 mmol) and 37% aqueous formaldehyde (15 μL, 0.17 mmol) were dissolved in 1:1 MeOH/CH2Cl2 (1.0 mL), and the resulting solution was stirred at room temperature for 5 min. Sodium triacetoxyborohydride (52 mg, 0.25 mmol) was added, and the reaction stirred at room temperature for an additional 45 min. The mixture was neutralized with saturated NaHCO3 solution and extracted with CH2Cl2 (2×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness. Flash chromatography (12 g ISCO CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes to 0:100 over 20 column volumes) provided the title compound (24 mg, 46%) as a yellow film: 1H NMR (300 MHz, CD3OD) δ 7.60-7.55 (m, 2H), 7.47-7.35 (m, 6H), 7.01-6.98 (m, 1H), 6.29-6.26 (m, 1H), 6.11 (d, J=2.7 Hz, 1H), 5.48 (s, 2H), 5.17 (s, 2H), 4.16-4.10 (m, 2H), 3.74-3.73 (m, 3H), 3.10-3.06 (m, 2H), 2.61 (s, 3H), 2.12-2.06 (m, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([C:17]([NH2:19])=O)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.O.ClCCl>C1COCC1>[NH2:19][CH2:17][CH:14]1[CH2:15][CH2:16][C:11]2([O:7][CH2:8][CH2:9][O:10]2)[CH2:12][CH2:13]1
Reactant: NC(=O)C1CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: NCC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 1.4 g (0.037 mole) of lithium aluminum hydride in 100 ml dry THF is added, portionwise, 4.9 g (0.026 mole) of 1,4-dioxaspiro[4,5]decane-8-carboxamide over one-half hour. This mixture is then refluxed 2 hours, then allowed to cool to room temperature. About 5 ml water is added cautiously and then stirred 15 minutes. Dichloromethane is then added and the insolubles filtered off. The organic layer is dried over MgSO4 and stripped to dryness, giving 3.48 g crude product. This material is vacuum-distilled to obtain 8-aminomethyl-1,4-dioxaspiro[4,5]decane (b.p. 84°-101° C. at 0.7 mm Hg.)
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:10](=[O:12])[NH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[N:5]=[CH:4]1)[CH3:2].Cl[CH2:16][P:17](=[O:20])([CH3:19])[CH3:18]>>[CH2:1]([N:3]1[C:11]2[C:10](=[O:12])[N:9]([CH2:16][P:17](=[O:20])([CH3:19])[CH3:18])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CP(C)(=O)CCl
Product: CCn1cnc2c1c(=O)n(CP(C)(C)=O)c(=O)n2C

Procedure:
The title substance was prepared from 5 g (0.0258 mol) of 7-ethyl-3-methylxanthine and 3.91 g (0.031 mol) of chloromethyl-dimethylphosphine oxide analogously to Example 67.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=O)[C:5]([CH:8]([C:14](OCC)=O)C(OCC)=O)=[N:6][CH:7]=1.F[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:19]([O:21][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH:8]=[C:5]2[NH:6][CH:7]=1
Reactant: Fc1ccccc1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: BrC1=CNC2=CCN(Oc3ccccc3)C2=C1
Temperature: 25 °C
Yield: 50 %

Procedure:
6-bromo-1H-pyrrolo[3,2-b]pyridin-1-ol (prepared as in Example 1: 200 mg, 1.0 mmol, 1.0 eq), fluorobenzene (485 mg, 5.0 mmol, 5.0 eq), and K2CO3 (690 mg, 5.0 mmol, 5.0 eq) in 2 ml of DMF were microwaved (160° C.) for 30 min. The reaction mixture was allowed to cool to room temperature, the solvent was evaporated, and the mixture was chromatographed (MeOH/DCM 1:20) to give a light yellow solid, 110 mg, in 50% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.[NH2:28][CH2:29][CH2:30][OH:31].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:28][CH2:29][CH2:30][OH:31])=[O:18])=[N:14][CH:15]=1
Reactant: NCCO
Reactant: Cc1cc(C(=O)O)ncc1C(Sc1ccc(F)cc1)c1cc(F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)NCCO)ncc1C(Sc1ccc(F)cc1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl) [(4-fluorophenyl)thio]methyl]-4-meth ylpyridine-2-carboxylic acid (483 mg, 1.24 mmol) obtained in Example 20 in methylene chloride (10 ml), 2-aminoethanol (0.083 ml, 1.36 mmol), 1-hydroxybenzotriazole (184 mg, 1.36 mmol), 4-methylmorpholine (0.150 ml, 1.36 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (262 mg, 1.36 mmol) were added at room temperature. After stirring for 4 hours at room temperature, water was added to the reaction mixture, and the mixture was washed with saturated aqueous ammonium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:3 was concentrated under reduced pressure, to obtain the title compound (481 mg, 1.11 mmol, 90%) as a colorless foamy substance.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH2:14][CH3:15])[CH:9]=[CH:8][N:7]=1)(=O)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[OH:4][CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH2:14][CH3:15])[CH:9]=[CH:8][N:7]=1
Reactant: CCOc1ccnc(COC(C)=O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOc1ccnc(CO)c1C
Yield: 47.5 %

Procedure:
28.2 g of 2-acetoxymethyl-3-methyl-4-ethoxy-pyridine was added dropwise to a 25% aqueous solution of sodium hydroxide, and the mixture was allowed to react for one hour at room temperature. Subsequently, the reaction liquid was diluted with toluene, and then the toluene phase was washed with water, dried over anhydrous magnesium sulfate, and then concentrated to dryness, to obtain 10.7 g of 2-hydroxymethyl-3-methyl-4-ethoxy-pyridine as an oily matter.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:6]([CH:8]=[C:9]([C@@H:11]3[CH2:13][C@@H:12]3[C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[N:10]=2)[N:7]=1.Br[C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:6]([C:8]([C:31]3[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:33][CH:32]=3)=[C:9]([C@@H:11]3[CH2:13][C@@H:12]3[C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[N:10]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reactant: Clc1cc(N2CCOCC2)c2nc([C@@H]3C[C@@H]3c3ccc4ccccc4n3)cn2n1
Product: CC(C)(C)OC(=O)c1ccc(-c2c([C@@H]3C[C@@H]3c3ccc4ccccc4n3)nc3c(N4CCOCC4)cc(Cl)nn23)cc1

Procedure:
Compound 79d (33 mg, 0.081 mmol) was coupled with tert-butyl 4-bromobenzoate (29 μL, 0.12 mmol) using the procedure described in Example 20, Step A to afford title compound 146. 1H NMR (400 MHz, CD3OD) δ (ppm): 7.93-8.08 (m, 4H), 7.72-7.85 (m, 3H), 7.66 (t, J=7.6 Hz, 1H), 7.41-7.50 (m, 1H), 7.24-7.31 (m, 1H), 6.12 (s, 1H), 4.05 (br. s., 4H), 3.95 (d, J=3.9 Hz, 4H), 2.80-2.93 (m, 2H), 1.87-2.00 (m, 2H), 1.58 (s, 9H) Mass Spectrum (LCMS, ESI pos.): Calcd. for C33H32ClN5O3: 582.2 (M+H). found: 582.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([NH2:10])[CH:3]=1.[N:11]([O-])=O.[Na+].O.O.Cl[Sn]Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([NH:10][NH2:11])[CH:3]=1
Reactant: O=N[O-]
Reactant: COc1ccc(Br)cc1N
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(Br)cc1NN
Yield: 89.1 %

Procedure:
The title compound was prepared by the general procedure described above for Preparations 2a-i using 4-bromo-2-aminoanisole (9.09 g), NaNO2 (3.45 g), and SnCl2.2H2O (22.6 g). Workup gave 8.7 g (89%) of (5-bromo-2-methoxyphenyl)hydrazine which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:16]1[NH:20][C:19]2[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:18]=2[N:17]=1.[CH3:27][O:28][CH2:29][CH2:30][NH2:31].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>CN(C=O)C.O>[CH3:27][O:28][CH2:29][CH2:30][NH:31][C:13]([C:11]1[S:12][C:8]([C:5]2[CH:6]=[N:7][C:2]([NH2:1])=[C:3]([C:16]3[NH:20][C:19]4[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:18]=4[N:17]=3)[CH:4]=2)=[CH:9][CH:10]=1)=[O:15]
Reactant: COc1ccc2nc(-c3cc(-c4ccc(C(=O)O)s4)cnc3N)[nH]c2c1
Reactant: COCCN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: O
Product: COCCNC(=O)c1ccc(-c2cnc(N)c(-c3nc4ccc(OC)cc4[nH]3)c2)s1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
14.2 157 mg (0.111 mmol) of 5-[6-amino-5-(6-methoxy-1H-benzimidazol-2-yl)pyridin-3-yl]thiophene-2-carboxylic acid are dissolved in 0.5 ml of DMF. 10 μl (0.114 mmol) of 2-methoxyethylamine, 14.9 mg (0.111 mmol) of HOBt, 21.2 mg (0.111 mmol) of EDC and 24.3 μl (0.221 mmol) of N-methylmorpholine are added. The reaction mixture is stirred at room temperature for 14 h, water is added, and the mixture is extracted with ethyl acetate. The organic phases are dried using sodium sulfate, filtered and evaporated. The residue is purified by means of RP-HPLC and lyophilised, giving N-(2-methoxyethyl)-5-[6-amino-5-(6-methoxy-1H-benzimidazol-2-yl)pyridin-3-yl]-thiophene-2-carboxamide; HPLC-MS [M+H]+ 424.2.
Reaction SMILES: CO.[CH2:3]([O:6][CH2:7][C@H:8]([NH:13]C(=O)C(F)(F)F)[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:4]=[CH2:5].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:3]([O:6][CH2:7][C@H:8]([NH2:13])[CH2:9][CH:10]([CH3:11])[CH3:12])[CH:4]=[CH2:5]
Reactant: C=CCOC[C@@H](CC(C)C)NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C=CCOC[C@H](N)CC(C)C
Yield: 95 %

Procedure:
Step AK (3): To a mixture of methanol (90 mL) and water (10 mL), (R)-N-(1-(allyloxy)-4-methylpentan-2-yl)-2,2,2-trifluoroacetamide (1.9 g, 7.5 mmol) and potassium carbonate (3.1 g, 22.5 mmol) were added. The mixture was heated at reflux for 16 h and concentrated in vacuum to remove methanol. The mixture was poured into excess NaOH (1 M) and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuum to yield (R)-1-(allyloxy)-4-methylpentan-2-amine (1.12 g, 95%) as a colorless oil. LC-MS (M+H)+=158.07.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].Br[CH:13]1[S:17][C:16](=[O:18])[NH:15][C:14]1=[O:19].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(Cl)(Cl)Cl.C(#N)C>C1COCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH:13]1[S:17][C:16](=[O:18])[NH:15][C:14]1=[O:19]
Reactant: Oc1ccc2ccccc2c1
Reactant: O=C1NC(=O)C(Br)S1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C1NC(=O)C(Oc2ccc3ccccc3c2)S1
Yield: 30.9 %

Procedure:
By a procedure similar to that of method B, a solution of 2-naphthol (5.0 g, 35 mmol) and 5-bromo-2,4-thiazolidinedione (6.8 g, 35 mmol) in THF (200 mL) was treated with lithium bis(tri-methylsilyl)amide (76 mL, 76 mmol, 1.0M in THF) to give, after chromatography (acid-washed silica gel, chloroform/acetonitrile), 5-(2-Naphthalenyloxy)-2,4-thiazolidinedione (2.8 g, 31% yield): mp 221°-222° C. (acetone/ethyl acetate); 1H NMR (DMSO-d6, 400 MHz) δ 6.52 (s, 1 H, OCH), 7.1-8.0 (m, 6 H, ArH), 10.57 (s, 1 H, ArH).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:16])=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].OO>C(O)(=O)C>[CH3:1][C:2]1[C:3]2[C:4](=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][N:16]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc(C(=O)c2ccccc2)c1N
Agent: OO
Solvent: CC(=O)O
Product: Cc1cccc2c(-c3ccccc3)onc12
Temperature: 0 °C
Reaction time: 72 h
Yield: 49 %

Procedure:
A solution of 8.4 g (0.04 mole) of 3-methyl-2-aminobenzophenone, 150 ml of acetic acid and 40 ml of 30% hydrogen peroxide was allowed to stand at ambient temperature for 3 days and the resulting solution was poured into 800 ml of ice-water mixture. The solid which precipitated was collected by filtration, washed with water and dried. This solid was recrystallized twice from isopropanol to yield 4.1 g (49%) of tan crystals, m.p. 73°-75° C.
Reaction SMILES: O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl:10][C:11]1[N:12]=[N:13][C:14](I)=[CH:15][CH:16]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Na+]>CC[N+](CC1C=CC=CC=1)(CC)CC.[Cl-].C([O-])(=O)C.C([O-])(=O)C.[Pd+2].O.C1COCC1>[Cl:10][C:11]1[N:12]=[N:13][C:14]([C:22]2[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(I)nn1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccc(Cl)nn2)cn1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
Water (253 mL) and THF (842 mL) were put in the reaction balloon. The reagents were added one by one to the stirred reaction mixture: potassium phosphate monohydrate 86.2 g (374 mmol) and BTEAC 2.25 g (9.88 mmol). Then 3-chloro-6-iodopyridazine, 45 g (187.2 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole, 46.73 g (224.6 mmol) were added and finally triphenylphosphine, 1.96 g (7.49 mmol) and palladiumdiacetate, 420 mg (1.87 mmol) were added. The reaction mixture was heated at 65° C. for 16 h. The reaction mixture was allowed to cool to 60° C. Then 935 mL water and 301.5 g sodium chloride were added. The mixture was stirred for 15 minutes and allowed to cool to 45° C. The phases were separated and the organic layer was washed with a solution of 45 g sodium chloride in 374 mL water. The organic layer was separated and stirred with magnesium sulphate (225 g) and charcoal (4.5 g). The mixture was filtered and evaporated. The evaporation residue was co-evaporated with toluene twice and evaporated further till a final volume of 200 ml. This residue was stirred for 16 h at room temperature. The resulting solids were collected by filtration. The solids were dried at reduced pressure affording 29.7 g of the title compound (152.6 mmol, yield 82%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[F:29])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:21]([F:29])[CH:22]=1
Reactant: Fc1cc(Br)c2cn[nH]c2c1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Fc1cc(Br)c2cnn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 40.3 %

Procedure:
To a solution of 4-bromo-6-fluoro-1H-indazole (1.0 g, 4.65 mmol) in dichloromethane (50 mL) was added 4-benzyloxy-3-fluorobenzeneboronic acid (2.29 g, 9.31 mmol), pyridine (0.75 mL, 9.28 mmol), copper acetate (1.26 g, 6.96 mmol) and powdered 4A molecular sieves (2 g). The reaction mixture was stirred at room temperature in the presence of air for 4 days. Celite was added to the mixture and stirred for 5 mins, then the mixture was filtered through a pad of celite and then the filtrate was washed with water, dried over magnesium sulphate, filtered and concentrated. The product was purified by silica gel chromatography eluting with 5-100% dichloromethane in hexane to yield the title compound (D7) (779 mg).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[O:23]1[C:28]2[CH:29]=[CH:30][C:31]([CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]Cl)=[CH:32][C:27]=2[O:26][CH2:25][CH2:24]1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][O:34][CH2:33][C:31]3[CH:30]=[CH:29][C:28]4[O:23][CH2:24][CH2:25][O:26][C:27]=4[CH:32]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: ClCCCCCOCc1ccc2c(c1)OCCO2
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCOCc2ccc3c(c2)OCCO3)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 5-((1,4-benzodioxan-6-yl)methoxy)pentyl chloride were reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(5-((1,4-benzodioxan-6-yl)methoxy)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][N+:15]([O-])=[C:14]([CH3:19])[C:13]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:24]C(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:24][CH2:19][C:14]1[C:13]([CH3:20])=[C:12]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:17]=[CH:16][N:15]=1)(=[O:23])[CH3:22]
Reactant: Cc1c(OCCOCc2ccccc2)cc[n+]([O-])c1C
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCc1nccc(OCCOCc2ccccc2)c1C
Reaction time: 1 h

Procedure:
A mixture comprising 6.5 g of 4-(2-benzyloxyethoxy-2,3-dimethylpyridine N-oxide and 56 ml of acetic anhydride was stirred at 80° to 90° C. for one hour and distilled to remove the acetic anhydride. The obtained residue was made weakly basic with an aqueous solution of sodium carbonate and extracted with methyl ethyl ketone. The extract was dried over magnesium sulfate and distilled to remove the methyl ethyl ketone. Thus, 7.0 g of 2-acetoxymethyl-4-(2-benzyloxyethoxy)-3-methylpyridine was obtained. This intermediate was dissolved in 90 ml of ethanol, followed by the addition of 1.43 g of sodium hydroxide. The obtained mixture was stirred at 40° C. for one hour, followed by the addition of water. The mixture was extracted with methyl ethyl ketone. The obtained extract was dried over magnesium sulfate to obtain 5.4 g of 4-(2-benzyloxyethoxy)-2-hydroxymethyl-3-methylpyridine.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:6])[CH3:5].F[C:8]1[C:13]([CH3:14])=[C:12]([I:15])[C:11]([CH3:16])=[CH:10][N:9]=1.CC(OC)(C)C>C1COCC1.O>[I:15][C:12]1[C:11]([CH3:16])=[CH:10][N:9]=[C:8]([O:6][CH:4]([CH3:5])[CH3:3])[C:13]=1[CH3:14]
Reactant: Cc1cnc(F)c(C)c1I
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Cc1cnc(OC(C)C)c(C)c1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60% oil dispersion, 191 mg) was added to a solution of IPA (0.77 mL) in THF (5 mL). After foaming was stopped, a solution of 2-fluoro-4-iodo-3,5-dimethylpyridine obtained in Preparation Example 29 (500 mg) in THF (5 mL) was added to the solution, and the mixture was stirred at mom temperature for two hours. The mixture was stirred at 50° C. for two hours, and the reaction mixture was then cooled to room temperature. The reaction mixture was cooled at 0° C., and MTBE (20 mL) and water (20 mL) were then added. The organic layer was separated. The organic layer was washed with brine. The combined aqueous layers were extracted with MTBE. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (490 mg).