Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.C1(S([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22]Br)=[N:20][CH:21]=2)(=O)=O)C=CC=CC=1>O>[CH3:1][O:2][CH2:22][C:19]1[N:20]=[CH:21][C:16]([OH:15])=[CH:17][CH:18]=1
Reactant: C[O-]
Reactant: O=S(=O)(Oc1ccc(CBr)nc1)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCc1ccc(O)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
Sodium methoxide (393 mg) was added to a methanol (20 ml) solution containing 5-(benzenesulfonyloxy)-2-(bromomethyl)pyridine (Beilstein Registry No. 7430370, 800 mg), followed by stirring at room temperature for 4 hours. Water was added to the reaction solution, followed by extraction with EtOAc. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: EtOAc) to obtain 6-(methoxymethyl)pyridin-3-ol (200 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH2:3]1.CCN(C(C)C)C(C)C.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39](O)=[O:40].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:23][C:15]1[CH:14]=[C:13]([NH:12][C:10](=[O:11])[NH:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][CH:2]([NH:1][C:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=3)=[O:40])[CH2:3]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: O=C(O)c1ccccn1
Reactant: Cc1cc(NC(=O)NCCN2CCC(N)C2)c2ccccc2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)NCCN2CCC(NC(=O)c3ccccn3)C2)c2ccccc2n1
Reaction time: 0.75 h

Procedure:
To a solution of 1-[2-(3-amino-pyrrolidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea (0.03 mmol) in DMF (0.3 mL) is added DIPEA (3 eq). The resulting solution is treated with a solution of pyridine-2-carboxylic acid (1.1 eq) in DMF (0.25 mL). A solution of TBTU (1.1 eq) in DMF (0.25 mL) is added. The reaction is stirred at 20 C for 45 min. The reaction mixture is evaporated to dryness. The residue is taken up in CH3CN/H2O/TFA (6:10:1; 1 mL) and is purified by preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]2[CH2:15][CH2:16][NH:17][CH2:18][C:7]1=2.C(N(CC)CC)C.[Cl:29][CH2:30][C:31](Cl)=[O:32].C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:29][CH2:30][C:31]([N:17]1[CH2:16][CH2:15][C:8]2[C:9]3[C:10]([N:6]([CH2:5][C:4]4[CH:19]=[CH:20][CH:21]=[C:2]([F:1])[CH:3]=4)[C:7]=2[CH2:18]1)=[N:11][CH:12]=[CH:13][CH:14]=3)=[O:32]
Reactant: Fc1cccc(Cn2c3c(c4cccnc42)CCNC3)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)N1CCc2c(n(Cc3cccc(F)c3)c3ncccc23)C1
Reaction time: 0.5 h

Procedure:
To a suspension of 9-(3-fluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine (500 mg) produced by operation in accordance with Example 1 in THF (10 mL) were sequentially added triethylamine (0.59 mL) and chloroacetyl chloride (0.135 mL), and the mixture was stirred for 30 minutes. The reaction mixture was poured into an aqueous saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (459 mg) having the following physical property values.
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][C:8]([CH3:30])=[CH:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:31]([O:33][C:34](=O)[C:35]([F:38])([F:37])[F:36])[CH3:32].O>CCCCCC.O1CCCC1>[F:36][C:35]([F:38])([F:37])[C:34]([O:33][CH2:31][CH3:32])=[CH:10][CH:9]=[C:8]([CH3:30])[CH3:7]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(C)=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=CC=C(C)C)C(F)(F)F
Yield: 41.7 %

Procedure:
96 ml of a 20% strength solution of n-butyl-lithium in hexane were added dropwise to a suspension of 82.2 g (0.2 mol) of dry 3,3-dimethylallyl-triphenylphosphonium bromide in 300 ml of anhydrous tetrahydrofuran at 0° C. under nitrogen, while stirring. The deep red solution thus obtained was stirred at 0° C. for a further 15 minutes and 28.4 g (0.2 mol) of trifluoroacetic acid ethyl ester were then added dropwise at 0°-10° C. The mixture was then stirred at room temperature until it was almost decolorized (about 12 hours). 600 ml of water were then added to the reaction mixture and the mixture was extracted 5 times with 200 ml of petroleum ether each time. The petroleum ether phases were dried over magnesium sulphate and the solvent was then stripped off in a rotary evaporator under a waterpump vacuum. 150 ml of n-hexane were added to the residue and the mixture was then filtered. The solvent was subsequently distilled off from the filtrate under normal pressure and the oily residue was then distilled in vacuo. 16.2 g (41.8% of theory) of 1,1,1-trifluoro-2-ethoxy-5-methyl-2,4-hexadiene were obtained as a slightly yellowish liquid with a boiling point of 72° C./36 mbar.
Reaction SMILES: [CH2:1]([S:4]([N:7]1[CH2:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)([C:11]#[N:12])[CH2:8]1)(=[O:6])=[O:5])[CH2:2][CH3:3]>N.CO.[Ni]>[CH2:1]([S:4]([N:7]1[CH2:10][C:9]([CH2:11][NH2:12])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:8]1)(=[O:5])=[O:6])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)N1CC(C#N)(c2ccccn2)C1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCCS(=O)(=O)N1CC(CN)(c2ccccn2)C1
Reaction time: 5 h

Procedure:
A solution of 1-(propylsulfonyl)-3-pyridin-2-ylazetidine-3-carbonitrile (II-1, 379 mg, 1.43 mmol) in 2 M NH3/MeOH (50 mL) was treated with excess Raney Ni and agitated under an atmosphere of H2 (40 psi) in a Parr apparatus. After 5 h, the reaction was filtered through Celite (MeOH wash) and concentrated under reduced pressure to afford 1-[1-(propylsulfonyl)-3-pyridin-2-ylazetidin-3-yl]methanamine (II-2) as a yellow oil. Analytical LCMS: single peak (214 nm), 1.791 min. This material was used in subsequent reactions without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([C:11](=[O:19])[CH2:12][NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:5][C:4]=1[Br:20]>>[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([CH:11]([OH:19])[CH2:12][NH:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)=[CH:5][C:4]=1[Br:20]
Reactant: N#Cc1cc(C(=O)CNC2CCCC2)cc(Br)c1N
Agent: Cl
Product: N#Cc1cc(C(O)CNC2CCCC2)cc(Br)c1N

Procedure:
m.p. of the hydrochloride: 177° C., was prepared from 4'-amino-3'-bromo-5'-cyano-2-cyclopentylamino-acetophenone analogous to Example 48.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([NH2:23])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)Cl.C(N(CC)CC)C.Cl[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>>[CH2:38]([O:37][C:35](=[O:36])[NH:23][C@@H:11]1[CH2:12][C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](N)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](NC(=O)OCc2ccccc2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 23 °C

Procedure:
To a solution of (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanamine (0.098 g, 0.00027 mol) in Methylene chloride (2.0 mL, 0.031 mol) at 0° C. was added triethylamine (0.076 mL, 0.00054 mol) and benzyl chloroformate (0.044 mL, 0.00031 mol). The reaction was warmed to 23° C. overnight. The reaction was quenched by addition of water3 and the mixture was extracted with methylene chloride (3×). The organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 8% EtOAc/hexanes) to obtain 73 mg (54%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)=[CH:6][C:5]2[C@@:17]3([CH2:28][O:29][C:4]=2[CH:3]=1)[C@H:22]([OH:23])[C@@H:21]([OH:24])[C@H:20]([OH:25])[C@@H:19]([CH2:26][OH:27])[O:18]3.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>N1C(C)=CC(C)=CC=1C.C(Cl)Cl>[C:31](=[O:32])([O:33][CH2:34][CH3:35])[O:27][CH2:26][C@H:19]1[O:18][C@@:17]2([C:5]3[CH:6]=[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=4)[C:2]([Cl:1])=[CH:3][C:4]=3[O:29][CH2:28]2)[C@H:22]([OH:23])[C@@H:21]([OH:24])[C@@H:20]1[OH:25]
Reactant: CCOC(=O)Cl
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)OC[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CCOC(=O)OC[C@H]1O[C@]2(COc3cc(Cl)c(Cc4ccc(CC)cc4)cc32)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.4 %

Procedure:
To a solution of 30 (12 mg, 28.5 μmol) in 2,4,6-collidine (100 μL) at −30° C. was added a solution of ethyl chloroformate (4 μL, 41.8 umol, 1.5 eq.) in DCM (100 μL). The mixture was kept at −30° C. for 1.5 hours, warmed to ambient temperature, and stirred overnight, after which additional ethylchloroformate (4 μL) was added. The reaction mixture was quenched with methanol, evaporated, and purified via HPLC to give 31 (7.5 mg, 53% yield). 1H NMR (300 MHz, CD3OD) δ 7.14 (s, 1H), 7.07 (s, 4H), 6.83 (s, 1H), 4.68 (d, J=10.2 Hz, 1H), 4.57 (d, J=10.5 Hz, 1H), 4.36 (dd, J=2.1, 11.4 Hz, 1H), 4.21 (dd, J=5.1, 11.4 Hz, 1H), 4.08 (q, J=7.2 Hz, 2H), 3.99 (s, 2H), 3.71 (d, J=9.6 Hz, 1H), 3.53-3.59 (m, 1H), 3.39 (t, J=8.7 Hz, 1H), 3.27-3.34 (m, 1H), 2.58 (q, J=7.5 Hz, 2H), 1.17-1.23 (m, 6H).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]1(C)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:22]([NH:30][C:31]1[CH:40]=[C:39]([OH:41])[CH:38]=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(O)CCCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C(OCC)(=O)C.O1CCCC1>[C:22]([NH:30][C:31]1[CH:40]=[C:39]([O:41][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:38]=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34])(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(O)cc1NC(=O)c1ccccc1
Reactant: Cc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: OC1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC2CCCCC2)cc1NC(=O)c1ccccc1
Reaction time: 5 h

Procedure:
0.20 mL of 40% diisopropyl azodicarboxylate /toluene was added dropwise to 1 mL of tetrahydrofuran solution containing 90 mg of methyl 2-(benzamido)-4-hydroxybenzoate, 0.035 mL of cyclohexanol and 0.10 g of triphenylphosphine at room temperature, and stirred at the same temperature for 5 hours. Ethyl acetate and 1.0 mol/L hydrochloric acid were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=10:1] to obtain 36 mg of methyl 2-(benzamido)-4-(cyclohexyloxy)benzoate as while solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[Br:11].[CH3:12]O.[OH-].[Na+]>Cl>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:12])=[O:9])=[CH:4][C:3]=1[Br:11]
Reactant: CO
Reactant: Nc1ncc(C(=O)O)cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cnc(N)c(Br)c1

Procedure:
6-Amino-5-bromopyridine-3-carboxylic acid (10 g, 50 mmol) is dissolved in saturated methanolic HCl (100 ml) and refluxed for 24 hours. The solvent, methanol, is re-moved under reduced pressure and the residue is dissolved in ice cold water. The aqueous solution is neutralized with 0.1N NaOH and the solid which separates is filtered; washed well with water and air dried to yield 10 g of product as a solid: mass spectrum 231 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2O.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)cc2c1O
Product: O=[N+]([O-])c1cnc2ccc(Cl)cc2c1Cl
Temperature: 0 °C

Procedure:
11 g (48.97 mmol) 6-chloro-3-nitro-quinolin-4-ol (Example 23b) in 80 ml POCl3 are heated and kept under reflux for 5 h (tlc-control). The cool reaction mixture is poured slowly into 1.5 l ice-water. The title compound separates as a solid. The mixture is stirred for 15 min. the temperature not exceeding 0-5° C. The solid is filtered off, washed with water and dissolved in 200 ml ethylacetate. The organic phase is washed with a mixture of 200 ml water and 38 ml 2N sodium hydroxide solution and again water. After drying over MgSO4, the solvent is evaporated almost to dryness; to the residue hexane is added and the product is isolated by filtration as a dark-grey powder. This material is used in the next step without further purification. mp: 118-120° C.; NMR (DMSO-d6): 9.43/s (1H); 8.43/d (1H), 8.25/d (1H), 8.10/d×d (1H); HPLC: tret=12.84 min (Grad 1).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18](I)[N:17]=2)=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25](C)[CH:26]=O>ClCCl>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18]([N:25]([CH3:26])[CH3:24])[N:17]=2)=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccccc1
Solvent: ClCCl
Product: Cc1nc(-c2cncc(N(C)C)n2)sc1C(=O)NCc1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To a sealed tube was added 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid benzylamide (See Example 2, 50 mg, 0.11 mmol, 1.0 equiv) and dimethyl formamide (1 mL). The reaction mixture was stirred at 100° C. After 18 hr, the reaction mixture was cooled to room temperature and diluted with dichloromethane washed with saturated NaHCO3, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (acetonitrile/water, 0.1% trifluoroacetic acid) to afford 2-(6-dimethylamino-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid benzylamide (32 mg, 80%). 1H NMR (400 MHz, CD2Cl2) δ 8.51 (s, 1H), 8.06 (s, 1H), 7.29-7.36 (m, 5H), 6.21 (bs, 1H), 4.59 (d, J=8.0 Hz, 2H), 3.17 (s, 6H), 2.71 (s, 3H); HRMS (M+H)+=354.13.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH2:13][C:14](O)=[O:15].B(F)(F)F.C(=O)([O-])O.[Na+]>C(Cl)Cl.O.O1CCCC1>[Cl:3][C:4]1[C:5]([CH2:13][CH2:14][OH:15])=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)Cc1c(Cl)cccc1[N+](=O)[O-]
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cccc(Cl)c1CCO
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
2.26 g (59.8 mmol) of sodium borohydride was added to 7 ml of tetrahydrofuran, and while cooling on ice, 15 ml of tetrahydrofuran solution containing 6.78 g (31.5 mmol) of the compound (137) obtained above was dropped to the solution through 20 minutes. Then, 15 ml of tetrahydrofuran solution containing 10 ml of borontrifluoride--ether complex was dropped to the solution through 10 minutes, and after stirring for 30 minutes as was, the solution was stirred for 1 hour at room temperature. To 130 ml of water containing 9.6 g of sodium hydrogen carbonate and 170 ml of methylene chloride, the reaction solution was added slowly, and the obtained solution was stirred overnight at room temperature. The organic layer was separated, and after drying over magnesium sulfate, the solvent was removed by distillation. To the residue, n-hexane was added to crystallize, and the crystals were filtered off and washed with n-hexane to obtain 5.43 g of the subject compound (138) in a 86% yield.
Reaction SMILES: [CH3:1][OH:2].C[O-].[Na+].[Br:6][C:7]1[CH:8]=[CH:9][C:10](Cl)=[N:11][CH:12]=1.O>CO>[CH3:1][O:2][C:10]1[CH:9]=[CH:8][C:7]([Br:6])=[CH:12][N:11]=1
Reactant: Clc1ccc(Br)cn1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(Br)cn1
Temperature: 90 °C
Reaction time: 24 h
Yield: 32.9 %

Procedure:
A 0.5 M sodium methoxide methanol solution (NaOMe in MeOH, 10.4 mL, 5.19 mmol) was added to 5-bromo-2-chloropyridine (96, 500 mg, 2.59 mmol) dissolved in methanol (10 mL) at room temperature, stirred at 90° C. for 24 hours, followed by adding water. Organic compounds were extracted with ethyl acetate and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 2-methoxy-5-bromopyridine (97a, 160 mg, 33%).
Reaction SMILES: [CH2:1]([N:6]1[C:10](=[O:11])[CH:9]([CH2:12][C:13]([OH:15])=[O:14])[S:8][CH:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH3:22][CH2:23]O>OS(O)(=O)=O>[CH2:1]([N:6]1[C:10](=[O:11])[CH:9]([CH2:12][C:13]([O:15][CH2:22][CH3:23])=[O:14])[S:8][CH:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CCO
Reactant: CC(C)CCN1C(=O)C(CC(=O)O)SC1c1ccccc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC1SC(c2ccccc2)N(CCC(C)C)C1=O

Procedure:
A solution of 2-(3-Isopentyl-4-oxo-2-phenylthiazolidin-5-yl)acetic acid (2.2 g, 7.2 mmol) in EtOH (20 ml) and H2SO4 (1 ml) was refluxed for 16 hours. The solution was evaporated to dryness and the residue was taken up in EtOAc and washed with sat. aq. Na2CO3 (3×), brine and evaporated to give the desired product as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)C.C(COC)OC.O>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Brc1ccccn1
Reactant: COc1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: CCOCC
Solvent: O
Product: COc1ccccc1-c1ccccn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.7 %

Procedure:
2-Bromopyridine (4.28 mL, 43.9 mmol), 2-methoxyphenylboronic acid (6.7 g, 43.9 mmol), palladium acetate (0.14 g, 0.62 mmol), triphenylphosphine (0.6 mg, 2.3 mmol) and potassium phosphate (9.40 g, 44.3 mmol) were added to a flask. A mixture solution of 10 mL of water and 40 mL of dimethoxyethane was added and reflux was performed for 6 hours. After cooling to room temperature, aqueous ammonium chloride solution (50 mL) and diethyl ether (100 mL) were added. The organic layer was separated. After extracting the residue using diethyl ether, the collected organic layer was dried with magnesium sulfate. After removing volatile materials, followed by purification via silica gel chromatography using n-hexane, 7.7 g (yield: 95%) of 2-(2′-methoxyphenyl)pyridine was obtained as colorless liquid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=2)[NH:15][CH:14]=1)=O)C>C1COCC1>[F:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:11][CH2:10][OH:9]
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccc(F)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1c[nH]c2ccc(F)cc12
Temperature: 0 °C
Yield: 97.9 %

Procedure:
To a suspension of LiAlH4 (8.60 g, 0.23 mol) in 400 mL of dry THF was added 5-fluoro-3-indoleglyoxylic acid ethyl ester (13.50 g, 0.057 mol) portionwise at room temperature. Preparation of this ester intermediate is given hereinbelow. The mixture was heated to reflux under Ar for 1 h and was then cooled at 0° C. and quenched according to the method of Fieser (Fieser and Fieser, "Reagents for Organic Synthesis", Vol. 1, pg. 584). The resulting slurry was filtered and the filter cake was washed with THF. The filtrate was dried (Na2SO4) and evaporated to give the product (10.00 g, 100%) as a yellow oil. It was used as such without further purification;
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[C:6]([NH:8][C:9]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])=O)[CH3:2]>ClCCl.CO.[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[C:6]1[NH:13][C:11](=[O:12])[C:10]2[C:9](=[C:17]([CH3:18])[CH:16]=[CH:15][CH:14]=2)[N:8]=1)[CH3:2]
Reactant: CCOc1ccccc1C(=O)Nc1c(C)cccc1C(N)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CO
Solvent: ClCCl
Product: CCOc1ccccc1-c1nc2c(C)cccc2c(=O)[nH]1
Temperature: 210 °C
Yield: 40.4 %

Procedure:
A mixture of 2-(2-ethoxybenzamido)-3-methylbenzamide (1.6 g, 0.0053 mol) and anhydrous zinc chloride (2.29 g, 0.016 mol) was heated at 210° C. for 5 minutes, then allowed to cool. The residue was dissolved in dichloromethane-methanol (90:10, 200 ml) and this solution washed with an aqueous solution of ethylenediamine tetraacetic acid disodium salt (12 g in 400 ml of water). The aqueous phase was then extracted with a mixture of dichloromethane-methanol (90:10, 2×50 ml) and the organic solutions combined, dried (Na2SO4) and evaporated under vacuum. The residue crystallized from ethanol to give the title compound as colorless needles (0.6 g, 40%), m.p. 177°-180° C. Found: C,72.94; H,5.76; N,9.98. C17H20N2O2 requires C,72.83; H,5.75; N,10.00%.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8](C(OCC)OCC)[C:7](=[O:19])[CH:6]2[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH2:33][CH2:34][O:35][CH3:36])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][N:21]=1>C(O)C>[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:19])[CH:6]2[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH2:33][CH2:34][O:35][CH3:36])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][N:21]=1
Reactant: CCOC(OCC)N1C(=O)C(c2ncnc3cc(OCCOC)c(OC)cc23)c2cc(Br)ccc21
Agent: Cl
Solvent: CCO
Product: COCCOc1cc2ncnc(C3C(=O)Nc4ccc(Br)cc43)c2cc1OC

Procedure:
2M Hydrochloric acid (2.75 ml, 5.5 mmol) was added to a solution of 4-(5-bromo-1-diethoxymethyloxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline (300 mg, 0.55 mmol) in ethanol (20 ml) at 90° C. The mixture was heated for 1 hour, the solid product was collected by filtration and purified on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluting with acetonitrile (using a gradient of 0 to 100%) in hydrochloric acid (pH2). Concentration of the fractions by evaporation gave a precipitate which was collected by filtration, washed with water to give a solid which was purified again by column flash chromatography using an increasingly polar mixture of methylene chloride/methanol (95/5 to 80/20) as eluent. After evaporation of the solvent, the resulting solid was dissolved in a minimum volume of methanol and a 2.9M solution of hydrogen chloride in ether was added to the solution. The solid was collected by filtration, washed with ether and dried under vacuum to give 4-(5-bromooxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline as a hydrochloride salt (74 mg, 30%) as an orange solid.