Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[C:11]([F:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]([F:34])([F:33])[O:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:22][CH:21]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:28]2[CH2:29][CH2:30][CH:25]([O:24][C:23]3[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:33])[F:34])=[CH:32][CH:31]=3)[CH2:26][CH2:27]2)=[C:11]([F:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(OCc2ccccc2)ccc1Br
Reactant: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Fc1cc(OCc2ccccc2)ccc1N1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1
Yield: 70.9 %

Procedure:
4-Benzyloxy-1-bromo-2-fluorobenzene (3.55 g, 12.6 mmol), 4-(4-trifluoromethoxyphenoxy)piperidine (3.0 g, 11.5 mmol), sodium tert-butoxide (1.55 g, 16.1 mmol) and toluene (60 ml) were mixed. Palladium acetate (0.10 g, 0.46 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.57 g, 0.92 mmol) were added thereto. The mixture was heated and refluxed under a nitrogen atmosphere for 4 hours. A saturated ammonium chloride aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=80:20→60:40), and the resulting crude crystal was washed with hexane-diethylether to afford the title compound as a white powder (3.76 g, yield 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([NH2:22])[CH2:19]2)=[N:14]1.[C:23]1([CH2:29][CH2:30][CH:31]=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O>ClC(Cl)C.C(O)(=O)C>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([NH:22][CH2:31][CH2:30][CH2:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19]2)=[N:14]1
Reactant: O=CCCc1ccccc1
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCC(N)C4)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(Cl)Cl
Product: COc1ccc2nccc(-n3cc4c(n3)CCC(NCCCc3ccccc3)C4)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
To a stirring solution of 2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine (50 mg, 0.17 mmol) and 3-phenylpropionaldehyde (20 mg, 0.2 mmol) in dichloroethane (2 mL) was added NaB(OAc)3H (37 mg, 0.17 mmol) and acetic acid (2 drops). The reaction mixture was stirred overnight at RT. Water (5 mL) was added, and the aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined organic layers were washed with brine (10 mL), dried (MgSO4), filtered, and concentrated. The crude material was purified on SiO2 (0-5% CH3OH/CH2Cl2) to give 24 mg (36%) of the title compound as a clear oil. MS (ESI): exact mass calculated for C25H27N5O, 413.22; m/z found, 414.5 [M+H]+. 1H NMR (400 MHz, CDCl3): 9.07 (s, 1H), 8.72-8.70 (m, 1H), 8.25-8.23 (m, 1H), 8.08-8.07 (m, 1H), 7.30-7.21 (m, 5H), 7.18-7.16 (m, 1H), 4.09 (s, 3H), 3.06-2.90 (m, 3H), 2.80-2.68 (m, 5H), 2.46-2.40 (m, 1H), 2.19-2.16 (m, 1H), 1.93-1.86 (m, 2H), 1.77-1.67 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C[O:11][C:12]1[CH:17]=CC=C[C:13]=1C=CC(=O)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:13][C:12](=[O:11])[CH3:17])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(F)c1
Reactant: COc1ccccc1C=CC(C)=O
Product: CC(=O)C=Cc1cccc(F)c1

Procedure:
The title compound was prepared from 3-fluoro-benzaldehyde (4.8 g, 40.0 mmol), following the procedure describing the synthesis of 4-(2-methoxy-phenyl)-but-3-en-2-one (example 1/a stage 1).
Reaction SMILES: [C:1]12([NH2:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:12]([CH2:15][P:16](=[O:21])([O:19]C)[O:17]C)(O)=[O:13].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]12([NH:11][C:12]([CH2:15][P:16](=[O:17])([OH:21])[OH:19])=[O:13])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: COP(=O)(CC(=O)O)OC
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CP(=O)(O)O)NC12CC3CC(CC(C3)C1)C2

Procedure:
Adamantylamine (0.045 mole) and dimethyl (carboxymethyl)phosphonate (0.04 mole) were dissolved in 100 ml. of methylene chloride. As the solution was stirred, dicyclohexylcarbodiimide was added portionwise. The solution was stirred overnight, and the mixture filtered. The filtrate was concentrated to a solid. It was recrystallized from an appropriate solvent such as methanol. m.p. 190°-4° C.; yield, 32%.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[CH:9])[CH3:5])[CH3:2].C([Li])CCC.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][CH:21]([C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)[OH:22])[CH3:5])[CH3:2]
Reactant: COc1ccc(C=O)cc1
Reactant: C#CCOC(C)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(C)OCC#CC(O)c1ccc(OC)cc1
Reaction time: 0.5 h

Procedure:
A solution of 6 g (47 mmol) of 1-(1-ethoxyethoxy)-2-propyne in 100 ml of tetrahydrofuran was treated at -78° under argon with 29.2 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -40° for 30 minutes and then a solution of 5.7 ml (47 mmol) of 4-methoxybenzaldehyde in 41 ml of tetrahydrofuran was added within 10 minutes. The reaction mixture was warmed to 0°, stirred at 0° for a further 1 hour and then treated with 80 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed in succession with saturated sodium chloride solution and with water dried over magnesium sulphate and concentrated. The residue was purified by flash chromatography on 500 g of silica gel (elution agent ether/hexane 1:1). There was obtained 4-(1-ethoxyethoxy)-1-(4-methoxyphenyl)-2-butyn-1-ol as an oil.
Reaction SMILES: O=[C:2]1[C:15]2[C:14]([C:16]([OH:18])=[O:17])=[CH:13][CH:12]=[CH:11][C:10]=2[C:9](=O)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2>[Zn].[NH4+].[OH-]>[C:14]1([C:16]([OH:18])=[O:17])[C:15]2[C:10](=[CH:9][C:8]3[C:3]([CH:2]=2)=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1cccc2c1C(=O)c1ccccc1C2=O
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Product: O=C(O)c1cccc2cc3ccccc3cc12
Reaction time: 3.5 h

Procedure:
To a 5 L 3-neck flask fitted with condenser, thermometer, and overhead stirrer was added 9,10-dihydro-9,10-dioxo-1-anthracenecarboxylic acid (90 g, 0.357 mol), Zn dust (Mallinckrodt, 250 g, 3.82 mol), CuSO4.5H2O (Mallinckrodt, 5 g), and 28% NH4OH (Mallinckrodt, 2500 mL). The mixture was heated slowly until a dark-red solution occurred as the temperature reached 85°. After 3.5 h the color of the solution faded to yellow. The reaction was heated an additional 1 h, and then cooled and the excess Zn filtered. The filter cake was washed with more NH4OH (100 mL) and then discarded. The filtrate was carefully acidified to pH 1 with conc. HCl added in portions over 1 h affording a light-green precipitate which was separated by filtration. The solid was washed with H2O (200 mL) and then recrystallized once from methoxyethanol/H2O (with a small amount of HCl) to give 65 g (82%) filtered, and dried at 75° of 1-anthracenecarboxylic acid mp 249°-250°, (C, H), (lit. mp 245°, Chemistry of Carbon Compounds IIIb, edited by E. H. Rodd, 1373 (1956), Elsevier, N.Y.).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])=[O:4].C1COCC1.[OH-].[Na+]>CO>[CH2:22]([N:10]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)(=[O:13])=[O:12])[C:9]1[CH:8]=[CH:7][S:6][C:5]=1[C:3]([OH:4])=[O:2])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1sccc1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2ccsc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 91.8 %

Procedure:
To a mixture of 1.494 g (3.583 mmol) of the product of Example 5 dissolved in 15 mL of methanol and 15 mL of THF was added 15 mL of 1N NaOH solution. The reaction mixture was stirred at room temperature for 36 h and the organics were removed in vacuo. The resulting mixture was acidified with 10% HCl and extracted with EtOAc. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was triturated with ether and filtered to provide 1.327 g (92%) of the desired carboxylic acid as a white solid. CI Mass Spec: 404 (M+H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:11][C:12]1[CH:43]=[CH:42][C:15]([C:16]([C:18]2[O:19][C:20]3[C:27]([Cl:28])=[CH:26][C:25]([CH2:29][CH2:30][CH3:31])=[C:24]([O:32]C(=O)C4C=CC(Cl)=CC=4)[C:21]=3[C:22]=2[CH3:23])=O)=[CH:14][CH:13]=1>CCOCC>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][C:18]2[O:19][C:20]3[C:27]([Cl:28])=[CH:26][C:25]([CH2:29][CH2:30][CH3:31])=[C:24]([OH:32])[C:21]=3[C:22]=2[CH3:23])=[CH:42][CH:43]=1
Reactant: CCCc1cc(Cl)c2oc(C(=O)c3ccc(Cl)cc3)c(C)c2c1OC(=O)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: CCCc1cc(Cl)c2oc(Cc3ccc(Cl)cc3)c(C)c2c1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 18.7 %

Procedure:
To an ice-cold suspension of aluminium chloride (2.1 gm, 16 mmoles) in ether (300 mL) was added slowly lithium aluminium hydride (2.6 gm, 68 mmoles). After stirring for a period of 10 minutes, 2-(p-chlorobenzoyl)-3-methyl-4-(p-chlorobenzoyloxy)-5-propyl-7-chlorobenzofuran (2.3 gm, 4.6 mmoles) in ether (10 mL) was added over a period of 2 minutes. The reaction mixture was stirred at room temperature for 15 minutes. It was cooled with an ice bath and ice was added slowly. When the vigorous reaction subsided, the organic layer was separated and the aqueous phase was extracted with ether. The organic phases were combined, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel. Elution with 15% ethylacetate in hexane yielded 0.30 gm (87%) of 2-(p-chlorobenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran, mp.76°-77° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[CH2:13]([O:15][C:16](=[O:41])[C:17]([O:36][CH2:37][CH2:38][CH2:39][CH3:40])([CH3:35])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH:28]2[CH2:32][NH:31][C:30](=[O:33])[N:29]2[CH3:34])=[CH:21][CH:20]=1)[CH3:14].[H-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH2:13]([O:15][C:16](=[O:41])[C:17]([O:36][CH2:37][CH2:38][CH2:39][CH3:40])([CH3:35])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH:28]2[CH2:32][N:31]([CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=3)[C:30](=[O:33])[N:29]2[CH3:34])=[CH:23][CH:24]=1)[CH3:14]
Reactant: CCCCOC(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)C(=O)OCC
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Product: CCCCOC(C)(Cc1ccc(OCCC2CN(Cc3cccc(C(F)(F)F)c3)C(=O)N2C)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Trifluoromethylbenzyl bromide (0.037 g, 0.157 mmol) and tetrabutyl ammonium iodide (catalytic amount) are added to a 0° C. suspension of 2-Butoxy-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester (0.043 g, 0.105 mmol) and sodium hydride (0.010 g, 0.26 mmol, 60% suspension on mineral oil), pre-stirred for 1 h at ambient temperature. The reaction mixture is stirred at ambient temperature for 48 h, diluted with ethyl acetate, and washed with 1N HCl and water. The organic layer is dried over MgSO4, concentrated in vacuo, and used in the next step. MS [EI+] 565 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]3[CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[S:16][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=1[N:32]=[C:33]=[O:34].O>C1COCC1>[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=1[NH:32][C:33]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]3[CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[S:16][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1)=[O:34]
Reactant: COC(=O)c1cc(-c2cc(Oc3ccc(N)cc3)ccn2)cs1
Reactant: Cc1ccc(F)c(N=C=O)c1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 4-[4-(4-aminophenoxy)pyridin-2-yl]thiophene-2-carboxylate (500 mg, 1.53 mmol) in anhydrous THF (10 ml) was added 2-fluoro-5-methyl-phenylisocyanate (255 mg, 1.68 mmol). The mixture was stirred at room temperature for one hour and poured into 200 ml of water. The resulting precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3-5% MeOH/CHCl3 to give methyl 4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}thiophene-2-carboxylate as off-white solid. Yield: 560 mg, 76%.
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][C:8](I)=[CH:9][CH:10]=2)[C:5](=[O:13])[C:4]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:15])=[CH:3]1.[CH2:25]([OH:28])[C:26]#[CH:27]>C(NCC)C.C(O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:27]#[C:26][CH2:25][OH:28])=[CH:9][CH:10]=2)[C:5](=[O:13])[C:4]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:15])=[CH:3]1
Reactant: C#CCO
Reactant: Nn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CCNCC
Product: Nn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Amino-N-(4-chlorobenzyl)-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.25 g) from Preparation No. 57, copper (I) iodide (32 mg), and bis(triphenylphosphine)palladium (II) chloride (19 mg) are suspended in diethylamine (8 mL). Propargyl alcohol (39 μL) is added and the mixture is allowed to stir at room temperature for 16 h. The mixture is diluted with ethanol and then concentrated in vacuo. The crude solid is triturated with dichloromethane and recrystallized in acetic acid to affording 76 mg of the title compound as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:10]=[CH:9][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[C:13]=3[CH2:12]2)=[CH:7][C:4]=1[C:5]#[N:6].C(N(CC)CC)C.[C:34](Cl)(=[O:37])[O:35][CH3:36]>C(Cl)Cl>[CH3:36][O:35][C:34]([N:22]1[CH2:23][CH2:24][C@H:20]([O:19][C:18]2[C:13]3[CH2:12][N:11]([C:8]4[CH:9]=[N:10][C:3]([O:2][CH3:1])=[C:4]([C:5]#[N:6])[CH:7]=4)[CH2:26][CH2:25][C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:21]1)=[O:37]
Reactant: COC(=O)Cl
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CC[C@H](Oc2ncnc3c2CN(c2cnc(OC)c(C#N)c2)CC3)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.3 %

Procedure:
To a solution of 2-methoxy-5-[4-((S)-pyrrolidin-3-yloxy)-7,8-dihydro-5H-pyrido[4,3-d]py rimidin-6-yl]-nicotinonitrile (prepared using intermediate 11 and method 1b, process step 2, example 1) (25.0 mg, 0.071 mmol) and triethylamine (0.04 mL, 0.29 mmol) in CH2Cl2 (2 mL) was added methyl carbonochloridate (0.006 mL, 0.078 mmol) and the mixture stirred at room temperature for 18 h. Diluted with CH2Cl2 (2 mL) and washed with sat. NaHCO3(aq) (1 mL). The organic layer was filtered through a phase separation tube and evaporated in vacuo. Purification was performed by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions by elution through an Isolute® SCX-2 cartridge, eluting with methanol, then with 2M ammonia in methanol. Basic fractions were concentrated in vacuo gave (S)-3-[6-(5-cyano-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid methyl ester (10 mg, 35% yield) as a yellow powder. 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.09-2.31 (m, 2H) 2.91 (t, 2H) 3.45-3.75 (m, 9H) 3.93 (s, 3H) 4.17 (s, 2H) 5.58-5.65 (m, 1H) 8.09 (d, 1H) 8.27 (d, 1H) 8.61 (s, 1H) LCMS: [M+H]+=411.1, Rt(1)=1.58 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:14])=[N:7][S:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11])=[O:4].C(=O)([O-])[O-].[K+].[K+].[Br:21][C:22]1[CH:39]=[C:38]([F:40])[C:25]([CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)=[C:24]([F:41])[CH:23]=1.ClCCl.ClCCl>CS(C)=O.CCOC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([O:14][CH2:26][C:25]2[C:38]([F:40])=[CH:39][C:22]([Br:21])=[CH:23][C:24]=2[F:41])=[N:7][S:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11])=[O:4]
Reactant: COC(=O)c1c(O)nsc1S(C)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)OCc2c(F)cc(Br)cc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1c(OCc2c(F)cc(Br)cc2F)nsc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 70 %

Procedure:
In a separate vessel, 3-Hydroxy-5-methanesulfonyl-isothiazole-4-carboxylic acid methyl ester (1.00 equiv, 18.5 g) was taken up in dimethylsulfoxide (185 mL, 10 volumes) and potassium carbonate (1.0 equiv, 10.8 g) was added. The toluene-4-sulfonic acid 4-bromo-2,6-difluoro-benzyl ester/dichloromethane solution from Example 6 was added to the 3-Hydroxy-5-methanesulfonyl-isothiazole-4-carboxylic acid methyl/potassium carbonate/dimethylsulfoxide slurry dropwise over 1 hour. The mixture was stirred at 25° C. for 16.5 hours. Dichloromethane (185 mL, 10 volumes) then water (185 mL, 10 volumes) were added and the layers were separated. The organic layer was dried over magnesium sulfate and filtered. The dichloromethane was removed under vacuum to leave an orange paste. The orange paste was diluted with 10 volumes of 1:1 EtOAc:Hexanes (v/v) and slurried at 25° C. for 16 hours. The mixture was filtered and the filter cake washed with 55-60 mL of 1:1 EtOAc:Hexanes (v/v) and dried to give 24.22 g of 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-methanesulfonyl-isothiazole-4-carboxylic acid methyl ester (70% yield). 1H NMR: (DMSO-d6) δ 7.57 (m, 2H); 5.46 (s, 2H); 3.80 (s, 3H); 3.57 (s, 3H). MS (API-ES pos): 442/444 (M+H)+; 205/207 (1,5-difluoro-3-bromotropylium ion), base.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][OH:13])=[CH:9][CH:8]=[CH:7]2>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=[O:13])=[CH:9][CH:8]=[CH:7]2
Reactant: Cc1cccc2cccc(CO)c12
Solvent: ClCCl
Product: Cc1cccc2cccc(C=O)c12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 1-L 4-neck equipped with an overhead stirrer, a condenser and a thermocouple was charged with 8-methyl-1-napthalenemethanol (18.5 g, 0.107 mol) in CH2Cl2 (500 mL) and stirred at room temperature under N2. Solid Mn(IV)O2 (61 g, 0.7 mol) was carefully added and the reaction was stirred at room temperature for 3 h, then at 40° C. for 6 h and then at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (500 mL), filtered and the filtrate was washed with 1N HCl and then dried over MgSO4. The resulting crude material was purified using silica gel chromatography. (8/2 hexane/ethyl acetate) to yield 8-methyl-naphthalene-1-carbaldehyde as a solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:12]([OH:14])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:49][C:50]1[S:51][CH:52]=[CH:53][N:54]=1.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:12]([NH:49][C:50]2[S:51][CH:52]=[CH:53][N:54]=2)=[O:14])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCCO2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCCO2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
A solution of 2-(4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (60 mg, 0.19 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluoro-phosphate (127 mg, 0.29 mmol), and 2-aminothiazole (28 mg, 0.29 mmol) in methylene chloride (5 mL) at 25° C. was treated with triethylamine (0.08 mL, 0.58 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water (10 mL) and extracted with methylene chloride 3×15 mL). The combined organic layers were sequentially washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a saturated sodium chloride solution (1×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 20/80 hexanes/ethyl acetate) afforded 2-(4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-2-yl)-N-thiazol-2-yl-propionamide (54 mg, 71%) as a colorless oil: EI-HRMS m/e calcd for C18H22N2O4S2 (M+) 394.1021. found 394.1021.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[O:28])[CH:22]=[CH:23][C:24]=1[F:25].CCCCCC.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:27]([NH:26][C:21]4[CH:22]=[CH:23][C:24]([F:25])=[C:19]([F:18])[CH:20]=4)=[O:28])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)c(F)c1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)c(F)c1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (0.16 g, 0.65 mmol) and 3,4-difluorophenyl isocyanate (76 μL, 0.65 mmol) in THF (10 mL) are reacted according to method C yielding the title product as a colorless foam after column chromatography with hexane-EtOAc.