Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:5]1[C:21]([O:22][CH2:23][C@@H:24]([N:29]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:20][C:8]2[N:9]([CH3:19])[C:10](=[O:18])[C:11]3[C:16]([C:7]=2[CH:6]=1)=[CH:15][CH:14]=[N:13][C:12]=3[CH3:17])([CH3:4])[CH3:3].NN>C(O)C>[NH2:29][C@@H:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][O:22][C:21]1[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])=[CH:6][C:7]2[C:16]3[C:11](=[C:12]([CH3:17])[N:13]=[CH:14][CH:15]=3)[C:10](=[O:18])[N:9]([CH3:19])[C:8]=2[CH:20]=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)N3C(=O)c4ccccc4C3=O)c(C(C)(C)O)cc21
Agent: NN
Solvent: CCO
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@@H](N)CC(C)C)c(C(C)(C)O)cc21
Temperature: 60 °C
Yield: 13.8 %

Procedure:
To a solution of (S)-2-(1-((9-(2-hydroxypropan-2-yl)-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)isoindoline-1,3-dione (200 mg, 0.152 mmol) in ethanol (5 mL), was added hydrazine (4.76 μl, 0.152 mmol) at RT then the mixture was heated to 60° C. for 4 h. The reaction mixture was filtered, concentrated and purified by prep. HPLC to afford (S)-8-((2-amino-4-methylpentyl)oxy)-9-(2-hydroxypropan-2-yl)-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one as white solid (9 mg, 0.021 mmol, 14% yield). LC/MS (ESI) m/e 398.0 [(M+H)+, calcd for C23H32N3O3 398.2]; LC/MS retention time (method G): tR=1.99 min. HPLC retention time (method A): tR=8.63 min; HPLC retention time (method B): tR=9.79 min. 1H NMR (400 MHz, METHANOL-d4) ppm 0.94-1.10 (m, 6H), 1.25-1.37 (m, 1H), 1.49-1.78 (m, 7H), 1.82-1.93 (m, 1H), 2.96-3.19 (m, 2H), 3.56-3.65 (m, 1H), 3.80 (s, 3H), 4.16-4.29 (m, 1H), 4.34-4.49 (m, 1H), 7.01-7.15 (m, 1H), 8.10-8.22 (m, 1H), 8.51-8.64 (m, 2H).
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].[C:12](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O.C(OCC)(=O)C>[CH:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCC(C)c1ccc(O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCC(C)c1ccc(OC)cc1
Reaction time: 0.5 h

Procedure:
2 g 4-sec-butyl-phenol are dissolved in 15 ml N,N-dimethylformamide, combined with 2.2 g potassium carbonate, stirred for 30 minutes and then combined with 830 μl methyl iodide. The mixture is stirred for 12 hours and then a further 600 mg potassium carbonate and 300 μl methyl iodide are added. After stirring for 3 hours the mixture is divided between water and ethyl acetate and the organic phase is washed with saturated aqueous sodium chloride solution. It is dried with magnesium sulphate and the solvents are eliminated in vacuo. The product thus obtained is further reacted directly.
Reaction SMILES: [F:1][CH:2]([F:39])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)=[CH:20][CH:19]=3)=[O:16])[N:12]([CH2:37][CH3:38])[N:11]=2)[CH:7]=[CH:8][CH:9]=1.[ClH:40].C(OCC)C>O1CCOCC1>[ClH:40].[F:39][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[C:13]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C@@H:24]4[O:29][CH2:28][CH2:27][NH:26][CH2:25]4)=[CH:22][CH:23]=3)=[O:16])[N:12]([CH2:37][CH3:38])[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCn1nc(-c2cccc(OC(F)F)c2)cc1C(=O)Nc1ccc([C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCn1nc(-c2cccc(OC(F)F)c2)cc1C(=O)Nc1ccc([C@H]2CNCCO2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of (S)-tert-butyl 2-(4-(3-(3-(difluoromethoxy)phenyl)-1-ethyl-1H-pyrazole-5-carboxamido)phenyl)morpholine-4-carboxylate (27 mg) (prepared in Example 41, b)) in Dioxane (40.8 μl) was added 4M−HCl in dioxane (117 μl, 470 μmol, Eq: 15). The reaction mixture was stirred at 60° C. overnight. To the mixture was added 2 ml of diethyl ether and stirred for 15 min at room temp. The mixture was filtered and concentrated in high vacuum to give the expected hydrochloride as a white solid (15 mg, 63%). MS (ISP): 443.1 ([M+H]+).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OCC(C)C)=O.CN1CCOCC1.[Br:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([NH2:45])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1>O1CCCC1.N1C=CC=CC=1>[Br:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([NH:45][C:9](=[O:11])[C:8]#[C:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)C#Cc1ccccc1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(C#Cc1ccccc1)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Yield: 0.7 %

Procedure:
A solution of 0.93 g of 3-phenyl-2-propynoic acid in 10 ml of tetrahydrofuran was cooled in an ice bath. A 0.82 ml portion of isobutyl chloroformate followed by a 0.69 ml portion of N-methyl morpholine were added. After about 1 minute a solution of 1.0 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 7 ml of pyridine was added. The reaction at 0° C. for 1 hr. The solvents were removed at reduced pressure and the solid was purified by chromatography on silica gel to give 0.01 g of N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-(3-phenyl-2-propynamide): mass spectrum (m/e): 443.2, 445.2 (M+H, electrospray).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:10])=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.CN(C=O)C.Cl[CH2:17][C:18](=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21].C([O-])([O-])=O.[K+].[K+]>O>[CH3:1][O:2][C:3]1[C:4]([CH3:10])=[C:5]([S:9][CH2:17][C:18](=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: COc1cccc(S)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(=O)CSc1cccc(OC)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-methoxy-2-methylbenzenethiol (2.52 g) and DMF (dry) (10 mL) were added methyl 4-chloroacetoacetate (2.114 mL) and K2CO3 (2.60 g) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (3.65 g).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH:3]1[O:5][CH2:4]1.[OH:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[OH:5][CH:3]([C:2]([CH3:7])([CH3:6])[CH3:1])[CH2:4][O:8][N:9]1[C:13](=[O:14])[C:12]2[C:11](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]1=[O:19]
Reactant: CC(C)(C)C1CO1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)C(O)CON1C(=O)c2ccccc2C1=O
Temperature: 75 °C
Yield: 13.9 %

Procedure:
To a solution of 3,3-dimethyl-1,2-epoxybutane (5.0 mL, 41.0 mmol) in DMF (100 mL) was added N-hydroxyphthalimide (8.03 g, 49.2 mmol) and triethylamine (6.90 mL, 49.2 mmol). The solution was heated at 75° C. for two days. The solution was cooled to room temperature, diluted with ethyl acetate and washed with water (2×), saturated potassium carbonate (3×), brine (2×), dried over Na2SO4 and concentrated to an orange solid. Purification using flash column chromatography (dichloromethane) provided the desired product as a white solid (1.50 g, 14%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][CH2:12][C:13](O)=[O:14])=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCOCC(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(CCOCCO)cc1
Yield: 96 %

Procedure:
The 2-(4-methoxyphenyl)ethoxyacetic acid obtained according to the preceding paragraph was reduced with lithium aluminum hydride in a manner analogous to that described in Example 1(b) to give 5.4 g (96%) of 2-[2-(4-methoxyphenyl)ethoxy]ethanol in the form of an oil which was homogeneous according to chromatography.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=1>Cl>[CH2:13]([CH:12]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH3:11])[N:7]=1)[C:3]([OH:17])=[O:2])[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)c1cc(C(=O)OC)cc(OC)n1
Agent: Cl
Product: CCC(CC)c1cc(C(=O)O)cc(OC)n1
Yield: 180.2 %

Procedure:
A solution of 2-(1-ethyl-propyl)-6-methoxy-isonicotinic acid methyl ester (1.17 g, 4.97 mmol) in 25% aq. HCl (25 mL) is stirred at 70° C. for 16 h. The solvent is evaporated and the residue is dried under HV to give the title compound (2.00 g) as a yellow solid; LC-MS: tR=0.94 min; [M+1]+=224.01.
Reaction SMILES: [C:1]1([CH:7]([OH:18])[C:8]#[C:9][CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)Cl>[C:1]1([C:7](=[O:18])[C:8]#[C:9][CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(C#CCOC1CCCCO1)c1ccccc1
Solvent: ClCCl
Product: O=C(C#CCOC1CCCCO1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a solution of 1-phenyl-4-(tetrahydro-2H-pyran-2-yloxy)but-2-yn-1-ol (3.0 g, 12.2 mmol) in DCM (50 mL) was added DMP (10.0 g, 24.4 mmol). The resulting solution was stirred for 30 min at room temperature and then the reaction mixture was poured into NaHCO3/NaS2O3 solution and stirred for overnight, extracted with DCM (3×150 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (3% ethyl acetate in petroleum ether) to afford 1-phenyl-4-(tetrahydro-2H-pyran-2-yloxy)but-2-yn-1-one as a light yellow oil (2.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.C(N(CC)C(C)C)(C)C.[C:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:24])[CH3:23]>ClCCl>[C:22]([N:25]1[CH2:30][CH2:29][N:28]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([Cl:1])[N:3]=2)[CH2:27][CH2:26]1)(=[O:24])[CH3:23]
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Reactant: CC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc(C(F)(F)F)c(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 13.3 %

Procedure:
To a solution of 2,6-dichloro-3-(trifluoromethyl)pyridine (2.38 g, 11.0 mmol) in anhydrous dichloromethane (20 ml) was added dropwise N,N-diisopropylethylamine (3.7 ml, 225 mmol). A solution of 1-acetylpiperazine (1.69 g, 13.2 mmol) in anhydrous dichloromethane (10 ml) was added dropwise at 0° C., and the mixture was stirred at room temperature for 5 hrs. The mixture was warmed, heated under reflux for 2.5 hrs, and stirred at room temperature for 14 hrs. The reaction mixture was diluted with dichloromethane and washed with water. The aqueous layer was extracted twice with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4→ethyl acetate→ethanol:ethyl acetate=1:20) to give 1-acetyl-4-[6-chloro-5-(trifluoromethyl)pyridin-2-yl]piperazine (451 mg, yield 13%) as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6].[H-].[Na+].[Br:11][C:12]1[CH:13]=[C:14](S(C)(=O)=O)[C:15]2[N:16]([C:18]([C:21]3[CH:32]=[CH:31][C:24]([C:25]([NH:27][CH:28]4[CH2:30][CH2:29]4)=[O:26])=[C:23]([CH3:33])[CH:22]=3)=[CH:19][N:20]=2)[N:17]=1>CS(C)=O>[Br:11][C:12]1[CH:13]=[C:14]([NH:1][CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6])[C:15]2[N:16]([C:18]([C:21]3[CH:32]=[CH:31][C:24]([C:25](=[O:26])[NH:27][CH:28]4[CH2:30][CH2:29]4)=[C:23]([CH3:33])[CH:22]=3)=[CH:19][N:20]=2)[N:17]=1
Reactant: Cc1cc(-c2cnc3c(S(C)(=O)=O)cc(Br)nn23)ccc1C(=O)NC1CC1
Reactant: NCCCS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(-c2cnc3c(NCCCS(=O)(=O)O)cc(Br)nn23)ccc1C(=O)NC1CC1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 41 mg (300 μmol) 3-aminopropane-1-sulfonic acid in 2 mL DMSO is added 24 mg (600 μmol) sodium hydride at rt. After 30 min, 90 mg (200 μmol) 4-[6-bromo-8-(methylsulfonyl)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methyl benzamide are added which was prepared according to intermediate example 516b to give after stirring for 2 h, the crude title compound which was used after evaporation of the solvent without further workup.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Br)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27].N1C=CC=CC=1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.[Cu]I>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([O:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Br)cc21
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Oc3ccccc3Cl)cc21
Yield: 82.9 %

Procedure:
A solution of 6-bromo-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (150 mg, 0.46 mmol), 2-chlorophenol (0.071 mL, 0.69 mmol), CuI (17 mg, 0.046 mmol), picolinic acid (23 mg, 0.092 mmol) and potassium phosphate (195 mg, 0.92 mmol) in DMSO (1 mL) was stirred at 85° C. overnight. The mixture was allowed to cool and then partitioned between EtOAc and water. The organic extract was washed with brine, dried (MgSO4) and evaporated in vacuo. Chromatography (SiO2; gradient elution with 2-10% ethyl acetate in petrol) gave the title compound (143 mg). MS: [M+H]+=375.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:32][CH2:33][CH3:34])[C:5]#[C:6][C:7](=[N:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]([F:11])(F)F)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:41][C:42]([CH3:46])([CH3:45])[CH2:43][NH2:44]>CS(C)=O>[C:42]([C:43]1[C:8]([F:11])=[C:7]([NH:12][C:13]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[C:5]([CH:4]([O:3][CH2:1][CH3:2])[O:32][CH2:33][CH3:34])[N:44]=1)([CH3:46])([CH3:45])[CH3:41]
Reactant: CC(C)(C)CN
Reactant: CCOC(C#CC(=NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(F)(F)F)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(C(C)(C)C)n1
Yield: 101.8 %

Procedure:
Using the procedure of Example 9, N-(5,5-diethoxy-1,1,1-trifluoropent-3-yn-2-ylidene)-1,1,1-triphenylmethanamine (2.328 g, 5 mmol), cesium carbonate (4.07 g, 12.50 mmol), 2,2-dimethylpropan-1-amine (1.307 g, 15.00 mmol) and anhydrous DMSO (20 mL) gave 2-(tert-butyl)-6-(diethoxymethyl)-3-fluoro-N-tritylpyridin-4-amine (2.61 g, 97%) as an off-white solid: mp 168-169.5° C.; 1H NMR (400 MHz, CDCl3) δ 7.28 (m, 15H), 6.16 (d, J=6.1 Hz, 1H), 5.71 (d, J=5.2 Hz, 1H), 5.01 (s, 1H), 3.29 (dd, J=9.5, 7.1 Hz, 2H), 3.17 (dq, J=9.4, 7.0 Hz, 2H), 1.36 (d, J=1.3 Hz, 9H), 1.01 (t, J=7.0 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 151.67 (d, J=9.9 Hz), 150.42 (d, J=5.9 Hz), 147.83 (d, J=249.5 Hz), 144.45, 141.00 (d, J=10.3 Hz), 128.91, 128.14, 127.12, 107.63, 102.63, 71.04, 61.35, 36.75 (d, J=5.1 Hz), 29.00 (d, J=3.5 Hz), 15.09; 19F NMR (376 MHz, CDCl3) δ −145.99; HRMS-ESI (m/z) [M+H]+ calcd for C33H37FN2O3, 512.2839. found, 512.2851.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[N:15]=[C:14](F)[CH:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[CH3:20][O-:21].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:6]2[C:7]3[N:15]=[C:14]([O:21][CH3:20])[CH:13]=[CH:12][C:8]=3[N:9]=[CH:10][N:11]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: C[O-]
Reactant: Fc1ccc2ncnc(Nc3cccc(Br)c3)c2n1
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ncnc(Nc3cccc(Br)c3)c2n1
Temperature: 90 °C
Yield: 82 %

Procedure:
4-(3-Bromoanilino)-6-fluoropyrido[3,2-d]pyrimidine (described in a previous experimental) (0.11 g, 0.34 mmol) is added to a solution of NaOMe (prepared by the addition of Na metal (31 mg, 1.38 mmol) to dry MeOH (15 mL). After heating in a pressure vessel at 90° C. for 3 h, the solution is concentrated to dryness and the residue is partitioned between EtOAc and water. Workup of the organic portion gives 4-(3-bromophenyl)amino-6-methoxypyrido[3,2-d]pyrimidine (92 mg, 82%). 1H NMR (CDCl3) δ 8.73 (1H, s), 8.66 (1H, brs), 8.18 (1H, m), 8.05 (1H, d, J=8.9 Hz), 7.83-7.80 (1H, m), 7.30-7.24 (2H, m), 7.23 (1H, d, J=8.9 Hz), 4.12 (3H, s).
Reaction SMILES: Cl.Cl.[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH2:11])[CH2:7]1)([CH3:5])[CH3:4].[CH3:30][CH:31]1[C:36](=O)[CH2:35][CH2:34][O:33][CH2:32]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:3]([C@:6]1([C:12]([N:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:23]=[CH:22][N:21]=3)[CH2:18][CH2:19]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH:11][CH:36]2[CH2:35][CH2:34][O:33][CH2:32][CH:31]2[CH3:30])[CH2:7]1)([CH3:5])[CH3:4]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](N)C1
Reactant: CC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)(C(C)C)C1
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentanamine dihydrochloride (140 mg, 0.31 mmol), 3-methyltetrahydro-4H-pyran-4-one (70 mg, 0.61 mmol) and triethylamine (0.21 mL, 1.5 mmol) in methylene chloride (10 mL) was added sodium triacetoxyborohydride (190 mg, 0.92 mmol). After being stirred overnight, the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried (MgSO4), concentrated and purified by flash chromatography on silica gel (EtOAc to 1% Et3N/EtOAc to 5% Et3N/EtOAc) to give 101 mg of product. The product was further separated by chiral HPLC to give isomer 1 and isomer 2. MS calculated for C25H37F3N4O2 (M+1) 483; found 483.2.
Reaction SMILES: [C:1]([CH:5]([C:9]([OH:11])=O)[C:6]([OH:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Mg+2].[Cl-].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35](C)([CH3:39])[C:36](O)=O)=[CH:31][C:30]=1[I:41])[CH3:28]>COCCOC>[C:1]([CH:5]([C:9](=[O:11])[C:35]([C:32]1[CH:33]=[CH:34][C:29]([CH2:27][CH3:28])=[C:30]([I:41])[CH:31]=1)([CH3:39])[CH3:36])[C:6]([OH:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1ccc(C(C)(C)C(=O)O)cc1I
Reactant: CC(C)(C)C(C(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: COCCOC
Product: CCc1ccc(C(C)(C)C(=O)C(C(=O)O)C(C)(C)C)cc1I
Reaction time: 2 h

Procedure:
Mono-tert-butyl malonic acid (72.5 g) was dissolved in DME (360 ml), added with TEA (189 ml) and magnesium chloride (29.63 g) and the mixture was stirred for 2 hrs. In a separate vessel, CDI (52.75 g) was added to the DME (360 ml) solution of 2-(4-ethyl-3-iodophenyl)-2-methylpropanoic acid (90 g) and stirred at room temperature for 1 hr to prepare a solution. This solution was then added dropwise to the aforementioned mixture, and the resulting solution was washed with DME (90 ml) and stirred at 70° C. for 3 hrs. The reaction mixture was diluted with isopropyl acetate (225 ml) and heptane (225 ml), and the organic layer was washed with 2 N hydrochloric acid (684 ml), 0.17 N hydrochloric acid (540 ml), 15% aqueous solution of ammonium chloride (540 ml), 1 N aqueous solution of sodium hydroxide (540 ml) and 15% brine (540 ml) in order. The organic layer was concentrated under reduced pressure to obtain the title compound as a crude product, which was used for the next step without further purification.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([O:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[C:22]=2[F:31])=[C:15]2[C:20]=1[N:19]=[CH:18][CH:17]=[CH:16]2)=[O:10])[CH3:7]>CC#N>[CH2:6]([O:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([C:21]2[C:22]([F:31])=[C:23]([O:29][CH3:30])[CH:24]=[C:25]([O:27][CH3:28])[C:26]=2[Cl:4])=[C:15]2[C:20]=1[N:19]=[CH:18][CH:17]=[CH:16]2)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2F)c2cccnc12
Reactant: O=S(=O)(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2cccnc12
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 66.2 %

Procedure:
Sulfuryl chloride (75 μL, 0.93 mmol) was added dropwise to a cold (−20° C.) solution of 5-(2-fluoro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid ethyl ester (Step 176.3) (330 mg, 0.93 mmol) in CH3CN (6 mL). The reaction mixture was stirred for 10 min at −20° C., quenched by addition of a saturated solution of NaHCO3, and concentrated. The residue was diluted in EtOAc and a saturated solution of NaHCO3. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc, 3:2) to provide 240 mg of the title compound as a white solid. Title compound: ESI-MS: 390.1 [M+H]+; tR=3.98 min (System 1); TLC: Rf=0.15 (Hex/EtOAc, 3:2).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[CH3:8][O:9][CH2:10]Cl>>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:8][O:9][CH3:10])[C:6]=1[Cl:7]
Reactant: COCCl
Reactant: Clc1nc[nH]c1Cl
Product: COCn1cnc(Cl)c1Cl

Procedure:
4,5-Dichloroimidazole was reacted with chloromethyl methyl ether to obtain 4,5-dichloro-1-methoxymethylimidazole (nD26.8 :1.5090). This compound was gradually crystallized after being allowed to stand (melting point: 41° to 44° C.).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[C:8](=[O:14])O[C:10](=[O:13])[C:11]=1[CH3:12].[NH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=1>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[C:8](=[O:14])[N:15]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:25])([F:26])[F:27])[CH:17]=2)[C:10](=[O:13])[C:11]=1[CH3:12]
Reactant: CC1=C(CCCCCCl)C(=O)OC1=O
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Solvent: CCO
Product: CC1=C(CCCCCCl)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A mixture of 9.46 g of 3-(5-chloropentyl)-4-methyl-2,5-furandione and 8.13 g of 4-amino-2-(trifluoromethyl)benzonitrile in 22 ml of ethanol was mixed under a nitrogen atmosphere with 2.5 g of an activated molecular sieve (0.3 nm), and it was stirred for 2 days at 90° C. For working-up, the molecular sieve was filtered off after cooling, washed with ethanol, and the combined ethanol solutions were concentrated by evaporation. The residue was taken up in ethyl acetate and washed with water as well as saturated sodium chloride solution. After drying on sodium sulfate and concentration by evaporation, it was chromatographed on silica gel with ethyl acetate/hexane/toluene, and 11.69 g of the title compound was thus obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][NH:21][C:20](=[O:24])[CH:19]=3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].Cl[CH2:26][C:27]1[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=1>>[F:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][N:21]([CH2:26][C:27]4[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=4)[C:20](=[O:24])[CH:19]=3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cn1cc(CCl)cn1
Reactant: Cc1ccc(Oc2ccc(COc3cc[nH]c(=O)c3)cc2)cc1F
Product: Cc1ccc(Oc2ccc(COc3ccn(Cc4cnn(C)c4)c(=O)c3)cc2)cc1F

Procedure:
The title compound was prepared by a procedure similar to that described for E21 starting from 4-[({4-[(3-fluoro-4-methylphenyl)oxy]phenyl}methyl)oxy]-2(1H)-pyridinone and 4-(chloromethyl)-1-methyl-1H-pyrazole. LC-MS (ESI): m/z 420 [M+H]+; 3.35 min (ret time).