Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[ClH:27].Cl.[NH2:29][CH2:30][CH2:31][O:32][NH2:33].N1C=CC=CC=1>C(O)C>[ClH:27].[ClH:27].[NH2:29][CH2:30][CH2:31][O:32][N:33]=[C:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]2[CH:25]=[CH:26][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1
Reactant: O=C(CCCN1CCC(C(=O)c2ccc(F)cc2)CC1)c1ccccc1
Reactant: NCCON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: NCCON=C(CCCN1CCC(C(=O)c2ccc(F)cc2)CC1)c1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A mixture of 4-[4-(4-fluorobenzoyl)-1-piperdinyl]-1-phenyl-1-butanone (5.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (2.21 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was stirred at 60° C., overnight, under nitrogen. The reaction mixture was evaporated, toluene was added and evaporated. The reaction mixture was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and evaporated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized twice from absolute ethanol/ether to give 2.3 g (34%) of product, mp 110°-115° C. (dec).
Reaction SMILES: [Li+].[OH-].[NH2:3][C:4]1[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][C:7]([CH2:8][C@@H:9]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([OH:33])[CH:30]=4)[NH:25][C:24]3=[O:34])[CH2:19][CH2:18]2)=[O:16])[C:10]([O:12]C)=[O:11])=[CH:6][C:5]=1[Cl:41].Cl>O.C1COCC1>[NH2:3][C:4]1[C:36]([C:37]([F:39])([F:38])[F:40])=[CH:35][C:7]([CH2:8][C@@H:9]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([OH:33])[CH:30]=4)[NH:25][C:24]3=[O:34])[CH2:19][CH2:18]2)=[O:16])[C:10]([OH:12])=[O:11])=[CH:6][C:5]=1[Cl:41]
Reactant: COC(=O)[C@H](CC(=O)N1CCC(N2Cc3cc(O)ccc3NC2=O)CC1)Cc1cc(Cl)c(N)c(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(N3Cc4cc(O)ccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 144 mg (6.00 mmol) LiOH in 15 mL water was added to a solution of 2.30 g (4.04 mmol) methyl(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(6-hydroxy-2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-4-oxo-butanoate in 30 mL THF and the reaction mixture was stirred for 1 h at RT. The organic solvent was eliminated i.vac., the residue was diluted with 50 mL water and acidified with 1 M HCl. The precipitate formed was filtered, washed with 10 mL water and dried at 50° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]([CH2:17][CH:18]2[O:22][CH2:21][CH2:20][O:19]2)[CH2:15][OH:16])[CH:10]=[CH:11][C:12]=1[Cl:13].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:16][CH2:15][CH:14]([C:9]1[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=1)[CH2:17][CH:18]1[O:19][CH2:20][CH2:21][O:22]1)(=[O:4])=[O:3]
Reactant: OCC(CC1OCCO1)c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(CC1OCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 101.4 %

Procedure:
Methanesulphonyl chloride (5.5 g) was added over 10 minutes to an ice-cooled solution of 2-(3,4-dichlorophenyl)-3-(1,3-dioxolan-2-yl)propan-1-ol (12 g) (see Preparation 15) and triethylamine (5.7 g) in dichloromethane (100 ml). The mixture was stirred for 30 minutes before further addition of dichloromethane (50 ml). The solution was then washed sequentially with water (3×50 ml) and brine (50 ml) before drying over anhydrous sodium sulphate. Removal of the solvent under reduced pressure gave 1-methanesulphonyloxy-2-(3,4-dichlorophenyl)-3-(1,3-dioxolan-2-yl)propane as a yellow oil (15.6 g) which solidified upon standing.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.[N+:19]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])([O-:21])=[O:20]>C(#N)C>[CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=2)=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Nc1ccc(NNC=O)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=CNNc1ccc(NC(=O)c2cccc([N+](=O)[O-])c2)cc1
Temperature: 60 °C
Yield: 64.3 %

Procedure:
68.2 g of 1-formyl-2-(4-aminophenyl)hydrazine and 60 ml of triethylamine were dissolved in 500 ml of acetonitrile. To the resulting solution, 70 g of 3-nitrobenzoyl chloride was added dropwise with stirring while keeping the solution temperature at less than 50° C., by which crystals precipitated. After being heated to 60° C. for a further 2 hours, it was cooled and poured into water. Crystals were filtered off and recrystallized from ethanol to obtain 72.8 g of 1-formyl-2-(4-(3-nitrobenzamido)phenyl)hydrazine. Yield: 54%. Melting point: 185°-187° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])=[C:11]([Cl:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[C:11]([Cl:23])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(OCc2ccccc2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cc1ccc(OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl [4-(benzyloxy)-2-chlorophenyl]acetate (1.0 g, 3.00 mmol) in DCM (8 ml) was treated with TFA (6.94 ml, 90 mmol) and the mixture stirred at RT for 30 min. The volatiles were removed in vacuo to afford the title compound. LC/MS (m/z): 299 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=2[CH3:30])=[CH:4][CH:3]=1.[CH2:31]([O:33][C:34](=[O:39])[C:35](Br)([CH3:37])[CH3:36])[CH3:32]>>[CH2:31]([O:33][C:34](=[O:39])[C:35]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:9]([CH3:30])=[C:8]2[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:37])[CH3:36])[CH3:32]
Reactant: CCCCCCCCCCCCn1c(C)c(-c2ccc(Cl)cc2)c2cc(O)ccc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCCCCCCCCCCn1c(C)c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 3-(4chlorophenyl)-1-dodecyl-2-methyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[N:24]([CH:25]([CH3:27])[CH3:26])[C:23]([CH3:28])=[N:22][CH:21]=4)[C:17]([F:29])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3]1.[C:30](O)(=[O:34])[C@H:31]([CH3:33])[OH:32].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[F:29][C:17]1[C:18]([C:20]2[N:24]([CH:25]([CH3:26])[CH3:27])[C:23]([CH3:28])=[N:22][CH:21]=2)=[N:19][C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][C:30](=[O:34])[C@@H:31]([OH:32])[CH3:33])[CH2:3]3)=[CH:12][CH:11]=2)=[N:15][CH:16]=1
Reactant: C[C@H](O)C(=O)O
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CC[C@H](N)C4)cc3)ncc2F)n1C(C)C
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc(-c2nc(Nc3ccc(N4CC[C@H](NC(=O)[C@H](C)O)C4)cc3)ncc2F)n1C(C)C
Yield: 30.4 %

Procedure:
N-{4-[(3S)-3-Aminopyrrolidin-1-yl]phenyl}-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-amine (Example 153; 220 mg, 0.556 mmol), L—lactic acid (61 mg, 0.667 mmol), HOBt mono hydrate (103 mg, 0.667 mmol) and Hunig's base (0.12 ml, 0.667 mmol) in DCM (5 ml) were reacted with EDAC (128 mg, 0.667 mmol) at room temperature under nitrogen for 18 hours. The mixture was diluted with DCM (20 ml) and washed with water (20 ml), 1 N aqueous potassium hydroxide (20 ml) and saturated aqueous sodium chloride (15 ml). The mixture was dried and after evaporation under reduced pressure purified by HPLC on a Phenomenex column, (0-50% acetonitrile/water, 0.2% TFA). The fractions were diluted with water (20 ml), basified with solid potassium carbonate, and extracted twice with EtOAc/DCM (20 ml, 2:1). The solution was washed with saturated aqueous sodium chloride (15 ml), dried and after evaporation under reduced pressure gave the title compound as a yellow solid, (79 mg, 30%). NMR: 1.20 (d, 3H), 1.37 (d, 6H), 1.90-2.04 (m, 1H), 2.11-2.27 (m, 1H), 2.47 (s, 3H), 3.00-3.09 (m, 1H), 3.20-3.47 (m, 3H), 3.91-4.00 (m, 1H), 4.32-4.47 (m, 1H), 5.38 (s, 1H), 5.40-5.49 (m, 1H), 6.49 (d, 2H), 7.30 (s, 1H), 7.32 (d, 2H), 7.76 (d, 1H), 8.40 (d, 1H), 9.06 (s, 1H); m/z 468.
Reaction SMILES: I[C:2]1[C:10]2[C:9]([C:11]#[N:12])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.C[CH2:38][OH:39]>[Cu]I>[CH3:38][O:39][C:2]1[C:10]2[C:9]([C:11]#[N:12])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1
Reactant: N#Cc1cccc2c1c(I)nn2C1CCCCO1
Reactant: CCO
Agent: [Cu]I
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Product: COc1nn(C2CCCCO2)c2cccc(C#N)c12
Temperature: 90 °C
Yield: 35.7 %

Procedure:
A mixture of 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonitrile (50 mg, 0.142 mmol), CuI (13.5 g 0.071 mmol), CsCO3 (2.7 mg, 0.0142 mmol), and 3,4,7,8-tetramethyl-1,10-phenanthroline (0.0142 mg, 3.5 mmol) in EtOH (0.5 mL) under nitrogen in a sealed vial was heated to 90° C. in a microwave oven for 100 min. The reaction mixture was quenched with water and extracted with EtOAc. The extract was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether:EtOAc to afford 3-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonitrile as white solid (13 mg, 35.7%). MS (ESI): m/z=258 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:17][C:18]1[O:22][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:20][C:19]=1[CH2:29][CH2:30]Br>CC(CC)=O>[CH3:17][C:18]1[O:22][C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:20][C:19]=1[CH2:29][CH2:30][O:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2sccc12
Reactant: Cc1oc(-c2ccccc2)nc1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1cccc2sccc12
Reaction time: 72 h
Yield: 77.2 %

Procedure:
5.15 g (0.034 mol) 4-hydroxybenzothiophene was dissolved in 130 ml methylethylketone and admixed with 9.4 g (0.068 mol) K2CO3 and 20 g (0.068 mol) 5-methyl-2-phenyl-4-(2-bromoethyl)oxazole. The preparation was boiled for 72 hours under reflux, evaporated, taken up in ethyl acetate and extracted three times by shaking with 2N NaOH. After cooling and evaporation of the organic phase, it was crystallized from ethyl acetate/isohexane. 8.8 g 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzothiophene of melting point 130°-132° C. is obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH2:4][CH:5]2[CH:8]([CH:9]=1)[C:7](=[CH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]2)[CH3:2].N12CCCN=C1CCCCC2.P([O-])(O)(O)=O.[K+].[N+:35]([CH3:38])([O-:37])=[O:36]>>[CH2:1]([C:3]1[CH2:4][CH:5]2[CH:8]([CH:9]=1)[C:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])([CH2:38][N+:35]([O-:37])=[O:36])[CH2:6]2)[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: CCC1=CC2C(=CC(=O)OC(C)(C)C)CC2C1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Product: CCC1=CC2C(C1)CC2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 7 h

Procedure:
Tert-butyl 3-ethylbicyclo[3.2.0]hept-3-en-6-ylideneacetate (1.32 g, 5.63 mmol) was dissolved in nitromethane (7 mL). To the solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (1.2 mL, 7.3 mmol) was added, and the mixture was heated with stirring at 50 to 60° C. for 7 hours. The mixture was allowed to cool, and a saturated aqueous solution of potassium dihydrogen phosphate was then added thereto, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the compound of interest as a colorless oil substance (1.39 g, 84%).
Reaction SMILES: C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(=O)[NH:22][CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([CH3:45])([CH3:44])[C:35]([N:37]3[CH:41]4[CH2:42][CH2:43][CH:38]3[CH2:39][CH2:40]4)=[O:36])[CH:32]=2)[NH:27][C:26]=1[C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[C:48]([CH3:53])[CH:47]=1)(C)(C)C>>[NH2:22][CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([CH3:45])([CH3:44])[C:35]([N:37]3[CH:38]4[CH2:39][CH2:40][CH:41]3[CH2:42][CH2:43]4)=[O:36])[CH:32]=2)[NH:27][C:26]=1[C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[C:48]([CH3:53])[CH:47]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCNC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCN)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 106.2 %

Procedure:
To a solution of {2-[5-[2-(7-azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-oxo-ethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}carbamic acid tert-butyl ester (728 mg in 30 mL methylene chloride) at 0° C. was added 1.5 mL anisole followed by 10.5 mL trifluoroacetic acid and the mixture stirred at 0° C. After 2 hours, the mixture was concentrated in vacuo and the residual acid quenched by the addition of 10% ammonium hydroxide in methanol. The concentrated was then purified by flash chromatography on silica gel (methylene chloride:10% ammonium hydroxide in methanol, 95:5; then 92:8) to give the title compound (627 mg).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH:18]([CH3:20])[CH3:19])=[CH:6][N:5]=[C:4]([NH2:21])[N:3]=1.C(Cl)Cl.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH:18]([C:10]1[CH:11]=[C:12]([O:16][CH3:17])[C:13]([CH3:15])=[CH:14][C:9]=1[O:8][C:7]1[C:2]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:3][C:4]([NH2:21])=[N:5][CH:6]=1)([CH3:20])[CH3:19]
Reactant: Nc1ccccc1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2Cl)cc1C
Solvent: ClCCl
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2Nc2ccccc2)cc1C
Temperature: 100 °C

Procedure:
A suspension of 4-chloro-5-(2-isopropyl-4-methoxy-5-methyl-phenoxy)-pyrimidin-2-ylamine (0.043 g, 0.14 mmol) in aniline (4 ml) was placed in a sealed tube and heated at 100° C. over night. Methylene chloride was added and insoluble solid was removed by filtration through celite. The combined methylene chloride filtrate was washed with water and dried over anhydrous sodium sulfate. After removal of the drying agent, the organic phase was concentrated under reduced pressure. The residue was purified with silica gel chromatography (2% methanol in methylene chloride) to yield a yellow oily residue, which was further purified with preparative TLC and HPLC (5 to 100% acetonitrile in water with 0.1% trifluoroacetic acid to yield 5-(2-Isopropyl-4-methoxy-5-methyl-phenoxy)-N4-phenyl-pyrimidine-2,4-diamine, M+H: 365.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C([O-])(=O)C>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21](=[O:22])[C:20](=[CH:15][C:14]1[CH:17]=[CH:18][C:11]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:12][CH:13]=1)[C:19]([O:27][CH2:28][CH3:29])=[O:26])[CH3:25]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=Cc1ccc(N2CCC3(CC2)OCCO3)cc1)C(=O)OCC
Temperature: 25 °C

Procedure:
A solution of 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzaldehyde (2.47, 10 mmol) (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) and diethyl malonate (2.0 g, 12.5 mmol) in toluene (100 mL) containing a catalytic quantity of piperidineum acetate was refluxed for 18 hours. After cooling to room temperature the solution was washed with water, dried over sodium sulfate and concentrated. Purification by column chromatography on silica gel using ethyl acetate/hexanes as the eluent gave the title compound as a yellowish gum; 1H NMR (300 MHz, CDCl3) δ 1.28 (t, J=7.1 Hz, 3H), 1.29 (t, J=7.1 Hz, 3H), 1.79 (t, J=5.8 Hz, 4H), 3.46 (t, J=5.8 Hz, 4H), 4.27 (q, J=7.1 Hz, 2H), 4.31 (q, J=7.1 Hz, 2H), 6.85 (d, J=8.9 Hz, 2H), 7.33 (d, J=8.9 Hz, 2H), 7.61 (s, 1H); MS (ES) m/z: 390.0 (MH+); HRMS Calcd. for C21H27NO6 (MH+): 390.1911. Found: 390.1910.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([F:10])[C:5]([O:7]CC)=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[O:22])[CH3:21].Cl>COCCOC>[F:11][C:4]([F:3])([F:10])[C:5](=[O:7])[CH2:21][C:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH3:12])=[O:22]
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1ccccc1C(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccccc1C(=O)CC(=O)C(F)(F)F
Temperature: 160 °C

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 202 mg, 8.0 mmol) in 1,2-dimethoxyethane (4 mL) was added drop-wise ethyl trifluoroacetate (954 μL, 8.0 mmol) followed by 1-(2-methoxyphenyl)ethanone (552 μL, 4.0 mmol) and the reaction was heated to 160° C. in a microwave for 15 minutes. Aqueous hydrochloric acid (1 N, 20 mL) was added and the mixture was extracted with tert-butyl methyl ether (3×10 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 10% tert-butyl methyl ether in heptanes) afforded the title compound as a red solid. Yield: 933 mg, 3.79 mmol, 95%. GCMS m/z 246 (M+). 1H NMR (400 MHz, CDCl3) δ 3.96 (s, 3H), 6.99 (s, 1H), 7.02 (br d, J=8.5 Hz, 1H), 7.08 (ddd, J=8, 7, 1.0 Hz, 1H), 7.55 (ddd, J=8.4, 7.4, 1.8 Hz, 1H), 7.99 (dd, J=7.9, 1.9 Hz, 1H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([C:12]([CH2:17][OH:18])([CH2:15][OH:16])[CH2:13][CH3:14])[OH:11]>C(N(CC)CC)C>[C:1]([OH:8])(=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:1]([OH:8])(=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:1]([OH:8])(=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([C:12]([CH2:17][OH:18])([CH2:15][OH:16])[CH2:13][CH3:14])[OH:11]
Reactant: O=C(Cl)c1ccccc1
Agent: CCC(CO)(CO)CO
Solvent: CCN(CC)CC
Product: O=C(O)c1ccccc1
Temperature: 100 °C

Procedure:
While stirring, 71 parts by weight of benzoyl chloride were dripped over 30 minutes to a mixed solution of 45 parts by weight of trimethylolpropane and 101 parts by weight of triethylamine maintained at 100° C., and the resulting mixture was stirred for an additional 30 minutes. After completion of the reaction, the temperature was lowered to room temperature and the resulting precipitates were collected by filtration. Thereafter, washing was performed by adding ethyl acetate-pure water. Subsequently, the organic phase was collected and ethyl acetate was distilled out under vacuum, whereby 126 parts by weight (at a yield of 85 percents) of white crystals were obtained. The molecular weight of the resulting compound was 446.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[NH2:17][CH2:18][CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:17][CH2:18][CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[N:3][CH:4]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: Oc1cccc(Nc2nc(NCCc3c[nH]c4ccccc34)ncc2F)c1
Yield: 52.4 %

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine (50 mg, 0.21 mmol) and tryptamine (100 mg, 0.62 mmol) gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(indol-3-yl)ethyl]-2,4-pyrimidinediamine (40 mg, 53%). 1H NMR (CD3OD): δ 3.01 (t, J=7.2 Hz, 2H), 3.61 (t, J=7.2 Hz, 2H), 6.51 (ddd, J=0.9, 2.1 and 8.1 Hz, 1H), 6.96 (td, J=0.9 and 7.2 Hz, 1H), 7.03-7.09 (m, 3H), 7.22 (d, J=7.5 Hz, 1H), 7.28-7.32 (m, 2H), 7.53 (d, J=7.8 Hz, 1H), 7.72 (d, J=4.5 Hz, 1H); 19F NMR (282 MHz, CD3OD): δ −171.72; LCMS: ret. time: 20.17 min.; 95.66%; MS (m/e): 364.05 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](F)=[CH:5][N:4]=1)#[N:2].[CH3:10][O-:11].[Na+]>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:11][CH3:10])=[CH:5][N:4]=1)#[N:2]
Reactant: C[O-]
Reactant: N#Cc1ccc(F)cn1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(C#N)nc1
Yield: 42.8 %

Procedure:
A solution of 2-cyano-5-fluoropyridine (0.65 g, 5.3 mmol) in sodium methoxide (1.83 mL of 25% wt. solution in methanol, 7.95 mmol) was stirred at 0° C. for 1.5 hours and 2 hours at ambient temperature. The reaction was then diluted with ethyl acetate and washed with water and brine. Removal of the solvent in vacuo afforded 304 mg (43%) of 2-cyano-5-methoxypyridine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:13](=[O:32])[N:12]1[CH:8]([CH2:9][CH:10]([O:33][C:34]([N:36]3[CH2:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][C:42]=4[F:45])[CH2:37]3)=[O:35])[CH2:11]1)[C:7](=[O:46])[NH:6]2)=[O:4].C([O-])(=O)C.[Na+]>COCCOC.O>[CH3:1][O:2][C:3]([C:5]12[CH2:23][CH:22]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[C:13](=[O:32])[N:12]1[CH:8]([CH2:9][CH:10]([O:33][C:34]([N:36]3[CH2:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][C:42]=4[F:45])[CH2:37]3)=[O:35])[CH2:11]1)[C:7](=[O:46])[NH:6]2)=[O:4]
Reactant: COC(=O)C12CC1C=CCCCCCC(NC(=O)OC(C)(C)C)C(=O)N1CC(OC(=O)N3Cc4cccc(F)c4C3)CC1C(=O)N2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)C12CC1CCCCCCCC(NC(=O)OC(C)(C)C)C(=O)N1CC(OC(=O)N3Cc4cccc(F)c4C3)CC1C(=O)N2
Temperature: 95 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
To 14-tert-butoxycarbonylamino-18-(4-fluoro-1,3-dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid methyl ester (392 mg, 0.61) in DME (3 mL) and water (1 mL) was added tosyl hydrazide (682 mg, 3.66 mmol) and sodium acetate (600 mg, 7.32 mmol). The reaction was heated to 95° C. and allowed to stir 1 hour. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica (40→60% EtOAc/Hexanes) to provide 14-tert-butoxycarbonylamino-18-(4-fluoro-1,3-dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadecane-4-carboxylic acid methyl ester (319 mg, 81% yield). LCMS found 644.8 [M+H]+.