Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:15](Cl)(=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[OH2:23].C(Cl)Cl>[OH-].[Na+]>[O:21]([C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:13](=[O:23])[CH2:14][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:14][CH:13]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O
Reactant: c1ccc(NOc2ccccc2)cc1
Reactant: CCCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCCC(=O)Nc1ccc(Oc2ccccc2)cc1

Procedure:
A suspension of p-phenoxyaminobenzene (3.4g, 0.019 mole) in aqueous sodium hydroxide (100 ml. 12% NaOH) was stirred magnetically. Hexanoyl chloride (2.80g, 0.021 mole) was added dropwise over five minutes. The suspension was stirred for one hour and shaken with water-methylene chloride. The organic layer was washed twice with water, dried over anh. sodium sulphate and evaporated to dryness, in vacuo. Weight of beige solid; 4.30g, 81%, m.p. 69°-76° C. A portion (4.14g) was crystallized from chloroform-hexane, filtered and dried for 16 hours at 48° C./10 mm. Weight of beige solid -- 2.24g, m.p. 96°-98.5° C., sinters at 93° C. Recrystallized from the same solvents gave 1.90g beige crystals, m.p. 98.5°-99.5° C.
Reaction SMILES: [C:1]([Si:5]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:6][CH2:7][C@H:8]([N:10]1[C:15]2=[N:16][C:17](Cl)=[N:18][CH:19]=[C:14]2[C@@H:13]([CH3:21])[N:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:11]1=[O:30])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([Si:5]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:6][CH2:7][C@H:8]([N:10]1[C:15]2=[N:16][C:17]([NH:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[N:18][CH:19]=[C:14]2[C@@H:13]([CH3:21])[N:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:11]1=[O:30])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccc1
Reactant: COc1ccc(N2C(=O)N([C@H](C)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3nc(Cl)ncc3[C@H]2C)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(N2C(=O)N([C@H](C)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3nc(Nc4ccccc4)ncc3[C@H]2C)cc1

Procedure:
A solution of 1-[2-(tert-butyl-diphenyl-silanyloxy)-1-(R)-methyl-ethyl]-7-chloro-3-(4-methoxy-phenyl)-(R)-4-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.32 g; 0.51 mmol) (from Example 14e supra) and aniline (0.12 mL; 1.32 mmol) (Aldrich) in toluene (0.25 mL, dried over molecular sieves) was heated in an oil bath at 110° C. for 1.75 hours. The reaction was diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by flash chromatography (Biotage 40L; 40:60 ethyl acetate-hexanes) to give 1-[2-(tert-butyl-diphenyl-silanyloxy)-1-(R)-methyl-ethyl]-3-(4-methoxy-phenyl)-4-(R)-methyl-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 0.30 g; 81.6%). This material showed an e.e. of ≧95%.
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)C=1CC(Cl)=O)(C)C.[C:49]12([CH2:59][C:60](Cl)=[O:61])[CH2:58][CH:53]3[CH2:54][CH:55]([CH2:57][CH:51]([CH2:52]3)[CH2:50]1)[CH2:56]2>>[C:49]12([CH2:59][C:60]([C:16]3[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=3)=[O:61])[CH2:58][CH:53]3[CH2:54][CH:55]([CH2:57][CH:51]([CH2:52]3)[CH2:50]1)[CH2:56]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)Cl
Product: CC(C)c1ccc(C(=O)CC23CC4CC(CC(C4)C2)C3)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetyl chloride was replaced with adamantaneacetyl chloride; 1H NMR(CDCl3): 1.21 (d, 12H), 1.6-2.0 (m, 15H), 2.15 (s, 2H), 3.4 (m, 2H), 7.15-7.25 (m, 3H) ppm.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[Br:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14]>CC(C)=O>[Br-:7].[CH3:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][N+:2]1([CH3:1])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COCCOCCBr
Reactant: CN1CCCC1
Solvent: CC(C)=O
Product: COCCOCC[N+]1(C)CCCC1
Product: [Br-]
Yield: 68 %

Procedure:
N-methylpyrrolidine (9.11 g, 0.1 mol), 1-bromo-2-(2-methoxy-ethoxy)ethane (10.0 g, 0.103 mol) and anhydrous acetone (40 cm3) was refluxed for 24 h. After evaporation under reduced pressure, the yellow solid was washed with diethylether. 1-[2-(2-methoxyethoxy)ethyl]-1-methylpyrrolidinium bromide was obtained as white solid in ca. 68% yield. δH (500.13 MHz, CDCl3) 3.98 (2H, m), 3.87 (6H, m), 3.68 (2H, m), 3.53 (2H, m), 3.40 (3H, s), 3.33 (3H, s), 2.29 (4H, m).
Reaction SMILES: [CH2:1]([C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:25]([CH:27]1[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28]1)[CH3:26].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:25]([CH:27]1[CH2:31][CH2:30][CH:29]([C:32]([O:24][C:21]2[CH:20]=[CH:19][C:18]([C:15]3[N:16]=[CH:17][C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:13][N:14]=3)=[CH:23][CH:22]=2)=[O:33])[CH2:28]1)[CH3:26]
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCC1CCC(C(=O)O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCCc1cnc(-c2ccc(OC(=O)C3CCC(CC)C3)cc2)nc1

Procedure:
4.9 g of 4-(5-undecyl-pyrimidin-2-yl)phenol, 1.5 g of 3-ethyl-cyclopentanecarboxylic acid and 2.1 g of dicyclohexylcarbodiimide are stirred for 24 h in 50 ml of dichloromethane at room temperature. Filtration, removal of the dichloromethane by distillation, purification by chromatography (silica gel; dichloromethane/heptane) and recrystallization from acetonitrile affords the target compound as colorless crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])=[C:7]([CH3:21])[CH:6]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1>[CH3:21][C:7]1[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:18])([F:19])[F:20]
Reactant: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1-c1ccccc1C(F)(F)F
Yield: 90.6 %

Procedure:
To a solution of (2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carboxylic acid methyl ester of Step B (1.9 g, 6.5 mmol) in tetrahydrofuran (30 mL) was added 1 N sodium hydroxide (13 mL, 13 mmol). The reaction mixture was heated at reflux overnight, then cooled and acidified with 2 N hydrochloric acid. The aqueous layer was extracted with ethyl acetate and the combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1.65 g of the title compound as a white solid, m.p. 171–174° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[N:24]=3)[C:10]3[C:11]([N:22]=2)=[N:12][C:13]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:14][CH:15]=3)=[CH:4][CH:3]=1>CC(O)=O.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[N:24]=3)[C:10]3[C:11]([N:22]=2)=[N:12][C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:14][CH:15]=3)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc3nc(-c4ccncc4)ccc3n2-c2ccnc(NC3CCCC3)n2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Fc1ccc(-c2nc3nc(C4CCNCC4)ccc3n2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 69.5 %

Procedure:
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(4-pyridinyl)imidazo[4,5-b]pyridine (example 7; 100 mg; 0.22 mmol) is dissolved in HOAc (120 ml) and hydrogenated over Pd/C (10%, 200 mg) in a Parr apparatus for 48 h at room temperature. The reaction mixture is filtered and evaporated to dryness delivering the title compound as yellow crystals, which are recrystallised from MeOH and gave the title compound as colorless crystals (70 mg; 65%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.O1CCCC1.[CH2:25]([Mg]Br)[CH:26]([CH3:28])[CH3:27].[BH4-].[Na+]>CO>[CH3:25][CH:26]([CH3:28])[CH2:27][CH:8]([C:6]1[CH:5]=[CH:4][C:3]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)=[C:2]([CH3:1])[CH:7]=1)[NH2:9]
Reactant: Cc1cc(C#N)ccc1-c1ccc(C(F)(F)F)cc1
Reactant: CC(C)C[Mg]Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(N)CC(C)C)ccc1-c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 76.6 %

Procedure:
A microwave reaction vial was charged with 2-methyl-4′-(trifluoromethyl)biphenyl-4-carbonitrile (500 mg, 1.91 mmol) and tetrahydrofuran (5 mL). To the mixture was added isobutylmagnesium bromide (2.87 mL, 5.74 mmol, 2M in THF). The reaction was heated at 100° C. in a microwave for 30 minutes. The reaction mixture was then carefully added to a solution of sodium borohydride (145 mg, 3.83 mmol) in methanol (5 mL). After stirring for 5 minutes, the mixture was concentrated to dryness. Purification by column chromatography gave 3-methyl-1-(2-methyl-4′-(trifluoromethyl)biphenyl-4-yl)butan-1-amine (470 mg). 1H NMR (400 MHz, CD3OD, δ): 7.72 (d, 2H), 7.50 (d, 2H), 7.24 (s, 1H), 7.19 (d, 2H), 3.94 (m, 1H), 2.27 (s, 3H), 1.65 (m, 2H), 1.49 (m, 1H), 0.95 (d, 3H), 0.92 (d, 3H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.[OH-].[Na+]>C(O)C>[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCBr
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: BrCCCCCSc1ccccc1
Reaction time: 8 h

Procedure:
A solution of 20 ml (0.2 mol) of thiophenol and 50.6 g (0.22 mol) of 1,5-dibromopentane in 200 ml of ethanol is heated to 40° C whilst stirring and 40 ml (0.2 mol) of 5N NaOH are added dropwise. Thereafter the mixture is stirred for 2 hours and after standing overnight the alcohol is evaporated in vacuo, the residue is extracted with methylene chloride and the extract is washed 3 to 4 times with water, dried and evaporated. A yellow oil is obtained in quantitative yield.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[CH:11]=[N:10][N:9]2[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=[C:8]2[C:7]=1[NH:21][C@@H:22]1[CH2:26][CH2:25][C@:24]([CH3:31])([C:27]([O:29]C)=[O:28])[C:23]1([CH3:33])[CH3:32])(=[O:5])[NH2:4]>C(O)C.C(OCC)(=O)C>[C:3]([C:6]1[CH:11]=[N:10][N:9]2[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=[C:8]2[C:7]=1[NH:21][C@@H:22]1[CH2:26][CH2:25][C@:24]([CH3:31])([C:27]([OH:29])=[O:28])[C:23]1([CH3:33])[CH3:32])(=[O:5])[NH2:4]
Reactant: COC(=O)[C@@]1(C)CC[C@@H](Nc2c(C(N)=O)cnn3cc(-c4ccccc4)cc23)C1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)[C@H](Nc2c(C(N)=O)cnn3cc(-c4ccccc4)cc23)CC[C@]1(C)C(=O)O
Temperature: 75 °C
Yield: 86.8 %

Procedure:
A 4.5 M aqueous potassium hydroxide (192 μl, 0.866 mmol) solution was added dropwise to a solution of (1S,3R)-methyl 3-(3-carbamoyl-6-phenylpyrrolo[1,2-b]pyridazin-4-ylamino)-1,2,2-trimethyl-cyclopentanecarboxylate (182 mg, 0.433 mmol) in ethanol (2885 μl). The reaction was heated at 75° C. for 24 hrs. The reaction was cooled to room temperature and concentrated under reduced pressure, yielding an oil. The oil was diluted with ethyl acetate and washed with water. The aqueous layer was acidified with 1.0 N HCl and was extracted with ethyl acetate (3×). The organic extracts were combined, dried with sodium sulfate, filtered and concentrated under reduced pressure, yielding (1S,3R)-3-(3-carbamoyl-6-phenylpyrrolo[1,2-b]pyridazin-4-ylamino)-1,2,2-trimethylcyclopentanecarboxylic acid (152.8 mg, 0.376 mmol, 87% yield) as a yellow solid. LC/MS found [M+H]+=407.0.
Reaction SMILES: [O:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].C(N(CC)CC)C.[C:15]1([C:21](Cl)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[C:15]1([C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:3]2[C:4](=[O:6])[CH2:5][O:1][C:2]2=[O:7])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1COC(=O)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1COC(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a solution of 1,3-oxazolidine-2,4-dione (60.7 g, 0.600 mol) and triethylamine (60.7 g, 0.600 mol) in methylene chloride (500 mL) was added triphenylmethyl chloride (167.3 g, 0.600 mol). After 30 minutes, the thick white solid was collected by vacuum filtration, washed with water (2 L) and dried in a vacuum desicator to give the title compound (201.4 g, 96%). A portion was recrystallized from chloroform to give white plates: mp 216°-218° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[O:9])[CH:6]=1.[C:18]([O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26](Cl)=[N:27][CH:28]=[N:29]2)=[CH:24][C:23]=1[O:33][CH3:34])(=[O:20])[CH3:19]>CC(N(C)C)=O.C(OCC)C>[C:18]([O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26]([NH:1][C:2]3[CH:3]=[N:4][N:5]([CH2:7][C:8]([NH:10][C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=4)=[O:9])[CH:6]=3)=[N:27][CH:28]=[N:29]2)=[CH:24][C:23]=1[O:33][CH3:34])(=[O:20])[CH3:19].[F:17][C:13]1[CH:12]=[C:11]([NH:10][C:8](=[O:9])[CH2:7][N:5]2[CH:6]=[C:2]([NH:1][C:26]3[C:25]4[C:30](=[CH:31][C:22]([OH:21])=[C:23]([O:33][CH3:34])[CH:24]=4)[N:29]=[CH:28][N:27]=3)[CH:3]=[N:4]2)[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cnn(CC(=O)Nc2cccc(F)c2)c1
Reactant: COc1cc2c(Cl)ncnc2cc1OC(C)=O
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Nc3cnn(CC(=O)Nc4cccc(F)c4)c3)ncnc2cc1O
Product: COc1cc2c(Nc3cnn(CC(=O)Nc4cccc(F)c4)c3)ncnc2cc1OC(C)=O
Temperature: 25 °C
Yield: 175.3 %

Procedure:
A solution of 2-(4-amino-1H-pyrazol-1-yl)-N-(3-fluorophenyl)acetamide (0.246 g, 1.05 mmol) and 4-chloro-6-methoxyquinazolin-7-yl acetate (see WO96/15118, 0.252 g, 1.0 mmol) in dimethylacetamide (5 ml) was heated at 90° C. for 2 hours. The mixture was allowed to cool to room temperature and then diluted with diethyl ether and filtered. The solid was washed with diethyl ether and then dried in vacuo to leave 4-[(1-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-4-yl)amino]-6-methoxyquinazolin-7-yl acetate as a mixture with 15% N-(3-fluorophenyl)-2-{4-[(7-hydroxy-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-1-yl}acetamide (0.358 g, 78% yield):
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]([F:17])([F:16])[F:15])[C:10]([C:18]#[N:19])=[CH:9][CH:8]=2)[CH3:4].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1.O>CN(C=O)C.CCOCC>[CH:22]1([CH2:21][N:6]2[C:7]3[C:12](=[C:11]([C:14]([F:17])([F:15])[F:16])[C:10]([C:18]#[N:19])=[CH:9][CH:8]=3)[CH:13]=[C:5]2[CH2:3][CH3:4])[CH2:24][CH2:23]1
Reactant: BrCC1CC1
Reactant: CCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC1CC1
Reaction time: 0.05 h
Yield: 64.2 %

Procedure:
To a slurry of hexanes-washed NaH (0.0112 g, 0.279 mmol) in DMF (1 mL) at 0° C. was added a solution of 2-ethyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.0332 g, 0.139 mmol) in DMF (1 mL), dropwise over 3 min. The mixture was stirred 30 min and bromomethylcyclopropane (0.030 mL, 0.28 mmol) was added via syringe. The mixture was stirred 5 h at rt, diluted with Et2O, poured into water, and the layers were separated. The aqueous layer was extracted with Et2O (×2), combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by RP-HPLC (C18 column, MeCN/H2O with 0.1% TFA), affording 0.0261 g of the title compound as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.55-7.47 (m, 2H), 6.59 (s, 1H), 4.07 (d, J=6.4 Hz, 2H), 2.84 (q, J=7.4 Hz, 2H), 1.44 (t, J=7.5 Hz, 3H), 1.24-1.01 (m, 1H), 0.66-0.57 (m, 2H), 0.41-0.32 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[C:12](O)=[C:11]([C:20](=O)[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]2=[O:29])[CH:6]=[CH:7][CH:8]=1)#[N:2].O.[NH2:31][NH2:32].O>CN(C=O)C>[CH2:21]([C:20]1[C:11]2[C:10](=[O:29])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=3)[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]=2[NH:32][N:31]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N#Cc1cccc(-n2c(=O)c(C(=O)Cc3ccccc3)c(O)c3cccnc32)c1
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(-n2c(=O)c3c(Cc4ccccc4)n[nH]c3c3cccnc32)c1
Temperature: 105 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a suspension of 1-(3-cyanophenyl)-4-hydroxy-3-(1-oxo-2-phenylethyl)-1,8-naphthyridin-2 (1H)-one (314 mg, 0.82 mmol, prepared in Synthetic Example 29) in DMF (4 ml) was added hydrazine monohydrate (80%, 132 μl, 4.12 mmol, 4.0 eq.), and the mixture was stirred at 100 to 110° C. for 2 hours. The reaction mixture was admixed with water, and filtered to give precipitates which were washed with water and dried to afford 3-benzyl-5-(3-cyanophenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (287 mg, 92%).
Reaction SMILES: C1CO[C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)C=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC=[C:37]([OH:41])[CH:36]=2)C(F)=CN=1.CC1OC(C)=CC=1CN>>[CH3:36][C:37]1[O:41][C:23]([CH3:22])=[CH:24][C:25]=1[CH2:20][NH:19][C:14]1[N:13]=[C:12]([NH:11][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=2)[C:17]([F:18])=[CH:16][N:15]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Cc1cc(CN)c(C)o1
Product: Cc1cc(CNc2ncc(F)c(Nc3cccc(O)c3)n2)c(C)o1
Yield: 59 %

Procedure:
In a manner analogous 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 (2,5-dimethyl-3-furyl)methylamine (80 mg, 0.63 mmol) gave N2-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine (40 mg, 59%). 1H NMR (acetone-d6): δ 2.14 (s, 6H), 4.37 (d, J=4.2 Hz, 2H), 5.96 (s, 1H), 6.77 (d, J=6.6 Hz, 1H), 7.23-7.28 (m, 2H), 7.44 (s, 1H), 8.11 (d, J=4.8 Hz, 1H), 9.05 (br, 1H), 9.75 (br, 1H); 19F NMR (282 MHz, acetone-d6): δ−165.77; LCMS: ret. time: 19.23 min.; purity: 94.89%; MS (m/e): 329.08 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[N+:10]([CH2:13][CH3:14])([O-:12])=[O:11].C([O-])(=O)C.[NH4+].O>C(O)(=O)C>[N+:10](/[C:13](/[CH3:14])=[CH:5]/[C:4]1[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: O=Cc1cccc(O)c1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: C/C(=C\c1cccc(O)c1)[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 6 h
Yield: 82.6 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (20 g, 0.16 mol) in acetic acid (40 mL) was added nitro ethane (32 mL, 0.45 mol) and ammonium acetate (8 g, 0.1 mol). The resulting mixture was stirred at 80° C. for 6 hours. The reaction mixture was poured into a solution of 400 mL of water and the precipitate was collected by filtration to obtain the title compound as a solid (23.68 g, 81%). MS (M+): 180.
Reaction SMILES: C([N:8]([CH2:21][CH:22]([OH:32])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[NH2:19])=[CH:14][N:13]=1)C1C=CC=CC=1.[H][H]>O1CCOCC1.[Pd]>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][NH:8][CH2:21][CH:22]([OH:32])[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])=[N:13][CH:14]=1)(=[O:20])[NH2:19]
Reactant: Cc1ccccc1OCC(O)CN(CCOc1ccc(C(N)=O)cn1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1ccccc1OCC(O)CNCCOc1ccc(C(N)=O)cn1

Procedure:
A solution of 22.6 g of crude 1-{N-benzyl-N-[2-(5-carbamoyl-2-pyridyloxy)-ethyl]-amino}-3-(2-methyl-phenyloxy)-2-propanol in 230 ml of dioxane is hydrogenated in the presence of 2.3 g of a palladium-on-charcoal catalyst (5% strength) at 20°-30° C. and under atmospheric pressure, until an equimolar amount of hydrogen has been taken up. The catalyst is filtered off and the filtrate is evaporated under reduced pressure. The residue is recrystallised from ethyl methyl ketone and gives 1-[2-(5-carbamoyl-2-pyridyloxy)-ethylamino]-3-(2-methyl-phenyloxy)-2-propanol, melting point 139°-141° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[N:12]=[C:11]([C:13](=[NH:16])OC)[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+:20]>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[N:12]=[C:11]([C:13]([NH2:20])=[NH:16])[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: COC(=N)c1cccc(Cc2ccc(Cl)cc2)n1
Reactant: [NH4+]
Agent: [Cl-]
Solvent: CCO
Product: Cl
Product: N=C(N)c1cccc(Cc2ccc(Cl)cc2)n1

Procedure:
A mixture of methyl 6-p-chlorobenzyl-2-picoline imidate (1.2 g, 0.00046 moles) and ammonium chloride (0.27 g, 0.0051 moles) in ethanol (10 ml) was refluxed for 6 hours. Removal of the ethanol in vacuo gave 6-p-chlorobenzyl-2-picoline amidine hydrochloride which was used in the final stage without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=O)[CH2:8][O:9][C:5]=2[CH:4]=1.[C:13]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:15])=[O:14].[C:36]1(C)C=CC=C[CH:37]=1>>[CH2:36]([O:15][C:13](=[O:14])[CH2:16][C:7]1[C:6]2[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:9][CH:8]=1)[CH3:37]
Reactant: COc1ccc2c(c1)OCC2=O
Reactant: Cc1ccccc1
Reactant: O=C(O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)Cc1coc2cc(OC)ccc12

Procedure:
A mixture of 6-methoxy-benzofuran-3 (2H)-one (1.64 g, 10 mmol) and (carboxymethylene)triphenylphosphorane (5.22 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, reaction mixture was concentrated and loaded over silica-gel column. The column was eluted with hexane (500 ml) and later with 25% ethyl acetate. The product, ethyl(6-methoxy-1-benzofuran-3-yl)acetate was obtained as a white oil. Yield: 1.8 g (76%); 235 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35](O)=[O:36])[CH:12]=[CH:13][CH:14]=1.[NH2:39][C:40]1[N:41]=[N:42][C:43]([Cl:46])=[CH:44][CH:45]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:46][C:43]1[N:42]=[N:41][C:40]([NH:39][C:35]([CH:16]2[CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:38])[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:33])([CH3:32])[CH3:34])[NH:17]2)=[O:36])=[CH:45][CH:44]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(Cl)nn2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 50.8 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 52c (0.3 g, 0.51 mmol) was reacted with 3-amino-6-chloro-pyridazine (Alfa) (0.15 g, 1.2 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.6 g, 4.6 mmol) in CH2Cl2 at room temperature for 48 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-chloro-pyridazin-3-yl)-amide as a yellow solid (0.15 g, 51%).