Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([C:21]2[C:30]([F:31])=[CH:29][CH:28]=[C:27]3[C:22]=2[N:23]=[C:24]([O:32][CH3:33])[CH:25]=[N:26]3)[C:17](OC)=[O:18])[CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].C(=O)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.C(#N)C.O>[F:31][C:30]1[C:21]([CH:16]([CH2:17][OH:18])[CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:4])[CH3:3])[CH2:14][CH2:13]2)=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][C:24]([O:32][CH3:33])=[N:23]2
Reactant: COC(=O)C(CN1CCC(NC(=O)OC(C)(C)C)CC1)c1c(F)ccc2ncc(OC)nc12
Agent: O=C=O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cnc2ccc(F)c(C(CO)CN3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: -35 °C
Reaction time: 7 h
Yield: 60 %

Procedure:
A solution of methyl 3-[4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-piperidinyl]-2-[6-fluoro-3-(methyloxy)-5-quinoxalinyl]propanoate (21.8 g, 47.2 mmol) in dry tetrahydrofuran (500 ml) was cooled in a CO2(s)/acetonitrile/water bath (−40 to −45° C.) and treated slowly with lithium aluminium hydride (1M in tetrahydrofuran, 76.2 ml). The mixture was stirred at −30 to −40° C. (internal temp.) for 7 h, with a further addition of lithium aluminium hydride (8 ml) after 5.5 h. Sodium hydroxide (2M) was added cautiously dropwise until a filterable precipitate was obtained. The mixture was diluted with ethyl acetate and filtered through kieselguhr, washed through with ethyl acetate and evaporated. The crude product was chromatographed on silica (1000 g), eluting with 0-6% methanol/dichloromethane to give the desired product (12.31 g), still containing some impurities, and later fractions containing a 1:1 mixture (7.58 g) of desired product and 1,1-dimethylethyl (1-{2-[6-fluoro-3-(methyloxy)-1,2-dihydro-5-quinoxalinyl]-3-hydroxypropyl}-4-piperidinyl)carbamate.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].CS([O-])(=O)=O.CS(Cl)(=O)=O.[Cl:35][C:36]1[CH:50]=[CH:49][C:39]2[S:40][C:41]3[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=3[CH2:43][NH:44][C:38]=2[CH:37]=1.C(N(C(C)C)CC)(C)C>C1COCC1.C1(C)C=CC=CC=1>[Cl:35][C:36]1[CH:50]=[CH:49][C:39]2[S:40][C:41]3[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=3[CH2:43][N:44]([CH2:4][CH:6]3[CH2:7][CH2:8][N:9]([CH2:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:10][CH2:11]3)[C:38]=2[CH:37]=1
Reactant: Clc1ccc2c(c1)NCc1ccccc1S2
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: [Al+3]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Clc1ccc2c(c1)N(CC1CCN(Cc3ccccc3)CC1)Cc1ccccc1S2

Procedure:
A sample of 1-benzylpiperidine-4-carboxylic acid ethyl ester is reduced to 1-benzylpiperidine-4-hydroxymethyl by treatment with lithium aluminum hydride (LiAlH4) in THF. This material is converted to its methane sulfonate by reaction with methanesulfonyl chloride. This material, 1-benzylpiperidine-4-methylmethane sulfonate, the product of Example 104, and diisopropylethyl amine are refluxed in toluene the provide the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([CH3:23])[NH:16][C:15]([CH2:24][O:25][CH2:26][CH2:27][NH:28][CH3:29])=[C:14]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([CH3:23])[NH:16][C:15]([CH2:24][O:25][CH2:26][CH2:27][N:28]([S:2]([CH3:1])(=[O:4])=[O:3])[CH3:29])=[C:14]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1=C(COCCNC)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=C(COCCN(C)S(C)(=O)=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
Methanesulphonyl chloride (0.144 g) was added to a solution of 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-[2-(methylamino)ethoxy methyl]-1,4-dihydropyridine (0.50 g) and triethylamine (0.126 g) in dichloromethane (15 ml). The mixture was stirred at room temperature for 1 hour, poured into ice-water and the layers separated. The organic layer was washed with water, dried (Na2SO4) and evaporated. Scratching the residual oil afforded a solid which was recrystallised from methanol to give the title compound (0.33 g), m.p. 93°-95° C. Found: C, 53.32; H, 5.97; N, 5.64. C22H29ClN2O7S requires C, 53.32; H, 5.92; N, 5.71%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:22].CO>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:22])[C:13](=[O:18])[CH2:12][CH2:11]3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCc2cc(-c3cccc(F)c3)ccc2N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN1C(=O)CCc2cc(-c3cccc(F)c3)ccc21
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
To a cooled (0° C.) solution of 6-(3-fluorophenyl)-3,4-dihydroquinolin-2(1H)-one (48 mg, 0.20 mmol) in anhydrous tetrahydrofuran (2 mL) was added 95% sodium hydride (10 mg, 0.40 mmol). The reaction mixture was stirred for 5 minutes, then warmed to 40° C. for 15 minutes under an atmosphere of dry N2. Iodomethane (142 mg, 1.00 mmol) was added, and the resulting mixture was stirred at room temperature for 15 hours. Methanol (2 mL) was added, and the mixture stirred for 10 minutes. Solvent was removed from the reaction mixture under reduced pressure, ethyl acetate (30 mL) and 30% ammonium chloride (10 mL) were added, the organic phase was washed with water (10 mL), 30% ammonium chloride (15 mL) and brine (15 mL), and the organic layer was concentrated under reduced pressure to give 6-(3-fluorophenyl)-1-methyl-3,4-dihydroquinolin-2(1H)-one. MS mz 256.1 (M+H), anal HPLC 92% in purity. 1H NMR (400 MHz; CDCl3) δ 7.46 (dd, J=8.6 Hz, 2.3 Hz, 1H); 7.30-7.42 (m, 3H); 7.25 (m, 1H); 6.98-7.10 (m, 2H); 3.39 (s, 3H); 2.97 (t, J=7.4 Hz, 2H); 2.70 (t, J=7.4 Hz, 2H).
Reaction SMILES: [Br-].[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH3+:14])[CH2:10][CH2:9]1.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl.OS([O-])(=O)=O.[K+].CC(OC)(C)C>[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([NH:14][S:23]([C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:27])[F:28])=[CH:22][CH:21]=2)(=[O:25])=[O:24])[CH2:12][CH2:13]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: [NH3+][C@H]1CC[C@H](CCCCCBr)CC1
Agent: O=S(=O)([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: O=S(=O)(N[C@H]1CC[C@H](CCCCCBr)CC1)c1ccc(C(F)(F)F)cc1
Reaction time: 1.5 h

Procedure:
A solution of 1.0 g (3.04 mmol) of trans-4-(5-Bromo-pentyl)-cyclohexylammonium bromide in 12 ml CH2Cl2 was first cooled at 0° C., treated with 0.8 g (3.27 mmol) 4-(trifluoromethyl)benzenesulfonylchloride and then with 1.2 ml (7.01 mmol; 2.3 equivalents) of Hünigsbase (during 30 min). After total 1.5 h at 0° C., the mixture was dissolved in aqueous 10% KHSO4/TBME (3×). The organic phases were washed with aqueous saturated NaHCO3 and aqueous 10% NaCl, dried over Na2SO4 and evaporated to give 1.38 g crude product which was crystallized (CH2Cl2/hexane) to give 1.26 g (91%) of pure trans-N-[4-(5-Bromo-pentyl)-cyclohexyl]-4-trifluoromethyl-benzenesulfonamide, MS: 454 (M−H−, 1Br).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]1.C1([O:23][C:24](=O)[NH:25][CH2:26][CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([F:37])[CH:35]=3)[NH:30][CH:29]=2)C=CC=CC=1>O1CCOCC1>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH:9][C:24]([NH:25][CH2:26][CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([F:37])[CH:35]=3)[NH:30][CH:29]=2)=[O:23])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CCC(N)CC1
Reactant: O=C(NCCc1c[nH]c2ccc(F)cc12)Oc1ccccc1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(NC(=O)NCCc2c[nH]c3ccc(F)cc23)CC1

Procedure:
The more polar diastereoisomer of 4-dimethylamino-4-phenyl-cyclohexylamine (271 mg, 1.24 mmole) was added to a solution of [2-(5-fluoro-1H-indol-3-yl)-ethyl]-carbamic acid phenyl ester (370 mg, 1.24 mmole) in dioxane (20 ml). The batch was then refluxed for 8 h. Working up was performed by removing dioxane by distillation and diluting the batch with water (10 ml). The batch was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and evaporated. The more polar diastereoisomer of 1-(4-dimethylamino-4-phenylcyclohexyl)-3-[2-(5-fluoro-1H-indol-3-yl)ethyl]urea was obtained after chromatography on silica gel with methanol as a colorless oil in a yield of 267 mg (51%).
Reaction SMILES: [CH3:1][N:2]([C:21]1[CH:29]=[C:28]2[C:24]([C:25]([CH3:30])=[N:26][NH:27]2)=[CH:23][CH:22]=1)[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=2)[N:4]=1.[C:31]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C.O>[CH3:31][N:26]1[C:25]([CH3:30])=[C:24]2[C:28]([CH:29]=[C:21]([N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=4)[N:4]=3)[CH:22]=[CH:23]2)=[N:27]1
Reactant: O=C([O-])[O-]
Reactant: Cc1n[nH]c2cc(N(C)c3ccnc(Nc4cccc(CS(C)(=O)=O)c4)n3)ccc12
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cc1c2ccc(N(C)c3ccnc(Nc4cccc(CS(C)(=O)=O)c4)n3)cc2nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a solution of N4-methyl-N4-(3-methyl-1H-indazol-6-yl)-N2-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine (Example 23) (389 mg, 0.92 mmol) in DMF (4 ml) was added Cs2CO3 (600 mg, 1.84 mmol) followed by iodomethane (64 ul, 1.02 mmol). The mixture was stirred at rt overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated. Purification of crude product by prep TLC provided 120 mg N4-(2,3-dimethyl-2H-indazol-6-yl)-N4-methyl-N2-{3-[(methylsulfonyl)methyl]-phenyl}-2,4-pyrimidinediamine. 1H NMR (300 MHz, d6DMSO) δ 9.23 (s, 1H), 7.84-7.86 (m, 2H), 7.74 (d, J=8.8 Hz, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.42 (s, 1H), 7.18 (t, J=7.8 Hz, 1H), 6.85-6.90 (m, 2H), 5.81 (d, J=5.8 Hz, 1H), 4.23 (s, 2H), 4.04 (s, 3H), 3.45 (s, 3H), 2.83 (s, 3H), 2.61 (s, 3H). MS (ES+, m/z) 437 (M+H).
Reaction SMILES: Cl.Cl.[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5].C(N(C(C)C)CC)(C)C.Cl[C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38]>>[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])[CH2:23][CH2:22]3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:5])=[O:6]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)nc2)cc1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)cn2)CC1
Yield: 97 %

Procedure:
The title compound (151 mg, 98%) was prepared as a white solid 5-[4-(methylsulfonyl)phenyl]-2-[(4-piperidinylmethyl)oxy]pyridine dihydrochloride (0.15 g, 0.36 mmol), diisopropylethylamine (0.26 mL, 1.43 mmol), and isopropyl chloroformate (1.0M in toluene, 0.40 mL, 0.40 mmol) in a manner similar to Example 66, Step 2. 1H NMR (400 MHz, CD3OD): δ 8.46 (d, 1H, J=2.4 Hz), 8.10-8.00 (m, 3H), 7.86 (d, 2H, J=8.3 Hz), 6.92 (d, 1H, J=8.5 Hz), 4.90-4.80 (m, 1H), 4.21 (d, 2H, J=6.3 Hz), 4.20-4.10 (m, 2H), 3.14 (s, 3H), 2.90-2.75 (m, 2H), 2.10-2.00 (m, 1H), 1.90-1.80 (m, 2H), 1.35-1.20 (m, 8H); LRMS (ESI), m/z 433 (M+H).
Reaction SMILES: [Na].Cl.[F:3][C:4]1[CH:5]=[C:6]([NH:11][NH2:12])[CH:7]=[CH:8][C:9]=1[F:10].C(O/[CH:16]=[CH:17]/[C:18]#[N:19])C.Cl.[OH-].[Na+]>O.C(O)C>[F:3][C:4]1[CH:5]=[C:6]([N:11]2[CH:16]=[CH:17][C:18]([NH2:19])=[N:12]2)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: NNc1ccc(F)c(F)c1
Reactant: CCO/C=C/C#N
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: Nc1ccn(-c2ccc(F)c(F)c2)n1
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
To ethanol (28 ml) was added sodium (0.407 g, 17.7 mmol), and the mixture was stirred about 30 minutes. To this, (3,4-difluorophenyl)hydrazine hydrochloride (1.00 g, 5.54 mmol) and (E)-3-ethoxyacrylonitrile (0.912 ml, 8.86 mmol) were added, and the reaction was heated to reflux for 16 hours. The reaction was diluted with water (30 ml) and acidified to pH 3 with 5M hydrochloric acid. The reaction was allowed to stir at ambient temperature for another 2 hours and was then neutralized (pH 7) by the addition of 5M sodium hydroxide. The reaction was concentrated to remove most of the ethanol. The resulting suspension was extracted twice with EtOAc, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography, eluting with a linear gradient of 20-100% EtOAc/hexanes to yield the desired product (0.250 g, 1.28 mmol, 23.1% yield).
Reaction SMILES: CO.[OH-].[Na+].C[O:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]#[C:17][CH:18]2[CH2:20][CH2:19]2)=[CH:10][CH:9]=1.Cl>O.C(OCC)(=O)C.O1CCOCC1>[CH:18]1([C:17]#[C:16][C:15]#[C:14][C:11]2[CH:10]=[CH:9][C:8]([C:7]([OH:21])=[O:6])=[CH:13][CH:12]=2)[CH2:20][CH2:19]1
Reactant: COC(=O)c1ccc(C#CC#CC2CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(C#CC#CC2CC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.3 %

Procedure:
Methanol (3.0 mL), 1,4-dioxane (3.0 mL), and a 20% aqueous solution (1.5 mL) of sodium hydroxide were added to 4-(4-cyclopropylbuta-1,3-diyn-1-yl)benzoic acid methyl ester (0.31 g) as obtained in Example 6-(1), whereafter the mixture was stirred for 2.5 hours at room temperature. Ethyl acetate and water were added, and the mixture was adjusted to pH 3 with 6 mol/L of hydrochloric acid to isolate the organic layer. The extract was dried over anhydrous magnesium sulfate, and then the desiccant was filtered out. The solvent was distilled off under reduced pressure to obtain 4-(4-cyclopropylbuta-1,3-diyn-1-yl)benzoic acid (dark brown solid) (0.28 g, 94%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12](I)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:20]([C@@H:22]1[CH2:27][CH2:26][CH2:25][C@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1)#[CH:21].O.C(OCC)(=O)C>CN(C)C=O.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:21]#[C:20][C@@H:22]3[CH2:27][CH2:26][CH2:25][C@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:23]3)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1I
Reactant: C#C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1C#C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reaction time: 0.75 h
Yield: 103.5 %

Procedure:
To a solution of N2-(3-fluorophenyl)-5-iodo-N4-propylpyrimidine-2,4-diamine (F2, 100 mg), bis(triphenylphosphine)palladium(II) dichloride (19 mg) and copper(I) iodide (10 mg) in N,N-dimethylformamide (2.7 mL), triethylamine (188 μL) and tert-butyl ((1S*,3R*)-3-ethynylcyclohexyl)carbamate (M3, 90 mg) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour and 45 minutes. To the reaction mixture, water and ethyl acetate were added. The organic layer was separated, washed successively with saturated ammonium chloride and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 94 to 60% hexane in ethyl acetate) to obtain tert-butyl ((1S*,3R*)-3-((2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)ethynyl)cyclohexyl)carbamate (M4, 130 mg) as yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][C:7](N)=[CH:6][C:5]=1[Cl:12].N([O-])=O.[Na+].[H+].[B-](F)(F)(F)[F:20]>Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([F:20])=[CH:6][C:5]=1[Cl:12]
Reactant: COC(=O)c1c(Cl)cc(N)cc1Cl
Reactant: F[B-](F)(F)F
Agent: Cl
Agent: O=N[O-]
Agent: [H+]
Product: COC(=O)c1c(Cl)cc(F)cc1Cl
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
4-Amino-2,6-dichlorobenzoic acid methyl ester (0.5 g) was suspended in 15% HCl (10 mL) and stirred for 30 min then cooled to 0-5° C. After addition of NaNO2 (188 mg) in small portions, the mixture was stirred for 30 min at that temperature. Precooled HBF4 (0.46 mL) was added and the mixture was stirred for 30 min. The resulting precipitate was collected and washed successively with cold water, MeOH and ether. The solid was then dried over conc. H2SO4 in a vacuum dessicator for a few days. The solid was heated with a bunsen burner until all the solid has melted. The resulting fumes were collected over water (distilling apparatus). The product was then recovered with Et2O. The solvent was evaporated and the crude product was purified by preparative TLC (silica gel; eluent: hexane/AcOEt 50:1 to 20:1) to give 2,6-dichloro-4-fluorobenzoic acid methyl ester (241 mg).
Reaction SMILES: [CH:1]1([CH:13]=[CH:14][C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Mg].CCCCCC.C(OCC)C>CO>[CH:1]1([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C=CC1CCCCCCCCCCC1
Agent: [Mg]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(=O)CCC1CCCCCCCCCCC1
Temperature: 160 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
To a solution of 12.6 g (50 mmol) of methyl 3-cyclododecylprop-2-enoate in 100 ml of methanol is added 3.6 g (150 mmol), 3 equiv) of magnesium metal (activated by prior heating to 160° C.) and the mixture is stirred at room temperature for 2 hours (ice bath cooling is applied when necessary to control exothermic excursions). The reaction mixture is digested with ice cold 2N hydrochloric acid and is extracted with ethyl ether (3 times). The combined ethereal extracts are washed with 2N hydrochloric acid and are dried over magnesium sulfate. Filtration and evaporation gives an oily solid. Flash chromatography on silica gel using hexane/ethyl ether (10:1) as eluting solvent affords 7.80 g of the title compound: IR 1748cm-1 ; NMR (CDCl3) δ 1.33 (m, 23H), 1.54 (t, 2H, J=8 Hz), 2.31 (t, 2H, J=8 Hz), 3.66(s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.C1N=C[N:19]([C:22](N2C=NC=C2)=[O:23])C=1.N>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:22]([NH2:19])=[O:23]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(I)cc1F
Agent: N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: NC(=O)Nc1ccc(I)cc1F
Temperature: 25 °C
Yield: 99.4 %

Procedure:
Under argon atmosphere, to a solution of 2-fluoro-4-iodoaniline 47 (20.0 g) and triethylamine (23.6 ml) in chloroform (200 ml) was added N,N-carbonyldiimidazole (27.4 g) with stirring under ice-cooling. After the completion of the addition, the mixture was stirred under ice-cooling for 15 min and at room temperature for 4 hrs. The reaction mixture was ice-cooled, and 28% aqueous ammonia (100 ml) was added dropwise. The mixture was stirred at room temperature for 1.5 hrs. The precipitated crystals were collected by filtration, washed with water and dried to give (2-fluoro-4-iodophenyl)-urea 78 (23.5 g, yield 98.8%) as pale-pink crystals.
Reaction SMILES: [CH:1](OC)([O:4][CH3:5])[O:2][CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:20][C:21]1[N:26]=[CH:25][C:24](C=O)=[CH:23][CH:22]=1>CO>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([CH:1]([O:4][CH3:5])[O:2][CH3:3])=[CH:25][N:26]=1
Reactant: COC(OC)OC
Reactant: O=Cc1ccc(Br)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(OC)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.3 %

Procedure:
Trimethyl orthoformate (643 μl, 5.9 mmol) and p-toluene sulphonic acid monohydrate (102 mg, 0.54 mmol) were added to 6-bromo-pyridine-3-carbaldehyde (1 g, 5.37 mmol) dissolved in MeOH (40 ml). The mixture was stirred for 24 h at room temperature and then partitioned between water and Et2O. The organic extract was washed with water, 5% Na2CO3, dried over Na2SO4 and evaporated under vacuo to give 1.2 g of 2-bromo-5-dimethoxymethyl-pyridine as a brown oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si](C(C)(C)C)(C)C)[CH2:10][C@H:9]1[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].[H-]>O1CCCC1>[F:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:22][CH2:21][C@@H:9]2[CH2:10][C@@H:11]([OH:13])[CH2:12][N:8]2[CH3:6])=[C:25]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH:26]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCOc1ccc(F)cc1CCc1ccc(F)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CN1C[C@H](O)C[C@H]1CCOc1ccc(F)cc1CCc1ccc(F)cc1
Yield: 59 %

Procedure:
398 mg of (2R,4R)-1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-2-[2-{4-fluoro-2-[2-(4-fluorophenyl)ethyl]phenoxy}ethyl]pyrrolidine [prepared as described in step (a) above] were dissolved in 10 ml of tetrahydrofiran, and the resulting solution was added dropwise to a suspension of 81 mg of lithium aluminum hydride in 10 ml of tetrahydrofuran, whilst ice-cooling and stirring. The resulting mixture was then heated under reflux for 1 hour. At the end of this time, the reaction mixture was cooled on ice, and sodium sulfate decahydrate was added in order to decompose any excess hydride. Insoluble substances were removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was then purified by silica gel column chromatography, using a 7:3 by volume mixture of methylene chloride and methanol as the eluent, to give 151 mg (yield 59%) of the title compound as a colorless oily substance.