Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]1[CH2:34][C:35](O)=[O:36]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:35](=[O:36])[CH2:34][C@H:29]5[CH2:30][O:31][CH2:32][CH2:33][O:28]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)C[C@H]1COCCO1
Agent: Cl
Product: O=C(C[C@H]1COCCO1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (54 mg, 74%), MS (ISP) m/z=459.5 [(M+H)+], mp 181° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) (S)-2-(1,4-dioxan-2-yl)acetic acid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:14]2[CH2:17][CH:16]([C:18]([NH:20][CH2:21][CH3:22])=O)[CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[OH-].[Na+]>O1CCCC1>[C:7]1([CH:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:14]2[CH2:17][CH:16]([CH2:18][NH:20][CH2:21][CH3:22])[CH2:15]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCNC(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCNCC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 85.3 %

Procedure:
To a suspension of 3.2 g (85 mmole) of lithium aluminum hydride in 50 ml of dry tetrahydrofuran was added dropwise, a solution of 8.5 g (28.0 mmole) of 1-(diphenylmethyl)-N-ethyl-3-azetidinecarboxamide in 50 ml of dry tetrahydrofuran. After the addition was complete, the reaction was refluxed for two hours, cooled to room temperature, and decomposed by the successive addition of 3.4 ml of water, 3.4 ml of 15% aqueous sodium hydroxide and 10.2 ml of water, titrating the final water addition to give a granular precipitate. The inorganic precipitate was removed by filtration, washed with tetrahydrofuran and evaporated in vacuo to give 6.7 g of 1-(diphenylmethyl)-N-ethyl-3-azetidinemethanamine as a heavy syrup. This was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:15]([O:17][CH2:18][CH3:19])=[CH2:16])CCC.[F-].[K+].C(OCC)C>CN(C)C=O.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>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[CH2:16])[N:5]=[CH:4][N:3]=1
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=C(OCC)c1ncnc(Cl)c1C
Temperature: 80 °C
Yield: 61.1 %

Procedure:
4,6-Dichloro-5-methylpyrimidine (2.0 g, 12.27 mmol), bis(triphenylphosphine)palladium(II) chloride (0.172 g, 0.245 mmol) and tributyl[1-(ethyloxy)ethenyl]stannane (4.48 ml, 13.25 mmol) were added together in N,N-dimethylformamide (DMF) (45.8 ml) and the resulting mixture was heated at 80° C. under argon for 18 hours. The reaction mixture was allowed to cool to room temperature and poured into an aqueous solution of potassium fluoride (10.4 g in 104 ml water). Diethyl ether (146 ml) was added and the solid was filtered, washed with diethyl ether (×2) and discarded. The filtrate was separated and the organic layer was washed with water, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by SP4 Biotage column chromatography eluting with a gradient of 0-20% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a yellow oil (1.49 g);
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6](Cl)[CH:5]=[C:4]([CH3:10])[C:3]=1[OH:11].[Cr](O)(O)(=O)=[O:13]>C(O)(=O)C>[CH3:1][C:2]1[C:3](=[O:11])[C:4]([CH3:10])=[CH:5][C:6](=[O:13])[C:7]=1[CH3:8]
Reactant: Cc1cc(Cl)c(C)c(C)c1O
Reactant: O=[Cr](=O)(O)O
Solvent: CC(=O)O
Product: CC1=CC(=O)C(C)=C(C)C1=O
Yield: 83.9 %

Procedure:
17.0 g (0.1 mole) of 2,3,6-trimethyl-4-chlorophenol obtained in Example 1 (A) was oxidized with a solution prepared by dissolving 15 g of chromic acid in 20 g of acetic acid. The reaction solution was treated in the same manner as in Example 1 to obtain 12.6 g of 2,3,6-trimethyl-p-benzoquinone (84% in yield).
Reaction SMILES: C(=O)(O)[O-].[Na+].S([O-])([O-])=O.[Na+].[Na+].[C:12]1([S:22](Cl)(=[O:24])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.Cl>O>[C:12]1([S:22]([OH:24])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: O
Product: O=S(O)c1cccc2ccccc12
Temperature: 25 °C
Yield: 62.4 %

Procedure:
To a vigorously stirred solution of sodium bicarbonate (8.4 g, 100 mmol) and anhydrous sodium sulphite (12 g, 95 mmol) in water (50 ml) at 70°-80° C., was added naphthalene-1-sulphonyl chloride (11.5 g, 50 mmol) in portions and with vigorous stirring. The temperature was kept at 70°-80° C. by intermittent heating. When the addition was complete, the mixture was heated and stirred at 70°-80° C. for a further hour. The mixture was then allowed to cool to room temperature over 4 hours and acidified with 2M hydrochloric acid. The precipitated solid was collected by filtration, washed with water, air dried and then recrystallised from aqueous ethanol to give naphthalene-1-sulphinic acid as a solid (6.0 g), m.p. 86 87° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]=[CH:13][N:14]([CH3:16])[CH3:15])#[N:2].C1CCCCC=1>CO.[Pd]>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([N:12]=[CH:13][N:14]([CH3:15])[CH3:16])=[C:3]([C:1]#[N:2])[CH:8]=1
Reactant: CN(C)C=Nc1ccc([N+](=O)[O-])cc1C#N
Agent: [Pd]
Solvent: CO
Solvent: C1=CCCCC1
Product: CN(C)C=Nc1ccc(N)cc1C#N
Yield: 90.7 %

Procedure:
A solution of N′-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine (30.0 g, 137 mmol), cyclohexene (200 mL) and 10% Pd on carbon (3.0 g) in methanol (1 L) was refluxed for 10 hours under a hydrogen atmosphere. The hot solution was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was recrystallized from dichloromethane/carbon tetrachloride to provide the product (23.4 g, 90%) as pale gray crystals.
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].[N:7]#[N:8].[CH3:9][C:10]([CH3:35])([O:12][C:13]([NH:15][C@H:16]([C:32]([OH:34])=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:14])[CH3:11].CO.CI>C(OCC)(=O)C>[N:7]#[N:8].[CH3:11][C:10]([CH3:35])([O:12][C:13]([NH:15][C@H:16]([C:32]([O:34][CH3:1])=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])=[O:14])[CH3:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: N#N
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CO
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.08 h

Procedure:
Cesium carbonate (2.14 g., 6.55 mmole) is added to a mixture of N2 -[(1,1-dimethylethoxy)carbonyl]-N6 -[(phenylmethoxy)carbonyl]-L-lysine (5.0 g., 13.10 mmole) and 20% aqueous methanol (30 ml.). The solution becomes homogeneous after 5 minutes, the methanol is stripped, and the residual water is removed azetropically with acetonitrile (twice). The resulting oil is taken up in dry methylene chloride (10 ml.) and treated with methyl iodide (1.6 ml., 2.0 eq.) at 25° in an argon atmosphere. After 4 hours the reaction mixture is taken up in ethyl acetate and washed successively with water, saturated sodium bicarbonate and brine, dried (MgSO4), and evaporated. The residue (4.7 g.) is chromatographed on silica (160 g.) eluting with hexane/ethyl acetate (3:1) to give 4.0 g. of N2 -[(1,1-dimethylethoxy)carbonyl]-N6 -[(phenylmethoxy)carbonyl]-L-lysine, methyl ester as an oil after evaporation. TLC (hexane/ethyl acetate; 2:1) major spot at Rf =0.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18]O)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:28])[N:13]2[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:49]>C(#N)C>[Br:49][CH2:18][C:16]1[CH:15]=[C:14]2[C:9]([CH2:10][NH:11][C:12](=[O:28])[N:13]2[C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:17]=1
Reactant: O=C1NCc2c(-c3ccccc3Cl)cc(CO)cc2N1c1c(Cl)cccc1Cl
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C1NCc2c(-c3ccccc3Cl)cc(CBr)cc2N1c1c(Cl)cccc1Cl

Procedure:
A solution of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-(hydroxymethyl)-3,4-dihydroquinazolin-2(1H)-one (500 mg, 1.15 mmol), triphenyl phosphine (363 mg, 1.38 mmol) and carbon tetrabromide (459 mg, 1.38 mmol) in acetonitrile (34 mL) was stirred at rt for 24 h. Removal of the solvent and subsequent purification by flash chromatography using 22% acetone/hexane as eluent provided 7-(bromomethyl)-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3,4-dihydroquinazolin-2(1H)-one as a white solid. 1H NMR (CDCl3, 500 MHz): δ 4.26 (d, 1H, J=14.7 Hz), 4.35 (abq, 2H, J=10.5 Hz), 4.44 (d, 1H, J=14.6 Hz), 5.01 (s, 1H), 6.18 (s, 1H), 6.96 (s, 1H), 7.30-7.60 (m, 7H). MS (API-ES+): 497 (M+H).
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[Si:13]([O:20][CH:21]([CH2:28][CH2:29][CH3:30])[CH2:22][C:23](OCC)=[O:24])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1COCC1>[CH3:9][O:8][P:7]([CH2:6][C:23](=[O:24])[CH2:22][CH:21]([O:20][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[CH2:28][CH2:29][CH3:30])(=[O:12])[O:10][CH3:11]
Reactant: COP(C)(=O)OC
Reactant: CCCC(CC(=O)OCC)O[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC(CC(=O)CP(=O)(OC)OC)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 36.2 %

Procedure:
n-Butyllithium (6.8 mL of a 1.6M solution in THF, 10.94 mmol) was added to a solution of dimethyl methylphosphonate (1.2 mL, 10.94 mmol) in THF (22 mL) at −78° C. After 0.5 h a solution of the ester 2 (2.0 g, 7.29 mmol) in THF (4 mL) was added. The reaction solution was allowed to warm to room temperature overnight on its own accord. After 16 h the reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic portion was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 2:1 hex/EtOAc followed by 1:1 hex/EtOAc) afforded 0.93 g (36%) of phosphonate 3 (see Scheme 1).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C@H:24]2[CH3:29])[N:3]=1.[CH2:30]([C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:30]([C:32]1[N:33]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@H:24]3[CH3:29])[N:3]=2)[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: C[C@@H]1COCCN1c1nc(Cl)nc2c1nc(CN1CCC(C(C)(C)O)CC1)n2C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOC[C@H]2C)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Temperature: 110 °C
Yield: 43.6 %

Procedure:
A mixture of 2-{1-[2-chloro-9-methyl-6-((R)-3-methylmorpholin-4-yl)-9H-purin-8-ylmethyl]piperidin-4-yl}propan-2-ol (120 mg, 0.28 mmol), 2-ethylbenzimidazole (46 mg, 0.31 mmol), tris(dibenzylideneacetone)dipalladium (7 mg, 2.5 mol %), XPhos (14 mg, 10 mol %) and Cs2CO3 (139 mg, 0.43 mmol) in dioxane (3 mL) was purged with argon then heated at 110° C. for 4 h in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH/DCM. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-20%) followed by (Si-PCC, MeOH:DCM, 0-10%) affording 781 as a white solid (65 mg, 43%). LCMS (method I): RT 2.64 min, [M+H]+ 533.3. 1H NMR (CDCl3, 400 MHz): δ 8.03-8.02 (1 H, m), 7.76-7.75 (1 H, m), 7.30-7.25 (2 H, m), 4.06-4.05 (1 H, m), 3.88 (3 H, s), 3.83 (2 H, s), 3.73 (2 H, s), 3.70-3.55 (2 H, m), 3.36 (2 H, q, J=7.48 Hz), 2.99-2.96 (2 H, m), 2.16-2.06 (2 H, m), 1.81-1.71 (2 H, m), 1.58 (2 H, brd s), 1.48-1.42 (6 H, m), 1.43-1.27 (3 H, m), 1.19 (6 H, s)
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=O)C.C(OC(C1C(C2C=CC(F)=CN=2)=NOC=1C)=O)C>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6]([CH2:4][OH:3])=[C:10]([CH3:11])[O:9][N:8]=2)=[N:13][CH:14]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cn2)noc1C
Agent: CCOC(=O)c1c(-c2ccc(F)cn2)noc1C
Product: Cc1onc(-c2ccc(Cl)cn2)c1CO
Yield: 73.2 %

Procedure:
As described for example 286c, 3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (1.26 g, 4.7 mmol) was converted, instead of 3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester, to the title compound (773 mg, 73%) which was obtained as an off white solid. MS: m/e=224.9 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:14](=[C:15]3[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]3)[CH:13]=[CH:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]2=1.[NH2:21][C:22]([CH3:27])([CH2:25][OH:26])[CH2:23][OH:24].C(N(CC)CC)C>O1CCCC1>[CH:10]1[C:11]2[CH:12]=[CH:13][C:14]3[C:5](=[CH:4][C:3]([CH2:2][NH:21][C:22]([CH3:27])([CH2:25][OH:26])[CH2:23][OH:24])=[C:20]4[C:15]=3[CH:16]=[CH:17][CH:18]=[CH:19]4)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: BrCc1cc2c3ccccc3ccc2c2ccccc12
Reactant: CC(N)(CO)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(CO)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A mixture of 6-bromomethylchrysene (4.82 g, 15 mmol), 2-amino-2-methylpropane-1,3diol (3.15 g, 30 mmol), and triethylamine (1.67 g, 16.5 mmol) was refluxed in tetrahydrofuran (75 mL) under nitrogen. After one hour all the solids had dissolved and NMR analysis indicated that the 6-bromomethylchrysene had been consumed. Water (150 mL) was added and the mixture was cooled to ambient temperature. The solids were collected by filtration, washed with water (3×30 mL), and dried in vacuo to give 3.67 g (71% yield) of 2-(6-chrysenylmethylamino)-2-methylpropane-1,3diol. 1H NMR (CDCl3) 1.19 (s, 3 H), 1.81 (br s, 1 H), 3.53 (d, J=5.0 Hz, 2 H), 4.39 (s, 2 H), 4.58 (t, J=5.0 Hz, 2 H), 7.78 (m, 4 H), 8.11 (m, 2 H), 8.45 (d, J=8.4 Hz, 1 H), 8.9 (m, 4 H).
Reaction SMILES: [CH2:1]([CH:3]1[NH:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4]1)[CH3:2].C1C=CC=CC=1.[Cl:20][CH:21]([Cl:25])[C:22](Cl)=[O:23]>C(N(CC)CC)C>[CH2:1]([CH:3]1[N:7]([C:22](=[O:23])[CH:21]([Cl:25])[Cl:20])[CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4]1)[CH3:2]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CCC1NCC(c2ccccc2)O1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCC1OC(c2ccccc2)CN1C(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Twenty-one and three tenths ml. of a solution containing 5.3 g of 2-ethyl-5-phenyl oxazolidine was diluted with 25 ml. of benzene and 3.1 g. of triethylamine was added. The mixture was cooled in a room temperature water bath and 4.4 g. of dichloroacetyl chloride was added dropwise with stirring. The stirring was continued for about 30 minutes after addition was complete. The solution was washed with water, separated, dried over magnesium sulfate and removed under vacuum. There was obtained a yield of 8.7 g. of the title compound, an oil, ND30 = 1.5600.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][NH:19][C:20]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21].C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:8][C:6]1[N:5]=[C:4]([CH3:9])[N:3]=[C:2]([N:25]2[CH2:26][CH2:27][CH:22]([C:20]([NH:19][CH2:18][C:12]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=3[Cl:10])=[O:21])[CH2:23][CH2:24]2)[N:7]=1
Reactant: Cc1nc(Cl)nc(Cl)n1
Reactant: O=C(NCc1ccc(Cl)cc1Cl)C1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Cl)nc(N2CCC(C(=O)NCc3ccc(Cl)cc3Cl)CC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.6 %

Procedure:
To a 25 mL round-bottomed flask was added 2,4-dichloro-6-methyl-1,3,5-triazine (800 mg, 2.79 mmol) and N-[(2,4-dichlorophenyl)methyl]-4-piperidinecarboxamide (859 mg, 2.79 mmol) in acetonitrile (8.7 mL). Diisopropylethylamine (1.46 mL, 8.36 mmol) was added to give a yellow suspension. The reaction mixture was stirred at room temperature for 15 minutes, at which time LC-MS showed the reaction was complete. This suspension was filtered through a Buchner funnel to afford 1-(4-chloro-6-methyl-1,3,5-triazin-2-yl)-N-[(2,4-dichlorophenyl)methyl]-4-piperidinecarboxamide (596 mg, 1.44 mmol, 52%) as a white solid which was used in the next step without further purification. MS (ES) m/e 416 [M+H]+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[Cl:13][C:14]1[CH:27]=[CH:26][C:25]2[CH:24]3[CH2:28][C:17]([CH2:29][N:30]4[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]4)([C:18]4[C:23]3=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:16]=2[CH:15]=1>O1CCCC1>[Cl:13][C:14]1[CH:27]=[CH:26][C:25]2[CH:24]3[CH2:28][C:17]([CH2:29][N:30]4[CH2:31][CH2:32][C:33]([C:7]5[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=5)([OH:36])[CH2:34][CH2:35]4)([C:18]4[C:23]3=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:16]=2[CH:15]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2cccnc2)CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Temperature: -75 °C
Yield: 80.9 %

Procedure:
To a cooled solution (-90° C.) of n-butyllithium (2.5M in hexane, 2.40 mL, 6.0 mmol, 1.5 eq) in tetrahydrofuran (40 mL) under nitrogen was added freshly distilled 3-bromopyridine (0.540 mL, 5.6 mmol, 1.4 eq). The metal-halogen exchange reaction was warmed to -75° C. and maintained for 1.5 h. During that time a dark green solution evolved with the appearance of fine particulate. A solution of 1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (1.35 g, 4.0 mmol) in tetrahydrofuran (10 mL) was then added dropwise with considerable lightening of the solution color to a deep yellow. The reaction was warmed to room temperature over 1 h and quenched with water (50 mL). The aqueous phase was extracted with ethyl acetate (3×60 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to an oil. The reaction mixture was purified by flash chromatography over silica gel (80 mL, eluent: ethyl acetate) to yield 1.35 g (81%) of the title compound as a white solid. TLC analysis (Rf 0.20, ethyl acetate). 1H NMR (D6-DMSO, 300 MHz) 8.69 (br s, 1H), 8.41 (d, J=4.5 Hz, 1H), 7.83 (dt, J=8.0 Hz, 1H), 7.29 (m, 5H), 6.95 (m, 3H), 5.05 (s, 1H), 4.35 (s, 1H), 3.41 (m, 2H), 3.34 (s, 1H), 2.75 (m, 4H), 1.92 (m, 2H), 1.62 (m, 2H) MS (CI, CH4) m/z 417 (M+1,100), 419 (36), 445 (M+29,15), 399 (15). The free base was dissolved in diethyl ether containing a small amount of methylene chloride, acidified with ethereal HCl, and the hydrochloride salt suspension was diluted with additional ether. The salt was filtered, washed with fresh ether and dried in vacuo (50° C., 13 pascal, 18 h) to yield a white solid, mp 225°-228° C. (dec).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[C@H:20]([CH3:21])[CH2:19][CH2:18][CH2:17][C@@H:16]2[CH3:22])[C:10]=1[F:23].[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[C:10]([F:23])=[C:11]([N:15]2[C@H:20]([CH3:21])[CH2:19][CH2:18][CH2:17][C@@H:16]2[CH3:22])[N:12]=[CH:13][N:14]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: C[C@@H]1CCC[C@H](C)N1c1ncnc(Cl)c1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1ncnc(N2[C@H](C)CCC[C@@H]2C)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.9 %

Procedure:
0.05 g of sodium hydride (60% oil suspention) was suspended in 2 ml of tetrahydrofuran. 0.3 ml of tetrahydrofuran solution of 0.09 g of 2-butyn-1-ol was added dropwise at room temperature therein, and the mixture was stirred for 10 minutes. Into the mixture was added dropwise 0.3 ml of tetrahydrofuran solution of 0.21 g of 6-chloro-4-(cis-2,6-dimethylpiperidino)-5-fluoropyrimidine at room temperature, and stirred for 6 hours at 60° C. After the reaction mixture was cooled to near room temperature, the reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.21 g of 4-(2-butynyloxy)-6-(cis-2,6-dimethylpiperidino)-5-fluoropyrimidine (hereinafter, referred to as Compound (49)).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([CH:14]([F:16])[F:15])[C@H:10]([O:17][C:18]2[N:19]=[N:20][C:21]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:26][CH:25]=3)[CH:23]=2)[CH2:9]1)=O)(C)(C)C.[ClH:41]>C(Cl)Cl.O1CCOCC1>[ClH:41].[ClH:41].[CH2:37]([C:21]1[N:20]=[N:19][C:18]([O:17][C@H:10]2[C@H:11]([CH:14]([F:16])[F:15])[CH2:12][CH2:13][NH:8][CH2:9]2)=[CH:23][C:22]=1[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)=[CH:26][CH:25]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCc1nnc(O[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2C(F)F)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCc1nnc(O[C@@H]2CNCC[C@H]2C(F)F)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 1 h

Procedure:
To a solution of (±)-trans-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-4-difluoromethyl-piperidine-1-carboxylic acid tert-butyl ester (0.32 mmol, 0.18 g) in DCM (0.75 mL) was added 4 N HCl in dioxane (0.75 mL). The solution was stirred for 1 hour. The solvents were removed with reduced pressure and the salt was triturated with diethyl ether and filtered to give (±)-trans-3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(4-difluoromethyl-piperidin-3-yloxy)-pyridazine dihydrochloride (0.14 g).