Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].FC(F)(F)S(O[C@H:13]([CH3:18])[C:14](OC)=[O:15])(=O)=O>>[CH3:18][C@H:13]1[C:14](=[O:15])[O:4][CH2:3][C:2]([CH3:6])([CH3:5])[NH:1]1
Reactant: CC(C)(N)CO
Reactant: COC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Product: C[C@@H]1NC(C)(C)COC1=O

Procedure:
In some embodiments, various compounds of the present invention may be prepared by a novel convergent synthetic approach for the preparation of 2-substituted morpholinols as outlined in Scheme 3. This approach utilizes a nucleophilic addition of Grignard reagents to (35)-3,5,5-trimethylmorpholin-2-one (15). Treatment of methyl (R)-(+)-lactate (13) with trifluoromethanesulfonic anhydride and 2,6-lutidine at 0° C., gives methyl (2R)-2-{[(trifluoromethyl)sulfonyl]oxy}propionate (14) in 77% yield. The alkylation of 2-amino-2-methyl-1-propanol with triflate 14 at −40° C. for 2 h and overnight at room temperature, and subsequent cyclization affords 15. The addition of the appropriate arylmagnesium bromide to 15 provides the desired compounds. The C-3 stereocenter of these compounds is derived from the lactate, rather than created by a synthetic transformation such as the Sharpless hydroxylation used in Scheme 1. In some embodiments, this center was then leveraged to create the second C-2 stereocenter. The resulting stereochemistry at C-2 was a result of either facial selectivity during the Grignard addition anti to the C-3 methyl group and/or a thermodynamic equilibrium of the final product to the S,S-configuration since the resulting product can ring open and close. The ring opened form loses its C-2 stereochemistry, forming a ketone. This route is more convergent than the Sharpless hydroxylation route, and in some embodiments, may be more reliable, requiring far less analytical work.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[CH3:2].Br[C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][NH:24]2)=[CH:20][CH:19]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[CH:5]=[C:6]([C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][NH:24]2)=[CH:20][CH:19]=1)[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1c[nH]c2ccccc12
Reactant: Brc1ccc2cc[nH]c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Product: CCOC(=O)C=C(c1ccc2cc[nH]c2c1)c1c[nH]c2ccccc12
Temperature: 114 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
A sealed tube flushed with N2 was charged with 3-(1H-indol-3-yl)-acrylic acid ethyl ester (323 mg, 1.5 mmol), 6-bromoindole (196 mg, 1 mmol), tetra-butylammonium bromide (64.4 mg, 0.2 mmol), TEA (209 μl, 1.5 mmol) and palladium-dichloro-[bis(tri-ortho-tolyl)phophine] (39.3 mg, 0.05 mmol). The mixture was stirred at 114° C. for 1 hour, cooled to room temperature, dissolved in DCM, and purified via flash chromatography (hexane/EtOAc) to afford 3-(1H-indol-6-yl)-3-(1H-indol-3-yl)-acrylic acid ethyl ester XXVI (250 mg, yellow oil) as a mixture of geometric isomers.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][NH2:25]>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:6]2[C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=[C:2]2[NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:28]([Cl:29])=[C:21]([Cl:20])[CH:22]=2)=[CH:14][CH:13]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: ClCc1ccc(Cl)cc1
Product: Clc1ccc(Cn2c(NCc3ccc(Cl)c(Cl)c3)nc3ccccc32)cc1

Procedure:
The title compound was prepared by Procedure C in two steps from 2-aminobenzimidazole, 4-chlorobenzyl chloride and, subsequently, 3,4-dichlorobenzaldehyde. The product was isolated by preparative LCMS to give the title compound as the free base (yellowish oil). Alternatively, the title compound can be prepared in two steps from 2-chlorobenzimidazole, 4-chlorobenzyl chloride and 3,4-dichlorobenzylamine by use of either Procedure B or by Procedure D. MS(ES+) m/z 416 (M+, 100). 1NMR (CDCl3) δ 4.70 (s, 2H), 5.23 (s, 2H), 7.08-7.33 (m, 11H), 7.46-7.50 (m, 1H).
Reaction SMILES: [CH2:1]1[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1>C1CCCCC1.C(OCC)(=O)C>[CH2:1]1[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: O=C(O)CCCCC1CCSS1
Temperature: -7.5 °C
Yield: 86.5 %

Procedure:
A solution which contained 20.0 g R-(+)-thioctic acid and 5.0 g S-(-)-thioctic acid in a mixture of 225 ml cyclohexane and 25 ml ethyl acetate was cooled off from 35 to 40° C. down to -5 to -10° C., filtered and dried. 17.3 g thioctic acid were obtained in the novel modification as first crystallizate. The R-(+)-thioctic acid content was 75.6% with a melting range of 49 to 54° C.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[C:10]1([CH:16]2[CH2:21][CH2:20][CH:19]([C:22]3[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[C:10]1([CH:16]2[CH2:17][CH2:18][CH:19]([C:22]3[C:23]4=[N:28][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:24]4[CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1C1CCC(c2ccccc2)CC1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(C3CCC(c4ccccc4)CC3)C2=N1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 29.2 mg) in THF (dry) (2 mL) was added 2-chloroethanesulfonyl chloride (0.046 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-phenylcyclohexyl)pyridin-2-amine (36.8 mg) in THF (dry) (2 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen overnight. The mixture was quenched with water at 0° C. carefully and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) and crystallized from EtOAc-hexane to give the title compound (15.7 mg) as an off-white crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([I:11])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](Cl)=[O:18].Cl>N1C=CC=CC=1>[I:11][C:4]1[S:3][C:2]([NH:1][C:17]([C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)=[O:18])=[N:6][C:5]=1[C:7]([F:10])([F:8])[F:9]
Reactant: Nc1nc(C(F)(F)F)c(I)s1
Reactant: O=C(Cl)c1cccs1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1nc(C(F)(F)F)c(I)s1)c1cccs1
Temperature: 0 °C
Yield: 72.8 %

Procedure:
2-Amino-5-iodo-4-trifluoromethylthiazole (1.2 g) was dissolved in pyridine (2 ml) and thiophene-2-carbonyl chloride (0.80 g) was added at room temperature with stirring. The mixture was stirred for 6 hr at room temperature. The mixture was poured into ice water and acidified with aqueous hydrochloric acid then extracted with chloroform The chloroform layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The solid thus obtained was recrystallized from methanol to give N-(5-iodo-4-trifluoromethylthiazol-2-yl)thiophene-2-carboxamide (1.2 g), m. p. 184-185° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C@@H:19]1[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20]1.O>CN(C=O)C.CCCCC>[CH3:24][C:21]1([CH3:25])[O:20][C@H:19]([CH2:18][O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:23][O:22]1
Reactant: CC1(C)OC[C@@H](CCl)O1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCC
Product: CC1(C)OC[C@@H](COc2cccc([N+](=O)[O-])c2)O1
Temperature: 160 °C
Yield: 52.1 %

Procedure:
A mixture of 3-nitrophenol 102 (2.00 g, 14.4 mmol), potassium carbonate (4.96 g, 35.9 mmol) and (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane 103 (2.55 mL, 18.7 mmol) in DMF (20 mL) was heated in a microwave reactor at 160° C. for 4 h. The crude reaction mixture was poured into H2O and extracted with dichloromethane (3×15 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by chromatography using ethyl acetate: pentane to obtain (R)-2,2-dimethyl-4-((3-nitrophenoxy)methyl)-1,3-dioxolane 104 (1.90 g, 52% yield) as an amber-colored oil.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.O>C1(C)C=CC=CC=1>[N:26]1([C:22]2[CH2:23][CH2:24][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:20][CH:21]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(N2CCCC2)CC1

Procedure:
Catalytic amounts of p-toluenesulfonic acid (0.47 g, 0.27 mmol) were added to a solution of N-Boc-4-piperidone (5 g, 25.12 mmol) and pyrrolidine (1.96 g, 27.63 mmol) in toluene (100 ml) and the mixture was stirred under reflux for 2 hours, using a water separator. The solution formed was concentrated to dryness in vacuo and the residue obtained was employed directly in the next stage.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:23]=2[N:24]=[CH:25][N:26]=1)[C@@H:15]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N#N.C([C@@]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO[C:41]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)[C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C@@H](O)C1)(=O)C(C)C>>[C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:23]=2[N:24]=[CH:25][N:26]=1)[C@@H:15]1[O:22][C@H:19]([CH2:20][O:21][C:41]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)[C:42]2[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=2)[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@](C(=O)C(C)C)(n3cnc4c(=O)[nH]c(N)nc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1
Agent: N#N
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1

Procedure:
This compound was prepared from N6 -benzoyl-2'-deoxyadenosine by the same procedure used for the preparation of N2 -isobutyryl-5'-O-(4,4'-dimethoxytrityl)-2'-deoxyguanosine.
Reaction SMILES: N(CN[C:5](N)=[O:6])=O.[OH-].[K+].[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:15]([CH3:20])=[C:14]2[CH2:21][C:22](O)=[O:23].N#N>ClCCl.C(OCC)C>[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:15]([CH3:20])=[C:14]2[CH2:21][C:22]([O:6][CH3:5])=[O:23]
Reactant: CC1=C(CC(=O)O)c2cc(F)ccc2C1
Reactant: NC(=O)NCN=O
Agent: N#N
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)CC1=C(C)Cc2ccc(F)cc21
Yield: 93 %

Procedure:
Nitrosomethylurea (99.5 mmol) is added in portions to a cold (0° C.) mixture of aqueous 50% KOH (50 ml) and diethylether (150 ml) at 0° C. The yellow ether solution of diazomethane (Note: explosive) is separated, is washed with water, and is added in portions to a solution of 5-fluoro-2-methylindene-3-acetic acid (90 mmol) in dichloromethane (200 ml). When the evolution of N2 ceases, the reaction is complete. After evaporation of the solvents, the residue is recrystallized from hexane to give methyl 5-fluoro-2-methyl-3-indenylacetate (yield 93%; m.p. 53° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH:19]1([NH2:28])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1>>[CH:19]1([NH:28][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][N:17]=[CH:18][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NC1CCc2ccccc21
Product: O=C(NC1CCc2ccccc21)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-(2,3-dihydro-1H-inden-1-yl)-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.43 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.57 mmol of indanylamine. LC/MS [10.69 min; 474 (M+1)]
Reaction SMILES: C(C(C)=O)C(C)C.[Cl:8][C:9]([Cl:25])=[C:10]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[N:26]#[C:27]Br.[CH2:29]([N:31](CC)CC)C>>[Cl:8][C:9]([Cl:25])=[C:10]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:27]#[N:26])=[CH:20][CH:19]=1)[C:11]1[CH:12]=[CH:13][C:14]([O:17][C:29]#[N:31])=[CH:15][CH:16]=1
Reactant: Oc1ccc(C(=C(Cl)Cl)c2ccc(O)cc2)cc1
Reactant: N#CBr
Reactant: CCN(CC)CC
Solvent: CC(=O)CC(C)C
Product: N#COc1ccc(C(=C(Cl)Cl)c2ccc(OC#N)cc2)cc1
Temperature: -20 °C
Yield: 98.2 %

Procedure:
A 4-necked 5-L flask, equipped with a mechanical stirrer, a thermometer, and an additional funnel, is charged with methyl isobutyl ketone (1500 g), 1,1-dichloro-2,2-bis(4-hydroxyphenyl)ethene (320 g), and cyanogen bromide (270 g). The resulting solution is cooled to −20° C. with a dry ice/acetone bath. To the stirring solution, triethylamine (240 g) in the additional funnel is added dropwise. The reaction temperature is maintained below −20° C. After the addition, the resulting mixture is allowed to warm up to 0° C. and quenched with dilute HCl aqueous solution. The organic layer is washed further with water a few times and concentrated under vacuum to afford 370 g of amber liquid, which solidifies as light tan color solids.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:9]=1)[CH2:4][CH:5]([OH:7])[CH3:6].[C:22]([NH:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:28]2[C:29]([O:31][C:32](=O)[C:27]=12)=[O:30])(=[O:24])[CH3:23].C(N(CC)CC)C.O>CN(C=O)C>[CH:17]1([O:16][C:10]2[CH:9]=[C:8]([CH:3]([N:2]3[C:32](=[O:31])[C:27]4[C:28](=[CH:34][CH:35]=[CH:36][C:26]=4[NH:25][C:22](=[O:24])[CH3:23])[C:29]3=[O:30])[CH2:4][CH:5]([OH:7])[CH3:6])[CH:13]=[CH:12][C:11]=2[O:14][CH3:15])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1ccc(C(N)CC(C)O)cc1OC1CCCC1
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(CC(C)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)cc1OC1CCCC1
Temperature: 85 °C

Procedure:
A stirred mixture of 4-amino-4-(3-cyclopentyloxy-4-methoxyphenyl)butan-2-ol hydrochloride(1.20 g, 3.80 mmol), 3-acetamidophthalic anhydride (0.78 g, 3.80 mmol) and triethylamine (0.38 g, 3.80 mmol) in DMF (15 mL) was heated at 80-90° C. for 7 hours. The mixture was allowed to cool to room temperature and poured into water (80 mL). The resulting mixture was extracted with EtOAC (3×30 mL). The combined ethyl acetate extracts were washed with water (30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (Silica gel, methylene chloride: EtOAC 8:2) to give N-{2-1-(3-cyclopentyloxy-4-meth-oxyphenyl)-3-hydroxybutyl]-1,3-dioxoisoindolin-4-yl}acetamide (1.3 g, 73%) as a white solid: 1H NMR (CDCl3) δ9.53 (s, 1H), 8.71 (d, J=8.4 Hz, 1H), 7.63 (t, J=7.7 Hz, 1H), 7.48 (d, J=7.3 Hz, 1H), 7.08-7.03 (m, 2H), 6.82 (d, J=8.2 Hz, 1H), 5.57-5.51 (dd, J=4.2, 11.6 Hz, 1H), 4.78 (m, 1H), 3.81 (s, 3H), 3.77-3.74 (m, 1H), 2.91-2.81 (m, 1H), 2.25 (s, 3H), 2.13-1.60 (m, 10H), 1.29 (d, J=6.1 Hz, 3H); 13C NMR (CDCl3) δ170.38, 169.21, 168.06, 149.70, 147.50, 137.33, 135.84, 131.54, 131.20, 124.71, 120.28, 117.93, 115.31, 115.07, 111.55, 80.45, 64.89, 55.97, 51.35, 39.92, 32.73, 24.91, 24.04, 23.76, 21.02.
Reaction SMILES: Cl.[C:2](N)(=O)[C:3]1C=CC=C[CH:4]=1.FC(F)(F)C(O)=O.[C:18]([C:21]1[CH:22]=[CH:23][C:24]([NH:37][C:38]([CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[O:39])=[C:25]([CH:36]=1)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27])(=[O:20])[CH3:19].Cl>ClCCl.C(OCC)C>[ClH:35].[C:18]([C:21]1[CH:22]=[CH:23][C:24]([NH:37][C:38]([CH:40]2[CH2:41][CH2:42][N:43]([CH:3]([CH3:4])[CH3:2])[CH2:44][CH2:45]2)=[O:39])=[C:25]([CH:36]=1)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27])(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc(NC(=O)C2CCNCC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reactant: NC(=O)c1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)c1ccc(NC(=O)C2CCN(C(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1

Procedure:
Using methods substantially equivalent to those described in Example 244-F, 5-acetyl-N-(5-chloropyridin-2-yl)-2-(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide hydrochloride (48 mg, 67%) was prepared from 5-acetyl-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylcarbonyl)amino]-benzamide trifluoroacetate. To a stirring solution of the purified product in dichloromethane was added 1.0 N hydrochloric acid in diethyl ether until precipitate formed. The mixture was filtered to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[NH:13]([C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1ncnc2c(Cl)cccc12
Reactant: Nc1ccccc1
Solvent: CCO
Product: Clc1cccc2c(Nc3ccccc3)ncnc12
Yield: 49.3 %

Procedure:
15 ml of ethanol were added to a mixture of 3.0 g of 4,8-dichloroquinazoline and 1.9 g of aniline, and then the mixture was heated. The reagents dissolved and immediately solidified. After cooling, the solidified product was collected, washed with ethanol and then recrystallized from ethanol to give 1.9 g (yield 48%) of the desired Compound No. 13 in the form of colourless crystals having a melting point of 206° C. (with decomposition).
Reaction SMILES: [NH:1]1[C:5]([NH:6][CH:7]=[C:8]([C:12]([O-:14])=O)[C:9]([O-:11])=[O:10])=[CH:4][CH:3]=[N:2]1.CN(C=O)C.[CH3:20][CH2:21]O>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[O:14]=[C:12]1[N:1]2[N:2]=[CH:3][CH:4]=[C:5]2[NH:6][CH:7]=[C:8]1[C:9]([O:11][CH2:20][CH3:21])=[O:10]
Reactant: O=C([O-])C(=CNc1ccn[nH]1)C(=O)[O-]
Reactant: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2ccnn2c1=O
Temperature: 25 °C

Procedure:
A solution of the 2-((1H-pyrazol-5-ylamino)methylene)malonate (4.0 g, 15.8 mmol) in Dowtherm (15 mL) was heated to 250° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, DMF/EtOH (10 mL, 1/1, v/v) was added to the mixture and formed precipitate was filtered, which was washed with EtOH and dried under vacuum to give ethyl 7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate; 1.9 g (58%). 1H NMR (300 MHz, DMSO) δ 13.01 (brs, 1H), 8.58 (s, 1H), 7.91 (d, J=2.1 Hz, 1H), 6.30 (d, J=1.8 Hz, 1H), 4.22 (q, J=7.2 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]12([C:11]3[CH:33]=[CH:32][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.FC(F)(F)C(O)=O>ClCCl>[C:1]12([C:11]3[CH:33]=[CH:32][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
To a solution of tert-butyl 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)piperazine-1-carboxylate (0.15 g, 0.42 mmol), prepared from the example 29, in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.15 g, 1.69 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated and diluted with dichloromethane. The organic layer was washed with aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give 2-(4-(adamantan-1-yl)phenoxy)-1-(piperazin-1-yl)ethanone as a white solid (0.11 g, 94.8% yield).
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[S:7])[CH:2]([CH3:4])[CH3:3].[Cl:8][C:9]1[CH:28]=[CH:27][C:12]2[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C@@H:16]3[C@H:21]([NH2:22])[CH2:20][CH2:19][CH2:18][N:17]3[C:11]=2[CH:10]=1>C1COCC1>[Cl:8][C:9]1[CH:28]=[CH:27][C:12]2[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C@@H:16]3[C@H:21]([NH:22][C:6]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[S:7])[CH2:20][CH2:19][CH2:18][N:17]3[C:11]=2[CH:10]=1
Reactant: N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Reactant: CC(C)CN=C=S
Solvent: C1CCOC1
Product: CC(C)CNC(=S)N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 12 %

Procedure:
Isobutyl isothiocyanate (3.35 mg, 0.03 mmol) was added to trans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (5 mg, 0.02 mmol) in 1 mL of THF. The resulting mixture was stirred at room temperature for 18 h. The mixture was evaporated under reduced pressure. Crystallisation from methanol gave trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-N′-(2-methylpropyl)thiourea (1 mg, 12%). Data: (m/z)=416 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.N1CCOCC1.[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:30]=1[C:31](Cl)=[O:32].C(O)C(N)(CO)CO>CO.O1CCOCC1>[ClH:28].[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:30]=1[C:31]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:16]=1)=[O:32]
Reactant: O=C(Cl)c1c(F)cccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(N)c2)CC1
Agent: NC(CO)(CO)CO
Solvent: CO
Solvent: C1COCCO1
Solvent: C1COCCN1
Product: Cl
Product: O=C(Nc1cccc(OC2CCNCC2)c1)c1c(F)cccc1Cl
Temperature: 106 °C
Reaction time: 2 h

Procedure:
Combine 4-(3-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (preparation 30, 100 mg, 0.342 mmol), dioxane (2 mL) and polymer bound morpholine resin (205 mg, 0.513 mmol) and add 2-chloro-6-fluoro-benzoyl chloride (0.048 mL, 0.376 mmol), shake (in a J-KEM® block) and heat at 106° C. After 2 hr., dilute with methanol (5 mL) and add tris-amine resin (100 mg), shake in a rotary evaporator overnight, filter, concentrate and use directly in the next step. Combine methanol (5 mL) and acetyl chloride (2.5 mL) and stir at 0° C. After 1 hr., add a solution of 4-[3-(2-chloro-6-fluoro-benzoylamino)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester in methanol (2 mL) and stir at room temperature. After 30 min., concentrate under reduced pressure, dissolve the residue in ethyl acetate (10 mL), wash with NaHCO3 (sat. aq., 10 mL), dry the organic layers over magnesium sulfate, filter and concentrate under reduced pressure to give 100 mg (84%, 2 steps) of the titled compound as the free base. Following a method similar to Example 2 gives the title compound as the hydrochloride salt (130 mg, off-white solid). Mp: 139-42° C.; mass spectrum (free base, ion spray): m/z=311.2 (M+1); 1H NMR (free base, CDCl3): 8.19 (bs, N—H), 7.41 (t, J=2.1 Hz, 1H), 7.35-7.29 (m, 1H), 7.26-7.20 (m, 2H), 7.07-7.02 (m, 2H), 6.70 (dd, J=2.3 Hz, 8.4 Hz, 1H), 4.43-4.36 (m, 1H), 3.11-3.04 (m, 2H), 2.74-2.67 (m, 2H), 2.50 (bs, N—H), 2.04-1.95 (m, 2H), 1.72-1.62 (m, 2H).