Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[Cl:18][C:19]1[N:24]=[C:23]2[S:25][C:26]([S:28](Cl)(=[O:30])=[O:29])=[CH:27][C:22]2=[CH:21][CH:20]=1>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:28]([C:26]2[S:25][C:23]3=[N:24][C:19]([Cl:18])=[CH:20][CH:21]=[C:22]3[CH:27]=2)(=[O:29])=[O:30])[C:4]1=[O:17])#[N:13]
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)nc2s1
Agent: Cl
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3cc4ccc(Cl)nc4s3)C2=O)c1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-benzonitrile hydrochloride as described in EXAMPLE 1, Part E using 6-chlorothieno[2,3-b]pyridine-2-sulfonyl chloride in place of benzo[b]thiophene-2-sulfonyl chloride. The crude product is purified by column chromatography eluting with a gradient of 10% EtOAc/CH2Cl2 to 25% EtOAc/CH2Cl2 to afford a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].OOS([O-])=O.[K+].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1>CN(C=O)C.O>[CH3:16][O:15][CH:14]([O:17][CH3:18])[CH2:13][N:12]1[C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=2[N:1]=[C:30]1[C:29]1[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=1
Reactant: COC(=O)c1cccc(N)c1NCC(OC)OC
Reactant: O=Cc1ccc(F)cc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc2nc(-c3ccc(F)cc3)n(CC(OC)OC)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a stirred solution of methyl 3-amino-2-(2,2-dimethoxyethylamino)benzoate (1.0 g, 3.9 mmol) from Step C of Example 13 in DMF (9 mL) and H2O (0.3 mL) were added oxone (1.6 g, 2.6 mmol) and 4-fluorobenzaldehyde (0.5 mL, 4.3 mmol) and the mixture was stirred overnight at room temperature. The reaction mixture was washed with saturated aqueous sodium bicarbonate, re-extracted with methylene chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure to give the crude material which was purified by column chromatography (silica gel, 5% to 100% ethyl acetate in hexanes) to afford methyl 1-(2,2-dimethoxyethyl)-2-(4-fluorophenyl)-1H-benzo[d]imidazole-7-carboxylate (1.1 g, 79%): 1H NMR (500 MHz, CDCl3) δ7.97 (dd, J=8.0, 1.0 Hz, 1H), 7.80 (dd, J=8.0, 1.0 Hz, 1H), 7.73-7.70 (m, 2H), 7.32 (t, J=8.0 Hz, 1H), 7.24-7.20 (m, 2H), 4.72 (d, J=5.0 Hz, 2H), 4.24 (t, J=5.0 Hz, 1H), 3.94 (s, 3H), 3.38-3.33 (m, 1H), 3.19 (s, 6H); MS (ESI+) m/z 359 (M+H).
Reaction SMILES: ClC[C:3]1[N:8]=[CH:7]C=[CH:5][N:4]=1.C1(=O)[N:13](C(S)C)C(=O)C2=CC=CC=C12.[NH2:23][CH2:24][CH2:25][S:26][CH2:27][C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.CN>>[C:5]([NH:4][C:3]([NH:8][CH3:7])=[N:23][CH2:24][CH2:25][S:26][CH2:27][C:28]1[N:29]=[CH:30][CH:31]=[CH:32][N:33]=1)#[N:13]
Reactant: ClCc1ncccn1
Reactant: NCCSCc1ncccn1
Reactant: CC(S)N1C(=O)c2ccccc2C1=O
Agent: CN
Product: CNC(=NCCSCc1ncccn1)NC#N

Procedure:
Reacting 2-chloromethylpyrimidine with phthalimidoethanethiol by the procedure of Example 1(i)(b) and then reacting the resulting 2-[(2-aminoethyl)thiomethyl]pyrimidine with dimethyl-N-cyanoimidodithiocarbonate and methylamine by the procedure of Example 3(d) gives N-cyano-N'-methyl-N"-[2-(2-pyrimidylmethylthio)ethyl]guanidine.
Reaction SMILES: [Cl:1][CH:2](O)[CH2:3][CH2:4][CH2:5][CH2:6]C.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.[C:15](=[O:18])(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:15][O:18][CH:14]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1
Reactant: C1=COCCC1
Reactant: O=C([O-])O
Reactant: CCCCCC(O)Cl
Agent: [Na+]
Solvent: ClCCl
Product: ClCCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 14.3-7g of 6 chloro-1-hexanol and 10.39 g of dihydropyran in 30 ml of methylene chloride was added 0.95 g of tosic acid monohydrate, and the mixture was stirred at room temperature for 18 hours, poured into 50 ml of a saturated sodium bicarbonate aqueous solution, stirred for 10 minutes and extracted three times with 100 ml of chloroform. The extracts were combined, washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, dried over magnesium sulfate, concentrated under a reduced pressure and dried in vacuo. The orange-colored oil thus obtained was vacuum-distilled to obtain 17.43 g of 2-(6-chlorohexyloxy)tetrahydropyran as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].C(=O)([O-])[O-].[K+].[K+].Cl.[N:58]1[CH:63]=[CH:62][CH:61]=[C:60]([CH2:64][Cl:65])[CH:59]=1>>[ClH:65].[OH:24][C@H:22]1[C@:21]2([O:25][CH3:26])[C@@:8]([OH:45])([C:9](=[O:44])[C:10]3[C:19]([C:20]2=[O:27])=[C:18]([OH:28])[C:17]2[C:16](=[O:29])[CH:15]=[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)[C:13](=[O:43])[C:12]=2[CH:11]=3)[C:7]2[C:2]([O:1][CH2:64][C:60]3[CH:59]=[N:58][CH:63]=[CH:62][CH:61]=3)=[C:3]([C:47]([O:49][CH3:50])=[O:48])[C:4]([CH3:46])=[CH:5][C:6]=2[CH2:23]1
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1c(C)cc2c(c1OCc1cccnc1)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Yield: 31.5 %

Procedure:
Following General Procedure: Method B using (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (35 mg, 0.050 mmol), potassium carbonate (21 mg, 0.15 mmol) and 3-picolyl chloride hydrochloride (25 mg, 0.15 mmol), the product was purified by preparative TLC (silica gel, 95:5 dichloromethane/methanol) and converted to hydrochloride to afford (6R,6aS,14aR)-methyl 6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-1-(pyridin-3-ylmethoxy)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate hydrochloride (13 mg, 31%) as an orange-red solid: 1H NMR (500 MHz, CDCl3) δ 14.21 (s, 1H), 8.79 (br s, 2H), 8.26 (d, J=4.1 Hz, 1H), 7.87 (br s, 1H), 7.41 (s, 1H), 6.92 (s, 1H), 6.89 (br s, 1H), 5.85 (s, 1H), 5.12 (d, J=11.2 Hz, 1H), 5.05 (d, J=11.3 Hz, 1H), 4.98 (br s, 1H), 4.66 (br s, 1H), 4.39 (br s, 1H), 3.85 (s, 3H), 3.81-3.74 (m, 1H), 3.72 (s, 3H), 3.65 (dd, J=19.3, 7.3 Hz, 1H), 3.60 (s, 3H), 3.43 (s, 1H), 3.40 (s, 3H), 3.36-3.31 (m, 1H), 3.14 (t, J=9.0 Hz, 1H), 2.51 (br s, 1H), 2.24 (s, 3H), 1.36 (d, J=6.1 Hz, 3H); MS (ESI+) m/z 789 (M+H); HPLC >99% (AUC), tR 12.34 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27](C)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:31]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:31])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)CCc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(Cl)c2)c1=O
Reactant: N
Solvent: O
Product: CC(C)CCc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(Cl)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3-chloro-4-fluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 102 mg, 61.8%). mp 154–156° C. 1H NMR (300 MHz, DMSO-d6) δ 0.75 (d, 6H), 1.4, (m, 3H), 2.48 (m, 2H), 7.54 (s, 2H), 7.6 (m, 1H), 7.69 (m, 2H), 7.93 (dd, 1H), 8.05 (m, 2H). MS (DCI/NH3) m/z 450 (M+H)+, 468 (M+NH4)+. Anal. calc. for C22H22FN2O3SCI.0.25 H2O: C, 58.86; H, 4.94; N, 6.24. Found: C, 59.23; H, 5.12; N, 6.00.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8].C(OCC)(=O)[CH2:20][C:21]([O:23]CC)=[O:22].[H-].[Na+].Cl>O1CCCC1>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[C:3]=1[CH2:2][CH2:20][C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1onc(-c2ccc(C(F)(F)F)cc2)c1CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(C(F)(F)F)cc2)c1CCC(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of 4-chloromethyl-5-methyl-3-(4-trifluoromethylphenyl)isoxazole (1.37 g) in tetrahydrofuran (50 ml) was added to a mixture of diethyl malonate (1.20 g), sodium hydride (60%, oil, 0.21 g) and tetrahydrofuran (20 ml) at 0° C. The mixture was stirred at 0° C. for 1 hr and then at room temperature overnight. The reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). A mixture of the obtained colorless oil, 6N hydrochloric acid (30 ml) and acetic acid (30 ml) was refluxed for 5 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated to give 3-[5-methyl-3-(4-trifluoromethylphenyl)-4-isoxazolyl]propionic acid (1.25 g, yield 84%). The crystals were recrystallized from ethanol-hexane. melting point: 138–139° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:16]([OH:18])=[O:17])[CH3:15])[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1.[CH3:26]NN=NC1C=CC(C)=CC=1>C(Cl)(Cl)Cl.CCOCC.CCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:16]([O:18][CH3:26])=[O:17])[CH3:15])[CH2:9][N:8]=[C:7]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:6]=2[CH:25]=1
Reactant: CC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)C(=O)O
Reactant: CNN=Nc1ccc(C)cc1
Solvent: CCCCC
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COC(=O)C(C)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
To a solution of 0.39 g. (0.001 mole) of 7-chloro-2-[(1-carboxyethylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine is added 0.164 g. (0.0011 mole) of 3-methyl-1-p-tolyltriazene. After standing at room temperature (22°-25° C.) overnight, the solution is concentrated, then diluted with ether, filtered and evaporated to give a solid. This solid is redissolved in chloroform, diluted with ether and pentane to give .17 g. of 7-chloro-2-[[1-(merhoxycarbonyl)ethylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:30][N:31]([CH3:43])[CH2:32][CH2:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>O1CCCC1>[CH3:30][N:31]([CH3:43])[CH2:32][CH2:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[CH:37][CH:36]=1
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)O
Reactant: CN(C)CCOc1ccc(CN)cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(S(N)(=O)=O)cc1C(=O)NCc1ccc(OCCN(C)C)cc1

Procedure:
To a cooled suspension of 14.3 g of 2-methoxy-5-sulfamoylbenzoic acid in 60 ml of tetrahydrofuran were successively added dropwise 6.25 g of triethylamine and 7.45 g of pivaloyl chloride with stirring. The mixture was stirred at the same temperature for 1 hour and then a solution of 10.0 g of 4-[2-(dimethylamino)ethoxy]-benzylamine in 40 ml of tetrahydrofuran was added dropwise with stirring. The mixture was stirred at room temperature for 14 hours and the solvent was evaporated. Hydrochloric acid (10%) was added to the residue and the aqueous solution was washed with ethyl acetate. The aqueous layer was made alkaline with potassium carbonate to give a precipitate, which was washed with water and ethyl acetate, of 16.6 g of colorless crystals. Recrystallization of the crystals from ethanol gave the title compound as colorless needles, m.p. 154°-155° C.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][NH:29][CH2:30][CH3:31]>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][N:29]([CH3:28])[CH2:30][CH3:31])[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:3]=1
Reactant: CCNC
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCN(C)CC1COc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 42 using [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), N-methylethanamine (0.5 ml), ACN (1 ml). MS m/z (rel. intensity, 70 eV) 303 (M+, 0.5), 84 (2), 73 (4), 72 (bp), 69 (2).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(N2CCNCC2)cc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (3 mL) was added dropwise with stiffing at 0° C. to a solution of t-butyl 4-(4-chlorophenyl)piperazine-1-carboxylate (360.6 mg, 1.21 mmol, 1.00 equiv) in dichloromethane (12 mL). The resulting solution was stirred for 3 h at 20° C. in an oil bath. The pH value of the solution was adjusted to 7-8 with a saturated solution of sodium bicarbonate. The resulting solution was extracted with 6×20 mL of dichloromethane, the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 264.5 mg (102%) of 1-(4-chlorophenyl)piperazine as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C(N(C(C)C)CC)(C)C.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>C(O)C>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3[nH]cnc23)CC1

Procedure:
To a solution of 6-chloropurine [CAS No. 87-42-3] (7.73 g) in ethanol (100 mL), diisopropylethylamine (26.1 mL) and piperazine-1-carboxylic acid t-butylester (11.16 g) were added, and this was heated under reflux for 16 hours. The solvent was removed under reduced pressure, and the residue was suspended in water (200 mL). The precipitate was collected by filtration, and then washed twice with 50 mL of water and twice with 50 mL of t-butyl methyl ether to give the title compound (13.99 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,6-dichloro-9H-purine (1.2 g, 6.35 mmol) in N,N-dimethylformamide (5 mL) was added morpholine (553 mg, 6.35 mmol) followed by diisopropylethyl amine (1.2 mL, 6.87 mmol), dropwise via a syringe. The solution was stirred at room temperature for 1 hour until precipitate formed. The reaction mixture was then poured into water and the precipitate was filtered. Upon drying under high vacuum, 2-chloro-6-morpholin-4-yl-9H-purine was isolated as an off-white solid. (1.5 g, 99%) LC/MS analysis method 7, mass (ES+) m/z 240.2 1H NMR (DMSO-d6): 13.21 (1H, brs), 8.15 (1H, s), 4.18 (4H, brs), 3.72 (4H, t)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:19])[C:9]2[CH:14]=[C:13]([F:15])[C:12]([CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24](C(=O)C)[CH2:23][CH2:22]2)[N:3]=1.FC(F)(F)C(O)=O.[CH3:37][S:38](N1CCC(N)CC1)(=[O:40])=[O:39]>>[NH2:1][C:2]1[C:7]([C:8]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])=[O:19])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1cc(C)c(F)cc1C(=O)c1cnc(NC2CCN(C(C)=O)CC2)nc1N
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(F)cc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 326 was used, starting with 1-[4-[4-amino-5-(5-fluoro-2-methoxy-4-methyl-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone (Example 341) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-4-methyl-phenyl)-methanone. MS (M+H)+, 436
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][NH:14][CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[C:24]1[N:29]([CH3:30])[C:28](=[O:31])[CH:27]=[C:26]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[N:25]=1.ClC1C=CNC(=O)N=1>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[CH2:15][N:14]([C:24]3[N:29]([CH3:30])[C:28](=[O:31])[CH:27]=[C:26]([C:32]4[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=4)[N:25]=3)[CH2:13][CH2:12][NH:11]2)=[CH:8][CH:9]=1
Reactant: Clc1ccc([C@@H]2CNCCN2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: Cl
Agent: O=c1nc(Cl)cc[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCN[C@H](c3ccc(Cl)cc3)C2)nc(-c2ccncc2)cc1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.3 %

Procedure:
To a suspension of (R)-2-(4-chlorophenyl)piperazine dihydrochloride (1.09 g, 4.05 mmol) in tetrahydrofuran (24 ml) was added triethylamine (2.82 ml, 20.3 mmol). After stirring for 15 min at room temperature, 2-chloro-3-methyl-6-(4-pyridyl)-3H-pyrimidin-4-one (748 mg, 3.38 mmol) was added portionwise. Upon disappearance of the chloropyrimidone, the reaction mixture was condensed under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give pale yellow solid, which was recrystallized from ethanol to afford (R)-2-(2-(4-chlorophenyl)piperazin-4-yl)-3-methyl-6-(4-pyridyl)-pyrimidin-4-one (998 mg, 77.4%) as white crystals. The enantiomer excess was determined by HPLC (>99% ee). The crystals were converted into its dihydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].Cl.[CH3:13][NH:14][O:15][CH3:16].C(N(CC)CC)C>ClCCl>[CH3:16][O:15][N:14]([CH3:13])[C:7](=[O:8])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[CH3:11]
Reactant: Cc1ccc(Br)cc1C(=O)Cl
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc(Br)ccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 5-bromo-2-methylbenzoate (see Japanese Unexamined Patent Publication No. 9-263549) (16.12 g) was dissolved in methanol (100 ml), and thereto was added 10% aqueous sodium hydroxide solution (50 ml). The mixture was stirred at 50° C. for 40 minutes. Under ice-cooling, the mixture was adjusted to pH 1 by addition of 10% aqueous hydrochloric acid solution, and diluted with water. Precipitated powder was collected by filtration, and dried to give 5-bromo-2-methylbenzoic acid (14.1 g). ESI-Mass m/Z 213/215 (M−H). (2) The above 5-bromo-2-methylbenzoic acid (10.0 g) was suspended in dichloromethane (100 ml), and thereto were added oxalyl chloride (8.1 ml) and N,N-dimethylformamide (2 drops). The mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure to give 5-bromo-2-methylbenzoyl chloride. This benzoyl chloride was dissolved in dichloromethane (200 ml), and thereto was added N,O-dimethylhydroxylamine hydrochloride (12.3 g). To the mixture was added dropwise triethylamine (20 ml) at 0° C., and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate, and washed successively with water, 10% aqueous hydrochloric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution, and brine. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give N-methoxy-N-methyl-5-bromo-2-methylbenzamide (12.25 g) as oil. APCI-Mass m/Z 258/260 (M+H). (3) A solution of the above N-methoxy-N-methyl-5-bromo-2-methylbenzamide (12.2 g) in tetrahydrofuran (100 ml) was cooled to −78° C. under argon atmosphere. To the mixture was added dropwise diisobutyl aluminum hydride (1.0 M toluene solution, 75 ml), and the mixture was stirred at the same temperature for one hour. 10% aqueous hydrochloric acid solution (50 ml) was added thereto, and the mixture was warmed to room temperature. The mixture was extracted with ethyl acetate twice, and washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine. The extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was solidified to give 5-bromo-2-methylbenzaldehyde (8.73 g). APCI-Mass m/Z 213/215 (M+H+MeOH—H2O).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:11](O)=[O:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1(NC2CCCCC2)CCCCC1.S(Cl)([Cl:34])=O>ClCCl>[CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:11]([Cl:34])=[O:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1ccc(C(=O)O)cc1C1(C)CCCCC1
Reactant: O=S(Cl)Cl
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Product: COc1ccc(C(=O)Cl)cc1C1(C)CCCCC1
Reaction time: 1 h
Yield: 99.3 %

Procedure:
In a round bottom flask, there are introduced 4.96 g (20 mmoles) of 3-(1-methylcyclohexyl)-4-methoxy benzoic acid, 75 ml of dichloromethane, and 4 ml (20 mmoles) of dicyclohexylamine. The reaction mixture is stirred for 1 hour. To the resulting solution, there are added 1.45 ml (20 mmoles) of thionyl chloride (SOCl2) and the mixture is stirred for 2 hours at ambient temperature. The reaction mixture is then evaporated to dryness and taken up in 200 ml of ether. The dicyclohexyl-ammonium chloride is filtered off and the solvent is evaporated, yielding 5.30 g (100% yield) of crude 3-(1-methylcyclohexyl)-4-methoxy benzoyl chloride which is used, as is, for the following synthesis:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(CC)CC>C1COCC1>[C:14]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(=O)oc2cc(OC(=O)c3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-hydroxy-4-methyl-chromen-2-one (0.5210 g, 3.0 mmol) and benzoyl chloride (0.4844 g, 0.4 mL, d=1.211 g/mL, 3.4 mmol) in THF (40 mL) was added Et3N (1 mL) at room temperature. The reaction mixture was stirred at room temperature overnight and filtered. The filtrate was concentrated to give the crude product 7-benzoyloxy-4-methyl-coumarin.