Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.[H-].[Na+].I[CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[N:7][N:8]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:9]=2[CH:10]=1
Reactant: IC1CCCC1
Reactant: COC(=O)c1cc(Br)cc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc2c1cnn2C1CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ice-cooled methyl 6-bromo-1H-indazole-4-carboxylate (2 g, 7.84 mmol) in 30 mL of DMF was treated with NaH (60%, 345 mg, 8.63 mmol) and the mixture was stirred for 1 hr at 0° C. Iodocyclopentane (2.31 g, 11.8 mmol) was then added and the mixture was stirred at 100° C. overnight. After cooling to RT, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water and brine, dried over MgSO4, filtered and evaporated. Hexanes was added to the brown oil and it was purified using silica gel chromatography (eluent: Hex/EtOAc, gradient 0 to 25%). The less polar product was evaporated to give an orange oil, and was dried on hivac overnight. The product was confirmed to be the alkylated 1-isomer as suggested by 2D HNMR, and was collected as 807 mg (32%). 1H NMR (400 MHz, DMSO-d6): δ 8.40 (s, 1H) 8.37 (s, 1H) 7.81 (d, J=1.52 Hz, 1H) 5.26 (quin, J=7.07 Hz, 1H) 3.95 (s, 3H) 2.08-2.17 (m, 2H) 1.93-2.01 (m, 2H) 1.82-1.92 (m, 2H) 1.64-1.73 (m, 2H); LCMS (ES+): m/z=323.3/325.3
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Br:16])[CH:15]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Br:16])[C:15]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Brc1cncc(Br)c1
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Br)cncc1Br
Reaction time: 0.75 h
Yield: 91.7 %

Procedure:
To a solution of LDA (2 M solution in THF/heptane/ethylbenzene) (2.26 g, 10.54 mL, 21.06 mmol) in anhydrous THF (20 mL) under nitrogen atmosphere cooled to −78° C. was added a solution of the 3,5-dibromopyridine (5.0 g, 21.10 mmol) in anhydrous THF (40 mL) at −78° C. The reaction mixture was allowed to stir at the same temperature for 45 minutes. Then, a solution of chloro(ethoxy)methanone (22.90 g, 211.02 mmol) was added slowly over 15 minutes. After stirring for 20 minutes, the reaction mixture was quenched with saturated aqueous NaHCO3. The mixture was extracted with ethyl acetate (3×100 mL), and the combined organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated, and the residue was purified through CombiFlash using 0-10% ethyl acetate in hexane to provide ethyl 3,5-dibromopyridine-4-carboxylate as pale yellow oil (5.98 g, 92% yield); 1H NMR (400 MHz, DMSO-d6): δ1.43 (t, 3H), 4.49 (q, 2H), 8.67 (s, 2H); M+307.9.
Reaction SMILES: [C:1]([C@@:3]1([N:34]2[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]2=[O:36])[O:33][C@H:7]([CH:8]([C:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[OH:9])[C@@H:5]([OH:6])[CH2:4]1)#[N:2].[C:43]([Si:47]([CH3:50])([CH3:49])Cl)([CH3:46])([CH3:45])[CH3:44].N1C=CN=C1>N1C=CC=CC=1>[C:1]([C@@:3]1([N:34]2[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]2=[O:36])[O:33][C@H:7]([CH:8]([C:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[OH:9])[C@@:5]([Si:47]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:50])[CH3:49])([OH:6])[CH2:4]1)#[N:2]
Reactant: COc1ccc(C(c2ccccc2)(c2ccc(OC)cc2)C(O)[C@H]2O[C@@](C#N)(n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Product: COc1ccc(C(c2ccccc2)(c2ccc(OC)cc2)C(O)[C@H]2O[C@@](C#N)(n3cc(C)c(=O)[nH]c3=O)C[C@@]2(O)[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1′-Cyano-5′-(4,4′-dimethoxytrityl)thymidine in anhydrous pyridine is added to a stirred solution of t-butyldimethylchlorosilane (1.5 equivalents) and imidazole (3.0 equivalents) in anhydrous pyridine at 0° C. The resulting reaction mixture is stirred at room temperature overnight. Pyridine is evaporated and the residue dissolved in ethyl acetate, washed with brine. The crude is directly used for the next reaction.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[S:18][C:19]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=3)=[O:28])=[CH:22][C:20]=2[N:21]=1.O1CCOCC1>CN(C)C=O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:19]3[S:18][C:17]([NH:16][C:2]4[C:11]5[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=5)[N:5]=[CH:4][N:3]=4)=[N:21][C:20]=3[CH:22]=2)=[O:28])=[CH:31][C:32]=1[C:37]([F:39])([F:38])[F:40]
Reactant: Nc1nc2cc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)ccc2s1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1cc2ncnc(Nc3nc4cc(NC(=O)Nc5ccc(Cl)c(C(F)(F)F)c5)ccc4s3)c2cc1OC

Procedure:
1-(4-Chloro-3-trifluoromethylphenyl)-3-[2-(6,7-dimethoxyquinazolin-4-ylamino)benzothiazol-5-yl]urea was prepared from 4-chloro-6,7-dimethoxyquinazoline (Fluorochem, 29 mg, 0.13 mmol) and 1-(2-aminobenzothiazol-5-yl)-3-(4-chloro-3-trifluoromethylphenyl)urea (Intermediate 5, 50 mg, 0.13 mmol) according to GP 1. Dimethylformamide was used as a solvent instead of dioxane. After removal of the solvent in vacuo, the residue was subjected to silica gel chromatography applying a dichloromethane-methanol gradient. The crude product was dissolved in dimethylformamide (2 mL) and water was added (2 mL). After storing in the fridge overnight, the resulting precipitate was filtered off, washed with water and dried (yellow solid, 7 mg, 12 μmol, 9%). LC/ESI-MS: m/z=575 [M(35Cl)+H]+; m/z=573 [M(35Cl)−H]−; Rt=4.17 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[C:21]3[O:23][CH2:24][O:25][C:18]=2[C:19]([F:27])=[C:20]3[F:26])[C:13]([F:28])=[CH:12][N:11]=1>>[F:27][C:19]1[C:18]2[O:25][CH2:24][O:23][C:21]([C:20]=1[F:26])=[CH:22][C:17]=2[NH:16][C:14]1[C:13]([F:28])=[CH:12][N:11]=[C:10]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([OH:1])[CH:3]=2)[N:15]=1
Reactant: Nc1cccc(O)c1
Reactant: Fc1cnc(Cl)nc1Nc1cc2c(F)c(F)c1OCO2
Product: Oc1cccc(Nc2ncc(F)c(Nc3cc4c(F)c(F)c3OCO4)n2)c1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 3-hydroxyaniline with 2-chloro-N4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine gave N4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. LCMS: purity: 85%; MS (m/e): 377 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH3:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([CH3:26])[C:20]=4[CH3:19])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: Cc1cccc(B(O)O)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(-c2ccc3c(c2)CC[C@H]2N(C)C(=O)CC[C@]32C)c1C
Yield: 25.4 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 2,3-dimethylphenylboronic acid (117 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×50 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 55 mg (25 %) of the title compound as an amorphous solid. mp 133°-140°. FDMS: m/e=333. α[D]589 =+61.90 (c=1.05, methanol).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([S:8][C:9]2[CH:14]=[C:13]([Cl:15])[C:12]([Cl:16])=[CH:11][C:10]=2[Cl:17])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:22](Cl)([Cl:24])=[S:23]>C(Cl)(Cl)Cl.O>[Cl:24][C:22]([O:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([S:8][C:9]2[CH:14]=[C:13]([Cl:15])[C:12]([Cl:16])=[CH:11][C:10]=2[Cl:17])=[O:7])=[CH:4][CH:3]=1)=[S:23]
Reactant: O=C(Sc1cc(Cl)c(Cl)cc1Cl)c1ccc(O)cc1
Reactant: S=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(Sc1cc(Cl)c(Cl)cc1Cl)c1ccc(OC(=S)Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
S-(2,4,5-Trichlorophenyl) 4-(hydroxy)thiobenzoate (5.4 g) in dry chloroform (70 ml) at -20° C. was treated sequentially with sodium hydroxide (0.78 g) in water (3 ml) and thiophosgene (1.85 ml). The solution was allowed to warm to room temperature and was stirred for a further 2 hours. The reaction mixture was then dried over calcium chloride and the filtered solution evaporated to give a crude solid. Purification by chromatography on silica gel using ethyl acetate/hexane mixtures as eluants afforded 3.4 g of the title compound.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15]O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>ClCCl>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][Cl:19])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCC(CO)CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCC(CCl)CC1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
To 800 ml of the dichloromethane solution of N-benzoyl-4-hydroxymethylpiperidine (C) obtained in Example 2, which contains about 1 mol of N-benzoyl-4-hydroxymethylpiperidine, there was added dropwise 109 ml (1.5 mol) of thionyl chloride over 2 hours with keeping the reaction temperature at 25° to 30° C. Then the obtained reaction mixture was stirred at room temperature for 1 hour and at 35° C. for 8 hours. After the completion of the reaction, the solvent and the excess of thionyl chloride were removed by distillation to obtain 248.96 g of N-benzoyl-4-chloromethylpiperidine (D) as a yellowish brown oily matter. The NMR spectrum of the obtained compound was measured. The result is shown below.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH2:13]([OH:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:21][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1
Reactant: CCCCCCCCO
Reactant: Fc1ccc(Br)cc1C(F)(F)F
Product: CCCCCCCCOc1ccc(Br)cc1C(F)(F)F

Procedure:
Using 4-bromo-1-fluoro-2-(trifluoromethyl)benzene as starting material, standard aromatic fluoro-substitution with n-octanol provided the title compound in quantitative yield. 1H NMR (400 MHz, CDCl3) δ 7.65 (δ, 1H, J=2.4 Hz), 7.55 (dd, 1H, J=8.8 Hz, J=2.4 Hz), 6.85 (d, 1H, J=8.8 Hz), 4.01 (t, 2H, J=6.4 Hz), 1.80 (m, 2H), 1.46 (m, 2H), 1.32 (m, 8H), 0.90 (t, 2H, J=5.6 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH:25]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]1>>[F:15][C:14]([F:17])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:3][C:2]([N:25]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reactant: OC1CCNC1
Product: Cc1nc2ccc(N3CCC(O)C3)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 92 %

Procedure:
The title compound was prepared from 1-(6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)-2,2,2-trifluoro-ethanone [example 3] and 3-pyrrolidinol according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 92%; MS: m/z=401 (M+H).
Reaction SMILES: [C:1]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])(OCC)=O.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22]CN>C(O)C>[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][CH2:1][N:6]1[C:7](=[O:16])[C:8]2=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]2[C:10]1=[O:11]
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NCCc1cccs1
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCc1cccs1
Reaction time: 22.5 h

Procedure:
N-Carboethoxyphthalimide (4.93 g, 22.5 mmol) was added to a solution of 2-(2-thienyl)ethylamine (2.75 g, 21.6 mmol) in ethanol (20 ml) and was stirred for 20-25 hours. The precipitated product was collected by filtration, washed with cold methanol and dried. The product obtained (5.45 g) was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[C:43]([NH2:51])(=[O:50])[C:44]1[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=1.C(OCC)(=O)C>CS(C)=O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][N+:47]4[CH:48]=[CH:49][C:44]([C:43](=[O:50])[NH2:51])=[CH:45][CH:46]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1nsc(N)n1
Reactant: NC(=O)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[n+]3ccc(C(N)=O)cc3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.9 %

Procedure:
To a stirred solution of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (IX-1) (E, 716 mg, 1 mmole) in dry DMSO (2 ml) was added isonicotinamide (244 mg, 2 mmoles). The mixture was stirred at room temperature for 1 hour and then poured into ethyl acetate (200 ml). The resulting precipitate was collected by filtration, washed well with ethyl acetate and dried. A stirred mixture of the quaternized material (400 mg) and sodium bisulfite (40 mg) in HCOOH (4 ml) was heated at 40°-50° C. for 1 hour, and evaporated to dryness under reduced pressure. The crude solid was dissolved in water (40 ml). After filtration of an insoluble material, the filtrate was chromatographed on a reverse phase column (packing of PrepPAK/C18, 100 ml) using water and 5%, 10%, 20% and 30% aqueous CH3OH as eluant. The fractions containing the desired compound were combined, evaporated and lyophilized to give 21 mg (3.8%) of the title compound (I-1H) (E) as a pale yellow powder. Mp. >180° C. (dec.).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CC[CH2:3][CH2:2]1.[O:23]1C=CC(N)=[N:24]1>>[CH3:13][C:12]1[C:7]([NH:6][C:1]2[CH:2]=[CH:3][O:23][N:24]=2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Nc1ccon1
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccon2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using isoxazol-3-amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.08 (s, 3H), 2.35 (s, 3H), 4.74 (d, J=2.8 Hz, 2H), 5.97 (bs, 1H), 6.98 (s, 1H), 7.17 (t, J=6.4 Hz, 1H), 7.31-7.44 (m, 2H), 7.63 (t, J=6.5 Hz, 1H), 8.17 (s, 1H), 8.56 (d, J=4.6 Hz, 1H); MS (ESI) m/z 297.8 (M+1)+.
Reaction SMILES: [I:1]I.[CH2:3]([NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH2:18])[N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([NH:10][C:11]1[C:16]([I:1])=[C:15]([CH3:17])[N:14]=[C:13]([NH2:18])[N:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: II
Reactant: Cc1cc(NCc2ccccc2)nc(N)n1
Solvent: CO
Product: Cc1nc(N)nc(NCc2ccccc2)c1I
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.7 %

Procedure:
Iodine (3.04 g, 12.0 mmol) was added to a solution of N4-benzyl-6-methylpyrimidine-2,4-diamine (2.33 g, 10.9 mmol) in anhydrous MeOH (50 mL) at 0° C. The reaction was allowed to warm to room temperature overnight. After 12 hours, an additional 0.5 equiv of iodine was added, and the reaction warmed to 50° C. After four hours, the reaction was cooled to room temperature and concentrated in vacuo. The residue was diluted with ethyl acetate (200 mL) and washed with 10% NaHSO3 (200 mL). The aqueous phase was separated and washed once more with ethyl acetate (200 mL). The organic phases were combined, washed with brine, separated and dried over Na2SO4. The filtrate was concentrated in vacuo to afford the product N4-benzyl-5-iodo-6-methylpyrimidine-2,4-diamine (3.14 g, 85% yield).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]2([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])OCC[O:44]2)[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:14](OC)=[O:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:55][C@@H](CC1C=CC(OCCCC)=CC=1)C(N)=O>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[O:44])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([OH:25])=[O:24])=[O:20])[C:14](=[O:15])[NH2:55])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C[C@H](N)C(N)=O)cc1
Reactant: CCCCCCCC1(CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc2ccc(OCCCC)cc2)C(=O)OC)[C@@](O)(CCOC)C(=O)OC(C)(C)C)OCCO1
Product: CCCCCCCC(=O)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(N)=O)[C@@](O)(CCOC)C(=O)O

Procedure:
An intermediate was synthesized by a method similar to that of No. 5534988, tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoate, except that (S)-2-amino-3-(4-butoxy-phenyl)-propionamide was used instead of (S)-2-amino-3-(4-butoxy-phenyl)-N-methyl-propionamide, and the title compound was obtained by a synthetic method similar to that of No. 5444958, (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-methoxy-ethyl)-12-oxo-nonadec-4-enoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COc1ccc2c(Cl)nncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1
Reaction time: 20 h
Yield: 79.4 %

Procedure:
A solution of 3,5-dichloro-4-methyl-pyridine (11.32 g, 70 mmoles) in dry DMF (100 ml) was stirred under N2 at room temperature, then added with 60% NaH in oil (2.8 g, 70 mmoles). After 1 hour at room temperature a solution of 1-chloro-6-methoxy-phthalazine (6.8 g, 35 mmoles), prepared as described in example 4, in DMF (250 ml) was added. The mixture was left at room temperature for 20 hours, then poured into water/ice (pH≅8) and extracted more times with CH2Cl2. The organic phases were washed with water, anhydrified and brought to dryness to give a solid which was triturated in isopropyl ether (100 ml) and filtered. The mother liquors were dried and the residue flash chromatographed with ethyl acetate to give 8.9 g of the title compound (yield: 79.5%). m.p.: 173-175° C. 1H-NMR (CDCl3) δ: 9.32(s,1H); 8.50(s,2H); 8.11(d,1H,J=9.0 Hz); 7.56(dd,1H); 7.20(d,1H,J=2.6 Hz); 4.90(s,2H); 4.00(s,3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:38])[C:7]=1[C:8]1[C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[N:27]=[C:26]([C:31]([O:33]C)=[O:32])[CH:25]=[CH:24]4)=[CH:17][CH:16]=2)=[C:11]([CH:35]([CH3:37])[CH3:36])[O:10][N:9]=1.CO.[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:38])[C:7]=1[C:8]1[C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[N:27]=[C:26]([C:31]([OH:33])=[O:32])[CH:25]=[CH:24]4)=[CH:17][CH:16]=2)=[C:11]([CH:35]([CH3:36])[CH3:37])[O:10][N:9]=1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cncc5Cl)noc4C(C)C)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1onc(-c2c(Cl)cncc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 100 °C

Procedure:
A solution of methyl 6-[4-({[3-(3,5-dichloro-4-pyridinyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (98 mg, 0.18 mmol) in THF (1.8 mL) was placed in a microwave reaction tube. Methanol (0.9 mL) was added followed by 1.0 N sodium hydroxide (0.27 mL, 0.27 mmol) before the tube was sealed and heated at 100° C. for 600 seconds. The solution was neutralized with 1 N HCl. The resulting mixture was partitioned between brine and ethyl acetate. The organic layer was separated and concentrated to yield 6-[4-({[3-(3,5-dichloro-4-pyridinyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid as a yellow powder (0.08 g, 80% as 0.25 ethyl acetate). 1H NMR (400 MHz, DMSO-d6): δ 13.37 (br s, approximately 1H), 8.81 (s, approximately 2H), 8.53 (d, J=9 Hz, 1H), 8.27 (s, 1H), 8.17-8.08 (m, 3H), 7.73 (d, J=9 Hz, 2H), 6.89 (d, J=9 Hz, 2H), 4.97 (s, 2H), 3.49 (septet, J=7 Hz, 1H), 1.34 (d, J=7 Hz, 6H). HRMS C28H21N3O4Cl2 m/z 534.0982 (M+H)+Cal; 534.0981 (M+H)+Obs.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH:22]1[CH:21]=[C:20]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[CH:8]=[CH:9][C:10]4[CH2:11][CH2:12][C:13](=[O:17])[NH:14][C:15]=4[CH:16]=3)[CH2:28][CH2:27]2)[C:19]([Cl:18])=[C:24]([Cl:25])[CH:23]=1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: O=C1CCc2ccc(OCCCCBr)cc2N1
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1

Procedure:
Conventional anhydrous aripiprazole crystals are prepared by well-known methods, as described in Example 1 of Japanese Unexamined Patent Publication No. 191256/1990. 7-(4-bromobutoxy)-3,4-dihydrocarbostyril, is reacted with 1-(2,3-dichlorophenyl)piperazine and the thus obtained crude aripiprazole crystals are re-crystallized from ethanol.