Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][C:12]1[C:13]2[C:20]([C:21]([C:23]3[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][N:24]=3)=[O:22])=[CH:19][N:18]([CH:30]([CH3:32])[CH3:31])[C:14]=2[N:15]=[CH:16][N:17]=1.NC1C2C(C(C3C=CN=C(NC(NC4C=CC=CC=4F)=O)C=3)=O)=CN(C(C)C)C=2N=CN=1>>[NH2:11][C:12]1[C:13]2[C:20]([C:21]([C:23]3[CH:28]=[C:27]([NH:29][C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[O:10])[CH:26]=[CH:25][N:24]=3)=[O:22])=[CH:19][N:18]([CH:30]([CH3:32])[CH3:31])[C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: CC(C)n1cc(C(=O)c2cc(N)ccn2)c2c(N)ncnc21
Reactant: O=C=Nc1ccccc1F
Agent: CC(C)n1cc(C(=O)c2ccnc(NC(=O)Nc3ccccc3F)c2)c2c(N)ncnc21
Product: CC(C)n1cc(C(=O)c2cc(NC(=O)Nc3ccccc3F)ccn2)c2c(N)ncnc21

Procedure:
The title compound was prepared from 1-fluoro-2-isocyanato-benzene (0.05 mL, 0.41 mmol) and (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(4-amino-pyridin-2-yl)-methanone (0.10 g, 0.34 mmol) by procedures analogous to those described for the preparation of 1-[4-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-2-yl]-3-(2-fluoro-phenyl)-urea. MS: 434.1 (MH+); HPLC Rf: 2.6 min. (HPLC method 2).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:35]=[CH:34][C:25]2[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=2[CH:23]=1.Cl>O1CCOCC1.COCCO>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)=[N:7][C:2]([NH:21][C:22]2[CH:35]=[CH:34][C:25]3[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=3[CH:23]=2)=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CC1(C)CCC(=O)Nc2ccc(Nc3ncc(Cl)c(Nc4ccccc4-n4cccn4)n3)cc21
Yield: 81.9 %

Procedure:
Combined (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine (82 mg, 0.268 mmol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (70 mg, 0.343 mmol), 4 N HCl in dioxane (80 ul) and 2-methoxyethanol (4 mL). Heated reaction at 120° C. for 16 hours. Evaporated off solvent and purified with normal phase chromatography to yield a beige solid, 7-[5-Chloro-4-(2-pyrazol-1-yl-phenylamino)-pyrimidin-2-ylamino]-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (104 mg, 82%). LCMS: m/z=474.34 (M+H+), 1H NMR (400 MHz, CD3OD) δ 8.41 (d, 1H, J=8.1 Hz), 8.02 (m, 2H), 7.84 (s, 1H), 7.60 (dd, 1H, J=8.3, 2.3 Hz), 7.52 (m, 2H), 7.42 (m, 1H), 7.30 (m, 1H), 6.91 (d, 1H, J=8.6 Hz), 6.55 (m, 1H), 4.59 (s, 1H), 2.32 (m, 2H), 2.11 (m, 2H), 1.35 (s, 6H).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][CH:10]=2)[CH2:3]1.[CH3:19][O:20][C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)=[O:22].N1C=CC=CC=1.O>O1CCCC1>[CH3:19][O:20][C:21](=[O:22])[C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:16][NH:15][C:13](=[O:14])[C:12]2[CH:11]=[CH:10][C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[O:7][C@H:6]([CH3:8])[CH2:5]3)=[CH:18][CH:17]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: C[C@@H]1CN(c2ccc(C(=O)NN)cc2)C[C@H](C)O1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(C(=O)NNC(=O)c2ccc(N3C[C@@H](C)O[C@@H](C)C3)cc2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 87.7 %

Procedure:
A mixture of 4-(cis-2,6-dimethylmorpholin-4-yl)benzoic acid hydrazide (458 mg), 4-methoxycarbonylbenzoyl chloride (622 mg) and pyridine (5 ml) in tetrahydrofuran (10 ml) was stirred for 6 hours at 0° C. The reaction mixture was added to water. The resulting precipitates were filtered, washed with water and dried to give 4-[N′-[4-(cis-2,6-dimethylmorpholin-4-yl)benzoyl]hydrazinocarbonyl]benzoic acid methyl ester (662.8 mg).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Cl:8].CCN(CC)CC.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C1COCC1.CN(C1C=CN=CC=1)C>[Cl:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][Cl:8])[S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: ClCCNCCCl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a suspension of bis(2-chloroethyl)amine hydrochloride (4.68 g, 26.2 mmol) in dry THF (50 mL) was added Et3N (18.3 mL, 131 mmol) at 0° C. and the mixture was stirred for 15 min. p-Toluenesulfonyl chloride (5.00 g, 26.25 mmol) and DMAP (a spatula pinch) were added. The reaction mixture was allowed to warm to room temperature and was stirred overnight. When TLC analysis showed complete conversion, the mixture was filtered to remove the Et3N.HCl and extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography to afford N,N-bis(2′-chloroethyl)-4-methylbenzenesulfonamide (6.22 g, 80% yield).
Reaction SMILES: [N:1](=[C:3]1[S:7][C:6]([CH3:9])([CH3:8])[N:5]=[C:4]1[CH3:10])[OH:2].[H-].[Na+].[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16]>O1CCCC1.C(OCC)C>[CH3:13][N:14]([CH3:18])[C:15]([O:2][N:1]=[C:3]1[S:7][C:6]([CH3:9])([CH3:8])[N:5]=[C:4]1[CH3:10])=[O:16]
Reactant: CC1=NC(C)(C)SC1=NO
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1=NC(C)(C)SC1=NOC(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.0 g (0.019 mol) of 5-oxo-2,2,4-trimethyl-3-thiazoline oxime are added portionwise to a suspension of 0.9 g of sodium hydride in 20 ml of tetrahydrofuran. The sodium hydride was liberated shortly before its use from a 55% suspension in oil by two-fold extraction with a small amount of absolute pentane. After completion of the hydrogen evolution, the mixture is stirred at room temperature for an additional 1 hour. 2.05 g (0.019 mol) of dimethylcarbamoyl chloride are added dropwise, and the reaction mixture is stirred at room temperature for 16 hours. The residue is then taken up in diethyl ether, and the organic phase is washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is subsequently distilled off, and the residue is recrystallized from diethyl ether/n-hexane to yield 5-oxo-2,2,4-trimethyl-3-thiazoline O-(dimethylcarbamoyl)oxime, m.p. 92°-95° C.
Reaction SMILES: Cl.[CH:2]1([NH:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])O.[Na+].O.[CH3:15][C:16]1[O:17][C:18]([CH3:24])=[CH:19][C:20]=1[C:21](Cl)=[O:22]>ClCCl>[CH:2]1([N:7]([C:21]([C:20]2[CH:19]=[C:18]([CH3:24])[O:17][C:16]=2[CH3:15])=[O:22])[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Reactant: ONC1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C(=O)N(O)C2CCCC2)c(C)o1
Temperature: 25 °C

Procedure:
27.5 Parts of N-cyclopentylhydroxylamine hydrochloride is dissolved in 200 parts of dichloromethane; a solution of 33.6 parts of sodium hydrogen carbonate in 300 parts of water is then added. At room temperature and while stirring thoroughly, 31.8 parts of 2,5-dimethylfuran-3-carboxylic chloride is dripped into this mixture. After stirring the mixture for 1 hour the organic phase is separated, dried over anhydrous sodium sulfate and evaporated. The oil which remains soon solidifies and the crystals obtained are stirred with petroleum ether, suction filtered and dried. There is obtained 14.3 parts of N-cyclopentyl-2,5-dimethylfuran-3-hydroxamic acid having a melting point of from 107° to 109° C. ##SPC9##
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Si:11]([O:18][C@@H:19]1[CH2:24][CH2:23][NH:22][CH2:21][C@H:20]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>CN(C=O)C>[Si:11]([O:18][C@@H:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:21][C@H:20]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNCC[C@H]1O[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2[N+](=O)[O-])CC[C@H]1O[Si](C)(C)C(C)(C)C
Yield: 98 %

Procedure:
Method 1 was followed using 1 eq each of 4-chloro-3-nitropyridine, tert-butyl (3R,4R)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate and triethylamine in DMF yielding tert-butyl(3R,4R)-4-(tert-butyldimethylsilyloxy)-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate, (98%). LCMS (m/z): 453.3 (MH+); LC Rt=4.01 min.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:12][CH:13]=O)[CH:8]=[N:9]2)=[N:4][CH:3]=1.C(O)(=O)C.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[C:7]([CH2:12][CH2:13][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH:6]=2
Reactant: C1CCNC1
Reactant: O=CCc1cnc2cc(Br)cnc2c1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Brc1cnc2cc(CCN3CCCC3)cnc2c1

Procedure:
To a stirred solution of the product from Example 153D (0.1 g, 0.4 mmol), acetic acid (0.4 mmol, 0.025 g) and pyrrolidine (0.44 mmol, 0.031 g) in dry THF (5 ml) NaBH(OAc)3 was added (0.6 mmol, 0.127 g). After 12 hr at room temperature the mixture was diluted with 50 mL of CH2Cl2 and washed successively with a saturated solution of sodium bicarbonate, brine and water. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified over silica using 10% MeOH in CH2Cl2. The desired compound was obtained in 40%. 1H NMR (CDCl3, 300 MHz) δ 1.60 (m, 4H), 2.20 (m, 4H), 2.75 (m, 4H), 8.30 (m, 1H), 8.40 (m, 1H), 8.90 (m, 1H), 9.05 (m, 1H). MS (ESI) [M+H]+ at 307.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=3)[NH:18][CH:17]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:26][Si:27]([CH3:35])([CH3:34])[CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31]>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][CH:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=3)[N:18]([S:30]([CH2:29][CH2:28][Si:27]([CH3:35])([CH3:34])[CH3:26])(=[O:32])=[O:31])[CH:17]=2)[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Reactant: C[Si](C)(C)CCS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2cn(S(=O)(=O)CC[Si](C)(C)C)c3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Sodium hydride (96 mg, 4.07 mmol) was added to a solution of N-tert-butoxycarbonyl-4-(5-fluoroindol-3-yl)piperidine (1.28 g, 4.07 mmol), [prepared as described in Step 1, above] in DMF (6 ml) at 0° C. and the reaction mixture was stirred for 30 min. 2-Trimethylsilylethanesulfonyl chloride (820 mg, 4.07 mmol) was added and the reaction mixture was slowly warmed to RT over 30 min. After 2.5 h, the reaction mixture was quenched with water (10 ml) and the product was extracted into methylene chloride. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Due to incomplete reaction the above steps were repeated on the isolated crude reaction mixture. The final residue was chromatographed (PTLC, SiO2, 20% ethyl acetate/hexanes) to afford N-tert-butoxycarbonyl-4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidine (84%) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[OH:12].[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=O)=[CH:17][CH:16]=1>S(Cl)(Cl)=O>[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]2[O:12][C:3]3[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=3[N:1]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1cccc(N)c1O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc2nc(-c3ccc(OC)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
Methyl 2-(4-methoxyphenyl)benzoxazole-7-carboxylate was prepared from methyl 3-aminosalicylate and 4-methoxybenzoyl chloride as described in Step A of Example 1. The crude material was suspended in thionyl chloride (15 mL) and the mixture heated to reflux overnight. After this time the reaction was cooled and concentrated to a dark oil. This oil was treated with methanol and the solution stirred at room temperature for 1 h. Subsequent concentration afforded a dark brown solid which was purified by column chromatography to afford a 24% yield of methyl 2-(4-methoxyphenyl)benzoxazole-7-carboxylate as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 8.19 (d, J=8.7 Hz, 2H), 8.04 (d, J=7.8 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.20 (d, J=8.7 Hz, 2H), 3.99 (s, 3H); 3.88 (s, 3H); MS (ESI) m/z 284 [M+H]+.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH2:19][CH3:20])(C(C)(C)C)(C)C>C1COCC1>[CH2:19]([C:10]1[CH:11]=[C:12]([C:15](=[O:18])[CH2:16][CH3:17])[CH:13]=[CH:14][C:9]=1[OH:8])[CH3:20]
Reactant: CCC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)c(CC)c1
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(O)c(CC)c1
Yield: 100 %

Procedure:
In a manner similar to that of Example 1(m), starting with 6.8 g (23 mmol) of 1-[4-(tert-butyldimethylsilanyloxy)-3-ethylphenyl]propan-1-one in 50 ml of THF, 4.1 g (100%) of the expected product are obtained in the form of a beige-colored oil.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[F:21][C:22]([F:32])([F:33])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:8]2[C:9]([O:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])=[CH:26][CH:25]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccc(OC(F)(F)F)cc2)c1
Yield: 47.3 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 4-trifluoromethoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (212 mg, yield: 47.3%).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:6]2[S:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([CH3:19])[C:7]=2[N:8]=1.[C:26](O)(=[O:30])[CH:27]([CH3:29])[OH:28]>>[Cl:2][C:3]1[N:4]=[C:5]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:6]2[S:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:26](=[O:30])[C@@H:27]([OH:28])[CH3:29])[CH2:15][CH2:14]3)=[C:9]([CH3:19])[C:7]=2[N:8]=1
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC(O)C(=O)O
Agent: Cl
Product: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12

Procedure:
Tert-butyl 4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate (777 mg) was subjected to General Procedure E to give the HCl salt of 2-chloro-7-methyl-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine. The HCl salt of 2-chloro-7-methyl-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (590 mg) was reacted with lactic acid via General Procedure B-2 to give (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:11]=3[N:12]=2)[CH:7]=1.[CH:30]1[C:35]([C:36]([OH:38])=[O:37])=[CH:34][C:33]2[C:39]([O:41][C:42](=O)[C:32]=2[CH:31]=1)=[O:40]>>[CH2:24]([NH:23][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[C:39](=[O:40])[C:33]3[C:32](=[CH:31][CH:30]=[C:35]([C:36]([OH:38])=[O:37])[CH:34]=3)[C:42]2=[O:41])=[CH:7][C:6]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][C:11]=2[N:12]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCNc1ccc(N)cc1-c1nc2cc(-c3ccccc3)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: CCCCCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 1b), from 2-(5-amino-2-hexylaminophenyl)-5-phenylbenzoxazole (237 mg, 0.61 mmol) and 1,2,4-benzenetricarboxylic anhydride (117 mg, 0.61 mmol) the title compound was obtained (129 mg, 38%). 1H NMR (DMSO) δ 8.46(m, 2H), 8.30(m, 1H), 8.08(m, 2H), 7.80(m, 4H), 7.49(m, 3H), 7.40(m, 1H), 7.02(m, 1H), 3.40(m, 2H), 1.75(m, 2H), 1.41(m, 6H), 0.91(m, 3H). MS 560 m/z (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38]O)[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:25]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][N:15]2[C:14](=[O:17])[N:11]3[N:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[C:9]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C:10]3=[N:16]2)[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: OCC1CCN(Cc2ccccc2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1n(CC2CCN(Cc3ccccc3)CC2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reaction time: 1 h
Yield: 10.2 %

Procedure:
To a THF solution (2 ml) of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (40 mg, 0.11 mmol), prepared as described in Example 1, (1-benzyl-4-piperidyl)methanol (27 mg 0.13 mmol), and triphenylphospine (86 mg, 0.32 mmol) was added diethyl azodicarboxylate (0.15 ml, 0.38 mmol). After 1 hour, the reaction mixture was concentrated. The crude material was purified by preparative HPLC to give the title compound, 2-((1-benzylpiperidin-4-yl)methyl)-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (6.1 mg, 10%) as a yellow solid. MS M+H=544; 1HNMR (CDCl3) δ 8.19 (1H), 7.42 (2H), 7.32-7.20 (9H), 7.11 (2H), 4.19 (1H), 4.02 (2H), 3.66 (2H), 2.63 (2H), 2.12 (2H), 1.91 (4H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15])=[N+]=[N-].[H][H]>C(O)C.O.[C].[Pd]>[NH2:1][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15]
Reactant: [N-]=[N+]=NCCn1c(=O)[nH]c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: NCCn1c(=O)[nH]c2ccccc21
Yield: 89.1 %

Procedure:
In 150 ml of ethanol was dissolved 1.3 g (6.4 mmol) of Compound i followed by addition of a suspension of 65 mg (5 w/w%) of 10% palladium-carbon in 2 ml of water. The mixture was stirred at room temperature for 4.5 hours, with hydrogen gas being bubbled into the mixture. The reaction mixture was then filtered and the filtrate was concentrated to give 1.01 g (89.1%) of 1-(2-aminoethyl)-2,3-dihydro-2-oxo-1H-benzimidazole (Compound j) as white crystals.
Reaction SMILES: C(O)(=O)C.[OH:5][CH:6]1[CH2:9][NH:8][CH2:7]1.[C:10](Cl)(=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>N1C=CC=CC=1>[C:10]([N:8]1[CH2:9][CH:6]([OH:5])[CH2:7]1)(=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: OC1CNC1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCC(=O)N1CC(O)C1
Temperature: 0 °C

Procedure:
Stir a suspension of 6.31 g of 3-hydroxyazetidine acetate in 150 ml dry pyridine until a solution results. Add 15.8 g stearoyl chloride at room temperature during ten minutes and stir for 21 hours at room temperature. Pour into 450 ml of an ice-water mixture, and extract once with 300 ml ethyl ether and then twice with 250 ml portions chloroform. Wash the combined extracts with three 150 ml portions of water, dry over anhydrous sodium sulfate and remove the solvents in vacuo. Stir the residue in 250 ml hexane and filter the resultant solid. Recrystallization from hexane affords pure 1-octadecanoyl-3-hydroxyazetidine, m.p. 86°-87.5° C.
Reaction SMILES: [NH:1]([C:3](=[S:5])[NH2:4])[NH2:2].[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[C:9]([F:16])[CH:8]=1>C1COCC1>[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH:2][NH:1][C:3](=[S:5])[NH2:4])=[O:12])=[C:9]([F:16])[CH:8]=1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: NNC(N)=S
Solvent: C1CCOC1
Product: NC(=S)NNC(=O)c1ccc(Br)cc1F
Reaction time: 1 h

Procedure:
Hydrazinecarbothioamide (6.8 g, 75 mmol) was added to a solution of 4-bromo-2-fluorobenzoyl chloride (11.8 g, 50.0 mmol) in THF (50 mL) at rt and stirred for 1 hour. The reaction mixture was concentrated to give 2-(4-bromo-2-fluorobenzoyl)-hydrazinecarbothioamide as a white solid, which was used directly in the next step without purification. MS (ESI): mass calcd. for C8H7BFN3OS, 290.95, m/z found, 292.1 [M+H]+.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][NH:7][C:8]([NH2:10])=[NH:9].[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+].[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH3:29])[C:23]=1[N:30]=[C:31]=[S:32])[CH3:21].Cl.CO>C1COCC1.CO>[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH3:29])[C:23]=1[NH:30][C:31]([NH:10][C:8](=[NH:9])[NH:7][CH3:6])=[S:32])[CH3:21]
Reactant: CNC(=N)N
Reactant: CCc1cccc(CC)c1N=C=S
Agent: Cl
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cccc(CC)c1NC(=S)NC(=N)NC
Yield: 107.2 %

Procedure:
To a stirred suspension of 7.3 g (30.0 mmol) of methylguanidine sulfate in THF (100 ml) was added 4.8 g (60.0 mmol) of 50% W/W aqueous NaOH. The mixture was stirred for one hour after which 5.0 g of anhydrous Na2SO4 was added and the mixture stirred for an additional hour. To the mixture was added dropwise over one hour a solution of 5.7 g (30.0 mmol) of 2,6-diethylphenylisothiocyanate in THF (40 ml) and the mixture was stirred for two hours at ambient temperature. The THF was removed under vacuum and the residue partitioned between H2O and CHCl3. The layers were separated and the aqueous layer extracted with CHCl3 (1×100 ml). The extracts were dried (MgSO4) and concentrated to give a yellow oil which was dissolved in MeOH and acidified with HCl/MeOH. The MeOH was removed under vacuum to give a viscous yellow oil which slowly crystallized on standing. Crystallization from MeOH/CH3C≡N gave 8.5 g (94 %) of the desired salt.