Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH2:4]([N:11]1[CH2:16][CH2:15][O:14][CH:13]([CH2:17]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CS(C)=O.O>[CH2:4]([N:11]1[CH2:16][CH2:15][O:14][CH:13]([CH2:17][C:1]#[N:2])[CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CCO2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCC1CN(Cc2ccccc2)CCO1

Procedure:
A mixture of finely ground sodium cyanide (39.6 g.) and 4-benzyl-2-(toluene-p-sulphonyloxymethyl)morpholine (144.4 g.) in dimethyl sulphoxide (600 ml.) is stirred and heated at 60°-65° C. for 3.5 hours. The mixture is cooled, diluted with water (6 l.) and extracted with ether (3 × 2 l.). The ether extracts are combined and washed with brine (2 × 1 l.) and dried over anhydrous magnesium sulphate and the solvent removed by evaporation in vacuo. The residue is recrystallised from petroleum ether (b.p. 40°-60° C.) to give 4-benzyl-2-cyanomethylmorpholine, m.p. 62° C.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2)=O.[C:24]([CH:29]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:26][CH2:27][CH3:28])=[O:25].[CH2:49](Cl)Cl>>[CH2:27]([O:26][C:24](=[O:25])/[CH:29]=[CH:49]/[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)(=[O:15])=[O:16])[CH2:6]2)[CH3:28]
Reactant: O=Cc1ccc2c(c1)CC(CNS(=O)(=O)c1ccc(Cl)cc1)C2
Reactant: ClCCl
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)/C=C/c1ccc2c(c1)CC(CNS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To 20 ml of methylene chloride, 1.29 g (3.68 mmol) of 5-formyl-2-[(4-chlorophenyl)sulfonylaminomethyl]indan and 1.28 g (3.68 mmol) of carboethoxymethylene triphenylphosphoran were added and stirred for 16 hours at room temperature. The reaction solution was purified by silica gel column chromatography.(chloroform), and the precipitates obtained were recrystallized from a solvent mixture of ethyl acetate and hexane. 1.18 g of colorless crystals were obtained. Yield: 77%
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1>>[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH:37][C:26]([N:17]2[CH2:16][CH2:15][C:12]3([C:11](=[O:20])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:19][CH2:18]2)=[O:25])=[CH:34][CH:33]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: NCc1ccc(F)cc1
Product: O=C(NCc1ccc(F)cc1)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and 4-Fluoro-benzylamine. MS (ESI): 466.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[Cl:16][CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>O1CCCC1.C(=O)([O-])[O-].[K+].[K+].[Zn]>[Cl:16][CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(CCCl)c1ccccc1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Product: Nc1ccc(C(=C(CCCl)c2ccccc2)c2ccccc2)cc1
Temperature: -10 °C
Reaction time: 3.5 h

Procedure:
Zinc (10.0 g, 0.154 mol) and tetrahydrofuran (THF) (120 ml) is added to the reaction vessel and cooled to −10° C. To the mixture is added dropwise titan tetrachloride (1 4.4 g, 0.076 mol) at about −10° C. After the addition is completed the mixture is refluxed for two hours. Then it is cooled to 40° C. and (4-Amino-phenyl)phenyl-methanone (5.1 g, 0.0258 mol) and 3-chloropropiophenone (4.36 g, 0.0258 mol) are dissolved in THF (50 ml) and added to the mixture. Refluxingis continued for additional 3.5 hours. The cooled reaction mixture is poured in aqueous potassium carbonate solution (14 g K2CO3+140 ml water) and allowed to stand over night. The mixture is filtered and the precipitate is washed three times with THF. The filtrate is evaporated to dryness. The residue is dissolved in ethyl acetate and washed with water. Yield 9.6 g Z-isomer being the only isomer.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([CH3:26])=[N:9]2)=CC=1.[CH3:29][N:30]1[C:35](=[O:36])[C:34]([C:37](O)=[O:38])=[CH:33][CH:32]=[N:31]1.Cl.FC1C=CC(NN)=CC=1>>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:37]([C:34]2[C:35](=[O:36])[N:30]([CH3:29])[N:31]=[CH:32][CH:33]=2)=[O:38])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([CH3:26])[C:11]=12
Reactant: Cn1nccc(C(=O)O)c1=O
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: Cl
Agent: NNc1ccc(F)cc1
Product: Cc1n[nH]c2nccc(Oc3ccc(NC(=O)c4ccnn(C)c4=O)cc3F)c12

Procedure:
Prepared by 2-step process from 3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline (prepared as in Example 5, Step D) and 2-methyl-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (prepared according to the 3-step procedure of Example 19, Steps A-C, substituting methylhydrazine for 1-(4-fluorophenyl)hydrazine hydrochloride) according to the procedure of Example 21, Steps A and B. The crude material was purified by silica gel flash column chromatography (3% MeOH in CH2Cl2) to afford 17 mg (64% for 2-step process) of the desired product. LRMS (ESI pos) m/e 395.2 (M+1). 1H-NMR (400 MHz, CD3OD/CDCl3) δ 8.30 (d, 1H), 8.25 (d, 1H), 8.17 (d, 1H), 8.02 (dd, 1H), 7.51 (m, 1H), 7.37 (t, 1H), 6.27 (d, 1H), 3.79 (s, 3H), 2.75 (s, 3H); 19F NMR (376 MHz, CD3OD/CDCl3) δ −128.3.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]1[CH3:20])[CH2:9][CH3:10]>C1C=CC=CC=1>[CH2:8]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:3]([CH2:2][C:1]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]([CH2:8][CH2:9][CH3:10])[C:12]=2[CH3:20])=[O:7])[C:4]([OH:6])=[O:5])=[C:12]1[CH3:20])[CH2:9][CH3:10]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCn1c(C)cc2ccccc21
Solvent: c1ccccc1
Product: CCCn1c(C)c(C(=O)CC(C(=O)O)c2c(C)n(CCC)c3ccccc23)c2ccccc21
Temperature: 25 °C
Yield: 3.3 %

Procedure:
A stirred solution of 20.0 g (0.204 mole) of maleic anhydride and 70.0 g (0.408 mole) of 1-n-propyl-2-methylindole in 200 ml of benzene was heated at reflux for a period of approximately eighteen hours and then allowed to cool to ambient temperature. The solid which separated from the cooled solution was collected by filtration, washed with fresh chilled benzene and dried in vacuo at 60° C. to obtain 3.0 g of 2,4-bis(1-n-propyl-2-methyl-3-indolyl)-4-oxobutanoic acid (Formula VII: R=CH3CH2CH2 ; R1 =CH3 ; Y=H) as a white solid melting over the range 210° to 215° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].I[CH2:26][O:27][C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:26][O:27][C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])=[O:13])(=[O:6])=[O:7]
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)O
Reactant: CC(C)OC(=O)OCI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)OCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Yield: 35.8 %

Procedure:
Following the general procedure for the preparation of acyloxyalkyl/alkoxycarbonyloxyalkyl carboxylic esters from carboxylic acids of Description 22, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (0.3 g, 0.79 mmol) dissolved in 5 mL of anhydrous toluene was reacted with 0.58 g (2.4 mmol) of methylethyl (iodomethoxy)formate in the presence of 0.27 g (1.0 mmol) of silver carbonate (Ag2CO3). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 0.14 g (36% yield) of the title compound (27a) as a colorless oil. Rf=0.59 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=1.07 (s, 3H), 1.08 (s, 3H), 1.31-1.34 (m, 6H), 2.25-2.32 (m, 2H), 3.32-3.36 (m, 2H), 3.63-3.65 (m, 2H), 3.90 (s, 1H), 3.96 (d, J=9.2 Hz, 1H), 4.21 (d, J=9.6 Hz, 1H), 4.37 (d, J=11.2 Hz, 1H), 4.64 (d, J=11.2 Hz, 1H), 4.89-4.95 (m, 1H), 5.78 (d, J=5.6 Hz, 1H), 5.87 (d, J=5.6 Hz, 1H), 7.30-7.37 (m, 5H) ppm. MS (ESI) m/z 495.02 (M+H)+, 516.98 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.C(N(C(C)C)CC)(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:38][S:39]([O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:14]1[CH2:13][C@@H:12]([C:10]2[CH:9]=[CH:8][C:6]3[O:7][C:2]([CH3:28])([CH3:1])[O:3][CH2:4][C:5]=3[CH:11]=2)[O:16][C:15]1=[O:17])(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCO)C(=O)O3)ccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOS(C)(=O)=O)C(=O)O3)ccc2O1
Reaction time: 0.5 h

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-{6-[2-hydroxyethoxy]hexyl}-1,3-oxazolidin-2-one (200 mg) in dichloromethane (14 ml) under nitrogen at 0° was treated with diisopropylethylamine (0.10 ml) followed by methanesulfonyl chloride (0.04 ml). The mixture was stirred at 0° for 0.5 h and sat. sodium bicarbonate solution (30 ml) was then added. The mixture was extracted with dichloromethane (30 ml) and the organic extract dried (Na2SO4). The solvent was evaporated in vacuo to give the title compound (240 mg). LCMS RT=3.22 min, ES+ve 472 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([C:11]2[N:12]=[C:13]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:14]3[S:19][C:18]([CH2:20][N:21]4[CH2:26]CN5CCC[C@H]5[CH2:22]4)=[CH:17][C:15]=3[N:16]=2)[CH:3]=1.Cl.C(OC([N:44]1[CH2:52][CH2:51][C:47]2(CNC2)[CH2:46][CH2:45]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH2:26]1[C:47]2([CH2:51][CH2:52][NH:44][CH2:45][CH2:46]2)[CH2:22][N:21]1[CH2:20][C:18]1[S:19][C:14]2[C:13]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[N:12][C:11]([C:4]3[CH:3]=[C:2]([F:1])[CH:10]=[C:9]4[C:5]=3[CH:6]=[CH:7][NH:8]4)=[N:16][C:15]=2[CH:17]=1
Reactant: Fc1cc(-c2nc(N3CCOCC3)c3sc(CN4CCN5CCC[C@H]5C4)cc3n2)c2cc[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC2
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cc(-c2nc(N3CCOCC3)c3sc(CN4CC5(CCNCC5)C4)cc3n2)c2cc[nH]c2c1

Procedure:
Prepared according to the method used in the preparation of 2-(6-fluoro-1H-indol-4-yl)-6-[(S)-1-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)methyl]-4-morpholin-4-yl-thieno-[3,2-d]pyrimidine using 2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester hydrochloride in place of (S)-octahydro-pyrrolo[1,2-c]pyrazine, followed by BOC-deprotection using TFA:DCM (1:1). The title compound was obtained as a white solid (29 mg, 49%).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1.[C:12]([O-])([O-])=O.[K+].[K+].CI.CCOCC>CN(C=O)C>[CH3:12][N:3]1[CH:4]=[C:5]([CH3:11])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]1=[O:1]
Reactant: O=C([O-])[O-]
Reactant: Cc1cnc(O)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc([N+](=O)[O-])c(=O)n(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a suspension of 10 g (63.6 mmol) 2-hydroxy-5-methyl-3-nitropyridine and 17.58 g (127 mmol) K2CO3 in 100 ml DMF, 5.96 ml (95 mmol) MeI was added at 0° C. Afterwards the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, diluted with water and extracted three times with CH2Cl2. The organic layers were combined, dried over Na2SO4, filtered and concentrated to obtain an orange slurry. The residue was treated with ether and the precipitate was filtered off and dried under high vacuum to obtain 9.74 g (57.9 mmol, 91% yield) of the title compound as an orange solid. LCMS: (M+H)=169; tR=0.47 min (LC-MS 6). HPLC: tR=1.70 min (HPLC 8). 1H-NMR (DMSO-d6, 400 MHz) δ ppm 8.30 (d, 1H) 8.08 (m, 1H) 3.50 (s, 3H) 2.09 (s, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([NH:20][CH3:21])=[O:19])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[Zn][CH2:24][CH:25]([CH3:27])[CH3:26].O.C(OCC)(=O)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][CH:25]([CH3:27])[CH2:26][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([NH:20][CH3:21])=[O:19])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CNC(=O)COC(=O)N1CCN(c2ccc(Br)nc2)CC1
Reactant: CC(C)C[Zn]Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)N1CCN(c2ccc(CC(C)C)nc2)CC1
Reaction time: 19 h

Procedure:
1.25 g (3.50 mmol) of 2-(methylamino)-2-oxoethyl 4-(6-bromo-3-pyridyl)-1-piperazinecarboxylate, prepared in step 9.1, and 0.12 g (0.17 mmol) of dichlorobis(triphenylphosphine)palladium (Pd(PPh3)2Cl2) suspended in 7 ml of tetrahydrofuran are introduced under an inert atmosphere. 17.50 ml (8.74 mmol) of a solution of bromoisobutylzinc (0.5M) in tetrahydrofuran are then added. Stirring is continued at room temperature for 19 hours. The reaction mixture is poured into 25 ml of water and 25 ml of ethyl acetate. The insoluble material is filtered off through glass fiber. The phases are separated by settling, the aqueous phase is extracted twice with ethyl acetate, the combined organic phases are dried over sodium sulfate and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by chromatography on silica gel, eluting with a 95/5 mixture of dichloromethane and methanol, followed by crystallization from diisopropyl ether. 0.36 g of product is obtained in the form of a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[N:27]([CH3:28])[C:26](=[O:29])[CH:25]=[C:24]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[N:23]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:22]2[N:27]([CH3:28])[C:26](=[O:29])[CH:25]=[C:24]([C:30]3[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=3)[N:23]=2)[CH2:10][CH:9]1[C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCN(C(=O)OC(C)(C)C)C(c3ccc(Cl)cc3)C2)nc(-c2ccncc2)cc1=O
Yield: 94.3 %

Procedure:
A solution of 4-(tert-butoxycarbonyl)-3-(4-chlorophenyl)piperazine (330 mg, 1.1 mmol), 2-chloro-3-methyl-6-(4-pyridyl)pyrimidin-4-one (246 mg, 1.1 mmol) and triethylamine (170 μl, 1.22 mmol) in tetrahydrofuran were refluxed. Usual workup and purification by silica gel column chromatography gave 2-(1-(tert-butoxy-carbonyl)-2-(4-chlorophenyl)-piperazine-4-yl)-3-methyl-6-(4-pyridyl)pyrimidin-4-one (500 mg, 93%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]3[CH2:13][C:14]4([CH2:19][CH:10]3[CH2:9]2)[O:18][CH2:17][CH2:16][O:15]4)=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>CC(C)=O>[CH2:31]([O:30][C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH:10]3[CH2:19][C:14]4([CH2:13][CH:11]3[CH2:12]2)[O:15][CH2:16][CH2:17][O:18]4)=[C:4]([F:20])[CH:3]=1)=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Nc1ccc(N2CC3CC4(CC3C2)OCCO4)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(Nc1ccc(N2CC3CC4(CC3C2)OCCO4)c(F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.2 %

Procedure:
2-(4-amino-2-fluorophenyl)-hexahydro-1H-spiro[cyclopenta[c]pyrrol-5,2′-[1,3]dioxolane] (74.7 mmol) prepared in the step 5 was dissolved in 300 ml of acetone, and 150 ml of a 10 wt % sodium carbonate aqueous solution was added. And then, the temperature was lowered to 0° C., 13.86 ml (97.1 mmol) of benzyl chloroformate was slowly added dropwise over 30 minutes, and the mixture was stirred for 12 hours while raising the temperature to room temperature. After the reaction was completed, the solvent was removed under reduced pressure, 300 ml of ethyl acetate was added, the mixture was washed with water and sodium chloride, and then, the organic layer was dried over magnesium sulfate and filtered and concentrated under reduced pressure. The concentrate was separated by column chromatography to obtain 24.1 g (78%) of the title compound, of which NMR data is as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7]=2[CH:14]=1.[CH3:15]O.S(Cl)(Cl)=O>O>[CH3:15][O:12][C:11]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][C:7]=2[CH:8]=1)=[O:13]
Reactant: COc1ccc2oc(C(=O)O)cc2c1
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1cc2cc(OC)ccc2o1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-Methoxybenzofuran-2-carboxylic acid (5.04 g, 26 mmol) was weighed into a 200 ml round bottom flask fitted with a stir bar, septum and nitrogen inlet. Anhydrous MeOH (50 ml) was added under nitrogen atmosphere. The solution was cooled in an ice bath and thionyl chloride (2.3 ml, 32 mmol) was added dropwise with vigorous stirring. After stirring for 72 h at room temperature, the reaction mixture was poured into water (150 ml) and the white solid was collected. The solid was dissolved in toluene (100 ml) and the solution was washed with 1M NaHCO3 and brine and dried over MgSO4. Removal of the organic layer provided 5-methoxybenzofuran-2-carboxylic acid methyl ester as a white solid (5.15 g).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([N:13]([CH3:15])[CH3:14])[N:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[O:25])=[CH:19][CH:18]=2)[N:3]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.O>CN1C(=O)N(C)CCC1>[CH3:14][N:13]([CH3:15])[C:6]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[N:3]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[O:25])=[CH:19][CH:18]=2)[N:5]=1
Reactant: C1COCCN1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N(C)C
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)Cc1c(N(C)C)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N1CCOCC1
Temperature: 150 °C
Yield: 93.6 %

Procedure:
A mixture of methyl {4-chloro-6-(dimethylamino)-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate (0.094 g, 0.19 mmol) and morpholine (0.048 mL, 0.55 mmol) in DMPU (2 mL) was heated at 150° C. in a sealed tube for 15 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc. The combined organic extracts was washed sequentially with 1N HCl, saturated NaHCO3, and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product thus obtained was chromatographed over silica gel eluting with 5% EtOAc in CH2Cl2 to give methyl {4-(dimethylamino)-6-morpholin-4-yl-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate (0.096 g, 95% yield) as an oil.
Reaction SMILES: [CH:1]1([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4C=CO[N:19]=4)=[CH:14][CH:13]=3)[C:10](=[O:23])[C:9](O)=[C:8]2[C:25](=O)[C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31]([OH:34])(=O)[CH3:32].O.[NH2:36][NH2:37]>O>[C:26]([C:25]1[C:8]2[CH:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:32]=[CH:31][O:34][N:19]=4)=[CH:14][CH:13]=3)[C:10](=[O:23])[C:9]=2[NH:36][N:37]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: NN
Reactant: CC(C)(C)C(=O)C1=C(O)C(=O)N(c2ccc(-c3ccon3)cc2)C1C1CCCCC1
Reactant: CC(=O)O
Solvent: O
Product: CC(C)(C)c1n[nH]c2c1C(C1CCCCC1)N(c1ccc(-c3ccon3)cc1)C2=O
Temperature: 85 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a mixture of 5-cyclohexyl-4-(2,2-dimethylpropionoyl)-3-hydroxy-1-(4-isoxazol-3-ylphenyl)-1,5-dihydropyrrol-2-one (0.10 g, 0.25 mmol) and acetic acid (1 mL) was added hydrazine monohydrate (0.036 mL, 0.75 mmol). The mixture was stirred at 85° C. for 3 hr. Water (80 mL) was added to the mixture, which was then extracted with ethyl acetate (100 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (80 mL×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane). The crude product was recrystallized from ethyl acetate to give 3-tert-butyl-4-cyclohexyl-5-(4-isoxazol-3-ylphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (0.072 g, 71%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([C:14]([O:16]CC)=[O:15])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)[CH3:2].O[Li].O.CO.Cl>C1COCC1.O>[CH2:1]([O:3][C:4]1[C:13]([C:14]([OH:16])=[O:15])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOC(=O)c1c(OCC)ccc2cccnc12
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOc1ccc2cccnc2c1C(=O)O
Temperature: 67 °C
Reaction time: 24 h
Yield: 85.3 %

Procedure:
To the title compound of Step C (1.3 g, 5.4 mmol) in THF (22 mL) and H2O (11 mL) was added LiOH hydrate (675 mg, 16.5 mmol) and MeOH. The mixture was heated at 67° C. for 12 h. Additional LiOH hydrate (675 mg, 16.5 mmol) was added and the heating was continued at 70° C. for 1 days. Additional LiOH hydrate (1.4 g, 33 mmol) was added and the heating was continued at 75° C. for 1 day. The reaction was allowed to cool to rt, acidified to pH=3 with 1N HCl (aq) and concentrated. Purification via prep HPLC gave the title compound (1 g, 84%). MS (ESI) mass calcd. for C12H11NO3, 217.1; m/z found 218.0 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH2:29][CH:28]3[CH2:30][CH:25]([CH2:26][CH2:27]3)[C:24]=2[CH:31]=[CH:32][CH:33]=[O:34])=[CH:19][CH:18]=1>C1COCC1.CCCCC>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH2:29][CH:28]3[CH2:30][CH:25]([CH2:26][CH2:27]3)[C:24]=2/[CH:31]=[CH:32]/[CH:33]([OH:34])[CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH3:10])=[O:8])=[CH:21][CH:22]=1
Reactant: O=CC=CC1=C(c2ccc(F)cc2)CC2CCC1C2
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: COC(=O)CC(=O)CC(O)/C=C/C1=C(c2ccc(F)cc2)CC2CCC1C2
Reaction time: 0.5 h

Procedure:
To a 0°-5° C. suspension of pentane-washed sodium hydride (0.43 g, 10.6 mmoles) in 10 ml anhydrous THF was added dropwise methyl acetoacetate. The solution was stirred for 30 minutes and n-butyl lithium (5.8 ml of a 1.6M solution in hexanes, 9.31 mmoles) was added dropwise. The solution was stirred for 20 minutes and a solution of 3-[3-(4-fluorophenyl)bicyclo [3.2.1]oct-2-en-2-yl]propenal (2.50 g, 9.75 mmoles) in 15 ml anhydrous THF was added. The resulting solution was stirred for 60 minutes and quenched with ether and aqueous HCl. The organic layer was washed with water and brine and dried (MgSO4). Removal of the volatiles in vacuo provided 3.3 g of the solid product which was used without further purification.