Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br)([O-:3])=[O:2].CN(C=O)C.[CH2:17]([S-:19])[CH3:18].[Na+]>O>[CH2:17]([S:19][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:18]
Reactant: CC[S-]
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10.0 g (46.3 mmol) of 2-nitrobenzyl bromide were introduced into 100 ml of DMF at 0° C., 3.89 g (46.3 mmol) of sodium ethanethiolate were added in portions, and the mixture was stirred at RT for 4 h. It was diluted with water and extracted with ethyl acetate, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 9/1) to result in 7.40 g (81% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.BrC1C=CC(N2CCC(=O)CC2)=CC=1.N1C[CH2:35][O:34][CH2:33]C1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:16][CH2:35][O:34][CH2:33][CH2:15]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CN(C)C1CCN(c2ccc(Br)cc2)CC1
Agent: O=C1CCN(c2ccc(Br)cc2)CC1
Product: Brc1ccc(N2CCC(N3CCOCC3)CC2)cc1
Yield: 97 %

Procedure:
The title compound was synthesized according to the synthesis of 1-(4-bromophenyl)-N,N-dimethylpiperidin-4-amine, except reacting 1-(4-bromophenyl)piperidin-4-one (500 mg, 1.97 mmol) with morpholine (0.21 mL, 2.36 mmol) for 25 h to give the title compound as a yellow solid (620 mg, 97%). 1H NMR (400 MHz, MeOD) δ 7.31 (d, J=8.2 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H), 3.87-3.67 (m, 6H), 2.71 (t, J=12.5 Hz, 2H), 2.67-2.62 (m, 4H), 2.37-2.36 (m, 1H), 2.04-1.97 (m, 2H), 1.72-1.56 (m, 2H); MS ESI 325.2 [M+H]+, calcd for [C15H21BrN2O+H]+ 325.08.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:7][C:8]1[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=1)[O:11][C:12]1[CH:21]=[CH:20][C:15]([O:16][CH2:17][CH2:18][NH2:19])=[CH:14][CH:13]=1.C(N(C(C)C)C(C)C)C>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=1)[O:11][C:12]1[CH:21]=[CH:20][C:15]([O:16][CH2:17][CH2:18][NH:19][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[CH:14][CH:13]=1
Reactant: CCOC(=O)Cl
Reactant: NCCOc1ccc(Oc2cccc(Cl)c2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)NCCOc1ccc(Oc2cccc(Cl)c2)cc1
Temperature: 25 °C

Procedure:
With stirring, a solution of 13 g of ethyl chloroformate in 20 ml of toluene is added dropwise to a solution of 24.8 g of 2-[4-(3-chlorophenoxy)phenoxy]ethylamine and 16.8 g ethyl diisopropylamine in 150 ml of toluene, and the mixture is thereafter stirred for 15 hours at this temperature. After cooling to room temperature, the reaction mixture is washed in succession with water, 1N hydrochloric acid and, finally, with a solution of sodium chloride and dried over sodium sulfate. The solvent is removed by vacuum distillation and the crude product is further purified by chromatography over silica gel with a 1:3 mixture of diethyl ether/hexane, affording the pure ethyl 2-[4-(3-chlorophenoxy)phenoxy]ethylcarbamate of m.p. 45°-46° C. The product so obtained is identical with that obtained in Example 1A.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH3:5])[C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:2]
Reactant: CCNCC
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
A stirred solution of 2.5 g of diethylamine and 3.5 g of triethylamine in 30 ml of methylene chloride was cooled in an ice bath while 4.9 g of benzoyl chloride was added dropwise. The cooling bath was removed and the mixture stirred at ambient temperature for 18 hours. The insolubles were removed by filtration followed by methylene chloride washing. The combined filtrates were washed with water and brine, dried and evaporated to a yellow oil which was distilled in a Kugelrohr still to give 5.91 g of the desired product as a colorless oil, 70°/300 mm.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][O:14][CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:17]1[CH2:20][CH:19]([C:21]#[N:22])[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:13][O:14][CH3:15])[C:10]([N:17]1[CH2:20][CH:19]([C:21]#[N:22])[CH2:18]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#CC1CNC1
Reactant: COC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
A 25 mL round-bottomed flask was charged with (R)-2-tert-butoxycarbonylamino-3-methoxy-propionic acid (0.475 g, 2.17 mmol), azetidine-3-carbonitrile hydrochloride (314 mg, 2.65 mmol) and HATU (832 mg, 2.19 mmol). Then added DMF (3.6 mL) followed by N,N-diisopropylethylamine (1.5 mL, 8.67 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (30 mL). The organic layer was washed once with saturated NaHCO3 and water. The combined aqueous layers were back extracted with EtOAc (25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 0-100% EtOAc) to afford 288 mg (47%) of [(R)-2-(3-cyano-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-carbamic acid tert-butyl ester as a viscous colorless oil.
Reaction SMILES: [CH2:1]([Zn]CC)C.C(O)(C(F)(F)F)=O.C(I)I.[CH2:16]([N:23]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([Cl:37])[CH:31]=1)[CH:24]([CH2:27][CH:28]=[CH2:29])[CH2:25][OH:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:16]([N:23]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([Cl:37])[CH:31]=1)[CH:24]([CH2:27][CH:28]1[CH2:1][CH2:29]1)[CH2:25][OH:26])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC[Zn]CC
Reactant: C=CCC(CO)N(Cc1ccccc1)c1ccc(F)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ICI
Product: OCC(CC1CC1)N(Cc1ccccc1)c1ccc(F)c(Cl)c1
Temperature: 25 °C

Procedure:
Diethylzinc (0.064 g, 0.526 mmol) was added to a flask containing CH2Cl2 (2 mL) at 0° C. A solution of TFA (0.052 ml, 0.526 mmol) in CH2Cl2 (1 ml) was slowly added to the flask containing diethylzinc over 20 min. A solution of CH2I2 (0.042 mL, 0.526 mmol) in CH2CH2 (1 mL) was added next over 20 min. followed by addition of 2-[benzyl(3-chloro-4-fluorophenyl)amino]pent-4-en-1-ol (7-5, 0.028 g, 0.088 mmol) in CH2Cl2 (1 mL). The resulting solution was warmed to 25° C. The reaction mixture was diluted with NaHCO3 (sat. aq) and extracted with CH2Cl2 (3×5 ml). The combined organic layers were dried with NaSO4, filtered, and concentrated. The crude residue was purified by reverse phase liquid chromotography (Semi Prep YMC C-18 Reverse Phase Column 5% CH3CN/H2O to 95% CH3CN/H2O with 0.1% TFA present) to yield 2-[benzyl(3-chloro-4-fluorophenyl)amino]-3-cyclopropylpropan-1-ol (9-2). MS 334.2 found 334.8 (M+H+) required.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:19]([CH:16]2[CH2:18][CH2:17]2)=[O:20])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(I)c1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(I)c1)C1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
1.53 g of 3-iodoaniline and 2.78 ml of triethylamine are dissolved in 25 ml of methylene chloride and treated dropwise at room temperature with a solution of 1.6 ml of cyclopropane carbonyl chloride in 10 ml of methylene chloride. The mixture is stirred at room temperature for a further 5 hrs., evaporated and poured into 50 ml of water. The mixture is made slightly acid with dil. hydrochloric acid and extracted three times with ethyl acetate. The residue is recrystallized from toluene. 1.47 g of cyclopropanecarboxylic acid (3-iodo-phenyl)-amide are isolated as a colourless solid. Yield: 74%. M.p.=133°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Cl:26])[C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[CH:21]=1)[C:5]([NH:7][CH2:8][CH2:9]Cl)=[O:6].N12CCCN=C1CCCCC2>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH2:9][CH2:8][N:7]=2)[CH:11]=[C:12]([Cl:26])[C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[CH:21]=1
Reactant: Cc1cc(CCCCCOc2c(Cl)cc(C(=O)NCCCl)cc2Cl)on1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(CCCCCOc2c(Cl)cc(C3=NCCO3)cc2Cl)on1
Yield: 65.7 %

Procedure:
To a solution of 1.0 g 3,5-dichloro-N-(2-chloroethyl)-4-{[5-(3-methyl-5-isoxazolyl)pentyl]oxy}benzamide in 75 ml methylene dichloride was added 0.92 g 1,8-diazabicyclo[5.4.0]undec-7-ene, and the mixture was heated at reflux for about 16 hrs. The reaction mixture was concentrated in vacuo and the residue partitioned between 150 ml ethyl acetate and 50 ml water. The organic layer was separated, washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel and eluted with 1:1 ethyl acetate:hexane. The eluted material was isolated, dissolved in ether and crystallized upon seeding to give 0.60 g (66%) of 5-{5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole, light yellow solid, m.p. 39°-40° C., identical with the compound of Example 105, as confirmed by thin layer chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[F:13][C:14]([F:21])([F:20])[C:15](OCC)=[O:16].C[O-].[Na+].Cl>COCCOC.O.CCOC(C)=O>[F:13][C:14]([F:21])([F:20])[C:15](=[O:16])[CH2:11][C:10]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=1)=[O:12]
Reactant: COc1ccc(C(C)=O)cc1Cl
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(C(=O)CC(=O)C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To stirred solution of 1-(3-chloro-4-methoxyphenyl)ethanone (2.2 g, 12 mmol) in DME was added ethyl trifluoroacetate (4.28 ml, 36 mmol) and sodium methoxide (4.25 g, 72 mmol), and the resulting reaction mixture was stirred at room temperature for 1 hour. EtOAc (200 ml) and water (50 ml) were added, and the pH of the aqueous layer was adjusted to 6 by addition of 1 N HCl solution. The organic layer was washed with brine (50 ml), dried over MgSO4, and concentrated in vacuo to give the title compound in quantitative yield. This was used for the next coupling step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6](Cl)=[O:7].[NH:14]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6]([C:18]1[NH:14][CH:15]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=1)=[O:7]
Reactant: COC(=O)c1cc[nH]c1
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Product: COC(=O)c1c[nH]c(C(=O)c2cc(OC)cc(OC)c2)c1

Procedure:
By the procedure of Example 64, but a 5 hour reaction time, 3,5-dimethoxybenzoyl chloride (4.0 g., 20 mmoles) was reacted with methyl pyrrole-3-carboxylate to yield, without recrystallization, methyl 5-(3,5-dimethoxybenzoyl)pyrrole-3-carboxylate (3.7 g., m.p. 115°-120° C., m/e 289).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1/[CH:13]=[CH:14]/[C:15]1[CH:50]=[CH:49][C:18]([CH2:19][N:20]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([C@@H:37]3[CH2:41][CH2:40][CH2:39][N:38]3C(OC(C)(C)C)=O)=[O:36])=[CH:30][CH:29]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:21]1([N:20]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([NH:34][C:35]([C@@H:37]3[CH2:41][CH2:40][CH2:39][NH:38]3)=[O:36])=[CH:32][CH:33]=2)[CH2:19][C:18]2[CH:17]=[CH:16][C:15](/[CH:14]=[CH:13]/[C@@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:50][CH:49]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1/C=C/c1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)OC(C)(C)C)cc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(CN(Cc2ccc(/C=C/[C@@H]3CCCN3)cc2)c2ccccc2)cc1)[C@@H]1CCCN1

Procedure:
To a solution of the product of Example 149G (50 mg, 0.073 mmol) dissolved in dichloromethane (0.3 mL) was added trifluoroacetic acid (2.7 mL) and the resultant solution stirred at room temperature for 20 minutes. The solution was then concentrated under vacuum, the residue dissolved in a chloroform/isopropanol mixture and extracted with aqueous sodium bicarbonate, the organic solution was then dried, filtered, and concentrated to afford the title compound. m/z 481 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12]C1C=CC=CC=1C)=[O:11].C[C:25]1[C:33]([N+:34]([O-:36])=[O:35])=[C:32]([O:37][CH2:38][CH2:39][NH2:40])[CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28].Cl>CN(C=O)C>[N+:34]([C:33]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:37][CH2:38][CH2:39][NH:40][C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([N:9]([C:4]2[CH:3]=[CH:8][CH:7]=[CH:6][C:5]=2[CH3:20])[C:10]([NH2:12])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:27]([OH:29])=[O:28])([O-:36])=[O:35]
Reactant: Cc1c(C(=O)O)ccc(OCCN)c1[N+](=O)[O-]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)NCCOc2ccc(C(=O)O)cc2[N+](=O)[O-])ccc1N(C(N)=O)c1ccccc1C
Reaction time: 8 h
Yield: 5.9 %

Procedure:
To a stirred solution of pentafluorophenyl ester of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (1.86 g, 3.87 mmol) and methyl 3-nitro-4-(2-aminoethoxy)benzoic acid (0.93 g, 3.87 mmol) in DMF (27 mL) was added Et3 N (0.90 mL, 6.46 mmol), and the resulting mixture was stirred overnight. The mixture was poured into 0.5 N HCl and the resulting solid was collected. The crude solid was dissolved in THF-0.25 N NaOH (1/1, 20 mL) and the resulting mixture was heated under reflux overnight. The mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, and evaporated. The crude solid was recrystallized from CHCl3-EtOH to give 60 mg (3% for 2 steps) 3-nitro-4-[2-[3-methoxy-4-[N-(2-methylphenyl)ureido]phenylacetyl]aminoethoxy]benzoic acid 257 as a yellow crystalline solid. mp 112–115° C.; 1H-NMR (DMSO-d6) d 2.24 (s, 3 H), 3.37–3.66 (m, 7 H), 3.84 (s, 3 H), 4.27–4.30 (m, 1 H), 6.74–8.56 (series of m, total 12 H); MS (FAB) m/z 523 (M++1); Anal. Calcd for C26H26N4O8.3/2H2O: C, 56.83; H, 5.32; N, 10.20. Found: C, 56.66; H, 4.90; N, 9.33.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1)CCC>CN(C=O)C.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.[Cu]=O>[NH2:1][C:2]1[N:3]=[C:4]([S:11][CH3:12])[C:5]([C:9]#[N:10])=[C:6]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:7]=1
Reactant: CSc1nc(N)nc(Br)c1C#N
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=[Cu]
Solvent: CN(C)C=O
Product: CSc1nc(N)nc(-c2cnccn2)c1C#N
Temperature: 25 °C
Yield: 31.2 %

Procedure:
To a stirred solution of 1.11 g (4.52 mmol) 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile in 10 ml dry DMF under argon at room temperature were added 2.00 g (5.42 mmol) 2-(tri-n-butylstannanyl)pyrazine, 190 mg (0.27 mmol) bis(triphenylphosphine)palladium(II) chloride and 431 mg (5.42 mmol) copper(II) oxide. The reaction mixture was heated at reflux for 18 h, then cooled to room temperature and concentrated in vacuo. Flash chromatography (ethyl acetate/hexane 1/1 then ethyl acetate) afforded 344 mg (31%) 2-amino-4-methylsulfanyl-6-pyrazin-2-yl-pyrimidine-5-carbonitrile as an off-white crystalline solid. EI-MS m/e (%): 244 (M+, 100), 243 ([M—H]+, 40), 190 (55).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([N:17]4[C:25](=[O:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]4=[O:27])[CH:12]3[O:11][CH2:10]2)[C:5]([Cl:28])=[CH:4][N:3]=1.Cl.[CH3:30][N:31]1[CH:35]=[C:34]([NH2:36])[CH:33]=[N:32]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:28][C:5]1[C:6]([NH:8][CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([N:17]4[C:25](=[O:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]4=[O:27])[CH:12]3[O:11][CH2:10]2)=[N:7][C:2]([NH:36][C:34]2[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=2)=[N:3][CH:4]=1
Reactant: Cn1cc(N)cn1
Reactant: O=C1c2ccccc2C(=O)N1C1COC2C(Nc3nc(Cl)ncc3Cl)COC21
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Nc2ncc(Cl)c(NC3COC4C3OCC4N3C(=O)c4ccccc4C3=O)n2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
To a solution of 2-(6-((2,5-dichloropyrimidin-4-yl)amino)hexahydrofuro[3,2-b]furan-3-yl) isoindoline-1,3-dione (370.0 mg, 0.88 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (354.2 mg, 2.65 mmol) in n-BuOH (10 mL) was added DIPEA (683.1 mg, 5.29 mmol). The mixture was stirred at 150° C. overnight. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (MeOH/CH2C12 (v/v)=1/30) to give the title compound as a red solid (140.0 mg, 33.1%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:17]([F:19])([F:18])[CH2:16][O:15][CH2:14][C:13]([NH2:20])=[N:12]3)[CH2:10][CH:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[N:32][CH:33]=1>>[Cl:27][C:28]1[CH:29]=[C:30]([C:2]2[CH:3]=[C:4]3[C@@:11]4([C:17]([F:19])([F:18])[CH2:16][O:15][CH2:14][C:13]([NH2:20])=[N:12]4)[CH2:10][CH:9]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH:31]=[N:32][CH:33]=1
Reactant: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(F)(F)COC1
Reactant: OB(O)c1cncc(Cl)c1
Product: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(-c4cncc(Cl)c4)cc32)C(F)(F)COC1
Yield: 7 %

Procedure:
The cross coupling reaction of (2RS,4R)-6-bromo-6′,6′-difluoro-2-phenyl-6′,7′-dihydro-2′H-spiro[chroman-4,5′-[1,4]oxazepin]-3′-amine (intermediate C3.4) with 5-chloropyridin-3-ylboronic acid yielded the title compound (7% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=O>C(O)C.N1CCCCC1>[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[NH:12][C:11]1=[O:17]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.7 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-carbonyl) 1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 3-[3,5-Dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (63.9 mg, 56%)
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]1[C:14]2([CH2:19][NH:18][CH2:17][CH2:16][CH2:15]2)[CH2:13][N:12]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].CCN(C(C)C)C(C)C>C(O)CCC>[CH3:7][N:6]1[C:2]([N:18]2[CH2:17][CH2:16][CH2:15][C:14]3([CH2:11][N:12]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:13]3)[CH2:19]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: CC(C)(C)OC(=O)N1CC2(CCCNC2)C1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc([N+](=O)[O-])c1N1CCCC2(CN(C(=O)OC(C)(C)C)C2)C1
Temperature: 120 °C
Yield: 64.7 %

Procedure:
5-Chloro-1-methyl-4-nitro-pyrazole (0.16 g; 0.99 mmol) and tert-butyl 2,8-diazaspiro[3.5]nonane-2-carboxylate (0.2 g, 0.88 mmol) were suspended in butan-1-ol (2 mL), followed by the addition of DIPEA (0.7 mL; 3.9616 mmol). The reaction mixture was heated at 120° C. for 2 days. Evaporated all solvent and purified the crude mixture by silica gel eluting with a gradient of 0-30% ethyl acetate in dichloromethane. Tert-butyl 6-(1-methyl-4-nitro-1H-pyrazol-5-yl)-2,6-diazaspiro[3.5]nonane-2-carboxylate (200 mg) was obtained a yellow oil in a 57% yield. MS (ESI) m/z: 352.2 [M+H+].
Reaction SMILES: CS[C:3](=[C:6]([C:12]([O:14]CC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:4][CH3:5].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)=[NH:26])=[CH:20][CH:19]=1>>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:12](=[O:14])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:3]([S:4][CH3:5])[N:26]=[C:25]2[C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)=[CH:22][CH:23]=1
Reactant: CSc1ccc(C(=N)Nc2ccc(C)cc2)cc1
Reactant: CCOC(=O)C(C(=O)OCC)=C(SC)SC
Product: CCOC(=O)c1c(SC)nc(-c2ccc(SC)cc2)n(-c2ccc(C)cc2)c1=O
Temperature: 115 °C
Yield: 20.2 %

Procedure:
A mixture of diethyl [bis(methylthio)methylene]malonate (2.64 g, 10 mmol) and N-(4-methylphenyl)-4-(methylthio)benzenecarboximidamide (2.6 g, 10 mmol) (prepared according to the procedure described in preparation 6) was heated at 110-120° C. for 2 hours. The gummy mass thus obtained was purified by column chromatography to give the title compound (0.86 g, yield 20.2%, mp 153-155° C., purity 99.81% by HPLC). 1H-NMR (CDCl3):δ 1.36-1.39 (t, 3H), 2.33 (s, 3H), 2.44 (s, 3H), 2.55 (s, 3H), 4.37-4.42 (q, 2H), 7.0-7.05 (m, 4H), 7.13-7.15 (d, 2H), 7.25-7.27 (d, 2H). IR (KBr) cm−1: 2981, 2924, 1693 (—C═O). MS m/z:427.1(M+)