Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]([CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:12]>C(Cl)Cl>[CH3:9][O:10][C:11](=[O:12])[CH:13]=[CH:7][C:5]1[S:6][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C=O)s1
Solvent: ClCCl
Product: COC(=O)C=Cc1ccc(C)s1
Reaction time: 72 h
Yield: 62.5 %

Procedure:
To 5-methyl-thiophene-2-carboxaldehyde (5 g, 40 mmol) in CH2Cl2 (100 mL) is added methyl (triphenylphosphoranylidene) acetate (13.3 g, 40 mmol). The solution is stirred for 72 hours. After this time, the solution is concentrated. The residue is slurried in Et2O. The solution is filtered through a bed of Celite. The collected liquid is concentrated. The residue is purified by column chromatography eluting with a gradient of 50% EtOAc/hexanes to 60% EtOAc/hexanes to give the title compound (4.5 g, 25 mmol) as an oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([NH2:14])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([Cl:28])[C:19]=1[S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1.Cl>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[C:20]([Cl:28])[C:19]=1[S:29]([NH:14][CH:3]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[C:2]([F:1])([F:15])[F:16])(=[O:31])=[O:30]
Reactant: NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Reactant: O=S(=O)(Cl)c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(NC(Cc1c[nH]c2ccccc12)C(F)(F)F)c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
A mixture of 100 mg (0.44 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethylamine and 137 mg (0.44 mmol) of 2,6-dichloro-4-(trifluoromethyl)benzenesulfonyl chloride in 8 mL of pyridine was stirred at room temperature for 2 hours, and warmed at 70° C. for 18 hours. The mixture was cooled to room temperature and diluted with 1 M HCl until acidic and extracted with ethyl acetate. The combined organic layers were washed with 1 N aqueous HCl, saturated aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, decanted, and concentrated in vacuo. The crude material was crystallized from ether-hexanes to afford 40 mg (18%) of the title compound as a colorless powder. MS: m/z 505 (M), 507 (M+2).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:11][C:12]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>CN(C=O)C>[OH:11][C:12]1[C:18]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: Nc1cccc(C(F)(F)F)c1O
Reactant: O=C=NCc1ccccc1
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)Nc1cccc(C(F)(F)F)c1O
Temperature: 80 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
To a solution of benzylisocyanate (74.56 mg, 0.56 mmol) in DMF (1.0 ml), 2-hydroxy-3-trifluoromethylaniline (100 mg, 0.56 mmol) was added. The reaction mixture was stirred at 80° C. for 16 hours. Chromatography of the resulting liquid on silica gel gave desired product (140 mg, 80%). EI-MS m/z 311.1 (M+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.C(N(C(C)C)CC)(C)C.[Cl:27][CH:28]([CH3:32])[C:29](Cl)=[O:30]>C1COCC1.C(OCC)(=O)C>[Cl:27][CH:28]([CH3:32])[C:29]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH:12]=1)=[O:30]
Reactant: CC(Cl)C(=O)Cl
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Cl)C(=O)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.7 %

Procedure:
To a solution of (3-quinoxalin-2-ylphenyl)amine (124 mg, 0.560 mmol) and diisopropylethylamine (DIEA, 111 μL, 0.672 mmol) in THF (5 mL), 2-chloropropionyl chloride (60 μL, 0.620 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 24 hrs and then diluted with ethyl acetate (20 mL). The organic phase was washed with water (20 mL), dried over MgSO4 and the solvent was evaporated in vacuo to afford 2-chloro-N-(3-(quinoxalin-2-yl)phenyl)propanamide (92 mg, 52% yield). LCMS calculated for C17H14ClN3O (M+H): 312.77. found 313. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.52 (1H, br.), 9.53 (1H, s), 8.55 m), 8.12-8.18 (2H, m), 8.05-8.08 (1H, m), 7.82-7.95 (3H, m), 7.55-7.60 (1H, m), 4.75 (1H, q, J=6.8 Hz), 1.68 (3H, d, J=6.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[Cl:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:15]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:15]=1[O:12][CH2:11][CH2:10][CH:9]=[CH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: OCCC=Cc1cccc(F)c1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1cccc(C=CCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.2 %

Procedure:
To a solution of 0.17 g of 4-(3-fluorophenyl)-3-buten-1-ol, 0.30 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol and 0.27 g of triphenylphosphine dissolved in 10 ml of tetrahydrofuran was added dropwise a solution of 0.20 ml of N,N-diisopropylazodicarboxylate dissolved in 5 ml of tetrahydrofuran, while stirring at room temperature. After the stirring was continued at room temperature for 24 hours, the reaction mixture was concentrated to obtain a residue. The residue was subjected to silica gel chromatography, which afforded 0.38 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(3-fluorophenyl)-3-butenyloxy)benzene (84% yield), nD25.5 1.5857.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[CH2:8]([C:15]1[CH:19]=[C:18]([CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[NH:17][N:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(OC)C=CC=CC=1.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C(Cl)Cl>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[OH:47][C:41]([C:43]([F:46])([F:45])[F:44])=[O:42].[CH2:8]([C:15]1[CH:19]=[C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[NH:17][N:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Cc3ccccc3)n[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: c1ccc(Cc2cc(C3CCNCC3)[nH]n2)cc1

Procedure:
To a solution of 4-(3-benzyl-(1H-pyrazol-5-yl))-1-(t-butoxycarbonyl)piperidine TFA salt (from Step A) in methylene chloride (1.5 mL) was added anisole (0.017 mL) and TFA (0.230 mL). After several h at rt, volatiles were removed under reduced pressure. Purification of the residue was done by preparative reverse-phase BPLC using a 9.4×250 mm Semi-preparative Zorbax SB-C18 column with a 15-25% acetonitrile gradient in water having 0.5% (v/v) TFA over 15 min at 6.0 mL per minute to give the title compound (40.7 mg) as a gel.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[NH:22]1[CH2:27][CH2:26][CH:25]([N:28]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[N:30]=[CH:29]2)[CH2:24][CH2:23]1.C(NC(C)C)(C)C>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:22]3[CH2:23][CH2:24][CH:25]([N:28]4[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[N:30]=[CH:29]4)[CH2:26][CH2:27]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: c1ccc2c(c1)ncn2C1CCNCC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Solvent: CC(C)NC(C)C
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(n2cnc3ccccc32)CC1

Procedure:
The crude product was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-piperidine-4-yl-1H-benzimidazole, 5 equivalent of diisopropylamine was added, preparative HPLC (method C) (23%, colourless crystals). HPLC-MS m/z=483.3 (M+1), Rt: 3.14 min.
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10]N1C(=O)CCC1=O>CN(C=O)C>[Cl:10][C:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccccc1
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ccccc1
Yield: 92.8 %

Procedure:
α-Chlorobenzaldoxime was prepared according to the method described in Part A of Example 595 by reacting benzaldoxime (11.5 g, 94.9 mmol) in DMF (20 mL) with N-chlorosuccinimide (12.6 g, 94.9 mmol). α-Chlorobenzaldoxime (13.7 g, 93%) was obtained as a white solid.
Reaction SMILES: C([O:3][CH3:4])=O.[CH3:5][C:6]1([C:13](=O)[CH3:14])[CH2:9][C:8]2([CH2:12][CH2:11][CH2:10]2)[CH2:7]1.[H-].[Na+]>CCOCC.CO>[CH3:5][C:6]1([CH:13]([CH:14]=[CH:4][OH:3])[CH2:14][CH2:13][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:9][C:8]2([CH2:12][CH2:11][CH2:10]2)[CH2:7]1
Reactant: COC=O
Reactant: CC(=O)C1(C)CC2(CCC2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CCCCCCC(C=CO)C1(C)CC2(CCC2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
A solution of 7.8 g (130.0 mmol) methyl formate and 4.91 g (32.4 mmol) of 2-methyl-2-acetylspiro[3.3]heptane in 8.0 ml of dry ether was dropped into a slurry of 1.2 g of sodium hydride in 180 ml of ether. A few drops of MeOH were added and the reaction mixture stirred for 1.5 hr at 25° C. The reaction mixture was cooled to -10° C and the reaction quenched by slow addition of water. The layers were separated and the aqueous layer extracted twice with ether. The combined organic extracts were washed with water and 1 N NaOH. The combined aqueous layers were acidified with 6 N HCl and extracted with ether. The ether extracts were washed with brine, then dried (MgSO4), filtered and evaporated in vacuo to yield 4.0 g of (2-methylspiro[3.3]hept-2-yl)(2-hydroxyvinyl)heptane as a yellow oil (69.5%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:22])[C:9]2[CH:21]=[CH:20][C:12]3[N:13]([CH2:18][CH3:19])[C:14]([NH:16][CH3:17])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][S:31]([NH2:34])(=[O:33])=[O:32])=[CH:26][CH:25]=1>>[ClH:1].[CH2:18]([N:13]1[C:12]2[CH:20]=[CH:21][C:9]([N:8]([CH3:22])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([CH2:30][S:31]([NH2:34])(=[O:32])=[O:33])=[CH:26][CH:25]=4)[N:7]=3)=[CH:10][C:11]=2[N:15]=[C:14]1[NH:16][CH3:17])[CH3:19]
Reactant: CCn1c(NC)nc2cc(N(C)c3ccnc(Cl)n3)ccc21
Reactant: Nc1ccc(CS(N)(=O)=O)cc1
Product: CCn1c(NC)nc2cc(N(C)c3ccnc(Nc4ccc(CS(N)(=O)=O)cc4)n3)ccc21
Product: Cl

Procedure:
The title compound was prepared following the procedure of Example 1 with N5-(2-Chloro-pyrimidin-4-yl)-1-ethyl-N2,N5-dimethyl-1H-benzoimidazole-2,5-diamine (79 mg, 0.25 mmol) and (4-amino-phenyl)-methanesulfonamide (46 mg, 0.25 mmol) as a white solid (110 mg, 88%). 1H NMR (300 MHz, d6-DMSO) δ 9.24 (s, 1H), 7.81 (d, J=6.0 Hz, 1H), 7.74 (m, 3H), 7.36 (d, J=8.1 Hz, 1H), 7.17-7.20 (M, 3H), 6.96 (d, J=8.4 Hz, 1H), 6.78 (s, 2H), 5.70 (d, J=6.0 Hz, 1H), 4.09-4.16 (m, 4H), 3.45 (s, 3H), 2.97 (d, J=4.5 Hz, 3H), 1.24 (t, J=6.9 Hz, 3H) ppm. MS (ESI) m/z=467 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].Cl>CC(O)CCC(O)C>[F:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: COCC1COc2cc3ncnc(Cl)c3cc2O1
Reactant: Nc1cccc(F)c1
Agent: CC(O)CCC(C)O
Agent: Cl
Product: COCC1COc2cc3ncnc(Nc4cccc(F)c4)c3cc2O1
Temperature: 25 °C

Procedure:
The titled compound of Example 7, 4-chloro-7-methoxy methyl-[1,4]dioxano[2,3-g]quinazoline (40 mg, 0.15 mmol) was dissolved in diisopropanol (2.5 ml), where was then added 3-fluoroaniline (33 mg, 0.3 mol) and concentrated hydrochloric acid of catalytic amount, followed by refluxing for 24 hours. Then, the reaction mixture was cooled down to a room temperature to obtain a solid, which was then filtered, washed with diisopropanol and dried under vacuum to prepare the titled compound (24 mg, 47%, m.p. 257-260° C.; mass (m/z;rel) 340.10).
Reaction SMILES: [NH2:1][C:2](=[N:5][C:6](=[O:9])[O:7][CH3:8])[O:3][CH3:4].[CH:10]([N:13]=[C:14]=[O:15])([CH3:12])[CH3:11].C(Cl)Cl.CN(C)C=O>C(N(CC)CC)C>[CH:10]([NH:13][C:14](=[O:15])[NH:1][C:2](=[N:5][C:6]([O:7][CH3:8])=[O:9])[O:3][CH3:4])([CH3:12])[CH3:11]
Reactant: COC(=O)N=C(N)OC
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)N=C(NC(=O)NC(C)C)OC
Reaction time: 72 h

Procedure:
A solution of 23 parts of methyl N-(1-amino-1-methoxymethylene)-carbamate, 16 parts of isopropyl isocyanate 60 parts of methylene chloride, and a catalytic amount of dimethylformamide and triethylamine is allowed to stand at room temperature for 3 days. The solvent is evaporated to afford 33 parts of crude methyl 4-isopropyl-N-methoxycarbonyl-allophanimidate, an oil, ND25 1.4823.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:17][CH2:16]1>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][N:24]([C:2]3[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=3)[CH2:23][CH2:22]2)[CH2:17][CH2:16]1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: C[Si](C)(C)C#Cc1ccc(Br)cc1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CN1CCN(C2CCN(c3ccc(C#C[Si](C)(C)C)cc3)CC2)CC1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A suspension of [(4-bromophenyl)ethynyl](trimethyl)silane (2.210 g, 8.73 mmol), Pd2(dba)3 (0.400 g, 0.436 mmol), 2-dicyclohexylphosphino-2′-(N,N′-dimethylamino)biphenyl (0.172 g, 0.436 mmol) in anhydrous THF (60 mL) was degassed and backfilled with Argon for three times. 1-Methyl-4-(piperidin-4-yl)piperazine (4.00 g, 21.82 mmol) was added and the mixture was degassed and backfilled with Argon for three times again. Finally LiHMDS 1 M in THF (17.46 mL) was added by a syringe and the mixture was heated to reflux for 2 h. After cooling to room temperature the reaction mixture was filtered on a pad of celite washing with THF (300 mL). The filtrate was evaporated under vacuum and the black oil so obtained was purified by flash chromatography on silica gel (DCM/MeOH/NH4OH 90/10/0.2) to afford the title compound as a yellow solid (2.55 g, 82%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].O.[CH2:8]([NH:10][CH:11]([CH3:24])[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH3:9].[C:25](Cl)(=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CC(C)=O>[CH2:8]([N:10]([CH:11]([CH3:24])[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)[C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH3:9]
Reactant: CCCCCCC(=O)Cl
Reactant: CCNC(C)CCCc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCC(=O)N(CC)C(C)CCCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
A 500 ml 3-neck round bottom flask fitted with a thermometer and addition funnel was charged with 7.65 g of sodium carbonate and 70 ml of water. To this mixture was added 6.8 g (0.029 mol) of N-ethyl-α-methyl-4-nitrobenzenebutanamine and 70 ml of acetone. The resulting mixture was cooled to slightly below 25° C. and 4.5 ml (0.029 mol) of heptanoyl chloride and 70 ml of acetone were added while maintaining the temperature of the mixture in the range of about 20°-25° C. The suspension was stirred at room temperature overnight and evaporated to dryness under reduced pressure. The residue was slurried in water and extracted three times with diethyl ether. The organic extracts were combined, washed with water, 2N hydrochloric acid, twice with water and finally a saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to provide 7.723 g of N-ethyl-N-[1-methyl-4-(4-nitrophenyl)butyl]heptanamide as an oil.
Reaction SMILES: [Se](=O)=[O:2].[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[C:15]=1[N+:16]([O-:18])=[O:17]>O1CCOCC1>[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH:14]=[O:2])=[N:11][C:10]=2[C:15]=1[N+:16]([O-:18])=[O:17]
Reactant: COc1ccc2sc(C)nc2c1[N+](=O)[O-]
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: COc1ccc2sc(C=O)nc2c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 18 h

Procedure:
12.8 g (0.115 mol; 6 equivalents) of selenium dioxide is added to 4.34 g (19.3 mmol) of 5-methoxy-2-methyl-4-nitro-1,3-benzothiazole in solution in 180 ml of anhydrous dioxan. The reaction mixture is stirred at 80° C. for 18 hours then the insoluble part is filtered and the solvent is evaporated off under reduced pressure. The expected aldehyde is obtained in the form of a yellow oil and purified on a silica column (eluent: ethyl acetate/heptane: gradient of 30% to 70%). Melting point: 154-155° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(OCC)(=O)C.N1C=CC=CC=1>[C:25]1([S:31]([NH:1][C:2]2[CH:3]=[C:4]([O:16][C:17](=[O:24])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:5]=[CH:6][C:7]=2[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1cc(OC(=O)c2ccccc2)ccc1OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Oc1ccc(OCc2ccccc2)c(NS(=O)(=O)c2ccccc2)c1)c1ccccc1
Temperature: 0 °C
Yield: 54.7 %

Procedure:
To a stirred solution of benzoic acid 3-amino-4-benzyloxy-phenyl ester (5.91 g, 18.5 mmol) (which was obtained in Example 16) in ethyl acetate (100 mL) and pyridine (20 mL) at 0° C. was added dropwise phenyl sulfonyl chloride (3.26 g, 18.5 mmol) in 50 mL of ethyl acetate. After one hour at 0° C. the mixture was warmed to room temperature and stirred at room temperature over night. The reaction mixture was washed with water and the organic layer was dried (MgSO4) and concentrated. Recrystallization from CH2Cl2/hexanes gave the title compound as a white solid (4.65 g, 61%); 1H NMR (300 MHz, CDCl3) δ 4.93(s, 2 H), 6.90–7.80(m, 15 H), 8.12(d, J=8.5 Hz, 2 H), 9.81(s, 1 H); MS (ES) m/z: 458.9 (MH+, 100%); HRMS Calcd. for C26H22NO5S(MH+): 459.1141. Found: 459.1151.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:11][S:12][CH2:13]Cl.C(N(CC)CC)C>>[C:1]([O:10][CH2:11][S:12][CH3:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CSCCl
Reactant: CCCCCCCC(=O)O
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)OCSC

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting octanoic acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 90° C./2 mm Hg, n20 1.4577.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3](OCC)=O.C=O.[C:14]([O-:17])(=[O:16])C.[K+].[C:19](O)(=O)[CH3:20]>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:19]([O:17][C:14]([CH:3]=[CH:2][C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:16])[CH3:20]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)[O-]
Reactant: CC(=O)O
Agent: [Cu+2]
Agent: C=O
Agent: [K+]
Solvent: O
Product: CCOC(=O)C=CC(=O)OCC

Procedure:
A mixture of 80 g of diethyl malonate, 30 g of paraformaldehyde, 5 g of potassium acetate, 5 g of copper (II) acetate monohydrate and 200 ml of acetic acid was heated at 90° to 100° C. for 2 hours. Acetic acid was removed from the reaction mixture under reduced pressure, and the residue was evaporated under reduced pressure to obtain 44 g of bis(ethoxycarbonyl)ethylene.
Reaction SMILES: Cl[CH:2]([Cl:4])C.[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([F:15])[CH:14]=1)[C:9](Cl)=[O:10].[O:16]1CCCOO1>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4].O>[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([F:15])[CH:14]=1)[C:9]([O:16][CH2:2][Cl:4])=[O:10]
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: CC(Cl)Cl
Reactant: C1COOOC1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: O
Product: O=C(OCCl)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 10 ml of dichloroethane were added 1.2 g of zirconium tetrachloride and 1 g of 3,5-difluorobenzoyl chloride, and the mixture was stirred at room temperature for 15 minutes. The mixture was cooled to 0° C., 0.19 g of trioxane was added, and the mixture was stirred for 10 minutes, and further stirred at room temperature for 1 hour. Water was added slowly at 0° C., the resultant solution was extracted with chloroform three times, and the organic layers were combined, washed with an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated to obtain 1 g of chloromethyl 3,5-difluorobenzoate.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:27]=[C:26]4[C:22]([CH2:23][CH2:24][NH:25]4)=[CH:21][C:20]=3[O:28][CH3:29])[NH:15][C:14]3=[N:30][CH:31]=[CH:32][C:13]=23)[C:3]=1[C:4]([NH2:6])=[O:5].Br[CH2:34][C:35](Cl)=[O:36].[CH3:38][NH2:39]>C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:27]=[C:26]4[C:22]([CH2:23][CH2:24][N:25]4[C:35](=[O:36])[CH2:34][NH:39][CH3:38])=[CH:21][C:20]=3[O:28][CH3:29])[NH:15][C:14]3=[N:30][CH:31]=[CH:32][C:13]=23)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CN
Reactant: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccnc-3[nH]1)NCC2
Reactant: O=C(Cl)CBr
Solvent: C1CCOC1
Product: CNCC(=O)N1CCc2cc(OC)c(Nc3nc(Nc4cccc(F)c4C(N)=O)c4ccnc-4[nH]3)cc21
Reaction time: 8 h
Yield: 18.5 %

Procedure:
A −40° C. solution of 2-fluoro-6-[(2-{[5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide (250 mg, 0.58 mmol) in THF (50 mL) was treated with a solution of bromoacetyl chloride (95 mg, 0.61 mmol) in THF (1 mL). One-third of the reaction mixture was treated with a solution of methylamine (2M in THF, 4 mL, 8 mmol). After stirring overnight the resulting mixture was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain 2-fluoro-6-[(2-{[1-(N-methylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide as a yellow solid (54 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.43 (s, 3H), 3.12-3.22 (m, 2H), 3.68 (s, 1H), 3.78 (s, 3H), 4.03-4.15 (m, 2H), 6.22 (s, 1H), 6.87 (t, J=9.34 Hz, 1H), 6.96 (s, 1H), 6.99 (s, 1H), 7.23-7.38 (m, 1H), 7.66 (s, 1H), 8.02 (s, 1H), 8.11 (s, 1H), 8.49-8.60 (m, 2H), 10.56 (s, 1H), 11.29 (s, 1H), a CH2 signal with 2 protons is missing, may overlap with water peak in sample; ESIMS (M+H)+=505.07.