Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:50])[NH:4][C@@H:5]([CH2:47]SC)[C:6](=[O:46])[NH:7][C@@H:8]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:9]([OH:38])[CH2:10][C@H:11]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[CH:28][CH:27]=1)[NH:12][C:13](=[O:24])[C@H:14]([C:20]([CH3:23])([CH3:22])[CH3:21])[NH:15][C:16](=[O:19])[O:17][CH3:18].O[O:52][S:53]([O-:55])=O.[K+].[CH3:57]O>O>[CH3:1][O:2][C:3](=[O:50])[NH:4][C@@H:5]([CH2:47][S:53]([CH3:57])(=[O:55])=[O:52])[C:6](=[O:46])[NH:7][C@@H:8]([CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C@@H:9]([OH:38])[CH2:10][C@H:11]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[CH:28][CH:27]=1)[NH:12][C:13](=[O:24])[C@H:14]([C:20]([CH3:23])([CH3:22])[CH3:21])[NH:15][C:16](=[O:19])[O:17][CH3:18]
Reactant: O=S([O-])OO
Reactant: COC(=O)N[C@@H](CSC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Reactant: CO
Agent: [K+]
Solvent: O
Product: COC(=O)N[C@@H](CS(C)(=O)=O)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Yield: 43 %

Procedure:
A solution of Example 153B (20 mg, 0.028 mmol) in methanol (0.28 mL) and water (0.28 mL) was treated with oxone (52 mg, 0.082 mmol) at 25° C. for 1 h. The solvents were evaporated, and the residue was partitioned between ethyl acetate/water, the organic layer was separated, washed with brine, dried over MgSO4, filtered, and the solvents were evaporated. The crude residue was purified by silica gel chromatography eluting with a gradient of dichloromethane, 100% ethyl acetate, to 95% ethyl acetate/5% methanol to give the title compound (9 mg, 43%). 1H NMR (300 MHz, MeOH-D6) δ ppm 0.86(s, 9H), 1.69-1.60(m, 2H), 2.70-2.63(m, 1H), 2.89-2.82(m, 3H), 2.93(s, 3H), 3.3-3.23(m, 1H), 3.45-3.39(m, 1H), 3.53(s, 3H), 3.67(s, 3H), 3.77-3.73(t, J=6.62 Hz, 1H), 3.81(s, 1H), 4.27-4.22(m, 1H), 4.33(m, 1H), 4.63-4.59(dd, J=8.09, 4.78 Hz, 1H), 7.19-7.12(m, 1H), 7.24-7.23(d, J=4.41 Hz, 4H), 7.30-7.27(d, J=8.09 Hz, 2H), 7.35-7.30(m, 1H), 7.80-7.78(d, J=8.09 Hz, 2H), 7.82(m, 1H), 7.87-7.84(dd, J=6.99, 1.84 Hz, 1H), 8.58-8.57(d, J=4.04 Hz, 1H).
Reaction SMILES: C([O-])(O)=[O:2].[Na+].Cl[CH2:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][C:9]=1[CH3:24].O>CS(C)=O.C(Cl)(Cl)Cl>[CH3:24][C:9]1[CH:10]=[C:11]([CH2:15][P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])[C:12]([CH3:14])=[CH:13][C:8]=1[CH:7]=[O:2]
Reactant: O=C([O-])O
Reactant: CCOP(=O)(Cc1cc(C)c(CCl)cc1C)OCC
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(Cc1cc(C)c(C=O)cc1C)OCC
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
DMSO (32 mL) was heated to 100° C. and then NaHCO3 (4.5 gm) was added all at once. The mixture was stirred vigorously as α-chloro-α'-diethylphosphono-2,5-dimethyl-p-xylene (7 mmol) in DMSO (45 mL) and chloroform (5 mL) was rapidly added. The mixture was stirred for 7 min. and then quickly cooled to room temperature. The reaction mixture was combined with H2O (350 mL) and extracted with 3×125 mL ethyl ether. The combined organic layers were washed with 5×150 mL H2O, dried over MgSO4, and concentrated on a rotatory evaporator to an oil. The crude material was chromatographed on silica gel (175 gm) using ethyl acetate as the eluting solvent. The appropriate fractions were pooled and concentrated to give the product as a clear oil.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[CH3:16][N:17](C)[CH:18]=[O:19]>>[CH2:7]([O:4][C:1]1[CH:11]=[CH:10][C:9]2[C:18](=[O:19])[NH:17][CH2:16][CH2:12][CH2:13][C:8]=2[CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Agent: [K+]
Solvent: O
Product: O=C1NCCCc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under atmosphere of argon, to a solution of the compound prepared in reference example 5 (4.79 g) in dimethylformamide (60 ml) were added potassium carbonate (11.2 g) and benzyl bromide (3.57 ml) at 0° C. and the mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added water and was extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride successively, and was dried over anhydrous magnesium sulfate and was concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:n-hexane=3:1) to give the title compound (3.8 g) having the following physical data.
Reaction SMILES: [CH2:1]=O.Cl.[CH3:4][NH:5][CH3:6].[CH2:7]([N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)[CH3:8]>[OH-].[Na+]>[CH3:4][N:5]([CH2:1][C:10]1[N:9]([CH2:7][CH3:8])[CH:13]=[CH:12][CH:11]=1)[CH3:6]
Reactant: CCn1cccc1
Reactant: C=O
Reactant: CNC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCn1cccc1CN(C)C
Yield: 97.6 %

Procedure:
A mixture of 35% aqueous formaldehyde solution (9 ml, 105 mmol) and dimethylamine hydrochloride (9.0 g, 110 mmol) was added to 1-ethylpyrrole (10.0 g, 105 mmol) with stirring under ice-cooling over a 90-minute interval, and then the resulting mixture was stirred at room temperature for 6 hours. After stirring, 10% aqueous sodium hydroxide solution (150 ml) was added to the reaction mixture, and the resulting mixture was extracted with ether. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of dichloromethane and methanol (9:1) as the eluent to afford 2-(N,N-dimethylaminomethyl)-1-ethylpyrrole (15.6 g, yield: 97%).
Reaction SMILES: IC.[Br:3][C:4]1[C:5]([Cl:14])=[CH:6][C:7]2[O:11][C:10](=[O:12])[NH:9][C:8]=2[CH:13]=1.[C:15](=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[Br:3][C:4]1[C:5]([Cl:14])=[CH:6][C:7]2[O:11][C:10](=[O:12])[N:9]([CH3:15])[C:8]=2[CH:13]=1
Reactant: O=c1[nH]c2cc(Br)c(Cl)cc2o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cn1c(=O)oc2cc(Cl)c(Br)cc21
Reaction time: 18 h

Procedure:
Iodomethane (0.579 ml . . . , 926 mmol) was added dropwise to a mixture of 5-bromo-6-chlorobenzo[d]oxazol-2(3H)-one (1.15 g, 4.63 mmol), potassium carbonate (1.599 g, 11.57 mmol) in DMSO (5 mL) at room temperature. The resulting mixture was stirred at this temperature for 18 h. Ethyl acetate (40 mL) was added and the mixture was stirred for 30 min and then filtered. The solution was washed with water (10 mL), brine (15 mL) and dried over Na2SO4. After filtration and concentration, a pale white solid was obtained (1.1 g). 1HNMR (400.342 MHz) δ 3.38 (s, 1H), 7.33 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=[N:54][C:49]2C=[CH:51][CH:52]=[CH:53][C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.NC1C=NC=CC=1>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:47][C:48]2[CH:49]=[N:54][CH:51]=[CH:52][CH:53]=2)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)Nc3cccnc3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.2 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.3 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27.3 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and 3-aminopyridine (11.3 mg, 0.08 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (3.3 mg, 9%). LC-MS m/z 598 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]([NH2:27])([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH3:21]>O1CCCC1>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][C:20]([NH:27][C:9](=[O:11])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:21])[CH3:19]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CN(C)CCC(C)(C)N
Solvent: C1CCOC1
Product: CN(C)CCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 69.4 %

Procedure:
N-(Benzyloxycarbonyloxy)succinimide (15.6 g, 1 equiv, 62.6 mmol) was added in one portion to a solution of N1,N1-3-trimethylbutane-1,3-diamine (8.15 g, 62.6 mmol) in tetrahydrofuran (100 mL). The reaction was left to stir at room temperature for 17 hours. The solvent was removed and the residue was taken up in a mixture of ethyl acetate (500 mL) and water (100 mL). The layers were separated and the organic layer washed with saturated sodium bicarbonate (2×100 mL), water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil. The crude oil was purified by flash chromatography (1% to 5% methanol in dichloromethane). The desired fractions were collected and concentrated to give a colorless oil (11.49 g, yield: 69.6%)1H NMR (CDCl3, 400 MHz): δ 1.35 (s, 6H), 1.67-1.72 (t, J=6.6, 2H), 2.23 (s, 6H), 2.36-2.40 (t, J=7.2, 2H), 6.46 (s, 1H), 7.27-7.36 (m, 5H); LRMS (ESI/APCI) m/z 265 [M+H]+.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][C:17]([CH2:22][OH:23])([OH:21])[CH2:16]1>CO>[OH:21][C:17]1([CH2:22][OH:23])[CH2:18][CH2:19][CH2:20][CH:15]([C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[OH:4])[CH2:16]1
Reactant: COCOc1ccc(C2CCCC(O)(CO)C2)c(OCOC)c1
Solvent: CO
Product: OCC1(O)CCCC(c2ccc(O)cc2O)C1
Yield: 23.6 %

Procedure:
(±)-3-[2,4-Bis(methoxymethoxy)phenyl]-1-(hydroxymethyl)cyclohexanol (29 mg), methanol (2 ml) and acidic ion exchange resin (300 mg) were heated under reflux for 3 hr. The reaction mixture was filtered and the resin was washed with methanol. The combined filtrate and washings were evaporated in vacuo and the crude residue was purified by preparative HPLC to furnish the title compound as a cream solid (5 mg, 24%). δH (CD3OD) 1.20-2.00 (8H, m), 2.89 (1H, tt), 3.61 (1H, d), 3.69 (1H, d), 6.20-6.26 (2H, m), 6.90 (1H, d); m/z (ES−) 237 (M−H)−.
Reaction SMILES: Cl[CH:2]([Cl:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH:11](=[O:14])[CH2:12][CH3:13].CCOCC.O>O1CCCC1>[Cl:10][C:2]1([C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[CH:11]([CH2:12][CH3:13])[O:14]1
Reactant: CCC=O
Reactant: CC(C)(C)OC(=O)C(Cl)Cl
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCC1OC1(Cl)C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
4 ml of tert.-butyl dichloroacetate and 2 ml of propanal diluted with 2 ml of tetrahydrofuran were mixed together and cooled to -20° C. 28 ml of 0.9M/l of potassium tert.-butylate in tetrahydrofuran were introduced over 12 minutes and at -20° C. followed by allowing the temperature to rise to 20° C. over 1 hour 20 minutes. 25 ml of ether and 25 ml of water were added, followed by stirring, decanting, and re-extracting with ether. The organic phase was washed with water saturated with sodium chloride, then dried and concentrated to dryness to obtain 4.7 g of 1,1-dimethylethyl 2-chloro-3-ethyloxirane carboxylate.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[CH2:25][CH2:26]Br>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:26][CH2:25][C:24]4[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=4[O:22][CH3:21])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: COc1ccccc1CCBr
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: COc1ccccc1CCN1CC(=O)N(c2cnn(Cc3c(C)noc3C)c2)C1=O
Yield: 52 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 6) and 2-methoxyphenethyl bromide. Yield: 52%. 1H NMR (DMSO-d6, 400 MHz): δ2.11 (s, 3H), 2.38 (s, 3H), 2.80 (t, J=7.2 Hz, 2H), 3.51 (t, J=7.2 Hz, 2H), 3.75 (s, 3H), 4.03 (s, 2H), 5.17 (s, 2H), 6.85 (t, J=7.2 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 7.16-7.21 (m, 2H), 7.73 (s, 1H), 8.13 (s, 1H). MS M+H calculated 410.2; found 410.1. Melting point: 97-98° C. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.14 μM.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:8][N:7]([CH3:9])[C:6](=O)[N:5]1[CH3:11].P(Cl)(Cl)(Cl)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>C(Cl)(Cl)Cl>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[Cl:1][CH2:2][CH2:3][CH:4]1[CH2:8][N:7]([CH3:9])[C:6](=[N:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:5]1[CH3:11]
Reactant: Nc1ccccc1
Reactant: CN1CC(CCCl)N(C)C1=O
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CC(CCCl)N(C)C1=Nc1ccccc1
Reaction time: 2 h
Yield: 50 %

Procedure:
To 8.0 g (0.045 mole) of 4-(2-chloroethyl)-1,3-dimethyl-2-oxo-imidazolidine was added 50 ml of phosphorus oxychloride, and the solution was refluxed for 18 hours, and concentrated in vacuo. The residue was dissolved in 25 ml of methylene chloride and added dropwise to 4.2 g (0.045 mole) of aniline stirring at room temperature. Stirring was continued for two hours. The solution was diluted with chloroform and washed with dilute sodium hydroxide solution. The chloroform was dried, filtered and concentrated in vacuo. The residue was dissolved in isopropyl alcohol and treated with 5.2 g (0.045 mole) fumaric acid, and the resulting fumarate was recrystallized from isopropyl alcohol and weighed 9.0 g (50% yield): m.p. 109°-112° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:4]([O:6][CH3:7])=[O:5].[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([Cl:24])[CH:23]=1)[CH2:20][N:19]([CH3:25])[CH2:18][CH:17]2[C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>N1C=CC=CC=1>[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([Cl:24])[CH:23]=1)[CH2:20][N:19]([CH3:25])[CH2:18][CH:17]2[C:26]1[CH:27]=[C:28]([S:32]([NH:2][CH:3]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:4]([O:6][CH3:7])=[O:5])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Reactant: COC(=O)CC(N)C(=O)OC
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)CC(NS(=O)(=O)c1cccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of dimethyl 2-aminosuccinate hydrochloride (107 mg, 0.54 mmol, 1.00 equiv) in pyridine (5 mL). This was followed by the addition of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (300 mg, 0.69 mmol, 1.27 equiv, 90%) in several batches. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane:methanol (50:1). This resulted in 200 mg (72%) of the title compound as a colorless oil
Reaction SMILES: C(OC(N1C2C(=CC3OC(F)(F)OC=3C=2)[C@H](O)CCC1)=O)(C)(C)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1.[C:53]([O:57][C:58]([N:60]1[C:73]2[C:65](=[CH:66][C:67]3[O:68][C:69]([F:75])([F:74])[O:70][C:71]=3[CH:72]=2)[C@@H:64]([N:76]=[N+]=[N-])[CH2:63][CH2:62][CH2:61]1)=[O:59])([CH3:56])([CH3:55])[CH3:54]>C1(C)C=CC=CC=1.CO.[Pd]>[C:53]([O:57][C:58]([N:60]1[C:73]2[C:65](=[CH:66][C:67]3[O:68][C:69]([F:75])([F:74])[O:70][C:71]=3[CH:72]=2)[C@@H:64]([NH2:76])[CH2:63][CH2:62][CH2:61]1)=[O:59])([CH3:56])([CH3:54])[CH3:55]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N=[N+]=[N-])c2cc3c(cc21)OC(F)(F)O3
Agent: [Pd]
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](O)c2cc3c(cc21)OC(F)(F)O3
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H](N)c2cc3c(cc21)OC(F)(F)O3
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-2,2-Difluoro-9-hydroxy-6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (1.9 mmol) in Toluene, add DPPA (2.5 mmol) and DBU (2.5 mmol). After heating the mixture at 65° C. for 14 h, remove solvent under vacuum and chromatograph the intermediate using ethyl acetate/hexane (5-20%) to elute. This provides (S)-9-Azido-2,2-difluoro-6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester as a colorless oil. To a solution of (S)-9-Azido-2,2-difluoro-6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (1.8 mmol) in methanol (20 mL) add a catalytic amount of Pd/C after purging the solution with nitrogen. Place a balloon of hydrogen on the reaction and purge the solution several times. After stirring for 1 h, purge the solution with nitrogen then filter through celite. Collect the filtrate and remove solvent under vacuum to provide the title compound as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:10])[C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+].Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH2:18][CH2:17]1.C(OCC)(=O)C.ClCCl>CS(C)=O>[Cl:28][C:24]1[CH:23]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:1]3[C:9]4[CH2:8][CH2:7][CH2:6][C:5](=[O:10])[C:4]=4[CH:3]=[CH:2]3)[CH2:21][CH2:20]2)[CH:27]=[CH:26][CH:25]=1
Reactant: O=C1CCCc2[nH]ccc21
Reactant: ClCCN1CCN(c2cccc(Cl)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C1CCCc2c1ccn2CCN1CCN(c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of 1,5,6,7-tetrahyro-indol-4-one (51.5 mmol) in DMSO (60 mL) was added powdered sodium hydroxide (53.9 mmol) and the mixture was stirred at ambient temperature for 0.5 h. 1-(2-Chloroethyl)-4-(3-chlorophenyl) piperazine (49.0 mmol) was then added as a solution in DMSO (20 mL) and the resulting mixture stirred at ambient temperature for 24 h then heated to approximately 60° C. for 2 h, after which time TLC (ethyl acetate:dichloromethane 1:1) showed complete reaction. The reaction was poured into ice cold water (300 mL) and stirred for 0.5 h. A solid mass formed and was separated by decanting the water. The aqueous layer was extracted with dichloromethane (100 mL). The solid mass was dissolved with dichloromethane (100 mL) and the combined organics were dried with sodium sulfate and the solvent removed under vacuum. The resulting sludge was triturated with hexanes (100 mL) for 2 h and the suspension vacuum filtered and washed with hexanes. The obtained solid was under vacuum resulting in a tan powder (14.57 g) as the titled compound, NEO-376).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.O=[C:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(O)(=O)C.[BH]C#N.[Na]>C(O)C>[CH2:27]([O:26][C:24]([CH:23]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:25])[CH3:28]
Reactant: CCCCCCCCC(=O)C(=O)OCC
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)CSc2ccccc21
Agent: [BH]C#N
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCCCCCC(NC1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O)C(=O)OCC
Reaction time: 3 h
Yield: 84.3 %

Procedure:
1.3 g of 3-amino-5-t-butoxycarbonylmethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 3.0 g of ethyl 2-ketodecanoate were dissolved in 10 ml of ethanol. After the addition of 0.3 ml of acetic acid, the resulting mixture was stirred for 3 hours. Then, a solution of 420 mg of sodium boron cyanide hydride in 7 ml of ethanol was added dropwise thereto. After this mixture was allowed to stand overnight, it was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with water, dried and then concentrated. The residue was purified by silica gel column chromatography using a 7:1 mixture of benzene and ethyl acetate as the eluent. Thus, there was obtained 1.8 g of the desired compound in the form of an oily material.
Reaction SMILES: [N:1]1([C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>[Ni].CO.C1COCC1>[N:1]1([C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(-c2cc3c(N4CCc5ccccc54)ncnc3[nH]2)cc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(-c2cc3c(N4CCc5ccccc54)ncnc3[nH]2)cc1
Reaction time: 10 h

Procedure:
400 mg of 4-(2,3-dihydroindol-1-yl)-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine (Example 6) are hydrogenated with 150 mg of Raney nickel in methanol/THF (35:20) at RT and normal pressure for 10 hours. The catalyst is filtered off and the solution is concentrated by evaporation. The residue is dissolved in THF and the product is precipitated by the addition of hexane. 4-(2,3-Dihydroindol-1-yl)-6-(4-amino-phenyl)-7H-pyrrolo[2,3-d]pyrimidine is obtained in the form of a colorless powder. M.p. >300° C.; FAB-MS: (M+H)+ =328 (corresponds to C20H17N5); Rf value (toluene-acetone--4:6)=0.21.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=C[C:3]=1CC#N.[OH-:12].[K+].Cl.[CH3:15][C:16]([OH:19])(C)[CH3:17]>>[Br:1][C:2]1[CH:3]=[CH:17][C:16]([OH:19])=[CH:15][C:7]=1[CH2:6][C:5]([OH:8])=[O:12]
Reactant: CC(C)(C)O
Reactant: [OH-]
Reactant: N#CCc1cc(O)ccc1Br
Agent: Cl
Agent: [K+]
Product: O=C(O)Cc1cc(O)ccc1Br
Temperature: 85 °C
Reaction time: 3 h

Procedure:
(2-Bromo-5-hydroxy-phenyl)-acetonitrile (1.4 g, 6.6 mmol) and potassium hydroxide (4.5 g, 78.9 mmol) were combined in tBuOH and stirred at 85° C. for 3 hours. Once no starting material was seen by analytical LCMS, the mixture was cooled to 0° C. and the pH was adjusted to pH 6 with 10% aqueous HCl. The solution was extracted with EtOAc to give the desired product as a colorless oil (1.5 g).