Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@@:5]([CH3:9])([CH:7]=O)[CH2:4][O:3]1.Cl.[NH2:12][OH:13].C([O-])([O-])=O.[Na+].[Na+]>O.CO>[CH3:1][C:2]1([CH3:10])[O:6][C@@:5]([CH3:9])([CH:7]=[N:12][OH:13])[CH2:4][O:3]1
Reactant: NO
Reactant: CC1(C)OC[C@](C)(C=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)OC[C@](C)(C=NO)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
(R)-2,2,4-Trimethyl-1,3-dioxolane-4-carbaldehyde (6.9 g, 48 mmol) was dissolved in 1:1 methanol water (100 mL), and hydroxylamine hydrochloride (3.3 g, 48 mmol) and Na2CO3 (2.5 g, 24 mmol) were added. The reaction was stirred at ambient temperature overnight. The methanol was removed in vacuo and the remaining material was extracted with CH2Cl2, dried over sodium sulfate, filtered and concentrated to afford (S)-2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde oxime (5.7 g, 36 mmol, 75% yield).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[CH2:6][CH2:7][C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[N:12]([CH2:20][C:21]2[CH:22]=[N:23][C:24]([C:27]3[C:32]4[O:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[C:31]=4[CH:30]=[CH:29][CH:28]=3)=[CH:25][CH:26]=2)[CH:11]=1)=[O:9].Cl>O1CCCC1.CO.O>[Cl:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:20][C:21]1[CH:22]=[N:23][C:24]([C:27]3[C:32]4[O:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[C:31]=4[CH:30]=[CH:29][CH:28]=3)=[CH:25][CH:26]=1)[CH:11]=[C:10]2[C:8](=[O:9])[CH2:7][CH2:6][C:5]([OH:40])=[O:4]
Reactant: COC(=O)CCC(=O)c1cn(Cc2ccc(-c3cccc4c3oc3ccccc34)nc2)c2ccc(Cl)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCC(=O)c1cn(Cc2ccc(-c3cccc4c3oc3ccccc34)nc2)c2ccc(Cl)cc12
Temperature: 25 °C
Yield: 98.2 %

Procedure:
2N Sodium hydroxide solution (1.45 mL, 2.9 mmol) was added dropwise to a stirred solution of methyl-4-[5-chloro-1-(6-dibenzofuran-4-yl-pyridin-3-ylmethyl)-1H-indol-3-yl]-4-oxo-butyrate (500 mg, 0.95 mmol) in tetrahydrofuran (10 mL) and methanol (2 mL). The clear reaction mixture was stirred at room temperature until the reaction was complete (TLC control), and then diluted with water (10 mL), and acidified to pH 3 with 2N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (2×20 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 5% methanol in methylene chloride as eluent, afforded the title compound as a white solid (475 mg, 98%): Rf: 0.35 (10% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 8.82 (1H, d, J=2 Hz, ArH), 8.76 (1H, s, ArH), 8.31 (1H, d, J=8 Hz, ArH), 8.18 (4H, m, ArH), 7.88 (1H, dd, J=8, 2 Hz, ArH), 7.72 (2H, d, J=9 Hz, ArH), 7.50 (2H, q, J=6 Hz, ArH), 7.40 (1H, t, J=7 Hz, ArH), 7.27 (1H, dd, J=8, 2 Hz, ArH), 5.65 (2H, s, CH2N), 3.16 (2H, t, J=7 Hz, CH2CO), 2.59 (2H, t, J=7 Hz, CH2CO); ESI-LCMS e/z calculated for C30H21ClN2O4 508.950, found 509 [M+H (35Cl)]+, 511 [M+H (37Cl)]+, 531 [M+Na (35Cl)]+, 533 [M+Na (37Cl)]+.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:13]=1[CH2:14][C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1>>[N:2]1([CH2:7][C:8]([N:18]2[CH2:19][C@H:15]([CH2:14][C:13]3[CH:37]=[CH:38][C:39]([F:41])=[CH:40][C:12]=3[F:11])[CH2:16][C@H:17]2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(O)Cn1cncn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2F)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2F)CN1C(=O)Cn1cncn1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(2,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 53, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(2,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide. Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.02 (s, 1H), 8.43 (s, 1H), 7.96 (s, 1H), 7.56 (d, 2H), 7.47-7.37 (m, 1H), 7.27-7.15 (m, 4H), 7.10-6.92 (m, 7H), 5.24 (q, 2H), 4.55-4.49 (m, 1H), 3.88-3.80 (m, 1H), 3.39-3.30 (m, 1H), 2.84-2.65 (m, 3H), 2.02-1.92 (m, 1H). MS (EI) for C28H24F3N5O3. found 535.9 (MH+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7]([NH:8][CH2:9][CH2:10][SH:11])=[N:6][S:5](=[O:12])[N:4]=1.COC1C(OC)=NS(=O)N=1.NCCS.CN.[CH3:29][N:30]([CH2:32][C:33]1[S:34][CH:35]=[C:36]([CH2:38]O)[N:37]=1)[CH3:31]>>[CH3:29][N:30]([CH2:32][C:33]1[S:34][CH:35]=[C:36]([CH2:38][S:11][CH2:10][CH2:9][NH:8][C:7]2[C:3]([NH:2][CH3:1])=[N:4][S:5](=[O:12])[N:6]=2)[N:37]=1)[CH3:31]
Reactant: CN(C)Cc1nc(CO)cs1
Reactant: CNC1=NS(=O)N=C1NCCS
Agent: CN
Agent: COC1=NS(=O)N=C1OC
Agent: NCCS
Product: CNC1=NS(=O)N=C1NCCSCc1csc(CN(C)C)n1

Procedure:
Reaction of 3-methylamino-4-(2-mercaptoethylamino)-1,2,5-thiadiazole 1-oxide [prepared by reacting 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide with 2-aminoethanethiol and methylamine according to the procedure described in Example 25, Step A] with about one equivalent of 2-dimethylaminomethyl-4-hydroxymethylthiazole [prepared in Example 34, Step D], produces the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7]Cl)[CH2:4][CH3:5])[CH3:2].[Na].[OH:10][C:11]1[CH:28]=[CH:27][CH:26]=[CH:25][C:12]=1[O:13][C:14](=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](=[O:17])[CH3:16]>CC(C)=O>[CH2:1]([N:3]([CH2:6][CH2:7][O:10][C:11]1[CH:28]=[CH:27][CH:26]=[CH:25][C:12]=1[O:13][C:14](=[CH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:15](=[O:17])[CH3:16])[CH2:4][CH3:5])[CH3:2]
Reactant: CC(=O)C(=Cc1ccccc1)Oc1ccccc1O
Reactant: CCN(CC)CCCl
Agent: [Na]
Solvent: CC(C)=O
Product: CCN(CC)CCOc1ccccc1OC(=Cc1ccccc1)C(C)=O

Procedure:
21 g of N,N-diethylaminoethyl chloride are added drop by drop to 35 g of the sodium salt of 3-o-hydroxyphenoxy-4-phenyl-3-butene-2-one suspended in 600 cc of anhydrous acetone. The mixture is heated under reflux for 4 hours, the sodium chloride is filtered off, and the filtrate is evaporated to dryness. The residue is dissolved in water and extracted a number of times with diethyl ether. The ether phase, after drying over Na2SO4, is evaporated to dryness and purified by distillation in a bulb apparatus. (B.P. 200°-210°/0.6 mm Hg).
Reaction SMILES: [NH3:1].[F:2][C:3]([F:15])([F:14])[C:4]1[CH:9]=[C:8](Cl)[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][N:5]=1>C1COCC1>[N+:11]([C:7]1[C:8]([NH2:1])=[CH:9][C:4]([C:3]([F:15])([F:14])[F:2])=[N:5][CH:6]=1)([O-:13])=[O:12]
Reactant: N
Reactant: O=[N+]([O-])c1cnc(C(F)(F)F)cc1Cl
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)ncc1[N+](=O)[O-]
Yield: 96 %

Procedure:
Ammonia gas is bubbled through a solution of 2-trifluoromethyl-4-chloro-5-nitro-pyridine (4.12 g, 18.23 mmol) in anhydrous THF at room temperature for 3 h. Removal of solvent under reduced pressure affords 5-nitro-2-trifluoromethyl-pyridin-4-ylamine (3.6 g, 96%); 1H NMR (300 MHz, CDCl3): δ 7.15 (s, 1H), 9.15 (s,1H).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:2]>C(O)CCC>[C:1]([O:3][CH2:4][CH2:5][CH2:6][CH3:7])(=[O:2])[C:1]([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:2]
Reactant: CCCCOC=O
Solvent: CCCCO
Product: CCCCOC(=O)C(=O)OCCCC

Procedure:
Experiment was run in the same manner as in Example 4 except that the catalyst was replaced by 1.0 wt.% palladium-on-silicon-carbide. As the result, it was found that n-butyl formate was produced in a space time yield of 202 g./l.-catalyst.hr and small amounts of di-n-butyl oxalate and n-butanol were by-produced.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[C:13](=O)[CH2:14][CH2:15][CH2:16][C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([O:22][C:23](=[O:30])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]([NH:29][CH2:28][CH2:27][CH2:26][CH2:25][NH:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:30])[CH2:14][CH2:15][CH2:16][C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1cnc2c1C(=O)CCC2
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCNC1CCCc2ncn(C(=O)OC(C)(C)C)c21
Temperature: 25 °C
Reaction time: 17 h
Yield: 48.4 %

Procedure:
To a solution of 7-oxo-4,5,6,7-tetrahydorbenzoimidazole-1-carboxylic acid tert-butyl ester (632 mg, 2.82 mmol) in CH2Cl2 (50 mL) at room temperature under inert atmosphere was added (4-amino-butyl)carbamic acid tert-butyl ester (745 mg, 4.23 mmol) followed by sodium triacetoxyborohydride (896 mg, 4.23 mmol). The reaction mixture was stirred at room temperature for 17 hours. Saturated sodium bicarbonate solution (20 mL) was added and the mixture was extracted with dichloromethane (3×30 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated. The resultant material was purified by column chromatography on silica gel (20:1:1 CH2Cl2: MeOH: NH4OH) to provide the product (558 mg, 48%): 1H NMR (CDCl3): δ 1.42 (s, 9H), 1.59 (s, 9H), 1.50-1.62 (m, 4H), 1.71-1.77 (2H), 1.82-2.00 (m, 2H), 2.06 (s, 1H), 2.73-2.87 (m, 4H), 3.09-3.13 (m, 2H), 3.33 (br s, 1H), 3.75-3.80 (m, 1H), 5.01 (br s, 1H), 7.96 (s, 1H).
Reaction SMILES: [C:1]1(=[O:17])[O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18]C1CCOC(=O)CCCCCCCCCC1>>[CH3:18][CH:13]1[CH2:14][CH2:15][O:16][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC1CCCCCCCCCCC(=O)OCC1
Reactant: O=C1CCCCCCCCCCCCCCO1
Product: CC1CCCCCCCCCCCC(=O)OCC1

Procedure:
Fragrance; In quality, it has an elegance like that of 15-pentadecanolide and a nitromusk-like characteristic similar to that of 12-methyl-14-tetradecanolide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:15]=2)[CH:10]=[C:9]1[C:25]1[CH:30]=[C:29](Cl)[N:28]=[N:27][C:26]=1[O:32][CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[C:37]([CH3:50])[C:36]=1[OH:51].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:15]=2)[CH:10]=[C:9]1[C:25]1[CH:30]=[C:29]([C:39]2[CH:38]=[C:37]([CH3:50])[C:36]([OH:51])=[C:35]([CH3:34])[CH:40]=2)[N:28]=[N:27][C:26]=1[O:32][CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1nnc(Cl)cc1-c1cc2ccc(CN3CCN(C)CC3)cc2n1C(=O)OC(C)(C)C
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1cc2ccc(CN3CCN(C)CC3)cc2n1C(=O)OC(C)(C)C
Yield: 90.7 %

Procedure:
500 mg 2-(6-Chloro-3-methoxy-pyridazin-4-yl)-6-(4-methyl-piperazin-1-ylmethyl)-indole-1-carboxylic acid tert-butyl ester, 233 mg 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, 180 mg sodium carbonate, and 98 mg tetrakis(triphenylphosphine)palladium(0) are dissolved in a mixture of 6.7 mL dimethoxyethane and 0.85 mL water. Argon is bubbled through the solution for 5 minutes. The mixture is heated to reflux for 5 hours. After diluting with EtOAc, the organic phase is washed with water and brine, dried with MgSO4 and concentrated in vacuo. 475 mg crude product are obtained.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[C:14]([O:21][CH3:22])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:23]2[CH2:27][CH2:26][CH2:25][CH:24]=2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>CCO>[C:23]1([C:11]2[NH:10][C:18]3[C:13]([CH:12]=2)=[C:14]([O:21][CH3:22])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: COc1ccc2c(cc(C3=CCCC3)n2S(=O)(=O)c2ccccc2)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2[nH]c(C3=CCCC3)cc2c1OC
Yield: 97.3 %

Procedure:
To 291 mg (0.76 mmol) of the phenylsulfonamide intermediate from step 3 in 50 mL EtOH was added 5 mL 10% NaOH solution. The reaction was heated to reflux overnight and then concentrated. The residue was dissolved in EtOAc, washed with 2N Na2CO3 solution, H2O, aqueous NaCl solution, dried (MgSO4), and concentrated under vacuum to yield 180 mg of 2-cyclopent-1-enyl-4,5-dimethoxy-1H-indole (97%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:11][C:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=O)[CH:3]=1.C[O-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:7])[NH:8][C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:11]2)=[CH:9][CH:10]=1
Reactant: NC(=O)c1ccc(F)cc1NC(=O)c1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=c1[nH]c(-c2cccnc2)nc2cc(F)ccc12
Temperature: 25 °C
Yield: 93.4 %

Procedure:
To a suspension of the benzamide compound (1.6 g, prepared in Reference example 3) in 60 mL of toluene was added sodium methoxide (853 mg). The solution was heated to reflux for one to three days. After cooling to room temperature, the mixture was quenched with ammonium chloride solution (30 mL) with a vigorously shaking. The mixture was cooled in refrigerator and the insoluble product was collected by filtration and dried in vacuum to give the title compound (1.39 g) as a white solid having the following physical data.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][C@H:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:19]1=[O:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(C)(C)C.Cl.C(OCC)(=O)C>C(O)C>[CH3:6][NH:8][CH2:9][CH2:10][C@H:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[C:19]1=[O:32])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN(CC[C@@H](c1ccccc1)N1C(=O)C2(CCCCC2)c2ccccc21)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCC[C@@H](c1ccccc1)N1C(=O)C2(CCCCC2)c2ccccc21
Reaction time: 16 h
Yield: 103.3 %

Procedure:
1′-[(1S)-3-(tert-butoxycarbonyl-methylamino)-1-phenylpropyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one (70 mg, 0.15 mmol) was dissolved in ethanol (3 mL) and 2N HCl in ethyl acetate (0.3 mL, 0.6 mmol) was added. The mixture was stirred 16 hours then concentrated under a stream of nitrogen. The residue was purified via chromatography (silica, 5% methanol saturated with ammonia in chloroform) to give 54 mg of 1′-[(1S)-3-(methylamino)-1-phenylpropyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one. The free base was dissolved in ether (2 mL) and treated with 1N hydrochloric acid in ether (0.16 mL, 0.16 mmol, 1 equivalent). The white precipitate was collected and dried under vacuum to give 54 mg of 1′-[(1S)-3-(methylamino)-1-phenylpropyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one hydrochloride.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][OH:9])[C:4]([O:6][CH3:7])=[O:5].[C:10]([O:14][C:15]([N:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([C:26](O)=[O:27])[C:20]=2[CH:19]=[CH:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)C(C)C)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C.O>[OH:9][CH2:8][C@H:3]([NH:2][C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[CH:19]=[CH:18][N:17]2[C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])=[O:27])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(C)(C)OC(=O)n1ccc2c(C(=O)O)cccc21
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CO)NC(=O)c1cccc2c1ccn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.8 %

Procedure:
To a solution of methyl (2S)-2-amino-3-hydroxypropanoate hydrochloride (1.25 g), 1-(tert-butoxycarbonyl)-1H-indole-4-carboxylic acid (2.10 g) and N-ethyl-N-isopropyl-2-propanamine (2.94 mL) in DMF (25.0 mL) was added dropwise DPPA (1.91 mL) at 0° C. and the mixture was stirred at ambient temperature for 3 days. The resulting mixture was diluted with water (50.0 mL) and extracted with EtOAc (75 mL). The organic layer was washed successively with 1M HCl aqueous solution, saturated NaHCO3 aqueous solution. and brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:MeOH=99:1) to afford tert-butyl 4-({[(1S)-1-(hydroxymethyl)-2-methoxy-2-oxoethyl]amino}carbonyl)-1H-indole-1-carboxylate (2.12 g) as a colorless syrup.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:19][CH2:18]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCNCC3)c2n1
Reactant: IC1CCCCC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCN(C4CCCCC4)CC3)c2n1

Procedure:
Prepared similarly to Example 82 from 2-(butyloxy)-8-(methyloxy)-9-[2-(4-piperidinyl)ethyl]-9H-purin-6-amine and iodocyclohexane.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=2[S:5][C:6]=1[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:11]([C:12](O)=[O:13])[C:10]=1[C:18]([OH:20])=O.Cl.[NH2:26][CH:27]1[CH2:33][CH2:32][C:31](=[O:34])[NH:30][C:28]1=[O:29]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=2[S:5][C:6]=1[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:11]2[C:10]=1[C:18](=[O:20])[N:26]([CH:27]1[CH2:33][CH2:32][C:31](=[O:34])[NH:30][C:28]1=[O:29])[C:12]2=[O:13]
Reactant: O=C(O)c1cccc(OCc2sc3ccccc3c2Cl)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4sc5ccccc5c4Cl)c3C2=O)C(=O)N1
Yield: 38 %

Procedure:
A mixture of 3-(3-chloro-benzo[b]thiophen-2-ylmethoxy)-phthalic acid (1.6 g, 4.4 mmol), alpha-amino-glutarimide hydrochloride (0.76 g, 4.6 mmol) in pyridine was refluxed overnight. The mixture was evaporated and the residue was purified by flash column chromatography (methanol/methylene chloride) to give 4-(3-chloro-benzo[b]thiophen-2-ylmethoxy)-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione as a white solid (0.76 g, 38% yield); HPLC: Waters Symmetry C1-8, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 5.26 min (98.7%); mp, 240-242° C.; 1H NMR (DMSO-d6) δ 2.02-2.06 (m, 1H, CHH), 2.54-2.62 (m, 2H, CH2), 2.83-2.95 (m, 1H, CHH), 5.10 (dd, J=6, 12 Hz, 1H, CH), 5.74 (s, 2H, CH2), 7.49-8.10 (m, 7H, Ar), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ21.94, 30.90, 48.79, 63.99, 116.26, 116.98, 118.36, 120.46, 121.39, 123.36, 125.57, 126.19, 132.93, 133.34, 135.42, 136.91, 137.04, 154.62, 165.05, 166.64, 169.85, 172.73. Anal Calcd For C22H15N2O5SCl+0.1H2O: C, 58.09; H, 3.32; N, 6.16; S, 7.05; Cl, 7.79. Found: C, 57.77; H, 3.06; N, 6.08; S, 6.87; Cl, 8.05.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][NH:7][CH2:6]1.F[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]2[N:26]=[C:25]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[NH:29][CH:28]=3)[CH:24]=[CH:23][N:22]=2)=[C:13]([O:36][CH3:37])[CH:12]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][N:7]([C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[NH:29][CH:28]=4)[CH:24]=[CH:23][N:22]=3)=[C:13]([O:36][CH3:37])[CH:12]=2)[CH2:6]1
Reactant: CN(C)C1CNC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Temperature: 140 °C
Yield: 72.1 %

Procedure:
N,N-Dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 140 mg, 0.81 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 68, 406 mg, 0.74 mmol) and DIPEA (0.514 mL, 2.94 mmol) in DMA (3 mL). The mixture was heated in a microwave at 140° C. for 0.5 h. The mixture was then part-purified by ion exchange chromatography, using an SCX column (20 g) and eluting with 0.35M methanolic ammonia. Appropriate fractions were combined nad concentrated in vacuo to provide an orange/brown gum. This gum was triturated with ethanol (15 mL) to give a solid which was collected by filtration and dried under vacuum to give the title compound (245 mg, 72%) as an orange solid; 1H NMR: 2.15 (6H, s), 3.17 (1H, dd), 3.76 (2H, dd), 3.97 (3H, s), 4.03-4.10 (2H, m), 6.29 (1H, s), 7.08 (1H, t), 7.14-7.21 (1H, m), 7.27 (1H, d), 7.45 (1H, d), 8.01 (1H, s), 8.28-8.37 (3H, m), 8.64 (1H, s), 11.79 (1H, s); m/z: ES+ MH+ 460.32.
Reaction SMILES: C1(S([CH2:10][CH2:11][CH2:12][CH:13]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=O)(=O)=O)C=CC=CC=1.CC(C)([O-])C.[K+].O.CCOCC>C1(C)C=CC=CC=1>[C:13]12[CH2:12][CH2:11][CH:10]=[C:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=2
Reactant: O=C1CCCCCCCCCCC1CCCS(=O)(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: C1=C2CCC=C2CCCCCCCCC1
Yield: 83.2 %

Procedure:
0.728 g (2 mmole) of 2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanone and 0.560 g (5 mmole) of potassium tert-butoxide in 8 ml of toluene were heated to reflux for 1 hour in a reaction vessel fitted with a water separator. After cooling to 10°, addition of water (15 ml), extraction with ether (2×15 ml), washing of the organic layer with brine (15 ml), then with water, drying over Na2SO4, evaporation and final distillation (0.02 Torr--bath temperature: 140°) there were isolated 0.340 g (83% yield) of the desired compound.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[C:3]=1[CH3:8].[CH3:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1>>[CH3:8][C:3]1[C:4](=[O:7])[CH2:5][CH2:6][C:2]=1[C:13]1[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=1
Reactant: CC1=C(Br)CCC1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC1=C(c2cnn(C)c2)CCC1=O
Yield: 16 %

Procedure:
Synthesized from 3-bromo-2-methylcyclopent-2-enone and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole according to the general procedure described for the Suzuki coupling. Purification by automated flash chromatography using gradient elution (0 to 100% ethyl acetate/hexanes) and further recrystallization yielded the product (21 mg, 16%) as a white solid. 1H NMR (CDCl3, 300 MHz): δ 7.80 (s, 1H), 7.70 (s, 1H), 2.84-2.80 (m, 2H), 2.52-2.48 (m, 2H), 1.95 (t, J=2.1 Hz, 3H). LCMS (ESI): mass calcd for (C10H12N2O) m/z 176.09; measured [M+H]+: m/z 177.09.