Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][N:5]1[N:9]=[N:8][C:7]([NH2:10])=[N:6]1.[C:12]1([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][O:2][C:3](=[O:11])[CH2:4][N:5]1[N:9]=[N:8][C:7]([NH:10][C:19](=[O:20])[CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:6]1
Reactant: COC(=O)Cn1nnc(N)n1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: COC(=O)Cn1nnc(NC(=O)C(c2ccccc2)c2ccccc2)n1

Procedure:
The title compound, white solid, m.p. 168-169° and MS: (neg. ions): m/e=350.2 (M+−H) was prepared in accordance with the general method of example 1 from (5-amino-tetrazol-2-yl)-acetic acid methyl ester and diphenylacetyl chloride.
Reaction SMILES: [F:1]C1C=C(N)C=CC=1OC1C=CN=C2C=C(C3N(C)C=CN=3)SC=12.[F:25][C:26]1[CH:27]=[C:28]([NH:48][C:49](=[O:62])[CH2:50][C:51]([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[O:60]C)=[O:52])[CH:29]=[CH:30][C:31]=1[O:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]2[CH:39]=[C:40]([C:42]3[N:43]([CH3:47])[CH:44]=[CH:45][N:46]=3)[S:41][C:34]=12.COC1C=CC=CC=1NC(=O)CC(O)=O.FC1C=CC=CC=1NC(=O)CC(O)=O>>[F:25][C:26]1[CH:27]=[C:28]([NH:48][C:49](=[O:62])[CH2:50][C:51]([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[O:60][F:1])=[O:52])[CH:29]=[CH:30][C:31]=1[O:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]2[CH:39]=[C:40]([C:42]3[N:43]([CH3:47])[CH:44]=[CH:45][N:46]=3)[S:41][C:34]=12
Reactant: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4nccn4C)sc23)c(F)c1
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Agent: COc1ccccc1NC(=O)CC(=O)O
Agent: O=C(O)CC(=O)Nc1ccccc1F
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccccc4OF)cc3F)c2s1
Yield: 5 %

Procedure:
Starting from the amine 9 and following the procedure described above for the compound 28a (example 8, step 2) but substituting acid 27 for the acid 29, title compound 30a was obtained as a white solid in 5% yield. 1H NMR (DMSO-d6) δ (ppm): 10.56 (s, 1H), 10.04 (s, 1H), 8.50 (d, 1H), 7099-7.95 (m, 1H), 7.88 (s, 1H), 7.86 (dd, 1H), 7.50 (t, 2H) 7.42 (dd, 1H), 7.40 (s, 1H), 7.29-7.24 (m, 1H), 7.17-7.14 (m, 1H), 7.03 (s, 1H), 6.69 (d, 1H), 4.00 (s, 3H), 3.64 (s, 2H). MS (m/z): 520.1 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[F:20][C:21]([F:33])([F:32])[C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C>ClCCl>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][N:17]([S:28]([C:24]5[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:32])[F:33])[CH:23]=5)(=[O:30])=[O:29])[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: c1nc(C2CC2)cnc1O[C@H]1C[C@H]2CNCCN2C1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N1CCN2C[C@@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 49B (200 mg, 0.674 mmol)) in dichloromethane (3 mL) was added 3-(trifluoromethyl)benzene-1-sulfonyl chloride (198 mg, 0.809 mmol) followed by triethylamine (0.3 mL). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by flash chromatography (ethyl acetate/hexane=1:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80 (m, 2H), 0.92 (m, 2H), 1.38 (m, 1H), 2.04-2.20 (m, 4H), 2.42 (m, 3H), 3.00 (m, 2H), 3.66 (m, 1H), 3.82 (m, 1H), 5.20 (m, 1H), 7.92 (m, 1H), 7.98 (m, 1H), 8.03 (m, 1H), 8.11 (m, 3H); MS (ESI) m/z 469 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH:13]=O)[CH2:9][CH2:8]1)=[O:5].C(O)(=O)C(O)=O.[CH3:26][NH:27][CH2:28][C:29]1[NH:33][N:32]=[C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][N:27]([CH3:26])[CH2:28][C:29]2[NH:33][N:32]=[C:31]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:30]=2)[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C[C@H]1CC[C@H](NC(=O)c2cc(Cl)ccc2Cl)CC1
Reactant: CNCc1cc(-c2ccccc2)n[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(Cc1cc(-c2ccccc2)n[nH]1)C[C@H]1CC[C@H](NC(=O)c2cc(Cl)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 25 mL round-bottomed flask is added trans-2,5-dichloro-N-(4-formylcyclohexyl)benzamide (200 mg, 0.666 mmol) and N-methyl-1-(3-phenyl-1H-pyrazol-5-yl)methanamine oxalate (277 mg, 0.999 mmol) in DCM (15 mL) to give a colorless solution. Acetic acid (0.153 mL, 2.67 mmol) and sodium triacetoxyborohydride (424 mg, 1.999 mmol) are added and the mixture stirred at room temp for 90 minutes. 1M sodium hydroxide solution (4 mL) is added and the mixture is stirred at room temp for 10 minutes. The mixture is passed through a phase separator and evaporated to give a colourless oil. The crude mixture is re-dissolved in the minimum amount of DCM and applied to a pre-packed 12 g silica gel column and eluted with 0-100% EtOAc/isohexane over 6 minutes then 100% EtOAc for 8 minutes. Pure product is recovered as a colourless oil. The oil is dissolved in the minimum amount of DCM and triturated/sonicated with 9:1 isohexane/EtOAc to give a colourless solid 124 mg, [MH+471.30].
Reaction SMILES: [NH2:1][C@@H:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:3]([N:5]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([CH3:25])[CH:19]=1)[CH2:6][CH2:7][C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)=[O:4].[N+:32]([CH:35]=[C:36]1[CH2:39][O:38][CH2:37]1)([O-])=O.CCN(CC)CC>C(Cl)Cl>[NH2:32][CH2:35][C:36]1([NH:1][C@@H:2]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:3]([N:5]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([CH3:25])[CH:19]=2)[CH2:6][CH2:7][C:8]2[CH:9]=[N:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)=[O:4])[CH2:39][O:38][CH2:37]1
Reactant: O=[N+]([O-])C=C1COC1
Reactant: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](N)c2ccccc2)cc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](NC2(CN)COC2)c2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A solution of (S)-2-amino-N-(3,4-dimethyl-phenyl)-2-phenyl-N-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-acetamide (50 mg, 0.11 mmol, prepared as in example 1) and 3-nitromethylene-oxetane (12 mg, 0.104 mmol, [CAS No. 922500-95-6]) in CH2Cl2 (0.5 mL) was treated with Et3N (11 mg, 0.11 mmol) at 0° C. After stirring for 30 min at ambient temperature, the mixture was concentrated, dissolved in MeOH (1 mL) and treated with a solution of HCO2NH4 (300 mg, 4.76 mmol) in H2O (0.5 mL), 10% Pd/C (100 mg) and the mixture stirred for 12 h at ambient temperature. After the addition of 1N Na2CO3 (15 mL), the aqueous layers were filtered then extracted with CH2Cl2 (3×15 mL) and the combined organic layers dried over sodium sulfate. Concentration and purification by chromatography (SiO2, CH2Cl2:MeOH=100:0 to 90:10) afforded the title compound (26 mg, 46%) as a light yellow oil. MS m/e: 513.5 [M+H]+.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:18]=[CH:17][C:8]2[CH2:9][CH:10]3[N:15]([CH2:16][C:7]=2[CH:6]=1)[CH2:14][CH2:13][CH2:12][CH2:11]3)([O-])=O>C(O)C.[Pd]>[ClH:1].[CH2:11]1[CH:10]2[N:15]([CH2:16][C:7]3[CH:6]=[C:5]([NH2:2])[CH:18]=[CH:17][C:8]=3[CH2:9]2)[CH2:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CN1CCCCC1C2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc2c(c1)CN1CCCCC1C2
Reaction time: 2 h
Yield: 95.3 %

Procedure:
8-Nitro-1,3,4,6,11,11a-hexahydro-2H-benzo[b]quinolizine hydrochloride (2.93 g, 10.9 mmol) was dissolved in ethanol (150 ml) and 10% palladium-on-carbon (0.4 g) was added and the solution was shaken on a Parr Hydrogenator for 2 h. The catalyst was filtered off and the catalyst was washed with water. The filtrate was concentrated and absolute ethanol was added and evaporated to drive off excess water. The resulting solid was taken up in hot ethanol (75 ml) and ether (100 ml) was added slowly. The precipitate which formed was collected and dried in the air to give the title compound as an off-white solid (2.48 g, 95%), m.p. 241-3° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([OH:17])=O)=[CH:11][N:10]1[CH3:18].[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([O:24][C:25]2[CH:26]=[CH:27][C:28]3[N:29]([CH:31]=[C:32]([NH:34][C:35]([CH:37]4[CH2:39][CH2:38]4)=[O:36])[N:33]=3)[CH:30]=2)=[C:22]([F:42])[CH:21]=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)C=O>[CH:37]1([C:35]([NH:34][C:32]2[N:33]=[C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]4[CH:40]=[CH:41][C:20]([NH:19][C:15]([C:12]5[C:13](=[O:14])[N:9]([C:3]6[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=6[F:1])[N:10]([CH3:18])[CH:11]=5)=[O:17])=[CH:21][C:22]=4[F:42])=[CH:30][N:29]3[CH:31]=2)=[O:36])[CH2:38][CH2:39]1
Reactant: Cn1cc(C(=O)O)c(=O)n1-c1ccc(F)cc1F
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccc(F)cc1F
Yield: 76.2 %

Procedure:
In the same manner as in Example 46 and using 2-(2,4-difluorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid (330 mg, 1.3 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (250 mg, 0.77 mmol), HATU (490 mg, 1.3 mmol), N,N-diisopropylethylamine (340 mg, 2.6 mmol) and N,N-dimethylformamide (15 mL) as starting materials, the title compound (330 mg, 76%) was obtained as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.C(O[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])C>CC#N>[N+:22]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:16]=1[NH:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)([O-:24])=[O:23]
Reactant: CCOc1ccncc1[N+](=O)[O-]
Reactant: NCc1ccc(CCC(=O)O)o1
Solvent: CC#N
Product: O=C(O)CCc1ccc(CNc2ccncc2[N+](=O)[O-])o1

Procedure:
The desired compound was prepared by heating a solution in CH3CN of 5-aminomethyl-2-carboxyethylfuran with 4-ethoxy-3-nitropyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][CH:25]([CH3:27])[CH3:26])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28].[Br:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34]([CH:38]=1)[C:35](O)=[O:36]>>[Br:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34]([CH:38]=1)[C:35]([N:24]([CH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][CH2:9][CH2:8][C:6]3[CH:5]=[CH:4][C:3]([OH:28])=[C:2]([Cl:1])[CH:7]=3)[N:16]=2)[CH:18]=1)[CH:25]([CH3:26])[CH3:27])=[O:36]
Reactant: CC(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1
Reactant: O=C(O)c1cncc(Br)c1
Product: CC(C)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(=O)c1cncc(Br)c1

Procedure:
2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol (compound 132) was coupled with 5-bromo-nicotinic acid following procedure D2. LC-MS showed the product had the expected M+H+ of 581. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 9.3 (s, 1H), 8.9 (s, 1H) 8.6 (s, 1H) 8.4 (s, 1H) 8.2 (d, 1H) 8.1 (s, 1H) 7.9 (d, 1H) 7.5 (m, 1H) 7.4 (m, 2H) 7.2 (s, 1H) 6.9 (d, 1H) 5.8 (s, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 3.1 (m, 1H) 2.9 (m, 2H) 1.2 (d, 6H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[OH-:15].C([N+](C)(C)C)C1C=CC=CC=1.O=O.C>N1C=CC=CC=1>[F:1][C:2]1[C:3](=[O:15])[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH:5]=2
Reactant: [OH-]
Reactant: Fc1ccc2c(c1)Cc1ccccc1-2
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=O
Solvent: c1ccncc1
Product: O=C1C(F)=CC=C2C1=Cc1ccccc12

Procedure:
2-Fluorofluorene (824.7 g, 4.48 mol) was dissolved in pyridine (4 L) and stirred. A 40% solution of Triton B (100 mL of benzyltrimethylammonium hydroxide 40% in pyridine according to a general procedure of U. Sprinzak, J. Amer. Chem. Soc. 80 (1958) 5449) was added and oxygen was bubbled into the vigorously stirred solution. This exothermic reaction was run for 20 hours whereupon an additional portion of the Triton B solution (50 mL) was added with continued stirring and oxygen addition for an additional 24 hours. The resulting dark green reaction mixture was treated with Norite (100 g, neutralized charcoal), stirred for 30 minutes and filtered through a Celite pad (diatomaceous earth filter aid). The filter pad was then washed with pyridine (1 L). The combined filtrates were concentrated to a small volume in vacuo with heat. A 5% solution of hydrochloric acid in water (1 L) was added and the pyridine was azeotrophed in vacuo with heat. This process was repeated until a total of 6-8 L of water were evaporated. The granular product was filtered and washed with water (4 L) and air dried. The yellow-orange product was melted and distilled through a large bore short path distillation apparatus (bp 167°-170° C.; 1.5 mm Hg) to yield into a chilled receiving flask the bright yellow 2-fluorofluorenone (600 g) with a m.p. 113°-115° C. and m/e+. 198 for C13H7FO.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15]#[N:16])[CH:9]=2)=[O:5])C.Cl>O1CCOCC1.O>[C:15]([C:10]1[CH:9]=[C:8]2[C:13]([CH:14]=[C:6]([C:4]([OH:5])=[O:3])[N:7]2[CH3:17])=[CH:12][CH:11]=1)#[N:16]
Reactant: CCOC(=O)c1cc2ccc(C#N)cc2n1C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(C(=O)O)cc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 6-Cyano-1-methyl-1H-indole-2-carboxylic acid ethyl ester (51 mg, 0.22 mmol) in 1,4-dioxane/water (5:1, 6 mL) add LiOH monohydrate (13 mg, 0.31 mmol). Stir the reaction mixture at rt overnight. Remove the solvent in vacuo and dissolve the residue in water (2 mL) to form a solution. Acidify with 1 M HCl solution to form a white suspension. Collect the solid by filtration and dry to give the desired product 6-cyano-1-methyl-1H-indole-2-carboxylic acid as a solid (44 mg, 0.22 mmol).
Reaction SMILES: CC1[NH:3]C=C(C#N)N=1.[I:9][C:10]1[NH:14][C:13]([C:15]2([CH3:19])[CH2:18][O:17][CH2:16]2)=[N:12][C:11]=1[C:20](F)(F)F.CC1NC=C(C(F)(F)F)N=1>>[I:9][C:10]1[NH:14][C:13]([C:15]2([CH3:19])[CH2:18][O:17][CH2:16]2)=[N:12][C:11]=1[C:20]#[N:3]
Reactant: CC1(c2nc(C(F)(F)F)c(I)[nH]2)COC1
Reactant: Cc1nc(C#N)c[nH]1
Agent: Cc1nc(C(F)(F)F)c[nH]1
Product: CC1(c2nc(C#N)c(I)[nH]2)COC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 16.3, except 5-iodo-2-(3-methyloxetan-3-yl)-4-(trifluoromethyl)-1H-imidazole (compound 202.2) was used in place of 2-methyl-4-(trifluoromethyl)-1H-imidazole (compound 16.2). m/z (ES+) 290 (M+H)+.
Reaction SMILES: [C@:1]12([CH3:11])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=O.S([CH2:22][N+:23]#[C-])(C1C=CC(C)=CC=1)(=O)=O>>[CH3:11][C:1]12[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:2]2[C:22]#[N:23]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)C2
Product: CC1(C)C2CCC1(C)C(C#N)C2

Procedure:
(1R)-(+)-Camphor was converted to the nitrile using tosylmethyl isocyanide according to the procedure of O. H. Oldenziel (O. H. Oldenziel, D. van Leusen, and A. M. van Leusen J.Org.Chem. 1977, 42, 3114).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Si]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)(C(C)(C)C)(C)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH:32]=[O:33].C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:28][C:29]1[CH:30]=[C:31]([CH:32]([OH:33])[CH:21]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)[OH:20])[CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccncc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OC(c1ccncc1)C(O)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C

Procedure:
To a stirring solution of diisopropylamine (14.9 g, 19.4 mL, 148 mmol) in tetrahydrofuran (500 mL) at -78° C. was added, dropwise, n-butyllithium (59 mL of a 2.5M solution in tetrahydrofuran). After ten minutes, a solution of 4-pyridylcarbinol t-butyldimethylsilyl ether (30 g, 134 mmol) in tetrahydrofuran (150 mL) was added dropwise and the temperature allowed to rise to -15° C. The solution was again cooled to -78° C. and a solution of 3,4-dichlorobenzaldehyde (25.9 g, 134 mmol) in tetrahydrofuran (150 mL) added dropwise. After the solution was allowed to warm to -20° C., it was poured into saturated aqueous sodium hydrogen carbonate (2 L). The aqueous layer was extracted with ethyl acetate (3×400 mL), the combined organic layers dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure. The resulting oil was dissolved in tetrahydrofuran (400 mL) and to this solution was added tetrabutylammonium fluoride (148 mL of a 1.0M solution in tetrahydrofuran) dropwise. After ten minutes, the reaction mixture was concentrated at reduced pressure and the resulting oil chromatographed on silica gel, eluting with 95:5 dichloromethane:methanol to give the title compound as a mixture of diastereomeric diols as a foam (31.7 g) which was used without further purification.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([NH2:29])=[N:23][C:24]=2Cl)(=[O:3])[CH3:2].[NH2:30][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(CC)CC)C>O1CCOCC1>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:20]2[N:21]=[C:22]([NH2:29])[N:23]=[C:24]([NH:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:25]=2[N:26]=[CH:27]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NN1CCCCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NN4CCCCC4)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 190 h
Yield: 70.9 %

Procedure:
9-(2',3',5'-Tri-O-acetyl-β-D-ribofuranosyl)-2-amino-6-chloro-(9H)-purine (6.0 g, 14 mmol) (prepared as described by Robins, M. J. and Uznanski, B., in Nucleic Acid Chemistry (Townsend, L. B. and Tipson, R. S., eds.,) John Wiley and Sons, Inc., 1986, 3, 144) was dissolved in dioxan (100 ml). 1-Aminopiperidine (1.83 ml, 16.95 mmol) was added followed by triethylamine (2.33 ml, 18.5 mmol) and the solution was stirred for 190 hours at room temperature. The reaction mixture was filtered, evaporated and the resultant residue was purified by column chromatography on silica gel eluting with ethyl acetate/cyclohexane (3/1) to afford 2',3',5'-tri-O-acetyl-2-amino-N-(1-piperidinyl)adenosine (4.88 g, 71%) as a foam which solidified on coevaporation with methanol: m.p. 77°-79° C. 1H NMR (400 MHz, Me2SO-d6) δ2.04 (6H, s, 2' and 3'-O-acetyl-CH3), 2.13 (3H, s, 5'-O-acetyl-CH3), 4.30 (2H, m, H-5'a and H-4'), 4.40 (1H, dd, H-5'b) 6.03 (1H, d, H-1').
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:17][N:16]=[CH:15][N:14]=1)=[CH:9]2)([O-])=O.O1CCCC1.O.NN>O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.CO>[S:17]1[C:13]([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[CH:7][CH:6]=[CH:5][C:4]=3[NH2:1])=[N:14][CH:15]=[N:16]1
Reactant: O=[N+]([O-])c1cccc2cc(-c3ncns3)[nH]c12
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1cccc2cc(-c3ncns3)[nH]c12
Yield: 97.2 %

Procedure:
A mixture of 7-nitro-2-(1,2,4-thiadiazol-5-yl)-1H-indole (0.41 g), iron(III) chloride hexahydrate (33 mg), activated carbon (0.33 g), tetrahydrofuran (12 mL) and methanol (6 mL) was heated under reflux for 20 min. To the reaction mixture was added hydrazine monohydrate (0.50 g) over 10 min while heating under reflux. The reaction mixture was heated under reflux for 2 hr, filtrated, and the filtrate was concentrated. The resulting crystals were washed with water, and dried to give the title compound (0.35 g, yield 94%) as colorless crystals. melting point>223° C. (decomposition).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[O:8]2)[CH2:4][CH2:3]1.[C:17]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)=[CH:27][CH:26]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[C:17]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([N:2]2[CH2:7][CH2:6][C:5]3([C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9](=[O:16])[O:8]3)[CH2:4][CH2:3]2)=[O:33])=[CH:27][CH:26]=1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Nc1ccc(C(=O)c2ccccc2)cc1)Oc1ccccc1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)c1ccc(NC(=O)N2CCC3(CC2)OC(=O)c2ccccc23)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 103.9 %

Procedure:
A mixture of spiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (48 mg), phenyl N-(4-benzoylphenyl)carbamate (58 mg) and triethylamine (0.14 mL) in chloroform (5 mL) was stirred at 80° C. for 2 hours. The reaction mixture was poured into water and extracted with chloroform (20 mL). The organic layer was washed with saturated saline solution (20 mL), then dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1 to 1/2) and recrystallized from ethyl ether-hexane to give the subject compound (81 mg) as colorless crystals (melting point 161-163° C.).
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]3[CH:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:13][C:14]=3[C:6]=2[C:5](=[O:19])[NH:4][CH:3]=1.[CH3:20][N:21]1CCCC1=O>>[CH3:18][O:17][C:15]([C:11]1[CH:12]=[CH:13][C:14]2[C:6]3[C:5](=[O:19])[NH:4][CH:3]=[C:2]([C:20]#[N:21])[C:7]=3[NH:8][C:9]=2[CH:10]=1)=[O:16]
Reactant: COC(=O)c1ccc2c(c1)[nH]c1c(Br)c[nH]c(=O)c12
Reactant: CN1CCCC1=O
Product: COC(=O)c1ccc2c(c1)[nH]c1c(C#N)c[nH]c(=O)c12
Temperature: 200 °C

Procedure:
A stirred mixture of methyl 4-bromo-1-oxo-2,5-dihydro-1H-pyrido[4,3-b]indole-7-carboxylate (0.820 g, 2.55 mmol) and Cuprous cyanide (0.229 g, 2.55 mmol) in N-Methyl-2-pyrrolidinone (25 mL) was heated at 200° C. for 2-4 hours. LC-MS showed complete conversion to the desired product plus minor debrominated product. The reaction mixture was cooled to room temperature then concentrated in vacuo. The residue was slurred in water and filtered. The solid residue was dried overnight under vacuum to give methyl-4-cyano-1-oxo-2,5-dihydro-1H-pyrido[4,3-b]indole-7-carboxylate as a brown solid. [0.672 g product, 2.51 mmol, 98% yield]. The product had an HPLC Retention Time=2.537 min [4 min grad, 10% MeOH/water to 90% MeOH/water, 0.1% TFA, YMC COMBISCREEN® ODS-A, 4.6×50 mm, 220 nM]; LC/MS+1 268.2
Reaction SMILES: [Na].[OH2:2].Cl.Cl.[CH3:5][O:6][CH2:7][C:8]1[N:9]=[C:10](N2CCNCC2)[C:11]2[S:17][CH2:16][CH2:15][CH2:14][C:12]=2[N:13]=1>CO>[OH:2][C:10]1[C:11]2[S:17][CH2:16][CH2:15][CH2:14][C:12]=2[N:13]=[C:8]([CH2:7][O:6][CH3:5])[N:9]=1
Reactant: O
Reactant: COCc1nc2c(c(N3CCNCC3)n1)SCCC2
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COCc1nc(O)c2c(n1)CCCS2

Procedure:
Sodium metal (0.46 g, 0.02 gr. atm.), was dissolved in methanol (I00 ml) and the product from step A was added. The reaction mixture was refluxed for 4 hours and then most of the solvent was removed in vacuo. The addition of water afforded 1.2 g of title compound which was dried and used in step C without further purification