Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[CH3:6][N:7]([CH3:29])[CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[N:23][CH:22]=3)=[CH:15][CH:14]=2)[CH2:9]1>>[CH:5]1([CH2:4][O:27][C:24]2[CH:25]=[CH:26][C:21]([C:20]([NH:19][C:16]3[CH:15]=[CH:14][C:13]([N:10]4[CH2:11][CH2:12][CH:8]([N:7]([CH3:29])[CH3:6])[CH2:9]4)=[CH:18][CH:17]=3)=[O:28])=[CH:22][N:23]=2)[CH2:3][CH2:2]1
Reactant: BrCC1CC1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(O)nc3)cc2)C1
Product: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(OCC4CC4)nc3)cc2)C1

Procedure:
(Bromomethyl)cyclopropane was reacted with N-[4-(3-dimethylaminopyrrolidin-1-yl)-phenyl]-6-hydroxynicotinamide by method H-a. This resulted in the product with the molecular weight of 380.22 (C22H28N4O2); MS (ESI): 381 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:10])=[O:9].C(N(CC)CC)C.[O:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[C:23](Cl)=O>O1CCCC1>[Br:7][C:5]1[S:4][C:3]2[C:8](=[O:9])[NH:10][C:23]([CH:19]3[CH2:20][CH2:21][CH2:22][O:18]3)=[N:1][C:2]=2[CH:6]=1
Reactant: NC(=O)c1sc(Br)cc1N
Reactant: O=C(Cl)C1CCCO1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]c(C2CCCO2)nc2cc(Br)sc12
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a mixture of 3-amino-5-bromothiophene-2-carboxamide (120 mg) produced in Example 1, step D, triethylamine (0.083 mL) and tetrahydrofuran (3.0 mL) was added tetrahydrofuran-2-carbonylchloride (80 mg) with stirring at room temperature. The reaction mixture was stirred for 10 min, and the reaction system was concentrated under reduced pressure. 2M Aqueous sodium hydroxide solution (1.0 mL) was added to the residue, and the mixture was stirred with heating at 120° C. for 2 hr. The mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (160 mg) as a pale-yellow solid.
Reaction SMILES: C([C:4]1([OH:33])[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:5]12[CH3:6])[C:18]1[CH:17]=[C:16]([O:22][CH2:23][CH3:24])[C:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:14][C:13]=1[CH2:12][CH2:11]3)C=C.C1OCCOCCOCCOCCOCCOC1.[CH3:52][CH:53](O)[CH3:54].[NH4+].[Cl-]>C1COCC1>[CH2:54]([C@@H:8]1[C@H:7]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:5]2([CH3:6])[C:4](=[O:33])[CH2:9]1)[C:18]1[CH:17]=[C:16]([O:22][CH2:23][CH3:24])[C:15]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:14][C:13]=1[CH2:12][CH2:11]3)[CH:53]=[CH2:52]
Reactant: C=CCC1(O)CC[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)c(OCC)cc4[C@H]3CC[C@@]21C
Reactant: CC(C)O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC[C@H]1CC(=O)[C@@]2(C)CC[C@@H]3c4cc(OCC)c(OCc5ccccc5)cc4CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
KH 30% in oil (89.98 mmol) was suspended in THF (50 ml), under N2 atmosphere. 17-Allyl-3-(benzyloxy)-2-ethoxy-estra-1,3,5(10)-trien-17-ol (7.7 g, 17.30 mmol) and 18-Crown-6 (88.25 mmol) were dissolved in THF (200 ml) and added dropwise in 40 min. The mixture was stirred for 3 h at RT. The mixture was carefully poured into IPA via canula. The mixture was poured into aq. sat. NH4Cl (1 l). The water layer was extracted with EtOAc (3×250 ml). The combined organic layers were washed with brine (1×500 ml), dried over Na2SO4 and concentrated in vacuo. Purification via filtration over Silica (eluens heptan to 40% DCM in heptan) provided 4.2 g (9.51 mmol, 55%) of (XXX-(C2-D)-2c).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=1>>[C:15]([C:7]1[C:8]([C:11]([F:12])([F:14])[F:13])=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=1)[C:2]([CH3:1])=[CH:10]2)#[N:16]
Reactant: CC(=O)Nc1ccc(OCCBr)cc1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: CC(=O)Nc1ccc(OCCn2c(C)cc3c(C(F)(F)F)c(C#N)ccc32)cc1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and N-{4-[(2-bromoethyl)oxy]phenyl}acetamide: 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.00 (d, J=8.6 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.39 (d, J=9.0 Hz, 2H), 6.72 (d, J=9.0 Hz, 2H), 6.55 (s, 1H), 4.65 (t, J=5.0 Hz, 2H), 4.21 (t, J=5.0 Hz, 2H), 2.55 (s, 3H), 1.95 (s, 3H); MS (ES) m/z 402 (M+1).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([N:30]=[C:31]=[O:32])[CH3:29]>C(Cl)Cl>[CH2:28]([NH:30][C:31]([N:13]1[CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9][C@@H:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:32])[CH3:29]
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Reaction time: 1 h
Yield: 68.6 %

Procedure:
A solution of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (73 mg, 0.2 mmol) in CH2Cl2 (0.5 mL) at 0° C. was treated with ethyl isocyanate (19 μL, 0.24 mmol) and stirred for 1 h, then evaporated and the residue purified by silica gel flash chromatography with 50% then 75% EtOAc/hexane as eluant to afford the title compound as a foam (60 mg, 69%) 1H NMR (CDCl3) 7.35-7.22 (m, 5H), 6.78 (d, J=8.8, 1H), 6.49 (br s, 1H), 6.40 (br d, J=7.5, 1H), 4.73-4.70 (m, 1H), 4.27-4.13 (m, 2H), 3.93 (br d, J=12.5, 1H), 3.79 (s, 3H), 3.43-3.00 (m, 7H), 2.75-2.67 (m, 2H), 1.96-1.91 (m, 2H), 1.90-1.79 (m, 3H), 1.64-1.59 (m, 2H), 1.04 (t, J=7.2, 3H). LC/MS (Method A) 6.86 min, [M+1]+ 438.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>C1COCC1>[O:29]=[C:22]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)Cc1ccsc1
Reactant: O=C(Cl)c1cccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)c1cccnc1)c1ccsc1
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
To a solution of ethyl 2-(thiophen-3-yl)acetate (2.3 g, 16.2 mmol) in anhydrous THF (20 mL) was added LiHMDS (19.4 mL, 19.44 mmol) at −78° C. After stirring at that temperature for 0.5 h, a solution of nicotinoyl chloride (2.8 g, 16.2 mmol) in anhydrous THF (10 mL) was added into the reaction mixture and stirred at −78° C. for 4 hours. The mixture was quenched with NH4Cl solution, extracted with EtOAc. The organic layer was concentrated in vacuo and purified by column on silca gel (1.7 g, yield 38%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:17])([CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]([Cl:18])=[CH:4][CH:3]=1.N1C=CC=CC=1.Br[CH2:26][C:27](Br)=[O:28]>CCOCC>[CH2:13]([C:8]1([C:9]([F:10])([F:11])[F:12])[C:7]2[CH:6]=[C:5]([Cl:18])[CH:4]=[CH:3][C:2]=2[NH:1][C:27](=[O:28])[CH2:26][O:17]1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C(Br)CBr
Reactant: CCCCC(O)(c1cc(Cl)ccc1N)C(F)(F)F
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCC1(C(F)(F)F)OCC(=O)Nc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred ice-cooled solution of 185 mg of 6-amino-3-chloro-α-butyl-α-(trifluoromethyl)benzyl alcohol in 15 ML of dry ether was added 0.100 mL of dry pyridine and 0.060 mL of bromoacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 8 mL of dry DMF and was treated at room temperature with 40 mg of 100% sodium hydride for 16 h. The reaction was partitioned between ethyl acetate and water and the ethyl acetate layer was washed with brine, dried, and evaporated. The crude product was purified first by column chromatography over silica gel (elution with ethyl acetate/hexanes 1:3), and then by preparative silica gel TLC (elution with 2.5% methanol in methylene chloride) affording 32 mg of the title compound as an amorphous solid: HRMS: Calcd. for C14H16NO2ClF3 (M+H)+: 322.082166. Found: 322.080685.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][C:20]=4[O:33][CH3:34])=[C:14]([CH2:35][CH2:36][CH3:37])[N:13]4[N:38]=[CH:39][CH:40]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][C:20]=3[O:33][CH3:34])=[C:14]([CH2:35][CH2:36][CH3:37])[N:13]3[N:38]=[CH:39][CH:40]=[C:12]23)[CH2:9][CH2:10]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2OC)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2OC)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-methoxybiphenyl-2-carbonitrile (1.1 g) in tetrahydrofuran (10 mL) was added 3M hydrochloric acid (10 mL), and the mixture was stirred at 60° C. for 5 hr. The mixture was allowed to cool, and diluted with ethyl acetate, and the mixture was neutralized with 8M aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (10 mL)-tetrahydrofuran (10 mL). Thereto was added sodium borohydride (0.075 g) at 0° C. After stirring for 2 hr, ethyl acetate and saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.93 g, 95%).
Reaction SMILES: [F:1][CH:2]([F:36])[O:3][C:4]1[CH:35]=[CH:34][CH:33]=[CH:32][C:5]=1[CH2:6][C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[CH:17]=[N:18][C:19]([N:22]4[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[CH2:24][CH2:23]4)=[N:20][CH:21]=3)[CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[CH3:31].[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][CH:2]([F:36])[O:3][C:4]1[CH:35]=[CH:34][CH:33]=[CH:32][C:5]=1[CH2:6][C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[CH:21]=[N:20][C:19]([N:22]4[CH2:27][CH2:26][CH:25]([C:28]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:29])[CH2:24][CH2:23]4)=[N:18][CH:17]=3)[CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[CH3:31]
Reactant: Cc1nc2ccc(-c3cnc(N4CCC(C(=O)O)CC4)nc3)cn2c1Cc1ccccc1OC(F)F
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1nc2ccc(-c3cnc(N4CCC(C(=O)NS(C)(=O)=O)CC4)nc3)cn2c1Cc1ccccc1OC(F)F
Yield: 23.8 %

Procedure:
A solution of Example 23 (0.138 g, 0.28 mmol) in DCM (6 mL) was treated with methanesulphonamide (0.1 g, 1.0 mmol 1), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.2 g, 1.0 mmol) and 4-(dimethylamino)pyridine (0.033 g, 0.28 mmol) and the mixture was heated to reflux for 3 days. The reaction mixture was concentrated in vacuo and the crude residue was partitioned between DCM (20 mL) and water (10 mL). The organic layer was concentrated in vacuo, and the crude residue purified by FCC on silica gel (eluting with 0-10% MeOH/DCM), to give the title compound (38 mg, 24%) as a white solid. HPLC-MS (pH 10): MH+ m/z 571.7 [M+H]+, RT 1.49 minutes.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].CN(C)C=O.[OH:19][CH:20]1[CH2:24][CH2:23][NH:22][C:21]1=[O:25]>O>[Si:10]([O:19][CH:20]1[CH2:24][CH2:23][NH:22][C:21]1=[O:25])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12]
Reactant: O=C1NCCC1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCNC1=O
Reaction time: 1 h
Yield: 11.4 %

Procedure:
In an ice bath, 300 mg of imidazole and 497 mg of tert-butyldimethylchlorosilane were added to a dimethylformamide (2 ml) solution of 255 mg of 3-hydroxypyrrolidin-2-one, and stirred for 1 hour. Water was added to the reaction liquid, extracted with ethyl acetate, and washed with hydrochloric acid (1 N) and saturated saline water. The organic layer was dried to obtain 370 mg of a crude product. 208 g of the product was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=9/1 to 2/8) to obtain 62 mg of the entitled compound as a white solid.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]([O:19][CH2:20][CH3:21])=N)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[SH2:28]>C1COCC1>[CH2:2]([O:9][C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]([O:19][CH2:20][CH3:21])=[S:28])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: S
Reactant: CCOC(=N)C1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=S)C1CCCN1C(=O)OCc1ccccc1
Temperature: -20 °C
Yield: 47 %

Procedure:
2-Ethoxycarbonimidoyl-pyrrolidine-1-carboxylic acid benzyl ester hydrochloride (42.8 g, 146.0 mmol) was dissolved in THF (150 mL) and cooled to −20° C. Pyridine (80 ml) was added to the reaction and H2S was bubbled through the reaction for 60 min. The reaction's temperature was maintained at −20° C. for 2 hours while stirring. The pH was adjust to pH=4 by addition of 5M HCl. The resulting solution was transferred to a separatory funnel and extracted with diethyl ether (3×100 mL). The organic layers were combined and washed with brine (100 ml). The organic layer was dried over MgSO4 and concentrated under vacuo to afford 20.0 g (47%) of 2-ethoxythiocarbonyl-pyrrolidine-1-carboxylic acid benzyl ester as a yellow oil.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[C@H:22]2[C@H:26]([OH:27])[C@H:25]([OH:28])[C@@H:24]([CH2:29][O:30][CH3:31])[O:23]2)=[C:15]([NH:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:14]=1.C(N(CC)CC)C>O1CCCC1>[OH:27][C@@H:26]1[C@H:25]([OH:28])[C@@H:24]([CH2:29][O:30][CH3:31])[O:23][C@H:22]1[N:19]1[CH:18]=[N:17][C:16]2[C:20]1=[N:21][C:13]([CH2:12][NH:11][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])=[N:14][C:15]=2[NH:32][CH2:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCCc4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCCc4ccccc4)nc(CNS(=O)(=O)c4ccccc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
Phenylsulfonylchloride (57 mg, 0.33 mmol) was added to a stirred solution of (2R,3R,4S,5R)-2-[2-(aminomethyl)-6-(phenethylamino)-9H-purin-9-yl]-5-(methoxymethyl)tetrahydro-3,4-furandiol (150 mg, 0.36 mmol) (preparation 48) and triethylamine (110 mg, 1.08 mmol) in tetrahydrofuran (24 ml). The reaction mixture was stirred for 30 min at room temperature and then the solvent was removed under reduced pressure. The residue was azeotroped with dichloromethane and then purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol (95:5) to give the title compound (180 mg) as a foam. MS: 577 (MNa+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:13]3[CH2:18][CH2:17][CH2:16][C@@H:15]4[C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=5[CH2:25][C@H:14]34)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 60 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1. Yield: 60% of theory; LC (method 1): tR=2.44 min; Mass spectrum (ESI+): m/z=318 [M+H]+; 1H NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 1.20-1.34 (m, 1H), 1.41-1.56 (m, 1H), 1.56-1.71 (m, 1H), 1.92-2.02 (m, 1H), 2.68-3.11 (m, 3H), 3.11-3.27 (m, 1H), 3.47-5.43 (very broad signals, 2H), 7.07-7.30 (m, 5H), 7.54-7.62 (m, 1H), 7.64-7.72 (m, 1H), 8.29 (s, 1H), 12.51-12.65 (m, 1H).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:6]2[N:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]=[C:9]([S:11][CH3:12])[N:10]=1>C(O)C>[NH:2]([C:5]1[C:6]2[N:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]=[C:9]([S:11][CH3:12])[N:10]=1)[NH2:3]
Reactant: CSc1nc(Cl)c2ncccc2n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CSc1nc(NN)c2ncccc2n1
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
Hydrazine hydrate (13.0 mL (13.3 g, 237 mmol)) was added at ambient temperature with stirring to a mixture of 16.7 g (79 mmol) of 4-chloro-2-methylthiopyrido[3,2-d]pyrimidine in 200 mL of ethanol. There was a slight exotherm and the mixture thickened and then became more mobile again. After 30 min, the volatile components were removed by evaporation under reduced pressure. The residue was diluted with water and the solids were recovered by filtration, washed with ether, and dried to obtain 15.7 g of the title compound as a brown powder melting above 300° C.
Reaction SMILES: OP([O-])(O)=O.[K+].OP([O-])([O-])=O.[K+].[K+].[NH2:14][C:15]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:16]=1[OH:22].[Cl:23][CH2:24][C:25](Cl)=[O:26]>O>[Cl:23][CH2:24][C:25]([NH:14][C:15]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:16]=1[OH:22])=[O:26]
Reactant: Nc1c(O)cccc1O
Reactant: O=C(Cl)CCl
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Product: O=C(CCl)Nc1c(O)cccc1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
KH2PO4 (17.2 g, 126.3 mmol) and K2HPO4 (8.2 g, 35.7 mmol) in 188 ml of distilled water were deoxygenated by passing argon through the mixture for 0.5 hour. 2-Aminobenzene-1,3-diol (1 g, 8.0 mmol) was added to the buffer solution and chloroacetyl chloride (0.64 ml, 8.0 mmol) was added slowly to the reaction mixture. After addition was completed, the reaction mixture was stirred at room temperature for 1.5 hours. Water was removed by freeze-drying and the residue was dissolved in 20% MeOH in DCM. The insoluble salt was removed by filtration, the solvent was evaporated to give the subtitled compound which was used without purification in the next step.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[NH:17][CH:16]=[C:15]2[C:23]1[N:31]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:25]2[CH:24]=1>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH:16]=[C:15]2[C:23]1[N:31]([S:32]([C:35]2[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=2)(=[O:34])=[O:33])[C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:25]2[CH:24]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1cc2[nH]cc(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)c2cc1OC
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CC(=O)OC(C)(C)C)c2cc1OC
Yield: 89.6 %

Procedure:
tert-Butyl 2-{5,6-dimethoxy-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]indol-1-yl)-acetate is prepared by following the procedure described in example 89c, but using 1.91 g of tert-butyl bromoacetate and 4 g of 2-(5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine. 4.5 g of tert-butyl 2-{5,6-dimethoxy-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]indol-1-yl}acetate are obtained, the characteristics of which are as follows:
Reaction SMILES: [N:1]#[C:2]Br.[Br:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][C:6]=1[CH3:12]>C(OCC)C.C1COCC1>[Br:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:2]#[N:1])=[CH:7][C:6]=1[CH3:12]
Reactant: Cc1cc(N)ccc1Br
Reactant: N#CBr
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(NC#N)ccc1Br
Yield: 26.4 %

Procedure:
A mixture of cyanogen bromide (0.550 g, 5.19 mmol), and (4-bromo-3-methylaniline (2.04 g, 11 mmol) (Aldrich Chemical Company) in diethyl ether/THF (8 mL) was stirred for 3 days under nitrogen. The reaction was filtered, the filtrate evaporated, and the residue flash chromatographed on silica gel using 9/1 Hexane/acetone to give (4-bromo-3-methylphenyl)cyanamide (0.289 g, 13%). HRMS: calcd for 2 C8H7BrN2+H+, 420.96579; found (ESI-FT/MS, [2M+H]+), 420.966.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(CC)CC.[Si:27]([O:34][C@@H:35]([CH3:61])[C@@H:36]([NH:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]#[N:58])=[C:53]([Cl:59])[C:52]=1[CH3:60])[C:37]([NH:39][NH:40][C:41](=[O:49])[C:42]1[CH:47]=[CH:46][C:45]([I:48])=[CH:44][CH:43]=1)=O)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>C(Cl)Cl>[Si:27]([O:34][C@@H:35]([CH3:61])[C@@H:36]([NH:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]#[N:58])=[C:53]([Cl:59])[C:52]=1[CH3:60])[C:37]1[O:49][C:41]([C:42]2[CH:43]=[CH:44][C:45]([I:48])=[CH:46][CH:47]=2)=[N:40][N:39]=1)([C:30]([CH3:32])([CH3:33])[CH3:31])([CH3:28])[CH3:29]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(I)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(I)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of triphenylphosphine (7.2 g, 27.5 mmol) in DCM (300 mL) was added 12 (7.0 g, 27.5 mmol) at 0° C. After 12 was dissolved completely, Et3N (7.7 mL, 55.2 mmol) was added, followed by a solution of N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-4-iodobenzohydrazide (8.6 g, 13.7 mmol) in DCM (100 mL). The reaction mixture was allowed to warm to room temperature and stirred for an additional 60 min. The reaction was quenched with saturated sodium thiosulfate (50 mL) and diluted with DCM (500 mL). The organic layer was separated and washed with water, brine, dried over Na2SO4 and filtered. After the solvent was removed, the residue was purified by flash chromatography to provide the title compound (7.3 g, 88%). 1H NMR (400 MHz, CDCl3, δ in ppm) 8.06 (d, J=8.6 Hz, 2H), 7.88 (d, J=8.6 Hz, 2H), 7.55 (d, J=8.4 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 5.56 (d, J=8.8 Hz, 1H), 5.00 (dd, J=2.0, 8.8 Hz, 1H), 4.74 (m, 1H), 2.59 (s, 3H), 1.62 (d, J=6.3 Hz, 3H), 1.07 (s, 9H), 0.28 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: O[CH2:2][C:3]#[N:4].[CH2:5]([NH2:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>CO>[CH2:5]([NH:11][CH2:2][C:3]#[N:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCN
Reactant: N#CCO
Solvent: CO
Product: CCCCCCNCC#N
Reaction time: 24 h

Procedure:
In a flask of 100 ml, 5.7 gr of hydroxyacetonitrile (0.1 mol) were mixed with 11 gr of hexylamine (0.11 mol) dissolved in 10 ml of MeOH. The temperature quickly raised during mixing. The solution was allowed to stand for 24 hours. The methanol was evaporated and the obtained liquid was distilled at 72° under 0.8 mm Hg.