Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][CH:3]1[O:7][C:6]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:5][CH2:4]1.[CH2:22]([C:25]1[C:35]([OH:36])=[C:34]([C:37](=[O:39])[CH3:38])[CH:33]=[CH:32][C:26]=1[O:27][CH2:28][CH2:29][CH2:30]Br)[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:37]([C:34]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH2:29][CH2:30][S:1][CH2:2][CH:3]2[O:7][C:6]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:5][CH2:4]2)=[C:25]([CH2:22][CH2:23][CH3:24])[C:35]=1[OH:36])(=[O:39])[CH3:38]
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)OC(CS)CS1
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCSCC2CSC(CCC(=O)OCC)(CCC(=O)OCC)O2)ccc(C(C)=O)c1O

Procedure:
The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 64 (1.0 g, 0.003 mol), 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1-bromopropane (described in U.S. Pat. No. 4,565,882, Example 14) (1.1 g, 0.0033 mol) and anhydrous potassium carbonate (1.6 g) in methyl ethyl ketone (15 ml). The crude product was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to give 1.54 g (90%) of the product as an oil.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])[C:6]=2[CH:16]=1.[CH:17]([Sn](CCCC)(CCCC)CCCC)=[CH2:18]>CN1CCCC1=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>[CH:17]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])[C:6]=2[CH:16]=1)=[CH2:18]
Reactant: CC(=O)NCCc1coc2ccc(I)cc12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: C=Cc1ccc2occ(CCNC(C)=O)c2c1

Procedure:
15 mmol of the product obtained in Step B, 16 mmol of vinyltributyltin and 0.43 mmol of tetrakis(triphenylphosphine)palladium are heated for 3 hours at 110° C., with stirring, in 30 ml of N-methylpyrrolidinone. After removal of the solvent by evaporation, the residue is taken up in 20 ml of dichloromethane and treated with an aqueous 10% potassium fluoride solution. Extraction, concentration under reduced pressure and chromatography on silica gel yield the pure title product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]2[CH2:16][O:15]2)=[CH:4][CH:3]=1.[C:17]1([CH2:23][CH2:24][OH:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[CH2:16][O:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C1CO1
Reactant: OCCc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)COCCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 14, Step 4, using 5-(4-bromo-phenyl)-3-methyl-4-oxiranyl-isoxazole and 2-phenyl-ethanol.
Reaction SMILES: [Cl:1][C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][N:24]=2)[CH2:19][CH2:18]1>C(Cl)(Cl)Cl>[ClH:1].[CH3:16][N:17]1[CH2:18][CH2:19][CH:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3])[N:24]=2)[CH2:21][CH2:22]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CN1CCC(c2nn(C(=O)OCC(Cl)(Cl)Cl)c3ccccc23)CC1
Product: Cl
Yield: 93.6 %

Procedure:
A mixture of 2.3 g of trichloroethyl chloroformate, 3.0 g of potassium carbonate, 2.1 g of 3-(1-methyl-4-piperidinyl)-1H-indazole and chloroform was heated under reflux for 16 hrs. The reaction mixture was cooled, filtered, and the filtrate was concentrated to a solid in vacuo. The solid was triturated with ethyl acetate, collected, and recrystallized from ethanol to yield 3.9 g (91%) of product, mp 190°-192° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:30][C:31]([CH3:36])=[C:32]([CH2:34]I)[N:33]=2)=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[O:30][C:31]([CH3:36])=[C:32]([CH2:34][O:1][CH:2]3[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=4[C:12]([OH:14])=[O:13])[CH2:3]3)[N:33]=2)=[CH:27][CH:28]=1
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Reactant: COc1ccc(-c2nc(CI)c(C)o2)cc1
Product: COc1ccc(-c2nc(COC3CCCC(OCc4cccc(C)c4C(=O)O)C3)c(C)o2)cc1

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-(4-methoxyphenyl)-4-iodomethyl-5-methyloxazole as starting materials in the procedure of Example XXXI, gave the product 71 of molecular weight 465.55 (C27H31NO6), MS(ESI): 466.37 (M+H+).
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH2:6]([O:13][C:14](Cl)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:17][C@H:18]([C@@H:39]1[CH2:43][C@@H:42]([CH:44]([CH3:46])[CH3:45])[C:41](=[O:47])[O:40]1)[CH2:19][N:20]1[C:25]([CH3:27])([CH3:26])[CH2:24][N:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][O:36][CH3:37])[C:22](=[O:38])[CH2:21]1.C(OCC)(=O)C>[Cl-].[Na+].O.O>[CH2:6]([O:13][C:14](=[O:15])[NH:17][C@H:18]([C@@H:39]1[CH2:43][C@@H:42]([CH:44]([CH3:45])[CH3:46])[C:41](=[O:47])[O:40]1)[CH2:19][N:20]1[CH2:21][C:22](=[O:38])[N:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][O:36][CH3:37])[CH2:24][C:25]1([CH3:27])[CH3:26])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COCOc1ccccc1N1CC(C)(C)N(C[C@H](N)[C@@H]2C[C@@H](C(C)C)C(=O)O2)CC1=O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COCOc1ccccc1N1CC(C)(C)N(C[C@H](NC(=O)OCc2ccccc2)[C@@H]2C[C@@H](C(C)C)C(=O)O2)CC1=O
Reaction time: 2 h
Yield: 96.1 %

Procedure:
206 mg of cesium carbonate (0.63 mmol) was added to a solution of 326 mg of N-{(S)-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]-2-[4-(2-methoxymethoxyphenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]ethyl}-2-nitrobenzenesulfonamide obtained in the above reaction (0.53 mmol) and 0.12 ml of thiophenol (content: 95%) (1.1 mmol) in N,N-dimethylformamide (5 ml) under a nitrogen atmosphere at room temperature, and the mixture was stirred at the same temperature for two hours. Brine was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1-10/1). 49 mg of sodium bicarbonate (0.57 mmol) and 78 μl of benzyloxycarbonyl chloride (0.53 mmol) were added to a solution of 209 mg of 4-{(S)-2-amino-2-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}1-(2-methoxymethoxyphenyl)-5,5-dimethylpiperazin-2-one obtained above (0.48 mmol) in a mixed solvent of ethyl acetate (3 ml) and water (3 ml) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Brine was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1) to obtain 263 mg of {(S)-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]-2-[4-(2-methoxymethoxyphenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]ethyl}carbamic acid benzyl ester (yield: 87%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH3:25][NH:26][C:27](=[O:43])[C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:31]3[CH:32]=[CH:33][C:28]([C:27]([NH:26][CH3:25])=[O:43])=[CH:29][CH:30]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCC3)nc(Cl)nc21
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CCC4)c23)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 65.7 %

Procedure:
To a degassed mixture of 2-chloro-4-cyclobutoxy-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (1.1 equiv) and tripotassium phosphate trihydrorate (3.0 equiv) in a 9:1 mixture of 1,4-dioxane and water (0.125 M) was added palladium 1,1-bis(diphenylphosphion)ferrocene dicholoride (0.1 equiv). The reaction mixture was stirred at 80° C. for 4 h. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (1% MeOH in DCM) to afford the desired product (65.7% yield) as a yellow solid. MS (ESI) m/z 487.2 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[H-].[Na+].[CH2:30](I)[CH3:31]>CN(C)C=O>[CH2:30]([N:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1)[CH3:31]
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)n1
Yield: 63.9 %

Procedure:
In the manner of Example 25, employing [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.27 g), dimethylformamide (25 ml), and ethyl iodide (0.87 g), the title compound (0.69 g) was obtained as a crystalline solid, m.p. 180-183° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(=C)[C:14]#[N:15].O.[CH3:18][C:19](C)([O-])C.[K+]>O1CCCC1>[CH2:1]([N:8]1[CH2:19][CH2:18][O:11][CH:10]([C:14]#[N:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(Cl)C#N
Reactant: CC(C)(C)[O-]
Reactant: OCCNCc1ccccc1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC1CN(Cc2ccccc2)CCO1
Temperature: -5 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A one-litre reactor with mechanical stirring, cooled by an ice bath, is charged with N-benzylethanolamine (172.2 g; 1 equiv. available from Aldrich Chemical Company). 2-Chloroacrylonitrile (100 g; 1 equiv. available from Aldrich Chemical Company) is added dropwise over 2 minutes. The temperature is maintained between 23° C. and 29° C. by means of the ice bath and subsequently a water bath at 15° C. After one night stirring at room temperature (water bath), the mixture is dissolved in tetrahydrofuran and transferred to a 2 L reactor which is cooled to −5° C. by ice/NaCl bath. The total volume of tetrahydrofuran is 1.35 L. Potassium tert-butoxide (148 g; 1.1 equiv.) is added by portions over 1 hour, keeping the reaction temperature at 0±2° C. After 1 hour post-stirring at 0° C., the mixture is quenched with saturated NaHCO3 (500 mL). The aqueous layer is extracted with diethyl ether (500 mL). Organic layers are dried over MgSO4 and evaporated to dryness. The title compound (149.8 g; 65%) is obtained after percolation of the 250 g dry residue on 1 kg of SiO2, eluting with the following gradient:
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17](CC3C=CC=CC=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)O.[ClH:28]>[Pd].C(OCC)(=O)C.CO>[ClH:28].[ClH:28].[CH3:27][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: CN(C)CCCC(O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)CCCCc1ccc(N2CCNCC2)cc1

Procedure:
Prepared analogously to example A20b) from 4-[4-[4-(dimethylamino)-1-hydroxybutyl]phenyl]-1-(phenylmethyl)piperazine by catalytic hydrogenation in the presence of palladium/charcoal and hydrochloric acid in a quantitative yield. Colourless, amorphous substance of Rf=0.37 (eluant:ethyl acetate/methanol 50/50/0.5 v/v/v).
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH:9]=[CH:10][C:11]3[C:16]([C:7]2=[N:6][C:5]=1[CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])(O)=[O:2].S(Cl)([Cl:21])=O>>[ClH:17].[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[CH:9][N:8]1[C:4]([C:1]([Cl:21])=[O:2])=[C:5]([CH3:18])[N:6]=[C:7]12
Reactant: O=S(Cl)Cl
Reactant: Cc1nc2c3cccc(Cl)c3ccn2c1C(=O)O
Product: Cc1nc2c3cccc(Cl)c3ccn2c1C(=O)Cl
Product: Cl

Procedure:
A mixture of 3-carboxy-7-chloro-2-methylimidazo[2,1-a]isoquinoline (2.5 g) and thionyl chloride (20 ml) was refluxed for 1 hour and evaporated in vacuo. The residual solid was washed with benzene and dried in a desiccator to give 7-chloro-3-chloroformyl-2-methylimidazo[2,1-a]isoquinoline hydrochloride (2.75 g).
Reaction SMILES: NCCCN1CCN(CCCNC2NC3C=CC=CC=3N=2)CC1.C([N:28]([CH2:56][CH:57]([CH3:59])[CH3:58])[CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][NH:41][C:42]([NH:44][C:45]2[CH:50]=[CH:49][C:48](OC)=[CH:47][C:46]=2[N+:53]([O-])=O)=S)[CH2:34][CH2:33]1)C(C)C.C(Cl)Cl.C(N(CC)CC)C.[BH4-].[Na+]>O>[NH:44]1[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[N:53]=[C:42]1[NH:41][CH2:40][CH2:39][CH2:38][N:35]1[CH2:36][CH2:37][N:32]([CH2:31][CH2:30][CH2:29][NH:28][CH2:56][CH:57]([CH3:59])[CH3:58])[CH2:33][CH2:34]1
Reactant: COc1ccc(NC(=S)NCCCN2CCN(CCCN(CC(C)C)CC(C)C)CC2)c([N+](=O)[O-])c1
Agent: NCCCN1CCN(CCCNc2nc3ccccc3[nH]2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)CNCCCN1CCN(CCCNc2nc3ccccc3[nH]2)CC1
Reaction time: 3 h

Procedure:
To a solution of [3-[4-(3-Amino-propyl)-piperazin-1-yl]-propyl]-(1H-benzimidazol-2-yl)-amine (Intermediate of example 44) (130 mg, 0.41 mmol) in CH2Cl2 (4 mL) isobutyraldehyde (62 μL, 0.46 mmol), triethylamine (26 μL, 0.16 mmol) and 3 Å molecular sieves are added. The reaction media is stirred for 3 h and cooled before NaBH4 (78 mg, 2.05 mmol) is added portionwise over 30 min. Stirring is left for 1.5 h, water (10 mL) is added and the media is filtered. Compound is extracted with CH2Cl2 (3×20 mL). Combined organic layers are dried over MgSO4. Crude compound is purified by thick-layer chromatography (CH2Cl2/MeOH/NH4OH: 90/10/1.2).
Reaction SMILES: C([O:8][CH2:9][C:10]1([O:23][CH3:24])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[OH:8][CH2:9][C:10]1([O:23][CH3:24])[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]1
Reactant: [H][H]
Reactant: COC1(COCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Yield: 78.5 %

Procedure:
20% palladium hydroxide on carbon (270 mg) was suspended in a MeOH (81 ml) solution of tert-butyl 4-[(benzyloxy)methyl]-4-methoxypiperidine-1-carboxylate (2.7 g), and stirred under a flow of hydrogen gas at room temperature for 4 hours. After filtering using Celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (EtOAc) to obtain tert-butyl 4-(hydroxymethyl)-4-methoxypiperidine-1-carboxylate (1.55 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:24][C:25]3[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=3)[NH2:28])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:24][C:25]3[CH:26]=[C:27]([NH:28][S:39]([CH3:38])(=[O:41])=[O:40])[CH:29]=[CH:30][CH:31]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cccc(C[C@@H]2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(C[C@@H]2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-3-{[2-(4,5-diphenyloxazol-2-yl)-1-cyclohexyl]methyl}aniline (70 mg) in dichloromethane (10 ml) were added pyridine (1 ml) and MsCl (0.032 ml). After stirred for 2 hours at the room temperature, the mixture was partitioned between ethyl acetate and water and the organic layer was washed with 1N-HCl, sat. NaHCO3, and brine. The dried solvent was evaporated in vacuo and the obtained solid was washed with ether to afford (S)-N-{3-{[2-(4,5-diphenyloxazol-2-yl)-1-cyclohexyl]methyl}phenyl}-methanesulfonamide (0.05 g).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[C:18](OC(=O)C)(=[O:20])[CH3:19]>CN(C)C=O>[C:18]([NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:1]2[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]2[OH:3])[C:11](=[O:12])[N:13]=1)(=[O:20])[CH3:19]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cytidine (1) (7.3 g, 30 mmoles) was suspended in anhydrous N,N-dimethylformamide (120 ml) and to it was added acetic anhydride (3.12 ml, 33 mmoles). The mixture was stirred at room temperature overnight. After removal of the DMF under reduced pressure, the resulting residue was triturated with excess of diethylether (~30 ml) and the crystalline product obtained collected by filtration, washed thoroughly with diethylether and air dried to get a quantitative yield of 2. A small portion was crystallized from ethanol/water mixture (1:1) to obtain crystals for analytical purposes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.C[CH:15]1[C:24]2[C:19](=[C:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:15]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c(-c3ccccn3)cccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2c(cccc2-c2ccccn2)C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-pyridin-2-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[N:4]([C:14](=[O:24])[CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.O>CCO.[Fe]>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:25])([CH3:1])[CH2:3][N:4]2[C:14](=[O:24])[CH2:15][NH:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CC(C)(C)c2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)N1CC(C)(C)c2ccc(N)cc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1-(3,3-Dimethyl-6-nitro-2,3-dihydro-indol-1-yl)-2-(N-Boc-amino)-ethanone (3.9 g) was dissolved in EtOH (30 ml) and Fe powder (3.1 g) NH4Cl (299 mg) and H2O (5 ml) were added. The reaction was stirred at 80° C. overnight. The reaction was filtered through Celite® and evaporated off the MeOH. The residue was partitioned between CH2Cl2 and sat'd NaHCO2. The organic layer was removed, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 25% EtOAc/hexane). The purified fractions were concentrated in vacuo to afford the compound as a white powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9][CH:10]=[CH2:11])[CH:3]=1.[NH2:20][NH2:21].[Al]>C(O)C>[NH:20]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9][CH:10]=[CH2:11])[CH:3]=1)[NH2:21]
Reactant: NN
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(Cl)ccn1
Agent: [Al]
Solvent: CCO
Product: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(NN)ccn1
Reaction time: 18 h
Yield: 85.7 %

Procedure:
A vial with a Teflon septum cap was charged with a solution of 1C (2 g, 7.0 mmol) and hydrazine (35% in water) (10 mL, 111 mmol, 15.75 equiv) in ethanol (10 mL). The solution was heated by an aluminum block set to 115° C. for 18 hours. The reaction was concentrated to give a pink oil. Purification by normal phase silica gel chromatography yielded 222A (1.67 g, 85%) as a yellow, foaming solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (d, J=5.7 Hz, 1H), 6.60 (s, 1H), 6.57 (dd, J=5.5, 2.4 Hz, 1H), 5.79-5.54 (m, 3H), 5.14-4.99 (m, 2H), 4.74-4.62 (m, 1H), 2.59 (t, J=6.7 Hz, 2H), 1.52-1.40 (m, 9H). MS (ESI) m/z: 279.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9](Cl)[N:8]=1)[CH3:2].C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>CC#N>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9]([NH:30][CH2:29][C:28]2[CH:31]=[CH:32][C:33]([O:35][CH3:36])=[CH:34][C:27]=2[O:26][CH3:25])[N:8]=1)[CH3:2]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CCOC(=O)COc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)COc1nc(NCc2ccc(OC)cc2OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
To a cooled (˜10° C.) solution of (6-chloro-3-nitro-pyridin-2-yloxy)-acetic acid ethyl ester (8.0 g, 30.8 mmol) in MeCN (80 mL) was added a solution of triethylamine (6.4 mL, 46 mmol) and 2,4-dimethoxybenzylamine (5.5 mL, 37 mmol). The mixture was then stirred for 16 hours at ambient temperature and then concentrated in vacuo. The residue was partitioned between EtOAc and aqueous potassium hydrogenphosphate solution. The EtOAc layer was then washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified using SiO2 chromatography (10-50% EtOAc/Petrol) to give [6-(2,4-dimethoxy-benzylamino)-3-nitro-pyridin-2-yloxy]acetic acid ethyl ester (9.53 g) as a yellow solid. MS: [M+H]+ 392
Reaction SMILES: [Br:1][C:2]1[CH:23]=[C:22]([O:24][CH3:25])[C:5]2[N:6]([CH2:18][CH2:19][O:20][CH3:21])[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[Br:26]Br.CCOC(C)=O>C(O)(=O)C>[Br:26][C:3]1[C:4]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=3)[N:6]([CH2:18][CH2:19][O:20][CH3:21])[C:5]=2[C:22]([O:24][CH3:25])=[CH:23][C:2]=1[Br:1]
Reactant: BrBr
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Br)cc(OC)c21
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(Br)cc(OC)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.2 %

Procedure:
To a solution of 403 mg (1.0 mmol) 5-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole in 8 ml glacial acetic acid, 240 mg (1.5 mmol) bromine is slowly added at 10° C. The reaction mixture is allowed to warm to room temperature and is stirred for 3 h. 250 ml EtOAc are added and this solution is washed 1 n NaOH (2×), water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is recrystallized from EtOAc/hexane to afford 30 mg of the title compound as colorless crystals.