Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C@@H:15]([CH2:18][CH2:19][C:20]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][C:23]=2[F:34])=[O:21])[C@@H:14]([C:35]([OH:37])=[O:36])[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[CH:38](N(CC)C(C)C)(C)C>ClCCl.CO>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C@@H:15]([CH2:18][CH2:19][C:20]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][C:23]=2[F:34])=[O:21])[C@@H:14]([C:35]([O:37][CH3:38])=[O:36])[CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: COc1ccc2ncc(F)c(C(=O)CC[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3C(=O)O)c2c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1CCC(=O)c1c(F)cnc2ccc(OC)cc12
Temperature: 20 °C
Reaction time: 1 h

Procedure:
1.58 cm3 of a thionyl chloride solution are added, at a temperature in the region of 20° C., under an argon atmosphere, to 3.33 g (7.23 mmol) of (3R,4R)-1-tertbutyloxycarbonyl-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-oxopropyl]piperidine-3-carboxylic acid in solution in 150 cm3 of dichloromethane. After stirring for 1 hour at a temperature in the region of 20° C., the reaction mixture is poured over a solution of 10.55 cm3 of N,N-diisopropylethylamine in 150 cm3 of methanol. After stirring for 16 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up with 150 cm3 of CH2Cl2, and washed with 3 times 50 cm3 of water and then 50 cm3 of a saturated aqueous sodium chloride solution. The organic phase is dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (2.7 kPa) to give 4 g of methyl (3R,4R)-1-tert-butyloxycarbonyl-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-oxopropyl]piperidine-3-carboxylate in the form of an orange oil.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:35][Si](C)(C)C.CCOCC>CC(CC)=O>[ClH:35].[CH3:34][N:2]([CH3:1])[C:3]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:4][CH2:5][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(=CC(=O)NCCCCCCc2c[nH]c3ccccc23)CC1
Solvent: CCOCC
Solvent: CCC(C)=O
Product: Cl

Procedure:
2-(4-Dimethylamino-4-phenylcyclohexylidene)-N-[6-(1H-indol-3-yl)hexyl]acetamide (78 mg, 0.17 mmol) was dissolved in ethyl methyl ketone (5 ml), and chlorotrimethylsilane (0.033 mol, 0.26 mmol) was added. After 1 h ether (10 ml) was added, and after 10 min the hydrochloride was isolated as a colourless solid with an m.p. of 160-164° C. in a yield of 87% (73 mg).
Reaction SMILES: [N:1]1([C:7](=[O:24])[CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:25]([O:29][C:30]([N:32]1[CH2:36][CH:35]([OH:37])[CH:34]([NH2:38])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>>[C:25]([O:29][C:30]([N:32]1[CH2:36][C:35](=[O:37])[CH:34]([NH:38][C:10](=[O:12])[CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[CH2:8][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:24])[CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CC(N)C(O)C1
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(=O)C(NC(=O)C(CC(=O)N2CCOCC2)CS(=O)(=O)Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid (120 mg, 0.34 mmol), 3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.74 mmol), prepared as in reference 13, EDC (0.3 g, 1.6 mmol), and HOBt (150 mg, 0.96 mmol) were combined. Dichloromethyl (10 mL) was added and then 4-methylmorpholine (0.5 mL). The mixture was stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (200 mL) the solution was washed with 1N aqueous HCl (50 mL), saturated aqueous NaHCO3 (50 mL) and brine (50 mL), dried with MgSO4 and evaporated under vacuum. The pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in DMSO (5 mL). Triethylamine (0.5 mL) and then SO3 pyridine complex (150 mg) were added and the mixture was stiffed at ambient temperature for 3 hours. After dilution with ethyl acetate (100 mL), the solution was washed with water (50 mL) and brine, dried with MgSO4 and evaporated under vacuum. The residue was purified by flash chromatography on silica gel. Eluent: 5% methanol in ethyl acetate. Yield: 40 mg 3-(4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyrylamino)-4-oxo-1-pyrrolidine-1-carboxylic acid tert-butyl ester as white solid as mixture of diastereomers; 1H NMR: (DMSO) 8.80–8.66 (m, 1H), 7.42–7.34 (m, 5H), 4.52–4.41 (m, 2H), 4.34–4.20 (m, 1H), 3.98–3.88 (m, 1H), 3.82 (d, J=18.5 Hz, 1H), 3.70–3.05 (m, 13H), 2.70–2.52 (m, 2H), 1.41 (s, 9H); MS: (M+H)+ 538.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:14](=O)[CH3:15].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH2:14][CH3:15])[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCNc1cc(Br)cc(C(=O)OC)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (1.0 g, 4.09 mmol) and acetaldehyde (180 mg, 4.09 mmol) in dichloroethane (10 mL), acetic acid (1.47 g, 24.58 mmol) was added and reaction stirred at room temperature for 30 minutes. Then sodium triacetoxyborohydride (2.6 g, 12.29 mmol) was added at 0° C., allowed to attain room temperature and stirring continued for 2 h. On completion, reaction mixture was diluted with dichloromethane, washed with water, saturated aqueous sodium bicarbonate solution and dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the desired compound (600 mg, 55%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10](CC=C)[C:9]=2[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:27][C:28]#[N:29].N1CCOCC1>CN(C=O)C.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>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:18])[N:7]([CH2:27][C:28]#[N:29])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Reactant: N#CCCl
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: [Cs+]
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CC#N)c(=O)c2[nH]c(Cl)nc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 26.1 %

Procedure:
To a mixture of 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (200 mg, 0.707 mmol) and Cs2CO3 (254 mg, 0.778 mmol) in anhydrous DMF (5 ml) was added chloroacetonitrile (0.054 ml, 0.85 mmol). The mixture was heated at 50° C. for 18 hours then allowed to cool to rt and degassed under a gentle vacuum then nitrogen introduced. This was repeated twice. Pd(PPh3)4 (82 mg, 0.071 mmol) was added and the mixture degassed once more, before morpholine (0.617 ml, 7.07 mmol) was added and the mixture left to stir for 3 hours at rt. The mixture was partitioned between 2M HCl(aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The residue was taken up in MeOH and passed down an amino-propyl SPE (5 g), eluting with MeOH followed by 5-10% AcOH/MeOH. The product fraction was concentrated giving the title compound 52 mg (26%); NMR; δH (400 MHz, d6-DMSO) 0.90 (t, 3H, J=7.5 Hz), 1.26-1.37 (m, 2H), 1.60-1.69 (m, 2H), 3.94 (t, 2H, J=7.5 Hz), 4.87 (s, 2H), 14.72 (br s, 1H); m/z 299.2 [MNH4+].
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)[C:9]([O:11]C)=O)[CH:5]=[N:4][CH:3]=[N:2]1.[C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH3:17].[Li]>>[C:20]([O:19][C:16](=[O:18])[CH2:17][C:9](=[O:11])[C:8]1[CH:13]=[CH:14][CH:15]=[C:6]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:7]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1cccc(-n2cncn2)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cncn2)c1

Procedure:
The title compound was prepared from methyl 3-[1,2,4]triazol-1-yl-benzoate [CAS-No. 167626-27-9] by treatment with lithium tert.-butyl acetate according to general procedure K (method b). Obtained as an orange liquid (2.41 g).
Reaction SMILES: C(NC1C=C(C=C(S(=O)(=O)N)C=1OC1C=CC=CC=1)C(N)=O)CCC.[CH2:26]([C:33]1[C:50]([S:51](=[O:54])(=[O:53])[NH2:52])=[CH:49][C:36]([C:37]([NH:39][CH2:40][CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=O)=[CH:35][C:34]=1[O:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([C:33]1[C:50]([S:51](=[O:54])(=[O:53])[NH2:52])=[CH:49][C:36]([CH2:37][NH:39][CH2:40][CH2:41][CH2:42][N:43]2[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]2)=[CH:35][C:34]=1[O:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCCOc1cc(C(=O)NCCCN2CCCCC2)cc(S(N)(=O)=O)c1Cc1ccccc1
Agent: CCCCNc1cc(C(N)=O)cc(S(N)(=O)=O)c1Oc1ccccc1
Product: CCCCOc1cc(CNCCCN2CCCCC2)cc(S(N)(=O)=O)c1Cc1ccccc1

Procedure:
By replacing in Example 289 3-n-butylamino-4-phenoxy-5-sulfamylbenzamide with an equimolar amount of 4-benzyl-3-n-butoxy-5-sulfamyl-N-(3'-piperidinopropyl)benzamide and following the procedure described, (4-benzyl-3-n-butoxy-5-sulfamylbenzyl)-3-piperidinopropylamine is obtained as a hemihydrate with a melting point of 98°-101° C.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:34])[CH:8]([O:31][CH2:32][CH3:33])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][CH:21]=2)[CH:11]=1)C>O.O1CCCC1>[CH2:32]([O:31][CH:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:24][CH:25]=2)[CH:11]=1)[C:7]([OH:34])=[O:6])[CH3:33]
Reactant: CCOC(=O)C(Cc1cccc(OCCCc2ccc(OS(C)(=O)=O)cc2)c1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(Cc1cccc(OCCCc2ccc(OS(C)(=O)=O)cc2)c1)C(=O)O
Yield: 109.3 %

Procedure:
Lithium hydroxide hydrate (91.1 mg; 2.7 mmole) in water (6.6 ml) was slowly added to a solution of 2-ethoxy-3-{3-[3-(4-methanesulfonyloxyphenyl)propoxy]phenyl}propanoic acid ethyl ester (described in Example 12d) (0.889 g; 1.97 mmole) in tetrahydrofuran (9 ml). After stirring at room temperature for 5 hours tetrahydrofuran was removed by evaporation in vacuo. The residue was washed with diethyl ether and ethyl acetate. The water phase was acidified with potassium hydrogen sulfate (1M), and extracted with ethyl acetate and dichloromethane. The organic phases were combined, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo to give 0.91 g of 2-ethoxy-3-[3-(3-{4-methanesulfonyloxyphenyl}propoxy)phenyl]propanoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]2[CH:19]=1)=[O:5])[CH3:2].[N+:20]([O-])([OH:22])=[O:21].[OH-].[Na+]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]2[C:19]=1[N+:20]([O-:22])=[O:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2cccc(C(=O)OCC)c2n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1nc2c(C(=O)OCC)cccn2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
Ethyl 2-ethoxycarbonylimidazo[1,2-a]pyridine-8-carboxylate (3.8 g, 14.5 m mol) was dissolved in conc. sulfuric acid (10 ml), and to the solution was slowly added 70% nitric acid (1.5 ml) at 10° C. The mixture was stirred at room temperature for 30 minutes, poured into ice water and adjusted to pH 7 by adding 20% sodium hydroxide. The precipitated crystals were filtered to obtain ethyl 2-ethoxycarbonyl-3-nitro-imidazo[1,2-a]pyridine-8-carboxylate (2.4 g, yield 53.8%) as crystals of m.p. 139°-140° C. A solution of the crystals in conc. hydrochloric acid (35 ml) was refluxed for 1.5 hours and cooled to room temperature. The precipitated crystals were collected by filtration and dried to give the object compound (1.2 g, yield 74.3%) of m.p.>300° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:27])[N:4]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:25])([CH3:24])[CH3:23])[N:17]=3)[CH:13]=[CH:12][C:11]=2[CH3:26])[C:5]([CH3:9])=[N:6][C:7]=1[OH:8].Cl[CH2:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:27])[N:4]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:25])([CH3:23])[CH3:24])[N:17]=3)[CH:13]=[CH:12][C:11]=2[CH3:26])[C:5]([CH3:9])=[N:6][C:7]=1[O:8][CH2:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38]
Reactant: Cc1ccc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)nc(O)c(Cl)c1=O
Reactant: Cc1cc(CCl)c(F)cc1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(COc2nc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ccc3C)c(=O)c2Cl)c(F)cc1F
Temperature: 60 °C
Yield: 39 %

Procedure:
To a solution of Intermediate 1 (50 mg, 0.13 mmol) in N,N-dimethylformamide (1.5 mL) was added 1-chloromethyl-2,4-difluoro-5-methyl-benzene from Step C (23 mg, 0.13 mmol), potassium carbonate (36 mg, 0.26 mmol) and 18-crown-6 (3 mg). The slurry was heated at 60° C. for five hours. After cooling to room temperature the reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a colorless oil. (27 mg, 39% yield). MS (M+H): 527; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.65 (s, 6H), 2.17 (s, 3H), 2.21 (s, 3H), 2.28 (s, 3H), 5.47-5.56 (m, 2H), 6.80-6.84 (m, 1H) 7.34-7.38 (m, 1H), 7.55-7.59 (m, 2H), 7.93 (s, 1H), 8.14 (d, J=7.05 Hz, 1H), 8.78 (d, J=5.09, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[S:24](N)([NH2:27])(=[O:26])=[O:25]>O1CCOCC1>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][N:13]([S:24]([NH2:27])(=[O:26])=[O:25])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(S(N)(=O)=O)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 61.5 %

Procedure:
To a solution of COMPOUND 249 (0.1882 g, 0.61 mmol) in 1,4-dioxane (25 mL) was added sulfamide (0.5826 g, 6.06 mmol), and stirred at 100° C. for 4 hours. The mixture was concentrated and water (20 mL) was added and extracted with CH2Cl2 (2×75 mL). The combined organic extracts were washed with water (2×30 mL), dried (Na2SO4), filtered and concentrated. Purification of the crude material by column chromatography on silica gel (33:1:1 CH2Cl2-MeOH—NH4OH) provided 0.1461 g (59%) of COMPOUND 342 as a white solid. 1H NMR (CDCl3) δ 1.80-1.88 (m, 2H), 1.95-2.00 (m, 2H), 2.08 (s, 6H), 2.48-2.58 (m, 3H), 3.76-3.82 (m, 6H), 4.76 (s, 2H), 7.06-7.11 (m, 2H), 7.37 (d, 2H, J=7.2 Hz), 8.33 (d, 2H, J=3.0 Hz). 13C NMR (CDCl3) δ 21.23, 30.29, 50.70, 58.21, 61.67. ES-MS m/z 390.4 (M+H). Anal. Calcd. for C19H27N5O2S.0.2(CH2Cl2): C, 56.73; H, 6.79; N, 17.23. Found: C, 56.44; H, 7.06; N, 17.08.
Reaction SMILES: C(O[C:6]([N:8]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][CH:10]=O)=[O:7])(C)(C)C.Cl.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C@@H:31]([NH2:36])CC(O)=O)=[CH:22]1.C([BH3-])#N.[Na+]>CO.C1COCC1.C(OCC)(=O)C>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C@H:31]2[NH:36][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]2=[O:7])=[CH:22]1
Reactant: N[C@@H](CC(=O)O)Cc1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)N(CC=O)CCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1[C@@H](Cc2c[nH]c3ccccc23)NCCN1CCc1ccccc1

Procedure:
Combine N-t-butoxycarbonyl-N-(2-oxo-ethyl)-2-phenyl-ethylamine (5.03 g, 19.0 mmol) and (R)-2-(1H-indol-3-yl)-1-carboxymethyl-ethylamine hydrochloride salt ((R)-tryptophan methyl ester hydrochloride salt) (4.9 g, 19.42 mmol) in methanol (50 mL) and stir for 30 minutes. Add sodium cyanoborohydride in solution (15.0 mL, 1M in THF, 15.0 mmol) and stir under an inert atmosphere for 16.5 hours. Concentrate in vacuo to obtain a residue. Dilute the residue with ethyl acetate and extract with water. Separate the layers, dry the organic layer over MgSO4, filter, and evaporate in vacuo. Chromatograph on silica gel eluting with 50% ethyl acetate/hexane to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([NH:12][CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C)=[O:11])[CH:5]=1)([O-:3])=[O:2].FC(F)(F)C(O)=O.C(Cl)[Cl:31]>>[ClH:31].[NH2:15][CH2:14][CH2:13][NH:12][C:10]([C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][N:7]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1cc([N+](=O)[O-])ccn1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NCCNC(=O)c1cc([N+](=O)[O-])ccn1

Procedure:
7.0 g of t-butyl [2-(4-nitropyridine-2-carboxamido)ethyl]carbamate were stirred at room temperature with 9 ml of methylene chloride and 9 ml of trifluoroacetic acid. Thereafter, the reaction mixture was concentrated under reduced pressure. The residue was converted with hydrogen chloride in ethanol into the hydrochloride and this was recrystallized from ethanol/ether. There was obtained N-(2-aminoethyl)-4-nitropyridine-2-carboxamide hydrochloride as white crystals, m.p. 193°-194°.
Reaction SMILES: [Se:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH:20]([Si:23]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])Cl)([CH3:22])[CH3:21].O>CN(C1C=CN=CC=1)C.ClCCl>[CH:20]([Si:23]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[O:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]2[Se:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][CH:8]=1)([CH3:22])[CH3:21]
Reactant: Oc1ccc(-c2ccc[se]2)cc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)[Si](Oc1ccc(-c2ccc[se]2)cc1)(C(C)C)C(C)C

Procedure:
8.0 g (35.9 mmol) of 4-selenophen-2-ylphenol are initially introduced together with 50 ml (0.36 mol) of triethylamine and 0.44 g (3.6 mmol) of DMAP in 100 ml of dichloromethane, and 20 ml (93.5 mmol) of triisopropylchlorosilane are added. When the addition is complete, the mixture is warmed under reflux for 3 h. After cooling, the reaction mixture is added to water, and the organic phase is separated off. The aqueous phase is extracted with dichloromethane, and the combined organic phase is washed with sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:MTBE=4:1). Further purification is carried out by further column chromatography (SiO2, n-heptane:toluene=4:1); triisopropyl-(4-selenophen-2-ylphenoxy)silane is obtained as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]([CH3:27])([C:20]([O:22]C(C)(C)C)=[O:21])[CH3:19])=[O:16])=[CH:10][CH:9]=2)[C:6](=[O:28])[CH:5]=[CH:4][C:3]=1[C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[F:37].C(O)(C(F)(F)F)=O.CCOCC>C(Cl)Cl>[NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]([CH3:19])([C:20]([OH:22])=[O:21])[CH3:27])=[O:16])=[CH:10][CH:9]=2)[C:6](=[O:28])[CH:5]=[CH:4][C:3]=1[C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[F:37]
Reactant: CC(C)(C)OC(=O)C(C)(C)NC(=O)Cc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(NC(=O)Cc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.2 %

Procedure:
To a solution of Intermediate 16 (0.05 g, 0.095 mmol) in DCM (2 ml) was added TFA (1 ml). The reaction mixture was stirred at RT for 5 hours and then concentrated under reduced pressure to leave a yellow oil. Trituration with Et2O afforded the title compound as an off-white solid (42 mg, 94%).
Reaction SMILES: [CH:1](O)=[O:2].[N+:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])#[C-:5].CC(C)([O-])C.[K+]>C1COCC1>[O:2]1[CH:1]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[N:4]=[CH:5]1
Reactant: [C-]#[N+]CC(=O)OC
Reactant: O=CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cocn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37 %

Procedure:
To a suspension of 1,1-carbonyldimidazole (90 g, 0.555 mol) in 400 ml of THF at 0° C. was added dropwise formic acid 25.5 g (0.555 mol) in 100 ml of THF over a 15 min period. The mixture was warmed to room temperature and stirred for 1.5 h. The resulting solution was added via canula to the anion of methyl isocyanoacetate (generated by addition of the methyl isocyanoacetate in 75 ml of THF to a suspension of potassium t-butoxide at 0° C. and stirring for 15 min) at 0° C. During the addition (exothermic), the reaction mixture reached to 20° C. and the ice-bath was removed, stirring the mixture at room temperature for 1 h. The above mixture was quenched with 100 ml of acetic acid followed by 200 ml of water, THF was removed in vacuo, and 1000 ml of chloroform was added to the residual mixture. The organic layer was washed with water (2×200 ml), saturated sodium bicarbonate solution (1×100 ml), water, brine, and dried over sodium sulfate and concentrated in vacuo. The resulting residue was chromatographed on silica (methylene chloride/hexane/ether 7:2:1) to afford 23.5 g (37%) of methyl 4-oxazolecarboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[N:9]=[CH:10][C:3]=12.O1CCOCC1.[ClH:30]>>[Cl-:30].[Cl-:30].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:11]3[CH2:16][CH2:15][NH2+:14][CH2:13][CH2:12]3)[NH+:9]=[CH:10][C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(N)ncnc32)CC1
Reactant: Cl
Solvent: C1COCCO1
Product: Nc1ncnc2c1c[nH+]n2C1CC[NH2+]CC1
Product: [Cl-]
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (4A-2; 1.30 g, 4.08 mmol) in 4M HCl dioxane (12 mL) was stirred for 1 hr. The reaction was concentrated, triturated with ether to give 4-amino-1-piperidinium-4-yl-1H-pyrazolo[3,4-d]pyrimidin-2-ium dichloride. For free base: dissolved the above salt in H2O and passed through Dowex 1X2-400, ion-exchange resin (—OH form). The resin was washed with H2O then MeOH. The filtrate was concentrated and dried in vacuo to give pure free base. 1H-NMR (500 MHz, d6 DMSO) δ 8.14 (s, 1H), 8.07 (s, 1H), 7.64 (bs, 2H), 4.57-4.67 (m, 1H), 3.05 (d, J=12.46 2H), 2.55-2.67 (m, 2H), 2.06 (bs, 1H), 1.90-2.12 (m, 2H), 1.73-1.80 (m, 2H). LRMS m/z (M+H) Calcd: 219.1, found: 219.1.