Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[C:15]([CH3:16])=[N:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@@H:19]1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:7]([C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N:11]2[C:15]([CH3:16])=[N:14][CH:13]=[N:12]2)=[O:9])[C@@H:19]1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][N:27]=1
Reactant: Cc1ccc(-n2ncnc2C)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1ccc(C(F)(F)F)cn1
Product: Cc1ccc(-n2ncnc2C)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using 5-methyl-2-(5-methyl-1H-1,2,4-triazol-1-yl)benzoic acid and N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 473 [M+1]+.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([OH:7])[CH3:6])([O-:3])=[O:2].C=O.Cl.ClC[O:13]CCl.[S:16]1[CH:20]=[CH:19]C=[C:17]1CC(O)=O>>[N+:1]([CH2:4][CH:5]([O:7][CH2:17][S:16][C:20](=[O:13])[CH3:19])[CH3:6])([O-:3])=[O:2]
Reactant: CC(O)C[N+](=O)[O-]
Reactant: O=C(O)Cc1cccs1
Reactant: ClCOCCl
Agent: C=O
Agent: Cl
Product: CC(=O)SCOC(C)C[N+](=O)[O-]

Procedure:
A quantity of 206 grams of 1-nitro-2-propanol was chloromethylated with 60 grams paraformaldehyde and excess hydrogen chloride according to the procedure given in Example I. The crude chloromethylether resulting was reacted with 154 grams of thiolacetic acid and then 154 grams of pyridine and distilled in vacuo after workup as described in Example I to give 123 grams of 1-nitro-2-acetylthiomethyloxy propane; structure confirmed by spectral analysis.
Reaction SMILES: [C:1]([C:4]1[C:5](=O)[C:6]2[NH:12][N:11]=[CH:10][C:7]=2[NH:8][CH:9]=1)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:16])=O>>[C:1]([C:4]1[C:5]([Cl:16])=[C:6]2[NH:12][N:11]=[CH:10][C:7]2=[N:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)c1c[nH]c2cn[nH]c2c1=O
Product: CC(=O)c1cnc2cn[nH]c2c1Cl
Temperature: 80 °C

Procedure:
A mixture of 6-acetyl-4,7-dihydro-7-oxo-1H-pyrazolo-[4,3-b]pyridine (D14, 1.6 g, 9 mmol) and phosphorus oxychloride (15 ml) was heated at 80° C. for 30 min. Excess reagent was removed in vacuo, water was added and the mixture was adjusted to pH 9 with 10% sodium carbonate solution. The resulting mixture was extracted with ethyl acetate (4×50 ml), and the extracts were washed with brine, dried (MgSO4) and evaporated in vacuo to leave the title compound as a yellow solid, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:24])OCC2C=CC=CC=2)[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:25]1([NH2:35])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)CCC1.[CH2:36]([N:39]([CH2:53][CH2:54][CH3:55])[C:40]([C:42]1[CH:43]=[C:44]([CH:48]=[C:49]([CH2:51]C)[CH:50]=1)C(O)=O)=[O:41])[CH2:37][CH3:38]>>[F:8][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([F:1])[CH:7]=1)[CH2:9][C@H:10]([NH:14][C:15](=[O:24])[C:44]1[CH:48]=[C:49]([CH3:51])[CH:50]=[C:42]([C:40]([N:39]([CH2:36][CH2:37][CH3:38])[CH2:53][CH2:54][CH3:55])=[O:41])[CH:43]=1)[C@H:11]([OH:12])[CH2:13][NH:35][CH2:25][C:34]1[CH:29]=[CH:30][CH:31]=[C:32]([O:41][CH2:40][CH:42]([CH3:43])[CH3:50])[CH:33]=1
Reactant: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)O)c1
Reactant: O=C(N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1)OCc1ccccc1
Reactant: NC1CCCc2ccccc21
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(OCC(C)C)c2)c1

Procedure:
Following the general procedure of EXAMPLEs 4, 5 and 6 and making non-critical variations but using tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V), H2N—CH2-phenyl-O-i-butyl (VI) and “5-Me-PHTH” (IX), the title compound is obtained, MH+=624.
Reaction SMILES: [BrH:1].[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[BrH:2].[Br-:1].[NH2:6][CH2:5][CH2:4][CH2:3][N+:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1ccncc1
Reactant: NCCCBr
Agent: Br
Solvent: CCO
Product: NCCC[n+]1ccccc1
Product: [Br-]
Yield: 76.5 %

Procedure:
A solution of 16.5 g of 3-bromopropanamine hydrobromide and 6.0 ml (5.9 g) of pyridine in 75 ml of ethanol was heated under reflux for 18 hours. The cooled reaction was filtered and the solid was washed with ethanol to give 17.0 g (76%) of 1-(3-aminopropyl)pyridinium bromide hydrobromide as colorless crystals, mp 178°-179°. The analytical sample was obtained by recrystallization from methanol and had mp. 176°-179° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33][CH2:34]O)=[C:29]([C:36]5[NH:37][C:38]6[C:43]([C:44]=5[CH3:45])=[CH:42][CH:41]=[CH:40][CH:39]=6)[N:28]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:23])=[O:24])[C:18]([C:27]4[CH:32]=[CH:31][C:30]5[CH2:33][CH2:34][N:37]6[C:38]7[CH:39]=[CH:40][CH:41]=[CH:42][C:43]=7[C:44]([CH3:45])=[C:36]6[C:29]=5[N:28]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(CCO)c(-c4[nH]c5ccccc5c4C)n3)cc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3c(C)c5ccccc5n3CC4)cc12

Procedure:
To a mixture of 2-(4-fluorophenyl)-5-(5-(2-hydroxyethyl)-6-(3-methyl-1H-indol-2-yl)pyridin-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (43 mg, 0.069 mmol) and triphenylphosphine (90 mg, 0.343 mmol) in THF (4 mL) was diisopropyl azodicarboxylate (0.067 mL, 0.343 mmol). The resultant mixture was stirred at ambient temperature for 16 h, diluted with EtOAc and washed successively with H2O (2×) and brine (1×). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a step gradient of 0-40-90% EtOAc/Hexanes as eluent. Further purification by silica gel column chromatography with a gradient of 0-10% EtOAc/CH2Cl2 as eluent, followed by lyophilization from CH3CN/H2O provided the title compound. 1H NMR δ (ppm) (CHCl3-d): 8.16 (1H, s), 8.07˜8.03 (2H, m), 7.70˜7.66 (3H, m), 7.47 (1H, d, J=7.77 Hz), 7.37 (1H, d, J=8.24 Hz), 7.32 (1H, D, J=7.1 Hz), 7.26˜7.22 (2H, m), 7.16 (1H, t, J=7.40 Hz), 5.95 (1H, br s), 4.34 (2H, t, J=6.37 Hz), 3.32 (3H, s), 3.28 (2H, t, J=6.4 Hz), 3.05 (3H, d, J=4.91 Hz), 2.83 (3H, s), 2.75 (3H, s). MS (M+H): 609.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[C:13]=1[CH2:14][N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C@@H:16]1[C:21](O)=[O:22].Cl.[NH2:33][CH:34]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:35]([OH:42])[C:36]([NH:38][CH:39]1[CH2:41][CH2:40]1)=[O:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH:39]1([NH:38][C:36](=[O:37])[CH:35]([OH:42])[CH:34]([NH:33][C:21]([C@H:16]2[CH2:17][CH2:18][C:19](=[O:20])[N:15]2[CH2:14][C:13]2[C:24]([C:28]([F:31])([F:29])[F:30])=[CH:25][CH:26]=[CH:27][C:12]=2[O:11][CH3:10])=[O:22])[CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40][CH2:41]1
Reactant: COc1cccc(C(F)(F)F)c1CN1C(=O)CC[C@@H]1C(=O)O
Reactant: NC(Cc1ccccc1)C(O)C(=O)NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1cccc(C(F)(F)F)c1CN1C(=O)CC[C@@H]1C(=O)NC(Cc1ccccc1)C(O)C(=O)NC1CC1
Reaction time: 8 h
Yield: 126.1 %

Procedure:
DIPEA (0.8 ml, 4.58 mmol) was added to a mixture of (R)-1-(2-methoxy-6-(trifluoromethyl)benzyl)-5-oxopyrrolidine-2-carboxylic acid (234 mg, 0.74 mmol) and 3-amino-N-cyclopropyl-2-hydroxy-4-phenylbutanamide hydrochloride (200 mg, 0.74 mmol) in DCM (50 mL). After stirring for 10 min HATU (337 mg, 0.89 mmol) was added and the stirring was continued overnight. The reaction mixture was diluted with DCM and water was added. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with saturated aqueous NaHCO3 solution, saturated aqueous NaCl solution and dried over MgSO4. Removal of the solvent in vacuo provided the title compound (498 mg, 95%, ca. 75% purity).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C@@H:9]([OH:12])[CH2:10][OH:11])[CH:2]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>N1C=CC=CC=1.ClCCl.CN(C)C=O>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:11][CH2:10][C@H:9]([O:12][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H](O)CCc1cccnc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OC[C@@H](CCc2cccnc2)O[Si](C)(C)C(C)(C)C)cc1
Yield: 66.8 %

Procedure:
Prepared according to the method described in Example 26d) from (2R)-4-(3-pyridyl)-1,2-butanediol (5 g) and para-toluenesulfonyl chloride (8.60 g) in pyridine (30 ml) and dichloromethane (30 ml). The resulting adduct was treated with imidazole (3.4 g) and tert-butyldimethylsilyl chloride (5.25 g) in dimethylformamide (20 ml) to give the sub-title compound as an oil (8.7 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35].O>ClCCl>[CH3:31][O:32][CH2:33][C:34]([NH:1][CH2:2][C:3]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:35]
Reactant: COCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COCC(=O)NCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
3.7 g of commercial tert-butyl 4-aminomethyl-4-phenyl-piperidine-1-carboxylate and 3 ml diisopropylethylamine are placed in 30 ml dichloromethane. Then 2.25 ml methoxyacetyl chloride are slowly added. The reaction mixture is stirred at ambient temperature until there is no further reaction, then mixed with water. The organic phase is evaporated to dryness. 4.7 g product are obtained in the form of an oil.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[N:17][CH:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:26]([C:38]1[S:42][C:41]([C:43](Cl)=[O:44])=[CH:40][CH:39]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].Cl>O>[CH2:26]([C:38]1[S:42][C:41]([C:43]([O:25][C:22]2[CH:21]=[CH:20][C:19]([C:16]3[N:15]=[CH:14][C:13]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:18][N:17]=3)=[CH:24][CH:23]=2)=[O:44])=[CH:40][CH:39]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCCCCCCCCc1ccc(C(=O)Cl)s1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCc1ccc(C(=O)Oc2ccc(-c3ncc(CCCCCC)cn3)cc2)s1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 50.4 %

Procedure:
15 ml of pyridine was added to 0.49 g (1.93×10-3 mol) of 4-(5-hexyl-2-pyrimidinyl)phenol, followed by cooling on an iced water bath. To the mixture, 0.61 g (1.93×10-3 mol) of 5-dodecylthiophene-2-carboxylic chloride was added, followed by stirring for 4.5 hours at room temperature. After the reaction, the reaction mixture was poured into 100 ml of water and acidified with conc. hydrochloric acid, followed by three times of extraction with 50 ml of isopropyl ether. The organic layer was washed with water repeatedly until the washing liquid reached neutrality, followed by drying with anhydrous magnesium sulfate and distilling-off of the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography with the use of a hexane/ethyl acetate (=10/1) mixture solvent and recrystallized from an ethanol/ethyl acetate mixture solvent to obtain 0.52 g of a pure product (yield: 50.5%). ##STR32##
Reaction SMILES: [Br:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.C(O)(C(F)(F)F)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:34][S:35][C:36]1[O:37][C:38]2[CH:44]=[C:43]([CH:45]=O)[CH:42]=[CH:41][C:39]=2[N:40]=1>C(Cl)Cl>[Br:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH:6][CH2:45][C:43]2[CH:42]=[CH:41][C:39]3[N:40]=[C:36]([S:35][CH3:34])[O:37][C:38]=3[CH:44]=2)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Nc1cc(Cl)c(Br)cc1[N+](=O)[O-]
Reactant: CSc1nc2ccc(C=O)cc2o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1nc2ccc(CNc3cc(Cl)c(Br)cc3[N+](=O)[O-])cc2o1
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution of 4-bromo-5-chloro-2-nitroaniline (550 mg, 2.19 mmol) from the previous step and TFA (2.26 mL) in DCM (10 mL) at −15° C. was added NaBH(OAc)3 (1.39 g, 5.37 mmol). Then a solution of 2-(methylthio)benzo[d]oxazole-6-carbaldehyde (465 mg, 2.41 mmol) in DCM (6 mL) was added to the mixture. After complete addition, the mixture was stirred at −10° C. to 0° C. for 2 h. The reaction mixture was diluted with DCM and washed sequentially with H2O, aq NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 5:1 to 2:1 petroleum ether/DCM to give 4-bromo-5-chloro-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitroaniline as a yellow solid (451 mg, 48.2%). 1H NMR (300 MHz, DMSO-d6) δ 8.81 (t, 1H), 8.34 (s, 1H), 7.66 (s, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.37 (d, J=6.9 Hz, 1H), 7.19 (s, 1H), 4.76 (d, J=6.3 Hz, 2H), 2.74 (s, 3H). LCMS (ESI) m/z 428 (M+H)+.
Reaction SMILES: CC([N:5]([C@H:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](Br)[CH:17]=2)[N:12]([C:20](=[O:22])[CH3:21])[C@@H:11]([CH3:23])[CH2:10]1)[C:6](=[O:8])[O-:7])(C)C.[CH3:24][N:25]([CH2:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:38]=1)[C:26](=[O:35])[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C.[C:61]1([CH3:67])[CH:66]=CC=C[CH:62]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:29]1([CH2:28][O:27][C:26](=[O:35])[N:25]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[N:12]([C:20](=[O:22])[CH3:21])[C@@H:11]([CH3:23])[CH2:10][C@H:9]4[NH:5][C:6]([O:7][C:61]([CH3:67])([CH3:66])[CH3:62])=[O:8])=[CH:39][CH:38]=2)[CH3:24])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CN(Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OCc1ccccc1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](N(C(=O)[O-])C(C)(C)C)C[C@@H]1C
Reactant: Cc1ccccc1
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: [K+]
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3ccc(CN(C)C(=O)OCc4ccccc4)cc3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Temperature: 25 °C
Yield: 69 %

Procedure:
A flask was charged with 1,1-dimethylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see intermediate 50) (1 g, 2.61 mmol), phenylmethyl methyl{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}carbamate (for a preparation see intermediate 82) (1.194 g, 3.13 mmol), tetrakis(triphenylphosphine)palladium(0) (0.151 g, 0.130 mmol) and potassium carbonate (0.541 g, 3.91 mmol) then filled with ethanol (10 mL) and toluene (10 mL). The resulting mixture was degassed under house vacuo for 30 min with several quenches with nitrogen, heated to reflux for 45 min then cooled to room temperature. The insoluble material was filtered off and most of the solvent was concentrated in vacuovacuo. The residue was partitioned between DCM (100 mL) and water (100 mL). The layers were separated and the organic phase was dried through a hydrophobic frit and concentrated in vacuovacuo. Purification of the residue by SP4 using a 40 G silica cartridge (gradient:0 to 50% AcOEt in Hexanes) gave phenylmethyl({4-[(2S,4R)-1-acetyl-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}methyl)methylcarbamate (1 g, 1.7 mmol, 69%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:12]NC(=O)C[C:8]=2[CH:14]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:17]I.CO.[CH3:21][N:22]([CH:24]=[O:25])C>O>[CH3:21][N:22]1[C:8]2[CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[S:12][CH2:17][C:24]1=[O:25]
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2SN1
Reactant: CI
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1C(=O)CSc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 11.5 ml of DMF was dissolved 500 mg of 6-nitro-2H-benzothiazin-3(4H)-one, and thereto was added 114 mg of sodium hydride of 55% purity under ice cooling, followed by 30 minutes of stirring at room temperature. To the reaction solution was added 444 μl of methyl iodide, and the whole was stirred at room temperature for 2 hours. To the reaction solution was added 2 ml of methanol under ice cooling, followed by 10 minutes of stirring at room temperature. Thereafter, water was added and the organic layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then the solvent was removed by evaporation. The obtained residue was purified by silica gel column chromatography (chloroform) to obtain 308 mg of 4-methyl-6-nitro-2H-1,4-benzothiazin-3(4H)-one.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16](O)=[O:17])[C:10]=2[S:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.ON1C2C=CC=CC=2N=N1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][N:38]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([O:49][CH3:50])[CH:42]=2)[CH3:39])=[CH:32][CH:31]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[CH3:39][N:38]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([O:49][CH3:50])[CH:42]=1)[CH2:37][CH2:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:16]([C:11]2[C:10]3[S:9][C:8]4[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:2](=[O:1])[C:15]=3[CH:14]=[CH:13][CH:12]=2)=[O:17])=[CH:31][CH:32]=1
Reactant: COc1ccc(CN(C)CCc2ccc(N)cc2)cc1OC
Reactant: O=C(O)c1cccc2c(=O)c3ccccc3sc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc(CN(C)CCc2ccc(NC(=O)c3cccc4c(=O)c5ccccc5sc34)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 9-oxo-4-thioxanthenecarboxylic acid* (0.8 g) and 1-hydroxybenzotriazole (0.42 g) in DMF (20 ml) was stirred at room temperature for 10 min. 4-Amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzenemethanamine (Intermediate 33(b) in EP-A-494623) (0.94 g) in DMF (20 ml) was then added, followed by dicyclohexylcarbodiimide (0.64 g) and the mixture was stirred at room temperature for 16 h and then filtered. The filtrate was concentrated in vacuo, treated with dilute sodium hydroxide solution and extracted with dichloromethane. The combined dried organic extracts were evaporated to leave an oil which was purified by column chromatography eluting with dichloromethane: methanol (95:5). The resulting solid was recrystallised from acetonitrile and filtered off to give the title compound as a solid (0.26 g),mp=180°.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]([CH2:15][CH:16]=[CH2:17])[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:15]([CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][NH2:8])[CH:16]=[CH2:17]
Reactant: C=CCC(CNC(=O)OC(C)(C)C)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCC(CN)C(=O)OC
Reaction time: 3 h
Yield: 121.5 %

Procedure:
Dissolve N-(t-butyloxycarbonyl)-2-(2-propenyl)-β-alanine, methyl ester (5.6 g, 23.0 mmol) in methylene chloride (25 mL) and treat with trifluoroacetic acid (15 mL). Stir for three hours and remove the volatiles in vacuo. Treat the residue with water, make basic with sodium hydroxide (1.0 g, 25 mmol) and extract with ethyl acetate. Separate the organic phase and dry (Na2SO4). Evaporate to give 4.0 g of the title compound as an oil in ethyl acetate.
Reaction SMILES: N[C:2]1[N:10]=[C:9]([C:11]#[C:12][C:13]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[N:6]2[CH3:19].C([OH:30])C=C.[OH-].[Na+]>C1COCC1>[F:26][C:22]1[CH:21]=[C:20]([C:5]2[N:6]([CH3:19])[C:7]3[C:3]([N:4]=2)=[C:2]([OH:30])[N:10]=[C:9]([C:11]#[C:12][C:13]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=3)[CH:25]=[CH:24][CH:23]=1
Reactant: Cn1c(-c2cccc(F)c2)nc2c(N)nc(C#CC3(O)CCCC3)nc21
Reactant: C=CCO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1c(-c2cccc(F)c2)nc2c(O)nc(C#CC3(O)CCCC3)nc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
To 50 mg of 1-{2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol were added 3.0 ml of allyl alcohol and 1.0 ml of 5M NaOH, the mixture was stirred at room temperature for 10 minutes, 1.0 ml of THF was added thereto and the mixture was stirred again at room temperature for 15 hours and 40 minutes. The solvent was evaporated and then 200 ml of ethyl acetate and water (1:1) were added and an extraction was carried out. The aqueous lyaer was extracted with 100 ml of ethyl acetate again and the all organic layers were combined and washed with water and with brine once each. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The resulting residue was purified by a p-TLC (CH2Cl2:MeOH=10:1), the resulting yellowish white crystals were suspended in diethyl ether and the suspenion was filtered to give 217 mg of the title compound as white crystals. The yield was 36%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:6][CH2:5]2.[NH:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.BrC1C=C2C(=CC=1)C[C:34](=[O:39])CC2.N1CCCC1>>[N:23]1([CH2:22][CH:18]2[CH2:19][CH2:20][CH2:21][N:17]2[C:34]([C:2]2[CH:11]=[CH:10][C:9]3[CH2:8][CH:7]([N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)[CH2:6][CH2:5][C:4]=3[CH:3]=2)=[O:39])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCc2cc(Br)ccc2C1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: Brc1ccc2c(c1)CCC(N1CCCC1)C2
Solvent: C1CCNC1
Product: O=C(c1ccc2c(c1)CCC(N1CCCC1)C2)N1CCCC1CN1CCCC1

Procedure:
(2-Pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-(6-pyrrolidin-1-yl-5,6,7,8-tetrahydro-naphthalen-2-yl)-methanone is prepared from 1-(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-pyrrolidine and (S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine in a manner substantially analogous to Procedure A. (See herein Example 1). Starting material, (6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-pyrrolidine, was prepared from 6-bromo-2-tetralone and pyrrolidine in a manner substantially analogous to Preparation 1. Mass Spectrum (APCI) 382 (M++1).