Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[CH:3]1([NH:6][C:7]([C:9]2[C:17]3[CH:16]=[C:15]([C:18]4[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:25][CH2:26][CH2:27][CH2:28][CH:29]5[CH2:34][CH2:33][N:32]([CH:35]6[CH2:37][CH2:36]6)[CH2:31][CH2:30]5)[N:19]=4)[S:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4]1.[CH:38]1(NC(C2C3C=C(C4C(C)=CN=C(NCCCC5CCNCC5)N=4)SC=3C=CC=2)=O)CC1>>[ClH:24].[ClH:1].[CH:3]1([NH:6][C:7]([C:9]2[C:17]3[CH:16]=[C:15]([C:18]4[C:23]([CH3:38])=[CH:22][N:21]=[C:20]([NH:25][CH2:26][CH2:27][CH2:28][CH:29]5[CH2:34][CH2:33][N:32]([CH:35]6[CH2:37][CH2:36]6)[CH2:31][CH2:30]5)[N:19]=4)[S:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4]1
Reactant: Cc1cnc(NCCCC2CCNCC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCC4CCN(C5CC5)CC4)ncc3Cl)cc12
Agent: Cl
Product: Cc1cnc(NCCCC2CCN(C3CC3)CC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1

Procedure:
Using the method of 2-{5-chloro-2-[3-(1-cyclopropylpiperidin-4-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-[5-methyl-2-(3-piperidin-4-ylpropylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and isolated as a yellow solid. ES+(m/z) 490 [M(free base)+H].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17]([CH3:19])=O)[N:3]=1.SC[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccc(C#N)o2)c1C#N
Reactant: SCCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1ccc(-c2nc(N)nc(SCCc3ccccn3)c2C#N)o1

Procedure:
From 2-amino-4-(5-cyano-furan-2-yl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 347 ([M—H]−, 100).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.Cl.[NH:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.P(=O)(O)(O)O.CCOC(C)=O>CC(O)=O>[NH:18]1[CH2:19][CH:20]=[C:21]([C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:22][CH2:23]1
Reactant: O=C1CCNCC1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: Cl
Agent: O=P(O)(O)O
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C1=C(c2c(-c3ccccc3)[nH]c3ccccc23)CCNC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.9 %

Procedure:
2-Phenylindole (25 g, 130 mmol) was stirred at 80° C. in AcOH (200 ml), and 4-piperidone hydrochloride hydrate (50 g, 376 mmol) and 1M phosphoric acid (100 ml) added. After a further 6 h, the mixture was poured into ice/ammonia, and extracted with EtOAc (3×200 ml). The combined organic layers were washed with water and brine, dried, and evaporated in vacuo to give a pale yellow solid. This was suspended in boiling EtOAc (200 ml), cooled to room temperature overnight, and the solid collected, washed with EtOAc and dried to give the title compound (26 g, 73%) as a pale yellow solid; δH (360 MHz, d6-DMSO) 2.00-2.10 (2H, m, NCH2CH2), 2.89 (2H, t, J 5, NCH2CH2), 3.40-3.45 (2H, m, NCH2CH), 5.78 (1H, br s, NCH2CH), 7.00 (1H, t, J 7, indole-H), 7.08 (1H, t, J 7, indole-H), 7.20-7.50 (5H, m, ArH), 7.69 (2H, d, J 7, ArH), 11.3 (1H, br s, indole NH); m/z (ES+) 275 (M++H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:47][CH:48]=[CH2:49])[CH:8]=[N:9][C:10]=1[N:11]1[C:15](=[O:16])[NH:14][C:13]([CH:17]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[C:32]([CH2:38][NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:31]=2)[C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:19]=2[F:28])=[N:12]1)=[O:5])C.[OH-].[Na+]>CO>[CH2:47]([N:7]1[C:6]([C:4]([OH:5])=[O:3])=[C:10]([N:11]2[C:15](=[O:16])[NH:14][C:13]([CH:17]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[C:32]([CH2:38][NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:31]=3)[C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:19]=3[F:28])=[N:12]2)[N:9]=[CH:8]1)[CH:48]=[CH2:49]
Reactant: C=CCn1cnc(-n2nc(C(Nc3ccc(C#N)c(CNC(=O)OC(C)(C)C)c3)c3cc(OC)c(OC)cc3F)[nH]c2=O)c1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCn1cnc(-n2nc(C(Nc3ccc(C#N)c(CNC(=O)OC(C)(C)C)c3)c3cc(OC)c(OC)cc3F)[nH]c2=O)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
To a mixture of 3-allyl-5-(3-{[3-(t-butoxycarbonylaminomethyl)-4-cyanophenylamino]-(2-fluoro-4,5-dimethoxyphenyl)methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-3H-imidazole-4-carboxylic acid ethyl ester (17 mg) and methanol (1 mL) there was added a 5N sodium hydroxide aqueous solution (0.10 mL), and the mixture was stirred overnight at room temperature. The mixture was purified by reverse-phase high performance liquid chromatography (acetonitrile/water mixed solvent, 0.1% acetic acid) to obtain the target compound (2.5 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]([N:16]([CH3:18])[CH3:17])=[C:11]1[C:6]=2[CH:7]=[CH:8][C:9]([NH2:19])=[CH:10]1.P(Cl)(Cl)(Cl)=O.[CH2:25]([N:27]([CH2:30][CH3:31])[CH:28]=O)[CH3:26]>CC(C)=O>[CH2:25]([N:27]([CH:28]=[N:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]([N:16]([CH3:17])[CH3:18])=[C:11]1[C:6]=2[CH:7]=[CH:8][C:9]([N:19]=[CH:28][N:27]([CH2:30][CH3:31])[CH2:25][CH3:26])=[CH:10]1)[CH2:30][CH3:31])[CH3:26]
Reactant: CCN(C=O)CC
Reactant: CN(C)c1nc2cc(N)ccc2c2ccc(N)cc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)=O
Product: CCN(C=Nc1ccc2c(c1)nc(N(C)C)c1cc(N=CN(CC)CC)ccc12)CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A suspension of 3,8-diamino-6-dimethylaminophenanthridine (500 mg) in N,N-diethylformamide (2 ml) was added to a mixture of phosphorus oxychloride (1.5 ml) and N,N-diethylformamide (5 ml), the temperature of the mixture being kept at 5° C. The resulting mixture was stirred for 30 minutes at room temperature, heated at 75°-80° C. for 2 hours, cooled, and diluted with acetone. The precipitate formed was filtered off and dissolved in water. The pH of the clear solution was adjusted to a value of 9 with aqueous ammonia. The solid thus obtained was filtered off, washed with water, dried, and purified by column chromatography over a neutral aluminum oxide column using benzene as the mobile phase. The product crystallized out from chloroform/diisopropyl ether. Yield 71%, melting point 124°-126° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:40]1([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:49]1[CH2:50][CH2:51][CH:46]([N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:47][CH2:48]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cc(C(=O)N3CCC(N4CCCCC4)CC3)ccc2[nH]1
Yield: 67 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-piperidinopiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a brown solid (67%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([I:41])=[CH:37][C:36]=2[F:42])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([CH:16]3[CH2:21][N:20](S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[CH2:19][CH2:18][NH:17]3)([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1>CN(C=O)C>[F:1][C:2]1[C:3]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([I:41])=[CH:37][C:36]=2[F:42])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([CH:16]3[CH2:21][NH:20][CH2:19][CH2:18][NH:17]3)([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)(C2CN(S(=O)(=O)c3ccccc3[N+](=O)[O-])CCN2)C1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)(C2CNCCN2)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 26.3 %

Procedure:
To a solution of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{4-[(2-nitrophenyl)sulfonyl]piperazin-2-yl}azetidin-3-ol (139.4 mg, 0.19 mmol) in DMF (1 mL) was added potassium carbonate (79 mg, 0.57 mmol) and thiophenol (21 μL, 0.21 mmol). The mixture was stirred for 45 min at room temperature then quenched with water. The aqueous mixture was extracted twice with ethyl acetate, and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by preparative reverse phase HPLC to provide 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-piperazin-2-ylazetidin-3-ol as a white solid (26.8 mg, 0.05 mmol). 1H NMR (400 MHz, CD3OD): 7.45 (dd, 1H), 7.36 (m, 1H), 7.32 (m, 1H), 7.03 (m, 1H), 6.62 (ddd, 1H), 4.51 (br dd, 1H), 4.31 (br dd, 1H), 4.17-3.92 (m, 4H), 3.73-3.56 (m, 3H), 3.46 (br m, 1H), 3.26 (m, 1H); MS (EI) for C20H20F3IN4O2: 533 (MH+).
Reaction SMILES: C=O.[F:3][C:4]([F:13])([F:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C1(B(O)O)C=CC=CC=1.[C:23](O)(=[O:26])CC.OO>C1C=CC=CC=1.C1COCC1.O>[OH:11][C:8]1[CH:7]=[CH:6][C:5]([C:4]([F:12])([F:13])[F:3])=[CH:10][C:9]=1[CH2:23][OH:26]
Reactant: CCC(=O)O
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: C=O
Agent: OB(O)c1ccccc1
Agent: OO
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: OCc1cc(C(F)(F)F)ccc1O
Reaction time: 1 h
Yield: 70.6 %

Procedure:
Paraformaldehyde (3.4 g, 0.114 mol) was added in 0.5 g portions over a six hour period to a refluxing mixture of 4-trifluoromethyl phenol (2.3 g, 0.0142 mol), phenyl boronic acid (2.1 g, 0.017 mol) and proprionic acid (530 μL, 7 mmol) in benzene with the azeotropic removal of water (Dean-Stark trap). When the addition was complete, the reaction was heated for an additional hour, then cooled with an ice bath, diluted with THF (30 mL) and treated with 5 mL of 30% hydrogen peroxide solution. After stirring for one hour, the mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was washed with NaHSO3 solution (1×50 mL), brine (1×50 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (30% ethyl acetate/hexanes) to afford 950 mg (35%) of the title compound as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.42 (d, 1H, J=9.1 Hz); 7.3 (s, 1H); 6.95 (d, 1H, J=9.1 Hz); 4.89 (s, 2H);
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][NH2:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(C)=O.O>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([NH:33][O:32][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][O:26]3)=[O:25])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccc(NC2CCN(Cc3ccccc3)CC2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(NC2CCN(Cc3ccccc3)CC2)nc1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.4 %

Procedure:
A mixture of (2E)-3-{6-[(1-benzyl-4-piperidyl)amino]-3-pyridyl}acrylic acid (430 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (157 mg), HOBt (181 mg) and EDCI (208 mg) in DMF (20 ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (9:1-8:2). The eluted fractions containing the desired product were collected and evaporated in vacuo to give (2E)-3-{6-[(1-benzyl-4-piperidyl)amino]-3-pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (180 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:25]([O-])=O.C([O-])=O.[K+]>C(O)C.[Pt]>[NH2:25][C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:11]=[CH:12][C:13]([CH2:16][N:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)=[CH:14][CH:15]=2)[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1[N+](=O)[O-]
Agent: [Pt]
Agent: O=C[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1N
Temperature: 80 °C

Procedure:
Alternatively a solution of N-(4-methyl-3-nitro-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide (60 g, 163 mmol) in ethanol 90% (300 ml) at room temperature under an atmosphere of nitrogen is treated sequentially with platinum (5%) on carbon (6.0 g) and potassium formate (68.5 g, 814 mmol). The resulting suspension is then heated at 80° C. for a period of 16 hrs. The reaction mixture is filtrated at 70° C. over a pad of Celite. Ethanol 90% (150 ml) and water (150 ml) are used to rinse the reactor. Ethanol is removed from the combined filtrates by distillation in vacuo at an external temperature 60° C. The crude product separates from the aqueous concentrate as an oil during the distillation, crystallizes upon subsequent cooling to 23° C. within 2 hrs and is filtered of with suction, washed with ethanol (200 ml) and dried in vacuo. Yield: 55 g of the title compound, 99% of theory, as yellowish crystals. (HPLC: 98.0% area).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]3=[N:16][S:17](=[O:21])(=[O:20])[CH2:18][CH2:19][N:14]3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1>C1COCC1.C(O)C.[C].[Rh]>[F:23][C:2]([F:1])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:15]3=[N:16][S:17](=[O:21])(=[O:20])[CH2:18][CH2:19][N:14]3[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(OC(F)(F)F)cc3)C2=N1
Agent: [Rh]
Solvent: C1CCOC1
Solvent: CCO
Product: O=S1(=O)CCN2CCCC(c3ccc(OC(F)(F)F)cc3)C2=N1
Temperature: 25 °C
Reaction time: 7 h
Yield: 100.8 %

Procedure:
A mixture of 5% rhodium-carbon (50% wet, 15 mg) and 9-[4-(trifluoromethoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (150 mg) in THF (30 mL) and ethanol (30 mL) was stirred under a hydrogen atmosphere at room temperature for 7 hr. The reaction mixture was filtered, the filtrate was concentrated to give the title compound (153 mg) as a gray white solid. The obtained solid was crystallized from THF and diisopropyl ether to give a gray white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:5]([CH3:14])[C:6]=1C(OC(C)(C)C)=O.C(O)C>Cl>[ClH:21].[NH2:1][C:2]1[S:3][C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:5]([CH3:14])[CH:6]=1
Reactant: Cc1c(-c2ccc(Cl)cc2)sc(N)c1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: Cc1cc(N)sc1-c1ccc(Cl)cc1

Procedure:
The above thiophene (2.0 g) in 10 ml of 6M HCl is heated at 80° for 33 hours. Ethanol is added, and the solvent and water are then removed. Ether is added to the residue, the suspension is filtered and the final solid is rinsed with ether to give 2-amino-4-methyl-5-(4-chlorophenyl)thiophene hydrochloric acid salt.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:13][O:14][C:15]([C:17]1[C:26]([O:27][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:29])=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[N:24]2)=[C:19]([C:36]#[C:37][CH2:38]OS(C)(=O)=O)[N:18]=1)=[O:16]>C(#N)C>[CH3:13][O:14][C:15]([C:17]1[C:26]([O:27][C:28]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:29])=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[N:24]2)=[C:19]([C:36]#[C:37][CH2:38][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:18]=1)=[O:16]
Reactant: COC(=O)c1nc(C#CCOS(C)(=O)=O)c2cccnc2c1OC(=O)c1ccccc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1nc(C#CCN2CCCCC2)c2cccnc2c1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred mixture of piperdine (207 μL, 2.09 mmol) and potassium carbonate (296 mg, 2.14 mmol) in dry acetonitrile (10 mL) was pipetted in 5-(3-methanesulfonyloxy-prop-1-ynyl)-8-(1-phenyl-methanoyloxy)-[1,6]naphthyridine-7-carboxylic acid methyl ester (230 mg, 0.522 mmol) in acetonitrile (1 mL) and the mixture was stirred at room temperature for 3 hours. The reaction was concentrated, filtered, and purified on the Gilson auto-prep running a 95-50% H2O (0.1% TFA)/CH3CN (0.09% TFA) gradient over 30 minutes to obtain the desired compound as a light brown oil.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[CH2:10][CH2:11][CH:12]1[CH:15]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[N:14]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:13]1=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F-].[K+].[Br-].[Br:41][CH:42]([CH2:49][CH3:50])[CH2:43][CH2:44][N+:45]([CH3:48])([CH3:47])[CH3:46]>C(#N)C>[Br-:41].[F:29][C:26]1[CH:25]=[CH:24][C:23]([N:14]2[C:13](=[O:30])[CH:12]([CH2:11][CH2:10][CH:9]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:15]2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:50][CH2:49][CH2:42][CH2:43][CH2:44][N+:45]([CH3:48])([CH3:47])[CH3:46])=[CH:18][CH:17]=2)=[CH:28][CH:27]=1
Reactant: CCC(Br)CC[N+](C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1C(=O)N(c2ccc(F)cc2)C1c1ccc(O)cc1)c1ccc(F)cc1
Agent: [Br-]
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OC(CCC1C(=O)N(c2ccc(F)cc2)C1c1ccc(OCCCCC[N+](C)(C)C)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
370 mg of 3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-1-(4-fluorophenyl)-4-(4-hydroxyphenyl)azetidin-2-one are dissolved in 3 ml of absolute acetonitrile. 300 mg of KF.alumina (1.15 mol/100 g) and 375 mg of (3-bromopentyl)-trimethylammonium bromide are then added. The reaction mixture is stirred at room temperature overnight and then filtered. The mother liquor is concentrated using a rotary evaporator and the residue is purified using a 5 g SiO2 cartridge (dichloromethane/methanol 4:1). The product is obtained as an oil.
Reaction SMILES: C(OC([NH:11][C@H:12]([CH2:31][CH2:32][CH2:33][NH:34]C(OCC1C=CC=CC=1)=O)[CH2:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][NH:20]C(OCC1C=CC=CC=1)=O)=[O:15])=O)C1C=CC=CC=1.[H][H]>CO.O.[C].[Pd]>[NH2:11][C@H:12]([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][NH2:20])=[O:15]
Reactant: O=C(C[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)NCCCNC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: NCCCNC(=O)C[C@H](N)CCCN
Yield: 100.1 %

Procedure:
In 18 ml of methanol were suspended 144 mg (0.238 mmol) of (R)-3,6-bis(benzyloxycarbonylamino)-N-(3-benzyloxycarbonylaminopropyl)hexanamide. To the resulting suspension was added a suspension of 81.0 mg of 10% palladium-carbon in 2 ml of water, followed by stirring. Hydrogen gas was passed through the resulting mixture at room temperature for 3 hours to effect the hydrogenolysis reaction. The palladium-carbon was filtered off from the reaction mixture obtained, and the filtrate was then concentrated to dryness. The residue obtained was dissolved in 1 ml of water and the resulting solution was subjected to chromatography on a column of "Amberlite CG-50" (trade name, NH4+ -form, 5 ml). After the column was washed with 25 ml of water, the column was eluted with aqueous ammonia at concentrations gradiently varying from 0.5% to 7.0% (0.5%-increased steps; 25 ml at each concentration). Fractions of the eluate as eluted with 4.0% to 6.0% aqueous ammonia were combined together and concentrated to dryness, to afford 48.2 mg of (R)-3,6-diamino-N-(3-aminopropyl)hexanamide as a colorless paste.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:10][CH:11]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=2)[CH2:12][O:13][Si](C(C)(C)C)(C)C)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.Cl.C(=O)=O.CC(C)=O.N>CCO.CO>[Br:1][C:2]1[N:3]([CH2:10][CH:11]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:31])[F:32])=[CH:25][CH:24]=2)[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(COc1ccc(OC(F)(F)F)cc1)Cn1cc([N+](=O)[O-])nc1Br
Agent: Cl
Agent: N
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CO
Solvent: CCO
Product: O=[N+]([O-])c1cn(CC(CO)COc2ccc(OC(F)(F)F)cc2)c(Br)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.3 %

Procedure:
Silyl ether 172 (3.42 g, 6.17 mmol) was treated with a solution of 1% HCl in 95% EtOH (desilylation conditions described by Cunico et al., 1980) (31 mL), and the mixture was stirred at room temperature for 12 h. The resulting solution was cooled (CO2/acetone), neutralised by dropwise addition of 7M NH3 in MeOH (6.6 mL) with stirring, and then concentrated to dryness and the residue was chromatographed on silica gel. Elution with 0-30% EtOAc/petroleum ether firstly gave foreruns, and then further elution with 40-50% EtOAc/petroleum ether gave 3-(2-bromo-4-nitro-1H-imidazol-1-yl)-2-{[4-(trifluoromethoxy)phenoxy]methyl}-1-propanol (174) (2.48 g, 91%) as a white solid: mp (CH2Cl2/pentane) 97-99° C.; 1H NMR (CDCl3) δ 7.88 (s, 1H), 7.17 (br d, J=8.5 Hz, 2H), 6.88 (dt, J=9.1, 3.0 Hz, 2H), 4.34 (dd, J=14.4, 7.4 Hz, 1H), 4.31 (dd, J=14.4, 7.1 Hz, 1H), 4.06 (dd, J=9.6, 5.7 Hz, 1H), 4.03 (dd, J=9.6, 4.8 Hz, 1H), 3.88 (dt, J=10.8, 4.4 Hz, 1H), 3.76 (dt, J=10.8, 4.9 Hz, 1H), 2.54 (m, 1H), 1.72 (t, J=4.4 Hz, 1H); HRFABMS calcd for C14H14BrF3N3O5 m/z [M+H]+ 442.0049, 440.0069. found 442.0053, 440.0063.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c12
Reactant: c1nc[nH]n1
Product: Cc1csc2nc(-n3cncn3)nc(NCc3ccc4c(c3)OCO4)c12

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.