Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[CH2:18]([N:6]1[CH2:5][CH2:4][CH2:3][CH2:8][CH2:7]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCC1CCNCC1
Reactant: BrCc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(CN2CCCCC2)cc1
Temperature: 57.5 °C
Yield: 98 %

Procedure:
To a stirred solution of 4-(hydroxymethyl)piperidine 38 (0.01 mol) and DIEA (0.02 mol) in anhydrous acetonitrile (20 ml) was added a solution of benzylbromide 39 (0.012 mol) in anhydrous acetonitrile (5 ml) at room temperature. The resulting mixture was heated at 55-60° C. for 12 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated on rotavapor and the residue was diluted with ethyl acetate (50 ml). The resulting ethyl acetate solution was washed with water, dried over anhydrous sodium sulfate (Na2SO4) and evaporated the solvent. The residue was purified by silica gel column chromatography using a gradient of 0 to 100% ethyl acetate and hexane to get the title piperidine 40 in 98% yield (2.00 g) yield. 1H NMR (400 MHz, CDCl3): δ 1.26-1.33 (2H, m); 1.43-1.52 (1H, m); 1.70 (2H, broad d); 1.96 (2H, broad t); 2.90 (2H, broad d); 3.48 (2H, s); 3.49 (2H, s); 7.30 (5H, m). MS (ESI): m/z=206.20 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:46])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([CH2:37][O:38]C3CCCCO3)[CH:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:38][CH2:37][C:33]1[CH:32]=[C:31]([C:27]2[CH:26]=[C:25]([C:24]3[CH2:23][C:22](=[O:46])[NH:21][C:9]4[CH:10]=[C:11]([C:17]([F:19])([F:18])[F:20])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=4[N:7]=3)[CH:30]=[CH:29][CH:28]=2)[CH:36]=[CH:35][N:34]=1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(COC4CCCCO4)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-ethoxy-2-(3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M263) (0.48 g, 0.73 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (270 mg, 81%).
Reaction SMILES: ClC1C(Cl)=CC(O)=C(OC)C=1.C(C1OC1)Cl.C([O-])([O-])=O.[K+].[K+].[F:23][C:24]([F:42])([F:41])[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[CH:33][C:34]3[N:35]([C:37](=[O:40])[NH:38][N:39]=3)[CH:36]=2)=[CH:27][CH:26]=1.[Cl:43][C:44]1[C:54]([Cl:55])=[CH:53][C:47]([O:48][CH2:49][CH:50]2[CH2:52][O:51]2)=[C:46]([O:56][CH3:57])[CH:45]=1>CN(C=O)C.O>[Cl:43][C:44]1[C:54]([Cl:55])=[CH:53][C:47]([O:48][CH2:49][CH:50]([OH:51])[CH2:52][N:38]2[C:37](=[O:40])[N:35]3[CH:36]=[C:31]([C:28]4[CH:29]=[CH:30][C:25]([C:24]([F:23])([F:41])[F:42])=[CH:26][CH:27]=4)[CH:32]=[CH:33][C:34]3=[N:39]2)=[C:46]([O:56][CH3:57])[CH:45]=1
Reactant: COc1cc(Cl)c(Cl)cc1OCC1CO1
Reactant: O=c1[nH]nc2ccc(-c3ccc(C(F)(F)F)cc3)cn12
Agent: COc1cc(Cl)c(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCC1CO1
Solvent: O
Product: COc1cc(Cl)c(Cl)cc1OCC(O)Cn1nc2ccc(-c3ccc(C(F)(F)F)cc3)cn2c1=O
Temperature: 70 °C
Yield: 27.2 %

Procedure:
4,5-dichloro-2-methoxyphenol (200.0 mg, 1.036 mmol), epichlorohydrin (958.6 mg, 10.36 mmol, 10 equiv.) and K2CO3 (1.43 g, 10.36 mmol, 10 equiv.) were placed in a 50 mL round bottomed flask under a nitrogen atmosphere. To the flask were added DMF (3 mL) at ambient temperature. The mixture was heated at 70° C. for 16 hour. To the mixture was added water (30 mL). And then the whole was extracted with EtOAc (30 mL×3). Combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under a reduced pressure. Crude product (2-((4,5-dichloro-2-methoxyphenoxy)methyl)oxirane, 248.7 mg, 0.998 mmol, 96.4%) was used for the subsequent step without further purification. 6-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (47.2 mg, 0.169 mmol), 2-((4,5-dichloro-2-methoxyphenoxy)methyl)oxirane (50.5 mg, 0.2028 mmol, 1.2 equiv.) and K2CO3 (46.8 mg, 0.339 mmol, 2.0 equiv.) were placed in a 50 mL round bottomed flask under a nitrogen atmosphere. To the flask were added DMF (3 mL) at ambient temperature. The mixture was heated at 80° C. for 1 hour. The mixture was filtered through Celite and the filtrate was injected to preparative HPLC to give compound 198 as a colorless oil (24.3 mg, 0.0460 mmol, 27.2%). LCMS (EI: 70 eV) 552 (M++2+Na), 551 (M++1+Na), 550 (M++Na), 530 (M++2), 529 (M++1), 528 (M+).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][OH:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[F:22][C:23]1[N:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][O:19][C:26]1[CH:27]=[N:28][C:23]([F:22])=[CH:24][CH:25]=1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: Oc1ccc(F)nc1
Reactant: CC(C)(C)CN(CCO)c1ccc(C#N)c(C(F)(F)F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Product: CC(C)(C)CN(CCOc1ccc(F)nc1)c1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 60 h

Procedure:
Synthesized as described in Example 27B from 4-[(2,2-dimethylpropyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 61C) and 6-fluoro-3-pyridinol (Example 51A) with the following exceptions: additional portions of ADDP and PBu3 (0.5 equiv ea) were added to the reaction mixture after 1 h, the reaction was stirred for 60 h, and the title compound was purified by flash chromatography (EtOAc/hexanes) followed by RP-HPLC (MeCN/H2O+0.1% TFA): MS (ESI) m/z 396 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.Cl.[CH:11](=O)/[CH:12]=[CH:13]/[CH3:14]>C1(C)C=CC=CC=1>[CH3:14][C:13]1[CH:12]=[CH:11][C:7]2[C:2](=[CH:3][C:4]([CH3:9])=[C:5]([OH:8])[CH:6]=2)[N:1]=1
Reactant: Cc1cc(N)ccc1O
Reactant: C/C=C/C=O
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccc2cc(O)c(C)cc2n1
Temperature: 100 °C

Procedure:
To 4-amino-2-methylphenol (5.0 g, 40.6 mmol) was added 6M HCl (100 mL) and heated to 100° C. with stirring. Toluene (30 mL) was added followed with the slowly addition of crotonaldehyde (6.7 mL, 81.2 mmol) at 100° C. The mixture was stirred at 100° C. for 2 hours, cooled to room temperature. The water layer was separated, neutralized by NaHCO3 solution. The solid formed was filtered and collected. LCMS-ESI+: calc'd for C11H11NO: 174.1 (M+H+); Found: 174.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:31])=[O:30])[CH:4]=1)#[N:2].[H-].[Na+].[CH3:34][S:35](Cl)(=[O:37])=[O:36].[Cl-].[NH4+]>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[S:35]([CH3:34])(=[O:37])=[O:36])=[C:5]([S:29]([CH3:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)=O)N(S(C)(=O)=O)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40.2 %

Procedure:
The reaction was carried out under argon. (4S)-4-{4-Cyano-2-[methylsulfinyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (444 mg, 1 mmol) was initially charged in dry THF (10 ml), and sodium hydride (60% in mineral oil; 56 mg, 1.4 mmol; 1.4 eq.) was added at 0° C. The mixture was warmed to RT and stirred for 20 min. A solution of methanesulfonyl chloride (160 mg, 1.4 mmol; 1.4 eq.) in THF (5 ml) was then slowly added dropwise. After a reaction time of 16 h, ammonium chloride solution (50 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→80:20). This gave the title compound as a solid (210 mg, 40% of theory).
Reaction SMILES: [ClH:1].[C:2]([CH2:4][CH:5]([N:21]1[CH:25]=[C:24]([C:26]2[C:27]3[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:28]=3[N:29]=[CH:30][N:31]=2)[CH:23]=[N:22]1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C@H:8]1[CH3:20])#[N:3]>O1CCOCC1>[ClH:1].[CH3:20][C@@H:8]1[CH2:9][NH:10][CH2:11][CH2:12][N:7]1[CH2:6][CH:5]([N:21]1[CH:25]=[C:24]([C:26]2[C:27]3[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:41])([CH3:40])[CH3:42])[C:28]=3[N:29]=[CH:30][N:31]=2)[CH:23]=[N:22]1)[CH2:4][C:2]#[N:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CNCCN1CC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
4.0 M of HCl in p-dioxane (3.0 mL, 0.012 mol) was added to a solution of diastereomeric tert-butyl (3R)-4-{3-cyano-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-methylpiperazine-1-carboxylate (0.50 g, 0.86 mmol) in 1,4-dioxane (5 mL). The reaction was stirred at room temperature for 80 minutes. Solvent was removed in vacuo to afford the product as a mixture of diastereomers and as the hydrochloride salt (470 mg, 98%). LCMS (M+H)+: 481.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10][CH3:11].[Mg].II.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.C1(OC(Cl)=O)C=CC=CC=1>O1CCCC1>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[S:10][CH3:11])[CH:18]=1
Reactant: COc1ccncc1
Reactant: COc1ccc(Br)c(SC)c1
Agent: II
Agent: O=C(Cl)Oc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccnc(-c2ccc(OC)cc2SC)c1
Temperature: 25 °C

Procedure:
A Grignard reagent was prepared from the product of step (d) above (12.3 g), magnesium (1.28 g) and iodine (1 crystal) in dry tetrahydrofuran (150 ml). 4-Methoxypyridine (5.76 g) was dissolved in dry tetrahydrofuran (300 ml) and stirred under nitrogen. The solution was cooled to -70°and treated with the above Grignard solution in one portion. After stirring for 10 minutes phenylchloroformate (6.6 ml) was added dropwise. After stirring at -70°for 30 minutes the mixture was allowed to warm up to room temperature. After stirring for 90 minutes the mixture was poured onto water and extracted with ether. The ether was washed with water and brine then dried and evaporated. The residue was taken up in toluene (250 ml) and stirred at room temperature. A solution of 3,4,5,6-tetrachloro-1,2-benzoquinone (13.0 g) in acetic acid (120 ml) was added dropwise. When addition was complete the mixture was stirred for a further 18 hours. The mixture was ice cooled and treated with a cold solution of sodium hydroxide (700 ml of 10%). After stirring for 10 minutes the mixture was filtered and separated. The aqueous filtrates were extracted with ether and the combined organic filtrates were extracted with dilute hydrochloric acid. The extracts were combined and basified with sodium hydroxide solution. The mixture was extracted with ether and the combined extracts washed with brine then dried and evaporated. Flash chromatography (1:1 ethyl acetate/petroleum ether) produced the subtitle compound as a clear oil 5.4 g. NMR (CDCl3) d 8.50 (d,1 H), 7.39 (d,1H), 7.60 (d,1H), 6.85 (d,1H), 6.77 (m,2H), 3.88 (s,3H), 3.86 (s,3H), 2.40 (s,3H).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18](O)=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:21][CH2:22][O:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:30])[CH:5]=1.[NH3:31]>O1CCCC1>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([NH2:31])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:21][CH2:22][O:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:30])[CH:5]=1
Reactant: O=C(O)COc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(CCOC(=O)C(F)(F)F)C2
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)COc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(CCOC(=O)C(F)(F)F)C2
Temperature: 50 °C
Reaction time: 16 h

Procedure:
{[(5,6-Dichloro-3-oxo-2,3,9,9a-tetrahydro-9a-(2-trifluoroacetoxyethyl)-1H-fluoren-7-yl]oxy}acetic acid (4.67 g, 10 mMole) is dissolved in tetrahydrofuran (30 ml) and 1,1-carbonyldiimidazole (1.78 g, 11 mMole) and the mixture stirred at ambient temperature for 30 minutes. The solution is saturated with ammonia gas and then stirred at ambient temperature for 24 hours and at 50° C. for 16 hours. Evaporation of the solvent and recrystallization from nitromethane yields [(5,6-dichloro-3-oxo-2,3,9,9a-tetrahydro-9a-(2-trifluoroacetoxyethyl)-1H-fluoren-7-yl)oxy]acetamide.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)([O-:5])=[O:4].C(OC([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][N:29]=2)[C:24]([CH2:31]Cl)=[CH:23]1)=O)(C)(C)C>C1COCC1>[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][N:10]2[CH2:31][C:24]1[C:25]2[C:30](=[N:29][CH:28]=[CH:27][CH:26]=2)[NH:22][CH:23]=1)([O-:5])=[O:4]
Reactant: CC(C)(C)OC(=O)n1cc(CCl)c2cccnc21
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc2c1ccn2Cc1c[nH]c2ncccc12
Reaction time: 4 h
Yield: 34 %

Procedure:
Sodium hydride (144 mg, 6 mmol) was added to a solution of 4-nitroindole (973 mg, 6 mmol) in THF, and the resulting mixture was stirred for 4 h. 1-(t-Butyloxycarbonyl)-3-chloromethyl-7-azaindole (Int-14, 1.5 g, 5.5 mmol) was then added. Upon completion (by TLC), the reaction was quenched with saturated aqueous ammonium chloride. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography to provide 3-[(4-nitro-1H-indol-1-yl)methyl]-1H-pyrrolo[2,3-b]pyridine (547 mg, 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3OCCO3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.[NH2:21]O>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:21])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(-c2ccc(C3OCCO3)cc2)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2ccc(C#N)cc2)cc1
Yield: 75 %

Procedure:
2.6 g of 2-[p-(4-methoxy phenyl)-phenyl]-1,3-dioxolane, 0.917 g of hydroxylamine hydrochloride, 40 ml of 1.8 M hydrochloric ethanol and 10 ml of ethanol are introduced into a 100 ml three-necked flask under nitrogen. The reaction mixture is heated to reflux for 4 hours then concentrated under vacuum. The residue is taken up in 30 ml of water, then 220 ml of methyl ter-butyl ether (MTBE) is added. The organic phase is separated and the aqueous phase is extracted with MTBE (2×20 ml). The organic phases are combined, washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulphate and concentrated under vacuum (yield: 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[Cl:11][C:12]1[N:13]=[C:14](Cl)[C:15]2[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[S:18][C:16]=2[N:17]=1>>[Cl:11][C:12]1[N:13]=[C:14]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:15]2[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[S:18][C:16]=2[N:17]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(Cl)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 2,4-dichloro-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-nitro-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][O:18][NH:19][CH3:20].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:17][O:18][N:19]([CH3:20])[C:13]([CH:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:15]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
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: CN(C)C=O
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 15 °C
Reaction time: 16 h
Yield: 106 %

Procedure:
A mixture of 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (5.0 g, 23 mmol), O,N-dimethylhydroxylamine hydrochloride (4.51 g, 46.5 mmol), DIPEA (9.00 g, 69.6 mmol), and HATU (17.6 g, 46.5 mmol) in DMF (50 mL) was stirred at 15° C. for 16 h. DMF was removed, the residue was extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and evaporated to give the crude product, which was purified by silica gel chromatography eluting with a 0-30% gradient of EtOAc in petroleum ether to afford tert-butyl 3-(N-methoxy-N-methylcarbamoyl)pyrrolidine-1-carboxylate (6.3 g, 90% yield) as pale yellow oil. LCMS (ESI) m/z: 203.2 [M-56+H+].
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:18]=[CH:17][C:8]2[C:9]([C:12](=[NH:16])OCC)=[N:10][O:11][C:7]=2[CH:6]=1)([O-:4])=[O:3].[NH3:19]>C(O)C>[C:12]([C:9]1[C:8]2[CH:17]=[CH:18][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][C:7]=2[O:11][N:10]=1)(=[NH:16])[NH2:19]
Reactant: N
Reactant: CCOC(=N)c1noc2cc([N+](=O)[O-])ccc12
Agent: Cl
Solvent: CCO
Product: N=C(N)c1noc2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In ethanol (100 ml) was dissolved ethyl 6-nitro- 1,2-benzisoxazole-3-formimidate hydrochloride (2.0 g) and the mixture was saturated with ammonia by passing through thereto ammonia gas under stirring at room temperature. The mixture was allowed to stand at room temperature overnight and then ethanol was distilled off under a reduced pressure. The crystalline residue was washed with ether and dissolved in water. The solution was neutralized with sodium bicarbonate and extracted with ether. The extract was distilled to remove ether to give the desired compound (1.2 g), which was recrystallized from chloroform. m.p. 182° to 185°C.
Reaction SMILES: [CH-:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li+].[CH3:11]OS(OC)(=O)=O.O>C(OCC)C>[CH3:11][C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]=1
Reactant: COS(=O)(=O)OC
Reactant: c1ccc2[cH-]ccc2c1
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC1=CCc2ccccc21
Yield: 94.6 %

Procedure:
Lithium indenide (9.60 g, 0.0786 moles) in diethylether (100 mL) was added dropwise to a solution of dimethylsulfate (9.91 g, 0.0786 moles) in diethylether (125 mL) over a period of 15 minutes. After the addition was complete, H2O (150 mL) was added to the reaction. The organic layer was then separated and washed with H2O (2×100 mL). Drying over MgSO4 followed by filtration and solvent removal yielded the desired product as a yellow oil (9.68 g, 94.7 percent).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].C([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=O)C>>[O:33]=[C:29]1[NH:30][CH2:31][CH2:32][N:28]1[C:2]1[CH:7]=[C:6]([N:30]2[CH2:31][CH2:32][NH:28][C:29]2=[O:33])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3Br)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCNC4=O)cc3N3CCNC3=O)CC2)c(C)c1
Yield: 26.9 %

Procedure:
Using (2,4-dibromophenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (258 mg) described in Preparation Example 237 and 1-acetylimidazolidin-2-one (219 mg) and by the reaction and treatment in the same manner as in Example 638, the title compound (71 mg) was obtained.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)(=O)=O.[CH3:17][S-:18].[Na+].O>CN(C=O)C>[CH3:17][S:18][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1
Reactant: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCCc1cccc([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
A solution of 3-nitrophenethyl methanesulfonate (6 g, 24.5 m mol) in DMF (30 mL) was stirred at room temperature, then sodium methyl mercaptide (22 g, 20%) was added, followed by stirring at 70° C. overnight. Water was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate 3 times. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated to give methyl(3-nitrophenethyl)sulfane (4.4 g, yield 91%). 1H NMR: 400 MHz CDCl3 δ 8.09-8.07 (m, 2H), 7.53-7.56 (m, 1H), 7.49-7.45 (m, 1H), 3.03-2.99 (m, 2H), 2.81-2.78 (m, 2H), 2.16 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[CH2:12][CH2:11][C@@H:10]([NH:13]C(OCC=C)=O)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CN1C(=O)CC(=O)N(C)C1=O>C(Cl)Cl.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:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCOC(=O)N[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55.8 %

Procedure:
A mixture of ((1R,3R)-3-allyloxycarbonylamino-cyclopentyl)-carbamic acid tert-butyl ester (890 mg, 3.13 mmol), 1,3-dimethylbarbituric acid (1.47 g, 9.39 mmol) and Pd(PPh3)4 (181 mg, 0.15 mmol) in DCM (30 mL) was stirred at ambient temperature for 90 minutes. The reaction mixture was concentrated under vacuum and purified by column chromatography on silica gel (gradient: 2M NH3 in methanol solution in DCM) to afford 350 mg (56%) ((1R,3R)-3-amino-cyclopentyl)-carbamic acid tert-butyl ester. LCMS (Method H, ESI): RT=0.36 min, m+H=200.9; 1H NMR (400 MHz, DMSO) δ: 6.77 (s, 1H), 3.90 (m, 1H), 3.31 (m, 1H), 1.87 (m, 2H), 1.54 (m, 2H), 1.37 (s, 10H), 1.18 (m, 1H).