Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8](=[O:23])[N:9]([CH2:13][C:14]1[CH:19]=[C:18]([CH:20]=[O:21])[CH:17]=[CH:16][C:15]=1[Cl:22])[CH:10]1[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].O>CC#N>[C:3]([O:7][C:8](=[O:23])[N:9]([CH2:13][C:14]1[CH:19]=[C:18]([CH2:20][OH:21])[CH:17]=[CH:16][C:15]=1[Cl:22])[CH:10]1[CH2:11][CH2:12]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N(Cc1cc(C=O)ccc1Cl)C1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1cc(CO)ccc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
NaBH4 (1.48 g, 37.7 mmol) was added to a sol. of (2-chloro-5-formyl-benzyl)-cyclopropyl-carbamic acid tert-butyl ester (11.7 g, 37.7 mmol) in CH3CN (113 mL) under N2. The mixture was stirred at rt for 1 h, and water (113 mL) was added. The mixture was stirred at rt for 5 min, and extracted with CH2Cl2 (3×). The combined org. layers were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (heptane/EtOAc 7:3) yielded the title compound (6.53 g, 56%). LC-MS: tR=0.96 min; ES+: 297.37.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8](=[O:12])[CH2:9][C:10]#[N:11])=[C:3]1[CH3:13].C1(C)C=CC=CC=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(N(CC)CC)C>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8](=[O:12])[CH:9]([C:28](=[O:29])[NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]#[N:11])=[C:3]1[CH3:13]
Reactant: Cc1cc(C(=O)CC#N)c(C)n1C
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)C(C#N)C(=O)Nc2ccccc2)c(C)n1C
Reaction time: 8 h

Procedure:
The suspension of 1.0 g of 1,2,5-trimethyl-β-oxo-3-pyrrolpropionitrile, 40 ml of toluene and 0.7 g of triethylamine is treated with 0.75 g of phenylisocyanate and warmed for 5 minutes on the steam cone until all is dissolved. After standing overnight, the precipitate formed is collected, taken up in methanol, and the solution added to the mixture of 3 ml of 5 N hydrochloric acid and 250 ml of water. The crude product formed is collected, washed with water, dissolved in 5% aqueous sodium hydroxide, filtered, and the alkaline filtrate acidified with 5 N hydrochloric acid. The precipitate is collected, washed with water, air-dried and recrystallized from ethanol, to yield the 1,2,5-trimethyl-β-oxo-α-phenylcarbamoyl-3-pyrrolpropionitrile melting at 158°-160°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][OH:28].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:25][CH2:26][CH2:27][OH:28]
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.9 %

Procedure:
A stirred solution of 10.1 grams (0.038 mole) of 2,6-dichloro-4-(phenylmethoxy)phenol (known compound) and 8.0 grams (0.058 mole) of potassium carbonate in 150 mL of DMF was cooled to 0–4° C. and 3.7 mL (0.041 mole) of 3-bromopropan-1-ol was slowly added. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it was stirred during an 18 hour period. After this time water was added to the reaction mixture, and the mixture was extracted with two 150 mL portions of diethyl ether. The combined extracts were dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield 11.8 grams of residual solid. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:24][OH:25]>CN(C=O)C.CC(=O)OCC>[C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21](=[NH:22])[NH:24][OH:25])=[CH:19][CH:20]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NO
Reactant: COC(=O)CN(Cc1ccc(C#N)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CN(Cc1ccc(C(=N)NO)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 85 %

Procedure:
Prepared using General Procedure 19. To a stirring solution of methyl 2-((tert-butoxycarbonyl)(4-cyanobenzyl)amino)acetate INT-74 (1.35 g, 4.44 mmol) in DMF (8 mL) was added TEA (1.546 mL, 11.09 mmol) followed by hydroxylamine hydrochloride (0.771 g, 11.1 mmol). After stirring at room temperature for 48 h the reaction mixture was diluted with EA (100 mL) and the washed with brine (2×150 mL). The crude product was purified by chromatography (MeOH/DCM) to afford 1.28 g (85%) of methyl 2-((tert-butoxycarbonyl)(4-(N-hydroxycarbamimidoyl)benzyl)amino)acetate INT-75 as a viscous oil. LCMS-ESI (m/z) calculated for C16H23N3O5: 337; found 338 [M+H]+, tR=1.17 min (Method 10).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[C:8]1([C:14](Cl)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1>O>[C:8]1([C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C#CCCCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: C#CCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A stirred mixture of 9.81 g. (0.10 moles) of 5-hexyn-1-ol, 33.5 g. (0.12 moles) of triphenylmethyl chloride, and 200 ml. of dry pyridine is refluxed for 60 minutes. The cooled mixture is poured into water and extracted with ether. The extract is washed successively with water, ice-cold N hydrochloric acid, water, saturated sodium bicarbonate solution, and saturated sodium chloride solution. The extract is dried with magnesium sulfate. The crude product obtained after evaporation of the solvent is purified by chromatography on Florisil to give an oil, ν max. 3290 (acetylenic hydrogen), 1600, 1072, and 705 cm-1 (triphenylmethoxy group).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=[O:5])=[O:4].[Li]CCCC.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C1COCC1.O>[CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1ccnc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)S(=O)(=O)n1ccnc1[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 24 h

Procedure:
Imidazole (Intermediate L1, available from Aldrich, 20.0 g, 0.29 mol), triethylamine (41.0 mL, 0.29 mol) and N,N-dimethylsulfamoyl chloride (31.6 mL, 0.29 mol) were added to benzene (320 mL). The reaction was stirred for 48 h at rt and then filtered. The filtrate was collected and concentrated under reduced pressure. Vacuum distillation of the crude produce (˜0.5 mmHg, 115-118° C.) afforded dimethylsulfamoyl) imidazole (Intermediate L2) 38.7 g (76%) as a clear and colorless oil. Upon cooling the product solidifies to give white crystals. 1-(Dimethylsulfamoyl) imidazole (Intermediate L2) (18.8 g, 0.11 mol) was added to THF (430 mL). The solution was cooled to −78° C. A solution of n-BuLi (70.9 mL, 1.6 M in hexane) was added dropwise to the reaction mixture. Upon completion, the solution was stirred for 1 h at −78° C. t-Butyldimethylsilylchloride (TBSCl) (17.8 g, 0.12 mol) in THF (50 mL) was added via cannula to the mixture. After the addition was completed the reaction mixture was warmed slowly to rt and stirred for 24 h. The mixture was diluted with water and the organic layer separated. The organic phase was washed with brine and then dried over Na2SO4. The mixture was filtered and the filtrate concentrated under reduced pressure. Column chromatography on SiO2 with 20% ethyl acetate/hexane afforded 1-dimethylsulfamoyl-2-t-butyldimethylsilyl imidazole (Formula 13) as a light yellow solid. Recrystallization from pentane gave 30 g (94%) of white crystals.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:41]([CH3:43])[CH3:42])[C:10]([O:12][CH:13]1[CH2:17][CH2:16][CH:15]([N:18]2[C:22]3[N:23]=[CH:24][N:25]=[C:26]([NH2:27])[C:21]=3[C:20]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:30][CH:29]=3)=[CH:19]2)[CH2:14]1)=[O:11])=O)(C)(C)C.[ClH:44].C(OCC)C>C(OCC)(=O)C>[ClH:44].[NH2:8][C@@H:9]([CH:41]([CH3:43])[CH3:42])[C:10]([O:12][CH:13]1[CH2:17][CH2:16][CH:15]([N:18]2[C:22]3[N:23]=[CH:24][N:25]=[C:26]([NH2:27])[C:21]=3[C:20]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:30][CH:29]=3)=[CH:19]2)[CH2:14]1)=[O:11]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OC1CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)[C@H](N)C(=O)OC1CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reaction time: 0.5 h

Procedure:
3-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoate (35 mg, 0.060 mmol) was dissolved in ethyl acetate (2.5 ml). Hydrogen chloride gas was passed through for 5 minutes. The flask was capped and the solution stirred for additional 30 minutes. Diethyl ether was added and precipitate formed. The solid was collected by filtration to give 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl (2S)-2-amino-3-methylbutanoate hydrochloride. The structure was confirmed by 1H NMR and LC/MS (MH+=486).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:20][S:21]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[O:12])[N:10]=2)[CH2:5]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCN(C(=O)c2csc(N3CC(O)C3)n2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2csc(N3CC(OS(C)(=O)=O)C3)n2)CC1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 3-hydroxy-1-[4-(4-methylpiperazine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (422 mg, 1.49 mmol) (obtained as described in Reference Example 30(2)) in methylene chloride (21 ml) were added methanesulfonyl chloride (0.14 ml, 1.79 mmol) and triethylamine (0.25 ml, 1.79 mmol) in an ice bath, and then the mixture was stirred for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:methanol (3:1) as the eluant to afford 3-methanesulfonyloxy-1-[4-(4-methylpiperazine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (537 mg, yield 100%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][NH:5][C:4](Br)([CH3:9])[CH:3]=1.[CH3:11][NH2:12]>CO>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH2:9][NH:12][CH3:11])[CH:3]=1
Reactant: CC1(Br)C=C(Cl)C(F)=CN1
Reactant: CN
Solvent: CO
Product: CNCc1cc(Cl)c(F)cn1
Temperature: 25 °C
Reaction time: 26 h
Yield: 70 %

Procedure:
4-Chloro-5-fluoro-alpha-bromo-2-picoline (1.37 g, 6.1 mmol), from Step 1 was dissolved in 15 mL of methanol in a pressure tube. Methylamine (3 mL of 40% aqueous solution) was added to the tube and the tube was sealed. The reaction mixture was stirred at ambient temperature for 26 hours and then the solvent was removed under reduced pressure. To the residue was added 50 mL of 10% aqueous sodium carbonate solution and the resultant aqueous mixture was extracted with 3×50 mL of methylene chloride. The organic combined extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dried in vacuo to give 754 mg g (70% yield) of the title compound; MS DCI-NH3M/Z: 175 (M+H)+ base; 1H NMR (CDCl3) d 2.50 (s, 3H), 3.90 (s, 2H), 7.47 (d, 1H), 8.42 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[N:10]1([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH:22]=O)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CCO>[I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8]/[N:9]=[CH:22]/[C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([O:18][CH2:17][CH2:16][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH:20]=2)=[N:6][CH:7]=1
Reactant: O=Cc1cccc(OCCN2CCOCC2)c1
Reactant: NNc1ccc(I)cn1
Solvent: CCO
Product: Ic1ccc(N/N=C/c2cccc(OCCN3CCOCC3)c2)nc1
Temperature: 25 °C
Yield: 86306.9 %

Procedure:
To a suspension of 5-iodo-2-hydrazinopyridine (6.62 g, 0.028 mmol) in EtOH (90 mL) was added 3-(2-morpholin-4-yl-ethoxy)-benzaldehyde (6.63 g, 0.028 mmol). The reaction was heated at reflux for 2 h under nitrogen, then cooled to RT. The resulting precipitate was collected by filtration and washed with EtOH to afford the title compound (10.93 g, 86%) as a white solid. LCMS (Method 1): Rt 2.37 min, m/z 453 [MH+]. 1H NMR (300 MHz, CD3OD): δ 8.24 (1 H, d, J 2.2), 7.90-7.84 (2 H, m), 7.36-7.18 (3 H, m), 7.12 (1 H, d, J 8.8), 6.94-6.89 (1 H, m), 4.19 (2 H, t, J 5.4), 3.72 (4 H, t, J 4.6), 2.83 (2 H, t, J 5.4), 2.62 (4 H, t, J 4.6).
Reaction SMILES: [I-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])C=CC=CC=1.CC(C)([O-])C.[K+].[NH2:33][C:34]1[N:39]=[C:38]([N:40]([CH3:47])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:37]=[C:36]([C:48]2[N:52]=[C:51]([N:53]3[CH2:58][CH2:57][C:56](=O)[CH2:55][CH2:54]3)[O:50][N:49]=2)[N:35]=1>O1CCOCC1.C(Cl)Cl>[CH3:47][N:40]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:38]1[N:39]=[C:34]([NH2:33])[N:35]=[C:36]([C:48]2[N:52]=[C:51]([N:53]3[CH2:54][CH2:55][C:56](=[CH:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH2:57][CH2:58]3)[O:50][N:49]=2)[N:37]=1
Reactant: FC(F)(F)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(N3CCC(=O)CC3)n2)n1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(N3CCC(=CCC(F)(F)F)CC3)n2)n1
Reaction time: 0.17 h
Yield: 11.9 %

Procedure:
To a solution of triphenyl-(3,3,3-trifluoro-propyl)-phosphonium iodide (146 mg, 0.30 mmol) in anhydrous dioxane (10 mL) at 0 C under nitrogen was added potassium tert-butoxide (34 mg, 0.3 mmol) portion-wise. The suspension was stirred for 10 min at 0 C and then added drop-wise to a solution of 1-{3-[4-amino-6-(methyl-phenyl-amino)-[1,3,5]triazin-2-yl]-[1,2,4]oxadiazol-5-yl}-piperidin-4-one (Intermediate 131, 55 mg, 0.150 mmol) in anhydrous dioxane (10 mL). The resulting reaction mixture was stirred at room temperature for 16 h and evaporated to dryness. The solid obtained was dissolved in DCM (25 mL) and washed with water (25 mL), a saturated ammonium chloride aq. solution (25 mL) and brine (25 mL). The organic phase was dried over magnesium sulfate, evaporated to dryness and purified by preparative HPLC-MS (Method B) to afford the title compound as an off-white solid (8 mg, 12%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[Cl:17][C:4]1[CH:3]=[C:2]([C:24]2[CH:25]=[CH:26][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Product: Cc1c2n(c3c(-c4ccc([N+](=O)[O-])cc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, yellow solid (79 mg, 89%), MS (ISP) m/z=356.5 [(M+H)+], mp 313.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-nitro-phenylboronic acid (54.3 mg, 0.325 mmol).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[OH-].[NH4+:13]>>[Br:1][C:2]1[C:10]2[C:9]([NH2:13])=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: [NH4+]
Reactant: Clc1ncnc2scc(Br)c12
Agent: [OH-]
Product: Nc1ncnc2scc(Br)c12
Temperature: 90 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
A suspension of 5-bromo-4-chlorothieno[2,3-d]pyrimidine (1 g, 4.01 mmol) in concentrated aqueous ammonium hydroxide (150 mL, 3852 mmol) was stirred overnight at 90° C. in a sealed vessel. The reaction was allowed to cool to room temperature and filtered. The white solid in the filter was air dried to afford 5-bromothieno[2,3-d]pyrimidin-4-amine (796 mg). LC/MS (ES) m/z=387.1 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH2:13])C)=[CH:2]1.[C:14](OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:14][C:2]1[NH:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH2:10][CH2:11][NH2:13]
Reactant: C[C@H](N)Cc1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1[nH]c2ccccc2c1CCN
Temperature: 25 °C

Procedure:
A mixture of (S)-2-(1H-Indol-3-yl)-1-methylethylamine (0.43 g, 2.5 mmol) and di-t-butyl dicarbonate (0.60 g, 2.75 mmol) in acetone is treated dropwise with aqueous K2CO3 (3.5 g, 25 mmol) at OC, allowed to warm to room temperature for 16 h, concentrated to an aqueous residue and extracted with EtOAc. The extracts are combined, dried over MgSO4 and concentrated in vacuo to dryness. This residue is chromatographed (silica gel, 10%–50% EtOAc in hexanes as gradient eluent) to give the protected ®-2-methyl tryptamine. A mixture of the protected tryptamine (0.17 g, 0.62 mmol) and 6-chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride (0.16 g, 0.62 mmol) in THF is treated with potassium t-butoxide (77 mg, 0.68 mmol) at room temperature, stirred for 1H, poured into saturated NaHCO3 and extracted with EtOAc. The extracts are combined, dried over Na2SO4 and concentrated in vacuo. The resultant residue is dispersed in THF and 4N HCl in dioxane, stirred for 16 h, concentrated in vacuo and purified by HPLC1 to afford the title product as a beige solid, 0.62 mg (35% yield), identified by NMR and mass spectral analyses. 1HPLC conditions: Hewlett Packard 1100 HPLC system; Waters Xterra C18, 2 mm×30 mm ID, 3 uM column; 5 uL injection; Solvent A: 0.02% TFA/water; Solvent B: 0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 0.2 min: 95% A; 3 min: 5% A; Flow rate 1.2 mL/min; Detection: 254 nm DAD.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=[O:7].[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1.N1C=CC=CC=1>O1CCCC1>[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:9][NH:8][C:6]([C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)=[O:7])=[O:16])=[CH:13][CH:12]=1
Reactant: NNC(=O)c1ccc[nH]1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(NNC(=O)c1ccc[nH]1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 0.750 g of 1H-pyrrole-2-carbohydrazide (5.99 mmol) in 50 ml tetrahydrofuran was added 1.315 g 4-bromobenzoyl chloride (5.99 mmol) and 1 ml pyridine (11.99 mmol) at room temperature under nitrogen. After one hour of stirring at room temperature, the desired product precipitated. The precipitate was filtered, washed with minimum dichloromethane and methanol and dried to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 10.47 (s, 1H), 10.04 (s, 1H), 7.84-7.88 (m, 2H), 7.75 (d, J=8.8, 1H), 7.75 (q, J=4.2, 1H), 6.91-6.95 (m, 2H), 6.33-6.15 (m, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Ni].C1(C)C(C)=CC=CC=1>[C:10]([NH:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:21][CH2:20]1)(=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OCCc1ccccc1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: [Ni]
Solvent: Cc1ccccc1C
Product: O=C(NC1CCN(CCc2ccccc2)CC1)c1ccccc1

Procedure:
2-Phenylethanol (0.61 g., 0.005 mole), 4-benzamidopiperidine (1.02 g., 0.005 mole) and Raney Nickel (W7, ca. 2g.) were stirred in xylene (50 ml.)and the mixture boiled under reflux for 16 hours. Liberated water was removed by means of a Dean and Stark apparatus. Filtration of the hot mixture provided a yellow solution which was stored at room temperature until crystallisation was complete. The title compound was obtained as cream needles (0.85 g.), m.p. 164°-7° C.
Reaction SMILES: [CH2:1]([O:6][C:7]1[C:8](=[O:14])[CH:9]=[CH:10][C:11](=[O:13])[CH:12]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].[CH:15]([C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1)=[CH2:16]>CO>[CH2:1]([O:6][C:7]1[C:8](=[O:14])[C:9]2[C:10](=[CH:16][CH:15]=[C:17]3[C:18]=2[CH2:19][CH2:20][CH2:21][CH2:22]3)[C:11](=[O:13])[CH:12]=1)[CH:2]=[C:3]([CH3:5])[CH3:4]
Reactant: C=CC1=CCCCC1
Reactant: CC(C)=CCOC1=CC(=O)C=CC1=O
Solvent: CO
Product: CC(C)=CCOC1=CC(=O)c2ccc3c(c2C1=O)CCCC3
Yield: 34.8 %

Procedure:
2-Prenyloxy-1,4-benzoquinone (3.0 g, 15.6 mM) and 1-Vinylcyclohexene (6.75 g, 62.5 mM) were dissolved in 50 ml of MeOH, and refluxed for 3 hours. 3-Prenyloxy-5,6,7,8-tetrahydro-1,4-phenanthrenequinone (1.61 g, 5.44 mM) was obtained in the same manner as in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][CH:12]([CH2:17][OH:18])[CH2:13][CH2:14][CH2:15][CH3:16])=O)[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)Cl>>[CH2:13]([CH:12]1[CH2:17][O:18][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:11]1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(CO)NC(=O)Nc1cccc(Cl)c1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCC1COC(Nc2cccc(Cl)c2)=N1
Reaction time: 8 h

Procedure:
Compound 978 (50 mg) was treated with POCl3 (1.0 mL). This was stirred overnight. The solvent was removed via reduced pressure distillation. The residue was washd with aqueous sodium bicarbonate and then dissolved in EtOAc. The solvent was dried, filtered and evaporated. The residue was dissolved in acetone (1 mL) and refluxed with water (2 mL) for 1.5 hrs. The solution was extracted with EtOAc, the organic layer evaporated and the residue chromatographed on silica to give the target compound. 1H NMR (300 MHz, CDCl3) δ=7.38 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.05 (br, 1H), 7.00 (d, 7.5 Hz, 1H), 4.47 (m, 1H), 3.95 (m, 2H), 1.8-1.2 (m, 6H), 0.95 (m, 3H). ESIMS=224.9 m/z (M+H)
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2].C(O[C:12]1(O[Si](C)(C)C)[CH2:14][CH2:13]1)C.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:12]1([N:6]2[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]2)[CH2:14][CH2:13]1
Reactant: N#CC1CCNCC1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#CC1CCN(C2CC2)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
5.0 g (45.4 mmol) of 4-cyanopiperidine were dissolved in 83 ml of methanol, and 11.9 g (68.1 mmol) of [(1-ethoxy-1-cyclopropyl)oxy]trimethylsilane, 2.9 ml (3.0 g, 49.9 mmol) of acetic acid and 6.0 g (91.0 mmol) of sodium cyanoborohydride were added. The reaction mixture was stirred at 60° C. for 16 h, cooled to RT and then filtered through kieselguhr, the filter cake was washed with methanol and the filtrate was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed twice with 1 N aqueous sodium hydroxide solution and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. Yield: 6.0 g (88% of theory)