Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH2:35]([NH2:39])[CH2:36][CH2:37][CH3:38].CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:35]([NH:39][C:27]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][CH:18]=1)=[O:33])[CH2:36][CH2:37][CH3:38]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCN
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and a solution of triphosgene (50 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, butylamine (22 μl) was added to the reaction solution, and the mixture was further stirred at room temperature overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 29 mg (yield 43%) of the title compound.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].[NH:11](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[CH2:12][C:13](O)=[O:14].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>ClCCl.C(OCC)(=O)C>[NH2:11][CH2:12][C:13]([NH:9][CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:10])=[O:14]
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)CN
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of the glycine tert-butyl ester hydrogen chloride salt (70) (484 mg, 2.9 mmol) in dichloromethane (25 mL) was added Fmoc-Gly-OH (71) (0.861 mg, 2.99 mmol), DIPEA (756 mg, 4.35 mmol) and HATU (1.3 g, 3.5 mmol). The reaction mixture was stirred at an ambient temperature for 16 h and then poured into ethyl acetate and was washed with water (3×) and brine (1×). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified via radial chromatography on a 2 mm plate eluting with 5% methanol/dichloromethane. Product containing fractions were concentrated under reduced pressure and treated with 20% piperidine/dichloromethane (10 mL) for 1 h, before being concentrated under reduced pressure and then purified twice via radial chromatography on a 2 mm plate eluting with a gradient of 5 to 10% methanol/dichloromethane to provide (200 mg, 37%): 1H-NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 4.00 (s, 2H), 3.39 (s, 2H), 1.47 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=C2[C:8](=[N:9][C:10]=1[CH3:11])[NH:7][N:6]=N2.[CH3:13][N:14](C)C1C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[N:31][C:32]2[CH:40]=[C:36]([C:37](Cl)=[O:38])[C:35]([OH:41])=[CH:34][CH:33]=2)=[CH:26][CH:25]=1.Cl>CN(C)C=O>[OH:41][C:35]1[CH:34]=[CH:33][C:32]([N:31]=[N:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)=[CH:40][C:36]=1[C:37]([NH:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:7]([N:6]=[CH:13][N:14]=2)[C:3]=1[OH:12])=[O:38]
Reactant: CN(C)c1ccccc1
Reactant: Cc1nc2[nH]nnc2c(O)c1N
Reactant: COc1ccc(N=Nc2ccc(O)c(C(=O)Cl)c2)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(N=Nc2ccc(O)c(C(=O)Nc3c(C)nc4ncnn4c3O)c2)cc1

Procedure:
5-Amino-4-hydroxy-6-methyltetraazaindene (0.5 g) was dissolved in dry N,N-dimethylformamide (10 ml) and dimethylaniline (0.37 g) added. 5-(4-Methoxyphenylazo)salicoyl chloride (0.88 g) was added portionwise at room temperature with stirring. After 12 hours the mixture was poured into iced dilute hydrochloric acid and the crude product collected, washed with water and dried. The material was extracted with a large volume of ether and crystallized in aqueous ethanol as the monohydrate (0.8 g, 61%), m.p. 323°-324° decomp., λmax (methanol)=354 nm.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[Br:5][CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=[O:8]>>[Br-:5].[C:7]([CH:6]([S:3][C:2]([NH2:4])=[NH2+:1])[CH2:10][CH3:11])([OH:9])=[O:8]
Reactant: NC(N)=S
Reactant: CCC(Br)C(=O)O
Product: CCC(SC(N)=[NH2+])C(=O)O
Product: [Br-]
Yield: 79 %

Procedure:
Example 1 was repeated with thiourea and 2-bromobutyric acid, affording the title compound in a yield of 79%.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH2:6][C:7]1([CH3:24])[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([O:20]C(=O)C)=[C:16]([CH2:17][CH2:18][CH3:19])[C:9]=2[O:8]1)C.B(F)(F)F.[CH3:30][CH2:31][O:32]CC>C(O)(=O)C.CCOCC>[C:31]([C:14]1[C:15]([OH:20])=[C:16]([CH2:17][CH2:18][CH3:19])[C:9]2[O:8][C:7]([CH3:24])([CH2:6][CH2:5][C:4]([OH:3])=[O:25])[CH2:12][CH2:11][C:10]=2[CH:13]=1)(=[O:32])[CH3:30]
Reactant: CCCc1c(OC(C)=O)ccc2c1OC(C)(CCC(=O)OCC)CC2
Reactant: CCOCC
Agent: FB(F)F
Solvent: CC(=O)O
Product: CCCc1c(O)c(C(C)=O)cc2c1OC(C)(CCC(=O)O)CC2
Temperature: 105 °C
Reaction time: 24 h
Yield: 72.1 %

Procedure:
To a stirred solution of 276 mg of racemic-7-acetoxy-3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester in 2 ml of glacial acetic acid was added 0.21 ml of boron trifluoride etherate, at room temperature. The mixture was stirred at 105° C. for 24 hours then cooled and diluted with ether. The ether solution was washed with water and brine and processed in the usual manner given 298 mg of a yellow-brown oil. This material was chromatographed on 30 g of silica gel. Elution with 4:1 toluene-ethyl acetate afforded 183 mg (72.1%) of racemic-6-acetyl-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid as an off-white solid, mp 154°-156° C.
Reaction SMILES: [C:1]([C:3]1[C:8]2[CH2:9][C:10](=O)[C:11]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].O.[NH2:21][NH2:22]>C(O)C>[C:1]([C:3]1[C:8]2[CH2:9][C:10](=[N:21][NH2:22])[C:11]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: NN
Reactant: N#Cc1cccc2c1CC(=O)c1cc(F)ccc1S2
Solvent: O
Solvent: CCO
Product: N#Cc1cccc2c1CC(=NN)c1cc(F)ccc1S2
Yield: 95 %

Procedure:
The mixture of 0.3 g of 9-cyano-2-fluoro-10,11-dihydrodibenzo[b,f]thiepin-11-one, 0.3 g of 100% hydrazine hydrate and 10 ml of ethanol was heated under reflux on waterbath for 5 hours. The reaction mixture was concentrated to 5 ml to separate crystals on cooling, which was collected by filtration. Recrystallization from ethanol afforded 0.3 g of 9-cyano-2-fluoro-10,11-dihydrodibenzo[b,f]thiepin-11-one hydrazone as pale yellow needles having a melting point of 220°-222° C.
Reaction SMILES: [Cl:1]Cl.[N+:3]([C:6]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:7]=1[NH2:8])([O-:5])=[O:4].C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:9]1[CH:10]=[C:11]([O:13][C:14]([F:15])([F:16])[F:17])[CH:12]=[C:6]([N+:3]([O-:5])=[O:4])[C:7]=1[NH2:8]
Reactant: Nc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Nc1c(Cl)cc(OC(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Chlorine gas was passed through a solution of 2-nitro-4-trifluoromethoxy-aniline (14.5 g) in carbon tetrachloride (175 ml). As the mixture was stirred it became solid and more carbon tetrachloride (50 ml) was added. Chlorine gas was passed through the reaction mixture until thin layer chromatography (silica gel, using petroleum ether (boiling range 60°-80° C.) containing ethyl acetate (30% by volume) as eluent) demonstrated the absence of starting material. Evaporation of the solvent under reduced pressure gave a dark orange solid, which on trituration with petroleum ether (boiling range 60°-80° C.) gave a 2-chloro-4-trifluoromethoxy-6-nitro-aniline as an orange solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:43])[CH2:3][C@@H:4]([C:33]([O:35]CC1C=CC=CC=1)=[O:34])[C:5]([CH2:23][N:24]1[C:28](=[O:29])[N:27]([CH3:30])[N:26]([CH3:31])[C:25]1=[O:32])([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:6]([O:8]CC1C=CC=CC=1)=[O:7]>CO.[Pd]>[C:19]([O:18][C:16]([C:5]([CH2:23][N:24]1[C:25](=[O:32])[N:26]([CH3:31])[N:27]([CH3:30])[C:28]1=[O:29])([C:6]([OH:8])=[O:7])[C@H:4]([C:33]([OH:35])=[O:34])[CH2:3][CH:2]([CH3:43])[CH3:1])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(Cn1c(=O)n(C)n(C)c1=O)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)O)C(Cn1c(=O)n(C)n(C)c1=O)(C(=O)O)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
2.464 g of 1,2-dibenzyl 1 -tert.butyl 4-methyl-1 -[(1,2-dimethyl-3,5-dioxo- 1,2,4-triazolidin-4-yl)methyl]-1,1,2(R)-pentanetricarboxylate were dissolved in 40 ml of methanol containing 0.25 g of 10% palladium-on-charcoal catalyst. The mixture was hydrogenated for 2 hours, the catalyst was removed by filtration and the solvent evaporated to give 1-(tert.butoxycarbonyl)-4-methyl-1-[(1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl) methyl]-1,2(R)-pentanedicarboxyic acid in the form of a colorless gum. The gum was dissolved in 60 ml of toluene containing 0.43 ml of N-methylmorpholine and the mixture was heated under reflux for 1 hour. The solution was washed with 5% aqueous citric acid solution, water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated to give 1.422 g of 2(R)-[1(R or S)-(tert.butoxycarbonyl)-2-(1,2-dimethyl-3,5-clioxo-1,2,4-triazolidin-4-yl) ethyl]-4-methylvaleric acid in the form of a waxy solid as an approximately 6:1 mixture of diastereoisomer 1 and diastereoisomer 2.
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][O:6][CH:5]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]=2[CH:3]=[CH:2]1.C1C(=O)N([I:26])C(=O)C1.CC(O)=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[I:26][C:2]1[S:1][C:9]2[CH2:8][CH2:7][O:6][CH:5]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)NCC1OCCc2sccc21
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCC1OCCc2sc(I)cc21
Yield: 583.8 %

Procedure:
A solution of tert-butyl (6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methylcarbamate (2.9 g, 1.3 mmol, 1 eq), NIS (5.2 g, 2.2 mmol, 2 eq), and AcOH (3 mL) in CHCl3 (50 mL) was stirred at room temperature for 7 hr. The reaction mixture was neutralized with triethyl amine, concentrated, and diluted with water. The mixture was extracted with n-hexane. The organic phase was dried over Na2SO4, concentrated, and purified by column chromatography to give the desired product (3 g).
Reaction SMILES: [ClH:1].O1CCOCC1.[O:8]([C:15]1[C:16]([NH:31][C:32]2[S:33][CH:34]=[C:35]([CH2:37][CH:38]3[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[CH2:40][CH2:39]3)[N:36]=2)=[N:17][CH:18]=[C:19]([S:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[CH:28]=[CH:29][S:30][C:23]=23)[CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl.CO>[ClH:1].[ClH:1].[O:8]([C:15]1[C:16]([NH:31][C:32]2[S:33][CH:34]=[C:35]([CH2:37][CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[N:36]=2)=[N:17][CH:18]=[C:19]([S:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[CH:28]=[CH:29][S:30][C:23]=23)[CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2csc(Nc3ncc(Sc4ccnc5ccsc45)cc3Oc3ccccc3)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: c1ccc(Oc2cc(Sc3ccnc4ccsc34)cnc2Nc2nc(CC3CCNCC3)cs2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
Added 4N HCl in dioxane (3.0 mL, 12.0 mmol) to a solution of tert-butyl 4-((2-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)thiazol-4-yl)methyl)piperidine-1-carboxylate (0.790 g, 1.25 mmol) in dichloromethane (4 mL) and methanol (4 mL). The reaction was stirred at ambient temperature for 3 hours. Concentrated, triturated with hexanes, filtered to afford the title compound (0.745 g, 98.5% yield) as a light yellow powder: 1H NMR (d-DMSO) δ 9.13 (m, 1H), 8.89 (m, 1H), 8.67 (d, 1H), 8.51 (d, 1H), 8.47 (s, 1H), 7.80 (d, 1H), 7.57 (s, 1H), 7.42 (t, 2H), 7.16-7.23 (m, 4H), 6.91 (s, 1H), 3.21 (m, 2H), 2.80 (m, 2H), 2.60 (d, 2H), 1.95 (m, 1H), 1.76 (m, 2H), 1.45 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]=O)=[C:4](Cl)[N:3]=1.[NH2:12][NH2:13].C(N(CC)CC)C.Cl.[CH:22]12[O:29][CH:26]([CH2:27][CH2:28]1)[CH2:25][NH:24][CH2:23]2>ClCCl.C(O)C>[Cl:1][C:2]1[N:3]=[C:4]2[NH:12][N:13]=[CH:9][C:5]2=[C:6]([N:24]2[CH2:23][CH:22]3[O:29][CH:26]([CH2:27][CH2:28]3)[CH2:25]2)[N:7]=1
Reactant: O=Cc1c(Cl)nc(Cl)nc1Cl
Reactant: NN
Reactant: C1CC2CNCC1O2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: Clc1nc(N2CC3CCC(C2)O3)c2cn[nH]c2n1
Temperature: -78 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
A nearly homogeneous suspension of 2,4,6-trichloro-pyrimidine-5-carbaldehyde (example 1, Scheme 28, 2.1 g, 10 mmol) in dichloromethane/ethanol (8:2, 100 mL) was cooled to −78° C. in a dry-ice/acetone bath. Anhydrous hydrazine (0.31 mL, 10 mmol) was added in drops via syringe, followed by triethylamine (4 mL), also via dropwise addition. The cooling bath was removed and after one hour, the opaque maroon mixture was treated with 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride (1.4 g, 9.4 mmol), followed by triethylamine (2 mL). The mixture was allowed to stir overnight. The maroon solid was collected by Buchner filtration, washed with ethanol, and then dried under house vacuum to give 3-(6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (0.82 g, 31%). MS (ES+): 266.2, 268.2 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:10]([CH:11]=1)[CH2:9][CH:8]([CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19](OC(C)(C)C)=O)[CH2:15][CH2:14]1)[O:7]2)([O-:3])=[O:2].C(N(CC)CC)C.[C:33]1([C:39]2[CH:46]=[CH:45][C:42](C=O)=[CH:41][CH:40]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[B-]C#N.[Na+].C(O)(=O)C>FC(F)(F)C(O)=O>[C:33]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:45][CH:46]=2)[CH:38]=[CH:37][C:36]([CH2:19][N:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH:8]3[O:7][C:6]4=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][N:10]4[CH2:9]3)[CH2:18][CH2:17]2)=[CH:35][CH:34]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(CC2Cn3cc([N+](=O)[O-])nc3O2)CC1
Agent: [B-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cn2c(n1)OC(CN1CCN(Cc3ccc(-c4ccccc4)cc3)CC1)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.7 %

Procedure:
A mixture of tert-butyl 4-(6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate prepared in Example 319 (400 mg, 1.13 mmol) and trifluoroacetic acid (10 ml) was stirred at room temperature for 4 hours. The reaction mixture was concentrated. The residue was dissolved in methylene chloride (10 ml) and neutralized with triethylamine (2 ml, 14.35 mmol). The resulting solution was concentrated under reduced pressure, and the residue was dissolved in methanol (10 ml). To the solution, 4-phenylbenzaldehyde (515 mg, 2.83 mmol), sodium cyanotrihydroborate (214 mg, 3.41 mmol) and acetic acid (0.21 mg, 3.67 mmol) were added in this order followed by stirring at room temperature overnight. The reaction mixture was concentrated. To the residue, water was added, and the solution was extracted with methylene chloride twice. The organic phases were combined, washed with a saturated sodium hydrogen-carbonate solution and a saturated saline solution in this order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1) to afford 2-[4-(biphenyl-4-ylmethyl)piperazin-1-ylmethyl]-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (188 mg, yield 40%) as a white powder.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)(O)[CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH3:15])=[CH:8][CH:7]=1.C(O)C.[ClH:34]>C(Cl)(Cl)Cl.CO>[ClH:34].[CH3:30][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9](/[C:12](/[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[C:13](\[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)/[CH2:14][CH3:15])=[CH:10][CH:11]=1
Reactant: CCC(c1ccccc1)C(O)(c1ccc(OCCN(C)C)cc1)c1cccc(O)c1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC/C(=C(/c1ccc(OCCN(C)C)cc1)c1cccc(O)c1)c1ccccc1

Procedure:
40.5 G. (0.1 mole) of the diastereomeric mixture of 1-[4'-(2-dimethylaminoethoxy)phenyl]-1-(3'-hydroxyphenyl)2-phenyl-n-butan-1-ol in 500 ml. ethanol are added to 25 ml. concentrated hydrochloric acid and refluxed for 2 hours. Then the solvent is removed in vacuo and the residue is crystallized from methanol/ ether (1/1). Obtained are colorless crystals having a melting point of 221° C. (dec.); Rf 0.25 [CHCl3 /CH3OH (7/3)]; yield 20.3 g. (48%).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH-].[K+].[OH:7][C:8]1[C:17]([CH:18]=[O:19])=[C:16]([O:20][CH3:21])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].Cl>CS(C)=O>[CH2:1]([O:7][C:8]1[C:17]([CH:18]=[O:19])=[C:16]([O:20][CH3:21])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(OC)c(C=O)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=CCOc1c(C(=O)OC)ccc(OC)c1C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 36 %

Procedure:
At room temperature, 23.2 g (0.192 mol) of allyl bromide were added dropwise to a mixture of 21.0 g (0.375 mol) of potassium hydroxide and 20.2 g (0.096 mol) of methyl 2-hydroxy-3-formyl-4-methoxybenzoate in 500 ml of dimethyl sulfoxide, and the mixture was stirred at room temperature for 4 hours. The mixture was subsequently added to 1.5 l of 3% strength aqueous hydrochloric acid with stirring and extracted with ethyl acetate. The combined organic phases were washed with water and dried, and the solvent was removed. Chromatography over silica gel using cyclohexane/ethyl acetate=1:2 gave 7.7 g (36% of methyl 2-allyloxy-3-formyl-4-methoxybenzoate in the form of a yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][N:3]=1.[C:13]([Cl:19])(=O)[CH2:14][C:15]([Cl:17])=O>C(#N)C.O>[Cl:17][C:15]1[CH:14]=[C:13]([Cl:19])[N:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:6]=[C:2]2[N:1]=1
Reactant: O=C(Cl)CC(=O)Cl
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Solvent: CC#N
Solvent: O
Product: Clc1cc(Cl)n2nc(-c3ccccc3)cc2n1
Reaction time: 2 h
Yield: 10 %

Procedure:
There was dissolved, in acetonitrile (20 mL), 3-amino-5-phenyl-pyrazole (1.00 g, 6.28 mM) in an argon gas atmosphere, malonyl chloride (672 μL, 6.91 mM) was added to the resulting solution with ice-cooling and the mixture was stirred for 2 hours. To this reaction liquid, there was further added malonyl chloride (210 μL, 2.15 mM) followed by stirring the mixture for one hour. This reaction liquid was diluted with water and then extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate and the solvent was then distilled off. After the addition of phosphoryl chloride (10 mL) to the resulting solid with ice-cooling, the resulting suspension was stirred for 4 hours, while refluxing the same with heating. The phosphoryl chloride was distilled off from the reaction liquid, the residue thus obtained was diluted with water and then extracted with methylene chloride. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and then the resulting residue was purified by the silica gel column chromatography (ethyl acetate/hexane=1:10) to thus give the title compound (168 mg, yield: 10%).
Reaction SMILES: [BH4-].[Na+].[I-].[CH3:4][NH+:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[CH:15]=2)[CH2:6]1>O.CO>[CH3:4][N:5]1[CH2:10][CH:9]=[CH:8][CH:7]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[CH:15]=2)[CH2:6]1
Reactant: C[NH+]1CCCC(c2cc3ccccc3o2)C1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CC=CC(c2cc3ccccc3o2)C1

Procedure:
A solution of 50 g of sodium borohydride in 100 ml of water is added dropwise, with stirring and external cooling, to a solution of 56.0 g of 1-methyl-3-(2-benzofuranyl)-piperidinium-iodide in 600 ml of methanol, the manner of addition being such that the reaction temperature does not exceed 35°. The solution is subsequently stirred for 15 hours at room temperature and again a solution of 50 g of sodium borohydride in 100 ml of water is added dropwise at a temperature not exceeding 35°. The methanol is thereupon evaporated off in vacuo; the aqueous phase remaining behind is extracted twice with 300 ml of chloroform each time, the chloroform solution dried over sodium sulphate, filtered, and concentrated by evaporation. The 1-methyl-3-(2-benzofuranyl)-1,2,3,6-tetrahydropyridine obtained is recrystallised from di-isopropylether, and then melts at 63°. The hydrochloride prepared therefrom with a solution of hydrogen chloride in ethyl acetate melts, after recrystallisation from ethyl acetate, at 244°-246°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].Cl.[NH2:13][CH2:14][CH:15]([OH:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1.[BH4-].[Na+]>CO.C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH:13][CH2:14][CH:15]([OH:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)([O-:3])=[O:2]
Reactant: COc1ccc(C(O)CN)cc1OC
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(C(O)CNCc2cccc([N+](=O)[O-])c2)cc1OC

Procedure:
m-Nitrobenzaldehyde (1.8 g) was added to a suspension of α-(aminomethyl)-3,4-dimethoxybenzyl alcohol hydrochloride in 25 ml methanol, triethylamine (2.8 ml) was further added dropwise at room temperature with stirring, and the resulting solution was heated under reflux for 30 minutes. After cooling, sodium borohydride (1.45 g) was added in small portions with stirring under ice cooling, and the mixture was stirred at room temperature for one hour and concentrated. The residue was treated with chloroform and water, and the chloroform layer was collected, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from ether/n-hexane, affording 3.3 g of pure α-[(3-nitrobenzylamino)methyl]-3,4-dimethoxybenzyl alcohol, m.p. 105°-107° C.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@H:4]([N:7]2[C:11]3=[C:12]4[S:18][CH:17]=[CH:16][C:13]4=[N:14][CH:15]=[C:10]3[N:9]=[C:8]2[C@H:19]([OH:21])[CH3:20])[CH2:3]1.C(N(CC)C(C)C)(C)C.[C:31](#[N:35])[CH2:32][CH2:33][CH3:34]>C(#N)C>[OH:21][C@@H:19]([C:8]1[N:7]([C@H:4]2[CH2:5][CH2:6][N:2]([CH2:34][CH2:33][CH2:32][C:31]#[N:35])[CH2:3]2)[C:11]2=[C:12]3[S:18][CH:17]=[CH:16][C:13]3=[N:14][CH:15]=[C:10]2[N:9]=1)[CH3:20]
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCNC1
Reactant: CCCC#N
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCN(CCCC#N)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38 %

Procedure:
To a mixture of (1R)-1-{1-[(3S)-pyrrolidin-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol hydrochloride (15 mg, 0.046 mmol) and N,N-diisopropylethylamine (24 μL, 0.14 mmol) in acetonitrile (0.2 mL) was added butanenitrile, 4-bromo- (5.1 μL, 0.051 mmol). The resulting mixture was stirred at rt for 4 h. The mixture was diluted and purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 6.3 mg (38%) of the desired product. LCMS calculated for C18H22N5OS (M+H)+: m/z=356.2. Found: 356.0.