Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br.[H-].[Na+]>CN(C=O)C>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:6]1[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=[C:2]1[CH3:1]
Reactant: Cc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)c(-c2ccccc2)n1CCCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
(Scheme 2 (E)) To a solution of 2-Methyl-4,5-diphenyl-1H-imidazole (2.0 g, 8.5 mmol) and 1,5-dibromopentane (3.01 g, 12.7 mmol) in DMF (100 mL) was added NaH (60% in mineral oil, 0.50 g, 12.7 mmol). The resulting mixture was stirred at rt for 1 hour, quenched by addition of water, extracted by CH2Cl2, washed by water, and then was dried over MgSO4. After filtration and concentration in vacuo, the residue was purified by flash chromatography (SiO2: EtOAc/Hexanes). This compound was obtained as a pale yellow oil (2.2 g, 5.7 mmol, 67% yield): 1H NMR (DMSO): δ1.20 (m, 2H), 1.47 (m, 2H), 1.64 (m, 2H), 2.41 (s, 3H), 3.45 (t, 2H), 3.72 (t, 2H), 7.16 (m, 3H), 7.31 (m, 4H), 7.55 (t, 3H). Mass Spec: 384.57 (MH+).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6](C(OC(C)(C)C)=O)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[CH:21][N:20]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[Cl:18][C:19]1[C:24]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:2]=2)[NH:8][N:7]=[CH:6]3)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: CC(C)(C)OC(=O)c1n[nH]c2cc(Br)ccc12
Reactant: CC1(C)OB(c2cccnc2Cl)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Clc1ncccc1-c1ccc2[nH]ncc2c1
Yield: 74.3 %

Procedure:
Analogous to the reaction conditions and work-up procedures used in the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole, 5-(2-chloropyridin-3-yl)-1H-indazole was obtained by heating the mixture of tert-butyl 6-bromo-1H-indazole-carboxylate (7.3 g, 24.6 mmol), 2-chloro-3-pyridine boronic acid pinacol ester (7.0 g, 29.5 mmol), Pd(PPh3)4 (2 g, 1.7 mmol) and aq.Na2CO3 (44 mL, 88 mmol) in 1,4-dioxane (200 mL) under argon atmosphere. The crude concentrate that was obtained after the extractive work-up dissolved in CH2Cl2, adsorbed on to silica gel and dried. Subsequent purification by flash silica gel column chromatography (Combiflash® companion System® with RediSep® silica gel column 120 g, 30-70% EtOAC/hexanes eluting solvent gradient upon dry powder loading) provided 5-(2-chloropyridin-3-yl)-1H-indazole as a white solid (4.2 g, 74%). 1H NMR (DMSO-d6): δ 13.21 (s, 1H), 8.43 (dd, 1H, J=1.7 and 4.7 Hz), 8.12 (s, 1H), 7.93 (dd, 1H, J=1.7 and 7.6 Hz), 7.84 (d, 1H, J=8.5 Hz), 7.59 (s, 1H), 7.52 (dd, 1H, J=4.7 and 7.6 Hz), 7.17 (d, 1H, J=8.5 Hz).LCMS: rt 6.17 min (A), purity 98%, MS (m/e) 230 (MH+).
Reaction SMILES: [OH:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>N1C=CC=CC=1>[C:15]([O:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(=O)NC1CCC(O)c2sccc21
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: NC(=O)NC1CCC(OC(=O)c2ccccc2)c2sccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 5 ml of pyridine, 0.53 g of 4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-ylurea is stirred and 0.39 g of benzoyl chloride added under a nitrogen atmosphere. The mixture is stirred at room temperature and after 1 hr, an additional 0.2 g of benzoyl chloride is added. After another 0.75 hr, the mixture is poured into H2O and the white precipitate is collected. The solid is washed with H2O, dried, dissolved in acetone-hexane and filtered to remove an insoluble material. The filtrate is evaporated to dryness and the acetone-hexane treatments are repeated twice to remove additional side product. The solid from the filtrate is recrystallized from ethyl acetate to give a solid with m.p. 199° C-205° C.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[OH-].[Na+].[C:12]([OH:20])(=[O:19])[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].C(Cl)Cl>C(O)C>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[C:12]([O-:20])(=[O:19])[CH2:13][CH2:14][CH2:15][C:16]([O-:18])=[O:17]
Reactant: O=C(O)CCCC(=O)O
Agent: CN(C)C(=N)NC(=N)N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: O=C([O-])CCCC(=O)[O-]
Yield: 86.9 %

Procedure:
10.0 g of metformin, 2.40 g of sodium hydroxide and 3.98 g of glutaric acid were stirred in 150 ml of ethyl alcohol at a temperature of 70° C., and then methylene chloride was added thereto. The produced inorganic salt was filtered and ethyl acetate was added to the filtered solution. The produced crystal was filtered and dried in hot air, thus obtaining 6.79 g (yield: 57.7%) of metformin glutarate.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)[CH:13]=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:22]=1[C:23]([NH2:25])=[O:24].OS([O-])=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[C:12]([C:13]3[NH:25][C:23](=[O:24])[C:22]4[C:21](=[CH:29][C:28]([O:30][CH3:31])=[CH:27][C:26]=4[O:32][CH3:33])[N:20]=3)[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: COc1cc(C=O)cc(N2CCN(C(C)C)CC2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)cc(N2CCN(C(C)C)CC2)c1
Temperature: 120 °C
Reaction time: 20 h
Yield: 79.1 %

Procedure:
To a solution of 3-(4-isopropylpiperazin-1-yl)-5-methoxybenzaldehyde (1.23 g, 4.68 mmol) in N,N-dimethylacetamide (20 mL) was added 2-amino-4,6-dimethoxybenzamide (0.59 g, 3.00 mmol), NaHSO3 (58.5 wt %, 0.87 g, 4.80 mmol) and p-toluenesulfonic acid monohydrate (1.82 g, 9.60 mmol). The reaction mixture was stirred at 120° C. for 20 h under nitrogen. After that time the reaction was cooled to rt and concentrated under reduced pressure. The residue was diluted with saturated Na2CO3 solution to adjust the pH to 12. The precipitated solids were collected by filtration, washed with water and dried under vacuum. The product was purified by flash column chromatography (silica gel, 86:10:4 dichloromethane/ethyl acetate/methanol followed by 86:10:4 dichloromethane/ethyl acetate/7 N NH3 in methanol) and prep. HPLC to give 2-(3-(4-isopropylpiperazin-1-yl)-5-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (1.04 g, 50%) as a white solid: mp 212-213° C.; 1H NMR (400 MHz, DMSO-d6): δ 11.99 (s, 1H), 7.36 (s, 1H), 7.20 (s, 1H), 6.76 (d, J=2.34 Hz, 1H), 6.60 (t, J=1.95 Hz, 1H), 6.53 (d, J=1.95 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H), 3.22 (t, J=4.29 Hz, 4H), 2.68 (quin, J=6.54 Hz, 1H), 2.58 (t, J=4.68 Hz, 4H), 1.01 (d, J=6.63 Hz, 6H); ESI MS m/z 437 [M−H]−.
Reaction SMILES: [CH3:1][C:2]([C:4]([CH3:7])([CH3:6])[CH3:5])=[O:3].[CH3:8][O:9][C:10](=[O:15])[C:11](OC)=[O:12]>>[CH3:8][O:9][C:10](=[O:15])[C:11]([CH2:1][C:2](=[O:3])[C:4]([CH3:7])([CH3:6])[CH3:5])=[O:12]
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)C(C)(C)C
Product: COC(=O)C(=O)CC(=O)C(C)(C)C

Procedure:
When a mixture, heated to 50° C., of pinacolin and oxalic acid dimethyl ester was added and the procedure was otherwise the same as in Example 6, a amount of 166.7 g of pivaloylpyruvic acid methyl ester (89% of the theoretical yield) were obtained. Purity: 99.3%.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6](O)=[O:7])[CH:3]([CH3:5])[CH3:4].CN1CCOCC1.[NH:23]1[CH2:31][CH2:30][CH2:29][C@H:24]1[C:25]([O:27][CH3:28])=[O:26].[ClH:32]>C1COCC1>[NH2:1][C@H:2]([C:6]([N:23]1[CH2:31][CH2:30][CH2:29][C@H:24]1[C:25]([O:27][CH3:28])=[O:26])=[O:7])[CH:3]([CH3:5])[CH3:4].[ClH:32]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)C(C)C
Temperature: -15 °C
Reaction time: 8 h

Procedure:
Boc-Val-OH (3.00 g, 13.8 mmol) was dissolved in 10 ml of dry THF and cooled down to −15° C. To the mixture CAIBE (1.80 ml, 13.8 mmol) and NMM (1.52 ml, 13.8 mmol) where added and the solution was stirred until the formation of the mixed anhydride was complete. Then the mixture was brought to −10° C. and NMM (1.52 ml, 13.8 mmol) was added followed by H-Pro-OMe.HCl (2.29 g, 13.8 mmol). The mixture was allowed to reach room temperature and left overnight. After removing the solvent and the usual workup the resulting ester 1 was taken without further characterisation. The ester 1 was dissolved in HCl/HOAc (5 ml, 6N) and left at 0° C. until the removal of the Boc-group was complete. The solvent was then removed and the resulting oil was treated with diethylether to give a white solid 2.
Reaction SMILES: CO[CH:3](OC)[C:4]1[CH:5]=[C:6](C=[CH:18][C:19]=1[CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])[CH2:21][N+:22]([O-])=O)[O:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.BrC1C(C(OC)OC)=CC(OCCCN2CCCCC2)=[N:39]C=1.[Li]CCCC.FC1C=CC=CC=1C=C[N+]([O-])=O>C1COCC1.C(O)(=O)C>[F:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:20]1[C:19]2[C:4](=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:39][CH:18]=2)[CH2:3][NH:22][CH2:21]1
Reactant: COC(OC)c1cc(OCCCN2CCCCC2)ncc1Br
Reactant: COC(OC)c1cc(OCCCN2CCCCC2)ccc1C(C[N+](=O)[O-])c1ccccc1F
Agent: O=[N+]([O-])C=Cc1ccccc1F
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Fc1ccccc1C1CNCc2cc(OCCCN3CCCCC3)ncc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
1-(3-{3-Dimethoxymethyl-4-[1-(2-fluoro-phenyl)-2-nitro-ethyl]-phenoxy}-propyl)-piperidine. A −78° C. solution of 5-bromo-4-dimethoxymethyl-2-(3-piperidin-1-yl-propoxy)-pyridine (359 mg, 0.962 mmol) in THF (8 mL) was treated with n-BuLi (2.5 M in hexanes; 0.4 mL). After 20 min at −78° C., the mixture was treated with a solution of 1-fluoro-2-(2-nitro-vinyl)-benzene (171 mg, 1.02 mmol) in THF (5 mL). After 20 min at −78° C., the mixture was treated with acetic acid (1 mL) and was allowed to warm to 0° C. The mixture was concentrated and the residue was chromatographed (SiO2; 1-10% 2 M NH3 in MeOH/DCM) to give the title compound (285 mg, 64%) as an oil. MS (ESI): mass calcd. for C24H32FN3O5, 461.23; m/z found, 462.5 [M+H]+. 1H NMR (CDCl3): 8.03 (s, 1H), 7.30-7.24 (m, 2H), 7.15-7.03 (m, 2H), 6.95 (s, 1H), 5.55 (t, 8.2, 1H), 5.43 (s, 1H), 5.02-4.92 (m, 2H), 4.34-4.27 (m 2H), 3.35 (s, 3H), 3.27 (s, 3H), 2.55-2.42 (m, 6H), 2.05-1.95 (m, 2H), 1.69-1.60 (m, 4H), 1.49-1.42 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Br/[CH:19]=[CH:20]/[CH3:21].II.[Mg]>C1COCC1.C(Cl)Cl>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])(/[CH:19]=[CH:20]/[CH3:21])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: C/C=C/Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C/C=C/C(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (636 mg) in THF (5 mL) at 0° C. was added Grignard reagent, which was freshly prepared from trans-1-bromo-1-propene (1.35 mL), a small iodine flake, and magnesium powder (382 mg) in THF (5 mL). The resulting mixture was then stirred at room temperature for 3 hr. The reaction was quenched with NH4Cl (sat. aq), filtered through a pad of Celite®, rinsed with EtOAc, the layers were separated, the aqueous layer extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield a yellow solid. The yellow solid was dissolved in a minimal amount of CH2Cl2 and triturated with hexanes to yield the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][C:12]([CH3:26])([CH2:23][CH2:24]C)[CH2:13][NH:14][C:15]1[N:16]([CH3:22])[N:17]=[C:18]([CH3:21])[C:19]=1[NH2:20].[K+].[Br-]>>[CH3:26][C:12]([CH3:11])([CH2:23][CH3:24])[CH2:13][NH:14][C:15]1[N:16]([CH3:22])[N:17]=[C:18]([CH3:21])[C:19]=1[NH:20][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCCC(C)(C)CNc1c(N)c(C)nn1C
Agent: [Br-]
Agent: [K+]
Product: CCC(C)(C)CNc1c(NCc2ccc(C#N)cc2)c(C)nn1C
Yield: 19 %

Procedure:
The title compound was prepared according to the procedure of Example 1, Step 5 except that 4-cyanobenzaldehyde was used in place of 4-pyridinecarboxaldehyde and N(3)-(2,2-dimethyl-pentyl)-2,5-dimethyl-2H-pyrazole-3,4-diamine was used in place of N(3)-(2,2-dimethyl-propyl)-2,5-dimethyl-2H-pyrazole-3,4-diamine. Yellow oil, yield: 19%, 1H NMR (300 MHz, CDCl3): δ0.83 (t, 3H), 0.89 (s, 6H), 1.28 (q, 2H), 2.10 (s, 3H), 2.61 (s, 2H), 3.59 (s, 3H), 4.04 (s, 2H), 7.42 (d, 2H), 7.61 (d, 2H), IR (KBr, cm−1): 3340m, 2961s, 2877m, 2226s, 1588m, 1565m, 1537m, 1462m, 1378m, 1365m, 1296w, 821w, MS (ES) m/z (relative intensity): 326 (M+H+, 100).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:11])=[N:8][CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>CN(C=O)C.O>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:4]1[C:5]2=[N:6][C:7]([CH3:11])=[N:8][CH:9]=[C:10]2[C:2]([I:1])=[N:3]1
Reactant: Fc1ccccc1CBr
Reactant: Cc1ncc2c(I)n[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncc2c(I)nn(Cc3ccccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
7.950 g (13.76 mmol) of 3-iodo-6-methyl-1H-pyrazolo[3,4-d]pyrimidine and 4.930 g (15.13 mmol) of caesium carbonate were initially charged in 20 ml of DMF, and 2.860 g (15.13 mmol) of 2-fluorobenzyl bromide dissolved in 5 ml of DMF were added. The reaction mixture was stirred at RT overnight, diluted with 100 ml of water and extracted with ethyl acetate. The organic phase was dried over sodium sulphate and concentrated on a rotary evaporator. The residue was purified by means of preparative HPLC (eluent: acetonitrile/water, gradient 30:70→95:5). 1.030 g of the target compound were obtained (20% of theory).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(=S)=S>[C:19]1([CH2:25][C:26]([C:4]2[CH:5]=[CH:6][C:1]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:2][CH:3]=2)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC(=O)CCCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)CCCCc1ccc(C(=O)Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 66 %

Procedure:
To a solution of 5.12 g of methyl 5-phenylvalerate in 25 ml of carbon disulfide, 7.10 g of anhydrous aluminium chloride was added under ice-cooling, and then 4.11 g of phenylacetyl chloride was added dropwise and stirring was continued at room temperature for 6 hours. The reaction mixture was poured into ice-water and extracted with methylene chloride. The methylene chloride layer was washed successively with water, aqueous potassium carbonate solution and water, dried, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride:n-hexane=2:1) to afford 5.45 g of colorless crystals. Recrystallization from isopropyl ether gave colorless flakes, mp 53.5°~54° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=[O:11])=[CH:5][CH:4]=1.CO>O1CCCC1>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1
Reactant: CSc1ccc(CC(=O)O)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CSc1ccc(CCO)cc1
Yield: 86.4 %

Procedure:
5.5 ml 1 M borane-tetrahydrofuiran complex was slowly added to a solution of 1 g (5.5 mmole) 4-(methylmercapto)phenyl acetic acid in 5 ml tetrahydrofuran at −10° C. The reaction mixture was allowed to reach room temperature and the reaction was followed by TLC. After completion 10 ml methanol was added and the solvents were evaporated. Diethyl ether and 2 M sodium hydroxide was added, the phases were separated, the organic phase was dried, filtered and evaporated in vacuo to give 0.8 g (yield 84.4%) of 2-[4-(methylmercapto)phenyl]-1-ethanol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[Cl:12][CH:13]([CH3:21])[CH2:14][S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16].CCCCCC>ClCCl>[CH3:9][O:8][C:6]1[N:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:19]([NH:18][S:15]([CH2:14][CH:13]([Cl:12])[CH3:21])(=[O:17])=[O:16])=[O:20])[N:7]=1
Reactant: COc1nc(N)nc(OC)n1
Reactant: CC(Cl)CS(=O)(=O)N=C=O
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1nc(NC(=O)NS(=O)(=O)CC(C)Cl)nc(OC)n1
Temperature: 0 °C
Yield: 90.4 %

Procedure:
15.6 g (0.1 mole) of 2-amino-4,6-dimethoxy-1,3,5-triazine were suspended in 150 ml of dichloromethane, and a solution of 19.5 g (0.106 mole) of 2-chloro-n-prop-1-yl-sulfonyl isocyanate in 100 ml of dichloromethane was added at 0° C., while stirring. The mixture was further stirred for 12 hours at room temperature and cooled to 0° C., and 300 ml of n-hexane were added. The precipitated reaction product was filtered off under suction, washed with n-hexane and dried. 30.7 g (90.5% of theory) of N-(4,6-dimethoxy-1,3,5-triazin-2-yl)-N'-(2-chloro-n-prop-1-yl-sulfonyl)-urea of melting point 139°-41° C. were obtained.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[CH:9]([CH:12]=O)[CH2:8][CH2:7][C:5]=2[N:6]=1.[N+]([O-])(O)=O.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH2:29])=[NH:28])=[CH:22][CH:21]=1.[OH-].[Na+]>COCCO>[CH3:1][C:2]1[S:3][C:4]2[C:10]3[N:29]=[C:27]([NH:26][C:23]4[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:30])[F:31])=[CH:25][CH:24]=4)[N:28]=[CH:12][C:9]=3[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: N=C(N)Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1nc2c(s1)C(=O)C(C=O)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O=[N+]([O-])O
Product: Cc1nc2c(s1)-c1nc(Nc3ccc(C(F)(F)F)cc3)ncc1CC2
Yield: 8.1 %

Procedure:
A mixture of 2-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazole-6-carbaldehyde (200 mg, 1.02 mmol), N-(4-trifluoromethyl-phenyl)-guanidine nitrate (273 mg, 1.02 mmol), NaOH (41 mg, 1.02 mmol) and 2-methoxyethanol (1.25 mL) was heated under reflux for 16 h. The reaction mixture was concentrated under vacuum. Flash column chromatography (20% EtOAc:hexane) followed by crystallisation from EtOAc gave the pure title compound as a white crystalline solid (30 mg, 8%): mp 212-213° C. Anal. RP-HPLC: tR 21.8 min (10-70% MeCN, purity 95%). 1H-NMR (CDCl3): δ 8.17 (s, 1H, Py-H), 7.71 (d, 2H, J 8.4, Ph-H), 7.52 (d, 2H, J 8.4, Ph-H), 7.16 (s, 1H, NH), 3.04 (t, 2H, J 6.6, CH2), 2.94 (t, 2H, J 6.6, CH2), 2.72 (s, 3H, CH3). MS (ESI−): m/z 360.95 (M−H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14]>O1CCCC1>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:3][C:2]=1[NH:1][C:16]([NH:15][CH2:13][CH3:14])=[O:17]
Reactant: CCN=C=O
Reactant: Nc1cc(S(N)(=O)=O)ccc1Cl
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(S(N)(=O)=O)ccc1Cl

Procedure:
To 3-amino-4-chlorobenzenesulfonamide (420 mg) in tetrahydrofuran (2 ml) solution, ethylisocyanate (180 μl) was added and the mixture was stirred under heating and reflux for 15 hours. The reaction solution was concentrated, then the residue was recrystallized from chloroform/methanol to obtain the title compound as a crude product (550 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(Cl)Cl>[CH3:12][S:13]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]#[N:11])=[CH:8][N:9]=1)(=[O:15])=[O:14]
Reactant: N#Cc1ccc(CCO)nc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaBH4 (2.5 g, 67 mmol) was added in small portions to a solution of 6-(2-oxoethyl)pyridine-3-carbonitrile (5.0 g, crude) in 80 mL of MeOH at 0° C. The mixture was stirred at room temperature for 30 minutes and poured to 50 mL of water. The mixture was extracted with EtOAc (100 mL×5) and the combined organic layer was condensed. The residue was purified by flash chromatography to afford 6-(2-hydroxyethyl)pyridine-3-carbonitrile. TEA (2.1 g, 21 mmol) was added drop wise to a solution of 6-(2-hydroxyethyl)pyridine-3-carbonitrile (3.0 g, 20 mmol) and MsCl (2.3 g, 20 mmol) in 200 mL of DCM at 0° C. The mixture was stirred at RT for 30 minutes and washed with water and brine, dried over anhydrous Na2SO4 and condensed under vacuum below 30° C. to afford the title compound which was used immediately without further purification.
Reaction SMILES: [NH:1]([C:5]1[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19]Br)=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:21])[NH:10]2)[C:2]([CH3:4])=[O:3].[N+](C1C(OCCCCBr)=CC=C2C=1C=CC(=O)N2)([O-])=O.C(OC(=O)C)(=O)C.[C:49]1([SH:55])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(O)(=O)C.[Zn]>[NH:1]([C:5]1[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][S:55][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:21])[NH:10]2)[C:2]([CH3:4])=[O:3]
Reactant: Sc1ccccc1
Reactant: CC(=O)Nc1c(OCCCCBr)ccc2[nH]c(=O)ccc12
Agent: O=c1ccc2c([N+](=O)[O-])c(OCCCCBr)ccc2[nH]1
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1c(OCCCCSc2ccccc2)ccc2[nH]c(=O)ccc12

Procedure:
Prepared analogous to Example 122 from 5-acetamino-6-(4-bromo-butoxy)-carbostyril [prepared by reduction with zinc in acetic acid of 5-nitro-6-(4-bromo-butoxy)-carbostyril in the presence of acetic acid anhydride] and thiophenol.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][CH:8](Cl)[C:9]1[CH:13]=[CH:12][S:11][CH:10]=1.[CH3:15][C:16](=[CH:18][CH3:19])[CH3:17].C(O)(C)(C)C>CCOCC>[Cl:7][C:8]1([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:18]([CH3:19])[C:16]1([CH3:17])[CH3:15]
Reactant: CC=C(C)C
Reactant: ClC(Cl)c1ccsc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: CC1C(C)(C)C1(Cl)c1ccsc1
Reaction time: 1 h
Yield: 40 %

Procedure:
Potassium-t-butoxide (2.0 g, 18 mmol) was added over 5 min to a rapidly stirred solution of 3-dichloromethylthiophene produced as in a) (1.00 g 6.0 mmol) in dry ether (10-20 ml) at 0° C., containing 2-methylbut-2-ene (>8 equiv.). After 1 h at 20° C., the products were worked up as in Example 3a) to give oils which contained no starting material, although traces of t-butanol were present. The product was a mixture of geometrical isomers (anti/syn=1.31) (0.7 g, 59%). Kugelrohr distillation (oven temperature 80° C. at 0.1mmHg) afforded the product as a colourless oil (0.47 g, 40%) with no change in the isomer ratio (Found M+ 200.0431. C10H13SCl requires M, 200.0426). Chromatography on silica with petroleum as eluent resulted in decomposition of the minor (syn) isomer affording pure major anti-isomer (27%) (Found M+ 200.0437. C10H13SCl requires M, 200.0426) which showed νmax (film) 752s, 773s, 838s, 1453m, 2927s, 2950s and 2996 m cm-1 ; δH (200 MHz; CDCl3) 0.85 (3H, s), 1.22 (3H, s), 1.24 (4H, m), 7.11 (2H, m), 7.24 (1H, q, J 3, 5 Hz); m/z 200 (M+), 185 (M -CH3), 165 (M+ -Cl). From the 1H n.m.r. of the mixture, the minor (syn) isomer showed δH (200 Mz; CDCl3) 0.94 (3H, s), 1.05 (3H, d, J 6.5 Hz), 1.35 (1H, q, J 6.5 Hz), 1.48 (3H, s), 7.05 (1H, dd, J 1.5, 5.0 Hz) and 7.25 (2H,m); m/z 200 (M+), 185 (M+ -CH3), 165 (M+ -Cl).