Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:50])[CH2:10][C:11]1[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)=[CH:28][CH:27]=2)[N:16]=1>C(Cl)Cl.C1CCCCC1>[CH3:49][C:46]1[CH:47]=[CH:48][C:11]([CH2:10][C:9]([NH2:8])=[O:50])=[C:12]([CH2:13][CH2:14][C:15]2[C:20]([C:21]([F:24])([F:22])[F:23])=[CH:19][N:18]=[C:17]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([CH:32]4[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]4)=[CH:30][CH:31]=3)[N:16]=2)[CH:45]=1
Reactant: Cc1ccc(CC(N)=O)c(CCc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)c1
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(CC(N)=O)c(CCc2nc(Nc3ccc(C4CCNCC4)cc3)ncc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 96.5 %

Procedure:
TFA (0.5 mL) was added to a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)-5-methylphenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A90) (0.106 g, 0.177 mmol) in DCM (5 mL) and the resulting mixture stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue partitioned between EtOAc (20 mL) and 2 M aqueous NaOH (20 mL). The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic layers washed with water (20 mL), brine (20 mL) and dried over MgSO4. The volatiles were removed in vacuo to give a solid which was suspended in DCM and cyclohexane. The resulting suspension was filtered to give the title compound 21 as a white solid (0.085 g, 96%); 1H NMR (400 MHz, d4-MeOH) δ 8.54 (s, 1H), 7.62 (d, J=8.6 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 7.14 (d, J=7.7 Hz, 1H), 7.06-6.98 (m, 2H), 3.62 (s, 2H), 3.28-3.21 (m, 2H), 3.15-3.08 (m, 2H), 3.08-3.01 (m, 2H), 2.86 (td, J=12.6, 2.6 Hz, 2H), 2.78-2.67 (m, 1H), 2.26 (s, 3H), 1.91 (d, J=12.0 Hz, 2H), 1.74 (qd, J=12.9, 4.0 Hz, 2H). LCMS-A: rt 4.94 min; m/z 498.3 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][CH:4]=1>Cl>[OH:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cn1
Agent: Cl
Product: O=Cc1ccc(O)nc1
Temperature: 100 °C
Yield: 34.8 %

Procedure:
To A 100 mL RB was charged with 6-methoxypyridine-3-carbaldehyde (1 g, 7 mmol) was added 3N HCl (20 mL) and then refluxed it at 100° C. for 12 h. RM was cooled slowly to RT. Solid was obtained up on cooling. It was filtered off on Buchner flask and dried under line vacuum to obtain the title compound as white crystals (0.3 g, Yield: 37%)
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:7]1[CH:8]=[C:9]([CH:13]([O:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([O:21]C)=[O:20])[CH3:14])[CH:10]=[CH:11][CH:12]=1)[CH:4]([CH3:6])[CH3:5].CCOCC.Cl>O1CCOCC1.CO>[CH2:3]([C:7]1[CH:8]=[C:9]([CH:13]([O:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([OH:21])=[O:20])[CH3:14])[CH:10]=[CH:11][CH:12]=1)[CH:4]([CH3:6])[CH3:5]
Reactant: COC(=O)c1cccc(OC(C)c2cccc(CC(C)C)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CO
Product: CC(C)Cc1cccc(C(C)Oc2cccc(C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
1N aqueous solution of sodium hydroxide (6 ml) was added to a solution of methyl 3-[1-(3-isobutylphenyl ) ethoxy]benzoate (1.40 g ) in a mixture of 1.4-dioxane (12 ml ) and methanol (6 ml ) . The reaction mixture was stirred at 25° C. for 18 hours, and then poured into a mixture of ether and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The crystalline residue was washed with hexane to give 3-[1-(3-isobutylphenyl ) ethoxy]benzoic acid (1.20 g) as colorless crystals.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CC#N
Product: Cc1c(F)c(N2CCNCC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
A suspension of 0.85 g (2.85 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 1.00 g (11.6 mmol) of anhydrous piperazine, and 20 ml of acetonitrile was refluxed for five hours, then stirred at room temperature overnight. The precipitate was filtered, washed with water and acetonitrile, and dried to give 0.91 g of the title compound, mp 205°-206° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][CH2:2][N:10]=[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]1[OH:17]
Reactant: Nc1ccccc1O
Reactant: CC(=O)c1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: OC1C=CC=CC1=NCCc1ccccn1
Temperature: 140 °C
Reaction time: 72 h
Yield: 33 %

Procedure:
450 μl (3 mmol) of 2-acetylpyridine (reagent 1), 331 mg (3 mmol) of 2-aminophenol (reagent 2) and a few mg of para toluene sulfonic acid were dissolved in 20 mL of dry toluene. The reaction mixture was stirred at a temperature of 140° C. for a period of time of 3 days. The solution was evaporated to dryness. After a chromatography on silica gel (heptane/AcOEt 8:2), 208 mg of ligand L27 were obtained as yellow solid with a yield of 33%.
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[N:7]([C:8]2[N:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)[NH:6][CH:5]=[C:4]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.Cl.O>C(O)(=O)C.O1CCOCC1.[Pd]>[ClH:1].[ClH:1].[NH2:15][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([N:7]2[C:3](=[O:2])[C:4]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:5][NH:6]2)=[N:13][CH:12]=1
Reactant: N#Cc1ccc(-n2[nH]cc(-c3cccnc3)c2=O)nc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: NCc1ccc(-n2[nH]cc(-c3cccnc3)c2=O)nc1
Reaction time: 96 h

Procedure:
10.0 g (38.0 mmol) of the compound from Example 12 are initially charged in 300 ml of acetic acid. 20 ml of a 4 N solution of hydrogen chloride in dioxane and 5.0 g (4.7 mmol) of palladium on carbon (10%) are added and the mixture is hydrogenated at RT under atmospheric pressure for 96 h. Water is then added until the organic solid formed has gone back into solution, and the catalyst is filtered off through silica gel. The filtrate is concentrated and the residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate mixture). The product obtained is then stirred in a 4 N solution of hydrogen chloride in dioxane for 30 min, and the solid is filtered off and dried under high vacuum. The solid is then dissolved in about 300 ml of water, and the solution is lyophilized.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[C:3]=1[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:37][CH:38]([CH3:40])[CH3:39])=[C:33]([CH:36]=1)[C:34]#[N:35]>CN(C=O)C>[C:34]([C:33]1[CH:36]=[C:29]([CH:30]=[CH:31][C:32]=1[O:37][CH:38]([CH3:40])[CH3:39])[CH2:28][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[C:3]=1[CH3:20])#[N:35]
Reactant: CC(C)Oc1ccc(CCl)cc1C#N
Reactant: CCOC(=O)CC1CCn2c1cc1c(C)c(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCn2c1cc1c(C)c(OCc3ccc(OC(C)C)c(C#N)c3)ccc12
Temperature: 65 °C
Yield: 79.5 %

Procedure:
To a solution of ethyl 2-(7-hydroxy-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (100 mg, 0.366 mmol) in DMF (3 mL) was added cesium carbonate (155 mg, 0.476 mmol), followed by 5-(chloromethyl)-2-isopropoxybenzonitrile (100 mg, 0.476 mmol). The reaction mixture was heated at 65° C. for 15 h and cooled down. The solid was filtered and washed with ethyl acetate. The combined solvent was evaporated, and the residue was purified by column chromatography to give the title compound (130 mg) as a colorless oil. LCMS m/z=447.7 [M+H]+; 1H NMR (400 ME-1z, CDCl3) δ ppm 1.32 (t, J=7.1 Hz, 3H), 1.42 (d, J=6.0 Hz, 6H), 2.25-2.32 (m, 1H), 2.42 (s, 3H), 2.58 (dd, J=16.0, 8.4 Hz, 1H), 2.82-2.92 (m, 2H), 3.73-3.80 (m, 1H), 3.95-4.02 (m, 1H), 4.08-4.15 (m, 1H), 4.20-4.27 (m, 2H), 4.62-4.69 (m, 1H), 4.96 (s, 2H), 6.13 (s, 1H), 6.83 (d, J=8.7 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 7.59 (dd, J=8.6, 2.2 Hz, 1H), 7.63 (d, J=2.1 Hz, 1H).
Reaction SMILES: [O:1]=[C:2](N1CCOC1=O)[CH2:3][CH2:4][CH:5]=O.[CH3:13][C:14]1([NH2:24])[CH2:23][CH2:22][C:17]2([O:21][CH2:20][CH2:19][O:18]2)[CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH3:13][C:14]1([N:24]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:1])[CH2:23][CH2:22][C:17]2([O:18][CH2:19][CH2:20][O:21]2)[CH2:16][CH2:15]1
Reactant: CC1(N)CCC2(CC1)OCCO2
Reactant: O=CCCC(=O)N1CCOC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: CC1(N2CCCC2=O)CCC2(CC1)OCCO2
Reaction time: 1 h
Yield: 8.9 %

Procedure:
Dissolve 4-oxo-4-(2-oxo-oxazolidin-3-yl)-butyraldehyde (7.35 g, 42.96 mmol) in DCE (400 mL). Add 8-methyl-1,4-dioxa-spiro[4.5]dec-8-ylamine (7.36 g, 42.96 mmol), and acetic acid (2.58 g, 42.96 mmol) at room temperature under nitrogen. Stir the solution for one hour and then add sodium triacetoxyborohydride (18.21 g, 85.92 mmol). Stir the reaction mixture for over night and then add water (400 mL). Extract the aqueous layer with dichloromethane (3×400 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 20-50% of EtOAc-Hexane) to give 0.92 g (9.0%) of 1-(8-Methyl-1,4-dioxa-spiro[4.5]dec-8-yl)-pyrrolidin-2-one as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:21][C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([Cl:33])[CH:24]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]3[CH:20]=2)=[CH:7][CH:6]=1.[CH3:35][N:36]([CH3:41])[CH2:37][C:38](O)=[O:39]>>[Cl:33][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[O:29][CH:30]([CH3:32])[CH3:31])[C:22]([NH:21][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]3[CH:20]=2)=[CH:7][CH:6]=1)[CH2:2][NH:1][C:38](=[O:39])[CH2:37][N:36]([CH3:41])[CH3:35])=[O:34]
Reactant: CN(C)CC(=O)O
Reactant: Cc1cccn2cc(-c3ccc(C[C@@H](CN)NC(=O)c4ccc(OC(C)C)c(Cl)c4)cc3)nc12
Product: Cc1cccn2cc(-c3ccc(C[C@@H](CNC(=O)CN(C)C)NC(=O)c4ccc(OC(C)C)c(Cl)c4)cc3)nc12

Procedure:
Following the procedure described above with N-((1S)-2-amino-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide and N,N-dimethylglycine provided the title product as a white solid. ESMS [M+H]+: 563.2.
Reaction SMILES: C(N[C:6]([C:8]([N:33]([CH3:37])[C:34](=[O:36])[CH3:35])([CH2:20][CH2:21][CH2:22][CH2:23][B:24]1[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]1)[CH2:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)=[O:7])(C)(C)C.[ClH:38].[C:39](OCC)(=[O:41])[CH3:40]>>[ClH:38].[NH2:12][CH2:11][CH2:10][CH2:9][C:8]([N:33]([CH3:37])[C:34](=[O:36])[CH3:35])([CH2:20][CH2:21][CH2:22][CH2:23][B:24]1[O:25][C:26]([CH3:31])([CH3:32])[C:27]([CH3:29])([CH3:30])[O:28]1)[C:6]([O:41][CH2:39][CH3:40])=[O:7]
Reactant: CCOC(C)=O
Reactant: CC(=O)N(C)C(CCCCB1OC(C)(C)C(C)(C)O1)(CCCNC(=O)OC(C)(C)C)C(=O)NC(C)(C)C
Agent: Cl
Product: CCOC(=O)C(CCCN)(CCCCB1OC(C)(C)C(C)(C)O1)N(C)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 4-(tert-butylcarbamoyl)-4-(N-methylacetamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)octylcarbamate (140 mg, 0.266 mmol) in ethyl acetate (2 mL) was treated with anh HCl (2 N in ethyl acetate, 10 mL) and stirred at room temp. After 30 min, the solution was concentrated to give crude ethyl 2-(3-aminopropyl)-2-(N-methylacetamido)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate hydrochloride as a white solid (130 mg). ESI MS found for C20H39BN2O5 m/z [399.5 (M+1)]. This material was used without further purification.
Reaction SMILES: [Br:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9](Cl)[C:4]=2[CH:3]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[CH3:20])[NH2:16].C(N(C(C)C)CC)(C)C>C(O)CCC>[Br:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH3:20])=[C:13]([OH:12])[CH:14]=3)[C:4]=2[CH:3]=1
Reactant: Cc1ccc(N)cc1O
Reactant: Clc1ncnc2[nH]c(Br)cc12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Nc2ncnc3[nH]c(Br)cc23)cc1O
Temperature: 120 °C
Yield: 70.3 %

Procedure:
6-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.41 mmol), prepared as in reference 1, is mixed with 3-hydroxy-4-methylaniline (150 mg, 1.22 mmol) and diisopropylethylamine (213 μL, 1.22 mmol) in n-butanol (1.3 mL). The mixture is heated to 120° C. for 18 hours, with stirring. The reaction is then cooled to ambient temperature and the solvent is removed. The resultant crude product is purified by flash column chromatography using a gradient of 3-5% MeOH in DCM to yield 5-(6-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-methyl-phenol (92 mg; 70%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[S:10])=[CH:4][CH:3]=1.[C:24]([O:28][C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])=[O:30])([CH3:27])([CH3:26])[CH3:25].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:24]([O:28][C:29](=[O:30])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](=[O:38])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12](=[O:23])[C:13]2[CH:14]=[CH:15][C:16]([C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:17][CH:18]=2)=[S:10])=[CH:4][CH:3]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Reactant: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(N)cc2)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCCCC(=O)Nc1ccc(NC(=S)NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.3 %

Procedure:
Thiourea 4 (100 mg, 0.31 mmol, 1 equiv.) was stirred in dry CH2Cl2 (5 mL) under N2 atmosphere and acid 31 (106 mg, 0.46 mmol, 1.5 equiv.) was added, followed by bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (214 mg, 0.46 mmol, 1.5 equiv.), and N,N-diisopropylethylamine (53 μL, 0.31 mmol, 1 equiv.). The reaction mixture was stirred at rt for 16 h then diluted with CH2Cl2 (20 mL) and washed with 1 M aqueous hydrochloric acid (1×10 mL), 1 M aqueous sodium hydroxide (1×10 mL), and saturated brine (1×10 mL). The organic phase was dried over MgSO4 and concentrated in vacuo to give a crude yellow oil which was purified with column chromatography on silica (25-50% ethyl acetate/petroleum ether) to give 32 (86 mg, 54%) as a colourless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][OH:7])=[CH:2]1.Cl[C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:12]=[N:11][CH:10]=1>>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([N:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)[N:14]=2)=[CH:2]1
Reactant: OCc1ccsc1
Reactant: Clc1cncc(N2CCNCC2)n1
Product: c1cc(COc2cncc(N3CCNCC3)n2)cs1
Temperature: 105 °C
Reaction time: 7.5 h
Yield: 64.7 %

Procedure:
The title compound was prepared according to the procedure of Example 20 starting from 3-thiophenemethanol (6.05 g, 53.0 mmol), K-t-BuO (0.897 g, 7.99 mmol) and 6-chloro-2-(1-piperazinyl)pyrazine (0.845 g, 4.25 mmol: obtained in Example 13, step 2). The reaction mixture was stirred at 105° C. for 7.5 h. Following chromatography on silica, solvents were evaporated off. The remaining oil was redissolved in ethyl acetetate and filtered through a short plug of alumina (5×3 cm) using ether/MeOH (96:4) as eluent. Solvent removal in vacuo gave 0.76 g (64%) of the title compound as a colorless oil. HRMS m/z for C13H16N4OS (M)+ calcd for 276.1045, found 276.1037. Anal. (C13H16N4OS.0.25 H2O) C, H, N.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](O)(=O)[CH2:11]C>O>[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:9])[CH2:10][CH3:11]
Reactant: O=C(O)c1ccccc1
Reactant: CCC(=O)O
Solvent: O
Product: CCC(=O)c1ccccc1

Procedure:
A mixture of 16 g/h of benzoic acid, 57 g/h of propionic acid and 14.5 g/h of water was evaporated in an evaporator and passed, together with 10 l/h of nitrogen, at 400° C., over 100 ml of a catalyst which contained 2.5% by weight of sodium oxide, the remainder being anatase. The reaction gases were then cooled and were collected in a receiver. From the discharged two-phase mixture, the organic phase was analyzed by gas chromatography. The conversion of both carboxylic acids was 100%. The selectivity with respect to propiophenone was 99%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:22](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH3:22][N:9]1[CH2:10][CH2:11][CH:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)C1CCNN1C(=O)OC(C)(C)C
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCC(C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 54.4 %

Procedure:
To a solution of di-tert-butylpyrazolidine-1,5-dicarboxylate (7 g, 25.7 mmol) dissolved in 1,2-dichloroethane (DCE) (80 mL) were added HCHO (2.224 g, 69.4 mmol), sodium triacetoxyborohydride (14.71 g, 69.4 mmol), and acetic acid (8 mL). The reaction was stirred at rt for appropriate time. The solvent was then removed and the residue was diluted with DCM and saturated NaHCO3 (150 mL). The aqueous layer was extracted with DCM. The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by silica gel column chromatography to afford 4 g (13.97 mmol, 54.3% yield) of bis(1,1-dimethylethyl) 2-methyl-1,5-pyrazolidinedicarboxylate as a pale yellow oil. LC-MS (ES) m/e 287.1 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH2:20][CH:19]([NH:24][S:25]([CH:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])[CH2:18]3)[CH:12]=[CH:13][CH:14]=1)#[N:8]>O1CCCC1>[NH2:8][CH2:7][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH2:20][CH:19]([NH:24][S:25]([CH:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])[CH2:18]3)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(C#N)c3)cc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(CN)c3)cc2C1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
A 1.0M solution of lithium aluminium hydride in tetrahydrofuran (8 ml) was cooled to 0° C. in an ice/methanol bath with stirring under argon. The solution was then treated dropwise with a solution of N-[5-(3-cyanophenyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (0.67 g, 1.97 mmol) in dry tetrahydrofuran (20 ml) over 15 mins. The cooling bath was removed and the whole mix stirred at reflux for 2 h. The reaction mix was allowed to cool to room temperature and quenched with water (0.8 ml), 10% NaOH (0.8 ml), and water again (1.2 ml). The reaction mix was dried over sodium sulphate, filtered and the filtrate evaporated under reduced pressure to give the title compound as a yellow oil (0.67 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[C:14]2[C:9](=[CH:10][C:11]([Cl:17])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:20]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:20])=[CH:13][CH:12]=[C:11]([Cl:17])[CH:10]=2)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c[nH]c2cc(Cl)ccc2c1=O
Product: CCOC(=O)c1cnc2cc(Cl)ccc2c1Cl

Procedure:
7-Chloro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester [76.0 g, 302 mmol, prepared as described by C. C. Price et al in J. Am. Chem. Soc., 68, 1204 (1946)]was refluxed for 4.5 h in 310 ml of POCl3. The resulting black solution was then concentrated in vacuo and the residue was dissolved in 100 ml of acetone. It was poured onto 1 kg of ice and brought to pH 7 with 50% NaOH. The mixture was then extracted with 3×125 ml of CH2Cl2 and the pooled extracts were dried over Na2SO4 and concentrated to a black solid that was dried in vacuo overnight affording 74.7 g (276 mmol, 92% crude yield) of 4,7-dichloro-3-quinolinecarboxylic acid ethyl ester that was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:4][CH:3]=1.[N:30]([C:33]1[C:34]([CH3:39])=[N:35][O:36][C:37]=1[CH3:38])=[C:31]=[O:32]>>[CH3:39][C:34]1[C:33]([NH:30][C:31]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:29])[CH2:9][N:10]3[C:14](=[O:15])[C:13]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:12]=[C:11]3[CH3:28])=[CH:6][CH:7]=2)=[O:32])=[C:37]([CH3:38])[O:36][N:35]=1
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(N)cc1
Reactant: Cc1noc(C)c1N=C=O
Product: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(NC(=O)Nc2c(C)noc2C)cc1

Procedure:
Synthesis in analogy to Example 6 starting from 3-[2-(4-amino-phenyl)-2-oxo-ethyl]-2-methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one and 4-isocyanato-3,5-dimethyl-isoxazole to yield 1-(3,5-dimethyl-isoxazol-4-yl)-3-{4-[2-(2-methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-acetyl]-phenyl}-urea. LC/MS at 254 nm; [M+H] 522; Rt 3.191 min.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:21][C:22]1[CH:23]=[C:24]([C:28]2[NH:32][N:31]=[N:30][N:29]=2)[CH:25]=[CH:26][CH:27]=1>>[NH:32]1[C:28]([C:24]2[CH:23]=[C:22]([NH:21][S:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:20])([F:19])[F:1])=[CH:4][CH:5]=4)[CH:10]=3)(=[O:17])=[O:16])[CH:27]=[CH:26][CH:25]=2)=[N:29][N:30]=[N:31]1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 64.2 %

Procedure:
The product was synthesized according to General Procedure 1, described in Example 1, starting with {3-[4-(trifluoromethyl)phenyl]phenyl}sulfonyl chloride (17.6 mg, 0.055 mmol) and 5-(3-amino-phenyl)tetrazole (8 mg, 0.05 mmol) yielding 14.3 mg (64%) of the title compound. MS (ESI+) calcd for C20H14F3N5O2S 445.082030, found 445.081660.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH3:19])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1.I([O-])(=O)(=O)=[O:22].[Na+].CO>O.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17]([CH2:18][CH3:19])=[O:22])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCSc1ccccc1-c1nc2cc(Br)cnc2n1C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCS(=O)c1ccccc1-c1nc2cc(Br)cnc2n1C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 90.8 %

Procedure:
A mixture of 6-bromo-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (0.20 g), sodium periodate (0.18 g), methanol (3 ml), water (1 ml), and THF (0.4 ml) was stirred at room temperature for 3.5 hours. Water was poured thereinto under ice-cooling, and then the precipitated solid was collected by filtration. The obtained solid was washed with water and hexane, and dried to give 0.19 g of 6-bromo-2-(2-ethylsulfinylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 43).