Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]1[O:9][CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:6]1[CH2:7][CH2:8][O:9][CH:4]([C:1](=[O:3])[CH3:2])[CH2:5]1
Reactant: CC(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C1CNCCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.7 %

Procedure:
To a solution of tert-butyl 2-acetylmorpholine-4-carboxylate (6.9 g, 30.0 mmol) in DCM (80 mL) was added TFA (20 mL). The mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated to give 1-(morpholin-2-yl)ethanone (3.9 g, crude) for next step.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)CCC.[NH2:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[C:22]([Cl:27])[N:21]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:19][C:20]1[N:21]=[C:22]([Cl:27])[CH:23]=[C:24]([C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)[N:25]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Nc1nc(Cl)cc(-c2ccco2)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 56.7 %

Procedure:
A solution of 2-(tributylstannyl)furan (35.7 g, 100 mmol) in DMF (100 mL) was treated with 2-amino-4,6-dichloropyrimidine (16.4 g, 100 mmol) and dichlorobis(triphenylphosphine)palladium (II) (3.51 g, 5.0 mmol). The suspension was stirred at 80° C. for 18 h, allowed to cool to room temperature and poured onto ice (400 g). The solid precipitate was filtered off, washed with water, dried in air, and the filtrate was extracted with EtOAc (300 mL), washed with water (100 mL), mixed with the solid precipitate and concentrated. The crude product was purified by chromatography [SiO2; EtOAc:toluene (0:1-1:9-2:3)] and the material with Rf 0.23 (isopropyl ether) was triturated with isohexane to give the title compound (11.1 g, 57%) as a yellow solid; mp. 133-140° C.; NMR δH (400 MHz, DMSO) 6.70 (1H, q, J 2.0 Hz), 6.95 (1H, s), 7.16 (2H, br s), 7.27 (1H, d, J 3.6 Hz) and 7.92 (1H, t, J 1.0 Hz).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=1)([OH:3])=[O:2]>CO.[Pd]>[C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1)([OH:3])=[O:2]
Reactant: COc1ccc(CC(=O)O)c(Oc2cccc([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CC(=O)O)c(Oc2cccc(N)c2)c1
Yield: 96.5 %

Procedure:
A solution of 2-carboxymethyl-5-methoxy-phenyl-oxy-(3-nitrobenzene) (57 g, 0.187 mol) and 10% Pd/C (11 g) was hydrogenated in MeOH (1000 mL) at 50 psi for 2 h. The solution was filtered through Celite® and the filtrate was concentrated. Flash chromatography (silica gel, 20% EtOAc/Hexane) yielded the title compound (49.3 g, 96%): MS (ES) m/e 274.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1(C)[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([NH:16][CH2:17][CH:18]([OH:25])[CH2:19][N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=N1.S(=O)(=O)(O)[OH:28].O>C(O)CC>[OH:25][CH:18]([CH2:19][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)[CH2:17][NH:16][C:13]([C:10]1[CH:11]=[CH:12][C:7]([C:4]([O:5][CH2:6][CH2:2][CH3:1])=[O:28])=[CH:8][CH:9]=1)([CH3:15])[CH3:14]
Reactant: O=S(=O)(O)O
Reactant: CC1(C)COC(c2ccc(C(C)(C)NCC(O)Cn3ccnc3)cc2)=N1
Solvent: O
Solvent: CCCO
Product: CCCOC(=O)c1ccc(C(C)(C)NCC(O)Cn2ccnc2)cc1

Procedure:
A mixture of 1-{1-[4-(4,4-dimethyl-2-oxazolin-2-yl)phenyl]-1-methylethylamino}-3-(imidazol-1-yl)propan2-ol (100 mg) and a solution of sulphuric acid in propan-1-ol (5 ml) [prepared by adding concentrated sulphuric acid (4 ml) and then water (5 ml) to propan-1-ol (50 ml) and making up to 100 ml with propan-1-ol] was heated on a steam bath for 18 hours. The mixture was evaporated under reduced pressure. The residue was basified with aqueous sodium hydroxide solution and then extracted with dichloromethane to give a residue which was purified by flash column chromatography on silica using ethyl acetate/triethylamine (9:1) with increasing amounts of ethanol to give propyl 4-{1-[2-hydroxy-3-(imidazol-1-yl)propylamino]-1-methylethyl}benzoate as an oil.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH2:19]([C:21]1[O:22][C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1)[CH3:20]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:26]([C:24]3[N:25]=[C:21]([CH2:19][CH3:20])[O:22][C:23]=3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:27])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: CCc1nc(C(=O)O)c(-c2ccccc2)o1
Product: CCc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)c2)c(-c2ccccc2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-ethyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 01: tR=0.97 min; [M+H]+=405.16.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:12]=[C:11]([Cl:21])[C:10]=1[F:22])(C)(C)C.Cl>CO.O1CCOCC1>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:12]=[C:11]([Cl:21])[C:10]=1[F:22])[CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18]
Reactant: CCN(CC)Cc1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCN(CC)Cc1cc(Cl)c(F)c(CN)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (3-chloro-5-diethylaminomethyl-2-fluoro-benzyl)-carbamic acid tert-butyl ester (115 mg, 0.33 mmol) in MeOH (1 mL) was added a solution of 4N HCl in dioxane (3 mL). The reaction mixture was stirred for 2 h at ambient temperature and the solvent was removed in vacuo to give the title compound. MS (LC/MS): 245.0 [M]+; tR (HPLC conditions c): 2.13 min.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:22][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: COc1ccc(CN)cc1
Solvent: CO
Product: COc1ccc(CN=C(NC#N)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 80.8 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 4-methoxybenzylamine (0.40 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 40 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from methanol-diethyl ether to give the title compound (0.50 g, 2.1 mmol, yield: 80%) as colorless powder.
Reaction SMILES: [CH3:1][C:2]1[N:3](C(=O)C)[CH:4]=[CH:5][N:6]=1.[O:10]1CC[CH2:12][CH2:11]1>>[CH3:1][C:2]1[NH:6][CH:5]=[C:4]([C:11](=[O:10])[CH3:12])[N:3]=1
Reactant: C1CCOC1
Reactant: CC(=O)n1ccnc1C
Product: CC(=O)c1c[nH]c(C)n1
Reaction time: 18 h
Yield: 45 %

Procedure:
5.75 g (46.3 mmol) of 1-(2-methyl-1-imidazolyl)ethanone was dissolved in 600 ml tetrahydrofuran and photolyzed in a quartz flask with a short wave u.v. light source (2537 nm) for 18 hours. The tetrahydrofuran solution was concentrated in vacuo to an oil and chromatographed on silica gel using 5% methanol in chloroform as eluent to give 2.6 g (45%) 1-(2-methyl-4-imidazolyl)ethanone, mp 123°-5°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:15]=[C:16]([C:24]([CH3:30])([S:26]([CH3:29])(=[O:28])=[O:27])[CH3:25])[CH:17]=[C:18]3[C:23]=2[N:22]=[CH:21][CH:20]=[CH:19]3)[CH:9]=1.[C:31]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)(=[O:33])[CH3:32]>CCOC(C)=O>[CH3:30][C:24]([C:16]1[CH:17]=[C:18]2[C:23](=[C:14]([C:10]3[CH:9]=[C:8]([C:3]4[C:2]([C:37]5[CH:38]=[CH:39][C:34]([C:31](=[O:33])[CH3:32])=[CH:35][CH:36]=5)=[CH:7][CH:6]=[CH:5][CH:4]=4)[CH:13]=[CH:12][CH:11]=3)[CH:15]=1)[N:22]=[CH:21][CH:20]=[CH:19]2)([S:26]([CH3:29])(=[O:28])=[O:27])[CH3:25]
Reactant: CC(C)(c1cc(-c2cccc(-c3ccccc3Br)c2)c2ncccc2c1)S(C)(=O)=O
Reactant: CC(=O)c1ccc(B(O)O)cc1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(-c2ccccc2-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)cc1

Procedure:
Prepared according to the general procedure Coupling-1 using bromide from step 1 and 4-acetylbenzeneboronic acid as starting material. Flash chromatography (Hex:EtOAc; 50:50) afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[S:29])=[CH:23][CH:22]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[NH:1][C:28]([NH:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:26][CH:25]=1)=[S:29]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1ccc(C(F)(F)F)cc1
Yield: 83.8 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.198 g, 0.82 mmol) and 4-(trifluoromethyl)phenyl isothiocyanate (0.169 g, 0.83 mmol) to give the product (0.306 g); m.p. 194-196° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:25]4[O:24][CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:18]=4[C:17]([F:33])=[C:16]([Cl:34])[CH:15]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.C(Cl)Cl.C(N(CC)C(C)C)(C)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>>[Cl:34][C:16]1[CH:15]=[C:14]([CH:12]([N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]3[C:10]([CH3:11])=[N:9]2)[CH3:13])[C:25]2[O:24][CH2:23][CH2:22][CH2:21][N:20]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:19][C:18]=2[C:17]=1[F:33]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nn(C(C)c2cc(Cl)c(F)c3c2OCCCN(C(=O)OC(C)(C)C)C3)c2ncnc(N)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nn(C(C)c2cc(Cl)c(F)c3c2OCCCN(S(C)(=O)=O)C3)c2ncnc(N)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyl 10-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-8-chloro-7-fluoro-3,4-dihydro-2H-1,5-benzoxazocine-5(6H)-carboxylate (8 mg, 0.02 mmol) was stirred in methylene chloride (80 μL, 1 mmol) with N,N-diisopropylethylamine (8.5 μL, 0.049 mmol) and cooled to 0° C. Methanesulfonyl chloride (1.6 μL, 0.021 mmol) was added and the mixture was stirred at 0° C. for 1 hr. The mixture was evaporated and diluted with methanol and purified by preparative LCMS (pH 10) to give Example 45. LCMS calculated for C19H23ClFN6O3S (M+H)+: m/z=469.1; found: 469.1. 1H NMR (300 MHz, CD3OD): δ 8.14 (s, 1 H), 7.65 (m, 1 H), 6.36 (m, 1 H), 4.58 (m, 2 H), 4.21 (m, 2 H), 3.52 (m, 2 H), 2.87 (s, 3 H), 2.60 (s, 3 H), 1.91 (m, 2 H), 1.80 (m, 3 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[CH3:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:27][CH2:26][C:23]2[CH:24]=[N:25][C:20]([CH3:19])=[CH:21][CH:22]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: Cc1ccc(CO)cn1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1ccc(COc2nc(N)nc(-c3ccco3)c2C#N)cn1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (6-methyl-pyridin-3-yl)-methanol hydrochloride and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1>C(O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3cccc(OC)c3)oc2C)cc1
Solvent: CCCCCC
Solvent: CCO
Product: COc1cccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)c(C)o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
Ethyl 3-[{[4-({1-[5-(3-methoxyphenyl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (1200 mg) which is a synthetic intermediate in Example 151 was dissolved in ethanol-hexane (6:4, volume ratio), and the solution was subjected to HPLC using CHIRALPAK AD (50 mmID×500 mL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.) and eluted with ethanol-hexane (6:4, volume ratio) as mobile phase at 30° C., a flow rate 60 mL/min. The fractions showing a peak with retention time 11.1 min were collected, and concentrated. The obtained amorphous compound (598 mg) was dissolved in ethanol (5 mL) and tetrahydrofuran (5 mL), lithium hydroxide (2.5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (20 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (518 mg, 92%).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][CH:9]=[C:10]([CH3:11])[C:6]=2[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][C:3]1=[O:18].S(Cl)([Cl:22])(=O)=O.N>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:7]2[S:8][C:9]([Cl:22])=[C:10]([CH3:11])[C:6]=2[C:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:4][C:3]1=[O:18]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1csc2c1c(-c1ccccc1)nc(=O)n2C
Agent: N
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)sc2c1c(-c1ccccc1)nc(=O)n2C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1.33 g of 1-methyl-4-phenyl-5-methyl-1,2-dihyrothieno[2,3-d] -pyrimidin-2-one in 35 of chloroform is added dropwise 1.62 g of sulfuryl chloride in 6 ml of chloroform. After stirring the reaction mixture for 5 hours at room temperature, the reaction mixture is neutralized with aqueous ammonia and then extracted with chloroform. The chloroform extracts are washed with water, dried, evaporated under reduced pressure to a residue to give crystals of 1-methyl-4-phenyl-5-methyl-6-chloro-1,2-dihydrothieno[2,3-d]pyrimidin-2-one, which are recrystallized from ethanol-ether to give crystals having a melting point of 190° - 191.5°C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:12]=[C:11]([S:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)[NH:10][N:9]=1.[C:23]1([S:29]([N:32]2[CH2:35][CH:34]([NH:36]C(=O)OC(C)(C)C)[CH2:33]2)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([S:29]([N:32]2[CH2:33][CH:34]([NH:36][C:17](=[O:19])[C:16]3[CH:20]=[CH:21][CH:22]=[C:14]([S:13][C:11]4[NH:10][N:9]=[C:8]([NH:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH:12]=4)[CH:15]=3)[CH2:35]2)(=[O:30])=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1cccc(Sc2cc(Nc3ccccn3)n[nH]2)c1
Reactant: CC(C)(C)OC(=O)NC1CN(S(=O)(=O)c2ccccc2)C1
Product: O=C(NC1CN(S(=O)(=O)c2ccccc2)C1)c1cccc(Sc2cc(Nc3ccccn3)n[nH]2)c1
Yield: 50.4 %

Procedure:
3-(3-(Pyridine-2-ylamino)-1H-pyrazol-5-ylthio)benzoic acid (0.060 g, 0.192 mmol) and tert-butyl 1-(phenylsulfonyl)azetidin-3-ylcarbamate (0.060 g, 0.192 mmol) were treated as described in Example 3, except that the purification was done on Prep HPLC (MeCN/H2O/0.1% TFA). This afforded the title material (0.049 g, 41%, trifluoroacetic acid salt) as a solid. 1H NMR 400 MHz DMSO-d6 δ (ppm): 3.73 (2H, dd, J=8.72, 6.44 Hz), 3.99 (2H, t, J=8.21 Hz), 4.32-4.46 (1H, m), 6.43 (1H, s), 6.99 (1H, t, J=6.19 Hz), 7.20 (1H, d, J=8.59 Hz), 7.32-7.50 (2H, m), 7.59-7.74 (4H, m), 7.75-7.82 (1H, m), 7.82-7.95 (3H, m), 8.21 (1H, d, J=4.55 Hz), 8.98 (1H, d, J=6.06 Hz), 10.76 (1H, s). HPLC ret. time (Condition B): 3.950 min.; 85%. LCMS (+ESI, M+H+) m/z 507, (−ESI M−H+) m/z 505, HRMS: calc. 507.1273, found 507.1264.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[O:7]2)[CH2:3][CH2:2]1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][N:28]2[C:36]3[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=3)[C:30]([C:39](O)=[O:40])=[C:29]2[CH3:42])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][N:28]2[C:36]3[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=3)[C:30]([C:39]([N:1]3[CH2:6][CH2:5][C:4]4([C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[C:8](=[O:15])[O:7]4)[CH2:3][CH2:2]3)=[O:40])=[C:29]2[CH3:42])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc2c(c1)c(C(=O)O)c(C)n2CCc1ccc(OC)c(OC)c1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Product: COc1ccc2c(c1)c(C(=O)N1CCC3(CC1)OC(=O)c1ccccc13)c(C)n2CCc1ccc(OC)c(OC)c1

Procedure:
Following the general procedure I as described above, the acylation of 3H-spiro[2-benzofuran-1,4′-piperidin]-3-one prepared as described in example 16 above, with commercially available 1-[2-(3,4-dimethoxy-phenyl)-ethyl]-5-methoxy-2-methyl-1H-indole-3-carboxylic acid, gave the title compound. ES-MS m/e (%): 555.3 (M+H+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10](Cl)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[CH3:13][CH:14]1[CH2:19][CH:18]([CH3:20])[CH2:17][NH:16][CH2:15]1>C(O)C>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([N:16]2[CH2:17][CH:18]([CH3:20])[CH2:19][CH:14]([CH3:13])[CH2:15]2)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC1CNCC(C)C1
Reactant: CC#CCOc1cc(Cl)ncn1
Solvent: CCO
Product: CC#CCOc1cc(N2CC(C)CC(C)C2)ncn1
Temperature: 25 °C
Reaction time: 10 h
Yield: 103.3 %

Procedure:
Into 3 ml of ethanol was resolved 0.3 g of 4-(2-butynyloxy)-6-chloropyrimidine, 0.56 g of 3,5-dimethylpiperidine (cis/trans=about 3/1) was added therein, and the mixture was stirred for 10 hours under reflux condition. The reaction mixture was cooled to near room temperature, and concentrated. Into the residue was added a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.44 g of 4-(2-butynyloxy)-6-(3,5-dimethylpiperidino)pyrimidine (hereinafter, referred to as Compound (7)). Compound (7) had the cis/trans diastereomer originated two methyls on the piperidine ring. The ratio of the cis/trans diastereomer was about 3.1/1.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][CH2:21][CH3:22])[CH2:16][CH2:15]2)=[C:10]([CH2:23][NH:24][CH3:25])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]1([CH:32]=[CH:33][CH2:34][C:35](Cl)=[O:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:15][CH2:16][C@H:17]([N:20]([CH2:21][CH3:22])[C:35](=[O:36])[CH2:34][CH:33]=[CH:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:18][CH2:19]2)=[C:10]([CH2:23][NH:24][CH3:25])[CH:9]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCN[C@H]1CC[C@H](c2ccc(C(=O)OC(C)(C)C)cc2CNC)CC1
Reactant: O=C(Cl)CC=Cc1ccccc1
Product: CCN(C(=O)CC=Cc1ccccc1)[C@H]1CC[C@H](c2ccc(C(=O)OC(C)(C)C)cc2CNC)CC1

Procedure:
from trans-4-(4-tert.butoxycarbonyl-methylaminomethylphenyl)-N-ethylcyclohexylamine and 4-phenyl-3-butenoylchloride. Colourless oil. Rf value: 0.74 (alumina, petroleum ether/ethyl acetate=2:1, v:v).
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]2[S:10][C:11]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:12][C:7]=2[CH:6]=1)=[O:4].[OH:17][CH:18]([CH2:21][OH:22])[CH2:19][NH2:20]>CO>[OH:17][CH:18]([CH2:21][OH:22])[CH2:19][NH:20][C:3]([C:5]1[S:9][C:8]2[S:10][C:11]([S:13]([NH2:16])(=[O:14])=[O:15])=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: NCC(O)CO
Reactant: COC(=O)c1cc2cc(S(N)(=O)=O)sc2s1
Solvent: CO
Product: NS(=O)(=O)c1cc2cc(C(=O)NCC(O)CO)sc2s1
Yield: 72.3 %

Procedure:
5-Methoxycarbonylthieno[2,3-b]thiophene-2-sulfonamide (0.83 g., 3 mmoles) and 2,3-dihydroxypropylamine (1.37 g., 15 mmoles) were dissolved in hot methanol and refluxed for 48 hours. The reaction was worked up by evaporating the methanol in vacuo. Water (7 mL) was added followed by the dropwise addition of conc. HCl until strongly acidic (~1.8 pH). The product crystallized out and was collected, washed with water and dried to give 0.90 g of crude product. Recrystallization from nitromethane gave 0.73 g of 5-(N-2,3-dihydroxypropylcarbamoyl)thieno[2,3-b]thiophene-2-sulfonamide, m.p. 117°-118° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[CH2:13]([CH:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:20](Cl)=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>N1C=CC=CC=1.C(#N)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:20](=[O:21])[CH:19]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCCCCCCCC(CCCCCC)C(=O)Cl
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCCCCCC(CCCCCC)C(=O)Nc1ccc(C(=O)OCC)cc1
Yield: 93.3 %

Procedure:
In a mixture of 40 ml of pyridine and 300 ml of acetonitrile was dissolved 82.5 g of 4-aminobenzoic acid ethyl ester and then 137.5 g of 2-hexyldecanoyl chloride was added dropwise to the solution thus formed at room temperature over a period of about 30 minutes. Thereafter, after keeping the mixture at 50° C. for 2 hours, the reaction mixture was allowed to cool and extracted with a mixture of ethyl acetate and an aqueous hydrochloric acid solution. The extract thus obtained was dried by magnesium sulfate and concentrated to provide 188 g of oily 4-(2-hexyldecanamido)benzoic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](B(O)O)=[CH:8][C:7]=2[CH:14]=1.Br[C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[CH:18][N:17]=1.CCN(CC)CC>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[CH:18][N:17]=3)=[CH:8][C:7]=2[CH:14]=1
Reactant: NC(=O)c1ccc(Br)nc1
Reactant: COc1ccc2oc(B(O)O)cc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc2oc(-c3ccc(C(N)=O)cn3)cc2c1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 31.7 %

Procedure:
5-methoxybenzofuran boronic acid (1.2 mmol), 6-bromonicotinamide (1.0 mmol), Pd(PPh3)2Cl2 (0.024 mmol) and NEt3 (317 μL) were mixed in EtOH (10 mL) in a 20 mL microwave vial. The mixture was stirred at 140° C. for 10 min in a microwave reactor. The mixture was filtered, the obtained precipitate was washed with water and EtOAc and dried under vacuum to afford the title compound (85 mg). 1H NMR δ ppm 9.14 (d, 1 H) 8.42 (dd, 1 H) 7.97-8.25 (m, 2 H) 7.63-7.80 (m, 2 H) 7.58 (d, 1 H) 7.22 (d, 1 H) 6.98 (dd, 1H) 3.81 (s, 3 H); MS m/z 269 (M+H).