Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:20])[C:4](=[O:19])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][C:8]([CH3:18])([CH3:17])[CH2:7]2)[N:6]=1.[C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)#[N:22].C([O-])([O-])=O.[Na+].[Na+]>CC1C=CC=CC=1C.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>[NH2:1][C:2]1[N:3]([CH3:20])[C:4](=[O:19])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:27]4[CH:28]=[C:23]([CH:24]=[CH:25][CH:26]=4)[C:21]#[N:22])[CH:14]=3)[O:9][C:8]([CH3:18])([CH3:17])[CH2:7]2)[N:6]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN1C(=O)C2(CC(C)(C)Oc3ccc(Br)cc32)N=C1N
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: Cc1ccccc1C
Product: CN1C(=O)C2(CC(C)(C)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 90 °C
Yield: 21.3 %

Procedure:
Pd(PPh3)4 (15.13 mg, 0.013 mmol) is added to the solution of 2′-amino-6-bromo-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (44.15 mg, 0.13 mmol) and 3-cyanophenylboronic acid (19.25 mg, 0.13 mmol) in dimethyl-benzene (5 mL) and an aqueous solution of Na2CO3 (2 M, 0.24 mL). The mixture is heated at 90° C. in an oil bath overnight. The mixture is concentrated to give the crude product, which is purified by preparative TLC to give the desired product 3-(2′-amino-1′,2,2-trimethyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (10 mg, 15%).
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[CH3:23].[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26](B(O)O)[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:26]4[CH:25]=[N:24][C:33]5[C:28]([CH:27]=4)=[CH:29][CH:30]=[CH:31][CH:32]=5)=[C:3]([CH3:23])[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(Br)sc2n1
Reactant: OB(O)c1cnc2ccccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(-c3cnc4ccccc4c3)sc2n1
Temperature: 100 °C
Yield: 31.7 %

Procedure:
To a solution of N-(2-bromo-3,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 77) (90 mg, 0.208 mmol) in 1,4-dioxane (2 mL) and water (1 mL) was added 3-quinolinylboronic acid (72.1 mg, 0.417 mmol), bis(triphenylphosphine)palladium(II) chloride (14.63 mg, 0.021 mmol) and potassium carbonate (101 mg, 0.730 mmol) and the reaction mixture heated at 100° C. for 30 min using a microwave reactor. The mixture was then filtered through celite, washing with DCM (30 mL×2) and the filtrate dried (phase separation cartridge) and concentrated. This residue was then purified by MDAP (basic conditions) and then further triturated with MeOH (2 mL) and dried, to afford the title compound (31.61 mg). LCMS (A) m/z: 480 [M+1]+, Rt 1.23 min (acidic).
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]2[C:20]([N:23]3[CH2:27]CC[CH2:24]3)=[N:21][N:22]=[C:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][N:29]1CCCC1=O>>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:28]#[N:29])[CH:15]=2)[N:10]2[C:20]([N:23]([CH3:27])[CH3:24])=[N:21][N:22]=[C:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2cc(Br)ccc2n2c(N3CCCC3)nnc2n1Cc1ccccc1
Reactant: CN1CCCC1=O
Product: CN(C)c1nnc2n(Cc3ccccc3)c(=O)c3cc(C#N)ccc3n12
Reaction time: 12 h
Yield: 90 %

Procedure:
In a 500 ml balloon flask, equipped with a shaker, refrigeration and nitrogen feeding, we add 10.8 g (27.1 mmol) of 4-benzyl-7-bromo-1-(pyrrolidin-1-yl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (example 164) in 100ml of N-methylpyrrolidinone (NMP). We add 4.4 g (49 mmol) of cuprous cyanide then heat the mixture, under shaking and under nitrogen for 12 hours. The solvent is eliminated by evaporation under vacuum; the residue is stirred in mixture of methylene chloride and 2N ammonia solution, the insoluble residue is eliminated by filtration, then the phases are separated by decantation. The organic phase is washed in a NaCl-saturated solution, dried on Na2SO4 and evaporated to give 24.0 g of crude product. This is purified by chromatography on silica column by elution using mixture of ethyl acetate 65/cyclohexane 35. The fractions pure in CCM are joined and evaporated under vacuum: we obtain 8.4 g of compound from example 237.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.[C:26]([CH2:28][C:29]1([N:40]2[CH:44]=[C:43](B3OC(C)(C)C(C)(C)O3)[CH:42]=[N:41]2)[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30]1)#[N:27].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[C:26]([CH2:28][C:29]1([N:40]2[CH:44]=[C:43]([C:2]3[CH:7]=[N:6][N:5]4[C:8]([C:11]5[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:12]=5)=[CH:9][N:10]=[C:4]4[CH:3]=3)[CH:42]=[N:41]2)[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30]1)#[N:27]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)cnn23)c1
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)C1
Temperature: 100 °C

Procedure:
A mixture of N-[3-(7-chloroimidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (600 mg, 2 mmol), tert-butyl 3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (760 mg, 1.9 mmol), tetrakis(triphenylphosphine)palladium(0) (94.9 mg, 0.0822 mmol) and potassium carbonate (570 mg, 4.1 mmol) in 1,4-dioxane (9.0 mL) and water (4 mL) was heated at 100° C. under an atmosphere of nitrogen for 4 h. After cooling, the reaction mixture was extracted with ethyl acetate (3×20 mL), and washed with brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in dichloromethane (0-10%) to afford the desired product. LCMS (M+H)+: m/z=596.2.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=[C:6]([Cl:14])[C:3]=1[CH2:4][OH:5].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:5][CH2:4][C:3]1[C:6]([Cl:14])=[CH:7][CH:8]=[C:9]([O:10][CH:11]([CH3:12])[CH3:13])[C:2]=1[Cl:1])(=[O:25])=[O:24]
Reactant: CC(C)Oc1ccc(Cl)c(CO)c1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(Cl)c(COS(C)(=O)=O)c1Cl
Temperature: 5 °C
Yield: 94.2 %

Procedure:
To a mixture of 2,6-dichloro-3-isopropoxybenzyl alcohol (1.65 g) and triethylamine (808 mg) in dichloromethane was added methanesulfonyl chloride (884 mg) in a few minutes at 5° C. After stirring for half an hour at 5° C., the mixture was washed with diluted hydrochloric acid and then with aqueous sodium bicarbonate solution, dried, and concentrated in vacuo. The residue was crystallized from n-hexane to give 2,6-dichloro-3-isopropoxybenzyl methanesulfonate (2.07 g).
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:12])[C@:4]1([CH3:11])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5]1.[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>CCOCC>[CH3:10][C:6]1([CH3:9])[O:5][C@:4]([CH3:11])([C:3]([Cl:12])=[N:2][O:1][S:14]([CH3:13])(=[O:16])=[O:15])[CH2:8][O:7]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OC[C@@](C)(C(Cl)=NO)O1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC1(C)OC[C@@](C)(C(Cl)=NOS(C)(=O)=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
(S)-N-hydroxy-2,2,4-trimethyl-1,3-dioxolane-4-carbimidoyl chloride (5.5 g, 28.4 mmol) was dissolved in Et2O (150 mL) and methanesulfonyl chloride (2.21 ml, 28.4 mmol) was added. Triethylamine (3.96 ml, 28.4 mmol) was added dropwise and the reaction was stirred at ambient temperature for 1 hour. The resulting solids were filtered and the filtrate concentrated. The residue was purified over silica gel (100% CH2Cl2) to afford (S)-2,2,4-trimethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoyl chloride (4.7 g, 17.3 mmol, 60.9% yield) as an amber oil.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11](C(=O)C(F)(F)F)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.O.C([O-])([O-])=O.[K+].[K+]>CO>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)C1CCN(C(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(c1ccc(Br)cc1)C1CCNCC1
Reaction time: 16 h
Yield: 91.3 %

Procedure:
To a solution of 1-[4-(4-bromo-benzoyl)-piperidin-1-yl]-2,2,2-trifluoroethanone (11.6 g, 31.9 mmol) (Palani A.; et al., J. Med. Chem., 2001, 44, 3339-3342) in MeOH (60 mL) and H2O (15 mL) at room temperature was added K2CO3 (10.0 g, 72.5 mmol) and the mixture was stirred for 16 hours to give (4-bromophenyl)-piperidin-4-yl-methanone as a pale yellow solid (7.81 g, 96%) following work-up and purification.
Reaction SMILES: [Na].[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][OH:6].F[C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[C:16]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1>CCOCC>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][O:6][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[C:16]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:17]([F:18])([F:19])[F:20])=[CH:11][CH:10]=1
Reactant: CN(C)CCO
Reactant: COc1ccc(C(=C(c2ccc(OC)cc2)C(F)(F)F)c2ccc(F)cc2)cc1
Agent: [Na]
Solvent: CCOCC
Product: COc1ccc(C(=C(c2ccc(OC)cc2)C(F)(F)F)c2ccc(OCCN(C)C)cc2)cc1
Temperature: 170 °C
Yield: 72.7 %

Procedure:
0.46 g (0.02 g.-atoms) of sodium are dissolved in 3.56 g (40 mmoles) of 2-dimethylamino-ethanol, 4.02 g (10 mmoles) of 1-(4-fluorophenyl)-3,3,3-trifluoro-1,2-bis-(4-methoxyphenyl)-propene are added, and the mixture is heated at 170° C. for one hour. The reaction mixture is cooled, diluted with 200 ml of ether, washed with water until neutral, dried and then evaporated. The residue is recrystallized from 45 ml of hexane. 3.43 g (73%) of the aimed compound are obtained; m.p.: 77°-79° C.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([O:7][CH2:8][CH3:9])[NH:4][C:3]=1[CH:10]=[O:11].[C:12]([O:16][C:17]([C:19]1[C:20]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31]Br)=[CH:27][CH:26]=2)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>>[C:12]([O:16][C:17]([C:19]1[C:20]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:4]3[C:3]([CH:10]=[O:11])=[C:2]([Br:1])[N:6]=[C:5]3[O:7][CH2:8][CH3:9])=[CH:27][CH:26]=2)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOc1nc(Br)c(C=O)[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
5-Bromo-2-ethoxy-3H-imidazole-4-carbaldehyde (3.0 g, 13.7 mmol), 4′-bromomethylbiphenyl-2-carboxylic acid t-butyl ester (4.8 g, 13.7 mmol), and potassium carbonate (1.9 g, 13.7 mmol), were dissolved in DMF (60 mL, 780 mmol), and the mixture was stirred at room temperature overnight. The reaction was quenched with water, and the mixture was extracted with EtOAc, washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated. The resulting material was purified by silica gel chromatography (0-30% EtOAc:hexanes) to yield intermediate (17a) (5.6 g). MS m/z: [M+H+] calcd for C24H25BrN2O4, 485.1. found 485.3. 1H-NMR (CDCl3): 9.58 (1H, s), 7.80 (1H, d), 7.50 (1H, t), 7.40 (1H, t), 7.30 (5H, m), 5.42 (2H, s), 4.57 (2H, q), 1.46 (3H, t), 1.18 (9H, s).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[C:27]([C:30]1[N:31]2[CH:37]=[N:36][CH:35]=[C:32]2[S:33][CH:34]=1)(=[O:29])[NH2:28]>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:36]3[CH:35]=[C:32]4[S:33][CH:34]=[C:30]([C:27](=[O:29])[NH2:28])[N+:31]4=[CH:37]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: NC(=O)c1csc2cncn12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc(C(N)=O)[n+]4c3)[C@H](C)[C@H]12
Yield: 8 %

Procedure:
The same procedure as in Example 1 was repeated except that 113 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 260 mg of 3-carbamoylimidazo[5,1-b]thiazole were used, thereby obtaining 9.6 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17](I)[CH2:18][CH2:19][CH3:20]>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:17][CH2:18][CH2:19][CH3:20])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: CCCCI
Reactant: Brc1ccc(Nc2ncccn2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCN(c1ccc(Br)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, N-(4-bromophenyl)pyrimidin-2-amine (160 mg) was added to a suspension of sodium hydride (33 mg) in anhydrous DMF (3 ml), and the resulting mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled to 0° C. and n-butyl iodide (0.080 ml) was added thereto, followed by stirring the resulting mixture at room temperature for 1 hour. Saturated brine was added to the reaction solution and the resulting mixture was extracted 3 times with ethyl acetate. Organic layers were washed 3 times with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: ethyl acetate/hexane=1/10) to obtain N-(4-bromophenyl)-N-butylpyrimidin-2-amine (194 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[Br:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][C:26]=1[O:32][CH3:33]>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:28]1[CH:29]=[CH:30][C:25]([Br:24])=[C:26]([O:32][CH3:33])[CH:27]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: COc1cc(I)ccc1Br
Product: COc1cc(C(=O)C(NC(=O)OC(C)(C)C)c2ccc(Cl)c(Cl)c2)ccc1Br

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 2-bromo-5-iodoanisole in analogy to Example 1a): MS (ISN): 488.1 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:24][CH3:25])[C:15]([NH:17][C:18]1([CH:22]=O)[CH2:21][CH2:20][CH2:19]1)=[O:16])=[CH:8][CH:7]=2)#[CH:2].C([O-])(=O)C.[Na+].Cl.[CH3:32][O:33][NH2:34].O>C(O)C>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:24][CH3:25])[C:15]([NH:17][C:18]1([CH:22]=[N:34][O:33][CH3:32])[CH2:19][CH2:20][CH2:21]1)=[O:16])=[CH:8][CH:7]=2)#[CH:2]
Reactant: CON
Reactant: C#Cc1cnc2ccc(OC(SC)C(=O)NC3(C=O)CCC3)cc2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C#Cc1cnc2ccc(OC(SC)C(=O)NC3(C=NOC)CCC3)cc2c1
Temperature: 65 °C
Yield: 81.3 %

Procedure:
To a solution of 2-(3-Ethynyl-quinolin-6-yloxy)-N-(1-formyl-cyclobutyl)-2-methylsulfanyl-acetamide (125 mg) in ethanol (10 ml) was added sodium acetate (50 mg) and O-methyl hydroxylamine hydrochloride (44 mg), at room temperature. The mixture was heated to 65° C. during 1 hour. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate (2×10 ml). The organic phase was washed with sat. aq NaCl solution, dried over anhydrous sodium sulphate, filtered and evaporated under vacuum. Purification by flash chromatography (ethyl acetate/cyclohexane, 1/1) gave 2-(3-ethynyl-quinolin-6-yloxy)-N-[1-(methoxyimino-methyl)-cyclobutyl]-2-methylsulfanyl-acetamide (110 mg) as a yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:50])[C@@H:5]([O:47][CH2:48][CH3:49])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[CH:15]=[CH:16]/[C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[C:26]/[CH:27]=[CH:28]/[CH2:29][O:30][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][C@H:38]([O:44][CH2:45][CH3:46])[C:39]([O:41]CC)=[O:40])=[CH:33][CH:32]=3)[CH:20]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C1COCC1.C(O)C>[C:39]([C@@H:38]([O:44][CH2:45][CH3:46])[CH2:37][C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:29]/[CH:28]=[CH:27]/[C:26]#[C:25][C:21]2[CH:20]=[C:19]([C:18]#[C:17]/[CH:16]=[CH:15]/[CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:47][CH2:48][CH3:49])[C:4]([OH:50])=[O:3])=[CH:12][CH:11]=3)[CH:24]=[CH:23][CH:22]=2)=[CH:36][CH:35]=1)([OH:41])=[O:40]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C/C#Cc2cccc(C#C/C=C/COc3ccc(C[C@H](OCC)C(=O)OCC)cc3)c2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCO[C@@H](Cc1ccc(OC/C=C/C#Cc2cccc(C#C/C=C/COc3ccc(C[C@H](OCC)C(=O)O)cc3)c2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (E)(E)(S)(S) 2-ethoxy-3-{4-[5-(3-{5-[4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-pent-3-en-1-ynyl}-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-propionic acid ethyl ester (example 5) (130 mg 0.2 mmol) in THF (3 mL) and ethanol (3 mL) was added 1N sodium hydroxide (1.5 mL). After stirring at room temperature for 2 h, the reaction mixture was concentrated in vacuo, added water and 1N hydrochloride acid to pH 1. The product was extracted with dichloromethane (×3) and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a crystalline product. The product was recrystallised from tetrachloromethane and petroleum ether to give 72 mg (58%) of the title compound.
Reaction SMILES: [SH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:19](Br)/[CH:20]=[C:21](/[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])\[CH3:22]>>[CH2:19]([S:1][C:2]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)/[CH:20]=[C:21](/[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])\[CH3:22]
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: O=c1c2ccccc2nc(S)n1-c1ccccc1
Product: CC(C)=CCC/C(C)=C/CSc1nc2ccccc2c(=O)n1-c1ccccc1
Yield: 57.6 %

Procedure:
The title compound was prepared in a yield of 57.6%, using 2-mercapto-3-phenyl-4(3H)-quinazolinone in place of 3-isobutyl-2-mercapto-4(3H)-quinazolinone and geranyl bromide in place of 2-chloromethylpyridine hydrochloride.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:17][CH2:16][N:15]3[CH2:18][C@@H:19]([OH:21])[CH2:20][C@@H:14]3[CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH:24]1([C:27]2[N:28]=[CH:29][C:30](O)=[N:31][CH:32]=2)[CH2:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>O1CCCC1>[CH:24]1([C:27]2[N:28]=[CH:29][C:30]([O:21][C@H:19]3[CH2:18][N:15]4[CH2:16][CH2:17][N:12]([S:9]([C:5]5[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=5)(=[O:11])=[O:10])[CH2:13][C@H:14]4[CH2:20]3)=[N:31][CH:32]=2)[CH2:26][CH2:25]1
Reactant: Oc1cnc(C2CC2)cn1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N1CCN2C[C@@H](O)C[C@@H]2C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
A mixture of (7S,8aR)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-ol (Example 17, 103 mg, 0.294 mmol), 5-cyclopropylpyrazin-2-ol (40 mg, 0.294 mmol) and triphenylphosphine (154 mg, 0.588 mmol) in tetrahydrofuran (1 mL) was stirred at room temperature for 1 hour. Then (E)-diisopropyl diazene-1,2-dicarboxylate (119 mg, 0.588 mmol) was added, and the reaction was continued at room temperature overnight. The solution was concentrated, and the residue was purified by chromatography on silica gel (ethyl acetate/hexane=3:2) to give the title compound (68 mg, 48% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.86 (m, 4H), 1.22 (m, 2H), 2.12 (m, 4H), 2.41 (m, 2H), 3.01 (m, 2H), 3.67 (m, 1H), 3.83 (m, 1H), 5.25 (m, 1H), 7.94 (m, 1H), 8.03 (m, 1H), 8.15 (m, 4H); MS (ESI) m/z 469 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Li]CCCC.[CH3:18][C:19]1[C:20](=O)[CH:21]([CH3:26])[CH:22]([CH3:25])[C:23]=1[CH3:24].Cl.N>C1COCC1>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([C:20]3[CH:19]([CH3:18])[C:23]([CH3:24])=[C:22]([CH3:25])[C:21]=3[CH3:26])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: CC1=C(C)C(C)C(C)C1=O
Reactant: Cc1ccc2cccc(Br)c2n1
Agent: Cl
Agent: N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C(C)C(c2cccc3ccc(C)nc23)=C1C
Temperature: 25 °C
Yield: 60 %

Procedure:
A solution of 4.4 q of 8-bromo-2-methylquinoline (20 mmol) in 50 ml of THF was cooled to −78° C., and 8.8 ml of n-BuLi (2.5 M in hexane, 22 mmol) were added dropwise with stirring. After the mixture had been stirred for 10 minutes, 3.5 g of 2,3,4,5-tetramethylcyclopentenone (25 mmol) were added dropwise, and the solution was warmed to room temperature, refluxed for one hour and cooled. Ice and hydrochloric acid were added to about pH 1, the mixture was neutralized using ammonia solution, the phases were separated, and the aqueous phase was extracted with pentane. After the combined organic extracts had been dried, the pentane was removed under reduced pressure, and the brown oil which remained was distilled under a high vacuum (b.p.: 115° C./0.01 mbar). 1-(2-Methyl-8-quinolyl)-2,3,4,5-tetramethylcyclopentadiene was obtained as a yellow, viscous oil in a yield of 60% (3.2 g).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[S:7]1[C:11]([CH2:12][CH2:13][NH2:14])=[CH:10][C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]1=2>C(Cl)(Cl)Cl.C(N(CC)CC)C>[S:7]1[C:11]([CH2:12][CH2:13][NH:14][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[CH:10][C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]1=2
Reactant: CCOC(=O)Cl
Reactant: NCCc1cc2ccccc2s1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCCc1cc2ccccc2s1
Reaction time: 0.5 h

Procedure:
Ethyl chloroformate (0.18 ml) was added dropwise to a stirred, ice-cooled solution of benzo[b]thiophene-2-ethanamine (300 mg) in a mixture of chloroform (8 ml) and triethylamine (0.28 ml) under nitrogen and stirring was continued at 0° for 30 min. The solution was evaporated, the residue was treated with water (10 ml), extracted with dichloromethane (3×10 ml) and the combined, dried organic extracts were evaporated to give an oily solid. This was purified by FCC eluting with System B (1:2) to give the title compound (313 mg), m.p. 65°-66°.