Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][CH2:5][C:6](Cl)=O.[NH2:10][NH:11][C:12]([NH2:14])=O.C1(C)C=CC=CC=1.C[S:23](O)(=O)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:9])[CH2:4][CH2:5][C:6]1[S:23][C:12]([NH2:14])=[N:11][N:10]=1
Reactant: CS(=O)(=O)O
Reactant: COC(=O)CCC(=O)Cl
Reactant: NNC(N)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CCc1nnc(N)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Chlorocarbonyl-propionic acid methyl ester (4.4 g, 29 mmol) is added dropwise to a stirred suspension of semicarbazide (4.0 g, 44 mmol) in THF (25 ml) at 0° C. After stirring at room temperature for 1 hour, the solvent is removed to give a white solid. Toluene (30 ml) is added followed by dropwise addition of methane sulfonic acid (3.37 ml, 52 mmol) then the reaction is heated at 70° C. for 3 hours. The mixture is concentrated in vacuo and methanol (30 ml) is added. Aqueous ammonia is then added with stirring until a basic mixture is obtained. The solvents are removed and the residue is purified by chromatography on silica eluting with chloroform:methanol (10:1) to give the titled product.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[NH:16]1[CH2:21][CH2:20]C[CH2:18][CH2:17]1.C12C(=CC=CC=1)[NH:27]C(=O)OC2=O>>[NH:16]1[CH2:17][CH2:18][N:27]=[C:21]1[CH2:20][NH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: C1CCNCC1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Nc1ccccc1C(=O)N1CCCCC1
Product: O=C(c1ccccc1NCC1=NCCN1)N1CCCCC1

Procedure:
1-(2-Aminobenzoyl)piperidine (prepared from piperidine and isatoic anhydride, using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give {2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]phenyl}(1-piperidinyl)methanone.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH2:4][CH2:3]1.C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4](=[CH:17][N:18]([CH3:20])[CH3:19])[CH2:3]1
Reactant: CC1(C)CCC(=O)c2ccccc21
Reactant: CCOC(OCC)N(C)C
Product: CN(C)C=C1CC(C)(C)c2ccccc2C1=O

Procedure:
The 3,4-dihydro-4,4-dimethyl-2-(dimethylaminomethylene)-1-(2H)-naphthalenone starting material was prepared from 4,4-dimethyl-1-tetralone (3.48 g, 20 mmol) and N,N-dimethylformamide diethyl acetal (10.5 ml, 60 mmol) to give the desired compund as bright yelikow crystals (3.53 g). δH (CDCl3) 8.05 (1H, ddd, J 7.7, 1.5, 0.5 Hz), 7.78 (1H, s), 7.42 (1H, m), 7.33-7.25 (2H,m), 3.12 (6H, s), 2.80 (2H, s) and 1.33 (6H, s).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23]O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[BrH:27].[C:28]1([PH+:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(#N)C>[Br-:27].[C:41]1([P+:34]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:25])[F:26])=[CH:4][CH:5]=3)=[CH:10][CH:11]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: Br
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: OCc1ccccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Solvent: CC#N
Product: FC(F)(F)c1ccc(-c2ccc(COc3ccccc3C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2)cc1
Product: [Br-]
Yield: 96.7 %

Procedure:
A solution of 11.7 g (32.65 mmol) of [2-(4′-trifluoromethylbiphenyl-4-ylmethoxy)phenyl]-methanol from Example 24A in 100 ml of acetonitrile is mixed with 10.64 g (31.02 mmol) of triphenylphosphonium hydrobromide and heated to reflux for 3 hours. The reaction solution is then concentrated to dryness, and the resulting oil is taken up and triturated in diethyl ether. The product crystallizes as a white solid during this. After filtration, the solid is dried in a oven at 50° C. overnight. 20.5 g (30 mmol, 92% yield) of crystalline product are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[CH:4]=O.[O-2].[Mg+2].CS(C)=O.[C:19]([CH2:21]P(=O)(OCC)OCC)#[N:20]>C(OC(=O)C)C>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[CH:4]=[CH:21][C:19]#[N:20]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=Cc1c(Br)cccc1[N+](=O)[O-]
Agent: [Mg+2]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#CC=Cc1c(Br)cccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
2-Bromo-6-nitrobenzaldehyde (30.4 g), magnesium oxide (75 g) and dimethyl sulfoxide (11.3 ml) were sufficiently stirred for one minute. Then, to the mixture was added diethyl (cyanomethyl)phosphonate (25.8 ml) and the mixture was stirred for further 2 hours. The stirring was stopped and the reaction mixture was allowed to stand overnight. Thereafter, ethylacetate was added thereto and the resulting mixture was stirred, followed by filtering. The filtrate was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate), to give 32 g of 3-(2-bromo-6-nitrophenyl)-2-propenenitrile (E isomer:Z isomer=3:1).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=[O:31])=[CH:4][CH:3]=1.[C:38](Cl)(=[O:41])[CH2:39][CH3:40]>>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:38](=[O:41])[CH2:39][CH3:40])=[C:8]2[CH2:28][C:29]([CH3:34])([CH3:35])[C:30]([OH:32])=[O:31])=[CH:4][CH:3]=1
Reactant: CCC(=O)Cl
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Product: CCC(=O)c1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc12

Procedure:
The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A of Example 47), but using propanoyl chloride in place of trimethylacetyl chloride in Step B.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH:8]=[O:9].C(N(CC)CC)C.[C:17]1([C:23](Cl)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[CH3:7][N:6]1[C:2]([NH:1][C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:3]([CH:8]=[O:9])[CH:4]=[N:5]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(C=O)c1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ncc(C=O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 70 h
Yield: 92 %

Procedure:
To a suspension of 5-amino-1-methylpyrazole-4-carbaldehyde (25 g, 200 mmol) and triethylamine (22.2 g, 220 mmol) in dichloromethane (500 ml) was added triphenylmethyl chloride (61.3 g, 220 mmol) at room temperature. The mixture was stirred at room temperature for 70 hours. The reaction mixture was washed with successively 10% aqueous citric acid solution, brine and 10% aqueous sodium hydrogencarbonate solution. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with ethyl acetate to give 1-methyl-5-triphenylmethylaminopyrazole-4-carbaldehyde (67.6 g) as a colorless solid.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=C1)=O.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([S:22][C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[C:25](O)=[O:26])=[CH:14]1.CN>C1COCC1>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([S:22][C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[C:25]([NH:3][CH3:1])=[O:26])=[CH:14]1
Reactant: O=C(O)c1ccccc1Sc1c[nH]c2ccccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1Sc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Carbonyldiimidazole (11 mmol) was added to a solution of 2-(1H-indol-3-ylsulfanyl) benzoic acid (Hamel, P.; Girard, M.; Tsou, N. N.; J. Heterocycl. Chem. 36, 1999, 643-652) (10 mmol) in dry THF (200 mL) and refluxed for 60 minutes under argon. Methyl amine (1M in THF; 40 ml) was added slowly to the reaction mixture and the mixture was stirred at room temperature for 16 hours. The mixture was evaporated in vacuo and the product purified by column chromatography on silica gel using ethyl acetate as an eluent.
Reaction SMILES: O[C:2]1([C:23]([F:26])([F:25])[F:24])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][S:13]([C:10]1[CH:9]=[CH:8][C:7]([N:5]2[CH:6]=[C:2]([C:23]([F:26])([F:25])[F:24])[N:3]=[C:4]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:14])=[O:15]
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccccn2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccccn2)cc1
Yield: 64.9 %

Procedure:
A mixture of 2-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine from step 2 (1.0 g, 2.6 mmol) and p-toluenesulfonic acid monohydrate (0.2 g, 2.7 mmol) in toluene (100 ml) was heated to reflux for 24 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude mixture (1.2 g) was chromatographed on silica gel using ethyl acetate/toluene (1/1) to give pure 2-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine (620 mg, 65%) as a white solid: mp (DSC) 184° C. Anal. Calc'd. for C16H12N3SO2F3 : C, 52.30, H, 3.29, N, 11.44. Found: C, 52.23, H, 3.23, N, 11.19.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8](I)=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1.[CH3:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([OH:29])[CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8]([N:26]3[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][C:25]3=[O:29])=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1
Reactant: Cc1ccnc(O)c1
Reactant: CNC(=O)c1c(I)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-n2ccc(C)cc2=O)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 80 °C
Reaction time: 10 h
Yield: 82.9 %

Procedure:
To a mixture of 5-bromo-2-iodo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (500 mg, 1.03 mmol), 4-methylpyridin-2-ol (168 mg, 1.54 mmol) and K2CO3 (283 mg, 2.05 mmol) in DMF (5 mL) was stirred at 80° C. for 10 hours and concentrated in vacuo to remove DMF. The reaction mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc=1:1) to give the product of 5-bromo-N-methyl-2-(4-methyl-2-oxopyridin-1 (2H)-yl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (400 mg, yield: 83%). 1H-NMR (CDCl3, 400 MHz) δ 8.32 (s, 1H), 7.85 (s, 1H), 7.67 (s, 1H), 7.22 (d, J=7.2 Hz, 1H), 6.52 (s, 1H), 6.28 (d, J=1.6 Hz, 1H), 3.32 (s, 3H), 3.06 (s, 3H), 2.89 (d, J=4.8 Hz, 3H), 2.31 (s, 3H). MS (M+H)+: 468/470.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3[O:14][CH:8]3[C:7]=2[CH:15]=1)#[N:2].[CH3:16][O:17][C:18]1[CH2:22][NH:21][C:20](=[O:23])[CH:19]=1.C(OC1CNC(=O)C=1)CCCCCCC>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([N:21]3[CH2:22][C:18]([O:17][CH3:16])=[CH:19][C:20]3=[O:23])[C:7]=2[CH:15]=1)#[N:2]
Reactant: COC1=CC(=O)NC1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: CCCCCCCCOC1=CC(=O)NC1
Product: COC1=CC(=O)N([C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2O)C1

Procedure:
Similarly, optionally replacing 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran with the appropriate compound of formula (2), and optionally replacing 4-methoxy-3-pyrrolin-2-one with the appropriate compound of formula (3), the following compounds of formula (I) are prepared:
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(=[O:7])=[O:6].[NH2:21][CH2:22][C@@H:23]([C:25]1[CH:26]=[CH:27][C:28]([OH:36])=[C:29]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:30]=1)[OH:24]>>[OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([NH:21][CH2:22][C@H:23]([OH:24])[C:25]3[CH:26]=[CH:27][C:28]([OH:36])=[C:29]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:30]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: O=C1CCN(c2ccc(S(=O)(=O)NCCO)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(S(=O)(=O)NCCO)cc3)CC2)ccc1O

Procedure:
The title compound was prepared according to the procedure of Example 1 from 0.12 g (0.4 mmol) of Reference Example 30, N-(2-hydroxyethyl)-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, and 0.12 g (0.5 mmol) of (R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-methanesulfonamide, yielding 0.22 g of an off-white solid; m.p. 78-81° C.; MS (ES) m/z 529.2 (MH+); HRMS (ES) Calcd. for C22H33N4O7S2 (MH+): 529.1785, Found: 529.1779.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([C:13]([O-])=[O:14])=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1.[Na+].N1C=CC=CC=1.C(Cl)(=O)C([Cl:28])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([C:13]([Cl:28])=[O:14])=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2nnnc2C(=O)[O-])cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COc1ccc(Cn2nnnc2C(=O)Cl)cc1
Temperature: 15 °C

Procedure:
Following the procedure of Example 3, the sodium salt produced in Example 5 is stirred with pyridine in benzene at 6° C. with rapid addition of oxalyl chloride. The mixture is stirred at 15° C. for one half hour, stripped and scrubbed twice with benzene to yield 1-(p-methoxybenzyl)-1H-tetrazole-5-carbonyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)ccc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 97.4 %

Procedure:
4-Bromo-2-nitro-phenol (Aldrich, 2.18 g, 10 mmol) was treated with K2CO3 (Aldrich, 2.76 g, 20 mmol) in DMF (Aldrich, 100 mL) at ambient temperature for 20 min. Benzyl chloride (Aldrich, 1.52 g, 12 mmol) was added. The mixture was stirred at 100° C. for 6 h. It was then poured into ice/water (200 mL) and stirred at ambient temperature for 10 hours. The white solid was filtered and dried to give the title compound (3.0 g, yield, 100%). 1H NMR (300 MHz, CDCl3) δ 5.23 (s, 2H), 7.01 (d, J=9.2 Hz, 1H), 7.31-7.49 (m, 5H), 7.58 (dd, J=9.0, 2.5 Hz, 1H), 7.98 (d, J=2.7 Hz, 1H) ppm. MS (DCI/NH3): 325 (M+H)+, 327 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].Br[CH2:37][CH2:38][F:39]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH2:37][CH2:38][F:39])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: FCCBr
Reactant: COc1ccc(CC2c3c(OC)ccc(O)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Product: COc1ccc(CC2c3c(OC)ccc(OCCF)c3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with 1-bromo-2-fluoro-ethane
Reaction SMILES: [F:1][C:2]1[C:3]([C:19]2[CH:20]=[N:21][NH:22][CH:23]=2)=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.[C:24]([CH:26]=[C:27]1[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]1)#[N:25].N12CCCN=C1CCCCC2>C(#N)C>[C:24]([CH2:26][C:27]1([N:22]2[CH:23]=[C:19]([C:3]3[C:2]([F:1])=[CH:7][N:6]=[C:5]4[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:4]=34)[CH:20]=[N:21]2)[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]1)#[N:25]
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)c(F)cnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3c(F)cnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a solution of 5-fluoro-4-(1H-pyrazol-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (2.00 g, 6.02 mmol) and tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (1.168 g, 6.02 mmol) in acetonitrile (20 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.8996 mL, 6.02 mmol). The mixture was stirred at room temperature overnight and concentrated. The residue was purified by silica gel chromatography (0-80% EtOAc/hexanes) to give 3.05 g (96.3%) of tert-butyl 3-(cyanomethyl)-3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate as a colorless oil. LC/MS found: 527.3 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[CH:18]=[CH:19]/[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][N:21]=2)=[N:8][CH:7]=1)=[O:5])C.[OH-].[Na+].O>CO>[NH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](/[CH:19]=[CH:18]/[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:9]2[S:10][C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=2)=[N:21]1
Reactant: CCOC(=O)c1cnc(Nc2ccccc2/C=C/c2n[nH]c3ccccc23)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnc(Nc2ccccc2/C=C/c2n[nH]c3ccccc23)s1
Temperature: 60 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
Compound 165 (0.02 g, 0.051 mmol) was dissolved in methanol (1.0 mL) and 1 mol/L aqueous sodium hydroxide solution (1.0 mol) was added thereto, followed by stirring at 60° C. for 3 hours. The reaction mixture was added with water, washed with ethyl acetate and the aqueous layer was neutralized using 6 mol/L hydrochloric acid. The precipitated solid was triturated in ethyl acetate to obtain Compound 166 (13 mg, 72%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][C:10](I)=[C:11]([CH3:13])[N:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])#[CH:24].[NH4+].[Cl-]>C(#N)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>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][C:10]([C:24]#[C:23][Si:25]([CH3:28])([CH3:27])[CH3:26])=[C:11]([CH3:13])[N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1C#C[Si](C)(C)C
Temperature: 32 °C
Reaction time: 4 h

Procedure:
Under a stream of Ar the above prepared (5-iodo-4-methyl-thiazol-2-yl)-carbamic acid tert-butyl ester (0.913 g, 2.68 mmol) was dissolved in 17 mL of acetonitrile and treated successively with triethylamine (1.12 mL, 3 eq.), Cul (0.051 g, 0.1 eq.), (Ph3P)2PdCl2 (0.188 g, 0.1 eq.), and ethynyltrimethylsilane (1.11 mL, 3 eq.). The flask was closed with a septum and allowed to stir for 4 h at 32° C. The reaction mixture was then poured onto icewater/NH4Cl, twofold extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/ethyl acetate=85/15) gave finally 0.592 g of the title compound as light brown foam.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[NH:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:3]1=[O:20].CS[C:24]1C=CC(N)=[CH:26][C:25]=1[C:31](F)(F)F.C(Cl)(Cl)=[O:36]>C(#N)C.C1(C)C=CC=CC=1>[CH3:1][C:2]([NH:6][C:5]([NH:4][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=1)=[O:7])([CH3:21])[C:3]([O:36][C:25]([CH3:31])([CH3:26])[CH3:24])=[O:20]
Reactant: CSc1ccc(N)cc1C(F)(F)F
Reactant: CSc1ccc(N2C(=O)NC(C)(C)C2=O)cc1C(F)(F)F
Reactant: O=C(Cl)Cl
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CSc1ccc(NC(=O)NC(C)(C)C(=O)OC(C)(C)C)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Compound 114.1 can be prepared by process “A”. To this end, 1.04 g of 4-methylsulfanyl-3-trifluoromethylphenylamine were dissolved in 25 ml of dry acetonitrile. This solution was added dropwise with stirring to a 20% solution, heated to 70° C., of phosgene in toluene, and then stirred at 80° C. for 2 h. The cooled reaction solution was concentrated under reduced pressure, and the residue was taken up with toluene and concentrated again under reduced pressure. Finally, the residue was dissolved in 25 ml of dry tetrahydrofuran and the solution was admixed with stirring with 0.88 g of tert-butyl 2-amino-2-methylpropionate hydrochloride. 1.05 ml of triethylamine were slowly added dropwise to the reaction mixture which was then stirred at room temperature for 4 h. The reaction mixture was admixed with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated. tert-Butyl 2-methyl-2-[3-(4-methylsulfanyl-3-trifluoromethylphenyl)ureido]propionate (molecular weight 392.13 (C17H23F3N2O3S); retention time Rt=2.40 min. [B]; MS (ESI): 337.26 (MH+−C4H8)) was obtained. The urea was dissolved in 20 ml of tetrahydrofuran, admixed with 4.9 ml of concentrated hydrochloric acid and stirred at 80° C. for 2 h. The cooled reaction mixture was concentrated under reduced pressure and the residue was admixed with ethyl acetate and water. The organic phase was removed, washed with saturated sodium hydrogen-carbonate solution and then with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel with 96/4 dichloromethane/methanol. 21.2 g (90% yield) of 5,5-dimethyl-3-(4-methylsulfanyl-3-trifluoromethylphenyl)imidazolidin-2,4-dione 114.1 were obtained. Molecular weight 318.06 (C13H13F3N2O2S); retention time Rt=1.93 min. [B]; MS (ES−): 317.07 (M−H+).
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[Cl:13][CH2:14][C:15](Cl)=O.C[N:19]([CH:21]=[O:22])C>>[CH3:15][C:14]([Cl:13])([C:21]([NH2:19])=[O:22])[C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CN(C)C=O
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1cc(Cl)ccc1N
Product: CC(Cl)(C(N)=O)c1ccc(Cl)cc1C(=O)O

Procedure:
To a solution of methyl 2-amino-5-chlorobenzoate (2.5 g) in DMF (25 mL) was added chloroacetyl chloride (1.4 mL) with ice cooling. The resulting white crystals were collected by filtration and washed with water. The resulting white crystals were dried to obtain methyl 5-chloro-2-(2-chloroacetamide)benzoate (5.4 g).