Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2].[CH3:12][C@H]1CN(C2C=CC(OC(F)(F)F)=CC=2)C[C@@H](C)N1S(C1C=CC=C2C=1C[C@@H](C(O)=O)C2)(=O)=O.[S:46]([C:50]1[CH:56]=[CH:55][C:53]([CH3:54])=[CH:52][CH:51]=1)([O-:49])(=[O:48])=[O:47]>>[S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-:4])(=[O:3])=[O:2].[CH3:12][O:47][S:46]([C:50]1[CH:56]=[CH:55][C:53]([CH3:54])=[CH:52][CH:51]=1)(=[O:49])=[O:48]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@@H]1CN(c2ccc(OC(F)(F)F)cc2)C[C@H](C)N1S(=O)(=O)c1cccc2c1C[C@@H](C(=O)O)C2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: COS(=O)(=O)c1ccc(C)cc1

Procedure:
The methyl ester precursor of (S)-4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid tosylate (hereinafter optionally referred to as “Compound 1 tosylate”) was used for this experiment instead of Compound 1 tosylate due to the unsuitability of the Compound 1 tosylate crystals for X-ray structure determination. Compound 1 tosylate methyl ester was prepared via an esterification of Compound 1 tosylate followed by recrystallization from isopropanol. Other experiments have established that the stereochemistry is retained in converting the methyl ester to Compound 1 tosylate.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[C:26]1[CH3:37]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]([CH3:24])[C:26]=2[CH3:37])=[O:35])=[O:8])[N:6]=1
Reactant: Cc1c(C(=O)O)c2ccccc2n1C
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Cc1c(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(N)sc2-c2cccc(F)c2)c2ccccc2n1C

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 1,2-Dimethyl-1H-indole-3-carboxylic acid. LC-MS (basic): tR=0.81 min; [M+H]+=504.4.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:15][CH2:14][C:13]3[CH:12]=[N:11][NH:10][C:9]=3[C:7]=2[CH:8]=1.Br.C(=O)(O)[O-].[Na+]>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[S:15][CH2:14][C:13]3[CH:12]=[N:11][NH:10][C:9]=3[C:7]=2[CH:8]=1
Reactant: COc1ccc2c(c1)-c1[nH]ncc1CS2
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1ccc2c(c1)-c1[nH]ncc1CS2
Temperature: 25 °C
Yield: 74.9 %

Procedure:
A mixture of 8-methoxy-1,4-dihydro[1]benzothiopyrano[4,3-c]pyrazole (6.75 g) and 47% hydrobromic acid (70.2 ml) was refluxed for 3 hours with stirring and allowed to cool to room temperature. The resulting precipitate was collected by filtration and recrystallized from water to give the salt, which was treated with aqueous sodium bicarbonate to give 8-hydroxy-1,4dihydro[1]benzothiopyrano[4,3-c]pyrazole (4.73 g).
Reaction SMILES: [CH2:1]([C:3]1([CH2:20][C:21]([C:24]([O:26]C)=[O:25])=[N:22][OH:23])[CH:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:11]=32)[CH2:6][CH2:5][CH2:4]1)[CH3:2].[OH-].[Na+].C(O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[CH2:1]([C:3]1([CH2:20][C:21]([C:24]([OH:26])=[O:25])=[N:22][OH:23])[CH:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:11]=32)[CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(CC(=NO)C(=O)OC)CCCN2CCc3c([nH]c4ccccc34)C21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC1(CC(=NO)C(=O)O)CCCN2CCc3c([nH]c4ccccc34)C21
Yield: 81 %

Procedure:
A mixture of 9.25 g. (0.025 mole) of (+)-ethyl-1-(2'-methoxycarbonyl-2'-hydroxyimino-ethyl)-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine, 8.0 g (0.2 mole) of solid sodium hydroxide, 100 ml. of ethanol and 5.0 ml. of water is acidified to a pH value of 6.3 by the addition of a solution of 16 g. of citric acid in 150 ml. of water. The solution is extracted six times with 50 ml. of dichloromethane each. The united organic phases are extracted with a saturated sodium chloride solution, the layers are separated, the organic phase is dried over anhydrous sodium sulfate, filtered and the filtrate is evaporated. To the residue 50 ml. of ether are added, the mixture is heated to boiling, then cooled, the precipitated product is filtered and dried. Thus 7.2 g. of the named compound are obtained, yield 81%. Mp.: 124° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)[Cl:13].C(Cl)(=O)C(Cl)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([Cl:13])=[O:8]
Reactant: Cc1ncc(Cl)cc1C(=O)O
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Cc1ncc(Cl)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Chloro-2-methyl-nicotinic acid (4.15 g, 24.2 mmol) is placed in a flask with DCM (100 mL) and oxalyl chloride (3.68 g, 29 mmol). DMF (200 μL) is added and the reaction mixture is stirred at r.t. for 1 hour (gas evolution). The mixture is filtered and the solvent is removed in vacuo to afford the title product which is used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH:4]([CH3:7])[CH2:5][CH3:6].[H-].[Na+].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[CH3:1][O:2][C:3](=[O:8])[C:4]([CH2:5][CH3:6])([CH3:7])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCC(C)C(=O)OC
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)(Cc1ccccc1)C(=O)OC
Reaction time: 16 h

Procedure:
202.7 g of α-methyl-butyric acid methyl ester are added dropwise to a suspension of 44 g of sodium hydride in 1.3 liters of tetrahydrofuran and the mixture is subsequently boiled at reflux with stirring for 16 hours. A solution of 204 cc of benzyl chloride in 500 cc of tetrahydrofuran is then added dropwise and the reaction mixture is boiled at reflux for a further 70 hours. Working up is effected by removing the tetrahydrofuran by distillation, cooling the mixture, adding 600 cc of petroleum ether and 30 cc of methanol, washing with 300 cc of 5% acetic acid and then with water. The crude, oily α-ethyl-α-methyl-dihydrocinnamic acid methyl ester, obtained after evaporating the solvent, is distilled at 15 mm of Hg and the fraction boiling at 130°-140° is used for the next reaction step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:14][CH:15]1[CH2:20][C:19](=[O:21])[O:18][C:17](=[O:22])[CH2:16]1>C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:19](=[O:21])[CH2:20][CH:15]([CH3:14])[CH2:16][C:17]([OH:22])=[O:18])=[CH:3][C:4]=1[C:10]([F:11])([F:12])[F:13])#[N:7]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CC1CC(=O)OC(=O)C1
Solvent: C1CCOC1
Product: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Yield: 114.1 %

Procedure:
A solution of 4-amino-2-(trifluoromethyl)benzonitrile (500 mg, 2.69 mmol) and 4-methyldihydro-2H-pyran-2,6(3H)-dione (344 mg, 2.69 mmol) in THF (15 mL) was stirred at 90° C. for 14 hr. The reaction solution was concentrated to give 5-(4-cyano-3-(trifluoromethyl)phenylamino)-3-methyl-5-oxopentanoic acid (964 mg, 3.07 mmol, 114%) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:15][C:14](=[O:16])[NH:13][NH:12]2)=[O:10])=[C:4]([C:17](=[O:24])[NH:18][CH:19]([CH:21]2[CH2:23][CH2:22]2)[CH3:20])[CH:3]=1.Cl[C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][N:27]=1.CC(C)([O-])C.[Na+].Cl>[C].[Pd].CC(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:12]([C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][N:27]=3)[N:13]=[C:14]([OH:16])[CH2:15]2)=[O:10])=[C:4]([C:17](=[O:24])[NH:18][CH:19]([CH:21]2[CH2:22][CH2:23]2)[CH3:20])[CH:3]=1
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(=O)NN1)C1CC1
Reactant: Clc1cccnc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CC(C)(C)O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(O)=NN1c1ncccc1Cl)C1CC1
Yield: 83.5 %

Procedure:
To a 2-methyl-2-propanol 3 ml mixed liquid comprising 0.10 g of N-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenyl)-5-oxopyrazolidine-3-carboxamide and 0.09 g of 2,3-dichloropyridine, 15 wt % of palladium-carbon (DeGussa type E105CA/W, manufactured by Aldrich) was added, and then 0.045 g of sodium t-butoxide was added. The mixed liquid was subjected to reaction under reflux for 9 hours. After the reaction liquid was stood to cool, it was poured to a 1 M HCl aqueous solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The organic layer was subjected to celite filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 1/1) to obtain 0.11 g of the desired product (melting point: 165 to 167° C.).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]2[CH:9]=[C:8]3[O:18][CH2:19][O:20][C:7]3=[CH:6][C:5]=2[O:4]1.[Cl:23]Cl>C(O)(C(F)(F)F)=O.[Zn]>[Cl:23][C:9]1[C:10]2[CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:3]([C:2]([F:21])([F:1])[F:22])[O:4][C:5]=2[CH:6]=[C:7]2[O:20][CH2:19][O:18][C:8]=12
Reactant: CCOC(=O)C1=Cc2cc3c(cc2OC1C(F)(F)F)OCO3
Reactant: ClCl
Agent: [Zn]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1=Cc2c(cc3c(c2Cl)OCO3)OC1C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 6-(trifluoromethyl)-6H-[1,3]dioxolo[4,5-g]chromene-7-carboxylate (500 mg, 1.58 mmoles) in 6 mL of TFA was added a solution of Cl2 6 mL, 0.28M) in TFA. After 30 min, another 6 mL of Cl2 solution was added and stirring continued. Zn dust (1.00 g, 15.3 mg-atm) was added, and stirred overnight. After concentration, the residue was chromatographed over silica gel using 20% EtOAc—hexane as eluent to give the title compound, 460 mg, as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C:3]#[C:4][C:5]1[CH:6]=[C:7]2[C@:18]3([CH2:22][O:21][C:20]([NH2:23])=[N:19]3)[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH:16]=3)[O:11][C:8]2=[N:9][CH:10]=1>CO.[Pd]>[CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]2[C@:18]3([CH2:22][O:21][C:20]([NH2:23])=[N:19]3)[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH:16]=3)[O:11][C:8]2=[N:9][CH:10]=1
Reactant: CC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)CCc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2

Procedure:
To a solution of (S)-3-(3,3-dimethylbut-1-ynyl)-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (60 mg, 0.146 mmol) in 5 mL of methanol was added Pd/C (5%) (156 mg, 1.462 mmol). The mixture was maintained under an atmosphere of hydrogen gas for 20 hours before being filtered through a celite plug, washing well with methanol. The filtrate was concentrated and the derived residue was purified by silical gel chromatography (12 g, 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (S)-3-(3,3-dimethylbutyl)-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a white solid.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[CH:6][C:7]=1[NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16]C)#[N:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:5]2[S:4][C:3]3[C:1]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[N:2][C:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[OH:16])=[N:8][C:7]=3[CH:6]=2)=[CH:20][CH:21]=1
Reactant: C1COCCN1
Reactant: COc1ccccc1C(=O)Nc1cc(-c2ccc(F)cc2)sc1C#N
Product: Oc1ccccc1-c1nc(N2CCOCC2)c2sc(-c3ccc(F)cc3)cc2n1
Temperature: 200 °C

Procedure:
A mixture of N-(2-cyano-5-(4-fluorophenyl)thiophen-3-yl)-2-methoxybenzamide (0.10 g, 0.57 mmol) and morpholine (0.20 mL) was heated in a microwave oven at 200° C. for 5 min. The reaction was purified by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give 2-(6-(4-fluorophenyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenol. LC/MS: m/z 408 (M+H)+ at 4.76 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][C:12]([C:18]#[N:19])=[C:11]3[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[S:5][C:4](=[S:26])[NH:3]1.IC.[CH:29](N(C(C)C)CC)(C)C>C(#N)C>[CH3:29][S:26][C:4]1[S:5][C:6](=[CH:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][C:12]([C:18]#[N:19])=[C:11]3[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:2](=[O:1])[N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: N#Cc1cnc2ccc(C=C3SC(=S)NC3=O)cc2c1-c1cccnc1
Solvent: CC#N
Solvent: CI
Product: CSC1=NC(=O)C(=Cc2ccc3ncc(C#N)c(-c4cccnc4)c3c2)S1

Procedure:
Similar procedure as described in example 41b was used, starting from 6-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-4-pyridin-3-yl-quinoline-3-carbonitrile (example 63d), iodomethane, and DIEA (diisopropylethylamine) in acetonitrile to give 6-(2-methylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-4-pyridin-3-yl-quinoline-3-carbonitrile. LC-MS m/e 389 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][C@@H:18]([NH:27][C:28](=[O:41])[CH2:29][C:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:32])[CH3:31])[C:17]2=[O:42])=[CH:11][CH:10]=1)#[N:2].C(N(CC)CC)C.[SH2:50].[OH-].[Na+]>N1C=CC=CC=1.O>[C:36]([O:35][C:34]([NH:33][C:30]([CH3:32])([CH3:31])[CH2:29][C:28]([NH:27][C@@H:18]1[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[C:3]([C:1](=[S:50])[NH2:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:14][CH:13]=2)[C:17]1=[O:42])=[O:41])=[O:40])([CH3:37])([CH3:39])[CH3:38]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C#N)cc2)C1=O)NC(=O)OC(C)(C)C
Reactant: S
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C(N)=S)cc2)C1=O)NC(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 82 %

Procedure:
A solution of 380 mg (0.67 mmol) of 3-[[1-[[2'-cyano-[1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]amino]-1,1-dimethyl-3-oxopropylcarbamic acid, 1,1-dimethylethyl ester (Example 69, Step D), in 5 mL of pyridine was placed in a bomb and treated with 5 mL of triethylamine and excess hydrogen sulfide was introduced under pressure. The bomb was sealed and heated for 12 hours at 90° C. The bomb was vented into 5 M sodium hydroxide and the contents poured into 40 mL of water, then extracted with ether (3×). The combined extracts were washed with water (3×), dried over magnesium sulfate, filtered and evaporated under vacuum to afford 330 mg (0.53 mmol, 82%) of product. 1H NMR (200 MHz,CDCl3): 1.38 (s,6H), 1.45 (s,9H), 1.90 (m,1H), 2.4-2.7 (m,4H), 2.92 (m,1H), 4.55 (m,1H), 4.94 (d,15 Hz,1H), 5.22 (d,15 Hz,1H), 5.31 (br s,1H), 6.50 (br s,1H), 6.70 (m,1H), 7.1-7.5 (m,12H), 7.82 (m,1H). FAB-MS (Li+ spike): calculated for C34H40N4O4S 600; found 607 (M+Li,65%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:14][C:15]([N:17]([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])=[O:4].[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]([CH2:14][C:15]([N:17]([CH3:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:16])[C:3](=[O:4])[CH2:2][NH:1][C:33]([NH:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=1)=[O:34]
Reactant: Cc1cccc(N=C=O)c1
Reactant: COc1ccccc1N(CC(=O)N(C)c1ccccc1)C(=O)CN
Product: COc1ccccc1N(CC(=O)N(C)c1ccccc1)C(=O)CNC(=O)Nc1cccc(C)c1
Yield: 67.8 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with 2-[2-amino-N-(2-methoxyphenyl)acetamido]-N-methyl-N-phenylacetamide (2.0 g) and 3-methylphenyl isocyanate (0.64 g), and after recrystallisation in ethyl acetate, 2-{N-(2-methoxyphenyl)-2-[3-(3-methylphenyl)ureido]acetamido}-N-methyl-N-phenylacetamide (1.5 g), m.p. 212° C., is obtained.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](C3ON=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.C[C:31]1[O:35][C:34]([C:36]2C=C(C=CC=2)N)=[CH:33][CH:32]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:31]3[O:35][C:34]([CH3:36])=[CH:33][CH:32]=3)[CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reactant: Cc1ccc(-c2cccc(N)c2)o1
Product: Cc1ccc(-c2cccc(Nc3nc(N[C@@H]4CCCC[C@@H]4N)ncc3C(N)=O)c2)o1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-(5-methylfuran-2-yl)aniline in step 1. MS: 407.5 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH:7]([CH3:9])[CH3:8])[S:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:11].[C:20]([O:23][CH:24]1[CH:29]([O:30][C:31](=[O:33])[CH3:32])[CH:28]([O:34][C:35](=[O:37])[CH3:36])[CH:27]([CH2:38][O:39][C:40](=[O:42])[CH3:41])[O:26][CH:25]1Br)(=[O:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].O>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.ClCCl>[C:20]([O:23][CH:24]1[CH:29]([O:30][C:31](=[O:33])[CH3:32])[CH:28]([O:34][C:35](=[O:37])[CH3:36])[CH:27]([CH2:38][O:39][C:40](=[O:42])[CH3:41])[O:26][CH:25]1[O:1][C:2]1[CH:6]=[C:5]([CH:7]([CH3:9])[CH3:8])[S:4][C:3]=1[C:10](=[O:11])[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:22])[CH3:21]
Reactant: COc1ccc(C(=O)c2sc(C(C)C)cc2O)cc1
Reactant: CC(=O)OCC1OC(Br)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2sc(C(C)C)cc2OC2OC(COC(C)=O)C(OC(C)=O)C(OC(C)=O)C2OC(C)=O)cc1
Temperature: 22 °C
Reaction time: 40 h

Procedure:
380 mg of (3-hydroxy-5-isopropyl-thiophen-2-yl)-(4-methoxy-phenyl)-methanone, 848 mg of 4,5-diacetoxy-6-acetoxymethyl-2-bromo-tetrahydro-pyran-3-yl acetate, 1.43 g of potassium carbonate and 71.1 mg of benzyltributylammonium chloride were dissolved in 20 ml of dichloromethane, and 1.20 ml of water were added. The reaction mixture was stirred at 22° C. for 40 h. 50 ml of water were added to the reaction mixture, which was extracted twice with 50 ml of dichloromethane each time. The combined organic phases were washed with 50 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (SiO2, ethyl acetate/n-heptane=1:1).
Reaction SMILES: Cl.[CH2:2]([O:5][C:6]([N:8]1[C@H:12]([CH:13]([OH:22])[C:14]2[S:18][C:17]3=[CH:19][N:20]=[CH:21][N:16]3[CH:15]=2)[CH2:11][C@@H:10]([O:23][Si](C(C)(C)C)(C)C)[CH2:9]1)=[O:7])[CH:3]=[CH2:4].C(=O)([O-])O.[Na+]>C(#N)C.C(OCC)(=O)C.O>[CH2:2]([O:5][C:6]([N:8]1[C@H:12]([CH:13]([OH:22])[C:14]2[S:18][C:17]3=[CH:19][N:20]=[CH:21][N:16]3[CH:15]=2)[CH2:11][C@@H:10]([OH:23])[CH2:9]1)=[O:7])[CH:3]=[CH2:4]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1cn2cncc2s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(O)c1cn2cncc2s1
Reaction time: 0.33 h

Procedure:
Concentrated hydrochloric acid (0.85 ml) is added dropwise to a solution of 899 mg of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-2-yl)methyl]pyrrolidine in 20 ml of dry acetonitrile under ice cooling, and the mixture is stirred at that temperature for 20 min. The reaction solution is diluted with 50 ml of ethyl acetate, water is added thereto, and the mixture is rendered weakly alkaline by addition of a saturated aqueous sodium hydrogencarbonate solution. The mixture is then extracted three times with ethyl acetate, and the organic layer is washed twice with saturated saline, dried over anhydrous magnesium sulfate and filtered. The solvent is removed by evaporation under reduced pressure to give a crude product of (3R,5S)-1-allyloxycarbonyl-3-hydroxy-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-2-yl)methyl]pyrrolidine. Triethylamine (0.46 ml) and 0.24 ml of methanesulfonyl chloride are successively added to a solution of this compound in 20 ml of THF, and the mixture is stirred under an argon stream at −14° C. for 50 min. Water is added to the reaction solution, and the mixture is extracted four times with ethyl acetate. The organic layer is washed once with saturated saline, dried over anhydrous magnesium sulfate and filtered, and the solvent is removed by evaporation under reduced pressure to give a crude product which is then purified by column chromatography on silica gel (ethyl acetate:methanol=9:1) to give 472.6 mg of (3R,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-2-yl)methyl]-3-methanesulfonyloxypyrrolidine (a diastereomer mixture) as a yellow viscous material.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:6]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1>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:10]([O:9][C:7]([N:5]1[CH:6]=[C:2]([C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)[CH:3]=[C:4]1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: OB(O)c1cccnc1
Reactant: COc1cc(-c2cc(Br)cn2C(=O)OC(C)(C)C)cc(OC)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COc1cc(-c2cc(-c3cccnc3)cn2C(=O)OC(C)(C)C)cc(OC)c1OC
Temperature: 25 °C
Yield: 13.6 %

Procedure:
A mixture of 4-bromo-1-tert-butoxycarbonyl-2-(3,4,5-trimethoxyphenyl)-pyrrole (2.0 g, 5.0 mmol, Example 76b), Pd(PPh3)4 (290 mg, 0.25 mmol) and pyridine-3-boronic acid (614 mg, 5.0 mmol) are evacuated for 10 min and set under argon atmosphere, followed by addition of degassed dimethoxyethane (DME, 10 ml) and 2 M aqueous Na2CO3 solution (10 ml). The reaction mixture is heated for 20 h to 80° C., cooled to room temperature and diluted with water and ethyl acetate. The organic layer is dried (MgSO4), filtered and the solvents are evaporated. The residue is chromatographed with ethyl acetate/hexane (1:1) to yield first 1-tert-butoxycarbonyl-4-(3-pyridyl)-2-(3,4,5-trimethoxy-phenyl)-pyrrole (280 mg, 12%) as a yellowish amorphous solid and then the title compound (700 mg, 45%) as a yellowish solid, 1H-NMR (300 MHz, DMSO-d6): 11.52 (br.s, 1H); 7.88 (br. s, 1H); 8.33 (br.d; J=6.0, 1H); 8.0-7.95 (m, 1H); 7.48 (br.s, 1H); 7.35-7.3 (m, 1H); 7.07 (br.s, 1H); 7.02 (s, 2H); 3.85 (s, 2MeO); 3.67 (s, MeO).