Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]2[C:12](=[O:28])[N:13]([CH3:27])[C:14](=[O:26])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:25])[CH:17]=2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][O:38]C1CCCCO1>CN(C)C=O.C(OCC)(=O)C>[OH:38][CH2:37][CH2:36][O:1][C:2]1[CH:3]=[C:4]([C:11]2[C:12](=[O:28])[N:13]([CH3:27])[C:14](=[O:26])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:25])[CH:17]=2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: BrCCOC1CCCCO1
Reactant: CN1C(=O)C(c2cn(C)c3ccccc23)=C(c2cc(O)cc3ccoc23)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)C(c2cn(C)c3ccccc23)=C(c2cc(OCCO)cc3ccoc23)C1=O
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 67.4 %

Procedure:
Add to a mixture of 3-(5-hydroxybenzofur-7-yl)-1-methyl-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione (2.5 g, 6.7 mmol) and potassium carbonate (2.78 g, 20.1 mmol) in N,N-dimethylformamide (40 ml), 2-(2-bromoethoxy)tetrahydropyran (3.04 ml, 20.1 mmol). Heat the mixture to 80° C. under nitrogen atmosphere for overnight. Diluted with ethyl acetate, wash with water, brine, dry over magnesium sulfate, filter and concentrate to red solid. Dissolve the solid in methanol (40 ml), add p-toluenesulfonic acid (3 g), stir for 20 minutes. Diluted with ethyl acetate, wash with water, brine, dry over magnesium sulfate, filter and concentrate to afford the title compound (1.88 g, 67%) as a red solid. HRMS: calculated 417.1450 found 417.1462.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]([NH:14][C:15](=[O:36])/[C:16](=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([O:34][CH3:35])[CH:23]=2)/[CH2:17][CH2:18][CH2:19]Cl)[CH3:13])=[CH:4]1.O.C(OCC)(=O)C>C1COCC1>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]([N:14]2[CH2:19][CH2:18][CH2:17]/[C:16](=[CH:21]\[C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]4)=[C:24]([O:34][CH3:35])[CH:23]=3)/[C:15]2=[O:36])[CH3:13])=[CH:4]1
Reactant: COc1cc(/C=C(\CCCCl)C(=O)NC(C)c2c[nH]c3ccccc23)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C2\CCCN(C(C)c3c[nH]c4ccccc34)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
EDC (384 mg), HOBT (271 mg) and IPEA (0.582 mL) were sequentially added to a solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (300 mg) and 1-(1H-indol-3-yl)ethylamine (130 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 12 hours. After confirming that the raw materials disappeared, ethyl acetate and water were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was sequentially washed with a saturated aqueous solution of ammonium chloride and brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: chloroform:methanol system) to obtain (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(1H-indol-3-yl)ethyl)amide (332 mg). Sodium hydride (containing mineral oil at 40%, 19.3 mg) was added to a solution of the resulting (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(1H-indol-3-yl)ethyl)amide (92 mg) in THF (3 mL) at 0° C., and the reaction solution was stirred at room temperature for 90 minutes. The reaction solution was cooled to 0° C., water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer was washed sequentially with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: chloroform:methanol system) to obtain (E)-1-[1-(1H-indol-3-yl)ethyl]-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidin-2-one as a racemate (37.3 mg). The compound (37 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase: ethanol) to obtain the title optically active substance with a retention time of 10 minutes (15 mg; >99% ee) and the title optically active substance with a retention time of 14 minutes (14.2 mg; >99% ee).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][N:23]=[N:22][CH:21]=1)CCC.[F-].[Cs+]>C(#N)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[N:22]1[CH:21]=[CH:20][C:25]([C:2]2[CH:3]=[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[OH:8])=[CH:24][N:23]=1
Reactant: Oc1ccc(-c2ccccc2)cc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Agent: I[Cu]I
Agent: [Pd]
Agent: [Cs+]
Solvent: CC#N
Product: Oc1ccc(-c2ccccc2)cc1-c1ccnnc1
Temperature: 45 °C
Yield: 32 %

Procedure:
3-Iodobiphenyl-4-ol (1 g, 3.4 mmol) was mixed with 4-(tributylstannyl)pyridazine (1.25 g 3.4 mmol), caesium fluoride (1.03 g 6.8 mmol), tetrakis(triphenylphosphine) palladium (0) (195 mg, 0.17 mmol) and copper iodide (128 mg 0.68 mmol) in acetonitrile (10 mL). The reaction was degassed 3 times before being placed under nitrogen and heated to 45° C. for 16 hours. The reaction was diluted with acetonitrile (20 mL), washed with heptane (2×20 mL) then absorbed onto silica and purified by silica gel column chromatography (ISCO™, 40 g, 50%-100% ethyl acetate in heptane gradient elution) to afford the title compound (270 mg, 32%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH:29]=O>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:29]=[N:1][C:2]2[C:3]([C:12]=1[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9]
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Reactant: O=CCc1ccccc1F
Product: Oc1cccc(-c2c(-c3ccccc3F)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (2-Fluoro-phenyl)-acetaldehyde following the procedure of Example 457: mp 186-187° C.; MS m/z 384, HRMS: calcd for C22H13F4NO+H+, 384.10060; found (ESI, [M+H]+), 384.1.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11][CH:12]([F:20])[C:13]1[O:17][C:16]([CH2:18][OH:19])=[CH:15][CH:14]=1.P([O-])(O)(O)=O.[Na+]>C(Cl)Cl.C(N(CC)CC)C>[F:11][CH:12]([F:20])[C:13]1[O:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1
Reactant: OCc1ccc(C(F)F)o1
Agent: O=C(Cl)C(=O)Cl
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1ccc(C(F)F)o1
Temperature: -60 °C
Yield: 70.4 %

Procedure:
A solution of 6.5 ml of DMSO (dimethyl sulfoxide) and 60 ml of methylene chloride was added at -60° C. under a nitrogen atmosphere to a solution of 3.84 ml of oxalyl chloride and 40 ml of methylene chloride. The reaction mixture was stirred at -60° C. and 3.6 g of 5-difluoromethyl,2-furanmethanol in solution in 30 ml of methylene chloride were added. The mixture was stirred for 2 hours at -60° C. and a solution of 16.1 ml of triethylamine and 30 ml of methylene chloride was added over 15 minutes. The reaction mixture was stirred for half an hour at -60° C., the temperature was allowed to rise to -20° C. The mixture was stirred for half an hour at this temperature and then poured into a solution of sodium dihydrogenphosphate and extracted with methylene chloride. The extract was dried and the 3.6 g of product were chromatographed on silica by eluting with an 8/2 hexane/ethyl acetate mixture to obtain after chromatography, 2.5 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[NH:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[H-].[Na+].[Cl:18][CH:19]=[CH:20][CH2:21]Cl>CN(C=O)C>[Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[N:4]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:21][CH:20]=[CH:19][Cl:18]
Reactant: ClC=CCCl
Reactant: CC(C)(C)OC(=O)Nc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC=CCl)c1ccccc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
A solution of 3.2 (350 mg, 1.29 mmol) in DMF (7 ml) was cooled to 0° C. and NaH (93 mg, 3.85 mmol) was added. The resulting mixture was stirred for 15 mins and 1,3 dichloropropene (358 μl, 3.85 mmol) was added. The mixture was allowed to warm to 25 ° C. and stirred for 15 h. The mixture was then concentrated. H2O (10 ml) was added to the residue and the solution was extracted with EtOAc (3×10 ml). The combined organic layers were dried with MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc/Hex 1:9) to afford 3.3 (400 mg, 89%) as a pale yellow oil. FABMS (NBA/NaI) 346 (M+H+ expected 346).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[C:22]([O:25][C:26]1[CH:27]=[C:28]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1)(=[O:24])[CH3:23]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:35]2[CH2:34][CH2:33][N:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([O:25][C:22](=[O:24])[CH3:23])[CH:27]=3)[CH2:37][CH2:36]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CC(=O)Oc1cccc(N2CCNCC2)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cccc(OC(C)=O)c3)CC2)c(OC)nc1C
Yield: 87 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-acetoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:10][C:7]2[CH:8]=[CH:9][C:2]([Br:1])=[C:3]([F:11])[C:4]=2[CH:5]=[O:6])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=Cc1c(O)ccc(Br)c1F
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)c(F)c2C=O)CC1
Yield: 93.9 %

Procedure:
In a manner similar to the method described in example 4a, 3-bromo-2-fluoro-6-hydroxy-benzaldehyde (3.69 g, 16.8 mmol) reacted with 4-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acid tert-butyl ester (4 g, 11.2 mmol, ASTATECH) and K2CO3 in N,N-dimethylformamide to give 4-(4-bromo-3-fluoro-2-formyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester as a brown oil (Yield 4.23 g, 94%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]([OH:34])=O)[CH2:27][CH2:26]1.Cl.[NH2:36][C@@H:37]([C@H:42]([OH:44])[CH3:43])[C:38]([O:40][CH3:41])=[O:39].CN1CCOCC1>ClCCl>[OH:44][C@H:42]([CH3:43])[C@H:37]([NH:36][C:32](=[O:34])[CH2:31][N:28]1[CH2:27][CH2:26][O:25][CH2:30][CH2:29]1)[C:38]([O:40][CH3:41])=[O:39]
Reactant: O=C(O)CN1CCOCC1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)CN1CCOCC1)[C@@H](C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
HATU (7.66 g, 20.1 mmol) was added to a solution of 2-morpholinoacetic acid (2.44 g, 16.8 mmol) and (2S,3R)-methyl 2-amino-3-hydroxybutanoate hydrochloride (2.84 g, 16.8 mmol) in dichloromethane (20 mL) at 0° C. N-Methylmorpholine (5.1 g, 50.4 mmol) was added and the reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=100:1 to 60:1) to afford (2S,3R)-methyl 3-hydroxy-2-(2-morpholinoacetamido)butanoate (2.1 g, 48% yield).
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][C:7]#[CH:8])[C:3]#[N:4].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:1][CH:2]([CH2:5][CH2:6][C:7]#[CH:8])[C:3]#[N:4])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: C#CCCC(O)C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCC(C#N)OS(C)(=O)=O
Yield: 87.4 %

Procedure:
A mixture of 2-hydroxy-5-hexynenitrile (8.0 g, 73.3 mmol) and dry triethylamine (10.1 g, 0.1 mol) in 50 ml of dry CH2Cl2 was treated with a solution of methanesulfonyl chloride (10.3 g, 90 mmol) in 50 ml of CH2Cl2, at 0° C. for 11/2 h. The reaction mixture was diluted with CH2Cl2, washed twice with cold 1.0N H2SO4, twice with water, and dried over MgSO4. The filtered CH2Cl2 solution was concentrated at 40° C./30 mm to give 12 g of pale yellow liquid. Purification of this material on 220 g of silica gel and eluted with ether-petroleum ether (1:1 parts by volume) gave 8.7 g (56% by weight yield from pentynal) of 2-[(methylsulfonyl)]-5-hexynenitrile as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[C:7]1([CH:13]([C:19](OCC)=[O:20])[C:14](OCC)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(N(CCCC)CCCC)CCC>[C:7]1([C:13]2[C:14]([OH:15])=[N:1][C:2]3[N:3]([N:4]=[CH:5][CH:6]=3)[C:19]=2[OH:20])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: Oc1nc2ccnn2c(O)c1-c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 9 g 3-amino pyrazole and 25.6 g diethyl phenylmalonate in N,N-dibutylbutan-1-amine was stirred at 185° C. over night. The reaction mixture consisted of two layers after cooling to room temperature. The top layer was removed and the lower layer was diluted with dichloromethane and methanol. The resulting solution was concentrated and extracted with a mixture of diethyl ether and 10% w/w NaOH solution. The organic layer was discarded and aqueous layer acidified with concentrated HCl. The precipitated product was collected by filtration.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:22]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][N:24]=[CH:23]1>O1CCCC1>[N:22]1([CH2:27][CH2:28][CH2:29][NH:30][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: O=C(O)c1ccccn1
Reactant: NCCCn1ccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(NCCCn1ccnc1)c1ccccn1

Procedure:
Following the general procedure of Example 14 and reacting the appropriate pyridinecarboxylic acid derivative with 1,1'-carbonyldiimidazole and 1H-imidazol-1-propanamine in tetrahydrofuran, the compounds of Examples 15-17 found in Table IV were prepared.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:28][CH2:27][CH2:26][CH2:25][Br:24])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc21
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2cc(OCCCCBr)ccc21
Temperature: 50 °C
Reaction time: 4 h
Yield: 475.3 %

Procedure:
9.41 g (40 mmol) 5-Hydroxy-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester in 90 ml acetone were treated with 16.6 g (6 mmol) K2CO3 (powdered) and 17.3 g (5 mmol) 1,4-dibromobutane. The suspension was stirred at 50° C. for 4 h, cooled to RT, filtered and concentrated. Column chromatography on silica gel with CH2Cl2 yielded 8.8 g (60%) 5-(4-Bromo-butoxy)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as colorless solid, MS: 370 (MH+, 1Br).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]>CN(C)C=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]2=[O:26])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Reaction time: 5 h
Yield: 68.3 %

Procedure:
4-Hydroxybenzaldehyde (24.4 g) and sodium hydride (4.8 g) in dry dimethylformamide (400 ml) were stirred at room temperature for 3 h. N-(3-Bromopropyl)phthalimide (55.0 g) was added and the reaction was stirred for a further 5 h. The mixture was poured onto ice and the resulting white solid was recrystallised from a mixture of dichloromethane and cyclohexane to yield the title compound (42.2 g) m.p. 120°-1°. TLC silica, ethyl acetate, Rf 0.7.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)=[C:21]([O:30][CH2:31][C:32]#[C:33][CH2:34][OH:35])[N:20]=[CH:19][N:18]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[Br:36][C:37]1[CH:38]=[N:39][C:40](Cl)=[N:41][CH:42]=1>C1COCC1>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH:16][C:17]2[C:22]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)=[C:21]([O:30][C:31]#[C:32][CH2:33][CH2:34][O:35][C:40]3[N:41]=[CH:42][C:37]([Br:36])=[CH:38][N:39]=3)[N:20]=[CH:19][N:18]=2)(=[O:14])=[O:15])=[CH:11][CH:12]=1)([CH3:5])([CH3:4])[CH3:6]
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCC#CCO)cc1
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OC#CCCOc2ncc(Br)cn2)cc1
Reaction time: 1 h

Procedure:
To a suspension of 88 mg of a 55% sodium hydride dispersion in mineral oil in 15 ml of dry THF 375 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamide (Example 12) was added. After stirring for 1 h, 170 mg of 5-bromo-2-chloropyrimidine was added. Stirring was continued for 60 h at 40° C. Eventually, the solvent was evaporated and the remaining residue was partitioned between 50 ml of 10% aqueous citric acid and 50 ml of ethyl acetate. The organic layer was separated and the aqueous layer was extracted two more times with 50 ml of ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated. The crude product was crystallised from 2-propanol containing a small amount of diethyl ether to give 168 mg of 4-tert.-butyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-butynyloxy)-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamide as beige crystals. LC-MS: tR=6.22 min, [M+1]+=624.28.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:28])[CH:12]([NH:16][C:17](=[O:27])[CH2:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)[CH2:13][CH2:14][CH3:15])[N:7]=[CH:6]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[OH:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:28])[CH:12]([NH:16][C:17](=[O:27])[CH2:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)[CH2:13][CH2:14][CH3:15])[N:7]=[CH:6]1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(CC(=O)OC)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(CCO)cn1

Procedure:
(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-acetic acid methyl ester was reduced using LAH to afford the title compound: C13 NMR (100 MHz, CDCl3) 12.8, 19.0, 34.3, 41.6, 49.8, 53.6, 61.1, 101.6, 101.8, 102.1, 108.4, 111.9, 112.1, 112.1, 134.0, 136.6, 162.0, 164.5, 170.3, 171.4; MS m/z 381.1 (M+1).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]([NH2:19])=[N:16][C:15]=2[CH3:20])=[CH:10][CH:9]=1>O1CCOCC1>[CH2:1]([NH:3][C:4]([NH:19][C:17]1[S:18][C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)=[C:15]([CH3:20])[N:16]=1)=[O:5])[CH3:2]
Reactant: CCN=C=O
Reactant: COc1ccc(-c2sc(N)nc2C)cc1
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc(C)c(-c2ccc(OC)cc2)s1

Procedure:
Ethyl isocyanate (1.2 ml, 14.18 mmol) is added to 5-(4-methoxy-phenyl)-4-methyl-thiazol-2-ylamine (Example 28b) (1.56 g, 7.09 mmol) in dioxane (100 ml). After 5 hours at 85° C. the reaction mixture is concentrated to yield 1-ethyl-3-[5-(4-methoxy-phenyl)-4-methyl-thiazol-2-yl]urea as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:19]([NH:21]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=[S:20])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>CO>[C:1]([O:5][C:6](=[O:46])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:19]([NH2:21])=[S:20])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)C(=S)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CO
Solvent: C1CCNCC1
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)C(N)=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a solution of 2-{[4-(2-{3-[(9H-fluorene-9-ylmethoxy)carbonyl]-1-heptylthioureido}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (3.1 g) synthesized in Example 629-1 in methanol (40 mL) was added piperidine (20 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and subjected to silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (2.0 g) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:13])=[C:9]([CH3:12])[C:10]=1[OH:11])=[O:5])[CH3:2].[CH2:14]([Cl:17])[CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>>[C:4]([C:6]1[NH:7][C:8]([CH3:13])=[C:9]([CH3:12])[C:10]=1[O:11][CH2:15][CH2:14][Cl:17])([O:3][CH2:1][CH3:2])=[O:5]
Reactant: ClCCBr
Reactant: CCOC(=O)c1[nH]c(C)c(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1[nH]c(C)c(C)c1OCCCl
Yield: 40.7 %

Procedure:
Using the method described in Example X, 18.3 g of 3-hydroxy-4,5-dimethyl-pyrrole-2-carboxylic acid ethyl ester, 20.5 g of 1,2-bromochloroethane and 18 g of anhydrous potassium carbonate give 10 g of 1-(2-carboethoxy-4,5-dimethyl-pyrrol-3-oxy)-2-chloroethane, of melting point 81°-83° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([N:16]=[C:17]=S)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:22]=[C:23]([NH2:37])[C:24]([NH2:36])=[CH:25][C:26]=1[N:27]1[CH2:31][CH2:30][CH:29]([CH2:32][N:33]([CH3:35])[CH3:34])[CH2:28]1.CC(C)N=C=NC(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17]2[NH:36][C:24]3[CH:25]=[C:26]([N:27]4[CH2:31][CH2:30][CH:29]([CH2:32][N:33]([CH3:35])[CH3:34])[CH2:28]4)[C:21]([Cl:20])=[CH:22][C:23]=3[N:37]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1
Reactant: CN(C)CC1CCN(c2cc(N)c(N)cc2Cl)C1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CN(C)CC1CCN(c2cc3[nH]c(Nc4cc(CNC(=O)OC(C)(C)C)ccc4Cl)nc3cc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4-Chloro-3-isothiocyanato-benzyl)-carbamic acid tert-butyl ester (111 mg, 0.4 mmol) was added to 4-chloro-5-(3-dimethylaminomethyl-pyrrolidin-1-yl)-benzene-1,2-diamine (100 mg, 0.4 mmol) in DMF (3 mL). The mixture was stirred at rt overnight, DIC (62.4 μL, 0.4 mmol) was added and stirring was continued at 80° C. for 3 h. The mixture was concentrated and the crude was purified by chromatography to give the sub-title compound.