Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[CH2:15][CH2:16][CH2:17][C:12]2=[C:11]2[C:7]=1[C:8]([C:32](=[O:36])[C:33]([NH2:35])=[O:34])=[C:9]([CH3:31])[N:10]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[S:26][C:27]([Br:30])=[CH:28][CH:29]=1.[OH-].[Li+].Cl>O1CCOCC1.O>[NH2:35][C:33](=[O:34])[C:32]([C:8]1[C:7]2[C:11](=[C:12]3[CH2:17][CH2:16][CH2:15][C:13]3=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:37])=[O:2])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[S:26][C:27]([Br:30])=[CH:28][CH:29]=2)[C:9]=1[CH3:31])=[O:36]
Reactant: COC(=O)COc1cc2c(c3c1c(C(=O)C(N)=O)c(C)n3Cc1ccccc1-c1ccc(Br)s1)CCC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cc3c(c2n1Cc1ccccc1-c1ccc(Br)s1)CCC3
Reaction time: 0.25 h
Yield: 51.2 %

Procedure:
A mixture of 2-[[3-(2-amino-1,2-dioxoethyl)-2-methyl-1-[2-(5-bromothiophen-2-yl)benzyl]-1,6,7,8-tetrahydrocyclopent[g]indol-4-yl]oxy]acetic acid methyl ester (50 mg, 0.086 mmol) in dioxane (5 mL) was warmed until a clear solution was obtained. This solution was treated with 1M lithium hydroxide solution (1 mL) at room temperature for 90 min. The pH was adjusted to ˜3 with hydrochloric acid. The mixture was diluted with water and stirred for 15 min. The resulting precipitate was collected via vacuum filtration to provide 25 mg (51%) of the title compound as a green solid. TOS MS ES+ exact mass calculated for C27H24BrN2O5S (p+1): m/z=567.0589. Found: 567.0603.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1[CH2:8]Br.Cl.[CH3:11][NH:12][NH:13][CH3:14].C(N(CC)CC)C>C(O)C>[CH3:11][N:12]1[CH2:2][C:3]2[N:4]=[CH:5][S:6][C:7]=2[CH2:8][N:13]1[CH3:14]
Reactant: BrCc1ncsc1CBr
Reactant: CNNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1Cc2ncsc2CN1C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
After 4,5-bis(bromomethyl)thiazole (600 mg) synthesized in 1) of Referential Example 109 was dissolved in ethanol (20 ml), and 1,2-dimethylhydrazine hydrochloride (294 mg) was added under ice cooling, triethylamine (1.23 ml) was added at a time, and the mixture was stirred for 30 minutes at room temperature and 30 minutes at 50° C. The solvent was distilled off, and the residue was purified by column chromatography on silica gel (methanol:dichloromethane=1:19) to obtain 5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[4,5-d]-pyridazine (90 mg) as a colorless oil.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[S:8][C:7]2[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:6]1=2)=[O:4].[OH-].[Na+].C1(C)C=CC=CC=1>CO.O.C(OCC)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:6]2[CH:5]([C:3]([OH:4])=[O:2])[CH:9]([C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[S:8][C:7]=2[CH:18]=1
Reactant: COC(=O)C1c2ccc(OC)cc2SC1c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: COc1ccc(C2Sc3cc(OC)ccc3C2C(=O)O)cc1
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of 2,3-dihydro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carboxylic acid methyl ester (0.7337 g, 2.21 mmol) in methanol (10 ml) at 5° C. was added 5 N sodium hydroxide (1 ml, 5 mmol) and water (5 ml). The resulting slurry was stirred at that temperature for 1 hour, then toluene (5 ml) was added, and the resulting mixture was stirred at room temperature for 16 hours. Additional 5 N sodium hydroxide (1 ml) was then added, and the mixture stirred an additional 16 hours. The reaction mixture was then diluted with water (5 ml) and diethyl ether (20 ml), and the layers separated. The aqueous layer was acidified to pH 1 with 1 N hydrochloric acid, and extracted with diethyl ether (2×50 ml). The ether layers were combined, dried (magnesium sulfate), filtered and concentrated to a foam, which was further dried in vacuo to afford 0.6146 g (88%) of title compound. IR (KBr) 3300-2800 (br), 2836, 1710, 1611, 1594, 1514, 1482, 1248, 1181, 1030 cm-1 ; 1H NMR (CDCl3): δ11.63 (br s, 1 H), 7.37 (d, 2 H, J=8.4 Hz); 7.24 (d, 1 H, J=8.4 Hz), 6.85 (d, 2 H, J=8.4 Hz), 6.78 (d, 1 H, J=2.2 Hz), 6.67 (dd, 1 H, J=8.4, 2.2 Hz), 5.38 (d, 1 H, J=7.5 Hz), 4.42 (d, 1 H, J=7.5 Hz), 3.79 (s, 6 H); 13C NMR (CDCl3): d 177.7, 160.7, 159.5, 142.8, 132.3, 128.7, 127.3, 126.0, 114.3, 111.0, 107.5, 60.3, 55.6, 55.4, 55.1. Anal. calcd. for C17H16O4S: C, 64.54; H, 5.10; S; 10.13. Found: C, 64.78; H, 5.14; S, 10.55.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[S:18]([CH2:24][C:25]#[N:26])([CH2:21][C:22]#[N:23])(=[O:20])=[O:19]>>[C:1]([C:5]1[CH:6]=[C:7](/[CH:8]=[C:21](/[S:18]([CH2:24][C:25]#[N:26])(=[O:20])=[O:19])\[C:22]#[N:23])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCS(=O)(=O)CC#N
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(/C=C(\C#N)S(=O)(=O)CC#N)cc(C(C)(C)C)c1O

Procedure:
M36 was prepared with 3,5-di-t-butyl-4-hydroxybenzaldehyde and sulfonyl diacetonitrile under similar conditions as described for M27.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1([CH2:21][CH3:22])[CH2:10][CH2:9][N:8](CC2C=CC(OC)=CC=2)[C:7]1=[O:20])[CH3:2].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[Ce].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1([CH2:21][CH3:22])[CH2:10][CH2:9][NH:8][C:7]1=[O:20])[CH3:2]
Reactant: CCOC(=O)CC1(CC)CCN(Cc2ccc(OC)cc2)C1=O
Agent: O=C([O-])[O-]
Agent: [Ce]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: O=[N+]([O-])O
Product: CCOC(=O)CC1(CC)CCNC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
To a solution of ethyl(3-ethyl-1-(4-methoxybenzyl)-2-oxopyrrolidin-3-yl)acetate (1.5 g) obtained in Step C in a mixed solvent of acetonitrile/water (3/1, 8 mL) was added ammonium hexanitratocerate(IV) (5.2 g), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added potassium carbonate, the solid was removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (900 mg).
Reaction SMILES: C1(C)C=CC=CC=1.Cl[CH2:9][C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:22].[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.Cl>>[CH3:22][C:11]1[CH:12]=[CH:13][CH:14]=[CH:9][C:10]=1[CH:15]([NH:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cccc(-c2ccccc2)c1CCl
Reactant: Nc1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccccc1C(Nc1ccncc1)c1ccccc1
Reaction time: 20 h
Yield: 31 %

Procedure:
250 Milliliters of toluene containing 10.8 grams (0.05 mole) of chloro(phenyl-o-tolyl)methane and 14.1 grams (0.15 mole) of 4-aminopyridine were heated under reflux with stirring for 20 hours. The reaction mixture was cooled and the resulting organic layer and solid material were stirred with 2 N hydrochloric acid. The toluene layer was removed and the gummy acidic extracts were basified with 5 N sodium hydroxide. The resulting oil was extracted into toluene and washed with water. After drying over magnesium sulphate, the solvent was removed and the residue was recrystallised from toluene to afford 3.58 grams (31% yield) of the title compound, m.p. 141°-143° C. The product may be recrystallised from a mixture of benzene and light petroleum (b.p. 100°-120° C.).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]O>C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([O:13][CH3:18])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)c1ccccc1C(=O)c1ccccc1

Procedure:
The ester methyl 2-benzoylbenzoate was prepared from the corresponding acid 2-benzoyl benzoic acid by Fischer esterification. One mole (226.23 grams) of 2-benzoylbenzoic acid was refluxed overnight in 1500 milliliters of methanol containing 2 grams of p-toluenesulfonic acid as catalyst. Cooling and rotary evaporation of the solvent afforded the ester as white crystals (melting point 145° C.) having a purity of about 99 percent. This material was used as such without further purification. Other esters can be prepared from their corresponding acids in a similar fashion.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>C1C=CC=CC=1.C(O)C.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>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: Cc1cc(Br)ccc1C#N
Reactant: COc1ccc(B(O)O)cc1
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: c1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccc(C#N)c(C)c2)cc1
Temperature: 75 °C
Yield: 102.7 %

Procedure:
4-Bromo-2-methylbenzonitrile (4.9 g, 25.0 mmol), Pd(PPh3)4 (578 mg) in benzene (50 mL) and 2.0 M aqueous solution of Na2CO3 (25 mL, 50.0 mmol) was treated with 4-methoxyphenylboronic acid (4.56 g, 30.0 mmol) in ethanol (20 mL) and heated at 75° C. for 17 hours. The mixture was allowed to cool to room temperature and the phases were separated. The aqueous phase was extracted with diethyl ether (3×40 mL). The original benzene layer and the diethyl ether extracts were combined, filtered over celite, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography over silica using a mixture of hexane/CH2Cl2 (3:1) to provide the title compound as a white powder (5.73 g, 85% yield). 1HNMR (300 MHz, CDCl3) δ2.35 (3H), 3.70 (s, 3H), 6.80-7.50 (m, 7H); MS (DCI) m/z 224 (M+H)+.
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[S:10][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[C:8]([C:15]([NH:17][NH2:18])=[O:16])[CH:7]=1>O.Cl>[Cl:5][C:6]1[S:10][C:9]([S:11](=[O:13])(=[O:14])[NH2:12])=[C:8]([C:15]([N:17]=[N+:18]=[N-:1])=[O:16])[CH:7]=1
Reactant: O=N[O-]
Reactant: NNC(=O)c1cc(Cl)sc1S(N)(=O)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NC(=O)c1cc(Cl)sc1S(N)(=O)=O
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
A solution of sodium nitrite (3.0 g; 43.4 mmol) in 20 ml of water was added dropwise with stirring at 0° C. to a solution of 5-chloro-2-sulfamoylthiophene-3-carbohydrazide (10.0 g; 39.1 mmol) in 80 ml of 1M hydrochloric acid and the mixture was stirred for 15 min. The precipitate was isolated by filtration, washed with water and dried to give 9.93 g (96%) of the title compound; 1H-NMR (DMSO-d6): δ 7.55 (s, 1H), 7.97 (br. s, 2H, NH2).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].CN(C=O)C.[NH2:11][C:12]1[S:13][C:14]2[C:19](O)=[N:18][C:17]([S:21][C@H:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:23])=[N:16][C:15]=2[N:30]=1>O1CCOCC1>[Cl:3][C:19]1[C:14]2[S:13][C:12]([NH2:11])=[N:30][C:15]=2[N:16]=[C:17]([S:21][C@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[N:18]=1
Reactant: C[C@H](Sc1nc(O)c2sc(N)nc2n1)c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: C[C@H](Sc1nc(Cl)c2sc(N)nc2n1)c1ccccc1
Temperature: 80 °C
Yield: 95 %

Procedure:
POCl3 (1 mL) was added to DMF (1 mL) in dioxane (6 mL). 2-Amino-5-{[(1S)-1-phenylethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-ol (1 g, 3.3 mmol) was added to the reaction in one portion. POCl3 (1 mL) was added and the reaction mixture was heated to 80° C. for about 30 min. The reaction was cooled to room temperature and poured onto ice. The resulting mixture was heated at reflux for about 5 h. The mixture was allowed to attain room temperature and was then extracted with EtOAc. The organic layer was passed through a layer of silica gel and concentrated to dryness to give the title compound (1 g, 95% yield).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:19]1[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[O:25])[CH2:20]1>>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]3[CH2:17][CH2:16][CH:15]([N:19]4[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=5)=[O:25])[CH2:20]4)[CH2:14][CH2:13]3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(c2ccc(N3CCCC3)cc2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccc(N4CCCC4)cc3)CC2)C1

Procedure:
The title compound was prepared as a white solid from the reductive amination of 4-(4-pyrrolidin-1-yl-phenyl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[S:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[N:16]1[CH2:17][CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:14]([CH2:13][N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)[CH2:15]1
Reactant: Clc1nc2ccccc2s1
Reactant: c1ccc(C2CCN(CC3CNCC3c3ccccc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(C2CCN(CC3CN(c4nc5ccccc5s4)CC3c3ccccc3)CC2)cc1
Temperature: 80 °C
Yield: 22 %

Procedure:
A mixture of 54 mg (0.16 mmol) of 3-(SR)-((4-phenyl)piperidin-1-yl)methyl-4-(SR)-phenylpyrrolidine (from Example 30, Step A), 53 mg (0.31 mmol) of (2-chloro)benzothiazole and 65 mg (0.47 mmol) of K2CO3 in 3 mL of DMF was heated at 80° C. for 1 h. The reaction mixture was cooled, partitioned between 25 mL of ether and 15 mL of H2O and the layers were separated. The organic layer was dried over MgSO4 and concentrated in vacuo. Flash chromatography on 15 g of silica gel using 1:1 v/v hexnaes/EtOAc as the eluant afforded 16 mg (23%) of the title compound as an oil. 1H NMR (500 MHz, CDCl3): δ1.79-3.04 (12H), 3.29 (q, J=8.9, 1H), 3.55 (t, J=9.0, 1H), 3.69 (t, J=9.6, 1H), 4.03-4.11 (m, 2H), 7.07-7.64 (14H). Mass Spectrum (NH3 -CI): 454 (M+.1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[H-].[Na+].[CH3:17][C:18]([CH3:31])([CH3:30])[C:19]([O:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20]>>[CH3:17][C:18]([CH3:31])([CH3:30])[C:19]([O:21][N:22]([S:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[S:2]([CH3:1])(=[O:4])=[O:3])(=[O:13])=[O:12])[C:23](=[O:24])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:20]
Reactant: CC(C)(C)OC(=O)NOC(=O)C(C)(C)C
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(OC(=O)C(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O

Procedure:
tert-Butyl [(2,2-dimethylpropanoyl)oxy]{[2-(methylsulfonyl)phenyl]sulfonyl}carbamate (46) is prepared from 2-methylsulfonylbenzenesulfonyl chloride, sodium hydride and [(tert-butoxy)carbonyl]amino 2,2-dimethylpropanoate according to Scheme 2. (1.5 g, 78%), 1H NMR (250 MHz, DMSO-d6) δ ppm 8.18-8.37 (2H, m), 7.94-8.15 (2H, m), 3.46 (3H, s), 1.30 (9H, s), 1.29 (9H, s).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][N:9]=1)=O.[F:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[N:18]/[NH:19][C:20](=[NH:22])[NH2:21])=[CH:13][CH:12]=1>C(O)C>[F:10][C:11]1[CH:12]=[CH:13][C:14](/[CH:17]=[N:18]/[N:19]2[CH:2]=[C:3]([C:5]3[S:6][CH:7]=[CH:8][N:9]=3)[N:21]=[C:20]2[NH2:22])=[CH:15][CH:16]=1
Reactant: O=C(CBr)c1nccs1
Reactant: N=C(N)N/N=C/c1ccc(F)cc1
Solvent: CCO
Product: Nc1nc(-c2nccs2)cn1/N=C/c1ccc(F)cc1
Reaction time: 10 h
Yield: 70.1 %

Procedure:
A solution of 2-bromo-1-(1,3-thiazol-2-yl)-1-ethanone (1.5 g, 7.2 mmol), and 2-[(E)-1-(4-fluorophenyl)methylidene]-1-hydrazinecarboximidamide (2.6 g, 14.4 mmol) was heated at reflux in ethanol (10 mL) for 2 h. The mixture was left at room temperature for additional 10 h, then the precipitate was filtered, washed with hot water and recrystallized from ethanol to give N1-[(E)-1-(4-fluorophenyl)methylidene]-4-(1,3-thiazol-2-yl)-1H-1,2-imidazole diamine 4 (1.45 g, 70%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13](OC)=[O:14].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1>[OH:14][CH2:13][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1ccc2ccccc2c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1c(CO)ccc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104.6 %

Procedure:
The product of Step A (4.5 g, 20.83 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) and cooled to 0° C. To this solution was added a 1 M solution of lithium aluminum hydride in tetrahydrofuran (31 mL). The mixture was stirred at this temperature for 30 min, allowed to warm up to room temperature, and stirred for an additional 30 min. Ethyl acetate (200 mL) was then added carefully to the reaction mixture to destroy the excess of lithium aluminum hydride. The mixture was then diluted with a 1 M solution of aqueous hydrogen chloride (100 mL), the organic layer was separated, dried (MgSO4), and concentrated to give an oil (4.1 g) which solidified: 1H NMR (CDCl3) δ 3.97 (s, 3H, CH3), 4.89 (s, 2H, CH2), 7.51 (m, 3H, Ar—H), 7.60 (m, 1H, Ar—H), 7.82 (m, 1H, Ar—H), 8.07 (m, 1H, Ar—H); MS (GC/MS) 188.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]=[C:6]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:7]2[S:12][C:11]3[N:13]=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:15]=[C:16]([CH3:17])[C:10]=3[C:8]=2[N:9]=1)[CH3:2].[OH:30]O>C(O)(=O)C>[CH2:1]([S:3]([C:4]1[N:5]=[C:6]([N:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]2)[C:7]2[S:12][C:11]3[N:13]=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:15]=[C:16]([CH3:17])[C:10]=3[C:8]=2[N:9]=1)=[O:30])[CH3:2]
Reactant: OO
Reactant: CCSc1nc(N2CCNCC2)c2sc3nc(-c4ccccc4)cc(C)c3c2n1
Solvent: CC(=O)O
Product: CCS(=O)c1nc(N2CCNCC2)c2sc3nc(-c4ccccc4)cc(C)c3c2n1

Procedure:
85 mg (0.2 mmol) 2-ethylthio-9-methyl-7-phenyl-4-piperazin-1-yl-pyrido[3′,2′:4,5]-thieno[3,2-d]pyrimidine, 3 ml glacial acetic acid and 0.04 ml hydrogen peroxide (60%) are stirred at room temperature for 48 h. Having removed the solvent, the residue is purified by means of flash chromatography (methanol/dichloromethane 1:20-1:3). 50 mg (57%) of the title substance is obtained. ESI-MS [m/z]: 438, melting point: 165-170° C.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7]([CH2:9][CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH:12]3[CH3:16])=[N:8][C:4]=2[CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20]>>[CH3:16][CH:12]1[CH2:13][CH2:14][CH2:15][N:11]1[CH2:10][CH2:9][C:7]1[NH:6][C:5]2[CH:17]=[CH:18][C:2]([C:24]3[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=3)=[CH:3][C:4]=2[N:8]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC1CCCN1CCc1nc2cc(Br)ccc2[nH]1
Product: CC1CCCN1CCc1nc2cc(-c3ccc(C#N)cc3)ccc2[nH]1

Procedure:
Compounds of formula (55) and (55a) can be prepared from 2(R)-methylpyrrolidine HCl (50) and ethyl acrylate (51) as shown in Scheme 6. 2(R)-Methylpyrrolidine HCl can be treated with potassium carbonate to provide 2(R)-methylpyrrolidine (41), which is reacted with ethyl acrylate (51) to provide 3-(2-methyl-pyrrolidin-1-yl)-propionic acid ethyl ester (52). Compound (52) is reacted with 4-bromo-benzene-1,2-diamine (53), which is produced by controlled hydrogenation of 2-amino-5-bromo-nitrobenzene, Chemical Abstracts number 875-51-4, to provide 5-bromo-2-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-1H-benzoimidazole (54). Compound (54) can be reacted with a 4-cyanophenylboronic acid to provide 4-{2-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-1H-benzoimidazol-5-yl}-benzonitrile (55). As previously described for Scheme 5, the amine compound (41) can be any amine of the formula HNRaRb, wherein Ra and Rb are as defined for R4 and R5. Also, the 4-cyanophenylboronic acid can be replaced with any boronic acid of the formula RcB(OH)2, wherein Rc is aryl or heteroaryl to provide compounds of general structure (55a). Additionally, compounds (55) and (55a) may be alkylated on the benzimidazole nitrogen by treatment with a base, such as cesium carbonate, and an alkylating agent, such as methyl iodide.
Reaction SMILES: O.O.Br[C:4]1[C:5]([CH3:16])=[CH:6][C:7]([O:14][CH3:15])=[C:8]([S:10]([OH:13])(=[O:12])=[O:11])[CH:9]=1>CO.[Pd]>[CH3:15][O:14][C:7]1[CH:6]=[C:5]([CH3:16])[CH:4]=[CH:9][C:8]=1[S:10]([OH:13])(=[O:12])=[O:11]
Reactant: COc1cc(C)c(Br)cc1S(=O)(=O)O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COc1cc(C)ccc1S(=O)(=O)O
Temperature: 2.5 °C
Reaction time: 16 h
Yield: 84.7 %

Procedure:
To a solution of 5-bromo-2-methoxy-4-methylbenzenesulfonic acid dihydrate (from (a), 125 g, 0.394 moles) in methanol (1.25 liters, 10 ml/g) was added 5% Palladium on carbon catalyst (12.5 g, 0.1 g/g) and the suspension was hydrogenated at 60° C. and 414 kPa (60 psi) for 16 hours. The reaction mixture was filtered over celite and concentrated to dryness. The crude product was slurried in dichloromethane (250 ml), cooled to 0-5° C. and the subtitle compound (67.5 g, 75% yield) isolated in two crops as a white crystalline solid
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=5)[N:27]=[CH:26][N:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.O[CH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[F:37][C:19]1[CH:18]=[C:17]([NH:16][C:14]([C:11]2([C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:10])[CH2:13][CH2:12]2)=[O:15])[CH:22]=[CH:21][C:20]=1[O:23][C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH2:39][CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1
Reactant: OCCCN1CCOCC1
Reactant: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc2cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.5 %

Procedure:
To a mixture of cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxy-6-methoxy-quinazolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (1.5 g, 2.96 mmol), 4-(3-hydroxypropyl)morpholine (0.623 mL, 4.5 mmol), triphenylphosphine (1.18 g, 4.5 mmol), and dichloromethane (50 mL) was added diisopropyl azodicarboxylate (0.886 mL, 4.5 mmol). The mixture was stirred at room temperature for 16 h, monitored by LCMS. After removal of solvent, the crude mixture was separated by flash column chromatography (silica), eluting with 5% methanol in dichloromethane to give N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (890 mg, 47% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.36 (br s, 1H), 10.05 (br s, 1H), 8.55 (s, 1H), 7.83 (m, 1H), 7.64 (m, 2H), 7.57 (s, 1H), 7.44 (m, 3H), 7.18 (t, 2H), 4.27 (m, 2H), 3.99 (s, 3H), 3.61 (m, 6H), 2.40 (m, 4H), 2.01 (m, 2H), 1.47 (m, 4H). LC/MS Calcd for [M+H]+ 634.2, found 634.3.