Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=1[N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[C:14]([N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)[CH:15]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)Nc2ccc(Br)cc2)cc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.8 %

Procedure:
A mixture of 4-bromophenyl isocyanate (0.179 g, 0.905 mmol) and 4-methoxy-3-(4-methyl-1-piperazinyl)benzeneamine (EP 0 533 267 A1) (0.200 g, 0.905 mmol) in toluene were stirred together at room temperature. After 24 h, the resultant precipitate was filtered off, washed with petrol and dried in vacuo to give the title compound as a white solid (0.265 g, 70%). m.pt 199-201° C.
Reaction SMILES: C([NH:4][C:5]([C@@H:26]1[CH2:30][CH2:29][N:28]([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])[CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21]C(C)(C)C(C)(C)[O:18]1)[C:6](NC(C)(C)C)=[O:7])(=O)C.[O:43]1CCOCC1.Cl>O>[NH2:4][C:5]([C@@H:26]1[CH2:30][CH2:29][N:28]([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N+:40]([O-:42])=[O:41])(=[O:32])=[O:33])[CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]([OH:18])[OH:21])[C:6]([OH:43])=[O:7]
Reactant: C1COCCO1
Reactant: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)[C@@H]1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C1
Agent: Cl
Solvent: O
Product: NC(CCCCB(O)O)(C(=O)O)[C@@H]1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C1
Temperature: 100 °C
Yield: 23 %

Procedure:
A solution of 2-acetamido-N-tert-butyl-2-((R)-1-(2-nitrophenylsulfonyl)pyrrolidin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide (500 mg, 0.8 mmol) in 1,4-dioxane (3 mL, 40 mmol) was treated with a 6M aqueous solution of hydrogen chloride (6 mL, 40 mmol) followed by heating to 100° C. for 24 h. At the end of the 24 hour period, the reaction mixture was diluted with water and filtered. The filtrate that was obtained was purified by HPLC using 5%-50% acetonitrile in water over 30 min. The product-containing fractions were concentrated, then dissolved in 1N HCl and frozen prior to lyophilization to afford 2-amino-6-borono-2-((R)-1-(2-nitrophenylsulfonyl)pyrrolidin-3-yl)hexanoic acid (79 mg, 20%) as a white foam. 1H NMR (400 MHz, DMSO-d6, Mixture of diastereoisomers) δ 8.55-8.35 (2H), 8.05-7.98 (m, 2H), 7.96-7.85 (m, 2H), 5.83 (t, J=6.5 Hz, 2H), 3.70-3.14 (m, 4H), 2.78-2.65 (m, 1H), 2.19-1.60 (m, 4H), 1.47-1.23 (m, 3H), 1.14-1.00 (m, 1H); ESI MS found for C16H24BN3O8S m/z 412.1 [M−OH)+; 410.2 (M−H2O)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.Cl.[O:12]=[C:13]1[CH2:18][O:17][CH2:16][CH2:15][N:14]1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([CH:28]2[CH2:32][CH2:31][CH2:30][NH:29]2)=[O:27])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:29]2[CH2:30][CH2:31][CH2:32][C@@H:28]2[C:26]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][C:13]3=[O:12])=[CH:24][CH:23]=2)=[O:27])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(N2CCOCC2=O)cc1)C1CCCN1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1CCCN1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.3 95 mg (0.61 mmol) of 4-chlorophenyl isocyanate are added to a solution of 200 mg (0.61 mmol) of N-[4-(3-oxomorpholin-4-yl)phenyl]pyrrolidine-2-carboxamide hydrochloride and 1 ml of triethylamine in 5 ml of methylene chloride, and the reaction solution is stirred at room temperature for two hours. The reaction solution is subsequently washed with 5 ml of 1N hydrochloric acid and 5 ml of water, and the methylene chloride solution is dried over sodium sulfate. After the solvent has been stripped off under reduced pressure, the crude product is recrystallised from ethanol/diethyl ether, giving 120 mg of the title compound (“A1”) as a white powder; ESI 443; m.p. 227.6°.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[CH2:16][CH2:15][CH2:14]2)=[CH2:10].[C:22]1([C:28]2[C:32]([C:33]([F:36])([F:35])[F:34])=[C:31]([C:37](F)=[O:38])[O:30][N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[C:22]1([C:28]2[C:32]([C:33]([F:36])([F:34])[F:35])=[C:31]([C:37]([CH:16]3[CH2:15][CH2:14][C:13]4[C:18](=[CH:19][CH:20]=[C:11]([CH:9]=[CH2:10])[CH:12]=4)[C:17]3=[O:21])=[O:38])[O:30][N:29]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(F)c1onc(-c2ccccc2)c1C(F)(F)F
Reactant: C=Cc1ccc2c(c1)CCCC2=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)CCC(C(=O)c1onc(-c3ccccc3)c1C(F)(F)F)C2=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 35 %

Procedure:
The LDA solution was cooled to −78° C. and 6-vinyl-3,4-dihydronaphthalen-1(2H)-one (Intermediate I-1B, 0.299 g, 1.736 mmol) dissolved in 1 mL of THF was added dropwise over a period of 2 min. The pale yellow reaction mixture was stirred at −78° C. for 20 min. Then, 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride (Intermediate 4, 0.450 g, 1.736 mmol) dissolved in 1 mL of THF was added dropwise over a period of 2 min. The reaction mixture was stirred at −78° C. for 20 min, brought to room temperature, and stirred at room temperature for 10 min. The reaction mixture was quenched with 1N hydrochloric acid (5 mL) and extracted into ethyl acetate (20 mL). The aqueous layer was re-extracted with ethyl acetate (10 mL). The combined organic layers were dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (hexane/ethyl acetate). Fractions corresponding to the product were collected and concentrated to yield 2-(3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl)-6-vinyl-3,4-dihydronaphthalen-1(2H)-one (0.25 g, 0.608 mmol, 35.0% yield) as a yellow solid. LC/MS M+1=412.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[C:5]([C:10]#[N:11])=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.C1(C2[O:27]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:9])=[O:27])[C:5]([C:10]#[N:11])=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1nc(N)nc(Oc2ccccc2)c1C#N
Solvent: ClCCl
Product: CS(=O)c1nc(N)nc(Oc2ccccc2)c1C#N
Reaction time: 24 h
Yield: 26.7 %

Procedure:
To a stirred suspension of 950 mg (3.68 mmol) 2-amino-4-methylsulfanyl-6-phenoxy-pyrimidine-5-carbonitrile in 20 ml dichloromethane was added 3.84 g (14.7 mmol) 3-phenyl-2-(phenylsulfonyl)oxaziridine and stirring continued for 24 hours at room temperature. The reaction mixture was then concentrated in vacuo and the residue resuspended in ether/hexane and filtered to afford 270 mg (27%) 2-amino-4-methanesulfinyl-6-phenoxy-pyrimidine-5-carbonitrile as a light yellow crystalline solid. ES-MS m/e (%): 275 (M+H+, 100).
Reaction SMILES: C1C=CC(O[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][C:10]#[N:11])=CC=1.[NH2:19][C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1>CCOCC>[C:10]([N:9]=[C:8]([O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:19][C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1)#[N:11]
Reactant: Nc1cncnc1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CCOCC
Product: N#CN=C(Nc1cncnc1)Oc1ccccc1
Reaction time: 96 h
Yield: 53.9 %

Procedure:
A stirred mixture of diphenyl cyanocarbonimidate (1.05 g, 0.00442 mol), 5-amino-pyrimidine (0.42 g, 0.00442 mol) and Et2O (15 mL) was kept at ambient temperature for 4 days and at reflux for one day. There was little reaction. The solvent was evaporated and the residue was mixed with DME and warmed at 50°-55° for 2 days. The mixture was cooled, diluted with Et2O and filtered; the solid was washed with Et2O and dried to give 0.57 g of N'-Cyano-N-(5-pyrimidyl)-O-phenylisourea product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]2=[O:17])=[CH:4][CH:3]=1.[I-].C[N+]1C=CN([C:25](=[O:34])[N:26]([CH3:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)C=1>>[CH3:16][C:11]1([CH3:15])[CH2:10][C:9](=[O:17])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][C:25](=[O:34])[N:26]([CH3:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:7][CH:6]=2)[C:13](=[O:14])[CH2:12]1
Reactant: CC1(C)CC(=O)N(c2ccc(O)cc2)C(=O)C1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Product: CN(C(=O)Oc1ccc(N2C(=O)CC(C)(C)CC2=O)cc1)c1ccccc1

Procedure:
The title product was prepared from 1-(4-hydroxyphenyl)-4,4-dimethylpiperidine-2,6-dione (233 mg, 1.00 mmol)) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (343 mg, 1.00 mmol) by applying general procedure 3 (192 mg, 52%, white solid). HPLC-MS m/z=367 (M+1); Rt=3.78 min.
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].P(Cl)(Cl)([Cl:17])=O.CCN(C1C=CC=CC=1)CC.C(=O)([O-])[O-].[Ca+2]>>[Cl:17][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCN(CC)c1ccccc1
Product: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Temperature: 90 °C

Procedure:
About 100 parts (0.43 mol) of 4-hydroxy-3,5-dinitrotoluene, about 750 parts by volume of phosphorus oxychloride and about 1250 parts by volume of diethylaniline which has been dried over calcium carbonate are heated together to about 90° C. for about 21/2 hours with stirring. The reaction mixture is poured onto ice and extracted with methylene chloride, and the methylene chloride is removed in a rotary evaporator. After recrystallization from ethanol, about 65 parts of 4-chloro-3,5-dinitrotoluene of melting point of about 112° C. to about 113° C. about 70% of the theoretical yield is obtained. About 52 parts (0.24 mol) of this isolated compound are dissolved in about 500 parts by volume of toluene and added dropwise to a boiling mixture of about 180 parts of deoiled iron into about 180 parts by volume of H2O, about 280 parts by volume of toluene and about 5 parts by volume of glacial acetic acid. After about 3 hours, the reaction mixture is removed from the iron by suction filtration and then extracted with boiling toluene. The water is removed in a separating funnel and the organic phase is removed under vacuum. About 34 parts (91% of theoretical) of 4-chloro-3,5-diaminotoluene, melting point about 116° C. are obtained as white needles from 1:1 benzene/cyclohexane.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[C:17]1([CH3:28])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[CH:23]=[CH:24]/[C:25](O)=[O:26]>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([NH:16][C:25](=[O:26])/[CH:24]=[CH:23]/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH3:28])[CH:13]=[N:12]1
Reactant: CC1(CCCCn2cc(N)cn2)OCCO1
Reactant: Cc1ccccc1/C=C/C(=O)O
Product: CC(=O)CCCCn1cc(NC(=O)/C=C/c2ccccc2C)cn1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-4-ylamine and (E)-3-o-tolyl-acrylic acid.
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH2:15][CH3:16])[C:5]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[NH:7][N:6]=1)[CH2:2][CH3:3].C1C(=O)N([Cl:24])C(=O)C1.[NH4+].[Cl-].CCOC(C)=O>CN(C=O)C>[Cl:24][C:9]1[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:14][CH2:15][CH3:16])=[N:6][NH:7][C:8]=1[C:10]([F:12])([F:13])[F:11]
Reactant: CCCN(CCC)c1cc(C(F)(F)F)[nH]n1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN(CCC)c1n[nH]c(C(F)(F)F)c1Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To N,N-dipropyl-5-(trifluoromethyl)-1H-pyrazol-3-amine (250 mg, 1.06 mmol) in DMF (5.3 mL) was added NCS (142 mg, 1.06 mmol). The resulting reaction mixture was stirred at 100° C. for 1 h and then poured into sat. aq. NH4Cl solution and EtOAc (1:1). The organic layer was washed sat. aq. NH4Cl solution (3×), and the combined aqueous layer was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (287 mg, 100%). 1H NMR (CDCl3) δ 3.23-3.14 (m, 4H), 1.59-1.44 (m, 4H), 0.88 (t, J=7.4 Hz, 6H); MS(ESI+) m/z 270.1 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:4]2([CH2:7][CH2:6][CH2:5]2)[CH2:3]1.OS(O)(=O)=O.[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[N+:20]([C:12]1[CH:13]=[CH:14][C:9]2[O:8][C:4]3([CH2:7][CH2:6][CH2:5]3)[CH2:3][C:2](=[O:1])[C:10]=2[CH:11]=1)([O-:22])=[O:21]
Reactant: O=C1CC2(CCC2)Oc2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C1CC2(CCC2)Oc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3,4-Dihydro-4-oxo-spiro[2H-1-benzopyran-2,1′-cyclobutane] (Example 3) (10 mmol) in glacial acetic acid (2 ml), conc. H2SO4 (10 mmol) was added at 0° C. and the mixture was stirred for 10 min. A chilled nitrating mixture [prepared from HNO3 (9 mmol) and Conc. H2SO4 (10 mmol)] was then added very slowly and the reaction mixture was allowed to warm up to room temperature and stirred for 5 h. reaction mixture was then quenched with water and the compound was extracted in dichloromethane. Organic layer was separated, dried on anhydrous MgSO4 and concentrated under vacuum. The crude product was then purified by column chromatography to afford the desired compound as a yellow solid.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:16]=[C:15]([C:17](=[O:23])[NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH:14]=[C:13]([Cl:24])[C:12]=1[C:25](Cl)=[O:26]>>[Cl:10][C:11]1[CH:16]=[C:15]([CH:14]=[C:13]([Cl:24])[C:12]=1[C:25]([C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)=[O:26])[C:17]([NH:18][CH2:19][CH2:20][O:21][CH3:22])=[O:23]
Reactant: c1cc2cc[nH]c2cn1
Reactant: COCCNC(=O)c1cc(Cl)c(C(=O)Cl)c(Cl)c1
Product: COCCNC(=O)c1cc(Cl)c(C(=O)c2c[nH]c3cnccc23)c(Cl)c1

Procedure:
3,5-Dichloro-N-(2-methoxyethyl)-4-(1H-pyrrolo[2,3-c]pyridin-3-ylcarbonyl)benzamide was prepared from 1H-Pyrrolo[2,3-c]pyridine and 2,6-dichloro-4-(2-methoxyethylcarbamoyl)benzene carbonyl chloride (Compound No. 14).
Reaction SMILES: C(Cl)(=O)C.[NH2:5][CH:6]([CH2:9][OH:10])[CH2:7][OH:8].[CH2:11]([O:18][CH2:19][N:20]1[C:28]2[C:27]([O:29][CH3:30])=[N:26][CH:25]=[N:24][C:23]=2[C:22]([CH:31]=O)=[CH:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([BH3-])#N.[Na+]>CO>[CH2:11]([O:18][CH2:19][N:20]1[C:28]2[C:27]([O:29][CH3:30])=[N:26][CH:25]=[N:24][C:23]=2[C:22]([CH2:31][NH:5][CH:6]([CH2:9][OH:10])[CH2:7][OH:8])=[CH:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(CO)CO
Reactant: COc1ncnc2c(C=O)cn(COCc3ccccc3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)Cl
Product: COc1ncnc2c(CNC(CO)CO)cn(COCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
Acetyl chloride (0.117 ml, 1.65 mmol) was added to a stirred solution of 2-aminopropane-1,3-diol (0.3 g, 3.29 mmol) and 5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidine-7-carbaldehyde (0.196 g, 0.659 mmol, prepared as in G. B. Evans, R. H. Furneaux, A, Lewandowicz, V. L. Schramm and P. C. Tyler, J. Med. Chem., 2003, 46, 3412) in MeOH (5 ml). Sodium cyanoborohydride (0.062 g, 0.988 mmol) was added and the mixture was stirred at rt overnight. The solvent was evaporated and the residue chromatographed on silica gel (CH2Cl2-MeOH-28% NH4OH, 95:5:0.5 then 9:1:0.05) to give 2-((5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)-propane-1,3-diol (0.188 g, 77%) as a colourless solid. 1H NMR (CD3OD) δ 8.42, (s, 1H), 7.65 (s, 1H), 7.25-7.16 (m, 5H), 5.75 (s, 2H), 4.50 (s, 2H), 4.10 (s, 3H), 4.03 (s, 2H), 3.68 (dd, J=11.2, 5.9 Hz, 2H), 3.58 (dd, J=11.2, 5.9 Hz, 2H), 2.81 (pentet, J=5.6 Hz, 1H). 13C NMR (CD3OD, 75.5 MHz, referenced to centre line of CD3OD at δ 49.0) δ 157.9, 150.8, 150.6, 138.7, 134.1, 129.3, 128.8, 128.6, 117.0, 116.2, 78.5, 71.5, 62.5 (CH2X2), 61.3, 54.3, 41.4. +ESMS Found 373.1865 (M+H)+ C19H25N4O4 requires 373.1876.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[C:8]([O:22][CH3:23])=[C:9]([O:20][CH3:21])[C:10]2[O:14][C:13]([CH2:16][Br:17])([CH3:15])[CH2:12][C:11]=2[C:18]=1[CH3:19])(=O)C.Cl>CO>[Br:17][CH2:16][C:13]1([CH3:15])[CH2:12][C:11]2[C:18]([CH3:19])=[C:7]([OH:6])[C:8]([O:22][CH3:23])=[C:9]([O:20][CH3:21])[C:10]=2[O:14]1
Reactant: COc1c(OC(C)=O)c(C)c2c(c1OC)OC(C)(CBr)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(O)c(C)c2c(c1OC)OC(C)(CBr)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
An aqueous 2.5N sodium hydroxide solution (20 ml) was added to a solution (20 ml) of 5-acetoxy-2-bromomethyl-2,3-dihydro-6,7-dimethoxy-2,4-dimethylbenzofuran (2.5 g) in methanol (20 ml), and the mixture was stirred under an atmosphere of argon at room temperature for 1 hour. The reaction mixture was made acidic with 3N hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=85:15) to obtain the title compound (1.9 g, 87%) as an oil.
Reaction SMILES: [CH2:1]([NH:9][C:10]([NH:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CS(O)(=O)=[O:22].OO>>[CH2:1]([NH:9][C:10]([NH:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([O:18][OH:22])=[O:17])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNC(=O)NC(=O)CCC(=O)O
Reactant: CS(=O)(=O)O
Agent: OO
Product: CCCCCCCCNC(=O)NC(=O)CCC(=O)OO

Procedure:
13.6 g (0.05 mol) of N-(N'-octylcarbamoyl)succinamic acid, 50 g of methanesulfonic acid and 6 g (0.15 mol) of hydrogen peroxide (85% strength by weight) are reacted and worked up as described in Example 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([SH:22])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[H-].[Na+].Cl.Cl[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:12]=[C:11]([S:22][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[NH:10][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccncc1
Reactant: COc1ccc(-c2nc(S)[nH]c2-c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(Sc3ccncc3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
3.12 g of 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazole is dissolved in 100 ml of absolute dimethylformamide and combined with 0.6 g of sodium hydride (80% strength in white oil). The mixture is further agitated for 30 minutes, and then 1.52 g of 4-chloropyridine hydrochloride is added. The mixture is refluxed under argon for 16 hours. Then the solution is poured into 300 ml of ice water, the product is extracted with ethyl acetate, the organic solution is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is recrystallized from acetone/ether, thus obtaining 3.19 g of 4,5-bis(4-methoxyphenyl)-2-(4-pyridylthio)imidazole, mp 177°-179°.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=O)[CH2:4][CH2:3]1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:26][CH2:25][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[CH2:8][N:5]2[CH2:6][CH2:7][C:2]([F:30])([F:1])[CH2:3][CH2:4]2)=[CH:34][CH:33]=1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(CN2CCC(F)(F)CC2)n3-c2ccc(Cl)cc2)CC1
Yield: 57 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 140, intermediate a)), 4-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (57%).
Reaction SMILES: [F:1][CH:2]([F:49])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH2:34][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:43]=[CH:44][CH:45]=[C:46]([O:47][CH3:48])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:49][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]([CH2:34][CH2:35][CH2:36][N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)[CH:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]3)[N:9]=2)[C:6]2[CH:43]=[CH:44][CH:45]=[C:46]([O:47][CH3:48])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN2CCOCC2)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN2CCOCC2)C2CCNCC2)n1
Yield: 75 %

Procedure:
Reaction of tert-butyl 4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl][3-(4-morpholinyl)propyl]amino}-1-piperidinecarboxylate with TFA in CH2Cl2 gave 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-N-(4-piperidinyl)-1,3,5-triazin-2-amine (75% yield over two steps): 1H NMR (DMSO-d6) (rotamers) δ 7.94 (t, J=7.6 Hz, 1H), 7.73 and 7.70 (2t, JHF=53.1, 53.0 Hz, 1H), 7.42-7.36 (m, 1H), 6.95 (d, J=8.1 Hz, 1H), 4.63-4.55 and 4.50-4.42 (2m, 1H), 3.98 (s, 3H), 3.80-3.77 (m, 4H), 3.70 (br, 4H), 3.59-3.47 (m, 6H), 3.08-3.03 (m, 2H), 2.60-2.53 (m, 2H), 2.36-2.33 (m, 6H), 1.85-1.59 (m, 6H).
Reaction SMILES: [CH3:1][Mg]Br.[CH:4]([C:6]1[C:14]2[S:13][CH2:12][CH:11]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:10]=2[C:9]([CH3:24])=[C:8]([NH:25][C:26](=[O:32])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:7]=1[CH3:33])=O>O>[CH2:4]([C:6]1[C:14]2[S:13][CH2:12][CH:11]([C:15]3[CH:16]=[CH:17][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:19][CH:20]=3)[C:10]=2[C:9]([CH3:24])=[C:8]([NH:25][C:26](=[O:32])[CH2:27][C:28]([CH3:30])([CH3:29])[CH3:31])[C:7]=1[CH3:33])[CH3:1]
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CS2
Reactant: C[Mg]Br
Solvent: O
Product: CCc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1SCC2c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
To methylmagnesium bromide (1.0 M, THF solution, 10 mL, 10 mmol) was added at 0° C. N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide (600 mg, 1.42 mmol) obtained in Example 163 and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was added to water and the product was extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the obtained residue in trifluoroacetic acid (3 mL) was added with ice-cooling triethylsilane (1.0 mL) and the resulting mixture was stirred at room temperature for 30 minutes. After the reaction solution was concentrated under reduced pressure, to the residue was added an aqueous saturated sodium hydrogen carbonate solution and the aqueous layer was made alkaline, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 345 mg (yield: 57%) of the title compound. Melting point: 172-173° C. (hexane-ethyl acetate).