Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([OH:15])([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][CH2:23][CH2:24][N:25]1[CH2:29]C[C@@H:27](O)[CH2:26]1>>[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][CH2:23][CH2:24][N:25]1[CH2:26][CH2:27][C@@H:1]([O:2][C:3](=[O:16])[C:4]([OH:15])([C:5]2[S:6][CH:7]=[CH:8][CH:9]=2)[C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:29]1
Reactant: O[C@@H]1CCN(CCCc2cccs2)C1
Reactant: COC(=O)C(O)(c1cccs1)c1cccs1
Product: O=C(O[C@@H]1CCN(CCCc2cccs2)C1)C(O)(c1cccs1)c1cccs1
Yield: 49.1 %

Procedure:
Prepared as described in Intermediate I-1 from 2-Hydroxy-2,2-dithien-2-ylacetic acid methyl ester and (3R)-1-(3-thien-2-ylpropyl)pyrrolidin-3-ol (Intermediate I-17). The yield was 0.83 g (49.1%) of the title product as an oil. A portion of this product was solidified by formation of the oxalate salt.
Reaction SMILES: Br[C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[SH:28]>CO>[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28][C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)C1(Br)CCCCC1
Reactant: Sc1ccccc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)C1(Sc2ccccc2Br)CCCCC1
Temperature: 65 °C

Procedure:
To a solution of 715 mg (3.2 mmol) of methyl 1-bromocyclohexane-1-carboxylate (J. Med. Chem. 1970, 13, 317) in MeOH (5 mL) was added diisopropylethylamine (0.9 mL, 5.2 mmol) and 2-bromobenzenethiol (0.55 mL, 4.7 mmol). The solution was heated to 65° C. under nitrogen for 2 h, then cooled and partitioned between ethyl acetate and 1 M HCl. The organic phase was washed twice with 1 M NaOH and brine, then dried over MgSO4 and concentrated. Purification by flash chromatography (10% EtOAc/hexanes) gave methyl 1-[(2-bromophenyl)sulfanyl]cyclohexanecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1)=[O:5].[NH:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(c1ccc(F)cc1)c1cc(Cl)ccc1Cl
Reactant: c1cc[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1ccc(-n2cccc2)cc1)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
134.6 g (0.500 mol) of 2,5-dichloro-4′-fluorobenzophenon, 50.3 g (0.750 mol) of pyrrole, 76.0 g (0.550 mol) of potassium carbonate, and 840 ml of N,N′-dimethylacetamide were added into a 2 L three-necked flask equipped with a stirrer, thermometer, cooling pipe, and nitrogen inlet tube. The reaction solution was heated by use of an oil bath and was allowed to react at 100 degrees C. in a nitrogen atmosphere for 3 hours. After the disappearance of material was confirmed by a thin layer chromatography, the mixture was cooled to ambient temperature. Then, the reaction solution was gradually poured into 3 L of water to cause coagulation. The product obtained by filtration was dissolved into 2.5 L of toluene was added, and then, by using a separating funnel washed by brine until the water layer becomes neutral. After the organic layer was dried by magnesium sulfate, the solvent was removed by an evaporator. The rough yield was 133.3 g. By using mixture solvent of hexane and ethyl acetate, the dried product was recrystallized for isolation to obtain 125.3 g (0.396 mol) of the intended refining material in 79.3% in yield.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]([C:13]2[S:17][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:15][C:14]=2[CH3:28])[CH2:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C:29]1[NH:33][C:32](=[O:34])[O:31][N:30]=1.B(Br)(Br)Br.CO>ClCCl>[OH:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]([C:13]2[S:17][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=3)=[N:15][C:14]=2[CH3:28])[CH2:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C:29]1[NH:33][C:32](=[O:34])[O:31][N:30]=1
Reactant: CCC(Oc1ccc(-c2noc(=O)[nH]2)c(OC)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CCC(Oc1ccc(-c2noc(=O)[nH]2)c(O)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
To a stirred solution of 136 mg of 3-(2-methoxy-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-phenyl)-4H-1,2,4-oxadiazol-5-one in 5 mL of dichloromethane at −70° C. was added 0.6 mL of a 1 M solution of boron tribromide in dichloromethane. After 1 h at −60° C., the reaction mixture was poured into methanol and a saturated aqueous solution of NaHCO3 then extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient of dichloromethane/methanol from 100/0 to 90/10) to give 22 mg of 3-(2-hydroxy-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-phenyl)-4H-1,2,4-oxadiazol-5-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:23])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21.[CH:24](=O)[CH3:25].[C:27](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:28].[Na+]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:23]([CH2:24][CH3:25])[CH2:27][CH3:28])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: CC=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCN(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-amine (45 mg, 0.122 mmol) in methanol (5.0 mL) and acetic acid (1.0 mL) was added acetaldehyde (0.10 mL, 1.64 mmol) at 0° C. The resultant mixture was stirred at 0° C. for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (346 mg, 1.64 mmol) at 0° C. After stirring at room temperature for 1 hr, the mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on a silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (50 mg, 0.120 mmol, 98%) as a white amorphous.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]2[S:10][C:11]([C:13]([OH:15])=O)=[CH:12][C:7]2=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:21]([CH:24]=1)[C:22]#[N:23]>>[C:22]([C:21]1[CH:24]=[C:17]([NH:16][C:13]([C:11]2[S:10][C:8]3=[N:9][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][CH:6]=[C:7]3[CH:12]=2)=[O:15])[CH:18]=[CH:19][C:20]=1[O:25][CH2:26][C:27]([CH3:29])([CH3:28])[CH3:30])#[N:23]
Reactant: CC(C)c1ccc2cc(C(=O)O)sc2n1
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Product: CC(C)c1ccc2cc(C(=O)Nc3ccc(OCC(C)(C)C)c(C#N)c3)sc2n1
Yield: 16.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using 6-isopropylthieno[2,3-b]pyridine-2-carboxylic acid (2 g) and 5-amino-2-neopentyloxybenzonitrile (1.9 g), the title compound (0.6 g) was obtained. melting point: 244-245° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([CH:16]=[O:17])[CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11].ClC1C=CC(C2(C=O)CCC2)=CC=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O.CO>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([CH:16]([OH:17])[C:1]#[N:2])[CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: O=CC1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: [C-]#N
Agent: O=CC1(c2ccc(Cl)cc2)CCC1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#CC(O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of sodium cyanide (19.5 g) in water (50 ml) was added dropwise over a period of 30 minutes to a solution of 1-(3,4-dichlorophenyl)cyclobutanecarbaldehyde [(62.16 g) prepared in a similar manner to that described in Example A for 1-(4-chlorophenyl)-cyclobutanecarbaldehyde] in methanol (70 ml) whilst the temperature was maintained at 20° C. by cooling. A saturated aqueous solution of sodium metabisulphite (81 ml) was added over a period of 20 minutes at 20° C. and the mixture was stirred for 16 hours and then poured into a mixture of ice and water. The resulting mixture was extracted with ether and the extracts were washed and dried. Evaporation of the solvent gave 2-[1-(3,4-dichlorophenyl)cyclobutyl]-2-hydroxyacetonitrile as a yellow oil which was used without further purification.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:6][CH:5]=1.[NH2:33][CH2:34][CH2:35][CH2:36][NH2:37].[C-]#N.[Na+].O>CO>[NH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:3](=[O:2])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:6][CH:5]=1
Reactant: NCCCN
Reactant: COC(=O)c1ccc(CN(Cc2ccccn2)C(c2ccccn2)c2ccccn2)nc1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NCCCNC(=O)c1ccc(CN(Cc2ccccn2)C(c2ccccn2)c2ccccn2)nc1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
A solution of 15 (473 mg, 1.11 mmol), 1,3-diaminopropane (1.1 ml, 13.1 mmol) and NaCN (7 mg, 0.14 mmol) in methanol (15 ml) was heated under reflux for 24 hours under an Argon atmosphere. After cooling to room temperature the mixture was poured into water (100 ml) and the aqueous layer was washed with ether (2×125 ml), followed by extraction with dichloromethane (3×75 ml). The combined dichloromethane layers were washed with water (50 ml), brine (50 ml) and dried (Na2SO4). Evaporation of the solvent afforded 16 (418 mg, 81%) as a slightly yellow sticky solid. 1H-NMR (CDCl3) δ1.71 (m, 2H), 2.91 (m, 2H), 3.54 (m, 2H), 3.91 (s, 2H), 3.96 (s, 2H), 5.29 (s, 1H), 7.09 (m, 3H), 7.60 (m, 7H), 8.03 (m, 1H), 8.43 (d, 1H, J=4.4 Hz), 8.52 (d, 2H, 4.8 Hz), 8.85 (s, 1H); 1H-NMR (CDCl3) δ30.41 (t), 39.34 (t), 40.51 (t), 56.79 (t), 57.14 (t), 71.86 (d), 121.81(d), 122.07 (d), 122.35 (d), 122.86 (d), 123.82 (d), 128.36 (s), 135.39 (d), 136.23 (d), 136.29 (d), 147.42 (d), 148.95 (d), 149.18 (d), 159.27 (s), 159.58 (s), 162.58 (s), 165.33(s); MS (CI): m/z 468 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:12][OH:13])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC(O)COCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(O)COCc1ccccc1
Reaction time: 3 h
Yield: 102.9 %

Procedure:
To a mixture of 1-O-benzyl-glycerol (27 mL, 0.16 mol) and t-butyldimethylsilyl chloride (25 g, 0.17 mol) in dry CH2Cl2 (250 mL) under N2 was added DMAP (0.8 g, 6.6 mmol) followed by the addition of TEA (23 mL, 0.17 mol). After 3 hours, the mixture was washed with H2O (2×100 mL), dried (MgSO4) and concentrated to give 1-O-benzyl-3-O-t-butyldimethylsilyl-rac-glycerol (40) (48.8 g, 100%) as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=1.[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.F[B-](F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:22])=[CH:18][N:17]=1
Reactant: NN1CCOCC1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NN1CCOCC1)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a solution of 6-(5-hydroxymethyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.21 mmol) in DMF (5 mL) was added 4-aminomorpholine (31 mg, 0.30 mmol), N,N,N′,N′-tetramethyl-O-(benzotriazole-1-yl)-uronium tetrafluoroborate (96 mg, 0.30 mmol) and N,N-diisopropyl ethylamine (0.15 mL, 0.84 mmol). The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent the residue was partitioned (ethyl acetate/aqueous saturated sodium bicarbonate solution) and the organic phase was dried (Na2SO4) and concentrated. Chromatography (silica, dichloromethane:methanol=100:0 to 97:3) afforded the title compound (41 mg, 47%) as a colorless oil. MS: m/e=412.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.COC1C=CC(C=O)=CC=1.P(=O)([O-])OC(CC)(CC)C1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C=Cc2ccccc2)cc1
Agent: CCC(CC)(O[PH](=O)[O-])c1ccccc1
Agent: COc1ccc(C=O)cc1
Product: Oc1ccc(C=Cc2ccccc2)cc1

Procedure:
In a similar manner, 4-methoxystilbene is synthesized from 4-methoxybenzaldehyde and diethylbenzyl phosphonate, and demethylated to obtain 4-hydroxystilbene (sample No. 13) as white needle crystals (melting point: 185°-186° C.).
Reaction SMILES: O=[C:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1)[CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([O:11]C)=O.[CH2:23]([NH2:26])[CH2:24][NH2:25]>O1CCOCC1>[F:20][C:19]([F:22])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([C:2]23[NH:26][CH2:23][CH2:24][N:25]2[C:9](=[O:11])[C:5]2[N:4]([CH:8]=[CH:7][CH:6]=2)[CH2:3]3)=[N:14][CH:15]=1
Reactant: COC(=O)c1cccn1CC(=O)c1ccc(C(F)(F)F)cn1
Reactant: NCCN
Solvent: C1COCCO1
Product: O=C1c2cccn2CC2(c3ccc(C(F)(F)F)cn3)NCCN12
Reaction time: 96 h
Yield: 83.5 %

Procedure:
To a solution of methyl 1-{2-oxo-2-[5-(trifluoromethyl)pyridin-2-yl]ethyl}-1H-pyrrole-2-carboxylate (85 mg, 0.26 mmol) in 1,4-dioxane (20 mL) was added ethane-1,2-diamine (0.65 mL, 9.7 mmol). The solution was heated at reflux. After 4 days the reaction was complete (monitored by LCMS). The mixture was then concentrated in vacuo to give an oily solid. The material was purified by flash chromatography (Biotage SP4, 12 g cartridge, gradient CH2Cl21CV, 0-10% MeOH in CH2Cl2 10 CV) to give 10a-[5-(trifluoromethyl)pyridin-2-yl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (70 mg, yield: 85%). ESI-MI m/z [M+H]+ 323.0.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:29]1[CH2:33][O:32][CH2:31][CH2:30]1.[H-].[Na+].C(C1[O:40]C1)Cl>CN(C=O)C.CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:29][CH:30]([OH:40])[CH2:31][O:32][CH3:33])[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: ClCC1CO1
Reactant: C1CCOC1
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COCC(O)Cn1c(C(C)(C)C)cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc21
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)cyclopropanecarboxamide (320 mg, 0.84 mmol) was dissolved in a mixture composed of anhydrous DMF (0.5 mL) and anhydrous THF (5 mL) under N2. NaH (60% in mineral oil, 120 mg, 3.0 mmol) was added at room temperature. After 30 min of stirring, the reaction mixture was cooled to −15° C. before a solution of epichlorohydrin (79 μL, 1.0 mmol) in anhydrous DMF (1 mL) was added dropwise. The reaction mixture was stirred for 15 min at −15° C., then for 8 h at room temperature. MeOH (1 mL) was added and the mixture was heated for 10 min at 105° C. in the microwave oven. The mixture was cooled, filtered and purified by preparative HPLC to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(2-hydroxy-3-methoxy-propyl)-1H-indol-5-yl)cyclopropanecarboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C[Al](C)C.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:30]=[CH:29][NH:28][C:27]=2[C:31](OC)=[O:32])=[CH:22][CH:21]=1)([O-:19])=[O:18]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(#N)C>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:31]([C:27]1[NH:28][CH:29]=[CH:30][C:26]=1[C:23]1[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:25][CH:24]=1)=[O:32]
Reactant: COC(=O)c1[nH]ccc1-c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CN)c(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(CNC(=O)c2[nH]ccc2-c2ccc([N+](=O)[O-])cc2)c(OC)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To 2.435 cm3 (15.84 mmol) of 2,4-dimethoxybenzylamine dissolved in 65 cm3 of toluene are added, at a temperature in the region of 20° C. under an argon atmosphere, 10.3 cm3 (20.59 mmol) of a 2M solution of trimethylaluminium in toluene, followed by addition of 1.95 g (7.92 mmol) of methyl 3-(4-nitrophenyl)-1H-pyrrole-2-carboxylate. After stirring for 1 hour at a temperature in the region of 20° C. and then for 16 hours at a temperature in the region of 60° C., the reaction mixture is diluted with 170 cm3 of ethyl acetate. The resulting solution is washed successively with three times 70 cm3 of saturated aqueous ammonium chloride solution and twice 50 cm3 of water and then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give a yellow solid, which is then stirred in 20 cm3 of acetonitrile at a temperature in the region of 5° C. for 30 minutes. After filtering through a No. 3 sinter funnel, the solid is washed with 10 cm3 of ice-cold acetonitrile and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 35° C. for 3 hours to give 1.96 g of 2-(2,4-dimethoxybenzylamino)carbonyl-3-(4-nitrophenyl)-1H-pyrrole in the form of a yellow solid; ES+: m/z=382: [M+H]+; ES−: m/z=380: [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH:15]([CH3:27])[CH2:16][NH:17][C:18]4[CH:23]=[N:22][N:21]([CH3:24])[C:20](=[O:25])[C:19]=4Cl)[CH2:11][CH2:10]3)=N[O:8][C:4]=2[CH:3]=1.C[OH:31].[OH-].[Na+].[H][H]>[Pd].O>[F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:27])[CH2:16][NH:17][C:18]3[CH:23]=[N:22][N:21]([CH3:24])[C:20](=[O:25])[CH:19]=3)[CH2:11][CH2:10]2)=[O:31])=[C:4]([OH:8])[CH:3]=1
Reactant: [H][H]
Reactant: CC(CNc1cnn(C)c(=O)c1Cl)N1CCC(c2noc3cc(F)ccc23)CC1
Reactant: CO
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CNc1cnn(C)c(=O)c1)N1CCC(C(=O)c2ccc(F)cc2O)CC1
Reaction time: 0.08 h
Yield: 73.8 %

Procedure:
Into a pressure-tight hydrogenating apparatus 1.64 g (0.0039 mole) of 5-{2-[4-(6-fluoro-1,2-benzisoxazole-3-yl)-piperidine-1-yl]-propylamino}-4-chloro2-methyl-2H-pyridazine-3-one, 150 ml of a solvent mixture (9:1 mixture of methanol and distilled water), 0.18 g (0.0456 mole) of sodium hydroxide and 3.2 g of a palladium/charcoal catalyst (composition: 8% of palladium, 28% of carbon and 64% of water) are weighed in. The reaction mixture is stirred at a hydrogen pressure of 10 atm. for 24 hours. The reaction mixture is heated to reflux temperature and stirred at this temperature for 5 minutes. The mixture is filtered hot and the catalyst is washed five times with 33 ml of a 1:1 mixture of methanol and dichloro methane each. The united mother lyes are evaporated. The precipitated crude product is recrystallized from a mixture of acetonitrile and water. Thus 1.12 g of the desired compound are obtained. Yield 73.8%.
Reaction SMILES: CN(C=O)C.[CH3:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[N:14][C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[C:12]2O.O=S(Cl)[Cl:26]>>[Cl:26][C:12]1[C:11]2[C:16](=[C:7]([CH3:6])[CH:8]=[CH:9][CH:10]=2)[N:15]=[N:14][C:13]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc2c(O)c(-c3ccccc3)nnc12
Solvent: CN(C)C=O
Product: Cc1cccc2c(Cl)c(-c3ccccc3)nnc12

Procedure:
Step 3: 2 Drops of DMF was added to a suspension of 8-methyl-3-phenylcinnolin-4-ol (60 mg) in SOCl2 (10 mL) and the reaction was refluxed for 0.5 hours. The reaction was concentrated, dilute with ethyl acetate and washed with water. The organic layer was dried over MgSO4 and concentrated to give crude 4-chloro-8-methyl-3-phenyl-cinnoline which was used for the next reaction without further purification. MS (ESI) m/z 255, 257;
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9](=[O:20])[N:8]([CH3:21])[C:6]=2[N:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[Cl:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:19])[C:12]=1[C:10]1[C:9](=[O:20])[N:8]([CH3:21])[C:6]2[N:7]=[C:2]([NH:1][C:22](=[O:24])[CH3:23])[N:3]=[CH:4][C:5]=2[CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Product: CC(=O)Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Temperature: 25 °C

Procedure:
A mixture of 64.2 mg (0.20 mmol) of 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one (from Example 12) and 1 mL of acetic anhydride was heated to reflux. The resulting solution was maintained at reflux for 20 minutes and concentrated at atmospheric pressure to about 0.25 mL volume. The solution was cooled to 25° C. and diluted with diethyl ether (1 mL). The separated crystals were filtered and washed with diethyl ether to provide N-[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl]acetamide, wt 44.0 mg; mp 258°-260° C.
Reaction SMILES: [CH3:1][C:2]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:15])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC(C)([O-])C.[K+]>CS(C)=O>[CH2:24]([N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:5]([CH2:4][CH2:3][C:2]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:1])[CH3:15])[C:6]1=[O:14])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(CCn1c(=O)[nH]c2ccccc21)NC(=O)OC(C)(C)C
Reactant: ClCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(CCn1c(=O)n(Cc2ccccc2)c2ccccc21)NC(=O)OC(C)(C)C

Procedure:
tert-butyl [1,1-Dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propyl]-carbamate, benzyl chloride and potassium-tert-butoxide are stirred overnight at ambient temperature in dimethylsulphoxide. The alkylation product tert-butyl [3-(3-benzyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-propyl]-carbamate obtained from the reaction is then treated with trifluoroacetic acid/dichloromethane in order to cleave the protective group. Mass spectroscopy [M+H]+=310.