Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[Cl:19])[C:6]=1SC)=O.[CH3:22][NH:23][NH2:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:19][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[N:7]1[CH2:8][CH2:9][CH2:10][C:5]2[C:3](=[O:2])[N:23]([CH3:22])[NH:24][C:6]1=2
Reactant: COC(=O)C1=C(SC)N(c2c(C)cc(C)cc2Cl)CCC1
Reactant: CNN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: Cc1cc(C)c(N2CCCc3c2[nH]n(C)c3=O)c(Cl)c1
Temperature: 130 °C
Reaction time: 24 h

Procedure:
1-(2-Chloro-4,6-dimethylphenyl)-2-methylsulfanyl-1,4,5,6-tetrahydropyridine-3-carboxylic acid methyl ester (4.99 g), methylhydrazine (16.4 mL), p-toluenesulfonic acid monohydrate (2.91 g), and methanol (75 mL) were combined in a glass vessel sealed with a Telfon™ screw cap. The reaction mixture was stirred in a 130° C. oil bath for 24 h, then cooled to room temperature and concentrated on the rotary evaporator. The residue was chromatographed on silica gel using a methanol/dichloromethane gradient to give 3.21 g of 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo-[3,4-b]pyridin-3-one, mp 95.9-99.9° C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:3]=1[NH:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.CCOC(C)=O>[Pd].CO>[F:1][C:2]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:3]=1[NH:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1ccc(NCCCCN2CCOCC2)c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(NCCCCN2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of 2-fluoro-N-(4-morpholinobutyl)-4-nitroaniline (1.19 g, 4.00 mmol) in mixed solvents of EtOAc (20 mL) and MeOH (20 mL) was added catalyst Pd/C (0.30 g). The reaction was stirred at rt under H2 for 2 h, then filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/MeOH (V/V)=10:1) to give the title compound as a white solid (1.07 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:6](OC)=[O:7].O.[NH2:17][NH2:18]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:6]([NH:17][NH2:18])=[O:7]
Reactant: NN
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)NN)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 70.6 %

Procedure:
To methyl 3-methoxy-4-nitrobenzoate (5.16 g, 24.5 mmol) in EtOH (250 mL) was added hydrazine monohydrate (5.95 mL, 122 mmol) in one portion. The reaction was heated at 80° C. overnight and concentrated upon completion by TLC. The residue was taken up in EtOAc, heated and hot filtered. The filtrate was concentrated and the residue was triturated with diethyl ether to provide the title compound (3.65 g, 17.3 mmol, 71%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.96 (s, 3H), 4.60 (br. s., 2H), 7.50 (dd, J=8.4, 1.5 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.93 (d, J=8.1 Hz, 1H), 10.05 (br. s., 1H).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:24])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:10]([N+:25]([O-])=O)[CH:9]=2)=[N:6][NH:5][C:4](=[O:28])[CH2:3]1.[H][H]>CN(C)C=O.[Pd]>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:24])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:10]([NH2:25])[CH:9]=2)=[N:6][NH:5][C:4](=[O:28])[CH2:3]1
Reactant: [H][H]
Reactant: COc1ccc(C(=O)Nc2ccc(C3=NNC(=O)CC3C)cc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc(C3=NNC(=O)CC3C)cc2N)cc1

Procedure:
203 gm of 5-methyl-6-[3-nitro-4-(4-methoxy-benzoylamino)-phenyl]-4,5-dihydro-2H-pyridazine-3-one were dissolved in 1.7 liters of dimethylformamide, and the solution was treated with hydrogen in the presence of 20 gm of 10% palladium charcoal for 2 hours at a pressure of 5 bar. After filtering off the catalyst, the filtrate was poured into 7.5 liters of ice water. The precipitated product was dried at 120° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8](/[CH:15]=[CH:16]/[CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[C:31]1[CH:36]=[C:35]([CH2:37]Cl)[CH:34]=[CH:33][C:32]=1[C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[C:31]1[C:32]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:33][CH:34]=[C:35]([CH2:37][O:1][C:2]2[CH:3]=[CH:4][C:5]([C@H:8](/[CH:15]=[CH:16]/[CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=2)[CH:36]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCOc1ccc(OC)cc1-c1cc(CCl)ccc1C(C)(C)C
Reactant: C/C=C/[C@H](CC(=O)OCC)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C/C=C/[C@H](CC(=O)OCC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3OCCCC)c2)cc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
A mixture of compound B (11 mg, 47 μmol), compound C (17 mg, 47 μmol), and cesium carbonate (23 mg, 70 μmol) in DMF (1.0 mL) was stirred for 16 hours at 23° C. The mixture was diluted with EtOAc, washed with water and brine, dried over MgSO4, and concentrated. The crude product was purified by silica gel flash chromatography (0-10% EtOAc/hexane) to afford compound 11.1 (21 mg, 81% yield) as a colorless oil. MS ESI (pos.) m/e: 576 (M+H2O), 581 (M+Na).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1B(O)O>>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: Cc1c2n(c3c(-c4ccc(Cl)cc4Cl)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, off-white solid (54 mg, 56%), MS (ISP) m/z=384.5 [(M+H)+], mp 257° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 2,4-dichloro-phenylboronic acid (62.0 mg, 0.325 mmol).
Reaction SMILES: CS(O[CH:6]([C:34]1[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=1)[CH2:7][O:8][CH2:9][C:10]1[N:11]=[CH:12][N:13](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:14]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[CH:14]1[N:13]=[CH:12][N:11]2[CH:6]([C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=3)[CH2:7][O:8][CH2:9][C:10]=12
Reactant: CS(=O)(=O)OC(COCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C2COCc3cncn32)cc1
Temperature: 80 °C

Procedure:
A solution of 1.00 mmol of 1-(4-cyanophenyl)-2-(1-trityl-1H-imidazol-4-ylmethoxy)ethyl methanesulphonate in 5 ml of N,N-dimethylformamide is mixed with 2.50 mmol of caesium carbonate and heated at 80° C. for 6 hours. The reaction mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate (2×). The combined organic phases are dried with sodium sulphate and evaporated. The title compound is obtained from the residue as yellowish crystals by flash chromatography (SiO2 60F). Rf=0.61 (dichloromethane-methanol-25% aqueous ammonia solution 200:10:1); Rt=3.54 (gradient II).
Reaction SMILES: C(=O)([O:7][C:8]1[N:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[C:10]([CH:17]([CH3:19])[CH3:18])[N:9]=1)OC(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:14]([C:12]1[CH:11]=[C:10]([CH:17]([CH3:19])[CH3:18])[N:9]=[C:8]([OH:7])[N:13]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1cc(C(C)C)nc(OC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cc(C(C)C)nc(O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
Tert-butyl 4,6-diisopropylpyrimidine-2-yl carbonate (42 mg) was dissolved in methylene chloride (4 mL). While the solution was cooled with ice, trifluoroacetic acid (1 mL) was added to the solution. The mixture was then stirred at room temperature (20 to 30° C.) for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride:methanol=10:1) to give 8.5 mg (30% yield) of the desired product as a brown amorphous.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:12](\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)/[C:13]([F:16])([F:15])[F:14])=[CH:7][CH:6]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[C:23]1(/[C:11](/[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:6][CH:7]=2)=[C:12](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)\[C:13]([F:16])([F:15])[F:14])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C1COCCN1
Reactant: FC(F)(F)/C(=C(\c1ccccc1)c1ccc(OCCBr)cc1)c1ccccc1
Product: FC(F)(F)/C(=C(\c1ccccc1)c1ccc(OCCN2CCOCC2)cc1)c1ccccc1
Reaction time: 1 h
Yield: 82.3 %

Procedure:
A mixture of 3.34 g (7.5 mmoles) of (E)-1-[4-(2-bromoethoxy)-phenyl]-1,2-diphenyl-3,3,3-trifluoro-propene, prepared as described in Example 7, and 13 g of morpholine is boiled for one hour. The reaction mixture is processed as described in Example 1, and the crude product is crystallized from hexane. 2.80 g (82.4%) of the aimed compound are obtained; m.p.: 84°-89° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH2:13][C:14](=[O:16])[CH2:15][C:11]=2[C:10]([C:17]([OH:19])=[O:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:21]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]1=[O:27].C(Cl)CCl>C(Cl)Cl>[O:27]=[C:22]1[CH2:23][CH2:24][C:25](=[O:26])[N:21]1[O:18][C:17]([C:10]1[C:11]2[CH2:15][C:14](=[O:16])[CH2:13][C:12]=2[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:9]=1)=[O:19]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C1Cc2c(C(=O)O)nn(Cc3ccccc3)c2C1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C1Cc2c(C(=O)ON3C(=O)CCC3=O)nn(Cc3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the intermediate from step C (1.34 g, 5.25 mmol) in CH2Cl2 (50 mL) was added N-hydroxy succinimide (1.21 g, 10.5 mmol) followed by EDC (2.01 g, 10.5 mmol). After stirring at room temperature for 18 hours, the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (200 mL), washed with saturated NaHCO3, solution and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. A yellow solid was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:48]=[CH:47][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:22]5[N:26]([CH:27]6[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]6)[C:25]6[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:24]=6[N:23]=5)[CH:18]=4)[N:13]=3)=[CH:10][C:9](C(N3CCCC3)=O)=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.C[C:50](C1C=C(OC)C=CC=1O)=[O:51]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:22]5[N:26]([CH:27]6[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]6)[C:25]6[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:24]=6[N:23]=5)[CH:18]=4)[N:13]=3)=[CH:10][C:9]([O:51][CH3:50])=[CH:8][CH:7]=2)=[CH:47][CH:48]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Reactant: COc1ccc(O)c(C(C)=O)c1
Product: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1

Procedure:
The title compound was synthesized in seven steps as described for Compound 204 except 2-hydroxy-5-methoxy acetophenone was used instead of Compound 18.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]#[N:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]3[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]=3[N:23]=[CH:24][N:25]=2)=[CH:16]1.N12CCCN=C1CCCCC2>C(#N)C>[C:13]([CH2:12][C:10]1([N:15]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]4[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:16]2)[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)#[N:14]
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cc[nH]c3)ncnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2ccc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)c2)C1
Yield: 82.8 %

Procedure:
A 100 mL round bottom flask fitted with overhead stirring, septa and nitrogen inlet was charged with tert-butyl-3-(cyanomethylene)azetidine-1-carboxylate (1.8 g, 9.5 mmol), 4-(1H-pyrrol-3-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 9.5 mmol) and acetonitrile (60 mL). The resulting solution was heterogeneous. 1,8-Diazabicyclo[5.4.0]undec-7-ene (1.4 mL, 9.5 mmol) was added portionwise via a syringe over 3 minutes at room temperature. The solution slowly becomes homogeneous and yellow in color. The reaction was allowed to stir at room temperature for 3 hours. The solution was concentrated by rotary evaporation to remove acetonitrile. EtOAc (100 mL) and brine (100 mL) were added. The organic phase was separated and the aqueous layer was extracted with 3×30 mL EtOAc. The combined extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo to yield an orange oil which was purified by flash chromatography (120 grams silica, 30-55% EtOAc/hexane, loaded with CH2Cl2). Desired fractions were combined and concentrated to yield a yellow oil which was placed on a high vacuum pump to give 4 g (83%) of tert-butyl 3-(cyanomethyl)-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidine-1-carboxylate as a white foam. LC-MS: [M+H]+=509.3.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].C(N(CC)CC)C.[CH2:12]([S:14](Cl)(=[O:16])=[O:15])[CH3:13]>ClCCl>[CH:2]([O:4][S:14]([CH2:12][CH3:13])(=[O:16])=[O:15])([CH3:3])[CH3:1]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)OC(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
To a solution of 2-propanol (2.4 mL, 32 mmol) in dichloromethane (50 were added triethylamine (3.5 ml, 25 mmol) and ethanesulfonyl chloride (2.0 mL, 21 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (2.4 g, 16 mmol, 75%).
Reaction SMILES: [K].Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[CH:5][N:4]=1.[OH:15][CH2:16][CH:17]1[O:21][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]([CH:28]([CH3:30])[CH3:29])[CH2:18]1>C(O)(C)(C)C>[CH:28]([N:19]1[CH2:18][CH:17]([CH2:16][O:15][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=3)[CH:6]=[CH:5][N:4]=2)[O:21][CH:20]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:30])[CH3:29]
Reactant: COc1ccc2ccnc(Cl)c2c1
Reactant: CC(C)N1CC(CO)OC1c1ccccc1
Agent: [K]
Solvent: CC(C)(C)O
Product: COc1ccc2ccnc(OCC3CN(C(C)C)C(c4ccccc4)O3)c2c1

Procedure:
0.3 g of potassium are dissolved in 15 cc of absolute tert.butanol, and 1.5 g of 1-chloro-7-methoxyisoquinoline and 1.7 g of 5-hydroxymethyl-3-isopropyl-2-phenyl-oxazolidine are added. The solution is heated to 50° for 1 hour, whereupon it is evaporated to dryness. The product is digested with water, extracted with ether, the ether phase is dried and the ether is distilled off. 1-(3-isopropyl-2-phenyl-5-oxazolidinylmethoxy)-7-methoxyisoquinoline is obtained as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][O:12][CH3:13])[NH2:5].N1C=CC=CC=1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][O:12][CH3:13]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COCCOc1ccc(N)cc1F
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: COCCOc1ccc(NC(=O)Oc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a stirred solution of 3-fluoro-4-(2-methoxyethoxy)aniline (2.0 g, 10.8 mmol, 1.0 eq) in acetone (50 mL) was added pyridine (2.5 mL, 32.4 mol, 3.0 eq.) and phenyl chloroformate (1.36 mL, 10.8 mmol, 1.0 eq.) at 0° C. and stirred at RT for 1 h. The solvent was evaporated, the residue diluted with EtOAc (50 mL), washed with water (100 mL), brine (20 mL) and evaporated again. The resulting residue was purified by column chromatography using EtOAc/PE (1:4) as eluent to yield phenyl 3-fluoro-4-(2-methoxyethoxy)phenylcarbamate (2.7 g, 76.8%) as a white solid (TLC system: EtOAc/PE (3:7), Rf: 0.5).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:21][C:20]2[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=2)[CH:6]=1)=[O:4]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COC(=O)c1c[nH]c2ccccc12
Product: COC(=O)c1cn(Cc2ccc([N+](=O)[O-])cc2)c2ccccc12

Procedure:
1-(4-Nitro-benzyl)-1H-indole-3-carboxylic acid methyl ester (I13220-11) was prepared from 1H-indole-3-carboxylic acid methyl ester and 4-nitrobenzyl bromide followed the procedure of Example 3 Step 1 as a yellow powder: 1H NMR (DMSO-d6) δ 3.83 (s, 3H), 5.70 (s, 2H), 7.23 (ddd, J=9.9, 4.6, 0.8 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 7.50 (ddd, J=9.9, 4.6, 0.8 Hz, 1H), 8.05 (ddd, J=9.9, 4.6, 0.8 Hz, 1H), 8.19 (d, J=8.8 Hz, 2H), 8.40 (s, 1H); MS (ESI) m/z 311 (MH+), 309 ([M−H]−).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][C:32](=[O:33])[NH:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1

Procedure:
200 mg (0.551 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reacted with 85 mg (0.716 mmol) of phenyl isocyanate in analogy to Example 16a. The title compound ##STR97## is obtained as white foam (160 mg, 60%). TLC: toluene/ethyl acetate (1:1) Rf =0.40, FD-MS: M+ =481, 483; IR: 1600-1690 cm-1.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([CH3:34])=[C:6]([C:8]2[N:9]([CH2:24][C:25]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[S:27][CH:26]=3)[N:10]=[C:11]3[C:16]=2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]3[CH2:20][CH:21]([CH3:23])[CH3:22])[N:7]=1.[C:35](Cl)(=[O:37])[CH3:36].C(=O)([O-])[O-].[K+].[K+]>C(N(CC)CC)C>[S:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:25]([CH2:24][N:9]2[C:8]([C:6]3[N:7]=[C:3]([NH:2][C:35](=[O:37])[CH3:36])[S:4][C:5]=3[CH3:34])=[C:16]3[C:11]([N:12]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13](=[O:19])[N:14]([CH3:18])[C:15]3=[O:17])=[N:10]2)=[CH:26]1
Reactant: Cc1sc(N)nc1-c1c2c(=O)n(C)c(=O)n(CC(C)C)c2nn1Cc1csc2ccccc12
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2csc3ccccc23)c(C)s1

Procedure:
3-(2-amino-5-methyl-1,3-thiazol-4-yl)-2-(1-benzothien-3-ylmethyl)-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione hydrochloride was reacted with excess acetyl chloride using triethylamine as a base. The resulting bis acetylated product is treated with potassium carbonate to give the title compound. Mass: 523.22 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[CH3:29][C:30](=[CH2:33])[CH2:31]O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:31][C:30](=[CH2:29])[CH2:33][O:15][C:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)=[O:16]
Reactant: C=C(C)CO
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=C(C)COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
Under inert condition a 500 mL round bottom flask with a magnetic stirrer was charged with 6.87 g (30 mmol) of 1-tert.-butyloxycarbonyl-piperidine-4-carboxylic acid, 110 mg (0.09 mmol) DMAP and 11.5 g (60 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride and 150 mL DCM. To the light yellow solution 3.25 g (45 mmol) 2-methyl-2-propen-1-ol was added. The reaction mixture was stirred over night at room temperature. The mixture was concentrated under vacuum, isolute-HM-N was added and evaporated to dryness. The residue was purified over silica eluting with heptane and ethyl acetate to yield after evaporation of the product containing fractions 7.3 g (86%) of the title compound as colourless oil. MS ISP (m/e): 306.2 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]([CH2:24][CH:25]=[CH:26][CH2:27]Br)[CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].[CH2:30]([O:32][P:33]([O:37]CC)[O:34][CH2:35][CH3:36])[CH3:31]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:29])[CH:4]([CH2:24][CH:25]=[CH:26][CH2:27][P:33]([O:34][CH2:35][CH3:36])([O:32][CH2:30][CH3:31])=[O:37])[CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21]
Reactant: CCOP(OCC)OCC
Reactant: COC(=O)C(CC=CCBr)CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O
Solvent: Cc1ccccc1
Product: CCOP(=O)(CC=CCC(CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)C(=O)OC)OCC
Yield: 44.5 %

Procedure:
A solution of 2-(4-bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid methyl ester 4B (140 mg, 0.30 mmol) and triethylphosphite (600 mg, 3.6 mmol) in toluene (30 mL) was stirred at reflux for 20 hours. The mixture was concentrated and chromatographed on silica gel eluting with ethyl acetate (60% to 100%)/hexanes, affording 2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid methyl ester 4C as an oil (70 mg, 43%); 1H NMR (300 MHz, CDCl3)1.27 (m, 6H), 1.79 (s, 3H), 2.0-2.7 (m, 8H), 3.37 (d, J=6.6 Hz), (s, 3H), 3.75 (s, 3H), 4.08 (m, 4H), 5.20 m, 3H), 5.45 (m, 2H) ppm.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH2:14][CH2:13][C:12](=[O:15])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25](Cl)[N:26]=[C:27]=[O:28])=[CH:21][N:20]=1>ClCCl>[Cl:18][C:19]1[N:20]=[CH:21][C:22]([CH:25]2[NH:26][C:27](=[O:28])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:16])([F:17])[F:1])[CH:4]=3)[C:10]3[CH2:14][CH2:13][C:12](=[O:15])[C:11]2=3)=[CH:23][CH:24]=1
Reactant: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CC1
Reactant: O=C=NC(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Product: O=C1CCC2=C1C(c1ccc(Cl)nc1)NC(=O)N2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-(3-(trifluoromethyl)phenylamino)cyclopent-2-enone (900 mg, 3.73 mmol) in dichloromethane (8 mL) is added dropweise to a solution of 2-chloro-5-(chloro(iso-cyanato)methyl)pyridine (intermediate 10, 757 mg, 3.73 mmol) in dichloromethane (7 mL). The mixture is stirred at room temperature for 2 h and concentrated, and the residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 160 mg; ESI mass spectrum [M+H]+=408; Retention time HPLC: 0.98 min (V011_S01).