Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]([C:23](=[O:35])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH2:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:22][NH:21][C:23](=[O:35])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCC(=O)NN
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.3 %

Procedure:
To a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (12.0 g, 43.5 mmol) and tert-butyl 4-hydrazinyl-4-oxobutylcarbamate (10.5 g, 47.8 mmol) in CH2Cl2 (360 mL) was added HATU (19.6 g, 52.2 mmol) and DIPEA (16.6 g, 130.5 mmol). The mixture was allowed to warm to rt, was stirred at rt for 12 hrs then diluted with CH2Cl2 (300 mL), washed with water (2×) and saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (gradient elution 50-80% EtOAc/petroleum ether) to afford tert-butyl 4-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-4-oxobutylcarbamate (19.3 g, 93%) as a white solid. ESI-MS (EI+, m/z): 476 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[F:15])[CH:10]=[O:11].[N+:16]([O-])([OH:18])=[O:17]>>[F:6][C:7]1[CH:8]=[C:9]([C:12]([N+:16]([O-:18])=[O:17])=[CH:13][C:14]=1[F:15])[CH:10]=[O:11]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccc(F)c(F)c1
Agent: O=S(=O)(O)O
Product: O=Cc1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To 520 cm3 of sulphuric acid, stirred and cooled to 0° C., 60 cm3 of fuming nitric acid are added in the course of 30 minutes. 100 g of 3,4-difluorobenzaldehyde are added in the course of 30 minutes at approximately 0° C. to the solution obtained. The temperature is allowed to rise to approximately 20° C. and the mixture is stirred for a further 3 hours at this temperature. After cooling to approximately 5° C., the reaction mixture is introduced in the course of 30 minutes with vigorous stirring into 1,200 g of crushed ice. The temperature is allowed to rise to approximately 20° C. and the mixture is extracted with twice 600 cm3 of toluene. The combined organic extracts are washed with 3 times 1,000 cm3 of water and concentrated under reduced pressure (20 kPa) to 50° C. 113 g of 3,4 -difluoro-6-nitrobenzaldehyde are obtained in the form of a brown oil, which is used in the subsequent synthesis without further treatment.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.Cl.[CH:15]1[C:27]2[CH:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH:24]1[C:25]2[CH:26]([N:28]3[CH2:33][CH2:32][N:31]([C:10]([C:6]4[CH:5]=[C:4]5[C:9](=[CH:8][CH:7]=4)[NH:1][CH:2]=[CH:3]5)=[O:12])[CH2:30][CH2:29]3)[C:27]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]=2[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: c1ccc2c(c1)-c1ccccc1C2N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc2[nH]ccc2c1)N1CCN(C2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Indole-5-carboxylic acid (17 mg, 0.11 mmole) and N-9-fluorenyl-piperazine dihydrochloride (32 mg, 0.1 mmole) were dissolved in 5 ml dichloromethane. To this solution was added triethylamine (2 eq. to neutralize HCl salt), catalytic DMAP and EDCI (33 mg, 0.11 mmole). The resulting mixture was stirred at room temperature overnight and was then worked up by washing sequentially with 1N HCl, saturated sodium bicarbonate, and saturated sodium chloride. The product was then purified by flash chromatography on silica gel (40:1 CHCl3/MeOH). 1H NMR (300 Mhz, CDCl3) δ 8.38 (s, 1H), 7.72-7.60 (m, 5H), 7.40-7.18 (m, 7H), 6.55 (d, 1H), 4.88 (s,1H), 3.60 (bs, 4H), 2.62 (bs, 4H).
Reaction SMILES: C([O:8][C:9]1[C:10]([C:20]([O:22][CH3:23])=[O:21])=[N:11][C:12]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:13][CH:14]=1)C1C=CC=CC=1.COCCOC>CO.[C].[Pd]>[OH:8][C:9]1[C:10]([C:20]([O:22][CH3:23])=[O:21])=[N:11][C:12]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:13][CH:14]=1
Reactant: COC(=O)c1nc(N2CCCC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: COCCOC
Product: COC(=O)c1nc(N2CCCC2)ccc1O
Yield: 100 %

Procedure:
6.10 g (19.5 mmol) of methyl 3-benzyloxy-6-(1-pyrrolidinyl)picolinate was catalytically reduced in 50 ml of methanol and 100 ml of 1,2-dimethoxyethane in the presence of 1.5 g of 10% palladium carbon. The catalyst was filtered off, and the solvent was distilled off, and the residue was crystallized from diisopropyl ether-n-hexane to obtain the desired product.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][C:14]=1[N+:25]([O-:27])=[O:26]>CS(C)=O>[CH3:6][O:5][C:3](=[O:4])[CH:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][C:14]=1[N+:25]([O-:27])=[O:26])[C:1]([O:8][CH3:9])=[O:7]
Reactant: O=[N+]([O-])c1cc(-c2ccccc2)ccc1F
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
Dimethyl malonate (10 mL) in 25 mL of dimethylsulfoxide was added dropwise to 3.5 g sodium hydride suspended in 25 mL dimethylsulfoxide and the mixture heated at 100° C. for 10 minutes. The mixture was cooled to room temperature and 4.7 g of 4-fluoro-3-nitrobiphenyl in 25 mL dimethylsulfoxide was added. The mixture was heated at 100° C. for 2 hours, cooled and quenched with 300 mL of saturated ammonium chloride solution. The mixture was extracted three times with ethyl acetate and the combined organic layers washed with water and brine and evaporated to give, as a yellow oil, crude dimethyl-3-nitrobiphenyl-4-malonate.
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].C([Li])CCC.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[N:19]2[CH2:22][CH:21]([C:23]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=3)=[O:24])[CH2:20]2)=[CH:14][CH:13]=1.[NH4+].[Cl-]>C1COCC1.CCOCC>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)[N:19]2[CH2:22][CH:21]([C:23]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=3)([OH:24])[C:2]([CH3:4])([CH3:3])[C:1]#[N:5])[CH2:20]2)=[CH:14][CH:13]=1
Reactant: O=C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: CC(C)C#N
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C#N)C(O)(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reaction time: 0.83 h

Procedure:
To a solution of 84 uL (0.928 mmol) of isobutyronitrile in 2 mL of THF was added a solution of 370 uL (0.928 mmol) of butyllithium (2.5M solution in hexanes), followed by stirring for 50 minutes at −55° C. to −40° C. Then a solution of 334 mg (0.773 mmol) of {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)methanone (as in Preparation 6) in THF was added at −78° C. and the solution was stirred for 5 h at −60° C. to −50° C. A solution of 2 mL of saturated NH4Cl was added to quench the reaction and the reaction mixture was poured into 30 mL of ether and washed with 5 mL of aq NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate=4:1 to afford the title compound. 1NMR(CDCl3) δ 1.24 (s, 3H), 1.34 (S, 3H), 2.58 (br, 1H), 3.12 (br, 1H), 3.40 (br, 2H), 3.60 (br, 1H), 4.26 (m, 1h) 4.43 (s, 1H), 6.76 (m, 1H), 7.06 (m, 2H), 7.25-7.34 (m, 8H); Mass Spectrum: m/e=501 (M+1 35Cl, 38Cl) and 503 (M+1 35Cl, 37Cl).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[O:9]=[C:10]1[N:15]([NH2:16])[CH2:14][C:13]([CH3:17])=[N:12][NH:11]1>Cl.C(O)C>[O:9]=[C:10]1[N:15]([N:16]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:14][C:13]([CH3:17])=[N:12][NH:11]1
Reactant: O=Cc1cccnc1
Reactant: CC1=NNC(=O)N(N)C1
Agent: Cl
Solvent: CCO
Product: CC1=NNC(=O)N(N=Cc2cccnc2)C1

Procedure:
26.8 g (0.25 mole) of pyridine-3-carbaldehyde and 1 drop of concentrated HCl are added at 60° C. to 32 g (0.25 mole) of 2,3,4,5-tetrahydro-3-oxo-4-amino-6-methyl-1,2,4-triazine dissolved in 250 ml of ethanol. After boiling for half an hour under reflux, the reaction mixture is cooled and the solid portion is isolated by filtration, washed with ether and dried to give the title compound of formula ##STR22## in the form of a colourless solid; m.p. 227°-228° C.; yield: 48 g (90%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[O:6][C:5]12[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1.Cl.O1CCOCC1>>[CH3:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[O:6][C:5]12[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: Cc1cc2n(c1)-c1ccccc1OC21CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc2n(c1)-c1ccccc1OC21CCNCC1
Reaction time: 1 h

Procedure:
To tert-butyl 2′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (second eluting fraction from step 2) (0.40 g, 1.1 mmol) was added hydrogen chloride in 1,4-dioxane (2.8 mL of 4.0 M, 11 mmol) and the mixture stirred 1 h, then filtered and rinsed with 1:1 ether/isopropanol to give 2′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] as a pink solid. ESI-MS m/z calc. 254.3, found 255.3 (M+1)+; Retention time: 1.16 minutes (3 min run).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=[CH:11][C:10](Br)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=[CH:11][C:10]([C:35]1[CH:36]=[C:31]([Cl:30])[C:32]([OH:47])=[C:33]([Cl:46])[CH:34]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-(3-acetyl-6-bromoquinolin-4-ylamino)cyclohexylcarbamate (40 mg, 0.087 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (50 mg, 0.195 mmol) to afford the crude product (46 mg) as a yellow solid: ESI MS m/z 544 [C28H31Cl2N3O4+H]+.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCOC(C)=O>[CH2:16]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:13](=[O:15])[CH3:14])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
A mixture of 1-(4-piperazin-1-yl-phenyl)-ethanone (500 mg, 2.45 mmol), benzaldehyde (312 mg, 2.94 mmol) and NaBH(OAc)3 (778 mg, 3.67 mmol) in AcOEt (15 ml) was stirred at room temperature overnight. The resulting solution was partitioned between water and DCM and the organic phase was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by silica gel chromatography (eluent: DCM/MeOH/NH4OH 95:5:0.2) to give 390 mg of 1-[4-(4-benzyl-piperazin-1-yl)-phenyl]-ethanone.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]=[N:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:31])[CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH:32]O.O>C(O)(=O)C>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]=[N+:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23](=[O:31])[CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:21]=2)[O-:32])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OO
Reactant: CCCCCCOc1ccc(N=Nc2ccc(OC(=O)CCOCCCC)cc2)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCOc1ccc(N=[N+]([O-])c2ccc(OC(=O)CCOCCCC)cc2)cc1
Reaction time: 30 h

Procedure:
0.81 g of the 4'-hexyloxy-4-α-butoxypropanoyloxyazobenzene was dissolved in 40 ml of glacial acetic acid and the mixture was stirred under heating at 50°-60° C. About 5 ml of 31% H2O2 aqueous solution was added dropwise to the mixture in about 6 hours. The mixture was further left standing for 4 hours at 50°-60° C., for 30 hours at room temperature, charged into 400 ml of deionized water and extracted with ether. The extract was washed with 50 ml of 5% Na2CO3 aqueous solution and deionized water, and then dried with anhydrous Na2SO4. After distilling off ether; the resultant yellow crystal was recrystallized in ethanol to obtain 0.3 g of 4'-hexyloxy-4-α-butoxypropanoyloxyazoxybenzene showing the following properties:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1.C([Li])CCC.[Br:24][C:25]1[CH:30]=[C:29]([O:31][CH2:32][O:33][CH3:34])[CH:28]=[CH:27][C:26]=1[CH2:35][C:36](=[O:38])[CH3:37].[Cl-].[NH4+]>CCOCC>[Br:24][C:25]1[CH:30]=[C:29]([O:31][CH2:32][O:33][CH3:34])[CH:28]=[CH:27][C:26]=1[CH2:35][C:36]([C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1)([OH:38])[CH3:37]
Reactant: CC(C)[Si](Oc1ccc(Br)nc1)(C(C)C)C(C)C
Reactant: COCOc1ccc(CC(C)=O)c(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: COCOc1ccc(CC(C)(O)c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cn2)c(Br)c1
Reaction time: 0.17 h
Yield: 45.4 %

Procedure:
To a solution of 2-bromo-5-(triisopropylsilyloxy)pyridine (26.6 g) in ether (80 mL) at −78° C. was added n-butyllithium (2.5 M in hexane, 32.2 mL) dropwise. After being stirred at the same temperature for 10 min, a solution of 1-(2-bromo-4-(methoxymethoxy)phenyl)propan-2-one (11 g) in diethylether (40 mL) was added dropwise. The mixture was stirred at −78° C. for 5 hr, and poured into iced saturated ammonium chloride and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to afford the title compound (9.6 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: CCc1cc2c(NCc3ccc(OC)c(OC)c3)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc(OC)c(OC)c3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-ethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-ethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([O:17][CH2:18][C:19]([CH2:24]Cl)([CH3:23])[CH2:20][C:21]#[N:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)C>[CH2:1]([C:21]1[CH2:20][C:19]([CH2:18][O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH3:24])[CH2:23][N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CC(CCl)(CC#N)COCc1ccccc1
Solvent: CCOCC
Product: CC1(COCc2ccccc2)CN=C(Cc2ccccc2)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A benzylmagnesium chloride solution in ether (224 ml, 1 M, 0.224 mol) is heated to 30° C. and a solution of 4-benzyloxy-3-chloromethyl-3-methylbutyronitrile (75%, 40 g, 0.126 mol) in diethyl ether (140 ml) is slowly added dropwise (30 min.). The suspension formed is kept at reflux by warming after complete addition. After 2 h, the ether (310 ml) is distilled off (45 min.) and then replaced by toluene abs. (210 ml). The yellow toluene suspension is heated to 100° C. and then stirred at this temperature for 2 h. The batch, which is cooled to room temperature, is treated with dil. HCl (10% strength, 100 ml) and stirred until, in addition to the aqueous and the toluene phase, a third, oily phase separates. The oil phase and water phase are separated off, and the toluene phase is extracted 2 times in a separating funnel with dil. HCl (100 ml). The oil phase combined with the HCl phases is washed with toluene (50 ml) and then adjusted to pH 8-9 with NaOH (32%). After stirring for 30 min., the separated oily base fraction is taken up with diethyl ether, and the alkaline water phase is extracted a further 3 times with ether (450 ml). The collected ether extracts are dried over Na2SO4 sicc. and concentrated. A red-brown oily residue of 39.64 g (96% of theory, 78% according to gc) remains.
Reaction SMILES: [N:1]1([C:8]2[C:9]([C:22]3[CH:32]=[CH:31][C:25]4[O:26][C:27]([F:30])([F:29])[O:28][C:24]=4[CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[N:1]1([C:8]2[C:9]([C:22]3[CH:32]=[CH:31][C:25]4[O:26][C:27]([F:30])([F:29])[O:28][C:24]=4[CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4c(c3)OC(F)(F)O4)c(N3CCCCCC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccc4c(c3)OC(F)(F)O4)c(N3CCCCCC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
To a solution of methyl 3-(azepan-1-yl)-2-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)quinoxaline-6-carboxylate (110 mg, 0.25 mmol) in methanol (30 mL) and water (1 mL) was added sodium hydroxide (40 mg, 1.00 mmol) with stirring overnight at room temperature. The resulting mixture was concentrated in vacuo and dissolved in water (10 mL), adjusted to 6 with HCl (3 N) and collected by filtration to give 3-(azepan-1-yl)-2-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)quinoxaline-6-carboxylic acid as a yellow solid (70 mg, 66%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:6]=2[C:5](=[O:21])[NH:4][C:3]1=[O:22].[OH2:23].[OH-].[Na+]>CO>[O:23]=[C:12]([CH3:11])[CH2:13][CH2:14][CH2:15][CH2:16][N:4]1[C:5](=[O:21])[C:6]2[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:22]
Reactant: O
Reactant: CCCCCCCCCCn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCn1cnc2c1c(=O)n(CCCCC(C)=O)c(=O)n2C
Yield: 85 %

Procedure:
80.3 g of 3-methyl-7-n-decyl-xanthine, 140 g of water, 90 g of methanol, 10 g of sodium hydroxide and 44.6 g of 1-bromohexanone-(5) are boiled under reflux for 4 hours. After acidification with 2 ml of concentrated sulphuric acid, the reaction mixture is filtered hot to remove the unreacted 3-methyl-7-n-decyl-xanthine and the filtrate is worked up as in Example 1. 66.1 g of a crude crystalline product are obtained and are recrystallised from 500 ml of diisopropyl ether. The 1-(5-oxohexyl)-3-methyl-7-(n-decyl)-xanthine which is obtained in 85% yield melts at 64°-66° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.[H-].[Na+].Cl.[CH:18](OCC)=[O:19]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[CH:18][OH:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC=O
Reactant: CCOC(=O)Cc1ccc(OC)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(=CO)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
8.9 ml of ethyl p-methoxyphenylacetate are dissolved in 80 ml of ethyl formate. 4.6 g of 50% NaH are added portionwise and then the mixture is stirred at ambient temperature for 12 hours. It is poured onto a 1N HCl solution and then extraction is carried out with AcOEt. Purification is carried out by chromatography on a silica column eluted with an AcOEt/heptane (05/95; v/v) mixture to produce 4.0 g of the expected compound in the liquid form.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:13]2=[CH:12][C:11]=1[C:19]([OH:21])=O.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([O:35][NH2:36])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:30][CH2:31][CH:32]([O:35][NH:36][C:19]([C:11]2[CH:12]=[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][N:14]3[C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[O:21])[CH2:33][CH2:34]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C(O)c1cc2ccncn2c1Nc1ccc(I)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(ON)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(ONC(=O)c2cc3ccncn3c2Nc2ccc(I)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
7-(2-Fluoro-4-iodo-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid (190 mg, 0.48 mmol), 4-aminooxy-piperidine-1-carboxylic acid tert-butyl ester (154 mg, 0.72 mmol), HOBt (106 mg, 0.79 mmol), EDCI hydrochloride (150 mg, 0.79 mmol) and DIPEA (120 μL, 0.72 mmol) were suspended in DMF (5 mL). The reaction was stirred at RT for 1 hour, during which time the reagents dissolved. The reaction mixture was concentrated in vacuo, the resultant residue dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-100% ethylacetate in cyclohexane) to yield the title compound as a brown solid (180 mg, 65%). LCMS (Method B): RT=3.69 min, M+H+−tBu=540 (100%), M+H+−Boc=496 (95%).