Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=O.[O:3]=[O+][O-].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:17]1([CH:23]([O:30][C:31]([C@@H:33]2[N:38]3[C:39](=[O:42])[C@@H:40]([NH2:41])[C@H:37]3[S:36][CH2:35][C:34]2=C)=[O:32])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CSC>CO>[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:11][CH:12]=1.[C:24]1([CH:23]([O:30][C:31]([C@@H:33]2[N:38]3[C:39](=[O:42])[C@@H:40]([NH2:41])[C@H:37]3[S:36][CH2:35][C:34]2=[O:3])=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C=C1CS[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=[O+][O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=O
Solvent: CO
Solvent: CSC
Product: N[C@@H]1C(=O)N2[C@@H](C(=O)OC(c3ccccc3)c3ccccc3)C(=O)CS[C@H]12
Temperature: -12 °C
Reaction time: 0.08 h

Procedure:
A stream of oxygen and ozone (containing 0.35 mmol of ozone per minute) is passed for 4 minutes through a solution, cooled to -60° C, of 0.553 g of the 4-methylphenylsulphonate of 7β-amino-3-methylene-cepham-4α-carboxylic acid diphenylmethyl ester in 50 ml of methanol. After a further 5 minutes, 0.3 ml of dimethyl sulphide is added to the solution which is pale blue in colour. The mixture is stirred for 15 minutes at -70° C, for 1 hour at -12° C and for one hour in an ice bath and is then evaporated. The residue is taken up in a small quantity of methylene chloride, diethyl ether is then added until the mixture turns cloudy, and the mixture is left to stand. The micro-crystalline pulverulent precipitate, which is reddish in colour, is filtered off and gives the 4-methylphenylsulphonate of 7β-amino-cepham-3-one-4α-carboxylic acid diphenylmethyl ester, which is principally in the enol form as the 4 -methylphenylsulphonate of 7β-amino-3-cephem-3-ol-4-carboxylic acid diphenylmethyl ester, melting point 143°-145° C (with decomposition); thin layer chromatogram (silica gel) Rf~0.28 (system: ethyl acetate/pyridine/water, 85:10:5); ultraviolet absorption spectrum (in ethanol): λmax = 262 mμ (ε = 3,050) and 282 mμ (ε = 3,020); infrared absorption spectrum (in methylene chloride): characteristic bands at 5.58 μ, 5.77 μ (shoulder), 6.02 μ and 6.22 μ.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[C:5]([N:7]([CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:11][CH:12]=O)[CH3:8])=[O:6].[NH:28]1[CH2:31][CH:30]([N:32]2[CH2:37][CH2:36][CH:35]([C:38]([N:40]3[CH2:43][CH2:42][CH2:41]3)=[O:39])[CH2:34][CH2:33]2)[CH2:29]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[N:40]1([C:38]([CH:35]2[CH2:36][CH2:37][N:32]([CH:30]3[CH2:29][N:28]([CH2:12][CH2:11][C@@H:10]([C:14]4[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=4)[CH2:9][N:7]([CH3:8])[C:5](=[O:6])[C:4]4[CH:21]=[C:22]([C:24]([F:26])([F:27])[F:25])[CH:23]=[C:2]([Br:1])[CH:3]=4)[CH2:31]3)[CH2:33][CH2:34]2)=[O:39])[CH2:41][CH2:42][CH2:43]1
Reactant: O=C(C1CCN(C2CNC2)CC1)N1CCC1
Reactant: CN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CN(C[C@@H](CCN1CC(N2CCC(C(=O)N3CCC3)CC2)C1)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.5 %

Procedure:
3-Bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see method 1; 0.16 g, 0.36 mmol) and 1-azetidin-3-yl-4-(azetidin-1-ylcarbonyl)piperidine (see method 2; 0.10 g, 0.47 mmol) were dissolved in methylene chloride (10 mL) together with a small amount of dry methanol (0.2 mL). To the resultant solution were added DIPEA (0.14 g, 1.08 mmol) and sodium triacetoxyborohydride (0.15 g, 0.72 mmol). The mixture was stirred under nitrogen for 4 h at RT. The mixture was diluted with methylene chloride and washed twice with saturated aqueous NaHCO3 and then with brine. The organic phase was filtered through a phase separator and the solvent was removed by evaporation. The product was purified by chromatography on silica gel (methanol-methylene chloride, 10:1). There was obtained 0.14 g (59%) of the title compound as a white foam. 1H NMR (500 MHz, CDCl3): δ 1.4-1.8 (cm, 6H), 2.1 (m, 1H) 2.2 (qn, 2H), 2.3-2.4 (cm, 2H), 2.5-3.5 (cm, 14H), 3.6 (d, 1H), 3.9 (t, 2H), 4.1 (t, 2H), 6.8-7.4 (cm, 6H), 7.7 (s, 1H); LCMS: m/z 654 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:4][N:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][N:37]([C:40](=[O:42])[CH3:41])[CH2:36][CH2:35]2)=[CH:30][CH:29]=1>CN(C=O)C.CCOC(C)=O>[CH2:12]([CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:27][C:28]1[CH:29]=[CH:30][C:31]([N:34]3[CH2:35][CH2:36][N:37]([C:40](=[O:42])[CH3:41])[CH2:38][CH2:39]3)=[CH:32][CH:33]=1)=[N:3][CH:4]=2)[CH2:14][CH3:15])[CH3:13]
Reactant: CCC(CC)n1cnc2cnc(Cl)nc21
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(CC)n1cnc2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Temperature: 140 °C
Yield: 24.5 %

Procedure:
To a mixture of 2-chloro-9-(1-ethyl-propyl)-9H-purine (90 mg, 0.4 mmol) and TsOH (1.6 mL, 0.2 M in 1,4-dioxane) in DMF (0.25 mL) is added 1-[4-(4-amino-phenyl)-piperazin-1-yl]-ethanone (105 mg, 0.5 mmol). The reaction mixture is sealed in a microwave reactor and heated at 140° C. for 30 min. The mixture is diluted with EtOAc and washed with NaHCO3 aqueous solution and brine. The organics are dried over Na2SO4, filtered and concentrated. The crude product is purified by preparative HPLC to give 40 mg of 1-(4-{4-[9-(1-ethyl-propyl)-9H-purin-2-ylamino]-phenyl}-piperazin-1-yl)-ethanone.
Reaction SMILES: [O:1]=[S:2]1(=[O:34])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:33])[N:14]([N:23]=[CH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:34]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:33])[N:14]([NH:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: COc1ccc(C=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CNn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 260A (0.045 g, 0.095 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.008 mL, 0.19 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.074 mL, 0.148 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water (5.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with methanol/diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.77 (s, 3 H) 3.82 (s, 2 H) 5.98 (s, 1 H) 6.95 (d, J=8.46 Hz, 2 H) 7.10 (t, J=7.54 Hz, 1 H) 7.30 (m, 2 H) 7.45 (d, J=8.46 Hz, 2 H) 7.56 (s, 2 H) 7.70 (t, J=9.38 Hz, 2 H) 8.10 (d, J=7.72 Hz, 1 H) 16.29 (m, 1 H). MS (ESI−) m/z 475 (M−H)−.
Reaction SMILES: [O:1]1[CH2:5][CH2:4]O[CH:2]1[C:6]1[CH:7]=[CH:8][C:9](F)=[C:10]([CH:13]=1)[C:11]#[N:12].[OH2:15].[NH2:16][NH2:17]>C(O)CCC>[O:15]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:13]=[C:10]2[C:9](=[CH:8][CH:7]=1)[NH:17][N:16]=[C:11]2[NH2:12]
Reactant: N#Cc1cc(C2OCCO2)ccc1F
Reactant: NN
Reactant: O
Solvent: CCCCO
Product: Nc1n[nH]c2ccc(C3OCCO3)cc12
Temperature: 110 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
To a solution of 5-(1,3-dioxolan-2-yl)-2-fluorobenzonitrile (567 mg, 3 mmol) in n-butanol (5 mL) was added hydrazine hydrate (1.47 mL, 30 mmol). The solution was heated to 110° C. for 2 h and cooled to room temperature. The solution was stirred overnight and the resulting precipitate was collected to give the title compound as a white solid (220 mg, 36%). 1H NMR (400 MHz, DMSO-d6) δ 11.44 (s, 1H), 7.78 (s, 1H), 7.28-7.26 (m, 1H), 7.21-7.19 (m, 1H), 5.72 (s, 1H), 5.37 (bs), 4.08-4.02 (m, 2H), 3.98-3.92 (m, 2H); MS ESI 206.0 [M+H]+, calcd for [C10H11N3O2+H]+ 206.1.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.C(N(CC)C(C)C)(C)C.[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1B(O)O>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Reactant: OB(O)c1ccc(F)cc1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc(F)cc1F
Yield: 55.5 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.081 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 g; 0.025 mmol), N,N-diisopropylethylamine (0.172 mL; 1.00 mmol) and 2,4-difluorophenylboronic acid (0.079 g; 0.500 mmol) in DME-water (1 mL) for 20 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-10%) in heptane furnished 0.056 g (55%) of the title compound.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])[NH:16][C:15](=[O:24])[N:14]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:13]3=[O:30])[CH:9]=1)=[O:4].[CH3:31][NH:32]C=O.C[O-].[Na+]>CN(C)C=O>[CH3:31][NH:32][C:3]([C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])[NH:16][C:15](=[O:24])[N:14]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:13]3=[O:30])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)cn1
Reactant: CNC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
A solution of 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro -quinazolin-6-yl)-1H-imidazole-4-carboxylic acid methyl ester (800 mg, 1.79 mmol) and N-methylformamide (0.357 ml, 6 mmol) in 5 ml of dimethylformamide is heated to 120° C. and sodium methylate (100 mg, 1.79 mmol) is added under stirring. After two hours at 120° C. another 100 mg of sodium methylate is added and stirring at 120° C. continued for additional two hours. After cooling to room temperature the solution is evaporated in vacuo and the residue chromatographed to give 560 mg (1.25 mmol, 70%) of 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H-imidazole-4-carboxylic acid methylamide, m.p. 292 -295° C., ES-MS: m/z447 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C@@H:11]([CH3:21])[C@H:12]([OH:20])[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:5]=[C:4]([Cl:22])[C:3]=1[NH:23][CH2:24][C:25](OCC)=[O:26].[CH3:30][O:31][CH2:32][CH2:33][NH2:34]>>[Cl:22][C:4]1[CH:5]=[C:6]([CH2:8][CH2:9][NH:10][C@@H:11]([CH3:21])[C@H:12]([OH:20])[C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)[CH:7]=[C:2]([Cl:1])[C:3]=1[NH:23][CH2:24][C:25]([NH:34][CH2:33][CH2:32][O:31][CH3:30])=[O:26]
Reactant: CCOC(=O)CNc1c(Cl)cc(CCN[C@@H](C)[C@H](O)c2ccc(O)cc2)cc1Cl
Reactant: COCCN
Product: COCCNC(=O)CNc1c(Cl)cc(CCN[C@@H](C)[C@H](O)c2ccc(O)cc2)cc1Cl
Temperature: 80 °C
Reaction time: 48 h

Procedure:
Ethyl N-[2,6-dichloro-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenyl]aminoacetate (44.3 mg) was dissolved in 2-methoxyethylamine (886 μl), and the solution was stirred for 48 hours at 80° C. The reaction mixture was concentrated in vacuo, and purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: dichloromethane/methanol=10/1) gave 2-[[2,6-dichloro-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenyl]amino]-N-(2-methoxyethyl)-acetamide (27.7 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:11][CH2:12][CH:13]([Br:15])[CH3:14].O>CN(C)C=O>[Br:15][CH:13]([CH3:14])[CH2:12][CH2:11][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccnc1
Reactant: CC(Br)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Br)CCOc1cccnc1
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-hydroxypyridine (1.00 g, 10.52 mmol) in N,N-dimethylformamide (DMF) (10 mL) was slowly added to a cold (0° C.), stirring slurry of sodium hydride (0.50 g of an 60% dispersion in mineral oil, 12.63 mmol) in DMF (5 mL). After stirring 30 min, 1,3-dibromobutane (2.50 g, 11.57 mmol) was slowly added drop-wise. The resulting mixture was stirred at 0-4° C. for 16 h. Cold water (10 mL) was added, and the mixture was extracted with ether (3×100 mL). The combined ether extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation to give 2.23 g (92.5%) of an oil.
Reaction SMILES: [OH2:1].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([CH:18]=O)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20][C:21]([NH2:32])([CH3:31])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>CS(C)=O>[CH3:31][C:21]([N:32]=[C:10]([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[CH:16][CH:18]=1)=[O:1])([CH3:20])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1
Reactant: O=CC(=O)c1ccccc1OCc1ccccc1
Reactant: O
Reactant: COc1ccc(CC(C)(C)N)cc1
Solvent: CS(C)=O
Product: COc1ccc(CC(C)(C)N=C(OCc2ccccc2)C(=O)c2ccccc2)cc1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
1.16 g of 2-benzyloxyphenylglyoxal hydrate are dissolved in one ml of dimethylsulfoxide, and a solution of 0.78 g of α,α-dimethyl-4-methoxyphenethylamine in 1.5 ml of dimethylsulfoxide is added thereto. The mixture is stirred at 23° C. for one hour, whereby a solution of α-(α,α-dimethyl-4-methoxyphenethylimino)-2-benzyloxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:18]=[CH:17][CH2:16][C:15]2[C:8]=1[CH:9]=[C:10]1[C:14]=2[CH:13]=[N:12][N:11]1[CH2:19][CH:20](O)[CH3:21].C(N(CC)CC)C.[N-:30]=[N+:31]=[N-:32].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:30]([CH:20]([CH3:21])[CH2:19][N:11]1[C:10]2=[CH:9][C:8]3[C:15]([CH2:16][CH:17]=[CH:18][C:7]=3[F:6])=[C:14]2[CH:13]=[N:12]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)Cn1ncc2c1=CC1=C(F)C=CCC=21
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(Cn1ncc2c1=CC1=C(F)C=CCC=21)N=[N+]=[N-]
Yield: 95.7 %

Procedure:
1 ml (12.9 mmol) of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.5 g (6.46 mmol) of (RS)-1-(7-fluoro-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-propan-2-ol and 3.6 ml (25.8 mmol) of triethylamine in 60 ml of dichloromethane and the mixture was stirred at this temperature for a further 1.5 hours. The reaction mixture was subsequently diluted with 100 ml of dichloromethane, washed twice with 50 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 50 ml of dichloromethane. The combined organic phases were washed with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellow oil obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 0.84 g (12.9 mmol) of sodium azide and the reaction mixture was heated to 90° for 5 hours while stirring. After cooling, the solution was poured into 70 ml of semi-saturated sodium chloride solution and extracted twice with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 80 ml of water and once with 80 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate). 1.59 g (96%) of (RS)-1-(2-azido-propyl)-7-fluoro-1,4-dihydro-indeno[2,1-c]pyrazole were obtained as a light yellow oil.
Reaction SMILES: [OH:1][N:2]=[C:3]([C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[C@H:7]([O:15][CH3:16])[O:6]1)[NH2:4].[C:17](O)(=O)[CH2:18][CH3:19].Cl.CN(C)CCCN=C=NCC>COCCOCCOC>[CH3:16][O:15][C@H:7]1[C@@H:8]2[O:9][C:10]([CH3:13])([CH3:14])[O:11][C@@H:12]2[C@@H:5]([C:3]2[N:4]=[C:17]([CH2:18][CH3:19])[O:1][N:2]=2)[O:6]1
Reactant: CO[C@@H]1O[C@H](C(N)=NO)[C@H]2OC(C)(C)O[C@@H]12
Reactant: CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: COCCOCCOC
Product: CCc1nc([C@H]2O[C@@H](OC)[C@@H]3OC(C)(C)O[C@@H]32)no1
Temperature: 60 °C
Yield: 67.9 %

Procedure:
A solution of (3aR,4R,6R,6aR)-N′-hydroxy-6-methoxy-2,2-dimethyl tetrahydrofuro[3,4-d][1,3]dioxole-4-carboximidamide (Preparation 35) (1.1 g, 4.74 mmol), propionic acid (0.39 g, 5.27 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.1 g, 5.74 mmol) in diethylene glycol dimethyl ether (10 ml) was heated under reflux at 60° C. for twelve hours and then heated at 110° C. for a further 3 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between water (50 ml) and a mixture of ether (25 ml) and pentane (25 ml). The organic phase was separated and the aqueous layer was extracted with more ether/pentane mixture (50 ml). The combined organic extracts were dried (anhydrous magnesium sulphate) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of diethyl ether:pentane (1:2 by volume) gradually changing to diethyl ether:pentane (1:1 by volume) to give the title compound (0.87 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].[CH:8]1([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:33])=[C:18]([NH:20][C:21](=[O:32])[C:22]3[CH:27]=[C:26](F)[CH:25]=[CH:24][C:23]=3[N+:29]([O-:31])=[O:30])[CH:19]=2)=[O:13])[CH2:10][CH2:9]1>>[CH:8]1([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:33])=[C:18]([NH:20][C:21](=[O:32])[C:22]3[CH:27]=[C:26]([NH:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5])[CH:25]=[CH:24][C:23]=3[N+:29]([O-:31])=[O:30])[CH:19]=2)=[O:13])[CH2:10][CH2:9]1
Reactant: CC(C)(CN)CO
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(NCC(C)(C)CO)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 13 which is concerned with the preparation of starting materials 3-amino-2,2-dimethylpropan-1-ol was reacted with N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[(3-hydroxy-2,2-dimethylpropyl)amino]-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.68 (m, 2H), 0.88 (s, 6H), 2.29 (s, 3H), 2.83 (m, 1H), 3.06 (d, 2H), 3.20 (s, 2H), 6.78 (m, 2H), 7.19 (s, 1H), 7.28 (d, 1H), 7.57 (d, 1H), 7.89 (s, 1H), 7.98 (d, 1H), 8.38 (d, 1H), 9.89 (s, 1M); Mass Spectrum: M+Na+ 463.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11].CO[C:16]1C(OC)=C[C:19]2[NH:20][C:21](CCCNC)=N[C:18]=2[CH:17]=1>>[CH3:21][NH:20][CH2:19][CH2:18][CH2:17][C:16]1[NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:12])([F:13])[F:1])[C:5]=2[N:11]=1
Reactant: CNCCCc1nc2cc(OC)c(OC)cc2[nH]1
Reactant: Nc1cccc(OC(F)(F)F)c1N
Product: CNCCCc1nc2c(OC(F)(F)F)cccc2[nH]1

Procedure:
Prepared from 3-trifluoromethoxy-benzene-1,2-diamine in analogy to the methods described for [3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[Br:14]Br>C(O)(=O)C.O>[Br:14][C:8]1[CH:7]=[C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1ccc(CCC(=O)O)cc1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(CCC(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a solution of 3-(4-methoxyphenyl)propionic acid (4.0 g, 22.2 mmol) in acetic acid (20 ml) was added bromine (3.9 g, 24.4 mmol) gradually dropwise at 10° C. and the mixture was stirred at room temperature for 30 minutes. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed serially with saturated saline and water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with hexane to provide the title compound (yield 5.0 g, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][O:25][C:12]3([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH2:11]2)=[CH:5][CH:4]=1.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][N:10]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][O:25][C:12]3([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[CH2:11]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)OCC2c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(CN2CC3(CCNCC3)OCC2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
To a solution of tert-butyl 8-[(4-methoxyphenyl)methyl]-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (500 mg, 1.11 mmol) in DCM (1 mL) was added HCl (3 mL of 4 M in dioxane, 11.05 mmol) dropwise. The reaction mixture was stirred overnight at room temperature. The solvent was concentrated in vacuo and the residue was dissolved in the minimum amount of DCM and precipitated with ether. The solvent was decanted and the residue was again washed with ether and dried to give 8-[(4-methoxyphenyl)methyl]-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane (400 mg, 93%). ESI-MS m/z calc. 352.2. found 353.7 (M+1)+; Retention time: 0.99 minutes (3 min run).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=O.[NH2:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[NH:15][N:14]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.CN1C(=O)N(C)CC1>[C:6]([C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=1)[CH2:1][NH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[NH:15][N:14]=1)([OH:8])=[O:7]
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CN1CCN(C)C1=O
Product: O=C(O)c1cccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Reaction time: 1 h

Procedure:
225 mg (1.50 mmol) of 3-formyl-benzoic acid are added to a solution of 261 mg (1.00 mmol) of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 26 ml of methanol, 13 ml of DMEU and 120 mg (2.0 mmol) of acetic acid under a N2 atmosphere. The reaction mixture is stirred for 1 hour, during which time a solid precipitates, and then 440 mg (7.0 mmol) of NaCNBH3 are added. Stirring is carried out for 5 days, the suspension changing to a clear solution. The methanol is evaporated off using a rotary evaporator. The residue is poured into 0.6 liter of water and stirred for 3 hours to complete the reaction. Filtering with suction, washing with water and diethyl ether, stirring in hot ethanol, cooling and filtering yield 3-(3-carboxy-benzylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (3-{[4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl-amino]methyl}-benzoic acid); m.p. 294-296° C.; HPLC: TRet (Grad5-40)=20.1; FAB-MS: (M+H)+ =395.