Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].Br[CH2:14][CH:15](OCC)OCC.O.[CH2:23](O)C>C1(C)C=CC=CC=1.P(=O)(O)(O)O>[S:1]1[C:2]2[C:3]([C:4]([O:6][CH3:23])=[O:5])=[CH:7][CH:8]=[CH:9][C:10]=2[CH:15]=[CH:14]1
Reactant: CCO
Reactant: CCOC(CBr)OCC
Reactant: O=C(O)c1ccccc1S
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cccc2ccsc12
Reaction time: 3.5 h

Procedure:
25.0 g of 2-sulfanylbenzoic acid was suspended in 125 mL of ethanol, to which 14.3 g of sodium hydroxide and 31.7 mL of 2-bromo-1,1-diethoxyethane was successively added and this suspension was stirred for 3.5 hours while heating it under reflux. The reaction mixture was concentrated under reduced pressure, and the resultant residue was dissolved in 250 mL of N,N-dimethylformamide, to which 15.1 mL of iodomethane and 67.2 g of potassium carbonate were added, and then this mixture was stirred for one hour at room temperature. The reaction mixture was added to a mixture of ethyl acetate and water, from which the organic phase was separated. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=2:1] to yield yellow oil. This product was dissolved in 250 mL of toluene, to which 100 mL of a 85% phosphoric acid was added, and this solution was stirred for 4.5 hours while heating it under reflux. The reaction mixture was cooled to room temperature, to which water was added, and filtered through Celite to separate the organic phase therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. Purification by silica gel column chromatography [eluent; hexane:ethyl acetate=10:1] to yield 20.5 g of methyl 1-benzothiophene-7-carboxylate as yellow oil.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[C:6]1(C)C=[CH:10][CH:9]=[CH:8][CH:7]=1.C#CCCCCCC.CN(P(N(C)C)(N(C)C)=[O:25])C>C1COCC1>[CH2:2]([OH:25])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: Cc1ccccc1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: [Li]CCCC
Agent: C#CCCCCCC
Solvent: C1CCOC1
Product: CCCCCCC#CCO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
In a 250-mL flask equipped with a stir bar, I-Pr2NH (7.34 g, 72.5 mmol) and THF (20 mL) were stirred under argon and cooled to 0° C. A 2.5-M solution of n-BuLi in toluene (29.0 mL, 72.5 mmol) was added slowly to the stirring solution. The reaction was stirred for 30 min at 0° C. and then cooled to −78° C. in a dry ice/acetone bath. Then 1-octyne was added slowly via syringe to the reaction and a white precipitate formed. To dissolve the precipitate, HMPA (23.6 g, 132 mmol) was added in one portion. The cloudy solution was stirred under argon at −78° C. for 30 minutes before warming to 0° C. when the precipitate dissolved. A solution of paraformaldehyde (CH2O)n (5.94 g, 198 mmol) in THF (60 mL) was stirred under argon at −78° C. The alkynyllitheate was then added via cannula with positive argon pressure to the (CH2O)n solution. The reaction was then allowed to warm slowly to room temperature. The reaction was quenched with water and extracted with Et2O. The organic layers were combined, washed with water and brine, dried with MgSO4, and concentrated. This produced 24.4 g of orange oil. The product was purified with flash column chromatography on silica gel (10% Et2O in hexane) to give 5.07 g of amber oil (55%):
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[C:11]([OH:13])=O.CN(C(ON1N=[N:29][C:24]2[CH:25]=[CH:26][CH:27]=[N:28][C:23]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:38](N(CC)C(C)C)(C)[CH3:39]>CN(C=O)C>[ClH:1].[N:28]12[CH2:27][CH2:26][CH:25]([CH2:38][CH2:39]1)[C@@H:24]([NH:29][C:11]([C:3]1[S:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]=1[Cl:1])=[O:13])[CH2:23]2
Reactant: O=C(O)c1sc2ccccc2c1Cl
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1sc2ccccc2c1Cl

Procedure:
356.7 mg (1.68 mmol) of 3-chloro-1-benzothiophene-2-carboxylic acid, 334 mg (1.68 mmol) of R-3-aminoquinuclidine dihydrochloride, 765.3 mg (2.01 mmol) of HATU, 780.5 mg (6.04 mmol) of N,N-diisopropylethylamine and 2.0 ml of DMF are reacted according to the general procedure (variant B). The reaction mixture is purified by preparative HPLC. The product is dissolved in 4M HCl in dioxane and then reconcentrated. 265 mg (44.2% of theory) of the title compound are obtained. The analytical data correspond to those of the racemate (example 14).
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]1=2.C(OCC)C.[CH3:20][N:21]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH2:22]1>CCCCCC>[CH3:20][N:21]1[CH2:26][CH2:25][CH2:24][C:23]([C:10]2[S:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=2)([OH:27])[CH2:22]1
Reactant: c1ccc2sccc2c1
Reactant: CN1CCCC(=O)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CN1CCCC(O)(c2cc3ccccc3s2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
26.5 ml of a 2N solution of n-butyllithium in hexane is added dropwise within 30 minutes to a solution of 7.0 g of benzo[b]thiophene in 50 ml of abs. diethyl ether at a reaction temperature of 5° to 10°. The solution is then stirred for a further 1 hour at 0°. There is then added dropwise, in the course of 30 minutes, a solution of 5.9 g of 1-methyl-3-piperidone in 50 ml of abs. diethyl ether, with the reaction temperature being maintained at 0° by external cooling. The reaction solution is stirred for a further 15 hours at room temperature, and is then poured, with stirring, onto 100 g of ice; the aqueous phase is separated, and extracted 3 times with 100 ml of ethyl acetate each time. The combined organic extracts are dried with sodium sulphate, filtered under suction and concentrated by evaporation. The residue is dissolved in 250 ml of 2N hydrochloric acid, and the acid solution is washed with diethyl ether. The aqueous solution is subsequently brought to a pH-value of 12 by the addition of 10 sodium hydroxide solution, and extracted with 500 ml of chloroform. The chloroform solution is dried with sodium sulphate, filtered with suction and concentrated by evaporation to obtain crude 1-methyl-3-(benzo[b]thien-2-yl)-3-piperidinol; the oxalate thereof is prepared, for example, from 1.8 g of free base in ethyl actate and 0.7 g of oxalic acid in 10 ml of ethyl acetate, and it melts at 165°-168° after recrystallisation from ethyl acetate.
Reaction SMILES: [N+]([O-])(O)=O.[CH:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[C:6]1=[O:15])[CH2:12]2.[OH-:16].[Na+]>OS(O)(=O)=O>[OH:16][C:11]12[CH2:13][CH:7]3[CH2:8][CH:9]([CH2:14][CH:5]([C:6]3=[O:15])[CH2:12]1)[CH2:10]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: O=C1C2CC3CC1CC(O)(C3)C2
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a mixture of H2SO4 (96%; 150 ml) and HNO3 (70%; 15 ml), cooled to 0° C. is added tricyclo[3.3.1.13,7 ]decan-2-one (10 g; 0.067 mole) and the mixture stirred at room temperature for 5 hrs. The reaction mixture is then poured over ice, basified to pH 8 using 50% NaOH, extracted into ether, dried over MgSO4 and evaporated to dryness. The resultant product is recrystallized from carbon tetrachloride to obtain 5-hydroxytricyclo[3.3.1.13,7 ]decan-2-one [(m.p. 314° C. (dec.)] which is used directly in step B.
Reaction SMILES: [I-].BrC1C=CC=C[N+]=1C.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:18]1([CH2:24][C:25](O)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CCCC)CCCC)CCC>C(Cl)Cl>[C:18]1([CH2:24][C:25]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: OCc1ccccc1
Agent: C[n+]1ccccc1Br
Agent: [I-]
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: O=C(Cc1ccccc1)OCc1ccccc1
Yield: 97 %

Procedure:
To a suspended CH2Cl2 (2 ml) solution of 2-bromo-1-methylpyridinium iodide (720 mg, 2.4 mmol) was added a mixture of benzyl alcohol (216 mg, 2.0 mmol), phenylacetic acid (272 mg, 2.0 mmol) and tri-n-butylamine (888 mg, 4.8 mmol) in CH2Cl2 (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and benzyl phenylacetate was isolated in 97% yield.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:7][C:6]1[CH:8]=[CH:9][C:10]([O:12][CH:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCCCCCCC(Br)C(=O)OCC
Reactant: CC(C)(C)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCC(Oc1ccc(O)c(C(C)(C)C)c1)C(=O)OCC
Yield: 37.5 %

Procedure:
116 g of tert-butylhydroquinone, 234 g of ethyl α-bromotetradecanoate and 170 g of potassium carbonate were mixed in 1.6 liters of acetone and reacted for 48 hours under refluxing and stirring. After the reaction, the acetone was distilled off and the residue was dissolved in one liter of ethyl acetate. The organic solvent layer was washed with water, dried with sodium sulfate and concentrated. The residue was recrystallized from 250 ml of n-hexane to obtain 110 g of a white solid. The melting point was 45° to 48° C.
Reaction SMILES: BrC1C=C(C=CC=1)[CH2:5][N:6]([C@@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:7]([C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[C:21]([OH:23])=[O:22])=[O:8].[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][CH:47]=1>>[C@@H:24]1([N:6]([CH2:5][C:44]2[CH:45]=[CH:46][CH:47]=[C:42]([C:38]3[S:37][CH:41]=[CH:40][CH:39]=3)[CH:43]=2)[C:7]([C:9]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=2[C:21]([OH:23])=[O:22])=[O:8])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Br)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Reactant: OB(O)c1cccc(-c2cccs2)c1
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(-c3cccs3)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O

Procedure:
The product from Example 15B (165 mg, 0.3 mmol) and 3-(2-thienyl)phenylboronic acid were processed as described in Example 85 to provide the title compound.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][C:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])[CH2:22][C:23](O)=[O:24]>>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:23](=[O:24])[CH2:22][C:21]([CH3:20])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[N:11]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(CC(=O)O)c1ccccc1
Reactant: Nn1nc(-c2ccc(Br)cc2)c2ccccc2c1=O
Product: CC(C)(CC(=O)Nn1nc(-c2ccc(Br)cc2)c2ccccc2c1=O)c1ccccc1

Procedure:
The products from Example 2A and 3-methyl-3-phenylbutanoic acid were treated using a method similar to that described in Example 51 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.38 (s, 1H), 8.39-8.42 (m, 1H), 7.88-8.04 (m, 2H), 7.76-7.81 (m, 2H), 7.70-7.77 (m, 1H), 7.53-7.58 (m, 2H), 7.42-7.46 (m, 2H), 7.25-7.36 (m, 2H), 7.15-7.21 (m, 1H), 2.62 (s, 2H), 1.47 (s, 6H); MS (ESI−) M/Z 474 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]3[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:21]4[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=4[N:19]=3)[CH2:13][CH2:12]2)[C:3]=1[NH2:35].S1C=CC=C1.C([O-])(=O)C.[K+].[H][H]>C(O)C.[Pd].CO>[F:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:22]2[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=[C:18]2[NH:17][CH:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][NH:8][C:4]3[C:3]([NH2:35])=[CH:2][N:7]=[CH:6][N:5]=3)[CH2:12][CH2:13]2)=[CH:29][CH:28]=1
Reactant: Nc1c(Cl)ncnc1NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: CCO
Solvent: c1ccsc1
Product: Nc1cncnc1NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Yield: 72.4 %

Procedure:
A mixture of 1.5 parts of 6-chloro-N4 -[2-[4-[[1[(4-fluorophenyl)methyl]-1H-benzimidazol-2yl]amino]-1piperidinyl]ethyl]4,5-pyrimidinediamine, 3 parts of a solution of thiophene in ethanol 4%, 1 part of potassium acetate and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 1 part of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The solid residue was taken up in water. The solution was treated with ammonia. The product was extracted with trichloromethane. The organic layer was separated, dried, filtered and evaporated. The residue was crystallized from a mixture of 4-methyl-2-pentanone, yielding 1 part (72.4%) of N4 -[2-[4-[[1[(4fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-4,5-pyrimidinediamine; mp. 207.7° C. (intermediate 165).
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[F:12][C:13]([F:36])([F:35])[C:14]([NH:16][C:17]1[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[C:24]([Cl:33])[C:23]=2[Cl:34])[N:20]=[CH:19][CH:18]=1)=[O:15]>C(O)(=O)C>[N+:8]([C:18]1[CH:19]=[N:20][N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[C:24]([Cl:33])[C:23]=2[Cl:34])[C:17]=1[NH:16][C:14](=[O:15])[C:13]([F:36])([F:35])[F:12])([O-:11])=[O:9]
Reactant: O=C(Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl)C(F)(F)F
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl)C(F)(F)F
Reaction time: 20 h
Yield: 77.6 %

Procedure:
2.4 ml (0.0258 mol) of acetic anhydride and 1.1 ml (0.025 mol) of 98% strength nitric acid are added in succession to 10 g (0.0235 mol) of 5-trifluoroacetamido-1-(2,3,6-trichloro-4-trifluoromethylphenyl)-pyrazole in 20 ml of glacial acetic acid at room temperature. After the mixture has been stirred for 20 hours, it is concentrated in vacuo, the residue is taken up in 100 ml of methylene chloride and the mixture is extracted with 400 ml of 5% strength aqueous sodium carbonate solution. The aqueous phase is acidified and extracted with 200 ml of methylene chloride. The combined organic phases are dried over magnesium sulphate and freed from the solvent in vacuo. 8.6 g (77.6% of theory) of 4-nitro-5-trifluoroacetamido-1-(2,3,6-trichloro-4-trifluoromethylphenyl)-pyrazole of melting point 136° C.-137° C. are obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[SH:37][C:38]1[N:42](C)[N:41]=[N:40][N:39]=1.[CH2:44](N(CC)CC)C.Cl>O1CCCC1.[Cl-].[Na+].O.C(OCC)(=O)C.O>[CH3:44][CH:2]([S:37][C:38]1[NH:42][N:41]=[N:40][N:39]=1)[C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: Cn1nnnc1S
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CBr)CS[C@H]12
Reactant: CCN(CC)CC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 0.75 h

Procedure:
A solution of diphenylmethyl 3-bromomethyl-7β-(2-thienylacetamido)-ceph-3-em-4-carboxylate (17.505 g.) and 5-mercapto-1-methyltetrazole (3.486 g.) in dry tetrahydrofuran (250 ml) was stirred at 10° and treated, over 5 minutes, with a solution of triethylamine (4.16 ml) in dry tetrahydrofuran (50 ml). The resulting suspension was stirred for a further 45 minutes (during which time the temperature was allowed to rise to ca. 20°) and then added, over 5 minutes, to a stirred mixture of 2N-hydrochloric acid (50 ml), water (700 ml), brine (700 ml.), and ethyl acetate (1.5 l.). The organic phase was separated, washed with 2N-hydrochloric acid, water and brine, treated with some charcoal and filtered through a pad of kieselguhr. The filtrate was dried and evaporated to a foam (20.6 g.). This foam was dissolved in hot methanol (200 ml.), and the solution cooled to give the ester as colourless plates (14.391 g., 77.5%), λmax. (EtOH) 264 nm. (ε 8,700), νmax. (CHBr3) 3420 (NH), 1780 (β-lactam), 1710 (CO2R), and 1680 and 1502 cm.-1 (CONH), τ (CDCl3) values include 3.40 (NH, doublet, J 9 Hz.), (C-7 H, double doublet, J 5 and 9 Hz.), 5.02 (C-6 H, doublet, J 5 Hz.), 6.19 (CH3).
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]([CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:8]2)[CH2:3][NH:2]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([C:27]2[CH:28]=[N:29][C:30]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[CH:32][C:31]=3I)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([C:27]2[CH:28]=[N:29][C:30]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[CH:32][C:31]=3[N:2]2[CH2:1][CH:9]3[CH:4]([CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:8]3)[CH2:3]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=S(=O)(c1ccc(F)cc1)c1cnc2c(I)cccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC2CNCC2C1
Product: CC(C)(C)OC(=O)N1CCC2CN(c3cccc4cc(S(=O)(=O)c5ccc(F)cc5)cnc34)CC2C1
Yield: 55 %

Procedure:
The title compound was prepared by analogy to the procedure of Example 1.3, except using tert-butyl hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate and 3-(4-fluorophenylsulfonyl)-8-iodoquinoline. 130 mg (55%) of the title compound were obtained as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CN(C(ON1N=[N:39][C:34]2[CH:35]=[CH:36][CH:37]=N[C:33]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CC1(N)CCC1>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:39][C:34]5([CH3:33])[CH2:37][CH2:36][CH2:35]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CC1(N)CCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CCC4)c3n2)c2ccc(F)cc21
Reaction time: 16 h
Yield: 13.9 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (59 mg, 0.19 mmol), HATU (91.20 mmol, 0.24 mmol) and DIPEA (49 mg, 0.38 mmol) in 6 mL of DMF, 1-methylcyclobutanamine (21.00 mg, 0.25 mmol) was added in one portion at room temperature and the reaction mixture was stirred for 16 hours. The solvent was evaporated at 80° C. under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 48% acetonitrile/52% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 70% acetonitrile/30% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(1-methylcyclobutyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (10 mg, 13.7%) as an off-white solid. MS: (M+H)+=379; 1H NMR (300 MHz, DMSO): δ 12.82 (s, 1H), 9.10 (s, 1H), 8.47-8.38 (m, 2H), 8.24 (s, 1H), 7.70 (d, 1H, J=8.7 Hz), 7.17 (t, 1H, J=9.2 Hz), 4.15 (s, 3H), 2.54-2.45 (m, 2H), 2.15-2.13 (m, 2H), 1.96-1.88 (m, 2H), 1.62 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:16][CH2:17][CH2:18][S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[I-].[Na+].C(OCC)C>C(C(C)=O)C>[ClH:16].[NH:1]=[C:2]1[N:6]([CH2:17][CH2:18][S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]2[CH:7]=[CH:8][C:9]([O:11][C:12]([F:15])([F:13])[F:14])=[CH:10][C:4]=2[S:3]1
Reactant: ClCCSc1ccccc1
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCC(C)=O
Product: Cl
Product: N=c1sc2cc(OC(F)(F)F)ccc2n1CCSc1ccccc1
Temperature: 20 °C
Yield: 33.1 %

Procedure:
The procedure is as in Example 21, starting with 2-amino-6-trifluoromethoxybenzothiazole (9.4 g), 1-chloro-2phenylthioethane (13.8 g) and sodium iodide (13.5 g) in methyl ethyl ketone (30 cc). The mixture is heated for 88 hours to boiling and then cooled to a temperature in the region of 20° C. Ethyl ether (250 cc) is added to the reaction medium and the precipitate formed is filtered off. The solid is suspended in distilled water (250 cc), treated with 1N sodium hydroxide (40 cc) and then extracted with ethyl ether (100 cc). After drying over magnesium sulphate and filtration, ethyl acetate (150 cc) is added to the filtrate, which is treated with 4N ethereal hydrogen chloride (10 cc). The precipitate formed is filtered off and recrystallized in 2-propanol (85 cc). 2-Imino-3-(2-phenylthioethyl)-6- trifluoromethoxybenzothiazoline hydrochloride (5.4 g), m.p. 174° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][O:7][CH:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1.[CH2:18]=O.Cl.[CH3:21][NH:22][CH3:23]>C(O)(=O)C>[CH3:21][N:22]([CH2:18][CH:10]1[CH2:9][CH:8]([O:7][CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:13][CH2:12][C:11]1=[O:14])[CH3:23]
Reactant: COc1cccc(COC2CCC(=O)CC2)c1
Reactant: C=O
Reactant: CNC
Agent: Cl
Solvent: CC(=O)O
Product: COc1cccc(COC2CCC(=O)C(CN(C)C)C2)c1
Temperature: 105 °C
Reaction time: 0.25 h

Procedure:
11.8 g (50 mmole) of compound (8), 0.84 g (28 mmole) paraformaldehyde and 2.26 g (28 mmole) dimethylamine hydrochloride were dissolved in 20 ml acetic acid and stirred for 15 minutes in a bath at 105° C. After evaporating off the solvent, the mixture was adjusted to an alkaline pH with aqueous sodium hydroxide solution and the Mannich base was extracted with dichloromethane. The solution was dried and the solvent was distilled off. 12.1 g (80% theoretical) of compound (9) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8](O)=[O:9].O=S(Cl)Cl.[BH4-].[Na+]>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH2:8][OH:9])[CH:11]=1
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1ccc([N+](=O)[O-])c(CO)c1
Temperature: 30 °C
Reaction time: 3 h
Yield: 64.2 %

Procedure:
To a solution of 5-methoxy-2-nitrobenzoic acid (20.0 g, 0.102 mol) in anhydrous THF (200 mL) was added SOCl2 (20 mL), the mixture was refluxed for 4 hours. The solvent was removed under reduced pressure and the residue was dissolved in anhydrous THF (100 mL). The solution was added dropwise to a suspension of NaBH4 (7.70 g, 0.202 mol) in anhydrous THF (100 mL) and DMF (140 mL) at 0° C. over a period of 30 minutes. The mixture was stirred at 30° C. for 3 hours, then quenched with ice-water (100 mL) and basified by 2M NaOH to pH 8. An EtOAc workup was followed by removal of solvent in vacuo and purification by column chromatography (PE/EtOAc=1/1) to give the product (12.0 g, yield 66%).