Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Br:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[NH:25][CH2:24][CH2:23]2>>[Br:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[N:25]([C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]3[CH2:14][CH2:13]3)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1)[CH2:24][CH2:23]2
Reactant: COc1cc(Br)c2c(c1)CCN2
Reactant: CC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Agent: Cl
Product: CC[C@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 138-140° C.; 1H NMR (300 MHz, CDCl3): δ 6.94 (s, 1 H), 6.89 (d, J=2.2 Hz, 1H), 6.75 (d, J=2.5 Hz, 1 H), 4.34-4.24 (m, 2 H), 4.10-4.01 (m, 1 H), 3.76 (s, 3 H), 3.09 (t, J=7.9 Hz, 2 H), 1.91-1.74 (m, 2 H), 1.06-0.98 (m, 1 H), 0.95-0.86 (m, 3 H), 0.79-0.72 (m, 1 H), 0.53-0.44 (m, 2 H), 0.35-0.24 (m, 1 H); HRMS (CI) calcd for C19H22N3O2BrCl (M+H)+: 438.0584; found m/z 438.0570.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.[C:12]([O:16][C:17](=O)[O-:18])([CH3:15])([CH3:14])[CH3:13].CO>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:5]2
Reactant: CC(C)(C)OC(=O)[O-]
Reactant: O=C1NCc2cc(Br)ccc21
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2cc(Br)ccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 1.5 mg of 5-bromo-1-oxo-isoindoline was dissolved in 20 ml of tetrahydrofuran, cooled down to 0° C. Then, 85 mg of N,N-dimethylaminopyridine and 3.0 ml of tert-butylcarbonate were added, and the mixture was stirred at room temperature for 30 min. Methanol was added to the reaction solution, and the solvents were distilled outunder reduced pressure. Water was added to the residues, extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, the residues were separated and purified by silicagel column chromatography (ethyl acetate/hexane=1/2), to obtain 300 mg of the above compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH:16]=O>>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH:16]=[C:4]([C:5](=[O:8])[CH2:6][CH3:7])[C:3](=[O:9])[C:2]([F:10])([F:11])[F:1]
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: CCC(=O)CC(=O)C(F)(F)F
Product: CCC(=O)C(=Cc1cc(Cl)cc(Cl)c1)C(=O)C(F)(F)F

Procedure:
The title compound was prepared by a similar method to that of Preparation 9 using 1,1,1-trifluorohexane-2,4-dione and 3,5-dichlorobenzaldehyde. The crude product was purified by flash chromatography on silica gel eluting with a solvent gradient of pentane gradually changing to pentane:ethyl acetate (5:1, by volume). The product was further purified by flash chromatography eluting with dichloromethane:pentane (1:10, by volume) to afford a mixture of the title compounds (500 mg) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[ClH:19].[CH3:20][CH:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)[CH3:22].C(N(CC)CC)C.C([BH3-])#N.[Na+]>C(O)C>[ClH:19].[CH3:37][O:36][C:30]1[CH:29]=[C:28]([CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH:21]([CH3:22])[CH3:20])[CH:14]2[CH2:13][CH2:12][C:11]([C:17]#[N:18])([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:16][CH2:15]2)[CH:33]=[CH:32][C:31]=1[O:34][CH3:35]
Reactant: COc1ccc(C2(C#N)CCCCC2)cc1OC
Reactant: COc1ccc(CCCCNC(C)C)cc1OC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(CCCCN(C(C)C)C2CCC(C#N)(c3ccc(OC)c(OC)c3)CC2)cc1OC

Procedure:
A solution of 4-(3,4-dimethoxyphenyl)-4-cyanocyclohexane (5 mmol), N-(1-methylethyl)-4-(3,4-dimethoxyphenyl) butylamine hydrochloride (5 mmol), triethylamine (6 mmol) and sodium cyanoborohydride (6 mmol) in 25 ml ethanol was stirred at 25° C. for 72 hours and worked up and recrystallized. ##STR8##
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:6])[CH3:5].[C:7]([NH:10][C:11]1[C:12]([I:27])=[C:13]([N:22]([C:24](=[O:26])[CH3:25])[CH3:23])[C:14]([I:21])=[C:15]([C:18]([O-:20])=[O:19])[C:16]=1[I:17])(=[O:9])[CH3:8].[Cs+].[I-].[Na+]>CN(C=O)C>[C:7]([NH:10][C:11]1[C:12]([I:27])=[C:13]([N:22]([C:24](=[O:26])[CH3:25])[CH3:23])[C:14]([I:21])=[C:15]([C:18]([O:20][CH2:2][O:3][C:4](=[O:6])[CH3:5])=[O:19])[C:16]=1[I:17])(=[O:9])[CH3:8]
Reactant: CC(=O)OCCl
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OCOC(C)=O)c(I)c(N(C)C(C)=O)c1I
Reaction time: 21 h

Procedure:
Chloromethylacetate (Neuenschwander, Markus et. al., Helv. Chim. Acta, 61 (1978) 2047) (2.30 g, 21.2 mmol) in dry DMF (100 ml) is added dropwise at 50° C. to a solution of cesium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (13.4 g, 17.7 mmol) and sodium iodide (133 mg, 0.89 mmol) in dry DMF (210 ml). The precipitate is removed by filtration after stirring for 21 hours and the solvent is removed at reduced pressure. The residue is dissolved in chloroform (200 ml) and washed four times with a saturated sodium hydrogen carbonate solution. After drying with magnesium sulfate the solvent is removed at reduced pressure to give the title compound:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][C:24]([NH2:26])=[O:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>>[O:27]=[C:11]1[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][C:24]([NH2:26])=[O:25])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12]1
Reactant: OB(O)c1ccccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(N)=O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CCC(N)=O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide and pyridine-2-boronic acid following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=0.932 min, m/z=430.1; 1H NMR (CDCl3) 1.52 (d, 3H), 1.90 (m, 1H), 2.13 (m, 1H), 2.21 (m, 4H), 2.45 (m, 1H), 2.82 (m, 1H), 5.15 (s, 1H), 5.35 (s, 1H), 5.65 (m, 1H), 6.98 (d, 2H), 7.13-7.32 (m, 6H), 7.56 (m, 1H), 7.65 (m, 3H), 8.57 (d, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.[S:9](Cl)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].CCOCC>C(N(CC)CC)C>[C:15]1([CH3:16])[CH:17]=[CH:18][C:12]([S:9]([C:5]2[NH:1][N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)c2nc(C(N)=O)n[nH]2)cc1

Procedure:
To a cooled, stirred mixture of 3.0 g. of 1,2,4-triazole- 3-carboxamide and 5.1 g. of tosyl chloride in 125 ml. of anhydrous ether is added rapidly 2.75 g. of triethylamine. The cooling bath is removed and the mixture is stirred at room temperature for 23 hours. The heterogeneous mixture is filtered and washed successively with ether, cold water and then ether and dried in vacuo for 4.5 hours yielding a crude colorless solid. This solid is heated in about 50 ml. of acetonitrile and the hot mixture is filtered. The filtrate is concentrated to a smaller volume of about 20 ml. in vacuo. A colorless solid separates from the filtrate, which is collected and washed with acetonitrile and air dried for 10 minutes. The product is then dried overnight in vacuo, m.p. 148°-150° C.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([O:22][C:23](=[O:41])[C@@H:24]([NH2:40])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:41])[CH:24]([NH:40][C:12](=[O:14])[CH:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH:15]([CH3:17])[CH3:16])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)[C@H](NC(=O)N1CCCCCC1)C(=O)O
Product: CC(C)C(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Yield: 48.2 %

Procedure:
A solution of the product from Example AC ((S)-2-[(azepane-1-carbonyl)-amino]-3-methyl-butanoic acid) (0.50 g, 2.07 mmol) and the product from Example A ((S)-2-amino-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (0.67 g, 2.07 mmol) were coupled according to the procedure described in Example AH. The crude reaction product was purified by chromatography (silica gel, EtOAc) to give the title compound as a white foam (0.55 g, 48%).
Reaction SMILES: C(#N)C.[OH:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][C:6]=1[O:21][CH3:22].Br[CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O>[CH:24]([O:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[CH:7][C:6]=1[O:21][CH3:22])([CH3:26])[CH3:25]
Reactant: COc1cc(CCNC(=O)OC(C)(C)C)ccc1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(CCNC(=O)OC(C)(C)C)ccc1OC(C)C
Temperature: 65 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a 250 mL round bottom flask containing acetonitrile (18.7 mL) was added tert-butyl 4-hydroxy-3-methoxyphenethylcarbamate (1.0 g, 3.74 mmol), 2-bromopropane (0.51 g, 4.11 mmol), and potassium carbonate (1.5 g, 11.22 mmol). The resulting suspension was stirred at 65° C. for 18 hours. A second addition of 2-bromopropane (0.51 g, 4.11 mmol) was performed and heating was continued for another 18 hours. The reaction mixture was concentrated reaction in vacuo. The resulting oil was dissolved in EtOAc and washed with H2O, aqeuous saturated sodium bicarbonate and brine, then dried with sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-100% EtOAc in Heptane) to afford tert-butyl 4-isopropoxy-3-methoxyphenethylcarbamate (0.81 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.84 (d, J=8.03 Hz, 1H), 6.67-6.75 (m, 2H), 4.37-4.70 (m, 2H), 3.86 (s, 3H), 3.27-3.46 (m, 2H), 2.68-2.81 (m, 2H), 1.45 (s, 9H), 1.37 (d, J=6.02 Hz, 6H).
Reaction SMILES: [F-].[Cs+].C([Sn](CCCC)(CCCC)[C:8]1[CH:13]=[CH:12][N:11]=[N:10][CH:9]=1)CCC.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:29]=[C:28](I)[C:27]([OH:31])=[CH:26][CH:25]=1>[Cu]I.C(#N)C>[N:11]1[CH:12]=[CH:13][C:8]([C:26]2[CH:25]=[C:24]([C:23]([F:33])([F:32])[F:22])[CH:29]=[CH:28][C:27]=2[OH:31])=[CH:9][N:10]=1
Reactant: Oc1ccc(C(F)(F)F)cc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Agent: [Cu]I
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: Oc1ccc(C(F)(F)F)cc1-c1ccnnc1
Temperature: 47.5 °C
Yield: 76.5 %

Procedure:
To a 5 L jacketed vessel was added acetonitrile (9 L) and the solvent was sparged with nitrogen for 2 hours. To the solvent was added cesium fluoride (335.8 g, 2.21 moles), 4-(tributylstannyl)pyridazine (408 g, 1.11 moles), 4-trifluoromethyl-6-iodophenol (318.33 g, 1.11 moles), palladium tetrakis triphenylphosphine (61.31 g, 53.05 mmole) and copper (I) iodide (40 g, 210 mmol) at 20° C. The resulting orange suspension was heated to 45-50° C. for 2 hours. The reaction was cooled and partitioned between ter-tbutylmethylether (2×5 L) and 2N (aq) HCl (2×5 L). The resulting biphasic solution was filtered and the layers separated. The aqueous phases were combined and basified with 4M (aq) sodium hydroxide solution (6 L) to obtain a pH=4-5. The resulting suspension was extracted into ethyl acetate (10 L) and the organic layer concentrated to dryness to afford the title compound (204 g, 60%) as an orange solid.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:16]([NH2:18])=[CH:15][C:14]([CH3:19])=[N:13][C:12]=3[S:11][C:10]=2[CH2:20][CH3:21])[CH:6]=[CH:7][CH:8]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:18][C:16]2[CH:15]=[C:14]([CH3:19])[N:13]=[C:12]3[S:11][C:10]([CH2:20][CH3:21])=[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:22])[CH3:1])[CH:4]=4)[C:17]=23)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCc1sc2nc(C)cc(N)c2c1-c1cccc(N(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: CCc1sc2nc(C)cc(NS(=O)(=O)c3ccc(Cl)cc3)c2c1-c1cccc(N(C)C)c1

Procedure:
Following general method outlined in Example 1, starting from 3-[3-(dimethylamino)phenyl]-2-ethyl-6-methylthieno[2,3-b]pyridin-4-amine (60 mg, 0.193 mmol) (Description 29) and 4-chlorobenzenesulfonyl chloride (81 mg, 0.385 mmol), the title compound (7.1 mg) was isolated as a TFA salt. LCMS (B) m/z: 486 [M+1]+, Rt 3.03 min.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:24]=1)=[O:4].[H][H]>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:24]=1)=[O:4]
Reactant: COC(=O)Nc1cn2cc(Sc3ccc([N+](=O)[O-])cc3)ccc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)Nc1cn2cc(Sc3ccc(N)cc3)ccc2n1

Procedure:
A suspension of 0.130 gms. of 2-(methoxycarbonylamino) 6-(p-nitrophenylthio) imidazo [1,2-a] pyridine in 30 ml. of glacial acetic acid is reduced at 40 psi. of hydrogen with 0.130 gm. of 5% palladium on carbon. When the uptake of hydrogen is complete, the catalyst is removed by filtration and the filtrate is evaporated to dryness in vacuo. The residue is stirred with saturated aqueous sodium bicarbonate and the resultant solids are collected by filtration, washed with water and dried in vacuo. The product melts 120°-175° C. Mass spectral data confirms the molecular ion of the product.
Reaction SMILES: CO[C:3]([C:5]1[C:10]([NH:11][C:12](=[O:21])[CH2:13][C:14]2[S:18][C:17]([Cl:19])=[N:16][C:15]=2[CH3:20])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:19][C:17]1[S:18][C:14]([C:13]2[C:12](=[O:21])[NH:11][C:10]3=[N:9][CH:8]=[CH:7][N:6]=[C:5]3[C:3]=2[OH:4])=[C:15]([CH3:20])[N:16]=1
Reactant: COC(=O)c1nccnc1NC(=O)Cc1sc(Cl)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(Cl)sc1-c1c(O)c2nccnc2[nH]c1=O
Temperature: 25 °C

Procedure:
3-[2-(2-Chloro-4-methyl-thiazol-5-yl)-acetylamino]-pyrazine-2-carboxylic acid methyl ester (Example 2.2) (1.020 g) was heated to 110° C. with potassium carbonate (1.08 g) in dry N,N-dimethylformamide (30 ml) for 3 hours. The reaction mixture was allowed to cool to ambient temperature, diluted with water and the mixture extracted with ethyl acetate. The aqueous fraction was acidified to pH 3 by addition of concentrated hydrochloric acid (36% by weight in water) and then extracted again with ethyl acetate. The organic fraction was washed with water, dried over magnesium sulfate, and concentrated to give Compound No. B1 of Table B (0.61g).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.C(N(CC)CC)C.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[Cl:26])[N:19]2[CH:27]=[N:28][C:29]([C:30]3[O:34][N:33]=[C:32]([CH:35]4[CH2:37][CH2:36]4)[N:31]=3)=[C:18]2[N:17]=1>CN(C=O)C>[Cl:26][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:25]=1[C:16]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[CH2:2][OH:1])=[N:17][C:18]1[N:19]2[CH:27]=[N:28][C:29]=1[C:30]1[O:34][N:33]=[C:32]([CH:35]2[CH2:37][CH2:36]2)[N:31]=1
Reactant: Clc1cccc2c1c(Cl)nc1c(-c3nc(C4CC4)no3)ncn12
Reactant: OC[C@H]1CCCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OC[C@H]1CCCN1c1nc2c(-c3nc(C4CC4)no3)ncn2c2cccc(Cl)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of (R)-2-hydroxymethylpyrrolidine (70 mg) and triethylamine (90 mg) dissolved in dry DMF (1 ml) was added dropwise to a stirred suspension of 5,6-dichloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-imidazo[1,5-a]-quinazoline (0.20 g) in dry DMF (5 ml) at 0° C. After 20 min. the reaction mixture was filtered. The filtrate was diluted with 15 ml of water and stirred at 0° C. for 10 min. The crystals which had formed were filtered off, rinsed with water, and dried to give the title compound as yellow crystals, m.p. 220°-221° C. Yield 0.15 g.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH2:13])[C:9]([N+:14]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O1CCCC1>CO.[Pd]>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH2:13])[C:9]([NH2:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1N
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(N)c(N)c(F)c1N
Yield: 108.4 %

Procedure:
A mixture of methyl 2,4-diamino-3-fluoro-5-nitrobenzoate (5) (40.0 g, 173.7 mmol) and 5% Pd/C (3.0 g, Type 487; 0.4 mol % Pd relative to starting material), in methanol (300.0 mL) and tetrahydrofuran (300.0 mL) was stirred at 2000 RPM, under hydrogen (˜3.5 bar), at 50° C. in a 1.5 L hydrogenation vessel. After 6 hours the vessel was purged with nitrogen and HPLC analysis indicated that no starting material remained. The mixture was then filtered under nitrogen pressure and the filter washed through with THF (160 mL), to give a clear yellow solution. The solvent was removed by rotary evaporation, to provide methyl 2,4,5-triamino-3-fluorobenzoate (9) 37.5 g (93.3% w/w by NMR) as a solid, yield ˜100%. 1H NMR (400 MHz, d6 DMSO) δ 3.69 (3H, s, NMe), 4.20 (2H, br s, NH2), 5.24 (2H, br s, NH2), 5.70 (2H, br s, NH2), 6.83 (1H, d, J 1, Ar—H). 13C NMR (100 MHz, d6 DMSO) δ 51 (CH3), 98 (C, d, J 5), 110 (CH, d, J 2), 125 (C, d, J 6), 131 (C, d, J 12), 133 (C, d, J 12), 139 (CF, d, J 225), 166 (C═O). νmax/cm-1 3480, 3461, 3373, 3356, 3280, 3163, 1679, 1655, 1314. MS APCI (+) m/z 200 (M+1) detected.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1.[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.O>C1(C)C=CC=CC=1>[C:12]1(=[O:17])[N:1]([CH2:2][CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4]2)[C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12
Reactant: NCC1Cc2ccccc2N1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CC1Cc2ccccc2N1
Yield: 105.1 %

Procedure:
A mixture of 2-aminomethylindoline (6.0 g, 40.48 mmol) and phthalic anhydride (6.30 g, 42.51 mmol) in toluene (600 mL) was refluxed for 4 h, while water generated during the reaction was removed by azeotropic distillation by using Dean-Stark apparatus. The mixture was concentrated to give a crude 2-phthalimidomethylindoline (11.84 g), which was used for the next step without further purification: 1H NMR (270 MHz, CDCl3) δ7.82 (m, 2H), 7.71 (m, 2H), 7.03 (d, 1H, J=7 Hz), 6.95 (dt, 1H, J=1,7 Hz), 6.61 (m, 2H), 4.19 (m, 1H), 3.86 (d, 2H, J=6 Hz), 3.18 (dd, 1H, J=16, 9 Hz), 2.93 (dd, 1H, J=16, 6 Hz).
Reaction SMILES: CO[C:3](=[O:24])[CH2:4][NH:5][C:6]([C:8]1[C:9]2[CH:16]=[N:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:10]=2[CH:11]=[N:12][CH:13]=1)=[O:7].O.[NH2:26][NH2:27].O>CCO>[NH:26]([C:3]([CH2:4][NH:5][C:6]([C:8]1[C:9]2[CH:16]=[N:15][N:14]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:10]=2[CH:11]=[N:12][CH:13]=1)=[O:7])=[O:24])[NH2:27]
Reactant: NN
Reactant: COC(=O)CNC(=O)c1cncc2c1cnn2-c1ccc(F)cc1
Solvent: CCO
Solvent: O
Product: NNC(=O)CNC(=O)c1cncc2c1cnn2-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of {[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-acetic acid methyl ester (0.50 g, 1.5 mmol) in EtOH (6 mL) was added hydrazine hydrate (2 mL) and the mixture was warmed at 60° C. After 18 hours, the mixture was cooled to room temperature and poured into water (100 mL). The solid was collected by filtration to afford 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid hydrazinocarbonylmethyl-amide (purity 90%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[CH3:11])=[CH:6][C:5]=1[N+:14]([O-])=O>CO.CCO.[Ni]>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:12])([F:13])[CH3:11])=[CH:6][C:5]=1[NH2:14]
Reactant: COC(=O)c1ccc(C(C)(F)F)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Solvent: CO
Product: COC(=O)c1ccc(C(C)(F)F)cc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.1 %

Procedure:
A solution of 4-(1,1-difluoro-ethyl)-2-nitro-benzoic acid methyl ester (1.61 g, 6.57 mmol) in MeOH (40 mL) was treated with Nickel-raney in EtOH (400 mL) and the mixture was stirred at r.t. for 5 h under H2 (0.1 bar). The mixture was then filtered and concentrated in vacuo to give 2-amino-4-(1,1-difluoro-ethyl)-benzoic acid methyl ester (1.30 g, 6.05 mmol, 92%) as a yellow oil. ESI-MS: m/z 216 [M+H]+, rt 6.30 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[NH:20][CH2:19][C:18]2[CH:21]=[CH:22][O:23][C:17]=2[CH2:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH:15]([CH3:14])[CH2:16][C:17]4[O:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1Cc2occc2CN1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1Cc2occc2CN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-methyl-4,5,6,7-tetrahydro-furo[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=[O:10])[S:5][C:6]=1[CH2:7][CH3:8].S(=O)(=O)(O)O.O.[CH3:18]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:18])=[O:10])[S:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1sc(C(=O)O)cc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCc1sc(C(=O)OC)cc1Br
Temperature: 50 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a solution of 4-bromo-5-ethyl-2-thiophenecarboxylic acid (1 g, 4.25 mmol) in methanol (21.27 ml) was added sulfuric acid (0.23 mL, 4.25 mmol). The resulting solution was stirred at 50° C. for 48 h. H2O (50 mL) was added and the reaction was cooled to 0° C. in an ice-bath. The pH was adjusted to ˜12 and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly without further purification providing methyl 4-bromo-5-ethyl-2-thiophenecarboxylate (1.060 g, 4.25 mmol, 100% yield): LCMS (ES) m/e 248, 250 (M, M+2)+.