Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[N:13]1([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:21]2[CH2:22][CH2:23][CH:18]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:19][CH2:20]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: C1CCN(C2CCNCC2)C1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCC(N3CCCC3)CC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 17 h

Procedure:
200 mg (1.170 mmol) 4-fluoro-2-methoxy-1-nitro-benzene are dissolvedjin 1 ml NMP, combined with 198 mg (1.284 mmol) 4-pyrrolidin-1-yl-piperidine and 300 μl diisopropylethylamine and stirred for 17 h at 80° C. Then the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier material used is C18-RP gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and 5% water and 95% acetonitrile at the finishing point.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[C:13]2[C:8](=[C:9]([CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][N:5]1[S@@](C1C=CC(C)=CC=1)=O.Cl.O.C(=O)([O-])[O-].[Na+].[Na+]>CCO.C1COCC1>[CH3:1][O:2][CH2:3][C@H:4]1[C:13]2[C:8](=[C:9]([CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][NH:5]1
Reactant: COC[C@H]1c2cccc(C)c2CCN1[S@](=O)c1ccc(C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COC[C@@H]1NCCc2c(C)cccc21
Temperature: 0 °C
Yield: 89 %

Procedure:
To a mixed solution of (1R)-1-(methoxymethyl)-5-methyl-2-[(R)-(4-methylphenyl)sulfinyl]-1,2,3,4-tetrahydroisoquinoline (2.47 g) in EtOH (45 mL) and THF (10 mL) was added concentrated hydrochloric acid (3.1 mL) under stirring at 0° C., followed by further stirring for 10 minutes. To the mixture was added saturated sodium carbonate water (50 mL), followed by extraction with EtOAc. The organic layer was washed with a 1 M aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:EtOH:aqueous ammonia) to obtain (1R)-1-(methoxymethyl)-5-methyl-1,2,3,4-tetrahydroisoquinoline (1.276 g).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=1.[K+].[CH2:25]([S:28]([NH-:31])(=[O:30])=[O:29])[CH2:26][CH3:27].Cl>CS(C)=O>[Cl:17][C:6]1[N:5]=[C:4]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=[C:2]([NH:31][S:28]([CH2:25][CH2:26][CH3:27])(=[O:30])=[O:29])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: CCCS([NH-])(=O)=O
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1Cl
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CCCS(=O)(=O)Nc1nc(-c2ncccn2)nc(Cl)c1Oc1ccccc1OC
Reaction time: 240 h
Yield: 99.9 %

Procedure:
To a solution of 4,6-dichloro-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl (prepared as described in [6] and [11]) (1.74 g) in DMSO (5 ml) was added n-propanesulfonamide potassium salt (1.77 g). Stirring was continued for 10 days at rt. The reaction mixture was poured onto ice/water and acidified by 2N HCl. The precipitate was filtered off, washed with water and dried at HV to give n-propanesulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (2.17 g) as a white powder. LC-MS: tR: 4.14, [M+H]+: 434.13.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(OCC)(=O)C.[ClH:38]>C(O)C>[ClH:38].[ClH:38].[O:2]=[C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][NH:4]1
Reactant: COc1ncccc1CN1CCC(CCc2ccccc2NCc2ccccc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=c1[nH]cccc1CN1CCC(CCc2ccccc2NCc2ccccc2)CC1

Procedure:
In ethanol (8 ml) was dissolved 294 mg of 1-[(2-methoxy-3-pyridinyl)methyl]-4-[2-[2-(benzylamino)phenyl]ethyl]piperidine. To the mixture was added 3 ml of a 4N-hydrogen chloride-ethyl acetate solution, followed by heating under reflux for 3 hours. After cooling as it was, the resulting precipitates were collected by filtration and recrystallized from ethanol, to give 273 mg of the title compound as a white powder.
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=O)(C)(C)C.C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.C(=O)([O-])[O-].[Na+].[Na+].[CH3:51][N:52]1C(=O)CCC1>[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[K+].[Fe+2].CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:19][C:10]1([CH3:18])[C:11]2[CH:12]=[N:13][C:14]([C:51]#[N:52])=[CH:15][C:16]=2[NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cl)cc21
Reactant: CN1CCCC1=O
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC1(C)CNc2cc(C#N)ncc21
Temperature: 185 °C
Yield: 15 %

Procedure:
A mixture of 6-chloro-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.405 g, 1.43 mmol), K4[Fe(CN)6](1.21 g, 2.86 mmol), Pd(OAc)2 (16 mg, 0.07 mmol), butyl di-1-adamantylphoshine (77 mg, 0.21 mmol) and sodium carbonate (0.304 g, 2.86 mmol) was slurried in NMP (14.3 mL) at ambient temperature. The reaction was heated under microwave irradiation at 185° C. for 2 h. The reaction was cooled to ambient temperature and filtered. The filtrate was dissolved in water and extracted with diethyl ether/petrol (1:1, 3×). The combined organic extracts were washed with brine (3×), dried over sodium sulfate, and solvent removed in vacuo. Chromatography (SiO2, gradient elution, 0-100%, EtOAc/petrol) gave the title compound (36 mg, 15%) as a colourless solid. MS: [M+H]+=174
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH3:19].O>CN(C=O)C>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH2:18][CH3:19]
Reactant: CCCBr
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (10.0 g) in DMF (120 ml) were added potassium carbonate (15.8 g) and 1-bromopropane (12.1 g), and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Then, water was added to the mixture, which was extracted with ethyl acetate and washed with 1N sodium hydroxide solution twice, with water three times and with saturated brine once. After dried with magnesium sulfate, the solvent was evaporated under reduced pressure to give 3-propoxybenzaldehyde (13.4 g) as colorless liquid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[C:5]([CH:12]=[CH:13][CH:14]=1)[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7].[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].N1C=CN=C1.O>CN(C=O)C>[Si:22]([O:1][CH2:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[C:5]([CH:12]=[CH:13][CH:14]=1)[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CON(C)C(=O)c1cccc(CO)c1[N+](=O)[O-]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1cccc(CO[Si](C)(C)C(C)(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
To a solution of Intermediate 37C (1.079 g, 4.49 mmol) and TBDMS-Cl (1.016 g, 6.74 mmol) in DMF (4 mL) was added imidazole (0.612 g, 8.98 mmol). The mixture was stirred at room temperature for 1 h. Water was added, and the mixture was extracted with EtOAc. The combined extracts were washed with 10% LiCl and brine, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by flash chromatography (SiO2, 40 g column, EtOAc/hexane=0-30%) to afford Intermediate 37D (1.25 g, 79%). HPLC: RT=3.05 min (CHROMOLITH® SpeedROD column 4 6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm), MS(ES): m/z=355.0 [M+H+]. 1H NMR (400 MHz, chloroform-d) δ 7.90 (d, J=7.7 Hz, 1H), 7.70-7.62 (m, 1H), 7.47 (d, J=7.7 Hz, 1H), 4.98 (s, 2H), 3.46 (br. s., 3H), 3.36 (br. s., 3H), 0.98 (s, 9H), 0.15 (s, 6H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8](B(O)O)[CH:9]=1)([CH3:3])[CH3:2].Br[C:16]1[CH:17]=[C:18]([CH:22]([C:27]2[O:28][C:29]([CH3:32])=[N:30][N:31]=2)[CH2:23][C:24]([OH:26])=[O:25])[CH:19]=[CH:20][CH:21]=1>CN(C=O)C.O.[NH4+].[Cl-]>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8]([C:20]2[CH:21]=[CH:16][CH:17]=[C:18]([CH:22]([C:27]3[O:28][C:29]([CH3:32])=[N:30][N:31]=3)[CH2:23][C:24]([OH:26])=[O:25])[CH:19]=2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1B(O)O
Reactant: Cc1nnc(C(CC(=O)O)c2cccc(Br)c2)o1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)C)cc1-c1cccc(C(CC(=O)O)c2nnc(C)o2)c1
Yield: 57 %

Procedure:
12.83 g (66.11 mmol) of 5-isopropyl-2-methoxybenzeneboronic acid, 48.97 g (150.3 mmol) and 18.7 g (60.1 mmol) of 3-(3-Bromo-phenyl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionic acid are heated together with 3 mmol of bis(triphenylphosphine)palladium (II)dichloride in 200 ml of DMF and 30 ml of water for 10 hours at 100° C. The reaction mixture is diluted with conc. NH4Cl solution (200 ml) and extracted with methyl-tetrahydrofurane. The organic phase is filtrated over Celite and 100 g of SiO2 and the solvent is removed in vacuo. The obtained crude 3-(5′-Isopropyl-2′-methoxy-biphenyl-3-yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionic acid is used directly in the next step. (Yield=57%, 28 g)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[N:10]1(C(OC(C)(C)C)=O)[CH2:15][CH2:14][CH:13]([C:16]([O-])=O)[CH2:12][CH2:11]1.[OH-].[Na+]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:16]([CH:13]3[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]3)=[N:1][C:2]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)[O-])CC1
Reactant: Nc1cc(F)ccc1O
Agent: [Na+]
Agent: [OH-]
Product: Fc1ccc2oc(C3CCNCC3)nc2c1
Temperature: 0 °C

Procedure:
500 mg 2-amino-4-fluorophenol and 900 mg mono-tert-butyl piperidine-1,4-dicarboxylate are heated in 5 g polyphosphoric acid at 200° C. for 4 h. After cooling the reaction mixture is combined with ice water and made basic with 50% NaOH solution. The precipitate is suction filtered, washed with water and dried. 290 mg (V-8) are obtained as a solid.
Reaction SMILES: CO[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][CH2:5][C:4]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH3:19][Mg]I.C(OCC)C.[Cl-].[NH4+]>O1CCCC1>[CH3:19][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][CH2:5][C:4]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: C[Mg]I
Reactant: CCOC(=O)C1=C(OC)c2ccccc2CCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C1=C(C)c2ccccc2CCC1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
A solution of ethyl 9-methoxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (4.00 g, 16.2 mmol) in tetrahydrofuran (60 ml) was cooled to −10° C., and methylmagnesium iodide (a 2M diethyl ether solution 16.2 ml, 32.5 mmol) was added dropwise thereto. The reaction mixture was stirred at −5° C. for 2 hours, poured into a cold aqueous ammonium chloride solution and then extracted twice with ethyl acetate. The extract solution was washed with an aqueous sodium hydrogen-carbonate solution and a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/98) to obtain 0.81 g of ethyl 9-methyl-6,7-dihydro-5H-benzocycloheptene-8-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH3:23][C:24]1([C:27]2[O:31][N:30]=[C:29]([NH:32][C:33](=O)[O:34]C3C=CC=CC=3)[CH:28]=2)[CH2:26][CH2:25]1.COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(NC(NC2ON=C(C(C)C)C=2)=O)C=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:33]([NH:32][C:29]2[CH:28]=[C:27]([C:24]3([CH3:23])[CH2:25][CH2:26]3)[O:31][N:30]=2)=[O:34])[CH:20]=[CH:21][CH:22]=1
Reactant: CC1(c2cc(NC(=O)Oc3ccccc3)no2)CC1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C5(C)CC5)on4)c3)c2cc1OC
Yield: 57.8 %

Procedure:
3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.3 mmol) and phenyl 5-(1-methylcyclopropyl)isoxazol-3-ylcarbamate (93 mg, 0.36 mmol) were reacted according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1-methylcyclopropyl)isoxazol-3-yl)urea as a colorless solid (80 mg, 58%). 1H NMR (300 MHz, DMSO-d6) δ 9.57 (brs, 1H), 9.01 (brs, 1H), 8.56 (s, 1H), 7.56-7.58 (m, 2H), 7.38-7.43 (m, 2H), 7.25 (m, 1H), 6.97 (m, 1H), 6.47 (s, 1H), 3.99-4.00 (2×s, 6H), 1.39 (s, 3H), 1.06-1.10 (m, 2H), 0.86-0.90 (m, 2H); LC-MS (ESI) m/z 462 (M+H)1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[CH3:19][S:20]([NH2:23])(=[O:22])=[O:21].C1CCN2C(=NCCC2)CC1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[O:15])=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(COc2cncc(Cl)c2)cc1
Reactant: CS(N)(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)c1ccc(COc2cncc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.9 %

Procedure:
To a suspension of 4-{[(5-chloropyridin-3-yl)oxy]methyl}benzoic acid (Preparation 17, 0.16 g, 0.60 mmol) in THF (6 mL) was added WSCDI (0.1 g, 0.62 mmol) and the reaction was heated at reflux for 30 minutes. The reaction mixture was cooled to room temperature and methanesulphonamide (0.060 g, 0.64 mmol) and DBU (0.09 g, 0.060 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour and then partitioned between DCM (30 mL) and aqueous hydrochloric acid (1 M, 8 mL). The organic layer was separated and dried over magnesium sulfate and evaporated in vacuo. The resulting crude was triturated with diethyl ether (4 mL) and methanol (1 mL) to afford the title compound as a beige solid (0.053 g, 51%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.Br[C:22]1[CH:23]=[C:24]([NH2:30])[C:25]([O:28][CH3:29])=[N:26][CH:27]=1.COCCOC>O>[CH3:29][O:28][C:25]1[C:24]([NH2:30])=[CH:23][C:22]([C:11]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=[CH:9][CH:10]=2)=[CH:27][N:26]=1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: COc1ncc(Br)cc1N
Solvent: O
Solvent: COCCOC
Product: COc1ncc(-c2ccnn2C2CCCCO2)cc1N
Temperature: 92 °C

Procedure:
To a 100 ml flask was added 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 14.1.B (6.0 g, 22 mmol), 5-bromo-2-methoxypyridin-3-amine (4 g, 20 mmol), 100 ml of DME, and 30 ml of water. Argon was then bubbled through the solution for 8 minutes at which time Pd(Ph3)4 (460 mg, 0.39 mmole) was added and argon was then bubbled through the solution for an additional 2 minutes. The reaction was then heated to 92° C. for 12 hours at which time the crude was quenched with brine and extracted with EtAc. The solvent was removed and the crude purifed on silica gel (eluting with 0-70% EtAc in Hexanes) to 2-methoxy-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-amine 14.1.C (5.3 g, 97. % yield).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:13]1([CH2:19][C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[NH2:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[C:3]([N:16]2[CH2:15][CH2:14][N:13]([CH2:19][C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[O:21])[CH2:18][CH2:17]2)[C:2]([Br:1])=[CH:7][N:6]=1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCN(CC(=O)N3CCCC3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (9 ml) was added 2-(piperazin-1-yl)-1-(pyrrolidin-1-yl)ethanone (0.108 g, 0.55 mmol) followed by diisopropylethylamine (0.10 ml, 0.55 mmol). The reaction mixture was heated at 45° C. for 22 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 70% ethyl acetate in dichloromethane and then 90% ethyl acetate in dichloromethane. The title compound was obtained as a yellow solid (0.162 g, 78%); 1H-NMR (500 MHz, DMSO-d6) 1.74 (m, 2H) and 1.85 (m, 2H) (pyrrolidine 3-CH2 and 4-CH2), 2.60 (br s, 4H, piperazine N(CH2)2), 3.04 (br s, 4H, piperazine N(CH2)2), 3.16 (s, 2H, NCH2CO), 3.27 (t, J=6.90 Hz, 2H) and 3.45 (t, J=6.70 Hz, 2H) (pyrrolidine 2-CH2 and 5-CH2), 7.02 (s, 2H, NH2), 8.16 (s, 1H, 6-H);
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:9])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[NH4+].[CH:12](O)=O>>[CH3:1][C:2]1[C:3]2[NH:9][CH:12]=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(N)c1N
Reactant: O=CO
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cccc2nc[nH]c12
Yield: 71 %

Procedure:
A solution of 3-methyl-1,2-diaminobenzene (5.00 g, 40.9 mmol) in formic acid (25 mL) was heated at 105° C. for 2 h. The reaction mixture was allowed to cool and then concentrated ammonium hydroxide (50 mL) was added dropwise. The mixture was extracted with dichloromethane (2×100 mL). The extracts were washed with brine, dried (Na2SO4), treated with charcoal, filtered, and evaporated to dryness. The residue was triturated with cold ether, filtered, and washed with cold ether, ether/hexane (1:1), and hexane to give 4-methylbenzimidazole (3.85 g, 71%) as a yellow solid.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([Br:10])=[CH:4][C:3]=2[O:2]1.[C:11]12(O)[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.S(=O)(=O)(O)O>C(Cl)Cl>[C:11]12([C:7]3[CH:6]=[C:5]([Br:10])[CH:4]=[C:3]4[O:2][CH2:1][O:9][C:8]=34)[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: Brc1ccc2c(c1)OCO2
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Brc1cc2c(c(C34CC5CC(CC(C5)C3)C4)c1)OCO2
Reaction time: 72 h
Yield: 52.9 %

Procedure:
To a mixture of 3,4-methylenedioxy-1-bromobenzene (5.00 g, 24.87 mmol) and 1-adamantanol (3.79 g, 24.87 mmol) in CH2Cl2 (50 mL) under an atmosphere of argon was added sulfuric acid (2.0 mL) at room temperature. After stirring for 3 days the resulting mixture was diluted with CH2Cl2 and washed with water. The aqueous layer was extracted with CH2Cl2 and the combined organics were washed successively with water, brine and dried (MgSO4). The mixture was filter, evaporated and the residue purified on silica gel (hexane) to give 4.41 g of 3-(1-adamantyl)-4,5-methylenedioxy-1-bromobenzene (53%) as a white solid, mp 135.5–136.0° C.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([NH2:10])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25]>>[CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([NH:10][S:24]([CH2:23][CH2:22][N:13]3[C:12](=[O:11])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=[O:21])(=[O:25])=[O:26])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Reactant: NC1CCN(C2CC2)CC1
Product: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)NC1CCN(C2CC2)CC1

Procedure:
2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid (1-cyclopropyl-piperidin-4-yl)-amide was prepared by an analogous procedure as described for example 1 i) starting from 154 mg (1.1 mmol) 1-cyclopropyl-piperidin-4-ylamine (obtainable as described in EP 1479676) and 300 mg (1 equiv.) 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride. The product was obtained in crude form as a colorless foam.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[NH:11][CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:17]=1)[CH2:9][C:8]2([CH3:29])[CH3:28])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:28][C:8]1([CH3:29])[C:7]2[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[NH:11][CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:17]=2)[CH2:9]1
Reactant: COC(=O)c1cc(C)c2c(c1)C(C)(C)CC(c1cccc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(=O)O)cc2c1NC(c1cccc(N3CCOCC3)c1)CC2(C)C
Temperature: 60 °C
Reaction time: 16 h
Yield: 66.6 %

Procedure:
To a stirred mixture solution of 4,4,8-trimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (1.4 g, 3.55 mmol) in methanol (5 mL) and tetrahydrofuran (10 mL) was added 30% sodium hydroxide in water (5 mL). The reaction mixture was stirred at 60° C. for 16 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 4,4,8-trimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.9 g, 66%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=381.0.
Reaction SMILES: C(OC([N:11]1[C:15](=[O:16])[CH2:14][C@@H:13]([C@H:17]([N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])[C:18]([OH:20])=[O:19])[O:12]1)=O)C1C=CC=CC=1.C(OCC)(=O)C>[Pd].C(O)C>[O:16]=[C:15]1[CH2:14][CH:13]([CH:17]([N:21]2[C:22](=[O:31])[C:23]3=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]3[C:25]2=[O:26])[C:18]([OH:20])=[O:19])[O:12][NH:11]1
Reactant: O=C(O)[C@H]([C@@H]1CC(=O)N(C(=O)OCc2ccccc2)O1)N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1CC(C(C(=O)O)N2C(=O)c3ccccc3C2=O)ON1
Reaction time: 2.75 h

Procedure:
A 7.48 g. (17.6 mM) quantity of (αS,5S) 2-[(benzyloxy)carbonyl]-3-oxo-α-phthalimido-5-isoxazolidine acetic acid is dissolved in 150 ml. of ethyl acetate and 75 ml. of 95% ethanol. The solution is treated with 1.5 g. of palladium black and hydrogenated at 25° C. and 1 atmosphere of pressure. The reaction is stopped after 165 minutes, filtered, and the filtrate is evaporated in vacuo to yield 3-oxo-α-phthalimido-5-isoxazolidine acetic acid as a residue.
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][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH:22]([CH3:28])[NH:21][CH2:20][CH2:19]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=4)[CH:22]3[CH3:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: COc1cc2c(cc1OC)C(C)NCC2
Product: COc1cc2c(cc1OC)C(C)N(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound as a solid.