Azzindani/Open_Reaction_Data huggingface dataset:
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])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.[ClH:19].[Cl:20][CH2:21][C:22]1[C:23]([N:33]([CH3:35])[CH3:34])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([CH3:32])=[CH:27][CH:26]=2>C1(C)C=CC=CC=1>[ClH:20].[ClH:19].[CH3:34][N:33]([CH3:35])[C:23]1[C:22]([CH2:21][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=2[OH:18])=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH3:32])[CH:29]=2)[N:24]=1
Reactant: Cc1ccc2nc(N(C)C)c(CCl)cc2c1
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCc1nc(O)c(Cc2cc3cc(C)ccc3nc2N(C)C)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 6.7 %

Procedure:
To a stirred solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (173 mg, 0.638 mmol) in toluene (10 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added 3-(chloromethyl)-N,N,6-trimethylquinolin-2-amine hydrochloride RBO 35154 (158 mg, 0.638 mmol) and the mixture was stirred at 150° C. for 1.5 h. After cooling to RT, the volatiles were removed and the residue was taken back in CH2Cl2 (20 mL). This solution was washed with water (3×10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:7 N NH3 solution in MeOH=100:0 to 95:5) gave after evaporation 20.2 mg of 4-((2-(dimethylamino)-6-methylquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol as a yellow solid. The free base was dissolved in MeOH (2 mL) and converted into salt by addition of a 0.19 M HCl solution in MeOH (0.525 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-(2-dimethylamino-6-methyl-quinolin-3-ylmethyl)-6,7-dimethoxy-1-propyl-soquinolin-3-ol dihydrochloride 36 as a yellow solid (22.2 mg, 6.7% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11]([C:16]([O:18]CC)=[O:17])=[CH:10]3)=[CH:4][CH:3]=1>[OH-].[Na+]>[CH3:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11]([C:16]([OH:18])=[O:17])=[CH:10]3)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(C)cc3)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(Oc2ccc3[nH]c(C(=O)O)cc3c2)cc1

Procedure:
Ethyl 5-(4-methylphenoxy)indole-2-carboxylate (1.0 g, 3.39 mmol) was hydrolysed in methanolic NaOH (3.2M, 6.0 mL) at reflux, for 1 hr. After work-up the product: 5-(4-methylphenoxy)indole-2-carboxylic acid was obtained as an almost white solid, 0.92 g (ca 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[N:9]2[C:10](=[O:33])[C:11]([CH2:31][NH2:32])=[C:12]([CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:13]([C:14]3[CH:19]=[CH:18]C=CC=3)=[C:8]2[S:7][CH2:6]1)=[O:4].COC([C@H]1N2C(=O)C(C#N)=C(CC3C4C(=CC=CC=4)C=CC=3)C(C3C=CC=CC=3)=C2SC1)=O.COC(C1N2C(=O)C(C#N)=C(CC3C4C(=CC=CC=4)C=CC=3)C(C3CC3)=C2SC1)=O>>[CH3:1][O:2][C:3]([C@H:5]1[N:9]2[C:10](=[O:33])[C:11]([CH2:31][NH2:32])=[C:12]([CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:13]([CH:14]3[CH2:18][CH2:19]3)=[C:8]2[S:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(CN)c(=O)n21
Agent: COC(=O)C1CSc2c(C3CC3)c(Cc3cccc4ccccc34)c(C#N)c(=O)n21
Agent: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(C#N)c(=O)n21
Product: COC(=O)[C@@H]1CSc2c(C3CC3)c(Cc3cccc4ccccc34)c(CN)c(=O)n21
Yield: 73 %

Procedure:
By following the procedure described for the preparation of 7a from 6a, 6b (46 mg, 0.11 mmol) gave 7b as a yellow solid (33 mg, 73%): [α]D−64 (c 0.25, CHCl3); IR X 2952, 1747, 1631, 1569, 1504, 1259, 1214 cm−1; 1H NMR (400 MHz, CDCl3) δ8.18 (d, J=8.2, 1H), 7.94-7.27 (m, 5H), 6.81 (d, J=6.8, 1H), 5.67 (d, J=7.3, 1H), 4.77-4.56 (m, 2H), 3.96-3.31 (m, 9H), 1.40 (m, 1H), 0.76-0.31 (m, 4H); 13C NMR (100 MHz, CDCl3) δ168.3, 161.1, 155.6149.5, 133.7, 133.7, 131.6, 128.7, 127.3, 126.4, 126.0, 125.5, 123.8, 123.4, 116.9, 115.7, 63.4, 53.5, 37.6, 32.6, 31.6, 11.8, 7.2, 7.1; HRMS (FAB+) calcd for C24H25N2O3S 421.1586, obsd 421.1593.
Reaction SMILES: [N:1]([CH:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[CH2:7]1)[CH3:5])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][CH:6]([CH:4]([NH2:1])[CH3:5])[CH2:7]2)=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: CC(N=[N+]=[N-])C1CCN(c2ccc(Cl)cc2[N+](=O)[O-])C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(N)C1CCN(c2ccc(Cl)cc2[N+](=O)[O-])C1
Temperature: 50 °C
Yield: 67.3 %

Procedure:
A mixture of 3-(1-azido-ethyl)-1-(4-chloro-2-nitro-phenyl)-pyrrolidine (214 mg, 0.7 mmol), triphenylphosphine (500 mg) and water (0.171 mL) in tetrahydrofuran (20 mL) was heated at 50° C. overnight. The resulting mixture was evaporated under reduced pressure; the residue was diluted with ethyl acetate, washed twice with water and once with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (DCM/MeOH) to give 127 mg (65% yield) of 1-[1-(4-chloro-2-nitro-phenyl)-pyrrolidin-3-yl]-ethylamine.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[S:8])[CH2:6][CH:5]=[CH:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].[OH-].[Na+].Br[CH:16]([CH3:20])[C:17]([OH:19])=[O:18]>O>[C:17]([CH2:16][CH2:20][S:8][C:7]1[C:2]([CH3:1])=[C:3]([CH:4]=[CH:5][CH:6]=1)[C:9]([O:11][CH3:12])=[O:10])([OH:19])=[O:18]
Reactant: CC(Br)C(=O)O
Reactant: COC(=O)C1=C(C)C(=S)CC=C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cccc(SCCC(=O)O)c1C

Procedure:
70 g (0.38 mol) of methyl 3-thio-2-methylbenzoate are dissolved in 400 ml of water and refluxed for 7 hours together with 30.8 g (0.77 mol) of sodium hydroxide solution and 58.8 g (0.45 mol) of bromopropionic acid. After cooling, the aqueous phase is washed using methyl tert-butyl ether. The aqueous phase is subsequently acidified using 2N HCl, the precipitate which has formed is filtered off with suction and washed with water, and the product is dried.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10]2.C(=O)([O-])O.[Na+]>ClCCl>[OH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10]2
Reactant: CCOC(=O)c1cc2cc(OC)ccc2[nH]1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.2 %

Procedure:
Boron tribromide (64.58 g) was added dropwise to a stirred solution of ethyl 5-methoxyindole-2-carboxylate (20 g) in dichloromethane (1000 ml) at −78° C. under an atmosphere of argon. The reaction was allowed to warm to room temperature and stirred for a further 2 hours. The reaction was poured into ice/s aqueous sodium hydrogen carbonate solution with stirring and extracted with ethyl acetate. Combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution, water, aqueous saturated sodium chloride solution and dried. The solution was concentrated in vacuo and the residue was purified by column chromatography using 0-60% diethyl ether, iso-hexane as eluent to yield product as a white solid (9.02 g, 48%). NMR: 1.31 (t, 3H), 4.29 (q, 2H), 6.79 (dd, 1H), 6.90 (dd, 1H), 7.22 (d, 1H), 8.84 (s, 1H), 11.52 (brs, 1H; m/z 206 M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[O:30][CH3:31])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O-:26])=[S:25])=[C:15]([CH2:18][CH:19]4[CH2:23][O:22][CH2:21][O:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:33]([O:39][CH2:40]I)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[O:30][CH3:31])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O:26][CH2:40][O:39][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[S:25])=[C:15]([CH2:18][CH:19]4[CH2:23][O:22][CH2:21][O:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C([O-])=S)=C(CC3COCO3)CS[C@H]12)c1csc(N)n1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OCOC(=O)C(C)(C)C)=C(CC3COCO3)CS[C@H]12)c1csc(N)n1
Yield: 83.7 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1,3-dioxolan-4-yl)methylthio-3-cephem-4-carboxylate (87 mg) as prepared in Example 29(b) was reacted with iodomethyl pivalate (80 mg) similarly to Example 28 for the esterification reaction. The resulting reaction solution was post-treated and the produced compound was recovered and purified similarly to Example 28 to give the titled compound (86 mg; 84%) .
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[C:20](OCC)(OCC)(OCC)[CH3:21]>CN(C=O)C>[CH3:20][C:21]1[N:6]([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]2=[O:14])[C:4](=[O:5])[C:3]2[C:2](=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:19])[N:1]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: Cc1cccc(N)c1C(=O)NC1CCC(=O)NC1=O
Solvent: CN(C)C=O
Product: Cc1cccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c12
Temperature: 25 °C
Yield: 42.4 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-methyl-benzamide (1.00 g, 3.8 mmol) and triethyl orthoacetate (0.9 mL, 4.9 mmol) in DMF (10 mL) was heated to reflux for 1 hour. The mixture was cooled to room temperature. To the solution, Celite (40 mL) was added, and the solvent was removed in vacuo. The solid was loaded on a SIM and purified with ISCO flash gel chromatography (silica gel, CH3OH/CH2Cl2) to give 3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as an off-white solid (0.46 g, 43% yield): HPLC: Waters Symmetry C1-8, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 25/75 CH3CN/0.1% H3PO4, 2.95 min (96%); mp: 292-294° C.; 1H NMR (DMSO-d6) δ 2.11-2.18 (m, 1H, CHH), 2.55-2.65 (m, 2H, CH2), 2.60 (s, 3H, CH3), 2.69 (s, 3H, CH3), 2.78-2.85 (m, 1H; CHH), 5.19 (dd, J=6, 11 Hz, 1H, NCh), 7.25 (d, J=8 Hz, 1H, Ar), 7.43 (d, J=8 Hz, 1H, Ar), 7.64 (t, J=8 Hz, 1H, Ar), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.82, 22.43, 23.32, 30.55, 56.33, 118.69, 124.73, 128.82, 133.72, 139.82, 148.34, 154.58, 161.03, 169.61, 172.60; LCMS: MH=286; Anal. Calcd. for C15H15N3O3+1H2O: C, 59.26; H, 5.68; N, 13.66. Found: C, 59.26; H, 5.68; N, 13.66.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][CH2:9][C:10]([C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:18])=[O:11].Cl>N1C=CC=CC=1>[C:1]([O:8][CH2:9][C:10]([C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:18])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)CO
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)COC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Acetic anhydride (0.42 ml) was added, under ice-cooling, to a pyridine solution (2.4 ml) of (S)-2-[[(S)-2-(hydroxyacetyl)1-pyrrolidinyl]carbonyl]-1-octanoylpyrrolidine (1.06 g) obtained in Example 14 and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 1% hydrochloric acid and extracted with ethyl acetate. The extract was washed with 1% hydrochloric acid, water, saturated sodium hydrogencarbonate and water in order, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give the title compound (1.02 g) (see Table 4).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].CSC.B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OCc1cnc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
A slurry of 5,6-dichloronicotinic acid (25.3 g, 132 mmol) in THF (30 mL, 4.4 M) is cooled to 0° C. and carefully treated with 2 M borane dimethyl sulfide/THF (100 mL, 200 mmol) via syringe under a stream of nitrogen. After 1 h, the cooling bath is removed. After stirring overnight the colution is re-cooled to 0° C. and carefully quenched with water (20 mL). The reaction volume is reduced in vacuo, 50% NaHCO3 (150 mL) is added and the mixture is extracted with ethyl acetate (2×150 mL). The organic layer is washed with saturated aq NaCl (100 mL) and dried over Na2SO4. The product is purified by MPLC (30-90% ethyl acetate in n-heptane) to provide 5,6-dichloro-pyridin-3-yl-methanol as a white solid (19.1 g, 81%): Rf 0.57 (25% ethyl acetate in n-heptane), 1H NMR (CDCl3, 300 MHz) δ 8.27 (d, J=2.3 Hz, 1 H), 7.84 (d, J=2.3 Hz, 1 H), 4.74 (s, 2 H); ESI-LCMS m/z calcd for C6H5Cl2NO: 177.0; found 178.0 (M+1)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.Br[C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=1>>[OH:1][C:2]1([C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=2)[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Cc1ccnc(Br)c1
Product: Cc1ccnc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)c1
Yield: 56 %

Procedure:
Obtained in 56% yield by an analogous method to Example 321, preparation of starting materials, starting from benzyl 4-oxo-1-piperidinecarboxylate and 2-bromo-4-methylpyridine.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[O:8])=[CH:5][CH:4]=1)=O.Cl.[OH:18][NH2:19].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:18][N:19]=[CH:1][C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[O:8])=[CH:5][CH:4]=1
Reactant: NO
Reactant: O=Cc1ccc(C(=O)NCC(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(NCC(F)(F)F)c1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 89.6 %

Procedure:
In a solution of 4.11 g of 4-formyl-N-(2,2,2-trifluoroethyl) benzoic acid amide in 30 ml of ethanol and 10 ml of water, 1.99 g of hydroxyamine hydrochloride and 2.51 g of anhydrous sodium acetate were added, stirred at room temperature for 3.5 hours. After the completion of the reaction, the reaction mixture was poured in 100 ml of water, and then extracted with ethyl acetate (30 ml×3), the organic phase was washed with 50 ml of saturated sodium hydrogen carbonate aqueous solution, then dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residual solid was washed with hexane to obtain 3.92 g of the aimed product as white crystal.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:38]([CH:35]3[CH2:37][CH2:36]3)=[O:39])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)C1CC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)C1CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with cyclopropanecarbonyl chloride (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C33H37N2O2Cl2 [(M+H)+] 563.2227, observed 563.2224.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=2[CH3:37])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=[C:13]3[C:12]4[C:16](=[CH:17][C:9]([C:6]5[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=5)=[CH:10][CH:11]=4)[NH:15][C:14]3=[O:18])[NH:31][C:30]=2[CH3:37])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCc1ccc(-c2ccc3c(c2)NC(=O)C3)cc1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Product: CCc1ccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C)c(C(=O)NCCN3CCCC3)c2C)cc1
Yield: 65.5 %

Procedure:
6-(4-Ethylphenyl)-1,3-dihydroindol-2-one (45 mg, 0.19 mmol) was condensed 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (50 mg) to give 60 mg (65%) of the title compound as a yellow-orange solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([CH2:12][C:13]([OH:15])=[O:14])[CH2:5]2.C([O-])([O-])=O.[K+].[K+].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>N1C=CC=CC=1>[N:22]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH:6]([CH2:12][C:13]([OH:15])=[O:14])[CH2:5]3)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: O=C(O)CC1Cc2cc(F)ccc2C1=O
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(O)CC1Cc2cc(-n3ccnc3)ccc2C1=O
Yield: 39.4 %

Procedure:
A mixture of 3.3 g of 5-fluoro-2,3-dihydro-1-oxo-1H-indene-2-acetic acid [prepared by following the procedure of G. Cignarella, M. Loriga, G. A. Pinna, M. A. Pirisi, P. Schaitti, and D. Selva, Il Farmaco, Ed. Sci. 37(2), 133-40 (1981)], 2.2 g of anhydrous K2CO3, 1.65 g of imidazole, and 0.15 g of CuO in 15 ml of pyridine is heated to reflux for 24 hours. The reaction mixture is filtered, the filtrate is diluted with water, and the pH of the solution is adjusted to 5. The solid is filtered, washed with water, and crystallized from ethanol to yield 1.6 g of the product, 2,3-dihydro-5-(1H-imidazol -1-yl)-1-oxo-1H-indene-2 acetic acid, mp 224°-226° dec.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[Cl:10].[H-].[Na+].CS(O[CH2:18][CH2:19][O:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)(=O)=O>CN(C)C=O>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([O:9][CH2:18][CH2:19][O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)=[CH:4][C:3]=1[Cl:10]
Reactant: CS(=O)(=O)OCCOc1ccc2ccccc2c1
Reactant: Oc1cc(Cl)c(Br)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cc(OCCOc2ccc3ccccc3c2)cc(Cl)c1Br
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
A stirred mixture of 4-bromo-3,5-dichlorophenol (1.9 g) in dimethylformamide (20 mL) under argon was treated with 55% sodium hydride (0.345 g), stirred for 30 minutes and treated with 2-(2-naphthalenyloxy)ethyl methanesulfonate (2.1 g). The mixture was heated at 60° C. overnight and evaporated to dryness. The residue was mixed with water and excess sodium hydroxide solution, the product was extracted twice with dichloromethane, and the organic layers were washed with water. The combined organic layers were dried (Na2SO4), filtered, evaporated and crystallized from dichloromethane-diethyl ether to provide 3.3 g of 2-[2-(4-bromo-3,5-dichlorophenoxy)ethoxy]naphthalene as a colorless solid, mp 140°-142° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]2[O:14][CH2:13]2)=[CH:8][CH:7]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1>>[CH:17]1([NH:20][CH2:13][CH:12]([OH:14])[CH2:11][O:10][C:9]2[CH:15]=[CH:16][C:6]([C:2]3[NH:3][CH:4]=[CH:5][N:1]=3)=[CH:7][CH:8]=2)[CH2:19][CH2:18]1
Reactant: c1c[nH]c(-c2ccc(OCC3CO3)cc2)n1
Reactant: NC1CC1
Product: OC(CNC1CC1)COc1ccc(-c2ncc[nH]2)cc1

Procedure:
A mixture of 3-[p-(2-imidazolyl)phenoxy]-1,2-epoxypropane (4.95 g., 0.023 m.) in cyclopropylamine (50 ml.) is refluxed at 60° for 30 hours. The mixture is concentrated under reduced pressure and the residue is chromatographed on silica gel, eluting with 5-10% MeOH-CHCl3 saturated with NH3. The free base (IV) (1.21 g., 19%) is crystallized as the dihydrochloride salt from EtOH-MeOH-ether (m.p. 214°-5°).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][NH:9][CH2:8][CH2:7][C:6]=2[CH:11]=1.C[Al](C)C.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)[C:21]([C:34](OCC)=[O:35])=[CH:20]2>>[O:10]1[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:34]([C:21]3[N:22]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=4)[C:23]4[C:19]([CH:20]=3)=[CH:18][C:17]([F:16])=[CH:25][CH:24]=4)=[O:35])=[CH:11][C:6]=2[CH2:7][CH2:8][NH:9]1
Reactant: Nc1ccc2c(c1)CCNO2
Reactant: CCOC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Agent: C[Al](C)C
Product: O=C(Nc1ccc2c(c1)CCNO2)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 29.2 %

Procedure:
The process is performed according to the method described in Example 6, starting with 0.090 g of 6-amino-2,3-dihydrobenzoxazine (WO 2003/049702), 0.5 ml of trimethylaluminum (2M in toluene) and 0.157 g of ethyl 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylate, obtained in step 1.1 of Example 1. 0.061 g of product is obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][N:37]([C:39]3([CH2:44][C:45]#[N:46])[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH:38]=2)O1>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:34]4[CH:35]=[N:36][N:37]([C:39]5([CH2:44][C:45]#[N:46])[CH2:43][CH2:42][CH2:41][CH2:40]5)[CH:38]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: CC1(C)OB(c2cnn(C3(CC#N)CCCC3)c2)OC1(C)C
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Product: CN1CCN(c2cc(N3CCc4ccc(-c5cnn(C6(CC#N)CCCC6)c5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and {1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]cyclopentyl}acetonitrile. LCMS(M+H)+: m/z=498.5
Reaction SMILES: Br[CH:2]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9][C:8]2[CH:7]=[N:6][N:5]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:4]=2[C:3]1=[O:30].[Cl-].[NH4+]>O1CCCC1.[Zn]>[C:26]([N:5]1[C:4]2[C:3](=[O:30])[CH2:2][C:10]3([CH2:11][CH2:12][N:13]([C:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[O:17])[CH2:14][CH2:15]3)[CH2:9][C:8]=2[CH:7]=[N:6]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)n1ncc2c1C(=O)C(Br)C1(CCN(C(=O)OCc3ccccc3)CC1)C2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CC(C)(C)n1ncc2c1C(=O)CC1(CCN(C(=O)OCc3ccccc3)CC1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a solution of benzyl 6-bromo-1-tert-butyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carboxylate (50.4 g, 106 mmol) in tetrahydrofuran (600 mL), was added saturated aqueous ammonium chloride (600 mL) and zinc powder (20.8 g, 319 mmol). The reaction was stirred for 30 minutes at room temperature. The reaction was filtered through Celite®. The phases of the filtrate were separated and the organic phase was washed with water and saturated aqueous sodium chloride. The organics were dried over magnesium sulfate, filtered, and concentrated to provide a foam. The foam was triturated once with ethyl acetate/heptanes and once with diethylether to afford the title compound (40.4 g, 96%) as a white solid. +ESI (M+H) 396.5; 1H NMR (400 MHz, CDCl3, δ): 7.24-7.38 (m, 6H), 5.11 (s, 2 H), 3.36-3.61 (m, 4 H), 2.74 (s, 2 H), 2.54 (s, 2 H), 1.64 (s, 9 H), 1.51 (br. s., 4 H).