Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[O:25][C:26]=1[CH3:27].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[O:25][C:26]=1[CH3:27])[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Reactant: Cc1oc(-c2ccccc2Cl)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc2c1ccn2Cc1nc(-c2ccccc2Cl)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 1 a] and 1 b], rac-2-ethoxy-3-(1H-indol-4-yl)-propionic acid ethyl ester was reacted with 4-chloromethyl-2-(2-chloro-phenyl)-5-methyl-oxazole in N,N-dimethylformamide in the presence of sodium hydride to yield rac-3-{1-[2-(2-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-2-ethoxy-propionic acid ethyl ester, which was subsequently saponified to yield rac-3-{1-[2- (2-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-2-ethoxy-propionic acid as light brown solid.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:14])[C:6](=[O:15])[CH:5]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([CH:19]2[CH2:20][CH2:21][N:16]([CH2:2][CH2:3][C:4]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:7]([CH3:14])[C:6](=[O:15])[CH:5]=3)[CH2:17][CH2:18]2)=[CH:23]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: Cn1c(=O)cc(CCBr)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(CCN2CCC(c3c[nH]c4ccccc34)CC2)c2ccccc21
Temperature: 0 °C
Yield: 74 %

Procedure:
A mixture of 4-(2-bromoethyl)-1-methyl-2(1H)-quinolinone (II-7) (500 mg, 1.88 mmol), 3-(4-piperidinyl)-1H-indole (376.5 mg, 1.88 mmol) and sodium hydrogencarbonate (236.9 mg, 2.82 mmol) in dry dimethylformamide 5 ml was allowed to react 90 ° C. for 3.5 hours. The reaction mixture was poured into ice-water and then the separated solid was filtered off by aspiration. The solid was washed with water and dried. The obtained solid was dissolved in developing solvent (chloroform: methanol=95:5) and purified by silica gel column chromatography. After removing first eluted impurity, a colorless solution was collected and the solvent was distilled off to give the desired product (III-17) (536 mg) as white crystals (yield 74.0%, mp 79°-81 ° C. (benzene-hexane)).
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([C:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH:8](Br)[C:7]=1O)=[O:5])[CH3:2].[F:17][CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(O)C.[Cl-].[Zn+2].[Cl-]>[CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([CH:6]1[C:7]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:19][CH2:18][F:17])[C:8]=2[CH2:9][CH:10]([CH3:12])[CH2:11]1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)C1=C(O)C(Br)CC(C)C1
Reactant: FCCNc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Product: CCN(CC)C(=O)C1CC(C)Cc2c1c1ccccc1n2CCF
Temperature: 50 °C
Reaction time: 3 h
Yield: 17.3 %

Procedure:
A mixture of 3-bromo-2-hydroxy-5-methyl-cyclohex-1-enecarboxylic acid diethylamide (47; prepared according to Example 11(d)) (2.0 g, 7 mmol) and (2-fluoro-ethyl)-phenyl-amine (24; prepared according to Example 4(a)) (1.9 g, 14 mmol) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (7 mL) and dry zinc chloride (2.86 g, 21 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed with 2 N HCl (30 mL), water (2×30 mL) and aqueous potassium carbonate solution (2×30 mL) then dried and concentrated in vacuo. The crude mixture was purified by SCX cartridge (40 mL) and then silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (0-100% B, 100 g, 12 CV, 85 mL/min) to afford 400 mg (17%) of 9-(2-fluoro-ethyl)-2-methyl-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (non-radioactive imaging agent 11) as a white solid. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δH 1.10-1.35 (9H, m, CH3 and N(CH2CH3)2), 1.95-2.10 (2H, m, 3-CH2), 2.30-2.50 (1H, m, 2-CH), 2.70-2.80 (2H, m, 1-CH2), 3.40-3.70 (4H, m, N(CH2CH3)2), 4.05-4.15 (1H, m, 4-CH), 4.30 (2H, dm, J=21 Hz, NCH2CH2F), 4.65 (2H, dm, J=41 Hz, NCH2CH2F), and 7.00-7.30 (4H, m, NCCHCHCHCH.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:2]1([NH:1][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(Nc2ccccc2)cc1
Yield: 83.6 %

Procedure:
A mixture of BINAP (1.6 g, 0.00257 mole), palladium acetate (0.23 g, 0.001 mole) and toluene (30 mL) was degassed with argon for 15 minutes. This mixture was then added to a mixture of aniline (5.0 g, 0.0536 mole), 4-bromobenzoic acid (12.9 g, 0.0644 mole) and cesium carbonate (52.47 g, 0.161 mole) in toluene (30 mL) (previously degassed with argon for 15 minutes). The resulting mixture was heated at reflux for 22 hours. The reaction mixture was then concentrated under reduced pressure. The resulting residue was acidified with 10% HCl and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel 60-120 mesh (15% ethyl acetate in hexane) to afford 9.55 g (83%) of 4-phenylamino-benzoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][CH:11]2[CH2:15][CH2:14][O:13][C:12]2=[O:16])=[O:9])=[CH:4][CH:3]=1.C[O-].[Na+].C(Cl)Cl.Cl>CO>[OH:13][CH2:14][CH2:15][CH:11]1[NH:10][C:8](=[O:9])[N:7]([CH2:6][C:5]2[CH:17]=[CH:18][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:12]1=[O:16]
Reactant: Cc1ccc(CNC(=O)NC2CCOC2=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(CN2C(=O)NC(CCO)C2=O)cc1
Yield: 72.7 %

Procedure:
A solution of crude 1-(4-methyl-benzyl)-3-(2-oxo-tetrahydro-furan-3-yl)-urea (48.5 g, assume 0.137 mol) in MeOH (1.5 L) was treated with sodium methoxide (21.1 g, 0.391 mol) and heated to reflux under N2 for 2 h until done by thin layer chromatography (9:1 CH2Cl2:MeOH). The reaction was cooled and the solvent removed in vacuo to give a residue that was combined with aqueous 1 N HCl (640 mL) and extracted with EtOAc. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford 24.72 g (73%) of crude 5-(2-hydroxy-ethyl)-3-(4-methyl-benzyl)-imidazolidine-2,4-dione as a yellow solid which was carried on in the next step without purification. MS (ES+) Calc'd for C13H17N2O3 (M+1) 249. Found m/z 249 (100%). 1H NMR.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)=[O:4].Cl[C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].O>C(OCCO)CCC>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]2[NH:11][C:14]3[N:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](=[O:17])[NH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: O=C(O)c1cccnc1Cl
Solvent: O
Solvent: CCCCOCCO
Product: COC(=O)c1ccc2c(c1)NC(=O)c1cccnc1N2
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A stirred mixture of 1.66 g (0.010 mol) of 4-methoxycarbonyl-o-phenylene-diamine and 1.58 g (0.010 mol) of 2-chloronicotinic acid in 5 ml of 2-butoxyethanol was heated to 140° C. for 2 h, during which time a dark solution, followed by formation of a green solid, was observed. The reaction mixture was poured into 50 ml of water and the solid collected and stirred in 10% sodium carbonate solution for 1 h. The resulting solid was collected, washed thoroughly with water, dried and crystallized from DMF to yield 1.1 g (40% of theory) of a beige crystalline product, m.p. 344°-349° C.
Reaction SMILES: [CH3:1][CH:2]([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:3][CH3:4].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1.Cl>[OH-].[Na+]>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:8][S:5]([CH:2]([CH2:3][CH3:4])[CH3:1])(=[O:7])=[O:6])=[O:18])=[CH:12][CH:11]=1
Reactant: CCC(C)S(N)(=O)=O
Reactant: O=C=Nc1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCC(C)S(=O)(=O)NC(=O)Nc1ccc(Br)cc1
Yield: 56.1 %

Procedure:
The general method of procedure A was followed with 2-butanesulfonamide (10 g, 73 mmole), 1N sodium hydroxide (73 ml), and 4-bromophenyl isocyanate (13.7 g). The filtrate from the reaction mixture was treated with 1N HCl and the resulting precipitate redissolved in 1N sodium hydroxide and reprecipitated with 1N HCl. The solid product was collected and dried at 65° C. under vacuum. The dissolution and precipitation procedure was repeated to provide 13.0 g of product which had the following analysis.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([NH:12][CH2:13][CH2:14][CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][S:17]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26]=O)[CH2:22][CH2:21]1)(=[O:19])=[O:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH2:26][CH:23]3[CH2:24][CH2:25][N:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH2:21][CH2:22]3)[CH2:13][CH2:14][CH3:15])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCCNC1CCc2ccc(Br)cc2C1
Reactant: CS(=O)(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCN(CC1CCN(S(C)(=O)=O)CC1)C1CCc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.6 %

Procedure:
To a solution of (7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine (536 mg, 2 mmol) and 1-methanesulfonyl-piperidine-4-carboxaldehyde (458 mg, 2.47 mmol) in dichloroethane (10 mL) was added sodium triacetoxyborohydride (551 mg, 2.6 mmol) in a single portion. The reaction was stirred at room temperature for 24 h. The reaction was concentrated in vacuo and partitioned between EtOAc (75 mL) and 5% aq. KOH (75 mL). The organic layer was dried (MgSO4), filtered, and concentrated to afford (7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-(1-methanesulfonyl-piperidin-4-ylmethyl)-propyl-amine (857 mg) 111 [M+H]+=444.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][OH:25])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].CN(C)C1C=CC=CC=1.[CH3:36][CH:37]([CH2:41][CH2:42][CH3:43])[C:38](Cl)=[O:39]>ClCCl.C(OCC)(=O)C>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:25][C:38](=[O:39])[CH:37]([CH3:36])[CH2:41][CH2:42][CH3:43])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CO
Reactant: CCCC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Product: CCCC(C)C(=O)OCC(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C
Yield: 19.8 %

Procedure:
In 20 ml of dichloromethane are dissolved 0.5 g of 16β-ethyl-17β-glycoloyloxy-4-estren-3-one and 0.2 ml of N,N-dimethylaniline, and 0.5 g of 2-methylvaleryl chloride is added to the above solution. The mixture is refluxed for 6 hours. After cooling, the reaction mixture is diluted with 150 ml of ethyl acetate and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 200 ml of diisopropyl ether-n-hexane (2:8), elution is carried out with 500 ml of a 1:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 0.126 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:15]Br>CCOCC>[Br:15][CH:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:11]1=[O:14]
Reactant: BrBr
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Solvent: CCOCC
Product: O=C1c2cc([N+](=O)[O-])ccc2CCC1Br

Procedure:
To a suspension of 9.56 g (0.05 mol) of 7-nitro-1-tetralone in 250 mL of ether was added bromine dropwise. The progress of the reaction was followed by thin layer chromatography (fl. silica gel/CH2Cl2). When all of the starting material had been consumed, the mixture was concentrated and cyclohexane was added. The white solid was removed by filtration to afford 2.25 g of 2-bromo-7-nitrotetralone, mp 94°-96° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[NH:12][N:11]=[CH:10][C:9](=O)[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:9]1[CH:8]=[C:7]([CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[N:12]=[N:11][CH:10]=1
Reactant: O=c1cn[nH]c(Cn2ccnc2)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cnnc(Cn2ccnc2)c1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
6-(imidazol-1-yl-methyl)-1H-pyridazin-4-one (X) is taken in phosphorus oxychloride under argon. The mixture is stirred in a 60° C. oilbath for 1.5 hour. The solvent is removed in vacuo and the residue is dissolved in water under icebath cooling. The solution is neutralized with solid NaHCO3 and the aqueous layer is extracted with MeCl2 to provide the corresponding 5-chloro-3-(imidazol-1-yl-methyl)-pyridazine (IV A).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].[Sb](Cl)(Cl)(Cl)(Cl)Cl>CC(C)=O>[CH3:2][C:3]1([CH3:5])[O:6][CH:5]2[CH:7]3[O:8][C:9]([CH3:11])([CH3:7])[O:10][C:9]3([CH2:11][OH:12])[O:4][CH:3]2[CH2:2][O:1]1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Solvent: CC(C)=O
Product: CC1(C)OCC2OC3(CO)OC(C)(C)OC3C2O1
Temperature: 61 °C
Reaction time: 8 h
Yield: 170.1 %

Procedure:
To 200 ml of acetone were added 10.0 g of L-sorbose and 89.7 mg of antimony pentachloride, and the mixture was refluxed with stirring in a water bath of 61° C. for 8 hours. During this reaction, the refluxing solvent was dried with 35 g of Molecular Sieves 3A interposed between the reaction vessel and the condenser. After completion of the reaction, the total volume of the reaction mixture was adjusted to 200 ml, and the quantitative analysis by gas chromatography (column: 3% Silicon OV-17, on Uniport HPS 3m, column temperature; 160° C.) indicated that there was obtained 12.29 g (85.1%) of 2,3:4,6-di-O-isopropylidene-α-L-sorbofuranose.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]([N:38]([CH3:46])[C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)=[O:37])[CH2:31][CH2:30]1.N1CCCCC1.O>CN(C)C=O>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]([N:38]([C:39]2[CH:44]=[CH:43][C:42]([NH:45]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:41][CH:40]=2)[CH3:46])=[O:37])[CH2:31][CH2:30]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN1CCN(CC(=O)N(C)c2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: O
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CN2CCN(C)CC2)cc1)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
10.5 g (30.0 mmol) of 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone (for preparation see WO 01/27081 mentioned above) and 8.60 g (33.0 mmol) N-[(4-methyl-piperazin-1-yl)-methylcarbonyl]-N-methyl-p-phenylenediamine (for preparation see WO 01/27081 mentioned above) are dissolved in 80 mL of dimethylformamide and stirred for 1 hour at 80° C. After cooling 6.50 mL of piperidine are added and the mixture is stirred for another two hours at ambient temperature. Water is added, the precipitate formed is suction filtered and washed with a little water. The residue is suspended in 200 mL of methanol, suction filtered and washed with cold water and diethyl ether. The substance is dried in vacuo at 110° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][NH2:13].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(CCN)c1OC
Product: COc1cccc(CCNC(C)=O)c1OC

Procedure:
In close analogy to the procedure described above, 2-(2,3-dimethoxy-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:16]=1[NH2:17]>>[Cl:1][C:2]1[N:11]=[C:10]([NH:17][C:16]2[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:15]=2[O:14][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: COc1ccc(OC)c(N)c1
Product: COc1ccc(OC)c(Nc2nc(Cl)nc3ccccc23)c1

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline and 2,5-dimethoxyaniline by a procedure similar to example 28 (98% yield). 1H NMR (CDCl3): 8.59 (d, J=3.0 Hz, 1H), 8.53 (s, broad, 1H), 7.78-7.87 (m, 3H), 7.57 (ddd, J=8.4, 6.6 and 1.8 Hz, 1H), 6.88 (d, J=9.0 Hz, 1H), 6.60 (dd, J=8.7 and 3.0 Hz, 1H), 3.97 (s, 3H), 3.87 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([OH:25])[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:45][N:46]1[CH2:50][CH2:49][CH:48]([CH2:51]O)[CH2:47]1.N(C(OCC)=O)=NC(OCC)=O.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([O:25][CH2:51][CH:48]5[CH2:49][CH2:50][N:46]([CH3:45])[CH2:47]5)[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O)c4n3)cnc2c1
Reactant: CN1CCC(CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1ccn2c(-c3ccc4cccc(OCC5CCN(C)C5)c4n3)cnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.8 %

Procedure:
To a solution of 2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-ol (300 mg, 0.90 mmol) in anhydrous THF (15 ml) were added at ambient temperature under a nitrogen atmosphere triphenylphosphine (352 mg, 1.34 mmol), (1-methylpyrrolidin-3-yl) methanol (155 mg, 1.34 mmol) and diethyl azodicarboxylate (0.21 ml, 1.34 mmol). The reaction mixture was stirred at ambient temperature under nitrogen atmosphere overnight. The mixture was treated with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with CH2Cl2 and EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated to afford the crude product. The crude product was purified by column chromatography on silica gel (elution with 10% MeOH/CH2Cl2) to afford partially purified product. This material was purified by silica gel chromatography (eluting with 10% 7N NH3/MeOH/CH2Cl2) to provide the title compound (34.2 mg, 9% yield) as a solid. MS ESI (+) m/z 433.2 (M+1) detected.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:24][CH:23]2[CH:21]([CH:22]2[C:25]2[NH:29][N:28]=[C:27]([C:30]3[CH:31]=[C:32]([O:37][C:38]([F:41])([F:40])[F:39])[C:33]([NH2:36])=[N:34][CH:35]=3)[CH:26]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:49][CH:50]1[CH2:52][CH2:51]1>CN(C)C=O>[Si:1]([O:18][CH:19]1[CH2:24][CH:23]2[CH:21]([CH:22]2[C:25]2[N:29]([CH2:49][CH:50]3[CH2:52][CH2:51]3)[N:28]=[C:27]([C:30]3[CH:31]=[C:32]([O:37][C:38]([F:41])([F:39])[F:40])[C:33]([NH2:36])=[N:34][CH:35]=3)[CH:26]=2)[CH2:20]1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCC1CC1
Reactant: CC(C)(C)[Si](OC1CC2C(C1)C2c1cc(-c2cnc(N)c(OC(F)(F)F)c2)n[nH]1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC1CC2C(C1)C2c1cc(-c2cnc(N)c(OC(F)(F)F)c2)nn1CC1CC1)(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 135.5 %

Procedure:
To a round-bottomed flask charged with 5-(5-(3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethoxy)pyridin-2-amine (0.40 g, 0.35 mmol) and cesium carbonate (0.68 g, 2.1 mmol) in N,N-dimethylformamide (4 mL) was added bromomethylcyclopropane (0.28 mg, 2.1 mmol) at 20° C. After 16 h, the reaction mixture was partitioned between ethyl acetate (20 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organics were washed with saturated aqueous sodium chloride solution (2×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (30% ethyl acetate in petroleum ether) afforded product as an orange oil (0.30 g, 69% yield). LCMS (ESI) [MH]+=633.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6])[CH3:2].[C:17]([O-:20])([O-])=[O:18].[Cs+].[Cs+]>>[CH2:1]([O:3][C:4](=[O:16])[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:12][CH2:11][CH2:10][NH:9][C:17]([O:20][C:7]([CH3:15])([CH3:8])[CH3:5])=[O:18])[CH:8]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)C(=O)c1cn(CCCNC(=O)OC(C)(C)C)c2ccccc12
Yield: 230.4 %

Procedure:
The general procedure 1 was then followed using the above product (7.14 mmol, 1.7 g), ethyl-2-(1H-indol-3-yl)-2-oxoacetate (4.6 mmol, 1.0 g) and Cs2CO3 (9.21 mmol, 3.0 g). The purification was achieved by column chromatography (petrol-ether:ethylacetate 1:1) to yield ethyl-2-(1-{3-[(tert.-butoxycarbonyl)amino]propyl}-1H-indol-3-yl)-2-oxoacetate (5.3 mmol, 74%) as pale yellow crystals. Mp 89-90° C. IR {tilde over (ν)} [cm−1]=3392; 2977; 2936; 1727; 1698; 1619; 1515. EI-MS m/z (rel. int.)=374 (8.9%; M+•.). 1H NMR (300 MHz, CDCl3) 8.45 (m; 2H; indole-H); 7.35 (m; 3H; indole-H); 4.63 (bs; 1H; NH); 4.41 (q; 3J=7.1 Hz; 2H; OCH2CH3); 4.24 (t; 3J=7.1 Hz; 2H; indole-CH2); 3.18 (q; 3J=6.1 Hz; 2H; CH2N); 2.09 (m; 2H; CH2CH2CH2); 1.44 (s; 9H; C(CH3)3); 1.43 (t; 3J=7.1 Hz; 3H; OCH2CH3).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[C:13]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:23][C:24](OCC)=[O:25].O.[OH-].[Na+]>O1CCCC1>[NH2:7][C:8]1[C:13]([CH:14]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)[OH:22])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:23][CH2:24][OH:25]
Reactant: CCOC(=O)Cc1cccc(C(=O)c2ccc(Br)cc2)c1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(CCO)cccc1C(O)c1ccc(Br)cc1
Yield: 54.9 %

Procedure:
To a stirred slurry of 3.3 g (0.087 mole) of lithium aluminum hydride in 75 ml of dry tetrahydrofuran a solution of 15.8 g (0.043 mole) of 2-amino-3-(4-bromobenzoyl) benzeneacetic acid, ethyl ester in 175 ml of tetrahydrofuran was added dropwise over a 20 min period. The mixture was then heated at reflux for 1.5 hr under nitrogen atomsphere. The mixture was cooled and treated successively with 3.3 ml of water, 3.3 ml of a 5% sodium hydroxide solution and 10 ml of water. The mixture was filtered through celite and the filter cake was washed thoroughly with tetrahydrofuran. The combined filtrate and tetrahydrofuran wash was concentrated under reduced pressure to give a solid residue. The solid was recrystallized from ethyl acetate to yield 7.6 g (54%) of the titled compound as gray solid, m.p. 128°-129° C.