Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH:12]([O:18][CH2:19][CH3:20])[C:13]([O:15]CC)=[O:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>O.CO>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH:12]([O:18][CH2:19][CH3:20])[C:13]([OH:15])=[O:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(OCC)Oc1ccc2ncccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC(Oc1ccc2ncccc2c1)C(=O)O
Reaction time: 0.08 h
Yield: 44.5 %

Procedure:
Ethyl 2-(6-quinolinyloxy)-2-(ethoxy)acetate (3.68 g) was added to a solution of sodium hydroxide (0.589 g) in water (10 ml) and methanol (30 ml) and stirred for 5 minutes. The solution was evaporated under reduced pressure, water added and the aqueous phase was washed with ethyl acetate. The aqueous phase was acidified with hydrochloric acid and extracted with ethyl acetate. The extracts were combined, dried over magnesium sulphate and evaporated under reduced pressure to give 2-(6-quinolinyloxy)-2-(ethoxy)acetic acid (1.47 g) as a cream solid.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:20])/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:4].[OH-].[Na+]>CO>[C:10]([N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C:3]([OH:4])=[O:2])(=[O:20])/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCC/C=C/C(=O)N1CCC[C@H]1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCC/C=C/C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.8 %

Procedure:
Compound 3 (0.84 g, 3 mmol) was dissolved in methanol (40 mL), and a 1 mol/L aqueous sodium hydroxide solution (4 mL, NaOH 4 mmol) was added thereto at room temperature, and the mixture was stirred for 20 hours. The solvent was distilled off under a reduced pressure, and the residue was then dissolved in water, and a 10% aqueous citric acid solution was added thereto to adjust its pH to about 4. The liquid mixture was extracted with dichloromethane, an organic layer was washed with water and saturated sodium chloride solution, and the washed extract was then dried over anhydrous sodium sulfate, to give an intended compound (0.72 g, 90%) in the form of a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[C:33](Cl)(=[O:36])[CH2:34][CH3:35].O>C(Cl)Cl>[C:33]([NH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[CH:9][CH:8]=[CH:7][CH:6]=2)(=[O:36])[CH2:34][CH3:35]
Reactant: CC(C)(C)OC(=O)NCCOCCNc1c(N)cnc2ccccc12
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1cnc2ccccc2c1NCCOCCNC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 44.6 %

Procedure:
A solution of tert-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (32.0 g, 92.0 mmol) in 300 mL of CH2Cl2 was treated with triethylamine (19.2 mL, 138.0 mmol). The reaction was chilled in an ice water bath and then propionyl chloride (9.40 mL, 108.2 mmol) was added dropwise. After stirring for 18 h, the reaction was treated with water (150 mL) and the layers were separated. The aqueous portion was extracted with CH2Cl2 (3×50 mL). The combined organic portions were washed with 1% Na2CO3, water, brine, dried over Na2SO4, filtered and concentrated to yield a red sticky solid. The solid was triturated with ether and filtered to yield 16.5 g of tert-butyl 2-(2-{[3-(propionylamino)quinolin-4-yl]amino}ethoxy)ethylcarbamate as an off white powder.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([O:7][CH3:8])[N:3]=1.C(N(CC)CC)C.[Br:16][CH2:17][C:18](Br)=[O:19]>C1COCC1.O.C(OCC)(=O)C>[CH3:8][O:7][C:4]1[N:3]=[C:2]([NH:1][C:18](=[O:19])[CH2:17][Br:16])[S:6][N:5]=1
Reactant: COc1nsc(N)n1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1nsc(NC(=O)CBr)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To an ice-cooled solution of 5-amino-3-methoxy-[1,2,4]thiadiazole (1.31 g, 10 mmol) in THF (25 mL) was added triethylamine (2.22 g, 11 mmol) followed by dropwise addition of bromoacetyl bromide (1.52 g, 15 mmol). The resulting mixture was stirred at room temperature for 16 h. The mixture was diluted with water (25 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers was dried (sodium sulfate), filtered and concentrated in vacuo. Purification by column chromatography on silica gel using a solvent gradient of a mixture of dichloromethane and methanol (98/2, 97/3 and 96/4) afforded 3-methoxy-5-bromoacetamido-[1,2,4]thiadiazole as a white solid (1.26 g, 50%). M.p. 198-199° C.; 1H-NMR (CDCl3) δ 13.10 (br. s, 1H, NH), 4.28 (s, 2H, CH2), 4.11 (s, 3H, OMe); 13C-NMR (CDCl3) δ 176.8 (C3), 166.9 (C5), 166.6 (C═O), 56.9 (OMe), 25.9 (CH2).
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[NH:11][CH:27]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:20]2=[O:19]
Reactant: Nc1ccc(Cc2cccc(Cl)c2Cl)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c[nH]c2ccc(Cc3cccc(Cl)c3Cl)cc2c1=O
Temperature: 250 °C
Yield: 67.6 %

Procedure:
4-(2,3-Dichlorobenzyl)phenylamine (10.0 g, 39.7 mmol) obtained in Step 2 was dissolved in toluene (100 ml) and diethyl ethoxymethylenemalonate (8.8 ml, 43.7 mmol) was added. The mixture was heated under reflux for 3 hrs. The reaction solution was concentrated under reduced pressure, and diphenyl ether (100 ml) was added to dissolve the residue. The mixture was stirred with heating at 250° C. for 3 hrs. After allowing the mixture to cool, n-hexane was added to the reaction solution and the precipitate was collected by filtration, washed with chloroform and vacuum-dried to give an object product (10.1 g, yield 68%) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]([Cl:17])([Cl:16])[C:13](Cl)=[O:14]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]2[C:8]([C:13](=[O:14])[C:12]([Cl:17])([Cl:16])[Cl:11])=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Clc1cccc2nccn12
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(c1cnc2cccc(Cl)n12)C(Cl)(Cl)Cl
Yield: 8.3 %

Procedure:
To a solution of 45.77 g (0.30 mol) of 5-chloroimidazo[1,2-a]pyridine and 120.9 g (0.99 mol) of 4-dimethylaminopyridine in 500 ml of chloroform was added dropwise 163.5 g (0.90 mol) of trichloroacetyl chloride. The mixture was heated for 43 hours under reflux. After cooling, the reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate/n-hexan=1:1) to give 7.41 g of the desired compound (8.3%, pale brown solid).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C@H:28]([O:30][CH2:31][C@H:32]([O:44][C:45]1[N:50]=[CH:49][N:48]=[C:47]2[N:51]([C:54]3[C:59]([Cl:60])=[CH:58][CH:57]=[CH:56][N:55]=3)[N:52]=[CH:53][C:46]=12)[C:33]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][N:37]=1)=[O:34])[CH3:29])(C(C)(C)C)(C)C>C1COCC1>[Cl:60][C:59]1[C:54]([N:51]2[C:47]3=[N:48][CH:49]=[N:50][C:45]([O:44][C@@H:32]([CH2:31][O:30][C@H:28]([CH3:29])[CH2:27][OH:26])[C:33]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][N:37]=4)=[O:34])=[C:46]3[CH:53]=[N:52]2)=[N:55][CH:56]=[CH:57][CH:58]=1
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(C#N)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](CO)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
Tetrabutylammonium fluoride (1M in THF) (0.973 mL, 0.97 mmol) was added to (2S)-3-((R)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-cyanopyridin-2-yl)propanamide (Intermediate AN3) (395 mg, 0.65 mmol) in THF (10 mL) under nitrogen. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl (10 mL), extracted with Et2O (3×15 mL), the combined organic layers were back washed with water (10 mL), dried (MgSO4), and evaporated to afford crude product. The crude product was purified by preparative chiral-HPLC on a Merck 50 mm 20 μm Chiralpak column, eluting isocratically with 30% EtOH in isohexane (modified with Et3N) as eluent to afford the product (95 mg, 29.6%). 1H NMR (400 MHz, CDCl3) δ1.17 (d, 3H), 2.71-2.78 (m, 1H), 3.56-3.72 (m, 2H), 3.78-3.87 (m, 1H), 4.09-4.16 (m, 1H), 4.26-4.32 (m, 1H), 6.01-6.05 (m, 1H), 7.46-7.50 (m, 1H), 7.94-7.98 (m, 1H), 7.99-8.04 (m, 1H), 8.32-8.36 (m, 1H), 8.45 (s, 1H), 8.54-8.56 (m, 1H), 8.60-8.63 (m, 1H), 8.64 (s, 1H), 9.51 (s, 1H); m/z (ESI+) (M+H)+=495.42; HPLC tR=1.75 min
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]([CH3:46])[C:14]2[N:15]=[C:16]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH2:37][CH2:36][CH:35]([N:38]5[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]5)[CH2:34][CH2:33]4)=[C:28]([CH3:45])[CH:27]=3)[C:17]([C:22]([NH2:24])=[O:23])=[N:18][C:19]=2[CH2:20][CH3:21])[CH2:9]1)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].C(O)C>[CH2:20]([C:19]1[N:18]=[C:17]([C:22]([NH2:24])=[O:23])[C:16]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][CH:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:34][CH2:33]3)=[C:28]([CH3:45])[CH:27]=2)=[N:15][C:14]=1[N:13]([CH3:46])[C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH3:21]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1N(C)[C@@H]1CCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1N(C)[C@@H]1CCNC1
Yield: 74 %

Procedure:
A mixture of 5-{[(3R)-1-benzylpyrrolidin-3-yl](methyl)amino}-6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (60 mg), and ethanol (21 mL) was reacted using a continuous hydrogenation reaction device (H-Cube (registered trademark); manufactured by ThalesNano) under the conditions of CatCart (registered trademark) 20% palladium hydroxide-supported carbon (manufactured by ThalesNano), a flow rate of 1 mL/min, a temperature of 50° C., and a pressure of 290 psi. The solvent was evaporated under reduced pressure to obtain 6-ethyl-3-(3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl amino)-5-{methyl[(3R)-pyrrolidin-3-yl]amino}pyrazine-2-carboxamide (38 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][CH:24]1[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27][CH2:26][O:25]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][CH:24]1[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27][CH2:26][O:25]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCOC(CON)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCOC(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.22 g, 0.80 mmol) in dry DCM (20 mL) were added tert-butyl 2-[(aminooxy)methyl]-1,4-oxazepane-4-carboxylate 131 (0.23 g, 0.93 mmol, US 2010/0168080 and J. Med. Chem. 2008, 51, 4601-4608), 1-hydroxybenzotriazole (0.15 g, 1.12 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.21 g, 1.12 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give tert-butyl 2-{[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}-1,4-oxazepane-4-carboxylate 132 (0.32 g, 80%) as a clear thick oil.
Reaction SMILES: CCN(C(C)C)C(C)C.C(OC([N:17]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26]O)=[CH:23][CH:24]=2)[CH:19]=[C:18]1[C:28]1[C:29](=[O:57])[N:30](COCC[Si](C)(C)C)[CH:31]=[C:32]([NH:34][C:35]([C:37]2[CH:38]=[N:39][N:40]([CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:41]=2)=[O:36])[CH:33]=1)=O)(C)(C)C.CS(Cl)(=O)=O.[CH3:63][C@H:64]1[CH2:69][CH2:68][CH2:67][C@@H:66]([CH3:70])[NH:65]1>ClCCCl.C(OCC)(=O)C>[CH3:63][C@H:64]1[CH2:69][CH2:68][CH2:67][C@@H:66]([CH3:70])[N:65]1[CH2:26][C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[NH:17][C:18]([C:28]1[C:29](=[O:57])[NH:30][CH:31]=[C:32]([NH:34][C:35]([C:37]3[CH:38]=[N:39][N:40]([CH2:42][C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH:41]=3)=[O:36])[CH:33]=1)=[CH:19]2
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(NC(=O)c3cnn(Cc4ccccc4)c3)cn(COCC[Si](C)(C)C)c2=O)cc2cc(CO)ccc21
Reactant: C[C@@H]1CCC[C@H](C)N1
Agent: CS(=O)(=O)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H]1CCC[C@H](C)N1Cc1ccc2[nH]c(-c3cc(NC(=O)c4cnn(Cc5ccccc5)c4)c[nH]c3=O)cc2c1
Temperature: 0 °C

Procedure:
The title compound was prepared by the route outlined in Scheme 8, following the same experimental procedures as for Example 51, with the following modification. Deprotection of intermediate (8e), 5-(tert-Butyl-dimethyl-silanyloxymethyl)-2-[5-{[1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylic acid tert-butyl ester, in the usual manner, yielded 2-[5-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester. DIPEA (153 μL, 0.9 mmol) and 2-[5-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester (0.2 g, 0.3 mmol) were stirred in 1,2-dichloroethane (5 mL) and cooled to 0° C. Methanesulfonyl chloride (27 μL, 0.36 mmol) was added drop wise at 0° C. and stirred for a further 2 hours at 0° C. cis-2,6-Dimethylpiperidine (118 μL 0.9 mmol) was added drop wise at 0° C. and then the reaction was allowed to attain ambient temperature. The reaction mixture was heated at reflux overnight followed by cooling to ambient temperature. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (30 mL), saturated sodium hydrogen carbonate solution (30 mL), brine, dried (Na2SO4) and concentrated in vacuo. The resultant crude product was taken up in methanol (1 mL) and loaded onto a 5 g SCX column. The column was flushed with methanol and then eluted with ammonia solution 7N in methanol. The eluent was concentrated in vacuo to afford the title compound as a light brown solid, 120 mg, 53%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH2:18][O:19][CH3:20])[NH:12][C:11](=[O:21])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)CCl.CN1CCOCC1.[N+:33]([C:36]1[CH:37]=[C:38]([C:42]2[CH2:43][CH2:44][N:45]([CH2:48][CH2:49][CH2:50][NH2:51])[CH2:46][CH:47]=2)[CH:39]=[CH:40][CH:41]=1)([O-:35])=[O:34]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:14]([C:15]([NH:51][CH2:50][CH2:49][CH2:48][N:45]3[CH2:44][CH:43]=[C:42]([C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([N+:33]([O-:35])=[O:34])[CH:37]=4)[CH2:47][CH2:46]3)=[O:17])=[C:13]([CH2:18][O:19][CH3:20])[NH:12][C:11](=[O:21])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COCC1=C(C(=O)O)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1
Reactant: NCCCN1CC=C(c2cccc([N+](=O)[O-])c2)CC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: COCC1=C(C(=O)NCCCN2CC=C(c3cccc([N+](=O)[O-])c3)CC2)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1
Reaction time: 18 h

Procedure:
A solution of (4R)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid (1.2 eq), EDC (1.5 Eq.), N-methylmorpholine (2.0 Eq.) in dichloromethane was stirred at room temperature for 15 minutes, followed by addition of 3-(4-(3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinyl)-1-propanamine (1.0 eq.) to the reaction mixture. The resulting solution was stirred for 18 hours, concentrated and chromatographed on silica to give (4R)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-N-[3-(4-(3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxamide.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.CCN(CC)CC.[N:16]1([S:22](Cl)(=[O:24])=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(#N)C>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:22]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)(=[O:24])=[O:23])=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: O=S(=O)(Cl)N1CCOCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1ccc(I)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 10 g of 4-iodoaniline (45.6 mmol) in 200 ml of acetonitrile there are added 6.41 ml of Et3N (45.6 mmol) and 8.47 g of morpholine-4-sulphonyl chloride (45.6 mmol). The reaction mixture is stirred for 16 hours at ambient temperature. The acetonitrile is evaporated off in vacuo, and the residue is taken up in 1N HCl and extracted with CH2Cl2. The organic phases are combined, washed with brine, dried (MgSO4) and treated with animal charcoal to yield the title product.
Reaction SMILES: [N:1]1([C:5]2[N:10]=[CH:9][C:8]([NH:11][C:12]([C:14]3[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[C:16]4[C:21]([CH:22]=3)=[CH:20][C:19](I)=[CH:18][CH:17]=4)=[O:13])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:32]1([CH:38]([SiH3:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+]>CN1CCCC1=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:1]1([C:5]2[N:10]=[CH:9][C:8]([NH:11][C:12]([C:14]3[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[C:16]4[C:21]([CH:22]=3)=[CH:20][C:19]([SiH2:45][CH:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:18][CH:17]=4)=[O:13])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: [SiH3]C(c1ccccc1)c1ccccc1
Reactant: O=C(Nc1ccc(N2CCC2)nc1)c1cc2cc(I)ccc2n1Cc1cccc(F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(N2CCC2)nc1)c1cc2cc([SiH2]C(c3ccccc3)c3ccccc3)ccc2n1Cc1cccc(F)c1
Yield: 11.4 %

Procedure:
Compound No. 12 was prepared according to a process similar to that described in stage 8.4, by reacting 0.15 g (0.28 mmol) of N-[6-(azetidin-1-yl)pyridin-3-yl]-5-iodo-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in stage 8.3, with 167 mg (0.84 mmol) of diphenylmethylsilane in the presence of 0.18 g (0.84 mmol) of potassium triphosphate and of 15 mg (0.03 mmol) of bis(tri-tert-butylphosphine)palladium in 2 ml of dry 1-methyl-2-pyrrolidinone (NMP). 19 mg of the expected product are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][N:13]=[C:12]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22][C:23]1[CH:24]=[C:25]2[C:29](=[N:30][CH:31]=1)[NH:28][CH:27]=[CH:26]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([O:22][C:12]3[C:11]4[C:16](=[CH:17][C:18]([O:19][CH3:20])=[C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:10]=4)[N:15]=[CH:14][N:13]=3)=[CH:31][N:30]=2)[CH:26]=[CH:27]1
Reactant: Oc1cnc2[nH]ccc2c1
Reactant: COc1cc2ncnc(Cl)c2cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3cnc4[nH]ccc4c3)c2cc1OCc1ccccc1
Yield: 60.6 %

Procedure:
A solution of 6-benzyloxy-4-chloro-7-methoxyquinazoline (0.449 g, 1.49 mmol), (EP1153920 production examples 28-30), 5-hydroxy-7-azaindole (0.22 g, 1.64 mmol) and potassium carbonate (0.28 g, 2.02 mmol) in DMF (5 ml) was stirred at 95° C. for 3 hours. The mixture was filtered and the filtrate was evaporated and dried overnight under vacuum. The residue was triturated under methylene chloride and ethyl acetate and the solid was filtered and dried under vacuum to give 4-(7-azaindol-5-yloxy)-6-benzyloxy-7-methoxyquinazoline (0.36 g, 60%).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[N:8]=[CH:7][C:6]2[CH:9]=[CH:10][NH:11][C:5]=2[CH:4]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[OH-].[K+]>CO>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH:22]=[C:23]([C:9]2[C:6]3[CH:7]=[N:8][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][C:5]=3[NH:11][CH:10]=2)[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CN(C)c1cc2[nH]ccc2cn1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN(C)c1cc2[nH]cc(C3=CCN(C(=O)OC(C)(C)C)CC3)c2cn1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
Dimethyl-(1H-pyrrolo[3,2-c]pyridin-6-yl)-amine (100 mg, 0.62 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (248 mg, 1.24 mmol) and potassium hydroxide (139 mg, 2.48 mmol) were added in MeOH (5 mL) and heated to reflux for 16 h. The reaction mixture was then cooled to room temperature and poured into ice water (20 mL). The mixture was extracted with 10% MeOH/CH2Cl2 (5×10 mL). The organic extracts was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica, 0-5% MeOH/CH2Cl2) to obtain 180 mg (85%) of the title compound. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.58. MS (electrospray): exact mass calculated for C19H26N4O2, 342.21; m/z found, 343.2 (M++H). 1H NMR (CDCl3, 400 MHz): 9.09 (br s, 1H), 8.76 (s, 1H), 6.90 (d, J=2.15 Hz, 1H), 6.32 (s, 1H), 6.10 (br s, 1H), 4.10-4.05 (m, 2H), 3.62 (t, J=5.87 Hz, 2H), 3.03 (s, 6H), 2.52-2.44 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])=[CH:13][CH:12]=1)([CH3:10])[CH3:9].O.[OH-].[Na+]>C1COCC1.C(OCC)C>[CH3:10][C:8]([C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:15][CH:16]=1)([CH3:7])[CH3:9]
Reactant: CC(C)(C)c1ccc(CCCC(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)c1ccc(CCCCO)cc1
Temperature: 0 °C
Yield: 97.5 %

Procedure:
To a stirred suspension of lithium aluminum hydride (4.0 g, 0.105 mol) in THF (100 mL) at 0° C. under a nitrogen atmosphere was added a solution of 4-[4-(1,1-dimethylethyl)-phenyl]butanoic acid (10.31 g, 0.0455 mol) in THF (80 mL). The reaction was heated to reflux for 6 hours. The reaction was cooled to 0° C. and water (4 mL), 15% NaOH (4 mL) and water (12 mL) were carefully added. Ethyl ether (150 mL) was added, the mixture warmed to ambient temperature, and the precipitated salts were removed by filtration. Removal of solvent gave 9.15 g of 4-[4-(1,1-dimethylethyl)phenyl]-butanol as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C@H:18]([CH:21]2[CH2:23][CH2:22]2)[CH2:19][CH3:20])[C:12]=1[N+:24]([O-])=O.Cl[Sn]Cl>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C@H:18]([CH:21]2[CH2:22][CH2:23]2)[CH2:19][CH3:20])[C:12]=1[NH2:24]
Reactant: CC[C@H](Nc1nccc(-c2cc(F)c(OC)cc2Cl)c1[N+](=O)[O-])C1CC1
Agent: Cl[Sn]Cl
Product: CC[C@H](Nc1nccc(-c2cc(F)c(OC)cc2Cl)c1N)C1CC1
Yield: 89.3 %

Procedure:
(S)-[4-(2-Chloro-5-fluoro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine (30 mg, 0.08 mmol) and SnCl2 (44 mg, 0.23 mmol) were treated substantially as described in Part D of Example 74a to yield 25 mg (92%) of (S)-4-(2-chloro-5-fluoro-4-methoxy-phenyl)-N2-(1-cyclopropyl-propyl)-pyridine-2,3-diamine.