Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[N:14][C:13]=2[C:19]([NH2:21])=[O:20])[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:22][C@@H:23]1[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>CN1C(=O)CCC1>[C:1]([C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[C:16]([NH:22][C@@H:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[N:15]=[N:14][C:13]=2[C:19](=[O:20])[NH2:21])[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Reactant: CC(C)(C)c1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1cc(Nc2cccc(C(C)(C)C)n2)c(C(N)=O)nn1
Temperature: 130 °C
Reaction time: 24 h
Yield: 46 %

Procedure:
A resealable pressure tube was charged with 4-(6-tert-butylpyridin-2-ylamino)-6-chloropyridazine-3-carboxamide (100 mg, 327 μmol) dissolved in NMP (2.00 mL) To this solution was added tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (70.7 mg, 327 μmol) and the reaction mixture was heated in an oil bath with stirring at 130° C. for 24 h. Added additional tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (70.7 mg, 327 μmol) and reaction continued for 24 h. Added more tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (70.7 mg, 327 μmol) and reaction continued for 72 h. The NMP was evaporated under high vacuum. The residue was purified by flash chromatography (silica gel 50 μm, 40 g, Analogix) eluting with 0 to 5% over 20 min (MeOH containing 10% NH4OH)/CH2Cl2 to yield tert-butyl (3R,4R)-4-(5-(6-tert-butylpyridin-2-ylamino)-6-carbamoylpyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (73 mg, 46.0% yield) as a yellow foam. 1H NMR (CHLOROFORM-d) δ: 11.45 (br. s., 1H), 8.33 (s, 1H), 8.14 (s, 1H), 8.06 (d, J=3.4 Hz, 1H), 7.52 (t, J=7.9 Hz, 1H), 6.91 (d, J=7.9 Hz, 1H), 6.66 (d, J=7.9 Hz, 1H), 5.65 (br. s., 1H), 5.37 (d, J=8.3 Hz, 1H), 3.38-4.31 (m, 6H), 1.63-2.23 (m, 2H), 1.46 (s, 9H), 1.39 (s, 9H); LC-MS 486.3 [M+H]+.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([NH:10][C:11]3[N:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH:13]=O)[CH:7]=[CH:6][C:5]=12.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30])[CH:20]=1.[Li+].CC([N-]C(C)C)C>>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([N:10]3[C:11]4[C:12](=[CH:15][CH:16]=[CH:17][N:18]=4)[CH:13]=[C:28]([CH2:27][CH2:26][CH2:25][C:21]4[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=4)[C:29]3=[O:30])[CH:7]=[CH:6][C:5]=12
Reactant: CCOC(=O)CCCCc1cccnc1
Reactant: O=Cc1cccnc1Nc1ccc2nsnc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=c1c(CCCc2cccnc2)cc2cccnc2n1-c1ccc2nsnc2c1
Yield: 48 %

Procedure:
The procedure of Example 1 was repeated using 2-(2,1,3-benzothiadiazol-5-ylamino)nicotinaldehyde (1.0 eq., prepared in Synthetic Example 1a)), ethyl 5-(pyridin-3-yl)pentanoate (1.5 eq., prepared in Synthetic Example 3) and LDA (1.5 eq.) to obtain 1-(2,1,3-benzothiadiazol-5-yl)-3-[3-(pyridin-3-yl)propyl]-1,8-naphthyridin-2(1H)-one (yield, 48%). The product was purified through flash column chromatography and recrystallization (mp 173.5–174.5° C./DMF).
Reaction SMILES: ClCCl.[Si:4]([O:11][CH2:12][C:13]1[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][CH:14]=1)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5].[C:20]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)#[N:21]>N1C=CC=CC=1>[Si:4]([O:11][CH2:12][C:13]1[N:18]=[C:17]([NH:19][S:34]([C:31]2[CH:30]=[CH:29][C:28]([C:25]3[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)(=[O:36])=[O:35])[CH:16]=[CH:15][CH:14]=1)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]
Reactant: N#Cc1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(NS(=O)(=O)c2ccc(-c3ccc(C#N)cc3)cc2)n1
Reaction time: 3 h
Yield: 69.5 %

Procedure:
To a solution of dichloromethane (3 mL) was added 6-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-amine (0.15 g, 0.63 mmol), 4′-cyanobiphenyl4-sulfonyl chloride (0.18 g, 0.63 mmol) and pyridine (1.0 mL). The mixture was stirred for 3 hours then was washed with saturated sodium bicarbonate (2×30 mL) and aqueous hydrochloric acid (2×30 mL, 0.1 N). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification was done using silica gel chromatography eluting with hexane: ethyl acetate (1:1) and combined fractions were concentrated to afford the above-titled intermediate as a white solid (0.21 g, 76%). HPLC: Rt4.236 min. (81% area). 1H NMR (400 MHz, CDCl3), δ: 7.89 (d, J=8.3 Hz, 2H), 7.60 (d, J=8.3 Hz, 2H), 7.52-7.49 (m, 4H), 7.43 (t, J=7.6 Hz, 1H), 6.87 (d, J=8.6 Hz, 1H), 6.59 (d, J=7.3Hz, 1H), 6.22 (d, J=8.0 Hz, 1H), 4.55 (s, 2H), 0.82 (s, 9H), 0.05 (s, 6H); LRMS (ESI): m/z: 480.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9](Cl)[C:8]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][CH:6]=1)[CH3:2].[CH2:18]([Zn]CC)[CH3:19]>O1CCOCC1.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([CH2:18][CH3:19])[C:8]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][CH:6]=1)[CH3:2]
Reactant: CC[Zn]CC
Reactant: CCOC(=O)c1cnc(N(CC)CC)c(Cl)c1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc(N(CC)CC)c(CC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-chloro-6-diethylamino-nicotinic acid ethyl ester (2.96 g, 11.5 mmol) in dioxane (50 mL), Pd(dppf) (470 mg, 0.576 mmol) is added under argon. To this mixture, diethyl zinc (8.53 g, 69.1 mmol, as a 1.1 M solution in toluene) is added dropwise. The mixture is stirred at 75° C. for 16 h before another portion of Pd(dppf) 94 mg, 0.115 mmol) and diethyl zinc (1.42 g, 11.5 mmol, as a 1.1 M solution in toluene) is added. Stirring is continued at 75° C. for 24 h. The reaction mixture is cooled to rt and carefully quenched with water. The mixture is filtered over celite and the filtrate is extracted twice with EA. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC (heptane:EA 9:1) to give 6-diethylamino-5-ethyl-nicotinic acid ethyl ester (2.40 g) as a colourless oil; LC-MS: tR=0.78 min, [M+1]+=251.19; 1H NMR (CDCl3): δ 1.15 (t, J=7.0 Hz, 6H), 1.27 (t, J=7.3 Hz, 3H), 1.40 (t, J=7.3 Hz, 3H), 2.65 (q, J=7.5 Hz, 2H), 3.36 (q, J=7.0 Hz, 4H), 4.37 (q, J=7.0 Hz, 2H), 7.99 (d, J=2.3 Hz, 1H), 8.76 (d, J=2.3 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[NH2:25]>O1CCCC1>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[NH:25][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=1[OH:1]
Reactant: COc1ccc(C(=O)O)c(O)c1
Reactant: Nc1ccc(F)cc1F
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=O)Nc2ccc(F)cc2F)c(O)c1

Procedure:
To a solution of 2-hydroxy-4-methoxybenzoic acid (1.68 g, 10 mmole) in tetrahydrofuran (40 mL) was added thionyl chloride (2.5 mL, 35 mmole) and refluxed 3 hr. The mixture was steamed (110° C.) by Dean-Stark. The residue was directly reacted with 2,4-difluorobenzenamine (1 mL, 10 mmole) in THF (40 mL) for 14 hr. The reaction mixture was concentrated and extracted with ethyl acetate, dried over anhydrous magnesium sulfate. Recrystallization of desired products from hot dichloromethane afforded the compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH:23]=2)[S:9]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[Br:35][CH2:36][CH2:37]Br.[OH-].[Na+]>O>[Br:35][CH2:36][CH2:37][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH:23]=2)[S:9]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])(=[O:11])=[O:10])=[CH:6][CH:7]=1
Reactant: BrCCBr
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(O)cc2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(OCCBr)cc2)c(C)c1
Temperature: 25 °C
Yield: 26 %

Procedure:
To a suspension of N-(4-hydroxy-phenyl)-2,4,6-trimethyl-N-[3-(tetrahydro-pyran-2-yloxy)-benzyl]-benzenesulfonamide (0.238 g, 0.49 mmol) and 1,2-dibromoethane (0.43 mL, 4.94 mmol) in 1 mL water was added sodium hydroxide (0.020 g, 0.49 mmol, dissolved in 0.1 mL of water). The reaction mixture was heated at reflux for 3 hr. and was cooled to room temperature. The reaction mixture was diluted with 10 mL water and the aqueous solution was washed with ethyl acetate (3×15 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried (magnesium sulfate), and concentrated. Medium pressure silica gel chromatography (25% ethyl acetate/hexanes) afforded 0.075 g of the title compound of Step E.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22]Br)[CH:7]=1)[CH3:2].[CH3:25][C:26]([SH:29])([CH3:28])[CH3:27]>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22][S:29][C:26]([CH3:28])([CH3:27])[CH3:25])[CH:7]=1)[CH3:2]
Reactant: CC(C)(C)S
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CBr)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CSC(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 15, Step 5, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and 2-methyl-2-propanethiol.
Reaction SMILES: C[Si](C)(C)[C:3]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:5][N:4]=1.C(OCC=[N+]=[N-])(=O)C.C([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)#C>>[N:26]1[CH:27]=[CH:28][CH:29]=[C:30]([C:3]2[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:5][N:4]=2)[CH:25]=1
Reactant: CCOC(=O)c1cc([Si](C)(C)C)n[nH]1
Reactant: C#Cc1ccccn1
Agent: CC(=O)OCC=[N+]=[N-]
Product: CCOC(=O)c1cc(-c2cccnc2)n[nH]1

Procedure:
Was prepared in a similar way to ethyl 3-(trimethylsilyl)-1H-pyrazole-5-carboxylate using diazoethyl acetate (Purchased from Aldrich) and 2-ethynyl-pyridine (Purchased from Aldrich)
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]([C:50]([O:52]C(C)(C)C)=[O:51])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.Cl>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][C:36]([NH:41][C@H:42]([C:50]([OH:52])=[O:51])[CH2:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)=[O:37])=[CH:31][CH:32]=2)=[CH:39][CH:40]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)N[C@@H](Cc3ccccc3)C(=O)O)cc2)cc1

Procedure:
The product from Example 100 (56 mg, 0.1 mmole) and H-Phe-OtBu HCl (52 mg, 0.2 mmole) were processed as in Example 213A-B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ12.22-12.98 (br.s, 1 H), 8.95 (s, 1 H), 8.10 (d, 1 H), 7.22 (m, 12 H), 7.10 (d, 2 H), 7.04 (t, 1 H), 6.96 (m, 2 H), 6.87 (m, 4 H), 4.45 (m, 1 H), 4.06 (s, 2 H), 4.02 (s, 2 H), 3.06 (dd, 1 H), 2.91 (s, 3 H), 2.84 (dd, 1 H), 2.42 (t, 2 H), 2.39 (s, 3 H), 2.06 (m, 2 H), 1.68 (m, 2 H); MS (APCI+) m/z 706 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:4][O:3]1.[C:5]([O:9][C:10]([N:12]([C:20]1[C:25]([CH3:27])([CH3:26])[S:24](=[O:29])(=[O:28])[CH2:23][C@@:22]([CH2:40][F:41])([C:30]2[CH:35]=[C:34]([N+:36]([O-])=O)[CH:33]=[CH:32][C:31]=2F)[N:21]=1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])([CH3:8])([CH3:7])[CH3:6]>>[NH2:36][C:34]1[CH:33]=[CH:32][C:31]2[O:3][C@@H:2]([CH3:1])[CH2:4][C@H:23]3[S:24](=[O:29])(=[O:28])[C:25]([CH3:27])([CH3:26])[C:20]([N:12]([C:10]([O:9][C:5]([CH3:7])([CH3:6])[CH3:8])=[O:11])[C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[N:21][C@:22]3([CH2:40][F:41])[C:30]=2[CH:35]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](CF)(c2cc([N+](=O)[O-])ccc2F)CS(=O)(=O)C1(C)C
Reactant: C[C@H]1CO1
Product: C[C@H]1C[C@@H]2[C@](CF)(N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S2(=O)=O)c2cc(N)ccc2O1
Yield: 36.5 %

Procedure:
In an analogous sequence of reactions to that described in the preparation of trans intermediate 31, but using (S)-2-methyloxirane instead of 2,2-dimethyloxirane, tert-butyl N-tert-butoxycarbonyl-N-[(3S)-3-(fluoromethyl)-3-(2-fluoro-5-nitro-phenyl)-6,6-dimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate (preparation described in the synthesis of intermediate 22) was converted to the title compound (420 mg, 0.756 mmol, 36.5%) as a white foam. MS m/z=578.0 (M+Na).
Reaction SMILES: [CH2:1]([C@H:4]([C@H:11]([OH:18])[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.Br[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH3:37])=[CH:31][CH:30]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:36]([O:35][C:32]1[CH:33]=[CH:34][C:29](/[CH:3]=[CH:2]/[CH2:1][C@H:4]([C@H:11]([OH:18])[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])=[CH:30][CH:31]=1)[CH3:37]
Reactant: C=CC[C@@H](C(=O)OC(C)C)[C@H](O)C(=O)OC(C)C
Reactant: CCOc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(/C=C/C[C@@H](C(=O)OC(C)C)[C@H](O)C(=O)OC(C)C)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a solution of diisopropyl (2R,3S)-2-allyl-3-hydroxybutanedioate (3.0 g; 11.6 mmol; 1.0 eq.) and DIEA (3.86 mL; 28.9 mmol; 2.4 eq.) in CH3CN (30.0 mL) was added 4-bromophenetole (2.0 mL; 13.9 mmol; 1.2 eq.). To this solution was added a mixture of tri-o-tolylphosphine (0.35 g; 1.16 mmol; 0.1 eq.) and palladium(II) acetate (0.03 g; 0.12 mmol; 0.01 eq.) in CH3CN (3.0 mL) which was sonicated before the addition to the reaction mixture. The reaction was stirred under argon at reflux for 2.5 h, cooled to RT and the solvents were evaporated under reduce pressure. The resulting residue was then taken up in EtOAc and washed with an aqueous saturated solution of NaCl. Evaporation of the solvent gave an oil (4.3 g). Purification by chromatography (SiO2, gradient from 20/80 EtOAc/c-hex to 100/0 EtOAc/c-hex) gave the title product as a colorless oil (4.41 g, 100%). M+(ESI): 379.3. 1H NMR (CDCl3, 300 MHz) δ 7.14 (d, J=8.6 Hz, 2H), 6.70 (d, J=8.6 Hz, 2H), 6.46 (d, J=15.6 Hz, 1H), 6.00-5.86 (m, 1H), 5.05-4.83 (m, 2H), 4.13 (dd, J=7.0 Hz, J=3.0 Hz, 1H), 3.90 (q, J=7.0 Hz, 2H), 3.10 (d, J=7.2 Hz, 1H), 2.89-2.78 (m, 1H), 2.70-2.55 (m, 1H), 2.52-2.35 (m, 1H), 1.27 (t, J=7.0 Hz, 3H), 1.22-1.00 (m, 12H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][CH2:7][CH:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH:24]([CH3:26])[CH3:25])[C:18](=[O:27])[CH2:17]3)[CH2:9]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:5][O:4][C:2](=[O:3])[NH:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH:24]([CH3:25])[CH3:26])[C:18](=[O:27])[CH2:17]3)[CH2:9]1
Reactant: CC(C)N1C(=O)Cc2cc(N3CC(CN)OC3=O)cc(F)c21
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)NC[C@H]1CN(c2cc(F)c3c(c2)CC(=O)N3C(C)C)C(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (0.097 ml, 1.26 mmol) is added dropwise to 5-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-7-fluoro-1-isopropyl-1,3-dihydro-indol-2-one (21, 0.355 g, 0.842 mmol) and diisopropylethylamine (0.616 ml, 3.37 mmol) in dichloromethane (4 ml) at 0° C. The reaction is stirred at 0° C. for 30 minutes and then allowed to warm at room temperature. The reaction mixture is diluted with dichloromethane, washed with water, citric acid and brine, dried (Na2SO4) and evaporated. The residue is purified to give the title compound as a solid. HPLC r.t. 4.42 min; 1H NMR (300 MHz, CDCl3) δ7.33 (d, J=1.2 Hz, 1H), 7.24 (dd, J=2.1, 14 Hz, 1H), 5.14 (br s, 1H), 4.80-4.92 (m, 1H), 4.75-4.84 (m, 1H), 4.05 (t, J=8.7 Hz, 1H), 3.81 (dd, J=6.6, 9 Hz, 1H), 3.71 (s, 3H), 3.57 (s, 2H), 3.52-3.65 (m, 2H), 1.44 (d, J=6.9 Hz, 6H); MS for C17H20FN3O5 m/z 366 (M+H)+.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:5]=[C:6]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]#[C:29][C:30]4([OH:36])[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H][H]>[Pd]>[CH3:3][C:4]1[CH:5]=[C:6]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH2:28][CH2:29][C:30]4([OH:36])[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cc(Nc2ncnc3ccc(C#CC4(O)CCCNC4)cc23)ccc1Oc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Product: Cc1cc(Nc2ncnc3ccc(CCC4(O)CCCNC4)cc23)ccc1Oc1ccccc1
Yield: 103 %

Procedure:
A mixture of 3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol dihydrochloride (100 mg, 0.19 mmol) and Pd/C (10%, 6 mg) was shaken in a Parr bottle with hydrogen at 50 psi overnight and filtered through a pad of Celite. The filtrate was concentrated to small volume and added dropwise into EtOAc with stirring. The solid was collected by suction filtration, rinsed with EtOAc, and further dried to yield 89 mg (89%) of yellow solid: 1H NMR (CD3OD) δ 1.69 (dt, 1H), 1.81(br d, 1H), 1.95 (t, 3H), 2.15 (m, 1H), 2.28 (t, 3H), 2.93 (t, 1H), 3.02 (m, 3H), 3.18 (d, 1H), 3.31(br, 1H), 6.94 (m, 3H), 7.08 (t, 1H), 7.34 (t, 2H), 7.55 (d, 1H), 7.66 (d, 1H), 7.78 (d, 1H), 8.02 (d, 1H), 8.58 (s, 1H), 8.73 (s, 1H); MS m/z (MH+) 455.2.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Li][CH2:16]CCC.CI>C1COCC1>[C:10]([O:9][C:8](=[O:14])[NH:7][S:4]([C:1]1([CH3:16])[CH2:2][CH2:3]1)(=[O:6])=[O:5])([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)C1CC1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NS(=O)(=O)C1(C)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
A solution of tert-butyl cyclopropylsulfonylcarbamate (4.3 g, 20 mmol) was dissolved in dry THF (100 ml) and cooled to −78° C. To this solution was added n-BuLi (17.6 ml, 44 mmol, 2.5 M in hexane) slowly. The reaction mixture was allowed to warm to room temperature over a period of 1.5 h. This mixture was then cooled to −78° C., and a solution of n-BuLi (20 mmol, 8 ml, 2.5M in hexane) was added, stirred for 1 h and a neat solution of methyl iodide (5.68 g, 40 mmol) was added. The reaction mixture was allowed to warm to room temperature with stirring overnight; then was quenched with aqueous saturated NH4Cl (100 ml) at room temperature. The mixture was extracted with EtOAc (100 ml). The organic layer was washed with brine; dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil which was crystallized from hexane to afford the product as a slightly yellow solid (3.1 g, 81%). 1H NMR (400 MHz, DMSO-d6): δ ppm 10.97 (s, 1H), 1.44 (s, 12H), 1.35-1.33 (m, 2H), 0.93-0.91 (m, 2H).
Reaction SMILES: [C:1](#[N:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)O.S(=O)(=O)(O)O.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]#[N:10])=[CH:19][CH:18]=1
Reactant: Clc1ccccc1
Reactant: N#CC(O)c1ccccc1
Agent: O=S(=O)(O)O
Product: N#CC(c1ccccc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 42.1 %

Procedure:
To a mixture of mandelonitrile (5 g) and chlorobenzene (15.7 g) was added sulfuric acid (9.8 ml) dropwise while the temperature of the mixture was maintained at 5°-10° C. After completion of dropwise addition, the mixture was stirred for another 1.5 hours. This reaction mixture was poured in ice-water and the syrup that had separated out was extracted into ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated to dryness. The group was purified by silica gel column chromatography to provide the title compound (3.6 g) as pale yellow syrup.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[CH:11]([N:17]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:19]=[C:18]1[C:27]([O:29]CC)=O)[CH2:10]2)=[O:5])[CH3:2].C([O-])(=O)C.[NH4+:36]>C(O)(=O)C>[CH2:1]([NH:3][C:4]([CH2:6][C:7]1[CH:15]=[CH:14][C:13]2[C:12]3[NH:36][C:27](=[O:29])[C:18]4[N:17]([CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:19]=4)[C:11]=3[CH2:10][C:9]=2[CH:8]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Cc1ccc2c(c1)CC(n1cc(C(=O)OCC)nc1C(=O)OCC)C2=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCNC(=O)Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nc(C(=O)OCC)cn12
Yield: 63.4 %

Procedure:
A mixture of 3.9 g of diethyl 1-[5-(N-ethylaminocarbonylmethyl)-1-oxoindan-2-yl]imidazole-2,4-dicarboxylate, 33.4 g of ammonium acetate and 200 ml of acetic acid is heated at reflux for 3 hours. The reaction mixture is evaporated on a rotary evaporator, 250 ml of distilled water are added to the evaporation residue and the residue is filtered. The solid obtained is washed with distilled water a number of times and dried in an oven. 2.2 g of ethyl 8-(N-ethylaminocarbonylmethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylate are obtained in the form of a light-brown solid melting above 300° C. (1H NMR spectrum in d6-DMSO, T=300K, δ in ppm (300 MHz): 1.05 (3H, t, J=6 Hz, CH3), 1.40 (3H, t, J=6 Hz, CH3), 3.12 (2H, m, NCH2), 3.48 (2H, s, CH2CO), 4.05 (2H, s, CH2), 4.40 (2H, q, J=6 Hz, CH2O), 7.32 (1H, d, J=8 Hz, arom. CH), 7.42 (1H, s, arom. CH), 7.83 (1H, d, J=8 Hz, arom. CH), 8.10 (1H, t, J=5 Hz, NH), 8.60 (1H, s, imidazole H)).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:22](=O)([O:26]CC)[O:23][CH2:24][CH3:25].[O-]CC.[Na+]>C(O)C>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:22]([O:23][CH2:24][CH3:25])=[O:26])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(CC(=O)OCC)cc1
Reactant: CCOC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCOc1ccc(C(C(=O)OCC)C(=O)OCC)cc1

Procedure:
The obtained ethyl 4-n-octyloxyphenylacetate (79 g), ethanol (140 ml), diethyl carbonate (300 ml) and sodium ethoxide (19.3 g) are mixed, and the mixture is heated with stirring while ethanol is distilling off. The reaction mixture is transferred into ice water and is acidified with hydrochloric acid. The organic layer is separated and the solvent is distilled off to give diethyl 4-n-octyloxyphenylmalonate (91.6 g).