Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:11][Mg]Br>CCOCC>[OH:10][C:1]1([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCc2ccccc21
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC1(O)CCc2ccccc21
Yield: 87.5 %

Procedure:
A solution of 25.05 g (0.190 mol) of 1-indanone in 250 ml of anhydrous ether was added over 45 min to a solution of 81.0 ml (0.243 mol) of 3.0M methyl magnesium bromide in ether under N2 whilst stirring magnetically. After completion of the addition, the reaction was heated to reflux for 40 min, allowed to cool, then quenched with 30 ml of saturated ammonium chloride solution. The ether layer was decanted from a white solid, washed with water (2×100 ml), then with saturated sodium chloride solution (100 ml), dried (K2CO3) and evaporated in vacuo to leave 24.64 g (88%) of the title product as an orange oil. NMR δ(CDCl3) 1.57 (3H, s), 2.16-2.24 (2H, m), 2.77-2.89 (1H, m), 2.97-3.09 (1H, m) 7.23-7.38 (4H, m).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12](B(O)O)=[CH:11][C:10]=3[CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)S(O[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH2:30][N:29]([CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:28][CH2:27]2)(=O)=O.C(N(CC)CC)C>C(O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]1([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[CH2:30][N:29]([CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:28][CH2:27]5)=[CH:11][C:10]=3[CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CCN1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Reactant: OB(O)c1cc2cc(C3CCCC3)ccc2o1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)CCN1CCc2cc(-c3cc4cc(C5CCCC5)ccc4o3)ccc2C1
Yield: 33.2 %

Procedure:
A mixture of 5-cyclopentylbenzofuran-2-ylboronic acid (78 mg, 0.34 mmol), tert-butyl 3-(6-(trifluoromethylsulfonyloxy)-3,4-dihydroisoquinolin-2(1H)-yl)propanoate (93 mg, 0.23 mmol), triethylamine (0.95 mL, 6.8 mmol) and bis(triphenylphosphine) palladium(II) chloride (16 mg, 0.02 mmol) in ethanol (5 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was purification by silica gel chromatography on ISCO system yielding the title compound (34 mg, 34% yield). 1H NMR (400 MHz, CDCl3) δ 7.59 (m, 2H), 7.40 (d, 2H), 7.15 (dd, 1H), 7.07 (d, 1H), 6.91 (s, 1H), 3.70 (s, 2H), 3.08 (m, 1H), 2.96 (dd, 2H), 2.85 (dd, 2H), 2.78 (dd, 2H), 2.54 (dd, 2H), 2.11 (m, 2H), 1.84 (m, 2H), 1.68 (m, 4H), 1.46 (s, 9H). MS (ESI) m/z: Calculated: 445.26; Observed: 446.00 (M++1).
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:8]=[C:9]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[C:33]([F:39])=[CH:32][C:31]=3[O:40][CH3:41])[C@H:14]2[CH3:42])[CH:10]=[CH:11][CH:12]=1>C1COCC1.Cl.CCOC(C)=O>[F:39][C:33]1[C:34]([CH:36]([CH3:38])[CH3:37])=[CH:35][C:30]([C:21]2[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:27])[F:28])=[CH:25][C:20]=2[CH2:19][N:15]2[C@@H:14]([CH3:42])[C@@H:13]([C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[CH:2]=[O:1])[O:17][C:16]2=[O:18])=[C:31]([O:40][CH3:41])[CH:32]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cccc(C3OCCCO3)c2)[C@@H]1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cccc(C=O)c2)[C@@H]1C

Procedure:
The solution of (4S,5R)-5-[3-(1,3-dioxan-2-yl)phenyl]-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (EXAMPLE 210) (380 mg, 0.647 mmol) in THF and 1N HCl (3:1) (4 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc and washed with NaHCO3 and brine. The organic layer was dried and concentrated in vacuo. The crude material was purified by flash chromatography (Si) to provide 3-((4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)benzaldehyde. LCMS calc.=530.19; found=530.4 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 10.03 (s, 1H); 7.88 (s, 0.5H); 7.87 (s, 0.5H); 7.77-7.52 (m, 5H); 7.37 (d, J=3.5 Hz, 0.5H); 7.36 (d, J=3.4 Hz, 0.5H); 7.02 (d, J=8.4 Hz, 0.5H); 6.99 (d, J=8.4 Hz, 0.5H); 6.71 (d, J=3.5 Hz, 0.5H); 6.69 (d, J=3.4 Hz, 0.5H); 4.17 (d, J=15.8 Hz, 0.5H); 6.98 (d, J=15.8 Hz, 0.5H); 3.78 (s, 3H); 3.85-3.71 (m, 1H); 3.26-3.19 (m, 1H); 1.30-1.26 (m, 4.5H); 1.19 (d, J=6.9 Hz, 1.5H); 0.53 (d, J=6.6 Hz, 1.5H); 0.40 (d, J=6.6 Hz, 1.5H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:25]([CH3:27])[CH3:26])=[N:10][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:25]([CH3:27])[CH3:26])=[N:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CN(C)c1ccccc1CSc1nccn1-c1ccc(N)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-n2ccnc2SCc2ccccc2N(C)C)nc1
Reaction time: 2 h

Procedure:
0.26 ml of acetyl chloride is added to a mixture of 0.98 g of 1-(5-amino-2-pyridyl)-2-[2-(dimethylamino)benzylthio]imidazole, 1 ml of triethylamine and 30 ml of methylene chloride under ice-cooling. The mixture is stirred at the same temperature for 2 hours, washed with water and a saturated aqueous sodium bicarbonate solution, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=30:1), and crystallized with isopropyl ether. The crystals are collected by filtration, whereby 0.82 g of 1-(5-acetylamino-2-pyridyl)-2-[2-(dimethylamino)benzylthio]imidazole is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:15][CH:14]2[C:13](=[O:16])[NH:12][C:11]3=[O:17])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]23[CH2:15][CH:14]2[C:13](=[O:16])[NH:12][C:11]3=[O:17])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C1NC(=O)C2(c3ccc([N+](=O)[O-])cc3)CC12
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C23CC2C(=O)NC3=O)cc1

Procedure:
To a solution of 25.9 g of 1-(4-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (preparation as described in DE-OS 2 740 562) in 700 ml of ethanol are added 1.4 g of 5% palladium/carbon catalyst. Hydrogenation is carried out under normal pressure and at room temperature with hydrogen. When the absorption of hydrogen is complete (theoretical amount: 7500 ml), the reaction mixture is diluted with 1 ml of ethanol and concentrated after removal of the catalyst. The product so obtained is recrystallised from ethanol, affording the title compound with m.p. 183°-185° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[CH3:26][O:27][C:28](=[O:33])[CH2:29][CH2:30][C:31]#[CH:32]>>[CH3:26][O:27][C:28](=[O:33])[CH2:29][CH2:30][C:31]#[C:32][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccn1
Reactant: C#CCCC(=O)OC
Product: COC(=O)CCC#Cc1ccc(C(CC(=O)c2ccnc(C)c2)c2ccccc2C)cc1

Procedure:
In analogy to example 85, step 1, from 3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 74, step 5) and pent-4-ynoic acid methyl ester was prepared the title compound as a brown oil, MS (ESI+): m/z=426.2067 ([M+H]+).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12](=[O:14])[NH:11][N:10]=2)=[CH:5][CH:4]=1.O1[CH:20]=[CH:19][C:18](=[O:21])[CH:17]=[CH:16]1.C(O)C>O>[O:21]=[C:18]1[CH:19]=[CH:20][N:2]([C:3]2[CH:4]=[CH:5][C:6]([C:9]3[S:13][C:12](=[O:14])[NH:11][N:10]=3)=[CH:7][CH:8]=2)[CH:16]=[CH:17]1
Reactant: Nc1ccc(-c2n[nH]c(=O)s2)cc1
Reactant: O=c1ccocc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=c1ccn(-c2ccc(-c3n[nH]c(=O)s3)cc2)cc1

Procedure:
A mixture of 5-(4-aminophenyl)-1,3,4-thiadiazol-2(3H)-one hydrochloride (1.25 g), 4H-pyran-4-one (0.58 g), ethanol (10 ml) and water (50 ml) was stirred under reflux under nitrogen for 31/2 hours. The cooled reaction mixture was filtered and the collected orange solid was washed with aqueous potassium hydrogen carbonate and water and was dried. The crude product (1.35 g) was treated with boiling dimethylformamide (200 ml) and the resultant suspension was cooled and filtered. The collected solid was washed with ethanol and ether, dried and suspended in water (100 ml). Sufficient aqueous sodium hydroxide (2N) was added to the suspension to form a solution which was filtered. The filtrate was acidified to pH 6 with hydrochloric acid which caused the precipitation of the title compound as a yellow solid, 0.96 g, m.p. 343°-4° C. (decomp).
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[C:31]([C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:31]([C:39]1[CH:44]=[CH:43][C:42]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)=[CH:41][CH:40]=1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: O=C(c1ccccc1)c1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1ccc(C(=O)c2ccccc2)cc1
Yield: 65 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 4-benzoylphenylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a white solid (65% yield); 1H-NMR (d6-DMSO) 1.11 (9H, s), 3.71 (2H, t), 4.15 (2H, t), 6.65 (1H, s), 7.37-7.39 (2H, m), 7.57-7.59 (2H, m), 7.68-7.71 (5H, m); MS ES(+) 366.2 (M++1); Anal. Calcd for C22H23NO4: C, 72.31; H, 6.34; N, 3.83. Found: C, 71.95; H, 6.24; N, 9.98. IR λmax=1695, 1645, 1604, 1360 cm−1.
Reaction SMILES: [C:1](=[O:20])([O:18][CH3:19])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([F:12])=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[BH4-].[Na+]>CO.Cl[Ni]Cl>[C:1](=[O:20])([O:18][CH3:19])[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([F:12])=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C1CCCC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Oc1cc(N)c(F)cc1C1CCCC1
Reaction time: 0.17 h
Yield: 68.1 %

Procedure:
To a solution of 2-cyclopentyl-4-fluoro-5-nitrophenyl methyl carbonate (2022 mg, 7.14 mmol) and NiCl2 (925 mg, 7.14 mmol) in methanol (10 mL) cooled to 0° C. was added NaBH4 (810 mg, 21.42 mmol) portion-wise. The reaction was stirred for 10 min then quenched with NaHCO3. The mixture was diluted with ethyl acetate and filtered through a pad of Celite. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (10% ethyl acetate/hexanes) provided 5-amino-2-cyclopentyl-4-fluorophenyl methyl carbonate (1232 mg, 68% yield) as brown solid. 1H NMR (400.0 MHz, DMSO-d6) δ 6.94 (d, J=12.6 Hz, 1H), 6.50 (d, J=8.2 Hz, 1H), 5.17 (s, 2H), 3.81 (s, 3H), 2.84 (dd, J=8.4, 17.2 Hz, 1H), 1.87-1.80 (m, 2H), 1.75-1.67 (m, 2H), 1.62-1.53 (m, 2H), 1.45-1.36 (m, 2H). MS (ESI) m/z (M+H): 255.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10][C@H:11]([CH2:19][C:20]#[CH:21])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:29]([CH2:32][CH2:33][OH:34])=[N+:30]=[N-:31].C(N(CC)C(C)C)(C)C>O1CCCC1.[Cu]I>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10][C@H:11]([CH2:19][C:20]1[N:31]=[N:30][N:29]([CH2:32][CH2:33][OH:34])[CH:21]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=NCCO
Reactant: C#CC[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1cn(CCO)nn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 33.9 %

Procedure:
Di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-prop-2-yn-1-yl-L-glutamate (150 mg, 377 μmol) and 2-azidoethanol (49 mg, 566 μmol) were dissolved in tetrahydrofuran (3.75 ml). To the solution, copper(I) iodide (7.2 mg, 38 μmol) and N,N-diisopropylethylamine (79 μl, 453 μmol) were added and the mixture was stirred for 12 h at room temperature. The mixture was then concentrated in vacuo and the residue was purified by preparative reversed phase HPLC to yield 62 mg (34%) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13](=[O:14])[NH:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([O:24][CH3:25])[CH:16]=2)=[N:10]1.Cl>CO.[Fe]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:11]2[NH:12][C:13](=[O:14])[N:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[N:10]=2)=[CH:16][C:17]=1[O:24][CH3:25]
Reactant: COc1cc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)[nH]2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: COc1cc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)[nH]2)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
To a solution of 1-(2,6-dichlorophenyl)-3-(3-methoxy-4-nitrophenyl)-1H-1,2,4-triazol-5(4H)-one (0.200 g, 0.52 mmol) in methanol (10 mL) was added iron powder (0.060 g, 1.84 mmol) and conc. HCl (2 mL). The reaction mixture was stirred at RT for 2 h. The reaction mass was quenched in water, basified with saturated sodium bicarbonate solution and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.150 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.80 (s, 3H), 5.34 (s, 2H), 6.66 (d, J=7.8 Hz, 1H), 7.18-7.21 (m, 2H), 7.58 (m, 1H), 7.69 (d, J=7.8 Hz, 2H), 12.27 (s, 1H); MS (m/z): 351.05 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH3:2].CC(C)([O-])C.[K+].[CH2:20]([O:22][C:23](=[O:35])[C:24]([CH3:34])=[C:25]=[CH:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[CH3:21].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C(=O)C>[CH2:20]([O:22][C:23](=[O:35])[CH:24]([CH3:34])/[C:25](=[CH:26]\[C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1)/[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH3:21]
Reactant: CCOC(=O)C(C)=C=Cc1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(C)/C(=C\c1ccc(F)cc1)C(C(=O)OCC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Malonic acid tert-butyl ester ethyl ester (30.08 g, 151.8 mmol) was added to a solution of potassium tert-butoxide (16.30 g, 138.0 mmol) in 200 mL of N,N-dimethyl acetamide, while the reaction temperature was maintained at ˜25° C. To the resulting mixture was then added the solution of 4-(4-fluoro-phenyl)-2-methyl-buta-2,3-dienoic acid ethyl ester prepared above, at such a rate that the reaction temperature was maintained between 20-28° C. After the addition was complete, the reaction mixture was stirred at room temperature for 20 minutes, when HPLC indicated completed reaction. The mixture was then treated with 100 mL of 1M citric acid and 150 mL of ice-water, and then extracted with 400 mL of methyl tert-butyl ether. The organic extract was separated and washed with 2×200 mL of water, and then concentrated to produce 56.36 g of a yellow oil, which was used in the next step without further purification.
Reaction SMILES: [F:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])=O.[C:12]([S@:16]([NH2:18])=[O:17])([CH3:15])([CH3:14])[CH3:13]>>[F:1][CH2:2]/[C:3](=[N:18]\[S@@:16]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:17])/[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=C(CF)c1ccccc1F
Product: CC(C)(C)[S@@](=O)/N=C(\CF)c1ccccc1F
Yield: 52 %

Procedure:
In a manner analogous to that described for the preparation of sulfinyl imine A2.1 the reaction of 2-fluoro-1-(2-fluoro-phenyl)-ethanone with (R)-tert-butylsulfinamide yielded the (R)-2-methyl-propane-2-sulfinic acid [2-fluoro-1-(2-fluoro-phenyl)-eth-(Z)-ylidene]-amide (52% of theory) as an orange oil. MS (ISP): m/z=260.2 [M+H]+.
Reaction SMILES: [C:1]([N:4]([CH3:38])[N:5]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[C:26](=[O:27])[C:25]3[S:28][C:29]([C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)=[CH:30][C:24]=3[N:23]=[CH:22]2)=[CH:15][CH:14]=1)C(OC(C)(C)C)=O)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:29]2[S:28][C:25]3[C:26](=[O:27])[N:21]([CH2:20][CH2:19][C:16]4[CH:17]=[CH:18][C:13]([NH:5][N:4]([CH3:38])[C:1](=[O:3])[CH3:2])=[CH:14][CH:15]=4)[CH:22]=[N:23][C:24]=3[CH:30]=2)=[CH:32][CH:33]=1
Reactant: CC(=O)N(C)N(C(=O)OC(C)(C)C)c1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N(C)Nc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
tert-Butyl 2-acetyl-1-[4-[2-[6-(4-chlorophenyl) -4-oxothieno[3,2-d]pyrimidin-3(4H)-yl]ethyl]phenyl]-2-methylhydrazinecarboxylate (356 mg) was dissolved in dichloromethane (6.5 ml), and trifluoroacetic acid (2.0 ml) was added. The reaction mixture was stirred at room temperature for 1.5 hr, and diluted with dichloromethane. The obtained diluted solution was washed with saturated aqueous sodium hydrogen carbonate solution, the organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The precipitated crystals were washed with ethyl acetate-diisopropyl ether to give the title compound (287 mg) as colorless crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:24])=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:23])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[Cl:9].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:36][CH:37]1[CH2:46][N:45]2[CH:40]([CH2:41][CH2:42][CH2:43][CH2:44]2)[CH2:39][CH2:38]1)(=O)=O>CN(C)C=O>[Cl:2][C:3]1[C:4]([F:24])=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH2:36][CH:37]4[CH2:46][N:45]5[CH:40]([CH2:41][CH2:42][CH2:43][CH2:44]5)[CH2:39][CH2:38]4)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CS(=O)(=O)OCC1CCC2CCCCN2C1
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3F)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3F)ncnc2cc1OCC1CCC2CCCCN2C1
Temperature: 70 °C
Reaction time: 38 h
Yield: 13.8 %

Procedure:
4-[(3,4-Dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-ol hydrochloride (469 mg, 1.20 mmol) was dissolved in dimethylformamide (1 mL) and potassium carbonate (828 mg, 6.00 mmol) was added followed by octahydro-2H-quinolizin-3-ylmethyl methanesulfonate (466 mg, 1.89 mmol) in dimethylformamide (1 mL). The mixture was stirred at 70° C. for 38 h and then was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown oil which was purified by column chromatography (15-20% methanol in dichloromethane). The purified material was crystallized from methanol to afford N-(3,4-dichloro-2-fluorophenyl)-6-(methyloxy)-7-[(octahydro-2H-quinolizin-3-ylmethyl)oxy]quinazolin-4-amine as a cream colored solid (83.4 mg, 0.165 mmol, 14% yield). 1H NMR (400 MHz, CDCl3): 8.69 (s, 1H), 8.53 (t, 1H), 7.34 (dd, 1H), 7.28-7.22 (m, 1H), 7.23 (s, 1H), 6.98 (s, 1H), 4.06-3.95 (m, 2H), 4.02 (s, 3H), 3.09 (d, 1H), 2.87 (d, 1H), 2.43-2.27 (m, 1H), 2.10-1.97 (m, 1H), 1.95-1.84 (m, 2H), 1.80-1.52 (m, 5H), 1.46-0.95 (m, 5H); MS (EI) for C25H27N4O2FCl2: 505 (MH+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:26]1([C:36](O)=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][N:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[CH:28][N:27]=4)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(O)c1nccc2ccccc12
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4nccc5ccccc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and isoquinoline-1-carboxylic acid as starting compounds. The crude product is purified by chromatography (silica gel and DCM/diethyl ether/methanol=5:5:1) to yield the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])#[CH:2].C([Li])CCC.CON(C)[C:27]([C:29]1[N:33]2[CH:34]=[CH:35][C:36]([O:38][CH2:39][CH2:40][O:41][CH3:42])=[CH:37][C:32]2=[N:31][CH:30]=1)=[O:28]>C1COCC1>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[C:2][C:27]([C:29]2[N:33]3[CH:34]=[CH:35][C:36]([O:38][CH2:39][CH2:40][O:41][CH3:42])=[CH:37][C:32]3=[N:31][CH:30]=2)=[O:28])[C:4]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16]
Reactant: COCCOc1ccn2c(C(=O)N(C)OC)cnc2c1
Reactant: C#Cc1cccc(OC)c1NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOc1ccn2c(C(=O)C#Cc3cccc(OC)c3NC(=O)OC(C)(C)C)cnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl 2-ethynyl-6-methoxyphenylcarbamate (1.77 g, 7.18 mmol) in THF (40 mL) was added butyllithium (0.919 g, 14.4 mmol) at −78° C., and the reaction was stirred for 1 hour. N-methoxy-7-(2-methoxyethoxy)-N-methylimidazo[1,2-a]pyridine-3-carboxamide (1.67 g, 5.98 mmol) in THF (55 mL) was then added to the reaction mixture dropwise. After the addition, the cold bath was removed and the reaction was warmed to ambient temperature. Following a 2 hour stir at ambient temperature, the reaction mixture was poured into cold saturated NH4Cl (40 mL) and EtOAc (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc, dried over Na2SO4, filtered and concentrated. The residue was triturated with DCM to give product as a solid. The DCM solution was concentrated and purified by flash column chromatography (EtOAc/MeOH 10:0 to 10:1) to provide the desired product.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([CH:5]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][CH2:6]1)=[O:4].CO.[H][H]>[Pd]>[CH3:1][N:2]([CH3:21])[C:3]([CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)=[O:4]
Reactant: CN(C)C(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)C1CCNCC1

Procedure:
Palladium (10.0 mg, 9.40E−6 mol) was added to a solution of benzyl 4-[(dimethylamino)carbonyl]piperidine-1-carboxylate (190.0 mg, 0.0006544 mol) in methanol (5.0 mL, 0.12 mol) under nitrogen. The mixture was hydrogenised with a balloon filled with hydrogen for 3 h. The mixture was filtered and the filtrate was concentrated to give the desired product.