Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[Br:12][C:13]1[N:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1>C(#N)C>[Br:12][C:13]1[N:14]=[CH:15][C:16]2[N:17]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=3)[N:19]=2)[CH:18]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: Nc1cnc(Br)cn1
Solvent: CC#N
Product: Oc1ccc(-c2cn3cc(Br)ncc3n2)cc1
Temperature: 110 °C
Yield: 31.4 %

Procedure:
4.66 g (corresponding to 21.6 mmol) of 2-bromo-4′-hydroxyacetophenone and 2.53 g (corresponding to 14.5 mmol) of 5-bromo-2-aminopyrazine were dissolved in 100 mL of acetonitrile. The resulting solution was refluxed in an oil bath at 110° C. for 3.5 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 10 mL of water and 10 mL of methanol. Then, about 20 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 10 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 1.32 g (corresponding to 4.55 mmol) of 6-bromo-2-(4′-hydroxyphenyl)imidazo[1,2-a]pyrazine (FIG. 11, Step 2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[NH:9][C:10]=2[N:11]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[N:9]([CH2:19][C:18]3[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)[C:10]=2[N:11]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1COc2ccc(Br)nc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)COc3ccc(Br)nc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A suspension of 6-bromo-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (2.0 g; prepared according to WO 01/30782) in DMF (40 mL) was treated with 4-methoxybenzyl chloride (1.18 mL) and Cs2CO3 (8.5 g) and stirred at rt for 2 h. The solvent was evaporated under reduced pressure and the residue was partitioned between EA and water. The org. layer was washed with brine, dried over MgSO4 and evaporated under reduced pressure. The residue was triturated with Hept, affording a beige solid (2.8 g, 92% yield).
Reaction SMILES: N12CCN(CC1)CC2.[F:9][B-:10]([F:13])([F:12])[F:11].F[B-](F)(F)F.F[N+:20]12[CH2:27][CH2:26][N+:23]([S:28]([OH:31])(=[O:30])=[O:29])([CH2:24][CH2:25]1)[CH2:22][CH2:21]2.ClS(O)(=O)=O.F[B-](F)(F)F.[Na+]>C1COCC1.C(#N)C>[F:9][B-:10]([F:13])([F:12])[F:11].[S:28]([N+:23]12[CH2:22][CH2:21][N:20]([CH2:27][CH2:26]1)[CH2:25][CH2:24]2)([OH:31])(=[O:29])=[O:30]
Reactant: O=S(=O)(O)[N+]12CC[N+](F)(CC1)CC2
Agent: C1CN2CCN1CC2
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)Cl
Solvent: C1CCOC1
Solvent: CC#N
Product: O=S(=O)(O)[N+]12CCN(CC1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Fluoro-4-sulfo-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) 1,4-Diazabicyclo[2.2.2]octane (11 g, 10 mmol) in THF (100 mL) is reacted with chlorosulfonic acid (11.6 g, 10 mmol) until the reaction is complete by TLC. The reaction is evaporated, diluted with acetonitrile (100 mL) and sodium tetrafluoroborate (40 g, 20 mmol) added. The solution is stirred overnight at room temperature and then filtered to remove all undissolved salts. The flitrate is evaporated to afford 1-sulfo-4-aza-1-azoniabicyclo[2.2.2]octane tetrafluoroborate.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([CH3:10])=[C:7]([CH:11]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:28][NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33]>>[C:1]([C:5]1[O:9][C:8]([CH3:10])=[C:7]([CH:11]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[O:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([N:29]([CH3:28])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:18])=[CH:20][CH:21]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCNC
Reactant: Cc1oc(C(C)(C)C)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Product: Cc1oc(C(C)(C)C)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 80.6 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-[(5-tert-butyl-2-methyl-3-furyl)(cyclohexyl)methoxy]benzoic acid (111 mg) as well as ethyl 3-(methylamino)propanoate (47 mg) to give the title compound (110 mg, 81%) as an amorphous compound.
Reaction SMILES: [CH2:1]([N:4]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)[C:2]#[CH:3].I[C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.C(N(CC)CC)C.C(OCC)(=O)C>C(#N)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:11]=[C:10]1[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]1[CH2:1][C:2]#[C:3][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C#CCN1C(=O)c2ccccc2Oc2ccccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CCN2C(=O)c3ccccc3Oc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
The title compound 434 (0.310 g, 1.24 mmol) and the methyl 4-iodobenzoate (0.390 g, 1.48 mmol) were stirred in acetonitrile (10.0 mL). Copper iodide (24 mg, 0.124 mmol) and dichlorobis(triphenylphosphine)palladium (87 mg, 0.124 mmol) were added followed by triethylamine (0.44 mL, 3.11 mmol). The reaction mixture was stirred at room temperature for 4 hours. The mixture was poor into ethyl acetate and the organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography (10-30% ethyl acetate in hexanes) to afford title compound 435 (285 mg, 60%) as a light brown solid. MS (m/z): 384.3 (M+H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][O:16][CH:17]([O:30][CH3:31])[C:18]1[C:27]([CH:28]=O)=[CH:26][C:25]2[CH2:24][CH2:23][CH2:22][NH:21][C:20]=2[N:19]=1.Cl.Cl.[NH2:34][CH2:35][CH2:36][N:37]([CH3:44])[CH2:38][C:39](OCC)=[O:40].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCCl>[CH3:15][O:16][CH:17]([O:30][CH3:31])[C:18]1[C:27]([CH2:28][N:34]2[CH2:35][CH2:36][N:37]([CH3:44])[CH2:38][C:39]2=[O:40])=[CH:26][C:25]2[CH2:24][CH2:23][CH2:22][NH:21][C:20]=2[N:19]=1
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Reactant: CCOC(=O)CN(C)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(OC)c1nc2c(cc1CN1CCN(C)CC1=O)CCCN2
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Sodium triacetoxyborohydride (3.10 g, 14.61 mmol) was added to a mixture of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 2.30 g, 9.74 mmol), ethyl 2-((2-aminoethyl)(methyl)amino)acetate dihydrochloride (intermediate 82, 2.6 g, 14.61 mmol) and triethylamine (6.75 ml, 48.7 mmol) in 1,2-dichloroethane (20 ml) at room temperature. The reaction mixture was stirred for 21 h at room temperature and additional sodium triacetoxyborohydride (2.6 g, 9.74 mmol) was added. After a further 4 h stirring at room temperature, again additional sodium triacetoxyborohydride (1.3 g, 4.87 mmol) was added and the reaction maintained at 4° C. for 2.5 days. The reaction mixture was then warmed to room temperature, saturated aqueous NaHCO3 solution added, the mixture extracted with DCM (3×), the combined organic layers dried over Na2SO4 and evaporated. The residue was applied to a 120 g RediSep® silica column as a DCM solution and purified by normal phase chromatography, eluting with a gradient from DCM to 10% MeOH in DCM. Product containing fractions were combined and evaporated to give the title compound as an orange foam. 1H NMR (400 MHz, CDCl3) δ 7.08 (s, 1H), 5.30 (s, br, 1H), 5.20 (s, 1H), 4.69 (s, 2H), 3.44-3.34 (m, 2H), 3.40 (s, 6H), 3.22-3.15 (m, 2H), 3.24 (s, 2H), 2.71-2.64 (m, 2H), 2.58-2.50 (m, 2H), 2.31 (s, 3H), 1.98-1.82 (m, 2H). (UPLC-MS 6) tR 0.33; ESI-MS 335.3 [M+H]+.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:4])[CH2:2][CH3:3].C([O-])=O.[NH4+].NC1C(Cl)=C2C(CCC(N(CCC)C(=O)CC)C2)=CC=1.ClC1C=CC=C2C=1CC(NCCC)CC2>CO.[Pd]>[C:1]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH2:7]1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Nc1cnc2ccccc2c1
Agent: [Pd]
Agent: CCCN(C(=O)CC)C1CCc2ccc(N)c(Cl)c2C1
Agent: CCCNC1CCc2cccc(Cl)c2C1
Solvent: CO
Product: CCC(=O)NC1CNc2ccccc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 17.4 g (86.9) 3-(N-propionyl)aminoquinoline and 20.0 g (317 mmol) ammonium formate in 150 ml methanol was added 1.0 g Pd/C cautiously under an inert atmosphere. After stirring at ambient temperature for 2 days the reaction stopped. The ratio between starting material and product was approximately 1:1 (monitored by GLC). The mixture was filtered on Celite and evaporated to a residue from which the product was extracted into diethyl ether. The ether solution was dried (magnesium sulfate), filtered and evaporated. The product/starting material mixture was then recharged in a similar manner using the same amounts of reactants. After additional 4 days the reaction was completed and worked-up as above to yield 9.7 g (55%) of reasonably pure material.: MS m/e 204 (M+, 4), 130 (100), 131 (45), 118 (8), 91 (5), 77 (5).
Reaction SMILES: NC1C(C(N)=[O:9])=C(N2CCC(C3N(C)C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1.[NH2:34][C:35]1[C:40]([C:41]#[N:42])=[C:39]([N:43]2[CH2:48][CH2:47][CH:46]([C:49]3[N:50]([CH2:62][CH2:63][N:64]4[CH2:67][CH2:66][CH2:65]4)[CH:51]=[C:52]([C:54]4[CH:59]=[CH:58][C:57]([F:60])=[C:56]([Cl:61])[CH:55]=4)[N:53]=3)[CH2:45][CH2:44]2)[N:38]=[CH:37][N:36]=1>>[NH2:34][C:35]1[C:40]([C:41]([NH2:42])=[O:9])=[C:39]([N:43]2[CH2:44][CH2:45][CH:46]([C:49]3[N:50]([CH2:62][CH2:63][N:64]4[CH2:65][CH2:66][CH2:67]4)[CH:51]=[C:52]([C:54]4[CH:59]=[CH:58][C:57]([F:60])=[C:56]([Cl:61])[CH:55]=4)[N:53]=3)[CH2:47][CH2:48]2)[N:38]=[CH:37][N:36]=1
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(Cl)c3)cn2CCN2CCC2)CC1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Product: NC(=O)c1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(Cl)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(3-chloro-4-fluorophenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=499, obsd.=499).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH3:11]
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 4-bromo-2-methyl-benzoic acid 10.0 g, 46.5 mmol) in methanol (100 mL) at room temperature was added sulfuric acid (conc. 1 mL) dropwise. The solution was heated at reflux for 16 h. The solution was removed from heat and sulfuric acid (conc. 0.5 mL) was added. The solution was heated at reflux 2 h then cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate, then with saturated sodium chloride. The solution was dried (MgSO4), filtered, and concentrated in vacuo to a crude colorless oil. Flash chromatography (SiO2, 5% ethyl acetate/hexane) gave the title compound as a colorless oil (9.2 g, 87%). 1H NMR (400 MHz, CDCl3): δ ppm 2.58 (s, 3 H) 3.88 (s, 3 H) 7.38 (dd, J=8.46, 1.89 Hz, 1 H) 7.42 (d, J=1.52 Hz, 1 H) 7.78 (d, J=8.34 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:47])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:21][CH2:22][C:23]4[C:28]([O:29][C@H:30]([CH2:32][CH:33]=C)[CH3:31])=[CH:27][C:26]([F:35])=[CH:25][C:24]=4[F:36])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:37])[C:12]=2[C@H:38]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[C:39]([OH:41])=[O:40])[CH2:7][CH2:6]1)[CH:2]=C>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.[Cu]I>[C:43]([O:42][C@@H:38]([C:12]1[C:13]([CH3:37])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:47])([O:4][CH2:1][CH:2]=[CH:33][CH2:32][C@H:30]([CH3:31])[O:29][C:28]2[C:23]([CH2:22][O:21][CH2:20]3)=[C:24]([F:36])[CH:25]=[C:26]([F:35])[CH:27]=2)[CH2:6][CH2:7]1)[C:39]([OH:41])=[O:40])([CH3:45])([CH3:44])[CH3:46]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3cc(COCc4c(F)cc(F)cc4O[C@@H](C)CC=C)nn23)CC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: [Cu]I
Solvent: ClCCCl
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)cc(F)c1COC3
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 8.3 %

Procedure:
To a solution of (S)-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2,4-difluoro-6-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid (0.030 g, 0.046 mmol) in DCE (4 mL) were added Hoveyda-Grubbs catalyst 2nd generation (7.16 mg, 0.011 mmol) and copper(I) iodide (8.70 mg, 0.046 mmol) and the mixture was stirred at 90° C. After 1.5 h, the mixture was cooled to rt and filtered and concentrated. The crude material was purified via preparative HPLC to afford (2S)-2-(tert-butoxy)-2-[(20S)-14,16-difluoro-4,20,26-trimethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13,15,17,22-octaen-3-yl]acetic acid (2.4 mg, 5.67% yield). 1H NMR (500 MHz, DMSO-d6) δ: 6.91 (d, J=11.7 Hz, 1H), 6.77 (t, J=9.5 Hz, 1H), 6.51 (s, 1H), 6.09-5.95 (m, 1H), 5.87 (d, J=8.1 Hz, 1H), 5.81-5.62 (m, 1H), 4.81-4.61 (m, 4H), 4.57-4.39 (m, 2H), 3.96-3.70 (m, 3H), 2.61-2.39 (m, 7H), 1.96-1.79 (m, 2H), 1.75-1.61 (m, 1H), 1.61-1.46 (m, 1H), 1.29 (s, 1H), 1.24-1.19 (m, 3H), 1.18-1.12 (m, 9H). LCMS (M+H) calcd for C33H43F2N4O6: 629.31. found: 629.3.
Reaction SMILES: [CH3:1][P:2]1(=[O:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]2[N:37]([CH3:58])[C:38]3[C:47]4[C:46](=[O:48])[NH:45][C:44]([CH:49](OC(=O)C)[CH:50]=[CH2:51])=[C:43]([CH3:56])[C:42]=4[CH:41]=[CH:40][C:39]=3[N:57]=2)=[C:31]([CH3:59])[CH:30]=1.C([O-])(=O)C>C1COCC1>[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]2[N:37]([CH3:58])[C:38]3[C:47]4[C:46](=[O:48])[NH:45][C:44]([CH:49]=[CH:50][CH2:51][N:5]5[CH2:6][CH2:7][P:2]([CH3:1])(=[O:8])[CH2:3][CH2:4]5)=[C:43]([CH3:56])[C:42]=4[CH:41]=[CH:40][C:39]=3[N:57]=2)=[C:31]([CH3:59])[CH:30]=1
Reactant: CP1(=O)CCNCC1
Reactant: C=CC(OC(C)=O)c1[nH]c(=O)c2c(ccc3nc(Nc4ccc(F)cc4C)n(C)c32)c1C
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C=CCN4CCP(C)(=O)CC4)[nH]c(=O)c3c2n1C
Reaction time: 0.33 h
Yield: 10.2 %

Procedure:
To a glass scintillation vial was added 4-methyl-[1,4]azaphosphinane 4-oxide (100 mg, 0.75 mmol). To a separate glass vial was added tris(dibenzylacetone)dipalladium (28 mg, 0.031 mmol), triphenylphosphine (30 mg, 0.12 mmol), and THF (2.5 mL). The resulting solution was stirred for 20 minutes, then acetic acid 1-[2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allyl ester (0.270 g, 0.621 mmol) was added as a solution in THF (7.0 mL), followed by TEA (0.90 mL, 12.2 mmol). Of the resulting solution, 2.4 mL (0.15 mmol total allylic acetate) was transferred to the vial containing 4-methyl-[1,4]azaphosphinane 4-oxide. The solution was stirred at room temperature for 20 h. The solvent was removed in vacuo and the resulting solid redissolved in MeCN (2 mL) and DMSO (2 mL). The solution was filtered, then purified directly by preperative reverse-phase HPLC (0% to 100% MeCN:H2O+0.1% formic acid) to give 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-[3-(4-methyl-4-oxo-4λ5[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (32 mg, 42%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6+TFA) δ 11.33 (br s, 1H), 10.68 (br s, 1H), 7.79 (d, 1H, J=8.6 Hz), 7.72 (d, 1H, J=8.6 Hz), 7.56 (dd, 1H, J1=5.5 Hz, J2=8.6 Hz), 7.35 (dd, 1H, J1=3.9 Hz, J2=9.8 Hz), 7.25 (td, 1H, J1=3.1 Hz, J2=8.6Hz), 7.19-7.15 (m, 2H), 6.54-6.48 (m, 1H), 4.18 (s, 3H), 4.10-4.00 (br s, 2H), 3.80-3.30 (br m, 4H), 3.16 (s, 3H), 2.36 (s, 3H), 3.31 (s, 3H), 2.30-2.10 (br m, 4H), 1.7-1.6 (br r, 3H); ESMS (m/z): found, 508.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[O:27]=[C:28]1[NH:33][C:32](=[O:34])[CH2:31][N:30]([CH2:35][C:36](O)=O)[CH2:29]1>>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17]2[N:18]=[C:36]([CH2:35][N:30]3[CH2:29][C:28](=[O:27])[NH:33][C:32](=[O:34])[CH2:31]3)[O:20][N:19]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: O=C(O)CN1CC(=O)NC(=O)C1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](c2noc(CN3CC(=O)NC(=O)C3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 55 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and (3,5-dioxo-1-piperazinyl)acetic acid, the title compound was obtained in 55% yield (99.0% purity by HPLC).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1[C:19]2[CH:18]([CH2:20][C:21]#[N:22])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.[Na].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[K+]>C1COCC1>[CH:7]1[C:19]2[CH:18]([CH2:20][CH2:21][NH2:22])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: N#CCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCCC1c2ccccc2-c2ccccc21
Temperature: -78 °C
Reaction time: 5 h

Procedure:
6.3 mL (6.3 mmol, 2.7 eq) of a 1 M solution of LiAlH4 in THF were dissolved in 20 mL of THF in a 250 mL flask under argon. The reaction medium was cooled to −78° C. and 478 mg (2.3 mmol, 1 eq) of (9H-fluoren-9-yl)-acetonitrile in solution in 20 mL of THF were added dropwise. The temperature was allowed to rise progressively to ambient temperature. Stirring was continued for 5 hours, then the medium was hydrolysed at 0° C. by addition of 30 mL of a sodium and potassium tartrate solution. The THF was evaporated and the aqueous phase was extracted with ethyl acetate. After drying over MgSO4 and evaporation of the solvent, the crude product was subjected to chromatography over silica gel (elution gradient: CH2Cl2—CH2Cl2/MeOH: 9/1 to CH2Cl2/MeOH/NH4OH: 9/1/0.5). The 2-(9H-fluoren-9-yl)-ethylamine was obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][SH:8])[NH2:6].Cl.C(OCC)(=O)C.[C:17]([Cl:36])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)C>[ClH:36].[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][S:8][C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[NH2:6]
Reactant: COC(=O)[C@H](N)CS
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)[C@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.1 %

Procedure:
D-Cysteine methyl ester hydrochloride (2.0 g) was suspended in N,N-dimethylformamide (12 mL), 4N hydrochloric acid/ethyl acetate solution (0.5 mL) was added, and the mixture was stirred at room temperature for 20 min. Trityl chloride (3.2 g) was added, and the mixture was stirred at 50° C. for 18 hr, diluted with diethyl ether, and poured into ice water. The mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The obtained residue was diluted with ethyl acetate, and 4N hydrochloric acid/ethyl acetate solution (5 mL) was added. The precipitated solid was collected by filtration to give the title compound (3.0 g, yield 64%) as a colorless amorphous solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH:23]([CH3:25])[CH3:24])=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])=[CH:12][CH:11]=[C:10]([Cl:22])[CH:9]=2)=[O:4].[OH-].[Na+]>C(O)C>[Cl:22][C:10]1[CH:9]=[C:8]2[C:13]([C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])=[C:5]([C:3]([OH:4])=[O:2])[C:6]([CH:23]([CH3:24])[CH3:25])=[N:7]2)=[CH:12][CH:11]=1
Reactant: COC(=O)c1c(C(C)C)nc2cc(Cl)ccc2c1-c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1nc2cc(Cl)ccc2c(-c2ccccc2F)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 6 step B from a mixture of 7-chloro-4-(2-fluoro-phenyl)-2-isopropyl-quinoline-3-carboxylic acid methyl ester and 1N NaOH in ethanol. White solid. MS (ESI): 342.0 (M+H)+.
Reaction SMILES: C(OC(=O)C)(=O)C.O[CH:9]([C:25]1[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=1)[CH:10]1[C:23](=[O:24])[N:14]2[C:15]3[C:20]([C:21]([CH3:22])=[C:13]2[CH2:12][CH2:11]1)=[CH:19][CH:18]=[CH:17][CH:16]=3>N1C=CC=CC=1>[CH3:22][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]2[C:23](=[O:24])[C:10](=[CH:9][C:25]3[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=3)[CH2:11][CH2:12][C:13]=12
Reactant: Cc1ncccc1C(O)C1CCc2c(C)c3ccccc3n2C1=O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: Cc1ncccc1C=C1CCc2c(C)c3ccccc3n2C1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (2.24 g) was added to a solution of 8,9-dihydro-7-[(hydroxy)(2-methylpridin-3-yl)methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one (1.35 g, a mixture of the isomers A and B) in pyridine (20 ml). After being stirred at 60° C. for 2 hours, the solution was evaporated in vacuo. The residue was diluted with chloroform, washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.27 g) were dissolved in toluene (30 ml). The solution was stirred at 60° C. for 2 hours and evaporated in vacuo. The residue was crystallized from ethyl acetate to give 8,9-dihydro-10-methyl-7-[(2-methylpyridin-3-yl)methylene]pyrido[1,2-a]indol-6(7H)-one (0.92 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[C:6]#[N:7].[ClH:12].O1CCOCC1.C(=O)([O-])[O-].[NH4+:23].[NH4+]>C(O)C>[ClH:12].[C:6]([C:5]1[CH:8]=[CH:9][C:10]([OH:11])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[NH:23])[NH2:7]
Reactant: [NH4+]
Reactant: COc1cc(C#N)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCO
Product: COc1cc(C(=N)N)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-methoxy-4-hydroxybenzonitrile (2.0 g, 13.4 mmol) were added ethanol (3 mL) and 4N hydrochloric acid/1,4-dioxane (27 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in ethanol (50 mL). Ammonium carbonate (6.4 g, 67 mmol) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, water was added and the mixture was freeze-dried to give the title compound (1.82 g).