Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1.[CH2:51](O)[CH2:52][CH2:53][CH2:54][CH2:55][CH3:56].C([O-])(O)=O.[Na+]>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:28][CH2:29][N:30]([CH2:33][C:34]([O:36][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[O:35])[CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1O
Reactant: CCCCCCO
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCCCOC(=O)CN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
Prepared analogously to Example 4d from 934 mg (1.35 mmol) (R)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 190 μL (0.11 mmol) 1-hexanol. The reaction solution was combined with 30 mL semisaturated NaHCO3 solution, extracted with 50 mL EtOAc and the organic phase was dried on Na2SO4. After the elimination of the desiccant and solvent the residue was purified by chromatography (silica gel, EtOAc/MeOH/NH3 90:10:1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]2[CH:23]=[CH:22][NH:21][N:20]=2)[CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]2[CH:23]=[CH:22][N:21]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[NH:8][CH:9]=[CH:10][C:3]=34)[N:20]=2)[CH:13]=1
Reactant: Oc1ccc(F)cc1-c1cc[nH]n1
Reactant: Brc1ccnc2[nH]ccc12
Product: Oc1ccc(F)cc1-c1ccn(-c2ccnc3[nH]ccc23)n1
Temperature: 25 °C

Procedure:
4-Bromo-1H-pyrrolo[2,3-b]pyridine (0.050 g, 0.00025 mol) and 4-fluoro-2-(1H-pyrazol-3-yl)phenol (0.150 g, 0.000842 mol) were heated neat to 160° C. for 5 h. The reaction was allowed to cool to rt and the residue was purified by prep LC-MS on a C-18 column eluting with a water/ACN gradient containing 0.2% TFA to give the title compound, (0.052 g, 20%, as an amorphous white solid, LC/MS (M+H)+295, 1H NMR (DMSO-d6) δ 12.01 (bs, 1H), 10.25 (bs, 1H), 8.81 (s, 1H), 8.35 (d, 1H, J=5.5), 7.77 (d, 1H, J=9.5), 7.64 (m, 1H), 7.59 (d, 1H, J=5.5), 7.32 (s, 1H), 7.09 (m, 1H), 7.05 (m, 1H), 7.01 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18](=[O:45])[CH2:19][CH2:20][C:21]([NH:23][CH2:24][C:25]2[C:26]([NH:38][CH:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[C:27]3[CH:35]=[N:34][N:33]([CH2:36][CH3:37])[C:28]3=[N:29][C:30]=2[CH2:31][CH3:32])=[O:22])=[CH:4][CH:3]=1.C[C@H:47]1[CH2:52][NH:51][CH2:50][CH2:49][N:48]1C(OC(C)(C)C)=O.C(O)(=O)C>CS(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:48]3[CH2:49][CH2:50][NH:51][CH2:52][CH2:47]3)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18](=[O:45])[CH2:19][CH2:20][C:21]([NH:23][CH2:24][C:25]2[C:26]([NH:38][CH:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[C:27]3[CH:35]=[N:34][N:33]([CH2:36][CH3:37])[C:28]3=[N:29][C:30]=2[CH2:31][CH3:32])=[O:22])=[CH:4][CH:3]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(Cl)c(-c2cccc(C=O)c2)c1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(Cl)c(-c2cccc(CN3CCNCC3)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.4 %

Procedure:
N-[(6-Chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}butanediamide (37.8 mg. 0.06 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial containing 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (0.18 mmol), acetic acid (3.6 mg, 0.6 mmol) and fitted with a magnetic stir bar. The resulting solution was stirred at room temperature for 4 h. MP-B(OAc)3H (0.6 mmol, 140 mg) was added and the solution was stirred for another 12 h. The polymer reagent was filtered and purification was completed via reversed phase HPLC using the Gilson (acidic conditions with 0.1% TFA in the solvents). The product after HPLC purification was dissolved in 3 mL of MeOH and passed through a 0.5 g amine column (washed with 8 mL of MeOH) to afford 6.92 mg of the title compound (16.4%). LC-MS m/z 701 (M+H)+, 1.19 min (ret time).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[CH3:43][N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1>C(OCC)(=O)C.C(OC(C)C)(C)C>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][N+:44]4([CH3:43])[CH2:48][CH2:47][CH2:46][CH2:45]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CN1CCCC1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1nsc(N)n1
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[N+]3(C)CCCC3)CS[C@H]12)c1nsc(N)n1
Reaction time: 1 h
Yield: 12.2 %

Procedure:
To a solution of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (IX-1) (Z/E=2/1, 150 mg, 0.21 mmole) in ethyl acetate (2 ml) was added a solution of 1-methylpyrrolidine (36 mg, 0.42 mmole) in ethyl acetate (1 ml) in one portion with stirring. The mixture was stirred for 15 minutes and diluted with isopropyl ether (10 ml) to form a precipitate, which was collected by filtration. A mixture of the solid (130 mg), formic acid (1 ml) and concentrated HCl (0.1 ml) was stirred at room temperature. After 1 hour, the reaction mixture was concentrated under reduced pressure, diluted with water (20 ml) and filtered. The aqueous solution was passed through a reverse phase column (the packing of PrepPAK-500/C18 cartridge, 100 ml), eluting with water and 10% CH3OH. The desired fractions were collected, and concentrated in vacuo to a small volume and freeze-dried to give 13 mg (12%) of the title compound (I-1A) (Z/E=1/1), melting at >280° C. (dec.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:2]=1.F[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[CH:2]=1
Reactant: c1cncc(CN2CCNCC2)c1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2CCN(Cc3cccnc3)CC2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
A suspension of 1-(pyridin-3-ylmethyl)piperazine (549 mg, 3.10 mmol), 4-fluorobenzonitrile (375 mg, 3.10 mmol), and K2CO3 (643 mg, 4.65 mmol) in DMF (50 mL) was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature and filtered, and the filtrate was washed with ethyl acetate (30 nL). The combined filtrate and washings were evaporated to dryness under reduced pressure. The crude residue was purified by MPLC on silica gel (3% MeOH in CH2Cl2) to afford the titled compound (326 mg, 38%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH2:74]([NH2:78])[CH:75]([CH3:77])[CH3:76]>CN(C=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:30][CH2:31][CH:32]([N:35]4[CH2:36][CH2:37][CH:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:33][CH2:34]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:78][CH2:74][CH:75]([CH3:77])[CH3:76])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: CC(C)CN
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NCC(C)C)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and isobutylamine (8.28 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (18.4 mg, 53%). LC-MS m/z 629 (M+H)+.
Reaction SMILES: [C:1]([NH:5][CH3:6])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:14][CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[C:1]([N:5]([CH3:6])[S:18]([CH2:17][CH2:16][CH2:15][Cl:14])(=[O:20])=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CNC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(C)(C)C)S(=O)(=O)CCCCl
Temperature: 0 °C
Yield: 72.7 %

Procedure:
1.74 g(0.02 mol) of t-butylmethylamine and 2 equivalents of triethylamine were dissolved in 100 ml of dichloromethane, which was stirred at 0° C. 3.54 g(0.02 mol) of 3-chloropropane sulfonyl chloride dissolved in 50 ml. of dichloromethane was added dropwise and the mixture was stirred for 1 hour at room temperature. The organic layer was washed with 1N HCl aqueous solution and dried over MgSO4 to obtain 3.31 g of the title compound(yield 73%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[N:12]=[C:11]3[C:23]2[N:28]=[C:27]([O:29][C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]3)[CH:26]=[N:25][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH:43]1([NH2:46])[CH2:45][CH2:44]1.CCN(C(C)C)C(C)C.Cl>C1COCC1>[CH:43]1([NH:46][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[N:12]=[C:11]4[C:23]3[N:28]=[C:27]([O:29][C@@H:30]4[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:40])[CH3:41])=[O:37])[CH2:31]4)[CH:26]=[N:25][CH:24]=3)[CH:5]=[CH:4][N:3]=2)[CH2:45][CH2:44]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(-c5ccnc(Cl)n5)cc34)n2)C1
Reactant: NC1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(-c5ccnc(NC6CC6)n5)cc34)n2)C1
Temperature: 120 °C
Yield: 65.5 %

Procedure:
A mixture of (3R)-tert-butyl 3-(6-(5-(2-chloropyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (172 mg, 0.290 mmol), cyclopropylamine (0.12 mL, 1.74 mmol) and DIPEA (0.25 mL, 1.45 mmol) in THF (1.5 mL) was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 30 min and heated at 140° C. for an additional 1 h. 1 M HCl (aq.) was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by silica gel chromatography, eluting with a gradient of 0-50% EtOAc in hexanes, to provide (3R)-tert-butyl 3-(6-(5-(2-(cyclopropylamino)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (116 mg, 0.19 mmol, 65% yield) as a clear oil. MS (ESI, pos. ion) m/z: 613.3 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH:9]([OH:28])[CH2:10][N:11]2[C:23]3[CH2:22][CH2:21][N:20]4[CH2:24][CH2:25][CH2:26][CH:19]4[C:18]=3[C:17]3[CH:16]=[C:15]([CH3:27])[CH:14]=[CH:13][C:12]2=3)[CH:6]=[CH:5][N:4]=1.Br>>[CH3:27][C:15]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:10][CH:9]([C:7]3[CH:6]=[CH:5][NH:4][C:3](=[O:2])[CH:8]=3)[OH:28])[C:23]3[CH2:22][CH2:21][N:20]4[CH:19]([C:18]=3[C:17]=2[CH:16]=1)[CH2:26][CH2:25][CH2:24]4
Reactant: COc1cc(C(O)Cn2c3c(c4cc(C)ccc42)C2CCCN2CC3)ccn1
Agent: Br
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2cc[nH]c(=O)c2)CCN2CCCC12
Temperature: 25 °C
Yield: 46.2 %

Procedure:
1-(2-Methoxy-pyridin-4-yl)-2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-ethanol (45 mg, 0.119 mmol) and 47% aqueous HBr (4 mL) and heated at 100° C. for 45 min. The reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was cooled to RT and basified with ammonia and extracted with EtOAc (2×25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated and the crude product was purified by reverse phase chromatography to obtain 20 mg of 4-(2-(2,3,5,6-tetrahydro-10-methyl-1H-indolizino[7,8-b]indol-7(11cH)-yl)-1-hydroxyethyl)pyridin-2(1H)-one. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.43 (d, 1H), 7.23 (m, 2H), 7.05 (t, 1H), 6.7 (m, 1H), 6.5 (d, 1H), 4.79 (m, 1H), 4.3 (m, 2H), 3.9 (m, 2H), 3.8 (m, 1H), 3.6 (m, 1H), 3.4 (m, 2H), 3.1 (m, 1H), 2.6 (m, 1H), 2.4 (s, 3H), 2.3 (m, 2H), 1.9 (m, 1H). Separation by chiral HPLC provided enantiomers II-132a-b.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)([CH3:30])[CH3:29].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([CH:28]([CH3:30])[CH3:29])[CH:36]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1nc(C)n(-c2cccc(C(C)C)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 3-isopropylphenylboronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.04 g, 78%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=2)[CH:7]=1.[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>>[S:20]1[CH:24]=[CH:23][C:22]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=3)[CH:7]=2)=[CH:21]1
Reactant: OB(O)c1ccsc1
Reactant: O=C(Nc1nc2ccc(Br)cn2n1)c1cccnc1
Product: O=C(Nc1nc2ccc(-c3ccsc3)cn2n1)c1cccnc1
Yield: 23.5 %

Procedure:
The title compound was prepared following procedure described for intermediate A1 step a), but starting from N-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B6), 75 mg; 0.24 mmol; 1.0 eq.) and 3-thienylboronic acid (60 mg; 0.47 mmol; 2.0 eq.). Purification by flash chromatography on silica (MeOH/EtOAc, 5:95) gave the title compound as a beige powder (18.1 mg, 23%). HPLC, Rt: 2.13 min. (purity 94.3%). LC/MS, M+(ESI): 322.3, M−(ESI): 320.2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][CH:8]([C:17]1[C:26]([CH3:27])=[C:25]([O:28]C(=O)C)[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:32])[CH:23]=2)[N:18]=1)[C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CO>O>[OH:7][CH:8]([C:17]1[CH:26]([CH3:27])[C:25](=[O:28])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:32])[CH:23]=2)[N:18]=1)[C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCC#CC(O)c1nc2ccc(F)cc2c(OC(C)=O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCCCCC#CC(O)C1=Nc2ccc(F)cc2C(=O)C1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.3 %

Procedure:
A solution of 135 mg (0.978 mmols) of potassium carbonate in 1 ml of water was added to a solution of 349 mg (0.978 mmols) of 2-(1-hydroxy-2-nonynyl)-3-methyl-4-acetoxy-6-fluoroquinoline, 20 ml of methanol and 2 ml of water and stirred at room temperature for 10 minutes. After neutralization with 1N hydrochloric acid, the solvent was distilled off under reduced pressure, followed by addition of 20 ml of chloroform to the resultant residue, washing with water and drying with sodium sulfate. The solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (Wako gel C-200) (solvent: n-hexane : ethyl acetate=1:1) to obtain 183 mg (yield 59 %) of 2-(1-hydroxy-2-nonynyl)-3-methyl-6-fluoro-4-quinolone.
Reaction SMILES: Cl[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:5]2[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[N:13]=1.[CH:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[CH3:12][S:11][C:8]1[N:9]=[CH:10][C:5]2[CH:4]=[C:3]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:2]([C:25]3[CH:26]=[CH:27][C:22]([CH:20]=[O:21])=[CH:23][CH:24]=3)=[N:13][C:6]=2[N:7]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CSc1ncc2cc(-c3ccccc3)c(Cl)nc2n1
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=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1

Procedure:
The mixture of 7-chloro-2-(methylthio)-6-phenylpyrido[2,3-d]pyrimidine (0.100 g, 0.347 mmol), 4-formylphenylboronic acid (0.13 g, 0.87 mmol), Cesium carbonate (0.34 g, 1.04 mmol) and bis(tri-t-butylphosphine)palladium (0.018 g, 0.035 mmol) in dioxane (5 mL) was heated to reflux overnight. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic layer was dried, filtered and concentrated. The residue was purified by silica gel chromatography (20% EtOAc in hexane) to give the title compound. LRMS m/z (M+H) Calcd: 358.4, found: 358.2.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COCCOC>[C:16]1([C:2]2[C:3]3[C:8]([CH:9]=[C:10]4[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1c2ccccc2cc2ccccc12
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: COCCOC
Product: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Yield: 85 %

Procedure:
Into a 200 mL three-neck flask were put 5.4 g (21 mmol) of 9-bromoanthracene, 2.6 g (21 mmol) of phenylboronic acid, 60 mg (0.2 mmol) of palladium(II) acetate (abbreviation: Pd(OAc)2), 10 mL (20 mmol) of potassium carbonate aqueous solution (2.0 mol/L), 260 mg (0.8 mmol) of tris(o-tolyl)phosphine (abbreviation: P(o-tolyl)3), and 20 mL of 1,2-dimethoxyethane (abbreviation: DME), and then the mixture was stirred at 80° C. in a nitrogen atmosphere for 9 hours. After the reaction, a precipitated solid was collected by suction filtration, dissolved in toluene, and filtered through Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), and alumina. The obtained filtrate was washed with water and saturated aqueous solution and magnesium sulfate was added so that the moisture was removed. This suspending solution was naturally filtered and the obtained filtrate was concentrated, whereby 22 g of a light-brown solid of 9-phenylanthracene, which was the object of the synthesis, was obtained in a yield of 85% (synthesis scheme (a-1)).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=4[Cl:26])[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH2:27]O)=[CH:8][CH:7]=1.[C-:29]#[N:30].[Na+].C(Cl)C1C=CC=CC=1>O1CCCC1.C(=O)([O-])O.[Na+].O.CS(C)=O.N1C=CC=CC=1>[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=4[Cl:26])[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH2:27][C:29]#[N:30])=[CH:8][CH:7]=1
Reactant: [C-]#N
Reactant: OCc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCc1ccccc1
Solvent: C1CCOC1
Product: N#CCc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.1 %

Procedure:
Thionyl chloride (0.53 mL, 7.22 mmol) was added to a stirred solution of [9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]methanol (1.38 g, 3.61 mmol) and pyridine (0.10 mL) in tetrahydrofuran (30 mL) at 0° C., and the mixture was stirred at room temperature for 90 min. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. A solution of sodium cyanide (354 mg, 7.22 mmol) in water (1.5 mL) was added to the resulting benzyl chloride in dimethylsulfoxide (12 mL), and the mixture was stirred at room temperature for 14 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and the precipitate was collected by filtration, washed with diisopropyl ether to give the title compound as a colorless powder (1.36 g, 3.47 mmol, 96% in 2 steps).