Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][CH:5]=[C:6]([C:31]([O:33][CH3:34])=[O:32])[C:7]=2[C:10]2[C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]([O:25][CH3:26])=[C:14]([O:16]C(=O)C3C=CC=CC=3)[CH:15]=2)[O:2]1.[H][H]>O1CCCC1.CO.[C].[Pd]>[CH2:1]1[O:9][C:8]2[C:3](=[CH:4][CH:5]=[C:6]([C:31]([O:33][CH3:34])=[O:32])[C:7]=2[C:10]2[C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]([O:25][CH3:26])=[C:14]([OH:16])[CH:15]=2)[O:2]1
Reactant: COC(=O)c1cc(OC)c(OC(=O)c2ccccc2)cc1-c1c(C(=O)OC)ccc2c1OCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC)c(O)cc1-c1c(C(=O)OC)ccc2c1OCO2
Yield: 96.4 %

Procedure:
Dimethyl 5,6-methylenedioxy-4'-methoxy-5'-benzoyloxy-2,2'-biphenyldicarboxylate (1.15 g) is dissolved in tetrahydrofuran (50 ml) and methanol (50 ml), and the solution is stirred under 40 psi hydrogen gas atmosphere in the presence of palladium-carbon (0.2 g) for 16 hours. After the reaction, the catalyst is filtered off, and the filtrate is evaporated into dryness under reduced pressure. The residue is treated with methanol to give dimethyl 5,6-methylenedioxy-4'-methoxy-5'-hydroxy-2,2'-biphenyl-dicarboxylate (0.86 g) as colorless crystal. M.p. 172°-173° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:37]([F:40])([F:39])[F:38])[N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:36])[CH2:16][C@H:17]([NH:28]C(OC(C)(C)C)=O)[CH2:18][C:19]3[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=3[F:27])[CH2:11][C:10]=12)=[O:5])[CH3:2].[ClH:41]>C(OCC)(=O)C>[ClH:41].[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:37]([F:39])([F:40])[F:38])[N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:36])[CH2:16][C@H:17]([NH2:28])[CH2:18][C:19]3[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=3[F:27])[CH2:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F)CC2
Yield: 99 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid ethyl ester 23a (0.09 g, 0.156 mmol) and 2 mL of ethyl acetate were added into the reaction flask. A solution of 2.7 N hydrochloric acid in 4 mL of ethyl acetate was then added to the flask. The reaction mixture was reacted at room temperature for 3 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid ethyl ester hydrochloride 23 (80 mg, yield 99%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.[Li][CH3:35]>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=3)([OH:13])[CH3:35])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=1
Reactant: [Li]C
Reactant: COc1nc2ccc(C(=O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: COc1nc2ccc(C(C)(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.42 h

Procedure:
To a flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanone (408 mg, 0.86 mmol, Intermediate 8: step b) was added THF (20 mL) and the solution was cooled to −78° C. MeLi (1.6 M in Et2O, 0.6 mL, 0.96 mmol) was then introduced. After 25 minutes, the reaction mixture was quenched with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc (4×40 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel (5% MeOH-DCM increasing to 10% MeOH) provided the title compound as a white amorphous solid. 1H NMR (500 MHz, CDCl3) δ 8.26 (d, J=1.7 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.50 (d, J=8.2 Hz, 3H), 7.40 (d, J=8.1 Hz, 2H), 7.04 (d, J=10.7 Hz, 1H), 4.35 (s, 2H), 4.07 (s, 3H), 3.14 (s, 3H), 2.29 (s, 3H), 1.95 (s, 3H); MS (ESI): mass calcd. for C25H23ClF3N3O2, 489.1, m/z found 490.1 [M+H]+. 1-(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-(1,2-dimethyl-1H-imidazol-5-yl)ethanol was purified by chiral chromatography (Chiracel OD (20 μM) diacel, 50×41 cm, heptane:ethanol with 2% isopropylamine (90:10)), to give 2 enantiomers. The first eluting enantiomer was Example 12b and the second eluting enantiomer was Example 12c.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C:19]1([CH2:23][C:24]([NH2:26])=[O:25])[CH2:22][O:21][CH2:20]1>>[C:24]([CH2:23][C:19]1([NH:18][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[CH2:22][O:21][CH2:20]1)(=[O:25])[NH2:26]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: NC(=O)CC1(N)COC1
Product: NC(=O)CC1(NC(=O)c2cnc(C3CC3)c(OCC3CC3)n2)COC1

Procedure:
The title compound was synthesized in analogy to Example 6 using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 50 mg, 0.21 mmol) and 2-(3-amino-oxetan-3-yl)-acetamide (31 mg, 0.24 mmol) as starting materials and isolated (30 mg, 41%) as white solid; LC-MS (UV peak area, ESI) 100%, 347.1710 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][C:10]([C:14]([OH:17])([CH3:16])[CH3:15])=[CH:9][C:8]=2[F:18])=[N:4][C:3]=1[C:19]([NH2:21])=[O:20].Cl[C:23]1[N:28]=[N:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:13][C:12]1[CH:11]=[C:10]([C:14]([OH:17])([CH3:16])[CH3:15])[CH:9]=[C:8]([F:18])[C:7]=1[C:5]1[S:6][C:2]([NH:1][C:23]2[N:28]=[N:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=2)=[C:3]([C:19]([NH2:21])=[O:20])[N:4]=1
Reactant: CC(C)(O)c1ccc(Cl)nn1
Reactant: CC(C)(O)c1cc(F)c(-c2nc(C(N)=O)c(N)s2)c(F)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(O)c1cc(F)c(-c2nc(C(N)=O)c(Nc3ccc(C(C)(C)O)nn3)s2)c(F)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A sealed tube was charged with a stir bar, 5-amino-2-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazole-4-carboxamide (52 mg, 0.17 mmol), 2-(6-chloropyridazin-3-yl)propan-2-ol (29 mg, 0.17 mmol), Pd2(dba)3 (15 mg, 0.017 mmol), X-PHOS (40 mg, 0.083 mmol), and potassium carbonate (23 mg, 0.17 mmol). The tube was evacuated and backfilled with argon 3×. Fully degassed tert-amyl alcohol (0.33 ml) was added and the reaction vessel was sealed and left to stir at 100° C. overnight. The reaction vessel was removed from the heat and allowed to cool to room temperature. The reaction mixture was taken up in ethyl acetate and washed with 100 mL water. The water layer was treated with concentrated ammonium hydroxide and extracted with ethyl acetate. The organic fractions were combined, dried over anhydrous magnesium sulfate, and filtered. To the organic layer was added 0.45 g of silica gel and the solvent was removed under reduced pressure. The compound on silica was purified by flash chromatography (500 ml gradient of 0-3% methanol/ethyl acetate) to afford the title compound as a light yellow solid. 1H NMR (500 MHz, d6-DMSO) δ 11.41 (s, 1H), 7.83 (d, 1H), 7.74 (s, 1H), 7.68 (d, 1H), 7.57 (s, 1H), 7.34 (d, 2H), 5.42 (s, 1H), 5.38 (s, 1H), 1.50 (s, 6H), 1.44 (s, 6H). LRMS (APCI) calcd for C20H22F2N5O3S [M+H]+ 450.1, found 450.0.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.B(Br)(Br)Br>ClCCl>[O:10]1[C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:11][C:7]=2[CH:8]=[CH:9]1
Reactant: COc1ccc2occc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2occc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 5-methoxybenzofuran (1) (0.50 g, 3.38 mmol) in dichloromethane (15 mL), boron tribromide (16.87 mL, 16.87 mmol, 1M solution in dichloromethane) was added slowly at 0° C. The reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was then cooled to 0° C., quenched with aqueous saturated NaHCO3 solution and extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4, and concentrated under reduced pressure to give compound (2) as an off white solid (300 mg) which was used in the next step without further purification.
Reaction SMILES: BrC1C=C(N2C3=NC=CC(C4C=NC5C(C=4)=CC=CC=5)=C3C(C)=C2)C=CC=1C#N.NCCCCC[OH:36].[OH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]1[CH:51]=[C:50]([N:52]2[C:56]3=[N:57][CH:58]=[CH:59][C:60]([C:61]4[CH:62]=[N:63][C:64]5[C:69]([CH:70]=4)=[CH:68][CH:67]=[CH:66][CH:65]=5)=[C:55]3[C:54]([CH3:71])=[CH:53]2)[CH:49]=[CH:48][C:45]=1[C:46]#[N:47]>>[OH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]1[CH:51]=[C:50]([N:52]2[C:56]3=[N:57][CH:58]=[CH:59][C:60]([C:61]4[CH:62]=[N:63][C:64]5[C:69]([CH:70]=4)=[CH:68][CH:67]=[CH:66][CH:65]=5)=[C:55]3[C:54]([CH3:71])=[CH:53]2)[CH:49]=[CH:48][C:45]=1[C:46]([NH2:47])=[O:36]
Reactant: Cc1cn(-c2ccc(C#N)c(NCCCCCO)c2)c2nccc(-c3cnc4ccccc4c3)c12
Reactant: NCCCCCO
Agent: Cc1cn(-c2ccc(C#N)c(Br)c2)c2nccc(-c3cnc4ccccc4c3)c12
Product: Cc1cn(-c2ccc(C(N)=O)c(NCCCCCO)c2)c2nccc(-c3cnc4ccccc4c3)c12
Yield: 31 %

Procedure:
According to Example 1(6), a crude product of 2-(5-hydroxypentylamino)-4-{(3-methyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile was prepared using compound (40f) instead of compound (1e) and using 5-amino-1-pentanol instead of trans-aminocyclohexanol and was used in the subsequent reaction without being purified. According to Example 1(7), compound (56) (the second stage yield: 31%) was prepared as a white solid using 2-(5-hydroxypentylamino)-4-{3-methyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile instead of compound (1f).
Reaction SMILES: [CH3:1][C:2]([N+:12]([O-])=O)([CH3:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH3:15][C:16]([OH:18])=[O:17]>[Pd].CO>[C:16]([OH:18])(=[O:17])[CH3:15].[NH2:12][C:2]([CH3:11])([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CC(C)(Cc1ccc(O)cc1)[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(N)Cc1ccc(O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
A one-gallon high-pressure reactor was charged with 4(2-methyl-2-nitropropyl)phenol (120 g, 614 mmol), HOAc (35.2 mL, 614 mmol), 5% Palladium on carbon (24 g) wetted with 2Bβ3EtOH (60 mL), and MeOH (1230 mL). The mixture was heated to 50° C. with agitation (600 rpm), and the reactor was purged with N2 and pressurized to 50 psi with H2. After 15.5 h the reactor was purged with N2, and the cooled mixture was filtered. The filter cake was washed with MeOH and the filtrate was concentrated to 514 g of slurry on a rotary evaporator. To this slurry was added EtOAc (2 L) with vigorous agitation. After stirring for 1 h, the resulting crystals were filtered and washed with a small amount of EtOAc. The product was dried overnight in a 45° C. vacuum oven to yield 118.83 g (86%) of product as small white needles (mp 211°-216° C. dec). This material was 99% pure by HPLC analysis, and while another 9.00 g of material was obtained from the mother liquor it was found to be only 88 % pure.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]([CH3:21])[C:18](O)=[O:19])[CH:11]=[CH:10]2>C(Cl)(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]([CH3:21])[C:18]([Cl:3])=[O:19])[CH:11]=[CH:10]2
Reactant: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc2cc(C(C)C(=O)Cl)ccc2c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
7 ml of thionyl chloride were cautiously added to a solution of 2.3 g of 2-(6-methoxy-2-naphtyl)propionic acid in 15 ml of anhydrous chloroform. The reaction mixture was stirred for 40 minutes at room temperature and then the solvent was evaporated at a reduced pressure, obtaining 2.23 g of 2-(6-methoxy-2-naphtyl)propionylchloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][C:10]=1[F:17])=[O:5])[CH3:2].B(Br)(Br)Br.CCO>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[F:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC1c1ccc(OC)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C1CC1c1ccc(O)cc1F
Temperature: -78 °C
Reaction time: 3 h
Yield: 166.4 %

Procedure:
After 2-(2-fluoro-4-methoxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.16 g, 0.67 mmol) obtained in Step B was dissolved in anhydrous DCM (10 mL), 1M BBr3 solution (3.36 mL, 3.35 mmol) was added thereto at −78° C., and the mixture was stirred at room temperature for 3 hours. After the termination of the reaction, EtOH was added thereto, and the mixture was stirred at room temperature for 30 minutes. The reactant was concentrated under reduced pressure, added with saturated sodium bicarbonate aqueous solution, and extracted with DCM. The organic layer was concentrated under reduced pressure and purified by column chromatography (eluent, EtOAc/Hex=1/4) to obtain the title compound (0.25 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C1C(=O)N([Br:18])C(=O)C1>CN(C=O)C.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[Br:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(CCO)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(CCO)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To a solution of 2-(4-amino-phenyl)-ethanol (5.10 g, 37.2 mmol) in 37 mL of DMF was added NBS (6.60 g, 37.1 mmol) and the mixture stirred overnight at RT. The reaction was diluted with 100 mL of water and extracted with EtOAc (3×100 mL). The organic layer was washed with brine (200 mL) and dried over Na2SO4. The title compound was purified by silica gel flash chromatography eluting with 50% EtOAc/hexanes to give 5.10 g (64%) of a white solid. Mass spectrum (ESI, m/z): Calcd. for C8H10BrNO, 216.0 (M+H), found 216.1.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])[CH:37]=[CH:36]2.[Cl:44][C:45]1[CH:46]=[C:47]([NH:52][C:53]2[N:54]=[CH:55][C:56]([CH2:59]O)=[N:57][CH:58]=2)[CH:48]=[CH:49][C:50]=1[Cl:51]>C1COCC1>[Cl:44][C:45]1[CH:46]=[C:47]([NH:52][C:53]2[N:54]=[CH:55][C:56]([CH2:59][O:32][C:33]3[CH:34]=[C:35]4[C:40](=[CH:41][CH:42]=3)[NH:39][C:38](=[O:43])[CH:37]=[CH:36]4)=[N:57][CH:58]=2)[CH:48]=[CH:49][C:50]=1[Cl:51]
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: OCc1cnc(Nc2ccc(Cl)c(Cl)c2)cn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1ccc2cc(OCc3cnc(Nc4ccc(Cl)c(Cl)c4)cn3)ccc2[nH]1
Reaction time: 0.17 h
Yield: 13.1 %

Procedure:
A solution of Ph3P (0.07 g, 0.267 mmol) in THF (1.7 mL) was cooled to 0° C. under N2 and DEAD (0.076 ml, 0.481 mmol) was added dropwise. The mixture was stirred for 10 min, then 6-hydroxyquinolin-2(1H)-one (0.072 g, 0.444 mmol) was added. After stirring for 5 min, a solution of (5-((3,4-dichlorophenyl)amino)pyrazin-2-yl)methanol (0.1 g, 0.370 mmol) in THF (2 mL) was added. The reaction was stirred at room temperature overnight. The mixture was concentrated and partially purified by flash chromatography on silica gel using 30-100% ethyl acetate in hexanes, then 5-10% methanol in ethyl acetate. The desired fractions were concentrated to a solid, which was redissolved in DMF. Water was added to the vigorously stirred solution until a suspension formed. After stirring 18 h, the off-white solid was filtered, washed with methanol, and dried to yield 6-((5-(3,4-dichlorophenylamino)pyrazin-2-yl)methoxy)quinolin-2(1H)-one (0.02 g, 13%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.67 (1H, s), 9.97 (1H, s), 8.40 (1H, d, J=1.00 Hz), 8.28 (1H, d, J=1.51 Hz), 8.20 (1H, d, J=2.26 Hz), 7.86 (1H, d, J=9.79 Hz), 7.49-7.64 (2H, m), 7.37 (1H, s), 7.17-7.32 (2H, m), 6.51 (1H, dd, J=9.54, 2.01 Hz), 5.12 (2H, s). LCMS: R.T.=4.09; [M+H]+=412.93.
Reaction SMILES: [OH:1][CH:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:13])N1C(C)C.[BH4-].[Na+].CC(C)=O.Cl.P([O-])([O-])(O)=O.[K+].[K+]>C(O)(C)C.O>[CH3:12][O:11][C:7]1[C:6]2[CH2:2][O:1][C:4](=[O:13])[C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: COc1nccc2c1C(O)N(C(C)C)C2=O
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: [BH4-]
Solvent: CC(C)=O
Solvent: CC(C)O
Solvent: O
Product: COc1nccc2c1COC2=O
Temperature: 50 °C
Reaction time: 0.58 h
Yield: 38.1 %

Procedure:
To a stirred solution of 19.40 g crude 3-hydroxy-2-isopropyl-4-methoxy-2,3-dihydro-pyrrolo[3,4-c]pyridin-1-one (87.29 mmol), as obtainable from example 14, in 300 mL isopropanol and 100 mL water were added at room temperature 5.160 g NaBH4 (130.9 mmol, 1.5 eq). After 3 h (<1.0% area 3-hydroxy-2-isopropyl-4-methoxy-2,3-dihydro-pyrrolo[3,4-c]pyridin-1-one), the reduction was quenched at 0° C. by addition of 34.0 mL acetone (474.4 mmol, 5.3 eq) and stirring was continued for 35 min at room temperature. The mixture was poured on 415 mL aqueous HCl (2.0 M, 829.3 mmol, 9.5 eq) at 0° C. and stirring was continued for 20 min at room temperature. The mixture was then heated to 50° C. overnight and was subsequently cooled to 0° C. Dipotassium hydrogen phosphate was added in order to adjust pH 3.0 and ca. 95% of the isopropanol were removed in a rotary evaporator (40° C./10 mbar). Water was added until the salts were dissolved and the mixture was extracted three times with 300 mL, in total 900 mL dichloromethane. The combined organic phases were dried over 50 g Na2SO4 (30 min) and filtered. The solid was washed with 100 mL dichloromethane. After evaporation of solvent in a rotary evaporator (40° C./25 mbar), the crude product (9.963 g, 69% w/w) was obtained as a light brown solid (HPLC purity 80.7% area). Purification was achieved by trituration with 30 mL ethyl acetate for 24 h at room temperature and subsequent addition of 60 mL heptane. The suspension was then allowed to stand for 24 h at 5° C. yielding the title product (5.486 g, 33.22 mmol, 40% w/w (68% over 2 steps), HPLC purity 95.1% area) as a beige solid.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:6])[CH3:5].[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>>[CH2:19]([N:21]([CH2:22][CH3:23])[CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:6])[CH3:5])[CH3:20]
Reactant: CCNCC
Reactant: CC(O)(CCCl)c1ccccc1-c1ccccc1
Product: CCN(CC)CCC(C)(O)c1ccccc1-c1ccccc1

Procedure:
2.6 g of 1-chloro-3-p-biphenylyl-butan-3-ol are heated with 30 ml of diethylamine at 150° for 15 hours in an autoclave, and the mixture is cooled and worked up in the customary manner to give 1-diethylamino-3-p-biphenylyl-butan-3-ol.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([S:7][CH:8]2[CH2:13][C:12](=[O:14])O[C:9]2=[O:10])=[N:5][N:6]=1.[CH2:15]([NH2:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1(C)C(C)=CC=CC=1>[CH2:15]([N:33]1[C:12](=[O:14])[CH2:13][CH:8]([S:7][C:4]2[S:3][C:2]([SH:1])=[N:6][N:5]=2)[C:9]1=[O:10])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Reactant: O=C1CC(Sc2nnc(S)s2)C(=O)O1
Solvent: Cc1ccccc1C
Product: CCCCCCCC/C=C\CCCCCCCCN1C(=O)CC(Sc2nnc(S)s2)C1=O

Procedure:
A mixture of 2-(2-mercapto-1,3,4-thiadiazol-5-ylthio)-succinic anhydride and oleylamine (1:1 molar ratio) in xylene was refluxed for three hours. After removing the solvent under reduced pressure, the reaction product was a light brown, viscous oil. Both its IR spectrum and elemental analysis appeared to be consistent with the proposed structure. A sample of N-(2-ethylhexyl)-2-(2-mercapto-1,3,4-thiadiazol-5-ylthio)-succinimide was similarly prepared.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]>ClC1C=CC=CC=1Cl>[CH3:3][C:2]1[C:3]2[CH2:2][CH2:1][O:4][C:5]=2[CH:6]=[C:7]([CH2:7][CH:6]=[CH2:5])[C:1]=1[OH:4]
Reactant: C=CCOCC=C
Solvent: Clc1ccccc1Cl
Product: C=CCc1cc2c(c(C)c1O)CCO2

Procedure:
In a manner analogous to that described above for 2a, 36 (1.00 g, 6.66 mmol) was alkylated with allyl bromide (1.76 g, 14.6 mmol) to give the allyl ether. The allyl ether (1.23 g) was thermally rearranged in 1,2-dichlorobenzene (8 mL) at 190° C. for 3.5 hours to afford, after chromatographic purification, compound 37. Recrystallization from hexane gave an analytical sample. 37: mp 60°-61° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:21][CH:20]([O:22][CH3:23])[CH2:19]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:24]([C:28]1[CH:29]=[C:30]2[C:35](=[C:36]([F:38])[CH:37]=1)[C:34](=[O:39])[N:33]([C:40]1[CH:50]=[CH:49][CH:48]=[C:47](B3OC(C)(C)C(C)(C)O3)[C:41]=1[CH2:42][O:43][C:44](=[O:46])[CH3:45])[N:32]=[CH:31]2)([CH3:27])([CH3:26])[CH3:25].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:24]([C:28]1[CH:29]=[C:30]2[C:35](=[C:36]([F:38])[CH:37]=1)[C:34](=[O:39])[N:33]([C:40]1[CH:50]=[CH:49][CH:48]=[C:47]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([CH2:17][N:18]5[CH2:21][CH:20]([O:22][CH3:23])[CH2:19]5)=[CH:13][N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=3)[C:41]=1[CH2:42][O:43][C:44](=[O:46])[CH3:45])[N:32]=[CH:31]2)([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: COC1CN(Cc2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)C1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COC1CN(Cc2ccc(Nc3cc(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4COC(C)=O)nn(C)c3=O)nc2)C1
Temperature: 110 °C
Yield: 90.4 %

Procedure:
6-Chloro-4-[5-(3-methoxy-azetidin-1-ylmethyl)-pyridin-2-ylamino]-2-methyl-2H-pyridazin-3-one (100 mg, 0.29 mmol, Eq: 1.0), acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (247 mg, 0.5 mmol, Eq: 1.75), bis(dibenzylideneacetone)palladium (8.2 mg, 0.014 mmol, Eq: 0.05), x-phos (13.6 mg, 0.028 mmol, Eq: 0.10), and tripotassium phosphate (121 mg, 0.57 mmol, Eq: 2.0) were added to a microwave vial. The vial was capped and purged with nitrogen. Butanol (2.3 ml) and water (0.5 ml) were added and the vial was purged again, then backfilled with nitrogen. The reaction was heated at 110° C. for 2.5 hrs in a sand bath. The crude reaction was filtered through celite and purified by chromatography using a gradient of 0% to 25% methanol in DCM. Fractions containing the desired product were combined with those in which the acetate protecting group had been removed during the course of the reaction to give 175 mg of material (approximately 92%).