Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([NH:33][C@H:34]([C:38]([NH2:40])=[O:39])[C@@H:35]([CH3:37])[OH:36])(OC(C)(C)C)=O.[ClH:41].O1CCOCC1.C(OCC)C>ClCCl>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[ClH:41].[NH2:33][C@H:34]([C:38]([NH2:40])=[O:39])[C@@H:35]([CH3:37])[OH:36]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: COc1ccc(/C=C(/C#N)c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[C@@H](O)[C@H](N)C(N)=O

Procedure:
(E)-3-(3-Amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-enenitrile-Boc-L-threonineamide (810 mg, 1.95 mmols) were dissolved in 10 ml of dichloromethane, and 5 ml of a solution of 4-M hydrochloric acid and dioxane were added thereto. The mixture was reacted at 60° C. for 3 hours. One-hundred milliliters of diethyl ether were added thereto, and the mixture was filtered. The resulting powder was purified twice through medium-pressure liquid chromatography (ODS, mixture of water and acetonitrile at a ratio of 75:25), and was dissolved in a small amount of methanol. A mixture of acetonitrile and ethyl acetate was added thereto, and the precipitate was collected by filtration to obtain 290 mg (0.607 mmols) of the final product in a yield of 31%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>O1CCCC1>[C:14]1([S:20]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
15.8 g Indole-5-carboxaldehyde were dissolved in 300 ml tetrahydrofuran and cooled to 0° C. Then, 5.12 g sodium hydride (55% in mineral oil) were added in small portions followed by slow, trop by trop addition of 15.2 ml of benzenesulfonyl chloride. The reaction mixture was then warmed up to ambient temperature and stirring continued for 16 hours. It was then poured onto ice, neutralized to pH 4 with HCl (1N) and extracted 3 times with ethyl acetate. The combined organic phases were washed with water, dried over magnesium sulfate and evaporated to give a crude product which was purified by chromatography (silicagel, eluent: gradient of n-heptane/ethyl acetate) to yield 4.09 g 1-benzenesulfonyl-1H-indole-5-carbaldehyde as rose solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:14][C:15]([OH:17])=O)[CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:5])[CH3:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:14][C:15](=[O:17])[C:13]2[CH:12]=[CH:11][S:10][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N(CCc1cccs1)CC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)N1CCc2sccc2C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.6 %

Procedure:
The product of step (b) (˜165 mmol, ˜42 g) was dissolved in 1 L of DCM. DMF (100 uL) was added followed slowly by oxalyl chloride (21.7 mL, 247 mmol). After 1 hour, the reaction was concentrated to dryness and the crude material was re-dissolved in DCE (1 L). AlCl3 (55 g, 410 mmol) was carefully added and the reaction was stirred at room temperature for ½ hour. The crude reaction was quenched with ice, washed with water (3×), and dried over MgSO4. The title product was purified by silica gel chromatography (30% EtOAc in Hexanes) to give 10.5 grams of the sub-title compound as a white solid. MS: ESI (positive): 240 (M+H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20]C(=O)OC(C)(C)C)[C:15]2[CH:28]=[C:11]([CH:12]=[CH:13][N:14]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4][C:3]1=[O:29].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:20][C@@H:16]1[C:15]2[CH:28]=[C:11]([CH:12]=[CH:13][N:14]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4][C:3](=[O:29])[C@H:2]([CH3:1])[CH2:19][CH2:18][CH2:17]1
Reactant: C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)c2cc(ccn2)-c2ccccc2NC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CCC[C@H](N)c2cc(ccn2)-c2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 45G (950 mg, 2.402 mmol) in DCM (20.300 ml) was added TFA (5.55 ml, 72.1 mmol) dropwise over 10 min. The dark brownish solution was stirred at rt for 1 hour. The reaction mixture was concentrated to give example 45H compound as a dark brownish gum. Used in next step without purification. MS (ESI) m/z: 296.2 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11][C:10](=[O:13])[CH:9]([CH:14]=[O:15])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[C:1]1([C:7]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11][C:10](=[O:13])[C:9]([CH:14]=[O:15])=[CH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CC1CC(c2ccccc2)(c2ccccc2)CCC1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: O=CC1=CC(c2ccccc2)(c2ccccc2)CCC1=O
Temperature: 0 °C
Yield: 27.2 %

Procedure:
A solution of 4,4-diphenyl-2-formylcyclohexanone (44.5 g) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (38 g) in dioxane (650 cc) is stirred for 30 minutes at 25° C. and then cooled to 0° C.; the solid is removed by filtration and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.06 mm, diameter 6 cm, height 63 cm), eluting with a mixture of cyclohexane and ethyl acetate (80:20 by volume) and collecting 50-cc fractions. Fractions 7 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The crystalline residue is stirred vigorously with isopropyl ether (200 cc) and the crystals obtained are drained, washed with isopropyl ether (2×50 cc) and dried. 4,4-Diphenyl-2-formyl-2-cyclohexen-1-one (12 g), m.p. 126° C., is obtained.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[O:17][CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12][O:11]1)C1C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].C(OCC)(=O)C>[CH2:14]1[C:13]2([CH2:16][O:17][CH:10]([CH2:9][OH:8])[O:11][CH2:12]2)[CH2:15]1
Reactant: [H][H]
Reactant: c1ccc(COCC2OCC3(CC3)CO2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: OCC1OCC2(CC2)CO1
Yield: 98.7 %

Procedure:
The 6-((benzyloxy)methyl)-5,7-dioxaspiro[2.5]octane (6.1 g, 26 mmol) obtained by the step (2a) was mixed with 20% palladium hydroxide (800 mg) and ethyl acetate (70 ml) and the mixture was stirred in a hydrogen atmosphere for 24 hours. The reaction vessel was purged with nitrogen and the catalyst was filtered off and then the solvent was distilled off to obtain the title compound (3.7 g, yield: 98.7%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[N:6][NH:5][C:4](=[O:15])[CH:3]=1.[OH-].[NH4+].[H][H]>[Pd].C(O)C>[CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][NH:5][C:4](=[O:15])[CH:3]=1
Reactant: Cc1cc(=O)[nH]nc1-c1ccc(Br)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(=O)[nH]nc1-c1ccccc1
Temperature: 50 °C

Procedure:
A 10.0 g. portion of 5-methyl-6-p-bromophenyl-3(2H)-pyridazinone and 1.0 g. of 10% palladium on carbon catalyst in 150 ml. of ethanol and 50 ml. of ammonium hydroxide is shaken under 40 lb. of hydrogen pressure for 4 hours in a Parr bottle, heated to 50° C. with an outside jacket. The reaction mixture is suction filtered and the filtrate concentrated to a white solid which is washed with water and air dried to afford 5-methyl-6-phenyl-3(2H)-pyridazinone as white crystals.
Reaction SMILES: [OH:1][C:2]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([C:25]#[N:26])=[CH:24][C:18]=2[N:17]=1)([C:4]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[CH3:3].C1C(=O)N([Cl:34])C(=O)C1>CN(C=O)C>[Cl:34][C:6]1[C:5]2[C:9](=[C:10]([CH3:15])[CH:11]=[C:12]([O:13][CH3:14])[C:4]=2[C:2]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([C:25]#[N:26])=[CH:24][C:18]=3[N:17]=2)([OH:1])[CH3:3])[NH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc(C)c2[nH]ccc2c1C(C)(O)c1nc2cc(C#N)ccc2[nH]1
Solvent: CN(C)C=O
Product: COc1cc(C)c2[nH]cc(Cl)c2c1C(C)(O)c1nc2cc(C#N)ccc2[nH]1
Temperature: 0 °C

Procedure:
To a solution of (−)-2-(1-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (Example 26-C) (20 mg, 0.058 mmol) in DMF (0.58 mL) was added NCS (14 mg, 0.1 mmol) at 0° C. The reaction was stirred in the ice bath for 1 hour. At this point, the reaction was quenched with a saturated solution of aq. Na2S2O3 at 0° C., and then the mixture was extracted with EtOAc and then the EtOAc layer was dried, concentrated, absorbed onto silica and purified by flash column chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.18-12.43 (m, 1H) 11.29 (br. s., 1H) 8.06 (s) 7.65-7.79 (m) 7.45-7.52 (m) 7.43 (d, J=3.03 Hz, 1H) 6.72 (s, 1H) 5.78-6.09 (m, 1H) 3.16 (s, 3H) 2.42 (s, 3H) 2.15 (s, 3H). HRMS calcd. for C20H17ClN4O2 (M+H)+ 381.1113. found 381.1123.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][CH2:26][OH:27])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.O>[OH:27][CH2:26][CH2:25][CH2:24][N:22]([CH3:23])[C:3]1[C:2]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: CN(CCCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CN(CCCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cccnc1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-6-((3-hydroxypropyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 165.1, 90 mg, 0.185 mmol), pyridin-3-ylboronic acid (22.7 mg, 0.185 mmol) and Na2CO3 (59 mg, 0.554 mmol) in a mixture of DME (4.0 mL), EtOH (0.54 mL) and water (0.80 mL) was flushed with argon for 5 min. Pd(PPh3)2Cl2 was added (6.5 mg, 0.0092 mmol) and the mixture was subjected to MW irradiation at 125° C. for 20 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure to give a residue that was triturated with THF and filtered. The filtrate was evaporated to dryness under reduced pressure and the crude product was purified by preparative LC-MS. TFA was removed using a SPE PL-HCO3 (StratoSpheres™ VariPure IPE) cartridge to afford the title compound. UPLC-MS (Condition 8) tR=2.05 min, m/z=447.1 [M+H]+, m/z=445.2 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22][O:23]C(=O)C)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[Na]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22][OH:23])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(COC(C)=O)c3c2c1COC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1ncc2[nH]c3cccc(CO)c3c2c1COC
Reaction time: 96 h
Yield: 94.7 %

Procedure:
5-Acetoxymethyl-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester (7.9 g) is taken up in a solution of sodium (1.4 g) in ethanol (100 ml) and left for 4 days at +4° C. The solution is concentrated, taken up in abundant ethyl acetate, washed alkali-free with water, dried with sodium sulfate and evaporated in a vacuum. By treatment with ethanol the residue yields 6.6 g of the title compound as colorless crystals with a melting point of 139°-140° C.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH:13]([CH3:14])[CH2:12][N:11]([C:15]2[C:24]([F:25])=[C:23]3[C:18]([C:19](=[O:32])[C:20]([C:29]([OH:31])=[O:30])=[CH:21][N:22]3[CH:26]3[CH2:28][CH2:27]3)=[C:17]([CH3:33])[C:16]=2[F:34])[CH2:10]1)=O)(C)(C)C.[ClH:35]>C(O)C>[ClH:35].[NH2:8][CH:9]1[CH:13]([CH3:14])[CH2:12][N:11]([C:15]2[C:24]([F:25])=[C:23]3[C:18]([C:19](=[O:32])[C:20]([C:29]([OH:31])=[O:30])=[CH:21][N:22]3[CH:26]3[CH2:28][CH2:27]3)=[C:17]([CH3:33])[C:16]=2[F:34])[CH2:10]1
Reactant: Cc1c(F)c(N2CC(C)C(NC(=O)OC(C)(C)C)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Cl
Solvent: CCO
Product: Cc1c(F)c(N2CC(C)C(N)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
A mixture comprising 7-(3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6, 8-difluoro-5-methyl1,4-dihydro-4-oxoquinoline-3-carboxylic acid (trans form) (125 mg), ethanol (4 ml) and 10% hydrochloric acid (4 ml) is refluxed for 30 minutes. After concentrating, the obtained residue is recrystallized from ethanol to give 7-(3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6, 8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid monohydrochloride (trans form) (63 mg), as pale yellow powder, m.p. 214°-216° C.
Reaction SMILES: [F:1][C:2]1[C:11]([NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])=[CH:10][CH:9]=[C:8]([F:19])[C:3]=1[C:4]([O:6]C)=O.[Cl:20][C:21]1[N:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=1>>[Cl:20][C:21]1[N:26]=[C:25]([CH2:27][C:4]([C:3]2[C:2]([F:1])=[C:11]([NH:12][C:13](=[O:14])[O:15][CH2:16][CH:17]=[CH2:18])[CH:10]=[CH:9][C:8]=2[F:19])=[O:6])[CH:24]=[CH:23][N:22]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: C=CCOC(=O)Nc1ccc(F)c(C(=O)OC)c1F
Product: C=CCOC(=O)Nc1ccc(F)c(C(=O)Cc2ccnc(Cl)n2)c1F
Yield: 60.2 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 11 using methyl 2,6-difluoro-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (80 g, 295 mmol) and 2-chloro-4-methylpyrimidine (41.6 g, 324 mmol) the title compound of Step E was obtained (65 g, 60.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.49-9.60 (m, 1H), 8.72-8.77 (m, 0.3H), 8.58-8.64 (m, 0.6H), 7.57-7.83 (m, 2H), 7.15-7.25 (m, 1H), 5.89-6.01 (m, 1H), 5.75-5.82 (m, 0.6H), 5.20-5.40 (m, 2H), 4.55-4.62 (m, 2H), m/z (ES+): 368 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH:10]=[O:11].[CH:12]([Mg]Br)([CH3:14])[CH3:13].C(OCC)C.[Cl-].[NH4+]>O1CCCC1.O>[CH3:13][CH:12]([CH3:14])[CH:10]([C:2]1[NH:1][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1)[OH:11]
Reactant: O=Cc1cc2ccncc2[nH]1
Reactant: CC(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C)C(O)c1cc2ccncc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
1H-Pyrrolo[2,3-c]pyridine-2-carboxaldehyde (125 mg, 0.86 mmol) was suspended in tetrahydrofuran (5 mL) at −30° C. under a nitrogen atmosphere. Isopropylmagnesium bromide in diethyl ether (0.87 mL, 1.74 mmol) was added dropwise. The reaction mixture was slowly warmed to room temperature. After stirring for ca. 3 h, the reaction mixture was cooled to −30° C. and additional 2.0 M isopropylmagnesium bromide in diethyl ether (0.22 mL, 0.44 mmol) was added. The reaction mixture was stirred for another 1 h, while warming to room temperature. The reaction mixture was poured into a 2:1 solution of saturated ammonium chloride and water, and extracted with ethyl acetate (3×). The combined organic extracts were washed with water and brine, dried over sodium sulfate, and concentrated. The crude product was purified by Biotage chromatography (2 to 10% methanol in methylene chloride) to provide 2-methyl-1-(1H-pyrrolo[2,3-c]pyridin-2-yl)-1-propanol (86 mg, 53%) as a white solid: mp 140-144° C.; 1H NMR (500 MHz, CD3OD) δ0.99 (6H, m), 2.01-2.25 (1H, m), 4.57-4.65 (1H, m), 6.38 (1H, s), 7.51 (1H, s), 8.00 (1H, s), 8.63 (1H, s); ESI MS m/z 191 [C11H14N2O+H]+; HPLC (Method A) >99% (AUC), tR=13.1 min.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Br[C:36]1[C:37]([N:56]2[CH2:60][CH2:59][O:58][C:57]2=[O:61])=[CH:38][C:39]2[O:43][C:42]([C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)=[C:41]([C:51]([NH:53][CH3:54])=[O:52])[C:40]=2[CH:55]=1.[F:62][C:63]1[C:64]2[CH:65]=[C:66]3[C:75]4[N:76]=[C:77]([Sn](C)(C)C)[CH:78]=[CH:79][C:74]=4[O:73][CH2:72][N:67]3[C:68]=2[CH:69]=[CH:70][CH:71]=1>O1CCOCC1.O.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:62][C:63]1[C:64]2[CH:65]=[C:66]3[C:75]4[N:76]=[C:77]([C:36]5[C:37]([N:56]6[CH2:60][CH2:59][O:58][C:57]6=[O:61])=[CH:38][C:39]6[O:43][C:42]([C:44]7[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=7)=[C:41]([C:51]([NH:53][CH3:54])=[O:52])[C:40]=6[CH:55]=5)[CH:78]=[CH:79][C:74]=4[O:73][CH2:72][N:67]3[C:68]=2[CH:69]=[CH:70][CH:71]=1
Reactant: C[Sn](C)(C)c1ccc2c(n1)-c1cc3c(F)cccc3n1CO2
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N3CCOC3=O)c(Br)cc12
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
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N3CCOC3=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 100 °C
Yield: 23.5 %

Procedure:
Pd2(dba)3 (10 mg, 0.01 mmol) and X-Phos (11 mg, 0.02 mmol) was added to the mixture of 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(2-oxooxazolidin-3-yl)benzofuran-3-carboxamide (100 mg, 0.23 mmol), 11-fluoro-2-(trimethylstannyl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (140 mg, 0.35 mmol) in dioxane/H2O (4 mL/0.2 mL) under N2. Then the reaction mixture was heated to 100° C. for 1 hour and filtered. The resulting residue was extracted with EtOAc. The combined organic phase was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether:EtOAc=1:2) to provide 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(2-oxooxazolidin-3-yl)benzofuran-3-carboxamide (32 mg, yield: 24%). 1H-NMR (CDCl3, 400 MHz) δ 8.01 (s, 1H), 7.94˜7.98 (m, 2H), 7.58 (s, 1H), 7.51 (m, 2H), 7.19˜7.23 (m, 4H), 7.11˜7.13 (d, J=8.0 Hz, 1H), 6.83˜6.88 (m, 1H), 6.12 (s, 1H), 6.00 (s, 2H), 4.37˜7.41 (m, 2H), 4.12˜4.14 (m, 2H), 3.00 (d, J=4.8 Hz, 3H). MS (M+H)+: 593.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][N:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][C@@H:20]1[CH2:25][OH:26].C(N(C(C)C)CC)(C)C>CS(C)=O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([N:22]3[CH2:23][CH2:24][NH:19][C@@H:20]([CH2:25][OH:26])[CH2:21]3)=[N:3][N:4]=2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Reactant: OC[C@H]1CNCCN1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: OC[C@H]1CN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CCN1
Yield: 83.4 %

Procedure:
Dissolve 1-chloro-4-(4-fluorophenyl)phthalazine (0.1 g, 0.39 mmol), (R)-piperazin-2-ylmethanol (0.07 g, 0.58 mmol) and diisopropylethylamine (0.34 mL, 1.93 mmol) in DMSO (1 mL). Stir the reaction at 120° C. for 64 h. Purify the reaction mixture by flash silica gel chromatography (0-10% 2 M ammonia/MeOH in CH2Cl2) to yield the title compound as a brown solid (0.11 g, 84%). ES/MS m/z 339.0 (M+1).
Reaction SMILES: C([Li])CCC.CCCCCC.C1COCC1.C(OP([CH2:25]/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])(OCC)=O)C.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>O>[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][C:43](=[CH:25][CH:26]=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C=CC=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 103.9 %

Procedure:
7.4 ml of 1.6M n-butyl lithium/hexane solution was dropwise added to a THF solution (30 ml) of 8.41 g of ethyl 4-diethylphosphonocrotonate below -50° C. and stirred for 15 minutes at --78° C. . To this was dropwise added 25 ml of a THF solution of 5.0 g of the above-mentioned 1-t-butyloxycarbonyl-4-piperidinone. This was stirred for 20 minutes at -78° C. and then for 2 hours at -10° C. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic layer was washed with 1N HCl, saturated NaHCO3, brine (twice each) and dried with magnesium sulfate. The solvent was removed by distillation under a reduced pressure. Thus, 7.70 g of ethyl 4-(1-t-butyloxycarbonyl-4-piperidylidene)-2-butenoate was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[N:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][CH:8]=1.O>C1(C)C=CC=CC=1>[N:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:9][CH:8]=1
Reactant: O=Cc1ccncc1
Reactant: Nc1nccs1
Solvent: Cc1ccccc1
Solvent: O
Product: c1cc(CNc2nccs2)ccn1
Reaction time: 3 h
Yield: 73.2 %

Procedure:
A mixture of 2-aminothiazole (3 g, 30 mmol) and 4-pyridinecarboxaldehyde (3.21 g, 30 mmol) in toluene (50 ml) was refluxed with a Dean-Stark water separator for 3 h. Solvent was removed under reduced pressure and the resulting yellow solid was dissolved in CH3OH (80 ml). The solution was carefully treated with sodium borohydride (1.8 g) and was stirred for 20 minutes. The reaction mixture was quenched with 1N NaOH and evaporated to dryness. The residue was dissolved in EtOAc, washed with brine and dried (MgSO4). Solvent was evaporated to give the crude intermediate N-(pyridin-4ylmethyl)-1,3-thiazol-2-amine as a brown solid (4.2 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:14].OO>C(O)(=O)C>[CH:3]1[C:2]([F:1])=[CH:10][C:9]2[NH:8][C:7]([O:14][C:6](=[O:12])[C:5]=2[CH:4]=1)=[O:11]
Reactant: O=C1Nc2cc(F)ccc2C1=O
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(F)ccc2c(=O)o1
Temperature: 25 °C

Procedure:
41 parts of 6-fluoroisatin are suspended in 500 parts of glacial acetic acid and 15 parts of concentrated sulfuric acid and 100 parts of 30 percent strength hydrogen peroxide solution are added at 30° C. A slightly exothermic reaction is observed and at 40°-45° C. a clear solution is temporarily produced. The temperature is not allowed to rise above 50° C., and after one hour the mixture is cooled to room temperature. The precipitate is filtered off and washed. 38 parts of 7-fluoroisatoic anhydride are obtained; melting point 229°-231° C., with decomposition.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C@H:10]1[CH2:13][C@@H:12]([CH:14]([OH:23])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11]1)(C)(C)C.[ClH:25]>O1CCOCC1>[ClH:25].[NH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:11][C@H:12]([CH:14]([OH:23])[CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)NCC[C@H]1C[C@@H](C(O)CCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: NCC[C@H]1C[C@@H](C(O)CCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.8 g of cis-{2-[3-(1-hydroxy-3-phenyl-propyl)-cyclobutyl]-ethyl}-carbamic acid tert-butyl ester and 25 mL of 4N HCl in dioxane was stirred at room temperature for 2 h, then concentrated to dryness and triturated with 50 mL of 5% ether in hexane and the solvents decanted. Drying under vacuum gave 0.8 g of the product as an amber resin: LCMS (m+1)=234.6.