Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH:12]([F:14])[F:13].[CH3:15][CH:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17].C([O-])([O-])=O.[K+].[K+].Cl>CS(C)=O.O>[F:13][CH:12]([F:14])[O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:21]1[CH2:22][CH2:23][N:18]([CH:16]([CH3:17])[CH3:15])[CH2:19][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(Br)c(OC(F)F)c1
Reactant: CC(C)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])cc2OC(F)F)CC1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
1-Bromo-2-difluoromethoxy-4-nitro-benzene (Step A, 2.0 g, 7.5 mmol, 1.0 eq.) and N-(2-propyl)piperazine (0.85 mL, 9.7 mmol, 1.3 eq.) were dissolved in 20 mL of DMSO. K2CO3 (1.5 g, 11.2 mmol, 1.5 eq.) and Bu4N+Br− (240 mg, 0.75 mmol, 0.1 eq.) were added and the mixture was heated to 120° C. The mixture was stirred for 3 h and cooled to RT, poured into H2O (200 mL) and 6 N HCl (20 mL). The aqueous solution was washed with EtOAc, and alkalinized with 6 N NaOH then extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated. The crude material was further purified by column chromatography (0-100% EtOAc in hexanes) providing pure 1-(2-difluoromethoxy-4-nitro-phenyl)-4-isopropyl-piperazine.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH:5]=[C:6]2[CH2:9][CH2:10][OH:11]>C(OCC)(=O)C.O=[Pt]=O>[CH3:1][C:2]1([CH3:12])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][CH2:10][OH:11]
Reactant: CC1(C)C2CC=C(CCO)C1C2
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CC1(C)[C@H]2CC[C@@H](CCO)[C@@H]1C2
Reaction time: 2.5 h
Yield: 91367.8 %

Procedure:
(−)-Nopol (Aldrich) (66.4 g, 0.40 mmol) was dissolved in ethyl acetate (500 mL). PtO2 (2.0 g) was added under N2 atmosphere. The mixture was hydrogenated at 41 psi. Uptake was completed within 2.5 hours. The mixture was filtered, washed with ethyl acetate and concentrated. The residue was distilled at 125-130° C./9.5 mm of Hg to afford 61.5 g of the title compound.
Reaction SMILES: [NH:1]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].C[I:27]>>[I-:27].[CH3:4][SH2+:5].[CH3:18][O:17][C:15](=[O:16])[C@H:10]([CH2:11][CH:12]([CH3:13])[CH3:14])[NH:9][C:7](=[O:8])[C@@H:2]([CH2:3][CH2:4][S:5][CH3:6])[NH:1][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20]
Reactant: CI
Agent: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C
Product: C[SH2+]
Product: [I-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Boc-D-Met-Leu-OCH3 (25 g, 66.5 mmol) was dissolved in methyl iodide (132 ml) and stirred at room temperature for 2 days. Concentration in vacuo gave 35.4 g (103%) of the sulfonium salt. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:13][NH2:14].[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)[CH2:17]1>>[CH3:12][O:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:6])[N:14]([CH3:13])[C:30]([C:29]3[CH:32]=[CH:33][C:26]([O:25][CH2:24][CH2:23][CH2:22][N:18]4[CH2:19][CH2:20][CH2:21][C@H:16]([CH3:15])[CH2:17]4)=[CH:27][CH:28]=3)=[N:1]2)=[CH:7][CH:8]=1
Reactant: C[C@H]1CCCN(CCCOc2ccc(C=O)cc2)C1
Reactant: COc1ccc(C(=O)O)c(N)c1
Reactant: CN
Product: COc1ccc2c(=O)n(C)c(-c3ccc(OCCCN4CCC[C@H](C)C4)cc3)nc2c1

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 2-amino-4-methoxybenzoic acid, methylamine and 4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy} benzaldehyde.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][CH2:10][O:9]2)=[CH:4][C:3]=1[F:14].C([Li])CCC.[Cl:20][C:21]1[CH:26]=[C:25](Cl)[C:24]([N:28]=[C:29]=[S:30])=[CH:23][N:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.CN(C=O)C>[O:9]1[CH2:10][CH2:11][CH2:12][O:13][CH:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:29]2[S:30][C:25]3[CH:26]=[C:21]([Cl:20])[N:22]=[CH:23][C:24]=3[N:28]=2)=[C:3]([F:14])[CH:4]=1
Reactant: Fc1cc(C2OCCCO2)ccc1Br
Reactant: S=C=Nc1cnc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2cnc(Cl)cc2s1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(4-bromo-3-fluorophenyl)-1,3-dioxane (3.12 g, 11.9 mmol) in 40 mL THF at −78° C. under argon was added butyllithium, 2.5 M solution in hexanes (5.26 mL, 13.1 mmol) slowly dropwise. The resulting solution was allowed to stir 1 h at −78° C., at which point a solution at ambient temp of 2,4-dichloro-5-isothiocyanatopyridine (2.45 g, 11.9 mmol) in 10 mL THF was added slowly via cannula. The dark red reaction mixture was allowed to stir 15 min, and was then removed from the bath and quenched by slow addition of sat'd aq. NH4Cl. The reaction mixture was diluted with 40 mL MTBE, and the organic layer washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting material was treated with sodium carbonate (1.90 g, 17.9 mmol) and 10 mL DMF. The reaction was heated under nitrogen to 80° C. An additional 5 mL DMF was added to give a stirrable slurry. After 30 min additional, the reaction mixture was cooled slightly and treated with 100 mL water. After 10 min stirring, the mixture was filtered, rinsing with water and MeOH. The solid was collected and dried in vacuo overnight to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-chlorothiazolo[4,5-c]pyridine as a tan solid. MS (ESI) m/z: calculated: 350.0; Observed: 351.0 (M++1).
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[O:11]=[C:12]1[CH2:21][CH2:20][CH2:19][C:18]2[CH:17]=[C:16]([C:22]([O:24][CH3:25])=[O:23])[CH:15]=[CH:14][C:13]1=2.B(F)(F)F.C(=O)=O.CC(C)=O>C1COCC1.CO>[OH:11][C:12]1([C:7]2[S:6][CH:10]=[CH:9][N:8]=2)[CH2:21][CH2:20][CH2:19][C:18]2[CH:17]=[C:16]([C:22]([O:24][CH3:25])=[O:23])[CH:15]=[CH:14][C:13]1=2
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Reactant: c1cscn1
Agent: FB(F)F
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COC(=O)c1ccc2c(c1)CCCC2(O)c1nccs1

Procedure:
A solution of n-butyllithium (2.3 M in hexanes) is pumped (push-pull syringe-pump) to a ⅛″ tee with a pressure gauge and 2 feet of ⅛″ stainless steel tubing (for pre-cooling). This tubing is connected to a ¼ inch T-mixer. Thiazole (0.5 M in THF) is pumped using a pump, 100 μL head (Fluid Metering, Inc., Syosset, N.Y. USA) to 2 feet of ⅛″ stainless steel tubing (for pre-cooling) connected to the same T-mixer. The T-mixer is connected to a static mixer ¼-34 (5.3 mL) (Koflo Corporation, Cary, Ill. USA) connected to a ¼″ elbow and ¼″ stainless steel tubing of 6 inches in length (3.3 mL). This 6-inch length tubing is connected to another ¼″ T-mixer which is also connected to a feed of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate and BF3 (0.5 M in THF, pumped with a FMI pump, 100 μL head), and to a second static mixer Koflo ¼-34 (5.3 mL) followed by a “loop” of ¼″ stainless steel (2.5 ft length, 16.8 mL). The reactor has a total volume of 30.7 mL, and is placed into a cold bath at −45° C. (±5° C., dry ice/acetone). The outlet stream is then connected to a ⅛″ T-mixer (outside of the cold bath) fed with methanol (FMI pump, 100 μL head) for in situ quenching, and is finally collected into an extractor containing MTBE and aqueous phosphoric acid (1.5 M). A flow diagram of the assembly is shown in FIG. 1.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH:10][C:11]([NH:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([O:22][CH3:23])[N:15]=1)=[S:12])(=[O:9])=[O:8].[Na].[CH3:31]I.O>C(#N)C.C(O)C>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH:10][C:11](=[N:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([O:22][CH3:23])[N:15]=1)[S:12][CH3:31])(=[O:8])=[O:9]
Reactant: CI
Reactant: COc1nc(NC(=S)NS(=O)(=O)c2ccccc2-c2ccccc2)nc(OC)n1
Agent: [Na]
Solvent: CC#N
Solvent: CCO
Solvent: O
Product: COc1nc(N=C(NS(=O)(=O)c2ccccc2-c2ccccc2)SC)nc(OC)n1
Yield: 47.2 %

Procedure:
4.31 g of 1-(2-biphenylylsulfonyl) 3-(4,6-dimethoxy-1,3,5-triazin-2-yl)thiourea were suspended in 50 ml of dry acetonitrile, and a solution of 0.3 g of metallic sodium in 10 ml of ethanol was added to the suspension, and the mixture was heated under reflux for 30 minutes. After cooling, 1.85 g of methyl iodide were added, and the mixture was heated under reflux for 5 hours. After cooling, the reaction mixture was poured into 100 ml of water, and extracted with methylene chloride. Methylene chloride was distilled off under reduced pressure from the extract, and the residue was recrystallized from ethanol to give 2.1 g of 1-(2-biphenylylsulfonyl) 3-(4,6-dimethoxy-1,3,5-triazin-2-yl) 2-methylisothiourea represented by the following formula: ##STR29##
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[CH:54](O[Na])([CH3:56])[CH3:55].[Cl-].[NH4+]>C(O)(C)C.C(N(CC)CC)C.ClCCl>[CH:54]([O:23][C:22]([C:21]1[N:20]=[C:19]([C:25]([F:27])([F:28])[F:26])[N:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:29][C:30]3[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=3[F:38])[CH2:14][C:15]=12)=[O:24])([CH3:56])[CH3:55]
Reactant: CC(C)O[Na]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)OC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Reaction time: 0.02 h
Yield: 57.8 %

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 2a (0.3 g, 0.54 mmol) was added into a 50 mL reaction flask, followed by addition of 10 mL of dichloromethane, 2 mL of isopropanol and 0.3 mL of triethylamine. After stirring for 1 minutes, bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.277 g, 1.09 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 2 hours, and then 10 mL of isopropanol and isopropoxysodium (0.177 g, 2.16 mmol) were added. The reaction mixture was stirred at room temperature for 1.5 hours and monitored by thin layer chromatography until the disappearance of the starting materials. 10 mL of saturated ammonium chloride was added to the reaction mixture, and white precipitates were formed. The precipitates were filtered through a pad of silica gel, and 50 mL of water was added to the filtrate. The filtrate was extracted with ethyl acetate (25 mL×5), and the combined organic phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (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 isopropyl ester 35a (0.185 g, yield 57.8%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][OH:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].CCCCCC.[CH3:19][O:20][CH2:21]Cl>O1CCCC1>[CH2:1]([N:3]([CH2:10][CH2:11][O:12][CH2:19][O:20][CH3:21])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: COCCl
Reactant: CCN(CCO)c1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCN(CCOCOC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
55.7 g (0.34 mol) of N-ethyl-N-(2-hydroxylethyl)aniline was dissolved in 250 ml of anhydrous tetrahydrofuran, and 162 ml (1.2-fold equivalent weight) of a 2.5M hexane solution n-butyllithium was dropwise added thereto over a period of 30 minutes at 0° C. in an atmosphere of argon, followed by stirring at 0° C. for 30 minutes. Next, to the reaction solution obtained, 30.0 g (1.09-fold equivalent weight) of methoxymethyl chloride was dropwise added, and the solution was heated and refluxed for 12 hours, followed by cooling. The precipitate formed was removed by filtration, and thereafter the filtrate obtained was concentrated under reduced pressure. The oily residue thus obtained was distilled under reduced pressure to obtain 63 g of N-ethyl-N-[2-(methoxymethyl)oxyethyl]aniline (yield: 89%).
Reaction SMILES: [N:1]1([S:5]([C:8]2[CH:13]=[CH:12][C:11](Cl)=[CH:10][N:9]=2)(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:15][O:16][CH2:17][C@H:18]([CH3:38])[O:19][C:20]1[CH:21]=[C:22]([OH:37])[CH:23]=[C:24]([C:26]2[NH:27][C:28]([C:31]3[O:32][C@@H:33]([CH3:36])[CH2:34][N:35]=3)=[CH:29][CH:30]=2)[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[N:1]1([S:5]([C:8]2[CH:13]=[CH:12][C:11]([O:37][C:22]3[CH:23]=[C:24]([C:26]4[NH:27][C:28]([C:31]5[O:32][C@@H:33]([CH3:36])[CH2:34][N:35]=5)=[CH:29][CH:30]=4)[CH:25]=[C:20]([O:19][C@@H:18]([CH3:38])[CH2:17][O:16][CH3:15])[CH:21]=3)=[CH:10][N:9]=2)(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Reactant: O=S(=O)(c1ccc(Cl)cn1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N3CCC3)nc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
2-(Azetidin-1-ylsulfonyl)-5-chloropyridine (170 mg, 0.73 mmol) synthesized in Example (119b) and 3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (230 mg, 0.70 mmol) synthesized in Example (116d) were dissolved in N,N-dimethylformamide (3.5 mL), and cesium carbonate (454 mg, 1.39 mmol) was added, followed by stirring at 100° C. for 2 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was carried out twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=5%-50%) to afford the desired compound (273 mg, yield 75%) as a white solid.
Reaction SMILES: CCC1C=CC(CC[O:11]C2C=CC(CC3SC(=O)NC3=O)=CC=2)=NC=1.Cl.C(O)[C@H]1[O:33][C@H:32]([O:34][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:31]([OH:46])[C@@H:30](O)[C@@H:29]1[OH:48]>>[C:32]([OH:33])(=[O:34])[CH:31]([CH2:30][C:29]([OH:48])=[O:11])[OH:46]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reactant: CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Agent: Cl
Product: O=C(O)CC(O)C(=O)O

Procedure:
Compound A (24.8 g), sucrose (Osaka-Toka. Co., Ltd., 28.7 g), crystalline cellulose (Avicel PH-101, Asahi Kasei Corporation, 8.0 g) and L-HPC (LH-31, Shin-Etsu Chemical Co., Ltd., 12.5 g) were thoroughly mixed to give a dusting powder. Malic acid crystal (Wako Pure Chemical Industries, Ltd.) was sieved with a round sieve to give malic acid crystal on 30 mesh (aperture 0.50 mm). The malic acid crystal (150 g) was fed into a centrifugal fluidized-bed granulator (CF-mini, Freund Corporation) and coated with the above-mentioned dusting powder while spraying an aqueous solution (6 w/v %) of hydroxypropylcellulose (HPC-SL, NIPPON SODA CO., LTD.). The obtained spherical granules were dried under reduced pressure in a constant temperature vacuum drying oven (DP43, YAMATO SCIENTIFIC CO., LTD.) at 40° C. for 16 hr, and sieved with a round sieve to give granules at the range of 16-30 mesh (aperture 0.50-1.00 mm). The granules (450 mg) were filled in No. 0 gelatin capsules (Capsugel) to give capsules having the following composition per capsule.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[CH:5]=[C:4]([C@@H:13]([NH:15][C:16](=[O:32])[O:17][CH2:18][CH:19]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:14])[N:3]=1.[CH2:33]([Sn](CCCC)(CCCC)C=C)[CH2:34]CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([CH:33]=[CH2:34])=[N:3][C:4]([C@@H:13]([NH:15][C:16](=[O:32])[O:17][CH2:18][CH:19]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]1=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:14])=[CH:5]2
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(Cl)n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=Cc1nc([C@H](C)NC(=O)OCC2c3ccccc3-c3ccccc32)cc2cccc(Cl)c12
Temperature: 25 °C

Procedure:
To a solution of (S)-(9H-fluoren-9-yl)methyl-1-(1,8-dichloroisoquinoline-3-yl)ethylcarbamate (346) (36 g, 77.7 mmol, 1.0 eq) in THF (300 mL) under argon, tributyl(vinyl)stannane (27 g, 85.5 mmol, 1.1 eq), Pd(OAc)2 (5.23 g, 23.3 mmol, 0.3 eq) and PPh3 (12.2 g, 46.6 mmol, 0.6 eq) were added, and the resulting mixture was stirred at reflux for 16 h. The mixture was allowed to cool to RT and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (2-30% ethyl acetate-petroleum ether) to afford (S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-1-vinylisoquinolin-3-yl)ethylcarbamate (347).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[NH:34][N:33]=[C:32]3[NH2:38])O1>>[NH2:38][C:32]1[C:31]2[C:35](=[CH:36][CH:37]=[C:29]([C:2]3[CH:3]=[CH:4][N:5]4[C:10]([C:11]=3[CH3:12])=[C:9]([CH:13]3[CH2:15][CH2:14]3)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]4=[O:20])[CH:30]=2)[NH:34][N:33]=1
Reactant: CC1(C)OB(c2ccc3[nH]nc(N)c3c2)OC1(C)C
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4[nH]nc(N)c4c3)ccn2c1=O
Yield: 24.2 %

Procedure:
Methyl 8-(3-amino-1H-indazol-5-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine (106.4 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (32 mg, 42%).
Reaction SMILES: [O:1]=[C:2]([CH3:16])[C@H:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].CO.[BH4-].[Na+]>C1COCC1>[OH:1][CH:2]([CH3:16])[C@H:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4]
Reactant: CC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)[C@@H](C)NC(=O)OCc1ccccc1

Procedure:
Under argon, 885 mg of benzyl [(2R)-3-oxobutan-2-yl]carbamate (Example 151A, 4 mmol, 1 equivalent) were initially charged in 13 ml of THF and 13 ml of methanol and, analogously to Example 133A, reacted with 227 mg of sodium borohydride (6 mmol, 1.5 equivalents) and worked up. This gave 830 mg (92% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:27])[N:4]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:25])([CH3:24])[CH3:23])[N:17]=3)[CH:13]=[CH:12][C:11]=2[CH3:26])[C:5]([CH3:9])=[N:6][C:7]=1[OH:8].Cl[CH2:29][C:30]1[N:31]=[C:32]([CH3:35])[O:33][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:27])[N:4]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:25])([CH3:23])[CH3:24])[N:17]=3)[CH:13]=[CH:12][C:11]=2[CH3:26])[C:5]([CH3:9])=[N:6][C:7]=1[O:8][CH2:29][C:30]1[N:31]=[C:32]([CH3:35])[O:33][CH:34]=1
Reactant: Cc1nc(CCl)co1
Reactant: Cc1ccc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)nc(O)c(Cl)c1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(COc2nc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ccc3C)c(=O)c2Cl)co1
Temperature: 60 °C
Yield: 25 %

Procedure:
To a solution of Intermediate 1 (509 mg, 1.32 mmol) in N,N-dimethylformamide (5 mL) was added 4-chloromethyl-2-methyl-oxazole from Step A (173 mg, 1.32 mmol), potassium carbonate (273 mg, 1.98 mmol) and 18-crown-6 (40 mg). The slurry was heated at 60° C. for eighteen hours. The reaction was allowed to cool to room temperature and then partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a colorless oil. (160 mg, 25% yield). MS (M+H): 482; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.64 (s, 6H), 2.17 (s, 3H), 2.20 (s, 3H), 2.50 (s, 3H), 5.40-5.48 (m, 2H), 7.54-7.58 (m, 2H), 7.66 (s, 1H), 7.93 (s, 1H), 8.13 (d, J=8.21 Hz, 1H), 8.77 (d, J=5.08, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][C:15]([NH:17][CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=2[F:29])=[O:16])=[CH:4][CH:3]=1.[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:37][CH2:36]1)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][C:15]([NH:17][CH2:18][C:19]4[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:20]=4[F:29])=[O:16])=[CH:4][CH:3]=3)=[CH:40][CH:39]=2)[CH2:36][CH2:37]1)=[O:34])[CH3:31]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)NCc1cc(C(F)(F)F)ccc1F
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)NCc4cc(C(F)(F)F)ccc4F)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-3-(2-fluoro-5-trifluoromethyl-benzyl)-urea and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl.[OH:2][CH:3]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH:4]([NH2:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37](Cl)=[O:38].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[OH:2][CH:3]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH:4]([NH:16][C:37]([C:28]1[CH:29]=[CH:30][C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=1)=[O:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a solution of (1RS,2SR)-1-hydroxy-1-(1-naphthalenyl)-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.39 mmol) in ethyl acetate (5 ml) were added 2-naphthoyl chloride (112 mg, 0.59 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under-reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (160 mg, 82%).