Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:7]2=1.[CH3:19][O-:20].[Na+]>CO.O>[Cl:18][C:15]1[CH:16]=[CH:17][C:7]2[C:6]3[C:11](=[C:2]([O:20][CH3:19])[N:3]=[CH:4][CH:5]=3)[C:10](=[O:12])[N:9]([CH3:13])[C:8]=2[CH:14]=1
Reactant: Cn1c(=O)c2c(Cl)nccc2c2ccc(Cl)cc21
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nccc2c1c(=O)n(C)c1cc(Cl)ccc21
Yield: 38.9 %

Procedure:
To a solution of 4,8-dichloro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (1.0 g, 3.58 mmol) in MeOH (1 mL) was added sodium methoxide (0.806 mL, 3.58 mmol). The resultant mixture was heated in a microwave at 80° C. for 25 min. The reaction mixture was then diluted with water (20 mL) and extracted with ethyl acetate (30 mL). The organic layer was separated, dried over sodium sulphate and evaporated to dryness to afford 8-chloro-4-methoxy-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (0.4 g, 1.391 mmol, 39% crude yield) as a brown solid. The material was carried on without further purification. LC/MS (ESI) m/e 274.8 [(M+H)+, calcd for C14H12ClN2O2, 275.0]; LC/MS retention time (method C): tR=2.06 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.[NH2:30]C1C=C2C(=CC=1)C(O)=CC=C2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[NH2:30][C:26]1[CH:25]=[C:24]2[C:29](=[CH:28][CH:27]=1)[C:20]([O:19][CH2:18][CH2:17][CH2:16][C:7]1[C:6]3[C:10](=[C:2]([Br:1])[CH:3]=[CH:4][CH:5]=3)[NH:9][C:8]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:21][CH:22]=[CH:23]2
Reactant: Nc1ccc2c(O)cccc2c1
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCOc1cccc2ccccc12
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCOc1cccc2cc(N)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of ethyl 7-bromo-3-(3-hydroxypropyl)-1H-indole-2-carboxylate (EXAMPLE 1C) (100 mg), 6-aminonaphthalen-1-ol (98 mg) and triphenylphosphine, polymer supported (204 mg 0.613 mmol) in tetrahydrofuran (4 ml) was added di-tert-butyl diazene-1,2-dicarboxylate (141 mg). The reaction mixture was stirred at room temperature for 3 hours. The insoluble material was filtered off and the filtrate was concentrated. The residue was purified by flash chromatography (ethyl acetate in hexanes) to provide the title compound.
Reaction SMILES: [C:1]1([C:13]2[C:14](=O)[NH:15][C:16](=[O:27])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[C:29](=[O:32])([O-])[O-].[K+].[K+].CI.[C:37](OCC)(=O)C>CN(C)C=O>[C:1]1([C:13]2[C:29](=[O:32])[N:15]([CH3:14])[C:16](=[O:27])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH3:37])[CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: CCOC(C)=O
Reactant: O=C([O-])[O-]
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccccc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(c2cn(C)c3ccccc23)=C(c2cn3c4c(cccc24)CCC3)C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl) pyrrole-2,5-dione (100 mg, see Example 1) in anhydrous dimethylformamide (5 ml) was added potassium carbonate (0.5 g) and methyl iodide (0.1 ml). The mixture was stirred at room temperature for 48 hours then poured into ethyl acetate. (100 ml), washed with water (100 ml), dried over anhydrous sodium sulfate and evaporated to give 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1-methylindol-3-yl)-1-methylpyrrole-2,5-dione as a red solid (93 mg). Step 2: To a solution of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1-methylindol-3-yl)-1-methylpyrrole-2,5-dione (93 mg) in methanol (5 ml) and ethylacetate (5 ml) was added 10% Pd—C (50 mg) and the mixture stirred at room temperature under 1 atmosphere of hydrogen for 48 hours. Toluene (50 ml) was added and the mixture again stirred at room temperature under 1 atmosphere of hydrogen for 2 hours. The mixture was then filtered through a pad of celite and evaporated to dryness to yield a residue. The residue was purified using silica gel chromatography eluting with 35-40% ethylacetate in hexanes to give (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1-methylindol-3-yl)-1-methylpyrrolidine-2,5-dione as a pale yellow solid (53 mg). 1H NMR (CDCl3) 400 MHz δ: 7.23 (s, 1H), 7.05-7.07 (m, 2H), 7.01 (d, 1H, J=7.2 Hz), 6.92-6.97 (m, 1H), 6.85 (t, 1H, J=7.2 Hz), 6.74 (d, 1H, J=6.8 Hz), 6.64 (d, 2H, J=6.4 Hz), 4.78 (m, 2H), 3.75-3.84 (m, 2H), 3.45 (s, 3H), 3.27 (s, 3H), 2.79 (t, 2H, J=5.6 Hz), 1.98 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[CH2:11](N)C1C=CC=CC=1.C([O-])([O-])OCC.C(OC(=O)C)(=O)C.[SH-:32]>C(O)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:9](=[S:32])[NH:10][CH:11]=[N:8][C:6]=2[CH:7]=1
Reactant: N#Cc1cnc(N)cc1N
Reactant: NCc1ccccc1
Reactant: [SH-]
Agent: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: Nc1cc2nc[nH]c(=S)c2cn1

Procedure:
2,4-Diamino-5-cyanopyridine can be cyclized directly to many 4-benzylamipnopyridopyrimidine derivatives by treatment with the benzylamine and formic acid at high temperature. For less nucleophilic amines 2,4-diamino-5-cyanopyridine is converted via ethyl orthoformate/acetic anhydride treatment, followed by cyclization with hydrosulfide ion in anhydrous conditions, to give 7-amino-4-thiono-3H-pyrido[4,3-d]pyrimidine. S-Alkylation and displacement with an appropriate amine gives the desired product. If R4 is not amino, the amine can be acylated, or reductively alkylated. Alternatively 2,4-diamino-5-cyanopyridine can be hydrolysed to the corresponding amide, and this species can be cyclized to 7-amino-4-oxo-3H-pyrido[4,3-d]pyrimidine with orthoformate. Diazotization of the 7-amine and replacement with fluorine allows for introduction of other amine and alkoxide nucleophiles at the end of the synthesis after the C4 substituent has been introduced in the usual manner. Diazotization and replacement of the amine with bromide allows for Stille couplings at the 7-position.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4=[C:22]([CH2:25][N:26]5[CH2:31][CH2:30][CH:29]([C:32]#[N:33])[CH2:28][CH2:27]5)[CH:23]=[CH:24][N:20]4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[N-:37]=[N+:38]=[N-:39].[Na+].[Cl-].[NH4+]>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4=[C:22]([CH2:25][N:26]5[CH2:27][CH2:28][CH:29]([C:32]6[NH:39][N:38]=[N:37][N:33]=6)[CH2:30][CH2:31]5)[CH:23]=[CH:24][N:20]4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Fc1cccc(Cn2ncc3cc(Nc4ncnn5ccc(CN6CCC(c7nnn[nH]7)CC6)c45)ccc32)c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 24.2 %

Procedure:
A mixture of 1-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl }-piperidine-4-carbonitrile (145 mg, 0.3 mmole), sodium azide (59 mg, 3 equiv.) and ammonium chloride (48 mg, 3 equiv.) in DMF (0.6 mL) in a sealed vial was stirred at 100° C. for 20 h. The reaction mixture was cooled to RT, diluted with DCM, washed with water, and dried (Na2SO4). Removal the solvent followed by radial chromatography (2 mm silica gel plate, gradient elution with DCM containing 2 to 7% 2 M NH3 in MeOH) afforded the title compound as a solid (38 mg, 24%); MS: 524 (M+H+); HPLC Ret Time: 1.13 min (Xterra 3.0×50 mm S7 C18 column, 2 min gradient, 5 ml/min).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[O:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.Cl.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[OH:32][C@@H:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]1[NH:25][C:16]1[O:17][C:13]2[CH:12]=[C:11]([O:10][C:8]3[CH:7]=[CH:6][N:5]=[C:4]([C:3]([NH:2][CH3:1])=[O:23])[CH:9]=3)[CH:22]=[CH:21][C:14]=2[N:15]=1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)oc3c2)ccn1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4O)oc3c2)ccn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To the solution of N-methyl-4-(2-(methylsulfinyl)benzo[d]oxazol-6-yloxy)picolinamide (25 mg, 0.075 mmol, 1.0 eq) in 1 mL of NMP was added (1R,2R)-2-aminocyclohexanol hydrochloride (17 mg, 0.112 mmol, 1.5 eq) and DIPEA (40 μL, 0.225 mmol, 3.0 eq) and reaction mixture stirred at room temperature for 48 hours. Thereafter, the product was purified via reverse phase HPLC. LC/MS (m/z) [383.1] (MH+)
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH:2]=C.[OH:18]OS([O-])=O.[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.CO>[OH:18][CH:2]1[CH2:1][C:4]2=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[C:13]2[O:14]1
Reactant: O=S([O-])OO
Reactant: C=CCc1c(C(=O)OC)ccc([N+](=O)[O-])c1O
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])c2c1CC(O)O2
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 96 %

Procedure:
Methyl 2-allyl-3-hydroxy-4-nitro-benzoate 1d (5.39 g, 22.70 mmol) was dissolved in 110 mL of the mixture solvent of dichloromethane and methanol (V/V=10:1), the reaction solution was cooled down to −78° C. and filled with oxone. After stirring for 50 minutes, oxone was removed from filling with. The reaction mixture was stirred for another 20 minutes, then filled with argon and stirred for 10 minutes. Triphenyl phosphine (17.80 g, 68.10 mmol) was added. After removing the dry ice bath, the resulting mixture was allowed to room temperature and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, added with 200 mL of ethyl acetate, washed with water (100 mL×3) and saturated sodium chloride solution (100 mL×3) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl 2-hydroxy-7-nitro-2,3-dihydrobenzofuran-4-carboxylate 1e (5.20 g, yield: 96.0%) as a brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[CH3:13]I>O>[CH3:13][S:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1ccc([N+](=O)[O-])cc1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 50.4 %

Procedure:
To a suspension of p-nitrothiophenol (20 g, 0.129 mol) in water (150 mL) was added an aqueous solution of sodium hydroxide (75 mL, 2 N) at room temperature. After the mixture was stirred for 15 minutes and cooled to 10° C., methyl iodide (57 g, 25 mL, 0.401 mol) was added slowly. The reaction mixture was allowed to warm to room temperature and stirred for 2.5 hours. The resulting mixture was extracted with diethyl ether (100 mL×3). The organic layers were combined, washed with water (200 mL) and brine (200 mL), dried over calcium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford 11 g of 1-(methylsulfanyl)-4-nitrobenzene as a yellow solid.
Reaction SMILES: Cl[C:2]([Cl:12])(OC(=O)OC(Cl)(Cl)Cl)Cl.C[N:14](C)[NH:15][C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=[N:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:27])[CH:21]=1)=[O:17].[CH2:38](Cl)Cl>>[Cl:12][C:2]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=[N:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:27])[CH:21]=2)[C:16](=[O:17])[N:15]([CH3:38])[N:14]=1
Reactant: ClCCl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(=NOCc1ccccc1)c1cccc(CNC(=O)NN(C)C)c1
Product: CC(=NOCc1ccccc1)c1cccc(Cn2c(Cl)nn(C)c2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.96 g (3.24 mmol) of triphosgene in 10 ml of dry methylene chloride was added dropwise a solution of 0.55 g (1.62 mmol) of 1,1-dimethyl-4-{3-(1-(benzyloxyimino)ethyl)benzyl}semicarbazide (produced in the following Reference Production Example 2) in 15 ml of dry methylene dhloride with ice-cooling. The mixture was removed from an ice bath, then allowed to warm to room temperature and heated under reflux for 4 hours. After allowing to cool to room temperature, the reaction mixture was poured into 40 ml of an about 5% aqueous solution of sodium bicarbonate, and the mixture was stirred for 0.5 hours. The organic layer was washed with water, dried and concentrated. The residue was subjected to silica gel preparative thin layer chromatography (developed with n-hexane:ethyl acetate=3:2) to obtain 0.27 g (0.74 mmol) of 5-chloro-2-methyl-4-{3-(1-(benzyloxyimino)ethyl)-benzyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (the compound 249 of the present invention).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:18][CH2:19][CH3:20].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].[H-].[Na+]>CN(C=O)C>[CH3:32][O:31][C:29](=[O:30])[CH2:28][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH2:18][CH2:19][CH3:20])[N:8]2[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCCc1cc2c(O)cccc2n1Cc1ccccc1-c1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cc2c(OCC(=O)OC)cccc2n1Cc1ccccc1-c1ccccc1
Yield: 56 %

Procedure:
1-([1,1′-Biphenyl]-2-ylmethyl)-4-hydroxy-2-propyl-1H-indole (794 mg, 2.8 mmol) was alkylated by treating with 0.22 mL (2.3 mmol) of methyl bromoacetate and 93 mg (2.3 mmol) of 60% NaH/mineral oil in DMF as described in Example 1, Part E. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 533 mg (56% yield) of [[1-([1,1′-biphenyl]-2-ylmethyl)-2-propyl-1H-indol-4-yl]oxy]acetic acid methyl ester.
Reaction SMILES: [NH2:1][C@H:2]([CH2:11][O:12][CH2:13][O:14][CH3:15])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N(C(C)C)CC)(C)C.Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].Cl[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33]>CO.O>[CH2:35]([O:34][C:32]([N:1]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[C@H:2]([CH2:11][O:12][CH2:13][O:14][CH3:15])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5])=[O:33])[CH:36]=[CH2:37]
Reactant: C=CCOC(=O)Cl
Reactant: COCOC[C@@H](N)CC(=O)OC(C)(C)C
Reactant: COC(=O)CBr
Solvent: O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N(CC(=O)OC)[C@H](COCOC)CC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
To a solution of tert-butyl(3S)-3-amino-4-(methoxymethoxy)butanoate (9.7 g, 44 mmol) and diisopropylethylamine (11.5 ml, 66 mmol) in methanol (300 ml) was dropped at room temperature methyl bromoacetate (6.2 ml, 66 mmol). The solution was stirred for 1 hour at 60° C. Additional methyl bromoacetate (2.1 ml, 22 mmol) and diisopropylethylamine (3.8 ml, 22 mmol) were added thereto and the mixture was stirred for 1 hour, cooled to room temperature and the solvent was removed. The residue was dissolved in chloroform (100 ml) and thereto were dropped at 0° C. allyl chloroformate (94 ml, 88 mmol) and then diisopropylethylamine (15.5 ml, 88 mmol). The mixture was stirred at the same temperature for 1 hour and at room temperature for 13 hours. To the reaction mixture was added water under cooling in an ice bath and the mixture was extracted three times with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The residue was purified with silica gel (230 g) chromatography (hexane/ethyl acetate=2/1→1/1) to give tert-butyl (3S)-3-[[(allyloxy)carbonyl](2-methoxy-2-oxoethyl)amino]-4-(methoxymethoxy)butanoate (11.7 g, 71%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:14])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:14][C:11]1([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC1(NC(=O)OC(C)(C)C)CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(NC(=O)OC(C)(C)C)CCNCC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
tert-Butyl (1-benzyl-4-methyl-4-piperidinyl)-carbamate obtained in Example 10-4 (1.01 g) was dissolved in methanol (20 mL), and 20% Pd(OH)2 on carbon (300 mg) was added. The mixture was stirred under hydrogen atmosphere (4 atm) at 20° C. for 2 hrs. The reaction mixture was diluted with ethyl acetate, filtered through a pad of Celite, and concentrated. The residual solid was triturated with hexane to give the title compound as white crystals (425 mg)
Reaction SMILES: [C:1]1([C@:11]23[CH2:16][C@H:15]2[CH2:14][C:13](=O)[CH2:12]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:24].[Na+].C(OCC)(=O)C.CO.C(N(CC)CC)C>CO>[C:1]1([C@:11]23[CH2:16][C@H:15]2[CH2:14][CH:13]([NH2:24])[CH2:12]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C[C@@H]2C[C@]2(c2cccc3ccccc23)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: NC1C[C@@H]2C[C@]2(c2cccc3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 346.7 %

Procedure:
To a solution of (1S,5S)-1-(1-naphthyl)bicyclo[3.1.0]hexan-3-one (0.7 g, 3.1 mmol) in methanol (87.5 mL) was added ammonium acetate (24.3 g, 310 mmol), stirred for 15 minutes at room temperature and sodium cyanoborohydride (1.58 g, 25 mmol) was added and the mixture was heated to 60° C. for 2 hours. The reaction was monitored by TLC (ethyl acetate/methanol/triethylamine (89:10:1)). The reaction mixture was concentrated under reduced pressure to remove methanol at 30° C., the crude mass was quenched with water (50 mL). The aqueous layer was extracted with ethyl acetate (3×150 mL). The aqueous layer was saturated with sodium chloride and re-extracted with ethyl acetate (3×150 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 2.4 g of crude oil, which was purified by preparative HPLC to 400 mg (57%) of 99% pure product. 1H NMR δ(300 MHz,CD3OD): 1.1-1.15 (1H,m), 1.21-1.24 (1H,m), 1.88-1.93 (2H,m), 2.24-2.31 (1H,m), 2.45-2.57 (1H,m), 2.90-2.92 (1H,m), 4.10-4.2 (1H,m), 7.37-7.57 (4H,m), 7.74-7.76 (1H,d, 6 Hz), 7.85-7.88 (1H,d,9 Hz), 8.20-8.29 (1H,m). 13CNMR (CD3OD): 140.74, 140.30, 135.51, 133.93, 129.81, 128.64, 127.76, 127.12, 127.01, 126.74, 126.59, 125.67 119.93, 54.97, 43.08, 40.42, 36.16, 34.53, 33.91, 25.88, 24.94, 23.70, 15.76. Purity: 98.5% (a/a) by HPLC. MS, M+(224).
Reaction SMILES: [Cl-].[F:2][CH2:3][C@@H:4]([NH3+:24])[C@H:5]([OH:23])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][N:15]=[C:14]([CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:13]=2)=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.[Cl:34][CH:35]([Cl:39])[C:36](Cl)=[O:37]>CN(C)C=O>[Cl:34][CH:35]([Cl:39])[C:36]([NH:24][C@H:4]([CH2:3][F:2])[C@H:5]([OH:23])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][N:15]=[C:14]([CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:13]=2)=[CH:8][CH:7]=1)=[O:37]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CS(=O)(=O)NCc1cc(-c2ccc([C@@H](O)[C@H]([NH3+])CF)cc2)on1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCc1cc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)on1
Temperature: 0 °C
Yield: 52.3 %

Procedure:
To a dimethylformamide (3 ml) solution of (1R,2S)-3-fluoro-1-hydroxy-1-(4-(3-(methylsulfonamidomethyl)isoxazol-5-yl)phenyl)propan-2-aminium chloride (150 mg, 0.40 mmol) is added diisopropylethylamine (0.255 g, 2 mmol). After cooling the reaction mixture to 0° C. dichloroacetyl chloride (62 mg, 0.42 mmol) is added. The reaction is stirred at 0° C. for twenty minutes then quenched by the addition of water (1 ml). The reaction mixture is concentrated to a volume of approximately two milliliters and subjected to reverse phase HPLC purification to give the title compound (95 mg): 1H NMR (400 MHz, CDCl3) 3.06 (s, 3H) 4.30-4.43 (m, 1H) 4.49 (d, J=6.32 Hz, 2H) 4.56-4.67 (m, 2H) 4.93 (m, br, 1H) 5.19-5.24 (m, 1H) 5.87 (s, 1H) 6.61 (s, 1H) 7.03 (d, J=9.09 Hz, 1H) 7.52 (d, J=8.08 Hz, 2H) 7.79 (d, J=8.59 Hz, 2H); m/z (Cl) 454, 456, 458 ([M+H]+.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[N:13]=[C:12](C(P(=O)(OC2C=CC=CC=2)OC2C=CC=CC=2)NC2C=CC=CC=2)[CH:11]=[CH:10][CH:9]=1.[CH3:38][C:39]1[C:47]2[C:43](=[CH:44][N:45]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[N:46]=2)[CH:42]=[C:41]([CH:56]=O)[CH:40]=1.Cl>C(O)(C)C.O1CCCC1>[Br:7][C:8]1[N:13]=[C:12]([C:1](=[O:4])[CH2:56][C:41]2[CH:40]=[C:39]([CH3:38])[C:47]3[C:43](=[CH:44][N:45]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[N:46]=3)[CH:42]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C=O)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: O=P(Oc1ccccc1)(Oc1ccccc1)C(Nc1ccccc1)c1cccc(Br)n1
Agent: Cl
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1cc(CC(=O)c2cccc(Br)n2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
To an oven-dried flask under nitrogen was charged with cesium carbonate (1.98 g, 6.09 mmol, 1.3 equiv, dried at 150° C. under high vacuum for 16 h) followed by diphenyl (6-bromopyridin-2-yl)(phenylamino)methylphosphonate (2.32 g, 4.68 mmol) and 7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-5-carbaldehyde (1.36 g, 4.68 mmol). Anhydrous tetrahydrofuran (9.6 mL) was introduced followed by anhydrous isopropanol (2.4 mL) via syringe under nitrogen. The yellow suspension was stirred at room temperature under nitrogen overnight (16.5 h). To the resulting suspension was added 1N hydrochloric acid (16 mL) and the resulting red solution was stirred at room temperature for 2 h until LCMS showed complete hydrolysis to the desired product. The reaction mixture was neutralized with 1N sodium hydroxide (12 mL) and then extracted with ethyl acetate (3×). The combined organic layers was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography to afford the desired product as a yellow oil (2.013 g, 93.6%). MS (ESI) [M+H]+=461. HPLC tR=2.09 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[C:12](Cl)(=O)[C:13](Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].C=C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:12][CH2:13][C:9](=[O:11])[CH2:8]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: C=C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2ccc(Br)cc2C1
Temperature: 25 °C

Procedure:
A solution of 3-bromophenylacetic acid (10.4 g, 48.4 mmol) in oxalyl chloride (50 mL, 0.57 mol) was stirred at ambient temperature for 5 min then at reflux for 5 h. The oxalyl chloride was removed in vacuo and the residue was dissolved in anhydrous CH2Cl2 (100 mL). This solution was added dropwise to a rapidly stirred, ice-cooled solution of AlCl3 (23.2 g, 174.2 mmol) in CH2Cl2 (500 mL). A stream of ethylene gas was blown into the vortex of the stirred solution during the addition and the reaction temperature was kept at <5° C. The reaction mixture was allowed to warm to ambient temperature and then poured onto ice and stirred vigorously. The organic portion was removed and the aqueous layer extracted with CH2Cl2 (2×200 mL). The combined CH2Cl2 fractions were passed through a 2″ pad of silica and concentrated to give a thick, red oil. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane::EtOAc—100:0 to 75:25, to provide the title compound as a pale yellow solid. MS: m/z=226 (M+1).