Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:24]([F:27])([F:26])[F:25])=[C:14]([N:17]3[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18]3)[CH:15]=2)[NH:10][C:9](=[O:28])[C:8]1=[O:29])=[O:5])[CH3:2].[Cl-].[OH:31][NH3+:32].C([O-])(=O)C.[Na+]>O.CCO>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:24]([F:27])([F:26])[F:25])=[C:14]([N:17]3[CH:21]=[CH:20][C:19]([CH:22]=[N:32][OH:31])=[CH:18]3)[CH:15]=2)[NH:10][C:9](=[O:28])[C:8]1=[O:29])=[O:5])[CH3:2]
Reactant: [NH3+]O
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(C=O)c3)cc21
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(C=NO)c3)cc21
Yield: 130 %

Procedure:
1.2 g (2.9 mmol) of the compound from Example 70, 0.4 g (6 mmol) of hydroxylammonium chloride and 0.48 g (6 mmol) of sodium acetate in 45 ml of H2O/EtOH (2:1) were refluxed for 30 minutes. The organic solvent was removed under reduced pressure, and the resulting aqueous phase was extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was recrystallized from ethanol to yield 1.6 g (70%) of the product. Melting point >250° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=O)=[CH:4][C:3]=1[CH3:12].CN.Cl.[BH3-][C:17]#[N:18].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:18][CH3:17])=[CH:4][C:3]=1[CH3:12]
Reactant: Cc1cc(CCC=O)ccc1F
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNCCCc1ccc(F)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
To a solution of 3-(4-fluoro-3-methylphenyl)propanal (1.0 g, 6 mmol) in 20 mL MeOH was added MeNH2HCl (556 mg, 7.2 mmol) followed by NaBH3CN (452 mg, 7.2 mmol) at room temperature. The mixture was stirred for 2 h at the room temperature. The reaction was quenched by pouring into 20 mL 5% aqueous NaOH and diluted with ethyl acetate. The mixture was extracted with more ethyl acetate (3×15 mL) and the combined organic layers washed with brine (2×10 mL) and dried over Na2SO4. The mixture was concentrated under reduced pressure and the product isolated by flash column chromatography eluting with 0% to 10% MeOH/DCM to provide 461 mg of the title compound as an colorless oil.
Reaction SMILES: [N:1]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][C@@H:3]2[CH2:6][NH:7][CH2:8][C@H:2]12.[CH3:23][C:24]([CH3:26])=O.C([BH3-])#N.[Na+]>CO.[OH-].[Na+]>[CH:24]([N:7]1[CH2:6][C@@H:3]2[C@@H:2]([N:1]([C:9]3[CH:10]=[CH:11][C:12]([C:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=4)=[CH:13][CH:14]=3)[CH2:5][CH2:4]2)[CH2:8]1)([CH3:26])[CH3:23]
Reactant: N#Cc1ccc(-c2ccc(N3CC[C@@H]4CNC[C@@H]43)cc2)cc1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N1C[C@H]2CCN(c3ccc(-c4ccc(C#N)cc4)cc3)[C@H]2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the product of Example 1E (26 mg, 0.09 mmole) in methanol (2 ml) was added acetone (132 μl, 1.8 mmole), and the mixture was stirred at room temperature for 1.5 hour. Sodium cyanoborohydride (28 mg, 0.44 mmole) was added and the mixture stirred overnight. The mixture was diluted with 2 ml 1N NaOH and extracted with dichloromethane (with 5% methanol) (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (elating with a mixture of 0.35% ammonium hydroxide and 3.5% methanol in dichloromethane) to provide the title compound. 1H NMR (CDCl3) δ ppm 7.63 (d, J=3.74 Hz, 4H) 7.50 (d, J=9.05 Hz, 2H) 6.64 (d, J=8.73 Hz, 2H) 4.16-4.22 (m, 1H) 3.48-3.55 (m, 1H) 3.31-3.38 (m, 1H) 2.90-3.01 (m, 2H) 2.74 (t, J=7.96 Hz, 1H) 2.46-2.52 (m, 2H) 2.31-2.39 (m, 1H) 2.10-2.20 (m, 1H) 1.90-1.99 (m, 1H) 1.06 (dd, J=6.24, 1.87 Hz, 6H); MS (M+H)+=332.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]([CH3:12])[N:6]=1)[CH3:3].[NH:13]1C=CN=[CH:14]1>C1(C)C(C)=CC=CC=1>[N:2]1([CH2:4][C:5]2[C:10]([OH:11])=[CH:9][CH:8]=[C:7]([CH3:12])[N:6]=2)[CH:1]=[CH:14][N:13]=[CH:3]1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(O)c(CN(C)C)n1
Solvent: Cc1ccccc1C
Product: Cc1ccc(O)c(Cn2ccnc2)n1
Yield: 76.3 %

Procedure:
The procedure described in Example 1 was repeated except that 2-dimethylaminomethyl-3-hydroxy-6-methylpyridine (16.6 g.) and imidazole (6.8 g.) were reacted in xylene (50 ml.) to afford 2-(imidazol-1-ylmethyl)-3-hydroxy-6-methylpyridine (yield, 14.42 g.), m.p. 153°-155° C. after recrystallization from isopropanol/petroleum ether (b.p. 60°-80° C.).
Reaction SMILES: [O:1]=[S:2]1(=[O:39])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([C:23]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:38])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[O:39]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([C:23]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:38])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(C(=O)C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(C(=O)C3CCNCC3)c2c1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
To a solution of tert-butyl 4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]carbonyl}piperidine-1-carboxylate (100 mg, 0.18 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature until the reaction was complete monitoring by LC/MS and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 1-10% methanol in dichloromethane) to afford 60 mg of the desired product. MS (ESI+) [(M+H)+] 450, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 (dd, J=7.83, 1.26 Hz, 1 H), 7.90 (d, J=7.07 Hz, 1 H), 7.68-7.56 (m, 2 H), 7.51-7.38 (m, 3 H), 7.34 (s, 1 H), 5.26 (brs, 2 H), 4.5 (brs, 2 H), 3.70-3.58 (m, 2 H), 3.37 (s, 2 H), 3.35-3.32 (m, 1 H), 3.14-3.03 (m, 2 H), 2.71 (td, J=12.25, 2.78 Hz, 2 H), 2.40 (s, 3 H), 1.79 (m, 2 H), 1.69-1.51 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].Cl.Cl.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23]2)[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23]2)[CH2:17][CH2:16]1)(=[O:11])=[O:10]
Reactant: c1ccc2c(c1)CCN(CC1CCNCC1)C2
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1cc(Cl)ccc1Cl)N1CCC(CN2CCc3ccccc3C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 131.8 %

Procedure:
2,5-dichlorobenzene-1-sulfonyl chloride (108.1 mg, 0.44 mmol) was added to a solution of 2-(piperidin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline dihydrochloride (92.1 mg, 0.40 mmol) and N,N-diisopropylethylamine (206.9.2 mg, 1.60 mmol) in CH2Cl2 (10 mL) and the mixture was stirred overnight at room temperature. The resulting solution was washed with water (3×10 mL), dried over Na2SO4, and evaporated to dryness. The free base was dissolved in ethyl acetate (1 ml). A 2.8 M solution of hydrogen chloride in ethanol (0.10 mL) was then added. The product was crystallized and collected by filtration, and vacuum dried to give a white solid (138 mg, 78%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[CH2:12]([OH:15])[C:13]#[CH:14].C(N(CC)CC)C>ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[CH:12]([OH:15])[C:13]#[CH:14])[CH:7]=[CH:8][N:9]=1
Reactant: Brc1cccc2ccncc12
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CC(O)c1cccc2ccncc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In an inert atmosphere. 0.068 g of bis(triphenylphosphine)palladium dichloride and 0.013 g of cuprous iodide was added with stirring to a deoxygenated solution of 1 g of 8-bromoisoquinoline, 0.56 mL of propargyl alcohol and 2 mL of triethylamine in 25 mL of dichloromethane. The mixture was stirred at room temperature for 2 hours and then at reflux for 20 hours. The cooled reaction was filtered and the filtrate was concentrated in vacuo. The residual oil was purified by HPLC (ethyl acetate-toluene; 2:3) to yield 0.4 g of -(8-isoquinolinyl)-2-propyne-1-ol, mp 138°-139° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>CN(C=O)C.C1(C)C=CC=CC=1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(I)cc1
Reaction time: 0.5 h

Procedure:
5 g (20 mmol) of 4-iodobenzoic acid, 30 ml of toluene and 5 drops of DMF were introduced into a round-bottomed flask. Heating was carried out to 40° C., 1.74 ml (24 mmol) of thionyl chloride was added and stirring was carried out for 30 minutes. Evaporation was carried out to dryness and 5.5 g (100%) of the crude acid chloride were recovered, which compound was employed as is in the continuation of the synthesis.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[C:13]([CH2:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17])#[N:14]>C(O)C.N1CCCCC1>[C:13]([C:15](=[CH:7][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[C:3]([OH:12])=[C:2]([Cl:1])[CH:9]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17])#[N:14]
Reactant: N#CCC(=O)Nc1ccccc1
Reactant: COc1cc(C=O)cc(Cl)c1O
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(C=C(C#N)C(=O)Nc2ccccc2)cc(Cl)c1O
Temperature: 25 °C
Yield: 74.1 %

Procedure:
To a solution of 5-chlorovanillin (728 mg, 3.9 mmol) and cyanoacetanilide (625 mg, 3.9 mmol) in ethanol (20 ml) were added 3 drops of piperidine, and the resulting mixture was refluxed for 2 hours. After cooling to room temperature, the resulting solid was filtered and washed with ethanol: water (1: 1) to give the objective 2-cyano-3-(3-chloro-4-hydroxy-5-methoxyphenyl) propenanilide (950 mg, 74% in yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=3)=[CH:12][C:11]([C:22]([OH:24])=O)=[N:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(CC)C(C)C)(C)C.ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:58]3[CH2:62][C:61](=[O:63])[NH:60][CH2:59]3)=O)=N2)C=CC=1>C(O)=O>[O:63]=[C:61]1[CH2:62][N:58]([C:22]([C:11]2[CH:12]=[C:13]([C:14]3[CH:15]=[C:16]([C:20]#[N:21])[CH:17]=[CH:18][CH:19]=3)[N:9]([C:5]3[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][CH:6]=3)[N:10]=2)=[O:24])[CH2:59][NH:60]1
Reactant: N#Cc1cccc(-c2cc(C(=O)O)nn2-c2cccc(C#N)c2)c1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(C#N)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 111A using 3.2 equivalents of N,N-diisopropylethylamine and with the addition of 0.1% formic acid in the preparative HPLC in analogy to the synthesis of the compound of Example 23. 16 mg (29% of theory) of the title compound are obtained.
Reaction SMILES: Cl.[C@@H:2]12[N:9]([CH2:10][C@@H:11]([C:13]3[C:14]([CH3:23])=[C:15]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[O:17][CH2:16]4)[OH:12])[C@@H:6](CC1)[CH2:5][NH:4][CH2:3]2.[CH3:24][C@H:25]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH:35]3[CH2:37][O:36]3)[CH:32]=2)[C:27](=[O:38])[O:26]1.CCN(C(C)C)C(C)C>C(O)C>[OH:36][CH:35]([C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:38])[O:26][C@H:25]([CH3:24])[CH2:34]2)[CH2:37][N:4]1[CH2:3][CH2:2][N:9]([CH2:10][C@H:11]([OH:12])[C:13]2[CH:21]=[CH:20][C:19]3[C:18](=[O:22])[O:17][CH2:16][C:15]=3[C:14]=2[CH3:23])[CH2:6][CH2:5]1
Reactant: C[C@H]1Cc2cc(C3CO3)ccc2C(=O)O1
Reactant: Cc1c([C@@H](O)CN2[C@@H]3CC[C@H]2CNC3)ccc2c1COC2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCN(CC(O)c3ccc4c(c3)C[C@@H](C)OC4=O)CC2)ccc2c1COC2=O
Temperature: 80 °C

Procedure:
To a solution of (R)-5-(1-hydroxy-2-(piperazin-1-yl)ethyl)-4-methylisobenzofuran-1(3H)-one (INTERMEDIATE 12) (150 mg, 0.54 mmol) in ethanol (2 mL) was added (3S)-3-methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one (INTERMEDIATE 24)(110 mg, 0.54 mmol) and Hunig's base (95 uL, 0.54 mmol). The mixture was heated to 80° C. for 20 hours. The solvent was removed using rotary evaporation and the crude oil was purified via by silica gel chromatography (0-7% MeOH in DCM) to yield (3R)-6-(1-hydroxy-2-{4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one as a diastereomeric mixture.
Reaction SMILES: C[Mg]Br.[NH:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[C:7]=2[CH:6]=[CH:5]1.[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH2:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>C(OCCCC)CCC.CN(C)C=O>[CH3:16][O:15][C:13]([C:8]1[C:7]2[C:6]([CH2:33][C:32]3[CH:31]=[CH:30][C:29]([O:28][CH2:27][C:18]4[CH:19]=[CH:20][C:21]5[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:17]=4)=[CH:36][CH:35]=3)=[CH:5][NH:4][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:14]
Reactant: ClCc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: C[Mg]Br
Solvent: CCCCOCCCC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2[nH]cc(Cc3ccc(OCc4ccc5ccccc5n4)cc3)c12
Temperature: 25 °C

Procedure:
A solution of methyl magnesium bromide in n-butyl ether (1.0M, 10.3 ml) was added dropwise to a solution of methyl indole-4-carboxylate (1.5 g) in dry dimethylformamide (15 ml) stirred under an atmosphere of nitrogen at room temperature. The mixture was stirred at room temperature for 20 minutes then a solution of 4-(quinolin-2-ylmethoxy)benzyl chloride (Example 1a) (2.35 g) in dry dimethylformamide (10 ml) added dropwise. The mixture was stirred at room temperature overnight, concentrated in vacuo, diluted with ethyl acetate and washed with water and a saturated solution of ammonium chloride; the organic phase was dried, filtered and evaporated. The residue was purified by chromatography on flash silica, eluting with petroleum spirit 40°-60° C.--diethyl ether (1:1) to give the product as a white solid. A small quantity was crystallised from petroleum spirit 40°-60° C.--diethyl ether (1:1), m.p. 148°-150° C.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[C:19]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]1>O1CCCC1>[C:7]([CH:9]=[C:19]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]1)#[N:8]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in tetrahydrofuran (30.7 mL) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (5.20 mL, 0.0322 mol) in tetrahydrofuran (39.12 mL). The reaction was warmed to room temperature and then cooled to 0° C. again. To the reaction mixture was added a solution of tert-butyl 3-oxoazetidine-1-carboxylate (5.0 g, 0.029 mol) in tetrahydrofuran (7.82 mL). The reaction was allowed to warm up to room temperature and stirred at room temperature overnight. After being quenched with water, the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and evaporated to dryness. The crude mixture was purified on silica gel, eluting with 0 to 70% EtOAc in hexanes, to give the desired product (5.40 g, 95%). LCMS (M+Na) 217.1.
Reaction SMILES: Br[C:2]1([CH:9]=[CH:8][CH:7]=[CH:6][CH:5]1Br)[CH:3]=[CH2:4].[N-:11]=[N+:12]=[N-:13].[Na+].[OH-].[Na+].C(=O)([O-])O.[Na+]>CS(C)=O.C(Cl)Cl>[N:11]([C:2]1([CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]1)[CH:3]=[CH2:4])=[N+:12]=[N-:13]
Reactant: C=CC1(Br)C=CC=CC1Br
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CS(C)=O
Product: C=CC1(N=[N+]=[N-])C=CC=CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 97.8 %

Procedure:
26.4 g of 1,2-dibromostyrene was dissolved in 150 ml of dimethylsulfoxide, then 9.8 g of sodium azide was added little by little at 15° to 18° C. in an atmosphere of nitrogen, and the mixture was stirred at room temperature for 10 hours. Then the reaction mixture was cooled to 10° C. and 10 g of a 50% aqueous sodium hydroxide solution was added dropwise thereto. After the addition the reaction mixture was stirred for 24 hours at room temperature, then 400 ml of a 2% aqueous sodium hydrogencarbonate solution was poured to it, and extraction with 150 ml of methylene chloride was carried out. After drying the extract liquid the solvent was distilled off under reduced pressure. 50 ml of n-hexane was added to the residue and the solution was treated by simple column chromatography, wherein the column was filled with 50 g of alumina (eluent: n-hexane). The solvent was removed from the elutant by distillation under reduced pressure, to obtain 14.4 g of 1-azidostyrene (B).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:11]([CH3:16])([CH2:14][OH:15])[CH2:12]O.C(C=P(CCCC)(CCCC)CCCC)#N.O.O.[Sn](Cl)Cl>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:11]1([CH3:16])[CH2:14][O:15][CH2:12]1)[NH2:8]
Reactant: CC(CO)(CO)c1ccc([N+](=O)[O-])cc1Br
Agent: CCCCP(=CC#N)(CCCC)CCCC
Agent: Cl[Sn]Cl
Solvent: c1ccccc1
Solvent: O
Product: CC1(c2ccc(N)cc2Br)COC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 26.4 %

Procedure:
2-(2-Bromo-4-nitrophenyl)-2-methylpropane-1,3-diol (0.145 g, 0.500 mmol) was dissolved in 2.5 mL of anhydrous benzene. Cyanomethylenetributylphosphorane (CMBP) (0.181 g, 0.750 mmol) was then added and the solution was allowed to stir at room temperature for 72 hours. The mixture was evaporated to dryness and then re-dissolved in 4 mL of EtOH. Tin(II) chloride dihydrate (0.564 g, 2.50 mmol) was then added and the resulting solution was heated at 70° C. for 1 hour. The mixture was cooled to room temperature and then quenched with a saturated aqueous solution of sodium bicarbonate. The mixture was then extracted three times with ethyl acetate. The combined ethyl acetate extracts were evaporated to dryness and purified by preparative LC/MS to yield 3-bromo-4-(3-methyloxetan-3-yl)aniline as a pale yellow oil (0.032 g, 32%) NMR (400 MHz, CD3CN) δ 7.13 (dd, J=0.7, 1.8 Hz, 1H), 6.94-6.88 (m, 2H), 6.75 (br s, 2H), 4.98 (d, J=5.6 Hz, 2H), 4.51 (d, J=6.1 Hz, 2H), 1.74 (s, 3H). ESI-MS m/z calc. 241.0, found; 242.1 (M+1)+ Retention time 0.53 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12]Cl)[N:6]=[CH:5]2.Cl.[C@H:15]12[CH2:21][C@H:18]([NH:19][CH2:20]1)[CH2:17][O:16]2.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:19]1[CH2:20][C@@H:15]3[CH2:21][C@H:18]1[CH2:17][O:16]3)[N:6]=[CH:5]2
Reactant: ClCCn1ncc2cc(Br)ccc21
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2c(cnn2CCN2C[C@@H]3C[C@H]2CO3)c1
Temperature: 90 °C
Reaction time: 19 h
Yield: 38.9 %

Procedure:
5-Bromo-1-(2-chloroethyl)-1H-indazole (183 mg, 0.703 mmol) was added to a suspension of (1S,4S)-(+)-5-aza-2-oxabicyclo[2.2.1]heptane hydrochloride (286 mg, 2.11 mmol), K2CO3 (485 mg, 3.52 mmol) and KI (117 mg, 0.703 mmol) in DMF (10 mL) under N2. The resulting suspension was stirred at 90° C. for 19 h. The suspension was cooled, and H2O (10 mL) was added. The aqueous solution was extracted with EtOAc, and the combined organic extracts were washed with brine. The organic solution was dried over Na2SO4 and concentrated under reduced pressure to afford clear viscous oil. Flash chromatography on silica gel (100:0 to 0:100 hexanes/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH)) gave the title compound (88 mg, 39%) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.95-7.92 (m, 1H), 7.87-7.84 (m, 1H), 7.45 (dd, J=8.7, 1.8 Hz, 1H), 7.34 (d, J=8.7 Hz, 1H), 4.43 (t, J=6.7 Hz, 2H), 4.34 (br s, 1H), 3.92 (d, J=7.8 Hz, 1H), 3.56 (dd, J=7.8, 1.5 Hz, 1H), 3.34 (br s, 1H), 3.15-3.01 (m, 2H), 2.92 (d, J=21.9 Hz, 1H), 2.81 (dd, J=9.9, 1.5 Hz, 1H), 2.47 (br d, J=9.9 Hz, 1H), 1.79-1.60 (m, 1H).
Reaction SMILES: [C:1]([O:10][CH2:11][CH:12]([CH2:14][O:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[I:35][C:36]1[CH:37]=[C:38]([CH2:42][CH2:43][C:44](O)=[O:45])[CH:39]=[CH:40][CH:41]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:10][CH2:11][CH:12]([CH2:14][O:15][C:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[O:13][C:44](=[O:45])[CH2:43][CH2:42][C:38]1[CH:39]=[CH:40][CH:41]=[C:36]([I:35])[CH:37]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)OCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CCc1cccc(I)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCC(=O)OCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)CCc1cccc(I)c1
Reaction time: 8 h
Yield: 73.2 %

Procedure:
1-Octanoyl-3-O-trityl-rac-glycerol (414 mg, 0.90 mmol), 3-(m-iodophenyl)propanoic acid (250 mg, 0.91 mmol) and DMAP were dissolved in CH2Cl2 (8.3 ml). DCC (206 mg, 1.00 mmol) was added and the mixture was stirred overnight. The mixture was then diluted with CH2Cl2. The organic and aqueous phases were separated and washed twice with 1 N HCl, once with saturated NaHCO3, once with H2O, and once with brine. The organic layer was then dried over MgSO4 and evaporated. Purification by chromatography on 12 g silica gel and with a hexanes:ethyl acetate (8:1) solvent yielded pure compound 44, 1-octanoyl-2-[3-(m-iodophenyl)propanoyl]-3-O-trityl-rac-glycerol (473.5 mg. 73% Yield).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[CH:9]=[C:8]([N:10]2[C:22]3[C:21]4[CH:20]=[C:19]([Br:23])[CH:18]=[CH:17][C:16]=4[N:15]=[CH:14][C:13]=3[N:12]([CH3:24])[C:11]2=[O:25])[C:7]([CH3:26])=[N:6]1.CO.[BH4-].[Na+]>C1COCC1>[Br:23][C:19]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[N:12]([CH3:24])[C:11](=[O:25])[N:10]([C:8]4[C:7]([CH3:26])=[N:6][N:5]([CH2:4][CH2:3][OH:2])[CH:9]=4)[C:22]=3[C:21]=2[CH:20]=1
Reactant: COC(=O)Cn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nn(CCO)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Temperature: 0 °C

Procedure:
A mixture of [4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-acetic acid methyl ester (Stage 101.1.1a, 60 mg, 0.139 mmol) and MeOH (0.021 ml, 0.519 mmol) in THF (1.5 ml) was cooled to 0° C. Then NaBH4 (14 mg, 0.370 mmol) was added and the RM was heated to 50° C. for 30 min. After that, the RM was quenched with saturated aqueous NaHCO3 (20 ml) and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give the title compound as a lightly yellow solid. (HPLC: tR 2.23 min (Method A); M+H=402, 404 Br-Pattern MS-ES)