Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[OH:22])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].CN(C)C1C=CC=CC=1.[Br:32][C:33]([CH3:38])([CH3:37])[C:34](Br)=[O:35].C(OCC)(=O)C>ClCCl>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:34](=[O:35])[C:33]([Br:32])([CH3:38])[CH3:37])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1O
Reactant: CC(C)(Br)C(=O)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)c1ccccc1
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)C(C)(C)Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In 30 ml of dichloromethane are dissolved 3.2 g of 16β-ethyl-17β-hydroxy-4-estren-3-one and 1.2 ml of dimethylaniline and, with stirring at room temperature (15°-25° C.), 1.0 ml of 2-bromo-2-methylpropionyl bromide is added to the above solution. The mixture is stirred at room temperature (15°-25° C.) for 16 hours, followed by addition of 300 ml of ethyl acetate. The mixture is washed with 10% phosphoric acid, water, 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride in that order and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 400 ml of diisopropyl ether-n-hexane (1:1), elution is carried out with 800 ml of the same solvent system. The eluate is evaporated under reduced pressure to remove the solvent, giving 2.6 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:6][N:7]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:8][CH2:9][C:10]=1[C:11]1[CH:12]=[N:13][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[Cl:29])=[CH:15][CH:16]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1>[C:33]([O:32][C:30]([N:7]1[CH2:8][CH2:9][C:10]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]3[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[Cl:29])=[CH:15][CH:16]=2)=[C:5]([C:3]([OH:4])=[O:2])[CH2:6]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: COC(=O)C1=C(c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)nc2)CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(Cl)c(OCCOc2ccc(C3=C(C(=O)O)CN(C(=O)OC(C)(C)C)CC3)cn2)c(Cl)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of compound C6 (1.00 g, 1.86 mmol) and aq. 1M LiOH (7.00 mL, 7.00 mmol) in THF (7.00 mL) was stirred at 70° C. overnight. Aq. 1M HCl was added until a pH of 4 was reached, and the mixture was extracted with EtOAc (3×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying under high vacuum yielded the crude title compound mixed with 6-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1′,3′-dicarboxylic acid 1′-tert-butyl ester (850 mg, 87%) that was used further without purification.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][C@H:24]1[CH2:34][C@@:33]2([CH3:36])[O:35][C@@:25]31[C@@H:37]1[C@@H:29]([N:30]([C:39]4[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[C:41]([C:47]([F:50])([F:49])[F:48])[CH:40]=4)[C:31](=[O:38])[C@H:32]21)[O:28][CH2:27][CH2:26]3.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(Cl)Cl>[CH3:36][C@:33]12[O:35][C@:25]3([C@@H:37]4[C@@H:29]([N:30]([C:39]5[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[C:41]([C:47]([F:49])([F:50])[F:48])[CH:40]=5)[C:31](=[O:38])[C@H:32]14)[O:28][CH2:27][CH2:26]3)[C:24](=[O:23])[CH2:34]2
Reactant: C[C@@]12C[C@H](O)[C@]3(CCO[C@H]4[C@@H]3[C@@H]1C(=O)N4c1ccc(C#N)c(C(F)(F)F)c1)O2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@]12CC(=O)[C@]3(CCO[C@H]4[C@@H]3[C@@H]1C(=O)N4c1ccc(C#N)c(C(F)(F)F)c1)O2
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
Dess-Martin periodinane (12 g, 28.3 mmol) was added to a solution of Example 3 (3.0 g, 7.6 mmol) in THF (20 mL) and CH2Cl2 (30 mL) at room temperature. The reaction mixture was stirred at room temperature for 18 h and CH2Cl2 (50 mL), aq. 15% Na2S2O3 solution (25 mL), and aq. 2M Na2CO3 solution (25 mL) were added. The mixture was stirred for 1 h and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 2.9 g (97%) of the Example 5.
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([CH:15]=[C:16]([CH2:22][CH3:23])[CH:17]([N+:19]([O-:21])=[O:20])[CH3:18])[C:12]([NH2:14])=[O:13])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>>[C:6]([CH2:8][O:9][N:10]=[C:11]([CH:15]=[C:16]([CH2:22][CH3:23])[CH:17]([N+:19]([O-:21])=[O:20])[CH3:18])[C:12]([NH2:14])=[O:13])([OH:7])=[O:5]
Reactant: CCC(=CC(=NOCC(=O)OC(C)(C)C)C(N)=O)C(C)[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: CCC(=CC(=NOCC(=O)O)C(N)=O)C(C)[N+](=O)[O-]
Yield: 48.2 %

Procedure:
2-t-Butoxycarbonylmethoxyimino-4-ethyl-5-nitro-3-hexenamide (80 mg) was treated with trifluoroacetic acid (1 ml) at ambient temperature for 2 hours. Excess trifluoroacetic acid was distilled off under reduced pressure to give a residue which was purified by preparative thin layer chromatography, eluting with a mixture of benzene, dioxane and acetic acid (14:5:1) to give 2-carboxymethoxyimino-4-ethyl-5-nitro-3-hexenamide (32 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](I)=[C:9]([CH2:11][O:12][CH3:13])[N:10]=[C:4]2[CH:3]=1.[F:15][C:16]1[CH:17]=[CH:18][C:19]2=[C:20]([CH:36]=1)[O:21][CH2:22][C:23]1[CH:33]=[C:32]([CH:34]=[O:35])[CH:31]=[CH:30][C:24]=1/[C:25]/2=[C:26](/[CH3:29])\[C:27]#[N:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH:34]([OH:35])[C:32]3[CH:31]=[CH:30][C:24]4/[C:25](=[C:26](/[CH3:29])\[C:27]#[N:28])/[C:19]5[CH:18]=[CH:17][C:16]([F:15])=[CH:36][C:20]=5[O:21][CH2:22][C:23]=4[CH:33]=3)=[C:9]([CH2:11][O:12][CH3:13])[N:10]=[C:4]2[CH:3]=1
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Reactant: COCc1nc2cc(Cl)ccn2c1I
Product: COCc1nc2cc(Cl)ccn2c1C(O)c1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 74.9 %

Procedure:
[step 4] Using 7-chloro-3-iodo-2-(methoxymethyl)imidazo[1,2-a]pyridine (700 mg, 2.17 mmol) obtained in step 3 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (318 mg, 1.09 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8F, step 4, (E)-2-(8-{[7-chloro-2-(methoxymethyl)imidazo[1,2-a]pyridin-3-yl](hydroxy)methyl}-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (400 mg, 75%) was obtained.
Reaction SMILES: [O:1]1[CH2:5][C@@H:4]([OH:6])[C@H:3]2[O:7][CH2:8][C@H:9]([OH:10])[C@@H:2]12.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[OH-].[K+]>O.C1(C)C=CC=CC=1>[CH3:18][C:17]1[CH:19]=[CH:20][C:14]([S:11]([O:6][C@H:4]2[CH2:5][O:1][C@@H:2]3[C@H:9]([OH:10])[CH2:8][O:7][C@H:3]23)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)O[C@H]2CO[C@H]3[C@@H]2OC[C@H]3O)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
In a 2 L flask, 100.0 g (0.684 mol) of (3R,3aR,6S,6aR)-hexahydrofuro[3,2-b]furan-3,6-diol (Isosorbide) were dissolved in 600 ml of water and 130, 5 g (0.684 mol) of Tosyl chloride dissolved in 600 ml of Toluene are added at 0° C. 49.5 g (0.751 mol) of potassium hydroxide (86%) in 170 ml of water were added dropwise over ½ h at 0° C. and the reaction was stirred for 1 hr at 0° C. and 5 h at room temperature. The organic phase was extracted, dried, filtered and concentrated under vacuum and after subjecting the crude reaction product to silica gel column chromatography and eluting with a 99/1 mixture of dichloromethane/methyl alcohol, 50.0 g of the product of the title were obtained after concentrating to dryness.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:14])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=O.[BH4-].[Na+]>C(#N)C.C(O)(C)C>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:3][C@@H:2]([NH2:1])[CH3:14])=[CH:6]1
Reactant: C[C@H](N)C(=O)c1c[nH]c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC#N
Product: C[C@H](N)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A solution of (S)-2-amino-1-(1H-indol-3-yl)-propan-1-one (0.47 g, 2.5 mmol, 1.0 eq.) in acetonitrile and isopropanol is treated portionwise with NaBH4 (285 mg, 7.49 mmol, 3.0 equiv.), heated at reflux temperature for 24 h, stirred at room temperature under N2 for 36 h, quenched with methanol, concentrated and partitioned between water and EtOAc. The EtOAc phase is dried over MgSO4 and concentrated in vacuo to afford the title product as a brown oil, identified by HPLC and mass spectral analyses.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:30](OC(N1CCN(C2C=NC(N)=CC=2)[C@@H](C)C1)=O)(C)(C)C.BrC1C(=O)N(C)C=C(Br)C=1>>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:15]=[N:16][C:11]([NH:10][C:4]3[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([Br:1])[CH:3]=3)=[CH:12][CH:13]=2)[C@@H:18]([CH3:30])[CH2:19]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)nc1
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Agent: Cn1cc(Br)cc(Br)c1=O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Yield: 83 %

Procedure:
Following the procedures as described for compound 101i, reaction of 130b (4.0 g) and 3,5-dibromo-1-methylpyridin-2(1H)-one (5.5 g) afforded 130c as a yellow solid (5.4 g, 83%). LCMS: [M+H]+ 478
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.Cl>>[N:24]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:13]=[CH:14]/[C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNCC1
Reactant: ClCCCCOc1ccccc1/C=C/c1nc2ccccc2o1
Agent: Cl
Product: C(=C/c1ccccc1OCCCCN1CCCCC1)\c1nc2ccccc2o1
Yield: 42 %

Procedure:
The title compound was prepared as described in Example 5 starting with (D) of Example 5 (2.5 g, 7.6 mmmol) and using piperidine in place of dibutylamine to produce 1.2 g (42% yield) of the title compound as the HCl salt, mp 230°-232° C. IR(KBr): 1600 cm−1. MS: 377(MH+). 1H NMR (DMSO): δ 7.91-6.95 (m, 10H), 3.99 (t, J=5.2 Hz, 2H), 3.10 (m, 6H), 1.75 (m, 10H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:8][CH:9]=1)=[O:4].[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][N:13]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[S:27]([CH:24]2[CH2:26][CH2:25]2)(=[O:29])=[O:28])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(CCCNCCCc2cccc(Cl)c2)s1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(CCCN(CCCc2cccc(Cl)c2)S(=O)(=O)C2CC2)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 117.1 %

Procedure:
To a solution of 5-{3-[3-(3-chloro-phenyl)-propylamino]-propyl}-thiophene-2-carboxylic acid methyl ester (51.5 mg, 0.1463 mmol), of Preparation 8, in CH2Cl2 (10 mL) at 0° C. was added cyclopropanesulfonyl chloride (22.6 mg, 0.161 mmol) and triethylamine (0.45 mL, 0.32 mmol). The reaction was warmed to room temperature and was stirred for 48 h. The reaction was heated at reflux for 48 h and additional triethylamine (0.45 mL) and cyclopropanesulfonyl chloride (22.6 mg) were added. The reaction was heated at reflux for 7.5 h, was cooled to room temperature and was stirred for 72 h. The reaction was heated at reflux for 24 h. The organic solution was washed sequentially with 5.5% aqueous HCI, water, saturated sodium bicarbonate solution, and brine. The organic solution was dried (MgSO4), filtered, and concentrated to provide the title compound of Step A (78.1 mg). MS 456 (M+).
Reaction SMILES: C1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)C=CC=CC=1.[CH3:17][C@H:18]1[NH:23][C@@H:22]([CH3:24])[CH2:21][N:20]([C:25]([C:27]2[C:28]([CH3:34])=[C:29]([CH:32]=O)[NH:30][CH:31]=2)=[O:26])[CH2:19]1>C(O)C.N1CCCCC1>[CH3:17][C@H:18]1[NH:23][C@@H:22]([CH3:24])[CH2:21][N:20]([C:25]([C:27]2[C:28]([CH3:34])=[C:29]([CH:32]=[C:13]3[CH:12]=[CH:8][CH:7]=[C:15]([N:11]4[C:12]5[C:8](=[CH:7][CH:15]=[CH:14][CH:13]=5)[CH2:9][C:10]4=[O:16])[CH2:14]3)[NH:30][CH:31]=2)=[O:26])[CH2:19]1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccccc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=C1C=CC=C(N2C(=O)Cc3ccccc32)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.9 %

Procedure:
To a solution of 4-phenyl-1,3-dihydro-indol-2-one (52.3 mg, 0.25 mmol) and 4-[(cis)3,5-dimethyl-piperazine-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-phenyl-1,3-dihydro-indol-2-one as a yellow solid (21.5 mg, 20%).
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:14](=[O:17])[CH2:15][CH3:16])=[CH:7]2.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl.C1(C)C=C(C)C=C(C)C=1>[CH3:13][O:12][C:11]1[CH:2]=[C:3]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([C:14](=[O:17])[CH2:15][CH3:16])[CH:5]=[CH:4]2
Reactant: CCC(=O)c1ccc2c(Br)c(OC)ccc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: Cc1cc(C)cc(C)c1
Product: CCC(=O)c1ccc2cc(OC)ccc2c1
Temperature: -5 °C

Procedure:
29.3 Grams of 5-bromo-6-methoxy-2-propionylnaphthalene are dissolved in 100 ml of anhydrous methylene chloride and in 20.8 ml of mesitylene. 20 Grams of anhydrous aluminum chloride are added portionwise to the reaction mixture cooled to -5° C. under strong stirring, while keeping the temperature below 20° C. The reaction mixture is kept for over 3 hours under stirring at room temperature, then it is slowly poured under strong stirring into a mixture made of 110 g of ice and of 35 ml of a 35% (w/v) aqueous solution of hydrochloric acid. The layers are separated after 15 minutes of stirring and the aqueous layer is discarded. The organic layer first is twice washed with 50 ml of a 6N aqueous solution of hydrochloric acid and then with 50 ml of water. The organic solution is then added with 50 ml of water and the pH is brought to 12 by means of a 30% (w/v) aqueous solution of sodium hydroxide.
Reaction SMILES: Cl.[CH2:2]1[C:6]2([CH2:10][CH2:9][NH:8][CH2:7]2)[CH2:5][CH2:4][O:3]1.C(N(CC)CC)C.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][C:29]([C:31]([N:33]3[CH2:36][CH:35]([O:37][C:38]4[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=4)[CH2:34]3)=[O:32])=[N:28][N:27]=2)=[CH:22][CH:21]=1.[Na].C([O-])(O)=O.[Na+]>ClCCl>[CH2:2]1[C:6]2([CH2:10][CH2:9][N:8]([CH2:42][C:41]3[CH:40]=[CH:39][C:38]([O:37][CH:35]4[CH2:36][N:33]([C:31]([C:29]5[O:30][C:26]([C:23]6[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=6)=[N:27][N:28]=5)=[O:32])[CH2:34]4)=[CH:45][CH:44]=3)[CH2:7]2)[CH2:5][CH2:4][O:3]1
Reactant: C1CC2(CCOC2)CN1
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4)C3)o2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CCC6(CCOC6)C5)cc4)C3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
2-Oxa-7-azaspiro[4.4]nonane HCl salt (0.057 g, 0.35 mmol) was dissolved in dichloromethane (2 ml). To the resulting solution was added triethylamine (0.052 ml, 0.38 mmol), followed by 4-(1-(5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)benzaldehyde (0.11 g, 0.29 mmol) and sodium triacetoxyhydroborate (0.123 g, 0.58 mmol). The mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with dichloromethane (10 ml) and shaken with NaHCO3 (sat. 2 ml). The two phases were separated using a phase separator. The organic phase was evaporated. The product was purified by preparative reverse-phase HPLC at pH 10 to give 0.066 g (46%) of the desired product as a solid. 1H NMR (400 MHz, CDCl3) δ 1.92 (ddd 4H), 2.42 (d, 1H), 2.62 (dd, 3H), 3.58 (d, 3H), 3.71 (d, 1H), 3.84 (ddd, 2H), 3.92 (s, 3H), 4.35 (d, 1H), 4.67 (dd, 1H), 4.77 (d, 1H), 5.04-5.19 (m, 2H), 6.75 (d, 2H), 7.05 (d, 2H), 7.29 (d, 2H), 8.12 (d, 2H). MS (APCI+) m/z 491.3 [M+H]+, LC purity: 97%
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][NH:5]2.C(N(CC)C(C)C)(C)C.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31]>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][N:5]2[C:30]([C:26]1[O:25][CH:29]=[CH:28][CH:27]=1)=[O:31]
Reactant: CC(=O)N1c2ccc(Br)cc2NC[C@@H]1C
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(Br)cc2N(C(=O)c2ccco2)C[C@@H]1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
A 100 mL round bottomed flask fitted with a nitrogen inlet was charged with (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.500 g, 1.858 mmol), 1,2-dichloroethane (20 mL), N,N-diisopropylethylamine (1.0 mL, 5.73 mmol), and furan-2-carbonyl chloride (0.366 mL, 3.72 mmol). The reaction mixture was heated to 50° C. for 2 h with magnetic stirring. After for 2 h, the reaction was washed with 1 N aqueous sodium hydroxide solution (15 mL). The organic layer was removed and set aside. The aqueous layer was washed with 1,2-dichloroethane (20 mL) and the organic layers were combined and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 2:1 hexanes-ethyl acetate) to afford (S)-1-(6-bromo-4-(furan-2-carbonyl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.58 g, 86% yield) as a viscous yellow oil. MS (ESI, pos. ion) m/z 417 [M+1]+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)(=[O:7])[CH3:6].[OH-].[Na+]>>[C:5]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([N+:1]([O-:4])=[O:2])=[CH:18][C:11]=2[CH2:10][CH2:9]1)(=[O:7])[CH3:6]
Reactant: CC(=O)N1CCc2ccccc2CC1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N1CCc2ccc([N+](=O)[O-])cc2CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a cooled solution of HNO3 (70%) at 10° C., 3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepine (6.8 g, preparation reported in WO 02/40471) was added portionwise over 20 min. After addition mixture was allowed to warm at rt. and stirred for further 4 h. Mixture was poured into ice and pH adjusted to 11 using NaOH (conc) then was extracted with DCM. The organic layer was collected and the aqueous phase extracted twice with DCM. The combined DCM layers were concentrated to provide the target compound (7.74 g), which was used in further conversions without any purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[CH:16]=[N:17][C:18]5[C:23]([CH:24]=4)=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:13][C:14]=3[C:5]=2[N:4]([CH:25]2[CH2:30][CH2:29][N:28](C(OCC3C=CC=CC=3)=O)[CH2:27][CH2:26]2)[C:3]1=[O:41].I[Si](C)(C)C>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[CH:16]=[N:17][C:18]5[C:23]([CH:24]=4)=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:13][C:14]=3[C:5]=2[N:4]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:3]1=[O:41]
Reactant: Cn1c(=O)n(C2CCN(C(=O)OCc3ccccc3)CC2)c2c3nc(-c4cnc5ccccc5c4)ccc3ncc21
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)n(C2CCNCC2)c2c3nc(-c4cnc5ccccc5c4)ccc3ncc21
Yield: 95.5 %

Procedure:
To a cooled (0° C.) yellow solution of compound 49 (5.0 g, 9.2 mL) in chloroform (130 mL) was added iodotrimethylsilane (TMSI) (9.0 mL, 64 mmol), dropwise, turning to an orange mixture. After 3 hours the reaction was quenched with methanol and concentrated. The resulting residue was slurried in diethyl ether and filtered solids, and the solids were washed with diethyl ether to remove all benzyl iodide. To the solids was then added 2 N sodium hydroxide (20 mL) and water (150 mL). With stirring the orange suspension slowly turned to a cream suspension. The solids were collected by filtration and purified by flash chromatography eluting with chloroform/7 N ammonia in methanol (0-10%) to afford Compound 118 (3.6 g, 96%).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH3:5]>Cl>[N+:13]([C:10]1[CH:9]=[CH:8][C:7]([O:6][CH:4]([CH3:5])[C:3]([OH:16])=[O:2])=[CH:12][CH:11]=1)([O-:15])=[O:14]
Reactant: COC(=O)C(C)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 25 °C
Yield: 73.3 %

Procedure:
A mixture of 2-(4-nitrophenoxy)-propionic acid methyl ester (80 g) and concentrated hydrochloride acid (800 ml) was refluxed for 6 hours. The reaction mixture was cooled to room temperature. The product was filtered off and dried to obtain pure 2-(4-nitrophenoxy)-propionic acid (55 g) as a white powder with a melting point of 139-140° C.
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]1([CH3:14])[CH:10]=[CH:9][CH:8]=[C:7]([CH:11](O)[CH3:12])[CH:6]=1>>[Br:2][CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH3:14])[CH:6]=1)[CH3:12]
Reactant: BrP(Br)Br
Reactant: Cc1cccc(C(C)O)c1
Product: Cc1cccc(C(C)Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.3 %

Procedure:
Phosphorus tribromide (4.28 g, 15.9 mmol) was added drop-wise to a stirred neat solution of 1-(m-tolyl)ethanol (0.9 g, 6.6 mmol) at 0° C. After being stirred to room temperature over 12 h, the reaction was carefully quenched with sat'd saturated aqueous NaHCO3 solution and the mixture was extracted with EtOAc. The organic extract was washed with water, dried with MgSO4, and conc. in vacuo to afford the title compound (1.2 g, 91%) as a colorless oil, that was used directly in the next step without further purification. LCMS 200 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[S:31](Cl)(=[O:33])=[O:32]>>[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[S:31]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:33])=[O:32]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Reactant: O=S(=O)(Cl)c1cccs1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCNS(=O)(=O)c3cccs3)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.5 g (1.4 mmol) of material from Example 50 and 14 mg (0.11 mmol) 2-thiophenesulfonyl chloride. NMR was consistent with the proposed compound.