Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[CH2:10][CH2:11][CH2:12][C:13]1[CH:17]=[CH:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[Si](C)(C)C.[Br:41]N1C(=O)CCC1=O>C1COCC1>[CH2:1]([O:8][C:9](=[O:25])[CH:10]([Br:41])[CH2:11][CH2:12][C:13]1[CH:17]=[CH:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)n1ccc(CCCC(=O)OCc2ccccc2)n1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ccc(CCC(Br)C(=O)OCc2ccccc2)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 27.5 g (80.0 mmol) of tert-butyl 3-[4-(benzyloxy)-4-oxobutyl]-1H-pyrazole-1-carboxylate from step D in 250 mL of anhydrous THF at −78° C. under an atmosphere of nitrogen was added 88 mL (88 mmol) of a 1.0 M solution of sodium bis(trimethylsilyl)amide in anhydrous THF. The resulting dark yellow solution was stirred for 1 h at −78° C. and then 12 ml (96 mmol) of chlorotrimethylsilane was added dropwise over 5 min. The resulting mixture was stirred for 25 min during which time the reaction became a light yellow color. Next, 16 g (88 mmol) of solid N-bromosuccinimide was added in one portion and the resulting mixture was stirred for 3 hrs at −78° C. followed by gradual warming to 0° C. over 1 h. The reaction was quenched with a saturated aqueous ammonium chloride solution and the aqueous phase extracted with ethyl acetate (3×200 mL). The combined organics were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo to afford the title compound as a yellow gum. The crude product appears to be a 1:1 mixture of starting material and desired product by NMR and was used without further purification in the next step. LC-MS: m/z (ES) 424 (MH)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.[Cl:19][C:20]1[C:25](Cl)=[N:24][CH:23]=[CH:22][N:21]=1>>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:25]2[C:20]([Cl:19])=[N:21][CH:22]=[CH:23][N:24]=2)[CH2:4][CH2:5]1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Clc1nccnc1Cl
Product: O=C(OCc1ccccc1)N1CCC(CNc2nccnc2Cl)CC1
Temperature: 100 °C

Procedure:
A mixture of benzyl 4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1) (1.25 g, 5.04 mmol) and 2,3-dichloropyrazine (0.25 g) was heated to 100° C. for 1 h. The reaction mixture was cooled and partitioned between EtOAc and pH5.2 citrate buffer. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent evaporated to give a crude product. Purification by flash column chromatography (5–50% EtOAc hexane) afforded the title compound. M.S (M+1): 361.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.O>C1(C)C=CC=CC=1.Cl.[Fe]>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]2[S:4][N:3]=[C:2]([Cl:1])[C:6]=2[CH:7]=1
Reactant: O=[N+]([O-])c1ccc2snc(Cl)c2c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc2snc(Cl)c2c1
Temperature: 25 °C

Procedure:
A solution of 3-chloro-5-nitro-1,2-benzisothiazole (2.00 g) in toluene is treated with iron powder (8.40 g, 325 mesh) and concentrated hydrochloric acid (8 drops), heated to reflux, treated dropwise with water (8.00 mL), refluxed for 35 minutes, cooled to room temperature, and filtered through diatomaceous earth. The resultant filtrate is concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and an ethyl acetate/hexanes solution (1:1) gives the title product.
Reaction SMILES: [CH3:1][CH:2]1[C:11](=O)[N:10]2[CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH:14]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[N:3]1[C:24]([O:26][CH2:27][CH3:28])=[O:25].Cl>C1COCC1.O>[CH3:1][CH:2]1[CH2:11][N:10]2[CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH:14]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[N:3]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)N1CCC2C(C1)c1cccc3c1N2C(=O)C(C)N3C(=O)OCC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC2C(C1)c1cccc3c1N2CC(C)N3C(=O)OCC
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a solution of diethyl 2-methyl-1-oxo-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (300 mg, 0.77 mmol) in THF (10 mL) at rt was added BH3THF complex (3.8 mL, 3.8 mmol) and refluxed for 5 hours. At rt 6N HCl (10 mL) was added and stirred for 0.5 hour before the solution was diluted with water (20 mL), and extracted with EtOAc (2×20 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford diethyl 2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (200 mg, 69%) as a clear oil. MS [M+H]+ 374.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][CH2:11][C:12](=O)[CH3:13])[CH:5]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([NH:24]N)[CH:21]=[CH:22][CH:23]=1>>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][C:11]2[C:21]3[C:20](=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=3)[NH:24][C:12]=2[CH3:13])[CH:5]=1
Reactant: NNc1cccc(Cl)c1
Reactant: COC(=O)c1ccnc(SCC(C)=O)c1
Agent: Cl
Product: COC(=O)c1ccnc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 2-(2-oxo-propylsulfanyl)-isonicotinic acid methyl ester and (3-chloro-phenyl)-hydrazine hydrochloride.
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH3:14])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:2]([CH3:4])[CH3:3])=[C:8]([O:13][CH3:14])[CH:7]=1
Reactant: COc1cc(Br)ccc1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(Br)ccc1OC(C)C
Temperature: 55 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
2-Bromopropane (3.39 mL, 36.2 mmol) was added to a suspension of 4-bromo-2-methoxy-phenol (5 g, 24.1 mmol), K2CO3 (6.67 g, 48.3 mmol) and DMSO (71 mL) at room temperature. The heterogeneous mixture was stirred at 55° C. for 2 hours, then cooled to room temperature and diluted with water. The reaction mixture was extracted with Et2O and the extract was washed successively with 10% aq. NaOH solution, water, then brine solution. The organics were separated and dried over sodium sulfate, filtered and concentrated in vacuo to give 4-bromo-1-isopropoxy-2-methoxy-benzene (5.83 g, 94%) as a pale yellow oil. ESI-MS m/z calc. 244.0. Found 245.0 (M+1)+; Retention time: 1.93 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.03-6.95 (m, 2H), 6.76 (dd, J=7.7, 1.1 Hz, 1H), 4.47 (dt, J=12.2, 6.1 Hz, 1H), 3.84 (s, 3H), 1.35 (d, J=6.1 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][N:16]([C:13]1[CH:12]=[CH:11][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:1][C:24]4[CH:25]=[CH:26][C:27]([N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)=[CH:28][CH:29]=4)[N:22]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:15][CH:14]=1)[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CN(c1ccc(-c2cccn3nc(N)nc23)cc1)S(C)(=O)=O
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5ccc(N(C)S(C)(=O)=O)cc5)cccn4n3)cc2)CC1

Procedure:
N-Methyl-N-(4-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (70.0 mg, 0.274 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (26.0 mg, 0.0476 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a tan solid (0.027 g, 23%). MP=205-206° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=6.5 Hz, 1H), 8.04 (d, J=7.7 Hz, 2H), 7.57-7.46 (m, 5H), 6.99-6.91 (m, 3H), 6.66 (s, 1H), 3.38 (s, 3H), 3.19-3.14 (m, 4H), 2.90 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=492 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:41])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:29][O:28][CH2:27][CH2:26][N:25]4[C:30](=[O:39])[CH:31]([NH2:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH3:40])[N:9]=2)[CH:7]=1.[C:42]([N:46]=[C:47]=[O:48])([CH3:45])([CH3:44])[CH3:43]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:41])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:29][O:28][CH2:27][CH2:26][N:25]4[C:30](=[O:39])[CH:31]([NH:38][C:47]([NH:46][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:48])[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH3:40])[N:9]=2)[CH:7]=1
Reactant: CC(C)(C)N=C=O
Reactant: Cn1cc(C#Cc2ccc(NC(=O)C3COCCN3C(=O)C(N)c3ccccc3)cc2)c(-c2cc(Cl)ccc2O)n1
Solvent: ClCCl
Product: Cn1cc(C#Cc2ccc(NC(=O)C3COCCN3C(=O)C(NC(=O)NC(C)(C)C)c3ccccc3)cc2)c(-c2cc(Cl)ccc2O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 9D (4.0 g, 7.02 mmol) in anhydrous CH2Cl2 (100 mL) was added tert-butyl isocyanate (12D, 3.21 mL, 28.07 mmol). The reaction mixture was stirred at rt overnight. It was concentrated to small volume and purified with silica column chromatography eluting with dichloromethane/EtOAc to give the title compound (13D) as white powder in good yield. 1H NMR (CDCl3, 500 MHz) δ 10.68 (s, 1H), 8.92 (s, 1H), 8.72 (s, 1H), 8.02 (d, 2H, J=8.0 Hz), 7.63 (s, 1H), 7.56 (d, 2H, J=8.0 Hz), 7.38 (s, 5H), 7.19 (d, 1H, J=8.0 Hz), 6.96 (d, 1H, J=8.5 Hz), 5.58 (d, 1H, J=6.0 Hz), 5.30 (s, 1H), 5.18 (d, 1H, J=6.5 Hz), 4.85 (d, 1H, J=11.5 Hz), 4.79 (s, 1H), 3.96 (s, 3H), 3.79 (d, 1H, J=11.5 Hz), 3.62 (br s, 2H), 3.44 (d, 1H, J=10.0 Hz), 3.11 (m, 1H), 1.29 (s, 9H). LCMS (ESI) m/z 669.25 (MH+), 570.23 (100). HPLC: tR=5.22 min.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:7]([O:6][CH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OC1CC=CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C1=CCC(OCc2ccccc2)C1

Procedure:
To a solution of cyclopent-3-en-1-ol [cf. J. Org. Chem., 32, 4138 (1967)] (7.00 g) and benzyl bromide (10.5 ml) in dimethylformamide (35 ml) is added gradually 60% sodium hydride (in oil) (3.68 g) with stirring under ice-cooling, and the mixture is stirred at room temperature for 1.5 hour. The reaction mixture is diluted with ethyl acetate and washed with water six times. The ethyl acetate solution thus obtained is dried over anhydrous magnesium sulfate, evaporated to dryness under reduced pressure, and then purified by medium pressure liquid column chromatography (eluent; n-hexane, n-hexane:ethyl acetate--50:1, v/v) to give 4-benzyloxycyclopent-1-ene (11.22 g) as an oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:7])=[C:4]([F:18])[CH:3]=1.[H-].[Na+].I[CH3:22]>CN(C=O)C>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]([CH3:22])[CH2:9][C:10]2[N:11]=[CH:12][CH:13]=[CH:14][N:15]=2)=[O:7])=[C:4]([F:18])[CH:3]=1
Reactant: O=C(NCc1ncccn1)c1ccc(Br)cc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ncccn1)C(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a flask was charged with 4-bromo-2-fluoro-N-(pyrimidin-2-ylmethyl)benzamide (74.5 mg, 0.24 mmol), NaH (60% dispersion in mineral oil, 11.5 mg, 0.288 mmol) in DMF (2 mL), to the slurry was added iodomethane (20 μl, 0.312 mmol) and to the resulting mixture was stirred at room temperature for 10 min, then was quenched by water (20 μl), concentrated and the crude residue was dissolved in EtOAc, washed with water, and brine, dried (Na2SO4), concentrated and 4-bromo-2-fluoro-N-methyl-N-(pyrimidin-2-ylmethyl)benzamide was obtained as oil (55.3 mg, 71%). LCMS (m/z): 324.1/326.1 (MH+), 0.66 min.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[SH:18][CH2:19][CH2:20][CH2:21][SiH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25]>C1(C)C=CC=CC=1>[C:8]([S:18][CH2:19][CH2:20][CH2:21][SiH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25])(=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: COC(OC)[SiH2]CCCS
Reactant: CCCCCCCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)SCCC[SiH2]C(OC)OC
Reaction time: 2 h
Yield: 95 %

Procedure:
In a four-necked flask of 1 L, 18.0 g of 3-mercaptopropyl dimethoxymethyl silane and 11.1 g of triethylamine are dissolved in 300 mL of toluene under a nitrogen atmosphere. To this solution is added 16.2 g of octanoic acid chloride dropwise over 30 minutes, which is stirred for 2 hours. Thereafter, the precipitates are filtered off and the solvent is removed by a rotary evaporator at 20 hPa/40° C. to obtain 29.0 g of 3-octanoylthio-propyl dimethoxymethyl silane.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]([OH:12])=O)[CH:9]=[C:4]2[CH:3]=[CH:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:15]2[N:22]=[C:10]([C:8]3[CH:9]=[C:4]4[CH:3]=[CH:2][NH:1][C:5]4=[N:6][CH:7]=3)[O:12][N:14]=2)[CH:17]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1cnc2[nH]ccc2c1
Agent: N
Product: c1cncc(-c2noc(-c3cnc4[nH]ccc4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (Adesis) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 6.71 (d, J=3.4 Hz, 1H), 7.66 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 7.70 (d, J=3.4 Hz, 1H), 8.47 (dt, J=8.1, 1.9 Hz, 1H), 8.78-8.86 (m, 2H), 9.05 (d, J=2.0 Hz, 1H), 9.28 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 264 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH2:20][CH:21]([CH3:23])[CH3:22].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][O:1][C:2]2[CH:19]=[CH:18][C:5]([C:6]([N:8]3[CH2:9][CH2:10][N:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][CH2:13]3)=[O:7])=[CH:4][C:3]=2[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:27][CH:26]=1
Reactant: CC(C)Cc1cc(C(=O)N2CCN(CC(C)C)CC2)ccc1O
Reactant: Clc1ccc(CBr)cc1
Product: CC(C)Cc1cc(C(=O)N2CCN(CC(C)C)CC2)ccc1OCc1ccc(Cl)cc1
Yield: 42.9 %

Procedure:
As in the case of Example 18, 1-(4-hydroxy-3-isobutylbenzoyl)-4-isobutylpiperazine (1.59 g) was benzylated with 4-chlorobenzyl bromide (1.03 g), thereby yielding 0.95 g of the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[H-].[Na+].[CH2:16](I)[CH2:17][CH3:18].[Na+].[Cl-]>CN(C)C=O>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH2:16][CH2:17][CH3:18])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1
Reactant: CCCI
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1cccc2c(Cl)cc(C)nc12
Reaction time: 1 h
Yield: 49.3 %

Procedure:
4-Chloro-8-hydroxy-2-methylquinoline (500 mg, 2.58 mmole) was suspended in dimethylformamide (4 mL) and mixed with sodium hydride (60% in paraffin liq., 113 mg). After stirring for 1 h, propyliodide (461 mg, 2.71 mmole) in dimethylformamide (1 mL) was added dropwise and the mixture was kept under stirring at RT for 16 hrs. Diluted NaCl solution was added and the mixture was extracted with ethyl acetate. The organic phases were dried, concentrated and the residue thus obtained was purified using silica gel chromatography, eluting with dichloromethane:methanol 95:5. Precipitation in isopropanol/iso-propyl ether/HCl gave the product (300 mg, 49%).
Reaction SMILES: [CH:1]1([C@H:6]([OH:21])[C@H:7]([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH:8]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH3:26][NH2:27]>C1COCC1>[CH:1]1([C@H:6]([OH:21])[C@H:7]([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH2:8][NH:27][CH3:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN
Reactant: O=C[C@H]([C@@H](O)C1CCCC1)N1C(=O)c2ccccc2C1=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC[C@H]([C@@H](O)C1CCCC1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (2S,3S)-3-cyclopentyl-3-hydroxy-2-(1,3-dioxoisoindolin-2-yl)propanal (1.339 g, 4.7 mmol) in dry THF (20 mL) was cooled to 0° C. Acetic acid (2.5 mL, 44 mmol), methylamine (33% in EtOH, 2.5 mL, 20 mmol), and NaHB(OAc)3 (4.4937 g, 21.3 mmol) were added sequentially in single portions. The ice bath was removed and the mixture was stirred for 2 h at rt. The solvent was stripped and the crude 2-((1S,2R)-1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)isoindoline-1,3-dione was used directly in the next step. LC-MS (3 min) tR=1.07, m/z=303 (M+1).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19]Cl)[C:12]=2[NH2:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>CS(C)=O.O>[N:22]([CH2:19][CH2:18][O:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:12]=1[NH2:21])=[N+:23]=[N-:24]
Reactant: Nc1c(CS(=O)(=O)c2ccccc2)cccc1OCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCCOc1cccc(CS(=O)(=O)c2ccccc2)c1N
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 2-benzenesulfonylmethyl-6-(2-chloro-ethoxy)-phenylamine (0.5 g, 1.53 mmoles) and sodium azide (0.15 g, 2.29 mmoles) in DMSO (10 mL) was stirred together in a round bottom flask under nitrogen at 90° C. for 3 hours. Reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAC, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. Crude compound was purified by normal phase HPLC using as eluent 40% EtOAc/hexane to afford the title compound as an off white solid (0.39 g, 1.17 mmoles).
Reaction SMILES: C([CH:8]([CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]1)[CH2:9][N:10]([C:20]1[CH:29]=[CH:28][C:23]2[O:24][CH2:25][CH2:26][O:27][C:22]=2[CH:21]=1)[CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO>[O:24]1[CH2:25][CH2:26][O:27][C:22]2[CH:21]=[C:20]([N:10]([CH:11]3[CH2:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:12]3)[CH2:9][CH2:8][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]3)[CH:29]=[CH:28][C:23]1=2
Reactant: c1ccc(CC(CN(c2ccc3c(c2)OCCO3)C2Cc3ccccc3C2)C2CCCCN2)cc1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: c1ccc2c(c1)CC(N(CCC1CCCCN1)c1ccc3c(c1)OCCO3)C2

Procedure:
To a stirred solution of compound 59 (1.55 g, 3 31 mmol) in methanol (30 mL) was added HCOONH4 (2.08 g, 33.11 mmol) and the solution was purged with nitrogen for 30 minutes. 10% Pd—C (0.4 g) was then added and the solution was refluxed for 6 hours. The reaction mixture was filtered through Celite® reagent and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with water and brine. The solution was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide compound 60.
Reaction SMILES: [O:1]=[O+][O-].[CH:4]([CH:6]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:9][CH2:8][C:7]1=[O:23])=C>CO>[CH:4]([CH:6]1[C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15]2)[CH2:9][CH2:8][C:7]1=[O:23])=[O:1]
Reactant: C=CC1C(=O)CCC12CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=[O+][O-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CCC(=O)C2C=O)CC1
Temperature: 25 °C

Procedure:
Ozone was bubbled into a solution of tert-butyl 1-vinyl-2-oxo-8-azaspiro[4.5]decane-8-carboxylate (0.168 g, 0.599 mmol) from Step B in methanol (6 mL) at −70° C. until a blue color persisted. Excess ozone was removed with a stream of nitrogen and then dimethyl sulfide (0.5 mL) was added. The mixture was allowed to warm to room temperature for 1 h and was then concentrated in vacuo without heating to afford the crude title compound which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([S:16](Cl)(=[O:18])=[O:17])[CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26].Cl>ClCCl.N1C=CC=CC=1>[CH2:25]([N:27]([CH2:28][CH3:29])[S:16]([C:7]1[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]([O:4][C:3]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:2]=2[Cl:1])[CH:6]=1)(=[O:18])=[O:17])[CH3:26]
Reactant: CCNCC
Reactant: CS(=O)(=O)Nc1ccc(S(=O)(=O)Cl)cc1Oc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1ccc(NS(C)(=O)=O)c(Oc2ccc(Cl)cc2Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-(2,4-Dichlorophenoxy)-4-methylsulphonylaminobenzene-sulphonic acid chloride (1.08 g, 2.50 mmol) was dissolved in dichloromethane (5 ml) and at 0° C. added dropwise to a solution of diethylamine (0.30 ml, 2.51 mmol) in pyridine (20 ml). The mixture was stirred for 1 hour at 0° C., acidified with 1N HCl and extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and the solvent was evaporated off. The residue was purified by chromatography (silica gel, CH2Cl2). Yield: 0.22 g=19% 13C (100 MHz, DMSO-d6) δ 149.98, 147.50, 136.21, 132.37, 130.43, 129.63, 129.21, 126.15, 123.56, 122.86, 122.72, 114.90, 41.77, 41.02, 14.02
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[CH3:21][O:22][CH2:23][CH2:24][NH2:25]>C(Cl)Cl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:25][CH2:24][CH2:23][O:22][CH3:21])=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reactant: COCCN
Solvent: ClCCl
Product: COCCNC(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reaction time: 12 h

Procedure:
The compound from Example 126c (1.0 g, 3.2 mmol) in CH2Cl2 was added to a mixture of 2-methoxyethanamine (722 mg, 9.61 mmol) in CH2Cl2. Mixture was stirred for 12 hours. Mixture was concentrated under vacuum giving the title compound, which was purified by silica gel column chromatography eluting with 50% EtOAc/hexane giving the title compound as a yellow oil (1.1 g, 100%).