Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:32]=[N:31][N:30]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][C:22]([CH3:29])([CH3:28])[NH:23][C:24]([CH3:27])([CH3:26])[CH:25]=2)[CH:19]=1)=[O:13].C([O-])([O-])=O.[K+].[K+].[CH2:45](Br)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.O>CN(C=O)C.C(Cl)Cl>[CH2:45]([N:36]1[CH2:37][CH2:38][CH:33]([N:30]2[C:16]3[N:17]=[C:18]([C:20]4[CH2:21][C:22]([CH3:28])([CH3:29])[NH:23][C:24]([CH3:26])([CH3:27])[CH:25]=4)[CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:3]4[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=4[CH3:1])=[O:13])[C:15]=3[CH:32]=[N:31]2)[CH2:34][CH2:35]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)nc3c2cnn3C2CCNCC2)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)nc3c2cnn3C2CCN(Cc3ccccc3)CC2)c(=O)[nH]1
Temperature: 80 °C
Reaction time: 12 h
Yield: 21.3 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(piperidin-4-yl)-6-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.1 g, 0.193 mmol) in DMF (1 mL), K2CO3 (0.032 g, 0.232 mmol) and benzyl bromide (0.04 g, 0.232 mmol) were added. Resulting reaction mixture was stirred at 80° C. for 12 h. On completion of reaction, water was added to it and extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by prep HPLC to provide the desired compound (21.3% yield). LCMS: 608.45 (M+1)+; HPLC: 94.92% (@ 254 nm) (Rt; 4.640); 1H NMR (DMSO-d6, 400 MHz) δ 11.54 (s, 1H), 9.70 (bs, 1H), 8.86 (s, 1H), 8.37 (s, 1H), 7.90 (s, 1H), 7.54-7.52 (m, 5H), 6.85 (s, 1H), 5.90 (s, 1H), 5.17 (m, 1H), 4.40 (m, 4H), 3.55 (d, 2H, J=12 Hz), 3.41-3.35 (m, 2H), 2.83 (m, 2H), 2.32-2.41 (m, 2H), 2.23 (s, 3H), 2.22-2.13 (m, 2H), 2.12 (s, 3H), 1.57 (s, 6H), 1.47 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:22])[CH2:10][S:11][C:12]2[NH:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][N:13]=2)=[CH:5][CH:4]=1)#[N:2].[BH4-].[Na+]>CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:22])[CH2:10][S:11][C:12]2[NH:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][N:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1cnc(SCC(=O)c2ccc(C#N)cc2)[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1cnc(SCC(O)c2ccc(C#N)cc2)[nH]1

Procedure:
The product from Step A (6.91 g, 21.9 mmol) was suspended in methanol (50 mL). Sodium borohydride (829 mg, 21.9 mmol) was added in portions at 0° C., and the suspension was stirred until it became homogeneous (1 hour). The reaction was quenched by the addition of saturated aqueous ammonium chloride until hydrogen evolution ceased. The resulting precipitate was filtered and washed with water (2×25 mL) to provide the title product as a white solid which was sufficiently pure for use in the next step.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[OH:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1.[C:24]1([CH2:30][O:31][C:32]([C:34]2([NH2:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[C:24]1([CH2:30][O:31][C:32]([C:34]2([NH:40][C:19]([C:18]3[CH:17]=[CH:16][C:15]([CH2:14][OH:13])=[CH:23][CH:22]=3)=[O:21])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]2)=[O:33])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)c1ccc(CO)cc1
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
Under ice-cooling, 6.94 g (36 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 5 g (33 mmol) of 4-(hydroxymethyl)benzoic acid, 7.7 g (33 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and 5.29 g (35 mmol) of 1-hydroxybenzotriazole in methylene chloride. After the mixture was stirred at room temperature overnight, the reaction solvent was distilled off under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate twice. The obtained organic layer was washed with a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine, and it was dried with anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography to obtain 6.83 g (56%) of the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>CC(O)=O>[N+:15]([C:10]1[CH:9]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=[CH:12][C:11]=1[OH:14])([O-:17])=[O:16]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Oc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-phenoxyphenol (10.0 g, 54 mmol) in 100 mL AcOH was added slowly dropwise nitric acid (69-70%, 3.2 mL, 54 mmol) over about 3 min from an addition funnel. The reaction became warm and was cooled with a water bath. After 1 h, the reaction was poured onto ice and allowed to warm to rt. A gummy solid resulted, which was partitioned between MTBE and water. The organic layer was washed 1× water, 1× brine, dried over sodium sulfate, filtered, and concentrated to a dark oil. This was adsorbed onto 36 g silica gel and dried, and purified in two parts by silica gel chromatography, ISCO, 0-10% EtOAC/hexanes. Product-containing fractions were combined and concentrated to give 2-nitro-4-phenoxyphenol as an orange oil. MS (ESI) m/z: Calculated: 231.1; Observed: 230.0 (M−−1).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[CH2:7][C:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=1)=[O:9].C(O)(C)C.C(O)(=O)C>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]([CH2:7][CH:8]([OH:9])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cc1cccc(Br)c1)Cc1cccc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: OC(Cc1cccc(Br)c1)Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
7.6 g (200 mmol) of sodium tetrahydridoborate were added at 0° C. to a solution of 36.8 g (100 mmol) of bis(3-bromobenzyl)ketone in a mixture of 500 ml of THF, 200 ml of isopropanol and 3 ml of acetic acid, and the mixture was stirred at 0° C. for a further 3 h. The ice bath was subsequently removed, and the mixture was stirred at room temperature for a further 12 h. After addition of 300 ml of saturated ammonium chloride solution, the organic phase was separated off, and the aqueous phase was extracted twice with 100 ml of dichloromethane. The combined organic phases were washed once with 500 ml of saturated sodium chloride solution and then freed from the solvent mixture in vacuo, giving 34.9 g (94 mmol), corresponding to 94.3% of theory, of the product in the form of an oil, 97% according to 1H-NMR, which were reacted further without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][N:14]2[S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:53]([O:55][CH2:56][CH2:57][O:58][NH2:59])=[CH2:54].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:53]([O:55][CH2:56][CH2:57][O:58][NH:59][C:19]([C:18]1[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:23])=[O:24])[N:13]=[CH:12]2)=[O:21])=[CH2:54]
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(Nc4ccc(I)cc4F)c(C(=O)O)ccc32)cc1
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1ccc2c(cnn2S(=O)(=O)c2ccc(C)cc2)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.7 %

Procedure:
To a solution of 4-(2-fluoro-4-iodo-phenylamino)-1-(toluene-4-sulfonyl)-1H-indazole-5-carboxylic acid (0.58 g, 1.05 mmol) in DMF (10 mL) was added EDCI (0.22 g, 1.1 mmol) followed by HOBt (0.16 g, 1.1 mmol) and the reaction mixture stirred at room temperature for 10 minutes. O-(2-vinyloxy-ethyl)-hydroxylamine (0.12 g, 1.1 mmol) and DIPEA (0.2 mL, 1.1 mmol) were added and the reaction stirred for 16 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with an aqueous saturated sodium bicarbonate solution (10 mL) before the aqueous fraction was extracted twice with ethyl acetate (2×10 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0-100% ethyl acetate in cyclohexane) to yield the title compound as a pale brown solid (439 mg, 66%). LCMS (Method B): RT=4.40 min, [M+H]+=637.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][C:13]3[CH:28]=[CH:27][C:16]([CH2:17][NH:18][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[O:20])=[CH:15][CH:14]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[CH:38]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[NH:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[CH2:38][N:11]([CH2:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:20])=[CH:15][CH:14]=1)[CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: O=C(NCc1ccc(CNC2CCCc3cccnc32)cc1)c1ccccn1
Reactant: O=Cc1nc2ccccc2[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C(NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1)c1ccccn1

Procedure:
Reaction of pyridine-2-carboxylic acid 4-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzylamide (AMD9397) (40 mg, 0.11 mmol), 1H-benzoimidazole-2-carbaldehyde (16 mg, 0.11 mmol), and NaBH(OAc)3 (68 mg, 0.32 mmol) for 2 h at 60° C. followed by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH 198:1:1) gave AMD9401 (28 mg, 52%) as a white foam. 1H NMR (300 MHz, CD3OD) δ 1.60-1.63 (m, 1H), 1.95-2.06 (m, 2H), 2.20-2.22 (m, 1H), 2.66-2.83 (m, 2H), 3.51 (d, 1H, J=13.2 Hz), 3.58 (d, 1H, J=13.2 Hz), 3.94 (d, 1H, J=15.3 Hz), 4.04-4.09 (m, 3H), 4.42 (br s, 2H), 7.09-7.15 (m, 4H), 7.20 (dd, 1H, J=7.8, 4.8 Hz), 7.20 (d, 1H, J=8.1 Hz), 7.28 (d, 2H, J=8.1 Hz), 7.41-7.47 (m, 2H), 7.48-7.52 (m, 2H), 7.91 (ddd, 1H, J=7.5, 7.5, 1.8 Hz), 8.06 (d, 1H, J=7.8 Hz), 8.55 (d, 1H, J=4.5 Hz), 8.60 (d, 1H, J=4.5 Hz); 13C NMR (75.5 MHz, CD3OD) δ 22.84, 24.33, 30.62, 44.13, 51.41, 56.15, 63.13, 123.55, 124.03, 128.13, 128.61, 130.80, 137.39, 138.95, 139.14, 139.51, 139.67, 148.35, 150.17, 151.40, 156.31, 158.31, 166.94. ES-MS m/z 503 (M+H). Anal. Calcd. for C31H30N6O.0.8H2O.0.3CH2Cl2: C, 69.30; H, 5.98; N, 15.49. Found: C, 69.63; H, 6.14; N, 15.19.
Reaction SMILES: C(N(CC)CC)C.C([O:11][C@@H:12]1[O:29][C@H:28]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[CH:33]=2)[C@@H:23]([O:24]C(=O)C)[C@H:18]([O:19]C(=O)C)[C@H:13]1[O:14]C(=O)C)(=O)C.CO.O>C(OCC)(=O)C.ClCCl>[Br:38][C:34]1[CH:33]=[C:32]([O:31][CH2:30][C@H:28]2[O:29][C@@H:12]([OH:11])[C@H:13]([OH:14])[C@@H:18]([OH:19])[C@@H:23]2[OH:24])[CH:37]=[CH:36][CH:35]=1
Reactant: CC(=O)O[C@@H]1O[C@H](COc2cccc(Br)c2)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: O[C@@H]1[C@@H](O)[C@H](O)O[C@H](COc2cccc(Br)c2)[C@H]1O

Procedure:
Triethylamine (1 mL) was added at room temperature to 1,2,3,4-tetra-O-acetyl-6-O-(3-bromophenyl)-β-D-glucopyranose (200 mg, 0.40 mmol) dissolved in 5: I methanol-water (6 mL). The reaction progress was monitored by LCMS and TLC (20% ethyl acetate-dichloromethane). Upon completion, the solvents were removed in vacuo to afford 6-O-(3-bromophenyl)-β-D-glucopyranose which was carried on without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:3]=1.[Br:14]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:14][C:7]([C:4]1[N:3]=[C:2]([CH3:1])[O:6][N:5]=1)([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C)c1noc(C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C)(Br)c1noc(C)n1
Temperature: 25 °C

Procedure:
A carbon tetrachloride (30 mL) solution containing the intermediate from Step B (1.9 g, 10.3 mmol), N-bromosuccinimide (3.56 g, 20 mmol) and AIBN (0.1 g) was heated at reflux for 4 hours. The solution was cooled to room temperature, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. m/z=263.0 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[NH2:15][NH2:16]>CCO>[NH:15]([C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1)[NH2:16]
Reactant: CN(C)S(=O)(=O)c1ccc(Cl)nc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(NN)nc1
Temperature: 80 °C
Yield: 85.1 %

Procedure:
A mixture of 1.9 g (8.8 mmol) of 6-chloro-N,N-dimethylpyridine-3-sulfonamide and 4.6 mL (91.5 mmol) of hydrazine monohydrate in 10 mL of EtOH is heated for 2 hours at 80° C. The precipitate obtained, after cooling to room temperature, is filtered off and then washed with 10 mL of EtOH and dried under vacuum. 1.62 g of 6-hydrazino-N,N-dimethylpyridine-3-sulfonamide are obtained in the form of a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][CH:20](OC(=O)C)[C:21]2[CH:30]=[CH:29][C:28]3[C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][C:24]([CH3:34])([CH3:33])[C:23]=3[CH:22]=2)[CH:15]=[CH:14][C:3]=1[C:4]([O:6]CC1C=CC=CC=1)=[O:5].C(O)C.C(O)(=O)C>[Pd].CCCCCC>[OH:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][C:24]([CH3:34])([CH3:33])[C:23]=3[CH:22]=2)[CH:15]=[CH:14][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(=O)OC(COc1ccc(C(=O)OCc2ccccc2)c(O)c1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Pd]
Solvent: CCO
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CC1(C)CCC(C)(C)c2cc(CCOc3ccc(C(=O)O)c(O)c3)ccc21
Reaction time: 4 h
Yield: 45.3 %

Procedure:
2 g (3.89 mmol) of benzyl 2-hydroxy-4-[2-acetoxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate obtained in Example 5(a), 100 ml of ethanol, 10 ml of acetic acid and 1.2 g of palladium on charcoal (10% to 50% water) are introduced into a reactor. The mixture is hydrogenated at 70° C., under a pressure of 7 bar, for 4 hours. The catalyst is filtered and washed with ethanol, and the filtrate is evaporated. The residue obtained is taken up in hexane, filtered and dried. 650 mg (46%) of the expected product of melting point 210°-212° C. are obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)(=[O:7])=[O:6].[Cl:27][C:28]1[CH:56]=[CH:55][C:31]([O:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]3[C@@H:43]([C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:52])[F:51])[CH:45]=4)[CH2:42][NH:41][C:40]3=[O:54])=[CH:35][CH:34]=2)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([O:32][C:33]2[CH:34]=[CH:35][C:36]([N:39]3[C@@H:43]([C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:52])([F:51])[F:53])[CH:45]=4)[CH2:42][N:41]([CH2:2][CH2:3][CH2:4][S:5]([N:8]([CH2:9][C:10]4[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=4)[CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)(=[O:7])=[O:6])[C:40]3=[O:54])=[CH:37][CH:38]=2)=[CH:55][CH:56]=1
Reactant: O=C1NC[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)CCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)CCCN2C[C@H](c3cccc(C(F)(F)F)c3)N(c3ccc(Oc4ccc(Cl)cc4)cc3)C2=O)cc1
Temperature: 80 °C
Reaction time: 14 h
Yield: 82.1 %

Procedure:
To a solution of 3-chloro-N,N-bis(4-methoxybenzyl)propane-1-sulfonamide (30.0 mg, 0.075 mmol) and (S)-1-(4-(4-chloro-phenoxy)-phenyl)-5-(3-(trifluoromethyl)-phenyl)-imidazolidin-2-one (20.0 mg, 0.046 mmol) in DMF (0.8 mL) is added Cs2CO3 (22 mg, 0.069 mmol) and KI (1 mg). The resulted mixture is stirred at 80° C. for 14 h and is cooled down to room temperature. The mixture is poured into water (5 mL) and extracted with EtOAc (3×3 mL). The combined organic layers are concentrated and purified by flash column chromatography to provide (S)-3-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N,N-bis(4-methoxybenzyl)propane-1-sulfonamide (30 mg, 82%). HPLC-MS calculated for C41H39ClF3N3O6S (M+H+) 794.2, found 794.2.
Reaction SMILES: Br[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>O1CCOCC1>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:6]2[CH:5]=[N:4][C:3]([N+:8]([O-:10])=[O:9])=[CH:2][N:7]=2)[CH2:20][CH2:19]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1nccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CN1CCN(c2cnc([N+](=O)[O-])cn2)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
In a 15 mL argon dried microwave reaction vial, was added bromonitropyrazine (300 mg, 1.47 mmol., Eq: 1.00) and K2CO3 (264 mg, 1.91 mmol., Eq: 1.3) under argon to give a light yellow slurry. N-methylpiperazine (192 mg, 212 μl, 1.91 mmol, Eq: 1.3) was added dropwise and the reaction mixture became an orange yellow thick slurry. Heated to 70° C. in an oil bath for 1.5 hrs then stirred at room temperature overnight. The reaction mixture was diluted with dioxane (10 mL), filtered through a fitted funnel and washed with DCM (10 mL). The combined filtrate and washes were concentrated to dryness to give a yellow solid (328 mg, yield 89%) which was used directly in the next step.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([Br:15])[C:13]=1[OH:14])[CH:9]=[O:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:14][C:13]1[C:6]([Br:5])=[CH:7][C:8]([CH:9]=[O:10])=[CH:11][C:12]=1[Br:15]
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Br)c(OCCBr)c(Br)c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
1,2-Dibromoethane (62 mL, 0.72 moles) was added to a mixture of 3,5-dibromo-4-hydroxybenzaldehyde (10 g, 36 mmoles) and potassium carbonate (25 g, 180 mmoles) in DMF (100 ml) and the resulting mixture was stirred vigorously at 70° C. for 16 hours. After cooling, the mixture was poured into water (300 mL) and extracted with ethyl acetate (400 mL). Water (200 mL) was added to the aqueous phase and this was extracted with ethyl acetate (150 mL). The combined organic phases were washed with saturated sodium chloride (3×150 mL), dried over MgSO4 and evaporated in vacuo. The residue was dissolved in refluxing 96% ethanol (60 mL). Water (15 mL) was added and after cooling, filtration, washing with 60% ethanol and drying 10.7 g (77%) of 4-(2-bromoethoxy)-3,5-dibromobenzaldehyde was isolated in two crops. M.p. 84-85° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].Cl.Cl.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:29][CH2:28][C:27]2[C:30]3[CH:20]1[CH2:21][C:22](=[O:35])[C:23]=3[C:24]([O:33][CH3:34])=[C:25]([O:31][CH3:32])[CH:26]=2>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:29][CH2:28][C:27]2[C:30]3[CH:20]1[CH2:21][C:22](=[O:35])[C:23]=3[C:24]([O:33][CH3:34])=[C:25]([O:31][CH3:32])[CH:26]=2)(=[O:10])=[O:9]
Reactant: COc1cc2c3c(c1OC)C(=O)CC3N(CCCCN)CC2
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Product: COc1cc2c3c(c1OC)C(=O)CC3N(CCCCNS(=O)(=O)c1ccccc1Cl)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 119 %

Procedure:
2-Chlorobenzenesulfonyl chloride (92.4 mg, 0.44 mmol) was added to a solution of 3-(4-Amino-butyl)-7,8-dimethoxy-2a,3,4,5-tetrahydro-2H-3-aza-acenaphthylen-1-one dihydro-chloride (150 mg, 0.40 mmol) and NN′-diisopropylethylamine (0.400 ml) in CH2Cl2 (20 mL) and the mixture was stirred overnight at room temperature. The resulting solution was washed with water (3×20 mL), dried over Na2SO4 and evaporated to dryness. The free base was dissolved in ethyl acetate (2 ml) and A 2.8 M solution of hydrogen chloride in ethanol was then added. The product was crystallized and collected by filtration, and vacuum dried to give a pale brown solid (135 mg, 66%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[CH:25]=[C:26]([N:30]([CH3:40])[S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)(=[O:33])=[O:32])[CH:27]=[C:28]([CH3:29])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:41]=[N+:42]=[N-:43].[Na+]>CN(C)C=O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:43][N:42]=[N:41][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:25]=[C:26]([N:30]([CH3:40])[S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)(=[O:32])=[O:33])[CH:27]=[C:28]([CH3:29])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)cc(N(C)S(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2c(C)cc(N(C)S(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-butyl-4-methyl-6-(N-benzenesulphonyl-methylamino)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][CH:6]=2.[CH3:13][O:14][C:15](=[O:20])[CH:16](Cl)[S:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:13][O:14][C:15](=[O:20])[CH:16]([O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[CH:3][C:2]([Br:1])=[CH:11]2)[S:17][CH3:18]
Reactant: COC(=O)C(Cl)SC
Reactant: Oc1ccc2ncc(Br)cc2c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(Oc1ccc2ncc(Br)cc2c1)SC
Reaction time: 2 h
Yield: 89.9 %

Procedure:
3-Bromo-quinolin-6-ol (17.47 g) (preparation described in Liebigs Ann Chem., 1966, 98-106), was dissolved in dry DMF (150 ml). Chloro-methylsulfanyl-acetic acid methyl ester (18.07 g) and dry potassium carbonate (43.12 g) were added at room temperature (rt). The resulting suspension was stirred for 2 hours after which time the reaction mixture was diluted with ethyl acetate and poured onto sat. sodium hydrogen carbonate (200 ml). The two phases were separated and the aqueous layer was extracted three times with ethyl acetate (3×200 ml). The combined organic layers were dried over magnesium sulphate, filtered and evaporated. The residue was purified by column chromatography (heptane/ethyl acetate 7:3) to provide (3-bromo-quinolin-6-yloxy)-methylsulfanyl-acetic acid methyl ester as yellowish solid (24 g).