Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([F:41])([F:40])[O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:36][C:35]3[CH:38]=[CH:39][C:32]([O:31][C:30]([F:29])([F:40])[F:41])=[CH:33][CH:34]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)Oc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 4-trifluoromethoxy-benz aldehyde. MS (ESI) m/z 551.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([CH3:24])=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][C:15]([CH3:24])=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)=[O:9]
Reactant: Cc1sc(N)nc1-c1ccccc1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: Cc1sc(NC(=O)c2cc(Br)ccc2O)nc1-c1ccccc1

Procedure:
Using 5-bromosalicylic acid and 2-amino-5-methyl-4-phenylthiazole as the raw materials, the same operation as the example 16 gave the title compound. (2-Amino-5-methyl-4-phenylthiazole: refer to Yakugaku Zasshi, 1961, 81, 1456.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1.N[N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:3]=1
Reactant: CN1CCN(N)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CCO
Product: CN1CCN(Nc2cc(Cl)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.4 %

Procedure:
A mixture of 35 g of 4-chloro-1,2-dinitrobenzene and 20 g of 1-amino-4-methylpiperazine in 200 ml of 96° EtOH is stirred for 24 hours at RT. The reaction mixture is evaporated under vacuum and the residue is chromatographed on silica using a DCM/AcOEt mixture (80/20; v/v) as the eluent to give 17.5 g of the expected product after crystallization from an iso ether/heptane mixture (50/50; v/v). M.p.=108° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]([CH3:17])[CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[C:7](=[O:16])[CH2:6]1.[Cl-].[Na+]>O.C(O)C>[CH3:3][N:4]([CH3:17])[CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[CH:7]([OH:16])[CH2:6]1
Reactant: CN(C)C1CCc2ccccc2C(=O)C1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(C)C1CCc2ccccc2C(O)C1
Temperature: 20 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
A solution of 8.7 g of sodium borohydride in 87 ml of water was added to a solution of 8.7 g of the product of Step A in 435 ml of ethanol and the mixture was stirred at 20° C for 11/2 hours and was then poured into ice water. The mixture was saturated with sodium chloride and was extracted with ethyl acetate. The organic phase was washed with aqueous sodium chloride solution, was dried and evaporated to dryness to obtain 8 g of raw 7-dimethylamino-5-hydroxy-6,7,8,9-tetrahydro [5H] benzocycloheptene which was used as is for the next step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:16][O:17][C:18]1[CH:29]=[CH:28][C:21]([O:22][CH:23](Br)[CH2:24][CH2:25][CH3:26])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:16][O:17][C:18]1[CH:29]=[CH:28][C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][O:1][C:2]2[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=2)[C:6]([O:8][CH3:9])=[O:7])=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(O)cc1C(=O)OC
Reactant: CCCC(Br)Oc1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCCCCOc2ccc(OC)cc2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 72.1 %

Procedure:
21.0 g (0.1 mol) of dimethyl 4-hydroxyphthalate, 25.9 g (0.1 mol) of p-methoxyphenoxy-l-bromobutane and 100 ml of acetonitrile were put in a 300-ml three-neck flask, and 6.91 g of potassium carbonate was added in three divided portions at two-hour intervals at 70° to 80° C. The reaction system was stirred further for 7 hours under reflux. The system was cooled to room temperature, and the salts formed and acetonitrile were taken out by filtration and distillation, respectively. Ethyl acetate and water were added to the residue, which was then washed well with water. Ethyl acetate was removed by distillation, and the residue was recrystallized from a mixed solvent of hexane/ethyl acetate (6/4, v/v). 28.0 g of the intended product was obtained, having a melting point of 68° C. The yield was 72.0%.
Reaction SMILES: [NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[C:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]1[NH:19][C:20](=[N:23][C:24]([O:26][CH3:27])=[O:25])[S:21][CH3:22].ClC1C=C(C=CC=1)C(OO)=[O:33]>C(Cl)Cl>[NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH3:11])=[O:33])=[C:4]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:3]1[NH:19][C:20](=[N:23][C:24]([O:26][CH3:27])=[O:25])[S:21][CH3:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCSC1=C(Cc2ccccc2)C(NC(=NC(=O)OC)SC)C(=N)C=C1
Solvent: ClCCl
Product: CCCS(=O)C1=C(Cc2ccccc2)C(NC(=NC(=O)OC)SC)C(=N)C=C1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-iminophenylmethyl-2-(3-carbomethoxy-S-methylisothioureido)-4-n-propylthiobenzene (4.02 g.; 0.01 mol) in methylene chloride (50 ml.), cooled to -5° C., is added 85% of m-chloroperoxybenzoic acid (2.02 g.; 0.01 mol). The mixture is stirred at -5° C. for 30 minutes and is washed with aqueous sodium bicarbonate solution. The methylene dichloride is evaporated from the organic solution to afford 1-iminophenylmethyl-2-(3-carbomethoxy-S-methylisothioureido)-4-n-propylsulfinylbenzene.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:32][C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)[CH:11]2[CH2:16][CH2:15][N:14]([C@H:17]([CH3:31])[CH2:18][CH2:19][NH:20][C:21]([C:23]3[C:24]([CH3:30])=[N:25][CH:26]=[N:27][C:28]=3[CH3:29])=[O:22])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[O:39]([NH2:41])[CH3:40].CC([O-])=O.[Na+]>CO>[CH3:40][O:39][N:41]=[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:32][C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)[CH:11]2[CH2:16][CH2:15][N:14]([C@H:17]([CH3:31])[CH2:18][CH2:19][NH:20][C:21]([C:23]3[C:24]([CH3:30])=[N:25][CH:26]=[N:27][C:28]=3[CH3:29])=[O:22])[CH2:13][CH2:12]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CON
Reactant: CC(=O)c1ccc(N(Cc2ccsc2)C2CCN([C@H](C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CON=C(C)c1ccc(N(Cc2ccsc2)C2CCN([C@H](C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of COMPOUND 293 in MeOH (3 mL) were added methoxylamine hydrochloride (15 mg, 0.18 mmol) followed by NaOAc (14 mg, 0.17 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 294 as a clear oil (31 mg, 82%) after work-up and purification. 1H NMR (CDCl3) δ 0.95-1.17 (m, 2H), 1.02 (d, 3H, J=6.6 Hz), 1.52-1.58 (m, 1H), 1.74-1.79 (m, 3H), 2.14 (s, 3H), 2.17 (t, 1H, J=11.7 Hz), 2.52 (s, 6H), 2.57 (t, 1H, J=11.4 Hz), 2.73-2.89 (m, 3H), 3.28-3.36 (m, 1H), 3.59-3.68 (m, 1H), 3.88 (s, 3H), 3.94 (s, 3H), 6.60 (d, 2H, J=9.0 Hz), 6.98-7.03 (m, 2H), 7.28 (dd, 1H, J=4.8, 3.0 Hz), 7.45 (d, 2H, J=9.0 Hz), 8.71 (br s, 1H), 8.89 (s, 1H). ES-MS m/z 549 (M+H).
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][C:7]2[NH:8][C:9]3[S:10][C:11]4[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=4[C:13]=3[C:14]([NH2:16])=[N:15][C:6]=2[CH:5]=1.[CH3:25][O:26][CH2:27][CH2:28][C@H:29]1[CH2:34]N[CH2:32][CH2:31][NH:30]1.C(N(C(C)C)CC)(C)C>CS(C)=O.C1(C)C=CC=CC=1.C(OCC)(=O)C.[OH-].[Na+]>[CH3:25][O:26][CH2:27][CH2:28][C@@H:29]1[NH:30][CH2:31][CH2:32][N:16]([C:14]2[C:13]3[C:12]4[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=4[S:10][C:9]=3[NH:8][C:7]3[CH:21]=[CH:22][C:4]([C:3]([F:2])([F:23])[F:24])=[CH:5][C:6]=3[N:15]=2)[CH2:34]1
Reactant: COCC[C@H]1CNCCN1
Reactant: NC1=Nc2cc(C(F)(F)F)ccc2Nc2sc3ccccc3c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COCC[C@H]1CN(C2=Nc3cc(C(F)(F)F)ccc3Nc3sc4ccccc4c32)CCN1
Temperature: 25 °C
Reaction time: 45 h
Yield: 35.9 %

Procedure:
Add 8-trifluoromethyl-11H-12-thia-6,11-diaza-dibenzo[a,f]azulen-5-ylamine hydrochloride (0.75 g, 2.0 mmol) to a solution of (S)-2-(2-methoxy-ethyl)-piperazine (0.58 g, 4.1 mmol) in dimethyl sulfoxide: toluene (1:8, 0.2M). Add diisopropylethylamine (1 equiv), heat to 110° C., and stir. After 45 hours, cool to ambient temperature, and dilute with ethyl acetate and 0.1 N NaOH. Separate the aqueous layer and extract it with ethyl acetate (3×). Wash all organics with a saturated solution of sodium chloride, and then dry (sodium sulfate), filter, and concentrate them under reduced pressure. Purify the oil by flash chromatography, eluting with a gradient of a 3% solution of 2M ammonia in methanol, in dichloromethane (0-100% in dichloromethane). Reconstitute the material in ethyl acetate and wash it with a saturated solution of sodium chloride (2×) to remove residual dimethylsulfoxide. Back extract the combined aqueous layers with ethyl acetate. Dry (sodium sulfate) the organic phases, filter, and concentrate them under reduced pressure to give the title compound (0.331 g). Mass spectrum (APCI+, m/e): 461 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]3[CH:13]=[C:14]([NH:22][CH:23]([CH3:28])[C:24]([O:26]C)=[O:25])[CH:15]=[N:16][C:17]=3[O:18][CH2:19][CH2:20][CH3:21])=[N:6][C:5]=2[C:4]([CH2:29][CH2:30][CH3:31])=[N:3]1.[OH-].[Na+]>CO.O.Cl>[CH3:1][N:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]3[CH:13]=[C:14]([NH:22][C@H:23]([C:24]([OH:26])=[O:25])[CH3:28])[CH:15]=[N:16][C:17]=3[O:18][CH2:19][CH2:20][CH3:21])=[N:6][C:5]=2[C:4]([CH2:29][CH2:30][CH3:31])=[N:3]1
Reactant: CCCOc1ncc(NC(C)C(=O)OC)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCOc1ncc(N[C@@H](C)C(=O)O)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The title compound of Example 83 in methanol (5 mL) was treated with a solution of sodium hydroxide (64 mg, 1.6 mmol) in water (2 mL) and the reaction mixture stirred at room temperature for 14 h. After concentration of the reaction mixture in vacuo, water (5 mL) was added and the solution acidified with conc. hydrochloric acid (5 drops) to afford a white precipitate, which was removed by filtration, and dried in vacuo to give the title compound as an off-white solid (180 mg, 0.43 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[F:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.N>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][C:19]=2[OH:23])=[O:10])=[CH:4][CH:3]=1
Reactant: Oc1cccc(F)c1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: N
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)cc1)c1ccc(F)cc1O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-chlorophenylacetyl chloride (27.6 g, 0.15 mol) in 1,2-dichloroethane (200 ml), cooled to 0° C. in an ice bath, under nitrogen is added slowly AlCl3 (21.8 g, 0.16 mol). The reaction mixture is stirred at 0° C. for 20 min. 3-fluorophenol (12.2 g, 0.11 mol) is added, and the reaction mixture is allowed to warm to room temperature, then heated at 90° C. for 16 h. The reaction mixture is cooled to room temperature, then poured cautiously into aqueous ammonia solution (500 ml) with vigourous stirring. The mixture is diluted with CH2Cl2 (250 ml) and filtered through Celite. The organic phase is separated, washed with water, brine and dried (MgSO4). The solvent is removed in vacuo, and the crude product is purified by flash chromatography on silica gel using iso-hexane:ethyl acetate (10:1 to 4:1) as the eluent to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[CH3:19][C:20]([OH:32])([C:22]([CH3:31])([CH3:30])[CH2:23][CH2:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[CH3:21]>>[CH3:21][C:20]([OH:32])([C:22]([CH3:31])([CH3:30])[CH2:23][CH2:24][C:25]1[S:26][C:27]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:28][CH:29]=1)[CH3:19]
Reactant: CC(C)(O)C(C)(C)CCc1cccs1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Product: CC1(C)CC(Nc2nccc(-c3ccc(CCC(C)(C)C(C)(C)O)s3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared analogous to Method C, starting from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 2,3,3-trimethyl-5-thiophen-2-yl-pentan-2-ol from Step A.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH:34]1[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[CH:34]1([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:32])=[O:33])[CH2:36][CH2:35]1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)C1CC1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)C3CC3)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-bromo-2-(cyclopropylsulfonyl)benzene. MS (ESI): mass calcd. for C19H16FN3O2S, 369.09; m/z found, 370.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.55-8.49 (m, 1H), 8.33 (s, 1H), 8.13 (dd, J=8.0, 1.2, 1H), 8.11-8.05 (m, 1H), 7.77 (m, 1H), 7.68 (m, 1H), 7.48 (dd, J=7.6, 1.1, 1H), 7.43-7.36 (m, 2H), 2.35-2.26 (m, 1H), 1.04-0.91 (m, 4H).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]1[CH:11]=[C:12]([CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[C:14]([CH3:16])[CH:15]=1.CC(N=NC(C#N)(C)C)(C#N)C>C(OCC)(=O)C>[Br:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)cc(CC(=O)O)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: Cc1cc(CBr)cc(CC(=O)O)c1

Procedure:
NBS (3.12 g) was added portionwise over 1 hour to a solution of 2-(3,5-dimethylphenyl)acetic acid (3.6 g) and AIBN (0.015 g) in ethyl acetate (100 mL) at 50° C. under nitrogen. More AIBN (0.015 g) was added and the mixture was heated to reflux for 3 hours. The reaction mixture was washed with 10% aqueous sodium chloride solution (2×200 mL), dried over magnesium sulphate, filtered and evaporated. The crude material was purified by flash silica chromatography using 20% ethyl acetate in isohexane containing 1% acetic acid as solvent. Fractions containing the product were evaporated to dryness to afford a solid which was triturated with cyclohexane (10 mL) to yield the subtitled compound as a white solid. Yield 2.10 g.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:49]=[N+:50]=[N-:51])(=O)=O)(C)C.C(O)(=O)C>C1COCC1>[CH3:20][O:19][C:17](=[O:18])[CH:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2])=[CH:15][CH:14]=1)[N:49]=[N+:50]=[N-:51]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: COC(=O)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C(N=[N+]=[N-])c1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
A solution of methyl 4-(N-BOC-aminomethyl)phenylacetate (9.34 g; 0.033 mol) in THF (100 mL) was stirred under argon at −78° C. and potassium bis(trimethylsilyl)amide (16.7 g, 0.084 mol) in THF (50 mL) was added. After stirring for 30 minutes, 2,4,6-triisopropylbenzene-sulfonyl azide (31.1 g, 0.101 mol) was added as a solid. After 5 minutes, acetic acid (10 mL, 0.175 mol) was added and the reaction warmed to room temperature. The reaction mixture was then partitioned between ethyl acetate (500 mL) and water (500 mL), separated and the organic layer dried (MgSO4). Evaporation of the solvent and purification of the residue by silica gel chromatography afforded the azide (7.1 g, 67%).
Reaction SMILES: [CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[F:15])[CH2:2][CH2:3][CH3:4].C(Cl)Cl>[Pd].CO>[CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[F:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CCCCN(CCCC)c1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a solution of N,N-di-n-butyl-2-fluoro-4-nitroaniline (4.03 g, 15 mmol) in mixed solvents of CH2Cl2 (70 mL) and MeOH (20 mL) was added catalyst Pd/C (0.40 g). The reaction mixture was stirred at rt under H2 overnight, and filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/CH2Cl2 (V/V)=8:1) to give the title compound as colorless oil (2.32 g, 65%).
Reaction SMILES: C[Si](Cl)(C)C.BrCCBr.C([N:17]1[CH2:20][CH:19](I)[CH2:18]1)(OC(C)(C)C)=O.Br[C:23]1[CH:24]=[C:25]([N:34]([CH2:41][CH3:42])[CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[C:26]([CH3:33])=[C:27]([CH:32]=1)[C:28]([O:30][CH3:31])=[O:29].C(Cl)Cl.[NH4+].[Cl-]>CC(N(C)C)=O.[Zn].[Cu]I.O>[NH:17]1[CH2:18][CH:19]([C:23]2[CH:24]=[C:25]([N:34]([CH2:41][CH3:42])[CH:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)[C:26]([CH3:33])=[C:27]([CH:32]=2)[C:28]([O:30][CH3:31])=[O:29])[CH2:20]1
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Solvent: BrCCBr
Solvent: O
Solvent: ClCCl
Product: CCN(c1cc(C2CNC2)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 65 °C
Yield: 128.8 %

Procedure:
To a dry flask was added zinc dust (186 mg, 2.85 mmol) and the flask was heated using a heat gun for a few minutes. Then anhydrous DMA (15 ml) was added under nitrogen whilst stirring vigorously and heating to 65° C. TMSCl (44 μl, 0.34 mmol) and 1,2-dibromoethane (30 μl, 0.34 mmol) were added and the reaction was stirred at 65° C. for 30 mins followed by the dropwise addition of N-Boc-3-iodoazetidine (624 mg, 2.20 mmol) as a solution in anhydrous DMA (5 ml). The reaction was then cooled to room temperature methyl 5-bromo-3-[ethyl(oxan-4-yl)amino]-2-methylbenzoate (470 mg, 1.32 mmol) was added as a solution in anhydrous DMA (10 ml). The resulting solution was degassed with nitrogen for 10 mins after which Pd(dppf)Cl2.DCM (32 mg, 0.04 mmol) and copper (I) iodide (15 mg, 0.08 mmol) were added as solids. The reaction was heated to 80° C. for 60 min and then cooled to room temperature followed by the addition of distilled water (50 ml) and saturated NH4Cl solution (10 ml). The aqueous phase was extracted with EtOAc (3×50 ml) and then the combined organics were washed with brine (20 ml), dried with Na2SO4, filtered and evaporated to dryness followed by heptane azeotrope to remove any residual DMA. The residue was purified over a 10 g Isolute column using 0%-25% EtOAc in heptane as the eluent to afford the title compound as a pale brown oil (565 mg). LC-MS 100%, 2.12 min (3.5 minute LC-MS method), m/z=433.2. To this oil was added DCM (4 ml) followed by TFA (1 ml) and the solution was stirred at room temperature for 2 h after which the solvent was evaporated and saturated aqueous NaHCO3 was added until pH7-8. The aqueous phase was extracted with DCM (3×30 ml), washed with brine (30 ml), dried with MgSO4, filtered and evaporated to afford the title compound yellow oil (440 mg). LC-MS 100%, m/z=333.1.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([S:11]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH3:26])[C:17]([CH3:28])([CH3:27])[CH:16]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].C(N1C2C(=CC=[C:38]([O:41]C)C=2)C(CS(Cl)(=O)=O)=CC1(C)C)C>C(#N)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([S:11]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:41][CH3:38])=[CH:22][CH:23]=3)[N:18]([CH2:25][CH3:26])[C:17]([CH3:27])([CH3:28])[CH:16]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: CCN1c2ccccc2C(CS(=O)(=O)N2CCC(C(=O)OC)CC2)=CC1(C)C
Reactant: CCN1c2cc(OC)ccc2C(CS(=O)(=O)Cl)=CC1(C)C
Solvent: CC#N
Product: CCN1c2cc(OC)ccc2C(CS(=O)(=O)N2CCC(C(=O)OC)CC2)=CC1(C)C
Yield: 69 %

Procedure:
(1-Ethyl-7-methoxy-2,2-dimethyl-1,2-dihydroquinol-4-yl-methanesulfonyl)-piperidine-4-carboxylic acid methyl ester (17) is prepared similarly to compound (10) from compound (16) in dry acetonitrile at room temperature.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[CH3:16][N:17]([CH3:28])[CH2:18][CH2:19][O:20][C:21]1[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:27][C:24]1[CH:25]=[N:26][C:21]([O:20][CH2:19][CH2:18][N:17]([CH3:28])[CH3:16])=[CH:22][CH:23]=1
Reactant: CN(C)CCOc1ccc(N)cn1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(OCCN(C)C)nc1
Yield: 43.8 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (170 mg, 0.71 mmol) was reacted with 6-[2-(dimethylamino)ethoxy]pyridin-3-amine (160 mg, 0.90 mmol) to afford the desired product (120 mg, 44%) as a light brown solid: 1H NMR (500 MHz, CDCl3) δ 11.63 (br s, 1H), 9.08 (s, 1H), 8.11 (d, J=8.8 Hz, 1H), 7.99 (d, J=2.7 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.41 (dd, J=8.8, 2.8 Hz, 1H), 6.80 (d, J=8.7 Hz, 1H), 4.46 (t, J=5.6 Hz, 2H), 2.76 (t, J=5.6 Hz, 2H), 2.74 (s, 3H), 2.36 (s, 6H); ESI MS m/z 386 [M+H]+
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:7]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)[N:6]=1)=[O:4].[OH-].[K+].CO>O>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([N:7]2[CH:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[CH2:9][C:5]([C:3]([OH:4])=[O:2])=[N:6]2)=[CH:18][CH:19]=1
Reactant: COC(=O)C1=NN(c2ccc(Br)cc2)C(c2ccccc2Cl)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1=NN(c2ccc(Br)cc2)C(c2ccccc2Cl)C1
Temperature: 100 °C
Reaction time: 12 h
Yield: 105.4 %

Procedure:
1-(4-Bromo-phenyl)-5-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid methyl ester (5.3 g, 13.5 mmol) prepared in Step 3 and a solution of potassium hydroxide (2.0 g, 35.6 mmol) in distilled water (25.0 mL) were added to methanol (25.0 mL). The reaction mixture was stirred at 100° C. for 12 hours and then concentrated under reduced pressure to discard methanol. The resulting residue was washed with diethyl ether, acidified by a 1N hydrochloric acid solution, and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 5.4 g of the titled compound as a white solid.