Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[Cl:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[S:40]([NH2:43])(=[O:42])=[O:41]>>[Cl:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[S:40]([NH:43][C:23]([NH:22][CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([N:4]2[C:5]([CH3:13])=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:2]([CH3:1])=[N:3]2)=[CH:19][CH:18]=1)=[O:24])(=[O:41])=[O:42]
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: NS(=O)(=O)c1ccc(F)cc1Cl
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(F)cc3Cl)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 2-chloro-4-fluorobenzenesulfonamide: 1H-NMR (CDCl3) δ 8.12-8.07 (1H, m), 7.46-7.04 (11H, m), 6.29 (1H, br.s), 3.42-3.36 (2H, m), 2.79-2.75 (2H, m), 2.29 (3H, s), 2.21 (3H, s).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]2[O:19][C:18]([N:20]3[CH:26]4[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]4)[CH2:22][CH2:21]3)=[N:17][C:14]2=[N:15][CH:16]=1>>[C:1]1([C:11]2[CH:12]=[C:13]3[O:19][C:18]([N:20]4[CH:26]5[CH2:25][CH2:24][N:23]([CH2:28][CH2:27]5)[CH2:22][CH2:21]4)=[N:17][C:14]3=[N:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cnc2nc(N3CCN4CCC3CC4)oc2c1
Product: c1ccc(-c2cnc3nc(N4CCN5CCC4CC5)oc3c2)cc1
Yield: 27 %

Procedure:
The title compound was prepared according to the procedure detailed in Example 44 using phenyl boronic acid and 4-(6-bromo-oxazolo[4,5-b]pyridin-2-yl)1,4-diaza-bicyclo[3.2.2]nonane (prepared in Example 47) in 27% yield: 1H NMR (CDCl3, 400 MHz) δ 8.48 (d, 1H, J=2.1 Hz), 7.62 (d, 1H, J=2.1 Hz), 7.57-7.55 (m, 2H), 7.47-7.43 (m, 2H), 7.40-7.34 (m, 1H), 4.62 (br s, 1H), 4.00 (t, 2H, J=5.8 Hz), 3.20-3.15 (m, 4H), 3.08-3.01 (m, 2H), 2.19-2.08 (m, 2H), 1.90-1.81 (m, 2H); MS (Cl) m/z 321.2 (M+1).
Reaction SMILES: N1C=CC=CC=1S[S:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH-:15][CH:16]=[CH:17][CH:18]=1)=[O:13].[CH-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.[Fe+2:24].C(S)[C@@H](O)[C@H](O)CS.CCN(CC)CC>CO>[SH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH-:18][CH:17]=[CH:16][CH:15]=1)=[O:13].[CH-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.[Fe+2:24]
Reactant: O=C(NCCSSc1ccccn1)c1ccc[cH-]1
Agent: [Fe+2]
Agent: O[C@H](CS)[C@H](O)CS
Agent: c1cc[cH-]c1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(NCCS)c1ccc[cH-]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.8 %

Procedure:
To a solution of 12 (113 mg, 0.28 mmol) dissolved in 6 mL of MeOH was added DTT (438 mg, 2.8 mmol) and Et3N (79 mL, 0.57 mmol). The solution was stirred at room temperature for 18 h, followed by evaporation of the solvent. The residue was dissolved in 15 mL of EtOAc and rinsed with H2O (8×15 mL) to remove excess DTT. After drying over MgSO4 and concentrating, the residue was purified by flash chromatography (hexanes/EtOAc, 1:1, v/v) to afford 46 mg (57%) of 13. 1H NMR 400 MHz (CDCl3) d 6.16 (br s, 1H), 4.66 (t, J=1.8 Hz, 2H), 4.33 (t, J=1.8 Hz, 2H), 4.19 (s, 5H), 3.53 (q, J=6.4 Hz, 2H), 2.75 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])=[C:22]([F:31])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([CH3:32])[CH:3]=1.Cl.[NH2:34][OH:35].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])=[C:22]([F:31])[CH:21]=2)[CH2:9]/[C:10](=[N:34]\[OH:35])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([CH3:32])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(OS(C)(=O)=O)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(OS(C)(=O)=O)c(F)c1

Procedure:
In analogy to example 151, step 3, methanesulfonic acid 4-[1-(4-chloro-2-methyl-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-2-fluoro-phenyl ester was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid, MS (ESI+): m/z=493.1 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]2[S:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=2)[C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][N:8]=1)=[O:5])[CH3:2].I[C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]([CH2:42][CH2:43][O:44][CH3:45])[CH:37]=[C:36]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[C:35]2=[O:51].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[N:8]=[CH:9][C:10]([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[N:38]([CH2:42][CH2:43][O:44][CH3:45])[CH:37]=[C:36]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[C:35]3=[O:51])=[C:11]([C:13]2[S:14][CH:15]=[C:16]([C:18]([F:19])([F:20])[F:21])[N:17]=2)[CH:12]=1)[CH3:2]
Reactant: CCOC(=O)c1cn(CCOC)c2ccc(I)cc2c1=O
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3CCOC)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
1-Ethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-2-yl)urea (0.171 g, 0.39 mmol, Intermediate 17), ethyl 6-iodo-1-(2-methoxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.155 g, 0.39 mmol, Intermediate 20), cesium carbonate (0.214 g, 0.66 mmol, Aldrich) and tris(dibenzylideneacetaone)palladium (0) (0.035 g, 0.04 mmol, Aldrich) or tetrakis(triphenylphosphine)palladium (0) (5 mol %, Strem) were combined in dioxane (2 mL)/water (0 mL) and heated to 100° C. The reaction mixture was stirred for 1 h. The reaction mixture was cooled to room temperature and then placed in an ice-bath. The resulting precipitate was collected by filtration and dried under vacuum to provide the desired product (0.090 g).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)[C:13](=[O:26])[CH:12]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.[N:27]1([C:32]2[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=2)[CH:31]=[CH:30][CH:29]=[N:28]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:20]1([CH2:19][CH2:18][CH2:17][N:14]2[CH:15]=[CH:16][C:11]([C:9]3[CH:8]=[N:7][N:6]4[C:2]([C:36]5[CH:35]=[CH:34][CH:33]=[C:32]([N:27]6[CH:31]=[CH:30][CH:29]=[N:28]6)[CH:37]=5)=[CH:3][N:4]=[C:5]4[CH:10]=3)=[CH:12][C:13]2=[O:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=c1cc(-c2cnn3c(Br)cnc3c2)ccn1CCCN1CCCCC1
Reactant: OB(O)c1cccc(-n2cccn2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=c1cc(-c2cnn3c(-c4cccc(-n5cccn5)c4)cnc3c2)ccn1CCCN1CCCCC1
Temperature: 120 °C

Procedure:
4-(3-Bromo-imidazo[1,2-b]pyridazin-7-yl)-1-(3-piperidin-1-yl-propyl)-1H-pyridin-2-one (1.0 eq, 0.096 mmol, 40 mg), [3-(1H-pyrazol-1-yl)phenyl]boronic acid (1.50 eq, 0.144 mmol, 28.5 mg) and Na2CO3 (2.0 eq, 0.192 mmol, 20.4 mg) are dissolved in DME/H2O (3/1 ml) and PdCl2(PPh3)2 (0.1 eq, 0.0096 mmol, 6.74 mg) is added. The reaction mixture is then heated in a microwave at 120° C. for 10 min. At the completion of this time the solvent is removed in vacuo and the product is purified by flash column chromatography eluting with CH2Cl2/MeOH (80:20) to give 1-(3-piperidin-1-yl-propyl)-4-[3-(3-pyrazol-1-yl-phenyl)imidazo[1,2-b]pyridazin-7-yl]-1H-pyridin-2-one as a yellow solid; [M+H]+=480
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.F[C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][C:42]=1[CH3:43])[C:38]#[N:39]>>[CH3:43][C:42]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][C:35]=1[N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1
Reactant: Cc1ccc(C#N)cc1F
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)cc1-n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 120 °C

Procedure:
To a mixture of 4-(1H-pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-d]-pyridine (0.050 g, 0.00016 mol) (see, Example 231, Step 1) and cesium carbonate (0.10 g, 0.00032 mol) in dry DMF (1.0 mL, 0.013 mol) was added 3-fluoro-4-methylbenzonitrile (0.043 g, 0.00032 mol). The reaction mixture was heated in sealed tube to 120° C. for 5.5 hours. The reaction was allowed to cool and partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated to give 4-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]benzonitrile as a crude product, LC/MS (M+H)+: 430.
Reaction SMILES: [NH2:1][CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH3:15][N:16]([CH3:30])[C:17]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:13]1[C:14]2[CH:2]([NH:1][CH:20]3[CH2:19][CH2:18][C:17]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)([N:16]([CH3:30])[CH3:15])[CH2:22][CH2:21]3)[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: NC1c2ccccc2-c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)C1(c2ccccc2)CCC(NC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.5 %

Procedure:
9-Aminofluorene (362 mg, 2 mmol) and 4-dimethylamino-4-phenylcyclohexanone (434 mg, 2 mmol) were dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (2 mmol) and sodium triacetoxyborohydride (600 mg) were added to this mixture and the mixture was stirred for 24 hours at RT. For working up, the mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (5×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product was chromatographed over silica gel with ethyl acetate/ethanol (1:1). 440 mg N′-(9H-fluoren-9-yl)-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained as a white solid which, for preparation of the hydrochloride, was dissolved in 2-butanone (10 ml), and 1.85 M ethanolic HCl (1.55 ml) was added. The mixture of N′-(9H-fluoren-9-yl)-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride obtained was filtered off with suction and dried (460 mg, m.p. 202-205° C.).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[N+](C1C=C(S(O[CH2:22][C@@H:23]2[CH2:25][O:24]2)(=O)=O)C=CC=1)([O-])=O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:22][CH:23]2[CH2:25][O:24]2)=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: Cc1ccc(O)cn1
Product: Cc1ccc(OCC2CO2)cn1

Procedure:
The title compound was prepared from 6-methyl-3-pyridinol and (2S)-oxiranylmethyl 3-nitrobenzenesulfonate in substantially the same manner as described in Example 123. The product was obtained as a brown oil; 1H NMR (400 MHz, DMSO-d6) δ 2.38 (s, 2.38, 1H), 2.68-2.70 (m, 1H), 2.81-2.84 (m, 1H), 3.30-3.34 (m, 1H), 3.83-3.87 (m, 1H), 4.34-4.38 (m, 1H), 7.15-7.17 (m, 1H), 7.28-7.31 (m, 1H), 8.15-8.16m (m, 1H); MS (ES) m/z: 165 (M)+.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH:12]=O)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2].[S:14]1[CH2:18][C:17](=[O:19])[NH:16][C:15]1=[O:20]>>[CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH:12]=[C:18]1[S:14][C:15](=[O:20])[NH:16][C:17]1=[O:19])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCc1[nH]c2ccccc2c1C=O
Reactant: O=C1CSC(=O)N1
Product: CCc1[nH]c2ccccc2c1C=C1SC(=O)NC1=O

Procedure:
2-Ethylindole-3-carbaldehyde (170 mg) was treated with thiazolidine-2,4-dione using the general procedure (C) to afford the title compound (50 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:12])[S:9][C:10]=1[NH2:11])=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.Br[C:56]1[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:12])[S:9][C:10]=1[NH:11][C:56]1[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=1)=[O:5])[CH3:2]
Reactant: Brc1cccnc1
Reactant: CCOC(=O)c1nc(C)sc1N
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(C)sc1Nc1cccnc1
Yield: 63.3 %

Procedure:
A Schlenck flask was charged with 5-amino-2-methyl-thiazole-4-carboxylic acid ethyl ester (0.33 g, 1.80 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.15 g, 0.26 mmol) and palladium dibenzylideneacetone (Pd2dba3)-chloroform complex (0.08 g, 0.08 mmol). Degassed dioxane (6.00 ml) was added, followed by 3-bromopyridine (0.23 g, 1.50 mmol). The flask was subjected to 5 cycles of evacuation and backfiring with argon. The reaction mixture was then transferred under argon to a microwave vial containing cesium carbonate (0.84 g, 2.60 mmol). The vial was then irradiated in a microwave oven at 150° C. for 10 min. The mixture was diluted with THF and the solids filtered, washing with THF. The filtrate was evaporated and the residue purified by flash chromatography (ethyl acetate/methanol) to yield 2-methyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester (0.25 g, 65%) as a light yellow solid, MS (ISP): m/e=264.1 (M+H+).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][NH:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:22]=[CH:23][CH:24]=2)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:3][CH:2]=1.[Cl:31][C:32]1[C:33]([OH:43])=[C:34]([S:39](Cl)(=[O:41])=[O:40])[CH:35]=[C:36]([Cl:38])[CH:37]=1.CCN(CC)CC>C(Cl)Cl>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]([CH2:9][C:10]2[CH:11]=[C:12]([CH:22]=[CH:23][CH:24]=2)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[S:39]([C:34]2[CH:35]=[C:36]([Cl:38])[CH:37]=[C:32]([Cl:31])[C:33]=2[OH:43])(=[O:40])=[O:41])=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: CC(C)(C)OC(=O)NCc1cccc(CNCc2ccc(-c3ccccc3)cc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cccc(CN(Cc2ccc(-c3ccccc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Reaction time: 1.5 h
Yield: 73.7 %

Procedure:
To a solution of tert-butyl 3-((biphenyl-4-ylmethylamino)methyl)benzylcarbamate (2.42 g, 6.01 mmol) in CH2Cl2 (30.0 mL) was added a solution of 3,5-dichloro-2-hydroxybenzene-1-sulfonyl chloride (1.65 g, 6.31 mmol) in CH2Cl2 (8.0 mL) at ice bath temperature followed by Et3N (2.5 mL, 18.0 mmol). The reaction mixture was stirred at ice bath temperature for 1.5 h and concentrated in vacuo. The residue was purified by flash chromatography on SiO2 eluting with CH2Cl2 to 8% of ethyl acetate in CH2Cl2 to give the product as a white glassy solid (2.78 g, 72.5%). 1H NMR (CDCl3): δ 9.18 (bs, 1H), 7.59-7.38 (m, 9H), 7.28-7.21 (m, 4H), 7.06 (m, 2H), 4.48 (s, 2H), 4.43 (s, 2H), 4.25 (s, 2H), 1.49 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[F:13][C:14]([F:21])([F:20])[C:15](=O)[CH2:16][C:17]#[N:18]>C1(C)C=CC=CC=1>[F:13][C:14]([F:21])([F:20])[C:15]1[CH:16]=[C:17]([NH2:18])[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:11])([F:12])[F:1])[N:10]=1
Reactant: NNc1ccccc1C(F)(F)F
Reactant: N#CCC(=O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Nc1cc(C(F)(F)F)nn1-c1ccccc1C(F)(F)F
Reaction time: 5 h
Yield: 62.1 %

Procedure:
A solution of 2-trifluoromethyl-phenylhydrazine (1.1 g, 6.3 mmol) and 4,4,4-trifluoro-3-oxobutyronitrile (0.82 g, 6.0 mmol) in toluene (3 mL, anhyd.) was heated at reflux. After 5 h the reaction mixture was allowed to cool, concentrated and purified by chromatography (silica, EtOAc/Hex, 0:100 to 25:75) to yield the title compound (1.1 g, 61%) as an amber liquid. 1H-NMR (CD2Cl2): δ 8.40 (1H, br s), 7.77 (1H, d), 7.59 (2H, m), 7.17 (1H, m), 3.56 (2H, s); Rf 0.45 (20% EtOAc/Hex).
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([C:33]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([F:43])[CH:36]=2)=O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH3:23]>C1COCC1>[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([C:33]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([F:43])[CH:36]=2)=[CH:9][C:10]#[N:11])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH3:23]
Reactant: CCOc1cc(C(=O)c2ccc(OC)c(F)c2)ccc1OC
Reactant: CCOP(=O)(CC#N)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1cc(C(=CC#N)c2ccc(OC)c(F)c2)ccc1OC
Temperature: 0 °C
Yield: 66.2 %

Procedure:
To a stirred solution of cyanomethylphosphonic acid diethyl ester (0.38 mL, 2.4 mmol) in THF (8 mL) in an ice bath was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 2.3 mL, 2.3 mmol) dropwise. The mixture was stirred at room temperature for 40 min. (3-Ethoxy-4-methoxy-phenyl)-(3-fluoro-4-methoxy-phenyl)-methanone (0.35 mg, 1.2 mmol) was added to the mixture. The mixture was refluxed overnight. The solution was poured into ice water (30 ml). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers was washed with water (50 mL), sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent and chromatography (Silica Gel) gave a mixture of (E/Z) 3-(3-ethoxy-4-methoxy-phenyl)-3-(3-fluoro-4-methoxy-phenyl)-acrylonitrile as an off-white solid (0.26 g, 69% yield) (isomer ratio is 1:0.8 by HNMR): mp: 122-124° C.; 1H NMR (DMSO-d6) δ 1.31 (t, J=7 Hz, 3H, CH3), 3.78 (s, 3H, CH3), [4.83 and 3.87 (2s)], 3.94 (s, 3H, CH3), 4.01 (q, J=7 Hz, 2H, CH2), [6.15 (s)], 6.21 (s, 1H, CH), 6.74 (dd, J=2, 8 Hz, 1H, Ar), 6.92-7.36 (m, 5H, Ar); 13C NMR (DMSO-d6) δ 14.56, 14.58, 55.49, 56.08, 56.16, 63.84, 93.60, 93.82, 111.39, 111.59, 112.07, 113.53, 113.65, 113.75, 115.34, 115.64, 116.69, 116.99, 118.56, 122.27, 122.33, 125.70, 125.74, 120.22, 126.27, 128.84, 129.59, 129.70, 130.12, 130.86, 130.96, 147.47, 147.89, 148.12, 148.28, 148.88, 149.04, 149.18, 150.27, 151.18, 152.79, 153.06, 159.99, 160.09; Anal. Calcd for C19H18NO3F: C, 69.71; H, 5.54; N, 4.28. Found: C, 69.55; H, 5.58; N, 4.25.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]1.CCN(C(C)C)C(C)C>C(O)CCC>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:12]1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2[N+](=O)[O-])C1
Yield: 98 %

Procedure:
To a 20 mL microwave vial containing 4-chloro-3-nitropyridine (Aldrich, 1.350 g, 8.515 mmol) and tert-butyl (3S)-piperidin-3-ylcarbamate (Combi-Blocks, 1.922 g, 9.597 mmol), 1-butanol (13.0 mL) was added, followed by DIPEA (2.213 g, 17.12 mmol). The reaction mixture was irradiated with microwaves at 130° C. for 1 h. The reaction mixture was then allowed to cool and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a yellow solid (2.69 g, 98%). LCMS calc. for C15H23N4O4 (M+H)+: m/z=323.2. found 323.2.
Reaction SMILES: NC1C=C([O:8]C)C=CC=1CCCO.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][OH:25])=[C:18]([N+:26]([O-:28])=[O:27])[CH:17]=1>>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([OH:8])=[O:25])=[C:18]([N+:26]([O-:28])=[O:27])[CH:17]=1
Reactant: COc1ccc(CCCO)c([N+](=O)[O-])c1
Reactant: COc1ccc(CCCO)c(N)c1
Product: COc1ccc(/C=C/C(=O)O)c([N+](=O)[O-])c1

Procedure:
In particular, 3-(2-amino-4-methoxyphenyl)propan-1-ol may be prepared by hydrogenation of 3-(4-methoxy-2-nitrophenyl)propan-1-ol obtained by reduction of (2E)-3-(4-methoxy-2-nitrophenyl)acrylic acid, resulting from the condensation of malonic acid with 4-methoxy-2-nitrobenzaldehyde. The latter may prepared by hydrolysis of 1-(dibromomethyl)-4-methoxy-2-nitrobenzene obtained by dibromination of 4-methyl 3-nitroanisole. Similarly, 2-[3-(dimethylamino)propyl]-5-methoxyaniline may be prepared by hydrogenation of the product resulting from the reaction between dimethyl amine and 3-(4-methoxy-2-nitrophertyl)propyl methanesulfonate. The latter may be obtained by methanesulfonylation of 3-(4-methoxy-2-nitrophenyl)propan-1-ol as described in the scheme below.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:32])[C:13]=2[NH:17][C:18](=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[C:22]([F:30])[CH:21]=2)[C:8]1=[O:33])[CH3:6])=[N+]=[N-].C(O)C.[Cl-].[NH4+].O>[Fe]>[NH2:1][CH2:4][C@H:5]([N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:32])[C:13]=2[NH:17][C:18](=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[C:22]([F:30])[CH:21]=2)[C:8]1=[O:33])[CH3:6]
Reactant: Cc1ccc2c(=O)n([C@H](C)CN=[N+]=[N-])ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(=O)n([C@H](C)CN)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Reaction time: 3 h
Yield: 53.3 %

Procedure:
A solution of (R)—N-(2-(1-azidopropan-2-yl)-6-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)-2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamide (0.6 g, 0.001 mol) in ethanol (50 mL, 0.8 mol) was heated at 85° C. A solution of ammonium chloride (0.6 g, 0.01 mol) in water (15 mL, 0.83 mol) was added followed by iron powder (0.6 g, 0.01 mol). The mixture was stirred at the same temperature for 3 hours and poured onto dichloromethane (200 mL) and extracted. The residue was purified by reverse phase HPLC to afford the desired product as a white solid (232 mg, yield 50%).