Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li].C1C2C(=CC=CC=2)C=CC=1.[NH2:12][C@@H:13]1[CH2:19][CH2:18][C@@H:17]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@@:14]1([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:15][C@H:16]2S(C1C=CC=CC=1)(=O)=O>O1CCCC1>[NH2:12][C@@H:13]1[CH2:19][CH2:18][C@@H:17]2[N:20]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C@@:14]1([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:15][CH2:16]2
Reactant: N[C@@H]1CC[C@H]2[C@H](S(=O)(=O)c3ccccc3)C[C@]1(c1ccccc1)N2Cc1ccccc1
Agent: [Li]
Solvent: c1ccc2ccccc2c1
Solvent: C1CCOC1
Product: N[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
Lithium (175 mg, 25 mmol) was added to a solution of naphthalene (3.2 g, 25 mmol) in tetrahydrofuran (25 mL), and the mixture sonicated for 2 hours. The green solution formed was then slowly added to a solution of (1R*,2R*,5S*,6R*)-2-amino-8-benzyl-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octane (Description 8; 2.0 g, 4.6 mmol) in tetrahydrofuran (50 mL), already cooled to −78° C. The mixture was stirred at −78° C. for 1 hour, then quenched with aqueous saturated ammonium chloride solution (50mL). After warming to ambient temperature, the mixture was extracted with ethyl acetate (2×100 mL) and the extracts dried (MgSO4). Concentration in vacuo yielded a solid, which was purified by silica chromatography to give the title compound as a gum (900 mg, 3.1 mmol).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.[CH2:17]=O.[NH2:19][C:20]1[CH:24]=[C:23]([NH2:25])[N:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:21]=1>>[NH2:19][C:20]1[C:24]([CH2:17][N:14]2[CH2:15][CH2:16][N:11]([C:10]3[C:5]4[O:4][CH2:3][CH2:2][O:1][C:6]=4[CH:7]=[CH:8][CH:9]=3)[CH2:12][CH2:13]2)=[C:23]([NH2:25])[N:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:21]=1
Reactant: C=O
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCO2
Reactant: Nc1cc(N)n(-c2ccccc2)n1
Product: Nc1nn(-c2ccccc2)c(N)c1CN1CCN(c2cccc3c2OCCO3)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1-(1,4-benzodioxan-5-yl)piperazine (0.8 g; prepared in a similar manner to that described in Example 2), 37-40% aqueous formaldehyde solution (0.27 ml) and industrial methylated spirit (10 ml) was stirred at ambient temperature under nitrogen for 18 hours, then a solution of 3,5-diamino-1-phenylpyrazole (0.63 g) in industrial methylated spirit (8 ml) was added dropwise. The mixture was stirred at ambient temperature for 2.5 hours, then the solvent was removed in vacuo, and the residue was purified by flash chromatography over silica using an approximately 9:1 mixture of dichloromethane and methanol as eluant. Appropriate fractions were combined and the solvents removed in vacuo to leave 3,5-diamino-4-[4-(1,4-benzodioxan-5-yl)piperazin-1-ylmethyl]-1-phenylpyrazole as a pale pink solid (0.38 g), m.p. 84-87° C.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH3:6].[CH2:8]([O:15][C:16](Cl)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:1]([O:7][C:16](=[O:17])[O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2][CH:3]=[CH:4][CH2:5][CH3:6]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC/C=C\CCO
Product: CCC=CCCOC(=O)OCc1ccccc1

Procedure:
Starting Material: cis-3-hexenol and benzylchloroformate.
Reaction SMILES: CN(C)C([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][O:13][Si](C)(C)C)[N:7]=[CH:6]1)=O.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=1>C(#N)C.Cl>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:7]2[C:8]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:9][N:5]=[CH:6]2)=[CH:22][CH:23]=1)#[N:28]
Reactant: CN(C)C(=O)n1cnc(CCCO[Si](C)(C)C)c1
Reactant: N#Cc1ccc(CBr)cc1
Agent: Cl
Solvent: CC#N
Product: N#Cc1ccc(Cn2cncc2CCCO)cc1
Reaction time: 0.25 h

Procedure:
A solution of 97.0 g of 1-dimethylcarbamoyl-4-(3-trimethylsilyloxypropyl) -1H-imidazole and 72.0 g of 1-bromomethyl-4-cyanobenzene in 500 ml of acetonitrile is refluxed for 10 h. The solution is cooled to 0° in an ice bath and ammonia gas is bubbled in for a few minutes. The mixture is then evaporated in vacuo to give a semisolid which is dissolved in 500 ml of 1N hydrochloric acid. The solution is allowed to stand at room temperature for 15 min and then is extracted with ether. The pH of the aqueous phase is adjusted to 9 with 50% sodium hydroxide solution and the mixture is then extracted with methylene chloride. The methylene chloride extracts are washed with water, dried over sodium sulfate and evaporated to give a semi-solid which is triturated with cold acetone to yield the title compound (b) as a white solid, m.p. 121°-123°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:15][NH2:16].O1CCCC1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([S:8]([NH:16][CH3:15])(=[O:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1S(=O)(=O)Cl
Reactant: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNS(=O)(=O)c1cc(F)ccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
A solution of 5-fluoro-2-nitrobenzene-1-sulfonyl chloride (2.0 g, 8.35 mmol) in dichloromethane (50 mL) was cooled using an ice water bath. 2M methylamine in tetrahydrofuran (5.0 mL, 10.0 mmol) was added. The resulting solution was stirred for 2 hours. The reaction mixture was washed with 2N HCl solution (2×100 mL), brine (100 mL) and then dried over magnesium sulphate. The solution was filtered before concentrating under reduced pressure to afford 5-fluoro-N-methyl-2-nitrobenzenesulfonamide (1.79 g, 7.64 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10]([F:26])=[N:11][CH:12]=[C:13]([C:15]3[S:23][C:22]4[CH2:21][CH2:20][N:19]([CH2:24][CH3:25])[CH2:18][C:17]=4[CH:16]=3)[CH:14]=2)[CH:3]=1.[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1>[F-].[K+].C(#N)C.C(OCC)(=O)C>[CH2:24]([N:19]1[CH2:20][CH2:21][C:22]2[S:23][C:15]([C:13]3[CH:14]=[C:9]([C:4]4[CH:3]=[C:2]([C:31]5[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=5)[N:7]=[CH:6][C:5]=4[NH2:8])[C:10]([F:26])=[N:11][CH:12]=3)=[CH:16][C:17]=2[CH2:18]1)[CH3:25]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCN1CCc2sc(-c3cnc(F)c(-c4cc(Cl)ncc4N)c3)cc2C1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCN1CCc2sc(-c3cnc(F)c(-c4cc(-c5cnn(C)c5)ncc4N)c3)cc2C1
Temperature: 120 °C
Yield: 54.6 %

Procedure:
A degassed mixture of 6′-chloro-5-(5-ethyl-4,5,6,7-tetrahydro thieno[3,2-c]pyridin-2-yl)-2-fluoro-[3,4′]bipyridinyl-3′-ylamine (1.05 g, 2.70 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (842 mg, 4.10 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (221 mg, 0.27 mmol) in 1N aqueous potassium fluoride solution (9 mL) and acetonitrile (9 mL) was heated under microwave irradiation at 120° C. for 20 minutes. The cooled reaction mixture was diluted with ethyl acetate (100 mL) then washed with water (75 mL). The organic phase was dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 40 g column, ISCO, 0-10% methanol in DCM) to afford the title compound as a white solid (641 mg, 55%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.44 (dd, J=2.5, 1.1 Hz, 1H), 8.13 (d, J=0.6 Hz, 1H), 8.07 (dd, J=8.7, 2.5 Hz, 1H), 7.89 (s, 1H), 7.85 (d, J=0.8 Hz, 1H), 7.32 (s, 1H), 7.12 (s, 1H), 3.94 (s, 3H), 3.61 (s, 2H), 3.00-2.94 (m, 2H), 2.93-2.85 (m, 2H), 2.68 (q, J=7.2 Hz, 2H), 1.21 (t, J=7.2 Hz, 3H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][C:22]2[C:25]([S:30][CH2:31][C:32]#[N:33])=[C:26]([Cl:29])[CH:27]=[CH:28][C:21]=2[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].Br[CH2:35][CH2:36]Br.CN(C=O)C>C1(C)C=CC=CC=1>[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][C:22]2[C:25]([S:30][C:31]3([C:32]#[N:33])[CH2:36][CH2:35]3)=[C:26]([Cl:29])[CH:27]=[CH:28][C:21]=2[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCC#N)c2CC1
Reactant: BrCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SC3(C#N)CC3)c2CC1
Temperature: 38 °C
Reaction time: 0.17 h
Yield: 62.1 %

Procedure:
Add sodium bis(trimethylsilyl)amide (5.4 mL, 5.4 mmol, 1M solution in THF) at room temperature under nitrogen to a solution of 3-tert-butoxycarbonyl-7-chloro-6-(1-cyano-methylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (380 mg, 1.1 mmol) in anhydrous toluene (4 mL). Stir the solution for 10 min, then add quickly 1,2-dibromoethane (2.8 mL, 32.4 mmol) followed by anhydrous DMF (4 mL). An exothermic reaction was observed and the reaction temperature increased to 38° C. Stir the mixture for 15 min at ambient temperature, then quench with methanol (2 mL). Concentrate in vacuo and purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to obtain 3-tert-butoxycarbonyl-7-chloro-6-(1-cyano-cyclopropylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (259 mg).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([NH:28][C:29]([NH:31]C(=O)CC2C=CC=CC=2)=[S:30])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:22][CH3:23])=[C:12]([C:15]([O:17]C(C)(C)C)=[O:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.NC1C=CC(OC2C3C(=CC(OC)=C(C(O)=O)C=3)N=CC=2)=C([F:64])C=1.F[CH:66]([C:73]1[C:78]([F:79])=[CH:77][CH:76]=[CH:75][CH:74]=1)[C:67](SN=C=O)=[O:68].CN(C)C(=O)C>C(O)C.C1(C)C=CC=CC=1>[F:79][C:78]1[CH:77]=[CH:76][CH:75]=[C:74]([F:64])[C:73]=1[CH2:66][C:67]([NH:31][C:29](=[S:30])[NH:28][C:26]1[CH:25]=[CH:24][C:3]([O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:22][CH3:23])=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[C:2]([F:1])[CH:27]=1)=[O:68]
Reactant: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2cc1C(=O)OC(C)(C)C
Reactant: O=C=NSC(=O)C(F)c1ccccc1F
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1C(=O)O
Solvent: CC(=O)N(C)C
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4c(F)cccc4F)cc3F)c2cc1C(=O)O

Procedure:
Similar to the synthesis of compound 1d, from compound 39c (98 mg), 2,6-difluorophenylacetyl thioisocyanate (128 mg), and a solvent mixture of N,N-dimethylacetamide (1.5 mL), toluene (1.5 mL), and ethanol (300 μL), compound 44a was yielded as a crude product (143 mg, yield: 89%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[N:9]=[CH:8]2)#[C:2][CH2:3][CH3:4].I[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28]>>[C:21]1(/[C:2](/[CH2:3][CH3:4])=[C:1](\[C:32]2[CH:33]=[CH:34][C:29]([CH:27]=[O:28])=[CH:30][CH:31]=2)/[C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[N:10]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:9]=[CH:8]3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Ic1ccccc1
Reactant: CCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Product: CC/C(=C(/c1ccc(C=O)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1

Procedure:
The title compound was prepared from Intermediate 3, iodobenzene, and (4-formylphenyl)boronic acid following General Procedure C. LCMS: 353 [(M-THP+H)+H]+.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3][CH2:2]1.[NH2:12][C:13]([NH2:15])=[S:14].[I:16]I>>[IH:16].[N:12]1[C:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[O:1][CH2:2][C:3]=2[S:14][C:13]=1[NH2:15]
Reactant: II
Reactant: O=C1CCOc2ccccc21
Reactant: NC(N)=S
Product: I
Product: Nc1nc2c(s1)COc1ccccc1-2
Temperature: 95 °C
Reaction time: 4.5 h
Yield: 66.9 %

Procedure:
A mixture of 4-chromanone (2.00 g; 13.5 mmol), thiourea (2.06 g; 27.0 mmol) and iodine (3.43 g; 13.5 mmol) were heated to 95° C. with stirring. After 4.5 hr., the mixture was allowed to cool to room temperature, triturated with methylene chloride, the solid material filtered off. The solid was further triturated with ethyl acetate, filtered and washed with ethyl acetate to provide 3.00 g of 4H-Chromeno[4,3-d]thiazol-2-ylamine hydroiodide 19 as an off white powder.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[N:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][C:54]=2[C:56]([OH:58])=O)[CH:49]=[CH:48][CH:47]=1.[NH2:59][C:60]1[CH:61]=[CH:62][CH:63]=[C:64]2[C:69]=1[N:68]=[CH:67][CH:66]=[CH:65]2>C(Cl)Cl.O>[N:68]1[C:69]2[C:64](=[CH:63][CH:62]=[CH:61][C:60]=2[NH:59][C:56]([C:54]2[CH:53]=[CH:52][CH:51]=[C:50]3[C:55]=2[N:46]=[CH:47][CH:48]=[CH:49]3)=[O:58])[CH:65]=[CH:66][CH:67]=1
Reactant: O=C(O)c1cccc2cccnc12
Reactant: Nc1cccc2cccnc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cccc2cccnc12)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (192 mg; 0.43 mmol), 1-hydroxybenzotriazole monohydrate (79 mg; 0.59 mmol) and triethylamine (0.200 ml; 1.44 mmol) are added to a solution of quinoline-8-carboxylic acid (50 mg; 0.29 mmol) dissolved in 5 ml of dry CH2Cl2. After stirring for 30 minutes at ambient temperature, 8-aminoquinoline (84 mg; 0.58 mmol) is added and the mixture is stirred for 4 hours 30 minutes at ambient temperature. Water (10 ml) is added and the product is extracted with CH2Cl2 (3×10 ml). The volume is reduced and the product is purified by silica gel chromatography, eluted with CH2Cl2/CH3OH (0 to 2%, v/v) then the solvent is evaporated under reduced pressure and the fractions containing a high proportion of products are repurified by silica gel chromatography, eluted with CH2Cl2/CH3OH (99.5/0.5; v/v). 24 is obtained after evaporation of the solvent in the form of a white powder (83 mg; 0.28 mmol, yield=96%). NMR-1H (250 MHz, CDCl3) δ, ppm: 15.13 (s, 1H); 9.25 (dd, 3J (H, H)=4.0 Hz, 4J (H, H)=2.0 Hz, 1H); 9.19 (dd, 3J (H, H)=7.5 Hz, 4J (H, H)=1.5 Hz, 1H); 9.00 (m, 2H); 8.32 (dd, 3J (H, H)=8.0 Hz, 4J (H, H)=2.0 Hz, 1H); 8.19 (dd, 3J (H, H)=8.0 Hz, 4J (H, H)=1.5 Hz, 1H); 8.01 (dd, 3J (H, H)=8.0 Hz, 4J (H, H)=1.5 Hz, 1H); 7.74 (dd, 3J (H, H)=7.5 and 8.0 Hz, 1H); 7.60 (m, 3H); 7.48 (dd, 3J (H, H)=4.5 and 8.0 Hz, 1H). NMR-13C (63 MHz, CDCl3) δ, ppm: 164.28; 149.48; 148.57; 145.60; 140.12; 137.59; 136.65; 136.18; 134.02; 132.10; 129.85; 128.41; 128.28; 127.50; 126.63; 121.75; 121.34; 121.12; 118.18. MS (CID, NH3): m/z=300 (MH+). UV/vis [DMSO/20 mM Tris-HCl pH=7.4 containing 150 mM NaCl (8/2, v/v)]: λ nm (ε M−1 cm−1)=261 (13,300, shoulder), 274 (14,800), 294 (12,200).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10](C=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([OH:25])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Oc2ccc(C=O)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Oc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-(4′-methylphenoxy)benzaldehyde (9.00 g, 41.63 mmol) in CHCl3 (75 mL) was treated with m-chloroperbenzoic acid (46-85%, 15.80 g, 52.00 mmol) and stirred for 3 h at room temperature. The reaction was washed with sat. aq. NaHSO3, sat. aq. NaHCO3, and water. The organic layer is concentrated and the residual oil taken up in MeOH (10 mL) containing a few drops of conc. HCL and stirred for 1 h at room temperature. The solvent is removed in vacuo and the resulting oil was chromatographed on silica gel (20% ethyl acetate/hexane) to afford 4-(4′-methylphenoxy)phenol.
Reaction SMILES: Cl[CH2:2][CH:3]=O.C([O:9][C:10](=[O:27])[C:11]1[C:16]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[Cl:25])=[CH:15][C:14]([NH2:26])=[N:13][CH:12]=1)(C)(C)C>CCO.CCOC(C)=O>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:16]2[C:11]([C:10]([OH:9])=[O:27])=[CH:12][N:13]3[CH:2]=[CH:3][N:26]=[C:14]3[CH:15]=2)=[C:19]([Cl:25])[CH:20]=1
Reactant: O=CCCl
Reactant: CC(C)(C)OC(=O)c1cnc(N)cc1Nc1ccc(Br)cc1Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)c1cn2ccnc2cc1Nc1ccc(Br)cc1Cl
Temperature: 80 °C
Reaction time: 5 h
Yield: 32.7 %

Procedure:
Chloroacetaldehyde (12 μL, 0.188 mmol) was added to a mixture of 6-amino-4-(4-bromo-2-chlorophenylamino)-nicotinic acid tert-butyl ester (42) (50 mg, 0.125 mmol) in EtOH (630 μL). After stirring the reaction mixture at 80° C. for 5 hours, an additional 12 μL of chloroacetaldehyde were added and heating was continued for 10 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc to give a cloudy semi-solution. The organic layer was washed with water, saturated NaHCO3 and brine. The organic layer contains a precipitate, which was collected by filtration to give the desired product (43) (15 mg, 33%). MS APCI (−) m/z 364, 366, (M−, Cl, Br pattern) detected. 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.31 (s, 1H), 7.91 (s, 1H), 7.80 (s, 1H), 7.65–7.54 (m, 2H), 6.91 (s, 1H).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)=[O:5].C1N=CN([C:23](N2C=NC=C2)=[O:24])C=1.[CH3:30][C:31]1[N:36]=[C:35]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:34]=[CH:33][CH:32]=1>CC#N>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([C:4](=[O:5])[CH:3]([NH:2][C:23]([N:40]2[CH2:41][CH2:42][N:37]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([CH3:30])[N:36]=3)[CH2:38][CH2:39]2)=[O:24])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][CH:8]=1)#[N:11]
Reactant: Cc1cccc(N2CCNCC2)n1
Reactant: CC(C)(C)C(N)C(=O)c1ccc(C#N)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CC#N
Product: Cc1cccc(N2CCN(C(=O)NC(C(=O)c3ccc(C#N)cc3)C(C)(C)C)CC2)n1
Reaction time: 1 h
Yield: 37.6 %

Procedure:
4-(2-Amino-3,3-dimethylbutanoyl)benzonitrile hydrochloride (Example 3, 50 mg, 0.23 mmol) was added to a solution of CDI (112 mg, 0.69 mmol) and TEA (0.035 mL, 0.25 mmol) in MeCN (5 mL). The reaction mixture was stirred at rt for 90 minutes before 1-(6-methylpyridin-2-yl)piperazine (CAS 55745-89-6, 205 mg, 1.16 mmol) was added. The mixture was stirred for 1 h and the solvent was evaporated under reduced pressure. The product was dissolved in methanol, filtered and purified by prep. HPLC yielding N-(1-(4-cyanophenyl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(6-methylpyridin-2-yl)piperazine-1-carboxamide (36.3 mg, 37%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].C(C1C=CC=C(C(C)(C)C)C=1O)(C)(C)C.C(N(CC)CC)C.O[C:45]1[CH:60]=[CH:59][C:48]([C:49]([O:51][CH2:52][CH:53]([CH3:58])[O:54][CH2:55][CH2:56][CH3:57])=[O:50])=[CH:47][CH:46]=1>S(Cl)(Cl)=O.C1COCC1>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][C:45]2[CH:60]=[CH:59][C:48]([C:49]([O:51][CH2:52][CH:53]([CH3:58])[O:54][CH2:55][CH2:56][CH3:57])=[O:50])=[CH:47][CH:46]=2)=[O:18])=[CH:20][CH:21]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: CCCOC(C)COC(=O)c1ccc(O)cc1
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Agent: CC(C)(C)c1cccc(C(C)(C)C)c1O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)OCC(C)OCCC)cc2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 52.3 %

Procedure:
2.9 g of 4-(6-acryloxyhexyloxy)benzoic acid was heat-refluxed for 2 hours in 10 ml of thionyl chloride in the presence of 2,6-di-t-butylphenol, followed by distilling-off of the thionyl chloride. Anhydrous THF and triethylamine were added to the reaction mixture, and a solution of 1.6 g of 2-methyl-2-propyloxyethyl 4-hydroxybenzoate in THF was added dropwise thereto at 0° C., followed by 4 hours of stirring at 50° C. The reaction mixture was subjected to extraction with ethyl acetate and column chromatography to obtain 1.8 g of the product. (Yield: 59 %)
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:14])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1.[H-].[Na+].[CH2:17](I)[CH3:18]>C1COCC1.CN(C=O)C.CCOC(C)=O>[CH2:17]([O:1][CH2:2][CH2:3][N:4]([CH3:14])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1)[CH3:18]
Reactant: CCI
Reactant: CN(CCO)c1ccc([N+](=O)[O-])cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOCCN(C)c1ccc([N+](=O)[O-])cn1
Reaction time: 8 h

Procedure:
(2-Hydroxy-ethyl)-methyl-(5-nitro-pyridin-2-yl)-amine (197 mg, 1 mmol) in THF (5 mL) and DMF (2 mL) was stirred with 60% NaH in oil (48 mg, 1.2 mmol) for 1 hr. The mixture was cooled and to this was added ethyl iodide (120 uL, 1.5 mmol). The reaction was allowed to stir overnight. The mixture was diluted with EtOAc, extracted with H2O and dried over MgSO4. The EtOAc layer was filtered, evaporated to dryness and used without further purification. Yield: 155 mg. ES-MS calcd for C10H15N3O3 (m/e) 225.25, obsd 225.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]#[N:19])[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:16])([F:15])[F:17])[N:11]=[C:10]([C:18]([NH:21][OH:22])=[NH:19])[N:9]=2)=[CH:6][CH:7]=1
Reactant: NO
Reactant: N#Cc1nc(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1nc(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A stirred mixture of 4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine-2-carbonitrile (example B.1) (0.5 g, 1.76 mmol), hydroxylamine hydrochloride (0.45 g, 6.48 mol) and sodium carbonate (0.37 g, 3.53 mol) in water (10 mL) and ethanol (10 mL) was heated under reflux conditions for 2 h. The ethanol was removed partly and the mixture stirred at room temperature for 1 h. The precipitate was collected by filtration, washed with water and dried to yield the title compound (0.53 g, 94%) as a light brown solid. MS (ISP) 316.9 [(M+H)+]; mp 243° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH2:21])=[O:20])[CH:14]=1.[C:23](Cl)(=[O:25])[CH3:24]>C(OCC)(=O)C.CCCCCC>[C:23]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH2:21])=[O:20])[CH:14]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: NC(=O)c1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)Nc1c(C(=O)c2cccc(C(N)=O)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-2-(3-aminocarbonylbenzoyl)-6-chloroindole (Example 128) and acetyl chloride. m.p.: 243-247° C. (ethyl acetate/hexane)