Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:11][N:12]([CH3:18])[C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][C:2]1[C:3]([N:15]2[CH2:16][CH2:17][C@H:13]([N:12]([CH3:18])[CH3:11])[CH2:14]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: CN(C)[C@H]1CCNC1
Reactant: O=Cc1cccc(Br)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)[C@H]1CCN(c2c(Br)cccc2C=O)C1
Temperature: 85 °C
Yield: 45.5 %

Procedure:
A 50 mL round bottom flask was charged with a magnetic stir bar, 3-bromo-2-fluorobenzaldehyde (0.555 g, 2.73 mmol), (S)-N,N-dimethylpyrrolidin-3-amine (0.312 g, 2.73 mmol), DMSO (5.47 ml), and potassium carbonate (0.378 g, 2.73 mmol). The mixture was heated to 85° C. overnight with stirring. The reaction was allowed to cool to ambient temperature, was diluted with water, and extracted into methylene chloride. The combined organic extract was dried with MgSO4, filtered, and conc. in vacuo to provide the product which was purified via silica gel chromatography (40 g) using ethyl acetate/MeOH (10:1) as eluent to afford (S)-3-bromo-2-(3-(dimethylamino)pyrrolidin-1-yl)benzaldehyde (0.369 g, 45.4%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.Cl.Cl[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:21])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1c(Cl)cnc2[nH]c(-c3ccc(O)c([N+](=O)[O-])c3)nc12
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(Cl)cnc2[nH]c(-c3ccc(OCCN4CCOCC4)c([N+](=O)[O-])c3)nc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
4-(6-Chloro-7-methyl-3H-imidazo[4,5-b]pyridin-2-yl)-2-nitrophenol (Example 248) (105 mg, 0.34 mmol), 4-(2-chloroethyl)morpholine hydrochloride (74 mg, 0.40 mmol) and sodium hydride (29 mg, 1.2 mmol) were dissolved in DMF (13 ml). The reaction mixture was stirred at 100° C. overnight and then quenched with water (5 ml) and evaporated. The residue was dissolved in CH3CN (4 ml) and a drop of TFA and purified by HPLC C18. The appropriate fractions were collected and concentrated in vacuo to afford the subtitle compound (100 mg, 60%).
Reaction SMILES: [C:1]([O:5][P:6]([CH:13]([OH:37])[C:14]1[CH:36]=[CH:35][C:17]([CH2:18][CH:19]([C:31]([O:33][CH3:34])=[O:32])[NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[CH:16][CH:15]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl.CCOC(C)=O>[C:9]([O:8][P:6]([C:13]([C:14]1[CH:36]=[CH:35][C:17]([CH2:18][CH:19]([C:31]([O:33][CH3:34])=[O:32])[NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[CH:16][CH:15]=1)=[O:37])([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: COC(=O)C(Cc1ccc(C(O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccc(C(=O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.3 %

Procedure:
To a solution of 9 (125 mg, 0.23 mmol) in CHCl3 (1 mL) was added celite (200 mg) and freshly activated 4A molecular sieves (230 mg). Pyridinium dichromate (219 mg, 0.58 mmol) was added and the mixture stirred at ambient temperature (4 hours). The reaction was diluted with EtOAc (5 mL) and filtered through a pad of Florisil (TLC grade). The Florisil was rinsed with EtOAc (30 mL) and combined filtrates taken to dryness by rotary evaporation under reduced pressure to afford crude 10 (85 mg, 70%). Silica gel chromatography [EtOAc/hexanes (1:1)]provided pure 10 (77 mg, 62%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[SH:11].[C:12]1(=O)[O:19][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1>CN1C(=O)CCC1.O>[F:8][C:7]1[C:2]2[N:1]=[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[S:11][C:3]=2[C:4]([F:10])=[CH:5][C:6]=1[F:9]
Reactant: Nc1c(F)c(F)cc(F)c1S
Reactant: O=C1CCCCC(=O)O1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)CCCCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 100 °C
Reaction time: 6 h
Yield: 25.5 %

Procedure:
A solution of adipic acid (10.0 g, 68 mmol) in acetic anhydride (50 ml) was heated to reflux for 3 hours. An excess of acetic anhydride was then distilled off in vacuo leaving adipic anhydride (7.4 g). 2-Amino-3,4,6-trifluorothiophenol (200 mg, 1.1 mmol) was dissolved in NMP (1 ml) under a nitrogen stream. To the resultant solution was gradually added adipic anhydride (143 mg, 1.1 mmol) and the mixture was stirred at 100° C. for 6 hours. After naturally cooling, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted with aqueous sodium bicarbonate. The alkaline phase was acidified with 10% hydrochloric acid and re-extracted with ethyl acetate. The combined organic phases were dried and then evaporated to yield a residue, which was recrystallized from acetonitrile to give 5-(4,5,7-trifluorobenzothiazol-2-yl)pentanoic acid (81 mg, 26%).
Reaction SMILES: [CH2:1]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Cl)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[C-]#N.[Na+].[CH3:24][N:25](C=O)C>C(OCC)(=O)C>[CH2:1]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12][C:24]#[N:25])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cc2ccccc2)cc1
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N#CCc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 4-benzylbenzyl chloride (198.34 g) in dimethylchloride (DMF) (50 ml) was added in turn sodium hydrogen carbonate (76.88 g) and sodium cyanide (56.07 g). In that case, the solution was cooled as occasion demands, since heat is slightly generated. After stirring at room temperature for 17 hours, DMF (100 ml) was further added. After stirring at room temperature for 67 hours, ethyl acetate (300 ml) was added, and the precipitate was filtered, washed with ethyl acetate (300 ml). The filtrate and the washings were combined, washed with saturated aqueouse sodium chloride solution (20 ml×4), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the title compound (189.69 g).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:16]=[CH:15][S:14][N:13]=1)SC)#[N:2].[NH2:17][CH2:18][CH2:19]SCC1C=CSN=1.C(N)C>>[C:1]([NH:3][C:4]([NH:17][CH2:18][CH3:19])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:16]=[CH:15][S:14][N:13]=1)#[N:2]
Reactant: CSC(=NCCSCc1ccsn1)NC#N
Reactant: NCCSCc1ccsn1
Agent: CCN
Product: CCNC(=NCCSCc1ccsn1)NC#N

Procedure:
Reacting N-cyano-N'-[2-(3-isothiazolylmethylthio)ethyl]-S-methylisothiourea, prepared from 3-[(2-aminoethyl)thiomethyl]isothiazole by the procedure of EXample 3(c) (i), with ethylamine by the procedure of Example 4 gives N-cyano-N'-ethyl-N"-[2-(3-isothiazolylmethylthio)ethyl]guanidine.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:52][C:53]1[CH:67]=[CH:66][C:56]([CH2:57][NH:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[CH:55][CH:54]=1>CC#N>[CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([NH:52][C:53]3[CH:67]=[CH:66][C:56]([CH2:57][NH:58][C:59](=[O:65])[O:60][C:61]([CH3:63])([CH3:64])[CH3:62])=[CH:55][CH:54]=3)=[O:17])=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ccc2ncc(C(=O)O)n2n1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCNc1ccc2ncc(C(=O)Nc3ccc(CNC(=O)OC(C)(C)C)cc3)n2n1
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a solution of 6-(butylamino)imidazo[1,2-b]pyridazine-3-carboxylic acid (150 mg, 0.64 mmol) in CH3CN (1 mL) were added BOP reagent (567 mg, 1.28 mmol), triethyl amine (0.26 mL, 1.92 mmol) and tert-butyl 4-aminobenzylcarbamate (143 mg, 0.64 mmol). The reaction was stirred for overnight. Then the reaction was purified ISCO column chromatography on silica gel (10% MeOH/DCM) to give tert-butyl 4-(6-(butylamino)imidazo[1,2-b]pyridazine-3-carboxamido)benzylcarbamate as white solid (280 mg, 100% yield). 20 mg was further purified by prep HPLC (neutral) to afford tert-butyl 4-(6-(butylamino)imidazo[1,2-b]pyridazine-3-carboxamido)benzylcarbamate (5 mg) as white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.10 (s, 1H), 7.76 (d, J=9.70 Hz, 1H), 7.67 (d, J=8.38 Hz, 2H), 7.32 (d, J=8.38 Hz, 2H), 6.90 (d, J=9.70 Hz, 1H), 4.62 (s, 1H), 4.24 (s, 2H), 3.47 (t, J=7.28 Hz, 2H), 1.79 (t, J=7.39 Hz, 2H), 1.46-1.57 (m, 10H), 1.02 (t, J=7.39 Hz, 3H); LRMS (ESI) m/e 439.9 [(M+H)+, calcd for C23H31N6O3 439.5].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[S:12][CH:13]=[CH:14][C:15]=1[CH:16]1OCCO1)([O-])=O>CC(C)=O.C(O)(=O)C.[Zn]>[S:12]1[C:11]2[CH2:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[NH:1][CH2:16][C:15]=2[CH:14]=[CH:13]1
Reactant: O=[N+]([O-])c1ccccc1Cc1sccc1C1OCCO1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: c1ccc2c(c1)Cc1sccc1CN2
Reaction time: 6 h
Yield: 72.4 %

Procedure:
A stirred solution of 4 gms of 2-[2-[(2-nitrophenyl)methyl]-3-thienyl]-1,3-dioxolane in acetone (50 ml) and acetic acid (90% 50 ml) is heated to 60° C. Zinc dust (10 gms) is slowly added and after the addition, reaction mixture is stirred for 6 hours. At the end, reaction mixture is filtered and the residue washed with acetone and concentrated. The brown residue is extracted with chloroform and washed well with water. The organic layer is dried (Na2SO4) and filtered and concentrated. The product is isolated by silica gel column chromatography by eluting with 20% ethyl acetate:hexane to give 2.0 g of the desired product as a pale yellow crystalline solid, m.p. 86° C. Mass Spectrum; M+ 202.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:27]=[CH:26][C:8]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH2:30](I)[CH2:31][CH3:32]>CN(C=O)C>[C:1]([N:4]([C:5]1[CH:27]=[CH:26][C:8]([C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[CH2:15][CH2:16]2)=[O:10])=[CH:7][CH:6]=1)[CH2:30][CH2:31][CH3:32])(=[O:3])[CH3:2]
Reactant: CCCI
Reactant: CC(=O)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(C(C)=O)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.7 g of 1-[4-(N-acetylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine, dissolved in 20 ml DMF, is added to a suspension of 0.23 g 50% NaH in 20 ml DMF. After 1.5 h of stirring at RT, 0.97 g n-propyl iodide, dissolved in 5 ml DMF, are added dropwise. The reaction mixture is stirred overnight. DMF is distilled off in vacuo, water is added, and the product is extracted with ethyl acetate. The organic phase is concentrated by evaporation, and the residue is crystallised from ether/petroleum ether; thus 1-[4-(N-acetyl-N-propylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine is obtained m.p. 112°-113°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:18][CH:14]4[CH2:15][CH:16]([CH2:17]2)[C:12]([NH2:19])([CH2:13]4)[CH2:11]3)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:26]([O:33][C:34](Cl)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.O>[CH2:26]([O:33][C:34](=[O:35])[NH:19][C:12]12[CH2:13][CH:14]3[CH2:18][C:10]([C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=4)([CH2:17][CH:16]1[CH2:15]3)[CH2:11]2)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NC12CC3CC1CC(c1ccc([N+](=O)[O-])cc1)(C3)C2
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC12CC3CC1CC(c1ccc([N+](=O)[O-])cc1)(C3)C2)OCc1ccccc1
Reaction time: 2 h
Yield: 66.9 %

Procedure:
To a stirred mixture of 1-(4-nitrophenyl)tricyclo[3.3.1.03,7]nonan-3-amine (2.0 g, 8.0 mmol) obtained in step III, K2CO3 (3.5 g, 24 mmol) in THF (80 mL), cooled to ice-bath temperature was added benzylchloroformate (50% w/v in Toluene, 2.2 mL, 12 mmol). After stirring the reaction mixture at r.t for 2 h, it was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure to obtain benzyl[2-(4-nitrophenyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]carbamate as an off-white solid (2.1 g) in 70% yield. M.R: 104.1-105.9° C.; m/z (M+1) 393; IR cm−1 3440, 2952, 1714, 1518, 1349, 1216, 757; 1H NMR (CDCl3) 300 MHz δ 8.12 (d, J=8.8 Hz, 2H), 7.50-7.27 (m, 7H), 5.20-5.0 (s (br), 2H), 2.65-2.55 (m, 1H), 2.50-1.55 (m, 11H). 13C NMR (CDCl3) 75 MHz δ 155.1, 154.2, 146.1, 136.4, 131.1, 128.5 (2C), 128.1 (2C), 126.6 (2C), 123.4 (2C), 66.3, 64.4, 49.248.0, 47.5, 43.8, 42.1, 40.8, 37.0.
Reaction SMILES: [Na].CS([O:6][CH2:7][C:8]1[C:17]2[C@@H:18]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[O:19][C:20]3([CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:16]=2[C:15]2[C@@H:14]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:13][C:12]([CH3:45])([CH3:44])[CH2:11][C:10]=2[N:9]=1)(=O)=O.[CH3:46]O>C(OCC)C>[Si:37]([O:36][C@H:14]1[CH2:13][C:12]([CH3:45])([CH3:44])[CH2:11][C:10]2[N:9]=[C:8]([CH2:7][O:6][CH3:46])[C:17]3[C@@H:18]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[O:19][C:20]4([CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:16]=3[C:15]1=2)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]
Reactant: CO
Reactant: CC1(C)Cc2nc(COS(C)(=O)=O)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C1(CCOCC1)O[C@@H]3c1ccc(C(F)(F)F)cc1
Agent: [Na]
Solvent: CCOCC
Product: COCc1nc2c(c3c1[C@@H](c1ccc(C(F)(F)F)cc1)OC31CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Temperature: 0 °C
Reaction time: 12 h

Procedure:
20 mg Sodium are dissolved in 3 ml methanol cooled to 0° C. and treated dropwise with a solution of 57 mg ((3R,95)-9-(tert-butyldimethylsilyloxy)-7,7-dimethyl-3-(4-(trifluoromethyl)phenyl)-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-4-yl)methyl methanesulfonate in 0.5 ml methanol. After stirring for 12 hours at room temperature the mixture is diluted with diethylether, washed with saturated aqueous ammonium chloride and dried with magnesium sulphate. The solvents are evaporated in vacuo. The product is directly used in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][N:8]([CH2:13][C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)[C:9]3=[O:12])=[CH:4][CH:3]=2)=[CH:22][CH:23]=1
Reactant: O=C1c2cc(O)ccc2CCN1Cc1cccnc1
Reactant: Clc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=C1c2cc(Oc3ccc(Cl)cc3)ccc2CCN1Cc1cccnc1
Yield: 61.6 %

Procedure:
A mixture of 4.97 g of 3,4-dihydro-7-hydroxy-2-(3-pyridylmethyl)-1 (2H)-isoquinolinone, 4.50 g of 4-bromochlorobenzene, 3.88 g of cupric oxide, 5.39 g of potassium carbonate and 30 ml of pyridine was refluxed under heating for 20 hours. After finishing the reaction, the insoluble material was filtered, and the filtrate was concentrated in vacuo. The resultant residue was chromatographed on a column of silica gel, eluting with ethyl acetate to give 4.39 g of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:31])[C:7]([CH2:18][NH:19][C:20]([C:22]3[CH:23]=[C:24]4NC=NC4=N[CH:27]=3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44]CC(C(O)=O)CC1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[CH3:32][O:36][C:37]([C:8]1[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5]([C:6](=[O:31])[C:7]=1[CH2:18][NH:19][C:20]([CH:22]1[CH2:23][CH2:24][N:39]([C:37]([O:36][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:38])[CH2:44][CH2:27]1)=[O:21])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc2nc[nH]c2c1
Product: COC(=O)c1c(CNC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
3-{[(1-tert-butoxycarbonyl-piperidine-4-carbonyl)-amino]-methyl}-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester was prepared starting from intermediate 1 and 1-tert-butoxycarbonyl-piperidine-4-carboxylic acid. MS calcd. for C29H33ClN3O6 [(M+H)+] 554.2, obsd. 554.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:11][N:10]([CH:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CS([Cl:39])(=O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([Cl:39])[CH2:11][N:10]([CH:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(F)cc2)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(C2(Cl)CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-(4-fluorophenyl)-1-diphenylmethyl-3-azetidinol (15) (4.0 g) and N,N-diisopropylethylamine (3.2 mL) in dichloromethane (100 mL) at 0° C. was added, dropwise, methanesulfonyl chloride (125 mL). The mixture was stirred at 0° C. for 18 hrs, then washed (water, brine) and dried (Na2SO4) and concentrated in vacuo. The crude product was recrystallised from hexane to give 3-(4-fluorophenyl)-3-chloro-1-(diphenylmethyl)azetidine (16) (22 g), m.p. 108-109° C. (hexane). Found: C, 75.13; H, 5.46; N, 3.93. C22H19CIFN C, 75.10; H, 5.44; N, 3.98%.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([CH:20]=[O:21])=[CH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2cccs2)s1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2ccc(Cl)s2)s1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.7 %

Procedure:
To a solution of 5-chloro-[2,2′]bithiophene (1.06 g, 5.28 mmol) in 12 mL of THF at −78° C. is added n-BuLi (4.4 mL of a 1.6M solution in hexanes, 6.99 mmol). After 15 minutes, DMF (0.97 mL, 14 mmol) is added and the resulting solution is allowed to warm to 0° C. After 15 min, the solution diluted with EtOAc and quenched with saturated NaHCO3 solution. The organic solution is washed with H2O and saturated NaCl solution, then dried over MgSO4, filtered and concentrated. The crude product is purified by flash column chromatography eluting with a gradient of 10% Et2O/hexanes to 20% Et2O/hexanes to yield the title compound (0.89 g, 3.89 mmol) as a white solid. 1H NMR (CDCl3, 300 MHz) δ9.87 (s, 1H), 7.70 (d, 1H), 7.20 (d, 1H), 7.15 (d, 1H), 6.91 (d, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:10][N:9]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([CH2:18][OH:19])=[CH:13][N:12]=2)[CH2:8][CH2:7][NH:6]1)=[O:4].Cl[C:21]1[NH:25][C:24]2[CH:26]=[C:27]([C:39]([F:42])([F:41])[F:40])[CH:28]=[C:29]([C:30]3[CH:35]=[C:34]([F:36])[C:33]([F:37])=[C:32]([F:38])[CH:31]=3)[C:23]=2[N:22]=1>CCO>[CH3:1][NH:2][C:3]([CH:5]1[CH2:10][N:9]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([CH2:18][OH:19])=[CH:13][N:12]=2)[CH2:8][CH2:7][N:6]1[C:21]1[NH:22][C:23]2[C:29]([C:30]3[CH:31]=[C:32]([F:38])[C:33]([F:37])=[C:34]([F:36])[CH:35]=3)=[CH:28][C:27]([C:39]([F:42])([F:40])[F:41])=[CH:26][C:24]=2[N:25]=1)=[O:4]
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F
Reactant: CNC(=O)C1CN(c2ncc(CO)cc2Cl)CCN1
Solvent: CCO
Product: CNC(=O)C1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3cc(F)c(F)c(F)c3)c2[nH]1

Procedure:
A mixture of 4-(3-chloro-5-hydroxymethyl-pyridin-2-yl)-piperazine-2-carboxylic acid methylamide from step (d) above (114 mg, 0.4 mmol) and 2-chloro-6-trifluoromethyl-4-(3,4,5-trifluoro-phenyl)-1H-benzoimidazole (140 mg, 0.4 mmol, Example 51b) in EtOH (1 mL) reacted under the conditions of Example 3c to give the title compound as a white solid. MS ESI, pos. ion) m/e: 599 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([OH:23])=[N:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1.O>CN(C=O)C>[F:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][O:23][C:9]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[NH:11][N:10]=2)=[CH:33][CH:34]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CS(=O)(=O)c1ccc(-c2[nH]nc(O)c2-c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2[nH]nc(OCc3ccc(F)cc3)c2-c2ccc(F)cc2)cc1
Reaction time: 0.75 h
Yield: 80 %

Procedure:
A mixture of 4-(4-fluorophenyl)-3-hydroxy-5-(4-(methylsulphonyl)phenyl)-pyrazole [(366 mg, 1.1 mmol), prepared according to the method of Example 5C, K2CO3 (152 mg, 1.1 mmol) in DMF (20 mL) at 50° C. was treated dropwise with a solution of 1-(bromomethyl)-4-fluorobenzene (0.141 mL, 1.1 mmol) in DMF (5 mL), and the mixture was stirred for 45 minutes. The reaction mixture was then poured into water and extracted with ethyl acetate. The acetate extract was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed (silica gel, 1:1 hexanes-ethyl acetate) to provide 3-(4-fluorobenzyloxy)-4-(4-fluorophenyl)-5-(4-(methyl-sulphonyl)phenyl)pyrazole (yield: 325 mg; 80%). MS (APCI+) m/z 441 (M+H)+; (APCI−) m/z 475 (M+Cl)−; 1H NMR (300 MHz, DMSO-d6) δ3.26 (s, 3H), 5.28 (s, 2H), 7.19 (m, 3H), 7.25 (m, 3H), 7.48 (m, 2H), 7.57 (d, J=9 Hz, 2H), 7.94 (d, J=9 Hz, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([CH2:25][O:26][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:23][CH:24]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(-c2nc(-c3ccccc3)cc(-c3ccccc3)n2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(-c2nc(-c3ccccc3)cc(-c3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of [4-(4,6-diphenylpyrimidin-2-yl)-phenyl]methanol, 0.38 g (1.11 mmol), triethylamine, 0.34 mL (2.45 mmol), and 6 mL of methylene chloride was cooled to 0° C. via ice-water bath. Methanesulfonyl chloride, 0.10 mL (1.23 mmol) was added dropwise over 5 minutes. The solution stirred for 2 h at 0° C. The solution was quenched with 20 mL of water and diluted with 20 mL of ethyl acetate. The organic layer was washed with water, sat. aq. NaCl, and dried (MgSO4). After the solution was concentrated, the residue was recrystallized with EtOAc-Heptane (1:2) to afford the desired product in 0.44 g (95%) as a yellow solid. 1H NMR (DMSO-d6) 8.77 (d, 2H, J=9.0), 8.44-8.41 (m, 4H), 8.30 (s, 1H), 7.68-7.61 (m, 8H), 5.37 (s, 2H), 3.11 (s, 3H).