Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:25]4[CH:26]=[CH:27][S:23][CH:24]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccsc1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccsc4)c3O2)cc1
Yield: 77.1 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 3-thiopheneboronic acid (0.334 g, 2.61 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.389 g (77%) of (±)-(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a light yellow solid. mp 90-92° C.; Anal. calcd. for C20H18O4S2: C, 62.15; H, 4.69. Found: C, 62.2; H, 4.72.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH3:16][CH:17]([CH3:23])[CH2:18][S:19](Cl)(=[O:21])=[O:20].[CH:24]1([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1>>[CH:24]1([C:27]2[CH:33]=[CH:32][C:30]([N:31]3[CH2:13][CH2:12][C:6]4([CH2:7][CH2:8][N:9]([S:19]([CH2:18][CH:17]([CH3:23])[CH3:16])(=[O:21])=[O:20])[CH2:10][CH2:11]4)[C:4]3=[O:5])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: Nc1ccc(C2CC2)cc1
Product: CC(C)CS(=O)(=O)N1CCC2(CCN(c3ccc(C4CC4)cc3)C2=O)CC1

Procedure:
Off-white solid. MS (ESI): 391.2 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-methyl-propane-1-sulfonyl chloride and 4-cylopropyl-aniline.
Reaction SMILES: [H-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([CH2:24][OH:25])([S:16][C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:26]I>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][C:13]([CH2:24][O:25][CH3:26])([S:16][C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CI
Reactant: Cc1cccc(SC2(CO)CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCC1(Sc2cccc(C)c2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of potassium hydride (0.18 g, dry weight, 4.5 mmol; obtained from washing 0.52 g of 35% potassium hydride dispersion in mineral oil with hexanes and drying under a stream of argon) in anhydrous THF (25 mL), N-tert-butoxycarbonyl-4-(3-tolylsulfanyl)-4-hydroxymethylpiperidine (0.96 g, 2.8 mmol; Example 106, Step B) in THF (5 mL) was added. The resultant mixture was stirred at room temp. for 1 h., and treated with methyl iodide (0.31 mL, 4.97 mmol). The reacting mixture was stirred at room temp. overnight. The product mixture was cooled to 0° C., quenched with water, and diluted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:8]2=[O:23])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C([O-])(O)=O.[Na+]>O.C1COCC1>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:9]2[CH2:10][CH2:11][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:25][CH:24]=3)[C:8]2=[O:23])=[CH:14][CH:15]=1)([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1ccc(CN2CCN(Cc3ccc(N)cc3)C2=O)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(CN2CCN(Cc3ccc(NS(C)(=O)=O)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 13.8 %

Procedure:
To a solution of 1-(4-aminobenzyl)-3-(4-tert-butylbenzyl)-imidazolidin-2-one (F) (410 mg, 1.22 mmol) and triethylamine (0.2 mL, 1.44 mmol) in abs. THF there was added a solution of methanesulphonyl chloride (0.12 mL, 1.56 mmol) in 0.8 mL of abs. THF within a period of 20 min. The reaction mixture was stirred over a period of 15 h at RT, sat. NaHCO3 solution (10 mL) was added, and the mixture was stirred for 30 min. H2O (30 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic phases were washed with sat. NaCl solution, dried over Na2SO4, and the solvent was removed in vacuo. Following purification, by column chromatography, of the residue (SiO2, EtOAc/cyclohexane 2:1), there were obtained the desired product N-{4-[3-(4-tert-butylbenzyl)-2-oxoimidazolidin-1-ylmethyl]phenyl}methanesulfonamide (4) (70 mg, 14% of theory, mp: 166-168° C.) and N-{4-[3-(4-tert-butylbenzyl)-2-oxoimidazolidin-1-ylmethyl]phenyl}-N,N-bis(methanesulfonyl)imide (G) (160 mg, mp: 184-187° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][C:8]2[N:12]=[C:11]([C@H:13]([CH2:18][CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:14][C:15](O)=[O:16])[O:10][N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:42][OH:43]>O1CCCC1>[NH3:9].[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][C:8]2[N:12]=[C:11]([C@H:13]([CH2:18][CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:14][C:15]([NH:42][OH:43])=[O:16])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(COc2ccc(Cl)cc2)no1
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: N
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(COc2ccc(Cl)cc2)no1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.1 %

Procedure:
A solution of (3R)-3-{3-[(4-chlorophenoxy)methyl]-1,2,4-oxadiazol-5-yl}-6-cyclohexylhexanoic acid (Preparation 57) (180 mg, 0.44 mmol) in anhydrous tetrahydrofuran (10 ml) was treated with 1,1′-carbonyldiimidazole (71 mg, 0.44 mmol) and the mixture stirred at room temperature under a nitrogen atmosphere for 2 hours. Hydroxylamine hydrochloride (30 mg, 0.44 mmol) was then added and the mixture stirred for 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed with brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (95:5:0.5) to afford the title compound as a glass (53 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:40][OH:41].C([O-])(O)=O.[Na+]>>[OH:41][N:40]=[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)[CH2:9][CH:10]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1cc(C(=O)CC(c2ccc(-c3ccc(C(=O)NCCC(=O)O)cc3)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2ccc(-c3ccc(C(=O)NCCC(=O)O)cc3)cc2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from 3-({4′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carbonyl}-amino)-propionic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (4:1) as a colorless oil, MS (ESI+): m/z=522.2376 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[S:10][N:9]=2)=[CH:4][CH:3]=1.Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:22].CCN(C(C)C)C(C)C>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH2:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)=[O:22])[CH2:15][CH2:14]3)[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: Clc1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)CN2CCN(c3nc(-c4ccc(Cl)cc4)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.9 %

Procedure:
A mixture of 3-(4-chlorophenyl)-5-(piperazin-1-yl)-1,2,4-thiadiazole (539 mg, 1.92 mmol), 2-bromo-4′-methoxyacetophenone (440 mg, 1.92 mmol) and DIPEA (744 mg, 1.01 ml, 5.76 mmol) in 10 mL EtOH was stirred for 2 h at RT. Another portion 2-bromo-4′-methoxyacetophenone (220 mg, 960 μmol) was added and stirring continued for 2 h. The reaction was filtered off and washed with MeOH (4×5 mL) and Et2O (2×5 mL). The filter cake was dried in vacuo at 50° C. to yield 526 mg (64%) of the title compound as white solid. MS (m/e): 429.2 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]([N:8]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=O)=O)[CH3:2].C([O-])(=O)C.[NH4+:31]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[N:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:31]=1)[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)CC(=O)N(CC(=O)c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)Cc1nc(-c2ccc(F)cc2)cn1-c1ccc(F)cc1
Yield: 8.8 %

Procedure:
1.2 g N-(4-fluoro-phenyl)-N-(2-(4-fluoro-phenyl)-2-oxo-ethyl)-malonamic acid ethyl ester and 1.8 g ammonium acetate in 20 mL concentrated acetic acid were refluxed 4 h. The reaction was evaporated. Water was added to the residue and the mixture was extracted with DCM. The organic layer was dried and evaporated. The residue was purified by chromatography on silica (100% dichlormethane) to yield 100 mg of the desired compound.
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17]C)=[CH:16][C:11]=2[O:10][C:9]=1[CH3:19])=[O:7])[CH:2]([CH3:4])[CH3:3].B(Br)(Br)Br>>[CH2:1]([NH:5][C:6]([C:8]1[C:12]2[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=2[O:10][C:9]=1[CH3:19])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc2c(C(=O)NCC(C)C)c(C)oc2c1
Agent: BrB(Br)Br
Product: Cc1oc2cc(O)ccc2c1C(=O)NCC(C)C

Procedure:
This material was prepared from 6-methoxy-2-methyl-benzofuran-3-carboxylic acid isobutyl amide 84a by treatment with BBr3 in a manner as previously described for example 1d. 1H NMR (DMSO-d6) δ9.53 (1H, s), 7.90 (1H, t, J=6.1 Hz), 7.44 (1H, d, J=8.3 Hz), 6.86 (1H, s), 6.74 (1H, dd, J=8.6, 1.8 Hz), 3.07 (2H, t, J=6.1 Hz), 2.52 (3H, s), 1.81 (1H, m). 0.90 (6H, d, J=6.8 Hz).
Reaction SMILES: CS(O[CH:6]([C:8]1[CH:21]=[C:20]2[C:11]([O:12][CH2:13][CH2:14][N:15]3[C:19]2=[N:18][C:17]([C:22]2[N:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[CH:24][N:23]=2)=[CH:16]3)=[CH:10][CH:9]=1)[CH3:7])(=O)=O.[NH:30]1[CH2:35][CH2:34][CH:33]([C:36]([OH:39])([CH3:38])[CH3:37])[CH2:32][CH2:31]1>O1CCOCC1>[CH:27]([N:26]1[C:22]([C:17]2[N:18]=[C:19]3[C:20]4[CH:21]=[C:8]([CH:6]([N:30]5[CH2:35][CH2:34][CH:33]([C:36]([OH:39])([CH3:38])[CH3:37])[CH2:32][CH2:31]5)[CH3:7])[CH:9]=[CH:10][C:11]=4[O:12][CH2:13][CH2:14][N:15]3[CH:16]=2)=[N:23][CH:24]=[N:25]1)([CH3:29])[CH3:28]
Reactant: CC(C)(O)C1CCNCC1
Reactant: CC(OS(C)(=O)=O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Solvent: C1COCCO1
Product: CC(c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2)N1CCC(C(C)(C)O)CC1
Temperature: 90 °C

Procedure:
To a solution of 1-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-13-yl}ethyl methanesulfonate from Example 146 (123 mg, 0.295 mmol) in dioxane (15 mL) was added 2-(piperidin-4-yl)propan-2-ol (422 mg, 2.95 mmol). The mixture was heated at 90° C. overnight. The solvent was removed and the residue was purified by Combi-flash eluting with a 5-95% gradient of CH3CN in 0.3% NH4HCO3 to give 152. The enantiomers were separated by chiral SFC (OD-H column, 15% EtOH isocratic) to give: 17.6 mg of one enantiomer and 13.0 mg of the other (22% total yield)
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[NH:17][C:16]2=O)=[C:4]([F:27])[CH:3]=1.P(Cl)(Cl)([Cl:30])=O.C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl-].[Na+].O>[Cl:30][C:16]1[N:15]([C:5]2[CH:6]=[C:7]([O:8][C:9]3[N:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[C:2]([Cl:1])=[CH:3][C:4]=2[F:27])[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=1
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(Oc2ncccn2)c(Cl)cc1F
Reactant: O=P(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1cc(C(F)(F)F)nc(Cl)n1-c1cc(Oc2ncccn2)c(Cl)cc1F
Yield: 49.9 %

Procedure:
A mixture of 3-[4-chloro-2-fluoro-5-(2-pyrimidinyloxy)phenyl]-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione(2.01 g, 0.005 mol), phosphorus oxychloride (3.83 g, 0.025 mol), triethylamine (2.02 g, 0.02 mol and toluene (7 ml) was heated under reflux for 2 hours. The reaction mixture was poured into brine, and extracted with ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel(40% ethyl acetate/hexane) to give compound III-2 (1.05 g, yield 49.9%) as a white solid, m.p.132-134.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:23]([OH:27])(=[O:26])[CH:24]=[CH2:25]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:23]([CH2:24][CH2:25][N:8]([CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=1)[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)([OH:27])=[O:26]
Reactant: COC(=O)c1ccc(OCCCNc2ccc(Cl)cc2)cc1
Reactant: C=CC(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OCCCN(CCC(=O)O)c2ccc(Cl)cc2)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Methyl 4-[3-[N-[4-chlorophenyl)amino]propoxy]benzoate (2.0 g) was dissolved in toluene (6 ml), and thereto was added acrylic acid (2.24 ml), and the mixture was heated with stirring at 100° C. for 24 hours. The reaction mixture was diluted with ethyl acetate, and washed successively with aqueous sodium bicarbonate solution 2 times and water once, and it was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixed solvent of chloroform/methanol [60:1 (v/v)] to give the oily desired product (1.64 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].CN(C)CCN(C)C.C([Li])CCC.I[CH3:25].[CH3:26][S:27]SC>O1CCCC1.O>[CH3:25][C:3]1([S:27][CH3:26])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: CI
Reactant: CSSC
Reactant: O=C1Cc2ccccc2N1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CSC1(C)C(=O)Nc2ccccc21
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
1,3-Dihydro-2H-indol-2-one (3.3 g,25 mmol) and tetramethylethylenediamine (6.4 g, 55 mmol) was dissolved in freshly distilled tetrahydrofuran under nitrogen and cooled to -75° C. in an acetone/dry ice bath. n-Butyllithium (2.5M, 22 ml, 55 mmol) was added and the mixture was stirred at -75° C. for 30 minutes. Iodomethane (3.57 g, 25 mmol) was added and the mixture was allowed to warm to -20° C., the mixture was recooled to -75° C. then dimethyl disulfide (2.35 g, 25 mmol) was added and the mixture was allowed to warm to room temperature. Water (5 ml) was added and the mixture was concentrated under reduced pressure to a yellow oil. Column chromatography on silica gel (eluent ethyl acetate/hexane) gave 3-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one as a yellow oil which solidified on standing.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[O:13])[CH:6]=[CH:5]2.[CH:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C>O1CCCC1>[C:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[O:13])[CH:6]=[CH:5]2)#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=Cc1ccc2cc(Br)ccc2n1
Reactant: C#CCCCCCCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCC#Cc1ccc2nc(C=O)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.5 %

Procedure:
A solution of 6-bromo-2-quinolinecarboxaldehyde (18.9 g), 1-decyne (12.2 g) and triethylamine (24.3 g) in dry tetrahydrofuran (300 ml) was chilled to 5° C. and degassed, under nitrogen. bis(Triphenylphosphine)palladium(II)chloride (0.56 g) and copper (I) iodide (0.08 g) were added to the reaction mixture, which was degassed and stirred under nitrogen at room temperature for 30 mins, and then heated at 40° C. for 19 hrs. The mixture was cooled to room temperature, the precipitate was filtered, and the filter cake was washed with ethyl acetate, and the filtrate was evaporated. The residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed on silica gel, eluting with heptane to heptane:2% ethyl acetate. The appropriate fractions were collected and evaporated. A 2 g-portion of the residue (23.4 g) was chromatographed, eluting with hexane:dichloromethane/2:1 give 1.3 g (64.0%) of product, mp 46.5°-47.5° C.
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5]([C:7]1[N:11]=[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])[N:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:8]=1)=O>O1CCCC1.CO>[OH:30][CH:23]([C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[N:9]1[C:10]([CH2:12][N:13]([CH3:14])[CH3:15])=[N:11][C:7]([CH2:5][OH:4])=[N:8]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)Cc1nc(CO)nn1-c1ccc(Cl)cc1C(O)c1ccccc1
Temperature: 0 °C

Procedure:
9.1 g (0.24 mole) of sodium borohydride is added portionwise at room temperature, with stirring, to a solution of 16.0 g (0.040 mole) of 1-(2-benzoyl-4-chlorophenyl)-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carboxylic acid methyl ester [see Example 2] in 320 ml of tetrahydrofuran and 320 ml of methanol. The temperature of the reaction solution rises during the addition to 40°. The reaction mixture is subsequently heated for one hour at 50°; 100 ml of ice water is then added, and the bulk of the tetrahydrofuran and of the methanol is evaporated off in vacuo. The aqueous residue is extracted twice with ethyl acetate. The organic phase is washed once with 1 N sodium hydroxide solution, and is then extracted three times with 2 N hydrochloric acid solution. Sodium carbonate is added to the aqueous acidified extracts until the pH-value reaches 10. The precipitated base is dissolved in ethyl acetate; the solution is washed twice with water and once with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo. The residue is triturated with ether and hexane, whereupon the reaction product precipitates in crystalline form. After filtration with suction and drying in vacuum, there is obtained 1-[2-(α-hydroxybenzyl)-4-chlorophenyl]-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-methanol, m.p. 121°-123°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCCO)o1
Reactant: Cc1ccccc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccccc1OCCCCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanol (1.32 g), 2-methylphenol (865 mg), tributylphosphine (1.21 g) and tetrahydrofuran (30 ml) was added 1,1′-(azodicarbonyl)dipiperidine (1.51 g) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[4-(2-methylphenoxy)butyl]oxazole was obtained as crystals (1.61 g, 96%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction. Recrystallization from acetone-isopropyl ether gave colorless prisms. Melting point 71-72° C.
Reaction SMILES: [N+](C1C=CSC=1C1C=CC(Cl)=CC=1)([O-])=O.[N+:16]([C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)([O-])=O>>[NH2:16][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1
Reactant: COc1ccc(-c2sccc2[N+](=O)[O-])cc1
Agent: O=[N+]([O-])c1ccsc1-c1ccc(Cl)cc1
Product: COc1ccc(-c2sccc2N)cc1
Yield: 79 %

Procedure:
The same procedures as described in Example 3 were carried out except that 3-nitro-2-(4-chlorophenyl)thiophene was replaced by 3-nitro-2-(4-methoxyphenyl)thiophene. The yield was 79%. 1 H-NMR(CDCl3, δ value):3.77(2H, brs), 3.83(3H, s), 6.65(1H, d, J=5.9), 6.96(2H, d, J=8.8), 7.07(1H, d, J=5.9), 7.43(2H, d, J=8.8)
Reaction SMILES: [Br:1][C:2]1[CH:25]=[C:24]2[C:5]([CH2:6][C:7]3([C:17]42[NH:21][C:20](=S)[C:19]([CH3:23])=[N:18]4)[CH2:12][CH2:11][CH:10]([C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[NH3:26]>>[Br:1][C:2]1[CH:25]=[C:24]2[C:5]([CH2:6][C:7]3([C:17]42[N:21]=[C:20]([NH2:26])[C:19]([CH3:23])=[N:18]4)[CH2:12][CH2:11][CH:10]([C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: CC1=NC2(NC1=S)c1cc(Br)ccc1CC21CCC(C(F)(F)F)CC1
Reactant: N
Product: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC(C(F)(F)F)CC1
Temperature: 110 °C
Yield: 21.5 %

Procedure:
6′-Bromo-5″-methyl-4-(trifluoromethyl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione (Example 124 Step 2, 40 mg, 0.09 mmol) was dissolved in ammonia (7 M in MeOH) (2 mL, 14.0 mmol) in a microwave vial. The vial was capped, and heated to 110° C. for min in a microwave reactor. The solution was concentrated, and the residue dissolved in ammonia (7 M in MeOH) (2 mL, 14.0 mmol) and heated to 110° C. in a microwave reactor. This cycle (concentration, addition of ammonia and heating) was repeated until all starting material was converted to product (6 times). The reaction mixture was cooled to r.t., concentrated in vacuo and purified by preparative chromatography to give the title compound (8 mg, 21% yield): 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.38 (m, 4 H) 1.42-1.59 (m, 3 H) 1.84-1.92 (m, 1 H) 1.98 (m, 1 H) 2.20 (s, 3 H) 2.76-2.94 (m, 2 H) 6.55-6.62 (m, 3 H) 7.22 (m, 1 H) 7.34 (m, 1 H); MS (APCI+) 416 [M+H]+.