Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH2:3]([CH2:10][C:11](=[O:13])[CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>CO>[Br:1][CH2:12][C:11](=[O:13])[CH2:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)CCc1ccccc1
Reactant: BrBr
Solvent: CO
Solvent: O
Product: O=C(CBr)CCc1ccccc1
Temperature: 8.5 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
A freshly prepared solution of bromine (258.9 g) in methanol (600 mL) was added dropwise during 1 h 20 min to a stirred solution of benzylacetone (222.3 g) in methanol (600 mL) at 7-10° C. An exothermic reaction took place, and to maintain the necessary temperature (7-10° C.), the flask should be immersed in a ice-water bath. When orange-red color of bromine disappeared, water (1500 mL) was added to the mixture and the obtained mixture was stirred overnight. The organic layer (on the bottom) was separated, water phase was extracted with dichloromethane (2×600 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. The oily residue was dissolved in hexane (2500 mL) and the obtained solution was kept overnight at −10° C. Precipitated fine crystals (needles) were filtered off, washed on filter with cold hexane, dried under reduced pressure at room temperature to give 1-bromo-4-phenyl-2-butanone (213.0 g, 63% yield), mp 39-40° C. 1H NMR (CDCl3) δ 2.95-3.00 (m, 4H); 3.83 (s, 2H); 7.16-7.30 (m, 5H).
Reaction SMILES: [CH3:1][N+:2]#[C-:3].[Li]CCCC.CCCCCC.[CH3:15][C:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:20])[C:17](Cl)=[O:18].[Na+].[Cl-]>C1COCC1>[CH3:20][C:16]([C:17]1[O:18][CH:1]=[N:2][CH:3]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:15]
Reactant: CC(C)(C(=O)Cl)c1ccccc1
Reactant: [C-]#[N+]C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(c1ccccc1)c1cnco1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 53.9 %

Procedure:
To a solution of methyl isocyanide (1.3 mmol, 1.3 eq.) in THF (5 mL) at −78° C. was added dropwise a solution of n-BuLi in Hexane (2.5 M, 1.3 mmol, 1.3 eq.). The resulting yellowish solution was stirred at −78° C. for an additional 45 min and 2-Methyl-2-phenylpropionyl chloride (1.0 mmol, 1.0 eq.) was slowly added. The mixture was stirred at −78° C. for an additional 1 h and allowed to warm to room temperature followed by the addition of saturated aqueous NaCl solution (5 mL). The mixture was extracted by EtOAc (3×5 mL) and the combined organic extracts were washed by saturated aqueous NaCl solution, dried by Na2SO4, filtered and evaporated in vacuo. The residue was further purified by flash chromatography (silica gel, 10% EtOAc/Hexanes) to afford 5-(1-Methyl-1-phenylethyl)oxazole as a colorless oil (101 mg, 54%). 1H NMR: δ (400 MHz, CDCl3) 7.74 (s,1H), 7.30 (m, 2H), 7.23 (m, 3H), 6.85 (s,1H), 1.69 (s, 6H). MS (M+H+): 188.1
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:21]([OH:23])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24]I>C1COCC1.CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:21][O:23][CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)O
Reactant: CI
Solvent: C1CCOC1
Solvent: CC#N
Product: COC[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
To a solution of (2S,4R)-4-benzyloxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (15.5 mmol; 5.0 g) in THF (135 mL) is added 1 M THF solution of borane THF complex (31 mmol; 31 mL) at 0° C. under nitrogen. The solution is stirred for 1 hour at room temperature, quenched by dropwise addition of 15 ml of MeOH. After concentrating, the mixture is diluted with dichloromethane and saturated aqueous ammonium chloride solution. The product is extracted twice with dichloromethane. The combined organic layer is washed with brine, dried over MgSO4, filtered, concentrated under reduced pressure to give the crude product. To a solution of crude material in MeCN (20 mL) were added Ag2O (46.5 mmol; 8.9 g) and MeI (155 mmol; 21.8 g) at room temperature, heated and stirred under reflux condition for 3 hours. After filtration and concentration, the resulting mixture is diluted with dichloromethane and saturated aqueous ammonium chloride solution. The product is extracted twice with dichloromethane. The combined organic layer is washed with brine, dried over MgSO4, filtered, concentrated under reduced pressure to give the crude (2S,4R)-4-benzyloxy-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (3.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.Br[C:14]1[CH:18]=[CH:17][S:16][CH:15]=1.BrC1SC=CC=1>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: Brc1ccsc1
Agent: Brc1cccs1
Product: COc1ccc(Nc2ccsc2)c([N+](=O)[O-])c1
Reaction time: 6 h

Procedure:
Reaction of 4-methoxy-2-nitroaniline (X: R=4-OMe) and 3-bromothiophene (XI: R'=3-Br) as described above for Example 55, but for only 6 hours, gave 4-methoxy-2-nitro-N-(3-thienyl)aniline (XIV: R'=4-OMe, 3-thienyl) (71%): mp (EtOAc/petroleum ether) 121-123° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1)#[CH:2].[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15](Br)[CH:16]=1>C(N(CC)CC)C.C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=2)[CH:16]=1
Reactant: Brc1cncc(Br)c1
Reactant: C#Cc1cccc(F)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Fc1cccc(C#Cc2cncc(Br)c2)c1
Temperature: 70 °C
Yield: 27.5 %

Procedure:
Add 1-ethynyl-3-fluorobenzene (250 mg, 2.11 mmol) to a mixture of 3,5-dibromopyridine (500 mg, 2.11 mmol) in triethylamine (4 mL) containing bis(triphenylphosphine)palladium (II) dichloride (28 mg, 0.04 mmol) and copper (I) iodide (15 mg, 0.08 mmol) and heat at 70° C. for 2 h. Cool to room temperature, dilute with ethyl acetate and an aqueous solution of ammonium chloride and separate the resulting layers. Wash the organic layer with an aqueous saturated solution of sodium chloride, dry (magnesium sulfate), filter and concentrate. Purify by silica gel chromatography, eluting with 0.5% ethanol in 50:50 dichloromethane:hexanes to give the title compound (160 mg, 28%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:9]([O:11][CH3:12])=[O:10].[I:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)([CH3:30])[CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=1>CN(C=O)C>[I:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([C:31]2[CH:32]=[CH:33][C:34]([O:37][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:9]([O:11][CH3:12])=[O:10])=[CH:35][CH:36]=2)([CH3:30])[CH:27]([CH3:28])[CH3:29])=[CH:24][CH:25]=1
Reactant: CC(C)C(C)(c1ccc(O)cc1)c1ccc(I)cc1
Reactant: COC(=O)C(Br)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1ccc(C(C)(c2ccc(I)cc2)C(C)C)cc1)c1ccccn1

Procedure:
Cesium carbonate (1.5 equiv.) followed by methyl bromo(pyridin-2-yl)acetate (5i) (1 equiv.) are added to a stirred solution of 5b (1 equiv.) in DMF at room temperature. After completion of reaction, the reaction mixture is quenched with saturated aqueous ammonium chloride, poured into saturated aqueous sodium bicarbonate and extracted three times with EtOAc. The combined organic extracts are washed with water, brine, dried (Na2SO4) and concentrated in vacuo to afford the title compound 5c.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[CH2:3].[SH2:9]>>[C:2]([SH:9])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:1])[CH3:3]
Reactant: S
Reactant: C=C(C)CC(C)(C)C
Product: CC(C)(C)CC(C)(C)S
Temperature: 45 °C

Procedure:
200 ml of dry sulphonated Amberlyst 15 resin are placed in a tubular reactor with a capacity of approximately 420 ml (length: 135 cm; bore: 20 mm). Liquid diisobutylene at a rate of 112 g/h (that is 1 mole/h) and 136 g/h of gaseous H2S (that is 4 moles of H2S per 1 of diisobutylene) are introduced continuously at the head of the reactor at a pressure of 10 bars. The reactants are mixed intimately before their entry into the reactor, where the reaction mixture is maintained at the temperature of 45° C. The liquid flowing continuously from the reactor is collected and the remaining hydrogen sulphide is degassed. Analyses are carried out both on the crude liquid reaction products and on the gaseous effluents from the reaction, with the aim of establishing the complete balance of the reaction.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[C:18](=[O:20])[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH:37]([C:39]1[CH:40]=[CH:41][C:42]([OH:50])=[C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:44]=1)[OH:38]>>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:29][CH2:30][CH:31]([NH:35][CH2:36][CH:37]([C:39]5[CH:40]=[CH:41][C:42]([OH:50])=[C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:44]=5)[OH:38])[CH2:32][CH2:33]4)=[CH:26][CH:27]=3)[C:18](=[O:20])[N:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(C=C3SC(NC4CCN(Cc5ccccc5)CC4)=NC3=O)cc2)CC1
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(C=C4SC(NC5CCN(Cc6ccccc6)CC5)=NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 1-{4-[2-(1-benzyl-piperdin-4-ylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl)-piperidin-4-one (which was obtained in Intermediate 21) and N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Intermediate 9) according to the procedure of Example 1 as a pale yellowish solid; mp>210° C. (dec.); 1 H NMR (300 MHz, DMSO-d6) δ1.20-1.40 (m, 2 H), 1.40-1.65 (m, 2 H), 1.70-2.00 (m, 4 H), 2.06 (brt, J=9.8 Hz, 2 H), 2.50-3.50 (m, 6 H), 2.92 (s, 3 H), 3.47 (s, 2 H), 3.70-4.00 (m, 2 H), 4.47 (dd, J=7.9, 4.3 Hz, 1 H), 6.81 (d, J=8.2 Hz, 1 H), 6.95-7.05 (m, 2 H), 7.17 (d, J=1.9 Hz, 1 H), 7.20-7.55 (m, 8 H); MS (ES) m/z:353.1 ((M+2H)2+, 100%); 705.1 (MH+, 5%); HRMS Calcd. for C36H45N6O5S2 (MH+): 705.2893. Found: 705.2921.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@H:14]([C:27]([N:29]([C@@H:41]([CH3:49])[CH:42]([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[N:39]=[CH:38][CH:37]=[CH:36]2)=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]>>[CH2:47]([O:46][CH:42]([O:43][CH2:44][CH3:45])[C@@H:41]([N:29]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[N:39]=[CH:38][CH:37]=[CH:36]2)[C:27](=[O:28])[C@@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4](=[O:5])[NH:3][CH2:1][CH3:2])[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:25])[CH3:23])[CH3:49])[CH3:48]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: CCNC(=O)NN(C)CC(=O)O
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N(Cc1cccc2cccnc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 51 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-(((S)-1,1-diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-6-oxohexylcarbamate (Compound IV-14) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[S:15])[NH2:14].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[OH:29])=O>CCOC(C)=O>[CH3:6][O:7][C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[S:15][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[OH:29])[N:14]=1
Reactant: COc1ccc(C(=O)CBr)c(O)c1
Reactant: COC(=O)CCCCC(N)=S
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCCCc1nc(-c2ccc(OC)cc2O)cs1
Temperature: 25 °C
Yield: 165.9 %

Procedure:
Add THF (50 mL, anhydrous) to a roundbottom flask containing 5-thiocarbamoyl-pentanoic acid methyl ester-(2.63 g, 15.0 mmol) and 2-bromo-1-(2-hydroxy-4-methoxy-phenyl)-ethanone (4.90 g, 15.0 mmol, 75% pure). Heat to reflux under N2 overnight. Cool to room temperature, add EtOAc, wash with saturated NaHCO3 solution, brine, and backextract from each aqueous layer with EtOAc. Dry combined organic layers over MgSO4 and concentrate to get 8 grams of a yellow solid. Adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 0-20% EtOAc/hexanes followed by flash chromatography on silica gel eluting with CHCl3 to afford the title compound (2.69 g, 56%). MS (IS) 322 (M+1)+.
Reaction SMILES: Br.Br.[OH:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][C:5]=1[CH3:17].Cl[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:3][C:4]1[C:5]([CH3:17])=[CH:6][C:7]([N:11]2[CH2:12][CH2:13][N:14]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=3)[CH2:15][CH2:16]2)=[CH:8][C:9]=1[CH3:10]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cc1cc(N2CCNCC2)cc(C)c1O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)cc(C)c1O
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 58.8 %

Procedure:
2.21 g (6 mmol) of 1-(4-hydroxy-3,5-dimethylphenyl)piperazine dihydrobromide, 1.14 g (6.25 mmol) of 2-chloro-5-trifluoromethylpyridine and 1.245 g (9 mmol) of K2CO3 in 27 ml of absolute DMF were reacted by the same procedure as described in Example 20. The mixture was subsequently stirred for 3.5 hours at 90° C. After evaporation of the DMF, the residue was mixed with water, and the oily crystalline material produced during this was filtered off under suction, dissolved in methanol and clarified using activated charcoal. After filtration, a little water was added to the filtrate, a crystalline precipitate being produced. This was filtered off under suction (yield 1.63 g) and chromatographed as described in Example 15 on a silica gel/CH2Cl2 column (diameter 2.0 cm, height 22 cm). In this fashion, 1.24 g (=59% yield) of 1-(4-hydroxy-3,5-dimethylphenyl)-4-(5-trifluoromethylpyrid-2-yl)piperazine, melting point 143°-44° C., were obtained;
Reaction SMILES: C([Li])CCC.[O:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[CH3:11][N:12]1[C:16]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:23]=2)=[N:15][C:14]([CH:35]=[O:36])=[N:13]1.O>O1CCCC1>[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:35]([C:14]1[N:15]=[C:16]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:23]=2)[N:12]([CH3:11])[N:13]=1)[OH:36]
Reactant: Cn1nc(C=O)nc1NCCCOc1cccc(CN2CCCCC2)c1
Reactant: c1ccoc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(C(O)c2ccco2)nc1NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 18 h

Procedure:
n-Butyllithium (1.55M in n-hexane, 5.96 ml) was added dropwise to a stirred solution of furan (0.16 ml) in anhydrous tetrahydrofuran (20 ml), under nitrogen at -40°. The stirred solution was allowed to warm slowly to 20°, heated under reflux for 3 h, added dropwise at 0° to a solution of 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-carboxaldehyde (1.0 g) in tetrahydrofuran (10 ml), and the resulting solution was stirred at 20° for 18 h. Water (20 ml) was added, the mixture concentrated, extracted with ethyl acetate and the extract was dried and evaporated. The residual oil (0.9 g) was chromatographed using System C to give the title compound (0.16 g) as a brown oil.
Reaction SMILES: [C:1]([CH:4]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][S:9][CH2:8][C@@H:7]([C:17]([OH:19])=[O:18])[NH:6][C:5]1=[O:20])(O)=O.N1CCCCC1.C=O.Cl>N1C=CC=CC=1>[CH2:1]=[C:4]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][S:9][CH2:8][C@@H:7]([C:17]([OH:19])=[O:18])[NH:6][C:5]1=[O:20]
Reactant: O=C(O)C1CCCCCCCSC[C@@H](C(=O)O)NC1=O
Agent: C=O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: C=C1CCCCCCCSC[C@@H](C(=O)O)NC1=O
Temperature: 65 °C
Reaction time: 2 h

Procedure:
(3R)-6-Carboxy-5-oxo-1-thia-4-azacyclotridecane -3-carboxylic acid (1.71 g, 5.64 mmol) is dissolved in pyridine (20 ml) and piperidine (0.096 g, 1.13 mmol) is added followed by paraformaldehyde (0.25 g, 8.46 mmol). The mixture is heated to 65° C. and stirred for 2 hours. The mixture is cooled to room temperature, poured into 6N hydrochloric acid (100 ml) and extracted with ethyl acetate (2×100 ml). The combined extracts are washed with brine (1×100 ml), dried (MgSO4) and solvent is evaporated to give (3R)-6-methylidene-5-oxo-1-thia-4-azacyclotridecane-3-carboxylic acid, m.p. 184°-186° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:13]3[N:12]=[C:11]([NH:16]C(=O)C(C)(C)C)[NH:10][C:9](=[O:23])[C:8]=3[C:7]=2[CH:24]=1.[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[NH2:16][C:11]1[NH:10][C:9](=[O:23])[C:8]2[C:7]3[CH:24]=[C:3]([CH2:2][NH:30][C:29]4[CH:31]=[CH:32][C:26]([F:25])=[CH:27][CH:28]=4)[CH:4]=[CH:5][C:6]=3[CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CC(C)(C)C(=O)Nc1nc2ccc3ccc(CBr)cc3c2c(=O)[nH]1
Reactant: Nc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc2ccc3ccc(CNc4ccc(F)cc4)cc3c2c(=O)[nH]1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
N-(9-Bromomethyl-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.97 g, 2.5 mmole) and 4-fluoroaniline (0.56 g, 5 mmole) (Aldrich) were dissolved in dimethylformamide (15 ml). The reaction was stirred for 30 minutes at 100° C., sodium bicarbonate (0.42 g, 5 mmole) added and the suspension stirred for a further 30 minutes. The dimethylformamide was removed in vacuo, the residue washed with methylene chloride and filtered. The filtrate was evaporated, and the residue was subjected to chromatography on a Waters Prep 500 instrument (silica cartridge, elution with ethyl acetate/methylene chloride (1:19)). Fractions containing product were concentrated in vacuo, the residue dissolved in a minimum amount of ethyl acetate, and the solution diluted with hexane until precipitate formed. The solid was collected by filtration and dried under high vacuum to give the title compound as a beige solid (0.305 g,29%). 1H NMR (DMSO-d6, 200 MHz) δ: 1.25 (s, 9H, t-butyl); 4.42 (d, J=6 Hz,2H, CH2); 6.33 (t,J=6 Hz, 1H, NH); 6.53-6.60 (m, 2H, Ar); 6.85 (t, J=8 Hz, 2H, Ar); 7.50 (d, J=10 Hz, 1H, Ar); 7.60 (dd, J=8, 2 Hz, 1H, Ar); 7.96 (d, J=8 Hz, 1H, Ar); 8.19 (d, J=8 Hz, 1H, Ar); 9.72 (s, 1H, Ar); 11.23 (s, 1H, NH); 12.28 (s, 1H, NH).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:9]=[CH:8][O:7][N:6]=1.O.[NH2:12][NH2:13]>C(O)C>[O:7]1[CH:8]=[CH:9][C:5]([CH2:4][C:3]([NH:12][NH2:13])=[O:2])=[N:6]1
Reactant: COC(=O)Cc1ccon1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)Cc1ccon1
Yield: 78 %

Procedure:
As described for example 112a, isoxazol-3-yl-acetic acid methyl ester in ethanol was reacted with hydrazine hydrate (2 equivalents) at rt for 16 h. After evaporation of the solvent the residue was chromatographed (SiO2, dichloromethane:methanol:aq.ammonia (25%)=100:0:0 to 90:10:1) to afford the title compound as a white solid (yield: 78%). MS: m/e=142.1 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3](=[O:30])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:57][C:58]1[CH:59]=[C:60](B(O)O)[CH:61]=[CH:62][C:63]=1[O:64][CH3:65]>>[F:57][C:58]1[CH:59]=[C:60]([C:2]2[C:3](=[O:30])[C:4]3[C:9]([C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]2)[CH:5]=3)[CH:61]=[CH:62][C:63]=1[O:64][CH3:65]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: O=C1C(Br)=C(c2ccc(F)cc2F)c2ccc(OCCN3CCS(=O)(=O)CC3)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3ccc(F)cc3F)c3ccc(OCCN4CCS(=O)(=O)CC4)cc3C2=O)cc1F
Yield: 74 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-[2-(1,1-dioxothiomorpholin-4-yl)ethoxy]-1H-inden-1-one obtained in Step 1 of Example 112 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and 3-fluoro-4-methoxyphenylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (74%).
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].Br[C:33]1[S:34][CH:35]=[C:36]([CH3:38])[N:37]=1>CCCCCC.C(OCC)(=O)C>[CH:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:12]2[C:11]3[C:24]([CH3:25])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])[C:8]([CH3:29])=[C:9]([C:33]4[S:34][CH:35]=[C:36]([CH3:38])[N:37]=4)[C:10]=3[O:14][CH2:13]2)=[CH:16][CH:17]=1)([CH3:23])[CH3:22]
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Reactant: Cc1csc(Br)n1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1csc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)n1
Yield: 62 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 2-bromo-4-methyl-1,3-thiazole, the title compound was synthesized in the same manner as in Example 107. Yield: 62%. Melting point: 240-241° C. (hexane-ethyl acetate).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:6]([CH3:12])=[CH:5][C:4]=1[OH:13])[CH3:2].[H-].[Na+].Br[CH2:17][C:18]#[N:19]>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:6]([CH3:12])=[CH:5][C:4]=1[O:13][CH2:17][C:18]#[N:19])[CH3:2]
Reactant: N#CCBr
Reactant: CCc1c(O)cc(C)c2sccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(OCC#N)cc(C)c2sccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
4-Ethyl-7-methyl-benzo[b]thiophen-5-ol (438 mg, 2 mmol) was dissolved in 10 ml DMF, and the reaction mixture was cooled to zero degrees C. Sodium hydride (66 mg, 3 mmol) was added and the reaction mixture was stirred 30 minutes at zero C. Bromoacetonitrile (170 ul, 3 mmol) was added, and the reaction mixture was stirred 10 minutes at zero degrees C., then allowed to warm to room temperature. The reaction was quenched after 1 hour at room temperature with water, diluted with ethyl acetate, washed with water, brine, and dried over magnesium sulfate. Solvent was removed in vacuo, and the residue chromatographed (10% ethyl acetate in hexanes) to give 422 mg of (4-Ethyl-7-methyl-benzo[b]thiophen-5-yloxy)-acetonitrile as an oil, 80%.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F-:13].[K+].O>S1(CCCC1)(=O)=O>[F:13][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: [F-]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: O=Cc1ccc(F)c([N+](=O)[O-])c1
Yield: 92.5 %

Procedure:
18.6 g (0.1 mol) of 4-chloro-3-nitrobenzaldehyde and 8.7 g (0.15 mol) of potassium fluoride in 100 ml of sulpholane are stirred for 1 hour at 180° C. The mixture is stirred with 300 ml of water and the aldehyde is extracted with methylene chloride. After the customary working-up , 17.1 g of 92% strength 4-fluoro-3-nitrobenzaldehyde are obtained.