Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:15][CH3:16])[CH:10]([OH:14])[C:11]([OH:13])=O)=O)(C)(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN1CCOCC1>>[CH2:31]([NH:38][C:11](=[O:13])[C@@H:10]([OH:14])[CH:9]([NH2:8])[CH2:15][CH3:16])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C(=O)O
Reactant: NCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CCC(N)[C@H](O)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid (300 mg, 1.29 mmol) was combined with EDC (400 mg, 2.1 mmol) and HOBt (400 mg, 2.6 mmol). A solution of benzylamine (0.22 mL) and 4-methylmorpholine (0.5 mL) in dichloromethyl (4 mL) was added in one portion. The mixture was stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (150 mL), the solution was washed with 1N aqueous HCl, water, saturated aqueous NaHCO3 solution and brine. The resultant mixture was dried with magnesium sulfate and evaporated under vacuum to yield (S)-3-amino-2-hydroxy-pentanoic acid benzylamide (380 mg) as a white solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19](Cl)(Cl)=[S:20]>C1(C)C=CC=CC=1>[CH2:3]1[CH2:2][O:1][C:6]2[CH:7]=[CH:8][C:9]([N:11]=[C:19]=[S:20])=[CH:10][C:5]=2[O:4]1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc2c(c1)OCCO2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: S=C=Nc1ccc2c(c1)OCCO2
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
To a mixture of 1,4-benzodioxan-6-amine (15.1 g; 100 mmol) and triethylamine (20.2 g; 200 mmol) in toluene (350 ml) was added dropwise over 10 min. thiophosgene (11.5 g; 100 mmol) in toluene (50 ml). The mixture was stirred at 80° C. for 30 min., cooled to room temperature and filtered. The filtrate was evaporated. The product was redissolved in toluene and concentrated in vacuo. The resulting oil was taken up in warm petroleum ether, which was filtered. The filtrate was concentrated to a small volume, which afforded 7.2 g of 3,4-ethylenedioxyphenylisothiocyanate.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([NH:6]C(=O)OCC2C=CC(OC)=CC=2OC)[N:3]=[CH:2]1.[CH3:21][O:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[C:33]1[C:42]2[C:37](=[CH:38][C:39]([S:43](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:45])=[O:44])=[CH:40][CH:41]=2)[CH:36]=[CH:35][N:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[C:33]1[C:42]2[C:37](=[CH:38][C:39]([S:43]([NH:6][C:4]3[N:3]=[CH:2][O:1][CH:5]=3)(=[O:44])=[O:45])=[CH:40][CH:41]=2)[CH:36]=[CH:35][N:34]=1
Reactant: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: COc1ccc(COC(=O)Nc2cocn2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Nc3cocn3)ccc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 9.2 %

Procedure:
In a 5-mL round bottom flask under N2 were dissolved 2,4-dimethoxybenzyl oxazol-4-ylcarbamate (100 mg, 0.359 mmol), perfluorophenyl 1-(2-methoxy-4-(trifluoromethyl)phenyl)isoquinoline-6-sulfonate (182 mg, 0.395 mmol) (Intermediate LLL) and cesium carbonate (351 mg, 1.078 mmol) in 1 mL of DMSO, and then the mixture was stirred at rt for 10 h. The reaction mixture was diluted with AcOEt then neutralized with NH4Cl/Ice. The aqueous phase was extracted 3× with AcOEt then the organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by MPLC (ISCO) with Hexanes:AcOEt 100:0 to 0:100 to afforded 1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(oxazol-4-yl)isoquinoline-6-sulfonamide (15 mg, 0.033 mmol, 9.29%) as a white solid. MS (ESI, positive ion) [M+1]+: 450.0.
Reaction SMILES: Cl[C:2]1[C:3]([CH:17]2[CH2:20][CH2:19][CH2:18]2)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.[NH3:21]>CO>[CH:17]1([C:3]2[C:2]([NH2:21])=[N:7][N:6]3[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: N
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Solvent: CO
Product: Nc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Temperature: 50 °C

Procedure:
6-Chloro-7-cyclobutyl-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (200 mg, 0.70 mmol) was suspended in methanol (8 ml). The mixture was saturated with ammonia and heated in a sealed tube at 50° C. overnight. The mixture was evaporated in vacuo, triturated (diethyl ether/hexane) and dried to give the title compound 1H NMR (360 MHz, d6-DMSO) δ 1.82-1.87 (1H, m), 1.99-2.35 (5H, m), 3.54-3.64 (1H, m), 7.34 (2H, vbs), 7.48-7.62 (3H, m), 8.08 (1H, s), 8.41 (2H, d, J=7.1 Hz); MS (ES+) m/e 266 [MH]+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([F:34])[CH:11]=1>>[CH:31]1([C:27]2[CH:28]=[C:29]([CH3:30])[C:24]([N:21]3[CH2:20][CH2:19][N:18]([C:16]([C:13]4[CH:14]=[CH:15][C:10]([N:4]5[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]5(=[O:8])=[O:7])=[CH:11][C:12]=4[F:34])=[O:17])[CH2:23][CH2:22]3)=[N:25][CH:26]=2)[CH2:32][CH2:33]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Reactant: C[C@H]1CNS(=O)(=O)C1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C[C@H](C)CS3(=O)=O)cc2F)CC1
Yield: 40.6 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (110 mg) described in Preparation Example 4 and (4-bromo-2-fluorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (227 mg) described in Preparation Example 121 and by the reaction and treatment in the same manner as in Example 4, the title compound (104 mg) was obtained.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[CH2:9]1[C:14](=O)[N:13](Br)[C:11](=O)[CH2:10]1.CC(N=NC(C#N)(C)C)(C#N)C.C(NCC)C>C(Cl)(Cl)(Cl)Cl>[CH2:11]([N:13]([CH2:14][CH3:9])[CH2:8][C:4]1[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][N:5]=1)[CH3:10]
Reactant: Cc1cc(I)ccn1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCNCC
Product: CCN(CC)Cc1cc(I)ccn1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Combine 4-iodo-2-methyl-pyridine (1.1 g, 5 mmol), NBS (0.98 g, 1.1 equiv.) and carbon tetrachloride (50 mL) in a round bottomed flask under nitrogen. Add AIBN (82 mg, 0.1 equiv.) and heat reaction overnight at reflux. Filter the reaction, washing with hexanes. Concentrate filtrate to approximately 10-20 mL volume. Redissolve in THF (20 mL) and cool to 0° C. under nitrogen. Add diethylamine (1.04 mL, 2 equiv.) dropwise via syringe and stir one hour at 0° C. Remove cooling bath and let warm to room temperature. After 6 hours total, concentrate to dryness and purify by silica gel (1:1 Hexanes:Ethyl Acetate→Ethyl Acetate) to give a tan liquid (0.51 g, 35% over 2 steps). MS (ES), m/z 291.0 (M+1).
Reaction SMILES: N(OC(C)(C)C)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:16])=[C:13]([CH:15]=1)N.[CH3:17][S:18]SC>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:16])=[C:13]([S:18][CH3:17])[CH:15]=1
Reactant: CSSC
Reactant: Cc1ccc(Cl)cc1N
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Product: CSc1cc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 504.3 %

Procedure:
t-Butyl nitrite (4 ml) was added to a mixture of 5-chloro-2-methylaniline (4 g) and dimethyl disulphide (26.3 g) in chloroform. After the reaction started t-butyl nitrite (17.7 ml) and 5-chloro-2-methylaniline (16 g) were added simultaneously. The mixture was stirred at room temperature for 2 hours and left to stand overnight. The mixture was washed with water, aqueous hydrochloric acid (2M), water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 4-chloro-2-methylsulphenyltoluene (24.6 g) as a red oil, NMR (CDCl3): 2.2(s,3H), 2.4(s,3H), 6.85(s,2H), 7.0(s, 1H).
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:8]=[C:9]([CH3:14])[C:10]([CH3:13])=[N:11][CH:12]=1.CON(C)[C:18]([C:20]1[C:29](=[O:30])[C:28]2[C:23](=[N:24][C:25]([CH3:31])=[CH:26][CH:27]=2)[N:22]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Br:39])[N:34]=2)[CH:21]=1)=[O:19].O>O1CCCC1>[Br:39][C:35]1[N:34]=[C:33]([CH2:32][N:22]2[C:23]3[C:28](=[CH:27][CH:26]=[C:25]([CH3:31])[N:24]=3)[C:29](=[O:30])[C:20]([C:18]([C:7]3[CH:12]=[N:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH:8]=3)=[O:19])=[CH:21]2)[CH:38]=[CH:37][CH:36]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2nc(C)ccc2c1=O
Reactant: Cc1cc(I)cnc1C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(=O)c(C(=O)c3cnc(C)c(C)c3)cn(Cc3cccc(Br)n3)c2n1
Reaction time: 1 h
Yield: 39.6 %

Procedure:
0.23 mL (0.469 mmol, 2M in THF) isopropylmagnesium chloride was added to a solution of 104.4 mg (0.448 mmol) of 5-iodo-2,3-dimethyl-pyridine in 1 mL of tetrahydrofuran. After the reaction was stirred for 40 min at room temperature 85 mg (0.204 mmol) of 1-(6-Bromo-pyridin-2-ylmethyl)-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid methoxy-methyl-amide in 0.6 mL of tetrahydrofuran was added and the reaction stirred for 1 h. Water was added and was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered and dried in vacuo. The crude product was purified by flash column chromatography using 20-100% ethyl acetate in hexane to yield 37.4 mg of 1-(6-Bromo-pyridin-2-ylmethyl)-3-(5,6-dimethyl-pyridine-3-carbonyl)-7-methyl-1H-[1,8]naphthyridin-4-one. LC-MSD, m/z for C23H19BrN4O2 [M+H]: 463.07 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 1.7 min
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:4]=1[CH2:5][N:6]1[C:12](=[O:13])[CH2:11][CH2:10][CH:9]([C:14](OCC)=[O:15])[CH2:8][CH2:7]1.[BH4-].[Li+].O>C1COCC1>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([CH2:14][OH:15])[CH2:10][CH2:11][C:12]1=[O:13]
Reactant: CCOC(=O)C1CCC(=O)N(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCC(CO)CCN1Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of ethyl 1-[2,4-bis(trifluoromethyl)benzyl]-7-oxoazepane-4-carboxylate (14.8 g) in THF (400 mL) was added lithium borohydride (4.5 g). The reaction mixture was stirred at 50° C. for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (12.0 g).
Reaction SMILES: O[CH:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[C:10]=1[CH:19]([CH3:21])[CH3:20])[C:3]([CH3:8])=[CH:4][C:5]([OH:7])=[O:6].[H][H]>C(O)(=O)C.[Pd]>[CH3:18][O:17][C:11]1[C:10]([CH:19]([CH3:21])[CH3:20])=[C:9]([CH2:2][CH:3]([CH3:8])[CH2:4][C:5]([OH:7])=[O:6])[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: [H][H]
Reactant: COc1ccc(C(O)C(C)=CC(=O)O)c(C(C)C)c1OC
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(CC(C)CC(=O)O)c(C(C)C)c1OC
Yield: 89.1 %

Procedure:
Compound 9 (7.00 g, 23.8 mmol) in 100 mL of acetic acid was hydrogenated on a Parr hydrogenator with 0.4 g of 10% palladium on carbon and 60 psi hydrogen pressure at 60° C. for 20 h. The reaction mixture was vacuum filtered through celite and the celite was washed with ether. The solvent was evaporated in a fume hood and the residual oil was distilled bulb to bulb (170° C./1 torr) to give 5.95 g (21.2 mmol, 89%) of 10 as an amber oil which crystallized on standing to form nearly colorless microcrystals: mp 100-101° C. (lit14 mp not reported); IR: 1710 (carbonyl) cm-1 ; 1H NMR δ0.982 (d, J=6.1 Hz, 3H), 1.33 (d, J=7.1 Hz, 6H), 2.0-2.7 (m, 5H), 3.14 (sept, J=7.1 Hz, 1H), 3.82 (s, 3H), 3.85 (s, 3H), 6.62 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H). Anal. (C16H24O4) C,H.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].[K].C(=O)([O-])[O-].I[CH2:19][CH:20]([CH3:23])[CH2:21][CH3:22]>CC(C)=O>[CH3:19][CH:20]([CH2:21][CH3:22])[CH2:23][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: CCC(C)CI
Reactant: COC(=O)c1cc([N+](=O)[O-])c[nH]1
Agent: O=C([O-])[O-]
Agent: [K]
Solvent: CC(C)=O
Product: CCC(C)Cn1cc([N+](=O)[O-])cc1C(=O)OC
Temperature: 25 °C
Yield: 70 %

Procedure:
Methyl 3-nitropyrrole-2-carboxylate (22) (2.7 g, 15.9 mmol), potassium, carbonate (6.5 g), and iodo-2-methylbutane (5.2 ml) were dissolved in 100 ml of acetone and refluxed for 10 hours. The reaction mixture was then cooled to room temperature, concentrated in vacuo, partitioned between 200 ml of dichloromethane and 200 ml of water and extracted with dichloromethane (2×200 ml). The combined organic layers were dried (sodium sulfate) and concentrated in vacuo. The resulting yellow oil was purified by flash chromatography to provide the substituted nitro pyrrole 23 (2.5 g, 70% yield). 1H NMR (DMSO-d6) δ 8.30 (d, 1H, J=2.0 Hz), 7.33 (d, 1H, J=1.9 Hz), 4.15 (d, 2H, J=7.4 Hz), 3.77 (s, 3H), 2.03 (m, 1H, J=3.1 Hz), 0.80 (d, 6H, J=6.7 Hz); 13C NMR (DMSO-d6) δ 160.30, 134.79, 129.80, 122.40, 112.76, 105.00, 56.63, 52.41, 29.72, 19.73; FABMS, 226.096 calcd, 226.095 found.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>O.C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[N:19][OH:20])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C(Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Yield: 66.2 %

Procedure:
A mixture of 1-(3,4-dichlorophenyl)-2-phenyl-ethan-1-one (Step 1) (12.5 g, 53.88 mmol), hydroxylamine hydrochloride (9.4 g, 135.4 mmol) and sodium acetate (268.5 mmol) in ethanol water (1:1, 250 mL) was heated at reflux for 4 hours, then was diluted with water (200 mL). The precipitate formed was filtered, dried and was recrystallized from hexane to afford 10 g (75%) of the desired product: mp 81°-82° C. 1H NMR (CDCl3) 7.50-7.06 (m, 9H), 4.18 (s, 2H). Found: Anal. Calc'd for C14H11NOCl2 :
Reaction SMILES: [I:1]I.[N+:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])([O-:5])=[O:4]>S(=O)(=O)(O)O>[I:1][C:13]1[CH:12]=[C:8]([CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:14]=1)[C:9]([OH:11])=[O:10]
Reactant: II
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(I)cc([N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 12 h
Yield: 97987.5 %

Procedure:
To a stirred solution of iodine (137.95 g, 0.5436 mmol) in filming sulfuric acid (250 ml) was added m-nitrobenzoic acid (64.6 g, 0.3866 mmol) at room temperature. The reaction mixture was slowly heated to 85° C. overs 2 hours and stirred at the same temperature for another 12 hours. The reaction mixture was cooled to room temperature and poured into ice, and the aqueous solution was extracted with dichloromethane. The organic phase was separated and washed with water, 2.0 M solution of Na2S2O3 and brine, and then dried over Na2SO4. Solvent was removed under reduced pressure to yield 3-iodo-5-nitrobenzoic acid as slight yellow solid 111 g, yield 98%. MS (M+H)=294.
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH:23]=[O:24])C.P(Cl)(Cl)(Cl)=O>O>[C:14]1([N:7]([C:1]2[CH:2]=[CH:3][C:4]([CH:23]=[O:24])=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 95 °C

Procedure:
101.4 g of triphenylamine and 35.5 mL of DMF were placed in a three-neck flask. While stirring and cooling in ice water, 84.4 mL of phosphorus oxychloride was dropped into the flask. The temperature was increased to 95° C. and the mixture was reacted for 5 hours. 4 L of warm water was poured into the flask and the mixture was stirred for one hour. A precipitate was collected and washed in a 1:1 mixture solution of ethanol/water. 4-(N,N-diphenylamino)benzaldehyde was obtained. The yield was 91.5 g (yield rate of 81.0%), and the melting point was 128.6°-130.1° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Al+3].[Cl-].[Cl-].[Cl-].Br[C:15]([CH3:20])([CH3:19])[C:16](Br)=[O:17].Cl>C(Cl)Cl>[OH:9][C:3]1[C:4]([CH3:8])=[C:5]2[C:6](=[CH:7][C:2]=1[CH3:1])[C:16](=[O:17])[CH:15]([CH3:20])[CH2:19]2
Reactant: Cc1cccc(C)c1O
Reactant: CC(C)(Br)C(=O)Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc2c(c(C)c1O)CC(C)C2=O
Reaction time: 0.33 h

Procedure:
Solution of 2,6-dimethylphenol (36.65 g, 0.3 mol) in CH2Cl2 (100 ml) was added to well stirred suspension of AlCl3 (120 g, 0.9 mol) in CH2Cl2 (200 ml). After 20 min, 2-bromoisobutyryl bromide (69 g, 0.3 mol) was added. Reaction mixture was stirred for 3 days, poured into HCl/crashed ice, organic phase was separated, water phase was extracted by CH2Cl2 (3×100 ml), combined organic fraction was washed by water, dried over MgSO4, and evaporated. Ether (70 ml) and hexane (70 ml) were added, resulting crystalline precipitate was filtered off and dried in vacuo. The yield 15.8 g (27.7%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][SH:10])=[CH:7][CH:6]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][C@@H:22](OS(C)(=O)=O)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[Na+]>CN(C)C=O>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([S:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Reactant: COc1ccc(CS)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CS[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.32 g of sodium hydride (as a 55% w/w dispersion in mineral oil) were added, whilst ice-cooling, to a solution of 16.86 ml of 4-methoxybenzyl mercaptan dissolved in 200 ml of dry dimethylformamide, and the mixture was then stirred at room temperature for 30 minutes. At the end of this time, a solution of 31.00 g of (3R)-1-t-butoxycarbonyl-3-methanesulfonyloxypyrrolidine [prepared as described in step (1) above] in 50 ml of dry dimethylformamide was added to the reaction mixture. The mixture was then stirred for 30 minutes whilst ice-cooling, after which it was allowed to stand overnight at room temperature. It was then poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel (eluted with a 5:1 by volume mixture of hexane and ethyl acetate), to afford 28.00 g of the title compound a pale-brown oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([NH:11][C:12]([C:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:22]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:21][C:20]=2[O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:16][N:15]=1)=[O:13])[CH3:10]>C(#N)C>[CH2:9]([NH:11][C:12]([C:14]1[C:18]([Br:1])=[C:17]([C:19]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:22]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:21][C:20]=2[O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:16][N:15]=1)=[O:13])[CH3:10]
Reactant: CCNC(=O)c1cc(-c2cc(CCc3ccccc3)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCNC(=O)c1noc(-c2cc(CCc3ccccc3)c(OCc3ccccc3)cc2OCc2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-Bromosuccinimide (207 mg, 1.16 mmol) was added to a suspension of 5-(2,4-Bis-benzyloxy-5-phenethylphenyl)-isoxazole-3-carboxylic acid ethylamide (564 mg, 1.06 mmol) in acetonitrile (20 mL). Ceric ammonium nitrate (290 mg, 0.53 mmol) was added and the reaction mixture was heated to reflux (affording homogeneous orange solution) and stirred for 30 minutes. The reaction mixture was allowed to cool to ambient temperature and acetonitrile was removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL) and the phases were separated. The organic phase was washed with saturated aqueous sodium chloride solution (50 mL) and dried over sodium sulphate. The mixture was filtered and the filtrate solvents were removed in vacuo to afford a yellow oil which was purified by flash chromatography on silica gel (20 g, IST) eluting with 10-30% ethyl acetate in hexane. This affords 5-(2,4-Bis-benzyloxy-5-phenethylphenyl)-4-bromo-isoxazole-3-carboxylic acid ethylamide as yellow oil (326 mg, 53%). LCMS: [M+H]+ 613, 611.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([CH3:13])[C:5]=1[O:14][CH3:15])([O-])=O.C(O)C.[H][H].[ClH:21]>[Pd].O>[ClH:21].[ClH:21].[NH2:1][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[C:6]([CH3:13])[C:5]=1[O:14][CH3:15]
Reactant: COc1c(C)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1c(C)cc(N)cc1N

Procedure:
105 g of 2,4-dinitro-6-methylanisole, 1.35 l of ethanol, 150 ml of water and 1 g of Pd/C (5% strength) were initially introduced into the autoclave and hydrogenated at 50° C. with a hydrogen pressure of 50 bar for 12 h. Subsequently, the mixture was cooled and then poured into 1.0 l of semiconcentrated HCl. The catalyst was filtered off, and the filtrate was evaporated to dryness on a rotary evaporator. The residue was extracted by boiling with 2×150 ml of ethanol, filtered off and dried overnight under reduced pressure.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][N:28]1[C:36]2[N:35]=[CH:34][CH:33]=[CH:32][C:31]=2[N:30]=[C:29]1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:40]2[CH2:41][CH2:42][N:37]([C:29]3[N:28]([CH3:27])[C:36]4[N:35]=[CH:34][CH:33]=[CH:32][C:31]=4[N:30]=3)[CH2:38][CH2:39]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Cn1c(N2CCNCC2)nc2cccnc21
Product: Cn1c(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc2cccnc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 3-methyl-2-(piperazin-1-yl)-3H-imidazo[4,5]pyridine.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:32]=[CH:31][C:18]4/[C:19](=[CH:28]/[C:29]#[N:30])/[C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[CH2:22][CH2:23][C:17]=4[CH:16]=3)[C:6]=2[CH:5]=[C:4]([C:33]([NH:35][NH2:36])=[O:34])[CH:3]=1.[C:37](OCC)(OCC)(OCC)[CH3:38]>>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:32]=[CH:31][C:18]4/[C:19](=[CH:28]/[C:29]#[N:30])/[C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[CH2:22][CH2:23][C:17]=4[CH:16]=3)[C:6]=2[CH:5]=[C:4]([C:33]2[O:34][C:37]([CH3:38])=[N:36][N:35]=2)[CH:3]=1
Reactant: CCCc1nc2c(C)cc(C(=O)NN)cc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Reactant: CCOC(C)(OCC)OCC
Product: CCCc1nc2c(C)cc(-c3nnc(C)o3)cc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Yield: 62 %

Procedure:
[step 1] Using (E)-{2-[4-methyl-6-(hydrazinocarbonyl)-2-propylbenzimidazol-1-yl]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (150 mg, 0.32 mmol) obtained in Example 70, step 1, and triethyl orthoacetate (10.5 mL) instead of triethyl orthoformate, and in the same manner as in Example 70, step 2, (E)-{2-[4-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-2-propylbenzimidazol-1-yl]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (100 mg, 62%) was obtained.