Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(CC)CC>O.[Cl-].[Na+].O>[C:10]1([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1cccc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1cccc(-c2ccccc2)c1
Yield: 92.6 %

Procedure:
3-Bromobenzonitrile (91 mg, 0.5 mmol), phenylboronic acid (91 mg, 0.75 mmol), and Pd(dtbpf)Cl2 (6 mg, 0.01 mmol) were added to a reaction tube equipped with a magnetic stir bar. Under a positive flow of argon while stirring, surfactant solution (1.0 mL, 2 wt % TPGS-M-PEG-750 in water), and Et3N (0.21 mL, 1.5 mmol) were added by syringe and stirred vigorously for 2 h. The reaction mixture was then diluted with brine and extracted with EtOAc. The solution obtained was dried over anhydrous MgSO4 and concentrated by rotary evaporation. The residue was purified by flash column chromatography eluting with 20% CH2Cl2/hexanes to afford the product (83 mg, 93%) as a slightly yellow oil.
Reaction SMILES: C(OC([N:8]1[C@H:12]([CH2:13][N:14]([CH2:21][CH3:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][C@H:12]([CH2:13][N:14]([CH2:21][CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][OH:10]
Reactant: CCN(C[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CCN(C[C@@H](N)CO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a stirred solution of (R)-4-[(ethyl-phenyl-amino)-methyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (608 mg) at r.t. in dioxane (5.5 ml) under an argon atmosphere was added HCl solution (4 M in dioxane; 4.54 ml). The mixture was stirred at r.t. overnight and concentrated. The residue was taken up in EtOAc and washed with 1N NaOH. The aqueous layer was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4 and concentrated. The crude product was purified by column chromatography (Isolute® SPE flash NH2 column, aminopropyl-functionalized silica; CH2Cl2/MeOH 9:1) to give (R)-2-amino-3-(ethyl-phenyl-amino)-propan-1-ol (297 mg, 84%) as off-white amorphous solid. MS (ISP): 195.3 ([M+H]+)
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: BrC1CCCCC1
Product: Clc1ccc(-c2nn(C3CCCCC3)c3c2CCNCC3)cc1
Yield: 11.4 %

Procedure:
The title compound (15 mg) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.40 mmol) using bromo-cyclohexane (1.5 mmol) in place of chloro-cyclobutane according to Example 238. MS (ESI): exact mass calculated for C19H24ClN3, 329.17; found, m/z 330.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.45-7.41 (m, 4H), 4.30-4.27 (m, 1H), 3.44-3.42 (m, 2H), 3.31-3.26 (m, 4H), 2.98-2.96 (m, 2H), 1.93-1.84 (m, 5H), 1.70-1.65 (m, 1H), 1.46-1.40 (m, 2H), 1.24-1.89 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([F:12])[CH:4]=1)#[N:2].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C.Cl.[CH3:45][C@@H:46]1[CH2:51][NH:50][CH2:49][CH2:48][N:47]1[CH2:52][CH:53]([N:57]1[CH:61]=[C:60]([C:62]2[C:63]3[CH:70]=[CH:69][N:68](COCC[Si](C)(C)C)[C:64]=3[N:65]=[CH:66][N:67]=2)[CH:59]=[N:58]1)[CH2:54][C:55]#[N:56]>C1COCC1>[C:55]([CH2:54][CH:53]([N:57]1[CH:61]=[C:60]([C:62]2[C:63]3[CH:70]=[CH:69][NH:68][C:64]=3[N:65]=[CH:66][N:67]=2)[CH:59]=[N:58]1)[CH2:52][N:47]1[CH2:48][CH2:49][N:50]([C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[F:12])=[O:9])[CH2:51][C@H:46]1[CH3:45])#[N:56]
Reactant: C[C@@H]1CNCCN1CC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)c2ccc(C#N)cc2F)CCN1CC(CC#N)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 0.25 h

Procedure:
A mixture of 4-cyano-2-fluorobenzoic acid (50.4 mg, 0.305 mmol, Alfa Aesar), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (107 mg, 0.282 mmol) and triethylamine (196 uL, 1.41 mmol) in THF (2.8 mL) was stirred for 15 minutes, followed by the addition of the diastereomeric 4-[(2R)-2-methylpiperazin-1-yl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride salt (130 mg, 0.23 mmol). After stirring for 2 hours, the reaction was partitioned between ethyl acetate and water. The organic layer was washed successively with water, 0.1 N NaOH and brine, dried over sodium sulfate and concentrated. To separate diastereomers, preparative HPLC-MS was used: Waters mass directed fractionation system, Waters SunFire C18 column, 5 μm particle size, 30×100 mm, mobile phase system: Aq(0.1% TFA)/AcN; flow rate 60 mL/min; separating gradient: 30.4-48.4% B in 12 minutes. Peak 1 (first to elute), and Peak 2 (second to elute) were subjected to the deprotection step separately: stirred for 1 hour in a 1:1 mixture of DCM/TFA, concentrated, then stirred for 30 minutes in a solution of ethylenediamine (0.2 mL) in methanol (1.5 mL). Purification via preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH afforded product (peak 1: 19 mg, peak 2: 23 mg, total 36% of theoretical). Peak 1: 1H NMR (400 MHz, d6-dmso) (rotamers): δ 12.11 (br s, 1H), 8.81 (d, 1H), 8.67 (s, 1H), 8.36 (s, 1H), 7.99-7.93 (m, 1H), 7.79-7.68 (m, 1H), 7.62-7.54 (m, 2H), 6.97 (dd, 1H), 4.93-4.83 (m, 1H), 3.85-3.66 (m, 1H), 3.36-2.08 (m, 10H), 0.90 and 0.71 ((each as d) together=3H); LCMS (M+H)+: 498.1. Peak 2: 1H NMR (400 MHz, d6-dmso) (rotamers): δ □12.08 (br s, 1H), 8.82 (d, 1H), 8.68 (d, 1H), 8.37 (d, 1H), 8.01-7.93 (m, 1H), 7.80-7.71 (m, 1H), 7.63-7.54 (m, 2H), 6.98 (t, 1H), 4.94-4.81 (m, 1H), 3.87-2.26 (m, 11H), 1.05 and 0.87 ((each as d) together=3H); LCMS (M+H)+: 498.1.
Reaction SMILES: CC1(C)[N:6](C(OC(C)(C)C)=O)[C:5]([CH3:20])([C:14]2[O:15][C:16]([CH3:19])=[N:17][N:18]=2)[CH2:4][O:3]1.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:6][C:5]([C:14]1[O:15][C:16]([CH3:19])=[N:17][N:18]=1)([CH3:20])[CH2:4][OH:3]
Reactant: Cc1nnc(C2(C)COC(C)(C)N2C(=O)OC(C)(C)C)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc(C(C)(N)CO)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 84 mg of tert-butyl 2,2,4-trimethyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)-1,3-oxazolidine-3-carboxylate in 1.5 ml of dichloromethane was added 500 μl of trifluoroacetic acid, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, methanol was added thereto, and the solvent was evaporated again to obtain 76 mg of 2-amino-2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-1-ol trifluoroacetate.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:4].[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1F.O>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1[N:6]([O:5][CH2:3][CH3:4])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: CCONS(=O)(=O)c1ccc(C)cc1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCON(c1ccc([N+](=O)[O-])cc1Cl)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 71.6 %

Procedure:
To a suspension of sodium hydride (60%, 0.18 g (4.50 mmol)) in 6.0 ml of DMF, N-ethoxy-p-toluenesulfonamide (0.90 g (4.18 mmol)) was added under cooling with ice and with stirring. To the resulting mixture, after 15 minutes' stirring under cooling with ice, 3-chloro-4-fluoronitrobenzene (0.70 g (3.99 mmol)) was added and the mixture was stirred under cooling with ice for one hour and at room temperature for 18 hours. The reaction mixture was then poured into water and extracted with diethyl ether. The extract was washed twice with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give crude crystals. These crystals were filtered while washing with diisopropyl ether to give 1.06 g (72%) of the title compound as pale yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][S:9][C:10]1[N:15]2[CH:16]=[CH:17][N:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1)=[O:5].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>O1CCCC1>[O:1]1[C:2]2[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=2[C:4](=[O:5])[N:6]([CH2:7][CH2:8][S:9][C:10]2[N:15]3[CH:16]=[CH:17][N:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)[C:23]1=[O:24]
Reactant: O=C(NCCSc1cccc2nccn12)c1ccccc1O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1oc2ccccc2c(=O)n1CCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.8 %

Procedure:
To a solution of 5-[2-[2-(hydroxy)benzoylamino]ethylthio]imidazo[1,2-a]pyridine (627 mg, 2.00 mmoles) in dry tetrahydrofuran (30 ml) was added 1,1'-carbonyldiimidazole (649 mg, 4.00 mmoles) and the mixture was stirred at room temperature for 15 hours. After the solvent was distilled off, chloroform was added to the residue, which was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent:ethyl acetate) to obtain 528 mg of the desired product (77.8%, colorless crystals).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:36]([NH:44][NH2:45])(=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CC1C=CC(C)=CC=1>[C:37]1([C:36]2[N:26]3[C:21]4[CH:20]=[C:19]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:18]([C:15]5[CH:16]=[CH:17][C:12]([C:8]6([NH:7][C:6](=[O:35])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH2:10][CH2:9]6)=[CH:13][CH:14]=5)=[N:28][C:22]=4[O:23][CH2:24][C:25]3=[N:45][N:44]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Reactant: NNC(=O)c1ccccc1
Solvent: Cc1ccc(C)cc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3-c3ccccc3)CO4)cc2)CCC1
Temperature: 150 °C
Yield: 39.3 %

Procedure:
A suspension of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (100 mg, 0.205 mmol) and benzoic acid hydrazide (84 mg, 0.615 mmol) in p-xylene (2 ml) was heated to 150° C. for 15 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 20% ethyl acetate in n-hexane) to give the title compound (46 mg, 40%). LCMS (Method D): RT=1.546 min, M+1=572. 1H NMR (500 MHz, CDCl3): 7.77-7.69 (2H, m), 7.64-7.57 (2H, m), 7.56-7.50 (1H, t), 7.49-7.41 (2H, t), 7.34-7.30 (2H, m), 7.28 (1H, s), 7.22-7.14 (3H, m), 6.95-6.90 (2H, dd), 5.65 (2H, s), 2.55-2.40 (3H, m), 2.15-2.01 (2H, m), 1.89-1.77 (1H, m), 1.46-1.24 (9H, bs).
Reaction SMILES: [CH2:1]([C:3]1[C:23]([NH2:24])=[C:6]2[C:7]([O:21][CH3:22])=[CH:8][CH:9]=[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])[N:5]2[N:4]=1)[CH3:2].[CH3:25][CH2:26][C:27](=O)[CH2:28][CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(O)(=O)C>[CH2:1]([C:3]1[C:23]([NH:24][CH:27]([CH2:28][CH3:29])[CH2:26][CH3:25])=[C:6]2[C:7]([O:21][CH3:22])=[CH:8][CH:9]=[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])[N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2c(-c3c(C)cc(C)cc3OC)ccc(OC)c2c1N
Reactant: CCC(=O)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCc1nn2c(-c3c(C)cc(C)cc3OC)ccc(OC)c2c1NC(CC)CC
Reaction time: 3 h

Procedure:
To a solution of 2-ethyl-4-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-amine (100 mg) in acetic acid (10 mL) there was added 3-pentanone (0.04 mL), and then sodium triacetoxyborohydride (85.0 mg) was slowly added at room temperature and the mixture was stirred for 3 hours. A 5 N aqueous sodium hydroxide solution was added while cooling on ice, and then extraction was performed with ethyl acetate, the organic layer washed with saturated aqueous sodium hydrogencarbonate and brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (10 g), and the title compound (69 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as yellow crystals.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([N:13]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH:14][C:15](=[O:41])[C@@H:16]([C@@H:21]([C:31](=[O:40])[NH:32][O:33]C1CCCCO1)[CH2:22]/[CH:23]=[CH:24]/[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:12])=O)(C)(C)C.[ClH:46]>O1CCOCC1.C(OCC)C>[ClH:46].[NH2:8][CH2:9][CH2:10][C:11]([N:13]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH:14][C:15](=[O:41])[C@@H:16]([C@@H:21]([C:31](=[O:40])[NH:32][OH:33])[CH2:22]/[CH:23]=[CH:24]/[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:12]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CCNC(=O)OC(C)(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CCN)[C@H](C/C=C/c1ccccc1)C(=O)NO

Procedure:
A solution of 0.47 g of (E)-2′-(N-tert.-butoxycarbonyl-β-alanyl)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)-carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 5 ml of 4M hydrogen chloride in dioxan was stirred for 2 hours at room temperature and diluted with diethyl ether. The solid was filtered off, washed with diethyl ether and dried to give 0.29 g of (E)-2′-(β-alanyl)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide hydrochloride in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:10]([O:17][CH2:18][C:19](N)=[NH:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:19]([CH2:18][O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:20]=1
Reactant: N#Cc1nccnc1N
Reactant: N=C(N)COCc1ccccc1
Solvent: CCO
Product: Nc1nc(COCc2ccccc2)nc2nccnc12

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 12.0 g )0.10 mole) of 3-amino-2-pyrazinecarbonitrile and 25.0 g (0.15 mole) of 2-(benzyloxy)acetamidine [prepared according to W. J. Haggerty Jr. and W. J. Rost, J. Pharm. Sci. 1969, 58, 50] in 400 ml of absolute ethanol. Refluxing time: 4 hours. Yld: 15.4 g (58%), m.p. 112°-114° C. An analytical sample was obtained by recrystallization from ethanol, followed by washing with dilute hydrochloric acid and finally recrystallization from ethyl acetate. M.p. 131°-133° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[N:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[N:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=4)[CH:27]=3)[CH2:23][C:22](=[O:40])[NH:21][C:9]=2[CH:10]=1
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)ccc3NC(=O)OC(C)(C)C)c2)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2cccc(C3=Nc4ccc(-c5ccccc5F)cc4NC(=O)C3)c2)nn1

Procedure:
The title compound was prepared from (2′-fluoro-3-{3-[3-(6-methoxy-pyridazin-3-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic acid tert-butyl ester (Example M37) (308 mg, 0.55 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (178 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].C[S-](C)[C:7]([S-])=[N:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11]>C(O)C>[F:11][C:10]([F:13])([F:12])[C:9]([N:8]=[C:7]1[NH:1][CH2:2][CH2:3][S:4]1)=[O:14]
Reactant: NCCS
Reactant: C[S-](C)C([S-])=NC(=O)C(F)(F)F
Solvent: CCO
Product: O=C(N=C1NCCS1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
Ethanol (20 mL) was added to 77 mg (1.0 mmol) of 2-aminoethanethiol, 216 mmol (1.0 mmol) of the dimethyl(2,2,2-trifluoroacetyl)carbonimidodithioate synthesized by the method described in Comparative Example 7 was added, and the mixture was stirred overnight at room temperature. Following reaction completion, the solvent was distilled off under reduced pressure, and purification was carried out by silica gel column chromatography (hexane/ethyl acetate=1:1), giving 100 mg of 2,2,2-trifluoro-N-(thiazolidin-2-ylidene)acetamide (yield, 51%). This reaction was carried out once more by the same synthesis method, giving a combined amount of 350 mg of 2,2,2-trifluoro-N-(thiazolidin-2-ylidene)acetamide.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[CH3:16][C:17]([C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[Cl:26])=O.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.C>C(O)C>[Cl:26][C:20]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=1[C:17]1[CH:16]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]2[C:2](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:1]=1
Reactant: CC(=O)c1cc(Cl)ccc1Cl
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CCO
Product: Clc1ccc(Cl)c(-c2cc(-c3ccccc3)c3ccccc3n2)c1
Reaction time: 24 h
Yield: 65 %

Procedure:
2-Aminobenzophenone (33 g) and 2,5-dichloroacetophenone (32 g) were placed in a flask together with 2.5 g of toluenesulfonic acid monohydrate. The mixture was heated and stirred at 160°-170° C. for 24 hours. The resulting mixture was diluted with ethanol (300 ml). The crystals was filtered to give 63 g crude product, which was treated with charcoal and recrystallized first from ethanol, followed by recrystallization from hexane and ethyl acetate to give monomer as white crystals (65%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1([O:19][CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(=S)=S.O>[CH3:20][O:19][C:13]1[CH:18]=[CH:17][C:16]([C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: COc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 0.5 h

Procedure:
The compound of formula 3a was prepared according to the procedure of Shani, J. etal., J. Med. Chem, 1985, 28, 1504. Thus, a mixture of 4-nitrobenzoyl chloride (90 g, 0.48 mol) and anisole (57.24 g, 0.53 mol) in carbon disulfide (450 mL) was stirred in a three neck round bottom flask equipped with nitrogen inlet, condenser and mechanical stirrer that was being cooled in an ice bath. Aluminum chloride (84.0 g, 0.63 mol) was added in portions and stirring continued at ice bath temperature for 30 minutes, then at room temperature for an additional 1 hour. The reaction mixture was cooled, treated with concentrated hydrochloric acid (150 mL), diluted with cold water (250 mL). The product was collected, filtered, washed, dried, and crystallized from ethyl acetate to give 4-(4-methoxybenzoyl)-nitrobenzene as an off-white solid, m.p. 120-122° C.; Analysis for C14H11NO4: Calc.: C, 65.3; H, 4.31; N, 5.44; Found: C, 65.22; H, 4.16; N, 5.69.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH:11]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[C:12]([CH3:17])([N+:14]([O-])=O)[CH3:13])=[CH:5][CH:4]=1.C(O)C>[Zn].C(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH:11]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[C:12]([CH3:17])([CH3:13])[N:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)CC(c2cccs2)C(C)(C)[N+](=O)[O-])cc1
Agent: [Zn]
Solvent: O=CO
Solvent: CCO
Product: COc1ccc(C2=NC(C)(C)C(c3cccs3)C2)cc1
Reaction time: 5 h

Procedure:
180 G. of zinc powder are added portionwise while stirring over a period of 5 hours to a solution of 194 g. of 4'-methoxy-4-methyl-4-nitro-3-(2-thienyl)-valerophenone in 400 ml. of ethanol and 400 ml. of formic acid. The temperature is held at 48°-50° C. during this addition. The zinc sludge is then filtered off and the filtrate strongly concentrated under reduced pressure. The residue is taken up in water and made alkaline with 3-N sodium hydroxide. The mixture is extracted with methylene chloride, the organic phase washed with water, dried over sodium sulfate and evaporated under reduced pressure. The oily residue is chromatographed on silica gel, elution being carried out firstly with pure benzene and then with benzene/acetone mixtures with increasing acetone content (up to 50% acetone). There is obtained 2-(p-methoxy-phenyl)-5,5-dimethyl-4-(2-thienyl)-1-pyrroline which melts at 84° C. after recrystallization from n-hexane.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][C@H:12]3[NH:23][CH2:22][CH2:21][C@@:18]4([C:19]=2[CH:20]=1)[C@H:13]3[CH2:14][CH2:15][CH2:16][CH2:17]4)(=[O:5])=[O:4].Br[CH2:27][CH:28]1[CH2:30][CH2:29]1>C(Cl)Cl>[CH:28]1([CH2:27][N:23]2[CH2:22][CH2:21][C@@:18]34[C:19]5[CH:20]=[C:7]([O:6][S:3]([C:2]([F:1])([F:24])[F:25])(=[O:5])=[O:4])[CH:8]=[CH:9][C:10]=5[CH2:11][C@@H:12]2[C@@H:13]3[CH2:14][CH2:15][CH2:16][CH2:17]4)[CH2:30][CH2:29]1
Reactant: O=S(=O)(Oc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3)C(F)(F)F
Reactant: BrCC1CC1
Solvent: ClCCl
Product: O=S(=O)(Oc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(CC1CC1)CC3)C(F)(F)F
Reaction time: 5 h
Yield: 77 %

Procedure:
To a solution of compound 38 (50 mg, 0.13 mmol) and TEA (74 μL, 0.53 mmol) in dry CH2Cl2 (2 mL) was slowly added (bromomethyl)cyclopropane (25 μL, 0.26 mmol) at 0° C. and the mixture stirred for 5 h. Solvent was removed under reduced pressure. The crude product was purified on a silica gel column chromatography (95:5 CH2Cl2/MeOH) to give a white solid (43 mg, 77% yield): 1H NMR (300 MHz, CDCl3) 0.19˜2.10 (m, 17H); 2.31 (d, J=13.8 Hz, 1H); 2.47˜2.59 (m, 2H); 2.78˜2.88 (m, 2H); 3.30 (s, 1H); 7.02˜7.06 (m, 1H); 7.13˜7.20 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[CH:2].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(I)cc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: COc1ccc(C#Cc2ccccc2)cc1
Reaction time: 24 h
Yield: 97 %

Procedure:
112 mg (1.1 mmol) of ethynylbenzene, 259 mg (1.1 mmol) of 4-methoxy-iodobenzene, 2 mg (10 μmol) of cupric iodide and 8 mg (10 μmol) of bis(triphenylphosphine)palladium(II) chloride were added to a round-bottomed flask. The round-bottomed flask was then purged 3 times with argon. 20 ml of distilled triethylamine were then added and the mixture was then stirred for 24 hours. The reaction medium was then diluted with 20 ml of a 6M solution of hydrochloric acid then extracted three times with 20 ml of dichloromethane. The organic phase was washed with 40 ml of a 1M solution of sodium hydroxide, then dried over sodium sulfate and the solvent was evaporated under reduced pressure. The crude product of the reaction was then purified by column chromatography using, as eluent, a petroleum ether/dichloromethane (7/3; v/v) mixture. The expected product was then isolated in the form of a yellow powder (m=201 mg; yield=97%).