Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]([C@H:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([F:19])=[CH:13][C:14]=3[F:18])[CH2:9]2)[C:6](=[S:20])[NH:5][CH:4]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27](O)=[O:28].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[F:18][C:14]1[CH:13]=[C:12]([F:19])[CH:11]=[C:10]2[C:15]=1[CH2:16][CH2:17][C@H:8]([N:7]1[C:3]([CH2:2][NH:1][C:27](=[O:28])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)=[CH:4][NH:5][C:6]1=[S:20])[CH2:9]2
Reactant: NCc1c[nH]c(=S)n1[C@H]1CCc2c(F)cc(F)cc2C1
Reactant: O=C(O)c1ccccn1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1c[nH]c(=S)n1[C@H]1CCc2c(F)cc(F)cc2C1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 20 %

Procedure:
A mixture of (S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (295 mg, 1 mmol), prepared as in Example 31, picolinic acid (123 mg, 1 mmol) and PyBOP (620 mg, 1.2 mmol) in 10 mL of dry DMF was stirred under argon at approximately 25° C. for 5 minutes and then N,N-diisopropylethylamine (0.58 mL, 3.3 mmol) was added. The mixture was stirred for approximately 12 hours and then 10 mL of water was added. The aqueous layer was extracted with ethyl acetate (3×10 mL) and the combined extracts were washed with water, dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with hexane/THF (1:1 to 8:2) to give (S)-N-[3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl]picolinamide (80 mg, 0.2 mmol), m.p. 216°-217° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:26]=[CH:25][CH:24]=[CH:23][C:9]=2[C:10]([NH:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:28]>C(O)C>[C:1]1([CH2:7][C:8]2[CH:26]=[CH:25][CH:24]=[CH:23][C:9]=2[C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:28]
Reactant: COC(=O)c1ccc(NC(=O)c2ccccc2Cc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])c1ccc(NC(=O)c2ccccc2Cc2ccccc2)cc1

Procedure:
A mixture of 4.90 g of methyl 4-[[2-(phenylmethyl)benzoyl]amino]benzoate in 100 ml of absolute ethanol and 3.50 ml of 10N sodium hydroxide is heated on a steam bath for 3 hours. The aqueous phase is filtered and the resulting solid collected and dried to give 4.25 g of the desired product m.p. 340°-346° C.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[C:4](=[O:7])[CH2:5][NH2:6].[Si:9]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([CH:24]=O)[CH:19]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>C(N(CC)CC)C>[Si:9]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][NH:6][CH2:5][C:4]([N:3]([CH3:8])[CH3:2])=[O:7])[CH:19]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(C=O)c1
Reactant: CN(C)C(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CNCc1cc(CO[Si](C)(C)C(C)(C)C)ccn1

Procedure:
By General Procedure A from N,N-dimethylglycineamide hydrochloride, triethylamine, and 4-{[(tert-butyldimethylsilyl)oxy]methyl}pyridine-2-carbaldehyde. Purification by column chromatography (0-10% MeOH in DCM) gave the title product as yellow oil. 1H NMR (300 MHz, chloroform-d): δ ppm 8.49 (d, 1H), 7.32 (s, 1H), 7.17 (d, 1H), 4.74 (s, 2H), 3.97 (s, 2H), 3.47 (s, 2H), 2.95 (d, 6H), 0.95 (s, 9H), 0.11 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:14]=[CH:13][C:10]([CH2:11]O)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.O=S(Cl)[Cl:17]>>[ClH:17].[CH3:1][C:2]1[N:3]([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][Cl:17])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Product: Cc1nccn1-c1ccc(CCl)cc1
Product: Cl

Procedure:
4-(2-Methylimidazol-1-yl)benzyl alcohol (1.28 g, 6.8 mmol) in SOCl2 (5 ml) was stirred at ambient temperature for 30 minutes and then volatiles removed under reduced pressure. The resultant crude product was washed with minimal dry Et2O and dried in vacuo to afford the titled compound (1.65 g, quant.) as white solids.
Reaction SMILES: [C:1]([O:5][C:6](=[O:79])[CH2:7][N:8]([CH2:71][C:72](=[O:78])[O:73][C:74]([CH3:77])([CH3:76])[CH3:75])[C:9](=[O:70])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[CH2:16][N:17]([CH2:59][C:60]1[CH:65]=[CH:64][C:63]([O:66][CH2:67][C:68]#[CH:69])=[CH:62][CH:61]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:58])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C@@H:29]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[NH:30][C:31](=[O:50])[NH:32][C@H:33]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])([CH3:4])([CH3:3])[CH3:2].[N:80]([CH2:83][CH2:84][CH2:85][NH2:86])=[N+:81]=[N-:82]>C1COCC1.O.C(Cl)Cl.[Cu].[O-]S([O-])(=O)=O.[Cu+2]>[NH2:86][CH2:85][CH2:84][CH2:83][N:80]1[CH:69]=[C:68]([CH2:67][O:66][C:63]2[CH:62]=[CH:61][C:60]([CH2:59][N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:58])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C@@H:29]([C:51]([O:53][C:54]([CH3:55])([CH3:56])[CH3:57])=[O:52])[NH:30][C:31](=[O:50])[NH:32][C@H:33]([C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:16][C:12]3[N:11]([CH2:10][C:9]([N:8]([CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:79])[CH2:71][C:72](=[O:78])[O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:70])[CH:15]=[CH:14][N:13]=3)=[CH:65][CH:64]=2)[N:82]=[N:81]1
Reactant: C#CCOc1ccc(CN(CCCCCC(=O)NCCCC[C@H](NC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Cc2nccn2CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)cc1
Reactant: [N-]=[N+]=NCCCN
Agent: [Cu+2]
Agent: [Cu]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCN(Cc1ccc(OCc2cn(CCCN)nn2)cc1)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.7 %

Procedure:
To a solution of (14S,18S)-tri-tert-butyl 1-(1-(2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-8,16-dioxo-2-(4-(prop-2-yn-1-yloxy)benzyl)-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylate (65 mg, 0.0586 mmol) and 3-azidopropan-1-amine (200 mg, 2.0 mmol) in THF (2.0 mL) and water (0.5 mL) was added copper powder (10 mg) and 1 N CuSO4 (0.05 mL). The mixture was stirred at room temperature for 2 h under nitrogen, diluted with DCM and washed with an aqueous saturated solution of EDTA. The solvent was evaporated under reduce pressure to afford a residue, which was purified by Biotage SP4 to afford (14S,18S)-tri-tert-butyl 2-(4-((1-(3-aminopropyl)-1H-1,2,3-triazol-4-yl)methoxy)benzyl)-1-(1-(2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-8,16-dioxo-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylate (17.5 mg, 25%). MS (ESI), 605.8 (M/2+H)′.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: C1COCCN1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCOCC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and morpholine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=373.
Reaction SMILES: [CH2:1]([CH:8]([C:12](=O)[CH3:13])[C:9](=O)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=1)[NH2:17]>>[CH2:1]([C:8]1[C:12]([CH3:13])=[N:17][N:16]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][OH:26])=[CH:22][CH:23]=2)[C:9]=1[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(Cc1ccccc1)C(C)=O
Reactant: NNc1ccc(CCO)cc1
Agent: Cl
Product: Cc1nn(-c2ccc(CCO)cc2)c(C)c1Cc1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from 3-benzylpentane-2,4-dione and 2-(4-hydrazinophenyl)ethanol hydrochloride: 1H-NMR (CDCl3) δ 7.39-7.15 (9H, m), 3.89-3.85 (2H, t, J=6.4 Hz), 3.48 (2H, s), 2.91 (2H, t, J=6.6 Hz), 2.29 (3H, s), 2.21 (3H, s).
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1C1CO1.OCC1OCCN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C1.[C:41]1([CH:51]2[CH2:53][O:52]2)[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][CH:42]=1.[CH:54]([N:56]1[CH2:61][CH2:60][N:59]([CH:62]=[O:63])[CH2:58][CH:57]1[CH2:64][OH:65])=[O:55]>>[CH:54]([N:56]1[CH2:61][CH2:60][N:59]([CH:62]=[O:63])[CH2:58][CH:57]1[CH2:64][O:65][C:51]([C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][CH:42]=1)([OH:52])[CH3:53])=[O:55]
Reactant: c1ccc2c(C3CO3)cccc2c1
Reactant: O=CN1CCN(C=O)C(CO)C1
Agent: OCC1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCO1
Agent: c1ccc2cc(C3CO3)ccc2c1
Product: CC(O)(OCC1CN(C=O)CCN1C=O)c1cccc2ccccc12

Procedure:
The same procedure as in (1) of Production Example 16 was repeated, except that the 2-(2-naphthyl)oxirane and the 2-hydroxymethyl-4-tritylmorpholine were replaced by 2-(1-naphthyl)oxirane and 1,4-diformyl-2-piperazinyl methanol, respectively, to obtain oily 2-[(1,4-diformylpiperazin-2-yl)methoxyl-1-(1-naphthyl)ethanol (compound No. 270).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17].C([O-])([O-])=O.[Na+].[Na+]>CO.[Pd]>[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=2)=[CH:20][CH:19]=1)#[N:17]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(I)cc(C(=O)OC)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(C(=O)OC)cc(-c2ccc(C#N)cc2)c1
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of dimethyl 5-iodoisophthalate (6 g, 18.75 mmol, 1 eq.), 4-cyanophenylboronic acid (2.95 g, 19.68 mmol, 1.05 eq.) and Na2CO3 (7.95 g, 74.98 mmol, 4 eq.) in 400 mL of MeOH was degassed by 4 thaw-freeze-pump cycles. Then 1.3 g of 5% Pd/C was added and nitrogen gas was bubbled through the solution for 10 min. The reaction under stirring was carried out at 80° C. for 1 h. Then, the mixture was filtered and washed with EtOH and CH2Cl2. All organic solvents were removed under vacuum and aqueous layer was extracted 4 times with CH2Cl2, the recombined organic layer were washed once with H2O, dried over MgSO4, filtered and evaporated under vacuum. An off-white solid was obtained with 85% yield.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:47]([C:49]1[C:50]([C:65]([F:68])([F:67])[F:66])=[C:51]2[C:55](=[CH:56][CH:57]=1)[N:54]([CH2:58]/[C:59](=[N:62]/[H])/[NH:60]O)[C:53]([CH3:64])=[CH:52]2)#[N:48]>CC#N>[CH3:64][C:53]1[N:54]([CH2:58][C:59]2[N:62]=[C:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:13])[F:12])[N:8]=3)[O:11][N:60]=2)[C:55]2[C:51]([CH:52]=1)=[C:50]([C:65]([F:67])([F:66])[F:68])[C:49]([C:47]#[N:48])=[CH:57][CH:56]=2
Reactant: [H]/N=C(/Cn1c(C)cc2c(C(F)(F)F)c(C#N)ccc21)NO
Reactant: O=C(O)c1cccc(C(F)(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)n2)n1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 45.9 %

Procedure:
To a solution of 6-(trifluoromethyl)-2-pyridinecarboxylic acid (ref: European Journal of Organic Chemistry (2003), (8), 1569-1575) (0.032 g, 0.169 mmol) in 2 mL of MeCN was added DIEA (0.022 g, 0.169 mmol) and HATU (0.064 g, 0.169 mmol). After stirring at rt for 2 min, (1Z)-2-[5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (0.050 g, 0.169 mmol) was added. After stirring at rt for 30 min, the mixture was heated in a sealed tube at 150° C. for 1.5 h. Upon cooling, the mixture was concentrated to dryness and the residue was purified by silica gel chromatography using a 5-50% EtOAc-hexanes gradient. The product was crystallized from CH2Cl2-hexanes to afford the title compound as a white solid (0.035 g, 46% yield): MS (ES) m/z 452 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[NH2:6].[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:28]=1[C:29](Cl)=[O:30].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:12][CH:13]=1)[NH:6][C:29]([C:28]1[C:27]([Cl:26])=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:36])=[O:30]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 92.8 %

Procedure:
To a suspension of 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrirnidinyl)-L-phenylalanine methyl ester hydrochloride salt (3.12 mmol, 1.15 g) and 2,6-dichlorobenzoyl chloride (3.51 mmol, 0.735 g) in dichloromethane (40 mL) was added diisopropylethylamine (9.36 mmol, 1.63 mL) at room temperature. After 1 min, everything went into solution and the clear yellow solution was stirred for 20 h at room temperature. The resulting brown solution was diluted with dichloromethane (50 mL). The dichloromethane layer was washed successively with 1N hydrochloric acid (2×50 mL), saturated sodium bicarbonate solution (50 mL), and brine solution (50 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product which was purified by silica gel chromatography using a Biotage (40m) column to afford 1.46 g (93% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester as an amorphous white solid. FAB-HRMS m/e calcd for C24H23Cl2N3O5 (M+H) 504.1093, found 504.1083.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6](=[O:17])[C:7]([N+:14]([O-:16])=[O:15])=[C:8]1[NH:13][CH2:12][CH2:11][CH2:10][S:9]1.[Cl:23]N1C(=O)CCC1=O.[O-][Si]([O-])=O.[Mg+2]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:23][N:13]1[CH2:12][CH2:11][CH2:10][S:9][C:8]1=[C:7]([N+:14]([O-:16])=[O:15])[C:6](=[O:17])[CH2:5][O:4][C:3]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(COc1ccc(Cl)cc1Cl)C(=C1NCCCS1)[N+](=O)[O-]
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(COc1ccc(Cl)cc1Cl)C(=C1SCCCN1Cl)[N+](=O)[O-]

Procedure:
3.6 g of 1 and 2.1 g of N-chlorosuccinimide were combined in 150 ml of carbon tetrachloride and the mixture was refluxed for 1 hour. The resulting mixture was filtered through Celite and the solvent was evaporated to give a liquid, which was triturated in ether, decolorized with activated charcoal and filtered through Celite and stripped of solvent to give a yellow cloudy liquid. This was passed through Florisil, using methylene chloride as eluent; then stripped to give an oil, which was kept in a refrigerator over a week-end. Part of the oil crystallized. On scratching, more crystals formed. Separation of the crystals gave 2, as bright yellow crystals, m.p. 103°-105°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])=[N:15]3)=O)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C(=O)([O-])[O-].[Na+].[Na+].O>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])=[N:15]3)=[N:31][OH:32])=[CH:4][CH:3]=1
Reactant: COc1ccccc1CNc1ccc2c(C(=O)c3ccc(F)cc3)cccc2n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccccc1CNc1ccc2c(C(=NO)c3ccc(F)cc3)cccc2n1
Yield: 64.3 %

Procedure:
A stirred suspension of (4-fluoro-phenyl)-[2-(2-methoxy-benzylamino)-quinolin-5-yl]-methanone (example 137) (60 mg, 0.155 mmol), hydroxylamine hydrochloride (32 mg, 0.46 mmol) and sodium carbonate (49 mg, 0.46 mmol) in EtOH (2 ml) was heated under reflux conditions for 28 h, the reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/ethyl acetate) to yield the title compound as white foam (40 mg, 64%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH3:33])([CH:10]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[N:21]=[CH:20]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].[S:34]1[CH:38]=[N:37][N:36]=[C:35]1[NH2:39]>>[C:1]([O:4][CH2:5][C:6]([CH:10]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[N:21]=[CH:20]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([CH3:33])[C:7]([NH:39][C:35]1[S:34][CH:38]=[N:37][N:36]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: Nc1nncs1
Reactant: CC(=O)OCC(C)(C(=O)O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Product: CC(=O)OCC(C)(C(=O)Nc1nncs1)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 39 %

Procedure:
Example 154 was prepared from 2-(acetoxymethyl)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanoic acid (75 mg, 0.168 mmol) and 1,3,4-thiadiazol-2-amine using General Coupling Method B to give 35 mg (39% yield). MS found: (M+H)+=530.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:13]([N:15]([CH2:18]C)CC)C.C(Cl)(Cl)=[O:21].CN>O1CCCC1>[CH3:12][C:5]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([NH:1][C:13]([NH:15][CH3:18])=[O:21])[S:3][CH:4]=1
Reactant: O=C(Cl)Cl
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1c(C)csc1N
Agent: CN
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)csc1NC(=O)NC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred ice-cooled solution of ethyl 2-amino-4-methyl-thiophene-3-carboxylate (1,85 g, 10 mmole) and triethyl amine (1,4 ml, 10 mmol) in dry tetrahydrofuran (50 ml) was added dropwise a phosgene solution (11 mmol, in toluene). The mixture was thereafter heated to reflux for 30 min, then cooled to room temperature and exposed to a gaseous stream of methylamine for 5 min. After additional stirring for 15 min, the mixture was filtered and the filtrate was evaporated to give the title compound as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24].[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[S:37]([Cl:40])(=[O:39])=[O:38]>>[ClH:40].[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:37]([C:28]3[CH:29]=[CH:30][C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:27]=3)(=[O:39])=[O:38])=[C:3]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(C)(=O)=O)c2)CC1
Product: CS(=O)(=O)Nc1cc(N2CCCNCC2)ccc1NS(=O)(=O)c1ccc2ccccc2c1
Product: Cl

Procedure:
The compound was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)- phenyl}methanesulfonamide and 2-napthalenesufonylchloride (103 mg, 0.455 mmol) to give before Boc-deprotection 120 mg of a purple solid. M+1 475.1 Calcd 474.14.
Reaction SMILES: [F:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Br[CH2:14][CH:15]([OH:19])[CH2:16][CH2:17]Br.C(=O)([O-])[O-].[Na+].[Na+]>>[F:1][C:2]1[C:8]([C:9]([F:10])([F:11])[F:12])=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]1[CH2:17][CH2:16][CH:15]([OH:19])[CH2:14]1
Reactant: OC(CBr)CCBr
Reactant: Nc1cccc(C(F)(F)F)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: OC1CCN(c2cccc(C(F)(F)F)c2F)C1
Temperature: 25 °C
Yield: 27.3 %

Procedure:
2-Fluoro-3-(trifluoromethyl)aniline (5.0 g) and 1,4-dibromobutan-2-ol (6.7 g) were stirred at 100° C. for 3 hr. After cooling to room temperature, to the reaction mixture was added saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10-50:50) to give the title compound (1.9 g, yield 27%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8](C=O)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[Br-].[C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:16])=[O:15].[CH2:41]1COCC1>>[CH2:1]([O:4][C:5]1([CH:41]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][C:14]([OH:16])=[O:15])[CH:6]=[CH:7][CH:8]=[CH:11][CH2:12]1)[CH2:2][CH3:3]
Reactant: C1CCOC1
Reactant: CCCOc1ccc(C=O)cc1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCCOC1(C=CCCCCC(=O)O)C=CC=CC1
Yield: 60 %

Procedure:
This compound was synthesized from p-propoxybenzaldehyde (3.26 g, 20 mmol, prepared from 1-bromopropane and 4-hydroxybenzaldehyde) and 5-carboxypentyltriphenylphosphonium bromide (9.50 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization (petroleum ether) afforded the product (3.15 g, 60%) as white crystals (mp: 52-53° C.). IR: 3450-2500, 1730 cm-1 ; 1H-NMR: 1.00 (t, 3H), 1.48 (m, 2H), 1.67 (m, 2H), 1.82 (m, 2H), 2.35 (m, 4H), 3.92 (t, 2H), 5.72+6.05 (m, 1H), 6.35 (d, 1H), 7.05 (q, 4H), 10.40 (bs, 1H). Anal. Calcd. for C16H22O3 : C, 73.25, H, 8.45%. Found: C, 73.15, H, 8.45%. Z:E=30:70.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].O.[Cl:10][C:11]([Cl:15])([Cl:14])[CH:12]=[O:13].C(N(CC)CC)C>C(Cl)CCl>[OH:1][C:2]1[CH:7]=[C:6]([CH:12]([OH:13])[C:11]([Cl:15])([Cl:14])[Cl:10])[CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: Oc1ccccc1O
Solvent: ClCCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Oc1ccc(C(O)C(Cl)(Cl)Cl)cc1O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
To the solution of 440 g of 1,2-dihydroxybenzene dissolved in 1L of ethylene dichloride was added 1036 g of trichloroacetaldehyde monohydrate and then the reaction solution was cooled down to 0° C. 102 g of triethylamine was slowly added dropwise thereto. The reaction solution was warmed to normal temperature, stirred for about 20 minutes, heated to 50° C. and then stirred for further 3 hours while maintaining the same temperature. After the reaction is completed, the reaction mixture was distilled under reduced pressure to remove ethylene dichloride. The residue was dissolved in 4L of ethylacetate, washed successively with 2400 ml of 0.5N-aqueous hydrochloric acid solution and 2L of saturated saline solution, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent to obtain 540 g of the title compound.