Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C(O[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=2)=[O:10])=C(F)C(F)=C(F)C=1F.[OH:37][CH2:38][CH2:39][NH2:40]>>[OH:37][CH2:38][CH2:39][NH:40][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[N:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=1)=[O:10]
Reactant: NCCO
Reactant: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)cc32)cc1
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)NCCO)cc32)cc1

Procedure:
The title compound was prepared from 2-oxo-3[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid pentafluorophenyl ester and 2-hydroxyethylamine according to Procedure K: mp>230° C.; Anal. Calcd for C17H17N5O5S: C, 50.61; H, 4.25; N, 17.36. Found: C, 50.53; H, 4.28; N, 17.27.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6]1)=[O:4].[Na+].[Br-:21].O.OOS([O-])=O.[K+]>CC(C)=O>[Br:21][C:14]1[CH:13]=[CH:12][C:11]([O:16][CH3:17])=[C:10]([CH:7]2[CH2:8][CH2:9][N:5]([C:3](=[O:4])[C:2]([F:1])([F:18])[F:19])[CH2:6]2)[CH:15]=1
Reactant: COc1ccccc1C1CCN(C(=O)C(F)(F)F)C1
Reactant: [Br-]
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(Br)cc1C1CCN(C(=O)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 111.1 %

Procedure:
To the title compound of Step A (2.75 g, 10.1 mmol) and NaBr (4.2 g, 41 mmol) in acetone (50 mL)/H2O (50 mL) at 0° C. was added Oxone (6.2 g, 10.1 mmol) portionwise over 1 h. After 3 h, the ice bath was removed and the reaction allowed to warm to rt. Then 5 wt % Na2S2O5 (aq.) was added and the mixture extracted with EtOAc (2×). The combined organics were washed with brine and dried to give 3.95 g (>98%) of the title compound. 1H NMR (CDCl3): 7.35 (dd, J=8.7, 3.8, 2.5 Hz, 1H), 7.25 (dd, J=5.5, 2.7 Hz, 1H), 6.77 (dd, J=8.7, 4.5 Hz, 1H), 4.13-4.06 (m, 1H), 3.94-3.82 (m, 4H), 3.75-3.57 (m, 2H), 3.51-3.41 (m, 1H), 2.37-2.05 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.ClC(Cl)(Cl)[C:14]([N:16]=C=O)=[O:15].[OH-].[K+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([C:14]([NH2:16])=[O:15])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: Brc1cnc2c(c1)CCCN2
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)N1CCCc2cc(Br)cnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a cooled (0° C.) solution of 6-bromo-1,2,3,4-tetrahydro-[1,8]naphthyridine (6.4 g, 30.0 mmol) in DCM (75 mL) is added a trichloroacetyl isocyanate (3.8 mL, 31.5 mmol). After stirring for 1 h at 0° C., a solution of methanolic KOH (1M, 10 mL) is added. The resulting mixture is allowed to warm and stir at room temperature for 16 h. The reaction is concentrated and purified by silica gel column (0-100% EtOAc in heptane) to afford the title compound (7.4 g).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH2:6]([O:8][C:9](=[O:16])[CH2:10][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[CH3:7].[Br:17]Br>C(O)(=O)C>[Br:17][CH:10]([C:11](=[O:15])[CH:12]([CH3:13])[CH3:14])[C:9]([O:8][CH2:6][CH3:7])=[O:16]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(Br)C(=O)C(C)C
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium acetate (1.9 g) in glacial acetic acid (15 ml) was added 4-methyl-3-oxo-pentanoic acid ethyl ester (2 g) and the reaction mixture cooled to 10° C. Bromine (0.7 ml) was then added dropwise. The resulting solution was allowed to warm to room temperature and stirred for 1 h. The reaction was complete (by TLC) and was concentrated in vacuum affording 3.8 g crude ethyl product which was used directly in the next synthetic step.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[CH:9]12[O:15][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14]2.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:15][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: C1CCC2OC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1nccn1C1CCCCC1O
Reaction time: 16 h

Procedure:
A suspension of 0.565 g (5 mmole) of 2-nitroimidazole, 50 ml of ethanol, 5.0 ml of cyclohexene oxide, and 0.25 g of potassium carbonate was refluxed with stirring under nitrogen for 16 hr. The resulting yellow solution was evaporated and the residue dissolved in 100 ml of chloroform and filtered. The filtrate was evaporated and the residue purified by preparative TLC with ethyl acetate: benzene (2:1) as eluant to provide 0.359 g (34.0%). It was recrystallized from ethyl acetate-ether, mp 141° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH3:16])[C:8]=2[N:9]=[C:10](Cl)[N:11]=1)[CH2:2][CH2:3][CH3:4].[CH2:17]([NH2:20])[CH:18]=[CH2:19].C(=O)([O-])O.[Na+]>>[CH2:17]([NH:20][C:10]1[N:11]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:7]2[S:15][CH:14]=[C:13]([CH3:16])[C:8]=2[N:9]=1)[CH:18]=[CH2:19]
Reactant: CCCCNc1nc(Cl)nc2c(C)csc12
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCCCC)c2scc(C)c2n1
Yield: 73.9 %

Procedure:
In a sealed tube were heated 307 mg (1.2 mmol) of 4-butylamino-2-chloro-7-methylthieno[3,2-d]pyrimidine and 1.10 g (19.2 mmol) of allylamine at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/8) to give 245 mg (yield: 73.8%) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[F:6][C:7]([F:17])([F:16])[C:8]([F:15])([F:14])[C:9]([F:13])([F:12])[CH:10]=O>O1CCCC1>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:10]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)[C:9]([F:13])([F:12])[C:8]([F:15])([F:14])[C:7]([F:17])([F:16])[F:6]
Reactant: c1cc[nH]c1
Reactant: O=CC(F)(F)C(F)(F)C(F)(F)F
Solvent: C1CCOC1
Product: FC(F)(F)C(F)(F)C(F)(F)C(c1ccc[nH]1)c1ccc[nH]1

Procedure:
Pyrrole (2; 50 mmol) and heptafluorobutyraldehyde (7; R=CF3CF2, as the hydrate, 25 mmol) were condensed in tetrahydrofuran in the presence of acid catalyst as described above to give bis-(pyrrol-2-yl) heptafluoroprop-1-ylmethane (8; R=CF3CF2) in >50% isolated yield. GCMS m/z; 314 (M+, 22%), 145 (100%); 1H NMR (δ, CDCl3 at 7.24); 4.92 (t, 1H), 6.22 (d, 4H), 6.75 (s, 2H), 8.07 (bs, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:17][CH:18]([F:20])[F:19]>>[F:19][CH:18]([F:20])[CH2:17][N:13]1[CH:14]=[C:10]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[N:11]=[C:12]1[CH3:15]
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: FC(F)CBr
Product: Cc1cc(C#Cc2cn(CC(F)F)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=262.1 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-bromo-1,1-difluoro ethane.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[C:25]([C:26]([NH2:28])=O)=[CH:24][CH:23]=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1>C(Cl)Cl.CO>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[C:25]([C:26]#[N:28])=[CH:24][CH:23]=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NC(=O)c1cccc2c1[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Solvent: ClCCl
Solvent: CO
Product: N#Cc1cccc2c1[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Yield: 66 %

Procedure:
The title compound is prepared from cis-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-10-carboxylic acid amide following a procedure analogous to that described in Example 42. Yield: 66% of theory; TLC: rf=0.45 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=357 [M+H]+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([C:11]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH:9]=[CH2:10].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C([O-])([O-])=O.[K+].[K+].Cl>C1(C)C=CC=CC=1>[CH2:8]([C:11]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][N:14]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:13][CH2:12]1)[CH:9]=[CH2:10]
Reactant: C=CCC1(C(=O)OCC)CCNCC1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CCC1(C(=O)OCC)CCN(CC(=O)OCC)CC1
Temperature: 80 °C

Procedure:
The crude TFA salt of ethyl 4-allyl-isonipecotate and ethyl bromoacetate (23.5 g, 141 mmol) were dissolved in toluene. To this solution was added anhydrous K2CO3 (70.7 g, 512 mmol), and the resulting suspension was warmed to 80° C. for 15 minutes. The reaction mixture was cooled down, and adjusted at pH=8.0 with dil.HCl. The resulting solution was worked-up by an ordinal procedure (extraction with ethyl acetate, washing with brine, drying over Na2SO4, concentration by evaporation) to provide 37.4 g of crude ethyl 4-allyl-N-ethoxycarbonylmethyl-isonipecotate, 56.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)=[C:2]=[S:3].[I:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[I:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH:17][C:2](=[S:3])[NH:1][C:4]1[CH:5]=[C:6]([S:10]([NH2:13])(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: NS(=O)(=O)c1cccc(N=C=S)c1
Reactant: Nc1ccccc1I
Product: NS(=O)(=O)c1cccc(NC(=S)Nc2ccccc2I)c1

Procedure:
The subject compound was prepared utilizing the procedure described above from 3-isothiocyanatobenzenesulfonamide and 2-iodoaniline. 1H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.52 (s, 1H), 8.01-7.37 (m, 9H), 7.04 (m, 1H); (M+H)+ (434).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:22])[CH2:10][N:11]2[CH2:14][CH:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)=[CH:5][CH:4]=1)#[N:2].C(=O)(O)[O-].[Na+].Cl.[NH2:29][OH:30]>CC(O)C.C(OCC)(=O)C>[OH:22][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([C:1](=[N:29][OH:30])[NH2:2])=[CH:8][CH:7]=1)[CH2:10][N:11]1[CH2:12][CH:13]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:14]1
Reactant: CC(C)(C)OC(=O)C1CN(CC(O)c2ccc(C#N)cc2)C1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1CN(CC(O)c2ccc(C(N)=NO)cc2)C1
Temperature: 85 °C
Yield: 99.1 %

Procedure:
To a mixture of tert-butyl 1-(2-(4-cyanophenyl)-2-hydroxyethyl)azetidine-3-carboxylate (100 mg, 0.331 mmol) and sodium bicarbonate (111 mg, 1.323 mmol) in 2-propanol was added hydroxylamine hydrochloride (22.98 mg, 0.331 mmol). The reaction mixture was heated at 85° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with H2O. The organic layer was dried with MgSO4, filtered, and concentrated to yield 110 mg of tert-butyl 1-(2-hydroxy-2-(4-(N′-hydroxycarbamimidoyl)phenyl)ethyl)azetidine-3-carboxylate. MS (m+1)=336. HPLC Peak RT=0.91 minutes (Analytical Method B).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[N:15]O)[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[O:17]1CCOCC1>>[CH3:1][N:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]2[C:10](=[O:17])[NH:15][CH2:11][CH2:12][CH2:13][C:14]1=2
Reactant: Cn1c2c(c3ccccc31)C(=NO)CCC2
Reactant: C1COCCO1
Product: Cn1c2c(c3ccccc31)C(=O)NCCC2

Procedure:
1,2,3,9-Tetrahydro-9-methyl-4H-carbazol-4-one oxime (24 g) and polyphosphoric acid (600 g) in dioxan (500 ml) were treated according to the method described for Intermediate 6. The solid (22 g) obtained by evaporation of the organic extracts was recrystallised from ethyl acetate (300 ml) to give a solid (19.2 g). This was purified by FCC eluting with System A (200:8:1) to give the title compound (5.5 g), m.p. 212°-215°.
Reaction SMILES: COC[O:4][C@@H:5]1[CH2:18][C@@H:17]2[C@H:8]([C@H:9]3[C@H:14]([CH2:15][CH2:16]2)[CH2:13][C@:12]2([CH3:24])[C@@H:19]([C:22]#[N:23])[CH2:20][CH2:21][C@H:11]2[CH2:10]3)[CH2:7][CH2:6]1.Cl>CO.ClCCl>[OH:4][C@@H:5]1[CH2:18][C@@H:17]2[C@H:8]([C@H:9]3[C@H:14]([CH2:15][CH2:16]2)[CH2:13][C@:12]2([CH3:24])[C@@H:19]([C:22]#[N:23])[CH2:20][CH2:21][C@H:11]2[CH2:10]3)[CH2:7][CH2:6]1
Reactant: COCO[C@H]1CC[C@@H]2[C@H](CC[C@@H]3C[C@@]4(C)[C@@H](CC[C@@H]4C#N)C[C@H]32)C1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: C[C@]12C[C@H]3CC[C@@H]4C[C@@H](O)CC[C@H]4[C@@H]3C[C@@H]1CC[C@@H]2C#N
Reaction time: 14 h
Yield: 93.9 %

Procedure:
To compound 9 (165 mg, 0.5 mmol) in methanol (9 mL) and dichloromethane (3 mL) was added 6 N HCl (10 ml) at room temperature. After 14 h, the product was extracted into EtOAc (50 mL×2). The combined extracts were dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 25% EtOAc in hexanes) to afford compound 10 (135 mg, 94%): mp 162-164° C.; [α]D20 +33.9 (c 0.31, CHCl3); 1H NMR (CDCl3) δ 4.06 (s, br, 1H), 0.86 (s, 3H); 13C NMR (CDCl3) δ 121.3, 66.1, 48.3, 47.9, 46.9, 44.9, 44.2, 40.2, 39.8, 38.1, 36.0, 33.8, 33.7, 32.6, 28.4, 26.3 (2C), 23.1, 14.2; IR νmax 3456, 2235, 1447 cm−1. Anal. Calcd for (C19H29NO): C, 79.39; H, 10.17; N, 4.87. Found: C, 79.60; H, 10.26; N, 4.92.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:27]2[C:32](=[O:33])[NH:31][C:30](=[O:34])[CH:29]=[N:28]2)[CH:5]=[C:6]([Cl:26])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([S:17]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)(=[O:19])=[O:18])[CH:10]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:27]2[C:32](=[O:33])[NH:31][C:30](=[O:34])[CH:29]=[N:28]2)[CH:5]=[C:6]([Cl:26])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([S:17]([N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)(=[O:18])=[O:19])[CH:10]=1
Reactant: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1S(=O)(=O)N1CCCCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1cnn(-c2cc(Cl)c(Oc3ccc(O)c(S(=O)(=O)N4CCCCC4)c3)c(Cl)c2)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a cooled (0° C.), stirred solution of 2-{3,5-dichloro-4-[4-methoxy-3-(piperidine-1-sulfonyl)-phenoxy]-phenyl}-2H-[1,2,4]triazine-3,5-dione (0.5 g) in dichloromethane (30 mL) was added boron tribromide (0.3 mL) and the resulting heterogeneous mixture was allowed to stir at room temperature for 6 h. Ice was added to the mixture and the resulting two-phase solution stirred for 1 h. Layers were separated and the organic phase was washed with water, brine, dried (Na2SO4) and concentrated in vacuo to afford an oil. Flash chromatography on silica gel (35% acetone/hexanes) afforded the title compound of this EXAMPLE as a colorless solid, 0.4 g. MS Calc.:513.4 Found:512.9.
Reaction SMILES: CC1C=CC([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[CH:39]=[CH:38][C:20]([O:21][C:22]4[CH:31]=[C:30]5[C:25]([CH:26]([C:32]([O:34]C)=[O:33])[CH2:27][CH2:28][O:29]5)=[CH:24][C:23]=4[C:36]#[N:37])=[CH:19][CH:18]=3)=[O:16])=[CH:10][CH:9]=2)=CC=1.O[Li].O.O1[CH2:48][CH2:47]OCC1.Cl>C1COCC1>[C:36]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:22]=1[O:21][C:20]1[CH:38]=[CH:39][C:17]([C:15](=[O:16])[NH:14][C:11]3[CH:10]=[C:9]([C:8]4[CH:13]=[CH:12][C:47]([CH3:48])=[CH:10][CH:9]=4)[CH:8]=[CH:13][CH:12]=3)=[CH:18][CH:19]=1)[O:29][CH2:28][CH2:27][CH:26]2[C:32]([OH:34])=[O:33])#[N:37]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(-c5ccc(C)cc5)cc4)cc3)c(C#N)cc21
Reactant: C1COCCO1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cccc(NC(=O)c3ccc(Oc4cc5c(cc4C#N)C(C(=O)O)CCO5)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 187.5 %

Procedure:
A mixture of methyl 7-(4-(4′-methylbiphenyl-4-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (33 mg, 0.063 mmol), 1M solution of LiOH—H2O (127.3 μl, 0.127 mmol), and THF (1.5 ml) was stirred for 17 hours at ambient temperature. The mixture was quenched with 4M HCl dioxane (47.73 μL, 0.190 mmol). The crude mixture was purified on silica gel (MeOH in dichloromethane with 1% acetic acid gradient) to provide 29.8 mg of the title compound as a white solid (93%). MS (apci) m/z=505.1 (M+H).
Reaction SMILES: O[C:2]1[C:7](CC=C(C)C)=[C:6]([O:13][CH3:14])[CH:5]=[CH:4][C:3]=1[C:15](=[O:17])C>C(O)C>[CH:15](=[O:17])[C:3]1[CH:2]=[CH:7][C:6]([O:13][CH3:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C)=O)c(O)c1CC=C(C)C
Solvent: CCO
Product: COc1ccc(C=O)cc1

Procedure:
In 5 ml of ethanol were dissolved 0.48 g of 2'-hydroxy-4'-methoxy-3'-(3-methyl-2-butenyl)acetophenone obtained in production Example 9 and 0.35 ml of p-anisaldehyde. The solution was cooled to 0° C. and 7.5 ml of a saturated ethanol solution of potassium hydroxide was added to the solution, and the mixture was stirred at 0° C. for 30 minutes and at room temperature for 4 days. After the reaction, 3 N hydrochloric acid was added to the reaction liquid under cooling to gradually make the liquid acidic, and the formed precipitate was recovered by filtration and recrystallized from methanol to obtain 0.47 g (yield=64.7%) of 2'-hydroxy-4,4'-dimethoxy-3'-(3-methyl-2-butenyl)chalcone in the form of a yellow needle.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10](=O)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:10]1[N:9]=[N:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][C:11]=1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=c1[nH]nc(-c2ccccc2)nc1Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: Clc1nnc(-c2ccccc2)nc1Cc1ccccc1

Procedure:
Heat a solution of 15 mmol (4 g) of 3-phenyl-5-benzyl-1,2,4-triazin-6-one obtained in Step C of Example 28 in 30 ml of phosphorus oxychloride to a temperature of 80° C. After cooling, pour into iced water, render alkaline and extract with ethyl acetate. Dry the organic phase, filter, evaporate to dryness and purify by chromatography on silica (eluant ethyl acetate/hexane: 27/75)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[Br:14]C1C(=O)C(Br)=CC(Br)(Br)C=1>C(Cl)Cl>[Br:14][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([O:2][CH3:1])[C:9]=1[C:10]([F:11])([F:12])[F:13]
Reactant: COc1c(N)cccc1C(F)(F)F
Reactant: O=C1C(Br)=CC(Br)(Br)C=C1Br
Solvent: ClCCl
Product: COc1c(N)ccc(Br)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
To a solution of compound 17C (200 mg, 1.05 mmol) in CH2Cl2 (2 mL) cooled to −20° C. was added dropwise a solution of 2,4,4,6-tetrabromo-2,5-cyclohexadienone (429 mg, 1.05 mmol) in CH2Cl2 (2 mL). After the addition, the reaction was stirred at rt overnight, then additional amount of 2,4,4,6-tetrabromo-2,5-cyclohexadienone (429 mg, 1.05 mmol) was added. The reaction was continued for 2 more days, then concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 10%-20% EtOAc/hexane to yield the title compound (47mg, 16% yield).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=O.[C:9]([O:13][C:14](=[O:21])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>[C:9]([O:13][C:14](=[O:21])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:7][C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: Cn1ccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1ccnc1CNCCCCNC(=O)OC(C)(C)C

Procedure:
Using General Procedure B, reaction of 1-methyl-1H-imidazole-2-carbaldehyde and (4-amino-butyl)-carbamic acid tert-butyl ester in CH2Cl2 and NaBH(OAc)3 gave {4-[(1-methyl-1H-imidazol-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as a sticky white foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:36])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:15][C@H:16]([CH2:24][N:25]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:14])[S:10][C:11]=1[Cl:12].NN>O1CCCC1.CO>[NH2:25][CH2:24][C@@H:16]([NH:15][C:13]([C:9]1[S:10][C:11]([Cl:12])=[C:7]([C:6]2[N:5]([CH3:36])[N:4]=[CH:3][C:2]=2[Br:1])[CH:8]=1)=[O:14])[CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Cn1ncc(Br)c1-c1cc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1-c1cc(C(=O)N[C@H](CN)CC2CCCCC2)sc1Cl
Reaction time: 12 h
Yield: 25 %

Procedure:
To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide (48 mg, 0.08 mmol) in tetrahydrofuran (0.41 ml) and methanol (0.41 ml) at 25° C. was added hydrazine (0.03 ml, 0.81 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH4OH)). The free base was then converted to the HCl salt by adding excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamide (11 mg, 0.02 mmol, 24% yield) as a yellow solid: LCMS (ES) m/z=459, 461 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (br. s., 1H) 7.96 (br. s., 4H) 7.74 (s, 1H) 4.21-4.26 (m, 1H) 3.77 (s, 3H) 2.92-2.99 (m, 2H) 1.73-1.79 (m, 1H) 1.62-1.67 (m, 4H) 1.49-1.51 (m, 1H) 1.25 (br. s., 2H) 1.06-1.13 (m, 2H) 0.95 (d, J=6.82 Hz, 1H) 0.82-0.89 (m, 1H).
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21](F)[CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[C:23]([CH:24]=1)[O:1][CH:2]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:11])[CH3:9]
Reactant: CCCCC(O)CCN(C)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Product: CCCCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared according to the method of Example 3 step (b) but using (3-hydroxyheptyl)methylcarbamic acid, 1,1-dimethylethyl ester and 4-chloro-2-fluoronitrobenzene.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[CH:27]=1)=[O:25])(C)(C)C>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH:15][C:22](=[O:21])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[CH:27]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1N
Product: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(F)ccc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (2-amino-4-fluoro-phenyl)-carbamic acid tert-butyl ester (Example J2) (170 mg, 0.75 mmol) and 3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow solid (323 mg).