Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:31]=[C:30]([O:32][CH2:33][CH:34]=[C:35]([Cl:37])[Cl:36])[CH:29]=[C:28]([Cl:38])[C:22]=1[O:23][CH2:24][CH2:25][CH2:26][OH:27].[C:39]([O:43][C:44](=[O:53])[NH:45][C:46]1[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=1)([CH3:42])([CH3:41])[CH3:40]>C1COCC1>[C:39]([O:43][C:44](=[O:53])[NH:45][C:46]1[CH:47]=[CH:48][C:49]([O:27][CH2:26][CH2:25][CH2:24][O:23][C:22]2[C:21]([Cl:20])=[CH:31][C:30]([O:32][CH2:33][CH:34]=[C:35]([Cl:37])[Cl:36])=[CH:29][C:28]=2[Cl:38])=[CH:50][CH:51]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.69 g of azadicarboxylic acid diisopropyl ester are added dropwise at 0–5° C. to a solution of 1.97 g of triphenylphosphine in 60 ml of THF. After 30 minutes at 0–5° C., 2.5 g of 3-[2,6-dichloro-4-(3,3-dichloroallyloxy)-phenoxy]-propan-1-ol and 1.5 g of (4-hydroxy-phenyl)-carbamic acid tert-butyl ester dissolved in 30 ml of tetrahydrofuran are added dropwise. After being stirred for 24 hours at room temperature, the reaction mixture is concentrated and then purified over silica gel. (4-{3-[2,6-Dichloro-4-(3,3-dichloroallyloxy)-phenoxy]-propoxy}-phenyl)-carbamic acid tert-butyl ester (compound 1.6) is obtained.
Reaction SMILES: [BH4-].[Na+].[H][H].[C:5]([C:7]1[CH:8]=[CH:9][C:10]([CH3:23])=[C:11]([CH:13]([CH2:19][N+:20]([O-])=O)[CH2:14][C:15](OC)=[O:16])[CH:12]=1)#[N:6]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:6][CH2:5][C:7]1[CH:8]=[CH:9][C:10]([CH3:23])=[C:11]([CH:13]2[CH2:19][NH:20][C:15](=[O:16])[CH2:14]2)[CH:12]=1
Reactant: COC(=O)CC(C[N+](=O)[O-])c1cc(C#N)ccc1C
Reactant: [H][H]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(CN)cc1C1CNC(=O)C1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
Adapting a literature known protocol (Osby and Ganem, Tetrahedron Lett., 1985, 26(52), 6413-6416), a mixture of nickel(II) dichloride hexahydrate (NiCl2 6H2O) (1.19 g, 5.0 mmol) in methanol (MeOH) (80 mL) is sonicated to effect complete dissolution. Solid sodium borohydride (NaBH4) (567 mg, 15.0 mmol) is added in small portions upon a black precipitate (Ni2B) is generated immediately and hydrogen gas is generated (exotherm!). After about 30 min, a solution of methyl 3-(5-cyano-2-methyl-phenyl)-4-nitro-butanoate (22b) (2.62 g, 10.0 mmol) in MeOH (20 mL) is added followed by portion-wise addition of more NaBH4 (1.13 g, 30.0 mmol) at room temperature. The reaction is monitored by TLC and/or LCMS till completion. The reaction mixture is filtered over Celite® 545 and the filter residue is washed with additional MeOH. The combined filtrates are partially evaporated under reduced pressure using a rotary evaporator and the crude material is heated to 50-60° C. to complete the lactamization. Purification by silica gel column chromatography with mixtures of (MeOH) and dichloromethane (DCM) furnishes the title compound 4-[5-(aminomethyl)-2-methyl-phenyl]pyrrolidin-2-one (22c).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:10]=2)[N:5]=[CH:4][C:3]=1[C:22]#[N:23].C(Cl)(=O)C([Cl:27])=O.CN(C=O)C>C(Cl)Cl>[Cl:27][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:10]=2)[N:5]=[CH:4][C:3]=1[C:22]#[N:23]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cnc2ccc(OCCCN3CCOCC3)nc2c1O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cnc2ccc(OCCCN3CCOCC3)nc2c1Cl
Reaction time: 1 h
Yield: 38 %

Procedure:
To a suspension of 4-hydroxy-6-(3-morpholin-4-yl-propoxy)-[1.5]naphthyridine-3-carbonitrile in anhydrous CH2Cl2 (150 ml) was added oxalyl chloride (2.7 ml, 31.8 mmol) and DMF (0.1 ml, 20%) at room temperature under nitrogen. The suspension became a clear dark brown solution. The resulting mixture was stirred for an additional 1 hr. The solvent was removed by rotary evaporation. The residue was dissolved in ice-water mixture, made basic with (NH4OH), and extracted with CH2Cl2. The extracts were washed (brine), dried (Na2SO4), and concentrated to give the title compound (400 mg, 38%). H-NMR δ(DMSO-d6): 1.88 (2H, m), 2.26-2.29 (6H, m), 2.51 (2H, m), 3.49 (2H,m), 4.34 (2H, m), 6.834 (1H, d, C7-H), 8.147 (1H, d, C8-H), 8.711 (1H, s, C2-H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[CH:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH:25]1[CH:29]=[CH:28][CH:27]=[N:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:25]1([C:2]2[CH:7]=[C:6]([C:8]3[N:12]4[CH:13]=[C:14]([NH:17][CH:18]5[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]5)[CH:15]=[CH:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:29]=[CH:28][CH:27]=[N:26]1
Reactant: OC1CCC(Nc2ccc3ncc(-c4ccnc(Cl)c4)n3c2)CC1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OC1CCC(Nc2ccc3ncc(-c4ccnc(-n5cccn5)c4)n3c2)CC1
Temperature: 25 °C

Procedure:
A mixture comprising [4-[3-(2-Chloro-pyridin-4-yl)-imidazo[1,2-a]pyridin-6-ylamino]-cyclohexanol (Example 2.1) (1 eq, 0.29 mmol, 100 mg), pyrazole (5 eq, 1.45 mmol, 99 mg) and cesium carbonate (3 eq, 0.87 mmol, 284 mg) in DMF (25 ml) is heated using microwave radiation at 145° C. for 6 hours. After cooling to room temperature, the mixture is loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The solvent is removed in vacuo and the crude product is triturated with ethyl acetate to afford the title compound; [M+H]+=375
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[CH:4][CH:3]=1.[BrH:11]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Br:11])=[CH:4][CH:3]=1
Reactant: Br
Reactant: CC(O)c1ccc(Cl)cc1
Product: Clc1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
In a 65 mL glass pressure vessel, 4-chlorophenylethanol (32.725 g, 209 mmol) was warmed to between 90 and 100° C. The vessel was charged with hydrogen bromide gas and the mixture was stirred at +1.38 to +1.93 bar for 4.5 h. The pressure was released and the reaction showed 99.18% conversion by HPLC. The mixture was allowed to cool to room temperature to leave 2-(4-chlorophenyl)ethyl bromide as a brown liquid (53.735 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][NH:15][CH:16]=[O:17])=[CH:10][CH:9]=1)=[O:6].C(=O)([O-])[O-].[Ca+2].[C:26](Cl)(Cl)=[S:27]>O1CCOCC1.O>[CH:16]([NH:15][NH:14][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:5]([C:4]2[CH:3]=[C:2]([N:1]=[C:26]=[S:27])[CH:20]=[CH:19][CH:18]=2)=[O:6])=[CH:13][CH:12]=1)=[O:17]
Reactant: S=C(Cl)Cl
Reactant: Nc1cccc(C(=O)Nc2ccc(NNC=O)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: O=CNNc1ccc(NC(=O)c2cccc(N=C=S)c2)cc1
Yield: 71.3 %

Procedure:
51 g of 2-[4-(3-aminobenzamido)phenyl]-1-formylhydrazine and 29 g of calcium carbonate were dispersed in a mixture of 120 ml of dioxane and 120 ml of water. To the dispersion, 25 g of thiophosgene was added under cooling with ice. After reacting under cooling with ice for 3 hours, the crystals deposited were collected by filtration to obtain 42 g of the object compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:27][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[N:17]=[C:16]([NH2:18])[N:15]4[N:19]=[C:20]([C:22]5[O:23][CH:24]=[CH:25][CH:26]=5)[N:21]=[C:14]4[N:13]=3)[CH2:11][CH:6]2[CH2:5][CH2:4]1.Cl[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[O:23]1[CH:24]=[CH:25][CH:26]=[C:22]1[C:20]1[N:21]=[C:14]2[N:13]=[C:12]([N:10]3[CH2:9][CH2:8][N:7]4[CH2:27][CH:3]([CH2:2][NH:1][C:29]5[N:34]=[CH:33][CH:32]=[CH:31][N:30]=5)[CH2:4][CH2:5][CH:6]4[CH2:11]3)[N:17]=[C:16]([NH2:18])[N:15]2[N:19]=1
Reactant: NCC1CCC2CN(c3nc(N)n4nc(-c5ccco5)nc4n3)CCN2C1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1nc(N2CCN3CC(CNc4ncccn4)CCC3C2)nc2nc(-c3ccco3)nn12
Temperature: 85 °C
Reaction time: 4 h

Procedure:
A solution of (7RS,9aRS)—S-(7-aminomethyl-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (1 eq.; see Example 9 above) and 2-chloropyrimidine (2 eq.) in DMSO was treated with K2CO3 (2 eq.). The mixture was stirred at around 85° C. for 4 hours. The reaction mixture was then filtered, and the filtrate was concentrated and purified by preparative HPLC using aqueous CH3CN (buffered with 0.1% TFA) to afford (7RS,9aRS)-2-furan-2-yl-5-[7-(pyrimidin-2-ylaminomethyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine as a white powder: 1H NMR (400 MHz, DMSO-d6) δ 1.60-1.86 (m, 4H), 2.21-2.30 (bs, 1H), 3.05-3.32 (m, 4H), 3.33-3.52 (m, 4H), 3.56-3.72 (m, 1H), 4.62-4.83 (m, 2H), 6.63 (t, J=4.8 Hz, 1H), 6.69 (dd, J=1.8, 3.4 Hz, 1H), 7.08 (d, J=3.4 Hz, 1H), 7.41 (t, J=5.6 Hz, 1H), 7.89 (d, J=1.8 Hz, 1H), 8.32 (d, J=4.8 Hz, 2H), 8.40-8.65 (m, 2H). MS m/z: 448 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=O)[CH3:2].[CH3:13][N:14]([CH3:22])[N:15]1[C:19](=[O:20])[CH2:18][S:17][C:16]1=[S:21]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[C:18]2[S:17][C:16](=[S:21])[N:15]([N:14]([CH3:22])[CH3:13])[C:19]2=[O:20])[CH:9]=[CH:10][C:11]=1[OH:12])[CH3:2]
Reactant: CN(C)N1C(=O)CSC1=S
Reactant: CCOc1cc(C=O)ccc1O
Product: CCOc1cc(C=C2SC(=S)N(N(C)C)C2=O)ccc1O
Yield: 59.3 %

Procedure:
3-Ethoxy-4-hydroxybenzaldehyde (45.7 g), N-dimethylaminorhodanine (53.35 g) and fused sodium acetate (92.4 g) were reacted in the manner described in Example 1 to provide 52.92 g of the subtitled intermediate. m.p. 194°-198° C.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Reactant: Clc1ccc(CCCCCCCCCCCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C=Cc1ccc(NCCCCCCCCCCCCCc2ccc(Cl)cc2)cc1

Procedure:
A mixture of ethyl p-aminocinnamate, 5.9 g. 13-(4-chlorophenyl)tridecyl bromide and one equivalent of anhydrous powdered potassium carbonate in 50 ml. hexamethylphosphoramide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated. Crystallization from acetonitrile provides the title compound as white crystals.
Reaction SMILES: C1(O[C:8]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[O:27])[CH2:14][CH2:13]2)=[N:9][C:10]#[N:11])C=CC=CC=1.[CH2:28]([NH2:30])[CH3:29]>O1CCCC1>[C:10]([NH:9][C:8]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH:20][C:19]2=[O:27])[CH2:16][CH2:17]1)=[N:30][CH2:28][CH3:29])#[N:11]
Reactant: CCN
Reactant: N#CN=C(Oc1ccccc1)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Solvent: C1CCOC1
Product: CCN=C(NC#N)N1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
N-cyano-4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboximidic acid phenyl ester (0.050 g; 0.14 mmol) was treated with a 2M Solution of ethylamine in tetrahydrofuran (2 mL) and subjected to microwave irradiation (temperature approximately 110° C.) for 0.5 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative reverse-phase liquid chromatography to give N-cyano-N′-ethyl-4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxamidine (0.01 g) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:26][C:27]1[CH:28]=[C:29]([C:33](=[N:35]O)[NH2:34])[CH:30]=[CH:31][CH:32]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:35]=[C:33]([C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([F:26])[CH:28]=4)[N:34]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: NC(=NO)c1cccc(F)c1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4cccc(F)c4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 34 mg (0.22 mmol, 1.1 eq.) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 55 mg (58% of theory)
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[C:10]([O:14][C:15]([N:17]1[CH2:24][C@H:23]2[C@H:19]([CH2:20][CH:21]([CH3:25])[CH2:22]2)[C@H:18]1[CH2:26][NH2:27])=[O:16])([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:24][C@H:23]2[C@H:19]([CH2:20][CH:21]([CH3:25])[CH2:22]2)[C@H:18]1[CH2:26][NH:27][C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])=[O:16])([CH3:12])([CH3:13])[CH3:11]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC1C[C@H]2CN(C(=O)OC(C)(C)C)[C@H](CN)[C@H]2C1
Solvent: C1CCOC1
Product: CC1C[C@H]2CN(C(=O)OC(C)(C)C)[C@H](CNC(=O)C(F)(F)F)[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl trifluoroacetate (0.7 mL, 1.4 eq) was added to a solution of (1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]-octane-3-carboxylic acid tert.-butyl ester (1.1 g) in dry THF (14 mL). The reaction mixture was stirred at RT for 1 h. Solvent and excess ethyl trifluoroacetate were evaporated in vacuo. The resulting product was then used for the next step without purification
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C:7]2[CH2:11][CH2:10][CH2:9][N:8]=2)=[CH:4][CH:3]=1.[CH2:14](Br)[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.C([O-])(O)=O.[Na+]>CO>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]2[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][N:8]3[C:7]=2[CH2:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Clc1ccc(CC2=NCCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Clc1ccc(-c2c(-c3ccccc3)cn3c2CCC3)cc1
Yield: 44.9 %

Procedure:
2-(4-Chlorobenzyl)-1-pyrroline (9 g, 50% strength, 25 mmol), dissolved in MeOH (75 ml) is treated with phenacyl bromide (4.97 g, 25 mmol) and then with NaHCO3 (2.5 g, 30 mmol) and stirred at RT for 16 h with exclusion of light. Precipitated crystallizate is filtered off with suction and washed with MeOH. 3.3 g (45%) of product are obtained after drying.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=[O:9])([O-])=O.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]2[NH:19][C:18]3[CH:17]=[CH:16][C:6]([NH:7][C:8](=[O:9])[C:10]4[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=4)=[CH:5][C:4]=3[N:1]=2)=[CH:26][CH:25]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccncc1
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(-c2nc3cc(NC(=O)c4ccncc4)ccc3[nH]2)cc1

Procedure:
Compound 205 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(pyridin-4-oyl)aniline and 4-methoxybenzaldehyde. [M+H]+ calcd for C20H16N4O2: 345.13; found: 345.00.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[OH:12])=[CH:4][CH:3]=1
Reactant: O=C1CCCc2ccc(Br)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OC1CCCc2ccc(Br)cc21

Procedure:
To a solution of 7-bromo-3,4-dihydro-2H-naphthalen-1-one (CAS#32281-97-3, 3.5 g, 0.015 mol) in methanol (7 mL) and dichloromethane (10 mL) at 0° C. is added sodium borohydride (1.47 g, 0.038 mol) in one portion. The cooling bath is removed and after 1.5 hours, the mixture is poured into water and the volatile organics are removed in vacuo. Extraction with dichloromethane, drying over sodium sulfate, filtering through a cotton plug and concentration in vacuo affords 7-bromo-1,2,3,4-tetrahydro-naphthalen-1-ol. 1H NMR (400 MHz, CDCl3) δ ppm 1.72 (d, J=6.3 Hz, 1 H), 1.74-1.90 (m, 2 H), 1.92-2.07 (m, 2 H), 2.62-2.71 (m, 1 H), 2.73-2.82 (m, 1 H), 4.73-4.77 (m, 1 H), 6.98 (d, J=8.2 Hz, 1 H), 7.31 (dd, J=8.2, 2.1 Hz, 1 H), 7.61 (d, J=2.1 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[CH2:13]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34](O)=[O:35])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[CH2:13]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([O:8][C:7]3[C:2]([F:1])=[C:3]([F:12])[C:4]([F:11])=[C:5]([F:10])[C:6]=3[F:9])=[O:35])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pentafluorophenol (11.5 mmol) is added at 0° to a mixture of 10.5 mmol 4'-n-octyloxy[1,1'-biphenyl]-4-ylcarboxylic acid and 10.5 mmol of dicyclohexylcarbodiimide in ethyl acetate. The mixture is stirred at 25° C. for a period of 18 hours whereupon a precipitate is formed. The reaction mixture is filtered, the filtrate washed with water and brine and dried, the solvent removed in vacuo to obtain pentafluorophenyl 4'-n-octyloxy[1,1'-biphenyl]-4-ylcarboxylate, C27H25F5O3, M.W. 492.5.
Reaction SMILES: C([O:3][C:4](=[O:12])[C:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=[O:6])C.Cl>CC(C)=O.O>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5](=[O:6])[C:4]([OH:12])=[O:3]
Reactant: CCOC(=O)C(=O)c1cccs1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)C(=O)c1cccs1

Procedure:
The thiophenyl oxo-acetic acid ethyl ester VII, VIIa or VIIb may be subjected to hydrolysis to provide the corresponding thiophenyl oxo-acetic acid IV, IVa or IVb. The hydrolysis may be carried out under either acidic or basic conditions. Basic hydrolysis can typically be carried out by treating a solution of a thiophenyl oxo-acetic acid ethyl ester such as VII, VIIa or VIIb (1.0 equivalent) in an aqueous mixture of an appropriate solvent such as methanol, tetrahydrofuran or 1,4-dioxane with a suitable base such as aqueous sodium hydroxide or potassium hydroxide (typically 1.5 equivalents) for a period of four to twenty hours at a temperature range of 0° C. to room temperature. The reaction mixture can be worked up by acidification with an appropriate acid such as hydrochloric acid or acetic acid followed by extraction with an appropriate solvent such as ethyl acetate or dichloromethane. The resulting organic layer may then be concentrated in vacuo to provide the thiophenyl oxo-acetic acid IV, IVa or IVb, respectively. If desired, the thiophenyl oxo-acetic acid IV, IVa or IVb could then be further purified by recrystallization or preparative HPLC. Alternatively, the hydrolysis of the thiophenyl oxo-acetic acid ethyl ester VII, VIIa or VIIb to the corresponding thiophenyl oxo-acetic acid IV, IVa or IVb may be carried out under acidic conditions. The acidic hydrolysis is typically carried out by refluxing a thiophenyl oxo-acetic acid ethyl ester such as VII, VIIa or VIIb in a mixture of acetone and water in the presence of hydrochloric acid for one to four hours. The reaction mixture is then extracted with an appropriate solvent such as dichloromethane and the organic layer concentrated in vacuo to provide the thiophenyl oxo-acetic acid IV, IVa and IVb, respectively.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][NH2:11])=[N:8][CH:9]=1)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:23])[CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18])[CH3:13].N1C=CC=CC=1>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[C:17]([CH3:18])=[N:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[C:20]=1[CH3:21])=[O:23])[CH3:13]
Reactant: NNc1ccc([N+](=O)[O-])cn1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)nn(-c2ccc([N+](=O)[O-])cn2)c1C

Procedure:
Similar to Example 1, equimolar amounts of (5-nitropyridin-2-yl)hydrazine and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. Analysis confirmed synthesis of the named product (m.p. 117° C.-119° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([F:11])[CH:10]=[C:2]([NH2:1])[CH:3]=1
Reactant: CO
Reactant: Nc1cc(F)cc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(N)cc(F)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 3-amino-5-fluoro-benzoic acid (25 g, 161 mmol) in methanol (300 mL) was added thionyl chloride (30 mL, 403 mmol) dropwise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-amino-5-fluoro-benzoic acid methyl ester (27.5 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8FNO2 (M+H)+: 170.16, observed: 169.9.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][NH2:18])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][NH:18][C:27](=[O:29])[CH3:28])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCC1OCCc2c1sc(N)c2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
To a ice water cooled solution of the above 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (1.5 g, 5.27 mmol) and triethylamine (1.5 ml) in dichloromethane (50 ml) was added dropwise acetylchloride (0.46 g, 5.80 mmol). The reaction mixture was allowed to reach room temperature and stirred for an additional 0.5 h. The reaction mixture was washed with water (2×25 ml), dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography on silicagel (1 L) using first ethyl acetate and later on a mixture of ethyl acetate and ethanol (20:1) as eluents. Pure fractions were collected and the solvent evaporated in vacuo affording 0.3 g (17%) of 7-(acetylamino-methyl)-2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.