Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(CCCCCCCCC(N)C(C)C)C(C)C.C(C1CC=CCCC=CCC(C(C)C)N=N1)(C)C.[CH3:37][CH2:38][CH:39]([CH:42]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH:45]([CH:54]([CH2:57][CH3:58])[CH2:55][CH3:56])[NH:44][NH:43]1)[CH2:40][CH3:41]>>[NH2:43][CH:42]([CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH:45]([NH2:44])[CH:54]([CH2:55][CH3:56])[CH2:57][CH3:58])[CH:39]([CH2:40][CH3:41])[CH2:38][CH3:37]
Reactant: CCC(CC)C1CCCCCCCCC(C(CC)CC)NN1
Agent: CC(C)C(N)CCCCCCCCC(N)C(C)C
Agent: CC(C)C1CC=CCCC=CCC(C(C)C)N=N1
Product: CCC(CC)C(N)CCCCCCCCC(N)C(CC)CC

Procedure:
If there are used in the manner described under (a), instead of 250 g (1 mol) of 3,12-diisopropyl-1,2-diaza-1,5,9-cyclododecatriene, 49 g (0.159 mol) of 3,12-di-(3-pentyl)-1,2-diazacyclododecane and correspondingly reduced amounts of catalyst and solvent, with the procedure otherwise remaining the same, there is obtained, after chromatographical purification and distillation, 26.8 g (54% of theory) of 4,13-diamino-3,14-diethylhexadecane in the form of colourless oil [b.p. 141°-143° C./0.004 Torr; nD20 =1.4666; IR (liquid) inter alia bands at 3378, 3278 and 1613 cm-1 ].
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[NH:9][C:8](=[O:17])[C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(O)=[O:2].C([O-])(=O)C.[NH4+].O[N:30]1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>O1CCCC1.O.C(N(CC)CC)C>[NH2:30][C:1]([CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[NH:9][C:8](=[O:17])[C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:2]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)COc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Agent: CC(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)COc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 31.3 %

Procedure:
To a solution of 4-carboxymethoxy-7-chloro-3-phenyl--2(1H)-quinolone (0.93 g Example 15) in tetrahydrofuran (50 ml) under nitrogen at room temperature, was added triethylamine (1.90 ml), ammonium acetate (0.50 g), 1-hydroxybenzotriazole (0.60 g) and 1-(3 dimethylaminopropyl)-3-ethyl carbodiimide (0.90 g). The reaction mixture was stirred at room temperature for 3 days, then poured into water (100 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with 1N citric acid (1×75 ml), water (1×75 ml), saturated sodium hydrogen carbonate (1×75 ml) and brine (1×75 ml), then dried (MgSO4), filtered and the solvent was removed in vacuo to leave a solid residue. Recrystallisation from MeOH gave the title compound (0.29 g). Mp 262°-264° C. Found: C, 66.31; H, 5.95; N, 7.46; C19H19N2O2Cl 0.1C6H14 0.6H2O requires C, 65.97; H, 5.93; N, 7.85%. δ (360 MHz, DMSO-d6) 3.91 (2H, s, OCH2CONH2), 7.25-7.45 (9H, m, Ph+6H+8-H+OCH2CONH2), 8.01 (1H, d, J=8.66 Hz, 5-H), 11.92 (1H, bs, NH). m/z (CI+), 329, (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][O:6][C:7]2=[O:12].CN1CCOCC1.[C:20]12([CH2:30][C:31](Cl)=[O:32])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>O1CCOCC1>[C:20]12([CH2:30][C:31]([NH:1][C:2]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][O:6][C:7]4=[O:12])=[O:32])[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]3)[CH2:21]1)[CH2:29]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Nc1cccc2c(=O)occc12
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1cccc2c(=O)occc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
To a solution of 5-amino-1H-isochromen-1-one (2.95 g, 18.3 mmol) and NMM (2.02 mL, 18.3 mmol) in 1,4 dioxane (55 mL) was added dropwise at room temperature a solution of 1-adamantaneacetic acid chloride (3.9 g, 18.3 mmol) in 1,4-dioxane (40 mL). The reaction mixture was stirred at room temperature for 3 h and then partitioned between DCM (400 mL) and water (200 mL). The layers were separated. The aqueous phase was washed with DCM (100 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was suspended in hexane (100 mL) and filtered off. The solid was collected on the filter and dried in vacuo to yield 2-adamantan-1-yl-N-(1-oxo-1H-isochromen-5-yl)-acetamide as a yellow solid (5.6 g, 16.7 mmol, 91%).
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:21]#[N:22])[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:24].[OH-].[NH4+]>FC(F)(F)C(O)=O>[C:1]1([NH:7][C:8]2([C:21]([NH2:22])=[O:24])[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 47.5 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
Aminonitrile 1 (2.0 g, 6.86 mmol) was dissolved in 11 mL of trifluoroacetic acid under a nitrogen atmosphere. Sulfuric acid (2.7 mL) was added dropwise. The light brown solution was stirred at 45-50° C. for 16 h. The reaction mixture was cooled to room temperature and slowly poured into an ammonium hydroxide 40 mL/ice mixture. The solution was filtered and the solids were collected to give 1.73 g of amide 2 in an 82% yield. mp 179-182° C.; 1H NMR (CDCl3) δ 7.33-7.16 (m, 5H), 6.89 (br s, 1H), 6.78 (t, 1H, J=7.33 Hz), 6.63 (d, 2H, J=7.33 Hz), 5.48 (s, 1H), 4.05 (s, 1H), 2.77-2.71 (m, 2H), 2.37-2.30 (m, 2H), 2.10 (t, 2H, J=11.91 Hz), 1.95 (br d, 2H, J=13.28 Hz); 13C NMR (CDCl3) 178.7, 143.8, 138.3, 129.3, 129.1, 129.0, 128.3, 127.2, 119.3, 116.2, 63.1, 58.3, 48.8, 31.4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([CH:10]=[C:11]([CH3:13])[CH3:12])[C:7]([O:14][CH3:15])=[N:6][CH:5]=1>C(O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([O:14][CH3:15])=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(OC)c(C=C(C)C)c1
Solvent: CCO
Product: COC(=O)c1cnc(OC)c(CC(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.6 %

Procedure:
A solution of 6-methoxy-5-(2-methyl-propenyl)-nicotinic acid methyl ester (300 mg, 1.36 mmol) in ethanol (5 mL) is added to a suspension of Pt(IV) oxide (40 mg) in ethanol (5 mL). The mixture is stirred under 1 atm of H2 at rt for 18 h. The catalyst is filtered off and the filtrate is concentrated. The crude product is purified on prep. TLC plates with heptane:EA 7:3 to give 5-isobutyl-6-methoxy-nicotinic acid methyl ester (260 mg) as a colourless oil; LC-MS: tR=1.08 min; [M+1]+=224.49.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:24])[N:5]([CH3:23])[C:6]1[N:7]2[CH:12]=[N:13][C:14]=1[C:15]1[N:19]=[C:18]([CH:20]2[CH2:22][CH2:21]2)[O:17][N:16]=1.[C-:25]#[N:26].[Na+]>CN(C)C=O.O>[C:25]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:24])[N:5]([CH3:23])[C:6]1[N:7]2[CH:12]=[N:13][C:14]=1[C:15]1[N:19]=[C:18]([CH:20]2[CH2:22][CH2:21]2)[O:17][N:16]=1)#[N:26]
Reactant: [C-]#N
Reactant: Cn1c(=O)c2c(Br)cccc2n2cnc(-c3noc(C4CC4)n3)c12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(C#N)cccc2n2cnc(-c3noc(C4CC4)n3)c12

Procedure:
To 140 mg 6-bromo-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)4,5--dihydro-4-methyl-5-oxo-imidazo(1,5-a)quinazoline in 5 ml dimethyl formamide (DMF) 40 mg cuprous cyanide was added. Thereafter further 5 ml DMF was added and the resulting mixture was heated to 130°-150° C. for 60 minutes with stirring. To this mixture 110 mg sodium cyanide in 5 ml water was added and thereafter further 30 ml water. The resulting mixture was extracted with 30 ml ethyl acetate and thereafter four times with 20 ml ethyl acetate. The combined organic phase was washed with water and dried with calcium chloride. Evaporation in vacuo gave 24 mg of the title compound. M.p. 115°-125° C.
Reaction SMILES: [OH-].[K+].F[C:4]1[C:5]([F:17])=[C:6]([F:16])[C:7]([F:15])=[C:8]2[C:13](=[O:14])[O:12]C(=O)[C:9]=12.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=1>O>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:24][C:4]2[C:5]([F:17])=[C:6]([F:16])[C:7]([F:15])=[C:8]([CH:9]=2)[C:13]([OH:12])=[O:14])=[CH:21][CH:20]=1
Reactant: OCc1ccc(F)cc1
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(OCc2ccc(F)cc2)c(F)c(F)c1F
Temperature: 100 °C
Yield: 46.7 %

Procedure:
8.4 g (0.15 mol) of potassium hydroxide are dissolved in 30 g of water, and 6.6 g (30mmol) of tetrafluorophthalic anhydride and 30 g (0.238 mol) of 4-fluorobenzyl alcohol are added. The mixture is heated at 100° C. for 12 hours after which the procedure as described in Example 2 is followed. It is advantageous not to allow the pH to fall below 3 prior to the extraction steps. This method gives 4.2 g (14 mmol, corresponding to 47%) of (4-fluorobenzyloxy) trifluorobenzoic acid (purity 80-85%).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)=[O:7])(=O)[CH3:2].[OH-].[Na+].Cl>O>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:1]([CH3:2])=[N:4][NH:5][C:6]2=[O:7])=[CH:10][CH:11]=1
Reactant: CC(=O)NNC(=O)Nc1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1n[nH]c(=O)n1-c1ccc(Br)cc1
Temperature: 130 °C

Procedure:
A large microwave tube was filled in with 2-acetyl-N-(4-bromophenyl)hydrazinecarboxamide (1.8 g, 6.62 mmol) and 2M aqueous NaOH (9 mL, 18 mmol). The reaction mixture was heated under microwave irradiation for 20 min at 130° C. Water (ca 18 mL) was added and the pH was adjusted to 4 by dropwise addition of aqueous HCl, with stirring. The thick precipitate was collected by filtration, washed with small amounts of cold water and dried. A small amount (220 mg) was purified by analytical preparation leading to 195 mg of the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[OH-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:18]([O:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NN1CCCC(O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN1CCCC(OCc2ccccc2)C1
Yield: 71 %

Procedure:
Dissolve 15 g (74.5 mmol) of tert-butyl(+/−)-3-hydroxypiperidinecarbamate while heating in 86.5 ml of toluene and successively add 11.9 ml of 50% sodium hydroxide solution (447 mmol), 2.53 g (7.5 mmol) of tetra-n-butylammonium hydrogen sulphate and 11.5 ml (96.9 mmol) of benzyl bromide. Stir the biphasic reaction mixture vigorously at 70° C. for 4 h. After cooling, add water and neutralize with conc. hydrochloric acid. Remove the organic phase, dry it over sodium sulphate and concentrate it under reduced pressure. Purify the crude product by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 30:1→10:1). 16.21 g of the target product are obtained (74.6% of theory).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.Br[CH2:40][C:41]1[S:42][CH:43]=[C:44]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[N:45]=1>ClCCCl.C(#N)C>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[N:20]([CH2:40][C:41]4[S:42][CH:43]=[C:44]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[N:45]=4)[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1csc(CBr)n1
Reactant: O=c1[nH]cc(C2c3ccccc3C=Cc3ccccc32)c(=O)[nH]1
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: CC#N
Solvent: ClCCCl
Product: CCOC(=O)c1csc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)n1
Temperature: 25 °C

Procedure:
To a slurry of the product of step (iii) (1.1 g) in dry 1,2-dichloroethane (20 ml) was added bis(trimethylsilyl)trifluoroacetamide (1.9 ml) under nitrogen. The mixture was heated under reflux for 1 hour until the mixture became a homogeneous solution. The solution was allowed to cool to room temperature and a solution of the product of step (ii) (0.83 g) in dry acetonitrile (10 ml) was added. The solution was then heated at reflux for 7 hours. The reaction mixture was allowed to cool and evaporated under reduced pressure. Purification was by chromatography eluting with 30% ethyl acetate in toluene. The resulting oil was triturated with diethyl ether/isohexane to give the product as a cream solid. Yield 1.52 g.
Reaction SMILES: [OH-].[K+].[C:3]1([C:9]2[NH:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:23][CH2:24][CH2:25][CH3:26]>CS(C)=O>[CH2:23]([N:10]1[CH:11]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[N:13]=[C:9]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:24][CH2:25][CH3:26]
Reactant: COc1ccc(-c2c[nH]c(-c3ccccc3)n2)cc1
Reactant: CCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCn1cc(-c2ccc(OC)cc2)nc1-c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Potassium hydroxide (4.36, 76 mmol, 1.3 eq.) is suspended in 40 ml of anhydrous DMSO, to the suspension is added a solution 2-phenyl-4-(4-methoxyphenyl)imidazole (15.02, 60 mmol) and bromobutane (8.63 g, 63 mmol, 1.05 eq.) in 80 ml of DMSO at room temperature over 2 h, the resulting mixture is stirred over 24 h, and then poured into 400 ml of ice-water, extracted with ethyl acetate (100 ml×4), washed with water and brine, dried over anhydrous sodium sulfate. The solvent is evaporated and the product is purified through flash chromatography to give 16.73 g of 4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazole. MS (+VE) m/z 307 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:7]=3[N:8]=[C:9]2O)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:7]=3[N:8]=[C:9]2[Cl:22])=[CH:4][CH:3]=1
Reactant: Oc1nc2c3ccccc3oc2c2ccc(Cl)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2c(c1)c(Cl)nc1c3ccccc3oc21
Reaction time: 0.17 h

Procedure:
A mixture of 19B (11.8 mmol) in POCl3 (20 mL) was refluxed for 2 hours. After reaction completed, POCl3 was evaporated under reduced pressure. The residue was added into crushed ice and stirred for 10 min. The solids were collected by filtration and dried to give 3.2 g of a crude product, which was dissolved in dichloromethane and purified by flash chromatography (petroleum ether 1:1) and concentrated to give a pure product M19 (3.1 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23]([C:28](O)=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:28]([C:23]3[C:22]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:29])=[CH:16][C:15]=2[F:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2F)CC1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(4-Amino-2-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.50 g, 1.7 mmol) and biphenyl-2-carboxylic acid (0.38 g, 1.9 mmol) in CH2Cl2 (30 mL) was added 1-hydroxybenzotriazole hydrate (0.27 g, 2.0 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.38 g, 2.0 mmol). After stirring at room temperature for 18 h, the reaction was diluted with 1 N NaOH (50 mL) and extracted with CH2Cl2 (3×50 mL). The organic extracts were combined, dried (Na2SO4), and concentrated. Chromatography of the resulting residue (SiO2: EtOAc/hexanes) yielded 4-{4-[(biphenyl-2-carbonyl)-amino]-2-fluoro-phenyl}-piperazine-1-carboxylic acid tert-butyl ester, which was further dissolved in MeOH (20 mL) and 4N HCl in dioxanes. After stirring for 5 h, the reaction mixture was concentrated down, neutralized with 1N NaOH, and extracted with EtOAc (3×75mL). The orgranic extracts were combined, dried (Na2SO4), and the solvent was evaporated under reduced pressure to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([CH2:7][N:8]([CH3:10])[CH3:9])[S:4][C:3]=1[CH:11]=O.[C:13](=[N:26][NH2:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[C:13](=[N:26][N:27]=[CH:11][C:3]1[S:4][C:5]([CH2:7][N:8]([CH3:10])[CH3:9])=[CH:6][C:2]=1[Br:1])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)Cc1cc(Br)c(C=O)s1
Reactant: NN=C(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CN(C)Cc1cc(Br)c(C=NN=C(c2ccccc2)c2ccccc2)s1
Temperature: 65 °C

Procedure:
To 3-bromo-5-dimethylaminomethyl-thiophene-2-carbaldehyde [4.30 g, 17.3 mmol, Intermediate (2)] in ethanol (40 mL) is added benzophenone hydrazone (3.75 g, 19.0 mmol). The solution was heated at 65° C. for 5 hours. The solvent is removed under reduced pressure. The residue is chromatographed through silica gel (n-heptane-ethyl acetate. 90:10 as eluant) to produce [5-(Benzhydrylidene-hydrazonomethyl)-4-bromo-thiophen-2-ylmethyl]-dimethyl-amine] 5.57 g, 75%, Intermediate (3)] as an orange oil. LC/MS: RT=2.72 minutes, 426.05 m/e (M+H).
Reaction SMILES: Cl[C:2]1[CH:12]=[C:11]([NH:13][CH:14]([CH3:16])[CH3:15])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.Cl.[CH3:18][O:19][NH:20][CH3:21].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH:14]([NH:13][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=[C:2]([N:20]([O:19][CH3:18])[CH3:21])[CH:12]=1)([CH3:16])[CH3:15]
Reactant: CCOC(=O)c1cnc(Cl)cc1NC(C)C
Reactant: CNOC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(N(C)OC)cc1NC(C)C
Temperature: 180 °C
Yield: 96.5 %

Procedure:
A mixture of ethyl 6-chloro-4-(isopropylamino)nicotinate (3.0 g, 12.4 mmol), O,N-dimethylhydroxylamine hydrochloride (35.0 g, 0.35 mol) in dioxane (10 mL) was heated at 180° C. for 6 h. After cooling to RT, the reaction mixture was neutralized with saturated Na2CO3 solution to pH 7-8. The aqueous mixture was concentrated under reduced pressure and was extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated to give ethyl 4-(isopropylamino)-6-(methoxy(methyl)amino)nicotinate (3.2 g, 97% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.48 (s, 1 H), 7.82 (d, J=7.2 Hz, 1 H), 6.10 (s, 1 H), 4.22 (q, J=7.2 Hz, 2 H), 3.77 (m, 4H), 3.18 (s, 3 H), 1.27 (t, J=7.2 Hz, 3 H), 1.20 (d, J=6.4 Hz, 6 H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:21]1[S:22][CH:23]=[N:24][N:25]=1>>[CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:14][CH2:15][N:16]([C:21]4[S:22][CH:23]=[N:24][N:25]=4)[CH2:17][CH2:18]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)C2
Reactant: Brc1nncs1
Product: Cc1c(C)c(N2CCN(c3nncs3)CC2)c(C)c2c1OC(C)C2
Yield: 13.9 %

Procedure:
By using 1-(2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (130 mg, 0.50 mmol) synthesized in Reference example 56 and 2-bromo-1,3,4-thiadiazole (165 mg, 1.0 mmol), the reaction was carried out in the same manner as Example 23 to synthesis the title compound 24 mg (yield 14%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[CH3:19])=[CH:5][CH:4]=1.CO.C(OCC)(=O)C.[I:28]I>[Cl-].[Na+].O.S([O-])([O-])(=O)=O.[Ag+2]>[I:28][C:8]1[CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[CH3:19])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: II
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2)c(C)c1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc(OC)c(I)c2)c(C)c1

Procedure:
Methyl 4′-methoxy-2-methylbiphenyl-4-carboxylate (1.2 g, 4.68 mmol), methanol (20 mL), ethyl acetate (5 mL), iodine (1.19 g, 4.68 mmol), and silver sulfate (1.46 g, 4.68 mmol) were stirred at room temperature for 2 hours to complete the reaction. Volatiles were removed under reduced pressure to afford a yellow solid. The resulting solid was treated with brine followed by ethyl acetate extractions. The combined extracts were dried over Na2SO4 followed by filtration and concentration to afford a purple oil. The resulting oil was purified on SiO2 (Biotage HorizonFlash system, 40+M cartridge) to afford a white powder as the desired methyl 3′-iodo-4′-methoxy-2-methylbiphenyl-4-carboxylate. LCMS calc.=382.01; found=383.15 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[C:6]=2[N:7]=1.CCO.[NH3:25]>>[N:18]1[C:19]2[C:14](=[CH:13][C:12]([CH2:11][N:8]3[C:6]4[N:7]=[C:2]([NH2:25])[N:3]=[CH:4][C:5]=4[N:10]=[N:9]3)=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: N
Reactant: Clc1ncc2nnn(Cc3ccc4ncccc4c3)c2n1
Solvent: CCO
Product: Nc1ncc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 120 °C
Yield: 90 %

Procedure:
A suspension of 6-((5-chloro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)methyl)quinoline (134 mg, 0.453 mmol) in NH3 saturated EtOH (3 mL) was heated at 120° C. in a sealed pressure tube for 2.5 h. After cooling to room temperature, EtOH (20 mL) was added to the reaction mixture. The precipitate was collected by filtration and dried to afford the desired product (112 mg, 90%). 1H NMR (300 MHz, DMSO-d6) δ 5.87 (s, 2H), 7.39 (br s, 2H), 7.51-8.04 (m, 4H), 8.34 (m, 1H), 8.89 (m, 1H), 9.21 (s, 1H); LCMS (APCI) m/z 278.2 (M+H+).
Reaction SMILES: [N:1](=[C:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])O>C(O)(=O)C.[Pt]=O>[NH2:1][CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CCCC1CCCC1=NO
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCOC(=O)CCCC1CCCC1N

Procedure:
12.8 g of oxime from Example I (3) are dissolved in 128 ml of glacial acetic acid, 1.3 g of platinum oxide are added and the mixture is hydrogenated in an autoclave under a hydrogen pressure of 10 atmospheres for 8 hours. After the catalyst has been filtered off with suction, the filtrate is concentrated in vacuo, the residue is taken up in methylene chloride and the mixture is extracted with 2N aqueous HCl. The HCl phase is rendered basic with sodium hydroxide solution and extracted with methylene chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:14][CH2:15]Br.[H-].[Na+]>CS(C)=O.CCOCC.CS(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2([C:11]#[N:12])[CH2:15][CH2:14]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N#CCc1cccc([N+](=O)[O-])c1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: N#CC1(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
A solution of 2-(3-nitrophenyl)acetonitrile (2.5 g, 15.42 mmol) and 1,2-dibromoethane (1.329 ml, 15.42 mmol) in DMSO/Et2O (1:1, 10 ml) was added dropwise to a suspension of NaH (1.233 g, 30.8 mmol) in DMSO (Volume: 10 ml, Ratio: 1.000), keeping the temperature at 0° C. Resulting mixture was stirred at ambient temperature for 24 h under N2 atm. The reaction mixture was quenched by addition of IPA (2 ml) and water; partitioned between water (300 ml) and EtOAc (300 ml). The aq. phase was re-extracted with EtOAc (300 ml). Combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by flash chromatography to afford 1-(3-nitrophenyl)cyclopropanecarbonitrile (1.799 g, 9.56 mmol).