Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[CH:14].O>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](Br)Br>[C:15]1([C:13]#[C:14][C:2]2[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ncc(C(F)(F)F)cc1Br
Reactant: C#Cc1ccccc1
Agent: Br[Cu]Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ncc(C(F)(F)F)cc1C#Cc1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Under an atmosphere of argon, to a solution of 3-bromo-5-(trifluoromethyl)pyridin-2-amine (the compound described in Bio. Org. Med. Chem., 9, 1715 (1999)) (163 mg) in triethylamine (1.5 mL), ethynylbenzene (82 μL), bis(triphenylphosphine)palladium dichloride (43 mg) and copper bromide (14 mg) were added. The reaction mixture was stirred for overnight at 60° C. To the reaction mixture, water was added and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to give the title compound (26 mg) having the following physical data.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1)[CH3:2].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[Cl:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C(=O)C.O1CCCC1>[Cl:46][C:45]1[CH:44]=[CH:43][C:26]([O:27][C:28]2[CH:29]=[CH:30][C:31]3[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]4[CH2:42][CH2:41]4)=[O:39])[N:36]=3)[N:33]=2)=[CH:25][C:24]=1[NH:23][C:8]([C:6]1[N:5]([CH3:11])[N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=1)=[O:10]
Reactant: CCc1cc(C(=O)O)n(C)n1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2Cl)n(C)n1
Yield: 64.2 %

Procedure:
Using 3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (188 mg, 1.22 mmol), tetrahydrofuran (4.5 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (107 μL, 1.22 mmol), N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (300 mg, 0.87 mmol) and N,N-dimethylacetamide (6.0 mL), and in the same manner as in Example 238, the title compound (268 mg, 64%) was obtained as a white powder.
Reaction SMILES: [C:1](ON=O)(C)([CH3:3])[CH3:2].C(Br)C=C.N[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.NC1C=CC=CC=1>CC#N>[CH2:3]([C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)[CH:1]=[CH2:2]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(C)(C)ON=O
Solvent: C=CCBr
Solvent: CC#N
Solvent: Nc1ccccc1
Product: C=CCc1ccc(C#N)cc1
Temperature: 43 °C
Yield: 37.2 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and allyl bromide (3.9 ml, 45.0 mmol) in CH3CN (3 ml), 4-aminobenzonitrile (354 mg, 3.0 mmol) was added during 20 minutes, while maintaining the temperature of the reaction mixture at 42-44° C. At the end of the addition of the aniline, extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture which then was stirred at 50° C. for three hours during which extra t-butylnitrite (180 μl, 1.5 mmol) was added. The volatile material in the reaction mixture was removed at reduced pressure. Heptane-ethyl acetate (10 ml, 1:1) was then added to the crude product and the mixture was filtered. Column chromatography (heptane-ethyl acetate 49:1) of the concentrated filtrate gave 160 mg (37%) 4-allyl-benzonitrile as a clear oil containing 16% of 4-bromo-benzonitrile. This corresponds to 30% yield of 4-allylbenzonitrile. 1H NMR (CDCl3, 400 MHz) δ 7.60, (m, 2H, J=8.3 Hz), 7.31, (m, 2H, J=8.3 Hz), 5.99-5.88, (m, 1H), 5.18-5.08, (m, 2H), 3.46, (d, 2H, J=6.7 Hz); Anal HRMS Calcd. for C10H9N (M): 143.0735. Found: 143.0734.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:14]#[C:15][NH2:16].[Na]>C1COCC1>[C:1]12([C:11]([NH:16][C:15]#[N:14])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: N#CN
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: [Na]
Solvent: C1CCOC1
Product: N#CNC(=O)C12CC3CC(CC(C3)C1)C2
Reaction time: 15 h
Yield: 85.2 %

Procedure:
1-Adamantanecarbonyl chloride (1.99 g, 0.010 mol) in 50 ml of THF was added drop-wise to a suspension of sodium cyanamide (1.92 g, 0.030 mol) in 100 ml of THF with stirring at ice bath temperature. The reaction was allowed to proceed at 25° C. for 15 hours. The reaction mixture was then extracted with ethyl acetate (100 ml). The separated aqueous portion (pH 10.5) was acidified to pH 1.5 with 10% HCl and extracted with ethyl acetate (3×60 ml). The ethyl acetate extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated in vacuo to dryness. The resulting white solid residue was triturated in a minimal amount of distilled water, filtered, and air-dried to give 1.74 g (85.2% yield) of crude 4 as white solid. This was recrystallized from ethyl acetate and petroleum ether to give 0.55 g (crop 1) of white crystalline powder. The filtrate was concentrated when further crystallization occurred to give 0.49 g (crop 2) of additional product giving a total yield of 50.9%, mp 168°-170° C. TLC: R f =0.58 in EtOAc/petroleum ether/AcOH (50:100:1), detected by UV quenching (weak) and reddish orange color with ferricyanide spray reagent; IR (Nujol, cm-1), 3210 (NH), 2230 (C≡N), 1710 (C=O); NMR (Silanor C, δ from TMS) 1.62-2.2 (m, aliphatic CH's). Anal. Calcd for C12H16N2O: C, 70.56; H, 7.90; N, 13.71. Found: C, 70.59; H, 8.04; N, 13.66.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][O:32][CH2:31]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][O:32][CH2:31]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCCCCC1CCCOC1
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 243 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(4-bromobutyl)tetrahydro-2H-pyran.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)=[CH:8]1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[C:4]([CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]2[NH:21][CH:20]=[CH:19][N:18]=2)=[CH:8]1)([OH:5])=[O:3]
Reactant: CCOC(=O)Cn1cc(Cc2ncc[nH]2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cn1cc(Cc2ncc[nH]2)c2ccccc21
Yield: 73.6 %

Procedure:
1-Ethoxycarbonylmethyl-3-(1-imidazolylmethyl)indole (0.98 g) was dissolved in ethanol (10 ml) and a solution of sodium hydroxide (0.25 g) in water (2 ml) was added. The mixture was heated under reflux for 2 hours and then evaporated. The residue was dissolved in 5 ml of water and the solution was just acidified with acetic acid. The solution was evaporated to dryness and the residue was stirred with a little water and the mixture was filtered to give 1-carboxymethyl-3-(1-imidazolylmethyl)indole, (0.65 g), m.p. 218°-220° C., raised to 223°-224° C. on crystallisation from water. Found: C, 65.47; H, 5.11; N, 16.19. C14H13N3O2 requires: C, 65.87; H, 5.13; N, 16.46.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:38]1([S:44](Cl)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:38]1([S:44]([NH:35][S:34]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:25]2[CH:26]=[CH:27][C:22]([CH2:21][N:6]3[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][N:8]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:16]([F:19])([F:18])[F:17])[C:7]3=[O:20])=[CH:23][CH:24]=2)(=[O:37])=[O:36])(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NS(=O)(=O)c2ccccc2)cc1
Temperature: 60 °C

Procedure:
The title compound was prepared from 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 13, Step C) according to the procedure of Example 14, except that a total of 2.4 equivalents of benzenesulfonyl chloride was used, and the mixture was heated at 60° C. for 4 hours. The crude produce was purified by flash chromotography on silica gel (gradient elution with 0.5-5% MeOH in CH2Cl2). The residue from evaporation of the product fractions was partitioned between CH2Cl2 and 1N HCl. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound as a cream-colored, sticky solid, homogeneous by TLC in 9:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 671 (M+1)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:9]([NH:16][C@H:17]2[CH2:22][CH2:21][C@@H:20]([CH2:23][OH:24])[CH2:19][CH2:18]2)=[N:10][CH:11]=[N:12][C:13]=1[CH2:14][CH3:15].C(N(CC)CC)C.O>ClCCl.CS(C)=O>[Cl:7][C:8]1[C:9]([NH:16][C@H:17]2[CH2:22][CH2:21][C@@H:20]([CH:23]=[O:24])[CH2:19][CH2:18]2)=[N:10][CH:11]=[N:12][C:13]=1[CH2:14][CH3:15]
Reactant: CCc1ncnc(N[C@H]2CC[C@@H](CO)CC2)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1ncnc(N[C@H]2CC[C@@H](C=O)CC2)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
6.7 g (86 mmol) of DMSO in 17 ml of dichloromethane were added under N2 to a solution of 5.5 g (43 mmol) of oxalyl chloride in 50 ml of dichloromethane at -78° C. After 5 minutes, a solution of 10.6 g (39 mmol) of the hydroxymethyl compound from Example 3 in 5.3 ml each of DMSO and dichloromethane was added, and the mixture was stirred for 1 hour at the temperature indicated. 35.6 g (350 mmol) of triethylamine were added dropwise. After 20 minutes, the mixture was allowed to warm to room temperature, 105 ml of H2O were added, extraction was carried out with dichloromethane, and removal of the solvent gave 9.5 g (35.5 mmol =91%) of the aldehyde as a white solid: m.p. 96° to 97° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=O)[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([NH2:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:33][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:25])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCN
Reactant: O=C(O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCCCCNC(=O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Yield: 87.7 %

Procedure:
Part C, Method 2. To a solution of 5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentanoic acid (2.0 g, 0.0057 mol) in toluene (35 mL) was added heptylamine (1.63 mL, 1.27 g, 0.011 mol) and then boron trifluoride etherate (1.35 mL, 1.56 g, 0.011 mol) and the reaction mixture was stirred at reflux for 120 hours using a Dean-Stark moisture trap. The reaction mixture was cooled, extracted with 0.1N NaOH, 0.1N HCl, and water, and the combined organic extracts were dried over magnesium sulfate and concentrated under vacuum. The residue was chromatographed and worked-up as described in Part C, Method 1, to give 5-(4,5-diphenyl-1H-imidazol-2-ylthio)-N-heptylpentanamide (2.35 g, 0.005 mol) as a white solid.
Reaction SMILES: S1[CH:5]=[CH:4][C:3](C(N2CCCC(C(OCC)=O)C2)=O)=[CH:2]1.[C:19]([N:27]1[CH2:32][CH2:31][CH2:30][CH:29]([C:33]([OH:35])=[O:34])[CH2:28]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)CCC>>[C:19]([N:27]1[CH2:32][CH2:31][CH2:30][CH:29]([C:33]([O:35][CH2:2][CH2:3][CH2:4][CH3:5])=[O:34])[CH2:28]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)C1CCCN(C(=O)c2ccccc2)C1
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccsc2)C1
Solvent: CCCCO
Product: CCCCOC(=O)C1CCCN(C(=O)c2ccccc2)C1

Procedure:
The reaction was run in the same manner as ethyl 1-(3-thiophenecarbonyl)-3-piperidinecarboxylate, starting with 1-benzoyl-3-piperidine carboxylic acid (500 mg; 2.1 mmol) and commercially available n-butanol (500 μl; 5.5 mmol). The crude product was distilled at 225° C./0.1 torr, giving n-butyl 1-benzoyl-3-piperidinecarboxylate (258.2 mg) as a light yellow oil. MS m/z (positive ion) 312 (M+Na+; 75), 290 (NH+; 100).
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)[CH:13]=[CH:12][N:11]=2)C=CC=CC=1.[CH3:27][NH:28][CH:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1>CN(C)C=O>[N+:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C:8](=[O:26])[N:28]([CH3:27])[CH:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[CH:15]=2)=[CH:22][CH:21]=1)([O-:25])=[O:24]
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)Oc1ccccc1
Reactant: CNC1CCN(C)CC1
Solvent: CN(C)C=O
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3)ccn2)CC1
Reaction time: 1 h
Yield: 21051 %

Procedure:
[4-(4-Nitrophenoxy)pyridin-2-yl]carbamic acid phenyl ester (150 mg) was dissolved in N,N-dimethylformamide (4 ml) under a nitrogen atmosphere, and then N-methyl-N-(1-methylpiperidin-4-yl)amine (0.186 mg) was added thereto, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (40 ml) and a saturated aqueous solution of ammonium chloride (10 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:1, then ethyl acetate). Fractions containing the target compound were concentrated under a reduced pressure to provide 3-[4-(4-nitrophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (117.7 mg, 71.5%) as a crude product.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:30]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])=[N:4][C:5]([CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=4)=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[N:6][C:7]=1[CH3:8].[C:37](OC(=O)C)(=[O:39])[CH3:38].C(N(CC)CC)C>C(#N)C.CN(C)C1C=CN=CC=1>[C:37]([O:29][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]2[CH:18]=[CH:17][C:16]([N:13]3[CH2:14][CH2:15][CH:10]([CH2:9][C:5]4[N:4]=[C:3]([C:30]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])[C:2]([OH:1])=[C:7]([CH3:8])[N:6]=4)[CH2:11][CH2:12]3)=[CH:21][CH:20]=2)=[CH:23][CH:24]=1)(=[O:39])[CH3:38]
Reactant: Cc1nc(CC2CCN(c3ccc(-c4ccc(CO)cc4)cc3)CC2)nc(C(=O)NCC(=O)O)c1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OCc1ccc(-c2ccc(N3CCC(Cc4nc(C)c(O)c(C(=O)NCC(=O)O)n4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.1 %

Procedure:
({[5-Hydroxy-2-{(1-[4′-(hydroxymethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid (0.13 g, 0.27 mmol) was dissolved in acetonitrile (8 mL), and acetic anhydride (0.063 mL, 0.67 mmol), triethylamine (0.092 mL, 0.66 mmol) and 4-dimethylaminopyridine (0.081 g, 0.66 mmol) were added, followed by stirring at room temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: dichloromethane/methanol), and a fraction corresponding to the Rf value=0.20 (dichloromethane/methanol=9/1) by thin layer chromatography was concentrated under reduced pressure. A mixed solvent of ethanol and water was added to the residue, whereby a solid was deposited. The resulting solid was collected by filtration, and dried under reduced pressure to afford the title compound (0.070 g, 0.13 mmol) as a pale yellowish white solid (yield 50%).
Reaction SMILES: [OH:1][CH:2]([CH2:18][S:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6][CH2:5]1.[OH:27]O.O.N>C(O)(=O)C>[OH:1][CH:2]([CH2:18][S:19]([C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)=[O:27])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6][CH2:5]1
Reactant: COc1ccccc1N1CCN(CC(O)CSc2ccc(F)cc2)CC1
Reactant: OO
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: COc1ccccc1N1CCN(CC(O)CS(=O)c2ccc(F)cc2)CC1
Reaction time: 1 h

Procedure:
To a solution of 1.85 g of 1-[2-hydroxy-3-(p-fluorophenylthio)propyl]-4-(o-methoxyphenyl)piperazine in 20 ml of glacial acetic acid is added dropwise 1.2 g of 35 % aqueous hydrogen peroxide solution under cooling, and the mixture is stirred at a temperature of 20° to 30°C for 1 hour. The reaction mixture is poured into water, neutralized with aqueous ammonia and extracted with benzene. The organic layer is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The oily residue is crystallized by cooling to give 1-[2-hydroxy-3-(p-fluorophenylsulfinyl)propyl]-4-(o-methoxyphenyl)piperazine, M.P. 164° to 165°C. Recrystallization from benzene gives white crystals, M.P. 167.5° to 168.5°C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][CH:10]([CH3:13])[C:11]#[N:12].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]([CH3:13])([CH3:9])[C:11]#[N:12])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc(Br)cn1

Procedure:
To a solution of 2,5-dibromopyridine (5.0 g, 21 mmol) and 2-methylpropanenitrile (1.6 g, 23 mmol) in toluene (50 mL) under nitrogen was added 2 N solution of NaHMDS in THF (12 mL, 23 mmol) dropwise at 0° C. The resulting solution was stirred at ambient temperature overnight before the addition of saturated aqueous NH4Cl solution (20 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL). All the organic solution was dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography with 1-3% ethyl acetate in hexane to afford the title compound as a light yellow solid. MS ESI [M+H]+ m/z 225, 227; 1H NMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 1.75 (s, 6H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([CH2:33][NH:34][C@@H:35]([CH3:43])[C:36]([O:38]C(C)(C)C)=[O:37])[CH:12]=[CH:13][C:14]=1[C:15]1[S:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[C:19]([C:24]1([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:26][CH2:25]1)[N:18]=2>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([CH2:33][NH:34][C@@H:35]([CH3:43])[C:36]([OH:38])=[O:37])[CH:12]=[CH:13][C:14]=1[C:15]1[S:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[C:19]([C:24]1([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][CH2:26]1)[N:18]=2
Reactant: C[C@H](NCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (1.0 mL, 12.98 mmol) was added to a solution of (S)-tert-butyl 2-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)methylamino)propanoate (140.6 mg, 0.279 mmol) in DCM (2.1 mL) at 25° C., and the resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was then concentrated in vacuo and the brown residue was taken up in DMSO (2.0 mL) and purified by rpHPLC (10-100% CH3CN/water+0.1% TFA) to provide (S)-2-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)methylamino)-propanoic acid as a light yellow solid. MS (ESI) m/z: Calculated: 447.1; Observed: 448.2 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[CH2:8][CH:9]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)[CH2:10][C:11](=O)[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32][NH2:33]>>[Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[CH2:8][CH:9]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=4)[CH2:10][C:11](=[N:33][CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[CH3:28])[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1
Reactant: CN(C)CCCN
Reactant: O=C1CC(c2ccc(C(F)(F)F)cc2)Cc2[nH]c3ccc(Cl)cc3c(=O)c21
Product: CN(C)CCCN=C1CC(c2ccc(C(F)(F)F)cc2)Cc2[nH]c3ccc(Cl)cc3c(=O)c21

Procedure:
By following the above procedure and using 7-chloro3-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1,9(2H,10H)acridinedione instead of 7-chloro-3-(3,4-dichlorophenyl)-3,4-dihydro-1,9(2H,10H)-acridinedione and N,N-dimethyl-1,3-propanediamine instead of N,N-diethylenediamine one obtains 7-chloro-1-[[3-(dimethylamino)propyl]imino]-1,3,4,10-tetrahydro-3-[4-(trifluoromethyl)phenyl]-9(2H)-acridinone; mp 211°-213° C. after recrystallization from ethanol.
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[NH:4][C:3](=[O:8])[NH:2]1.[CH2:9]([NH2:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C[Si](C)(C)N[Si](C)(C)C>S([O-])([O-])(=O)=O.[NH4+].[NH4+].O1CCOCC1>[CH2:9]([NH:21][C:5]1[CH2:6][O:1][NH:2][C:3](=[O:8])[N:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=C1CONC(=O)N1
Reactant: CCCCCCCCCCCCN
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: CCCCCCCCCCCCNC1=NC(=O)NOC1
Yield: 88.2 %

Procedure:
A solution of 1.16 g (0.010 mole) of 6H-1,2,4-oxadiazin-3,5(2H,4H)-dione, 5 mg of ammonium sulfate, 2.22 g (0.012 mole) of dodecylamine and 20 ml of hexamethyldisilazane in 40 ml of freshly distilled dry dioxane is refluxed for 17 hours. After cooling, the dioxane and hexamethyldisilazane are removed in vacuo and the syrupy residue is dried on a vacuum pump for 2 hours. The resulting semi-solid residue is triturated with 100 ml of petroleum ether and filtered to yield 2.5 g (88 percent) of 5-dodecylamino-6H-1,2,4-oxadiazin-3(2H)-one.
Reaction SMILES: C([O:3][C:4](=[O:11])[CH2:5][N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)C.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>>[N+:17]([C:9]1[CH:8]=[N:7][N:6]([CH2:5][C:4]([OH:3])=[O:11])[CH:10]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)Cn1cccn1
Agent: O=S(=O)(O)O
Product: O=C(O)Cn1cc([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
Six conical flasks were charged with pyrazol-1-yl-acetic acid ethyl ester (6×9.66 g, 6×62.6 mmol) and concentrated sulphuric acid (6×20 ml) was added. The solutions were cooled to 0° C. and concentrated nitric acid (6×10 ml) was added dropwise. The reaction mixtures were allowed to warm to room temperature and left standing for 18 hours. The combined organic mixtures were poured into ice (50 ml) and extracted with ethyl acetate (5×500 ml). The combined organic extracts were washed with brine (500 ml), dried (MgSO4), filtered and concentrated under reduced pressure to leave a yellow solid. Recrystallisation from ethyl acetate afforded the title compound as an off-white solid (20.97 g, 33% yield).