Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:28])[C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C1COCC1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:30]=[CH:29][C:7]([C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:28])[C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C(OCCCCCCOC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)OCCCCCCOC(=O)c2ccc(N)cc2)cc1
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
40.1 g 6-[(4-nitrobenzoyl)oxy]hexyl 4-nitrobenzoate (96.3 mM) were suspended in 300 ml of ethyl acetate and 300 ml of THF and 4.0 g of palladium on charcoal (10%) were added. The resulting mixture was hydrogenated at atmospheric pressure until the theoretical amount of hydrogen was consumed. The mixture was then filtered, the cake was washed with DMF and the filtrate was evaporated. The residue was suspended in 200 of cyclohexane. It was stirred for 30 min. and then the solids were filtered off, washed with cyclohexane and dried to give 33.2 g (93.1 mM, 97%) of 6-[(4-aminobenzoyl)oxy]hexyl 4-aminobenzoate as beige crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:18]([OH:20])=O.[NH2:21][C:22]1[NH:26][N:25]=[N:24][N:23]=1>O1CCCC1>[CH3:1][O:2][C:3]1[C:7]2[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:18]([NH:21][C:22]1[NH:26][N:25]=[N:24][N:23]=1)=[O:20]
Reactant: COc1c(C(=O)O)oc2ccc(-c3ccccc3)cc12
Reactant: Nc1nnn[nH]1
Solvent: C1CCOC1
Product: COc1c(C(=O)Nc2nnn[nH]2)oc2ccc(-c3ccccc3)cc12
Temperature: 25 °C

Procedure:
A mixture of 0.90 g (0.0034 mole) of 3-methoxy-5-phenyl-2-benzofurancarboxylic acid and 0.55 g (0.0034 mole) of 1,1-carbonylbis(1H-imidazole) in 25 ml of tetrahydrofuran is stirred at reflux for one hour. To the mixture is added 0.29 g (0.0034 mole) of anhydrous 5-aminotetrazole, and the new mixture is stirred at reflux for an additional 16 hours. Cooling to room temperature results in precipitation of 3-methoxy-5-phenyl-N- 1H-tetrazol-5-yl-2-benzofurancarboxamide. The precipitate is filtered and recrystallized from methanol to yield 0.90 g 80% yield) of analytically pure tetrazole, mp 260°-262° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:6][C:5]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:4]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[C:3]1=[O:29].CN1C(=O)C(C2C=CC3C(=CC=CC=3)C=2)=C(C2C=CN=CC=2)C=C1C1CCNCC1.[CH3:60][CH:61]1[CH2:63][O:62]1>CN(C=O)C>[OH:62][CH:61]([CH3:63])[CH2:60][N:10]1[CH2:11][CH2:12][CH:8]([C:7]2[N:2]([CH3:1])[C:3](=[O:29])[C:4]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)=[C:5]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:6]=2)[CH2:9]1
Reactant: Cn1c(C2CCNC2)cc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Reactant: CC1CO1
Agent: Cn1c(C2CCNCC2)cc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Solvent: CN(C)C=O
Product: CC(O)CN1CCC(c2cc(-c3ccncc3)c(-c3ccc4ccccc4c3)c(=O)n2C)C1
Temperature: 80 °C
Yield: 26 %

Procedure:
To a solution of 1-methyl-3-naphthalen-2-yl-6-pyrrolidin-3-yl-1H-[4,4′]bipyridinyl-2-one (prepared following the same method as described for 1′-methyl-5′-naphthalen-2-yl-1,2,3,4,5,6-hexahydro-1′H-[4,2′;4′,4″]terpyridin-6′-one, Scheme 12) (0.5 g, 1.3 mmol) in dry DMF (5 mL) was added 2-methyl-oxirane (2.6 mmol, 150 mg) and then heated at 80° C. for 5 h. After cooling down to RT the solvent was removed under vacuum and the residue was purified by flash chromatography (2%, 2M methanol ammonia in DCM) to obtain the title compound (150 mg, 26%) as a yellow solid. MS (ES+): 440 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:10]2[NH:14][CH:13]=[N:12][N:11]=2)=[C:5]([Br:9])[C:6]=1[C:7]#[N:8].O1CCCC1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Br:1][C:2]1[S:3][C:4]([C:10]2[N:14]=[CH:13][N:12]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][O:20]3)[N:11]=2)=[C:5]([Br:9])[C:6]=1[C:7]#[N:8]
Reactant: C1=COCCC1
Reactant: N#Cc1c(Br)sc(-c2nnc[nH]2)c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(Br)sc(-c2ncn(C3CCCCO3)n2)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
2,4-Dibromo-5-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile (0.80 g, 2.4 mmol) was placed in a 500 mL round bottom flask and tetrahydrofuran (50 mL, 600 mmol) was added. To the resulting solution were added dihydropyran (1.31 mL, 14.4 mmol) and p-toluenesulfonic acid monohydrate (0.683 g, 3.59 mmol). The mixture was stirred for 3 h at rt. The solution was then poured into 20 mL water and extracted with 40 mL ethyl acetate twice. The combined organic layers were evaporated in vacuo. The residue was purified by column chromatography using 0-35% EtOAc in hexane to afford a solid product (0.842 g, yield 84%). LCMS: (AA) ES+, 417, 419, 421. 1H NMR (300 MHz, CDCl3) δ: 8.38 (s, 1H), 5.55-5.60 (m, 1H), 4.06-4.10 (m, 1H), 3.68-3.78 (m, 1H), 2.15-2.28 (m, 1H), 2.01-2.13 (m, 2H), 1.66-1.80 (m, 3H).
Reaction SMILES: [CH2:1](/[C:3](=[CH:8]\[CH3:9])/[CH:4]=[CH:5]/[CH2:6]O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.ClCCl>[CH2:1]([C:3](=[CH:8][CH3:9])[CH:4]=[CH:5][CH2:6][N:33]1[C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]2[C:29]1=[O:39])[CH3:2]
Reactant: C/C=C(/C=C/CO)CC
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC=C(C=CCN1C(=O)c2ccccc2C1=O)CC
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.8 %

Procedure:
To a mixture of (E,E)-4-ethyl-2,4-hexadien-1-ol (1.0 g), triphenylphosphine (2.29 g), phthalimide (1.17 g), and tetrahydrofuran (30 ml) at room temperature was added a solution of diethyl azodicarboxylate (1.52 g) in tetrahydrofuran (5 ml). The mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with dichloromethane, washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (hexane-dichloromethane, 2:3) to give 0.42 g of N-(4-ethyl-2,4-hexadien-1-yl)phthalimide as crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[S:11][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[CH:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:36])=[C:30]([S:32](Cl)(=[O:34])=[O:33])[CH:31]=1.CCN(CC)CC>C(Cl)Cl>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:36])=[C:30]([S:32]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]3[S:11][C:12]([C:15](=[O:16])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[CH3:23])=[CH:13][N:14]=3)[CH:4]=2)(=[O:34])=[O:33])[CH:31]=1
Reactant: Cc1ccccc1C(=O)c1cnc(Nc2cccc(CN)c2)s1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)c1cnc(Nc2cccc(CNS(=O)(=O)c3cc(F)ccc3C)c2)s1

Procedure:
A mixture of 35.8 mg (0.1 mmol)[2-(3-aminomethyl-phenylamino)-thiazol-5-yl]-o-tolyl-methanone; hydrochloride, 25 mg (0.12 mmol) 5-fluoro-2-methyl-benzenesulfonyl chloride (commercially available) and 69 ul (0.5 mmol) NEt3 in 3 ml DCM was stirred at 60° C. for 16 h. After evaporation of the volatiles the residue was taken up in 1.5 ml MeOH/formic acid 2/1 and subjected to reversed phase HPLC purification eluting with a gradient of acetonitrile/water. After evaporation of the product fractions 31 mg (62%) of the title compound was obtained.
Reaction SMILES: [C:1]([O:4][C@H:5]([C:7]1[O:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][CH:18]=[C:17](Br)[C:16]=3[CH:21]=2)=[N:10][N:11]=1)[CH3:6])(=[O:3])[CH3:2].[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[C:1]([O:4][C@H:5]([C:7]1[O:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][CH:18]=[C:17]([C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([O:24][C:23]([F:22])([F:34])[F:35])[CH:26]=4)[C:16]=3[CH:21]=2)=[N:10][N:11]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](C)c1nnc(-c2ccc3occ(Br)c3c2)o1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: CC(=O)O[C@@H](C)c1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Yield: 75 %

Procedure:
In the same manner as in Reference Example 19 and using (1S)-1-[5-(3-bromo-1-benzofuran-5-yl)-1,3,4-oxadiazol-2-yl]ethyl acetate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and [3-(trifluoromethoxy)phenyl]boronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 75%) was obtained as colorless crystals.
Reaction SMILES: C([CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:18]2[S:19][CH:20]=[C:21]([S:23]([CH3:25])=[O:24])[N:22]=2)[C:10]1=[O:26])[C:6]([O-:8])=[O:7])(C)(C)C.C(Cl)Cl>C(O)(C(F)(F)F)=O>[CH3:25][S:23]([C:21]1[N:22]=[C:18]([N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:9]([CH2:5][C:6]([OH:8])=[O:7])[C:10]2=[O:26])[S:19][CH:20]=1)=[O:24]
Reactant: CS(=O)c1csc(-n2c(=O)n(C(C(=O)[O-])C(C)(C)C)c3ccccc32)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)c1csc(-n2c(=O)n(CC(=O)O)c3ccccc32)n1

Procedure:
(±)-tert-Butyl{3-[4-(methylsulfinyl)-1,3-thiazol-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetate from Step D (100 mg, 0.254 mmol) was dissolved in TFA (3 mL) and CH2Cl2 (3 mL) and the mixture was stirred at ambient temperature for 3 h, then concentrated in vacuo to give the title compound. MS: m/z=338 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].O.ON1C2C=CC=CC=2N=N1.[Br:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:40]=1[CH2:46][CH2:47][NH2:48].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[Br:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:40]=1[CH2:46][CH2:47][NH:48][C:17]([C:16]1[CH:20]=[CH:21][C:13]([O:12][C:11]2[CH:10]=[C:9]3[C:4]([CH:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:7][O:8]3)=[CH:3][C:2]=2[Cl:1])=[CH:14][CH:15]=1)=[O:19]
Reactant: NCCc1ccc(Cl)cc1Br
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4Br)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.9 %

Procedure:
To a stirred solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1; 1.32 g; 3.52 mmol), 1-hydroxybenzotriazole hydrate (0.59 g; 3.85 mmol) and 2-(2-bromo-4-chlorophenyl)ethanamine (Preparation 5; 0.904 g; 3.85 mmol) in dry dimethylformamide (10 mL) was added 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.806 g; 4.02 mmol) at ambient temperature. After stirring at ambient temperature for 5 hours, the solution was diluted with 100 mL of water, stirred for 10 minutes longer and then extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage 40M), eluting with hexane and ethyl acetate to provide ethyl 7-(4-(2-bromo-4-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate as a white solid (1.21 g). MS (apci, pos) m/z=594.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].[CH3:50][C@@H:51]1[O:56][C@H:55]([CH3:57])[CH2:54][NH:53][CH2:52]1>>[C:28]([C:32]1[N:33]=[C:34]([N:53]2[CH2:52][C@H:51]([CH3:50])[O:56][C@H:55]([CH3:57])[CH2:54]2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Product: C[C@@H]1CN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C[C@H](C)O1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (2S,6R)-2,6-dimethylmorpholine and isolated as white solid (13.1 mg, 67%). MS (m/e): 415.5 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>C(#N)C>[C@H:15]1([NH:14][C:11]2[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:26]4[CH2:31][CH2:30][S:29][CH2:28][CH2:27]4)[CH:25]=[CH:24][C:9]=3[N:10]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: C1CSCCN1
Solvent: CC#N
Product: O=C(CN1CCSCC1)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Yield: 75.8 %

Procedure:
Prepared from 2-chloro-N-[2-((R)-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 3 step A) (100 mg, 0.281 mmol) and thiomorpholine (0.141 ml, 1.405 mmol) in acetonitrile (1 ml) according to the procedure described for Example 3 step B. Obtained the title compound as an off-white foam (90 mg, 76%), MS (ISP) m/e=423.2 [(M+H)+].
Reaction SMILES: COC(C1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[N:6]=1)=O.C1COCC1.C[Mg]Cl.Cl.[C:24]([O:28]C)([CH3:27])([CH3:26])[CH3:25]>O>[F:12][C:11]([F:14])([F:13])[C:7]1[N:6]=[C:25]([C:24]([OH:28])([CH3:27])[CH3:26])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(C)(C)C
Reactant: COC(=O)c1cccc(C(F)(F)F)n1
Agent: C[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)c1cccc(C(F)(F)F)n1
Temperature: 0 °C
Yield: 90 %

Procedure:
Add 6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (80.0 g, 390 mmol) to a mixture of THF (240 mL) and tert-butylmethyl ether (400 mL). Add the solution slowly to a 3 M methylmagnesium chloride in THF (390 mL, 1.17 moles) and maintain 8° C. to 16° C. Cool the mixture to 0° C. and add a mixture of 5 M hydrochloric acid (257 mL, 1.29 moles) and water (200 mL). Separate the phases and concentrate the organic phase under reduced pressure. Add heptane (160 mL) and cool the mixture to 5° C. Collect the precipitate by vacuum filtration and rinse the solid with heptane (20 mL) followed by pentane (30 mL). Vacuum dry the solid to afford the title compound as a tan solid (72.3 g, 352 mmol, 90%). 1H NMR (400 MHz, DMSO d6) δ 8.04 (t, J=7.7 Hz, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.69 (d, J=7.0 Hz, 1H), 5.40 (s, 1H), 1.43 (s, 6H). HRMS (ESI) m/z (M+H)+ calcd for C9H10F3NO: 206.0787, found 206.0787.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]([N:27]=[N+:28]=[N-:29])[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])(=O)=O.[CH:32]1[C:44]2[CH:43]([CH2:45][O:46][C:47]([NH:49][C@@H:50]([CH2:58][SH:59])[C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[O:48])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]=2[CH:35]=[CH:34][CH:33]=1.C([O-])([O-])=O.[K+].[K+]>CCO>[N:27]([C@H:8]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:7][S:59][CH2:58][C@@H:50]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[NH:49][C:47](=[O:48])[O:46][CH2:45][CH:43]1[C:44]2[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=2[C:37]2[C:42]1=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N+:28]=[N-:29]
Reactant: CCCCCCCCCCCCCCCCOC[C@H](COS(=O)(=O)C(F)(F)F)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)[C@H](CS)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)N=[N+]=[N-]
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-2-azido-3-(hexadecyloxy)propyl trifluoromethanesulfonate (1 eq), (R)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-mercaptopropanoate (8, 2 eq) and K2CO3 (1 eq) in EtOH (0.1 M) was stirred for 30 min at 60° C. The reaction mixture was filtered and washed with DCM. The filtrate was concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-20% EtOAc/Hex to give (5R,9R)-tert-butyl 9-azido-1-(9H-fluoren-9-yl)-3-oxo-2,11-dioxa-7-thia-4-azaheptacosane-5-carboxylate.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([CH:7](Br)[CH:8](Br)[C:9]#[N:10])=[CH:3][CH:2]=1.[CH3:19][O-:20].[Na+]>CO>[C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([C:7]([O:20][CH3:19])=[CH:8][C:9]#[N:10])=[CH:3][CH:2]=1
Reactant: N#CC(Br)C(Br)c1ccc(-c2ccccc2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=CC#N)c1ccc(-c2ccccc2)cc1
Reaction time: 2 h

Procedure:
3-(4-Biphenylyl)-2,3-dibromopropionitrile (16 grams) and sodium methoxide (4.7 grams) in 500 ml. of methanol were reacted in an ice bath. A solid precipitated at once and then the reaction mixture was stirred for 2 hours. The final product was determined by NMR to be a mixture of 3-(4-biphenylyl)-3-methoxyacrylonitrile plus 3-(4-biphenylyl)-3,3-dimethoxypropionitrile.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CN(C)C=O.[CH3:30][N:31]([CH2:33][CH2:34]Cl)[CH3:32]>C1C=CC=CC=1>[C:1]([O:9][CH:10]1[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:34][CH2:33][N:31]([CH3:32])[CH3:30])[C:13]=2[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCCl
Reactant: O=C(OC1CCc2[nH]c3ccccc3c2C1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CN(C)CCn1c2c(c3ccccc31)CC(OC(=O)c1ccccc1)CC2

Procedure:
The 3-benzoyloxy-9-[2-(dimethylamino)ethyl]-1,2,3,4-tetrahydrocarbazole was prepared by following an alkylation procedure similar to that described in Example 11 and using 13.1 g. of 3-benzoyloxy-1,2,3,4-tetrahydrocarbazole and 1.93 g. of sodium hydride (50% in mineral oil) in 150 ml. of dimethylformamide, and 4.9 g. of (dimethylamino)ethyl chloride in 10 ml. of benzene. An ethereal solution of the crude product was filtered through alumina and the concentrated ethereal eluate was treated with ethereal hydrogen chloride to give after recrystallizaton from isopropyl alcohol - ether 5.6 g. of 3-benzoyloxy-9-[2-(dimethylaino)ethyl]-1,2,3,4-tetrahydrocarbazole hydrochloride, m.p. 222°-225°C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1.[S:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[S:15].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[C:19]3[S:13][C:14](=[S:15])[NH:16][C:17]3=[O:18])=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccc2ncncc2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=S)SC1=Cc1ccc2ncncc2c1
Temperature: 130 °C
Reaction time: 12 h
Yield: 100.1 %

Procedure:
The suspension of 6-quinazolinecarboxaldehyde (example 1a, 1.5 g, 9.5 mmol), rhodanine (1.26 g, 9.5 mmol) and sodium acetate (3.11 g, 38 mmol) in acetic acid (10 mL) was stirred at 130° C. for 12 h. After cooling to room temperature, water (40 mL) was added. The solid was collected by filtration, washed with water and dried to obtain 5-quinazolin-6-ylmethylene-2-thioxo-thiazolidin-4-one (2.6 g, 100%) as a solid. LC-MS m/e 274 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH3:12].C(=O)(O)[O-].[Na+].Br[CH:19]([CH2:24][CH3:25])[C:20]([O:22][CH3:23])=[O:21]>>[CH3:12][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[NH:1][CH:19]([CH2:24][CH3:25])[C:20]([O:22][CH3:23])=[O:21]
Reactant: CCC(Br)C(=O)OC
Reactant: Cc1ccc2ccccc2c1N
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC(Nc1c(C)ccc2ccccc12)C(=O)OC
Yield: 86.3 %

Procedure:
144.2 g (0.92 mole) of 1-amino-2-methylnaphthalene are stirred with 90.2 g (1.08 moles) of sodium bicarbonate and 507 g (2.8 moles) of methyl 2-bromobutyrate at from 120° to 125° C. for 18 hours. The mixture is cooled, and thereafter the precipitate is filtered off under suction, the filtrate is concentrated under reduced pressure, and the residue is distilled under reduced pressure. 204.3 g (79.5% of theory) of methyl 2-(2-methylnaphth-1-ylamino)-butyrate are obtained as a colorless oil. Boiling point: 148°-150° C./0.25 mbar; nD25 =1.5779.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C[O-].[Na+].[Na].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CO>[CH2:14]([S:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCBr
Reactant: Sc1ccc(Br)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCCCCCCCCCSc1ccc(Br)cc1
Reaction time: 1 h
Yield: 91.6 %

Procedure:
4-Bromothiophenol (100 g) was added dropwise to a solution of sodium methoxide prepared from sodium (13.4 g) and dry methanol (400 ml). The solution was stirred for 1 hour and then a mixture of 1-bromodecane (128.6 g) and dry methanol (150 ml) was added over 10 minutes. The oily suspension was refluxed for 4 hours and was then concentrated by distilling off about 300 ml of solvent. Water (750 ml) was added and the mixture was stirred vigorously while cooling. The solid product was collected, washed with water and then crystallized from ethanol to give 4-(decylthio)bromobenzene (159.5 g), m.p. 37°-39° C. [Elemental analysis: C,58.0; H,7.7; Br,24.5; S,9.7%; calculated: C,58.36; H,7.60; Br,24.31; S,9.73%].
Reaction SMILES: CCN=C=NCCCN(C)C.CS(C)=O.[CH3:16][O:17][C:18](=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:32][OH:33].FC(F)(F)C([O-])=O.[NH+]1C=CC=CC=1>C1C=CC=CC=1>[CH3:16][O:17][C:18](=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH:26]1[CH:32]=[O:33]
Reactant: COC(=O)CCCCCCN1C(=O)CCCC1CO
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])C(F)(F)F
Agent: c1cc[nH+]cc1
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: COC(=O)CCCCCCN1C(=O)CCCC1C=O
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
EDCI (212 mg, 1.10 mmol) and DMSO (0.10 mL, 1.48 mmol) were added sequentially to a solution of 7-(2-hydroxymethyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester (100 mg, 0.37 mmol) in benzene (4.0 mL) at rt. The mixture was cooled to 0° C. and pyridinium trifluoroacetate (79 mg, 0.41 mmol) was added. The reaction was allowed to warm to rt and then was stirred at rt for 3.5 h. The solution was decanted from the oily residue and the residue was washed with benzene (3×3 mL). The combined benzene phases were concentrated in vacuo to afford crude 7-(2-formyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester that was used without further purification.