Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11](SC)[C:10]=2[F:17])[CH2:5][CH2:4]1)[CH3:2].[S:18](=[O:22])(=O)(O)[OH:19].OO.[C:25](OCC)(=O)C.CO>[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH2:1]([N:3]1[CH2:4][CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:18]([CH3:25])(=[O:22])=[O:19])[C:10]=2[F:17])[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CC=C(c2cccc(SC)c2F)CC1
Reactant: CCOC(C)=O
Reactant: O=S(=O)(O)O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: CCN1CC=C(c2cccc(S(C)(=O)=O)c2F)CC1

Procedure:
Preparation according to preparation 64: 1-ethyl-4-[2-fluoro-3-(methylthio)phenyl]-1,2,3,6-tetrahydropyridine (22.5 g, 89.6 mmol), sulfuric acid (1 M, 180 ml), sodium tungstate (0.296 g, 0.89 mmol), hydrogen peroxide (30%, 22.9 ml, 224 mmol). Flash column chromatography (ethyl acetate/methanol, 1:1) gave the title compound (17.2 g). MS m/z (rel. intensity, 70 eV) 283 (M+, 63), 268 (bp), 146 (51), 110 (87), 56 (59).
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C@@H:7]([C:9]([NH2:11])=[O:10])[NH2:8])=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[C:27](O)=[O:28])=[O:20])([CH3:17])([CH3:16])[CH3:15].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)C>[NH2:11][C:9](=[O:10])[C@@H:7]([NH:8][C:27]([C@@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26][N:21]1[C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])=[O:28])[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:13][CH:12]=1
Reactant: NC(=O)[C@@H](N)Cc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(I)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
4-Iodo-(L)-phenylalaninamide (2 g), (2S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (2.4 g) and disopropylethylamine (3 mL) were dissolved in DMF (10 mL) and to the solution was added 2-(1-H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (3.3 g). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether (200 mL) then washed with water (250 mL) and brine (4×250 mL). The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Crude product was purified by flash silica chromatography eluting with ethyl acetate to give the sub-title compound (2.88 g) as an oil.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][CH2:17][CH2:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][O:16][CH2:14][CH3:15])=[CH:27][CH:26]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOCCOc1ccc(CBr)cc1
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCOc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reaction time: 3 h
Yield: 58.5 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 1.0 g of 2-t-butyl-4-chloro-5-hydroxy-3(2H)-pyridazinone and 1.3 g of 4-(2-ethoxyethoxy)-benzyl bromide, and then 1.0 g of anhydrous potassium carbonate was added thereto. The mixture was heated with stirring on an oil bath at 90° to 100° C. for 3 hours, poured into water, extracted with benzene, washed with water and dried over anhydrous sodium sulfate. Benzene was distilled off under reduced pressure and the resulting oil was purified by means of column chromatography (on silica gel, eluting with benzene/ethyl acetate=18/1) and recrystallization (from n-hexane-benzene) to obtain 1.1 g of the aimed compound, m.p. 82.0°~83.0° C.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([OH:25])=O)[CH:19]=[CH:20][CH:21]=1.[Cl:26][C:27]1[S:28][CH:29]=[CH:30][CH:31]=1.ClCCCl>CCOCC>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([C:29]2[S:28][C:27]([Cl:26])=[CH:31][CH:30]=2)=[O:25])[CH:19]=[CH:20][CH:21]=1
Reactant: Clc1cccs1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCCl
Solvent: CCOCC
Product: O=C(Cc1cccc(Cl)c1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 500-mL round-bottomed flask was added silica gel 60 (21 g, 350 mmol) and the flask was heated with a heat gun under high vacuum for 30 min. The system was cooled to room temperature and phosphorus pentoxide (8.75 mL, 148 mmol) was added. The mixture was stirred at 110° C. (oil bath) under high vacuum for 120 min. The mixture was allowed to cool to room temperature. 3-chlorophenylacetic acid (15.6 g, 91 mmol), 2-chlorothiophene (33.8 mL, 366 mmol) and DCE (50 mL) were added. The reaction mixture was stirred at reflux for 4 hours. LCMS analysis showed the reaction was complete. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with ether (300 mL) and filtered. The organic solution was concentrated under reduced pressure. The residue was triturated with hexane to afford the title compound as an off-white solid. The hexane mother liquid was concentrated and purified by flash chromatography (SiO2, 0 to 30% EtOAc/Hex, a gradient elution) provided another batch of the title compound as a light yellow solid. Mass Spectrum (ESI) m/z=271 (M+1).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)[N:8]=1.[NH3:31]>CN(C)C=O>[F:30][C:2]([F:1])([F:29])[CH2:3][N:4]=[C:5]([NH2:31])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:8]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCSc1nccc(NC(=S)NCC(F)(F)F)n1
Reactant: N
Solvent: CN(C)C=O
Product: NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-[3-(2,2,2-trifluoroethyl)thioureido]-[(3-phthalimido)propylthio]pyrimidine (0.4 g.), N,N-dimethylformamide (5 ml.), saturated ethanolic ammonia (10 ml.) and yellow mercuric oxide (280 mg.) was stirred at room temperature for 3 hours and then filtered and the filtrate evaporated to dryness. A solution of the residue in ethanol (10 ml.) was treated with hydrazine hydrate (1 ml.), the mixture heated under reflux for 1 hour and then evaporated to dryness. The residue was stirred with 1N hydrochloric acid and then filtered and the filtrate basified with 17N NaOH. The mixture was extracted with ether and the combined ether extracts dried and evaporated to dryness to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[(3-amino)propylthio]pyrimidine which was used without further purification.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[CH:10]=2)[C:5]1=[O:21].O.[OH-].[Na+]>C(O)(=O)C>[Br:1][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[CH:10]=2)[C:5](=[O:21])[N:4]([CH3:3])[CH:13]=1
Reactant: BrBr
Reactant: Cc1ccc(-c2ccc3c(=O)n(C)ccc3c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(-c2ccc3c(=O)n(C)cc(Br)c3c2)cn1
Temperature: 25 °C
Reaction time: 0.28 h
Yield: 67.2 %

Procedure:
Bromine (97 mg, 0.61 mmol) in acetic acid (0.61 mL) was added dropwise to 2-methyl-6-(6-methylpyridin-3-yl)isoquinolin-1-one (160 mg, 0.64 mmol) in acetic acid (6 mL) at 0° C. After stirring at room temperature for 17 min, water (22 mL) was added and the pH was adjusted to 7-8 with 1M NaOH. Extractive work up with ethyl acetate and purification by silica gel chromatography (PE:EA=2:1 to 3:2) gave the title compound (135 mg, 64.3%) as a yellow solid. LCMS: 329.0 (M+H)+
Reaction SMILES: C(O)(=O)C.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][NH:12][C:13](=[O:35])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=O)[CH3:22])=[C:16]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[CH:15]=1>CO>[CH3:22][C:21]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[C:16]2[CH:15]=[C:14]([C:13](=[O:35])[NH:12][CH2:11][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=3)[CH:19]=[CH:18][C:17]=2[N:20]=1
Reactant: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1NCc1ccc2c(c1)OCO2
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nc2ccc(C(=O)NCc3ccccn3)cc2n1Cc1ccc2c(c1)OCO2
Temperature: 70 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
Two milliliters of acetic acid and 5 ml of methanol were added to 0.490 g of N-(2-pyridylmethyl)-4-acetylamino-3-(3,4-methylenedioxybenzylamino)benzamide, and the mixture was stirred at 70° C. for 8 hours. The reaction solution was concentrated under reduced pressure. The residue was purified through silica-gel column chromatography (eluent: a mixture of ethyl acetate and methanol at a ratio of 9:1), and was then crystallized from ethyl acetate. The crystals were separated through filtration, and were dried to give 0.270 g of 2-methyl-1-(3,4-methylenedioxybenzyl)-6-[(2-pyridylmethyl)carbamoyl]-benzimidazole (243).
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:27])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:26])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:25])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:3][C:4]([OH:6])=O.[CH2:28]([CH2:30][NH2:31])[OH:29]>>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:27])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:26])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:25])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:3][C:4]([NH:31][CH2:30][CH2:28][OH:29])=[O:6]
Reactant: NCCO
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)NCCO
Yield: 93 %

Procedure:
The procedure of Example 1 was repeated except that 7.4 g of 3,7,11,15,19-pentamethyl-2,6,10,14,18-eicosapentaenoic acid and 1.8 ml of ethanolamine were used as starting materials. 7.7 g (yield 93%) of the title compound as a colorless oil was obtained.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)=[CH:18][CH:17]=1
Reactant: CSc1ccc(C2=C(Br)CCC2)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1ccc(C2=C(c3ccc(F)cc3)CCC2)cc1

Procedure:
Under nitrogen, 1.5 g (5.6 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio)benzene (Step 2) was reacted with 1.5 g (11 mmol) of 4-fluorophenylboronic acid (Lancaster) in 30 mL of toluene, 20 mL of ethanol, and 25 mL of 2M Na2CO3 in the presence of 250 mg of Pd(PPh3)4. The reaction was vigorously stirred at reflux overnight and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, dried (MgSO4), and reconcentrated. Purification by silica gel chromatography with hexane gave 1-[2-(4-fluorophenyl)cyclopenten-1-yl]-4-(methylthio)benzene (41 in Synthetic Scheme X when R5 =SCH3, R10 =F, and R1, R2, R3, R4, R6, R7, R8, R9, R11, and R12 =H) as a colorless solid. mp 46-47° C.; NMR (CDCl3) d 2.04 (m, J=7 Hz, 2H), 2.45 (s, 3H), 2.86, (t, J=7 Hz, 4H), 6.86-6.94 (m, 2H), 7.08 (br s, 4H), 7.10-7.18 (m, 2H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[N:10]1([C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:22]([O-])(=O)C.[Na+].C=O>>[N:21]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:22][C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)[CH2:12][CH2:11]1
Reactant: CC(=O)[O-]
Reactant: c1cnc2[nH]ccc2c1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: C=O
Agent: [Na+]
Product: c1cnc(N2CCN(Cc3c[nH]c4ncccc34)CC2)nc1

Procedure:
1H-pyrrolo[2,3-b]pyridine (47 mg, 0.40 mmol), 2-(1-piperazinyl)pyrimidine (65 mg, 0.48 mmol), sodium acetate (72 mg, 0.53 mmol), and formaldehyde (0.48 mmol) were processed as described in Example 18 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.42 (m, 4H) 3.68 (m, 4H) 4.05 (s, 2H) 5.59 (s, 1H) 6.60 (m, 1H) 7.08 (m, 2H) 7.37 (m, 2H 8.07 (m, 2H). (ESI) m/z 295 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH:2]=[CH2:3].[C:13](Cl)(Cl)=[O:14].C(N(CC)CC)C.[CH:24]1([CH2:27][NH:28][CH2:29][CH:30]=[CH2:31])[CH2:26][CH2:25]1>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([N:4]([C:13]([N:28]([CH2:29][CH:30]=[CH2:31])[CH2:27][CH:24]1[CH2:26][CH2:25]1)=[O:14])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCNCC1CC1
Reactant: O=C(Cl)Cl
Reactant: C=CCNCC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CCN(CC(=O)OC(C)(C)C)C(=O)N(CC=C)CC1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of tert-butyl N-allylglycinate (Senokuchi et al. J. Med. Chem. 1995, 38, 2521) (308 mg, 1.80 mmol) in anhydrous THF (10 mL) was added phosgene (0.89 mL of a 20% solution in toluene, 1.80 mmol), then triethylamine (0.25 mL, 1.80 mmol). The resulting solution was stirred at 0° C. for 1 h, then N-(cyclopropylmethyl)prop-2-en-1-amine from Step A (200 mg, 1.80 mmol) was added, followed by triethylamine (0.75 mL, 5.40 mmol). The reaction mixture was allowed to warm to ambient temperature and stirring was continued for 18 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product, which was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 90:10 to provide the title compound. MS: m/z=309 (M+1).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C@H:3]([N:28]1[CH2:32][CH2:31][C@H:30]([NH:33]C(=O)OC(C)(C)C)[CH2:29]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[C:16]([O:23][CH2:24][C@@H:25]([OH:27])[CH3:26])[CH:17]=[CH:18][CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1.[Cl:43]CCl>FC(F)(F)C(O)=O>[ClH:43].[ClH:43].[NH2:33][C@H:30]1[CH2:31][CH2:32][N:28]([C@H:3]([C:4]2[CH:5]=[CH:6][C:7]3[N:8]([C:10]([C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[C:16]([O:23][CH2:24][C@@H:25]([OH:27])[CH3:26])[CH:17]=[CH:18][CH:19]=5)[N:14]=4)=[N:11][N:12]=3)[CH:9]=2)[C:2]([F:41])([F:42])[F:1])[CH2:29]1
Reactant: C[C@H](O)COc1cccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](O)COc1cccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](N)C5)C(F)(F)F)cn34)nc12
Product: Cl
Yield: 25 %

Procedure:
A solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(8-((S)-2-hydroxypropoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.11 g, 0.19 mmol) in dichloromethane (1 mL) and trifluoroacetic acid (2 mL) was stirred at ambient temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was by reverse phase chromatography on C18 (0-80% acetonitrile/water). The material isolated after purification was dissolved in methanol (0.5 mL) and added dropwise to hydrochloric acid (2M in diethyl ether; 5 mL). The resulting salt was collected by vacuum filtration to provide the title compound (0.026 g, 25%). LCMS APCI (+) m/z 487 (M+H).
Reaction SMILES: C([O:5][C:6]([CH2:8][CH:9]1[C:21]2[N:20]3[CH:22]=[CH:23][N:24]=[C:19]3[C:18](=[O:25])[NH:17][C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2)=[O:7])(C)(C)C.CS(C)=O.Cl.C(=O)([O-])O.[Na+]>C(OCC)C.O>[C:6]([CH2:8][CH:9]1[C:21]2[N:20]3[CH:22]=[CH:23][N:24]=[C:19]3[C:18](=[O:25])[NH:17][C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)CC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)CC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: 20 °C
Reaction time: 107 h
Yield: 42 %

Procedure:
A mixture of 1 g of 10-(tert-butoxycarbonyl-methyl)-5H,10H-imidazo[l,2-a]indeno[1,2-e]pyrazin-4-one, 5 ml of dimethyl sulphoxide and 25 ml of 3N hydrochloric acid in ethyl ether is stirred, under cover of argon, for 107 hours at a temperature in the region of 20° C. After concentration under reduced pressure, the residue is crystallized from 30 ml of acetone. The solid obtained is treated with 50 ml of water and 7 ml of saturated sodium hydrogen carbonate solution; three extractions with dichloromethane (3×50 ml) are performed on this mixture, the aqueous phase is filtered and the aqueous solution is acidified with 8 ml of 1N hydrochloric acid. The precipitate formed is filtered off, washed with water and dried at 80° C. under vacuum (1 mmHg; 0.13 kPa) to give 0.35 g of 10-(carboxymethyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one in the form of a greenish solid melting above 260° C. (Analysis, % calculated C: 64.05, H: 3.94, N: 14.94, O: 17.06, % found C: 63.7, H: 3.2, N: 14.9).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][N:6]([CH3:11])[CH2:7][CH2:8][C:9]=2[N:10]=1.C([Li:16])CCC.[C:17](=[O:19])=[O:18]>C(OCC)C>[CH3:11][N:6]1[CH2:7][CH2:8][C:9]2[N:10]=[C:2]([C:17]([O-:19])=[O:18])[S:3][C:4]=2[CH2:5]1.[Li+:16]
Reactant: CN1CCc2nc(Br)sc2C1
Reactant: O=C=O
Reactant: [Li]CCCC
Solvent: CCOCC
Product: CN1CCc2nc(C(=O)[O-])sc2C1
Product: [Li+]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Bromo-5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine (531 mg) was dissolved in absolute diethyl ether (20 ml), n-butyllithium (1.54N hexane solution, 1.63 ml) was added dropwise at −78° C., and the mixture was stirred for 30 minutes with ice cooling. After passing carbon dioxide into the reaction mixture at −78° C. for 1 hour, the mixture was warmed to room temperature. The reaction mixture was concentrated under reduced pressure to obtain the title compound (523 mg) as a pale brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C1COCC1.N(CC)CC.[Cu]I.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>[CH3:13][Si:14]([CH3:16])([CH3:15])[C:17]#[C:18][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C1CCSc2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc2c(c1)C(=O)CCS2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 1.00 g (4.11 mmol) 2,3-dihydro-6-bromo-(4H)-1-benzothiopyran-4-one and 78.3 mg (0.41 mmol) CuI in 15.0 ml THF and 6.0 ml Et2NH was sparged with argon for 5 minutes. To this solution was added 2.0 ml (1.39 g, 14.2 mmol) of (trimethylsilyl)acetylene followed by 288.5 mg (0.41 mmol) of bis(triphenylphosphine)palladium(II) chloride. The resulting dark solution was stirred at room temperature for 3 days and then filtered through a pad of Celite, which was washed with EtOAc. The filtrate was washed with H2O and saturated aqueous NaCl before being dried over MgSO4. The title compound was isolated as an orange oil by column chromatography (4% EtOAc-hexanes). 1H NMR (CDCl3): δ 8.13 (1H, d, J=1.9 Hz), 7.36 (1H, dd, J=2.1, 8.2 Hz), 7.14 (1H, d, J=8.2 Hz), 3.19 (2H, d, J=6.3 Hz), 2.91 (2H, d, J=6.3 Hz), 0.21 (9H, s).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)[N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)n2)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)c1

Procedure:
The title compound was prepared from 6′-bromo-4-methyl-6-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl (example E.96) (0.393 g, 1.0 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.283 g, 1.1 mmol) according to the general procedure VI. Obtained as a white solid (0.500 g, 95%). MS (ISP) 526.3 [(M+H)+].
Reaction SMILES: [CH2:1]1[O:15][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23]>C(O)C>[CH2:22]([NH:23][CH2:1][CH:2]([OH:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][NH:16][CH2:1][CH:2]([OH:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCC1CO1
Reactant: NCCCCCCN
Solvent: CCO
Product: CCCCCCCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-tetradecene oxide (91.8 g.) and hexamethylenediamine (25 g.) and recrystallization of the resulting product (71 g., m.p. 118°-121° C.) from ethanol gave N,N'-(1,6-hexylene)-bis[2-hydroxytetradecylamine] (I: R = CH3 (CH2)11, R' = H, X = (CH2)6, Z = H) (55.3 g., m.p. 122°-126° C.).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].ClC(Cl)(Cl)C(=N)O[C:16]([CH3:19])([CH3:18])[CH3:17].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C1COCC1.C1CCCCC1>[CH3:1][C:2]1[C:3]([O:11][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:4][CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1c(OC(C)(C)C)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-methyl-3-nitrophenol K1 (1.1 g; 7.18 mmol) in THF (13 mL) was added cyclohexane (27 mL; a solution was maintained). tert-Butyl trichloroacetimidate K2 (5.36 mL; 28.73 mmol) was added followed by a catalytic amount of boron trifluoride etherate (143.8 □L; 1.14 mmol) and the reaction was stirred at room temperature for 15 h. The reaction was incomplete (by analytical HPLC) and an additional amount of tert-butyl trichloroacetimidate (1.4 mL; 7.51 mmol) was added (reaction remains in solution). The reaction was complete after stirring at room temperature for 5 h. Solid sodium bicarbonate was added, and the mixture was filtered, rinsed with dichlormethane and evaporated to dryness to provide a white solid. The solid was triturated with dichloromethane, the white solid filtered and discarded (=trichloroacetimide). The filtrate was concentrated and loaded onto a flash column for purification (hexane:EtOAc 9:1) to provide the pure 2-methyl-3-tert-butoxynitrobenzene K3 (1.17 g; 78%). Homogeneity by HPLC (TFA) @ 220 nm: 96%