Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:24](=[O:29])[C:25]([O:27][CH3:28])=[O:26].N1(C2C=CC(NC(=O)C(OC)=O)=CC=2)CCOCC1>>[C:18]([O:17][C:16]([NH:15][CH2:14][C@H:11]1[CH2:10][CH2:9][C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:24](=[O:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:7][CH:6]=2)[CH2:13][CH2:12]1)=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: COC(=O)C(=O)Cl
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Agent: COC(=O)C(=O)Nc1ccc(N2CCOCC2)cc1
Product: COC(=O)C(=O)Nc1ccc([C@H]2CC[C@H](CNC(=O)OC(C)(C)C)CC2)cc1

Procedure:
Prepared from tert-butyl {[trans-4-(4-aminophenyl)cyclohexyl]methyl}carbamate and methyl chlorooxoacetate by method described for Intermediate 1, method D3.
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.[C:6](ON1C(=O)CCC1=O)([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]>O1CCOCC1>[N:1]1([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: C1=CCNC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CC=CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
To a solution of 2,5-dihydro-1H-pyrrole (30 g, 434 mmol, 96% from Alfa Aesar) in dioxane (1000 mL, 0.43 M solution) was added CbzOSu (130 g, 521 mmol). After being stirred at room temperature for 18 h, the reaction mixture was concentrated to around 300 mL, diluted with 1000 mL of EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The desired benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate was obtained in 91% yield (80.0 g) as a colorless oil by flash column chromatography. Rf==0.6 (30% EtOAc in hexanes). 1H NMR (CDCl3, 400 MHz): δ 7.32 (5H, m), 5.80 (2H, m), 5.77 (2H, s), 4.22 (4H, m). LC/MS (uplc): MH+ 204.2, 160.1 (−44), 0.86 min.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:25])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[C:16]([OH:18])[C:15]([F:19])=[CH:14][C:13]=1[F:20])[CH:9]=[C:8]([C:21]([OH:23])=[O:22])[C:7]2=[O:24].[CH3:27][NH2:28]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:28][CH3:27])=[C:4]([F:25])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[C:16]([OH:18])[C:15]([F:19])=[CH:14][C:13]=1[F:20])[CH:9]=[C:8]([C:21]([OH:23])=[O:22])[C:7]2=[O:24]
Reactant: CN
Reactant: O=C(O)c1cn(-c2cc(O)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(O)c(F)cc3F)c2c1Cl
Temperature: 25 °C
Reaction time: 21 h
Yield: 84.1 %

Procedure:
8-Chloro-6,7-difluoro-1-(2,4-difluoro-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (200 mg) and an aqueous solution (about 40%; 550 mg) of methylamine were added to pyridine (1,200 mg), and the mixture was stirred at room temperature for 21 hours. The reaction mixture was concentrated under reduced pressure, and ethanol (1 ml) was added to the residue. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (173 mg) as a pale brown powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:16]1[C:25]([CH3:26])=[N:24][C:23]2[C:18](=[CH:19][C:20]([F:28])=[C:21]([F:27])[CH:22]=2)[N:17]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[F:27][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[F:28])[N:17]=[C:16]([NH:15][CH2:14][C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]1)[C:25]([CH3:26])=[N:24]2
Reactant: Cc1nc2cc(F)c(F)cc2nc1NC[C@@H]1CCCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2cc(F)c(F)cc2nc1NC[C@@H]1CCCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-2-[(6,7-Difluoro-3-methylquinoxalin-2-ylamino)methyl]-piperidine-1-carboxylic acid tert butyl ester (0.524 g) was dissolved in trifluoroacetic acid (15 ml) and stirred at room temperature for 3 hours. The solution was then evaporated and the residue chromatographed over silica gel, eluting with 0 to 10% (9:1 methanol—concentrated ammonia solution) in dichloromethane. The title compound was obtained as a white solid (0.289 g), MH+ 293.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:15]([NH:17][NH2:18])=[O:16].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][NH:17][C:15](=[O:16])[C:14]2[CH:19]=[CH:20][C:21]([CH3:22])=[C:12]([OH:11])[CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)NN)cc1O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NNC(=O)c2ccc(Cl)cc2)cc1O
Temperature: 85 °C

Procedure:
A mixture of 4-chlorobenzoyl chloride (0.92 mL, 7.22 mmol) (Aldrich), 3-hydroxy-4-methyl-benzoic acid hydrazide (1.0 g, 6.02 mmol) (from Example 6 supra) and triethylamine (1.36 mL) in tetrahydrofuran (20 mL) was heated at 85° C. for 1 day. The reaction mixture was partitioned between ethyl acetate and water. The precipitate washed with ethyl acetate and dichloromethane and dried to give 3-hydroxy-4-methyl-benzoic acid N′-(4-chloro-benzoyl)-hydrazide. (Yield 1.28 g, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)=[C:14]([C:26]([O:28][CH3:29])=[O:27])[NH:13][C:12]=2[C:30]([O:32][CH3:33])=[O:31])=[C:5]([O:34][CH2:35][O:36][CH3:37])[CH:4]=1.[CH3:38][O:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][C:48]=1[O:49][CH3:50])[CH2:43][CH2:44]Br.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O.C(Cl)Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)=[C:14]([C:26]([O:28][CH3:29])=[O:27])[N:13]([CH2:44][CH2:43][C:42]3[CH:46]=[CH:47][C:48]([O:49][CH3:50])=[C:40]([O:39][CH3:38])[CH:41]=3)[C:12]=2[C:30]([O:32][CH3:33])=[O:31])=[C:5]([O:34][CH2:35][O:36][CH3:37])[CH:4]=1
Reactant: COc1ccc(CCBr)cc1OC
Reactant: COCOc1cc(OC)c(OC)cc1-c1c(C(=O)OC)[nH]c(C(=O)OC)c1-c1ccc(OC)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCOc1cc(OC)c(OC)cc1-c1c(-c2ccc(OC)c(OC)c2)c(C(=O)OC)n(CCc2ccc(OC)c(OC)c2)c1C(=O)OC
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 94.4 %

Procedure:
A stirred mixture of 8 (297 mg, 0.58 mmol, 1.0 equiv), 3,4-dimethoxyphenethyl bromide (9,15 707 mg, 2.88 mmol, 5.0 equiv), and K2CO3 (398 mg, 2.88 mmol, 5 equiv) in DMF (5.8 mL) under Ar was warmed to 70° C. After 2.5 h, the mixture was cooled to 25° C. and solvent was removed in vacuo. Chromatography (SiO2, 3.5×15 cm, 20% EtOAc/CH2Cl2) provided 10 (372 mg, 94% yield) as a yellow oil: FABHRMS (NBA/NaI) m/z 702.2553 (M+Na+, C36H41NO12 requires 702.2526).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.O[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]=[CH:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26].[OH2:33]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:25](=[O:26])[CH:24]=[CH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:17]=1
Reactant: O=C(C=Cc1ccccc1O)c1ccccc1
Reactant: O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccccc3C(=O)C=Cc3ccccc3)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 2-hydroxychalcone (300 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (30 mg, yield 16%).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:27])[N:14]([N:23]=[C:24]([CH3:26])[CH3:25])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:27])[N:14]([NH:23][CH:24]([CH3:25])[CH3:26])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: CC(C)=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 233A (0.044 g, 0.11 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.010 mL, 0.28 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran 0.085 mL, 0.17 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with dichloromethane to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.99 (m, 6 H) 3.94 (m, 1 H) 5.65 (d, J=4.41 Hz, 1 H) 7.04 (t, J=7.35 Hz, 1 H) 7.28 (m, 2 H) 7.51 (m, 2 H) 7.66 (d, J=7.72 Hz, 1 H) 7.75 (d, J=8.46 Hz, 1 H) 8.06 (dd, J=8.09, 1.47 Hz, 1 H) 16.28 (s, 1 H). (ESI−) m/z 397 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO.CCOCC>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: Nc1ccccc1
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Solvent: CCOCC
Solvent: CCO
Product: CSc1nc(Cl)c(C#N)c(Nc2ccccc2)n1
Reaction time: 0.5 h
Yield: 59 %

Procedure:
4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbonitrile [Santilli, et al., J. Heterocycl. Chem. 1971, 8, 445–453] (0.222 grams (hereinafter “g”), 1.0 millimoles (hereinafter “mmol”)) in EtOH (2 mnililiters (hereinafter “mL”)) and Et2O (mL) was treated with aniline (184 microliter (hereinafter “uL”), 2.0 mmol) in EtOH (1 mL). A clear solution formed initially but rapidly formed a heavy precipitate. The mixture was stirred 30 minutes (hereinafter “min”) and was filtered, and the solid was washed with 1:1 Et2O, EtOH and then Et2O, dried to afford 162 miligrams (hereinafter “mg”) (59%) of the title compound as a white solid. LC MS m/e=277 (NM+), Rt=2.32 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3S(C3C=CC(C)=CC=3)(=O)=O)=[C:15]([C:32]3[O:33][C:34]([CH2:37]Cl)=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1.[CH3:39][CH:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)[CH3:41].[OH-].[Na+]>C(O)(C)C>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][NH:19]3)=[C:15]([C:32]3[O:33][C:34]([CH2:37][N:45]4[CH2:46][CH2:47][N:42]([CH:40]([CH3:41])[CH3:39])[CH2:43][CH2:44]4)=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CCl)o4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Reactant: CC(C)N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)N1CCN(Cc2nnc(-c3cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc4[nH]ncc34)o2)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 17.9 %

Procedure:
N-(2-Chloro-5-{4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-methylphenyl)sulfonyl]-1H-indazol-6-yl}-3-pyridinyl)methanesulfonamide (25 mg, 0.042 mmol) and 1-(1-methylethyl)piperazine (500 mg, 3.90 mmol) were placed a vial and heated in a microwave at 90° C. for 15 mins. The 1-(1-methylethyl)piperazine was blown off under a stream of nitrogen and the residue suspended in isopropanol (2 ml) and 2M sodium hydroxide (1 ml) added. The mixture was stirred at room temperature for 2 h. The solvent was blown off under a stream of nitrogen and the residue purified by Mass Directed Automated Preparative HPLC (Method B) to give the title compound as a pale yellow gum (4 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:4]2[N:3]=1.[C:23]1([NH2:30])[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1>>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[N:4]3[N:3]=[C:2]([NH:29][C:25]4[CH:26]=[CH:27][CH:28]=[C:23]([NH2:30])[CH:24]=4)[C:11]4[C:6]([C:5]3=[N:12][N:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)=[CH:16][CH:17]=1
Reactant: COc1ccc(-c2nnc3c4ccccc4c(Cl)nn23)cc1
Reactant: Nc1cccc(N)c1
Product: COc1ccc(-c2nnc3c4ccccc4c(Nc4cccc(N)c4)nn23)cc1

Procedure:
Starting from 6-chloro-3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine (compound B1) and m-phenylene-diamine, the title compound can be obtained analogously to one of the procedures as described for compound A1.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:11]([CH:12]=O)=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7].[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15].[CH:19]1C=CC=CC=1>>[CH3:1][C:2]1[O:3][C:4]2[C:11]([CH:12]([N:16]([CH2:17][CH3:18])[CH2:14][CH3:15])[CH3:19])=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7]
Reactant: c1ccccc1
Reactant: CCNCC
Reactant: Cc1oc2c(C=O)cccc2c1C
Product: CCN(CC)C(C)c1cccc2c(C)c(C)oc12
Temperature: 25 °C
Yield: 11 %

Procedure:
1.8 g (10.3 mmol) of 2,3-dimethyl-7 -formylbenzofuran, 80 ml of benzene, 4A molecular sieve and 3.19 ml (30.8 mmol) of diethylamine are introduced into a 250 ml three-necked flask equipped with a reflux condenser. The mixture is heated at reflux for 16 hours, cooled to room temperature and then filtered to remove the molecular sieve. The filtrate is concentrated under vacuum and is introduced, with 100 ml of anhydrous tetrahydrofuran, into a 250 ml three-necked flask equipped with a reflux condenser. The solution is cooled to 0° C. by an ice bath and 20 ml of a 3.0 molar solution of methylmagnesium bromide in tetrahydrofuran are added. The reaction mixture is heated at reflux for 26 hours, 8 ml of a 3.0 molar solution of methylmagnesium bromide in tetrahydrofuran are again added and stirring is continued under reflux for 12 hours. The mixture is cooled by an ice bath, 50 ml of a saturated ammonium chloride solution are added and extraction is carried out with ethyl acetate (3×200 ml). The organic phases are combined, dried over magnesium sulphate and concentrated under vacuum. The residue is purified by chromatography on a silica column (elution solvent: 5% methanol in dichloromethane). 0.281 g (Yield: 11%) of 2,3-dimethyl-7-[1-(diethylamino)ethyl]benzofuran is obtained in the form of a colourless oil.
Reaction SMILES: [OH:1][C:2]([CH2:24][CH:25]=[CH2:26])([CH2:21][CH:22]=[CH2:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:20])([CH3:19])[C:15]([O:17][CH3:18])=[O:16].O[C:28](CC=C)(CC=C)CCCCCCCCCCCC(C)(C)C(O)=O.CC(C)(CCCCCCCCCCCC(CC=C)(O)CC=C)CO>>[CH3:18][O:17][CH:15]([O:16][CH3:28])[C:14]([CH3:19])([CH3:20])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([CH2:24][CH:25]=[CH2:26])([OH:1])[CH2:21][CH:22]=[CH2:23]
Reactant: C=CCC(O)(CC=C)CCCCCCCCCCCC(C)(C)C(=O)O
Reactant: C=CCC(O)(CC=C)CCCCCCCCCCCC(C)(C)C(=O)OC
Agent: C=CCC(O)(CC=C)CCCCCCCCCCCC(C)(C)CO
Product: C=CCC(O)(CC=C)CCCCCCCCCCCC(C)(C)C(OC)OC

Procedure:
##STR16## Methyl 14-hydroxy-2,2-dimethyl-14-(2-propenyl)-16-heptadecenoate ##STR17## 14-Hydroxy-2,2-dimethyl-14-(2-propenyl)-16-heptadecenal; ##STR18## 14-Hydroxy-2,2-dimethyl-14-(2-propenyl)-16-heptadecenoic acid ##STR19## and 2,2-Dimethyl-14-(2-propenyl)-16-heptadecene-1,14-diol.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32][C:33]1[CH:34]=[C:35]([C:47]([O:49][CH3:50])=[O:48])[C:36]2[NH:37][C:38]3[CH:39]=[C:40]([OH:46])[CH:41]=[CH:42][C:43]=3[C:44]=2[N:45]=1.[O:51]1[CH2:56][CH2:55][N:54]([CH2:57][CH2:58]O)[CH2:53][CH2:52]1>C1COCC1>[Br:32][C:33]1[CH:34]=[C:35]([C:47]([O:49][CH3:50])=[O:48])[C:36]2[NH:37][C:38]3[CH:39]=[C:40]([O:46][CH2:58][CH2:57][N:54]4[CH2:55][CH2:56][O:51][CH2:52][CH2:53]4)[CH:41]=[CH:42][C:43]=3[C:44]=2[N:45]=1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(O)ccc12
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)nc2c1[nH]c1cc(OCCN3CCOCC3)ccc12
Reaction time: 1 h
Yield: 53.4 %

Procedure:
Diethyl azodicarboxylate (790 μL, 5.0 mmol) was added to a solution of triphenylphosphine (1.31 g, 5.0 mmol), methyl 2-bromo-7-hydroxy-5H-pyrido[3,2-b]indole-4-carboxylate (800 mg, 2.49 mmol) and 2-morpholinoethanol (610 μL, 5.0 mmol) in dry THF (12 mL) at room temperature under nitrogen. After 1 hr, the reaction was partitioned between EtOAc and water and the organic phase was washed with brine and dried over sodium sulfate. The solvent was removed and the residue was taken up in a 1:1 mixture of DCM:MeOH and the product was captured on a SCX cartridge and released with a 1:1 mixture of 2 N NH3 in MeOH:DCM. The solvent was removed and the product was purified by radial chromatography (step gradient elution with DCM containing 0 to 3% MeOH) to afford methyl 2-bromo-7-(2-morpholinoethoxy)-5H-pyrido[3,2-b]indole-4-carboxylate (577 mg, 1.33 mmol, 53% yield) as a tan solid. MS (ESI) m/z 434.0 (M+H). 1H NMR (400 MHz, chloroform-d) δ ppm 9.48 (1H, s), 8.21 (1H, d, J=9.32 Hz), 7.88 (1H, s), 6.89-7.00 (2H, m), 4.22 (2H, t, J=5.67 Hz), 4.04 (3H, s), 3.70-3.80 (3H, m), 3.69-3.81 (4H, m), 2.86 (2H, t, J=5.67 Hz), 2.55-2.65 (4H, m).
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].[CH3:6][O:7][C:8]1[CH:21]=[CH:20][C:11]([C:12]([CH2:14][C:15](OCC)=[O:16])=O)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:16][C:15]1[CH:14]=[C:12]([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:21][CH:20]=2)[N:5]=[C:2]([CH3:3])[N:4]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(-c2cc(O)nc(C)n2)cc1
Reaction time: 8 h
Yield: 25.5 %

Procedure:
1.89 g of acetamidine hydrochloride and 4.44 g of etyl paramethoxybenzoylacetate were dissolved in 40 ml of ethanol. After addition of 5.52 g of potassium carbonate, the solution was refluxed with stirring for 8 hours, and then evaporated in vacuo. 5 g of sodium hydroxide was dissolved in 30 ml of water and this was added to the evaporated residue. Add ether, then extract, the aqueous layer was neutralized with acetic acid. The resulting precipitations were filtered off, washed with water and dried. Then 1.1 g of crystals were obtained. Melting point is 270° to 272° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[C:5]([CH3:8])[O:4][N:3]=1.[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1.ClCCl>[C:9]1([S:15]([N:1]([C:2]2[C:6]([Br:7])=[C:5]([CH3:8])[O:4][N:3]=2)[S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1onc(N)c1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1onc(N(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 25 h
Yield: 72.9 %

Procedure:
3-Amino-4-bromo-5-methylisoxazole (5.31 g, 30 mmol) was dissolved in dry pyridine (30 ml). Benzenesulfonyl chloride (5.24 ml, 42 mmol) was added dropwise with stirring at ambient temperature. N,N-(Dimethyl)aminopyridine (100 mg) was added and stirring was continued at 50° C. for 25 h. The reaction mixture was diluted with dichloromethane (200 ml), washed with 1N HCl (6×100 ml) and the organic phase was dried over magnesium sulfate. The solvent was removed under reduced pressure to yield a crude product which was purified by column chromatography using 9: 1, hexanes/ethyl acetate as eluent to give N-(benzenesulfonyl)-N-(4-bromo-5-methyl-3-isoxazolyl)benzenesulfonamide (7 g, 51% yield, Rf =0.27 using 3:1, hexanes/ethyl acetate as eluent) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7](Cl)[N:6]=1)=[O:4].[Cl:13][C:14]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:15]=1[NH2:16]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:14]=2[Cl:13])[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C)c(Cl)n1
Reactant: Nc1ccc(Cl)cc1Cl
Product: COC(=O)c1ccc(C)c(Nc2ccc(Cl)cc2Cl)n1

Procedure:
6-(2,4-Dichloro-phenylamino)-5-methyl-pyridine-2-carboxylic acid methyl ester was synthesized in analogy to Example 5 b, using 6-chloro-5-methyl-pyridine-2-carboxylic acid methyl ester (CAN 178421-22-2) and 2,4-dichloroaniline as starting materials, MS (EI): m/e 311.3 [M+H]+.
Reaction SMILES: [CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7](O)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:31][O:32][C:33](=[O:42])[CH2:34][C:35]1([CH2:38][CH2:39][CH2:40][NH2:41])[CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7]([NH:41][CH2:40][CH2:39][CH2:38][C:35]2([CH2:34][C:33]([O:32][CH3:31])=[O:42])[CH2:36][CH2:37]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Reactant: COC(=O)CC1(CCCN)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CC1(CCCNC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C2CCCC2)CC1
Temperature: 0 °C

Procedure:
A solution of 591 mg (1.51 mmol) of cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxa-diazin-4-yl)methyl]phenyl}acetic acid (enantiomer 2), 376 mg (1.81 mmol) of methyl[1-(3-amino-propyl)cyclopropyl]acetate hydrochloride, 859 mg (2.26 mmol) of HATU and 1 ml of N,N-diiso-propylethylamine in 10 ml of DMF was stirred at room temperature overnight. After the reaction had ended, the mixture was poured into ice-water, the phases were separated and the aqueous phase was extracted three times with tert-butyl methyl ether. The combined organic phases were dried over sodium sulfate, and, after filtration, the solvent was removed to dryness under reduced pressure. The crude product obtained was purified by preparative RP-HPLC. This gave 233 mg (0.43 mmol, 28.5% of theory) of the title compound as a colorless oil.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[N:10][C:11](=[O:14])[NH:12][CH:13]=1.Br[CH2:16][S:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[O:18]>CN(C=O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:17]([CH2:16][N:10]2[CH:9]=[C:8]([Cl:7])[CH:13]=[N:12][C:11]2=[O:14])=[O:18])=[CH:20][CH:21]=1
Reactant: O=S(CBr)c1ccc(Cl)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ncc(Cl)cn1CS(=O)c1ccc(Cl)cc1

Procedure:
Potassium tert-butoxide (4 mmol) in DMF (10 ml) was added to a solution of 5-chloropyrimidin-2-one (4 mmol) in DMF (40 ml). The mixture was stirred at room temperature for 10 min before 1-bromomethylsulfinyl-4-chlorobenzene (see Preparation 5) (4 mmol) was added. The resultant mixture was stirred at 60° C. for 2 days, the solvent distilled off at reduced pressure, the residue triturated with water, the insoluble material dried and washed with a little chloroform before recrystallization from DMSO; the crystalline material was also washed with a little methanol and finally with water; yield 0.30 g (25%), m.p. 262° C. (Found: C43.63; H2.68. Calc. for C11H8Cl2N2O2S: C43.59; H2.67)1H NMR (DMSO-d6): δ 5.12 (CH2), 7.60 (Ph, b.s.), 8.19 and 8.62 (H-4, H-6, d, J 4 Hz). IR (KBr): 1660 (CO), 1060 cm-1 (SO) MS (70 eV; m/e (rel int. %): 302 (0.5, M), 159 (6), 145 (33), 143 (100).