Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].O=[C:8]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:9][CH2:10][C:11]([O: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][CH2:26][CH3:27])=[O:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC=CC=1.C1COCC1>[CH2:33]([O:32][C:30]([CH2:29][CH2:28][C:8](=[CH2:1])[CH2:9][CH2:10][C:11]([O: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][CH2:26][CH3:27])=[O:12])=[O:31])[CH3:34]
Reactant: CC(C)(C)[O-]
Reactant: CCCCCCCCCCCCCCOC(=O)CCC(=O)CCC(=O)OCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: C=C(CCC(=O)OCC)CCC(=O)OCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 156.5 %

Procedure:
Potassium t-butoxide (0.195 g, 1.73 mmol) was added to a stirred suspension of methyl triphenylphosphonium bromide (0.618 g, 1.73 mmol) in dry benzene (8 mL), which was maintained under argon at room temperature. After stirring for 30 min, the reaction mixture was cooled to 0° C. and a solution of ketone 3.17 (0.46 g, 1.16 mmol) in dry THF was added rapidly. The reaction mixture was quenched after 30-60 minutes at 0° C. with brine (~10 mL), extracted with EtOAc (3×20 mL), and the combined organic layer was washed with water (1×10 mL) and dried (Na2SO4). The residue obtained after concentration was purified by flash column chromatography over silica gel using hexane:EtOAc (95:5) giving 3.18 as a liquid (0.72g, 71.5%); IR (neat) 1738 (C=O) and 1647 cm-1 ; 1H NMR (CDCl3) δ 0.85(distorted t, 3H, CH3 (CH2)13), 1.20-1.40 (m, 25 H, CH3 (CH2)11CH2CH2OCO, CH3CH2OCO), 1.60 (m, 2 H, CH3 (CH2)11CH2CH2OCO), 2.35 (m, 4 H, OCCH2CH2 (C=CH2)CH2CH2CO), 2.45 (m, 4 H, OCCH2CH2 (C=CH2)CH2CH2CO), 4.00-4.15 (m, 4H, CH3 (CH2)11CH2CH2OCO, CH3CH2O), 4.75 (s, 2 H, =CH2); 13C NMR (CDCl3) δ 14.09, 14.20, 22.66, 25.89, 28.60, 29.23, 29.33, 29.50, 29.56, 29.62, 31.00, 31.03, 31.89, 32.64, 60.35, 64.61, 109.75, 146.37, 173.08, 173.181. Anal. Calcd for C24H44O4 : C, 72.67; H, 11.19. Found: C, 72.63; H, 11.23.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([OH:19])[CH:3]=1.Br[CH2:21][CH2:22][CH2:23]Cl.[H-].[Na+].[CH3:27][SH:28]>CN(C=O)C>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([O:19][CH2:21][CH2:22][CH2:23][S:28][CH3:27])[CH:3]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Reactant: ClCCCBr
Reactant: CS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCCSC
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of tetrabutylammonium salt of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (10.54 g, 20 mmoles) (prepared in Preparation No. 3) in DMF (100 ml) was added 1-bromo-3-chloropropane (3.268 g, 2.2 ml, 20.76 mmoles) and the mixture stirred for 2 hours at ambient temperature and another 30 minutes at 40° C. The mixture was cooled to 0° C and poured over sodium hydride (1.0 g of 60% mineral oil dispersion, 25 mmoles, washed with n-pentane) under nitrogen. The mixture was stirred in the cold while methyl mercaptan gas was bubbled in until evolution of hydrogen ceased. The mixture was heated at 35°-40° C. for 2 hours, poured into water (700 ml) and after standing for 1 hour the resultant solid was isolated by suction to give after drying in air 7.06 g (94%) of crude product, mp. 58°-59° C. This was dissolved in methylene chloride and filtered over a short column packed with silica and alumina. The filtrate was concentrated and the residue crystallized from ether to give 4.95 g (66%) of the title compound as a white solid, mp. 79°-80° C.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[CH:6]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:10][CH:9]=1)=[O:7].Cl>C(OCC)C.O1CCCC1>[OH:7][CH:6]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:10][CH:9]=1)[CH2:3][CH:2]=[CH2:1]
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Reactant: C=CC[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC(O)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
A 1.0M solution (200 ml, 200 ml) of allylmagnesium bromide in diethyl ether was dropped into a solution of t-butyl 4-formylbenzoate (30.9 g, 150 mmol) in anhydrous tetrahydrofuran, while stirring the latter under cooling with ice in a nitrogen stream. After the completion of the dropping, the obtained mixture was further stirred for 30 minutes, followed by the addition of 220 ml of 1N hydrochloric acid cooled with ice. The obtained mixture was vigorously stirred. The aqueous layer was further extracted with diethyl ether. The organic layers were combined, washed with an aqueous solution of common salt, dried and concentrated. The residue was purified by silica gel column chromatography to give t-butyl 4-(1-hydroxy-3-butenyl)benzoate. Yield: 8.2 g.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH3:47])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH3:47])[CH:42]=[CH:43][N:44]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCC)cc2)CCCN3CCC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCC)cc2)CCCN3CCC)cc1
Reaction time: 1 h
Yield: 65.4 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[[1-propylimidazol-2-yl]methyl]sulfanyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (430 mg) in dichloromethane (10 ml) was added dropwise a 70% solution of 3-chloro-perbenzoic acid (238 mg) in dichloromethane (10 ml) at −78° C. After stirring as such for 1 hour, the dry ice-acetone bath was removed, and an aqueous sodium thiosulfate solution was added with vigorous stirring. The mixture was returned to room temperature and stirred for 30 minutes, after which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous brine, and was dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was separated and purified with basic silica gel column chromatography (hexane:ethyl acetate=1:4→ethyl acetate) and re-crystallized from diisopropyl ether-ethyl acetate to give 8-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[[1-propylimidazol-2-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (288 mg) as yellow crystals (Compound 20).
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([CH2:12][CH2:13][CH:14]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:14][CH2:13][CH2:12][CH:10]2[O:9][N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:11]2)[CH2:26][CH2:25]1
Reactant: O=CCCC1CC(c2ccccc2)=NO1
Reactant: Clc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Clc1ccccc1N1CCN(CCCC2CC(c3ccccc3)=NO2)CC1
Yield: 78.1 %

Procedure:
3-(3-Phenyl-4,5-dihydroisoxazol-5-yl)propanal (20.7 mg, 0.094 mmol), 1-(2-chlorophenyl)piperazine hydrochloride (20.0 mg, 0.086 mmol), molecular sieve (5 beads), NaBH(OAc)3 (54.5 mg, 0.257 mmol) and diisopropylethylamine (26.9 L, 0.085 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 25.8 mg (87.2%) of the target compound was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1[CH:4]=[C:5]([CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH2:24][O:25][CH3:26])=[C:18]([CH3:27])[CH:17]=2)[CH:13]=1)[C:6]([O:8]CC)=[O:7].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCO.CCOC(C)=O>[CH3:28][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]2[CH:17]=[C:18]([CH3:27])[C:19]([O:23][CH2:24][O:25][CH3:26])=[C:20]([CH3:22])[CH:21]=2)[CH:13]=1)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1cc(/C=C/c2cc(C)c(OCOC)c(C)c2)cc(N(C)C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCOc1c(C)cc(/C=C/c2cc(C(=O)O)cc(N(C)C)c2)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.9 %

Procedure:
To a solution of Compound 4 (1.046 g, 2.728 mmol) in THF and EtOH ( 8/4 mL) was added 2 N NaOH (2.728 mL, 5.456 mmol) at room temperature. The reaction mixture was stirred overnight (about 18 hours) at room temperature and diluted with EtOAc and acidified with 5% citric acid. The solution was washed with saturated brine and dried with Na2SO4. The solution was filtered and concentrated. Compound 5 (0.94 g, 97%) was obtained without further purification (TLC indicated a pure compound). 1H-NMR (500 MHz, DMSO-d6) δ 7.47 (s, 1H), 7.31 (s, 2H), 7.12-7.16 (m, 4H), 4.94 (s, 2H), 3.51 (s, 3H), 2.98 (s, 6H), 2.25 (s, 6H); 13C-NMR (125 MHz, DMSO-d6) δ 167.75, 154.18, 150.47, 137.92, 132.56, 131.62, 130.63, 128.12, 127.43, 126.86, 114.89, 114.16, 111.62, 98.51, 56.71, 40.03, 16.55; ESI-MS: m/z (MH+): 356.1856 (calc'd), 356.1854 (found).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11].Cl.Cl[CH2:15][C:16]1[N:17]=[CH:18][S:19][CH:20]=1.[CH3:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1>>[F:11][C:5]1[CH:6]=[C:7]([O:10][CH2:15][C:16]2[N:17]=[CH:18][S:19][CH:20]=2)[CH:8]=[CH:9][C:4]=1[C:3]([N:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[CH2:27][N:23]1[CH2:24][CH2:25][CH2:26][C@H:22]1[CH3:21])=[O:12]
Reactant: ClCc1cscn1
Reactant: COC(=O)c1ccc(O)cc1F
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Agent: Cl
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(OCc2cscn2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedures D and E using 2-fluoro-4-hydroxy-benzoic acid methyl ester [CAS 197507-22-5], 4-(chloromethyl)thiazole hydrochloride [CAS 7709-58-2], and 2-(R)-methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) m/e 404.2
Reaction SMILES: [CH3:1][C:2]1[C:15]([CH3:16])=[CH:14][C:13]2[C:12](=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[NH:18]O)[C:5](=[O:20])[C:4]=2[CH:3]=1.CO.COCCO.Cl>[Zn].O>[CH3:1][C:2]1[C:15]([CH3:16])=[CH:14][C:13]2[C:12](=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[NH2:18])[C:5](=[O:20])[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1C)C(=O)c1c(NO)cccc1C2=O
Agent: Cl
Agent: [Zn]
Solvent: CO
Solvent: O
Solvent: COCCO
Product: Cc1cc2c(cc1C)C(=O)c1c(N)cccc1C2=O
Temperature: 75 °C

Procedure:
50 Parts of 2,3-dimethyl-5-hydroxylaminoanthraquinone was stirred into a mixture of 700 parts of ethyleneglycol monomethyl ether, 200 parts of water and 60 parts of a 35 % aqueous hydrochloric acid, and the mixture was then heated to 75°C. To the mixture there was added little by little 16 parts of zinc dust over 1 hour. The reaction mixture was maintained at 75°C for additional 3 hours, then cooled to 25°C and filtered. The residue was washed with water and dried to obtain 43.6 parts of 2,3-dimethyl-5-aminoanthraquinone of a purity of 95 %.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1.[Cu](C#N)C#N.Cl[Si:16](Cl)([CH3:18])[CH3:17].[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1Br>BrCCBr.CCOCC>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([Si:16]([C:24]2[CH:25]=[CH:26][C:21]([Br:20])=[CH:22][CH:23]=2)([CH3:18])[CH3:17])=[CH:4][CH:5]=1
Reactant: Brc1ccccc1Br
Reactant: C[Si](C)(Cl)Cl
Reactant: Brc1ccc(Br)cc1
Agent: N#C[Cu]C#N
Agent: [Mg]
Solvent: CCOCC
Solvent: BrCCBr
Product: C[Si](C)(c1ccc(Br)cc1)c1ccc(Br)cc1
Yield: 36 %

Procedure:
A 100 mL three-neck flask was equipped with an addition funnel, condenser, and stir bar. The flask was flame dried, flushed with argon and charged with magnesium (1.04 g, 42.8 mmol) and 5 mL of dry ether. A few drops of 1,2-dibromoethane was added to activate the magnesium and caused the ether to reflux. p-Dibromobenzene (10 g, 42.4 mmol) in 40 mL of ether was added dropwise at such a rate as to maintain reflux. After complete addition, the reaction mixture was heated to maintain reflux for an additional five hours. Upon cooling to room temperature copper cyanide (0.1 g, 1.1 mmol) was introduced. The reaction mixture was then cooled to 0 C. and dichlorodimethylsilane (2.55 g, 19.8 mmol) was added dropwise through the addition funnel causing the reaction to warm slightly. The reaction mixture was stirred overnight at room temperature. The product mixture was poured over ice and the organic layer was separated and dried over anhydrous sodium sulfate. The ether was removed by vacuum and a yellow oily solid was recovered. The crude product (5c) was fractionally sublimed under full vacuum. The first fraction contained non-reacted dibromobenzene and 2.6 g (36% yield) of 5c was collected for the second fraction. 1 H NMR (in CDCl3): d, 7.47 ppm 4H; d, 7.32 ppm 4H; s, 0.51 ppm 6H.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH:8]([C:20]2O[C:22](CC)=[CH:23][CH:24]=2)[C:9]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl[CH2:39][CH2:40]Cl>>[CH2:1]([C:3]1[O:7][C:6]2[C:8]3[C:9]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:10]=4[C:11](=[O:12])[NH:13][C:20]=3[CH2:24][CH:23]=[C:22]([CH2:39][CH3:40])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: ClCCCl
Reactant: CCc1ccc(C(c2ccc(CC)o2)c2ccc(OC)cc2C(N)=O)o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCC1=CCc2[nH]c(=O)c3cc(OC)ccc3c2-c2oc(CC)cc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
Under argon, 2-formyl-5-methoxybenzoic acid (10 mmol) and 2-ethylfuran (40 mmol) were dissolved in abs. dioxane (20 ml), and after 10 minutes of stirring at room temperature, conc. perchloric acid (0.3 ml) was added. The resulting reaction mixture was subsequently stirred at 60° C. for 1 h, then poured into water and stirred. Filtration and drying of the resulting precipitate gave 2-[bis(5-ethyl-2-furyl)methyl]-5-methoxybenzoic acid in the form of a colourless solid (60% of theory). 2-[Bis(5-ethyl-2-furyl)methyl]-5-methoxybenzoic acid (10 mmol), dicyclohexylcarbodiimide (2.27 g, 11 mmol) were dissolved in abs. dichloromethane (90 ml) and stirred at room temperature for 10 min. Aqueous ammonia (4 ml) was then added, and the resulting reaction mixture was then stirred at room temperature for 1 h. Filtration, concentration under reduced pressure and subsequent purification by column chromatography (gradient ethyl acetate/n-heptane) of the residue that remained gave 2-[bis(5-ethyl-2-fury))methyl]-5-methoxybenzamide (982 mg, 28% of theory) in the form of a colourless solid. Under argon, abs. 1,2-dichloroethane (10 ml) was added to 2-[bis(5-ethyl-2-furyl)methyl]-5-methoxybenzamide (706 mg, 2 mmol) and p-toluenesulphonic acid bound to macroporous polystyrene resin (2 mmol). The resulting reaction mixture was stirred at a temperature of 100° C. for 1 h, after cooling to room temperature filtered off through Celite and concentrated under reduced pressure. Purification of the residue that remained by column chromatography (gradient ethyl acetate/n-heptane) gave 2,4-diethyl-10-methoxy-6,7-dihydro-8H-furo[2′,3′:3,4]cyclohepta[1,2-c]isoquinolin-8-one (51 mg, 8% of theory) in the form of a colourless solid. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 11.66 (br. s, 1H, NH), 8.31 (d, 1H), 7.68 (d, 1H), 7.38 (dd, 1H), 6.47 (s, 1H), 5.35 (t, 1H), 3.87 (s, 3H), 2.79 (q, 2H), 2.68 (m, 2H), 2.33 (q, 2H), 1.30 (t, 3H), 0.96 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[N:7][C:6]=2[CH:13]=1.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[C:25]=1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:20][C:21]3[S:22][CH:23]=[C:24]([C:33]4[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=4)[C:25]=3[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:12])=[N:7][C:6]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)c1c(-c2ccc(Cl)cc2)csc1N
Reactant: O=C(O)c1nc2cc(Br)ccc2o1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1c(-c2ccc(Cl)cc2)csc1NC(=O)c1nc2cc(Br)ccc2o1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a suspension of 5-bromobenzo[d]oxazole-2-carboxylic acid (2A, 60 mg, 0.25 mmol) in DCM (5 ml) at room temperature was added oxalyl chloride (0.2 ml) and catalytic amount of DMF. The mixture was stirred at room temperature for 17 hours. The solvent was removed under vacuum to dryness. The residue was dissolved in DCM (5 ml) followed be addition of tert-butyl 2-amino-4-(4-chlorophenyl)thiophene-3-carboxylate (1A, 62 mg, 0.2 mmol) and DIEA (0.3 ml). The mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with DCM (5 ml) washed with 1N aqueous HCl (3×5 ml), water (1×5 ml), 1N aqueous NaOH (3×5 ml) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under vacuum to give analytically pure 3A which was used in the next step without further purification. LC-MS: calcd. for C23H18BrClN2O4S: 532 (M+1); found: 532.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[Cl:7][C:8]1[C:12]([S:13][CH2:14][CH3:15])=[N:11][S:10][N:9]=1.[OH2:16]>C1COCC1>[Cl:7][C:8]1[C:12]([S:13]([CH2:14][CH3:15])(=[O:1])=[O:16])=[N:11][S:10][N:9]=1
Reactant: CCSc1nsnc1Cl
Reactant: O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1nsnc1Cl
Reaction time: 8 h

Procedure:
A solution of Oxone (84 g, 0.137 mol) in H2O (400 mL) was rapidly stirred as 3-chloro-4-ethylthio-1,2,5-thiadiazole (12.2 g, 0.067 mol) in THF (200 mL) was added. After stirring overnight, the THF was evaporated and the residue extracted with ether (3×). The extracts were washed with H2O, aqueous NaHCO3, and brine then the solvent dried and evaporated to give a clear liquid (13.6 g). (Compound 4).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:26]=[C:25]([NH2:27])[C:24]([F:28])=[CH:23][N:22]=1>>[F:28][C:24]1[C:25]([NH2:27])=[N:26][C:21]([NH:19][CH2:18][CH:15]2[CH2:14][CH2:13][N:12]([S:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:10])=[O:11])[CH2:17][CH2:16]2)=[N:22][CH:23]=1
Reactant: Nc1nc(Cl)ncc1F
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Product: Nc1nc(NCC2CCN(S(=O)(=O)CCc3ccccc3)CC2)ncc1F

Procedure:
EXAMPLE 95 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 2-chloro-5-fluoro-pyrimidin-4-ylamine: MS (m+1)=394.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][C@H:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][C@H:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:38][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]
Reactant: COc1ccc(C[C@@H]2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: O=C(Br)CBr
Reactant: NCc1ccccc1
Product: COc1ccc(C[C@H]2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1OC

Procedure:
prepared by reaction of (1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with benzylamine
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]P(=O)(OC)OC.[CH3:17][O:18][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][C:23]#[C:24][CH2:25][N:26]1[C:31](=[O:32])[CH2:30][CH2:29][CH2:28][CH:27]1[CH:33]=O>C1COCC1>[CH3:17][O:18][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][C:23]#[C:24][CH2:25][N:26]1[CH:27](/[CH:33]=[CH:5]/[C:4](=[O:3])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:28][CH2:29][CH2:30][C:31]1=[O:32]
Reactant: COC(=O)CCCC#CCN1C(=O)CCCC1C=O
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC(=O)/C=C/C1CCCC(=O)N1CC#CCCCC(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.3 %

Procedure:
Sodium hydride (60% dispersion in oil, 37 mg, 0.91 mmol) was added to a solution of dimethyl 2-oxoheptylphosphonate (217 mg, 0.83 mmol) in THF (4 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 50 min at rt, the solution was recooled to 0° C. and 7-(2-formyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (crude from previous reaction, ˜0.92 mmol) in THF (2 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with acetic acid and water (1:1, 15 mL) and extracted with EtOAc (3×40 mL). The combined organic phase was washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (10%→50% EtOAc/CH2Cl2, gradient) afforded 175 mg (58%) of the title compound.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1>O1CCCC1>[NH2:7][C:4]1[CH:5]=[CH:6][C:1]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13])=[CH:2][CH:3]=1
Reactant: Nc1ccc(N)cc1
Reactant: O=C1C=CC(=O)O1
Solvent: C1CCOC1
Product: Nc1ccc(NC(=O)/C=C\C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
Under a nitrogen atmosphere, into a reaction vessel were charged 25.17 g (0.233 mol) of 1,4-phenylenediamine and 230 ml of tetrahydrofuran. A solution prepared by dissolving 22.84 g (0.233 mol) of maleic anhydride in 50 ml of tetrahydrofuran was dropped into this under cooling with ice over a period of about 1 hour, then, the mixture was stirred at room temperature overnight. After completion of the reaction, the deposited crystal was isolated by filtration, washed twice with 40 ml of tetrahydrofuran, dried at 40° C. for 5 hours, to obtain 46.92 g of coarse (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoic acid as an orange powder. To 46.92 g of coarse (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoic acid was added 250 ml of methanol, and the mixture was stirred at 50° C. for 1 hour and cooled, then, filtrated and washed twice with 20 ml of methanol. The resultant crystal was dried, to obtain 42.67 g of (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoic acid as a yellow-orange powder. Yield: 88.8%.