Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(O)[CH:8]=[C:6]([CH3:7])[CH:5]=[C:3]([OH:4])[CH:2]=1.[CH2:10]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH2:17]([N:16]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:1]1[CH:2]=[C:3]([OH:4])[CH:5]=[C:6]([CH3:7])[CH:8]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Cc1cc(O)cc(O)c1
Reactant: CCCCCCNCCCCCC
Product: CCCCCCN(CCCCCC)c1cc(C)cc(O)c1

Procedure:
Orcinol (5-resorcinol) was aminized by di-n-hexylamine, so as to obtain 1-di-n-hexylamino-3-methyl-5-hydroxybenzene. The hydroxy group thereof was etherized with methyl iodide, and then nitrosoized so as to obtain 1-di-n-hexylamino-3-methyl-4-nitroso-5-methoxybenzene.
Reaction SMILES: [Al].[Pb](Br)Br.Cl.[Cl:6][C:7]1[CH:12]=[C:11]([CH:13](O)[C:14](Cl)([Cl:16])[Cl:15])[CH:10]=[CH:9][C:8]=1[OH:19]>CO>[Cl:6][C:7]1[CH:12]=[C:11]([CH:13]=[C:14]([Cl:16])[Cl:15])[CH:10]=[CH:9][C:8]=1[OH:19]
Reactant: Oc1ccc(C(O)C(Cl)(Cl)Cl)cc1Cl
Agent: Br[Pb]Br
Agent: Cl
Agent: [Al]
Solvent: CO
Product: Oc1ccc(C=C(Cl)Cl)cc1Cl
Yield: 87 %

Procedure:
Aluminium (3.64 g, 0.089 mol), leadbromide (2.23 g, 0.0089 mol) and 36% HCl (15.13 ml, 0.178 mol) were added to 200 ml of methanol, the mixture was stirred, and 2-chloro-4-(2,2,2-trichloro-1-hydroxyethyl)phenol (24.55 g, 0.089 mol) obtained in Step 1 was added thereto. The mixture was stirred at 60° C. for 4 hours. The solvent was removed therefrom under a reduced pressure. Ice was added to the reaction mixture and resulting mixture was washed three times with n-hexane and ether (1:1). The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (ethyl acetate:n-hexane=1:4) to obtain the title compound (17.3 g, 87%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([O:9][CH3:10])[CH2:7][CH3:8].[CH3:11][CH:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH2:14][C:13]1=[O:19]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([O:9][CH3:10])[CH2:7][CH3:8].[O:18]=[C:17]([CH2:12][CH3:11])[CH2:16][CH2:15][CH2:14][C:13]([OH:19])=[O:9]
Reactant: CC1C(=O)CCCC1=O
Agent: CCC(CCCCBr)OC
Product: CCC(=O)CCCC(=O)O

Procedure:
1-Bromo-5-methoxyheptane (Compound XX) is a reagent used for preparing preferred compounds X and XX. Compound XX is prepared in accordance with Reaction Scheme 3, starting from commercially available 2-methyl-1,3-cyclohexanedione. Thus, with reference to Reaction Scheme 3, 2-methyl-1,3-cyclohexanedione is reacted with base (Ba(OH)2) to yield 5-oxoheptanoic acid (Compound XXI). The oxo function of 5-oxoheptanoic acid (Compound XXI) is thereafter reduced, and the resulting hydroxy group, as well as the carboxylate function, are methylated to give methyl 5-methoxyheptanoate (Compound XXII). The carboxylate group of the latter is reduced (LiAlH4) to give 5-methoxy-1-heptanol (Compound XXIII), which is thereafter reacted with carbontetrabromide to yield 1-bromo-5-methoxyheptane (compound XX). ##STR6##
Reaction SMILES: C1(S([NH:10][C:11]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:12]=2/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])(=O)=O)C=CC=CC=1.Br[CH2:28][C:29]([C:31]1[CH:36]=[C:35]([CH2:37][CH3:38])[CH:34]=[CH:33][N:32]=1)=[O:30]>>[CH3:18][O:17][C:15](=[O:16])[CH2:14][C:13]1[C:12]2[C:11](=[CH:22][CH:21]=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:19]=2)[NH:10][C:28]=1[C:29]([C:31]1[CH:36]=[C:35]([CH2:37][CH3:38])[CH:34]=[CH:33][N:32]=1)=[O:30]
Reactant: CCc1ccnc(C(=O)CBr)c1
Reactant: COC(=O)/C=C/c1cc(C(F)(F)F)ccc1NS(=O)(=O)c1ccccc1
Product: CCc1ccnc(C(=O)c2[nH]c3ccc(C(F)(F)F)cc3c2CC(=O)OC)c1

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-2-phenylsulfonylamino-5-(trifluoromethyl)cinnamate (step 2 of Example 151) and 2-bromoacetyl-4-ethylpyridine (Preparation is described in Example 57).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([S:6]([O-:8])=[O:7])=[CH:2]1.[Na+].Br[C:11]1[CH:19]=[CH:18][C:17]2[N:16]([CH3:20])[C:15]3[CH2:21][CH:22]4[NH:26][CH:25]([C:14]=3[C:13]=2[C:12]=1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24][CH2:23]4>>[S:1]1[CH:5]=[CH:4][C:3]([S:6]([C:11]2[CH:19]=[CH:18][C:17]3[N:16]([CH3:20])[C:15]4[CH2:21][CH:22]5[NH:26][CH:25]([C:14]=4[C:13]=3[C:12]=2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24][CH2:23]5)(=[O:8])=[O:7])=[CH:2]1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Reactant: O=S([O-])c1ccsc1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccsc4)ccc31)C1CCC(C2)N1
Yield: 31 %

Procedure:
Intermediate 25 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude material was purified by flash column chromatography (SiO2, hexane/ethyl acetate 55:45) to give tert-butyl 2-(3-thienyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (130 mg, 31%) as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.20 (s, 1H), 8.02-8.53 (m, 1H), 7.66-7.74 (m, 1H), 7.28-7.37 (m, 3H), 5.26 (br s, 1H), 4.70 (br s, 1H), 3.61 (s, 3H), 3.38 (br s, 1H), 2.50 (d, J=15.9 Hz, 1H), 2.12-2.41 (m, 2H), 1.89-2.00 (m, 1H), 1.57-1.68 (m, 1H), 1.48 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>C1COCC1.CCOC(C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:19]([C:18]2[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=2)[OH:20])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,4-dibromobenzene (42.4 mmol, 10 g) in THF (100 mL) at −78° C. was added dropwise n-BuLi (42.4 mmol, 2 M in hexane). The mixture was stirred at −78° C. for 0.5 h., 4-fluorobenzaldehyde (42.4 mmol, 5.3 g) was added. The mixture was stirred at −78° C. for 1 h and then warmed to r.t. The reaction mixture was diluted with EtOAc, washed with NaHCO3 and brine. The organic extract was dried (anhyd. MgSO4) and concentrated under reduced pressure to give an oil. Chromatography gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[I:12].N([O-])=O.[Na+].[N-:17]=[N+:18]=[N-].[Na+]>C1COCC1.Cl.O>[N:1]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[I:12])=[N+:17]=[N-:18]
Reactant: COC(=O)c1ccc(N)c(I)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: [N-]=[N+]=Nc1ccc(C(=O)O)cc1I
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To a solution of methyl 4-amino-3-iodobenzoate (10.0 g, 36.1 mmol) in THF (200 ml), 1M hydrochloric acid (75 ml) and water (300 ml) was added sodium nitrite (2.5 g, 36.1 mmol) under ice-cooling, and the mixture was stirred for 30 min. Sodium azide (2.5 g, 36.1 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 6 hr and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (370 ml), 8M aqueous sodium hydroxide solution (20 ml) and water (30 ml), and the reaction mixture was stirred at room temperature for 18 hr. Methanol was evaporated under reduced pressure, and the obtained residual aqueous solution was acidified (pH<3) with 6M hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration, washed with water and dried to give the title compound as a pale-yellow powder (9.05 g, 95%).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC>O>[CH2:1]([NH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)(=[O:13])=[O:14])[CH3:2]
Reactant: CC(=O)N[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCN[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(C)cc1

Procedure:
Twenty-three grams of trans-N-(2-ACETAMIDOCYCLOHEXYL)-p-TOLUENESULFONAMIDE was added in portions to a stirred suspension of 7 grams of lithium aluminium hydride and 500ml of anhydrous ether. The mixture was stirred and refluxed for 17 hours. The mixture was decomposed by dropwise addition of water and filtered. The filter cake was extracted with a total of 750 ml of boiling ethyl acetate. The organic portions were combined, dried over magnesium sulfate, then evaporated to dryness. The residue was slurried with ether and filtered. On recrystallization from ether there was obtained trans N-(2-ETHYLAMINOCYCLOHEXYL)-p-TOLUENESULFONAMIDE, mp. 112-4°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[CH3:17][N:18]([CH3:32])[C:19]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH:22]2[CH2:21][CH2:20][C:19]([N:18]([CH3:32])[CH3:17])([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:24][CH2:23]2)[CH2:15][CH:16]=1
Reactant: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)C1(c2ccccc2)CCC(N2CC=C(c3c[nH]c4ccc(Cl)cc34)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-chloro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (170 mg, 0.79 mmole) and 4-dimethylamino-4-phenylcyclohexanone (171 mg, 0.79 mmole) were dissolved in dry 1,2-dichloro-ethane (10 ml). Glacial acetic acid (0.79 mmole) and sodium triacetoxy boron hydride (300 mg, 1.4 mmole) were added to this mixture. The reaction mixture was then stirred for 24 hours at RT. The reaction mixture was worked up by distilling off the 1,2-dichloroethane and diluting with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (4×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The diastereoisomer mixture was obtained as a colourless solid in a yield of 340 mg (100%).
Reaction SMILES: [OH-].[K+].O.[C:4]1([SH:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]1([N:17]2[CH2:22][C:21]3[C:23]4[C:32]([C:33](Cl)=[CH:34][C:20]=3[N:19]=[CH:18]2)=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=4)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C)C=O>[C:11]1([N:17]2[CH2:22][C:21]3[C:23]4[C:32]([C:33]([S:10][C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=5)=[CH:34][C:20]=3[N:19]=[CH:18]2)=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=4)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cc2c(c3cc4ccccc4cc13)CN(c1ccccc1)C=N2
Reactant: Sc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: C1=Nc2cc(Sc3ccccc3)c3cc4ccccc4cc3c2CN1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 40 parts of potassium hydroxide in 60 parts of water is added to a solution of 66 parts of thiophenol in 1,000 parts of dimethylformamide and 171 parts of 2-phenyl-6-chloroanthrapyrimidine are then introduced. The mixture is stirred for 16 hours at room temperature and afterwards for a further hour at 50°-60°C. After cooling to room temperature, the colorant, which has precipitated in orange crystalline platelets, is filtered off, washed with DMF and alcohol and dried at 80°-90°C in vacuo. 194 parts (93.2% of theory) are obtained of 2-phenyl-6-phenylmercaptoanthrapyrimidine, which dyes polyester in bulk in fast, yellow shades.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:10]/[S@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])/[CH3:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][S@:11]([C:13]([CH3:14])([CH3:16])[CH3:15])=[O:12])[CH3:9])=[CH:6][CH:7]=1
Reactant: C/C(=N\[S@@](=O)C(C)(C)C)c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](N[S@@](=O)C(C)(C)C)c1ccc(Br)cc1
Temperature: -50 °C

Procedure:
(S,E)-N-(1-(4-bromophenyl)ethylidene)-2-methylpropane-2-sulfinamide (0.5 g, 1.66 mmol) was dissolved in THF/H2O=50:1 (10 mL) and cooled to −50° C. Then NaBH4 (0.19 g, 4.97 mmol) was added. The resulting mixture was warmed to RT over 3 h and then concentrated. The residue was purified by column chromatography to afford the titled compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][C:11]1=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:24]([O:26]C=O)C>C(COC)OC>[CH:24]([CH:17]([CH2:16][C:13]1[CH:14]=[CH:15][N:10]([CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:11](=[O:23])[CH:12]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:26]
Reactant: CCOC=O
Reactant: CCOC(=O)CCc1ccn(Cc2ccccc2)c(=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1ccn(Cc2ccccc2)c(=O)c1
Temperature: 0 °C
Yield: 67.7 %

Procedure:
To a cooled (0° C.), stirred suspension of 50% sodium hydride in oil (6.37 g) in dimethoxyethane (80 ml) was added dropwise over 25 minutes a mixture of ethyl β-(N-benzyl-2-oxo-4-pyridyl)propionate (30.29 g) and ethylformate (11.80 g), whilst maintaining the reaction temperature between 5°-8° C. The reaction mixture was allowed to warm slowly to room temperature overnight and then was poured on to ice. A brown solution formed which was extracted successively with petroleum ether (40°-60° C.) (60 ml) and diethyl ether (70 ml). The combined organic extracts were washed with water. The combined aqueous layer and aqueous washings were taken to pH 5 with glacial acetic acid. The solution was cooled whereupon a solid appeared which was collected by filtration, washed with water, washed with ethyl acetate and dried in vacuo to yield ethyl α-formyl-β-(N-benzyl-2-oxo-4-pyridyl)propionate (22.52 g), m.p. 140°-143° C.
Reaction SMILES: [Cl-].[NH4+].[F:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([F:13])[C:5]=1[N:14]1[CH2:18][CH:17]=[CH:16][CH2:15]1>CCO.O.[Fe]>[N:14]1([C:5]2[C:4]([F:3])=[CH:9][C:8]([NH2:10])=[CH:7][C:6]=2[F:13])[CH2:18][CH:17]=[CH:16][CH2:15]1
Reactant: O=[N+]([O-])c1cc(F)c(N2CC=CC2)c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(F)c(N2CC=CC2)c(F)c1
Yield: 99.2 %

Procedure:
Ammonium chloride (1.18 g, 22.1 mmol) is added to a mixture of 1-(2,6-difluoro-4-nitrophenyl)-2,5-dihydro-1H-pyrrole (Step 1, 0.5 g, 2.21 mmol) dissolved in EtOH/water (2:1, 18.0 mL) and heated to reflux. Iron powder (0.37 g, 6.63 mmol) is added in portions over one hour. After refluxing for another 45 min, the reaction mixture is cooled, filtered, and extracted three times with dichloromethane. The organic layers are washed with saline, dried (MgSO4) and concentrated to provide the title compound (0.43 g, >95%), MS (m/z): [N+H]+=197; 1H NMR (300 MHz, CDCl3): δ 3.63 (bs, 2H), 4.10 (s, 4H), 5.84 (s, 2H), 6.17 (d, 2H).
Reaction SMILES: C1(NC(=[S:10])NC)CCCC1.[CH:11]1([N:17]=[C:18]=[N:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>O1CCOCC1>[CH:20]1([NH:19][C:18]([NH:17][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[S:10])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CNC(=S)NC1CCCC1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: S=C(NC1CCCCC1)NC1CCCCC1

Procedure:
2.44 g of N-[4 -(β-<2-methoxy-5-methyl-benzamido>-ethyl)-benzenesulfonyl]-N'-cyclopentyl-methyl-thio-urea (I) were dissolved together with 1.03 g of dicyclohexylcarbodiimide in 20 ml of hot dioxane. The whole was allowed to cool and to stand for several days. Thereupon, the N,N'-dicyclohexyl-thiourea that had formed (melting point 176° - 178° C) was filtered off with suction. The filtrate which contained the N-[4-(β-<2-methoxy-5-methyl-benzamido>ethyl)-benzenesulfonyl]-N'-cyclopentyl-methyl-carbodiimide (II) in dissolved state, was combined with about 5 ml of water. The whole was shortly heated on a water bath and concentrated. The residue was dissolved in a mixture of toluene, ether and dilute aqueous ammonia, while shaking. The aqueous phase was separated. The toluene/ether phase was extracted again with dilute ammonia. The aqueous extracts were united and acidified. There was obtained a precipitate, constituting the N-[4-(β-<2-methoxy-5-methyl-benzamido>-ethyl)-benzenesulfonyl]-N'-cyclopentylmethylurea (III). After recrystallization from methanol, the sulfonylurea was found to melt at 148° - 150° C.
Reaction SMILES: O1CCCC1.[OH-].[Na+].[CH:8]1([C:14]2[CH:45]=[CH:44][C:17]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[N:27]=[C:28]([N:31]([CH2:33][C:34]5[CH:43]=[CH:42][C:37]([C:38]([O:40]C)=[O:39])=[CH:36][CH:35]=5)[CH3:32])[S:29][CH:30]=4)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Cl>O.CO>[CH:8]1([C:14]2[CH:45]=[CH:44][C:17]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[N:27]=[C:28]([N:31]([CH2:33][C:34]5[CH:35]=[CH:36][C:37]([C:38]([OH:40])=[O:39])=[CH:42][CH:43]=5)[CH3:32])[S:29][CH:30]=4)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)c1ccc(CN(C)c2nc(-c3ccc(OCc4ccc(C5CCCCC5)cc4)cc3)cs2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(Cc1ccc(C(=O)O)cc1)c1nc(-c2ccc(OCc3ccc(C4CCCCC4)cc3)cc2)cs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
Tetrahydrofuran (250 ml), methanol (250 ml) and a 2N-aqueous sodium hydroxide solution (95.0 ml, 190 mmol) were added to methyl 4-(N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylaminomethyl)benzoate (50.0 g, 94.9 mmol) obtained in Example 2(4), and the mixture was heated under reflux for 40 min under an argon atmosphere. Water (310 ml) was added to the reaction mixture and the mixture was cooled to room temperature. 2N-Hydrochloric acid (95.0 ml, 190 mmol) was added dropwise and the mixture was stirred for 90 min. The resulting crystals were collected by filtration, washed with water (700 mL) and dried to give the title compound (48.5 g, yield 99.7%).
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][CH:3]1[CH:11]=[CH:10][CH2:9][CH2:8][CH:4]1[C:5]([OH:7])=O.[CH:14]([NH2:17])([CH3:16])[CH3:15].C>C(O)C>[CH:14]([N:17]1[C:1](=[O:13])[CH2:2][C:3]2[CH2:11][CH2:10][CH2:9][CH2:8][C:4]=2[C:5]1=[O:7])([CH3:16])[CH3:15]
Reactant: O=C(O)CC1C=CCCC1C(=O)O
Reactant: CC(C)N
Agent: C
Solvent: CCO
Product: CC(C)N1C(=O)CC2=C(CCCC2)C1=O
Temperature: 25 °C

Procedure:
A mixture of tetrahydrohomophthalic acid (92 g., 0.5 mole) and isopropylamine (59 g., 1 mole) is heated by an oil bath until molten for 90 minutes. The hot mixture is then poured into 600 ml. of ethanol, treated with carbon black and filtered. The mixture is concentrated to about 300 ml. and slowly cooled to room temperature. 2-Isopropylisoquinoline-1,3(2H,4H)-dione precipitates and is collected by filtration.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.O>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: COc1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)nc(Cl)nc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(Nc2nc(Cl)nc3c2c(I)cn3S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 110 °C
Reaction time: 20 h
Yield: 83.3 %

Procedure:
A mixture of 2,4-dichloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (260 mg, 0.556 mmol), p-anisidine (75 mg, 0.610 mmol) and DIEA (0.300 mL, 1.72 mmol) in dioxane (5 mL) was stirred at 110° C. for 20 h. Water and EtOAc were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 2-chloro-5-iodo-N-(4-methoxyphenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (257 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].[CH3:8][Si:9](Cl)([CH3:11])[CH3:10].C(N(CC)CC)C.O>C1COCC1.CCOCC>[CH3:8][Si:9]([CH3:11])([CH3:10])[O:1][CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4]
Reactant: C[Si](C)(C)Cl
Reactant: O=C1OCCC1O
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)OC1CCOC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.1 %

Procedure:
A solution of 10.0 g (98 mmol) of α-hydroxy-γ-butyrolactone in 100 mL of anhydrous THF under argon was cooled to 0-5° C. with magnetic stirring. Addition of 14 mL (110 mmol) of trimethylsilyl chloride and 16 mL (115 mmol) of triethylamine immediately produced a white precipitate. The suspension was warmed to room temperature and stirred for 4 hours. The suspension was poured into a separatory funnel containing 100 mL of H2O and 500 mL of ether. The organic layer was washed with 50 mL of H2O, 50 mL of brine, dried (MgSO4) and concentrated. Purification (Kugelrohr distillation) provided 14.7 g (90% yield) of α-trimethylsilyloxy-γ-butyrolactone bp 80-100° C. (8 mm Hg).
Reaction SMILES: [C:1]([C:7]([O:9][CH3:10])=[O:8])#[C:2][C:3]([O:5][CH3:6])=[O:4].[F:11][C:12]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>CO>[F:11][C:12]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:13]=1/[N:14]=[C:2](\[CH2:1][C:7]([O:9][CH3:10])=[O:8])/[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Cc1cccc(N)c1F
Solvent: CO
Product: COC(=O)C/C(=N\c1cccc(C)c1F)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
At 0° C., dimethyl acetylenedicarboxylate (8.70 mL, 70.4 mmol) was added dropwise to a solution 2-fluoro-3-methylaniline (7.34 g, 58.7 mmol) in MeOH (58.7 mL). After stirring at room temperature overnight, the reaction mixture was concentrated to dryness. The residue was purified by silica gel flash chromatography (gradient 0-60% EtOAc/Hexanes) to give (E)-dimethyl 2-(2-fluoro-3-methylphenylimino)succinate (7-14, 14.59 g, 93%). LRMS m/z (M+H)+ 268.3 found, 268.1 required.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])([O-:3])=[O:2].[H-].[Na+].[CH3:19][O:20][CH2:21][CH2:22]Br>CN(C=O)C.C(OCC)(=O)C>[CH3:19][O:20][CH2:21][CH2:22][N:10]1[C:11]2[C:7](=[CH:6][C:5]([C:13]([F:16])([F:14])[F:15])=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[CH:9]1
Reactant: COCCBr
Reactant: O=[N+]([O-])c1cc2[nH]ccc2cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCn1ccc2cc(C(F)(F)F)c([N+](=O)[O-])cc21
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
6-nitro-5-(trifluoromethyl)-1H-indole (50 mg, 0.22 mmol) was dissolved in DMF (2 mL) and treated with sodium hydride (35 mg, 0.87 mmol) to form a dark red opaque solution. The solution was stirred for 20 minutes and then added dropwise to a solution of 2-bromoethyl methyl ether (121 mg, 82 μL, 0.87 mmol) in 1 mL DMF. The reaction mixture was heated at 50° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with 50% saturated NaHCO3 (2×10 mL) and brine. The organic layer was dried over Na2SO4, filtered and dried to obtain 1-(2-methoxyethyl)-6-nitro-5-(trifluoromethyl)-1H-indole, which was used in the next step without further purification.