Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:12]2[CH2:18][CH:17]([CH:19]([CH3:21])[CH3:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:22])=[CH:6][CH:5]=1.O[Li].O.O[NH:38][C:39](=[NH:41])[CH3:40].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([N:11]([CH:12]2[CH2:18][CH:17]([CH:19]([CH3:20])[CH3:21])[CH2:16][CH2:15][NH:14][C:13]2=[O:22])[CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]3[O:33][N:41]=[C:39]([CH3:40])[N:38]=3)=[CH:5][CH:6]=2)(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: CC(=N)NO
Reactant: COC(=O)c1ccc(CN(C2CC(C(C)C)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(-c2ccc(CN(C3CC(C(C)C)CCNC3=O)S(=O)(=O)c3ccc(Cl)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-{[(4-Chloro-benzenesulfonyl)-(5-isopropyl-2-oxo-azepan-3-yl)-amino]-methyl}-benzoic acid methyl ester (0.30 g, 0.60 mmol) was saponified to the acid using LiOH.H2O (0.04 g, 0.90 mmol). The acid (0.10 g, 0.21 mmol) was dissolved in THF (3 ml) and added dropwise to a solution of 1,1-carbonyl diimidazole (CDI, 0.04 g, 0.23 mmol) in THF (0.5 ml). After 30 min, N-hydroxy-acetamidine (0.04 g, 0.23 mmol) was added. A further two equivalents each of CDI and N-hydroxy-acetamidine were added during a further 48 h stirring at r.t. The reaction mixture was concentrated and crude, coupled amidine was purified over silica gel (gradient ethyl acetate to ethyl acetate/methanol 15%): white solid 0.09 g (73%); MS: m/e=535.5 (MH+). Purified amidine (0.08 g, 0.15 mmol) cyclised in the presence of tetrabutylammonium fluoride (1 M, THF 5 ml) over 36 h at r.t. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organice extracts were washed with water, brine, dried (MgSO4), filtered and concentrated under reduced pressure. The concentrated, crude product was purified using preparative RP(C18) chromatography: lyophilisate 15 mg; MS: m/e=517.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[C:22]=3[Cl:28])=[O:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].C(O)=[O:34].O.C(=O)(O)[O-].[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([OH:34])[C:22]=3[Cl:28])=[O:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:29]([F:30])([F:31])[F:32]
Reactant: O=CO
Reactant: O=C(c1ccnc(Cl)c1Cl)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1ccnc(O)c1Cl)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 1 dram vial was charged with 4-chloro-N-[5-chloro-2-(2,3-dichloro-pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (15 mg, 0.028 mmol), formic acid (0.39 mL) and water (0.13 mL). The heterogeneous solution was warmed to 100° C. and stirred overnight. The following day, starting material remained; therefore, an additional 0.26 mL of formic acid was added. The reaction was subsequently warmed to 110° C. and stirred overnight. The resultant mixture was neutralized with saturated aqueous sodium bicarbonate, diluted with EtOAc, and the organic layer washed with saturated sodium bicarbonate. The combined organics were dried with sodium sulfate, concentrated in vacuo, and purified via automated silica gel chromatography to afford the desired hydroxypyridine: 1H NMR (400 MHz, CD3OD) δ 8.26-8.38 (m, 1 H), 8.17-8.20 (m, 2 H), 8.02-8.07 (m, 1 H), 7.72-7.76 (m, 1 H), 7.34-7.37 (m, 1 H), 6.17-6.20 (m, 1 H); MS (ES) (M+H)+ expected 525.9, found 525.9.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=2[O:18][CH3:19])[CH2:3]1>[Pd].C(O)C.[H][H]>[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[C:13]([CH:12]=[CH:11][C:10]=2[O:18][CH3:19])[NH2:15])[CH2:3]1
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])cc1N1C[C@@H](C)N[C@@H](C)C1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)cc1N1C[C@@H](C)N[C@@H](C)C1

Procedure:
cis-3,5-Dimethyl-1-[2-(methyloxy)-5-nitrophenyl]piperazine (D1) (10 g, 38 mmol) and 10% palladium on charcoal were dissolved in ethanol (200 ml) and hydrogenated at room temperature under an atmosphere hydrogen for 16 hours. The mixture was filtered through celite and the filtrate concentrated in vacuo to afford the title product (D2). MS (ES+) m/e 236 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]Br.C(O)C.[S:11]([O-:14])([O-:13])=[O:12].[Na+:15].[Na+]>O>[Na+:15].[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:11]([O-:14])(=[O:13])=[O:12]
Reactant: O=S([O-])[O-]
Reactant: BrCCCCCBr
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])CCCCCBr
Yield: 44.8 %

Procedure:
To a solution of 1,5-dibromopentane (23.2 g, 101 mmol), ethanol (40 mL) and water (40 mL) was dropwise added a solution of sodium sulfite (4.24 g, 33.6 mmol) in water (15 mL) under heating under reflux over 2 hr. After heating under reflux for 2 hr, the solvent was distilled away under reduced pressure and n-hexane/ethanol was added. The precipitated crystals were washed with n-hexane and dried in vacuo to give the title compound (3.81 g, 45%).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].O.[C:12](=[S:15])([S-:14])[NH2:13].[NH4+]>C(O)C>[CH3:9][O:8][C:6]([CH2:5][CH2:4][C:3]1[N:13]=[C:12]([SH:15])[S:14][CH:2]=1)=[O:7]
Reactant: COC(=O)CCC(=O)CBr
Reactant: NC(=S)[S-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)CCc1csc(S)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
To a mixture of methyl 5-bromolevulinate (1.22 g), water (5.2 ml) and ethanol (2.6 ml) was added ammonium dithiocarbamate (642 mg) at room temperature. After stirring at room temperature for 2 hours, the resulting crystal was collected by filtration and washed with a cold mixture of water and ethanol at first and diisopropyl ether (×2) to give 4-(2-methoxycarbonylethyl)-2-mercaptothiazole (0.61 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([NH:11][C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[C:22](=[O:26])[CH:23]([Cl:25])[CH3:24]>ClCCCl>[S:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[NH:11][C:5]1[CH:6]=[CH:7][C:8]([C:22](=[O:26])[CH:23]([Cl:25])[CH3:24])=[CH:9][CH:10]=1
Reactant: CC(Cl)C(=O)Cl
Reactant: c1ccc(Nc2nc3ccccc3s2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(Cl)C(=O)c1ccc(Nc2nc3ccccc3s2)cc1
Temperature: 80 °C
Yield: 96.7 %

Procedure:
Aluminium(III)chloride (0.666 mol) was added portionwise at RT to a solution of N-phenyl-2-benzothiazolylamine (0.222 mol) and 1,2dichloro-1-propanone (0.233 mol) in 1,2-dichloroethane (500 ml) and the mixture was stirred and heated at 80° C. for 2 hours. The mixture was poured into ice and extracted with CH2Cl2. The organic layer was decanted, dried filtered and the solvent was evaporated, yielding 68 g of (±)-1-[4-(2-benzothiazolylamino)phenyl]-2-chloro-1-propanone (95.7%) (interm. 22).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:7]1[N:8]=[C:9]([NH:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:10][CH:11]=1)\[C:4]([OH:6])=[O:5].[C:32]1([C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[N+]=[N-])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(O)(=O)C>ClCCl>[OH:1]/[N:2]=[C:3](/[C:7]1[N:8]=[C:9]([NH:12][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[S:10][CH:11]=1)\[C:4]([O:6][CH:38]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:5]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=C(O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(OC(c1ccccc1)c1ccccc1)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(Z)-2-Hydroxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (4.2 g) as a suspension in dichloromethane (150 ml) was treated with a solution of diphenyldiazomethane (1.91 g) in dichloromethane (50 ml) in a dropwise fashion, over 5 min. After 2 h stirring at room temperature, acetic acid (1 ml) was added and stirred for a further 30 min. The solution was washed with saturated sodium bicarbonate and water, dried and filtered. Removal of solvent in vacuo gave a yellow crisp foam which was purified by chromatography on silica gel eluting with ethyl acetate/hexane. The title compound was obtained as a white solid; νmax (CH2Cl2) 1735, 1520 and 1490 cm-1 ; δH (CDCl3) 6.16 (1H, s), 7.17 (1H, s). 7.22-7.50 (25H, m). [Mass spectrum: +ve ion (thioglycerol) MNa+ (596)].
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:27]([OH:29])=O)[CH2:6][S:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].Cl.C(SCCN)(=O)C.Cl.[C:39]([S:47][CH2:48][CH2:49][NH2:50])(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl.CCOCC>[C:1]([NH:4][C@H:5]([C:27]([NH:50][CH2:49][CH2:48][S:47][C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:29])[CH2:6][S:7][C:8]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: NCCSC(=O)c1ccccc1
Agent: CC(=O)SCCN
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCSC(=O)c1ccccc1
Yield: 62 %

Procedure:
The coupling reaction of 7 (7.41 mmol) is carried out according to Method B described in the first synthetic route (example 1): S-acetylcysteamine hydrochloride was replaced by S-benzoylcysteamine hydrochloride (T. Wieland and E. Bokelman, Ann. Chem., 1952, 576, 20-34. After the various treatments, the expected compound is isolated by flash chromatography on a silica gel column (eluent: CH2Cl2/ether 15%). 12 is collected in the form of a colorless foam with a yield of 62%. Rf (AcOEt/petroleum ether, 7/3): 0.42. [α]D20=+10.8° (c 1.11, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].[CH3:25][O:26][C:27]([C:29]1[CH:34]=[N:33][C:32](Cl)=[CH:31][N:30]=1)=[O:28]>>[CH3:25][O:26][C:27]([C:29]1[CH:34]=[N:33][C:32]([O:9][CH2:8][C:6]2[CH:5]=[CH:4][C:3]([CH:10]([CH3:24])[C:11]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=3)([OH:16])[C:12]([F:15])([F:14])[F:13])=[C:2]([Cl:1])[CH:7]=2)=[CH:31][N:30]=1)=[O:28]
Reactant: CC(c1ccc(CO)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1cnc(Cl)cn1
Product: COC(=O)c1cnc(OCc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cn1

Procedure:
The title compound was prepared in analogy to Example 93, step 7 from 3-(2-chloro-4-hydroxymethyl-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (obtained in Example 120, step 1) by alkylation with methyl-5-chloro-2-pyrazinecarboxylate [CAS Reg. No. 33332-25-1]. MS (m/e)=516.1 [MH+].
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:18][CH2:19][C:20]#[N:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:18][CH2:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)[C@H](CCC#N)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CCc1nnn[nH]1)NC(=O)OCc1ccccc1
Temperature: 85 °C

Procedure:
3.20 g (11.0 mmol) ethyl (2S)-2-(benzyloxycarbonyl-amino)-4-cyano-butyrate are dissolved in 40 ml of toluene and 1.08 g (16.5 mmol) sodium azide and 2.28 g (16.5 mmol) triethylamine-hydrochloride are added. The reaction mixture is heated to 85° C. for 24 hours, cooled to ambient temperature and extracted with water. The combined aqueous phases are acidified to pH 2 with semiconc. hydrochloric acid, the resulting precipitate is suction filtered, washed with water and dried at 50° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([I:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([O:6]C)=O.[NH2:14][CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18].C[Al](C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:11]([I:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([NH:14][CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])=[O:6]
Reactant: CCCC(N)CCC
Reactant: COC(=O)c1cc(Cl)cc(I)c1N
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCC(CCC)NC(=O)c1cc(Cl)cc(I)c1N
Temperature: 100 °C
Reaction time: 16 h
Yield: 315.7 %

Procedure:
Added successively to a solution of 3 g of methyl 2-amino-5-chloro-3-iodobenzoate in 100 cm3 of toluene, under an inert atmosphere and at a temperature close to 20° C., are 2.2 g of 4-aminoheptane then 12 cm3 of a 2M solution of trimethylaluminum in toluene. The reaction mixture is heated, while stirring, for 16 h at 100° C., then it is cooled to 20° C. in order to then be poured over a mixture of 250 g of water/ice and 150 cm3 of ethyl acetate. The suspension obtained is filtered over a Celite 545 pellet. The aqueous phase is extracted with 3 lots of 100 cm3 of ethyl acetate. The organic phases are combined then washed with 100 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 12 g of crude product obtained are purified by flash chromatography over silica (column: 200 g; particle size: 15-40 μm; eluent: 100% dichloromethane). After concentrating the fractions under reduced pressure, 3.21 g of 2-amino-5-chloro-3-iodo-N-(1-propylbutyl)benzamide are obtained.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]([Cl:13])([Cl:12])[C:6]1[N:10]=[C:9](Cl)[S:8][N:7]=1.[CH3:14][N:15]([C:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1)[C:16](=[O:19])[CH2:17][OH:18].O>C(C(C)=O)C(C)C>[CH3:14][N:15]([C:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1)[C:16](=[O:19])[CH2:17][O:18][C:9]1[S:8][N:7]=[C:6]([C:5]([Cl:13])([Cl:12])[Cl:4])[N:10]=1
Reactant: Clc1nc(C(Cl)(Cl)Cl)ns1
Reactant: CN(C(=O)CO)C1=CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CN(C(=O)COc1nc(C(Cl)(Cl)Cl)ns1)C1=CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
3.1 g (0.07 mol) of lithium hydroxide hydrate are added in portions, at 0° C., to 16.7 g (0.07 mol) of 3-trichloromethyl-5-chloro-1,2,4-thiadiazole and 11.8 g (0.07 mol) of hydroxyacetic acid N-methyl-N-cyclohex-1-enylamide in 100 ml of methyl isobutyl ketone, and the mixture is stirred for 30 minutes at 0° C. and then overnight at 25° C. After water has been added, the reaction product which separates out as a solid is filtered off under suction, washed and dried. 22.0 g (84.8% of theory) of 3-trichloromethyl-1,2,4-thiadiazol-5-yl-oxyacetic acid N-methyl-N-cyclohexen-1-yl-amide are obtained in the form of beige-colored crystals of melting point 78° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])([C:6]#[CH:7])[CH3:5].[Li]CCCC.[C:16]([C:18]1[CH:29]=[CH:28][C:21]([C:22](N(OC)C)=[O:23])=[CH:20][CH:19]=1)#[N:17]>C1COCC1>[CH3:5][C:4]([O:3][Si:2]([CH3:10])([CH3:9])[CH3:1])([CH3:8])[C:6]#[C:7][C:22]([C:21]1[CH:28]=[CH:29][C:18]([C:16]#[N:17])=[CH:19][CH:20]=1)=[O:23]
Reactant: CON(C)C(=O)c1ccc(C#N)cc1
Reactant: C#CC(C)(C)O[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C#CC(=O)c1ccc(C#N)cc1)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 133.1 %

Procedure:
To a −78° C. stirred solution of trimethyl (2-methylbut-3-yn-2-yloxy) silane (3.3 g, 20.00 mmol) in dry THF (45 mL), n-BuLi (4.1 mL, 9.00 mmol, 1.6 M in hexane) was added dropwise over 10 minutes under an inert atmosphere. The reaction mixture was stirred for 30 min at −78° C., and then a solution of 4-cyano-N-methoxy-N-methylbenzamide (2.0 g, 10.00 mmol) in dry THF (15 mL) was added to the reaction mixture and stirring was continued for an additional 1 h at −78° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 15% EtOAc in hexanes to afford 4-(4-methyl-4-(trimethylsilyloxy)pent-2-ynoyl)benzonitrile (3.8 g, 68%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([O:10]CC)=[O:9])=[CH:4][N:5]=[N:6][CH:7]=1.[OH-].[Na+].Cl>O.C1COCC1>[CH3:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[CH:4][N:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cnncc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnncc1C(=O)O
Temperature: 60 °C
Reaction time: 1 h
Yield: 185.1 %

Procedure:
To a solution of ethyl 5-methylpyridazine-4-carboxylate (240 mg, 1.4 mmol) in H2O/THF was added 7.5 N aq. NaOH (1.25 eq, 0.25 mL) and the mixture was stirred for 1 hour at 60° C. Concentrated HCl was added to pH 2 and subsequently the volatiles were removed in vacuo. The residue was first stirred with EtOAc and the solids were collected by filtration. Then stirred with THF and the solids were again collected by filtration. The solids were extracted with MeOH and removal of the volatiles afforded 5-methylpyridazine-4-carboxylic acid (358 mg) as a brown solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Br:9][CH2:10][CH2:11]Br.[OH-].[K+]>CO>[Br:9][CH2:10][CH2:11][O:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1
Reactant: BrCCBr
Reactant: Oc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1cccc(OCCBr)c1

Procedure:
A mixture of resorcinol (88 g), 1,2-dibromoethane (180 g) and potassium hydroxide (44.8 g) was stirred under reflux in methanol (600 ml) for 24 hours. The reaction mixture was cooled. The residual solid was removed by filtration and the filtrate was evaporated to give 3-(2-bromoethoxy)phenol as an oil which was essentially pure as indicated by thin layer chromatography (tlc) [using silica plates and 10% v/v methanol in dichloromethane as eluant] and was used without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>C(O)(=O)C.O.[Zn]>[Br:19][C:7]1[CH:6]=[C:5]([NH2:8])[C:4]([NH2:9])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(N)c(N)cc1Br
Reaction time: 2.5 h
Yield: 83.2 %

Procedure:
To the solution of 4-methyl-2-nitro-phenylamine (1 g, 1 eq.) in 15 mL of acetic acid was added NBS (1.4 g, 1.2 eq.). The reaction was allowed to stir for 2.5 hours. Reaction was then diluted with 15 mL of water and Zn dust (1.29 g, 3 eq.) was added. Reaction was stirred for 1 hour, filtered and then pH was adjusted to ˜7 with ammonia. The aqueous layer was extracted with CH2Cl2 twice, dried over Na2SO4, concentrated and adsorbed on silica. Purification by flash column chromatography (60:40 hexanes/EtOAc) afforded 1.1 g (83 %) of product as off-white solid. MS (electrospray): mass calculated for C7H9BrN2, 201.06; m/z found 202.2, [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:18])[C@H:5]([CH3:17])[NH:6]C(OCC1C=CC=CC=1)=O)[CH3:2].[BrH:19].CCOCC>C(O)(=O)C>[BrH:19].[CH2:1]([NH:3][C:4](=[O:18])[C@H:5]([CH3:17])[NH2:6])[CH3:2]
Reactant: CCNC(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCNC(=O)[C@H](C)N

Procedure:
10 g (0.04 mol) of N-benzyloxycarbonyl-L-alanine ethylamide were stirred for 1 hour in 50 ml of 4-N hydrobromic acid in acetic acid. To the solution were added 300 ml of dry ether and, after stirring for a few minutes, the white solid was allowed to settle and the ether decanted from the solid. The yield of L-alanine ethylamide hydrobromide obtained was 8.0 g (96.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]=[O:13].[H-].[Na+].CI.[C:18](=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:18])[CH:7]=[C:6]2[CH:12]=[O:13]
Reactant: O=C([O-])O
Reactant: COc1ccc2[nH]cc(C=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(C=O)cn2C
Yield: 99 %

Procedure:
5-Methoxyindole-3-carboxaldehyde (300 mg, 1.71 mmol) was added in portions over 5 min to a suspension of sodium hydride (82 mg, 2.05 mmol, 60% dispersion in mineral oil) in DMF (8 mL) stirring under argon. The mixture was stirred for 30 min, methyl iodide (0.13 mL, 2.05 mmol) was added and the mixture was stirred for 1 h. Sodium bicarbonate (10%, 40 mL) was added and the mixture was extracted with EtOAc (4×). The combined organic layers were washed with sodium bicarbonate (10%, 2×) and saturated NaCl, dried (MgSO4), filtered and evaporated. Column chromatography of the crude product (50:50 EtOAc:hexanes) afforded 43 (320 mg, 99%) as a light yellow solid; Rf=0.35 (50:50 EtOAc:hexanes); mp=130–1320C; lit mp=132–133° C.53; 1H NMR (CDCl3): δ 9.95 (s, 1H), 7.79 (d, 1H, J=2.4 Hz), 7.62 (s, 1H), 7.25 (d, J=8.8 Hz), 6.96 (dd, 1H, J=2.4 and 8.9 Hz), 3.90 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: CO[C:3]1[C:4](=[O:10])[C:5](=[O:9])[C:6]=1[O:7][CH3:8].Cl.[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C.Cl>CO>[CH3:8][O:7][C:6]1[C:5](=[O:9])[C:4](=[O:10])[C:3]=1[NH:12][C:13]1[CH:14]=[C:15]([CH:19]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: COc1c(OC)c(=O)c1=O
Reactant: COc1ccc(C(NC(=O)c2ccccc2)c2cccc(N)c2)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC(=O)c2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Reaction time: 0.17 h
Yield: 75.9 %

Procedure:
3,4-dimethoxy-3-cyclobutene-1,2-dione (428 mg) was added to a solution of N-[(3-aminophenyl)-(4-methoxyphenyl)methyl]benzamide hydrochloride (555 mg) [prepared as described in step (d) above] in methanol (15 ml) at ambient temperature. After stirring for 10 minutes, a solution of triethylamine (153 mg) in methanol (10 ml) was added dropwise to the mixture. This mixture was stirred at ambient temperature for 1 hour. The reaction mixture was then slightly acidified with hydrochloric acid (0.5N) and extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column using a 1:1 by volume mixture of hexane and ethyl acetate as the eluant, to afford the title compound (505 mg) as a white foamy solid.