Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[ClH:3].[NH2:4][C@@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:17]CC3C=CC=CC=3)[C:11]=2[C:15]#[N:16])[C@H:6]1[OH:25]>[H][H].[Pd]>[ClH:3].[NH2:4][C@@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:17])[C:11]=2[C:15]#[N:16])[C@H:6]1[OH:25]
Reactant: [H][H]
Reactant: N#Cc1c(OCc2ccccc2)ccc2c1CC[C@@H](N)[C@@H]2O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N#Cc1c(O)ccc2c1CC[C@@H](N)[C@@H]2O

Procedure:
In 20 ml. of methanol is dissolved 200 mg. of trans-2-amino-6-benzyloxy-5-cyano-1-hydroxy-1,2,3,4-tetrahydronaphthalene hydrochloride, followed by the addition of 30 mg. of 5% palladium-on-carbon. The mixture is agitated in hydrogen streams at room temperature for 30 minutes. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is recrystallized from methanol-ethyl acetate. The procedure yields white crystals of trans-2-amino-5-cyano-1,6-dihydroxy-1,2,3,4-tetrahydronaphthalene hydrochloride. Yield 136 mg.; melting point: 259°-261° C(decomp.).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8][OH:9])=[CH:5][CH:4]=1)#[N:2].ClN1C(=O)CCC1=O.[CH:20]([CH2:22][C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24])=[CH2:21].C(N(CC)CC)C.Cl>O.CN(C=O)C>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]2[CH2:21][CH:20]([CH2:22][C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24])[O:9][N:8]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: C=CCC(=O)OCC(C)C
Reactant: N#Cc1ccc(C=NO)cc1
Agent: Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)COC(=O)CC1CC(c2ccc(C#N)cc2)=NO1
Temperature: 4 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of DMF (262.0 L), 4-cyanobenzaldoxime (46 kg, 342.1 mol), and N-chlorosuccinimide (54 kg, 389.4 mol) was added isobutyl vinylacetate (95 kg. 665.7 mol). The solution was cooled to 2-6° C., and triethylamine (40 kg. 388.6 mol) was slowly added over a period of 4 h. The reaction was stirred at the same temperature for an addition 1 h. Water (330.0 L) and hydrochloric acid (1 N, 49 L) were added. The crude product was collected by filtration, washed with water (555.0 L), and redissolved in toluene (500.0 L, 40° C.). The organic layer was washed with water (291.0 L) and dried by azeotropic distillation (removing about 250 L of toluene). Heptane (300.0 L) was added, and the reaction was cooled at 0-5° C. for 3 h. The product was collected by filtration and washed with toluene/heptane (150.0 L, 1/2 ratio). The product was dried under vacuum at 55-60° C. to constant weight: 81.8 kg, 90% yield, mp 98-100° C.; 1H NMR (CDCl3) ∂ 0.96 (6H), 1.96 (1H), 2.70 (1H), 2.92 (1H), 3.15 (1H), 3.56 (1H), 3.90 (2H), 5.20 (1H), 7.70 (2H), 7.80 (2H). Anal. Calcd. for C16H18N2O3: C, 67.12; H, 6.34; N. 9.78. Found: C, 67.06; H, 6.20; N, 9.76.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([NH:24][CH2:25][CH:26]=[CH2:27])[C:20](OC)=[O:21])=[CH:15][CH:14]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:20](=[O:21])[CH:19]([C:16]3[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=3)[N:24]([CH2:25][CH:26]=[CH2:27])[C:10]2=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CCNC(C(=O)OC)c1ccc(O)cc1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: C=CCN1C(=O)N(c2ccc(Cl)c(Cl)c2)C(=O)C1c1ccc(O)cc1
Yield: 54 %

Procedure:
1.1 equivalent of 3,4-dichlorophenyl isocyanate is added to a solution of 3.5 g of methyl 2-(4-hydroxyphenyl)-2-(2-propenyl)aminoacetate in 50 mL of anhydrous THF in a 50 mL flask equipped with a magnetic stirrer, under nitrogen. After heating under reflux for 4 hours, the product is concentrated then crystallised in isopropyl ether. The solid is filtered and washed with isopropyl ether to yield 3.2 g of white powder (Yd=54%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][Br:6].[CH3:10][N:11]([CH3:13])[CH3:12].CO>C(OCC)C>[Br-:6].[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N+:11]([CH3:13])([CH3:12])[CH3:10]
Reactant: CN(C)C
Reactant: Cc1cccc(CBr)c1
Solvent: CO
Solvent: CCOCC
Product: Cc1cccc(C[N+](C)(C)C)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A] 3-Methylbenzyl bromide (24.64 g, 1.33×10−1 mol, Aldrich) is dissolved in 221 g of diethyl ether in a 500 ml round bottomed flask. A 33% (w/w) solution of trimethylamine in methanol (35.80 g, 2.00×10−1 mol, Acros) is added all at once, forming a precipitate almost immediately. The reaction mixture is allowed to stir overnight at room temperature and is then filtered and washed three times with diethyl ether. The resulting powder is dried in a vacuum oven overnight to obtain 3-methylbenzyl trimethylammonium bromide.
Reaction SMILES: C(COC)OC.[CH2:7]([O:9][C:10](=[O:46])[C:11]([CH3:45])([CH3:44])[CH2:12][C:13]1[N:14]([CH2:28][C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[C:15]2[C:20]([C:21]=1[S:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][C:18]([OH:27])=[CH:17][CH:16]=2)[CH3:8].Br[C:48]1[CH:49]=[CH:50][C:51]([O:54][CH2:55][CH3:56])=[N:52][CH:53]=1.C(=O)([O-])[O-].[K+].[K+]>C(OC)(C)(C)C.O>[CH2:7]([O:9][C:10](=[O:46])[C:11]([CH3:45])([CH3:44])[CH2:12][C:13]1[N:14]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:48]3[CH:53]=[N:52][C:51]([O:54][CH2:55][CH3:56])=[CH:50][CH:49]=3)=[CH:31][CH:30]=2)[C:15]2[C:20]([C:21]=1[S:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][C:18]([OH:27])=[CH:17][CH:16]=2)[CH3:8]
Reactant: CCOc1ccc(Br)cn1
Reactant: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(-c2ccc(OCC)nc2)cc1
Temperature: 75 °C
Reaction time: 19 h
Yield: 80.2 %

Procedure:
To a stirring mixture of dimethoxyethane (16.5 L) and water (6.6 L) in a 50 L reaction flask under nitrogen was added 3-{3-tert-butylsulfanyl-5-hydroxy-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid ethyl ester (1652.19 g), 5-bromo-2-ethoxypyridine (650.30 g), and potassium carbonate (605.03 g). The mixture was sparged with nitrogen for 30 minutes to remove dissolved oxygen gas, and then tetrakis(triphenylphosphine)palladium(0) (59.15 g) was added, and the reaction mixture was heated to 65-85° C. over 2 hours and stirred at 65-85° C. under nitrogen for 19 hours. Once no starting material was seen by tlc analysis, the reaction was cooled to 40° C. and water (6.6 L) was added. Ethyl acetate (6.6 L) was added, and the mixture was agitated for 20 minutes and then allowed to separate over 1.5 hours. The aqueous layer was separated, and additional water (6.6 L) was added to the organic layer. The mixture was agitated for 2 minutes and then allowed to separate over 1 hour, with additional ethyl acetate (1.4 L) added to facilitate phase separation. The aqueous layer was separated, and the two aqueous layers were combined. Ethyl acetate (5.0 L) was added to the combined aqueous layer, and the mixture was agitated for 3 minutes and allowed to separate over 2 minutes. The aqueous layer was separated, and the two organic layers were combined and treated with activated carbon, Novit Neutral (446.43 g). The mixture was stirred for 17 hours at room temperature, and then filtered through a 1-2″ pad of Celite. The reaction flask was rinsed twice with ethyl acetate (1.25 L) and filtered through the pad of Celite, and the filtrate was concentrated to give the crude material. Methyl tert-butyl ether (8.2 L) was added to the solids, and the mixture was agitated for 1.5 hours and filtered. The flask was rinsed with methyl tert-butyl ether (1 L) three times and then filtered through the filter cake. The isolated solids were dried in a drying oven at 25° C. under vacuum for 3 days to give the desired product (1314 g).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([C:10]2[C:11]([CH3:25])=[C:12](C([O-])=O)[C:13](C3C=CC=CC=3)=[CH:14][CH:15]=2)[C:8]2[CH:26]=[CH:27][C:28]([C:30](=[O:37])[CH:31]([CH2:33][C:34]([OH:36])=[O:35])[CH3:32])=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-:38].[Na+].[CH2:40]([OH:42])[CH3:41]>>[CH2:1]([C:5]1[N:9]([CH2:10][C:15]2[CH:25]=[CH:11][C:12]([C:4]3[C:41]([C:40]([OH:42])=[O:38])=[CH:5][CH:1]=[CH:2][CH:3]=3)=[CH:13][CH:14]=2)[C:8]2[CH:26]=[CH:27][C:28]([C:30](=[O:37])[CH:31]([CH2:33][C:34]([OH:36])=[O:35])[CH3:32])=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCO
Reactant: [OH-]
Reactant: CCCCc1nc2cc(C(=O)C(C)CC(=O)O)ccc2n1-c1ccc(-c2ccccc2)c(C(=O)[O-])c1C
Agent: [Na+]
Product: CCCCc1nc2cc(C(=O)C(C)CC(=O)O)ccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared is analogous manner to Example 72 from methyl 4'-[(2-n-butyl-5-(2-carboxymethyl-propionyl)-benzimidazol-1-yl(-methyl]biphenyl-2-carboxylate and aquous sodium hydroxide/ethanol.
Reaction SMILES: [NH2:1][C:2]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.O[CH2:11][C:12]1(N)[CH2:16][CH2:15][CH2:14][CH2:13]1.OCCN.C1(=O)CCCCC1>>[CH2:3]1[C:2]2([CH2:7][O:9][C:11]3([CH2:12][CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:1]2)[CH2:6][CH2:5][CH2:4]1
Reactant: NC1(CO)CCCC1
Reactant: NC1(C(=O)O)CCCC1
Solvent: O=C1CCCCC1
Solvent: NCCO
Product: C1CCC2(CC1)NC1(CCCC1)CO2

Procedure:
1-Aminocyclopentanecarboxylic acid was converted to the methyl ester according to Method B1c, Step 1. The ester reduced to 1-hydroxymethylcyclopentanamine according to Method B1c, Step 2. The hydroxyethylamine was reacted with cyclohexanone according to Method B4a, Step 1 to give 6-aza-13-oxadispiro[4.1.5.2]tetradecane. The oxazolidine was reduced according to Method B4a, Step 2 to give 1-(cyclohexylamino)-1-(hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOCl2 according to Method B7b to 1-(cyclohexylamino)-1-(chloromethyl)cyclopentane. The 2-chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford 1-cyclohexyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro[4.4]nonane.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:50]([O:52][C:53](=[O:56])[CH2:54][NH2:55])[CH3:51]>CN(C=O)C.O>[CH2:50]([O:52][C:53](=[O:56])[CH2:54][NH:55][C:22](=[O:24])[C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:26][CH:25]=1)[CH3:51]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CNC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
DIPEA (5.12 g, 6.85 mL, 0.59 mmol) was added to a stirred solution of 4-benzyloxy benzoic acid (2 g, 8.7 mmol) in DMF (18 mL). HOBT (1.3 g, 9.5 mmol) and EDCI.HCl (4.2 g, 21.7 mmol) were added at room temperature. After 2 minutes glycine ethyl ester HCl (1.47 g, 10.5 mmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification using column chromatography (silica gel of mesh size of 60-120 using 40% EtOAc in Hexane as eluent) afforded 2.47 g (90.1% yield) of (4-Benzyloxy-benzoylamino)-acetic acid ethyl ester. LCMS Purity %: 98.6, 1H NMR (DMSO): δ 8.9 (t, 1H), 7.8 (d, 2H), 7.5 (m, 5H), 7.2 (d, 2H), 5.4 (s, 2H), 4.2 (q, 2H), 4.0 (d, 2H), 0.8 (t, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][C:5]([O:12][CH3:13])=[CH:4][C:3]=1[CH:14]([NH:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)[C:15]1[NH:19][C:18](=[O:20])[N:17]([C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:16]=1.C([Cl:39])(=O)C.[Cl-].[NH4+].C([N:44](CC)CC)C.Cl>CO>[ClH:39].[F:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][C:5]([O:12][CH3:13])=[CH:4][C:3]=1[CH:14]([NH:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH2:44])=[NH:33])=[CH:34][CH:35]=1)[C:15]1[NH:19][C:18](=[O:20])[N:17]([C:21]2[N:22]=[CH:23][CH:24]=[CH:25][N:26]=2)[N:16]=1
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C#N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Reactant: CCN(CC)CC
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Reaction time: 18.5 h
Yield: 84.3 %

Procedure:
A suspension of 4-{[[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl](5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]-triazol-3-yl)methyl]amino}benzonitrile (5.12 g, 97.6% purity, 10.5 mmol) and methanol (15 mL) was cooled to 5° C. or below. Acetyl chloride (15 mL, 211 mmol) was slowly added thereto, and the resulting mixture was stirred at 10° C. or below for 18.5 hours. To the mixture obtained, methanol (25 mL) was added, and the resulting mixture was stirred for 1 hour or more. The mixture was concentrated at 10° C. or below under reduced pressure, and further subjected to azeotropic distillation twice with methanol (20 mL). The methanol (15 mL) was added to the residue to dissolve the same, and the resulting mixture was cooled to 10° C. or below. Ammonium chloride (5.05 g, 94.5 mmol) followed by a solution of triethylamine (14.6 mL, 105 mmol) in methanol (15 mL) was added thereto at 20° C. or below. The resulting mixture was stirred at room temperature for 18 hours, and 2 N hydrochloric acid (50 mL) was added thereto at 20° C. or below, and the resulting mixture was stirred at room temperature for 18 hours or more. After cooling to 10° C. or below, the suspension obtained was filtered and sequentially washed with water (10 mL) and tert-butyl methyl ether (10 mL). The solid obtained was dried at 40° C. under reduced pressure to obtain the captioned compound (4.7 g) as a white solid.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=1.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16].[OH-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[C:15]([NH:19][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([Cl:5])=[N:7][CH:8]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC(C)(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)NC(=O)c1ccc(Cl)nc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
25.7 ml (349 mMol) Thionylchloride and 0.5 ml (6.35 mMol) DMF were added to a suspension of 50.0 g (317 mMol) 6-chloro-nicotinic acid in 250 ml toluene and the reaction mixture was heated to 80° C. for 2 hours. After cooling to 10° C., 100.5 ml (952 mMol) tert.-butylamine were added over 40 minutes and stirring was pursued for 30 minutes at the same temperature. 250 ml Aqueous sodium hydroxide 2N were added and the mixture was stirred 30 minutes at room temperature. Dilution with 300 ml water and extraction with ethyl acetate yielded 63.3 g (94%) N-tert.-butyl-6-chloro-nicotinamide as a beige powder of m.p.=108-110° C.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C(O)(C)C.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[N+:28]([O-:30])=[O:29])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CS(C)=O>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]2[CH2:7][C@H:27]2[N+:28]([O-:30])=[O:29])=[CH:22][CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)O
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)cc1
Agent: C[S+](C)(C)=O
Agent: [I-]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 25.3 %

Procedure:
Trimethylsulfoxonium iodide (0.62 g, 2.82 mmol) was added in portions to a solution of t-BuOH (0.32 g, 2.82 mmol) in dry DMSO (5 mL). After 10 min a solution of 1-(benzyloxy)-4-[(E)-2-nitrovinyl]benzene (0.60 g, 2.35 mmol) in DMSO (5 mL) was transferred via canula and the mixture was stirred at room temperature for 6 h. The reaction was poured over water (10 mL) and extracted with Et2O (3×10 mL); the organic layers were washed with brine (2×15 mL), dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the residual orange oil was purified by column chromatography on silica gel (5% EtOAc/hexanes) affording 0.16 g of 1-(benzyloxy)-4-[(trans)-2-nitrocyclopropyl]benzene [Rf=0.5 (20% EtOAc/hexanes), white solid, 26% yield].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([OH:14])=O)[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:33]([O:37][C:38]([N:40]1[CH2:46][CH2:45][CH:44]([OH:47])[CH:43]([NH2:48])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].O>CN(C)C=O>[C:33]([O:37][C:38]([N:40]1[CH2:41][CH2:42][CH:43]([NH:48][C:12]([C:10]2[S:11][C:7]3[C:6]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:14])[CH:44]([OH:47])[CH2:45][CH2:46]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)O)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CCC3O)nc12
Reaction time: 16 h
Yield: 79 %

Procedure:
0.50 g 4-Methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 0.31 g 1,1′-carbonyl-diimidazole in 25 ml dimethylformamide were stirred at room temperature for 16 hours. 0.43 g 4-amino-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester were added and stirring was continued for 16 hours at room temperature. Water was added and the mixture was extracted with ethylacetate. Chromatography on silicagel with dichloromethane/methanol 98:2 yielded 0.68 g (79%) 4-hydroxy-5-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-azepane-1-carboxylic acid tert-butyl ester as a yellow solid; M.p.: 71–73° C.; MS (ISP): m/e=507 (M+H+).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:3])[CH3:2].S(Cl)([Cl:22])(=O)=O.CCCCCC.C(OCC)(=O)C>ClCCl>[C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([Cl:22])[CH:9]=[C:8]1[C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)c1cccn1CCOC(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)c1cc(Cl)cn1CCOC(C)=O
Yield: 41 %

Procedure:
The resulting ethyl 1-(2-acetoxyethyl)pyrrole-2-glyoxalate prepared as in Preparation I (40.5 g, 0.16 mol.) is dissolved in anhydrous dichloromethane (900 ml.) and cooled to -70°. Recently distilled sulfuryl chloride (13.7 ml., 0.17 mol.) is added in a dropwise manner. When the addition is completed, the solution is allowed to come to room temperature spontaneously. After two hours at this temperature TLC (silica gel; hexane:ethyl acetate; 80:20) shows the absence of starting material. The solvent is removed in vacuo and the oily residue is dissolved in dichloromethane (300 ml.) and washed to neutrality with water. The organic phase is dried over sodium sulfate and evaporated to dryness in vacuo. The residue, which weighed 63 g. is purified by column chromatography on silica gel (800 g.) using hexane ethyl acetate (90:10) as the eluting solvent. This procedure yields 19 g. (41% yield) of ethyl 1-(2-acetoxyethyl)4-chloropyrrole-2-glyoxalate (Formula V where Y is Cl) having the following physical constants:
Reaction SMILES: Cl[C:2]1[NH:17][C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)[CH:9]=[C:4]2[CH:3]=1.CCN(CC)CC.CO>C1COCC1.[Pd]>[F:16][C:12]1[CH:11]=[C:10]([C:8]2[CH:9]=[C:4]3[CH:3]=[CH:2][NH:17][C:5]3=[N:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Fc1cccc(-c2cnc3[nH]c(Cl)cc3c2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: Fc1cccc(-c2cnc3[nH]ccc3c2)c1
Reaction time: 3 h
Yield: 115.7 %

Procedure:
A mixture of chloride 6 (5.23 g, 21.3 mmol), 10% Pd/C (2.7 g), Et3N (3.6 mL, 25.8 mmol) in THF:MeOH=5:1 (180 mL) was stirred under H2 overnight. More 10% Pd/C (1.3 g) was added and stirring was continued for 3 h. Catalyst was removed by filtration and the solution was concentrated to dryness in vacuum. The residue was purified by SGC with CH2Cl2:AcOEt as eluent in gradient (up to 20% AcOEt) to afford 7 (5.23 g, 88%), greenish powder. 1H NMR (400 MHz, CDCl3) δ 6.59 (dd, J=3.5, 2.0 Hz, 1H), 7.04-7.10 (m, 1H), 7.33-7.37 (m, 1H), 7.40-7.48 (m, 3H), 8.14 (d, J=2.1 Hz, 1H), 8.57 (d, J=2.1 Hz, 1H), 9.91 (bs, 1H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([C:11]#[N:12])=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].CI.[CH2:17](OC(=O)C)C>CN(C=O)C.CCCCCC>[Br:1][C:2]1[C:10]2[C:9]([C:11]#[N:12])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH3:17])[CH:3]=1
Reactant: N#Cc1cccc2[nH]cc(Br)c12
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CI
Product: Cn1cc(Br)c2c(C#N)cccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-Bromo-1H-indole-4-carbonitrile (I-146a: 500 mg, 2.272 mmol) was added dropwise to a stirred mixture of NaH (0.218 g, 9.0833 mmol) in dry DMF (15 mL) at 0° C. over a period of 10 minutes. This was followed by the addition of methyl iodide and the resulting mixture was stirred at 0° C. for 2 hours. The reaction was monitored by TLC (10% ethylacetate in hexane). The reaction mixture was quenched with ice water; the precipitate formed was collected and dried to afford 0.400 g of the crude product.
Reaction SMILES: BrC1C=CC([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:18])[C:9]=2[C:19](=[O:21])[CH3:20])=CC=1.NC1C2C(=CC=CC=2)N=C(C)C=1C(=O)C.[Br:39][C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=1)CBr>>[Br:39][C:40]1[CH:47]=[C:46]([CH:45]=[CH:42][CH:41]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([CH3:18])[C:9]=1[C:19](=[O:21])[CH3:20]
Reactant: CC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)cc1
Reactant: BrCc1cccc(Br)c1
Agent: CC(=O)c1c(C)nc2ccccc2c1N
Product: CC(=O)c1c(C)nc2ccccc2c1NCc1cccc(Br)c1

Procedure:
1-(4-(3-Bromobenzylamino)-2-methylquinolin-3-yl)ethanone was synthesized by the same process as described for 1-(4-(4-bromo-benzylamino)-2-methylquinolin-3-yl)ethanone (Example 1, Intermediate 2c) starting from 1-(4-amino-2-methylquinolin-3-yl)ethanone and 3-bromobenzyl bromide. Melting point: 109° C.; MS(ES+): 369/371.
Reaction SMILES: COC(=O)C([N:6]1[C@H:9]([S:10][C:11](=[O:13])[CH3:12])[C@@H:8]([O:14][CH3:15])[C:7]1=[O:16])=O>CO.C(Cl)Cl>[C:11]([S:10][C@H:9]1[NH:6][C:7](=[O:16])[C@@H:8]1[O:14][CH3:15])(=[O:13])[CH3:12]
Reactant: COC(=O)C(=O)N1C(=O)[C@H](OC)[C@H]1SC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CO[C@H]1C(=O)N[C@@H]1SC(C)=O

Procedure:
A solution of 71.20 mg of 2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-oxoacetic acid methyl ester (crude product) in 10 ml of 1% aqueous methanol is stirred overnight at room temperature. The reaction mixture is diluted with methylene chloride, washed with water, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed over silica gel with toluene/ethyl acetate (9:1) and yields the title compound.