Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:12](Cl)=[O:13]>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:6]=[C:12]=[O:13])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1ccccc1Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccccc1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
0.23 g (1.5 mmol) of 2-chlorobenzamide and 0.19 g (1.6 mmol, 1.1 eq) of oxalyl chloride were added to 10 ml of 1,2-dichloroethane and then the mixture was stirred for 8 hours at 100° C. The reaction solution was cooled down to room temperature. The reaction solvent and excessive oxalyl chloride were removed by distillation under reduced pressure to obtain 2-chlorobenzoyl isocyanate in an oily state. 10 ml of fresh 1,2-dichloroethane and 0.28 g (1.5 mmol) of 2,3-dichloro-4-cyano aniline were successively added thereto, reacted for 2 hours and filtered to obtain 0.25 g (Yield 45%) of the title compound as a solid.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:12](OCC)(OCC)[O:13][CH2:14][CH3:15].C(OC(=O)C)(=O)C>>[CH2:14]([O:13]/[CH:12]=[C:4](/[C:3](=[O:10])[CH:2]([F:11])[F:1])\[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:15]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)C(F)F
Solvent: CC(=O)OC(C)=O
Product: CCO/C=C(\C(=O)OCC)C(=O)C(F)F
Temperature: 100 °C
Yield: 74.8 %

Procedure:
To a freshly prepared solution of sodium ethoxide (prepared by addition of 1.11 g, 48.35 mmol Na metal in 8 mL EtOH) in EtOH was added a solution of ethyl difluoroacetate (5.0 g, 40.29 mmol) in EtOAc (9 mL) at rt and the reaction mixture was heated at 65° C. for 2 h. Then the reaction mixture was quenched with 1N HCl at rt and the pH was adjusted to 6-7. Then the reaction mixture was extracted with EtOAc and the organic layer was washed with water and brine, separated, dried, filtered and concentrated to afford 5.5 g of ethyl 4,4-difluoro-3-oxobutanoate which was taken to the next step without further purification. To a mixture of ethyl 4,4-difluoro-3-oxobutanoate (5.5 g, 33.11 mmol) and triethyl orthoformate (12 mL, 66.26 mmol) was added acetic anhydride (27.0 g, 265.0 mmol) and the reaction mixture was heated at 100° C. for 12 h. Then the reaction mixture was concentrated to afford 5.5 g of the title product which was taken to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:17]1[N:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[N:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Reactant: Cc1ccc(Cl)nn1
Product: Cc1ccc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)nn1

Procedure:
The title compound, MS: m/e=309.3 (M+H+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 3-chloro-6-methyl-pyridazine.
Reaction SMILES: [C:1]([C:4]1[S:8][CH:7]=[N:6][CH:5]=1)(=[O:3])[CH3:2].[BrH:9].[Br:10]CC(C1C=C(C)C=CN=1)=O>>[BrH:10].[Br:9][CH2:2][C:1]([C:4]1[S:8][CH:7]=[N:6][CH:5]=1)=[O:3]
Reactant: Cc1ccnc(C(=O)CBr)c1
Reactant: CC(=O)c1cncs1
Agent: Br
Product: O=C(CBr)c1cncs1

Procedure:
* 5-bromoacetylthiazole hydrobromide was prepared from 5-acetylthiazole according to the procedure for preparing 2-bromoacetyl-4-methylpyridine hydrobromide described in step 2 of Example 31.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[NH:8][CH3:9].CN(C=O)C.OOS([O-])=O.[K+].[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1>O>[CH3:9][N:8]1[C:7]2[CH:6]=[CH:5][C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:3][C:2]=2[N:1]=[C:26]1[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=Cc1cccnc1
Reactant: CNc1ccc(NS(C)(=O)=O)cc1N
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(-c2cccnc2)nc2cc(NS(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N-(3-amino-4-(methyl amino) phenyl) methane sulfonamide (0.3 g, 0.0013 mol) in the mixture of DMF (10 ml) and water (2 ml) was added OXONE® (1.02 g, 0.0016 mol) and followed by nicotinaldehyde (0.16 g, 0.0015 mol) was added portion wise with constant stirring. The reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was concentrated on a high vacuo pump and diluted with cold water (10 ml) and extracted with ethyl acetate (3×15 ml). The combined organic layers were washed with brine dried over Na2SO4 and concentrated in vacuo and purified by column chromatography on silica gel to afford the desired product N-[1-methyl-2-(pyridin-3-yl)-1H-benzimidazol-5-yl]methanesulfonamide (363) as a brown solid. 1H NMR (400 MHz, DMSO-d6), δ: 9.53 (bs, 1H), 9.04 (s, 1H), 8.75-8.77 (d, J=4.0 Hz, 1H), 8.28-8.26 (d, J=8.0 Hz, 1H), 7.68-7.57 (m, 3H), 7.24-7.21 (d, J=8.4 Hz, 1H), 3.89 (s, 3H), 2.91 (s, 3H). LCMS (ES) m/e MS (M+1=244), Purity 95.64%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.[CH2:14]([N:16]([CH2:20][CH3:21])[C:17](Cl)=[O:18])[CH3:15].O>N1C=CC=CC=1>[CH2:14]([N:16]([CH2:20][CH3:21])[C:17](=[O:18])[O:13][C:3]1[C:2]([Cl:1])=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:12])=[CH:5][CH:4]=1)[CH3:15]
Reactant: O=C1NCCc2ccc(O)c(Cl)c21
Reactant: CCN(CC)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCN(CC)C(=O)Oc1ccc2c(c1Cl)C(=O)NCC2
Temperature: 100 °C
Reaction time: 5 h
Yield: 91.5 %

Procedure:
A mixture of 8-chloro-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (1e, 5.6 g, 28 mmol), and diethylcarbamic chloride (4.3 g, 31 mmol) in pyridine (100 mL) was stirred at 100° C. for 5 hours. To the reaction mixture was added H2O (300 mL). The mixture was extracted with EtOAc (2×200 mL). The combined organic layers were washed with 1 N HCl (2×300 mL) and brine (300 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography (EtOAc) to give 8-chloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl diethylcarbamate (1f, 7.6 g, 90%) as brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:19])[CH:16]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CC(C)=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:19][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:16]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1Cc2ccc(O)cc2C1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc2c(c1)CC(CNC(=O)OC(C)(C)C)C2
Yield: 87.7 %

Procedure:
Dissolved in 20 ml of acetone were 1.85 g (6.20 mmol) of 2-(t-butoxycarbonylaminomethyl)-5-hydroxyindane, and 1.52 g (11.0 mmol) of potassium carbonate and 1.10 g (6.60 mmol) of ethyl bromoacetate were added to the solution. The mixture was refluxed for 3.5 hours. After cooling, solids were separated by filtration, and the filtrate was concentrated. The resultant residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2) to obtain 1.90 g of a colorless crystal. Yield; 80%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][O:13][C:14]([C:22]([F:25])([F:24])[F:23])([C:18]([F:21])([F:20])[F:19])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N+](=[CH2:30])=[N-]>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14]([C:18]([F:19])([F:20])[F:21])([C:22]([F:23])([F:24])[F:25])[C:15]([O:17][CH3:30])=[O:16])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: COC(=O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F

Procedure:
A solution of 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionic acid (1.2 g.) in ether (20 ml.) is treated at 0° C. with an excess of an ethereal solution of diazomethane. The solution is evaporated, and the residue is recrystallised from light petroleum (b.p. 40°-60° C.) to give methyl 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionate (1.1 g.), m.p. 61.5°-62.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][CH2:8][C:5]2=[N:6][CH:7]=1.C([O-])(=O)C.[K+].C(O)(=O)C.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCOC(C)=O>[CH:20](=[C:8]1/[CH2:9][CH2:10][C:4]2[C:5]/1=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Brc1cnc2c(c1)CCC2
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Brc1cnc2c(c1)CC/C2=C\c1ccccc1
Temperature: 145 °C
Yield: 59.4 %

Procedure:
To a mixture of 3-bromo-6,7-dihydro-5H-cyclopenta[b]pyridine (1.83 g, 9.24 mmol) and potassium acetate (0.980 g, 9.99 mmol) in acetic acid (30 mL, 520 mmol) was added benzaldehyde (1.90 ml, 18.7 mmol). The reaction mixture was heated to 145° C. (oil bath temperature) in a sealed pressure tube for 3 d, cooled to room temperature and additional benzaldehyde (4 mL) and KOAc (1.83 g) were added. The reaction mixture was heated to 145° C. (oil bath temperature) in a sealed pressure tube for 2 d and cooled to room temperature. The reaction mixture was diluted with EtOAc. The organic phase was washed with 5 M NaOH, water and brine and dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (5% to 10% EtOAc in heptane) to give (E)-7-benzylidene-3-bromo-6,7-dihydro-5H-cyclopenta[b]pyridine (1.57 g, 5.49 mmol, 59% yield) as a yellow solid. MS m/z=286.0 [M+H]+. Calculated for C15H12BrN 285.0.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]([NH2:11])([CH3:10])[CH3:9].C([O-])(=O)C.[Na+]>CCOCC.C(OC(=O)C)(=O)C>[CH:8]([N:11]1[C:4](=[O:5])[CH:3]=[CH:2][C:1]1=[O:7])([CH3:10])[CH3:9]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CC(C)N1C(=O)C=CC1=O
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 8.4 %

Procedure:
A cooled (5° C.) stirred solution of maleic anhydride (29.4 g, 0.30 mole) in anhydrous ether (150 mL) under nitrogen was treated dropwise over 45 min with a solution of isopropylamine (35.5 g, 0.60 mole) in anhydrous ether (100 mL) at a rate to keep the pot temp <20° C. The mixture was then stirred at 10° C. for 15 min, filtered, and the filter cake rinsed with anhydrous ether and dried in vacuo to afford a white solid. This was taken up in acetic anhydride (250 mL), treated with anhydrous sodium acetate (12.3 g, 0.15 mole), and heated to 75° C. with stirring for 4.5 h, then at 100° C. for 1.5 h. The mixture was concentrated in vacuo and the residue taken up in methylene chloride (300 mL), washed with saturated aqueous sodium bicarbonate (200 mL), water (200 mL), dried (MgSO4), and concentrated in vacuo. The residue was distilled (approx. 5 mm pressure) to afford two products; one an N-isopropylmaleimide that distilled at 82° C. (13.0 g), the other an acetate adduct of N-isopropylmaleimide that distilled at 154° C. (12.9 g). The acetate adduct was dissolved in 4:1 acetonitrile/triethylamine (100 mL), heated to 65° C. for 4 h, then concentrated in vacuo. The residue was dissolved in methylene chloride and filtered through a pad of silica gel (eluted with methylene chloride) to afford an additional 3.5 g of N-isopropylmaleimide. Total yield was 16.5 g of N-isopropylmaleimide (40%).
Reaction SMILES: [NH:1]1[C:9]2[C:4]3[C:5](=[CH:10][CH:11]=[CH:12][C:3]=3[C:2]1=[O:13])[CH:6]=[CH:7][CH:8]=2.[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[N+:14]([C:6]1[C:5]2[C:4]3[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:13])[C:3]=3[CH:12]=[CH:11][CH:10]=2)([O-:16])=[O:15]
Reactant: O=C1Nc2cccc3cccc1c23
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=C1Nc2ccc([N+](=O)[O-])c3cccc1c23
Temperature: 25 °C
Yield: 51.8 %

Procedure:
To a mixture of 33.9 g (0.200 mol) benz[cd]indol-2(1H)-one in 150 ml glacial acetic acid was added dropwise 16.5 ml (0.260 mol) nitric acid. At first, there was a very minor exotherm and then, over the course of one hour, the reaction temperature rose to 50° C. The reaction mixture was gradually cooled to room temperature with a cold water bath. A thick dark green paste resulted. This mixture was filtered, washed with 50% aqueous acetic acid, and pulled as dry as possible. The resulting wet filter cake was refluxed in 600 ml methanol and then cooled to 0° C. The mixture was filtered, washed with cold methanol and dried in vacuo to yield 22.2 g (51% theory) of 6-nitrobenz[cd]indol-2(1H)-one. TLC (CHCl3 :MeOH 95:5) showed the product to be essentially one spot material.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[C:13](Br)=[N:12][C:11]([Br:15])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:18][NH2:19]>O1CCOCC1>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[C:13]([NH:18][NH2:19])=[N:12][C:11]([Br:15])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)nc1Br
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ncc(Br)nc1NN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(3,5-Dibromo-pyrazin-2-yl)-carbamic acid tert-butyl ester (600 mg, 1.7 mmol) was dissolved in dioxane (10 mL) and cooled on an ice bath. Hydrazine monohydrate (3 mL, 61.7 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the remaining residue was re-dissolved in a mixture of ethylacetate, water and brine. The phases were separated and the aqeuous phase was extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with brine, dried over sodium sulphate, filtrated and concentrated in vacuo to give (5-bromo-3-hydrazino-pyrazin-2-yl)-carbamic acid tert-butyl ester as the crude product.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:18]([NH:27][C:28](=[O:30])[CH3:29])[C:17]([CH3:31])=[C:16]([Cl:32])[CH:15]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:32][C:16]1[CH:15]=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:18]([NH:27][C:28](=[O:30])[CH3:29])[C:17]=1[CH3:31]
Reactant: CC(=O)Nc1c(C)c(Cl)cc(C(C)N)c1-c1cccc(F)c1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(=O)Nc1c(C)c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c1-c1cccc(F)c1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (22 mg, 0.11 mmol), N-[6-(1-aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl]acetamide (32 mg, 0.10 mmol), and N,N-diisopropylethylamine (0.035 mL, 0.20 mmol) in isopropyl alcohol (0.4 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C22H21ClFN6O (M+H)+: m/z=439.1. found: 439.3.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH2:17])=[S:16])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.Br[CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=O>C(O)C>[CH3:1][C:2]1[O:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[S:16][C:27]4[CH2:28][CH2:29][CH2:30][CH:25]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:19][CH:20]=5)[C:26]=4[N:17]=3)=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Reactant: Cc1nc(C)c(-c2ccc(NC(N)=S)cc2)o1
Solvent: CCO
Product: Cc1nc(C)c(-c2ccc(Nc3nc4c(s3)CCCC4c3ccccc3)cc2)o1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A solution of [4-(2,4-dimethyl-oxazol-5-yl)-phenyl]-thiourea (124 mg, 0.50 mmol) and 2-bromo-6-phenyl-cyclohexanone (139 mg, 0.55 mmol) in ethanol (5 ml) was heated to reflux over night. The precipitated solid was filtered off after cooling to room temperature and dried to yield the title compound (170 mg, 85%) as a light brown solid. MS ISP (m/e): 402.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.37 (br s, 1H, NH), 7.53 (d, 2H), 7.42 (d, 2H), 7.30 (t, 2H), 7.20 (t, 1H), 7.12 (d, 1H), 4.05 (m, 1H), 2.72 (m, 2H), 2.39 (s, 3H), 2.24 (s, 3H), 2.12 (m, 1H), 1.70-1.88 (m, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[NH:14][N:13]=[N:12][N:11]=2)=[N:8][CH:9]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH2:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C1(C)C=CC=CC=1>[NH:14]1[C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:1]([O:3][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])=[O:2])=[CH:9][N:8]=2)=[N:11][N:12]=[N:13]1
Reactant: CCCCCCCCCCCCCCCCO
Reactant: O=C(O)c1ccc(-c2nnn[nH]2)nc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOC(=O)c1ccc(-c2nnn[nH]2)nc1

Procedure:
A mixture of 1.65 g (8.6 mmol) of 5-carboxy-2-(5-tetrazolyl)-pyridine , 0.1 ml of concentrated sulfuric acid and 3.64 g (15 mmol) of 1-hexadecanol in 50 ml of toluene is refluxed for 48 h. The hot solution is filtered in order to eliminate the non-reacted starting material. The filtrate on cooling yields crystals of the title compound, m.p. 139°-140°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Br:11]N1C(=O)CCC1=O>CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:9][CH3:10])[CH2:8][Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C)cc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: COc1ccc(CBr)cc1Br
Temperature: 25 °C
Yield: 99.7 %

Procedure:
2-Bromo-4-methyl anisole 14 (2.2 mL, 14.9 mmol) was dissolved in dichlomethane (30 mL) and N-bromosuccinimide (3.75 g, 16.4 mmol) was added followed by AIBN (26.0 mg). The reaction was heated to reflux for 19 hrs., then cooled to room temperature and the precipitate was filtered off. The filtrate was diluted with dichloromethane and washed with 0.5 M aqueous sodium bicarbonate, followed by water. The organic mixture was dried over sodium sulfate, filtered and concentrated under vacuum to yield 15 (4.16 g, 100%). The benzyl bromide was used as the crude material without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:34]I)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:34][O:14][C:11]2[CH:12]=[N:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(Cl)cc2)C1
Reactant: Oc1ccc(-c2ccc(Cl)cc2)nc1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(Cl)cc3)nc2)CCN(C(=O)c2ccc(Cl)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 6-(4-chloro-phenyl)-pyridin-3-ol (Preparation 23) and 1-(4-chloro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 13) to afford the racemate as a white solid (56 mg, 27%)
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.[CH2:40]([O:42]C(=O)CN1C2C(=CC(N)=CC=2)C=C1)[CH3:41]>>[CH2:40]([O:42][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:41]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CCOC(=O)Cn1ccc2cc(N)ccc21
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that (5-amino-indol-1-yl)-acetic acid ethyl ester (prepared in two steps from 5-nitroindole) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (CDCl3) 8.21 (1H, s), 7.70 (1H, s), 7.47 (2H, m), 7.27 (1H, m), 7.05 (4H, m), 6.47 (1H, d), 4.79 (2H, s), 4.68 (2H, m), 4.39 (1H, d), 4.20 (1H, d), 2.78 (1H, m), 2.18-1.07 (19H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 58.02; H, 7.08; N, 9.62%; C32H37N5O5.C7H17NO5.1.9H2O.0.6C4H8O2 requires: C, 58.23; H, 7.39; N, 9.84%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[NH2:25][C:26]1[CH:38]=[CH:37][C:29]2[N:30]([CH3:36])[CH:31]=[CH:32][S:33](=[O:35])(=[O:34])[C:28]=2[CH:27]=1.Cl>CN1C(=O)CCC1.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:25][C:26]3[CH:38]=[CH:37][C:29]4[N:30]([CH3:36])[CH2:31][CH2:32][S:33](=[O:35])(=[O:34])[C:28]=4[CH:27]=3)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24]
Reactant: CN1C=CS(=O)(=O)c2cc(N)ccc21
Reactant: CN1C(=O)N(c2c(F)cccc2Br)Cc2cnc(S(C)(=O)=O)nc21
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CN1CCS(=O)(=O)c2cc(Nc3ncc4c(n3)N(C)C(=O)N(c3c(F)cccc3Br)C4)ccc21
Temperature: 120 °C
Yield: 31.1 %

Procedure:
83 mg 3-(2-bromo-6-fluorophenyl)-3,4-dihydro-7-methanesulphonyl-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one and 85 mg 7-Amino-4-methyl-4H-benzo[1,4]thiazin-1,1-dioxide (starting material n)) in 0.8 ml NMP were treated with 0.2 ml 2M HCl in ether and heated to 120° C. for 6 hrs. The mixture was purified by preparative HPLC-MS to yield 34 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH2:5].[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>C(O)(=O)C>[O:17]=[C:16]1[C:15]2[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13](=[O:18])[N:5]1[CH:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: COC(=O)CCC(C(=O)OC)N1C(=O)c2ccccc2C1=O

Procedure:
A stirred mixture of L-glutamic acid dimethyl ester (2.0 g, 11.4 mmol) and phthalic anhydride (1.7 g, 11.4 mmol) in acetic acid (30 mL) is heated to refluxed for one hour. The solvent is removed in vacuo to yield dimethyl 2-(1,3-dioxoisoindolin-2-yl)-pentane-1,5-dioate which is further purified through chromatography.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([OH:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=1>>[CH2:1]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH:23]([OH:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
Benzyl bromide (21.9 g) and potassium carbonate (35.3 g) were added to a solution of ethyl 3-(4-hydroxyphenyl)lactate (22.4 g) in dimethylformnamide (220 ml). The mixture was stirred at 50° C. for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified via chromatography silica gel column using hexane/ethyl acetate=7/3 as the eluant to give the desired compound (31.0 g) as a pale yellow oil.