Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH:23]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:16][C:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:30])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: O=C(O)C1CCCCC1
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)NC(=O)C3CCCCC3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methylquinoline-3-carboxylate (Example 26b) and cyclohexanecarboxylic acid as brown solid (28%). MS 414 (MH+).
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][CH2:12]O>ClCCl>[CH3:1][C@H:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:12][CH2:11][NH:9]1
Reactant: OCCBr
Reactant: C[C@H](N)c1ccccc1
Solvent: ClCCl
Product: C[C@@H]1NCCc2ccccc21
Temperature: 51 °C
Reaction time: 52 h
Yield: 88312.6 %

Procedure:
108.23 g(0.903 mmole) of (S)-(-)-α-methylbenzylamine was dissolved in 140 ml of dichloromethane and 144.0 g(1.071 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51° C. for 52 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and the residue was subjected to fractional distillation to obtain 117.4 g of the title compound, which had a pale yellow color.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([S:21](Cl)(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].C(N(CC)CC)C>ClCCl>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([S:21]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)(=[O:22])=[O:23])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: c1ccc2c(c1)CCCN2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1,2,3,4-Tetrahydroquinoline (0.29 ml) was added to a suspension of 3,4-dimethoxybenzene sulphonyl chloride (0.50 g) in dichloromethane (15 ml) at room temperature. Triethylamine (0.44 ml) was added and the resulting mixture stirred for 24 hours at room temperature. The reaction mixture was then diluted with dichloromethane (20 ml) and washed successively with saturated aqueous sodium hydrogen carbonate solution (10 ml), 2N hydrochloric acid (10 ml) and saturated aqueous sodium chloride solution (10 ml). Drying over magnesium sulphate and concentration in vacuo provided a yellow oil. Purification by column chromatography eluting with 30% ethyl acetate in hexane provided the title compound as a colourless oil (0.60 g) which solidified on standing.
Reaction SMILES: [BrH:1].Cl[C:3]1[C:12]2[N:13]=[C:14]([NH2:21])[N:15]([CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1.[NH3:22]>CO>[BrH:1].[NH2:21][C:14]1[N:15]([CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[C:3]([NH2:22])[C:12]=2[N:13]=1
Reactant: N
Reactant: CC(C)(O)Cn1c(N)nc2c(Cl)nc3ccccc3c21
Agent: Br
Solvent: CO
Product: CC(C)(O)Cn1c(N)nc2c(N)nc3ccccc3c21
Temperature: 150 °C

Procedure:
1-(4-Chloro-2-amino-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol hydrobromide (2.00 g, 5.38 mmol) and ammonia (50 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated overnight in an oven at 150° C. The solvent was removed under reduced pressure, and the residue was suspended in acetonitrile, isolated by filtration, washed with warm acetonitrile (2×100 mL), washed with diethyl ether (100 mL), washed with methanol, and dried under high vacuum to provide 1.02 g of 1-(2,4-diamino-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol hydrobromide as a white powder, mp >230° C.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:16])[C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.N1C=CC=CC=1>C(Cl)Cl>[F:17][C:18]1[CH:23]=[C:22]([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]([CH3:15])=[C:6]2[C:4]([N:3]([O:2][CH3:1])[CH3:16])=[O:5])[CH:21]=[CH:20][CH:19]=1
Reactant: CON(C)C(=O)c1[nH]c2ccccc2c1C
Reactant: OB(O)c1cccc(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1c(C)c2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 12.5 %

Procedure:
Activated molecular sieves (18 g) 4 Å were placed in an oven dried flask and cooled to room temperature under nitrogen. To the flask was charged with N-methoxy-N,3-dimethyl-1H-indole-2-carboxamide (1.5 g, 6.9 mmol), (3-fluorophenyl)boronic acid (2.9 g, 21 mmol), cupric acetate (1.9 g, 10 mmol), methylene chloride (130 mL) and pyridine (2.2 mL, 27 mmol). The reaction mixture was stirred at room temperature for 2 days. The mixture was filtered through a pad of Celite. The filtrate was concentrated and purified on silica gel (eluting with 0-30% EtOAc/hexane) to give the desired product (0.27 g, 12%). LCMS calculated for C18H18FN2O2(M+H)+: m/z=313.1. Found: 313.0.
Reaction SMILES: [OH-].[Li+].[C:3]([NH:6][C@@H:7]1[C@@H:12]([CH2:13][CH:14]=[O:15])[CH2:11][C:10]([C:16]([O:18]C)=[O:17])=[CH:9][C@H:8]1[O:20][CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])(=[O:5])[CH3:4]>C1COCC1>[C:3]([NH:6][C@@H:7]1[C@@H:12]([CH2:13][CH:14]=[O:15])[CH2:11][C:10]([C:16]([OH:18])=[O:17])=[CH:9][C@H:8]1[O:20][CH:21]([CH2:22][CH3:23])[CH2:24][CH3:25])(=[O:5])[CH3:4]
Reactant: CCC(CC)O[C@@H]1C=C(C(=O)OC)C[C@H](CC=O)[C@H]1NC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(CC)O[C@@H]1C=C(C(=O)O)C[C@H](CC=O)[C@H]1NC(C)=O
Reaction time: 12 h
Yield: 80.3 %

Procedure:
Aqueous lithium hydroxide solution (0.1N, 15 mL) was added to a room temperature solution of Example 7A (30 mg, 0.092 mmol) in THF (3 mL). The solution was stirred for 12 hours, acidified to pH 5-6 with DOWEX® 50WX2-200 ion-exchange resin, filtered and concentrated. The concentrate was purified by flash chromatography on silica gel using acetic acid/ethyl acetate (1/5) to afford 23 mg (100%) of the desired product as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[C:23]([Br:24])=[CH:22][CH:21]=[CH:20][N:19]=1>>[Br:24][C:23]1[C:18]2[N:19]([CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ncccc1Br
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Product: Cc1onc(-c2ccccc2)c1-c1cn2cccc(Br)c2n1
Yield: 48 %

Procedure:
As described for Example 1, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) was converted, using 2-amino-3-bromopyridine instead of 2-aminopyridine, to the title compound (85 mg, 48%) which was obtained as a yellow gum. MS: m/e=354.0/356.1 [M+H]+.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:23])([CH2:17][CH2:18]1)[C:12]([C:13](=[O:15])[CH3:14])=[CH:11][CH2:10]2)[CH2:7][CH2:6]3.S(=O)(=O)(O)O.[C:29](=O)(O)[O-:30].[K+].O>CO>[OH:1][C@@H:3]1[C@@H:2]([O:30][CH3:29])[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:23])[C@H:9]3[CH2:10][CH:11]=[C:12]2[C:13](=[O:15])[CH3:14])[CH2:4]1
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: CO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(C(C)=O)=CC[C@@H]32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2α,3α-Epoxy-5α-pregn-16-en-20-one (500 mg.) in methanol (30 ml.) was treated with concentrated sulphuric acid (0.1 ml.). The reaction solution was stirred at room temperature for 10 minutes, and then potassium bicarbonate solution (10%, 6 ml.) and water were added and the precipitate was extracted into chloroform. The chloroform solution was evaporated to an oil which was purified by preparative TLC in ethyl acetate/petrol (1/2), to give, as the major product title compound (255 mg) as colourless plates (from ethyl acetate/petrol), m.p. 186°-189°, [α]D (c, 0.82) + 62° , λmax (EtOH) 239 nm (ε 8370).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[CH:5]=[CH:4][C:3]=1B(O)O.[CH2:32]([O:34][C:35]([C:37]1[CH:42]=[CH:41][C:40](C2C=CC(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)=C(F)C=2F)=[CH:39][CH:38]=1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([C:3]2[CH:4]=[CH:5][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])=[C:7]([F:8])[C:2]=2[F:1])=[CH:39][CH:38]=1)=[O:36])[CH3:33]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)cc1
Reactant: OB(O)c1ccc(OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c1F
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)cc1
Yield: 88 %

Procedure:
2′,3′-Difluoro-4′-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-biphenyl-4-carboxylic acid ethyl ester (13B) was prepared from 2,3-difluoro-4-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-phenylboronic acid (11B) as described in the preparation 2′,3′-difluoro-4′-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-biphenyl-4-carboxylic acid ethyl ester (13A) yielding 2′,3′-difluoro-4′-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-biphenyl-4-carboxylic acid ethyl ester (13B) as a white solid (88%).
Reaction SMILES: [S:1]1[C:5]([C:6](=[O:8])[CH3:7])=[CH:4][C:3]2[CH2:9][CH2:10][C:11]3[C:16]([C:2]1=2)=[CH:15][CH:14]=[CH:13][CH:12]=3.[Al+3].[Cl-].[Cl-].[Cl-].[C:21](Cl)(=[O:23])[CH3:22].Cl>C(Cl)Cl>[S:1]1[C:5]([C:6](=[O:8])[CH3:7])=[CH:4][C:3]2[CH2:9][CH2:10][C:11]3[C:16]([C:2]1=2)=[CH:15][CH:14]=[C:13]([C:21](=[O:23])[CH3:22])[CH:12]=3
Reactant: CC(=O)c1cc2c(s1)-c1ccccc1CC2
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCc1cc(C(C)=O)sc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.9 %

Procedure:
To a solution of 1-(4,5-dihydronaphtho[1,2-b]thiophen-2-yl)ethanone (5b) (30 g, 131 mmol) in 500 mL of DCM at 0° C., AlCl3 (52.6 g, 394 mmol) was added portion wise and after 15 min, acetyl chloride (18.69 ml, 263 mmol) was added dropwise at the same temperature over 30 min and the mixture was stirred at room temperature for 48 hr. The reaction mass was slowly added to ice water and acidified with 2 N HCl solution and extracted with DCM, and the organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound as an yellow solid (5c) (28.3 g, 80%). m/z 270.0 (M+).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:38])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH:32]3O)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl>C(Cl)(Cl)Cl.C(OCC)C>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:38])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:31]3[CH:32]=[CH:33][O:34][CH2:35][CH2:36]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: Cc1ccccc1-c1cc(N2CCOCC2O)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1-c1cc(N2C=COCC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a solution of 65 mg (0.11 mmol) (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-morpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide in 2 ml chloroform were added a few drops of a 2.3 N hydrochloric acid solution in diethyl ether. After stirring at room temperature for 2 h, the organic layer was washed with saturated sodium carbonate solution, dried (magnesium sulfate) and evaporated. The residue was purified by flash-chromatography to give 47 mg (75%) of the title compound as white foam. MS m/e (%): 564 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:5]2[C:10]([CH3:11])=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:18][N:19]([CH3:29])[C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>ClCCl.C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:13][CH2:14][N:15]([C:27]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([N:19]([CH3:29])[CH3:18])=[CH:21][CH:22]=3)=[O:28])[CH2:16][CH2:17]2)[C:5]2[C:10]([CH3:11])=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: CN(C)c1ccc(N=C=O)cc1
Reactant: Cc1csc2nc(N)nc(N3CCNCC3)c12
Solvent: ClCCl
Solvent: CC#N
Product: Cc1csc2nc(N)nc(N3CCN(C(=O)Nc4ccc(N(C)C)cc4)CC3)c12
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of Example 22 (70 mg, 0.28 mmol) in dichloromethane (2 mL) and acetonitrile (2 mL) was added 4-(dimethylamino)phenyl isocyanate (48 mg, 0.29 mmol). The reaction mixture was stirred overnight. The solvents were evaporated in vacuo and the crude residue was purified by flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually increasing from 1% to 4% methanol in dichloromethane), yielding the title compound (75 mg) as a white powder. 13C NMR δ (75 MHz, CDCl3) 171.76, 164.09, 158.58, 155.98, 147.34, 129.12, 128.44, 122.79 (2C), 114.11 (2C), 113.95, 113.07, 49.96 (2C), 43.42 (2C), 40.79 (2C), 16.75. MS (m/z) 412 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C-:23]#[N:24].[Na+]>CS(C)=O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:13]([CH3:14])[C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]([CH2:2][C:23]#[N:24])[N:12]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(N(C)c2nc(CC#N)nc3ccccc23)cc1
Temperature: 120 °C

Procedure:
A mixture of (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (50 mg, 0.14 mmol) and NaCN (21 mg, 0.43 mmol) in DMSO was heated by microwave for 10 min at 120° C. The reaction was quenched with H2O, diluted with EtOAc and the layers separated. The aqueous phase was extracted with EtOAc (2×5 mL), washed with brine, filtered over Na2SO4 and concentrated. Purification by gradient MPLC (SiO2, EtOAc/hexanes, 0-50%) gave the desired compound. 1H NMR (CDCl3) δ 7.74 (d, 1H), 7.56 (m, 1H), 7.13 (d, 2H), 7.02 (m, 1H), 6.94 (m, 3H), 4.04 (s, 2H), 3.85 (s, 3H), 3.62 (s, 3H); LC-MS (ESI+; 305 ([M+H]+)) and (ESI−; 303 ([M−H]−)).
Reaction SMILES: O.[OH-].[Li+:3].C[O:5][C:6](=[O:19])[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[CH:11]=[N:10][CH:9]=1>C1COCC1.O>[Li+:3].[Br:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[N:10][CH:9]=[C:8]2[CH2:7][C:6]([O-:19])=[O:5]
Reactant: COC(=O)Cc1cncc2ccc(Br)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])Cc1cncc2ccc(Br)cc12

Procedure:
Sodium borohydride (1.12 g, 29.6 mmol) is added portionwise to a cooled (0° C.) solution of 6-bromoisoquinoline[J Chem Soc Perkin Trans 2, 1998, 437] (1.544 g, 7.42 mmol) in acetic acid (10 ml) and acetic anhydride (3 ml). After heating at 60° C. for 4 hours, the mixture is cooled, evaporated and diluted with water. After adjustment to pH10 with potassium carbonate and extraction with ethyl acetate, the combined organic phases are washed twice with 0.5N HCl and brine, then dried over sodium sulphate. Evaporation affords 1-(6-bromo-1H-isoquinolin-2-yl)-ethanone, MH+ 253. Glyoxylic acid (0.812 g, 8.80 mmol) is added to mixture of 1-(6-bromo-1H-isoquinolin-2-yl)-ethanone (1.50 g, 5.90 mmol) in 6N HCl (20 ml). The reaction is heated at 100° C. for 2 hours, cooled to RT and washed with ethyl acetate. After evaporation, the residue is taken into methanol (20 ml), concentrated sulphuric acid (10 drops) is added and the mixture heated at reflux for 14 hours. After partial evaporation of the solvent, the resultant solid is collected by filtration, washed with methanol and dried to afford (6-bromo-isoquinolin4-yl)-acetic acid methyl ester hydrochloride, MH+ 281. Lithium hydroxide hydrate (8.5 mg, 0.20 mmol) is added to a cooled (0° C.) solution of (6-bromo-isoquinolin-4-yl)-acetic acid methyl ester (50 mg, 0.18 mmol) in 3:1 THF-water (3 ml). After 1 hour the solvent is evaporated to afford (6-bromo-isoquinolin-4-yl)-acetic acid lithium salt, MH+ 266.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.Cl.[NH2:36][C@@H:37]([C:41]([O:43]C(C)(C)C)=[O:42])[CH:38]([CH3:40])[CH3:39].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[O:16])[C@H:9]2[C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([NH:36][C@@H:37]([C:41]([OH:43])=[O:42])[CH:38]([CH3:40])[CH3:39])=[O:32])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)[C@@H](NC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Reaction time: 0.08 h

Procedure:
[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetic acid, (50.0 mg, 0.10 mmol) was dissolved in DCM (2 ml). tert-Butyl D-valinate hydrochloride (28.4 mg, 0.14 mmol) and N-methylmorpholine (3.0 μl, 0.31 mmol) were added. After 5 minutes, TBTU (43.7 mg, 0.14 mmol) was added and the mixture was stirred overnight. The intermediate tert-butylester of the title compound was confirmed. M/z: 637.1 (M−H). The solvent was removed under reduced pressure. The yellow residue was dissolved in formic acid (1.5 ml) and heated at 50° C. for 5 h. The solvent was evaporated and the residue was purified by preparative HPLC on a C8 column. A gradient from 20 to 50% MeCN in 0.1 M ammonium acetate buffer was used as eluent. After lyophilisation, the title compound was obtained as a white solid (30.5 mg, 51%). 1H-NMR (400 MHz, DMS-d6): 0.74 (t, 6H), 1.98-2.07 (m, 1H), 3.84 (brs, 1H), 4.32 (d, 1H), 4.35 (s, 1H), 4.36 (s, 1H), 4.50 (brs, 2H), 5.16 (d, 1H), 6.96 (d, 2H), 7.10-7.17 (m, 2H), 7.19-7.24 (m, 2H), 7.31-7.38 (m, 4H), 7.66 (brs, 1H), 7.99-8.04 (m, 2H). M/z: 583.0 (M+H) and 581.0 (M−H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]([N:22]([CH3:29])[CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:15]([CH3:21])=[C:16]([CH:20]=2)[C:17]([OH:19])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][CH2:64][C:65]1[C:66](=[O:73])[NH:67][C:68]([CH3:72])=[CH:69][C:70]=1[CH3:71]>CN(C=O)C>[CH3:71][C:70]1[CH:69]=[C:68]([CH3:72])[NH:67][C:66](=[O:73])[C:65]=1[CH2:64][NH:63][C:17]([C:16]1[CH:20]=[C:12]([CH:10]2[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:11]2)[CH:13]=[C:14]([N:22]([CH3:29])[CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[C:15]=1[CH3:21])=[O:19]
Reactant: Cc1c(C(=O)O)cc(C2CN(C(=O)OC(C)(C)C)C2)cc1N(C)C1CCOCC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CN(C(=O)OC(C)(C)C)C3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
To a stirred solution of 5-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-2-methyl-3-[methyl(oxan-4-yl)amino]benzoic acid (47 mg, 0.12 mmol) in DMF (2 ml) were added DIPEA (40 μl, 0.23 mmol) and HATU (53 mg, 0.14 mmol) at 0° C. The reaction was stirred at 0° C. for 5 min after which time 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 22 mg, 0.13 mmol) was added and the reaction was warmed room temperature for 16 h. The reaction mixture was then poured onto distilled water (50 ml) and the aqueous phase was extracted with DCM (3×50 ml), washed with brine (50 ml) dried (Na2SO4), filtered and evaporated to give an oil. The product was then purified using a 5 g silica Isolute column eluting with 0% to 5% MeOH in DCM and evaporated to afford the title compound as a colourless oil (44 mg, 67%). LC-MS 96%, m/z=539.4, 1H NMR (500 MHz, Chloroform-d) δ 11.68 (s, 1H), 6.95 (t, J=5.8 Hz, 1H), 6.92 (d, J=4.2 Hz, 2H), 5.88 (s, 1H), 4.47 (d, J=5.8 Hz, 2H), 4.20 (t, J=8.7 Hz, 2H), 3.90 (d, J=11.2 Hz, 2H), 3.86-3.73 (m, 2H), 3.62-3.50 (m, 1H), 3.26 (t, J=10.8 Hz, 2H), 2.89 (ddd, J=14.6, 10.8, 3.7 Hz, 1H), 2.55 (s, 3H), 2.33 (s, 3H), 2.20 (s, 3H), 2.14 (s, 3H), 1.75-1.47 (m, 4H), 1.39 (d, J=5.7 Hz, 9H).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[NH:8][C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[Na+].[Na+].[CH2:21](I)[CH2:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C>[CH2:21]([N:8]1[C:7]2[N:6]=[CH:5][N:4]([CH2:1][CH:2]=[CH2:3])[C:12]=2[C:11](=[O:13])[NH:10][C:9]1=[O:14])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: C=CCn1cnc2[nH]c(=O)[nH]c(=O)c21
Reactant: CCCCCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CCCCC
Yield: 56 %

Procedure:
7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.61 g, 3.2 mmol), sodium carbonate (0.60 g, 5.7 mmol) and pentyl iodide (0.64 g, 3.2 mmol) were stirred in DMF (5 ml) at 50° C. for 18 h. The solution was cooled, separated between ethyl acetate and brine and the organics isolated, dried (MgSO4) and concentrated. Chromatography over silica (gradient elution dichloromethane to 5:1 dichloromethane/ethyl acetate) provided the title compound as a pale yellow solid (0.47 g, 56%). m/z 263[MH+]
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=C.[O:10]=[O+][O-].[BH4-].[Na+]>CO.C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:10]
Reactant: C=CCCCCCCBr
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OCCCCCCCBr
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
A solution of 8-bromo-1-octene (5.0 g, 26 mmol) in a mixture of 25 mL of MeOH and 5 mL of CH2Cl2 was cooled to -50° C. and treated with O3 until a blue color persisted (45 min) and then for an additional 10 min. The mixture, at -40° C., was purged with N2 for 10 min, allowed to warm to -20° C., under N2, and kept at -20° C. while 1.3 g (34 mmol) of sodium borohydride was added in portions over 30 min (evolution of H2 was evident at each addition). The mixture was stirred 30 min more at -20° C. and quenched with the dropwise addition of 20 mL of H2O. This mixture was stirred for 10 min, and extracted with hexane; the organic extracts were washed with water, then brine, dried (Na2SO4) and concentrated to give 3.65 g (72%) of 7-bromo-1-heptanol: NMR (CDCl3) δ1.44 (m, 9H), 1.85 (m, 2H), 3.41 (t, 2H), 3.65 (t, 2H).