Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)C>[C:1]1([C:2]2[C:2]3[CH:3]=[C:4]4[C:5]([CH2:3][CH2:4][CH2:5]4)=[CH:6][C:1]=3[CH2:6][CH:1]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Product: C1=C(c2ccccc2)c2cc3c(cc2C1)CCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 180.5 %

Procedure:
3,5,6,7-Tetrahydro-s-Hydrindacen-1(2H)-one (12.00 g, 0.06967 moles) was stirred in diethylether (200 mL) at 0° C. as PhMgBr (0.105 moles, 35.00 mL of 3.0 M solution in diethylether) was added slowly. This mixture was then allowed to stir overnight at room temperature. After the reaction period the mixture was quenched by pouring over ice. The mixture was then acidified (pH=1) with HCl and stirred vigorously for 2 hours. The organic layer was then separated and washed with H2O (2×100 mL) and then dried over MgSO4. Filtration followed by the removal of the volatiles resulted in the isolation of the desired product as a dark oil (14.68 g, 90.3% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1>>[C:8]1([C:5]2[N:6]=[CH:7][C:2]([N:20]3[CH2:24][CH2:23][CH2:22][CH:21]3[CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)=[N:3][C:4]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C(CCC1CCCN1)COC1CCCCO1
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Product: c1ccc(-c2ncc(N3CCCC3CCCCOC3CCCCO3)nc2-c2ccccc2)cc1

Procedure:
In the same manner as in the step 1 of Example 9, except that 2-chloro-5,6-diphenylpyrazine was used in place of 2-chloro-5,6-di-p-tolylpyrazine and (±)-1-(2-pyrrolidinyl)-4-(2-tetrahydropyranyloxy)butane was used in place of 4-(methylamino)-1-butanol, the desired compound was prepared as a yellowish crystal having a melting point of 94 to 96° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:7](=[O:8])[C:5](=[O:6])[O:4][CH2:3]1.[H][H]>C1COCC1>[CH3:1][C:2]1([CH3:9])[C@@H:7]([OH:8])[C:5](=[O:6])[O:4][CH2:3]1
Reactant: CC1(C)COC(=O)C1=O
Reactant: [H][H]
Solvent: C1CCOC1
Product: CC1(C)COC(=O)[C@@H]1O
Temperature: 50 °C
Reaction time: 45 h

Procedure:
0.0025 m-mole of rhodium-1,5-cyclooctadienechloride complex and 0.0065 m-mole of one of the asymmetric ligand compounds indicated in Table 2 were dissolved in 10 ml of THF, and 5 m-mole of ketopantolactone was added thereto. Reduction was carried out at a hydrogen atmosphere of 50 atm. The mixture was stirred at 50° C. for 45 hours. The reaction mixture was concentrated under reduced pressure and distilled under reduced pressure to obtain optically active (R)-(-)pantolactone. The results are shown in Table 2.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([NH2:12])[N:9]=[C:8]2[NH:13][N:14]=[CH:15][C:7]=12.[H-].[Na+].[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br)([O-:20])=[O:19].O>CN(C=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([NH2:12])[N:9]=[C:8]2[N:13]([CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=3)[N:14]=[CH:15][C:7]=12
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: Nc1nc(-c2ccco2)c2cn[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(-c2ccco2)c2cnn(Cc3cccc([N+](=O)[O-])c3)c2n1
Reaction time: 0.33 h
Yield: 46.8 %

Procedure:
A solution of 4-(2-furyl)-1H-pyrazolo[3,4-d]pyrimidine-6-amine (603 mg, 3 mmol) in DMF (3 mL) at 0° C. was treated with NaH (120 mg, 60%, 3 mmol), stirred for 20 min, treated with 3-nitrobenzyl bromide (648 mg, 3 mmol), stirred at room temperature for 1 h, poured into water, extracted with EtOAc, dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography (EtOAc:Heptane, 1:1) to give the title compound as a cream solid (472 mg, 47%). A portion of the solid (70 mg) was suspended in MeOH, treated with HCl in dioxan (4-M, 1 mL), diluted with diethyl ether and filtered to give the hydrochloride salt of the title compound (79 mg, 100%) as a yellow solid.
Reaction SMILES: [CH3:1]I.[Br:3][C:4]1[CH:5]=[CH:6][C:7](=[O:10])[NH:8][CH:9]=1>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH3:1])=[N:8][CH:9]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: COc1ccc(Br)cn1
Temperature: 50 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
Silver carbonate (16.0 g, 57.8 mmol) and methyl iodide (6.5 mL, 103 mmol) were sequentially added to a solution of 5-bromopyridin-2(1H)-one (15.0 g, 86.2 mmol) in benzene (225 mL). The mixture was stirred for 16 h at 50° C. After cooling to room temperature, the mixture was filtered through celite and concentrated. Purification by chromatography using 1-5% ethyl acetate in pet ether provided 12 g of the desired compound: 1H NMR (300 MHz, CDCl3) 8.15-8.25 (narrow m, 1H), 7.63 (dd, J=9, 3 Hz, 1H), 6.63 (d, J=9 Hz, 1H), 3.92 (s, 3H).
Reaction SMILES: [N:1]([C:4]1([CH3:17])[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12][N:11]=2)[CH2:6][CH2:5]1)=[C:2]=[S:3].[NH3:18]>>[CH3:17][C:4]1([NH:1][C:2]([NH2:18])=[S:3])[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12][N:11]=2)[CH2:6][CH2:5]1
Reactant: N
Reactant: Cc1cc(N2CCC(C)(N=C=S)CC2)ncn1
Product: Cc1cc(N2CCC(C)(NC(N)=S)CC2)ncn1
Temperature: 50 °C
Yield: 853.2 %

Procedure:
A solution of 4-(4-isothiocyanato-4-methylpiperidin-1-yl)-6-methylpyrimidine (1.18 g, 0.53 mmol) in ammonia (7 M in MeOH, 13.6 mL, 95.0 mmol) was stirred in a sealed tube at room temperature for 3 h and then heated at 50° C. for 18 h. After cooling to room temperature the mixture was evaporated. Purification by chromatography (silica gel, 50 g, 0 to 20% methanol in dichloromethane) afforded the title compound (1.2 g, 100%) as a white foam.
Reaction SMILES: ClC1C=C(C=CC=1)C(O[CH:8]1[C:13](=[O:14])[NH:12][C:11]([CH3:15])=[C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[S:9]1)=O.[CH3:25][NH2:26]>>[CH3:15][C:11]1[NH:12][C:13](=[O:14])[CH:8]([NH:26][CH3:25])[S:9][C:10]=1[C:16]1[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=1
Reactant: CN
Reactant: CC1=C(c2ccncc2)SC(OC(=O)c2cccc(Cl)c2)C(=O)N1
Product: CNC1SC(c2ccncc2)=C(C)NC1=O

Procedure:
2-(3-Chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one and methylamine were reacted to give the titled compound as pale brown needles.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:9][CH2:10][C:11]#[CH:12])=[N:5][CH2:6][CH2:7][SH:8])#[N:2].Cl.Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[C:1]([NH:3][C:4]([NH:9][CH2:10][C:11]#[CH:12])=[N:5][CH2:6][CH2:7][S:8][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)#[N:2]
Reactant: C#CCNC(=NCCS)NC#N
Reactant: ClCc1ccccn1
Agent: Cl
Product: C#CCNC(=NCCSCc1ccccn1)NC#N

Procedure:
The ethanolic solution of the product of Step A is reacted with about an equimolar amount of 2-chloromethylpyridine hydrochloride and about two equivalents of base to produce the title product.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].I[CH2:33][CH2:34][CH2:35][N:36]1[C:40]2[CH:41]=[CH:42][C:43](=O)[CH2:44][C:39]=2[NH:38][C:37]1=[O:46].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:33][CH2:34][CH2:35][N:36]3[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=4[NH:38][C:37]3=[O:46])[CH2:8][CH2:7]2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23]
Reactant: O=C1C=Cc2c([nH]c(=O)n2CCCI)C1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1
Temperature: 65 °C
Yield: 77.3 %

Procedure:
A mixture of tert-butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (500 mg, 1.19 mmol, 1 equiv), 1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one-one (358.8 mg, 1.19 mmol, 1 equiv), and potassium carbonate (493.4 mg, 3.57 mmol, 3 equiv) in N,N-dimethylformamide was heated at 65° C. for 16 h. After cooling to ambient temperature, the crude mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, concentrated, and the crude residue was purified using preparatory thin layer chromatography in 10% methanol in dichloromethane to afford the title compound (548 mg, 77.4%); 1H NMR (400 MHz, DMSO-d6): δ 1.52 (s, 9H); 1.61 (d, 2H, J=12.8 Hz), 1.83 (t, 2H, J=6.8 Hz); 2.36 (t, 2H, J=6.8 Hz); 2.54-2.73 (m, 6H); 3.86 (t, 2H, J=6.8 and 6.4 Hz); 4.58 (s, 2H); 4.61 (s, 2H); 6.77 (t, 1H, J=7.6 and 7.2 Hz); 6.85 (d, 2H, J=8 Hz); 6.97 (d, 1H, J=2.8 Hz); 7.18-7.25 (m, 3H); 7.48-7.55 (m, 2H); 7.79-7.84 (m, 2H); 10.81 (s, 1H); MS for C35H41N5O4 m/z 596.16 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=3[CH:9](Cl)[CH2:10][C:4]=2[CH:3]=1.[C:19]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:21][CH2:22][CH3:23])=[O:20]>C(Cl)(Cl)Cl>[C:19]([N:24]1[CH2:29][CH2:28][N:27]([CH:9]2[C:8]3[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:7]=3[S:6][C:5]3[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][C:4]=3[CH2:10]2)[CH2:26][CH2:25]1)([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)N1CCNCC1
Reactant: Fc1ccc2c(c1)C(Cl)Cc1cc(Cl)ccc1S2
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(C2Cc3cc(Cl)ccc3Sc3ccc(F)cc32)CC1
Temperature: 0 °C

Procedure:
24 G. of 2,10-dichloro-8-fluoro-10,11-dihydro-dibenzo[b,f]thiepin in 80 ml. of chloroform are heated together with 38.4 g. of 1-carbethoxy-piperazine under reflux conditions for 20 hours. The reaction mixture is poured over ice water and extracted with chloforom. The organic phase is dried over magnesium sulfate and evaporated under reduced pressure, whereby there is obtained oily 1-carbethoxy-4-(2-chloro-8-fluoro-10,11-dihydro-dibenzo [b,f]thiepin-10-yl)-piperazine. 24.5 G. of 1-carbethoxy-4-(2-chloro-8-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-piperazine, 350 ml. of ethyleneglycol, 19 g. of potassium hydroxide and 1.5 ml. of water are heated together at 160° for 1 hours. The reaction mixture is poured over water and extracted with chloroform. The organic phase is washed with water, dried over magneisum sulfate and evaporated under reduced pressure, whereby there is obtained 1-(2-chloro-8-fluoro-10,11-dihydro-dibenzo[b,f]-thiepin-10-yl)-piperazine as a thick oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[CH3:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][CH:13]([C:12](=[O:17])[CH3:11])[C:14](=[O:16])[CH3:15])=[CH:5][CH:4]=1
Reactant: CC(=O)CC(C)=O
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(CC(C(C)=O)C(C)=O)cc1

Procedure:
4-methoxybenzyl chloride was condensed with 2,4-pentanedione as described in Example 6 to give 3-(4-methoxybenzyl)-2,4-pentanedione as an yellow oil. The crude product was treated first with bromine and then with pyridine as described in Example 12 to give the title compound, Mp 71°-72° C.
Reaction SMILES: [F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(OCC)(=O)C>[F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][Br:15])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(OC(F)(F)C(F)F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: FC(F)C(F)(F)Oc1cccc(CBr)c1

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (10.2 g, 49.0 mmol) in ethyl acetate (80 ml) were added N-bromosuccinimide (9.6 g, 53.9 mmol) and 2,2′-azobis(isobutyronitrile) (161 mg, 0.98 mmol), and the mixture was heated under reflux for 5 hrs. The reaction solution was concentrated and crystals were filtered with hexane. The filtrate was concentrated to give 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene. To a solution of ethyl 3-(3-chlorophenyl)-3-oxopropanoate (10.0 g, 44.1 mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% in oil, 1.76 g, 44.1 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene prepared earlier in 1,2-dimethoxyethane (50 ml), and the mixture was stirred overnight at room temperature. The reaction solution was poured into water (300 ml), and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1) to give the objective substance (7.5 g, 39%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=O)[CH3:2].[N+:16]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([O-:18])=[O:17].Cl.[N+]([C:30]1C=CC(N)=C[CH:31]=1)([O-])=O>C(O)CCC>[CH2:1]([O:3][C:4](=[O:15])[CH:5]=[C:6]([NH:23][C:22]1[CH:24]=[CH:25][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)[CH2:2][CH2:30][CH3:31]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CC(=O)c1cccc(F)c1
Agent: Cl
Solvent: CCCCO
Product: CCCCOC(=O)C=C(Nc1ccc([N+](=O)[O-])cc1)c1cccc(F)c1
Temperature: 118 °C
Yield: 434.3 %

Procedure:
Into a dry 2 L round-bottom flask was placed 106.3 grams (0.506 moles) of 3-(3-fluorophenyl)-3-oxo-propionic acid ethyl ester, 63.0 grams (0.456 moles) of 4-nitro-aniline and 4.0 grams (0.023 moles) of 4-nitro-aniline hydrochloride. To the mixture was added 1.3 L of n-butanol, the flask was fitted with a Soxhlet extractor (cup volume of 0.3 L), condenser and nitrogen inlet. Dry, activated 4 Å sieves (200 grams) were placed in the extractor cup and the reaction mixture heated to reflux temperature of 118° C. under nitrogen and maintained at that temperature for 90 hours. The reaction mixture was decanted while hot from a small amount of solids and chilled to −15° C. for 48 hours Crystalline solids were collected by vacuum filtration. The crystals were washed with 0.2 L of cold ethanol and two 0.2 L portions of hexanes and vacuum dried at 50° C. overnight to yield 35.8 grams (20.8% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([NH:12][C:13]([C:15]1[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:19]([CH2:33][CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])=[CH:18]3)=[O:14])[CH2:7][CH2:6][CH2:5]2.[CH:40]1([S:43]([NH2:46])(=[O:45])=[O:44])[CH2:42][CH2:41]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:40]1([S:43]([NH:46][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][C:19]2[N:20]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:21](=[O:25])[C:22]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:13]([NH:12][C@H:8]2[C:9]4[C:4](=[CH:3][C:2]([F:1])=[CH:11][CH:10]=4)[CH2:5][CH2:6][CH2:7]2)=[O:14])=[CH:24][CH:23]=3)(=[O:45])=[O:44])[CH2:42][CH2:41]1
Reactant: O=C(O)CCCCc1cc2cc(C(=O)N[C@@H]3CCCc4cc(F)ccc43)ccc2c(=O)n1-c1ccc(F)cc1
Reactant: NS(=O)(=O)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CCCCc1cc2cc(C(=O)N[C@@H]3CCCc4cc(F)ccc43)ccc2c(=O)n1-c1ccc(F)cc1)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
A mixture of (R)-5-(6-((6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoic acid (10 mg, 0.019 mmol), cyclopropanesulfonamide (3.43 mg, 0.028 mmol, 1.50 equiv.), DMAP (4.61 mg, 0.038 mmol, 2.0 equiv.) and EDC (7.23 mg, 0.038 mmol, 2.0 equiv.) in DCM (1 mL) was stirred at room temperature overnight. The residue was purified by column chromatography on silica gel eluting with 0-3% CH2Cl2/MeOH to give 7.8 mg of (R)-3-(5-(cyclopropanesulfonamido)-5-oxopentyl)-N-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinoline-6-carboxamide as a white solid. LCMS [M+H]+=634. 1H NMR (DMSO, 500 MHz) δ ppm: 8.18 (dd, J=8.0, 3.5 Hz, 2H), 7.91 (d, J=8.0 Hz, 1H), 7.43-7.36 (m, 4H), 7.26 (t, J=7.0 Hz, 1H), 7.00 (t, J=8.5 Hz, 2H), 6.66 (s, 1H), 5.26-5.22 (m, 1H), 2.85-2.74 (m, 3H), 2.30-2.15 (m, 4H), 2.09 (t, J=7.0 Hz, 2H), 2.00-1.96 (m, 2H), 1.91-1.76 (m, 2H), 1.45-1.39 (m, 4H), 1.10-1.00 (m, 4H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([CH3:13])([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].O>C1(C)C=CC=CC=1>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:23])[N:5]([C:6]([CH3:12])([CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: O=C=Nc1ccccc1F
Reactant: CCOC(=O)C(C)(C)NCCCCl
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(C)(C)N(CCCCl)C(=O)Nc1ccccc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A solution of ethyl 2-(3-chloropropylamino)isobutyrate (7.5 g) prepared according to Example 3-(1) in toluene (45 mL) was cooled to 0° C. To the solution was added 2-fluoropheyl isocyanate (5 g), and the mixture was stirred overnight at 0° C. to room temperature. Water was added to the reaction solution and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 10.9 g of crude ethyl 2-[3-(2-fluorophenyl)-1-(3-chloropropyl)ureido]isobutyrate.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:22]([O:25][C@@H:26]([CH3:32])[CH2:27][CH2:28][CH2:29][CH2:30]Br)(=[O:24])[CH3:23]>CS(C)=O>[C:22]([O:25][C@@H:26]([CH3:32])[CH2:27][CH2:28][CH2:29][CH2:30][N:14]1[C:15](=[O:17])[C:16]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=[N:10][C:11]=2[N:12]([CH3:19])[C:13]1=[O:18])(=[O:24])[CH3:23]
Reactant: CC(=O)O[C@@H](C)CCCCBr
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@@H](C)CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a stirring suspension of 7-benzyl-3-methylxanthine (0.512 g, 2 mmol) in dimethyl sulfoxide (10 ml) was added 95% sodium hydride (50.5 mg, 2.0 mmol) in one portion. After stirring for 30 minutes, (S)-5-acetoxy-1-bromohexane (0.490 g, 2.2 mmol) was added neat. After stirring at room temperature for 12 hours, the reaction was quenched by addition of water (50 ml) and extracted with ethyl acetate (3x 50 ml). The combined extracts were washed with saturated aqueous sodium bicarbonate solution (50 ml), with saturated aqueous sodium chloride solution (50 ml) and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave a residue which was purified by flash chromatography on silica gel eluting with ethyl acetate to give (S)-1-(5-acetoxyhexyl)-7-benzyl-3-methylxanthine (0.700 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[C:7](Cl)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Ca+2].[Cl-].[C:14]([O:18][C:19](=[O:39])[NH:20][C@@H:21]1[C:24](=[O:25])[NH:23][C@@H:22]1[CH2:26][CH2:27][C:28](=[O:38])[CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])([CH3:17])([CH3:16])[CH3:15].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:10])[C:7]([N:23]1[C:24](=[O:25])[C@@H:21]([NH:20][C:19]([O:18][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:39])[C@H:22]1[CH2:26][CH2:27][C:28](=[O:38])[CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N[C@@H]1CCC(=O)CO[Si](C)(C)C(C)(C)C
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(C(=O)C(=O)OC(C)(C)C)[C@@H]1CCC(=O)CO[Si](C)(C)C(C)(C)C
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
To a solution of 490.7 g (3.0 Mol) chloro-oxo-acetic acid tert-butyl ester (6) in 4.41 l methylene chloride was added 577 g (5.7 Mol) calcium chloride. The suspension was cooled to 0-5° C. A cold (0° C.) solution of 575 g (1.48 Mol) (2R, 3S)-[2-[4-(tert-butyl-dimethyl-silanyloxy)-3-oxo-butyl]-4-oxo-azetidin-3-yl]-carbamic acid tert-butyl ester (5) and 385 g (3.0 Mol) N,N-diisopropylethylamine was added at such a rate that the temperature does not rise above 5° C. (1.5 h). The reaction mixture was warmed to 23° C. and stirred for 1 h. The solids were removed by filtration and washed with 1.0 l methylene chloride. The combined filtrates were extracted with 1.5 l water, twice with 1.5 l sodium bicarbonate 5% and once again with 1.5 l water. The aqueous phases were extracted with 1.0 l methylene chloride. The combined organic phases were dried over 500 g sodium sulfate and filtered. The solids were washed with 1 l methylene chloride. The combined filtrates were concentrated to a volume of 5.0 l. To this solution 20 l n-hexane was added and the mixture was concentrated to a volume of 10 l. The product was allowed to crystallize while stirring at room temperature for 16 h. The precipitate was collected by filtration, washed with 4 l n-hexane and dried at 0.1 torr at 40° C. to yield 550 g of (2R, 3S)-{3-tert-butoxy carbonylamino-2-[4-(tert-butyl-dimethyl-silanyloxy)-3-oxo-butyl]-4-oxo-azetidin-1-yl}-oxo-acetic acid tert-butyl ester (7) as colorless crystals (69% Th.); m.p.: 102-103° C.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([Mg]Br)[CH:22]=[CH:23][CH:24]=1.[NH4+].[Cl-]>O1CCCC1.O=O>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:8][CH2:7][C:6]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([O:18][CH3:17])[CH:24]=2)([OH:9])[CH2:5][CH2:4]1
Reactant: COc1cccc([Mg]Br)c1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: O=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc(C2(O)CCC(c3ccccc3)(N(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(dimethylamino)-4-phenylcyclohexanone (4.34 g, 20 mmol) was dissolved in absolute tetrahydrofuran (60 ml) with the exclusion of oxygen, mixed with 3-methoxyphenyl magnesium bromide solution (45 ml, 45 mmol, 1N) with ice cooling and boiled to reflux for 2 h. For work up the batch was mixed with saturated NH4Cl solution (50 ml) with ice cooling and stirred for 10 min at room temperature. The aqueous phase was separated off and extracted with ethyl acetate (3×25 ml). The combined organic phases were dried over Na2SO4 and then concentrated to low volume. A raw product was isolated that was purified by chromatography [silica gel 60 (50 g); ethyl acetate (1000 ml), methanol (1000 ml)]. 2.5 g (38%, mp 116-117° C.) of more non-polar and 2.78 g (43%, mp 139-140° C.) of more polar product were obtained. Both could be recrystallised from ethyl acetate.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][O:19][CH2:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.FC(F)(F)C(O)=O>>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][O:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)CCOCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCOCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 76.5 %

Procedure:
A mixture of tert-butyl 3-[(6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl)methoxy]propanoate (2.80 g, 6.8 mmol) and trifluoroacetic acid (15 ml) was stirred at 0° C. for 3 hrs. The mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate-hexane to give the titled compound (1.78 g, 74%), which was recrystallized from ethanol to give prisms (1.66 g, 69%).