Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([N+:16]([O-])=O)=[C:9]([O:14][CH3:15])[CH:10]=2)[CH2:5]1.[H][H]>C(OCC)(=O)C.[Pd].CO>[F:1][CH2:2][CH2:3][N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([NH2:16])=[C:9]([O:14][CH3:15])[CH:10]=2)[CH2:5]1
Reactant: COc1cc2c(cc1[N+](=O)[O-])CN(CCF)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2c(cc1N)CN(CCF)CC2
Yield: 99.6 %

Procedure:
2-(2-fluoroethyl)-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (assumed 1.07 mmol from previous reaction) was dissolved in ethyl acetate (5 mL), treated with 10% palladium on carbon (50 mg, Aldrich), and then diluted with methanol (10 mL). The mixture was stirred under 60 psi of hydrogen pressure for 16 h in a Fischer-Porter apparatus. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite and the filtrate was concentrated to provide 2-(2-fluoroethyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-isoquinolinamine (239 mg, 100%). 1H NMR (400 MHz, CDCl3) δ ppm 2.80-2.93 (m, 6 H), 3.51 (bs, 2 H), 3.61 (s, 2 H), 3.80 (s, 3 H), 4.58-4.75 (dt, JHF=47.6, J=4.9 Hz, 2 H), 6.37 (s, 1 H), 6.50 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:17]1[S:18][CH:19]=[C:20]([C:22]2[S:23][CH:24]=[C:25]([C:27](=O)[NH2:28])[N:26]=2)[CH:21]=1)([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:17]1[S:18][CH:19]=[C:20]([C:22]2[S:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)[CH:21]=1)([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: NC(=O)c1csc(-c2csc(C(O)(Cn3cncn3)c3ccc(F)cc3F)c2)n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1csc(-c2csc(C(O)(Cn3cncn3)c3ccc(F)cc3F)c2)n1

Procedure:
The compound (B) obtained in the step (2) of the above-described Process I is dissolved in pyridine and reacted with phosphorus oxychloride to obtain 1-(2,4-difluorophenyl)-1-(4-(4-cyanothiazol-2-yl)-thiophen-2 yl)-2-(1H-1,2,4-triazol-1-yl)ethanol.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][N:8]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:21][CH:20]=1)[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][N:8]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](=[O:27])(=[O:28])[NH2:26])=[CH:21][CH:20]=1)[CH2:9][C:10]([OH:12])=[O:11]
Reactant: Cn1ccnc1CN(CCc1ccc(S(N)(=O)=O)cc1)CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1ccnc1CN(CCc1ccc(S(N)(=O)=O)cc1)CC(=O)O

Procedure:
Synthesis of [Re(CO)3][2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylphenethyl)-amino)acetic acid]. To a solution tert-butyl 2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylphenethyl)amino)acetate (110 mg, 0.27 mmol) in DCM (3.0 mL) and TFA (3.0 mL) was stirred at room temperature for overnight. Solvent was removed under reduced pressure to give 2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylphenethyl)amino)acetic acid. A solution of 2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylphenethyl)amino)acetic acid, [NEt4]2[ReBr3(CO)3] (270 mg, 0.35 mmol) and K2CO3 (78 mg) in MeOH (6.0 mL) was stirred at 90° C. for 4 h at a pressure tube. The reaction mixture was purified using Amberchrom™ (CG-161) resin eluting with MeOH/H2O to give the title compound (105 mg, 63%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J=8.0 Hz, 2H), 7.57 (d, J=8.0 Hz, 2H), 7.36 (d, J=0.8 Hz, 1H), 7.25 (s, 2H), 7.15 (d, J=1.2 Hz, 1H), 4.76 (d, J=16.4 Hz, 1H), 4.58 (d, J=16.0 Hz, 1H), 4.03 (d, J=16.8 Hz, 1H), 3.67 (d, J=16.8 Hz, 1 H), 3.65-3.49 (m, 2H), 3.17-3.09 (m, 2H); ESMS m/z: 623 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][CH:7]=[CH:6][CH:5]=2.[F:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].S(=O)(=O)(O)O.CCOCC>[N+](C1C=CC=CC=1)([O-])=O>[O:14]=[C:3]1[C:2]2[N:1]=[C:18]([C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[F:15])[O:19][C:11]=2[C:10](=[O:13])[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: NC1=C(Cl)C(=O)c2ccccc2C1=O
Reactant: O=C(Cl)c1ccccc1F
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccccc2C(=O)c2oc(-c3ccccc3F)nc21
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 29.6 %

Procedure:
To a solution of 6.0 g (28.8 mmol) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 120 mL of nitrobenzene, 17.10 mL (144.0 mmol) of 2-fluorobenzoic acid chloride are added with protection from light. After 10 min of stirring at 80° C., 0.20 mL of concentrated sulfuric acid is added. The reaction mixture is heated to reflux for 18 h. After complete cooling, ether is added to produce a yellow precipitate, which is filtered through fritted glass and washed with ether. This solid is then purified on a flash column (support: silica; conditioning: heptane; eluant: dichloromethane/heptane, 60/40) to produce 2.5 g of 4,9-dihydro-4,9-dioxo-2-(2-fluorophenyl)-naphtho[2,3-d]oxazole in the form of yellow crystals.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(N(CC)CC)C.C1(C)C=CC(S([N:30]=[N+:31]=[N-])(=O)=O)=CC=1>C(#N)C>[N+:30](=[C:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH2:9][Si:10]([CH3:11])([CH3:13])[CH3:12])=[O:6])=[N-:31]
Reactant: CC(=O)CC(=O)OCC[Si](C)(C)C
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)C(=[N+]=[N-])C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.6 %

Procedure:
To a solution of trimethylsilylethyl acetoacetate (10.6 g, 50.0 mmol) and triethylamine (7.10 mL, 51.5 mmol) in acetonitrile (85 mL) was added in an ice-bath p-toluenesulfonyl azide (10.0 g, 50.7 mmol) and the reaction mixture stirred at room temperature for 20 h. After evaporation of the solvent in vacuo, the residue was extracted with Et2O (90 mL) and this extract was washed with a solution of KOH (3.0 g) in H2O (83 mL) and again a solution of KOH (0.9 g) in H2O (30 mL), then brine, and dried (Na2SO4). Evaporation of the solvent in vacuo gave 11.6 g of a crude oil which was purified by column chromatography (SiO2, 150 g) eluting with 20% EtOAc/Hexanes, to obtain 9.65 g (42.3 mmol, yield 84.5%) of the title compound as yellowish oil: Rf 0.44 (20% EtOAc/Hex); ir (neat)νmax : 2130 (C=N2), 1715 (ester), and 1660 (ketone) cm-1 ; uv (CH2Cl2)λmax : 257 nm (ε7200); 1Hmr (CDCl3)δ: 0.07 (9H, s, SiMe3), 1.03 (2H, `t` J=8 Hz, CH2Si), 2.47 (3H, s, COCH3), and 4.30 (2H, `t` J=8 Hz, CO2CH2 ppm.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#N.[OH2:13].[OH-:14].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]([OH:14])=[O:13]
Reactant: COc1cc(Cl)c(C#N)cc1Br
Reactant: O
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(Cl)c(C(=O)O)cc1Br
Temperature: 100 °C
Yield: 98 %

Procedure:
To a solution of 5-bromo-2-chloro-4-methoxybenzonitrile (3, 30.6 g, 124 mmol) in ethanol (450 mL)/H2O (225 mL) was added sodium hydroxide (124 g, 3.1 mol). The solution was refluxed at 100° C. overnight, cooled to room temperature and evaporated to remove ethanol. The aqueous layer was cooled to 0° C., acidified with concentrated hydrogen chloride (190 mL). The generated white solid was filtered, washed with water and dried in vacuo to yield the title compound (32 g, 122 mmol, 98%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]=[C:11](Cl)[CH2:12][Cl:13])=[C:4]([F:15])[CH:3]=1.[CH3:16][O:17][C:18](=[O:28])[C:19]1[CH2:27][CH2:26][CH2:25][CH2:24][C:20]=1[C:21](N)=[O:22].C(N(CC)CC)C.[OH2:36]>C1C=CC=CC=1>[CH3:16][O:17][C:18](=[O:28])[C:19]1[CH2:27][CH2:26][CH2:25][CH2:24][C:20]=1[C:21]([N:10]([C:11](=[O:36])[CH2:12][Cl:13])[C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Cl:1])=[CH:3][C:4]=1[F:15])=[O:22]
Reactant: COC(=O)C1=C(C(N)=O)CCCC1
Reactant: COc1cc(N=C(Cl)CCl)c(F)cc1Cl
Reactant: O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(=O)C1=C(C(=O)N(C(=O)CCl)c2cc(OC)c(Cl)cc2F)CCCC1
Reaction time: 1.5 h

Procedure:
First, 1.47 g of N-(4-chloro-2-fluoro-5-methoxyphenyl)-2-chloroacetimidoylchloride and 1.00 g of 3,4,5,6-tetrahydrophthalamic acid monomethyl ester were dissolved in 20 ml of benzene, and 570 mg of triethylamine dissolved in 5 ml of benzene was added to the solution at room temperature. After that the stirring was continued for 1.5 hr at 60° C. After letting the reaction liquid stand to cool the same, it was poured into iced water, and then the organic layer was separated therefrom. The organic layer was washed first with water and then with saturated brine, and then dried by using anhydrous magnesium sulfate. The solvent was concentrated, and then methanol was added to the residue. The produced crystals were filtered out, then washed with methanol, and then dried to obtain 1.18 g of N-(2-chloroacetyl)-N-(4-chloro-2-fluoro-5-methoxyphenyl)-3,4,5,6-tetrahydrophthalamic acid methyl ester. The melting point was 109° C.
Reaction SMILES: N#N.[OH-:3].[K+].[CH:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12].Cl[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1>CS(C)=O>[CH3:12][C:6]1[CH:5]=[C:10]([CH:9]=[CH:8][CH:7]=1)[O:11][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][O:3][C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([CH3:12])[CH:5]=3)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1
Reactant: [OH-]
Reactant: ClCc1ccc(-c2ccc(CCl)cc2)cc1
Reactant: Cc1cccc(O)c1
Agent: N#N
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cccc(OCc2ccc(-c3ccc(COc4cccc(C)c4)cc3)cc2)c1
Yield: 91.4 %

Procedure:
A 250 mL 3-neck flask equipped with a heating mantle, mechanical stirrer and N2 blanket was charged with KOH pellets (7.26 g, 0.11 mol based on 85% actives), DMSO (100 mL) and m-cresol (12.0 g, 0.11 mol). With stirring, the mixture was warmed to 100 C for 2 hours during which time the KOH pellets dissolved and the solution became a dark brown. To the solution was added solid 4,4′-bischloromethyl-1,1′biphenyl (12.6 g, 0.05 mol) over a period of 5 minutes. During the addition, the heating mantle was removed to facilitate air cooling and the rate of addition limited such that the reaction exotherm did not cause the internal temperature to exceed 115 C. The reaction mixture quickly became a thick slurry. After holding the reaction mass at 100 C for 4 additional hours, the mixture was stirred at room temperature overnight during which time the slurry became more fluid. The reaction mass was poured into a beaker containing 300 mL rapidly stirred water resulting in the immediate precipitation of the product, and a dissolution of the KCl byproduct. The solid product was collected via vacuum filtration and washed well with water. The light tan paste was dried in a forced air oven at 70 C for several hours providing 19.2 g (97.5%) crude product. GPC analysis of the product using a UV detector demonstrated very high purity (>99%). If desired, the product may be re-crystallized from toluene (250 mL) giving 18.0 g (91.4% yield) fine crystals. 1H and 13C-NMR, IR, GC/MS all confirm the identity and purity of the product. MP=151 C.
Reaction SMILES: [F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:30]=[CH:29][C:20]([O:21][C:22]2[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=2)=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].Br[CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>>[F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:30]=[CH:29][C:20]([O:21][C:22]2[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=2)[O:28][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: Cc1c(N(Cc2ccc(Oc3cccc(O)c3)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Reactant: CCOC(=O)CCCBr
Product: CCOC(=O)CCCOc1cccc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 120B and ethyl 4-bromobutyrate were processed as described in Example 116A to provide the title compound.
Reaction SMILES: CO[C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5]OC.[CH3:19][C:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[C:22]([CH3:27])[N:21]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[CH3:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[CH3:15])[C:8]([C:4]1[C:3](=[O:18])[C:24]2[C:25](=[C:20]([CH3:19])[N:21]=[C:22]([CH3:27])[CH:23]=2)[NH:26][CH:5]=1)=[O:17]
Reactant: COC=C(C(=O)OC)C(=O)c1ccc(C)c(C)c1
Reactant: Cc1ccc(N)c(C)n1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cc2c(=O)c(C(=O)c3ccc(C)c(C)c3)c[nH]c2c(C)n1
Temperature: 250 °C
Yield: 7.3 %

Procedure:
0.50 g (2.01 mmol) of 2-(3,4-Dimethyl-benzoyl)-3-methoxy-acrylic acid methyl ester and 0.25 g (2.01 mmol) of 2,6-Dimethyl-pyridin-3-ylamine were heated at 100° C. for two hours. After cooling to room temperature 30 mL of diphenyl ether was added and heated at 250° C. for two hours. The reaction was allowed to cool to room temperature and hexane was added. The brown precipitate was collected by filtration to yield 45 mg of 3-(3,4-Dimethyl-benzoyl)-6,8-dimethyl-1H-[1,7]naphthyridin-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:18])[C:5]([O:15][CH2:16][CH3:17])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][C:12]([OH:14])=[O:13].O=S(Cl)Cl.[CH3:23]O>>[Cl:1][C:2]1[CH:3]=[C:4]([F:18])[C:5]([O:15][CH2:16][CH3:17])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][C:12]([O:14][CH3:23])=[O:13]
Reactant: CO
Reactant: CCOc1c(F)cc(Cl)c2[nH]cc(CC(=O)O)c12
Solvent: O=S(Cl)Cl
Product: CCOc1c(F)cc(Cl)c2[nH]cc(CC(=O)OC)c12
Temperature: 25 °C
Yield: 82 %

Procedure:
To a solution of 30-9 (582 mg, 6.4 mmol) in CH3OH (20 mL) was added SOCl2 (1 mL). The mixture was refluxed for 2 h before it was cooled to room temperature, the solvent was removed under reduce pressure. The resulting residue was partitioned between water (30 mL) and ethyl acetate (30 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were combined, washed with brine (3×20 mL), dried over Na2SO4, filtered and concentrated to afford 30-10 (500 mg, 82%) as a light yellow solid. LRMS: calc 285.0 and found: 286.1 [M+1].
Reaction SMILES: [C:1]1([C:7]2[C:18]3[CH:17]=[C:16]4[C:12]([CH2:13][CH2:14][CH2:15]4)=[CH:11][C:10]=3[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][Li].[Si:21]([CH3:25])([CH3:24])(Cl)[Cl:22]>C1COCC1>[Cl:22][Si:21]([CH3:25])([CH3:24])[CH:9]1[C:10]2[C:18](=[CH:17][C:16]3[CH2:15][CH2:14][CH2:13][C:12]=3[CH:11]=2)[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8]1
Reactant: C1=C(c2ccccc2)c2cc3c(cc2C1)CCC3
Reactant: C[Si](C)(Cl)Cl
Agent: [Li][Li]
Solvent: C1CCOC1
Product: C[Si](C)(Cl)C1C=C(c2ccccc2)c2cc3c(cc21)CCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
1,2,3,5-Tetrahydro-7-phenyl-s-indacene, dilithium salt (12.2075 g, 0.05102 moles) in THF (50 mL) was added dropwise to a solution of Me2SiCl2 (19.5010 g, 0.1511 moles) in THF (100 mL) at 0° C. This mixture was then allowed to stir at room temperature overnight. After the reaction period the volatiles were removed and the residue extracted and filtered using hexane. The removal of the hexane resulted in the isolation of the desired product as a yellow oil (15.1492 g, 91.1 % yield).
Reaction SMILES: CN(C)C=O.[C:6]([N:10]1[C:15](=[O:16])[C:14]([Br:17])=[C:13]([SH:18])[CH:12]=[N:11]1)([CH3:9])([CH3:8])[CH3:7].[C:19]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>O>[C:6]([N:10]1[C:15](=[O:16])[C:14]([Br:17])=[C:13]([S:18][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][CH:25]=2)[CH:12]=[N:11]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CC(C)(C)n1ncc(S)c(Br)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Br)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
To a dimethylformamide solution of 4.4 g of 2-tert.-butyl-4-bromo-5-mercapto-3(2H)-pyridazinone and 4.7 g of 4-tert.-butylbenzyl bromide was added 3.5 g of sodium carbonate. The resulting reaction liquid was stirred at 80° C. for 4 hours, allowed to cool to room temperature, incorporated with water and extracted with benzene. The benzene layer was washed with 3% aqueous solution of sodium hydroxide and then with water, dried and then freed of benzene by distillation to give yellowish brown solid. The solid was recrystallized from a mixed solvent of benzene and n-hexane to obtain white crystals (yield: 64%).
Reaction SMILES: [Br:1][C:2]1[C:9]([O:10][CH2:11][CH3:12])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C1(C)C=CC(S(O)(=O)=[O:20])=CC=1.[C:24]1([CH3:30])C=CC=CC=1>>[Br:1][C:2]1[C:9]([O:10][CH2:11][CH3:12])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[O:20][CH2:24][CH2:30][O:5]1
Reactant: Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOc1cccc(C=O)c1Br
Product: CCOc1cccc(C2OCCO2)c1Br
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of 2-bromo-3-ethoxybenzaldehyde (128 g, 0.56 mol) and glycol (253 mL, 4.49 mol) in toluene (600 mL) was added p-toluenesulfonic acid (10 g, 0.06 mol). The reaction flask had a Dean and Stark condenser attached and the reaction mixture was refluxed to remove the water for 4 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the target compound (132 g, yield 86%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:15]([CH2:22][CH3:23])[C:16](=[O:21])[CH2:17][C:18]([CH3:20])=[O:19])[CH3:14].[CH:24](=[O:33])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>CCCCCC.O>[CH2:22]([N:15]([CH2:13][CH3:14])[C:16](=[O:21])[CH2:17][C:18](=[O:19])[CH2:20][CH:24]([OH:33])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:23]
Reactant: O=CC=Cc1ccccc1
Reactant: CCN(CC)C(=O)CC(C)=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CC(C)NC(C)C
Product: CCN(CC)C(=O)CC(=O)CC(O)C=Cc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 84.9 %

Procedure:
2.65 cm3 of diisopropylamine are introduced into a three-necked, round-bottomed flask equipped with a septum and a dropping funnel and are then cooled to -10° C. 10.4 cm3 of n-butyllithium in solution in hexane at 1.6 mol/liter (16.6 mmol) are then slowly added and the mixture is then stirred for 15 minutes. 1.40 g of N,N-diethylacetoacetamide (8.65 mmol) are then slowly added and the mixture is then stirred for 15 minutes. 1.0 g of cinnamaldehyde (7.57 mmol) is added. The mixture is stirred for 25 minutes and then 2 cm3 of concentrated hydrochloric acid and 25 cm3 of water are added. Extraction is carried out with 2 times 25 cm3 of dichloromethane. The combined organic phases are washed with 4 times 50 cm3 of water and dried over sodium sulphate. After filtration and concentration to dryness, there is obtained, with a yield of 85%, 1.86 g of N,N-diethyl-7-phenyl-5-hydroxy-3-oxo-6-heptenamide, the structure of which is confirmed by the proton nuclear magnetic resonance spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.O=[Si]=O.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1)[CH:12]=[O:13]
Reactant: OCc1cc(Cl)cc(C(F)(F)F)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: O=[Si]=O
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1cc(Cl)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 58.7 %

Procedure:
To a stirred suspension of (3-chloro-5-(trifluoromethyl)phenyl)methanol (Reference Example 30, 1.98 g, 9.40 mmol) and celite 545 (6.00 g) in methylene chloride (60.0 mL) was added pyridinium chlorochromate (6.10 g, 28.30 mmol) at room temperature. After 1 h, the reaction mixture was diluted with diethyl ether (200 mL), and filtered through silica gel and the filter cake was washed with 1:1 solution of diethyl ether/hexanes. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate 49:1) to provide 3-chloro-5-(trifluoromethyl)benzaldehyde (1.15 g, 56% (overall for 3 steps)) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[O:14][C:13](=[O:15])[NH:12][CH2:11]2)[C:5]([O:16][CH2:17][CH3:18])=[C:4]([CH:19](O)[CH3:20])[CH:3]=1.CN(C)C=O.S(Cl)([Cl:29])=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[O:14][C:13](=[O:15])[NH:12][CH2:11]2)[C:5]([O:16][CH2:17][CH3:18])=[C:4]([CH:19]([Cl:29])[CH3:20])[CH:3]=1
Reactant: CCOc1c(C(C)O)cc(Cl)c(C#N)c1C1CNC(=O)O1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1c(C(C)Cl)cc(Cl)c(C#N)c1C1CNC(=O)O1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 6-chloro-3-ethoxy-4-(1-hydroxyethyl)-2-(2-oxo-1,3-oxazolidin-5-yl)benzonitrile (58 mg, 0.19 mmol) (mixture of four diastereomers from step 4), N,N-dimethylformamide (36 μL) in methylene chloride (1 mL), thionyl chloride (40.0 μL, 0.56 mmol) was added and the mixture was stirred at room temperature for 20 minutes The mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate, filtered and concentrated to give the desired compound as a mixture of four diastereomers, 55 mg, 91%. LCMS calculated for C14H15Cl2N2O3 (M+H)+: m/z=329.0; found: 329.1.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH:16]([C:19]1[N:20]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:21](=[O:29])[C:22]2[C:27]([CH3:28])=[N:26][S:25][C:23]=2[N:24]=1)[CH2:17][CH3:18])[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:51][C:52]([CH3:54])=O>C(O)(=O)C>[CH2:30]([N:20]1[C:21](=[O:29])[C:22]2[C:27]([CH3:28])=[N:26][S:25][C:23]=2[N:24]=[C:19]1[CH:16]([N:6]([CH2:5][CH2:4][CH2:3][NH:2][CH:52]([CH3:54])[CH3:51])[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[CH2:17][CH3:18])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)=O
Reactant: CCC(c1nc2snc(C)c2c(=O)n1Cc1ccccc1)N(CCCN)C(=O)c1ccc(C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC(c1nc2snc(C)c2c(=O)n1Cc1ccccc1)N(CCCNC(C)C)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-(3-amino-propyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-propyl]-4-methyl-benzamide hydrogen chloride (method 13g) (1.24 g, 2.54 mmol), in the presence of molecular sieves (2 g,) was added acetone (1 mL) and the mixture was stirred at room temperature for 2 h. Analysis of the reaction mixture by MS showed the completion of the schiff's base formation. To this mixture was added two drops of acetic acid followed by sodium triacetoxyborohydride (220 mg) and the mixture was stirred overnight. The reaction mixture was filtered and the filtrate was washed with water, dried (Na2SO4) and concentrated to get the crude product which was purified by column chromatography (silica gel) using 0-30 % EtOAc in hexanes. N-[1-(5-Benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-propyl]-N-(3-isopropylamino-propyl)-4-methyl-benzamide was isolated as a white foam. Yield 0.206 g (15%). m/z 532 (MH+); 1H NMR (DMSO-d6, 96° C.) δ: 0.65 (t, 3H), 1.05 (d, 6H), 1.26-1.48 (m, 1H), 1.65-1.70 (m, 1H), 1.80-1.98 (m, 1H), 2.00-2.17 (m, 1H), 2.35 (s, 3H), 2.63 (b, 2H), 2.80 (s, 3H), 3.05 (b, 1H), 3.40 (t, 2H), 4.90 (d, 1H), 5.50 (bs, 1H), 5.80 (d, 1H), 7.35-7.00 (m, 9H).