Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:26])[CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:14].[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:32]([CH:37]=1)[C:33](OC)=[O:34]>C1COCC1>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[C:32]([C:33](=[O:34])[CH:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([O:15][CH2:13][CH3:14])=[O:26])[CH:37]=1
Reactant: CCOC(=O)COCc1ccccc1
Reactant: COC(=O)c1cc(Cl)ccc1OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(OCc1ccccc1)C(=O)c1cc(Cl)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
In a flame-dried flask were placed dry THF (4 ml) and diisopropylamine (1.21 g, 0.012 mol). n-Butyllithium (1.55M in hexane, 7.7 ml, 0.012 mol) was added dropwise at -10° C. under argon. After stirring for 0.5 h at 0° C., a solution of ethylphenylmethoxyacetate (2.33 g, 0.012 mol) in dry THF (4 ml) was added dropwise at -78° C. After one h methyl 5-chloro-2-phenylmethoxybenzoate (2.21 g, 0.008 mol) in dry THF (4 ml) was added. Stirring was continued for an additional 2 h at -78° C. and the reaction mixture was quenched with 2 ml of EtOH at -20° C. The quenched mixture was poured into 50 ml of 10% aqueous HCl solution and extracted with ether. The ether layer was washed with water, dried (Na2SO4), filtered and concentrated under reduced pressure affording a light yellow oil. Purification by flash chromatography (silica gel) using toluene-CHCl3 (5:1) as eluent afforded 1.96 g (56%) of ethyl 5-chloro-β-oxo-α,2-bis(phenylmethoxy)benzenepropanoate as white crystals (EtOH): mp 64°-65° C.; IR (KBr) 1735 (ester) and 1685 (conjugated carbonyl) cm-1 ; NMR (CDCl3, 90 MHz) δ 1.16 (t, 3H, OCH2CH3) 4.13 (q, 2H, OCH2CH3), 4.55 (dd, 1H, OCH2Ph, JAB =12.6 Hz), 4.60 (dd, 1H, OCH2Ph, JAB =12.6 Hz), 5.07 (s, 2H, OCH2Ph), 5.28 (s, 1H, CHCO2Et), 6.85 (d, 1H, ArH, J=8.9 Hz), 7.05-7.50 (m, 11H, ArH), 7.64 (d, 1H, ArH, J=2.5 Hz). Anal calcd. for C25H23ClO5 : C, 68.41; H, 5.28; Cl, 8.07. Found: C, 68.14; H, 5.28; Cl, 8.09.
Reaction SMILES: CC1(C)C2([CH2:10][S:11](O)(=[O:13])=[O:12])C(CC1CC2)=O.[CH3:16][O:17][C:18]1[CH:35]=[CH:34][C:33]2[C@H:32]3[N:23]([C:24](=[O:36])[C@@H:25]4[C@H:30]([CH2:31]3)[NH:29][CH2:28][CH2:27][CH2:26]4)[CH2:22][CH2:21][C:20]=2[CH:19]=1.CN1CCOCC1.CS(Cl)(=O)=O>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:35]=[CH:34][C:33]2[C@H:32]3[N:23]([C:24](=[O:36])[C@@H:25]4[C@H:30]([CH2:31]3)[N:29]([S:11]([CH3:10])(=[O:13])=[O:12])[CH2:28][CH2:27][CH2:26]4)[CH2:22][CH2:21][C:20]=2[CH:19]=1
Reactant: COc1ccc2c(c1)CCN1C(=O)[C@H]3CCCN[C@H]3C[C@@H]21
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc2c(c1)CCN1C(=O)[C@H]3CCCN(S(C)(=O)=O)[C@H]3C[C@@H]21
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
A mixture of 660 g of the d-10-camphorsulfonic acid salt of (8aS,12aS,13aS)-3-methoxy-5,6,8a,9,10,11,12,12a,13,13a-decahydroisoquino[2,1-g][1,6]naphthyridin-8-one (IA) in 8 litres of methylene chloride and 404 g of N-methylmorpholine was cooled in an ice bath to 10° C. and 153 ml of methanesulfonyl chloride was added over 30 minutes, allowing the temperature to rise to 16° C. The mixture was stirred at 10°-16° C. for 90 minutes, then washed sequentially with water, IN hydrochloric acid, and water. The organic layer was dried over sodium sulfate and the solvent removed under reduced pressure. The residue was crystallized from methanol to give (8aS,12aS,13aS)-3-methoxy-12-methanesulfonyl-5,6,8a,9,10,11,12,12a,13,13a-decahydroisoquino[2,1-g][1,6]naphthyridin-8-one, m.p. 138°-140° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.O>C(Cl)Cl>[Si:10]([O:6][CH2:5][C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][CH:7]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: OCc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a solution of 3-bromobenzyl alcohol (5.00 g, 26.7 mmol) in freshly drieddimethylformamide (10 mL) was added t-butyldimethylsilyl chloride (5.13 g, 33 mmol) and imidazole (4.56 g, 67 mmol). The resulting solution was stirred overnight at ambient temperature. The reaction mixture was poured into water and extracted (3x, 50 mL 1:1 ether:hexanes). The combined organic layers were washed (2x, brine), dried over MgSO4, filtered, and concentrated in vacuo to give a colorless oil which was passed througha short silica gel plug using 10% methylene chloride:hexanes to give pure 3-(t-butyldimethylsilyloxymethyl)bromobenzene (7.9 g, 98%). 1H NMR (300 MHz, CDCl3) δ 7.47 (1H, br s), 7.37 (1H, dt, J =7, 1 Hz), 7.16-7.25 (2H, m), 4.24 (2H, s), 0.94 (9H, s), 0.11 (6H, s). MS m/e 318/320(M+NH4)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Cl[CH2:13][Si:14]([CH3:23])([CH3:22])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CS(C)=O.C(OCC)C>[CH3:13][Si:14]([CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1)([CH3:22])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1
Reactant: C[Si](C)(CCl)c1ccc(F)cc1
Reactant: CC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(=O)Cc1ccc(OC[Si](C)(C)c2ccc(F)cc2)cc1
Temperature: 0 °C

Procedure:
30 g of 1-(4-hydroxyphenyl)-propan-2-one and 45.5 g of chloromethyl-dimethyl-(4-fluorophenyl)-silane in 400 ml of dimethyl sulfoxide are stirred with 42 g of potassium carbonate and 2 g of potassium iodide for 12 hours at 70° C. The reaction mixture is poured into 1.6 liters of ice water and 500 ml of diethyl ether are added; the ether phase is extracted by washing several times with water and saturated sodium chloride solution and dried over sodium sulfate; the solvent is evaporated off. Distillation at 150° C. (0.01 mbar) yields the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:5]([O:7]CC)=[O:6].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)c1ccc(N2CCCC2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(N2CCCC2)c(Cl)c1
Temperature: 40 °C
Yield: 59.2 %

Procedure:
A mixture of ethyl 3-chloro-4-(1-pyrrolidinyl)benzoate (D39) (685 mg, 2.71 mmol) and aqueous sodium hydroxide (2M, 1.36 mL, 2.72 mmol) in ethanol (15 mL) was heated at 40° C. for 17 h. Further sodium hydroxide (1.36 mL, 2.72 mmol) was added and the reaction heated for a further 8 h. The mixture was concentrated and the residue dissolved in water (100 mL). The aqueous phase was washed with ethyl acetate (2×100 mL) and then acidified to pH 6. A white solid formed and hence was filtered off, washed with water and dried in a vacuum oven to give the title compound as an off-white solid (362 mg). MS (ES): C11H1235ClNO2 requires 225; found 226 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[F:18].[H][H]>C(O)(=O)C.[C].[Pd]>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)=[CH:4][C:3]=1[F:18]
Reactant: Oc1ccc(-c2cc(F)c(F)c3ccoc23)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Oc1ccc(-c2cc(F)c(F)c3c2OCC3)cc1
Yield: 59 %

Procedure:
The compound (568 mg, 2.31 mmol) of Step 1 was dissolved in acetic acid (25 mL), and a catalytic amount of 10% palladium-carbon was added thereto, and stirred in a hydrogen atmosphere of 4 atm overnight. The insoluble material was filtered off, and the solvent was distilled away under reduced pressure. The resulting residue was purified by reversed-phase HPLC in the same manner as in Step 2 of Example 1 to thus obtain the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:8]2[NH:9][C:10](=[O:13])[CH2:11][O:12][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15])[CH3:2].[CH2:17](C1C([N+]([O-])=O)=CC2NC(=O)COC=2C=1)[CH3:18].C([Mg]Br)C>>[CH2:1]([C:3]1[C:8]2[NH:9][C:10](=[O:13])[CH2:11][O:12][C:7]=2[CH:6]=[C:5]([CH2:17][CH3:18])[C:4]=1[N+:14]([O-:16])=[O:15])[CH3:2]
Reactant: CCc1c([N+](=O)[O-])ccc2c1NC(=O)CO2
Reactant: CCc1cc2c(cc1[N+](=O)[O-])NC(=O)CO2
Agent: CC[Mg]Br
Product: CCc1cc2c(c(CC)c1[N+](=O)[O-])NC(=O)CO2

Procedure:
The title compound is synthesized from either 5-ethyl-6-nitro-3-oxo-3,4-dihydro-(2H)-1,4-benzoxazine or from 7-ethyl-6-nitro-3-oxo-3,4-dihydro-(2H)-1,4-benzoxazine and ethyl magnesium bromide, using the procedure illustrated in Example 37.
Reaction SMILES: OCCCCCCCCCCCCCCC[C:17]([O:19][CH:20]([O:22][C:23](=[O:40])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]CCCCCCCCCO)C)=[O:18].N1C=CC=CC=1.C(OCCCCCCCCCCCCCCCC([Cl:82])=O)(=O)CCCCCCCCCCCCCCC>C1COCC1>[Cl:82][C:17]([O:19][CH2:20][O:22][C:23](=[O:40])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:18]
Reactant: CC(OC(=O)CCCCCCCCCCCCCCCO)OC(=O)CCCCCCCCCCCCCCCO
Reactant: CCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Cl)OCOC(=O)c1ccccc1
Reaction time: 2 h
Yield: 145.8 %

Procedure:
Ethylidene bis (16-hydroxyhexadecanoate) (4.38 g, 7.67 mmol) was dissolved in THF (80 ml) and pyridine (0.61 g, 7.71 mmol) was added. 16-hexadecanoyloxyhexadecanoyl chloride (4.18 g, 7.90 mmol) was dissolved in THF (20 ml) and added dropwise. After 3 days at room temperature the mixture was filtered and the filtrate was left at -20° C. for 2 hours. The precipitated product was filtered and purified by flash chromatography (silicagel, chloroform) to give 2.4 g (29%) of the title compound. 1H NMR (300 MHz, CDCl3): δ0.85 (t, 3H, CH3), 1.2-1.4 (s, 90H, --CH2 --), 1.45 (d, 3H, --O--CH(CH3)--O--), 1.5-1.7 (m, 14H, --CH2 --), 2.25 (m, 8H, --CH2 --C(O)--O--), 3.60 (t, 2H, --CH2 --OH), 4.05 (t, 4H, --C(O)--O--CH2 --), 6.85 (q, 1H, --O--CH(CH3)--O--). 13C NMR (75 MHz, CDCl3): δ13.7, 19.1, 22.2, 24.2, 24.6, 25.2, 25.5, 28.2, 28.5, 28.7, 28.8, 29.0, 29.2, 31.5, 32.3, 33.7, 34.0, 62.5, 64.0, 88.0, 171.5, 173.5.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1.[NH2:20][CH2:21][CH2:22][NH:23][C:24]([N:26]([CH3:28])[CH3:27])=[O:25]>C(O)(C)C>[CH3:27][N:26]([CH3:28])[C:24]([NH:23][CH2:22][CH2:21][NH:20][CH2:15][CH:14]([OH:16])[CH2:13][O:12][C:11]1[CH:17]=[CH:18][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH:2]([CH3:19])[CH3:1])=[CH:9][CH:10]=1)=[O:25]
Reactant: CC(C)COCCOc1ccc(OCC2CO2)cc1
Reactant: CN(C)C(=O)NCCN
Solvent: CC(C)O
Product: CC(C)COCCOc1ccc(OCC(O)CNCCNC(=O)N(C)C)cc1

Procedure:
8 g of 3-(4-(2-(2-methylpropoxy)ethoxy)phenoxy)-1,2-epoxypropane and 14 g of N-2-aminoethyl-N',N'-dimethylurea was warmed (60°-70° C.) in 150 ml of isopropanol over night. The mixture was evaporated and the residue dissolved in ethyl acetate. The ethyl acetate phase was washed with water (twice), fresh water was then added and pH lowered to 5 with hydrochloric acid. Fresh ethyl acetate was then added to the water phase and pH was rised to 9.5. The organic phase was separated off, dried, and evaporated. The residue was recrystallized from a small amount of ethyl acetate. Yield 3 g. M.p. 75° C. (base). The structure was determined using NMR-analysis.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.C(OP([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])(OCC)=O)C.[H-].[Na+]>CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:45]/[C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:22][N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.80 g), ethyl diethylphosphonoacetate (0.40 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.080 g) under ice-cooling. The mixture was stirred at room temperature for 3 hrs. The reaction mixture was poured into ice water and the precipitated solid was collected by filtration to give ethyl (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoate as pale-brown crystals (0.85 g, yield 96%). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 177-178° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[O:37][N:36]=[C:35]([CH2:38][CH3:39])[N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:38]([C:35]1[N:34]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[O:37][N:36]=1)[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Reactant: CCc1noc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (7.70 g; compound B50) is reacted with 5-(chloromethyl)-3-ethyl-1,2,4-oxadiazole (2.64 g; compound D7) in the presence of potassium carbonate (2.49 g) in DMF (50 ml). Using WU1 a solid is obtained which is recrystallized from EtOAc (400 ml) at 65° C. to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=O.[F:22][C:23]1[CH:24]=[C:25]([CH2:30]C#N)[CH:26]=[CH:27][C:28]=1[F:29]>>[F:22][C:23]1[CH:24]=[C:25]([C:30]2[O:3][N:1]=[C:4]3[CH:5]=[CH:6][C:7]([C:10]4[N:14]([C:15]5[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=5)[N:13]=[CH:12][CH:11]=4)=[CH:8][C:9]=23)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: N#CCc1ccc(F)c(F)c1
Reactant: Cc1ccc(-n2nccc2-c2ccc([N+](=O)[O-])cc2)cc1
Product: Cc1ccc(-n2nccc2-c2ccc3noc(-c4ccc(F)c(F)c4)c3c2)cc1

Procedure:
The title compound, light yellow solid (22 mg, 16%), MS (ISP) m/z=388.3 [(M+H)+], mp 198° C., was prepared in accordance with the general method of example 1 from 5-(4-nitro-phenyl)-1-p-tolyl-1H-pyrazole (intermediate E) (100 mg, 353 μmol) and commercially available 2-(3,4-difluoro-phenyl)-acetonitrile (see also example 39).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:3]=1.[Br-].[CH2:25]([Zn+])[CH:26]([CH3:28])[CH3:27].C1COCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:25]([C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:3]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C[Zn+]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)n3cnnc23)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c2nncn12
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A 50 mL round bottom flask was charged with tert-butyl 4-(5-bromo-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)piperazine-1-carboxylate (0.5 g, 1.3 mmol), Pd(PPh3)2Cl2 (140.3 mg, 0.20 mmol) and toluene (8 mL) under N2. To the above was injected a 2 M solution of isobutylzinc(II) bromide in THF (10.4 mL, 5.2 mmol). The resulting mixture was stirred under N2 at 20° C. for 0.5 h then 100° C. overnight. Work-up: the reaction mixture was filtered. The filter cake was washed with EtOAc (10 mL) and the filtrate was extracted with more EtOAc (10 mL×3). The combined organic solutions were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 2% methanol in dichloromethane, to afford 0.30 g (64%) of tert-butyl 4-(5-isobutyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)piperazine-1-carboxylate as a yellow solid. MS m/z: 361 (M+H+).
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])OC.C[O-].[Na+].[CH3:10][O:11][C:12]1[C:13]([O:24][CH3:25])=[CH:14][C:15]2[S:21][CH2:20][CH2:19][CH2:18][C:17](=[O:22])[C:16]=2[CH:23]=1.Cl>>[CH3:10][O:11][C:12]1[C:13]([O:24][CH3:25])=[CH:14][C:15]2[S:21][CH2:20][CH2:19][CH:18]([C:1]([O:4][CH3:5])=[O:6])[C:17](=[O:22])[C:16]=2[CH:23]=1
Reactant: COc1cc2c(cc1OC)C(=O)CCCS2
Reactant: COC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: COC(=O)C1CCSc2cc(OC)c(OC)cc2C1=O
Temperature: 0 °C
Yield: 79 %

Procedure:
To dimethyl carbonate (87 g) is added sodium methoxide (10.5 g), to the mixture is added 7,8-dimethoxy-3,4-dihydro-1-benzothiepin-5(2H)-one(11.0 g) obtained in Reference Example 7. The mixture is heated for two hours under reflux. The reaction mixture is poured into ice-water and acidified (pH 3) with 2N hydrochloric acid, followed by extraction with ethyl acetate. The organic layer is washed with a saturated aqueous saline solution, dried, and concentrated under reduced pressure. The residue is recrystallized from hexane - methylene chloride to afford methyl 7,8-dimethoxy5-oxo-2,3,4,5-tetrahydro-1-benzothiepin-4-carboxylate as colorless needles (10.8 g), m.p. 132°-133° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:19])[CH2:10][S:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:19])/[C:10](/[S:11][C:12]2[CH:13]=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=2)=[CH:25]\[C:24]2[CH:27]=[CH:28][C:21]([Br:20])=[CH:22][CH:23]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)CSc2ccc(Br)cc2)cc1
Reactant: O=Cc1ccc(Br)cc1
Product: COc1ccc(C(=O)/C(=C\c2ccc(Br)cc2)Sc2ccc(Br)cc2)cc1

Procedure:
The title compound is prepared by the methods described in Synthesis Example 1. A solution of 1-(4-methoxyphenyl)-2-(4-bromophenylthio)ethanone (10 mmol) and 4-bromobenzaldehyde (10 mmol) was subjected to the procedure described as Method B in part C of Synthesis Example 1 and the product obtained was purified by column chromatography.
Reaction SMILES: [F:1][CH:2]([CH:8]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][F:10])[C:3]([O:5]CC)=[O:4].[ClH:19]>>[ClH:19].[F:1][CH:2]([CH:8]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][F:10])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(F)C(CF)NCc1ccccc1
Agent: Cl
Product: O=C(O)C(F)C(CF)NCc1ccccc1
Temperature: 100 °C
Yield: 80 %

Procedure:
A solution of ethyl 2,4-difluoro-3-benzylamino-butanoate prepared as in Step B (1.240 g, 4.8 mM) in 1 N hydrochloric acid (30 ml) is heated at 100° C. for 4 hours. The solvent is removed in vacuo. The crude product is taken off several times in isopropanol and the alcohol evaporated evaporated in vacuo. 2,4-Difluoro 3-benzylamino-butanoic acid, hydrochloride is obtained as a white solid, recrystallized from ethanol/ether: 1.010 g (yield about 80%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4](/[N:12]=[C:13]2\C(Cl)=NSS\2)[CH:3]=1.[CH2:19]([NH2:24])[CH2:20][CH2:21][CH2:22][NH2:23].N#N>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:8])[N:23]3[CH2:22][CH2:21][CH2:20][CH2:19][NH:24][C:13]3=[N:12]2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Br)cc1/N=c1/ssnc1Cl
Reactant: NCCCCN
Agent: N#N
Solvent: O
Solvent: C1CCOC1
Product: O=c1c2ccc(Br)cc2nc2n1CCCCN2
Temperature: 25 °C

Procedure:
To a stirred solution of (E)-methyl 4-bromo-2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)benzoate (100 mg, 0.27 mmol, 1 eq) in THF was added butane-1,4-diamine (0.027 mL, 0.27 mmol, 1 eq) dropwise under N2 and the reaction was heated at reflux for 3 hours. After it was cooled to rt, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the desired product, which was purified by silica gel chromatography. MS (ESI): 294, 296 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16](C(OCC4C=CC=CC=4)=O)[C@@H:15]([CH2:29][CH2:30][S:31][CH3:32])[C:14]3=[O:33])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1>Br.C(O)(=O)C.CCOCC>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][C@@H:15]([CH2:29][CH2:30][S:31][CH3:32])[C:14]3=[O:33])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CSCC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CSCC[C@@H]1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Reaction time: 1 h
Yield: 42 %

Procedure:
1-(4-Amino-quinazolin-7-ylmethyl)-4-benzyloxycarbonyl-3-(S)-(2-methylsulfanyl-ethyl)-piperazin-2-one (100 mg, 0.215 mmol) is dissolved in 5 ml of 30% hydrogen bromide in acetic acid. The mixture is stirred for 1 hour, diluted with ethyle ether. The ether is decanted and the resulting solid is washed thoroughly with ethyle ether. The resulting crude product is purified by column chromatography eluting with a 4/2/1 mixture of CH2Cl2/MeOH/NH4OH (30% in H2O). with a gradient of 5% MeOH:CH2Cl2 to 10% MeOH:CH2Cl2. The resulting product is purified by another column chromatography eluting with a gradient of 20% MeOH:CH2Cl2 to 50% MeOH:CH2Cl2. The title bound (30 mg, 42% yield) is obtained as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:43])[CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:32](=[N:40][C:41]#[N:42])OC5C=CC=CC=5)[CH2:28][CH2:27]4)[CH2:20][CH2:19]3)[C:5]2=[N:6][CH:7]=1.[OH-].[NH4+:45]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:43])[CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:32](=[NH:45])[NH:40][C:41]#[N:42])[CH2:28][CH2:27]4)[CH2:20][CH2:19]3)[C:5]2=[N:6][CH:7]=1
Reactant: N#CN=C(Oc1ccccc1)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Product: N#CNC(=N)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
Phenyl 4-[2-[4-(3-bromo-8-chloro-6,11-dihydro-5 H-benzo[5,6] cyclohepta[1,2-b]pyridin-11-yl)-1-piperazinyl]-2-oxoethyl]-N-cyano-1-piperidinecarboximidate (2.62 g) (Formula 2.0, prepared as described in Example 1 above) was dissolved in 2-propanol (50 ml) and concentrated ammonium hydroxide (4 ml) was added. The mixture was stirred at 25° C. for 24 h and then evaporated to dryness. The residue was triturated with diethyl ether (2×250 ml) and the ether was discarded. The remaining product was chromatographed on a silica gel column (60×2.5 cm) using 4% (10% concentrated ammonium hydroxide in methanol)-dichloromethane as the eluant to give the title compound (Formula 3.0) (1.967 g;85%), FABMS: m/z 584.2 (MH+).