Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:7]2[CH2:8][CH2:9][CH2:10][N:11]=[C:6]2[S:5][C:4]=1[C:12]([OH:14])=O.C(OCC)C>S(Cl)(Cl)=O>[ClH:1].[CH3:2][C:3]1[N:7]2[CH2:8][CH2:9][CH2:10][N:11]=[C:6]2[S:5][C:4]=1[C:12]([Cl:1])=[O:14]
Reactant: CC1=C(C(=O)O)SC2=NCCCN21
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CC1=C(C(=O)Cl)SC2=NCCCN21
Yield: 198.4 %

Procedure:
In 75 ml of thionylchloride was suspended 10.0 g of 3-methyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid hydrochloride obtained in Example 27, followed by reflux under heating for 30 minutes. After dissolving completely, the reaction mixture was cooled. To the reaction mixture was added anhydrous diethylether under cooling with ice. The formed crystals were collected by filtration and dried over under reduced pressure to yield 10.7 g of 3-methyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carbonylchloridehydrochloride. In 5 ml of pyridine were dissolved 490 mg of this crystal and 0.2 ml of 3,5-dimethylaniline, followed by stirring at room temperature for 6 hours. The reaction mixture was concentrated and to the concentrate was added 5% sodium hydrogencarbonate aqueous solution. The precipitated crystals were collected by filtration and washed with diethylether. The resulting powder was suspended in diethylether. To the suspension was added 0.5 ml of saturated hydrogenchloride aqueous solution, followed by stirring at room temperature. The precipitated crystals were collected by filtration. The crystals were recrystallized from ethanol to obtain 216 mg of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=3I)=[CH:13][CH:12]=2)[CH:5]=1.C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=3[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)=[CH:13][CH:12]=2)[CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COC(=O)c1cccc(Cc2ccc(COc3ccc(C(C)=O)c(O)c3I)cc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(Cc2ccc(COc3ccc(C(C)=O)c(O)c3-c3ccccn3)cc2)c1
Temperature: 100 °C
Yield: 60.9 %

Procedure:
A mixture of 3-[4-(4-acetyl-3-hydroxy-2-iodo-phenoxymethyl)-benzyl]-benzoic acid methyl ester (417 mg, 0.808 mmol), 2-tributylstannanyl-pyridine (1.72 g, 4.67 mmol), and tetrakis(triphenylphosphine)palladium(0) (111 mg, 0.096 mmol) in toluene (19 mL) is thoroughly degassed, placed under nitrogen and heated at 100° C. for 16 hours. After cooling to room temperature, the reaction mixture is concentrated in vacuo. The residue thus obtained is purified by flash chromatography (20% to 40% ethylacetate in hexanes) to give 230 mg of the title compound as a yellow oil: MS (m/z): 468 (M+1); 1H NMR (CDCl3) δ 8.74 (m, 1H), 7.87 (m, 2H), 7.78 (m, 2H), 7.56 (d, J=8.0 Hz, 1H), 7.36-7.27 (m, 3H), 7.17 (d, J=8.0 Hz, 2H), 7.11 (d, J=8.0 Hz, 2H), 6.60 (d, J=9.0 Hz, 1H), 5.14 (s, 2H), 3.99 (s, 2H), 3.89 (s, 3H), 2.61 (s, 3H).
Reaction SMILES: C1COCC1.C[O:7][C:8](=[O:31])[C:9]1[CH:14]=[CH:13][C:12]([C:15](=[C:23]2[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH2:24]2)[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.[OH-].[Na+]>C(O)C>[CH3:29][C:26]1([CH3:30])[CH2:25][CH2:24][C:23](=[C:15]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:12]2[CH:13]=[CH:14][C:9]([C:8]([OH:31])=[O:7])=[CH:10][CH:11]=2)[CH2:28][CH2:27]1
Reactant: COC(=O)c1ccc(C(=C2CCC(C)(C)CC2)c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CCC(=C(c2ccc(O)cc2)c2ccc(C(=O)O)cc2)CC1
Temperature: 65 °C
Yield: 85.9 %

Procedure:
To a solution of THF (2 mL) and ethanol (2 mL) containing 4-[(4,4-dimethyl-cyclohexylidene)-(4-hydroxy-phenyl)-methyl]-benzoic acid methyl ester (171) (0.16 g, 0.457 mmol) was added 1 N NaOH (4 mL). The reaction mixture was heated at 65° C. for 4 h. The reaction mixture was partially concentrated to remove the EtOH and THF. To the basic aqueous mixture was added 1 N HCl to pH˜1 (according to litmus paper). The acidic aqueous solution was extracted with dichloromethane and the organic extract washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was triturated with dichloromethane, filtered, and dried to give 0.132 g (85%) of the title compound 172 as a white powder. 1H NMR (400 MHz, DMSO-d6): δ 0.93 (s, 6 H), 1.32 (s, 4 H), 2.12-2.19 (m, 4 H), 6.66 (d, J=8.3 Hz, 2 H), 6.84 (d, J=8.4 Hz, 2 H), 7.14 (d, J=8.1 Hz, 2 H), 7.83 (d, J=8 Hz, 2 H), 9.33 (s, 1 H), 12.74 (s, 1 H). HRMS (ESI) Calcd for C22H23O3: 335.1647 (M−H)−. Found: 335.1640.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27]OS(C)(=O)=O)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[N:33]1([CH2:27][CH2:26][O:25][C:21]2[CH:20]=[C:19]3[C:24]([C:15]([C:8]4[C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)=[N:11][N:10]5[CH2:12][CH2:13][CH2:14][C:9]=45)=[CH:16][CH:17]=[N:18]3)=[CH:23][CH:22]=2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCCOc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Product: c1ccc(-c2nn3c(c2-c2ccnc4cc(OCCN5CCOCC5)ccc24)CCC3)nc1
Yield: 100 %

Procedure:
Heat methanesulfonic acid 2-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-ethyl ester (87 mg, 0.19 mmol) with morpholine (1 mL) at 50° C. for 4 hours. Remove the morpholine in vacuo and then extract the product with isopropyl alcohol:chloroform (1:3). Wash the organic layer with sodium chloride and dry over sodium sulfate. Concentrate in vacuo to give the desired title product as a slight yellow solid (83 mg, 100%). MS ES+ m/e 442.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:26]([O:29][CH2:30][C:31]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=[CH:33][C:32]=1[N:46]1[CH2:58][CH2:57][N:49]2[C:50]3[CH2:51][CH2:52][CH2:53][CH2:54][C:55]=3[CH:56]=[C:48]2[C:47]1=[O:59])(=[O:28])[CH3:27].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:26]([O:29][CH2:30][C:31]1[C:32]([N:46]2[CH2:58][CH2:57][N:49]3[C:50]4[CH2:51][CH2:52][CH2:53][CH2:54][C:55]=4[CH:56]=[C:48]3[C:47]2=[O:59])=[CH:33][CH:34]=[CH:35][C:36]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:28])[CH3:27]
Reactant: Cn1cc(Br)cc(Nc2ccn(CCO[Si](C)(C)C(C)(C)C)n2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccn(CCO[Si](C)(C)C(C)(C)C)n3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 27.2 %

Procedure:
A mixture of 163a (800 mg, 1.88 mmol), 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a (1.3 g, 2.82 mmol), sodium acetate (308 mg, 3.76 mmol), PdCl2(dppf) (153 mg, 0.188 mmol) and K3PO4 (1 g, 3.76 mmol) suspended in CH3CN (50 mL) and water (3 mL) was heated at 110° C. for 12 h under argon atmosphere. The mixture was then evaporated and the residue was purified by reverse phase Combi-flash eluting with 0.3% NH4HCO3 in 1:5 water/CH3CN to give 163b as a brown solid (350 mg, 29%). MS: (M+H)+ 685
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]([C:9]1[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH3:19])[C:12]([OH:20])=[CH:11][CH:10]=1)=[O:8])[CH2:2]2.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23]>>[F:26][C:25]([F:28])([F:27])[S:22]([O:20][C:12]1[C:13]2[C:18](=[C:17]([CH3:19])[CH:16]=[CH:15][CH:14]=2)[C:9]([C:7]([N:3]2[CH2:2][CH:1]3[CH:5]([CH2:6]3)[CH2:4]2)=[O:8])=[CH:10][CH:11]=1)(=[O:23])=[O:21]
Reactant: Cc1cccc2c(O)ccc(C(=O)N3CC4CC4C3)c12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cccc2c(OS(=O)(=O)C(F)(F)F)ccc(C(=O)N3CC4CC4C3)c12

Procedure:
The desired intermediate was prepared by treating 3-azabicyclo[3.1.0]hexan-3-yl(4-hydroxy-8-methylnaphthalen-1-yl)methanone (above step-2 intermediate) with Tf2O using the similar procedure as described in Step-8 of Intermediate-22.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]O)=[CH:5][CH:4]=1.P(Br)(Br)[Br:14]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][Br:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCO)cc1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: COc1ccc(CCCBr)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
To a solution of 3-(p-methoxyphenyl)-1-propanol (16.6 g; 0.1 mol) in 250 mL of toluene, cooled to 0° C., was added dropwise 26 mL of phosphorus tribromide (0.27 mol). Following completion of the addition, the reaction was stirred at room temperature for 1 hour, then refluxed for an additional hour. The reaction was cooled and poured onto ice, the layers were separated, and the organic phase washed with saturated sodium bicarbonate (3×) and brine (3×). The crude material obtained upon drying and evaporation of the solvent was chromatographed, eluting with 10% EtOAc/hexane, to obtain 14 g (61%) of 3-(p-methoxyphenyl)-1-propylbromide.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([NH:13][NH2:14])=[O:12])=[CH:9][N:8]=1.CN1CCOCC1>ClCCl>[Cl:1][CH2:2][C:3]([NH:14][NH:13][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][C:7]([Cl:6])=[N:8][CH:9]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: NNC(=O)c1ccc(Cl)nc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(CCl)NNC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
Chloroacetyl chloride (2.8 mL, 34.9 mmol) was added dropwise to an ice-cooled solution of 6-chloronicotinic acid hydrazide (5 g, 29.1 mmol) and 4-methylmorpholine (4.8 mL, 43.7 mmol) in dichloromethane (100 mL) and the reaction was stirred at room temperature for 3 hours. The resulting precipitate was then filtered off, slurried with dichloromethane, re-filtered, washed with dichloromethane (×3) and dried to afford the title compound as a beige solid in 57% yield, 4.1 g
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]([OH:11])[CH2:8][CH:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:6]1)=[O:4].C(N(CC)CC)C.CS(C)=O.C(Cl)Cl>>[CH3:15][O:14][C:12]([CH:7]1[CH2:8][C:9](=[O:11])[CH2:10][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1)=[O:13]
Reactant: COC(=O)C1CC(O)CC(C(=O)OC)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)C1CC(=O)CC(C(=O)OC)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
To a mixture of 5-hydroxy-cyclohexane-1,3-dicarboxylic acid dimethyl ester from step 1 (3.00 g, 13.9 mmol) and triethylamine (5.80 mL, 41.6 mmol) in dimethyl sulfoxide (6.00 mL, 84.5 mmol) and DCM (0.60 mL, 9.36 mmol) was added portion-wise sulfur trioxide-pyridine complex (5.08 g, 31.9 mmol) at 10° C. The reaction mixture was stirred at room temperature for 2 hrs and then quenched with water (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×40 mL) and concentrated under reduced pressure. The residue was purified by CombiFlash® system (gradient: 0 to 50% ethyl acetate in DCM over 30 min) to give 2.2 g (74%) the title compound, 5-oxo-cyclohexane-1,3-dicarboxylic acid dimethyl ester. 1H NMR (400 MHz, CDCl3): δ 3.72 (s, 6H), 2.61-2.75 (m, 2H), 2.31-2.47 (m, 3H), 1.83 (ddt, J=2.9, 13.5, 34.4 Hz, 2H), 1.53 (q, J=13.2 Hz, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Br[CH2:45][C:46]1[CH:47]=[C:48]([CH:53]=[CH:54][CH:55]=1)[C:49]([O:51][CH3:52])=[O:50].BrCC1OC(C(F)(F)F)=CC=1>>[O:21]=[C:2]1[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:45][C:46]1[CH:47]=[C:48]([CH:53]=[CH:54][CH:55]=1)[C:49]([O:51][CH3:52])=[O:50]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: COC(=O)c1cccc(CBr)c1
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COC(=O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and methyl 3-(bromomethyl)benzoate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, methyl 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate was obtained (93%) as a colorless solid: mp 97-98° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ8.04 (s, 1H), 8.02-7.96 (m, 1H), 7.58-7.52 (m, 1H), 7.49-7.42 (m, 1H), 7.25-7.17 (m, 2H), 7.09-7.00 (m, 1H), 6.78 (d, J=7.5 Hz, 1H), 6.56 (s, 1H), 6.45 (s, 1H), 5.16 (d, J=15.7 Hz, 1H), 5.02 (d, J=9.0 Hz, 1H), 4.89 (d, J=15.7 Hz, 1H), 4.74 (d, J=9.0 Hz, 1H), 4.60-4.52 (m, 2H), 3.93 (s, 3H), 3.13-2.96 (m, 2H); 13C NMR (75 MHz, CDCl3) δ178.1, 166.7, 162.0, 161.4, 141.9, 136.3, 132.8, 131.9, 130.9, 129.3, 129.2, 128.9, 128.4, 124.1, 123.7, 120.2, 120.1, 119.1, 109.2, 93.4, 80.7, 72.5, 57.9, 52.3, 43.9, 29.2; MS (ES+) m/z 428.1 (M+1).
Reaction SMILES: S1C=CC(CC(O)=[O:8])=C1.C(S)CCS.[CH:15]1([N:21]=[C:22]=[N:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>CN(C)C1C=CN=CC=1.C(Cl)Cl.CC(C)=O>[CH:24]1([NH:23][C:22]([NH:21][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:8])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)Cc1ccsc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: SCCCS
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C

Procedure:
As shown in Reaction 1, 2-(thiophene-3-yl)acetic acid) (1 g, 7.03 mmol), propane-1,3-dithiol (0.753 g, 7.03 mmol), and 4-dimethylaminopyridine (4-DMAP) (2.014 g, 1.75 mol) were dissolved in 80 ml of methylene chloride in a three-neck round bottom flask, after which stirring was performed at 60° C. in a nitrogen atmosphere. The stirred mixture solution was slowly added with N,N′-dicyclohexylcarbodiimide (DCC) (2.89 g, 14.06 mol) dissolved in 20 ml of methylene chloride, and was then allowed to react for 9 hours. The reaction solution was washed using saturated aqueous Na2CO3, dried over MgSO4, and filtered. The remaining solvent was removed by rotary evaporation to obtain a yellowish solution. This solution was diluted with acetone, and cooled to 0° C., to obtain residual 1,3-dicyclohexylurea (“DCU”) as a precipitate. This precipitate was removed by filtration through a paper filter, and addition of acetone and removal of the DCU precipitate were repeated until DCU precipitate was no longer evident in the solution. Finally, the remaining solvent was removed by rotary evaporation, and the crude purified using a silica column eluted with a solution of methylene chloride and methanol (60:1 v/v), thereby producing after collection of the fractions and removal of the solvent, S-3-mercaptopropyl-2-(thiophene-3-yl)ethanethioate (“MTE”) (the monomer) as a pure yellow compound. The characteristic H1-NMR spectrum (in acetone-d6) of the product is shown in FIG. 1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[CH2:11])[CH2:8][C@H:7]1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Na+].[Cl-].[OH-].[Na+]>>[CH2:15]([O:14][C:12]([C@H:7]1[CH2:8][C:9](=[CH2:11])[CH2:10][C@@H:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:13])[CH3:16]
Reactant: C=C1C[C@@H](C(=O)OCC)[C@H](C(=O)OCC)C1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Product: C=C1C[C@H](C(=O)OCC)[C@@H](C(=O)OCC)C1
Temperature: 7 °C
Yield: 44.5 %

Procedure:
An emulsion of 1.1 g racemic trans-4-Methylene-cyclopentane-1,2-dicarboxylic acid diethyl ester (Merck 8.14188.0010) in an aqueous buffer (potassium phosphate 5 mM, NaCl 0.1 M) was adjusted to pH 7.0. Under stirring at 7° C. the hydrolysis was performed with 14 mg lipase PN from Phycomyces nitens [Wako Chemicals GmbH Nissanstrasse 2 D-41468 Neuss Germany; catalog # 122-02651] under pH control (pH-stat, 1M NaOH). After consumption of 2.4 ml 1 M NaOH solution within 24 h the reaction mixture was extracted twice with 250 ml t-butyl methyl ether. The organic phase was subsequently washed with 250 ml saturated sodium bicarbonate and 250 ml saturated NaCl solution. Evaporation and drying in vacuo overnight yielded 0.49 g of the title compound 41a. MS: 226.0 (M)+; chiral GC: ee >99% (BGB-175, 30 m×0.25 mm; H2, 120 kPa, Split 1/20; 100-180° C., 2° C./min; Inj.-T.: 200° C.; Dect.-T.: 220° C.).
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[C@:3]([C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)([OH:5])[CH3:4].[H][H]>[Pt]=O.CO>[CH3:1][CH:2]([CH3:12])[C@:3]([CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7]1)([OH:5])[CH3:4]
Reactant: CC(C)[C@@](C)(O)c1cnccn1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: CC(C)[C@@](C)(O)C1CNCCN1
Yield: 93.6 %

Procedure:
Platinum oxide (4.673 g, 20.58 mmol) was placed in a Parr bottle. Methanol (140 mL) was added under an atmosphere of nitrogen followed by (R)-(+)-3-methyl-2-(pyrazin-2-yl)butan-2-ol (17.1 g, 102.9 mmol). The reaction mixture was shaken in a PARR hydrogenator overnight with a hydrogen pressure of 60 psi. Lc/Ms after this time indicate that the reaction was complete. The suspension was filtered through a pad of celite under a nitrogen atmosphere, rinsing with methanol. The crude mixture was concentrated in vacuo. The residue was re-dissolved in dichloromethane, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as viscous light yellow oil (16.6 g, 93%); 1H NMR (CDCl3) 0.82-1.08 (9H, m), 1.81 (1H, m), 2.20-3.17 (10H, m); MS ES(+) 173.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([NH:22][C:23](=O)[CH2:24][N:25]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=3)[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:51])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([NH:22][C:23](=[S:51])[CH2:24][N:25]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=3)[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1NC(=O)CN(C(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1NC(=S)CN(C(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Temperature: 100 °C
Yield: 82.2 %

Procedure:
To a solution of 4-(3-{2-[tert-butoxycarbonyl-(3,4-difluoro-phenyl)-amino]-acetylamino}-4-methyl-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (160 mg) in toluene (4 ml) was added Lawesson's reagent (100 mg) and the reaction heated at 100° C. for 2.5 hr. After cooling to room temperature, the solvent was removed in vacuo to afford a yellow powder. Purification by NPHPLC (0-5% MeOH in CH2Cl2) afforded 4-(3-{2-[tert-butoxycarbonyl-(3,4-difluoro-phenyl)-amino]-thioacetylamino}-4-methyl-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (120 mg). This was taken up in CH2Cl2 (1 ml) and trifluoroacetic acid (0.63 ml) added. After 2 hr stirring the reaction was poured into aqueous K2CO3 and the organic layer was separated, washed with aqueous K2CO3 and brine, dried (Na2SO4) and concentrated to leave yellow crystals. They were purified further by reverse phase HPLC to afford the title compound (14 mg).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.[CH3:29][NH:30][CH3:31].[BH4-].[Na+]>>[CH3:29][N:30]([CH2:25][C:24]1[CH:27]=[CH:28][C:21]([CH:13]2[NH:12][C:7]3[C:6]4[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=4[CH:10]=[CH:9][CH:8]=3)[CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:22][CH:23]=1)[CH3:31]
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Reactant: CNC
Agent: [BH4-]
Agent: [Na+]
Product: CN(C)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
4-(3-Oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (59 mg, 0.16 mmol) and dimethylamine (5 mL) were added and the mixture was stirred at room temperature for 2 h. Then 20 mg of sodium borohydride was added and stirred for another 2 h. The resulting mixture was evaporated under reduced pressure and purified by prep-HPLC to give 8-(4-((dimethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (20 mg, yield 32%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.18 (s, 6H), 4.28-4.30 (d, J=8 Hz, 1H), 4.72-4.74 (d, J=8 Hz, 1H), 7.06-7.08 (m, 2H), 7.13-7.20 (m, 6H), 7.23-7.25 (m, 2H), 7.54-7.65 (m, 2H). LC-MS (ESI) m/z: 397 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:41]([O:45][C:46](=[O:58])[N:47]([C:55](=[O:57])[CH3:56])[C:48]1[CH:53]=[CH:52][C:51](Br)=[CH:50][CH:49]=1)([CH3:44])([CH3:43])[CH3:42].BrC1C=CC(NC(=O)C)=CC=1.C(=O)(OC(C)(C)C)OC(C)(C)C.COC(=O)C1C=CC(Br)=CC=1>C(#N)C.CN(C1C=CN=CC=1)C>[C:41]([O:45][C:46](=[O:58])[N:47]([C:55](=[O:57])[CH3:56])[C:48]1[CH:49]=[CH:50][C:51]([N:27]2[C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=[C:15]([C:12]4[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=5)[CH2:30][C:31]5[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=5)=[N:14][CH:13]=4)[C:16]=3[CH2:29][CH2:28]2)=[CH:52][CH:53]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CC(=O)N(C(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: CC(=O)Nc1ccc(Br)cc1
Agent: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(N(C(C)=O)C(=O)OC(C)(C)C)cc3)cn2)cc1

Procedure:
From bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (81 mg) and acetyl-(4-bromo-phenyl)-carbamic acid tert-butyl ester (prepared from N-(4-bromo-phenyl)-acetamide and di-t butyl carbonate in acetonitrile in the presence of DMAP, 94 mg) instead of 4-bromobenzoic acid methyl ester in Example 1-D-08, in the same manner as Example 1-D-08, a crude product of acetyl-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-carbamic acid tert-butyl ester was obtained, and then the PMB groups were removed according to Deprotection method 1, to obtain the desired compound (D-43) as a pale yellow powder (7 mg, 17%).