Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@@H:2]([CH3:23])[C@@H:3]([NH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:9])[C:4]([OH:6])=[O:5].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:17]1([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[NH:7][C@H:3]2[C:4](=[O:6])[O:5][C@H:2]2[CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@H](O)[C@@H](NC(=O)OCCCCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1OC(=O)[C@@H]1NC(=O)OCCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 50.4 %

Procedure:
Under nitrogen atmosphere at 0° C., to a stirred mixture of (2R,3S)-3-hydroxy-2-(6-phenylhexoxycarbonylamino)-butanoic acid (0.25 g, 0.78 mmol) in dry CH2Cl2 (25 mL), Et3N (0.33 mL, 2.35 mmol) and subsequently TBTU (0.30 g, 1.2 mmol) were added. The mixture was left stirring 1 h at 0° C. and 15 h rt. Upon full conversion of the starting material, the organics were removed under reduced pressure, and the resulting crude product absorbed over silica gel and purified by typical column chromatography, eluting with Cy/AcOEt (from 100:0 to 0:100) to afford the title compound (0.12 g, 50%) as white solid. MS (ESI) m/z: 306 [M−H]+; (ESI) m/z: 304 [M−H]−. 1H NMR (DMSO-d6): δ 1.26-1.39 (m, 4H), 1.34 (d, J=6.4 Hz, 3H), 1.48-1.65 (m, 4H), 2.54-2.61 (m, 2H), 3.91-4.06 (m. 2H), 4.84 (dq, J=6.3 Hz, 1H), 5.41 (dd, J=6.1, 9.4 Hz, 1H), 7.11-7.31 (m, 5H), 8.19 (d, J=9.4 Hz, 1H).
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]3[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([CH3:29])[CH:21]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:1]1([C:7]2[O:8][C:9]3[C:17]([O:18][C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][C:22]=4[CH3:29])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=c1cc(N2CCOCC2)oc2c(O)cccc12
Reactant: Cc1cc(F)ccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(F)ccc1Oc1cccc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.6 %

Procedure:
To a mixture of 2-(4-morpholinyl)-8-hydroxy-4H-1-benzopyran-4-one (77 mg, 0.31 mmol), 4-fluoro-2-methylphenylboronic acid (48 mg, 0.31 mmol) and copper acetate (57 mg, 0.31 mmol) suspended in dichloromethane (3.1 ml) was added triethylamine (216 uL, 1.56 mmol) and the mixture was stirred at room temperature for 24 h. The solvent was removed and the product chromatographed through a silica column with 0-10% methanol in dichloromethane to yield an off white solid (37 mg).
Reaction SMILES: N#N.[CH3:3][O:4][C:5](=[O:21])[CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)=[CH:10][CH:11]=1>CO.[Pd]>[CH3:3][O:4][C:5](=[O:21])[CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)Cc1ccc(-c2cccc([N+](=O)[O-])c2)s1
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: COC(=O)Cc1ccc(-c2cccc(N)c2)s1
Temperature: 25 °C
Reaction time: 22 h
Yield: 74.1 %

Procedure:
(The following reaction is done in an N2 atmosphere.) Dissolve [5-(3-Nitro-phenyl)-thiophen-2-yl]-acetic acid methyl ester (56) (3.15 mg, 11.35 mmol) in MeOH (225 mL) and add Pd on carbon (10% (w/w) Pd content, 1.20 g, 1.13 mmol) followed by NH4CO2H (7.15 g, 113.4 mmol) at rt. Degas the reaction mixture carefully (flush with N2) and stir it for 22 h at rt. Filtrate reaction mixture through a short pad of celite and remove solvent. Purify the obtained crude product by preparative radial chromatography (silica gel, EtOAc/CyH 1+3) to obtain [5-(3-Amino-phenyl)-thiophen-2-yl]-acetic acid methyl ester (57) (2.08 g, 74%) as a yellow solid. 1H NMR (400 MHz, CDCl3): 3.73 (s, 3H); 3.81 (s, 2H); 6.59 (dd, 1H, J1=7.8 Hz, J2=2.0 Hz); 6.86 (br.d, 1H, J=3.5 Hz); 6.88 (t, 1H, J=1.9 Hz); 6.97 (br.d, 1H, J=7.6 Hz); 7.09 (d, 1H, J=3.5 Hz); 7.13 (t, 1H, J=7.7 Hz).
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[CH:6]([NH:8][CH:9]([P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])[C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])=[S:7].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.C(Cl)Cl>[Cl:17][C:14]([Cl:15])([Cl:16])[CH2:13][O:12][C:10]([CH:9]([P:18]([O:20][CH2:21][CH3:22])([O:23][CH2:24][CH3:25])=[O:19])[N:8]=[CH:6][S:7][CH2:2][C:3](=[O:5])[CH3:4])=[O:11]
Reactant: CC(=O)CCl
Reactant: CCOP(=O)(OCC)C(NC=S)C(=O)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(N=CSCC(C)=O)C(=O)OCC(Cl)(Cl)Cl

Procedure:
A solution of chloro-2-propanone (0.470 q., 5.08 mMol) in acetone (4 ml.) is added dropwise during 15 minutes to a rapidly stirring mixture of trichloroethyl α-thioformamido-diethylphosphonoacetate (1.783 g., 4.62 mMol), K2CO3 (0.702 g., 5.08 mMol), and acetone (6 ml.). After having been stirred for 15 hours at room temperature, the mixture is diluted with methylene chloride (30 ml.) and filtered to remove salts. The filtrate is evaporated under reduced pressure to yield 2-oxo-propyl N-(trichloroethoxycarbonyl-diethylphosphonomethyl)-thioformimidate.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:27])=[C:14]([CH:26]=1)[C:15]([O:17][C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16]>C(OCC)(=O)C>[Cl:27][C:13]1[CH:12]=[CH:11][C:10]([N:9]=[C:2]=[O:1])=[CH:26][C:14]=1[C:15]([O:17][C:18]([CH3:24])([CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)C(C)(C)OC(=O)c1cc(N)ccc1Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)OC(=O)c1cc(N=C=O)ccc1Cl

Procedure:
A solution of 40 g of diphosgene in 150 ml of ethyl acetate is heated to 65° C. while stirring. To this solution is added dropwise a solution of 40 g of ethyl 2-(5-amino-2-chloro-benzoyloxy)-2-methyl-propionate in 70 ml of ethyl acetate. After completion of the addition the reaction mixture is heated to reflux temperature for 3 hours. Thereafter, the solvent is distilled off. The residue is distilled in a bulb-tube at 200°-230° C. and 0.1 torr. In this manner there is obtained ethyl 2-(2-chloro-5-isocyanato-benzoyloxy)-2-methyl-propionate,
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6]([O:8]CC)=O.[CH2:19]([NH2:21])[CH3:20]>C(O)C>[CH2:19]([NH:21][C:6](=[O:8])[CH:5]([O:4][C:3]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:2]=1[Cl:1])[CH3:11])[CH3:20]
Reactant: CCN
Reactant: CCOC(=O)C(C)Oc1cc([N+](=O)[O-])ccc1Cl
Solvent: CCO
Product: CCNC(=O)C(C)Oc1cc([N+](=O)[O-])ccc1Cl

Procedure:
A mixture of 2.74 g. of ethyl α-(2-chloro-5-nitrophenoxy)propionate, 0.77 g. of 70% aqueous solution of ethylamine and 15 ml. of ethanol was kept at room temperature for one night. The precipitate was separated by a filtration and recrystallized from a mixture of benzene-cyclohexane to obtain 2.5 g. of the object compound (melting point of 148° to 149° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([C:11]([OH:13])=[O:12])[CH2:9][N:8](CC2C=CC=CC=2)[CH2:7]1)=[O:5])[CH3:2].C(O[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(C)(C)C.CCOC(C)=O>CCO.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([C:11]([OH:13])=[O:12])[CH2:9][N:8]([C:26]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:32])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O
Reaction time: 5 h

Procedure:
A mixture of (3S*,4S*)-1-benzyl-pyrrolidine-3,4-dicarboxylic acid monoethyl ester (10 g, 36.1 mmol), di-tert-butylcarbonate (7.9 g, 39.6 mmol) and Pd(OH)2/C 20% (1 g, 50% wet) in EtOH (200 mL) is stirred under hydrogen atmosphere for 5 h. The crude material is filtered over a pad of Celite and concentrated. 1H-NMR indicates that the title compound is obtained cleanly. TLC, Rf (AcOEt)=0.17. MS (LC-MS): 286.1 [M−H]−.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH:24]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[C@H:25]([C:36](O)=[O:37])[CH2:26][CH2:27][CH2:28][NH:29][C:30](=[NH:35])[NH:31][N+:32]([O-:34])=[O:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[NH:24]([C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])[C@H:25]([C:36]([NH:22][CH2:21][C:20]([O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:23])=[O:37])[CH2:26][CH2:27][CH2:28][NH:29][C:30](=[NH:35])[NH:31][N+:32]([O-:34])=[O:33]
Reactant: N=C(NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)N[N+](=O)[O-]
Reactant: NCC(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: N=C(NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)OCc1ccccc1)N[N+](=O)[O-]
Reaction time: 4 h

Procedure:
353 g of tosylate of glycine benzyl ester (H-Gly-o-Bzl, Tosylate) are dissolved in 2 liters of DMF; 115 g of NEM then 353 g of Z-Arg(NO2)-OH and finally 500 g of BOP are added. The pH of the medium is adjusted to 7 with the aid of NEM and using pH indicating paper on samples of the reaction medium diluted with water. The reaction medium is stirred and the state of advance of the reaction followed by TLC. After 4 hrs., the reaction is complete and the medium evaporated to dryness in vacuo at 35°. The residue of evaporation is taken up in 2 liters of ethyl acetate and 2 liters of water. Under these conditions, a solid is obtained which is drained and washed successively in solid phase with a 5% aqueous solution of HKSO4 +K2SO4, with pure water, with a 5% aqueous solution of NaHCO3 and finally water.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[N+:12]([CH:15]=[C:16](SC)[S:17][CH3:18])([O-:14])=[O:13]>C(O)C>[N+:12]([CH:15]=[C:16]([S:17][CH3:18])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)([O-:14])=[O:13]
Reactant: NCCSCc1ccccn1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: CSC(=C[N+](=O)[O-])NCCSCc1ccccn1
Yield: 29.4 %

Procedure:
A solution of 2-[(2-aminoethyl)thiomethyl]pyridine (5.0 g) and 1-nitro-2,2-bis-methylthioethylene (5.28 g) in ethanol was heated under reflux for 3 hours. Concentration and chromatographic purification of the product on a column of silica gel with elution by iso-propyl alcohol-ethylacetate (1:5) gave 1-nitro-2-methylthio-2-[2-(2-pyridylmethylthio)ethylamino]ethylene (2.49 g), m.p. 95.5°-96.5°.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][N:9]([CH3:41])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:27]3[C:22](=[CH:23][C:24]([C:28]4[CH:29]=[C:30]([NH2:34])[CH:31]=[CH:32][CH:33]=4)=[CH:25][CH:26]=3)[N:21]([C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)[CH:20]=2)=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:8][N:9]([CH3:41])[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:27]3[C:22](=[CH:23][C:24]([C:28]4[CH:29]=[C:30]([NH:34][C:1](=[O:3])[CH3:2])[CH:31]=[CH:32][CH:33]=4)=[CH:25][CH:26]=3)[N:21]([C:35]3[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=3)[CH:20]=2)=[CH:17][CH:18]=1
Reactant: CN(C)CCOc1ccc(-c2cn(-c3ccncc3)c3cc(-c4cccc(N)c4)ccc23)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-c2ccc3c(-c4ccc(OCCN(C)C)cc4)cn(-c4ccncc4)c3c2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Acetic anhydride (4.8 μL, 0.5.1 μmol) was added to a mixture solution of 3-(3-(4-(2-(dimethylamino)ethoxy)phenyl)-1-(pyridin-4-yl)-1H-indol-6-yl)benzenamine (2.2 mg, 4.9 μmol) in pyridine (0.4 mL) at room temperature. After stirring for 15 hours at room temperature, the reaction solution was added to saturated sodium bicarbonate aqueous solution and then extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The residue was purified by chromatography (preparative TLC, DCM:MeOH=10:1). The target compound (1.5 mg) was obtained as white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])=[N:6][CH:7]=1.C([Li])(C)(C)C.[CH2:20]([N:23]1[C@@H:28]([CH3:29])[CH2:27][O:26][C:25](=[O:30])[CH2:24]1)[CH2:21][CH3:22].[NH4+].[Cl-]>C1COCC1.C1(C)C=CC=CC=1>[CH3:14][C:9]1[N:8]([C:5]2[N:6]=[CH:7][C:2]([C:25]3([OH:30])[O:26][CH2:27][C@H:28]([CH3:29])[N:23]([CH2:20][CH2:21][CH3:22])[CH2:24]3)=[CH:3][CH:4]=2)[C:12]([CH3:13])=[CH:11][CH:10]=1
Reactant: CCCN1CC(=O)OC[C@@H]1C
Reactant: Cc1ccc(C)n1-c1ccc(Br)cn1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCN1CC(O)(c2ccc(-n3c(C)ccc3C)nc2)OC[C@@H]1C

Procedure:
5-bromo-2-(2,5-dimethyl-pyrrol-1-yl)-pyridine (1.5 g 5.9 mmol) was azeotroped with toluene and dissolved in THF (20 ml). This mixture was cooled to −78 C. and t-butyllithium (1.7M in pentane, 7 ml, 11.9 mmol) was added maintaining the temperature below −70 C. The material from example 62 was dissolved in THF (20 ml) and added to the mixture immediately on completion of the t-butyllithium addition. The mixture was allowed to stir at −78° C. for 30 minutes at which time NH4Cl (10% aq, 150 ml) was added and the mixture extracted into EtOAc (200 ml), dried with magnesium sulphate, filtered and evaporated. Flash chromatography on SiO2 eluting with a stepped gradient from 25% EtOAc/pentane to 50% EtOAc/pentane gave the title compound as mixture of diastereoisomers in approximately 3.5:1 ratio as a yellow oil (480 mg).
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][N:6]([CH:8]3[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]3)[CH2:5]2)[CH2:3][O:2]1.[H-].[Na+].[Si:17]([O:24][CH2:25][C@H:26]1[CH2:37][CH2:36][C:35]2[S:34][C:33]3[C:28](=[C:29](Cl)[N:30]=[CH:31][N:32]=3)[C:27]1=2)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C1COCC1>[Si:17]([O:24][CH2:25][C@H:26]1[CH2:37][CH2:36][C:35]2[S:34][C:33]3[C:28](=[C:29]([O:14][CH:11]4[CH2:10][CH2:9][CH:8]([N:6]5[CH2:7][C:4]6([CH2:1][O:2][CH2:3]6)[CH2:5]5)[CH2:13][CH2:12]4)[N:30]=[CH:31][N:32]=3)[C:27]1=2)([C:20]([CH3:23])([CH3:21])[CH3:22])([CH3:19])[CH3:18]
Reactant: OC1CCC(N2CC3(COC3)C2)CC1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCc2sc3ncnc(Cl)c3c21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCc2sc3ncnc(OC4CCC(N5CC6(COC6)C5)CC4)c3c21
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
To a solution of 4-[2-oxa-6-azaspiro[3.3]heptan-6-yl]cyclohexan-1-ol (250 mg, 1.27 mmol, 1.19 equiv) in 15 mL of freshly distilled THF was added sodium hydride (60% dispersion in mineral oil, 169.9 mg, 4.25 mmol, 4.00 equiv) in portions at 0° C. under nitrogen. The resulting solution was stirred for 0.5 h at this temperature. Then (3S)-3-[[(tert-butyldimethylsilyl)oxy]methyl]-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraene (377 mg, 1.06 mmol, 1.00 equiv) was added and the resulting solution was allowed to react, with stirring, for an additional 2 h at ambient temperature. After completion of the reaction, the reaction mixture was quenched by the addition of 20 mL of saturated aqueous NH4Cl and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate to give the desired (3S)-3-[[(tert-butyldimethylsilyl)oxy]methyl]-12-[(4-[2-oxa-6-azaspiro[3.3]heptan-6-yl]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraene (0.5 g, 91%) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[H-].[Na+].Cl.Cl[CH2:19][C:20]1[N:21]([CH3:27])[C:22](=[N:25][CH3:26])[S:23][CH:24]=1>CN(C=O)C>[CH3:27][N:21]1[C:20]([CH2:19][N:7]2[CH2:6][CH2:5][NH:4][CH2:3][C:2]2=[O:1])=[CH:24][S:23]/[C:22]/1=[N:25]\[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: CN=c1scc(CCl)n1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C/N=c1\scc(CN2CCNCC2=O)n1C
Yield: 94.4 %

Procedure:
tert-Butyl 3-oxopiperazine-1-carboxylate (1.5 g) was dissolved in DMF (50 mL), and sodium hydride (0.3 g) was added thereto. With ice cooling, N-(4-chloromethyl-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine hydrochloride (1.6 g) was added thereto, and the mixture was mixed at 80° C. for 3 hours. The solvent was distilled off, and the residue was poured into water, then extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off to give 1-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)-2-piperazinone (1.7 g) as a pale brown oily matter (a crude product). The resulting oily matter was dissolved in concentrated hydrochloric acid (5 mL) and mixed at room temperature for 1 hour. After concentrating the reaction solution, the residue was dissolved in dichloromethane (30 mL), and triethylamine (1.4 mL) was added thereto. With ice cooling, 3-((6-chloro-2-naphthyl)sulfonyl)propionic acid (1.5 g), HOBt (0.84 g) and WSC (1.0 g) were added thereto, and the mixture was mixed at room temperature for 16 hours. The reaction solution was basified with an aqueous potassium carbonate solution, then extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified with a basic silica gel column to give the title compound (0.25 g) as a colorless powder.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[N:9][N:10]2[CH2:15][CH2:14][CH2:13][NH:12][C:11]=12.C(N(C(C)C)C(C)C)C.[C:25]([O:29][C:30]([NH:32][CH2:33][C:34](ON1C(=O)CCC1=O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:25]([O:29][C:30]([NH:32][CH2:33][C:34]([NH:6][C:7]1[CH:8]=[N:9][N:10]2[CH2:15][CH2:14][CH2:13][NH:12][C:11]=12)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: Nc1cnn2c1NCCC2
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cnn2c1NCCC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 81.3 %

Procedure:
To a solution of 3-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine sulfuric acid salt (2.96 g) and N-ethyldiisopropylamine (2.59 g) in methylene chloride (70 ml) was added N-[2-(tert-butoxycarbonylamino)acetoxy]succinimide (2.72 g). The mixture was stirred at room temperature for 14 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 6% methanol/chloroform to give 3-[2-(tert-butoxycarbonylamino)acetyl]amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (2.4 g) as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[CH:23]=[CH:22][C:9]2[N:10]([CH2:19][O:20][CH3:21])[C:11](=[O:18])[C:12]3[CH:13]=[CH:14][CH:15]=[N:16][C:17]=3[C:8]=2[CH:7]=1>ClCCl.CO.[Pd]>[CH3:24][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:23]=[CH:22][C:9]2[N:10]([CH2:19][O:20][CH3:21])[C:11](=[O:18])[C:12]3[CH2:13][CH2:14][CH2:15][NH:16][C:17]=3[C:8]=2[CH:7]=1
Reactant: COCn1c(=O)c2cccnc2c2cc(OCCN(C)C)ccc21
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COCn1c(=O)c2c(c3cc(OCCN(C)C)ccc31)NCCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.9 %

Procedure:
The compound (40 mg, 0.122 mmol) prepared in step 6 was dissolved in dichloromethane/methanol (5 ml), added with 10%-palladium (Pd) (4 mg). The resulting mixture was stirred under hydrogen gas for one day at room temperature. Once the reaction was completed, the solution was filtered with celite and the filtrate was concentrated to dryness. The residue was then purified by flash column chromatography (chloroform:methanol=10:1) to obtain the title compound (40 mg, yield: 99%, white solid).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[N:8]=[C:9]([C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:6]=2[S:5][C:4]=1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(OC([NH:39][C:40]1([C:43](O)=[O:44])[CH2:42][CH2:41]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[NH2:39][C:40]1([C:43]([N:29]2[CH2:30][CH2:31][N:26]([CH2:25][C:4]3[S:5][C:6]4[C:11]([N:12]5[CH2:13][CH2:14][O:15][CH2:16][CH2:17]5)=[N:10][C:9]([C:18]5[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=5)=[N:8][C:7]=4[C:3]=3[CH3:2])[CH2:27][CH2:28]2)=[O:44])[CH2:42][CH2:41]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(CN2CCN(C(=O)C3(N)CC3)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Yield: 100.8 %

Procedure:
Crude HCl salt of 5-(7-methyl-4-morpholino-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (74 mg) was reacted with 70 mg 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid via General Procedure B, treated with TFA and purified via reverse phase HPLC to yield 89.1 mg of 351 after reverse phase HPLC purification. MS (Q1) 510.3 (M)+.
Reaction SMILES: [Br:1][C:2]1[N:10]([CH2:11][O:12][CH2:13][CH3:14])[C:9]2[C:8](=[O:15])[NH:7][C:6](=[O:16])[N:5]([CH3:17])[C:4]=2[N:3]=1.[H-].[Na+].[C:20]([O:23][CH:24]([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28]Cl)(=[O:22])[CH3:21]>CS(C)=O>[C:20]([O:23][C@H:24]([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28][N:7]1[C:8](=[O:15])[C:9]2[N:10]([CH2:11][O:12][CH2:13][CH3:14])[C:2]([Br:1])=[N:3][C:4]=2[N:5]([CH3:17])[C:6]1=[O:16])(=[O:22])[CH3:21]
Reactant: CCOCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(=O)OC(C)CCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOCn1c(Br)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
8-Bromo-7-ethoxymethyl-3-methylxanthine (prepared as described for CT12440) (3.03 g, 10 mmol) was added to a suspension of sodium hydride (264 mg, 11 mmol) in anhydrous dimethylsulfoxide (60 ml). After stirring for 30 minutes, (R) 5-acetoxy-1-chlorohexane (1.963 g, 11 mmol) was added and the mixture was heated at 70-80° C. for 12 hours. After cooling to room temperature, the reaction was quenched by the addition of water (150 ml) and extracted with 10% methanol-ethyl acetate (3×25 ml). The combined extracts were washed with water (2×50 ml), with saturated aqueous sodium chloride solution (50 ml), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 30% ethyl acetate-hexane to provide (R)-1-(5-acetoxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (2.77 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:17](=[O:18])[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:6][C:5]([N:9]2[C:10](=[O:19])[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=3[C:17]2=[O:18])=[C:4]([F:20])[CH:3]=1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Yield: 34.8 %

Procedure:
2-(4-Chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (3 g) was dissolved in dimethylformamide (100 ml), and anhydrous potassium carbonate (0.8 g) was added tereto. To the resultant mixture was added methyl bromoacetate (1.8 g), and the mixture was heated at 70°-80° C. for 3 hours. After being allowed to cool, water was added to the mixture, which was then extracted with ether, and the extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography to give 1.3 g of 2-(4-chloro-2-fluoro-5-methoxycarbonylmethoxyphenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (Compound No. 1). M.P., 98°-99.5° C.