Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[N:13]2[C:14]3[N:9]([C:10]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=4)=[CH:11][CH2:12]2)[N:8]=[CH:7][C:6]=3[C:5](=[O:25])[N:4]=1.[CH:26]([NH2:29])([CH3:28])[CH3:27].C(O)C>C(O)(=O)C>[CH3:27][CH:26]([NH:29][C:3]1[N:13]2[C:14]3[N:9]([C:10]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=4)=[CH:11][CH2:12]2)[N:8]=[CH:7][C:6]=3[C:5](=[O:25])[N:4]=1)[CH3:28]
Reactant: CC(C)N
Reactant: CSc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)Nc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
To a suspension of 5.0 g of 5-(methylthio)-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one in 35 ml of acetic acid is added 2.64 g of isopropylamine. The reaction mixture is heated on a steambath for 18 hours. The resulting solution is cooled to room temperature and 17 ml of ethanol added. The mixture is cooled to 10° C. and 35 ml of ethanol and 20 g of ice added. The mixture is stirred for an additional 30 minutes at -10° C. The product is collected by filtration, washed with ethanol (2×20 ml) and air-dried to give 3.2 g (62.3%) of the desired product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[S:16])[NH2:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:18][C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=O.C(OCC)C>C1COCC1>[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:16][CH:18]=[C:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[N:15]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2csc(C3CCNCC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (2.47 mmol) and 4-(2-Bromo-acetyl)-benzoic acid (2.47 mmol) were mixed in THF (12 mL). After stirring at room temperature for 5 minutes the mixture was heated to 80° C. for 2 hours. The volume was reduced to 5 mL and diethylether (5 mL) was added. The mixture was then cooled to −20° C. and filtered. The solid was washed with a small amount of diethylether and dried. m/z=289.1 in MS ES+, which was characterized by hplc and MS and used in the next step without any further purification.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.CCCCCC.C([Li])CCC.C([N:24]([CH2:33][CH3:34])[C:25]([C:27]1[CH:31]=[CH:30][O:29][C:28]=1[CH3:32])=[O:26])C.[CH2:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44]CC#N)=[CH:40][CH:39]=1)[CH3:36].Cl>C1COCC1>[CH2:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:34][C:33]2[NH:24][C:25](=[O:26])[C:27]3[CH:31]=[CH:30][O:29][C:28]=3[CH:32]=2)=[CH:40][CH:39]=1)[CH3:36]
Reactant: CCN(CC)C(=O)c1ccoc1C
Reactant: CCOc1ccc(CCC#N)cc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc(CCc2cc3occc3c(=O)[nH]2)cc1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 15.5 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (11.6 mL, 68.8 mmol) in THF (100 mL) was added 1.6 M n-butyllithium hexane solution (39.0 mL, 62.4 mmol) at −78° C., and the mixture was warmed to −20° C. and stirred at the same temperature for 10 min. To this solution was added a solution of N,N-diethyl-2-methylfuran-3-carboxamide (11.3 g, 62.5 mmol) in THF (10 mL), and the mixture was further stirred for 1 hr. To the solution was added 3-(4-ethoxyphenyl)propanenitrile (11.5 g, 65.6 mmol), and the mixture was stirred at room temperature for hr. 6N Hydrochloric acid was added thereto and the mixture was extracted twice with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (2.74 g, yield 15%) as a white solid.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([CH2:2][CH2:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc2cc[nH]c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)CCc1ccc2cc[nH]c2c1
Reaction time: 1 h
Yield: 106.5 %

Procedure:
6-(2-Hydroxyethyl)-indole (72.5 mg, 0.45 mmol) was mixed with Et3N (126 mg, 1.35 mmol) in 2 ml of dichloromethane at 0 to 5° C. Methane sulfonyl chloride (61.6 mg, 0.54 mmol) was added and the mixture stirred for 1 hr, diluted with dichloromethane, washed with brine, dried and concentrated to give 107 mg of the title compound (quantitative yield).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[NH2:27][C:28]([CH3:43])([CH3:42])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]([CH3:40])[C:32]1=[O:41]>>[CH3:43][C:28]([NH:27][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:42])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]([CH3:40])[C:32]1=[O:41]
Reactant: CCOC(O)C(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Reactant: Cn1c(=O)n(CCC(C)(C)N)c2ccccc21
Product: Cn1c(=O)n(CCC(C)(C)NCC(O)c2cc(O)cc3c2OCC(=O)N3)c2ccccc21

Procedure:
Prepared according to General Method 2 from 357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-1,2-dihydroxy-ethyl)-4H-benzo[1,4]oxazin-3-one and 233 mg (1 mmol) 1-(3-amino-3-methyl-butyl)-3-methyl-1,3-dihydro-benzimidazol-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@H:9]([C:10]([O:12][CH3:13])=[O:11])[O:8][C:7]([CH2:24][CH3:25])([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=2)[O:6]1)=[O:4].[BrH:26].BrBr>ClCCCl>[CH3:1][O:2][C:3]([C@H:5]1[C@H:9]([C:10]([O:12][CH3:13])=[O:11])[O:8][C:7]([CH:24]([Br:26])[CH3:25])([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH:21]([CH3:22])[CH3:23])=[CH:18][CH:19]=2)[O:6]1)=[O:4]
Reactant: Br
Reactant: CCC1(c2ccc(CC(C)C)cc2)O[C@@H](C(=O)OC)[C@H](C(=O)OC)O1
Agent: BrBr
Solvent: ClCCCl
Product: COC(=O)[C@@H]1OC(c2ccc(CC(C)C)cc2)(C(C)Br)O[C@H]1C(=O)OC

Procedure:
To a solution in 1,2-dichloroethane (70 ml) of 2-ethyl-2-[4-(2-methylpropyl)-phenyl]-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethylester (7.0 g; 20 mmoles obtained according to ex. 29), deoxygenated and added with hydrobromic acid (0.324 g; 4 mmoles), it is added dropwise in 1 h under inert atmosphere at +15° C., a solution of bromine (3.20 g; 20 mmoles) in 1,2-dichloroethane (7.0 ml) previously deoxygenated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH:11]([OH:16])[CH2:12][C:13](O)=[O:14])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].O.[NH2:19][NH2:20]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]([OH:16])[CH2:12][C:13](=[O:14])[NH:19][N:20]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: NN
Reactant: Cc1c(Cl)cc(C(=O)C(O)CC(=O)O)cc1Cl
Solvent: O
Solvent: CCO
Product: Cc1c(Cl)cc(C2=NNC(=O)CC2O)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.9 %

Procedure:
A mixture of 2.77 g of 4-(3,5-dichloro-4-methylphenyl)-3-hydroxy-4-oxobutyric acid (prepared as described in Preparation 1), 0.5 g of hydrazine hydrate (100%) and 20 ml of ethanol was stirred at room temperature for 6 hours. The resulting white powder was then collected by filtration, to give 1.77 g (yield 65%) of the desired Compound No. 7, melting at 253°-256° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([CH2:17]O)[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23](=[O:57])[N:24]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]3[N:34]=[CH:35][N:36](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:37]=3)=[CH:28][N:27]=2)[CH:25]=1.CCN(C(C)C)C(C)C.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([CH2:17][N:34]2[C:33]([CH2:32][C:29]3[CH:30]=[CH:31][C:26]([N:24]4[CH:25]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]4=[O:57])=[N:27][CH:28]=3)=[CH:37][N:36]=[CH:35]2)[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Reactant: N#Cc1ccc(CO)cc1OCc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution (-78° C.) of 2-benzyloxy-4-hydroxymethyl-benzonitrile from step 2 (100 mg, 0.42 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (221 mg, 0.42 mmol) in CH2Cl2 (2.1 ml) was added DIEA (325 μl, 0.92 mmol) followed immediately by the addition of Tf2O (160 μl, 0.63 mmol). The reaction mixture was stirred at -78° C. for 1 hour and was then transferred to an ice bath and stirred at 0° C. for another hour. The solvent was removed in vacuo. The residue was then dissolved in MeOH and heated to 60° C. for several hours. The MeOH was then removed in vacuo and the residue treated with saturated NaHCO3 (5 mL) and extracted with CH2Cl2 (2×10 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography [4% MeOH(5% NH4OH)/CH2Cl2 ] to yield the final product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[C:21]([CH3:22])=[CH:20][S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:16]2[C:21]([CH3:22])=[CH:20][S:19][C:17]=2[N:18]=1
Reactant: Cc1csc2nc(Cl)nc(Cl)c12
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1csc2nc(Cl)nc(NCc3cccc([N+](=O)[O-])c3)c12

Procedure:
Following the procedure of Example 1, the reaction of 3-nitrobenzylamine with 2,4-dichloro-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-5-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]([C:16]1NC(=O)C=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[CH:21]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C[O:34]P(CC(=O)[C@@H](NC(OC(C)(C)C)=O)CC1C=CC=CC=1)(=O)OC.[N+](C1C=CC(C=O)=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:32])[NH:7][C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16](=[O:34])/[CH:21]=[CH:20]/[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COP(=O)(CC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)OC
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)c1cc(-c2ccc([N+](=O)[O-])cc2)cc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)/C=C/c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
{1-[4-(4-Nitro-phenyl)-6-oxo-1,6-dihydro-pyridin-2-yl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester: A suspension of ((S)-3-tert-butoxycarbonylamino-2-oxo-4-phenyl-butyl)-phosphonic acid dimethyl ester (1.114 g, 3 mmol, Resmini, M. et al., Tetrahedron Asymmetry, 2004, 15, 1847.), 4-nitrobenzaldehyde (0.453 g, 3 mmol) and potassium carbonate (0.415 g, 3 mmol) in ethanol (60 mL) was stirred at rt for 5 h. The reaction mixture was diluted with EtOAc, washed with water, brine, and dried over Na2SO4, filtered and concentrated to give 1.276 g of [(E)-(S)-1-benzyl-4-(4-nitro-phenyl)-2-oxo-but-3-enyl]-carbamic acid tert-butyl ester as a yellow solid. This yellow solid was suspended in ethanol (30 mL), then 1-ethoxycarbonylmethyl-pyridinium chloride (0.605 g, 3 mmol) and ammonium acetate (4.63 g, 60 mmol) were added. The reaction mixture was stirred at rt for 10 min, then heated at 80° C. for 5 h to yield a white suspension. The reaction was cooled to rt and the solid was collected by filtration, washed with methanol, and dried in vacuo (50° C.) to give 0.85 g (62%) of 64A as a white solid. LCMS m/z 436.3 (M+H)+. 1HNMR (400 MHz, DMSO-D6) δ: 1.26 (s, 9H), 2.76-2.82 (m, 1H), 3.01-3.06 (m, 1H), 4.68-4.74 (m, 1H), 6.54-6.60 (m, 2H), 7.18-7.29 (m, 5H), 7.40 (d, J=9.2 Hz, 1H), 7.91 (d, J=8.8 Hz, 2H), 8.34 (d, J=8.8 Hz, 2H), 11.96 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:18])[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[NH:7][CH:8]=1)[CH3:2].I[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:1]([C:3]1[C:4](=[O:18])[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[N:7]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:8]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)CI
Reactant: CCc1c[nH]c(CCc2ccc(F)cc2)nc1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cn(CC(=O)OC(C)(C)C)c(CCc2ccc(F)cc2)nc1=O
Yield: 78.8 %

Procedure:
5-Ethyl-2-[2-(4-fluorophenyl)ethyl]-1H-pyrimidin-4-one (B40) (955 mgs) in dichloromethane (20was treated with t-butyl iodoacetate, (2.82 g) and diisopropylethylamine (2.03 mls) at room temperature for 3 days. The solution was washed with saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulphate. The solution was concentrated to give a semi-solid which was triturated with ether:dichloromethane, 5:1, giving the title compound as a white solid, (1.101 g, 79%), 1H-NMR (CDCl3) δ 1.16 (3H, t), 1.47 (9H, s), 2.47 (2H, q), 2.74 (2H, t), 3.14 (2H, t), 4.27 (2H, s), 6.90 (1H, s), 6.98 (2H, m) and 7.17 (2H, m). (APCI+) Found (M+1)=361, C20H25FN3 requires 360.
Reaction SMILES: N1C=CC=CC=1.[NH:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1.[CH2:24]([O:28][C:29](Cl)=[O:30])[CH:25]([CH3:27])[CH3:26]>C(Cl)Cl>[CH2:24]([O:28][C:29]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1)=[O:30])[CH:25]([CH3:27])[CH3:26]
Reactant: c1cc(-c2noc(C3CCNCC3)n2)ccn1
Reactant: CC(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)COC(=O)N1CCC(c2nc(-c3ccncc3)no2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of pyridine (18 μl, 0.22 mmol) and 4-(5-piperidin-4-yl-[1,2,4]oxadiazol-3-yl)pyridine (Example 51, 50 mg, 0.22 mmol) in CH2Cl2 (4 ml) was treated with isobutylchloroformate (54 mg, 0.43 mmol). The reaction was stirred at rt for 18 h then quenched with saturated aqueous NaHCO3 (1 ml). The organic phase was separated, evaporated and the residue purified by flash chromatography (IH-EtOAc, 1:1 to 0:1) to afford the title compound: RT=3.42 min, m/z (ES+)=331.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)[CH3:11].C(N(CC)C(C)C)(C)C>C(O)CCC>[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:7]2[C:2]([Cl:1])=[C:3]([NH2:9])[N:4]=[CH:5][N:6]=2)=[CH:19][CH:20]=1)[CH3:11]
Reactant: Nc1ncnc(Cl)c1Cl
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CCOC(=O)Cc1ccc(Nc2ncnc(N)c2Cl)cc1
Temperature: 115 °C
Yield: 65.3 %

Procedure:
To a vial with stirbar were added 5,6-dichloro-pyrimidin-4-ylamine (1.4 g, 8.537 mmol, 1.0 eq), (4-amino-phenyl)-acetic acid ethyl ester (4.3 g, 23.993 mmol, 2.8 eq), N,N-diisopropylethylamine (4.5 ml, 25.611 mmol, 3.0 eq), dissolved in n-butanol (100 ml). The reaction suspension was flushed with nitrogen and heated to 115° C. for 8 days. The mixture was concentrated in vacuo, dissolved in EtOAc, washed with water (2×) and brine (1×), dried over sodium sulfate, and concentrated in vacuo. The crude mixture was purified using Biotage column chromatography eluting from 30-70 EtOAc/hexanes. Fractions containing the desired product were combined and concentrated under reduced pressure to afford (4-(6-amino-5-chloro-pyrimidin-4-ylamino)-phenyl)-acetic acid ethyl ester (1.71 g, 49% yield) as white crystals. MS: m/z=307 [M+H]+. 1H-NMR (DMSO-d6) δ 8.41 (s, 1H), 7.93 (s, 1H), 7.55 (d, 2H), 7.19 (d, 2H), 6.76 (bs, 2H), 4.11 (q, 2H), 1.21 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH:21]4[CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[NH2:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][N:32]=1>>[O:27]1[CH2:28][CH2:29][N:24]([C:4]2[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([S:18]([CH:21]5[CH2:23][CH2:22]5)(=[O:20])=[O:19])[CH2:16][CH2:17]4)[S:8][C:6]=3[N:7]=[C:2]([C:34]3[CH:33]=[N:32][C:31]([NH2:30])=[N:36][CH:35]=3)[N:3]=2)[CH2:25][CH2:26]1
Reactant: O=S(=O)(C1CC1)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: Nc1ncc(B(O)O)cn1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3cc(CN4CCN(S(=O)(=O)C5CC5)CC4)sc3n2)cn1

Procedure:
2-Chloro-4-morpholin-4-yl-6-[4-(cyclopropane-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[2,3-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 308. NMR (DMSO): 0.90-0.92 (2H, m), 0.97-1.00 (2H, m), 2.53-2.58 (4H, m), 2.60-2.64 (1H, m), 3.20-3.23 (4H, m), 3.74-3.77 (4H, m), 3.80 (2H, s), 3.88-3.91 (4H, m), 7.08 (2H, br), 7.52 (1H, s), 9.08 (2H, s). MS (ESI+): MH+ 517.22 (50%)
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11](=O)[NH:10][C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:8]2.O=P(Cl)(Cl)[Cl:22]>CC#N>[Cl:22][C:11]1[C:12]2[C:7](=[CH:6][CH:5]=[N:4][C:3]=2[O:2][CH3:1])[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1nccc2cc(-c3ccccc3)[nH]c(=O)c12
Solvent: CC#N
Product: COc1nccc2cc(-c3ccccc3)nc(Cl)c12

Procedure:
8-Methoxy-3-phenyl-2,7-naphthyridin-1(2H)-one (80 mg, 0.32 mmol) is dissolved in CH3CN (2 mL) and POCl3 (59 uL, 0.64 mmol) The mixture is stirred at 80° C. for 3 hours. POCl3 is removed and neutralized with sat. NaHCO3. The compound is extracted with CHCl3 and the organic layer is dried (Na2SO4) and evaporated to yield the crude compound and used for the next step without any further purification. MS m/z 271.1 (M+1).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[C:6]([OH:10])(=[O:9])[CH:7]=[CH2:8].[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13].[CH2:16]([C:18]([CH2:23]O)([CH2:21]O)[CH2:19][CH3:20])O.C1CC=CC=1>>[CH3:20][CH2:19][C:18]([CH2:23][O:14][C:11]([CH:12]=[CH2:13])=[O:15])([CH2:21][O:9][C:6]([CH:7]=[CH2:8])=[O:10])[CH2:16][O:4][C:1]([CH:2]=[CH2:3])=[O:5]
Reactant: CCC(CO)(CO)CO
Reactant: C=CC(=O)O
Agent: C1=CCC=C1
Product: C=CC(=O)OCC(CC)(COC(=O)C=C)COC(=O)C=C

Procedure:
Trimethylolpropane triacrylate (177.8 g, 0.60 mole) and cyclopentadiene (112.0 g, 1.8 mole) were stirred at 25-40° C. for 21 hours to obtain Diels-Alder adduct of TMPTA-CPD. The obtained TMPTA-CPD (165.0 g, 0.33 mole), fumaric acid (38.3 g, 0.33 mole) and THQ (0.07 g) were heated to 190° C. in 3 hours under nitrogen and held for 12 hours to obtain a oligomeric acid with an acid number of 55 mg KOH/g, glycidyl methacrylate (28.4 g, 0.20 mole) and benzyltriethylammonium chloride (0.15 g) were heated to 110-120° C. and held for 2 hours to obtain an acrylic ester with an acid number of 22. The resulting acrylic ester was dissolved in styrene with 0.04 g of THQ to obtain a resin with 30% styrene. The resin solution has a viscosity of 430 cps, gel time 9.0 min, cure time 12.0 min, and peak exotherm 210° C.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:25]([OH:30])(=[O:29])[CH:26]([CH3:28])O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([O:22][CH:26]([C:25]([OH:30])=[O:29])[CH3:28])=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Reactant: CC(O)C(=O)O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(OC(=O)c1ccc(NCCCCCCCCC2CCCCC2)cc1)C(=O)O

Procedure:
A flask containing 10.0 g. 4-(8-cyclohexyloctylamino)-benzoic acid, 3.3 g. lactic acid, 500 mg. toluenesulfonic acid and 500 ml. toluene is equipped with a Soxhlet extractor charged with activated Å Linde molecular sieves. The solution is refluxed for 24 hours, during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and left to cool, whereupon the product separates as off-white crystals.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[C:11](NC2C=CN(COCC[Si](C)(C)C)N=2)[CH:10]=C[CH:8]=1)(=O)=O.Cl.Cl[C:29]1[C:30](F)=C(C=C[CH:42]=1)C(N1CCNCC1)=O>C(Cl)(Cl)Cl>[CH:29]([N:12]([CH2:11][CH3:10])[CH:7]([CH3:6])[CH3:8])([CH3:30])[CH3:42]
Reactant: O=C(c1cccc(Cl)c1F)N1CCNCC1
Reactant: C[Si](C)(C)CCOCn1ccc(Nc2cccc(COS(C)(=O)=O)n2)n1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCN(C(C)C)C(C)C

Procedure:
A mixture of 10 mg of 6-(methanesulfonyloxymethyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridin-2-amine, 40 mg of 1-(3-chloro-2-fluorobenzoyl)piperazine hydrochloride obtained in Reference Example 1, 27 μl of N,N-diisopropylethylamine and 1 ml of chloroform was stirred at 60° C. for 5 hours. The reaction solution was diluted with chloroform, and then washed with water and brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by a silica gel column chromatography(eluent: chloroform to chloroform/methanol=20/1) to give the title compound.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][CH:25]=1)/[C:13](=[O:19])[NH:14]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[C:1]1([C:7]#[C:8][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2/[C:12](=[CH:20]/[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)/[C:13](=[O:19])[NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: O=C1Nc2cccc(Br)c2/C1=C/c1ccc[nH]1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2cccc(C#Cc3ccccc3)c2/C1=C/c1ccc[nH]1

Procedure:
Using general Method D above, phenyl acetylene (32 mg, 0.31 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 9) (46.3 mg, 0.16 mmol) using (Ph3P)4Pd (8 mg) (Aldrich) and CuI (1.5 mg) (Aldrich) as catalyst in DMF (2 mL) and Et3N (3 mL) as solvent at 85° C. for 18 h, yielding (Z)-1,3-dihydro-4-(phenylethynyl)-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 41 mg, 83%)
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([C:6]1([CH3:8])[CH3:7])C[CH2:3][CH:2]2C.[C:11]([OH:14])(=[O:13])[CH3:12].[O:15](O)O>C(Cl)(Cl)Cl>[C:11]([OH:14])(=[O:13])[CH3:12].[C:5]12([OH:15])[CH2:9][CH:1]([C:6]1([CH3:8])[CH3:7])[CH2:2][CH2:3][C:11]2([OH:14])[CH3:12]
Reactant: OOO
Reactant: CC1CCC2CC1C2(C)C
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC1(O)CCC2CC1(O)C2(C)C

Procedure:
The mixture was extracted with 50% EtOAc/hexanes two times. The combined organic extract was washed with 10% NaHSO3 solution and water, dried over anhydrous Na2SO4 and concentrated to afford the crude product as a tan oil (2.85 g). The pinanediol acetate 3 was purified by silica gel chromatography, eluting with 5˜50% EtOAc/hex, to yield a nearly colorless oil (2.03 g, 84%) containing a small amount of a less polar pinane-keto-alcohol acetate byproduct. IR (CHCl3): 3450, 3000, 2927, 2870, 1730, 1475, 1455, 1388, 1370, 1230, 1128, 1042, and 605 cm−1. 1HNMR (400 MHz, CDCl3): δ 4.26-4.38 (m, 2H), 4.03-4.09 (m, 1H), 3.15 (s, 1H, OH), 2.89 (d, J=6.2 Hz, 1H, OH), 2.46-2.54 (m, 1H), 2.18-2.26 (m, 1H), 2.10 (t, J=5.8 Hz, 1H), 2.06(s, 3H), 1.92-2.05 (m, 2H), 1.79-1.87 (m, 1H), 1.63-1.70 (m, 1H), 1.38 (d, J=10.4 Hz, 1H), 1.27 (s, 3H), 0.94 (s, 3H).