Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=1[NH2:17].[Cl:18][C:19]1[C:24]([N:25]=[C:26]=S)=[C:23]([CH3:28])[CH:22]=[CH:21][N:20]=1>C(#N)C>[Cl:18][C:19]1[C:24]([NH:25][C:26]2[NH:1][C:2]3[C:7]4[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=4[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=3[N:17]=2)=[C:23]([CH3:28])[CH:22]=[CH:21][N:20]=1
Reactant: Cc1ccnc(Cl)c1N=C=S
Reactant: COC(=O)c1cc(N)c(N)c2c1OC(C)(C)C2
Solvent: CC#N
Product: COC(=O)c1cc2nc(Nc3c(C)ccnc3Cl)[nH]c2c2c1OC(C)(C)C2
Yield: 229.8 %

Procedure:
The title compound was prepared following the procedure described for Step-1 of Intermediate-3 using methyl 4,5-diamino-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylate (Intermediate-1, 1.00 g, 0.450 mmol), acetonitrile (10.0 mL), 2-chloro-3-isothiocyanato-4-methylpyridine (Step 1 product, 0.95 g, 0.521 mmol) and N,N-di-isopropyl carbodimide (2.0 mL) to afford 0.400 g of the desired product. 1HNMR (DMSO-d6): δ 1.42 (s, 6H), 2.24 (s, 3H), 2.98 (s, 2H), 3.72 (s, 3H), 7.31 (s, 1H), 7.37 (d, J=4.8 Hz, 1H), 8.15 (d, 1H), 10-11 (s, 2H); MS [M+H]+: 387.24.
Reaction SMILES: [N:1]1[C:6](C)=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8]>C1(C)C=CC=CC=1>[CH2:3]1[CH2:2][CH2:8][N:1]2[C:6](=[N:1][CH2:2][CH2:3][CH2:4]2)[CH2:5][CH2:4]1
Reactant: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: C1CCC2=NCCCN2CC1

Procedure:
A mixture of 5.0 g of product of Step 3 and 2.13 g of 2,6-lutidine is heated at 143° C. for 30 minutes. Two drops of DBU are added and the reaction mixture is heated for additional 1 hour and 30 minutes, cooled and worked up as in (b) above to give 4.23 g of the desired product. The reaction can also be carried out in excess of 2,6-lutidine and a catalytic amount of DBU without solvent or in the presence of toluene as solvent giving similar results.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C.Cl.[I-:47].[NH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([NH:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][N+:58]=2[CH3:63])=[CH:52][CH:51]=1>ClCCCl>[I-:47].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([NH:48][CH2:49][C:50]3[CH:55]=[CH:54][C:53]([NH:56][C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][N+:58]=4[CH3:63])=[CH:52][CH:51]=3)=[O:22])[CH:17]=2)[CH3:14])(=[O:11])=[O:12])=[C:5]([CH3:24])[CH:4]=1
Reactant: C[n+]1ccccc1Nc1ccc(CN)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [I-]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCc3ccc(Nc4cccc[n+]4C)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AD using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (50 mg, 0.13 mmol), CDI (33 mg, 0.2 mmol), DIPEA (0.14 mL, 0.81 mmol) and 2-{[4-(aminomethyl)phenyl]amino}-1-methylpyridinium iodide hydrochloride (53 mg, 0.14 mmol) in DCE (1.0 mL).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([N+:12]([O-:14])=[O:13])=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:25][O:26][CH2:27][CH2:28][OH:29]>CN1CCCC1=O>[CH3:25][O:26][CH2:27][CH2:28][O:29][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([N+:12]([O-:14])=[O:13])=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[CH:3]=1
Reactant: O=[N+]([O-])c1c(NCCO)cc(Cl)cc1NCCO
Reactant: COCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COCCOc1cc(NCCO)c([N+](=O)[O-])c(NCCO)c1
Temperature: 0 °C

Procedure:
0.09 mole (25 g) of 4-chloro-2-(β-hydroxyethyl)amino-6-(β-hydroxyethyl)aminonitrobenzene, synthesized in stage 1 of example 2, was added to a solution of 11.9 g of pelletized potash in 60 ml of 2-methoxyethanol and 25 ml of N-methylpyrrolidone and heated for 4 hours over a boiling water bath. The reaction medium was diluted with 350 ml of ice water and the desired product obtained by high pressure liquid chromatography (HPLC). About 150 ml of the aqueous solution obtained by dilution of the reaction medium were injected onto a C18RD chromatographic column (Instrument: Waters Prep 500). The desired product was eluted by a 40% methanol--60% water solution. After evaporation of the fractions containing the desired product, a dry extract was obtained which was recrystallized from isopropanol. After recrystallization, it melted at 116° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH2:9][S:8][CH2:7]1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].[Br-]>[Na+].[I-].CO.CC#N>[F:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[CH2:9][S:8][CH2:7]3)[CH2:21][CH2:20]2)=[CH:17][CH:18]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C1CSCN1CCCCBr
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [I-]
Solvent: CC#N
Solvent: CO
Product: O=C1CSCN1CCCCN1CCN(c2ccc(F)cc2)CC1
Temperature: 100 °C
Yield: 69.2 %

Procedure:
A mixture of 3-(4-bromobutyl)-4-thiazolidinone (4.01 g), 1-(4-fluorophenyl)piperazine (3.35 g), K2CO3 (4.64 g), NaI (150 mg) and CH3CN (150 ml) was heated at 100° C. (bath temperature) under N2 for 18 h. TLC analysis (silica gel, 8% MeOH/CHCL3) showed one major product at Rf =0.36, and the absence of starting bromide. The reaction mixture was cooled to room temperature and concentrated in vacuo to an oil which was taken up in EtOAc. The mixture was filtered to remove the precipitate and the filtrate concentrated in vacuo to an amber oil which solidified under vacuum. The solid (5.86 g) was dissolved in CHCl3 and flash chromatographed (silica gel) and thereafter recrystallized from hexane/CH2Cl2 to yield in two crops 3.93 g of white crystals, mp 83°-85° C. TLC analysis showed a trace of slower moving impurity. Recrystallization from hexane/CH2Cl2 afforded 3.1 g of white needles which were still slightly impure by TLC. The material was again flash chromatographed (silica gel) and recrystallized from hexane/CH2Cl2 to give 2.67 g of pure product, mp 84°-85° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=O)[O:14]C2C=CC=CC=2)[CH:7]=1.[CH3:50][N:51]([CH3:57])[C@H:52]1[CH2:56][CH2:55][NH:54][CH2:53]1>CN(C)C=O>[CH3:50][N:51]([CH3:57])[C@H:52]1[CH2:56][CH2:55][N:54]([C:13]([NH:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]4([C:40]([NH:41][C:42]5[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=5)=[O:49])[CH2:39][CH2:38]4)=[O:36])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)=[O:14])[CH2:53]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CN(C)C=O
Product: CN(C)[C@H]1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)c(F)c3)ccn2)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 35.8 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (60.8 mg) in N,N-dimethylformamide (1.0 ml) was added (3S)-(−)-3-dimethylaminopyrrolidine (41.7 mg), followed by stirring at room temperature for 7 hr. The reaction mixture was partitioned between ethyl acetate and 1N sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:2, and the precipitated solid was collected by filtration. This was dried under aeration to provide the titled compound as white powder (18.5 mg, 35.8%).
Reaction SMILES: [CH3:1][CH:2]1[C:11](=[O:12])[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5](=[C:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]1=2.[CH3:24][Li].[Cl-].[NH4+]>C1C=CC=CC=1.C(OCC)C>[CH3:1][CH:2]1[C:11]([CH3:24])([OH:12])[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5](=[C:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]2)[C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]1=2
Reactant: CC1C(=O)c2sccc2C(=C2CCN(C)CC2)c2ccccc21
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC1c2ccccc2C(=C2CCN(C)CC2)c2ccsc2C1(C)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 11.0 g of 9-methyl-4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen10(9H)-one in 150 ml of benzene was added dropwise in a nitrogen atmosphere at 25°-30° to a solution of 150 ml of diethylether and 43 ml of 2 molar methyllithium in diethylether. The reaction mixture was stirred for 3 hours at room temperature and then treated with 500 ml of 20% w/v aqueous ammonium chloride. The organic phase was separated off and worked up to give solid 9,10-dihydro9,10-dimethyl-4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-10-ol which was further reacted in crude form.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[N:9][CH:8]=1)=[O:5].[CH3:18][O:19][CH2:20][CH2:21][N:22]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[N:23]1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:25]2[CH:24]=[N:23][N:22]([CH2:21][CH2:20][O:19][CH3:18])[CH:26]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[N:9][CH:8]=1)=[O:5]
Reactant: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccnnc1
Product: COCCn1cc(-c2cnc(N)c(C(=O)Nc3ccnnc3)c2)cn1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridazin-4-yl-nicotinamide (see step 1 in the synthesis of “A16”) with 1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole gives the compound “A24”;
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[CH2:10][C:11]1([C:16]([OH:18])=O)[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[Cl:42][C:43]1[CH:44]=[C:45]([C:49]2[CH:54]=[CH:53][C:52]([CH2:55][C@@H:56]([C:58]3[NH:62][N:61]=[N:60][N:59]=3)[NH2:57])=[CH:51][CH:50]=2)[CH:46]=[CH:47][CH:48]=1>C1COCC1>[Cl:42][C:43]1[CH:44]=[C:45]([C:49]2[CH:50]=[CH:51][C:52]([CH2:55][C@H:56]([NH:57][C:16]([C:11]3([CH2:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15]3)=[O:18])[C:58]3[NH:62][N:61]=[N:60][N:59]=3)=[CH:53][CH:54]=2)[CH:46]=[CH:47][CH:48]=1
Reactant: O=C(CC1(C(=O)O)CCCC1)OCc1ccccc1
Reactant: N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)c1nnn[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(CC1(C(=O)N[C@@H](Cc2ccc(-c3cccc(Cl)c3)cc2)c2nnn[nH]2)CCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39 %

Procedure:
To a suspension of 1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxylic acid (197 mg, 0.750 mmol) in THF (8 ml) at room temperature was added EDC.HCl (192 mg, 1.000 mmol) and HOBT (134 mg, 0.875 mmol). The mixture was stirred at room temperature for 10 minutes and was added a solution of (S)-2-(3′-chlorobiphenyl-4-yl)-1-(1H-tetrazol-5-yl)ethanamine (187 mg, 0.625 mmol) in THF and TEA (0.174 ml, 1.250 mmol). The mixture was stirred overnight at room temperature. The reaction was quenched by brine and was extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (silica gel, 1 to 3% EtOH/DCM) and gave the title compound: 134 mg (yield: 39%). LCMS (condition B): 544.3 (M+1); retention time=1.44 min.
Reaction SMILES: [O:1]([CH2:8][C@H:9]([NH2:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:15][C@@H:16]1[C@H:20]([O:21]C(=O)C)[C@@H:19]([CH2:25][O:26]C(=O)C)[O:18][C@H:17]1[N:30]1[CH:38]=[N:37][C:36]2[C:31]1=[N:32][C:33]([CH3:40])=[N:34][C:35]=2Cl)(=O)C.C(N(CC)CC)C>O1CCOCC1>[CH3:40][C:33]1[N:34]=[C:35]([NH:11][C@H:9]([CH3:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:36]2[N:37]=[CH:38][N:30]([C:31]=2[N:32]=1)[C@@H:17]1[O:18][C@H:19]([CH2:25][OH:26])[C@@H:20]([OH:21])[C@H:16]1[OH:15]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C[C@@H](N)COc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1nc(N[C@H](C)COc2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 50 °C
Yield: 50.5 %

Procedure:
(R)-1-phenoxy-2-propylamine (0.56 g, 3 mmol) was reacted with 9-(2,3,5-tri- O-acetyl-β-D-ribofuranosyl)-6-chloro-2-methyl-9H-Purine (0.43 g, 1 mmol) [prepared from 2-methylinosine (Journal of Organic Chemistry, 1967, 32, 3258-3260) by standard acylation and chlorination steps] in dioxan (20 ml) in the presence of triethylamine (0.41 g, 4 mmol). The reaction mixture was heated at 50° C. for 70 h, and at 90° C. for 3 h. before being filtered and evaporated. The product (after purification by flash chromatography) was debenzoylated with methanolic ammonia to provide the title 2-methyl- N-[(R)-1-phenoxy-2-propyl]adenosine (after column chromatography) as a foam (0.21 g, 50%), 1H NMR (DMSO-d6)δ 1.30 (3H, d, --CH3), 2.43 (3H, s, --CH3), 3.53-3.60 (1H, m, H-5'a), 3.66-3.73 (1H, m, H-5'b), 3.94 (1H, dd, --C--H), 3.99 (1H, q, H-4'), 4.12-4.22 (2H, m, H-3' and --C--H), 4.54 (1H, dd, H-2'), 4.76 (1H, m, --CH3C H--), 5.20, 5.52 (2H, 2d, 2' and 3'-OH), 5.73 (1H, t, 5'-OH), 5.87 (1H, d, H-1'), 6.90-7.31 (5H, t, m, t, Ar--H), 7.74 (1H, br d, N--H), 8.28 (1H, s, H-8).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1>O>[CH2:3]1[O:4][C:5]2([CH2:10][CH2:9][N:8]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)[CH2:7][CH2:6]2)[O:1][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1CC2(CCN1)OCCO2
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
1,4-Dioxa-8-azaspiro[4,5]decane (7.88 g) was dissolved in N-methyl-2-pyrrolidine (50 mL), and diisopropylethylamine (9.5.8 mL) and 4-fluoronitrobenzene (7.06 g) were successively added. The mixture was stirred at room temperature for 2 hr. The reaction mixture was added to iced water, and the precipitated solid was collected by filtration to give N-(4-nitrophenyl)-4-piperidone ethylene ketal (10.6 g) as a yellow powder.
Reaction SMILES: [N+:1]([CH2:4][C:5]([CH3:9])=[CH:6][CH2:7][OH:8])([O-:3])=[O:2].[Cl:10][C:11]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>C1C=CC=CC=1>[N+:1]([CH2:4][C:5]([CH3:9])=[CH:6][CH2:7][O:8][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:11]=1[Cl:10])([O-:3])=[O:2]
Reactant: CC(=CCO)C[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: c1ccccc1
Product: CC(=CCOC(=O)c1ccc(Cl)cc1Cl)C[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To 0.1 Mol of 4-nitro-3-methyl-2-butenol in benzene was added 0.1 Mol of 2,4-dichlorobenzoylchloride and stirred overnight. The benzene was removed, the residue taken up in sat. sodiumbicarbonate solution and extracted with ether. The crude product was purified by column chromatography over silica gel using methylenechloride as eluting solvent. A yellowish oil was obtained.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][N:12]=[C:11]2[NH:18][CH:19]=[C:20]([C:25]([O:27]C)=O)[C:21]([O:23][CH3:24])=[O:22])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[O:27]=[C:25]1[N:12]2[CH:13]=[N:14][C:15]3[CH:16]=[CH:17][C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:5])[CH3:4])=[CH:9][C:10]=3[C:11]2=[N:18][CH:19]=[C:20]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C(=CNc1ncnc2ccc(NC(=O)C(C)(C)C)cc12)C(=O)OC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: COC(=O)c1cnc2c3cc(NC(=O)C(C)(C)C)ccc3ncn2c1=O
Temperature: 260 °C
Yield: 81.4 %

Procedure:
A mixture of dimethyl [{6-pivalamido-4-quinazolinylamino}methylene]propanedioate (24.5 g) and diphenyl ether (150 ml) was heated at 260° C. for 20 minutes and cooled to ambient temperature. To the reaction mixture was added hexane to give crystals, which were filtered off, washed with hexane and dissolved in chloroform (400 ml) under heating. Insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure to 200 ml and allowed to stand under cooling. The precipitated crystals were filtered off and washed with chloroform to give crystalline methyl 4-oxo-10-pivalamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate (18.29 g). The mother liquor was concentrated under reduced pressure to give crystals, which are purified by a column chromatography on silica gel (50 g) (Developing solvent: 5% methanol-chloroform solution) and recrystallized from chloroform to give the same object compound (3.2 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[C:5](C#N)=[CH:4][N:3]=1.C[Mg+].[Br-].CC[O:20][CH2:21][CH3:22].Cl.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[C:5]([C:21](=[O:20])[CH3:22])=[CH:4][N:3]=1
Reactant: CCOCC
Reactant: N#Cc1cnc(N)c2ccc(F)cc12
Agent: C[Mg+]
Agent: Cl
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: CC(=O)c1cnc(N)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
To the solution of 1-amino-6-fluoro-isoquinoline-4-carbonitrile (3 g, 1 eq) in toluene (100 mL) is added 3M MeMgBr in ether (53 mL, 10 eq) at 0° C., then the mixture is stirred at RT for 2 h, then refluxed overnight. The reaction is cooled down and acidified by 2 N HCl aq. to pH˜3, then neutralized by Sat'd NaHCO3 aq (300 mL), extracted by dichloromethane (3×150 mL). The organic layer is dried over Na2SO4, filtered, concentrated to give product 1-(1-amino-6-fluoro-isoquinolin-4-yl)-ethanone (0.8 g, 24%). LC/MS m/z=205 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][P:6](=[O:13])([O:10]CC)[O:7]CC>Cl.CCO>[F:18][C:2]([F:1])([F:19])[C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][P:6](=[O:7])([OH:10])[OH:13]
Reactant: CCOP(=O)(Cc1ccccc1C(F)(F)F)OCC
Agent: Cl
Solvent: CCO
Product: O=P(O)(O)Cc1ccccc1C(F)(F)F
Yield: 46.5 %

Procedure:
The diethyl 2-trifluoromethylbenzylphosphonate (1.22 g, 4.12 mmol) was dissolved in a mixture of 50 mL of conc hydrochloric acid and 5 mL of EtOH and was heated at reflux temperature for 17 hours. After cooling the mixture in an ice bath, white crystalline acid was collected to give 0.46 g, 46% of the desired product, mp=190°-192° C.; D.C.I.M.S. [MH+, 241].
Reaction SMILES: C([O:9][C@H:10]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:12]([CH2:13][CH2:14][C:15]3[C:16]4[C@:29]([CH3:37])([CH2:30][CH2:31][C:32]=32)[C@@H:19]([C@H:20]([CH3:28])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH:17]=4)[C:11]1([CH3:39])[CH3:38])(=O)C1C=CC=CC=1.CO.O>O1CCCC1>[CH3:39][C:11]1([CH3:38])[C@@H:10]([OH:9])[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@H:12]1[CH2:13][CH2:14][C:15]1[C:16]3[C@:29]([CH3:37])([CH2:30][CH2:31][C:32]=12)[C@@H:19]([C@H:20]([CH3:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:18][CH:17]=3
Reactant: C[C@H](Cc1ccccc1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](Cc1ccccc1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Yield: 43.1 %

Procedure:
—Potassium hydroxide (0.45 g) was added to a solution of compound 13 (0.84 g) in a mixture of tetrahydrofuran (8.4 ml), methanol (8.4 ml) and water (0.45 ml). The mixture was heated under reflux overnight. After cooling, water was added and the resulting precipitate collected by filtration. The residue was washed with water and dried. Column chromatography and crystallization from dichloromethane/acetone afforded (3β,5α,20R)-4,4,20-trimethyl-21-phenylpregna-8,14-dien-3-ol (1) (0.29 g). M.p. 179-186° C. The product contained 30% (w/w) of (3β,5α,20R)-4,4,20-trimethyl-21-phenylpregna-6,8(14)-dien-3-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:27]=[C:26]([N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:34][CH3:35])[CH:24]=4)[CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH:6]=[CH:7][CH:8]=1.[Br:36][C:37]1[C:45]2[C:40](=[N:41][CH:42]=[N:43][C:44]=2Cl)[NH:39][N:38]=1>>[Br:36][C:37]1[C:45]2[C:40](=[N:41][CH:42]=[N:43][C:44]=2[N:31]2[CH2:30][CH2:29][N:28]([C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:34][CH3:35])[CH:24]=4)[CH:19]=[C:18]([C:16]4[CH:15]=[CH:14][N:13]=[C:12]([NH:11][CH2:10][CH2:9][C:5]5[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=5)[N:17]=4)[CH:27]=3)[CH2:33][CH2:32]2)[NH:39][N:38]=1
Reactant: COc1cccc(CCNc2nccc(-c3cc(N4CCNCC4)c4cc(OC)ccc4c3)n2)c1
Reactant: Clc1ncnc2[nH]nc(Br)c12
Product: COc1cccc(CCNc2nccc(-c3cc(N4CCN(c5ncnc6[nH]nc(Br)c56)CC4)c4cc(OC)ccc4c3)n2)c1

Procedure:
4-{4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-6-methoxy-2-naphthyl}-N-[2-(3-methoxyphenyl)ethyl]pyrimidin-2-amine was synthesized according to General Procedure E except N-[2-(3-methoxyphenyl)ethyl]-4-(6-methoxy-4-piperazin-1-yl-2-naphthyl)pyrimidin-2-amine and 3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine were used. 4-{4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-6-methoxy-2-naphthyl}-N-[2-(3-methoxyphenyl)ethyl]pyrimidin-2-amine 180 was isolated as a pale yellow solid. M.p.=200-203° C. 400 MHz 1H NMR (DMSO-d6) δ: 12.8 (br s, 1H), 8.36 (m, 3H), 8.04 (s, 1H), 7.94 (d, J=9 Hz, 1H), 7.74 (s, 1H), 7.24 (m, 3H), 6.91 (m, 2H), 6.72 (d, J=9.4 Hz, 1H), 6.19 (m, 1H), 4.25 (m, 4H), 4.01 (s, 3H), 3.81-3.76 (m, 5H), 3.41-3.39 (m, 4H), 3.00 (t, J=7.3 Hz, 2H); Experimental Elemental Analysis (0.26 equivalents of water)=59.04% C, 4.83% H, 18.00% N; Calculated Elemental Analysis 59.05% C, 4.88% H, 18.78% N; LCMS (m/z): 667 [M+H].
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][C:10](=[O:69])[NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26](=[O:68])[NH:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:67]=[CH:66][C:35]([C:36]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][C:59]([O:61]C(C)(C)C)=[O:60])=[CH:40][CH:39]=2)=[O:37])=[CH:34][CH:33]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][C:10](=[O:69])[NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26](=[O:68])[NH:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][C:59]([OH:61])=[O:60])=[CH:40][CH:39]=2)=[O:37])=[CH:66][CH:67]=1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCNc1ccc(C(=O)c2ccc(OCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCN3C(=O)C=CC3=O)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCOCCOCCOCCOCCNc1ccc(C(=O)c2ccc(OCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCN3C(=O)C=CC3=O)cc2)cc1
Reaction time: 1 h
Yield: 116 %

Procedure:
tert-butyl 1-((4-(4-((1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,19-dioxo-7,10,13,16-tetraoxa-4,20-diazatricosan-23-yl)oxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oate (7.36 g, 7.85 mmol) was dissolved in a solution of DCM:TFA (2:1, 50 ml) and left to stir for ca. 1 h. Upon completion, reaction was then concentrated under reduced pressure, co-evaporated with toluene, and dried on oil pump overnight to yield 8.35 g of crude 1-((4-(4-((1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,19-dioxo-7,10,13,16-tetraoxa-4,20-diazatricosan-23-yl)oxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oic acid as yellow oil.