Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]([CH2:12][CH3:13])[C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:8][C:4]=1[C:5]([OH:7])=O)[CH3:2].Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.CN(C)C=O.C(OCC)(=O)C>[C:29]([C:28]1[CH:27]=[CH:26][C:25]([CH:22]2[CH2:23][CH2:24][N:19]([C:5]([C:4]3[C:3]([CH2:1][CH3:2])=[CH:11][C:10]([CH2:12][CH3:13])=[C:9]([CH:8]=3)[C:14]([O:16][CH3:17])=[O:15])=[O:7])[CH2:20][CH2:21]2)=[CH:32][CH:31]=1)#[N:30]
Reactant: CCc1cc(CC)c(C(=O)OC)cc1C(=O)O
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc(CC)c(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
To a round-bottom flask, were added a solution of 2,4-diethyl-5-(methoxycarbonyl)benzoic acid (compound 204.5, 500 mg, 2.12 mmol, 1.00 equiv), 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 470 mg, 2.12 mmol, 1 equiv), EDC.HCl (810 mg, 4.24 mmol, 2.00 equiv), and 4-dimethylaminopyridine (520 mg, 4.24 mmol, 2 equiv) in N,N-dimethylformamide (15 mL). The reaction was stirred overnight at 25° C. Upon reaction completion, the reaction mixture was diluted with 30 mL of ethyl acetate, then washed with 1×20 mL of NH4Cl (aq.) and 1×20 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography with a solvent mixture of ethyl acetate and petroleum ether (1:1) to yield 500 mg (60%) of the title compound as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.CN([CH:26]=[O:27])C>C1COCC1>[C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([CH:26]=[O:27])=[C:11]([Cl:16])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)CCc1cc(Cl)cc(Cl)c1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1cc(Cl)c(C=O)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a solution of 3-(3,5-dichlorophenyl)-propionic acid tert butyl ester (1 g, 3.6 mmol) in THF (50 mL) at −78° C. was added dropwise s-butyllithium (1.4 M cyclohexanes; 5.7 mL, 2.2 eq). The resulting red-colored homogeneous solution was stirred under nitrogen at −78° C. for 1 h, at which time DMF (560 mL, 2 eq) was added. After 30 minutes, the reaction was quenched with saturated ammonium chloride solution at. The mixture was allowed to reach ambient temperature and the volatiles were removed under reduced pressure. The residue was partitioned between water and ethyl acetate and the combined organic fractions were dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by chromatography using 20% ethyl acetate/n-heptanes as eluent to give 3-(3,5-dichloro-4-formylphenyl)-propionic acid tert-butyl ester. 1H-NMR (CDCl3, 400 MHz): δ 10.45 (s, 1H), 7.23 (s, 2H), 2.90 (t, J=7.45 Hz, 2H), 2.55 (t, J=7.45 Hz, 2H), 1.35-1.44 (m, 10H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[CH:13]=3)=[CH:10][C:9]([NH2:21])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([O:26][C:27]([NH:29][C@H:30]([CH2:34][NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[C:39]([O:38][C:36](=[O:37])[NH:35][CH2:34][C@@H:30]([NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[C:31](=[O:32])[NH:21][C:9]1[CH:10]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[CH:13]=2)[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)([CH3:42])([CH3:41])[CH3:40]
Reactant: CCCc1cccc(-c2cc(N)nn2-c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)NC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cccc(-c2cc(NC(=O)[C@@H](CNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)nn2-c2ccccc2)c1
Yield: 91.5 %

Procedure:
To a solution of 1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-ylamine (177 mg) prepared according to the same procedures as Preparation 8 in DMF (1.8 ml) were added (R)-2,3-bis-tert-butoxycarbonylaminopropionic acid (292 mg), HOBt.H2O (147 mg) and WSC.HCl (184 mg), and the mixture was stirred at room temperature for 2 hours. To this reaction solution were added water and a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to give the titled compound (329 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH:14][CH2:15][C:16]([O:18]C)=O)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[NH3:20].C>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH:14][CH2:15][C:16]([NH2:20])=[O:18])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: COC(=O)CNC(C(=O)OC(C)(C)C)c1cccs1
Reactant: N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(NCC(N)=O)c1cccs1
Reaction time: 15 h

Procedure:
A mixture of 7.4 g of the compound from Example 3 and 50 ml of concentrated methanolic ammonia is left to stand at room temperature for 15 h. The solvent is stripped off, the residue is treated with active charcoal in hot ethyl acetate, and the mixture is filtered. The residue remaining after evaporation of the solvent is stirred with diethyl ether, filtered off with suction and dried.
Reaction SMILES: [S:1]1[CH2:5][CH:4]=[CH:3][C:2]1=[O:6].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[H-].[Na+]>C1C=CC=CC=1>[CH2:23]([O:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: O=C1C=CCS1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCOc1cccs1
Reaction time: 24 h

Procedure:
A mixture of 20 g (0.2 mole) of 3-thiolen-2-one [R. T. Hawkins, Journal Heterocyclic Chemistry, 11, (3), 291-4 (1974)], 61.1 g (0.2 mole) of 1-bromohexadecane, and 4.8 g (0.2 mole) of sodium hydride in dry benzene is refluxed with stirring for 24 hours after which the solvent is removed and the product distilled to give 2-hexadecyloxythiophene.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([CH2:10]I)[CH2:8][CH2:7][N:6]1[C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])=[O:4].C([O-])([O-])=O.[K+].[K+].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(#N)C>[CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([CH2:10][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:8][CH2:7][N:6]1[C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])=[O:4]
Reactant: COC(=O)[C@@H]1[C@H](CI)CCN1[C@@H](C)c1ccccc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@@H]1[C@H](CN2CCOCC2)CCN1[C@@H](C)c1ccccc1
Temperature: 50 °C
Reaction time: 62 h

Procedure:
A mixture of (2S,3R)-3-iodomethyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid methyl ester (Step 5.5) (7.07 mmol), K2CO3 (21.22 mmol) and morpholine (10.61 mmol) in acetonitrile (24 mL) was stirred at 50° C. for 62 h. The reaction mixture was poured onto ice water and extracted with EtOAc (3×). The combined organic layers were successively washed with water and brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a yellow oil. HPLC: tR=2.56 min (method A); ESI-MS: [M+H]+ 333.
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:14]([CH3:16])[CH3:15]>>[CH2:18]([N:17]([CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CCCCCCCCCC1CO1
Reactant: CC(C)CNCCCCCCNCC(C)C
Product: CCCCCCCCCC(O)CN(CCCCCCN(CC(C)C)CC(O)CCCCCCCCC)CC(C)C

Procedure:
Condensation of 1-undecene oxide and N,N'-di(isobutyl)hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[N-isobutyl-2-hydroxyundecylamine] (I: R = CH3 (CH2)8, R' = (CH3)2CHCH2, X = (CH2)6, Z = H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].CC1(C)C(C)(C)OB([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]3[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]3)[CH:25]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>C1COCC1>[OH:15][CH:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:28]1[CH:29]=[CH:24][CH:25]=[C:26]([CH:30]3[O:31][C:32]([CH3:38])([CH3:37])[C:33]([CH3:36])([CH3:35])[O:34]3)[CH:27]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:14]
Reactant: CC1(C)OB(c2cccc(C3OC(C)(C)C(C)(C)O3)c2)OC1(C)C
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1oc(=O)c2ccccc2c1-c1cccc(C2OC(C)(C)C(C)(C)O2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
4-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate A2, 4.05 g, 15.05 mmol), 4,4,5,5-tetramethyl-2-(3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-1,3,2-dioxaborolane (Intermediate G2, 5 g, 15.05 mmol), X-Phos-Pd-G2 (1.184 g, 1.505 mmol) and K3PO4.H2O (9.81 g, 30.1 mmol) were dispersed in THF (42 ml) and deoxygenated under argon, then water (42 mL) was added and the mixture stirred at rt overnight. The reaction was diluted with AcOEt (250 ml) and washed with 0.2 M of HClaqueous (250 ml), once with saturated NaClaqueous, anhydrified over Na2SO4 and the solvent removed under reduced pressure. The crude was purified via flash chromatography on silica gel using a Biotage 100G+50 G SNAP with a gradient of hexane and AcOEt to give the title compound (5.4 g, 91%) as dark oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl[CH2:11][C:12]([OH:14])=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(O)CCl
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: O=C(O)CNc1ccc(Cl)c(Cl)c1

Procedure:
Using the procedure set forth in U.S. Pat. No. 3,598,859, N-(3,4-dichlorophenyl)glycine was prepared using 3,4-dichloroaniline (Aldrich) and 2-chloroacetic acid (Aldrich).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[CH:40]=[CH:39][C:38]([CH2:41]Br)=[CH:37][CH:36]=1)(=[O:28])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[CH2:1]([C:5]1[N:6]([CH2:41][C:38]2[CH:39]=[CH:40][C:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:26](=[O:28])(=[O:27])[NH:25][C:21]([CH3:22])([CH3:24])[CH3:23])=[CH:36][CH:37]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)[nH]1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Yield: 61 %

Procedure:
By the procedure of Example 13, Step A, 5-n-butyl-2,4-dihydro-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step A) was alkylated with [2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl bromide (from Example 12, Step D). Flash chromatography of the crude product on silica gel (gradient elution with 0.5-5% MeOH in CH2Cl2) gave a 61% yield of the title compound as cream-colored crystals, mp 168°-170° C.; satisfactory purity by TLC in 98:2 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 587 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[C:12]([Cl:17])[N:11]=1.O>O1CCCC1>[Cl:9][C:10]1[N:11]=[C:12]([Cl:17])[CH:13]=[C:14]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[N:15]=1
Reactant: Cc1ccc(N)cc1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Nc2cc(Cl)nc(Cl)n2)cc1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
6.4 g of p-toluidine was dissolved in 50 ml of tetrahydrofuran, and 5.5 g of 2,4,6-trichloropyrimidine was dropwise added thereto with stirring at room temperature. After being stirred for 1 hour, 200 ml of water was added to the reaction mixture. The crystal thus precipitated was taken out by filtration and dried to obtain 6.6 g of 2,4-dichloro-6-p-toluidinopyrimidine, which had a m.p. of 162° to 166° C. Next, 2.4 g of phenol and 8.6 g of potassium carbonate were dispersed in 30 ml of N,N'-dimethylimidazolin-2-one, and 2.54 g of the previously prepared 2,4-dichloro-6-p-toluidinopyrimidine was added thereto with stirring and then heated at 150° C. for 2 hours. After the reaction solution was cooled, 100 ml of ethyl acetate was added thereto. The solution was then washed with water and extracted. The resulting ethyl acetate extract was concentrated, and methanol was added to the residue for crystallization. Accordingly, 3.4 g of the intended Coupler (12) was obtained, which had a m.p. of 151° to 152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[F-:15].[K+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([F:15])(=[O:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)F)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
2--Chloro-5-nitro benzene sulphonylchloride (40 parts) was stirred in p-dioxane (48 parts) at room temperature. Potassium fluoride (10 parts) dissolved in water (35 parts) was added, and the mixture heated to 70° C. Stirred at 70° C. for 4 hours then cooled to room temperature and poured onto ice/water. Allowed to stand for 2 days then filtered off the precipitate and dried in air to yield the product 2-chloro-5-nitro benzene sulphonylfluoride (36 parts).
Reaction SMILES: C(O[C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([O:15]CC=C)([CH2:8]3)[CH2:6]1)[CH2:12]2)C=C.ClC1C=CC=C(C(OO)=[O:27])C=1>ClCCl>[C:7]12([OH:15])[CH2:8][CH:9]3[CH2:10][CH:11]([CH2:12][CH:5]([CH2:14]3)[CH:6]1[OH:27])[CH2:13]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOC12CC3CC(C1)CC(OCC=C)(C3)C2
Solvent: ClCCl
Product: OC1C2CC3CC(C2)CC1(O)C3
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.8 %

Procedure:
The obtained 1,3-bis(2-propenyloxy)adamantane {5.96 g, yield: 80.1%, purity by gas chromatography: 96.0%, purity by gel permeation chromatography (hereinafter referred to as GPC): 99.5%} was dissolved in 30 ml of dichloromethane. Thereto was added 14.3 g (0.058 mol) of 70% m-chloroperbenzoic acid, followed by stirring at room temperature for 16 hours. Then, the reaction mixture was washed with 30 ml of a 25% aqueous sodium sulfite solution and further with water twice. The reaction mixture was subjected to distillation to remove dichloromethane, whereby was obtained crude 1,3-bis(glycidyloxy)adamantane {6.70 g, yield: 79.8% (from adamantanediol), purity by gas chromatography: 96.1%, GPC purity: 99.7%, colorless liquid}. The liquid was subjected to distillation at 0.1 mmHg at 140° C. to obtain, as a colorless transparent liquid, 1,3-bis(glycidyloxy)adamantane {5.36 g, yield: 63.8% (from adamantanediol), purity by gas chromatography: 98.3%, GPC purity: 99.8%}.
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6]([NH:9][N:10]=[C:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)N.[OH-].[Na+].CN([CH:23]=[O:24])C>>[CH:23]([C:17]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][NH:9][CH:6]=1)=[O:24]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(C)=NNC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1n[nH]cc1C=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
POCl3 (532 mL) was added drop-wise to DMF (1 L) at 0° C. over 1 h. The solution was stirred at 0° C. for 1 h, and then product (1-B) (200 g, 0.9 mol) was added in small portions while the reaction temperature was maintained below 5° C. After the addition, the reaction was heated to 80° C. and stirred for another 4 hours. The solution was poured into ice water, and the pH was adjusted to 7 with 2 M NaOH, while maintaining the temperature below 5° C. After standing overnight, the solid was filtered, washed with H2O, and dried in vacuo to give crude product (2-B) (46 g, 30%, for two steps) as a yellow solid. 1H NMR (300 MHz, d-DMSO): δ 14.14 (br, 1H), 10.27 (s, 1H), 8.52 (br, 1H), 4.38 (q, 2H), 1.35 (t, 3H). LC-MS (M+H)+=169.
Reaction SMILES: [NH:1]([C:8]1[C:13]([CH2:14]OCC)=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([OH:32])[CH2:28][N:29]([CH3:31])[CH3:30])=[CH:21][CH:20]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:34]([NH2:36])=[O:35]>>[NH:1]([C:8]1[C:13]([CH2:14][NH:36][CH:34]=[O:35])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([OH:32])[CH2:28][N:29]([CH3:30])[CH3:31])=[CH:21][CH:20]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCc1cnc(Nc2ccc(OCC(O)CN(C)C)cc2)nc1Nc1ccccc1
Reactant: NC=O
Agent: Cl
Product: CN(C)CC(O)COc1ccc(Nc2ncc(CNC=O)c(Nc3ccccc3)n2)cc1
Yield: 24 %

Procedure:
4-Anilino-5-(ethoxymethyl)-2-{4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]anilino}pyrimidine (Example 86, 70 mg, 0.16 mmol) was dissolved in formamide (5 ml). Ethereal hydrogen chloride (1.0M; 0.19 ml, 0.19 mmol) was added, and the mixture was heated on power level 2 in a Toshiba Deltawave III domestic microwave oven (650 W) for 90 seconds. Excess formamide was removed by vacuum distillation and the residue was triturated with ethanol and diethyl ether, giving the product as a hygroscopic dihydrochloride salt (20 mg, 24%). NMR: 2.18 (s, 6H), 2.2-2.45 (m, 2H), 3.75-3.9 (m, 3H), 4.21 (d, 2H), 4.76 (br d, 1H), 6.79 (d, 2H), 7.01 (t, 1H), 7.29 (dd, 2H), 7.52 (d, 2H), 7.71 (d, 2H), 7.92 (s, 1H), 8.13 (d, 1H), 8.69 (t, 1H), 8.92 (s, 1H), 8.94 (s, 1H); MS (MH+): 437.4.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=2[F:20])[NH:5][CH:4]=1)[CH3:2].[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[C:24]([NH2:29])[N:23]=1.Cl.[OH-].[Na+]>O>[Cl:21][C:22]1[N:23]=[C:24]([NH2:29])[N:25]=[C:26]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([O:12][C:10]3[CH:9]=[CH:8][N:7]=[C:6]4[NH:5][CH:4]=[C:3]([CH2:1][CH3:2])[C:11]=34)=[C:14]([F:20])[CH:15]=2)[CH:27]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CCc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1c[nH]c2nccc(Oc3ccc(Nc4cc(Cl)nc(N)n4)cc3F)c12

Procedure:
50 mg (0.18 mmol) of 4-[(3-ethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3-fluoroaniline and 32 mg (0.19 mmol) of 4,6-dichloropyrimidine-2-amine are suspended in 5 ml of water. 27 μl of 37% strength hydrochloric acid are added, and the mixture is heated at reflux overnight. Using 1N aqueous sodium hydroxide solution, the pH is then adjusted to 10, resulting in the precipitation of crystals. The crystals are filtered off with suction and purified by preparative HPLC.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][N:14]=1>>[Br:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)[CH:18]=1
Reactant: Brc1ccnc(Br)c1
Reactant: O=Cc1ccc(B(O)O)cc1
Product: O=Cc1ccc(-c2cc(Br)ccn2)cc1

Procedure:
Alternatively, as illustrated in Scheme 40, Example 2, the phenylboronic acid 40.1 is coupled, as described above, with 2,4-dibromopyridine 40.14 to afford 4-(4-bromo-2-pyridyl)benzaldehyde 40.15. The product is then reacted with a dialkyl mercaptoethyl phosphonate 40.16, the preparation of which is described in Zh. Obschei. Khim., 1973, 43, 2364, to yield the thioether 40.17. Equimolar amounts of the reactants are combined in dimethylformamide at 80° in the presence of potassium carbonate, to effect the displacement reaction.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[OH:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([NH:18][NH2:19])=[O:17]>C(O)(=O)C>[OH:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([NH:18][N:19]=[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[NH:7][C:6]1=[O:11])=[O:17]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1ccccc1O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccccc1O
Temperature: 100 °C
Yield: 84 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 2-hydroxybenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 344 mg of the title compound (84%) as a yellow solid in 98.5% purity by HPLC (Rt: 4.61, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:22])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[NH2:6].[C:23]([S:26][CH2:27][CH:28]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:29](O)=[O:30])(=[O:25])[CH3:24]>CO>[CH3:2][O:3][C:4](=[O:22])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][CH:9]=1)[NH:6][C:29](=[O:30])[CH:28]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:27][S:26][C:23](=[O:25])[CH3:24]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
React O-benzyl-L-tyrosine methyl ester hydrochloride (2.77 g) and 3-acetylthio-2-benzylpropionic acid (2.05 g) in a manner similar to that described in Example 1, Step 1 to give a yellow-orange oil. Chromatograph this oil on a column of silica gel (2.5L) and elute with CH2Cl2 : ethyl acetate 98:2 to give Isomer A, a white solid (0.84 g) m.p. 108°-109°; [α]D26 =-39.8° (MeOH); overlap Isomer A and Isomer B (0.80 g); and Isomer B, white solid (0.45 g), m.p. 92°-93°, [α]D26 =+19.2° (MeOH).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[C:35]1([CH2:41][S:42](Cl)(=[O:44])=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCOCC1>[NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([S:42]([CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:44])=[O:43])[CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(F)cc3)sc2n1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Nc1nc(N2CCN(S(=O)(=O)Cc3ccccc3)CC2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 11.5 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (80 mg, 0.22 mmol) in 1,4-dioxane (4 ml) was added diisopropylethylamine (0.49 mmol, 81 μL) and phenylmethanesulfonyl chloride (0.25 mmol). The reaction was stirred at 90° C. for 16 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compound (13 mg) which was characterized by its mass spectrum: MS m/z (%): 513 ([M+H]+, 100).