Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.FC(F)(F)C(O)=O.[OH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30]([C:33]3([C:36]([N:38]4[CH2:42][CH2:41][C@@:40]5([C:46]6[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=6[C:44](=[O:51])[O:43]5)[CH2:39]4)=[O:37])[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.[N:52]1[CH:57]=[CH:56][C:55](O)=[CH:54][CH:53]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>>[N:52]1[CH:57]=[CH:56][C:55]([O:20][CH:21]2[CH2:22][CH2:23][N:24]([C:27]3[N:32]=[CH:31][C:30]([C:33]4([C:36]([N:38]5[CH2:42][CH2:41][C@@:40]6([C:46]7[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=7[C:44](=[O:51])[O:43]6)[CH2:39]5)=[O:37])[CH2:34][CH2:35]4)=[CH:29][CH:28]=3)[CH2:25][CH2:26]2)=[CH:54][CH:53]=1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCC(O)CC5)nc4)CC3)C2)c2ccccc21
Reactant: Oc1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCC(Oc6ccncc6)CC5)nc4)CC3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl azodicarboxylate (3.0×10−1 μL, 0.00019 mol) was added to a mixture of (1R)-1′-({1-[6-(4-hydroxypiperidin-1-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one trifluoroacetate (salt) (42 mg, 0.000077 mol, example 172), 4-pyridinol (18 mg, 0.00019 mol) and triphenylphosphine (5.0×10−1 mg, 0.00019 mol) in tetrahydrofuran (1.0 mL, 0.012 mol). The reaction mixture was stirred at room temperature overnight. The crude product was purified by prep-LCMS. LC/MS: 511.2 (M+H+).
Reaction SMILES: CCCCCC.[H-].[K+].[OH:9][C:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:23])[C:14]=2[CH:13]=[CH:12][CH:11]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:28][C@H:29]1[O:31][CH2:30]1)(=O)=O>C1COCC1>[O:31]1[CH2:30][C@H:29]1[CH2:28][O:9][C:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:23])[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: O=C1c2ccccc2-c2c(O)cccc21
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: [H-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1c2ccccc2-c2c(OC[C@@H]3CO3)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
A stirred suspension of hexane washed potassium hydride (0.204 g, 5 mmol) in THF was treated in one portion with 4-hydroxy-9-fluorenone (1.0 g, 5.1 mmol). To the purple suspension was added (S)-glycidyl nosylate (1.0 g, 5 mmol) and the mixture was stirred at ambient temperature overnight. The reaction was partitioned with EtOAc. The organic phase was washed with H2O, brine and dried (Na2SO4). The solvent was removed in vacuo to provide crude product. Purification by flash chromatography (CH2Cl2-hexane 3:1) provided 0.210 g of product as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4](O)=[CH:5]C(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.Cl.NCCCC(O)=O.Cl[C:32]1[CH:33]=[C:34]([CH:48]=[CH:49][C:50]=1Cl)[CH2:35][N:36]([CH3:47])[C:37]([C:39]1[CH2:40][N:41]([CH3:46])[C:42](=[O:45])[C:43]=1[OH:44])=[O:38]>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:46][N:41]1[CH2:40][C:39]([C:37](=[O:38])[N:36]([CH2:35][C:34]2[CH:48]=[CH:49][CH2:50][CH2:32][CH:33]=2)[CH3:47])=[C:43]([OH:44])[C:42]1=[O:45]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Agent: C=O
Agent: Cl
Agent: NCCCC(=O)O
Product: COC(=O)CCCN1CC(C(=O)N(C)CC2=CCCC=C2)=C(O)C1=O
Yield: 9 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 4-aminobutyrate hydrochloride as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber oil (18.9 mg, 9% yield). 1H NMR (300 MHz, CDCl3) δ: 7.41 (m, 2H), 7.09 (m, 1H), 4.60 (s, 2H), 4.18 (s, 2H), 3.65 (s, 3H), 3.55 (t, 2H, J=7.32), 3.03 (s, 3H), 2.36 (t, 2H, J=7.32), 1.94 (t, 2H, J=6.95). HRMS (M+H) calcd for C18H21N2Cl2O53: 415.0827. found: 415.0831.
Reaction SMILES: [OH:1][C:2]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)=[CH:4][O:3]1.[CH3:25]O>>[CH3:25][O:1][C:2]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:6](=[O:7])[C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:13]=2)=[CH:4][O:3]1
Reactant: CO
Reactant: O=C(O)CCc1ccc(C2=COC(O)(c3ccccc3)C2=O)cc1
Product: COC1(c2ccccc2)OC=C(c2ccc(CCC(=O)O)cc2)C1=O
Yield: 83 %

Procedure:
A solution of 3.36 g of 2-hydroxy-2-phenyl-4-[4-(2-carboxyethyl)phenyl]-3(2H)-furanone in 150 ml of methanol was heated under reflux under a nitrogen atmosphere for 17 hrs. The reaction mixture was evaporated and the residue was recrystallized from methylene chloride-petroleum ether to give 2.28 g (83%) of 2-methoxy-2-phenyl-4-[4-(2-carboxyethyl)phenyl]-3-(2H)-furanone as colorless crystals, m.p. 117°-120°C, after drying at 50°C for 1 hr. under vacuum.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[CH3:19])=[CH:10][CH:9]=1>>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[S:15][C:16]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:17][C:18]=2[CH3:19])=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2sccc2C)cc1
Reactant: O=S(=O)(Cl)Cl
Product: COc1ccc(-c2sc(S(=O)(=O)Cl)cc2C)cc1

Procedure:
The above sulfonyl chloride, EI-MS: M=304.1, was prepared analogous to Example 50 using 2-(4-methoxy-phenyl)-3-methyl-thiophene in the first step.
Reaction SMILES: [Cl:1][C:2](Cl)([O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].[Sb](Cl)(Cl)(Cl)(Cl)Cl.[FH:22]>>[Cl:1][C:2]([F:22])([O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: FC(F)(F)C(Cl)(Cl)Oc1ccc(Cl)cc1
Reactant: F
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Product: FC(F)(F)C(F)(Cl)Oc1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 89.8 %

Procedure:
A 500 ml polytetrafluoroethylene reactor equipped with stirrer, thermometer and reflux condenser is charged with 55.9 g (0.2 mol) of 4-(1,1-dichloro-2,2,2-trifluoroethoxy)chlorobenzene in 100 ml of hydrogen fluoride. 3.0 g (0.01 mol; corresponding to 5 mol%) of antimony pentachloride are added at a temperature in the range from -5° C. to 0° C. The resultant hydrogen chloride is removed from the reactor through the reflux condenser. After 20 minutes at 0° C., the evolution of hydrogen chloride ceases. Excess hydrogen fluoride is removed by distillation, the residue is dissolved in 200 ml of methylene chloride and the solution is extracted with water. The organic phase is separated by distillation, affording 47.3 g (89.8% of theory) of 4-(1-chloro-1,2,2,2-tetrafluoroethoxy)chlorobenzene. Boiling point 181° C., nD25 =1.4362.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][C:8]2[CH:16]=[CH:15][C:11]3[S:12][CH:13]=[CH:14][C:10]=3[CH:9]=2)=[CH:5][CH:4]=1)[CH3:2].C([Li])CCC.CCCCCC.[P:30](Cl)([O:35][CH2:36][CH3:37])([O:32][CH2:33][CH3:34])=[O:31]>C1COCC1>[CH2:33]([O:32][P:30]([C:13]1[S:12][C:11]2[CH:15]=[CH:16][C:8]([CH2:7][C:6]3[CH:17]=[CH:18][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)=[CH:9][C:10]=2[CH:14]=1)(=[O:31])[O:35][CH2:36][CH3:37])[CH3:34]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCc1ccc(Cc2ccc3sccc3c2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOP(=O)(OCC)c1cc2cc(Cc3ccc(CC)cc3)ccc2s1
Reaction time: 1 h

Procedure:
To a solution of 5-(4-ethylbenzyl)benzo[b]thiophene (1.50 g) in THF (11.8 mL) was added 2.44 M n-butyllithium/n-hexane solution (2.9 mL) at −78° C., and the reaction mixture was stirred for 1 hr at same temperature. Diethyl chlorophosphate (0.9 mL) was added to the reaction mixture at −78° C., and the reaction mixture was stirred for 0.5 hr at −78° C. The reaction was quenched by the addition of saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/2) to give the title compound (1.79 g) as a colorless oil.
Reaction SMILES: Br.C(OC([N:12]1[C@H:17]([CH3:18])[CH2:16][N:15]([CH2:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24]([Cl:30])=[CH:25][CH:26]=[N:27]3)=[CH:22][CH:21]=2)[C:14](=[O:31])[C@@H:13]1[CH3:32])=O)C1C=CC=CC=1.C(N(CC)CC)C>C(O)(=O)C.C(OCC)(=O)C>[Cl:30][C:24]1[C:23]2[C:28](=[CH:29][C:20]([CH2:19][N:15]3[CH2:16][C@@H:17]([CH3:18])[NH:12][C@@H:13]([CH3:32])[C:14]3=[O:31])=[CH:21][CH:22]=2)[N:27]=[CH:26][CH:25]=1
Reactant: C[C@@H]1CN(Cc2ccc3c(Cl)ccnc3c2)C(=O)[C@H](C)N1C(=O)OCc1ccccc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C[C@@H]1CN(Cc2ccc3c(Cl)ccnc3c2)C(=O)[C@H](C)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
A 33% solution of hydrogen bromide in acetic acid (10 mL) is added to (2S,6R)-4-(4-chloro-quinolin-7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (1.04 g, 2.38 mmol). The reaction is left to stir at room temperature for one hour. The reaction mixture is diluted with ethyl acetate and stirred vigorously to force the product to precipitate out of solution. The ethyl acetate is decanted off and the precipitate is purified on a silica gel column (1% triethylamine/3% methanol/methylene chloride) to 582 mg (81% yield) of (3S,5R)-1-(4-chloro-quinolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one as a white solid.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][Cl:12]>>[Cl:12][CH2:11][CH2:10][CH2:9][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: ClCCCBr
Product: ClCCCSc1ccccc1

Procedure:
Prepared by Procedure R and Scheme Z using benzenethiol and 1-bromo-3-chloropropane: 1H NMR (400 MHz, CDCl3) δ 7.37-7.34 (m, 2H), 7.32-7.26 (m, 2H), 7.19 (tt, 1H, J=1.4, 7.3 Hz), 3.67 (t, 2H, J=6.6 Hz), 3.08 (t, 2H, J=6.6 Hz), 2.06 (qt, 2H, J=6.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.FC(C1C=CC(F)=CC=1)C[NH2:16]>S(Cl)(Cl)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:16])=[O:12]
Reactant: O=C(O)Cc1ccc(F)cc1F
Reactant: NCC(F)c1ccc(F)cc1
Solvent: O=S(Cl)Cl
Product: NC(=O)Cc1ccc(F)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 12.7 %

Procedure:
Preparation of 2,4-difluorophenylethylamine 2,4-Difluorophenylacetic acid (5 g, 29 mmol) in thionyl chloride (50 mL) was heated at reflux for 10 min and the excess thionyl chloride removed by distillation. The acid chloride in dichloromethane (10 mL) was added to a cooled (−78° C.) solution of NH3 (20 mL) in dichloromethane (250 mL). Triethylamine (40 mL) was added and the reaction stirred at ambient temperature for 60 min. The solvents were then evaporated and the remaining solid dissolved in diethyl ether (500 mL). The organic solution was washed with 10% HCl (4×100 mL), 1 N NaOH (4×100 mL), dried over anhydrous MgSO4, filtered and concentrated to afford 630 mg (13%) of 2,4-difluorophenylacetamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([NH:11][C@H:12]([C:31]([OH:33])=[O:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:16][CH:15]=1)=[O:10].C(=O)(O)[O-].[Na+].I[CH2:40][CH3:41].O>CN(C=O)C>[CH2:40]([O:32][C:31](=[O:33])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:18][CH:19]=1)[NH:11][C:9]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])=[O:10])[CH3:41]
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cccc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.9 %

Procedure:
To a suspension of N-[(2,6-difluorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine (0.743 mmol, 340 mg) and sodium bicarbonate (5.94 mmol, 499 mg) in DMF (3.8 mL) was added iodoethane (5.94 mmol, 0.475 mL) at room temperature. The mixture was stirred for 48 h at room temperature. Then, the reaction mixture was poured into water (100 mL) and was extracted with ethyl acetate (3×25 mL). The combined extracts were washed with brine solution (80 mL) and were dried over anhydrous sodium sulfate. Filtration of the drying agent and concentration of the filtrate gave the crude product which was purified by silica gel chromatography using a Biotage (40s) column to obtain 335 mg (93% yield) of N-[(2,6-difluorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine ethyl ester as a crystalline white solid: mp 218-219° C. ES-HRMS m/e calcd for C25H25F2N3O5 (M+Na) 508.1654, found 508.1660.
Reaction SMILES: C(C(C)=O)C(C)C.[Br:8][C:9]([Br:25])=[C:10]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[N:26]#[C:27]Br.[CH2:29]([N:31](CC)CC)C>>[Br:8][C:9]([Br:25])=[C:10]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:27]#[N:26])=[CH:20][CH:19]=1)[C:11]1[CH:12]=[CH:13][C:14]([O:17][C:29]#[N:31])=[CH:15][CH:16]=1
Reactant: N#CBr
Reactant: Oc1ccc(C(=C(Br)Br)c2ccc(O)cc2)cc1
Reactant: CCN(CC)CC
Solvent: CC(=O)CC(C)C
Product: N#COc1ccc(C(=C(Br)Br)c2ccc(OC#N)cc2)cc1
Temperature: -20 °C

Procedure:
A 4-necked 5-L flask, equipped with a mechanical stirrer, a thermometer, and an additional funnel, is charged with methyl isobutyl ketone (1500 g), 1,1-dibromo-2,2-bis(4-hydroxyphenyl)ethene (420 g), and cyanogen bromide (270 g). The resulting solution is cooled to −20° C. with a dry ice/acetone bath. To the stirring solution, triethylamine (240 g) in the additional funnel is added dropwise. The reaction temperature is maintained below −20° C. After the addition, the resulting mixture is allowed to warm up to 0° C. and quenched with dilute HCl aqueous solution. The organic layer is washed further with water several times and concentrated under vacuum to afford the desired product.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10](=[O:16])OC(C)(C)C)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.[C:24]([C:26]1[CH:27]=[C:28]([CH:44]([CH3:46])[CH3:45])[C:29]2[O:33][C:32]([C:34]3[CH:42]=[CH:41][C:37](C(O)=O)=[CH:36][CH:35]=3)=[N:31][C:30]=2[CH:43]=1)#[N:25].CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[C:24]([C:26]1[CH:27]=[C:28]([CH:44]([CH3:46])[CH3:45])[C:29]2[O:33][C:32]([C:34]3[CH:42]=[CH:41][C:37]([C:10]([NH:9][CH2:8][CH:5]4[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]4)=[O:16])=[CH:36][CH:35]=3)=[N:31][C:30]=2[CH:43]=1)#[N:25]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Reactant: CC(C)(C)OC(=O)NCC1CCC(=O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCC(=O)CC4)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
To a solution of tert-butyl [(4-oxocyclohexyl)methyl]carbamate (5.0 g, 22.00 mmol) in dichloromethane (100 ml) was added trifluoroacetic acid (10 ml). The mixture was stirred for 1 h at room temperature, and then concentrated and co-concentrated with toluene (5 ml). A suspension of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (INTERMEDIATE 2, 6.13 g, 20 mmol), o-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (15.2 g, 40.1 mmol), 1-hydroxybenzotriazole (4.0 g, 29.6 mmol), and diisopropylethylamine (20 ml, 115 mmol) in dichloromethane (100 ml) was stirred for 5 min at room temperature, and then a solution of the deprotected amine in dichloromethane (100 ml) was added. The mixture was stirred overnight at 25° C. The mixture was filtered and then diluted with 300 ml of saturated sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted with 2×100 ml of dichloromethane. The combined organics were washed with 100 ml of brine, dried (sodium sulfate), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 65i column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes. The resulting product was repurified by flash chromatography on a Biotage Horizon, 65i column, eluting with 1 column volume of 100% hexanes followed by a gradient of 0 to 100% acetone in hexanes over 10 column volumes. The resulting product was crystallized from dichloromethane to provide the title compound (5.52 g, 13.29 mmol, 66.4% yield). Mass spectrum (ESI) 416.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:29]([CH3:30])=[C:28]([C:31]([OH:33])=O)[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[N:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.[C:73]([NH:76][NH2:77])(=[O:75])[CH3:74].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:29]([CH3:30])=[C:28]([C:31]([NH:77][NH:76][C:73](=[O:75])[CH3:74])=[O:33])[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)NN
Reactant: Cc1c(C(=O)O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)ncc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NNC(=O)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a solution of 12 2-[5-(4-tert-Butoxycarbonyl-piperazin-1-yl)-pyridin-2-ylamino]-7-cyclopentyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (120 mg, 0.23 mmol), HBTU (130.9 mg, 0.345 mmol) and HOAt (46.97 mg, 0.345 mmol) in dry DMF (15 mL) is added a solution of acetic hydrazide (34.09 mg, 0.46 mmol) and diisopropylethylamine (121 ul, 0.693 mmol) in dry DMF (5 mL). The reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and extracted with ethyl acetate three times. The organic layers are combined, washed with brine and dried over anhydrous sodium sulfate. The solvent is evaporated and the crude product is purified by preparative HPLC to give 4-{6-[6-(N′-Acetyl-hydrazinocarbonyl)-7-cyclopentyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (120 mg, 75.4%). [M+H]+=578.32.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:14][N:15]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16]1[CH:21]=[C:20](Br)[N:19]=[C:18](Br)[CH:17]=1.[CH3:31][N:32]([CH:34]=[O:35])C>CCCCCC>[C:31]1([NH:32][C:34]([C:20]2[CH:21]=[C:16]([N:15]([CH3:14])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:17]=[C:18]([O:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=3)[N:19]=2)=[O:35])[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CN(C)C=O
Reactant: CN(Cc1ccccc1)c1cc(Br)nc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: CN(Cc1ccccc1)c1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)Nc2ccccc2)c1
Temperature: 25 °C

Procedure:
1.56 g (0.0080×1.2 mol) of 3-(trifluoromethyl) phenol was dissolved in about 20 ml of DMF. The solution was further mixed with 0.34 g (ca. 60% in mineral oil; 0.0080×1.06 mol) of NaH and then with 2.85 g (0.0080 mol) of 4-{methyl(phenylmethyl)amino}-2,6-dibromo pyridine. After treating the solution under reflux for about 6 hours, the obtained reaction solution was allowed to stand for cooling to room temperature. After the reaction solution was distributed in hexane-saturated sodium bicarbonate water, the organic phase of the obtained solution was washed with saturated brine and dried with anhydrous sodium sulfate. The resultant solution was concentrated and then purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), and the obtained eluate was subjected to recrystallization using hexane, thereby obtaining an aimed product.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=[O:12].[C:13]([NH2:21])(=[S:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1.[CH2:22](O)[CH3:23]>>[Cl:11][C:7]1[CH:6]=[CH:5][C:4]2[C:3]3([O:12][CH2:22][CH3:23])[N:21]=[C:13]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)[S:20][CH:2]3[CH2:10][C:9]=2[CH:8]=1
Reactant: NC(=S)c1cccnc1
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Reactant: CCO
Product: CCOC12N=C(c3cccnc3)SC1Cc1cc(Cl)ccc12
Temperature: 70 °C
Reaction time: 8 h

Procedure:
1 g of 2-bromo-5-chloroindan-1-one and 622 mg of thionicotinamide are suspended in 10 ml of dry ethanol, and the mixture is stirred at room temperature for 2 h and at 70° C. for 8 h. The reaction mixture is cooled, and the precipitate is filtered off with suction, washed with ethanol, stirred with a little water, again filtered off with suction and dissolved in 50 ml of ethyl acetate. This solution is rendered alkaline with triethylamine, treated with 30 ml of water and the organic phase is separated off, washed with water, dried over magnesium sulfate and concentrated in vacuo, and finally the residue is chromatographed on silica gel using ethyl acetate/n-heptane 1/1. 6-Chloro-3a-ethoxy-2-pyridin-3-yl-8,8a-dihydro-3aH-indeno[1,2-d]thiazole of melting point 89-90° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]([CH3:24])[CH2:13][C:14]2[N:15]([CH3:23])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:11])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[C:30](OC(=O)C)(=[O:32])[CH3:31]>C1COCC1>[C:30]([NH:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]([CH3:24])[CH2:13][C:14]2[N:15]([CH3:23])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:11])=[CH:4][CH:3]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(/C=C/C(=O)N(C)Cc2cc3ccccc3n2C)cn1
Yield: 95.5 %

Procedure:
To a stirred suspension of (E)-3-(6-aminopyridin-3-yl)-N-methyl-N-[(1-methyl-1H-indol-2-yl)methyl]acrylamide (0.50 g, 1.56 mmole) and NaHCO3 (0.51 g, 6.09 mmole) in THF (75 mL) was added acetic anhydride (0.38 g, 3.74 mmole). The reaction was heated at reflux for 24 hrs and then concentrated. The remaining residue was extracted with EtOAc and purified on silica gel (95:5 CHCl3/CH3OH) to give the title compound (0.54 g, 96%) as an off-white solid: MS (ES) m/e 363 (M+H)+.
Reaction SMILES: [C:1](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:2].[NH2:16][C:17]1[C:18]([CH3:29])=[C:19]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:20]([N:22]([CH3:24])[CH3:23])=[O:21].C(N(CC)C1C=CN=CC=1)C>C(Cl)Cl>[CH3:23][N:22]([CH3:24])[C:20]([C:19]1[C:18]([CH3:29])=[C:17]([N:16]=[C:1]=[O:2])[C:27]([CH3:28])=[CH:26][CH:25]=1)=[O:21]
Reactant: Cc1ccc(C(=O)N(C)C)c(C)c1N
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CCN(CC)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)N(C)C)c(C)c1N=C=O

Procedure:
A solution of di-tert-butyl dicarbonate (0.081 g) in methylene chloride (1.6 ml) and a solution of 3-amino-N,N,2,4-tetramethylbenzamide (J. Chem. Soc., Perkin Trans, I. 1973, 1-4; 0.072 g) in methylene chloride (1.0 ml) were added in turn to a solution of 4-diethylaminopyridine (0.004 g) in methylene chloride (0.4 ml). The resultant mixture was stirred at ambient temperature for 20 minutes. There was thus obtained a solution of 3-(N,N-dimethylcarbamoyl)-2,6-dimethylphenylisocyanate which was used without further purification.