Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[C:10]([O:12]CC)=O)=[CH:4][C:3]=1[F:16].[NH2:17][C@@H:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][C@@H:19]1[OH:27]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[C:10]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[O:12])=[CH:4][C:3]=1[F:16]
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCOC(=O)C(=O)Nc1ccc(Cl)c(F)c1
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Cl)c(F)c1)C(=O)N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution containing ethyl 2-(4-chloro-3-fluorophenylamino)-2-oxoacetate (1) (1.73 g, 7.05 mmol) in 20 mL dioxane in a round-bottom flask was added (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol (1.16 g, 7.76 mmol) and both a stir bar and a reflux condenser were equipped. The reaction was heated to reflux for 72 hours and then allowed to cool to room temperature. The crude reaction mixture was concentrated in vacuo. The solid was collected by filtration with a 1:1 mixture of hexanes and dichloromethane to give 2.04 g (83%) of TK-II-103 as an off-white flakey solid; [α]29D=−112.1° (c=0.48, DMSO): 1H NMR (500 MHz, DMSO-d6) δ 11.19 (s, 1H), 8.36 (d, J=8.7 Hz, 1H), 7.97, (dd, J=2, 11.7 Hz, 1H), 7.77, (d, J=8.8 Hz, 1H), 7.59, (t, J=8.7 Hz, 1H), 7.28-7.18, (m, 4H), 5.46, (d, J=4.9 Hz, 1H), 5.25, (dd, J=5.2, 8.6 Hz, 1H), 4.52, (dd, J=4.6, 8.6 Hz, 1H), 3.14, (dd, J=4.9, 16.2 Hz, 1H), 2.88, (d, J=16.1 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 159.3, 158.8, 156.8, (d, JCF=242.5 Hz), 141.0, 140.8, 138.2, (d, JCF=10 Hz), 131.6, 127.7, 126.5, 125.0, 124.1, 117.5 (d, JCF=2.9 Hz), 114.5 (d, JCF=17.5 Hz), 108.6, (d, JCF=25 Hz), 71.6, 56.9. HRMS (ES+) m/z 371.0572 [(M+Na)+; calcd for C17H14ClFN2O3: 371.0575].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH2:22])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1.CN([C:35]([O:39]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH:22][C:35](=[O:39])[C:25]4[CH:24]=[CH:29][CH:28]=[CH:27][N:26]=4)=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccnc1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12)c1ccccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
To a mixture of (R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Example 6, Step A; 30 mg, 0.1 mmol), nicotinic acid (25 mg, 0.2 mmol), and HATU (77 mg, 0.2 mmol) was added 0.7 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.053 mL, 0.3 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred for 3 hours. The reaction mixture was diluted with EtOAc (15 mL), washed with water and brine (5 mL each), concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 57% acetonitrile/water to yield the final product as a yellowish solid (30 mg, 74% yield). MS (apci) m/z=403.2 (M+H).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][OH:10])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11](OCC(F)(F)F)=[O:12]>O1CCCC1>[OH:10][N:9]([C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])[CH:11]=[O:12]
Reactant: O=COCC(F)(F)F
Reactant: C[C@H](NO)c1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)N(O)C=O
Temperature: 65 °C
Yield: 89 %

Procedure:
A solution of Example 2B (1.5 g, 10.95 mmol) in tetrahydrofuran (15 mL, 10 vols) was treated with the 2,2,2-trifluoroethyl formate reagent (92% wt, 7.6 g, 54.7 mmol, 5 equiv). The resulting mixture was heated at 65° C. for 18 hours and concentrated. The concentrate was distilled under vacuum (170° C. at 1.6 mm Hg) to provide 1.6 g (89%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.00 (s, 1H), 7.54-7.30 (m, 5H), 4.93 (q, 1H, J=7 Hz), 1.82 (d, 3H, J=7 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25](O)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C(N3CCNC(=O)C3)=O)C=2)C=C(F)C=1.[S:56]1[CH2:60][CH2:59][NH:58][CH2:57]1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25]([N:58]3[CH2:59][CH2:60][S:56][CH2:57]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:10])([F:12])[F:11])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccc(Cl)nc2)n1
Reactant: C1CSCN1
Agent: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Product: O=C(c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccc(Cl)nc2)n1)N1CCSC1

Procedure:
170 mg (0.28 mmol, 76% purity) of the compound of Example 40A is reacted analogously to the synthesis of the compound of Example 4 with 27 mg (0.30 mmol) of thiazolidine. 96 mg (62% of theory) of the title compound is obtained.
Reaction SMILES: [N+:1]([C:4]1[N:8]=[C:7]([N+:9]([O-:11])=[O:10])[NH:6][N:5]=1)([O-:3])=[O:2].[BH4-:12].[K+:13].[H][H]>>[N+:1]([C:4]1[N:8]=[C:7]([N+:9]([O-:11])=[O:10])[N:6]([B-:12]([N:5]2[C:4]([N+:1]([O-:3])=[O:2])=[N:8][C:7]([N+:9]([O-:11])=[O:10])=[N:6]2)([N:5]2[C:4]([N+:1]([O-:3])=[O:2])=[N:8][C:7]([N+:9]([O-:11])=[O:10])=[N:6]2)[N:5]2[C:4]([N+:1]([O-:3])=[O:2])=[N:8][C:7]([N+:9]([O-:11])=[O:10])=[N:6]2)[N:5]=1)([O-:3])=[O:2].[K+:13]
Reactant: [BH4-]
Reactant: O=[N+]([O-])c1n[nH]c([N+](=O)[O-])n1
Reactant: [H][H]
Agent: [K+]
Product: O=[N+]([O-])c1nc([N+](=O)[O-])n([B-](n2nc([N+](=O)[O-])nc2[N+](=O)[O-])(n2nc([N+](=O)[O-])nc2[N+](=O)[O-])n2nc([N+](=O)[O-])nc2[N+](=O)[O-])n1
Temperature: -196 °C
Reaction time: 0.5 h

Procedure:
A 150 mL glass ampule equipped with a grease-free high-vacuum PTFE valve and a TEFLON™ coated stir bar was flamed-out under vacuum. Inside the dry-box, the ampule was loaded with 588 mg (4.00 mmol) 3,5-dinitro-1H-1,2,4-triazole and 53.9 mg (1.00 mmol) potassium borohydride. The ampule was connected to a vacuum line, evacuated and cooled to −196° C. About 5 mL of dry dimethoxyethane was slowly condensed into the ampule. The ampule was closed and allowed to warm to ambient temperature. As soon as the solvent melted and contacted the solid mixture at the bottom of the ampule, gas evolution started. The mixture was then stirred for about 30 minutes at ambient temperature. The clear, light yellow solution was cooled to −196° C., and 1.5 mmol of evolved hydrogen (determined by p, V, T measurements) were pumped off. The ampule was closed off and heated to 60° C. while stirring. After 3 hours, an orange solution was obtained and the temperature was first raised to 80° C. and, after an additional 8 hours, to 110° C. After 24 hours, the solution was allowed to cool to ambient temperature and then cooled to −196° C. An additional 2.50 mmol of evolved hydrogen (determined by p, V, T measurements) was pumped off. The reaction mixture was allowed to warm to ambient temperature. Subsequent evacuation to a constant weight over 24 hours resulted in an orange solid of potassium tetrakis(3,5-dinitro-1H-1,2,4-triazolyl)borate, 1.0 mmol. Decomposition temperature: 165° C. (DTA).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.O[C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][CH:31]=1>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][C:30]2[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][CH:31]=2)[N:10]=[CH:9]1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CC(=O)c1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol of (4-hydroxyphenyl)ethanone are treated as described in Example 76.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]#N)[CH:5]=1.C1(C)C=CC=CC=1.CC(C[AlH]CC(C)C)C.CC[O:31]CC>CCCCCC>[CH3:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1[O:8][N:7]=[C:6]([CH:9]=[O:31])[CH:5]=1
Reactant: CCOCC
Reactant: CC(C)(C)Cc1cc(C#N)no1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)Cc1cc(C=O)no1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(2,2-dimethyl-propyl)-isoxazole-3-carbonitrile (821 mg, 5 mmol) in Et2O (15 mL) and n-hexane (50 mL) was added dropwise at −78° C. an 1.7M toluene solution of DIBAL (11.8 mL, 20 mmol) keeping the temperature below −70° C. The mixture was stirred at −78° C. for 1 h. The reaction was quenched with EtOAc (7.5 mL), allowed to warm to 0° C., then sat. NH4Cl solution (25 mL) and 1M HCl (50 mL) were added and the mixture stirred at room temperature for 2 h. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (cyclohexane to cyclohexane-EtOAc 80:20) to furnish title compound as a colorless oil: TLC (cyclohexane-EtOAc 80:20) Rf=0.44; ESIMS [M+H]+=168; 1H NMR (400 MHz, DMSO-d6): δ 10.06 (s, 1H), 6.66 (s, 1H), 2.74 (s, 2H), 0.92 (s, 9H).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[Br:15][C:16]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:17]=1[C:18](Cl)=[O:19].[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28]1>>[Br:15][C:16]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:17]=1[C:18]([N:6]1[CH:7]([C:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[NH:27][CH:28]=2)[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)=[O:19]
Reactant: c1ccc2[nH]ccc2c1
Reactant: COc1ccc(Br)c(C(=O)Cl)c1
Reactant: c1ccc2c(c1)cnc1ccccc12
Product: COc1ccc(Br)c(C(=O)N2c3ccccc3-c3ccccc3C2c2c[nH]c3ccccc23)c1

Procedure:
(2-Bromo-5-methoxy-phenyl)-[6-(1H-indol-3-yl)-6H-phenanthridin-5-yl]-methanone was prepared from phenanthridine, 2-bromo-5-methoxybenzoyl chloride, and indole according to GP 2. Yield, 30%. (+)-ESI-MS: m/z=509 [M(79Br)+H]+, 392 [M(79Br)-indole+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([NH2:18])=[C:8]([NH2:19])[N:7]=1.C(N(CC)CC)C.CN(C)[CH:29]=[O:30]>>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:7]=[C:8]2[NH:19][C:29](=[O:30])[NH:18][C:9]2=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: CN(C)C=O
Reactant: Nc1cc(-c2ccncc2)c(-c2ncco2)nc1N
Solvent: CCN(CC)CC
Product: O=c1[nH]c2cc(-c3ccncc3)c(-c3ncco3)nc2[nH]1
Reaction time: 4 h
Yield: 45 %

Procedure:
A solution of 2-(1,3-oxazol-2-yl)-3,4′-bipyridine-5,6-diamine (Intermediate 10, 0.077 g, 0.3 mmol), N,N′-carbonyldiimidazole (0.146 g, 0.9 mmol) and triethylamine (91 mg, 0.9 mmol) in N,N-dimethylformamide (1 mL) was heated to 100° C. in a sealed tube. After 4 hours, the mixture was cooled and concentrated in vacuo. Water was added to the residue and the solid that separated was washed with water and dried to give the title compound (0.038 g, 45%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.C1[CH2:11][O:10]CC1.C([N-]C(C)C)(C)C.[Li+].Cl.[OH2:21]>>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:11]([OH:10])=[O:21]
Reactant: O
Reactant: Brc1ccoc1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Product: O=C(O)c1occc1Br
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-bromo furan (51.0 g; 0.347 mol) and THF (250 ml) was added lithiumdiisopropylamide (191 ml; 0.382 mol; 2 M solution in heptane/THF/ethylbenzene) at −70° C. The mixture was stirred for 1 hour at −70° C. Solid carbondioxide (100.3 g; 2.28 mol) was added and the mixture was stirred until the carbondioxide was gone. Water (50 ml) was addded followed by aqueous hydrochloric acid (380 ml; 2M). The tetrahydrofuran was evaporated. The mixture was extracted with diethylether (3×100 ml). The combined ether phase was extracted with aqueous sodium hydroxide (3×100 ml; 2M). The aqueous phase was cooled on ice and acidified with aqueous hydrochloric acid (100 ml; 10M). The mixture was extracted with ether (3×100 ml). The combined ether phase was evaporated. Yield 36 g (54%). Mp. 118.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:50])[CH2:7][C@H:8]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33](=[O:49])[CH2:34][CH2:35][CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)[CH2:28]1)=[O:26])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.CO.[Pd]>[C:1]([O:5][C:6](=[O:50])[CH2:7][C@H:8]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33](=[O:49])[CH2:34][CH2:35][CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)[CH2:28]1)=[O:26])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[CH:14]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(C#Cc2cccc(O)c2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(CCc2cccc(O)c2)c1
Reaction time: 4 h
Yield: 62.2 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-{5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (200 mg, 0.29 mmol) in ethyl acetate (8.5 mL) and methanol (1.4 mL) was stirred for 7 hours at room temperature under a hydrogen atmosphere in the presence of palladium on charcoal (10%, 20 mg), while the addition of palladium on charcoal (10%, 20 mg) was repeated after 4 hours. The suspension was filtrated through celite, which were washed thoroughly with methanol. The solution was concentrated under reduced pressure and the residue was purified by preparative HPLC to yield 125 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-{5-[2-(3-hydroxyphenyl)ethyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:11][C:12]1[C:17](B(O)O)=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:11][C:12]1[C:17]([C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: OB(O)c1cccnc1F
Reactant: Clc1ncnc2[nH]ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Fc1ncccc1-c1ncnc2[nH]ccc12
Temperature: 25 °C
Yield: 17 %

Procedure:
A mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (7.68 g, 50 mmol), 2-fluoropyridin-3-ylboronic acid (10.57 g, 75 mmol), and tetrakis(triphenylphosphine)palladium(0) (2.89 g, 2.5 mmol) was suspended in DME (300 mL) and aqueous sodium carbonate (10%) (50 mL, 100 mmol). The suspension was heated at reflux over night, cooled to r.t. and the reaction mixture was partitioned between EtOAc (300 mL) and NaHCO3 (aq., sat., 200 mL). The aqueous layer was washed with EtOAc twice. The organic layers were combined and washed with brine, then loaded on silica and purified via flash column (EtOAc:hexane=50-95%) on ISCO to give 4-(2-fluoropyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine as a light yellow solid with a green tint (1.85 g, 17% yield). MS (ESI, pos. ion) m/z: 214 [M+H]+
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:7][CH:8]([F:14])[C:9](OCC)=[O:10])([CH3:6])=[O:5])[CH3:2].[OH-].[NH4+:16]>C(O)C>[NH2:16][C:9](=[O:10])[CH:8]([F:14])[CH2:7][P:4]([CH3:6])(=[O:5])[O:3][CH2:1][CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)C(F)CP(C)(=O)OCC
Agent: [OH-]
Solvent: CCO
Product: CCOP(C)(=O)CC(F)C(N)=O
Yield: 86.7 %

Procedure:
A solution of ethyl 3-[ethoxy(methyl)phosphoryl]-2-fluoropropanoate (12.6 g, 55.6 mmol), ethanol (15 mL), and concentrated ammonium hydroxide (14.8 N, 5.6 mL, 83 mmol) were stirred at room temperature for 16 h. The solvent was evaporated and the residue chromatographed on a wet-packed silica gel column (5.5×31 cm) eluting with 90:10 methylene chloride/methanol. The appropriate fractions were combined and evaporated to give 9.5 g (86%) of ethyl (3-amino-2-fluoro-3-oxopropyl)(methyl)phosphinate as a clear oil. Data: 1H NMR (300 MHz, CDCl3) δ6.62 (s, 1H), 6.33 (s, 1H), 5.10-5.42 (m, 1H), 4.02-4.18 (m, 2H), 2.19-2.70 (m, 2H), 1.60 (d, J=14 Hz, 3H), 1.34 (m, 3H)
Reaction SMILES: [CH:1]([C:12]([O:14]CC)=O)([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:12]([CH:1]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:14])=[CH:20][CH:19]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(C(=O)NCc1ccc(Cl)cc1)C(=O)OCC
Yield: 30.5 %

Procedure:
Triethyl methanetricarboxylate (2.32 g) and 4-chlorobenzylamine (1.42 g) are stirred at room temperature for 16 h. Insoluble material is filtered off and the filtrate is purified by column chromatography (hexanes/acetone, 5/1) to give 1 g (12%) of the title compound as an oil which slowly solidifies. Physical characteristics: MS (ESI+) m/z 330 (M+H)+. 1H NMR (CDCl3) δ7.70, 7.31, 7.26, 4.48, 4.38, 4.28, 1.30.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][CH:18]([CH2:35][CH2:36][CH3:37])[CH2:19][N:20]1[C:28]2[C:23](=[CH:24][C:25](/[C:29](/[CH3:34])=[CH:30]/[C:31](O)=[O:32])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>>[CH3:17][CH:18]([CH2:35][CH2:36][CH3:37])[CH2:19][N:20]1[C:28]2[C:23](=[CH:24][C:25](/[C:29](/[CH3:34])=[CH:30]/[C:31]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:32])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: CCCC(C)Cn1ccc2cc(/C(C)=C/C(=O)O)ccc21
Product: CCCC(C)Cn1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
0.56 g of compound 14 was obtained in a similar manner to those described in the Examples 1 and 2 using 1.56 g of ethyl 4-(2-aminophenoxy)butyrate and 1.0 g of 3-[1-(2-methylpentyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [OH-].[K+].[C:3]([C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[CH:6]=1)#[N:4].C1(C)C=CC=CC=1.Cl[CH:27]([CH3:32])[CH2:28][N:29]([CH3:31])[CH3:30]>C(C(C)=O)C.C(OCC)C>[CH3:30][N:29]([CH3:31])[CH2:28][CH:27]([N:8]1[C:7]2[CH:6]=[C:5]([C:3]#[N:4])[CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:32]
Reactant: N#Cc1ccc2c(c1)Nc1ccccc1S2
Reactant: CC(Cl)CN(C)C
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCC(C)=O
Product: CC(CN(C)C)N1c2ccccc2Sc2ccc(C#N)cc21

Procedure:
Powdered potassium hydroxide (96.7 g) is added to a suspension of 2-cyanophenothiazine (242 g) in methyl ethyl ketone (2.2 liters). The temperature of the mixture rises spontaneously to 24° C. and the mixture is brought to 60° C. for half an hour while stirring. The toluene solution of 2-chloro-1-dimethylaminopropane prepared above is added in the course of 30 minutes. The mixture is heated under reflux for 12 hours. After cooling, the mixture is transferred to a separating funnel and washed with distilled water (2×2 liters). The organic phase is dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give an oil, which is diluted in ethyl ether (2 liters). The solution obtained is cooled and primed by scratching. The crystallized yellow precipitate is removed by filtration. The mother liquors are concentrated to dryness under reduced pressure (100 mm Hg; 13.3 kPa) at 30° C. to give a brown oil which is purified by chromatography on a column (height: 80 cm; diameter: 8.5 cm) of silica (0.2-0.06 mm), eluting with an 80:20 (by volume) mixture of cyclohexane and ethyl acetate and collecting 1-liter fractions. Fractions 7 to 16 are combined and concentrated to dryness at 50° C. under reduced pressure (30 mm Hg; 4 kPa) to give 10-[(2RS)-1-dimethylamino-2-propyl]-2-phenothiazinecarbonitrile (54.8 g) in the form of a brown oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@H:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1)[C:6]([O:8]CC1C=CC=CC=1)=[O:7].[H][H]>CO.[C].[Pd]>[CH3:1][O:2][CH2:3][O:4][C@H:5]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:21][CH:22]=1)[C:6]([OH:8])=[O:7]
Reactant: COCO[C@H](Cc1ccc(N2CCOCC2)cc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COCO[C@H](Cc1ccc(N2CCOCC2)cc1)C(=O)O
Yield: 113.2 %

Procedure:
To a solution of benzyl (R)-2-methoxymethoxy-3-(4-morpholinophenyl)propionate (1.66 g) in methanol (8.6 ml) was added 10% palladium-carbon (0.2 g), and hydrogenation was carried out in a hydrogen atmosphere at atmospheric pressure and room temperature for 100 minutes. After the catalyst was filtered off, the solvent was distilled off under reduced pressure. The residue was further subjected to azeotropic distillation with isopropyl ether-hexane to provide 1.44 g of (R)-2-methoxymethoxy-3-(4-morpholino-phenyl)propionic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C[Si](Cl)(C)C.C(N(CC)CC)C.CC([O:28][C:29]1[C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=[CH:31][CH:30]=1)=O>C(Cl)Cl>[C:35]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)(=[O:36])[C:34]1[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=1)[OH:28]
Reactant: CC(C(=O)O)c1ccc(N)cc1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C(=O)O)c1ccc(NC(=O)c2ccccc2O)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 52.4 %

Procedure:
A slurry of 58.6 g (0.355 mol) of 2-(4-aminophenyl)propionic acid and 500 ml of methylene chloride was treated with 90.11 ml (77.13 g. 0-710 mol) of trimethylsilyl chloride and was heated to reflux for 120 min. The reaction mixture was cooled to 0° C. and treated with 184.44 ml (107.77 g, 1.065 mol) of triethylamine. After stirring for 5 minutes, this mixture was treated with a solution of 70.45 g (0.355 mol) of O-acetylsalicyloyl chloride and 150 ml of methylene chloride. The reaction mixture was warmed to 25° C. and stirred for 64 hr. The volatiles were removed in vacuo. The residue was stirred in 2N aqueous sodium hydroxide for one hour and acidified with 2 M aqueous sulfuric acid. The solid was recrystallized twice from ethanol/water to give a tan solid. Isolation by filtration afforded 53.05 g of (52% yield) of 2-(4-(N-salicyloyl)aminophenyl)propionic acid.