Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:20](=[O:28])[CH2:21]P(OC)(OC)=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl-].[Li+].[F:40][C:41]([F:55])([F:54])[C:42]1[CH:43]=[C:44]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[CH:45]=O>C(#N)C>[F:40][C:41]([F:54])([F:55])[C:42]1[CH:43]=[C:44]([CH:45]=[CH:21][C:20](=[O:28])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH:47]=[C:48]([C:50]([F:51])([F:52])[F:53])[CH:49]=1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COP(=O)(CC(=O)C(Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)OC
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
A solution of the product of part (b) (69.0 g) in acetonitrile (600 ml) was stirred with diisopropylethylamine (43.3 g), and anhydrous lithium chloride (14.13 g) for 30 minutes before adding 3,5-bistrifluoromethylbenzaldehyde (55 g) in acetonitrile (200 ml). The reaction was stirred for two hours then the solvent was removed and the residue partitioned between ethyl acetate and water. The organic phase was washed with 10% citric acid (500 ml), water (500 ml), saturated sodium bicarbonate (500 ml) and water (500 ml). The solution was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica using ethyl acetate/petroleum ether (1:4) to yield the title compound as a pale yellow solid, mp=137°-138° C.; found: C, 59.23; H, 4.79; N, 5.35; C26H24F6N2O3 requires C, 59.32; H, 4.60; N 5.32%.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:15]3[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[CH:19][C:20]=3[C:21](=[O:22])[C:13]=2[C:12]2[C:7](=[CH:8][C:9]([N+:25]([O-])=O)=[CH:10][CH:11]=2)[C:6]1=[O:28].CO.C(OCC)(=O)C>O1CCCC1>[NH2:25][C:9]1[CH:8]=[C:7]2[C:12]([C:13]3[C:21](=[O:22])[C:20]4[CH:19]=[C:18]([O:23][CH3:24])[CH:17]=[CH:16][C:15]=4[C:14]=3[N:5]([CH2:4][CH2:3][CH2:2][Br:1])[C:6]2=[O:28])=[CH:11][CH:10]=1
Reactant: COc1ccc2c(c1)C(=O)c1c-2n(CCCBr)c(=O)c2cc([N+](=O)[O-])ccc12
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)c1c-2n(CCCBr)c(=O)c2cc(N)ccc12
Reaction time: 24 h
Yield: 58.9 %

Procedure:
6-(3-Bromopropyl)-9-methoxy-3-nitro-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione (80, 1.00 g, 2.26 mmol) was dissolved in tetrahydrofuran (60 mL), methanol (20 mL), and ethyl acetate (30 mL) and transferred to a Parr shaker flask. The reaction vessel was purged with argon for 10 min and then palladium-charcoal (10%, 20 mg) was added. The reaction mixture was shaken for 24 h under an atmosphere of hydrogen (60 psi). The solid was filtered off, the solvent removed under vacuum, and the compound purified by silica gel column chromatography, eluting with ethyl acetate. The product was obtained as a brown solid (0.55 g, 59%): mp 330° C. (dec). IR (Film) 3367, 1696, 1655, 1506, 1480, 1431, 1293, 1229, 1016, 834, 787, 665 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 8.35 (d, J=8.6 Hz, 1H), 7.67-7.62 (m, 2H), 7.06 (d, J=2.5 Hz, 1H), 7.0.1-6.94 (m, 2H), 4.51 (t, J=6.0 Hz, 2H), 3.84 (s, 3H), 3.75 (dd, J=7.5 Hz, J=6.6 Hz, 2H), 2.30 (br p, J=8.5 Hz, 2H); EIMS m/z (rel intensity) 413 (M+, 46), 333 ([M-HBr)]+, 100); HRESIMS m/z calcd for C20H17N2O3Br, 413.0501 (MH+). found, 413.0505 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:17]([O:19]C)=[O:18])[CH:10]=[C:11]([CH:16]=2)[C:12]([O:14]C)=[O:13])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>CO.O>[F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:16]=[C:11]([C:12]([OH:14])=[O:13])[CH:10]=[C:9]([CH:8]=2)[C:17]([OH:19])=[O:18])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(Oc2ccc(F)cc2)cc(C(=O)OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(Oc2ccc(F)cc2)cc(C(=O)O)c1
Temperature: 80 °C
Yield: 11.6 %

Procedure:
A mixture of dimethyl 5-(4-fluorophenoxy)isophthalate (3.8 g, 12.49 mmol) and sodium bicarbonate (1.2 g, 14.28 mmol) in MeOH (100 mL) and water (15 mL) was heated at 80° C. overnight. An additional 500 mg of sodium bicarbonate was added to the reaction mixture and continued to heat at 100° C. for 6 h. HPLC showed a mixture of monoacid (major), diacid (minor) and a small amount of starting material. Prep HPLC provided diacid, 5-(4-fluorophenoxy)isophthalic acid (0.4 g, 1.448 mmol, 11.60% yield) and monoacid, 3-(4-fluorophenoxy)-5-(methoxycarbonyl)benzoic acid (2.2 g, 7.58 mmol, 60.7% yield) as a white solid.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH:13]1([C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)[CH2:15][CH2:14]1>CN(C=O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([CH:13]2[CH2:15][CH2:14]2)=[CH:17][CH:18]=1)=[O:4]
Reactant: Nc1ccc(C2CC2)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CN(C)C=O
Product: Nc1ccccc1C(=O)Nc1ccc(C2CC2)cc1
Temperature: 135 °C
Yield: 56.2 %

Procedure:
Isatoic anhydride (0.393 g, 2.41 mmol) and 4-cyclopropylaniline (0.320 g, 2.41 mmol) were dissolved in DMF (5 mL) and heated at 135° C. for 5 hours. The reaction mixture was concentrated, and purified by silica gel chromatography, eluting with 30% ethyl acetate/heptane to 100% ethyl acetate, to afford 2-amino-N-(4-cyclopropylphenyl)benzamide as a white solid (0.342 g, 56%).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:30])[C@H:7]([CH3:29])[CH2:8][C@@H:9]1[O:13][C:12]([CH3:15])([CH3:14])[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:10]1[CH2:23][C@H:24]([CH3:28])[CH2:25][CH2:26][OH:27])[CH2:2][CH2:3][CH3:4].[Na].[OH2:32]>C(Cl)(Cl)(Cl)Cl.C(#N)C.C(Cl)Cl.C(O)(C)C.O.[Ru](Cl)(Cl)Cl>[CH2:1]([NH:5][C:6](=[O:30])[C@H:7]([CH3:29])[CH2:8][C@@H:9]1[O:13][C:12]([CH3:15])([CH3:14])[N:11]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@H:10]1[CH2:23][C@H:24]([CH3:28])[CH2:25][C:26]([OH:32])=[O:27])[CH2:2][CH2:3][CH3:4]
Reactant: O
Reactant: CCCCNC(=O)[C@H](C)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@H](C)CCO
Agent: Cl[Ru](Cl)Cl
Agent: [Na]
Solvent: CC#N
Solvent: ClCCl
Solvent: CC(C)O
Product: CCCCNC(=O)[C@H](C)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@H](C)CC(=O)O
Reaction time: 1 h

Procedure:
A solution of 311 mg of 3-[N-tert-butoxycarbonyl-4(S)-[4-hydroxy-2(S)-methylbutyl]-2,2-dimethyl-1,3-oxazolidin-5(S)-yl]-2-(R)-methyl-propionic acid (N-butyl)amide in a mixture of 4.8 ml of carbon tetrachloride and 4.8 ml of acetonitrile is added to a mixture of 928 mg of sodium metaperiodidate, 19 mg of ruthenium(III) chloride hydrate and 0.6 ml of water while stirring vigorously. After 1 h, the mixture is diluted with 30 ml of methylene chloride and 5 ml of isopropanol, and the aqueous phase is separated off and extracted with methylene chloride. The combined organic phase is concentrated, the residue is taken up in 10 ml of toluene and the mixture is concentrated again. The dark-coloured residue is purified by FC over 25 g of silica gel with a 50:50:1 mixture of hexane, ethyl acetate and glacial acetic acid: Rf (B)=0.18; FAB-MS: (M+H)+ =443.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([S:8][CH2:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[CH:19]=3)[CH:13]=[C:12]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:11]=2)=[N:5][N:4]=1)[CH3:2].C(=O)([O-])O.[Na+]>C(Cl)Cl.B(Br)(Br)Br>[CH2:1]([C:3]1[S:7][C:6]([S:8][CH2:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=3)[CH:13]=[C:12]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH:11]=2)=[N:5][N:4]=1)[CH3:2]
Reactant: CCc1nnc(SCc2cc(N3CCOCC3)cc(NCc3cccc(OC)c3)n2)s1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1nnc(SCc2cc(N3CCOCC3)cc(NCc3cccc(O)c3)n2)s1
Temperature: 2 °C

Procedure:
To a solution of the compound (18.2 mg) obtained in Example 2 in methylene chloride (0.5 ml), boron tribromide (a 1.0M methylene chloride solution, 0.30 ml) was added at -78° C., and the temperature was raised to about 2° C. over a period of 3.6 hours. Then, a saturated sodium hydrogen carbonate aqueous solution (20 ml) was added thereto. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by thin layer chromatography for separation (silica gel 60F254, manufactured by Merck Company, chloroform:methanol=10:1) to obtain the above identified compound (14.9 mg) as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:22]([NH2:24])=[O:23])=[N:10][N:11]([C:13]4[CH:18]=[C:17]([F:19])[C:16]([NH2:20])=[C:15]([F:21])[CH:14]=4)[C:12]=3[C:4]=2[CH:3]=1.[Cl:27][C:28]1[CH:36]=[N:35][CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:20][C:16]1[C:15]([F:21])=[CH:14][C:13]([N:11]2[C:12]3[C:4]4[CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]5[CH:33]=[CH:34][N:35]=[CH:36][C:28]=5[Cl:27])[CH:26]=[CH:25][C:5]=4[CH2:6][CH2:7][C:8]=3[C:9]([C:22]([NH2:24])=[O:23])=[N:10]2)=[CH:18][C:17]=1[F:19]
Reactant: NC(=O)c1nn(-c2cc(F)c(N)c(F)c2)c2c1CCc1ccc(N)cc1-2
Reactant: O=C(O)c1ccncc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1nn(-c2cc(F)c(N)c(F)c2)c2c1CCc1ccc(NC(=O)c3ccncc3Cl)cc1-2
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.4 %

Procedure:
To a mixture of the product from step 3 (0.75 g, 0.0021 mol) and 3-chloroisonicotinic cid (0.33 g, 0.0023 mol) in 20 mL of DMF was added 1 mL of diisopropylethylamine, followed by the addition of HATU (0.9 g, 0.0023 mol). The reaction was stirred at room temperature for 16 h and concentrated. The crude was purified by reverse phase HPLC to give 0.15 g of 1-(4-amino-3,5-difluorophenyl)-8-[(3-chloroisonicotinoyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide as a pale white solid (15% yield); 1HNMR (DMSO, 400 MHz) δ: 10.56 (s, 1H), 8.76 (s, 1H), 8.63 (d, 1H), 8.56 (s, 1H), 7.54 (d, 1H), 7.49 (dd, 1H), 7.35 (m, 2H), 7.31 (s, 1H), 6.71 (m, 2H), 5.88 (s, 2H), 2.92 (m, 4H); Anal. Calcd. for C24H17FClN6O2+0.5H2O: C, 57.21; H, 3.60; N, 16.68. Found: C, 56.91; H, 3.70; N, 16.64.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.O.[CH3:17]O>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(O)cc1

Procedure:
4-Hydroxybenzoic acid (10 g) was dissolved in methanol (200 ml.), concentrated sulphuric acid (2 ml.) was added and the mixture boiled under reflux for 18 hours. The resulting mixture was poured into iced water, extracted with 2×100 ml. of diethyl ether, washed with 2×100 ml. saturated sodium bicarbonate solution, 1×100 ml. of water, dried and evaporated to give methyl 4-hydroxybenzoate. The phenolic ester was benzylated using method 1A to give the title compound, m.p. 99°C.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C>[N:12]([C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)=[N+:13]=[N-:14]
Reactant: Clc1nccc2ncccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1nccc2ncccc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
A solution of 5-chloro-1,6-naphthyridine (500 mg, 3.04 mmol) in DMF (5 mL) was stirred at room temperature. Sodium azide (592 mg, 9.12 mmol) was added to the mixture, and the mixture was stirred at 80° C. for 4 h. The mixture was cooled to room temperature and filtered through Celite to remove a white solid. The filtrate was diluted with EtOAc (25 mL) and washed with brine (5×5 mL). The combined organic layers were dried with Na2SO4, filtered, and the solvent was removed under reduced pressure to yield 5-azido-1,6-naphthyridine as a yellow solid, which was used in the next step without further purification (500 mg, yield 96%). ESI MS: m/z 172 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@@H:4]([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[C:20]([F:23])([F:22])[F:21])[C:12]1=[O:24])[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:21])([F:22])[F:23])[C:12]2=[O:24])[C:3]([OH:25])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A solution (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester (350 mg, 0.98 mmol) in tetrahydrofuran (5 mL) at room temperature was treated with a solution of lithium hydroxide monohydrate (82 mg, 1.96 mmol) in water (5 mL). The reaction mixture was then stirred at room temperature for 1 h. The reaction mixture was then acidified to pH=2 with a 1 N aqueous hydrochloric acid solution and extracted with ethyl acetate (3×20 mL). The combined organic layers were then dried over magnesium sulfate, filtered to remove the drying agent, and the filtrate concentrated in vacuo to afford (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (293 mg, 88%) as a colorless oil: [α]28D=−5.3° (c=0.19, methylene chloride); HR-ES(+) m/e calcd for C17H18NO3F3 [M+H]+ 342.1312, observed 342.1310; 1H NMR (300 MHz, DMSO-d6) δ ppm 13.13 (br. s., 1H), 8.02 (t, J=8.15 Hz, 2H), 7.68-7.85 (m, 1H), 4.82 (dd, J=4.23, 11.17 Hz, 1H), 4.69 (s, 2H), 1.02-2.20 (m, 11H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[C:7]([OH:9])=O.[NH2:10][CH:11]1[CH2:15]CC[CH:12]1C(O)=O>>[CH:11]([NH:10][C:7]([C@H:3]1[CH2:4][CH2:5][CH2:6][C@H:2]1[NH2:1])=[O:9])([CH3:15])[CH3:12]
Reactant: NC1CCCC1C(=O)O
Reactant: N[C@@H]1CCC[C@@H]1C(=O)O
Product: CC(C)NC(=O)[C@H]1CCC[C@H]1N

Procedure:
The chiral compound (1S,2R)-2-aminocyclopentane-carboxylic acid isopropylamide is prepared analogously to this procedure using (1S,2R)-2-aminocyclopentanecarboxylic acid. In addition, a number of amides are prepared in this way starting from 2-aminocyclopentanecarboxylic acid (racemic or chiral).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](/[C:8](=[N:10]/[C:11]2[C:16]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH:20]([CH3:22])[CH3:21])/[CH3:9])[CH:5]=[CH:4][CH:3]=1.[CH3:23][Al](C)C.[OH-].[K+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[C:16]([CH:17]([CH3:18])[CH3:19])=[CH:15][CH:14]=[CH:13][C:12]=2[CH:20]([CH3:22])[CH3:21])([CH3:23])[CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: C[Al](C)C
Reactant: C/C(=N\c1c(C(C)C)cccc1C(C)C)c1cccc(Br)n1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC(C)(C)c1cccc(Br)n1
Temperature: 25 °C

Procedure:
In argon atmosphere, to a solution of 3.61 g (10.0 mmol) of N-[(1E)-1-(6-bromopyridin-2-yl)ethylidene]-2,6-diisopropylaniline in 80 ml of dry toluene cooled to 0° C. a solution of 1.44 g (20.0 mmol) of AlMe3 in 20 ml of dry toluene was added dropwise by vigorous stirring for ten minutes. The resulting mixture was slowly warmed to room temperature, stirred for 25 min at 40° C., cooled to 0° C., and then 80 ml of 5% KOH was added dropwise for 1 h at this temperature. The aqueous layer was separated, the organic layer was washed with 80 ml of water, 80 ml of brine, dried over Na2SO4, and then evaporated to dryness. Yield 3.52 g (94%) of yellowish crystalline solid. Anal. calc. for C20H27BrN2: C, 64.00; H, 7.25, N, 7.46. Found: C, 64.11; H, 7.19; N, 7.40. 1H NMR (CDCl3): δ 7.48-7.54 (m, 2H, 4, 5-H in pyridine), 7.34 (dd, J=6.9 Hz, J=1.6 Hz, 1H, 3-H in pyridine), 7.04-7.08 (m, 3H, 3, 4, 5-H in 2, 6-iPr2C6H3), 3.98 (br.s, 1H, NH), 3.15 (sep, J=6.9 Hz, 2H, CHMe2), 1.44 (s, 6H, Me2C), 7.08 (d, J=6.9 Hz, 12H, CHMe2).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH2:19][CH:18]([CH3:20])[CH2:17][CH2:16][N:15]3[CH:21]=2)=[C:8]([CH3:22])[CH:7]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:20][CH:18]1[CH2:17][CH2:16][N:15]2[CH:21]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:7][C:8]=3[CH3:22])[N:13]=[C:14]2[CH2:19]1
Reactant: Cc1cc(OCCCCl)ccc1-c1cn2c(n1)CC(C)CC2
Reactant: C1CCNCC1
Product: Cc1cc(OCCCN2CCCCC2)ccc1-c1cn2c(n1)CC(C)CC2
Temperature: 25 °C

Procedure:
The product of Step A (49 mg) and piperidine (1.0 mL) were heated at 100° C. for 2 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous portion was extracted with a fresh portion of ethyl acetate (2×10 mL) and the organic portions combined and washed with brine (10 mL). The organic portions were dried over magnesium sulfate, filtered and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (45 mg). 1H-NMR (CD3OD) δ 7.47 (d, J=8.4 Hz, 1H), 6.99 (s, 1H), 6.78 (m, 2H), 4.13 (m, 1H), 4.07 (t, J=6.0 Hz, 2H), 3.98 (m, 1H), 2.99 (m, 1H), 2.89 (m, 6H), 2.41 (m, 4H), 2.10 (m, 4H), 1.75 (m, 5H), 1.60 (m, 2H), 1.18 (d, J=6.5 Hz, 3H)
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[S:6][CH2:5][NH:4][C@H:3]1[C:7](N)=[O:8].[OH-].[Na+].CC1(C)SCNC1C(N)=[O:20]>C(O)C(C)C>[CH3:1][C:2]1([CH3:10])[S:6][CH2:5][NH:4][C@H:3]1[C:7]([OH:20])=[O:8]
Reactant: CC1(C)SCNC1C(N)=O
Reactant: CC1(C)SCN[C@H]1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)CO
Product: CC1(C)SCN[C@H]1C(=O)O
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Optically active (4S)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid amide (5.0 g, 31.3 mmol), sodium hydroxide (0.25 g, 11.2 mmol) and i-butyl alcohol (50 ml) were placed in a 200-ml three-necked flask attached with a stirrer, thermometer and reflux condenser and stirred at 110° C. for 2 hours. After completion of the reaction, the reaction mixture was analyzed by liquid chromatography. As a result, it was found that the residual ratio of the 5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid amide was 82.3%, and the racemization ratio of the optically active (4S)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid amide was 97.5%.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[C:23]([O:27][CH3:28])(=[O:26])[CH2:24][SH:25]>>[CH3:28][O:27][C:23](=[O:26])[CH2:24][S:25][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:22])=[N:4][CH:3]=1
Reactant: COC(=O)CS
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCOCC1
Product: COC(=O)CSc1cnc(NC(=O)N(C2CCCCC2)C2CCOCC2)s1

Procedure:
Prepared as described in general procedure (D) using 3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(tetrahydro-pyran-4-yl)-urea and methyl thioglycolate
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:15])=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24].[CH:27](=O)[CH3:28]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:27][CH3:28])[CH2:19][CH2:18]2)=[O:15])=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24]
Reactant: O=C(NC1CCNCC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CC=O
Product: CCN1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 199 from 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(piperidin-4-yl)thiophene-2-carboxamide (0.2 g, 0.46 mmol) and acetaldehyde (81.0 mg, 1.38 mmol). The title compound was obtained as a solid (8.0 mg, 4% yield). 1H NMR (400 MHz, d6-DMSO) δ:8.98 (2H, m), 8.73 (1H, m), 8.52 (1H, s), 4.28 (1H, m), 3.67 (2H, m), 3.17 (1H, m), 2.97 (2H, m), 2.16 (2H, m), 1.79 (2H, m), 1.58 (2H, m), 1.03 (3H, m). MS m/z: 461.08, 463.09 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(F)(F)F)=[C:4]([F:15])[CH:3]=1.[NH2:16][C:17]1[N:22]=[C:21]([NH2:23])[C:20]([CH2:24][C:25]2[CH:26]=[C:27]([O:40][CH2:41][CH3:42])[C:28](I)=[C:29]([O:31][S:32]([CH2:35][CH:36]([CH3:38])[CH3:37])(=[O:34])=[O:33])[CH:30]=2)=[CH:19][N:18]=1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:28]2[C:27]([O:40][CH2:41][CH3:42])=[CH:26][C:25]([CH2:24][C:20]3[C:21]([NH2:23])=[N:22][C:17]([NH2:16])=[N:18][CH:19]=3)=[CH:30][C:29]=2[O:31][S:32]([CH2:35][CH:36]([CH3:37])[CH3:38])(=[O:33])=[O:34])=[CH:3][C:4]=1[F:15]
Reactant: O=C(Nc1ccc(Br)cc1F)C(F)(F)F
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)CC(C)C)c1I
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)CC(C)C)c1-c1ccc(N)c(F)c1
Yield: 79.8 %

Procedure:
Starting from 241 mg (0.84 mmol) N-(4-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-acetamide and 215 mg (0.42 mmol) 2-methyl-propane-1-sulphonic acid 5-(2,4-diamino-pyrimidin-5-ylmethyl)-3-ethoxy-2-iodo-phenyl ester, 164 mg of the title compound are obtained as a pale brown foam.
Reaction SMILES: [OH:1][C:2]1([C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][N:4]([C:6]([O:8]CC2C=CC=CC=2)=O)[CH2:3]1.CCN(C(C)C)C(C)C.[F:38][C:39]1[C:40]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([I:56])=[CH:52][C:51]=2[F:57])=[C:41]([CH:45]=[CH:46][C:47]=1[F:48])C(F)=O>[Pd].CO>[F:38][C:39]1[C:40]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([I:56])=[CH:52][C:51]=2[F:57])=[C:41]([C:6]([N:4]2[CH2:5][C:2]([C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([OH:1])[CH2:3]2)=[O:8])[CH:45]=[CH:46][C:47]=1[F:48]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C1(O)CN(C(=O)OCc2ccccc2)C1
Reactant: O=C(F)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
1,1-Dimethylethyl (2R)-2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate (60.8 mg, 0.16 mmol) and 10% Pd/C (30 mg) were taken into methanol (2 mL) and the mixture hydrogenated at ambient pressure for one hour. The suspension was then filtered through a celite pad and concentrated then dried in vacuo to a colorless solid. The solid amine was taken into THF (1 mL) followed by addition of DIPEA (42 μL, 0.24 mmol) and 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (63 mg, 0.16 mmol), prepared using procedures similar to those described in Reference 1, and the mixture stirred at room temperature for 30 minutes. The reaction mixture was partitioned with ethyl acetate and 1 N aqueous hydrochloric acid and the organic layer washed with brine, dried over anhydrous magnesium sulfate then filtered and concentrated. Purification of the residue by silica gel flash chromatography using hexanes:ethyl acetate 3:2 as eluent afforded 1,1-dimethylethyl (2R)-2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (74.9 mg, 74% yield) as an amorphous solid. 1,1-Dimethylethyl (2R)-2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate 1H NMR (400 MHz, CDCl3): 8.53 (br s, 0.5H), 8.40 (br s, 0.5H), 7.41-7.38 (dd, 1H), 7.34-7.31 (dt, 1H), 7.17-7.14 (m, 1H), 6.86-6.79 (m, 1H), 6.63-6.587 (m, 1H), 4.24-3.90 (m, 4H), 3.37-3.23 (m, 1H), 2.90-2.80 (m, 1H), 1.85-1.54 (m, 7H), 1.43 (s, 9H); MS (EI) for C26H29F3IN3O4: 576 M-C4H9+).