Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH:29]([C:63]2[CH:68]=[C:67]([CH2:69][CH3:70])[CH:66]=[C:65]([OH:71])[C:64]=2[F:72])[C:30]2[N:31]([C:44]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:32]=[C:33]([C:35]3[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=3[C:37]([NH2:39])=[O:38])[N:34]=2)=[CH:24][CH:23]=1)#[N:21].O[C@@H:74]1[CH2:78][CH2:77][O:76][CH2:75]1>C1COCC1>[C:20]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH:29]([C:63]2[CH:68]=[C:67]([CH2:69][CH3:70])[CH:66]=[C:65]([O:71][C@H:74]3[CH2:78][CH2:77][O:76][CH2:75]3)[C:64]=2[F:72])[C:30]2[N:31]([C:44]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[CH:32]=[C:33]([C:35]3[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=3[C:37]([NH2:39])=[O:38])[N:34]=2)=[CH:24][CH:23]=1)#[N:21]
Reactant: O[C@@H]1CCOC1
Reactant: CCc1cc(O)c(F)c(C(Nc2ccc(C#N)cc2)c2nc(-c3ccccc3C(N)=O)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1cc(O[C@H]2CCOC2)c(F)c(C(Nc2ccc(C#N)cc2)c2nc(-c3ccccc3C(N)=O)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 101.4 %

Procedure:
To a solution of triphenylphosphine (40.6 mg, 0.155 mmol) in 1 mL THF at 0° C., was added diethyl azidodicarboxylate (24.5 μL, 0.155 mmol), dropwise. The mixture was stirred at 0° C. for 20 min, then a solution of Intermediate 188.6 (36 mg, 0.052 mmol) and (R)-3-hydroxytetrahydrofuran (8.3 μL, 0.103 mmol) in 1 mL THF was added dropwise. The mixture was stirred at 0° C. for 15 min and at rt for 14 h, then was concentrated. The crude residue was purified by flash chromatography (0 to 100% EtOAc/hexanes gradient) to afford 40.5 mg of Intermediate 204.1, contaminated with triphenylphosphine. LCMS (2 min gradient) RT=2.00 min, 768.25 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH2:23](O)[CH3:24].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCO
Reactant: O=C(O)CCCc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 4-[4-(5-nitropyridin-2-yloxy)phenyl]butanoic acid (9.98 g, 33.01 mmol) in dichloromethane were added ethanol (5.59 mL, 99.01 mmol), 4-dimethylaminopyridine (400 mg, 3.27 mmol), triethylamine (13.81 mL, 99.08 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.6 g, 39.65 mmol) under ice cooling, and the resulting solution was stirred for 20 minutes under ice cooling and then for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate, and the ethyl acetate layer was washed with 1 N hydrochloric acid, a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 6.77 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:17])(=[N:12][C:13](=O)[CH2:14][CH3:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].B.O1CCCC1.O.CO>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:17])(=[N:12][CH2:13][CH2:14][CH3:15])=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCC(=O)N=S(C)(=O)c1ccc([N+](=O)[O-])cc1
Agent: B
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCCN=S(C)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
351 mg (1.37 mmol) (RS)—S-(4-nitrophenyl)-N-propionyl-S-methylsulfoximide (Example 9a) are dissolved in 15 ml dichloromethane and treated dropwise with borane-tetrahydrofuran complex (1.0 M solution in tetrahydrofuran, Aldrich) with ice-cooling. The mixture is stirred for 3 hours at 0° C. Next it is cautiously treated with ca. 10 ml water/methanol (1:1), stirred for 30 minutes and extracted with dichloromethane. The organic phase is dried over sodium sulphate and concentrated. After chromatographic purification (silica gel, hexane/ethyl acetate (0-50% ethyl acetate)), 146 mg (44%) of the desired product is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:5][C:4]=1[OH:16])#[N:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27]>CC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[CH:12][CH:13]=[CH:14][N:15]=2)=[CH:5][C:4]=1[O:16][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])#[N:2]
Reactant: N#Cc1ccc(Nc2ncccn2)cc1O
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)=CCOc1cc(Nc2ncccn2)ccc1C#N
Yield: 30 %

Procedure:
Following the general procedure for O-alkylation of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-cyano-5-(pyrimidin-2-ylamino)phenol (10 mg, 0.047 mmol) and Cs2CO3 (16 mg, 0.049 mmol) in acetone (2.0 mL) was treated with 4-bromo-2-methyl-2-butene (5.5 μL, 0.14 mmol) at room temperature. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 6/4) in 30% yield (4 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4](C(O)=O)[C:5]2[C:14]([CH:15]=1)=[N:13][C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH:6]=2.N1C2C(=CC=CC=2)C(=O)C1=O.Cl>[OH-].[K+].O>[CH:3]1[CH:4]=[C:5]2[CH:6]=[C:7]3[C:12](=[N:13][C:14]2=[CH:15][CH:2]=1)[CH:11]=[CH:10][CH:9]=[CH:8]3
Reactant: O=C(O)c1cc(Cl)cc2nc3ccccc3cc12
Agent: Cl
Agent: O=C1Nc2ccccc2C1=O
Agent: [K+]
Solvent: O
Product: c1ccc2nc3ccccc3cc2c1

Procedure:
3-Chloroacridinecarboxylic acid. The isatin product from step (a) was refluxed in 300 mL of 10% KOH solution in water for ca. 48 h. The solution was cooled and acidified to pH 2-3 with HCl. The yellow solid was suction filtered after 1 h and then washed with water. The solid was air-dried over night, washed with CH2Cl2 and then air-dried yielding 23.76 g of the acridine acid. 1H NMR (DMSO-d6) δ7.72-8.30 (m, 7H).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12](Cl)[C:13]3[N:14]([C:16](=[O:23])[N:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[N:18]=3)[CH:15]=2)[CH:5]=1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>C1COCC1.CCOC(C)=O>[C:19]([N:17]1[C:16](=[O:23])[N:14]2[CH:15]=[C:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:25])[N:11]=[C:12]([NH:29][CH:26]([CH3:28])[CH3:27])[C:13]2=[N:18]1)([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(C)N
Reactant: COC(=O)c1cccc(-c2cn3c(=O)n(C(C)(C)C)nc3c(Cl)n2)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Nc1nc(-c2cccc(C(=O)O)c2)cn2c(=O)n(C(C)(C)C)nc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 580 mg of 3-(2-tert-butyl-8-chloro-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-benzoic acid methyl ester and 944 mg of isopropylamine in THF (8.0 mL) was stirred at ambient temperature. After 72 h, the reaction was diluted with EtOAc and washed with water followed by sat. sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated to an orange semi-solid. This material was dissolved in 1,4-dioxane (6.0 mL) and 2N KOH (1.0 mL) was added. This mixture was heated at reflux for 16 h, cooled to ambient temperature and the solvent removed. The residue was dissolved in water and the pH adjusted to 3 with 2N HCl prior to extraction with 9:1 chloroform/MeOH (3×). The organic extracts were washed with sat. sodium chloride solution, dried over sodium sulfate, filtered, and concentrated to leave 3-(2-tert-butyl-8-isopropylamino-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-benzoic acid as a yellow solid. MS (M+H+)=370.4.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[C:25](=[O:27])[CH3:26])[C:5]1=[O:30])[CH:2]=[CH2:3].C[Si](C)(C)[C:34]([F:37])([F:36])[F:35].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[C:25]([OH:27])([CH3:26])[C:34]([F:37])([F:36])[F:35])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(C)=O)C1=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(C)(O)C(F)(F)F)C1=O
Reaction time: 2 h

Procedure:
A solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-2-oxopentan-3-yl)piperidin-2-one (30 mg, 0.065 mmo; Example 149, Step B) and trimethyl(trifluoromethyl)silane (48.5 μL, 0.327 mmol) in THF (0.5 mL) was treated with 1 M tetrabutylammonium fluoride solution in THF (196 μL, 0.196 mmol) at 0° C. After being stirred for 2 h, the reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and saturated NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by the flash chromatography on silica gel (eluent: 10 to 20% EtOAc/Hexane, gradient elution) to provide the title compound as the major product.
Reaction SMILES: Cl.NO.C([N:7](CC)C(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([NH:26][C:27]([NH:29]C(OCC)=O)=S)=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1>CO.CCO>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21]3[N:22]([N:7]=[C:27]([NH2:29])[N:26]=3)[CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1ncccc1-c1ccc(F)cc1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CO
Product: Nc1nc2c(-c3ccc(F)cc3)cccn2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of hydroxylamine hydrochloride (370 mg, 5.32 mmol) and N,N-diisopropylethylamine (543 μL, 3.19 mmol) in MeOH (2 mL) and EtOH (2 mL) was added a solution of N-(3-(4-fluoro-phenyl)-pyridin-2-yl)-N′-ethoxycarbonyl-thiourea (340 mg, 1.06 mmol) in MeOH (2 mL) and EtOH (2 mL). The reaction mixture was stirred at room temperature for 1 hour and then at 60° C. for 3 hours. The solvents were evaporated and saturated aqueous NaHCO3 solution was added to the residue. The aqueous phase was extracted with CH2Cl2, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using dichloromethane/methanol (with 10% ammonia) as eluent. The title compound was obtained as a white solid (205 mg, 84%).
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]2[O:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:7](=O)[C:6]=2[CH:19]=1.C>O1CCOCC1.C(O)C.S(=O)(=O)(O)O.[Pd]>[OH:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]2[O:10][CH2:9][CH:8]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[CH2:7][C:6]=2[CH:19]=1
Reactant: O=c1c(-c2ccc(F)cc2)coc2cc(O)c(O)cc12
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: CCO
Product: Oc1cc2c(cc1O)OCC(c1ccc(F)cc1)C2

Procedure:
6,7-Dihydroxy-3-(4-fluorophenyl)-4H-1-benzopyran-4-one (1.2 g), dissolved in a mixture of dioxan/ethanol 4:6 (40 ml), is hydrogenated for 24 h at room temperature over palladium 5% on active charcoal (0.48 g) in the presence of a few drops of conc. sulphuric acid. After filtration of the catalyst, the filtrate is evaporated to dryness under vacuum. An oil is obtained which crystallizes to give 3,4-dihydro-6,7-dihydroxy-3-(4-fluorophenyl)-2H-1-benzopyran, m.p. 135°-137°.
Reaction SMILES: NC1C=CC(C2C=NN(CCCO)C=2)=C2C=1C(=O)N(C)C2.[CH3:22][C:23]1([CH3:48])[O:27][C@@H:26]([CH2:28][N:29]2[CH:33]=[C:32]([C:34]3[CH:42]=[CH:41][C:40]([N+:43]([O-])=O)=[C:39]4[C:35]=3[CH2:36][N:37]([CH3:47])[C:38]4=[O:46])[CH:31]=[N:30]2)[CH2:25][O:24]1>>[NH2:43][C:40]1[CH:41]=[CH:42][C:34]([C:32]2[CH:31]=[N:30][N:29]([CH2:28][C@H:26]3[CH2:25][O:24][C:23]([CH3:48])([CH3:22])[O:27]3)[CH:33]=2)=[C:35]2[C:39]=1[C:38](=[O:46])[N:37]([CH3:47])[CH2:36]2
Reactant: CN1Cc2c(-c3cnn(C[C@H]4COC(C)(C)O4)c3)ccc([N+](=O)[O-])c2C1=O
Agent: CN1Cc2c(-c3cnn(CCCO)c3)ccc(N)c2C1=O
Product: CN1Cc2c(-c3cnn(C[C@H]4COC(C)(C)O4)c3)ccc(N)c2C1=O
Yield: 57.2 %

Procedure:
Prepared analogously to Compound 1C replacing Compound 1D with 4-(1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (Compound 5D, 1.96 g) to afford 1.03 g of the desired product (90%). 1H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J=0.5 Hz, 1H), 7.75 (d, J=0.8 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 6.62 (d, J=8.3 Hz, 1H), 6.07 (s, 2H), 4.38-4.47 (m, 3H), 4.24 (dd, J=1.4, 5.7 Hz, 2H), 4.01 (dd, J=6.3, 8.6 Hz, 1H), 3.78 (dd, J=5.7, 8.5 Hz, 1H), 3.03 (s, 3H), 1.24-1.35 (m, 6H). MS (ESI): m/z 343.15 [M+H]+. UPLC: tR=1.09 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[CH:10][S:11][C:5]=2[N:4]=[CH:3]1.[C:19]12([CH2:29][C:30](Cl)=[O:31])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2>N1C=CC=CC=1>[C:19]12([CH2:29][C:30]([NH:1][N:2]3[C:7](=[O:8])[C:6]4[C:9]([C:12]5[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=5)=[CH:10][S:11][C:5]=4[N:4]=[CH:3]3)=[O:31])[CH2:26][CH:25]3[CH2:24][CH:23]([CH2:22][CH:21]([CH2:27]3)[CH2:20]1)[CH2:28]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Nn1cnc2scc(-c3ccc(F)cc3)c2c1=O
Solvent: c1ccncc1
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1cnc2scc(-c3ccc(F)cc3)c2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
3-Amino-5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4(3H)-one (100 mg, 0.383 mmol) was stirred in pyridine (3 mL) at 25° C. 1-Adamantaneacetyl chloride (204.1 mg, 0.96 mmol) was slowly added and the reaction mixture was allowed to stir at 25° C. for 2 hours. The reaction mixture was concentrated to dryness. The resulting material was dissolved in DMSO (3 mL), filtered through a glass microfiber frit and purified by preparative HPLC [Waters XBridge RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide), with UV detection at 254 nm]. Fractions containing the desired product were pooled and concentrated under vacuum to afford the title compound as a white solid (68 mg, 41%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54-1.70 (m, 12H), 1.92 (br s, 3H), 2.07 (s, 2H), 7.19-7.27 (m, 2H), 7.49-7.56 (m, 2H), 7.62 (s, 1H), 10.90 (br s, 1H); MS (DCI/NH3) m/z 438 (M+H)+. Elemental Analysis calculated for C24H24FN3O2S: C, 65.88; H, 5.53; N, 9.60. Found C, 65.64; H, 5.48; N, 9.55.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17](Cl)=[C:18](Br)[N:19]=[C:14]2[CH:13]=[C:12]1[CH:22]1[CH2:24][CH2:23]1)[CH3:2].N#N.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:19]=[C:14]2[CH:13]=[C:12]1[CH:22]1[CH2:24][CH2:23]1)[CH3:2]
Reactant: CCOC(=O)CCCCCCn1c(C2CC2)cc2nc(Br)c(Cl)nc21
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CCCCCCn1c(C2CC2)cc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 60 °C
Reaction time: 12 h

Procedure:
A mixture comprising 7-(2-bromo-3-chloro-6-cyclopropyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acid ethyl ester (Intermediate D) (400 mg, 0.933 mmol) in 1,4-dioxane (8 ml) degassed with N2 was treated with phenylboronic acid (120 mg, 0.980 mmol), potassium carbonate (284 mg, 2.052 mmol) and PdCl2(dppf)-CH2Cl2-adduct (76 mg, 0.093 mmol). The reaction mixture was stirred at 60° C. for 12 hours. After cooling to RT and degassing with N2, phenylboronic acid (171 mg, 1.399 mmol) and PdCl2(dppf)-CH2Cl2-adduct (76 mg, 0.093 mmol) were added and stirring continued at 110° C. for 24 hours. The mixture was treated with ice-cooled water and the aqueous was extracted with diethyl ether. The organic portion was dried (Na2SO4) and concentrated under reduced pressure. Purification of the crude product on silica eluting with 5% EtOAc in iso-hexane afforded the titled compound:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([C:6]([F:9])=[CH:7][CH:8]=1)[NH2:5].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([NH:5][CH:13]([C:15]2[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[C:6]([F:9])=[CH:7][CH:8]=1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: Nc1c(F)ccc(Cl)c1F
Agent: Br
Product: CC(Nc1c(F)ccc(Cl)c1F)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 47.8 %

Procedure:
3-chloro-2,6-difluoroaniline (133 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(3-chloro-2,6-difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (47 mg, 47%) as a white solid. Mass Spectrum: M+H+ 492. NMR Spectrum (DMSOd6): 1.56 (d, 3H), 2.74 (bs, 3H), 2.97 (bs, 3H), 3.50-3.58 (m, 4H), 3.70-3.80 (m, 4H), 5.37-5.46 (m, 1H), 5.57 (s, 1H), 5.99 (d, 1H), 6.81 (ddd, 1H), 6.94 (ddd, 1H), 7.72 (d, 1H), 7.76 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([CH2:15][CH3:16])([C:13]#[N:14])[C:9]2=[O:17])[CH:5]=[CH:4][N:3]=1>CCCCCC.CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH2:15][CH3:16])([C:13]#[N:14])[C:9]2=[O:17])[CH:5]=[CH:4][N:3]=1
Reactant: CCC1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Solvent: CCCCCC
Solvent: CC(C)O
Product: CC[C@]1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Yield: 44.9 %

Procedure:
1-(2-Chloropyrimidin-4-yl)-3-ethyl-2-oxopyrrolidine-3-carbonitrile (7.8 g) obtained in Step A of Example 2 was resolved by HPLC (column: CHIRALPAK IC, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/2-propanol=200/800) to give the title compound (3.5 g) having a shorter retention time.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH:10]3[S:12][C:7]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)([NH:8][CH2:9]3)[C:6]=2[CH:19]=1.S[CH2:21][CH2:22][OH:23]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH:10]([S:12][CH2:21][CH2:22][OH:23])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: OCCS
Reactant: Clc1ccc2c(c1)C1(c3ccccc3)NCC(N2)S1
Solvent: C1CCOC1
Product: OCCSC1CN=C(c2ccccc2)c2cc(Cl)ccc2N1

Procedure:
A solution of 7-chloro-2,3,4,5-tetrahydro-5-phenyl-2,5-epithio-1H-1,4-benzodiazepine (1g. ) and 2-mercaptoethanol (1 ml) in THF (15 ml) was heated under reflux overnight. The resulting solution was concentrated under reduced pressure and then diluted with ether to induce crystallization of the product. The product was filtered out and washed with ether to give the above-named compound, m.p. 135°-140° (dec.).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([OH:25])[C@@H:14]([CH2:26][O:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[O:13][C@@H:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:45](Cl)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:45]([O:25][C@@H:15]1[C@@H:14]([CH2:26][O:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[O:13][C@H:10]([O:11][CH3:12])[C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:16]1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CO[C@H]1O[C@H](COS(=O)(=O)c2ccc(C)cc2)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@H]1O[C@H](COS(=O)(=O)c2ccc(C)cc2)[C@@H](OC(=O)c2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Methyl 2,3-di-O-benzyl-6-O-p-toluenesulfonyl-α-D-glucopyranoside (J. Org. Chem., 2001, 66, 5965-5975) (163.9 g, 310 mmol) was dissolved in methylene chloride (1.5 L) and 4-dimethylaminopyridine (43.5 g, 352 mmol) and triethylamine (49.0 mL, 352 mmol) were added thereto. Benzoyl chloride (43.2 mL, 372 mmol) was dropwise thereto and the mixture was stirred at 0° C. for 1 hour. After diluted hydrochloric acid (2N, 500 mL) was added to the reaction mixture and the mixture was extracted with methylene chloride (1 L), the organic layer was washed with saturated aqueous sodium hydrogencarbonate (1 L) and saturated brine (1 L) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 1:1, V/V) to obtain the desired title compound (196 g, yield 99%) as a colorless solid.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[N:9][NH:10]2)([O-:5])=[O:4].[CH3:15][O:16][C:17](Cl)=[O:18].O>CN(C=O)C>[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[N:9][N:10]2[C:17]([O:16][CH3:15])=[O:18])([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)n1ncc2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (0.3 g, 12.5 mmol) suspended in DMF (5 mL) at 0° C. was treated with 4-nitro-1H-indazole (1.33 g, 10 mmol). After stirring at room temperature for 1 hour, the mixture was treated with methylchloroformate (0.9 mL). After stirring at room temperature for 3 hours, the mixture was carefully treated with water and filtered to provide the title compound (1.2 g). 1H NMR (300 MHz, DMSO-d6) δ 4.19 (s, 3H), 7.9 (t, 1H), 8.38 (d, 1H), 8.62 (d, 1H), 8.85 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]([F:10])([F:9])[F:8])[C:3]([OH:5])=[O:4].[OH-].[Na+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O1CCOCC1>[CH2:17]([O:16][C:14]([NH:1][CH:2]([CH2:6][C:7]([F:10])([F:9])[F:8])[C:3]([OH:5])=[O:4])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(CC(F)(F)F)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(NC(CC(F)(F)F)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.1 %

Procedure:
To a solution of 2-amino-4,4,4-trifluorobutyric acid (543 mg, 3.45 mmol) in aq. 1N NaOH (13 mL, 13.0 mmol), a solution of benzyl chloroformate (0.600 mL, 4.26 mmol) in dioxane (5 mL) was added. The mixture was stirred at room temperature for 18 h. It was then washed with EtOAc. The aqueous solution was acidified to pH 1-2 with 6N HCl. The product was extracted with EtOAc. The EtOAc phase was dried over Na2SO4, concentrated in vacuo to give 2-(benzyloxycarbonylamino)-4,4,4-trifluorobutanoic acid (202 mg).