Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]([O:27][CH3:28])=[O:26].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:4]([C:3]1[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:2]=1[O:1][CH:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:18]=1)[C:25]([O:27][CH3:28])=[O:26])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1ccc(O)c(C(=O)c2ccccc2)c1
Reactant: COC(=O)Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(Oc1ccc(C)cc1C(=O)c1ccccc1)c1ccccc1
Yield: 18.8 %

Procedure:
To a solution of 1.00 g (4.72 mmol) of 2-hydroxy-5-methylbenzophenone and 1.19 g (5.19 mmol) of methyl 2-bromophenylacetate in 10 mL of acetone was added 1.30 g (9.44 mmol) of K2CO3 and the mixture was stirred and refluxed for 14 hours. The mixture was cooled, filtered and evaporated in vacuo and the residue was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 0.320 g (19%) of the title compound.
Reaction SMILES: C(OC(N(C1C=CC=CC=1)CC(NC1C=CC=CC=1C(C1C=CC=CC=1)=O)=O)=O)C=C.[CH2:32]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([C:48]([C:50]2[CH:56]=[CH:55][CH:54]=[CH:53][C:51]=2[NH2:52])=[O:49])[CH2:44][CH2:43]1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[CH2:57]([O:60][C:61]([C:63]1[CH:64]=[C:65]([NH:69][C:70](=[O:76])[NH:71][CH2:72][C:73](O)=[O:74])[CH:66]=[CH:67][CH:68]=1)=[O:62])[CH:58]=[CH2:59]>>[CH2:32]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([C:48]([C:50]2[CH:56]=[CH:55][CH:54]=[CH:53][C:51]=2[NH:52][C:73]([CH2:72][NH:71][C:70](=[O:76])[NH:69][C:65]2[CH:64]=[C:63]([CH:68]=[CH:67][CH:66]=2)[C:61]([O:60][CH2:57][CH:58]=[CH2:59])=[O:62])=[O:74])=[O:49])[CH2:44][CH2:43]1)=[O:41])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: C=CCOC(=O)c1cccc(NC(=O)NCC(=O)O)c1
Reactant: Nc1ccccc1C(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: C=CCOC(=O)N(CC(=O)Nc1ccccc1C(=O)c1ccccc1)c1ccccc1
Product: C=CCOC(=O)c1cccc(NC(=O)NCC(=O)Nc2ccccc2C(=O)C2CCN(C(=O)OCc3ccccc3)CC2)c1
Yield: 65.2 %

Procedure:
According to the method for the synthesis of the compound 6b, the titled compound (780 mg) is prepared using 2-(N-(benzyloxycarbonyl)piperidine-4-carbonyl)aniline (677 mg) and 2-(benzyloxycarbonylglycilamino)benzophenone (compound 46) (556 mg) as starting materials. Yield 65%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]#[N:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:12])[CH:6]=2.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[OH:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)[CH:3]=[C:4]2[C:13]#[N:14])=[CH:9][CH:8]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: N#Cc1cc(Br)cc2ccc(O)cc12
Product: COc1ccc(-c2cc(C#N)c3cc(O)ccc3c2)cc1

Procedure:
The title compound was prepared by reacting 3-bromo-7-hydroxy-1-naphthonitrile (0.249 g, 1.00 mmol) with 4-methoxyphenylboronic acid (0.21 g, 1.4 mmol) according to Method A to yield 0.19 (69%) of a light yellow solid: mp 226° C.; 1H NMR (DMSO-d6): δ 3.82 (3H, s), 7.07 (2H, d, J=8.82 Hz), 7.26 (1H, dd, J=2.32 Hz, J=8.90 Hz), 7.37 (1H, d, J=2.27 Hz), 7.80 (2H, d, J=8.80 Hz), 8.02 (1H, d, J=8.96 Hz), 8.37 (1H, d, J=1.85 Hz), 8.44 (1H, d, J=1.43 Hz), 10.48 (1H, bs); MS (ESI) m/z 274 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:35])[N:9]3[CH2:34][CH2:33][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:20][N:19]=[C:18]([CH2:21][N:22]4C(=O)C5=CC=CC=C5C4=O)[N:17]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:36]>CN>[NH2:22][CH2:21][C:18]1[N:17]=[C:16]([C:15]2[N:14]=[CH:13][N:12]3[C:6]4[CH:5]=[CH:4][C:3]([F:36])=[C:2]([Cl:1])[C:7]=4[C:8](=[O:35])[N:9]4[CH2:34][CH2:33][C@H:10]4[C:11]=23)[O:20][N:19]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3ccc(F)c2Cl)n1
Agent: CN
Product: NCc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3ccc(F)c2Cl)n1
Reaction time: 1 h
Yield: 98 %

Procedure:
16 g (31.85 mmol) of (S)-8-chloro-7-fluoro-12,12a-dihydro-1-(3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were treated with 100 ml of methylamine (33% in ethanol). The solution was stirred at 70° for 1 hour and subsequently cooled. The suspension obtained was filtered and the crystallizate was partially dissolved in 100 ml of methylene chloride. By filtering and evaporating the filtrate there were obtained 11.7 g (99%) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was used without further purification as the starting material for the Example described hereinafter.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-:19])=O)=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].Cl.Cl.[CH2:25]([NH:32][NH2:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CC(O)=O>[CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:19])[N:32]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[NH:33][C:14](=[O:15])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: CCCN(CCC)C1Cc2cc3c(=O)[nH]n(Cc4ccccc4)c(=O)c3cc2C1

Procedure:
Using procedure 51, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.349 g, 1 mmol) was treated with benzylhydrazine dihydrochloride (0.27 g, 1.4 mmol) in HOAc (20 mL) Purification using silica gel, eluting with 19:1 CH2Cl2 /MeOH, afforded a solid that was converted to an HCl salt and recrystallized from EtOAc/MeOH to give 135 as a white solid (m.p. 219-220° C.).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.Cl>CC(C)=O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]=[O:2])=[CH:7][CH:8]=1
Reactant: COC(COc1ccc(Cl)cc1)OC
Agent: Cl
Solvent: CC(C)=O
Product: O=CCOc1ccc(Cl)cc1
Yield: 24 %

Procedure:
4-Chlorophenoxyacetaldehyde dimethylacetal (1.0 g) was dissolved in acetone (10 ml), to which 2N hydrochloric acid (1.0 g) was added, and the mixture was heated under reflux for 8 hours. After the reaction mixture was concentrated, water was added and the mixture was extracted with ethyl acetate. The extracts were dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 4-chlorophenoxyacetaldehyde as a crude product.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([CH3:7])[NH2:6].[CH2:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:10]#[C:11][CH3:12]>>[CH3:2][O:3][C:4](=[O:8])[C@H:5]([NH:6][S:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:9][C:10]#[C:11][CH3:12])=[CH:19][CH:18]=1)(=[O:22])=[O:21])[CH3:7]
Reactant: COC(=O)[C@@H](C)N
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: CC#CCOc1ccc(S(=O)(=O)N[C@H](C)C(=O)OC)cc1

Procedure:
According to the procedure of Example 20, 0.500 g (3.58 mmol) of D-alanine methyl ester hydrochloride and 0.877 g (3.58 mmol) of 4-but-2-ynyloxy-benzenesulfonyl chloride provided 0.532 g of the NH-sulfonamide ester, (2R)-2-(4-but-2-ynyloxy-benzenesulfonylamino)-propionic acid methyl ester, as a white solid. Electrospray Mass Spec 312.1 (M+H)+.
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]12[CH2:29][O:28][C@@H:27]([CH:30]3[CH2:33][CH2:32][O:31]3)[CH2:26][C@H:25]1[CH2:24][S:23][C:22]([NH:34]C(=O)C1C=CC=CC=1)=[N:21]2>CO>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]12[CH2:29][O:28][C@@H:27]([CH:30]3[CH2:33][CH2:32][O:31]3)[CH2:26][C@H:25]1[CH2:24][S:23][C:22]([NH2:34])=[N:21]2
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CCO3)C[C@H]2CS1)c1ccccc1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CCO3)C[C@H]2CS1
Temperature: 80 °C

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (95%, 7.5 mg, 47 μmol) was added to a solution of N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(oxetan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C33) (19 mg, 43 μmol) in methanol (0.5 mL), and the reaction mixture was heated at 80° C. for 3.5 hours. After cooling and removal of solvent in vacuo, purification was carried out via reversed phase HPLC (Column: Waters XBridge C18, 5 μm; Mobile phase A: 0.03% ammonium hydroxide in water (v/v); Mobile phase B: 0.03% ammonium hydroxide in acetonitrile (v/v); Gradient: 20% to 60% B), providing the product as a gum. Yield: 11.7 mg, 34.4 μmol, 73%. LCMS m/z 341.2 [M+H+]. 1H NMR (600 MHz, DMSO-d6) δ 7.35 (ddd, J=9.2, 9.2, 7.0 Hz, 1H), 7.16-7.22 (m, 1H), 7.07-7.11 (m, 1H), 4.55-4.60 (m, 1H), 4.46-4.51 (m, 1H), 4.34-4.38 (m, 1H), 3.90 (dd, J=10.5, 2.2 Hz, 1H), 3.64-3.69 (m, 1H), 3.59 (d, J=10.1 Hz, 1H), 2.46-2.75 (m, 5H), 1.54-1.62 (m, 1H), 1.36-1.41 (m, 1H).
Reaction SMILES: C(=O)(OC(C)(C)C)N.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2([NH:22][C:23]([C@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][N:26]3C(OC(C)(C)C)=O)=[O:24])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)=[O:12]>>[NH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@@H:25]1[C:23]([NH:22][C:19]1([C:16]2[CH:15]=[CH:14][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:18][CH:17]=2)[CH2:21][CH2:20]1)=[O:24]
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)(C)OC(N)=O
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3)CC2)cc1
Yield: 100.3 %

Procedure:
The title compound (D13) (490 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (R)-tert-butyl 2-((1-(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)piperidine-1-carboxylate (D6) (650 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1I>>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: Brc1ccccc1I
Reactant: COc1ccc(S)cc1
Product: COc1ccc(Sc2ccccc2Br)cc1

Procedure:
Prepared from 4-methoxy-benzenethiol and 1-bromo-2-iodo-benzene.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:8][C:7](=O)[CH2:6][CH2:5][C:4]([CH3:11])([CH3:10])[P:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][C:21]([CH:27]([CH3:29])[CH3:28])=[CH:20][C:19]=1[CH:30]([CH3:32])[CH3:31].C(O)COCCO.O.NN.[OH-].[K+]>CCCCCCC.C(OCC)(=O)C>[CH3:33][C:2]1([CH3:1])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]([CH3:10])([CH3:11])[P:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[C:19]([CH:30]([CH3:31])[CH3:32])=[CH:20][C:21]([CH:27]([CH3:29])[CH3:28])=[CH:22][C:23]=1[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CCC(=O)CC2(C)C)c(C(C)C)c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: O
Product: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CCCCC2(C)C)c(C(C)C)c1
Temperature: 210 °C
Reaction time: 7 h
Yield: 78.5 %

Procedure:
A round bottom flask was charged with 2,2,7,7-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphepan-4-one (1.06 g, 2.29 mmol, 1.0 equiv) and purged with nitrogen for 15 minutes. Nitrogen-sparged diethylene glycol (12.0 mL, 126 mmol, 55 equiv) was added and the flask was equipped with a Claisen adapter and a Dean-Stark trap. The mixture was charged with hydrazine hydrate (1.01 mL, 11.4 mmol, 5 equiv, 55 wt % hydrazine) and potassium hydroxide (641 mg, 11.4 mmol, 5 equiv). The mixture was immersed in an oil bath at 175° C. under a nitrogen atmosphere. The temperature of the bath was gradually increased to 210° C. over 40 minutes and kept at that temperature for 7 hours. The reaction mixture was cooled to room temperature under a positive pressure of nitrogen and then the reaction mixture was diluted with heptane (20 mL) and ethyl acetate (20 mL). The phases were partitioned, and the organic layer was collected. The aqueous layer was washed with ethyl acetate (3×20 mL). The combined organic fractions were washed once with aqueous saturated sodium chloride (50 mL), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude product was purified by silica gel column chromatography (80-g column; gradient: 1.5 column volumes heptane, ramp up to 92:8 heptane:ethyl acetate over 8.5 column volumes, hold at 92:8 for 2 column volumes) to afford the title compound as a white solid (810 mg, >99 area % by HPLC, 79% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.00-7.83 (m, 1H), 7.33-7.26 (m, 2H), 7.22-7.13 (m, 1H), 6.97 (s, 2H), 2.91 (hept, J=6.9 Hz, 1H), 2.48 (hept, J=6.7 Hz, 2H), 1.77-1.60 (m, 6H), 1.60-1.47 (m, 2H), 1.29 (d, J=6.9 Hz, 6H), 1.21 (dd, J=8.2, 4.4 Hz, 12H), 0.96 (d, J=6.7 Hz, 6H), 0.82 (s, 3H), 0.78 (s, 3H). 13C NMR (100 MHz, CDCl3) δ ppm 148.0, 147.7, 147.2, 145.8, 137.0 (d, J=34 Hz), 136.7, 136.2 (d, J=2 Hz), 131.7 (d, J=7 Hz), 126.9, 125.1, 119.9, 46.3 (d, J=17 Hz), 35.1, 34.8, 34.3, 32.1, 31.9, 31.1 (d, J=3 Hz), 28.8 (d, J=3 Hz), 26.7, 26.2 (d, J=3 Hz), 24.4, 22.9 (d, J=2 Hz). 31P NMR (CDCl3, 202 MHz) δ ppm 20.1 (s). HRMS (TOF-ESI+) calcd for [M, C31H47P]+ 450.3415. Found 450.3429.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])(=[O:20])=[O:19])C1C=CC=CC=1>[Pd].C1COCC1>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([N:13]1[C:14]2[C:10](=[C:9]([OH:8])[CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12]1)(=[O:19])=[O:20]
Reactant: O=S(=O)(c1ccccc1F)n1ccc2c(OCc3ccccc3)cccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1F)n1ccc2c(O)cccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 40.2 %

Procedure:
A 500 mL round-bottomed flask equipped with a magnetic stirrer was charged with a solution of 4-benzyloxy-1-(2-fluorobenzenesulfonyl)-1H-indole (21.48 g, 0.056 mol) in 200 mL freshly distilled THF, followed by 5% palladium on carbon (0.100 g, 0.8 mol %). The flask was sealed with a rubber septum and purged with hydrogen gas at atmospheric pressure. The solution was stirred at ambient temperature for 6 hours. The catalyst was removed by filtration through celite, and the filtrate concentrated in vacuo. The resulting crude solid was recrystallized from ethyl ether (75 mL) to give 1-(2-fluorobenzenesulfonyl)-4-hydroxy-1H-indole as a white solid (6.55 g, 40%). MS: (M−H)−=290.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:15][N:12]([CH2:13][CH2:14]2)[CH2:11][CH:10]=[CH:9]3)=[CH:4][N:3]=1.[C:16]1([C:22]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:23]2[CH:27]=[C:26]([Sn](CCCC)(CCCC)CCCC)[N:25]=[CH:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:47]1([C:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:23]2[CH:27]=[C:26]([C:2]3[CH:7]=[CH:6][C:5]([C:8]45[CH2:15][N:12]([CH2:13][CH2:14]4)[CH2:11][CH:10]=[CH:9]5)=[CH:4][N:3]=3)[N:25]=[CH:24]2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: Brc1ccc(C23C=CCN(CC2)C3)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: C1=CC2(c3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)nc3)CCN(C1)C2
Temperature: 85 °C

Procedure:
0.25 g (0.94 mmol) of 5-(2-bromopyrid-5-yl)-1-azabicyclo[3.2.1]oct-3-ene (WO 03/057 697) dissolved in 3 ml of tetrahydrofuran, 1.24 g (2.07 mmol) of 1-triphenylmethyl-4-tributylstannylimidazole and 0.06 g (0.08 mmol) of bis(triphenylphosphine)dichloropalladium are successively introduced into a 10 ml three-necked round-bottomed flask. The mixture is then heated at 85° C. for 15 hours and then diluted in 10 ml of chloroform and 10 ml of saturated aqueous sodium carbonate solution.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:26])[C@@H:7]1[CH2:11][C@@H:10]([NH:12][C:13](=[O:18])[CH2:14][N:15]([CH3:17])[CH3:16])[CH2:9][N:8]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].CO.C(O)(=O)C>O.O1CCCC1>[C:22]([O:21][C:19]([N:8]1[CH2:9][C@H:10]([NH:12][C:13](=[O:18])[CH2:14][N:15]([CH3:16])[CH3:17])[CH2:11][C@H:7]1[C:6]([OH:26])=[O:5])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)[C@@H]1C[C@@H](NC(=O)CN(C)C)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)CC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of lithium hydroxide monohydrate (40 mg) in water (1 mL) was added to a solution of N-tert-butoxycarbonyl-trans-4-(N,N-dimethylglycylamino)-L-proline methyl ester (A, 264 mg) in tetrahydrofuran (3 mL)-methanol (1 mL) at 0° C. After stirring at room temperature for 4 hr, acetic acid (55 L) was added to the reaction mixture at 0° C. The resulting solution was evaporated in vacuo to afford the crude title compound, which is used in the subsequent step.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]2[C:8](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:10]=[CH:11][C:4]=2[O:3]1.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]#[CH:32].C(N(CC)CC)C.CN(C)C=O>CCOCC.O>[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]#[C:32][C:8]1[C:5]2[CH:6]=[CH:7][C:2](=[O:1])[O:3][C:4]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=c1ccc2c(OS(=O)(=O)C(F)(F)F)cccc2o1
Reactant: C#CCCCCOC1CCCCO1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1ccc2c(C#CCCCCOC3CCCCO3)cccc2o1
Temperature: 100 °C
Yield: 66.8 %

Procedure:
A mixture of 1.47 g (5 mmol) of trifluoromethanesulfonic acid 2-oxo-2H-1-benzopyran-5-yl ester (preceding example), 1.0 g (5.5 mmol) of rac-6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexyne, 75 mg of cuprous iodide, 0.3 g (0.428 mmol) of dichloro-bis(triphenylphosphine)palladium(II), 7.5 mL of triethylamine, and 35 mL of dry N,N-dimethylformamide was stirred and heated at 100° C. for 24 hr. The reaction mixture was cooled, poured into water, and worked-up with ether in the usual manner. The dark-brown, oily residue was flash chromatographed on silica gel. Elution with 2:1 hexane-ethyl acetate gave 1.09 g (67%) of rac-5-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]-2H-1-benzopyran-2-one as an orange oil.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH2:20]([NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[CH3:21]>C(#N)C>[CH2:20]([NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][N:26]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]3[CH:12]3[CH2:14][CH2:13]3)=[CH:4][C:3]=2[F:19])[CH2:25]1)[CH3:21]
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CCNCC1CCNC1
Solvent: CC#N
Product: CCNCC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A suspension of 5.7 g (20 mmole) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 10.3 (80 mmole) of 3-ethylaminomethylpyrrolidine and 125 ml of acetonitrile was stirred at room temperature for 0.5 hours after an initial exotherm (60° C.). The solid was removed by filtration, washed with acetonitrile, and dried in vacuo to give 6.0 g (80%) of the title compound, mp 268°-270° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:27]([OH:29])=O)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:16][C@H:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][C@@H:18]3[OH:26])=[O:15])[CH:9]=2)=[CH:6][N:7]=1.[C:30]1([CH2:36][N:37]2[CH2:43][CH2:42][CH2:41][CH2:40][C@H:39]([NH2:44])[CH2:38]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C.C1COCC1.C(OCC)(=O)C.CCOCC>[NH2:1][C:2]1[C:3]([C:27]([NH:44][C@H:39]2[CH2:40][CH2:41][CH2:42][CH2:43][N:37]([CH2:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:38]2)=[O:29])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:16][CH:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][C@@H:18]3[OH:26])=[O:15])[CH:9]=2)=[CH:6][N:7]=1
Reactant: N[C@H]1CCCCN(Cc2ccccc2)C1
Reactant: Nc1ncc(-c2cccc(C(=O)N[C@H]3c4ccccc4C[C@@H]3O)c2)nc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Nc1ncc(-c2cccc(C(=O)NC3c4ccccc4C[C@@H]3O)c2)nc1C(=O)N[C@H]1CCCCN(Cc2ccccc2)C1
Reaction time: 8 h
Yield: 12 %

Procedure:
3-Amino-6-[3-({[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)phenyl]pyrazine-2-carboxylic acid (1.0 eq) was dissolved in DMF-THF and treated with (3S)-1-(phenylmethyl)azepan-3-amine (1.46 eq), EDCI (1.2 eq) and HOBt (1.2 eq) at ambient temperature. After being stirred overnight, the reaction mixture was quenched by addition of aqueous sodium bicarbonate followed by extraction with ethyl acetate (20 mL×3). The aqueous phase was extracted once with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride then dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo gave a crude oil, which was purified by preparative HPLC to yield a crude oil, which was dissolved in ethyl acetate (10 mL), and treated with 1M HCl in ether (5 mL). The resulting precipitation was filtered, washed with methanol (2×20 mL), and dried to afford 122 mg (12% yield) of 3-amino-6-[3-({[(2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)phenyl]-N-[(3S)-1-(phenylmethyl)azepan-3-yl]pyrazine-2-carboxamide (122 mg, 15% yield).: 1H NMR (400 MHz, DMSO-d6): δ 8.98 (s, 1H), 8.90 (m, 1H), 8.75 (s, 1H), 8.63 (m, 2H), 8.11 (m, 1H), 7.95 (m, 2H), 7.62 (m, 2H), 7.58 (m, 1H), 7.42 (m, 1H), 7.20 (m, 3H), 7.08 (m, 1H), 5.50 (m, 1H), 4.51 (m, 1H), 4.49 (m, 1H), 4.46 (m, 1H), 4.40 (m, 1H), 3.50 (m, 1H), 3.65 (m, 2H), 3.20 (m, 2H), 2.85 (m, 1H), 2.10 (m, 1H), 1.80 (m, 2H), 1.58 (m, 1H); MS (EI) for C34H36N6O3: 577.08 (MH+).