Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:10]2[CH:4]([NH:5][C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[NH:8][C:9]2=[O:11])[CH2:3][CH2:2]1.[C:16]1(=[O:30])[N:20]([CH2:21][C:22](Cl)=[O:23])[C:19](=[O:25])[C:18]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:17]12.C(=O)([O-])O.[Na+]>ClCCCl>[C:19]1(=[O:25])[N:20]([CH2:21][C:22]([N:5]2[CH:4]3[CH2:3][CH2:2][CH2:1][CH:10]3[C:9](=[O:11])[NH:8][C:7]3[CH:12]=[CH:13][CH:14]=[CH:15][C:6]2=3)=[O:23])[C:16](=[O:30])[C:17]2=[CH:29][CH:28]=[CH:27][CH:26]=[C:18]12
Reactant: O=C1Nc2ccccc2NC2CCCC12
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C1Nc2ccccc2N(C(=O)CN2C(=O)c3ccccc3C2=O)C2CCCC12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.1 %

Procedure:
To a suspension of 2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (2.02 g, 10 mmol) in 1,2-dichloroethane (15 mL) was added phthalimidoacetyl chloride (2.24 g, 10 mmol),and the mixture was stirred for 15 minutes at room temperature. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate (10 mL) to give precipitate, which was filtered off. The aqueous layer of the filtrate was seperated. The organic layer was washed with water, dried over magnesium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure. The concentrate was combined with the precipitate filtered previously, which was washed with methanol, followed by recrystallization from chloroform-methanol to give 2.42 g (yield 62%) of a cis-trans mixture (3:2). m.p. 293°-294° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:9](F)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[C:15]([O-])([O-])=[O:16].[K+].[K+]>CO>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:9]([O:16][CH3:15])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(F)c(C#N)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc(C(=O)O)c(Cl)cc1C#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 2-chloro-4-cyano-5-fluorobenzoate (840 mg; 3.93 mmol; 1 eq.) and K2CO3 (2 717.55 mg; 19.66 mmol; 5 eq.) in MeOH (16.80 mL) was stirred at RT for 24 hours. The reaction mixture was concentrated and the residue was taken up in water. The aqueous layer was washed with EtOAc then the aqueous phase was acidified with HCl cc and extracted with EtOAc. The combined organic phases were washed with water, brine, dried over MgSO4 and concentrated affording the title compound as a yellow solid used without further (0.63 g, 75%). 1H NMR (DMSO-d6, 300 MHz) δ 14.05 (br s, 1H), 8.04 (s, 1H), 7.51 (s, 1H), 3.96 (s, 3H). HPLC (Method A) Rt 3.11 min (Purity 88.5%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[F:8][C:9]([F:20])([F:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]=[C:17]=[S:18].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([F:8])([F:19])[F:20])[C:17]1=[S:18])[CH3:2]
Reactant: CCNCC(=O)O
Reactant: FC(F)(F)c1ccccc1N=C=S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CC(=O)N(c2ccccc2C(F)(F)F)C1=S
Yield: 18.7 %

Procedure:
The tide compound was prepared by the procedure described in Example 4 using 9.2 g of N-ethyl glycine, 10.2 g of 2-(trifluoromethyl)-phenyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. The residue was further purified by flash chromatography on silica gel (methylene chloride). Crystallization from ethanol afforded the title compound (2.7 g), m.p. 82°-85° C. Anal. Calcd. for. C12H11F3N2O S: C, 50.00; H, 3.85; N,9.72. Found: C, 50.00; H, 3.61; N, 9.61. Mass spectrum (EI, M.+) m/z 288.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([NH2:33])=[CH:27][C:26]=1[F:34].C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([NH:33][C:2]2[N:3]=[CH:4][C:5]3[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[C:6]=3[N:21]=2)=[CH:27][C:26]=1[F:34]
Reactant: COC(=O)c1cc(OC)c(N)cc1F
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cc(OC)c(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.4 %

Procedure:
To a mixture of 0.67 g (0.0021 mole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20), 0.63 g (0.00317 mole) of 4-amino-2-fluoro-5-methoxy-benzoic acid methyl ester and 30 mL of dioxane was added 0.05 g (0.00021 mole) of palladium (II) acetate and 1.91 g (0.00588 mole) of cesium carbonate. The mixture was stirred at room temperature for 5 minutes and then heated to 100 degrees for 18 hours. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes-ethyl acetate (60:40) to give 0.81 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-benzoic acid methyl ester (I-168).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:27][CH2:28][CH3:29])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:26])[CH3:2].CC(C)([O-])C.[K+].[C:36]1([CH3:47])[CH:41]=[CH:40][C:39]([NH:42][C:43](=[O:46])[CH2:44]Br)=[CH:38][CH:37]=1.[Cl-].[Na+]>CS(C)=O>[CH2:28]([O:27][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:44][C:43]([NH:42][C:39]2[CH:40]=[CH:41][C:36]([CH3:47])=[CH:37][CH:38]=2)=[O:46])([NH:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[O:17])[C:7]1=[O:26])[CH3:29]
Reactant: Cc1ccc(NC(=O)CBr)cc1
Reactant: CCOC(CN1C(=O)C(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C)cc2)(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
To a solution of 0.397 g of (RS)-1-(2,2-diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one in 4 ml of dry dimethyl sulfoxide was added 1 ml of a 1M solution of potassium t-butoxide in dry dimethyl sulfoxide at room temperature under a nitrogen atmosphere, followed by stirring for 30 minutes. To the mixture was added dropwise a solution of 0.228 g of N-p-tolyl-2-bromoacetamide in 2 ml of dry dimethyl sulfoxide, followed by stirring at the same temperature for 30 minutes. The reaction mixture was poured into an aqueous solution of sodium chloride and extracted with ethyl ether. The ethyl ether layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give 0.35 g (65%) of the title compound.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[NH2:3].[Br:10][C:11]1[S:15][C:14]([C:16](=[O:24])[CH2:17][C:18](=O)[C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=1.N1C=CC=N1>CO>[Br:10][C:11]1[S:15][C:14]([C:16](=[O:24])[CH2:17][C:18](=[N:3][NH:2][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)[C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=1
Reactant: NNc1ccncc1
Reactant: COC(=O)C(=O)CC(=O)c1ccc(Br)s1
Agent: Cl
Agent: c1cn[nH]c1
Solvent: CO
Product: COC(=O)C(CC(=O)c1ccc(Br)s1)=NNc1ccncc1
Temperature: 25 °C

Procedure:
4-Hydrazinopyridine hydrochloride (366 mg, 2.51 mmol) and methyl 4-(5-bromothiophen-2-yl)-2,4-dioxobutanoate (724 mg, 2.5 mmol) were suspended in MeOH (12 mL) and heated to reflux to afford a yellow solution. After refluxing for 24 hours the reaction was allowed to cool to ambient temperature and was concentrated under reduced pressure to afford an orange oil. LC/MS analysis showed it to be a mixture of two isomers of the hydrazone with a small amount of cyclized pyrazole present. This material was carried on the dehydrative cyclization to prepare the cyclized pyrazole. MS(ES): 384 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:17])([CH3:16])[C@H:3]1[OH:18].[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[OH:18][C@H:3]1[C@H:2]([NH:1][C:26]([NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:27])[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=[CH:11][C:6]=2[O:5][C:4]1([CH3:16])[CH3:17]
Reactant: CC1(C)Oc2ccc(C(F)(F)F)cc2[C@@H](N)[C@@H]1O
Reactant: O=C=Nc1ccccc1
Solvent: CCO
Product: CC1(C)Oc2ccc(C(F)(F)F)cc2[C@@H](NC(=O)Nc2ccccc2)[C@@H]1O
Yield: 69.2 %

Procedure:
A suspension of (trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-trifluoromethyl-2H-1-benzopyran (0.5 g, 1.9 mmol) (prepared according to D. R. Buckle et al., J. Med. Chem., 1990, 33, p. 3028) in ethanol (5 ml) under argon was treated with phenylisocyanate (0.23 g, 1.9 mmol) and the reaction was heated at reflux temperature for 4 hours. The product precipitated out of the reaction. The reaction was then concentrated in vacuo and the residue was triturated with isopropyl ether and hexanes to give the title compound as a colorless solid (0.5 g), m.p. 174°-175° C.: 1H NMR (CDCl3) δ7.4 (s, 1H), 7.32 (d, J=9.8 Hz, 1H), 7.17 (m, 5H), 7.0 (m, 1H), 6.77 (d, J=8.2 Hz, 1H), 5.22 (br d, 1H), 4.80 (br t, 1H), 3.45 (d, J=9.4 Hz, 1H), 1.37 (s, 3H), 1.12 (s, 3H); 13C NMR (CDCl3) 157.0, 156.5, 139.1, 137.3, 129.4, 126.5, 125.0, 124.7, 122.0, 121.7, 118.0, 79.6, 76.4, 51.4, 26.3, 18.2; IR (KBr) 1118.5, 1264.8, 1332.1, 1443.4, 1500.9, 1558.3, 1598.8, 16477.8, 2981.4, 3391.3 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][CH2:18][CH2:19][CH2:20]O)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:46]I>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][CH2:18][CH2:19][CH2:20][I:46])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: II
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCO)C(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCCI)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
A modified procedure described in Tetrahedron 2001, 57, 4759-4766 was followed. To a vigorously stirred solution of alcohol 25 (640 mg, 2.11 mmol), imidazole (359 mg, 5.28 mmol), and PPh3 (1.38 g, 5.28 mmol) in CH2Cl2 (20 mL) was added with I2 (1.07 g, 4.22 mmol) portionwise over 15 minutes. The resulting suspension was stirred for an additional 2 hrs and quenched with saturated Na2S2O3 (10 mL). The phases were separated and the aqueous layer was extracted with additional portions of CH2Cl2. The combined extracts were dried (MgSO4) and evaporated in vacuo. The solid residue was suspended in hexane/EtOAc (10/1 v/v, 15 mL) and the liquid decanted. This operation was performed two more times and the decanted liquid fractions were combined and evaporated in vacuo to give a yellow oil. Purification by flash chromatography (silica gel; hexanes→hexanes/EtOAc, 20/1) gave the title compound 30 (851 mg, 98%) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.C(Cl)CCl.[CH2:22]([O:29][CH2:30][C:31](O)=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:31](=[O:32])[CH2:30][O:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:6]=2[N:14]=1
Reactant: O=C(O)COCc1ccccc1
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: NC(=O)c1cc2c3ccccc3n(C(=O)COCc3ccccc3)c2nc1N
Temperature: 25 °C
Reaction time: 23 h
Yield: 21.8 %

Procedure:
To a solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 150 mg, 0.663 mmol) in pyridine (7 mL) was added EDC (210 mg, 1.10 mmol), DMAP (85 mg, 0.693 mmol) and benzyloxyacetic acid (142 μL, 0.994 mmol) and the mixture was stirred at RT under an atmosphere of Ar. After 23 h, the reaction was quenched with water (20 mL), poured into a separatory funnel containing EtOAc (100 mL) and washed with water (75 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated. The crude product was purified by HPLC (Phenomenex Luna 15 μm C18, aqueous HCOOH/CH3CN) to yield 2-amino-9-[(benzyloxy)acetyl]-9H-pyrido[2,3-b]indole-3-carboxamide (28, 54 mg, 22%). NH4OAc standard conditions. DAD Retention time=7.6 min. M+H=375. 1H NMR (300 MHz, DMSO-d6): δ 8.76 (s, 1H), 8.52-8.49 (m, 1H), 8.04 (br s, 1H), 7.83-7.77 (m, 3H), 7.47-7.29 (m, 8H), 5.30 (s, 2H), 4.72 (s, 2H).
Reaction SMILES: [CH:1]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.N1C=CC=CC=1.Cl[C:16]([O:18][CH3:19])=[O:17]>C(Cl)Cl>[C:16](=[O:17])([O:18][CH3:19])[O:8][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: COC(=O)Cl
Reactant: OC1C=CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)OC1C=CCCCC1
Temperature: 10 °C
Yield: 94.9 %

Procedure:
To a solution of cyclohept-2-enol (8.3 g, 74.0 mmol) in DCM (227 ml) and pyridine (35.9 ml, 444 mmol), was added methyl chloroformate (14.24 ml, 185 mmol) with cooling in an ice bath at such a rate that T<10° C. Once addition was complete, the reaction was allowed to mix and warm to ambient temperature overnight. The reaction mixture was washed with 2×150 mL 1N aqueous hydrochloric acid. The combined washes were back-extracted with 100 mL DCM. The combined DCM layers were then washed with 150 mL of an aqueous saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (11.95 g, 70.2 mmol, 95% yield) as an oil that was used without further purification. 1H NMR (400 MHz, DMSO-d6) 5 ppm 5.83 (dddd, J=11.81, 7.03, 5.17, 2.15 Hz, 1H), 5.65 (d, J=11.71 Hz, 1H), 5.17 (d, J=6.64 Hz, 1H), 4.71 (d, J=4.30 Hz, 1H), 3.69 (s, 2H), 1.99-2.23 (m, 2H), 1.79-1.94 (m, 2H), 1.56-1.72 (m, 3H), 1.34 (d, J=3.51 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[C:6]([S:15]C#N)=[CH:7][C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].SC[C@H]([C@@H](CS)O)O.P([O-])([O-])([O-])=O>CCO>[NH2:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([SH:15])[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:14][C:9]=2[N:10]=1
Reactant: CC(C)(C)c1cc2nc(N)sc2cc1SC#N
Agent: O=P([O-])([O-])[O-]
Agent: O[C@H](CS)[C@H](O)CS
Solvent: CCO
Product: CC(C)(C)c1cc2nc(N)sc2cc1S

Procedure:
The title compound was prepared according to General Method 14 using 5-tert-butyl-6-thiocyanato-benzothiazol-2-yl-amine (Example L-1; 8 g, 30 mmol), dithiothreitol (18.7 g, 121 mmol), EtOH (200 mL), and phosphate buffer (50 mL). MS (APCI): 239 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=O)[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:10]2)=[CH:4][CH:3]=1.O1CCOCC1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[S:40])[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:10]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nn(Cc2ccc(I)cc2)c2ncccc2c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1nn(Cc2ccc(I)cc2)c2ncccc2c1=S
Temperature: 25 °C

Procedure:
Ethyl 1-[(4-iodophenyl)methyl]-4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxylate (800 mg, 1.84 mmol) was suspended in toluene (5 mL) and dioxane (5 mL) and placed into a preheated oil bath to 110° C. Lawesson's Reagent (409 mg, 1.01 mmol, 0.55 equiv) was added portionwise over 45 minutes and after an additional 30 minutes at 110° C., the mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 95:5; dichloromethane:methanol), providing the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=2)=[C:11]([CH3:24])[N:10]=[N:9]1.FC1C=[CH:30][C:29]([N:32]2C(COC3C=CC(C(O)=O)=CN=3)=C(C)N=N2)=[CH:28]C=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:32][CH:29]([CH3:30])[CH3:28])=[O:21])=[CH:17][N:16]=2)=[C:11]([CH3:24])[N:10]=[N:9]1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: Cc1nnn(-c2ccccc2F)c1COc1ccc(C(=O)O)cn1
Product: Cc1nnn(-c2ccccc2F)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 78 %

Procedure:
As described for example 62, 6-((1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)nicotinic acid (55 mg, 0.17 mmol), instead of 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid, was converted to the title compound (48 mg, 78%) which was obtained as a white foam. MS: m/e=370.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[C:10]1(O)(C)[CH:15]=[CH:14][C:13](C)=[CH:12][CH2:11]1.[OH-].[Na+].C(Br)CCCCC>C(O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH2:14][CH2:15][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CC1=CCC(C)(O)C=C1
Reactant: Cc1ccc(C)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCCCCCBr
Product: CCCCCCOc1cc(C)ccc1C
Temperature: 80 °C

Procedure:
In 250 g of ethanol were dissolved 250 g (2.05 mol) of 2,5-dimethylphenol (or p-xylenol), 90 g (2.25 mol) of sodium hydroxide and 371 g (2.25 mol) of n-hexyl bromide. The solution was heated for 2 hours in an oil bath at 80° C. Water, 500 g, was added to the reaction mixture, from which an oily matter was separated. Vacuum distillation of the oily matter yielded 384 g of 2,5-dimethyl-1-n-hexyloxy-benzene. Next, 129 g (0.625 mol) of 2,5-dimethyl-1-n-hexyloxybenzene was dissolved in 625 g of 1,2-dichloroethane. To the solution kept in an ice bath, 100 g (0.625 mol) of bromine was added dropwise at a temperature below 5C. At the end of dropwise addition, 500 g of water was added. The organic layer was separated therefrom and washed with 300 g of an aqueous solution of 5 wt % sodium hydrogen carbonate. The organic layer was concentrated to remove the solvent, leaving an oily matter. Vacuum distillation (boiling point 114-124° C./0.5 Torr) of the oily matter yielded 174 g of 4-bromo-2,5-dimethyl-n-hexyloxybenzene.
Reaction SMILES: C([O:4][C@@:5]1([CH2:35][CH3:36])[C:32]2[CH:31]=[C:30]3[N:11]([CH2:12][C:13]4[C:14]3=[N:15][C:16]3[C:17]5[C:18]=4[N:19]([CH2:26][CH2:27][CH2:28][CH3:29])[CH:20]=[N:21][C:22]=5[CH:23]=[CH:24][CH:25]=3)[C:10](=[O:33])[C:9]=2[CH2:8][O:7][C:6]1=[O:34])(=O)C.NN.Cl>CO>[CH2:26]([N:19]1[C:18]2=[C:13]3[CH2:12][N:11]4[C:30](=[CH:31][C:32]5[C@:5]([CH2:35][CH3:36])([OH:4])[C:6](=[O:34])[O:7][CH2:8][C:9]=5[C:10]4=[O:33])[C:14]3=[N:15][C:16]3[C:17]2=[C:22]([CH:23]=[CH:24][CH:25]=3)[N:21]=[CH:20]1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN1C=Nc2cccc3nc4c(c1c23)Cn1c-4cc2c(c1=O)COC(=O)[C@@]2(CC)OC(C)=O
Agent: Cl
Agent: NN
Solvent: CO
Product: CCCCN1C=Nc2cccc3nc4c(c1c23)Cn1c-4cc2c(c1=O)COC(=O)[C@]2(O)CC
Reaction time: 1 h
Yield: 67.5 %

Procedure:
To a solution of (9S)-9-acetoxy-1-butyl-9-ethyl-1H,12H-pyrano[3″,4″:6′,7′]indolizino[1′,2′:6,5]pyrido[4,3,2-de]quinazoline-10,13(9H,15H)-dione (6.1 mg, 0.013 mmol) in MeOH (2 ml) cooled in an ice-bath was added anhydrous hydrazine (100 μl) and the mixture was stirred for 1 hr. at room temperature. Aqueous 1 N HCl solution was added dropwise to acidify the reaction mixture, and the mixture was stirred for 1 hr. at room temperature. After concentrated under reduced pressure, the residue was extracted with CH2Cl2 (30 ml) and the CH2Cl2 solution was washed with brine, dried over MgSO4 and evaporated. The residue was purified by column chromatography (dichloromethane/methanol=20/1) to give pure product (3.9 mg, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C:11]([O:13][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)Cc1ccc(Br)cc1
Reaction time: 46 h
Yield: 89.3 %

Procedure:
To a suspension of (R)-4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoic acid (5.02 g, 14.01 mmol) and NaHCO3 (3.53 g, 42.0 mmol) in DMF (20 mL) is added Benzyl bromide (5.10 mL, 42 mmol) at room temperature under nitrogen. After stirring for 46 hours, the reaction is diluted with H2O (200 mL), and then precipitated solid is collected and washed with H2O (500 mL) and then with heptane (200 ml) to give (R)-benzyl 4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate (5.61 g, 89%). HPLC retention time=1.56 minutes (condition B); MS (ES+)=392.1 (m-tBu+2); 348.1 (m-Boc+2; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.39 (s, 9 H) 2.48 (A of ABX, Jab=15.9 Hz, Jax=5.6 Hz, 1 H) 2.54 (B of ABX, Jab=15.9 Hz, Jbx=5.3 Hz, 1 H) 2.72-2.88 (m, 2 H) 4.11 (br s, 1 H) 5.02 (br s, 1 H) 5.10 (A of AB, J=12.1 Hz, 1 H) 5.16 (A of AB, J=12.1 Hz, 1 H) 7.00 (d, J=8.1 Hz, 2 H) 7.34-7.39 (m, 7 H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26](O)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3([C:26]([NH:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)CCCN
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)O)CCCC3)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)NCCCC(=O)OC(C)(C)C)CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-1-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)cyclopentanecarboxylic acid (15 mg, 0.040 mmol), tert-butyl 4-aminobutanoate hydrochloride (8.55 mg, 0.044 mmol), HATU (16.62 mg, 0.044 mmol), and TEA (0.017 mL, 0.119 mmol) in DMF (0.4 mL) was stirred at room temperature overnight. The mixture was acidified with 1M HCl and purified by HPLC. LCMS m/z=519.7 [M+H]+.