Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[N:4][C:5]([CH:9]2[CH2:11][CH2:10]2)=[N:6][C:7]=1Cl.[NH3:15].Cl>O>[NH2:15][C:7]1[N:6]=[C:5]([CH:9]2[CH2:11][CH2:10]2)[N:4]=[C:3]([C:12]([OH:14])=[O:13])[C:2]=1[Cl:1]
Reactant: O=C(O)c1nc(C2CC2)nc(Cl)c1Cl
Reactant: N
Agent: Cl
Solvent: O
Product: Nc1nc(C2CC2)nc(C(=O)O)c1Cl
Temperature: 80 °C
Yield: 105.3 %

Procedure:
A 3-L flask was charged with 5,6-dichloro-2-cyclopropyl-4-pyrimidinecarboxylic acid (280 g, 1.2 mol), ammonia (28 wt % in water, 350 g, 5.76 mol) and water (1.26 L). The reaction mixture was heated at 80° C. for 5 h, and excess water (about 600 mL) was removed by distillation at 50° C./9 kPa. After cooling to 20° C., the reaction mixture was acidified to pH 2 with aqueous hydrochloric acid (132 g, 110 mL, 1.32 mol), cooled to 5° C., and filtered. The filtered wet cake was washed with water (2×200 mL) and dried in a vacuum-oven at 55° C. to give about 270 g of the title compound as a monohydrate, which contained 8.3 wt % of water measured by Karl Fischer titration, and decomposed at 152° C. (after crystallization from hot ethanol).
Reaction SMILES: C(OC(CO[N:8]=[C:9]([C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)[C:10]([O:12][CH3:13])=[O:11])=O)C.[H][H]>C(O)C.[Pd]>[NH2:8][CH:9]([C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: [H][H]
Reactant: CCOC(=O)CON=C(C(=O)OC)c1ccn(C)n1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C(N)c1ccn(C)n1

Procedure:
2.61 g (9.69 mmol) methyl ethoxycarbonyl-methoxyimino-(1-methyl-pyrazol-3-yl)-acetate are hydrogenated in 60 ml of ethanol with 1.1 g 5% palladium charcoal for 16 h at 50° C. under 3.4 bars pressure in a hydrogen atmosphere. Then the mixture is suction filtered and the filtrate is evaporated down completely i. vac.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([I:9])=[CH:7][CH:6]=[CH:5][N:4]=1.ClC1C(C[N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH:28]=[CH2:29])[C:19](=[O:21])[CH3:20])=CC(F)=C(Cl)N=1>>[I:9][C:8]1[C:3]([CH2:2][N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH:28]=[CH2:29])[C:19](=[O:21])[CH3:20])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1ccccc1N(Cc1cc(F)c(Cl)nc1Cl)C(C)=O
Reactant: BrCc1ncccc1I
Product: C=Cc1ccccc1N(Cc1ncccc1I)C(C)=O
Yield: 70 %

Procedure:
Compound 51C (8.5 mg, 70%) was prepared from bb (5.2 mg, 0.032 mmol) and 51B (9.7 mg, 0.33 mmol) by a route analogous to that used for the preparation of 1C. HPLC Rt=2.929 min.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[CH3:40][C:41]1[O:45][N:44]=[C:43]([C:46](Cl)=[O:47])[CH:42]=1>>[CH3:40][C:41]1[O:45][N:44]=[C:43]([C:46]([O:1][CH:2]2[CH2:20][CH:19]3[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]4[C:16]([C:22]([NH:24][S:25]([CH:28]5[CH2:30][CH2:29]5)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]3=[O:21])[CH2:15]4)[CH2:3]2)=[O:47])[CH:42]=1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: Cc1cc(C(=O)Cl)no1
Product: Cc1cc(C(=O)OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCCC(NC(=O)OC(C)(C)C)C(=O)N3C2)no1
Yield: 26.1 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 5-methylisoxazole-3-carbonyl chloride (188 mg, 1.06 mmol). The final trituration (diethyl ether/hexane) and filtration gave 31 mg (26%) of 18-(5-methylisoxazole-3-carbonyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 99.9% pure (HPLC), MS m/z 676 (M−H)−, HRMS: calcd. 678.2809 and found 678.2795 (M+H)+, mp 157-159° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.[H][H]>[Pt].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[N:11][CH:10]=[CH:9][CH:8]=2
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2cccnc12
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cccnc12

Procedure:
1,1-Dimethylethyl N-{4-[(3-nitro[1,5]naphthyridin-4-yl)amino]butyl}carbamate (42.7 g, 0.12 mole), platinum on carbon (2 g) and ethyl acetate (500 mL) were combined and then hydrogenated on a Parr apparatus at 30 psi (2.1 Kg/cm2) hydrogen pressure for 1 hour. The catalyst was removed by filtration and rinsed with ethyl acetate. The filtrate was concentrated under vacuum to provide 1,1-dimethylethyl N-{4-[(3-amino[1,5]naphthyridin-4-yl)amino]butyl}carbamate as a bright yellow-orange solid.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][C:16]=4[CH:6]2[CH2:5][CH:4]([C:18]([OH:20])=[O:19])[CH2:3]1)[NH:11][CH:10]=3.[OH-].[K+].[C:23]1(C)[CH:28]=CC(S(OC(C)C)(=O)=O)=C[CH:24]=1>CS(C)=O>[CH3:24][CH:23]([N:11]1[C:12]2[C:17]3[C:9]([CH2:8][C@@H:7]4[C@@H:6]([C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH2:5][CH:4]([C:18]([OH:20])=[O:19])[CH2:3][N:2]4[CH3:1])=[CH:10]1)[CH3:28]
Reactant: CN1CC(C(=O)O)CC2c3cccc4[nH]cc(c34)CC21
Reactant: Cc1ccc(S(=O)(=O)OC(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)n1cc2c3c(cccc31)[C@H]1CC(C(=O)O)CN(C)[C@@H]1C2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
To a 250 ml, three-neck round bottom flask was added 15.0 g (50.8 mmol) of 92% pure 9,10-dihydrolysergic acid, 18.08 g (277.7 mmol) of 86% pure powdered potassium hydroxide and 150 ml of DMSO. The mixture was stirred for approximately 15 minutes and 14.3 g (66.8 mmol) of p-toluenesulfonic acid, 1-methylethyl ester was added dropwise to the reaction mixture over a period of about 10 minutes. The reaction mixture was stirred at room temperature for approximately 24 hours and poured into 750 ml of ice water. The mixture was washed with 150 ml of ethyl acetate, and the aqueous phase was separated and the pH was adjusted to 5 with glacial acetic acid. The mixture was cooled in the freezer and the precipitated solid was collected by vacuum filtration. The solid was washed with water and dried in vacuo to provide 12.8 g of the title compound. A second crop of 0.82 g of the desired compound was obtained. The purity of the first crop material was 99.6% and the purity of the second crop material was 98.8% as determined by HPLC. Exact mass: theory 312.18378; found 312.18485.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[CH:3]([OH:38])[CH2:4][C@@H:5]([NH:10][C:11]1[C:16]([F:17])=[CH:15][N:14]=[C:13]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([F:27])[CH:25]=3)[N:20](S(C3C=CC(C)=CC=3)(=O)=O)[CH:19]=2)[N:12]=1)[C:6]([CH3:9])([CH3:8])[CH3:7].C[O-].[Na+].C([O-])(O)=O.[Na+]>CCOC(C)=O>[F:40][C:2]([F:1])([F:39])[CH:3]([OH:38])[CH2:4][C@@H:5]([NH:10][C:11]1[C:16]([F:17])=[CH:15][N:14]=[C:13]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([F:27])[CH:25]=3)[NH:20][CH:19]=2)[N:12]=1)[C:6]([CH3:7])([CH3:8])[CH3:9]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H](CC(O)C(F)(F)F)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@@H](CC(O)C(F)(F)F)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (4R)-1,1,1-trifluoro-4-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhexan-2-ol, 182a, (0.053 g, 0.091 mmol) was added NaOMe (0.019 g of 25% solution in MeOH, 0.091 mmol). The reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was diluted into EtOAc and aqueous saturated NaHCO3 solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (EtOAc/Hexanes) to afford 26 mg of the desired product, 66: 1H NMR (400 MHz, CDCl3) δ 9.40 (s, 1H), 8.47 (dd, J=9.3, 2.7 Hz, 1H), 8.15 (s, 1H), 8.10 (d, J=2.7 Hz, 1H), 7.99 (d, J=2.8 Hz, 1H), 5.54 (s, 1H), 4.84 (d, J=7.5 Hz, 1H), 4.23 (t, J=9.9 Hz, 1H), 3.91 (s, 1H), 2.07-1.97 (m, 1H), 1.62 (t, J=13.0 Hz, 1H), 1.01 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.42 minutes (M+H) 430.44.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:70])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56]([C:58]4[S:59][CH:60]=[C:61]([C:63]5[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=5)[N:62]=4)=[O:57])=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:69])[C:36]([O:38]C)=[O:37]>>[CH3:33][CH:34]([CH3:70])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:50]=[CH:51][C:52]([NH:55][C:56]([C:58]4[S:59][CH:60]=[C:61]([C:63]5[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=5)[N:62]=4)=[O:57])=[CH:53][CH:54]=3)=[CH:45][CH:46]=2)[C:41]1=[O:69])[C:36]([OH:38])=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4nc(-c5ccccc5)cs4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4nc(-c5ccccc5)cs4)cc3)cc2C1=O
Yield: 82 %

Procedure:
The compound of example 624 was prepared analogous to the compound of example 98 by hydrolysis of compound of example 623.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][CH:5]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[Cl:23])[C:4]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].Cl.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH:31]1[CH2:36][CH2:37][C:38]([OH:40])=[O:39]>>[Cl:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[CH:5]1[N:6]=[C:7]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:8][C:3]([CH2:2][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH:31]2[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[C:4]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncccc2F)=NC1c1ccc(F)cc1Cl
Reactant: O=C(O)CCC1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2CCC(=O)O)NC(c2ncccc2F)=NC1c1ccc(F)cc1Cl
Yield: 35.7 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(3-fluoropyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.72 g, 1.53 mmol) was reacted with 3-(morpholin-3-yl)propanoic acid hydrochloride (0.3 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.3 g, 36%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=O)[NH:6][N:7]=1)[CH3:2].[NH2:10][C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][C:12]=1[OH:18].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([C:8]2[NH:17][C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([OH:18])[C:11]=3[N:10]=2)[NH:6][N:7]=1)[CH3:2]
Reactant: Nc1cccc(O)c1N
Reactant: CCc1cc(C=O)[nH]n1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1cc(-c2nc3c(O)cccc3[nH]2)[nH]n1

Procedure:
Starting with 100 mg of 5-ethyl-2H-pyrazole-3-carboxaldehyde, 100 mg of 2,3-diaminophenol, and 153 mg of sodium metabisulphite, in 1 ml of ethanol and 3 ml of dimethylformamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by a reverse-phase HPLC (5 mm, C18 phase, dimensions: 100×25 mm, flow rate 20 ml/min, elution gradient: acetonitrile/0.07% TFA-water/0.07% TFA from 5-95 to 95-5 (v/v)), and desalification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol), 16 mg of 2-(5-ethyl-2H-pyrazol-3-yl)-4-hydroxy-1H-benzimidazole are obtained in the form of a brown lacquer, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1O[C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=2)=[N:13][N:14]=1)[CH3:2].FC(F)(F)C([O-])=O.[CH3:33][NH3+:34].CN>>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:34]([CH3:33])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=2)=[N:13][N:14]=1)[CH3:2]
Reactant: C[NH3+]
Reactant: CCCCCc1ccc(-c2nnc(-c3ccccc3SCC)o2)cc1
Agent: CN
Agent: O=C([O-])C(F)(F)F
Product: CCCCCc1ccc(-c2nnc(-c3ccccc3SCC)n2C)cc1

Procedure:
2-[2-(Ethylthio)phenyl]-5-(4-pentylphenyl)-1,3,4-oxadiazole (1-E) (100 mg, 0.28 mmol), methylammonium trifluoroacetate (1.64 g, 11.34 mmol, prepared by combining equal amounts of methylamine and trifluoroacetic acid in ether followed by evaporation in vacuo) and methylamine (2M/MeOH, 5.68 mL, 11.34 mmol) were stirred together in a glass bomb at 150° C. for 2.5 d. The mixture was evaporated in vacuo and the residue partitioned between methylene chloride and water. The organic phase was washed with water, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by preparative TLC (silica gel, ethyl acetate:hexane, 7:3) to provide 3-[2-(ethylthio)phenyl]-4-methyl-5-(4-pentylphenyl)-4H-1,2,4-triazole (1-F). MS m/z 366 (M+1). 1H NMR (500 MHz, CDCl3): δ 0.96 (t, 3H); 1.29 (t, 3H); 1.40 (m, 4H); 1.73, (m, 2H); 2.73, (t, 2H); 2.90 (q, 2H); 3.58 (s, 3H); 7.37 (m, 3H); 7.55 (m, 3H); 7.72, (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[Br:12][CH2:13][CH2:14]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:12][CH2:13][CH2:14][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: BrCCBr
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(Cl)c(OCCBr)c1
Yield: 42.8 %

Procedure:
To a solution of 2-chloro-5-nitro-phenol (13, 0.87 g, 5 mmol) in acetone (10 mL) were sequentially added 1,2-dibromoethane (14, 0.85 ml, 10 mmol) and K2CO3 (1.45 g, 10.5 mmol). The mixture was heated under reflux over night. To work up, the solids were filtered and the filtrate was concentrated. The residue was purified by chromatography (silica gel) eluting with hexanes first, then EtOAc to yield 15 (600 mg).
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH:8](O)/[CH:9]=[CH:10]/[C:11]1[N:12]([CH:29]([CH3:31])[CH3:30])[C:13](=[O:28])[C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:3][C:4]([OH:6])=[O:5].C1(N=C=NC2CCCCC2)CCCCC1.O>ClCCl>[OH:1][CH:2]1[CH2:7][CH:8](/[CH:9]=[CH:10]/[C:11]2[N:12]([CH:29]([CH3:31])[CH3:30])[C:13](=[O:28])[C:14]3[C:19]([C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:5][C:4](=[O:6])[CH2:3]1
Reactant: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)O)c(-c2ccc(F)cc2)c2ccccc2c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: O
Product: CC(C)n1c(/C=C/C2CC(O)CC(=O)O2)c(-c2ccc(F)cc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of a 1:1 mixture of the erythro- and threo-diastereoisomers of (E)-3,5-dihydroxy-7-[4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinolin-3-yl]hept-6-enoic acid (0.35 g; prepared as described in Example 5) in dichloromethane (25 ml) was treated with dicyclohexylcarbodiimide (0.18 g) and the resulting solution was stirred at room temperature for 1 hour. The solution was treated with water (20 ml), and stirred for 30 minutes. The layers were then separated and the aqueous phase was extracted with dichloromethane (210 ml). The combined extracts were dried over magnesium sulphate and evaporated to dryness. The resulting residue was triturated with diethyl ether (10 ml) and the insoluble material was filtered off. Evaporation of the ethereal solution gave a pale yellow solid, which was triturated with petroleum ether (b.p. 60°-80° C.; 10 ml) and filtered, to give (E)-4-hydroxy-6-[2-{4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinolin-3-yl}ethenyl]-3,4,5,6-tetrahydro-2H-pyran-2-one, in the form of a pale yellow solid (0.21 g), m.p. 151°-154° C. [Elemental analysis: C, 70.8; H, 5.74; N, 3.35%; calculated: C, 71.24; H, 5.74; N, 3.32%].
Reaction SMILES: [H-].[Na+].CS(O[CH2:8][CH2:9][CH2:10][C:11]1[NH:12][C:13]2[CH:14]=[CH:15][C:16]([N+:24]([O-:26])=[O:25])=[C:17]([C:20]([O:22][CH3:23])=[O:21])[C:18]=2[CH:19]=1)(=O)=O>CN(C=O)C.C(OCC)(=O)C>[N+:24]([C:16]1[CH:15]=[CH:14][C:13]2[N:12]3[CH2:8][CH2:9][CH2:10][C:11]3=[CH:19][C:18]=2[C:17]=1[C:20]([O:22][CH3:23])=[O:21])([O-:26])=[O:25]
Reactant: COC(=O)c1c([N+](=O)[O-])ccc2[nH]c(CCCOS(C)(=O)=O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1c([N+](=O)[O-])ccc2c1cc1n2CCC1
Yield: 95.3 %

Procedure:
Sodium hydride (60% dispersion in oil, 0.096 g) was added to a solution of methyl 2-(3-methanesulfonyloxypropyl)-5-nitro-1H-indole-4-carboxylate (Intermediate 20, 0.460 g) in DMF (12 mL) and the resultant mixture was stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate and washed with water and brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to give methyl 7-nitro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (0.320 g) as a brown solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][CH:13]=[C:12]([N+:20]([O-:22])=[O:21])[C:11]2=O>CN(C=O)C>[Cl:3][C:11]1[C:10]2[C:15](=[CH:16][C:17]([O:18][CH3:19])=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2[nH]cc([N+](=O)[O-])c(=O)c2cc1OC
Solvent: CN(C)C=O
Product: COc1cc2ncc([N+](=O)[O-])c(Cl)c2cc1OC
Temperature: 100 °C
Yield: 83.8 %

Procedure:
Phosphorus oxychloride (1.69 g, 11 mmol) was added to a suspension of 6,7-dimethoxy-3-nitro-1,4-dihydroquinolin-4-one (2.5 g, 10 mmol) in anhydrous DMF (20 ml) and the mixture was heated at 100° C. for 30 minutes. The mixture was cooled and poured onto ice/water. The precipitate was collected by filtration, washed with water and dried under vacuum to give 4-chloro-6,7-dimethoxy-3-nitroquinoline (2.25 g, 83%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:18]([NH:19][NH2:20])=[CH:17][C:15](=[O:16])[N:14]([CH2:21][CH2:22][CH2:23][CH3:24])[C:12]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][N:26]=[C:27]=S.CO>CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:18]2[NH:19][N:20]=[C:25]([NH:26][CH3:27])[C:17]=2[C:15](=[O:16])[N:14]([CH2:21][CH2:22][CH2:23][CH3:24])[C:12]1=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN=C=S
Reactant: CCCCn1c(=O)cc(NN)n(CCOCc2ccccc2)c1=O
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCn1c(=O)c2c(NC)n[nH]c2n(CCOCc2ccccc2)c1=O
Yield: 40 %

Procedure:
A solution of 1-(2-benzyloxyethyl)-3-butyl-6-hydrazinouracil (2.1 g, 6.3 mM) and methyl isothiocyanate (1.36 ml, 20 mM) in DMF (20 ml) was stirred at 120° C. for 20 hours. To the solution was added 50% methanol (20 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol/water gave pale yellow crystals (0.94 g, 40%), m.p. 214°-216° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:26])[NH:14][C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][S:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:26])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[S:28][CH3:27])=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(Br)cc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CSc1ccccc1-c1ccc(NC(=O)C2CCCN2C(=O)OC(C)(C)C)c(C(F)(F)F)c1

Procedure:
2-(4-Bromo-2-trifluoromethyl-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.92 g, 4.4 mmol), 2-(methylthio)benzene boronic acid (0.88 g, 5.2 mmol), and tetrabutylammonium bromide (70 mg, 0.22 mmol) were combined in 40 mL toluene, added 4.4 mL of a 2M aqueous Na2CO3 solution followed by tetrakistriphenylphosphine palladium(0) (0.253 g, 0.22 mmol). Heated reaction at reflux 4 hours, cooled, concentrated, redissolved in EtOAc (250 mL), washed with water (3×200 mL), brine (200 mL), dried with MgSO4, filtered, and concentrated. Purified on a silica gel column eluted with 20% EtOAc in hexanes. Combined and concentrated pure fractions to yield title compound. (1.8 g, 85%) APCI (AP−): 479.1 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](O)(=[O:12])[CH:10]=[CH2:11]>C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:8][CH2:11][CH2:10][C:9]2=[O:12]
Reactant: Oc1ccc(F)cc1
Reactant: C=CC(=O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: O=C1CCOc2ccc(F)cc21
Temperature: 40 °C
Yield: 147.3 %

Procedure:
A 400 ml stainless steel Parr reactor was charged with para-fluorophenol (28.4 grams), acrylic acid (28.8 grams), and an inhibitor phenothiazine (0.02 grams). The system was sealed, evacuated and cooled in dry ice/acetone before the anhydrous hydrogen fluoride (117 grams) was condensed into the system. The mixture was then warmed to 40° C. for one hour thirty minutes with stirring before being heated to 100° C. for four hours thirty minutes. The excess HF was them removed and the system cooled to 0° C. and opened to give 62 grams of brown oil which was washed with D.I. water to give 50 grams of material to be extracted. The 6-Fluoro-4-Chromanone was collected and recrystallized from methanol/water. The HPLC yield was 75%, isolated 52%.
Reaction SMILES: C(O[C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])CCC.[Cl:18][C:19]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:20]=1[CH2:21][NH2:22]>O1CCCC1>[Cl:18][C:19]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:20]=1[CH2:21][NH:22][C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:14])([CH3:15])[CH2:12][CH3:13]
Reactant: NCc1cc(Cl)ccc1Cl
Reactant: CCCCOc1c(NC(C)(C)CC)c(=O)c1=O
Solvent: C1CCOC1
Product: CCC(C)(C)Nc1c(NCc2cc(Cl)ccc2Cl)c(=O)c1=O
Yield: 88.5 %

Procedure:
Tetrahydrofuran (13 mL), 3-butoxy-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione (1,20 g, 5 mmol) and 2,5-dichlorobenzylamine (0.88 g, 5 mmol) were stirred together for approximately 64.5 hours. Removal of solvent and thorough trituration of the residue with diethyl ether gave 1.51 g of a light yellow solid. As purification of this material by three recrystallizations from acetonitrile was unrewarding, the recovered crude product was subjected to HPLC. The solid isolated from the appropriate fractions was recrystallized from acetonitrile to afford 0.598 g of the title compound as a white solid: mp 195°-196° C. MS (m/z) 340/342/344 (M+). HPLC indicates a major component (>99%).
Reaction SMILES: C(O)(=O)C.C(OC(=O)C)(=O)C.[Cl:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:19]([O:21][CH3:22])=[O:20].[N+:28]([O-])([OH:30])=[O:29]>O>[Cl:12][CH2:13][CH2:14][O:15][C:16]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([N+:28]([O-:30])=[O:29])=[C:18]([CH:17]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(OC)c(OCCCl)c1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COC(=O)c1cc(OCCCl)c(OC)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 86 %

Procedure:
To acetic acid (42 mL) and acetic anhydride (8.5 mL) was added methyl 3-(2-chloroethoxy)-4-methoxybenzoate (4.0 g, 16.3 mmol) followed by 70% nitric acid (2.8 mL) and the mixture heated at 50° C. for 1 hour. The mixture was poured into H2O, filtered, and washed with H2O to give methyl 5-(2-chloroethoxy)-4-methoxy-2-nitrobenzoate (4.08 g, 14.1 mmol, 86%). 1H NMR (300 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.38 (s, 1H), 4.43 (t, 2H), 3.99 (t, 2H), 3.94 (s, 3H), 3.85 (s, 3H).