Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8](=[CH2:12])[C:9]([OH:11])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][C:33]([C:39]#[N:40])=[C:32]2[NH:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[C:44]([Cl:49])[CH:43]=1.C(=O)(O)[O-].[Na+]>C1COCC1.N1C=CC=CC=1>[Cl:49][C:44]1[CH:43]=[C:42]([NH:41][C:32]2[C:31]3[C:36](=[CH:37][CH:38]=[C:29]([NH:28][C:9](=[O:11])[C:8]([CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[CH2:12])[CH:30]=3)[N:35]=[CH:34][C:33]=2[C:39]#[N:40])[CH:47]=[CH:46][C:45]=1[F:48]
Reactant: C=C(CN1CCOCC1)C(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(F)c(Cl)c1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: C=C(CN1CCOCC1)C(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 9.3 %

Procedure:
Partially dissolved 1.37 g (8.00 mmol) 2-morpholin-4-ylmethyl-2-propenoic acid in 50 ml THF and chilled to 0° C. under N2. Added 1.06 ml (9.6 mmol) N-methylmorpholine and 833 μl (6.4 mmol) isobutyl chloroformate. Stirred at 0° C. for 1 hour and added a solution of 1.00 g (3.20 mmol) 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-3-quinolinecarbonitrile in 5 ml pyridine. Stirred overnight at 25° C. Poured onto a mixture of ice and saturated sodium bicarbonate, extracted with ethyl acetate, dried organic layer with brine and sodium sulfate, and stripped solvent to a small volume. Loaded onto a column of silica gel, eluted with 1% methanol/ethyl acetate, stripped solvent from desired fractions and dried under vacuum, giving 139 mg of yellow-orange solid: mass spectrum (electrospray m/e): M+H=465.8, 468.0.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[CH:3]=1.[C:12](=[O:15])([O-])[O-].[Cs+].[Cs+].O>FC1C=CC(O)=CC=1.CC(N(C)C)=O.C(OCC)(=O)C>[F:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([O:15][C:12]2[CH:6]=[CH:5][C:4]([F:11])=[CH:3][CH:2]=2)[CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Reactant: O=C([O-])[O-]
Agent: Oc1ccc(F)cc1
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(F)cc(Oc2ccc(F)cc2)c1
Temperature: 50 °C
Yield: 296.7 %

Procedure:
Under an argon atmosphere and at room temperature, in a 500-mL pear-shaped evaporating flask, 4-fluorophenol (18.5 g) and 1,3-difluoro-5-nitrobenzene (25.0 g) were dissolved in DMA (300 mL). The reaction system was added with cesium carbonate (15.3 g) and stirred. The reaction system was then heated to 50° C., stirred for 3 hours, then heated to 65° C., stirred for 1 hour and further heated to 85° C. and stirred for 1 hour. The reaction solution was allowed to cool to room temperature, diluted with ethyl acetate and added with water to extract an organic layer. The aqueous layer was added with ethyl acetate to extract an organic layer. The organic layer was combined and washed with water and a saturated sodium chloride solution and the solvent was then distilled off under reduced pressure to give the titled compound (35.0 g) having the following physical properties.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:19]1[CH:20]=[N:21][CH:22]=[CH:14][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccncc1F
Product: O=C(O)c1ccncc1NCc1cccc(C(F)(F)F)c1
Yield: 39 %

Procedure:
The title compound was prepared in 39% yield from 3-trifluoromethyl-benzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.47 (br s, 1H), 8.12 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.74 (s, 1H), 7.57-7.69 (m, 4H), 4.67 (s, 2H). [M+H] calc'd for C14H11F3N2O2, 297. found 297.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:20]([NH2:22])=[O:21])[CH:14]=[C:15]([CH2:18][OH:19])[CH:16]=2)[N:11]=[CH:10][N:9]=1.C(N(C(C)C)C(C)C)C.[CH3:35][O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1>C(Cl)Cl>[OH:19][CH2:18][C:15]1[CH:16]=[C:17]2[C:12](=[C:13]([C:20]([NH2:22])=[O:21])[CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:7][CH2:6][C:5]1[CH:23]=[CH:24][CH:25]=[C:3]([NH:2][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][C:37]([O:36][CH3:35])=[CH:38][CH:39]=2)[CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NC(=O)c1cc(CO)cc2c(NCc3cccc(N)c3)ncnc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cccc(CNc3ncnc4c(C(N)=O)cc(CO)cc34)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
The reaction mixture of 4-[(3-aminobenzyl)amino]-6-(hydroxymethyl)quinazoline-8-carboxamide hydrochloride (20 mg; 0.06 mmol; 1.00 eq.) and N-ethyl-N-isopropylpropan-2-amine (0.03 ml; 0.17 mmol; 3.00 eq.) in DCM was added 4-methoxybenzoyl chloride (11 mg; 0.06 mmol; 1.10 eq.). The reaction mixture was stirred at RT for 1 hr. Purified by HPLC, to get the title compound (18 mg, yield 71%) MS (M+1) 458.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([Br:14])=[CH:12][CH:11]=[C:10]([O:15][CH2:16][CH2:17][CH2:18][OH:19])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][O:28][C:29]([CH2:31][CH2:32][C:33](Cl)=[O:34])=[O:30].O>ClCCl>[CH2:1]([C:8]1[C:13]([Br:14])=[CH:12][CH:11]=[C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:33](=[O:34])[CH2:32][CH2:31][C:29]([O:28][CH3:27])=[O:30])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCOc1ccc(Br)c(Cc2ccccc2)n1
Reactant: COC(=O)CCC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)OCCCOc1ccc(Br)c(Cc2ccccc2)n1

Procedure:
509 mg of 2-benzyl-3-bromo-6-(3-hydroxypropyl)oxypyridine (Example 165a) was dissolved in 5 ml of dichloromethane. While stirring under ice-cooling, 0.33 ml of triethylamine and 0.29 ml of 3-methoxycarbonylpropionyl chloride were added thereto. After the temperature of the reaction solution was returned to room temperature and the reaction solution was stirred for 30 minutes, water was added to the reaction solution. The mixture was extracted with ethyl acetate, and the organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 20% ethyl acetate/hexane as an eluent for separation and purification, to give 643 mg of the target compound.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:25])[N:6]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16](Cl)[N:15]=2)[CH:9]=1)[CH:2]=[CH2:3].[NH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1>>[CH2:1]([O:4][C:5](=[O:25])[N:6]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=3)[N:15]=2)[CH:9]=1)[CH:2]=[CH2:3]
Reactant: NCCc1ccc(O)cc1
Reactant: C=CCOC(=O)N(Cc1cccc(-c2ccnc(Cl)n2)c1)C(C)(C)C
Product: C=CCOC(=O)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1)C(C)(C)C
Yield: 91 %

Procedure:
tert-Butyl-[3-(2-chloro-pyrimidin-4-yl)-benzyl]-carbamic acid allyl ester from the above reaction was coupled with tyramine following procedure F to give the title product in 91% yield. LC-MS showed the product had the expected M+H+ of 461. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) 8.3 (d, 1H)) 7.9 (m, 2H) 7.4 (m, 1H) 7.3 (m, 1H) 7.0 (d, 2H) 6.9 (d, 1H) 6.7 (d, 2H) 5.9 (m, 1H) 5.3 (m, 2H) 5.1 (m, 2H) 4.7 (s, 2H) 4.6 (d, 2H) 3.7 (m, 2H) 2.9 (m, 2H) 1.41 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][CH2:17][CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21].C(N(CC)CC)C>ClCCl>[CH2:20]([O:19][CH:18]([O:22][CH2:23][CH3:24])[CH2:17][CH2:16][NH:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH3:21]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CCOC(CCN)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(CCNc1c([N+](=O)[O-])cnc2ccccc12)OCC
Yield: 98.4 %

Procedure:
The general method described in Step 1 of Example 1 was used to react 4-chloro-3-nitroquinoline (20.3 g, 97.1 mmol), 1-amino-3,3-diethoxypropane (25.0 g, 116 mmol) and triethylamine (33.8 g, 333 mmol) in dichloromethane for 15 hours to provide (3,3-diethoxypropyl)-(3-nitroquinolin-4-yl)amine (30.5 g) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[N:12]O)[CH2:7][CH2:6][CH2:5]2.[OH-:14].[Na+].CO.C(Cl)Cl>O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:14])[NH:12][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: [OH-]
Reactant: Nc1ccc2c(c1)CCCC2=NO
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Nc1ccc2c(c1)CCCNC2=O
Temperature: 100 °C

Procedure:
6-Amino-3,4-dihydro-2H-naphthalen-1-one oxime (1.80 g, 10.2 mmol) and polyphosphoric acid (30 ml) were mixed together. The viscous mixture was heated to 100° C. with vigorous stirring as the mixture became homogeneous. After cooling to room temperature, the mixture was diluted with water (30 ml). 15% aqueous sodium hydroxide was added until the mixture became basic. Extraction with ethyl acetate (50 ml), drying over anhydrous magnesium sulfate, and concentration yielded a brown oil. Preparative TLC (5% MeOH/CH2Cl2) afforded 7-Amino-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (Bioorganic & Medicinal Chem. Lett., 2003, 13 4197) as a light brown oil, 21 mg. 1H NMR (400 MHz, DMSO-d6) δ 7.53 (s, 1H), 7.14-7.22 (m, 1H), 6.42-6.47 (m, 1H), 6.33 (s, 1H), 5.44 (s, 2H), 2.87-2.93 (m, 2H), 2.53-2.60 (m, 2H), 1.78-1.87 (m, 2H); MS (m/e) 177 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:18]=[C:17]([C:19]([N:21]2[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)=[O:20])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:30]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:31][C:32](=[CH2:40])[C:33]([O:35]C(C)(C)C)=[O:34])[CH:15]=2)[N:10]=1>ClCCl>[CH2:44]([O:43][C:41](=[O:42])[CH:30]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([NH2:8])[N:18]=[C:17]2[C:19]([N:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)=[O:20])[CH2:31][C:32](=[CH2:40])[C:33]([OH:35])=[O:34])[CH3:45]
Reactant: C=C(CC(C(=O)OCC)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(CC(C(=O)OCC)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1)C(=O)O
Temperature: 23 °C
Reaction time: 3 h

Procedure:
200 μl of trifluoroacetic acid are added to 100 mg of O1-tert-butyl O5-ethyl 4-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-methylenepentanedioate in 1 ml of dichloromethane, and the mixture is stirred at 23° C. for 3 h. The mixture is subsequently evaporated to dryness in vacuo and reacted further directly.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]2=[N:5][CH:4]=1)#[CH:2].Br[C:27]1[S:31][C:30]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[C:6]2[N:7]([C:3]([C:1]#[C:2][C:27]3[S:31][C:30]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:29][CH:28]=3)=[CH:4][N:5]=2)[CH:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Product: NS(=O)(=O)c1ccc(C#Cc2cnc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)cn23)s1

Procedure:
The title compound was prepared from 3-ethynyl-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.18) (360 mg, 1 mmol) and commercially available 5-bromothiophene-2-sulfonamide (221 mg, 1 mmol) according to general procedure II. Obtained as an off-white solid (300 mg, 57%). MS (ISP) 516.2 [(M+H)+]; mp 248–250° C.
Reaction SMILES: C([O-])(=O)C.[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([C:17]2[CH:22]=[CH:21][N+:20]([CH2:23][CH2:24][CH3:25])=[CH:19][CH:18]=2)[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH3:6].[BH4-].[Na+]>CO.CCOC(C)=O>[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([C:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH3:25])[CH2:19][CH:18]=2)[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH3:6]
Reactant: CCC[n+]1ccc(-c2ccc([N+](=O)[O-])c(OCC)c2)cc1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCN1CC=C(c2ccc([N+](=O)[O-])c(OCC)c2)CC1
Reaction time: 2 h
Yield: 76.4 %

Procedure:
To 4-[3-(ethyloxy)-4-nitrophenyl]-1-propylpyridinium acetate (0.84 g, 2.42 mmol) in 25 mL of MeOH at 0° C. was added, NaBH4 (0.275 g, 7.28 mmol) over 1 h. The mixture was allowed to come to rt over 2 h. The solvent was reduced to approximately 5 mL and then diluted with EtOAc, washed with conc. NaHCSO3, dried (Na2SO4), filtered, rotovaped down, and purified by flash chromatography to give the title compound of step D (0.536 g, 1.85 mmol, 76%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.80 (d, J=8.61 Hz, 1H), 7.23 (d, J=1.46 Hz, 1H), 7.11 (dd, J=8.42, 1.65 Hz, 1H), 6.37 (t, J=3.57 Hz, 1H), 4.23 (q, J=6.96 Hz, 2H), 3.06 (d, J=3.11 Hz, 2H), 2.58 (t, J=5.59 Hz, 2H), 2.44-2.50 (m, 2H), 2.29-2.35 (m, 2H), 1.41-1.51 (m, J=7.36, 7.36, 7.36, 7.36, 7.36 Hz, 2H), 1.31 (t, J=6.96 Hz, 3H), 0.85 (t, J=7.33 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:9])(I)[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[C:11]1[N:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1.O.[NH4+].[Cl-]>CS(C)=O.[Cu]>[F:1][C:2]([F:9])([C:11]1[N:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Cc1ccc(Br)nn1
Reactant: CCOC(=O)C(F)(F)I
Agent: [Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccc(C)nn1
Reaction time: 0.83 h
Yield: 97.1 %

Procedure:
This procedure is derived from the general method of T. Taguchi, et al. (Tetrahedron Lett., 1986, 27, 6103-6106). Ethyl difluoroiodoacetate (0.355 mL, 651 mg, 2.60 mmol) was added to a rapidly stirred suspension of copper powder (333 mg, 5.24 mmol) in DMSO (6.5 mL) at rt. After 50 min., 3-bromo-6-methylpyridazine (300 mg, 1.73 mmol) was added in DMSO (1.0 mL). After 20 h, the mixture was transferred to a separatory funnel containing water (25 mL) and saturated aq. NH4Cl (25 mL), and extracted with ethyl acetate (2×50 mL). The organic extracts were washed with saturated aq. brine, dried (sodium sulfate), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with 70:30 v/v hexanes/ethyl acetate, gave 363 mg of the title compound as an amber liquid. For the title compound:
Reaction SMILES: [CH:1]1([CH2:7][C@H:8](NC(=O)OC(C)(C)C)[CH2:9]NCC)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[N:31]1[C:36](=[O:37])C[CH2:34][C:32]1=O)(OCC[Si](C)(C)C)=O.C1C[O:41]CC1>>[CH:1]1([CH2:7][CH2:8][CH2:9][O:41][C:36](=[O:37])[NH:31][CH2:32][CH3:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: C1CCOC1
Reactant: CCNC[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Product: CCNC(=O)OCCCC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a solution of (S)-tert-butyl 1-cyclohexyl-3-(ethylamino)propan-2-ylcarbamate (338 mg) and TeocOSu (386 mg, 1.49 mmol) in THF was added TEA (0.6 mL). The resulting solution was stirred at rt for 30 min and evaporated. The residue was purified through chromatography on silica gel to give (S)-2-(trimethylsilyl)ethyl 2-(N-tert-butoxycarbonyl)amino)-3-cyclohexylpropyl-(ethyl)carbamate (287 mg, 45% over 2 steps).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[N:11]O)[S:5][C:6]=1[N+:7]([O-:9])=[O:8].C(OC(=O)C)(=O)C>CCCCCCC.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:10]#[N:11])[S:5][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1sc(C=NO)cc1Br
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cc(Br)c([N+](=O)[O-])s1
Reaction time: 2 h
Yield: 85.5 %

Procedure:
A 5-L, three neck, round bottom flask equipped with a temperature probe, mechanical stirrer, and a reflux condenser was charged with 4-Bromo-5-nitro-thiophene-2-carbaldehyde oxime (Example 25: step c; 441.0 g, 1.76 mol). Acetic anhydride (2.5 L) was added causing an endothermic reaction from 22° C. to 17° C. The resulting yellow slurry was heated to reflux. At 100° C. the reaction became a black solution. After 2 hours at 130° C., TLC analysis (2:1 heptane/EtOAc) showed reaction completion and the heat was removed. The mixture was transferred to a rotary evaporator and concentrated to dryness. The residue was diluted with CH2Cl2 (3 L), and H2O (3 L). The layers were separated and the organic layer was washed with H2O (3 L), dried over MgSO4, and concentrated to give the desired title compound as a tan solid (350.85 g, 86%). 1H-NMR (DMSO): δ 8.3 (1H, s).
Reaction SMILES: C(N)(=N)[C:2]1C=C[N:5]=[CH:4][CH:3]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([NH2:18])=[NH:17]>>[NH2:5][C:4]1[CH:3]=[CH:2][N:18]=[C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=2)[N:17]=1
Reactant: N=C(N)c1ccncc1
Reactant: N=C(N)c1ccccn1
Product: Nc1ccnc(-c2ccccn2)n1

Procedure:
Following the procedure described in Example A-1 but using in place of isonicotinamidine a molar equivalent quantity of the appropriate pyridine carboxamidine, i.e., Q-C(=NH)NH2, the 4-amino-2-Q-pyrimidines of Examples A-10 through A-13 are obtained:
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH2:9][CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[ClH:21].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:18][CH:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][C:6]3[C:5]4[CH:19]=[CH:20][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)[CH2:17][CH2:16]2)=[CH:24][CH:23]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: OC1CCN(CCCc2noc3cc(F)ccc23)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: Cl
Product: Fc1ccc2c(CCCN3CCC(Oc4ccc(Cl)cc4)CC3)noc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
To a solution of 9.5 g of 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)-propyl]-4-hydroxypiperidine, 4.5 g of 4-chlorophenol and 9.8 g triphenylphosphine in 250 ml of benzene, cooled with an ice-bath, was slowly added over one hour a solution of 6.4 g of diethyl azodicarboxylate in 60 ml of benzene. After stirring one hr at ambient temperature, the reaction mixture was filtered and then concentrated to an oil. The oil was treated with ethereal hydrogen chloride to give 4.6 g (32%) of product, mp 209°-211° C. Recrystallization from ethyl acetate/methanol gave the analytical sample, mp 212°-213° C. (dec).
Reaction SMILES: [O:1]=[V:2].Cl.Cl.Cl.[C:6]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:11]=[CH:10][C:9]([Si:12]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[OH:13])=[CH:8][CH:7]=1>>[O-2:13].[C:17]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:14]([Si:12]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)([C:9]2[CH:10]=[CH:11][C:6]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:7][CH:8]=2)[O:13][V+2:2]([O:13][Si:12]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)([C:9]2[CH:10]=[CH:11][C:6]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:7][CH:8]=2)[C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)[O:1][Si:12]([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:30][CH:31]=2)([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:9]2[CH:10]=[CH:11][C:6]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:7][CH:8]=2)=[CH:19][CH:18]=1
Reactant: O[Si](c1ccc(-c2ccccc2)cc1)(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Reactant: O=[V]
Agent: Cl
Product: [O-2]
Product: c1ccc(-c2ccc([Si](O[V+2](O[Si](c3ccc(-c4ccccc4)cc3)(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccccc4)cc3)O[Si](c3ccc(-c4ccccc4)cc3)(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccccc4)cc3)(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccccc4)cc3)cc2)cc1

Procedure:
vanadium oxytrichloride is reacted with tri-(p-chlorophenyl)-silanol [m.p. 127°-128°C] to produce tris-[tri-(p-chlorophenyl)-siloxy]vanadium oxide [m.p. 181°C.]; vanadium oxytrichloride is reacted with tri-(p-bromophenyl)-silanol [m.p. 120°-121°C.] to produce the tris-[tri-(p-bromophenyl)-silox]-vanadium oxide [m.p. 175°C.]; and vanadium oxytrichloride is reacted with tri-4-biphenylyl-silanol [m.p. 199°-200°C.] to produce tris-[tri-(4-biphenylyl)-siloxy]-vanadium oxide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]([NH:8][C:9]1[C:10]([CH2:18][CH2:19][CH3:20])=[N:11][N:12]([CH3:17])[C:13]=1[C:14]([NH2:16])=[O:15])=O)[CH3:2].[OH-].[Na+].OO.C(O)C>O>[CH2:1]([O:3][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]1[NH:16][C:14](=[O:15])[C:13]2[N:12]([CH3:17])[N:11]=[C:10]([CH2:18][CH2:19][CH3:20])[C:9]=2[N:8]=1)[CH3:2]
Reactant: CCCc1nn(C)c(C(N)=O)c1NC(=O)c1ccccc1OCC
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3ccccc3OCC)nc12

Procedure:
4-(2-Ethoxybenzamido)-1-methyl-3-n-propylpyrazole-5-carboxamide (223 g, 0.676 mol) was added portionwise to a solution of sodium hydroxide (54 g, 1.35 mol) and 30% hydrogen peroxide solution (224 ml) in water (2000 ml). Ethanol (700 ml) was added and the resulting mixture heated under reflux for 2.5 hours, cooled, then evaporated under vacuum. The resulting solid was treated with 2N hydrochloric acid (380 ml), with external cooling, and the mixture was extracted with dichloromethane (1×700 ml, 3×200 ml). The combined organic extracts were washed successively with saturated aqueous sodium carbonate solution (3×400 ml) and brine (300 ml), then dried (Na2SO4) and evaporated under vacuum.
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([O:27][CH2:28][CH2:29][O:30][C:31](=[O:48])[CH2:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N:41]([CH2:45][CH2:46][Cl:47])[CH2:42][CH2:43][Cl:44])=[CH:37][CH:36]=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)C1C=CC=CC=1>[Pd].O1CCOCC1>[OH:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([O:27][CH2:28][CH2:29][O:30][C:31](=[O:48])[CH2:32][CH2:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([N:41]([CH2:42][CH2:43][Cl:44])[CH2:45][CH2:46][Cl:47])=[CH:39][CH:40]=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2OCCOC(=O)CCCc1ccc(N(CCCl)CCCl)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2OCCOC(=O)CCCc1ccc(N(CCCl)CCCl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10% palladium on carbon (320.7 mg) was placed into an eggplant type flask (100 ml), followed by dropwise addition of 1,4-dioxane (15 ml) at 0° C. To this mixture was added a 1,4-dioxane (15 ml) solution of 1-[3-benzyloxy-1,3,5(10)-estratriene-17β-oxy]-2-[4-[p-[bis(2-chloroethyl)amino]phenyl]-butyryloxy]ethane (I-5) dropwise at 0° C. The mixture was heated to room temperature and stirred under hydrogen gas for one hour. The reaction mixture was filtered through filter paper while washing with 1,4-dioxane, and the filtrate was concentrated under reduced pressure to produce an oily substance (0.27 g). It was purified by silica gel chromatography (hexane/ethyl acetate=3:1) to obtain 1-[3-hydroxy-1,3,5(10)-estratriene-17β-oxy]-2-[4-[p-[bis(2-chloroethyl)amino]phenyl]butyryloxy]ethane (0.26 g) (Rf: 0.25, hexane/ethyl acetate=3:1) as oily substance.