Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[O:5][C:6]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=O)[CH2:21][CH3:22])=[CH:15][C:7]=2[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:3])=[O:2].B#B.Cl>O1CCCC1>[N+:1]([C:4]1[O:5][C:6]2[CH:18]=[CH:17][C:16]([NH:19][CH2:20][CH2:21][CH3:22])=[CH:15][C:7]=2[C:8]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: CCC(=O)Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Product: CCCNc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1

Procedure:
To a solution of 1.8 g. of 2-nitro-3-phenyl-5-propionamidobenzofuran in 50 ml. of tetrahydrofuran is added 10 ml. of 1 N diborane, and the solution is stirred for about 18 hours under a nitrogen atmosphere. To this mixture is cautiously added 5 ml. of 6 N hydrochloric acid. The mixture is heated to its reflux temperature and maintained at reflux for about 30 minutes. The solution is evaporated to provide a residue which is partitioned between cold sodium bicarbonate solution and chloroform. The chloroform extracts are dried, then evaporated to provide a red residue which is recrystallized from aqueous ethanol to provide red crystals of 2-nitro-3-phenyl-5-(n-propyl)aminobenzofuran, m.p. 158°-160° C.
Reaction SMILES: C([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[C:17]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=4)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:30]>C(O)C.[Pd]>[ClH:30].[F:29][C:24]1[CH:23]=[C:22]([C:17]2[C:18]3[C:19]4[CH2:20][CH2:21][NH:8][CH2:9][CH2:10][C:11]=4[NH:12][C:13]=3[CH:14]=[CH:15][CH:16]=2)[CH:27]=[C:26]([F:28])[CH:25]=1
Reactant: Fc1cc(F)cc(-c2cccc3[nH]c4c(c23)CCN(Cc2ccccc2)CC4)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Fc1cc(F)cc(-c2cccc3[nH]c4c(c23)CCNCC4)c1
Yield: 46.5 %

Procedure:
A mixture of 3-benzyl-10-(3,5-difluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.35 g, 0.90 mmol), 1 N hydrochloric acid (0.9 mL, 0.9 mmol) and Pd/C (10%, 0.5 g) in ethanol (50 mL) was reacted in a manner similar to Example 8 to give 0.14 g of the title compound as a cream-colored solid: mp>267° C. (dec.); 1H NMR (400 MHz, DMSO-d6) δ 11.42, 9.57, 7.37, 7.30-7.25, 7.11-7.07, 6.84, 6.78-6.76, 3.35-3.27, 3.25-3.18, 3.16-3.08, 2.63-2.56; IR (drift) 3259, 2956, 2861, 2811, 2778, 2699, 2641, 2455, 1622, 1591, 1458, 1332, 1113, 985, 749 cm−1; HRMS (FAB) calcd for C18H16F2N2+H: 299.1360, found: 299.1369.
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[S:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH:34]=[C:33]1[C:41]([OH:43])=O.Cl.[NH2:45][C@@H:46]([C:48]1[S:52][C:51]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[CH:50][CH:49]=1)[CH3:47]>O.C(Cl)Cl>[S:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH:34]=[C:33]1[C:41]([NH:45][C@@H:46]([C:48]1[S:52][C:51]([C:53]([O:55][C:56]([CH3:57])([CH3:59])[CH3:58])=[O:54])=[CH:50][CH:49]=1)[CH3:47])=[O:43]
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: C[C@@H](N)c1ccc(C(=O)OC(C)(C)C)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H](NC(=O)c1cc2ccccc2s1)c1ccc(C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 2-dram vial was added triethylamine (0.156 mL, 1.12 mmol), HATU (0.106 g, 0.28 mmol), 1-benzothiophene-2-carboxylic acid (0.050 g, 0.28 mmol), and DCM (3 mL). The solution was stirred at rt for 30 min, then transferred to another 2-dram vial containing solid (R)-tert-butyl 5-(1-aminoethyl)thiophene-2-carboxylate hydrochloride. The mixture was stirred at rt for 16 h. To the reaction was then added DCM (3 mL) and water (1 mL). After separation, the aqueous layer was extracted with DCM (2×3 mL). The combined organic phases were evaporated to dryness to give (R)-tert-butyl 5-(1-(benzothiophene-2-carboxamido)ethyl)thiophene-2-carboxylate as a brown solid. LC-MS: (FA) ES+ 388.
Reaction SMILES: N1CCCCC1.[Br:7][CH:8]([C:14](Br)([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[CH2:15][F:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10].O>CCOCC>[Br:7][C:8](=[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[CH2:15][F:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(Br)C(Br)(CF)c1cccc(OC)c1
Solvent: C1CCNCC1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(Br)=C(CF)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102 %

Procedure:
Piperidine (0.22 ml) is added to a solution of ethyl 2,3-dibromo-3-(3'-methoxyphenyl)-4-fluorobutyrate (0.80 g) in ether (10 ml). The reaction mixture is stirred at room temperature for 3 hours and water is added. Ether extraction gives essentially pure ethyl 2-bromo-3-(3'-methoxyphenyl)-4-fluoro-2-butenoate (0.65 g).
Reaction SMILES: [Mg].F[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1Br.[CH:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[C:11]12[CH2:10][C:14](=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]2=1
Reactant: Fc1ccccc1Br
Reactant: C1=CCC=C1
Agent: [Mg]
Solvent: C1CCOC1
Product: C1=C2CC(=C1)c1ccccc12
Reaction time: 1 h
Yield: 40 %

Procedure:
10 g of magnesium turnings which are covered with approximately 75 cm3 of anhydrous tetrahydrofuran are placed in a round flask fitted with a condenser, a thermometer, a nitrogen inlet, a dropping funnel, and protected from atmospheric moisture by a calcium chloride tube. 25 cm3 of a solution, prepared beforehand, of 65 g of ortho-fluorobromobenzene and 26 g of cyclopentadiene in 200 cm3 of anhydrous tetrahydrofuran are then added. The formation of the organomagnesium compound is initiated by heating the reaction mixture locally with a hairdryer, and the solvent is then kept at boiling point by dropwise addition of the remaining solution. The whole addition is completed in approximately 1 hour. The mixture is then filtered at ambient temperature and the solution is concentrated under reduced pressure. The solution is taken up again in ether and the ether phase is washed with ammonium chloride, separated by gravity and dried over magnesium sulphate; the solvent is then removed by evaporation under vacuum. The residue is then distilled and benzonorbornadiene, whose boiling point is 82°-83° C. at a pressure of 16 millibars, is obtained in a yield of 40%.
Reaction SMILES: [Na].[OH:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13].Cl.[CH3:15][C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH2:21]Cl>C(O)C>[CH3:15][C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH2:21][O:2][N:3]1[C:4](=[O:13])[C:5]2=[CH:12][CH:11]=[CH:10][CH:9]=[C:6]2[C:7]1=[O:8]
Reactant: Cc1[nH]cnc1CCl
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1[nH]cnc1CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 48.7 %

Procedure:
A mixture of 1 g of sodium and 80 ml of ethanol was cooled in an ice-bath and 7.12 g of N-hydroxyphthalimide was added thereto and the mixture was stirred at room temperature. The mixture was cooled in an ice-bath and 3.16 g of 5-methyl-4-chloromethylimidazole hydrochloride was added thereto. The resulting mixture was stirred for 2 hours. The solvent was distilled off and SSB was added to the residue and the mixture was extracted with chloroform. The extract was washed with SSC and dried with sodium sulfate and concentrated to dryness. The residue was washed with ether to give 2.37 g of N-((5-methylimidazole-4-yl)methoxy)phthalimide with mp 155°-156° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[C:8]1=[O:28].[CH2:36]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[N:50]1[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[CH3:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:53]2[CH2:54][CH2:55][CH2:56][N:50]([C:42]3[N:41]([CH2:40][CH2:39][O:38][CH2:36][CH3:37])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:51][CH2:52]2)([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:8]1=[O:28]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1ccc(CC2(CCOS(C)(=O)=O)CCN(Cc3cc(OC)c(OC)c(OC)c3)C2=O)cc1
Product: CCOCCn1c(N2CCCN(CCC3(Cc4ccc(OC)cc4)CCN(Cc4cc(OC)c(OC)c(OC)c4)C3=O)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzyl)-3-(4-methoxyphenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give the title compound.
Reaction SMILES: [Br:1]C1N=C(N)C([N+]([O-])=O)=CC=1.C[O:13][C:14]1[N:19]=[C:18]([NH2:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][CH:15]=1>Br.C(O)(=O)C>[BrH:1].[NH2:20][C:18]1[N:19]=[C:14]([OH:13])[CH:15]=[CH:16][C:17]=1[N+:21]([O-:23])=[O:22]
Reactant: COc1ccc([N+](=O)[O-])c(N)n1
Reactant: Nc1nc(Br)ccc1[N+](=O)[O-]
Agent: Br
Solvent: CC(=O)O
Product: Nc1nc(O)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 95 %

Procedure:
6-Bromo-3-nitro-pyridin-2-ylamine. To a glass pressure vessel containing 6-methoxy-3-nitro-pyridin-2-ylamine (5.0 g, 29.5 mmol) was added 30% hydrogen bromide/acetic acid (60 mL). The vessel was sealed, and the contents were heated to 60° C. for 24 h. The reaction mixture was cooled, and the solvent was removed in vacuo giving 6.8 g (>95%) of crude 6-amino-5-nitro-pyridin-2-ol hydrobromide (HPLC: Rt=5.46). This material (2.0 g, 8.5 mmol) was taken up in toluene (30 mL), followed by phosphorus pentoxide (2.4 g, 17.0 mmol) and tetrabutyl ammonium bromide (3.2 g, 9.7 mmol). The mixture was heated to reflux for 4 h. The reaction mixture was cooled to 0° C., diluted with saturated NaHCO3, and extracted with ethyl acetate (3×100 mL). The combined organics were washed with water (100 mL) and dried (Na2SO4) to afford 1.18 g (64%) of 6-bromo-3-nitro-pyridin-2-ylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH2:8][CH:9]=O)[CH:7]=1.[CH3:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[N:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH2:8][CH2:9][N:26]2[CH2:27][CH2:28][N:23]([C:19]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:20]=3[CH:21]=[CH:22][C:13]([CH3:12])=[N:14]4)[CH2:24][CH2:25]2)[CH:7]=1
Reactant: Cc1ccc2c(N3CCNCC3)cccc2n1
Reactant: O=CCc1cc(Br)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1ccc2c(N3CCN(CCc4cc(Br)ccc4F)CC3)cccc2n1
Yield: 95 %

Procedure:
The title compound was prepared in 95% yield from (5-bromo-2-fluorophenyl)acetaldehyde (0.98 g), 2-methyl-5-(1-piperazinyl)quinoline (0.51 g) and sodium triacetoxyborohydride (0.95 g) according to the procedure described for Example 131.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>C(N(CC)CC)C.[Cu]I.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>[CH2:12]([O:11][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccc(C2(OCc3ccccc3)CC2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(C2(OCc3ccccc3)CC2)cc1
Temperature: 70 °C
Yield: 88.3 %

Procedure:
Using General Procedure D; 1-bromo-4-(1-benzyloxycyclopropyl)-benzene (Intermediate 69, 160.0 mg, 0.53 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (10.0 mg, 0.05 mmol) and then sparged with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (37.0 mg, 0.05 mmol). The resulting reaction mixture was heated to 70° C. for 5 d. The title compound (150.0 mg, 83%) was isolated by chromatography (0-3% EtOAc-hexanes) as a pale-yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4](Cl)=[O:5].[NH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1.Cl.[Al+3].[Cl-].[Cl-].[Cl-].[Na+].[Cl-]>CC(C)=O.O>[CH2:2]1[C:15]2[C:16]3=[C:11]([CH2:10][CH2:9][CH2:8][N:7]3[C:4](=[O:5])[CH2:3]1)[CH:12]=[CH:13][CH:14]=2
Reactant: O=C(Cl)CCCl
Reactant: c1ccc2c(c1)CCCN2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCc2cccc3c2N1CCC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
A solution of 3-chloropropanoyl chloride (9.1 ml, 95.0 mmol) in 20 ml dry acetone was added dropwise to a solution of 1,2,3,4-tetrahydroquinoline (26.6 g, 0.20 mol) in 80 ml dry acetone and the mixture was refluxed for 1 h. After cooling to ambient temperature the solution was poured into 500 ml stirred 2N HCl and extracted with ethyl acetate (3×150 ml). After washing with 1N HCl and brine and drying over MgSO4 the solvent was removed under reduced pressure and the crude product was obtained as a pale yellow solid. This was added portionwise to a molten mixture of AlCl3 (60.0 g, 0.45 mol) and NaCl (17.5 g, 300 mmol) at 150° C. and stirred for additional 30 minutes. On cooling, excess aluminum chloride was decomposed by the addition of a chilled mixture of 20 ml concentrated hydrochloric acid and 500 ml water. Extraction with ethyl acetate (3×200 ml), followed by drying over MgSO4 and removal of the solvent gave 1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]quinolin-3-one (15.6 g, 83.3 mmol, 88%) as a yellow solid.
Reaction SMILES: C(=O)(OCC)[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Br:22])[CH:20]=3)[NH:15][C:14](=[O:23])[C@@H:13]2[CH2:24][CH3:25])(=[O:11])=[O:10])=[CH:5][CH:4]=1.IC.[CH2:32]([C@@H]1N(S(C2C=CC(O)=CC=2)(=O)=O)C2C(=CC=C(F)C=2)N(CCC)C1=O)C>>[Br:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:32])[C:14](=[O:23])[C@H:13]([CH2:24][CH3:25])[N:12]2[S:9]([C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=1)(=[O:10])=[O:11]
Reactant: CCCN1C(=O)[C@H](CC)N(S(=O)(=O)c2ccc(O)cc2)c2cc(F)ccc21
Reactant: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3cc(Br)ccc3NC(=O)[C@@H]2CC)cc1
Solvent: CI
Product: CC[C@H]1C(=O)N(C)c2ccc(Br)cc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
4-{[(2S)-7-Bromo-2-ethyl-3-oxo-3,4-dihydroquinoxalin-1 (2H)-yl]sulfonyl}phenyl ethyl carbonate (see Example 33) was treated with iodomethane according to the procedure for the preparation of (3S)-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-1-propyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 20) to yield (3S)-6-bromo-3-ethyl-4-[(4-hydroxyphenyl)sulfonyl]-1-methyl-3,4-dihydroquinoxalin-2(1H)-one. MS (ESI) m/z 425/427 ([M+H]+); MS (ESI) m/z 423/425 ([M−H]−); Anal. Calcd for C17H17BrN2O4S: C, 48.01; H, 4.03; N, 6.59. Found: C, 48.07; H, 4.27; N, 6.37.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[CH2:16][N:15]([C:17](=[O:26])[C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=3)[CH2:14][CH2:13][N:12]2[C:27](=[O:36])[CH2:28][NH:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:7]=[CH:8][C:9]=1[Cl:10].CCN(C(C)C)C(C)C.[C:46](O)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[C:46]([N:33]1[CH2:32][CH2:31][CH:30]([NH:29][CH2:28][C:27]([N:12]2[CH2:13][CH2:14][N:15]([C:17](=[O:26])[C:18]3[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH3:24])[CH:23]=3)[CH2:16][CH:11]2[C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=2)=[O:36])[CH2:35][CH2:34]1)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1cc(C)cc(C(=O)N2CCN(C(=O)CNC3CCNCC3)C(c3ccc(Cl)c(Cl)c3)C2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)cc(C(=O)N2CCN(C(=O)CNC3CCN(C(=O)c4ccccc4)CC3)C(c3ccc(Cl)c(Cl)c3)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a solution of compound obtained from Example 9 (0.23 g, 0.4 10 mmol) in CH2Cl2 (5 mL) was added Hunig's base (0.13 g, 1.0 mmol). This was followed by the addition of benzoic acid (49 mg, 0.4 mmol), HOBT (54 mg, 0.4 mmol), Et3N (40 mg, 0.4 mmol) and DEC (77 mg, 0.4 mmol) at 0° C. The solution was gradually warmed to RT and stirred overnight. After reaction was complete, the solution was diluted with CH2Cl2 (50 mL) and washed with saturated NaHCO3 solution (30 mL, 2×) and brine (20 mL, 3×). The organic layer was dried over MgSO4, filtered and concentrated to give crude material as an oil. The product was purified by chromatography on flash grade silica gel (50 g), eluting with 5% [NH4OH/MeOH (1:9)]/CH2Cl2 to give the title compound as a white solid (0.18 g), m.p. 94°-96° C.; FAB MS [M+1]+ 35 Cl 607.3.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#[N:13])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=O)C.CN(C)C=O.[BH4-].[Na+].BrC1[CH:30]=[CH:29][CH:28]=[CH:27]N=1>O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:30]=[CH:29][CH:28]=[CH:27][N:13]=2)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: Brc1ccccn1
Reactant: CC(=O)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2ccccn2)cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A solution of 5.85 g. of 1-acetamido-2-nitro-4-thiocyanatobenzene in 20 ml. dimethylformamide is cooled, under nitrogen, to about 0°C. and 1.14 g. of sodium borohydride is added. The exothermic reaction is controlled to less than about 30°C., then the mixture is stirred for 1 hour at 20°-30°C. 6 Ml. of 2-bromopyridine is added and the mixture warmed slowly to about 110°C. and kept at that temperature for 1 hour. The mixture is cooled, diluted with water, and filtered. The crude product is recrystallized from aqueous methanol, yielding 1-amino-2-nitro-4-(pyrid-2-ylthio)benzene.
Reaction SMILES: C1N2CN3CN(C2)C[N:2]1C3.N.Cl[CH2:13][C:14]([N:16]([C:18]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:19]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O)[CH3:17])=[O:15]>C(O)C>[Cl:32][C:29]1[CH:30]=[CH:31][C:18]2[N:16]([CH3:17])[C:14](=[O:15])[CH2:13][N:2]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]=2[CH:28]=1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: CN(C(=O)CCl)c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: N
Solvent: CCO
Product: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of ethanol (600 ml) and hexamethylenetetramine (39.1 g., 0.279 mol) was stirred and saturated with ammonia. With ammonia bubbling into the mixture it was slowly heated to reflux. Over a period of 41/2 hours, 2-(2-chloro-N-methylacetamido)-5-chlorobenzophenone (40 g., 0.124 mol) was added in increments yielding ##STR6## which was not isolated. Refluxing was continued for 2 hours longer. The reaction mixture was then distilled to dryness in vacuo at 50° C. The residue was stirred with toluene (250 ml), heated to reflux and heated with two increments of para-toluene sulfonic acid. Reflux was continued for one hour. After cooling to 70° C., the toluene was washed with hot water to remove soluble salts and distilled to dryness in vacuo. The residue was dissolved in hot ethanol (111 mol) and the solution cooled at -10° C. for one hour. The crystalline 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one obtained was isolated and weighed 29 g., melting point 129° to 131° C. Concentration of the mother liquor by ca. 50% gave a second crop weighing 2.0 g. melting at 127° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([N:13]1[C:18](=[O:19])[CH:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16](=O)[NH:15][C:14]1=[O:28])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[Cl:3][C:16]1[NH:15][C:14](=[O:28])[N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:18](=[O:19])[C:17]=1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1NC(=O)N(Cc2ccccc2)C(=O)C1Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: O=c1[nH]c(Cl)c(Cc2ccccc2)c(=O)n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To 16.8 ml of 50% ethanol, 78.7 ml (844 mmol) of phosphorus oxychloride was added drop by drop, with stirring under ice cooling conditions. To this solution, 30.83 g (100 mmol) of 3,5-dibenzylpyrimidine-2,4,6(1H,3H)-trione was added little by little. This mixture was stirred at 50° C. for 30 minutes and then at 100° C. for 90 minutes. After cooling, the reaction mixture was poured into ice water and stirred for 1 hour. The resulting precipitate was collected by filtration, washed with water and n-hexane and dried to yield 32.62 g (99.8%, light white crystal) of the desired product.
Reaction SMILES: [OH:1][N:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][C:5](=NO)[CH2:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CS(O)(=O)=O>O1CCCC1>[OH:1][N:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][C:5]([O:28][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([O:28][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCCCCO
Reactant: ON=C1CC(c2ccccc2)N(O)C(c2ccccc2)C1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: CCCCCCOC1(OCCCCCC)CC(c2ccccc2)N(O)C(c2ccccc2)C1
Yield: 20.2 %

Procedure:
A solution of 10.0 g (0.035 mole) 1-hydroxy-2,6-diphenyl-4-piperidone oxime, 22.0 g (0.22 moles) 1-hexanol and 7.0 g (0.073 moles) methanesulfonic acid in 250 mL tetrahydrofuran is heated at 60° C. for 12 hours. The solution is then washed three times with 10% aqueous sodium carbonate solution. The organic phase is dried over anhydrous sodium sulfate and concentrated. 3.2 g (20% yield) of the title compound is isolated as a clear oil after purification by LC (silica gel, ethyl acetate:hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[Br:19]Br>C(Cl)(Cl)Cl>[Br:19][CH:10]1[C:9](=[O:14])[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:15]([F:16])([F:17])[F:18])[CH:4]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: BrBr
Reactant: O=C1CCCCC1c1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClC(Cl)Cl
Product: O=C1C(Br)CCCC1c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
2-(4-Chloro-3-trifluoromethyl-phenyl)-cyclohexanone (50 mg, 0.18 mmol) was dissolved in chloroform (1 mL). To this solution bromine (30.3 mg, 0.19 mmol) in chloroform (0.5 mL) was added drop wise at room temperature. The reaction was stirred for 1½ hours at room temperature. The solvent was removed under reduced pressure to yield the crude title compound (53 mg) which was used directly in the next step without further purification.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.CC([O-])=O.[Na+].[CH:26]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)=[CH2:27].C(OCC)(=O)C>[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:31]1[CH:32]=[CH:33][C:28](/[CH:26]=[CH:27]/[C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=3)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=2)=[CH:29][CH:30]=1
Reactant: C=Cc1ccncc1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(C=O)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2cc(C=O)ccc21
Temperature: 100 °C
Yield: 51.5 %

Procedure:
To a suspension of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-carbaldehyde (87 mg, 0.22 mmol), NaOAc (36 mg, 0.44 mmol), nBu4NCl (61 mg, 0.44 mmol), and Pd(OAc)2 (8.0 mg, 0.036 mmol) in DMF (2 mL) under argon was added 4-vinylpyridine (0.05 mL, 0.46 mmol). The resulting mixture was heated in a sealed vial at 100° C. for 14 hours. Ethyl acetate (200 mL) was added and the solution was washed with water (20 mL) and brine (3×20 mL), dried over Na2SO4 and concentrated. The residue was chromatographed (5 g silica SPE tube, Silicycle, 1-2% MeOH in CH2Cl2, repeated for mixed fractions) gave the title compound as a yellow solid (43 mg, 52%). 1H NMR (400 MHz, CDCl3 plus a drop of CD3OD) δ 10.07 (s, 1H), 8.52 (m, 3H), 7.97 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.8 Hz, 1H); 7.60 (d, J=16.4 Hz, 1H); 7.48 (m, 3H); 5.73 (s, 2H), 3.56 (m, 2H), 0.86 (m, 2H), −0.12 (s, 9H).