Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 89.6 %

Procedure:
To a solution of 3,5-dichlorobenzoic acid (50 g, 0.26 mol) in sulfuric acid (250 mL) at 0° C. was added nitric acid (18 g, 0.28 mol) dropwise, and the mixture warmed slowly to ambient temperature. After 5 hours the mixture was poured onto ice, and the white precipitate collected by filtration. The solid was washed with water (3×30 mL), and dried in vacuo to afford 55 g (90% yield) of 3,5-dichloro-2-nitrobenzoic acid; NMR (CDCl3) 8.3 (s, 1), 8.0 (s, 1) ppm.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4](C)[C:5](=O)OC(C)(C)C.N1C=CC=CC=1.[C:19]([Cl:26])(=[O:25])[O:20][CH2:21][CH2:22][O:23][CH3:24]>C(OCC)(=O)C>[ClH:26].[C:19](=[O:25])([O:1][CH2:2][CH2:3][NH:4][CH3:5])[O:20][CH2:21][CH2:22][O:23][CH3:24]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: COCCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CNCCOC(=O)OCCOC
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Synthetic Example 1 and ethyl acetate (20 mL) was added pyridine (1.62 mL), and a solution of 2-methoxyethyl chlorocarbonate (2.77 mL) in ethyl acetate (5 mL) was slowly added dropwise, followed by stirring at room temperature overnight. The reaction solution was concentrated under reduced pressure, and extracted with ethyl acetate (50 mL). The extract was washed with 5% aqueous solution of citric acid (50 mL), and saturated saline (50 mL), and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was dissolved in diethyl ether (2 mL), and added 4N hydrogen chloride-ethyl acetate solution (5 mL). After stirring at room temperature for 30 minutes, diethyl ether (10 mL) was added, and stirred overnight. The depositting solid was collected by filtration, and dried under reduced pressure to give title compound as white solid (1.56 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O.C(Cl)Cl>CN(C)C=O>[CH2:22]([N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:10])[C@H:12]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:13]([NH2:15])=[O:14])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NC(=O)[C@H](NS(=O)(=O)c1ccc(Cl)cc1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: NC(=O)[C@@H](c1ccccc1)N(Cc1ccccc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 50 °C

Procedure:
To a solution of (R)-2-(4-chloro-benzenesulfonylamino)-2-phenyl-acetamide (350 mg, 1.1 mmol) in 4 mL of dimethylformamide are added benzylbromide (0.18 mL, 1.1 mmol) and potassium carbonate (179 mg, 1.3 mmol). The reaction is heated overnight at 50° C., poured into water/methylene chloride and extracted with methylene chloride. The combined organics are dried with sodium sulfate, concentrated in vacuo, and the resultant residue purified on silica gel chromatography to provide the title compound. C13 NMR (100 MHz, CDCl3) 50.3, 64.8, 127.6, 128.4, 128.6, 129.0, 129.1, 129.3, 129.4, 130.2, 133.9, 136.8, 138.6, 139.4, 171.7. MS 415.1 m/z (M+1).
Reaction SMILES: C([O:8][C:9]1[C@@H:14]([C@H:15]([CH2:17][OH:18])[OH:16])[O:13][C:11](=[O:12])[C:10]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[CH2:20]([O:19][C:10]1[C:11]([O:13][C@H:14]([C@H:15]([CH2:17][OH:18])[OH:16])[C:9]=1[OH:8])=[O:12])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCCCCOC1=C(OCc2ccccc2)[C@@H]([C@@H](O)CO)OC1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCOC1=C(O)[C@@H]([C@@H](O)CO)OC1=O
Yield: 86.4 %

Procedure:
3-O-Benzyl-2-O-octadecylascorbic acid (2.1 g) was dissolved in ethyl acetate (25 ml), and 5% Pd-C (0.5 g) was added to the solution to conduct catalytic reduction at atmospheric pressure. The catalyst was filtered out, and the filtrate was concentrated under reduced pressure. The reaction product was recrystallized from isopropyl ether-ethyl acetate to give 2-O-octadecylascorbic acid (1.5 g). m.p. 127°-128° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[Cl:21][C:22]1[C:23]([C:29](O)=[O:30])=[N:24][CH:25]=[C:26]([Cl:28])[CH:27]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:23]3[C:22]([Cl:21])=[CH:27][C:26]([Cl:28])=[CH:25][N:24]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Reactant: O=C(O)c1ncc(Cl)cc1Cl
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ncc(Cl)cc3Cl)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 3,5-dichloro-pyridine-2-carboxylic acid following procedure I yielded the 3,5-dichloro-pyridine-2-carboxylic acid [3-((R)-2-amino-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-amide which, after treatment with hydrochloric acid in dioxane (4N), evaporation and trituration with diethylether, gave the title compound as a white solid. MS (ISP): m/z=461.2 [M+H]+, 463.1 [M+2+H]+.
Reaction SMILES: [C:1](=[O:3])=[O:2].[N+]([O-])([O-])=[O:5].[Sr+2:8].[N+:9]([O-:12])([O-:11])=[O:10]>>[C:1](=[O:5])([O-:3])[O-:2].[Sr+2:8].[N+:9]([O-:12])([OH:11])=[O:10]
Reactant: O=C=O
Reactant: O=[N+]([O-])[O-]
Agent: [Sr+2]
Product: O=C([O-])[O-]
Product: O=[N+]([O-])O

Procedure:
In second reactor stage RB, carbon dioxide reacts with strontium nitrate, thereby precipitating strontium carbonate product and forming byproduct HNO3.
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[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:50]=[CH:49][C:39]([C:40]([NH:42][CH2:43][CH2:44][CH2:45][N:46]([CH3:48])[CH3:47])=[O:41])=[CH:38][CH:37]=1.[CH:51]([OH:54])(C)C>>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:35][C:36]4[CH:50]=[CH:49][C:39]([C:40]([NH:42][CH2:43][CH2:44][CH2:45][N:46]([CH3:47])[CH3:48])=[O:41])=[CH:38][C:37]=4[O:54][CH3:51])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN(C)CCCNC(=O)c1ccc(N)cc1
Reactant: CC(C)O
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Product: COc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
A mixture of 0.0562 g (0.18 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.0514 g (0.27 mmole) of toluenesulfonic acid monohydrate, 0.0398 g (0.18 mmole) of 4-amino-N-(3-dimethylamino-propyl)-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 20 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-methanol-triethylamine (80:20:2) to give 0.0645 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-3-methoxy-benzamide (I-254) as a white solid.
Reaction SMILES: CO[C:3]1[CH:19]=[C:18]2[C:10]([O:11][C:12](=[O:20])[C:13]3[CH:14]=[CH:15][O:16][C:17]=32)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2.[CH:21]1C2C(=CC=C3C=2OC(=O)C2C=COC3=2)C=CC=1.OC1C2C(=O)OC3C(=CC(OC)=C4C=3C=CC=C4)C=2OC1>>[CH3:21][C:14]1[C:13]2[C:12](=[O:20])[O:11][C:10]3[C:18](=[CH:19][CH:3]=[C:4]4[C:9]=3[CH:8]=[CH:7][CH:6]=[CH:5]4)[C:17]=2[O:16][CH:15]=1
Reactant: COc1cc2c3occc3c(=O)oc2c2ccccc12
Reactant: O=c1oc2c3ccccc3ccc2c2occc12
Agent: COc1cc2c3c(c(=O)oc2c2ccccc12)C(O)CO3
Product: Cc1coc2c1c(=O)oc1c3ccccc3ccc21

Procedure:
6-Methoxy-11,15-dioxa-cyclopenta[a]phenanthren-12-one (4e) The procedure was identical to that used for the preparation of 4a: 85% yield (starting with 12 mg 3e); mp 194-195° C.; LC/MSD-Trap-positive (m/z, %): 267 (M++1, 100), 289 (M++Na, 30); 1H NMR δ 4.11 (1H, s, OCH3-6), 7.07 (1H, d, J=2.1 Hz, H-17), 7.13 (1H, s, H-7), 7.68 (3H, m, H-2, 3, 16), 8.31 (1H, dd, J=1.8 Hz, 6.9 Hz, H-4), 8.57 (1H, dd, J=1.8 Hz, 7.8 Hz, H-1).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=O)[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)#[N:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:14].C1C=CC=CC=1>>[N:9]1[CH:10]=[CH:11][C:6]([C:5]2[S:14][C:1]([NH2:2])=[CH:3][N:4]=2)=[CH:7][CH:8]=1
Reactant: N#CCNC(=O)c1ccncc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccccc1
Product: Nc1cnc(-c2ccncc2)s1
Yield: 100.5 %

Procedure:
A mixture of N-(cyanomethyl)isonicotinamide (0.665 g, 4.1 mmol) and phosphorus pentasulfide (1.8 g, 8.3 mmol) in benzene (5.00 ml, 56 mmol) was allowed to refluxed for 24 hours. The mixture was concentrated and the residue was purified by CombiFlash using 0-10% methanol/DCM to give 730 mg of 2-(pyridin-4-yl)thiazol-5-amine 5.3C. 400 MHz 1H NMR (CD3OD) δ: 8.51 (d, J=8.0 Hz, 2H), 7.72 (d, J=8.0 Hz, 2H), 7.07 (s, 1H). LCMS (ES+) m/z 178.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([Cl:6])=[O:5].Cl.[C:8]([N:11]1[C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[S:13][CH:12]1[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[O:29][CH2:30][CH2:31][CH2:32][N:33]([CH2:37][CH2:38][OH:39])[CH:34]([CH3:36])[CH3:35])(=[O:10])[CH3:9].C(N(CC)CC)C.O>C(Cl)Cl>[ClH:6].[C:8]([N:11]1[C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[S:13][CH:12]1[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[O:29][CH2:30][CH2:31][CH2:32][N:33]([CH:34]([CH3:35])[CH3:36])[CH2:37][CH2:38][O:39][C:4](=[O:5])[CH2:3][O:2][CH3:1])(=[O:10])[CH3:9]
Reactant: COc1ccc(OCCCN(CCO)C(C)C)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COCC(=O)OCCN(CCCOc1ccc(OC)cc1C1Sc2cc(Cl)ccc2N1C(C)=O)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methoxyacetyl chloride (0.08 ml, 0.87 mmol) was added to a solution of 3-acetyl-6-chloro-2-[2-(3-(N-(2-hydroxyethyl)-N-isopropylamino)propoxy)-5-methoxyphenyl]benzothiazoline hydrochloride (300 mg, 0.58 mmol) in triethylamine (0.41 ml, 2.90 mmol) and methylene chloride (1.0 ml) under ice-cooling. The mixture was stirred at room temperature for two hours, then water (50 ml) was added to the reaction mixture, and the whole was extracted with ethyl acetate (50 ml). The ethyl acetate layer was washed with saturated brine (50 ml) and dehydrated with anhydrous magnesium sulfate. Ethyl acetate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol=50/1). The obtained oily matter was dissolved in ethyl acetate (1 ml), and then a 4 N solution (0.2 ml) of hydrogen chloride in ethyl acetate was added thereto under ice-cooling. The mixture was concentrated under reduced pressure to give 340 mg (quantitatively) of the target compound.
Reaction SMILES: [OH-].[Na+].O.Cl.[CH2:5]([NH2:7])[CH3:6].[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13]>CO>[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:7][CH2:5][CH3:6])=[O:13]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCNC(=O)c1cccc(Br)c1
Reaction time: 0.08 h
Yield: 95.2 %

Procedure:
To a solution of sodium hydroxide (3.80 g) in methanol (50 ml)—water (15 ml) was added by portions ethylamine hydrochloride (7.80 g) at 0° C. and the mixture was stirred for 5 min. 3-Bromobenzoyl chloride (5.53 g) was added dropwise and the mixture was stirrd at room temperature for 1 h. Methanol was evaporated under reduced pressure, and ethyl acetate was added to the residue for partitioning. The organic layer was washed with water and brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound (5.47 g) as colorless powder crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[C:31]([C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32].CCN(C(C)C)C(C)C>C1COCC1>[C:31]([C:35]1[CH:36]=[CH:37][C:38]([NH:39][C:24]([C:16]2[C:17]3[O:21][C:20]([CH3:22])([CH3:23])[CH2:19][C:18]=3[C:12]3[NH:11][C:10]([NH:9][C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:14][C:13]=3[CH:15]=2)=[O:25])=[CH:40][CH:41]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(C(C)(C)C)cc3)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 40.8 %

Procedure:
The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.100 g, 0.266 mmol), thionyl chloride (2.0 mL), 4-tert-butylaniline (0.079 g, 0.400 mmol), THF (10.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on neutral alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.055 g of the desired product. 1HNMR (DMSO-d6): δ 1.21 (s, 9H), 1.55 (s, 6H), 3.13 (s, 2H), 7.27-7.46 (m, 6H), 7.55 (d, J=8.7 Hz, 2H), 9.67 (s, 1H), 11.20 (s, 2H); MS [M+H]+: 507.50.
Reaction SMILES: C1(C[N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[CH2:9]2)C=CC=CC=1.[H][H]>[Pd].CO>[CH3:16][CH:15]([NH:14][CH2:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH3:17]
Reactant: CC(C)NCC1CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)NCC1CCNC1
Yield: 76.4 %

Procedure:
A mixture of 13.4 g (58.0 mmol) of 1-phenylmethyl-N-(2-propyl)-3-pyrrolidinemethanamine, 1.0 g of 20% palladium on carbon and 130 ml of methanol was shaken in an atmosphere of hydrogen at about 4.5×105Pa and room temperature for 24 hours. The catalyst was removed by filtration through Celite; the filtrate concentrated and distilled in vacuo to give 6.3 g of N-(2-propyl)-3-pyrrolidinemethanamine, bp 58°-60° C./3.5 mm.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][N:9]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl.C(OCC)(=O)C>[CH3:1][C@H:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][N:9]=2)[CH2:4][CH2:5][N:6]([C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:38])[CH2:7]1
Reactant: C[C@@H]1CNCCN1c1nnc(-c2ccccc2)c2ccccc12
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccccc2)c2ccccc12
Reaction time: 0.08 h
Yield: 75.3 %

Procedure:
(R)-1-(2-methylpiperazin-1-yl)-4-phenylphthalazine (JK-10) (200 mg, 0.65 mmol) was dissolved in 5 mL of dichloromethane at room temperature. To this solution was added triethylamine (0.18 mL, 1.3 mmol, 2 eq) and benzoyl chloride (0.083 mL, 0.72 mmol, 1.1 eq). After 5 minutes, the reaction was diluted with 75 mL of ethyl acetate and washed with 5 mL of sat. NaHCO3, 5 mL of water, and 5 mL of brine. The organic phase was dried over MgSO4, filtered, and concentrated. Purification by column chromatography (35% ethyl acetate in hexanes) afforded 200 mg (75% yield) of (R)-(3-methyl-4-(4-phenylphthalazin-1-yl)piperazin-1-yl)(phenyl)methanone (4). MS (M+H)+=409.1
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14](OC)=[C:13]([CH:19]=O)[CH:12]=2)[CH:3]=1.CN.[C:23]([BH3-])#[N:24].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(O)(=O)C.CO>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:19][NH:24][CH3:23])[CH:12]=2)[CH:3]=1
Reactant: [BH3-]C#N
Reactant: COc1ccc(Oc2cc(Cl)ccc2C#N)cc1C=O
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cccc(Oc2cc(Cl)ccc2C#N)c1
Yield: 67.5 %

Procedure:
4-Chloro-2-(3-formyl-4-methoxy-phenoxy)-benzonitrile (1.00 g, 3.48 mmol), methylamine (2M in methanol, 5.2 ml, 10.4 mmol) and sodium cyanoborohydride (0.24 g, 3.8 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (75 ml) for 18 h. The solvent was removed in vacuo. The residue was treated with 10% aqueous sodium carbonate and extracted with ethyl acetate. The ethyl acetate layer was separated and washed with water, brine and dried over MgSO4. After filtration, fumaric acid (0.40 g, 3.4 mmol) was added to the filtrate and the solvent removed in vacuo. The residue was triturated with ethyl acetate overnight, filtered and dried to give 4-chloro-2-(3-methylaminomethyl-phenoxy)-benzonitrile fumarate (892 mg, 61%) as a white solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(O)(=O)C.[C:9]([C:14]1[C:15](=[O:33])[CH2:16][CH:17]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[C:23]([CH3:31])[C:22]=2[CH3:32])[CH2:18][C:19]=1[OH:20])(=[O:13])[CH2:10][CH2:11][CH3:12].O>C(OC(=O)C)(=O)C>[C:9]([C:14]1[C:19](=[O:20])[CH2:18][CH:17]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([N+:1]([O-:4])=[O:2])=[C:23]([CH3:31])[C:22]=2[CH3:32])[CH2:16][C:15]=1[OH:33])(=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCC(=O)C1=C(O)CC(c2c(C)c(C)cc3ccccc23)CC1=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCCC(=O)C1=C(O)CC(c2c(C)c(C)c([N+](=O)[O-])c3ccccc23)CC1=O
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
A mixture of fuming nitric acid (0.42), glacial acetic acid (0.27 g) and acetic anhydride (0.27 g) was added dropwise to a solution of 2-butyryl-5-(2,3-dimethylnaphth-1-yl)-3-hydroxy cyclohex-2-en-1-one (1.5 g) in acetic anhydride (8 ml) at 0° C. The mixture was stirred for 1 hr at 5°-10° C. and at 50° C. for 10 min. The cooled mixture was poured into water (150 ml) which was subsequently extracted with ether. The organic fraction was washed successively with a saturated sodium bicarbonate solution and with water. The dried (Na2SO4) organic extract was evaporated under reduced pressure and the residue was purified by column chromatography over silica with dichloromethane elution to give 2-butyryl-3-hydroxy-5-(2,3-dimethyl-4-nitronapth-1-yl)cyclohex-2-en-1-one a yellow foam. Pmr spectrum (CDCl3 ; δ in ppm): 1.03 (3H,t); 1.49-1.89 (2H,m); 2.40-3.89 (6H,m); 2.37 (3H,s); 2.52 (3H,s); 4.06-4.69 (1H,m); 7.32-7.66 (3H,m); 8.00-8.29 (1H,m); 18.38 (1H,s).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.[F:12][C:13]([F:47])([F:46])[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:17]=[C:16]([C:30]2[CH:31]=[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:37]=3)[CH:33]=[CH:34][CH:35]=2)[N:15]=1>C1COCC1>[OH:2][CH2:1][CH2:3][NH:4][S:42]([C:38]1[CH:37]=[C:36]([C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([C:16]3[N:15]=[C:14]([C:13]([F:12])([F:46])[F:47])[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=4)[N:17]=3)[CH:31]=2)[CH:41]=[CH:40][CH:39]=1)(=[O:43])=[O:44]
Reactant: O=S(=O)(Cl)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(NCCO)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Temperature: 0 °C
Yield: 67.8 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of ethanolamine (0.071 g, 1.16 mmol), triethylamine (0.06 ml, 0.42 mmol) and THF (2 ml) was added drop wise a solution of 3′-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonyl chloride (example I.3) (0.21 g, 0.39 mmol) in THF (3 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.15 g, 69%). MS (ISP) 567.7 [(M+H)+]; mp 153° C.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6]N(C=O)C.C(O[CH:14](OCC)[CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C.C([O-])([O-])=O.[Na+].[Na+].C[O-].[Na+].[NH:36]([CH2:38][CH2:39][OH:40])[NH2:37]>C(Cl)(Cl)Cl>[CH2:17]([O:16][C:15]1[CH:14]=[N:37][N:36]([CH2:38][CH2:39][OH:40])[CH:6]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NNCCO
Reactant: CCOC(COCc1ccccc1)OCC
Reactant: CN(C)C=O
Agent: C[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: OCCn1cc(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.6 %

Procedure:
POCl3 (12.9 ml, 141.2 mmol) was added to DMF (10.9 ml, 141.2 mmol) at 0° C. The reaction was immediately warmed to ambient temperature and stirred for 30 minutes. ((2,2-diethoxyethoxy)methyl)benzene (10.6 g, 47.1 mmol) was added as a solution in 80 mL of chloroform. The solution was stirred at 75° C. for 3.5 hours. The solution was cooled, poured over ice water, and neutralized with Na2CO3. The residue was extracted with chloroform and the organic layer was dried with Na2SO4 and concentrated. The residue was re-dissolved in MeOH (450 mL). NaOMe (25% in MeOH, 58 ml, 253 mmol) was added followed by 2-hydrazinylethanol (10.6 g, 139 mmol). The reaction stirred overnight at ambient temperature. The material was concentrated in vacuo followed by dilution with saturated NH4Cl solution. The material was extracted with EtOAc, dried (Mg2SO4), and concentrated. Flash chromatography gave 2-(4-(benzyloxy)-1H-pyrazol-1-yl)ethanol (1.81 g, 13% yield).