Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([O:6][CH2:7][C:8]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.O1CCCC1.[N:43]1[C:50](Cl)=[N:49][C:47]([Cl:48])=[N:46][C:44]=1[Cl:45].C([O-])([O-])=O.[Na+].[Na+]>CC(C)=O.O>[Cl:48][C:47]1[N:46]=[C:44]([Cl:45])[N:43]=[C:50]([NH:35][C:32]2[CH:31]=[CH:30][C:29]([O:28][CH2:27][C:8]([CH2:9][O:10][C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:50]4[N:49]=[C:47]([Cl:48])[N:46]=[C:44]([Cl:45])[N:43]=4)=[CH:15][CH:16]=3)([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:50]4[N:49]=[C:47]([Cl:48])[N:46]=[C:44]([Cl:45])[N:43]=4)=[CH:22][CH:21]=3)[CH2:7][O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:50]4[N:49]=[C:47]([Cl:48])[N:46]=[C:44]([Cl:45])[N:43]=4)=[CH:37][CH:36]=3)=[CH:34][CH:33]=2)[N:49]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(OCC(COc2ccc(N)cc2)(COc2ccc(N)cc2)COc2ccc(N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Clc1nc(Cl)nc(Nc2ccc(OCC(COc3ccc(Nc4nc(Cl)nc(Cl)n4)cc3)(COc3ccc(Nc4nc(Cl)nc(Cl)n4)cc3)COc3ccc(Nc4nc(Cl)nc(Cl)n4)cc3)cc2)n1
Temperature: -10 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of 1,3-bis(4-aminophenoxy)-2,2-bis[(4-aminophenoxy)methyl]propane (5.00 grams, 10.0 mmol; prepared as described in Part C of this Example) in 120 milliliters of a mixture of dry acetone and tetrahydrofuran (1:1 (v/v)) was added dropwise to a solution of cyanuric chloride (7.75 grams, 42.0 mmol; obtained from Aldrich Chemical Co.) in 200 milliliters of dry acetone at −10° C. This mixture was stirred for 1 hour at −10° C. and was then added, with Na2CO3 (4.45 grams, 42.0 mmol), to 1.5 liters of cold water to give a precipitate. The white solid was filtered off, dried, and dissolved in dichloromethane to remove insoluble material (hydrolyzed product). The resulting solution was filtered over CELITE and dried with magnesium sulfate. Volatiles were removed under reduced pressure, and the residue was dried under vacuum to afford pure 1,3-bis(4-[N-(2,4-dichloro-1,3,5-triazin-6-yl)amino]phenoxy)-2,2-bis[(4-[N-(2,4-dichloro-1,3,5-triazin-6-yl)amino]phenoxy)methyl]propane (9.20 grams, 8.42 mmol, 84 percent yield) as a white solid: softening point 143–145° C.; mp 240–250° C.; IR (KBr) 3366, 3268, 3123, 2947, 1609, 1550, 1506, 1386, 1318, 1219, 1167, 1019, 846, 829, 794 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 4H), 7.40 (d, 8H, 3J=9.0 Hz), 6.96 (d, 8H, 3J=9.0 Hz), 4.36 (s, 8H); 13C NMR (100 MHz, CDCl3) δ 171.46, 164.44, 156.93, 129.12, 123.93, 115.39, 66.90, 45.11; MS (FAB, 3-nitrobenzyl alcohol) m/e 1092.7; Anal. Calcd for C41H28Cl8N16O4: C, 45.08; H, 2.58; N, 20.52. Found: C, 45.07; H, 2.58; N, 20.12.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]3[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)=[CH:3][CH:2]=1.C1C(=O)N([Br:28])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:28][CH2:20][C:1]1[CH:2]=[CH:3][C:4]([C:7]2[O:8][C:9]3[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc2nc(-c3ccc(C)cc3)oc12
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc2nc(-c3ccc(CBr)cc3)oc12
Yield: 77.2 %

Procedure:
To a mixture of methyl 2-p-tolylbenzo[d]oxazole-7-carboxylate (1 g, 3.74 mmol) in CCl4 (7 mL) was added NBS (665 mg, 3.74 mmol) and BPO (52 mg, 0.37 mmol), heated to reflux for 24 hr, then the solvent was evaporated, and purified by silica gel chromatography (petroleum ether:ethyl acetate=100:1-50:1) to obtain methyl 2-(4-(bromomethyl)phenyl)benzo[d]oxazole-7-carboxylate as a white solid (1.0 g, yield 77%). LC-MS (ESI) m/z 346 [M+1]+.
Reaction SMILES: [Na].[OH:2][C:3]([CH:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])=[CH:4][N+:5]([O-:7])=[O:6].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].O>C1COCC1>[CH2:29]([O:28][C:26]([CH2:25][O:2][C:3]([CH:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])=[CH:4][N+:5]([O-:7])=[O:6])=[O:27])[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: COc1ccccc1OC(C(O)=C[N+](=O)[O-])c1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)COC(=C[N+](=O)[O-])C(Oc1ccccc1OC)c1ccccc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
To 3.23 g of 2-hydroxy-3-phenyl-3-(2-methoxy-phenoxy)-1-nitropropene sodium salt dissolved in 50 ml of anhydrous THF there was added at 0° C. 16.7 g of ethyl bromoacetate. After 2 hours at 0° C. the mixture was stirred at room temperature for 48 hours. The mixture was poured into water and extracted with ethyl acetate. The organic extracts were washed with water, dried over Na2SO4 and concentrated to dryness. The residue was separated by column chromatography on silica gel (mobile phase:ethyl acetate/cyclohexane 1/1), to obtain 2.70 g of 2-ethoxycarbonylmethyloxy-3-phenyl-3-(2-methoxy-phenoxy)-1-nitropropene (oil). Yield 70%.
Reaction SMILES: C(O)(=[O:3])C.[CH2:5]([S:15][CH:16]([CH2:20][C:21]([OH:23])=[O:22])[C:17]([OH:19])=[O:18])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].OO.[OH2:26]>>[CH2:5]([S:15]([CH:16]([CH2:20][C:21]([OH:23])=[O:22])[C:17]([OH:19])=[O:18])(=[O:3])=[O:26])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O
Reactant: CC(=O)O
Reactant: CCCCCCCCCCSC(CC(=O)O)C(=O)O
Agent: OO
Product: CCCCCCCCCCS(=O)(=O)C(CC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 400 ml beaker equipped with a heating mantle, alcohol thermometer, 50 ml dropping funnel, and a stirrer, 100 ml of glacial acetic acid was heated to about 50° C. To this was added 101.32 g of the dry solid C10H21SCH(COOH)CH2COOH.12H2O described above, with stirring and heating to obtain a thick white slurry. Via the dropping funnel, 22.64 ml of 70% H2O2 was then added over a period of 114 minutes at 45°-53° C., resulting in an exothermic reaction. Agitation was then continued for 31/2 hours at 47°-53° C. The resulting homogeneous solution was diluted with 50 ml of water and then cooled to ambient temperature, becoming a thick white slurry which was then held overnight. The slurry was cooled to 5°-10° C., and the solids were collected by filtration. The solids were dissolved in 515 ml of ethyl acetate. This solution was filtered to remove a small amount of insoluble material, washed with three 200 ml portions of water and transferred to a 4,000 ml beaker. Enough ethylacetate was then boiled off to reduce the solution volume to about 300 ml. Heating was discontinued, and with agitation, 1,500 ml of petroleum ether was added via a dropping funnel, resulting in the precipitation of a white solid product. The slurry was cooled to 5°-10° C., and the solids were recovered by filtration. The solids were washed by reslurrying in petroleum ether, again recovered by filtration, and dried overnight at ambient temperature. The resulting product weighed 34.63 g, and NMR analysis in DMSO-D6 showed that it was n-decylsulfonylsuccinic acid, C10H21SO2CH(COOH)CH2COOH. Water was not present at detectable levels, and the only detectable impurity was about 0.2% of fumaric acid. The yield was 53.7% of the theoretical amount, based upon the amount of the sulfide used.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[F:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[C:21](I)[CH:20]=1>>[CH2:13]([C:7]1([CH2:15][CH3:16])[C:6]2[CH:17]=[C:2]([NH:1][C:21]3[CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=[C:19]([F:18])[CH:20]=3)[CH:3]=[CH:4][C:5]=2[N:10]([CH3:11])[C:9](=[O:12])[O:8]1)[CH3:14]
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Reactant: O=[N+]([O-])c1cc(F)cc(I)c1
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3cc(F)cc([N+](=O)[O-])c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 1-fluoro-3-iodo-5-nitrobenzene according to the coupling protocol of example 2. 1H NMR (DMSO-d6): δ 8.92 (s, 1H), 7.53 (t, J=1.8 Hz, 1H), 7.36 (dt, J=8.6, 2.2 Hz, 1H), 7.21 (dd, J=8.7, 2.4 Hz, 1H), 7.12 (d, J=8.7 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 7.03 (dt, J=11.1, 2.2 Hz, 1H), 3.29 (s, 3H), 2.01 (m, 4H), 0.82 (t, J=7.3 Hz, 6H); MS (ESI) m/z 374 ([M+H]+); MS (ESI) m/z 372 ([M−H]−); Anal. calcd for C19H20FN3O4: C, 61.12; H, 5.40; N, 11.25. Found: C, 60.33; H, 5.17; N, 10.51.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].Cl[CH2:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[NH:31][C:32](=[O:38])[O:33][CH2:34][CH2:35][O:36][CH3:37]>CC(C)=O>[CH3:37][O:36][CH2:35][CH2:34][O:33][C:32]([NH:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=1[CH2:23][NH:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:38]
Reactant: Cc1nc2c(N)cccn2c1C=O
Reactant: COCCOC(=O)Nc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COCCOC(=O)Nc1cccc(C)c1CNc1cccn2c(C=O)c(C)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.2 %

Procedure:
A mixture of 2.0 g (11.41 mmol) of 8-amino-2-methylimidazo[1,2-a]pyridine-3-carboxaldehyde, 1.21 g (11.41 mmol) of anhydrous sodium carbonate, 0.17 g (1.14 mmol) of sodium iodide and 3.5 g (13.6 mmol) of 2-methoxyethyl 2-chloromethyl-3-methylphenylcarbamate in 30 ml of acetone is stirred at RT for 24 h and concentrated in a Rotavapor. The residue is treated with 100 ml of water and extracted with ethyl acetate, and the organic phase is dried with magnesium sulphate and concentrated in vacuo. The residue is recrystallized from toluene. 3.31 g (73%) of the title compound of m.p. 153°-155° C. are obtained.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[NH2:13][C@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[C@H:14]1([NH:13][C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH3:32])[N:7]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccccc1-c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12

Procedure:
The title compound, MS: m/e=351.5 (M+H+), was prepared in accordance with the general method of example 63 from 5-iodo-2-chloroquinoline, (R)-1-aminoindane and ortho-tolylboronic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:3]=1[C:4]([O:6][CH:7]([CH3:17])[CH2:8][N:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH3:10])=[O:5].[CH3:24][I:25]>ClCCCl.C(Cl)Cl>[I-:25].[CH3:10][N+:9]([CH3:24])([CH2:8][CH:7]([O:6][C:4](=[O:5])[C:3]1[C:18]([CH3:23])=[CH:19][C:20]([CH3:22])=[CH:21][C:2]=1[CH3:1])[CH3:17])[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: Cc1cc(C)c(C(=O)OC(C)CN(C)C2CCCCC2)c(C)c1
Reactant: CI
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(C)c(C(=O)OC(C)C[N+](C)(C)C2CCCCC2)c(C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(cyclohexyl(methyl)amino)propan-2-yl 2,4,6-trimethylbenzoate (0.30 g, 0.946 mmol) in DCE (5 mL), methyl iodide (0.12 mL, 1.892 mmol) was added. The resultant reaction mixture was stirred at rt for 16 hours. The reaction mixture was diluted with DCM and concentrated to dryness. The crude product was subjected to column chromatography to obtain N,N-dimethyl-N-[2-((2,4,6-trimethylbenzoyl)oxy)propyl]cyclohexanaminium iodide. Yield: 0.109 g (25%). 1H NMR (400 MHz, CDCl3) δ 6.86 (s, 2H), 5.70-5.67 (m, 1H), 4.52-4.48 (d, J=14 Hz, 1H), 3.83-3.77 (m, 1H), 3.70-3.64 (m, 1H), 3.34 (s, 3H), 3.28 (s, 3H), 2.29-2.01 (m, 10H), 2.01-1.98 (m, 1H), 1.84 (m, 1H), 1.64-1.62 (d, J=6 Hz, 4H), 1.47-1.38 (m, 4H), 1.13-1.08 (m, 2H). LCMS: m/z=332.2 [M+], RT=3.01 min (Column: Y, Program: P1). HPLC: 99.53% (200 nm), RT 4.11 min (Mobile phase: A: ACN, B: 0.05% TFA in water, Column: Zorbax® SBC18 (50*4.6 mm) 1.8μ.
Reaction SMILES: C[O:2][CH2:3][C:4]1[O:8][C:7]([C:9]([O:11][CH3:12])=O)=[CH:6][CH:5]=1.[CH2:13]([NH2:16])[CH2:14][NH2:15]>>[CH3:12][O:11][CH2:9][C:7]1[O:8][C:4]([C:3]([NH:15][CH2:14][CH2:13][NH2:16])=[O:2])=[CH:5][CH:6]=1
Reactant: NCCN
Reactant: COCc1ccc(C(=O)OC)o1
Product: COCc1ccc(C(=O)NCCN)o1

Procedure:
Using Compound c and anhydrous ethylenediamine, the corresponding procedure of Example 1 was repeated to give 5-(methoxymethyl)-N-(2-aminoethyl)-2-furancarboxamide (Compound d) as light yellow oil.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[C:9]([C:10]([OH:12])=[O:11])=[C:8]([O:13][CH3:14])[CH:7]=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:5]1[CH:6]=[CH:7][C:8]([O:13][CH3:14])=[C:9]([C:4]=1[CH3:3])[C:10]([OH:12])=[O:11]
Reactant: COc1cccc(C)c1C(=O)O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(Br)c(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
A mixture of bromine (102 ml, 2.0 mol) and acetic acid (225 ml) is added to a mixture of 63A (304.0 g, 1.8 mol),), sodium acetate (164.0 g, 2.0 mol) and acetic acid (3.0 l) at a temperature of 10 to 15° C. The reaction mixture is stirred at room temperature for 16 hours. The solid material is collected by vacuum filtration, washed with water and dried yielding off-white crystals 321.0 g (72.6.%), mp 81-83° C.
Reaction SMILES: [P:1]([O-:6])([O:4]C)[O:2][CH3:3].Br[C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:4][P:1]([C:12]1[CH:11]=[C:10](/[CH:14]=[CH:15]/[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:9]=[CH:8][CH:13]=1)([O:2][CH3:3])=[O:6]
Reactant: CC(C)(C)OC(=O)/C=C/c1cccc(Br)c1
Reactant: COP([O-])OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COP(=O)(O)c1cccc(/C=C/C(=O)OC(C)(C)C)c1
Temperature: 100 °C

Procedure:
Dimethyl phosphite (0.089 ml, 0.971 mmol), tert-butyl (2E)-3-(3-bromophenyl)acrylate (0.25 g, 0.883 mmol), triethylamine (0.369 ml, 2.65 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.153 g, 0.132 mmol) were combined and allowed to heat for approximately eight hours at 100° C. The reaction was cooled and filtered over celite, washing with ethyl acetate. The filtrate was concentrated under reduced presesure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane, followed by CH2Cl2/MeOH. MS: calc'c 299 (MH+), exp 299 (MH+).
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:7]2[CH2:8][C@H:4]([CH2:5][CH2:6]2)[C@H:3]1[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C.Cl[S:27]([C:30]1[CH:42]=[CH:41][C:33]2[O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:32]=2[CH:31]=1)(=[O:29])=[O:28]>C(Cl)Cl>[CH:31]1[C:32]2[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[O:34][C:33]=2[CH:41]=[CH:42][C:30]=1[S:27]([NH:1][C@@H:2]1[C@H:7]2[CH2:8][C@H:4]([CH2:5][CH2:6]2)[C@H:3]1[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc2oc3ccccc3c2c1
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@H]2CC[C@H](C2)[C@H]1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCC/C=C\C[C@@H]1[C@H]2CC[C@H](C2)[C@H]1NS(=O)(=O)c1ccc2oc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
Methyl (Z)-7-[(1S,2R,3R,4R)-3-aminobicyclo[2.2.1]hept-2-yl]-5-heptenoate (II-1) (251 mg, 1.00 mmol) was dissolved in methylene chloride (8 ml) and triethylamine (0.238 ml, 2.00 mmol) was added thereto under a nitrogen atmosphere. To the mixture was added 2-chlorosulfonyldibenzofuran (350 mg, 1.31 mmol) under ice-cooling, and the mixture was stirred for 30 min and allowed to warm up to room temperature. The reaction mixture was purified by column chromatography on silica gel (n-hexane/ethyl acetate (1:4)) and recrystallized from n-hexane (10 ml) to yield methyl (Z)-7-[(1S, 2R, 3R, 4R)-3-(2-dibezofuryl)sulfonylaminobicyclo[2.2.1]hept-2-yl]-5-heptenoate (1a-1) (342 mg, 0.710 mmol). Yield 71%, mp 115-116° C.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2].[CH3:10][C:11]([CH3:13])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCCCCC>[OH:2][CH2:1][C:3]1([CH2:4][CH3:5])[CH2:8][O:9][C:11]([CH3:13])([CH3:10])[O:7][CH2:6]1
Reactant: CC(C)=O
Reactant: CCC(CO)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: O
Product: CCC1(CO)COC(C)(C)OC1

Procedure:
In a 3-liter reaction vessel, 292.1 g (2.18 mol) of trimethylolpropane, 474.0 g (8.17 mol) of acetone, 6.0 g (0.0315 mol) of p-toluene sulfonic acid monohydrate, and 900 ml of hexane were placed and refluxed for 24 hours with removing the formed water off the reaction system. The reaction product was neutralized with aqueous solution of sodium hydroxide, and distilled under a reduced pressure to give 5-hydroxymethyl-5-ethyl-2,2-dimethyl-1,3-dioxane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13](C3C([N+]([O-])=O)=C(S([O-])(=O)=O)C=CC=3)[CH2:12]2)=[O:10])=[C:4]([C:36](=[O:43])[NH:37][CH:38]([CH:40]2[CH2:42][CH2:41]2)[CH3:39])[CH:3]=1.[Br-:44].[Na+].S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([Br:44])[CH2:12]2)=[O:10])=[C:4]([C:36](=[O:43])[NH:37][CH:38]([CH:40]2[CH2:42][CH2:41]2)[CH3:39])[CH:3]=1
Reactant: [Br-]
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(c2cccc(S(=O)(=O)[O-])c2[N+](=O)[O-])=NN1c1ncccc1Cl)C1CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Reaction time: 2 h
Yield: 102.2 %

Procedure:
10.0 g of 5-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylcarbamoyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl2-nitrobenzene sulfonate was dissolved in 30 mL of acetic acid, and after adding 2.4 g of sodium bromide, 1.3 mL of 98 mass % concentrated sulfuric acid was dropwise added at room temperature. After completion of the dropwise addition, heating was carried out at an internal temperature of from 40 to 50° C. for about two hours. After completion of the reaction, the reaction solution was dropwise added into 60 mL of a 8 mass % sodium hydroxide aqueous solution to obtain 8.3 g of the desired product in a crystal form.
Reaction SMILES: [CH:1]([N:4]1[C:32](=[O:33])[C:31]2[N:12]3[CH2:13][CH2:14][C:15]4[CH:16]=[C:17]([O:29][CH3:30])[C:18]([C:21]5[C:22]([CH3:28])=[N:23][N:24]([CH3:27])[C:25]=5[CH3:26])=[CH:19][C:20]=4[C:11]3=[C:10]([C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)[C:9]=2[CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:39](OC(=O)C)(=[O:41])[CH3:40].O.C(OCC)(=O)C>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:39]([N:7]1[CH2:8][C:9]2[C:10]([C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)=[C:11]3[C:20]4[CH:19]=[C:18]([C:21]5[C:22]([CH3:28])=[N:23][N:24]([CH3:27])[C:25]=5[CH3:26])[C:17]([O:29][CH3:30])=[CH:16][C:15]=4[CH2:14][CH2:13][N:12]3[C:31]=2[C:32](=[O:33])[N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(cc1-c1c(C)nn(C)c1C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCNC3
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2c(cc1-c1c(C)nn(C)c1C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCN(C(C)=O)C3
Reaction time: 0.5 h

Procedure:
To 32 mg of 10q in 200 μl of pyridine 30 μl of acetic anhydride and 1 mg of DMAP were added. The mixture was stirred for ½ hr, then water and ethyl acetate were added and stirring was continued for ½ hr at RT. The product was extracted into ethyl acetate and washed twice with water, dried, concentrated and the residues were treated with diethyl ether to provide 25 mg of 10r, as white crystalline material. Mp: 178-180° C. Rf 0.15 (heptane/acetone 1/1). NMR (CDCl3) δ 1.33 (bm, 6, N-isoC3H7), 1.90+1.94 (2×s, 6, 2×CH3-pyrrazole), 2.00 (s, 3, N—CH3), 3.70 (s, 3, NCH3), 3.80 (s, 3, OCH3), 4.65 (m, 1, CH isoC3H7), 6.79 and 6.89 (2×s, 2, ArH), 6.93, 7.08 and 7.36 (3×m, 3, thiophene).
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[CH3:29][C:30]1[C:35]([CH3:36])=[C:34]([S:37][CH3:38])[N:33]=[N:32][C:31]=1[NH2:39].C(N(CC)C(C)C)(C)C>C(#N)CCC>[CH3:36][C:35]1[C:34]([S:37][CH3:38])=[N:33][N:32]2[C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]4([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]4)=[CH:7][CH:6]=3)[N:39]=[C:31]2[C:30]=1[CH3:29]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: CSc1nnc(N)c(C)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCC#N
Product: CSc1nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c(C)c1C
Temperature: 125 °C
Yield: 19 %

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [that was prepared in a manner analgous to that described for Intermediate Example Int-1-A] (540 mg, ˜80% purity, 0.970 mmol, 1.0 eq), 4,5-dimethyl-6-(methylsulfanyl)-pyridazin-3-amine (that was prepared in a manner analgous to that described for Intermediate Example Int-35, Step 1, 181 mg, ˜50% purity, 1.07 mmol, 1.1 eq) and N,N-diisopropylethylamine (170 μL, 0.970 mmol, 1.1 eq) in butyronitrile (4.7 mL) was heated for 4 hours at 125° C. On cooling the reaction mixture was concentrated in vacuo. The crude mixture was purified via reversed phase preparative HPLC to give 105 mg (19% yield) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[C:6]([CH:25]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][C:16]=2[F:24])[CH2:11][CH2:10]1)=[O:8].C([Sn](CCCC)(CCCC)[C:37]([O:39]CC)=[CH2:38])CCC.Cl>C1(C)C=CC=CC=1.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>[C:37]([C:2]1[CH:3]=[CH:4][C:5]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)=[C:6]([CH:25]=1)[C:7]([N:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][C:16]=2[F:24])[CH2:13][CH2:14]1)=[O:8])(=[O:39])[CH3:38]
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(Br)ccc3N3CCOCC3)CC2)c(F)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C(C)=O)ccc3N3CCOCC3)CC2)c(F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a suspension of 1-{4-[4-(5-Bromo-2-morpholin-4-yl-benzoyl)-piperazin-1-yl]-3-fluoro-phenyl}-ethanone (160 mg, 0.33 mmol) in toluene (2 ml) were added PdCl2(PPh3)2 (5 mg, 0.0065 mmol) and tributyl(1-ethoxyvinyl) tin (125 ul, 0.36 mmol). The mixture was heated to 100° C. for 6 hours. The mixture was cooled in an ice bath and 2N HCl (0.55 ml) was added. The mixture was stirred at room temperature overnight. The mixture was filtered. The organic layer was separated and 10% aqueous KF solution was added. The mixture was stirred at room temperature for 3 hours and filtered. The organic layer was dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude gum was chromatographed on silica gel, eluent: heptane/ethylacetate 0%-50% (10 minutes) to provide the title compound (15 mg, 10%) as a white solid MS (m/e): 454.2 (M+H, 100%).