Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6](=[O:11])[C:7](C)(C)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N)(C)(C)C.C(N(CC)CC)C.C(Cl)(=O)CC>>[C:1]([NH:5][C:6](=[O:11])[CH2:7][CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)C(C)(C)C
Agent: CCC(=O)Cl
Solvent: CC(C)(C)N
Solvent: CCN(CC)CC
Product: CCC(=O)NC(C)(C)C
Yield: 95 %

Procedure:
In a fashion similar to the preparation of LtBu,tBuH, treatment of tert-butylamine (11.3 mL, 105 mmol) and triethylamine (14.9 mL, 105 mmol) with propionyl chloride (8.9 mL, 100 mmol) afforded LEt,tBuH as white crystalline solid (12.27 g, 95%) upon sublimation at 55° C./0.05 Torr: mp 90-92° C.
Reaction SMILES: Br[CH:2](Br)[CH2:3][C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2.C=CBr.CC(C)([O-])C.[K+]>COCCOCCOCCOC.O>[C:3]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2)#[CH:2]
Reactant: BrC(Br)CC12CC3CC(CC(C3)C1)C2
Agent: C=CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOCCOCCOC
Product: C#CC12CC3CC(CC(C3)C1)C2
Temperature: 160 °C

Procedure:
A solution of 45 g (0.17 mol) of 1-bromoadamantane in 60 ml of vinyl bromide was cooled to -65° C. and 10 g of aluminum bromide was added portionwise over 2 h. The mixture was then poured on to 500 g of ice, neutralized with 10% aqueous sodium carbonate solution, and extracted with 3×100 ml of methylene chloride. The combined extracts were dried (MgSO4) and evaporated to yield 70 g of an oil containing 1-(2,2-dibromoethyl)adamantane and polyvinyl bromide (NMR). This oil was dissolved in 100 ml of triglyme, 38 g (0.34 mol) of potassium t-butoxide added, nd the mixture heated at 160° C. for 3 h. The mixture was cooled, diluted with 300 ml of water and extracted with 3×100 ml of hexane. The combined hexane extracts were dried (MgSO4) , and distilled to give 12 g (52% based on 1-bromoadamantane) of 1 -ethynyladamantane: mp 82°-83° C.; bp 95-100 (l mm); NMR δ1.9-2.6 ppm.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[N:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])[S:11][N:10]=1.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>O1CCCC1>[CH2:19]([NH:21][C:22]([N:10]1[C:9](=[O:8])[N:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])[S:11]1)=[O:23])[CH3:20]
Reactant: CCCCOc1nc(O)ns1
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOc1nc(=O)n(C(=O)NCC)s1

Procedure:
1 ml of triethylamine was added to a solution of 17.4 g of 3-hydroxy-5-n-butoxy-1,2,4-thiadiazole in 150 ml of tetrahydrofuran and then 12 ml of ethyl isocyanate were added dropwise with stirring. The mixture was stirred for 2 hours at 20° C and was concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel and elution with a 7-3 benzene-ethyl acetate mixture yielded 18.5 g of 2-(N-ethylcarbamoyl)-5-n-butoxy-1,2,4-thiadiazole-3-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.[CH:11]1([N:14]2[C:18]([C:19]3[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=3)=[CH:17][N:16]=[CH:15]2)[CH2:13][CH2:12]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:25][C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:18]3[N:14]([CH:11]4[CH2:13][CH2:12]4)[CH:15]=[N:16][CH:17]=3)[N:24]=2)=[O:10])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: Nc1cccc(-c2cncn2C2CC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cncn2C2CC2)n1)c1cc(Cl)ccn1
Yield: 47.1 %

Procedure:
A solution of 4-chloro-pyridine-2-carboxylic acid (141 mg, 0.895 mmol), 6-(3-cyclopropyl-3H-imidazol-4-yl)-pyridin-2-ylamine (150 mg, 0.750 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (342 g, 0.899 mmol), and N-methylmorpholine (250 μL, 2.70 mmol) in N,N-dimethylformamide was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, the residue suspended in acetonitrile, and the solid isolated by filtration, washed with water (80 mL), acetonitrile (80 mL) and diethyl ether (80 mL), and dried under reduced pressure to afford 4-chloro-N-(6-(1-cyclopropyl-1H-imidazol-5-yl)pyridin-2-yl)picolinamide as a white powder (120 mg, 47% yield). M+1=340.1
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][N:10]([CH3:21])[C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[C:4]([CH3:22])[N:3]=1.[CH3:23][O-:24].[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([O:24][CH3:23])[C:5]([CH2:9][N:10]([CH3:21])[C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[C:4]([CH3:22])[N:3]=1
Reactant: C[O-]
Reactant: Cc1nc(Cl)nc(Cl)c1CN(C)[C@H]1CCCc2ccccc21
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)nc(C)c1CN(C)[C@H]1CCCc2ccccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a flask containing (1S)-(2,4-dichloro-6-methyl-pyrimidin-5-ylmethyl)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (6.41 g, 19.06 mmol) is added MeOH (100 mL) and the solution is cooled to 0° C. using an ice bath. NaOMe (0.5 M, 38 mL) is added via addition funnel over 20 min. Once addition is complete, the ice bath is removed and the reaction is allowed to proceed overnight warming to room temperature. HOAc (2.0 mL) is added and the reaction mixture is allowed to stir for 10 min, followed by concentration at reduced pressure. The resulting oil is dissolved in EtOAc (100 mL) and washed sat. NaHCO3 (100 mL), brine (100 mL) and dried over Na2SO4. Flash chromatography on SiO2 using first CHCl3 followed by 20:1 hexanes:Et2O affords the title compound as a colorless oil. [mass expected (331.84); mass found (331.28)]
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]1[O:20][C:19]2[CH:21]=[C:22]([Cl:27])[C:23]([CH2:25]Cl)=[CH:24][C:18]=2[O:17]1.CCN(CC)CC>O1CCCC1>[Cl:27][C:22]1[C:23]([CH2:25][N:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:15][CH2:14]2)=[CH:24][C:18]2[O:17][CH2:16][O:20][C:19]=2[CH:21]=1
Reactant: c1ccc(OCCN2CCNCC2)cc1
Reactant: ClCc1cc2c(cc1Cl)OCO2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1cc2c(cc1CN1CCN(CCOc3ccccc3)CC1)OCO2
Temperature: 60 °C

Procedure:
1-[2-(phenoxy)-ethyl]piperazine (200 mg, 0.974 mmol), 6-chloropiperonyl chloride (200 mg, 0.974 mmol), and Et3N (415 μL, 3 mmol) were combined in tetrahydrofuran (THF 20 mL). The reaction mixture was heated at 60° C. for 12 h. The reaction mixture was cooled and extracted with ethyl acetate (EtOAc). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated. The crude residue was chromatographed on silica (20% EtOAc/Hexanes) and the product fractions were collected and evaporated to an amber solid (186 mg, 51%). 1H NMR (CDCl3) δ: 2.5-2.7 (m, 8H), 2.8 (t, 2H), 3.5 (s, 2H), 4.1 (t, 2H), 5.9 (s, 2H), 6.81 (s, 1H), 6.9-6.94 (m, 3H), 6.96-6.98 (m, 1H), 7.26-7.3 (m, 1H). MS ELS+ 376. CHN: calc., 64.08, 6.18, 7.47; found, 63.87, 6.12, 7.44. mp: 72-76° C.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=1[NH2:24]>ClCCl.N1C=CC=CC=1>[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=1[NH:24][C:1](=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:24][C:23]1[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:22]=1[Cl:21])=[O:13]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1Cl)c1ccccc1SSc1ccccc1C(=O)Nc1ccc(Cl)cc1Cl
Yield: 18.5 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 2,4-dichloroaniline (1.89 g, 11.7 mmol) in 15 mL of pyridine. The crude product was triturated with a hot mixture of ethyl acetate, ethanol and methanol (1:1:1) and filtered to yield 0.64 g of the title compound, mp 227-228° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[CH2:10][CH2:9]1)#[N:2].CCN(CC)CC.[C:46](OC(=O)C)(=[O:48])[CH3:47]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[CH2:10][CH2:9]1)[C:29]1[CH:34]=[CH:33][C:32]([O:35][C:46](=[O:48])[CH3:47])=[CH:31][CH:30]=1)#[N:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(O)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)cccc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a solution of COMPOUND 117 (51 mg, 0.10 mmol) in CH2Cl2 (2 mL) were added Et3N (0.04 mL, 0.29 mmol) followed by acetic anhydride (0.02 mL, 0.21 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 137 as a white solid (48 mg, 85%) following work-up and purification. 1H NMR (CDCl3) δ 0.97-1.18 (m, 2H), 1.00 (d, 3H, J=6.3 Hz), 1.50-1.58 (m, 1H), 1.70-1.74 (m, 3H), 2.15 (t, 1H, J=11.1 Hz), 2.24 (s, 3H), 2.31 (s, 6H), 2.55 (t, 1H, J=10.5 Hz), 2.74-2.87 (m, 3H), 3.24-3.31 (m, 1H), 3.57-3.63 (m, 1H), 3.77 (s, 2H), 3.85-3.91 (m, 1H), 6.51 (d, 2H, J=8.4 Hz), 6.84 (d, 2H, J=8.1 Hz), 6.93-7.05 (m, 3H), 7.43-7.52 (m, 4H), 8.38 (br s, 1H). 13C NMR (CDCl3) δ 14.53, 20.27, 22.20, 30.06, 31.46, 32.06, 40.96, 44.70, 49.60, 53.28, 57.84, 61.68, 113.66, 115.15, 120.06, 123.21, 128.42, 129.52, 130.36, 131.08, 131.64, 132.01, 135.21, 139.77, 143.16, 143.23, 147.35, 170.96, 171.27. ES-MS m/z 533 (M+H). Anal. Calcd. for C34H40N4O3.0.6H2O: C, 72.47; H, 7.37; N, 9.94. Found. C, 72.38; H, 7.25; N, 9.83.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:13])[NH:8]3.[H-].[Na+].Br[CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.O>CN(C=O)C>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][CH:18]([CH2:17][N:8]2[C:9]3[N:5]4[C:4](=[N:3][C:2]([CH3:1])=[C:6]4[C:7]2=[O:13])[CH:12]=[CH:11][CH:10]=3)[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: Cc1nc2cccc3[nH]c(=O)c1n23
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cccc3n(CC4CCN(C(=O)OC(C)(C)C)CC4)c(=O)c1n23
Yield: 62.9 %

Procedure:
To a suspension of 735 mg (4.24 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one in 15 ml of DMF was added, while stirring under ice-cooling, 187 mg (4.68 mmol) of 60% sodium hydride (dispersion in oil). The mixture was stirred for 20 minutes at the same temperature. To the mixture was added a solution of 1.18 g (4.24 mmol) of 4-bromomethyl-1-tert-butoxycarbonylpiperidine in 5 ml of DMF. The mixture was stirred for one hour at 100° C. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to give 988 mg of the desired compound (62.8%, pale yellow solid).
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][SH:4].O.CS([C@H:11]1[NH:14][C:13](=[O:15])[C@H:12]1[NH:16][C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)=O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:3]([S:4][C@H:11]1[NH:14][C:13](=[O:15])[C@H:12]1[NH:16][C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH:2]([CH3:5])[CH3:1]
Reactant: CS(=O)(=O)[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)CS
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)CS[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 90 °C

Procedure:
A solution of zinc acetate (0.7 g, 3 mmol) in toluene (15 mL) and 2-methyl-propanethiol (0.72 g, 8 mmol) was refluxed for 45 min in an apparatus equipped with a Dean-Stark trap to azeotrope water. (3R,4R)-4-(Methylsulfonyl)-3-(triphenylmethylamino)azetidin-2-one (1.5 g, 36 mmol) was added and the mixture was heated to 90° C. for 2 h. The mixture was concentrated and the residue was triturated with ethyl acetate and the insoluble material was removed by filtration. The filtrate was concentrated and the residue was chromatographed on silica gel eluted with 20% ethyl acetate:hexane. The fractions containing the product were combined, concentrated to give the title compound. MS(ES) m/e 417 [M+H]+.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](O)=[O:46])([CH3:44])[CH3:43])=[CH:33][C:32]=2[CH3:49])=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=1)(=O)C.[NH2:53][CH2:54][CH2:55][CH2:56][OH:57].NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](=[O:46])[NH:53][CH2:54][CH2:55][CH2:56][OH:57])([CH3:44])[CH3:43])=[CH:33][C:32]=3[CH3:49])=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: NCCCO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)NC(C)(C)C(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(C)(N)C(N)=O
Product: Cc1cc(OCCC(=O)NC(C)(C)C(=O)NCCCO)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole and 3-amino-1-propanol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide, respectively.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([CH3:15])([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)[CH3:5].Cl.[C:18]([NH2:23])(=[NH:22])[CH:19]([CH3:21])[CH3:20].CN(C)C(N(C)C)=N>CN(C=O)C.O>[CH:19]([C:18]1[NH:22][CH:2]=[C:3]([C:4]([CH3:15])([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=2)[CH3:5])[N:23]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(C(=O)CBr)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)C(=N)N
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nc(C(C)(C)c2cccc([N+](=O)[O-])c2)c[nH]1
Yield: 29.7 %

Procedure:
A solution of 1-bromo-3-methyl-3-(3-nitro-phenyl)-butan-2-one (2.28 g, 8.0 mmol), isobutyramidine hydrochloride (3.58 g, 23.7 mmol) and 1,1,3,3-tetramethylguanidine (2.4 mL, 19.1 mmol) in DMF (10 mL) was heated at reflux for 24 h. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated to afford 2-isopropyl-4-[1-methyl-1-(3-nitro-phenyl)-ethyl]-1H-imidazole (0.65 g, 30%) as a cream-coloured solid.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[C:13]([F:19])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:20]C)[CH:3]=1.[CH2:22]([Sn](CCCC)(CCCC)CCCC)[CH:23]=[CH2:24]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH2:24]([C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:19])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([OH:20])[CH:3]=1)[CH:23]=[CH2:22]
Reactant: COc1cc(Br)c2oc(-c3ccc(OC)c(F)c3)nc2c1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Product: C=CCc1cc(O)cc2nc(-c3ccc(O)c(F)c3)oc12

Procedure:
The title compound was prepared in substantially the same manner as described in Example 24, Route c, step b, from 7-bromo-2-(3-fluoro-4-methoxyphenyl)-5-methoxy-1,3-benzoxazole; allyltributyltin and dichlorobis(tri-o-tolylphosphine)palladium, followed by demethylation according to Example 20, step e. The desired product was obtained as a light pink solid, m.p. 169–171° C.; MS m/e 284 (M−H)+.
Reaction SMILES: OC1[C:11]2[C:6](=[C:7]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:8]3=[CH:9][CH:10]=2)[O:5][C:4](=O)C=1.[CH2:18](OCC)C>COCCOCCOCCOC.[Pd]>[CH3:4][O:5][C:6]1[C:7]2[C:8](=[C:12]([CH2:16][CH3:18])[CH:13]=[CH:14][CH:15]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc2c1ccc1c(O)cc(=O)oc12
Reactant: CCOCC
Agent: [Pd]
Solvent: COCCOCCOCCOC
Product: CCc1cccc2c(OC)cccc12
Yield: 8.5 %

Procedure:
5-Methoxy-1-tetralone (5) (4 g, 22.6 mmol) was dissolved in 50 mL anhydrous diethyl ether, stirred, and cooled down on ice to 0° C. Ethylmagnesium bromide (19 mL, 56.8 mmol) was added dropwise to the solution, producing copious precipitation. The mixture was then heated to reflux and stirred for 10 h. After cooling, cold water was added slowly to the reaction mixture, which was then extracted with diethyl ether three times. The organic layer was evaporated to afford crude product 6. Without purification, zinc chloride (15 g, 114 mmol) was added to a solution of 6 in benzene (35 mL), then concentrated hydrochloride acid (12 mL) was added to the solution at room temperature. The reaction mixture was heated to reflux for 5 h, cooled, extracted with diethyl ether three times, and the organic layer was evaporated to afford crude product. Purification by column chromatography gave 7 (2 g). To a solution of 7 (2 g) in triglyme (15 mL) was added 10% Pd/C (2 g) and the mixture was heated to reflux for 3 days. After cooling, diethyl ether was added to the mixture and it was filtered on Celite, then washed with diethyl ether to provide compound 8.50% yield; 1H NMR δ1.37 (3H, t, J=7.8 Hz, CH3CH2—), 3.10 (2H, q, J=7.8 Hz, CH3CH2—), 4.01 (3H, s, OCH3), 6.82 (1H, d, J=7.8 Hz, H-2), 7.36-7.44 (3H, m, H-3, 6, 7), 7.64 (1H, d, J=8.7 Hz, H-4), 815 (1H, d, J=8.4 Hz, H-8).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]3[C:10](=[CH:11][C:12](I)=[CH:13][CH:14]=3)[N:9]2[CH:25]=1)=[O:5])[CH3:2].[SH:26][C:27]1[CH:28]=[C:29]([C:33]2([C:39]#[N:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]3[C:10](=[CH:11][C:12]([S:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]5([C:39]#[N:40])[CH2:34][CH2:35][O:36][CH2:37][CH2:38]5)[CH:28]=4)=[CH:13][CH:14]=3)[N:9]2[CH:25]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2c(cc(-c3ccccc3)c3ccc(I)cc32)n1
Reactant: N#CC1(c2cccc(S)c2)CCOCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn2c(cc(-c3ccccc3)c3ccc(Sc4cccc(C5(C#N)CCOCC5)c4)cc32)n1
Temperature: 60 °C

Procedure:
1v (262 mg, 0.59 mmol), 4-(3-Mercapto-phenyl)-tetrahydro-pyran-4-carbonitrile (1w, 130 mg, 0.59 mmol), Pd2dba3 (14 mg, 0.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (17 mg, 0.03 mmol), and iPr2NEt (0.27 mL, 1.9 mmol) were dissolved in 1,4-dioxane (2 mL) and degassed with N2 for 10 minutes. The mixture was heated at 60° C. for 2 hours, then cooled to room temperature and concentrated. The residue was purified by silica gel chromatography to give the desired product, 1z.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([N:16]3[CH2:23][CH2:22][CH2:21][C@@H:17]3[C:18]([OH:20])=[O:19])(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:24][C:25]([NH2:27])=[NH:26])=[N:5][CH:4]=1.[H-].[Na+].[C:30](OC(=O)[C@H]1CCCN1NS(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)([CH3:33])([CH3:32])[CH3:31]>COCCOC.CCOC(C)=O>[C:30]([O:19][C:18](=[O:20])[C@H:17]1[CH2:21][CH2:22][CH2:23][N:16]1[S:13]([C:9]1[CH:8]=[C:7]2[C:12]([C:3]([Cl:2])=[CH:4][N:5]=[C:6]2[NH:24][C:25]([NH2:27])=[NH:26])=[CH:11][CH:10]=1)(=[O:15])=[O:14])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1NS(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N3CCC[C@@H]3C(=O)O)cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)[C@H]1CCCN1S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C
Yield: 75.9 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-D-proline hydrochloride ##STR41## Guanidine hydrochloride (220 mg, 2.3 mmol) was added in one portion to a stirred suspension of NaH (55 mg, 80% dispersion by wt in mineral oil, 1.83 mmol) in DME (8 mL) and the mixture was heated at 60° C. under N2 for 30 min. 1-{[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]amino}-D-proline t-butyl ester (250 mg, 0.58 mmol) was added and the mixture heated at reflux for 5 h. The cooled mixture was diluted with EtOAc, washed with water, brine, dried (MgSO4) and the solvents evaporated in vacuo. The residue was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880NH3 (97:3:0.3) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-D-proline t-butyl ester (200 mg, 0.44 mmol) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[O:7][C:6]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:5]2.CO.[NH3:23]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:7])[NH:23][C:6]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:5]2
Reactant: COC(=O)CCCCc1cc2cc(Br)ccc2c(=O)o1
Reactant: N
Solvent: CO
Product: COC(=O)CCCCc1cc2cc(Br)ccc2c(=O)[nH]1
Reaction time: 8 h

Procedure:
A mixture of methyl 5-(6-bromo-1-oxo-1H-isochromen-3-yl)pentanoate (1.5 g, 4.42 mmol) in 7 N ammonia in MeOH (63.2 ml, 442 mmol, 100.0 equiv.) was left standing at room temperature overnight. The mixture was concentrated, diluted with EtOAc, and added 1 N HCl until pH 4. The mixture was vigorously stirred for 10 min, extracted with EtOAc (2×20 mL), washed with brine, dried over Na2SO4, filtered and evaporated to dryness to yield 1.26 g of methyl 5-(6-bromo-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate which was used as such without any further purification.