Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[NH:15][C:16](=[O:19])[CH2:17][Br:18].C(Cl)Cl>C(N(CC)CC)C>[C:1]1([S:7]([O:11][C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=2)[NH:15][C:16](=[O:19])[CH2:17][Br:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CBr)Nc1cccc(O)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CBr)Nc1cccc(OS(=O)(=O)c2ccccc2)c1

Procedure:
To a mixture of 4.4 g. of benzene sulfonyl chloride and 5.7 g. of 3'-hydroxy bromoacetanilide in 100 ml. of methylene chloride is added dropwise 2.6 g. of triethylamine. The product is recovered by washing with cold water, drying and removal of the solvent. There is obtained 9.0 g. of the title compound, nD30 = 1.5830.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=2)[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.Br[CH2:16][CH2:17][CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:19][CH2:18][CH2:17][CH2:16][O:14][C:10]1[CH:9]=[C:8]([C:1]2[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: OCCCBr
Reactant: Oc1cccc(-c2cccc(O)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCCOc1cccc(-c2cccc(O)c2)c1

Procedure:
26.0 g (0.140 mol) of biphenyl-3,3′-diol and 10.0 g of 3-bromo-1-propanol are dissolved in 300 ml of acetone, and, after addition of 19.3 g (0.140 mol) of potassium carbonate, the mixture is heated under reflux overnight. The batch is subsequently filtered and evaporated, and the residue is chromatographed on silica gel with toluene/ethyl acetate (1:1), giving 3′-(3-hydroxypropoxy)biphenyl-3-ol as colourless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]2[NH:6][C:7](=[O:35])[C@H:8]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)[N:9]([CH2:12][C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][C:18]([OH:20])=[O:19])=[O:14])[C:10](=[O:11])[C:4]=2[CH:3]=1.[CH2:38]([N:45]=[C:46]=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C>[CH2:38]([NH:45][C:46](=[O:47])[NH:1][C:2]1[CH:37]=[CH:36][C:5]2[NH:6][C:7](=[O:35])[C@H:8]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)[N:9]([CH2:12][C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][C:18]([OH:20])=[O:19])=[O:14])[C:10](=[O:11])[C:4]=2[CH:3]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1ccc2c(c1)C(=O)N(CC(=O)NC(CC(=O)O)c1ccccc1)[C@@H](Cc1ccc(O)cc1)C(=O)N2
Solvent: CN(C)C=O
Product: O=C(O)CC(NC(=O)CN1C(=O)c2cc(NC(=O)NCc3ccccc3)ccc2NC(=O)[C@@H]1Cc1ccc(O)cc1)c1ccccc1
Temperature: 45 °C
Yield: 31.5 %

Procedure:
To a solution of 3-(R,S)-{2-[7-amino-3-(S)-(4-hydroxy-benzyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-phenyl-propionic acid (0.1 mmol, 50mg) in DMF (2.5 mL) was added benzylisocyanate (31 μl 0.25 mmol). The mixture was shaken at 45° C. over night until no starting material was detected by HPLC. Afterwards the solution was concentrated in vacuo. The crude product was purified by RP-HPLC to give 3-(R,S)-{2-[7-(3-benzyl-ureido)-3-(S)-(4-hydroxy-benzyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-phenyl-propionic acid (20 mg): MS 634 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:18]3[S:19][CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[N:22]=3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:41][CH2:42][C:43]([O:45]CC)=[O:44]>C(O)C.O1CCCC1.[OH-].[Na+].O.Cl>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:18]3[S:19][CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:25][CH:24]=4)[N:22]=3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:41][CH2:42][C:43]([OH:45])=[O:44]
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccc(C(F)(F)F)cc4)cs3)cc2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)CCc1ccc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccc(C(F)(F)F)cc4)cs3)cc2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
The yellow oil obtained in Example 43 was dissolved in a mixed solvent of ethanol (5 mL) and tetrahydrofuran (5 mL), and 2N aqueous sodium hydroxide solution (2 mL) was added. The mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and neutralized with 1N hydrochloric acid. The precipitated solid was collected by filtration, washed with water and dried to give the title compound (300 mg, yield 47%, 2 steps) as colorless crystals.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:35])([F:34])[C:12]1[N:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=4)[NH2:30])[CH2:23][CH2:22]3)[CH:19]=[CH:20][C:15]2=[N:14][N:13]=1.[C:36](O)(=[O:38])[CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[F:35][C:11]([F:10])([F:34])[C:12]1[N:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[C:29]([NH:30][C:36](=[O:38])[CH3:37])[CH:31]=[CH:32][CH:33]=4)[CH2:23][CH2:22]3)[CH:19]=[CH:20][C:15]2=[N:14][N:13]=1
Reactant: Nc1cccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
DIPEA (123 μl, 0.70 mmol) was added to 3-[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]aniline (obtained as described in Example 616) (85 mg, 0.23 mmol), acetic acid (16 μl, 0.28 mmol) and HATU (107 mg, 0.28 mmol) in DMA (2 mL). The resulting solution was stirred at ambient temperature for 2 hours then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile as eluents. Fractions containing the desired compound were evaporated to dryness to give N-[3-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenyl]acetamide (89 mg, 94%) as a solid.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([Si](C)(C)C)=[CH:9]2)(=[O:4])=[O:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][S:2]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)(=[O:4])=[O:3]
Reactant: C[Si](C)(C)c1cc2cc(CS(C)(=O)=O)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Cc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
5-[(Methylsulfonyl)methyl]-2-(trimethylsilyl)-1H-indole (2) (1.5 g, 0.00534 mol) was dissolved in CH2Cl2 (70 mL). Trifluoroacetic acid (2 mL) was added and the mixture was stirred at RT for 2 h. The solvent was concentrated in vacuo and the residue was dissolved in EtOAc and extracted with sat. NaHCO3 and then with brine. The organic phase was dried over MgSO4, filtered and evaporate in vacuo. Silica gel chromatography (50-100% EtOAc gradient in hexane) of the concentrate gave the product 0.57 g, 51%) as a brown oil.
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10].[C:18]([C:20]1[CH:37]=[CH:36][C:23]([O:24][CH2:25][CH:26]([NH:28][C:29](=[O:35])[C@H:30]([CH2:32][CH2:33][CH3:34])[NH2:31])[CH3:27])=[CH:22][CH:21]=1)#[N:19].O>C(Cl)Cl>[C:18]([C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][CH:26]([NH:28][C:29](=[O:35])[C@H:30]([CH2:32][CH2:33][CH3:34])[NH:31][C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])[CH3:27])=[CH:36][CH:37]=1)#[N:19]
Reactant: CCC[C@H](N)C(=O)NC(C)COc1ccc(C#N)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: CCC[C@H](NC(=O)Oc1ccccc1)C(=O)NC(C)COc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 54.7 %

Procedure:
0.5 g of N-methylmorpholine, and subsequently 0.8 g of phenyl chloroformate were added to a suspension containing 1.4 g of N1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-norvalinamide suspended in 40 ml of methylene chloride at -15° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.1 g of the desired product in the form of a colorless plated crystal (yield: 57%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:22]=[C:21]2[C:12]([N:13]3[C:18]([CH2:19][O:20]2)=[N:17][NH:16][C:15](=[O:23])[C@H:14]3[CH3:24])=[CH:11][C:10]=1[C@@H:25]1[CH2:30][CH2:29][NH:28][CH2:27][C@@H:26]1[CH3:31].C=O.[BH3-][C:35]#N.[Na+].C([O-])(O)=O.[Na+]>CC(O)=O.CO>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:22]=[C:21]2[C:12]([N:13]3[C:18]([CH2:19][O:20]2)=[N:17][NH:16][C:15](=[O:23])[C@H:14]3[CH3:24])=[CH:11][C:10]=1[C@@H:25]1[CH2:30][CH2:29][N:28]([CH3:35])[CH2:27][C@@H:26]1[CH3:31]
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4c(F)cccc4F)c([C@@H]4CCNC[C@@H]4C)cc3N21
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4c(F)cccc4F)c([C@@H]4CCN(C)C[C@@H]4C)cc3N21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a mixture of (R)-7-(2,6-difluoro-phenyl)-4-methyl-6-((3R,4R)-3-methyl-piperidin-4-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.005 g, 0.012 mmol) in AcOH (0.2 mL) and MeOH (2 mL) was added paraformaldehyde (0.004 g, 0.117 mmol) and the reaction mixture was stirred at ambient temperature for 1 h. NaBH3CN (0.002 g, 0.029 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. Aqueous saturated NaHCO3 solution (30 mL) was added and the reaction mixture was extracted with EtOAc (3×50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative TLC (eluting with 20% MeOH in EtOAc) to give (R)-7-(2,6-difluoro-phenyl)-6-((3R,4R)-1,3-dimethyl-piperidin-4-yl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.0041 g, 79%). 1H NMR (400 MHz, CD3OD): 7.47-7.54 (m, 1H), 7.13 (t, J=7.91 Hz, 2H), 6.96 (s, 1H), 6.89 (s, 1H), 4.94-4.96 (m, 1H), 4.67 (m, 2H), 3.58 (m, 1H), 2.89-3.11 (m, 3H), 2.82 (s, 3H), 2.44-2.60 (m, 2H), 2.26-2.42 (m, 1H), 1.94 (m, 2H), 1.51 (d, J=6.4 Hz, 3H), 0.94 (d, J=7.4 Hz, 3H). LC/MS (Table 1, Method 4) Rt=1.656 min.; MS m/z: 441 [M+H]+. SFC (Table 2, Method 28), Rt=4.708 min.
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1)=[N+:13]=[N-:14]>>[ClH:1].[ClH:1].[NH:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[CH2:15][N:12]1[CH:5]=[C:4]([CH2:3][CH2:2][C:6]2[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=2)[N:14]=[N:13]1
Reactant: C#CCCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCc1nc2ccccc2[nH]1
Agent: Cl
Product: Nc1nc(CCc2cn(Cc3nc4ccccc4[nH]3)nn2)c[nH]1
Yield: 95.9 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.061 g, 0.361 mmol) was reacted with 2-azidomethyl-1-H-benzimidazole (0.075 g, 0.433 mmol) following the general procedure for click reactions outlined above to produce 4-{2-[1-(1H-Benzoimidazol-2-ylmethyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1H-imidazol-2-ylamine dihydrochloride (0.066 g, 48%) of a yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.05 (s, 1H), δ 7.68 (m. 2H), δ 7.48 (m, 2H), δ 6.38 (s, 1H), δ 6.15 (s, 2H′), δ 2.90 (t, 2H), δ 2.76 (t, 2H) ppm; 13C (75 MHz, CD3OD) δ 147.4, 146.9, 146.8, 131.3, 127.0, 126.4, 124.1, 114.1, 109.2, 44.7, 24.0, 23.9 ppm; HRMS (ESI) calcd for C15H17N8 (M+) 309.1570. found 309.1572.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=3)=[CH:33][CH:32]=2)[CH2:29][CH2:30]1)=[O:27])[CH3:24]
Reactant: CC(C)=CCCC(C)Nc1c(C)noc1-c1ccc(Br)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCC=C(C)C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1,5-dimethyl-hex-4-enyl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1]OS(OC)(=O)=O.[OH:8][C:9]1[CH:17]=[CH:16][C:12]2[CH2:13][CH2:14][O:15][C:11]=2[CH:10]=1>[OH-].[Na+]>[CH3:1][O:8][C:9]1[CH:17]=[CH:16][C:12]2[CH2:13][CH2:14][O:15][C:11]=2[CH:10]=1
Reactant: COS(=O)(=O)OC
Reactant: Oc1ccc2c(c1)OCC2
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(c1)OCC2
Reaction time: 3 h

Procedure:
Dimethylsulfate (35 ml) was added over a period of 3 hours to a stirred solution of 6-hydroxy-2,3-dihydrobenzofuran (12.0 g) dissolved in 200 ml of 10% sodium hydroxide. The solution was stirred for an additional 3 hours after dimethylsulfate addition was completed. The solution was then extracted with ether, the ether extracts combined, dried, and evaporated to give a residue which was distilled (140° C. at 0.5 mm) to yield 6-methoxy-2,3-dihydrobenzofuran.
Reaction SMILES: BrC(CC)C(O)=O.O.[C:9]1([S:15]([CH:18]([CH2:22][CH3:23])[C:19](O)=[O:20])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.S(Cl)([Cl:26])=O>C(OCC)(=O)C.CN(C=O)C>[C:9]1([S:15]([CH:18]([CH2:22][CH3:23])[C:19]([Cl:26])=[O:20])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCC(C(=O)O)S(=O)(=O)c1ccccc1
Reactant: O=S(Cl)Cl
Agent: CCC(Br)C(=O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(C(=O)Cl)S(=O)(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2-Bromobutyric acid, (200 g, 1.2 mol), sodium benzenesulfinate,(236 g, 1.44 mol) and water(1000 mL) were heated to 80° C. After about 1 hour the clear solution had turned cloudy and an oil had precipitated out. After heating at 80° C. for a total of 2 hours the mixture was cooled with good stirring. The oil solidifies and the crystals were filtered off, washed with water and air-dried. Yield 162.5 g. 2-Phenylsulfonylbutyric acid (47.8 g, 0.21 mol) was suspended/dissolved in ethyl acetate (400 mL) to which was added DMF (0.5 mL), thionyl chloride (76 mL, 1.05 mol) and the mixture heated to 70° C. for 2 hrs. After this period the solution was cooled, concentrated under reduced pressure and co-evaporated with ethyl acetate (×1). The resulting pale yellow oil was used as such in the preparation of inventive coupler IC-1.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[N:12]([S:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)(=[O:27])=[O:26])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C1=C(c2c[nH]c3ccncc23)CC2CCCN2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(C2=CCN3CCCC3C2)c2cnccc21

Procedure:
from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole (10 mg, 0.0418 mmol), benzenesulfonyl chloride (20 mg, 0.113 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])[N:5]=[CH:4][C:3]=1[NH:16][C@@H:17]1[CH2:22][C@@H:21]2[CH2:23][C@@H:19]([C:20]2([CH3:25])[CH3:24])[C@H:18]1[CH3:26].[OH-].[Na+].C(OCC)(=O)C>O1CCOCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[N:5]=[CH:4][C:3]=1[NH:16][C@@H:17]1[CH2:22][C@@H:21]2[CH2:23][C@@H:19]([C:20]2([CH3:25])[CH3:24])[C@H:18]1[CH3:26]
Reactant: CCOC(=O)CCn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Br)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CCC(=O)O)c(=O)c1Br)C2(C)C
Yield: 74.4 %

Procedure:
Ethyl 3-{5-bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}propanoate (453 mg, 1.06 mmol) in 1,4-dioxane (4 mL) was stirred with 1 M aqueous sodium hydroxide (2.93 mL, 2.93 mmol) at room temperature for 1 hour. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with 1 M hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (314 mg, 80% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([OH:26])=O)(=[O:17])=[O:16])=[O:13])[N:4]=1.[CH3:27][Li].O.Cl>O1CCCC1.CCOCC>[C:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[S:15]([NH:14][C:12]([NH:11][C:5]1[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=1)=[O:13])(=[O:17])=[O:16])(=[O:26])[CH3:27]
Reactant: [Li]C
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)O)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(C)=O)n1
Reaction time: 4 h

Procedure:
A mixture containing 0.85 g of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-carboxybenzenesulfonamide in 50 ml of anhydrous tetrahydrofuran was treated with 40 ml of a 1.4 molar solution of methyl lithium (low halide, Aldrich) in ether at 25° under a nitrogen atmosphere. The mixture was stirred for 4 hours at 25° and was then poured into 500 ml of water containing 10 ml of concentrated hydrochloric acid. The precipitated oil was extracted into methylene chloride and the oil on evaporation of solvent was purified by preparative thin layer chromatography on silica gel (Analtec, 2000 micrron, 20×20 plates) by elution with ethyl acetate/hexane in a one to one ratio. The isolated product was recrystallized from a 1-chlorobutane and hexane mixture to give 0.1 g, m.p. 126°-8°. The infrared absorption showed a broadened carbonyl peak at 1710 cm-1, and the absence of the 3500 and 3400cm-1 peaks of the starting material. The nuclear magnetic resonance spectrum showed peaks at 2.6 ppm, s, 3H, ##STR58## 4.0 ppm, s, 6H, CH3O of pyrimidine; 5.7 ppm, s, 1H, pyrimidine proton at position 5; and 7.3-7.7 ppm and 8.0 ppm, m, 4H, aromatic, which are consistent with the desired structure.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].C(O)C.Br[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(OCC)(=O)C.CCCCCC>[CH3:2][C:1]1[S:3][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:4]=1
Reactant: CC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1csc(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
Thioacetamide (7.6 g, 100 mmol) was added to ethanol (60 mL), and the resultant suspension was cooled to 0° C. and treated with ethyl bromopyruvate (12.5 mL, 100 mmol). The resultant solution was stirred for five minutes at 0° C. at which time the ice bath was removed and the solution was allowed to warm to ambient temperature. After 0.5 h at ambient temperature, the solution was heated to reflux. After 12 h, the solvents were removed in vacuo, and the resultant crude product was taken up in ethyl acetate (300 mL). The organic phase was washed with saturated aqueous NaHCO3 (50 mL), and the basic aqueous solution was then extracted with additionalethyl acetate (2×50 mL). The combined organic solutions were washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford a yellow waxy solid. The crude product was dissolved in a small amount of hot ethyl acetate, diluted with hot hexane, and the resultant solution was allowed to cool to ambient temperature, seeded with a small amount of crude product, and transferred to the freezer. After 16 h the crystalline product was collected, washed with cold 8:1 hexane:ethyl acetate, and allowed to dry under high vacuum to afford ethyl 2-methyl-1,3-thiazole-4-carboxylate (11.76 g, 69% yield) as large brownish crystals. M.p. 56–58.5° C. 1H NMR (CDCl3, 300 MHz) δ 8.06 (s, 1H), 4.43 (q, 2H), 2.78 (s, 3H), 1.42 (t, 3H). MS (EI ionization) 171 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([Li])(C)(C)C.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:23])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: O=C(Cl)c1ccccc1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
5-Bromoindole(1.0 g, 5.10 mmol) was dissolved in THF (10 mL) and the resulting solution was cooled to −78° C. t-Butyl lithium (1.7 M in pentane, 10.5 mL, 17.9 mmol) was added dropwise and the solution stirred for 30 minutes before being added to a solution of benzoyl chloride (0.86 g, 6.12 mmol) in THF (10 mL) at −78° C. via cannula. The reaction mixture was allowed to warm to room temperature and was stirred overnight and was then quenched with saturated ammonium chloride and diluted with ethyl acetate. The organic phase was washed with water and brine, dried (Na2SO4), filtered and concentrated. Silica gel chromatography using 20% hexane in ethyl acetate as the eluent provided the title compound as a beige solid (0.40 g, 35%).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.Cl[CH2:14][C:15]1[N:16]=[CH:17][N:18]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=1>CS(C)=O.O>[Cl:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:14][C:15]1[N:16]=[CH:17][N:18]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:19]=1
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Clc1cccc2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Clc1cccc2c1ccn2Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 0.5 h

Procedure:
A mixture of powdered KOH (7 mmol) in DMSO (12 mL) at room temperature (rt) under N2 was stirred for 0.5 h. 4-Chloro-1H-indole (Intermediate A1) (1.67 mmol) was added and the mixture was allowed to stir for 2 h at rt. The 4-chloromethyl-1-trityl-1H-imidazole (prepared according to the procedures in: James, L. K. et al; J. Med. Chem. 1997, 20, 721. and Cordi, A. A. et al Eur. J. Med. Chem. 1990, 25, 557, incorporated herein by reference) (Intermediate A2) (1.19 mmol) was added and the mixture was stirred at rt for 18 h. The solution was diluted with H2O and extracted with ethyl acetate. The organic phase was washed with H2O, dried over MgSO4, filtered and evaporated to give the crude product. The residue was purified by chromatography on SiO2 with 1-2% MeOH in CH2Cl2 to give 4-chloro-1-(1-trityl-1H-imidazol-4-ylmethyl)-1H-indole (Intermediate A3). The protected imidazole compound (Intermediate A3) was mixed with H2O (3 mL) and acetic acid (6 mL) and heated to reflux for 1 to 2 h. The mixture was cooled to rt and made basic with 2M NaOH. The aqueous layer was extracted with ethyl acetate (2×15 mL) and the combined organic layers were dried over Na2SO4. This mixture was filtered, freed of solvent and purified by chromatography with 5% NH3:MeOH in CH2Cl2 to give 4-(4-chloro-indol-1-ylmethyl)-1,3-dihydro-imidazole (Intermediate A4) (˜20% over two steps).