Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=C1CCCC1[O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:11]([O:13][CH3:14])=[O:12].N1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)C=CC=1.Cl>O>[C:26]1([CH2:25][C:9]2[C:8]([OH:7])=[C:17]([O:18][CH3:19])[CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])[CH2:27][CH2:28][CH2:29][CH:24]=1
Reactant: C=C1CCCC1Oc1cc(C(=O)OC)ccc1OC
Reactant: c1ccc2ncccc2c1
Agent: Cl
Solvent: O
Product: COC(=O)c1ccc(OC)c(O)c1CC1=CCCC1
Temperature: 190 °C
Reaction time: 1 h

Procedure:
12.7 g of methyl 3-(2-methylenecyclopentyloxy)-4-methoxybenzoate are treated with 50 ml of quinoline and the mixture is stirred at 190° C. for 1 h. After cooling, it is treated with water, adjusted to pH 3 using 2N HCl and extracted with ethyl acetate. The residue which remains after concentrating the solvent is chromatographed on a silica gel column using ethyl acetate/petroleum ether (4:6). The chromatographically pure fractions are concentrated and dried in a high vacuum. 10.2 g of the title compound are obtained as a yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[C:14](C)=[N:13][NH:12][C:11]=3[NH2:16])[S:9][C:5]=2[CH:4]=1.[NH2:19][C:20]1[CH:21]=[C:22]([S:26]([NH:29][CH3:30])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>>[NH2:16][C:11]1[NH:12][N:13]=[CH:14][C:10]=1[C:8]1[S:9][C:5]2[CH:4]=[C:3]([CH2:2][NH:19][C:20]3[CH:21]=[C:22]([S:26]([NH:29][CH3:30])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=3)[CH:18]=[CH:17][C:6]=2[N:7]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(CBr)cc2s1
Reactant: CNS(=O)(=O)c1cccc(N)c1
Product: CNS(=O)(=O)c1cccc(NCc2ccc3nc(-c4cn[nH]c4N)sc3c2)c1

Procedure:
The title compound (9 mg) was prepared starting from 40 mg of 4-(6-bromomethylbenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine and excess 3-amino-N-methylbenzenesulfonamide. MS (m/z, ES+): 429.2 (M+1, 100%).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([CH2:11][C:12]3[CH:13]=[CH:14][N:15]4[C:20]=3[C:19]([NH:21][C:22]3[CH:23]=[C:24]5[C:28](=[CH:29][CH:30]=3)[N:27]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[N:26]=[CH:25]5)=[N:18][CH:17]=[N:16]4)[CH2:7][CH2:6]2)[O:4]CC1>C1COCC1.Cl.C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:38][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][N:27]1[C:28]2[C:24](=[CH:23][C:22]([NH:21][C:19]3[C:20]4=[C:12]([CH2:11][N:8]5[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]5)[CH:13]=[CH:14][N:15]4[N:16]=[CH:17][N:18]=3)=[CH:30][CH:29]=2)[CH:25]=[N:26]1
Reactant: Fc1cccc(Cn2ncc3cc(Nc4ncnn5ccc(CN6CCC7(CC6)OCCO7)c45)ccc32)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Temperature: 25 °C
Reaction time: 168 h
Yield: 38.5 %

Procedure:
A solution of [5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (54 mg, 0.105 mmole) in a mixture of THF (1 mL) and 1 N aq. HCl (1 mL) containing 16 drops of conc. HCl was left stirring a RT for 7 days. The reaction was diluted with DCM and neutralized with sat. aq. NaHCO3 solution. After drying (Na2SO4), the solvent was removed to leave the title compound as an oil (19 mg, 39%). MS: 488 (M+H2O+H)+; HPLC Ret Time: 2.35 min (YMC Xterra ODS S7 C18, 3.0×50 mm column, 5 min gradient (component B was varied from 20 to 60%), 5 mL/min).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:7]=[CH:8][S:9][C:10]=1/[CH:11]=[CH:12]\[S:13][C:14]1[C@H:15]([CH3:28])[C@@H:16]2[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[N:17]2[C:18]=1[C:19]([O-:21])=[O:20])(=[O:3])[CH3:2].[Na+].[CH:30]1([O:36][C:37]([O:39][CH:40](I)[CH3:41])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[C:1]([O:4][CH2:5][C:6]1[N:7]=[CH:8][S:9][C:10]=1/[CH:11]=[CH:12]\[S:13][C:14]1[C@H:15]([CH3:28])[C@@H:16]2[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[N:17]2[C:18]=1[C:19]([O:21][CH:40]([O:39][C:37]([O:36][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:38])[CH3:41])=[O:20])(=[O:3])[CH3:2]
Reactant: CC(I)OC(=O)OC1CCCCC1
Reactant: CC(=O)OCc1ncsc1/C=C\SC1=C(C(=O)[O-])N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Agent: [Na+]
Product: CC(=O)OCc1ncsc1/C=C\SC1=C(C(=O)OC(C)OC(=O)OC2CCCCC2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Yield: 91.8 %

Procedure:
In the same manner as in Example 81, 159 mg of the title compound was prepared from 130 mg of sodium (1R,5S,6S)-2-[[(Z)-2-(4-acetoxymethylthiazol-5-yl)ethen-1-yl]thio]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate prepared in Example 79 and 104 mg of 1-(cyclohexyloxycarbonyloxy)ethyl iodide.
Reaction SMILES: [CH2:1]([S:3][C:4]([S:6][CH2:7][CH2:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])=[S:5])[CH3:2].[N+](=[CH2:21])=[N-]>C(OCC)(=O)C.C(O)(=O)C>[CH3:21][O:14][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[C:9](=[O:10])[CH2:8][CH2:7][S:6][C:4]([S:3][CH2:1][CH3:2])=[S:5]
Reactant: C=[N+]=[N-]
Reactant: CCSC(=S)SCCC(=O)N1CCC[C@H]1C(=O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCSC(=S)SCCC(=O)N1CCC[C@H]1C(=O)OC

Procedure:
A solution of 1-[3-[[(ethylthio)thiocarbonyl]thio]propanoyl]-L-proline in ethyl acetate is treated with an ethereal solution of diazomethane until persistent yellow color. After discharging the yellow color with a few drops of acetic acid, the solvents are removed in vacuo to yield 1-[3-[[(ethylthio)thiocarbonyl]thio]propanoyl]-L-proline methyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:16])[NH:4][C:5](=[O:15])[N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:7]=1.I[CH3:18]>>[Br:1][C:2]1[C:3](=[O:16])[N:4]([CH3:18])[C:5](=[O:15])[N:6]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH:7]=1
Reactant: CC(C)(C)OC(=O)n1cc(Br)c(=O)[nH]c1=O
Reactant: CI
Product: Cn1c(=O)c(Br)cn(C(=O)OC(C)(C)C)c1=O
Reaction time: 1.5 h
Yield: 57 %

Procedure:
The title compound was obtained according to the procedure described for Example 16 (Step 1), starting from tert-butyl 5-bromo-2,4-dioxo-pyrimidine-1-carboxylate (1.43 g, 4.92 mmol); iodomethane was used herein and the reaction was stirred under nitrogen for 1.5 hrs. The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 70:30) to afford the title compound (0.85 g, 57%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.62 (s, 9H), 3.40 (s, 3H), 8.18 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH2:11])=[CH:8][C:6]=2[N:7]=1.[C:18](Cl)(=[O:20])[CH3:19]>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH:11][C:18](=[O:20])[CH3:19])=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine (40 mg) was reacted with 21 μL of acetyl chloride via General Procedure G to give N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)acetamide.
Reaction SMILES: [N:1]1([C:6]2[C:7](=[O:13])[NH:8][C:9](=[O:12])[NH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][CH2:23][Cl:24].O>CN(C=O)C>[Cl:24][CH2:23][CH2:22][CH2:21][N:10]1[CH:11]=[C:6]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:7](=[O:13])[NH:8][C:9]1=[O:12]
Reactant: ClCCCBr
Reactant: O=c1[nH]cc(N2CCCC2)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c(=O)n(CCCCl)cc1N1CCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 5-(1-pyrrolidinyl)-2,4(1H,3H)-pyrimidinedione (507 mg, commercially available from Interchim Intermediates) and K2CO3 (386 mg) in dry DMF (10 mL) was stirred for 1 hour at room temperature. 1-Bromo-3-chloropropane (0.28 mL) was added and the mixture was stirred at room temperature for 20 hours. Water was added and the resulting mixture was extracted with ethyl acetate. The organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by a silica flash chromatography (eluting with A: dichloromethane, B: dichloromethane/methanol=9/1 at ratio A:B=6:4) to give the title compound as a colourless oil (150 mg).
Reaction SMILES: [NH2:1][C:2]1[S:10][C:9]2[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5][C:4]=2[C:3]=1[C:18]([O:20]CC)=O.C(O)(=O)C.[CH:27](N)=[NH:28]>CN(C=O)C>[O:20]=[C:18]1[NH:28][CH:27]=[N:1][C:2]2[S:10][C:9]3[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:5][C:4]=3[C:3]1=2
Reactant: CCOC(=O)c1c(N)sc2c1CN(C(=O)OC(C)(C)C)CC2
Reactant: N=CN
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2sc3nc[nH]c(=O)c3c2C1
Temperature: 100 °C
Yield: 56.4 %

Procedure:
5-tert-Butyl 3-ethyl 2-amino-6,7-dihydrothieno[3,2-c]pyridine-3,5(4H)-dicarboxylate from Example 73A (780 mg, 2.39 mmol) was dissolved in DMF (8 mL), and formamidine acetate (373 mg, 3.58 mmol) was added. The reaction mixture was heated to 100° C. overnight. The solvent was then removed in vacuo, and the residue was dissolved in ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was triturated with tert-butyl methyl ether, and the precipitate was collected by suction filtration to yield 414 mg (56%) of the title compound as a tan solid. The mother liquor was concentrated and purified by preparative HPLC to yield a second batch of 36 mg (5%).
Reaction SMILES: [OH:1][C:2]1[C:10]2[NH:9][C:8]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH:31]([CH2:35][CH2:36][CH2:37]Br)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:8]2[N:7]([CH2:37][CH2:36][CH2:35][CH:31]3[CH2:32][CH2:33][CH2:34][N:29]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:30]3)[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:37][CH2:36][CH2:35][CH:31]4[CH2:32][CH2:33][CH2:34][N:29]([C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:28])[CH2:30]4)[C:10]=3[N:9]=2)=[CH:14][CH:15]=1
Reactant: Oc1cccc2nc(COc3ccc(Cl)cc3)[nH]c12
Reactant: CC(C)(C)OC(=O)N1CCCC(CCCBr)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(CCCOc2cccc3c2nc(COc2ccc(Cl)cc2)n3CCCC2CCCN(C(=O)OC(C)(C)C)C2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-hydroxy-2-(4-chlorophenoxymethyl)benzimidazole (500 mg, 1.82 mmol) in dry N,N-dimethylformamide (8 ml) was treated with sodium hydride (60% in mineral oil, 162 mg, 4.0 mmol, 2.2 eq). The resulting mixture was stirred at room temperature under a stream of nitrogen for about one hour. To this reaction mixture (RS) 3-[1-(t-butoxycarbonyl)piperidin-3-yl)propyl bromide (4.0 mmol, 2.2 eq) was added and the resulting mixture was stirred for three hours at 70° C. The reaction was quenched by the addition of 10 ml of water. The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined and washed with water (2×10 ml), and then brine (1×10 ml), and then dried over magnesium sulfate. The solvents were removed in vacuo to yield a light brownish crude material. The desired title product was further purified by flash chromatography.
Reaction SMILES: C([SiH2][O:6][C:7](C1C=CC=CC=1)(C1C=CC=CC=1)[C:8]12[CH:23]([OH:24])[CH:12]([CH:13]([N:15]3[CH:20]=[CH:19][C:18](=[O:21])[NH:17][C:16]3=[O:22])[O:14]1)[O:11][N:10]([CH3:25])[CH2:9]2)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:24][CH:23]1[C:8]2([CH2:7][OH:6])[O:14][CH:13]([N:15]3[CH:20]=[CH:19][C:18](=[O:21])[NH:17][C:16]3=[O:22])[CH:12]1[O:11][N:10]([CH3:25])[CH2:9]2
Reactant: CN1CC2(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)OC(n3ccc(=O)[nH]c3=O)C(O1)C2O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN1CC2(CO)OC(n3ccc(=O)[nH]c3=O)C(O1)C2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 54 (1 mmol) in THF (5 mL) was added TBAF (2.5 mmol, 2.5 mL of a 1 M solution in THF). After stirring at room temperature for 2 hours, mixture was concentrated. Purification of the resultant residue by silica gel chromatography gave compound 55 near quantitative yield
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[NH:4][C:5]1[S:6][C:7]2[C:13]([CH:14]([OH:18])[CH:15]([Br:17])[CH3:16])=[CH:12][CH:11]=[C:10]([O:19][CH3:20])[C:8]=2[N:9]=1>O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:21])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14](=[O:18])[CH:15]([Br:17])[CH3:16])=[CH:12][CH:11]=[C:10]([O:19][CH3:20])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(C(O)C(C)Br)c2s1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)Nc1nc2c(OC)ccc(C(=O)C(C)Br)c2s1
Temperature: 70 °C

Procedure:
5.0 g of [7-(2-bromo-1-hydroxy-propyl)-4-methoxy-benzothiazol-2-yl]-carbamic acid methyl ester 0.0133 Mol) were suspended in water (30 ml) and 2.0 g of CrO3 (0.02 Mol), dissolved in acetic acid (30 ml), were added. The reaction mixture was heated to 70° C. for 2 hrs. and then evaporated to dryness. The residue was taken up in sat. NaHCO3 (200 ml), extracted 4× with ethyl acetate (200 ml each) and the combined organic phases were dried over MgSO4. The title compound was obtained as orange crystals (74%); F.p.: 199-201° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][CH3:13])=[C:7]([N+:14]([O-])=O)[CH:6]=1)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:29]([N:36]1[C:40](=[O:41])[C:39](=[C:42]2[N:46]([CH3:47])[C:45]3[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=3[S:43]2)[S:38][CH2+:37]1SC)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:36]1[C:40](=[O:41])[C:39](=[C:42]2[N:46]([CH3:47])[C:45]3[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=3[S:43]2)[S:38][C:37]1=[N:14][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[NH:11][CH2:12][CH3:13])[C:4]([NH:3][CH2:1][CH3:2])=[O:17])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCNC(=O)c1ccc(NCC)c([N+](=O)[O-])c1
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNC(=O)c1ccc(NCC)c(N=C2SC(=C3Sc4ccccc4N3C)C(=O)N2Cc2ccccc2)c1

Procedure:
In a manner similar to Example 30, intermediate N-ethyl-4-ethylamino-3-nitrobenzamide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. MS(ESI): 544 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1.Br>CCOCC.C(O)C.[Pt]=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2=CCCCC2)cc1
Agent: O=[Pt]
Agent: Br
Solvent: CCO
Solvent: CCOCC
Product: Brc1ccc(C2CCCCC2)cc1

Procedure:
1-Bromo-4-(1-cyclohexen-1-yl)benzene was hydrogenated in an ether ethanol solvent containing 50% HBr using a platinum oxide catalyst to give the desired product, b.p. 121°-126°C/3 mm.
Reaction SMILES: C[O:2][C:3](OC)([OH:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8][CH:7]=1>O1CCOCC1.[Pd]>[CH:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:14])=[O:2])=[CH:7][CH:8]=1)=[O:13]
Reactant: COC(O)(C=Cc1ccc(C=O)cc1)OC
Agent: [Pd]
Solvent: C1COCCO1
Product: O=Cc1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
A solution of 16.7 g of 4-formylcinnamic acid dimethyl acetal in 200 ml of dioxane was hydrogenated in the presence of 1 g of 5% palladium-on-carbon at room temperature and atmospheric pressure. After about 61/2 hrs., the theoretical volume of hydrogen was consumed and the uptake ceased. The reaction mixture was filtered through Celite and the filter cake was washed with 300 ml of dioxane. The filtrate was concentrated to a final volume of 200 ml, 200 ml of 1N hydrochloric acid was added, the solution was stirred at room temperature for 4 hrs. and then evaporated to dryness. The residue was dissolved in 700 ml of methylene chloride, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to a final volume of 100 ml and the solution was allowed to stand at 0° for 16 hrs. The precipitate was collected, washed with 1:1 methylene chloride-petroleum ether and dried at 55° for 4 hrs. under vacuum to give 10.9 g (81%) of 4-formyldihydrocinnamic acid as colorless crystals, m.p. 134°-138°.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[CH:12]([Mg]Br)=[CH2:13].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:9][CH:13]=[CH:12]2
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1cccc(F)c1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Fc1ccc2cc[nH]c2c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-3-fluoro-1-nitrobenzene (13 g) in anhydrous THF (80 mL) was added 1 M vinylmagnesium bromide in THF (178 mL) dropwise at −78° C. slowly. Then the mixture was allowed to warm to RT and stirred for 2 hours. TLC indicated the reaction was complete. The reaction mixture was poured into saturated NH4Cl solution, the organic phase was separated by extraction with EtOAc (3×200 mL). Purification by column chromatography afforded of 7-bromo-6-fluoro-1H-indole (D140) (3 g) as a brown oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.Cl[CH2:21][C:22]1[C:23]([CH3:39])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1.O>CN(C)C=O>[CH3:39][C:23]1[C:22]([CH2:21][O:19][C:6]2[CH:7]=[CH:8][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[N:15]3)=[C:4]([CH3:3])[CH:5]=2)=[CH:27][CH:26]=[C:25]([C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]([F:37])([F:38])[F:36])=[CH:32][CH:33]=2)[N:24]=1
Reactant: Cc1nc(-c2ccc(OC(F)(F)F)cc2)ccc1CCl
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(-c3ccc(OC(F)(F)F)cc3)nc2C)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
26 mg (0.66 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 153 mg (0.66 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 8.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 200 mg (0.66 mmol) 3-chloromethyl-2-methyl-6-(4-trifluoromethoxy-phenyl)-pyridine were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 16 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, n-heptane, and ether. The residue was dried at 40° C. in vacuum to give 300 mg (91%) of the title compound as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH2:5][OH:6].C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[O:6]
Reactant: Cc1ccc(CO)cc1Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C=O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To a solution of 3-chloro-4-methylbenzyl alcohol (2.00 g) and triethylamine (8.9 ml) in a dimethyl sulfoxide (10 ml) was added sulfur trioxide-pyridine complex (4.47 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into ice water, and extracted with ether. The organic layer was washed with 1N hydrochloric acid, saturated brine and a saturated aqueous sodium hydrogencarbonate solution, dried over magnesium sulfate, and concentrated to dryness under reduced pressure to give the objective compound (1.40 g) as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]([S:22]([NH2:25])(=[O:24])=[O:23])=[C:19]([CH3:26])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:27].[CH:31]1([C:34](O)=[O:35])[CH2:33][CH2:32]1>>[CH:31]1([C:34]([NH:25][S:22]([C:20]2[S:21][C:17]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:28])[C:2]([CH3:1])([CH3:29])[CH3:30])=[C:7]([CH3:27])[CH:8]=3)([CH2:13][CH3:14])[CH2:15][CH3:16])=[CH:18][C:19]=2[CH3:26])(=[O:24])=[O:23])=[O:35])[CH2:33][CH2:32]1
Reactant: O=C(O)C1CC1
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c(S(=O)(=O)NC(=O)C2CC2)s1
Yield: 60 %

Procedure:
Using a procedure analogous to Example 163, 5-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid amide and cyclopropanecarboxylic acid give the title compound (60%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:9]Br)=[N:4][C:5]([F:8])=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>ClCCl>[Br:1][C:2]1[C:3]([CH2:9][NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[N:4][C:5]([F:8])=[CH:6][CH:7]=1
Reactant: COc1ccc(CN)cc1
Reactant: Fc1ccc(Br)c(CBr)n1
Solvent: ClCCl
Product: COc1ccc(CNCc2nc(F)ccc2Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.9 %

Procedure:
To a solution of 3-bromo-2-bromomethyl-6-fluoro-pyridine (2.70 g, 10.0 mmol, 1.0 equiv) in dichloromethane (20 mL) was added a solution of 4-methoxybenzylamine (2.74 g, 20.0 mmol, 2.0 equiv) in dichloromethane (5 mL) and the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with dichloromethane, washed with H2O, dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, eluted with petrol—EtOAc 0-50%) to afford (3-bromo-6-fluoro-pyridin-2-ylmethyl)-(4-methoxy-benzyl)-amine (1.2 g). MS: [M+H]+=326.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:53]([O:57][CH2:58][CH3:59])(=[O:56])[CH2:54]O>C1COCC1.C(OCC)(=O)C>[CH2:58]([O:57][C:53](=[O:56])[CH2:54][O:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([O:24][C:23]2[CH:32]=[CH:33][C:20]([CH2:19][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=3[CH3:18])=[CH:21][CH:22]=2)[CH:26]=1)[CH3:59]
Reactant: CCOC(=O)CO
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(O)c3)cc2)cccc1[N+](=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 61F (1.29 g, 2.93 mmoles), triphenylphophine (1.54 g, 5.86 mmoles), and di-t-butylazodicarboxylate (1.01 g, 4.40 mmoles) in anhydrous THF (6 mL) were treated with ethyl glycolate (0.35 mL, 3.66 mmoles). The reaction was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with H2O, brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by chromatography on a pre-packed Biotage silica gel column (hexanes to 10% ethyl acetate:hexanes) to provide the title compound.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].O1CCOCC1.[Br:18]N1C(=O)CCC1=O>COCCO>[Br:18][C:7]1[NH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][C:8]=1[CH2:10][OH:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCc1nc(CO)c[nH]1
Solvent: C1COCCO1
Solvent: COCCO
Product: CCCCc1nc(CO)c(Br)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29 %

Procedure:
10 g of 2-butyl-1H-imidazole-4-methanol (obtained by EP 0,253,310) were introduced into 150 ml of dioxane and 150 ml of 2-methoxyethanol with stirring and 12.7 g of N-bromo succinimide were added. The mixture was stirred at 40° C. for 2 hours and the reaction medium was allowed to cool down to ambient temperature for 90 minutes. After evaporation, the crystals were taken up in 250 ml of ethyl acetate and 150 ml of water and extraction was carried out with ethyl acetate. The extracts were washed with water, dried and filtered. Activated charcoal was added to the solution which was stirred for 10 minutes, followed by filtration and evaporation. The crystals were solubilized in 64 ml of hot ethyl acetate and then the solution stood for 90 minutes at 0° C. After separation, the crystals were washed with ethyl acetate, then with methylene chloride and separated and dried to obtain 4.39 g of the expected product melting at 160 ° C.