Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH2:15]([N:17](CC)CC)C.CN>O1CCCC1.CCCCCC>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:17][CH3:15])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CCN(CC)CC
Agent: CN
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(SC)nc1NC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
To a solution of 4-chloro-2-methylsulfanyl-5-pyrimidinecarboxylate ethyl ester (18.66 g, 80.4 mmol) in 260 mL of tetrahydrofuran was added triethylamine (34 mL, 244 mmol), followed by 30 mL of a 40% aqueous solution of methylamine. The solution was stirred for 30 minutes at 25° C. then concentrated in vacuo and partitioned between chloroform and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to provide a white solid. The solid was suspended in hexane and filtered to provide 14.70 g (81%) of 4-methylamino-2-methylsulfanyl-5-pyrimidinecarboxylate ethyl ester; mp 91-93° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[CH:3]=1.[O:22]1[CH:26]=[CH:25][C:24]([C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:28])=[CH:23]1.C(N(C(C)C)C(C)C)C>C(#N)C>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:4]1[CH:3]=[C:2]([N:32]2[CH2:33][CH2:34][N:29]([C:27]([C:24]3[CH:25]=[CH:26][O:22][CH:23]=3)=[O:28])[CH2:30][CH2:31]2)[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:10]=[C:6]2[N:5]=1
Reactant: O=C(c1ccoc1)N1CCNCC1
Reactant: Clc1cc(-c2ccco2)nc2cc(-c3ccccc3)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(c1ccoc1)N1CCN(c2cc(-c3ccco3)nc3cc(-c4ccccc4)nn23)CC1
Temperature: 100 °C
Yield: 99.2 %

Procedure:
A mixture of 7-chloro-5-(furan-2-yl)-2-phenylpyrazolo[1,5-a]pyrimidine (0.148 g, 0.5 mmol, 1.0 eq), furan-3-yl(piperazin-1-yl)methanone (0.180 g, 1.0 mmol, 2.0 eq,) and N-ethyl-N-isopropylpropan-2-amine (0.129 g, 1.0 mmol, 2.0 eq) in acetonitrile (5.0 mL) was heated at 100° C. for 3 hr. The completed reaction was purified by chromatography (Biotage 25 g, EtOAc/Hexane) to afford (4-(5-(furan-2-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)(furan-3-yl)methanone (0.218 g, 99%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.03-8.00 (m, 2H), 7.83 (m, 1H), 7.62 (m, 1H), 7.52-7.47 (m, 3H), 7.45-7.41 (m, 1H), 7.23 (dd, J=3.5, 0.7 Hz, 1H), 6.93 (s, 1H), 6.65 (m, 1H), 6.62 (dd, J=3.5, 1.8 Hz, 1H), 6.60 (s, 1H), 4.08 (b, 4H), 3.92 (b, 4H). 13C NMR (125 MHz, CDCl3) δ 164.1, 155.4, 152.4, 151.8, 150.1, 148.5, 144.3, 143.8, 143.2, 132.9, 129.0, 128.7, 126.4, 120.6, 112.6, 110.9, 110.1, 92.9, 88.9, 48.3. LCMS retention time: 3.20 min; purity at 215 nm=100%. HRMS m/z calculated for C24H27N5O2 ([M+H]+): 440.1717. found 440.1715.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][N:26]=[C:27]1[C:35]2[C:30](=[CH:31][C:32]([CH:36]=O)=[CH:33][CH:34]=2)[CH2:29][CH2:28]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])/[CH:22]=[CH:36]/[C:32]3[CH:31]=[C:30]4[C:35](=[CH:34][CH:33]=3)[C:27](=[N:26][O:25][CH3:24])[CH2:28][CH2:29]4)=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CON=C1CCc2cc(C=O)ccc21
Product: CON=C1CCc2cc(/C=C/C(=O)c3ccc(OC4CCN(C(=O)OC(C)(C)C)CC4)cc3)ccc21
Yield: 75 %

Procedure:
The title compound (0.9 g, 75%) was prepared from the product of Step 1 and the product of Example 1 Step 2 using the method of Example 2 Step 1. 1H NMR (CDCl3) 8.03 (2H, d, J 8.8 Hz), 7.80 (1H, d, J 15.6 Hz), 7.72 (1H, d, J 8.4 Hz), 7.56 (3H, m), 6.98 (2H, d J 8.8 Hz), 4.6 (1H, m), 4.01 (3H, s), 3.70 (2H, m), 3.35 (2H, m), 3.07 (2H, m), 2.92 (2H, m), 1.95 (2H, m), 1.80 (2H,m), 1.47 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=1)[CH:20]=[CH:21][C:22](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:22](/[CH:21]=[CH:20]/[C:19]3[CH:25]=[CH:26][CH:27]=[C:17]([C:16]([F:15])([F:28])[F:29])[CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1cccc(C(F)(F)F)c1
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(C(F)(F)F)c3)nc2n(CC)c1=O

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 3.0 g (13.9 mmol) of 3-trifluoromethylcinnamic acid. Then, the resultant crude crystals were recrystallized from acetonitrile/water to give 2.07 g (yield of Compound 156 as white needles.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[C:9]32[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[NH:23][C:22]3=[O:31])[CH:7]=1.[C:39](Cl)(=[O:41])[CH3:40].C(N(CC)CC)C>O1CCCC1>[C:39]([N:36]1[CH2:37][CH2:38][CH:33]([O:32][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=2[CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[C:9]32[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[NH:23][C:22]3=[O:31])[CH2:34][CH2:35]1)(=[O:41])[CH3:40]
Reactant: O=C1CC(c2cc(Br)ccc2OC2CCNCC2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(Cl)c2)N1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(Oc2ccc(Br)cc2C2CC(=O)NC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Yield: 46.7 %

Procedure:
In a manner similar to the method described in Example 38b, racemic (2′S,3S,4′R)-4′-[5-bromo-2-(4-piperidinyloxy)-phenyl]-6-chloro-2′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (85 mg, 0.14 mmol) was reacted with acetyl chloride (13 mg, 0.17 mmol), triethylamine in tetrahydrofuran to give the title compound as a white solid (Yield: 43 mg).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:29])=[CH:23][CH:22]=1
Reactant: Cc1ccc(-c2nn(N)c(=O)c3ccccc23)cc1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: Cc1ccc(-c2nn(NC(=O)Cc3ccc(Cl)cc3)c(=O)c3ccccc23)cc1

Procedure:
The product of Example 135A and 2-(4-chlorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.71 (s, 1H), 8.38-8.41 (m, 1H), 7.89-8.02 (m, 2H), 7.72-7.75 (m, 1H), 7.46-7.49 (m, 2H), 7.38-7.44 (m, 4H), 7.36-7.40 (m, 2H), 3.70 (s, 2H), 2.41 (s, 3H); MS (APCI+) M/Z 404 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[C:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)(=[O:22])[CH3:21]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:32]1[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([C:20](=[O:22])[CH3:21])=[CH:28][CH:27]=3)[CH2:34][CH2:33]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2ccc(C(C)=O)cc2)CC1
Yield: 90 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(4-acetylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 90%). 1H NMR (200 MHz, CDCl3): δ 2.54 (s, 3H), 3.42-3.48 (m, 4H), 3.79 (s, 3H), 4.14 (s, 4H), 6.89 (d, J=9.0 Hz, 2H), 7.10-7.50 (m, 3H), 7.69-7.80 (m, 1H), 7.91 (d, J=7.8 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=[CH:18][C:13]=1[C:14]([O:16]C)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCO.[OH-].[K+]>O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=[CH:18][C:13]=1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)cc1OCCNC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCCOc1cc(S(C)(=O)=O)ccc1C(=O)O
Temperature: 70 °C
Yield: 90.7 %

Procedure:
A mixture of methyl 2-(2-t-butoxycarbonylaminoethoxy)-4-methylsulfonylbenzoate (8.6 g, 23 mmol), EtOH (200 mL), and KOH (6.5 g, 115 mmol) in water (200 mL) was heated to 70° C. for 4 hours. The EtOH was removed in vacuo and the residue was diluted with CH2Cl2. The mixture was acidified with satd citric acid and partitioned. The organic layer was dried (Na2SO4) and concentrated to give the desired product as a solid (7.5 g, 91%).
Reaction SMILES: FC1(F)CC1C[N:6]1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O.[F:22][C:23]1([F:42])[CH2:25][CH:24]1[CH2:26][N:27]1[C:31](=[O:32])[N:30]([C:33]2[S:34][C:35]([C:39](O)=[O:40])=[C:36]([CH3:38])[N:37]=2)[CH:29]=[N:28]1.[Cl-].[NH4+]>>[F:22][C:23]1([F:42])[CH2:25][CH:24]1[CH2:26][N:27]1[C:31](=[O:32])[N:30]([C:33]2[S:34][C:35]([C:39]([NH2:6])=[O:40])=[C:36]([CH3:38])[N:37]=2)[CH:29]=[N:28]1
Reactant: Cc1nc(N2CCN(CC3CC3(F)F)C2=O)sc1C(=O)O
Reactant: Cc1nc(-n2cnn(CC3CC3(F)F)c2=O)sc1C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1nc(-n2cnn(CC3CC3(F)F)c2=O)sc1C(N)=O
Yield: 62 %

Procedure:
Following the procedure as describe in Example 16, making variations as required to replace 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(1-((2,2-difluorocyclopropyl)methyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with ammonium chloride, the title compound was obtained as a colourless solid in 62% yield: mp 273-275° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1H), 7.60 (br, 2H), 4.02-3.79 (m, 2H), 2.52 (s, 3H), 2.20-2.05 (m, 1H), 1.72-1.60 (m, 1H), 1.48-1.37 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ 163.1, 151.7, 151.4, 150.0, 132.4, 123.5, 114.4 (t), 42.7 (d), 20.8, 17.3, 14.9; MS (ES+) m/z 316.0 (M+1).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Mg].Br[C:17]1[S:21][C:20]([C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:25]([C:37]3[S:38][C:39](Br)=[CH:40][CH:41]=3)=[CH:24][C:23]=2[O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:19][CH:18]=1>C1COCC1.C(OCC)(=O)C>[CH2:7]([C:6]1[CH:5]=[CH:4][S:3][C:2]=1[C:17]1[S:21][C:20]([C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:25]([C:37]3[S:38][C:39]([C:2]4[S:3][CH:4]=[CH:5][C:6]=4[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:40][CH:41]=3)=[CH:24][C:23]=2[O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCOc1cc(-c2ccc(Br)s2)c(OCCCCCCCC)cc1-c1ccc(Br)s1
Reactant: CCCCCCCCc1ccsc1Br
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1cc(-c2ccc(-c3sccc3CCCCCCCC)s2)c(OCCCCCCCC)cc1-c1ccc(-c2sccc2CCCCCCCC)s1
Temperature: 25 °C
Yield: 30 %

Procedure:
A solution of 2-bromo-3-octylthiophene (1.800 grams, 6.533 mmol) in 7 milliliters of anhydrous THF was added slowly over a period of 20 minutes to a mechanically stirred suspension of magnesium turnings (0.238 grams, 9.79 mmol) in 3 milliliters of THF in a 250 milliliter round-bottomed flask under an inert argon atmosphere. The resultant mixture was stirred at 60° C. for 4 hours, and then cooled down to room temperature. The resultant mixture was then added via a cannula to a mixture of 1,4-bis(5-bromo-2-thienyl)-2,5-dioctyloxybenzene (1.650 grams, 2.513 mmol) and [1,3-bis(diphenylphosphinopropane]dichloronickel (II) (0.057 gram, 0.105 mmol) in 20 milliliters of anhydrous THF in a 250 milliliter round-bottomed flask under an inert atmosphere, and refluxed for 48 hours. Subsequently, the reaction mixture was diluted with 200 milliliters of ethyl acetate, was washed twice with water and dried with anhydrous magnesium sulfate. A brown solid, obtained after evaporation of the solvent, was purified by column chromotography on silica gel and recrystallized yielding 1,4-bis[5-(3-octyl-2-thienyl)-2-thienyl]-2,5-dioctyloxybenzene as a yellow crystalline product in 30 percent yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:23])[C:3]=1[CH3:24].[CH3:25][O:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)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>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:30]5[CH:31]=[N:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=5)[C:3]([CH3:24])=[C:4]([CH3:23])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1cc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc(Cl)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)cc(C)c2C)cn1
Temperature: 80 °C
Yield: 87.1 %

Procedure:
To N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (100 mg, 0.29 mmol), 6-methoxypyridin-3-ylboronic acid (67 mg, 0.44 mmol) and tetrakis(triphenylphosphine)palladium (0) (34 mg, 0.029 mmol) in 1,2-dimethoxyethane (3.0 mL), 2 M Na2CO3 (438 μL, 0.87 mmol) was added. The reaction mixture was stirred and heated at 80° C. for 15 hours under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (5 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(6′-methoxy-3,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide as a white solid (105 mg, 86.6%). ESI-MS m/z calc. 415.5. found 416.5 (M+1)+. Retention time 1.66 minutes.
Reaction SMILES: C[O:2][C:3]1[CH2:8][CH:7]=[C:6]([C:9]([OH:12])([CH3:11])[CH3:10])[CH2:5][CH:4]=1.[CH3:13][C:14]([C:22]1[CH:23]=[C:24](O)[CH:25]=[C:26]([CH:28]=1)[OH:27])([CH3:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].B(F)(F)F.CCOCC.Cl>C1C=CC=CC=1>[OH:27][C:26]1[C:25]2[C@H:5]3[CH2:4][C:3](=[O:2])[CH2:8][CH2:7][C@H:6]3[C:9]([CH3:11])([CH3:10])[O:12][C:24]=2[CH:23]=[C:22]([C:14]([CH3:13])([CH3:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:28]=1
Reactant: COC1=CCC(C(C)(C)O)=CC1
Reactant: CCCCCCC(C)(C)c1cc(O)cc(O)c1
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(=O)C[C@H]21
Temperature: 24 °C
Reaction time: 5 h

Procedure:
A solution of 504 mg. of 1-methoxy-4-(1-hydroxy-1-methylethyl)-1,4-cyclohexadiene and 708 mg. of 5-(1,1-dimethylheptyl)resorcinol in 25 ml. of benzene was stirred at 24° C. while 5 ml. of boron trifluoride diethyl etherate was added in one portion. The reaction mixture was stirred at 24° C. for five hours. The reaction mixture then was added to 20 ml. of 6N hydrochloric acid solution. After allowing the benzene solvent to evaporated from the aqueous acid solution, the solution was extracted several times with diethyl ether. The ethereal extracts were combined, washed with water and with aqueous sodium bicarbonate solution, and dried. Evaporation of the solvent under reduced pressure provided an oil, which was crystallized from hexane to afford dl-cis-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one.
Reaction SMILES: [CH:1]1([C:5]2[C:14](I)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:16][CH3:17])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:18][N:19](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[C:18]([C:14]1[C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:6][C:7]([CH2:16][CH3:17])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])#[N:19]
Reactant: CN(C)C=O
Reactant: CCc1cc(C2CCC2)c(I)cc1C(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCc1cc(C2CCC2)c(C#N)cc1C(=O)OC
Temperature: 100 °C
Reaction time: 15 h
Yield: 82 %

Procedure:
To a round-bottom flask, which was purged and maintained with a nitrogen atmosphere, was added a solution of methyl 4-cyclobutyl-2-ethyl-5-iodobenzoate (compound 181.4, 5.50 g, 16.0 mmol, 1.00 equiv) in N,N-dimethylformamide (150 mL). Zinc cyanide (2.78 g, 23.7 mmol, 1.50 equiv) and Pd(PPh3)4 (1.83 g, 1.59 mmol, 0.10 equiv) were added to the reaction mixture. The resulting solution was stirred at 100° C. for 15 h under nitrogen. After cooling to ambient temperature, the reaction was carefully quenched with 300 mL of FeSO4 (aq., sat.) and diluted with ethyl acetate. The resulting mixture was stirred vigorously then filtered through celite and washed with 1 M FeSO4, water, and ethyl acetate. The layers were separated and the aqueous phase was extracted with 2×300 mL of ethyl acetate. The combined organic layers were washed with 2×300 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:100-1:50) as eluent to furnish 3.20 g (82%) of methyl 5-cyano-4-cyclobutyl-2-ethylbenzoate as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:10][CH3:11])[CH2:8][CH2:7][O:6][CH2:5][CH:4]1[OH:9].[H-].[Na+].I[CH2:15][CH3:16]>C1COCC1>[CH2:15]([O:9][CH:4]1[C:3]([O:10][CH3:11])([O:2][CH3:1])[CH2:8][CH2:7][O:6][CH2:5]1)[CH3:16]
Reactant: COC1(OC)CCOCC1O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC1COCCC1(OC)OC
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 4,4-dimethoxytetrahydro-2H-pyran-3-ol (2.0 g, 12 mmol) in THF (20 mL) cooled in an ice bath was slowly added sodium hydride (0.60 g, 15 mmol) and the resulting slurry was stirred for 1 h. lodoethane (1.5 mL, 19 mmol) was added and the mixture was stirred at room temperature overnight. More sodium hydride (0.6 g) and iodoethane (3 mL) were added and stirring was continued another overnight. The reaction was quenched with water. The resulting solution was extracted with EtOAc twice and ether twice. The combined extracts were dried, concentrated and purified on silica gel (20% EtOAc/hexanes) to give 2.1 g (90%) of desired product. 1H NMR (CDCl3) δ 3.32-4.00 (7H, m), 3.30 (3H, s), 3.20 (3H, s), 2.05-1.70 (2H, m), 1.25-1.22 (3H, m).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8](O)=[O:9])[N:3]=1.C(Cl)(=O)C([Cl:17])=O.CN(C)C=O>COCCOC>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([Cl:17])=[O:9])[N:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CO/N=C(\C(=O)O)c1nsc(N)n1
Solvent: COCCOC
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)Cl)c1nsc(N)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 30.0 ml of 1,2-dimethoxyethane (DME), 10.0 g of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetic acid were stirred at -20° C., followed by the dropwise addition of a chlorinating reagent, which had been prepared beforehand by gradually adding 6.97 g of oxalyl chloride at 5° C. to a mixture of 100 ml of DME and 4.0 g of N,N-dimethylformamide (DMF) and then reacting them for 30 minutes. After they were reacted for 5 minutes, the reaction mixture was poured into 200 ml of ice water to precipitate crystals. The crystals were collected by filtration, washed with 100 ml of ice water, collected by filtration and then, stirred for 30 minutes in 100 ml of n-hexane. After filtration, the resulting crystals were dried under reduced pressure, whereby the title compound was obtained. Yield: 8.2 g (75.1%). Purity: 94.1%.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:17])=[C:13]([CH3:16])[CH2:14]O)=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.P(Br)(Br)[Br:25]>CCCCC>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:17])=[C:13]([CH3:16])[CH2:14][Br:25])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)c1ccc(C(C)=C(C)CO)cc1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCCCC
Product: CCC(C)(C)c1ccc(C(C)=C(C)CBr)cc1
Temperature: -5 °C
Reaction time: 3 h

Procedure:
A mixture of 72 g of 3-(p-tert.amyl-phenyl)-2,3-dimethyl-allyl alcohol and 7.2 ml of pyridine in 500 ml of n-pentane is cooled down to -5° C. At this temperature there are added dropwise while stirring over a period of 2 hours 40.2 g of phosphorus tribromide in 500 ml of n-pentane and the mixture is stirred at room temperature for 3 hours. The mixture is poured on to 500 g of ice and stirred up for 30 minutes. The pentane phase is separated and the aqueous phase is back-extracted with n-pentane. The combined n-pentane phases are washed neutral with saturated sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. The crude 3-(p-tert.amyl-phenyl)-2,3-dimethyl-allyl bromide obtained [NMR: 60 Mc, CDCl3 →1-CH2 =3.9 and 4.1 ppm (2s)] was used in the process without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:20])[C:11]3[N:12]([C:14]([C:17]([OH:19])=O)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.O[NH:22][C:23](=[NH:34])[C:24]1[CH:29]=[CH:28][C:27]([S:30](=[O:33])(=[O:32])[NH2:31])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH3:20])[C:11]3[N:12]([C:14]([C:17]4[O:19][N:34]=[C:23]([C:24]5[CH:25]=[CH:26][C:27]([S:30]([NH2:31])(=[O:32])=[O:33])=[CH:28][CH:29]=5)[N:22]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Reactant: Cc1cc(-c2ccc(Cl)cc2)cn2c(C(=O)O)cnc12
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(-c3nc(-c4ccc(S(N)(=O)=O)cc4)no3)cnc12

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-8-methyl-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.33) (143 mg, 0.5 mmol) and N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (MeOH) as an off-white solid (143 mg, 61%). MS (EI) 465.1 [(M)+]; mp 311° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[CH2:13][CH:12]1[C:14]1[NH:18][N:17]=[N:16][N:15]=1.I[CH3:20].[OH-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[CH2:13][CH:12]1[C:14]1[N:18]=[N:17][N:16]([CH3:20])[N:15]=1
Reactant: CI
Reactant: O=C1Nc2ccc(Br)cc2C12CC2c1nnn[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1nnc(C2CC23C(=O)Nc2ccc(Br)cc23)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
A suspension containing 5′-bromo-2-(tetrazole-5-yl)-spiro[cyclopropane-1,3′-[3H]indol]-2′(1′H)-one (153 mg, 0.5 mmol), iodomethane (85 mg, 0.6 mmol) and sodium hydroxide (20 mg, 0.5 mmol) in 5 mL of DMF was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness in vacuo. The solid residue was chromatographed using hexane and ethyl acetate (v/v 1:1) as eluent. The chromatographed material gave the title compound in 34% yield (55 mg). MS m/z 320 [M+1]+. 1H NMR (CDCl3): δ 8.52 (s, 1H), 7.27 (m, 1H), 7.04 (br, 1H), 6.80 (m, 1H), 4.34 (s, 3H), 3.35 (t, 1H), 2.48 (m, 1H), 2.05 (m, 1H).