Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]4[OH:34])=[CH:17][CH:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[CH2:36][C:37]1[CH:38]=[CH:39][C:40]2[O:45][CH2:44][C:43](=[O:46])[N:42]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:41]=2[CH:52]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:23][CH:22]4[O:34][CH2:36][C:37]4[CH:38]=[CH:39][C:40]5[O:45][CH2:44][C:43](=[O:46])[N:42]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:41]=5[CH:52]=4)=[CH:19][CH:20]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccc4c(c3)OCO4)cc2)C(O)C1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4ccc5c(c4)OCO5)cc3)cc21

Procedure:
Analogously to Method D, 0.600 g of tert-butyl 4-{4-[3-(benzo[1,3]dioxol-5-yloxy)propoxy]phenyl}-3-hydroxypiperidine-1-carboxylate and 0.385 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a colourless oil. Rf=0.13 (1:2 EtOAc-heptane); Rt=5.68.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CN(C=O)C.O>[N:20]1([C:2]2[S:3][C:4]3[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cccc2nc(Br)sc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc2nc(N3CCOCC3)sc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.7 %

Procedure:
To 0.200 g (0.77 mmol) of 2-bromo-7-nitro-1,3-benzothiazole in 2 mL of DMF was added 0.21 g (1.5 mmol) of potassium carbonate and 81 μL (0.93 mmol) of morpholine. The mixture was stirred at room temperature for 72 h and diluted with water. The precipitate that formed was collected by filtration and purified by flash chromatography eluting with a 33% ethyl acetate/hexanes mixture to give 0.075 g (37%) of the title compound as a cream colored powder.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[C:17]#[CH:18].[CH:23](=[O:25])[CH3:24]>C1COCC1.CCCCCC>[OH:25][CH:23]([CH3:24])[CH:18]=[CH:17][C:16]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: C#CC(=O)OCC
Reactant: CC=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C=CC(C)O
Temperature: -10 °C
Reaction time: 1.17 h

Procedure:
2,2,6,6-Tetramethylpiperidine (74.16 g, 0.525 mot) is dissolved in THF (600 ml) and cooled to −45° C. nBuLi is added (0.022 mol g−1 in hexane, 228.3 g, 0.500 mol) and is allowed to warm to −10° C. The reaction mixture is cooled to −70° C. Then ethyl propiolate (49.05 g, 0.500 mol) is added dropwise over 25 min at ≦−66° C. After additional stirring for 70 min at −72° C., acetaldehyde (23.35 g, 0.530 mol) in cold THF (30 ml) is added dropwise in 30 min at ≦−67° C. After stirring at −72° C. for 1 hour the reaction mixture is quenched with 2 M HCl (700 ml) and extracted with tBuOMe (650 and 400 ml). The organic phases are washed with saturated NaHCO3 (200 ml) and brine (3×125 ml) successively. The combined organic phases are dried with Na2SO4 and evaporated under reduced pressure at 40° C. Filtration over SO2 (150 g) with tBuOMe:heptane fraction (0.5 l) and tBuOMe (0.2 l) yields crude 20 (rac-Ethyl 4-hydroxypent-2-enoate) (6744 g, 90%, HPLC: ˜90 area %) as a brown oil. The crude product is used in the next step without further purification. 1H-NMR- and GC-analysis corresponded to an analogous synthesis of 20 (rac-Ethyl 4-hydroxypent-2-inoate) with LDA as base.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br-:18].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O.C(=O)([O-])O.[Na+]>C1COCC1>[Br:18][CH2:16][C:15]([C:7]1[CH:8]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)=[O:17]
Reactant: [Br-]
Reactant: CC(=O)c1cc(C(C)(C)C)cc(C(C)(C)O)c1
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.7 %

Procedure:
1-[3-tert-Butyl-5-(1-hydroxy-1-methylethyl)phenyl]ethanone (O2.100; 50 mg) was initially charged in THF (5 ml) while stirring at RT, and admixed with phenyltrimethylammonium tribromide (80 mg). After stirring at RT for 3 h, the mixture was left to stand overnight and admixed with water and saturated sodium hydrogencarbonate solution. Then it was extracted three times with EA, and the combined EA phases were dried over sodium sulfate, filtered and concentrated. The residue was purified using silica gel (10 g cartridge, n-heptane/EA gradient). 42 mg of the title compound were obtained. LC-MS rt: 1.10 min [M+H—H2O]+: 295.1 (met. b)
Reaction SMILES: C[O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:7]=1[Cl:13].[C:15]12([CH2:25][CH2:26][C:27]3[NH:31][C:30]([CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[N:29][C:28]=3[C:38](O)=[O:39])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2>>[C:15]12([CH2:25][CH2:26][C:27]3[NH:31][C:30]([CH:32]4[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]4)=[N:29][C:28]=3[C:38]([NH:12][C:10]3[CH:9]=[CH:8][C:7]([Cl:13])=[C:6]([CH:5]=[CH:4][C:3]([OH:2])=[O:14])[CH:11]=3)=[O:39])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2
Reactant: COC(=O)C=Cc1cc(N)ccc1Cl
Reactant: O=C(O)c1nc(C2CCCCC2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Product: O=C(O)C=Cc1cc(NC(=O)c2nc(C3CCCCC3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)ccc1Cl

Procedure:
3-(5-Amino-2-chloro-phenyl)-acrylic acid methyl ester (prepared in two steps from 2-chloro-5-nitro-benzaldehyde) was reacted with 5-(2-adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) according to the procedure of Example 20, step d. The methyl ester was hydrolysed using the same procedure as in Example 36, step d to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 10.80 (1H, br s), 8.25 (1H, d), 7.96 (1H, d), 7.87 (1H, d), 7.55 (1H, d), 6.44 (1H, d), 2.94 (3H, m), 1.98-1.33 (27H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 55.45; H, 7.91; N, 6.97%. C38H55ClN4O8.5.0 mols H2O requires: C, 55.57; H, 7.98; N, 6.82%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13](F)[CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][CH:5]2[NH2:16].[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([CH2:27][C:28](O)=[O:29])=[C:21]2[CH3:31].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][CH:5]2[NH:16][C:28](=[O:29])[CH2:27][C:22]1[NH:23][C:24]2[C:20]([C:21]=1[CH3:31])=[CH:19][C:18]([F:17])=[CH:26][CH:25]=2
Reactant: NC1CC2(CCC2)Oc2c(F)cc(F)cc21
Reactant: Cc1c(CC(=O)O)[nH]c2ccc(F)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(CC(=O)NC2CC3(CCC3)Oc3ccc(F)cc32)[nH]c2ccc(F)cc12

Procedure:
The title compound was prepared from Intermediate 6 (200 mg, 0.963 mmol) and (5-fluoro-3-methyl-1H-indol-2-yl)acetic acid (200 mg, 0.963 mmol) in presence of EDCI.HCl (276 mg, 1.145 mmol), HOBt (221 mg, 1.145 mmol) and triethylamine (401 μl, 3.003 mmol) in dichloromethane (10 ml) as described in Example 1 to give 18 mg of the product as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.52-1.74 (m, 4H), 1.88-1.95 (m, 2H), 2.08-2.25 (m, 2H), 2.40 (s, 3H), 3.70 (s, 2H), 5.23 (q, J=8.7 Hz, 1H), 5.68 (d, J=9.0 Hz, 1H), 6.61-6.66 (m, 2H), 6.72-6.89 (m, 2H), 7.07-7.18 (m, 2H), 8.01 (s, 1H); ESI-MS (m/z) 397.33 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][C:21]([C:27]([O:29]C)=[O:28])=[CH:20][C:19]=3[CH:31]=2)[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][C:21]([C:27]([OH:29])=[O:28])=[CH:20][C:19]=3[CH:31]=2)[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH3:3]
Reactant: CCCOc1cccc(CCCOc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOc1cccc(CCCOc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 63.4 %

Procedure:
To methyl 7-[3-(3-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (765 mg) dissolved in THF-methanol (15-7.5 ml) was added a 2 M aqueous solution of potassium carbonate (1.5 ml), and the resulting mixture was stirred at 60° C. for 18 hours. The reaction mixture was treated with 1 N hydrochloric acid to bring the pH to 2. The resulting mixture was extracted with ethyl acetate and the organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. After concentration under reduced pressure to remove the solvent, the precipitated crystals were washed with hexane-ethyl acetate to obtain 7-[3-(3-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (470 mg) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:36][CH2:37][O:38][Si:39]([C:52]([CH3:55])([CH3:54])[CH3:53])([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=O)=O>>[Si:39]([O:38][CH2:37][CH2:36][CH:16]([N:11]1[CH:12]=[C:13]([O:14][CH3:15])[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:28]#[N:29])=[CH:9][C:10]1=[O:27])[C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])([C:52]([CH3:53])([CH3:54])[CH3:55])([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)[Si](OCCOS(=O)(=O)C(F)(F)F)(c1ccccc1)c1ccccc1
Reactant: COc1cn(CC(=O)OCc2ccccc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Product: COc1cn(C(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(=O)OCc2ccccc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
1.00 g (2.45 mmol) of benzyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in the presence of 2.69 ml (2.69 mmol, 1.1 eq.) of bis(trimethylsilyl)lithium amide (1M in tetrahydrofuran) and 1.59 g (3.67 mmol, 1.5 eq.) of 2-{[tert-butyl(diphenyl)silyl]oxy}ethyl trifluoromethanesulphonate were reacted according to General Method 7B. Yield: 708 mg (40% of theory)
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:18]1([CH2:24][C:25](O)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[C:18]1([CH2:24][C:25]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: OCc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)OCc1ccccc1
Yield: 98 %

Procedure:
To a suspended CH2Cl2 (2 ml) solution of 2-chloro-1-methylpyridinium iodide (306 mg, 1.2 mmol) was added a mixture of benzyl alcohol (108 mg, 1.0 mmol), phenylacetic acid (136 mg, 1.0 mmol) and 2,6-lutidine (257 mg, 2.4 mmol) in CH2Cl2 (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and benzyl phenylacetate was isolated in 98% yield.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[F:7][C:8]([F:16])([F:15])[C:9]([CH2:11][C:12](=O)[CH3:13])=O.C([O-])([O-])=O.[K+].[K+]>O>[CH3:13][C:12]1[NH:6][C:4](=[O:5])[C:3]([C:1]#[N:2])=[C:9]([C:8]([F:16])([F:15])[F:7])[CH:11]=1
Reactant: N#CCC(N)=O
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(C(F)(F)F)c(C#N)c(=O)[nH]1
Temperature: 23 °C
Reaction time: 15 h
Yield: 52.5 %

Procedure:
To a solution of 2-cyanoacetamide (14.0 g, 166 mmol) and trifluoroacetylacetone (20.0 ml, 166 mmol) in H2O (332 ml) was added K2CO3 (6.60 g, 47.9 mmol). The mixture was stirred at 23° C. for 15 h. The precipitated solid was filtered with Buchner funnel, washed with ice cold H2O, and dried with hot air (60° C., 16 h) to give the titled compound (17.6 g, 52%). 1H NMR (400 MHz, DMSO-d6): δ ppm 2.38 (s, 3H), 6.66 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([CH2:4][S:5][CH3:6])=[O:3].C([Li])CCC.CCCCCC.[F:18][C:19]1[CH:26]=[C:25](F)[C:24]([F:28])=[CH:23][C:20]=1[C:21]#[N:22]>C1COCC1>[F:18][C:19]1[CH:26]=[C:25]([CH:4]([S:2]([CH3:1])=[O:3])[S:5][CH3:6])[C:24]([F:28])=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: CSCS(C)=O
Reactant: N#Cc1cc(F)c(F)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSC(c1cc(F)c(C#N)cc1F)S(C)=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
(Methylsulfinyl)(methylthio)methane (3.16 g, 0.0255 mol) was dissolved in 50 mL of dry THF under argon and then cooled to −78° C. Butyllithium in hexane (16 mL 1.6M, 0.0256 mol) was added dropwise with stirring. The mixture was stirred for 15 min. Meanwhile a solution of 2,4,5-trifluorobenzonitrile (2.0 g; 0.013 mol) in 50 mL of dry THF was cooled to −78° C. under argon and the former solution was added through a cannula to the latter solution over a period of 3-5 min. After 30 min, the cooling bath was removed and when the reaction had reached room temperature it was poured into 200 mL of water. The THF was evaporated and the remaining aqueous layer was extracted three times with diethyl ether. The combined ether phase was washed with water, dried (Na2SO4) and evaporated. The crude product started to crystallise and could be used as such in the next step. Yield: 2.8 g (84%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([CH:11]2[CH2:13][O:12]2)=[CH:4][CH:3]=1.[OH:14][CH:15]([C:23]1[CH:32]=[CH:31][C:26]2[C:27](=[O:30])[O:28][CH2:29][C:25]=2[C:24]=1[CH3:33])[CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CCO>[F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([CH:11]([OH:12])[CH2:13][N:20]2[CH2:21][CH2:22][N:17]([CH2:16][CH:15]([OH:14])[C:23]3[CH:32]=[CH:31][C:26]4[C:27](=[O:30])[O:28][CH2:29][C:25]=4[C:24]=3[CH3:33])[CH2:18][CH2:19]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(O)CN2CCNCC2)ccc2c1COC2=O
Reactant: Cc1c(C2CO2)ccc(F)c1C#N
Solvent: CCO
Product: Cc1c(C(O)CN2CCN(CC(O)c3ccc4c(c3C)COC4=O)CC2)ccc(F)c1C#N

Procedure:
6-Fluoro-2-methyl-3-oxiran-2-ylbenzonitrile (69.2 mg, 0.391 mmol), 5-(1-hydroxy-2-piperazin-1-ylethyl)-4-methyl-2-benzofuran-1(3H)-one (54.0 mg, 0.195 mmol) was dissolved in EtOH (5 ml) then microwaved at 150° C. for 1 hr. Evaporated off ethanol and the residue was purified by mass directed hplc to yield 6-fluoro-3-(1-hydroxy-2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-2-methylbenzonitrile.
Reaction SMILES: [O:1]=[C:2]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[CH:3]=[CH:4][Sn](CCCC)(CCCC)CCCC.[NH2:25][C:26]1[N:31]=[C:30]([NH2:32])[C:29](I)=[C:28]([CH3:34])[N:27]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN(C)C=O>[NH2:25][C:26]1[N:31]=[C:30]([NH2:32])[C:29]([CH:4]=[CH:3][C:2]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:1])=[C:28]([CH3:34])[N:27]=1
Reactant: Cc1nc(N)nc(N)c1I
Reactant: CCCC[Sn](C=CC(=O)c1ccc(Cl)cc1)(CCCC)CCCC
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(N)c1C=CC(=O)c1ccc(Cl)cc1

Procedure:
This compound is prepared in a manner analogous to that of Step E of Example 4, using 2.9 grams of (0.0064 mole) of 1-oxo-1-(4-chlorophenyl)-3tributylstannyl-2-propene, 1.2 grams (0.0048 mole) of 2,4-diamino-5-iodo-6-methylpyrimidine (prepared in Step B Example 3), 0.04 gram of tri-2-furylphosphine and 0.04 gram (catalyst) of tris(dibenzylidineacetone)dipalladium(0) in 30 mL of N,N-dimethylformamide, yielding 2,4-diamino-6-methyl-5-[3-(4-chlorophenyl)-3-oxo-1-propenyl]pyrimidine.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[Cl:7][C:8]1[S:12][C:11]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18].C(N(CC)CC)C>O1CCOCC1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][S:13]([C:11]1[S:12][C:8]([Cl:7])=[C:9]([N+:17]([O-:19])=[O:18])[CH:10]=1)(=[O:15])=[O:14]
Reactant: CN(C)CCN
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(C)CCNS(=O)(=O)c1cc([N+](=O)[O-])c(Cl)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 48.6 %

Procedure:
To a stirred solution of N,N-dimethylethylenediamine (0.67 g, 7.6 mmol) in dioxane (25 ml) was added at room temperature 5-chloro-4-nitrothiophene-2-sulfonyl chloride (2.0 g, 7.64 mmol) and triethylamine (1.17 ml, 8.4 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by flash chromatography on silica gel (dichloromethane/methanol), and subsequent crystallization from ethyl acetate to yield 5-chloro-4-nitro-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (1.16 g, 48%) as a light brown solid. MS (ISP) 312.0 [(M−H)−], mp 178° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16](=O)[C:11]2[C:12]([CH3:15])=[CH:13][O:14][C:10]=2[CH2:9]1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl>C(O)C>[ClH:24].[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17]/[C:16](=[N:23]\[NH:22][C:19]([NH2:21])=[NH:20])/[C:11]2[C:12]([CH3:15])=[CH:13][O:14][C:10]=2[CH2:9]1
Reactant: N=C(N)NN
Reactant: Cc1coc2c1C(=O)CC(c1ccccc1Br)C2
Agent: Cl
Solvent: CCO
Product: Cc1coc2c1/C(=N/NC(=N)N)CC(c1ccccc1Br)C2
Temperature: 90 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a mixture of 6-(2-bromophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.28 g) and aminoguanidine hydrochloride (102 mg) were added ethanol (20 ml) and 6N hydrochloric acid (0.080 ml), and the mixture was stirred at 90° C. for 2 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-6-(2-bromophenyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 45) (0.31 g).
Reaction SMILES: N[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:27][CH2:28][C:29]([F:32])([F:31])[F:30].N([O-])=O.[Na+].CC#N.O.[ClH:41]>O.Cl[Cu]>[Cl:41][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:27][CH2:28][C:29]([F:32])([F:31])[F:30]
Reactant: CCOC(=O)C1(c2cc(OCC(F)(F)F)c(N)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1(c2cc(OCC(F)(F)F)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Temperature: 70 °C
Reaction time: 0.67 h

Procedure:
Ethyl 1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.280 g, 0.64 mmol) was dissolved in a mixture of MeCN/H2O/HCl 10 mL/10 mL/4 mL at 0° C. A solution of NaNO2 (0.066 g, 0.96 mmol) in water (2 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (0.32 g, 3.2 mmol) in water (2 mL) was added drop wise at 0° C. The reaction mixture was heated to 70° C. for 1 h and the solvent was evaporated. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na2SO4, filtered and concentrated to give oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate as a yellow oil (0.110 g).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[C:4]([OH:14])[CH:3]=1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>C(OCC)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[C:4]([O:14][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH:3]=1
Reactant: C[C@H](Oc1ccc(Cl)cc1O)C(=O)O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: C[C@H](Oc1ccc(Cl)cc1Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 90 °C

Procedure:
To a solution of (2S)-2-(4-chloro-2-hydroxyphenoxy)-propanoic acid (0.216 g) and 1-fluoro-4-nitro-benzene (0.127 g) in NUT (3 ml) was added potassium carbonate (0.276 g) and the reaction heated at 90° C. for 2 h. After cooling to RT, water and diethylether were added. The aqueous layer was separated and extracted again with diethylether. The aqueous layer was isolated, acidified to pH 2 and extracted with diethylether. This later extract was dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 30-50% ethylactate/isohexane+1% AcOH, yield 0.2 g
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][O:32][CH2:31]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][O:32][CH2:31]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCCCC1CCCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 243 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(4-bromobutyl)tetrahydro-2H-pyran.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([OH:19])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([O:19][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: ClCCN1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(Br)c(O)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)Oc2ccc(Br)c(OCCN3CCCCC3)c2)cc1
Yield: 106.6 %

Procedure:
4-Bromo-3-hydroxyphenyl 4-methylbenzenesulfonate (17.6 g), potassium carbonate (7.32 g), 1-(2 chloroethyl)piperidine hydrochloride (9.2 g) and acetone (300 ml) were stirred at reflux for 3 h, the reaction mixture filtered and evaporated to give the product as light brown foam (24.2 g).