Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[S:7](Cl)([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8].[CH3:18][O:19][C@H:20]1[C@H:25]([OH:26])[C@@H:24]([OH:27])[C@H:23]([N:28]2[C:37]3[C:38]4[NH:46][C:45]5[C:44]([Cl:47])=[CH:43][CH:42]=[CH:41][C:40]=5[C:39]=4[C:48]4[C:53](=[O:54])[NH:52][C:50](=[O:51])[C:49]=4[C:36]=3[C:30]3[CH:31]=[CH:32][CH:33]=[C:34]([Cl:35])[C:29]2=3)[O:22][C@@H:21]1[CH2:55][OH:56]>O1CCCC1>[Cl:47][C:44]1[C:45]2[NH:46][C:38]3[C:37]4[N:28]([C@@H:23]5[O:22][C@H:21]([CH2:55][OH:56])[C@@H:20]([O:19][CH3:18])[C@H:25]([OH:26])[C@H:24]5[O:27][S:7]([C:10]5[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=5)(=[O:9])=[O:8])[C:29]5[C:30](=[CH:31][CH:32]=[CH:33][C:34]=5[Cl:35])[C:36]=4[C:49]4[C:50](=[O:51])[NH:52][C:53](=[O:54])[C:48]=4[C:39]=3[C:40]=2[CH:41]=[CH:42][CH:43]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CO[C@H]1[C@H](O)[C@@H](O)[C@H](n2c3c(Cl)cccc3c3c4c(c5c6cccc(Cl)c6[nH]c5c32)C(=O)NC4=O)O[C@@H]1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CO[C@H]1[C@H](O)[C@@H](OS(=O)(=O)c2ccc(C)cc2)[C@H](n2c3c(Cl)cccc3c3c4c(c5c6cccc(Cl)c6[nH]c5c32)C(=O)NC4=O)O[C@@H]1CO

Procedure:
1 equivalent of potassium carbonate and 1 equivalent of tosyl chloride are added to a solution of 1.7 mmol of rebeccamycin in 200 ml of tetrahydrofuran. After 48 hours' reflux and concentration under reduced pressure, chromatography of the residue over silica gel (cyclohexane/ethyl acetate 70/30) enables the expected product to be isolated.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].[I-:10].[Na+]>CC(=O)CC>[I:10][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9]
Reactant: [I-]
Reactant: C=CCCCCCCBr
Agent: [Na+]
Solvent: CCC(C)=O
Product: C=CCCCCCCI

Procedure:
A mixture of 8-bromo-1-octene (1.34 g, 7 mmol) and sodium iodide (5.25 g, 35 mmol) in 2-butanone (15 ml) was stirred under reflux for 1 h. The mixture was concentrated in vacuo to a half of its original volume and hexane and water was added. Organic layer was washed with 5% aqueous sodium thiosulfate, saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate and concentrated in vacuum. Purification by flash chromatography on silica gel (hexane) gave 8-iodo-1-octene as colorless oil. yield: 1.54 g (92%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][OH:10].C(N(CC)CC)C.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:2]2[O:3][CH2:4][CH2:5][O:1]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: OCCCCC1OCCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCCC2OCCO2)cc1
Reaction time: 8 h

Procedure:
To a stirred solution of the alcohol of step 4 (0.50 g, 3.4 mmol, 1.0 equiv.) in CH2Cl2 (50 mL) at room temperature was added triethylamine (0.62 mL, 4.4 mmol, 1.3 equiv.) followed by p-toluenesulfonylchloride (TsCl, 0.71 g, 3.7 mmol, 1.1 equiv.) and 4-dimethylaminopyridine (50 mg, 0.4 mmol, 0.1 equiv.). The resulting mixture was stirred at that temperature for 8 h. The mixture was diluted with CH2Cl2 (100 mL) washed with sat. aq. NaHCO3 (100 mL) and brine (2×100 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. While concentrating, the temperature was maintained below 40° C., as the compound had been reported as unstable above this temperature (Wennekes et al. 2008). Due to this instability, the compound was used in the next step crude. 1H NMR (500 MHz, CDCl3) δ=7.79 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 4.80 (t, J=4.6 Hz, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.96-3.88 (m, 2H), 3.87-3.78 (m, 2H), 2.45 (s, 3H), 1.75-1.65 (m, 2H), 1.65-1.57 (m, 2H), 1.50-1.41 (m, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ=144.9, 133.5, 130.0, 128.1, 104.4, 70.6, 65.1, 33.3, 29.0, 20.1, 14.4 ppm.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[C:11]([C:23]([C:25]2C=CC=CN=2)=S)[CH:10]=1.C[Mg+].[Br-].C1C[O:37]CC1>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[C:11]([C:23]([CH3:25])=[O:37])[CH:10]=1
Reactant: O=C1c2ccccc2-c2cc(C(=S)c3ccccn3)cc(COC3CCCCO3)c21
Reactant: C1CCOC1
Agent: C[Mg+]
Agent: [Br-]
Product: CC(=O)c1cc(COC2CCCCO2)c2c(c1)-c1ccccc1C2=O
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
1-(2-Tetrahydropyranyl)oxymethyl-3-(2-pyridyl)thiocarbonyl-9-fluorenone (470 mg) was dissolved in THF (10 ml) and cooled to -15° under N2. A solution of MeMgBr in THF (1.2 eq) was added dropwise over 5 minutes and the reaction allowed to stir at -15° C. for 0.5 hour. The reaction was quenched with saturated ammonium chloride solution, diluted with EtOAc, and washed with water, sat'd NaCl solution then dried and evaporated to give a residue which was chromatographed on silica gel gave the product (233 mg).
Reaction SMILES: [N+]([C:4]1[S:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1)([O-])=O.[Cl:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][C:4]1[S:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1
Reactant: Oc1cccc(Cl)c1
Reactant: N#Cc1ccc([N+](=O)[O-])s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(Oc2cccc(Cl)c2)s1
Temperature: 60 °C
Reaction time: 4 h
Yield: 72.6 %

Procedure:
5-Nitro-thiophene-2-carbonitrile (5.00 g, 32.5 mmol), 3-chloro-phenol (6.90 mL, 65.0 mmol) and potassium carbonate (13.4 g, 97.5 mmol) were suspended in dimethylsulfoxide (50 mL), and the mixture was stirred at 60° C. for 4 hours. Water was added to the reaction mixture at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with water twice, and further washed with brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel silica gel column chromatography (hexane:ethyl acetate=20:1), and the title compound (5.56 g, 23.6 mmol, 73%) was obtained as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8](OC)[O:9]C)[C:3]=1[CH3:13].C([Li])CCC.C[O:20][B:21](OC)[O:22]C>CC(C)=O.Cl>[CH:8]([CH:4]1[CH:5]=[CH:6][CH:7]=[CH:2][C:3]1([B:21]([OH:22])[OH:20])[CH3:13])=[O:9]
Reactant: COC(OC)c1cccc(Br)c1C
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)=O
Product: CC1(B(O)O)C=CC=CC1C=O
Reaction time: 18 h
Yield: 38 %

Procedure:
The 1-bromo-3-dimethoxymethyl-2-methyl-benzene ((Example 6: step c) 500 mg, 2 mmol), butyllithium (2.5 M, 1 mL, 2.5 mmol), and trimethylborate (2.3 mL, 20 mmol) were reacted as in Example 5: step b. After aqueous workup, the residue was dissolved in acetone (18 mL) and HCl (1N, 2 mL). After standing for 18 h at rt, the volatile components were removed in vacuo and the residue was purified by SiO2 flash chromatography (25–40% EtOAc in hexanes) to give the title compound (126 mg, 38%). The title compound exists as a mixture of boronic acids and anhydrides in CDCl3, therefore the reported NMR signals represent pairs or groups of related signals. 1H-NMR (CDCl3): δ 10.44 (s, 1H), 8.38 (dd, 1H, J=1.4, 7.4 Hz), 7.49 (t, 1H, J=7.5 Hz), 3.12 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[S:11][C:12]([CH3:17])=[CH:13][C:14]=2[C:15]#[N:16])=[C:5]([N+:18]([O-])=O)[CH:4]=1)#[N:2].[Sn](Cl)(Cl)(Cl)[Cl:22]>C(O)C.Cl>[ClH:22].[NH2:16][C:15]1[C:14]2[CH:13]=[C:12]([CH3:17])[S:11][C:10]=2[NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:18]=1
Reactant: Cl[Sn](Cl)(Cl)Cl
Reactant: Cc1cc(C#N)c(Nc2ccc(C#N)cc2[N+](=O)[O-])s1
Agent: Cl
Solvent: CCO
Product: Cc1cc2c(s1)Nc1ccc(C#N)cc1N=C2N
Temperature: 85 °C

Procedure:
To a suspension of 2-(4-Cyano-2-nitro-phenylamino)-5-methyl-thiophene-3-carbonitrile, prepared as described in the previous step, (0.52 g) in ethanol (5 mL), was added tine chloride (1.36 g, 7.2 mmol) in 6 N HCl. The mixture was heated in an 85° C. oil bath for 3 hours and then cooled in ice bath. The solid was filtered, washed with water, and dried to brown give the title compound as a brown solid containing inorganic salt, which was used in the next step without additional purification. LC-MS: m/z 255 (M+1 of free base). 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 11.18 (br, 1H), 10.09 (s, 1H), 9.35 (br, 1H), 8.94 (br, 1H), 7.54 (d, 1H), 7.27 (s, 1H), 6.95 (d, 1H), 2.26 (s, 3H).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH3:16])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[F:25][C:26]([F:35])([F:34])[C:27]1[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=1>O1CCCC1>[F:25][C:26]([F:34])([F:35])[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH3:16])=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:29][CH:28]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(Br)c1ccc(OCC(C)Oc2ccc(F)cc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccc(C(F)(F)F)cc1)c1ccc(OCC(C)Oc2ccc(F)cc2)cc1

Procedure:
As described in Example 71, methyl bromo{p-[2-(p-fluorophenoxy)propoxy]phenyl}acetate (0.017 mole) is reacted with 2.75 g of α,α,α-trifluoro-p-cresol in 75 ml of tetrahydrofuran at 80° C. for 18 hrs to give the product as a pale amber gum.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[CH:17]=[CH:16][C:10]([O:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27]([O:33][CH2:34]Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>CN(C)C=O>[C:27]([O:33][CH2:34][O:14][C:13](=[O:15])[CH2:12][O:11][C:10]1[CH:16]=[CH:17][C:7]([CH2:6][C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]
Reactant: O=C(O)COc1ccc(Cc2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCOC(=O)COc1ccc(Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8.3 g (0.06 mol) of 4-(4'-chlorobenzyl)-phenoxy acetic acid in 50 ml of dimethylformamide are added 6.0 g (0.06 mol) of triethylamine, whereafter the mixture is stirred for 30 minutes at room temperature and, after adding 9.0 (0.06 mol) of chloromethyl pivalate, is heated for 6 hours in an oil bath at 85°-90° C. The residue which is obtained by concentration by evaporation at reduced pressure in a Buchi rotary evaporator is washed with water and extracted with ether. The ethereal solution is once again washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation in the Buchi rotary evaporator, an oil being obtained which quickly solidifies. By recrystallisation from ether/n-hexane, 9.5 g of product are obtained in the form of white crystals with the melting point 54°-55° C.
Reaction SMILES: C([Li])CCC.[CH3:6][CH:7]([CH3:17])[CH2:8][CH2:9][O:10][CH:11]1[NH:15][C:14](=[O:16])[CH2:13][CH2:12]1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCCCCC.O1CCCC1>[C:18]([N:15]1[CH:11]([O:10][CH2:9][CH2:8][CH:7]([CH3:17])[CH3:6])[CH2:12][CH2:13][C:14]1=[O:16])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)CCOC1CCC(=O)N1
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)CCOC1CCC(=O)N1C(=O)c1ccccc1

Procedure:
12.8 cm3 of a 1.5M solution of butyllithium in hexane is added at -70° C. to a solution of 3.3 g of 5-(3-methylbutoxy) pyrrolidin-2-one in 140 cm3 of tetrahydrofuran. The mixture is maintained for 20 minutes at this temperature, then a solution of 2.7 g of benzoyl chloride in 20 cm3 of tetrahydrofuran is added. The solution is returned to ambient temperature, concentrated to dryness under reduced pressure and chromatographed on silica (eluent: hexane-ethyl acetate 7-3) 3.5 g of expected product is obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].Cl[C:15]([CH3:19])([CH3:18])[C:16]#[CH:17]>CCOCC.O.[Cu]>[CH3:3][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:15]([CH3:19])([CH3:18])[C:16]#[CH:17])[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C#CC(C)(C)Cl
Agent: [Cu]
Solvent: CCOCC
Solvent: O
Product: C#CC(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
To a mixture of 1-(1,1-dimethylethoxycarbonyl)piperazine (3.29 g), copper powder (20 mg), cuprous chloride (20 mg), ether (4 ml), and water (1 ml) under nitrogen at 0° is added a solution of 3-chloro-3-methyl-1-butyne in ether (1 ml) in 4 portions over 15 min. The mixture is stirred at 20°-25° for 2 hr, diluted with ether (25 ml) and water (10 ml), and the layers are separated. The aqueous layer is extracted with ether (3×25 ml), and the combined organic layer is washed with saline (25 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a solid which is then chromatographed on silica gel (70-230, 100 g), eluting with ethyl acetate/hexane (25/75). Pooling of fractions giving an Rf =0.48 by TLC (ethyl acetate/hexane, 50/50) and removal of solvent under reduced pressure gives the title compound, mp 105.5°-107°.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10](O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(OCC)(=O)C.S(Cl)([Cl:23])=O.Cl>CN(C=O)C>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([Cl:23])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cl)C=Cc1ccc([N+](=O)[O-])cc1
Yield: 99.2 %

Procedure:
193.2 g (1 mole) of 4-nitrocinnamic acid and 650 g of ethyl acetate were placed in a reaction vessel. While 200 g of thionyl chloride with some drops of DMF was dropped into the reaction mixtures, the reaction mixtures were refluxed with stirring until the generation of hydrogen chloride gas stopped. The reacted solution was concentrated until a solid could be precipitated and was poured into hexane and then the precipitated solid was separated by filtration and dried. 210 g of 4-nitrocinnamoyl chloride was yielded. 64.5 g (0.3 mole) of 4-nitrocinnamoyl chloride and 300 g of acetone were placed in a reaction vessel. The reaction mixtures were heated at 50° C. with stirring under a nitrogen current. 41.73 g (0.3 mole) of 4-nitrophenol, 60 g of pyridine, and 300 g of acetone were added dropwise to the above reaction vessel using a dropping funnel. After the completion of the addition, the reaction mixtures were refluxed with stirring under a nitrogen current for 2 hours. After the reaction, a precipitate was separated by filtration, and the filtrated solid was washed by water and dried. 90 g of light yellow colored needle-like crystals ((4-nitrophenyl)-4-cinnamate)was yielded.
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[SH:12])[CH:5]=[CH:4][CH:3]=1.Cl[C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(N(CC)CC)C>CO>[N:15]1[CH:16]=[CH:17][CH:18]=[N:19][C:14]=1[S:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[N:2]=[CH:3][CH:4]=[CH:5]2
Reactant: Clc1ncccn1
Reactant: Sc1cccc2cccnc12
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: c1cnc(Sc2cccc3cccnc23)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 210 mg. (1.06 m mole) of quinoline-8-thiol hydrochloride in 5 ml. of dry methanol was added 128 mg. (1.05 mmol) of 2-chloropyrimidine in 2 ml. of the same solvent followed by 0.148 ml (1 mmol) of dry triethylamine. The reaction mixture was allowed to stir at room temperature overnight followed by the removal of the methanol in vacuo. The residue was partitioned between a saturated sodium bicarbonate solution and ethyl acetate. The organic phase was separated, dried and concentrated. The residue was redissolved in chloroform and concentrated without heat. The residue was triturated with ethyl acetate, filtered and dried, 170 mg., m.p. 165°-168° C.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[OH:7][C@@H:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:10]([CH2:11][CH2:12][C@@H:13]3[C:22]2=[CH:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][CH2:16][C:17]2=O)[CH2:9]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1>[OH:7][C@@H:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:10]([CH2:11][CH2:12][C@@H:13]3[C:22]2=[CH:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][CH2:16]/[C:17]/2=[CH:1]/[CH3:2])[CH2:9]1
Reactant: CC(C)(C)[O-]
Reactant: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C/C=C1/CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)C3=CC[C@]12C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of potassium tert-butoxide in THF (1 M, 230 mL, 231 mmol) was added drop wise to a suspension of ethyltriphenylphosphonium bromide (88.7 g, 239 mmol) in THF (150 mL) over 1 h at 25° C. The resulting dark red colored mixture was stirred for an additional 1 h at 25° C. A solution of compound 1.3 (23.0 g, 79.7 mmol) in THF (230 mL) was added slowly to the red-colored mixture at 25° C. The resulting mixture was stirred for 3-4 h, at which point it was determined to be complete by TLC. The reaction was quenched by adding saturated aqueous NH4Cl solution (75 mL). The phases were separated and the aqueous layer was extracted three times with EtOAc (3×150 mL). The organic fractions were combined, washed with saturated brine solution (100 mL), dried over Na2SO4 (75 g), and filtered. The filtrate was concentrated under vacuum and the crude solid was purified by column chromatography [49 mm (W)×600 mm (L), 60-120 mesh silica, 300 g] eluting with ethyl acetate/hexanes (1:9). The fractions containing product were combined and concentrated, providing compound 1.5 (19.1 g, 80.0%) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:18][O:17]2)=[CH:10][CH:9]=1.[NH:23]1[CH:27]=[N:26][CH:25]=[N:24]1.Cl>O.CS(C)=O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([CH2:18][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)([OH:17])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:10][CH:9]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)C1(CCc2ccc(Cl)cc2)CO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)C(O)(CCc1ccc(Cl)cc1)Cn1cncn1
Temperature: 110 °C
Yield: 41.6 %

Procedure:
5.3 g (0.05 mole) of sodium carbonate were added to a mixture of 245.2 g (1 mole) of 2-(4-chlorophenylethyl)-2-tert.-butyl-oxirane (97.2% pure), 72.5 g (1 mole) of 1,2,4-triazole (95.2% pure) and 380 ml of dimethylsulphoxide at room temperature, while stirring, and the mixture was then heated at 110° C. for 4 hours. Thereafter, the reaction mixture was poured into 1 liter of water and neutralized with dilute aqueous hydrochloric acid. The liquid phase was decanted off from the solid and the residue was dissolved in 1 liter of toluene. The solution was extracted with water, the phases were separated and the organic phase was dried and concentrated by stripping off the diluent under reduced pressure. 128 g (42% of theory) of 1-(4-chlorophenyl)-3-(1,2,4-triazol-1-ylmethyl)-4,4-dimethyl-pentan-3-ol were obtained in this manner in the form of a solid.
Reaction SMILES: [CH:1]1([CH2:4]OC2C=C(CC3C(N)=NC(N)=NC=3)C=C(OCC)C=2C2C=CC(O)=CC=2)[CH2:3][CH2:2]1.Cl.ClCCN1CCOCC1.C1(CO[C:46]2[CH:51]=[C:50]([CH2:52][C:53]3[C:54]([NH2:60])=[N:55][C:56]([NH2:59])=[N:57][CH:58]=3)[CH:49]=[C:48]([O:61][CH2:62][CH3:63])[C:47]=2[C:64]2[CH:69]=[CH:68][C:67]([O:70][CH2:71][CH2:72][N:73]3[CH2:78][CH2:77][O:76][CH2:75][CH2:74]3)=[CH:66][CH:65]=2)CC1>>[CH:1]1([CH2:4][C:46]2[CH:51]=[C:50]([CH2:52][C:53]3[C:54]([NH2:60])=[N:55][C:56]([NH2:59])=[N:57][CH:58]=3)[CH:49]=[C:48]([O:61][CH2:62][CH3:63])[C:47]=2[C:64]2[CH:65]=[CH:66][C:67]([O:70][CH2:71][CH2:72][N:73]3[CH2:74][CH2:75][O:76][CH2:77][CH2:78]3)=[CH:68][CH:69]=2)[CH2:3][CH2:2]1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC2CC2)c1-c1ccc(O)cc1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC2CC2)c1-c1ccc(OCCN2CCOCC2)cc1
Agent: Cl
Agent: ClCCN1CCOCC1
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(CC2CC2)c1-c1ccc(OCCN2CCOCC2)cc1

Procedure:
Starting from 2′-cyclopropylmethoxy-4′-(2,4-diamino-pyrimidin-5-ylmethyl)-6′ethoxy-biphenyl-4-ol (example 8h) (300 mg; 0.74 mmol) and 4-(2-chloroethyl)-morpholine hydrochloride (170 mg; 0.89 mmol), 129 mg (25%) 5-[2-cyclopropylmethoxy-6-ethoxy-4′-(2-morpholin-4-yl-ethoxy)-biphenyl-4-ylmethyl]-pyrimidine-2,4-diamine are obtained as a colourless powder.
Reaction SMILES: P(Cl)(Cl)(OCl)=O.[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:21]=2)[CH:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].CN(C)[CH:32]=[O:33]>>[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:21]=2)[C:16]([CH:32]=[O:33])=[CH:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Reactant: CN(C)C=O
Agent: O=P(Cl)(Cl)OCl
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)Cc1ccc2c(C=O)cn(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
18 mg (0.12 mmol) of phosphoryl oxychloride was added gradually to 4 ml of a solution of 25 mg (0.09 mmol) of methyl (1-benzylindol-6-yl)acetate, as obtained in a) above, in dimethyl formamide, at room temperature, and the resulting mixture was stirred for 30 minutes. After this time, an excess of a 2N aqueous solution of sodium hydroxide was added to the mixture, which was then stirred for 10 minutes. The aqueous layer was extracted with methylene chloride and the extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then the solvent was removed by evaporation under reduced pressure. The residue was subjected to column chromatography (eluent: a 25% v/v solution of ethyl acetate in hexane) to yield 23 mg (83%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7](I)[C:3]=1[C:4]([OH:6])=[O:5].[N:14]1[NH:15][N:16]=[CH:17][CH:18]=1>>[F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N:15]2[N:16]=[CH:17][CH:18]=[N:14]2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: c1cn[nH]n1
Reactant: COc1ccc(I)c(C(=O)O)c1F
Product: COc1ccc(-n2nccn2)c(C(=O)O)c1F

Procedure:
The title compound was synthesized following the same general protocol as described in Example A11 using 2-fluoro-6-iodo-3-methoxybenzoic acid and 2H-1,2,3-triazole. ESI-MS (m/z): 238 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:8]([OH:14])[C:9]([CH3:13])([CH3:12])[CH2:10][Cl:11])=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:8]([O:14][C:22](=[O:24])[CH3:23])[C:9]([CH3:12])([CH3:13])[CH2:10][Cl:11])=[CH:20][CH:21]=1
Reactant: CC(C)(CCl)C(O)C(Oc1ccc(Cl)cc1)n1cncn1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC(C(Oc1ccc(Cl)cc1)n1cncn1)C(C)(C)CCl
Temperature: 100 °C
Yield: 65 %

Procedure:
23.1 g (0.07 mol) of 1-(4-chlorophenoxy)-1-(1,2,4-triazol-1-yl)-3,3-dimethyl-4-chloro-butan-2-ol were dissolved in 100 ml of acetic anhydride and the solution was heated to 100° C. for 12 hours. Thereafter, it was concentrated by distilling off excess acetic anhydride in vacuo. The oil which remained was taken up in 150 ml of diisopropyl ether and the product was allowed to crystallize out at 0° C. 17 g (65% of theory) of 1-(4-chlorophenoxy)-1-(1,2,4-triazol-1-yl)-2-acetoxy-3,3-dimethyl-4-chloro-butane of melting point 111°-117° were obtained.