Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([OH:18])[CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:9]1=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)([O-:22])=[O:21].C(N(CC)CC)C>C(#N)C>[Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([OH:18])[CH2:14][C:15]([O:17][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=2)=[O:16])[CH2:10][C:9]1=[O:19])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(O)CC(=O)O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 48 h

Procedure:
The crude carboxylic acid is suspended in anhydrous acetonitrile (150 ml) and treated with p-nitrobenzyl bromide (7.56 g, 35 mμol) and triethylamine (4.9 ml, 35 mμol). The resulting solution is kept at room temperature for 2 days and then in a refrigerator for 3 days. The reddish orange solution is evaporated under vacuum and the residue shaken with ethyl acetate (100 ml, 2×50 ml) and filtered to remove triethylammonium bromide. The ethyl acetate filtrate is washed with water (3×100 ml) and brine, dried with magnesium sulfate, filtered, and evaporated under vacuum to an amber oil (13.62 g). Crystallization from diethyl ether affords N-(t-butyldimethylsilyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-hydroxypropyl]azetidin-2-one (6.84 g) as an off-white powder. Chromatography of the mother liquors on a silica gel column using 1:1 toluene-ethyl acetate as eluting solvent affords addition product (3.14 g) as an oil which solidifies.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.[OH-].[K+].[K].Br[CH2:12][Cl:13]>CCO.CC#N>[Cl:13][CH2:12][S:1][C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1
Reactant: ClCBr
Reactant: Cc1nnc(S)s1
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CC#N
Solvent: CCO
Product: Cc1nnc(SCCl)s1
Temperature: 0 °C
Yield: 164.4 %

Procedure:
2-Mercapto-5-methyl-1,3,4-thiadiazole (41.4 g, 313 mmol) was added to an ice-bath cooled (5° C.) aqueous solution of 85% KOH (20.7 g, 313 mmol) in EtOH (160 mL). The ice bath was removed and the mixture stirred until complete dissolution occurred (30 min). The solvent was then evaporated to leave a viscous oil which solidified. The resulting potassium salt was dissolved in CH3CN (200 mL), and the solution was cooled in an ice bath and treated with bromochloromethane (121 g, 939 mmol). The ice in the bath was allowed to melt and the mixture was further stirred at R.T. for 25 h. The reaction mixture was partitioned between EtOAc and H2O. The organic phase was dried (MgSO4) and evaporated. The residue was purified by passing through a pad of silica gel, eluted first with CH2Cl2 and then with 5% CH3CN/CH2Cl2 to afford 93.0 g (76.0%) of 2-[(chloromethyl)-thio]-5-methyl-1,3,4-thiadiazole.
Reaction SMILES: [Mg].[CH3:2][O-:3].[Mg+2].[CH3:5][O-:6].[CH2:7](C1C=CC(O)=CC=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]C.C=O.[C:25](O)(=O)[CH3:26]>O.C1(C)C=CC=CC=1.CO>[CH2:2]([O:3][C:7]1[C:8](=[CH:9][CH:10]=[CH:25][CH:26]=1)[CH:5]=[O:6])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: CC(=O)O
Reactant: C[O-]
Agent: C=O
Agent: [Mg+2]
Agent: [Mg]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCOc1ccccc1C=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A 2-liter round-bottomed flask was charged with magnesium (12 g, 0.49 mol), methanol (285 ml), toluene (120 ml) and magnesium methoxide (10 ml solution of 7.4% by weight magnesium methoxide in methanol). The reaction mixture was heated to reflux and the magnesium dissolved. Para-nonyl phenol (112.4 g) was added in one portion to the reaction mixture. The flask was then rigged for a fractional vacuum distillation and an azeotrope of methanol/toluene was distilled off to an internal temperature of 70° C. at a pressure of 350 nun Hg. Glacial acetic acid (28.5 ml, 0.5 mole) was added to the reaction mixture over a 1 hour period while maintaining the reaction temperature at 70° C. and the pressure at 350 mm Hg. When the addition of glacial acetic acid was complete, solid paraformaldehyde (46 g, a commercial sample containing 5-7% by weight water) was added over a 105 minute period. The reaction mixture was maintained at a temperature of 65° C. and a pressure of 350 mm Hg. During the addition of paraformaldehyde and the volatile reaction by-products were continually removed. When the paraformaldehyde addition was complete, the reaction temperature was increased to 75° C. and maintained at that temperature for an additional 3 hours. Sulfuric acid (300 ml, 10% wow) was added to the reaction mixture, which was then stirred for 1 hour. After phase separation, the organic phase was washed twice with 200 ml portions of water. The washed organic phase was then separated, dried and rendered free of the solvent to yield crude-nonyl salicylaldehyde. A 67% yield was obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:19][CH3:20])=[CH:8][C:9]([N+:16]([O-])=O)=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12].[Cl-].[NH4+]>O.CO.[Fe]>[NH2:16][C:9]1[CH:8]=[C:7]([O:19][CH3:20])[C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(OCCCCl)c(OC)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(OCCCCl)c(OC)cc1N
Yield: 93 %

Procedure:
Med. Chem., 44, 3965 (2001) describes a process for preparing a 4-alkoxy-5-halogenoalkoxyanthranilic acid compound from a 4-alkoxy-5-halogenoalkoxy-2-nitrobenzoic acid compound. For example, methyl 5-(3-chloropropoxy)-4-methoxy-2-nitrobenzoate is reacted with a very excessive amount of iron and ammonium chloride in a mixture of water and methanol, to give methyl 2-amino-5-(3-chloropropoxy)-4-methoxybenzoate (i.e., methyl 5-(3-chloropropoxy)-4-methoxyanthranilate) in 93% yield.
Reaction SMILES: [ClH:1].[CH3:2]N(C)C=O.C([O-])([O-])OCC.[CH2:13]([NH:20][C:21]1[C:26]([NH2:27])=[C:25](Cl)[N:24]=[CH:23][N:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:23]1[N:22]=[C:21]2[C:26]([N:27]=[CH:2][N:20]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:25][N:24]=1
Reactant: Cl
Reactant: CN(C)C=O
Reactant: Nc1c(Cl)ncnc1NCc1ccccc1
Agent: CCOC([O-])[O-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Clc1ncc2ncn(Cc3ccccc3)c2n1
Reaction time: 72 h

Procedure:
To a solution of 4.0 M of hydrochloric acid in 1,4-dioxane (2.3 mL) in N,N-dimethylformamide (10.0 mL, 0.129 mol) was added ethyl orthoformate (2.00 mL, 0.0120 mol) and N4-benzyl-6-chloropyrimidine-4,5-diamine (500 mg, 0.002 mol). The mixture was stirred for 3 days. The reaction was quenched by addition of triethylamine (1.5 mL, 0.011 mol), extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, water, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (3 to 5% MeOH/DCM) to obtain 336 g (60%). LC/MS: Rt=1.49 min, ES' 245.08 (AA standard).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:13]([O-])([OH:15])=[O:14].S(=O)(=O)(O)O>CC(C)=O.CCCCCC>[N+:13]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:6][CH:5]=1)([O-:15])=[O:14]
Reactant: c1ccc(-c2cccnc2)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(-c2cccnc2)cc1
Temperature: 70 °C
Reaction time: 96 h

Procedure:
3-Phenylpyridine (25.0 g, 0.161 mole) is added carefully and with cooling (ice-bath) to 70% nitric acid (140 ml). The resulting solution is stirred and, when TLC (1:1 acetone-hexane) shows no reaction after 24 hr, it is heated in a 70° C. oil bath. Some reaction is observed by TLC but it is very slow and so, after 4 days, concentrated sulfuric acid (50 ml) is added. The mixture is stirred over several days at room temperature after which the starting material is entirely consumed. The solution is poured onto ice and the mixture is made alkaline by the cautious addition of 50% aqueous NaOH. The mixture is extracted 3 times with ethyl acetate. (650 ml), the combined organic layers are washed with brine, dried over MgSO4, filtered, and reduced in volume to 400 ml. Crystallization occurred, giving a first crop of 13.139 g of tilted product, melting point of 145°-148° C. and, from the concentrated filtrate, a second crop of 4.16 g (total 17.299 g, 0.0865 mole, 53%) of product, melting point 143°-147° C.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Mg]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.BrCCCCCC1CCCCC1.[Mg].BrCCBr.[CH3:31][Si:32]([CH3:41])([CH3:40])[C:33]1[O:37][CH:36]=[C:35]([CH:38]=[O:39])[CH:34]=1.S(=O)(=O)(O)O>O1CCCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:38]([C:35]2[CH:34]=[C:33]([Si:32]([CH3:41])([CH3:40])[CH3:31])[O:37][CH:36]=2)[OH:39])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: Br[Mg]CCCCCC1CCCCC1
Agent: BrCCCCCC1CCCCC1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: C[Si](C)(C)c1cc(C(O)CCCCCC2CCCCC2)co1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-cyclohexylpentyl-magnesium bromide (1.32 mmol, prepared from 0.31 g., 1.32 mmol 1-bromo-5-cyclohexylpentane and 2.88 mmol magnesium, with a catalytic amount of 1,2-dibromoethane as initiator), in 2.5 ml anhydrous tetrahydrofuran at 0° under argon was added dropwise 5-trimethylsilyl-3-furaldehyde (0.23 g., 1.40 mmol) in 2.5 ml tetrahydrofuran. This solution was allowed to warm to room temperature, stirred for one hour, and then poured over crushed ice containing several drops of concentrated sulfuric acid. The resulting mixture was partitioned between ethyl ether and 5% sodium bicarbonate. The organic portion was washed with water, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give a colorless oil (0.173 g.). This material was purified by flash chromatography (silica, 90% petroleum ether/ethyl ether) to give the desired alcohol.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39](Cl)=[O:40]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:39]([C:35]3[S:34][CH:38]=[CH:37][CH:36]=3)=[O:40])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1cccs1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cccs4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 47.6 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.620 g, 4.07 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione hydrochloride (0.600 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, 2-thiophene-carbonyl chloride (0.3 g, 2.03 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 6:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-2-thienylcarboxamide (0.35 g, 47%) as a white solid: mp 192-194° C.; 1H NMR (DMSO-d6) δ d 11.16 (s, 1H), 9.18 (t, J=5.8 Hz, 1H), 7.88-7.72 (m 5H), 7.20-7.17 (dd, J=3.9 and 4.7 Hz, 1H), 5.22-5.15 (dd, J=5.5 and 12.7 Hz, 1H), 4.94 (d, J=5.8 Hz, 2H), 2.98-2.85 (m, 1H), 2.66-2.50 (m, 2H), 2.11-2.06 (m, 1H); 13C NMR (DMSO-d6) δ d 172.72, 169.80, 167.51, 166.93, 161.52, 139.26, 139.14, 134.83, 133.14, 131.53, 131.11, 128.51, 127.96, 127.12, 121.93, 48.89, 38.09, 30.93, 21.99; Anal. Calcd. For C19H15N3O5S: C, 57.42; H, 3.80; N, 10.57. S, 8.07. Found: C, 57.80; H, 3.93; N, 10.22; S, 7.99.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].S(Cl)([Cl:19])(=O)=O>C(OCC)C>[Cl:19][CH:9]([C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)C(Cl)C(=O)c1ccccc1F
Yield: 97.2 %

Procedure:
Using ethyl 3-(2-fluorophenyl)-3-oxopropanoate (1.0 g, 4.75 mmol), sulfuryl chloride (771 mg, 5.7 mmol) and diethyl ether (50 mL) as starting materials and in the same manner as in Example 20(i), the title compound (1.13 g, 97%) was obtained as a colorless oil.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:11]1[C:40](=[O:41])[N:13]2[C:14]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)=[O:28])=[C:15]([S:18](C3C=CC=CC=3)(=O)=O)[C@H:16]([CH3:17])[C@H:12]12)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N+:42]([C:45]1[CH:58]=[CH:57][C:48]([CH2:49][O:50][C:51]([NH:53][CH2:54][CH2:55]S)=[O:52])=[CH:47][CH:46]=1)([O-:44])=[O:43]>>[Si:1]([O:8][C@@H:9]([C@H:11]1[C:40](=[O:41])[N:13]2[C:14]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)=[O:28])=[C:15]([S:18][CH2:55][CH2:54][NH:53][C:51]([O:50][CH2:49][C:48]3[CH:57]=[CH:58][C:45]([N+:42]([O-:44])=[O:43])=[CH:46][CH:47]=3)=[O:52])[C@H:16]([CH3:17])[C@H:12]12)[CH3:10])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S(=O)(=O)c3ccccc3)[C@H](C)[C@H]12
Reactant: O=C(NCCS)OCc1ccc([N+](=O)[O-])cc1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H](C)[C@H]12
Yield: 86 %

Procedure:
Following a procedure similar to that described in Example 19(c), but using 4-nitrobenzyl (1R,5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-phenylsulfonyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 46) and 2-(4-nitrobenzyloxycarbonyl)aminoethylmercaptan as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 86%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([OH:23])=[CH:18][C:17]=3[CH3:24])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].[CH3:32][C:33]1[N:38]=[C:37]([CH2:39]O)[CH:36]=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:22][C:21]1[CH:20]=[C:19]([O:23][CH2:39][C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:32])[N:38]=2)[CH:18]=[C:17]([CH3:24])[C:16]=1[C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][O:8][C:6]2[CH:5]=[CH:4][C:3]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:2]([F:1])[CH:7]=2)[CH:11]=1
Reactant: Cc1cccc(CO)n1
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(O)cc3C)c2)cc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(OCc4cccc(C)n4)cc3C)c2)cc1F
Yield: 86.8 %

Procedure:
To a solution of ethyl 3-{2-fluoro-4-[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy]phenyl}propanoate (1.2 g, 2.84 mmol), (6-methylpyridin-2-yl)methanol (0.39 g, 3.12 mmol) and triphenylphosphine (0.95 g, 3.61 mmol) in tetrahydrofuran (24 mL) was added diisopropyl azodicarboxylate (40% toluene solution, 1.54 mL, 3.12 mmol) at room temperature with stirring. The reaction mixture was stirred at room temperature for 12 hrs., and an equivalent amount of the aforementioned reagents ((6-methylpyridin-2-yl)methanol, triphenylphosphine and diisopropyl azodicarboxylate) were added. The mixture was further stirred at the same temperature for 12 hrs. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/1) to give the title compound (1.3 g, yield 87%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=3)[CH:8]=[CH:7][C:6]=2[C:5](=[O:25])[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[OH:25][CH:5]1[CH2:4][CH2:3][C:2]([CH3:1])([CH3:26])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:19]=3)[CH:8]=[CH:7][C:6]1=2
Reactant: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of methyl [4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-phenyl]-acetate (Compound 4) in 5 mL MeOH at 0° C. was added NaBH4 (18.0 mg, 0.48 mmol). The reaction was stirred at 0° C. for 2 hours and then quenched by the addition of H2O. The solution was diluted with Et2O and washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and the solvents were removed under reduced pressure. Column chromatography (20-40% EtOAc-hexanes) afforded 140.0 mg (87%) of the title compound as a colorless oil.
Reaction SMILES: [S:1]1[CH2:6][CH2:5]O[CH2:3][CH2:2]1.C([N:10](CC)C(C)C)(C)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH:23]([CH2:27][NH:28][C:29](=[O:40])OC2C=CC([N+]([O-])=O)=CC=2)[CH2:22]1>ClCCl>[Cl:16][C:17]1[CH:18]=[C:19]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH:23]([CH2:27][NH:28][C:29]([N:10]2[CH2:5][CH2:6][S:1][CH2:2][CH2:3]2)=[O:40])[CH2:22]1
Reactant: CCN(C(C)C)C(C)C
Reactant: C1CSCCO1
Reactant: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)N1CCSCC1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
1,4-Thioxane (0.02 g) and N,N-diisopropylethylamine (0.04 ml) were added to a solution of Intermediate 10 (0.08 g) in dichloromethane (2 ml). The mixture was stirred at 23° C. for 16 h, and the solvent evaporated in vacuo. The residue was dissolved in dichloromethane (3 ml), and the solution shaken with polystyrene methyl isocyanate resin (Argonaut Technologies, 0.14 g, 1.45 mmol/g) for 2 h. The solution was drained from the resin, and the resin washed with dichloromethane (6 ml) and methanol (3 ml); the combined filtrate and washings were concentrated in vacuo. The residue was purified further by solid phase extraction (Isolute SCX sulphonic acid column), eluting with methanol followed by 10% 0.880 ammonia solution in methanol, to give the title compound as a pale yellow gum (0.065 g).
Reaction SMILES: [C:1](=[O:4])([OH:3])[O-].[Na+].Cl.[NH2:7][OH:8].[C:9]1([O:15][C:16](Cl)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[O:3]([C:1]([NH:7][O:8][C:16]([O:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:17])=[O:4])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NO
Reactant: O=C([O-])O
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(NOC(=O)Oc1ccccc1)Oc1ccccc1
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
To a solution of sodium bicarbonate (21.5 g, 0.256 mol) in water (150 ml) at 0° C. was added hydroxylamine hydrochloride (8.8 g, 0.127 mol). The reaction mixture was stirred for 30 min. and phenylchloroformate (60 g, 0.383 mol) was introduced directly into the vigorously stirred mixture. Sodium bicarbonate (32.3 g, 3.85 mol) in water (300 ml) was added to the mixture. The mixture was stirred for 30 min., the ice-bath removed and stirring continued for an additional 2 h at room temperature. The resultant suspension was filtered and the filter cake washed with water. The wet filter cake was collected, suspended in hexane, filtered and again washed with hexane. The solid was kept at 0° C. overnight to afford N,O-bis-phenoxycarbonylhydroxylamine (23.5 g, 68%) as a solid. Melting point: 80-82° C. 1H NMR (CDCl3, 200 MHz): δ 7.26(m, 5H), 7.42 (m, 5H) and 8.54 (s, 1 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[N:5]=[C:4]([O:16][CH3:17])[N:3]=1.Cl.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=1)([O-:21])=[O:20].C(N(C(C)C)CC)(C)C>CCO>[CH3:17][O:16][C:4]1[N:3]=[C:2]([NH:30][CH2:29][CH2:28][C:25]2[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:27][CH:26]=2)[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[N:5]=1
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: COc1cccc(-c2cc(Cl)nc(OC)n2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1cccc(-c2cc(NCCc3ccc([N+](=O)[O-])cc3)nc(OC)n2)c1
Temperature: 170 °C
Yield: 50.9 %

Procedure:
To a solution of 4-chloro-2-methoxy-6-(3-methoxy-phenyl)-pyrimidine [80 mg, 0.32 mmol, Intermediate (53)] and 2-(4-nitro-phenyl)-ethylamine hydrochloride (77.6 mg, 0.38 mmol) in EtOH (1.1 mL) is added diisopropyl-ethylamine (0.139 mL, 0.80 mmol). The reaction mixture is heated under microwave at 170° C. for 45 minutes. Solvent is removed and residue is subjected to flash column chromatography (silica gel: 10-50% ethyl acetate/heptane) to afford [2-methoxy-6-(3-methoxy-phenyl)-pyrimidin-4-yl]-[2-(4-nitro-phenyl)-ethyl]-amine [62 mg, 51%, Example 43(b)] as a solid. LC/MS: RT=2.57 minute, MS: 381 (M+H). 1H NMR (300 MHz, (CD3)2SO): □8.14 (2H, d, J=9.8 Hz), 7.53 (2H, d, J=9.8 Hz), 7.52 (3H, m), 7.38 (1H, t, J=8.6 Hz), 7.01 (1H, m), 6.58 (1H, s), 3.84 (3H, s), 3.79 (3H, s), 3.6 (2H, m), 2.99 (2H, m). IC50=0.9 nM
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[S:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=4)=[CH:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=[C:7]([F:30])[C:3]=1[C:4]([NH2:6])=[O:5].B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[S:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=4)=[CH:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=[C:7]([F:30])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: COc1ccc(-c2ccc3sc(COc4ccc(F)c(C(N)=O)c4F)nc3c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC(=O)c1c(F)ccc(OCc2nc3cc(-c4ccc(O)cc4)ccc3s2)c1F
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 2.7 %

Procedure:
Compound 2,6-difluoro-3-[5-(4-methoxy-phenyl)-benzothiazol-2-ylmethoxy]-benzamide (0.095 g, 0.223 mmol) was dissolved in 5 ml of DCM and cooled to −70° C. To this, BBr3 (0.1 ml 0.156 mmol) was added drop wise. After complete addition, reaction mixture was stirred at r.t. for 30 min. The reaction mixture was quenched with MeOH. Reaction mixture was concentrated and purified by column chromatography to obtain (0.0025 g, 3%) compound as white solid. 1H NMR (DMSO-d6, 400 MHz); δ 5.70 (s, 2H), 6.88 (d, 1H, J=8.4 Hz (o-coupling), 7.10 (m, 1H), 7.41 (m, 2H), 7.60 (d, 2H, J=8.8 Hz, (o-coupling), 7.71 (d, 2H), 7.89 (broad s, 1H), 8.13-8.17 (m, 2H), 9.62 (broad s, 1 H); MS ES+ (413.0).