Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27]2[N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH2:30][N:31]=2)[CH2:10]1)(C(C)(C)C)(C)C.Cl.C(=O)(O)[O-].[Na+]>CO>[OH:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[C@H:11]([C:27]2[N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH2:30][N:31]=2)[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C2=NCCN2C(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCN=C1[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.6 %

Procedure:
To a solution of (2S,4R)-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)-2-[1-(4-nitrobenzyloxycarbonyl)-2-imidazolin-2-yl]pyrrolidine (1.4 g) in methanol was added conc. hydrochloric acid (0.4 ml). After stirring at ambient temperature for 20 hours, saturated aqueous sodium bicarbonate (3 ml) was added thereto. The mixture was evaporated, extracted with ethyl acetate, and washed with water and brine successively. The dried organic layer was evaporated, the obtained oil was subjected to a column chromatography on silica gel and eluted with a mixture of dichloromethane and methanol (20:1, V/V) to give (2S,4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-[1-(4-nitrobenzyloxycarbonyl)-2-imidazolin-2-yl]pyrrolidine (660 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]([CH3:24])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8].[CH3:29][N:30]([CH3:35])[S:31](Cl)(=[O:33])=[O:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]([CH3:24])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][N:21]([S:31](=[O:33])(=[O:32])[N:30]([CH3:35])[CH3:29])[CH2:22][CH2:23]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8]
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCNCC2)C1
Reactant: CN(C)S(=O)(=O)Cl
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCN(S(=O)(=O)N(C)C)CC2)C1

Procedure:
Compound 765 was prepared from 4-hydroxy-5-oxo-1-(2-piperazin-1-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide and dimethylsulfamoyl chloride using the method described for compound 759. The title compound was purified by preparative HPLC (C18, ODS-A, S-75 μm, 30% acetonitrile/water/0.5% HCl) and isolated as a brown solid (0.0231 g, 19% yield). HRMS (M+H) calcd for C21H30N5Cl2O5S: 534.13448. found: 534.1322.
Reaction SMILES: [CH:1]([OH:6])(O)[CH2:2][CH2:3][CH3:4].[O-:7][CH2:8][CH2:9][CH2:10][CH3:11].[K+].Cl[CH2:14][CH:15]=[CH:16][C:17]1C=CC=C[CH:18]=1>>[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][O:6][CH2:1][C:2]1[CH:3]=[CH:4][C:16]([CH:17]=[CH2:18])=[CH:15][CH:14]=1
Reactant: ClCC=Cc1ccccc1
Reactant: CCCC[O-]
Reactant: CCCC(O)O
Agent: [K+]
Product: C=Cc1ccc(COCCCCO)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Butanediol (40 ml; 40.68 g; 0.452 mol) was stirred in a 100 ml round bottomed flask, and treated portionwise with potassium butoxide (17.60 g; 0.144 mol). The initial reaction was exothermic. The reaction mixture was stirred for 1.5 hours at room temperature. The resulting cloudy solution was then treated with chloromethyl styrene (20.00 g; 0.131 mol). The styrene formed an upper, pale green layer, (the colouration being due to the presence of inhibitor), whose color darkened considerably on the addition of 18-crown-6 (0.49 g; 1.86×10-3 mole). The flask was stoppered, protected from light, and stirred for 28 hours at room temperature. The mixture was then poured into water (120 ml) and extracted with dichloromethane (4×50 ml). The combined organic extracts were dried (MgSO4) and evaporated to give viscous yellow oil (932.7 g). This oil was distilled from a small amount of CuCl to give a product showing some impurities on TLC. The oil was then chromatographed on silica gel, initially eluting with dichloromethane/petrol (1:1) to remove the impurities. The product was then eluted off the column with ethyl acetate/petrol (1:1). Evaporation of the solvent gave a colourless oil, which was distilled to give the desired styrylbutyl alcohol as a colourless oil b.pt. 150°-152°/0.4 mbar. Yield 18.70 g; 69.2%.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]([C:5]1[N:6]=[C:7]([C:13]2[CH:14]=[N:15][C:16]([NH:19][C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:17][CH:18]=2)[S:8][C:9]=1[C:10]([OH:12])=O)=[O:4].C1C=C[C:29]2N(O)N=[N:32][C:30]=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.C(N)C>CN(C)C=O.C(OCC)(=O)C>[CH2:30]([NH:32][C:10]([C:9]1[S:8][C:7]([C:13]2[CH:14]=[N:15][C:16]([NH:19][C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:17][CH:18]=2)=[N:6][C:5]=1[C:3]([N:2]([CH3:1])[CH3:25])=[O:4])=[O:12])[CH3:29]
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)Nc1ccc(-c2nc(C(=O)N(C)C)c(C(=O)O)s2)cn1
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc(C(=O)N(C)C)c(C(=O)NCC)s2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.4 %

Procedure:
To a stirred solution of 4-[(dimethylamino)carbonyl]-2-(6-{[(ethylamino)carbonyl]amino}pyridin-3-yl)-1,3-thiazole-5-carboxylic acid (Example 53, 0.12 g, 3.3 mmol) in dry dimethylformamide (2 mL), HOBT (0.101 g, 6.6 mmol), N-methylmorpholine (0.108 mL, 9.9 mmol), EDC hydrochloride (0.126 g, 6.6 mmol), ethylamine (2 M in tetrahydrofuran, 0.13 mL, 3.3 mmol) were added at 0° C. and stirred overnight at room temperature. After completion of the reaction, reaction mixture was diluted with ethyl acetate (20 mL) and was washed with water (1×20 mL), 2 N hydrochloric acid (1×20 mL), and sodium bicarbonate solution (1×20 mL). The organic layer was dried, concentrated under reduced pressure and the residue was triturated with acetonitrile (1 mL). The obtained solid was filtered and dried to afford 0.018 g (20%) of the title compound as white solid. MS (APCI): 391 (M+H+) for C18H23N5O3S; NMR: δ 1.06 (t, 3H), 2.86 (s, 3H), 2.99 (s, 3H), 3.17 (q, 4H), 7.60 (d, 1H), 7.76 (br s, 1H), 8.22 (dd, 1H), 8.72 (br t, 1H), 8.78 (s, 1H), 9.52 (br s, 1H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[F:9][C:10]([F:46])([F:45])[C:11]1[CH:12]=[C:13]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:14][N:15]([C:32]1[N:33]=[N:34][N:35]([CH3:37])[N:36]=1)[C@H:16]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]2[CH:23]=[C:24]([C:28]([F:31])([F:30])[F:29])[C:25]([CH3:27])=[CH:26][C:17]1=2.N1C=CC=CC=1>C(Cl)Cl>[F:45][C:10]([F:9])([F:46])[C:11]1[CH:12]=[C:13]([CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=1)[CH2:14][N:15]([C:32]1[N:33]=[N:34][N:35]([CH3:37])[N:36]=1)[C@H:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:4](=[O:5])[CH:3]([CH2:7][CH3:8])[CH2:1][CH3:2])[C:18]2[CH:23]=[C:24]([C:28]([F:29])([F:30])[F:31])[C:25]([CH3:27])=[CH:26][C:17]1=2
Reactant: CCC(CC)C(=O)Cl
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(CC)C(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc(C)c(C(F)(F)F)cc21
Reaction time: 1 h
Yield: 106.7 %

Procedure:
Add 2-ethyl-butyryl chloride (0.014 g, 0.108 mmol) dropwise under an atmosphere of nitrogen to a 0° C. cooled solution of (S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine (Example 3, Step 18) (0.060 g, 0.108 mmol) and pyridine (0.010 g, 0.108 mmol) in methylene chloride (5 mL). After stirring for 1 h, wash the reaction with saturated aqueous sodium bicarbonate solution (10 mL), 2N aqueous hydrogen chloride solution (10 mL), and brine (10 mL). Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to afford the title compound as a colorless gum (0.075 g, 98%). 1H NMR (CDCl3, 300 MHz) δ 0.71-2.16 (m, 16H), 2.34-2.43 (m, 1H), 2.43 (s, 3H), 2.50-2.41 (m, 1H), 4.14 (s, 3H), 4.25-4.67 (m, 2H), 6.89 (bs, 1H), 7.43 (s, 1H), 7.75 (s, 2H), 7.85 (s, 1H); ESI MS m/z 651 [C29H31F9N6O+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][Mg]Br.C(#N)C1C=CC=CC=1>O1CCCC1>[C:4]1([C:8]([OH:9])([CH3:10])[CH3:11])[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1cccc(Cl)c1
Solvent: N#Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccccc1

Procedure:
When n is the bridging group --C(CH3)2 --, an appropriately substituted or unsubstituted phenyl methyl ketone, for example, methyl (3-chlorophenyl) ketone, is prepared by the reaction of methylmagnesium bromide and an appropriate benzonitrile in tetrahydrofuran. The ketone is in turn treated with methylmagnesium bromide in tetrahydrofuran, yielding the corresponding 2-phenylpropan-2-ol, which is then converted to the 2-bromo-2-phenylpropane by the treatment of the alcohol with lithium bromide and trimethylsilyl chloride in acetonitrile. The Grignard reagent of the 2-bromo-2-phenylpropane is then prepared and reacted with 1,4-cyclohexanedione mono-ethylene ketal in tetrahydrofuran, yielding the corresponding 1-(2-phenylpropan-2-yl)-1-cyclohexen-4-one. The so-prepared cyclohexenone is reduced with hydrogen gas in the presence of 10% palladium on charcoal, yielding the 4-(2-phenylpropan-2-yl)cyclohexanone, which is in turn reacted with cyanoguanidine, as previously described, yielding the targeted 2,4-diamino-6-(2-phenylpropan-2-yl)-5,6,7,8-tetrahydroquinazoline. Example 7 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][NH:10][S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:5][CH2:4]1.C(Cl)CCl.[CH2:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][CH:29]1[C:38](O)=[O:39]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[S:11]([NH:10][CH2:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([CH2:2][NH:1][C:38]([CH:29]2[CH2:30][CH2:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28]2)=[O:39])[CH2:4][CH2:5]1)(=[O:13])=[O:12]
Reactant: NC[C@H]1CC[C@H](CNS(=O)(=O)c2ccc3ccccc3c2)CC1
Reactant: O=C(O)C1CCc2ccccc2C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NC[C@H]1CC[C@H](CNS(=O)(=O)c2ccc3ccccc3c2)CC1)C1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of naphthalene-2-sulfonic acid-(4-aminomethyl-trans-cyclohexylmethyl)amide (0.5 g, 1.4 mmol), EDC (0.54 g, 2.8 mmol), and DMAP (0.34 g, 2.8 mmol) in methylene chloride (30 mL) was stirred at room temperature for 0.5 h. 1,2,3,4-tetrahydronaphthalen-2-carboxylic acid (0.24 g, 1.4 mmol) was added to the reaction mixture and stirred at room temperature till the completion of the reaction (by TLC). The reaction mixture was washed with saturated ammonium chloride (3×30 mL), dried over sodium sulfate and concentrated in vacuo. The residue was flash chromatographed over silica gel to afford white solid (0.66 g, 99%); mp 225-6° C.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]([NH:13][NH2:14])=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].Cl[C:17](=[N+:19]([CH3:21])[CH3:20])Cl.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]1([S:7]([CH2:10][C:11]2[O:12][C:17]([N:19]([CH3:21])[CH3:20])=[N:14][N:13]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[N+](C)=C(Cl)Cl
Reactant: NNC(=O)CS(=O)(=O)c1ccccc1
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)c1nnc(CS(=O)(=O)c2ccccc2)o1

Procedure:
To 3.0 g (14.0 mmol) of benzenesulfonyl-acetic acid hydrazide in 100 mL of CHCl3, 3.41 g (21.0 mmol, 1.5 eq) of dichloromethylene-dimethyl-ammonium chloride and 3.90 mL (28.0 mmol, 2 eq) of triethyl-amine were added. The solution was stirred at reflux for 1 hour, partitioned between aqueous NaOH 0.5M and EtOAc. The combined organic phases were dried over Na2SO4, filtered, evaporated, and column chromatography on silica gel with CH2Cl2/MeOH 100:1 afforded 0.59 g /15%) of (5-benzenesulfonylmethyl-[1,3,4]oxadiazol-2-yl)-dimethyl-amine as a white solid, MS: 268 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[N:14]=[C:13]([CH2:15]O)[CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:19])=O.C(=O)([O-])O.[Na+]>O>[Cl:19][CH2:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[N:14]=1
Reactant: OCc1cccc(Oc2ccnc(Cl)c2)n1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: ClCc1cccc(Oc2ccnc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
A mixture of 6-[(2-chloro-4-pyridyl)oxy]-2-pyridine-methanol (10.2 g, 0.043 mol) and thionyl chloride (10 mL) is stirred at room temperature for 90 minutes. Excess thionyl chloride is hydrolyzed by adding water to the reaction mixture until no further reaction is observed. The reaction mixture is then neutralized with saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic extracts are combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the title product (10.6 g, 97%).
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([CH:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20](=[O:28])(=[O:27])[NH:19]2)=[CH:9]1)(C)(C)C.Br[CH2:31][CH2:32][CH2:33][O:34][CH3:35]>>[CH3:35][O:34][CH2:33][CH2:32][CH2:31][N:19]1[CH:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:29])[CH:9]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:20]1(=[O:28])=[O:27]
Reactant: Cc1ccc2c(c1)c(C1NS(=O)(=O)c3ccccc31)cn2CC(=O)OC(C)(C)C
Reactant: COCCCBr
Product: COCCCN1C(c2cn(CC(=O)O)c3ccc(C)cc23)c2ccccc2S1(=O)=O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 2, step c) and 3-bromo-1-methoxy propane. 1H NMR (DMSO-d6) 7.95-7.92 (m, 1H), 7.60 (d, J=3.6 Hz, 1H), 7.58 (s, 1H), 7.28 (d, J=8.1 Hz, 1H), 7.12-7.09 (m, 1H), 7.02 (t, J=7.2 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.79 (t, J=7.5 Hz, 1H), 5.89 (s, 1H), 4.57 (s, 2H), 3.44-3.03 (m, 4H), 3.01 (s, 3H), 2.45 (s, 3H), 1.71 (quint., J=6.6 Hz, 2H); MS: ESI (negative): 427 (M−H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][C:6](=O)[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>>[CH3:1][C:2]1([CH3:22])[O:7][C:6](=[S:32])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Product: CC1(C)OC(=S)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21

Procedure:
The product was prepared, from 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluorobenzonitrile and Lawesson's reagent using the procedure of Example 9, as a yellow solid: 248–249° C.; 1H-NMR (DMSO-d6) δ 12.3 (s, 1H), 8.15 (bs, 1H), 8.02 (d, 1H, J=10.48 Hz), 7.85–7.78 (m, 3H), 7.13 (d, 1H, J=8.92 Hz), 1.71 (s, 6H); MS(APCI) m/z 313([M+H]+, 100%); Anal. Calc. For C17H13FN2OS: C, 65.37, H, 4.19, N, 8.97. Found: C, 65.26, H, 4.31, N, 8.61.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2.N([O-])=O.[Na+].N(O)=O.[BrH:19]>O>[Br:19][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2
Reactant: Nc1ccc2c(c1)COC2=O
Reactant: Br
Agent: O=NO
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C1OCc2cc(Br)ccc21
Reaction time: 0.5 h

Procedure:
A mixture of 16.8 gm 5-aminophthalide in 34 ml 48% aqueous hydrobromic acid was cooled to 0° in an ice bath and a solution of 7.8 gm sodium nitrite in 15 ml water was added at less than 5°, using internal ice cooling as necessary. The nitrosation mixture was stirred for an additional 30 minutes at about 0° with an excess of nitrous acid (positive to starch-iodide test paper). After 30 minutes, the diazonium salt was added portion wise over about 35 minutes to a mixture of 28.2 gm freshly prepared cuprous bromide and 18 ml 48% aqueous hydrobromic acid at room temperature (the bulk of the diazonium salt was maintained at about 0°). The temperature of the reaction mixture rose to about 38° and considerable frothing occurred. The mixture was stirred for an hour, then the product was filtered off and washed neutral with water. After recrystallization from 100 ml isopropanol the product weighed 15.7 gm and melted at 153°-157°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:14][N:13]=[C:12]([CH2:15]Cl)[N:11]=1)=[O:8].[CH3:20][NH2:21]>>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:14][N:13]=[C:12]([CH2:15][NH:21][CH3:20])[N:11]=1)=[O:8]
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CCl)ns1
Reactant: CN
Product: CNCc1nsc(NC(=O)NCc2cccc(F)c2)n1

Procedure:
A solution of 1-(3-Fluorobenzyl)-3-(3-(chloromethyl)-1,2,4-thiadiazol-5-yl)urea (Intermediate XXV) and excess methyl amine (2.0M solution in THF) was heated for 15 min at 60° C. under microwave irradiation. Filtered off insolubles and removed solvent in vacuo to give title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7]Cl.[C:13]([O-:18])(=[O:17])[C:14]([CH3:16])=[CH2:15].[K+].[I-].[K+].C1(C=CC(O)=CC=1)O>CN(C)C=O>[C:13]([O:18][CH2:7][CH2:6][O:5][C:4]1[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=1[O:2][CH3:1])(=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: C=C(C)C(=O)[O-]
Reactant: COc1ccccc1OCCCl
Agent: Oc1ccc(O)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCOc1ccccc1OC
Temperature: 100 °C
Yield: 78.1 %

Procedure:
Then 25.1 g of 2-(o-methoxyphenoxy) ethyl chloride, 33.40 g of potassium methacrylate, 11.17 g of potassium iodide, 50 ml of N,N-dimethylformamide, and a small amount of hydroquinone were placed in a 200 ml-flask equipped with a stirring device and a cooling pipe. The mixture was heated at 100° C. and stirred. The reacted mixture was refined by column chromatography using silica gel, and 24.8 g of 2-(o-methoxyphenoxy)ethyl methacrylate was produced.
Reaction SMILES: C([O:3][C:4](=[O:15])[CH:5]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([Br:14])[CH:8]=1)[CH3:6])C.CO.[Li+].[OH-].Cl>O.C1COCC1>[Br:14][C:9]1[CH:8]=[C:7]([CH:5]([CH3:6])[C:4]([OH:15])=[O:3])[CH:12]=[C:11]([Cl:13])[CH:10]=1
Reactant: CCOC(=O)C(C)c1cc(Cl)cc(Br)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C(=O)O)c1cc(Cl)cc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-Bromo-5-chloro-phenyl)-propionic acid ethyl ester (2.0 g, 6.9 mmol) in 2:2:1 MeOH:THF:H2O was treated with 1N aqueous LiOH (3 mL) and stirred at room temperature overnight. The mixture was acidified with 10% aqueous HCl (10 mL) and extracted three times with EtOAc. The combined organic layers were concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.I(O)(=O)(=O)=O.O>CO>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH:3]2[CH:4]=[C:5]3[C:14](=[N:13][C:12]4[C:7]([S:6]3)=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:1]=[CH:2]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(N)cc1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: [O-][I+3]([O-])([O-])O
Solvent: O
Solvent: CO
Product: COc1ccc(NC2C=CC3=Nc4ccccc4SC3=C2)cc1
Temperature: 25 °C

Procedure:
Phenothiazine, 0.5 g/0.0025M, and p-anisidine, 0.307 g/0.0025M, were dissolved in 50 ml of methanol and stirred at ambient temperature. Periodic acid, 3.4 g/0.015M, was dissolved in 40 ml of methanol and the solution added in one portion to the stirring phenothiazine mixture. The reaction mixture was stirred for 20 minutes and then poured into 100 ml of water with solid residue being collected by a Buchner funnel. The solid was stirred with 200 ml of a 1:1 mixture of MeOH/H2O and collected. The red-brown solid was dried to yield 0.72 g (91% theory) of the desired product having a melting point of 135°-136° C. (lit. 148°-149° C.).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([OH:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19].[Br:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26].C(OCC)(=O)C>C(Cl)Cl.O>[Br:21][CH2:22][CH2:23][CH2:24][C:25]([O:20][CH:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=[CH2:1])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])=[O:26]
Reactant: O=C(Cl)CCCBr
Reactant: C=CCCCCCCCC(O)CCCCCCCC=C
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCCCCCCCC(CCCCCCCC=C)OC(=O)CCCBr
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.9 %

Procedure:
To a solution of the alcohol 249 (5.6 g, 20 mol) in anhydrous DCM (300 mL) was added slowly and carefully Bromobutryl chloride (20 mmol) at 0° C. under inert atmosphere. The reaction mixture was warmed to room temperature, stirred for 20 h and monitored by TLC (silica gel, 10% ethyl acetate in hexanes). Upon completion of the reaction, mixture was diluted with water (400 mL) and organic layer was separated out. Organic phase was then washed with sat. solution of NaHCO3 (1×400 mL) followed by brine (1×100 mL) and concentrated under vacuum. Crude product was then purified by silica gel (100-200 mesh) column, eluted with 2-3% ethyl acetate in hexane solution to give 6 g (90%) of desired product 250 as colorless liquid. 1H NMR (400 MHz, CDCl3) δ 5.80 (ddt, J=16.9, 10.2, 6.7 Hz, 2H), 5.05-4.81 (m, 5H), 3.46 (t, J=6.5 Hz, 2H), 2.48 (t, J=7.2 Hz, 2H), 2.17 (p, J=6.8 Hz, 2H), 2.11-1.93 (m, 4H), 1.65-1.44 (m, 4H), 1.43-1.17 (m, 19H). 13C NMR (101 MHz, cdcl3) δ 172.51, 139.37, 114.35, 77.54, 77.23, 76.91, 74.86, 34.31, 33.99, 33.01, 32.96, 29.65, 29.56, 29.24, 29.09, 28.11, 25.52.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:5])C.C1(P([C:19]2[CH:24]=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([SiH:27]([CH2:30]C)[CH2:28][CH3:29])[CH3:26]>C(OC(=O)C)C>[CH2:25]([Si:27]([CH2:24][CH3:19])([CH2:28][CH3:29])[CH:30]=[CH:1][CH2:2][CH2:3][OH:5])[CH3:26]
Reactant: C#CC(C)O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Product: CC[Si](C=CCCO)(CC)CC
Temperature: 25 °C
Reaction time: 72 h
Yield: 86 %

Procedure:
A 50 ml reaction flask was charged with 1-butyne-3-ol and a catalytic amount of bis(1,5-cyclooctadiene)-di-Rh(I)-dichloride and triphenylphosphine under an inert atmosphere. Triethylsilane was slowly added to the reaction flask through a dropping funnel. The reaction mixture was stirred at room temperature for 72 hours and then concentrated at the rotary evaporator. The product was chromatographed through SiO2 in a hexane:ethylacetate solution (95:5 to 70:30) to yield 86% of a yellow liquid. Purity according to gas chromatography was 96% trans and 3.4% cis product.