Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2](/[N:6]=[CH:7]/[C@H:8]1[CH2:13][CH2:12][C@:11]2([OH:28])[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C@@H:17]([CH2:18][C@@H:19]([OH:27])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3)[C:3]([NH2:5])=[NH:4]>C(O)C.[Pt](=O)=O>[C:3]([NH:2][NH:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@:11]2([OH:28])[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C@@H:17]([CH2:18][C@@H:19]([OH:27])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3)(=[NH:4])[NH2:5]
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=N/NC(=N)N)CC[C@]12O
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](CNNC(=N)N)CC[C@]12O
Reaction time: 8 h
Yield: 65.5 %

Procedure:
A mixture of 0.50 g of (E)-17β-guanidinoiminomethyl-5β-androstane-3β,14β-diol hydrochloride (prepared following the procedure described in DE 4,227,626 for similar compounds) and 0.40 g of platinum dioxide in 25 ml of ethanol was hydrogenated at 4.2 atm and room temperature for 8 hrs under shaking. The mixture was filtered and the solution evaporated under reduced pressure. The residue was cristallized from ethanol/ethyl acetate to give 0.30 g of the title compound (I-aa) as a white solid, hydrochloride.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[OH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[CH:14]2.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:22]=1[CH2:23]Br>O>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:22]=1[CH2:23][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[CH:14]2
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: Clc1cccc(Cl)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2cccc(OCc3c(Cl)cccc3Cl)c2n1
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
To a mixture of sodium hydride (40% in oil, 24 mg) and N,N-dimethylformamide (1 ml) was added 8-hydroxy-2-methylquinoline (80 mg) in an ice-water bath. The mixture was stirred for 30 minutes at the same temperature and then 2,6-dichlorobenzyl bromide (120 mg) was added therein. The reaction mixture was stirred at ambient temperature for 1 hour. To this mixture was added water (0.5 ml) in an ice-water bath. The precipitates were corrected by vacuum filtration and washed with water (3 ml) to give 8-(2,6-dichlorobenzyloxy)-2-methylquinoline (117 mg) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[N:15]([CH:16]=2)[CH:14]=[CH:13][S:12]3)=[CH:5][CH:4]=1.[CH2:17]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28]([C:30]2[C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=[CH:32][N:31]=2)=O)=[C:20]1[CH3:39])[CH3:18].C(OC(=O)C)(=O)C.[OH-].[NH4+]>O>[CH2:17]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28]2([C:16]3[N:15]4[C:11]([S:12][CH:13]=[CH:14]4)=[N:10][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:30]3=[N:31][CH:32]=[CH:33][CH:34]=[C:35]3[C:36](=[O:37])[O:38]2)=[C:20]1[CH3:39])[CH3:18]
Reactant: COc1ccc(-c2cn3ccsc3n2)cc1
Reactant: CCn1c(C)c(C(=O)c2ncccc2C(=O)O)c2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCn1c(C)c(C2(c3c(-c4ccc(OC)cc4)nc4sccn34)OC(=O)c3cccnc32)c2ccccc21
Reaction time: 1 h
Yield: 123.6 %

Procedure:
A mixture of 0.92 gram of 6-p-methoxy phenylimidazo[2,1-b]thiazole, 0.69 gram of (1-ethyl-2-methylindol-3-yl)(3-carboxypyridin-2-yl)ketone and 20 ml. of acetic anhydride was stirred 2.5 hours at 50° C. The reaction solution was poured into 250 ml. of water and adjusted to pH 9.8 with ammonium hydroxide. After one hour stirring the solid material was filtered and washed with water to give 1.44 grams (95%) of desired product, mp. 115°-118° C. The infrared spectrum showed a strong 1770 cm-1 lactone carbonyl peak. A solution of the product on silica gel produced a purple color.
Reaction SMILES: C([BH3-])#N.[Na+].[Cl:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][NH2:13])=[CH:8][CH:7]=1.[C:14]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([CH3:28])[CH:26]=O)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>CO>[C:14]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH:25]([CH3:28])[CH2:26][NH:13][CH2:12][C:9]2[CH:10]=[N:11][C:6]([Cl:5])=[CH:7][CH:8]=2)=[CH:22][CH:23]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Reactant: NCc1ccc(Cl)nc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(CNCc1ccc(Cl)nc1)Cc1ccc(C(C)(C)C)cc1
Reaction time: 4 h

Procedure:
Route A: After suspending 620 mg (9.84 mmol) of sodium cyanoborohydride in 2 ml of absolute methanol, 700 mg (4.91 mmol) of 6-chloro-3-pyridylmethylamine was added thereto. Subsequently, to this was added a solution of 1.0 g (4.90 mmol) 3-(4-t-butylphenyl)-2-methylpropionaldehyde/2 ml absolute methanol by portions and then, stirring was conducted at room temperature for 4 h.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH2:13]([S:15][C:16]1[C:17]([C:22]([NH2:24])=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=1)[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].C1N2CCN(CC2)C1>O.CS(C)=O>[CH2:13]([S:15][C:16]1[C:17]([C:22]([NH:24][C:2]2[CH:7]=[CH:6][C:5]([S:8][C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=2)=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=1)[CH3:14]
Reactant: FC(F)(F)Sc1ccc(Cl)nc1
Reactant: CCSc1cccnc1C(N)=O
Agent: C1CN2CCN1CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CCSc1cccnc1C(=O)Nc1ccc(SC(F)(F)F)cn1
Temperature: 70 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
A mixture of 0.64 g of 2-chloro-5-trifluoromethylsulfanylpyridine, 0.54 g of 3-ethylsulfanylpicolinic acid amide, 1.96 g of cesium carbonate, 0.33 g of DABCO and 5 mL of DMSO was stirred at 70° C. for 1 hour. Water was added to the reaction mixture cooled to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.40 g of 3-ethylsulfanyl-N-(5-trifluoromethylsulfanylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 48).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>O>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: CN1CCNCC1
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
50 g (0.247 Mol) of 1-Bromo-4-nitro-benzene and 55 mL. (0.495 Mol) of 1-methyl-piperazine are heated for 26 h at 80° C. After cooling, the reaction mixture is taken up in water and extracted with CH2Cl2CH3OH (8:2). The combined organic layers are dried (Na2SO4), filtered and evaporated under reduced pressure. The crude product is recrystallized from ethanol to obtain 1-methyl-4-(4-nitro-phenyl)-piperazine. Title compound: ES-MS: 443.0 [M+H]+; Rf=0.38 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH2:8]([O:10][C:11](/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=[O:12])[CH3:9].Cl>CN(C)C=O.C(OCC)(=O)C>[CH2:8]([O:10][C:11]([C@@H:13]1[CH2:4][C@H:14]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=[O:12])[CH3:9]
Reactant: C[S+](C)C
Reactant: CCOC(=O)/C=C/c1cccc(OC)c1
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1cccc(OC)c1
Reaction time: 0.33 h
Yield: 18 %

Procedure:
To a solution of sodium hydride (1.0 g, 60% in oil) in N,N-dimethylformamide (50 ml) was added trimethylsulfonium iodide (6.1 g) at ambient temperature under N2 and stirred for 20 minutes. To the solution was added dropwise a solution of trans-1-ethoxycarbonyl-2-(3-methoxyphenyl)ethylene (5.2 g) in N,N-dimethylformamide (10 ml) and stirred for 2 hours. The reaction mixture was poured into a mixture of ethyl acetate (100 ml) and 1N-hydrochloric acid (100 ml). The organic layer was washed with water, saturated sodium bicarbonate aqueous solution, and brine, and then dried over magnesium sulfate. The solution was evaporated and the residue was chromatographed (hexane:ethyl acetate=4:1) to give trans-1-ethoxycarbonyl-2-(3-methoxyphenyl)cyclopropane (1.0 g).
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.CO[C:9](=[O:38])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH:17][C:18](=[O:37])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]34[CH2:36][CH:31]5[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]5)[CH2:28]3)[CH2:34]4)=[CH:23][CH:22]=2)[CH:11]=1.Cl>C1(C)C=CC=CC=1>[C:27]12([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:18]([NH:17][C:12]4[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=4[OH:16])[C:9]([NH2:2])=[O:38])=[O:37])=[CH:22][CH:23]=3)[CH2:28][CH:29]3[CH2:35][CH:33]([CH2:32][CH:31]([CH2:30]3)[CH2:36]1)[CH2:34]2
Reactant: COC(=O)c1ccc(O)c(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc(O)c(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
Ammonium chloride (6.5 mg, 0.12 mmol) in anhydrous toluene 2 ml was treated with trimethyl aluminium (in 2.0 M Hexane, 0.26 ml, 0.51 mmol) under nitrogen. After 0.25 h, It was added 3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-4-hydroxy-benzoic acid methyl ester (50.1 mg, 0.12 mmol) in toluene 4 ml. The mixture was stirred for 3 h at 80° C. After cooling, the reaction mixture was treated with diluted HCl until no foaming more. The reaction mixture was separated with ethyl acetate and sodium bicarbonate. The organic phase was washed by brine, dried (MgSO4 anh), and concentrated. The residue was purified by preparative TLC(CH2Cl2:MeOH=15:1) to give 3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-4-hydroxy-benzamide as a white-solid (12.9 mg, 25.6%-yield).
Reaction SMILES: [CH:1]([C:3]1[S:7][CH:6]=[C:5]([C:8]([OH:10])=[O:9])[CH:4]=1)=[O:2].I[CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:12]([O:9][C:8]([C:5]1[CH:4]=[C:3]([CH:1]=[O:2])[S:7][CH:6]=1)=[O:10])[CH3:13]
Reactant: CCI
Reactant: O=Cc1cc(C(=O)O)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(C=O)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
5-Bromo-3-thiophenecarboxylic acid (4.14 g) was dissolved in tetrahydrofuran (50 ml), and the mixture was cooled to -78° C. n-Butyllithium (1.6M in hexane, 27.5 ml) was slowly added dropwise. The resulting mixture was stirred at the same temperature for 1 hour, and N,N-dimethylformamide (3.1 ml) was added. The mixture was warmed slowly to room temperature and concentrated under reduced pressure. The concentrate was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 5-formyl-3-thiophenecarboxylic acid (3.12 g). 5-Formyl-3-thiophenecarboxylic acid (3.12 g) was dissolved in N,N-dimethylformamide (50 ml), and iodoethane (1.58 ml) and potassium carbonate (2.76 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water and extracted with ethyl acetate. The extract was washed with 5 % potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-formyl-3-thiophenecarboxylic acid ethyl ester (0.71 g). 5-Formyl-3-thiophenecarboxylic acid ethyl ester (1.47 g) synthesized in this manner in methylene chloride (10 ml) was slowly added dropwise to diethylaminosulfur trifluoride (DAST) (1.2 ml) in methylene chloride (10 ml) at room temperature. The mixture was stirred at room temperature for 15 hours, and saturated aqueous sodium bicarbonate was added. The organic layer was collected, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-difluoromethyl-3-thiophenecarboxylic acid ethyl ester (0.7 g). 5-Difluoromethyl-3-thiophenecarboxylic acid ethyl ester was dissolved in a mixture of ethanol (5 ml) and tetrahydrofuran (5 ml), and 1N aqueous sodium hydroxide (5 ml) was added. The mixture was stirred at room temperature for 1 hour and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-difluoromethyl-3-thiophenecarboxylic acid (0.58 g) as crystals.
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]=[N+:25]=[N-:26])=[CH:14][C:6]=2[C:5]1=[O:27])[CH:2]=[CH2:3].C1(C2CCCCCCCC2)BCCCCCCC1.[OH-].[Na+].OO.S([O-])([O-])(=[O:52])=S.[Na+].[Na+]>O1CCCC1.CCO>[OH:52][CH2:3][CH2:2][CH2:1][N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]=[N+:25]=[N-:26])=[CH:14][C:6]=2[C:5]1=[O:27]
Reactant: O=S([O-])([O-])=S
Reactant: C=CCN1CCCc2ccc(OCCCCCCCCN=[N+]=[N-])cc2C1=O
Agent: B1CCCCCCCC1C1CCCCCCCC1
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCCCCCCCOc1ccc2c(c1)C(=O)N(CCCO)CCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 42 %

Procedure:
A solution of 2-allyl-8-(8-azidooctyloxy)-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one (920 mg, 2.48 mmol) in tetrahydrofuran (20 mL) was treated with 9-borabicyclononane (0.5M/THF, 10 mL, 5.00 mmol), and the mixture was stirred under argon at room temperature for 18 hours. The mixture was then cooled in an ice bath, and EtOH (5 mL) followed by 15% aqueous NaOH (10 mL) and 30% H2O2 (15 mL) were added. The mixture was stirred for 1 hour, then saturated aqueous sodium thiosulfate was added (20 mL). The solution was partitioned between ethyl acetate and brine, and the combined ethyl acetate layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by chromatography over silica gel to yield 400 mg (42%) of 2-(3-hydroxypropyl)-8-(8-azidooctyloxy)-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one as a colorless oil; 1H NMR(CDCl3) d7.20(d, J=3 Hz, 1H), 7.04(d, J=6 Hz, 1H), 6.91(dd, J=3, 6 Hz, 1H), 3.96(t, J=6 Hz, 2H), 3.72(t, J=6 Hz, 2H), 3.61(t, J=6 Hz, 2H), 3.26(t, J=6 Hz, 2H), 3.18(t, J=6 Hz, 2H), 2.73(t, J=6 Hz, 2H), 2.02(t, J=6 Hz, 2H), 1.77(m, 4H), 1.60(m, 2H), 1.36(m, 8H).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18](OC(F)(F)F)=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[F:26][C:27]([F:47])([F:46])C1C=CC(N2C=NC(C3C=CC(N)=CC=3)=N2)=CC=1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]([C:27]([F:47])([F:46])[F:26])=[CH:19][CH:20]=3)[N:11]=2)=[CH:8][CH:9]=1)=[C:2]=[S:3]
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Product: FC(F)(F)c1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Yield: 94 %

Procedure:
Prepared according to the procedure reported in (WO 2011017513) for 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole from 4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)aniline and isolated as a white solid (10.6 g, 94%): 1H NMR (300 MHz, CDCl3) δ 8.07 (s, 1H), 7.73-7.41 (m, 2H), 7.41-7.05 (m, 4H), 6.92-6.63 (m, 2H); ESIMS m/z 347 ([M+H]+).
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].C([Li])CCC.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].O>C1COCC1.C(Cl)Cl.CO>[Si:27]([C:3]1([OH:4])[C:5]2[O:9][C@@H:8]3[C@@:7]45[CH2:21][CH2:20][N:18]([CH3:19])[C@@H:15]([C@@H:14]4[CH:13]=[CH:12][C@@H:10]3[OH:11])[CH2:16][C:17]([C:6]5=2)=[CH:1][CH2:2]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CN1CC[C@]23C4=C5O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1CC4=CCC5(O)[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 56.1 %

Procedure:
To a stirred suspension of anhydrous morphine (7.01 mmol) at -78° C. in anhydrous THF (15 ml) was added 1.6M butyllithium (4.8 ml, 0.492 g, 7.68 mmol) over 8 minutes. 42 minutes later, a solution of TBDMS chloride (1.27 g, 8.43 mmol) in anhydrous THF (10 ml) was added over 10 minutes. The mixture was left to warm up gradually to room temperature overnight by which time all the material had gone into solution. Water was then added to the mixture which was extracted with dichloromethane several times. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered and the solvent removed in vacuo to leave an off-white film. Chromatography over silica using CH2Cl2 /MeOH (5:1) as eluent afforded the product as a white solid (1.58 g, 56%). Recrystallization from Et2O/petrol (boiling point 40°-60°) gave white crystalline needles (1.37 g), m.p.=120°-122° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)=O.[CH3:14][N:15]([CH3:21])[CH2:16]/[CH:17]=[CH:18]\[CH2:19][NH2:20]>>[CH3:14][N:15]([CH3:21])[CH2:16]/[CH:17]=[CH:18]\[CH2:19][NH:20][CH2:1][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1
Reactant: CN(C)C/C=C\CN
Reactant: CCOC(=O)c1ccnc(C=O)c1
Product: CCOC(=O)c1ccnc(CNC/C=C\CN(C)C)c1

Procedure:
By General Procedure A from ethyl 2-formylpyridine-4-carboxylate, (Z)—N1,N1-dimethylbut-2-ene-1,4-diamine. Purification by column chromatography (DCM/MeOH/NH4OH, 90:10:1) gave the title compound as yellow viscous oil. 1H NMR (300 MHz, CDCl3): δ 8.8 (d, 1H), 7.8 (s, 1H), 7.7 (d, 1H), 5.7 (m, 2H), 4.34 (q, 2H), 4.0 (s, 2H), 3.4 (d, 2H), 2.9 (d, 2H), 2.2 (s, 6H), 1.32 (t, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C@H:23]2[O:27]C(C3C=CC=CC=3)=[N:25][C@@H:24]2[C:34]([O:36]C)=[O:35])[CH:12]=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1.Cl>>[CH:12]1[C:11]([C@@H:23]([OH:27])[C@H:24]([NH2:25])[C:34]([OH:36])=[O:35])=[CH:10][C:9]([OH:8])=[C:14]([OH:15])[CH:13]=1
Reactant: COC(=O)[C@H]1N=C(c2ccccc2)O[C@@H]1c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: Cl
Product: N[C@H](C(=O)O)[C@H](O)c1ccc(O)c(O)c1
Temperature: 25 °C
Yield: 72 %

Procedure:
Methyl (4S, 5R)-5-(3,4-dibenzyloxyphenyl)-2-phenyl-2-oxazoline-4-carboxylate (157 mg, 0.50 mmol), was added to 1N-hydrochloric acid (5 ml) with stirring, and the mixture was refluxed for 17 hours. After cooling to room temperature, the reaction mixture was washed with ether and neutralized with 1N sodium hydroxide to obtain precipitated crystals. The precipitated crystal then was filtered to obtain 76 mg (0.36 mmol, yield: 71%) of L-threo DOPS.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]2[C:8]3[C:9]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[N:10][C:11]4[C:16]([C:7]=3[C:6](=[N:26][OH:27])[C:5]=2[CH:4]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4.COC1C=CC2[C:35]3[C:36](N4CCNCC4)=[N:37]C4C([C:34]=3C(=O)C=2C=1)=CC=CC=4.C(C1OC1)Cl>>[NH2:37][CH2:36][CH2:35][CH2:34][O:27][N:26]=[C:6]1[C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:8]=2[C:23]2[CH:24]=[CH:25][C:3]([O:2][CH3:1])=[CH:4][C:5]1=2
Reactant: COc1ccc2c(c1)C(=NO)c1c-2c(N2CCNCC2)nc2ccccc12
Reactant: COc1ccc2c(c1)C(=O)c1c-2c(N2CCNCC2)nc2ccccc12
Solvent: ClCC1CO1
Product: COc1ccc2c(c1)C(=NOCCCN)c1c-2c(N2CCNCC2)nc2ccccc12

Procedure:
9-Methoxy6-(piperazin-1-yl)-11H-indeno[1,2-c]quinolin-11-one O-3-aminopropyl oxime (6t) was prepared substantially according to the procedures as set forth in the above Synthesis Example 18, except that compound 6p and 3-bromopropylamine·Br were used in place of compound 5x and epichlorohydrin, respectively, giving the title compound at a yield of 41%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]([CH3:15])=[CH:5]2.II.[F:18][C:19]([F:28])([F:27])[C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]([CH3:15])=[C:5]2[S:26][C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:27])[F:28])=[CH:25][CH:24]=1
Reactant: Cc1cc2cc(F)ccc2n1CC(=O)O
Reactant: FC(F)(F)c1ccc(S)cc1
Agent: II
Product: Cc1c(Sc2ccc(C(F)(F)F)cc2)c2cc(F)ccc2n1CC(=O)O

Procedure:
Prepared by the method of example 26 step c) using the product of example 26 step b) (0.55 g), iodine (0.98 g) and 4-trifluoromethylbenzenethiol (0.67 g) to give the subtitle compound as a solid (0.25 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].CO.C(N(CC)CC)C.Cl.[NH2:25][CH:26]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:27]([O:29][CH3:30])=[O:28]>>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([CH:26]([N:25]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[N+:1]([O-:3])=[O:2])[C:9]2=[O:14])[C:27]([O:29][CH3:30])=[O:28])=[CH:36][CH:35]=1
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: COC(=O)C(N)c1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 50 °C

Procedure:
A round bottom flask was charged with 5-nitro-isochromen-1-one (2.5 g, 0.013 mol), methanol (40 mL, 1 mol), triethylamine (4 mL, 0.03 mol) and methyl 2-amino-2-(4-chlorophenyl)acetate hydrochloride (4.0 g, 0.017 mol) and the reaction heated at 50° C. for 4 hours. The solvent was removed and the residue purified by flash chromatography (40 g silica gel, 0-10% MOH/DCM) to yield the product as a yellow solid. MS m/z=373.3 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([N:22]2[CH2:27][CH2:26][N:25]([C:2]3[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=3)[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(O)CNS(=O)(=O)c1ccc(F)cc1
Product: O=C(O)CNS(=O)(=O)c1ccc(N2CCN(c3ccccc3)CC2)cc1

Procedure:
In a manner similar to Example 3(b), (4-fluoro-benzenesulfonylamino)-acetic acid was condensed with 4-phenyl-piperazine to give the title compound, mp 120-124° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>C(Cl)Cl>[Br:1][C:2]1[C:3]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1
Reactant: O=S(=O)(O)Cl
Reactant: O=c1[nH]c2cc(Br)ccc2o1
Solvent: ClCCl
Product: O=c1[nH]c2cc(Br)c(S(=O)(=O)Cl)cc2o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of commercially-available 5-bromobenzo[d]oxazol-2(3H)-one (35-1, 500 mg, 2.336 mmol) in DCM (23 mLl) at RT was added chlorosulfonic acid (1565 μl, 23.36 mmol). The mixture became a solution that was stirred at RT. After 18 h, The solution was cooled to 0° C. and carefully quenched with ice chips and then partitioned between water (15 mL) and EtOAc (150 mL). The aqueous layer was extracted with 3×30 mL DCM. The combined organics were dried over Na2SO4, filtered, concentrated to give 35-2 as a white solid, which was carried forward without further purification.