Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][N:9]2[C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:20]=2[Cl:19])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: O=C1CCNc2cc(Cl)ccc21
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C1CCN(C(=O)c2ccc(Cl)cc2Cl)c2cc(Cl)ccc21
Yield: 88.1 %

Procedure:
To a mixture of 7-chloro-2,3-dihydro-4(1H)-quinolinone (25 g), pyridine (32 g) and dioxane (200 ml) was added 2,4-dichlorobenzoylchloride (37 g) dropwise under cooling at 0° C. to 5° C. with stirring. The mixture was allowed to react at room temperature for additional 3 hours. The reaction mixture was subjected to the procedure described in example 2, and 43 g of 7-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4-(1H)-quinolinone was obtained as white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:14])([CH3:13])[N:9]=[CH:10]2)=[CH:5][C:4]=1[OH:15].[BH4-].[Na+].O.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:13])([CH3:14])[NH:9][CH2:10]2)=[CH:5][C:4]=1[OH:15]
Reactant: COc1cc2c(cc1O)CC(C)(C)N=C2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1O)CC(C)(C)NC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
To a solution of 223 (1.67 mg, 8.2 mmol) in ethanol (30 ml) at 0° C. was added sodium borohydride (618 mg, 16.3 mmol). The reaction mixture was stirred at rt for 3 h. Water (50 ml) was added and the aqueous layer neutralised (2M HCl) and extracted with ethyl acetate (3×60 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound (1.34 mg, 80%) as a white solid. mp=170-173° C. 1H NMR (270 MHz; DMSO-d6) 1.04 (6H, s, 2×CH3), 2.42 (2H, s, CH2), 3.70 (3H, s, OCH3), 3.72 (2H, s, CH2), 6.43 (1H, s, CH), 6.54 (1H, s, CH), 8.60 (1H, brs, NH). LC/MS (ES+) tr=1.19 min, m/z 208.23 (M++H). HRMS (ES+) calcd. for C12H17NO2 (M++H) 208.1332, found 208.1322.
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>>[C:13]([NH:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Product: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1

Procedure:
reacting L-histidine with benzyl chloroformate, resulting in an Nα-carbobenzoxy-L-histidine;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:9]=[C:8]([CH:10]=O)[C:7]=2[CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:19][CH2:20][O:21][C:22]([CH2:24]P(OCC)(OCC)=O)=[O:23]>O1CCOCC1>[CH2:20]([O:21][C:22](=[O:23])[CH:24]=[CH:10][C:8]1[C:7]2[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[CH:9]=1)[CH3:19]
Reactant: COc1ccc2c(c1)C(C=O)=C2
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)C=CC1=Cc2ccc(OC)cc21

Procedure:
5.5 g (34 mmol) of 5-methoxybenzocyclobutene-1-carboxaldehyde and 13.8 g (42 mmol) of caesium carbonate are introduced under argon into 55 ml of dioxan. While stirring, 8.7 g (39 mmol) of phosphonoacetic acid triethyl ester are added and the whole is then heated at 80° for 2 hours. The reaction mixture is then concentrated, taken up in dichloromethane and washed with water. The organic phase is dried over sodium sulphate and concentrated by evaporation. The crude product so obtained is purified by chromatography on silica gel. 3-(5-methoxybenzocyclobuten-1-yl)acrylic acid ethyl ester is obtained; Rf=0.5, hexane/diethyl ether (4:1).
Reaction SMILES: [C:1]1([C:7]2[NH:19][C:18]3[CH:17]=[CH:16][C:15]4[C:10](=[C:11]([NH2:21])[N:12]=[C:13]([NH2:20])[N:14]=4)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH3:24][N:19]1[C:18]2[CH:17]=[CH:16][C:15]3[C:10](=[C:11]([NH2:21])[N:12]=[C:13]([NH2:20])[N:14]=3)[C:9]=2[CH:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CI
Reactant: Nc1nc(N)c2c(ccc3[nH]c(-c4ccccc4)cc32)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(-c2ccccc2)cc2c3c(N)nc(N)nc3ccc21

Procedure:
In a manner similar to that recorded in Example 2 (Method A), 6.88 g. 8-phenyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 300 ml. dry dimethylformamide is treated with 1.44 g. ca. 50% sodium hydride-mineral oil dispersion and the salt is reacted with 4.26 g. methyl iodide for 3 hours. The crude product is recrystallized from methanol (twice) and from acetonitrile to give 3.54 g. title compound, m.p. 295.0-296.5 (dec., softens 288°).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][NH2:12])=[CH:4][CH:3]=1.[F:13][C:14]([F:24])([F:23])[C:15](=[O:22])[CH:16]=[C:17](SC)SC>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:10][CH2:11][NH:12][C:17]2=[CH:16][C:15](=[O:22])[C:14]([F:24])([F:23])[F:13])=[CH:4][CH:3]=1
Reactant: NCCNCc1ccc(Cl)nc1
Reactant: CSC(=CC(=O)C(F)(F)F)SC
Solvent: CC#N
Product: O=C(C=C1NCCN1Cc1ccc(Cl)nc1)C(F)(F)F
Yield: 68.9 %

Procedure:
A solution of 77 mg (0.42 mmol) of the N-((6-chloropyridin-3-yl)methyl)ethane-1,2-diamine obtained by the foregoing method in 8 mL of anhydrous acetonitrile was added to 60 mg (0.28 mmol) of 1,1,1-trifluoro-4,4-bis(methylthio)-3-buten-2-one obtained by the foregoing method, and the mixture was refluxed under heating for 40 minutes. Following reaction completion, the reaction mixture was returned to room temperature and concentrated under reduced pressure, after which ethyl acetate and water were added, and liquid-liquid extraction was carried out. The organic phase was washed with anhydrous magnesium sulfate, then concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (hexane/ethyl acetate=3:1), giving 59 mg of the target compound (yield, 69%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH2:11][CH2:12][NH:13][C:14](=[O:38])[C@H:15]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:16][C@H:17]([C:28]([OH:30])=[O:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:5])C.[OH-].[Na+]>CO>[C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH2:11][CH2:12][NH:13][C:14](=[O:38])[C@H:15]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[NH:16][C@H:17]([C:28]([OH:30])=[O:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ncsc1CCNC(=O)[C@H](Cc1ccccc1)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ncsc1CCNC(=O)[C@H](Cc1ccccc1)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reaction time: 2 h

Procedure:
A mixture comprising 535 mg of the product prepared in Example 11, 4-ethoxycarbonyl-5-{2-[N-((1S)-1-carboxy-2-(3-indolyl)ethyl)-(L)-phenylalanyl]aminoethyl}thiazole, 1.5 ml of 2N sodium hydroxide solution and 2 ml of methanol was stirred for 2 hours under ice-cooling. After the solvent was removed by evaporation, 1.5 ml of 2N hydrochloric acid solution was added to the residue. The obtained solid was collected by filtration and washed successively with water and then ether to give 285 mg of 4-carboxy-5-{2-[N-((1S)-1-carboxy-2-(3-indolyl)ethyl)-(L)-phenylalanyl]aminoethyl}thiazole.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][NH:14][CH:13]([C:17]([OH:19])=[O:18])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1F)([O-:22])=[O:21].C(N(CC)CC)C.CS(C)=O>O.C1C=CC=CC=1.C(O)(=O)C>[C:1]([N:11]1[CH2:16][CH2:15][N:14]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N+:20]([O-:22])=[O:21])[CH:13]([C:17]([OH:19])=[O:18])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1c1ccccc1[N+](=O)[O-]

Procedure:
A mixture of 12.0 g. (0.04 mole) of 4-carbobenzoxy-piperazine- 2-carboxylic acid, 8.4 g. (0.06 mole) of o-nitrofluorobenzene, 16 g. of triethylamine and 100 ml. of dimethylsulfoxide is heated at 90° for 81/2 hours, cooled, diluted with water (300 ml.) and extracted with ether. The aqueous phase is then acidified with dilute hydrochloric acid and extracted with ether. The combined ether extracts are diluted with 1/3 its volume of pentane. The ether-pentane solution is washed with water, dried (MgSO 4) and concentrated to give 14 g. of yellow-orange glassy product. Thin layer chromatography analysis (10% acetic acid in benzene on a silica gel plate) shows 1 main spot with a faint second impurity spot.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[F:7][C:8]([F:12])([F:11])[CH:9]=[CH2:10]>N(C(C)(C)C#N)=NC(C)(C)C#N.C(C1C=CC=CC=1)(=O)CCCCCCC.C1(C)C=CC=CC=1>[F:7][C:8]([F:12])([F:11])[CH2:9][CH2:10][S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C(O)CCS
Reactant: C=CC(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCCCCCC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(O)CCSCCC(F)(F)F
Temperature: 60 °C
Reaction time: 27 h
Yield: 82.5 %

Procedure:
A 100 mL stainless steel Parr reactor was charged with azobisisobutyronitrile (AIBN, 0.231 g, 1.41 mmol), toluene (45 mL), 3-mercaptopropionic acid (3.40 g, 32.0 mmol), and octanophenone (526.2 mg) as an internal standard, and was purged and pressure checked with nitrogen (N2). The reactor was cooled with dry ice and the 3,3,3-trifluoropropene (3.1 g, 32.3 mmol) was condensed into the reactor. The ice bath was removed and the reactor heated to 60° C. and stirred for 27 hours. The internal yield of the reaction was determined to be 80% by use of the octanophenone internal standard. The pressure was released and the crude mixture removed from the reactor. The mixture was concentrated by rotary evaporation and 50 mL of 10% sodium hydroxide was added. The solution was washed with methyl tert-butylether (50 mL) then acidified to pH˜1 with 6 N hydrochloric acid. The product was extracted with 100 mL methyl tert-butylether, dried over magnesium sulfate (MgSO4), filtered, and concentrated to give the crude titled compound as an oil (5.34 g, 26.4 mmol, 83%): 1H NMR (400 MHz, CDCl3) δ 2.83 (td, J=7.1, 0.9 Hz, 2H), 2.76-2.64 (m, 4H), 2.47-2.30 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 177.68, 125.91 (q, J=277.1 Hz), 34.58 (q, J=28.8 Hz), 34.39, 26.63, 24.09 (q, J=3.3 Hz); 19F NMR (376 MHz, CDCl3) δ −66.49.
Reaction SMILES: C([O:3][C:4](=O)/[C:5](/[CH3:18])=[CH:6]/[CH2:7][CH2:8][C:9]1[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]=1[CH3:17])C.[H-].C([Al+]CC(C)C)C(C)C>>[CH3:18]/[C:5](=[CH:6]\[CH2:7][CH2:8][C:9]1[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]=1[CH3:17])/[CH2:4][OH:3]
Reactant: CCOC(=O)/C(C)=C/CCC1=C(C)CCCC1(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CC1=C(CC/C=C(\C)CO)C(C)(C)CCC1
Yield: 93 %

Procedure:
2,6,6-Trimethyl-1-cyclohexene-1-acetaldehyde is reacted with methoxymethyl triphenylphosphonium chloride in the presence of potassium tert-butoxide, followed by conversion to the dimethyl acetal and subsequent hydrolysis, as described in Example 1 above, to provide 3-(2,6,6-trimethyl-1-cyclohexen-1yl)propanal (80% yield) as a colorless oil after distillation in vacuo. This material (6.8 g) is reacted with triethyl 2-phosphonopropionate (10.6 ml) by the method of example 14(B) above, to provide 6.58 g (2E)-2-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-pentenoic acid ethyl ester as a colorless oil after chromatography. This ester is reduced with diisobutylaluminum hydride by the method described in example 14(B) above, to provide (2E)-2-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-pentenol as a colorless oil (93%) after chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:29][C:28]5[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:27]=5[N:26]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:35])[CH2:15][N:14](OC(C)(C)C)[CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])[CH3:2].[ClH:41]>O1CCOCC1>[ClH:41].[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:29][C:28]5[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:27]=5[N:26]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:35])[CH2:15][NH:14][CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CN(OC(C)(C)C)C1)C2c1ccc(Sc2nc3cc(F)ccc3[nH]2)o1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CNC1)C2c1ccc(Sc2nc3cc(F)ccc3[nH]2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
A solution of 6-tert-butyloxy-9-[5-(5-fluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-2,4,5,7,8,9-hexahydro-pyrrolo[3,4-b]-1,7-naphthyridine-3-carboxylic acid ethyl ester (0.380 g, 0.64 mmol) in dioxane (20 ml) is combined with 4 N HCl in dioxane (2.32 ml) and the mixture is stirred at room temperature for 16 hours. The formed insoluble material is collected by filtration, washed with dioxane (40 ml), pentane (40 ml), diisopropylether (40 ml) and dried under vacuum to yield 323 mg of 9-[5-(5-fluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]-1,7-naphthyridine-3-carboxylic acid ethyl ester hydrochloride as a orange-brown powder. Yield=95%. Analytical LC/MS method B: m/z=492 (negative ion mode [M−H]−), m/z=494 (positive ion mode [M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:7]=[C:6]2[C:22]1[C:23]2[CH:30]=[C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=4)[NH:33][CH:32]=3)[N:28]([S:42]([C:45]3[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=3)(=[O:44])=[O:43])[C:24]=2[N:25]=[CH:26][N:27]=1.[H-].[Na+].[CH3:54]I>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)(=[O:13])=[O:14])[CH:7]=[C:6]2[C:22]1[C:23]2[CH:30]=[C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=4)[N:33]([CH3:54])[CH:32]=3)[N:28]([S:42]([C:45]3[CH:46]=[CH:47][C:48]([CH3:51])=[CH:49][CH:50]=3)(=[O:44])=[O:43])[C:24]=2[N:25]=[CH:26][N:27]=1
Reactant: COc1ccc2[nH]cc(-c3cc4c(-c5cn(S(=O)(=O)c6ccc(C)cc6)c6ccc(OC)cc56)ncnc4n3S(=O)(=O)c3ccc(C)cc3)c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c(-c4cn(S(=O)(=O)c5ccc(C)cc5)c5ccc(OC)cc45)ncnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(5-methoxy-1-[(4-methylphenyl)sulfonyl]-1H-indol-3-yl)-6-(5-methoxy-1H-indol-3-yl)-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [270 mg, Reference Example 10] in dimethylformamide (10 mL) was added the sodium hydride (10 mg, 60% dispersion in oil) and methyl iodide (0.025 mL) under inert atmosphere. The solution was stirred for 16 hours at room temperature and the solvent was evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate The organic phase was separated, then dried over magnesium sulfate and then evaporated under reduced pressure. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (50:50, v/v) to give the title compound (93 mg) as an amorphous solid. MS: 732 [MH]+. LCMS (Method B) RT=4.68 minutes.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([CH:21]([OH:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:51][C:52]1[CH:53]=[CH:54][C:55](O)=[N:56][CH:57]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([CH:21]([O:31][C:55]2[CH:54]=[CH:53][C:52]([Cl:51])=[CH:57][N:56]=2)[CH2:22][O:23][Si:24]([C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:26])[CH3:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cn1
Reactant: CC(C)(C)[Si](C)(C)OCC(O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCC(Oc1ccc(Cl)cn1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 40 °C
Yield: 44 %

Procedure:
(SR)-1-[(3SR,4RS)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(tert-butyl-dimethyl-silanyloxy)-ethanol (described herein above) (13.2 mg. 0.0275 mmol) and PPh3 (PPh3 polymer bound, 3 mmol PPh3/g resin) (18 mg, 0.055 mmol) were suspended in THF (2 mL). To the mixture were added 5-chloro-pyridin-2-ol (7 mg, 0.055 mmol) and then DBAD (13 mg, 0.055 mmol). The reaction mixture was stirred at 40° C. over night. The mixture was diluted with ethyl acetate and filtered on celite and concentrated under vacuo. The residue was purified by TLC (SiO2, EtOAc/H, 1:4) yielded 7.2 mg (44%) of the title compound as a colorless oil. ES-MS m/e: 593.3 (M+H+).
Reaction SMILES: [Cl-].[NH4+].[CH3:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N+:17]([O-])=O)=[CH:6][CH:5]=1>C(O)C.O.[Fe]>[CH3:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH2:17])=[CH:6][CH:5]=1
Reactant: Cc1ccc(Oc2ccncc2[N+](=O)[O-])cn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(Oc2ccncc2N)cn1
Yield: 78.6 %

Procedure:
To a refluxing mixture of iron powder (2.55 g, 45.93 mmol) and ammonium chloride (307 mg, 5.74 mmol) in ethanol (45 mL) and water (8 mL) was added 4-(6-methyl-pyridin-3-yloxy)-3-nitropyridine (AMR01121, 1.93 g, 8.35 mmol) and the resulting mixture was stirred at reflux for 2 h. After removal of the solvent, the residue was diluted in aqueous sodium hydrogen carbonate (40 mL) and extracted with DCM (3×20 mL). The organic layer was dried (MgSO4), filtered and evaporated. Flash master chromatography of the crude product using DCM to DCM/MeOH 9:1 gradient as eluent gave 4-(6-methylpyridin-3-yloxy)-pyridin-3-ylamine (1.32 g, 79%) as an orange solid, mp 74-79° C.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][Cl:22]>CC(C)=O>[Cl:22][CH2:21][CH2:20][O:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]=2[CH:11]=1
Reactant: ClCCBr
Reactant: N#Cc1nc2ccc(O)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1nc2ccc(OCCCl)cc2s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.8 %

Procedure:
A suspension of 2-cyano-6-hydroxybenzothiazole (1.0 g, 5.68 mmol) in acetone (5 mL) was prepared in a 50-mL 2-necked round-bottomed flask fitted with a reflux condenser. Anhydrous potassium carbonate (1.57 g, 11.3 mmol) was added to the reaction mixture and the suspension turned to a yellow solution. Then 1-bromo-2-chloroethane (1.06 g, 0.56 mL, 7.38 mmol) was added by syringe and the reaction mixture was heated at reflux using a heated stir plate and oil bath. The reaction was monitored periodically by RP HPLC. After 5 hours the reaction appeared to be about 30% complete. Additional 1-bromo-2-chloroethane was added (2.84 mmol, 0.21 mL) and the reaction was refluxed overnight. HPLC analysis indicated the reaction was about 50% complete. Additional 1-bromo-2-chloroethane (2.84 mmol, 0.21 mL) and potassium carbonate (0.60 g, 4.37 mmol) were added and the reaction was refluxed for the rest of the day (about 7 h). The reaction was about 64% complete, and it was refluxed overnight. The next morning the reaction was found to be about 84% complete. Additional 1-bromo-2-chloroethane (2.84 mmol, 0.21 mL) and potassium carbonate (0.60 g, 4.37 mmol) were added and the reaction was refluxed for the rest of the day (about 7 h). At this point the reaction was about 92% complete. The reaction mixture was allowed to cool to room temperature and it was then filtered through glass fiber paper and rinsed with acetone. The filtrate was concentrated to give a yellow-brown solid. The crude solid (1.3 g) was purified on silica gel (100 g) using 4:1 heptane-ethyl acetate. Fractions containing product were pooled and concentrated to give 1.0 g (74%) of the desired product as an off-white solid. The structure was confirmed by 1H NMR analysis in DMSO-d6.
Reaction SMILES: [I:1][C:2]1[CH:11]=[N:10][C:5]2[NH:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:12]1([S:18]([N:9]2[CH2:8][CH2:7][NH:6][C:5]3[N:10]=[CH:11][C:2]([I:1])=[CH:3][C:4]2=3)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Ic1cnc2c(c1)NCCN2
Solvent: c1ccncc1
Product: O=S(=O)(c1ccccc1)N1CCNc2ncc(I)cc21
Temperature: 100 °C
Yield: 23 %

Procedure:
7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (300 mg) was dissolved in anhydrous pyridine. Phenylsulfonyl chloride (1.0 eq) was added and the reaction mixture was heated to 100° C. in a microwave oven for 10 minutes. Silica gel chromatography gave the title compound as a pale orange solid (23% yield). M.p. 145-146° C., LCMS: m/z=407.71 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.94-2.99 (m, 2H), 3.74 (t, J=5.0 Hz, 2H), 4.83 (bs, 1H), 7.45-7.49 (m, 2H), 7.58-7.65 (m, 3H), 8.06 (d, J=2.0 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[CH2:13]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1CCCCC1>C1(C)C=CC=CC=1>[CH2:13]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10](=[O:12])[CH3:11])=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: CCCCCCOc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCCCCCOc1ccc(CC(C(C)=O)c2ccc(OC)cc2)cc1
Yield: 46 %

Procedure:
49.2 g of 3-(4-methoxyphenyl)-2-propanone and 61.8 g of 4-hexyloxybenzaldehyde were added to 100 ml of toluene containing 4 ml of piperidine. The resultant mixture was heated at reflux temperature overnight after which the solvent was removed in vacuo to afford the desired subtitled intermediate (46% yield), b.p. 230°-235° C.
Reaction SMILES: [C:1](=[O:11])([O:6][CH:7]([CH3:10])[CH2:8][Cl:9])[O:2][CH2:3][CH2:4][Cl:5].C1(=O)OCCO1.C=CC.[Cl:21]Cl.C(=O)([O-])[O-].C1OC1C.C1OC1>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.ClCCCl.C(Cl)(Cl)Cl>[C:1](=[O:11])([O:6][CH:7]([CH3:10])[CH2:8][Cl:9])[O:2][CH2:3][CH2:4][Cl:5].[Cl:9][CH2:8][CH:7]([Cl:21])[CH3:10]
Reactant: ClCl
Agent: CC(CCl)OC(=O)OCCCl
Agent: CC1CO1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Solvent: C1CO1
Solvent: C=CC
Product: CC(Cl)CCl
Temperature: -60 °C

Procedure:
A mixture of 3.02 g (0.015 g mole) of 2-chloroethyl 1-chloro-2-propyl carbonate and 0.051 g (0.00015 g mole) of tetrabutylphosphonium bromide was heated at 190° C.-192° C. in a 10 ml reaction flask equipped with magnetic stirrer and a distillation head connected to a receiver containing 11.9 g of chloroform cooled to -60° C. The 2-chloroethyl 1-chloro-2-propyl carbonate starting material was prepared by reacting 1.5 moles of ethylene carbonate with about two moles each of propylene and chlorine at about room temperature as shown in Japanese Pat. No. 46,921/78. After 3 hours of heating, a residue of 0.20 g remained in the reaction flask and the receiver had gained 2.15 g in total weight. Nuclear magnetic resonance spectroscopic and chromatographic analyses of the reaction products indicated that 97 percent of the starting carbonate had been converted to a mixture of 83 percent of the theoretical quantity of propylene oxide and 6 percent of the theoretical amount of ethylene oxide together with corresponding yields of 1,2-dichloroethane and 1,2-dichloropropane, respectively.