Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][Cl:4].C([O-])([O-])=O.[K+].[K+].[F:11][C:12]1[CH:13]=[C:14]([SH:19])[CH:15]=[CH:16][C:17]=1[F:18]>CN(C=O)C.CC(=O)OCC>[Cl:4][CH2:3][CH2:2][S:19][C:14]1[CH:15]=[CH:16][C:17]([F:18])=[C:12]([F:11])[CH:13]=1
Reactant: ClCCBr
Reactant: Fc1ccc(S)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1ccc(SCCCl)cc1F
Reaction time: 16 h
Yield: 94.2 %

Procedure:
5.7 ml (68.4 mmol) of 1-bromo-2-chloroethane and 1.9 g (13.7 mmol) of K2CO3 were added to a solution of 2.0 g (13.7 mmol) of 3,4-difluorothiophenol in DMF (20 ml). Stirring was then carried out for 5 h at 60° C. and for 16 h at RT. The mixture was then diluted with EA (50 ml) and washed in succession with 1 M aq. Na2CO3 solution and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. There were obtained as residue 2.7 g (12.9 mmol, 95%) of (2-chloroethyl)-(3,4-difluorophenyl)sulfane, which was reacted further without additional purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:14][C:5]2[S:6][C:7]([C:9]([O:11]CC)=[O:10])=[CH:8][C:4]=2[CH2:3]1.O.[OH-].[Li+]>CC(O)C.O1CCCC1>[CH3:1][C:2]1([CH3:15])[CH2:14][C:5]2[S:6][C:7]([C:9]([OH:11])=[O:10])=[CH:8][C:4]=2[CH2:3]1
Reactant: CCOC(=O)c1cc2c(s1)CC(C)(C)C2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC1(C)Cc2cc(C(=O)O)sc2C1
Temperature: 65 °C
Yield: 86.1 %

Procedure:
To a solution of 131c (16.0 g, 71.0 mmol) in propan-2-ol (200 mL), tetrahydrofuran (200 mL), and water (200 mL) was added lithium hydroxide (6.82 g, 284 mmol). See FIG. 15. The reaction mixture was heated at 65° C. for 5 h. The organic solvents were removed under reduced pressure. The pH of the residue was adjusted to 1.0 with hydrochloride acid (12M). The precipitate was collected by filtration and dried in vacuo to afford 131d (12.0 g, 86%) as a white solid. MS-ESI: [M+H]+ 196.9
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([C:13]3=[O:20])[CH2:11]1)[CH2:17]2.CS(O)(=O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:16]23[CH2:18][CH:12]4[CH2:11][CH:10]([CH2:19][CH:14]([C:13]4=[O:20])[CH2:15]2)[CH2:17]3)[CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Agent: CS(=O)(=O)O
Product: O=C1C2CC3CC1CC(c1cc(Br)ccc1O)(C3)C2
Temperature: 80 °C
Yield: 78.1 %

Procedure:
The mixture of 4-bromophenol (3.11 g, 17.98 mmol), 5-hydroxy-2-adamantanone (2.49 g, 14.98 mmol), and MeSO3H (7 mL) was stirred with heating at 80° C. (oil-bath) for 5 h. The resulting mixture was quenched with H2O (40 mL) and filtered. The precipitate was washed several times with H2O, 5% NaHCO3, and CH2Cl2 and dried to give 3.76 g (79%) of 5-(5′-bromo-2′-hydroxyphenyl)-2-adamantanone as a white solid, mp 287-289° C. 1H NMR 8 (DMSO-d6) 1.82-2.45 (m, 13H, AdCH and AdCH2), 6.71 (d, J=8.5 Hz, 1H, 3′-ArH), 7.10 (d, J=2.4 Hz, 1H, 4′-ArH), 7.16 (dd, J=2.4 Hz, 8.5 Hz, 1H, 6′-ArH), 9.78 (s, 1H, OH).
Reaction SMILES: [CH:1]1([CH:6]2[S:10][C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])=[N:8][C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.C[Si](Cl)(C)C.[B-](F)(F)(F)[F:34].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C1COCC1>[CH:1]1([C:6]2([F:34])[S:10][C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])=[N:8][C:7]2=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: F[B-](F)(F)F
Reactant: O=C1N=C(Nc2ccccc2F)SC1C1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)Cl
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: C1CCOC1
Product: O=C1N=C(Nc2ccccc2F)SC1(F)C1CCCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A dry 100 mL round-bottomed flask was charged with 5-cyclopentyl-2-(2-fluorophenylamino)thiazol-4(5H)-one (0.200 g, 0.717 mmol) and 6.0 mL of THF. This solution was cooled to −78° C., and LDA (2.0 M in THF/heptane/ethyl benzene, 1.43 mL, 2.86 mmol) was added. The resulting brown solution was allowed to stir at that temperature for 1 h, then TMSCl (0.623 g, 0.725 mL, 5.74 mmol) was added. The solution was warmed to room temperature and allowed to stir for an additional 1 h. The solution was concentrated in vacuo to remove the volatiles and then redissolved in 10 mL of CH3CN. Selectfluor (0.508 g, 1.43 mmol) was added at room temperature, and the resulting solution was stirred for 2 h. The reaction was quenched with saturated aqueous NaHCO3, and the resulting mixture was thoroughly extracted with CH2Cl2. This combined organic extracts were dried and concentrated in vacuo to give an oil which was purified by column chromatography (100% to 70% hexanes/30% ethyl acetate) to give the title compound as a colorless oil. Mass Spec (M+H)+; 297.1.
Reaction SMILES: [C:1]([O:6][CH:7]1[CH:13]2O[CH:15]3[CH:8]1OC(=O)[CH:11]3[CH2:12]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:17][C:18]1C=C[C:21](C=C)=[CH:20][CH:19]=1>>[C:1]([O:6][C:7]1[C:8]2[C:15](=[C:18]([OH:17])[CH:19]=[CH:20][CH:21]=2)[CH:11]=[CH:12][CH:13]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC1C2CC3C(=O)OC1C3O2
Reactant: C=Cc1ccc(O)cc1
Product: C=C(C)C(=O)Oc1cccc2c(O)cccc12

Procedure:
3-oxo-2,7-dioxatricyclo[4.2.1.04,8]nonan-9-yl methacrylate:PAG Monomer 1=0.30:0.30:0.30:0.10
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[CH2:16][OH:17])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[OH:17][CH2:16][C@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C@@H:10]1[N:9]([C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CBr
Reactant: C[C@H](N[C@H]1CCCC[C@@H]1CO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CN([C@@H](C)c1ccccc1)[C@H]1CCCC[C@@H]1CO

Procedure:
A solution of (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11) (339.1 g) dissolved in acetonitrile (2.2 L) was charged to a reactor followed by ethyl bromoacetate (12) (234.2 mL) and anhydrous sodium carbonate (224.2 g) under nitrogen. The contents were heated to reflux temperature for NLT 18 hours with vigorous agitation. Acetonitrile was distilled under vacuum to about 1 L volume, cooled to <30° C. and diluted with 0.75 L of heptanes and 1.0 L of water. The aqueous layer was separated and extracted with heptanes (2×0.75 L), and the combined organic layers were washed with water (0.75 L) followed by 0.75 L 3.5 M aqueous sodium chloride solution. The heptane layer was dried with anhydrous magnesium sulfate and concentrated under vacuum to afford 557.8 g of ethyl 2-((1S,2S)-2-(hydroxymethyl)cyclohexyl)((S)-1-phenylethyl)amino) acetate (13) as the major isomer.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[CH:16][N:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.ClC1C=CC(C=C[N+]([O-])=O)=CC=1>C(N)C1C=CC=CC=1>[CH2:18]([N:17]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[CH:16]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(-c3ccc(Cl)cc3)cn(Cc3ccccc3)c2CC1
Agent: O=[N+]([O-])C=Cc1ccc(Cl)cc1
Solvent: NCc1ccccc1
Product: Clc1ccc(-c2cn(Cc3ccccc3)c3c2CCNCC3)cc1

Procedure:
1-Benzyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-pyrrolo[2,3-d]azepine-6-carboxylic acid tert-butyl ester. The desired compound (54.2 mg) was prepared from the compound of Example 59, Step B (0.56 g), 280 μL of benzylamine, and 0.49 g of 1-chloro-4-(2-nitro-vinyl)-benzene as in Example 1, Step A. MS (ESI): exact mass calculated for C26H29ClN2O2, 436.19; found, m/z 437.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([N+:21]([O-:23])=[O:22])=[C:17](F)[CH:18]=2)[NH:13][C:12](=[O:24])[C:11]1=[O:25])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH2:1]([O:3][P:4]([CH2:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([N+:21]([O-:23])=[O:22])=[C:17]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:18]=2)[NH:13][C:12](=[O:24])[C:11]1=[O:25])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc21)OCC
Reactant: C1COCCN1
Product: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(N3CCOCC3)cc21)OCC
Yield: 181.8 %

Procedure:
140 mg of (6-nitro-7-fluoro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl)methanephosphonic acid diethyl ester is heated with 129 mg of morpholine for 1.5 hours to 120° C. bath temperature. After concentration by evaporation in a vacuum, the residue is chromatographed on silica gel with toluene:glacial acetic acid:water=10:10:1. After concentration by evaporation of the corresponding fractions, 300 mg of (7-morpholino-6-nitro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl)methanephosphonic acid diethyl ester is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:22]=[C:23](\[F:29])/[C:24]([O:26]CC)=[O:25])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10]1.[OH-].[Na+].[Na+].[Cl-]>CO>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:22]=[C:23](\[F:29])/[C:24]([OH:26])=[O:25])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10]1
Reactant: CCOC(=O)/C(F)=C/c1cnc(N[C@@H]2CCCN(CC3CCCCC3)C2)c(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C(F)=C/c1cnc(N[C@@H]2CCCN(CC3CCCCC3)C2)c(Cl)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
The mixture of ethyl (2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoroacrylate (0.73 g) and 1N-NaOH (3.44 mL) in MeOH (20 mL) was stirred at 60° C. for 3 hr. To the reaction mixture was added 1N-NaCl 3.44 mL and the mixture was evaporated in vacuo to give (2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoroacrylic acid (0.68 g).
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1.[OH-].[Na+:22]>O1CCCC1.CO>[Na+:22].[N:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][CH2:11][S:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([O-:20])=[O:2])=[CH:9][CH:8]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(SCCCc2ccncc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C([O-])c1ccc(SCCCc2ccncc2)cc1
Yield: 100.7 %

Procedure:
Heat a stirring solution of 4-(3-pyridin-4-yl-propylsulfanyl)-benzoic acid methyl ester (174 mg, 0.605 mmol) (Intermediate 10) and 2N sodium hydroxide (0.42 mL, 0.848 mmol) in 1:1 tetrahydrofuran/methanol (4 ml) to reflux temperature for 18 h. The reaction is allowed to cool and then concentrated in vacuo to obtain 180 mg (99%) of the title compound. MS (ES+) m/e 274.0 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:20][OH:21])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].S([O-])([O-])(=O)=O.[Na+].[Na+].[F:29][C:30]([F:38])(S(F)(=O)=O)C(O)=O>C(#N)C.C(OCC)C.[Cu]I>[CH2:13]([O:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:20][O:21][CH:30]([F:38])[F:29])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC(CO)C(=O)OCc1ccccc1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: [Cu]I
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](COC(F)F)C(=O)OCc1ccccc1
Temperature: 60 °C
Yield: 39.2 %

Procedure:
To a stirred solution of the compound of Formula XII(a), benzyl 2-(tert-butoxycarbonylamino)-3-hydroxypropanoate (1 g, 3.38 mmol) in acetonitrile (10 mL) was added copper(I) iodide (64.4 mg, 0.338 mmol) and sodium sulfate (48.1 mg, 0.338 mmol). The resulting mixture was stirred at 60° C. and treated with 2,2-difluoro-2-fluorosulfonylacetic acid (524 μL, 5.08 mmol), dropwise, as a solution in acetonitrile (2 mL) over a period of 1.5 h. Upon completion of the addition, the mixture was stirred for a further 30 min then cooled to room temperature. The mixture was diluted with diethyl ether and washed with brine (2×), water (3×) and brine (1×). The organic phase was dried, filtered and concentrated in vacuo then chromatographed in 0-30% ethyl acetate in hexanes, to provide the compound of Formula XIII(a), (S)-2-tert-butoxycarbonylamino-3-difluoromethoxy-propionic acid benzyl ester (458 mg, 40%) as a colorless sticky oil. 1H NMR (300 MHz, CDCl3): δ (ppm) 7.32-7.38 (m, 5H), 6.18 (wt, 1H), 5.28 (dd, 1H), 5.19 (dd, 2H), 4.55 (dt, 1H) 4.22 (td, 1H), 4.15 (m, 2H), 1.38 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH:5]=O.[CH3:13][C:14]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[CH:17]=1)=[O:15].[OH-].[Na+]>CO>[OH:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:13]/[C:14]([C:16]2[CH:17]=[C:18]([O:24][CH3:25])[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=2)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12]
Reactant: COc1cc(OC)cc(C(C)=O)c1
Reactant: CCOc1ccc(C=O)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1ccc(/C=C/C(=O)c2cc(OC)cc(OC)c2)cc1O
Yield: 35.3 %

Procedure:
A mixture of 3-hydroxy-4-ethoxybenzaldehyde (0.413 g, 2.5 mmol), 3,5-dimethoxyacetophenone (0.448 mg, 2.5 mmol) and 50% w/v of aqueous sodium hydroxide (3.98 ml, 0.049 mol) in methanol (5 ml) at room temperature for 18 h. The yellow solid that precipitated was filtered and sequentially washed with cold methanol and ether and finally dried in a vacuum dessicator. Purification by column chromatography (SiO2, petroleum:ether (40:60 v/v) with an increasing gradient of ethyl acetate) yielded 0.29 g (36%) of a yellow solid. 1H-NMR (CDCl3) δ 7.7 (d, 1H), 7.2 (m, 2H), 7.1 (d, 3H), 6.8 (d, 1H), 6.5 (t, 1H), 5.7 (s, 1H), 4.1 (q, 2H), 3.9 (s, 6H), 1.4 (t, 3H). 13C-NMR (CDCl3) δ 190.1, 160.9, 148.2, 146.1, 144.9, 140.6, 128.5, 122.7, 120.3, 113.1, 111.4, 106.3, 105.0, 64.7, 55.7, 14.8. Mass Spectrum m/e (M+1) 329. Anal. Calcd. for C19H20O5.0.5H2O: C, 69.5; H, 6.14. Found C, 69.62; H, 6.16.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]2[N:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21]([O:23]CC)=[O:22])=[N:17][CH:18]=2)[CH2:8]1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]2[N:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[N:17][CH:18]=2)[CH2:8]1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3cccc(OC)c3)C2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(CN2CC[C@@H](Nc3cnc(/C=C/C(=O)O)cn3)C2)c1
Temperature: 55 °C
Reaction time: 0.75 h

Procedure:
To a solution of ethyl (2E)-3-(5-{[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (362 mg) in methanol (2.9 mL) was added 1N NaOH aq. (947 uL), which was stirred at 55° C. for 45 minutes. The reaction mixture was added 1N HCl aq. (947 uL), and evaporated in vacuo to give (2E)-3-(5-{[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylic acid, which was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1)([O-])=O>[Pd].C(O)C>[CH:13]1[C:7]2[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[C:4]([NH2:1])[CH:14]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCCN2
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)OCCCN2
Yield: 96.6 %

Procedure:
3-Nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (281 mg, 1.45 mmol) and 10% Palladium on Carbon (50% Wet) (77 mg) in Ethanol (10 mL) was shaken under an atmosphere of Hydrogen (50 psi) for 5 h, filtered and conc. to give 6,7,8,9-Tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamine (230 mg, 97%). 1H-NMR (CDCl3): 6.58 (d, 1H, J=8.1 Hz), 6.40 (s, 1H), 6.27 (d, 1H, J=8.1 Hz), 4.01 (m, 2H), 3.39 (br s, 3H), 3.10 (m, 2H), 1.97 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:54][C:55]1[S:56][CH:57]=[CH:58][N:59]=1>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]([NH:54][C:55]2[S:56][CH:57]=[CH:58][N:59]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1nccs1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(Cl)c(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1nccs1)C(OC1CCOCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
A solution of rac-(3,4-dichloro-phenyl)-[(tetrahydro-pyran-4-yl)oxy]-acetic acid (90 mg, 0.30 mmol) in dichloromethane (10 mL) was treated with BOP reagent (195 mg, 0.44 mmol), triethylamine (0.12 mL, 0.88 mmol), and 2-aminothiazole (44 mg, 0.44 mmol) at 25° C. After the resulting brownish-orange solution was stirred 16 h at 25° C., it was diluted with water (10 ml) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (1×10 mL), 1N sodium hydroxide solution (1×10 mL), 1N hydrochloric acid (1×10 mL) and brine (1×10 mL), then were dried over sodium sulfate and evaporated in vacuo. The residual material was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) to give rac-2-(3,4-dichloro-phenyl)-2-[(tetrahydro-pyran-4-yl)oxy]-N-thiazol-2-yl-acetamide (98 mg, 86% yield) as a white foam: EI-HRMS m/e calcd for C16H16Cl2O3N2S (M+) 386.0258, found 386.0261.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][C:10]1=[O:25])=[N:5]2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH:10]1[OH:25])=[N:5]2
Reactant: O=C1CCCc2nc3cc(Cl)ccc3c(NCc3ccc(F)cc3)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CCCc2nc3cc(Cl)ccc3c(NCc3ccc(F)cc3)c21
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
In 100 ml of dry THF was added 4.06 g of 6-chloro-3,4-dihydro-9-(4-fluorobenzylamino)acridin-1(2H)-one and the mechanically stirred solution was cooled to 10° C. under a nitrogen atmosphere. To the reaction was added 5.8 ml of 1M LiAlH4 in THF over 15 minutes. After 1/2 hour the reaction was complete by TLC analysis, so it was quenched with 1 ml of saturated ammonium chloride solution and the inorganic salts were filtered off. The filtrate was evaporated to a solid which was recrystallized from dichloromethane to yield 3.18 g of solid. The compound went through a crystal structure change at 176°-177° C. before melting at 187°-188° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[CH2:8][N:9]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15](=[O:38])[CH2:16][NH:17][C:18](=[O:37])[C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=2[NH:29]C(OC(C)(C)C)=O)[CH2:10]1)(=[O:3])[CH3:2].[OH-].[Na+]>O1CCOCC1.Cl>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[CH2:8][N:9]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15](=[O:38])[CH2:16][NH:17][C:18](=[O:37])[C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[CH:21][C:20]=2[NH2:29])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(CN2CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)C2)cc1NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(CN2CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3N)C2)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The resulting (R)-1-(3-acetylamino-4-methoxybenzyl)-3-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine was dissolved in a 50% dioxane solution of 6 M hydrochloric acid, and the obtained solution was stirred at room temperature for 2 hours, adjusted to pH 10 with a 5 M NaOH solution and extracted with ethyl acetate. The organic layer was concentrated and purified by preparative TLC (SiO2) to thereby provide (R)-1-(3-acetylamino-4-methoxybenzyl)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (Compd. No. 2152) (3.7 mg, 8%). The purity was determined by RPLC/MS (100%). ESI/MS m/e 508.3 (M++H, C24H28F3N5O4).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][N:5]=1)[CH3:2].Cl[SiH:12]([CH3:14])[CH3:13].[Mg].O>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([SiH:12]([CH3:14])[CH3:13])=[CH:6][N:5]=1)[CH3:2]
Reactant: C[SiH](C)Cl
Reactant: CCOc1ccc(Br)cn1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc([SiH](C)C)cn1
Yield: 42.9 %

Procedure:
A mixture of 18.2 g (0.09 mol) of 2-ethoxy-5-bromopyridine (can be obtained from 2,5-dibromopyridine and sodium methanolate in DMSO), 11.4 g (0.12 mol) of chlorodimethylsilane and 50 ml of anhydrous tetrahydrofuran (THF) is added dropwise to 2.4 g (0.10 mol) of magnesium turnings in 10 ml of anhydrous THF, a strongly exothermic reaction occurring. The reaction is completed by refluxing for two hours. The mixture is then poured into water and extracted repeatedly with n-hexane, The extracts are washed with water and saturated sodium chloride solution, dried and evaporated, and the residue is distilled. 7 g (43%) of 2-ethoxy-5-dimethylsilylpyridine are obtained as a colorless oil of boiling point 7=140°-150° C.
Reaction SMILES: C(O)(=O)/C=C\C(O)=[O:5].[CH2:9]([N:12]1[CH2:17][CH2:16][C:15]2([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([O:31][CH3:32])[C:25]=3[CH2:24][C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:14][CH2:13]1)[CH:10]=[CH2:11].[OH-].[Na+]>C(O)(=O)C.O.[O-2].[O-2].[O-2].[Cr+6]>[CH2:9]([N:12]1[CH2:13][CH2:14][C:15]2([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([O:31][CH3:32])[C:25]=3[C:24](=[O:5])[C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:16][CH2:17]1)[CH:10]=[CH2:11]
Reactant: C=CCN1CCC2(CC1)c1ccccc1Cc1c(OC)cccc12
Reactant: O=C(O)/C=C\C(=O)O
Agent: [Cr+6]
Agent: [Na+]
Agent: [O-2]
Solvent: O
Solvent: CC(=O)O
Product: C=CCN1CCC2(CC1)c1ccccc1C(=O)c1c(OC)cccc12
Reaction time: 3 h

Procedure:
1'-Allyl-4-methoxy-9,10-dihydroanthracene-9-spiro-4'-piperidine maleate (7.2 g.) in glacial acetic acid (20 ml.) is treated dropwise with stirring with chromium trioxide [60 ml. of a solution of CrO3 (21 g.) in glacial acetic acid (190 ml.) and water (10 ml.)]. The reaction mixture is stirred for 3 hours, diluted with water, basified (NaOH), and extracted with ether. The ether extract is washed with water and with brine, dried (MgSO4) and evaporated to give a solid which is recrystallised from cyclohexane to give 1'-allyl-4-methoxy-10-oxo-9,10-dihydroanthracene-9-spiro-4'-piperidine, m.p. 115-117°C.