Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:29])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[CH:20][OH:21])=[CH:11][C:10]=1[O:30][CH3:31])C1C=CC=CC=1.Br>C(O)(=O)C>[OH:21][CH:20]=[C:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:18]([NH:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:30][CH3:31])[CH:11]=1)=[O:29]
Reactant: COc1cc(CCNC(=O)C(=CO)c2ccc(C)cc2)ccc1OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: COc1cc(CCNC(=O)C(=CO)c2ccc(C)cc2)ccc1O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 40.2 %

Procedure:
Two grams (2.00 g) of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-3-hydroxy-2-(4-methylphenyl)acrylamide (4.79 mmol), 1.21 g (7.19 mmol) of 48% hydrobromic acid and 20 ml of acetic acid were mixed and stirred at 80° C. for 1.5 hours. The solvent was distilled off from the reaction mixture under reduced pressure and the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to give 630 mg of 3-hydroxy-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-(4-methylphenyl)acrylamide.
Reaction SMILES: C1([Br:7])CCCCC1.[Br-].[CH:9]1([N+:15]([CH3:28])([CH3:27])[CH:16]2[CH2:21][CH:20]([CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:18][C:17]2([OH:26])[CH3:25])[CH2:14][CH2:13]C[CH2:11][CH2:10]1>>[Br-:7].[CH:9]1([N+:15]([CH3:28])([CH3:27])[CH:16]2[CH2:21][CH:20]([CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:18][C:17]2([OH:26])[CH3:25])[CH2:14][CH2:13][CH2:11][CH2:10]1
Reactant: BrC1CCCCC1
Reactant: CC(C)C1CCC(C)(O)C([N+](C)(C)C2CCCCC2)C1
Agent: [Br-]
Product: CC(C)C1CCC(C)(O)C([N+](C)(C)C2CCCC2)C1

Procedure:
By analogues procedure using cyclohexyl bromide there was also prepared cyclohexyl dimethyl (1-hydroxy-p-menth-2-yl) ammonium bromide.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]=[C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH:11]=[CH:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)=[CH:4][CH:3]=1.I[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].ClC1C=CC=CC=1Cl>[C:28]1([CH3:31])[CH:29]=[CH:30][C:25]([N:1]([C:2]2[CH:23]=[CH:22][C:5]([CH3:6])=[CH:4][CH:3]=2)[C:2]2[CH:23]=[CH:22][C:5]([CH:6]=[C:7]3[C:8]4[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=4[CH:10]=[CH:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]3=4)=[CH:4][CH:3]=2)=[CH:26][CH:27]=1
Reactant: Nc1ccc(C=C2c3ccccc3C=Cc3ccccc32)cc1
Reactant: Cc1ccc(I)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=C3c4ccccc4C=Cc4ccccc43)cc2)cc1
Reaction time: 7 h
Yield: 75 %

Procedure:
7.90 g (26.7 m moles) of the previously obtained 5-(4-amino-benzylidene)-5H-dibenzo[a,d]cycloheptene, 22.0 g (101 m mole) of p-iodotoluene, 11.0 g (79.6 m moles) of anhydrous potassium carbonate and 2.2 g of copper powder were added to 30 ml of o-dichlorobenzene, and the resulting mixture was stirred and refluxed over an oil bath kept at about 190° C. for 7 hours. After the end of reaction, the reaction mixture was subjected to filtration by suction, and the filtrate was washed successively with an aqueous 3-5% sodium thiosulfate solution and an aqueous saturated NaCl solution. The organic layer was dried over anhydrous sodium sulfate and then the solvent was removed therefrom under reduced pressure. The residue was admixed with about 60 ml of acetone, and the precipitated crystal was recovered therefrom by filtration, and recrystallized from ethyl acetate-n-hexane solvent mixture, whereby 9.52 g of 5-[4(di-p-tolylamino)benzylidene]-5H-dibenzo[a,d]cycloheptene was obtained (yield: 75.0%). The melting point was 168.0°-169.0° C. Elemental analysis as C36H29N was as follows:
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=O)[CH2:11][CH2:10]1.Cl>C(O)C>[CH:12](=[C:11]1[C:1](=[O:8])[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:9][CH2:10]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCOc2ccccc21
Agent: Cl
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)COc2ccccc21

Procedure:
(66) To a solution of benzaldehyde (430 mg, 4.05 mmol) and 4-chromanone (500 mg, 3.37 mmol) in 8.4 ml of ethanol heated almost to boiling was added 1.7 ml of concentrated hydrochloric acid dropwise. After refluxing for 2 days, the solution was cooled overnight, and a precipitate formed. The precipitate was recrystallized from ethanol to afford 367 mg (46.1%) of white flakes: mp 111.8-113.4° C. (lit. mp 112° C., Powell, J. Am. Chem. Soc., 1923, 45, 2708-2711). 1H NMR (250 MHz) δ 8.06-8.02 (dd, 1H), 7.90 (s, 1H), 7.54-7.31 (m, 6H), 7.09 (t, 1H), 7.00-6.96 (d, 1H), 5.37 (s, 2H), 13C NMR (62.7 MHz) 182.4, 161.3, 137.7, 136.1, 134.6, 131.1, 130.2, 129.7, 128.9, 128.1, 122.1, 118.1, 67.8 ppm.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:10]([CH2:12][CH2:13][O:14][CH3:15])[CH3:11])[N:3]=1.[Br:16][C:17]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:18]=1[CH:19]=[O:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:10]([CH2:12][CH2:13][O:14][CH3:15])[CH3:11])[N:3]=2)=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: COCCN(C)c1nc(Cl)ccc1C#N
Reactant: O=Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCN(C)c1nc(Oc2ccc(Br)c(C=O)c2)ccc1C#N
Temperature: 80 °C
Yield: 74.1 %

Procedure:
To a solution of 6-chloro-2-[(2-methoxy-ethyl)-methyl-amino]-nicotinonitrile (4) (11.6 g, 51.9 mmol) in DMF (anhydrous, 300 mL) were added 2-bromo-5-hydroxy-benzaldehyde (10.4 g, 51.9 mmol) and K2CO3 (14.3 g, 103.8 mmol). The reaction was heated at 80° C. for 16 hours. DMF was evaporated in vacuo. Purification was accomplished by silica gel chromatography, eluting with 5%-30% EtOAc gradient, to afford 15 g (75% yield) of the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.34 (s, 1H), 7.75-7.69 (m, 2H), 7.67 (d, J=8.6 Hz, 1H), 7.28-7.23 (m, 1H), 6.26 (d, J=8.6 Hz, 1H), 3.56 (t, J=5.5 Hz, 2H), 3.36 (t, J=5.5 Hz, 2H), 3.25 (s, 3H), 3.24 (s, 3H).
Reaction SMILES: [OH-].[Li+].[I:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:7]([O:9]C)=[O:8].Cl>C1COCC1.CO.O.O>[I:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1ccc(OC)c(I)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)cc1I
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Lithium hydroxide (72 mg, 1.71 mmol) was added to a mixture of methyl 3-iodo-4-methoxybenzoate (100 mg, 0.342 mmol) in 3.0 mL of a 3:1:1 THF-MeOH-water solution at room temperature. The mixture was stirred for eight hours in the dark and than diluted with H2O (2 mL). The solution was acidified to pH=2 by the dropwise addition of concentrated HCl. The solution was extracted twice with EtOAc (10 mL portions) and the combined organic layers dried (Na2SO4), filtered, and concentrated to afford acid 26 (95 mg, 100%) as a yellow solid that was suitable for use without further purification: 1H NMR (400 MHz, DMSO) δ 8.24 (d, J=2.0 Hz, 1H), 7.92 (dd, J=2.0, 8.7 Hz, 1H), 7.07 (d, J=8.7 Hz, 1H), 3.88 (s, 3H).
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:10]([NH:12][N:13]1[CH2:17][CH2:16][C@H:15]([N:18]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:14]1)=[O:11].CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:61]([N:68]1[CH2:75][CH2:74][CH2:73][C@@H:69]1[C:70](O)=[O:71])([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62]>CN(C=O)C>[C:61]([N:68]1[CH2:75][CH2:74][CH2:73][C@@H:69]1[C:70]([NH:8][C@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:10]([NH:12][N:13]1[CH2:17][CH2:16][C@H:15]([N:18]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:14]1)=[O:11])=[O:71])([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@H](N)Cc2ccc(Cl)cc2)C1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@H]2CCCN2C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.8 %

Procedure:
To a solution of (2R)-2-amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA, prepared in Example 1, (100 mg, 0.188 mmol) in DMF (3 mL) were added DIPEA (66.1 mL, 0.381 mmol), EDC (48.7 mg, 0.252 mmol), HOBT (43.6 mg, 0.322 mmol), and (2R)-N-BOC-proline (40.9 mg, 0.190 mmol). After the reaction mixture was stirred at rt for 12 h, DMF was removed in vacuo, and the residue was diluted with a saturated aqueous NaHCO3 solution and EtOAc. The organic layer was extracted with EtOAc and subsequently washed with a saturated aqueous NaHCO3 solution, water and an aqueous 1N HCl solution. The organic solution was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chomatography (eluent: EtOAc/Hex=2/1) to give the title compound (107 g, 90.8%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:20][N:19]([CH3:21])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:22]([O:25][CH2:26][C:27]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=[CH:29][C:28]=1[N:42]1[CH2:54][CH2:53][N:45]2[C:46]3[CH2:47][CH2:48][CH2:49][CH2:50][C:51]=3[CH:52]=[C:44]2[C:43]1=[O:55])(=[O:24])[CH3:23].C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:22]([O:25][CH2:26][C:27]1[C:28]([N:42]2[CH2:54][CH2:53][N:45]3[C:46]4[CH2:47][CH2:48][CH2:49][CH2:50][C:51]=4[CH:52]=[C:44]3[C:43]2=[O:55])=[CH:29][CH:30]=[CH:31][C:32]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:20][N:19]([CH3:21])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:24])[CH3:23]
Reactant: CN1CC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CN(C)C4)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 150 °C
Yield: 48.1 %

Procedure:
A sealed tube was charged with the mixture of 172a (167 mg, 0.48 mmol), 2-(2-(hydroxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one 114a (231 mg, 0.48 mmol), Pd(dppf)Cl2 (39 mg, 0.048 mmol), and Na2CO3 (101 mg, 0.96 mmol) in N,N-dimethylformamide (18 mL). The system was evacuated and then refilled with N2. And the reaction mixture was heated at 150° C. under microwave irradiation for 1 h. Then, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography eluting with 15:1 methylene chloride/methanol to give 172b as a brown solid (140 mg, 50%). MS: [M+H]+ 606.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:29][CH3:30])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14](OC2C=CC=CC=2)=[O:15])=[CH:6][C:5]=1[CH2:23][N:24]([CH3:28])[C:25](=[O:27])[CH3:26].[NH2:31][C:32]1[CH:39]=[C:38]([NH:40][CH2:41][CH2:42][O:43][C:44]([F:47])([F:46])[F:45])[C:35]([C:36]#[N:37])=[CH:34][N:33]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH4+].[Cl-]>C1COCC1>[C:36]([C:35]1[C:38]([NH:40][CH2:41][CH2:42][O:43][C:44]([F:45])([F:47])[F:46])=[CH:39][C:32]([NH:31][C:14]([N:11]2[C:12]3[C:7](=[CH:6][C:5]([CH2:23][N:24]([CH3:28])[C:25](=[O:27])[CH3:26])=[C:4]([CH:3]([O:2][CH3:1])[O:29][CH3:30])[N:13]=3)[CH2:8][CH2:9][CH2:10]2)=[O:15])=[N:33][CH:34]=1)#[N:37]
Reactant: N#Cc1cnc(N)cc1NCCOC(F)(F)F
Reactant: COC(OC)c1nc2c(cc1CN(C)C(C)=O)CCCN2C(=O)Oc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1CN(C)C(C)=O)CCCN2C(=O)Nc1cc(NCCOC(F)(F)F)c(C#N)cn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of phenyl 7-(dimethoxymethyl)-6-((N-methylacetamido)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 54A, 145 mg, 0.349 mmol) and 6-amino-4-((2-(trifluoromethoxy)ethyl)amino)nicotinonitrile (intermediate 102E, 103 mg, 0.419 mmol) in THF (6 ml) was slowly added 1M LHMDS in THF (0.699 ml, 0.699 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 30 min, then left to warm to room temperature overnight. The reaction mixture was poured into saturated NH4Cl solution. The aqueous was extracted with DCM (×2). The combined organic extracts were concentrated under reduced pressure. Purification of the crude product by chromatography on silica eluting with 0-100% EtOAc in heptane, then eluting with 0-100% (DCM:MeOH+0.1% NH3 9:1) in DCM afforded the title compound. (UPLC-MS 3) Rt=1.07 min; MS m/z [M+H]+ 566.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4](=[O:14])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.P(=O)(O)(O)O>COCCO.O>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([CH:6]2[CH2:5][C:4](=[O:14])[C:3]3[C:2](=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:1]2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(C=CC(=O)c2ccccc2O)cc1
Agent: O=P(O)(O)O
Solvent: O
Solvent: COCCO
Product: Cc1ccc(C2CC(=O)c3ccccc3O2)cc1

Procedure:
The 2'-Hydroxy-4-methylchalcone of Example 13 (7.3 g.) was boiled under reflux with a solution of 85% phosphoric acid (22 ml.) in 2-methoxyethanol (219 ml.) for 8 hrs. The reaction mixture was diluted with water (1 liter) and the oily precipitate extracted into dichloromethane (300 ml.). The organic extract was separated and washed with water and saturated sodium bicarbonate solution. Filtration and evaporation gave a residue of 4'-methylflavanone contaminated with the starting chalcone.
Reaction SMILES: [OH:1][C:2]1[C:12](I)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[CH3:14][N:15](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]([C:12]1[C:2]([OH:1])=[N:3][CH:4]=[C:5]([CH:11]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:15]
Reactant: CCOC(=O)c1cnc(O)c(I)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)c1cnc(O)c(C#N)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 716 mg (2.44 mmol) of ethyl 6-hydroxy-5-iodonicotinate and 573 mg (4.88 mmol) of zinc cyanide in 10 mL of DMF was added 169 mg (0.15 mmol) of tetrakis(triphenylphosphine)palladium(0). After stirring at 80° C. overnight, the mixture was filtered through a cake of Celite. The filtrate was washed with brine (10 mL), H2O (3×10 mL), and brine (10 μL), dried over MgSO4, and concentrated. Chromatography on a Biotage 40M cartridge using 4:1 v/v EtOAc/hexanes as the eluant gave 222 mg of the title compound: 1H NMR (500 MHz, CD3OD) δ 1.29 (d, J=7.1, 3H), 4.28 (q, J=7.1, 2H), 8.31 (d, J=2.5, 1H), 8.42 (d, J=2.8, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[O:22][CH2:23][C:24](O)=[O:25].C([NH2:29])=O>>[CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[O:22][CH2:23][C:24]([NH2:29])=[O:25]
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](OCC(=O)O)CC[C@H]4[C@@H]3CC[C@@H]12
Reactant: NC=O
Product: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](OCC(N)=O)CC[C@H]4[C@@H]3CC[C@@H]12
Temperature: 25 °C

Procedure:
4-Methyl-5α-4-azaandrostan-3-on-17β-yloxyacetic acid (40 mg) and formamide (0.8 ml) were heated at 178°-180° C. under N2 for 18 hours. The mixture was cooled to room temperature and poured onto ice-water. The crude product was extracted with CH2Cl2 and dried (Na2SO4). Removal of solvent gave the crude product which was recrystallized from CH2Cl2 -hexane with trace MeOH to give title product, m.p. 222°-225° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH:4]([N:16]1[CH2:21][CH2:20][N:19]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23])[CH:18]([CH2:34][O:35][CH3:36])[C:17]1=O)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.CO>C1COCC1>[CH3:1][O:2][C:3](=[O:38])[CH:4]([N:16]1[CH2:21][CH2:20][N:19]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:23])=[O:24])[CH:18]([CH2:34][O:35][CH3:36])[CH2:17]1)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: COCC1C(=O)N(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CO
Product: COCC1CN(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 2-[3-methoxymethyl-4(2-nitro-benzenesulfonyl)-2-oxo-piperazin-1-yl]-3-naphthalen-2-yl-propionic acid methyl ester, 60, (5.6 g, 10.4 mmol) in anhydrous THF (10 mL) is added 1.0M borane-tetrahydrofuran complex (31.2 mL) at −20° C. The reaction mixture is stirred at this temperature overnight. Methanol (3 mL) is added to the reaction mixture at −20° C. and allowed to stir for twenty minutes. Additional methanol (6 mL) is and the reaction mixture is allowed to warm to the room temperature. The solvent is removed in vacuo and the product purified over silica (EtOAc/Hexane, 1:1) to afford 3.5 g (64% yield) of the desired product. 1H NMR (CDCl3, δ): 8.05 (m, 1H), 7.75 (m,3H), 7.62 (m, 4H), 7.50 (m, 2H), 7.30 (dd, J=8.4, 2.1 Hz, 1H), 3.94 (t, J=6.3 Hz, 1H), 3.66 (s, 3H), 3.58 (t, J=6.8 Hz, 1H), 3.30–2.95 (m, 7H), 2.82 (s, 3H), 2.79 (m, 2H), 2.40 (dt, J=12.7, 4.3 Hz, 1H); 13C NMR, δ 171.8, 148.0, 136.0, 134.1, 133.7, 132.4, 132.0, 131.5, 128.1, 127.9, 127.7, 126.3, 125.8, 124.5, 69.5, 68.7, 58.7, 53.8, 52.8, 51.6, 46.6, 42.8, 35.4.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C@@H:11]([CH3:14])[CH2:12][OH:13])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:15]N1C(=O)CCC1=O>C(#N)C>[Br:15][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([NH:10][C@@H:11]([CH3:14])[CH2:12][OH:13])=[N:6][CH:7]=1
Reactant: C[C@@H](CO)Nc1ncccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: C[C@@H](CO)Nc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 15 h
Yield: 104.1 %

Procedure:
A solution of (S)-2-(3-nitropyridin-2-ylamino)propane-1-ol (4.88 g, 24.75 mmol) in acetonitrile (50 mL) was cooled to 0° C. and treated with N-bromosuccinimide (4.40 g, 24.75 mmol) in one portion. The ice bath was left in place and allowed to slowly expire over 15 h. The solution was then concentrated under reduced pressure in order to remove most (>90%) of the acetonitrile. The concentrated solution was dissolved in ethyl acetate and washed with half-saturated aqueous sodium bicarbonate solution (2×75 mL) and 5% aqueous sodium chloride solution (1×75 mL). The ethyl acetate solution was then concentrated under reduced pressure to afford (S)-2-(5-bromo-3-nitropyridin-2-ylamino)propane-1-ol (7.11 g) as a dark yellow solution which was used in the next step without purification. MS (ESI, pos. ion) m/z 276. 278 [M+1]+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C@H:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([I:17])[CH:12]=1)[CH2:8][OH:9].CCN(CC)CC>C1COCC1>[Cl:1][CH2:2][C:3]([NH:6][C@@H:7]([CH2:8][OH:9])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([I:17])[CH:12]=1)=[O:4]
Reactant: N[C@@H](CO)Cc1cccc(I)c1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)N[C@@H](CO)Cc1cccc(I)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Chloroacetylchloride (1.05 mL, 13.1 mmol) was added dropwise to a 0° C. solution of (R)-2-amino-3-(3-iodo-phenyl)-propan-1-ol A-8 (3.03 g, 10.9 mmol) and Et3N (1.98 mL, 14.2 mmol) in THF (50 mL) under argon and the resulting suspension was warmed to RT and stirred for 30 min. The reaction mixture was cooled back to 0° C. before being quenched with water and concentrated in vacuo. The remaining aq. phase was extracted with EtOAc (2×) and the combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give the title compound as a cream solid that was used further without purification. LC-MS B: tR=0.71 min; [M(35Cl)+H]+=353.75.
Reaction SMILES: [OH-].[Na+].FC(F)(F)C(O)=O.C[O:11][C:12](=[O:45])[CH2:13][CH2:14][CH2:15][N:16]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42](=[O:44])[NH2:43])[C:17](=[O:35])[C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][NH:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[CH:21]=[C:20]([Cl:34])[CH:19]=1.Cl>O1CCOCC1>[C:42]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[N:16]([C:17](=[O:35])[C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][NH:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[CH:21]=[C:20]([Cl:34])[CH:19]=1)[CH2:15][CH2:14][CH2:13][C:12]([OH:45])=[O:11])(=[O:44])[NH2:43]
Reactant: COC(=O)CCCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)c1ccccc1C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccccc1N(CCCC(=O)O)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Yield: 100.6 %

Procedure:
2M Aqueous sodium hydroxide (0.200 ml) was added to a stirred solution of 4-((2-carbamoyl-phenyl)-{3-chloro-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoyl}-amino)-butyric acid methyl ester trifluoroacetate (0.030 g) in 1,4-dioxan (1 ml). 2M Aqueous hydrochloric acid (0.2 ml) was added after 16 h. The reaction mixture was evaporated in vacuo and the residue was subjected to preparative hplc to give the title compound (0.024 g) as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.CS([C:17]1[S:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[N:25]=1)(=O)=O>ClC(Cl)Cl>[S:18]1[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[N:25]=[C:17]1[NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CS(=O)(=O)c1nc2cnccc2s1
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(Nc2nc3cnccc3s2)CC1
Reaction time: 1 h
Yield: 76 %

Procedure:
A mixture of 8.5 parts of ethyl 4-amino-1-piperidinecarboxylate and 2.6 parts of 2-(methylsulfonyl)thiazolo[4,5-c]pyridine was molten together for 1 hour at 120° C. After cooling, the mixture was taken up in trichloromethane. The whole was washed with water and sodium hydroxide, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in warm 2,2'-oxybispropane. The product was filtered off and dried, yielding 2.8 parts (76%) of ethyl 4-[(thiazolo[4,5-c]-pyridin-2-yl)amino]-1-piperidinecarboxylate; mp. 213° C. (66).