Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[O:11][C:12]([C:15]23[CH2:22][CH2:21][C:18]([CH2:23][CH2:24][CH2:25][C:26]4([CH3:31])OCC[O:27]4)([CH2:19][CH2:20]2)[CH2:17][CH2:16]3)=[N:13][N:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[O:11][C:12]([C:15]23[CH2:22][CH2:21][C:18]([CH2:23][CH2:24][CH2:25][C:26](=[O:27])[CH3:31])([CH2:19][CH2:20]2)[CH2:17][CH2:16]3)=[N:13][N:14]=1
Reactant: COc1ccc(-c2nnc(C34CCC(CCCC5(C)OCCO5)(CC3)CC4)o2)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: COc1ccc(-c2nnc(C34CCC(CCCC(C)=O)(CC3)CC4)o2)c(Cl)c1

Procedure:
2-(2-Chloro-4-methoxyphenyl)-5-{4-[3-(2-methyl-1,3-dioxolan-2-yl)propyl]bicyclo[2.2.2]oct-1-yl}-1,3,4-oxadiazole (5-G) (0.200 g) was stirred in a mixure of 90% acetone/10% water (20 mL). p-Toluenesulfonic acid (15 mg) was added to the solution. The reaction was heated to reflux for 1 h. The volume was reduced by evaporation of acetone in vacuo. The mixture was then layered with ethyl acetate (25 mL) and saturated sodium bicarbonate solution (25 mL). The ethyl acetate layer was extracted and dried (MgSO4). Solvent was removed in vacuo to afford pure 5-{4-[5-(2-chloro-4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]bicyclo[2.2.2]oct-1-yl}pentan-2-one (5-H).
Reaction SMILES: CO.[NH2:3][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[OH:6]>CC(C)CC(=O)C>[NH2:3][CH2:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[OH:6]
Reactant: NCC(O)c1cccc(Cl)c1
Solvent: CC(=O)CC(C)C
Solvent: CO
Product: NC[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
To 20 ml of methanol were added 1.70 g of the concentrate obtained in the same manner as in Example 295, containing 1.29 g (7.50 mmol) of 2-amino-1-(3-chlorophenyl)ethanol, and 2.88 g (7.50 mmol) of L-di-p-toluoyltartaric acid (hereinafter abbreviated as L-PTTA), and the resultant mixture was heated for dissolution and added with 20 ml of 4-methyl-2-pentanone. The mixture was cooled to room temperature and left over night to give crystals. The crystals precipitated was isolated by filtration to afford 1.69 g (2.63 mmol) of (R)-2-amino-1-(3-chlorophenyl)ethanol.L-PTTA salt. The yield of the compound relative to (R)-2-amino-1-(3-chlorophenyl)ethanol in the concentrate was 70.1%.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[C:9]([O:10][CH2:11][O:12][CH3:13])=[CH:8][C:7]([O:14][CH2:15][O:16][CH3:17])=[C:6]([CH2:18][CH3:19])[C:5]=1[CH2:20][C:21]([O:23]C)=[O:22].[OH-].[Li+].O.Cl>CO>[C:21]([CH2:20][C:5]1[C:6]([CH2:18][CH3:19])=[C:7]([O:14][CH2:15][O:16][CH3:17])[CH:8]=[C:9]([O:10][CH2:11][O:12][CH3:13])[C:4]=1[C:3]([OH:25])=[O:2])([OH:23])=[O:22]
Reactant: CCc1c(OCOC)cc(OCOC)c(C(=O)OC)c1CC(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1c(OCOC)cc(OCOC)c(C(=O)O)c1CC(=O)O
Temperature: 60 °C
Reaction time: 30 h
Yield: 92.4 %

Procedure:
The above-obtained 3-ethyl-2-(methoxycarbonylmethyl)-4,6-bis(methoxymethoxy)benzoic acid methyl ester (1.1 g, 3.0 mmol) was dissolved in methanol (3 mL) and the obtained solution was added with 4.0 mol/L aqueous lithium hydroxide solution (15 mL, 60 mmol) followed by stirring at 60° C. for 30 hours. The reaction mixture was added with water and 6.0 mol/L hydrochloric acid and the pH value was adjusted to 3. Then, the mixture was extracted with ethyl acetate 3 times. The organic layers were combined and dried over anhydrous sodium sulfate. Then, the solvent was evaporated under reduced pressure to obtain 2-(carboxymethyl)-3-ethyl-4,6-bis(methoxymethoxy)benzoic acid (0.91 g, 94%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]#[N:16])[CH:10]=2)[N:6]=1.[Cl:17][C:18]1[N:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[N:23]=[CH:22][C:21]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]([C:15]#[N:16])[CH:10]=3)[N:6]=[C:2]2[CH3:1])=[CH:20][CH:19]=1
Reactant: Cc1nc(C#Cc2ccnc(C#N)c2)c[nH]1
Reactant: OB(O)c1ccc(Cl)nc1
Product: Cc1nc(C#Cc2ccnc(C#N)c2)cn1-c1ccc(Cl)nc1

Procedure:
The title compound, MS: m/e=320.0, 322.1 (M+H+), was prepared in accordance with the general method of example 7 from 4-(2-Methyl-1H-imidazol-4-ylethynyl)-pyridine-2-carbonitrile and 6-chloro-3-pyridinyl-boronic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:16].C(OOC(=O)C1C=CC=CC=1)(=[O:24])C1C=CC=CC=1.C(Cl)(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[OH:24][CH:5]1[C:4]2[C:9](=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[C:8](=[O:16])[CH2:7][CH2:6]1
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reactant: COc1ccc([N+](=O)[O-])c2c1CCCC2=O
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc([N+](=O)[O-])c2c1C(O)CCC2=O
Temperature: 25 °C

Procedure:
2.0 gm of 5-methoxy-8-nitro-1-tetralone (described in Japanese Patent Laid-open (ko-kai) 279891/1989 and also in U.S. Pat. No. 4,939,255) and 2.05 gm of N-bromosuccinic imide were dissolved in 50 ml of carbon tetrachloride. After the addition of a catalytic amount of benzoyl peroxide, the mixture was heated under reflux for 4 hours and then cooled to room temperature, followed by the addition of 50 ml of chloroform. The mixture was washed with 10% aqueous solution of sodium hydroxide, water, and saturated brine in this order, and dried over anhydrous sodium sulfate. To the residue obtained by removing the solvent were added 5 ml of tetrahydrofuran, 5 ml of ethanol, 8 ml of water, and 250 mg of calcium carbonate, and the mixture was heated under reflux. A residue was obtained by removing the solvent from the reaction mixture, which, after the addition of 50 ml of water, was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography using chloroform-ethyl acetate (4:1) as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 1.49 gm of light yellow powder of the title compound.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.[CH3:15][N:16]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24].C(N(CC)CC)C.O1CCCC1>ClCCl.O>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:30]([C:29]3[CH:28]=[CH:27][C:26]([N:16]([CH3:15])[C:17](=[O:25])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:24])=[CH:34][CH:33]=3)=[O:31])[CH2:6][C:5]=12
Reactant: Cc1ccccc1C(=O)N(C)c1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)N(C)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.5 %

Procedure:
A mixture of 0.27 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 0.518 g of 4-[N-methyl-N-(2-methylbenzoyl)amino]benzoyl chloride, 0.182 g of triethylamine and 7 ml of tetrahydrofuran is stirred at room temperature for 3 hours. To the mixture is added 0.29 g of 4-[N-methyl-N-(2-methylbenzoyl) amino]benzoyl chloride and 0.10 g of triethylamine in 2 ml of dichloromethane and the mixture stirred for 2 days. The mixture is poured into water and extracted with dichloromethane. The extract is washed with water, 1N HCl, 1N NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo and the residue crystallized from dichloromethane-hexane to give 0.38 g of crystals, m.p. 168°-170° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Br:27])[CH:25]=2)[NH:20][CH:19]=1)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].Cl>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Br:27])[CH:25]=2)[NH:20][CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2ccc(Br)cc12)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.3 %

Procedure:
3-(N-Benzyloxycarbonyl-2(R)-pyrrolidinylcarbonyl)-5-bromo-1H-indole (Preparation 1; 0.67 g, 1.57 mmol) was dissolved in dry tetrahydrofuran (20 ml) and, at room temperature under nitrogen, lithium borohydride (2M solution in tetrahydrofuran; 1.2 ml, 2.4 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours, heated under reflux for 16 hours, then allowed to cool to room temperature. 2N Hydrochloric acid (10 ml) was added dropwise and the reaction mixture then partitioned between ethyl acetate and water. The separated organic phase was washed with saturated aqueous sodium bicarbonate solution (2×) and brine (1×), dried (Na2SO4), and evaporated under reduced pressure to give a colourless oil. Purification by column chromatography on silica gel, eluting with dichloromethane, gave the title compound as an oil (0.32 g). Rf 0.20 (SS 1). Found: C,59.94; H,5.07; N,6.58. C21H21BrN2O2 ; 0.10 CH2Cl2 requires C,60.08; H,5.07; N,6.64%. δ(CDCl3)--mixture of rotamers: 1.63-1.90(4H,m), 2.60-2.82(1H,m), 3.10-3.28(1H,m), 3.30-3.54(2H,m), 4.18(1H,m), 5.15-5.25(2H,m), 5.30(0.2H,s,CH2Cl2), 6.90 and 6.95(1H, 2×s), 7.05-7.50(7H,m), 7.70 and 7.85(1H, 2×s), 8.25(1H,br s).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[C:18](=[O:43])[NH:19][C@H:20]1[CH2:24][CH2:23][N:22]([C@@H:25]([CH2:31][NH:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:35]=2[CH3:41])[C@@H:26]([OH:30])[CH2:27][CH2:28][CH3:29])[C:21]1=[O:42])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][C:9]=1[C:18]([NH:19][C@H:20]1[CH2:24][CH2:23][N:22]([C@@H:25]([CH2:31][NH:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:35]=2[CH3:41])[C@@H:26]([OH:30])[CH2:27][CH2:28][CH3:29])[C:21]1=[O:42])=[O:43]
Reactant: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)N1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2NC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)N1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2N)C1=O
Yield: 66.2 %

Procedure:
The compound {2-[(3S)-1-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-2-oxo-pyrrolidin-3-ylcarbamoyl]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (9 mg) was dissolved in 3 mL of 2:1 CH2Cl2/TFA. The resultant solution was stirred for 3 h and then concentrated in vacuo. The residue was dissolved in TFA and concentrated in vacuo; this procedure was repeated. Lyopholization (H2O/MeCN) afforded the title compound as a white powder (5 mg). MS found: (M+H)+=521.5.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH2:33][NH:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:52](I)[CH3:53]>CN(C=O)C.CCOC(C)=O>[C:24]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:22][C:21]([C:17]2[O:18][C:19]([CH3:20])=[C:15]([CH2:14][CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:41])=[C:7]([CH2:33][N:34]([CH2:52][CH3:53])[C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])[CH:8]=3)[N:16]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1CNC(=O)OC(C)C
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(Cc1cc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)ccc1CCC(=O)O)C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A solution of 3-[4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-2-(isopropoxycarbonylamino-methyl)-phenyl]-propionic acid methyl ester (200 mg, 0.36 mmol) in DMF (15 mL) was treated with sodium bis(trimethylsilyl)amide (132 mg, 0.719 mmol). Ethyl iodide (112 mg, 0.719 mmol) was added, and the reaction mixture was stirred overnight at room temperature under N2. The mixture was diluted with EtOAc (100 mL) and washed with brine (100 mL), then water (100 mL). The organic layer was dried (MgSO4) and concentrated to the penultimate ester as white solid (179 mg). The material was dissolved in EtOH (20 mL), treated with 5N NaOH (20 mL), and stirred at room temperature overnight. The mixture was acidified with 1N HCl (10 mL) and extracted with EtOAc (50 mL). The organics were dried (MgSO4) and concentrated to give a white solid (201 mg). MS [EI+] m/z 571 (M+H)+. Anal. Calculated for C34H38N2O6: C, 71.6; H, 6.7; N, 4.9. Found: C, 70.8; H, 6.8; N, 5.0.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH:14]([O:18][CH2:19][C:20]3[C:21]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:35])=[N:22][O:23][C:24]=3[CH:25]3[CH2:27][CH2:26]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C.[OH-].[K+].Cl>C(O)C.O1CCCC1>[CH:25]1([C:24]2[O:23][N:22]=[C:21]([C:28]3[C:29]([Cl:35])=[CH:30][CH:31]=[CH:32][C:33]=3[Cl:34])[C:20]=2[CH2:19][O:18][CH:14]2[CH2:15][CH2:16][CH2:17][N:11]([C:8]3[CH:7]=[CH:6][C:5]([C:4]([OH:36])=[O:3])=[CH:10][CH:9]=3)[CH2:12][CH2:13]2)[CH2:27][CH2:26]1
Reactant: CCOC(=O)c1ccc(N2CCCC(OCc3c(-c4c(Cl)cccc4Cl)noc3C3CC3)CC2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CCCC(OCc3c(-c4c(Cl)cccc4Cl)noc3C3CC3)CC2)cc1
Temperature: 60 °C
Reaction time: 14 h
Yield: 99 %

Procedure:
To a solution of 8.28 g (15.64 mmol) of 4-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-azepan-1-yl}-benzoic acid ethyl ester (Isomer B) in 50 mL of Ethanol and 150 mL of tetrahydrofuran, is added potassium hydroxide (55.16 g, 78.19 mmol). The resulting mixture is stirred at 60° C. for 14 hours. The mixture is cooled to room temperature and acidified with 2N HCl to pH 5-6. The solvent is removed under vacuum, the resulting slurry is diluted with CH2Cl2 (150 mL) and washed with water (2×80 mL). The organic layer is dried (MgSO4), filtered and concentrated to afford 7.76 g of the title compound as a white solid (98%). MS (m/e): 501 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[O:30](S(C(F)(F)F)(=O)=O)[S:31]([C:34]([F:37])([F:36])[F:35])(=O)=[O:32]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[S:31]([O:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[O:14])=[CH:4][CH:3]=1)(=[O:32])=[O:30]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cccc2c(O)ccc(C(=O)N3CCOCC3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc2c(OS(=O)(=O)C(F)(F)F)ccc(C(=O)N3CCOCC3)c12
Reaction time: 0.17 h

Procedure:
To a solution of (4-hydroxy-8-methylnaphthalen-1-yl)(morpholino)methanone (above Step-7 intermediate) (1 equiv) in dry CH2Cl2 (4 mL) under nitrogen was added DIPEA (3 equiv) at 0° C. and the mixture was stirred for 10 min. To this, Tf2O (1.5 equiv) was added drop wise and the reaction mixture was stirred for another 1.5 h at 0° C. Then it was slowly quenched with water (10 mL) and the aqueous layer was extracted with CH2Cl2 (4×10 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried (Na2SO4) and filtered. The solvent was removed under reduced pressure and the residue was purified by column to give the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N+:12]([O-])([OH:14])=[O:13]>>[N+:12]([C:9]1[CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[CH:7][C:8]=1[Br:11])([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Product: CS(=O)(=O)c1ccc(Br)c([N+](=O)[O-])c1

Procedure:
4-methylsulfonyl-bromobenzene was reacted with nitric acid to obtain 2-nitro-4-methylsulfonyl-bromobenzene melting at 126° C. which was reacted with N-hydroxy-phthalimide to obtain 0-(4-methylsulfonyl-2-nitro-phenoxy)-phthalimide melting at 215° C. The latter was reacted to obtain 0-(4-methylsulfonyl-2-nitro-phenyl)-hydroxylamine melting at 190° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc2C1
Reactant: ClCCCN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2cc(OCCCN3CCCCC3)ccc2C1

Procedure:
To a round-bottom flask, equipped with stir bar and septum, is placed 6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1 g, 4.01 mmol), KI (599 mg, 4.01 mmol) and NaH (162 mg, 95% dry, 6.42 mmol). Then, dry DMF (20 mL, 0.5 M) is added via syringe followed by N-(3-chloropropyl)piperidine (0.85 mL, 5.2 mmol). The reaction is allowed to stir at 70 degrees overnight. In the morning, the reaction is quenched with water, extracted into EtOAc (3×20 mL) and dried over brine. Column chromatography in 9:1 DCM:MeOH affords 6-(3-piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester an orange oil (1 g, 67%). Mass sec hit M+1, 375; LCMS>95% @230 nm and ELSD. In a similar manner the Examples 35, 139, and 164 are prepared:
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@@H:16]([C:28](=[O:43])[N:29]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH2:40][CH2:41][OH:42])[CH3:30])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)C)(C)(C)C.C(=O)([O-])O.[Na+].O>ClCCl>[OH:42][CH2:41][CH2:40][O:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][CH2:31][N:29]([CH3:30])[C:28](=[O:43])[C@H:16]([NH:14][CH3:13])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1
Reactant: CN(CCc1ccccc1OCCO)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1ccccc1OCCO
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
At 0° C., trifluoroacetic acid (4 ml) was added to a solution of N-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl ester (986 mg, 1.95 mmol) in dichloromethane (4 ml). The solution was stirred for 3 h at 0° C. Dichloromethane (50 ml) was added. A saturated solution of sodium hydrogen carbonate (30 ml) was added. Solid sodium hydrogen carbonate was added until pH 7 was obtained. Water was added until a clear solution was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (2×20 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 730 mg of (2R)-N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)(=[O:14])=[O:13].Cl>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:9])[F:11])=[CH:4][C:3]=1[S:12]([N:15]1[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1)(=[O:14])=[O:13]
Reactant: Cc1ccc(C(F)(F)F)cc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(C(F)(F)F)cc1S(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-dimethylethyl 4-{[2-methyl-5-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinecarboxylate (may be prepared as described in Description 29) (2.1 g, 5.14 mmol) in 1,4-dioxane (50 mL) was treated by HCl 4M in dioxane (6.43 mL, 25.7 mmol). The reaction mixture was stirred overnight at room temperature. LCMS showed a mixture of starting material and product so 8 ml of 4M HCl in dioxane were added. LCMS after 2 h showed still some starting material so 5 ml of 4M HCl in dioxane were added. LCMS after 2 h showed traces of starting material.
Reaction SMILES: CS(O[C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[CH2:7]1)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O>[N:24]([C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[CH2:7]1)=[N+:25]=[N-:26]
Reactant: CS(=O)(=O)O[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 102.5 %

Procedure:
To a solution of (3S)-3-methanesulfonyloxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (5.33 g, 15.0 mmol) (obtained as described in Reference Example 53(3)) in dimethylformamide (159 ml) was added sodium azide (1.07 g, 16.5 mmol), and the mixture was stirred in an oil bath (100° C.) for 3.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed successively with 10% aqueous sodium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (3:1→1:2) as the eluant to afford (3R)-3-azido-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (4.48 g, yield 100%) as a colorless oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:13][C:14]1[CH:31]=[CH:30][C:29]2[C@@H:28]3[C@H:19]([C@H:20]4[C@@:24]([CH2:26][CH2:27]3)([CH3:25])[C:23](O)([C:32]([F:35])([F:34])[F:33])[CH2:22][CH:21]4[CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:18][CH2:17][C:16]=2[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>N1C=CC=CC=1>[CH2:6]([O:13][C:14]1[CH:31]=[CH:30][C:29]2[C@@H:28]3[C@H:19]([C@H:20]4[C@@:24]([CH2:26][CH2:27]3)([CH3:25])[C:23]([C:32]([F:34])([F:35])[F:33])=[CH:22][CH:21]4[CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:18][CH2:17][C:16]=2[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)C(=O)OCCCCC1CC(O)(C(F)(F)F)[C@@]2(C)CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@H]12
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCCCCC1C=C(C(F)(F)F)[C@@]2(C)CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@H]12
Temperature: 25 °C
Yield: 77.6 %

Procedure:
Phosphorylchloride (0.25 ml; 200 μmol) was added to a solution of 2,2-Dimethylpropionic acid 4-(3-benzyloxy-17-hydroxy-17-trifluoromethyl-estra-1,3,5(10)-trien-15-yl)-butylester (80.0 mg; 136 μmol) in pyridine (2.50 ml) and the resulting mixture is heated under reflux for 24 h. Then, the mixture was allowed to cool to RT, diluted with ice water and extracted with ether. The combined organic phases were dried over MgSO4 and the solvent was evaporated. The residue was purified by column chromatography (SiO2, DCM) yielding the title compound (60.0 mg, 78%) as colorless oil.