Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1.CC(C)([O-])C.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.O1CCOCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:1][C:2]2[CH:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(Oc2ccccc2)cc1N
Reactant: Fc1ccc(I)cc1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Oc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 51.5 %

Procedure:
To dioxane 5.0 mL solution of methyl 2-amino-4-phenoxybenzoate 0.34 g were added 1-fluoro-4-iodobenzene 0.18 mL,1,1′-bis(diphenylphosphino)ferrocene 93 mg,1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex 46 mg and sodium tert-butoxide 0.15 g at room temperature, and it was heated and refluxed under nitrogen atmosphere for 3 hours. After the reaction mixture was cooled to room temperature,10% citric acid aqueous solution and ethyl acetate were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate=20:1] to give methyl 2-(4-fluoroanilino)-4-phenoxybenzoate 0.036 g of colorless oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH3:5].[C:12](OC(=O)C)(=[O:14])[CH3:13].CO>C(O)(=O)C>[CH3:1][N:2]([CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH3:5])[C:12](=[O:14])[CH3:13]
Reactant: CNCC(C)c1ccncc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)N(C)CC(C)c1ccncc1
Reaction time: 8 h

Procedure:
dl-4-(1-Methylaminoprop-2-yl)pyridine (4.5 g.) in acetic acid (15 ml.) was treated cautiously with acetic anhydride (10 ml.) followed by allowing the mixture to stand at ambient temperature overnight. Methanol (20 ml.) was then added to destroy excess acetic anhydride, followed by evaporation in vacuo (at 40° C.) to remove methanol and methyl acetate. The residue was diluted with water and treated portionwise with sodium carbonate (anhydrous) until alkaline (pH 10-12). The oily suspension was extracted with chloroform (3×60 ml.) and the bulked extracts were dried (Na2CO3) and evaporated to dryness in vacuo to give a near-colorless oil (6.8 g.). The oil was distilled to give pure dl-4-(1-[N-methylacetamido]prop-2-yl)pyridine (3 g.), b.p. 138°-140°/0.4 mm Hg. (as a colorless oil).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:8]=1)#[N:2].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[NH2:45][C@@H:46]([CH3:63])[CH2:47][N:48]1[CH:52]=[CH:51][C:50]([C:53]2[CH:60]=[C:59]([F:61])[C:56]([C:57]#[N:58])=[C:55]([Cl:62])[CH:54]=2)=[N:49]1>C(Cl)Cl.CN(C=O)C>[Cl:62][C:55]1[CH:54]=[C:53]([C:50]2[CH:51]=[CH:52][N:48]([CH2:47][C@@H:46]([NH:45][C:12]([C:10]3[N:11]=[C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]4[CH:9]=3)=[O:14])[CH3:63])[N:49]=2)[CH:60]=[C:59]([F:61])[C:56]=1[C:57]#[N:58]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: N#Cc1ccc2nc(C(=O)O)cn2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn2cc(C#N)ccc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.4 %

Procedure:
6-Cyanoimidazo[1,2-a]pyridine-2-carboxylic acid (0.770 mmol, 0.144 g), HOBt (0.770 mmol, 0.104 g) and DIPEA (1.539 mmol, 0.199 g) were dissolved in DCM (5 ml) and DMF (1 ml). EDCI (0.770 mmol, 0.148 g) was added and the resulting mixture was stirred for 10 min at RT. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.592 mmol, 0.22 g) dissolved in small amount of DCM was added and the reaction mixture was stirred overnight at RT. The mixture was diluted with DCM, washed with 1M Na2CO3 and water. The organic phase was dried, filtered and evaporated. The crude product was purified by trituration from ACN. 0.054 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.15 (d, 3H), 4.31-4.45 (m, 2H), 4.46-4.57 (m, 1H), 7.00 (d, 1H), 7.61-7.66 (m, 1H), 7.72-7.77 (m, 1H), 7.86-7.92 (m, 2H), 7.93-7.96 (m, 1H), 8.35-8.37 (m, 1H), 8.69 (d, 1H), 9.34-9.37 (m, 1H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]([OH:60])=O)(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(N(CC)CC)C.[OH:68][CH2:69][C@@H:70]([C@@H:72]([C@@H:74]([CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH3:89])[OH:75])[OH:73])[NH2:71]>C(Cl)Cl>[C:12]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]([NH:71][C@H:70]([C@@H:72]([C@@H:74]([CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH3:89])[OH:75])[OH:73])[CH2:69][OH:68])=[O:60])(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@@H](N)CO
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)[C@H](O)CCCCCCCCCCCCCC
Temperature: 30 °C
Reaction time: 2.42 h
Yield: 75.1 %

Procedure:
p-Toluenesulphonic acid (13.55 g; 71.1 mmoles) was added to a refluxing solution of 27-stearoyloxyheptacosanoic acid (53.45 g; about 77.1 mmoles) and triethylamine (100 ml) in methylene chloride (2 l; free of alcohol) under nitrogen. After refluxing for 1 hour phytosphingosine (18.6 g; purity 94%; 55 mmoles) was added and refluxing was continued for 145 minutes. After cooling the reaction mixture to 30° C. the precipitate was filtered off and washed with methylene chloride (1 l). This solid was dissolved in hot, ethanol-free ##STR11## chloroform and filtered off while warm. The filtrate was allowed to cool. The precipitate formed was filtered off, washed with chloroform (250 ml) and acetone (2×200 ml) and dried in vacuo affording 41 g of the title product.
Reaction SMILES: [CH:1]1[N:5]([C@@H:6]2[O:10][C@@H:9]3[CH2:11][O:12][P:13]([OH:16])([O:15][C@H:8]3[C@H:7]2[OH:17])=[O:14])[C:4]2[NH:18][C:19]([NH2:23])=[N:20][C:21](=[O:22])[C:3]=2[N:2]=1.[P:24]([O:36][CH2:37][C@H:38]1[O:42][C@@H:41]([N:43]2[C:52]3[N:51]=[CH:50][N:49]=[C:47]([NH2:48])[C:46]=3[N:45]=[CH:44]2)[C@H:40]([OH:53])[C@@H:39]1[OH:54])([O:27][P:28]([O:31]P(O)(O)=O)([OH:30])=[O:29])(=[O:26])[OH:25].P(O)(O)(O)=O.N1C(=O)C2NC=NC=2N=C1N>>[P:13]([O:12][CH2:11][C@H:9]1[O:10][C@@H:6]([N:5]2[C:4]3[N:18]=[C:19]([NH2:23])[NH:20][C:21](=[O:22])[C:3]=3[N:2]=[CH:1]2)[C@H:7]([OH:17])[C@@H:8]1[OH:15])([O:26][P:24]([OH:36])([OH:27])=[O:25])(=[O:14])[OH:16].[P:24]([O:36][CH2:37][C@H:38]1[O:42][C@@H:41]([N:43]2[C:52]3[N:51]=[CH:50][N:49]=[C:47]([NH2:48])[C:46]=3[N:45]=[CH:44]2)[C@H:40]([OH:53])[C@@H:39]1[OH:54])([O:27][P:28]([OH:30])([OH:31])=[O:29])(=[O:25])[OH:26]
Reactant: Nc1nc(=O)c2ncn([C@@H]3O[C@@H]4COP(=O)(O)O[C@H]4[C@H]3O)c2[nH]1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: O=P(O)(O)O
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
The cGMP present in the sample is then converted to GMP with phosphodiesterase. The GMP is combined with ATP in the presence of guanine monophosphate kinase to yield guanosine-5′-diphosphate (GDP) and ADP.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15].O.C(OCC)(=O)C>C(O)(=O)C.[Fe]>[N+:14]([C:6]1[C:5]2[C:10]([CH:9]=[CH:8][CH:7]=1)=[N:11][C:3](=[O:2])[CH:4]=2)([O-:16])=[O:15]
Reactant: COC(=O)Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1C=c2c([N+](=O)[O-])cccc2=N1
Temperature: 50 °C
Yield: 73.2 %

Procedure:
4.43 g (18.45 mmol) of methyl-(2,6-dinitrophenyl)-acetate is added in 38.8 ml of glacial acetic acid and 11 ml of water and mixed with 3.75 g of iron powder and stirred for four more hours. In this case, heating to 40 to 60° C. takes place. The reaction mixture is added to ice water, mixed with ethyl acetate and vigorously stirred for ten minutes. The mixture is filtered through a glass-fiber filter, the organic phase is separated, and the aqueous phase is extracted twice more with ethyl acetate. The combined organic extracts are washed with brine, dried, and the solvent is spun off after the desiccant is filtered off. The residue is chromatographed on silica gel (mobile solvent methanol/dichloromethane). 2.38 g of 4-nitro-indol-2-one is isolated. The nitro compound is mixed again in glacial acetic acid/water with 2.7 g of iron powder, and the above-described cycle is passed through another time. 1.63 g of the desired amine is isolated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8].Br[C:20]1C=CC(OC)=CC=1C>>[Br:1][C:2]1[C:3]([CH3:20])=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8]
Reactant: COc1ccc(Br)cc1C(=O)c1ccc(C)cc1
Reactant: COc1ccc(Br)c(C)c1
Product: COc1cc(C)c(Br)cc1C(=O)c1ccc(C)cc1

Procedure:
Employing the same general procedure as for the preparation 5-bromo-2-methoxy-4′-methylbenzophenone (Compound H), 780 mg (3.9 mmol) of 4-bromo-1-methoxy-3-methylbenzene (Compound E) was converted into the title compound using 260 mg (1.9 mmol) of aluminum chloride, 0.6 mL (0.7 g, 4.7 mmol) of p-toluoyl chloride and 17 mL of dichloromethane. Purification by flash chromatography (silica, 5% ethyl acetate in hexane) gave the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1(O)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)[CH2:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[O:17][C:19]2([CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:23][CH2:24]2)[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN(CC(=O)c2ccccn2)Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1ccccc1)C=C(c1ccccn1)O2
Temperature: 80 °C
Yield: 47.4 %

Procedure:
To tert-butyl 4-[[benzyl-[2-oxo-2-(2-pyridyl)ethyl]amino]methyl]-4-hydroxy-piperidine-1-carboxylate (190 mg, 0.43 mmol) in benzene (11 mL) was added 4-methylbenzenesulfonic acid (99 mg, 0.52 mmol) and reaction mixture was heated at 80° C. for 30 minutes. The reaction mixture was cooled, diluted with ethyl acetate and washed sequentially with sat. NaHCO3 and brine solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give residue, which was purified using silica gel column chromatography using EtOAc/DCM (10-100%) as eluent to give tert-butyl 8-benzyl-10-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undec-9-ene-3-carboxylate (86 mg, 45%). ESI-MS m/z calc. 421.5. Found 422.2 (M+1)+; Retention time: 1.42 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 8.40-8.34 (m, 1H), 7.56 (dd, J=4.0, 3.5 Hz, 1H), 7.37-7.27 (m, 6H), 7.07 (s, 1H), 6.92 (d, J=1.5 Hz, 1H), 4.22 (s, 2H), 3.99-3.76 (m, 2H), 3.17 (t, J=11.8 Hz, 2H), 2.78 (s, 2H), 1.83 (s, 2H), 1.44 (s, 9H), 1.40 (d, J=4.4 Hz, 2H).
Reaction SMILES: S([O:5][C@H:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(C)(=O)=O.[Cl:13][C:14]1[C:15]([O:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:13][C:14]1[C:15]([O:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C@H:6]([CH3:12])[C:7]([OH:9])=[O:8])=[CH:27][CH:26]=2)=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=1.[Cl:13][C:14]1[C:15]([O:24][C:25]2[CH:26]=[CH:27][C:28]([O:5][C@H:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:29][CH:30]=2)=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=1
Reactant: Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Reactant: CCOC(=O)[C@@H](C)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H](C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Product: C[C@@H](Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)O

Procedure:
(R)-2-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]propionic acid is prepared as follows: A suspension of ethyl (R)-2-mesyloxypropionate (0.392 g, 2.0 mmol), 4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenol (0.578 g, 2.0 mmol) and potassium carbonate (0.276 g, 2.0 mmo.) in 8 ml of DMSO is heated at 80° for 24 hours. The reaction mixture is cooled and worked up to give ethyl (R)-2-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]propionate. The propionate is hydrolyzed by stirring it (0.80 g, 2.22 mmol) in 10 ml of ethanol with sodium hydroxide (0.10 g, 2.50 mmol) in 1 ml of water overnight. The ethanol is then removed in vacuo from the reaction mixture. The residue is acidified with HCl and extracted with ether. The organic fraction is washed with brine until neutral and dried over sodium sulfate. Solvent is removed to give (R)-2-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]propionic acid.
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([OH:14])=[O:13])[CH2:4]1.[CH3:15][C:16](Cl)([CH3:18])[CH3:17].[Cl-].CN1CCCC1=[O:27]>C([O-])(=O)C1C=CC=CC=1.C([N+](CCCC)(CCCC)CCCC)CCC>[OH:27][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:16]([CH3:18])([CH3:17])[CH3:15])=[O:13])[CH2:4]1
Reactant: CC1(C)O[C@H](CCl)C[C@H](CC(=O)O)O1
Reactant: CC(C)(C)Cl
Reactant: CN1CCCC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])c1ccccc1
Agent: [Cl-]
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
Solid tetrabutylammonium benzoate obtained as above (126.47 g, 0.348 mole) was added in one portion to a mechanically stirred solution of the chloride (4R-cis)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid, 1,1-dimethylethyl ester prepared as in step (d) of Example 1 above (32.3 g, 0.116 mole) in HPLC grade 1-methyl-2-pyrrolidinone (465 ml) under argon. The resulting solution was stirred at 100° C. (internal temperature). After 30 to 60 minutes the reaction mixture became homogeneous and brown in color. The progress of the reaction was followed by TLC and GC analysis (TLC: Rf =0.47 for the chloride starting material; Rf =0.35 for the title compound (silica gel, Ether: Hexane, 4:6, visualization by Ce(SO4)2 spray). After 6.5 hours the reaction was completed.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([O:35][CH3:36])=[O:34])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C:16]2([CH2:30]OC(C)(C)O[CH2:26]2)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH2:61][CH2:62][CH2:63][N:64]1[CH2:69][CH2:68][N:67](C(OC(C)(C)C)=O)[CH2:66][CH2:65]1.[S:77](N)([NH2:80])(=[O:79])=[O:78]>CO.C1COCC1>[NH2:80][S:77]([N:67]1[CH2:68][CH2:69][N:64]([CH2:63][CH2:62][N:61]2[CH2:30][C:16]3([CH2:15][N:14]4[C:13]5[CH:12]=[C:11]([C:33]([O:35][CH3:36])=[O:34])[CH:10]=[CH:9][C:8]=5[C:7]([CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[C:21]4[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[O:18][CH2:17]3)[CH2:26]2)[CH2:65][CH2:66]1)(=[O:79])=[O:78]
Reactant: NS(N)(=O)=O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC1(COc2ccccc2-3)COC(C)(C)OC1
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC1(COc2ccccc2-3)CN(CCN2CCN(S(N)(=O)=O)CC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
Cat. TsOH monohydrate was added to a suspension of methyl 14′-cyclohexyl-2,2-dimethylspiro[1,3-dioxane-5,7′-indolo[1,2-e][1,5]benzoxazocine]-11′-carboxylate in MeOH/THF 1:2 (0.03 M), and the solution was stirred at RT for 3 h. Filtration on a pad of neutral alumina using EtOAc as eluent afforded after evaporation of the solvent in vacuo methyl 14-cyclohexyl-7,7-bis(hydroxymethyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (quant). This material was dissolved in dry MeCN (0.2M) and DIPEA (4.0 eq) and trifluoromethane sulfonic anhydride (3.5 eq) was added at 0° C. The mixture was stirred at 0° C. for 15 min, then more DIPEA (4 eq) was added at RT. Tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (2 eq) was added, and the mixture was stirred at 70° C. for 1 h. After removal of the solvent in vacuo EtOAc was added, the solution was washed with H2O and brine, dried over Na2SO4 and the solvent was removed in vacuo. The crude methyl 1-{2-[4-(tert-butoxycarbonyl)piperazin-1-yl]ethyl}-14′-cyclohexylspiro[azetidine-3,7′-indolo[1,2-e][1,5]benzoxazocine]-11′-carboxylate was taken in DCM/TFA 3:1 (0.13M) and stirred at RT for 2 h. The mixture was evaporated to dryness and the residual material was dissolved in EtOAc. The solution was washed with sat. aq. NaHCO3 and brine. The organic phase was dried over Na2SO4 and the solvent evaporated in vacuo. The residue was dissolved in dry dioxane (0.06M) and sulfamide (5 eq) was added. The mixture was stirred at reflux for 3 h, then overnight at RT. The residue obtained after evaporation was purified by FC (EtOAc/MeOH, 9:1) to afford the title compound in 40% yield. (ES+) m/z 622 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21](O)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[N:46]1([C:52]2[CH:59]=[CH:58][CH:57]=[CH:56][C:53]=2[C:54]#[N:55])[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>C(Cl)Cl.C(N(CC)CC)C>[C:17]([O:16][C:14](=[O:15])[NH:13][CH:11]1[CH2:10][CH:9]([C:21]([N:49]2[CH2:48][CH2:47][N:46]([C:52]3[CH:59]=[CH:58][CH:57]=[CH:56][C:53]=3[C:54]#[N:55])[CH2:51][CH2:50]2)=[O:22])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12]1)([CH3:18])([CH3:20])[CH3:19]
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)NC1CC(C(=O)O)N(Cc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CC(C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1
Reaction time: 8 h

Procedure:
The mixture of 1-benzyl-4-tert-butoxycarbonylamino-pyrrolidine-2-carboxylic acid, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride, N-hydroxybenzotriazole, 2-piperazin-1-yl-benzonitrile and triethylamine in DCM is stirred overnight. The crude product is purified to afford {1-benzyl-5-[4-(2-cyano-phenyl)-piperazine-1-carbonyl]-pyrrolidine-3-yl}carbamic acid tert-butyl ester (41).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[NH:15][CH2:16][CH2:17][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)C)=[CH:5][CH:4]=1.[C:26]1(C(C)CCNC2CCCCC2C2C=CC(O)=CC=2)C=CC=CC=1>>[C:25]1([CH2:20][CH2:18][CH2:17][CH2:16][NH:15][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]2[C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:26]=1
Reactant: COc1ccc(C2CCCCC2NCCC(C)c2ccccc2)cc1
Reactant: CC(CCNC1CCCCC1c1ccc(O)cc1)c1ccccc1
Product: Oc1ccc(C2CCCCC2NCCCCc2ccccc2)cc1

Procedure:
Following the general method of example 1 (2RS,3SR)-[2-(4-methoxy-phenyl)-cyclohexyl]-(3-phenyl-butyl)-amine (0.95 g, 2.81 mmol) was converted to (1RS,2SR)-4-[2-(3-phenyl-butylamino)-cyclohexyl]-phenol, giving 0.45 g of a light brown solid. MS: m/e=324.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[N:10]=[CH:9]2)=[CH:4][C:3]=1[F:22].N1C=CC=CC=1.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>ClCCl.C(=O)(O)[O-].[Na+]>[CH2:33]([O:32][C:30]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][O:14][Si:15]([C:18]([CH3:19])([CH3:21])[CH3:20])([CH3:16])[CH3:17])[N:10]=[CH:9]2)=[CH:4][C:3]=1[F:22])=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cn(-c2ccc(N)c(F)c2)cn1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OCc1cn(-c2ccc(NC(=O)OCc3ccccc3)c(F)c2)cn1
Temperature: -20 °C

Procedure:
1-Amino-4-(4-t-butyldimethylsilyloxymethylimidazol-1-yl)fluorobenzene (36.1 g) was dissolved in dry dichloromethane (450 ml), treated with pyridine (11.3 ml), then stirred under argon while cooling to −20° C. Benzyl chloroformate (17.7 ml) in dichioromethane (50 ml) was added dropwise, maintaining the temperature. The mixture was then allowed to warm to ambient temperature over 1 hour, then stirred for a further 1.5 hours. The mixture was diluted with aqueous sodium bicarbonate (250 ml), and the organic layer separated. A further extraction with dichloromethane (200 ml) was made, the combined organic layers dried over magnesium sulfate, and solvent evaporated. The resulting oil was re-evaporated with toluene, and purified by chromatography on silica (500 g) in a sinter column, eluting with a gradient from CH2Cl2 to 50% EtOAc in CH2Cl2. Evaporation, then re-evaporation with toluene gave solid product (51 g).
Reaction SMILES: [N:1]1[C:9]2[CH:8]([NH2:10])[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:11][CH2:12][O:13]C(C)=O.[NH4+].[OH-]>C(Cl)Cl.CO>[N:1]1[C:9]2[C@H:8]([NH:10][C:12](=[O:13])[CH3:11])[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: NC1CCc2cccnc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N[C@@H]1CCc2cccnc21
Reaction time: 7 h

Procedure:
Following the general procedure, 6,7-dihydro-5H-[1]pyrindin-7-ylamine(271 mg, 2.02 mmol), CALB (81 mg) and EtOAc (6.5 mL) were stirred for 7 hours. The conversion determined from 1H NMR by integration of the peaks at 5.17 ppm (CHNHAc) and 4.21 ppm (CHNH2) was 55%. Flash chromatography of the material on silica gel using 1:10 MeOH:CH2Cl2 followed by 1:1:4 NH4OH:MeOH:CH2Cl2 furnished (R)-N-(6,7-dihydro-5H-[1]pyrindin-7-yl)acetamide ((194 mg, 41%). The two enantiomers of the acetamide could not be resolved by GC nor HPLC, and hence the % ee had to be determined indirectly. A small sample of the acetamide was treated with 1N HCl to convert it to the amine, and the resulting amine was resolved by chiral GC (chiral GC method: 85° C. for 120 min, ramp rate 5° C./min to 210° C., final time 5 min; (S)-enantiomerrt=124.3 min, (R)-enantiomerrt=126.1 min) to give % ee of 79%; [α]D=−41° (c 1.49, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 1.75-1.89 (m, 1H), 2.07 (s, 3H), 2.80-2.98 (m, 3H), 5.19-5.27 (m, 1H), 6.32 (br s, 1H), 7.14 (dd, 1H, J=7.5, 5.0 Hz), 7.55 (d, 1H, J=7.5 Hz), 8.39 (d, 1H, J=4.5 Hz); 13C NMR (CDCl3) δ 23.6, 28.3, 33.9, 55.7, 123.0, 133.3, 137.2, 148.2, 148.4, 162.7, 171.0. The unreacted (S)-6,7-dihydro-5H-[1]pyrindin-7-ylamine (was isolated in 42% yield (113 mg) and 99% ee (chiral GC, (S)-enantiomerrt=124.3 min, (R)-enantiomerrt=126.1 min) and displayed spectra identical to the starting material: 1H NMR (CDCl3, 300 MHz) δ 1.68-1.88 (m, 1H), 2.50-2.61 (m, 3H), 2.75-2.86 (m, 1H), 2.92 (ddd, 1H, J=13.2, 9.0, 3.0 Hz), 4.32 (dd, 1H, J=7.8, 7.8 Hz), 7.08 (dd, 1H, J=7.8, 4.8 Hz), 7.51 (d, 1H, J=7.8 Hz), 8.40 (d, 1H, J=4.8 Hz). The dark color of the amine after purification by column chromatography prevented determination of its optical rotation.