Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:5]2[O:6][C:7]3[C:8](=[C:10]([C:14]([OH:16])=O)[CH:11]=[CH:12][CH:13]=3)[N:9]=2)[CH2:4][CH2:3]1.Cl.Cl.[NH2:19][C@H:20]1[CH:25]2[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]2)[CH2:21]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:22]12[CH2:27][CH2:26][CH:25]([CH2:24][CH2:23]1)[C@H:20]([NH:19][C:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:7]3[O:6][C:5]([C:2]4([CH3:1])[CH2:3][CH2:4]4)=[N:9][C:8]=13)=[O:16])[CH2:21]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: CC1(c2nc3c(C(=O)O)cccc3o2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2nc3c(C(=O)N[C@@H]4CN5CCC4CC5)cccc3o2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.5 %

Procedure:
A mixture of 2-(1-methylcyclopropyl)benzoxazole-4-carboxylic acid (60 mg, 0.27 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (67 mg, 0.34 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (103 mg, 0.54 mmol) and 1-hydroxybenzotriazole (73 mg, 0.54 mmol) in DMF (2 mL) was stirred at room temperature for 5 min, then triethylamine (0.11 mL, 0.81 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(1-methylcyclopropyl)benzoxazole-4-carboxamide (69 mg, 79%) as a light brown semi-solid: 1H NMR (500 MHz, CDCl3) δ 9.61 (d, J=7.3 Hz, 1H), 8.10 (dd, J=7.8, 1.0 Hz, 1H), 7.55 (dd, J=8.0, 0.9 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 4.34-4.28 (m, 1H), 3.55 (m, 1H), 3.10-3.00 (m, 2H), 2.96-2.88 (m, 2H), 2.82-2.74 (m, 1H), 2.12-2.02 (m, 2H), 1.80-1.75 (m, 2H), 1.65 (s, 3H), 1.64-1.57 (m, 1H), 1.52-1.48 (m, 2H), 1.10-1.05 (m, 2H); MS (ESI+) m/z 326 (M+H).
Reaction SMILES: [Br:1]Br.[Br:3][CH2:4][CH:5]1[O:9][C:8](=[O:10])[NH:7][CH2:6]1.[OH-].[K+]>>[Br:1][N:7]1[CH2:6][CH:5]([CH2:4][Br:3])[O:9][C:8]1=[O:10]
Reactant: O=C1NCC(CBr)O1
Reactant: BrBr
Agent: [K+]
Agent: [OH-]
Product: O=C1OC(CBr)CN1Br

Procedure:
2.67 grams (0.0166 moles) bromine were added to 3 grams (0.0166 moles) 5-bromomethyl-2-oxazolidinone and the reaction mixture was chilled to 0°-5° C. with stirring. Chilled 50% potassium hydroxide was added slowly until the red Br2 color disappeared. Proton NMR Data: δ3.7(m, 4 protons), 5.1(m, 1 proton) Elemental analysis Bromine 60.43 Theory 61.8.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[C:49]([Cl:52])[CH:48]=[CH:47][C:46]=1[C:53]([F:56])([F:55])[F:54]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:46]([C:53]([F:55])([F:56])[F:54])=[CH:47][CH:48]=[C:49]([Cl:52])[C:50]=3[Cl:51])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1CBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3c(C(F)(F)F)ccc(Cl)c3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-3,4-dichloro-1-(trifluoromethyl)benzene and isolated as white solid. MS(m/e): 509.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.ClC([O-])=O.O=S(Cl)Cl.[C:19]1(OC(Cl)=O)C=CC=C[CH:20]=1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.N=C=N.C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.ON1C(=O)CCC1=O>C(O)C.CN1C(=O)CCC1.CN(C=O)C.ClCCCl.C(Cl)Cl>[CH2:19]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1)[CH3:20]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N=C=N
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)c1ccc(Cl)nc1

Procedure:
6-Chloronicotinic acid 51 is activated by reacting with a chloroformate activating agent such as SOCl2, phenylchloroformate, or p-nitrophenyl chloroformate, or a carbodiimide activating agent such as CDI, DCC, or EDC in the presence of HOBt and N-hydroxysuccinimide in a polar aprotic solvent such as CH2Cl2, 1,2-dichloroethane, DMF, or NMP, and heating. An alcohol such as ethanol is then added to form 6-chloronicotinic acid ethyl ester 71.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][N:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][OH:14].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][NH:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:8][CH:9]=1
Reactant: NCCCO
Reactant: O=Cc1ccc(Br)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: OCCCNCc1ccc(Br)nc1
Reaction time: 0.17 h
Yield: 54.6 %

Procedure:
To a solution of 6-bromonicotinaldehyde (1.25 g, 6.72 mmol) in DCM (25 mL) was added 3-aminopropan-1-ol (1.514 g, 20.16 mmol) and acetic acid (0.385 mL, 6.72 mmol), and the reaction mixture was stirred for 10 min. Sodium triacetoxyborohydride (3.56 g, 16.80 mmol) was added and the reaction mixture was stirred at RT overnight. The reaction mixture was then diluted with EtOAc and extracted with water. The organic phase was discarded. The aqueous phase was concentrated and the resultant solid was stirred with a mixture of DCM and acetone then filtered. The filtrate was collected, dried over Na2SO4, and concentrated to give a yellowish material, which upon trituration with Et2O afforded title compound 196 (0.9 g, 55% yield) as an off-white solid. MS: 246 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:12][CH2:13][O:14][CH3:15].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:13][O:14][CH3:15])=[CH:4][N:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(Br)nc1
Reaction time: 72 h
Yield: 42 %

Procedure:
2-Bromo-5-hydroxypyridine (1 mmol) is dissolved in DMF (2.5 ml) and NaH (1.4 eq., 60% suspension in liquid paraffin) is added. After 30 min 1-Bromo-2-methoxy-ethane (1.1 eq.) is added and the reaction solution is stirred 3 days. The reaction solution is pored into water and extracted with methyl-tert.-butyl ether. The combined organic layers are dried over MgSO4 and the solvent is removed in vacuo. 2-Bromo-5-(2-methoxyethoxy)-pyridine is obtained after column chromatography as colorless powder in a yield of 42%; HPLC (method C): 1.48 min; LC-MS (method A): 1.11 min, 231.95 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[C:14]([F:21])=[CH:15][C:16]([F:20])=[C:17]([NH2:19])[CH:18]=3)[C:8]([CH3:12])=[N:9]2)=[CH:4][N:3]=1.[CH3:22][NH2:23]>CCOC(C)=O>[NH2:19][C:17]1[C:16]([F:20])=[CH:15][C:14]([F:21])=[C:13]([C:7]2[C:8]([CH3:12])=[N:9][C:10]3[C:5]([CH:6]=2)=[CH:4][N:3]=[C:2]([NH:23][CH3:22])[CH:11]=3)[CH:18]=1
Reactant: Cc1nc2cc(Cl)ncc2cc1-c1cc(N)c(F)cc1F
Reactant: CN
Solvent: CCOC(C)=O
Product: CNc1cc2nc(C)c(-c3cc(N)c(F)cc3F)cc2cn1
Temperature: 120 °C
Yield: 98.1 %

Procedure:
Heat a solution of 5-(7-chloro-2-methyl-1,6-naphthyridin-3-yl)-2,4-difluorobenzenamine (0.55 g, 1.799 mmol) in methylamine (33% in EtOH, 10 mL, 1.799 mmol) at 120° C. with microwave irradiation for 12 h. Add additional methylamine (33% in EtOH, 2 mL), heat the mixture at 120° C. for 12 h, add more methylamine (33% in EtOH, 2 mL) and irradiate at 120° C. for 15 h. Dilute the mixture with EtOAc, wash with satd. NaHCO3 (2×), dry and evaporated to yield the title compound (0.53 g, 98%). MS(ESI) m/z: 301.1 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3].Br[C:32]1[S:33][C:34]([CH:37]=[O:38])=[CH:35][N:36]=1.C(=O)(O)[O-].[Na+]>COCCOC.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:26]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:32]3[S:33][C:34]([CH:37]=[O:38])=[CH:35][N:36]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:30])[O:4][CH:2]([CH3:3])[CH3:1])[CH2:8][C@@H:9]1[CH3:29])(=[O:28])[CH3:27]
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: O=Cc1cnc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)N1c2ccc(-c3ncc(C=O)s3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
1-Methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 52) (108 mg, 0.259 mmol), 2-bromo-1,3-thiazole-5-carbaldehyde (74.7 mg, 0.389 mmol), sodium bicarbonate (32.7 mg, 0.389 mmol) and tetrakis(triphenylphosphine)palladium(0) (30.0 mg, 0.026 mmol) were stirred at 100° C. in 1,2-dimethoxyethane (DME) (4 mL) under nitrogen for 16 h then cooled to room temperature. A saturated NaHCO3 aqueous solution (1 mL) was added and the resulting mixture was stirred at 100° C. for 4 h then cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM and the organic phase was filtered through celite then concentrated in vacuo to give 1-methylethyl [(2S,4R)-1-acetyl-6-(5-formyl-1,3-thiazol-2-yl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (104 mg, 0.259 mmol, 100%) which was used in the next step without further purification. LCMS (method G): Retention time 0.91 min, [M+H]+=402.0
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:38])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([S:12][C@@H:13]1[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:31])[O:15][CH2:14]1)[CH3:11].[H-].[Na+].[CH2:41]([O:44][P:45]([O:51][CH2:52][C:53]1[CH:57]=[CH:56][S:55][C:54]=1[C:58](Cl)=[O:59])([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])[CH:42]=[CH2:43].P([O-])([O-])([O-])=O>COCCOC>[CH2:48]([O:47][P:45]([O:51][CH2:52][C:53]1[CH:57]=[CH:56][S:55][C:54]=1[C:58]([O:38][C@:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([S:12][C@@H:13]1[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:31])[O:15][CH2:14]1)[CH3:11])=[O:59])([O:44][CH2:41][CH:42]=[CH2:43])=[O:46])[CH:49]=[CH2:50]
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: C=CCOP(=O)(OCC=C)OCc1ccsc1C(=O)Cl
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C=CCOP(=O)(OCC=C)OCc1ccsc1C(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A solution of 4-[(1E,3E)-4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-1,3-butadienyl]-3-fluorobenzonitrile (699.1 mg, 1.29 mmol) described in Reference example 1 in 1,2-dimethoxyethane (10 ml) was cooled to 0° C., and sodium hydride (55% dispersion in mineral oil; 67.5 mg, 1.55 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 3 hours. To the mixture was added a solution of the crude 3-[[bis(allyloxy)phosphoryl]oxymethyl]-2-thenoyl chloride obtained above in 1,2-dimethoxyethane (2 ml), and the mixture was stirred at room temperature for 20 minutes and cooled to 0° C., then a phosphate buffer solution (pH 7) was added to the reaction mixture to stop the reaction, and the product was extracted with ethyl acetate. The crude product was subjected to chromatography on a silica gel (40 g) column (eluent; ethyl acetate:hexane=3:2˜5:1) to give the title compound (520.6 mg, 48% yield) as a pale yellow amorphous solid.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[CH3:87][S:88]([N:91]1[CH2:95][CH2:94][CH2:93][CH:92]1[C:96]([OH:98])=O)(=[O:90])=[O:89]>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][C:96]([CH:92]1[CH2:93][CH2:94][CH2:95][N:91]1[S:88]([CH3:87])(=[O:89])=[O:90])=[O:98])[CH2:19][CH2:18]2
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CS(=O)(=O)N1CCCC1C(=O)O
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)C3CCCN3S(C)(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 17 %

Procedure:
The title compound was prepared in 17% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 1-(methylsulfonyl)pyrrolidine-2-carboxylic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 705.5 (M+H)+, 2.04 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.5 Hz, 2H), 7.20 (d, J=8.2 Hz, 2H), 6.88 (s, 1H), 5.29 (dd, J=1.5, 6.1 Hz, 1H), 4.76 (d, J=1.5 Hz, 1H), 4.10 (dd, J=3.1, 8.8 Hz, 1H), 3.60 (ddd, J=3.5, 7.0, 10.2 Hz, 1H), 3.40 (dt, J=6.4, 9.6 Hz, 1H), 2.96 (s, 3H), 2.62-2.52 (m, 2H), 2.42 (dd, J=8.2, 11.6 Hz, 1H), 2.31 (dddd, J=3.2, 3.4, 6.4, 9.7 Hz, 1H), 2.21-2.16 (m, 1H), 2.16-2.10 (m, 1H), 2.03 (tdd, J=3.2, 6.6, 13.0 Hz, 1H), 1.99-1.89 (m, 2H), 1.82-1.75 (m, 1H), 1.75-1.72 (m, 1H), 1.70 (s, 3H), 1.69-1.66 (m, 1H), 1.58-1.46 (m, 6H), 1.46-1.29 (m, 5H), 1.28-1.22 (m, 1H), 1.14 (d, J=13.1 Hz, 2H), 1.09 (s, 3H), 1.03 (s, 3H), 1.01 (s, 3H), 0.93 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].Br[CH2:11][CH2:12][CH2:13][Cl:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(Cl)(Cl)Cl>[Cl:14][CH2:13][CH2:12][CH2:11][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1ccccc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: N#Cc1ccccc1OCCCCl
Yield: 97.5 %

Procedure:
A mixture of 2-cyanophenol (50.0 g, 0.42 mole), 1-bromo-3-chloropropane (67.7 g, 0.43 mole), and potassium carbonate (58.0 g, 0.42 mole) was heated overnight at gentle reflux in 500 ml of acetone. The reaction mixture was stripped to dryness and the residue was dissolved in chloroform. The chloroform layer was extracted several times with 5% sodium hydroxide. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and the solvent was removed, to give a brown oil (80.09 g). A ten gram portion of this oil was subjected to flash chromatography on silica gel with 10% ethyl acetate-hexanes and 20% ethyl acetate-hexanes used for elution. Fractions were combined and solvent removed in vacuo. The clear oil obtained was dried 18 hrs in vacuo at room temperature and 8 hrs at 80° C. in vacuo. This furnished 5.24 g (50.0% yield--based on aliquot taken) of clear oil.
Reaction SMILES: C(N1CCCC1)C1C=CC=CC=1.[CH2:13]([N:20]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCCCCCCC.CCCCCCCCCC>CCCCCC>[CH2:13]([N:20]1[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OC1CCN(Cc2ccccc2)C1
Agent: c1ccc(CN2CCCC2)cc1
Solvent: CCCCCCCCCC
Solvent: CCCCCC
Solvent: CCCCCCCC
Product: O[C@@H]1CCN(Cc2ccccc2)C1

Procedure:
It has been found that alkane-degrading microorganisms are excellent biocatalysts for the hydroxylation of N-benzylpyrrolidine to optically active N-benzyl-3-hydroxy-pyrrolidine. Examples are bacteria degrading n-alkane containing 4 or more C-atoms. By screening with a microtiter plate, 25 of a set of 70 strains degrading n-hexane, n-octane, n-decane, or n-dodedane, were found to be able to catalyse this hydroxylation (example 5). The enantioselectivity and relative activity of 14 selected alkane-degrading strains are shown in table 3 (example 6). Hydroxylation of N-benzylpyrrolidine with Pseudomonas putida P1 gave (R)-N-benzyl-3-hydroxypyrrolidine in 62% e.e.; hydroxylation of N-benzylpyrrolidine with the isolate HXN-1100 gave (R)-N-benzyl-3-hydroxypyrrolidine in 70% e.e.; surprisingly, hydroxylation of N-benzylpyrrolidine with the isolate HXN-200 gave (S)-N-benzyl-3-hydroxypyrrolidine in 53% e.e. (Pseudomonas putida P1 was isolated with n-octane as carbon source by van Beilen, J., ETH Zurich; the isolates HXN-1100 and HXN-200 were isolated with n-hexane as carbon source by Engesser, K.-H. and Plaggemeier, Th., University of Stuttgart; all these strains are in the strain collection of institute of Biotechnology, ETH Zurich).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:17]=2[C:18]([F:21])([F:20])[F:19])[NH:14][C:13](=[O:22])[C:12]([C:23]([O:25]CC)=[O:24])=[CH:11]3)[CH:7]=1.[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]=[C:36]=[O:37]>C(OCC)(=O)C>[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36]([O:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:17]=2[C:18]([F:21])([F:20])[F:19])[NH:14][C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]3)[CH:7]=1)=[O:37]
Reactant: CCOC(=O)c1cc2cc(-n3cnc(CO)c3)c(C(F)(F)F)cc2[nH]c1=O
Reactant: O=C=Nc1ccccc1Br
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1Br)OCc1cn(-c2cc3cc(C(=O)O)c(=O)[nH]c3cc2C(F)(F)F)cn1
Temperature: 50 °C
Reaction time: 1.25 h
Yield: 38.1 %

Procedure:
To a suspension of the compound of Example 17 (100 mg, 262 μmol) in ethyl acetate (3 ml) was added 2-bromophenyl isocyanate (104 mg, 524 μmol), and the mixture was refluxed for 24 hours. After cooling, the precipitated crystals were collected by filtration, washed with ethyl acetate, and then dried under reduced pressure. These were suspended into ethanol (3 ml), 1 mol/L aqueous solution of lithium hydroxide (903 μl) and successively water (3 ml) were added, and the mixture was stirred for 75 minutes at 50° C. Ice water was added to the reaction mixture, the insolubles were filtered off. then the pH value was brought to 4 with 3 mol/L hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and then dried under reduced pressure, thereby obtaining 55.0 mg of title compound as colorless powder. Yield 34%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([S:16]([CH:19]=[CH2:20])(=[O:18])=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:26][CH:25]1[C:37]([NH2:39])=[O:38])=[O:23].[CH:40]1([NH2:43])[CH2:42][CH2:41]1>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([S:16]([CH2:19][CH2:20][NH:43][CH:40]3[CH2:42][CH2:41]3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:26][CH:25]1[C:37]([NH2:39])=[O:38])=[O:23]
Reactant: C=CS(=O)(=O)N1CCC(Oc2ccc(CC(=O)N3CCN(c4ccccc4C)CC3C(N)=O)c(OC)c2)CC1
Reactant: NC1CC1
Solvent: CO
Product: COc1cc(OC2CCN(S(=O)(=O)CCNC3CC3)CC2)ccc1CC(=O)N1CCN(c2ccccc2C)CC1C(N)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(2-Methoxy-4-(1-ethenylsulfonyl-4-piperidyloxy)phenylacetyl)-4-(2-methylphenyl)piperazine-2-carboxamide (69 mg, 0.12 mmol) was dissolved in methanol (4 ml), treated with cyclopropylamine (0.0072 ml, 10 mg, 0.18 mmol), and stirred at ambient temperature under nitrogen for 18 hours. An additional 0.014 ml of cyclopropylamine was added and the mixture stirred another 72 hours at ambient temperature. The reaction was concentrated in vacuo and the residue was chromatographed on silica gel eluted with 4% methanol in methylene chloride. The combined product fractions were evaporated to dryness in vacuo. The residue was reconcentrated from ether to give 1-(2-methoxy-4-(1-(2-(N-cyclopropylamino)ethylsulfonyl)-4-piperidyloxy)phenylacetyl)-4-(2-methylphenyl)piperazine-2-carboxamide: mp 69°-110° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[CH3:48][N:49]1[CH:53]=[CH:52][N:51]=[C:50]1[C:54](O)=[O:55]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:54]([C:50]2[N:49]([CH3:48])[CH:53]=[CH:52][N:51]=2)=[O:55])[CH2:42][CH2:41]1
Reactant: Cn1ccnc1C(=O)O
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccnc1C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 70 %

Procedure:
The desired compound was prepared according to the procedure of Example A27, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 1-methyl-1H-imidazole-2-carboxylic acid as starting materials in 70% yield. LCMS for C29H31ClN9O2 (M+H)+: m/z=572.2.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[CH3:14]N(C=O)C>>[F:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:14])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(F)cc1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
Sodium hydride 4.59 g (7.64 g as 60% mineral oil dispersion) was suspended in DMF (64 ml) under a nitrogen atmosphere. To this was added 4-fluoro-2-nitrophenol in 64 ml DMF over 30 minutes at room temperature. Stirring continued for 15 minutes. Methyl iode was then added over 15 minutes. The mixture was further stirred for 3 hours. The precipitates which formed were filtered off and the filtrate was evaporated to dryness. The residue was dissolved in benzene and the filtrate washed with water, aqueous sodium hydroxide and with brine. This solution was dried over sodium sulfate and evaporated to give 21.1 g of the title compound: m.p. 60° C.