Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1>>[F:16][C:17]([F:31])([F:32])[C:18]1[CH:19]=[C:20]([C:2]2[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=2)[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(I)cc1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CCOC(=O)/C=C(\C)c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1

Procedure:
The colourless solid, (E)-ethyl 3-(3′,5′-bis-trifluoromethyl-biphenyl-4-yl)-but-2-enoate was prepared from (E)-ethyl 3-(4-iodophenyl)-but-2-enoate (example 91a) and 3,5-bis-(trifluoromethyl)phenyl boronic acid by a procedure analogous to that described in example 91b.
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]([OH:30])([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Brc1cccc2ccccc12
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: OC1(c2cccc3ccccc23)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.4 %

Procedure:
A solution of 48.7 mL (63.3 mMol) sec-butyllithium (1.3 M in tetrahydrofuran) was added to a solution of 10.0 gm (42.2 mMol) 1-bromonaphthalene in 200 mL tetrahydrofuran at -78° C. The reaction mixture was stirred at that temperature for 1.5 hours and to it was then added a solution of 8.2 mL (44.3 mMol) 1-benzyl-4-piperidone in 40 mL tetrahydrofuran dropwise. The reaction mixture was allowed to warm to room temperature and was then quenched by the addition of 2N sodium hydroxide. The resulting mixture was extracted well with diethyl ether. The combined organic extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane which contained 0-2% methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 4.34 gm (32%) of the desired compound as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[CH:11][C:10]=2[C:18]([OH:20])=O)=[C:4]([F:21])[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:44][O:45][CH2:46][C@@H:47]([OH:49])[CH3:48].CCN(C(C)C)C(C)C>O1CCOCC1.C(OCC)(=O)C>[OH:49][C@@H:47]([CH3:48])[CH2:46][O:45][NH:44][C:18]([C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:15]=[N:16][CH:17]=2)[C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:21])=[O:20]
Reactant: O=C(O)c1ccc2cncn2c1Nc1ccc(Br)cc1F
Reactant: C[C@H](O)CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H](O)CONC(=O)c1ccc2cncn2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.5 %

Procedure:
To a solution of 5-(4-bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (271 mg, 0.77 mmol) in dioxane (3.9 mL) was added HOBT (306 mg, 2.3 mmol) and EDCI (442 mg, 2.3 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes then (S)-1-aminooxy-propan-2-ol hydrochloride (294 mg, 2.3 mmol) and DIPEA (1.2 mL, 6.9 mmol) were added, the mixture was then stirred for 60 hours at ambient temperature. The reaction mixture was diluted with ethyl acetate then washed with a saturated aqueous solution of sodium bicarbonate followed by water and brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0 to 100%, ethyl acetate in dichloromethane, then gradient 0 to 10%, methanol in dichloromethane) to afford the title compound as a green/yellow solid (80 mg, 25%). LCMS (method A): RT=5.71 min, [M+H]+=423/425. 1H NMR (DMSO-d6): 8.10 (1 H, s), 7.51 (1 H, dd, J=10.87, 2.22 Hz), 7.43 (1 H, s), 7.39 (1 H, d, J=9.31 Hz), 7.18-7.14 (1 H, m), 6.88 (1 H, d, J=9.31 Hz), 6.51 (1 H, t, J=8.85 Hz), 4.69 (1 H, s), 3.68-3.59 (1 H, m), 3.42 (2 H, d, J=5.81 Hz), 0.95 (3 H, d, J=6.35 Hz).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:11]2[C:6]([CH:7]=[CH:8][C@H:9]([CH3:29])[C@@H:10]2[CH2:12][CH2:13][C@H:14]2[O:19][C:18](=[O:20])[CH2:17][C@H:16]([O:21][Si](C(C)(C)C)(C)C)[CH2:15]2)=[CH:5][CH2:4][CH2:3]1.[CH2:30]([C:32]([CH2:38][CH3:39])([CH2:36][CH3:37])[C:33](Cl)=[O:34])[CH3:31]>>[CH2:30]([C:32]([CH2:38][CH3:39])([CH2:36][CH3:37])[C:33]([O:1][C@@H:2]1[C@H:11]2[C:6]([CH:7]=[CH:8][C@H:9]([CH3:29])[C@@H:10]2[CH2:12][CH2:13][C@H:14]2[O:19][C:18](=[O:20])[CH2:17][C@H:16]([OH:21])[CH2:15]2)=[CH:5][CH2:4][CH2:3]1)=[O:34])[CH3:31]
Reactant: CCC(CC)(CC)C(=O)Cl
Reactant: C[C@H]1C=CC2=CCC[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCC(CC)(CC)C(=O)O[C@H]1CCC=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 61.6 %

Procedure:
A procedure similar to that described in Example 6, above, was followed, but using 1.26 g (3.0 mmol) of (4R,6R)-6-{2-[(1S,2S,8S,8aR)-1,2,6,7,8,8a-hexahydro-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyl-dimethylsilyloxy-2H-pyran-2-one [prepared as described in Japanese Patent Kokai Application No. Sho 59-175450] and 2.22 g (13.6 mmol) of 2,2-diethylbutyryl chloride, to provide 800 mg of the title compound.
Reaction SMILES: C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C(O)=CC4C[CH2:22][O:23]C=4C=3)C2=O)C=CC=CC=1.[OH:34][C:35]1[C:36]([CH:44]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][C:51]=3[O:53][CH3:54])[N:46]([CH2:55][C:56]3[O:57][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:59][CH:60]=3)[C:45]2=[O:65])=[CH:37][C:38]2[O:42][CH2:41][O:40][C:39]=2[CH:43]=1>>[OH:34][C:35]1[C:36]([C:44]2([CH2:22][OH:23])[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][C:51]=3[O:53][CH3:54])[N:46]([CH2:55][C:56]3[O:57][C:58]([C:61]([F:63])([F:62])[F:64])=[CH:59][CH:60]=3)[C:45]2=[O:65])=[CH:37][C:38]2[O:42][CH2:41][O:40][C:39]=2[CH:43]=1
Reactant: COc1cccc2c1C(c1cc3c(cc1O)OCO3)C(=O)N2Cc1ccc(C(F)(F)F)o1
Reactant: O=C1C(c2cc3c(cc2O)CCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Product: COc1cccc2c1C(CO)(c1cc3c(cc1O)OCO3)C(=O)N2Cc1ccc(C(F)(F)F)o1

Procedure:
Following the procedure as described in PREPARATION 26C, and making non-critical variations to replace 1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1-benzofuran-6-yl)-1,3-dihydro-2H-indol-2-one with 3-(6-hydroxy-1,3-benzodioxol-5-yl)-4-methoxy-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one, the title compound was obtained (64%): MS (ES+) m/z 500.4 (M+23).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH3:16])([C:13]([OH:15])=O)[CH2:11][O:10][C:9]1([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:32][C:33](=[NH:35])[CH3:34]>CN(C=O)C>[CH3:17][C:9]1([CH3:18])[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:12]([CH3:16])([C:13]2[O:15][N:35]=[C:33]([CH3:34])[N:32]=2)[CH2:11][O:10]1
Reactant: CC(=N)NO
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OCC1(C)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1noc(C2(C)COC(C)(C)N2C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
To a solution of 430 mg of 3-(tert-butoxycarbonyl)-2,2,4-trimethyl-1,3-oxazolidine-4-carboxylic acid in 4 ml of DMF was added 296 mg of 1,1′-carbonyldiimidazole, followed by stirring at room temperature for 2 hours. To the reaction mixture was added 146 mg of N-hydroxyacetamidine, followed by stirring at room temperature for 1 hour, at 110° C. for 2 hours, and then at 130° C. overnight. The reaction mixture was left to be cooled to room temperature and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 390 mg of tert-butyl 2,2,4-trimethyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-1,3-oxazolidine-3-carboxylate.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:19][CH3:20])[CH2:18][CH2:17][CH2:16][C:5]2([O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6]2)[CH2:4]1.F[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[N+:30]([O-:32])=[O:31])[C:25]#[N:26].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH2:19]([C:3]1([CH2:2][NH:1][C:28]2[CH:27]=[C:24]([CH:23]=[CH:22][C:29]=2[N+:30]([O-:32])=[O:31])[C:25]#[N:26])[CH2:18][CH2:17][CH2:16][C:5]2([O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([CH3:14])([CH3:15])[CH3:13])[CH2:6]2)[CH2:4]1)[CH3:20]
Reactant: CCC1(CN)CCCC2(CN(CC(C)(C)C)C(=O)O2)C1
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC1(CNc2cc(C#N)ccc2[N+](=O)[O-])CCCC2(CN(CC(C)(C)C)C(=O)O2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
To a yellow solution containing 7-(aminomethyl)-7-ethyl-3-neopentyl-1-oxa-3-azaspiro[4.5]decan-2-one (0.195 g, 0.690 mmol) and 3-fluoro-4-nitrobenzonitrile (0.126 g, 0.760 mmol) in MeCN (6.90 ml) was added potassium carbonate (0.191 g, 1.381 mmol). The reaction was stirred at rt for 16 h. The reaction was filtered through a frit, and the filtrate was concentrated onto florisil for purification on a 12 g silica gel column (5-25% EtOAc/hexanes, 30 min gradient; 25-55% EtOAc/hexanes, 5 min gradient; 30 mL/min elution; 254 nm detection) to afford the title compound (0.232 g, 75% yield) as an orange solid. MS (m/z) 429.2 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[OH:24]>>[F:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[O:24][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: Oc1cccc(F)c1F
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCOc1cccc(F)c1F

Procedure:
Quantities: 1-bromooctane (34.9 g, 0.18 mol), potassium carbonate (50 g, 0.36 mol) and compound from Example 37 (21.7 g, 0.17 mol). The experimental procedure was as described in Example 38.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:3]1.Cl[CH2:37][C:38]1[CH:39]=[CH:40][C:41]2[O:46][CH:45](CCCOC)[C:44](=[O:52])[NH:43][C:42]=2[CH:53]=1>>[CH3:15][O:14][CH2:11][CH2:10][CH2:9][N:43]1[C:42]2[CH:53]=[C:38]([CH2:37][O:1][CH:2]3[CH:7]([C:8]4[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=5)=[CH:10][CH:9]=4)[CH2:6][CH2:5][N:4]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:3]3)[CH:39]=[CH:40][C:41]=2[O:46][CH2:45][C:44]1=[O:52]
Reactant: COCCCC1Oc2ccc(CCl)cc2NC1=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3cccc(C(F)(F)F)c3)cc2)C(O)C1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4cccc(C(F)(F)F)c4)cc3)cc21

Procedure:
Analogously to Method D, 0.560 g of tert-butyl 3-hydroxy-4-{4-[3-(3-trifluoromethylphenoxy)propoxy]phenyl}piperidine-1-carboxylate and 0.339 g of 6-chloromethyl-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a yellowish oil. Rf=0.30 (1:1 EtOAc-heptane); Rt=6.15.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].C(N(CC)CC)C.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:11]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[N:3]1)(=[O:13])[CH3:12]
Reactant: Cc1n[nH]c2ccccc12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)n1nc(C)c2ccccc21
Temperature: 20 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
3-Methyl-1H-indazole (6.157 g, 44.6 mmol) in CH2Cl2 (100 mL) was treated with acetic anhydride (22.75 g, 223 mmol), triethylamine (22.5 g, 228 mmol) and DMAP (0.54 g, 4.5 mmol). The mixture was stirred 1 h at 20° C., poured into water (100 mL) and extracted with CH2Cl2 (2×100 mL). The extracts were dried (Na2SO4), concentrated and the residue recrystallised from hexane to give the title compound (4.12 g, 66%) as a white crystalline solid; mp 70°-71° C. (from hexane); 1H NMR (360 MHz, CDCl3) δ 8.41 (d, J=8.4 Hz, 1H, indazole), 7.64 (d, J=8.4 Hz, 1H, indazole), 7.54 (t, J=8.4 Hz, 1H, indazole), 7.35 (t, J=8.4 Hz, 1H, indazole), 2.75 (s, 3H, Ac), 2.58 (s, 3H, Me); MS (CI+) m/e 175 (M+H+); Anal. calcd for C10H10N2O: C, 68.95; H, 5.97; N, 16.08. Found: C, 68.80; H, 5.58; N, 16.18.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:19]3[S:24][C:23]([CH2:25][N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:22]([CH3:32])[C:20]=3[N:21]=2)=[CH:12][N:11]=1.[C:39](O)(=[O:43])[C@H:40]([CH3:42])[OH:41]>>[OH:41][C@@H:40]([CH3:42])[C:39]([N:29]1[CH2:28][CH2:27][N:26]([CH2:25][C:23]2[S:24][C:19]3[C:18]([N:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)=[N:17][C:16]([C:13]4[CH:12]=[N:11][C:10]([NH:9][CH3:8])=[CH:15][CH:14]=4)=[N:21][C:20]=3[C:22]=2[CH3:32])[CH2:31][CH2:30]1)=[O:43]
Reactant: C[C@H](O)C(=O)O
Reactant: CNc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)c(C)c3n2)cn1
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(=O)[C@H](C)O)CC4)c(C)c3n2)cn1

Procedure:
The crude TFA salt of N-methyl-5-(7-methyl-4-morpholino-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-2-yl)pyridin-2-amine was reacted with L-lactic acid via General Procedure B to give 56 mg of 375 after reverse phase HPLC purification. MS (Q1) 512.3 (M)+
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16](OC)=[O:17])[CH2:13][O:14][CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+]>CO>[OH:17][CH2:16][C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][O:14][CH3:15]
Reactant: COC[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: COC[C@@H](CO)NC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of methyl N-[(benzyloxy)carbonyl]-O-methyl-L-serinate (60 g, 0.22 mol) in methanol (600 mL) was added lithium borohydride (39.2 g, 1.80 mol). After 2 hours, the reaction mixture was quenched with saturated aqueous ammonium chloride solution, partially concentrated under reduced pressure, and diluted with water. The mixture was extracted with ethyl acetate (3×100 mL), and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via chromatography on silica gel to give benzyl [(2R)-1-hydroxy-3-methoxypropan-2-yl]carbamate. MS ESI calc'd. for C12H18NO4 [M+H]+ 240. found 240. 1H NMR (400 MHz, CDCl3) δ 7.56-7.30 (m, 5H), 5.52 (br s, 1H), 5.08 (s, 2H), 3.84 (d, J=16.0 Hz, 2H), 3.76-3.64 (m, 1H), 3.63-3.52 (m, 2H), 3.38 (s, 3H), 2.55 (bs, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH:4]=[CH:3][C@H:2]1[C@@H:6]([OH:19])[CH2:7][NH:8]C(=O)OCC1C=CC=CC=1.[Cl-].[NH4+].CC1C=CC(S(O[C@@H]2CO[C@@H]3[C@@H](Br)CO[C@H]23)(=O)=O)=CC=1.N>O.CC(O)C.[Zn].CO>[NH2:8][CH2:7][C@@H:6]([C@@H:2]1[CH:3]=[CH:4][CH2:5][O:1]1)[OH:19]
Reactant: O=C(NC[C@H](O)[C@@H]1C=CCO1)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@@H]3Br)cc1
Agent: N
Agent: [Cl-]
Solvent: CC(C)O
Solvent: O
Solvent: CO
Product: NC[C@H](O)[C@@H]1C=CCO1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
Preparation of Benzyl (S)-2-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethylcarbamate (17); Zinc and ‘One-pot’ procedure. A solution of ammonium chloride (560 mg, 10.5 mmol) in water (7 mL) was added to a solution of bromotosylate (46) (2.86 g, 7.88 mmol) in propan-2-ol (14 mL) under argon. Zinc dust (560 mg, 8.67 mmol) was then added in portions over 4 minutes then the suspension stirred for 16 hours before filtering through celite in vacuo. The filter cake was washed with diethyl ether (60 mL). Hydrochloric acid (1M, 60 mL) was added to the filtrate then the organic phase separated. The aqueous layer was extracted with diethyl ether (60 mL) then the combined organic phase was washed with brine (60 mL), then dried (MgSO4), filtered and reduced in vacuo. The residue was dissolved in ammonium hydroxide (18 mL) and a solution of ammonia in propan-2-ol (12 mL, 2.0M, 24 mmol) then divided into three equal portions and heated in sealed tubes at 75° C. for 16 hours. The mixtures were combined using methanol then the solvents were removed in vacuo. The residue was azeotroped with diethyl ether (3×10 mL) to obtain (S)-2-amino-1-((S)-2,5-dihydrofuran-2-yl)ethanol which was used without further purification.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][N:11]=1>O.C(O)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[N:2][OH:3])=[CH:12][N:11]=1
Reactant: NO
Reactant: O=Cc1ccc(Br)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
Add hydroxylamine hydrochloride (1.494 g, 21.504 mmol) and a solution of NaHCO3 (2.71 g, 32.256 mmol) in water (15 mL) to a solution of 2-bromo-5-formyl-pyridine (2 g, 10.752 mmol, prepared by following the procedure described in J. Org. Chem. 2004, 69, 250-262) in absolute ethanol (100 mL). Stir the mixture at room temperature for 2 h. Concentrate in vacuo and partition the residue between EtOAc and water. Extract the aqueous phase with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (9:1, 4:1) to afford the desired intermediate as a solid (1.362 g, 63%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[CH:7]=[C:6]2[CH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)#[N:2].[NH:21]1[C:29]2[C:24](=[C:25]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH3:13][CH2:12][N:8]1[C:9]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[C:6]([CH:14]2[CH2:19][CH2:18][CH:17]([N:33]3[CH2:34][CH2:35][N:30]([C:25]4[C:24]5[CH:23]=[CH:22][NH:21][C:29]=5[CH:28]=[CH:27][CH:26]=4)[CH2:31][CH2:32]3)[CH2:16][CH2:15]2)=[CH:7]1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: CCn1cc(C2CCC(=O)CC2)c2cc(C#N)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCn1cc(C2CCC(N3CCN(c4cccc5[nH]ccc45)CC3)CC2)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
A solution of 4-(5-cyano-1-ethyl-indol-3-yl)-cyclohexanone (1.5 g, 5.6 mmol), 1-(indol-4-yl)piperazine (1.19 g, 5.9 mmol), sodium triacetoxyborohydride (1.73 g, 8.2 mmol) and acetic acid (0.9 ml, 15 mmol) in 1,2-dichloroethane (30 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1N sodium hydroxide (10 ml), extracted with methylene chloride (3×80 ml), and washed with brine (3×80 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (2.5% methanol-ethyl acetate) afforded 0.98 g (39%) of product as a white solid: mp 226° C. (dec.).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@H:7]([F:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(=O)[NH2:2].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl.O>[C:1]([C@@H:4]1[CH2:8][C@H:7]([F:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])#[N:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(N)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97470.1 %

Procedure:
To a stirred suspension of tert-butyl (2S,4S)-2-carbamoyl-4-fluoropyrrolidine-1-carboxylate (50 g, 0.2155 mmol) in dry dichloromethane (500 ml) was added triethylamine (87.06 g, 0.862 mmol) and the mixture was cooled to 0° C. Trifluoroacetic anhydride (58.83 g, 0.2801 mmol) was added over period of 10 min and the mixture was stirred for 30 min at same temperature under nitrogen atmosphere. The mixture was diluted with water (300 ml) and the layers were separated. The aqueous layer was extracted with dichloromethane (100 ml). The combined organic phase was washed with 1N HCl (200 ml), 5% aqueous NaHCO3 (100 ml) and water (2×300 ml). The solution was dried over anhydrous Na2SO4 and then evaporated under reduced pressure to give 45 g of the product as a pale yellow solid; 1H NMR (CDCl3, 300 MHz) δ 1.49-1.53 (d, 9H, rotomer), 2.25-2.47 (m, 1H), 2.64 (t, J=14.7 Hz, 1H), 3.52 (dd, J=9.6, 3.6 Hz, 0.5H, rotomer), 3.64 (dd, J=9.3, 3.3 Hz, 0.5H, rotomer), 3.73-3.94 (m, 1H), 4.64 (d, J=8.7 Hz, 0.6H, rotomer), 4.76 (d, J=8.7 Hz, 0.4H, rotomer), 5.31 (br d, J=51.3 Hz, 1H).
Reaction SMILES: [ClH:1].Cl.C1(O)CCCCC1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:40]2([OH:46])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[C:25]([N:27]2[CH2:31][CH2:30][C@@H:29]([NH:32]C(=O)OC(C)(C)C)[CH2:28]2)=O)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[ClH:1].[ClH:1].[NH2:32][C@@H:29]1[CH2:30][CH2:31][N:27]([CH2:25][CH:24]([C:40]2([OH:46])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:23][CH:22]=2)[CH2:28]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)C(c2ccc(OCc3ccccc3)cc2)C2(O)CCCCC2)C1
Agent: Cl
Solvent: OC1CCCCC1
Product: N[C@@H]1CCN(CC(c2ccc(OCc3ccccc3)cc2)C2(O)CCCCC2)C1

Procedure:
In an analogous manner to Example 1, step 2, 1-{2-(3R)-3-aminopyrrolidin-1-yl]-1-[4-(benzyloxy)phenyl]ethyl}cyclohexanol dihydrochloride was prepared from tert-butyl {(3R)-1-[[4-(benzyloxy)phenyl](1-hydroxycyclohexyl)acetyl]pyrrolidin-3-yl}carbamate. MS (ESI) m/z 395; HRMS: calcd for C25H34N2O2+H+, 395.26930; found (ESI, [M+H]+), 395.2684.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][C:15](=[O:18])[N:14]([CH2:19][CH2:20][O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[C:13]=2[CH:32]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[OH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][C:15](=[O:18])[N:14]([CH2:19][CH2:20][O:21][Si:22]([CH:23]([CH3:25])[CH3:24])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[C:13]=2[CH:32]=1
Reactant: CC(C)[Si](OCCN1C(=O)COc2ccc(COC3CCCCO3)cc21)(C(C)C)C(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CC(C)[Si](OCCN1C(=O)COc2ccc(CO)cc21)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
The solution of 7.24 g of 6-(tetrahydropyran-2-yloxymethyl)-4-(2-triisopropylsilanyloxyethyl)-4H-benzo[1,4]oxazin-3-one in 130 ml of ethanol is admixed with 0.392 g of pyridinium p-toluenesulphonate and stirred at 60° C. over 3 hours. The reaction mixture is cooled and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.48 (1:1 EtOAc-heptane); Rt=5.51.