Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][S:7][CH:8]([S:11][CH3:12])[S:9][CH3:10].[Si:13]([N:20]1[C@H:23]([CH2:24]I)[CH2:22][C:21]1=[O:26])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1COCC1>[Si:13]([N:20]1[C@H:23]([CH2:24][C:8]([S:11][CH3:12])([S:9][CH3:10])[S:7][CH3:6])[CH2:22][C:21]1=[O:26])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CSC(SC)SC
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1CI
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSC(C[C@@H]1CC(=O)N1[Si](C)(C)C(C)(C)C)(SC)SC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
n-Butyllithium (19.4 ml of 2.5 M hexane solution, 48.5 mmol) is added slowly by syringe to a solution of tri(methylthio)methane (7.47 g, 48.5 mmol) in 150 ml of freshly distilled THF at -78° C. The resulting solution is stirred at -78° C. for 30 min. prior to the addition of a solution of (4S)-1-(tert-butyldimethylsilyl)-4-iodomethylazetidin-2-one (15.0 g, 46.15 mmol) in 50 ml of THF. This solution is stirred at -78° C. for 30 min., then quenched by addition of saturated aqueous ammonium chloride solution. The reaction mixture is allowed to warm to room temperature, then poured into ether (250 ml), washed with water (2×100 ml) brine (100 ml) and dried over magnesium sulfate. Removal of solvents in vacuo gives an oil which is crystallized from petroleum ether to give 13.3 g (82%) of (4S)-1-(t-butyldimethylsilyl)-4-(2,2,2-tri(methylthio)ethyl)azetidin-2-one as colorless prisms. m.p. 61°-62° C. IR(CHCl3, CM-1) 2918, 2850, 1730; n.m.r. (CDCl3) δ4.0 (m,1), δ3.35 (dd,1,J=5.5, 16), δ2.83 (dd,1,J=3.16) δ2,5 (ABq,2) δ2,15 (s,9), δ0.98 (s,9), δ0.25 (s,6).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:16]1)[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:14])[CH:10]=2)[CH:5]=1.[C:27]([C@@H:31]1[CH2:36][CH2:35][C@H:34](O)[CH2:33][CH2:32]1)([CH3:30])([CH3:29])[CH3:28].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[C:27]([C@H:31]1[CH2:36][CH2:35][C@H:34]([O:14][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[CH:5]=[C:4]([CH:3]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:16]2)[C:2]([F:1])([F:25])[F:26])[CH:13]=[CH:12]3)[CH2:33][CH2:32]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Reactant: COC(=O)C1CCN(C(c2ccc3cc(O)ccc3c2)C(F)(F)F)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1CCN(C(c2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirring mixture of methyl 1-(2,2,2-trifluoro-1-(6-hydroxynaphthalen-2-yl)ethyl)piperidine-4-carboxylate (300 mg, 0.8 mmol), cis-4-(t-butyl)cyclohexanol (245 mg, 1.6 mmol, 2 eq) and PPh3 (420 mg, 1.6 mmol, 2 eq) in THF (3 mL) was added DIAD (323 g, 1.6 mmol, 2 eq) at room temperate under N2 atmosphere. The mixture was stirred at 80° C. for 2 h, diluted with ethyl acetate (10 mL) and washed with water (5 mL*3). The organic solvent was removed in vacuum and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:1) to give methyl 1-(1-(6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)-2,2,2-trifluoroethyl)piperidine-4-carboxylate (130 mg, yield: 31%) as a yellow solid. ESI-MS (M+1)+: 506.1. 1HNMR (400 MHz, CDCl3) δ: 7.86˜7.80 (m, 3H), 7.46 (d, J=8.8 Hz, 1H), 7.27 (s, 1H), 7.16 (d, J=8.8 Hz, 1H), 4.68˜4.66 (m, 1H), 4.39˜4.36 (m, 1H), 3.56 (s, 3H), 3.32˜3.30 (m, 2H), 2.65˜2.64 (m, 1H), 2.44-2.43 (m, 1H), 2.30-2.27 (m, 3H), 1.93-1.90 (m, 3H), 1.80-1.79 (m, 2H), 1.44˜1.41 (m, 2H), 1.29˜1.27 (m, 3H), 1.14˜1.13 (m, 1H), 0.90 (s, 9H).
Reaction SMILES: [CH2:1]([N:4]([CH2:10]Cl)[C:5](=[O:9])[CH:6]([Cl:8])[Cl:7])[CH2:2][CH3:3].[CH2:12]([O:14][CH2:15][CH2:16][OH:17])[CH3:13].[Na].C(OC(O)C)C>O>[CH2:1]([N:4]([CH2:10][O:17][CH2:16][CH2:15][O:14][CH2:12][CH3:13])[C:5](=[O:9])[CH:6]([Cl:8])[Cl:7])[CH2:2][CH3:3]
Reactant: CCOCCO
Reactant: CCCN(CCl)C(=O)C(Cl)Cl
Agent: CCOC(C)O
Agent: [Na]
Solvent: O
Product: CCCN(COCCOCC)C(=O)C(Cl)Cl

Procedure:
A solution containing N-propyl-N-chloromethyldichloroacetamide (21.9 g., 0.1 mole) and 2-ethoxyethanol (30 ml.) is weighed in a flask equipped as in Example 1. A solution prepared from metallic sodium (2.3 g., 0.1 mole) with ethoxyethanol (20 ml.) is added to the solution under stirring and cooling by water in such a rate that the temperature of the mixture is maintained below 35° C. After the addition is complete, the mixture is stirred for an additional 2 hours at room temperature. Then, the bulk of ethoxyethanol is removed under reduced pressure and the residue is dissolved in chloroform (80 ml.). The chloroform solution is washed with water (2×100 ml.), dried over anhydrous sodium sulfate and the solvent is distilled under reduced pressure to give 32.2 g. (90.0%) of the named product as an oil; nD25 =1.4651.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@H:9]1[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:23][C:24]1[CH:29]=[C:28](Br)[CH:27]=[C:26]([Br:31])[CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][C@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[CH2:12][C@H:9]1[CH:10]([OH:11])[C:28]1[CH:29]=[C:24]([Br:23])[CH:25]=[C:26]([Br:31])[CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Reactant: Brc1cc(Br)cc(Br)c1
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1cc(Br)cc(Br)c1
Yield: 57 %

Procedure:
(2S,4R)-N-t-Butoxycarbonyl-4-t-butyldimethylsiloxy-2-(α-hydroxy-3,5-dibromobenzyl)pyrrolidine (19.6 g, yield: 56.9%) was prepared as a yellow oily substance, from (2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (20 g, 60.8 mmol), 1,3,5-tribromobenzene (19.13 g, 60.8 mmol) and 1.6M n-butyl lithium-hexane solution (49.4 ml, 79.04 mmol), in the same manner as in Reference Example 111-1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH2:14][N:15](C)[C:16](=O)OC(C)(C)C)=[CH:8][C:6]=2[CH:7]=1>Cl.O1CCOCC1>[CH3:16][NH:15][CH2:14][CH2:13][NH:12][C:9]1[CH:10]=[CH:11][C:5]2[O:4][C:3]([CH2:2][OH:1])=[CH:7][C:6]=2[CH:8]=1
Reactant: CN(CCNc1ccc2oc(CO)cc2c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNCCNc1ccc2oc(CO)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 116 %

Procedure:
74 mg of tert-butyl [2-(2-hydroxymethylbenzofuran-5-ylamino)ethyl]methylcarbamate are dissolved in 10 ml of HCl/dioxane (4N) and stirred at room temperature for two hours. Evaporation in a rotary evaporator gives 59 mg of the desired product (HCl salt).
Reaction SMILES: C([SiH](CC)CC)C.C([O:12][NH:13][C:14]([C@@:16]1([F:44])[CH2:20][CH2:19][CH2:18][C@H:17]1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=[C:35]([CH3:43])[CH:34]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])=[O:15])(C)(C)C>FC(F)(F)C(O)=O>[F:44][C@:16]1([C:14]([NH:13][OH:12])=[O:15])[CH2:20][CH2:19][CH2:18][C@H:17]1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=[C:35]([CH3:43])[CH:34]=2)=[CH:27][CH:26]=1)(=[O:23])=[O:24]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCC[C@]3(F)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCC[C@]3(F)C(=O)NO)cc2)c2ccccc2n1
Temperature: 45 °C
Reaction time: 7 h
Yield: 89.5 %

Procedure:
Triethylsilane (0.1 mL, 0.63 mmol) was added to a solution of (1R,2R)-N-(tert-butoxy)-1-fluoro-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentane carboxamide (0.13 g, 0.25 mmol) in trifluoroacetic acid (2 mL). The reaction mixture was stirred at 45° C. for 7 h, and then concentrated and chased three times with methanol/toluene. The residue was purified using silica chromatography, eluting with a gradient of 5-10% MeOH/CH2Cl2 to afford (1R,2R)-1-fluoro-N-hydroxy-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxamide (0.106 g, 91%). MS: 474.1 (M+H)+
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:36])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:35]=[CH:34][C:26]([C:27]([O:29]C(C)(C)C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:37]([C:40]([CH3:42])=[CH2:41])[CH2:38][CH2:39][C@:5]1([CH2:43][NH:44][CH2:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1)[CH2:4][CH2:3]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:36])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:34][CH:35]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:37]([C:40]([CH3:42])=[CH2:41])[CH2:38][CH2:39][C@:5]1([CH2:43][NH:44][CH2:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1)[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCc3ccccn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(CNCCc3ccccn3)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
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 74 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((2-(pyridin-2-yl)ethylamino)methyl)-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 (0.119 g, 0.127 mmol) in DCM (1 ml) was added TFA (0.4 ml, 5.19 mmol). The mixture was stirred at rt for 3.5 h and the mixture was concentrated under reduced pressure. The residue was purified by prep. HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure to give the title compound as a light-yellow foam (61 mg, 0.094 mmol, 74.3% yield). LCMS: m/e 647.4 (M−H)−, 2.20 min (method 6). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.42-8.48 (m, 1H),7.95 (d, J=8.28 Hz, 2H), 7.65 (td, J=7.65, 1.76 Hz, 1H), 7.17-7.24 (m, 2H), 7.14 (d, J=8.03 Hz, 2H), 5.29 (d, J=4.52 Hz, 1H), 4.71 (br. s., 1H), 4.61 (br. s., 1H), 3.45-3.59 (m, 2H), 3.18-3.32 (m, 3H), 2.74 (d, J=12.30 Hz, 1H), 2.45 (br. s., 1H), 1.70 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H), 0.98-2.13 (m, 24H), 0.96 (s, 3H), 0.94 (br. s., 3H), 0.92 (br. s., 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C=P(C)(C)C)#N.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23]2>C1(C)C=CC=CC=1>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23]2
Reactant: OCCOCc1ccccc1
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Agent: CP(C)(C)=CC#N
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(F)ccc2n1CCOCc1ccccc1
Temperature: 20 °C
Yield: 88.1 %

Procedure:
94 μl (0.657 mmol) of 2-benzyloxyethanol and 50.4 mg (0.438 mmol) of (cyanomethylene)trimethylphosphorane (Tet. Lett., 1996, 37, 2459-2462) are added to a solution of 68 mg (0.329 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate in 2 ml of toluene, stirred at 20° C. The reaction mixture is heated at 110° C. for 12 hours and then concentrated under reduced pressure, taken up in 20 ml of ethyl ether, filtered over a celite buffer and concentrated under reduced pressure. The residue obtained is purified by preparative HPLC, elution being carried out with a mixture of water, acetonitrile and trifluoroacetic acid. 99 mg of a yellow oil are thus isolated.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccccc1OCc1ccccc1
Temperature: 25 °C
Yield: 83 %

Procedure:
Methyl 2-hydroxyphenylacetate (21.0 g) was dissolved in dry DMF (200 ml), and dry potassium carbonate (19.35 g) was added in one portion. Benzyl bromide (23.94 g) in dry DMF (50 ml) was added dropwise to this mixture, with stirring, at room temperature. After eighteen hours the mixture was poured into water (500 ml) and extracted with ether (2×400 ml). The extracts were washed with water (3×150 ml) and brine (100 ml), dried and filtered through silica gel (50 g; Merck 60), then concentrated under reduced pressure to afford a yellow oil. Distillation at 160° C. and 0.05 mmHg afforded methyl 2-benzyloxyphenylacetate as a clear, colourless oil (26.99 g; 83% yield), infrared maximum (film): 1730 cm-1 ; 1H nmr (CDCl3, 90 MHz): delta 3.60 (3H, s), 3.75 (2H, s), 4.10 (2H, s), 6.80-7.40 (9H, m) ppm.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Li])CCC.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[C:29](=O)[CH2:28][CH2:27][CH2:26]2>CCOCC.C1COCC1>[CH3:34][O:33][C:32]1[CH:31]=[C:30]2[C:25](=[CH:24][C:23]=1[O:22][CH3:21])[C:26]([C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)=[CH:4][CH:3]=1)=[CH:27][CH2:28][CH2:29]2
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Reactant: COc1cc2c(cc1OC)C(=O)CCC2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(c1ccc(OCCN3CCCC3)cc1)=CCC2
Temperature: -78 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
A solution of 6.75 g (0.025 moles) of 1-(2-(4-bromophenoxy)ethyl)pyrrolidine in 250 ml of ether was cooled to −78° C. under N2. Several ml of THF were added to maintain a clear solution. 16.7 ml of 1.6 M n-butyllithium was added dropwise keeping the temperature below −70° C. After stirring at −78° C. for 1 hour, a solution of 5 g (0.024 moles) of 6,7-dimethoxy-1-tetralone in 25 ml of THF was added dropwise during 1 hour keeping the temperature below −70° C. After stirring for 2.5 hours at −78° C., the reaction was quenched by addition of 100 ml of 2N HCl. The reaction was allowed to warm to room temperature and the pH was adjusted to 7 by addition of 5N NaOH. The Et2O layer was separated and the aqueous layer was extracted 2 times with EtOAc. The combined Et2O/EtOAc layers were dried over Na2SO4 and evaporated to give 9 g of crude product, which was purified on 400 g of silica gel eluting with 95/5 CH2Cl2/MeOH to remove starting tetralone then with 85/15 CH2Cl2/MeOH to give 3.3 g of product.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C@H:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:35]=[CH:34][C:33]([C:36](O)=[O:37])=[C:32]([F:39])[CH:31]=1)[CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[Cl:47][C:48]1[CH:57]=[C:56]2[C:51]([CH2:52][C:53]([CH3:66])([CH3:65])[C:54](=[O:64])[N:55]2[CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)=[N:50][CH:49]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(OCC)(=O)C.CN(C)C=O>[Si:1]([O:18][CH2:19][CH2:20][C@H:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:35]=[CH:34][C:33]([C:36]([N:61]2[CH2:60][CH2:59][CH:58]([N:55]3[C:56]4[C:51](=[N:50][CH:49]=[C:48]([Cl:47])[CH:57]=4)[CH2:52][C:53]([CH3:65])([CH3:66])[C:54]3=[O:64])[CH2:63][CH2:62]2)=[O:37])=[C:32]([F:39])[CH:31]=1)[CH3:22])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ccccc1-c1ccc(C(=O)O)c(F)c1
Reactant: CC1(C)Cc2ncc(Cl)cc2N(C2CCNCC2)C1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ccccc1-c1ccc(C(=O)N2CCC(N3C(=O)C(C)(C)Cc4ncc(Cl)cc43)CC2)c(F)c1
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To an N,N-dimethylformamide solution (6 ml) of 2′-{[(1R)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-methylpropyl]oxy}-3-fluorobiphenyl-4-carboxylic acid (387 mg) were added at room temperature 7-chloro-3,3-dimethyl-1-piperidin-4-yl-3,4-dihydro-1,5-naphthyridin-2(1H)-one trifluoroacetate (Reference Example 10) (291 mg), diisopropylethylamine (0.497 ml) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (298 mg), followed by stirring overnight. The reaction solution was diluted with ethyl acetate, washed sequentially with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 1-{1-[(2′-{[(1R)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-methylpropyl]oxy}-3-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}-7-chloro-3,3-dimethyl-3,4-dihydro-1,5-naphthyridin-2(1H)-one (530 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[Cl:11])[C:5](O)=[O:6].S(Cl)([Cl:16])=O>>[Br:1][C:2]1[C:3]([Cl:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[Cl:11])[C:5]([Cl:16])=[O:6]
Reactant: O=C(O)c1cc(F)c(Cl)c(Br)c1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(F)c(Cl)c(Br)c1Cl

Procedure:
58.3 g (0.2 mol) of 3-bromo-2,4-dichloro-5-fluorobenzoic acid are refluxed for 4 hours in 350 ml of thionyl chloride until the gas evolution ceases. Excess thionyl chloride is removed by distillation, and the residue is fractionated.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:17][CH2:18][CH3:19])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[S:16][CH:15]=[N:14][CH:13]=2)=[N:7]1)[CH3:2].Br[C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:18]([O:17][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]1[C:10]([NH:11][C:21]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=2[CH3:30])=[CH:9][C:8]([C:12]2[S:16][CH:15]=[N:14][CH:13]=2)=[N:7]1)[CH3:19]
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Reactant: CCOC(Cn1nc(-c2cncs2)cc1N)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CCOC(Cn1nc(-c2cncs2)cc1Nc1cc([N+](=O)[O-])ccc1C)OCC

Procedure:
Under nitrogen, 2.93 g (10.4 mmol) of the compound of Example 81A together with 2.47 g (11.4 mmol) of 2-bromo-4-nitrotoluene, 233 mg (1.04 mmol) of palladium(II) acetate, 901 mg (1.56 mmol) of xantphos [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene] and 10.2 g (31.1 mmol) of caesium carbonate in 43 ml of 1,4-dioxane were heated under reflux for 3 h. After cooling, the mixture was filtered through Celite, the filter cake was washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The crude product obtained in this manner was purified on a Biotage system (100 g Snap column; mobile phase gradient ethyl acetate/0-8% methanol). This gave 3.26 g (75% of theory) of the title compound.
Reaction SMILES: C(CC(=O)C)(=O)C.O.[NH3:9].Br[C:11]1[CH:12]=[C:13]([CH3:29])[C:14]([C:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH2:19][CH:18]=2)=[N:15][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.CC(O)=CC(C)=O.CC(O)=CC(C)=O.[Cu]>[CH3:29][C:13]1[CH:12]=[C:11]([NH2:9])[CH:16]=[N:15][C:14]=1[C:17]1[CH2:22][CH2:21][CH:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:19][CH:18]=1
Reactant: Cc1cc(Br)cnc1C1=CCC(N2CCOCC2)CC1
Reactant: N
Agent: [Cu]
Agent: CC(=O)C=C(C)O
Agent: O=C([O-])[O-]
Solvent: CC(=O)CC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N)cnc1C1=CCC(N2CCOCC2)CC1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
Acetylacetone (0.31 ml) and 28% ammonia water (1.78 ml) were added to a suspension of 4-[4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-1-yl]morpholine (2 g), copper acetylacetonate (466 mg) and cesium carbonate (3.86 g) in N,N-dimethylformamide (12 ml), sealed in a tube under nitrogen atmosphere and stirred at 100° C. for 20 hours. After completion of the reaction, the reaction solution was left stand to room temperature and concentrated. The resulting residue was diluted with water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (chlorofolin/methanol) to give the titled compound (1.31 g) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:9][CH:8]2[CH:4]([CH2:5][CH:6]([C:10]([O:12]CC3C=CC=CC=3)=[O:11])[CH2:7]2)[CH2:3]1>CCOC(C)=O.[Pd]>[F:1][C:2]1([F:20])[CH2:3][CH:4]2[CH:8]([CH2:7][CH:6]([C:10]([OH:12])=[O:11])[CH2:5]2)[CH2:9]1
Reactant: O=C(OCc1ccccc1)C1CC2CC(F)(F)CC2C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)C1CC2CC(F)(F)CC2C1
Reaction time: 2.5 h

Procedure:
A stirred suspension of 10% Pd—C (12.53 mg) in a solution of benzyl 5,5-difluorooctahydropentalene-2-carboxylate (33 mg) in EtOAc (5 mL) was hydrogenated under balloon pressure for 2-3 h. The suspension was filtered and evaporated to dryness to afford a mixture of endo/exo isomers of Cap-12 as a white semi-solid. 1H NMR (400 MHz, chloroform-d) δ 3.04-2.93 (m, 1H), 2.88-2.76 (m, 2H), 2.40-2.26 (m, 2H), 2.15-2.04 (m, 2H), 1.87-1.71 (m, 4H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:12](=[O:23])[NH:13][C:14]1[S:15][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[N:17][N:18]=1)[CH2:9][CH2:10][CH3:11])(C)(C)C.Cl>O1CCOCC1>[C:19]([C:16]1[S:15][C:14]([NH:13][C:12](=[O:23])[CH:8]([NH2:7])[CH2:9][CH2:10][CH3:11])=[N:18][N:17]=1)([CH3:21])([CH3:20])[CH3:22]
Reactant: CCCC(NC(=O)OC(C)(C)C)C(=O)Nc1nnc(C(C)(C)C)s1
Agent: Cl
Solvent: C1COCCO1
Product: CCCC(N)C(=O)Nc1nnc(C(C)(C)C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.8 %

Procedure:
A mixture of [1-(5-tert-butyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-butyl]-carbamic acid tert-butyl ester (8.9 g) in dioxane (60 ml) was treated with 4 N HCl in 1,4-dioxane (20 ml). The mixture was stirred at rt overnight, then concentrated to dryness and pumped in vacuo to give the title compounds as a white solid (7.0908 g, 93%), APCI M+1=257.4
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[C:7]([C:11]([Br:14])=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].[CH3:18][Si](C=[N+]=[N-])(C)C.C(OCC)C>CO.O1CCCC1>[C:1]([NH:4][C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[C:7]([C:11]([Br:14])=[CH:12][CH:13]=1)[C:8]([O:10][CH3:18])=[O:9])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(=O)Nc1ccc(Br)c(C(=O)O)c1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1c(Br)ccc(NC(C)=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 120 h
Yield: 66.4 %

Procedure:
To a mixed solution of 3-(acetylamino)-6-bromo-2-nitrobenzoic acid (2.00 g, 6.60 mmol) in methanol (20 mL) and tetrahydrofuran (5 mL) was added 2M trimethylsilyldiazomethane/diethyl ether solution (10.6 mL, 21.1 mmol) under ice-cooling, and the mixture was stirred at room temperature for 5 days. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=25/75→60/40) to give the title compound (1.39 g, yield 66%).