Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1.[I:16]I.C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCC>C(#N)C>[I:16][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CCc1cccc(OC)c1
Reactant: II
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)CCc1cc(OC)ccc1I
Temperature: 25 °C
Yield: 0.1 %

Procedure:
To a solution of ester 25 (1.618 g, 7.77 mmol) in acetonitrile (100 mL), iodine (1.972 g, 7.77 mmol) and n-butyltriphenylphosphonium peroxodisulfate (6.455 g, 7.77 mmol) were added and refluxed for 45 min. The reaction mixture was cooled to room temperature and the excess of iodine was removed by dropwise addition of 1M Na2S2O3 solution. The colourless solution was transferred to a separatory funnel and the organic layer was separated and dried over Na2SO4. Evaporation of the solvent followed by means of column chromatography on silica gel (hexane/isopropylether 10:1) gave 1.982 mg of iodinated ester 26 as a yellowish oil. Yield 76%. 1H NMR (300 MHz, CDCl3) δ ppm: 7.65 (d, J=8.7 Hz, 1H), 6.82 (d, J=3.0 Hz, 1H), 6.51 (dd, J1=8.7 Hz, J2=3.0 Hz, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.76 (s, 3H), 3.00 (t, J=7.9 Hz, 2H), 2.60 (t, J=7.9 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ ppm: 172.4, 160.0, 144.0, 139.9, 115.5, 114.1, 88.6, 60.5, 55.3, 35.9, 34.4, 14.2; HRMS (EI) m/z: calcd for C12H15IO3: 334.0065. found: 334.0082.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][NH:12][C:13](=O)[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])[CH2:16]2)=[O:10])=[C:4]([Cl:26])[CH:3]=1.C([O-])([O-])=O.[K+].[K+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][N:17]([C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[CH2:16]3)=[N:12][NH:11][C:9]2=[O:10])=[C:4]([Cl:26])[CH:3]=1
Reactant: O=C(C[C@@H]1CCN(C(=O)C2CC2)C1)NNC(=O)Nc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2Cl)C1
Temperature: 120 °C
Reaction time: 5 h
Yield: 45.7 %

Procedure:
To a suspension of N-(4-bromo-2-chlorophenyl)-2-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetyl}hydrazinecarboxamide (1.3 g, 2.93 mmol) in water (60 mL) was added K2CO3 (2.025 g, 14.65 mmol). The reaction flask was equipped with a reflux condenser and heated to reflux (bath=120° C.) with stirring. After 5 h (analysis by LCMS indicated no starting material remained), the reaction mixture was cooled to room temperature and filtered to collect a small amount of white precipitate (this was determined to contain very little product and was discarded). The aqueous filtrate was adjusted to pH˜5.5 with 1N aq HCl and extracted with ethyl acetate (2×). The combined organics were dried over Na2SO4, filtered, and evaporated to provide the title product (570 mg, 1.339 mmol, 46% yield) as a foam. The product was determined to be 75% pure by LCMS (UV214) and was carried on in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 7.80 (dt, J=2.3, 5.7 Hz, 1H), 7.68-7.52 (m, 1H), 7.28-7.22 (m, 1H), 4.01-3.35 (m, 2H), 3.34-2.99 (m, 1H), 2.74-2.08 (m, 3H), 1.82-1.66 (m, 1H), 1.59-1.51 (m, 1H), 1.12-0.91 (m, 1H), 0.83-0.69 (m, 1H).
Reaction SMILES: O.C[N+]1([O-])CC[O:6]CC1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([F:38])=[C:15]([C@:17]23[CH2:26][O:25][C@@H:24]([CH2:27][OH:28])[CH2:23][C@H:22]2[CH2:21][S:20][C:19]([NH:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:18]3)[CH:16]=1.CC(O)C>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:30]([NH:29][C:19]1[S:20][CH2:21][C@@H:22]2[CH2:23][C@H:24]([C:27]([OH:6])=[O:28])[O:25][CH2:26][C@:17]2([C:15]2[CH:16]=[C:11]([Br:10])[CH:12]=[CH:13][C:14]=2[F:38])[N:18]=1)(=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: O=C(NC1=N[C@@]2(c3cc(Br)ccc3F)CO[C@@H](CO)C[C@H]2CS1)c1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: CC#N
Solvent: CC(C)O
Solvent: O
Product: O=C(NC1=N[C@@]2(c3cc(Br)ccc3F)CO[C@@H](C(=O)O)C[C@H]2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 113.7 %

Procedure:
N-Methylmorpholine N-oxide monohydrate (3.38 g, 25.0 mmol) and tetrapropylammonium perruthenate (0.147 g, 0.417 mmol) were added to a solution of N-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C33) (2.0 g, 4.17 mmol) in acetonitrile (75 mL). The reaction mixture was allowed to stir at room temperature for 16 hours. 2-Propanol (200 mL) was added to the reaction mixture and the resulting solution was left stirring at room temperature for 35 minutes. After that time, the reaction mixture was concentrated under reduced pressure. The oily residue was partitioned between aqueous 0.25 M sodium hydroxide (200 mL) and a 1:1 solution of diethyl ether:ethyl acetate (200 mL each). The layers were isolated and the organic layer was washed with aqueous 0.25 M sodium hydroxide (3×200 mL). The combined aqueous layers were then acidified to pH 1 with 2 M aqueous hydrochloric acid (300 mL). The now heterogeneous mixture was extracted with ethyl acetate (4×200 mL). The combined organics were then dried over sodium sulfate, filtered and concentrated under reduced pressure to give the product (2.34 g) as a purple solid, which was taken directly to the following step. LCMS m/z 495.1 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 8.08-8.11 (m, 1H), 7.50-7.64 (m, 4H), 7.17-7.22 (m, 1H), 4.39 (dd, J=11.8, 2.8 Hz, 1H), 4.20 (d, J=12.1 Hz, 1H), 4.04-4.07 (m, 1H), 3.06 (dd, J=12.9, 4.3 Hz, 1H), 2.92 (dd, J=13.7, 3.1 Hz, 1H), 2.13-2.18 (m, 1H), 2.05-2.09 (m, 1H), 1.99-2.02 (m, 4H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]([OH:11])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C.Cl.[F:34][C:35]([F:55])([F:54])[C:36]1[CH:41]=[CH:40][C:39]([C@@H:42]([C:44]2[C:49]([C:50]([F:53])([F:52])[F:51])=[CH:48][CH:47]=[CH:46][N:45]=2)[NH2:43])=[CH:38][CH:37]=1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]([NH:43][C@@H:42]([C:39]1[CH:40]=[CH:41][C:36]([C:35]([F:55])([F:34])[F:54])=[CH:37][CH:38]=1)[C:44]1[C:49]([C:50]([F:51])([F:52])[F:53])=[CH:48][CH:47]=[CH:46][N:45]=1)=[O:11]
Reactant: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F
Reactant: O=C(O)CCc1ccccn1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCc1ccccn1)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(pyridin-2-yl)propanoic acid (89 mg, 0.586 mmol, Oakwood) and DCM (4 mL) were added CDI (95 mg, 0.586 mmol) and DIPEA (0.20 mL, 1.148 mmol). After 0.5 hours, the reaction was treated with a solution of (S)-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methanamine hydrochloride (Intermediate 1) (125 mg, 0.390 mmol) in DCM (1.5 mL). The solution was stirred at rt. After 4 days, the resulting product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (4 g), eluting with 0% to 60% EtOAc in hexane, to provide the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ ppm 8.79 (d, J=3.8 Hz, 1H), 8.45 (d, J=4.8 Hz, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.44-7.52 (m, 3H), 7.34-7.43 (m, 3H), 7.03-7.12 (m, 2H), 6.63 (d, J=8.0 Hz, 1H), 3.11 (td, J=6.7 & 2.5 Hz, 2H), 2.74 (td, J=7.2 & 2.5 Hz, 2H). MS (ESI pos. ion) m/z: 454.0 (M+H).
Reaction SMILES: [N:1]1([C:7]2[CH:38]=[CH:37][C:10]([CH2:11][CH:12]3[C:21]4[C:16](=[CH:17][C:18]([O:22]CC5C=CC=CC=5)=[CH:19][CH:20]=4)[CH2:15][CH2:14][N:13]3[C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd]>[N:1]1([C:7]2[CH:38]=[CH:37][C:10]([CH2:11][CH:12]3[C:21]4[C:16](=[CH:17][C:18]([OH:22])=[CH:19][CH:20]=4)[CH2:15][CH2:14][N:13]3[C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Fc1ccc(N2CCc3cc(OCc4ccccc4)ccc3C2Cc2ccc(N3CCCCC3)cc2)cc1
Agent: [Pd]
Product: Oc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(N2CCCCC2)cc1

Procedure:
1-{4-(N-Piperidyl)benzyl}-2-(4-fluorophenyl}-6-phenylmethoxy-1,2,3,4-tetrahydroisoquinoline (0.25 g, 0.49 mmol) was treated with H2 in 10% Pd/C as described in Example 14. D to yield 1-{4-(N-piperidyl)benzyl}-2-(4-fluorophenyl}-1,2,3,4-tetrahydroisoquinoline-6-ol. Treatment of the free base with conc. HCl in ether produces a fine white solid. The precipitate is filtered and dried under high vacuum to yield the title compound. (0.096 g, 47% yield): m.p. 177-179° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.Cl.CON.C(=O)([O-])[O-].[K+].[K+].[NH2:22][NH2:23]>COCCOC.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:9]=[C:8]2[C:5]([CH:6]=[N:22][NH:23]2)=[C:4]([F:11])[CH:3]=1
Reactant: O=Cc1c(F)cc(Cl)cc1F
Reactant: NN
Agent: CON
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Fc1cc(Cl)cc2[nH]ncc12
Temperature: 35 °C
Reaction time: 24 h
Yield: 48.3 %

Procedure:
4-Chloro-2,6-difluoro-benzaldehyde (15 g, 85 mmol) was dissolved in 1,2-dimethoxyethane 170 ml). O-Methyl-hydroxylamine hydrochloride (7.1 g, 85 mmol) and potassium carbonate (12.9 g, 93.5 mmol) were then added and the mixture was stirred at 35° C. for 24 h. The reaction was filtered, rinsed with dichloromethane, evaporated and redissolved in DMF (170 ml). Hydrazine (2.9 ml 93.5 mmol) was added and the reaction was stirred at 100° C. for 1 h. After cooling, water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with water and sodium chloride solution then dried over sodium sulfate. The solvent was evaporated to leave a solid which was purified by silica gel chromatography (diethyl ether/hexanes) to give 7 g (49%) of 6-chloro-4-fluoro-1H-indazole. (M+H)+=171.
Reaction SMILES: [B-](F)(F)(F)F.[N+:6](=[O:8])=[O:7].N1C(C)=CC(C)=CC=1C.[C:18]([O:22][C:23]([NH:25][C@H:26]([CH2:28][OH:29])[CH3:27])=[O:24])([CH3:21])([CH3:20])[CH3:19]>C(#N)C>[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH3:27])[CH2:28][O:29][N+:6]([O-:8])=[O:7])=[O:24])([CH3:20])([CH3:21])[CH3:19]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: CC#N
Product: C[C@@H](CO[N+](=O)[O-])NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
In 200 ml of dry acetonitrile were suspended 17.9 g of nitronium tetrafluoroboron, and 17.5 ml of 2,4,6-collidine were added dropwise thereto at -5° C. to 0° C. under a nitrogen stream. The reaction mixture was stirred at 0° C. for 30 minutes, 10.7 g of N-t-butoxycarbonyl-L-alaninol were added thereto, and the mixture was stirred at room temperature for 1 hour and 20 minutes. Then, the solvent was distilled off under reduced pressure and ethyl acetate was added to the residue. The insolubles were filtered off and the filtrate was evaporated to dryness under reduced pressure. The thus obtained yellow oil was purified by silica gel column chromatography employing cyclohexane-ethyl acetate (9:1) as an eluent to obtain 7.12 g of the desired compound as a colorless oil.
Reaction SMILES: COC[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH:6]=[CH:7][C:8]([O:10]CC)=O.CO[CH2:19][N:20](CC1C=CC=CC=1)[CH2:21][Si](C)(C)C>>[CH2:19]1[NH:20][CH2:21][C@@H:7]2[CH2:8][O:10][C:13]3[CH:14]=[CH:15][CH:16]=[CH:4][C:5]=3[C@@H:6]12
Reactant: CCOC(=O)C=Cc1ccccc1COC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Product: c1ccc2c(c1)OC[C@H]1CNC[C@H]21

Procedure:
Ethyl 2-methoxymethyl-cinnamate and N-methoxymethyl-N-trimethylsilylmethyl-benzylamine were treated, in an analogous manner as described in Examples 3A-C.
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5]CC)=O.[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>O1CCOCC1>[OH:1][CH2:2][C:3]([N:12]1[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]1)=[O:5]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)CO
Solvent: C1COCCO1
Product: CN1CCN(C(=O)CO)CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Ethyl 2-hydroxyacetate (6.85 g, 65.8 mmol, 1.0 eq) and 1-methylpiperazine (5.26 g, 52.6 mmol, 0.8 eq) were dissolved in 1,4-dioxane (10 mL) in a sealed tube and the mixture was stirred at 120° C. overnight. The mixture was allowed to cool to RT and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (2% MeOH-DCM) to afford the product 2-hydroxy-1-(4-methyl piperazin-1-yl)ethanone.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:32]=[CH:31][C:14]([O:15][C:16]([CH3:30])([CH3:29])[C:17]([O:19][C@H:20]3[CH2:25][C@H:24]([CH3:26])[CH2:23][C:22]([CH3:28])([CH3:27])[CH2:21]3)=[O:18])=[CH:13][CH:12]=2)=[O:7])=[CH:4][CH:3]=1>[K+].[Br-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:32]=[CH:31][C:14]([O:15][C:16]([CH3:29])([CH3:30])[C:17]([O:19][C@H:20]3[CH2:25][C@@H:24]([CH3:26])[CH2:23][C:22]([CH3:27])([CH3:28])[CH2:21]3)=[O:18])=[CH:13][CH:12]=2)=[O:7])=[CH:33][CH:34]=1
Reactant: C[C@H]1C[C@H](OC(=O)C(C)(C)Oc2ccc(CCNC(=O)c3ccc(Cl)cc3)cc2)CC(C)(C)C1
Agent: [Br-]
Agent: [K+]
Product: C[C@@H]1C[C@H](OC(=O)C(C)(C)Oc2ccc(CCNC(=O)c3ccc(Cl)cc3)cc2)CC(C)(C)C1

Procedure:
The reaction is carried out under the same conditions as in Example 3 and with the same proportions of reactants. After chromatography on a silica column, the product can be recrystallized from ethyl acetate to give the title derivative in the form of white crystals melting at 122° C. (capillary). Thin layer chromatography under the conditions already described shows a single spot whose Rf of 0.2 is identical to that of the product of Example 3. The IR spectrum run in KBr has the same principal characteristic bands as in Example 3, although the fine bands between 1000 and 600 cm-1 are markedly different.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([CH2:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=2)[C:21]#[N:22])=[N:13][N:12]=1)[CH3:2].[NH:28]1[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[S:15][C:11]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][N:28]4[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29]4)[CH:7]=[CH:6][CH:5]=3)=[N:12][N:13]=2)[CH:17]=[CH:18][C:19]=1[CH2:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CCc1c(C=O)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Reactant: O=C(O)C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1c(CN2CCC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.6 %

Procedure:
To a solution of 5-[5-(2-ethyl-3-formylphenyl)-1,3,4-thiadiazol-2-yl]-2-(2-methylpropyl)benzonitrile (D27) (100 mg, 0.266 mmol) in Ethanol (10 mL) stirred at room temperature was added 3-pyrrolidinecarboxylic acid (123 mg, 1.065 mmol) and AcOH (0.15 mL, 2.62 mmol). The reaction mixture was stirred at room temperature for 10 min, and sodium triacetoxyborohydride (110 mg, 0.522 mmol) was added. The reaction mixture was continuously stirred overnight. The reaction was quenched with water, and EtOH was evaporated in vacuo. The mixture was extracted by EA for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated, and purified by Mass Directed AutoPrep to afford 1-[(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-ethylphenyl)methyl]-3-pyrrolidinecarboxylic acid (E48) (55 mg) as a off-white solid.
Reaction SMILES: C(OC([N:8]([CH3:18])[C@@H:9]([CH2:13][C:14]([CH3:17])([CH3:16])C)[C:10]([OH:12])=O)=O)(C)(C)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)=[CH:23][CH:22]=1.FC(F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[CH3:18][NH:8][C@@H:9]([C:10]([NH:35][C@@H:32]1[C@@H:30]2[C@@H:29]([CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:37])([F:19])[F:36])=[CH:26][CH:25]=3)[CH2:31]2)[CH2:34][CH2:33]1)=[O:12])[CH2:13][CH:14]([CH3:16])[CH3:17]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cc3)C[C@@H]21
Agent: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: CN[C@H](CC(C)C)C(=O)N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting (S)-N-(tert-butoxycarbonyl)-N-methyl-D-leucine for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-[4-(trifluoromethyl)phenyl]octahydrocyclopenta[c]pyrrol-4-amine from Example 607 for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.36 (d, J=7.4, 1H), 7.57 (d, J=8.6, 2H), 6.63 (d, J=8.7, 2H), 4.46-4.37 (m, 1H), 3.56 (dd, J=10.1, 3.0, 1H), 3.38 (dd, J=10.0, 7.6, 1H), 3.30-3.19 (m, 2H), 3.02 (dd, J=9.9, 3.7, 1H), 2.73 (ddd, J=13.1, 8.2, 6.7, 2H), 2.46 (s, 3H), 2.18-2.09 (m, 1H), 2.11-2.01 (m, 1H), 2.00-1.87 (m, 2H), 1.80-1.58 (m, 3H), 1.39 (dtd, J=13.2, 8.0, 5.2, 1H), 0.94 (d, J=6.6, 3H), 0.88 (d, J=6.6, 3H); MS (ESI+) m/z 398 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([O:13][CH2:14][C:15]([CH3:17])([CH3:16])[N:8]3[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21])[C:11]=1[F:12].[N+:22]([O-])([O-:24])=[O:23].[K+]>OS(O)(=O)=O>[F:1][C:2]1[C:3]([N+:22]([O-:24])=[O:23])=[C:4]2[C:9]3=[C:10]([O:13][CH2:14][C:15]([CH3:17])([CH3:16])[N:8]3[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21])[C:11]=1[F:12]
Reactant: CC1(C)COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC1(C)COc2c(F)c(F)c([N+](=O)[O-])c3c(=O)c(C(=O)O)cn1c23
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
A solution of 8 (7.5 g, 25.4 mmol) in concentrated H2SO4 (30 mL) was treated portionwise at 0° C. with solid KNO3 (3.9 g, 38.6 mmol). After stirring at 0° C. for 2 h, the reaction mixture was poured into 500 mL of ice-water and the resulting precipitate was removed by filtration and washed with ice-cold water. The resulting solid was dried to yield 9 as a yellow solid (7.6 g, 87% yield).
Reaction SMILES: II.Br[CH2:4][CH2:5][CH2:6][O:7][CH3:8].Br[C:10]1[CH:15]=[C:14]([CH:16]([O:19][CH3:20])[O:17][CH3:18])[C:13]([Cl:21])=[CH:12][N:11]=1.CCOC(C)=O>C1COCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:13]1[C:14]([CH:16]([O:19][CH3:20])[O:17][CH3:18])=[CH:15][C:10]([CH2:4][CH2:5][CH2:6][O:7][CH3:8])=[N:11][CH:12]=1
Reactant: COCCCBr
Reactant: COC(OC)c1cc(Br)ncc1Cl
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: II
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCCc1cc(C(OC)OC)c(Cl)cn1
Temperature: 25 °C
Yield: 62 %

Procedure:
To a suspension of Mg (911 mg, 37.5 mmol) and iodine (one crystal) in dry THF (30 mL) was added dropwise 5% of the total amount of 1-bromo-3-methoxypropane (4.59 g, 30.0 mmol). The mixture was heated to reflux with the help of a heat gun until the Grignard-formation started. The rest of the 1-bromo-3-methoxypropane was added slowly, while an exothermic reaction proceeded. After the end of the addition, the reaction mixture was stirred under reflux for 20 min, and was allowed to cool to rt. This Grignard-sol. (1M in THF, 23.5 mL, 23.5 mmol) was added dropwise to a mixture of 2-bromo-5-chloro-4-dimethoxymethyl-pyridine (2.50 g, 9.38 mmol) and Ni(dppp)Cl2 (495 mg, 0.938 mmol) in THF (50 mL) at 0° C. The reaction mixture was stirred at rt for 30 min, and was then heated to reflux for 2 h. The mixture was allowed to cool to rt, and was dissolved with EtOAc. This mixture was washed with aq. sat. NaHCO3. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane→EtOAc/heptane 1:1) yielded the title compound (1.51 g, 62%). LC-MS: tR=0.80 min; ES+: 260.15.
Reaction SMILES: C1C=CC(OP(OC2C=CC=CC=2)([N:10]=[N+:11]=[N-:12])=O)=CC=1.[Si:20]([O:27][C@@H:28]([C@H:33]1[CH2:37][O:36][C:35]([CH3:39])([CH3:38])[N:34]1[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@@H:29]([CH3:32])[CH2:30]O)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[N:10]([CH2:30][C@H:29]([CH3:32])[C@H:28]([C@H:33]1[CH2:37][O:36][C:35]([CH3:39])([CH3:38])[N:34]1[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[O:27][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
Diphenylphosphonic azide (1.3 mL, 5.9 mmol) was added to a mixture of tert-butyl (4R)-4-((1R,2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-2-methylpropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.2 g, 3.0 mmol), diisopropyl azodicarboxylate (1.2 mL, 5.9 mmol) and PPh3 (1.6 g, 5.9 mmol) in THF (20 mL). The mixture was stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluting with 0-15% EtOAc in hexanes) to provide the sub-title compound (1.09 g, 86%). LCMS calc. for C15H33N4O2Si (M+H-Boc)+: m/z=329.2. found 329.2.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4].Cl.Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[N:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[N:22]1[CH:27]=[CH:26][CH:25]=[N:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:2][C:3]([NH:5][C:6]2[CH:19]=[CH:18][C:9]3[O:10][C:11]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[C:8]=3[CH:7]=2)=[O:4])[CH2:30][CH2:29]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(CCl)Nc1ccc2oc3c(c2c1)CCCCC3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(CN1CCN(c2ncccn2)CC1)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 12.1 %

Procedure:
Following the procedure of Example 40, 2-chloro-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.13 g, 0.45 mmol), 1-(pyrimidyl)piperazine dihydrochloride (0.13, 0.56 mmol), and cesium carbonate (0.58 g, 1.8 mmol) in acetonitrile (5 mL) provided 2-(4-pyrimidin-2-ylpiperazin-1-yl)-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.022 g) after purification by flash column chromatography (elution with 3% methanol-1% ammonia-dichloromethane). MS (ES) m/z 406.3 ([M+H]+).