Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH2:16][NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][CH:3]=1.[Cl:33][C:34]1[C:35]2[CH:45]=[CH:44][CH:43]=[CH:42][C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[Cl:33][C:34]1[C:35]2[CH:45]=[CH:44][CH:43]=[CH:42][C:36]=2[S:37][C:38]=1[C:39]([N:17]([CH2:16][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[CH:18]1[CH2:19][CH2:20][CH:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:22][CH2:23]1)=[O:40]
Reactant: COc1ccc(-c2ccc(Cl)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Product: COc1ccc(-c2ccc(Cl)cc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 34 (348 mg, 0.76 mmol) is treated with 3-chloro-benzo[b]thiophene-2-carbonyl chloride (210 mg, 0.91 mmol) using Method D to give the title compound.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH3:19])[C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:19][C:10]1[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:18][C:11]=1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC(=O)C(C)NC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1oc(-c2ccccc2)nc1C
Temperature: 90 °C
Yield: 48.1 %

Procedure:
To a crude mixture of ethyl 4-(benzoylamino)-3-oxopentanoate (0.6 g, 2.28 mmol) in DMF (4 mL) at rt, was added POCl3(1.04 g, 6.84 mmol). The resulting solution was heated at 90° C. for 1 hour, then cooled down to rt, and poured into ice for 30 minutes. The aqueous solution was carefully added to a saturated aqueous solution of NaHCO3. Phases were separated with EtOAc and the combined organic extracts were dried over MgSO4 and solvent removed under reduced pressure. The crude material was purified on Biotage small column using a solvent gradient of 0 to 50% EtOAc/Hexane. This gave ethyl (4-methyl-2-phenyl-1,3-oxazol-5-yl)acetate (0.269 g 48% yield) as yellowish oil. ES-MS m/z 246.2 ((MH)+); HPLC RT (min.) 2.77; 1H NMR (CDCl3) δ 8.01–7.98 (m, 2H), 7.45–7.41 (m, 3H), 4.20 (q, 2H), 3.71 (s, 2H), 2.21 (s, 3H), 1.28 (t, 3H).
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.O.[OH-].[Li+]>CO.O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COC(=O)c1ccc(-n2cccn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(-n2cccn2)cc1
Yield: 97.2 %

Procedure:
To a solution of methyl 4-(1H-pyrazol-1-yl)benzoate of Step A (0.529 g, 2.62 mmol) in methanol (20 mL) and water (4 mL) was added lithium hydroxide monohydrate (0.220 g, 5.23 mmol) and the reaction mixture heated to reflux for 2 hours. The cooled reaction mixture was concentrated in vacuo to remove methanol and then diluted with water (40 mL). The resulting aqueous solution was washed with diethyl ether (40 mL), then acidified to pH 3 by the addition of concentrated hydrochloric acid. The solid product was filtered and dried in vacuo at 50° C. overnight to afford the title compound (0.479 g, 97%) as a white solid, m.p. 270-272° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)([OH:16])=[O:15].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[N:13][S:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)(=[O:11])=[O:12])=[CH:19][CH:18]=1)([OH:16])=[O:15]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(C=NS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc1

Procedure:
In a similar manner to Example 2, 2.02 g (10 mmol) of 3-nitrobenzenesulfonamide, 1.50 g (10 mmol) of 4-carboxybenzaldehyde and 20 mg of TsOH in 150 mL of toluene were heated for 5 hours to yield 3.23 g (97%) of SULF-6 as a white powder: IR (Nujol) 3200-2500 (br), 1685, 1554, 1379, 1352, 1165 cm-1 ; 1H NMR (DMSO-d6, TMS ext std)δ 9.24 (s, 1), 8.47 (s, 1), 7.9-6.9 (m, 7).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1I)[CH:11]=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.CN(C=O)C>[CH:4]1[N:3]2[C:2]([CH2:6][O:7][C:8]3[CH:9]=[C:10]([CH:11]=[O:12])[CH:13]=[CH:14][C:15]=32)=[N:1][CH:5]=1
Reactant: O=Cc1ccc(I)c(OCc2ncc[nH]2)c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=Cc1ccc2c(c1)OCc1nccn1-2
Temperature: 110 °C
Yield: 31.9 %

Procedure:
To a vial, were added copper(I) iodide (27.8 mg, 0.146 mmol), 3-(1H-imidazol-2-ylmethoxy)-4-iodobenzaldehyde (127.7 mg, 0.389 mmol), cesium carbonate (267 mg, 0.819 mmol) and a stir bar. The reaction vial was purged with Argon 3 times. The (R,R)-(−)-N,N′-dimethyl-1,2-cyclohexanediamine (50 mg, 0.352 mmol) and DMF (2 ml) were added. The mixture was heated at 110° C. for 1 h. LCMS showed product formation. The mixture was filtered and purified on reverse phase HPLC to afford desired product (24.8 mg, 0.124 mmol, 31.8% yield).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[N:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[N:10]=2)[CH2:7][CH2:6][CH:5]([N:17]2[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)=[O:23])[CH2:18]2)[CH2:4][CH2:3]1
Reactant: COc1cccc(C2(O)CCC(=O)CC2)n1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: COc1cccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)n1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(6-methoxy-pyridin-2-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[S:8][C:7]([C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([O:20]CCCC)=[O:19])[CH2:14][CH2:13]2)([OH:11])[CH3:10])=[N:6][CH:5]=1.Cl.O>CO>[Br:3][C:4]1[S:8][C:7]([C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]2)([OH:11])[CH3:10])=[N:6][CH:5]=1
Reactant: CCCCOC(=O)[C@H]1CC[C@H](C(C)(O)c2ncc(Br)s2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(O)(c1ncc(Br)s1)[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Sodium hydroxide (3.0 M in H2O, 5.98 mL, 17.93 mmol) was added to a solution of racemic butyl trans-4-[1-(5-bromo-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylate (2.0 g, 5.12 mmol) in methanol (6 mL) and heated to 70° C. for 3 hour. Then, the reaction was cooled to room temperature and acidified with hydrochloric acid (3.0 M in H2O). Water (10 mL) was added and the mixture was stirred overnight at which point crystallization occurred. The reaction was filtered and the filter cake was washed with water and then dried under a nitrogen bag to afford racemic trans-4-[1-(5-bromo-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylic acid as a white solid. MS ESI calc'd. for C12H17BrNO3S [M+H]+ 334, 336. found 334, 336. 1H NMR (600 MHz, DMSO-d6) δ 11.92 (s, 1H), 7.69 (s, 1H), 5.91 (s, 1H), 2.03-1.93 (m, 1H), 1.92-1.85 (m, 1H), 1.85-1.77 (m, 2H), 1.62-1.51 (m, 1H), 1.48-1.35 (m, 4H), 1.25-1.08 (m, 3H), 1.04-0.88 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C@H:5]([CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[NH2:6])[CH3:2].[C:15]([O:19][C:20](=[O:24])[CH:21](Br)[CH3:22])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CN(P(N(C)C)(N(C)C)=O)C>[C:15]([O:19][C:20](=[O:24])[C@H:21]([CH3:22])[NH:6][C@H:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCCCCSC[C@H](N)C(=O)OCC
Reactant: CC(Br)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCSC[C@H](N[C@@H](C)C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In 20 ml of HMPA were dissolved 8.6 g of S-pentyl-L-cysteine ethyl ester and 8.2 g of 2-bromopropionic acid t-butyl ester. To the solution was added 5.5 ml of triethylamine. The solution was stirred at room temperature for 24 hours. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The extract was sufficiently washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (a 1:2 mixture of ether and n-hexane as an eluent), producing the α-isomer of the title compound as a colorless oil from the first eluate. Yield 3.9 g.
Reaction SMILES: [C:1]1([CH:7]([CH2:33][CH3:34])[C:8]([O:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:32])[C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3)[CH2:15][CH2:14]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.C(Cl)(Cl)[Cl:42].C1(C(CC)C(Cl)=O)C=CC=CC=1>>[ClH:42].[C:1]1([CH:7]([CH2:33][CH3:34])[C:8]([O:10][CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([C:19](=[O:32])[C:20]3[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=3)[CH2:17][CH2:18]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(Cl)Cl
Agent: CCC(C(=O)Cl)c1ccccc1
Agent: CCC(C(=O)OCCN1CCN(C(=O)c2cc(OC)c(OC)c(OC)c2)CC1)c1ccccc1
Solvent: c1ccncc1
Product: Cl

Procedure:
To a solution of 16.2 g (0.05 mole) of N-[2-(2-phenyl-2-ethylacetoxy)ethyl]-N'-(3,4,5-trimethoxybenzoyl)piperazine and 4.75 g (0.06 mole) of pyridine in 50 ml of anhydrous chloroform 10.0 g (0.055 mole) of 2-phenyl-2-ethylacetyl chloride were added dropwise. The reaction mixture, treated as described in Example 1 yield the title product. M.p. 207° C. (ethanol).
Reaction SMILES: C([O:4][C:5]1[C:6]([C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:7]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:8]([CH2:15][CH3:16])=[C:9]([O:11]CC=C)[CH:10]=1)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:22]([C:6]1[C:5]([OH:4])=[CH:10][C:9]([OH:11])=[C:8]([CH2:15][CH3:16])[C:7]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19])(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C=CCOc1cc(OCC=C)c(C(=O)c2ccccc2)c(CC(=O)OC)c1CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCc1c(O)cc(O)c(C(=O)c2ccccc2)c1CC(=O)OC
Temperature: 80 °C
Reaction time: 5 h
Yield: 101.6 %

Procedure:
Methyl 3,5-diallyloxy-2-benzoyl-6-ethylphenylacetate (0.29 g, 0.72 mmol) obtained in Example 5, Step 4 was dissolved in acetic acid (5.0 mL) in an atmosphere of argon. To the solution were added triphenylphosphine (74 mg, 0.28 mmol) and palladium (II) acetate (16 mg, 0.071 mmol), followed by stirring at 80° C. for 5 hours. To the reaction mixture were further added triphenylphosphine (0.15 g, 0.57 mmol) and palladium (II) acetate (32 mg, 0.14 mmol), followed by stirring at 100° C. for 13 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9-3/1) to obtain Compound 5 (0.23 g, 60%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=3)=[CH:11][CH:10]=2)[C:5](=[O:23])[CH2:4][O:3]1.[CH3:24][NH2:25]>CO.O1CCCC1>[C:21]([C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][NH:6][C:2](=[O:1])[O:3][CH2:4][C:5]([NH:25][CH3:24])=[O:23])=[CH:14][CH:13]=2)[CH:20]=[CH:19][CH:18]=1)#[N:22]
Reactant: CN
Reactant: N#Cc1cccc(-c2ccc(CCN3C(=O)COC3=O)cc2)c1
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)COC(=O)NCCc1ccc(-c2cccc(C#N)c2)cc1
Yield: 48.6 %

Procedure:
2.0 g (6.53 mmol) of 4′-[2-(2,4-dioxo-1,3-oxazolidin-3-yl)ethyl]-3-biphenylcarbonitrile, prepared in step 11.2., are dissolved in a mixture of 13 ml of methanol and 9.8 ml of a 2N solution of methylamine (19.6 mmol) in tetrahydrofuran. The solution is left to react overnight and then evaporated to dryness and the residue is purified by chromatography on silica gel, eluting with a 96/4 then 95/5 mixture of dichloromethane and methanol. The product is recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 1.07 g of product in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10](COCC[Si](C)(C)C)[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:22][C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([O:28]C)=O)[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[NH:41]1CCCN2CCCN=[C:42]12.CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(Cl)Cl.O>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:22][C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([NH:41][CH3:42])=[O:28])[N:12]=2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(Cn2nc(N(COCC[Si](C)(C)C)S(=O)(=O)c3ccc(Cl)s3)c3c(OC)cccc32)c1
Reactant: C1CN=C2NCCCN2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)c1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(OC)cccc32)c1
Temperature: 110 °C
Yield: 75 %

Procedure:
Methyl 3-{[3-[[(5-chloro-2-thienyl)sulfonyl]({[2-(trimethylsilyl)ethyl]oxy}methyl)amino]-4-(methyloxy)-1H-indazol-1-yl]methyl}benzoate (for a preparation see Intermediate 31) (70 mg, 0.112 mmol) in a Biotage microwave vial was added 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (Aldrich) (7.83 mg, 0.056 mmol) and methylamine solution in THF (2M, 1.125 mL). The reaction vessel was sealed and heated in a Biotage Initiator microwave oven using initial very high absorption level to 80° C. for 75 min. The reaction mixture was diluted with DCM (2 mL) and water (3 mL). The organic phase was separated, and the aqueous layer was further extracted with DCM (2 mL). The combined organic solutions were dried through an hydrophobic frit and concentrated under a nitrogen stream in a blowdown unit. The residue was treated TBAF in THF (1M, 1.125 mL, 1.125 mmol). The reaction vessel was sealed and heated in a Biotage Initiator at 110° C. for 15 min (very high absorption level). The solvent was removed under a nitrogen stream in a blowdown unit (T=35° C. overnight), dissolved in 1:1 MeOH-DMSO (2 mL) and purified by Mass Directed AutoPrep on standard C18 column using Acetonitrile Water with a TFA modifier (Method B). The solvent was removed under a stream of nitrogen in a Radleys blowdown apparatus to give the title compound (41.7 mg, 75%) LCMS (System A) RT=1.03 min, ES+ve m/z 491/493 (M+H)+.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2Br)[CH2:15]1)([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.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:15]1)([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
Reactant: Brc1ccccc1OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: C1CNCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(C(c2ccccc2)N2CC(Oc3ccccc3N3CCNCC3)C2)cc1
Temperature: 90 °C
Yield: 54.6 %

Procedure:
1-Benzhydryl-3-(2-bromo-phenoxy)-azetidine (3.6 g, 9.16 mmol), piperazine (946 mg, 11 mmol), BINAP (427 mg, 1.38 mmol), Pd2dba3 (410 mg, 0.46 mmol) and sodium tert-butoxide (1.23 g, 12.8 mmol) were dissolved into toluene (100 mL). The solution was degassed under vacuum and bubbled with nitrogen. The vessel was sealed under nitrogen and heated to 90° C. for about 24 hours. Diethyl ether (500 ml) was added, and the solution was filtered through a bed of celite. The solution was concentrated to an orange oil. Purification by silica gel chromatography [1% NH3 in methanol/ethyl acetate (1 L), 5% NH3 in methanol/ethyl acetate (1 L), and 10% NH3 in methanol/ethyl acetate (1L)] gave the title compound as an orange powder (2.0 g, 65%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH:4]([N:15]1[C:21](=[O:22])[CH2:20][CH2:19][N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH2:17][CH2:16]1)[CH2:5][CH2:6]O[Si](C(C)(C)C)(C)C.B(Br)(Br)[Br:35]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:33])[CH:4]([N:15]1[C:21](=[O:22])[CH2:20][CH2:19][N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH2:17][CH2:16]1)[CH2:5][CH2:6][Br:35]
Reactant: COC(=O)C(CCO[Si](C)(C)C(C)(C)C)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)C(CCBr)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 9.3 %

Procedure:
A solution of 1.03 g (2.12 mmol) of (rac)-4-(tert-butyl-dimethyl-silanyloxy)-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-butyric acid methyl ester in 6 ml of CH2Cl2 was treated at 0° C. with 2.33 ml (2.33 mmol, 1M in CH2Cl2) of boron tribromide and kept 2.5 h at this temperature. The solution was warmed to RT cooled (0° C.) and treated again with 2.33 ml (2.33 mmol, 1M in CH2Cl2) of boron tribromide. After 1 h at this temperature, the reaction was extracted with cold sat. aq. NaHCO3 and EtOAc solution (3×). The organic phases were washed with sat. aq. NaHCO3 solution, dried over Na2SO4 and evaporated to give 1.14 g of the crude compound. Purification by flash silica gel column ((n-heptane:EtOAc 95:5, 1:1 to EtOAc) gave 0.086 g (11%) of the title compound as light yellow oil, MS: 437.1 (MH+, 1Br) and
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([CH2:11][CH2:12][CH2:13]2)[C@H:9]1[CH2:16][NH:17]CC1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([CH2:11][CH2:12][CH2:13]2)[C@H:9]1[CH2:16][NH2:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1CNCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1CN
Reaction time: 16 h

Procedure:
A solution of (1S,2S,5R)-2-(benzylamino-methyl)-3-aza-bicyclo[3.3.0]-octane-3-carboxylic acid tert.-butyl ester (354 mg) in EtOH (17 mL) was treated with Pd/C 10% (141 mg) and stirred under hydrogen (1 bar) for 16 h. After filtration through celite and removal of the solvents the title compound was obtained as an oil which was used without further purification.
Reaction SMILES: [C:1]([N:4]1[C@H:8]([C@H:9]([OH:12])CO)[C@@H:7]([OH:13])[CH2:6][NH:5]1)(=[O:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+].[BH4-].[Na+]>C(O)C.O>[C:1]([N:4]1[C@H:8]([CH2:9][OH:12])[C@@H:7]([OH:13])[CH2:6][NH:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1NC[C@H](O)[C@H]1[C@H](O)CO
Agent: [BH4-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCO
Product: CC(=O)N1NC[C@H](O)[C@H]1CO
Temperature: 5 °C
Yield: 75.8 %

Procedure:
A solution of 19 (80 mg, 0.42 mmol) in ethanol (5 mL) was added dropwise to a stirred solution of sodium periodate (150 mg, 0.7 mmol) in water (5 mL) at such a rate so as to maintain the reaction temperature at 5° C. On completion, sodium borohydride (135 mg, xs) was added portionwise to the resulting suspension at such a rate so as to maintain the reaction temperature at 0° C. and on complete addition the reaction was allowed to warm to r.t. Flash chromatography grade silica was added to the reaction and the resulting suspension was concentrated in vacuo to afford a white solid. The solid was purified by chromatography to afford 20 (51 mg, 76%) as a colourless oil. 1H NMR δ 4.43 (dd, J=5.7, 3.3 Hz, 1H), 3.91 (q, J=4.7 Hz, 1H), 3.75 (d, J=4.7 Hz, 1H), 3.31 (m, 1H), 3.28 (dd, J=11.8, 5.7 Hz, 1H), 2.75 (dd, J=11.8, 5.5 Hz, 1H), 2.17 (s, 3H). 13C NMR δ 173.9, 76.5, 68.2, 62.5, 55.8, 21.7. HRMS (MH+) calc. for C6H13N2O3: 161.0926. Found 161.0920.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:20]N(C)C(=O)C>>[C:3]([O:7][C:8]([N:10]([CH3:20])[C@@H:11]1[CH2:12][CH2:13][C@H:14]([C:17]([OH:19])=[O:18])[CH2:15][CH2:16]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium hydride (0.22 g) is added to a solution of cis-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (0.49 g) in N,N-dimethylacetamide (5 mL) chilled in an ice bath. The cooling bath is removed and the mixture is stirred at room temperature for 1.5 h. Then, the mixture is cooled in an ice bath and methyl iodide (0.63 mL) is added. The cooling bath is removed and the mixture is stirred at room temperature overnight. 1 M aqueous NaOH solution (6 mL) is added and the mixture is stirred at room temperature for another 12 h. Then diethyl ether is added and the aqueous phase is separated. The organic phase is extracted three times with water and the aqueous extracts and phase are combined and acidified using 2 M aqueous KHSO4 solution. The acidic aqueous phase is extracted with diethyl ether and the combined organic extracts are dried (Na2SO4). The solvent is evaporated to afford the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:15]#[C:16][Si](C)(C)C)=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:7]=1.BrCl>>[Br:1][C:2]1[C:3]([C:15]#[CH:16])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: C[Si](C)(C)C#Cc1ncc(-c2ccc(Cl)cc2)cc1Br
Agent: ClBr
Product: C#Cc1ncc(-c2ccc(Cl)cc2)cc1Br

Procedure:
The product was prepared analogously to Example 7.1d starting from 3-bromo-5-(4-chlorophenyl)-2-trimethylsilanylethynylpyridine. Yield: 0.44 g (55% of theoretical); C13H7BrClN (M=292.558); calc.: molpeak (M+H)+: 292/294/296 (BrCl); found: molpeak (M+H)+: 292/294/296 (BrCl); HPLC-MS: 6.21 minutes (method B).
Reaction SMILES: [N+:1]([C:4]1[C:14]([N+:15]([O-])=O)=[CH:13][C:12]2[CH:11]3[CH2:18][CH:7]([CH2:8][N:9]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:10]3)[C:6]=2[CH:5]=1)([O-])=O>CO.[OH-].[OH-].[Pd+2]>[NH2:1][C:4]1[C:14]([NH2:15])=[CH:13][C:12]2[CH:11]3[CH2:18][CH:7]([CH2:8][N:9]([C:19](=[O:24])[C:20]([F:23])([F:21])[F:22])[CH2:10]3)[C:6]=2[CH:5]=1
Reactant: O=C(N1CC2CC(C1)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc12)C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Nc1cc2c(cc1N)C1CC2CN(C(=O)C(F)(F)F)C1

Procedure:
1-(4,5-Dinitro-10-aza-tricyclo[6.3.1.02,7 ]dodeca-2(7), 3,5-trien-10-yl)-2,2,2-triflouro-ethanone (3.0 g, 8.70 mmol) was hydrogenated in MeOH (30 ml) under H2 (45 psi) over Pd(OH)2 (300 mg of 20 wt %/C, 10% wt). After 2.5 hours the reaction was filtered through a Celite pad and rinsed with MeOH (30 ml). The solution was concentrated to a light brown oil which crystallized (2.42 g, 96% ). (TLC 10% MeOH/CH2Cl2 Rf0.56). APCl MS m/e 286.2[(M+1)+]. mp 129-131° C.