Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5](/[CH:6]=[CH:7]/[C:8]2[CH:16]=[CH:15][C:11]([N:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1C[O:22][CH2:21]C1.[Li]CCCC>CN(C=O)C>[CH3:13][N:12]([CH3:14])[C:11]1[CH:15]=[CH:16][C:8]([CH:7]=[CH:6][C:5]2[CH:17]=[CH:18][C:2]([CH:21]=[O:22])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: CN(C)c1ccc(/C=C/c2ccc(Br)cc2)cc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: CN(C)c1ccc(C=Cc2ccc(C=O)cc2)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a round bottom flask compound 17 (300 mg, 1 mmol) was transferred followed by THF (5 mL). The heterogeneous solution was cooled at −78° C. and n-BuLi (1.6M in hexane, 1 mmol) was added dropwise over 5 min, followed by DMF (1.5 mL). The reaction mixture was stirred at −78° C. for 3 hours then it was quenched by water (1 mL) and the mixture was extracted with ether (2×25 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated under reduced pressure to give compound 18. 18: 60% yield; yellow powder; 1H NMR (400 MHz, CDCl3) δ9.96 (s, 1H), 7.83 (d, 2H, J=8.2 Hz), 7.60 (d, 2H, J=8.2 Hz), 7.44 (d, 2H, J=8.8 Hz), 7.22 (d, 1H, J=16.2 Hz), 6.94 (d, 1H, J=16.2 Hz), 6.72 (d, 2H, J=8.8 Hz), 3.01 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 191.8, 150.8, 144.7, 134.7, 134.6, 132.7, 130.4, 128.4, 126.4, 124.9, 122.8, 112.4, 40.5; HRMS calc for C17H17NO 252.1384 found 252.1383.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH:15]=O)=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:29]([NH:32][CH3:33])([CH3:31])[CH3:30]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH2:15][N:32]([CH:29]([CH3:31])[CH3:30])[CH3:33])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CNC(C)C
Reactant: CCOC(=O)c1c(C=O)c2cc(F)ccc2n1Cc1cccc2ccccc12
Product: CCOC(=O)c1c(CN(C)C(C)C)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
5-Fluoro-3-formyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (from Example 76.1.) was reacted with i-propylmethyl amine as described in Example 86.1. to give 5-fluoro-3-[(isopropyl-methyl-amino)-methyl]-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a colorless solid. MS: 403.5 ([M−H]−).
Reaction SMILES: CC1C=C(C=C([N+]([O-])=O)C=1)C(O)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=1)[C:19]([O:21]C)=[O:20].[OH-].[Na+]>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=1)[C:19]([OH:21])=[O:20]
Reactant: COC(=O)c1cc(OC)cc([N+](=O)[O-])c1
Agent: Cc1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(C(=O)O)cc([N+](=O)[O-])c1

Procedure:
Using a procedure analogous to that described for the preparation of 89B, 93B was reacted with sodium hydroxide to give 93C. LC/MS 198 (M+H).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:27]([O:30][C:31]1[CH:40]=[C:39]([CH3:41])[C:38]([Br:42])=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34])(=[O:29])[CH3:28]>C(Cl)(Cl)(Cl)Cl>[C:27]([O:30][C:31]1[CH:40]=[C:39]([CH2:41][Br:8])[C:38]([Br:42])=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34])(=[O:29])[CH3:28]
Reactant: COC(=O)c1cc(Br)c(C)cc1OC(C)=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(CBr)cc1OC(C)=O

Procedure:
NBS (0.71 g, 4.01 mmol) and benzoyl peroxide (0.07 g, 0.20 mmol) were added to a solution of methyl 2-(acetyloxy)-5-bromo-4-methylbenzoate (may be prepared as described in Description 3; 1.15 g, 4.01 mmol) in carbon tetrachloride (20 ml). The mixture was heated at reflux for 18 hours, cooled and the solvent removed in vacuo. Purification by SP4 (10-20% ethyl acetate/hexane) yielded the title compound as a pale yellow oil. 1.38 g.
Reaction SMILES: CO[C:3]([C:5]1[C:10]([NH:11][C:12](=[O:23])[CH2:13][C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=2[Cl:22])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].O.Cl>CN(C)C=O>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[C:13]1[C:12](=[O:23])[NH:11][C:10]2=[N:9][CH:8]=[CH:7][N:6]=[C:5]2[C:3]=1[OH:4]
Reactant: COC(=O)c1nccnc1NC(=O)Cc1c(F)ccc(F)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2nccnc2c(O)c1-c1c(F)ccc(F)c1Cl
Reaction time: 16 h
Yield: 76.6 %

Procedure:
3-[2-(2-Chloro-3,6-difluoro-phenyl)-acetylamino]-pyrazine-2-carboxylic acid methyl ester (4.15 g) (Example 1.1) was heated with potassium carbonate (1.67 g) in N,N-dimethylformamide (50 ml) at 110° C. for 2 hours and then stored at ambient temperature for 16 hours. Water was added and the reaction mixture was acidified with aqueous hydrochloric acid (concentrated). A precipitate formed which was isolated by filtration. The residue was washed successively with water and hexane to produce 7-(2-chloro-3,6-difluoro-phenyl)-8-hydroxy-5H-pyrido[2,3-b]pyrazin-6-one as a brown solid (2.88 g). 1H-NMR (400 MHz, d6-DMSO): 7.34-7.42 (m, 1H), 7.51-7.59 (m, 1H), 8.59 (d, 1H), 8.72 (d, 1H), 12.0 (bs, 1H), 12.4 (s, 1H) ppm.
Reaction SMILES: [N:1]([CH:4]([O:16][CH2:17][CH2:18][O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O)=[N+:2]=[N-:3].C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)C(=O)C1.FC(F)(F)C(O)=O.[NH2:51][CH2:52][CH2:53][NH:54][C:55](=[O:60])[C:56]([F:59])([F:58])[F:57].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][O:19][CH2:18][CH2:17][O:16][CH:4]([N:1]=[N+:2]=[N-:3])[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10](=[O:12])[NH:51][CH2:52][CH2:53][NH:54][C:55](=[O:60])[C:56]([F:59])([F:58])[F:57])[CH:8]=1)[CH3:25]
Reactant: NCCNC(=O)C(F)(F)F
Reactant: CCOC(=O)COCCOC(COc1cccc(C(=O)O)c1)N=[N+]=[N-]
Agent: CN(C)c1ccncc1
Agent: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COCCOC(COc1cccc(C(=O)NCCNC(=O)C(F)(F)F)c1)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.5 %

Procedure:
3-[2-Azido-2-(2-ethoxycarbonylmethoxy-ethoxy)-ethoxy]-benzoic acid (0.212 g, 0.6 mmol) was stirred with N,N′-disuccinimidyl carbonate (0.184 g, 0.72 mmol) and DMAP (0.088 g, 0.72 mmol) in dry DMF (1 ml) at room temperature. After 10 minutes, trifluoroacetic acid salt of N-(2-amino-ethyl)-2,2,2-trifluoro-acetamide (0.194 g, 0.72 mmol) was added followed by diisopropylethylamine (DIPEA) (0.251 ml, 1.44 mmol). The reaction mixture was then stirred at room temperature for 17 hours. All the solvents were evaporated under reduced pressure and the residues were partitioned between DCM (50 ml) and aqueous NaH2PO4 (1 N, 50 ml). The aqueous layer was further extracted with DCM (2×25 ml). All the DCM extracts were combined, dried over MgSO4 and evaporated under reduced pressure. The residue was purified by column chromatography (1×20 cm). The title compound, eluted with 1% methanol in DCM, was obtained as an oil (0.255 g, 86.6%). ES-MS, m/z 490.10 (M−1).
Reaction SMILES: C(N)C1C=CC=CC=1.C(OC([NH:19][C@H:20]([C:22]([NH:24][C@H:25]([P:27](=[O:30])([OH:29])[OH:28])[CH3:26])=[O:23])[CH3:21])=O)C1C=CC=CC=1>>[NH2:19][C@H:20]([C:22]([NH:24][C@H:25]([P:27](=[O:28])([OH:30])[OH:29])[CH3:26])=[O:23])[CH3:21]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)P(=O)(O)O
Solvent: NCc1ccccc1
Product: C[C@H](N)C(=O)N[C@@H](C)P(=O)(O)O

Procedure:
In a manner analogous to Example 10(b), starting from the benzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-L-alanyl)-amino]-ethylphosphonic acid there was obtained (1R)-1-(L-alanylamino)-ethylphosphonic acid of melting point 295°-296° C (decomposition); [α]D20 = -45.6° (c = 1% in water).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[CH2:16]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([CH:33]([CH3:35])[CH3:34])=[CH:26][C:27]([CH3:32])([CH3:31])[O:28]2)=[CH:23][C:22]=1[C:36](=O)[CH3:37])[CH2:17][CH2:18][CH3:19]>>[CH2:16]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([CH:33]([CH3:35])[CH3:34])=[CH:26][C:27]([CH3:32])([CH3:31])[O:28]2)=[CH:23][C:22]=1/[C:36](/[CH3:37])=[C:6](/[F:7])\[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:17][CH2:18][CH3:19]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CCCCOc1cc2c(cc1C(C)=O)C(C(C)C)=CC(C)(C)O2
Product: CCCCOc1cc2c(cc1/C(C)=C(/F)C(=O)OCC)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (0.44 mL, 1.75 mmol) and 1-(7-butoxy-4-isopropyl-2,2-dimethyl-2H-chromen-6-yl)-ethanone (Compound 65, 184 mg, 0.58 mmol) were reacted to give the title compound as a pink oil after purification by flash chromatography (silica gel, 1:9 ethyl acetate/hexane).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.CCN(C(C)C)C(C)C.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CN(C=O)C>[N+:12]([C:4]1[CH:3]=[C:2]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(Br)cc(C(F)(F)F)c1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(N2CCOCC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 50 %

Procedure:
Dissolve 1-bromo-3-nitro-5-(trifluoromethyl)benzene (270 mg, 1 mmol) and DIEA (258 mg, 2 mmol) in DMF (5 mL), add morpholine (174 mg, 2 mmol). Stir the reaction at 120° C. overnight. Cool to room temperature; remove the volatiles under reduced pressure to give a crude residue. Purification of the residue by chromatography (silica gel, EtOAc:PE=1:5) affords the product (138 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:20]([O:23][C@@H:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[C:7]([CH3:17])=[C:6]1[CH3:18].Cl.[CH:31]([C:34]1[CH:35]=[C:36]([C@@H:40]([NH2:42])[CH3:41])[CH:37]=[CH:38][CH:39]=1)([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCN(C(C)C)C(C)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:20]([O:23][C@@H:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14](=[O:15])[NH:42][C@H:40]([C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([CH:31]([CH3:33])[CH3:32])[CH:35]=3)[CH3:41])=[CH:11][CH:12]=2)[C:7]([CH3:17])=[C:6]1[CH3:18]
Reactant: COC(=O)[C@H](C)Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](C)Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1
Reaction time: 15 h

Procedure:
The (S)-1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid (71 mg, 0.17 mmol), the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride (53 mg, 0.27 mmol) and HATU (88 mg, 0.23 mmol) were dissolved in DMF (3 mL) and DIEA (0.15 mL). It was stirred for 15 h. The solution was filtered and purified by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([CH2:8][C:9]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:10])=[O:7])([CH3:4])[CH3:3].[CH3:19][CH2:20][C:21](=O)[CH2:22][C:23](=O)[CH2:24][CH3:25].C[O-].[Na+]>CO>[CH2:20]([C:21]1[CH:22]=[C:23]([CH2:24][CH3:25])[C:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[C:9]([OH:10])[C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:19]
Reactant: CC(C)(C)OC(=O)CC(=O)CC(=O)OC(C)(C)C
Reactant: CCC(=O)CC(=O)CC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1cc(CC)c(C(=O)OC(C)(C)C)c(O)c1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
A mixture of di-tert-butyl 1,3-acetonedicarboxylate (10 g, 38.7 mmol), 3,5-heptanedione (6.5 g, 50.3 mmol) and sodium methoxide (2.7 g, 50.3 mmol) in methanol (100 mL) was stirred at room temperature overnight. Methanol was removed via rotary evaporation and the resulting orange sludge was partitioned between diethyl ether (100 mL) and 10% aqueous hydrochloric acid (100 mL). The separated aqueous layer was extracted with diethyl ether (50 mL×2). The combined organic portions were washed with saturated aqueous sodium chloride (20 mL), dried over sodium sulfate, filtered through a pad of silica (20 mm×40 mm) and concentrated in vacuo to yield a yellow oil (13.23 g, 97%): 1H NMR (300 MHz, CDCl3): δ 1.20 (t, 6H), 1.60 (s, 18H) 2.74 (q, 4H), 6.55 (s, 1H), 11.73 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:25]=[C:26]([O:28][CH:29]([CH3:31])[CH3:30])[CH:27]=1)[O:8][CH2:9][C@@H:10]1[C@:19]2([CH3:20])[C@H:14]([C:15]([CH3:22])(C)[CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12][C@@:11]1([CH3:24])O)[CH3:3].Cl[Sn](Cl)(Cl)Cl.[CH2:37](Cl)Cl>>[CH3:24][C@@:11]12[CH2:12][CH2:13][C@@H:14]3[C@:15]([CH3:22])([CH2:16][CH2:17][CH2:18][C:19]3([CH3:20])[CH3:37])[C@H:10]1[CH2:9][O:8][C:7]1[C:25]2=[C:26]([O:28][CH:29]([CH3:30])[CH3:31])[CH:27]=[C:5]([O:4][CH:2]([CH3:3])[CH3:1])[CH:6]=1
Reactant: ClCCl
Reactant: CC(C)Oc1cc(OC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)cc(OC(C)C)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Product: CC(C)Oc1cc2c(c(OC(C)C)c1)[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CO2
Temperature: -78 °C
Yield: 23 %

Procedure:
To a solution of (1S,2R,4aS,8aS)-1-[3,5-bis(propan-2-yloxy)phenoxy-methyl]-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (48) (0.90 g, 2.1 mmol) in CH2Cl2 (20 mL), cooled to −78° C., a solution of SnCl4 (0.97 mL, 8.3 mmol) in CH2Cl2 (10 mL) was added dropwise. The temperature was maintained at −78° C. for 4 h, after which the reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched with water (50 mL). The organic layer was separated, dried (Na2SO4) and concentrated. Purification by column chromatography on silica gel (Hexanes/toluene, 1:1) gave (1R,10R,11S,16S)-1,11,15,15-tetramethyl-3,5-bis(propan-2-yloxy)-8-oxatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene (Compound No. 49) (0.20 g, 23%) as a tan solid. 1H NMR (CDCl3): δ 5.95 (d, 1H), 5.87 (d, 1H), 4.50 (m, 1H), 4.40 (m, 1H), 4.22 (m, 1H), 3.95 (t, 1H), 3.10 (m, 1H) 1.78-1.40 (m, 7H), 1.37 (m, 15H), 1.25-1.00 (m, 4H) 0.92 (s, 3H), 0.87 (s, 3H), 0.82 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH:13][C:14]([O:16][CH3:17])=[O:15])[CH2:10][C@@H:9]1[C@H:18]1[O:22][C:21]([CH3:24])([CH3:23])[N:20]([C:25](=[O:27])[CH3:26])[C@H:19]1[CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:10][C@@H:9]1[C@H:18]1[O:22][C:21]([CH3:24])([CH3:23])[N:20]([C:25](=[O:27])[CH3:26])[C@H:19]1[CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C=C1C[C@H]([C@H]2OC(C)(C)N(C(C)=O)[C@H]2Cc2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC1C[C@H]([C@H]2OC(C)(C)N(C(C)=O)[C@H]2Cc2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1

Procedure:
Combine (R)-2-[(4S,5S)-3-Acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-[1-methoxycarbonyl-methylidene]-pyrrolidine-1-carboxylic acid tert-butyl ester (as mixture of isomers Z/E) (0.010 g, 0.02 mmol), 10% palladium on carbon (4 mg) and methanol (2 mL) and stir for 3 hours under 1 atmosphere of hydrogen. Add filter agent, filter and concentrate under reduced pressure to provide the desired compound as a mixture of cis and trans isomers, (0.01 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](B(O)O)=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1Br)=[O:23].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN1C(=O)CCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:29]4[CH:28]=[N:27][CH:26]=[CH:25][C:24]=4[C:22]([O:21][CH3:20])=[O:23])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccncc1Br
Reactant: OB(O)c1ccnc2c1cnn2-c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccncc1-c1ccnc2c1cnn2-c1ccc(F)cc1
Yield: 21.2 %

Procedure:
Example 12 was prepared according to the general procedure of Example 1, except that the reaction mixture was heated at 105° C. for 1 h in a mixture of NMP (1.0 mL) and water (50 μL) and using the following materials: Intermediate 5A (49.4 mg, 0.192 mmol), 3-bromopyridine-4-carboxylic acid methyl ester (0.035 mL, 0.268 mmol), potassium carbonate (93 mg, 0.671 mmol), and PdCl2(dppf).CH2Cl2 (9 mg, 0.012 mmol). Example 12 was isolated as a tan solid (14.2 mg, 19.8%). Purification was done by preparative HPLC (Condition A) using a Phenomenex Luna Axia 30×100 mm S10 column from 30% Solvent B to 100% Solvent B over 12 min, ret. T=10.7 min. LC/MS (Condition B): ret. T=3.6 min, (M+H)+ 349.14. Analytical HPLC: (Condition A): >90%, ret. T=22.18 min, (Condition B): >95%, ret. T=22.85 min, (Condition C): >95%, ret. T=17.14 min, (Condition D): >95%, ret. T=13.96 min.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[C:26]([C:27](=[O:36])[C:28](=[N+:34]=[N-:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][C:24]([I:37])=[CH:23][N:22]=1.O>C(OC(C)C)(C)C.C(Cl)(Cl)Cl>[Cl:20][C:21]1[C:26]([C:27](=[O:36])[C:28](=[N:34][NH2:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][C:24]([I:37])=[CH:23][N:22]=1
Reactant: CCOC(=O)C(=[N+]=[N-])C(=O)c1cc(I)cnc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(C)OC(C)C
Product: CCOC(=O)C(=NN)C(=O)c1cc(I)cnc1Cl
Reaction time: 18 h
Yield: 70.8 %

Procedure:
Triphenylphosphine(1.95 g) is added in one portion to a solution of ethyl 3-(2-chloro -5-iodo-3-pyridinyl)-2-diazo-3-oxopropanoate (Preparation 19, 2.57 g) in diisopropyl ether (25 mL) and chloroform (15 mL) at room temperature. The yellow solution is stirred under nitrogen for 18 h. The mixture is then treated with water (0.125 mL), heated to reflux for 2 h, and then stirred overnight at room temperature. The mixture is filtered, and the solids are washed with hexane and dried to give 1.83 g of the title compound. After concentration, the filtrate is purified by flash chromatography on silica gel eluted with 10% ethyl acetate/hexane to provide an additional 0.36 g to yield a combined total of 2.19 g (85%) of the title compound as a pale yellow solid. Physical characteristics: 1H NMR (300 MHz, CDCl3) δ 1.39, 1.63, 4.38, 7.94, 8.63; IR (drift) 3378, 3182, 1675, 1651, 1568, 1564, 1483, 1324, 1303, 1286, 1199, 923, 770, 664, 620 cm−1; MS (ESI+) m/z 382 (M+H)+. Anal. Found: C, 31.78; H, 2.43; N, 10.91; Cl, 9.63.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)([C:13]([F:16])([F:15])[F:14])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClC(Cl)C>[Cl:23][C:21]1[CH:22]=[C:17]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:18]=[C:19]([Cl:24])[CH:20]=1
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCN(Cc2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
The solution of 1-benzyl-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (5.7 g) and 1-chloroethyl chloroformate (4.4 g) in dichloroethane was heated to reflux for 3 hours. The mixture was cooled to room temperature and then concentrated under the reduced pressure. Methanol was added to the resultant residue, which was then heated with stirring at 60° C. for two hours. The mixture was cooled to room temperature, to which was then added water. The solution was washed twice with the mixed solvent of hexane and ethyl acetate (9:1). The solution was alkalized with sodium hydrogen carbonate and then extracted with ethyl acetate three times. The organic layer was combined, which was then washed with brine and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under the reduced pressure to yield 3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (4.2 g). 1H-NMR (CDCl3) δ: 2.24-2.33 (1H, m), 2.51-2.56 (1H, m), 2.97-3.07 (1H, m), 3.19-3.26 (2H, m), 3.74 (1H, d), 7.25 (2H, d), 7.35 (1H, t)
Reaction SMILES: Br[C:2]1[C:3]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:30])=[N:4][O:5][C:6]=1[C:7]1[CH:8]=[N:9][N:10]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11]=1[C:12]([F:15])([F:14])[F:13].[O:31]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[Cl:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[C:3]1[C:2]([C:33]2[CH:34]=[CH:35][O:31][CH:32]=2)=[C:6]([C:7]2[CH:8]=[N:9][N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:11]=2[C:12]([F:15])([F:14])[F:13])[O:5][N:4]=1
Reactant: OB(O)c1ccoc1
Reactant: Fc1cccc(-n2ncc(-c3onc(-c4c(F)cccc4Cl)c3Br)c2C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: Fc1cccc(-n2ncc(-c3onc(-c4c(F)cccc4Cl)c3-c3ccoc3)c2C(F)(F)F)c1
Temperature: 100 °C
Yield: 16.9 %

Procedure:
The tube was charged with 4-bromo-3-(2-chloro-6-fluorophenyl)-5-(1-(3-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole (30 mg, 0.06 mmol), tetrakis(triphenylphosphine)palladium(0) (0.010 g), 1.5 mL 1,2-Dimethoxyethane and was purged with argon. Then furan-3-ylboronic acid (0.012 g, 0.1 mmol) and an aqueous solution of cesium carbonate (0.05 g in 0.2 mL) were added. The reaction mixture was heated under microwave irradiation to 100° C. for 2 h. The solvent was evaporated and the product was isolated by column chromatography (hexane:ethyl acetate 25: I) to obtain 5 mg (17%) of a yellowish solid of example I-13. As a major side reaction, hydrodebromination was observed.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH3:22][C:23]1([CH3:33])[C@H:28]2[CH2:29][C@@H:24]1[CH2:25][CH2:26][C@H:27]2[CH2:30][CH2:31]O>C(#N)C>[CH3:22][C:23]1([CH3:33])[C@H:28]2[CH2:29][C@@H:24]1[CH2:25][CH2:26][C@H:27]2[CH2:30][CH2:31][Br:20]
Reactant: BrBr
Reactant: CC1(C)[C@H]2CC[C@@H](CCO)[C@@H]1C2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC1(C)[C@H]2CC[C@@H](CCBr)[C@@H]1C2
Temperature: 0 °C

Procedure:
15.6 g triphenylphosphine were dissolved in 300 ml acetonitrile, and 3.02 ml bromine were added to the solution in drops with vigorous stirring at a temperature of 0° C. Then a solution of 10 g cisdihydronopol (=2-((1S,2S,5S)6,6-dimethylbicyclo[3,1,1]hept-2-yl)-ethanol) in 100 ml acetonitrile was added, and the reaction mixture was heated to 100° C. (bath temperature) for 5 hours. The reaction mixture was worked up by distilling off the solvent under reduced pressure, and the residue was purified chromatographically over silica gel using dichloromethane as eluent. 12.0 g 2-((1S,2S,5S)-6,6dimethylbicyclo[3,1,1]hept-2-yl)-ethyl bromide were obtained.