Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH:17][S:18]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])(=[O:20])=[O:19])[CH:11]=1.Br[CH2:32][CH2:33][CH2:34]Br>CN(C)C=O>[CH3:7][O:8][C:9]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:34][CH2:33][CH2:32][N:17]([S:18]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[O:28][CH3:29])(=[O:19])=[O:20])[C:12]=2[CH:11]=1)=[O:30]
Reactant: COC(=O)c1ccc(O)c(NS(=O)(=O)c2cc(Cl)ccc2OC)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCCO2
Temperature: 60 °C
Yield: 89.9 %

Procedure:
Potassium carbonate (818 mg, 5.92 mmol) was added to a solution of 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoic acid methyl ester (example 30, step 1; 1.00 g, 2.69 mmol) and 1,3-dibromopropane (597 mg, 2.96 mmol) in N,N-dimethylformamide (17 mL), and the suspension was heated at 60° C. for 5 h, then the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) produced 9-(5-chloro-2-methoxy-benzenesulfonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-2-carboxylic acid methyl ester (996 mg, 90%). White solid, MS (ISP)=412.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].ClC1C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)=C2N=C(C3C=CC(CN4CCOCC4)=CC=3)NC2=NC=1.[NH2:42][C:43]1[C:48]([NH2:49])=[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])[C:46]([Cl:61])=[CH:45][N:44]=1.[CH3:62][O:63][C:64]1[CH:71]=[C:70]([N:72]2[CH2:77][CH2:76][N:75]([CH3:78])[CH2:74][CH2:73]2)[CH:69]=[CH:68][C:65]=1[CH:66]=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:61][C:46]1[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])=[C:48]2[N:49]=[C:66]([C:65]3[CH:68]=[CH:69][C:70]([N:72]4[CH2:73][CH2:74][N:75]([CH3:78])[CH2:76][CH2:77]4)=[CH:71][C:64]=3[O:63][CH3:62])[NH:42][C:43]2=[N:44][CH:45]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc(N2CCN(C)CC2)ccc1C=O
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCN(C)CC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 62 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 2-Methoxy-4-(4-methyl-piperazin-1-yl)-benzaldehyde were reacted to produce the title compound (62%). 1H NMR (d-chloroform): 13.76 (br s, 1H), 8.21 (d, J=8 Hz, 1H), 7.97 (d, J=8 Hz, 1H), 7.80 (s, 1H), 6.62 (d, J=8 Hz, 1H), 6.47 (s, 1H), 6.46 (m, 1H), 6.42 (br s, 1H), 6.07 (br s, 1H), 5.40 (t, J=9 Hz, 1H), 4.11 (s, 3H), 3.65-3.90 (m, 4H), 3.40-3.60 (m, 2H), 3.16 (s, 1H), 3.03 (m, 1H), 2.99 (s, 1H), 2.92 (s, 3H), 2.72) d, J=8 Hz, 1H), 2.32 (d, J=9 Hz, 1H), 1.80-2.10 (m, 2H), 1.68 (d, J=9 Hz, 1H). MS: 509.14 (M+H). HPLC retention time: 1.82 minutes (G Method).
Reaction SMILES: [CH:1]1[N:6]=[C:5]([NH2:7])[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][O:17][P:18]([O:21][P:22]([O:25][P:26]([O-:29])([OH:28])=[O:27])([O-:24])=[O:23])([OH:20])=[O:19])[C@@H:13]([OH:30])[C@H:12]3[OH:31])[C:3]=2[N:2]=1.[Na+].[Na+].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[P:18]([O:17][CH2:16][C@H:14]1[O:15][C@@H:11]([N:10]2[C:3]3[N:2]=[CH:1][N:6]=[C:5]([NH2:7])[C:4]=3[N:8]=[CH:9]2)[C@H:12]([OH:31])[C@@H:13]1[OH:30])([O:21][P:22]([O:25][P:26]([OH:28])([OH:29])=[O:27])([OH:24])=[O:23])(=[O:19])[OH:20]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)([O-])OP(=O)([O-])O)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
Adenosine-5'-triphosohate: ATP disodium salt (A 7699) was purchased from Sigma Chemical Company Ltd., Poole, Dorset U.K. Brain Heart Infusion Broth (BHI)--Unipath Ltd. was used to grow the inoculum. Serial dilutions of broth culture were made using 0.1M potassium phosphate buffer (pH 7).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][N:11]=2)=[CH:6][CH:5]=1.[BH4-].[Na+]>CO>[F:21][C:2]([F:1])([F:20])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][NH:11]2)=[CH:8][CH:9]=1
Reactant: FC(F)(F)Oc1ccc(C2=NCCc3ccccc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: FC(F)(F)Oc1ccc(C2NCCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The above 1-(4-trifluoromethoxyphenyl)-3,4-dihydro-isoquinoline (0.40 g, 1.4 mmol) was dissolved in methanol (20 mL) and sodium borohydride (0.08 g, 2.1 mmol) was added slowly. The reaction mixture was stirred at room temperature for 2.5 hours. The mixture was evaporated in vacuo, redissolved in 1 N NaOH (20 mL) and extracted with dichloromethane (50 mL). The organic phase was dried (MgSO4), filtered and evaporated in vacuo. The remaining oil (0.35 g) was purified by column chromatography on silica gel eluting with a mixture of dichloromethane and methanol (9:1). This afforded 0.56 g (56%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1.IC[C@H]1CCN(C(OC(C)(C)C)=O)C1>>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Cc2cccc(F)c2)C1
Agent: CC(C)(C)OC(=O)N1CC[C@H](CI)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](Cc2cccc(F)c2)C1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 99 starting with tert-butyl (S)-3-iodomethylpyrrolidine-1-carboxylate (Intermediate 118).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)[CH3:3].[NH2:19][C:20]1[N:25]=[C:24]([NH2:26])[C:23]([C:27]#[N:28])=[C:22](Cl)[N:21]=1.CCN(CC)CC>C(#N)C>[NH2:19][C:20]1[N:25]=[C:24]([NH2:26])[C:23]([C:27]#[N:28])=[C:22]([NH:1][CH:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[N:14]2[CH2:17][CH:16]([OH:18])[CH2:15]2)[CH3:3])[N:21]=1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Reactant: CC(N)c1nc2ccn(C)c2cc1N1CC(O)C1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1N1CC(O)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 4.3 %

Procedure:
To a 10 mL vial were added 1-(5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)azetidin-3-ol (75 mg, 0.304 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (62.0 mg, 0.365 mmol) and Et3N (0.085 mL, 0.61 mmol) in acetonitrile (2 mL). The resulting yellow solution was heated to 90° C. and stirred overnight. The crude product was purified by preparative HPLC eluting with 20-40% ACN in water (with 0.05% ammonium bicarbonate). The fractions containing the desired product were combined and lyophilized to give the title compound as a pale yellow solid (5 mg, 5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30-1.40 (m, 4 H), 3.47-3.58 (m, 1 H), 3.67-3.75 (m, 1 H), 3.75-3.80 (m, 4 H), 4.05-4.14 (m, 1 H), 4.20-4.33 (m, 1 H), 4.51-4.63 (m, 1 H), 5.40-5.53 (m, 1H), 5.57-5.68 (m, 1 H), 6.38-6.53 (m, 3 H), 6.54-6.66 (m, 2 H), 6.76-6.86 (m, 1 H), 7.10-7.20 (m, 1 H), 7.36-7.46 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C18H21N9O, 380; found 380.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24]1([CH2:30][C:31](O)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH2:30][C:31]([O:23][C@@:9]2([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12][C@@H:13]3[C@H:8]2[CH2:7][CH2:6][N:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: O=C(O)Cc1ccccc1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)Cc1ccccc1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and phenyl-acetic acid to yield (3aR,4S,7aR)-methyl 4-(2-phenylacetoxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester elimination ion); RT=7.221 min; LC-MS Method II
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][CH2:7]2)[N:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:4][N:3]1[C:29]1[CH:41]=[CH:40][CH:39]=[CH:38][C:30]=1[C:31]([O:33]C(C)(C)C)=[O:32]>Cl.O1CCOCC1>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:11]2)[N:5]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:4][N:3]1[C:29]1[CH:41]=[CH:40][CH:39]=[CH:38][C:30]=1[C:31]([OH:33])=[O:32]
Reactant: CC(C)(C)OC(=O)c1ccccc1N1CN(c2ccccc2)C2(CCN(CCCC(=O)c3ccccc3)CC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CCCN1CCC2(CC1)C(=O)N(c1ccccc1C(=O)O)CN2c1ccccc1)c1ccccc1
Yield: 43.4 %

Procedure:
A solution of tert-butyl 2-(4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoate (410 mg, 0.741 mmol, 1 equiv) in 4M hydrogen chloride solution in dioxane was stirred at ambient temperature for 5 h. The mixture was concentrated in vacuo and purified using preparative thin layer chromatography in 10% methanol in dichloromethane. The isolated mixture was treated with 4M hydrogen chloride solution in dioxane to afford the hydrogen chloride salt of the title compound as a white powder (160 mg, 43.5%); 1H NMR (400 MHz, DMSO-d6): δ 2.05-2.08 (m, 4H); 3.04 (m, 2H); 3.16 (m, 2H); 3.22 (t, 2H, J=6.8 and 7.4 Hz); 3.56-3.71 (m, 4H); 5.10 (s, 2H); 6.84 (t, 1H, J=7.2 Hz); 7.14 (s, 1H); 7.16 (s, 1H); 7.25-7.29 (m, 2H); 7.52-7.57 (m, 3H); 7.63-7.68 (m, 2H); 7.71-7.75 (m, 1H); 7.94 (dd, 1H, J=1.2 Hz); 7.98-8.00 (m, 2H); 10.61 (bs, 1H); 13.22 (bs, 1H); MS for C30H31N3O4 m/z 498.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[NH:29][C:28]([CH2:30][CH:31]3[CH2:35][CH2:34][O:33][CH2:32]3)=[N:27][N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].O1CCC(C(NN)=O)CC1.O1CCC(CC(NN)=O)C1>>[CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[NH:29][C:28]([CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[N:27][N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: Cc1cc(C)c(-c2nnc(CC3CCOC3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: NNC(=O)C1CCOCC1
Agent: NNC(=O)CC1CCOC1
Product: Cc1cc(C)c(-c2nnc(C3CCOCC3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), using tetrahydro-2H-pyran-4-carbohydrazide (compound 137.2) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+) 470 (M+H)+.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CC[O:19]CC1.ClC(OCC(C)C)=O.C(N1[C:40]([NH2:41])=[C:39]([NH2:42])[C:37](=[O:38])N(CC=C)C1=O)C=C>O1CCCC1.C(OCC)C>[C:1]1([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:1]([CH:7]1[C:11](=[O:19])[CH:10]([CH2:9][CH:8]=[CH2:12])[C:37](=[O:38])[C:39]([NH-:42])=[C:40]1[NH2:41])[CH:2]=[CH2:3]
Reactant: C=CCn1c(N)c(N)c(=O)n(CC=C)c1=O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)[C@@H]1CCC[C@H]1c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC1C(=O)C([NH-])=C(N)C(CC=C)C1=O
Temperature: 25 °C
Yield: 87.8 %

Procedure:
Dissolve trans-2-phenyl-cyclopentanecarboxylic acid (1.0 g, 5.3 mmol), prepared according to F. G. Bordwell and J. Almy, J. Org. Chem., 38, 571 (1973), in tetrahydrofuran (20 ml) and add N-methylmorpholine (0.58 ml, 5.3 mmol). Cool the reaction to -20° C. and add isobutyl chloroformate (0.69 ml, 5.3 mmol). Stir the reaction for 30 minutes, add 1,3-diallyl-5,6-diaminouracil (1.2 g, 5.3 mmol, in 4 ml dimethylformamide) and stir at -20° C. for 3 hours. Warm to room temperature and dilute the reaction with diethyl ether (400 ml). Separate the layers and rinse the organic layer with saturated sodium bicarbonate (2×200 ml), 50% aqueous sodium chloride (2×300 ml), dry over anhydrous magnesium sulfate, filter and concentrate under vacuum. Purify the residue by radial chromatography (2% to 5% methanol/chloroform, 2 mm plate) to provide trans-2-phenyl-cyclo-pentanecarboxylic acid (3,5-diallyl-2-amino-4,6-dioxo-cyclohex-1-enylamide (0.51 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH2:11][CH3:12])[C:5]([C:6]([OH:8])=O)=[C:4]([CH2:13][CH3:14])[CH:3]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Cl:48][C:49]1[CH:56]=[CH:55][C:52]([CH2:53][NH2:54])=[CH:51][CH:50]=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:13][CH3:14])[C:5]([C:6]([NH:54][CH2:53][C:52]2[CH:55]=[CH:56][C:49]([Cl:48])=[CH:50][CH:51]=2)=[O:8])=[C:9]([CH2:11][CH3:12])[CH:10]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCc1cc(Br)cc(CC)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cc(Br)cc(CC)c1C(=O)NCc1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 75 %

Procedure:
To a solution of 4-bromo-2,6-diethyl-benzoic acid (0.30 g, 1.20 mmol) in dichloromethane (3.6 ml) are added diisopropylethylamine (0.58 ml, 3.56 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.54 g, 1.42 mmol) at 0° C. and the mixture is stirred for 20 min followed by the addition of 4-chloro-benzyl amine (0.17 ml, 1.42 mmol). The resulting mixture is stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC) the reaction mixture is diluted with dichloromethane (20 ml) and washed with water (30 ml). The organic layer is dried over sodium sulfate and concentrated in vacuo. The resulting crude product is purified column chromatography (silica gel, 25% ethyl acetate/hexane) to obtain 4-bromo-N-[(4-chlorophenyl)-methyl]-2,6-diethyl-benzamide (0.34 g, 0.90 mmol, 75%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[N:5][O:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[OH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:35]=[C:34]3[C:29]([CH:30]=[CH:31][C:32]([C:36]([O:38][CH3:39])=[O:37])=[CH:33]3)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[C:4]1[C:3]([CH2:2][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:35]=[C:34]4[C:29]([CH:30]=[CH:31][C:32]([C:36]([O:38][CH3:39])=[O:37])=[CH:33]4)=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)=[C:7]([CH:8]([CH3:10])[CH3:9])[O:6][N:5]=1
Reactant: COC(=O)c1ccc2ccc(-c3ccc(O)cc3)cc2c1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc2c1
Yield: 79.3 %

Procedure:
A solution of 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (0.12 g, 0.36 mmol), methyl 7-(4-hydroxyphenyl)-2-naphthalenecarboxylate (0.084 g, 0.30 mmol), and cesium carbonate (137 mg, 0.42 mmol) in dimethylformamide (0.73 mL) was heated to 65° C. for 3 hours. The solution was partitioned between ethyl acetate and water. The organic layer was dried with magnesium sulfate, filtered and concentrated. The filtrate was purified by chromatography (silica gel, hexane to 3:7 ethyl acetate:hexanes) to provide the title compound (0.130 g, 68.4% as 1.0 ethyl acetate). 1H NMR (DMSO-d6): 8.66 (s, 1H), 8.34 (s, 1H), 8.04-8.00 (m, 2H), 7.94-7.90 (m, 2H), 7.69 (d, J=9 Hz, 2H), 7.62 (d, J=8 Hz, 2H), 7.55-7.51 (m, 1H), 6.91 (d, J=9 Hz, 2H), 4.87 (s, 2H), 3.90 (s, 3H), 3.46 (septet, J=7 Hz, 1H), 1.33 (d, J=7 Hz, 6H). ESI-LCMS m/z 546 (M+H)+.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@@H:18]([CH2:20][N:21]=[N+:22]=[N-:23])[O:17][C:16]3=[O:24])=[CH:11][C:10]=2[F:25])[CH2:5][CH:4]1[F:26].CSC.C(Cl)(=O)C>>[O:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@@H:18]([CH2:20][N:21]=[N+:22]=[N-:23])[O:17][C:16]3=[O:24])=[CH:11][C:10]=2[F:25])[CH2:5][CH:4]1[F:26]
Reactant: COC1(OC)CCN(c2ccc(N3C[C@@H](CN=[N+]=[N-])OC3=O)cc2F)CC1F
Solvent: CC(=O)Cl
Solvent: CSC
Product: [N-]=[N+]=NC[C@@H]1CN(c2ccc(N3CCC(=O)C(F)C3)c(F)c2)C(=O)O1
Temperature: 40 °C
Reaction time: 96 h
Yield: 69 %

Procedure:
To the mixture of (S)-{3-[4-(4,4-dimethoxy-3-fluoropiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-azide (0.5 mmol), freshly fused zinc chloride (1.5 mmol), dimethyl sulphide (2.5 mmol), acetyl chloride (1.5 mmol) in tetrahydrofuaran (50 ml) was stirred at 40° C. for 4 days. To this reaction mixture extracted with the ethyl acetate water mixture and organic layer was dried over sodium sulfate. The removal of the solvent afforded a residue, which was chromatographed over silica gel afforded title compound in 69% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[C:10]1(B2OC(C)(C)C(C)(C)O2)[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=2)[CH:3]=1
Reactant: Nc1ccc(Br)cc1I
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
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: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1ccc(Br)cc1C1=CCCCC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 86.9 %

Procedure:
To a mixture of 4-bromo-2-iodo-phenylamine (2.00 g, 6.71 mmol), 2-cyclohex-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.40 g, 6.71 mmol) and Pd(PPh3)4 (388 mg, 0.336 mmol) in 40 mL of 1,4-dioxane was added 2.0 M aq Na2CO3 solution (26.8 mL, 53.7 mmol). After stirring at 80° C. for 5 h under Ar, the reaction was cooled to RT. The mixture was treated with EtOAc (100 mL), washed with H2O (3×30 mL) and brine (20 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (10-20% EtOAc/hexane) to give 1.47 g (87%) of the title compound as a light brown oil. Mass spectrum (ESI, m/z): Calcd. for C12H14BrN, 252.0 (M+H), found 252.0.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:5]=1[C:12](=[O:14])[CH3:13]>CO>[Cl:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:5]=1[CH:12]([OH:14])[CH3:13]
Reactant: CC(=O)c1c(Cl)ccc(F)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
Sodium borohydride (90 mg, 2.4 mmol) was added to a solution of 2′,6′-dichloro-3′-fluoro-acetophenone (Aldrich, catalog #52, 294-5) (207 mg, 1 mmol) in 2 mL of anhydrous CH3OH. The reaction mixture was stirred at room temperature for 1 h then was evaporated to give a colorless oil residue. The residue was purified by flash chromatography (eluting with 0→10% EtOAc in hexanes) to give compound A1 as a colorless oil (180 mg; 0.88 mmol; 86.5% yield); MS (APCI) (M-H)− 208; 1H NMR (400 MHz, chloroform-D) δ ppm 1.64 (d, J=6.82 Hz, 3H) 3.02 (d, J=9.85 Hz, 1H) 6.97-7.07 (m, 1H) 7.19-7.33 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[NH:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C1COCC1>[CH3:8][CH:4]1[NH:3][CH:2]([CH3:1])[CH2:7][N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5]1
Reactant: CCOC(=O)CBr
Reactant: CC1CNCC(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CC(C)NC(C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
To a solution of 2,6-dimethylpiperazine (500 mg, 4.378 mmol, 1.0 eq) in THF were added K2CO3 (1.2 g, 8.75 mmol, 2.2 eq.) and ethyl 2-bromoacetate (731 mg, 4.378 mmol, 1 eq). The mixture was stirred at RT for 4 h and then quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to afford the product in 34% yield (0.3 g). LC-MS (ESI): Calculated mass: 200.0; Observed mass: 201.0 [M+H]+ (rt: 0.102 min).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[I:18])=O.B.CSC.O>O1CCCC1.ClCCl.O1CCCC1>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[I:18]
Reactant: O=C(Cc1ccccc1I)Nc1ccccc1I
Agent: B
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Ic1ccccc1CCNc1ccccc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a suspension of 1.39 g (3 mmol) of 2-iodo-N-(2-iodophenyl)benzeneacetamide in 30 ml of tetrahydrofuran-dichloromethane (1:1) is added 3.75 ml of 2.0 molar borane-dimethylsulfide in tetrahydrofuran. The solution is stirred 1 hour at room temperature and then refluxed for 16 hours. The mixture is cooled and water slowly added dropwise until gas evolution ceases. The volatile are removed under vacuum and the aqueous residue made alkaline with 2N sodium hydroxide. The mixture is extracted with ether (50 ml) and the extract is washed with brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filter pad is washed with ether and the filtrate evaporated. The residual solid is washed with isooctane to give 1.20 g of white solid. Recrystallization from diethylether/hexane gives white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][CH:15]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[NH2:27]>>[F:23][C:24]1[CH:25]=[C:26]([NH:27][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COc1ccc(N)cc1F
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Cl)cc3)c2)o1
Product: COc1ccc(NC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1F

Procedure:
N-(3-Fluoro-4-methoxyphenyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carbonyl chloride and 3-fluoro-4-methoxyaniline using method K. NMR; δH [2H6]—DMSO 10.35,(1H, b), 8.04,(2H, d), 7.90,(1H, dd), 7.78-7.75,(2H, m)7.59-7.51,(4H, m), 7.17,(1H, t), 3.82,(3H, s), 2.57,(3H, s), 2.33,(3H, s). LCMS; retention time 3.50 min, MH+ 418.