Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[Na+].Br[C:14]1[CH:22]=[CH:21][C:20]2[N:19]([CH3:23])[C:18]3[CH2:24][CH:25]4[NH:29][CH:28]([C:17]=3[C:16]=2[C:15]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]4>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:14]2[CH:22]=[CH:21][C:20]3[N:19]([CH3:23])[C:18]4[CH2:24][CH:25]5[NH:29][CH:28]([C:17]=4[C:16]=3[C:15]=2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]5)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)[O-])cc1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Agent: [Na+]
Product: COc1ccc(S(=O)(=O)c2ccc3c(c2C(=O)OC(C)(C)C)c2c(n3C)CC3CCC2N3)cc1
Yield: 34 %

Procedure:
Intermediate 14 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude product was purified by flash column chromatography (8:2 hexanes/ethyl acetate) to give tert-butyl 2-(4-methoxyphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (106 mg, 34%) as a light-yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.17 (s, 1H), 7.88 (d, J=8.7 Hz, 2H), 7.60-7.71 (m, 1H), 7.27-7.32 (m, 1H), 6.92 (d, J=9.0 Hz, 2H), 5.26 (br s, 1H), 4.69 (br s, 1H), 3.82 (s, 3H), 3.59 (s, 3H), 3.40 (br s, 1H), 2.49 (d, J=16.2 Hz, 1H), 2.12-2.39 (m, 2H), 1.88-2.01 (m, 1H), 1.53-1.72 (m, 1H), 1.38 (br s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16]C2C=CC(C(N3CCC3)=O)=CC=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[C:29]([O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][C:38](Br)=[CH:37][C:36]=1[F:42])([CH3:32])([CH3:31])[CH3:30].COC(C1C=C(O)C2CC(C)(C)OC=2C=1)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:38]2[CH:39]=[CH:40][C:35]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:43])=[C:36]([F:42])[CH:37]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2)c2c(c1)OC(C)(C)C2
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1F
Agent: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Product: COC(=O)c1cc(Oc2ccc(C(=O)OC(C)(C)C)c(F)c2)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 35b, from 4-bromo-2-fluoro-benzoic acid tert-butyl ester and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e). 1H NMR (400 MHz, CDCl3) δ 7.86 (t, J=8.59 Hz, 1 H) 7.25-7.31 (m, 1 H) 7.24 (s, 1 H) 6.74 (dd, J=8.84, 2.02 Hz, 1H) 6.65 (dd, J=11.87, 2.27 Hz, 1 H) 3.88 (s, 3 H) 2.87 (s, 2 H) 1.59 (s, 9 H) 1.48 (s, 6 H); LCMS for C23H25FO6 m/z 439.00 (M+Na)+.
Reaction SMILES: C(O[C:6](=[O:31])[NH:7][C@H:8]([C:10](=[O:30])[NH:11][C@H:12]([B:17]1[O:25][C@H:24]2[C@:19]([CH3:29])([C@H:20]3[CH2:26][C@@H:22]([CH2:23]2)[C:21]3([CH3:28])[CH3:27])[O:18]1)[CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:9])(C)(C)C.[C:32]1([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][C@@H:39]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([O:52][CH3:53])[C:45]=2[O:54][CH3:55])C(O)=O)[CH:33]=1>>[C:32]1([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][C@@H:39]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([O:52][CH3:53])[C:45]=2[O:54][CH3:55])[C:6]([NH:7][C@H:8]([C:10](=[O:30])[NH:11][C@H:12]([B:17]2[O:25][C@H:24]3[C@:19]([CH3:29])([C@H:20]4[CH2:26][C@@H:22]([CH2:23]3)[C:21]4([CH3:28])[CH3:27])[O:18]2)[CH2:13][CH:14]([CH3:15])[CH3:16])[CH3:9])=[O:31])[CH:33]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reactant: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)c(OC)c1OC
Product: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)c(OC)c1OC

Procedure:
The title compound is prepared as described in example 1 but using {(S)-1-[(R)-3-Methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester and (S)-2-(Biphenyl-3-ylamino)-3-(2,3,4-trimethoxy-phenyl)-propionic acid.
Reaction SMILES: [O:1]1[CH2:6][C:5](=[O:7])[NH:4][C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[Br:12]Br>CC(O)=O>[Br:12][N:8]1[CH:3]2[C:2]([O:1][CH2:6][C:5](=[O:7])[NH:4]2)=[CH:11][CH:10]=[CH:9]1
Reactant: BrBr
Reactant: O=C1COc2cccnc2N1
Solvent: CC(=O)O
Product: O=C1COC2=CC=CN(Br)C2N1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.4 %

Procedure:
To a solution of 2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (5.00 g, 33.3 mmole) in HOAc (100 mL) was added Br2 (2.6 mL, 50.0 mmole). After stirring for 48 hours at RT, the reaction solution was concentrated to an orange solid, which was suspended in 1N NaOH (50 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine and dried over Na2SO4. Flash chromatography on silica gel (9:1 CHCl3/MeOH containing 5% NH4OH) and drying under high vacuum gave the title compound (5.49 g, 72%) as a yellow solid: MS (ES) m/e 230 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.Cl[Sn]Cl.Cl>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(-c2ccccn2)c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc(Cl)c(-c2ccccn2)c1
Temperature: 60 °C
Yield: 94.7 %

Procedure:
4-chloro-3-(pyridin-2-yl)nitrobenzene (1.47 g, 6.26 mmol) was suspended in EtOH (35 mL), and the SnCl2 (3.87 g; 20.4 mmol) and conc. HCl (5 mL) were added and rinsed in with a further 5 mLs EtOH. The solution was placed in a 40° C. oil bath and heated to 60° C. The solution was stirred at 60° C. for 1½ hr., cooled to RT and diluted with 1 N HCl (100 mL). This solution was poured into an Et2O/1 N HCl solution (100 mL:150 mL) and extracted. The aqueous layer was diluted with EtOAc (250 mL), cooled to 0° C., and made basic with 10 N NaOH (50 mL). This solution was extracted (EtOAc, 2×), and the combined organics were washed with brine and dried over Na2SO4 and charcoal. Suction filtration through celite gave a clear colorless solution which was concentrated to yield 4-chloro-3-(pyridine-2-yl)aniline (1.21 g, 5.93 mmol, 94% yield) as a cream colored crystalline solid which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([OH:11])/[CH:7]=[CH:8]\[CH2:9][OH:10].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][S:2]([O:10][CH2:9]/[CH:8]=[CH:7]\[CH2:6][O:11][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OC/C=C\CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OC/C=C\COS(C)(=O)=O
Reaction time: 3 h

Procedure:
In an ice bath, 26 ml of methanesulfonyl chloride was added dropwise in to a mixture of 10 g of cis-2-buten-1,4-diol, 63 ml of triethylamine and 1000 ml of ethyl acetate, followed by stirring at the same temperature for 3 hours. Then, the insoluble matters were removed by filtration. The filtrate was further filtered through silica gel and washed with ethyl acetate. Then, the filtrate was evaporated, to give 21.4 g of cis-1,4-bis(methanesulfonyloxy)-2-butene.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:10][CH:9]=1)=[O:6].[OH-].[NH4+:25]>>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:25])=[O:2])=[CH:9][CH:10]=1
Reactant: [NH4+]
Reactant: COC(=O)CC(=O)Nc1ccc(COc2cccc(F)c2)cc1
Agent: [OH-]
Product: NC(=O)CC(=O)Nc1ccc(COc2cccc(F)c2)cc1
Yield: 37 %

Procedure:
The title compound is prepared in analogy to example 3 from N-[4-(3-Fluoro-phenoxymethyl)-phenyl]-malonamic acid methyl ester and and ammonium hydroxide. Yield=37%. Colorless solid. MS: m/e=303.2 (M++H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.CC1C([N+]([O-])=O)=C2C(=CC=1)N=CC=C2.[NH2:27][C:28]1[N:33]=[C:32]([NH2:34])[C:31]([CH2:35]O)=[CH:30][N:29]=1.[ClH:37]>C(O)(=O)C>[ClH:37].[ClH:37].[NH2:27][C:28]1[N:33]=[C:32]([NH2:34])[C:31]([CH2:35][C:9]2[CH:10]=[C:11]([CH3:12])[C:2]([NH2:1])=[C:3]3[C:8]=2[N:7]=[CH:6][CH:5]=[CH:4]3)=[CH:30][N:29]=1
Reactant: Cc1ccc2ncccc2c1N
Reactant: Nc1ncc(CO)c(N)n1
Agent: Cc1ccc2ncccc2c1[N+](=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(Cc2cnc(N)nc2N)c2ncccc2c1N
Yield: 40 %

Procedure:
A mixture of 5-amino-6-methylquinoline (2.16 g, 13.7 mmol), prepared by reduction of 6-methyl-5-nitroquinoline (R. Long and K. Schofield, J. Chem. Soc. 1953, 2350), 2,4-diamino-5-hydroxymethylpyrimidine (1.91 g, 13.6 mmol), concentrated hydrochloric acid (1.9 mL), and glacial acetic acid was refluxed for 2 hr. The cooled reaction mixture was filtered and the precipitate washed with ether and dried (4.17 g). Recrystallization from aqueous ethanol with hydrochloric acid gave title compound as red-orange solid (2.08 g, 40%); mp >290° dec. Anal. Calcd for C15H16N6.2HCl.2H2O: C, 46.28; H, 5.70; N, 21.59; Cl, 18.21. Found: C, 46.13; H, 5.61; N, 21.66; Cl, 18.25.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C@@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[CH:27][C:28]3[NH:29][C:30]4[C:35]([C:36]=3[CH:37]=2)=[CH:34][CH:33]=[CH:32][CH:31]=4)O1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[C@@H:9]([O:8][C:5]1[N:6]=[N:7][C:2]([C:25]3[CH:26]=[CH:27][C:28]4[NH:29][C:30]5[C:35]([C:36]=4[CH:37]=3)=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:3][CH:4]=1)[CH2:10]2
Reactant: Clc1ccc(O[C@H]2CN3CCC2CC3)nn1
Reactant: CC1(C)OB(c2ccc3[nH]c4ccccc4c3c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Product: c1ccc2c(c1)[nH]c1ccc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)cc12

Procedure:
The product of Example 9A (0.173 g, 0.72 mmol) was coupled with the product of Example 38A (0.267 g, 0.91 mmol) under the catalysis of dichlorobis(triphenylphosphine)palladium(II) (Aldrich, 5.3 mg, 0.007 mmol) and 2-(dicyclohexylphosphino)biphenyl (Strem Chemicals, 7.3 mg, 0.021 mmol) at 150° C. for 10 min. according to the procedure of Example 29A. The title product was purified by preparative HPLC (Xterra™, column, Xterra RP-18 5 μm, 30×100 mm. Eluting Solvent, MeCN/H2O (NH4HCO3, 0.1 M, pH=10) (v. 40/60 to 70/30 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid. 1H NMR (300 MHz, CD3OD) δ 1.45-1.62 (m, 1H), 1.68-1.92 (m, 2H), 2.00-2.15 (m, 1H), 2.27-2.40 (m, Hz, 1H), 2.75-3.05 (m, 5H), 3.43-3.59 (m, Hz, 1H), 5.22-5.42 (m, Hz, 1H), 7.16-7.24 (m, 1H), 7.28 (d, J=9 Hz, 1H), 7.36-7.44 (m, 1H), 7.45-7.52 (m, 1H), 7.57 (d, J=8 Hz, 1H), 8.02 (dd, J=9, 2 Hz, 1H), 8.17 (t, J=9 Hz, 2H), 8.67 (s, 1H) ppm; MS (DCI/NH3) m/z 371 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15]/[C:16](/[NH2:19])=[N:17]/[OH:18])[N:13]=2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:33](Cl)(=[O:35])[CH3:34]>CC(C)=O>[C:33]([O:18]/[N:17]=[C:16](\[NH2:19])/[CH2:15][CH2:14][C:12]1[N:13]=[C:9]([NH:8][C:5]2[C:4]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[S:10][CH:11]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: N/C(CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1)=N\O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)O/N=C(\N)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
To a suspension of (Z)-3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-N′-hydroxypropanamidine (0.200 g, 0.460 mmol) and K2CO3 (0.070 g, 0.506 mmol) in acetone (5 mL), cooled in an ice bath, was added a solution of acetyl chloride (0.032 mL, 0.460 mmol) in 3 mL acetone and the mixture was allowed to slowly warm to ambient temperature. The reaction was concentrated to dryness, dissolved in CH2Cl2 and washed with water, dried over Na2SO4, and concentrated to give the title compound (0.205 g, 93.4% yield) that was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([CH3:14])[C:11](O)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].CSC.B.B>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]([CH3:14])[CH2:11][OH:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[C@@H](C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: C[C@@H](CO)c1ccc([N+](=O)[O-])cc1
Reaction time: 3 h
Yield: 96.1 %

Procedure:
A 500 ml three necked round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel, reflux condenser and a continuous nitrogen purge is charged with (2R)-2-(4-nitrophenyl)propanoic acid (8.12 g, 41.6 mmol) and THF (120.0 mL). To this solution was added 10.0 M borane dimethylsulfide (10.56 ml, 105.66 mmol) over a period of 30.0 minutes at room temperature. Reaction is quite exothermic with evolution of gas (exotherm can be controlled by the rate of addition of borane solution). The reaction is then refluxed for 5.0 hours, brought to room temperature and then quenched very carefully with saturated potassium carbonate solution (100.0 mL). Foaming observed during the quench can be controlled by the rate of addition of the carbonate solution. After 3.0 hours of stirring, the top organic layer is separated and the aqueous layer back extracted with methylene chloride (130.0 mL). The combined organic layer is then washed with saturated brine (100.0 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure at 50° C. to afford (2R)-2-(4-nitrophenyl)propan-1-ol (7.24 g, 96%); 1H nmr (CDCl3, 300 MHz) δ 1.29 (d, 3H, J=7.02 Hz), 1.69 (b. triplet, OH), 3.05 (m, 1H), 3.72 (m, 2H), 7.39 (d, 2H), 8.15 (d, 2H); 13C nmr (CDCl3, 300 MHz) δ 17.61, 25.82, 42.61, 68.17, 123.92, 128.61, 146.90, 152.24.
Reaction SMILES: [CH3:1][C@@:2]12[CH2:9][CH2:8][CH2:7][N:6]1[C@@H:5]([C:10]([Cl:13])([Cl:12])[Cl:11])[O:4][C:3]2=[O:14].[CH:15](NC(C)C)(C)C.ClC(Cl)(Cl)[C@H]1OC(=O)[C@H]2N1CCC2.ICC>>[CH2:1]([C@@:2]12[CH2:9][CH2:8][CH2:7][N:6]1[C@@H:5]([C:10]([Cl:13])([Cl:12])[Cl:11])[O:4][C:3]2=[O:14])[CH3:15]
Reactant: CC(C)NC(C)C
Reactant: C[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Agent: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@H]12
Solvent: CCI
Product: CC[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Yield: 30.2 %

Procedure:
The reaction was carried out following a similar procedure to that described for the preparation of oxazolidinone 8 using n-butyllithium (1.31 M, 28.3 cm3, 37.1 mmol), diisopropylamine (5.2 cm3, 37.1 mmol), oxazolidinone 7 (6.0 g, 24.7 mmol) and iodoethane (5.9 cm3, 73.8 mmol) to afford oxazolidinone 9 (3.05 g, 46%) as a light red oil that solidified on standing to a pale brown solid: mp 76-77° C.: [α]D +18.5 (c 0.25 in CHCl3): δH (300 MHz; CDCl3) 1.04 (3 H, t, J 7.5, CH3), 1.60-1.80 (1H, m, CHAHBCH3), 1.72-1.99 (4H, m, CHAHBCH3, Proβ-HAHB and Proγ-H2), 2.20-2.30 (1H, m, Proβ-HAHB), 3.22-3.29 (2H, m, Proδ-H2) and 5.00 (1 H, s, NCH); δC (75 MHz; CDCl3) 8.4 (CH3, CH3), 25.5 (CH2, CH2CH3), 30.9 (CH2, Proγ-C), 35.6 (CH2, Proβ-C), 58.6 (CH2, Proδ-C), 72.5 (quat., Proα-C), 100.9 [quat., C(Cl3)], 102.5 (CH, NCH) and 176.9 (quat., CO); m/z (EI+) 272.0014 (MH+.C9H1335ClN3O2 requires 272.0012).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].S(=O)(=O)(O)O.O.[C:18](=O)(O)[O-].[Na+]>CO>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:18])=[O:7])=[CH:4][C:3]=1[OH:11]
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc(I)c(O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(I)c(O)c1

Procedure:
A solution of 4-iodo-3-hydroxybenzoic acid (2.71 g, 10 mmol) and sulphuric acid (0.7 ml) in methanol (17 ml) is refluxed for 6 h. 20 ml of water are added and the mixture is basified with sodium bicarbonate until neutral. The mixture is extracted with ethyl ether (60 ml). The organic phase is washed with twice 30 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is purified by flash chromatography on a column of silica (50% ethyl acetate, 50% heptane).
Reaction SMILES: BrC1N=CNC=1CSCCN.[N+](C=C(SC)SC)([O-])=O.[N+:21]([CH:24]=[C:25](SC)[NH:26][CH2:27][CH2:28][S:29][CH2:30][C:31]1[NH:35][CH:34]=[N:33][C:32]=1[Br:36])([O-:23])=[O:22].[NH2:39][CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1>>[N+:21]([CH:24]=[C:25]([NH:39][CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1)[NH:26][CH2:27][CH2:28][S:29][CH2:30][C:31]1[NH:35][CH:34]=[N:33][C:32]=1[Br:36])([O-:23])=[O:22]
Reactant: NCCSCc1ccccn1
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1Br
Agent: CSC(=C[N+](=O)[O-])SC
Agent: NCCSCc1[nH]cnc1Br
Product: O=[N+]([O-])C=C(NCCSCc1ccccn1)NCCSCc1[nH]cnc1Br

Procedure:
When 4-bromo-5-[(2-aminoethyl)thiomethyl]imidazole (from the dihydrobromide (4.8 g)) is reacted with 1-nitro-2,2-bis-methylthioethylene (2.0 g) according to the procedure of Example 8(i) and the resultant 1-nitro-2-methylthio-2-[2-((4-bromo-5-imidazolyl)methylthio)ethylamino]ethylene reacted with 2-[(2-aminoethyl)thiomethyl]pyridine by the procedure of Example 1 (a) (ii), the title compound is produced.
Reaction SMILES: [O-]CC.[Na+].[C:5]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][CH2:29][Cl:30]>C(O)C.CCOCC.O>[C:5]([CH:13]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][CH2:29][Cl:30])[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: ClCCCc1ccccc1CCl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(Cc1ccccc1CCCCl)C(=O)c1ccccc1
Reaction time: 1 h

Procedure:
A stirred solution of sodium ethoxide (from 0.53 g. sodium) in ethanol (80 ml.) was treated with ethyl benzoylacetate (4.42 g.). After 1 hour, -(o-chloromethylphenyl)propyl chloride (4.57 g.) was added and stirring was continued for 24 hours. The mixture was then diluted with ether (100 ml.) and water (100 ml.). The organic layer was separated, washed with saturated brine (50 ml.), dried (MgSO4) and evaporated to give ethyl 2-benzoyl-3-(o-(3-chloropropyl)phenyl]propanoate (A) as a yellow oil (7.66 g.), NMR: 1.1 (3H,t), 2.1 (2H,m), 2.7-3.7 (6H,m), 4.1 (2H,m), 4.65 (1H,t) and 7.0-8.2 (9H,m)ppm, which was used without further purification.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15](=[O:16])[CH2:14][C:9]2([CH2:13][CH:12]=[CH:11][CH2:10]2)[CH2:8][C:7]1=[O:17].CC[O:20]C(C)=O.CCCCCC>>[OH:20][CH:11]1[CH2:12][CH2:13][C:9]2([CH2:8][C:7](=[O:17])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[C:15](=[O:16])[CH2:14]2)[CH2:10]1
Reactant: CCOC(C)=O
Reactant: O=C1CC2(CC=CC2)CC(=O)N1CCCCBr
Solvent: CCCCCC
Product: O=C1CC2(CCC(O)C2)CC(=O)N1CCCCBr
Yield: 75 %

Procedure:
This compound was prepared from 8-(4-bromobutyl)-8-azaspiro[4.5]dec-2-ene-7,9-dione according to the procedure as a viscous liquid. Flash chromatography in EtOAc/hexane (3:2) afforded the title compound in 75% yield as a clear oil; IR (neat) 3450, 2956, 1725, 1670, 1436, 1394, 1355, 1267, 1137 cm-1 ; 1H NMR (CDCl3) 6 5.32 (s, IH), 4.24 (b s, lH), 3.81 (t, J=7.1 Hz, 2H), 3.42 (t, J=7.1 Hz, 2H), 2.82 (s, 2H), 2.61 (s, 2H), 2.09-1.53 (m, 10H); mass spectrum, m/z (relative intensity) 320 (M.H+2, 61), 318 (M+H, 68), 302 (25), 300 (25), 260 (28), 258 (28), 137 (28), 135 (30), 95 (100).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:31])[C:16]=3[C@H:32]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([O:35][CH3:36])=[O:34])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3].[CH2:42]([C:46]1[CH:47]=[C:48](B2OC(C)(C)C(C)(C)O2)[CH:49]=[CH:50][CH:51]=1)[CH2:43][CH:44]=[CH2:45].C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:25]=[C:26]([C:50]6[CH:49]=[CH:48][CH:47]=[C:46]([CH2:42][CH2:43][CH:44]=[CH2:45])[CH:51]=6)[CH:27]=[CH:28][CH:29]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:31])[C:16]=3[C@H:32]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([O:35][CH3:36])=[O:34])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3]
Reactant: C=CCN1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(Br)c5)nn34)c(Cl)c21
Reactant: C=CCCc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCc1cccc(-c2cccc(-c3cc4nc(C)c([C@H](OC(C)(C)C)C(=O)OC)c(-c5ccc6c(c5Cl)N(CC=C)CCO6)n4n3)c2)c1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 61.5 %

Procedure:
A mixture of (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (75 mg, 0.117 mmol), 2-(3-(but-3-en-1-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (45.4 mg, 0.176 mmol) and 2N Na2CO3 (0.117 mL, 0.234 mmol) in DMF (1 mL) was degassed for 15 min. tetrakis(triphenylphosphine)pallafium(0) (9.48 mg, 8.20 μmol) was then added and the degassing was continue for another 5 min. The mixture was then heated at 90° C. for 16 h. After cooling to room temperature, water was added and the mixture was extracted with ether (2×25 mL), washed with brine (15 mL), dried (Na2SO4), filtered and concentrated. Crude was then purified by biotage (0-15% EtOAc/hexane) to afford (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3′-(but-3-en-1-yl)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (50 mg, 0.072 mmol, 61.7% yield) as light yellow solid. 1H NMR (500 MHz, CDCl3) δ: 8.05 (t, J=1.6 Hz, 1H), 7.85-7.82 (m, 1H), 7.57-7.54 (m, 1H), 7.45 (dd, J=4.6, 2.5 Hz, 3H), 7.41-7.35 (m, 1H), 7.21 (d, J=7.6 Hz, 1H), 7.00 (d, J=5.0 Hz, 2H), 6.95-6.93 (m, 1H), 6.11-6.00 (m, 1H), 5.91 (ddt, J=17.0, 10.3, 6.6 Hz, 1H), 5.35 (dd, J=17.2, 1.6 Hz, 1H), 5.26 (dd, J=10.2, 1.6 Hz, 1H), 5.12-5.07 (m, 2H), 5.04-5.00 (m, 1H), 4.27 (t, J=4.4 Hz, 2H), 3.79-3.72 (m, 1H), 3.67 (s, 3H), 3.63 (dd, J=15.1, 6.1 Hz, 1H), 3.28-3.17 (m, 2H), 2.86 (s, 3H), 2.83-2.78 (m, 2H), 2.49-2.41 (m, 2H), 1.20 (s, 9H). LCMS (M+H)=691.5.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Cl[C:9]1[N:14]=[CH:13][C:12]2[N:15]=[C:16]([C:26]3[CH:27]=[C:28]([CH3:34])[C:29](=[O:33])[N:30]([CH3:32])[CH:31]=3)[N:17]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH3:19])[C:11]=2[CH:10]=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>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:1]1([CH2:4][O:5][C:9]2[N:14]=[CH:13][C:12]3[N:15]=[C:16]([C:26]4[CH:27]=[C:28]([CH3:34])[C:29](=[O:33])[N:30]([CH3:32])[CH:31]=4)[N:17]([CH:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH3:19])[C:11]=3[CH:10]=2)[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: Cc1cc(-c2nc3cnc(Cl)cc3n2C(C)c2ccccn2)cn(C)c1=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: Cc1ccccc1
Product: Cc1cc(-c2nc3cnc(OCC4CC4)cc3n2C(C)c2ccccn2)cn(C)c1=O
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 33.5 %

Procedure:
Cyclopropyl methanol (7.4 mg; 0.103 mmol) is dissolved in toluene (1 ml) and added to NaH 60% w/w (8.3 mg; 0.348 mmol). The mixture is stirred at 70° C. for 15 min under a nitrogen atmosphere. Then a mixture of (5-[6-Chloro-1-(1-pyridin-2-yl-ethyl)-1H-imidazo[4,5-c]pyridin-2-yl]-1,3-dimethyl-1H-pyridin-2-one II-21′ (30 mg; 0.079 mmol), BINAP (9.8 mg; 0.016 mmol), Pd2(dba)3 (7.2 mg; 0.008 mmol) is added in toluene (1 ml) and stirred for 2 hours at 100° C. The reaction mixture is evaporated and dissolved in DMF. The mixture is purified using reversed phase column chromatography (Method: prep. HPLC3). The product containing fractions are lyophilized to afford the desired compound.