Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:29]=[CH:28][C:10]2[C:11]([CH2:14][O:15][C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH:18]=[C:19]([C:25](O)=[O:26])[NH:20]4)=[CH:12][O:13][C:9]=2[CH:8]=1)[CH3:2].[NH2:30][CH:31]1[CH2:36][CH2:35][C:34]([CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][C@H:43]([OH:46])[C@@H:42]([CH3:47])[CH2:41]2)([OH:37])[CH2:33][CH2:32]1>>[OH:37][C:34]1([CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][C@H:43]([OH:46])[C@@H:42]([CH3:47])[CH2:41]2)[CH2:35][CH2:36][CH:31]([NH:30][C:25]([C:19]2[NH:20][C:21]3[C:17]([CH:18]=2)=[C:16]([O:15][CH2:14][C:11]2[C:10]4[CH:28]=[CH:29][C:7]([O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])=[CH:8][C:9]=4[O:13][CH:12]=2)[CH:24]=[CH:23][CH:22]=3)=[O:26])[CH2:32][CH2:33]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reactant: CCOCCOc1ccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Product: CCOCCOc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCC(O)(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized analogously to example 1 from 4-[6-(2-ethoxy-ethoxy)-benzofuran-3-ylmethoxy]-1H-indole-2-carboxylic acid 30c and amine 14.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[NH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:8][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:17]=2)=[CH:2][CH:1]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
At room temperature, p-aminophenol (0.51 g, 4.70 mmol, 1 eq) was dissolved in N,N-dimethylformamide (10 mL). To the resulted solution, potassium tert-butoxide (0.53 g, 4.70 mmol, 1 eq) was added in portions and the resulted mixture was stirred for 0.5 hours. Tert-butyl 4-chloropicolinate (1 g, 4.70 mmol, 1 eq) and potassium carbonate (45 mg, 0.33 mmol, 0.07 eq) were added, and the mixture was heated to 80° C. and stirred for 2 hours. The mixture was cooled to room temperature and ethyl acetate (50 mL) was added. The mixture was filtered to remove the undissolved material and the filtrate was washed with saturated brine (20 mL×2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (dicloromethane:ethyl acetate=30:1) to give the title compound (805 mg, purity 96%, yield 60%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=O)[NH:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:30]>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[NH:30][C:16]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)=[CH:15][N:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2ccc(Br)cc2)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Temperature: 140 °C
Yield: 56.3 %

Procedure:
A mixture of 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbarnoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g, 3.6 mmol) and ammonium acetate (1.4 g, 18.2 mmol) in xylene (15 mL) was heated in a sealed tube at 140° C. for 2 hours. The volatile component was removed in vacuo, and the residue was dissolved in ethyl acetate (150 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a white solid (795 mg, 56%). m/z 391.8, 393.8 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH2:18][NH:19][S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:15]=[N:16][CH:17]=3)[CH:8]=2)[NH:3]1.[Cl:25]N1C(=O)CCC1=O.O>CN(C=O)C.CCOC(C)=O>[Cl:25][C:5]1[CH:6]=[C:7]([C:12]2[CH:13]=[C:14]([CH2:18][NH:19][S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:15]=[N:16][CH:17]=2)[CH:8]=[C:9]2[C:4]=1[NH:3][C:2](=[O:1])[CH2:11][CH2:10]2
Reactant: CCS(=O)(=O)NCc1cncc(-c2ccc3c(c2)CCC(=O)N3)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)NCc1cncc(-c2cc(Cl)c3c(c2)CCC(=O)N3)c1
Yield: 33.4 %

Procedure:
To a solution of ethanesulfonic acid [5-(2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-ylmethyl]-amide (example 55, 0.681 g, 0.197 mmol) in DMF (1 mL) heated to 65° C. was added N-chloro-succinimide (0.034 g, 0.256 mmol) and the reaction mixture was stirred at this temperature over night. The mixture was diluted with EtOAc, poured into water (5 mL) and extracted with EtOAc (2×10 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by reverse phase HPLC on a Gemini-NX column, eluting with a MeOH—H2O (0.05% TEA) gradient to give the title compound (0.025 g, 33%) as a colorless amorphous solid. MS: 380.4 (M+H+).
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[CH:19]=[C:18]2[CH:25]=O>>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[CH:19]=[C:18]2[CH2:25][NH:6][CH3:5]
Reactant: Cn1cc(C=O)c2cc(Cl)ccc21
Reactant: COC(=O)CNc1ccc(Br)cn1
Product: CNCc1cn(C)c2ccc(Cl)cc12
Yield: 93 %

Procedure:
According to the procedure of Preparation 13 (c), except substituting 5-chloro-1-methyl-1H-indole-3-carboxaldehyde for the, 3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (2.1 g, 93%) was obtained as an amber oil: MS (ES) m/e 209.0 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH:12]1([C:15](=[O:22])[CH2:16][C:17]([CH:19]2[CH2:21][CH2:20]2)=[O:18])[CH2:14][CH2:13]1.O>FC(F)(F)C(O)=O>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:16]([C:15]([CH:12]2[CH2:14][CH2:13]2)=[O:22])[C:17]([CH:19]2[CH2:21][CH2:20]2)=[O:18])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=C(CC(=O)C1CC1)C1CC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(C=C(C(=O)C2CC2)C(=O)C2CC2)cc1
Temperature: 20 °C

Procedure:
The procedure described in Example 19 was repeated by using 3.0 g 4-carboxybenzaldehyde and 3.06 g 1,3-dicyclopropyl-1,3-propanedione. Yield 1.7 g, mp 175°-178° C. in trifluoroacetic acid (10 ml) thionylchloride (4 ml) and catalytic amount of water (0,05 ml) were added at room temperature. The solution was stirred over right at 20° C. The solvent was evaporated and the residue was destilled in vacuo, bp 110° C./1,5 mbar. Yield 5,3 g (41%).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].Br[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17](OC)=[CH:16][CH:15]=1)=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[CH2:13]([O:12][C:10]([CH2:9][S:4][CH2:3][C@@H:2]([C:5]([OH:7])=[O:6])[NH2:1])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N[C@H](CS)C(=O)O
Reactant: COc1ccc(COC(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](CSCC(=O)OCc1ccccc1)C(=O)O

Procedure:
D-cysteine is S-alkyl substituted with p-methoxybenzyl bromoacetate in presence of sodium carbonate in a THF-water medium. The S-benzyloxycarbonylmethylcysteine thus obtained is N-acylated with (R)-3-tetradecanoyloxytetradecanoic acid chloride, and the S-alkyl-N-acyl-D-cysteine derivative is then with (2R)-5-amino-2-[(R)-3-hydroxytetradecanoylamino]pentan-1-ol amine {obtained by hydrogenolysis of the (2R)-5-amino-2-[(R)-3-benzyloxy-tetradecanoyl-amino]pentan-1-ol, see 4.1.1.} in presence of IIDQ. The thus obtained product is selectively O-acylated in its primary position with the ester derived from reacting HOBt with 7-(p-methoxybenzyloxy-carbonylamino)heptanoic acid. The two p-methoxybenzyl groups are then removed by treating the ester with aqueous trifluoroacetic acid. C59H112N4O10S. MM 1069.64.
Reaction SMILES: C(O[C:4](=[O:23])[CH:5]=[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=1)[CH3:7])C.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>CCCCCCC>[CH2:16]([O:15][C:11]1[CH:10]=[C:9]2[C:14]([C:4]([OH:23])=[CH:5][C:6]([CH3:7])=[N:8]2)=[CH:13][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)C=C(C)Nc1cccc(OCc2ccccc2)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCCC
Solvent: c1ccc(-c2ccccc2)cc1
Product: Cc1cc(O)c2ccc(OCc3ccccc3)cc2n1
Temperature: 250 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
3.67 g (11.8 mmol) of 3-(3-benzyloxy-phenylamino)-but-2-enoic acid ethyl ester were added dropwise within 20 minutes to 5.5 ml of Dowtherm A heated at 250° C. (metal bath temperature). The solution was stirred further 10 minutes at 250° C. (bath temperature), cooled to RT and then treated with 20 ml of heptane. The brown viscous oil that had formed was isolated and triturated with 45 ml of AcOEt. The brown solid obtained was filtered off by suction, washed with AcOEt and dried in a high vacuum to give 1.19 g (35%) of 7-benzyloxy-2-methyl-quinolin-4-ol. ISP mass spectrum, m/e: 266.3 (M+1 calculated for C17H15NO2: 266).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:58]([CH3:61])([CH3:60])[CH3:59])[C:14]([NH:16][C@@H:17]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@@H:18]([O:47][CH2:48]SC)[CH2:19][C@@H:20]([NH:34][C:35](=[O:46])[C@H:36]([C:42]([CH3:45])([CH3:44])[CH3:43])[NH:37][C:38]([O:40][CH3:41])=[O:39])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=2)=[O:15])[C:9]1=[O:62])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:64][N:65]([CH3:70])[CH2:66][C:67]([OH:69])=[O:68].IN1C(=O)CCC1=O.Cl>O1CCOCC1>[CH3:64][N:65]([CH2:66][C:67]([O:69][CH2:48][O:47][C@H:18]([C@@H:17]([NH:16][C:14](=[O:15])[C@@H:13]([N:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:62])[C:58]([CH3:61])([CH3:60])[CH3:59])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:19][C@H:20]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:24][CH:23]=1)[NH:34][C:35](=[O:46])[C@H:36]([C:42]([CH3:45])([CH3:43])[CH3:44])[NH:37][C:38](=[O:39])[O:40][CH3:41])=[O:68])[CH3:70]
Reactant: CN(C)CC(=O)O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](OCSC)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1I
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](OCOC(=O)CN(C)C)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product from Example 195A (0.045 g, 0.052 mmol) in 1,2-dichloromethane (1.5 mL) were added molecular sieves (4 Å, 0.24 g), N,N-dimethylglycine hydrochloride (0.075 g, 0.537 mmol), followed by N-iodosuccinimide (0.013 g, 0.058 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction was filtered through celite. The filtrate was diluted with ethyl acetate and was washed with a mixture of dilute NaHCO3 and Na2S2O3, dried over MgSO4, filtered and evaporated. The residue was dissolved in ether and 2 equivalents of 4 N HCl in dioxane were added. The crude product was purified by chromatography on silica gel eluting with a gradient starting with dichloromethane and ending with methanol to give the title compound as the bis hydrochloride salt (0.037 g, 77% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.87 (s, 9 H), 0.88 (s, 9 H), 1.60-1.73 (m, 2 H), 2.22 (s, 6 H), 2.29 (q, J=9.6 Hz, 1 H), 2.54-2.84 (m, 6 H), 2.93 (q, J=8.8 Hz, 1 H), 3.08-3.24 (m, 4 H), 3.53 (s, 3 H), 3.72-3.76 (m, 1 H), 3.87 (d, J=9.6 Hz, 1 H), 4.11-4.35 (m, 5 H), 5.26 (d, J=6.6 Hz, 1 H), 5.37 (d, J=6.6 Hz, 1 H), 6.78 (d, J=9.6 Hz, 1 H), 6.94-7.15 (m, 5 H), 7.22-7.40 (m, 8 H), 7.82-7.95 (m, 6 H), 8.63 (m, 1 H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][CH:4]=1)=[O:2].[H][H]>O1CCCC1.[Ni]>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([B:9]([OH:11])[OH:10])=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: OCc1ccc(B(O)O)cc1
Yield: 97 %

Procedure:
15 g (100 mmol) of 4-formylphenylboronic acid were dissolved in 200 ml of tetrahydrofuran, and 0.25 g of Raney nickel were added. A stream of hydrogen was passed through the reaction mixture for 8 hours, giving 14.8 g (97 mmol) of 4-(hydroxymethyl)phenylboronic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1.O>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:24]2[CH:25]=[CH:26][C:22]([CH3:21])=[N:23]2)=[C:6]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[CH:7]=1
Reactant: Cc1cc[nH]n1
Reactant: O=C(c1cc(Br)ccc1F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccn(-c2ccc(Br)cc2C(=O)C(F)(F)F)n1
Temperature: 110 °C

Procedure:
1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone (2.20 g, 8.12 mmol) from Step 1, K2CO3 (1.68 g, 12.2 mmol), and 3-methyl-1H-pyrazole (1.33 g, 16.2 mmol) were stirred in toluene (10 mL). The reaction was then heated to 110° C. for 16 h. The reaction was cooled, and water and EtOAc were added. The toluene-EtOAc layer is removed in vacuo, and then the reaction is extracted with water and EtOAc, washed with brine, and dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided 1-[5-bromo-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-trifluoroethanone.
Reaction SMILES: ClCCC[N:5]1[C:10](=O)[C:9]2[C:12](F)=[CH:13][CH:14]=[CH:15][C:8]=2[Si:7](C)(C)[CH2:6]1.C(N(CC)CC)C.C1(N2CCNCC2)C=CC=CC=1.C(O)(=O)C(O)=O>C1(C)C=CC=CC=1.CC(C)=O.C([O-])(=O)C([O-])=O>[SiH2:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH2:10][NH:5][CH2:6]1
Reactant: C[Si]1(C)CN(CCCCl)C(=O)c2c(F)cccc21
Agent: O=C(O)C(=O)O
Agent: O=C([O-])C(=O)[O-]
Agent: c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)CNC[SiH2]2

Procedure:
The procedure is carried out as in Example 11, using 1.15 g of 3-(3-chloropropyl)-1,1-dimethyl-5-fluoro-4-oxo-1,2,3,4-tetrahydro-3,1-benzazasiline, 1.1 cm3 of triethylamine and 1.3 g of 1-phenylpiperazine in 23 cm3 of toluene (23 cc). After purification by flash chromatography on a silica column under a nitrogen stream at moderate pressure (0.5-1.5 bar) with a dichloromethane-methanol mixture (98.5-1.5 by volume) as eluent, 0.3 g of 1,1-dimethyl-5-(4-phenyl-1-piperazinyl)-3- [3-(4-phenyl-1-piperazinyl)-propyl]-4-oxo-1,2,3,4-tetrahydro-3,1-benzazasiline; melting point =166° C., and 0.3 g of an oil are obtained, which oil, when dissolved in 3 cm3 of acetone and treated with 0.24 g of oxalic acid, yield 1,1-dimethyl-5-fluoro-4-oxo-3-3-(4-phenyl-1-piperazinyl) 3-propyl]-1,2,3,4,-tetrahydro-3,1-benzazasiline in the oxalate form; melting point =99° C.
Reaction SMILES: [Zn](CC)CC.[CH:6]1([CH:12]=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[C:14]1(C)[CH:19]=CC=[CH:16][CH:15]=1>>[CH3:19][CH:14]=[CH:15][CH2:16][C@@H:12]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[OH:13]
Reactant: Cc1ccccc1
Reactant: O=CC1CCCCC1
Agent: CC[Zn]CC
Product: CC=CC[C@H](O)C1CCCCC1
Temperature: 0 °C
Yield: 75 %

Procedure:
A 10 mL Schlenk flask was charged with 3.5 mg (0.015 mmol) (−)-MIB and a stir bar. Under a nitrogen atmosphere in a glovebox, the di(2-methyl-propene)zinc reagent (89.5 mg, 0.51 mmol) was weighed and added to the Schlenk flask. Toluene (1.5 mL) was added, followed by 3.1 equiv Et2Zn (115 μL, 1.13 mmol). After cooling to 0° C., cyclohexanecarboxaldehyde (40.8 mg, 0.36 mmol) was added dropwise. After the reaction was complete (2 h), it was quenched with saturated aq NH4Cl. The organic and aqueous layers were separated and the aqueous layer was extracted with diethyl ether (3×25 mL). The combined organic layers were washed with brine, dried over MgSO4 and concentrated. The crude product was purified by column chromatography on silica (70:20:10, hexanes:CH2Cl2:EtOAc) to afford the title compound as a colorless oil in 75% yield (45.8 mg, 0.27 mmol). 1H NMR and 13C{1H} NMR spectra for this compound were identical to the previously reported literature data.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH2:12][CH2:13][Cl:14])[CH2:9][N:8]([CH3:15])[C:7](=O)[C:6]=2[CH:17]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].[S-2].[K+].[K+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH2:12][CH2:13][Cl:14])[CH2:9][N:8]([CH3:15])[C:7](=[S:19])[C:6]=2[CH:17]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1CC(CCCl)Oc2ccc(Br)cc2C1=O
Agent: [K+]
Agent: [S-2]
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2ccc(Br)cc2C1=S
Yield: 72.6 %

Procedure:
To a solution of 11.0 g (0.035 mole) of 7-bromo-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one in 150 ml of dry toluene was added a mixture of 13.4 g (0.07 mole) of phosphorus pentasulfide and 13.4 g of potassium sulfide which has been ground together. The reaction mixture was heated at reflux for 5 hr under a nitrogen atmosphere. The mixture was filtered hot and the filtrate concentrated under reduced pressure. The residue was dissolved in chloroform. The chloroform solution was washed twice with dilute aqueous sodium hydroxide, dried over magnesium sulfate and concentrated under reduced pressure to give 8.5 g (72%) of yellow solid. The solid was recrystallized from ethanol, m.p. 118°-120° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([C:12]([NH2:14])=[O:13])[CH2:7][CH2:6][CH2:5]2.[C:15]([O:19][C:20](=[O:38])[NH:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:28]=1)([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O>[C:15]([O:19][C:20](=[O:38])[NH:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([C:2]2[CH:11]=[N:10][C:9]3[N:8]([C:12](=[O:13])[NH2:14])[CH2:7][CH2:6][CH2:5][C:4]=3[CH:3]=2)[CH:28]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: NC(=O)N1CCCc2cc(Br)cnc21
Reactant: CC(C)(C)OC(=O)NCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Temperature: 100 °C
Yield: 94.2 %

Procedure:
6-Bromo-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (79 mg, 0.31 mmol), [5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylmethyl]-carbamic acid tert-butyl ester (205 mg, 0.61 mmol) and 2.0 M Na2CO3 aqueous solution (0.31 mL, 0.61 mmol) are dissolved in 2.0 mL of 1,4-dioxane. Argon gas is bubbled through the solution for 5 min. Then PdCl2dppf (16 mg, 0.021 mmol) is added. The mixture is heated at 100° C. for 2 hrs and the mixture is cooled down to room temperature. Then 30 mL of EtOAc and 20 mL of water are added and the organic layer is separated. The aqueous layer is extracted with EtOAc (2×20 mL). The organic layers are combined, dried and concentrated to give the crude product. Purification by flash column chromatography affords 112 mg of [5-(8-carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-ylmethyl]-carbamic acid tert-butyl ester
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][CH:25]=[CH:24][N:19]3[C:20](=[O:23])[C:21]=2I)[CH2:3][CH2:2]1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][CH:25]=[CH:24][N:19]3[C:20](=[O:23])[C:21]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:3][CH2:2]1
Reactant: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccccc2)c1OCC1CC1
Yield: 15.1 %

Procedure:
The title compound was prepared from Intermediate 2 (100 mg, 0.231 mmol) and phenylboronic acid (33 mg, 0.276 mmol) using Pd[(C6H5)3P]4 (26 mg, 0.023 mmol) and sodium carbonate (48 mg, 0.461 mmol) in toluene (5 ml) and ethanol (2 ml) and water (2 ml) according to the procedure outlined in Example 1 to yield crude product which was purified by column chromatography to afford 15 mg of the desired product; 1H NMR (300 MHz, CDCl3) δ 0.32 (d, J=4.2 Hz, 2H), 0.57 (d, J=7.2 Hz, 2H), 0.99-1.70 (m, 1H), 3.76-3.82 (m, 5H), 6.78-6.82 (m, 3H), 6.91-6.98 (m, 3H), 7.36-7.43 (m, 4H), 7.93 (d, J=6.5 Hz, 1H), 8.27 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 431.33 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)=[O:22])[CH:16]=2)=[CH:26][CH:25]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: OB(O)c1ccc(Cl)cc1
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: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2ccc(Cl)cc2)c1
Yield: 45.8 %

Procedure:
4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 4-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.033 g (45%) of 4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH:6]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:7]([NH:9][CH:10]1[C:23](=[O:24])[N:12]2[CH:13]([C:18]3[NH:22][N:21]=[N:20][N:19]=3)[C:14]([CH3:17])([CH3:16])[S:15][C@H:11]12)=[O:8])=[O:4].CN(C)C=O.[SH:36][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:40]1[CH:41]=[CH:42][C:37]([S:36][CH2:2][C:3]([NH:5][CH:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]([NH:9][CH:10]2[C:23](=[O:24])[N:12]3[CH:13]([C:18]4[NH:22][N:21]=[N:20][N:19]=4)[C:14]([CH3:17])([CH3:16])[S:15][C@H:11]23)=[O:8])=[O:4])=[CH:38][CH:39]=1
Reactant: CC1(C)S[C@@H]2C(NC(=O)C(NC(=O)CBr)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Reactant: Sc1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)S[C@@H]2C(NC(=O)C(NC(=O)CSc3ccncc3)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Reaction time: 3 h
Yield: 33 %

Procedure:
To a stirred solution of 644 mg. of 6-(2-[2-bromoacetamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 15 ml. of N,N-dimethylformamide is added 45 mg. of 4-mercaptopyridine followed by 0.19 ml. of triethylamine. Stirring is continued for 3 hours at 25° C., and then the reaction solution is added dropwise into 200 ml. of vigorously stirred chloroform. The precipitate is removed by filtration, and the filtrate is added dropwise with stirring to 400 ml. of hexane. This causes the product to precipitate. After being slurried with methylene chloride, it weighs 228 mg. (33% yield), m.p. 182°-198° C. (dec.). IR (KBr disc): 1780 cm-1 (β-lactam) and 1667 cm-1 (amide I). NMR (DMSO-d6 /D2O): 8.33 ppm (d,4H), 7.33 (s,5H), 5.60 ppm (m,3H), 5.15 ppm (s,1H), 3.68 ppm (s,2H), 1.47 ppm (s,3H), 1.00 ppm (s,3H).