Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:13][N:14](C=O)C>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.[C-]#N.[Zn+2].[C-]#N>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]#[N:14])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Clc1ccnc2ccc(I)cc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2nccc(Cl)c2c1
Temperature: 50 °C
Reaction time: 17 h

Procedure:
A pyrex reaction tube was charged with Pd(PPh3)4(200 mg, 173 μmol), 4-chloro-6-iodoquinoline (1.00 g, 3454 μmol), zinc cyanide (406 mg, 3454 μmol) and DMF. The tube was purged with argon, sealed, and the heterogeneous mixture was stirred at 50° C. for 17 h. The mixture was poured into water and the resulting solids were filtered, washed with water, and dried. The crude material was purified by silica gel chromatography, 0-5% MeOH/DCM to provide 4-chloroquinoline-6-carbonitrile as a white solid. MS: [M+H]=189.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([O:35][CH3:36])=[O:34])=[CH:12][C:13]=3[N:14]3[CH2:20][CH2:19][CH:18]([NH:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[C:17]4[CH:29]=[CH:30][CH:31]=[CH:32][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:37]C(O)=O.C=O.[BH3-]C#N.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([O:35][CH3:36])=[O:34])=[CH:12][C:13]=3[N:14]3[CH2:20][CH2:19][CH:18]([N:21]([CH3:37])[CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[C:17]4[CH:29]=[CH:30][CH:31]=[CH:32][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCC(NCCN1CCCC1)c1ccccc1-3
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCC(N(C)CCN1CCCC1)c1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 13-cyclohexyl-5-[(2-pyrrolidin-1-ylethyl)amino]-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (prepared as in Example 3) was dissolved in DCM and the pH adjusted to 6 with AcOH; 37% aq HCHO and, after 30 min NaCNBH3 (3 eq), were added and the mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc and washed with IN NaOH and brine, dried and evaporated affording methyl 13-cyclohexyl-5-[methyl(2-pyrrolidin-1-ylethyl)amino]-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate. Hydrolysis of the foregoing methyl ester was done with IM aqueous KOH (6 eq) in dioxane (0.1M) at 60 ° C.; the reaction was complete in 2 h, and the title compound was obtained in 29% yield after RP-HPLC purification and lyophilisation (Conditions: Column: Waters X-TERRA MS C18, 10 micron, 19×150 mm; Gradient: A: H2O+0.1% TFA; B: MeCN+0.1% TFA; 75% A isocratic for 3 min, linear to 20% A in 12 min).
Reaction SMILES: C([O:8][CH2:9][C:10]1[S:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:13][N:14]=1)C1C=CC=CC=1.BrB(Br)Br>ClCCl>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[S:11][C:10]([CH2:9][OH:8])=[N:14][N:13]=1
Reactant: c1ccc(COCc2nnc(-c3ccccn3)s2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: OCc1nnc(-c2ccccn2)s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
The compound prepared in Example 147 (0.295 g) was dissolved in dichloromethane (7 mL) and cooled to 0° C. Tribromoborane (0.3 mL) was added slowly and the reaction was allowed to warm and then was stirred overnight. The reaction was quenched with ethyl acetate/sodium hydrogen carbonate aqueous solution and the organic phase was washed with brine, dried over magnesium sulfate and filtered. The solution was concentrated and purified by column chromatography using an eluant of 5% methanol/dichloromethane to provide the title compound (0.10 g) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH:15]([CH2:16][NH:17][CH2:18]2)[CH2:14]1)=[O:12].Cl[C:22]1[N:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH:15]([CH2:16][N:17]([C:22]3[N:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]=3)[CH2:18]2)[CH2:14]1)=[O:12]
Reactant: Cc1ccnc(Cl)n1
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(OC)c1
Product: COc1ccc(C(=O)N2CC3CN(c4nccc(C)n4)CC3C2)c(OC)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 38 and 2-chloro-4-methylpyrimidine. MS (ESI): mass calculated for C20H24FN4O3, 368.43; m/z found 369.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([F:16])[C@@H:13]([OH:17])[C@H:12]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([Si:32]([CH3:35])([CH3:34])Cl)([CH3:31])([CH3:30])[CH3:29].C(N(CC)CC)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([F:16])[C@@H:13]([O:17][Si:32]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:35])[CH3:34])[C@H:12]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(OCc1ccccc1)[C@@H]1[C@H](O)[C@@H](F)CN1C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@H]1[C@@H](C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C[C@@H]1F
Temperature: 25 °C

Procedure:
To a solution of (2S,3S,4S)-4-fluoro-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid dibenzyl ester (1.90 g, 5.09 mmol) in DMF (40 mL) were added tert-butyldimethylchlorosilane (0.844 g, 5.60 mmol), triethylamine (0.709 ml, 5.09 mmol) and DMAP (0.062 g, 0.509 mmol). The reaction mixture was stirred 25° C. for 1 week. Then quenched by addition of a saturated aqueous solution of NaHCO3. The layers were separated and the organic extract was dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 9:1). MS (UPLC): 588.4 [M+H]+, 505.5 [M+NH4]+, 510.4 [M+Na]+; tR (HPLC conditions f): 2.90 min.
Reaction SMILES: [BrH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]O>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][Br:1]
Reactant: COc1cccc(CO)c1
Reactant: Br
Product: COc1cccc(CBr)c1
Reaction time: 96 h
Yield: 89.3 %

Procedure:
To cooled (15° to 20° C.) hydrobromic acid (3.22 kg) (48%) is added 3-methoxybenzyl alcohol (1 kg) dropwise over a period of 1 hour. A slight exotherm results with pot temperature rising from 20° to 23° C. After the addition, the reaction mixture was stirred at 23° to 27° C. for four days. The product separated as an oil during this period. The reaction mixture was transferred to a separatory funnel, and the lower layer containing the product was separated. The aqueous phase was extracted with methylene chloride (750 mL). The methylene chloride extract was combined with the main product and washed with water (500 mL×3). The pH of the last wash was 6.5 to 7.0. The product was dried over anhydrous sodium sulfate (200 g), filtered and concentrated under reduced pressure (bath temperature 50° to 55° C.) to remove most of the solvent, then further concentrated at 40° to 45° C. under 5 mm Hg to constant weight to yield 1.30 kg (89% yield) of crude product. The presence of 5.5% of starting material in this product does not interfere with the subsequent alkylation reaction.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]2[C:10]3([CH2:29][O:30][C:4]=2[CH:3]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:11]3=[O:28].Cl.[NH2:32][OH:33].C(N(CC)CC)C>C(O)C>[OH:33][N:32]=[C:8]([C:7]1[C:2]([OH:1])=[CH:3][C:4]2[O:30][CH2:29][C:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[C:11]3=[O:28])[C:5]=2[CH:6]=1)[NH2:9]
Reactant: COc1ccc(CN2C(=O)C3(COc4cc(O)c(C#N)cc43)c3ccccc32)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(CN2C(=O)C3(COc4cc(O)c(C(N)=NO)cc43)c3ccccc32)cc1
Yield: 99.3 %

Procedure:
To a stirred solution of 6-hydroxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile (0.84 g, 2.10 mmol) and hydroxylamine hydrochloride (0.20 g, 2.9 mmol) in ethanol (50 mL) was added triethylamine (0.40 mL, 2.9 mmol). The reaction mixture was stirred at reflux for 18 h and concentrated in vacuo. The residue was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford N′,6-dihydroxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carboximidamide (0.90 g, 99%): MS (ES+) m/z 431.9 (M+1).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH3:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:1][C:2]#[CH:3])[CH2:8][CH2:7]1
Reactant: CN1CCNCC1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C#CCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
Propargyl bromide (23.8 g, 200 mmol) was added dropwise to a mixture of 1-methyl-piperazine (20 g, 200 mmol) and cesium carbonate (65 g, 200 mmol) in 350 mL of acetone. The mixture was stirred overnight under nitrogen at room temperature. The inorganic salts were then filtered off, and the solvent was removed. The residue was dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts were then evaporated to give 7.5 g of 1-methyl-4-prop-2-ynyl-piperazine: mass spectrum (m/e): M+H 139.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28](OCC)=[O:29])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH:36]([OH:38])[CH3:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28]([NH:34][CH2:35][CH:36]([OH:38])[CH3:37])=[O:29])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CC(O)CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O
Product: CC(O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (±)-1-amino-2-propanol employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (CDCl3) δ 14.5 (1H, br), 10.32 (1H, m), 8.54 (1H, s), 7.15 (2H, dd, J=8.5, 5.5 Hz), 7.08 (1H, s), 7.02 (2H, t, J=8.5 Hz), 4.88 (2H, m), 4.11 (2H, s), 4.05 (1H, m), 3.61 (1H, m), 3.51-3.44 (4H, m), 3.35 (1H, m), 2.20 (1H, d, J=4 Hz), 2.04 (2H, m, J=7 Hz), 1.89 (2H, m, J=7 Hz), 1.26 (3H, d, J=6 Hz); HRMS calcd for C25H27FN4O5+H+: 483.2044. Found: 483.2029.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10][O:11][CH3:12])[N:5]=[CH:4][N:3]=1.[CH3:13][C:14]1([C@@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:9][O:8][C:7]1[C:2]([NH:26][C@H:23]2[CH2:22][CH2:21][C@@H:20]([C:14]3([CH3:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:25][CH2:24]2)=[N:3][CH:4]=[N:5][C:6]=1[CH2:10][O:11][CH3:12]
Reactant: COCc1ncnc(Cl)c1OC
Reactant: CC1([C@H]2CC[C@@H](N)CC2)CCCCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COCc1ncnc(N[C@H]2CC[C@@H](C3(C)CCCCC3)CC2)c1OC

Procedure:
2.83 g (15 mmol) of 4-chloro-5-methoxy-6-methoxymethylpyrimidine [Collection Czechoslov. Chem. Commun. 33 (1968) 2266], 2.93 g (15 mmol) of cis-4-(1-methylcyclohexyl)cyclohexylamine and 3.03 g (30 mmol) of triethylamine are heated under reflux in 10 ml of toluene for 6 hours. After cooling, the mixture was subjected to extraction by stirring with water, and the organic phase was dried and concentrated. For purification it was chromatographed on silica gel (eluent: ethyl acetate). 1.2 g (23% of theory) of pure cis isomer were obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH2:21][NH2:22].C1N=CN([C:28](N2C=NC=C2)=[O:29])C=1>C1COCC1>[O:29]=[C:28]1[NH:22][CH2:21][C:3]2[C:2](=[CH:7][CH:6]=[C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:10][CH2:9]3)[CH:4]=2)[NH:1]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(CN)c2)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)CNC(=O)N3)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 66.2 %

Procedure:
To a solution of compound 17 (1.38 g, 4.5 mmol) in THF (20 mL) at room temperature was CDI (0.80 g, 4.95 mmol) and the reaction was stirred at 80° C. for 6 hr. The mixture was cooled to room temperature and the solid formed was filtered, washed with diethyl ether to afford 0.99 g (72%) of compound 10 as an off-white foam. IR (KBr) νmax. cm−1: 3210, 3162 (NH), 3032 (Ar—H), 1691 (C═O), 1607, 1515, 1419 (C═C). 1H NMR (500 MHz, CDCl3) δ=1.47 (s, 9H, (CH3)3C); 3.06 (m, 4H, 2CH2); 3.52 (m, 4H, 2CH2); 4.49 (s, 2H, CH2); 6.69 (m, 2H, aromatic-H), 6.74 (m, 1H, aromatic-H); 7.82 (br.s, 1H, NH); 13C NMR (125.7 MHz, CDCl3) δ=28.60 (CH3)3C), 43.35 (CH2), 43.90 (CH2), 50.66 (CH2), 80.10 (CH3)3C), 112.11 (aromatic-C), 112.28 (aromatic-C), 117.19 (aromatic-C), 130.18 (aromatic-C), 134.88 (aromatic-C), 143.18 (aromatic-C), 154.62 (CO), 155.93 (C═O). Calculated (%) for C17H24N4O3 (332.18); C, 61.43; H, 7.28; N, 16.86. found (%) C, 61.38; H, 7.32; N, 16.81.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]([C:9](=[O:34])[NH:10][C:11]1([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22](B4OC(C)(C)C(C)(C)O4)=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH2:13][CH2:12]1)[CH:6]([CH3:8])[CH3:7].[CH3:36][O:37][C:38](=[O:63])[NH:39][CH:40]([C:44]([N:46]1[CH2:50][CH2:49][CH2:48][CH:47]1[C:51]1[NH:52][C:53]([C:56]2[CH:61]=[CH:60][C:59](Br)=[CH:58][CH:57]=2)=[CH:54][N:55]=1)=[O:45])[CH:41]([CH3:43])[CH3:42].C([O-])([O-])=O.[K+].[K+]>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.O>[CH3:36][O:37][C:38](=[O:63])[NH:39][CH:40]([C:44]([N:46]1[CH2:50][CH2:49][CH2:48][CH:47]1[C:51]1[NH:52][C:53]([C:56]2[CH:61]=[CH:60][C:59]([C:22]3[CH:23]=[CH:24][C:19]([C:16]4[NH:15][C:14]([C:11]5([NH:10][C:9](=[O:34])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:35])[CH:6]([CH3:8])[CH3:7])[CH2:12][CH2:13]5)=[N:18][CH:17]=4)=[CH:20][CH:21]=3)=[CH:58][CH:57]=2)=[CH:54][N:55]=1)=[O:45])[CH:41]([CH3:43])[CH3:42]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)NC1(c2ncc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)[nH]2)CC1)C(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: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)NC(C(=O)NC1(c2ncc(-c3ccc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)cc3)[nH]2)CC1)C(C)C
Temperature: 80 °C
Reaction time: 3 h
Yield: 1.5 %

Procedure:
[2-Methyl-1-(1-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl]-cyclopropylcarbamoyl)-propyl}-carbamic acid methyl ester (85 mg, 0.21 mmol) and (1-(2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl)-2-methyl-propyl)-carbamic acid methyl ester (97 mg, 0.21 mmol) in 3:1 DME/H2O (2.5 mL) were treated with Pd(PPh3)4 (10 mg, 0.0084 mmol) and K2CO3 (2 M solution, 0.42 mL, 0.84 mmol). The mixture was stirred in a sealed tube at 80° C. for 3 hours. The mixture was filtered through a fritted glass funnel and concentrated. The mixture was subjected to a reverse phase HPLC column (5-95% MeCN—H2O; 0.1% TFA modifier) to afford (1-{2-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyrylamino)-cyclopropyl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (2.3 mg, 2%) as a white solid (TFA salt): 1H NMR (CD3OD, 300 MHz) 7.93 (s, 2H), 7.84 (m, 4H), 5.20 (m, 1H), 4.23 (d, J=7.2 Hz, 2H), 4.01 (m, 2H), 3.83 (m, 4H), 3.70 (s, 3H), 3.66 (s, 3H), 3.38 (m, 2H), 2.57 (m, 2H), 2.18 (m, 4H), 2.04 (m, 4H), 1.75 (m, 4H), 1.58 (m, 4H), 0.95 (m, 12H); MS (ESI) m/z 725 [M+H]+.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:19][C@H:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[C:13]3[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:12]=3[C:11]2=[O:26])[CH:5]=1.[CH:28](OCCl)=[O:29]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:25][S:24][C:21]1[N:22]=[CH:23][C:12]2[C:11](=[O:26])[N:10]([C:6]3[CH:5]=[C:4]([C:3]4[NH:27][C:28](=[O:29])[O:1][N:2]=4)[CH:9]=[CH:8][CH:7]=3)[CH2:19][C@H:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[C:13]=2[N:20]=1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(N)=NO)c1)C2=O
Reactant: O=COCCl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3noc(=O)[nH]3)c1)C2=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 110.6 %

Procedure:
(S)—N′-hydroxy-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzamidine (200 mg, 0.52 mmol) obtained in Step 1 of Example 75 was dissolved in pyridine (3.0 mL), and the mixture was stirred at 90° C. for 4 hours after adding chloromethyl formate (0.12 mL, 1.56 mmol) under ice-cooled conditions. The mixture was diluted with chloroform, washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by concentrating the mixture under reduced pressure was then purified by silica gel column chromatography to give (S)-3-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,2,4-oxadiazol-5(4H)-one (236 mg, quantitative).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[CH:10]([CH3:23])[N:9]=1.[C:24](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:24])[C:11](=[O:22])[CH:10]([CH3:23])[N:9]=1
Reactant: O=C([O-])[O-]
Reactant: CC1N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2NC1=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CC1N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
95 g (0.30 M) of rac-5-(o-fluorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one are dissolved in 1 liter of absolute acetone and treated with 60 g of powdered potassium carbonate and 43 g of dimethyl sulphate. The mixture is stirred at room temperature for 4 hours and left to stand in a refrigerator for 48 hours. The mixture is then concentrated, treated with ice-water and extracted several times with methylene chloride. The organic solution is dried over sodium sulphate, filtered and concentrated. The residue is crystallised from ethyl acetate/petroleum ether, there being obtained rac-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one which melts at 154°-156° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[C:6]([CH:14]=[C:15]([NH2:17])[CH:16]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].CCN(CC)CC.[Cl:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[C:6]([CH:14]=[C:15]([NH:17][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][Cl:26])[CH:16]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8]
Reactant: O=C(Cl)CCCCl
Reactant: COC(=O)c1cc(N)cc(C(=O)OC(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(NC(=O)CCCCl)cc(C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
A suspension of 5-amino-isophthalic acid 1-tert-butyl ester 3-methyl ester (D79) (3.4 g, 13.5 mmol, 1 equiv) in CH2Cl2 (25 ml) was treated with NEt3 (2.32 g, 23 mmol, 1.1 equiv) and cooled to 0° C. 4-chlorobutyryl chloride (1.6 g, 15.7 mmol, 1.1 equiv) was added dropwise and the resulting solution was stirred at 0° C. for 3 h then allowed to warm to room temperature and washed with 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. The residue was triturated with iso-hexane and Et2O to give 5-(4-chloro-butanoylamino)-isophthalic acid 1-tert-butyl ester 3-methyl ester (D80) (4.5 g, 94%) as a white solid.
Reaction SMILES: [CH3:1][C@@:2]12[CH2:19][CH2:18][C@@H:17]3[C@:12]([CH3:22])([CH2:13][CH2:14][CH2:15][C:16]3([CH3:21])[CH3:20])[C@H:11]1[CH2:10][S:9][C:8]1[C:3]2=[C:4]([OH:24])[CH:5]=[C:6]([OH:23])[CH:7]=1.[CH3:25][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[CH3:25][O:23][C:6]1[CH:7]=[C:8]2[C:3]([C@@:2]3([CH3:1])[C@H:11]([CH2:10][S:9]2)[C@:12]2([CH3:22])[C@H:17]([C:16]([CH3:20])([CH3:21])[CH2:15][CH2:14][CH2:13]2)[CH2:18][CH2:19]3)=[C:4]([OH:24])[CH:5]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CSc4cc(O)cc(O)c4[C@]3(C)CC[C@@H]12
Solvent: ClCCl
Solvent: CO
Product: COc1cc(O)c2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C

Procedure:
(1R,10R,11S,16S)-1,11,15,15-Tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3,5-diol (Compound No. 26) (346 mg, 1.0 mmol) was dissolved in MeOH (4 mL) and CH2Cl2 (12 mL). Trimethylsilyl diazomethane (0.80 mL, 2.0 M in ether, 1.6 mmol) was added portionwise over 29 h at room temperature, monitoring the reaction by 1H NMR. The mixture was then concentrated and purified by chromatography on silica gel (Hexanes/EtOAc, 4:1) followed by recrystallization from MeOH/water to give (1R,10R,11S,16S)-5-methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-ol (Compound No. 29) (142 mg, 39%) as a white solid. 1H NMR (CDCl3): δ 6.21 (d, 1H), 5.95 (d, 1H), 4.72 (s, 1H), 3.69 (s, 3H), 3.30 (m, 1H), 2.91 (m, 1H), 2.78 (m, 1H), 1.85-1.40 (m, 8H), 1.39 (s, 3H), 1.20-1.00 (m, 2H), 0.96 (s, 3H), 0.95 (m, 1H), 0.85 (s, 3H), 0.84 (s, 3H). MS m/z 359 (C22H32O2S−H+).
Reaction SMILES: [OH:1][C@H:2]([C@H:5]1[O:9][C:8](=[O:10])[C@H:7]([CH3:11])[CH2:6]1)[CH2:3][CH3:4].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:12]([O:1][C@H:2]([C@@H:5]1[CH2:6][C@@H:7]([CH3:11])[C:8](=[O:10])[O:9]1)[CH2:3][CH3:4])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC[C@H](O)[C@@H]1C[C@@H](C)C(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC[C@H](OC(=O)c1ccccc1)[C@@H]1C[C@@H](C)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
To a solution of (3R,5S)-5-[(1S)-1-hydroxypropyl]-3-methyl-tetrahydrofuran-2-one (compound 28g, 1.0 g, 6.3 mmol), TEA (3.2 g, 31.2 mmol) and DMAP (100 mg) in DCM (50 mL) was added benzoyl chloride (1.8 g, 12.6 mmol) slowly at 0° C. The mixture was stirred at 25° C. for 4 hours and then quenched by saturated NaHCO3 solution, extracted with EtOAc (100 mL) twice. The organic layers were combined, washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:20 to 1:5 EtOAc in petroleum ether) to afford 1.4 g of [(1S)-1-[(2S,4R)-4-methyl-5-oxo-tetrahydrofuran-2-yl]propyl] benzoate (compound 28h) as a colourless oil.