Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:29]3[CH:30]=[C:31](OS(C(F)(F)F)(=O)=O)[CH:32]=[CH:33][C:28]=3[N:27]3[C:42]([CH3:45])=[N:43][N:44]=[C:26]3[C@H:25]([CH2:46][C:47]([O:49]CC)=[O:48])[N:24]=2)=[CH:19][CH:18]=1.O>COCCOC.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.C(OCC)(=O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:29]3[CH:30]=[C:31]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH:32]=[CH:33][C:28]=3[N:27]3[C:42]([CH3:45])=[N:43][N:44]=[C:26]3[C@H:25]([CH2:46][C:47]([OH:49])=[O:48])[N:24]=2)=[CH:21][CH:22]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2-n2c(C)nnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1nnc2n1-c1ccc(-c3ccccc3)cc1C(c1ccc(Cl)cc1)=N[C@H]2CC(=O)O
Temperature: 120 °C

Procedure:
Sodium carbonate (35.8 mg), phenylboronic acid (22.5 mg) and bis(triphenylphosphine)palladium(II) chloride (10.8 mg) were added to a 2-5 ml microwave vial. A solution of ethyl ((4S)-6-(4-chlorophenyl)-1-methyl-8-{[(trifluoromethyl)sulfonyl]oxy}-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)acetate (for a preparation see Intermediate 2) (83.4 mg) in DME (3 ml) and water (1 ml) was added to the microwave vial. The reaction mixture was heated at 120° C. for 90 min (microwave). Ethyl acetate (2 ml) was added and the water layer was separated and acidified with glacial acetic acid. The water layer was extracted with ethyl acetate (3×5 ml) and the organic layer was dried and the solvent evaporated. The residue was chromatographed (0-10% methanol:DCM) to give [(4S)-6-(4-chlorophenyl)-1-methyl-8-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetic acid as a white oil (30.1 mg), which was used without further purification in the subsequent reaction. LCMS (formate): MH+ 443/445, RT 1.09 min
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].CN(C=O)C.IC>O>[CH3:10][O:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(O)c(C)c1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
2,4-dimethylphenol (7.5 g, 0.062 mol) and anhydrous potassium carbonate (25.4 g, 0.18 mol) were dissolved into DMF (75 mL) and then iodomethane (8.83 g, 0.062 mol) was dropped under an ice bath. The system was stirred overnight at room temperature. At the end of reaction, the reaction system was added with water and then extracted with ethyl acetate, and the organic phase was washed with saturated brine, then dried and evaporated in vacuum to obtain 7.11 g of the product (85%) by column chromatography.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]3[CH:20]=[N:21][CH:22]=[N:23][CH:24]=3)=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:59][C:60]1[S:61][CH:62]=[CH:63][N:64]=1>C(Cl)Cl.O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[C:18][C:19]3[CH:20]=[N:21][CH:22]=[N:23][CH:24]=3)=[CH:15][CH:16]=2)[C:8]([NH:59][C:60]2[S:61][CH:62]=[CH:63][N:64]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(C#Cc2cncnc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(C#Cc2cncnc2)cc1
Yield: 47.8 %

Procedure:
A solution of 3-cyclopentyl-2-(4-pyrimidin-5-ylethynyl-phenyl)-propionic acid (150 mg, 0.53 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (376 mg, 0.85 mmol), triethylamine (0.22 mL, 1.59 mmol) and 2-aminothiazole (85 mg, 0.85 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 18 h. At this time, the reaction was diluted with water (10 mL). The organic phase was separated and washed with a 1N aqueous sodium hydroxide solution, and a saturated aqueous sodium chloride solution. The aqueous layers were each back-extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-pyrimidin-5-ylethynyl-phenyl)-N-thiazol-2-yl-propionamide (102 mg, 54%) as a white solid: mp 149-151 ° C.; EI-HRMS m/e calcd for C23H22N4OS (M+) 402.1514, found 402.1516.
Reaction SMILES: [N:1]1([C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[NH:8][CH:9]=[N:10]3)[CH:5]=[CH:4][N:3]=[CH:2]1.C(O[C@@H:19]1[O:41][C@H:40]([CH2:42][O:43][C:44](=[O:51])[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@@H:30]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@H:20]1[O:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=O)C.C([O-])(O)=O.[Na+].O>CC#N>[C:22]([O:21][C@@H:20]1[C@H:30]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:40]([CH2:42][O:43][C:44](=[O:51])[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[O:41][C@H:19]1[N:10]1[CH:9]=[N:8][C:7]2[C:11]1=[N:12][CH:13]=[N:14][C:6]=2[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1cn(-c2ncnc3nc[nH]c23)cn1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(OC[C@H]1O[C@@H](n2cnc3c(-n4ccnc4)ncnc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.4 %

Procedure:
6-(Imidazol-1-yl)purine (52 mg, 0.28 mmol) was suspended in a solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (160 mg, 0.32 mmol) in dried CH3CN (10 mL). Stannic chloride (0.10 mL, 0.22 g, 0.85 mmol) was added, and the mixture very rapidly became a clear solution. The solution was stirred at ambient temperature for 4 h. NaHCO3 (0.8 g) and H2O (0.1 mL) were added sequentially, and the suspension was stirred for 1 h. The clear solution layer was separated, and the residue was extracted with CH3CN. The extracts and the solution layer were combined, and volatiles were evaporated in vacuo. The residue was chromatographed (CH2Cl2/MeOH, 1:90→1:15) to give 9-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-6-(imidazol-1-yl)purine (179 mg, quantitative): 1H NMR (500 MHz, CDCl3) δ 4.72 (dd, J=4.3, 12.2 Hz, 1H), 4.88 (br s, 1H), 4.95 (dd, J=3.0, 12.3 Hz, 1H), 6.29 (“t”, J=5.2 Hz, 1H), 6.47-6.50 (m, 2H), 7.24 (s, 1H), 7.35-7.60 (m, 9H), 7.93 (d, J=7.6 Hz, 2H), 8.03 (d, J=7.6 Hz, 2H), 8.07 (d, J=7.6 Hz, 2H), 8.28 (s, 1H), 8.35 (s, 1H), 8.65 (s, 1H), 9.13 (s, 1H); 13C NMR (125 MHz, CDCCl3) δ 165.0, 164.3, 164.1, 152.1, 151.5, 144.9, 142.2, 136.6, 132.9, 132.8, 132.4, 129.7, 128.8, 128.7, 128.2, 127.5, 127.2, 122.0, 116.3, 86.4, 79.9, 72.9, 70.3, 62.3; HRMS m/z 653.1749 (MNa+[C34H26N6O7Na]=653.1761).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][O:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[N:6]1)=[O:4].N12CCCN=C1CCCCC2.BrC(Cl)(Cl)Cl>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[O:8][CH:9]=1)=[O:4]
Reactant: COC(=O)C1COC(C2CCN(C(=O)OC(C)(C)C)CC2)=N1
Solvent: ClC(Cl)(Cl)Br
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1coc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[4,5-dihydro-4-(methoxycarbonyl)-2-oxazolyl]-1-piperidinecarboxylate (i.e. the product of Example 7, Step B) (2.89 g, 9.26 mmol) in 100 mL of dichloromethane at 0° C. was added 1.52 mL (10.18 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the reaction mixture was stirred for 10 minutes at 0° C. Bromotrichloromethane (1 mL, 10.18 mmol) was added dropwise over 7 minutes, and the reaction mixture was stirred for 6 h at 0° C. The mixture was washed with saturated aqueous ammonium chloride (2×50 mL), the aqueous phase was extracted with ethyl acetate (2×25 mL), and the combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 25-75% of ethyl acetate in hexanes as eluant to give 1.41 g of the title compound as white crystals.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]([F:12])[CH:8]=[C:7]([OH:13])[C:6]=2[C:5]([CH2:14][CH2:15][OH:16])=[CH:4]1)[CH3:2].[C:17](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[C:7]([O:13][CH3:17])[CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([CH2:14][CH2:15][OH:16])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(CCO)c2c(O)cc(F)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCn1cc(CCO)c2c(OC)cc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
39-2 (318 mg, 1.43 mmol) was dissolved in DMF (5 mL) and then potassium carbonate (236 mg, 1.71 mmol) and methyl iodide (98 uL, 1.56 mmol) were added. The reaction mixture was stirred at room temperature overnight, concentrated under vacuum and then water added. A solid was filtered to afford 39-3 (313 mg, 90%) as a light purple solid. LCMS: calc 326.2. found 327.1 [MH]+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]([F:16])([F:15])[F:14])[CH:10]=2)[O:5][C:4]([CH3:18])([CH3:17])[C@H:3]1[OH:19].C(N(CC)CC)C.[N+:27]([C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33])([O-:29])=[O:28].C(N)(=O)C1C=CC=CC=1>ClCCl>[OH:19][C@H:3]1[C@H:2]([NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=2[N+:27]([O-:29])=[O:28])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]([F:16])([F:14])[F:15])[CH:10]=2)[O:5][C:4]1([CH3:17])[CH3:18]
Reactant: CC1(C)Oc2ccc(OC(F)(F)F)cc2[C@@H](N)[C@@H]1O
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Agent: NC(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)Oc2ccc(OC(F)(F)F)cc2[C@@H](NC(=O)c2ccccc2[N+](=O)[O-])[C@@H]1O
Temperature: 15 °C
Yield: 47 %

Procedure:
(3S,4R)-4-Amino-2,2-dimethyl-6-(trifluoromethoxy)-chroman-3-ol [prepared by the method of Quagliato et al. Biorg. & Med. Chem. Let. 1991 1, 39; (2.75 g, 10 mmol)] and triethylamine (1.39 mL, 10 mmol) were stirred together in dichloromethane (25 mL) at 0° C. To this solution was added a solution of 2-nitrobenzoylchloride (1.32 mL, 10 mmol) in dichloromethane (10 mL). The ice bath was allowed to gradually warm to 15° C. overnight. The crude benzamide was diluted with dichloromethane (50 mL), washed with water (2×10 mL), dried (MgSO4) and concentrated to afford 2.0 g (47%) of white solid: m.p. 189°-190° C.; 1H NMR (DMSO-d6): δ 9.17 (d, 1H), 8.04 (d, 1H), 7.81 (m, 2H), 7.71 (t, 1H), 7.33 (s, 1H), 7.16 (d, 1H), 6.86 (d, 1H), 5.86 (d, 1H), 4.96 (br t, 1H), 3.64 (dd, 1H), 1.42 (s, 3H), 1.19 (s, 3H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([NH2:18])[CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1.O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:12]([N:18]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])[CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCC1CCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1CC1CCCO1

Procedure:
19.8 g (134 mmol) of phthalic anhydride were dissolved in 500 ml of chloroform. To the resultant solution, 10 g (99 mmol) of tetrahydrofurfurylamine were added with stirring. The resultant mixture was subjected to a reflux overnight while the reactant water yielded was distilled off. The thus obtained reaction mixture was allowed to cool and then was poured into 300 ml of aqueous solution of saturated sodium hydrogencarbonate. Thereafter, an organic solvent layer was separated from the reaction mixture. The residual water layer was subjected to an extraction twice with chloroform and the extract thus obtained was combined with the organic solvent layer which was previously separated.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].B([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(O)O.C(N(CC)CC)C>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:7][O:6][C:4]([C:3]1[CH:8]=[C:9]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH:10]=[CH:11][C:2]=1[C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=[O:5]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(N2CCCC2=O)ccc1Br
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)O)cc1
Temperature: 100 °C

Procedure:
A stirred solution of methyl 2-bromo-5-(2-oxopyrrolidin-1-yl)benzoate (D52, 1.7 g; 5.73 mmol) in DMF (13 ml) was treated with 4-boronobenzoic acid (0.95 g,5.73 mmol) under argon, followed by tetrakis(triphenylphosphine)palladium (O) (104 mg) and triethylamine (2.34 ml, 0.02 mol). After heating for 18 h at 100° C., the reaction mixture was concentrated under reduced pressure and the residue partitioned between 10% aqueous Na2CO3 solution and ethyl acetate. The basic aqueous layer was acidified with 5M HCl acid, precipitating the crude product as a white solid, which was recrystallised from ethanol (137 mg, 7%).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:29][C:30]1[C:35]([Cl:36])=[CH:34][C:33]([O:37][CH3:38])=[CH:32][C:31]=1[Cl:39]>C1COCC1.O.CCOCC>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@H:15]([CH2:29][C:30]1[C:31]([Cl:39])=[CH:32][C:33]([O:37][CH3:38])=[CH:34][C:35]=1[Cl:36])[CH2:16][CH:17]=[CH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: COc1cc(Cl)c(CBr)c(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: C=CC[C@@H](Cc1c(Cl)cc(OC)cc1Cl)C(=O)N1C(=O)OCC1Cc1ccccc1
Temperature: -60 °C
Yield: 76 %

Procedure:
Stir a mixture of (R)-4-benzyl-3-pent-4-enoyl-oxazolidin-2-one (5.0 g, 19.3 mmol) and tetrahydrofuran (75 mL) in a 250 mL round bottom flask at −75° C. Transfer 2 M LDA (14.5 mL) to the flask via syringe and add at a rate such that the internal temperature does not reach above −60° C. After the addition is complete, allow the reaction to stir at −25° C. for 30 min then cool to about −60° C. At this point, add a solution of 2-bromomethyl-1,3-dichloro-5-methoxy-benzene (7.76 g, 28.96 mmol) in THF (25 mL). After the addition is complete, the reaction vessel is allowed to slowly warm up to 0° C., and maintain the internal reaction temperature at 0° C. for 4 hr. Quench the reaction with 30 mL aqueous 1N hydrochloric acid. Transfer the mixture to a 500 mL separatory funnel and dilute with 100 mL water and 100 mL ether. Separate the layers and extract the aqueous layer with ether. Dry the combined organic phase over anhydrous sodium sulfate, filter and concentrate to give a thick oil. Purify by silica gel chromatography using hexanes:ethyl acetate to obtain 6.65 g, (76%) of a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=O)[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].[OH-].[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:20][OH:21])[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Cc2cccc(Cl)n2)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(Cc2cccc(Cl)n2)=NO)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a solution of 2-(6-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone (37.4 g, 142.9 mmol) in methanol (500 mL) was added hydroxylamine hydrochloride (49.7 g, 714.5 mmol) followed by the addition of a sodium hydroxide solution (28.6 g, 714.5 mmol in 50 mL of water). The resulting suspension was heated at reflux for 2 hours and then allowed to cool to room temperature. The mixture was concentrated and water was added to the resulting slurry. A white precipitate formed, which was collected by filtration, washed with water and dried to give 2-(6chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone oxime (38.7 g, 97%) as a white solid. 1H NMR (CDCl3): δ 8.23 (b, 1H), 7.63 (d, 2H), 7.48 (d,1 H), 7.12 (m, 2H), 6.83 (dd, 2H), 4.33 (s, 2H), 3,76 (s, 3 H); MS m/z 277 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]([CH3:21])([CH3:20])[CH2:9][C:10]1[C:18]2[C:13](=[C:14](O)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25][O:26][C:27](=[O:30])CCl.CN(C)[CH:33]=[O:34]>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]([CH3:21])([CH3:20])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([C:27]([O:26][CH2:25][O:34][CH3:33])=[O:30])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CCl
Reactant: CC(C)(Cc1c[nH]c2c(O)cccc12)NC(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COCOC(=O)c1cccc2c(CC(C)(C)NC(=O)OC(C)(C)C)c[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 30 %

Procedure:
A solution of [2-(7-hydroxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester (609 mg, 2.0 mmol) is dissolved in dry dimethylformamide (30 ml) under a nitrogen atmosphere and treated with sodium hydride (84 mg, 2.1 mmol, 60% dispersion in oil) added portion-wise over a 10 minute period. The mixture is cooled in an ice/water bath and methyl-2-chloroacetate (434 mg, 4.0 mmol) is added drop-wise over 20 minutes. The ice bath is removed and the mixture stirred at room temperature for 15 hours. The reaction is then quenched with saturated brine and extracted with ethyl acetate. The ethyl acetate layer is dried and concentrated to give a crude residue, which is purified by silica gel chromatography (gradient elution, chloroform with 1%-10% of 20% methanol in acetonitrile) to give 230 mg of [2-(7-(methoxycarbomethoxy)-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester (30%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH2:24](N(CC)CC)C.[CH2:31]([O:35][C:36](Cl)=[O:37])[CH:32](C)[CH3:33].C(OCC)(=O)C.C(Cl)Cl>C(Cl)Cl>[CH3:24][CH2:33][CH2:32][CH2:31][O:35][C:36]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1)=[O:37]
Reactant: CC(C)COC(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCOC(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 3 h

Procedure:
To a stirred solution of 0.15 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 2 ml of methylene chloride is added 0.10 g of triethylamine followed by 0.10 g of isobutylchloroformate. The reaction mixture is stirred for 3 hours and then quenched with 1N NaOH. The organic layer is evaporated in vacuo to a residue which is stirred in 5 ml of tetrahydrofuran for 1 hour, then evaporated in vacuo to a residue. The residue is extracted with ethyl acetate-methylene chloride, washed with brine, dried (Na2SO4), filtered through hydrous magnesium silicate and evaporated in vacuo to give a residue which is stirred with ethyl acetate-methylene chloride to give 0.22 g of cream colored solid. MS(CI): 404(M+H).
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:39]=[C:38]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][CH:24]([N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:32])[CH2:3][CH2:4]2)=[O:9])[CH:37]=[CH:36][CH:35]=1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(Cl)c1)N1CCC(N2CCCC2)CC1
Yield: 93 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 169), 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a brown oil (93%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([S:45]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=3)(=[O:47])=[O:46])[CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1
Reactant: COC(=O)Cc1cc(C2CCNCC2)c2cc(F)ccc2c1
Reactant: O=S(=O)(Cl)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccccn3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
Diisopropylethylamine (0.4 mL, 2.3 mmol) was added at 0° C. to a solution of (6-fluoro-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 100 mg, 0.24 mmol) in CH2Cl2 (6 mL). The solution was stirred at room temperature for 30 min and then a solution of pyridine-2-sulfonyl chloride (which may be prepared as described above; 213 mg, 1.2 mmol) in CH2Cl2 (1 mL) was added. The mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure The residue was purified by chromatography on silica gel using a Biotage purification system, eluting with 25% ethyl acetate/hexanes, to give {6-fluoro-4-[1-(pyridine-2-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (32 mg, 30%) as a white solid. MS cald. for C23H24FN2O4S [(M+H)+]: 443, obsd. 443.3.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]1[CH:12]=[CH:13][C:14](=[O:17])[NH:15][CH:16]=1.[C:18](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:18][N:15]1[CH:16]=[C:11]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[CH3:1])[CH:12]=[CH:13][C:14]1=[O:17]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(-c2ccc(=O)[nH]c2)cccc1[N+](=O)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(=O)n(C)c2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 5-(2-methyl-3-nitrophenyl)pyridin-2-one (9) (0.92 g, 4.0 mmol), DMF (40 mL), potassium carbonate (1.21 g, 8.80 mmol) and iodomethane (625 mg, 4.40 mmol) and purged with nitrogen. The reaction mixture was stirred at room temperature for 2 h. After this time the reaction was cooled to room temperature and partitioned between ethyl acetate (150 mL) and water (75 mL). The organic layer was separated and washed with water (2×50 mL) followed by brine (100 mL) and dried over magnesium sulfate. The drying agent was then removed by filtration and the filtrate concentrated under reduced pressure to afford 0.92 g (94%) of 1-methyl-5-(2-methyl-3-nitrophenyl)pyridin-2-one (10) as a white solid: mp 157-159° C.; 1H NMR (300 MHz, CDCl3) 7.81 (dd, 1H, J=7.8, 1.8 Hz), 7.41 (dd, 1H, J=7.8, 1.8 Hz), 7.38 (d, 1H, J=7.5 Hz), 7.53 (d, 1H, J=9.3 Hz), 7.32 (dd, 1H, J=9.3, 2.7 Hz), 7.27 (d, 1H, J=1.5 Hz), 6.68 (d, 1H, J=9.3 Hz), 3.62 (s, 3H), 2.37 (s, 3H); MS (ESI+) m/z 245 (M+H).