Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:23]([CH:24]=[O:25])=[CH:22][CH:21]=[C:7]3[C:8]3([CH2:14][CH2:13][N:12](C(=O)C(F)(F)F)[CH2:11][CH2:10]3)[O:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].O>CO>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:23]([CH:24]=[O:25])=[CH:22][CH:21]=[C:7]3[C:8]3([CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)[O:9][C:4]=2[CH:3]=1
Reactant: O=Cc1ccc2n1-c1ccc(Cl)cc1OC21CCN(C(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=Cc1ccc2n1-c1ccc(Cl)cc1OC21CCNCC1

Procedure:
To 7′-chloro-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbaldehyde (510 mg, 1.28 mmol) dissolved in MeOH (5.1 mL) was added K2CO3 (371 mg, 2.69 mmol) in one portion at room temperature. Water was added (2 mL), and organic solvent was removed under vacuum. The mixture was extracted with DCM (3×10 mL). The organics were combined, dried, filtered, and concentrated to give 7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde as a yellow oil, which was used as is for the following step. ESI-MS m/z calc. 302.1. found 303.3 (M+1)+; Retention time: 1.07 minutes (3 min run).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:9]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[C@H:8]([C:17](=[O:25])[N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[O:7][C:6]([C:26]([O:28]C)=[O:27])=[CH:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(N(CC)CC)C>O1CCCC1>[NH2:1][C@@H:4]1[C@@H:9]([NH:10][C:11](=[O:16])[C:12]([F:14])([F:13])[F:15])[C@H:8]([C:17](=[O:25])[N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[O:7][C:6]([C:26]([OH:28])=[O:27])=[CH:5]1
Reactant: CCCN(CCC)C(=O)[C@@H]1OC(C(=O)OC)=C[C@H](N=[N+]=[N-])[C@H]1NC(=O)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CCC)C(=O)[C@@H]1OC(C(=O)O)=C[C@H](N)[C@H]1NC(=O)C(F)(F)F
Temperature: 23 °C
Reaction time: 1.5 h

Procedure:
To a solution of (4S,5R,6R)-4-azido-6-(dipropylcarbamoyl)-5-(2,2,2-trifluoroacetylamino)-5,6-dihydro-4H-pyran-2-carboxylic acid, methyl ester (1 g) in dry tetrahydrofuran (10 ml) was added triphenylphosphine (0.75 g) and the reaction was stirred under nitrogen at 23° C. for 1.5 hours. To this was added water (2 ml) and triethylamine (2 ml) and the mixture was stirred for 16 hours at 23° C. The solvent was removed in vacuo and the residue was chromatographed over silica (Merck 9385, 50 g) using medium pressure (ca 4 psi) and dichloromethane/methanol (15:1 v/v) as the eluant. The required fractions were combined and the solvent removed in vacuo to give the title compound as a white solid. (0.87 g). 1H NMR (250 MHz, D6 -DMSO) 9.25 (1H, d, J=9 Hz), 5.90 (1H, d, J=3 Hz), 4.79 (1H, d, J=9 Hz), 4.00 (1H, m), 3.71 (3H, s), 3.58 (1H, m), 3.40 (2H, m), 3.16 (1H, m), 2.95 (1H, m), 1.84 (2H, s), 1.57 (2H, m), 1.40 (2H, m), 0.81 (6H, m), Mass analysis: C16H24F3N3O5. 0.5 H2O. Required: C, 47.52; H, 6.23; N, 10.39. Found: C, 47.68; H, 6.05; N, 10.10.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]4[N:28]5[CH2:29][CH2:30][NH:31][CH2:32][C:27]5=[N:26][CH:25]=4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[N:35]=2)[N:4]=1)[CH3:2].[BH-](OC(C)=O)(OC(C)=O)O[C:43](C)=O.[Na+].C=O>CO>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]4[N:28]5[CH2:29][CH2:30][N:31]([CH3:43])[CH2:32][C:27]5=[N:26][CH:25]=4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[N:35]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(-c5cnc6n5CCNC6)ccn34)c12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(-c5cnc6n5CCN(C)C6)ccn34)c12
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
To N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide (5 mg, 0.0094 mmol; prepared as in Example 59) in MeOH (4 mL) was added NaBH(OAc)3 (8.0 mg, 0.038 mmol), and HCHO (as a 35% aqueous solution) (15 mg, 0.19 mmol). The reaction mixture was stirred for 30 minutes then concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) to provide the final product (3.2 mg). MS (ES+APCI) m/z=546 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1.C(N(CC)CC)C.[CH3:24][C:25]([O:28][C:29]([NH:31][C:32](N1C=CC=N1)=[N:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:30])([CH3:27])[CH3:26]>CO>[CH3:27][C:25]([O:28][C:29]([NH:31][C:32]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[N:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:30])([CH3:24])[CH3:26]
Reactant: O=C(O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.7 %

Procedure:
To a solution of piperidine-4-carboxylic acid trifluoroacetate salt (0.20 g, 0.82 mmol) in methanol (10 mL), triethylamine (0.20 mL, 1.6 mmol) and N,N′-bis{[(2-methyl-2-propanyl)oxy]carbonyl}-1H-pyrazole-1-carboximidamide (0.30 g, 0.98 mmol) was added and the reaction mixture stirred at room temperature for 18 h. The solvent was evaporated under reduced pressure and the resulting residue dissolved in ethyl acetate and washed with brine. The organic layer was dried and concentrated to dryness to obtain the title compound (200 mg, 76%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:11]O)=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH3:10].S(Cl)([Cl:15])=O>>[ClH:15].[Cl:15][CH2:11][C:4]1[C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=[CH:6][N:5]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccnc(CO)c1OC
Product: COc1ccnc(CCl)c1OC
Product: Cl
Temperature: 25 °C
Yield: 84.6 %

Procedure:
A solution of (3,4-dimethoxypyridin-2-yl)methanol (1 g, 5.91 mmol) in CH2CH2 (11.82 mL) was treated dropwise with thionyl chloride (1 mL, 13.70 mmol) with stirring at room temperature. The reaction mixture was stirred for 2 h, and then concentrated directly in vacuo. The resulting residue was washed with 3×10 mL Et2O, the resulting solids collected by filtration, and then dried under reduced pressure to afford the title compound as a white solid (1.12 g, 85%), which was used in the subsequent step without further purification. Data for 1-1: LC/MS: rt=0.58 min, m/z (M+H)=188.09 found; 188.04 required. 3,4-dimethoxy-2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}-pyridine (1-2)
Reaction SMILES: OO.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[C:12](=[O:24])[C@@H:11]([CH2:25][C:26]#[N:27])[O:10][C@H:9]([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[C:8]=2[CH:38]=1.C(=O)([O-])[O-:40].[K+].[K+]>C(O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[C:12](=[O:24])[C@@H:11]([CH2:25][C:26]([NH2:27])=[O:40])[O:10][C@H:9]([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[C:8]=2[CH:38]=1
Reactant: Cc1nccn1CCCCN1C(=O)[C@@H](CC#N)O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CCO
Product: Cc1nccn1CCCCN1C(=O)[C@@H](CC(N)=O)O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Temperature: 60 °C
Yield: 37.9 %

Procedure:
Hydrogen peroxide solution (30% w /v in H2O, 4 ml) was added to a suspension of trans-7-chloro-5-(1-naphthyl)-1-(4-(2-methylimidazol-1-yl)butyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetonitrile (250 mg, 0.5 mmol) and potassium carbonate (69 mg, 0.5 mmol) in ethanol (10 ml). The mixture was heated at 60° C. for 18 hours. The solvent was removed under reduced pressure, the resulting residue dissolved in dichloromethane and washed with brine. The organic layer was dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane/methanol/ammonia solution 97:3:1) to give a colorless oil. The oil was triturated with hot ethyl acetate/diethyl ether/hexane to give the title compound (98 mg, 38%)as a colorless solid.
Reaction SMILES: [O-:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[Na+].[Na+].Cl[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[N:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][CH2:19][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:9]3)=[CH:4][CH:3]=2)=[CH:23][CH:24]=1
Reactant: O=S(=O)([O-])c1ccc2ccc([O-])cc2c1
Reactant: ClCCCc1ccncc1
Agent: [Na+]
Product: O=S(=O)(O)c1ccc2ccc(OCCCc3ccncc3)cc2c1
Yield: 42.3 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 26B, sodium 7-oxidonaphthalene-2-sulfonate (Pfaltz and Bauer, 200 mg, 0.75 mmol) and 4-(3-chloropropyl)pyridine (116 mg, 0.75 mmol) were converted to the title compound (109 mg, 43%). 1H NMR (DMSO-d6) δ 8.65, (s, 1H), 8.58 (s, 1H), 8.12 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.62 (d, J=5.7 Hz, 1H), 7.57 (dd, J=8.5, 1.9 Hz, 2H), 7.44 (s, 1H), 7.27 (d, J=8.7, 1H), 4.20 (t, J=6.5 Hz, 2H), 3.10 (t, J=7.7 Hz, 2H), 2.30-2.21 (m, 2H); MS(ESI+) m/z 344.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([C:29]2[CH:33]=[CH:32][O:31][CH:30]=2)=[O:28])=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1>>[O:31]1[CH:32]=[CH:33][C:29]([C:27]([NH:26][C:23]2[CH:22]=[CH:21][C:20]([CH3:19])=[C:25]([C:2]3[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=4)=[O:7])=[CH:4][N:3]=3)[CH:24]=2)=[O:28])=[CH:30]1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Product: COc1ccc(NC(=O)c2ccc(-c3cc(NC(=O)c4ccoc4)ccc3C)nc2)cc1

Procedure:
6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-(4-methoxyphenyl)-nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate 2) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 13) using General Method B. LCMS: retention time 3.19 min, MH− 428. NMR: δH [2H6]-DMSO 10.38, (1H, s), 10.00, (1H, s), 9.19, (1H, s), 8.38, (2H, m), 7.83, (1H, s), 7.80, (1H, s), 7.76, (1H, s), 7.73-7.69, (3H, m), 7.32, (1H, s), 7.01, (1H, s), 6.96, (2H, d), 3.76, (3H, s), 2.34, (3H, s).
Reaction SMILES: N([O-])=O.[Na+].[ClH:5].[CH3:6][S:7][C:8]1[N:9]=[CH:10][C:11](N)=[N:12][CH:13]=1>O>[Cl:5][C:11]1[CH:10]=[N:9][C:8]([S:7][CH3:6])=[CH:13][N:12]=1
Reactant: Cl
Reactant: CSc1cnc(N)cn1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CSc1cnc(Cl)cn1
Reaction time: 1 h
Yield: 26 %

Procedure:
Sodium nitrite (50.9 g, 0.74 mol) was dissolved in water (150 mL), followed by dropwise addition into a 5N aqueous hydrochloric acid solution (1.0 L) at 0° C. over 1 hour. Subsequently, 5-(methylsulfanyl)pyrazine-2-amine (40.4 g, 0.28 mol) synthesized in Example (97a) was added at 0° C. over 40 minutes, and stirring was carried out at 0° C. for 1 hour. The reaction solution was brought back to room temperature, and water (500 mL) was added, followed by extraction with ethyl acetate (1.0 L). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-20%) to afford the desired compound (11.9 g, yield 26%) as a white solid.
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](=S)[NH2:23])C1C=CC=CC=1.CI.[F:27][C:28]1[CH:38]=[CH:37][C:31]([CH2:32][N:33]([CH:35]=O)[NH2:34])=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+]>C(#N)C.CN(C=O)C>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH:35]=[N:23][C:22]([C:10]3[N:11]=[C:12]4[N:17]([C:18](=[O:19])[C:9]=3[OH:8])[CH2:16][CH2:15][O:14][C:13]4([CH3:20])[CH3:21])=[N:34]2)=[CH:37][CH:38]=1
Reactant: CC1(C)OCCn2c1nc(C(N)=S)c(OCc1ccccc1)c2=O
Reactant: NN(C=O)Cc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CI
Solvent: CN(C)C=O
Product: CC1(C)OCCn2c1nc(-c1ncn(Cc3ccc(F)cc3)n1)c(O)c2=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carbothioamide (0.042 g, 0.122 mmol, 1.0 equiv) in acetonitrile (1.2 mL) under a nitrogen atmosphere, was added MeI (0.038 mL, 0.61 mmol, 5 equiv). The reaction was heated at 40° C. (oil bath) for 1 h. The reaction was then cooled to ambient temperature and concentrated in vacuo. N-(4-Fluorobenzyl)formohydrazide (0.045 g, 0.268 mmol, 2.2 equiv) was then added to the residue followed by DMF (1.5 mL) and the solution was heated at 140° C. (oil bath). After stirring 1 h, the reaction was cooled to ambient temperature stirred 17 h. The reaction was added to a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×3). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo. The crude product was purified by reverse phase preparatory HPLC and trituration from ether to provide the title compound (0.024 g, 53% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.10 (s, 1H), 7.29-7.35 (m, 2H), 7.07-7.14 (m, 2H), 5.44 (s, 2H), 4.02-4.10 (m, 4H), 1.68 (s, 6H); LCMS (ES+, (M+H)+) m/z 372.20.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:25]([SH:28])[CH:26]=[CH2:27].F[C:30]1[C:31]([S:36]([NH2:39])(=[O:38])=[O:37])=[N:32][CH:33]=[CH:34][CH:35]=1>C(#N)C>[CH2:25]([S:28][C:30]1[C:31]([S:36]([NH2:39])(=[O:38])=[O:37])=[N:32][CH:33]=[CH:34][CH:35]=1)[CH:26]=[CH2:27]
Reactant: NS(=O)(=O)c1ncccc1F
Reactant: C=CCS
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCSc1cccnc1S(N)(=O)=O

Procedure:
33.2 g (0.24 mol) of potassium carbonate as well as 1.32 g (0.005 mol) of 18-crown-6 and 15.8 g (0.17 mol) of 80% allylmercaptan in 50 ml of acetonitrile are added to a solution, cooled to +5° C., of 17.62 g (0.1 mol) of 3-fluoropyridin-2-ylsulfonamide in 400 ml of acetonitrile.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.C(OCC)(=O)C>[CH3:29][C:25]1([CH3:28])[CH2:24][CH2:23][N:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:13]3[CH:12]=[N:11][C:6]4[NH:7][C:8]5[CH:9]=[N:10][C:2]([C:34]6[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=6)=[CH:3][C:4]=5[C:5]=4[CH:14]=3)=[CH:16][CH:17]=2)[CH2:27][CH2:26]1
Reactant: CC1(C)CCN(Cc2ccc(-c3cnc4[nH]c5cnc(Br)cc5c4c3)cc2)CC1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc3c(cn2)[nH]c2ncc(-c4ccc(CN5CCC(C)(C)CC5)cc4)cc23)cn1
Temperature: 130 °C
Yield: 38.5 %

Procedure:
A degassed mixture of 6-bromo-3-[4-(4,4-dimethylpiperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (200 mg, 0.45 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (185 mg, 0.89 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37 mg, 0.05 mmol) in 2N aqueous sodium carbonate solution (5 mL) and acetonitrile (5 mL) was heated under microwave irradiation at 130° C. for 20 minutes. The cooled reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (75 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 10 g column, Biotage, 0-15% methanol in DCM) to afford the title compound as a white solid (78 mg, 38%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.85 (d, J=1.1 Hz, 1H), 8.81 (d, J=2.2 Hz, 1H), 8.79 (d, J=2.2 Hz, 1H), 8.33 (d, J=1.1 Hz, 1H), 8.08 (s, 1H), 8.06 (d, J=08 Hz, 1H), 7.70 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.1 Hz, 2H), 4.00 (s, 3H), 3.63 (s, 2H), 2.51 (t, J=5.0 Hz, 4H), 1.46 (t, J=5.6 Hz, 4H), 0.96 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C@@H:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[CH3:11])[C:6]=2[CH:20]=1.C(O[C:26]([N:28]1[CH2:33][CH:32]=[C:31](B(O)O)[CH2:30][CH2:29]1)=[O:27])(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C@H:10]([N:7]1[C:6]2[CH:20]=[C:2]([C:31]3[CH2:30][CH2:29][N:28]([C:26]([C@H:29]4[CH2:30][CH2:31][CH2:32][CH2:33][NH:28]4)=[O:27])[CH2:33][CH:32]=3)[CH:3]=[CH:4][C:5]=2[N:9]=[CH:8]1)[CH3:11]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(Br)cc21
Reactant: CC(C)(C)OC(=O)N1CC=C(B(O)O)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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(C3=CCN(C(=O)[C@H]4CCCCN4)CC3)cc21
Temperature: 100 °C

Procedure:
A mixture of (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d]imidazole (1.3 g, 3.5 mmol), (N-t-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)boronic acid pincol ester (1.2 g, 3.9 mmol), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 0.20 g, 0.18 mmol), and 2 M aqueous potassium carbonate (5.3 mL, 10.5 mmol) in toluene (10 mL) and ethanol (5 mL). The mixture was purged with nitrogen for 5 min, and then heated at 100° C. for 2 h. After cooling to room temperature, the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. The resulting crude material was purified by flash chromatography (SiO2, 0-100% ethyl acetate in hexanes) to afford the desired product in 90% purity (1.6 g, 3.4 mmol, 97%). MS: (ES) m/z calculated for C25H28Cl2N3O [M+H]+472.2, found 472.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17].C([O:23][C:24]([NH:26][C@@H:27]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[S:42](=[O:44])(=[O:43])[N:41](C(C)(C)C)[C:40](=[O:49])[CH:39]=2)=[CH:34][CH:33]=1)[C:28](O)=[O:29])=O)(C)(C)C.[CH2:50](Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:18])[C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:28](=[O:29])[C@@H:27]([NH:26][C:24](=[O:23])[CH3:50])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[S:42](=[O:44])(=[O:43])[NH:41][C:40](=[O:49])[CH:39]=2)=[CH:34][CH:33]=1
Reactant: ClCCCl
Reactant: COC(=O)c1c(O)cccc1OCCCCN
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)cc1)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@H](Cc1ccc(C2=CC(=O)NS2(=O)=O)cc1)NC(C)=O
Temperature: 40 °C
Reaction time: 4 h
Yield: 53.6 %

Procedure:
21-A (Bioorg. & Medchem. Lett. (2003), 13, 3129–3132) (8 mg, 0.029 mmol) was added to a DCM (0.1 M) solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-(2-tert-butyl-1,1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)phenyl]propanoic acid (12 mg, 0.027 mmol), EDC (5 mg, 0.027 mmol), HOBt (3.6 mg, 0.027 mmol) and DIEA (10 μL, 0.029 mmol). The reaction was stirred at 40° C. for 4 h and then concentrated. The crude was purified by reverse phase HPLC to afford 21-B (8.1 mg, 44%).
Reaction SMILES: B(O)(O)[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[C:11](=[O:14])([O-])[O-].[Cs+].[Cs+].[C:17](Cl)(=O)[CH2:18][CH2:19]C>C1(C)C=CC=CC=1.CCOCC.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>[CH3:8][C:5]1[CH:4]=[CH:3][C:2]([C:11](=[O:14])[CH2:17][CH2:18][CH3:19])=[CH:7][CH:6]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCCC(=O)Cl
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCC(=O)c1ccc(C)cc1
Temperature: 100 °C
Yield: 75.2 %

Procedure:
p-Tolylboronic acid (0.150 g, 1.10 mmol), tetrakis(triphenylphosphine)palladium(0) (0.064 g, 0.055 mmol), and cesium carbonate (1.80 g, 5.52 mmol) were suspended in toluene (25 mL). The reaction mixture was purged under a vigorous flow of nitrogen for 15 minutes. Butyryl chloride (0.344 mL, 3.31 mmol) was added, and the reaction mixture was heated at 100° C. under an atmosphere of nitrogen for 24 h. The reaction mixture was cooled to ambient temperature and diluted with ether (100 mL). The organic layer was extracted sequentially with water (10 mL), aqueous sodium bicarbonate (10 mL), and aqueous sodium chloride (10 mL). The organic layer was dried (magnesium sulfate), filtered, and concentrated. Purification of the residue by flash column chromatography (7.5% ether/petroleum ether) afforded 1-(4-methylphenyl)-1-butanone as a colorless oil (0.134 g, 0.827 mmol): 1H NMR (CDCl3, 400 MHz) δ 7.86 (d, 2H), 7.25 (d, 2H), 2.92 (t, 2H), 2.41 (s, 3H), 1.76 (sx, 2H), 1.00 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[CH2:12][CH2:11]3)[CH:5]=[CH:6][CH:7]=1.[BrH:18].[Br:19]Br>C(O)(=O)C.O>[Br:18][CH:12]1[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:9]=2)[C:13]1=[O:17].[Br:18][C:12]1([Br:19])[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:9]=2)[C:13]1=[O:17]
Reactant: O=C1CCc2cc(-c3cccc(Cl)c3)ccc21
Reactant: Br
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccc(-c3cccc(Cl)c3)cc2CC1(Br)Br
Product: O=C1c2ccc(-c3cccc(Cl)c3)cc2CC1Br
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2.42 g (10 mmol) of 5-(3-chlorophenyl)indan-1-one are dissolved in 30 ml of glacial acetic acid and, after addition of 10 μl of a 48% strength HBr solution in water, treated dropwise while stirring with a solution of 0.77 ml (15 mmol) of bromine in 7 ml of glacial acetic acid. After the reaction mixture has been stirred at room temperautre for 3 h, it is poured into a mixture of 100 g of ice with 70 ml of water and 100 mg of NaHSO3and stirred. The resulting 25 suspension is extracted by shaking with 200 ml of dichloromethane, and the organic phase is then washed with water (3×100 ml), dried over magnesium sulfate, concentrated in vacuo and purified by chromatography on silica gel with toluene/ethyl acetate 50/1. 2-Bromo-5-(3-chlorophenyl)indan-1-one, is obtained with a melting point of 110° C., in addition to a little 2,2-dibromo-5-(3-chlorophenyl)indan-1-one.