Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]2=[N:10][C:9]=1[CH:19]([OH:22])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:22][CH:19]([C:9]1[N:10]=[C:11]2[CH2:18][CH2:17][CH2:16][CH2:15][N:12]2[C:13](=[O:14])[C:8]=1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:20][CH3:21])(=[O:33])=[O:32]
Reactant: CCC(O)c1nc2n(c(=O)c1Cc1ccccc1)CCCC2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(OS(C)(=O)=O)c1nc2n(c(=O)c1Cc1ccccc1)CCCC2
Temperature: 0 °C
Yield: 100 %

Procedure:
A mixture of 0.084 g (0.28 mmol) of the product (24) from Step 8 and 0.08 mL (0.56 mmol) of triethylamine in 2.5 mL of anhydrous DCM was cooled to 0° C. Then was added dropwise 0.03 mL (0.34 mmol) of methanesulfonyl chloride and the resulting mixture was allowed to warm to ambient temperature under nitrogen. Excess DCM was added and the reaction mixture was washed with water, saturated NaHCO3 and brine. The organic layer was then dried over MgSO4 and the solvent was removed in vacuo yielding 0.106 g (0.28 mmol, 100%) of 1-(3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-2-yl)propyl methanesulfonate (25) as a tan oil.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]4[NH:29][CH:30]=[CH:31][N:32]=4)=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:8][C:9]([O:11]CC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>O1CCOCC1>[C:1]1([CH:7]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]4[NH:32][CH:31]=[CH:30][N:29]=4)=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(c1ccccc1)c1c[nH]c2cc(OCCCNc3ncc[nH]3)ccc12
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CC(c1ccccc1)c1c[nH]c2cc(OCCCNc3ncc[nH]3)ccc12

Procedure:
25 mg (0.058 mmol) of 10 are stirred at 70° C. for 36 hours in 1 ml of dioxane together with 0.3 ml of 1N HCl (0.3 mmol), giving 3-phenyl-3-{6-[3-(imidazol-2-ylamino)propoxy]indol-3-yl}propionic acid. Preparative HPLC gives 3-phenyl-3-{6-[3-(imidazol-2-ylamino)propoxy]indol-3-yl}propionic acid trifluoroacetate.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1OS(C(F)(F)F)(=O)=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([NH:19][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccccc1
Reactant: O=S(=O)(Oc1ccc2ccccc2c1)C(F)(F)F
Product: c1ccc(Nc2ccc3ccccc3c2)cc1
Yield: 98 %

Procedure:
Using the general procedure for anilines with 66.8 mg (0.242 mmol) of 2-naphthyltriflate and 30.0 μl (0.329 mmol) of aniline yielded N-phenyl-2-naphthylamine as a white solid (52 mg, 98%), whose NMR spectra were identical to commercial material available from Aldrich.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@@H:4]1[CH2:8][CH:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[CH:31]1[C:39]2[C:38]3[CH:40]=[CH:41][CH:42]=[CH:43][C:37]=3[O:36][C:35]=2[C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=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>[CH3:1][O:2][C:3](=[O:30])[C@@H:4]1[CH2:8][CH:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:43]4[C:37]5[O:36][C:35]6[CH:34]=[CH:33][CH:32]=[CH:31][C:39]=6[C:38]=5[CH:40]=[CH:41][CH:42]=4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: OB(O)c1cccc2c1oc1ccccc12
Reactant: COC(=O)[C@@H]1CC(Oc2ccc(-c3ccc(Br)cc3)cc2)CN1C(=O)OC(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: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CC(Oc2ccc(-c3ccc(-c4cccc5c4oc4ccccc45)cc3)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 75 %

Procedure:
A solution of 4-(4′-bromobiphen-4-yloxy)-N-tert-butoxycarbonyl-proline methyl ester (476 mg, 1 mmol), 4-dibenzofuranylboronic acid (222 mg, 1.05 mmol) and Pd(PPh3)4 (52 mg, 5% mol) in toluene (10 mL) and ethanol (2.5 mL) was heated until the solution became clear and subsequently treated with 2 M K2CO3 (1.5 mL). The reaction mixture was heated to reflux for 2 h, cooled to room temperature, diluted with ethyl acetate (100 mL). The organic layer was washed successively with 2% aq HCl and sat. aq NaCl, dried over MgSO4, filtered and concentrated. Purification by flash column chromatography (2-10% ethyl acetate in heptane) gave 4-(4′-dibenzofuran-4-yl-bipheny-4-yloxy)-N-tert-butoxycarbonyl-proline methyl ester (423 mg, 75%) as a foam. 1H NMR (CDCl3), δ 7.97 (m, 4H), 7.71 (dd, J=1, 8 Hz, 2H), 7.62 (m, 4H), 7.45 (m, 3H), 6.90 (dd, J=1, 9 Hz, 2H), 4.96 (m, 1H), 4.52 (m, 1H), 3.78 (m, 5H), 2.52 (m, 2H), 1.46 (s, 9H). LCMS 464 (M+−100).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.[K].[O:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].[I-].[Na+].O>CN(C)C=O>[N:15]1[CH:14]=[CH:13][N:12]2[C:7]([S:6][CH2:5][CH2:4][CH2:3][CH2:2][N:19]3[C:20](=[O:22])[CH2:21][O:17][C:18]3=[O:23])=[CH:8][CH:9]=[CH:10][C:11]=12
Reactant: O=C1COC(=O)N1
Reactant: ClCCCCSc1cccc2nccn12
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COC(=O)N1CCCCSc1cccc2nccn12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 6.30 g (26.2 mmol) of 5-(4-chlorobutylthio)imidazo[1,2-a]pyridine and 3.64 g (26.2 mmol) of oxazolidine-2,4-dione potassium salt in 100 ml of N,N-dimethylformamide, 3.92 g (26.2 mmol) of sodium iodide was added, followed by stirring at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to yield 5.70 g (71.4%, light orange crystal) of the desired product.
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:30])[CH2:20][C:21]4[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=4[C:23]([OH:25])=[O:24])[CH:15]=[CH:16][CH:17]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:31](OCC)C.[N+](=C)=[N-]>C(OCC)C.C(Cl)Cl>[CH3:31][O:24][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[CH2:20][C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12](/[CH:11]=[CH:10]/[C:7]2[S:8][CH:9]=[C:5]([CH:1]3[CH2:2][CH2:3][CH2:4]3)[N:6]=2)[CH:13]=1)=[O:30]
Reactant: O=C(Cc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Reactant: CCOCC
Agent: C=[N+]=[N-]
Solvent: ClCCl
Product: COC(=O)c1ccccc1CC(=O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1

Procedure:
A suspension of 2.1 g of (E)-2-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid in 200 ml of ethyl ether/methylene chloride (1:3 v/v) was treated with an excess of an ethyl ether solution of diazomethane. After 10 min the excess of diazomethane was removed with a stream of nitrogen, the remaining solvents were removed in vacuo and the residual materials were taken up into methylene chloride. This solution was washed with water (2×15 ml) and dried (MgSO4). Removal of the volatiles in vacuo and recrystallization from ethyl acetate yielded 2.2 g of (E)-2-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid methyl ester as an off-white solid, m.p. 143°-144° C.
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([CH2:17][NH:18][C:19]([CH:21]2[CH:26]3[CH:22]2[CH2:23][NH:24][CH2:25]3)=[O:20])[CH:7]=1)[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CO>C(Cl)Cl>[C:34]([N:24]1[CH2:25][CH:26]2[CH:22]([CH:21]2[C:19]([NH:18][CH2:17][C:8]2[CH:7]=[C:6]([CH2:2][CH:3]([CH3:5])[CH3:4])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:9]=2)=[O:20])[CH2:23]1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)Cc1cc(CNC(=O)C2C3CNCC32)nn1-c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)Cc1cc(CNC(=O)C2C3CN(C(=O)c4ccccc4)CC32)nn1-c1ccccc1
Reaction time: 0.08 h
Yield: 83.1 %

Procedure:
The 6-((5-isobutyl-1-phenyl-1H-pyrazole-3-yl)methylcarbamoyl)-3-azabicyclo[3.1.0]hexane hydrochloride (367 mg, 0.979 mmol) prepared in Example 11 was dissolved in 4.9 mL of methylene chloride and triethylamine (273 μL, 1.96 mmol) was added dropwise at 0° C. After stirring for 5 minutes, benzoyl chloride (125 μL, 1.08 mmol) was added dropwise. 10 minutes later, after stirring at room temperature for 3 hours, the completion of the reaction was confirmed by TLC (CH2Cl2:MeOH=20:1). After the reaction was completed, the reaction mixture was extracted with methylene chloride after adding water, 1 N HCl and saturated sodium bicarbonate. The organic layer was dried with anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography (CH2Cl2:MeOH=20:1) to obtain 360 mg (83.2%) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](I)[CH:5]=[CH:4][N:3]=1.[O:10]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.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:1][C:2]1[C:7]([Cl:8])=[C:6]([C:20]2[CH:21]=[CH:22][C:17]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:18][CH:19]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: Clc1nccc(I)c1Cl
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: C1COCCO1
Product: Clc1nccc(-c2ccc(Oc3ccccc3)cc2)c1Cl
Temperature: 150 °C

Procedure:
To a mixture of intermediate compound D6 (0.5 g, 1.826 mmol) in 1,4-dioxane (11.25 ml) under a nitrogen atmosphere were added 4-phenoxyphenyl boronic acid [C.A.S. 51067-38-0] (0.469 g, 2.191 mmol), Pd(PPh3)4 (0.105 g, 0.0913 mmol) and NaHCO3 (3.75 ml, aqueous sat. solution). The reaction mixture was subjected to microwave heating at 150° C. for 5 min. After cooling, the mixture was filtered through a pad of diatomaceous earth and washed with EtOAc. The filtrate was evaporated in vacuo and the residue was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate compound D36 (0.498 g, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](F)([F:12])[C:5](=O)[NH:6]2>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([F:12])=[CH:5][NH:6]2
Reactant: O=C1Nc2cccc(Br)c2C1(F)F
Solvent: C1CCOC1
Product: Fc1c[nH]c2cccc(Br)c12
Temperature: 0 °C
Reaction time: 16 h
Yield: 38.3 %

Procedure:
Reagent A (2.85 mL, 3.709 mmol) was added dropwise to a solution of 4-bromo-3,3-difluoro-1,3-dihydro-indol-2-one (400 mg, 1.61 mmol) in tetrahydrofuran (8.1 mL) at 0° C. The mixture was stirred at 0° C. for 3.5 hours and at room temperature for 16 hours. Further, Reagent A (3.0 mL) was added to the reaction mixture, followed by stirring at room temperature for three hours. The reaction mixture was quenched with 3 M HCl (4.8 mL) and then extracted with ethyl acetate (×2). The organic layers were combined and sequentially washed with water and saturated brine, and then dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 4-bromo-3-fluoro-1H-indole as a yellow oil (132 mg, 38%).
Reaction SMILES: [Br:1]Br.[C:3]([O:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][C:14]=1[OH:15])(=[O:5])[CH3:4]>C(Cl)(Cl)Cl.Br.C(O)(=O)C>[C:3]([O:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([C:16](=[O:18])[CH2:17][Br:1])[CH:12]=[CH:13][C:14]=1[OH:15])(=[O:5])[CH3:4]
Reactant: BrBr
Reactant: CC(=O)OCCc1cc(C(C)=O)ccc1O
Agent: Br
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCc1cc(C(=O)CBr)ccc1O

Procedure:
A solution of bromine (0.8 ml, 2.5g) in chloroform (20 ml) was added over 20 min to a stirred solution of 1-[3-[2-(acetyloxy)ethyl]-4-hydroxyphenyl]ethanone (3.26 g ) in chloroform (50 ml) containing a few drops of 45% hydrogen bromide in acetic acid. The red solution was diluted with ER (200 ml) washed with water (100 ml), 8% sodium bicarbonate (100 ml), brine (100 ml), dried and evaporated to give the title compound as an oil which solidified on standing to give a pale pink solid (4.1 g) m.p. 89°-92°. Two recrystallisations from chloroform gave a sample with m.p. 98°-99°.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].CN(C1C=CC=CN=1)C.C(N(CC)CC)C>C(Cl)Cl>[C:1]([OH:4])(=[O:3])[CH3:2].[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[S:20]([CH3:23])(=[O:22])=[O:21])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CS(=O)(=O)Nc1ccccc1OCc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(C(=O)OCc1ccccc1)c1ccccc1OCc1ccccc1

Procedure:
1 g (0.003 mol) of 4-benzyloxy-3-(methansulfonylamino)benzene acetate (WO 96/04233) in 20 ml of methylene chloride, 0.50 ml (0.0033 mol) of 95% benzyl chloroformate, 0.006 g of dimethylaminopyridine and 0.46 ml (0.0033 mol) of triethylamine is stirred at 50° C. for 10 hours. The solvent is evaporated, the residue is taken up in methylene chloride, washing with water is carried out, the two phases are separated, the organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated under reduced pressure. Purification is carried out by chromatography on a column of silica gel, elution being carried out with ethyl acetate. The title compound is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:27]([Cu])#[N:28]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:27]#[N:28])[N:11]=1)=[O:5])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1

Procedure:
Prepared in analogy to that of Example 105(a) from 2,3,7-tribromo-1-(4-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and CuCN. The title compound, ESI MS (m/z): 496 (M+H)+.
Reaction SMILES: C1(C)C=CC([C:7]([C@:9](C(O)=O)([OH:24])[C@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=[O:8])=CC=1.[F:29][C:30]1[C:35]([C@@H:36]([NH:38][CH2:39][C@@H:40]([OH:42])[CH3:41])[CH3:37])=[CH:34][CH:33]=[C:32]([F:43])[N:31]=1>[OH-].[Na+]>[F:29][C:30]1[C:35]([C@@H:36]([N:38]2[CH2:39][C@H:40]([CH3:41])[O:42][C:7](=[O:8])[C:9]2=[O:24])[CH3:37])=[CH:34][CH:33]=[C:32]([F:43])[N:31]=1
Reactant: C[C@H](O)CN[C@@H](C)c1ccc(F)nc1F
Reactant: Cc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: C[C@H]1CN([C@@H](C)c2ccc(F)nc2F)C(=O)C(=O)O1
Temperature: 145 °C
Yield: 115.4 %

Procedure:
(S)-1-[(S)-1-(2,6-difluoropyridin-3-yl)ethylamino]propan-2-ol (+)-di-p-toluoyl-D-tartrate (199 g) was dissolved in 5 N aqueous sodium hydroxide (450 mL), water (1,000 mL), and 50% toluene-THF (2,000 mL), and the organic layer was separated. The aqueous layer was washed with 50% toluene-THF (800 mL) three times. The organic layers were combined and concentrated under reduced pressure. Then, diethyl oxalate (200 mL) was added to the residue, and the reaction solution was heated and stirred at 140 to 150° C. Three hours later, the reaction solution was diluted with toluene (500 mL) and then ice-cooled while stirring. The precipitated crystals were collected by filtration, washed with toluene and diethyl ether, and then air-dried to obtain 103 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.[CH:17]([C:19]1[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[N:23][CH:24]=1)=[CH2:18]>[OH-].[Na+].[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6]([CH2:18][CH2:17][C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[N:23][CH:24]=3)[C:5]=2[CH2:4][CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: C=Cc1ccc(C(=O)O)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C(=O)O)nc2)CCN(C)CC1
Temperature: 90 °C
Yield: 2.1 %

Procedure:
The title compound was prepared by following general procedure 4. To a solution of 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (200 mg, 0.93 mmol) in 50% aq. NaOH solution (3 mL) was added, tetra n-butyl ammonium chloride (12 mg, 0.046 mmol) followed by 5-vinylpicolinic acid (153 mg, 1.0 mmol). The reaction mixture was heated at 90° C. for overnight, and the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography to afford 7 mg of 5-(2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl)picolinic acid as the TFA salt.
Reaction SMILES: [Br-].[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][Zn+].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[N:13]=1>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>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[F:2])[N:13]=1
Reactant: Brc1cccc(Br)n1
Reactant: Fc1ccccc1C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: Fc1ccccc1Cc1cccc(Br)n1
Temperature: 68 °C

Procedure:
A solution of 2-fluoro-benzylzinc bromide was added to 2,6-dibromo-pyridine (1.25 g, 5.27 mmol) then tetrakis(triphenylphosphine)palladium(0) (0.122 g, 0.106 mmol) was added and the reaction was heated to 68° C. for 4 hours. After cooling, silica gel was added to the reaction and it was concentrated to near-dryness. The silica gel was loaded onto a column of silica gel for purification to afford thet title compound.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl.CN(C)[CH2:7][CH:8]([CH3:24])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20](=[O:23])[NH:21][N:22]=2)=[CH:13][CH:12]=1)=[O:10].C(O)(=O)C>O>[C:1]([CH2:7][CH:8]([CH3:24])[C:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[CH:19][C:20](=[O:23])[NH:21][N:22]=2)=[CH:15][CH:16]=1)=[O:10])#[N:2]
Reactant: [C-]#N
Reactant: CC(CN(C)C)C(=O)c1ccc(-c2ccc(=O)[nH]n2)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(CC#N)C(=O)c1ccc(-c2ccc(=O)[nH]n2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
Potassium cyanide (0.32 g) was added to a cooled (5° C.) solution of 6-[4-(3-dimethylamino-2-methylpropionyl)phenyl]pyridazin-3(2H)-one hydrochloride (1.28 g) and acetic acid (0.25 ml) in water (30 ml). The solution was stirred for 2 hours at less than 23° C., then cooled and a further amount of potassium cyanide (0.32 g) was added. After stirring for one hour the temperature was raised to 50° C. and the reaction mixture was stirred for 2 hours to afford 6-[4-(3-cyano-2-methylpropionyl)phenyl]pyridazin-3(2H)-one (0.61 g), m.p. 196°-201° C. (dec), ν(C=N) 2240 cm-1.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:19][C:20]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:23]=[C:22]([NH2:32])[CH:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:32][C:22]3[CH:21]=[C:20]([CH3:19])[N:25]=[C:24]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)[N:23]=3)=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: Clc1cccc(Cl)c1-c1nc2ccnc(Br)c2s1
Reactant: Cc1cc(N)nc(N2CCOCC2)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc3nc(-c4c(Cl)cccc4Cl)sc23)nc(N2CCOCC2)n1
Temperature: 25 °C
Yield: 31.1 %

Procedure:
To a microwave tube was added 4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (60 mg, 0.17 mmol), 6-methyl-2-morpholinopyrimidin-4-amine (0.043 g, 0.22 mmol), Pd2(dba)3 (0.013 g, 0.017 mmol), XantPhos (0.017 g, 0.034 mmol) and Cs2CO3 (0.11 g, 0.34 mmol) in dioxane (3.0 mL). The mixture was degassed with N2 for 10 minutes and then irradiated in a microwave reactor at 160° C. for 2 hours. After cooling to room temperature the solid was removed via filtration. The filtrate was concentrated under reduced pressure and the residue was purified with reverse phase column chromatography eluting with a 0-60% gradient of CH3CN in 0.5% NH4HCO3 to give the desired product as a white solid (25 mg, 31% yield). 1H NMR (500 MHz, DMSO-d6): δ 10.31 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 7.41 (d, J=5.5 Hz, 1H), 7.44-7.28 (m, 2H), 7.68-7.67 (m, 1H), 6.40 (s, 1H), 3.55-3.54 (m, 8H), 2.21 (s, 3H). LCMS (Method A): RT=6.53 min, m/z: 473.1 [M+H+].
Reaction SMILES: C([N:4]([CH2:14][C@@H:15]1[O:19][C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]3)=[C:23]([F:35])[CH:22]=2)[CH2:16]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:13])[CH2:11][CH3:12])=[O:6])(=O)C.[C:36](Cl)(=O)OCOC(=O)C(C)C>ClCCl>[O:33]=[S:30]1(=[O:34])[CH2:31][CH2:32][CH:27]([C:24]2[CH:25]=[CH:26][C:21]([N:17]3[CH2:16][C@H:15]([CH2:14][NH:4][C:5]([O:7][CH2:8][O:9][C:10](=[O:13])[CH:11]([CH3:36])[CH3:12])=[O:6])[O:19][C:18]3=[O:20])=[CH:22][C:23]=2[F:35])[CH2:28][CH2:29]1
Reactant: CCC(=O)OCOC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Reactant: CC(C)C(=O)OCOC(=O)Cl
Solvent: ClCCl
Product: CC(C)C(=O)OCOC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Yield: 91 %

Procedure:
Following general procedure C, (S)-5-aminomethyl-3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-oxazolidin-2-one (2) (344.1 mg, 1.00 mmol), dichloromethane (9 mL) and isobutyroyloxymethyl carbonochloridate (7c) gave the titled product in 91% yield (446.3 mg, 0.92 mmol). 1H NMR (400 MHz, CDCl3): δ 7.48 (dd, 1H), 7.23 (t, 1H), 7.16 (dd, 1H), 5.73 (q, 2H), 5.28 (t, 1H), 4.80 (sept, 1H), 4.05 (t, 1H), 3.79 (dd, 1H), 3.67 (ddd, 1H), 3.57 (dt, 1H), 3.12-3.19 (m, 4H), 3.09 (dt, 1H), 2.55 (sept, 1H), 2.34-2.46 (m, 2H), 2.15-2.22 (m, 2H), 1.14 (dd, 6H). MS-APCI (m/z+): 487 (M+H).