Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:15])([CH3:14])[CH2:7][N:8]2[C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Br.C([O-])([O-])=O.[Na+].[Na+]>CO.O>[CH3:14][C:6]1([CH3:15])[C:5]2[C:9](=[CH:10][C:2]([N:1]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:3][CH:4]=2)[N:8]([C:11](=[O:13])[CH3:12])[CH2:7]1
Reactant: BrCCOCCBr
Reactant: CC(=O)N1CC(C)(C)c2ccc(N)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)N1CC(C)(C)c2ccc(N3CCOCC3)cc21
Temperature: 150 °C
Reaction time: 2.5 h

Procedure:
A mixture of 1-(6-amino-3,3-dimethylindolin-1-yl)ethanone (5 g, 24.5 mmol), 1-bromo-2-(2-bromoethoxy)ethane (6.25 g, 26.9 mmol), and Na2CO3 (5.19 g, 49 mmol) in MeOH (25 mL) was heated to 150° C. in a sealed tube. After 2.5 h, the mixture was cooled to rt. The reaction mixture was diluted with water (100 mL). The resulting solid was filtered, washed with water (300 mL), and dried in the air to give 1-(3,3-dimethyl-6-morpholinoindolin-1-yl)ethanone as a grey solid: 1H NMR (500 MHz, DMSO-d6) δ ppm 7.74 (1H, s), 7.06 (1H, d, J=8.1 Hz), 6.61 (1H, dd, J=8.2, 2.1 Hz), 3.82 (2H, s), 3.67-3.76 (4H, m), 2.95-3.06 (4H, m), 2.13 (3H, s), 1.26 (6H, s). Mass Spectrum (ESI) m/e=275.2 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[Na+].[Cl-]>CN1CCCC1=O>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])[CH2:15][CH2:14]1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CN1CCNCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])ccc1N1CCN(C)CC1
Temperature: 120 °C
Yield: 92.3 %

Procedure:
A homogeneous mixture of 4-fluoro-3-methylnitrobenzene 1 (20 g, 129 mmol) and N-methylpiperazine 3 (25.82 g, 258 mmol) in N-methylpyrrolidone (NMP) (10 mL) was refluxed (120° C.) under N2 for 24 hours. The reaction mixture upon cooling to room temperature was poured over a saturated NaCl solution (100 mL). The resulting solid was sonicated for approx. 30 seconds, filtered, washed with ice-cold water (2×10 mL) and dried under high vacuum to obtain 4-(4-methylpiperazinyl)-3-methylnitrobenzene 5 (28 g, 92%). 1H NMR (CD3OD): δ 8.02 (m, 2H), 7.13 (d, 1H, J=9.3 Hz), 3.08 (m, 4H), 2.66 (m, 4H), 2.38 (s, 6H); LCMS: purity: 99%, MS (m/e): 236 (MH+).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][N:26]1[C:30](=[O:31])[C:29]([CH3:33])([CH3:32])[NH:28][C:27]1=[O:34]>>[CH3:25][N:26]1[C:30](=[O:31])[C:29]([CH3:33])([CH3:32])[N:28]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:6][N:7]=2)[C:27]1=[O:34]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)nc3)CC2)nc1C
Reactant: CN1C(=O)NC(C)(C)C1=O
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4(C)C)nc3)CC2)nc1C
Yield: 63.1 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (156 mg) described in Preparation Example 205 and 3,5,5-trimethylimidazolidine-2,4-dione (63 mg) described in Preparation Example 218 and by the reaction and treatment in the same manner as in Example 536, the title compound (114 mg) was obtained.
Reaction SMILES: [CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2].[CH3:29][C:30]([CH3:36])([CH3:35])[CH2:31][CH2:32]C=O>>[CH3:29][C:30]([CH3:36])([CH3:35])[CH2:31][CH2:32][C:21]1[C:20]2[CH:19]=[CH:18][C:17]([F:22])=[CH:16][C:15]=2[N:14]=[C:13]2[C:23]3[N:10]([CH2:11][C:12]=12)[C:9](=[O:26])[C:8]1[CH2:7][O:6][C:5](=[O:27])[CH2:4][C@@:3]([CH2:1][CH3:2])([OH:28])[C:25]=1[CH:24]=3
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(F)cc3nc2-1
Reactant: CC(C)(C)CCC=O
Product: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)ccc1c2CCC(C)(C)C

Procedure:
The product of Example 84 is treated with 4,4-dimethylpentanal according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: [C:1]([O-:4])([O-:3])=O.[K+].[K+].[NH:7]1[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8]1>CC(C)=O>[C:9]([O:3][C:1]([N:7]1[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8]1)=[O:4])([CH3:11])([CH3:10])[CH3:8]
Reactant: O=C(O)C1CNC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Yield: 91 %

Procedure:
Using a procedure analogous to Example 1-C (K2CO3, acetone), azetidine-3-carboxylic acid gave the title compound as a solid (3.61 g, 91%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2Br)[CH:6]=1)[CH3:2].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[F:38])=[C:24](B(O)O)[CH:25]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:22]2[CH:21]=[C:20]([Cl:19])[CH:25]=[CH:24][C:23]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[F:38])[CH:6]=1)[CH3:2]
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccc(F)cc1F
Reactant: CCOC(=O)c1cc(C)cc(C2=C(Br)CCC2)c1
Product: CCOC(=O)c1cc(C)cc(C2=C(c3cc(Cl)ccc3OCc3ccc(F)cc3F)CCC2)c1

Procedure:
Prepared by general procedure B(iii) but using 3-(2-bromocyclopent-1-enyl)-5-methylbenzoic acid ethyl ester instead of 3-(2-bromo-cyclopent-1-enyl)-6-methyl benzoic acid ethyl ester and using [5-chloro-2-(2,4-di-fluorobenzyloxy)phenyl]boronic acid instead of (5-chloro-2-benzyloxyphenyl)boronic acid.
Reaction SMILES: [C:1]1([Si:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(Cl)[Cl:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][Si:17]([CH3:20])([CH3:19])[OH:18].C(N(CC)CC)C>O1CCCC1>[CH3:16][Si:17]([CH3:20])([CH3:19])[O:18][Si:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[Cl:8]
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)O[Si](Cl)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
The following were ingredients were introduced into a stirrer-equipped four-neck flask: 164.8 g (651.2 mmol) diphenyldichlorosilane and 300 mL tetrahydrofuran. The resultant mixture was stirred at room temperature while a mixture of 60 g (542.7 mmol) of 81.4% pure trimethylsilanol and 65.9 g (651.2 mmol) of triethylamine was added dropwise. Stirring at room temperature was continued for an additional hour following completion of the addition, at which time the salt formed as a by-product of the reaction was removed by filtration. The filtrate was then distilled under reduced pressure to yield 118.7 g of a fraction boiling at 136.5° C.-142° C. under of 2 mm Hg, equivalent to a 71.4% yield of trimethylsiloxydiphenylchlorosilane. Analysis of this product by gas chromatography (GLC), nuclear magnetic resonance (NMR), and infrared spectrochemical analysis (IR) confirmed it to be trimethylsiloxydiphenylchlorosilane with the following structural formula. ##STR6##
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][N:15]=1.[CH3:17][O:18][CH2:19][CH2:20]Br.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)C>CN(C)C=O>[CH3:17][O:18][CH2:19][CH2:20][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][N:15]=1
Reactant: COCCBr
Reactant: Nc1nccnc1-c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCCn1c(-c2nccnc2N)nc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.4 %

Procedure:
3-(1H-benzimidazol-2-yl)pyrazin-2-amine (0.302 g, 0.14 mmol) was dissolved in N,N-dimethyl formamide (10 mL) and treated with 2-bromoethyl methyl ether (0.15 mL, 0.16 mmol) and cesium carbonate (0.475 g, 1.4 mmol). The mixture was stirred at ambient temperature for 20 hours and then filtered through celite. The filtrate was concentrated and partitioned between ethyl acetate and water. The mixture was extracted into ethyl acetate (×3) and the combined organic layers were washed with water, and then with saturated sodium chloride. The organics were dried over magnesium sulfate, filtered and concentrated. Trituration with diethyl ether afforded the title compound as tan solids (0.275 g, 0.10 mmol).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].I.CS[C:18]1[NH:19][CH2:20][C:21](=[O:23])[N:22]=1.C(N(CC)CC)C>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:18]2[NH:19][CH2:20][C:21](=[O:23])[N:22]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CSC1=NC(=O)CN1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Agent: I
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)Cc1ccc(CSCCNC2=NC(=O)CN2)o1

Procedure:
2-(5-Dimethylaminomethylfuran-2-ylmethylthio)ethylamine (4.00 g), 2-methylthio-imidazolin-4-one hydroiodide (9.63 g) and triethylamine (7.27 g) were refluxed in ethanol (50 ml) for 6 hours.
Reaction SMILES: [CH2:1]([C@H:3]1[C:7](=[O:8])[NH:6][C:5]2([CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[S:4]1)[CH3:2].FC(F)(F)C(O)=[O:18].OO>O>[CH2:1]([CH:3]1[C:7](=[O:8])[NH:6][C:5]2([CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[S@:4]1=[O:18])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC[C@@H]1SC2(CCN(C)CC2)NC1=O
Agent: OO
Solvent: O
Product: CCC1C(=O)NC2(CCN(C)CC2)[S@]1=O
Temperature: 0 °C

Procedure:
A solution of AF267B (1.72 gr, 0.008 mol) in water (2.5 ml) was cooled (ice-water bath) and trifluoroacetic acid (3.5 ml) was added. To the cold stirred obtained mixture was added hydrogen peroxide (30%, 0.57 ml, 0.008 mol), the cooling bath was removed and the reaction mixture was stirred at room temperature over night Sodium sulfite was added and the pH of the solution was adjusted to 9 with a saturated solution of sodium carbonate. The aqueous phase was extracted with dichloromethan (2×100 ml) and then with ethyl acetate (1×50 ml). The organic extracts were combined, dried (MgSO4) and the solvent was evaporated. Flash chromatography (silica-gel 60, 230-400 mesh, Merck 1.09385, elution with methanol/chloroform/ammonium hydroxide 10:89:1 v/v) gave AF300. 1H NMR (CDCl3) δ 1.19 (t, j=7.3 Hz, 3H, CH3), 1.85-2.0 (m, 5H), 2.17 (m, 1H), 2.27 (m, 1H), 2.34 (s, 3H, NCH3), 2.6 (m, 2H), 3.30 (dd, j=3.56, 11.13 Hz,: CH3CH2CH), 6.37 (br NH) ppm; MS (EI) m/e 230 (M+).
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][OH:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>>[CH3:1][N:2]([CH2:9][CH2:10][O:11][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CN(CCO)c1ccccn1
Product: CN(CCOc1ccc(C=O)cc1)c1ccccn1

Procedure:
The title compound was prepared from 2-(N-methyl-N-(2-pyridyl)amino)ethanol (8.9 g) and 4-fluorobenzaldehyde by a similar procedure to that described in Preparation 22.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([OH:16])[C@H:12]([NH2:15])[CH2:13][F:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:17][CH:18]([Cl:23])[C:19](OC)=[O:20].C(N(CC)CC)C>CO>[Cl:17][CH:18]([Cl:23])[C:19]([NH:15][C@H:12]([CH2:13][F:14])[C@@H:11]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=1)[OH:16])=[O:20]
Reactant: COC(=O)C(Cl)Cl
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CF)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.8 %

Procedure:
To a solution of (1R,2S)-1-[4-(methylsulfonyl)phenyl]-2-amino-3-fluoro-1-propanol (5 g, 0.02 moles) in methanol (50 ml) was added methyl dichloroacetate (14.5 g; 0.10 g) and triethylamine (2.05 g, 0.02 mole) and stirred at room temperature for 18 hours. After completion of reaction, methanol was distilled off from the reaction mass, toluene (25 ml) and water (5 ml) were added. The product thus precipitated was filtered, washed with methylene chloride (20 ml) and crystallized from 2-propanol/water (5:1) to give 5 g of title compound having purity 99.20% by HPLC.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH2:14])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2.[F:17][C:18]([F:30])([F:29])[C:19]1[N:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH:14][S:25]([C:22]3[CH:23]=[N:24][C:19]([C:18]([F:30])([F:17])[F:29])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Nc1cc(OC(F)(F)F)cc2cccnc12
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)nc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(OC(F)(F)F)cc2cccnc12)c1ccc(C(F)(F)F)nc1
Yield: 42.9 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-trifluoromethoxy-quinolin-8-ylamine (Intermediate 46) (75 mg, 0.32 mmol), 6-(trifluoromethyl)pyridine-3-sulfonyl chloride (96 mg, 0.39 mmol), DMAP (cat.), pyridine (0.05 ml, 0.65 mmol) and DCM (2 ml) gave the title compound (60 mg, 42%) after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=1)[CH2:13][N:14]1[CH2:21][CH:20]2[CH:22]([OH:23])[CH:16]([CH2:17][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]2)[CH2:15]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][CH:12]([CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=1)[CH2:13][N:14]1[CH2:21][CH:20]2[CH:22]([OH:23])[CH:16]([CH2:17][N:18]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:19]2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC2CN(CC(COc3ccc(C#N)cc3)NC(=O)OCc3ccccc3)CC(C1)C2O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CN(CC(N)COc3ccc(C#N)cc3)CC(C1)C2O
Yield: 64.1 %

Procedure:
tert-Butyl 7-[2-{[(benzyloxy)carbonyl]amino}-3-(4-cyanophenoxy)propyl]-9-hydroxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from step (i) above; 6.17 g; 11.2 mmol) was dissolved in ethanol (56 mL; 85%) and hydrogenated over Pd/C (5%). The resultant mixture was filtered, the solvent was evaporated and the crude product was purified by chromatography on silica (toluene:ethyl acetate:isopropanol; 8:1:1) which gave 2.99 g (64%) of the tide compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[O:16]1[C:18]2([CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH2:17]1>CO>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:17][C:18]2([OH:16])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: C1CC2(CCO1)CO2
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCN(CC2(O)CCOCC2)CC1

Procedure:
To a stirred solution of tert-butyl(piperidin-4-ylmethyl)carbamate (22.3 g, 104 mmol) in methanol was added 1,6-dioxaspiro[2.5]octane (14.2 g, 124 mmol, Satyamurthy, Nagichettiar et al., Phosphorus Sulfur, 1984, 19, 113) at ambient temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:25]OS(C)(=O)=O)=[O:23])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:37]=1.[C:38]([O-:41])(=[S:40])[CH3:39].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([CH:24]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:25][S:40][C:38](=[O:41])[CH3:39])=[O:23])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:37]=1
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OCC(C(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1)c1ccccc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)SCC(C(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1)c1ccccc1

Procedure:
Dissolve 0.3 g (0.56 m mole) of 8-chloro-11-[1-(2-methanesulfonyloxy-1-phenylethylcarbonyl)-4-piperidylidene]-6,11-dihydro-5H-benzo-[5,6]cyclohepta-[1,2-b]pyridine (Formula 5.6 of Example 83) in 5 mL of DMF and add 0.2 g (0.6 m mole) of cesium thioacetate (preparation described in Synthetic Communications, 13, 553, 1983). Stir the reaction at 80° C. for twenty hours then concentrate under vacuo. Purify the residue by silica gel chromatography using 70% EtOAc and 30% hexane as the solvent. The product is obtained as a light brown solid, mp=92.7°-93° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=O.[CH2:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]C.[OH-].[K+]>>[CH2:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[O:1][CH2:5][CH2:4][NH2:3])[CH2:8][CH2:7][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C1NCCO1
Reactant: CCCCCCCCCc1ccccc1O
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCc1ccccc1OCCN

Procedure:
To a 250 mL round bottom flask equipped with a thermocouple, heating mantle, nitrogen inlet/outlet, a condenser and a stir bar was added 2-oxazolidinone (6.72 g, 77.2 mmole), 2-nonylphenol (10.0 g, 45.4 mmole), potassium hydroxide (255 mg, 4.5 mmole) and ExxonMobil™ Aromatic 100 solvent (70 mL). The resulting mixture was heated to reflux temperature for 3 h. Reaction progress was monitored by TLC and 1H NMR. The reaction mixture was then cooled, filtered over Celite® and the solvent were evaporated under reduced pressure. The crude material was purified using flash column chromatography to give the amine. 1H NMR (DMSO-d6, 400 MHz) δ 7.26-7.12 (m, 2H), 6.88-6.81 (m, 2H), 3.87 (dd. 2H, J=5.8, 5.8 Hz), 2.86 (dd, 2H, J=5.8, 5.8 Hz), 1.75-0.42 (m, 19H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[N:9]1([C:16]([C:18]2[CH:22]=[C:21]([CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[S:20][CH:19]=2)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C(O)(=O)C.O>[N:9]1([C:16]([C:18]2[CH:22]=[C:21]([CH:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[S:20][C:19]=2[Cl:1])=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C(c1csc(C2CCOCC2)c1)N1CCCCCC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1cc(C2CCOCC2)sc1Cl)N1CCCCCC1
Temperature: 100 °C
Yield: 64.4 %

Procedure:
N-Chlorosuccinimide (0.024 g, 0.18 mmol) was added to a solution of azepan-1-yl-[5-(tetrahydro-pyran-4-yl)-thiophen-3-yl]-methanone (53 mg) in acetic acid (2 mL). The reaction mixture was heated to 100° C. for 3 minutes using microwave irradiation, then diluted with water and purified by HPLC, eluting with 20%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound (38 mg). LCMS m/z 328.17 [M+H]+ RT=10.59 min (Analytical Method 1). 1H NMR (400 MHz, CHCl3-d): δ 6.6 (s, 1H), 4.05 (m, 2H), 3.7 (m, 2H), 3.5 (m, 2H), 3.4 (m, 2H), 2.9 (m, 1H), 1.9-1.5 (m, 12H).
Reaction SMILES: C1(C[O:8][CH2:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([N:21]4[CH2:25][C@H:24]([C:26]([O:28][CH3:29])=[O:27])[O:23][C:22]4=[O:30])=[CH:18][CH:19]=3)[CH2:14][C@H:13]2[CH3:31])=[O:11])C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[OH:8][CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([N:21]3[CH2:25][C@H:24]([C:26]([O:28][CH3:29])=[O:27])[O:23][C:22]3=[O:30])=[CH:18][CH:19]=2)[CH2:14][C@H:13]1[CH3:31])=[O:11]
Reactant: [H][H]
Reactant: COC(=O)[C@H]1CN(c2ccc3c(c2)C[C@@H](C)N3C(=O)COCc2ccccc2)C(=O)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@H]1CN(c2ccc3c(c2)C[C@@H](C)N3C(=O)CO)C(=O)O1

Procedure:
A mixture of methyl (5R)-3-[(2R)-2,3-dihydro-1-[(phenylmethoxy)acetyl]-2-methyl-1H-indol-5-yl]-2-oxo-5-oxazolidinecarboxylate (Step 1, 0.301 g, 0.71 mmol) and Pearlman's catalyst (0.032 g) in methanol (30 mL) is shaken on a Parr apparatus under a 36 psi hydrogen atmosphere for approximately 24 h, during which additional Pearlman's catalyst (0.044 g) is added. The catalyst is removed by filtration through a pad of Celite, and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on a Biotage Flash 40S silica gel cartridge (2% MeOH/CH2Cl2 eluent) to give the title compound, MS (ESI+) for C16H18N2O6 m/z 335 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[C:17]([C:27](=[O:30])[NH:28][CH3:29])[C:16]=3[CH:31]=2)[C:10]=1[CH3:11])[C:5](O)=[O:6].[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1([NH2:41])[CH2:40][CH2:39]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[C:10]([CH3:11])=[C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[C:17]([C:27]([NH:28][CH3:29])=[O:30])[C:16]=3[CH:31]=2)[CH:8]=[C:4]([C:5](=[O:6])[NH:41][C:38]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=3)[CH2:40][CH2:39]2)[CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)cc(F)c3C)cc12
Reactant: NC1(c2ccccn2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccccn5)CC4)cc(F)c3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-fluoro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methyl benzoic acid (0.2 g, 0.47 mmol, 1 eq), 1-(pyridin-2-yl)cyclopropanamine (0.075 g, 5.5 mmol, 1.2 eq) (60% purity), HOBT (0.81 g, 0.015 mmol, 1.7 eq), EDC.HCl (0.16 g, 00.83 mmol, 1.8 eq) in DCM at ambient temperature and under nitrogen was added Diisopropylethylamine (0.30 g, 2.3 mmol, 5.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer is further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and further purification was done using preparative HPLC. Yield: 0.1 g (50%). 1H NMR (400 MHz, CDCl3): δ 1.39-1.42 (m, 2H), 1.67-1.70 (m, 2H), 2.21-2.22 (d, 3H, J=2.24 Hz), 2.9-3.0 (d, 3H, J=4.88 Hz), 5.98-5.99 (s, 1H), 7.06-7.09 (dd, 1H, J=5.2, 7.2 Hz), 7.18-7.36 (m, 5H), 7.53-7.62 (m, 4H), 7.76 (d, 1H, J=1.36 Hz), 7.94-7.97 (m, 2H), 8.4 (s, 1H). LCMS: (ES+) m/z=538.2 (M+H). LCMS Method: Column-Atlantis dC18 (50×4.6 mm-5 μm) A: 10 mM NH4OAc; B: acetonitrile
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]=[C:9]([Si](C)(C)C)[S:10][CH:11]=1.[C:16]([C:19]1[S:23][C:22]([CH3:24])=[N:21][C:20]=1[CH3:25])(=[O:18])[CH3:17].[Cl-].[NH4+]>O1CCCC1>[CH3:24][C:22]1[S:23][C:19]([C:16]([C:9]2[S:10][CH:11]=[C:7]([CH3:6])[N:8]=2)([OH:18])[CH3:17])=[C:20]([CH3:25])[N:21]=1
Reactant: CC(=O)c1sc(C)nc1C
Reactant: Cc1csc([Si](C)(C)C)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1csc(C(C)(O)c2sc(C)nc2C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M solution in hexanes, 5.1 ml ) was added dropwise to a stirred solution of 4-methyl-2-trimethylsilylthiazole (from 4-methylthiazole, n-butyllithium and trimethylsilylchloride) (2 g) in anhydrous tetrahydrofuran (40 ml ) at -70° C. under an atmosphere of dry nitrogen. After 30 minutes, 5-acetyl-2,4-dimethylthiazole (2 g) in tetrahydrofuran (10 ml) was added dropwise. After 1 hour the mixture was allowed to warm to room temperature. After a further 2 hours, saturated aqueous ammonium chloride solution was added. The organic phase was separated, washed, dried and evaporated. The residue was dissolved in tetrahydrofuran (2 ml) and tetrabutylammonium fluoride (640 mg) was added. The mixture was stirred overnight and then worked up in the usual fashion to give the title compound.