Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:40])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH:25]3[CH2:29][O:28]C(C)(C)[N:26]3C(OC(C)(C)C)=O)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:39])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.Cl>C(OCC)(=O)C>[NH2:26][C@@H:25]([CH2:24][NH:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:39])[CH:19]=2)[N:14]=[C:13]([N:5]2[CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[S:2](=[O:40])(=[O:1])[CH2:3][CH2:4]2)[CH:22]=1)[CH2:29][OH:28]
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3COC(C)(C)N3C(=O)OC(C)(C)C)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC[C@H](N)CO)c2c1
Yield: 39.5 %

Procedure:
A mixture of tert-butyl 4-({[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (251 mg) and a solution of hydrochloride in ethyl acetate (13 mL, 4 N) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was dissolved in water, and basified with a saturated aqueous solution of sodium bicarbonate to about pH 9, and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by preparative HPLC to give 74.6 mg of the desired product as a white solid. MS obsd. (ESI+) [(M+H)+] 427, 1H NMR (400 MHz, CD3OD) δ ppm 8.04 (dd, J=1.2, 8.0 Hz, 1 H), 7.98 (d, J=7.2 Hz, 1 H), 7.86 (s, 1 H), 7.72-7.66 (m, 2 H), 7.55-7.46 (m, 2 H), 6.20 (s, 1 H), 5.31 (s, 2 H), 4.57 (s, 2 H), 3.93-3.62 (m, 7 H), 2.47 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[C@@H:16]([OH:17])[C:15](=[O:18])[NH:14][C:13]3[CH:19]=[CH:20][C:21]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][C:12]=3[S:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[CH3:31][N:32]([CH2:34][CH2:35]Cl)[CH3:33].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C1C=CN=CC=1.CC(C)=O>[CH3:31][N:32]([CH3:33])[CH2:34][CH2:35][N:14]1[C:13]2[CH:19]=[CH:20][C:21]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:22][C:12]=2[S:11][C@@H:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[C@@H:16]([OH:17])[C:15]1=[O:18]
Reactant: COc1ccc([C@@H]2Sc3cc(Oc4ccccc4)ccc3NC(=O)[C@@H]2O)cc1F
Reactant: CN(C)CCCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3cc(Oc4ccccc4)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1F
Yield: 49 %

Procedure:
400 mg of (±)-cis-2-(3-fluoro-4-methoxyphenyl)-2,3- dihydro-3-hydroxy-8-phenoxy-1,5-benzothiazepin-4(5H)-one [prepared as described in step (c) above] were alkylated with 210 mg of dimethylaminoethyl hydrochloride hydrochloride, 202 mg of potassium carbonate and small amounts of 4-dimethylaminopyridine and 18-crown-6 in 30 ml of acetone in the same manner as described in Example 1(d). The product was then extracted and purified as described in Example 1(d), to give 230 mg of the title compound as a gum.
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[N:11](C(OC(C)(C)C)=O)[CH:12]=[CH:13][CH:14]=3)[N:4]2[N:3]=1.[CH:23]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:9]1[N:4]2[N:3]=[C:2]([NH:1][C:28]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:29])[N:22]=[C:5]2[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)n1cccc1-c1cccc2nc(N)nn12
Reactant: O=C(Cl)C1CCCC1
Product: O=C(Nc1nc2cccc(-c3ccc[nH]3)n2n1)C1CCCC1

Procedure:
The title compound was prepared following procedure and work up described for example 9, but starting from tert-butyl 2-(2-amino[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1H-pyrrole-1-carboxylate ((A6), 50 mg; 0.17 mmol; 1.0 eq.) and cyclopentanecarbonyl chloride (44 mg; 0.33 mmol; 2.0 eq.) as a white solid (25.4 mg, 51%). HPLC, Rt: 3.17 min. (purity 99.7%). LC/MS, M+(ESI): 296.4, M−(ESI): 294.3.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:25].N([O-])=O.[Na+].[BrH:30]>O1CCOCC1.O.[Cu]Br>[Br:30][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1N
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br

Procedure:
In a solution of 0.50 g of 3-(4-amino-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 1.0 ml of 1,4-dioxane and 2.0 ml of water, 1.0 ml of 47% hydrobromic acid was added, and stirred under reflux with heat for 1 hour. Then, the reaction mixture was cooled with ice, and a solution of 0.10 g of sodium nitrite in 1.0 ml of water was slowly added dropwise with stirring at a temperature of 5° C. or less, after the completion of the addition dropwise, continued to stir at the same temperature for further 1 hour. The diazo mixture was slowly added dropwise in a mixture of 1.0 ml of 47% hydrobromic acid and 0.28 g of copper (I) bromide at 60° C. with stirring, after the completion of the addition dropwise, continued to stir at 60° C. for further 2 hours. After the completion of the reaction, 10 ml of water was added in the reaction mixture, extracted with ethyl acetate (20 ml×2), the organic phases together were washed with water, then dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:10) to obtain 0.43 g of the aimed product as pale yellow crystal.
Reaction SMILES: CCCCCC[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].CO[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH2:22][CH2:21][CH2:20][CH2:19]2.C1(C)C(C2C(C)=CC=CC=2)=CC=CC=1>C1(C)C=CC=CC=1.Cl[Ni](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>[CH3:13][C:12]1[CH:7]=[CH:8][C:9]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][CH:11]=1
Reactant: COc1ccc2c(c1)CCCC2
Reactant: CCCCCCCCCCCCC
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccccc1-c1ccccc1C
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc3c(c2)CCCC3)cc1
Temperature: 110 °C
Yield: 29 %

Procedure:
The Grignard reagent (1 M in ether, 5.0 mmol) was placed under vacuum to remove all volatiles. Toluene (5.0 mL) was then added to the Grignard reagent. In a separate reaction flask was placed NiCl2(PPh3)2 (62.0 mg, 0.0948 mmol), tridecane (282 mg, 1.532 mmol, as an internal standard), and 6-methoxy-1,2,3,4-tetrahydronaphthalene (334 mg, 2.059 mmol). The Grignard reagent in toluene was then transferred to this mixture under a nitrogen atmosphere at room temperature. The resulting solution was warmed to 110° C. for 15 hours. A sample was withdrawn and quenched with an aqueous sodium citrate solution (1 M). The aqueous solution was extracted with ethyl acetate. GC analysis of the organic phase showed the presence of 6-(4-methylphenyl)-1,2,3,4-tetrahydronaphthalene (0.598 mmol, 29% yield), bitoluene (0.419 mmol), and 6-methoxy-1,2,3,4-tetrahydronaphthalene (1.043 mmol) in the reaction mixture.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][CH2:7][CH:6]1[N:9]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[N:11]=[CH:10]1)=O.CSC.B>O1CCCC1>[N+:14]([C:12]1[N:11]=[CH:10][N:9]([CH:6]2[CH2:7][CH2:8][CH:5]2[CH2:3][OH:2])[CH:13]=1)([O-:16])=[O:15]
Reactant: COC(=O)C1CCC1n1cnc([N+](=O)[O-])c1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: O=[N+]([O-])c1cn(C2CCC2CO)cn1
Yield: 37.9 %

Procedure:
A mixture of the 2-(4-Nitro-imidazol-1-yl)-cyclobutanecarboxylic acid methyl ester (2.640 g, 0.01105 mol), borane-dimethyl sulfide complex (1M in tetrahydrofuran) (33.2 mL, 0.0332 mol) and tetrahydrofuran (10 mL) was heated at reflux for 17 hours. The reaction was quenched by water. The volatile solvent was evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate three times. The combined extracts were washed with brine and dried over sodium sulfate. The solvent was then evaporated under reduced pressure to yield [2-(4-Nitro-imidazol-1-yl)-cyclobutyl]-methanol (0.825 g, 0.00419 mol) as a white solid. M+1=198.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.Cl>CO.C(=O)([O-])[O-].[Na+].[Na+].[Pt]=O>[CH3:1][O:2][C:3]1[C:8]([C:9]([F:10])([F:12])[F:11])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: COc1c(-c2ccncc2)cccc1C(F)(F)F
Agent: O=[Pt]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: COc1c(C2CCNCC2)cccc1C(F)(F)F
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of 4-[2-methoxy-3-(trifluoro-methyl)phenyl]pyridine (0.42 g, 1.66 mmol) in methanol (10 ml), was added platinum oxide (0.10 g) and hydrochloric acid (0.1 ml, cone) and the reaction mixture was hydrogenated at 50 psi for 1 h under hydrogen. Filtration through a pad of celite and evaporation of the filtrate gave 0.48 g of crude product as the hydrochloric acid salt. The salt was dissolved in aqueous sodium carbonate (10%, 50 ml) and extracted with ethylacetate (3×50 ml). The combined organic phases was dried (MgSO4), filtered and evaporated to dryness to give the title compound (0.38 g). MS m/z (relative intensity, 70 eV) 260 (M+, 2), 258 (M+, 7), 229 (14), 228 (bp) 59 (15).
Reaction SMILES: Cl[C:2](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[CH:3]([CH3:5])[CH3:4].Cl.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[NH:20][NH2:21].C(N(CC)CC)C>C1COCC1>[NH2:8][C:7]1[N:20]([C:14]2[C:13]([Cl:12])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:19])[N:21]=[C:2]([CH:3]([CH3:5])[CH3:4])[C:6]=1[C:9]#[N:10]
Reactant: NNc1c(Cl)cccc1Cl
Reactant: CC(C)C(Cl)=C(C#N)C#N
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)c1nn(-c2c(Cl)cccc2Cl)c(N)c1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.2 %

Procedure:
A solution of (1-chloro-2-methylpropylidene)methane-1,1-dicarbonitrile (9.4 g, 61 mmol) in THF (250 mL) was treated with 2,6-dichlorophenylhydrazine hydrochloride (13.0 g, 61 mmol) followed by triethylamine (12.3 g, 122 mmol). The reaction was then heated to reilux for 18 h. The reaction was then cooled to room temp and partitioned between EtOAc (150 mL) and 1N NaOH (100 mL). The aqueous layer was extracted with EtOAc (2×150 mL) and the combined organic layers were washed with 10% aq. citric acid (150 mL), sat. aq. NaHCO3 (150 mL), and brine (150 mL). The organic layer was dried (MgSO4), filtered, and evaporated. The crude product was recrystallized from EtOAc/hexane to yield the desired pyrazole (11.2 g, 62%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:9]([C:15]2[NH:19][N:18]=[N:17][N:16]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:30][CH3:31]>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[C:9]([C:15]2[N:16]=[N:17][N:18]([CH2:30][CH3:31])[N:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(CC)n1
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
To a solution of 10.0 g (0.028 mole) of ethyl 3,3-bis(4-fluorophenyl)-2-(1H-tetrazol-5-yl)-2-propenoate [prepared in Example 2] in 75 mL of N,N-dimethylformamide was added 1.2 g of 60% sodium hydride (0.03 mole) in mineral oil was added. After stirring for 0.5 hour, the sodium hydride had dissolved and 8.5 g (0.056 mole) of iodoethane was added. The solution was stirred at room temperature for 16 hours, diluted to 400 mL with water and extracted with CH2Cl2. The extracts were dried and concentrated in vacuo. The residue was triturated with hexane to remove mineral oil. The residue was absorbed onto silica gel by dissolving in CH2Cl2 and adding dry silica gel, then concentrating in vacuo to a dry powder. This material was transferred to the top of a silica gel column and eluted with 10% (v/v) ethyl acetate in hexane to give 4.9 g (45.5%) of the title compound; m.p.=113°-114.5° C.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].C([O-])(O)=O.[Na+].[CH3:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=O.[OH-].[Na+].Cl>O>[C:13]([C:18]1[NH:6][C:4](=[O:5])[NH:3][N:2]=1)([CH3:17])([CH3:14])[CH3:12]
Reactant: NNC(N)=O
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1n[nH]c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62 %

Procedure:
Semicarbazide hydrochloride (25.0 g, 224 mmol) was dissolved in water (200 mL). NaHCO3 (40.0 g, 476 mmol) was slowly added to the solution over 30 min at RT followed by the addition of trimethylacetyl chloride (30.0 g, 249 mmol). The mixture was stirred at RT for 12 h. Solids were collected by filtration, washed with cold water, and dried in vacuo. A solution of NaOH (20.0 g, 500 mmol) in water (200 mL) was added. The mixture was stirred at 100° C. for 2 h, cooled with an ice-bath, and neutralized by the drop-wise addition of concentrated HCl. The solids were collected by filtration, washed with water, and dried in vacuo to afford 3-(tert-butyl)-1H-1,2,4-triazol-5(4H)-one (19.6 g, 61.9%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.26 (s, 1H), 11.04 (s, 1H), 1.16 (s, 9H); MS (ESI) m/z: 142.1 (M+H+).
Reaction SMILES: [N:1]([CH2:4][C:5]1[O:9][N:8]=[C:7]([CH3:10])[C:6]=1[C:11]1[C:12]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=O)=[N:13][N:14]([CH3:16])[CH:15]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[C:12]3[C:11](=[CH:15][N:14]([CH3:16])[N:13]=3)[C:6]3[C:7]([CH3:10])=[N:8][O:9][C:5]=3[CH2:4][N:1]=2)=[CH:20][CH:21]=1
Reactant: Cc1noc(CN=[N+]=[N-])c1-c1cn(C)nc1C(=O)c1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1noc2c1-c1cn(C)nc1C(c1ccc(Cl)cc1)=NC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
To a solution of (4-(5-(azidomethyl)-3-methylisoxazol-4-yl)-1-methyl-1H-pyrazol-3-yl)(4-chlorophenyl)methanone (0.03 g, 0.08 mmol) in anhydrous THF (10 mL), was added triphenylphosphine (32 mg, 0.12 mmol) at room temperature. The mixture was stirred for 12 h at room temperature. The mixture was concentrated and the residue was purified by flash chromatography eluting with (petroleum ether/ethyl acetate=1:3) to afford the title compound as a white solid (15 mg, 60% yield). LC/MS: m/z 312 [M+H]+; 1H NMR (300 MHz, CDCl3) δ 7.62 (d, J=9 Hz, 3H), 7.36 (d, J=9 Hz, 2H), 4.87 (s, 2H), 4.08 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: O.C(=O)([O-])[O-].[Na+].[Na+].O.CC1(C)C(C)(C)OB([C:17]2[CH:29]=[CH:28][C:20]3[N:21]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:23][C:19]=3[CH:18]=2)O1.Br[C:32]1[CH:33]=[C:34]([O:38][CH2:39][CH2:40][NH:41][C:42](=[O:46])[CH2:43][O:44][CH3:45])[CH:35]=[N:36][CH:37]=1>[Pd].C1COCC1>[C:25]([NH:24][C:22]1[S:23][C:19]2[CH:18]=[C:17]([C:32]3[CH:33]=[C:34]([O:38][CH2:39][CH2:40][NH:41][C:42](=[O:46])[CH2:43][O:44][CH3:45])[CH:35]=[N:36][CH:37]=3)[CH:29]=[CH:28][C:20]=2[N:21]=1)(=[O:27])[CH3:26]
Reactant: COCC(=O)NCCOc1cncc(Br)c1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC(=O)NCCOc1cncc(-c2ccc3nc(NC(C)=O)sc3c2)c1
Reaction time: 0.17 h
Yield: 26 %

Procedure:
A Biotage high recovery microwave vessel was charged with sodium carbonate hydrate (0.048 g, 0.38 mmol), 0.15 mL water and a stirbar. The slurry was sonicated and stirred for 10 minutes. An inert atmosphere inlet was placed over the vessel and the remaining reagents were added under a flow of nitrogen. To the vessel was added N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.043 g, 0.14 mmol), 100 mg Pd FibreCat® palladium catalyst, and N-(2-(5-bromopyridin-3-yloxy)ethyl)-2-methoxyacetamide (0.0247 g, 0.085 mmol) dissolved in 1 mL THF. The vessel was sealed, and irritated using a Biotage personal chemistry microwave reactor to 130° C. for 25 minutes. The cooled reaction was diluted with 5 mL THF, and filtered through a 0.22 μm PTFE membrane. The catalyst was washed with THF (2×5 mL), and the combined filtrates were concentrated in vacuo. The residue was sonicated in 2 mL water, and filtered. The precipitate was then dissolved in 3 mL MeOH, filtered, and concentrated in vacuo. The crude was purified using a 19×150 mm Waters Xterra Prep C18 OBD column (100 Å pore diameter, 5 μm particle size, spherical shape, PN 186002381; Gradient: 0→5 min@20 mL/min, 10% B; 5.0→35 min@20 mL/min, linear gradient to 40% B; 35→45@20 mL/min, isocratic at 40% B, 45→55 min@20 mL/min, step to 100% B; 55→60 min@20 mL/min, step to 10% B; 60 min end; A=10.7 mM NH4HCO3 in water, pH adjusted to 8.6 with concentrated NH4OH; B acetonitrile). A band that eluted from 24.2 to 26.0 minutes was isolated. The solvent was removed in vacuo to afford N-(2-(5-(2-(N-actyl)aminobenzo[d]thiazol-6-yl)pyridin-3-yloxy)ethyl)-2-methoxyacetamide. (0.0090 g, 26% yield). 1H NMR (400 MHz, DMF) δ ppm 2.34 (s, 3H) 3.37 (s, 3H) 3.70 (q, J=5.84 Hz, 2H) 3.89 (s, 2H) 4.35 (t, J=5.97 Hz, 2H) 7.81 (dd, J=2.54, 1.96 Hz, 1H) 7.83 (s, 1H) 7.85 (s, 1H) 7.86-7.90 (m, J=8.41, 1.86 Hz, 1H) 8.32 (d, J=2.25 Hz, 1H) 8.47 (d, J=1.47 Hz, 1H) 8.62 (br. s., 1H) 12.35 (br. s., 1H). 13C NMR (101 MHz, DMF) δ ppm 22.46 (s, 1 C) 38.02 (s, 1 C) 58.54 (s, 1 C) 66.92 (s, 1 C) 71.91 (s, 1 C) 118.91 (s, 1 C) 120.35 (s, 1 C) 121.07 (s, 1 C) 125.49 (s, 1 C) 132.82 (s, 1 C) 133.22 (s, 1 C) 136.79 (s, 1 C) 137.04 (s, 1 C) 140.37 (s, 1 C) 149.26 (s, 1 C) 155.35 (s, 1 C) 159.21 (s, 1 C) 169.69 (s, 1 C) 169.72 (s, 1 C). HPLC-MS: retention time=1.12 min (99.3%@215 nm; 98.1% @254 nm; m/z=401.1, calculated for C19H20N4O4S+H+=401.1).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][C:12]([F:15])=[CH:11][CH2:10]1)(C)(C)C.[ClH:17].CC(O)=O>>[ClH:17].[F:15][C:12]1[CH2:13][CH2:14][CH:9]([CH2:8][NH2:7])[CH2:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCC1CC=C(F)CC1
Agent: Cl
Solvent: CC(=O)O
Product: NCC1CC=C(F)CC1

Procedure:
tert-Butyl[(4-fluorocyclohex-3-en-1-yl)methyl]carbamate (1.62 g, 7.06 mmol) was stirred in 25 mL of 1M HCl/AcOH at rt for 2 h. The solvent was evaporated and the product was precipitated in ether, filtered and dried under vacuum. Yield: 1.13 g (97%). 1H NMR (400 MHz, CD3OD) δ 1.44-1.53 (m, 1 H), 1.80-1.89 (m, 2 H), 1.90-1.98 (m, 1 H), 2.16-2.23 (m, 2 H), 2.26-2.34 (m, 1 H), 2.88 (d, J=6.25 Hz, 2 H), 5.12-5.19 (m, 1 H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5]3=[C:6]([CH2:11][CH2:12][C:13](=[O:14])[N:4]3[CH2:3][CH2:2]1)[CH:7]=[CH:8][CH:9]=2.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([C:8]1[CH:9]=[C:10]2[C:5]3=[C:6]([CH2:11][CH2:12][C:13](=[O:14])[N:4]3[CH2:3][CH2:2][CH2:1]2)[CH:7]=1)=[O:22]
Reactant: O=C(Cl)CCCCCBr
Reactant: O=C1CCc2cccc3c2N1CCC3
Product: O=C(CCCCCBr)c1cc2c3c(c1)CCC(=O)N3CCC2

Procedure:
Using 2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one and 6-bromohexanoyl chloride according to the same method as that of Reference Example 1, the title compound (3.90 g) was obtained as colorless crystals having a melting point of 52-53° C.
Reaction SMILES: Br[CH:2]([C:6]1[CH:7]=[CH:8][C:9]([O:16][CH3:17])=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:11]=1)[C:3](=O)[CH3:4].[C:18]([NH:21][C:22]([NH2:24])=[S:23])(=[O:20])[CH3:19]>C(O)C>[CH3:17][O:16][C:9]1[CH:8]=[CH:7][C:6]([C:2]2[S:23][C:22]([NH:21][C:18](=[O:20])[CH3:19])=[N:24][C:3]=2[CH3:4])=[CH:11][C:10]=1[S:12](=[O:14])(=[O:13])[NH2:15]
Reactant: COc1ccc(C(Br)C(C)=O)cc1S(N)(=O)=O
Reactant: CC(=O)NC(N)=S
Solvent: CCO
Product: COc1ccc(-c2sc(NC(C)=O)nc2C)cc1S(N)(=O)=O

Procedure:
5-(1-Bromo-2-oxo-propyl)-2-methoxy-benzenesulfonamide (Example 30b) (0.2 g, 0.64 mmol) and N-acetylthiourea (0.075 g, 0.64 mmol) in ethanol (3 ml) are stirred at 70° C. for 4 hours. The mixture is concentrated and the residue is recrystallised from ethanol to give an off-white solid. MH+ (ESMS): Mp 341.9° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-])=O.[C:17](Cl)(=O)[C:18](Cl)=O>C(Cl)Cl.CN(C=O)C>[CH2:17]([O:9][C:7]([C:6]1[CH:5]=[C:4]([CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=1)[NH2:1])=[O:8])[CH3:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(N)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of 3-nitro-5-trifluoromethylbenzoic acid (0.36 g, 1.53 mmol) in CH2Cl2 (20 mL) was added oxalyl chloride (0.58 g, 4.60 mmol) followed by DMF (3 drops). An immediate evolution of gas occurred and the reaction was stirred for 18 h. The solvent was removed under reduced pressure, the resulting oil was dissolved in THF (80 mL) and cooled to 0° C. To the cooled solution was added EtOH (5 mL) in THF (15 mL) and the mixture was stirred for 18 h at room temperature. The mixture was concentrated to remove the THF and the resulting precipitate was filtered and dried. The solid was dissolved in EtOH (25 mL) and 10% Pd/C (0.12 g) was added and the suspension was stirred for 15 h under a blanket of H2. The reaction was filtered through celite and the filtrate evaporated to dryness to provide 3-ethoxycarbonyl-5-trifluoromethylaniline as a yellow oil. This compound was then coupled to 2-chloro-4-trifluoromethyl pyrimidine-5-carbonyl chloride as described above to provide the title compound in a 12% yield; m.p. 67°-71° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([CH3:17])=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:7]2.[CH2:19]([N:23]=[C:24]=[O:25])[CH2:20][CH2:21][CH3:22].O>C(Cl)(Cl)Cl>[CH2:19]([NH:23][C:24]([NH:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([CH3:17])=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:7]2)=[O:25])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCN1CCc2c(C)cc(C)c(N)c21
Reactant: CCCCN=C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCN1CCc2c(C)cc(C)c(NC(=O)NCCCC)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.1 %

Procedure:
7-Amino-4,6-dimethyl-1-hexylindoline (800 mg) was dissolved in chloroform (20 ml) and butyl isocyanate (400 mg) was added, which was followed by stirring at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent:chloroform-methanol=1:0-50:1) and recrystallized from ethanol to give 450 mg of the title compound.