Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:14]2[N:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:8]3=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[CH:3]=1.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]>CS(C)=O.[Cl-].[NH4+]>[CH2:25]([N:28]([C:2]1[C:14]2[N:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:8]3=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[CH:3]=1)[CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]
Reactant: CCCNCCC
Reactant: Cc1cc(C)c(-c2c3nc(C)cc(Cl)c3n3ccncc23)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CCCN(CCC)c1cc(C)nc2c(-c3c(C)cc(C)cc3C)c3cnccn3c12
Temperature: 130 °C

Procedure:
To a solution of 4-Chloro-2-methyl-10-(2,4,6-trimethylphenyl)pyrido-[2′,3′:4,5]pyrrolo[1,2-a]pyrazine (23 mg) in DMSO (0.5 mL) is added dipropylamine (0.1 mL) and the resulting mixture is heated at 130° C. for 3.5 days. The mixture is then allowed to cool to room temperature, diluted with aqueous ammonium chloride, and extracted twice with ethyl ether. The extracts are combined, washed with saturated brine, dried (Na2SO4), filtered, concentrated in vacuo, and chromatographed (10 to 20% ethyl acetate in hexane) to give 14.3 mg of the title compound (compound 6, Table 1) as a yellow, glassy oil: 0.90 (t, 6 H), 1.6 (m, 4 H), 2.03 (s, 6 H), 2.38 (s, 3 H), 2.62 (s, 3 H), 3.2 (br, 4 H), 6.81 (s, 1 H), 7.02 (s, 2 H), 7.60 (d, 2 H), 8.6 (m, 2 H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7]([NH:8][CH2:9][CH2:10][SH:11])=[N:6][S:5](=[O:13])(=[O:12])[N:4]=1.[CH3:14][N:15]([CH2:17][C:18]1[O:22][C:21]([CH2:23]O)=[CH:20][CH:19]=1)[CH3:16]>Cl>[CH3:14][N:15]([CH2:17][C:18]1[O:22][C:21]([CH2:23][S:11][CH2:10][CH2:9][NH:8][C:7]2[C:3]([NH:2][CH3:1])=[N:4][S:5](=[O:13])(=[O:12])[N:6]=2)=[CH:20][CH:19]=1)[CH3:16]
Reactant: CN(C)Cc1ccc(CO)o1
Reactant: CNC1=NS(=O)(=O)N=C1NCCS
Agent: Cl
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1ccc(CN(C)C)o1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A mixture containing 3-methylamino-4-(2-mercaptoethylamino)-1,2,5-thiadiazole 1,1-dioxide (1.0 g; 4.5 mmoles) [prepared in Step A] and 5-dimethylaminomethyl-2-furanmethanol (0.82 g; 4.5 mmoles) [prepared according to the procedure in J. Chem. Soc., 4728 (1958)] in 20 ml of concentrated hydrochloric acid was stirred in an ice-water bath for 2 hours and then allowed to stand at 0° for 64 hours. The reaction mixture was stirred at ambient temperature for 23 hours, evaporated without heating under reduccd pressure and the residue partitioned between water and methylene chloride. The aqueous phase was made basic with sodium bicarbonate and extracted with methylene chloride. The combined organic phase was washed with saturated brine solution, dried and evaporated under reduced pressure. The residue was placed on 25 g of silica gel and chromatographed using a gradient elution of methylene chloride-methanol. The appropriate fraction was evaporated and the product crystallized from methanol. Recrystallization from methanol yielded the title compound, mp 92°-96° .
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[OH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[C:15](=[O:20])[CH2:14]2)[CH2:9][CH2:8]1.C(N(CC)CC)C>C1COCC1>[CH3:4][S:1]([O:6][C@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[C:15](=[O:20])[CH2:14]2)[CH2:11][CH2:12]1)(=[O:3])=[O:2]
Reactant: CN1CCN([C@H]2CC[C@H](O)CC2)CC1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN([C@H]2CC[C@H](OS(C)(=O)=O)CC2)CC1=O

Procedure:
109 g of mesyl chloride in 250 ml THF are added dropwise to 150 g (trans)-1-hydroxy-4-(4-methyl-3-oxo-piperazin-1-yl)-cyclohexane and 162 ml triethylamine in 2300 ml THF in such a way that the temperature does not exceed 35° C. After 25 min the suspension is filtered and washed with 300 ml THF. The filtrate is evaporated down in vacuo at 40° C. to a total mass of 520 g. 230 ml ethyl acetate are added to the suspension. After 15 min the mixture is filtered and the precipitate is washed with 230 ml of ethyl acetate and 150 ml of methyl-tert-butyl ether. After drying, 153.1 g product are obtained.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32]N)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:28][CH:27]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccc(Cl)cc3)n2)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and (4-chloro-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=426.6 (M+H)+
Reaction SMILES: Cl[C:2]1[NH:3][CH2:4][N:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([N+:12]([O-:14])=[O:13])[C:8]([F:15])=[CH:7]2.C([O-])([O-])=O.[K+].[K+]>CC#N>[NH:5]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cc2c(cc1F)=NCNC=2Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cc2c(Nc3ccccc3)ncnc2cc1F
Yield: 345.9 %

Procedure:
Compounds 6 (3 g, 13.18 mmole) and 17 (3.9 g, 13.18 mmole) were combined in CH3CN (25 mL) and heated for one hr. Mass spectroscopy indicated no starting material. Saturated K2CO3 was added and the reaction was extracted 3× with EtOAc. The organic layers were combined, washed with brine and concentrated in vacuo to give 6.48 g of 7 (78.4%).
Reaction SMILES: F[C:2]1[C:7]([NH:8][C:9]([C:11]2[CH:12]=[C:13]3[CH:19]=[CH:18][N:17]([CH3:20])[C:14]3=[N:15][CH:16]=2)=O)=[CH:6][CH:5]=[C:4]([F:21])[N:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[F:21][C:4]1[N:3]=[C:2]2[S:31][C:9]([C:11]3[CH:12]=[C:13]4[CH:19]=[CH:18][N:17]([CH3:20])[C:14]4=[N:15][CH:16]=3)=[N:8][C:7]2=[CH:6][CH:5]=1
Reactant: Cn1ccc2cc(C(=O)Nc3ccc(F)nc3F)cnc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cn1ccc2cc(-c3nc4ccc(F)nc4s3)cnc21
Temperature: 130 °C
Yield: 167.1 %

Procedure:
To a suspension of 1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (2,6-difluoro-pyridin-3-yl)-amide (300 mg, 1.04 mmol) in toluene in a sealable vial was added Lawesson's Reagent (210 mg, 0.52 mmol). The vial was capped and heated to 130° C. for 12 h, cooled to room temp, and loaded directly onto a silica gel column and purified by flash column chromatography (0 to 100% EtOAc in hexanes) to afford 5-fluoro-2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-thiazolo[5,4-b]pyridine (247 mg, 83% yield). ES MS (M+H+)=285; 1H NMR δ (ppm)(DMSO-d6): 8.99 (1H, d, J=2.23 Hz), 8.64 (1H, s), 8.66-8.53 (1H, m), 7.67 (1H, d, J=3.50 Hz), 7.38 (1H, dd, J=8.74, 1.80 Hz), 6.65 (1H, d, J=3.49 Hz), 3.87 (3H, s).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=[O:19])[C:9]([CH3:20])=[C:8]([CH3:21])[N:7]=1)[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.[CH3:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>C(Cl)Cl>[CH2:12]([N:11]1[C:10](=[O:19])[C:9]([CH3:20])=[C:8]([CH3:21])[N:7]=[C:6]1[C@H:2]([NH:1][C:34](=[O:35])[C:33]1[CH:37]=[CH:38][C:30]([CH3:29])=[CH:31][CH:32]=1)[CH:3]([CH3:4])[CH3:5])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1nc([C@H](N)C(C)C)n(Cc2ccccc2)c(=O)c1C
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N[C@@H](c2nc(C)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.9 %

Procedure:
To 2-((R)-1-amino-2-methyl-propyl)-3-benzyl-5,6-dimethyl-3H-pyrimidin-4-one (50 mg, 0.175 mMol) and triethylamine (49 μL, 0.350 mMol) in CH2Cl2 was add 4-methyl-benzoyl chloride (21 μL, 0.157 mMol) was added. The reaction was stirred at RT for 48 h, quenched with water and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried (Na2SO4), filtered, and evaporated to give the title compound (50 mg, 72%) as colorless oil. MS (ES) m/e 404.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][NH:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[NH:16]([C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[C@H:17]([C:43](O)=[O:44])[CH2:18][C:19]1[N:23]=[CH:22][N:21]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(#N)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][N:6]([C:43](=[O:44])[C@@H:17]([NH:16][C:46]([O:48][CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)=[O:47])[CH2:18][C:19]1[N:23]=[CH:22][N:21]([C:24]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:20]=1)[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9]
Reactant: COC(=O)CCNCC(=O)OC(C)(C)C
Reactant: O=C(N[C@@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CCN(CC(=O)OC(C)(C)C)C(=O)[C@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of the compound from Step 1 (0.434 g, 2 mmol) in methylene chloride (10 mL) was added Cbz-His(Trt)-OH (1.062 g, 2 mmol), triethylamine (0.8 mL, 5.7 mmol) and HBTU (0.758 g, 2 mmol) dissolved in acetonitrile (10 mL). The reaction mixture was stirred overnight at room temperature. The solution was concentrated, the residue taken up in ethyl acetate and washed three times with saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo. Chromatography was carried out on silica gel, using 30% hexanes in ethyl acetate as eluent, to give an oil; 1.38 g (94% yield). MS-APCI: M+1=732.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Br[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][C:18]=1[CH2:30][CH2:31][CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[O:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][CH2:13][O:1][C:2]2[CH:3]=[C:4]([S:8]([NH2:11])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=2)=[C:18]([CH2:30][CH2:31][CH3:32])[CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NS(=O)(=O)c1cccc(O)c1
Reactant: CCCc1cc(Oc2ccccc2)ccc1OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1cccc(S(N)(=O)=O)c1
Temperature: 25 °C

Procedure:
A solution of 3-hydroxybenzenesulfonamide (0.5 g, 2.89 mmol) and 1-(3-bromopropoxy)-4-phenoxy-2-propylbenzene (1.01 g, 2.89 mmol) with cesium carbonate (1.04 g, 3.18 mmol) in dry DMF (10 mL) was stirred at 50° C. for 5 h. The reaction suspension was cooled to room temperature and concentrated under vacuum to an orange residue. The residue was partitioned between ethyl acetate and water. The ethyl acetate phase was dried over sodium sulfate, filtered, and concentrated to an oil. The oil was chromatographed over silica gel with hexanes/ethyl acetate (2:1) to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]([CH2:24][CH:25]3[O:27][CH2:26]3)[C:20](OC)=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]3[CH2:24][CH:25]([CH2:26][NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:27][C:20]3=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Product: COc1ccc(-c2ccc(S(=O)(=O)NC3CC(CNc4ccccc4)OC3=O)cc2)cc1
Temperature: 80 °C

Procedure:
To a solution of methyl 2-[(4′-methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-4,5-epoxypentanoate 1d (0.5 g, 1.28 mmol) in aniline (0.17 mL, 1.92 mmol) is added magnesium perchlorate (2 mg, 0.009 mmol) and the resulting mixture is heated for 4 h at 80° C. The resulting mixture is cooled to room temperature, and then the mixture is diluted with water, and extracted three times with EtOAc. The combined EtOAc layer is washed with water, brine, dried over MgSO4 and concentrated to an oil which is purified by column chromatography eluting with hexane/EtOAc (7:3) to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:12]2[CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][C:8](=[O:20])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:21][CH3:22].Cl[C:24]1[N:29]=[C:28]([NH:30][C@@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]2[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:27]([Cl:42])=[CH:26][N:25]=1.Cl.O1CCOCC1>COCCO>[CH2:13]([N:10]1[CH2:11][C:12]2[C:2]([NH:1][C:24]3[N:29]=[C:28]([NH:30][C@@H:31]4[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]4[NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[C:27]([Cl:42])=[CH:26][N:25]=3)=[C:3]([O:21][CH3:22])[CH:4]=[CH:5][C:6]=2[NH:7][C:8](=[O:20])[CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COc1ccc2c(c1N)CN(Cc1ccccc1)CC(=O)N2
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: COc1ccc2c(c1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)CN(Cc1ccccc1)CC(=O)N2
Temperature: 90 °C

Procedure:
To a solution of 6-amino-4-benzyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (75 mg, 0.25 mmol) and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (85 mg, 0.25 mmol) in 2-methoxyethanol (2 mL) was added 4N HCl-dioxane (0.20 mL). The mixture was heated to 90° C. for two hours whereupon LCMS showed complete consumption of the aniline. After being cooled to room temperature, triethylamine was added to pH 9 and the crude product was purified by preparative tlc (7% MeOH-DCM) to afford N-{(1R,2R)-2-[2-(4-benzyl-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6-ylamino)-5-chloro-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a light brown foam; 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.02 (s, 2H), 7.35 (m, 5H), 7.10 (d, J=8 Hz, 1H), 7.03 (d, J=8 Hz, 1H), 6.78 (m, 1H), 4.65 (m, 1H), 4.30 (m, 1H), 3.70 (s, 3H), 3.65 (s, 2H), 3.60 (s, 2H), 3.26 (s, 2H), 2.89 (s, 3H), 1.97 (m, 2H), 1.68 (m, 2H), 1.38 (m, 2H), 1.25 (m, 2H); MS (m/e) 601 (M+1).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([OH:25])[C@@H:22]([OH:26])[CH:21]1[OH:27])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:30](OC)([CH3:32])[CH3:31].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CC(C)=O>[Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@H:23]2[O:25][C:30]([CH3:32])([CH3:31])[O:26][C@H:22]2[CH:21]1[OH:27])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@@H](O)[C@@H](O)C1O)(c1ccccc1)c1ccccc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)O[C@@H]2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C(O)[C@@H]2O1
Temperature: 60 °C
Reaction time: 2 h
Yield: 54.9 %

Procedure:
To a stirred solution of (2R,3S,5R)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]tetrahydrofuran-2,3,4-triol (compound 25a, 33 g, 85 mmol) in acetone (250 mL) was added 2,2-dimethoxypropane (13.2 g, 127 mmol) and p-toluene sulfonic acid (1 g, 5.8 mmol). After being stirred at 60° C. for 2 hours, the resulting solution was adjusted to pH 7.0 by addition of saturated NaHCO3 solution and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:11 EtOAc in petroleum ether) to afford 20 g of (3aS,5R,6aS)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-6-ol (compound 25b).
Reaction SMILES: [C:1]1([C:10]2[CH2:18][CH2:17]C[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=2)CCCCCCNN=1.S(C1C=CC(C)=CC=1)([O-])(=O)=[O:20]>CCCCCC>[CH2:1]1[C:10]2([CH2:11][CH2:12][CH:13]=[CH:14][CH2:15]2)[CH2:18][CH2:17][O:20]1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: C1=C(C2=NNCCCCCC2)CCCCCCC1
Solvent: CCCCCC
Product: C1=CCC2(CC1)CCOC2
Temperature: 110 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Diazabicyclononene (DBN) (76.2 g., 0.61 mole) was stirred and heated at 90° C. while the tosylate from Part E above (133.2 g. (0.43 mole)) was added portionwise. When the addition was completed the mixture was stirred at 110° C. for one hour then cooled in an ice-water bath. The mixture was then diluted with hexane causing the precipitation of salts. The resulting suspension was filtered and the solid filtered salts were washed with hexane. The hexane solution was concentrated on a rotating evaporator to a residue of 210 g. of a pale yellow liquid. This liquid was distilled to give 84.6 g. (74% yield) of the 2-oxaspiro[4.5]dec-7-ene as a relatively pure material which was not further purified.
Reaction SMILES: Br[C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[O:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14]C=O.C(=O)([O-])[O-].[K+].[K+].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Cu]>[Cl:21][C:19]1[CH:20]=[CH:2][C:3]2[O:4][CH2:5][O:6][C:7]3[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=3[NH:14][C:17]=2[CH:18]=1
Reactant: O=CNc1cc(Cl)ccc1OCOc1ccc(Cl)cc1Br
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Clc1ccc2c(c1)Nc1cc(Cl)ccc1OCO2
Temperature: 20 °C
Reaction time: 10 h

Procedure:
A suspension of 4.1 g. (0.01 moles) of (2-bromo-4-chlorophenoxy)-(2-formamido-4-chlorophenoxy)-methane (m.p.: 148° to 149° C.), 2.1 g. (0.015 moles) of potassium carbonate, 0.5 g. (0.008 gatom) of copper powder and 30 ml. of Dowtherm® A is heated up to 190° C. and is kept at this temperature for 10 hours, while stirred vigorously. Thereafter the reaction mixture is filtered and from the filtrate the solvent is distilled off in vacuo. The remaining tar is boiled in a mixture of 45 ml. of ethanol and 4.5 ml. of a 20% aqueous sodium hydroxide solution for one hour, then cooled to 20° C. It is then neutralized with a 37% aqueous hydrochloric acid solution and the solvent is eliminated. The residue is extracted three times with 80 ml. portions each of hot cyclohexane, the combined extracts are decoloured while hot and the solvent is eliminated. Recrystallization of the crude product from carbon tetrachloride affords a white product weighing 0.6 g. (21.4%) and melting at 194° to 196° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12]CC)=[O:11])[CH2:6][CH2:5]1>C(O)C>[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C1CCN(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC(C(=O)O)CC1
Reaction time: 20 h
Yield: 99.1 %

Procedure:
12.5 cm3 of a 4 N aqueous sodium hydroxide solution are added, at 20° C., to 7.60 g of ethyl 1-methyl-4-piperidinecarboxylate in solution in 35 cm3 of ethanol. After stirring for 20 hours, the reaction mixture is concentrated to a reduced volume and then neutralized with 12.5 cm3 of a 4 N aqueous hydrochloric acid solution and finally concentrated to dryness under reduced pressure (2.7 kPa). The residue is stirred in 60 cm3 of anhydrous ethanol, and then filtered. The filtrate is concentrated to dryness under reduced pressure (2.7 Kpa) at 20° C., to give 6.3 g of 1-methyl-4-piperidinecarboxylic acid in the form of a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16].Cl[C:18]1[C:23]([Cl:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1>>[Cl:24][C:23]1[C:18]([O:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[N:19][CH:20]=[C:21]([N+:25]([O-:27])=[O:26])[CH:22]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Reactant: Oc1ccccc1-c1nc2ccccc2s1
Product: O=[N+]([O-])c1cnc(Oc2ccccc2-c2nc3ccccc3s2)c(Cl)c1

Procedure:
2-(Benzo[d]thiazol-2-yl)phenol was reacted with 2,3-dichloro-5-nitro pyridine to obtain 2-(2-(3-chloro-5-nitropyridin-2-yloxy)phenyl)benzo[d]thiazole which was further converted to 6-(2-(benzo[d]thiazol-2-yl)phenoxy)-5-chloropyridin-3-amine as per the procedure described in preparation 2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:33]=[C:34](/[CH:36]=[CH:37]/[CH2:38][O:39][CH3:40])[CH:35]=1)[CH2:5][N:6]([CH:30]1[CH2:32][CH2:31]1)[C:7]([C@H:9]1[C@H:14]([C:15]2[CH:20]=[CH:19][N:18]([CH3:21])[C:17](=[O:22])[CH:16]=2)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)=[O:8].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:33]=[C:34](/[CH:36]=[CH:37]/[CH2:38][O:39][CH3:40])[CH:35]=1)[CH2:5][N:6]([CH:30]1[CH2:32][CH2:31]1)[C:7]([C@H:9]1[C@H:14]([C:15]2[CH:20]=[CH:19][N:18]([CH3:21])[C:17](=[O:22])[CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:8]
Reactant: COC/C=C/c1cc(Br)cc(CN(C(=O)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2c2ccn(C)c(=O)c2)C2CC2)c1
Agent: Cl
Solvent: ClCCl
Product: COC/C=C/c1cc(Br)cc(CN(C(=O)[C@@H]2CNCC[C@H]2c2ccn(C)c(=O)c2)C2CC2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a CH2Cl2 solution (0.1 M) of trans-tert-butyl 3-{[{3-bromo-5-[(1E)-3-methoxyprop-1-en-1-yl]benzyl}(cyclopropyl)amino]carbonyl}-4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)piperidine-1-carboxylate (1 eq.) from the previous step was added HCl (4.0 M dioxane solution, 30 eq.). The resulting solution was stirred at RT for 45 min. Following the removal of the volatiles in vacuo, the resulting residue was directly loaded onto a SiO2 column packed with 93:7 (v/v) CH2Cl2:2.0 M NH3 in MeOH. Elution with the same solvent system furnished the title compound. MS (ESI+, M+H): 516.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]([CH2:24][O:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]#[N:33])[CH2:28][CH2:27]3)=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[N-:34]=[N+:35]=[N-:36].[Na+].[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:15]([CH2:24][O:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]4[NH:36][N:35]=[N:34][N:33]=4)[CH2:28][CH2:27]3)=[N:14][CH:13]=2)([CH3:10])[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(COC2CCN(C#N)CC2)n1-c1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(COC2CCN(c3nnn[nH]3)CC2)n1-c1ccc(F)cc1
Temperature: 100 °C
Yield: 47 %

Procedure:
A mixture of 4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)methoxy)piperidine-1-carbonitrile, NaN3 (59 mg, 0.9 mmol), and NH4Cl (50 mg, 0.9 mmol) in DMF (2 mL) was heated at 100° C. overnight. The crude product was purified by HPLC (10-99%, MeCN/H2O with 0.05% TFA) to give the title product as a white solid (45 mg, 47%). MS (EI) m/z 530.3 [M+H]+.