Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[O:39]1[C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][CH2:42][CH2:41][CH2:40]1>>[NH2:30][C:29]1[S:28][C:27]([CH:40]2[CH2:41][CH2:42][CH2:43][CH2:44][O:39]2)=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][NH2:8])[CH2:15][CH2:14]1)=[O:24]
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Reactant: CC1(C)OB(C2=CCCCO2)OC1(C)C
Product: Cn1ncc(NC(=O)c2nc(C3CCCCO3)sc2N)c1N1CCC(CN)CC1
Yield: 20 %

Procedure:
Following the procedure for Example 281, tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 3,4-dihydro-2H-pyran-6-boronic acid pinacol ester gave 290 as a yellow solid (27 mg, 20% over three steps). 1H NMR (400 MHz, d4-MeOD) δ 7.34 (s, 1H), 4.46-4.41 (m, 1H), 4.02-3.95 (m, 1H), 3.63 (s, 3H), 3.67-3.51 (m, 1H), 3.12-2.97 (m, 4H), 2.53 (d, J=6.6 Hz, 2H), 2.07-1.98 (m, 1H), 1.97-1.79 (m, 1H), 1.76 (d, J=12.5 Hz, 2H), 1.68-1.53 (m, 4H), 1.49-1.36 (m, 1H), 1.36-1.21 (m, 2H). LCMS (ES+) m/z 420 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:34][C:35]([N:37]([CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)[CH3:38])=[O:36]>[Cu]I.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:34][C:35]([N:37]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[CH3:38])=[O:36])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Reactant: CN(C(=O)CCl)C1CCCCC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CN1CCc2c(n(CC(=O)N(C)C3CCCCC3)c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.6 %

Procedure:
The title compound was prepared by following general procedure 7. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.43 mmol), was taken into DMF. CuI (8 mg, 0.043 mmol), L-proline (10 mg, 0.086 mmol), K3PO4 (183 mg, 0.86 mmol) were added to the solution and stirred for 10 min. at RT. 2-Chloro-N-cyclohexyl-N-methylacetamide (98 mg, 0.51 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 56 mg of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-cyclohexyl-N-methylacetamide as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:31])[C:12]2[O:18][C:17]3[C:19]([Cl:27])=[CH:20][C:21]([NH:23][CH2:24][CH2:25]Cl)=[CH:22][C:16]=3[CH2:15][S:14](=[O:29])(=[O:28])[C:13]=2[CH:30]=1)=[O:8]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:31])[C:12]2[O:18][C:17]3[C:19]([Cl:27])=[CH:20][C:21]([NH:23][CH2:24][CH2:25][NH:4][CH:1]4[CH2:3][CH2:2]4)=[CH:22][C:16]=3[CH2:15][S:14](=[O:28])(=[O:29])[C:13]=2[CH:30]=1)=[O:8]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Reactant: NC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCNC3CC3)cc(Cl)c1O2
Temperature: 110 °C
Reaction time: 5 h

Procedure:
Cyclopropylamine (0.819 g, 1.4 mmol) and tetrabutylammonium iodide (0.010 g, 0.027 mmol) were sequentially added with stirring to a solution of the carboxylic acid of Example 56k (0.59 g, 1.2 mmol) in dry methanol (10 mL). The reaction mixture was stirred at 110° C. for 5 h in an atmosphere of nitrogen. It was concentrated, treated with a methanolic HCl solution (15 mL) and refluxed for 2 h. The reaction mixture was concentrated, treated with an aqueous sodium bicarbonate solution to pH 7, water and extracted with n-butanol. The organic layer was washed with water, brine, dried and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.120 g, (22%); 1H NMR (DMSO-d6): δ 0.20 (d, 2H, CH2), 0.40 (d, 2H, CH2), 2.10 (m, 1H, CH), 2.60 (s, 3H, CH3), 2.80 (t, 2H, CH2), 3.10 (d, 2H, CH2), 3.90 (s, 3H, OCH3), 5.15 (s, 2H, CH2), 6.10 (t, 1H, NH), 6.70 (s, 1H, Ar), 6.72 (s, 1H, Ar), 8.10 (s, 1H, Ar), 8.20 (s, 1H, Ar); MS: m/e (CI+) 451 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8](C)(C)O[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])(=O)=O.Cl>CN(C)C=O.O.CO>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[C:11]=1[C:10]([O:9][CH3:8])=[O:12]
Reactant: CC1(C)OC(=O)c2c(O)cccc2O1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1c(O)cccc1OCC(F)(F)F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
A mixture of 5-hydroxy-2,2-dimethyl-4H-1,3-benzodioxin-4-one (123 g, 633 mmol, Synth. Commun. 1994, 24, 1025), potassium carbonate (262 g, 1.9 mol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (95.8 mL, 665 mmol) in N,N-dimethylformamide (600 mL) was stirred at 50° C. for 30 min. Then methanol (300 mL) was added to the mixture, and stirring was continued for 5 h at that temperature. After cooling to room temperature, the mixture was diluted with water (500 mL) and neutralized with 2N hydrochloric acid. Product was extracted with a mixture of ethyl acetate-hexane (5:1, 500 mL×3). Combined organic layers were washed with water (500 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residual solid was recrystallized from methanol-water to afford 125 g (79%) of the desired product as colorless crystals.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][OH:14])[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=2)[N:6]=1)(=O)=O.[C-:23]#[N:24].[Na+].C(OCC)(=O)C>CS(C)=O>[OH:14][CH2:13][CH2:12][CH2:11][C:9]1[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=2)[N:6]=[C:5]([C:23]#[N:24])[N:10]=1
Reactant: Cc1ccc(-c2cc(CCCO)nc(S(C)(=O)=O)n2)cc1C
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccc(-c2cc(CCCO)nc(C#N)n2)cc1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the solution of 2-methylsulfanyl-4-(3-hydroxypropyl)-6-(3,4-dimethyl-phenyl)pyrimidine (5.8 g) in a mixed solvent of methanol and water (110 ml, 10:1) was added OXONE (35 g). The mixture was stirred at room temperature for 3 hours, then diluted with ethyl acetate (500 ml). The mixture was washed with water (3×500 ml). Organic layer dried over sodium sulphate, solvent removed under reduced pressure to give 2-methanesulphonyl-4-(3-hydroxypropyl)-6-(3,4-dimethylphenyl)-pyrimidine as crude product. To a stirred solution of above 2-methylsulphonyl-4-(3-hydroxypropyl)-6-(3,4-dimethylphenyl)pyrimidine in dimethylsulfoxide (50 mL), was added sodium cyanide (2.9 g). The mixture was stirred at room temperature for 4 hours, then poured into ethyl acetate (300 mL) and washed with water (2×200 mL). The organic layer was dried over sodium sulphate, solvent evaporated at reduced pressure, the above residue was flashed on silica gel using Petrol/EtOAc (1:1) as eluent to give 4-(3-Hydroxy-propyl)-6-(3,4-dimethylphenyl)-pyrimidine-2-carbonitrile as product (4.8 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([S:18]([N:21]=[CH:22][N:23]([CH3:25])[CH3:24])(=[O:20])=[O:19])=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=2[N+:26]([O-])=O)=[CH:4][CH:3]=1.[H][H]>CN(C)C=O.[Ni]>[NH2:26][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([S:18]([N:21]=[CH:22][N:23]([CH3:25])[CH3:24])(=[O:20])=[O:19])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(-c2ccc(C)cc2)c(S(=O)(=O)N=CN(C)C)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N)c(-c2ccc(C)cc2)c(S(=O)(=O)N=CN(C)C)c1

Procedure:
A solution of 28 g (0.07 mole) of methyl 4-(4-methylphenyl)-3-nitro-5-dimethylaminomethyleneaminosulfonyl-benzoate in 200 ml of dimethylformamide is hydrogenated with 3 g of Raney nickel at 50° and with hydrogen under a pressure of 50 atmospheres, for 10 hours in an autoclave. After filtering, the filtrate is introduced into ice-water and the precipitate is filtered off and recrystallized from dimethylformamide/MeOH.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]2[S:14][C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=3)=[N:12][N:11]=2)=[N:4][C:5](SC)=[N:6][CH:7]=1.OOS([O-])=O.[K+].[NH2:29][CH2:30][CH2:31][N:32]1[C:36]([CH3:38])([CH3:37])[C:35](=[O:39])[NH:34][C:33]1=[O:40].C(N(C(C)C)CC)(C)C>CC(C)=O.O.CC(O)C>[Cl:1][C:2]1[C:3]([C:10]2[S:14][C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][N:11]=2)=[N:4][C:5]([NH:29][CH2:30][CH2:31][N:32]2[C:36]([CH3:37])([CH3:38])[C:35](=[O:39])[NH:34][C:33]2=[O:40])=[N:6][CH:7]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCN
Reactant: CSc1ncc(Cl)c(-c2nnc(Nc3ccc(F)cc3)s2)n1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Cl)c(-c2nnc(Nc3ccccc3)s2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
5-(5-Chloro-2-(methylthio)pyrimidin-4-yl)-N-(4-fluorophenyl)-1,3,4-thiadiazol-2-amine (0.637 g, 1.7 mmol) was dissolved in 300 mL acetone. Oxone (6.3 g, 10.3 mmol) was dissolved in 300 mL H2O and added in one portion to the acetone solution and allowed to stir overnight at room temperature. The acetone was removed under vacuum, the resulting precipitate was obtained by filtration. LC/MS analysis indicates a mixture of both sulfoxide and sulfone. This solid mixture was dried briefly in a vacuum oven. This material was charged to a microwave reaction vessel along with 1-(2-aminoethyl)-5,5-dimethyl-imidazolidine-2,4-dione (0.588 g, 3.4 mmol), diisopropyl ethylamine (0.60 mL, 3.4 mmol) and 15 mL IPA. This reaction was heated under microwave conditions to 170° C. for 1200 s. Upon cooling 0.545 g (67% yield) of product was obtained by filtration. MS (M+H)+ 477.
Reaction SMILES: C[O-].[Na+].[OH:4][C:5]1[CH:15]=[CH:14][C:8]2[NH:9][C:10](=[O:13])[CH2:11][S:12][C:7]=2[CH:6]=1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH:25]=O)=[CH:17]1>CN(C=O)C>[OH:4][C:5]1[CH:15]=[CH:14][C:8]2[NH:9][C:10](=[O:13])[C:11](=[CH:25][C:18]3[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:16][CH:17]=3)[S:12][C:7]=2[CH:6]=1
Reactant: O=C1CSc2cc(O)ccc2N1
Reactant: O=Cc1c[nH]c2ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(O)cc2SC1=Cc1c[nH]c2ccccc12
Temperature: 140 °C

Procedure:
Sodium methoxide (0.54 g, 10 mmol) was added in one portion to a solution of 7-hydroxy-2H-1,4-benzothiazin-3(4H)-one (0.91 g, 5 mmol) and indole-3-carboxaldehyde (1.09 g, 7.5 mmol) in dry DMF (5 ml). The mixture was heated at 140° C. for 48 h, allowed to cool and poured into ice water (60 ml). The solid was collected by filtration. The filtrate was acidified to pH=2 with 10% hydrochloric acid and the precipitated solid was collected by filtration. Both precipitates were put together, boiled with toluene and filtered hot to give a solid which was purified by silica gel chromatography using a gradient of (9:1) to (8:2) n-hexane/ethanol as the mobile phase.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][C:15](OCC)=[O:16]>CN(C=O)C>[N:1]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:12][CH2:13][CH2:14][C:15]1=[O:16]
Reactant: CCOC(=O)CCCBr
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(N2CCCC2=O)cc1
Reaction time: 0.83 h

Procedure:
19.2 g (140 mmol) 4-amino-benzoic acid are refluxed for 20 hours together with 25.8 ml (180 mmol) ethyl 4-bromobutyrate in 100 ml DMF. After evaporation i. vac. the residue is combined with 100 ml of water and 50 ml petroleum ether and vigorously stirred for 50 minutes. The precipitate is filtered off, recrystallised from ethanol and dried at 80° C.
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].[C:15]([O:19][C:20](=[O:54])[CH2:21][C:22]1([CH2:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[O:26][N:25]=[C:24]([C:27]2[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:28]=2[CH2:34][CH2:35][C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])[CH2:23]1)([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1.CN1C(=O)CCC1>C(#N)C>[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:33][C:31]2[CH:30]=[CH:29][C:28]([CH2:34][CH2:35][C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])=[C:27]([C:24]3[CH2:23][C:22]([CH2:46][C:47]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:53])([CH2:21][C:20](=[O:54])[O:19][C:15]([CH3:18])([CH3:16])[CH3:17])[O:26][N:25]=3)[CH:32]=2)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)Nc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cc(O)ccc2CCC(=O)OCc2ccccc2)=NO1
Agent: Cl
Solvent: CC#N
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cc(OC(=O)c3ccc(NC(=N)N)cc3)ccc2CCC(=O)OCc2ccccc2)=NO1
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
4-Carbamimidamidobenzoyl chloride hydrochloride (96 mg) was added to a mixture of benzyl 3-(2-(5,5-bis(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-hydroxyphenyl)propanoate (227 mg), pyridine (0.2 mL), and NMP (0.2 mL) at 50 C, and the obtained mixture was stirred at 50 C for 30 minutes. 4-Carbamimidamidobenzoyl chloride hydrochloride (96 mg) was further added thereto, and the obtained mixture was stirred overnight at 50 C. To the reaction mixture, acetonitrile was added. The precipitate was filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane, subsequently methanol/ethyl acetate) to obtain the title compound (163 mg).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][N:14]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:15][CH2:16][C@H:17]([NH:21]C(OC(C)(C)C)=O)[C:18]([OH:20])=[O:19])[C:10]([OH:12])=[O:11])=O)(C)(C)C>C(O)(C(F)(F)F)=O>[NH2:8][C@@H:9]([CH2:13][N:14]([C:29]([O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:30])[CH2:15][CH2:16][C@H:17]([NH2:21])[C:18]([OH:20])=[O:19])[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)C(=O)OCc1ccccc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CCN(C[C@H](N)C(=O)O)C(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S,S)-2,7-Bis(tert-butyloxycarbonylamino)-4-benzyloxycarbonyl-4-azaoctanedioic acid (0.29 g, 0.37 mmol) was dissolved in TFA (10 ml), the solution stirred at ambient temperature for 2 hours and the TFA distilled off to yield the title compound which was used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:21][C:22]#[N:23])[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1.[Cl-].[NH4+].[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1)[CH2:21][C:22]1[NH:28][N:27]=[N:26][N:23]=1
Reactant: COc1ccc(Oc2c(Cl)cc(CC#N)cc2Cl)cc1C(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2c(Cl)cc(Cc3nnn[nH]3)cc2Cl)cc1C(C)C
Yield: 33.4 %

Procedure:
To a stirred solution of 3,5-dichloro-4-(4-methoxy-3-isopropylphenoxy)-phenylacetonitrile (160 mg) in 3.0 ml of dimethyl formamide, ammonium chloride (500 mg) and sodium azide (600 mg) was added at reflux. After 2 hours the reaction mixture was concentrated, treated with 6 M hydrochloric acid and extracted several times with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and concentrated. The residue was purified by column chromatography (silica gel, 96:4:1 chloroform/methanol/acetic acid) to give 60 mg (34%) of 3,5-dichloro-4-(4-methoxy-3-isopropylphenoxy)benzyltetrazole.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[C:5]([F:11])[CH:4]=1)#[N:2].Cl.[C:13]([O:17][C:18](=[O:22])[CH2:19][NH:20][CH3:21])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:20]([CH3:21])[CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:22])=[C:5]([F:11])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: CNCC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1F
Temperature: 50 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
A mixture of 4-cyano-2-fluorobenzyl bromide (250 g, 1.17 mol), sarcosine tert-butyl ester hydrochloride (212.2 g, 1.17 mol) and potassium carbonate (484 g, 3.50 mol) in acetone (2 L) was stirred 24 hours at 50° C. and 18 hours at RT. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken up with water (1 L) and extracted with ethyl acetate (2×1 L). The combined organic layers were washed with water (1 L), dried (MgSO4) and concentrated under vacuum to give the title compound as a yellow-brown oil (325 g, quantitative). 1H NMR (DMSO-d6, 300 MHz) δ 7.82 (dd, J=9.9, 1.4 Hz, 1H), 7.70 (dd, J=7.9, 1.5 Hz, 1H), 7.64 (m, 1H), 3.78 (s, 2H), 3.23 (s, 2H), 2.27 (s, 3H), 1.42 (s, 9H). LC/MS (Method B): 279.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[C:10]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[CH3:10][N:3]1[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]1[CH3:1]
Reactant: O=C([O-])[O-]
Reactant: Cc1nc([N+](=O)[O-])c[nH]1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1nc([N+](=O)[O-])cn1C
Temperature: 25 °C
Yield: 45 %

Procedure:
To a mixture of 2-methyl-4-nitro-1H-imidazole (10.0 g, 78.7 mmol) and K2CO3 (21.7 g, 160 mmol) in DMF (80 mL) was added CH3I (13.4 g, 94 mmol) dropwise while stirring at room temperature. The mixture was stirred for 2 h. Water (200 mL) was then added to the mixture. The resulting suspension was filtered, washed with water, and dried in vacuo to afford 337a as a white solid (5.0 g, 45%). MS-ESI: [M+H]+ 142.1.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([F:21])([F:20])([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[O:8].[NH:24]1[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]1>>[Br:1][C:2]1[C:3]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([F:21])([F:20])([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(S(F)(F)(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: O[C@@H]1CCNC1
Product: O=C(Nc1ccc(S(F)(F)(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(4-(pentafluorosulfanyl)phenyl)nicotinamide (Stage 216.2) and (R)-pyrrolidin-3-ol to afford a solid. UPLC-MS (Condition 3) tR=1.16 min, m/z=490.1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH:15]([C:17]([O:19]C)=[O:18])[CH2:14][CH2:13][N:12]2[C:21]([O:23][CH3:24])=[O:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br-].[Li+].C(N(CC)CC)C.O>CC#N>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH:15]([C:17]([OH:19])=[O:18])[CH2:14][CH2:13][N:12]2[C:21]([O:23][CH3:24])=[O:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(C)(C)C)cc2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)N1CCC(C(=O)O)CC1c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
To a solution of dimethyl 2-(4-tert-butylphenyl)piperidine-1,4-dicarboxylate (10.937 g, 32.80 mmol) in MeCN (100 mL) was added lithium bromide (6.58 mL, 262.42 mmol), triethylamine (18.19 mL, 131.21 mmol) and water (2 mL). The resulting mixture was heated under reflux for 3 h, then cooled to room temperature. The solvents were evaporated and the residue dissolved in water. The aqueous layer was washed with MTBE, then acidified by the addition of 3.8 N HCl. The aqueous layer was extracted three times with DCM. The combined organic layers were dried over MgSO4 and evaporated. 2-(4-tert-Butylphenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (9.5 g, 91%) was isolated as a light brown foam. MS m/z 320 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:7][C:6]=2[CH:16]=1.[Na+].[I-:18].CNCCNC.N>O.[Cu]I.O1CCOCC1>[I:18][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:7][C:6]=2[CH:16]=1
Reactant: [I-]
Reactant: Brc1ccc2oc(CN3CCCC3)nc2c1
Agent: [Cu]I
Agent: CNCCNC
Agent: N
Solvent: O
Solvent: C1COCCO1
Product: Ic1ccc2oc(CN3CCCC3)nc2c1

Procedure:
71 mg (0.36 mmol) CuI, 1 g (3.55 mmol) 5-bromo-2-pyrrolidin-1-ylmethyl-benzoxazole and 1.07 g (7.15 mmol) NaI are successively placed in a flask in an argon atmosphere. Then 0.08 mL (0.73 mmol) N,N′-dimethylethylenediamine and 3.5 mL 1,4-dioxane are added and the reaction mixture is refluxed for 14 h. The reaction mixture is then combined with 20 mL concentrated ammonia solution at RT, diluted with 100 mL water and extracted with DCM. The organic phase is extracted three times with water and dried over Na2SO4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][NH:11]1.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17].O>O1CCCC1>[C:15]([N:14]1[CH2:13][CH2:12][NH:11][C:10]1=[N:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])(=[O:19])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)C(=O)Cl
Reactant: Clc1ccc(N=C2NCCN2)c(Cl)c1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(=O)N1CCNC1=Nc1ccc(Cl)cc1Cl

Procedure:
A mixture of 11.5 g 2-(2,4-dichlorophenylimino)imidazolidine 1.7 g sodium hydride (80 percent dispersion in oil) and 80 ml dry tetrahydrofuran was stirred and refluxed for one and a half hours, and a solution of 5.9 g isobutyryl chloride in 20 ml dry tetrahydrofuran was then added dropwise. The mixture was stirred and refluxed for five hours and then cooled and poured into iced water to give a solid which was dried over phosphorus pentoxide. Recrystallisation with charcoal from ethanol gave the novel compound 1-isobutyryl-2-(2,4-dichlorophenylimino)imidazolidine, melting point 147°-148° C.