Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[O:10])[CH:2]=1.[NH2:22][C:23]1[C:27]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:26][N:25]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:24]=1.C(N(C(C)C)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[C:31]([O:30][C:29]([NH:28][C:27]1[C:23]([NH:22][C:17]([C:16]2[CH:15]=[CH:14][C:13]([CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:21][CH:20]=2)=[O:19])=[N:24][N:25]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:26]=1)=[O:35])([CH3:34])([CH3:32])[CH3:33]
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCc1cccnc1
Reactant: CC(C)(C)OC(=O)Nc1cn(-c2ccccc2)nc1N
Agent: CCN(CC)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cn(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)OCc2cccnc2)cc1
Temperature: 60 °C

Procedure:
A solution of 4-({[(pyridin-3-ylmethoxy)carbonyl]amino}methyl)benzoic acid (0.1 g, 0.35 mmol), tert-butyl (3-amino-1-phenyl-1H-pyrazol-4-yl)carbamate (0.096 g, 0.35 mmol), and N,N-diethylisopropylamine (0.049 g, 0.35 mmol) in methylene chloride (5 mL) was treated with BOP (0.23 g, 0.52 mmol) and heated to 60° C. for 1 hour. The reaction was loaded directly onto a silica column and purified by flash chromatography (0-3% methanol/methylene chloride) to give pyridin-3-ylmethyl {4-[({4-[(tert-butoxycarbonyl)amino]-1-phenyl-1H-pyrazol-3-yl}amino)carbonyl]benzyl}carbamate as a white solid. 1H NMR (CD3OD) δ 8.57 (s, 1H), 8.48 (d, J=4.99 Hz, 1H), 8.38 (s, 1H), 7.97 (d, J=7.92 Hz, 2H), 7.87 (d, J=7.92 Hz, 1H), 7.72 (d, J=7.92 Hz, 2H), 7.44 (m, 5H), 7.27 (t, J=7.33 Hz, 1H), 5.18 (s, 2H), 4.38 (s, 2H), 1.50 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](C=C[CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].[NH2:32][CH:33](C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.CN1C=CC=C1C(O)=O.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:33][N:32]1[CH:31]=[CH:2][CH:3]=[C:4]1[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cn1cccc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3cccn3C)nn2)cc(OC)c1OC
Yield: 95 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (200 mg, 0.65 mmol), 1-methyl-1H-pyrrole-2-carboxylic acid (106 mg, 0.85 mmol), diisopropylethylamine (0.33 mL, 1.9 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (360 mg, 0.94 mmol) in dimethylformamide (5 mL) gave 1-methyl-N-(1-{3-[(3,4,5-trimethoxyphenyl)-amino]-1,2,4-triazin-6-yl}ethyl)-1H-pyrrole-2-carboxamide (256 mg, 95%) as a yellow solid. MS m/z 412 (M+1).
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[F:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Reactant: Oc1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: N=C(N)N1CCC(CCC(=O)Oc2ccc(F)cc2)CC1
Reaction time: 96 h
Yield: 50.1 %

Procedure:
A mixture of 2.00 g of 1-amidino-4-piperidinepropionic acid hydrochloride and 0.95 g of p-fluorophenol was suspended in 20 ml of dry pyridine. To the suspension was added with stirring and ice-cooling 1.74 g of dicyclohexylcarbodiimide and the resulting mixture was allowed to stand at room temperature for 4 days. After removal of any insoluble materials, the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue to give crystals which were then recrystallized from methanol-ether to obtain 1.4 g (yield: 50.0%) of p-fluorophenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 131° to 133° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[CH:13]([OH:14])[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:2]=1.[C:17]1(O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:17]1([O:14][CH:13]2[CH:12]3[CH2:11][CH2:10][N:9]([CH2:16][CH2:15]3)[CH:8]2[CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1ccccc1
Reactant: OC1C2CCN(CC2)C1Cc1cccnc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: c1ccc(OC2C3CCN(CC3)C2Cc2cccnc2)cc1

Procedure:
The manner in which 3-(phenyloxy)-2-(3-pyridylmethyl)-1-azabicyclo[2.2.2]octane of the present invention is synthesized can vary. For example, pyridine-3-carboxaldehyde and quinuclidin-3-one hydrochloride (commercially available from Aldrich) are reacted together in the presence of methanolic potassium hydroxide as described in Neilsen and Houlihan, Org. React. 16: 14-38 (1968). This aldol condensation product, 2-(3-pyridylmethylene)-1-azabicyclo[2.2.2]octan-3-one, is then dissolved in methanol and hydrogenated in the presence of Raney nickel catalyst to afford 2-(3-pyridylmethyl)-1-azabicyclo[2.2.2]octan-3-ol. This alcohol is then etherified with phenol via Mitsunobu coupling with diethylazidocarboxylate and triphenylphosphine, as described by Guthrie et al., J. Chem. Soc., Perkin Trans I45: 2328 (1981), to afford the desired product, 3-(phenyloxy)-2-(3-pyridylmethyl)-1-azabicyclo[2.2.2]octane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16](=O)[CH3:17].C([O-])(=O)C.[NH4+].C([BH3-])#[N:25].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH:16]([NH2:25])[CH3:17]
Reactant: CC(=O)c1ccc(F)cc1-c1cc(F)ccc1F
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1ccc(F)cc1-c1cc(F)ccc1F

Procedure:
The title compound was prepared from 1-(2′,5′,5-trifluoro-1,1′-biphenyl-2-yl)ethanone (650 mg, 2.6 mmol), anhydrous methanol (10 mL), ammonium acetate (4.0 g, 52 mmol), and sodium cyanoborohydride (326 g, 5.2 mmol) according to the procedure and in the same manner as described in Example 105, step b. The crude amine was immediately used without further purification in Example 116, step c;
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[OH:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[O:33][C:32](=[O:40])[CH:31]=1>CN(C)C1C=CN=CC=1.ClCCCl>[OH:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[O:33][C:32](=[O:40])[C:31]=1[C:11](=[O:13])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)c1c(O)c2ccccc2oc1=O
Reaction time: 1 h
Yield: 19.5 %

Procedure:
4-Nitrophenylacetic acid (4.5 g, 25 mmol) and then dicyclohexylcarbodiimide (5.4 g, 26 mmol) were added to a 1,2-dichloroethane (160 ml) suspension of 4-hydroxycoumarin (4.00 g, 24.6 mmol) at room temperature, after which 4-dimethylaminopyridine (0.15 g, 1.2 mmol) was added and stirring carried out for 1 hour at 60° C. and then further 4-dimethylaminopyridine (0.30 g, 2.4 mmol) added and stirring carried out for 23 hours at 85° C. The dicyclohexylurea was filtered off while the solution was still warm, then the reaction solution washed with dilute hydrochloric acid (50 ml), after which the aqueous layer was extracted with dichloromethane. After drying with anhydrous sodium sulphate, the solvent was distilled off and separation and purification performed by column chromatography. When recrystallization was performed from ethyl acetate, 4-hydroxy-3-(4-nitrophenylacetyl)-coumarin (1.56 g, 19%) was obtained as yellow crystals. Tetrahydrofuran (50 ml), methanol (18 ml) and concentrated hydrochloric acid (5 ml) were added to the compound (1.00 g, 3.1 mmol) obtained, then Pd-C (5%, containing 100% of water, 150 mg) added and the atmosphere replaced by hydrogen. The raw material was consumed in 4 hours and then the hydrogen replaced by argon.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[O:22])[N:7]2[CH3:21].Br[C:24]1[CH:25]=[C:26]([CH2:30][OH:31])[CH:27]=[N:28][CH:29]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:31][CH2:30][C:26]1[CH:25]=[C:24]([C:11]2[C:3]([O:2][CH3:1])=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH3:21])[C:6](=[O:22])[CH2:5]3)[CH:29]=[N:28][CH:27]=1
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)ccc2c1CC(=O)N2C
Reactant: OCc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1c(-c2cncc(CO)c2)ccc2c1CC(=O)N2C
Temperature: 120 °C

Procedure:
To 4-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one, prepared as described in Example 37a (80 mg, 0.264 mmol) was added (5-bromo-pyridin-3-yl)-methanol (CAS#37669-64-0, 55 mg, 0.29 mmol), 1,2-dimethoxyethane (3.0 mL), and 2 M aqueous sodium carbonate (0.330 mL, 066 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (120 mg, 0.013 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 3 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was partially purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 10%). Further purification was accomplished via reverse phase HPLC (7 to 40% acetonitrile/water w/0.1% NH4OH) to furnish 5-(5-hydroxymethyl-pyridin-3-yl)-4-methoxy-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 285.1240 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 3.24 (s, 3H), 3.75 (s, 3H), 3.78 (s, 2H), 4.71 (s, 2H), 6.84 (d, J=81 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 8.45 (d, J=1.8 Hz, 1H), 8.55 (d, J=2.0 Hz, 1H)
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16](Cl)[N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[N:22]1([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[CH:26]=[CH:25][N:24]=[CH:23]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:33][C:30]3[CH:29]=[CH:28][C:27]([N:22]4[CH:26]=[CH:25][N:24]=[CH:23]4)=[CH:32][CH:31]=3)[N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: CCOC(=O)C1CCN(c2ncnc(Cl)c2[N+](=O)[O-])CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2ncnc(Oc3ccc(-n4ccnc4)cc3)c2[N+](=O)[O-])CC1
Temperature: 90 °C
Yield: 91.2 %

Procedure:
A mixture of 1-(6-chloro-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester (63 mg, 0.2 mmol), 4-imidazol-1-yl-phenol (42 mg, 0.26 mmol) and potassium carbonate (36 mg, 0.26 mmol, 1 equivalent) in anhydrous DMF (1 ml) was heated to 90° C. overnight. The resulting residue was purified by Flash Chromatography (hexanes:ethyl acetate=1:1) to give 1-[6-(4-Imidazol-1-yl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester [A1] as a yellow solid (80 mg, 92%). 1H NMR (CDCl3, 400 MHz)δ 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.22 (t, 2H), 3.96-4.03 (m, 2H), 4.15 (q, 2H), 7.38-7.42 (m, 2H), 7.46 (t, 1H), 7.55-7.59 (m, 3H), 8.17 (s, 1H), 8.90-8.92 (m, 1H). Exact mass calculated for C21H22N6O5 438.17, found 439.2 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:19]2[C:27]3[C:26](Cl)=[N:25][CH:24]=[N:23][C:22]=3[N:21]([CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:20]=2)=[O:18])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:35]C1C2C(C(C3C=CC=C([N+]([O-])=O)C=3)=O)=CN(C3CCCC3)C=2N=CN=1>>[C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:19]2[C:27]3[C:26]([NH2:35])=[N:25][CH:24]=[N:23][C:22]=3[N:21]([CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:20]=2)=[O:18])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC#Cc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(Cl)c23)c1
Reactant: Nc1ncnc2c1c(C(=O)c1cccc([N+](=O)[O-])c1)cn2C1CCCC1
Product: CC(C)(C)OC(=O)NCC#Cc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)c1

Procedure:
The title compound was prepared from {3-[3-(4-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-prop-2-ynyl}-carbamic acid tert-butyl ester (452 mg, 0.94 mmol) by a procedure analogous to that described for (4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-nitro-phenyl)methanone. MS: 460.3/360.3 (MH+); HPLC Rf: 6.45 min. (HPLC method 4).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][N:14]2[CH:18]=[C:17]([I:19])[CH:16]=[N:15]2)(=O)=O)=CC=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(#N)C>[I:19][C:17]1[CH:16]=[N:15][N:14]([CH2:13][CH2:12][N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[CH:18]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCn2cc(I)cn2)cc1
Solvent: CC#N
Product: CN1CCN(CCn2cc(I)cn2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.6 %

Procedure:
A solution of 2-(4-iodo-1H-pyrazol-1-yl)ethyl 4-methylbenzenesulfonate (Preparation 58, 377 mg, 0.961 mmol) in acetonitrile (6 mL) was treated with 1-methylpiperazine (1.1 mL, 9.88 mmol). The resulting mixture was stirred at room temperature for 3 days. The majority of the solvent was removed under reduced pressure and the residue partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous layer was extracted with EtOAc twice and the combined organic layers washed with water, brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 15% MeOH in DCM to give the title compound (208 mg, 68%).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[N:14]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)=[N+:15]=[N-:16].N(C1C=C(O)C=CC=1)=[N+]=[N-]>>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([N:14]2[CH:3]=[C:4]([C:5]3[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=3)[N:16]=[N:15]2)=[CH:18][CH:19]=1
Reactant: [N-]=[N+]=Nc1ccc(O)cc1
Reactant: C[Si](C)(C)C#Cc1ccc(O)cc1
Agent: [N-]=[N+]=Nc1cccc(O)c1
Product: Oc1ccc(-c2cn(-c3ccc(O)cc3)nn2)cc1
Yield: 59.9 %

Procedure:
4-BPT was prepared in a similar manner as 3-BPT, using 4-TMSE-phenol (3.50 g, 18.4 mmol) and 4-azidophenol (3.73 g, 27.9 mmol) instead of 3-TMSE-phenol and 3-azidophenol. This gave 2.79 g (60% yield) of a purple crystal. 1H NMR (MeOD-d4, 300 MHz, ppm): 8.62 (s, 1H, triazol-H), 7.75-7.68 (m, 4H, Ar—H), 6.99 (d, 2H, J=9.0 Hz, Ar—H), 6.90 (d, 2H, J=8.7 Hz, Ar—H). 13C NMR (MeOD-d4, 75 MHz, ppm): 159.7, 159.3, 149.8, 131.0, 128.4, 123.4, 123.0, 119.4, 117.3, 116.9.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P:11](=[O:18])(OCC)[O:12][CH2:13][CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:20]>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P:11]([Cl:20])(=[O:18])[O:12][CH2:13][CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOP(=O)(Cl)Cc1ccc([N+](=O)[O-])cc1
Temperature: 30 °C
Reaction time: 24 h
Yield: 84.3 %

Procedure:
This method is a modification of that outlined by Doak and Freedman (Ref. 178). Diethyl (p-nitrophenyl)methylphosphonate (7.16) (1.0 g, 3.6 mmol) in DCM (10 ml) was added dropwise to a solution of PCl5 (0.9 g, 4.32 mmol) in CCl4 (20 ml) under an inert atmosphere. The reaction was stirred at 30° C. and the progress of the chlorination was followed by 31P NMR which showed the reaction was complete after 24 h. Solvent and phosphoryl chloride were removed in vacuo to yield a pale yellow, moisture-sensitive oil (0.8 g, 90%) which was used without further purification. δH (250 MHz, CDCl3) 1.40 (3H, t, J 7.5 Hz, CH3), 3.60 (2H, d, 2JPH 22.5 Hz, Ar--CH2), 4.25-4.43 (2H, m, JHP 8.5 Hz, J 7.5 Hz,CH2), 7.5 (2H, d, J 7.5 Hz, Ar--H), 8.20 (2H, d, J 7.5 Hz, Ar--H); δP (101 MHz, CDCl3) 35.94 (s).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.C(Cl)(Cl)Cl.[I:15]I>CC(O)=O>[I:15][C:4]1[NH:3][C:2]([CH3:1])=[N:6][C:5]=1[C:7]([F:10])([F:9])[F:8]
Reactant: Cc1nc(C(F)(F)F)c[nH]1
Reactant: II
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1nc(C(F)(F)F)c(I)[nH]1
Temperature: 60 °C
Reaction time: 3 h
Yield: 107.1 %

Procedure:
To 2-methyl-4-(trifluoromethyl)-1H-imidazole (1 g, 6.7 mmol) was added CHCl3 (4.5 mL) and AcOH (13.5 mL) followed by I2 (1.78 g, 6.99 mmol) and HIO4.2H2O (1.52 g, 6.7 mmol), and the resulting reaction mixture was stirred at 60° C. for 3 h. The reaction mixture was then poured into ice cold 10% aqueous sodium bisulphite solution (100 mL) and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo to obtain 5-iodo-2-methyl-4-(trifluoromethyl)-1H-imidazole (1.98 g) which was used as such in next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:4][C:3]1=[O:14].O=[C:16]1N(C(OCC2C=CC=CC=2)=O)[C@H](C(O)=O)CN1.CI.[H-].[Na+]>CN(C)C=O>[CH3:1][N:2]1[CH2:6][CH:5]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[N:4]([CH3:16])[C:3]1=[O:14]
Reactant: CN1CC(C(=O)OC(C)(C)C)NC1=O
Reactant: O=C(O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CC(C(=O)OC(C)(C)C)N(C)C1=O
Temperature: -10 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A stirred solution of 1,1-dimethylethyl 1-methyl-2-oxo-4-imidazolidinecarboxylate (1.75 g, 8.74 mmol) (prepared as described in step (i) of Example 49 from 5-(1,1-dimethylethyl)1-(phenylmethyl)3-methyl-2-oxo-1,5-imidazolidinedicarboxylate, itself prepared as described in step (ii) of Example 13, starting originally from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) in N,N-dimethylformamide (22 ml) was cooled to −10° C. under argon, and then the methyl iodide (2.186 ml, 35.0 mmol) was added. Sodium hydride (60% dispersion in oil) (0.329 g, 8.22 mmol) was then added portion wise. The reaction mixture was allowed to warm to RT while stirring under argon overnight. The solvent was evaporated in vacuo and then the residue partitioned between ethyl acetate (40 ml) and brine (30 ml). The aqueous layer was re-extracted with ethyl acetate (×2) and then the combined organic extracts were washed with water (×2, 50 ml), brine (50 ml) and dried over magnesium sulphate. The solvent was evaporated in vacuo. The crude product was purified by flash-silica gel chromatography, eluting with 25-100% ethyl acetate/iso-hexane. The fractions containing product were combined and solvent evaporated in vacuo to give a yellow oil, 1,1-dimethylethyl 1,3-dimethyl-2-oxo-4-imidazolidinecarboxylate (1.48 g, 79% yield). (ii) A solution of 1,1-dimethylethyl 1,3-dimethyl-2-oxo-4-imidazolidinecarboxylate (1.92 g, 8.96 mmol) in dichloromethane (12 ml)/trifluoroacetic acid (6.00 ml) was stirred at room temperature for 24 hours. The solution was evaporated and the residue was co-evaporated with toluene (×3) and then dichloromethane (×2). The product was then dried to give crude 1,3-dimethyl-2-oxo-4-imidazolidinecarboxylic acid (1.65 g) which was dissolved in dichloromethane (90 ml) to give a ˜0.1M solution in dichloromethane which was used in subsequent reactions. LC/MS [M+H]+=159.
Reaction SMILES: [CH:1](=[N:8][S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([CH2:24][N+:25]#[C-:26])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(COC)OC>[CH3:13][N:12]([CH3:14])[S:9]([N:8]1[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:26][N:25]=[CH:24]1)(=[O:11])=[O:10]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CN(C)S(=O)(=O)N=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: CN(C)S(=O)(=O)n1cncc1-c1ccccc1

Procedure:
N-Benzylidene-N',N'-dimethylsulphamide (6.36 g) was stirred with p-toluenesulphonylmethyl isocyanide (9.75 g ) and potassium carbonate (8.28 g) in methanol and dimethoxyethane for 18 hours. The mixture was filtered and the filtrate evaporated and recrystallised from ethyl acetate/hexane to give crude 1-dimethylsulphamoyl-5-phenylimidazole.
Reaction SMILES: [S:1]1[C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=[CH:2]1.[Br:16]Br.O>C(O)(=O)C>[Br:16][C:2]1[S:1][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccccc2Oc2sccc21
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=C1Nc2ccccc2Oc2sc(Br)cc21
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 80.7 %

Procedure:
Thieno[2,3-b][1,5]benzoxazepin-4(5H)-one (2 g) was suspended in acetic acid (30 ml) and a solution of bromine (1.5 g) in acetic acid (10 ml) was added dropwise over 30 minutes. The mixture was stirred at room temperature for 35 minutes and poured into water. The precipitated crystals were collected by filtration and washed with water and diisopropyl ether to give 2-bromothieno[2,3-b][1,5]benzoxazepin-4(5H)-one (2.2 g).