Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:11]([O:12][CH2:13][C:14]4[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=4[F:21])=[CH:10][CH:9]=[CH:8][N:7]3[C:22]=2[C:23]([O:25]CC)=[O:24])[CH2:3][CH2:2]1.[OH-].[Li+]>CO.C1COCC1>[CH:1]1([C:4]2[N:5]=[C:6]3[C:11]([O:12][CH2:13][C:14]4[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=4[F:20])=[CH:10][CH:9]=[CH:8][N:7]3[C:22]=2[C:23]([OH:25])=[O:24])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1c(C2CC2)nc2c(OCc3c(F)cccc3F)cccn12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1c(C2CC2)nc2c(OCc3c(F)cccc3F)cccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
410 mg of ethyl 2-cyclopropyl-8-[(2,6-difluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxylate (Example 24A, 1.1 mmol, 1 equivalent) were initially charged in 15 ml of methanol/THF (1:1), and 5.5 ml of a 1 N aqueous lithium hydroxide solution (5.5 mmol, 5 equivalents) were added. The reaction mixture was stirred at RT overnight. Another 5.5 ml of 1 N aqueous lithium hydroxide solution were added, and the mixture was stirred at RT for another night. The mixture was then concentrated under reduced pressure and the residue was taken up in water and acidified with 1 N aqueous hydrochloric acid. The precipitated product was filtered off and dried under high vacuum. This gave 293 mg (77% of theory) of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:13][CH2:12][C@:11]2([CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)[C:10]1=[O:26]>C(OCC)(=O)C>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:13][CH2:12][C@:11]2([CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)[C:10]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC[C@]2(CCN(c3ccccc3Cl)C2=O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1N(c2ccccc2Cl)CC[C@]12CCCNC2
Reaction time: 2 h

Procedure:
Hydrogen chloride (4.0 M in 1,4-dioxane, 2.0 mL) was added to a solution of tert-butyl (5S)-2-(2-chlorophenyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate (0.103 g, 0.000283 mol) in ethyl acetate (0.5 mL) and the mixture was stirred for 2 h. Then the solvent was removed in-vacuo to afford the desired product. LC-MS: 265.2 (M+H).+
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([F:18])[CH:12]=3)[C:3]=12.[C:32]1([CH3:41])[CH:37]=[CH:36][CH:35]=[C:34]([N:38]=[C:39]=[O:40])[CH:33]=1>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:39]([NH:38][C:34]4[CH:33]=[C:32]([CH3:41])[CH:37]=[CH:36][CH:35]=4)=[O:40])=[C:13]([F:18])[CH:12]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(N)c(F)c3)c3c(N)ncnc32)CC1
Reactant: Cc1cccc(N=C=O)c1
Solvent: c1ccncc1
Product: Cc1cccc(NC(=O)Nc2ccc(-c3nn(C4CCN(C(=O)OC(C)(C)C)CC4)c4ncnc(N)c34)cc2F)c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 30.8 %

Procedure:
tert-Butyl 4-[4-amino-3-(4-amino-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (600 mg, 1.41 mmol) was dissolved in pyridine (25 mL) and cooled to 0° C. m-Tolylisocyanate (206 mg, 1.54 mmol) was added and the reaction was stirred at 0° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure to yield the crude product as a brownish-yellow foam (841 mg). Purification by column chromatography on silica gel using a 25% to 50% ethyl acetate/heptane gradient followed by 5% methanol/dichloromethane as the eluent afforded tert-butyl 4-(4-amino-3-{3-fluoro-4-[(3-toluidinocarbonyl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate as a light yellow solid (243 mg, 0.434 mmol). HPLC-RT: 17.82 min. (flow rate: 1 mL/min λ=254 nm Gradient: 5% to 85% acetonitrile/0.1M aqueous ammonium acetate gradient over 20 min.; Deltapak C18, 300 A, 5 μm, 150×3.9 mm column); m/z (MH+)=561.4.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][CH2:19]N2CCSCC2)=[C:12]([NH2:26])[CH:11]=1)=[O:5]>C(OCC)(=O)C.C(O)C>[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][CH2:19][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:12]([NH2:26])[CH:11]=1)=[O:5]
Reactant: COC(=O)CCNC(=O)c1ccc(NCCCN2CCSCC2)c(N)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)CCNC(=O)c1ccc(NCCCCc2ccccc2)c(N)c1

Procedure:
The same procedure is used as in (2). Rf value: 0.68 (silica gel; ethyl acetate/ethanol=9:1)
Reaction SMILES: [OH:1][C@H:2]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2/[CH:12]=[CH:13]/[C:14](OC)=[O:15])[CH2:3]1.[AlH](CC(C)C)CC(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CCCCCC>[OH:15][CH2:14]/[CH:13]=[CH:12]/[C@@H:11]1[C@:18]2([CH3:26])[C@H:8]([C@H:7]3[C@H:21]([CH2:20][CH2:19]2)[C@:22]2([CH3:25])[C:4]([CH2:3][C@@H:2]([OH:1])[CH2:24][CH2:23]2)=[CH:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: COC(=O)/C=C/[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2/C=C/CO
Yield: 95.1 %

Procedure:
To a solution of 4.85 g of methyl (E)-3β-hydroxypregna-5,20-diene-21-carboxylate (Pouzar, V. et al., Collect. Czech. Chem. Commun, 1990, 55,1243), in 200 ml of anhydrous tetrahydrofurane, 81 ml of i-Bu2AlH (1M) in hexane were added dropwise in a nitrogen atmosphere at -78° C. After two hours the reaction mixture was treated with an aqueous solution of citric acid (30 g in 100 ml of water). The mixture was filtered on Celite and the residue washed with ethyl acetate. The organic solution was dehydrated over anhydrous sodium sulfate and evaporated to dryness under vacuum, to give 4.25 g of (E)-21-hydroxymethylpregna-5,20-dien-3β-ol as a white solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:32][C:33]1[CH:38]=[C:37]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([C:11]([N:8]4[CH2:7][CH2:6][N:5]([CH:1]5[CH2:2][CH2:3][CH2:4]5)[CH2:10][CH2:9]4)=[O:12])=[CH:21][CH:20]=3)[CH:16]=[C:17]2[C:22]([N:24]2[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH:36]=[CH:35][N:34]=1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1ccnc(Cl)c1)N1CCN(C2CCC2)CC1
Yield: 32 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), 2-chloropyridine-4-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (32%).
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=O)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C>[N:23]([CH2:6][C@@H:7]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCCCC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])CC1CCCCC1
Temperature: 50 °C
Yield: 65 %

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-3-cyclohexylpropyl methanesulfonate (13.3 g, 39.3 mmol) from Step 1 was dissolved in anhydrous DMF (140 mL). Solid NaN3 (5.18 g, 79.7 mmol) was added and the reaction was warmed to 50° C. for 5 h. The reaction mixture was permitted to cool to rt and the solvent was removed under reduced pressure (150 Torr, 55° C.). This material was taken up into Et2O (150 mL), washed with water (3×10 mL) and brine (3×10 mL), dried (Na2SO4), decanted, and stripped to give 13.9 g crude product. This was separated on a silica column using a gradient from 0-100% EtOAc in hexanes. Solvent was stripped from appropriate fractions to give (S)-tert-butyl 1-azido-3-cyclohexylpropan-2-ylcarbamate (7.21 g, 65%) as a clear oil. 1H NMR (CDCl3) δ 0.60=1.80 (m 12H), 1.40 (s, 9H), 2.86 (d, 1H), 3.29 (d, 1H), 4.85 (d, 1H), 4.51 (m, 1H), 8.00 (s, 1H). MS ESI +ve m/z 183 (M(−BOC)+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12>CN(C=O)C>[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH:64][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[F:10])=[O:24])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: O=C(O)c1cc2cccc(F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cccc(F)c2oc1=O
Temperature: 25 °C

Procedure:
DIEA (46.0 μL, 0.26 mmol) was added to 8-fluoro-3-carboxy-coumarin (50.3 mg, 0.24 mmol) and HATU (100.5 mg, 0.26 mmol) in 2 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (50.0 mg, 0.24 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo for final product: LCMS (ESI) m/z 400 (MH+).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[C:8]2[CH2:15][C:14](=[O:16])[NH:13][C:9]=2[N:10]=[CH:11][N:12]=1.CN(C)CCN(C)C.Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:28]=1[CH2:36]Br>C1COCC1>[Cl:6][C:7]1[C:8]2[C:15]3([CH2:36][C:28]4[C:27](=[CH:32][CH:31]=[C:30]([N+:33]([O-:35])=[O:34])[CH:29]=4)[CH2:26]3)[C:14](=[O:16])[NH:13][C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: O=[N+]([O-])c1ccc(CBr)c(CBr)c1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1Nc2ncnc(Cl)c2C12Cc1ccc([N+](=O)[O-])cc1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Butyllithium (0.29 ml, 0.74 mmol, 2.5 M) was added to a stirred solution of 4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one from Step B (50 mg, 0.295 mmol) at −78° C. in THF (30 mL). After complete addition of butyllithium, N,N,N′,N′-tetramethylethane-1,2-diamine (0.31 mL, 0.77 mmol) was added. After 1 h at −78° C., 1,2-bis(bromomethyl)-4-nitrobenzene (91 mg, 0.295 mmol, described in Intermediate 2) was added and the reaction warmed to ambient temperature. After 8 h, the reaction was quenched with H2O and the mixture was partitioned between EtOAc and H2O. The aqueous solution was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=317 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(OCC)(=O)C>[C:24](=[O:25])([O:26][CH2:27][CH3:28])[O:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[Cl:9]
Reactant: Oc1c(Cl)cc(-c2ccccc2)cc1Cl
Reactant: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1c(Cl)cc(-c2ccccc2)cc1Cl
Reaction time: 8 h
Yield: 90.7 %

Procedure:
40.6 g (0.17 mol) of 3,5-dichloro-4-hydroxybiphenyl (prepared according to J. C. Colbert et al., JACS 56, 202 (1934)) and 17.2 g (0.17 mol) of triethylamine are dissolved in 170 ml of ethyl acetate and admixed dropwise with 18.4 g (0.17 mol) of ethyl chloroformate at 10° C. The reaction solution is stirred overnight and washed with water, and the organic phase is concentrated. For further purification, the crude product (51.2 g) is chromatographed over silica gel using the system chloroform. 48 g (yield 90.8% of theory) of (2,6-dichloro-4-phenyl-phenyl) ethyl carbonate are obtained as an oil, log p (pH 7.5): 4.65.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12][C@@H:13]([C:16]([OH:18])=[O:17])[CH2:14][OH:15].C([O-])([O-])=O.[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:12][C@H:13]([CH2:14][OH:15])[C:16]([OH:18])=[O:17])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(F)ccc(C#N)c1Cl
Reactant: N[C@H](CO)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(N[C@H](CO)C(=O)O)ccc(C#N)c1Cl
Temperature: 75 °C
Reaction time: 24 h
Yield: 29.3 %

Procedure:
2-chloro-4-fluoro-3-methylbenzonitrile (500 mg, 2.95 mmol) was mixed together with H-D-Ser-OH (682 mg, 6.49 mmol) in DMSO (20 mL). K2CO3 (856 mg, 6.19 mmol) was added to the reaction mixture and stirred at 75° C. for 24 h. The reaction mixture was cooled to room temperature and poured slowly in to a 10% citric acid solution and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times to get the crude product. The crude product was chromatographed with a gradient of hexanes/EtOAc and then with EtOAc, 100% to give the final product (220 mg): 1H NMR (500 MHz, DMSO-d6, δ in ppm) 7.47 (d, J=9 Hz, 1H), 6.57 (d, J=9 Hz, 1H), 6.13 (br s, 1H), 3.62 (m, 2H), 2.18 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:15][C:9]2=[CH:10][N:11]=[C:12]([Cl:14])[CH:13]=[C:8]2[CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:14][C:12]1[CH:13]=[C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[NH:15][C:9]2=[CH:10][N:11]=1
Reactant: CCOC(=O)c1cc2cc(Cl)ncc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2cc(Cl)ncc2[nH]1

Procedure:
Route A: To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (Preparation 17, 1.78 g, 7.9 mmol) in ethanol (70 mL) was added sodium hydroxide solution (5.2 mL, 2M, 10.3 mmol) and the mixture heated under reflux for 2 h. The solvent was removed in vacuo and the solid dissolved in water (150 mL) and acidified to pH 4 with acetic acid to give the title compound as a brown solid that was isolated by filtration. δH (CD3OD): 7.13 (1H, s), 7.68 (1H, s), 8.58 (1H, s); m/z (ES+)=197 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:18])([CH3:17])[O:6][CH2:7][CH2:8][CH2:9][CH:10]([C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)[OH:11])([CH3:4])[CH3:3].O[C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[C:22]#[N:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:28][C:26]1[CH:27]=[CH:20][C:21]([C:22]#[N:23])=[C:24]([O:11][CH:10]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH2:9][CH2:8][CH2:7][O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:17])[CH3:18])[CH:25]=1
Reactant: N#Cc1ccc(Cl)cc1O
Reactant: CC(C)(C)[Si](C)(C)OCCCC(O)c1ccsc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCC(Oc1cc(Cl)ccc1C#N)c1ccsc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 65.4 %

Procedure:
The product from step (b) (1.164 g, 4.06 mmol) was dissolved in anhydrous tetrahydrofuran (80 ml) and 2-hydroxy-4-chlorobenzonitrile (624 mg, 4.06 mmol) and triphenylphosphine (1.172 g, 4.47 mmol) added. The solution was cooled to 0° C. and diethyl azodicarboxylate (0.71 ml, 4.47 mmol) added dropwise. The reaction was allowed to warm to room temperature and stirred for a further 18 h. The reaction was concentrated in vacuo and the residue chromatographed on flash silica, eluting with hexane:ethyl acetate (4:1), to afford the title compound as a colourless oil (1.12 g, 65%).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:21][N:22]=[C:23]=[O:24]>C(Cl)Cl.C(N(CC)CC)C>[CH3:21][NH:22][C:23]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:24]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=NC(=O)NC)N1Cc2ccccc2-c2ccccc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.0 g of ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate are placed in 10 ml of methylene chloride. After the addition of one drop of triethylamine, 0.41 g of methyl isocyanate in 5 ml of methylene chloride is added dropwise. The mixture is then left to stir at room temperature for 2 days. The reaction mixture is poured on to ice-water and extracted twice with methylene chloride. The extracts are washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The oily residue is chromatographed on silica gel with n-hexane-acetone (4:1) as the eluent, and there is obtained ethyl 5,7-dihydro-N-methylcarbamoyl-6H-dibenz[c,e]azepine-6-carboximidate in 2 isomeric forms: isomer A (eluted first), m.p. 176°-178° C.; isomer B: m.p. 137°-139° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6]C)=O.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[Li]>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([C:14]1[S:13][CH:17]=[CH:16][CH:15]=1)([C:14]1[S:13][CH:17]=[CH:16][CH:15]=1)[OH:6]
Reactant: [Li]c1cccs1
Reactant: COC(=O)c1cc(Br)ccc1N
Product: Nc1ccc(Br)cc1C(O)(c1cccs1)c1cccs1

Procedure:
Prepared from methyl 2-amino-5-bromobenzoate and 2-thienyllithium using the procedure similar to example 6. 1H-NMR (CDCl3) δ 7.35 (dd, J=5.3, 1.1 Hz, 2H), 7.26 (dd, J=8.4,2.3 Hz, 1H), 6.98 (m, 2H), 6.82 (d, J=2.3 Hz, 1H), 6.79 (m, 2H), 6.62 (d, J=8.4 Hz, 1H), 5.45 (br s, 1H), 3.86 (br s, 2H); Anal. Calc. For C15H12BrNOS2: C, 49.18; H, 3.30; N, 3.82. Found: C, 49.62; H, 3.47; N, 3.60.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]1[C:22]2[C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1>>[C:2]1([CH2:1][C:21]2([OH:23])[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:22]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: O=C1c2ccccc2-c2ccccc21
Product: OC1(Cc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
from benzylmagnesium chloride and 9-fluorenone;
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:37])C(=O)C1>CN(C=O)C>[Br:37][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:10])[CH3:1]
Reactant: CC(C)CCCCCCO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)CCCCCCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a solution of 7-methyl-octan-1-ol (1.20 g, 8.33 mmol) in DMF (20 mL) was added triphenylphosphine (2.43 g, 9.26 mmol). The solution was cooled to 0° C. and NBS (1.60 g, 8.99 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (1 mL). The solution was diluted with ether (100 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford 1-bromo-7-methyl-octane (1.28 g, 74%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 3.41 (2H, t, J=6.6 Hz), 1.85 (2H, m), 1.52 (1H, m), 1.42 (2H, m), 1.28 (4H, m), 1.17 (2H, m), 0.87 (3H, s), 0.85 (3H, s); 13C NMR (75 MHz, CDCl3) δ 39.16, 34.34, 33.14, 29.34, 28.52, 28.24, 27.51, 22.94.
Reaction SMILES: O[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18].C(=O)([O-])O.[Na+].P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(Cn2nc(C)c(C(=O)c3ccccc3)c2O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(Cn2nc(C)c(C(=O)c3ccccc3)c2Cl)cc1
Temperature: 40 °C

Procedure:
A solution containing 400 mg of [5-hydroxy-1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl]-phenyl-methanone in 5 ml of phosphorus oxychloride was heated at 40° C. for 30 min. The mixture was poured into iced saturated sodium hydrogen carbonate and extracted with dichloromethane three times. The combined extracts were washed with brine then dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using diethyl ether/hexane (1:3) for the elution to give 170 mg of [5-chloro-1-(4-methoxybenzyl)-3-methyl -1H-pyrazol-4-yl]-phenyl-methanone as a yellow gum.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH:9]1([CH:15]=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.O>CS(C)=O>[CH:9]1([CH:15]2[O:16][CH2:4]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C[S+](C)(C)=O
Reactant: O=CC1CCCCC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C1CCC(C2CO2)CC1
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
Sodium hydride (4.5 g, 187.5 mmol) and trimethylsulfoxonium iodide (41.25 g, 187.5 mmol) were combined in a 3-neck flask equipped with a mechanical stirrer and an addition funnel. Dimethyl sulfoxide (DMSO) was added slowly, over a 30 min period, until 200 mL had been added. Gas was evolved throughout the addition. A solution of cyclohexane carboxaldehyde (21.8 mL, 180 mmol) in 50 mL of DMSO was added dropwise to the reaction mixture over a 15 min period. The reaction mixture was heated to 55° C. and stirred at 55° C. for 30 min. The reaction mixture was cooled to ambient temperature and poured into 500 mL of water. The aqueous solution was extracted with 3×100 mL of diethyl ether. The combined ether extracts were washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product was distilled (44° C., 0.1 mm) to give 14 g (62% yield) of 1-cyclohexyl ethylene oxide as a clear colorless liquid.
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=3[N:8]=[N:7]2)[CH2:4][CH2:3][CH2:2]1.[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:16][C:14]1[C:9]2[N:8]=[N:7][N:6]([CH2:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)[C:10]=2[CH:11]=[CH:12][C:13]=1[OH:15]
Reactant: Oc1ccc2c(c1)nnn2CC1CCC1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: Oc1ccc2c(nnn2CC2CCC2)c1Br

Procedure:
A solution of 1-(cyclobutylmethyl)-1H-benzotriazol-5-ol (3-4, 280 mg, 1.38 mmol, 1 equiv) and pyridinium tribromide (551 mg, 1.72 mmol, 1.25 equiv) in chloroform (20 mL) was stirred at 23° C. for 4 h. The mixture was concentrated and the residue partitioned between saturated aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 4-bromo-1-(cyclobutylmethyl)-1H-benzotriazol-5-ol (3-5) as an orange solid. 1H NMR (300 MHz, CDCl3) δ 7.38 (d, 1H, J=8.9 Hz), 7.25 (d, 1H, J=8.9 Hz), 5.92 (br s, 1H), 4.60 (d, 2H, J=7.0 Hz), 2.96 (p, 1H, J=7.6 Hz), 2.06 (m, 2H), 1.89 (m, 4H) ppm. LRMS m/z (M+H) 283.9 found, 284.0 required.