Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][CH:5]=1)[CH3:2].C([O:19][N:20]=O)CC(C)C.Cl>C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][C:9](=[N:20][OH:19])[C:10]2=[O:13])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2c(c1)C(=O)CC2
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOc1ccc2c(c1)C(=O)C(=NO)C2
Temperature: 7.5 °C

Procedure:
A solution of 6-ethoxy-1-indanone and isoamylnitrite (1.5 eq.) in ethyl acetate arecooled to approximately 0° C. and concentrated hydrochloric acid (1.1 acid equivalents) is added at a rate to keep the temperature below 40° C. After the addition is completed the slurry is stirred at 5-10° C. until analysis indicated that all of the starting material is consumed. The product is filtered and rinsed with cold ethyl acetate. The oxime product (5) can be easily purified by refluxing as a slurry in anhydrous ethanol, cooling filtering, and then washing the solid with more ethanol and then drying (m.p. 220° C. decomp.).
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([CH:40]4[CH2:45][CH2:44][CH:43]([O:46][C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)[CH2:42][CH2:41]4)[C:38]([CH3:53])=[C:37]([OH:54])[C:36]3=[O:55])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([CH:40]4[CH2:41][CH2:42][CH:43]([O:46][C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=5)[CH2:44][CH2:45]4)[C:38]([CH3:53])=[C:37]([O:54][CH3:3])[C:36]3=[O:55])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: CC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1C1CCC(Oc2ccccc2)CC1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: OCCO
Solvent: CO
Product: COC1=C(C)C(C2CCC(Oc3ccccc3)CC2)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (9 eq), ethylene glycol/Et2O (1/3 v/v, 40 ml), 1-(1H-Benzo[d]imidazol-6-yl)-3-hydroxy-4-methyl-5-(4-phenoxycyclohexyl)-1H-pyrrol-2(5H)-one (0.900 g, 2.23 mmol, 1 eq) and MeOH (10 ml) and was purified by preparative HPLC; yield: 0.051 g (12.2%); MS m/z: 418.2 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 12.52 (b, 1H), 8.26-8.25 (d, 1H), 7.67-7.53 (m, 2H), 7.27-7.15 (m, 3H), 4.80-4.72 (m, 1H), 4.50 (s, 0.5H), 4.20 (m, 1H), 3.86 (s, 3H), 2.03-1.90 (m, 4H), 1.69-1.65 (m, 2H), 1.46-1.39 (m, 2H), 1.21-0.99 (m, 2H); HPLC (METHOD [A]): rt 13.30 min (97.08%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:23]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCN2C(=NCCC2)CC1>C1COCC1>[NH2:23][C@H:16]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:10][CH:11]=1
Reactant: CON(C)C(=O)[C@H](Cc1ccc(NC(=O)OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CON(C)C(=O)[C@@H](N)Cc1ccc(NC(=O)OC(C)(C)C)cc1
Reaction time: 0.17 h

Procedure:
To a solution of compound 61 (1.50 g, 2.75 mmol) in THF (20 mL) was added DBU (1.5 mmol, 229 μL). After 10 minutes, TLC analysis indicated complete consumption of starting material. 1 M aq. HCl (30 mL) and EtOAc (25 mL) were added and the layers were separated. The organic layer was extracted with 1 M aq. HCl and the combined aqueous layers were basified with Na2CO3 until pH 10. This layer was extracted with EtOAc (3×) and the latter combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The title compound was obtained as a colorless oil (yield: 0.75 g, 2.34 mmol, 85%). 1H NMR (400 MHz, CDCl3) δ=7.62 (s, 1H), 7.33 (d, J=8.14 Hz, 2H), 7.09 (d, J=8.43 Hz, 2H), 4.02-3.95 (m, 1H). 3.57 (s, 3H), 3.16 (s, 3H), 2.98 (dd, J=13.30, 5.56 Hz, 1H), 2.65 (dd, J=13.25, 7.71 Hz, 1H), 1.93 (s, 2H), 1.49 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3) δ=175.13, 152.66, 137.04, 131.64, 129.29, 118.28, 79.54, 60.96, 52.38, 40.41, 31.82, 27.94 ppm. [α]D23=+19.6 (c=1, CHCl3). HRMS: calcd. for C16H25N3O4 324.19178 [M+H]+. found 324.19193.
Reaction SMILES: N#N.Cl[CH2:4][C:5]1[N:6]=[C:7]([C:10](=[O:12])[CH3:11])[S:8][CH:9]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C>[N:13]([CH2:4][C:5]1[N:6]=[C:7]([C:10](=[O:12])[CH3:11])[S:8][CH:9]=1)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)c1nc(CCl)cs1
Agent: N#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1nc(CN=[N+]=[N-])cs1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(4-chloromethyl-thiazol-2-yl)-ethanone (1.08 g, 6.13 mmol) in dry DMF (21 mL) and treated with NaN3 (1.20 g, 18.39 mmol) at 65° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 1-(4-(azidomethyl)-thiazol-2-yl)-ethanone as a yellow oil. To a solution of the crude azide (200 mg, 1.10 mmol) in THF (6 mL) were added polymer-supported Ph3P (2.0 eq.) and water (2 mL). The reaction mixture was stirred at 60° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The org. layer was dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a brown oil after purification by FC (CH2Cl2-MeOH-Et3N). LC-MS-conditions 01: tR=0.26 min; [M+H]+=157.04.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13](O)=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[OH:14][CH2:13][CH2:12][CH:10]1[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)O)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CCO)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid (1 g, 4.65 mmol) in tetrahydrofuran (5 ml) was cooled to 0° C. and treated with borane tetrahydrofuran complex (7.00 ml, 7 mmol) dropwise by syringe. After 1 hour at 0° C. the solution was allowed to warm to room temperature and stirred overnight and then it was quenched with 20 ml of 1M aqueous NaOH. The separated aqueous layer was extracted with ether (2×15 ml), dried with magnesium sulfate, filtered and concentrated to give the title compound which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[N:26])[C:22]([F:27])=[CH:21][C:20]=2[N+:28]([O-])=O)[C:12]=1[F:31])=[O:8].S(S([O-])=O)([O-])=O.[Na+].[Na+].O>C1COCC1.CCOC(C)=O>[NH2:28][C:20]1[CH:21]=[C:22]([F:27])[C:23]([C:25]#[N:26])=[CH:24][C:19]=1[O:18][C:13]1[C:12]([F:31])=[C:11]([CH2:10][NH:9][C:7]([C:6]2[N:5]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:38])[CH3:39])[CH:4]=[N:3][C:2]=2[Cl:1])=[O:8])[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)c(F)cc2[N+](=O)[O-])c1F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)c(F)cc2N)c1F
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(5-cyano-4-fluoro-2-nitrophenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (450 mg, 0.752 mmol) in THF (3 ml) was added sodium hydrosulfite (85% tech.) (924 mg, 4.51 mmol) in solution of Water (6.00 ml) and the reaction mixture was stirred at 60° C. for one hour. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give N-({3-[(2-amino-5-cyano-4-fluorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (386 mg, 0.679 mmol, 90% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.76 (t, 1H), 7.98 (s, 1H), 7.39-7.49 (m, 1H), 7.34 (t, 1H), 6.70 (s, 2H), 6.56-6.68 (m, 2H), 5.49 (s, 2H), 4.47 (d, 2H), 3.39 (t, 2H), 0.75 (t, 2H), −0.08 (s, 9H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[C:12]=1[O:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[Br:17][C:13]1[C:12]([O:18][CH3:19])=[C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1c(Br)cccc1Br
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1c(Br)cccc1-c1ccccc1
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A mixture of phenylboronic acid (3.4 g, 28.7 mmol), 2,6-dibromoanisole (22.3 g, 83.8 mmol, 3 equiv.) and palladium tetrakistriphenylphosphine (0.6 g) in ethylene glycol dimethyl ether (50 mL) and a solution of potassium carbonate (10.8 g, 0.078 mol) in water (50 mL) were kept at reflux under nitrogen with good stirring overnight. After cooling, the reaction mixture was partitioned between ethyl acetate (800 mL) and water (400 mL). The organic phase was washed with water (2×400 mL), dried over sodium sulfate and filtered. The solvent was removed in vacuo and the residue was chromatographed on silica (360 g) with heptane (5 L) to afford 6.55 g of pure product (87%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34](OCC)=[O:35])=[C:28]([N+:39]([O-])=O)[CH:27]=2)[CH2:17][CH2:16]1)([CH3:7])[CH3:6])[CH3:2].O=C1COC2C=CC(OCCCCN3CCN(C4C=CC=CC=4OCCCC(OCC)=O)CC3)=CC=2N1>>[CH3:6][C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][C:34](=[O:35])[NH:39][C:28]=3[CH:27]=2)[CH2:17][CH2:16]1)([CH3:7])[C:4]([O:3][CH2:1][CH3:2])=[O:42]
Reactant: CCOC(=O)COc1ccc(OCCCCN2CCN(c3ccccc3OC(C)(C)C(=O)OCC)CC2)cc1[N+](=O)[O-]
Agent: CCOC(=O)CCCOc1ccccc1N1CCN(CCCCOc2ccc3c(c2)NC(=O)CO3)CC1
Product: CCOC(=O)C(C)(C)Oc1ccccc1N1CCN(CCCCOc2ccc3c(c2)NC(=O)CO3)CC1

Procedure:
The compound 17c was synthesized from 16c following the same protocol described for the synthesis of compound 17a. Yellow oil (0.13 g, 50%). 1H NMR (400 MHz, CDCl3): δ 1.24 (t, J=7.6 Hz, 3H); 1.58 (s, 6H); 1.70-1.78 (m, 4H); 2.48 (t, J=7.6 Hz, 2H); 2.65 (br s, 4H); 3.12 (br s, 4H); 3.90 (t, J=6.0 Hz, 2H); 4.24 (q, J=7.6 Hz, 2H); 4.53 (s, 2H); 6.40 (d, J=2.8 Hz, 1H); 6.48 (dd, J=2.8 Hz; 8.8 Hz, 1H); 6.78-6.97 (m, 5H); 9.21 (br s, 1H). MS (ESI): m/z=512.3 (M+H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:9](#[N:12])[CH2:10]O>CCOCC>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:10][C:9]#[N:12])[CH2:5][CH2:4]1
Reactant: N#CCO
Reactant: COC1CCNCC1
Solvent: CCOCC
Product: COC1CCN(CC#N)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
4-Methoxypiperidine (286) (10.1 g, 87.6 mmol) was added dropwise to a stirred aqueous solution of glycolonitrile (55%, 10.0 g, 96.4 mmol) at 5° C. and the solution was stirred at 70° C. for 1 h. The solution was cooled, diluted with Et2O (50 mL) and washed with water (2×20 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give nitrile 287 (10.25 g, 76%) as a colourless oil: 1H NMR δ 3.51 (s, 2H, CH2CN), 3.35 (s, 3H, OCH3), 3.21-3.28 (m, 1H, CHO), 2.72-2.78 (m, 2H, CH2N), 2.40-2.46 (m, 2H, CH2N), 1.90-1.98 (m, 2H, CH2N), 1.60-1.69 (m, 2H, CH2).
Reaction SMILES: [CH:1]1([CH:7]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16](C4C=CC=CC=4OC)[C:10]=3[S:9](=[O:26])(=[O:25])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][O:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>[Pd]>[CH:1]1([CH:7]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:33]4[CH:32]=[CH:31][CH:30]=[C:29]([O:28][CH3:27])[CH:34]=4)[C:10]=3[S:9](=[O:26])(=[O:25])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccccc1-c1cccc2c1S(=O)(=O)NC(C1CCCCC1)N2
Reactant: COc1cccc(B(O)O)c1
Agent: [Pd]
Product: COc1cccc(-c2cccc3c2S(=O)(=O)NC(C2CCCCC2)N3)c1

Procedure:
Synthesis as for compound 80 (using 3-methoxyphenylboronic acid for the Pd-cat. cross coupling). M.p. 108-115° C.
Reaction SMILES: O[CH:2]1[C:7]2[CH:8]=[C:9]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])[S:10][C:6]=2[S:5](=[O:20])(=[O:19])[N:4]([CH2:21][CH:22]=[CH:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH2:3]1.CS(OS(C)(=O)=O)(=O)=O.N1C(C)=CC=CC=1C.C1CN2C(=NCCC2)C1.C(=O)(O)[O-].[Na+]>C1COCC1.CN(C=O)C>[CH3:18][C:15]([NH:14][S:11]([C:9]1[S:10][C:6]2[S:5](=[O:20])(=[O:19])[N:4]([CH2:21][CH:22]=[CH:23][CH2:24][N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH:3]=[CH:2][C:7]=2[CH:8]=1)(=[O:12])=[O:13])([CH3:16])[CH3:17]
Reactant: CC(C)(C)NS(=O)(=O)c1cc2c(s1)S(=O)(=O)N(CC=CCN1CCOCC1)CC2O
Agent: C1CN=C2CCCN2C1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: CC(C)(C)NS(=O)(=O)c1cc2c(s1)S(=O)(=O)N(CC=CCN1CCOCC1)C=C2
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of the product from Step A (0.64 g, 1.34 mmol) in anhydrous THF (30 mL) under nitrogen were added methanesulfonic anhydride (0.349 g, 2.00 mmol) and 2,6-lutidine (0.431 g, 4.02 mmol). After 30 min, an additional quantity of methanesulfonic anhydride (0.349 g, 2.00 mmol) and 2,6-lutidine (0.431 g, 4.02 mmol) was added and the reaction continued for 30 min. Evaporation of the solvent provided a residue which was dissolved in anhydrous DMF (50 mL) and DBN (1 mL) was added. This mixture was heated at reflux temperature for 1 h, cooled, poured into a saturated solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate (2×100 mL). The combined extracts were dried over (MgSO4), filtered and evaporated to a residue which was purified by column chromatography (silica, 5% methanol/methylene chloride) to give a viscous oil (0.35 g, 57%).
Reaction SMILES: [C:1]1(=O)O[C:4](=O)[CH:3]=[CH:2]1.C1CC=CC=1.[CH2:13]1[CH:17]2C(C(O)=O)[CH:19](C(O)=O)[CH:14]1[CH:15]=[CH:16]2>O>[CH2:1]1[CH:19]2[C@@H:14]3[CH:13]=[CH:17][C@H:16]([CH:4]2[CH:3]=[CH:2]1)[CH2:15]3
Reactant: O=C1C=CC(=O)O1
Reactant: O=C(O)C1C2C=CC(C2)C1C(=O)O
Agent: C1=CCC=C1
Solvent: O
Product: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49 %

Procedure:
Maleic anhydride (88.3 g, 0.90 mole) and water (150.0 g) was stirred at 20-30° C. under nitrogen, cyclopentadiene (30.0 g, 0.45 mole) was added dropwise over 1 hour and stirred at 25° C. for 6 hours, it was heated to 101° C. and held for 20 hours until 92% of nadic acid was converted to NBLCO2H as detected by GC. The wet crystal was filtered out and recrystallized from water to obtain 40.3 g of NBLCO2H with a yield of 49%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:10][N:11]1[CH2:16][CH2:15][CH:14](O)[CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH2:13][CH2:12]1
Reactant: CN1CCC(O)CC1
Reactant: N#Cc1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(Oc2cccc(C#N)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.1 %

Procedure:
To a solution of 3-hydroxy-benzonitrile (500 mg, 4.17 mmol), 1-methyl-piperidin-4-ol (467 mg, 4.17 mmol) and triphenyl phosphine (1.64 g, 6.26 mmol) in tetrahydrofuran (40 mL) was added diisopropyl azodicarboxylate (1.23 μL, 6.26 mmol) dropwise. The reaction mixture was stirred for 4 hr at rt. The solution was concentrated to dryness and the residue was chromatographed using ethyl acetate then ethyl acetate/methanol (8:1) to give the title compound (380 mg, 42%). MS (DCI/NH3) m/z 217 (M+1)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.60 (m, 2H) 1.91 (m, 2H) 2.15 (m, 2H) 2.16 (s, 3H) 2.60 (m, 2H) 4.46 (m, 1H) 7.28 (dd, J=7.67, 1.84 Hz, 1H) 7.35 (d, J=7.36 Hz, 1H) 7.45 (m, 2H).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:44])[NH:10]C1C=C(C2N=C(NC3C=C4C(=CC=3)N(C(OC(C)(C)C)=O)N=C4)C3C(=CC=CC=3)N=2)C=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([NH:8][C:9](=[O:44])[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)NCc5ccccc5)c4)nc4ccccc34)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)NCc1ccccc1

Procedure:
To tert-butyl 5-(2-(3-(3-benzylureido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (30 mg, 0.051 mmol) was added a solution of 1:1 TFA:CH2Cl2 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and left under high vacuum for several hours. The crude product was triturated with ethyl ether to afford 14344-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-3-benzylurea. (25 mg, 100%)
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([OH:14])[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:28]([O:31][CH2:32][CH2:33]Br)(=[O:30])[CH3:29]>CN(C)C=O>[C:28]([O:31][CH2:32][CH2:33][O:14][C:4]1[C:3]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=[C:2]([NH2:1])[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:5]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OCCBr
Reactant: Cc1ccc(-c2c(O)nn(Cc3ccccc3)c2N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1nn(Cc2ccccc2)c(N)c1-c1ccc(C)cc1
Reaction time: 8 h

Procedure:
To a stirring suspension of 5-amino-1-benzyl-4-(4-methylphenyl)-1H-pyrazol-3-ol (Preparation 42) (2.4 g) and cesium carbonate (8.4 g) in dimethylformamide (30 ml) under nitrogen at room temperature was added 2-bromoethyl acetate (1.44 g) and the reaction mixture stirred overnight. The reaction was quenched with 2M hydrochloric acid (100 ml) and extracted into ethyl acetate (2×100 ml). The two combined organic extracts were further washed with water (2×100 ml), then dried (MgSO4) and the solvent removed under reduced pressure to give the crude material. This was purified using the Biotage™ Flash 40 system (90 g Silica) with a gradient elution of hexane (75% to 30%) and ethyl acetate (25% to 70%) to yield the title product as a brown oil.(1.75 g, ca. 60%)
Reaction SMILES: [F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:8]1([CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S+:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC(S(Cl)(=O)=[O:35])=CC=1.[O-][O-].[Na+].[Na+]>ClCCl.O>[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:8]1([CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S+:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:35]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccccc1[S+](c1ccccc1)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [O-][O-]
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1[S+](=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
(Tolyl)diphenylsulphonium hexafluorophosphate (1.08 g, 2.57 mmol) and p-toluenesulphonyl chloride (2.38 g, 12.5 mmol) are dissolved with stirring in dichloromethane (40 ml), with cooling in ice-water. A solution of sodium peroxide (2.42 g, 31 mmol) in water (30 ml) is added dropwise over 20 minutes. After further stirring overnight the reaction mixture is diluted with dichloromethane and water. The mixture is allowed to separate and the dichloromethane containing layer collected, dried over magnesium sulphate, filtered and evaporated in vacuo. The resulting solid is slurried in water and collected. It is further washed with water and ether to yield (tolyl)diphenylsulphoxonium hexafluorophosphate (0.73 g, 65%) identical to authentic material.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([N:30]1[C:38]2[C:33](=[C:34]([OH:39])[CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31]1)(=[O:29])=[O:28].[C:40]([O:44][C:45](=[O:51])[N:46]([CH2:48][CH2:49]O)[CH3:47])([CH3:43])([CH3:42])[CH3:41].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:40]([O:44][C:45](=[O:51])[N:46]([CH2:48][CH2:49][O:39][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:33]=1[CH:32]=[CH:31][N:30]2[S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[F:20])(=[O:28])=[O:29])[CH3:47])([CH3:43])([CH3:42])[CH3:41]
Reactant: O=S(=O)(c1ccccc1F)n1ccc2c(O)cccc21
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(CCOc1cccc2c1ccn2S(=O)(=O)c1ccccc1F)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 72 h

Procedure:
A 100 mL flask equipped with a magnetic stirrer and a rubber septum was charged with triphenyl phosphine (0.506 g, 0.0019 mol) and 1-(2-fluorobenzenesulfonyl)-4-hydroxy-1H-indole (0.330 g, 0.0012 mol), and purged with N2. The mixture was cooled to 0° C. and freshly distilled THF was added (45 mL). A solution of 2-hydroxyethyl methylcarbamic acid tert-butyl ester (0.317 g, 0.0018 mol) and diethylazodicarboxylate (0.337 g, 0.0019 mol) in 5 mL of THF was added dropwise at 0° C. to give a yellow solution. The reaction mixture was warmed to ambient temperature and stirred for 72 hours, concentrated in vacuo and the resulting crude oil was purified by flash chromatography using a 25:75 of hexanes/ethyl acetate mixture to give 2-[1-(2-fluorobenzenesulfonyl)-1H-indol-4-yloxy]ethyl methylcarbamic acid tert-butyl ester as a clear oil (0.483 mg; 89%). 1H NMR (300 MHz, CDCl3) δ: 1.44 (bs, 9 H), 3.01 (s, 3 H), 3.65 (bs, 2 H), 4.19 (bs, 2 H), 6.65 (d, 1 H, J=8.03), 6.76 (d, 1 H, J=3.77), 7.09 (t, 1 H, J=8.67). 7.17 (t, 1 H, J=8.11), 7.28 (t, 1 H, J=7.73), 7.44 (d, 1 H, J=8.29), 7.55 (m, 2 H), 803 (t, 1 H, J=7.44).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([C:20]([NH2:22])=[O:21])[CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]>[Pd].CO>[CH2:1]([O:3][P:4]([CH2:9][C@H:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C@@H:12]([C:20]([NH2:22])=[O:21])[CH2:11]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1cc(C(N)=O)nc2ccccc12)OCC
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(C[C@@H]1C[C@H](C(N)=O)Nc2ccccc21)OCC
Reaction time: 24 h

Procedure:
A mixture of 500 mg of 4-(diethylphosphonomethyl)-quinoline-2-carboxamide and 1 g of 10% palladium on charcoal in 75 ml of methanol is hydrogenated at 3 atmospheres pressure for 24 hours, filtered and evaporated to dryness. Chromatography on silica gel using methanol/methylene chloride (1:10) as eluant yields cis-4-(diethylphosphonomethyl)-1,2,3,4-tetrahydroquinoline-2-carboxamide.
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.[BH4-].[Na+].O>CO>[CH3:1][N:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=1
Reactant: CN(CCOc1ccc(C=O)cc1)c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(CCOc1ccc(CO)cc1)c1ccccn1
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of 4-[2-(methyl-2-pyridylamino)ethoxy]benzaldehyde (15.0 g) in methanol (70 ml), sodium borohydride (1.11 g) was added at 0° C. in portions. After stirring for 30 minutes, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4), and then concentrated. The residue was subjected to column chromatography on silica gel, and 4-[2-(methyl-2-pyridylamino)ethoxy]benzylalcohol (14.3 g, yield 94%) was obtained from a fraction eluted with ethyl acetate-hexane (1:1, v/v) as an oil.