Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>O1CCCC1>[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:35])[O:18][C:15]2[CH:16]=[C:17]3[C:12]([CH2:11][CH2:10][CH2:9][N:8]3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:13][CH:14]=2)=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (800 mg, 3.34 mM) and triethylamine (0.5 mL) in dry tetrahydrofuran (THF, 5 ml) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 4-fluorophenyl isocyanate (570 mg/ml, 5.01 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was quenched with distilled water (1 mL) followed by the extraction with chloroform (3×15 mL). The combined fractions of chloroform was again washed with water and dried over sodium sulphate. Further concentration of chloroform fraction under vacuum afforded the crude product, which was cystallize with methanol-ether (1:5) to yield 8d as solid. Yield: 1.06 g, 84.23%.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[NH:11]1[CH:15]=[CH:14][N:13]=[C:12]1[C:16]#[CH:17].[CH:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[NH:11]1[CH:15]=[CH:14][N:13]=[C:12]1[C:16]#[C:17][CH:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:25]
Reactant: O=Cc1ccccc1
Reactant: C#Cc1ncc[nH]1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: OC(C#Cc1ncc[nH]1)c1ccccc1
Temperature: 25 °C

Procedure:
Place lithium hexamethyldisilazane (3 mL of a 1M solution in tetrahydrofuran, 3 mmol) under argon atmosphere and cool to 0° C.. Add 2-imidazolylacetylene (276 mg, 3 mmol) in tetrahydrofuran (20 mL) and stir at 0° C. until anion formation is complete. Add a solution of benzaldehyde (297 mg, 2.8 mmol) in tetrahydrofuran, remove the ice bath and stir at room temperature until the reaction is complete. Pour onto ethyl ether and water, separate the organic layer and dry (MgSO4). Filter and evaporate the solvent in vacuo. Purify by silica gel chromatography to yield the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[Al]>O.CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:20]2[CH2:21][CH2:22][CH:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:18][CH2:19]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Al]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCC(c3ccccc3)CC2)cc1
Temperature: 190 °C
Reaction time: 0.08 h
Yield: 86.3 %

Procedure:
An oven-dried 20 mL microwave tube was charged with 4-fluoronitrobenzene (0.752 mL, 7.02 mmol), 4-phenylpiperidine (1.166 g, 7.02 mmol), and potassium carbonate (0.970 g, 7.02 mmol) under nitrogen, anhydrous DMSO (7 mL) was added, the tube was sealed with an aluminum crimp cap, and heated in a microwave reactor (Personal Chemistry, 300 W, 2.4 bar) at 190° C. for 10 minutes. TLC (SiO2, 5% EtOAc/hexanes) showed complete reaction. The reaction was poured into water (50 mL), stirred for 5 minutes, and vacuum filtered in a Büchner funnel. The collected yellow solids were washed with water (2×10 mL) and Et2O (5 mL), and the bright yellow solid was dried in vacuo to provide the title compound (1.712 g, 6.06 mmol, 86%). 1H NMR (400 MHz, CDCl3) δ ppm 1.73-1.90 (m, 2 H), 2.00 (d, J=13.34 Hz, 2 H), 2.73-2.86 (m, 1 H), 3.02-3.17 (m, 2 H), 4.10 (d, J=13.23 Hz, 2 H), 6.87 (d, J=9.43 Hz, 2 H), 7.23 (t, J=7.75 Hz, 3 H), 7.33 (t, J=7.43 Hz, 2 H), 8.14 (d, J=9.33 Hz, 2 H); MS (ESI+) m/z 283 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:13][C:14]1[C:15]([C:19]2[CH:32]=[CH:31][C:22]([CH2:23][S:24][CH2:25][CH2:26]C(OC)=O)=[CH:21][CH:20]=2)=[N:16][O:17][CH:18]=1)=[O:12])[CH3:9].SCC[S:36]([O-:39])(=[O:38])=[O:37].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:13][C:14]1[C:15]([C:19]2[CH:20]=[CH:21][C:22]([CH2:23][S:24][CH2:25][CH2:26][S:36]([OH:39])(=[O:38])=[O:37])=[CH:31][CH:32]=2)=[N:16][O:17][CH:18]=1)=[O:12])[CH3:9]
Reactant: O=S(=O)([O-])CCS
Reactant: COC(=O)CCSCc1ccc(-c2nocc2NC(=O)OC(C)c2ccccc2Cl)cc1
Agent: [Na+]
Product: CC(OC(=O)Nc1conc1-c1ccc(CSCCS(=O)(=O)O)cc1)c1ccccc1Cl
Yield: 39.3 %

Procedure:
Reaction similar to that of Step B-7 of Example 1 was carried out using Compound 1 (100 mg, 0.256 mmol) and sodium 2-mercaptoethanesulfonate (127 mg, 0.774 mmol) to give the title compound (50 mg, 39%).
Reaction SMILES: [Mg].BrCCBr.Cl[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[CH3:14].[C:15]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>O1CCCC1>[Cl:13][C:9]1[C:8]([CH3:14])=[C:7]([C:15]2([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCCCC1
Reactant: Cc1c(Cl)cccc1Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: Cc1c(Cl)cccc1C1(O)CCCCC1
Temperature: 25 °C

Procedure:
Under a nitrogen blanket, 96 g (4 moles) of magnesium shavings in 60 ml of absolute THF (tetrahydrofuran) are placed in a receiver. At 65° C., 1 ml of 1,2-dibromoethane is added and then a solution of 644 g (4 moles) of 2,6-dichlorotoluene in 1.5 liters of absolute THF is dripped in over a period of 21/4 hours. The mixture is then stirred under reflux for 4 hours and cooled to room temperature, and 352.8 g (3.6 moles) of cyclohexanone in 250 ml of absolute THF is added under a nitrogen blanket. After the reaction the Grignard reaction mixture is worked up as usual and the solvent is substantially removed by distillation under reduced pressure. The residue is subjected to incipient distillation (30° to 107° C./0.27 mbar). The crude product remaining (676 g), which already consists to the extent of 90% of 1-(3'-chloro-2'-methylphenyl)-cyclohexanol, can be purified further by column chromatography using toluene as eluant.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:22][N:21](S(C4C=CC(C)=CC=4)(=O)=O)[C:18]3=[N:19][CH:20]=2)=[CH:11][C:5]=1[C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[C:2]=[O:3].C(N(C(C)C)C(C)C)C.[CH:51]([OH:54])([CH3:53])[CH3:52]>C(Cl)Cl>[CH:51]([O:54][C:2](=[O:3])[NH:1][C:4]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:22][NH:21][C:18]3=[N:19][CH:20]=2)=[CH:11][C:5]=1[C:6](=[O:7])[N:8]([CH3:9])[CH3:10])([CH3:53])[CH3:52]
Reactant: CC(C)O
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N=C=O)c(C(=O)N(C)C)c3)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(NC(=O)OC(C)C)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Yield: 48.7 %

Procedure:
Into a 3 mL reation vial were added 2-isocyanato-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (30 mg, 0.053 mmol), methylene chloride (1 mL), iPr2EtN (21 μL, 0.060 mmol), and isopropyl alcohol (50 μL, 6.5 mmol). The solution was stirred at room temperature for at least 12 h and monitored by HPLC. The reaction mixture was concentrated then re-dissolved in MeOH (1 mL), and cooled to 0° C. and treated with 100 μL 50% (w/w) aqueous KOH for 30 min or until Ts-removal was complete. The reaction was quenched by addition of 500 μL glacial acetic acid and then concentrated in vacuum. Purification by mass-triggered HPLC (formic acid ACN/H2O gradient) followed by lyophilization provided 12.2 mg of the title compound as a white powder. 1H-NMR (500 MHz, d6-DMSO) δ=11.91 (br.s, 1H), 8.96 (br.s., 1H), 8.53 (d, J=2.0 Hz, 1H), 8.15 (d, J=2.0 Hz, 1H), 7.73 (m, 3H), 7.60 (d, J=9.0 Hz, 1H), 7.59 (s, 1H), 7.29 (dd, J=1.5, 7.2 Hz, 1H), 7.12 (d, J=7 Hz, 1H), 7.04 (t, J=7 Hz, 1H), 4.84 (m, 1H), 3.81 (s, 3H), 2.97, 2,92 (br s, 6H), 1.23 (d, J=6, 6H); MS: m/z 473.1 [M+H+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[S:29](Cl)(=[O:31])=[O:30]>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[S:29]([C:4]1([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)(=[O:31])=[O:30]
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Product: Nc1nc(N)c2c(OCC3(S(=O)(=O)c4ccc(F)cc4F)CCNCC3)cccc2n1
Yield: 99 %

Procedure:
The sulfonamide was obtained by reacting 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) and 2,4-difluorobenzenesulfonyl chloride (79 mg; 0.37 mmol) via Method AA to yield 80 mg. (99% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.86 (m, 1H), 7.61 (m, 1H), 7.33 (m, 2H), 7.12 (br s, 2H), 6.75 (d, J=8.0 Hz, 1H), 6.51 (d, J=7.6 Hz, 1H), 5.93 (br s, 2H), 3.97 (d, J=6.0 Hz, 2H), 3.71 (br d, J=12.0 Hz, 2H), 2.56 (t, J=12 Hz, 2H), 2.0 (s, 1H), 1.85 (d, J=10.4 Hz, 2H), 1.34 (m, 2H). MS m/z (ESI) 451 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7]C)=O.[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C[O-].[Na+].CO>O>[C:13]1([N:19]([C:5](=[O:7])[C:4]2[CH:9]=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=2)[NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NNc1ccccc1
Reactant: COC(=O)c1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NN(C(=O)c1ccc(Cl)c(Cl)c1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture consisting of 71.8 g. (0.35 mole) methyl 3,4-dichlorobenzoate, 37.9 g. (0.35 mole) phenylhydrazine, 21.6 g. (0.40 mole) sodium methoxide, and 175 ml. methanol was heated at the reflux temperature for 22 hrs. After cooling the reaction mixture to about 25°C., it was poured into 500 ml. water. The aqueous mixture was filtered and the solids that collected on the filter were dissolved in 500 ml. ethanol. Refrigeration caused crystals to form which were recovered by filtration. There was thus obtained 3,4-dichlorobenzoic acid phenylhydrazide melting at 169° to 172°C. An analytical sample melting at 171.5° to 173° C. was obtained by recrystallization from ethanol.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=[C:2]1[NH2:12].[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16]N>CO>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:12][C:2]1[CH2:1][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: NC1=NC=Cc2ccccc2C1
Reactant: COC(CN)OC
Solvent: CO
Product: COC(CNC1=NC=Cc2ccccc2C1)OC
Reaction time: 16 h
Yield: 99.6 %

Procedure:
A mixture of 3.16 g of 1H-3-benzazepin-2-amine, 4.17 g of 2,2-dimethoxyethanamine and 50 ml of methanol was stirred for 16 hours at reflux temperature. The reaction mixture was evaporated and the residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 95:5). The eluent of the desired fraction was evaporated and the residue was stirred in hexane. The precipitate was filtered off, yielding 4.9 g (100% ) of N-(2,2-dimethoxyethyl)-1H-3-benzazepin-2-amine (interm. 28).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[C:14]([CH2:23][C:24]([O:26]C)=O)=[C:13]3[CH3:28])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:29][NH2:30]>CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[C:14]([CH2:23][C:24]([NH:30][CH3:29])=[O:26])=[C:13]3[CH3:28])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1c(C)n(-c2ccnc3cc(Cl)ccc23)c2ccc(OC)cc12
Reactant: CN
Solvent: CO
Product: CNC(=O)Cc1c(C)n(-c2ccnc3cc(Cl)ccc23)c2ccc(OC)cc12

Procedure:
Methyl 1-(7-chloroquinol-4-yl)-5-methoxy-2-methylindol-3-ylacetate (1.7g.) in methanol (50ml.) containing 30% w/v methylamine solution (25ml.) was refluxed for 10 hours. The solvents were evaporated in vacuo and the residue crystallised from a 1:1 v/v mixture of benzene and cyclohexane to give 1-(7-chloroquinol-4-yl)-5-methoxy-N,2-dimethylindol-3-ylacetamide, m.p. 168°-169° C.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C@H:8]([CH3:13])[CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:14].[CH3:15]N1C[C@H](C)C2C(Cl)=C(Cl)C=CC=2CC1>>[CH3:15][N:10]1[CH2:9][C@@H:8]([CH3:13])[C:7]2[C:2]([Br:1])=[C:3]([Cl:14])[CH:4]=[CH:5][C:6]=2[CH2:12][CH2:11]1
Reactant: C[C@@H]1CNCCc2ccc(Cl)c(Br)c21
Reactant: C[C@H]1CN(C)CCc2ccc(Cl)c(Cl)c21
Product: C[C@@H]1CN(C)CCc2ccc(Cl)c(Br)c21

Procedure:
Compound 11 was prepared from (S)-9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine utilizing a similar procedure as described herein for the preparation of Compound 9. 1H NMR (400 MHz, CDCl3) δ 7.18 (d, J=8 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 3.94-3.88 (m, 1H), 3.29 (ddd, J=15, 12, 2 Hz, 1H), 2.98-2.93 (m, 1H), 2.90 (ddd, J=15, 6, 1 Hz; 1H), 2.36-2.32 (m, 4H) 2.13 (t, J=11 Hz, 1H), 1.33 (d, J=7 Hz, 3H). MS calculated for C12H15Cl2N+H: 288, observed: 288.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[C:32]([S:51][CH2:52][CH2:53][NH2:54])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([NH:54][CH2:53][CH2:52][S:51][C:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)[nH]2)c1
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To 5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (940 mg, 2.1 mmol) synthesized in Example (18a), 2-(tritylthio)ethaneamine (1.01 g, 3.17 mmol) synthesized in Example (25a) and 4-dimethylaminopyridine (13 mg, 0.1 mmol) were added, followed by dissolution in dichloromethane (50 mL), and subsequently WSCI•HCl (445 mg, 2.3 mmol) was added at room temperature, and stirring was carried out for 1 hour under nitrogen atmosphere. The reaction solution was diluted with dichloromethane (150 mL), washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-55%) to afford the desired product (1.08 g, yield 69%) as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:14][C:15]1[CH:20]=[C:19]([N+]([O-])=O)[CH:18]=[CH:17][N:16]=1>C1COCC1>[CH2:3]([O:10][CH2:11][CH2:12][O:13][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:14])[CH:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: OCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc(OCCOCc2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.7 %

Procedure:
Sodium hydride (50% in mineral oil; 0.54 g, 11.35 mmol) was added portionwise to a solution of 2-benzyloxylethanol (1.72 g, 11.4 mmol) in THF (15 mL) at r.t. under nitrogen. After 15 min. 2-chloro-4-nitro-pyridine (1.20 g, 7.57 mmol) was added and the reaction mixture stirred at r.t. overnight. The reaction mixture was quenched by slowly pouring onto ice and concentrated to remove the organic solvent. The residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine then dried over sodium sulfate, filtered and concentrated. The crude material was subjected to column chromatography over silica gel (60-120 mesh) using 5%-25% ethyl acetate in petroleum ether as eluent to afford 4-(2-benzyloxy-ethoxy)-2-chloro-pyridine (1.91 g, 96%) as an oily liquid.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH:5]([C:8](O)=[O:9])[CH2:4][CH2:3]1.S(Cl)([Cl:14])=O>>[CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH:5]([C:8]([Cl:14])=[O:9])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(C(=O)O)CC1
Reactant: O=S(Cl)Cl
Product: CC1(C)CCC(C(=O)Cl)CC1
Reaction time: 3 h

Procedure:
To 5 g of 4,4-dimethyl-cyclohexylcarboxylic acid was added an excess of thionyl chloride, and the mixture was heated with stirring for 3 hours. After the reaction, the remaining thionyl chloride was distilled off in a vacuum, 10 ml of benzene was added to the residue and the mixture was distilled in a vacuum, giving oily 4,4-dimethylcyclohexylcarbonyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([O:26][C:27](=[O:41])[NH:28]/[C:29](=C(/OCC)\CCC)/[C:30]([NH:32][NH2:33])=O)([CH3:25])([CH3:24])[CH3:23]>C(O)C>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][N:21]3[C:6]([CH2:8][CH2:13][CH3:12])=[N:33][N:32]=[C:30]3[CH2:29][NH:28][C:27]([O:26][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:41])=[CH:18][CH:19]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC/C(OCC)=C(\NC(=O)OC(C)(C)C)C(=O)NN
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CN)cc1
Solvent: CCO
Product: CCCc1nnc(CNC(=O)OC(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 50 °C
Yield: 30366.2 %

Procedure:
4′-Aminomethylbiphenyl-2-carboxylic acid t-butyl ester (1.5 g, 5.2 mmol) and [1-ethoxy-but-(E)-ylidene-hydrazinocarbonylmethyl] carbamic acid t-butyl ester (1.0 g, 3.5 mmol) were combined and dissolved in ethanol (50 mL). The mixture was heated at 50° C. for 2 hours and then 70° C. overnight. The mixture was then cooled and concentrated. The product was purified by silica gel chromatography (0-20% MeOH:DCM) to obtain intermediate (23a) (400 g). MS m/z: [M+H+] calcd for C29H38N4O4, 507.6. found 507.3.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16](Cl)=[N:15][C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33]([C:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:19]3[S:20][C:12]([CH2:11][N:8]4[CH2:9][CH2:10][CH:5]([C:3]([NH:2][CH3:1])=[O:4])[CH2:6][CH2:7]4)=[CH:13][C:14]=3[N:15]=2)=[CH:32][N:31]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Reactant: CNC(=O)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CNC(=O)C1CCN(Cc2cc3nc(-c4cnc(OC)nc4OC)nc(N4CCOCC4)c3s2)CC1

Procedure:
1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidine-4-carboxylic acid methylamide was reacted with 2,4-dimethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine in General Procedure A. Purification on silica yielded 108. NMR (CDCl3): 1.84-1.89 (m, 4H, 2×CH2), 2.10-2.18 (m, 3H, CH2+CH), 2.84 (d, 3H, CH3, J=4.8 Hz), 3.03-3.06 (m, 2H, CH2), 3.83 (s, 2H, CH2), 3.88-3.90 (m, 4H, 2×CH2), 4.02-4.05 (m, 4H, 2×CH2), 4.08 (s, 3H, CH3), 4.11 (s, 3H, CH3), 5.47 (sbr, H, NH), 7.30 (s, H, ArH), 8.93 (s, H, ArH). MS: (ESI+): MH+=514.27
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]([CH3:3])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: CN(C)Cc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)Cc1ccccc1N1CCNCC1
Yield: 76 %

Procedure:
To tert-butyl 4-{2-[(dimethylamino)methyl]phenyl}-piperazine carboxylate (Step 2) (0.68 g, 2.1 mmol) dissolved in CH2Cl2 (12 mL) was added TFA (6 mL). After stirring the reaction at RT for 1 h, the solvent was concentrated in vacuo and the residue was partitioned between CH2Cl2 and satd NaHCO3. The organic layer was washed with brine and the combined aqueous layer were extracted with a mixture of CH2Cl2 and 30% MeOH. The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give dimethyl[(2-piperazinylphenyl)methyl]amine as a yellow oil (0.35 g). MS m/z: 220 (M+H). Calc'd for C13H21N3: 219.33.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5]23[CH:11]([CH2:12][CH2:13][CH:4]2[CH2:3]1)[C:10]1[CH:14]=[CH:15][C:16]([C:18]2[CH:19]=[C:20]([C:24](=O)[CH3:25])[CH:21]=[CH:22][CH:23]=2)=[CH:17][C:9]=1[CH2:8][CH2:7]3.Cl.[NH2:28][OH:29].N1C=CC=CC=1>C(O)C>[CH3:1][N:2]1[CH2:6][C:5]23[CH:11]([CH2:12][CH2:13][CH:4]2[CH2:3]1)[C:10]1[CH:14]=[CH:15][C:16]([C:18]2[CH:19]=[C:20]([C:24](=[N:28][OH:29])[CH3:25])[CH:21]=[CH:22][CH:23]=2)=[CH:17][C:9]=1[CH2:8][CH2:7]3
Reactant: CC(=O)c1cccc(-c2ccc3c(c2)CCC24CN(C)CC2CCC34)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NO)c1cccc(-c2ccc3c(c2)CCC24CN(C)CC2CCC34)c1
Yield: 18.8 %

Procedure:
1-[3-(8-Methyl-5,6,6a,7,8,9,10,11-octahydro-4bH-benzo[4,5]indeno[1,7a-c]pyrrol-2-yl)-phenyl]-ethanone (Example 2)(10.0 mg, 0.028 mmol), hydroxylamine hydrochloride (2.9 mg, 0.042 mmol), and pyridine (226 μL, 0.28 mmol) were heated in ethanol (1 mL) at 80° C. for 3 h. The mixture was quenched with water (1 mL), extracted with CH2Cl2 (2 mL×4). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 5% methanol in dichloromethane, providing 1.9 mg (18.3%) of the title compound.
Reaction SMILES: O=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[N:6]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]([C:19]([O:21][CH3:22])=[O:20])=[CH:4][C:3]1=2.[CH2:23]([Mg]Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:23](=[C:2]1/[C:3]2[CH:4]=[C:5]([C:19]([O:21][CH3:22])=[O:20])[N:6]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:7]=2[CH2:8][CH2:9][CH2:10]/1)\[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1cc2c(n1COCC[Si](C)(C)C)CCCC2=O
Reactant: Cl[Mg]Cc1ccccc1
Product: COC(=O)c1cc2c(n1COCC[Si](C)(C)C)CCC/C2=C\c1ccccc1

Procedure:
The title compound was synthesized from methyl 4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (900 mg, 2.78 mmol) and benzylmagnesium chloride (3.4 mL, 2M in THF, 6.8 mmol) according to General Procedure 3. In this example, additional benzylmagnesium chloride (1.7 mL, 2M in THF, 3.4 mmol) was added after 2 h. The crude product (900 mg) was used in the next step without further purification. LC/MS: 50%, m/z=397.