Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:16].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)Cn1nnc2c(Br)c(O)ccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CC(C)(C)Cn1nnc2c(Br)c(Oc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Bromo-1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-ol (1-6) (100 mg, 0.352 mmol, 1.0 equiv.), copper(II) acetate (63.9 mg, 0.352 mmol, 1.0 equiv.), phenylboronic acid (86 mg, 0.704 mmol, 2.0 equiv.) and freshly milled 4 Å molecular sieves were dried in vacuo and then suspended in anhydrous CH2Cl2 (3.5 mL) and TEA (245 μl, 1.760 mmol, 5.0 equiv.). The mixture was stirred ambient temperature for 18 hours, after which the mixture was filtered. The filtrate was concentrated in vacuo and the residue was purified via reverse phase HPLC (water/acetonitrile gradient containing 0.1% TFA) to provide 422. 1H NMR (CDCl3) δ 7.42 (1H, d, J=8.87 Hz), 7.36-7.30 (2H, m), 7.21 (1H, d, J=8.87 Hz), 7.12-7.07 (1H, m), 6.95 (2H, dd, J=7.97, 1.44 Hz), 4.40 (2H, s), 1.06 (9H, s) ppm. LRMS m/z (M+H) 360.0 and 362.0 (intensity ratio ˜1:1) found, 360.1 and 362.1 required.
Reaction SMILES: C([O:3][C:4]1[C:5](=[O:17])[C:6](=O)[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])C.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>CS(C)=O>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:6]1[C:5](=[O:17])[C:4](=[O:3])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15]
Reactant: CCOc1c(Nc2ccccc2O)c(=O)c1=O
Reactant: COc1ccccc1N
Solvent: CS(C)=O
Product: COc1ccccc1Nc1c(Nc2ccccc2O)c(=O)c1=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethoxy-4-(2-hydroxyanilino)-cyclobut-3-ene-1,2-dione (50 mg, 0.21 mmol) in DMSO (1.5 mL) was added 2-methoxyaniline (0.024 mL, 0.21 mmol) and reaction was stirred at 110° C. overnight. Reaction was purified on HPLC (acetonitrile:water) and product was concentrated down. Solid was dried in vacuo. LC-MS (m/z) 311.4 (M+).
Reaction SMILES: [C:1]1([CH3:9])[C:2]([NH2:8])=[CH:3][C:4]([NH2:7])=[CH:5][CH:6]=1.Cl.[CH3:11][C:12](=[CH2:14])[CH3:13]>>[C:12]([C:5]1[CH:6]=[C:1]([CH3:9])[C:2]([NH2:8])=[CH:3][C:4]=1[NH2:7])([CH3:13])([CH3:11])[CH3:14]
Reactant: C=C(C)C
Reactant: Cc1ccc(N)cc1N
Agent: Cl
Product: Cc1cc(C(C)(C)C)c(N)cc1N
Temperature: 180 °C

Procedure:
A 300 cc Hastalloy C pressure vessel equipped with a mechanical stirrer was used for producing t-butyltoluenediamine. Approximately 100 grams or 0.819 moles of 2,4-toluenediamine were charged to the vessel along with 5 grams of 36% aqueous hydrochloric acid. The vessel was sealed and purged with nitrogen, leaving a 33 psig nitrogen blanket. The vessel contents then were heated to 180° C. with continuous stirring. Isobutylene then was introduced into the reactor and 53.4 grams or 0.06 moles were added over 15 minutes. On addition of the isobutylene, the pressure in the reactor increased to 766 psig. The reaction mixture was maintained at 180° C. for 24 hours with constant stirring. At the end of the 24 hour period the pressure had dropped to 524 psig. The contents were then cooled to 160° C. and stirring discontinued. At that time the reactor was vented and the reaction product analyzed for composition.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:17])C=1.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccnc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc[n+]([O-])c1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.4 %

Procedure:
A solution of 2-bromo-3-methylpyridine (10.0 mL, 0.0898 mol) in dichloromethane (150 mL) at 0° C. was treated with mCPBA (˜77%, 22.1 g, 0.0987 mol) in three equivalent portions. The mixture was warmed to room temperature, stirred for 18 hours, cooled to 0° C., and treated with 1N NaOH (50 mL). The organic phase was washed with 1N NaOH and saturated NaHCO3, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with ethyl acetate and 9:1 ethyl acetate/methanol to provide 7.83 g (47%) of the desired product. MS (DCI/NH3) m/z 187.9 (M+H)+; 1H NMR (CDCl3) δ 8.28-8.26 (m, 1H), 7.15-7.09 (m, 2H), 2.46 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C([O:11][CH2:12][CH:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:6]([C:12]([OH:11])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:19]=[N:5]2)=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: CCOCC(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(F)ccc2c1O
Temperature: 100 °C
Yield: 67.6 %

Procedure:
Under a nitrogen atmosphere, 3-fluoroaniline (50.0 g, 0.45 mol) and diethyl ethoxymethylmalonate (91 mL, 0.45 mol) were combined and heated at 100° C. for 3 hours. The reaction was allowed to cool to ambient temperature and it solidified. Dowtherm A (200 mL) was added and the reaction mixture was heated at 240° C. for 4 hours. The reaction mixture was allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration, washed with hexane and then dried in a vacuum oven to provide 71.5 g of ethyl 7-fluoro-4-hydroxy-3-quinolinecarboxylate.
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:10])[CH2:4][C:5]([O:7]CC)=[O:6].[CH3:11][N:12]([CH3:14])[CH3:13]>O>[OH:10][C@H:3]([CH2:4][C:5](=[O:6])[O-:7])[CH2:2][N+:12]([CH3:14])([CH3:13])[CH3:11]
Reactant: CCOC(=O)C[C@@H](O)CCl
Reactant: CN(C)C
Solvent: O
Product: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Temperature: 80 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
400 g of crude ethyl (+) (R)-4-chloro-3-hydroxybutyrate, prepared according to Example 8, and 1 l of 45% trimethylamine in H2O are placed in a 2-liter reactor. The reaction mixture is heated to 80° C. and kept at this temperature for 15 h. After cooling and removing the excess of trimethylamine under nitrogen flow, the aqueous solution is extracted with 1.9 l of methylene chloride and analyzed with HPLC. L-carnitine is obtained with 75% yield.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]1N.Cl.[NH:13]1[CH2:19][CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.Cl>CCO>[CH:8]1[C:9]2[C:17]3[CH2:18][CH2:19][NH:13][CH2:14][CH2:15][C:16]=3[N:1]3[C:10]=2[C:5]([CH2:4][CH2:3][CH2:2]3)=[CH:6][CH:7]=1
Reactant: O=C1CCCNCC1
Reactant: NC1C=Cc2ccccc2N1
Agent: Cl
Solvent: CCO
Product: c1cc2c3c(c1)c1c(n3CCC2)CCNCC1
Temperature: 20 °C
Yield: 25.2 %

Procedure:
To a solution of 3,4-dihydro-[(2H)-quinolinamine (1.0 g, 14 mmol) and hexahydro-4H-azepin-4-one hydrochloride (1.0 g, 14 mmol) in EtOH (13 mL) was added concentrated HCl (1.2 mL). The reaction was stirred at reflux for 14 h, then cooled to 20° C. A brown precipitate was filtered from the reaction mixture, affording the title compound (800 mg, 45%) as a brown solid. 1H NMR (CD3OD, 300 MHz) δ 2.14–2.23 (m, 2H), 2.91 (t, 2H, J=6.0 Hz), 3.16–3.21 (m, 2H), 3.27–3.33 (m, 2H), 3.39–3.50 (m, 4H), 4.04 (t, 2H, J=5.7 Hz), 6.70 (d, 1H, J=6.9 Hz), 6.87–6.93 (m, 1H), 7.22 (d, 1H, J=8.0 Hz) ppm. MS (ESI): 227.2 (base, M+H).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].Br[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[OH:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CCCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCCCO)c21

Procedure:
Using general Method D above, 5-hexyn-1-ol (56 mg, 0.57 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (110 mg, 0.38 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (13 mg) (Aldrich) and Cul (7 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 14 h to yield (Z)-1,3-dihydro-4-(6-hydroxy-1-hexynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH3:22])[CH:18]=4)[N:13](CC4C=CC=CC=4OC)[C:12](=[O:32])[C:11]=3[C:33]([O:35]C)=[O:34])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[K+].O1C2C=CC(C3C4C(=CC=C(OCC)C=4)N([CH2:61][C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=4[O:68][CH3:69])C(=O)C=3C(O)=O)=CC=2OC1>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH3:22])[CH:18]=4)[N:13]=[C:12]([O:32][CH2:61][C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=4[O:68][CH3:69])[C:11]=3[C:33]([OH:35])=[O:34])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOc1ccc2c(c1)c(-c1ccc3c(c1)OCO3)c(C(=O)OC)c(=O)n2Cc1ccccc1OC
Reactant: CCOc1ccc2c(c1)c(-c1ccc3c(c1)OCO3)c(C(=O)O)c(=O)n2Cc1ccccc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCOc1ccc2nc(OCc3ccccc3OC)c(C(=O)O)c(-c3ccc4c(c3)OCO4)c2c1

Procedure:
A solution of 0.5 g of methyl 4-(1,3-benzodioxol-5-yl)-1,2-dihydro-6-ethoxy-1-(2-methoxybenzyl)-2-oxoquinoline-3-carboxylate and 6 ml of 5N KOH in 10 ml of methanol is boiled under reflux for 2 hours. The usual working up results in 4-(1,3-benzodioxol-5-yl)-1,2-dihydro-6-ethoxy-1-(2-methoxybenzyl)-2-oxoquinoline-3-carboxylic acid, m.p. 225°-226°. Analogously, the O-alkylation product 4-(1, 3-benzodioxol-5-yl)-6-ethoxy-2-(2-methoxybenzyloxy)quinoline-3-carboxylic acid is obtained from methyl 4-(1,3-benzodioxol-5-yl)-6-ethoxy-2-(2-methoxybenzyloxy) quinoline-3-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH:13]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:14]([O:16]C)=O)[C:7]2=[O:12].[NH3:25]>CO>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH:13]([C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:14]([NH2:25])=[O:16])[C:7]2=[O:12]
Reactant: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c(N)cccc2c1=O
Reactant: N
Solvent: CO
Product: NC(=O)C(c1ccc(Cl)cc1)n1ccc2c(N)cccc2c1=O
Temperature: 70 °C

Procedure:
A pressure tube was charged with methyl 2-(5-amino-1-oxoisoquinolin-2(1H)-yl)-2-(4-chlorophenyl)acetate (1.35 g, 0.00394 mol) and ammonia in methanol (7 mL, 2M solution) was added and the reaction heated at 70° C. for 16 hours. The reaction mixture was cooled to room temperature and checked for completion. The reaction was only 20% complete. Further heating of the reaction for another 6 hours did not seem to help in the progress of the reaction. The solvent was removed and the residue was purified by flash chromatography to obtain the product as a light yellow solid. MS m/z=328.2 (M+H).
Reaction SMILES: [H][H].[O:3]=[C:4]1[CH:16](C(OC(C)(C)C)=O)[N:8]2[C:9]3[C:14]([CH:15]=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3>C1(C)C=CC=CC=1>[CH:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[CH:15]=[C:7]1[CH2:6][CH2:5][C:4](=[O:3])[CH2:16][N:8]12
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C1C(=O)CCc2cc3ccccc3n21
Solvent: Cc1ccccc1
Product: O=C1CCc2cc3ccccc3n2C1

Procedure:
Compounds of formula (I) wherein R3 represents hydrogen may be prepared from the respective tert-butyl 7-oxo-6,7,8,9-tetrahydropyrido[1,2-a]indole-6-carboxylate derivatives (5). Decarboxylation by reaction with silica gel in an aprotic solvent such as toluene gives the corresponding 8,9-dihydropyrido[1,2-a]indol-7(6H)-one derivatives (9). Reductive amination with ammonium acetate in the presence of a reducing agent such as NaBH3CN in a mixture of AcOH and EtOH and subsequent Boc protection yields the corresponding tert-butyl (6,7,8,9-tetrahydropyrido[1,2-a]indol-7-yl)carbamate derivatives (10). Friedel-Craft acylation by reaction with oxalyl chloride in an aprotic solvent such as DCM, followed by esterification with MeOH and subsequent reduction with triethylsilane in the presence of TFA gives the corresponding methyl 2-(7-amino-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate (11). Reaction with an appropriate heteroaryl halide like R4—Cl in the presence of a base such as K2CO3 in an aprotic solvent such as DMA and subsequent saponification with a base such as NaOH furnished the compounds of formula (I).
Reaction SMILES: S(Cl)(C)(=O)=O.[C:6]([N:9]1[CH2:14][CH2:13][C:12](O)([Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]1)(=[O:8])[CH3:7].C(N(CC)CC)C.[Na+].[Cl-]>ClCCl>[C:6]([N:9]1[CH2:10][CH:11]=[C:12]([Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:13][CH2:14]1)(=[O:8])[CH3:7]
Reactant: CCCC[Sn](CCCC)(CCCC)C1(O)CCN(C(C)=O)CC1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC[Sn](CCCC)(CCCC)C1=CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Under an inert atmosphere, 1.3 equivalents of mesyl chloride in 15 ml of dichloromethane are added dropwise to a solution of 0.16 mmol of the compound obtained in Step A and 2.8 equivalents of triethylamine in 1 litre of dichloromethane at 0° C. After stirring the mixture at ambient temperature for 4 days, a saturated aqueous solution of NaCl is added. After extraction, drying, filtration and concentration of the organic phase under reduced pressure, chromatography of the residue on silica gel (dichloromethane/ethanol: 97/3) enables the expected product to be isolated.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.[B:29](OC)([O:32]C)[O:30]C.Cl>O1CCCC1>[F:16][C:17]1[C:18]([C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)=[CH:19][CH:20]=[CH:21][C:22]=1[B:29]([OH:32])[OH:30]
Reactant: Fc1ccccc1-c1ccncc1
Reactant: COB(OC)OC
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc(-c2ccncc2)c1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 66.4 %

Procedure:
A cooled (−78° C.) solution of n-butyllithium (15.2 ml of a 2.5 M solution in hexanes, 38.0 mmol) in tetrahydrofuran (100 ml) was treated with 2,2,6,6-tetramethylpiperidine (6.69 ml, 39.8 mmol) and stirring at −78° C. was continued for 15 min. The reaction was then treated with a cooled (0° C.) solution of 4-(2-fluorophenyl)pyridine (6.26 g, 36.1 mmol) in tetrahydrofuran (20 ml) added dropwise over 10 min. This mixture was stirred at −78° C. for 2 h and then treated with trimethyl borate (8.16 ml, 72.3 mmol) added dropwise over 5 min. The reaction was stirred at −78° C. for 10 min then allowed to warm to ambient temperature. Next, 2 N hydrochloric acid (10 ml) was added and the mixture stirred for 30 min, then evaporated to dryness. The residue was stirred with 2 N hydrochloric acid (100 ml) for 1 h and then taken to pH 14 with 2 N sodium hydroxide (ca. 150 ml). This was washed with diethyl ether and the aqueous layer was cooled to 0° C. and adjusted to pH 8 with 36% hydrochloric acid. After stirring at 0° C. for 1 h the resulting solid was collected by filtration and dried to afford 5.20 g (66%) of 2-fluoro-3-(pyridin-4-yl)benzeneboronic acid as a white solid: MS (ES+) m/z 218 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([OH:11])=[N:5][NH:6]2.O.Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15]>N1C=CC=CC=1>[CH2:17]([O:16][C:14]([N:6]1[C:7]2[C:3](=[C:2]([Br:1])[CH:10]=[CH:9][CH:8]=2)[C:4]([OH:11])=[N:5]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)Cl
Reactant: Oc1n[nH]c2cccc(Br)c12
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)n1nc(O)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a room temperature suspension of 4-Bromo-1H-indazol-3-ol CLXXXIII (3.19 g, 15.0 mmol) in pyridine (13 ml) and H2O (20 ml) was dropwise added ethyl chloroformate (1.43 ml, 15.0 mmol). After stirring 18 hours at room temperature, the mixture was cooled to 0° C., and the precipitate was filtered and washed with cold AcOH (10 ml in 5 ml of H2O). The solid was dried in vacuo affording 4-Bromo-3-hydroxy-indazole-1-carboxylic acid ethyl ester CLXXXIV as a yellow powder (2.97 g, 69% yield).
Reaction SMILES: [CH3:1]C1CCCN(C)C1(C)C.C([Li])CCC.[CH:16]1([CH2:19][CH:20]=[CH:21][CH2:22][CH:23]2[CH2:25][O:24]2)[CH2:18][CH2:17]1>CC(OC)(C)C>[CH:16]1([CH2:19][CH:20]2[CH:22]3[CH:21]2[CH2:1][CH2:25][CH:23]3[OH:24])[CH2:18][CH2:17]1
Reactant: C(=CCC1CO1)CC1CC1
Reactant: CC1CCCN(C)C1(C)C
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Product: OC1CCC2C(CC3CC3)C12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of tetramethylpiperidine (0.624 ml, 3.7 mmol) in MTBE (5 mL) was added n-butyllithium 2.5M hexanes (1.5 ml, 3.7 mmol) at −78° C. The solution was slowly warmed to approx 0° C. and was added via cannula to a solution of 2-(4-cyclopropyl-but-2-enyl)-oxirane (0.288 g, 1.898 mmol) in MTBE (2 mL) over 10 min at 0° C. The mixture was allowed to warm to rt, stirred overnight, washed with 1N HCl (2×), and brine. The organics were dried over MgSO4, filtered, and concentrated to give 6-cyclopropylmethyl-bicyclo[3.1.0]hexan-2-ol as clear oil; 1H NMR (400 MHz, CDCl3): δ 4.19 (d, 1H, J=5.5 Hz), 2.15–2.06 (m, 1H), 1.75 (dd, 1H, J1=11.0 Hz, J2=9.7 Hz), 1.69–1.52(m, 4H), 1.42 (dd, 1H, J1=8.1 Hz, J2=6.2 Hz), 0.98–0.87 (m, 2H), 0.75–0.68 (m, 1H), 0.46–0.41 (m, 2H), 0.03 (dd, 2H, J1=9.1 Hz, J2=4.7 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.[N:17]1([CH2:23][CH2:24]O)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:24][CH2:23][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(OCCN3CCOCC3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a stirring solution of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-phenol (2.55 g, 11.58 mmol), 2-morpholin-4-ylethanol (1.60 mL, 1.73 g, 13.2 mmol) and triphenyl phosphine (3.64 g, 13.9 mmol) in methylene chloride (60 mL) at 0° C. was added dropwise DIAD (2.82 g, 13.9 mmol). The reaction was allowed to warm to room temperature and stir overnight. After 18 hours, additional portions of triphenyl phosphine (1.51 g, 5.8 mmol), 2-morpholin-4-ylethanol (0.70 mL, 5.8 mmol), and DIAD (1.17 g, 5.8 mmol) were added. After stirring an additional 2 hours at room temperature the reaction was concentrated and the residue purified by flash chromatography (5% to 25% EtOAc in CHCl3) to provide the product as a white solid (2.855 g, 74%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:22][C:21](Cl)=[N:20][C:19]=4[CH:18]=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:33][O:34][C:35]1[N:40]=[C:39]([O:41][CH3:42])[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1>>[CH3:33][O:34][C:35]1[N:40]=[C:39]([O:41][CH3:42])[C:38]([C:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[C:24]3[S:25][C:17]([CH2:16][N:13]4[CH2:14][CH2:15][N:10]([S:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)(=[O:9])=[O:8])[CH2:11][CH2:12]4)=[CH:18][C:19]=3[N:20]=2)=[CH:37][N:36]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Reactant: O=S(=O)(c1ccccc1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(=O)(=O)c5ccccc5)CC4)cc3n2)c(OC)n1

Procedure:
6-(4-Benzenesulfonyl-piperazin-1-ylmethyl)-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (described above) 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 260. NMR (400 MHz, CDCl3): 2.56-2.58 (4H, m, CH2), 3.04 (4H, m, CH2), 3.74-3.77 (6H, m, CH2), 3.88-3.91 (4H, m, CH2), 3.98 (3H, s, CH3), 4.01 (3H, s, CH3), 7.21 (1H, s, ar), 7.47-7.51 (2H, m, ar), 7.54-7.58 (1H, m, ar), 7.71 (2H, d (J=7.13), ar), 8.84 (1H, s, ar). (M+H)+ 598.28
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:26])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ccc(NC(=O)c3nc(C)oc3-c3ccccc3)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-methyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 05: tR=0.87 min; [M+H]+=408.12.
Reaction SMILES: Cl.[I:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]N.[NH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.Cl>FC(F)(F)CO>[I:2][C:3]1[C:4]2[NH:9][C:14]3[CH2:15][CH2:16][NH:11][CH2:12][C:13]=3[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: NNc1ccccc1I
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: OCC(F)(F)F
Product: Ic1cccc2c3c([nH]c12)CCNC3
Temperature: 25 °C
Yield: 69 %

Procedure:
To a solution of 2-iodophenyl hydrazine hydrochloride (1.0 eq.) and 4-piperidone (1.0 eq.) in 2,2,2-trifluoroethanol was added 12 N HCl (2.0 eq.). The reaction mixture was heated at 60–65° C. for 3 h and cooled to rt. then filtered. The residue was purified by column chromatography to provide 6-iodo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole in 69% yield.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1B(O)O>>[O:6]1[CH2:7][CH2:8][C:4]2[CH:3]=[C:2]([C:12]3[S:11][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:9][C:5]1=2
Reactant: Brc1ccc2c(c1)CCO2
Reactant: OB(O)c1cccs1
Product: c1csc(-c2ccc3c(c2)CCO3)c1

Procedure:
The above 5-bromo-2,3-dihydrobenzo[b]furan and thiophene-2-boronic acid were treated in a manner similar to Reference Example 20-(1) to give the desired 2-(2,3-dihydro-5-benzo[b]furanyl)thiophene as pale yellow crystals. APCI-Mass m/Z 203 (M+H).