Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:20][CH2:21][OH:22])[CH:16]=[C:17]([Br:19])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:20][CH2:21][O:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:16]=[C:17]([Br:19])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCO)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCOS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
Add 4-[4-bromo-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (10.0 g; 0.027 mol; 1.0 equiv), TEA (11.6 mL; 0.080 mol; 3.0 equiv) to DCM (150 mL) and cool to 0° C. Add drop-wise mesyl chloride (2.6 mL; 0.032 mol; 1.2 equiv) and stir for 30 min. Quench the reaction with saturated NaHCO3 aqueous and extract with DCM. Evaporate the organic layer to give the title compound (10.2 g; 84%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[H-].[Na+].Br[CH2:18][CH:19]([CH3:21])[CH3:20]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:18][CH:19]([CH3:21])[CH3:20])=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1
Reactant: CC(C)(C)c1cc(Br)ccc1CCN
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)CNCCc1ccc(Br)cc1C(C)(C)C
Yield: 30 %

Procedure:
In a manner analogous to example 1 c, the process is carried out by a reaction of 4 g (16 mmol) of (4-bromo-2-tert-butylphenyl)ethylamine (example 1b) with 1.4 g (34 mmol) of 60% sodium hydride and with 3.7 ml (34 mmol) of 1-bromo-2-methylpropane. 1.5 g of (4-bromo-2-tert-butylphenyl)ethylisobutylamine are obtained in the form of an oil (yield=30%).
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH3:17])([CH3:16])[N:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:11]=2[CH:24]=1)([OH:6])=[O:5]>C(OCC)C.O1CCCC1>[CH3:3][O:5][C:4]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH3:17])([CH3:16])[N:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:11]=2[CH:24]=1)=[O:6]
Reactant: C=[N+]=[N-]
Reactant: CC1(C)N=C(c2ccccn2)c2cc(C(=O)O)ccc2O1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)C(c1ccccn1)=NC(C)(C)O2

Procedure:
A solution of diazomethane in diethyl ether was added to a solution of Compound 113 (0.70 g) in tetrahydrofuran (5 ml) at room temperature until the starting material disappeared. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 6-methoxycarbonyl-2,2-dimethyl-4-(2-pyridyl)-2H-1,3-benzoxazine (0.49 g) (Compound 6).
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.Br[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1C.C(=O)([O-])[O-].[K+].[K+].II.[OH-].[K+]>[Cu].O.C1(C)C=CC=CC=1>[CH3:11][C:12]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:1]=1[NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(Br)c(C)c1
Reactant: O=CNc1ccccc1
Agent: [Cu]
Agent: II
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(Nc2ccccc2)c(C)c1
Temperature: 170 °C

Procedure:
12.1 g (0.1 mol) of formanilide, 22.1 g (0.11 mol) of 2-bromo-5-methoxytoluene of the formula (101), 13.8 g (0.1 mol) of anhydrous potassium carbonate, 2.0 g (0.0079 mol) of iodine and 1.6 g (0.025 mol) of copper powder are initially placed in a 100 ml sulfonating flask fitted with an anchor stirrer, thermometer, condenser and oil bath, and the mixture is stirred. It is heated to 170° C. and then stirred at 170° C. for 22 hours, to give a black melt. This melt is then cooled to 80° C., a little toluene is added, and the solution is filtered. The residue is rinsed with toluene. The toluene filtrate is distilled with steam spray (distillate: water/toluene/unreacted 2-bromo-5-methoxytoluene) to leave a residue which comprises a mixture of black oil and water. The black oil is boiled under reflux for 25 hours with 250 g of 50% potassium hydroxide solution. The product obtained is extracted with toluene and washed with hot water. The toluene phase is dried over sodium sulfate, filtered and concentrated. The residue which remains comprises 17.0 g of the compound of the formula ##STR12## as black crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:6]([CH3:7])[CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[NH2:17].C(N(CC)CC)C.[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>>[CH3:1][C:2]1[CH:6]([CH3:7])[CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[NH:17][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: CC1=CC(C)C(C)=C1c1cc(C)cc(C)c1N
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: CC1=CC(C)C(C)=C1c1cc(C)cc(C)c1NC(=O)C(C)(C)C

Procedure:
The same experiment as in Example 49 was performed using 0.600 g (2.64 mmol) of 2-(2,3,5-trimethylcyclopenta-1,4-dienyl)-4,6-dimethylphenylamine, 0.321 g (3.17 mmol) of triethylamine, and 0.382 g (3.17 mmol) of pivaloyl chloride (0.727 g, 89%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][OH:6].[CH2:8](CS([O-])(=O)=O)[CH2:9][CH:10]([CH2:12][CH2:13][CH2:14][CH:15]([CH2:17][CH2:18][CH2:19][CH:20]([CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH3:21])[CH3:16])[CH3:11]>>[CH2:8]([O:6][CH2:5][CH2:4][CH2:3][OH:7])[CH2:9][CH:10]([CH2:12][CH2:13][CH2:14][CH:15]([CH2:17][CH2:18][CH2:19][CH:20]([CH2:22][CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])[CH3:21])[CH3:16])[CH3:11]
Reactant: OCCCO
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCCS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOCCCO
Temperature: 60 °C
Reaction time: 4 h
Yield: 87.6 %

Procedure:
Sodium hydride was added carefully to a solution of 1,3-propanediol (7.6 g, 100 mmol) in anhydrous N,N-DMF (30 mL). Phytanylmethanesulfonate (1.5 g, 4 mmol) was added and the mixture was heated to 60° C. and stirred for 4 h. The reaction mixture was then poured into ice/H2O, extracted with dichloromethane, dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using 20% ethyl acetate/hexanes to give 3-(phytanyloxy)propan-1-ol (1.25 g, 87% yield)
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][NH2:10])[CH:4]=[C:5]([CH3:7])[N:6]=1.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[CH2:19][CH2:20][CH:21]=O>>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[CH2:19][CH2:20][CH:21]1[NH:10][CH2:9][CH2:8][N:3]2[C:2]([CH3:1])=[N:6][C:5]([CH3:7])=[C:4]12
Reactant: Cc1cn(CCN)c(C)n1
Reactant: O=CCCc1ccc(Cl)cc1Cl
Product: Cc1nc(C)n2c1C(CCc1ccc(Cl)cc1Cl)NCC2

Procedure:
Prepared according to the previously described general procedure (GP11) by reaction of 2-(2,4-dimethyl-imidazol-1-yl)-ethylamine with 3-(2,4-dichloro-phenyl)-propionaldehyde. LC-MS: tR=0.64 min.; [M+H]+=324 g/mol.
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:6]([Cl:26])=[CH:7][C:8]([NH:19][CH2:20][C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)=[C:9]([CH:18]=1)[C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])(=[O:4])=[O:3].[CH3:27][O:28][C:29](=[O:39])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37]Cl)=[O:35].C1CN2C(=NCCC2)C1.C(#N)C>ClCCl>[Cl:26][C:6]1[CH:7]=[C:8]([NH:19][CH2:20][C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)[C:9]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:15])[Cl:16])=[O:11])=[CH:18][C:5]=1[S:2]([NH:1][CH2:37][O:36][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][C:29]([O:28][CH3:27])=[O:39])(=[O:3])=[O:4]
Reactant: COC(=O)CCCCC(=O)OCCl
Reactant: NS(=O)(=O)c1cc(C(=O)OCC(Cl)(Cl)Cl)c(NCc2ccco2)cc1Cl
Agent: C1CN=C2CCCN2C1
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)CCCCC(=O)OCNS(=O)(=O)c1cc(C(=O)OCC(Cl)(Cl)Cl)c(NCc2ccco2)cc1Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2,2,2-trichloroethyl 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoate (0.060 mole), chloromethyl 6-methoxy-6-oxohexanoate (0.060 mole), DBN (1,5-diazabicyclo[4.3.0]non-5-ene, Aldrich) (0.060 mole) and dry acetonitrile (100 mL) is stirred at ambient temperature for 10 hours. The reaction mixture is diluted with dichloromethane (200 mL) and extracted with sodium bicarbonate solution, washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which is purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give methyl 6-(2-chloro-4-[(2-furanylmethyl)amino]-5-(2,2,2-trichloroethoxycarbonyl)phenylsulfonamidomethoxy)(6-oxo)hexanoate.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=3)[CH:9]=2)[N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:3]=1.C(N(C(C)C)CC)(C)C.[Br:39][CH2:40][C:41](Cl)=[O:42]>O1CCCC1>[CH2:16]([N:14]1[CH:15]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:3]=[C:2]3[NH:1][C:41](=[O:42])[CH2:40][Br:39])[N:12]=[N:13]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(-c3cn(Cc4ccccc4)nn3)ccc21
Reactant: O=C(Cl)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(NC(=O)CBr)c2cc(-c3cn(Cc4ccccc4)nn3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of Example 64A (500 mg, 1.28 mmol) in tetrahydrofuran (12 mL) was added diisopropylethylamine (0.22 mL, 1.28 mmol). The reaction mixture was stirred at ambient temperature for about 15 minutes then 2-bromoacetyl chloride (0.11 mL, 1.2 mmol) was added. The reaction mixture was stirred at ambient temperature for about 16 hours then additional 2-bromoacetyl chloride (0.11 mL, 1.2 mmol) was added. The reaction mixture was stirred for an additional 15 minutes then concentrated under reduced pressure to provide the title compound as a brown solid. This material was used without further purification.
Reaction SMILES: [CH2:1]([C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19]C(=O)OCCC)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[OH-].[K+]>C(O)COCCO.O>[CH2:1]([C@H:7]1[CH2:8][CH2:9][C@H:10]([C:13]2[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)[CH2:11][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCC[C@H]1CC[C@H](c2ccc(NC(=O)OCCC)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: C=CCCCC[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 3.33 g of crude propyl p-[trans-4-(5-hexenyl)cyclohexyl]phenylcarbamate and 150 ml of a 10 percent solution of potassium hydroxide in diethylene glycol/water (vol. 4:1) was boiled at 120° C. for 2 hours, then cooled to room temperature and partitioned between 150 ml of methylene chloride and 150 ml of water. The aqueous phase was back-extracted twice with 150 ml of methylene chloride each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the brown, crystalline residue (3 g) on 70 g of silica gel with ethyl acetate/petroleum ether (vol. 20:80) gave 2.18 g (88%) of p-[trans-4-(5-hexenyl)cyclohexyl]aniline as light yellowish crystals (purity 98.1%); Rf value 0.20 (ethyl acetate/petroleum ether vol. 1:5).
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([F:26])=[CH:20][C:19]=3[OH:27])(O)[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.S(Cl)(Cl)=O.C(O)(=O)C>ClC(Cl)C.[Zn]>[C:29]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([F:26])=[CH:20][C:19]=3[OH:27])[C:9]2=[O:28])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1cc(C2(O)C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)c(O)cc1F
Agent: [Zn]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cc(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)c(O)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.3 %

Procedure:
To a solution of 1-(diphenylmethyl)-3-(4-fluoro-2-hydroxy-5-methoxyphenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one (6.60 g, 14.5 mmol) in dichloroethane (100 mL) were added triethylamine (4.55 g, 45.0 mmol) and thionyl chloride (3.57 g, 30.0 mmol) at 0° C. The reaction mixture was heated at reflux for 1 h. The reaction mixture was cooled down to ambient temperature and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (100 mL) and acetic acid (10 mL) and zinc dust (6.54 g, 100.0 mmol) were added in small portions at ambient temperature. The reaction mixture was stirred at ambient temperature for 16 h and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography with a 20% to 80% gradient of ethyl acetate in hexanes to afford 1-(diphenylmethyl)-3-(4-fluoro-2-hydroxy-5-methoxyphenyl)-1,3-dihydro-2H-indol-2-one (1.10 g, 17%) as a colorless solid: MS (ES+) m/z 440.2 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][OH:9])[N:3]=[CH:2]1.CCN(CC)CC.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl>[Si:21]([O:9][CH2:8][CH2:7][CH2:6][C:4]1[N:3]=[CH:2][O:1][CH:5]=1)([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22]
Reactant: OCCCc1cocn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCc1cocn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a sol. of 3-oxazol-4-yl-propan-1-ol (1.14 g, 8.96 mmol) in dry CH2Cl2 (25 mL) at 0° C. were added Et3N (3.12 mL, 22.4 mmol) and TBDMS-Cl (2.02 g, 13.4 mmol). The reaction mixture was stirred at rt overnight, and the mixture was concentrated under reduced pressure. The residue was diluted in Et2O, and the mixture was washed with water. The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane/Et2O; 30:1→1:1) yielded the title compound (1.84 g, 85%). LC-MS: tR=1.06, ES+: 242.28.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.C([Li])(C)(C)C.[CH3:26][C:27]([CH3:29])=[O:28].O>O1CCCC1>[CH:12]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:27]([OH:28])([CH3:29])[CH3:26])[CH:3]=[C:4]2[CH:10]=[CH:9]1)([CH3:14])[CH3:13]
Reactant: CC(C)=O
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(C)(C)O)cnc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To 5-bromo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (2, 2.0 g, 5.66 mmol, prepared as described in Example 4) in tetrahydrofuran (20.0 mL), cooled in a −78° C. acetone/dry ice bath, under an atmosphere of nitrogen, was added tert-butyllithium (1.7 M in tetrahydrofuran, 7.3 mL, 12 mmol) dropwise. After 20 minutes, acetone (0.830 mL, 11 mmol) was added dropwise to the reaction. The reaction was stirred for 30 minutes at −78° C. and then allowed to reach room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane to give the compound (9, 1.30 g, 69%). MS (ESI) [M+H+]+=333.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[CH:3]=[CH:2]1.Cl.O.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=O.Cl>CO>[N:12]1([C:3]2[C:4]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[NH:1][CH:2]=2)[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]1
Reactant: O=C1CCCCN1
Reactant: c1cnc2cc[nH]c2c1
Agent: Cl
Solvent: CO
Solvent: O
Product: C1=CCN(c2c[nH]c3cccnc23)CC1

Procedure:
To a stirred solution of Na (2.53 g, 110 mmol, 11 eq) in absolute methanol (50 ml) at room temperature was added the appropriate pyrrolopyridine (10.00 mmol) and piperidone monohydrate hydrochloride (4.60 g, 30.0 mmol, 3.0 eq). The resultant mixture was then heated at reflux under nitrogen for 2-24 hours depending on the substrate. The resultant reaction mixture was cooled, and concentrated hydrochloric acid (37%, 9.0 ml, 110 mmol) wasadded dropwise with vigorous stirring. The resultant mixture was then evaporated under reduced pressure, and the residual slurry placed in water(50 ml). This aqueous mixture was extracted with ethyl acetate (5×50 ml), and these extracts were combined, dried (Na2SO4), and evaporated under reduced pressure. The residue was either triturated directly or column chromatographed using silica gel (approximately 100 g) and elution with the appropriate solvent system yielding the desired 3-(1,2,5,6-tetrahydropyridyl)pyrrolopyridine, one of Compounds 1a-1m or compound 2, 3a, 3b, 3c or 4.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[C:13](I)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[CH2:22]([O:24]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:23]>>[F:21][C:18]([F:19])([F:20])[C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][NH:8][CH2:9]2)=[CH:14][C:13]=1[C:22](=[O:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(I)c(C(F)(F)F)cc2C1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Product: CC(=O)c1cc2c(cc1C(F)(F)F)CNC2

Procedure:
Prepared in analogy to Example A47 from 5-iodo-6-trifluoromethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A35(d)) and 1-ethoxyvinyltributylstannane. White solid. MS (m/e): 230.3 ([M+H]+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=3)[NH2:12])[O:8][C:4]=2[CH:3]=1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19].O>N1C=CC=CC=1>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([NH:12][C:21]([NH:20][CH2:18][CH3:19])=[O:22])[CH:13]=[CH:14][CH:15]=3)[O:8][C:4]=2[CH:3]=1
Reactant: Nc1cccc(-c2nc3ccc(Br)cc3o2)c1
Reactant: CCN=C=O
Solvent: O
Solvent: c1ccncc1
Product: CCNC(=O)Nc1cccc(-c2nc3ccc(Br)cc3o2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
To a solution of 3-(6-bromobenzoxazol-2-yl)aniline (Compound of Example 267) (925 mg) in pyridine (15 ml) was added ethyl isocyanate (680 mg) at room temperature, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with 1 N hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate and water, successively, and dried over MgSO4. The solvent was distilled off under reduced pressure, and the resulting crystals were collected by filtration to obtain N-[3-(6-bromobenzoxazol-2-yl)phenyl]-N′-ethylurea (986 mg, 86%).
Reaction SMILES: C([O:5][C:6](/[CH:8]=[CH:9]/[C:10]1[N:18]([CH3:19])[C:17]2[C:16](=[O:20])[N:15]([CH3:21])[C:14](=[O:22])[N:13]([CH3:23])[C:12]=2[N:11]=1)=[O:7])(C)(C)C.[OH-].[Na+]>CN(C=O)C.O>[C:6](/[CH:8]=[CH:9]/[C:10]1[N:18]([CH3:19])[C:17]2[C:16](=[O:20])[N:15]([CH3:21])[C:14](=[O:22])[N:13]([CH3:23])[C:12]=2[N:11]=1)([OH:7])=[O:5]
Reactant: Cn1c(=O)c2c(nc(/C=C/C(=O)OC(C)(C)C)n2C)n(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(/C=C/C(=O)O)n2C)n(C)c1=O
Yield: 49 %

Procedure:
8-(trans-2-tert-Butyloxycarbonylvinyl)-1,3,7-trimethylxanthine (76 mg, 238 μmol) was dissolved in 3 ml TFA and stirred for 1 h. After evaporation, the residue was triturated with ether to provide the pure product 8-(trans-2-Carboxyvinyl)-1,3,7-trimethylxanthine (55 mg, 88% yield). mp: 278d °C. 1H NMR DMSO-d6 : d 3.27 (s, 3H, NCH3), 3.44 (s, 3H, NCH3), 4.02 (s, 3H N7CH3), 6.78 (d, 1H, J=15.4 Hz), 7.55 (d, 1H, J=15.4 Hz), 8.4 (br s, 1H, COOH). MS (CI NH3) m/e 265 (MH+). Alternatively, compound 8-(trans-2-Carboxyvinyl)-1,3,7-trimethylxanthine was prepared from 8-(trans-2-tert-Butyloxycarbonylvinyl)-1,3,7-trimethylxanthine in DMF/water (1:1) solution by saponification with sodium hydroxide in 49% yield.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CN(C)C=O.[C:12]([O:16][C:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=C2)=[O:18])([CH3:15])([CH3:14])[CH3:13].O1CCCC1>ClCCl>[C:12]([O:16][C:17]([C:19]1[CH:27]=[C:26]2[C:25](=[CH:21][CH:20]=1)[NH:24][CH:23]=[C:2]2[CH:1]=[O:5])=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)c1ccc2[nH]ccc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc2[nH]cc(C=O)c2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
0.4 ml (4.87 mmol) oxalylchloride are dissolved in a three-neck flask under nitrogen in 15 ml absolute dichloromethane and cooled to 0° C. Thereafter, 0.4 ml absolute dimethylformamide dissolved in 15 ml absolute dichloromethane is added. The mixture is stirred on ice cooling for 20 minutes, gas generation and the formation of a colorless precipitate being observed. Then, 1.00 g (4.64 mmol) tert-butylindole-5-carboxylate is added and the reaction mixture is allowed to heat to room temperature. Stirring is continued for another 20 min, the suspension is transferred using tetrahydrofurane to a round flask and concentrated on a rotary evaporator. The residue is taken up in 40 ml tetrahydrofurane, mixed with 50 ml 20% sodium acetate solution and heated under reflux for 30 minutes. After cooling down, 30 ml 5% sodium hydrogen carbonate solution are added, extracted three times using ethyl acetate, the volume of the combined organic phases is concentrated to about 150 ml and washed with saturated NaCl solution. The organic phase is dried on sodium sulfate and the solvent is removed on the rotary evaporator. Recrystallization of the crude product from n-hexane/ethyl acetate supplies the product as a solid.
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH2:27][N:26]3[CH:34]=[CH:35][CH:36]=[C:25]3[CH2:24]2)=[O:22])=[C:17]([Cl:37])[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:37][C:17]1[CH:16]=[C:15]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:20]=[CH:19][C:18]=1[C:21]([N:23]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH2:27][N:26]2[CH:34]=[CH:35][CH:36]=[C:25]2[CH2:24]1)=[O:22]
Reactant: OB(O)c1cccc2ccccc12
Reactant: O=C(c1ccc(Br)cc1Cl)N1Cc2cccn2Cc2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-c2cccc3ccccc23)cc1Cl)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C

Procedure:
1-Naphthaleneboronic acid (0.52 g, 3.00 mmol) was added to a mixture of (4-bromo-2-chlorophenyl)-(5H, 11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone of Step A (1.27 g, 3.15 mmol) and sodium carbonate (0.53 g, 4.98 mmol) in toluene (22.5 mL), ethanol (4.5 mL) and water (9 mL). The resultant solution was purged with nitrogen for 10 minutes, then tetrakis(triphenylphosphine)palladium (0.18 g, 0.06 mmol) was added. The reaction mixture was heated to reflux for 76 hours. The solution was cooled to ambient temperature, then filtered through a pad of Celite, which was subsequently rinsed with ethyl acetate. The combined filtrate was diluted to 100 mL water/ethyl acetate (1:1). The aqueous layer was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to yield a brown oil. Purification by flash chromatography on silica gel eluting with hexane-ethyl acetate (5:1) resulted in a white solid which was dried under vacuum (0.62 g), m.p. 115–117.5° C.