Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH:23]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH3:30])[C:24]3=[O:31])[CH:20]=2)[N:15]([CH2:32][CH2:33][CH3:34])[CH:14]=1)[C:6](O)=[O:7].Cl.CN(C)CCCN=C=NCC.[CH3:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[S:54]([NH2:57])(=[O:56])=[O:55].Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH:23]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH3:30])[C:24]3=[O:31])[CH:20]=2)[N:15]([CH2:32][CH2:33][CH3:34])[CH:14]=1)[C:6]([NH:57][S:54]([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[CH3:47])(=[O:55])=[O:56])=[O:7]
Reactant: CCCN1CCC(Cc2ccc3c(c2)c(Cc2ccc(C(=O)O)cc2OC)cn3CCC)C1=O
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCN1CCC(Cc2ccc3c(c2)c(Cc2ccc(C(=O)NS(=O)(=O)c4ccccc4C)cc2OC)cn3CCC)C1=O
Reaction time: 18 h
Yield: 95.2 %

Procedure:
A mixture of 3-methoxy-4-[1-propyl-5-(1-propyl-2-oxopyrrolidin-3-ylmethyl)indol-3-ylmethyl]-benzoic acid (0.3 g), 4-dimethylaminopyridine (0.095 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.149 g), and 2-methylbenzenesulfonamide (0.122 g) was dissolved in methylene chloride (10 ml), and the solution was stirred under a nitrogen atmosphere for 18 h. The mixture was poured into 1M hydrochloric acid, extracted with ethyl acetate (twice), and the extract washed with 1M hydrochloric acid, water, and brine. The dried (MgSO4) solution was evaporated and the residue precipated from a mixture of methanol and lM hydrochloric acid to give 3-methoxy-N-(2-methylphenylsulfonyl)-4-[1-propyl-5-(1-propyl-2-oxopyrrolidin-3-ylmethyl)indol-3-ylmethyl]-benzamide (0.38 g, 95%) as an off-white solid; mp 98-115°.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:20][CH3:21])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>>[CH2:13]([O:12][C:10]1[C:9]([O:20][CH3:21])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([N:1]=[CH:24][N:25]([CH3:27])[CH3:26])[CH:11]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cc(OC)c(OCc2ccccc2)cc1N
Reactant: COC(OC)N(C)C
Product: COC(=O)c1cc(OC)c(OCc2ccccc2)cc1N=CN(C)C
Temperature: 100 °C

Procedure:
A stirred mixture of 70.0 g (244 mmol) of methyl 2-amino-4-benzyloxy-5-methoxybenzoate (Phytochemistry 1976, 15, 1095) and 52 ml of dimethylformamide dimethyl acetal was heated at 100° C. for 1.5 h, cooled, and evaporated directly under high vacuum to give 81.3 g of off-white solid, mp 134-140° C.; NMR (CDCl3) d 3.01 (s, Me2N).
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:13]3[CH2:15][CH:16]([CH3:19])[CH2:17][CH2:18][C:12]=3[C:11]([CH3:21])([CH3:20])[O:10][C:9]=2[CH:8]=[C:7]([CH:22]([CH3:30])[CH:23]([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:6]=1)(=[O:3])[CH3:2].C(Cl)(Cl)Cl.C(O)(=[O:37])C>>[C:1]([O:4][C:5]1[C:14]2[C:13]3[CH2:15][CH:16]([CH3:19])[CH2:17][C:18](=[O:37])[C:12]=3[C:11]([CH3:20])([CH3:21])[O:10][C:9]=2[CH:8]=[C:7]([CH:22]([CH3:30])[CH:23]([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCCCCC(C)C(C)c1cc(OC(C)=O)c2c(c1)OC(C)(C)C1=C2CC(C)CC1
Reactant: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCCCCC(C)C(C)c1cc(OC(C)=O)c2c(c1)OC(C)(C)C1=C2CC(C)CC1=O

Procedure:
To a stirring mixture of 1-acetoxy-3-(1,2-dimethylheptyl)-7,8,9,10-tetrahydro-6,6,9-trimethyl-6H-dibenzo[ b,d]pyran (5.21 g., 12.6 mmole) in 35 ml. of 50% acetic acid and 10 ml. of chloroform under a nitrogen atmosphere, was added dropwise a solution of ceric ammonium nitrate (27.63 g., 50.4 mmole) in 70 ml. of 50% acetic acid. After the addition was complete, the reaction mixture was stirred over a steam bath. After 3 hours the mixture was poured onto ice with stirring. It was extracted into ether and the organic solvents were removed under reduced pressure. The residue was again taken up in ether, washed to neutrality with 5% NaHCO3, washed with water and dried over Na2SO4. Evaporation of the solvents in vacuo left 8.34 g. (23%) of crude product whose tlc showed a blue fluorescent spot (silica gel, Rf 0.66, 1:1 EtOAc/hexane).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:3]=1.[C:14](OCC)(=[O:19])[CH2:15][C:16]([CH3:18])=O.C(OCC)(=O)C>C(O)(=O)C>[CH3:1][C:2]1[C:6]2[C:5](=[N:7][C:14]([OH:19])=[CH:15][C:16]=2[CH3:18])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:3]=1
Reactant: Cc1cc(N)n(-c2ccccn2)n1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(O)nc2c1c(C)nn2-c1ccccn1
Temperature: 25 °C
Yield: 63.1 %

Procedure:
A solution of 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-amine (5.1 g, 29 mmol) and ethyl acetoacetate (3.8 g, 30 mmol) in acetic acid (14 mL) was stirred at 100° C. for 4 hours. The solution was cooled to room temperature and ethyl acetate was added thereto. The resulting crude crystals were collected by filtration, and recrystallized from ethanol to give the title compound (4.4 g, 62% yield).
Reaction SMILES: [C:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:14]=2[CH:15]=1)(=[O:3])[CH3:2].[CH3:22][Mg]Br>C1COCC1>[F:10][C:9]1[C:4]([C:1]([OH:3])([CH3:22])[CH3:2])=[C:5]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:14]=3[CH:15]=2)[CH:6]=[N:7][CH:8]=1
Reactant: CC(=O)c1c(F)cncc1-c1cc2cc(C#N)ccc2o1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(O)c1c(F)cncc1-c1cc2cc(C#N)ccc2o1
Temperature: -78 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
To 2-(4-acetyl-5-fluoropyridin-3-yl)benzofuran-5-carbonitrile 11b (200 mg, 0.714 mmol) in THF (3.57 mL) at −78° C. was added methylmagnesium bromide (3M in Et2O, 0.714 mL, 2.142 mmol). The mixture was stirred for 1 hr at −78° C., and then for 1 hr at 0° C. The mixture was quenched with saturated NH4Cl and extracted with EtOAc two times, dried over magnesium sulfate, filtered and concentrated. The residue was purified via Biotage (10-40% EtOAc/heptane; SNAP25 column), and then purified on Waters mass directed preparative-HPLC (ACN—H2O—NR4OH, Xbridge Preparation C18 column, 30×100 mm) giving the title compound 11 (60 mg, 28%). 1H NMR (400 MHz, MeOD) δ ppm 1.70 (d, J=1.96 Hz, 6H) 6.94 (s, 1H) 7.55-7.71 (m, 2H) 8.00-8.11 (m, 1H) 8.39 (s, 1H) 8.53 (d, J=3.73 Hz, 1H). LC-MS (M+1) 297.1, t=1.50 min.
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].O1CCCC1.[H-].[Na+].[Br:12][C:13]1[CH:14]=[CH:15][C:16](Cl)=[N:17][CH:18]=1>O>[F:1][CH2:2][CH2:3][O:4][C:16]1[CH:15]=[CH:14][C:13]([Br:12])=[CH:18][N:17]=1
Reactant: OCCF
Reactant: Clc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: FCCOc1ccc(Br)cn1
Reaction time: 0.08 h
Yield: 40.4 %

Procedure:
2-Fluoroethanol (259 mg, 3.90 mmol) was added to a solution of anhydrous tetrahydrofuran (10 mL) containing sodium hydride (NaH 60%, 94 mg, 3.90 mmol) under nitrogen, stirred for 5 minutes, and 5-bromo-2-chloropyridine (96, 500 mg, 2.59 mmol) was added thereto and stirred at room temperature for 3 hours. Water was added to the reaction mixture and organic compounds were extracted with ethyl acetate and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 2-(2-fluoroethoxy)-5-bromopyridine (97b, 230 mg, 40%).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[CH:11][CH:12]=2)[C:7]1=[O:29])C.[Li+].[OH-]>CO>[C:25]([O:24][C:22]([N:19]1[CH2:18][CH2:17][N:16]([C:10]2[CH:9]=[C:8]3[C:13]([CH2:14][CH2:15][N:6]([CH2:5][C:4]([OH:30])=[O:3])[C:7]3=[O:29])=[CH:12][CH:11]=2)[CH2:21][CH2:20]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)CN1CCc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)C(=O)N(CC(=O)O)CC3)CC1

Procedure:
Ethyl [7-(4-t-butoxycarbonylpiperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone-2-yl]acetate (1-4) (2.9 g, 6.95 mmol), 1N LiOH (20.9 mL, 20.9 mmol) and MeOH (50 mL) were stirred for 16 hours at room temperature. The solvent was removed, the residue was taken up in EtOAc and washed with 1N HCl. Repeated extraction of the aqueous phase followed by washing of the bulked organic layers with brine (5 mL), drying (MgSO4) and evaporation afforded 1-5 as a solid. 1H NMR (CD3OD): d1.48 (9H, s), 2.99 (2H, t), 3.20 (4H, m), 3.62 (6H, m), 4.31 (2H, s), 7.22 (2H, s), 7.60 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]=[O:16])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C[Si](C)(C)[C:19]([F:22])([F:21])[F:20].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.COC(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]([OH:16])[C:19]([F:22])([F:21])[F:20])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C=O)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(Br)cc(C(O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 3-bromo-5-formylbenzoate (Merck patent case No. 22407 PV; 5.7 g, 20.0 mmol) in THF (133 mL) at 0° C. were added trimethyl(trifluoromethyl)silane (4.44 mL, 30.0 mmol) and activated 4 Å molecular sieves. Tetrabutylammonium fluoride (1.0 M in THF; 6.0 mL, 6.0 mmol) was added dropwise. The reaction mixture was warmed to ambient temperature. After 3 h, aqueous 1N HCl (25 mL) and tert-butyl methyl ether (100 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12]([CH2:17][OH:18])=[CH:11]3)[CH:5]=[CH:6][CH:7]=1.[C:19](Cl)(=[O:21])[CH3:20]>>[C:19]([O:18][CH2:17][C:12]1[NH:13][C:14]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[CH:16][CH:15]=2)(=[O:21])[CH3:20]
Reactant: Cc1cccc(-c2ccc3[nH]c(CO)cc3c2)c1
Reactant: CC(=O)Cl
Product: CC(=O)OCc1cc2cc(-c3cccc(C)c3)ccc2[nH]1

Procedure:
A mixture of (5-bromo-1H-indol-2-yl) methanol (9 g, 39.8 mmol), 3-methylbenzeneboronic acid (6.14 g, 43.78 mmol), potassium carbonate (13.75 g, 99.5 mmol), palladium(II) acetate (0.045 g) and tetrabutylammonium bromide (12.84 g, 39.8 mmol) in 10% dioxane in water (degassed, 0.38 L) was stirred at 70° C. The reaction was monitored by TLC. Additional 3-methylbenzeneboronic acid (5.6 g, 39.8 mmol) was added. After no 5-bromo-1-(4-tert-butylbenzyl)-1H-indole was detected by TLC, the reaction was cooled to room temperature and the solvent was decanted. The residual thick oil was stirred with hexane. The hexane was decanted and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was separated, washed with water filtered and concentrated. The residue was purified by flash column chromatography using hexane/ethyl acetate (55:45) as an eluant to give [5-(3-Methylphenyl)-1H-indol-2-yl]methanol as a brown solid (6.0 g). Reaction of [5-(3-Methylphenyl)-1H-indol-2-yl]methanol with acetyl chloride according to the procedure described in step 4 of Example 1 afforded the title compound as an oil (3.94 g); Mass spectrum (ESI, [M−H]−) m/z 278. 1H NMR (400 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.46 (s, 1H), 7.42-7.36 (m, 3H), 7.30 (s, 1H), 7.10 (d, 1H, J=7.48 Hz), 6.50 (s, 1H), 2.37 (s, 3H), and 2.07 ppm (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH3:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH2:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1.S(Cl)(Cl)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:19]2[CH2:20][CH2:21][CH2:22][C@H:18]2[CH2:17][N:13]2[CH2:14][CH2:15][CH2:16][C@H:12]2[CH3:11])=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Solvent: O=S(Cl)Cl
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(Br)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C using commercially available 4-bromo benzoic acid, 2-(R)-methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine, and thionyl chloride in place of oxalyl chloride. (MS (ES+) 352.3 (M+H)+
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:42][CH:43]1[CH2:48][CH2:47][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:45][CH2:44]1>ClCCl>[CH2:1]([O:8][CH2:9][C:10]([NH:42][CH:43]1[CH2:48][CH2:47][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:45][CH2:44]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)COCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COCc1ccccc1)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.4 %

Procedure:
2.00 g (12.0 mmol) of benzyloxyacetic acid was dissolved in 40 mL of dichloromethane and 2.77 g (14.4 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 2.21 g (14.4 mmol) of 1-hydroxybenzotriazole 1 hydrate, 2.52 mL (18.1 mmol) of triethylamine and 2.52 g (13.2 mmol) of 4-amino-1-benzylpiperidine were added thereto under ice-cooling, followed by stirring of the mixture at room temperature for 18 hours. Dichloromethane was added to the reaction mixture and the mixture was washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated NaCl solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel chromatography (eluting solvent: ethyl acetate/methanol=100/0-90/10) to obtain 2.82 g (yield: 69%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[C:9](O)=[CH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=O)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(O)COCCO>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]2[C:8]3[C:9](=[CH:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[CH:17]=3)[NH:23][N:22]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccc(Cl)cc1)c1cc2ccccc2cc1O
Solvent: OCCOCCO
Solvent: O
Product: Clc1ccc(-c2n[nH]c3cc4ccccc4cc23)cc1

Procedure:
A solution of 37 g. of the 3-(p-chlorobenzoyl)-2-naphthol of Step 2, above, in a mixture of 300 ml. of diethylene glycol and 75 ml. of hydrazine hydrate is refluxed for 4 hours. It is then cooled and poured on ice-water to yield a precipitate which is collected by filtration. This solid is crystallized from a mixture of methylene chloride (dichloromethane) and ether (1:3) to yield the title product, m.p. 192°.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][CH2:9][N:10]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:11](=[O:22])[NH:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].I[CH:49]([CH3:51])[CH3:50]>CC(C)=O>[CH:49]([O:17][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([NH:12][C:11]([N:10]([CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:22])[CH:14]=1)([CH3:51])[CH3:50]
Reactant: CC(C)I
Reactant: O=C(O)c1cccc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CC(C)OC(=O)c1cccc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)c1
Yield: 99 %

Procedure:
200 mg (0.41 mmol, 1 eq.) of product of Example 45 are dissolved in 2 mL of acetone and 2 mL of dry DMF under argon. 283 mg (2.05 mmol, 5 eq.) of K2CO3 and 328 μL (3.28 mmol, 8 eq.) of 2-iodopropane, the mixture is heated under reflux for 2 hours. The medium is then concentrated and taken up in water and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water then brine, dried over MgSO4, filtered and concentrated. The oil obtained is freed from DMF by entraining the DMF to the rotary evaporator with ethyl acetate, then dried with a vane pump. The product is obtained in the form of white crystals (m=214 mg, yield=99%).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:21]3[C:20](=[O:22])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=[O:23])[C:12]=3[C:11](Br)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:35]=[CH:34][C:29]([NH:30][C:31](=[O:33])[CH3:32])=[CH:28][CH:27]=1>N1C=CC=CC=1>[CH:1]1([NH:7][C:8]2[C:21]3[C:20](=[O:22])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=[O:23])[C:12]=3[C:11]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([NH:30][C:31]([CH3:32])=[O:33])=[CH:34][CH:35]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: O=C1c2ccccc2C(=O)c2c(NC3CCCCC3)ccc(Br)c21
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(Nc2ccc(NC3CCCCC3)c3c2C(=O)c2ccccc2C3=O)cc1

Procedure:
1-Nitroanthraquinone is refluxed with an excess of cyclohexylamine in o-dichlorobenzene to yield 1-cyclohexylamino anthraquinone which is further brominated in aqueous pyridine to yield the corresponding 1-cyclohexylamino-4-bromoanthraquinone. This compound is further condensed with p-amino acetanilide to yield 1-cyclohexylamino-4-(p-acetaminoanilino)anthraquinone as a bright green pleochroic dye having an optical order parameter 0.7.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].[Cl:9][C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[O:13][CH:14]([C:16]1[S:20][C:19]([N:21]=[C:22]=[O:23])=[N:18][N:17]=1)[CH3:15]>C1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[O:13][CH:14]([C:16]1[S:20][C:19]([NH:21][C:22](=[O:23])[N:5]([CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])[CH3:6])=[N:18][N:17]=1)[CH3:15]
Reactant: CC(Oc1cccc(Cl)c1)c1nnc(N=C=O)s1
Reactant: CNCC(OC)OC
Solvent: c1ccccc1
Product: COC(CN(C)C(=O)Nc1nnc(C(C)Oc2cccc(Cl)c2)s1)OC

Procedure:
4.9 grams (0.036 mole) of methylaminoacetaldehyde dimethylacetal was slowly added to a warm 30 milliliter benzene solution containing 10.2 grams (0.036 mole) of the 5-[1-(3-chlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer (prepared above). The resulting solution was refluxed for 15 minutes, cooled, topped on a roto-vac at 70° C. to 14.5 grams of a pink solid residue which was recrystallized from a minimum amount of ethylacetate/hexane solution. The fluffy precipitate was filtered off, and dried in a vacuum oven at 80° C. to 10.3 grams of fluffy white crystals of 3-[5-[1-(3-chlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl]-1-methyl-1-(2,2-dimethoxyethyl)urea. Melting point 127°-130° C.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[CH:12]([CH:13]=[CH2:14])[O:11]C(=O)[NH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>O1CCOCC1.O>[OH:11][C@H:12]([C@@H:8]([NH2:9])[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:13]=[CH2:14]
Reactant: C=CC1OC(=O)N[C@H]1CC1CCCCC1
Agent: [Ba+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=C[C@H](O)[C@@H](N)CC1CCCCC1

Procedure:
To the resultant 5S-diastereomer from Example 4 (2.06 g, 9.84 mmol) in dioxane (180 ml) and water (120 ml) was added barium hydroxide octahydrate (6.24 g, 19.8 mmol). The mixture was refluxed for 18 h, cooled, filtered, concentrated, taken up in water and extracted with ethyl acetate which was dried over Na2SO4 and evaporated to afford 1.64 9 (91%) of the desired product, m.p.: 59°-61° C.
Reaction SMILES: [CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1)[CH3:2].Cl[C:14]1[N:15]=[C:16]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[C:17]2[N:23]=[C:22]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]3)[CH:21]=[CH:20][C:18]=2[N:19]=1>>[CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]1[C:14]1[N:15]=[C:16]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[C:17]2[N:23]=[C:22]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]3)[CH:21]=[CH:20][C:18]=2[N:19]=1)[CH3:2]
Reactant: CCn1[nH]c2ccccc2c1=O
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: CCn1c(=O)c2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)ccc2n1

Procedure:
Following General Procedure C, 2-ethyl-1H-indazol-3(2H)-one and 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 were reacted to give 104. LCMS (MH+)=532.3. 1H-NMR (DMSO-d6): δ 8.39 (d, 1H), 8.09 (d, 1H), 7.82 (d, 1H), 7.78 (m, 1H), 7.70 (m, 1H), 7.33 (m, 1H), 4.54 (s, 4H), 4.32 (m, 2H), 4.00 (s, 1H), 3.85 (m, 4H), 3.68 (s, 2H), 2.90 (m, 2H), 1.97 (m, 2H), 1.64 (m, 2H), 1.29 (m, 2H), 1.16 (m, 1H), 1.07 (t, 3H), 1.03 (s, 6H)
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8]([CH2:11][NH:12][CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:24]=O.[OH-].[Na+]>O1CCOCC1>[C:1]([CH:5]1[CH2:10][CH2:9][C:8]([CH2:11][N:12]([CH3:24])[CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=O
Reactant: CC(C)(C)C1CC=C(CNCc2cccc3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(CC1=CCC(C(C)(C)C)CC1)Cc1cccc2ccccc12

Procedure:
0.8 g of N-(4-tert.butyl-1-cyclohexenylmethyl)-1-naphthylmethylamine are reacted with 13 ml of 1N NaH2PO3 -solution and brought into solution by the addition of 15 ml of dioxane. Following addition of 1.1 ml 37% formaline solution the mixture is warmed to 60° for 1/2 hour, made alkaline with caustic soda and extracted with ether. Following drying and evaporation of the organic phase the pure product is obtained as an oil.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=2[CH:6]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>C(OCC)(=O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([C:16]3[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=3)=[CH:6][C:5]=2[CH:7]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Clc1ccc2sc(Br)cc2c1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cc3cc(Cl)ccc3s2)cc1

Procedure:
The compound was prepared in the same manner as described in Preparation 48, Step B, from 2.06 g (8.32 mmol) 2-bromo-5-chlorobenzothiophene and 2.44 g (17.95 mmol) 4-methylbenzeneboronic acid and isolated by crystallization from ethyl acetate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([C:15]([N:17]([CH:31]([CH3:33])[CH3:32])[C@@H:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)=[O:16])[C:12]([CH3:14])=[CH:13][C:8]=2[O:7][C:6]([CH3:35])([CH3:34])[C:5]1=[O:36].C(N(CC)CC)C.[C:44](Cl)(=[O:46])[CH3:45]>O1CCCC1>[C:44]([NH:1][CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([C:15]([N:17]([CH:31]([CH3:32])[CH3:33])[C@@H:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:19]3)=[O:16])[C:12]([CH3:14])=[CH:13][C:8]=2[O:7][C:6]([CH3:34])([CH3:35])[C:5]1=[O:36])(=[O:46])[CH3:45]
Reactant: CC(=O)Cl
Reactant: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCN)C(=O)C(C)(C)O2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCCN1C(=O)C(C)(C)Oc2cc(C)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl (3R)-3-[{[4-(2-aminoethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (200 mg) were added triethyl-amine (0.040 ml), tetrahydrofuran (3 ml), acetyl chloride (0.04 ml) under ice-cooling, and the mixture was stirred at room temperature for one hour. After the reaction was complete, the mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to give the title compound (80 mg) as colorless amorphous.