Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]([CH2:44][C:45]([NH:47][C@H:48]([C:53](O)=[O:54])[CH2:49][CH:50]([CH3:52])[CH3:51])=[O:46])=[CH:36]1>CO>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH:9][C:53](=[O:54])[CH:48]([NH:47][C:45](=[O:46])[CH2:44][C:37]2[C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[NH:35][CH:36]=2)[CH2:49][CH:50]([CH3:52])[CH3:51])[CH2:5][CH2:4]1
Reactant: CC(C)C[C@H](NC(=O)Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CN(C)C1(c2ccccc2)CCC(N)CC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: CC(C)CC(NC(=O)Cc1c[nH]c2ccccc12)C(=O)NC1CCC(c2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The more polar diastereomer of (4-dimethylamino-4-phenyl-cyclohexyl)amine (143 mg, 0.66 mmole) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (272 mg, 0.98 mmole) were added to a solution of N-(3-indolylacetyl)-L-leucine (189 mg, 0.66 mmole) in MeOH and stirred for 24 h at room temperature. Working up was performed by removing MeOH by distillation. The residue was re-dissolved with water, adjusted to pH 11 with 5M NaOH and extracted with ethyl acetate. The organic phase was dried with Na2SO4 and then evaporated. The product was obtained as a colorless oil in a yield of 320 mg (100%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](Cl)=[N:9]2)=[N:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:9]2)=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)cc2n1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Product: Brc1cnc2ccc(N3CCOCC3)nc2c1
Temperature: 140 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
A mixture of 7-bromo-2-chloro-1,5-naphthyridine (F-31) (200 mg, 0.82 mmol, 1.0 eq) and morpholine (10 mL) was stirred in a sealed-tube at 140° C. overnight. The reaction mixture was cooled to RT, diluted with ethyl acetate (150 mL) and then washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the desired product 7-bromo-2-morpholino-1,5-naphthyridine (F-32) (180 mg, 74.7% yield). ESI-MS m/z: 294.01 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[C:15]3[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=2)[O:5][CH:6]=1>CO.[OH-].[OH-].[Pd+2]>[CH3:1][C:2]1[N:3]=[C:4]([C:7]2[C:15]3[C:14]([C:16]4[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=4)[NH2:22])=[N:13][CH:12]=[N:11][C:10]=3[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[CH:8]=2)[O:5][CH:6]=1
Reactant: Cc1coc(-c2cn(COCC[Si](C)(C)C)c3ncnc(-c4cccc([N+](=O)[O-])c4)c23)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1coc(-c2cn(COCC[Si](C)(C)C)c3ncnc(-c4cccc(N)c4)c23)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-methyl-2-(4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)oxazole (0.30 g, 0.66 mmol) in methanol (20 mL), was added Pd(OH)2 on carbon (300 mg, 10 wt. %). The flask was purged with hydrogen and was stirred for 4 hours at room temperature under hydrogen atmosphere (1 atm). The reaction was filtered, and concentrated in vacuo to afford crude 3-(5-(4-methyloxazol-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)aniline as a colorless oil. LRMS (ESI) calc'd for C22H28N5O2Si [M+H]+: 422, found 422.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7]([NH2:9])=[O:8])[CH3:2].Br[CH2:17][C:18](=O)[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7]2[O:8][CH:17]=[C:18]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[N:9]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: CCOc1ccc(C(N)=O)cc1OCC
Reactant: COC(=O)CCC(=O)CBr
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc(CCC(=O)OC)co2)cc1OCC
Temperature: 130 °C
Reaction time: 16 h

Procedure:
A 40 g quantity of 3,4-diethoxybenzamide and 80 g of methyl 5-bromo-4-oxopentanoate (containing about 35% of methyl 3-bromo-4-oxopentanoate) were added to 400 ml of dimethylformamide, and the mixture was stirred at 130° C. for 16 hours. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. Ethyl acetate (500 ml) and saturated sodium bicarbonate solution (500 ml) were gradually added with stirring, and stirring was continued. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:8 to 1:4) to give 18 g of white powdery methyl 3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]propionate.
Reaction SMILES: [N+:1]([C:4]1[CH:56]=[CH:55][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]4[NH:20][C:19]([CH:21]=[C:22]5[N:54]=[C:25]([C:26]([C:38]6[CH:43]=[CH:42][C:41]([O:44][C:45]7[CH:50]=[CH:49][C:48]([N+:51]([O-])=O)=[CH:47][CH:46]=7)=[CH:40][CH:39]=6)=[C:27]6[NH:37][C:30](=[CH:31][C:32]7[CH:33]=[CH:34][C:35]=3[N:36]=7)[CH:29]=[CH:28]6)[CH:24]=[CH:23]5)=[CH:18][CH:17]=4)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.Cl.O.O.Cl[Sn]Cl.N>C(Cl)(Cl)Cl.O>[NH2:1][C:4]1[CH:56]=[CH:55][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]4[NH:20][C:19]([CH:21]=[C:22]5[N:54]=[C:25]([C:26]([C:38]6[CH:43]=[CH:42][C:41]([O:44][C:45]7[CH:50]=[CH:49][C:48]([NH2:51])=[CH:47][CH:46]=7)=[CH:40][CH:39]=6)=[C:27]6[NH:37][C:30](=[CH:31][C:32]7[CH:33]=[CH:34][C:35]=3[N:36]=7)[CH:29]=[CH:28]6)[CH:24]=[CH:23]5)=[CH:18][CH:17]=4)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(-c3c4nc(cc5ccc([nH]5)c(-c5ccc(Oc6ccc([N+](=O)[O-])cc6)cc5)c5nc(cc6ccc3[nH]6)C=C5)C=C4)cc2)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: N
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1ccc(Oc2ccc(-c3c4nc(cc5ccc([nH]5)c(-c5ccc(Oc6ccc(N)cc6)cc5)c5nc(cc6ccc3[nH]6)C=C5)C=C4)cc2)cc1
Reaction time: 24 h
Yield: 66.9 %

Procedure:
To a solution of 5,15-bis-[4-(4-nitrophenoxy)phenyl]porphyrin (70 mg, 0.095 mmol) in CHCl3 (10 ml), saturated with concentrated HCl, SnCl2.2H2O (105 mg, 0.475 mmol) was added and the mixture was kept under magnetic stirring, at room temperature for 24 h, then cold water was added, the mixture was neutralized with a solution 15% of ammonia, and the organic phase was extracted, dried on Na2SO4, then the solvent was removed by evaporation. The crude product was purified by chromatography on silica gel (THF to THF/DMF 9/1), to give 43 mg of title product (yield 67%).
Reaction SMILES: [CH3:1][CH:2]([C:4](=[O:16])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[CH3:3].[H][H]>[Ni].C1COCC1>[NH2:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][C:4](=[O:16])[CH:2]([CH3:1])[CH3:3])=[CH:12][CH:11]=1
Reactant: CC(C)C(=O)CCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)C(=O)CCc1ccc(N)cc1

Procedure:
A mixture of 13.6 g (62 mmol) of 2-methyl-5-(4-nitro-phenyl)-pentan-3-one (Y. Huang, L. Shi, S. Li, Synthesis, 1988, 975-977), 400 mL of THF, and 2.6 g of Raney Nickel was shaken in a hydrogen atmosphere (24 p.s.i.) at 25° C. for 56 hours. The catalyst was filtered, and the filtrate was concentrated to give the title compound. 1H NMR (CDCl3) δ 1.01 (d, 6 H), 2.46-2.55 (m, 1 H), 2.65-2.83 (m, 4 H), 3.55 (br s , 2 H), 6.56 (d, 2 H), 6.92 (d, 2 H).
Reaction SMILES: [CH3:1]/[CH:2]=[C:3](/[C:5]([O:7][C@@H:8]1[C@:16]23[C@H:20]([C@@:21]([C@:25]45[O:30][C@@:29]4([CH3:31])[C@H:28]4[C@:32]6([OH:38])[C@H:36]([O:37][C@@H:26]5[CH2:27]4)[O:35][CH:34]=[CH:33]6)([CH3:24])[C@H:22]([OH:23])[C@H:14]4[C@H:15]2[C@:11]([C:44]([O:46][CH3:47])=[O:45])([CH2:12][O:13]4)[C@H:10]([O:48][C:49]([CH3:51])=[O:50])[CH2:9]1)[C@@:19]([OH:43])([C:39]([O:41][CH3:42])=[O:40])[O:18][CH2:17]3)=[O:6])\[CH3:4].[H][H]>O.O.[Pt](=O)=O.C(OCC)(=O)C>[CH3:1]/[CH:2]=[C:3](/[C:5]([O:7][C@@H:8]1[C@:16]23[C@H:20]([C@@:21]([C@:25]45[O:30][C@@:29]4([CH3:31])[C@@H:28]4[C@:32]6([OH:38])[C@@H:36]([O:37][C@H:26]5[CH2:27]4)[O:35][CH2:34][CH2:33]6)([CH3:24])[C@H:22]([OH:23])[C@H:14]4[C@H:15]2[C@:11]([C:44]([O:46][CH3:47])=[O:45])([CH2:12][O:13]4)[C@H:10]([O:48][C:49]([CH3:51])=[O:50])[CH2:9]1)[C@@:19]([OH:43])([C:39]([O:41][CH3:42])=[O:40])[O:18][CH2:17]3)=[O:6])\[CH3:4]
Reactant: [H][H]
Reactant: C/C=C(\C)C(=O)O[C@H]1C[C@@H](OC(C)=O)[C@@]2(C(=O)OC)CO[C@H]3[C@@H](O)[C@@](C)([C@]45O[C@@]4(C)[C@@H]4C[C@H]5O[C@@H]5OC=C[C@@]54O)[C@H]4[C@]1(CO[C@]4(O)C(=O)OC)[C@@H]32
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: O
Product: C/C=C(\C)C(=O)O[C@H]1C[C@@H](OC(C)=O)[C@@]2(C(=O)OC)CO[C@H]3[C@@H](O)[C@@](C)([C@]45O[C@@]4(C)[C@H]4C[C@@H]5O[C@H]5OCC[C@@]54O)[C@H]4[C@]1(CO[C@]4(O)C(=O)OC)[C@@H]32
Reaction time: 1.25 h

Procedure:
40.8 mg. azadirachtin A (5.67×1031 5 mole) were dissolved in 4 ml. ethyl acetate and 20 mg. platinum dioxide dihydrate were added thereto. The mixture was stirred and hydrogen passed therethrough for 75 minutes, the course of the reaction being monitored by HPLC. After the disappearance of the azadirachtin A peak, the reaction was discontinued and the reaction mixture centrifuged. The supernatant solution was evaporated and purified on silicon dioxide thin layer chromatography plates using the elution agent chloroform/acetone (7:3 v/v); Rf 0.33. Yield: 28.2 mg. (69% of theory).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[C:11](#[N:13])[CH3:12].[H-].[Na+:15].C(OC)(C)(C)C>C1COCC1>[C:11]([CH:12]=[C:3]([C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1)[O-:4])#[N:13].[Na+:15]
Reactant: CC#N
Reactant: COC(=O)c1cnccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: N#CC=C([O-])c1cnccn1
Reaction time: 0.5 h

Procedure:
A solution of 1.5 g (10.9 mmol) of methylpyrazine-2-carboxylate and 446 mg (10.9 mmol) of acetonitrile in 16.5 ml of THF was added dropwise to a suspension, heated under reflux, of 434 mg of sodium hydride (60% strength suspension in mineral oil) in 10 ml of THF. The reaction mixture was heated under reflux for 20 h. After cooling, 50 ml of methyl tert-butyl ether were added and the mixture was stirred for 30 minutes. The precipitate formed was filtered off with suction over a frit and dried under oil pump vacuum. This gave 1.77 g (96% of theory) of the title compound which was used without further characterization for the next step.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([O:44][CH3:45])[CH2:11][N:12]1[C:20](=[O:21])[C:19]2[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:17]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]([F:41])([F:40])[F:39])[CH:32]=3)=[N:16][C:15]=2[N:14]([CH3:42])[C:13]1=[O:43])(C(C)(C)C)(C)C.Cl>C(O)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:18]2[C:19]3[C:20](=[O:21])[N:12]([CH2:11][CH:10]([O:44][CH3:45])[CH2:9][OH:8])[C:13](=[O:43])[N:14]([CH3:42])[C:15]=3[N:16]=[C:17]2[O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]([F:41])([F:39])[F:40])[CH:32]=2)=[CH:28][CH:27]=1
Reactant: COC(CO[Si](C)(C)C(C)(C)C)Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Agent: Cl
Solvent: CCO
Product: COC(CO)Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Reaction time: 0.17 h
Yield: 14.7 %

Procedure:
To a solution of 1-(3-(tert-butyldimethylsilyloxy)-2-methoxypropyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (150 mg, 0.22 mmol) in ethyl alcohol (5 mL) was added concentrated HCl (0.1 mL). The reaction was stirred for 10 minutes. Then it was concentrated and purified by preparative HPLC to give 7-(4-chlorobenzyl)-1-(3-hydroxy-2-methoxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (18 mg, 16.2% yield) as white solid. 1H-NMR (DMSO-d6) δ 7.63-7.59(t, 1H), 7.50(s, 1H), 7.45-7.43(m, 5H), 7.34-7.32(d, 1H), 5.44(s, 2H), 4.65-4.62(t, 1H), 4.12-4.08(q, 1H), 3.84-3.79(q, 1H), 3.53-3.41(m, 2H), 3.29-3.28(d, 6H). LCMS retention time 3.089 min; LCMS MH+ 555.
Reaction SMILES: [C:1]1([C:6]2[CH:30]=[CH:29][C:9]([C:10]([NH:12][CH2:13][C:14]3[C:15]([CH2:20][NH:21]C(=O)OC(C)(C)C)=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:11])=[C:8]([NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.O1CCOCC1>CO>[NH2:21][CH2:20][C:15]1[C:14]([CH2:13][NH:12][C:10](=[O:11])[C:9]2[CH:29]=[CH:30][C:6]([C:1]3[CH2:5][CH2:4][CH2:3][CH:2]=3)=[N:7][C:8]=2[NH:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=2)=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)OC(=O)NCc1ncccc1CNC(=O)c1ccc(C2=CCCC2)nc1NCCc1cccc(F)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCc1ncccc1CNC(=O)c1ccc(C2=CCCC2)nc1NCCc1cccc(F)c1
Temperature: 25 °C
Yield: 25 %

Procedure:
tert-butyl (3-((6-cyclopentenyl-2-(3-fluorophenethylamino)nicotinamido)methyl)pyridin-2-yl)methylcarbamate was dissolved in MeOH (1 mL) and allowed to stir at room temperature. HCl/dioxane (4M, 2 mL) was added dropwise and stirred until complete. The reaction mixture was concentrated, diluted with EtOAc, washed with saturated sodium bicarbonate, brine and dried (Na2SO4). The organics were concentrated and purified by RP-HPLC with a mixture of acetonitrile and H2O to give N-((2-(aminomethyl)pyridin-3-yl)methyl)-6-cyclopentenyl-2-(3-fluorophenethylamino)nicotinamide as a solid (0.026 g, 25%). LC/MS (M+H+) m/z 446.2.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:12])[C:9]([F:11])=[CH:10][C:2]=1[Br:1]
Reactant: CO
Reactant: O=C(O)c1cc(F)c(F)cc1Br
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(F)c(F)cc1Br
Temperature: 80 °C
Yield: 28 %

Procedure:
To a solution of 2-bromo-4,5-difluoro-benzoic acid (5 g, 21.10 mmol) in methanol (100 mL) was added concentrated sulfuric acid (0.21 mL, 2.11 mmol) at 0° C. The reaction mixture was then heated at 80° C. for 4 hours. After cooling to room temperature, the mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, then brine, dried over sodium sulfate, filtered, and concentrated to afford the crude product 2-bromo-4,5-difluoro-benzoic acid methyl ester (1.48 g, 28%) as a clear oil, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([NH:19][C:20]([N:22]3[CH2:24][CH2:23]3)=[O:21])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:25])[C:11](=[O:26])[CH2:10][N:9]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[C:37]([OH:41])([CH3:40])([CH3:39])[CH3:38]>>[C:37]([O:41][CH2:24][CH2:23][NH:22][C:20]([NH:19][C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH3:25])[C:11](=[O:26])[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:14]=2[CH:15]=1)=[O:21])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)O
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(NC(=O)N3CC3)ccc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CN1C(=O)CN=C(c2ccccc2F)c2cc(NC(=O)NCCOC(C)(C)C)ccc21
Reaction time: 0.33 h

Procedure:
2 g (0.0057 M) of N-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-1-aziridinecarboxamide in 50 ml of tert.butanol are treated with 3 ml of 25% sulphuric acid. After 20 minutes, the mixture is made alkaline with 10% sodium bicarbonate solution and extracted several times with methylene chloride. The methylene chloride solution is dried over sodium sulphate, filtered and concentrated. The residue is purified on a 80 g silica gel column using ethyl acetate as the eluting agent and recrystallised from ethyl acetate. There is obtained 1-(2-tert.butoxyethyl)-3-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]urea which melts at 177° C.
Reaction SMILES: [CH3:1][N:2](C=O)C.C1COCC1.CN(C)[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][C:19]([N+:23]([O-:25])=[O:24])=[CH:20][CH:21]=2)[NH:16][CH:15]=1.[C-]#N.[K+]>O>[N+:23]([C:19]1[CH:18]=[C:17]2[C:22]([C:14]([CH2:13][C:1]#[N:2])=[CH:15][NH:16]2)=[CH:21][CH:20]=1)([O-:25])=[O:24]
Reactant: CN(C)Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#CCc1c[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Yield: 36 %

Procedure:
To a mixture of DMF (35 mL) and Mel (74.6 g, 0.53 mol) in water (35 mL) and THF (400 mL) was added dimethyl-(6-nitro-1H-indol-3-ylmethyl)-amine (23 g, 0.105 mol). After the reaction mixture was refluxed for 10 min, potassium cyanide (54.6 g, 0.84 mol) was added and the mixture was kept refluxing overnight. The mixture was then cooled to room temperature and filtered. The filtrate was washed with brine (300 mL×3), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give (6-nitro-1H-indol-3-yl)-acetonitrile (B-9-a) (7.5 g, 36%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH2:6]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:19]([O:21]C(C)(C)C)=[O:20])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[CH:7]=[CH2:8].C(N(CC)CC)C.C(#N)C>>[CH2:6]([N:9]([C:2]([O:4][CH3:5])=[O:3])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:19]([OH:21])=[O:20])[CH2:17][CH2:18]2)=[CH:12][CH:11]=1)[CH:7]=[CH2:8]
Reactant: COC(=O)Cl
Reactant: C=CCNc1ccc(C2(C(=O)OC(C)(C)C)CC2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CCN(C(=O)OC)c1ccc(C2(C(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (34 μL, 0.00044 mol) was added to a mixture of tert-butyl 1-[4-(allylamino)phenyl]cyclopropanecarboxylate (6.0×10−1 mg, 0.00022 mol) and triethylamine (92 μL, 0.00066 mol) in acetonitrile (1.0 mL, 0.019 mol) at rt. The reaction mixture was stirred at rt for 30 minutes, then was washed with water, and then extracted with EtOAc (3×). The organic layers were combined and concentrated. To the residue was added 4.0M HCl in dioxane and the reaction was stirred at rt for 2 h. The solvent was removed in-vacuo and used in the following step. LC/MS: 276.2 (M+H+).
Reaction SMILES: [CH2:1]([N:3]([CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[C:4]1[CH:5]=[C:6]([CH:15]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]2)[CH:7]=[C:8]([C:11]([O:13]C)=[O:12])[C:9]=1[CH3:10])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:22]([O:21][C:19]([N:17]1[CH2:18][CH:15]([C:6]2[CH:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[C:9]([CH3:10])=[C:8]([CH:7]=2)[C:11]([OH:13])=[O:12])[CH2:16]1)=[O:20])([CH3:24])([CH3:25])[CH3:23]
Reactant: CCN(c1cc(C2CN(C(=O)OC(C)(C)C)C2)cc(C(=O)OC)c1C)C1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(c1cc(C2CN(C(=O)OC(C)(C)C)C2)cc(C(=O)O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.7 %

Procedure:
To a stirred solution of tert-butyl 3-{3-[ethyl(oxan-4-yl)amino]-5-(methoxycarbonyl)-4-methylphenyl}azetidine-1-carboxylate (78 mg, 0.18 mmol) in THF (2 ml) and MeOH (0.1 ml) was added 2M NaOH solution (0.9 ml, 1.8 mmol) and the reaction was stirred at room temperature for 16 h followed by heating at 50° C. for 22 h. The reaction was cooled to room temperature and the solvent removed in vacuo after which the aqueous solution was adjusted to pH5 using 1M HCl. The product was extracted into DCM (2×50 ml), dried with Na2SO4 and filtered to afford the title compound as a colourless oil (54 mg, 72%). LC-MS 100%, 1.70 min (3.5 minute LC-MS method), m/z=419.2, 1H NMR (500 MHz, MeOD) δ 7.77 (s, 1H), 7.55 (s, 1H), 4.36 (t, J=8.2 Hz, 2H), 3.90 (d, J=27.0 Hz, 5H), 3.71 (t, J=6.5 Hz, 1H), 3.36 (t, J=11.3 Hz, 3H), 2.55 (s, 3H), 1.92-1.81 (m, 1H), 1.64 (d, J=55.8 Hz, 3H), 1.49-1.42 (m, 10H), 0.93 (s, 3H).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C1C=C([C:17]23[CH2:26][CH:21]([O:22][C:23]2([CH3:25])[CH3:24])[N:20]([CH3:27])[CH2:19][CH2:18]3)C=CC=1>CC(C)=O>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:17]1([C:23]([CH3:25])([CH3:24])[OH:22])[CH2:26][CH2:21][N:20]([CH3:27])[CH2:19][CH2:18]1
Reactant: CN1CCC2(c3cccc(C(F)(F)F)c3)CC1OC2(C)C
Reactant: COc1ccccc1
Solvent: CC(C)=O
Product: COc1ccccc1C1(C(C)(C)O)CCN(C)CC1

Procedure:
4-(2'-Methoxyphenyl)-α,α,1-trimethyl-4-piperidinemethanol was prepared from anisole by the procedure described in Example 3 except that acetone was used in place of cyclopentanone in the preparation of III; m.p. 110°-111°; NMR (in CDCl3): τ2.6-3.1 (m, 4H); 6.2 (s, 3H); 6.7-8.5 (m, 9H); 7.9 (s, 3H) and 8.9 (broad s, 6H). Anal. Calcd. for C16H25NO2 : C, 72.96; H, 9.57; N, 5.32. Found: C, 73.02; H, 9.56; N, 5.41.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6](B1OC(C)(C)C(C)(C)O1)=[CH:5]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:29][C:30]1[CH:35]=[C:34]([N:36]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[N:33]2[N:53]=[CH:54][C:55](I)=[C:32]2[N:31]=1>O1CCOCC1.O>[Cl:29][C:30]1[CH:35]=[C:34]([N:36]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:42])[CH3:43])[N:33]2[N:53]=[CH:54][C:55]([C:6]3[CH:7]=[N:8][C:9]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:11][CH:10]=4)=[C:32]2[N:31]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(I)cnn12
Reactant: CC1(C)OB(c2cnc3ccc(F)cc3c2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccc(F)cc4c3)cnn12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
6-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (3.65 mmol, 996.4 mg), K3PO4 (9.12 mmol, 1933.6 mg), and PdCl2(dppf)CH2Cl2 (0.30 mmol, 248 mg) was added to a solution of 5-chloro-3-iodo-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (3.04 mmol, 1684.3 mg) in dioxane (18 mL) and H2O (3 mL). The resulting solution was stirred at 80° C. under argon overnight. The mixture was diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation and purification by column chromatography afforded 5-chloro-3-(6-fluoroquinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine: LCMS tR=3.36 Min (5 min run, UV254nm). Mass calculated for, M+ 581.2, observed LC/MS m/z 582.2 (M+H).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-:19].[K+].BrBr>C1(C)C=CC=CC=1>[C:1]1([NH:7][C:8](=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH3:16])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])O
Reactant: CSc1ccccc1C(=O)Nc1ccccc1
Agent: BrBr
Agent: [K+]
Solvent: Cc1ccccc1
Product: CS(=O)c1ccccc1C(=O)Nc1ccccc1

Procedure:
To a 1000 ml four-necked flask equipped with a stirrer, a thermometer, and a condenser, 48.6 g (0.2 mol) of N-phenyl-2-(methylthio)benzamide obtained in Example 1, 300 g of toluene, and 200 g of a 10% by weight aqueous solution of potassium bicarbonate are placed. To the above mixture in the flask, 32.0 g (0.2 mol) of bromine is added dropwise while stirring at a temperature of from 10° to 15° C. to be allowed to react with each other for about 10 minutes. After completion of the reaction, the produced white crystals are filtered and then recrystallized from a mixture of water and ethanol (1:9) to give 48.7 g of N-phenyl-2-(methylsulfinyl)benzamide (melting point: 194° to 195° C.). The yield of the product against N-phenyl-2-(methylthio)benzamide is 94%.