Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][NH:20]4)=[CH:14][C:13]([CH2:26][N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:12][N:11]=2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>[NH4+].[Cl-].O.C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][NH:20]4)=[CH:14][C:13]([CH2:26][N:27]3[CH2:28][CH2:29][N:30]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:31][CH2:32]3)=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(CN3CCNCC3)cc2-c2nc(C)nc3[nH]cnc23)cn1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2ncc(CN3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
The crude residue from Step 1 was taken up in DCM (3 mL, 46.6 mmol), cooled to 0° C. and then DIEA (0.132 mL, 0.755 mmol) and methanesulfonyl chloride (0.029 mL, 0.378 mmol) were added. The mixture was stirred at the same temperature for 1 h and then diluted with NH4Cl(aq) and water (10 mL each) and diluted with DCM (10 mL). The separated aqueous layer was extracted with DCM (2×15 mL) and the combined organic layers were washed with brine, dried over Na2SO4, concentrated and chromatographed through a Redi-Sep pre-packed silica gel column (DCM to 10% MeOH in DCM) to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-amine (21 mg, 16%) as a yellow solid. LCMS (API-ES) m/z 510 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 13.58 (br. s., 1H) 12.62 (br. s., 1H) 9.73 (br. s., 1H) 8.62 (s, 1H) 8.54 (d, J=2.54 Hz, 1H) 8.22 (d, J=1.56 Hz, 1H) 8.18 (dd, J=8.90, 2.45 Hz, 1H) 6.85 (d, J=8.80 Hz, 1H) 3.85 (s, 3H) 3.56 (s, 2H) 3.01-3.18 (m, 4H) 2.86 (s, 3H) 2.86 (s, 3H) 2.53 (br. s., 4H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:19][C@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@H:23]([O:30][Si:31]([C:44]([CH3:47])([CH3:46])[CH3:45])([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:22][CH2:21]2)=[N:4][C:5]([N:8]2[C:12]3[CH:13]=[C:14]([C:17]#[N:18])[CH:15]=[CH:16][C:11]=3[N:10]=[CH:9]2)=[N:6][CH:7]=1.[C:48]1(C)C=CC=C[CH:49]=1.COC(OC)N(C)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CCOC(C)=O>[Si:31]([O:30][C@H:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:20]([N:19]2[C:48]([CH3:49])=[N:1][C:2]3[C:3]2=[N:4][C:5]([N:8]2[C:12]4[CH:13]=[C:14]([C:17]#[N:18])[CH:15]=[CH:16][C:11]=4[N:10]=[CH:9]2)=[N:6][CH:7]=3)[CH2:21][CH2:22]1)([C:44]([CH3:47])([CH3:46])[CH3:45])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)[Si](O[C@@H]1CC[C@@H](Nc2nc(-n3cnc4ccc(C#N)cc43)ncc2N)c2ccccc21)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Agent: COC(OC)N(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Product: Cc1nc2cnc(-n3cnc4ccc(C#N)cc43)nc2n1[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c2ccccc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A 50 ml round bottom flask was charged with 0.09 g (0.14 mmol) of 3-(5-amino-4-((1R,4R)-4-(tert-butyldiphenylsilyloxy)-1,2,3,4-tetrahydronaphthalen-1-ylamino)pyrimidin-2-yl)-3H-benzo[d]imidazole-5-carbonitrile (prepared from 3-(5-nitro-4-thiocyanatopyrimidin-2-yl)-3H-benzo[d]imidazole-5-carbonitrile and (1R,4R)-4-(tert-butyldiphenylsilyloxy)-1,2,3,4-tetrahydronaphthalen-1-amine via same procedure as in Example H, step 1 and Example B, step 3). 20 ml of toluene was then added, followed by 0.028 g (0.21 mmol) of N,N-dimethylformamide dimethylacetal, and a catalytic amount of pyridinium p-toluenesulfonate. The resulting mixture was stirred at 100° C. overnight (condenser used with flask). The mixture was cooled to room temp, diluted with 100 ml EtOAc and washed with approx 10 ml water. The organic layer was dried over MgSO4 and concentrated in vacuo, and purified by column chromatography (eluting with 1% MeOH in DCM), to give 0.06 g (65%) of the titled compound. Compound was single peak by HPLC and had an M+H of 660 by MS.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[H][H].[N+:14]([C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32])[C:20]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=O)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32])[CH2:20][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)([O-:16])=[O:15]
Reactant: [H][H]
Reactant: O=C(c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)N1CCOCC1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
Sodium borohydride (3.36 g, 89 mmol, 2.1 eq.) was ground, placed in a nitrogen-flushed flask and suspended in TFIF (120 mL). After cooling to ˜0° C., boron trifluoride etherate (11.3 mL, 89 mmol, 2.1 eq.) was added via syringe. This reaction is mildly exothermic and some hydrogen evolution was noted. 4-(3,4-Dinitrobenzoyl)morpholine (11.91 g, 42 mmol, 1.0 eq.) was added as a solid in one portion, the vessel being rinsed with an additional portion of THF (20 mL). The ice-bath was removed and the suspension stirred at r.t. for 3 h before cooling again in ice. Methanol (100 mL) was added cautiously (hydrogen evolution) then the mixture was brought to reflux for 1 h. The mixture was concentrated in vacuo then the residue was partitioned between ethyl acetate (100 mL) and 1:1 saturated sodium bicarbonate solution/water (100 mL). The organic phase was separated, washed with water (50 mL) then brine (100 mL) and dried (MgSO4). The initial bicarbonate wash was extracted a second time with ethyl acetate (50 mL), this extract then being washed with the same aqueous washes used for the first extract before drying (MgSO4), combination and concentration to afford 10.97 g of crude material. Recrystallisation from methanol (45 mL, 10 mL wash) gave the title compound (9.34 g, 83%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[N:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][CH2:7][NH:8][C:9](=O)[C:10](F)(F)F)[CH3:2].[Br:22][C:23]1[N:27]2[N:28]=C(F)C=[CH:31][C:26]2=[N:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC>[CH2:1]([O:3][C:4](=[O:21])[N:5]([CH2:6][CH2:7][NH:8][C:9]1[CH:10]=[CH:31][C:26]2[N:27]([C:23]([Br:22])=[CH:24][N:25]=2)[N:28]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:2]
Reactant: CCOC(=O)N(CCNC(=O)C(F)(F)F)c1ccccc1
Reactant: Fc1ccc2ncc(Br)n2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)N(CCNc1ccc2ncc(Br)n2n1)c1ccccc1
Temperature: 85 °C
Yield: 52.1 %

Procedure:
Crude phenyl-[2-(2,2,2-trifluoro-acetylamino)-ethyl]-carbamic acid ethyl ester (2.2 g, 7.3 mmol) was combine with 3-bromo-6-fluoro-imidazo[1,2-b]pyridazine (892.5 mg, 4.1 mmol) and potassium carbonate [584-08-7] (2.9 g, 20.6 mmol) in a 20% (v/v) solution of water in 1,2-dimethoxyethane (25 mL) and heated to 85° C. for 5 d. The reaction mixture was then partitioned between water and ethyl acetate and the extract flash chromatographed (silica gel eluted with 100% ethyl acetate) to yield 863.1 mg of white crystalline powder, mp. 160-161° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (t, J=7.06 Hz, 2H) 2.51 (dt, J=3.58, 1.85 Hz, 1H) 3.35 (s, 1H) 3.46 (q, J=6.39 Hz, 2H) 3.90 (t, J=6.50 Hz, 2H) 4.04 (q, J=7.06 Hz, 2H) 6.65 (d, J=9.70 Hz, 1H) 7.19-7.25 (m, 1H) 7.31-7.39 (m, 4H) 7.48 (s, 1H) 7.69 (d, J=9.70 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 14.16, 38.85, 47.84, 60.82, 98.79, 112.62, 125.31, 125.99, 126.79, 128.63, 130.18, 136.35, 141.81, 153.79, 154.64. LRMS (ESI) m/z 403.9/405.9 [(M+H)]+, calc'd for C17H18BrN6O2: 404.27.
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH2:4]([O:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19]OS(C)(=O)=O)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[CH2:4]([O:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:19][S:2][CH3:1])=[O:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CS(=O)(=O)OCC1CCCN1C(=O)OCc1ccccc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSC[C@@H]1CCCN1C(=O)OCc1ccccc1
Yield: 78.9 %

Procedure:
To a suspension of 1.81 g (25.8 mmol) sodium methanethiolate in 25 ml methanol was added a solution of 1.35 g (4.31 mmol) 2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid benzyl ester in 25 ml methanol. Conversion was monitored by thin layer chromatography. After complete consumption of the starting material the reaction mixture was diluted with ethyl acetate and washed with two portions of water. The organic layer was dried over sodium sulfate. Flash chromatography gave 0.89 g (3.4 mmol, 78%) (S)-2-methylsulfanylmethyl-pyrrolidine-1-carboxylic acid benzyl ester as a light yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11]C2C=C(F)C=CC=2F)(=[O:10])=[O:9])=[CH:4][CH:3]=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.O>C1COCC1>[C:5]1([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: O=S(=O)(Nc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1
Temperature: 22 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
To a solution of 4-chloro-N-[5-fluoro-2-fluorophenyl]benzenesulfonamide (500 mg, 1.65 mmol), triphenylphosphine (909 mg, 3.47 mmol) and 5S-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pentanol (719 mg, 3.30 mmol) in THF (7 mL) was added diisopropylazodicarboxylate (0.682 mL, 3.47 mol) dropwise at 0° C. under nitrogen. The resulting mixture was allowed to warm to 22° C. with stirring. Stirring was continued for a period of 12 h followed by the addition of 15 mL of H2O. The mixture was extracted with ether (3×15 mL). The combined organic extracts were washed with NaHCO3 and sat. brine. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:5 ethyl acetate:hexanes) of the concentrate afforded 466 mg of 4-chloro-N-[5-fluoro-2-flurophenyl]-N-[(R)-1-methyl-4-[(1,1-dimethylethyl)-dimethylsilyl]oxy)butyl]benzene-sulfonamide as a yellow oil in 56% yield.
Reaction SMILES: O[C@@H:2]1[CH2:7][N:6]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[C@H:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][CH2:3]1.N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:44]([O:51][NH2:52])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(#N)C>[CH2:44]([O:51][NH:52][C@H:2]1[CH2:7][N:6]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[C@H:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][CH2:3]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@H](O)CN1C(=O)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)C(F)(F)F
Temperature: 0 °C
Yield: 84.5 %

Procedure:
After a solution of 10.22 g (34.38 mmol) of (2S,5S)-tert-butyl 5-hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate in dehydrated acetonitrile (113 mL) was cooled from −30 to −40° C. under argon atmosphere, 4.4 mL (37.78 mmol) of 2,6-lutidine was added, and then 5.92 mL (36.09 mmol) of trifluoromethanesulfonic acid anhydride was added dropwise over 10 minutes, followed by further allowing to react at −30° C. for 15 minutes. To this reaction mixture was added 8.46 g (68.73 mmol) of benzyloxyamine (washed with acetonitrile (5 mL)), followed by raising the temperature to 0° C. within 30 minutes, and further 4.4 mL (37.78 mmol) of 2,6-lutidine was added, followed by allowing to react at 0 to 5° C. for 3.5 days. This reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate (200 mL) and washed sequentially with water (200 mL), 10% aqueous citric acid solution (200 mL×3 times), 6.5% aqueous sodium hydrogencarbonate solution (100 mL) and saturated brine (100 mL). Each aqueous layer was back-extracted with ethyl acetate (100 mL), the organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was applied to silica gel column chromatography (hexane/ethyl acetate=4/1) to afford 11.69 g of the title compound as a colorless oil (yield 85%). Enantiomeric excess: 99.0% ee (CHIRALPAK AD-H, 4.6×150 mm, UV 210 nm, hexane/ethanol=9/1, flow rate 1 mL/min., retention time 4.5 min.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH2:24]([N:31]=[C:32]=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([NH:31][C:32]([NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)NCc4ccccc4)nc3cc21

Procedure:
Benzyl-3-[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-urea was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.48 mmol) and benzylisocyanate (0.05 ml, 0.41 mmol). After purification by flash chromatography (dichloromethane/methanol 94:6) the title compound was obtained as a light grey powder (26 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:5]([C:16]([OH:18])=O)=[CH:4][N:3]=1.[CH:19]1[CH:20]=[CH:21][C:22]2[N:27]([OH:28])[N:26]=[N:25][C:23]=2[CH:24]=1.CC[N:31]=C=NCCCN(C)C.Cl.N.O1CCOCC1>ClC(Cl)C>[N:27]1([O:28][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=3)[C:5]([C:16]([NH2:31])=[O:18])=[CH:4][N:3]=2)[C:22]2[CH:21]=[CH:20][CH:19]=[CH:24][C:23]=2[N:25]=[N:26]1
Reactant: On1nnc2ccccc21
Reactant: Cc1ccc(Nc2nc(Cl)ncc2C(=O)O)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CC(Cl)Cl
Product: Cc1ccc(Nc2nc(On3nnc4ccccc43)ncc2C(N)=O)cc1

Procedure:
2-Chloro-4-(4-methylanilino)pyrimidine-5-carboxylic acid was treated with HOBt and WSC-HCl in dichloroethane and then, under ice-cooling, allowed to undergo the reaction by adding 0.5 M ammonia-1,4-dioxane solution to obtain 2-(benzotriazol-1-yloxy)-4-(4-methylanilino)pyrimidine-5-carboxamide (light yellow powder).
Reaction SMILES: ClC1C=NC(N2CC(NC3C=CC(F)=CC=3F)C2)=C(C=1)C([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=O.[F:37][C:38]1[CH:39]=[N:40][C:41]([O:44][CH:45]2[CH2:48][N:47]([C:49]3[N:57]=[CH:56][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:54][C:50]=3[C:51]([OH:53])=O)[CH2:46]2)=[N:42][CH:43]=1.Cl.NC1(C2C=CC(C(OC)=O)=CC=2)CC1>>[F:37][C:38]1[CH:43]=[N:42][C:41]([O:44][CH:45]2[CH2:48][N:47]([C:49]3[N:57]=[CH:56][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:54][C:50]=3[C:51]([NH:9][C:10]3([C:13]4[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=4)[CH2:12][CH2:11]3)=[O:53])[CH2:46]2)=[N:40][CH:39]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2ncc(F)cn2)C1
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Nc4ccc(F)cc4F)C3)CC2)cc1
Agent: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(C(F)(F)F)cnc3N3CC(Oc4ncc(F)cn4)C3)CC2)cc1

Procedure:
The title compound (D182) (36 mg) was prepared according to the experimental procedure described in Description (D169) starting from 2-(3-((5-fluoropyrimidin-2-yl)oxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinic acid (D131) (42 mg, 0.117 mmol) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (27 mg, 0.117 mmol).
Reaction SMILES: C1(CBr)CC1.CC1C=CC(S(O[CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=O)=O)=CC=1.[CH3:23][C:24]1[N:25]=[C:26]([N:34]2[CH2:38][CH2:37][NH:36][C:35]2=[O:39])[S:27][C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[CH:18]1([CH2:17][N:36]2[CH2:37][CH2:38][N:34]([C:26]3[S:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:24]([CH3:23])[N:25]=3)[C:35]2=[O:39])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Agent: BrCC1CC1
Product: CCOC(=O)c1sc(N2CCN(CC3CCCC3)C2=O)nc1C
Yield: 62 %

Procedure:
Following the procedure as described in Example 10, making variations as required to replace cyclopropylmethyl bromide with cyclopentylmethyl 4-methylbenzenesulfonate to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 62% yield: 1H NMR (300 MHz, CDCl3) δ 4.20 (q, J=7.2 Hz, 2H), 4.04-3.99 (m, 2H), 3.52-3.41 (m, 2H), 3.17 (d, J=7.5 Hz, 2H), 2.46 (s, 3H), 2.16-1.08 (m, 12H); MS (ES+) m/z 338.3 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:9]([O:10][CH3:11])=[C:8]([Cl:12])[C:7]([F:13])=[CH:6][C:4]=1N.N([O-])=O.[Na+].[BrH:18]>O>[Cl:2][C:3]1[C:9]([O:10][CH3:11])=[C:8]([Cl:12])[C:7]([F:13])=[CH:6][C:4]=1[Br:18]
Reactant: Br
Reactant: COc1c(Cl)c(N)cc(F)c1Cl
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1c(Cl)c(F)cc(Br)c1Cl
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To 165 ml of a mixture of concentrated hydrochloric acid and water (1:1) was added 52.5 g of 2,4-dichloro-5-fluoro-3-methoxyaniline (0.25 mol). The resultant was stirred to be a slurry, and cooled to 0-5° C. Over 30 minutes, a solution of sodium nitrite (18.2 g) in water (50 ml) was added dropwise to the slurry. The resulting solution was added slowly to a solution of cuprous bromide (0.299 mol) and hydrobromic acid (160 ml). The reactant was stirred for 2 hours, and kept overnight. The resulting mixture was wet-distilled and the distilled materials were extracted with toluene. The oil layer was washed with 10% aqueous solution of NaOH, concentric sulfuric acid and water, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel chromatography eluting with n-hexane-dichloromethane to give 58.1 g of 2,4-dichloro-5-fluoro-3-methoxybromobenzene (0.212 mol) in 84.9% yield.
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:16][C:17]1[C:22]([CH2:23][Cl:24])=[N:21][CH:20]=[CH:19][N:18]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[H-].[Na+]>C1COCC1>[C:1]([N:4]1[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:16][C:17]2[C:22](=[N:21][CH:20]=[CH:19][N:18]=2)[CH2:23]1)(=[O:3])[CH3:2].[ClH:24]
Reactant: CCOC(=O)C(Cc1nccnc1CCl)(NC(C)=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)OCC)Cc2nccnc2CN1C(C)=O
Product: Cl
Reaction time: 0.5 h
Yield: 85 %
Yield: 84.4 %

Procedure:
To a solution of 1b (1.1 g, 2.36 mmol) in 40 mL THF was added NaH (170 mg, 4.25 mmol, 60% oil dispersion) under N2 and the solution was stirred for 30 min. The reaction was carefully quenched with water and extracted from sat NaHCO33× with EtOAc. The organic layers were dried with MgSO4, filtered, concentrated, and chromatographed on SiO2 using 75% EtOAc in hexane to give 640 mg of 1c as an HCl salt (85% yield). MS found: (M+H)+=322.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:22])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=O)C.C[N:24](C)C=O.[NH2-].[Na+]>C1(C)C=CC=CC=1>[Cl:15][C:11]1[CH:12]=[CH:13][C:14]2[C:9](=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:7]([CH3:22])[C:6]=2[C:4]([NH2:24])=[O:3])[CH:10]=1
Reactant: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Reactant: CN(C)C=O
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cn1c(C(N)=O)c2ccc(Cl)cc2c1-c1ccccc1

Procedure:
A solution of 12.4 g. of 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid ethyl ester in 70 ml. of dimethylformamide is treated under an atmosphere of argon at room temperature with 0.1 mol. of sodium amide (8.0 g. of a 50% suspension in toluene) and then stirred at 100° C. for 2 hours. After cooling, the mixture is poured on to 400 ml. of ice-water and the precipitate is removed by filtration, washed with water and dissolved in methylene chloride. The organic solution is washed with water, dried over sodium sulfate and concentrated to dryness. The residue is dissolved in chloroform and chromatographed on 800 g. of silica gel using chloroform/n-heptane/ethanol (10:10:1) for the elution. The uniform fractions are combined and evaporated. After recrystallization from acetonitrile, there is obtained 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid amide in the form of yellowish crystals having a melting point of 241°-244° C. (decomposition).
Reaction SMILES: [CH3:1][N:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([CH2:18][CH2:19][C:20]([O:22]C)=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:24].[OH-].[Na+].O>CO>[CH3:1][N:2]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:24]
Reactant: COC(=O)CCc1c(-c2ccccc2)n(C)c(=O)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(-c2ccccc2)c(CCC(=O)O)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
1.2 g (3.7 mmol) of methyl 2-methyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-4-propanoate are dissolved in 80 ml of methanol in a 250 ml round-bottomed flask, 0.25 g (6.25 mmol) of sodium hydroxide pellets and 1 ml of water are added and then the mixture is stirred at room temperature for 1 h and at reflux for 2 h. The mixture is cooled, the solvent is evaporated under reduced pressure, the residue is taken up in 50 ml of water and 50 ml of diethyl ether, and 36% hydrochloric acid is added dropwise. The insoluble material is collected by filtering, is washed with water and is dried. 0.91 g (2.96 mmol) of white solid is obtained. Melting point: 138°-140° C.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C@H:7]([C:15]([OH:17])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N[C@@H:19](C(O)=O)CC1C=CC=CC=1>CO>[CH3:19][O:16][C:15](=[O:17])[C@H:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:6]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1ccccc1
Yield: 12.6 %

Procedure:
5.8 ml of 95% sulfuric acid was added to 33 ml of methanol and heat-refluxed. Subsequently, methanol was removed under reduced pressure and water was added to provide 15 ml of CH3SO4H solution. 2.7 g L-Phe and 0.3 g (D-Phe/L-Phe=11.1%) D-Phe were added thereto and dissolved by heat, following which was then cooled with ice. The separated crystals were isolated by suction filtration and washed with a small amount of cold water. Yield, 3.73 g. The results of HPLC analysis using an optically active column revealed that the crystals contained 1.66 g L-Phe and 0.049 g (D-Phe/L-Phe=2.9%) D-Phe. In addition, 41 mg of L-phenylalanine methyl ester was also produced as a result of esterification of L-Phe with the methanol remaining in the CH3SO4H solution.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1([CH3:24])[C:12](=[O:13])[CH:11]2[C:6](=[C:7]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:15]=[C:8]3[C:9](=[O:14])[CH2:10]2)[CH:5]=[N:4]1.Cl.[CH2:26]([N:28]([CH2:32][CH3:33])[CH2:29][CH2:30][Cl:31])[CH3:27]>>[ClH:31].[ClH:1].[CH3:2][C:3]1([CH3:24])[C:12](=[O:13])[CH:11]2[C:6](=[C:7]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:15]=[C:8]3[C:9](=[O:14])[CH:10]2[CH2:27][CH2:26][N:28]([CH2:32][CH3:33])[CH2:29][CH3:30])[CH:5]=[N:4]1
Reactant: CCN(CC)CCCl
Reactant: CC1(C)N=CC2=C3N=C(c4ccccc4)N=C3C(=O)CC2C1=O
Agent: Cl
Product: CCN(CC)CCC1C(=O)C2=NC(c3ccccc3)=NC2=C2C=NC(C)(C)C(=O)C21

Procedure:
Prepared analogous to Example 23 from 5.1 gm of 7,7-dimethyl-2-phenyl-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione hydrochloride and 3.4 gm of 2-diethylamino-ethyl chloride hydrochloride,