Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([O:15][C:16]2[C:21]([Cl:22])=[CH:20][C:19]([S:23]([N:26]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=3[O:42][CH3:43])[C:27]3[CH:32]=[CH:31][N:30]=[CH:29][N:28]=3)(=[O:25])=[O:24])=[C:18]([F:44])[CH:17]=2)[C@H:11]([C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:22][C:21]1[C:16]([O:15][C@@H:12]2[CH2:13][CH2:14][C@H:9]([OH:8])[CH2:10][C@H:11]2[C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)=[CH:17][C:18]([F:44])=[C:19]([S:23]([N:26]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=2[O:42][CH3:43])[C:27]2[CH:32]=[CH:31][N:30]=[CH:29][N:28]=2)(=[O:25])=[O:24])[CH:20]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@@H]3CC[C@H](O)C[C@H]3c3ccnn3C)cc2F)c(OC)c1
Yield: 82.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 120c by using the 4-{[(1R,2S,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (272 mg, 0.364 mmol) prepared in Example 164b, tetrabutyl ammonium fluoride (1.0 M solution in THF; 0.729 mL, 0.729 mmol) and THF (5.0 mL), to yield the title compound (189 mg, 82%) as a colorless amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]I)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[C:21]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22]1.[NH4+].[Cl-].C[CH2:30][O:31]CC>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:30]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[OH:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOCC
Reactant: O=C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(CI)CC1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Product: CC(C)(C)OC(=O)N1CCC(CC(O)C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.36 g (4.2 mmol) of 1-t-butoxycarbonyl-4-iodomethylpiperidine in 40 mL of ether at −78° C. was carefully added 5.8 mL (9.35 mmol) of t-butyl lithium (1.7 N on pentane). After stirring for 30 min, to the reaction mixture was added dropwise 0.95 mL (10.73 mmol) of cyclopentanone and the reaction mixture was stirred at −78° C. for 2 h. To the reaction mixture was added 5 mL of sat'd NH4Cl solution and the reaction mixture was warmed to rt. The reaction mixture was partitioned between sat'd NH4Cl solution and ether. The aqueous fraction was extracted with ether and the combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ether, 4:1) to give 0.36 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[Sn](CCCC)(CCCC)CCCC.Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]3[C:48]4[C:43](=[CH:44][C:45]([O:49][CH3:50])=[CH:46][N:47]=4)[N:42]=[CH:41][CH:40]=3)=[CH:34][CH:33]=2)=[N:23][N:22]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:50][O:49][C:45]1[CH:44]=[C:43]2[C:48]([C:39]([O:38][C:35]3[CH:36]=[CH:37][C:32]([NH:31][C:24]4[C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[C:21]([C:3]5[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=5)=[N:22][N:23]=4)=[CH:33][CH:34]=3)=[CH:40][CH:41]=[N:42]2)=[N:47][CH:46]=1
Reactant: COc1cnc2c(Oc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: COc1cnc2c(Oc3ccc(Nc4nnc(-c5nccn5C)c5ccccc45)cc3)ccnc2c1
Temperature: 100 °C
Yield: 29.4 %

Procedure:
In a nitrogen purged sealed tube was added 1,4-dioxane (1.35 mL), and the solution was purged with nitrogen for 5 minutes, then sealed. 1-Methyl-2-(tributylstannyl)-1H-imidazole (0.311 g, 0.837 mmol), 4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine (0.120 g, 0.279 mmol) were added to the tube, which was then purged with nitrogen and sealed. To the tube was added 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.102 mg, 0.140 mmol), and the tube was purged with nitrogen, sealed, and heated to 100° C., while stirring the reaction for 17 hours. The reaction was cooled to RT, and concentrated. The concentrate was purified using reverse phase chromatography, the product fractions were concentrated, extracted into DCM, washed once with sodium carbonate and once with water, upon which the title compound precipiated. The solids were filtered, washed with water, air dried to yield N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)-4-(1-methyl-1H-imidazol-2-yl)phthalazin-1-amine (0.039 g) as light yellow solid. MS [M+H]=476.0; Calc'd 475.5 for C27H21N7O2.
Reaction SMILES: [C:1]([O:7][C:8]1[CH:21]=[C:20]([CH:22]=[O:23])[C:11]2[C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:13][S:14][C:10]=2[CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CC(C)=[O:26].[O-][Mn](=O)(=O)=O.[K+]>O>[CH3:3][C:2]([CH3:4])([CH3:5])[C:1]([O:7][C:8]1[CH:9]=[C:10]2[S:14][CH:13]=[C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:11]2=[C:20]([C:22]([OH:26])=[O:23])[CH:21]=1)=[O:6]
Reactant: CC(C)=O
Reactant: COC(=O)Cc1csc2cc(OC(=O)C(C)(C)C)cc(C=O)c12
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)Cc1csc2cc(OC(=O)C(C)(C)C)cc(C(=O)O)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-formyl-3-(2-methoxy-2-oxoethyl)-1-benzothiophen-6-yl pivalate (150 mg), acetone (1 mL) and water (1 mL) was added KMnO4 (85 mg, 0.54 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (145 mg).
Reaction SMILES: COC1(C)[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:5]=2[O:4]1.Cl>CO>[CH2:13]([O:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:6]([OH:7])[C:5]=1[OH:4])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC1(C)Oc2cccc(OCc3ccccc3)c2O1
Agent: Cl
Solvent: CO
Product: Oc1cccc(OCc2ccccc2)c1O

Procedure:
A mixture of 2-methoxy-2-methyl-4-benzyloxy-1,3-benzodioxole (13.6 g., 0.05 mole), methanol (210 ml.) and 5N hydrochloric acid (210 ml.) is stirred under reflux in an atmosphere of nitrogen for 10 hours. Most of the methanol is distilled off under vacuum and the product then extracted with ether. The ethereal solution is washed with water, dried over magnesium sulfate followed by calcium sulfate and evaporated to dryness to yield the crude 3-benzyloxy-catechol which can be recrystallized from di-isopropyl ether.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=[O:18])[N:10]([CH3:19])[C:9]2[CH:20]=[CH:21][CH:22]=[N:23][C:8]1=2)=[O:6].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>CN(C)C=O>[ClH:1].[CH2:24]([N:26]([CH2:27][CH3:28])[CH2:2][CH2:3][CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=[O:18])[N:10]([CH3:19])[C:9]2[CH:20]=[CH:21][CH:22]=[N:23][C:8]1=2)=[O:6])[CH3:25]
Reactant: CCNCC
Reactant: CN1C(=O)c2ccccc2N(C(=O)CCCCl)c2ncccc21
Solvent: CN(C)C=O
Product: CCN(CC)CCCC(=O)N1c2ccccc2C(=O)N(C)c2cccnc21
Product: Cl
Yield: 54 %

Procedure:
4.3 gm of 11-(4-chlorobutyryl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4]benzodiazepin-6-one and 1.9 gm of diethylamine were allowed to stand in 70 ml of dimethylformamide for 3 weeks at room temperature. Then the reaction mixture was evaporated in vacuo to dryness, and the residue was recrystallized from isopropanol. The hydrochloride, M.p.: 233°-235° C., was obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][CH2:8][CH2:9][CH2:10][CH2:11]Br.[OH:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[O:24][CH3:25]>CC#N>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][O:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[O:24][CH3:25]
Reactant: BrCCCCBr
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCCCCBr)c(OC)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 79.6 %

Procedure:
Potassium carbonate (0.758 g, 0.48 mmol) was added to a solution of 1,4-dibromo butane (1.18 g, 5.49 mmol) and methyl 4-hydroxy-3-methoxybenzoate (0.5 g, 2.74 mmol) in CH3CN (10 mL). After stirring for 12 h at 80° C., the organic phase was evaporated under reduced pressure and the crude material was partitioned between water and CH2Cl2. The aqueous layer was extracted with CH2Cl2 (3×20 mL). The organic phase was dried using Na2SO4 and evaporated to give the crude methyl 4-(4-bromobutoxy)-3-methoxybenzoate which was purified by column chromatography using hexanes:ethyl acetate to give the pure product as a colorless solid (0.692 g, 80%). 1H NMR (400 MHz, CDCl3): δ 7.61 (d, 1H, J=8.3 Hz), 7.51 (s, 1H), 6.83 (d, 1H, J=8.2 Hz), 4.07 (t, 2H, J=5.7 Hz), 3.87 (s, 3H), 3.85 (s, 3H), 3.47 (t, 2H, J=6.4 Hz), 2.04-2.00 (m, 4H). LC-MS (ESI) Calcd for C13H17BrO4 [M+H]+: 317.03, 319.03. Found: 316.90, 318.90.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[C:14]([C:19](O)=[O:20])[CH:13]=3)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:44]12([NH2:54])[CH2:53][CH:48]3[CH2:49][CH:50]([CH2:52][CH:46]([CH2:47]3)[CH2:45]1)[CH2:51]2>O.CCN(CC)CC.CN(C=O)C>[C:44]12([NH:54][C:19]([C:14]3[CH:13]=[C:12]4[C:17]([CH:18]=[C:10]([C:7]5[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=5)[NH:11]4)=[CH:16][CH:15]=3)=[O:20])[CH2:51][CH:50]3[CH2:49][CH:48]([CH2:47][CH:46]([CH2:52]3)[CH2:45]1)[CH2:53]2
Reactant: O=C(O)c1ccc2cc(-c3ccc([N+](=O)[O-])cc3)[nH]c2c1
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NC12CC3CC(CC(C3)C1)C2)c1ccc2cc(-c3ccc([N+](=O)[O-])cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an oven dried Argon cooled 100 mL flask, 605 mg acid 6, 493 mg EDCI.HCl, 348 mg of HOBt were added. While under Argon atmosphere, 30 mL of dry DMF and 1.79 mL of Et3N were added and the mixture was stirred at room temperature for 15 min. After this, 389 mg of 1-adamantylamine was added and the resulting mixture was heated at 60° C. with continuous stirring for a period of 16 hrs when TLC indicated the reaction was complete. The mixture was cooled to 0° C. and poured into water. The resulting yellow solid was collected and filtered to give the crude amide that was further purified by chromatography over silica gel using 50–90% ethyl acetate in hexane as eluent. Evaporation of the solvent yielded 600 mg of pure 7.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[C:8]([F:14])[CH:7]=1.C(OC(=O)C(OC1C=CC(C#N)=C(F)C=1)C)(C)(C)C>>[CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH2:13])=[C:8]([F:14])[CH:7]=1
Reactant: COC(=O)COc1ccc(C#N)c(F)c1
Agent: CC(Oc1ccc(C#N)c(F)c1)C(=O)OC(C)(C)C
Product: COC(=O)COc1ccc(CN)c(F)c1

Procedure:
The compound of Formula (5.0.19) was prepared in a manner analogous to that described in Preparation 10, substituting (4-cyano-3-fluoro-phenoxy)-acetic acid methyl ester for the corresponding 2-(4-cyano-3-fluoro-phenoxy)-propionic acid tert-butyl ester material.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][C@@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[Br:1][C:2]1[C:3]([N:11]2[CH2:12][CH2:13][NH:14][CH2:15][C@H:10]2[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncccc1Br
Reactant: C[C@@H]1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@@H]1CNCCN1c1ncccc1Br
Temperature: 240 °C
Yield: 21.7 %

Procedure:
A mixture of 3-bromo-2-chloropyridine (2 g, 9 mmol, Aldrich), (R)-(−)-2-methylpiperazine (1.5 g. 15 mmol) and N,N-diisopropylethylamine (1 mL, 5.8 mmol) in NMP (1 mL) was heated in a microwave synthesizer for 60 min at 240° C. The reaction mixture was concentrated and purified by silica gel chromatography, eluting with 10% MeOH in dichloromethane to give 0.5 g (22%) of (2R)-1-(3-bromopyridin-2-yl)-2-methylpiperazine MS (ESI, pos. ion). MS m/z: 256 (M+1), and 0.75 g (33%) of (3R)-1-(3-bromopyridin-2-yl)-3-methylpiperazine. MS m/z: 256 (M+1).
Reaction SMILES: C1C2C(COC([C@@H:18]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:19]([NH:21][C:22]3[N:26]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:25]=[C:24]([C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[CH:23]=3)=[O:20])=O)C3C(=CC=CC=3)C=2C=CC=1.CCCC[N+:50](CCCC)(CCCC)CCCC.[F-].O>C(Cl)Cl>[NH2:50][C@@H:18]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:19]([NH:21][C:22]1[N:26]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:25]=[C:24]([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH:23]=1)=[O:20]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)Cn1nc(-c2ccncc2)cc1NC(=O)[C@H](Cc1ccccc1)C(=O)OCC1c2ccccc2-c2ccccc21
Agent: [F-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Cn1nc(-c2ccncc2)cc1NC(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.9 %

Procedure:
To a rt solution of 26.B (341 mg, 0.63 mmol) in CH2Cl2 (5 mL) was added TBAF (available from Aldrich) (1.0 M, 3.2 mL, 3.2 mmol). The resulting mixture was stirred at rt for 12 hr, treated with water (15), and extracted with 30% iPrOH/CHCl3 (3×15 mL). The combined organic layers were washed with water, brine and dried over MgSO4. After removal of organic solvent under reduced pressure, purification of the residue by flash chromatography on silica gel using 0-10% MeOH/CH2Cl2 for elution gave the title product 26.C as colorless solid (141 mg, 71%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[C:34](O)=[O:35]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:34]([C:25]2[CH:26]=[CH:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:24]=2)=[O:35])=[O:8])[N:6]=1
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccc3ccccc3n2)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with Quinoline-2-carboxylic acid. LC-MS (basic): tR=0.83 min; [M+H]+=488.4.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:30]([NH:32][CH2:33][C:34]([NH:36][C@H:37]([C:55]([OH:57])=[O:56])[CH2:38][CH2:39][CH2:40][NH:41][C:42](=[NH:54])[NH:43]S(C1C=CC(C)=CC=1)(=O)=O)=[O:35])=[O:31])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:29])[N:8](C(OCC1C=CC=CC=1)=O)C(OCC1C=CC=CC=1)=O.[S:65]1[CH:69]=[CH:68][N:67]=[CH:66]1.C1(OC)C=CC=CC=1.N#N>CSCC.CCOCC.CCCCCC>[NH2:1][C@@H:2]([C:30]([NH:32][CH2:33][C:34]([NH:36][C@H:37]([C:55]([OH:57])=[O:56])[CH2:38][CH2:39][CH2:40][NH:41][C:42](=[NH:43])[NH2:54])=[O:35])=[O:31])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:29].[S:65]1[CH:69]=[CH:68][N:67]=[CH:66]1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)CNC(=O)[C@@H](CCCNC(=N)N(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CCSC
Agent: N#N
Agent: c1cscn1
Solvent: COc1ccccc1
Solvent: CCOCC
Solvent: CCCCCC
Product: N=C(N)NCCC[C@@H](N)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 60 %

Procedure:
A 100 mg portion of Boc-(D)-Arg(Cbz2)-Gly-Arg(Tos)-Thiazole, 1 mL of anisole and 4 drops of MeSEt were placed in HF-cleavage vessel and cooled under liquid N2. HF (10 mL) was then condensed into the reaction mixture and stirred at 0° C. for 1.25 h. HF was removed under vacuum to give a gum-like residue which was titrated with 20 mL of 50% Et2O-hexane and the organic wash removed by filtration. The gum residue was dissolved in 30 mL of 30% aq. HOAc and filtered through the above sintered funnel. The filtrate was lyophilized to give a powder which was purified by RP-HPLC to give 28 mg (60% yield) of (D)-Arg-Gly-Arg-thiazole. FAB-MS (M+H)+=455.2
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11](=[O:12])[NH:10][C:9]2[N:8]=[C:7]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)[CH:6]=[CH:5][C:4]=2[C:3]1=[O:19].Cl.[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][N:33]([CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:7]2[N:8]=[C:9]3[C:4]([C:3](=[O:19])[C:2]([CH3:20])([CH3:1])[C:11](=[O:12])[NH:10]3)=[CH:5][CH:6]=2)[CH2:32][CH2:31]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: CC1(C)C(=O)Nc2nc(OCCCC=O)ccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC1(C)C(=O)Nc2nc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)ccc2C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 30 %

Procedure:
To a solution of 4-(6,6-dimethyl-5,7-dioxo-5, 6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.520 g, 1.88 mmol) in DCE (6 mL) was added 1-(2,3-dichloro-phenyl)-piperazine hydrochloride (0.503 g, 1.88 mmol) followed by Et3N (0.53 mL, 3.76 mmol). The mixture was stirred for 20 minutes at room temperature and NaBH(OAc)3 (0.56 g, 2.60 mmol) was added. The reaction was stirred for 2.5 h and quenched with saturated NaHCO3 and water. The mixture was extracted with EtOAc and the organic layer was washed with saturated NaHCO3, water and brine, dried over Na2SO4 and concentrated. Purification by liquid chromatography on silica gel (0–5% MeOH/CH2Cl2) gave a white solid (0.277 g, 0.564 mmol, 30%). MS: APCI: M+1: 491.1 (Exact Mass: 490.15).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C(=CC=C([O:49][C:50]([F:53])([F:52])[F:51])C=2)OC=1C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:49][C:50]([F:53])([F:52])[F:51])[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=c1c(I)c(-c2ccccc2)oc2ccc(OC(F)(F)F)cc12
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(OC(F)(F)F)cc4c3=O)cc2)CCC1
Yield: 100 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-2-phenyl-6-trifluoromethoxy-chromen-4-one was reacted to give the title compound as a pale yellow oil (90 mg, 100%). LCMS (Method B): RT=5.07 min, [M+Na]+=574.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[N:12]=[C:13]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=12.C(N(CC)C(C)C)(C)C.[CH3:36][N:37]([CH3:41])[C:38](Cl)=[O:39]>CN(C=O)C>[NH2:20][C:16]1[C:15]2[N:14]([C:13]([CH:21]3[CH2:26][CH2:25][N:24]([C:38]([N:37]([CH3:41])[CH3:36])=[O:39])[CH2:23][CH2:22]3)=[N:12][C:11]=2[C:3]2[NH:2][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=[CH:18][N:17]=1
Reactant: Nc1nccn2c(C3CCNCC3)nc(-c3cc4ccccc4[nH]3)c12
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)N1CCC(c2nc(-c3cc4ccccc4[nH]3)c3c(N)nccn23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(1H-indol-2-yl)-3-piperidin-4-ylimidazo[1,5-a]pyrazin-8-amine hydrochloride (30.0 mg, 0.0679 mmol), N,N-diisopropylethylamine (59.1 μL, 0.340 mmol) and DMF (1.00 mL) was treated with N,N-dimethylcarbamoyl chloride (6.23 μL, 0.0679 mmol) and stirred at rt for 1 h prior to semi-preparative HPLC to afford the isolated title compound. 1H NMR (400 MHz, CD3OD) ppm: 8.32 (br. s., 1H), 7.59-7.66 (m, 2H), 7.46 (d, 1H, J=8.3 Hz), 7.15-7.22 (m, 1H), 7.01-7.10 (m, 2H), 6.74 (s, 1H), 3.82 (d, 2H, J=12.6 Hz), 3.34-3.42 (m, 1H), 2.97-3.09 (m, 2H), 2.87 (s, 6H), 1.95-2.09 (m, 4H); MS (ES+): m/z 404.14 [MH+].
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1.[OH:14][CH2:15][C:16]#[C:17][C:18]1[N:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:28])[CH:23]=[C:22]([C:29](OCC)=[O:30])[C:21]2=[O:34]>C(Cl)Cl>[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:11][C:29]([C:22]2[C:21](=[O:34])[C:20]3[C:25](=[CH:26][CH:27]=[C:18]([C:17]#[C:16][CH2:15][OH:14])[N:19]=3)[N:24]([CH3:28])[CH:23]=2)=[O:30])=[CH:8][CH:7]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn(C)c2ccc(C#CCO)nc2c1=O
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2nc(C#CCO)ccc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 52 %

Procedure:
Trimethylaluminum (2M in toluene, 42 μL) is added dropwise to a room temperature solution of 4-chlorobenzylamine (17 μL) in CH2Cl2 (1 mL) under nitrogen. The solution is stirred for 5 minutes before the addition in one portion of ethyl 6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro[1,5]naphthyridine-3-carboxylate (Preparation 60, 20 mg). The resulting suspension is stirred at room temperature for 3.5 h. The reaction mixture is partitioned with dil. aq. HCl (2 mL) and extracted with CH2Cl2 (2×2 mL). After drying over MgSO4, the extracts are concentrated under vacuum. The crude residue is purified by flash chromatography (9 g silica, 10% methanol/CH2Cl2) to give 14 mg (52%) of the title compound as a It. yellow solid. Physical Characteristics: Rf (15% methanol/CH2Cl2)=0.53; 1H NMR (DMSO-d6) δ10.32, 8.90, 8.31, 7.90, 7.40, 7.36, 5.5, 4.58, 4.39, 4.01; HRMS (FAB) m/z 382.0963 (C20H16ClN3O3+H). Anal. Found (C20H16ClN3O3.0.24 H2O): C, 62.21; H, 4.21; N, 10.75.
Reaction SMILES: [CH2:1]1[NH:6][C:4](=[O:5])[NH:3][CH2:2]1.[CH2:7]([N:9]([CH2:14][CH3:15])[S:10](Cl)(=[O:12])=[O:11])[CH3:8]>>[CH2:7]([N:9]([CH2:14][CH3:15])[S:10]([N:3]1[CH2:2][CH2:1][NH:6][C:4]1=[O:5])(=[O:12])=[O:11])[CH3:8]
Reactant: O=C1NCCN1
Reactant: CCN(CC)S(=O)(=O)Cl
Product: CCN(CC)S(=O)(=O)N1CCNC1=O

Procedure:
A mixture of 51.6 g of ethylene urea and 90 g of N,N-diethyl-sulphamoyl-chloride is heated at 110° for 3 hours. The reaction mixture is cooled and triturated with 300 ml of methanol, filtered and the filtrate evaporated off to dryness and the residue dissolved in 5% methanol in chloroform and chromatographed on a column of silica gel. That fraction which elutes with 5% methanol in chloroform is recrystallized from a mixture of methylenechlorid and hexane to give 1-(N,N-diethylsulphamoyl)-2-oxo-tetrahydroimidazole which melts at 80°-82°.