Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:13])[NH:9][N+]([O-])=O.[H][H].Cl>CO.[Pd].CC(O)C>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:9])[NH2:13]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=N)N[N+](=O)[O-])C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=N)N)C(=O)O

Procedure:
Boc-hArg(NO2)-Amp (1.5 g) was dissolved in HPLC grade MeOH (120 ml) and to the clear solution was added the Pd—C catalyst (10%, Aldrich). A small stir bar was placed in the flask and the reaction mixture was stirred under a slow stream of hydrogen overnight after incorporating the 5-6N HCl in 2-propanol solution (1.5 ml). After the overnight reaction, the solution was filtered and the solvent evaporated. The white crystalline product was dried under vacuum to give 1.61 g of the Boc-hArg-Amp intermediate product.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4](O)[CH:3]=1.[CH2:11]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>>[CH2:11]([N:15]([CH2:16][CH2:17][CH2:18][CH3:19])[C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1)[CH2:12][CH2:13][CH3:14]
Reactant: Cc1cc(O)cc(O)c1
Reactant: CCCCNCCCC
Solvent: O
Product: CCCCN(CCCC)c1cc(C)cc(O)c1
Temperature: 200 °C
Reaction time: 48 h
Yield: 61 %

Procedure:
A 300 milliliter Parr minibomb was charged with orcinol monohydrate, 42 grams, 0.3 mole and di-n-butylamine, 128 milliliters. The bomb was sealed and heated to 200° C. At this temperature the internal pressure of the bomb was 90 pounds per square inch as registered on the gauge. After 48 hours at 200°, the bomb was cooled and the light brown syrup analyzed by thin-layer chromatography. The excess di-n-butylamine was removed by distillation at 20 Torr and the product was further purified by filtration through a silica gel column using ethyl acetate as the eluent. The product 3-dibutylamino-5-methylphenol was isolated in 61% yield: 43 grams. This material was not further characterized but used directly in the subsequent reaction.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]([CH2:37][CH:38]=O)[C:34](=[O:40])[CH:33]=[CH:32]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:38][CH2:37][N:35]4[C:36]5[C:31](=[CH:30][CH:29]=[CH:28][C:27]=5[CH3:26])[CH:32]=[CH:33][C:34]4=[O:40])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: Cc1cccc2ccc(=O)n(CC=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cccc2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
To 2 mL of a chloroform solution containing 0.24 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.14 g of (8-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde, 20 μL of acetic acid and 0.22 g of sodium triacetoxyborohydride were added, and stirred at room temperature overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; hexane:ethyl acetate=1:1], to give 0.13 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(8-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white foam.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[S:4].[CH2:7]([O:14][N:15]1[C:24](=[O:25])[C:23]2[CH:26]=[C:27]([OH:29])[CH:28]=[C:21]3[C:22]=2[C:17](=[CH:18][CH:19]=[CH:20]3)[C:16]1=[O:30])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>CN(C=O)C.O>[CH3:1][N:2]([CH3:6])[C:3]([O:29][C:27]1[CH:28]=[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:22]2=[C:23]([CH:26]=1)[C:24](=[O:25])[N:15]([O:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:16]3=[O:30])=[S:4]
Reactant: CN(C)C(=S)Cl
Reactant: O=C1c2cccc3cc(O)cc(c23)C(=O)N1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=S)Oc1cc2c3c(cccc3c1)C(=O)N(OCc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of excess dimethylthiocarbamoyl chloride in DMF (20 mL) was added to a mixture of 2-benzyloxy-5-hydroxy-benzo[de]isoquinoline-1,3-dione (3.5 g, 11.0 mmol) and sodium hydroxide (0.9 g, 22 mmol) in water (50 mL) at 0° C. The mixture was stirred vigorously at room temperature for 2 hours. The solid formed was filtered, washed with water, and dried. The crude product (0.5 g) was purified by column chromatography (silica gel using 2% methanol in chloroform). Fractions containing the target compound were combined, concentrated, and recrystallized from chloroform:ether mixture to give 0.3 g of the title compound, mp 211-214° C.;
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][C:14]=2[Cl:23])[C:9]=1[CH:10]1[CH2:12][CH2:11]1)=O.[NH2:24][C:25]([NH2:27])=[NH:26]>>[CH:10]1([C:9]2[N:8]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][C:14]=3[Cl:23])[N:7]=[CH:6][C:5]=2[C:3]([NH:26][C:25]([NH2:27])=[NH:24])=[O:2])[CH2:11][CH2:12]1
Reactant: N=C(N)N
Reactant: COC(=O)c1cnn(-c2ccc(S(C)(=O)=O)cc2Cl)c1C1CC1
Product: CS(=O)(=O)c1ccc(-n2ncc(C(=O)NC(=N)N)c2C2CC2)c(Cl)c1

Procedure:
coupling said 5-cyclopropyl-1-(2-chloro-4-methanesulfonylphenyl)-1H-pyrazole-4-carboxylic acid methyl ester with guanidine to form N-{5-cyclopropyl-1-(2-chloro-4-methanesulfonylphenyl)-1H-pyrazole-4-carbonyl}-guanidine.
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.N1C=CC=CC=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([NH:28][C:29]([C:31]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])[CH3:27])=[CH:22][CH:21]=1.[Na+].[Cl-]>ClCCl>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([NH:28][C:29]([C:31]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:32][CH2:33][N:34]([C:7]([Cl:10])=[O:6])[CH2:35][CH2:36]2)=[O:30])[CH3:27])=[CH:22][CH:21]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@H](NC(=O)C1(c2ccccc2)CCNCC1)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H](NC(=O)C1(c2ccccc2)CCN(C(=O)Cl)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
To a solution of triphosgene (172 mg, 0.6 mmol) in dichloromethane (6 mL) at 0° C. under an argon atmosphere was added a solution of pyridine (106 μL, 1.32 mmol) in dichloromethane (3 mL) and a solution of 4-phenyl-piperidine-4-carboxylic acid [(S)-1-(4-fluoro-phenyl)-ethyl]-amide (195 mg, 0.6 mmol) in dichloromethane (6 ml). After stirring at room temperature for 12 h the reaction mixture was poured into ice water, the aqueous layer was saturated with NaCl, then extracted 6 times with dichloromethane, the combined organic layers were dried over Na2SO4 and the solvents were evaporated. The residue was purified by flash chromatography over a 10 g silica gel column with n-heptane and ethyl acetate to yield 233 mg 4-[(S)-1-(4-fluoro-phenyl)-ethylcarbamoyl]-4-phenyl-piperidine-1-carbonyl chloride. MS ISN (m/e): 387.4 [(M−H)−].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:18]([O:20][CH2:21][C:22](O)=O)[CH3:19].[OH-].[Na+]>O>[CH2:18]([O:20][CH2:21][C:22]1[N:12]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:19]
Reactant: CC(C)CCNc1c(N)cnc2ccccc12
Reactant: CCOCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOCc1nc2cnc3ccccc3c2n1CCC(C)C
Temperature: 155 °C

Procedure:
3-Amino-4-(3-methylbutylamino)quinoline (7 g, 0.03 mole; Example 106) was combined with ethoxyacetic acid (8 mL, 0.08 mole) and heated at 150-160° C. for about 2 hours. The reaction mixture was cooled to room temperature, diluted with water (100 mL), made basic with sodium hydroxide and then extracted with ethyl acetate. The extract was dried over magnesium sulfate then evaporated to provide the crude product as a crystalline solid. The solid was recrystallized from hexane to provide the desired product as a solid, m.p. 64-65° C. Analysis: Calculated: %C, 72.7; %H, 7.8; %N, 14.1; Found: %C, 72.5; %H, 7.7; %N, 14.1.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([CH2:14][OH:15])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>ClCCl>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([CH:14]=[O:15])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: OCc1ccc(-c2cccc(C(F)(F)F)c2)o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc(-c2cccc(C(F)(F)F)c2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the compound (0.45 g) obtained in Example 130b in dichloromethane (4 mL) was cooled in an ice bath, and Dess-martin reagent (0.94 g) was added. After stirring at room temperature for 1 hr, water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium thiosulfate solution, dried over magnesium sulfate, and concentrated under reduced pressure to give a crude title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([O:8][CH3:9])[CH:7]=1.[C:11](OCC)(=[O:16])[CH2:12][C:13]([CH3:15])=O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:10][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[O:8][CH3:9])[NH:1][C:13]([CH3:15])=[CH:12][C:11]2=[O:16]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1cc(N)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COc1cc2[nH]c(C)cc(=O)c2cc1Cl
Temperature: 90 °C
Yield: 45.3 %

Procedure:
A solution of 5-amino-2-chloroanisole (10.0 g, 63.5 mmol), ethyl acetoacetate (8.1 ml, 63.5 mmol) and catalytic para-toluene sulfonic acid (302 mg, 1.59 mmol) in 65 ml benzene over 4 A molecular sieves was stirred 6 hours at reflux (90° C. external temperature). The reaction mixture was then filtered and concentrated in vacuo. A mixture of the resulting residue and 6.4 ml DOWTHERM A was heated to 250° C. for 20 min. The reaction mixture was cooled to room temperature, and the precipitate was washed with hexanes and ethyl acetate to give 6.43 g (45% yield) of 6-chloro-7-methoxy-2-methylquinolin-4(1H)-one as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ 11.54 (bs, 1H), 7.94 (s, 1H), 7.02 (s, 1H), 5.86 (s, 1H), 3.94 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7]([NH:9][C@H:10]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=O)=[O:13])[CH3:11])=[O:8])[CH3:6])(=[O:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:37]([O:39][C:40](=[O:49])[C@:41]([C:44](=[O:48])[N:45]([CH3:47])[NH2:46])([CH3:43])[OH:42])[CH3:38]>O1CCCC1>[CH2:37]([O:39][C:40](=[O:49])[C@:41]([C:44](=[O:48])[N:45]([CH3:47])[NH:46][C:16](=[O:18])[C@@H:15]1[CH2:19][CH2:20][CH2:21][N:14]1[C:12](=[O:13])[C@H:10]([CH3:11])[NH:9][C:7](=[O:8])[C@H:5]([CH3:6])[NH:4][C:1](=[O:3])[CH3:2])([CH3:43])[OH:42])[CH3:38]
Reactant: CCOC(=O)[C@](C)(O)C(=O)N(C)N
Reactant: CC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@](C)(O)C(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)NC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of acetylalanylalanylproline (0.66 mole) and N-methylmorpholine (0.66 mole) in dry tetrahydrofuran (25 ml) at -20° to -25° is added isobutylchloroformate (0.66 mmole). After 10 minutes a solution of 2-azaalanyl-l-lactic acid ethyl ester (0.66 mmole, example 3, step B) in tetrahydrofuran (2 ml) is added dropwise and the mixture is allowed to warm to room temperature over a period of 1 hour and stirred for a further 3 hours. The precipitate is removed by filtration, and the filtrate is concentrated to dryness. Chromatography of the residue on a silica gel (30 gm) and elution with 8% methanol in chloroform yields acetylalanylalanylprolyl-2-azaalanyl-l-lactic acid ethyl ester.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH2:14]1)=O>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH2:14]1
Reactant: COc1cccc([C@H]2CCCN(C(=O)[C@H]3COc4ccccc4O3)C2)c1
Solvent: C1CCOC1
Product: COc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Yield: 35 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(3-methoxyphenyl)piperidin-1-yl]-methanone (21 mg, 0.059 mmol) was treated with BH3 THF according to the above general procedure. Flash chromatography gave 7.0 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]([C:12]#[N:13])([CH2:10][CH3:11])[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].N>C(O)C.[Ni]>[C:1]([O:5][C:6](=[O:14])[C:7]([CH2:12][NH2:13])([CH2:10][CH3:11])[CH2:8][CH3:9])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCC(C#N)(CC)C(=O)OC(C)(C)C
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCC(CC)(CN)C(=O)OC(C)(C)C

Procedure:
29.21 g of 2-cyano-2-ethylbutyric acid tert-butyl ester, dissolved in 300 ml of ethanol, which contains 4% ammonia, are hydrogenated after normal pressure at 40° in the presence of 6 g of Raney nickel. After separating off from the catalyst, the batch is concentrated by evaporation in vacuo and the liquid that remains is distilled in vacuo to yield 2-aminomethyl-2-ethylbutyric acid tert-butyl ester, boiling point 65° at 0.6 mbar.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:37]=[CH:36][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]3[C:24]4[C:19](=[N:20][CH:21]=[C:22]([O:25][Si](C(C)C)(C(C)C)C(C)C)[CH:23]=4)[NH:18][CH:17]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:37]=[CH:36][C:6]([CH2:7][NH:8][C:9]2[N:10]=[CH:11][C:12]([CH2:15][C:16]3[C:24]4[C:19](=[N:20][CH:21]=[C:22]([OH:25])[CH:23]=4)[NH:18][CH:17]=3)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CC(C)[Si](Oc1cnc2[nH]cc(Cc3ccc(NCc4ccc(C(F)(F)F)cc4)nc3)c2c1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1cnc2[nH]cc(Cc3ccc(NCc4ccc(C(F)(F)F)cc4)nc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To (4-Trifluoromethyl-benzyl)-[5-(5-triisopropylsilanyloxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (85, 0.13 g, 0.23 mmol) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (3 mL, 1.0M in tetrahydrofuran, 3 mmol). The reaction mixture was stirred at room temperature overnight, and then was stirred at 65° C. for 48 hours. The reaction mixture was concentrated and purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a viscous liquid (P-0061, 0.062 g, 66%). MS (ESI) [M+H+]+=399.19.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[NH:54]1[CH:58]=[N:57][C:56]([C:59](O)=[O:60])=[N:55]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:59]([C:56]2[N:57]=[CH:58][NH:54][N:55]=2)=[O:60])[CH2:48]1
Reactant: O=C(O)c1nc[nH]n1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCN(C(=O)c2nc[nH]n2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 68 %

Procedure:
The desired compound was prepared according to the procedure of Example D97, step A, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 1H-1,2,4-triazole-3-carboxylic acid as the starting materials in 68% yield. LCMS for C26H26ClN10O2 (M+H)+: m/z=545.0.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:10][O:9][C:7]([C:5]1[N:6]=[C:2]([N:21]2[CH2:20][CH2:19][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:23][CH2:22]2)[S:3][CH:4]=1)=[O:8]
Reactant: COC(=O)c1csc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1csc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 150 °C
Yield: 35.1 %

Procedure:
Methyl 2-chlorothiazole-4-carboxylate (500 mg, 2.82 mmol), N-Boc-piperazine (655 mg, 3.52 mmol) and DIPEA (736 uL, 4.22 mmol) were dissolved in DMA (10 mL) and the reaction mixture was heated in a microwave reactor at 150° C. for 45 min. The reaction mixture was partitioned between EtOAc (40 mL) and water (40 mL) and the organic fraction was washed with water (40 mL) and brine (40 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound as a white solid (324 mg, 35.1%). LCMS (ES+): 350.1 [MNa]+. HPLC: Rt 6.04 min, 100% purity.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[C:17]4[CH2:18][CH2:19][CH:20]([C:22]([O:24]CC)=[O:23])[CH2:21][C:16]=4[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[C:17]4[CH2:18][CH2:19][CH:20]([C:22]([OH:24])=[O:23])[CH2:21][C:16]=4[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCc2c(sc3ncnc(Nc4cccc(Br)c4)c23)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CCc2c(sc3ncnc(Nc4cccc(Br)c4)c23)C1
Yield: 86 %

Procedure:
In a 15 mL round-bottom flask were placed 100 mg (0.23 mmol, 1 equiv) of ethyl 4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate in 3 mL of methanol and 1.5 mL of THF. The mixture was stirred until all solids dissolved and then 0.93 mL (0.93 mmol, 4 equiv) of 1N NaOH was added. The reaction was allowed to stir at rt for 16 h and then organic solvents were concentrated in vacuo. The resulting residue was re-dissolved in H2O (10 mL) and the solution was acidified to pH 5 with 1N HCl. Once the solution was slightly acidic a white solid precipitated; the precipitate was filtered and washed with water (15 mL) and dried in a hi-vac oven overnight to provide 80 mg (87%) of the desired product, 1, as a pure white solid. 1H-NMR (DMSO-d6) δ 12.20 (s, 1H), 8.42 (s, 1H), 8.42 (s, 1H), 7.95 (t, 1H), 7.67–7.64 (m, 1H), 7.30–7.21 (m, 2H), 3.25–2.81 (m, 5H), 2.34–2.18 (m, 1H), 1.83–1.97 (m, 1H); LCMS RT=2.94 min; [M+H]+=406.2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23](Br)[O:22][C:18]=2[N:19]=[CH:20][N:21]=1.[CH3:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[CH3:35])[O:22][C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)CCCCCNc1ncnc2oc(Br)c(-c3ccc(OC)cc3)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3C)c(-c3ccc(OC)cc3)c12
Reaction time: 15 h

Procedure:
Add 0.5 ml of 2 M aqueous potassium carbonate solution to a mixture of 224 mg (0.50 mmol) 6-{[6-bromo-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester and 29 mg (0.03 mmol) tetrakis(triphenylphosphine)palladium(0) in 2.5 ml 1,2-dimethoxyethane. Next, add 85 mg (0.63 mmol) (2-methylphenyl)boronic acid and stir the mixture for 15 h under reflux. Filter the reaction mixture and purify directly by preparative RP-HPLC (gradient: water/acetonitrile). 68 mg (30% of theor.) of the desired product is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[N+:10]([CH:12](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:13])#[C-:11].C([O-])([O-])=O.[K+].[K+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:11]=[N:10][C:12]=2[CH3:13])=[N:6][CH:7]=1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ncoc1-c1ccc(Br)cn1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A mixture of 5-bromopicolinaldehyde (7.80 g, 41.9 mmol), 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (8.78 g, 41.9 mmol), and K2CO3 (7.53 g, 54.5 mmol) in MeOH (150 mL) was heated at reflux for 3 hr. The reaction was then cooled to room temperature, the MeOH was evaporated at reduced pressure, and the crude material was partitioned between EtOAc and water. The separated aqueous layer was extracted twice with EtOAc. The combined organic extract was washed twice with water, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was chromatographed on silica gel (Analogix® SF65-600 column, 0% to 50% EtOAc/hexane) to afford 7.32 g (73%) of the title compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.78 (dd, J=2.4, 0.6, 1H), 8.44 (s, 1H), 8.15 (dd, J=8.5, 2.4, 1H), 7.64 (dd, J=8.5, 0.6, 1H), 2.50 (s, 3H). MS (DCI+) m/z 239/241 (M+H).
Reaction SMILES: S(O)(O)(=O)=O.CS[C:8](=[NH:10])[NH2:9].[OH-].[Na+].[N:13]1([CH2:20][C:21]2[S:22][C:23]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:25]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CO>[C:8]([N:28]([C:26]([C:23]1[S:22][C:21]([CH2:20][N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:25][CH:24]=1)=[O:27])[NH2:29])(=[NH:9])[NH2:10]
Reactant: NNC(=O)c1ccc(CN2CCCCCC2)s1
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N=C(N)N(N)C(=O)c1ccc(CN2CCCCCC2)s1
Temperature: 25 °C
Reaction time: 240 h
Yield: 114.2 %

Procedure:
6.07 g (21.7 mmol) of S-methylisothiourea sulfate and 43.5 ml (43.5 mmol) of 1 N NaOH were added to 11.0 g (43.4 mmol) of 2-(hexahydro-1H-azepin-1-yl)methylthiophene-5-carboxylic acid hydrazide, methanol was added to the reaction mixture until it became uniform solution (about 130 ml) and then the resulting solution was stirred at room temperature for 10 days. After removing insoluble matter by filtration, the solvent was evaporated and the resulting residue was directly subjected to a silica gel column chromatography, which was eluted with chloroform-methanol-aqueous ammonia (40:10:1) to give 7.32 g of the title compound.