Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[CH2:13][NH:12]1)[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[CH2:22]([N:12]1[CH2:13][C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CNN1C1C2CC3CC(C2)CC1C3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CN(Cc2ccccc2)N1C1C2CC3CC(C2)CC1C3
Reaction time: 24 h
Yield: 51.3 %

Procedure:
Under an argon atmosphere, a solution of 2-(adamantan-2-yl)-1,2-diazetidin-3-one (10.2 mg, 0.05 mmol) in N,N-dimethylformamide (1 mL), potassium carbonate (28.0 mg, 0.100 mmol) and benzyl bromide (35.0 mg, 0.100 mmol) were added at room temperature, and the resultant was stirred at the same temperature for 24 hours. The reaction solution was added with water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, the obtained residue was purified using Preparative Thin-Layer chromatography (hexane:ethyl acetate=2:1), and the title compound (7.60 mg, 48.6%) was obtained as a colorless oil.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:6]=1[Cl:21])C=C.C(N(CC)[C:25]1[CH:30]=CC=C[CH:26]=1)C>>[CH2:30]([C:10]1[C:9]([Br:11])=[CH:8][C:7]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[C:6]([Cl:21])[C:5]=1[OH:4])[CH:25]=[CH2:26]
Reactant: C=CCOc1cc(Br)cc(Cc2ccc(OC)cc2)c1Cl
Reactant: CCN(CC)c1ccccc1
Product: C=CCc1c(Br)cc(Cc2ccc(OC)cc2)c(Cl)c1O
Temperature: 200 °C
Reaction time: 45 h
Yield: 91 %

Procedure:
The mixture of bromide 184 (2.52 g, 6.85 mmol) in N,N-diethylaniline (8 mL) was stirred at 200° C. for 45 hours. The mixture was cooled to rt and extracted with EtOAc/aq. 1N HCl solution (100 mL/100 mL). The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the desired product 185 (2.3 g, 91%).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[N:5][CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:3]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].C1C(=O)N([Br:34])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:34][CH2:1][C:2]1[NH:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[N:5][CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:3]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2nccs2)=NC1c1ccccc1[N+](=O)[O-]
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a solution of ethyl 6-methyl-4-(2-nitrophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (7.45 g, 20 mmol) in carbon tetrachloride (100 mL) was added NBS (3.74 g, 21 mmol) under N2 at 60° C. The mixture was stirred at 60° C. for 10 minutes, and cooled to 25° C. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=3/1) to give the title compound as a yellow solid (6.32 g, 70%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][CH2:13][CH3:14])[CH3:11])=[CH:5][CH:4]=1.[O:15]=[C:16]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[CH2:23][CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:13]([N:12]([CH:10]([CH3:11])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:24][CH2:23][N:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:16]1=[O:15])[CH3:14]
Reactant: O=CCN1CCCCCC1=O
Reactant: CCNC(C)Cc1ccc(OC)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCN(CCN1CCCCCC1=O)C(C)Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 91.9 %

Procedure:
A mixture of [2-(4-methoxyphenyl)-1-methylethyl]ethylamine (0.53 g, 2.75 mmole), (2-oxo-azepan-1-yl)acetaldehyde (0.5 g, 3.2 mmole), and sodium triacetoxyborohydride (0.88 g, 4.1 mmole) in 1,2-dichloroethane (15 mL) was stirred at room temperature for 60 hours. The mixture was concentrated, and the residue was partitioned between diethyl ether (50 mL) and saturated aqueous sodium bicarbonate (25 mL). The organic solution was extracted with 5% hydrochloric acid (20 mL), and the aqueous acidic phase was washed with diethyl ether and the pH was adjusted to 12 with 25% sodium hydroxide. The mixture was extracted with dichoromethane, and the organic phase was dried (sodium sulfate) and concentrated to give 1-(2-{ethyl-[2-(4-methoxyphenyl)-1-methylethyl]amino}ethyl)-azepan-2-one 11 (0.84 g) as a viscous oil, which was converted to the dibenzoyl-L-tartrate salt, Anal.: Calcd. for C38H46N2O10: C, 66.07; H, 6.71; N, 4.06%. Found C, 64.69; H, 6.45; N, 3.90%.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]([C:11]#[N:12])[CH2:6][CH2:7][CH2:8][C:9]#[N:10])#[N:2].[C:13]([N:15]=[C:16]([NH2:18])[NH2:17])#[N:14].C[O-].[Na+]>CS(C)=O>[NH2:14][C:13]1[N:15]=[C:16]([NH2:18])[N:17]=[C:1]([CH2:3][CH2:4][CH:5]([C:11]2[N:17]=[C:16]([NH2:18])[N:15]=[C:13]([NH2:14])[N:12]=2)[CH2:6][CH2:7][CH2:8][C:9]2[N:17]=[C:16]([NH2:18])[N:15]=[C:13]([NH2:14])[N:10]=2)[N:2]=1
Reactant: N#CN=C(N)N
Reactant: N#CCCCC(C#N)CCC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1nc(N)nc(CCCC(CCc2nc(N)nc(N)n2)c2nc(N)nc(N)n2)n1
Temperature: 130 °C
Yield: 70.6 %

Procedure:
161 g (1 mole) of 1,3,6-tricyanohexane and 277.2 g (3.3 moles) of dicyandiamide were added to 750 g of dimethyl sulfoxide as the reaction medium, followed by further addition of 68 g (1 mole) of sodium methylate as the catalyst. The mixture was stirred under heating at 130° C for 3 hours in a nitrogen atmosphere. After completion of the reaction the reaction mixture was cooled to 25° C to precipitate the reaction product, followed by separating the crude reaction product by filtration. Purification was conducted by dissolving the crude product in excess amount of dimethyl sulfoxide at 135° C and then precipitating the product by cooling. After repeating this procedure 5 times, 292 g of 1,3,6-tris(4,6-diamino-1,3,5-triazine-2-yl)hexane as a white powder were obtained.
Reaction SMILES: [CH3:1][S:2]([N:5](S(C)(=O)=O)[C:6]1[N:11]=[C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([F:22])=[CH:14][CH:13]=2)[CH:9]=[C:8]([CH:23]([CH3:25])[CH3:24])[N:7]=1)(=[O:4])=[O:3].[OH-].[Na+]>CO>[CH3:1][S:2]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([F:22])=[CH:14][CH:13]=2)[CH:9]=[C:8]([CH:23]([CH3:25])[CH3:24])[N:7]=1)(=[O:3])=[O:4]
Reactant: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(N(S(C)(=O)=O)S(C)(=O)=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(NS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 2-(bismethanesulfonyl)amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine product from Example 10B above (0.204 g) was dissolved in methanol (5 mL) and treated at room temperature with 2.5N sodium hydroxide solution (0.2 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated to dryness and recrystallized to afford 2-(methanesulfonyl)amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine as a crystalline material, m.p. 276-276.9° C. (prior decomposition at 273° C.).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10](N)[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][O:14][CH3:15])[N:8]=2)[N:3]=1.C(O)(=[O:18])C>[OH-].[Na+]>[NH2:1][C:2]1[NH:11][C:10](=[O:18])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][O:14][CH3:15])[N:8]=2)[N:3]=1
Reactant: CC(=O)O
Reactant: COCc1cnc2nc(N)nc(N)c2n1
Agent: [Na+]
Agent: [OH-]
Product: COCc1cnc2nc(N)[nH]c(=O)c2n1
Yield: 83 %

Procedure:
The diaminopteridine, vide supra, was hydrolyzed in 1N NaOH at 70° C. for 3 hr. The resulting basic solution was then acidified with acetic acid, and the yellow product was filtered, washed with 95% ethanol and ethyl ether, and dried under vacuum overnight to yield 0.5 g (83%) of 2-amino-6-methoxymethyl-4(3H)-pteridinone as a yellow powder: UV (0.1N NaOH) λmax 255 nm (22300), 277.5 nm sh (6200), 364 nm (7100); NMR: δ (d6 -DMSO) 3.36 (s, OMe); 4.53 (s, CH2O); 7.32 (br s, NH2); and 8.63 (s, 7-H). Anal. calcd. for C8H9N5O2.7/10H2O: C, 43.72; H, 4.77; N, 31.86. Found: C, 43.77; H, 4.77; N, 31.63.
Reaction SMILES: [OH:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[N:5]([CH3:14])[C:4](=[O:15])[C:3]=1[C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=1[CH3:24].[N+:25]([O-])([OH:27])=[O:26]>C(Cl)(Cl)Cl>[CH3:13][O:12][N:9]1[CH2:10][CH2:11][C:6]2([N:5]([CH3:14])[C:4](=[O:15])[C:3]([N+:25]([O-:27])=[O:26])([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=3[CH3:24])[C:2]2=[O:1])[CH2:7][CH2:8]1
Reactant: CON1CCC2(CC1)C(O)=C(c1c(C)cc(C)cc1C)C(=O)N2C
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Product: CON1CCC2(CC1)C(=O)C(c1c(C)cc(C)cc1C)([N+](=O)[O-])C(=O)N2C
Temperature: 0 °C
Reaction time: 72 h

Procedure:
To a solution of 4-hydroxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P2.2) (150 mg, 0.454 mmol) in chloroform (5 ml) at −5° C. was added fuming nitric acid (0.038 ml, 57.8 mg, 0.917 mmol) in chloroform (0.5 ml) dropwise. The reaction mixture was stirred at 0° C. for 30 minutes and at room temperature for three days, poured on ice water (10 ml), the layers were separated, the water phase extracted with ethyl acetate (3×20 ml), the combined organic phases washed with water (15 ml) and brine (15 ml), dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/cyclohexane 1:3). Yield: 90 mg of 8-methoxy-1-methyl-3-nitro-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]decane-2,4-dione (title compound P1.13) as a white solid, mp 127-129° C.
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][N:14]1[C:18]2[CH:19]=[C:20]([C:23]([O:25]C)=[O:24])[CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.O>[C:3]([O:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][N:14]1[C:18]2[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH:27][C:28]1[CH:29]=[C:30]([O:38][CH3:39])[C:31]([O:36][CH3:37])=[C:32]([O:34][CH3:35])[CH:33]=1)=[O:9])([CH3:5])([CH3:4])[CH3:6]
Reactant: COC(=O)c1ccc2nc(Nc3cc(OC)c(OC)c(OC)c3)n(CCCNC(=O)OC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Nc2nc3ccc(C(=O)O)cc3n2CCCNC(=O)OC(C)(C)C)cc(OC)c1OC
Temperature: 25 °C

Procedure:
Lithium hydroxide (2.18 g, 6 eq) is added to a solution of methyl 1-{3-[(tert-butoxycarbonyl)amino]propyl}-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-6-carboxylate (4.4 g, 1 eq) in a mixture of tetrahydrofuran (40 ml) and water (30 ml). The mixture is heated under reflux for 18 hours then cooled down to ambient temperature and concentrated under reduced pressure at 40° C. Dichloromethane (150 ml) and water (100 ml) are added to the residue. The mixture is acidified by the addition of acetic acid to pH 5. After decantation and extractions, the combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The solid obtained is washed with ethyl ether (3.95 g; 93%).
Reaction SMILES: ClC[C:3]([N:5]([CH2:16][CH:17]1[C:25]2[C:20](=[CH:21][C:22]([C:26]#[N:27])=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)[CH2:6][CH2:7][NH:8][C:9](=O)OC(C)(C)C)=[O:4].CCO.C([O-])([O-])=O.[K+].[K+]>Cl.O1CCOCC1>[O:4]=[C:3]1[CH2:9][NH:8][CH2:7][CH2:6][N:5]1[CH2:16][CH:17]1[C:25]2[C:20](=[CH:21][C:22]([C:26]#[N:27])=[CH:23][CH:24]=2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NCCN(CC1CCc2cc(C#N)ccc21)C(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCO
Product: N#Cc1ccc2c(c1)CCC2CN1CCNCC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of tert-Butyl (2-{(chloroacetyl)[(5-cyano-2,3-dihydro-1H-inden-1-yl)methyl]amino}ethyl)carbamate (125 mg, 0.32 mmol) in HCl/dioxane (20 mL) was stirred at RT for 12 hours and then concentrated to dryness. To the residue was added 2 mL EtOH and K2CO3 (300 mg, 2.0 mmol). The resulting mixture was heated to reflux for 4 hours before cooled to RT and filtered. The filtrate was concentrate and the residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to dryness to give 1-[(2-Oxopiperazin-1-yl)methyl]indane-5-carbonitrile. MS m/z: 256 [M+1]+.
Reaction SMILES: Cl.[CH3:2][N:3]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:4]([C:6]1[CH:14]=[CH:13][C:9]2=[N:10][O:11][N:12]=[C:8]2[CH:7]=1)=[O:5].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)(Cl)Cl>[CH3:2][N:3]([CH:15]1[CH2:20][CH2:19][N:18]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:17][CH2:16]1)[C:4]([C:6]1[CH:14]=[CH:13][C:9]2=[N:10][O:11][N:12]=[C:8]2[CH:7]=1)=[O:5]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)c1ccc2nonc2c1)C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C(=O)c1ccc2nonc2c1)C1CCN(S(C)(=O)=O)CC1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
N-Methyl-N-piperidin-4-yl-[2,1,3]-benzoxadiazole-5-carboxamide hydrochloride (0.38 g, 1.3 mmol) was suspended in chloroform (70 ml) and triethylamine (2 ml) was added. A solution of methane sulfonyl chloride (0.14 g, 1.26 mmol) in chloroform (10 ml) was added and the mixture was stirred at 20° C. for 2 h. The mixture was washed with water (50 ml) and H2SO4 (→pH 2) and NaHCO3 solution (50 ml) and the aqueous re-extracted with dichloromethane (2×50 ml). The combined organics were dried (MgSO4), concentrated under vacuum, and the crude product was purified on a silica gel column eluting with dichloromethane/THF (85:15) to give a white crystalline product, after crystallization from MTBE/hexane (204 mg). Mp=177-179° C., 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J=9.3 Hz, 1H); 7.85 (s, 1H); 7.42 (d, J=9.3 Hz, 1H); 4.75-4.46 and 4.10-3.90 and 3.10-2.40 (m, 5H); 2.92 (s, 3H), 2.83 (s, 3H) and 2.10-1.70 ppm (m, 4H).
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1Br)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].[CH2:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O)[CH3:25]>COCCOC>[CH2:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][CH2:7][C:6]([OH:5])=[O:17])[CH3:25]
Reactant: CCc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)COc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCc1ccccc1-c1cc(F)ccc1OCC(=O)O
Yield: 69.6 %

Procedure:
A solution of (2-bromo-4-fluoro-phenoxy)-acetic acid-t-butyl ester (2.00 g, 6.55 mmol) in DME (16 ml)/2M Na2CO3 (11.46 ml, 22.93 mmol) was treated with 2-ethylphenylboronic acid (1.96 g, 13.10 mmol), and Pd[PPh3]4 (757 mg, 0.655 mmol) in a microwave oven at 150° C. for 10 min. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 5-20% ethyl acetate/hexanes gradient to afford 1.25 g of colorless oil (t-butyl ester). This material was dissolved in 4N HCl/dioxane (10 ml) and stirred at rt overnight. Concentration under reduced pressure afforded the product as colorless oil (1.08 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:20])[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: COc1ccc(CN=C=O)cc1
Product: COc1ccc(CNC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cc1

Procedure:
Example 2 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-(isocyanatomethyl)-4-methoxybenzene (19.5 μl) to give the title compound (0.0257 g). LC-MS (System A): Rt 2.23 mins, Mass Spectrum m/z 438 [MH+].
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([O:10][CH3:11])[CH:4]=1)[CH3:2].C1C(=O)N([Br:19])C(=O)C1>CC#N>[Br:19][C:8]1[CH:7]=[C:6]([F:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc(F)c(OC)c1
Solvent: CC#N
Product: CCc1cc(OC)c(F)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.6 %

Procedure:
To a solution of 4-ethyl-1-fluoro-2-methoxy-benzene (WO 2010/090537, 12.2 g, 79.1 mmol) in MeCN (150 mL) was added a solution of NBS (14.4 g, 80.7 mmol) in MeCN (50 mL). The resulting solution was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was diluted with diethyl ether (150 mL). Precipitated solid was removed by filtration and the filtrate was washed with sodium sulfite aqueous solution (100 mL) and brine (100 mL), dried over MgSO4 and concentrated in vacuo to give the title compound as a yellow oil (18 g) in a 97% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]2[CH:6]=[C:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:15]>C1(C)C=CC=CC=1.CO>[CH3:1][C:2]1[CH:13]=[CH:12][C:5]2[CH:6]=[C:7]([C:9]([O:11][CH3:15])=[O:10])[O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2cc(C(=O)O)oc2c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2ccc(C)cc2o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 67.1 %

Procedure:
To a solution of 6-methylbenzofuran-2-carboxylic acid (11 g, 62.4 mmol) in 468 mL of toluene and 156 mL of MeOH was added 2N TMS-CHN2 (46.8 mL, 94 mmol) dropwise at room temperature. The reaction was stirred at room temperature for 6 hr. The reaction was then quenched by addition of acetic acid dropwise at 0° C. until the yellow color vanished, and gas evolution ceased. The reaction was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography, 100% Heptane-10% Ethyl Acetate/90% Heptane, to give methyl 6-methylbenzofuran-2-carboxylate (7.96 g). 1H NMR (400 MHz, DMSO-d6) δ 2.46 (s, 3H), 3.88 (s, 3H), 7.20 (dd, J=8.3, 1.0 Hz, 1H), 7.53 (s, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.71 (d, J=1.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[N:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1>CCCCO>[Br:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]2)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[N:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1cccc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Product: COc1cccc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)n1
Temperature: 160 °C
Reaction time: 48 h
Yield: 26.9 %

Procedure:
A solution of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-methoxypicolinamide (228 mg, 0.624 mmol) in n-BuOH (5 mL) was treated with (R)-tert-butyl piperidin-3-ylcarbamate (375 mg, 1.87 mmol) and stirred at 160° C. for 48 hours in a sealed tube. The mixture was concentrated in vacuo, and the residue diluted with water (25 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo and purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 5-85% CH3CN/water gradient; 25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(6-methoxypicolinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (91.5 mg, 27% yield) as a solid. LCMS (APCI+) m/z 445.1, 447.1, 454.1 (M+H)+, Retention time=4.03 minutes (Method 2).
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>>[CH2:1]([S:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH3:3]
Reactant: CCCSc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCSc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-propylthio-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:10]([NH:12][NH2:13])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:24](O)(=[O:26])[CH3:25]>C1COCC1>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:10]([NH:12][NH:13][C:24]([CH3:25])=[O:26])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 50 ml of THF is dissolved 2.0 g of Z-Phe-NHNH2, followed by adding 1.4 ml of anhydrous acetic acid and 0.9 ml of TEA under ice-cooling, and the mixture is stirred for 2 hours at room temperature. The precipitated crystals are collected by filtration, washed well with diethyl ether and recrystallized from ethyl acetate to give 1.9 g of crystals, m.p. 205°-206° C., [α]D23 -16.4° (c=0.50, DMF), Rf1 =0.60.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[CH:16]=[CH:15][C:11]2[N:12]=[CH:13][S:14][C:10]=2[CH:9]=1>C(N(CC)CC)C.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][Si:2]([C:5]#[C:6][C:8]1[CH:16]=[CH:15][C:11]2[N:12]=[CH:13][S:14][C:10]=2[CH:9]=1)([CH3:4])[CH3:3]
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ccc2ncsc2c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc2ncsc2c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
Trimethylsilylacetylene (106 ml), copper (I) iodide (0.948 g), and bis(triphenylphosphine) palladium(II) dichloride (1.75 g) were added to 6-bromobenzothiazole (53.3 g) in triethylamine (260 ml), and the mixture was stirred for 2.5 hours at 80° C. After the solvent was evaporated, the resultant residue was loaded on a short column (silica gel; hexane:ethyl acetate=2:1) for elution. The residue from the eluate was recrystallized from a mixed solvent of hexane-ethyl acetate, and consequently, 6-trimethylsilanylethynylbenzothiazole (20.0 g) was obtained as a colorless powder (mp: 104.5-105.0° C.). By repeated subjecting the filtrate to recrystallization repeated (n-hexhane-ethyl acetate), secondary crystals (12.1 g), tertiary crystals (9.68 g), and quaternary crystals (4.61 g) were obtained as a colorless powder.