Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:8]2[CH:12]=[C:11]([N+:13]([O-])=O)[C:10]([CH3:16])=[N:9]2)[CH:7]=1.C(OCC)(=O)C>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([NH2:13])[C:10]([CH3:16])=[N:9]2)[CH:5]=[N:4][CH:3]=1
Reactant: Cc1nn(-c2cncc(F)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1nn(-c2cncc(F)c2)cc1N
Reaction time: 3 h
Yield: 73.8 %

Procedure:
To a solution of 3-fluoro-5-(3-methyl-4-nitro-1H-pyrazol-1-yl)pyridine (3.133 g, 14.10 mmol) in ethanol (28.2 ml) was added ethyl acetate until all of the starting material went into solution. The solution was degassed and 10% palladium on carbon (0.750 g, 0.705 mmol) was added and the reaction was stirred in a parr hydrogenator at 40 psi for 3 hours. The solution was filtered through celite with ethyl acetate and concentrated to give 1-(5-fluoropyridin-3-yl)-3-methyl-1H-pyrazol-4-amine (2.000 g, 10.41 mmol, 73.8%) as a brown solid: mp 136.0-138.0° C.; 1H NMR (400 MHz, CDCl3) δ 8.67-8.59 (m, 1H), 8.27 (d, J=2.5 Hz, 1H), 7.73 (dt, J=9.9, 2.3 Hz, 1H), 7.45 (s, 1H), 3.01 (s, 2H), 2.28 (s, 3H); EIMS m/z 192.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][CH2:11][CH2:10][S:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].Cl.Cl[CH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH3:23]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.[OH-].[Na+].O>[CH3:23][N:19]1[CH2:20][CH2:21][CH2:22][CH:18]1[CH2:17][CH2:16][N:12]1[CH2:11][CH2:10][S:9][C:8]2[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]1=2
Reactant: CN1CCCC1CCCl
Reactant: O=[N+]([O-])c1ccc2c(c1)SCCN2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: CN1CCCC1CCN1CCSc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
A mixture of 7-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine (1 g, 5.10 mmol), 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (1.876 g, 10.19 mmol), and tetrabutylammonium bromide (0.082 g, 0.255 mmol) in dichloromethane (10 mL) and 50% NaOH solution (10 mL) was stirred at room temperature for 16 hours (overnight). The reaction was then diluted with dichloromethane (5 mL) and water (20 mL), and the mixture was transferred to a separatory funnel. The organic layer was removed, and the aqueous layer was extracted into dichloromethane (2×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The red crude material was subjected to column chromatography on silica gel using the Biotage purification system (80 g silicycle column; gradient: dichloromethane 3CV then ramp to 6:94 (2M NH3 in methanol):dichloromethane over 15CV; 254 nm; flow: 45 mL/min) to give the title compound as yellow-orange solid (0.827 g, 52.8%). 1H-NMR (DMSO-d6) δ 7.87 (dd, J=3.0, 9.0 Hz, 1H), 7.83 (d, J=3.0 Hz, 1H), 6.79 (d, J=9.3 Hz, 1H), 3.79-3.76 (m, 2H), 3.46 (t, J=8.1 Hz, 2H), 3.08-3.05 (m, 2H), 2.99-2.92 (m, 1H), 2.23 (s, 3H), 2.10-2.06 (m, 2H), 1.92-1.78 (m, 2H), 1.66-1.61 (m, 2H), 1.54-1.47 (m, 2H); ESI-MS (m/z, %): 308 (MH+, 100).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](O)=[O:9].ClC(Cl)C(OC(=O)C(Cl)Cl)=O.[CH2:22]1[O:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23]1>ClC(Cl)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([C:27]1[CH:28]=[CH:29][C:24]2[O:23][CH2:22][O:30][C:25]=2[CH:26]=1)=[O:9]
Reactant: c1ccc2c(c1)OCO2
Reactant: COCCCCCC(=O)O
Agent: O=C(OC(=O)C(Cl)Cl)C(Cl)Cl
Solvent: CC(Cl)Cl
Product: COCCCCCC(=O)c1ccc2c(c1)OCO2
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.5 %

Procedure:
In 50 ml of dichloroethane were dissolved 7.31 g (0.05 mole) of 6-methoxy hexanoic acid and 14.39 g (0.06 mole) of dichloroacetic anhydride. To the resulting solution were added 7.93 g (0.065 mole) of methylenedioxybenzene and 0.71 g of boron trifluoridediethyl ether complex and the resulting mixture was then stirred at 70° C. for 6 hours. After completion of the reaction, the reaction solution was cooled and washed with 5% aqueous sodium carbonate solution and water in this order. The organic layer was concentrated under reduced pressure to obtain 11.2 g of 4-(6-methoxyhexanoyl)-1,2-methylenedioxybenzene.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C[Si](C)(C)N[Si](C)(C)C.Cl[Si](C)(C)C>C1(C)C=CC=CC=1>[OH:5][CH2:4][C:3]1[C:2](=[O:1])[NH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)c1cccnc1O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: Cc1ccccc1
Product: O=c1[nH]cccc1CO
Reaction time: 2 h
Yield: 57.8 %

Procedure:
To a solution of 2-hydroxynicotinic acid (3-067-01) (5.0 g) in toluene (70 mL), and to the reaction mixture were added hexamethyldisilazane (HMDS, 19 mL) and chlorotrimethylsilane (TMSCl, 0.23 mL), and the reaction mixture was heated under reflux. After stirring for 2 h, the solvent was removed, and toluene was added to the residue. To the reaction mixture was added diisobutylaluminium hydride (DIBAL, 2 M toluene solution, 90 mL) at −78° C., after stirring for 4 h, the reaction was quenched with methanol. The insoluble substance was filtered off on Celite, and the filtrate was evaporated under reduced pressure. To the residue were added water and ethyl acetate, and the organic layer was separated, and then the aqueous layer was extracted with three times with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous magnesium sulfate, and evaporated to give 3-hydroxymethyl-2(1H)-pyridone (7-008-01) (2.6 g, 59%) as a white solid.
Reaction SMILES: [ClH:1].O=[C:3]([CH3:23])[CH2:4][C:5]1[CH2:6][N:7]([CH3:22])[CH2:8][CH2:9][CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[C:11]=12.[CH:24]([NH2:27])([CH3:26])[CH3:25].Cl.C([BH3-])#N.[Na+]>CO>[ClH:1].[ClH:1].[CH:24]([NH:27][CH:3]([CH3:23])[CH2:4][C:5]1[CH2:6][N:7]([CH3:22])[CH2:8][CH2:9][CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[C:11]=12)([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: COc1ccc2c(c1)CCC1CCN(C)CC(CC(C)=O)=C21
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CCC1CCN(C)CC(CC(C)NC(C)C)=C21

Procedure:
The solution of 0.84 g of 1-(2-oxopropyl)-9-methoxy-3-methyl-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepine hydrochloride, 1.28 ml of isopropylamine, 0.66 ml of 4.4 N methanolic hydrochloric acid and 0.17 g of sodium cyanoborohydride in 13 ml of methanol is refluxed overnight. Additional 0.085 g of sodium cyanoborohydride are added and the whole is again refluxed for 5 hours. The mixture is cooled, acidified to pH=1 with concentrated hydrochloric acid and the methanol evaporated. The aqueous solution is washed with diethyl ether, rendered basic to pH=10-11 with 3 N aqueous sodium hydroxide and extracted with diethyl ether. The ether extract is evaporated, the residue dissolved in acetone and 0.4 ml of 8 N ethanolic hydrochloric acid are added, to yield the 1-(2-isopropylaminopropyl)-9-methoxy-3-methyl-3,4,5,5 a,6,7-hexahydro-2H-naphth[1,2-d]azepine dihydrochloride melting at 257°-260° with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24](I)[CH:25]=[CH:26][C:17]=4[C:16]=3[N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C[C:30]([O:32]C(C)=O)=[O:31].C(O[Li])=O.[Li+].[Cl-].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:30]([OH:32])=[O:31])[CH:25]=[CH:26][C:17]=4[C:16]=3[N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(I)cc2NC(=O)C3)cc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(C(=O)O)cc2NC(=O)C3)cc1OC
Temperature: 80 °C

Procedure:
To a solution of 2-(3,4-dimethoxy-phenylamino)-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-30) (0.60 g, 1.20 mmol) in dry DMF (8 mL) was added Ac2O (0.23 mL, 2.44 mmol), HCOOLi (0.19 g, 3.66 mmol), LiCl (0.155 g, 3.66 mmol), and Pd(OAc)2 (0.01 g, 0.06 mmol). Lastly, i-Pr2NEt (0.42 mL, 2.44 mmol) was added and the mixture heated for 16 h at 80° C. in a sealed tube. The reaction mixture was then diluted with CH2Cl2 (30 mL), and the organic layer was washed with H2O (3×30 mL), dried over MgSO4, filtered and concentrated in vacuo to give crude product as a yellow solid. The solid was treated with EtOAc and sonicated to provide a white solid which was collected by filtration to provide I-53 (0.33 g, 71%): HRMS Calcd. for C21H18N4O5: 407.1355, Found 407.1364.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C@@H:11]([CH2:28][N:29]2[CH:34]3[CH2:35][C:36](=[O:38])[CH2:37][CH:30]2[CH2:31][O:32][CH2:33]3)[CH2:10]1)(=[O:8])=[O:7].[CH3:39][Mg]Br>C1COCC1>[CH3:39][C:36]1([OH:38])[CH2:35][C@H:34]2[N:29]([CH2:28][C@H:11]3[CH2:10][N:9]([S:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)(=[O:7])=[O:8])[CH2:14][CH2:13][N:12]3[C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[C@H:30]([CH2:31][O:32][CH2:33]2)[CH2:37]1
Reactant: C[Mg]Br
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2C3COCC2CC(=O)C3)cc1)C(F)(F)F
Solvent: C1CCOC1
Product: CC1(O)C[C@H]2COC[C@@H](C1)N2C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 0 °C

Procedure:
A 25-mL round-bottomed flask was cooled to 0° C. and charged with 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (50 mg, 0.087 mmol, Example 106) and THF (5 mL). Methylmagnesium bromide was added (3.0M in THF, 0.15 mL, 0.44 mmol, Sigma-Aldrich, St. Louis, Mo.) and after 20 min another 0.5 equivalent of methylmagnesium bromide was added. The reaction was then quenched with MeOH (50 mL), concentrated onto silica gel, and purified via column chromatography (12 g silica gel, 0 to 100% hexanes in EtOAc). The material was purified further via reverse-phase preparative HPLC using a Phenomenex Gemini C18 column (30×150 mm, 10 μm) eluting with 0.1% TFA in CH3CN/H2O (5% to 100% over 15 min) to give (1R,5S)-7-methyl-9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) (10 mg) as a mixture of two isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[O:12][C:11]3[CH:13]=[CH:14][C:15]([CH2:17][C:18]([C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[NH:22][CH:21]=4)=[O:19])=[CH:16][C:10]=3[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>CC(=O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)[O:12][C:11]3[CH:13]=[CH:14][C:15]([CH2:17][C:18]([C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]([CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH:21]=4)=[O:19])=[CH:16][C:10]=3[O:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCBr
Reactant: O=C(Cc1ccc2c(c1)OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)O2)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCn1cc(C(=O)Cc2ccc3c(c2)OC(c2ccc(Cl)cc2)(c2ccc(Cl)cc2)O3)c2ccccc21
Yield: 88.6 %

Procedure:
A suspension of 3-[(2,2-di[4-chlorophenyl]-1,3-benzodioxolan-5-yl)methylcarbonyl]-1H-indole (8.9 g) (see Preparation 10) in 2-butanone (200 ml) was treated with anhydrous potassium carbonate (12.2 g) and ethyl 4-bromobutanoate (5.2 g). The mixture was heated under reflux for 16 hours, filtered and evaporated. Flash chromatography (silica, eluant=dichloromethane) gave the title compound as a crystalline solid (9.68 g).
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([CH3:19])([CH3:18])[CH2:12][C:13](=[O:17])[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:25](O)[CH3:26]>>[CH2:25]([O:15][C:14](=[O:16])[C:13](=[O:17])[CH2:12][C:11]([C:5]1[C:6]2[O:10][CH2:9][O:8][C:7]=2[C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:19])[CH3:18])[CH3:26]
Reactant: CCO
Reactant: CC(C)(CC(=O)C(=O)O)c1ccc(Br)c2c1OCO2
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=O)CC(C)(C)c1ccc(Br)c2c1OCO2

Procedure:
300 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-4-methyl-2-oxo-valeric acid and 0.1 ml of sulfuric acid (96%) in 5 ml of ethanol are heated for 4 hours to 70° C. Then, the batch is concentrated by evaporation in a vacuum and added to water. It is extracted with ethyl acetate, washed with brine, dried and concentrated by evaporation in a vacuum. 272 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-4-methyl-2-oxo-valeric acid-ethyl ester is obtained as a yellow oil. This ester and 0.32 ml of trifluoromethyl-trimethylsilane in 4 ml of THF are mixed with 0.14 ml of a tetrabutylammonium fluoride solution (1 M in THF) at −70° C. It is stirred for 1 hour at −70° C., for 1.5 hours at −0° C., for 1 hour a and for 2 hours at room temperature. Another spatula-tip full of tetrabutylammonium fluoride is added, and after stirring is continued for 20 minutes, it is added to water. It is extracted with ethyl acetate, washed with water, dried with sodium sulfate and concentrated by evaporation in a vacuum. 297 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid-ethyl ester is obtained as a yellow oil. This oil is mixed in 5 ml of ether at 0° C. with 29 mg of lithium aluminum hydride, and stirred for 1 hour at 0° C. and for another 10 hours at room temperature. The batch is added to dilute hydrochloric acid, extracted with ethyl acetate, washed with water, dried with sodium sulfate and concentrated by evaporation in a vacuum. 164 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol is obtained as a yellow oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:28]=[CH:27][C:16]([C:17]([C@@H:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[C:24]([OH:26])=[O:25])=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>[Pd].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.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.COCCOC>[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([C@@H:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[C:24]([OH:26])=[O:25])=[O:18])=[CH:27][CH:28]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccc(B(O)O)cc1
Reactant: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: COCCOC
Product: Nc1ccc(-c2ccc(C(=O)[C@@H]3CCC[C@H]3C(=O)O)cc2)cc1
Temperature: 160 °C
Yield: 64.6 %

Procedure:
A mixture of 4-aminophenylboronic acid hydrochloride (0.21 g, 1.2 mmol), trans-2-(4-bromo-benzoyl)-cyclopentanecarboxylic acid (0.30 g, 1 mmol), tetrakis(triphenylphosphine) palladium (0) (10 mg), 2 M aqueous sodium carbonate solution (0.5 mL), ethanol (2 mL), and ethylene glycol dimethyl ether (3 mL) was heated under microwave condition to 160° C. for 30 min. The crude reaction mixture was adsorbed onto silica gel and flash chromatography (eluting with ethyl acetate and hexanes) yielded 0.2 g of trans-2-(4′-amino-biphenyl-4-carbonyl)-cyclopentanecarboxylic acid as a brown solid. LCMS calcd for C19H19NO3 (m/e) 309, obsd 310 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[OH:19].CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C.C(N(CC)CC)C>[NH2:1][C:2]1[C:3]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[OH:19])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccnc1C(=O)O
Reactant: Nc1ccc(F)cc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1nccnc1C(=O)Nc1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.3 %

Procedure:
3-Aminopyrazine-2-carboxylic acid (5 g) and 2-amino-5-fluorophenol (5.9 g) were dissolved into DMF (30 ml). Triethylamine (5.8 g) and HATU (19.2 g) were added to the mixture. The resulting mixture was stirred at room temperature for 24 hours. Ethyl acetate (100 ml) was added to the mixture. The resulting mixture was washed with brine (20 ml×3). The organic phase was dried and concentrated. The resulting residue was purified by chromatography on silica gel to give 3-amino-N-(4-fluoro-2-hydroxyphenyl)pyrazine-2-carboxamide (6 g). NMR Spectrum: (DMSOd6, 400 MHz) 6.60 (m, 2H), 7.50 (br s, 2H), 7.80 (s, 1H), 8.30 (m, 2H), 10.2 (s, 1H), 10.8 (s, 1H); Mass spectrum: MH+ 249.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[Cl:13][CH2:14][C:15]([CH3:19])([OH:18])[C:16]#[CH:17]>>[Cl:13][CH2:14][C:15]([C:16]1[N:8]([S:9]([CH3:12])(=[O:11])=[O:10])[C:3]2[C:2]([CH:17]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2)([OH:18])[CH3:19]
Reactant: CS(=O)(=O)Nc1ccccc1I
Reactant: C#CC(C)(O)CCl
Product: CC(O)(CCl)c1cc2ccccc2n1S(C)(=O)=O

Procedure:
This compound was prepared using the general Sonagashira procedure as described in General Example C, from N-(2-iodo-phenyl)-methanesulfonamide (1.65 g, 5.55 mmol) and 1-chloro-2-methyl-but-3-yn-2-ol (0.79 g, 6.66 mmol) to yield a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[S:13](Cl)(=[O:15])=[O:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:17][N:18]1[C:22]2=[N:23][CH:24]=[C:25]([CH2:27][NH2:28])[CH:26]=[C:21]2[CH:20]=[CH:19]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[S:13](=[O:15])(=[O:14])[NH:28][CH2:27][C:25]1[CH:26]=[C:21]2[CH:20]=[CH:19][N:18]([CH3:17])[C:22]2=[N:23][CH:24]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)Cl)c(Cl)c1
Reactant: Cn1ccc2cc(CN)cnc21
Product: CCOC(=O)c1ccc(S(=O)(=O)NCc2cnc3c(ccn3C)c2)c(Cl)c1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from ethyl 3-chloro-4-(chlorosulfonyl)benzoate and (1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine (step-1 of Example 35).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:25][C:26](=O)[NH:27][C:28]1[N:29]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:30]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:32]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([NH:21][C:26]([NH:27][C:28]3[N:29]([C:37]4[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=4)[N:30]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:32]=3)=[O:25])[CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N)ccn2)CC1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccnc(OC3CCN(C(=O)OC(C)(C)C)CC3)c2)cc1
Temperature: 25 °C
Yield: 46.9 %

Procedure:
Heat a solution of 4-(4-amino-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (Preparation 20, 1 g, 3.41 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Preparation 38, 1.38 g, 3.41 mmol), and diisopropylethylamine (1.2 mL, 6.82 mmol) in DMSO (15 mL) at 60° C. for 5 d. Cool the resulting mixture to room temperature and partition between water and ethyl acetate using saturated aq. sodium chloride solution to aid phase separation. Extract the aqueous layer with ethyl acetate, wash the combined organic layers twice with water, dry over sodium sulfate and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with a gradient of ethyl acetate in dichloromethane to give 877 mg (43% yield) of 4-{4-[3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-pyridin-2-yloxy}-piperidine-1-carboxylic acid tert-butyl ester. LCMS ES+(m/z) 549 [M+H].
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[N:6]=1.[CH2:14]([NH2:17])[CH2:15][NH2:16].C([O-])(O)=O.[Na+]>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([NH:16][CH2:15][CH2:14][NH2:17])[S:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: Brc1ccc(-c2csc(Br)n2)cc1
Reactant: NCCN
Agent: O=C([O-])O
Agent: [Na+]
Product: NCCNc1nc(-c2ccc(Br)cc2)cs1
Temperature: 130 °C
Yield: 97.4 %

Procedure:
2-Bromo-4-(4-bromophenyl)-1,3-thiazole (2.0 g, 6.2 mmol), prepared in step 2 of Example 1, was dissolved in ethylenediamine (10.0 mL, 185 mmol) and heated to 130° C. for 2 h. The mixture was cooled and poured into saturated NaHCO3 and extracted with ether. The ether extracts were combined and washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give N-[4-(4-bromophenyl)-1,3-thiazol-2-yl]ethane-1,2-diamine (1.8 g, 97%) as a yellow solid. HRMS: calcd for C11H12BrN3S+H+, 298.00080; found (ESI, [M+H]+), 298.0012. Analytical HPLC: retention time 7.0 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[Cl:18][C:19]1[CH:32]=[C:31]2[C:22]([N:23]=[C:24]3[C:29](=[C:30]2Cl)[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:19]1[CH:32]=[C:31]2[C:22]([N:23]=[C:24]3[C:29](=[C:30]2[N:4]2[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([N:11]5[CH2:16][CH2:15][O:14][CH2:13][CH2:12]5)[CH:6]=4)[C:2]([CH3:17])([CH3:1])[CH2:3]2)[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:21][CH:20]=1
Reactant: Clc1ccc2nc3c(c(Cl)c2c1)CCCC3
Reactant: CC1(C)CNc2cc(N3CCOCC3)ccc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC1(C)CN(c2c3c(nc4ccc(Cl)cc24)CCCC3)c2cc(N3CCOCC3)ccc21

Procedure:
Prepared according to procedure T using 4-(3,3-dimethylindolin-6-yl)morpholine (0.2 g, 0.86 mmol), 7,9-dichloro-1,2,3,4-tetrahydroacridine (0.434 g, 1.72 mmol), cesium carbonate (0.561 g, 1.72 mmol), Pd2(dba)3 (0.079 g, 0.086 mmol) and (±) BINAP (0.084 g, 0.129 mmol) in 1,4-dioxane (2 mL). The crude residue was purified by HPLC to give 7-chloro-9-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-1,2,3,4-tetrahydroacridine. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.04 (1H, d, J=9.5 Hz), 7.85 (2H, m), 7.14 (1H, d, J=8.3 Hz), 6.47 (1H, d, J=8.3 Hz), 5.84 (1H, s), 3.90 (2H, m), 3.60 (4H, m), 3.17 (2H, t, J=6.4 Hz), 2.89 (4H, m), 2.59 (2H, m), 1.79 (4H, m) 1.41 (3H, s), 1.37 (3H, s). Mass Spectrum (ESI) m/e=449 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][NH:4][C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10]([SH:12])[S:11][C:7]=2[CH:6]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>ClCCl>[SH:12][C:10]1[S:11][C:7]2[CH:6]=[C:5]([N:4]([CH2:3][CH:2]([CH3:15])[CH3:1])[C:25]([NH:24][C:21]3[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:27])[F:28])=[CH:23][CH:22]=3)=[O:26])[CH:14]=[CH:13][C:8]=2[N:9]=1
Reactant: CC(C)CNc1ccc2nc(S)sc2c1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: CC(C)CN(C(=O)Nc1ccc(C(F)(F)F)cc1)c1ccc2nc(S)sc2c1
Reaction time: 8 h
Yield: 64.1 %

Procedure:
Into 50 ml round bottomed flask were added 6-[(2-methylpropyl)amino]-1,3-benzothiazole-2-thiol (52.36 mg, 0.22 mmol), dichloromethane (10 ml), and α,α,α-trifluoro-p-tolyl isocyanate (41.1 mg, 0.22 mmol). The reaction mixture was stirred 8 h, filtered, and the solid that was obtained was triturated with chloroform, followed with chloroform/methanol (9:1 mixture) to give 60 mg (64%) of the title compound. 1H NMR (DMSO-d6) δ=0.84 (d, 6H), 1.66 (m, 1H), 3.49 (d, 2H), 7.30 (s, 2H), 7.50 (d, 2H), 7.60 (d, 2H), 7.71 (s, 1H); ESIMS: m/z 424 (M−H).