Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[I:5]Cl.[CH3:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1.C([O-])(=O)C.[Na+]>O>[I:5][C:11]1[CH:10]=[N:9][N:8]([CH3:7])[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=1
Reactant: ClI
Reactant: Cn1nccc1-c1ccc(C(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1ncc(I)c1-c1ccc(C(F)(F)F)cc1
Reaction time: 4 h
Yield: 83.8 %

Procedure:
An acetic acid (3.3 mL) solution of iodine monochloride (2.64 g) was added dropwise to an acetic acid (22 mL) solution that contained 1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole (3.70 g) and sodium acetate (1.38 g) at a room temperature, and the obtained solution was then stirred for 4 hours. Thereafter, water (250 mL) was added to the reaction solution, and the obtained solution was then stirred for 30 minutes. Then, a precipitated solid was collected by filtration, and was then washed with water. The obtained solid was dissolved in ethyl acetate, and the obtained solution was then washed with water and a saturated sodium hydrogencarbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated under a reduced pressure. Thereafter, the residue was purified by column chromatography (silica gel 60N, hexane:ethyl acetate=5:1 to 7:3), so as to obtain the title compound (4.80 g) in the form of a brownish-red oily substance.
Reaction SMILES: C[O-].[Na+].[CH3:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[C:13]([C:17](=O)[CH3:18])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.C(OCC)=O.C(CC(N)=O)#N.[O:31]=[C:32]1[NH:39]C=C[CH:36]=[C:33]1[C:34]#[N:35]>O.C(OCC)C>[CH3:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[C:13]([C:17]3[NH:39][C:32](=[O:31])[C:33](=[CH:36][CH:18]=3)[C:34]#[N:35])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: N#Cc1ccc[nH]c1=O
Reactant: CC(=O)c1cccc(N2CCN(C)CC2)c1
Agent: C[O-]
Agent: N#CCC(N)=O
Agent: [Na+]
Solvent: CCOC=O
Solvent: O
Solvent: CCOCC
Product: CN1CCN(c2cccc(-c3ccc(C#N)c(=O)[nH]3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 5.3 g. (0.098 mole) of sodium methoxide in 100 ml. ethyl ether under nitrogen is cooled to 3° and treated dropwise with a solution of 18.4 g. (0.084 mole) of m-(4-methyl-1-piperazinyl)acetophenone and 6.25 g. (0.084 mole) of ethyl formate in 100 ml. ethyl ether while keeping the temperature below 5°. When the addition is completed, the mixture is allowed to stir at room temperature overnight. 100 ml. water is then added and the layers separated. The ethyl ether layer is washed with an additional 75 ml. water. The pH of the aqueous layer is adjusted to pH 9 with acetic acid. 10.6 g. (0.126 mole) of cyanoacetamide is then added and the solution heated at 90° for 6 hours. A solid formed which is collected and dried. Recrystallization from DMSO/water gives 14.8 g. (60.2%) of pure 6-m-(4-methyl-1-piperazinyl)-phenyl]-1,2-dihydro-2-oxonicotinonitrile, m.p. 264°-267° d., as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][CH2:9][CH2:10][C:11](Cl)=[O:12]>O1CCCC1>[Cl:8][CH2:9][CH2:10][C:11]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:12]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)CCCl
Solvent: C1CCOC1
Product: O=C(CCCl)Nc1ccccc1
Yield: 69.4 %

Procedure:
A solution of 5.6 g (0.06 mole) of aniline in 50 ml of tetrahydrofuran was added dropwise to a solution of 5.0 g (0.04 mole) of 3-chloropropionyl chloride in 50 ml of tetrahydrofuran. The reaction mixture was mechanically stirred and the temperature maintained between 5° and 15° C. throughout the addition. After the final addition, the solution was filtered to remove solid precipitates, and the filtrate was concentrated under reduced pressure to give a white solid. The solid was recrystallized from benzene and petroleum ether (30°-60° C.) to yield 5.1 g (69%) of white solid, mp 114°-115° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:18]([O-])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][F:16])[C:10](=[O:17])[CH2:9]1>C(OCC)(=O)C.CN(C=O)C>[NH2:18][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][F:16])[C:10](=[O:17])[CH2:9]2)=[C:2]([F:1])[CH:3]=1
Reactant: O=C1CN(c2ccc([N+](=O)[O-])cc2F)CCN1CCF
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCN(CCF)C(=O)C2)c(F)c1

Procedure:
3-Fluoro-4-(4-{2-fluoroethyl}-3-oxopiperazin-1-yl)nitrobenzene (4.35 g) is dissolved in a mixture of ethyl acetate (250 ml) and DMF (5 ml), and the solution flushed with argon. Palladium (10% on carbon, 200 mg) is added and the mixture hydrogenated under ambient pressure. After gas uptake had ceased, the mixture is filtered through celite and solvent removed. The residue is taken up in ethyl acetate, washed twice with water, dried over magnesium sulfate and the solvent is removed to give 5-amino-2-[4-(2-fluoroethyl)-3-oxopiperazin-1-yl]fluorobenzene which is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([NH:9][CH:10]([CH3:30])[C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]3)[CH2:15][CH2:14]2)=[O:12])=[C:4]([O:31][CH3:32])[CH:3]=1.[Br-].[CH:34]1([Zn+])[CH2:37][CH2:36][CH2:35]1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1COCC1.CC(O)=O.CC(O)=O.[Pd]>[Cl:1][C:2]1[C:7]([CH:34]2[CH2:37][CH2:36][CH2:35]2)=[CH:6][C:5]([NH:9][CH:10]([CH3:30])[C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]3)[CH2:15][CH2:14]2)=[O:12])=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: COc1cc(Cl)c(I)cc1NC(C)C(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Reactant: [Zn+]C1CCC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(Cl)c(C2CCC2)cc1NC(C)C(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 65 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
A mixture of tert-butyl 3-(4-(2-((4-chloro-5-iodo-2-methoxyphenyl)amino)propanoyl)piperazin-1-yl)azetidine-1-carboxylate (673 mg, 1.162 mmol), cyclobutylzinc bromide (5.11 mL, 2.556 mmol, 0.5 M in THF), Pd(Oac)2 (52 mg, 0.23 mmol), S-Phos (95 mg, 0.23 mmol) in THF (10 mL) was stirred at 65° C. under argon for 16 h. The mixture was allowed to cool to RT, quenched with aqueous NH4Cl solution and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether=1:1) to afford the desired product (565 mg, 96% yield) as a light yellow solid. ESI-MS m/z: 507.6[M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:8]=1.CN(C)C=[O:28].[CH:30]([N:33](CC)C(C)C)(C)[CH3:31].Cl.C(=N)(OCC)C>>[C:14]([OH:28])(=[O:13])[CH3:15].[Cl:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[O:5][CH2:6][C:7]1[CH:8]=[C:9]([O:13][CH2:14][CH:15]2[CH2:16][CH2:17][N:18]([C:30](=[NH:33])[CH3:31])[CH2:19][CH2:20]2)[CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: Clc1ccccc1OCc1cccc(OCC2CCNCC2)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CCOC(C)=N
Agent: Cl
Product: CC(=N)N1CCC(COc2cccc(COc3ccccc3Cl)c2)CC1
Product: CC(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 40 mg (0.109 mmol) of 1-[(2-chlorophenoxy)methyl]-3-[(piperidin4-yl)methoxy]benzene hydrochloride as prepared in the preceding step, in 1 mL of N,N-dimethylformamide containing 100 μL (0.908 mmol) of N,N-diisopropylethylamine was added 40 mg (0.325 mmol) of ethyl acetimidate hydrochloride. The reaction mixture was stirred at ambient temperature for 3 days. The reaction mixture was concentrated in vacuo and the residue was quenched with 1 N sodium hydroxide, extracted into methylene choride, dried (K2CO3), and concentrated. The residue was dissolved with 1 mL of methylene chloride and then treated with 500 μL of glacial acetic acid. The solution was then applied directly to preparative thin layer chromatography using methylene chloride/methanol/glacial acetic (83:15:2) as developing solvent to provide 33.8 mg of the title compound as a gum. 1H-NMR (300 MHz, DMSO-d6) δ 7.45 (dd, 1 H, J=1.5, 7.9 Hz), 7.27-7.34 (m, 2 H), 7.20-7.23 (dd, 1 H, J=1.4, 8.3 Hz), 6.89-7.04(m, 4 H), 5.76 (s, 2 H), 4.07 (d, 2H, J=14 Hz), 3.87 (d, 2 H, J=6.2 Hz), 3.05 (t, 2 H, J=13 Hz), 2.22 (s, 3 H), 2.05-2.13 (m, 1 H), 1.85 (d, 2 H), 1.71 (br s , 3 H), and 1.18-1.38 (m, 2 H). Mass spectrum (MALDI-TOF; α-cyano4-hydroxycinnamic acid matrix matrix) calcd. for C21H25N2O2: 373.2 (M+H). Found: 373.0.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]([OH:11])[C:8]([OH:10])=O)=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[C:30]([C:32]1[CH:33]=[CH:34][C:35]2[O:40][C:39]([CH3:42])([CH3:41])[CH2:38][CH:37]([NH:43]C(NC3C=CC=CC=3)=O)[C:36]=2[CH:53]=1)#[N:31].CN(C)CCCCCN=C=N.Cl>>[C:30]([C:32]1[CH:33]=[CH:34][C:35]2[O:40][C:39]([CH3:42])([CH3:41])[CH2:38][CH:37]([NH:43][C:8](=[O:10])[CH:7]([OH:11])[C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=3)[C:36]=2[CH:53]=1)#[N:31]
Reactant: CC1(C)CC(NC(=O)Nc2ccccc2)c2cc(C#N)ccc2O1
Reactant: O=C(O)[C@H](O)c1ccccc1
Agent: CN(C)CCCCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Product: CC1(C)CC(NC(=O)C(O)c2ccccc2)c2cc(C#N)ccc2O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 110.4 %

Procedure:
To a solution of R-(-)-mandelic acid (22.1 g, 0.14 mole) and 1-hydroxybenzotriazole hydrate (19.6 g, 0.14 mole) cooled to 0° C. was added successively N-methylmorpholine (16.2 g, 0.16 mole), 4-amino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (29.4 g, 0.14 mole, Example 8, part D) and 1-(3-dimethylaminopropyl)-2-ethylcarbodiimide.HCl (27.9 g, 0.14 mole). The reaction mixture was stirred 0.5 hours at 0° C. and two hours at room temperature. The solvent was recovered under vacuum and the residue was partitioned between 5% aqueous HCl and ethyl acetate. The organic fraction was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo to obtain 52 g of yellow gum. The crude diastereomer mixture was chromatographed on silica eluting with 1:1 hexane/ethyl acetate to obtain 23.2 g (47.7%) of Isomer A. m.p.=120-121° C., [α]D25 =-39.5°. 1H NMR (CDCl3) δ 7.43-7.34 (m, 7H), 6.81 (d, J=8.20 Hz, 2H), 5.23 (m, 1H), 5.13 (d, J=3.52 Hz, 1H), 4.27 (m, 1H), 2.08 (dd, J=5.86 and 13.78 Hz, 1H), 1.71 (d, J=12.31 Hz, 1H), 1.42 (s, 3H), 1.36 (s, 3H). 13C NMR (CDCl3) δ 173.26, 158.09, 139.60, 133.30, 132.46, 129.27, 129.18, 126.88, 123.39, 119.62, 118.99, 103.64, 77.00, 74.50, 42.33, 39.59, 29.77, 25.05. MS: (M+H)+ @337.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(C)c23)cc1Cl
Reactant: c1c[nH]cn1
Product: COc1ccc(CNc2nc(-n3ccnc3)nc3sc(C)c(C)c23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6-dimethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6-dimethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:20])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][CH:7]=1.C(O)(=O)C.[H][H]>[Pd].C(O)C>[NH2:1][CH2:2][C@H:3]([OH:20])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: NC[C@H](O)COc1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: NC[C@H](O)COc1ccc(O)cc1
Reaction time: 2 h

Procedure:
A mixture of (2S)-1-amino-3-(4-benzyloxy-phenoxy)-propan-2-ol (which was obtained in Intermediate 4) (0.9 g, 3.3 mmol), 0.2 mL of acetic acid and 10% palladium on carbon (0.3 g) in 70 mL of ethanol was pressurized with 20 psi hydrogen and shaken over 2 hours. The catalyst was then removed by filtering through a short pad of silica gel and the solvent was removed to give the title compound as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ1.86 (s, 1 H), 2.66 (dd, J=12.8, 5.3 Hz, 1H), 2.85 (dd, J=12.8, 3.5 Hz, 1H), 3.79-3.95 (m, 3 H), 6.67 (d, J=6.6 Hz, 2H), 6.75 (d, J=6.6 Hz, 2 H); MS (ES) m/z: 183.1 (MH+); HRMS Calcd. for C9H13NO3(MH+): 183.0895. Found: 183.0892.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:34])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27](Cl)[C:28](OCC)=[O:29])=[CH:22][N:21]=1)([CH3:17])[CH2:9][CH2:8]2)(=O)C.[NH2:35][C:36](N)=[S:37].S1(CCCC1)(=O)=[O:40].Cl>O.COCCO>[OH:4][C:5]1[C:6]([CH3:34])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]3[S:37][C:36](=[O:40])[NH:35][C:28]3=[O:29])=[CH:22][N:21]=1)([CH3:17])[CH2:9][CH2:8]2
Reactant: NC(N)=S
Reactant: O=S1(=O)CCCC1
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3c(C)c(OC(C)=O)c(C)c(C)c3O2)nc1
Agent: Cl
Solvent: O
Solvent: COCCO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cn1)O2

Procedure:
The procedure described in Example 3 was repeated, but using 3.8 g of ethyl 3-[2-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)pyridin-5-yl]-2-chloropropionate (prepared as described in Preparation 38), 0.77 g of thiourea, 5.0 ml of sulfolane, 4.5 ml of ethylene glycol monomethyl ether, 1.5 ml of concentrated hydrochloric acid and 4.5 ml of water, to give the title compound, softening at 87°-94° C.
Reaction SMILES: [C:1]([O:7][CH2:8]I)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CC(N(C)C)=O.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:27][C:28]([C@H:30]2[CH2:35][CH2:34][C@H:33]3[C@H:36]4[C@H:46]([CH2:47][CH2:48][C@:31]23[CH3:32])[C@:44]2([CH3:45])[C:39]([CH:40]=[C:41]([C:49]([O-:51])=[O:50])[CH2:42][CH2:43]2)=[CH:38][CH2:37]4)=[O:29])([CH3:26])[CH3:25])=[CH:20][CH:19]=1.[Na+].[OH-].[Na+]>C(OCC)(=O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:27][C:28]([C@H:30]2[CH2:35][CH2:34][C@H:33]3[C@H:36]4[C@H:46]([CH2:47][CH2:48][C@:31]23[CH3:32])[C@:44]2([CH3:45])[C:39]([CH:40]=[C:41]([C:49]([O:51][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:50])[CH2:42][CH2:43]2)=[CH:38][CH2:37]4)=[O:29])([CH3:25])[CH3:26])=[CH:20][CH:19]=1
Reactant: COc1ccc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C(=O)[O-])CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C(=O)OCOC(=O)C(C)(C)C)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Reaction time: 1 h

Procedure:
1 ml of pivaloyloxymethyl iodide was added, whilst ice-cooling, to 15 ml of a dimethylacetamide solution containing 196 mg of sodium 17β-{N-[1(4-methoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylate (prepared by reacting the compound obtained as described in Example 2 with sodium hydroxide in a conventional salification process). The resulting solution was then stirred for 1 hour, whilst ice-cooling, after which it was diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography using a gradient elution method, with solutions of from 1 to 3% by volume of acetone in methylene chloride as the eluent, to give 157 mg of the title compound.
Reaction SMILES: FC1C(F)=CC([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15](CCS(C)(=O)=O)C(=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=C(OC)C=1.[CH3:40][O:41][C:42]1[C:47](B(O)O)=[CH:46][CH:45]=[CH:44][N:43]=1.CCCCCCC.C[CH2:59][O:60][C:61]([CH3:63])=[O:62]>>[CH3:59][O:60][C:61](=[O:62])[CH2:63][NH:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:47]1[C:42]([O:41][CH3:40])=[N:43][CH:44]=[CH:45][CH:46]=1
Reactant: COc1ncccc1B(O)O
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)CNc1cnccc1-c1cccnc1OC

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-ylamino)-acetic acid methyl ester (example 176, intermediate b) and 2-methoxypyridine-3-boronic acid (CAS RN 163105-90-6) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light yellow oil (73%). MS (ESI): m/z=274.119 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].S(Cl)(Cl)=O.[CH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: c1ccccc1
Reactant: COc1cc(C(=O)O)ccc1Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)c2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 4-bromo-3-methoxybenzoic acid (1.00 g, 4.33 mmol), thionyl chloride (0.77 mL, 0.010 mol) and a drop of DMF and the reaction was refluxed for 2 h. The excess thionyl chloride was then distilled off and the residual thionyl chloride was removed oh the pump. Benzene (20 mL, 0.2 mol) and aluminum trichloride (0.676 g, 5.07 mmol) were added to the reaction mixture. The reaction mixture turned yellow in color on addition of AlCl3. The reaction mixture was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:24])[CH2:22]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:24])[CH2:22][N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1
Reactant: Cc1ccccc1NC(=O)CCl
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1NC(=O)CN1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.9 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(2-methyl-phenyl)-2-chloroacetamide (37 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 29.3 mg (63%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.62 (t, J=4 Hz, 4H), 3.20 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 7.05 (t, J=6 Hz, 1H), 7.10 (m, 2H), 7.58 (t, J=5 Hz, 1H), 7.78 (d, J=6 Hz, 1H), 8.12 (d, J=5 Hz, 1H), 9.40 (s, 1H); MS (ESI/APCI+) m/e 311 (M+H)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: CC(=O)c1ccc(Br)s1
Reactant: OB(O)c1ccc(O)cc1
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: [Na+]
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2ccc(O)cc2)s1
Temperature: 100 °C

Procedure:
A flame-dried test tube under N2 was charged with 1-(5-bromothiophen-2-yl)ethanone (250 mg, 1.22 mmol), p-hydroxyphenylboronic acid (1.2 equiv, 1.40 mmol, 202 mg), and 2.0 mL 1,4-dioxane. To the yellow solution, tetrakistriphenylphosphinepalladium(0) (6 mol %, 0.0731 mmol, 84 mg) and 2 M aqueous sodium carbonate (2.0 equiv, 2.44 mmol, 2.0 mL) were added. The yellow mixture was heated to 100° C. for 18 h. The resulting yellow-brown mixture was cooled to rt, adsorbed onto Celite in vacuo, and purified by silica gel chromatography to afford the desired product as an analytically pure yellow solid (51 mg, 19% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:32])([CH3:31])[C:4]([N:6]1[CH2:11][CH:10]=[C:9]([C:12]2[NH:30][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH:20][C:21]4[CH:29]=[CH:28][C:24]5[N:25]=[CH:26][S:27][C:23]=5[CH:22]=4)[C:14]=3[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].C(Cl)CCl.CCOC(C)=O>CS(C)=O>[CH3:31][C:3]([CH3:32])([CH:2]=[O:1])[C:4]([N:6]1[CH2:7][CH:8]=[C:9]([C:12]2[NH:30][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH:20][C:21]4[CH:29]=[CH:28][C:24]5[N:25]=[CH:26][S:27][C:23]=5[CH:22]=4)[C:14]=3[CH:13]=2)[CH2:10][CH2:11]1)=[O:5]
Reactant: CC(C)(CO)C(=O)N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: ClCCCl
Product: CC(C)(C=O)C(=O)N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 6-[1-(3-hydroxy-2,2-dimethylpropanoyl)-1,2,3,6-tetrahydropyridin-4-yl]-N-1,3-benzothiazol-6-yl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 110) (150 mg, 0.33 mmol) in DMSO (4 mL) was added EDC (190 mg, 1 mmol). The reaction mixture stirred at rt for 5 h. The mixture was taken up in a large amount of EtOAc and extracted with water. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo, which afforded the title compound as a yellow solid. MS (ES+): m/z: 446.93 (100) [MH+]. HPLC: tr=2.53 min (ZQ2000: polar—5 min). 1H NMR (400 MHz, DMSO-d6): δ=1.37 (s, 6H) 3.39-3.69 (m, 3H), 3.70-4.22 (m, 3H), 6.21 (bs, 1H), 6.82 (s, 1H), 6.84 (d, J=1.6 Hz, 1H), 7.87 (dd, J=1.6, 8.8 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 8.34 (s, 1H), 8.91 (d, J=2.0 Hz, 1H), 9.23 (s, 1H), 9.62 (s, 1H), 12.03 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH:16]1[CH2:20][CH:19]([CH3:21])[C:18](=[O:22])[O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].BrC[CH:26]=[C:27]([CH3:29])[CH3:28]>>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([C@@H:16]1[CH2:20][C@@H:19]([CH2:21][CH:26]=[C:27]([CH3:29])[CH3:28])[C:18](=[O:22])[O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC1CC([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)OC1=O
Reactant: CC(C)=CCBr
Product: CC(C)=CC[C@@H]1C[C@@H]([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)OC1=O
Yield: 84 %

Procedure:
Prepared analogously to the synthesis of [(S)-1-(4-Methyl-5-oxo-tetrahydrofuran-2-yl)-2-phenylethyl]carbamic acid t-butyl ester in Journal of Organic Chemistry (1986) 51(21), 3921, using 4-bromo-2-methyl-2-butene in place of methyl iodide, to afford D30 in 84% yield.