Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][NH2:40]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:40][CH2:39][CH2:38][N:37]([CH3:41])[CH3:36])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CN(C)CCN
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 95.5 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (20 mg, 0.04 mmol) in THF (3 mL) was added N,N-dimethyl-1,2-ethanediamine (0.022 mL, 0.20 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH [7]+NH4OH[3]) provided the title compound as a white solid (20 mg, 95%). LC-MS m/z 524 (M+H)+; 1H-NMR (MeOD) δ 1.27 (d, 6H), 2.14 (s, 6H), 2.33 (s, 3H), 2.37 (m, 2H), 3.22 (m, 2H), 4.09 (s, 2H), 4.23 (m, 1H), 7.15 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:11]2[CH2:12][O:13][CH2:14][C:15](=O)[N:10]2[CH2:9][CH2:8][CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH2:12]1[CH:11]2[CH:6]([CH2:4][OH:3])[CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][O:13]1
Reactant: CCOC(=O)C1CCCN2C(=O)COCC12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1CCCN2CCOCC12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 66 (114 mg, 0.5 mmol) in 5 ml of anhydrous THF is added LAH (40 mg, 1.0 mmol) and the mixture refluxed for 9 hours. The mixture is cooled to 0° C. and treated successively with 0.04 ml of water, 3N aqueous sodium hydroxide (0.04 ml, 0.12), and 0.12 ml of water. The mixture is stirred for 15 min. and then extracted three times with DCM. The combined organic phases are dried over anhydrous sodium sulphate and evaporated under educed pressure. The residual pale yellow oil (75 mg) is purified by chromatography (Biotage 12Si, I=7.5 cm, DCM/MeOH/conc. Ammonia 95:4.5:0.5).
Reaction SMILES: [Br:1][C:2]1[C:3]([Br:26])=[CH:4][C:5]2[N:11]([C:12](=[O:19])[CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:10]3[N:20]=[CH:21][CH:22]=[CH:23][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:25]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28]>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([Br:26])=[CH:4][C:5]2[N:11]([C:12](=[O:19])[CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:10]3[N:20]=[CH:21][CH:22]=[CH:23][C:9]=3[C:8](=[S:28])[NH:7][C:6]=2[CH:25]=1
Reactant: CCN(CC)CC(=O)N1c2cc(Br)c(Br)cc2NC(=O)c2cccnc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CCN(CC)CC(=O)N1c2cc(Br)c(Br)cc2NC(=S)c2cccnc21

Procedure:
In the manner given in Example 1, 8,9-dibromo-6,11-dihydro-11-[(diethylamino)acetyl]-5H-pyrido[2,3-b][1,5]-benzodiazepin-5-one is reacted with phosphorus pentasulfide in pyridine to give 8,9-dibromo-6,11-dihydro-11-[(diethylamino)acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH2:15][CH:14]([NH:16][C:17](=[O:34])[CH2:18][NH:19][C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=4)[N:22]([CH3:33])[N:21]=3)[CH2:13]2)[CH2:8][CH2:7]1)=[O:5])C.O.O.[OH-].[Li+]>C1COCC1.CO>[CH3:33][N:22]1[C:23]2[C:28](=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[C:20]([NH:19][CH2:18][C:17]([NH:16][CH:14]2[CH2:13][N:12]([CH:9]3[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]3)[CH2:15]2)=[O:34])=[N:21]1
Reactant: CCOC(=O)C1CCC(N2CC(NC(=O)CNc3nn(C)c4ccc(C(F)(F)F)cc34)C2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(C(=O)O)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
4-{3-[2-(1-Methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetylamino]-azetidin-1-yl}-cyclohexane carboxylic acid ethyl ester (from Example 32, 350 mg, 0.773 mmol) in THF (2 mL), MeOH (2 mL) and distilled water (2 mL) was treated with lithium hydroxide monohydrate (87 mg, 1.93 mmol) at room temperature for 1 hour. The reaction mixture was acidified to pH=5 and extracted with DCM:IPA (3:1) solvent three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title compound as colorless solid.
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1([C:17]([NH:19][C@H:20]([C:25]([O:27]C)=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>CO>[C:1]([S:5][CH2:6][C:7]1([C:17]([NH:19][C@H:20]([C:25]([OH:27])=[O:26])[CH2:21][CH:22]([CH3:23])[CH3:24])=[O:18])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)C1(CSC(C)(C)C)CCc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](NC(=O)C1(CSC(C)(C)C)CCc2ccccc2C1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve N-[[1,2,3,4-tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-L-leucine, methyl ester (146 mg, 0.36 mmol) in methanol (3 mL). Add a solution of lithium hydroxide monohydrate (1 mL in water, 1 mmol) and stir at room temperature under argon for 16 hours. Evaporate the solvent in vacuo without heat and acidify with 2N hydrochloric acid. Extract into methylene chloride (2X), dry (MgSO4) and evaporate the solvent in vacuo to give the title compound as as white foam (142 mg, 100%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][CH2:12][OH:13])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C1(C=CC(O)=CC=1)O>C(O)=O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:11][CH:12]=[O:13])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C#CCO)cc1
Agent: Oc1ccc(O)cc1
Solvent: O=CO
Product: CC(C)c1ccc(C=CC=O)cc1
Yield: 76 %

Procedure:
A mixture of 250 g of 75% strength aqueous formic acid, 50 g of p-isopropylphenylethynylcarbinol and 0.5 g of hydroquinone is refluxed for 1 hour and then worked up as described in Example 1 to give 38 g (corresponding to 76% of theory) of p-isopropylcinnamaldehyde having a boiling point of 90°-95° C./0.06 mbar.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]([CH3:30])[C:10]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][C:14]=3[N:13]=[C:12]([NH:23]C(=O)C(C)(C)C)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]([CH3:30])[C:10]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][C:14]=3[N:13]=[C:12]([NH2:23])[N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N(C)c2nc(NC(=O)C(C)(C)C)nc3[nH]c4ccccc4c23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cccc(N(C)c2nc(N)nc3[nH]c4ccccc4c23)c1
Yield: 93 %

Procedure:
Using the general procedure described above, the reaction of 9 (90 mg, 0.22 mmol) and 1 N NaOH provided 66 mg of AAG105 as a white solid in 93% yield. TLC Rf 0.27 (chloroform-methanol 15:1); mp 245.3-245.7° C.; 1H NMR (DMSO-d6) δ 3.48 (s, 3H, OCH3), 3.71 (s, 3H, NCH3), 6.20 (s, 2H, NH2, exch), 5.75-7.15 (m, 8H, Ar—H), 11.22 (s, 1H, 9-NH, exch). Anal. Calculated (C18H17N5O. 0.17H2O): C, 67.05; H, 5.42; N, 21.72. Found: C, 67.06; H, 5.37; N, 21.56.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=4)C=C3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O>O1CCCC1.FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:22]3[CH:17]=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=3)[CH2:10][CH2:9]2)=[CH:24][CH:25]=1
Reactant: Fc1ccc(CCN2CCC(n3ccc4ccc(Br)cc43)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(CCN2CCC(Nc3cccc(Br)c3)CC2)cc1
Reaction time: 3 h
Yield: 54.5 %

Procedure:
Under ice cooling, a 1 M solution (20 ml) of a borane/tetrahydrofuran complex in tetrahydrofuran was added dropwise into a solution of 1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-bromoindole (3.9 g) in trifluoroacetic acid (50 ml) followed by stirring for 3 hr. After adding water thereto and concentrating under reduced pressure, the reaction mixture was basified by adding ethanol and a 5 N aqueous solution of sodium hydroxide and then stirred for 30 min. Next, a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added thereto and the layers were separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The residue was then purified by silica gel column chromatography (toluene/acetone system) to give the title compound (2.0 g) as a white powder (yield: 51%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([C:12]1[CH:17]=[C:16]([F:18])[C:15]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)=[C:14]([F:27])[CH:13]=1)[CH2:10][CH3:11].C(C1C=C(F)C(I)=C(F)C=1)CC.FC1C=C([B:48]([OH:50])[OH:49])C=C(F)C=1.B(OC)(OC)OC>C1COCC1>[CH2:9]([C:12]1[CH:13]=[C:14]([F:27])[C:15]([C:19]2[CH:24]=[C:23]([F:25])[C:22]([B:48]([OH:50])[OH:49])=[C:21]([F:26])[CH:20]=2)=[C:16]([F:18])[CH:17]=1)[CH2:10][CH3:11]
Reactant: CCCc1cc(F)c(-c2cc(F)cc(F)c2)c(F)c1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: CC(C)[N-]C(C)C
Agent: CCCc1cc(F)c(I)c(F)c1
Agent: COB(OC)OC
Solvent: C1CCOC1
Product: CCCc1cc(F)c(-c2cc(F)c(B(O)O)c(F)c2)c(F)c1

Procedure:
0.6 mol of lithium diisopropylamide is added at 0° C. to a mixture of 0.5 mol of 4'-propyl-2',6',3,5-tetrafluorobiphenyl (prepared from 4-propyl-2,6-difluoroiodobenzene and 3,5-difluorophenylboronic acid analogously to Example 23C). 0.5 mol of trimethyl borate and 500 ml of THF, and the mixture is stirred for two hours.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:17]=[C:18]([S:35](=[O:38])(=[O:37])[NH2:36])[C:19]=1[O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:23][CH:22]=1)[C:12]([O:14]CC)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>[OH-].[Na+]>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:17]=[C:18]([S:35](=[O:38])(=[O:37])[NH2:36])[C:19]=1[O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:23][CH:22]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(NCc2ccccc2)c(Oc2ccc(OCc3ccccc3)cc2)c(S(N)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1Oc1ccc(OCc2ccccc2)cc1
Reaction time: 40 h

Procedure:
A solution of ethyl 3-benzylamino-4-(4-benzyloxyphenoxy)-5-sulphamyl-benzoate (2 g) in 1N sodium hydroxide (45 ml) was left standing at room temperature for 40 hours. Then the reaction mixture was adjusted to a pH of 2.5 by addition of 4N hydrochloric acid. The precipitated 3-benzylamino-4-(4-benzyloxyphenoxy)-5-sulphamyl-benzoic acid was isolated by filtration and recrystallized from aqueous ethanol. After drying, the compound was obtained with a melting point of 249°-251° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])=[N:8][C:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:10][CH:11]=1)=[O:5])C.Cl>C(O)C>[C:20]1([CH3:25])[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=[C:9]([C:12]2[N:13]=[CH:14][CH:15]=[CH:16][N:17]=2)[N:8]=1
Reactant: CCOC(=O)c1cnc(-c2ncccn2)nc1Oc1ccccc1C
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1Oc1nc(-c2ncccn2)ncc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a solution of 0.33 g (0.98 mmol) 4-o-tolyloxy-[2,2′]bipyrimidinyl-5-carboxylic acid ethyl ester in 15 ml ethanol 3.68 ml 0.4 N NaOH was added and the resulting solution was stirred for 2 hrs at RT. The pH of the solution was adjusted to 4 with 1N HCl. The aqueous solution was extracted three times with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and evaporated. The resulting solid was triturated twice with diethyl ether, filtered off and dried to give 0.26 g (85%) 4-o-tolyloxy-[2,2′]bipyrimidinyl-5-carboxylic acid as a light yellow solid, MS (ISN): 307.3 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:59])[C:10]2[C:5](=[CH:6][C:7]([CH2:11][O:12][CH:13]3[CH:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[O:37][CH3:38])=[CH:21][CH:20]=4)[CH2:17][CH2:16][N:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:14]3)=[CH:8][CH:9]=2)[N:4]([CH2:46][CH2:47][O:48][Si](C(C)C)(C(C)C)C(C)C)[CH2:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[OH:48][CH2:47][CH2:46][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([CH2:11][O:12][CH:13]3[CH:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[O:37][CH3:38])=[CH:21][CH:20]=4)[CH2:17][CH2:16][N:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:14]3)[CH:6]=2)[C:2]([CH3:59])([CH3:1])[CH2:3]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)N(CCO[Si](C(C)C)(C(C)C)C(C)C)CC3(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)N(CCO)CC3(C)C)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The solution of 0.595 g of tert-butyl 3-[3,3-dimethyl-1-(2-triisopropylsilanyloxyethyl)-2,3-dihydro-1H-indol-6-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 8.0 ml of tetrahydrofuran is admixed with tetrabutylammonium fluoride solution (1M in tetrahydrofuran) and stirred at 60° C. over 1 hour. The reaction mixture is cooled, admixed with water (15 ml) and extracted with tert-butyl methyl ether (2×15 ml). The organic phases are washed successively with water (15 ml) and brine (15 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.13 (1:1 EtOAc-heptane); Rt=5.72.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[H-].[Na+].Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[S:22]([N:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)(=[O:24])=[O:23].C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[S:22]([N:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)(=[O:24])=[O:23]
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc([N+](=O)[O-])ccc2Cl)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc([N+](=O)[O-])ccc2Oc2cc(Cl)ccc2Cl)CC1
Temperature: 75 °C
Reaction time: 0.08 h
Yield: 11.6 %

Procedure:
To a solution of 2,5-dichlorophenol (0.414 g, 2.54 mmol) in THF (20.00 mL) stirred in an ice bath was added NaH (0.101 g, 2.54 mmol) slowly. After addition, the mixture was stirred for 5 min. Compound 38 (0.790 g, 1.95 mmol) was then added and the resulting reaction mixture was heated to 75° C. overnight. The reaction was monitored by HPLC. However, the reaction was not complete after 16 hrs (HPLC), so THF was evaporated and 18-crown-6 (1.057 g, 4.00 mmol), DMF (15 mL), and K2CO3 (0.553 g, 4.00 mmol) were added. The reaction mixture was heated to 100° C. for another 16 hrs, at which time HPLC indicated that the reaction was complete by absence of starting material. The reaction mixture was cooled to room temperature, and water (0.250 mL) was added. The reaction mixture was extracted thrice with EtOAc. Combined extracts were washed sequentially with 1N NaOH, water, and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residual was dissolved in a minimal amount of DCM and purified with chromatography using a gradient of 5 to 30% EtOAc in hexanes. Pure fractions were combined and evaporated in vacuo. The resulting solid was triturated with DCM and hexanes, and then filtered to afford compound 39 as a white/yellow powder (0.120 g, 100% HPLC purity, 10.0% yield). 1H NMR (500 MHz, DMSO-d6): δ 8.59 (d, J=2 Hz, 1H), 8.42 (dd, J1=2 Hz, J2=8 Hz, 1H), 7.76 (d, J=8 Hz, 1H), 7.66 (d, J=3 Hz, 1H), 7.50 (dd, J1=2 Hz, J2=8 Hz, 1H), 7.10 (d, J=8 Hz, 1H), 3.40 (m, 4H), 3.25 (m, 4H), 1.37 (s, 9H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:17]C)=[O:16])[CH2:11][CH2:10]1.F[C:20]1[N:25]=[CH:24][C:23]([C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([NH:33][C:34]3[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][N:35]=3)[N:27]=2)=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN1C(=O)CCC1>[CH3:32][C:30]1[CH:29]=[C:28]([NH:33][C:34]2[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][N:35]=2)[N:27]=[C:26]([C:23]2[CH:24]=[N:25][C:20]([O:7][CH2:8][C@H:9]3[CH2:10][CH2:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][CH2:14]3)=[CH:21][CH:22]=2)[CH:31]=1
Reactant: COC(=O)[C@H]1CC[C@H](CO)CC1
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(F)nc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(OC[C@H]3CC[C@H](C(=O)O)CC3)nc2)c1
Temperature: 130 °C

Procedure:
A flask was charged with potassium carbonate (0.028 g, 0.200 mmol), methyl trans-4-(hydroxymethyl)cyclohexanecarboxylate (0.034 g, 0.200 mmol), 6′-fluoro-4-methyl-N-[4-(trifluoromethyl)pyridin-2-yl]-2,3′-bipyridin-6-amine (0.032 g, 0.1 mmol), NMP (1 mL), and DIEA (0.035 mL, 0.20 mmol). The vial was sealed and heated to 130° C. for 72 hours. Aqueous NaOH (1M, 0.5 mL) was added, and the vial was heated in a microwave for 10 minutes at 110° C. The mixture was filtered through a CELITE cartridge, washing with NMP (3 mL). The residue, dissolved in 3 mL of NMP, was purified by mass triggered reverse phase HPLC (21-55% Acetonitrile/Water with a 0.1% Ammonium Hydroxide modifier on a Waters X-Bridge C18 19 mm×100 mm) to yield trans-4-{[(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}-2,3′-bipyridin-6′-yl)oxy]methyl}cyclohexanecarboxylic acid. MS ESI calcd. for C25H26F3N4O3 [M+H]+ 487. found 487. rhSyk IC50=3 nM.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1.COC1C=CC([SH:29]2(=S)PP(=S)(C3C=CC(OC)=CC=3)S2)=CC=1.O>CN(C)P(=O)(N(C)C)N(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:29])[CH2:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1
Reactant: COc1ccc(P2(=S)P[SH](=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CCC(c2ccccc2F)c2cc(Cl)ccc2N1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: Fc1ccccc1C1CCC(=S)Nc2ccc(Cl)cc21
Temperature: 25 °C

Procedure:
30 g of 7-chloro-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one are dissolved in 105 ml of hexamethylphosphoric acid triamide and treated with 22 g of 2,4-bis-(4-methoxyphenyl)-1,2,3,4-dithiadiphosphetane-2,4-disulphide. The mixture is heated to 100° for 1 hour, again cooled to room temperature and poured into 1.41 l of water. The mixture is extracted four times with ethyl acetate and the organic extracts are washed with water. The ethyl acetate solution is dried, filtered and evaporated in vacuo. After crystallization of the residue from ethanol, there is obtained 7-chloro-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1-benzazepine-2-thione of melting point 190°.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]#[C:17][C:18]3[CH:19]=[C:20]([C:24]([N:26]=[S:27]([C:30]4[CH:31]=[C:32]([CH2:36][C:37](O)=[O:38])[CH:33]=[CH:34][CH:35]=4)([CH3:29])=[O:28])=[O:25])[CH:21]=[N:22][CH:23]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]([CH3:40])=[N:3]1.[NH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>>[CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]#[C:17][C:18]3[CH:23]=[N:22][CH:21]=[C:20]([CH:19]=3)[C:24]([N:26]=[S:27]([CH3:29])([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][C:37]([NH:41][CH2:42][CH2:43][N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[O:38])[CH:31]=3)=[O:28])=[O:25])[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]([CH3:40])=[N:3]1
Reactant: NCCN1CCOCC1
Reactant: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=S(C)(=O)c4cccc(CC(=O)O)c4)c3)c2)n(C)n1
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=S(C)(=O)c4cccc(CC(=O)NCCN5CCOCC5)c4)c3)c2)n(C)n1
Yield: 54 %

Procedure:
In a manner similar to that described in Example 500, {3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl}acetic acid and 4-(2-aminoethyl)morpholine were reacted to give the title compound (54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][C:12]([O:14]CC)=[O:13].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)CC(Cc1ccccc1OC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1CC(CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.3 %

Procedure:
Ethyl 4-(2'-methoxyphenyl)-3-phenylbutyrate (5.7 g, 19 mmol), from Step 3, was dissolved in 25 mL of methanol and 14 mL of 50% aqueous sodium hydroxide solution was added in one portion. The reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was concentrated and the residue was partitioned between 100 mL of diethyl ether and 100 mL of water. The layers were separated and the aqueous layer was adjusted to pH 6 with 6M aqueous hydrochloric acid solution and extracted with 3×100 mL of diethyl ether. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 5.1 g (99% yield) of the title compound as a colorless oil. The 1H NMR spectrum was identical to the spectrum reported for the product of Step 5 of Method A, Example 1.
Reaction SMILES: C(Cl)(=O)C(C)(C)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C.[CH3:28][C@@H:29]([NH:38][CH3:39])[C@H:30]([OH:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.C1COCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([N:38]([C@H:29]([CH3:28])[C@H:30]([OH:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:39])=[O:18])=[CH:13][CH:14]=1
Reactant: CN[C@H](C)[C@H](O)c1ccccc1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]([C@H](O)c1ccccc1)N(C)C(=O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pivaloyl chloride (7.8 ml, 63.3 mmol) was added dropwise to a DCM/THF solution (100 ml/20 ml) containing 4-bromophenylacetic acid (13.59 g, 63.2 mmol). DIEA (11.0 ml, 63.1 mmol) was then added dropwise (exotherm). After stirring at room temperature for 1 hour the solution was poured slowly into a DCM/THF solution (100 ml/20 ml) containing (1R, 2R)-(−)-pseudoephedrine (10.5 g, 63.5 mmol) and DIEA (11.0 ml, 63.1 mmol). After stirring overnight at room temperature the solution was concentrated and the residue partitioned between EtOAc and water. The organic phase was washed with aqueous 1N NaOH (2×), aqueous 1N HCl (3×), brine and dried over MgSO4. The solution was filtered and concentrated. The oil residue was diluted with 100 ml of toluene and concentrated. The residue was then dissolved in ethyl ether and triturated with hexanes to give the title compound as a white solid. The compound is a 3:1 mixture of amide rotational isomers by proton NMR: 1H NMR (400 MHz, asterisk denotes minor rotamer, CDCl3): δ 7.42 (d, J=8.3 Hz, 2 H); 7.39-7.27 (m, 5 H); 7.11*(d, J=8.4 Hz, 2H); 7.04 (d, J=8.3 Hz, 2 H); 4.64-4.42 (m, 1 H); 4.07-3.94 (m, 1H); 3.82-3.70 (m, 1H); 2.94*(s, 3H); 3.63 (s, 2 H); 2.82 (s, 3 H); 1.12 (d, J=7.0 Hz, 3 H); 0.86*(d, 3H, J=7.0 Hz). LC1 3.23 min. (M+H)=362