Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[S:16])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[CH2:17](Br)[CH3:18].CC[O-].[Na+]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:16][CH2:17][CH3:18])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: N#Cc1c(-c2ccccc2)nc(N)[nH]c1=S
Reactant: CCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCSc1nc(N)nc(-c2ccccc2)c1C#N

Procedure:
From 2-amino-4-phenyl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile, ethyl bromide and sodium ethylate in ethanol. EI-MS m/e (%):256 (M+, 29), 255 ([M—H]+, 100).
Reaction SMILES: [OH-].C[N+](C)(C)C.[C:7]([OH:11])(=[O:10])[CH2:8][OH:9].Br[CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15]>CN(C)C=O>[OH:9][CH2:8][C:7](=[O:11])[O:10][CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)C(C)Br
Reactant: O=C(O)CO
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)C(C)OC(=O)CO
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Tetramethylammonium hydroxide (25% in methanol) was added to a stirring solution of glycolic acid (3.8 g, 50 mmol) in 5 mL dimethylformamide cooled on ice until a pH of 7 was indicated by moistened pH paper. Methyl 2-bromopropionate (6.1 mL, 55 mmol) was added and the reaction was stirred at room temperature for 5 d. The reaction mixture was filtered, the solids were washed with ethyl ether, and the combined filtrate and ether solution was washed with 5% NaCl/5% NaHCO3. Sufficient ethyl ether was added to effect rapid separation of the phases, the aqueous phase was extracted with CH2Cl2, and the organic phases were combined and dried with MgO4. The solvent was removed and the resulting residue was distilled under reduced pressure to give the title compound: b .p. 64° C./0.05 mm Hg; 1H NMR δ1.53 (d, 3H, J=7.2 Hz), δ2.78 (bs, 1H), δ3.77 (s, 3H), δ4.24 (d, 1H, J=17.4 Hz), δ4.31 (d, 1H, J=17.4 Hz), δ5.22 (q, 1H, J=7.1 Hz), HRMS calcd for C6H9O5Tms (M-CH3) 219.0688, obsd 219.0708.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:20]=[C:19]([CH3:21])[N:18]([C:22]3[C:23](=[O:29])[CH2:24][CH2:25][C:26]=3[O:27]C)[N:17]=2)=[CH:12][CH:11]=1.[F:30][C:31]1[CH:32]=[CH:33][C:34]([CH:37]=O)=[N:35][CH:36]=1.Cl>O1CCCC1.CC(C)=O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:20]=[C:19]([CH3:21])[N:18]([CH:22]3[C:23](=[O:29])/[C:24](=[CH:37]\[C:34]4[CH:33]=[CH:32][C:31]([F:30])=[CH:36][N:35]=4)/[CH2:25][C:26]3=[O:27])[N:17]=2)=[CH:12][CH:11]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:20]=[C:19]([CH3:21])[N:18]([CH:22]3[C:23](=[O:29])/[C:24](=[CH:37]/[C:34]4[CH:33]=[CH:32][C:31]([F:30])=[CH:36][N:35]=4)/[CH2:25][C:26]3=[O:27])[N:17]=2)=[CH:12][CH:11]=1
Reactant: COC1=C(n2nc(-c3ccc(Cl)cc3)cc2C)C(=O)CC1
Reactant: O=Cc1ccc(F)cn1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(Cl)cc2)nn1C1C(=O)C/C(=C/c2ccc(F)cn2)C1=O
Product: Cc1cc(-c2ccc(Cl)cc2)nn1C1C(=O)C/C(=C\c2ccc(F)cn2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of lithium diisopropylamide (1.8 M in tetrahydrofuran/heptane/ethylbenzene, 0.25 ml, 0.45 mmol) was added drop wise to a solution of 2-[3-(4-chloro-phenyl)-5-methyl-pyrazol-1-yl]-3-methoxy-cyclopent-2-enone (124 mg, 0.41 mmol) in anhydrous tetrahydrofuran (1 ml) at −78° C., under nitrogen, and allowed to stir at this temperature for 30 minutes. 5-Fluoro-pyridine-2-carbaldehyde (56 mg, 0.45 mmol) was then added drop wise and the reaction stirred at −78° C. for a further 30 minutes. The reaction was then allowed to warm to room temperature over 30 mins and quenched by the addition of 1 M hydrochloric acid (5 ml) and extracted with dichlormethane (3×10 ml) to give 186 mg of crude material. The crude material was dissolved in acetone (2 ml) and 2 M hydrochloric acid (2 ml) added. This solution was heated in the microwave (using “normal” absorbtion) for 1 h at 120° C. This solution was extracted with dichloromethane (2×10 ml) and the organics dried over magnesium sulfate and reduced in vacuo. The crude material was purified by reverse phase preparative HPLC (eluting with acetonitrile/water) to give 2-[3-(4-chloro-phenyl)-5-methyl-pyrazol-1-yl]-4-[1-(5-fluoro-pyridin-2-yl)-meth-(Z)-ylidene]-cyclopentane-1,3-dione (22 mg) and 2-[3-(4-chloro-phenyl)-5-methyl-pyrazol-1-yl]-4-[1-(5-fluoro-pyridin-2-yl)-meth-(E)-ylidene]-cyclopentane-1,3-dione (5 mg).
Reaction SMILES: [N+](C1C=CC([C:10]2[C:11]([S:20](C3C(C4C=CC([N+]([O-])=O)=CC=4)=CC4C(=CC=CC=4)N=3)(=O)=[O:21])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=CC=1)([O-])=O.C[N:43]([CH:45]=O)C>C(O)C.[Pd]>[NH2:43][C:45]1[CH:17]=[CH:18][C:13]([S:20]([C:11]2[CH:10]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[O:21])=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc3ccccc3nc2S(=O)(=O)c2nc3ccccc3cc2-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: CN(C)C=O
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(S(=O)c2ccc3ccccc3n2)cc1

Procedure:
4--Nitrophenyl-2-quinolylsulfone (9.0 mmoles, 2.7 g) was dissolved in 200 ml ethanol and 75 ml DMF and was then hydrogenated over 2.2 g 5% Pd/C at room temperature for 3 hr. The reaction mixture was then filtered through celite and condensed to afford 2-(4-aminophenylsulfinyl)quinoline.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:35][C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)[C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH2:26][C:27]2C=[CH:31][CH:30]=[CH:29][C:28]=2C#N)([C:17](=[O:25])[NH:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[CH3:42][OH:43].[OH-:44].[Na+]>O1CCCC1>[NH2:7][C@@H:8]([CH2:35][C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)[C:9]([N:11]1[CH2:12][CH2:13][C:14]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:17]([NH:18][C@H:19]2[CH2:20][CH2:21][C@H:22]([C:42]([OH:44])=[O:43])[CH2:23][CH2:24]2)=[O:25])[CH2:15][CH2:16]1)=[O:10]
Reactant: [OH-]
Reactant: CO
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCC(Cc2ccccc2C#N)(C(=O)NC2CCCCC2)CC1
Agent: [Na+]
Solvent: C1CCOC1
Product: N[C@@H](Cc1cccs1)C(=O)N1CCC(C(=O)N[C@H]2CC[C@H](C(=O)O)CC2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (S)-{2-[4-(2-cyanobenzyl)-4-cyclohexylcarbamoyl-piperidin-1-yl]-2-oxo-1-thiophen-2-ylmethyl-ethyl}-carbamic acid tert-butyl ester (0.346 mmol; 200 mg) (prepared by reacting trans-4-amino-cyclohexanecarboxylic acid methyl ester with (S)-2-tert-butoxycarbonylamino-3-thiophen-2-yl-propionic acid), in tetrahydrofuran (1 mL) and methanol (1 mL) was added a 1M NaOH solution (0.376 mmol; 0.376 mL). The resulting mixture was stirred overnight at room temperature. The mixture was then purified via reverse phase HPLC. The desired fractions were combined and lyophilized. The resulting residue was dissolved in tetrahydrofuran (3 mL) and a 4N HCl in dioxane solution (4 mL) was added. The resulting mixture was stirred for 4 hours at room temperature and evaporated. The residue was triturated with diethyl ether to yield 4-{[1-(2-(S)-amino-3-thiophen-2-yl-propionyl)-4-phenyl-piperidine-4-carbonyl]-amino}-trans-cyclohexanecarboxylic acid as a hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21]CC)=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].[OH-].[Na+].O>C(O)C.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)=[CH:4][C:3]=1[C:24]([F:27])([F:25])[F:26]
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3ccc(Cl)c(C(F)(F)F)c3)cs2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cnn(Cc2nc(-c3ccc(Cl)c(C(F)(F)F)c3)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
To a mixed solution of the compound (270 mg, 0.66 mmol) obtained in Example 40a in ethanol/tetrahydrofuran (v/v=1/1, 8 ml) was added 2N aqueous sodium hydroxide solution (2.0 mL, 4.0 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the aqueous layer was washed with diethyl ether, neutralized with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (ethanol-hexane) to give the title compound (67 mg, 18%) as pale-yellow crystals.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@@H:3]([C:14]([O:16]CC)=O)[NH:2]1.O.[NH2:20][NH2:21]>CN(C)C=O>[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@@H:3]([C:14]([NH:20][NH2:21])=[O:16])[NH:2]1
Reactant: CCOC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: NNC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Reaction time: 8 h
Yield: 74 %

Procedure:
A mixture of ethyl (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (4.9 g), hydrazine hydrate (10 ml) and dimethylformamide (50 ml) is allowed to stand at room temperature overnight. The reaction mixture is is distilled under reduced pressure to remove the solvent. The residue is treated with ethyl acetate to give the title compound (3.40 g, 74%) as powder.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.CCOCC>C1COCC1>[CH3:1][C:2]1[C:3]([CH:16]([OH:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Cc1cc2c(cc1C(C)O)C(C)(C)CCC2(C)C
Reaction time: 3 h

Procedure:
To a solution of 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone (500 mg; 2.0 mmol) in dry THF (5 ml) was added slowly LiAlH4 (80 mg; 2.0 mmol) at 0° C. The reaction mixture was stirred for 3 hours, and then water (20 ml) was added. Ether (50 ml) was added and the mixture was filtered through filter aid. The organic phase was separated and the water phase was extracted with ether. The combined organic phases were dried and evaporated to give the title compound in 504 mg (100%) yield.
Reaction SMILES: C([S@@]([N:7]=[CH:8][CH2:9][CH2:10][C:11]([CH3:23])([CH3:22])[C:12](OCC1C=CC=CC=1)=[O:13])=O)(C)(C)C.[F:24][C:25]1[CH:26]=[C:27]([Mg]Br)[CH:28]=[CH:29][C:30]=1[CH3:31]>C1(C)C=CC=CC=1.C1COCC1>[F:24][C:25]1[CH:26]=[C:27]([C@H:8]2[NH:7][C:12](=[O:13])[C:11]([CH3:23])([CH3:22])[CH2:10][CH2:9]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: CC(C)(CCC=N[S@@](=O)C(C)(C)C)C(=O)OCc1ccccc1
Reactant: Cc1ccc([Mg]Br)cc1F
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc([C@@H]2CCC(C)(C)C(=O)N2)cc1F
Temperature: 25 °C

Procedure:
To a stirred solution of benzyl (Ss)-5-[(tert-butylsulfinyl)imino]-2,2-dimethylpentanoate (1.00 g, 2.96 mmol, described in Intermediate 3) in toluene (28 mL) at −78° C. was added 3-fluoro-4-methylphenylmagnesium bromide (11.9 mL of a 0.5 M solution in THF, 5.93 mmol). The reaction mixture was warmed to ambient temperature for 2 h, and then heated at reflux for 2 h. The solvent was removed in vacuo and the crude solid dissolved in DMSO (5 mL). The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=236 (M+1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][NH2:41])[CH:35]=1>>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([NH:41][CH2:40][C:36]4[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=4)=[O:30])=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])(=[O:16])=[O:17])=[CH:11][CH:10]=1
Reactant: NCc1cccnc1
Reactant: COc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Agent: O=C(Cl)C(=O)Cl
Product: COc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4cccnc4)cc3)oc2C)cc1
Yield: 51.3 %

Procedure:
Reaction of oxalyl chloride (76 λL, 0.88 mmol) and benzoic acid 35 (226 mg, 0.58 mmol) with subsequent coupling to 3-pyridinylmethylamine (65 λL, 0.64 mmol) gave benzamide 36 (142 mg, 51%) as a white powder: mp (MeOH/EtOAc) 189-191° C.; 1H NMR δ 9.22 (t, J=5.8 Hz, 1H, CONH), 8.57 (d, J=1.7 Hz, 1H, H-2′), 8.47 (dd, J=4.7, 1.6 Hz, 1H, H-6′), 8.00 (dd, J=8.6, 1.8 Hz, 2H, H-2, H-6), 7.91 (dd, J=8.6, 1.8 Hz, 2H, H-3, H-5), 7.74 (ddd, J=8.0, 2.1, 1.4 Hz, 1H, H-4′), 7.70 (ddd, J=8.9, 3.0, 2.0 Hz, 2H, H-2″, H-6″), 7.36 (ddd, J=7.9, 4.7, 0.7 Hz, 1H, H-5′), 7.13 (ddd, J=8.9, 3.0, 2.0 Hz, 2H, H-3″, H-5″), 4.60 (s, 2H, CH2SO2), 4.51 (d, J=5.8 Hz, 2H, CH2N), 3.84 (s, 3H, OCH3), 2.13 (s, 3H, CH3); 13C NMR δ 165.5, 163.3, 157.9, 149.8, 148.9, 148.0, 135.3, 135.1, 134.8, 130.4 (2), 129.8, 128.8, 128.0 (2), 126.1, 125.3 (2), 123.4, 114.3 (2), 55.7, 53.0, 40.4, 9.6; MS m/z 477.6 (MH+, 100%). Anal. calcd for C25H23N3O5S.½CH3OH: C, 62.06; H, 5.11; N, 8.51. Found: C, 61.85; H, 4.88; N, 8.62%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1.C(N(CC)CC)C.O(S(C)(=O)=O)S(C)(=O)=O.[CH3:49][C:50]1[C:54]2[CH:55]=[C:56]([NH2:60])[CH:57]=[C:58]([CH3:59])[C:53]=2[O:52][N:51]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:60][C:56]2[CH:57]=[C:58]([CH3:59])[C:53]3[O:52][N:51]=[C:50]([CH3:49])[C:54]=3[CH:55]=2)[C:9]2[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[CH:14]([CH3:16])[CH3:15])=[CH:6][CH:7]=1
Reactant: Cc1noc2c(C)cc(N)cc12
Reactant: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(C)C)c1C(Nc1cc(C)c2onc(C)c2c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a stirred solution of ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-isopropyl-1H-pyrazole-3-carboxylate (Step 46.11) (500 mg, 1.085 mmol) and triethylamine (0.756 mL, 5.42 mmol) in CH2Cl2 (10 mL) cooled down to 0° C. was added Ms2O (378 mg, 2.170 mmol) and the reaction was stirred for 1 hr at this temperature. 3,7-dimethylbenzo[d]isoxazol-5-amine (Step 46.6) (194 mg, 1.193 mmol) was added and the reaction mixture was allowed to warm up to RT and stir for 1 hr. The reaction was quenched with aq. NaH2PO4 solution and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/EtOAc 10-100%) to afford the title product (460 mg, 0.684 mmol, 63% yield) as yellow amorphous solid. tR: 1.38 min (LC-MS 2); ESI-MS: 605 [M+H]+ (LC-MS 2); Rf=0.25 (hexane/EtOAc 1:1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[C:9](OC)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:24][C:25]1[C:31]([OH:32])=[CH:30][C:28]([NH2:29])=[C:27]([F:33])[CH:26]=1.Cl.CN([CH:38]=[O:39])C>CC(O)CCC.C(O)(C)C>[Cl:24][C:25]1[C:31]([OH:32])=[CH:30][C:28]([NH:29][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)=[CH:9][CH:10]=3)[N:5]=[C:4]([O:39][CH3:38])[CH:3]=2)=[C:27]([F:33])[CH:26]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: COc1cc2c(Cl)ccnc2cc1OCCCc1cccnc1
Reactant: CN(C)C=O
Agent: Cl
Solvent: CC(C)O
Solvent: CCCC(C)O
Product: COc1cc(Nc2cc(O)c(Cl)cc2F)c2ccc(OCCCc3cccnc3)cc2n1
Yield: 62 %

Procedure:
To a suspension of 4-chloro-6-methoxy-7-(3-(3-pyridyl)propoxy)quinoline (150 mg, 0.46 mmol) in 2-pentanol (5 ml) was added 4-chloro-2-fluoro-5-hydroxyaniline (91 mg, 0.55 mmol), (as described in EP 61741 A2), and 5M hydrogen chloride in isopropanol (0.1 ml). The mixture was heated at reflux for 15 minutes and DMF (3 ml) was added. The mixture was heated at reflux for 5 hours and the volatiles were removed by evaporation. The residue was triturated with isopropanol, collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-methoxy-7-(3-(3-pyridyl)propoxy)quinoline (150 mg, 62%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C:21]1[N:22]=[N:23][N:24]([CH3:26])[N:25]=1)[C@@H:8]1[C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[C:18]([CH3:19])[C:13]=2[NH:12][CH2:11][CH2:10][CH2:9]1.[Na].[CH:37]([C@H:39]1[CH2:44][CH2:43][C@H:42]([C:45]([O-:47])=[O:46])[CH2:41][CH2:40]1)=O.[NH4+].[Cl-].[C:50]1(C)C=CC=CC=1>O.C(#N)C>[CH3:50][O:47][C:45]([C@H:42]1[CH2:43][CH2:44][C@H:39]([CH2:37][N:12]2[C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[C@@H:8]([N:7]([CH2:6][C:5]3[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=[C:3]([C:2]([F:34])([F:1])[F:35])[CH:4]=3)[C:21]3[N:22]=[N:23][N:24]([CH3:26])[N:25]=3)[CH2:9][CH2:10][CH2:11]2)[CH2:40][CH2:41]1)=[O:46]
Reactant: Cc1cc(C)c2c(c1)[C@@H](N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)CCCN2
Reactant: Cc1ccccc1
Reactant: O=C[C@H]1CC[C@H](C(=O)[O-])CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CC#N
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)cc(C)c32)CC1
Temperature: 60 °C

Procedure:
Cool a suspension of (5S)—N-[3,5-bis(trifluoromethyl)benzyl]-7,9-dimethyl-N-(2-methyl-2H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-amine (3.40 g, 6.82 mmol), sodium triacetoxyborohydrate (3.01 g, 13.64 mmol), and ACN (28 mL) to −12° C. to −10° C. in an ice/acetone bath and add a solution of (trans)-4-formylcyclohexanecarboxylate (2.03 g, 11.93 mmol) in toluene (18.5 mL) over 30 min via a syringe pump (0.66 mL/min). Continue stirring the reaction in an ice/acetone bath for 2 hours. Add 44 mL of 10% (by weight) NH4Cl in water to the reaction and stir for 30 min at room temperature. Stop stirring and there are two layers. Separate the layers, concentrate the organic layer down to one volume of solvent. Add 24 mL of ethanol and concentrate to a solid (or to one volume). Add 24 mL of ethanol, 2 mL of water and heat to 60° C. (still a suspension). Add 2 mL of water dropwise. Allow the suspension to cool to room temperature and stir overnight at room temperature. After stirring overnight at room temperature, cool the suspension to −10° C. for 0.5 h, then filter. Wash the filter solids with 3 mL of −10° C. EtOH:water (4:1). Dry the solids overnight in a vacuum oven at 50° C. to give 4.24 g of methyl-trans-4-{[(5S)-5-{[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}-7,9-dimethyl-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]methyl}cyclohexanecarboxylate as a colorless solid. HPLC shows 99.75% pure.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[O-:39][CH2:40][CH3:41].[Na+].O1CCCC1.CS(C)(=O)=O>O1CCCC1>[CH2:40]([O:39][C:14]1[N:13]=[C:12]([NH:11][C@H:7]2[CH2:8][CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6]2)[C:17]([C:18]2[N:19]=[C:20]3[CH:26]=[CH:25][NH:24][C:21]3=[N:22][CH:23]=2)=[CH:16][N:15]=1)[CH3:41]
Reactant: CC[O-]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Agent: CS(C)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ncc(-c2cnc3[nH]ccc3n2)c(N[C@H]2CCCN(S(C)(=O)=O)C2)n1

Procedure:
In a tetrahydrofuran solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, sodium ethoxide/tetrahydrofuran was used to displace the methylsulfone similar to the example above and the de-protection step was similar to step 5, Example 76 to give [2-ethoxy-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-4-yl]-((S)-1-methanesulfonyl-piperidin-3-yl)-amine. MS (ES+): 418.
Reaction SMILES: [C:1]([Cl:5])(Cl)(Cl)Cl.CN(C)P(N(C)C)N(C)C.O=C1[CH2:21][C@@H:20]([C@H:22]([N:39]2[C:43](=[O:44])[C:42]3=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]3[C:40]2=[O:49])[C:23]([O:25][CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[O:19][NH:18]1.[Cl-].[Cl-].CN(C)P(N(C)C)N(C)C>O1CCCC1.C(OCC)(=O)C>[Cl:5][C:1]1[CH2:21][C@@H:20]([C@H:22]([N:39]2[C:40](=[O:49])[C:41]3=[CH:48][CH:47]=[CH:46][CH:45]=[C:42]3[C:43]2=[O:44])[C:23]([O:25][CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[O:19][N:18]=1
Reactant: O=C1C[C@@H]([C@@H](C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)c3ccccc3C2=O)ON1
Reactant: ClC(Cl)(Cl)Cl
Agent: CN(C)P(N(C)C)N(C)C
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(OC(c1ccccc1)c1ccccc1)[C@H]([C@@H]1CC(Cl)=NO1)N1C(=O)c2ccccc2C1=O
Reaction time: 0.03 h
Yield: 39.7 %

Procedure:
To 192 μl (2 mmole) of carbon tetrachloride in 25 ml of dry tetrahydrofuran under N2 at room temperature is added 310 μl (1.9 mmole) of hexamethylphosphorous triamide dropwise over one minute. Within two minutes 590 mg. (1.3 mmole) of (αS,5S)-oxo-α-phthalimido-5-isoxazolidine acetic acid, benzhydryl ester acid in approximately 5 ml of dry THF is added rapidly. The heterogeneous solution in stirred at 45° for 48 hours. Alternatively, to 590 mg. (1.3 mmole) of (αS,5S)-oxo-α-phthalimido-5-isoxolidine in 20 ml. of dry tetrahydrofuran under N2 at room temperature is added 610 mg. (2.6 mmole) of hexamethylphosphorous triamide dichloride (prepared by hexachloroethane in acetonitrile with hexamethylphosphorous triamide according to R. Appel and H. Scholer, Chem. Ber., 110, 2382 (1977)). The solution is refluxed for 48 hours. The reaction is taken up in 150 ml of ethyl acetate and washed with 50 ml of 0.1N hydrochloric acid followed by brine and then dried over sodium sulfate. After concentrating in vacuo the residue is chromatographed on 50 g of silica gel with 30% ethyl acetate hexane (200 ml elution) which yields 200 mg of crude product (33% yield), 245 mg of starting material (42%). The crude product yielded (α5,5S) 3-chloro-4,5-dihydro-α-phthalimido-5-isoxazole acetic acid as needles, m.p. 178°-9° upon recrystallization from methanol.
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH3:34])[C:22]([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH3:33])[CH:25]=3)=[O:23])=[CH:16][CH:15]=2)[CH:9]=[CH:10][C:11]=1[O:12]C.C(=O)=O.CC(C)=O.O>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH3:34])[C:22]([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH3:33])[CH:25]=3)=[O:23])=[CH:16][CH:15]=2)[CH:9]=[CH:10][C:11]=1[OH:12]
Reactant: COc1ccc(-c2ccc(CN(C)C(=O)c3cn(C)c4ccccc34)cc2)cc1Br
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: O
Solvent: CC(C)=O
Product: CN(Cc1ccc(-c2ccc(O)c(Br)c2)cc1)C(=O)c1cn(C)c2ccccc12
Reaction time: 3 h
Yield: 71.2 %

Procedure:
Boron tribromide (44.8 mL of a 1 M solution in methylene chloride; 44 mmol) was added under nitrogen dropwise over 30 minutes to a solution of N-[(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methyl]-N,1-dimethyl-1H-indole-3-carboxamide (6.8 g, 14.7 mmol), prepared in the previous step, in 150 mL of methylene chloride at dry ice-acetone temperature. After the addition the dry ice-acetone bath was replaced with an ice bath and the stirring continued for 3 h. At ice bath temperature 60 mL of water was added dropwise. The reaction was then partitioned between additional amounts of methylene chloride and water. The aqueous layer was separated and extracted three times with methylene chloride. The combined extracts were dried (MgSO4) and the solvent removed under reduced pressure to give N-[(3′-bromo-4′-hydroxy-1,1′-biphenyl-4-yl)methyl]-N,1-dimethyl-1H-indole-3-carboxamide (4.7 g, 71%) as a solid, mp 237-239° C. Elemental Analysis for C24H21BrN2O2. Calc'd: C, 64.15; H, 4.71; N, 6.23. Found: C, 62.15; H, 4.63; N, 5.97.